Gary Null's Anti-Aging Protocol for Nursing Homes: Nutrients ...

Gary Null’s Anti-Aging Protocol for 

Nursing Homes: Nutrients 

Scientifically Proven to be 

Beneficial to Cognition and the 

Overall Body 

Prepared by: Gary Null, Ph.D., and Doug Henderson, Esq. 

Copyright © Gary Null & Associates, Inc., 2005 

All Rights Reserved 

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PROTOCOL DISCLAIMER: 

The attached protocol is not in any way to be construed as a prescription to cure the 

condition, but as a suggested nutritional component only. 

This protocol was initially requested by a physician from Gary Null & Associates for a 

specific patient, for whose condition this protocol is to be employed under the physician’s 

directions. 

Firstly, patient’s diagnosis, treatment, and medications must be considered in determining 

if any of the suggested vitamins, minerals, foods, and herbs in contraindicated. Special 

considerations should be given to pregnant and nursing mothers. 

Secondly, the attached protocol must be implemented in gradual steps. Begin with low 

doses of one or two items of the protocols suggested items to determine the patient’s 

acceptance and tolerance. Once it is determined that the patient has adapted, the dosage 

should be increased in gradual steps. 



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Gary Null’s Anti-Aging Protocol for Nursing Homes: Nutrients Scientifically Proven to 

be Beneficial to Cognition and the Overall Body............................................................... 1 

PROTOCOL DISCLAIMER:......................................................................................... 2 

Nursing Home Intervention Study: Introduction............................................................ 5 

NURSING HOMES, DYING FROM NEGLECT – 16 References .............................. 6 

INFECTION – 76 Studies............................................................................................. 10 

ANTIDEPRESSANTS – 109 Studies........................................................................... 32 

THE HIGH COST OF MEDICAL CARE – 49 Studies............................................... 65 

MALNUTRITION – 30 Studies................................................................................... 80 

MEDICAL ERRORS & ADVERSE DRUG REACTIONS – 76 Studies.................... 89 

NURSING HOME PROTOCOL................................................................................ 112 

Vitamin B1 – 120 Studies........................................................................................... 202 

Vitamin B12 – 64 Studies........................................................................................... 217 

Pantothenic Acid (B5) – 47 Studies............................................................................ 222 

Calcium Carbonate - 86 Studies ................................................................................. 226 

Magnesium – 68 Studies........................................................................................... 233 

Ginkgo Biloba – 33 Studies........................................................................................ 237 

L-Phenylalanine – 33 Studies ..................................................................................... 240 

L-Glutathione – 67 Studies......................................................................................... 243 

L-Taurine – 94 Studies ............................................................................................... 249 

Choline Bitartrate – 63 Studies................................................................................... 265 

Inositol – 56 Studies ................................................................................................... 273 

L- Carnitine – 93 Studies............................................................................................ 277 

L-Cysteine – 50 Studies.............................................................................................. 287 

Blue Cohosh Root – 2 Studies .................................................................................... 292 

Siberian Ginseng Root – 40 Studies ........................................................................... 292 

Rosemary Leaves – 17 Studies ................................................................................... 295 

Apsartic Acid – 21 Studies ......................................................................................... 296 

L-Glutamine – 58 Studies........................................................................................... 298 

L-Tyrosine – 53 Studies.............................................................................................. 302 

Linoleic Acid – 56 Studies.......................................................................................... 306 

Linolenic Acid – 10 Studies........................................................................................ 311 

Caprylic Acid - 9 Studies............................................................................................ 312 

Glycerophosphorylcholine – 11 Studies..................................................................... 312 

Phosphatidylserine – 13 Studies ................................................................................. 314 

Pregenolone -23 Studies ............................................................................................. 315 

Benfotiamine – 32 Studies.......................................................................................... 317 

SUPER ANTIOXIDANTS......................................................................................... 320 

Vitamin A – 41 STUDIES.......................................................................................... 320 

Vitamin C – 51 STUDIES ......................................................................................... 323 

Vitamin E - 78 Studies............................................................................................ 327 

Vitamin B6 - 28 STUDIES........................................................................................ 335 

Magnesium - 86 Studies .......................................................................................... 338 

Zinc – 50 STUDIES.................................................................................................... 349 

Selenium – 50 STUDIES............................................................................................ 356 

Copper – 60 Studies.................................................................................................... 362 



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Quercetin – 20 STUDIES ........................................................................................... 368 

Astaxanthin – 20 STUDIES........................................................................................ 370 

L-Carnosine - 28 Studies ......................................................................................... 374 

Lycopene – 50 Studies........................................................................................... 377 

Rosemary Leaf Powder - 20 STUDIES...................................................................... 380 

Tocotrienols – 40 STUDIES....................................................................................... 383 

Raspberry Leaf Powder - 10 Studies ......................................................................... 388 

Citrus Bioflavonoids – 11 STUDIES.......................................................................... 389 

Rutin – 16 STUDIES .................................................................................................. 391 

Billberry - 17 Studies............................................................................................... 392 

Red Wine Concentrate – 14 STUDIES....................................................................... 396 

Grape Skin Extract – 48 STUDIES ............................................................................ 398 

China Green Tea Leaf Powder - 100 Studies ............................................................ 402 

Reduced L-Glutathione - 13 CITATIONS ................................................................. 423 

L-Cysteine – 22 STUDIES ......................................................................................... 425 

Coenzyme Q10 – 43 STUDIES.................................................................................. 429 

N-Acetylcysteine (NAC) - 40 STUDIES.................................................................... 434 

Alpha Lipoic Acid – 20 STUDIES............................................................................. 443 

Superroxide Dismutase – 51 STUDIES...................................................................... 446 

Taurine........................................................................................................................ 450 

Pycnogenol – 20 STUDIES ........................................................................................ 454 

Licorice Root – 21 STUDIES..................................................................................... 458 

BroccolI Stem - 26 STUDIES .................................................................................. 460 

Lutein - 21 STUDIES ................................................................................................ 462 

Cabbage Leaf – 10 STUDIES..................................................................................... 464 

Carrot Root - 11 STUDIES......................................................................................... 466 

Milk Thistle Leaf - 27 STUDIES ............................................................................... 467 

Bromelain – 49 STUDIES .......................................................................................... 473 

Nutrients That Have Demonstrated The Ability To Slow Down the Rate at Which We 

Age.............................................................................................................................. 477 

Acetyl-L-Carnitine - 49 ABSTRACTS ..................................................................... 477 

Alpha Lipoic Acid - 70 ABSTRACTS....................................................................... 503 

Mixed Tocopherols - 398 Studies............................................................................... 547 

Glycerylphosphorylcholine – 4 Studies...................................................................... 596 

Carnosine - 47 ABSTRACTS................................................................................... 598 

Magnesium - 570 CITATIONS .................................................................................. 621 

Quercetin - 30 ABSTRACTS ..................................................................................... 718 

L-Carnosine - 15 Studies ........................................................................................... 737 

Cayenne – 267 Studies................................................................................................ 739 

Phosphatidylserine – 19 Studies ................................................................................. 741 

Ginkgo Biloba Leaf Powder – 25 Studies .................................................................. 743 

Linoleic Acid – 29 Studies.......................................................................................... 745 

Inositol – 6 Studies ..................................................................................................... 748 



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Nursing Home Intervention Study: Introduction 

The current health status of many of the individuals living in nursing homes is directly 

related to their nutritional intake. Numerous studies have concluded that these individuals 

suffer from multiple nutritional deficiencies. From the Clinton Administration Report on 

the Quality of Nursing Homes: "The report concludes that the private Joint Commission 

on accreditation of Healthcare Organizations (JCAHO) survey process was not effective 

in protecting the health and safety of nursing home residents". Also, the office of the 

Health Care Financing Administration stated that "Five and a half years seems a long 

time for Clinton to discover that hundreds of people are still dying from malnutrition, 

dehydration, sepsis from bedsores and even physical abuse while in nursing homes". 

The problems of malnutrition and dehydration are due in particular to the institutional 

food provided by vendors who have used RDA’s which have been shown to be, A) both 

insufficient and, B) grossly inadequate for people who have compromised immune 

systems and multiple nutritional deficiencies. 

This proposal carefully examines the scientific literature which cites the actual 

therapeutic dosages in relation to the category of illnesses that the majority of people in 

nursing homes fall into. 

We conclude, after reviewing thousands of scientific articles and using data from test 

groups of 300 individuals, most of whom are in senior citizen age groups, that nutrition 

and exercise, as presented in this proposed protocol, played a key role in the health and 

well-being of the senior citizens. In January of 1997 I enrolled 300 people into a 

"Reverse the Aging Process Study" whicCreated by dhendersonh would last for 18 

months. 18 months later 65 people completed the study. 235 people became controls. 

This was not a double blind study. It was an observation of changes in their blood 

chemistry, weight, physical dimensions, physical appearance, memory, energy levels, 

sleep patterns, bowel movements, night time urination, muscle strength, digestion, 

olfactory senses, visual senses, tactile senses, skin texture, hair texture and stress levels. 

This was a lifestyle modification study. 52% of participants had lower cholesterol and 

tryglyceride levels. 68% of participants had increased DHEA levels. 78% of participants 

had a significant improvement in their fat / muscle ratio. 90% of participants had an 

increase in bowel movements. 92% of participants had a decreased need for sleep. 95% 

of participants had increased energy levels, and stress levels were lowered by 97%. In 

addition, numerical diaries had been kept by the participants reflecting subjective data. 

This data cited improvements that affected the participants in their overall quality of life. 



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We can also conclude that this protocol would benefit the vast majority of people in 

nursing homes and hospices. The following is not a theoretical model, it is an actual 

model. Harry Biele, a 90 year old man who just 10 years ago had chronic sinusitis, 

asthma, arthritis, enlarged prostate, a pre-cancerous lower bowel and main coronary 

artery blockage is now a marathoner living life to its fullest. His cardiologist has taken 

away all medication like beta blockers, and his general practitioner has taken away his 

inhalers for asthma. He is not an exception. Harry is the example of someone who has 

taken positive action toward his own health. He improved his nutrition by applying a 

protocol similar to this one. Exercise became part of Harry’s daily ritual. He now appears 

to be closer to 70 than 90. 

All senior citizens and baby boomers can improve their health. This is the scientific 

literature that justifies the use of recommended supplements in this protocol. Applying 

this protocol can play an important role in anyone’s life. 

Gary Null Ph.D. 

NURSING HOMES, DYING FROM NEGLECT – 16 References 

The term ‘nursing home’ implies two things: one, that nurses are taking care of the 

elderly and, two, that, instead of an institution, people are living in a home. Three 

separate reports that took over ten years to complete show us that neither assumption is 

correct. 

During President Clinton’s term in office, The Clinton Administration Report on the 

Quality of Nursing Homes was prepared. The five and one-half year report concluded 

that "The private Joint Commission on accreditation of Healthcare Organizations 

(JCAHO) survey process was not effective in protecting the health and safety of nursing 

home residents." Also, the office of the Health Care Financing Administration analyzed 

the report and stated that "Five and a half years seems a long time… to discover that 

hundreds of people are still dying from malnutrition, dehydration, sepsis from bedsores 

and even physical abuse while in nursing homes". (1) 

Congressman Waxman sponsored a report published in 2001 called "Abuse of Residents 

is a Major Problem in U.S. Nursing Homes." The report found that one third - 5,283 of 

the nations’ 17,000 nursing homes - were cited for an abuse violation in the two-year 

period studied, January 1999 - January 2001. (2) 

The major findings of the report were: 

1. There were more than 9,000 abuse violations during the two-year period. 

2. Ten-percent of nursing homes had physical harm violations to residents. 

3. Over 40-percent, or 3,800 abuse violations, were only discovered after a formal 

complaint was filed, usually by concerned family members. 



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4. Many verbal abuse violations were reported. 

5. There were reports of sexual abuse. 

The third report was an exhaustive study of nurse-to-patient ratios in nursing homes. 

Although mandated by Congress in 1990, the study was not begun until 1998. (3) The 

report found that dangerously understaffed nursing homes lead to neglect, abuse, overuse 

of medications, and overuse of physical restraints. About the report, a spokesperson for 

The National Citizens’ Coalition for Nursing Home Reform said, "They compiled two 

reports of three volumes each thoroughly documenting the number of hours of care 

residents must receive from nurses and nursing assistants to avoid painful, even 

dangerous, conditions such as bedsores and infections. Yet it took the Department of 

Health and Human Services and Secretary Tommy Thompson only four months to 

dismiss the report as ‘insufficient.’" (4) 

The main categories of abuse in nursing homes that cause harm in the elderly are: 

1. Overuse of medication and side effects of medication 

2. Overuse of physical restraints 

3. Malnutrition, dehydration, and nutrient deficiency 

1. OVERUSE OF MEDICATION AND SIDE EFFECTS OF MEDICATION 

A 2003 study surveyed drug use in the elderly population. Dr. Robert Epstein, chief 

medical officer of Medco Health Solutions Inc. (a unit of Merck & Co.), conducted the 

study on drug trends. (5) Medco oversees drug benefit plans for more than 60 million 

Americans, including 6.3 million senior citizens who received more than 160 million 

prescriptions. Data analysis showed that the average senior receives 25 prescriptions 

annually. A total of 7.9 million medication alerts were triggered in the group of 6.3 

seniors. When compared with 1999 statistics, twice as many medication alerts occurred in 

2003. About 2.2 million of those alerts indicated excessive dosages unsuitable for senior 

citizens and about 2.4 million indicated clinically inappropriate drugs for the elderly. 

In a "snapshot" survey of 818 residents of residential care facilities for the elderly, 94% 

were receiving at least one medication at the time of the interview. The average intake of 

medications was five per resident; the authors noted that many of these drugs were given 

without a documented diagnosis justifying their use. (6) 

Let’s also look at the irony of lack of proper pain medication for patients that really need 

it. In one study, the authors concluded that older patients suffering pain were more likely 

to go untreated. In this study pain management was evaluated in a group of 13,625 cancer 

patients aged 65 or over living in nursing homes. Overall, almost 30% or 4,003 patients 

reported pain. More than 25% or (1,000) patients with pain received absolutely no pain 

relief medication. Another 16% received a World Health Organization (WHO) level one 

drug (mild pain reliever); 32% received a WHO level two drug (moderate pain reliever); 

and only 26% received adequate pain-relieving morphine for their cancer pain. (7) 



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2. OVERUSE OF RESTRAINTS 

Study after study concludes that physical restraints are a preventable cause of death. (8,9) 

Nursing home administrators argue that they must use physical restraints to prevent falls. 

In fact, they cause more injury and death because people naturally fight against such 

imprisonment. Studies show that the use of restraints carries a higher mortality rate and 

economic burden than no restraints. (10,11,12) In one study a mortality rate of 1 in every 

1,000 nursing home deaths was found to be due to physical restraints, including bedrails. 

(13) In these studies, descriptions of frail, elderly people suffocated between the mattress 

and bed rails, being hung by bed restraints, and with heads crushed between bed rails 

gives graphic testament to their dangers. 

It appears that drugs are used to "restrain" nursing home residents as much as physical 

restraints. Sarah Green-Burger, in her 2000 review, reminds us that nursing home 

resident-rights include freedom from physical and chemical restraints. She says drug 

"restraints" are known to decrease appetite and impede eating. There is also provision for 

reasonable accommodation of individual needs, which should assure a healthy diet and a 

suitable environment conducive to eating. 

3. MALNUTRITION, DEHYDRATION, AND NUTRIENT DEFICIENCY 

According to Green-Burger studies on nursing home populations, conducted over the last 

ten years, show that from 35% to 85% of U.S. nursing home residents are malnourished. 

(14) This can be directly measured by a simple weight scale; 30% to 50% of residents are 

substandard in bodyweight. These findings directly contravene specific components of 

The Nursing Home Reform Act of 1987 (NHRA) to prevent both malnutrition and 

dehydration. They also mean that nursing homes are failing our elderly on many levels. 

In order for such abuse to exist there is no proper assessment of residents, no 

individualized care, improper physician supervision, insufficient nursing staff, and little 

attention to quality of life care and service. The law specifically mandates that nursing 

homes must meet residents’ nutrition and hydration needs. But according to Green- 

Burger "… the level of malnutrition and dehydration in some American nursing homes is 

similar to that found in many poverty-stricken developing countries where inadequate 

food intake is compounded by repeated infections." 

The Green-Burger study goes on to emphasize the seriousness of malnutrition and 

dehydration, which can result in repeated infections (including urinary tract infections 

and pneumonia), pressure ulcers, anemia, hypotension, confusion and impaired cognition, 

decreased wound healing, and hip fractures. Beyond physical signs and symptoms 

nutritionally-impaired residents become weak, fatigued, bedridden, apathetic, and 

depressed. Often residents are transferred to hospital for acute illness, and if 

malnourished or dehydrated, we know that they suffer increased morbidity and require 

longer lengths of stay. Green Burger states that compared with well-nourished 

hospitalized nursing home residents, they have a five-fold increase in mortality in the 

hospital. 



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Green-Burger identifies four key issues that need to be addressed for the prevention and 

treatment of malnutrition and dehydration: 1) inadequate staffing, 2) poor environment, 

3) insufficient data collection, and 4) lack of enforcement. We would add a fifth: 

improved nutritional intake in the form of healthier diets and nutrient supplements. 

TIP OF THE ICEBERG 

While conditions in many nursing homes appear very serious, there is evidence that what 

we know is only the tip of the iceberg. In fact, deaths caused by malnutrition, 

dehydration, and physical restraints are rarely recorded on death certificates. Even though 

1 in 5 people die in nursing homes, the autopsy rate is only 0.8%. (15) Thus, we have no 

way of knowing the true causes of death. 

Dr. Steven Miles, professor of Geriatric Medicine at the University of Minnesota, in an 

in-depth study found many barriers to researching accidental deaths in nursing homes. 

(16) He found that adverse drug reactions or the late consequences of falls may go 

unrecognized as the cause of death. A substantial barrier was found to be nursing home 

staff who conceal some accidental deaths. Dr. Miles reports on one anecdotal series 

where attempts were made to cover up four out of eight lethal accidents. Miles says, 

obviously, "The success of these efforts cannot be known since successful efforts will not 

be countable." In a review of 17 nursing home deaths, Dr. Miles found that in 8 of 17 

there was an effort to conceal the fact that a death was caused by asphyxiation by bedrails 

or physical vest restraints. 

REFERENCES: 

1. http://www.hhs.gov/asl/testify/t980728b.html 

2. CNN – Washington senate briefing, Abuse of Residents is a Major Problem in U.S. 

Nursing Homes - live coverage July 30, 2001. 

3. Report to Congress: Appropriateness of Minimum Nurse Staffing Ratios In Nursing 

Homes. Phase II Final Report. December 24, 2001. 

4. Press Release. Consumer Group Criticizes Thompson Letter Dismissing Report on 

Dangerous Staffing Levels in Nursing Homes. The National Citizens’ Coalition for 

Nursing Home Reform. March 22, 2002. 

5. Overmedication of U.S. Seniors. Reuters Health, May 21, 2003. 

6. Williams BR, et al. Medication use in residential care facilities for the elderly. Ann 

Pharmacother. 1999 Feb;33(2):149-55. 

7. Bernabei R, et al. Management of pain in elderly patients with cancer. SAGE Study 

Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 1998 Jun 

17;279(23):1877-82. 



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8. Miles SH, Irvine P. Deaths caused by physical restraints. Gerontologist. 1992 

Dec;32(6):762-6. 

9. Annas GJ. The Last Resort: The Use of Physical Restraints in Medical Emergencies. N 

Engl J Med. 1999 Oct 28;341(18):1408-12. 

10. Robinson BE. Death by destruction of will. Lest we forget. Arch Intern Med. 1995 

Nov.13;155(20):2250-1. 

11. Capezuti E. et al. The relationship between physical restraint removal and falls and 

injuries among nursing home residents. J Gerontol A Biol Sci Med Sci. 1998 

Jan;53(1):M47-52. 

12. Phillips CD, Hawes C, Fries BE. Reducing the use of physical restraints in nursing 

homes: will it increase costs? Am J Public Health. 1993 Mar;83(3):342-8. 

13. Parker K., et al. Deaths caused by bedrails. J Am Geriatr Soc. 1997 Jul;45(7):797- 

802. 

14. Green-Burger S, Kayser-Jones J, Prince-Bell J. Malnutrition and Dehydration in 

Nursing Homes: Key Issues in Prevention and Treatment. National Citizens' Coalition for 

Nursing Home Reform. June 2000. 

http://www.cmwf.org/programs/elders/burger_mal_386.asp 

15. Katz PR, Seidel G. Nursing home autopsies. Survey of physician attitudes and 

practice patterns. Arch Pathol Lab Med. 1990 Feb;114(2):145-7. 

16. Miles SH. Concealing accidental nursing home deaths. HEC Forum. 2002 

Sep;14(3):224-34. 

INFECTION – 76 Studies 

1. Notice to Readers: Fourth Decennial International Conference on 

Nosocomial and Healthcare-Associated Infections. 

MMWR, February 25, 2000 / 49(07);138. 

This article reports that every year in the U.S., approximately 2,000,000 patients develop 

hospital-acquired infections and 88,000 die from them. The cost of hospital-acquired 

infections has been estimated at $4.6 billion. These estimates are conservative, because 



10

they do not take into account nosocomial infections occurring in patients in nursing 

homes, outpatient clinics, dialysis centers and other health care centers. 

2. Mortality associated with nosocomial infections: analysis of multiple causeof-death 

data. 

White MC. 

J Clin Epidemiol 1993 Jan;46(1):95-100. 

This article emphasizes that hospital-acquired infections are among the 10 leading cause 

of death in the U.S. 

3. The nationwide nosocomial infection rate. A new need for vital statistics. 

Haley RW, Culver DH, White JW, Morgan WM, Emori TG. 

Am J Epidemiol 1985 Feb;121(2):159-67. 

The results of this study indicate that in 1985, the incidence of hospital-acquired 

infections in the U.S. was 5.7 per 100 patients. Extrapolation of these data to the 6,449 

acute-care hospitals revealed that every year, in the U.S., approximately 2 million 

infections occur in hospitalized patients. However, after adjustment for accuracy of 

detection methods, trend toward a nationwide increase in infection rates, and number of 

infections in nursing home patients, the estimated number of yearly nosocomial 

infections increased to 4 millions. The authors emphasizes that these data greatly exceed 

previous evaluations, and call for correct statistics to properly address the problem. 

4. Trends in infectious disease hospitalizations in the United States, 1980-1994. 

Simonsen L, Conn LA, Pinner RW, Teutsch S. 

Arch Intern Med 1998 Sep 28;158(17):1923-8. 

The results of this study show that from 1980 to 1994, mortality rates in individuals 

hospitalized for infectious disease doubled, from 1.9% to 4.0%. 

5. Trends in infectious diseases mortality in the Unites States. 

Pinner RW, et al. 

JAMA 1996 Jan 17;275(3):189-93. 

The results of this study show that from 1980 to 1992, death due to infectious diseases in 

the U.S. increased 58%, from 41 to 65 deaths per 100,000 population. Of note, death due 

to infectious diseases increased 6.3 times in individuals aged 25- to 44-years-old, from 6 



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to 38 deaths per 100,000 population. These data indicate that despite previsions of a 

decline in rates of infectious diseases in the U.S., mortality rates from infectious diseases 

have actually been progressively increasing in recent years. 

6. Nosocomial bloodstream infections. Secular trends in rates, mortality, and contribution 

to total hospital deaths. 

Pittet D, Wenzel RP. 

Arch Intern Med 1995 Jun 12;155(11):1177-84. 

The results of this study show that the incidence of hospital-acquired bloodstream 

infections increased threefold in the period from 1980 to 1992, from a rate of 6.7 to 18.4 

infections per 1,000 discharges. Population-attributable risk of death from this 

complication also rose during this period, from 3.55 to 6.22 deaths per 1,000 discharges. 

7. Nosocomial enterococci resistant to vancomycin--United States, 1989-1993. 

MMWR Morb Mortal Wkly Rep 1993 Aug 6;42(30):597-9. 

This article reports that from 1989 to 1993, the rate of enterococci responsible for 

hospital-acquired infections that acquired resistance to the antibiotic vancomycin 

increased by more than 20 folds. The majority of these bacteria are resistant to all 

available antibiotics. In the intensive care units, the percentage of vancomycin-resistant 

enterococci strains increased from 0.4% in 1989 to 13.6% in 1993. 

8. Emerging and reemerging microbial threats. Nosocomial fungal infections. 

Henderson VJ, Hirvela ER. 

Arch Surg 1996 Mar;131(3):330-7. 

This article shows that the rate of fungal hospital-acquired infections increased steadily in 

the past 25 years, from a rate of 2.0 infections per 1000 discharges to as high as 6.6 

infections per 1000 discharges. 

9. Hospital-acquired candidemia. The attributable mortality and excess length of stay. 

Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. 

Arch Intern Med 1988 Dec;148(12):2642-5. 

The results of this study show that from 1977 to 1984, the incidence of hospital-acquired 

bloodstream infections caused by Candida species in the U.S. tripled. Patients with 

fungemia have a 3-fold increased risk of dying, compared to uninfected, closely matched 



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patients. Hospital length of stay in patients who survived the bloodstream infection was 

70 days, as compared to 40 days in matched controls. Candida infections were 

responsible for 10% of all bloodstream infections. 

10. Secular trends in the epidemiology of nosocomial fungal infections in the United 

States, 1980-1990. 

National Nosocomial Infections Surveillance System. 

Beck-Sague C, Jarvis WR. 

J Infect Dis 1993 May;167(5):1247-51. 

This article reports on the increase in the incidence of hospital-acquired fungal infections 

in U.S. hospitals, as determined by evaluation of data submitted to the National 

Nosocomial Infections Surveillance System. The rate of this complication increased from 

2.0 per 1000 discharges in 1980 to 3.8 per 1000 discharges in 1990, an almost two-fold 

increase. Candida species accounted for three-quarters of infections. Patients with a 

central intravascular catheter had a 3-fold increased risk of developing a fungal 

bloodstream infection, compared to those without it. Thirty percent of patients with 

hospital-acquired fungemia died, compared to 17% of those with bloodstream infections 

due to other microorganisms. 

11. Accuracy of reporting nosocomial infections in intensive-care-unit patients to the 

National Nosocomial Infections Surveillance System: a pilot study. 

Emori TG, et al. 

Infect Control Hosp Epidemiol 1998 May;19(5):308-16. 

The results of this study indicate that the National Nosocomial Infections Surveillance 

(NNIS) System is not a reliable indicator of the true incidence of nosocomial infections in 

hospital settings. This system was instituted under the sponsorship of the Centers for 

Disease Control (CDC) to monitor rates of hospital-acquired infections through 

voluntarily reporting of this complication by participating hospitals. The accuracy of the 

system in reflecting the rate of nosocomial infections was evaluated by reviewing the 

charts of 1,136 patients admitted to the intensive care units of 9 hospitals. There were 611 

reports of hospital-acquired infections submitted to the NNIS system for this cohort. 

However, when some trained epidemiologists evaluated retrospectively the charts of the 

patients, they identified 340 extra infections that had not been previously reported. These 

data indicate that the voluntary system of reporting of hospital-acquired infections is 

significantly underestimating the true incidence of nosocomial infections in U.S. 

hospitals, and, as a consequence, all studies that utilize data from the NNIS system are 

misrepresenting the real magnitude of the problem. 



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Influence of nosocomial infection on mortality rate in an intensive care unit. 

Bueno-Cavanillas A, et al. 

Crit Care Med 1994 Jan;22(1):55-60. 

The results of this study show that patients who develop hospital-acquired infections have 

a twofold increased risk of death, compared to uninfected patients. The increased risk of 

death persists even after adjustment for several confounding factors, and is particularly 

high in younger patients with less severe disease. 

12. A survey of nosocomial infections and their influence on hospital mortality rates. 

Dinkel RH, Lebok U. 

J Hosp Infect 1994 Dec;28(4):297-304. 

The results of this study show that even after controlling for possible confounders, 

patients who develop a hospital-acquired infection have a two-fold increased risk of 

death, compared to patients without this complication. The risk of death increases by 

three-folds in patients hospitalized for trauma who develop a hospital-acquired infection. 

13. Nosocomial infections in elderly patients in the United States, 1986-1990. 


Emori TG, et al. 

Am J Med 1991 Sep 16;91(3B):289S-293S. 

This study reports that from 1986 to 1990, 89 hospitals submitted to the National 

Nosocomial Infections Surveillance (NNIS) system a total of 101,479 reports of hospitalacquired 

infections occurring in 75,398 adult patients. In 12% of the infections the 

patients died. In 54% of elderly patients that died an in 59% of younger patients that died 

the infection was judged to be related to their death. Bloodstream infections and 

pneumonias were associated with the highest mortality rates. 

14. The impact of surgical-site infections in the 1990s: attributable mortality, excess 

length of hospitalization, and extra costs. 

Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. 

Infect Control Hosp Epidemiol 1999 Nov;20(11):725-30. 

The results of this study, conducted on 255 pairs of matched surgical patients with and 

without surgical site infection, indicate that infected patients have a 2.2-fold increased 

risk of dying, a 60% increased risk of being admitted to an intensive care unit, and a 

twofold increased hospital length of stay, compared to uninfected patients. In addition, 

patients who survive a surgical site infection are approximately 6 times more likely to be 



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eadmitted to the hospital in the 30-days following discharge, compared to uninfected 

patients. The study estimated that, after the inclusion of the second hospital admission, 

each surgical site infection was associated with an excess hospital stay of 12 days and 

with an excess cost of $5,038 per patient. The authors highlight that the implementation 

of measures designed to reduce the rates of surgical site infections will likely result in a 

significant reduction of infection-related morbidity, mortality and health care costs. 

15. Nosocomial infections in surgical patients in the United States, January 1986-June 

1992. 

National Nosocomial Infections Surveillance (NNIS) System. 

Horan TC, Culver DH, Gaynes RP, Jarvis WR, Edwards JR, Reid CR. 

Infect Control Hosp Epidemiol 1993 Feb;14(2):73-80. 

This study reports that from 1986 to 1992, 106 hospitals reported to the National 

Nosocomial Infections Surveillance System a total of 59,351 hospital-acquired infections 

occurring in 48,168 surgical patients. The probability that these infections were related to 

the death of the patients ranged from 22% for urinary tract infections, to 90% for 

organ/space surgical site infections. 

16. Infection in surgical patients: effects on mortality, hospitalization, and postdischarge 

care. 

DiPiro JT, Martindale RG, Bakst A, Vacani PF, Watson P, Miller MT. 

Am J Health Syst Pharm 1998 Apr 15;55(8):777-81. 

The results of this study show that 12% of patients who undergo moderate to high-risk 

surgical procedures develop hospital-acquired infections. Mortality rates in infected 

patients are 14.5%, as compared to 1.8% in uninfected patients. In addition, hospital 

length of stay more than triples in infected versus uninfected patients (14 days vs. 4 

days), and so does the number of patients who require health care assistance after hospital 

discharge (24% of infected patients versus 7% of uninfected ones). 

17. Nosocomial infection, indices of intrinsic infection risk, and in-hospital mortality in 

general surgery. 

Delgado-Rodriguez M, et al. 

J Hosp Infect 1999 Mar;41(3):203-11. 

The results of this study show that patients who develop a surgical site infection or a 

bloodstream infection have a 4.5-fold and 17.3-fold increased risk of dying, respectively, 

compared to uninfected patients. 



15

18. Nosocomial infection in surgery wards: a controlled study of increased duration of 

hospital stays and direct cost of hospitalization. 

Vegas AA, Jodra VM, Garcia ML. 

Eur J Epidemiol 1993 Sep;9(5):504-10. 

The results of this study show that hospital-length of stay increases by an average of 14 

days in patients who develop hospital-acquired wound infections. The study was 

conducted on a sample of patients from a general and digestive surgical ward, to assess 

the effect that hospital-acquired infections had on the length of their hospital stay. 

Infected and uninfected patients were matched for age, diagnosis, surgical procedure, 

and, when possible, underlying conditions, elective or emergency surgery, and invasive 

devises. Length of hospital stay increased by l2.6 days in patients who developed 

superficial wound infection, compared to those without infection. Wound infections, 

either superficial or deep, and other infections were associated with an extra 14.3 and 7.3 

days of hospital stay, respectively. 

19. Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, 

mortality, cost, and prevention. 

Jarvis WR. 

Infect Control Hosp Epidemiol 1996 Aug;17(8):552-7. 

This study shows that in the U.S., every year, approximately 2 million infections occur in 

hospital patients, leading to substantial increase in morbidity, mortality, and health care 

costs. Hospital length of stay increases by 1 to 4 days in patients who contract urinary 

tract infections, by 7-8 days in those with surgical site infections, by 7 to 21 days in those 

with bloodstream infections, and by 7 to 30 days in those with pneumonia. Costs 

associated with these infections have been estimated at $550-$600 for each urinary tract 

infection, $2,700 for each surgical site infection, $3,000 to $40,000 for each bloodstream 

infection, and $5,000 for each pneumonia. 

20. Nosocomial pneumonia and mortality among patients in intensive care units. 

Fagon JY, Chastre J, Vuagnat A, Trouillet JL, Novara A, Gibert C. 

JAMA 1996 Mar 20;275(11):866-9. 

The results of this study show that 16.6% of patients admitted to an intensive care unit in 

France develop hospital-acquired pneumonia. The study, conducted on 1978 consecutive 

patients, also showed that patients who developed pneumonia while in the hospital had a 

twofold increased rate of death, compared to those without pneumonia, and this increase 

was unrelated to the severity of underlying diseases. 



16

21. Hospital-acquired pneumonia. Attributable mortality and morbidity. 

Leu HS, Kaiser DL, Mori M, Woolson RF, Wenzel RP. 

Am J Epidemiol 1989 Jun;129(6):1258-67. 

The results of this study show that 30% of patients who develop hospital-acquired 

pneumonia die. In one third of patients the infection is judged to be directly responsible 

for the death of the patient. 

22. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable 

mortality and hospital stay. 

Fagon JY, Chastre J, Hance AJ, Montravers P, Novara A, Gibert C. 

Am J Med 1993 Mar;94(3):281-8. 

The results of this study show that the development of hospital-acquired pneumonia is 

associated with a two-fold increased risk of death in mechanically ventilated patients, and 

with a significant prolongation of hospital length of stay, from a median of 21 days to a 

median of 34 days. The increase in death rates is independent from underlying diseases. 

23. Guidelines for Prevention of Nosocomial Pneumonia. 

MMWR January 03, 1997 / 46(RR-1);1-79. 

This article reports that pneumonia accounts for 15% of all hospital-acquired infections 

(HAIs), and is the second most frequent HAI after urinary tract infections. The incidence 

of nosocomial pneumonia has been estimated at approximately 6 per 1000 hospitalized 

patients, and is significantly higher in university hospitals, compared to non-teaching 

hospitals. Reported mortality rates range from 20% to 50%, and in 30% to 33% of cases 

the death is directly attributed to the infection contracted in the hospital. Conservative 

estimates place the total costs of this complication at $1.2 billion per year. Bacteria 

responsible for the infections are found everywhere in the hospital and are frequently 

spread from patient to patient through contaminated hands of health care workers. The 

risk of spreading the infection could be considerably reduced by adhesion to simple handwashing 

practices. However, doctors rarely comply with this practice, and as a 

consequence the use of gloves has been promoted in order to reduce cross-contamination. 

Unfortunately, transmission of infection has been reported even with use of gloves, and is 

attributable to either breaks in the glove, or to the omission by health care workers to 

change their gloves between contacts with different patients. 



17

24. Hand washing. A modest measure with big effects. 

Handwashing Liaison Group. 

BMJ 1999;318:686-686 ( 13 March ). 

This article highlights that hand washing, a simple preventive measure effective in 

reducing the spread of in-hospital infections, is frequently disregarded as such by health 

care workers, who often fail to perform it. The incidence of in-hospital infections is 

significantly high, with an estimated 9% of patients acquiring an infection while being in 

the hospital. Hands are an important vehicle of transfer of pathogenic bacteria from one 

patient to the other. The majority of physicians, however, fail to decontaminate their 

hands after contact with patients. One study documented hand washing in only 9% of 

physicians, and another documented senior physicians washing their hands only twice 

during a 21-hour ward shift. Failure of physicians to recognize the risks associated with 

non-compliance reflects a system of belief that is deeply ingrained and of difficult 

solution. The authors emphasize how physicians need to recognize that hand 

contamination is an important mean of transfer of pathogenic bacteria before hand 

washing practices can be integrated as part of normal duty care. 

25. Current guidelines for the treatment and prevention of nosocomial infections. 

Bergogne-Berezin E. 

Drugs 1999 Jul;58(1):51-67. 

This article highlights that in the U.S., 5% to 10% of patients admitted to the hospital 

develop a hospital-acquired infection. The incidence of this complication is particularly 

high in the intensive care units, where it occurs in as many as 28% of patients. There are 

preventive measures that could reduce the incidence of hospital-acquired infections, and 

they include improvement in nursing practices, decreased rates of antibiotic prescribing, 

and shortened hospital stay. These measures could significantly lower health care costs 

and infection-related morbidity and mortality. 

26. Nosocomial Hepatitis B Virus Infection Associated with Reusable Fingerstick Blood 

Sampling Devices -- Ohio and New York City, 1996. 

MMWR. March 14, 1997 / 46(10);217-221. 

This article reports on two outbreaks of hepatitis B virus infection that occurred in 

diabetic patients from an Ohio nursing home and a New York City hospital. In both 

instances, an epidemiologic investigation revealed that patients became infected because 

the health-care personnel did not change fingerstick devices for blood-glucose monitoring 

between patients. 



18

27. Nosocomial transmission of hepatitis B virus associated with the use of a springloaded 

finger-stick device. 

Polish LB, et al. 

N Engl J Med 1992 Mar 12;326(11):721-5. 

This article reports on the case of 26 diabetic patients who developed hepatitis B virus 

infection in a California hospital. Epidemiologic investigation revealed that the virus was 

spread from one infected patient to the others due to nursing practices of utilizing the 

same blood glucose monitoring fingerstick device for several patients. 

28. Hospital infection rates in England out of control. News. 

Kmietowicz, Z. 

BMJ 2000;320:534 ( 26 February ). 

This letter explains that in England, every year, at least 100,000 patients develop 

hospital-acquired infections and 5,000 of them die from the complication. Hospitalacquired 

infections affect approximately 1 every 10 hospitalized patients, for an annual 

cost of £1bn ($1.6 billion). Very little effort is put in the prevention of infections, as 

shown by the scant participation of clinicians and hospital chief executives to the 

problem. In some areas, for example, 1 infection control nurse is in charge of 1,000 beds, 

and only 1 of 5 hospitals surveyed has the minimum number of infection control doctors 

recommended by the Royal College of Pathologists -1 physician per 1,000 beds. These 

resources are obviously insufficient to guarantee an effective control of the spread of 

pathogens among hospitalized patients, a negligence that results not only in excess length 

of hospital stay and health care costs, but also in significant morbidity and mortality. 

29. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, 

extra costs, and attributable mortality. 

Pittet D, Tarara D, Wenzel RP. 

JAMA 1994 May 25;271(20):1598-601. 

The results of this study show that patients who develop hospital-acquired bloodstream 

infections have an over three-fold increased risk of dying and an almost two-fold increase 

in hospital length of stay, compared to uninfected ones. The study was conducted on 86 

pairs of patients from a surgical intensive care unit (SICU), with and without bloodstream 

infection, who were matched for age, sex, length of hospital stay and number of 

discharge diagnoses. Fifty percent of patients with bloodstream infection died, compared 

to 15% of those without this complication. In addition, patients who survived the 

infection spent an additional 24 days in the hospital and an additional 8 days in the SICU, 

compared to controls (54 vs. 30 days and 15 vs. 7 days, respectively). Health care costs 

attributable to the bloodstream infection were estimated at $40,000 per patient. 



19

30. Microbiological factors influencing the outcome of nosocomial bloodstream 

infections: a 6-year validated, population-based model. 

Pittet D, Li N, Woolson RF, Wenzel RP. 

Clin Infect Dis 1997 Jun;24(6):1068-78. 

This study reports that, between 1986 and 1991, a total of 1745 patients developed 

hospital-acquired bloodstream infections in a 900-bed tertiary care hospital, and 35% of 

them died from this complication. 

31. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. 

A multicenter prospective study in intensive care units. French ICU Group for Severe 

Sepsis. 

Brun-Buisson C, et al. 

JAMA 1995 Sep 27;274(12):968-74. 

The results of this study, conducted on 11,828 consecutive patients admitted during a 

two-month period to 170 intensive care units in France, show that overall, 9.0% of 

patients developed signs of severe bloodstream infection and 56% of them died in the 4 

weeks following the infection. 

32. The Second National Prevalence Survey of infection in hospitals--overview of the 

results. 

Emmerson AM, Enstone JE, Griffin M, Kelsey MC, Smyth ET. 

J Hosp Infect 1996 Mar;32(3):175-90. 

The results of this study, conducted on over 37,000 patients from 157 hospitals in the UK 

and Ireland, show that nosocomial infections (infections acquired in the hospital) occur in 

9% of patients, and are more frequent in teaching hospital, compared to non-teaching 

ones. 

33. Epidemiology of infection in ICUs. 

Spencer RC. 

Intensive Care Med 1994 Nov;20 Suppl 4:S2-6. 

This study reports the results of the European Prevalence of Infection in Intensive Care 

Study (EPIC), the largest study on Intensive Care Unit (ICU)-related infections in 

Western Europe, that was conducted on a cohort of 10,038 patients admitted to 1417 

adult ICUs from 17 countries. Overall, 21% of ICU patients developed a minimum of one 



20

hospital-acquired infection. Pneumonia was the most frequent infection (47% of cases), 

followed by other lower respiratory tract infections (18%), urinary tract infections (18%), 

and bloodstream infections (12%). 

34. The impact of nosocomial infections on patient outcomes following cardiac surgery. 

Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. 

Chest 1997 Sep;112(3):666-75. 

This study evaluated the frequency of hospital-acquired infections in a cohort of 605 

consecutive patients admitted for cardiac surgery. After the surgery, 22% of patients 

developed at least one hospital-acquired infection. The risk of this complication was 

associated with the duration of mechanical ventilation and urinary tract catheterization, 

and with the initiation of empiric antibiotic therapy after surgery. Infected patients had a 

two-fold increased risk of dying, compared to uninfected ones. 

35. The impact of nosocomial infections on patient outcomes following cardiac surgery. 

Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. 

Chest 1997 Sep;112(3):666-75. 

The results of this study, conducted on a sample population of 605 patients who 

underwent cardiac surgery in an U.S. hospital, show that approximately 22% of patients 

developed at least one hospital-acquired infection. Infected patients had a 4-fold 

increased risk of dying, compared to uninfected ones. In addition, hospital length of stay 

in patients who survived was two times greater in infected versus uninfected patients (20 

days versus 9.7 days). These data indicate that hospital-acquired infections are associated 

with significant mortality, increased length of stay, and health care costs. 

36. Epidemiology of Nosocomial Infection and Resistant Organisms in Patients Admitted 

for the First Time to an Acute Rehabilitation Unit. 

Mylotte JM, Graham R, Kahler L, Young L, Goodnough S. 

Clin Infect Dis 2000 Mar;30(3):425-432. 

The results of this study indicate that 16.5% of patients admitted to an acute rehabilitation 

center develop at least one hospital-acquired infection. Urinary tract infections, surgical 

site infections, Clostridrium difficile diarrhea and bloodstream infections accounted for 

30%, 17%, 15% and 13% of the infections, respectively. 



21

37. Incidence of hospital-acquired infections associated with caesarean section. 

Henderson E, Love EJ. 

J Hosp Infect 1995 Apr;29(4):245-55. 

This study, conducted on a cohort of 1335 women who underwent caesarean section in a 

Canadian teaching hospital, shows that the rate of hospital-acquired infections in women 

delivered by primary and secondary caesarean section, was 42.1% and 46.1%, 

respectively. Women delivered by primary section had significantly higher incidence of 

deep wound infections, endometritis and bacteraemia, compared to those delivered by 

secondary section. Hospital-acquired infections resulted in increased length of hospital 

stay. 

38. Post-discharge surveillance and infection rates in obstetric patients. 

Couto RC, Pedrosa TM, Nogueira JM, Gomes DL, Neto MF, Rezende NA. 

Int J Gynaecol Obstet 1998 Jun;61(3):227-31. 

The results of this study show that women who deliver by Cesarean section have an 

almost 50-fold increased risk of developing hospital-acquired surgical site infections, 

compared to women who deliver by the vaginal route. The study evaluated the incidence 

of this complication in 2431 women who delivered vaginally and 2032 women who 

delivered by Cesarean section, by monitoring patients during their hospital stay and up to 

30 days after hospital discharge. While the incidence of hospital-acquired surgical site 

infections detected during hospital stay was 1.6% in women who underwent Cesarean 

section, this rate increased to 9.6% when cases detected by post-discharge surveillance 

were included. By comparison, rates of infections in women who delivered by the vaginal 

route were significantly lower, occurring in only 0.2% of cases. These findings indicate 

that unless data collected after hospital discharge are included in the estimates of the 

incidence of surgical site infections after Cesarean delivery, the true prevalence of this 

complication can be substantially underestimated. 

39. Occurrence of nosocomial bloodstream infections in six neonatal intensive care units. 

Brodie SB, et al. 

Pediatr Infect Dis J 2000 Jan;19(1):56-65. 

This study evaluated prospectively the incidence of hospital-acquired bloodstream 

infections in neonates weighing less than 1,500 g admitted to six neonatal intensive care 

units (NICUs). Almost 20% of neonates developed a hospital-acquired bloodstream 

infection, and the risk of this complication was significantly associated with use of 

Broviac catheters and intravenous nutrition supplements. Since these infections are 

associated with substantial morbidity and mortality, preventive measures are urgently 

needed. 



22

40. Nosocomial infections in pediatric intensive care units in the United States. 


Richards MJ, Edwards JR, Culver DH, Gaynes RP. 

Pediatrics 1999 Apr;103(4):e39. 

The results of this study show that approximately 6% of children admitted to a pediatric 

intensive care unit (ICU) develop hospital-acquired infections. In the study, 6290 

infections occurred in a cohort of 110,709 patients admitted to 61 pediatric ICUs, 

according to data collected through the National Nosocomial Infections Surveillance 

System -a voluntary system of reporting of hospital-acquired infections. The most 

common type of infection was bloodstream infection (28%), followed by pneumonia 

(21%), and urinary tract infection (15%). These complications were almost always 

associated with use of invasive devices. 

41. Nosocomial infections among neonates in high-risk nurseries in the United States. 


Gaynes RP, Edwards JR, Jarvis WR, Culver DH, Tolson JS, Martone WJ. 

Pediatrics 1996 Sep;98(3 Pt 1):357-61. 

This study reports data submitted by 99 hospitals participating in the National 

Nosocomial Infections Surveillance system, a voluntary, hospital-based, reporting system 

established to monitor rates of hospital-acquired infections, indicating that from 1986 to 

1994, a minimum of 13,179 neonates in high-risk nurseries developed this complication. 

The most common hospital-acquired infections were bloodstream infections, followed by 

pneumonias and gastrointestinal infections. 

42. Hospital-acquired morbidity on a neurology service. 

Shafer SQ, Brust JC, Healton EB, Mayo JB. 

J Natl Med Assoc 1993 Jan;85(1):31-5. 

This study evaluated prospectively the charts of 1317 consecutive patients admitted over 

a 3-year period to the neurology department of a city hospital, to determine the incidence 

of hospital-acquired infections in this sample population. Overall, 6.8% of patients 

developed at least one hospital-acquired infection, which consisted of a bloodstream 

infection in almost half of the cases. The authors emphasize that these data greatly exceed 

previously reported estimates. 



23

43. Surveillance of nosocomial infections in geriatric patients. 

Beaujean DJ, et al. 

J Hosp Infect 1997 Aug;36(4):275-84. 

The results of this study, conducted on 300 geriatric patients admitted to a medical ward 

of a hospital in the Netherlands, show that one third of patients developed at least one 

hospital-acquired infection (126 infections in 100 patients). Fifty-nine percent of the 

infections were urinary tract infections, and 20% were infections of the gastrointestinal 

tract. Seventy percent of patients with asymptomatic urinary tract infection received 

antibiotics. Age, dehydration, and the presence of a urinary catheter were all significant 

risk factors for the development of hospital-acquired infections. Hospital length of stays 

increased by twofold in infected versus uninfected patients. 

44. Hospital-acquired pressure ulcers: risk factors and use of preventive devices. 

Perneger TV, Heliot C, Rae AC, Borst F, Gaspoz JM. 


The results of this study, conducted on 2373 patients who did not have pressure ulcers 

upon admission to a university hospital, show that 10% of them developed this 

complication during their hospital stay. The study detected suboptimal use of special 

devices (such as mattresses, cushions, and beds) for the prevention of this complication. 

45. Pressure ulcers, hospital complications, and disease severity: impact on hospital costs 

and length of stay. 

Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR. 

Adv Wound Care 1999 Jan-Feb;12(1):22-30. 

The results of this study, conducted on a sample population of 286 patients aged 55 and 

older, show that those who developed pressure ulcers had, after controlling for several 

confounders, increased length of hospital stay (21 vs. 13 days) and increased incidence of 

hospital-acquired infections (46% vs. 20%) and other complications (86% vs. 43%), 

compared to those who did not. Hospital costs for patients with incident pressure ulcers 

were estimated at $29,048 compared to 13,819 in those without this ailment. 

46. Epidemiology of infectious and iatrogenic nosocomial diarrhea in a cohort of general 

medicine patients. 

McFarland LV. 

Am J Infect Control 1995 Oct;23(5):295-305. 



24

The results of this study, conducted on 382 patients admitted over an 11-month period to 

the general medicine ward of a county hospital, show that the incidence of hospitalacquired 

diarrhea in this cohort was 33%. The risk of developing this complication 

increased with increasing patient age, length of stay, number of antibiotics and 

nasogastric tube feeding. Patients with hospital-acquired diarrhea had an increased risk of 

developing a second infection, of having a prolonged hospital length of stay, and of 

dying, than patients without this condition. 

47. Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in a 

cohort of hospitalized patients. 

McFarland LV, Surawicz CM, Stamm WE. 

J Infect Dis 1990 Sep;162(3):678-84. 

The results of this study show that the incidence of hospital-acquired diarrhea caused by 

Clostidrium difficile, as evaluated in a cohort of 399 patients, was 7.8 per 100 patients. 

C. difficile accounted for one fifth of all hospital-acquired diarrhea, and the risk of 

developing C. difficile-associated diarrhea increased by 2-3 folds in individuals using 

cephalosporin, penicillin, enemas, gastrointestinal stimulants, or stool softeners. 

48. Nosocomial infections in the ICU: the growing importance of antibiotic-resistant 

pathogens. 

Weber DJ, Raasch R, Rutala WA. 

Chest 1999 Mar;115(3 Suppl):34S-41S. 

This study indicates that patients in intensive care units have a 5-10 fold increased risk of 

developing a hospital-acquired infection, compared to those admitted to other hospital 

units. A major contributor to the morbidity and mortality associated with this 

complication is the antibiotic-resistance of the pathogens involved in the infection. 

Measures of prevention include proper handwashing, patient isolation, proper 

disinfection and sterilization techniques, and judicious use of antibiotics, as demonstrated 

by the fact that hospitals with the highest rates of hospital-acquired infections also have 

the highest rates of antibiotic use. 

49. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality 

among critically ill patients. 

Kollef MH, Sherman G, Ward S, Fraser VJ. 

Chest 1999 Feb;115(2):462-74. 

The results of this study, conducted on 2000 patients admitted to a medical or surgical 

intensive care unit, show that 25% of hospitalized patients with community- or hospital- 



25

acquired infections receive inappropriate antibiotic treatment. Mortality rates in patients 

receiving inadequate antibiotic treatment are 42%, compared to 17.7% in patients 

appropriately treated. After logistic regression analyses it was shown that inappropriate 

antibiotic treatment was the strongest determinant of hospital mortality for the entire 

(infected and uninfected) patient cohort, and resulted in a 4.3-fold increased risk of death. 

50. Appropriateness of antibiotic therapy in long-term care facilities. 

Jones SR, Parker DF, Liebow ES, Kimbrough RC 3d, Frear RS. 

Am J Med 1987 Sep;83(3):499-502. 

This study evaluated the appropriateness of antibiotic therapy in patients of two nursing 

homes in Portland, Oregon, over a 3-month period. One hundred twenty infections 

occurred during the study period. Antibiotic treatment was judged appropriate only in 

49% of cases, and inappropriate and unjustified in 42% and 9% of cases, respectively. 

51. Method of physician remuneration and rates of antibiotic prescription. 

Hutchinson JM, Foley RN. 

CMAJ 1999 Apr 6;160(7):1013-7. 

The results of this study, conducted on 476 Canadian doctors, show that physicians who 

are paid for fee-for-service and those with greater volume of patients are much more 

likely to prescribe antibiotics, compared to doctors paid by salary and with smaller 

patient volume. These findings indicate that factors unrelated to medical conditions play 

an important role in physicians' attitude toward antibiotic prescribing. 

52. Antimicrobial use for pediatric upper respiratory infections: reported practice, actual 

practice, and parent beliefs. 

Watson RL, Dowell SF, Jayaraman M, Keyserling H, Kolczak M, Schwartz B. 

Pediatrics 1999 Dec;104(6):1251-7. 

This study was conducted on a sample of 366 pediatricians and family physicians from 

Georgia to determine their antibiotic prescribing practices in pediatric patients with upper 

respiratory tract infections (URTIs). While 97% of them reported that widespread use of 

antibiotics was a major contributor to the development of antibiotic resistant bacterial 

strains, they nevertheless prescribed antibiotics in 72% of visits for URTIs. In addition, 

contrary to published guidelines for the management of pediatric patients with these 

conditions, 86% of physicians prescribed antibiotics in patients with bronchitis regardless 

of the duration of cough, and 42% prescribed antibiotics for the common cold. 

Interestingly, physicians who prescribed the most antibiotics also had the highest rates of 

return office visits (up to 30% more). The authors conclude that antibiotic prescribing 



26

practices in pediatric patients with URIs often are in disagreement with published 

guidelines, in spite of physicians' knowledge of the role of injudicious use of antibiotics 

in the development of antibiotic resistance. 

53. Antibiotic prescribing for children with colds, upper respiratory tract infections, and 

bronchitis. 

Nyquist AC, Gonzales R, Steiner JF, Sande M. 

JAMA. 1998 Mar 18;279(11):875-7. 

This study evaluated the rates of antibiotic prescribing in 531 children younger than 18 

years diagnosed with common cold, upper respiratory tract infections (URTIs) or 

bronchitis. Forty-four percent of children with common cold, 46% of those with URTIs, 

and 75% of those with brochitis received an antibiotic prescription. Extrapolation of these 

data to the entire U.S. population revealed that in 1992, physicians wrote 6.5 million 

prescriptions for children with URTIs or common cold and 4.7 million prescriptions for 

children with bronchitis, despite the fact that, as emphasized in the article, antibiotic 

treatment is typically ineffective in these conditions. These data indicate that 21% of all 

antibiotic prescriptions written for children younger than 18 in 1992 (over 11 million 

prescriptions) are unnecessary. 

64. Systematic review of the treatment of upper respiratory tract infection. 

Fahey T, Stocks N, and Thomas T. 

Arch Dis Child 1998;79:225-230 ( September ). 

The results of this meta-analysis, conducted on 6 randomized, placebo-controlled studies 

involving 1,699 children, show that antibiotic treatment does not improve clinical 

outcome or reduce rates of complications in children with upper respiratory tract 

infections. The authors conclude that there is no evidence from randomized trials 

supporting the use of antibiotics in the management of children with upper respiratory 

tract infections. 

65. Outcomes After Judicious Antibiotic Use for Respiratory Tract Infections Seen in a 

Private Pediatric Practice. 

Pichichero, ME. et al. 

Pediatrics 2000 Apr;105(4):753-759. 

The results of this study show that antibiotic treatment is not routinely recommended in 

the management of children with respiratory tract infections without a concomitant 

bacterial infection. The study was conducted on a sample of 383 infants and children 

younger than 12 with respiratory tract infections, to evaluate the effects of a reduction of 



27

antibiotic prescribing rates on the incidence of return office visits or subsequent bacterial 

infections. In the study, physicians prescribed antibiotics only when a bacterial infection 

was confirmed or presumed, resulting in only 23% of children receiving a prescription. 

Of note, more than half of the antibiotic prescriptions were written for children who were 

diagnosed with middle ear infections, even though current evidence (presented later in 

this text) indicates that antibiotics are no better than placebo in the management of this 

condition. Evaluation of the frequency of subsequent unscheduled return visits revealed 

that only 29% of children who did not receive antibiotics returned for an additional visit, 

compared to 44% of those treated with antibiotics. These data further support judicious 

use of antibiotics in children and infants with respiratory tract infections, i.e. avoidance of 

antibiotic treatment when there are no signs of bacterial infection. Less than 1 every 5 

infants or children who present with respiratory tract infections require antibiotic 

treatment. Untreated children had lower rates of subsequent return office visits or 

bacterial infections, compared to treated children. Physicians should comply with current 

evidence demonstrating the safety and effectiveness of judicious antibiotic use, especially 

in consideration of the worldwide increase in antibiotic resistant bacteria, leading to a 

staggering increase in morbidity, mortality and health care costs due to untreatable 

infections. 

66. Decreasing Antibiotic Use in Ambulatory Practice. Impact of a Multidimensional 

Intervention on the Treatment of Uncomplicated Acute Bronchitis in Adults. 

Gonzales, R. et al. 

JAMA 1999;281:1512-1519. 

The results of this study show that an intervention program consisting of office-based 

patient educational materials and clinician educational meetings resulted in a decline in 

antibiotic prescribing rates from 74% to 48% in patients with uncomplicated bronchitis. 

No differences in office return visits were observed in the month following the first visit, 

between the institutions with reduced antibiotic prescribing and those with rates of 

antibiotic prescribing of 80%, indicating that use of these drugs is unnecessary in the 

routine management of patients with uncomplicated bronchitis. 

67. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and 

bronchitis by ambulatory care physicians. 

Gonzales R, Steiner JF, Sande MA. 

JAMA 1997 Sep 17;278(11):901-4. 

The results of this study show that although antibiotics have been shown to be largely 

ineffective in treating colds, upper respiratory tract infections and bronchitis, they are 

nevertheless prescribed to 51%-66% of patients diagnosed with these conditions. This 

study demonstrates that in 1992, an estimated 12 million antibiotic prescriptions, or one 

fifth of all antibiotics prescriptions filled during that year, were written for patients with 



28

colds, upper respiratory tract infections or bronchitis, despite lack of evidence of their 

effectiveness in the management of these ailments (more than 90% of upper respiratory 

infections -including bronchitis and colds- note the authors, are caused by a virus and are 

therefore impervious to antibiotics.) This practice has contributed to the spread of 

antibiotic-resistant bacteria and consequent infections in community settings. 

68. Antibiotics and upper respiratory infection: do some folks think there is a cure for the 

common cold. 

Mainous AG 3d, Hueston WJ, Clark JR. 

J Fam Pract 1996 Apr;42(4):357-61. 

The results of this study show that 60% of patients who present with a complaint of 

common cold receive an antibiotic prescription. This practice leads to an estimated 

annual cost of $37.5 millions for unnecessary treatment of a condition that is not 

improved by antibiotic treatment. 

69. Trends in antimicrobial drug prescribing among office-based physicians in the United 

States. 

McCaig LF, Hughes JM. 

JAMA 1995 Jan 18;273(3):214-9. 

The results of this study indicate that from 1980 to 1992, rates of prescribing of more 

expensive antibiotics with a broader antibacterial spectrum have been increasing, while 

prescribing of cheaper antibiotics with a narrower spectrum have been decreasing. The 

authors emphasize that this trend leads to an increase use of health care resources and has 

a potential deleterious effect on the insurgence of antibiotic resistance. 

70. Factors associated with antibiotic use for acute bronchitis. 

Gonzales R, Barrett PH Jr, Crane LA, Steiner JF. 

J Gen Intern Med 1998 Aug;13(8):541-8. 

The results of this study show that physicians in primary care office practices prescribe 

antibiotics to 85% of patients with acute bronchitis. The authors could not identify 

clinical factors that explained the high rates of antibiotic prescribing and conclude that it 

seems feasible that a diagnosis of acute bronchitis is interpreted by physicians as an 

indication for antibiotic treatment, despite available evidence indicating the contrary. 



29

71. Treatment of acute bronchitis in adults. A national survey of family physicians. 

Oeffinger KC, Snell LM, Foster BM, Panico KG, Archer RK. 

J Fam Pract 1998 Jun;46(6):469-75. 

The results of this study show that family physicians prescribe antibiotics to 75% of 

nonsmoking and otherwise healthy adult patients with acute bronchitis and to 90% of 

smoking and otherwise healthy adult patients with acute bronchitis, despite evidence 

from clinical trials indicating that antibiotics are largely ineffective in the management of 

this condition. The authors emphasize how the increasing prevalence of antibiotic 

resistance calls for a change in the management of patients with acute bronchitis. 

72. Antimicrobials for acute otitis media? A review from the international primary care 

network. 

Froom, J. et al. 

BMJ 1997;315:98-102 (12 July). 

This article highlights that even though there is no scientific evidence demonstrating that 

antibiotics are effective in the treatment of middle ear infections, this condition represent 

the most frequent reason for prescribing antibiotics in outpatient settings in the U.S. The 

seven randomized studies that evaluated the effectiveness of antibiotics in children with 

middle ear infection showed little or no benefits compared to placebo. The authors 

conclude that there is no convincing evidence in support of the use of these drugs in 

children with middle ear infections, and the management of this condition should 

therefore be reevaluated. Changing treatment practices is especially important since 

injudicious use of antibiotics is a major factor implicated in the development of antibiotic 

resistance and the consequent increase in morbidity, mortality, and health care costs 

associated with untreatable infections. 

73. Primary care based randomised, double blind trial of amoxicillin versus placebo for 

acute otitis media in children aged under 2 years. 

Damoiseaux, Roger A M J et al. 

BMJ 2000;320:350-354 ( 5 February ). 

The results of this randomized study indicate that use of antibiotics is inappropriate not 

only in older children with middle ear infections but also in those aged 6 months to 2 

years. In the study, 240 children under 2 years diagnosed with middle ear infection were 

randomly assigned to receive antibiotics or placebo. Signs of inflammation, pain and 

crying were no different in the group receiving antibiotics, compared to that receiving 

placebo. One every 7 or 8 treated children showed symptomatic improvement at day 4 of 

infection, but there were no improvements at day 11 or 42. The small benefits observed 

in a 13% of children do not justify routine antibiotic use in children of this age group 

with middle ear infection. 



30

74. Quantitative systematic review of randomised controlled trials comparing antibiotic 

with placebo for acute cough in adults. 

Fahey T, Stocks N, Thomas T. 

BMJ 1998 Mar 21;316(7135):906-10. 

This study is a meta-analysis of 9 randomized, placebo-controlled trials evaluating the 

efficacy of antibiotics in the treatment of individuals with acute cough. The results of the 

analysis revealed that antibiotics neither improve symptoms nor speed up recovery time 

in individuals with acute cough, while causing significantly more side effects compared 

to placebo. These data indicate that antibiotic treatment is inappropriate in individuals 

with acute cough. 

75. National trends in the use of antibiotics by primary care physicians for adult patients 

with cough. 

Metlay JP, Stafford RS, Singer DE. 


The results of this study show that primary care physicians' rates of antibiotic prescribing 

for adult patients presenting with cough increased significantly from 1980 to 1994. In 

particular, in 1980 an estimated 59% of patients who went to their doctor with a 

complaint of cough received an antibiotic prescription, as compared to 70% of patients 

who presented with cough in 1994. These data indicate an increasing trend of antibiotic 

prescribing for patients with cough, despite increasing evidence of the lack of efficacy of 

antibiotic treatment in this condition. 

76. Outpatient visits for infectious diseases in the United States, 1980 through 1996. 

Armstrong GL, Pinner RW. 

Arch Intern Med 1999 Nov 22;159(21):2531-6. 

The results of this study show that every year 129 million outpatient visits, or 

approximately 20% of all outpatient visits to physicians are for infectious diseases. Of 

these, the majority (38%), are for upper respiratory tract infections, followed by middle 

ear infections (15.1%) and lower respiratory tract infections. These data indicate that over 

half of all visits for infectious diseases (approximately 68.5 million annual visits) are for 

upper respiratory tract infections or otitis, conditions that are typically not improved by 

antibiotics and for which antibiotics are first choice treatment. 



31

ANTIDEPRESSANTS – 109 Studies 

1. Trends in the prescribing of antidepressant pharmacotherapy: office-based visits, 1990- 

1995. 

Sclar DA. et al. 

Clin Ther 1998 Jul-Aug;20(4):871-84; 870. 

The results of this study show that the number of office visits resulting in prescription of 

an antidepressant drug increased from 16,534,268 in 1990 to 28,664,796 in 1995, a 

73.4% increase. A diagnosis of depression was documented in 6.7% of the U.S. 

population in 1990, and in 7.1% in 1995, a 16.4% increase. The large increase in number 

of prescriptions, not matched by a similar increase in the prevalence of depression, 

suggests that the criteria for prescribing antidepressant medications have loosened during 

the study period. A variation in rates of prescribing of different class of drugs was also 

noticed, with a decline in use of tricyclic antidepressants (from 42% to 25%), and an 

increase in use of selective serotonin reuptake inhibitors (from 37% to 65%). 

2. Association between selective serotonin reuptake inhibitors & upper gastrointestinal 

bleeding 

population based case-control study. 

de Abajo, FJ, García Rodríguez LA, Montero D. 

BMJ 1999;319:1106-1109 ( 23 October ). 

The results of this study show that users of the antidepressants selective serotonin 

reuptake inhibitors (SSRIs) have a significantly increased risk of upper gastrointestinal 

(GI) bleeding, compared to nonusers. The study was conducted on 1651 patients 

hospitalized with upper GI bleeding, and 10,000 matched controls. Use of SSRIs was 

associated with a 3-fold increased risk of bleeding, compared to nonuse. The incidence of 

this complication was estimated at 1every 8,000 prescriptions. Combined use of SSRIs 

and aspirin was associated with a 7-fold increased risk of GI hemorrhage, and combined 

use of SSRIs and non-steroidal anti-inflammatory drugs resulted in a 15.6-fold increased 

risk. The authors emphasize that the large increase in risk of GI hemorrhage observed in 

their study could have important public health implications due to the frequent use of 

both classes of drugs in industrialized countries. 

3. Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) 

antidepressants. 

Seven case reports and review of the literature. French. 

Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, Ollagnier M. 

Rev Med Interne 2000 Feb;21(2):152-60. 



32

The results of this study suggest that intake of the antidepressants selective serotonin 

reuptake inhibitors is associated with an increased risk of developing hemorrhagic 

syndromes. This adverse effect is under-recognized and under-reported, and may be due 

to a decrease in concentration of platelet serotonin, leading to platelet dysfunction. 

4. Antidepressant Medication Use and Breast Cancer Risk. 

Cotterchio M, Kreiger N, Darlington G, and Steingart A. 

Am J Epidemiol 2000;151:951-57. 

The results of this study indicate that women who take antidepressants are at significantly 

higher risk of developing breast cancer, compared to the general population. The 

association between antidepressant drugs and breast cancer first emerged from animal 

and epidemiological data. This case-control study, conducted to further test the 

hypothesis, found that users of selective serotonin reuptake inhibitors (SSRIs) and 

tryciclic antidepressants have a 7- and 2-fold increased risk of breast cancer, respectively, 

compared to nonusers. The finding of a large increase in risk of breast cancer in users of 

SSRIs may have public health implications owing to the high prevalence of use of this 

class of drugs. 

5. Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the 

morphology of serotonergic nerve terminals using serotonin immunohistochemistry. 

Kalia M, et al. 

Brain Res 2000 Mar 6;858(1):92-105. 

The results of this study indicate that short-term exposure to selective serotonin reuptake 

inhibitors (SSRIs) results in changes of rat brain cells, which resemble those induced by 

the recreational drug Ecstasy. SSRIs work by increasing the concentration of serotonin in 

the brain through inhibition of their re-uptake by brain cells. Their mode of action is 

similar to that of the recreational drug Ecstasy, which also increases the concentration of 

serotonin at the receptor site through a double action of inhibited reuptake and stimulated 

secretion from brain cells. While Ecstasy-induced brain damage has been well 

demonstrated in both animal and human studies, there are no data on the effects of SSRIs 

on brain cells. This study documented that, after only 4 days of intake of SSRIs, rat brain 

cells underwent morphological changes characterized by swelling and acquisition of a 

corkscrew shape, indicative of occurred damage. These findings indicate that SSRIs, the 

most commonly prescribed class of antidepressant drugs, cause damage in animal brain 

cells, after only 4 days of exposure. More studies on humans are needed, before these 

drugs can be considered safe. 



33

6. Discontinuation symptoms and psychotropic drugs 

Young, A. and Haddad P. 

Lancet 2000; 355: 1181 - 1190. 

This letter emphasizes that 35% to 78% of individuals who take the antidepressants 

selective reuptake inhibitors (SSRIs) for several months, experience, upon abrupt 

treatment interruption, physical and psychological symptoms such as: changes in mood, 

affect, appetite and sleep, dizziness, fatigue, anxiety, agitation, nausea, headache, and 

sensory disturbance. The symptoms are so typical that the clinical entity "SSRI 

discontinuation syndrome" is now widely accepted, after its existence had been negated 

for several years following the introduction of SSRIs on the market. Symptoms are 

usually mild and short-term, but occasionally can be severe and long lasting. They have 

often been interpreted as a sign of relapse into depression, leading to re-institution of 

treatment. The authors propose that all new psychotropic drugs be tested in double-blind 

placebo-controlled studies lasting several weeks beyond the actual drug trial, in order to 

properly monitor adverse reactions that may occur only upon discontinuation of 

treatment. 

7. Hormonal markers of stress response following interruption of selective serotonin 

reuptake inhibitor treatment. 

Michelson D, et al. 

Psychoneuroendocrinology 2000 Feb;25(2):169-77. 

The results of this study show that following abrupt interruption of treatment with 

selective serotonin reuptake inhibitors patients develop signs of activation of a stress 

response, as shown by significantly increased plasma levels of IGF-1 and heart rate. 

8. Antidepressant discontinuation reactions. 

Haddad P, Lejoyeux M, and Young A. 

BMJ 1998;316:1105-1106 ( 11 April ). 

This article reports on the frequency and nature of adverse reactions occurring upon 

discontinuation of antidepressant treatment. It explains that the existence of 

discontinuation reactions is often unrecognized by clinicians and that the extent of their 

occurrence is largely unknown because very few studies have ever addressed this issue. 

Discontinuation reactions usually start after few days of interruption of antidepressant 

treatment, and may consist of nausea, diarrhea, abdominal pain, insomnia, nightmares, 

headaches, lethargy, anxiety, and irritability. With selective serotonin-reuptake inhibitors, 

withdrawal is more commonly associated with symptoms such as dizziness, paraesthesia, 

numbness, and electric shock-like sensations. Results of a double blind placebo 

controlled study have shown that adverse reactions occur in 35% of patients after 

discontinuation of a 12-week treatment with the serotonin reuptake inhibitor paroxetine. 



34

Such reactions usually resolve within one day to three weeks, but occasionally they can 

be more severe and persist chronically, causing substantial morbidity. 

9. Discontinuation symptoms after treatment with serotonin reuptake inhibitors 

a literature review. 

Zajecka J, et al. 

J Clin Psychiatry 1997 Jul;58(7):291-7. 

The results of this study indicate that discontinuation of selective serotonin-reuptake 

inhibitor therapy is associated with the development of a cluster of symptoms including 

dizziness, light-headedness, insomnia, fatigue, anxiety, nausea, headache, and sensory 

disturbance. These symptoms may last up to three weeks after interruption of treatment, 

and may be relieved by restarting antidepressant therapy (!). 

10. Antidepressant-induced sexual dysfunction during treatment with moclobemide, 

paroxetine, sertraline, and venlafaxine. 

Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. 

J Clin Psychiatry 2000 Apr;61(4):276-81. 

The results of this study indicate that 30%-70% of patients who take the selective 

serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline experience sexual 

dysfunction as a side effect of treatment. Impairment in drive and/or desire occurs more 

frequently in men than women, while impairment in level of arousal and orgasm is 

experienced at similar rates by both sexes. These data indicate that the majority of 

patients treated with SSRIs experience sexual dysfunction. The low rates of this 

complication reported in previous studies were due to underreporting and was not 

confirmed in subsequent trials. 

11. Sexual dysfunction induced by serotonin reuptake antidepressants. 

Labbate LA, Grimes J, Hines A, Oleshansky MA, Arana GW. 

J Sex Marital Ther 1998 Jan-Mar;24(1):3-12. 

The results of this study show that the antidepressants selective serotonin reuptake 

inhibitors negatively affect sexual functios. The study was conducted on 61 individuals 

who took these drugs for at least two months. Both men and women experienced a 

significant worsening of quality of orgasm after 1 and 2 months of treatment, compared 

to baseline. Women reported failure to achieve an orgasm significantly more often than 

men, while both sexes experienced prolongation of time to orgasm induction after 1, 2, 

and 3 months of treatment, compared to baseline. 



35

12. Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy. 

Nafziger AN, et al. 

J Clin Psychiatry 1999 Mar;60(3):187-90. 

The results of this study show that 35% of healthy volunteer who took the antidepressant 

fluvoxamine developed, after 4 weeks of treatment, sexual dysfunction. 

13. Adverse reactions of selective serotonin reuptake inhibitors 

reports from a spontaneous reporting system. 

Spigset O. 

Drug Saf 1999 Mar;20(3):277-87. 

This study evaluated 1202 spontaneous reports on 1861 adverse reactions to selective 

serotonin reuptake inhibitors (SSRIs), and found that 22.4% of such reports consisted of 

neurological disturbances, 20% of psychiatric disorders, and 18% of gastrointestinal 

symptoms. The elderly were particularly susceptible to Parkinsonism, confusion, 

hallucinations, and hypotension, while younger patients experienced more frequently 

hematological, endocrine, and sexual dysfunction. Akathisia and aggression occurred 

more frequently in men than women. 

14. A survey of antidepressant drug use in Parkinson's disease. Parkinson Study Group. 

Richard IH, et al. 

Neurology 1997 Oct;49(4):1168-70. 

The results of this study indicate that approximately 26% of patients with Parkinson's 

disease (PD) are given antidepressant medications, which consist, in over half of the 

cases, of serotonin reuptake inhibitors (SSRIs). Forty-three percent of physicians of the 

Parkinson Study Group showed concern that use of SSRIs might induce worsening of 

motor function in PD patients, and 37% of physicians had at least one patient in which 

they believed such aggravation occurred. 

15. Prenatal exposure to fluoxetine (Prozac) produces site-specific & age-dependent 

alterations in brain serotonin transporters in rat progeny 

Evidence from autoradiographic studies. 

Cabrera-Vera TM, Battaglia G. 

J Pharmacol Exp Ther 1998 Sep;286(3):1474-81. 



36

The results of this study show that prenatal exposure to the selective serotonin reuptake 

inhibitor fluoxetine (Prozac) induces changes in the density of brain serotonin 

transporters in rats, which are particularly evident in regions of the limbic system, such as 

the hypothalamus, hippocampus and amygdala. These data indicate that fluoxetine alters 

brain function in rats exposed to the drug while in uterus. 

16. Pregnancy outcome following first-trimester exposure to fluoxetine. 

Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, et al. 

JAMA 1993 May 5;269(17):2246-8. 

The results of this study show that women who use the antidepressant fluoxetine (Prozac) 

in the first trimester of pregnancy have approximately a 2-fold increased risk of 

miscarriage, compared to nonusers. 

17. Birth outcomes in pregnant women taking fluoxetine. 

Chambers CD, et al. 

N Engl J Med, 335(14):1010-5 1996 Oct 3. 

This study evaluated pregnancy outcome of women who took the antidepressant 

fluoxetine (a serotonin uptake inhibitor) while expecting, and compared it to that of 

women who did not take the drug. In infants exposed to the drug, the incidence of three 

or more minor anomalies was 15.5% vs. 6.5% in controls. Infants exposed to fluoxetine 

during the third trimester had, compared to those exposed only during the first and 

second trimester, reduced birth weight and length, an almost 5-fold increased risk of 

premature delivery, a 2.6-fold increased risk of being admitted to special-care nurseries, 

and an almost 9-fold increased risk of experiencing respiratory difficulties, cyanosis on 

feeding, and jitteriness. 

18. Antidepressants and suicidal risk. 

Muller-Oerlinghausen B, Berghofer A. 

J Clin Psychiatry 1999;60 Suppl 2:94-9; discussion 111-6. 

This article emphasizes that selective serotonin reuptake inhibitors and other non-lithium 

antidepressants may increase the risk of suicide in certain patients by inducing akathisia 

(a condition characterized by restlessness and psychomotor agitation and associated with 

self-destructive impulses) and by liberating suppressed energies that may be used to act 

upon suicidal thoughts. 



37

Reexposure to fluoxetine after serious suicide attempts by three patients: the role of 

akathisia. 

Rothschild AJ. et al. 

J Clin Psychiatry, 52(12):491-3 1991 Dec. 

This article describes three cases of attempt suicide after induction of akathisia in patients 

on fluoxetine therapy. When re-exposed to the drug, all three patients re-developed 

akathisia and precipitated in suicidal thoughts, strongly suggesting a relation of causality 

between drug exposure and suicidal impulse. 

19. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. 

Song F. et al. 

BMJ 1993 Mar 13;306(6879):683-7. 

This study presents the results of a meta-analysis of 63 randomized controlled studies 

comparing the efficacy of selective serotonin reuptake inhibitors (SSRIs) to that of 

tricyclic antidepressants as first line treatment for depression. The analysis revealed that 

SSRIs are no more effective than tryciclics in the management of depression. Dropouts 

rate were similar for both class of drugs, but slightly more patients reported side effects 

as a reason for dropping out in the tryciclic group compared to those in the SSRI group 

(18.8% v 15.4%). The authors concluded that "Routine use of selective serotonin 

reuptake inhibitors as the first line treatment of depressive illness may greatly increase 

cost with only questionable benefit". This study is important since it shows that SSRIs are 

not significantly better than classic antidepressant drugs, in spite of advertising 

campaigns claiming the superiority of SSRIs in the treatment of depression due to their 

excellent safety records. The underreporting of SSRI-related adverse reactions is also 

partly responsible for the vast increase in prescribing rates of these drugs. 

20. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly 

depressed patients. 

Cohn CK. et al. 

J Clin Psychiatry, 51 Suppl B():28-33 1990 Dec. 

In this study, 241 elderly individuals suffering from depression were randomized to 

receive an 8-week treatment with either amitriptyline (a tricyclic antidepressant) or 

sertraline (a serotonin uptake inhibitor). Over 30% of patients in the sertraline group and 

35% in the amitriptyline group withdrew from the study because of drug-related side 

effects or laboratory abnormalities. 



38

The cost of antidepressant drug therapy failure: a study of antidepressant use patterns in a 

Medicaid population. 

McCombs JS, et al. 

J Clin Psychiatry, 51 Suppl():60-9; discussion 70-1 1990 Jun. 

The results of this study, conducted on a cohort of 2344 patients with major depressive 

disorders on antidepressant medications, show that only in 3.5% of patients the pattern of 

use of antidepressant was indicative of successful treatment. In 12.6 of patients, pattern of 

antidepressant use suggested treatment failure. In the remaining 84% of cases the efficacy 

of treatment could not be clearly classified. 

21. The adequacy of reporting randomized, controlled trials in the evaluation of 

antidepressants. 

Streiner DL, et al. 

Can J Psychiatry, 43(10):1026-30 1998 Dec. 

This study examined the statistical and methodological validity of 69 randomized control 

trials that compared the efficacy of two antidepressant drugs with that of placebo. Criteria 

scores were defined as minimal and ideal. Zero percent of the studies met all of the ideal 

criteria for reporting clinical trials. Only 9 of 69 articles met the minimal criteria to be 

included in metaanalytical studies. These data indicate that the quality of the majority of 

studies on antidepressant drugs is extremely poor. 

22. Hyponatremia in relation to treatment with antidepressants: 

A survey of reports in the World Health Organization database for spontaneous reporting 

of adverse drug reactions. 

Spigset O, et al. 

Pharmacotherapy 1997 Mar-Apr;17(2):348-52. 

The results of this study show that from 1968 to 1993, 668 cases of antidepressant-related 

hyponatremia were spontaneously reported to the World Health Organization. In over 

half of the patients, the reaction occurred within two weeks of starting antidepressant 

treatment. 

23. Relative mortality from overdose of antidepressants. 

Henry JA, et al. 

BMJ, 310(6974):221-4 1995 Jan 28. 



39

This study reports on the case of 1606 deaths from antidepressant toxicity, occurring in 

the period from 1987 to1992. Over 80% of these deaths were associated to amitriptyline 

and dothiepin use. 

24. Antidepressant-treated patients in ambulatory care. Mortality during a nine-year 

period after first treatment. 

Bingefors K. et al. 

Br J Psychiatry, 169(5):647-54 1996 Nov. 

The results of this study show that, in individuals over 65 years of age, treatment with 

antidepressant is significantly associated with increased risk of long-term mortality, 

especially from cardiovascular causes. 

25. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. 

Reilly, J G. et al. 

Lancet 2000; 355: 1048 - 1052. 

The results of this study show that use of psychotropic drugs is associated with a 

significantly increased risk of heart arrhythmias. The study was conducted on 495 

psychiatric patients and 101 healthy individuals who served as control. As a marker for 

increased risk of arrhythmias the authors used the lengthening of the QT interval on the 

electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged 

QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an 

abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic 

drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, 

compared to non-users. The risk increased with increasing doses of drugs, and was 

increased by more than 8 times in users of very high doses. These findings may explain 

some cases of sudden unexplained death occurring in patients taking psychotropic drugs, 

as this type of death has been linked to cardiac rhythm abnormalities. 

26. Relative mortality from overdose of antidepressants 

Henry JA, et al. 

BMJ 1995;310:221-224 (28 January). 

The results of this study show that for every million prescriptions written for 

antidepressant drugs, approximately 30 people die from overdose. Tricyclic drugs are 

associated with the highest incidence of death (34 deaths per million prescriptions), and 

selective serotonin reuptake inhibitors with the lowest (2 deaths per million prescription). 



40

27. Imipramine overdose complicated by toxic megacolon. 

Ross JP, et al. 

Am Surg, 64(3):242-4 1998 Mar. 

This article emphasizes that tricyclic antidepressants are responsible for approximately 20 

to 25% of drug overdoses leading to hospitalization. Death occurs primarily from 

cardiovascular complications. Respiratory disturbances, urinary retention, constipation, 

and intestinal obstruction are common signs of toxicity. Less frequent complications 

include: pancreatitis, intestinal perforation, and gangrene of the large intestine. 

28. Cardiotoxic side effects associated with tricyclic antidepressant overdose. 

Keis NA. 

AACN Clin Issues Crit Care Nurs, 3(1):226-32 1992 Feb. 

This article emphasizes that intake of excessive doses of tricyclic antidepressants is 

associated with a significant risk of cardiotoxicity, especially during the first 24 hours 

from the overdose. 

PSYCHOTROPIC DRUGS 

"Psychotropic drugs" is a term that refers to drugs that have an effect on the 

psychological function, including antidepressants, antipsychotics or neuroleptics, antianxiety 

drugs, and hallucinogens. 

29. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients 

Reilly JG. et al. 

Lancet 2000; 355: 1048 - 1052. 

The results of this study show that use of psychotropic drugs is associated with a 

significantly increased risk of heart arrhythmias. The study was conducted on 495 

psychiatric patients and 101 healthy individuals who served as control. As a marker for 

increased risk of arrhythmias the authors used the lengthening of the QT interval on the 

electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged 

QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an 

abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic 

drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, 

compared to non-users. The risk increased with increasing doses of drugs, and was 

increased by more than 8 times in users of very high doses. These findings may explain 



41

some cases of sudden unexplained death occurring in patients taking psychotropic drugs, 

as this type of death has been linked to cardiac rhythm abnormalities. 

30. Dopamine-antagonistic, anticholinergic, and GABAergic effects on declarative and 

procedural memory functions. 

Rammsayer TH, Rodewald S, Groh D 

Brain Res Cogn Brain Res. 2000 Jan;9(1):61-71. 

The results of this study show that the psychotropic drugs haloperidol and midazolam (a 

benzodiazepine used for sedation) significantly impair memory functions in healthy 

individuals. The study was conducted on 80 healthy volunteers who were randomly 

assigned to receive haloperidol, midazolam, scopolamine, or placebo. Adverse effects on 

immediate and delayed word recall tests were observed with all three drugs, but were 

more pronounced in individuals taking midazolam. All drugs provoked severe 

impairment on object recognition tests, and these effects were particularly strong in 

individuals receiving midazolam. The results of this study indicate that use of these drugs 

is associated with significant memory-related problems in healthy individuals. 

31. A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and 

psychomotor functions in healthy elderly volunteers. 

Beuzen JN, Taylor N, Wesnes K, Wood A. 

J Psychopharmacol (Oxf) 1999;13(2):152-8. 

The results of this study show that the antipsychotic drug haloperidol produces significant 

cognitive and psychomotor impairment in elderly individuals, and these effects don't 

seem to improve with treatment. The study was conducted on 14 healthy elderly 

individuals who were randomly assigned to receive haloperidol, olanzapine (a new 

antipsuchotic drug), or placebo for 4 days. On day 1 of treatment, significant impairment 

in attention, memory, and motor control was observed in both groups receiving 

antipshycotic drugs. On day 4 of treatment, the cognitive and psychomotor deficits were 

attenuated in patients who took olanzapine, (indicating adaptation to these side effects), 

but had worsened in patients taking haloperidol. These data indicate that patients taking 

haloperidol may be experiencing significant deterioration of cognitive and motor skills 

from the drug. These powerful adverse effects must be taken in consideration when 

prescribing haloperidol to elderly individuals, as the drug may precipitate their overall 

health status and may render them unsuitable for independent living. Since other 

antipsychotic drugs don't share the same persistency of effects, haloperidol use should be 

replaced with safer alternatives. 

32. Effects of haloperidol and amisulpride on motor and cognitive skill learning in 

healthy volunteers. 



42

Peretti CS, Danion JM, Kauffmann-Muller F, Grange D, Patat A, Rosenzweig P. 

Psychopharmacology (Berl). 1997 Jun;131(4):329-38. 

The results of this study show that intake of haloperidol is associated with impaired 

cognitive functions in healthy individuals. The study was conducted on 60 healthy 

individuals who were randomized to receive haloperidol, amisulpride (a drug used in the 

treatment of depression and dysthymia), or placebo. Those who received haloperidol 

showed the greatest deficits in higher cognitive functions as evaluated through a battery 

of tests performed immediately after and some time after drug administration, while those 

who received amisulpride demonstrated cognitive slowing only at tests performed at 

distance from drug intake. 

33. Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy 

volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) 

antipsychotic. 

Ramaekers JG, et al. 

J Clin Psychopharmacol 1999 Jun;19(3):209-21. 

The results of this study show that haloperidol significantly impairs cognitive and motor 

performance in healthy individuals. The study was conducted on 21 healthy volunteer 

who were randomly assigned to receive the atypical neuroleptic amisulpride, the classic 

neuroleptic haloperidol, or placebo, for 5 consecutive days. Significant cognitive and 

psychomotor deficits were observed at day 5 of treatment in individuals taking 

amisulpride and haloperidol. Additionally, practically every individual who took 

haloperidol exhibited extrapiramidal symptoms ranging from akatisia (restlessness of 

movements, an urge to move about constantly, often associated with anxiety and 

agitation) to acute dystonia (sustained abnormal postures or muscle spasms), and mental 

disturbances. These data indicate a high rate of severe adverse effects associated with 

neuroleptic intake. Interestingly, several of the adverse effects of haloperidol resemble 

symptoms found in schizophrenic patients, thus raising the question of whether they are 

due to the disease or to the treatment. 

34. Managing antipsychotic-induced acute and chronic akathisia. 

Miller CH, Fleischhacker WW. 

Drug Saf 2000 Jan;22(1):73-81. 

This article emphasizes that 5% to 37% of patients treated with antipsychotic drugs 

develops akathisia, a condition characterized by a feeling of restlessness accompanied by 

anxiety, agitation, and an urge to move about that leads patients to continuously rock 

while sitting or standing, to lift their feet as if marching on the spot and to cross and 

uncross their legs while sitting. Since currently there is no satisfactory treatment for this 



43

complication, the only remedy is to prevent its occurrence by reducing the intake of 

drugs, or switching to safer antipsychotic drugs. 

35. Antipsychotic-induced life-threatening 'esophageal dyskinesia'. 

Horiguchi J et al. 

Int Clin Psychopharmacol 1999 Mar;14(2):123-7. 

This article describes a potentially fatal adverse reaction to antipsychotic drugs, 

esophageal dyskinesia, consisting of abnormal movements affecting the lower portion of 

the pharynx and the upper portion of the esophagus. A case of a patient who died from 

asphyxiation of food is reported. 

36. Effects of the clozapine national registry system on incidence of deaths related to 

agranulocytosis. 

Honigfeld G. 

Psychiatr Serv, 47(1):52-6 1996 Jan. 

Clozapine is an antipsychotic drug with a high potential of inducing white blood cell 

suppression, and is administered only to patients whose weekly blood tests show no 

evidence of toxicity. From its release in 1990 until December 1994, 382 cases of 

agranulocytosis and 12 related deaths have been identified through a national patient 

registry maintained by the drug manufacturer. From results of clinical research performed 

prior to the release of the drug in the market, the expected number of cases of 

agranulocytosis and death was 995 and 149, respectively, raising the question of whether 

such a drug should have been approved in the first place. 

37. A survey of sudden death associated with the use of antipsychotic or antidepressant 

drugs: 49 cases in Finland. 

Mehtonen OP; Aranko K; Mälkonen L; Vapaatalo H. 

Acta Psychiatr Scand, 84(1):58-64 1991 Jul. 

The antipsychotic class of drugs phenothiazines causes disturbances of the cardiac 

rhythm, and while their use has been associated with the occurrence of sudden death, a 

causal link has not been clearly demonstrated. This study shows that in 46 of 49 cases of 

sudden death reported in users of antipsychotic or antidepressant drugs, individuals were 

taking therapeutic doses of phenothiazines, which consisted of the drug thioridazine in 

over half the cases. The high representation of this class of drugs in individuals with 

sudden death is indicative of a causal association. 



44

38. Assessment of EPS and tardive dyskinesia in clinical trials. 

Collaborative Working Group on Clinical Trial Evaluations. 

J Clin Psychiatry 1998;59 Suppl 12:23-7. 

This article explains that approximately 50%-75% of individuals who take conventional 

antipshycotic drugs develop acute extrapyramidal symptoms (EPS) such as akathisia, 

dystonia and parkinsonism. Although the incidence of such symptoms is less frequent 

with the new antipsychotic drugs, the authors still caution to use them at doses below the 

EPS-producing levels until more data on their long-term effects are available. 

39. Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, 

and association with tardive dyskinesia. 

Muscettola G, et al. 

J Clin Psychopharmacol 1999 Jun;19(3):203-8. 

This study evaluated the prevalence of signs of extrapyramidal syndrome (EPS) 

(akathisia, dystonia and parkinsonism) in a cohort of 1,559 patients treated with antipsychotic 

drugs. EPS was present in approximately 30% of patients, with 65% of these 

patients presenting with signs of parkinsonism such as rigidity, tremors and slowness of 

movements. These data indicate a high rate of severe and disabling adverse reactions 

associated with neuroleptic use. 

40. Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao 

Extrapyramidal Syndromes Study III. 

van Harten PN, et al. 

Am J Psychiatry 1998 Apr;155(4):565-7. 

The results of this study, conducted on a cohort of patients with a history of antipsychotic 

drug use of more than 3 months, show that the incidence of tardive diskinesia increases 

by 3-folds in patients who had 3 or more treatment interruptions, compared to those who 

had 2 or less breaks in drug therapy. 

41. Incidence of tardive dyskinesia in early stages of low-dose treatment with typical 

neuroleptics in older patients. 

Jeste DV, et al. 

Am J Psychiatry 1999 Feb;156(2):309-11. 

This study evaluated the incidence of tardive dyskinesia (a syndrome characterized by 

potentially irreversible, involuntary abnormal movements usually of the trunk and face, 

associated with use of antipsychotic drugs) in a cohort of 307 outpatients over 45 year of 



45

age treated with low-dose antipsychotic drugs. In patients who had not used this type of 

drugs in the past, the incidence of tardive dyskinesia was 3.4% after 1 month and 6% 

after 2 months of use. After 1 year, the syndrome developed approximately in 25% of 

patients, and in 37% of those who had a history of antipsychotic drug use of over 30 

days. 

42. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. 

Woerner MG, et al. 

Am J Psychiatry 1998 Nov;155(11):1521-8. 

The results of this study, conducted on a cohort of 261 patients on antipsychotic drugs, 

show that after 1, 2, and 3 years of cumulative treatment, 25%, 34%, and 53% of patients 

who started taking the drugs at age 55 or above developed tardive dyskinesia. 

43. Incidence and risk factors for severe tardive dyskinesia in older patients. 

Caligiuri MP, et al. 

Br J Psychiatry 1997 Aug;171:148-53. 

The results of this study show that after 1, 2, and 3 years of treatment with antipsychotic 

drugs, the incidence of severe tardive diskinesia in middle-aged and elderly individuals is 

2.5%, 12% and 23%, respectively. The authors concluded affirming, "Conventional 

neuroleptics may be prescribed to older patients only when necessary and at the lowest 

effective dosage". 

44. Transient and intermittent oral dyskinesia appearing in a young woman ten days after 

neuroleptic treatment. 

Tawara Y, et al. 

Clin Neuropharmacol 1997 Apr;20(2):175-8. 

This article reports on the case of a 22-year-old woman initiated on antipsychotic drugs 

who developed severe extrapiramidal signs and tardive diskinesia lasting for 6 days, after 

only 9 days of treatment. 

45. Neuroleptic drug exposure and treatment of parkinsonism in the elderly 

a case-control study. 

Avorn J, Bohn RL, Mogun H, Gurwitz JH, Monane M, Everitt D, Walker A. 

Am J Med 1995 Jul;99(1):48-54. 



46

The results of this study show that elderly patients who take antipsychotic drugs have a 

significant increased risk of developing symptoms of Parkinson's disease requiring 

initiation of pharmacological treatment. The study was conducted on a cohort of 3,512 

patients aged 65 and older who received a new prescription for the treatment of 

Parkinson's disease and a similar number of controls without symptoms of parkinsonism. 

Users of neuroleptic drugs had a 5.4-fold increased risk of being treated for 

parkinsonism, compared to nonusers. Of note, users of neuroleptic drugs also had an over 

two-fold increased risk of receiving a drug with indications for idiopathic Parkinson's 

disease and not appropriate in individuals with drug-induced parkinsonism. The authors 

estimated that 37% of all prescriptions for the treatment of Parkinson's disease are due to 

neuroleptic drug use. In 71% of patients neuroleptic treatment was not discontinued in 

spite of the occurrence of parkinsonian symptoms. These data indicate that 

extrapyramidal symptoms of parkinsonism are a frequent complication of neuroleptic 

treatment. Physicians however, often fail to recognize that these symptoms are drugrelated, 

as shown by the high rate of inappropriate prescribing of drugs that are not 

indicated for drug-induced parkinsonism, resulting in inappropriate management of the 

condition and failure of optimization of treatment regimens. 

46. Drug-induced cognition disorders in the elderly: incidence, prevention and 

management. 

Gray SL, Lai KV, Larson EB. 

Drug Saf 1999 Aug;21(2):101-22. 

This article highlights that elderly individuals are particularly at risk of developing drugrelated 

delirium and dementia. Although practically every drug has the potential of 

worsening cognitive function in the elderly, those more commonly implicated are 

benzodiazepines, opioids, anticholinergics, and tricyclic antidepressants. The risk is 

particularly high in elderly frail individuals who are taking several medications at once, 

such that a careful evaluation should always be conducted to exclude the possibility of 

drug-related cognitive impairment in this age group. 

47. Increased morbidity and mortality related to asthma among asthmatic patients who 

use major tranquillisers. 

Joseph KS, et al. 

BMJ 1996;312:79-81 (13 January). 

The results of this study show that use of neuroleptic drugs in asthmatic patients with 

psychosis is associated with a 3.2-fold increased risk of death or near-death from asthma, 

compared to nonuse. 



47

48. Association of venous thromboembolism and clozapine. 

Staffan Hägg, Olav Spigset, Torbjörn G Söderström. 

Lancet 2000; 355: 1155 - 1156. 

The results of this study show that the antipsychotic drug clozapine is associated with a 

significantly increased risk of death from venous thromboembolism. The researchers 

evaluated cases of deep venous thrombosis and pulmonary embolism that occurred in 

individuals treated with clozapine, reported to the Swedish Adverse Reactions Advisory 

Committee from April 1989 through March 2000. Of the 12 patients who experienced 

venous thromboembolism, 5 died (42%). Median age of patients was 38 years. Only one 

had known risk factors for thromboembolism (contraceptive use). Sixty-seven percent of 

the cases occurred during the first 3 months of clozapine treatment. Overall, from 20,000 

to 70,000 Swedish patients take clozapine, indicating that the risk of this complication is 

at least 1 per 2-6,000 treated patients. The actual risk, however, is likely to be higher, in 

view of the fact that reporting of adverse events is spontaneous (not mandatory), such 

that a substantial number of cases may be missed due to under-reporting. 

49. Myocarditis and cardiomyopathy associated with clozapine. 

Jens G Kilian, Kristin Kerr, Christopher Lawrence, David S Celermajer. 

Lancet 1999; 354: 1841-45. 

The results of this study show that individuals taking the anti-psychotic drug clozapine 

have a 1,000-2,000-fold increased risk of death from myocarditis, compared to non-users. 

The study was conducted after two young, physically healthy patients died unexpectedly 

soon after initiation of treatment. The authors investigated the risk of adverse 

cardiovascular effects by searching for cases of myocarditis and cardiomyopathy in the 

Australian Adverse Reaction Committee register, a voluntary reporting system. They 

found 15 reports of myocarditis and 8 of cardiomyopathy. Six patients died, 5 from 

myocarditis, and 1 from cardiomyopathy. All cases of myocarditis occurred within 3 

weeks of initiation of treatment, whether cardiomyopathy occurred up to 3 years after 

initiation of treatment. From 1993 to 1999, 8,000 patients were started on clozapine in 

Australia. Among these 8,000 patients, a minimum of 23 cases of myocarditis and 

cardiomyopathy occurred, including 6 deaths. The number of patients who suffered these 

complications may, however be higher, since reporting of adverse events is not 

mandatory. Extrapolation of this data indicates that approximately 1 in 500 young 

individuals who are treated with clozapine for schizophrenia will have fatal and nonfatal 

myocarditis in the first month of treatment. These estimates are conservative, due to 

likely underreporting. Since myocarditis is a very rare cause of death worldwide 

(approximately 4 deaths per 1,000,000 individuals), these figures represent a 1000-2000 

increased risk of death from the disease in patients taking clozapine, compared to the 

general population. In addition, users of clozapine have a 5-fold increased risk of 

cardiomyopathy, compared to non-users. This article further highlights the risks 

associated with use of this drug, which has been found to cause potentially fatal 

agranulocytosis (marked decrease in the number of white blood cells) in one every 100 



48

treated patients, and deep venous thrombosis in at least 1 in 2-6-000 patients (based on 

spontaneous reporting), the latter complication being fatal in over 40% of cases. 

PSYCHOTROPIC DRUGS USED FOR 

ADULTS AND THE ELDERLY 

50. Prescribing trends in psychotropic medications: primary care, psychiatry, and other 

medical specialties. 

Pincus HA, Tanielian TL, Marcus SC, Olfson M, Zarin DA, Thompson J, Magno Zito J. 

JAMA 1998 Feb 18;279(7):526-31. 

The results of this study show that in 1985, in the U.S., 32.73 million visits to officebased 

primary care physicians resulted in prescription of psychotropic drugs. In 1994, the 

number of such visits increased to 45.64 million. Psychiatrists and primary care 

physicians' visits for depression doubled from 1988 to 1994, and visits for stimulants 

more than quadrupled. In addition, of the visits for depression, those paid to psychiatrists 

in 1994 resulted in a higher rate of drug prescribing, compared to 1988. 

51. Expenditures for psychotropic medications in the United States in 1985. 

Zorc JJ. et al. 

Am J Psychiatry 1991 May;148(5):644-7. 

This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for 

outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and 

sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants. 

52. The direct economic costs of insomnia in the United States for 1995. 

Walsh JK, Engelhardt CL. 

Sleep 1999 May 1;22 Suppl 2:S386-93. 

The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment 

of insomnia. 

53. Psychotropic prescribing for the elderly in office-based practice. 

Aparasu RR, Mort JR, Sitzman S. 

Clin Ther 1998 May-Jun;20(3):603-16. 



49

The results of this study show that 17% of visits by the elderly to office-based physicians 

result in the prescription of at least one inappropriate psychotropic drug. According to the 

study, in 1995, approximately 12 million visits by the elderly to their doctors resulted in 

prescription of a psychotropic drugs, primarily antidepressants and antianxiety drugs. In 

over 2 million visits, patients received a minimum of one potentially inappropriate 

psychotropic medication. The high rates of inappropriate prescribing, coupled with the 

particular susceptibility of elderly patients to experiencing drug-related adverse effects, 

raises concerns on the quality of care offered by physicians in ambulatory settings. 

54. Determinants of psychotropic drug usage in a general intensive care unit. 

Stolker J. et al. 

Gen Hosp Psychiatry 1998 Nov;20(6):371-6. 

The results of this study show that 36% and 17.5% of patients admitted to a Dutch 

general intensive care unit receive benzodiazepines and antipsychotics, respectively. 

55. Psychotropic drug use and polypharmacy in a general hospital. 

Salzman C. 

Gen Hosp Psychiatry, 3(1):1-9 1981 Mar. 

The results of this study show that approximately 43% of patients admitted to a general 

Boston teaching hospital received psychotropic drugs. Drugs were given mainly for sleep 

problems or to reduce anxiety. The authors found high rates of inappropriate prescribing 

of antipsychotic drugs, which were given to control symptoms such as nausea, pain, or 

agitation rather than psychosis, and of antidepressant drugs, which were given 

irrespective of signs of depression, or below therapeutic doses in patients with 

depression. 

56. Psychotropic use among older residents of board and care facilities. 

Spore D. et al. 

J Am Geriatr Soc, 43(12):1403-9 1995 Dec. 

The results of this study, conducted on 2054 elderly residents from 410 board and care 

facilities in 10 states, indicate that approximately 35% of them were receiving a 

minimum of one psychotropic drug. Simultaneous use of 2 or more psychotropic drugs 

occurred in 30% of psychotropic drug users. 



50

57. Regulatory environment and psychotropic use in board-and-care facilities: results of a 

10-state study. 

Spore D. et al. 

J Gerontol A Biol Sci Med Sci, 51(3):M131-41 1996 May. 

The results of this study, conducted on a sample population of 2,949 residents from 493 

board-and-care facilities in 10 states, show that 41% of them were primarily or routinely 

being prescribed a minimum of one psychotropic drug. Twenty-one percent of residents 

were on antipsychotic drugs. About half of the individuals currently on psychotropic 

drugs did not have any psychiatric diagnosis in the previous year. 

58. Psychotropic drug intake in residents newly admitted to nursing homes. 

Wancata J. et al. 

Psychopharmacology (Berl) 1997 Nov;134(2):115-20. 

The results of this study indicate that prescribing of psychotropic drugs to nursing home 

residents occurs irrespective of prior history of psychiatric conditions. The study, 

conducted on a cohort of 262 individuals admitted to nursing homes in Austria, show that 

the prevalence of use of psychotropic drugs rose from 45.5% in the 3 months before 

admission, to 72% in the 2 weeks after admission, to 79% during the first six months of 

stay. 

59. Psychotropic drug use in Sydney nursing homes. 

Snowdon J. et al. 

Med J Aust, 163(2):70-2 1995 Jul 17. 

The results of this study, conducted on all residents of 46 nursing homes in Sydney, show 

that 59% of them were regularly receiving psychotropic drugs, and 7% of them were 

receiving them on an "as required" basis. Benzodiazepines, antipsychotics, hypnotics, 

antidepressants and anxiolytics were taken regularly by 32.3%, 27.4%, 26.6%, 15.6% and 

8.6% of individuals, respectively. 

60. A follow-up survey of psychotropic drug use in Sydney nursing homes. 

Snowdon J. 

Med J Aust 1999 Apr 5;170(7):299-301. 

The results of this study show that 48.5% of Sidney nursing home residents receive at 

least one psychotropic drug regularly, and another 4.5% "as required". Antipshychotic 

drugs were taken by 27.6% of residents. Anticonvulsants, who were not considered in 

this study as psychotropic drugs, were given to 13% of residents. 



51

61. Use of psychotropic medications for persons with mental retardation who live in 

Oklahoma nursing homes. 

Spreat S. et al. 

Psychiatr Serv, 49(4):510-2 1998 Apr. 

The results of this study, conducted on a cohort of 1,056 individuals with mental 

retardation living in Oklahoma nursing homes, show that 32% of them were taking 

antipsychotic medications, 16% were taking anxiolytic drugs, and 6% were taking 

antidepressants. Use of antipsychotics, a class of drugs associated with a high risk of 

severe complications, was not always justified by patients' clinical history. The high rates 

of prescribing of antipsychotic drugs make the authors question the appropriateness of 

placing individuals with mental retardation in nursing homes. 

62. Use of psychotropic medication in Oklahoma: a statewide survey. 

Spreat S. et al. 

Am J Ment Retard, 102(1):80-5 1997 Jul. 

The results of this study indicate that 22.5%, 9.3%, and 5.9% of mentally retarded 

individuals are prescribed antipsychotic drugs, anxiolytics and antidepressant 

medications, respectively. Rates of prescribing for mentally retarded individuals living in 

institutions or intermediate care facilities are significantly higher. 

63. Frequency of and determinants for psychotropic drug use in an institution for the 

mentally retarded. 

Linaker OM. 

Br J Psychiatry 1990 Apr;156:525-30. 

The results of this study, conducted on a cohort of 168 mentally retarded individuals 

institutionalized in Norway, show that 49% of them were receiving antipsychotic drugs. 

Only in a small percentage of cases the prescription of these drugs could be justified by a 

psychiatric diagnosis. 

64. Prevalence and prediction of psychotropic drug use in California developmental 

centers. 

Stone RK. et al. 

Am J Ment Retard, 93(6):627-32 1989 May. 



52

The results of this study show that, on average, 35.4% of developmentally disabled 

individuals institutionalized in California are treated with psychotropic drugs, with 26.8% 

of them receiving antipsychotic medications. Rates of prescription of psychotropic drugs 

varied greatly among institutions, ranging from 13.7% to 63.6% of the individuals. 

65. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a 

controlled, double-blind study. 

Cohen-Mansfield J, et al. 

Arch Intern Med 1999 Aug 9-23;159(15):1733-40. 

This double-blind placebo controlled study evaluated the effect of discontinuation of 

treatment with haloperidol, thioridazine, and lorazepam, three psychotropic drugs 

commonly used to control patient behavior, in residents of a nursing home. The behavior 

of patients who were slowly switched to placebo did not differ from that of patients who 

continued taking the drugs, questioning the efficacy of these medications in managing 

patient agitation. The authors conclude that an attempt to discontinue the use of such 

drugs should be routinely performed in nursing home settings. 

66. Long-stay patients with long-stay drugs. A case review; a cause for concern. 

Fottrell E, et al. 

Lancet 1976 Jan 10;1(7950):81-2. 

The results of this study, conducted on a cohort of 200 long-term psychiatric patients, 

show that approximately half of them were being prescribed unnecessary or excessive 

medications. 

67. Clonidine impairs sustained attention and memory in Alzheimer's disease. 

Riekkinen Jr P, Laakso MP, Jakala P, Riekkinen P Jr. 

Neuroscience 1999;92(3):975-82. 

The results of this study indicate that clonidine at doses of 2 microg/kg significantly 

disrupts attention and short-term memory in approximately one-third of Alzheimer 

patients. The negative effects of clonidine on attention were observed only in tests that 

were demanding for the patients, while those requiring simpler processing remained 

unaffected. 



53

68. Psychotropic drug use and cognitive decline among older men and women. 

Dealberto MJ. et al. 

Int J Geriatr Psychiatry, 12(5):567-74 1997 May. 

The results of this study, conducted on a cohort of 1200 individuals without cognitive 

impairment at baseline, show that users of non-benzodiazepine psychotropic drugs have a 

5-fold increased risk of cognitive decline compared to nonusers. 

69. Benzodiazepine use and cognitive function among community-dwelling elderly. 

Hanlon JT, et al. 

Clin Pharmacol Ther 1998 Dec;64(6):684-92. 

The results of this study, conducted on 2765 elderly individuals living in the community 

and followed up for 3 years, show that current users of benzodiazepines experience 

significant worsening of memory function, compared to non-users. The association 

between benzodiazepine use and memory decline is dose-dependent, and exists with both 

short- and long-acting drugs. 

70. Cognitive impairment in long-term benzodiazepine users. 

Golombok S, Moodley P, Lader M. 

Psychol Med 1988 May;18(2):365-74. 

The results of this study indicate that long-term use of benzodiazepines is associated with 

significant cognitive impairment, particularly for tasks involving sustained attention and 

visual-spatial ability. 

71. Anterograde amnesia linked to benzodiazepines. 

Mejo SL. 

Nurse Pract 1992 Oct;17(10):44, 49-50. 

This article highlights that use of benzodiazepines is associated with disruption of longterm 

memory, a symptom that is often unrecognized by patients who take the drugs. The 

author concludes that is important that patients be fully informed on the side effects of 

treatment, and that the minimum possible dose be prescribed for the shortest period of 

time, in order to reduce the occurrence of treatment-induced adverse events. 



54

72. Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients. 

Foy A, O'Connell D, Henry D, Kelly J, Cocking S, Halliday J. 

J Gerontol A Biol Sci Med Sci 1995 Mar;50(2):M99-106. 

The results of this study show that use of benzodiazepines significantly increases the risk 

of cognitive impairment in elderly individuals. The study was conducted on 418 

individuals aged 59-88, with normal cognitive function upon admission to the hospital. 

During hospitalization, 10.8% of patients developed cognitive impairment. Patients who 

reported use of benzodiazepines were 3.5 times more likely to develop cognitive 

impairment, compared to nonusers. Overall, benzodiazepine use accounted for 30% of all 

cases of cognitive disruption. 

73. Fatal myocardial infarction and use of psychotropic drugs in young women. 

Thorogood M. et al. 

Lancet, 340(8827):1067-8 1992 Oct 31. 

The results of this study show that current use of psychotropic drugs in women aged 16 to 

39 is associated with a 17-fold higher incidence of fatal myocardial infarction, compared 

to nonuse. 

74. Use of psychotropic drugs and risk of myocardial infarction: a case-control study in 

Finnish farmers. 

Penttinen J. et al. 

Int J Epidemiol, 25(4):760-2 1996 Aug. 

The results of this study, conducted on a cohort of 3172 male farmers, show that users of 

psychotropic drugs have a 2.5-fold increased risk of myocardial infarction, compared to 

nonusers. The risk of heart attack increased by 5.4-folds in users of antidepressants. 

75. Psychotropic medication use and risk of epithelial ovarian cancer. 

Harlow BL; et al. 

Cancer Epidemiol Biomarkers Prev, 7(8):697-702 1998 Aug. 

The results of this study, conducted on cohort of 563 women with ovarian cancer and 523 

controls, show that users of psychotropic drugs for 6 or more months had a 60% 

increased risk of invasive ovarian cancer, compared to nonusers. In women who first 

used psychotropic drugs before menopause for more than two years, the risk increased by 

almost three times. 



55

PSYCHOTROPIC DRUGS IN PREGNANCY 

76. Psychotropic drug use during pregnancy: weighing the risks. 

Cohen LS. et al. 

J Clin Psychiatry, 59 Suppl 2():18-28 1998. 

This article discusses some of the risks associated with use of psychotropic drugs by 

pregnant women, which include malformations, neonatal toxicity, and neurological and 

behavioral impairment. Additionally, it emphasizes that since the safety and efficacy of 

these drugs in the expecting mother has never been tested, nor their use has been 

approved by the FDA, a careful evaluation of the risks and benefits of treatment should 

be conducted before psychotropic drugs are taken during pregnancy. 

77. Psychotropic drug use in pregnancy and perinatal death. 

Laegreid L. et al. 

Acta Obstet Gynecol Scand, 71(6):451-7 1992 Aug. 

This study analyzed psychotropic drug use in a sample population of 73 mothers of dead 

infants and in a control cohort of mothers of surviving infants, and found that 

psychotropic drug use was significantly associated with perinatal death. 

78. Use of psychotropic drugs and pregnancy outcome. 

Larivaara P; et al. 

J Clin Epidemiol, 49(11):1309-13 1996 Nov. 

The results of this study, conducted on a cohort of 7933 pregnant women and their 8030 

babies, show that use of psychotropic drugs during pregnancy is significantly associated 

with an increased need for hospital observation. In particular, 80.8%, and 38.3% of 

regular and occasional psychotropic drug users required hospital observation, compared 

to 27.4% of nonusers. In addition, bleeding was significantly more frequent in users vs. 

nonusers (23% vs. 13%), and infant mean birth weight was significantly lower among 

regular users. 

79. Neurodevelopment in late infancy after prenatal exposure to benzodiazepines--a 

prospective study. 

Laegreid L. et al. 

Neuropediatrics, 23(2):60-7 1992 Apr. 



56

This study evaluated neurodevelopment and growth in 17 children of mothers who used 

therapeutic doses of benzodiazepines (BZD) throughout pregnancy. Follow up was 

performed at 6, 10, and 18 months of age. Children exposed to BZD had slightly reduced 

head circumference at birth and throughout follow up, compared to children of women 

who were not exposed to BZD. Craniofacial abnormalities were present in 5 infants. 

Gross motor development was impaired at 6 and 10 months while fine motor 

development was impaired throughout follow up. Deviating muscle tone and movements 

were found more frequently in children exposed to BZD compared to controls. These 

data indicate that exposure to therapeutic levels of BZD during pregnancy is associated 

with a significantly higher risk of abnormal development in the offspring. 

80. Mental development in late infancy after prenatal exposure to benzodiazepines--a 


Viggedal G, Hagberg BS, Laegreid L, Aronsson M. 

J Child Psychol Psychiatry 1993 Mar;34(3):295-305. 

The results of this study show that continuous use of benzodiazepines during pregnancy 

is associated with significant impairment of mental development in the offspring. 

81. Benzodiazepine use in pregnancy and major malformations or oral cleft: metaanalysis 

of cohort and case-control studies. 

Dolovich LR, et al. 

BMJ 1998;317:839-843 ( 26 September ). 

This article presents the results of a meta-analysis of 23 selected studies investigating 

whether use of benzodiazepine during the first trimester of pregnancy increases the risk 

of major malformations or oral cleft in the offspring. While cohort studies did not detect 

an increased incidence of major malformations or oral cleft, analysis of case-control 

studies revealed a 3-fold increase in incidence of major malformations and an 80% 

increase in incidence of oral cleft alone in the offspring of benzodiazepine users, 

compared to controls. 

DRUGS, FALLS AND HIP FRACTURES 

82. Injurious falls in nonambulatory nursing home residents: a comparative study of 

circumstances, incidence, and risk factors. 

Thapa PB. et al. 

J Am Geriatr Soc 1996 Mar;44(3):273-8. 



57

The results of this study show that ambulatory nursing home residents who take 

psychotropic drugs have a 2.5-fold increased risk of falls resulting in injuries, compared 

to those not on these drugs. 

83. Psychotropic drugs and risk of recurrent falls in ambulatory nursing home residents. 


Am J Epidemiol 1995 Jul 15;142(2):202-11. 

The results of this study show that 36% of all recurrent falls in ambulatory nursing home 

residents can be attributed to psychotropic drug use. 

84. Relationship between the administration of selected medications and falls in 

hospitalized elderly patients. 

Gales BJ. et al. 

Ann Pharmacother, 29(4):354-8 1995 Apr. 

The results of this study, conducted on a sample group of 100 patients aged 70 and older 

who fell and 100 control subjects of the same age, show that benzodiazepine use in fallers 

was 2.7 times more frequent that in non users. Sixty-five percent of patients who fell 

while taking long-acting benzodiazepines, were taking higher than recommended doses 

of the drug. Congestive heart failure, treatment with digoxin and use of 3 or more 

psychotropic drugs were all factors positively associated with an increased risk of falls. 

85. Falls, injuries due to falls, and the risk of admission to a nursing home. 

Tinetti ME, et al. 

N Engl J Med 1997 Oct 30;337(18):1279-84. 

The results of this study, conducted on a sample group of 1103 elderly individuals living 

in the community, show that those who fall are at significantly increased risk of being 

admitted to a nursing home, compared to the remaining population. In particular, the risk 

of being admitted to a nursing home increases by 3 times in those with one noninjurious 

fall, by 5.5-times in those with multiple noninjurious falls, and by more than 10 times in 

those with one or more injurious fall. These data suggest that interventions aiming at 

reducing the incidence of falls can substantially reduce the number of admission to 

nursing homes. 

86. Potential adverse outcomes of psychotropic and narcotic drug use in Canadian 

seniors. 



58

Ebly EM. et al. 

J Clin Epidemiol 1997 Jul;50(7):857-63. 

The results of this study, conducted on a large population of elderly individuals with 

intact cognition, show that the incidence of falls is 3 times greater in users of two or more 

psychotropic drugs, compared to nonuser (42.6% versus 13.9%). These data indicate that 

psychotropic drug-related adverse effects may significantly increase the risk of falls in 

elderly individuals. 

87. Effects of central nervous system polypharmacy on falls liability in communitydwelling 

elderly. 

Weiner DK. et al. 

Gerontology 1998;44(4):217-21. 

The results of this study, conducted on a cohort of 305 community-dwelling elderly 

individuals, show that use of one psychotropic drug is associated with a 54% increased 

risk of falls, while use of two or more psychotropic drugs is associated with a 137% 

increased risk of falls. The authors conclude that the dose-response effect is indicative of 

a relation of causality between use of psychotropic drugs and falls. 

88. Antidepressants and the risk of falls among nursing home residents. 


N Engl J Med 1998 Sep 24;339(13):875-82. 

The results of this study, conducted on a sample population of 2428 nursing home 

residents, show that use of the antidepressants tricyclics, serotonin-reuptake-inhibitors 

and trazodone, is associated with a 2.0-, 1.8- and 1.2-fold increased risk of falls, 

respectively. 

89. Risk factors for falls as a cause of hip fracture in women. The Northeast Hip Fracture 

Study Group. 

Grisso JA. et al. 

N Engl J Med 1991 May 9;324(19):1326-31. 

The results of this study show that use of long-acting barbiturates in the elderly is 

associated with a 5.2-fold increased risk of hip fractures. 



59

90. Opioid analgesics and the risk of hip fracture in the elderly: codeine and 

propoxyphene. 

Shorr RI. et al. 

J Gerontol 1992 Jul;47(4):M111-5. 

The results of this study, conducted on a cohort of 4,500 elderly individuals and 24,041 

matched controls, show that users of the commonly prescribed anti-pain medications 

codeine or propoxyphene have a 60% increased risk of hip fractures, compared to 

nonusers. The risk of hip fractures increases by 2.2-times in new users of the drugs, and 

by 2.6 times in those who take them in combination with a psychotropic drug. These 

findings are important, especially in consideration of the widespread prescribing of antipain 

medications to elderly individuals. 

91. Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years 

old: a community-based prospective study. 

Guo Z. et al. 

Am J Epidemiol 1998 Nov 1;148(9):887-92. 

The results of this study, conducted on a sample group of 1,608 individuals aged 75 and 

older, show that those using the opioid analgesic propoxyphene have a two-fold increased 

risk of hip fractures, compared to nonusers. In addition, use of potassium supplements 

was associated with a 45% reduction in hip fracture risk. 

92. Cyclic antidepressants and the risk of hip fracture. 

Ray WA, et al. 

Arch Intern Med 1991 Apr;151(4):754-6. 

The results of this study show that elderly individuals using tricyclic antidepressants have 

a 60% increased risk of hip fractures, compared to nonusers. 

93. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of 

hip fractures in elderly people. 

Liu B, et al. 

Lancet 1998 May 2;351(9112):1303-7. 

The results of this study, performed on a sample group of 8,239 elderly individuals with 

hip fracture and five controls matched to each subject, show that use of the 

antidepressants selective serotonin-reuptake inhibitors, secondary-amine tricyclics and 

tertiary-amine tricyclics, was associated with a 2.4-, 2.2-, and 1.5-fold increased risk of 



60

hip fractures, respectively, compared to nonuse. New use of each class of drugs resulted 

in a further increase in the risk of hip fractures. 

94. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. 

Ray WA, et al. 

JAMA 1989 Dec 15;262(23):3303-7. 

The results of this study, conducted on a cohort of 4501 elderly individuals with hip 

fracture and 24,041 controls, show that use of long-acting benzodiazepines is associated 

with a 70% increased risk of hip fractures. 

95. Effect of a single dose of diazepam on balance measures in older people. 

Cutson TM, Gray SL, Hughes MA, Carson SW, Hanlon JT. 

J Am Geriatr Soc 1997 Apr;45(4):435-40. 

The results of this study show that diazepam adversely affects balance control in elderly 

individuals. The researchers evaluated the effects of a single dose of diazepam on balance 

in 12 healthy individuals aged 65 and older. Administration of the drug was associated 

with prolongation of the latency time of the muscle of the lower leg in response to a 

sudden perturbation, and with impaired performance at neuropsychological tests of 

attention. These findings seem to confirm the epidemiological finding of an increased 

risk of falls associated with use of benzodiazepines. 

96. Psychotropic drug use and the risk of hip fracture. 

Ray WA; Griffin MR; Schaffner W; Baugh DK; Melton LJ 3d. 

N Engl J Med, 316(7):363-9 1987 Feb 12. 

The results of this study, conducted on a cohort of 1021 elderly patients with hip fracture 

and 5606 controls, show that use of long-acting hypnotics-anxiolytics, tricyclic 

antidepressants, and antipsychotics drugs is associated with an 80%, 90%, and 2-fold 

increased risk of hip fractures, respectively, compared to nonuse. The risk of fractures 

increases with increasing doses of these drugs, thus suggesting a relation of causality 

between drug use and injurious falls. 

97. Diuretic drug use and the risk for hip fracture. 

Heidrich FE, et al. 

Ann Intern Med 1991 Jul 1;115(1):1-6. 



61

The results of this study, conducted on a cohort of 462 elderly patients hospitalized for 

hip fractures and 462 matched controls, show that current use of thiazide diuretics is 

associated with a 60% increased risk of hip fractures, compared to nonuse. Use of the 

diuretic furosemide was associated with an almost 4-fold increased risk of fracture. 

98. Psychotropics, thiazide diuretics and hip fractures in the elderly. 

Cumming RG. et al. 

Med J Aust 1993 Mar 15;158(6):414-7. 

The results of this study, conducted on a sample group of 209 individuals with hip 

fracture and 207 controls, show that use of the benzodiazepine temazepan is associated 

with a 3.5-fold increased risk of hip fractures, compared to nonuse. Intake of thiazide 

diuretics in this study was not associated with a higher risk of fractures. 

99. Rheumatoid arthritis, corticosteroid therapy and hip fracture. 

Cooper C, et al. 

Ann Rheum Dis 1995 Jan;54(1):49-52. 

The results of this study show that patients with rheumatoid arthritis and those taking 

corticosteroids have a 2.0- and 2.7-fold increased risk of hip fractures, respectively, 

compared to patients without this condition and not using these drugs. After adjusting for 

functional impairment, the risk decreased in patients with RA, but remained high in those 

taking corticosteroids. 

100. Hip fractures and fluoridation in Utah's elderly population. 

Danielson C, et al. 

JAMA 1992 Aug 12;268(6):746-8. 

The results of this large ecological study, conducted on all elderly individuals from three 

communities in Utah who presented with hip fractures over a 7-year period, show that 

men and women living in fluoridated areas had a 41% and 27% increased risk of hip 

fractures, respectively, compared to those living in areas without fluoridated water. 

101. Quality of life related to fear of falling and hip fracture in older women: a time trade 

off study. 

Salkeld, G. et al. 

BMJ 2000;320:341-346 ( 5 February ). 



62

The results of this study, conducted on a sample group of 194 women aged 75 and older, 

show that 80% of them would rather die than lose their independence and be admitted to 

a nursing home after a bad hip fracture. 

PSYCHOTROPIC DRUGS AND MOTOR VEHICLE ACCIDENTS 

102. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. 

Ray WA. et al. 

Am J Epidemiol, 136(7):873-83 1992 Oct 1. 

The results of this study, conducted on a cohort of 16,262 individuals aged 65 and older, 

show that users of benzodiazepines have a 50% increased risk of motor vehicle crashes, 

compared to nonusers. Use of tricyclic antidepressants was associated with an over 

twofold increased risk of crashes, and the risk increased with increasing drug dosage, 

being 5.5-times higher in users of 125 mg or more of amitriptyline, compared to nousers. 

103. Association of road-traffic accidents with benzodiazepine use. 

Barbone F, et al. 

Lancet 1998 Oct 24;352(9137):1331-6. 

The results of this study show that use of long half-life benzodiazepines (used to treat 

anxiety) and of short half-life hypnotics (zopiclone) is associated with an increased risk 

of motor vehicle crash in individuals aged 18 and older. The risk increases with 

increasing doses of benzodiazepine. 

104. Benzodiazepine use among the elderly in the community. 

Kirby M, et al. 

Int J Geriatr Psychiatry 1999 Apr;14(4):280-4. 

The results of this study show that 17% of community-dwelling elderly individuals in 

Ireland take benzodiazepines, which are, in over 50% of cases, of the long-acting form. 

The high rate of prescription of long-acting benzodiazepines causes concern, since these 

drugs have been associated with an increased risk of hip fractures and motor vehicle 

crashes in the elderly. 

ANTIPSYCHOTICS 



63

105. Growth patterns in the developing brain detected by using continuum mechanical 

tensor maps. 

Thompson PM, Giedd JN, Woods RP, MacDonald D, Evans AC, Toga AW. 

Nature 2000 Mar 9;404(6774):190-3. 

The results of this study show that brain cells continue to grow and organize at least into 

puberty. The researchers scanned the brain of children at intervals of up to 4 years, from 

the age of 3 to 15 years. They observed waves of growth at the fiber system that relays 

information between the right and left side of the brain, throughout the follow-up period, 

with growth occurring predominantly in the frontal regions, associated with the planning 

of new actions, earlier in age, and subsequently in the mid- and posterior regions of the 

brain, where associative thinking and language are regulated. These data indicate that 

brain development can be affected throughout puberty, contradicting previous theories 

which viewed the brain as essentially organized by the time a child reach the age of 6. 

The effects of psychotropic drugs on the evolving brain must be carefully evaluated, 

since these drugs have the potential of interfering with its development. 

106. A comparison of prazepam, diazepam, lorazepam and placebo in anxious outpatients 

in non-psychiatric private practices. 

Zung WW; et al. 

J Clin Psychiatry, 42(7):280-4 1981 Jul. 

The results of this double-blind, randomized, placebo controlled study, show that the 

anxiolytics prazepam, diazepam, lorazepam, or placebo were all effective in relieving 

anxiety and depression in patients predominantly depressed with anxiety, while only 

placebo and prazepam reduced both symptoms in patients predominantly anxious with 

depression. These data suggest that anxyolytics are no better than placebo in the 

management of patients with anxiety and depression. 

107. Benzodiazepines for depression? A review of the literature. 

Birkenhäger TK; et al. 

Int Clin Psychopharmacol, 10(3):181-95 1995 Sep 

This study shows that combination therapy with benzodiazepines and tricyclic 

antidepressants (TCA) for treatment of depression is not superior, beyond the first few 

weeks of treatment, to monotherapy with TCAs. 



64

108. Worsening of symptoms of multiple sclerosis associated with carbamazepine. Letter. 

Ramsaransing G, Zwanikken C, De Keyser J. 

BMJ 2000;320:1113 ( 22 April ). 

This article reports on the worsening of symptoms of multiple sclerosis associated with 

use of carbamazepine, a tricyclic drug used to treat some forms of pain, convulsions, 

epilepsy, and manic episodes. The case of five patients with severe aggravation of disease 

following initiation of treatment and with symptoms resolution after carbamazepine 

discontinuation is presented. In one case, the onset of new symptoms (loss of the ability 

to walk) was interpreted as progression of disease and the patient, rather than having 

carbamazepine treatment interrupted, was aggressively treated with intravenous 

corticosteroids without improvement. Only after being discharged from the hospital, 

carbamazepine was stopped and the patient resumed her ability of walking. 

109. Hypericum extract versus imipramine or placebo in patients with moderate 

depression: randomised multicentre study of treatment for eight weeks. 

Philipp M. et al. 

BMJ 1999;319:1534-1539 ( 11 Dec ). 

This double blind, placebo controlled study shows that the herbal supplement hypericum 

extract (St. John's Wort) (1050 mg per day) is as effective as the antidepressant 

imipramine (100 mg per day) in alleviating symptoms in moderately depressed patients. 

Furthermore while patients in the hypericum arm reported improvement in the physical 

scale of a quality of life questionnaire, patients in the imipramine arm did not. Patients 

taking hypericum experienced the same rate of adverse reactions of patients taking 

placebo, and less than half the rate of those taking imipramine. 

THE HIGH COST OF MEDICAL CARE – 49 Studies 

1. Hospital expenditures in the United States and Canada. 

Redelmeier DA, et al. 

N Engl J Med 1993 Mar 18;328(11):772-8. 



65

The results of this study indicate that hospital costs in the U.S. are considerably higher 

than in Canada. In 1987, the cost of each patient' admission to an acute care hospital was 

24% higher in the U.S. than in Canada, and 46% higher in California than in Ontario. 

Total hospital expenditures were significantly lower in Canada even though Canadian 

hospitals had more hospital beds (5.4 vs. 3.9 per 1000 individuals) more admissions (142 

vs. 129 per 1000 individuals) and longer stays (11.2 vs. 7.2 days) than U.S hospitals. 

Higher administrative costs were partly responsible for the increase in hospital expenses 

observed in the U.S. Applying the same spending patterns of Canada would have saved to 

the U.S. over $30 billion in 1985 alone. 

2. The cost of inappropriate admissions: a study of health benefits and resource utilization 

in a department of internal medicine. 

Eriksen BO, Kristiansen IS, Nord E, Pape JF, Almdahl SM, Hensrud A, Jaeger S. 

J Intern Med 1999 Oct;246(4):379-87. 

The results of this study show that approximately 1 every 4 patients are inappropriately 

admitted to the hospital. The study was conducted on 422 consecutive patients who were 

admitted to a teaching hospital over a 6-week period. In 102 of them (24%), the 

admission was judged to be inappropriate. The average cost of each inappropriate 

admission was estimated at $2532, significantly lower than that of appropriate admissions 

($5800). Overall, unnecessary admissions accounted for 12% of the total hospital costs. 

3. The costs of adverse drug events in hospitalized patients. Adverse Drug Events 

Prevention Study Group. 

Bates DW; et al. 

JAMA, 277(4):307-11 1997 Jan 22-29. 

The results of this study indicate that over a 6-month period, 190 of the 4108 admissions 

to a tertiary hospital occurred as a consequence of an adverse drug event (ADE). Of 

these, 60 were preventable. The authors estimated at $5.6 million the annual cost of all 

admissions for ADEs in a 700-bed teaching hospital, and at $2.8 million the cost of 

preventable ADEs. These data indicate that ADEs account for a substantial fraction of 

total hospital costs. Implementation of measures aimed at reducing the occurrence of 

these events would translate in significant health care savings and in reduction of patients' 

morbidity and mortality. 

4. Involvement of HMO-based pharmacists in clinical rounds at contract hospitals. 

Yee DK; Veal JH; Trinh B; Bauer S; Freeman CH. 

Am J Health Syst Pharm, 54(6):670-3 1997 Mar 15. 



66

The results of this study indicate that the recommendations of a managed care pharmacist 

participating to clinical rounds saved, over a 14-month period, an estimated $523,907 to 

the hospital. These data indicate that inappropriate drug treatment is an important source 

of extra health care expenses in hospital settings. 

5. Pharmacist participation on physician rounds and adverse drug events in the intensive 

care unit. 

Leape LL, et al. 

JAMA 1999 Jul 21;282(3):267-70. 

The results of this study, conducted in the intensive care unit of a teaching hospital, show 

that participation of a senior pharmacist to clinical rounds decreased the rate of 

preventable adverse events caused by prescription errors by 66%. 

6. Impact of a pharmacist on medication discontinuation in a hospital-based geriatric 

clinic. 

Phillips SL; Carr-Lopez SM. 

Am J Hosp Pharm, 47(5):1075-9 1990 May. 

This study evaluated the effect of a pharmacist on doctors' drug prescription practices in a 

geriatric ambulatory care clinic. Before pharmacist intervention, 72 patients received 414 

prescriptions, 246 of which were for drugs associated with adverse drug reactions in the 

elderly. After intervention, there was a 32% reduction in total number of prescription 

with a direct overall cost saving of $3872 over a six-month period. 

7. Drug-related emergency department visits and hospital admissions. 

Prince BS; Goetz CM; Rihn TL; Olsky M. 

Am J Hosp Pharm, 49(7):1696-700 1992 Jul. 

The results of this study show that 2.9% of visits to the emergency department of a 

tertiary care hospital are due to drug-related problems. Twenty-four percent of these 

visits result in hospital admission, and the average cost of each admission is $8888. 

8. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and 

attributable mortality. 

Classen DC; Pestotnik SL; Evans RS; Lloyd JF; Burke JP. 

JAMA, 277(4):301-6 1997 Jan 22-29. 



67

The results of this study indicate that 2.43% of hospital admissions are complicated by 

adverse drug events (ADEs). ADEs are associated with a prolonged length of stay of 1.91 

days, an increased cost of $2262 per event, and an almost doubled risk of death. 

9. Medication errors: 1977 to 1988. Experience in medical malpractice claims. 

Kuehm SL; Doyle MJ. 

N J Med, 87(1):27-34 1990 Jan. 

This article shows that from 1977 to 1988, MIIENJ paid US$30,144,636 in indemnity 

from medical malpractice suits due to medication errors. 

10. Pressure ulcers, hospital complications, and disease severity: impact on hospital costs 

and length of stay. 

Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR. 

Adv Wound Care 1999 Jan-Feb;12(1):22-30. 

The results of this study, conducted on a sample population of 286 patients aged 55 and 

over, show that those who developed pressure ulcers had significantly increased length of 

hospital stay (21 vs. 13 days) and incidence of hospital-related infections (46% vs. 20%) 

and other complications (86% vs. 43%), compared to those who did not. Hospital costs 

for patients with incident pressure ulcers were estimated at $29,048, more than two-fold 

higher than the costs for patients without this ailment ($13,819). 

11. Sedative-hypnotic use and increased hospital stay and costs in older people. 

Zisselman MH, Rovner BW, Yuen EJ, Louis DZ. 

J Am Geriatr Soc 1996 Nov;44(11):1371-4. 

The results of this study, conducted on a cohort of 856 consecutive elderly patients 

admitted to a tertiary care teaching hospital, show that those with sedative-hypnotic (S/H) 

use exceeding the Health Care Financing Administration (HCFA) guidelines had, 

compared to patients with S/H use within recommended values or not on these drugs, 

longer hospital stay (21.5 days vs 12.3 days vs 6.7 days), increased hospital costs 

($29,245 vs $15,219 vs $7,516), and greater severity of illness. These data indicate that 

appropriate use of sedative-hypnotic drugs could reduce morbidity and substantially cut 

health care costs. 

12. Expenditures for psychotropic medications in the United States in 1985. 

Zorc JJ. et al. 

Am J Psychiatry 1991 May;148(5):644-7. 



68

This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for 

outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and 

sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants. 

13. The direct economic costs of insomnia in the United States for 1995. 

Walsh JK, Engelhardt CL. 

Sleep 1999 May 1;22 Suppl 2:S386-93. 

The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment 

of insomnia. 

14. Reevaluation of continuous oxygen therapy after initial prescription in patients with 

chronic obstructive pulmonary disease. 

Oba Y, Salzman GA, Willsie SK. 

Respir Care 2000 Apr;45(4):401-6. 

The results of this study show that lack of reevaluation of the need of home oxygen 

therapy in patients with chronic obstructive pulmonary disease (COPD) costs the nation 

an estimated extra $106-$153 million per year. In the study, 57 patients with COPD were 

prescribed home oxygen therapy. Of the 55 that returned for follow-up, only 19 (35%) 

were properly evaluated as to the need for continuous oxygen therapy, and in 

approximately 60% of them, oxygen treatment was discontinued. These data indicate that 

the majority of patients with COPD assigned to home oxygen therapy are needlessly kept 

on treatment. The lack of reevaluation of patients' need for oxygen treatment goes against 

recommended guidelines issued by the Third Oxygen Therapy Consensus Conference, 

which recommend patients' reassessment within 1 to 3 months after initiation of oxygen 

therapy. This omission results in unnecessary discomfort for the patient and in an 

estimated extra health care expenses of $106 to $153 million per year in the U.S. alone. 

15. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. 

Wolfe MM, et al. 

N Engl J Med. 1999 Jun 17;340(24):1888-99. Review. 

This article emphasizes that every year in the U.S., at least 103,000 individuals are 

hospitalized for serious gastrointestinal toxicity from nonsteroidal antiinflammatory 

drugs (NSAID) use, and an estimated 16,500 will not survive the complication. Based on 

these estimates, death from gastrointestinal complications of NSAIDs represents the 15th 

cause of death in the U.S. Unfortunately these figures are conservative since they do not 

take in account users of over-the-counter NSAIDs. The cost of NSAID gastrointestinal 



69

toxicity has been estimated at approximately $15,000 to $20,000 per hospitalization, 

leading to total annual health care expenses exceeding $2 billion. 

16. Cost of medication-related problems at a university hospital. 

Schneider PJ, Gift MG, Lee YP, Rothermich EA, Sill BE. 

Am J Health Syst Pharm 1995 Nov 1;52(21):2415-8. 

This study estimated at $1.5 million the costs associated with drug-related complications 

in a medical center hospital during the year 1994. 

17. Cost implications of malpractice and adverse events. 

Korin J. 

Hosp Formul 1993 Jan;28 Suppl 1:59-61. 

This study shows that each year approximately 5% of hospitalized patients develop 

hospital-acquired infections, for a total annual cost of $10 billion. Over three-quarters of 

these expenses are due to increased length of hospital stay for intravenous antibiotic 

therapy. 

18. Notice to Readers: Fourth Decennial International Conference on Nosocomial and 

Healthcare-Associated Infections. 

MMWR, February 25, 2000 / 49(07);138. 

This article reports that every year in the U.S., approximately 2,000,000 patients develop 

hospital-acquired infections and 88,000 die from them. The cost of hospital-acquired 

infections has been estimated at $4.6 billion. These estimates are conservative, since they 

do not take into account infections occurring in patients in nursing homes, outpatient 

clinics, dialysis centers and other health care centers. 

19. Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, 

mortality, cost, and prevention. 

Jarvis WR. 

Infect Control Hosp Epidemiol, 17(8):552-7 1996 Aug. 

The results of this study indicate that every year in the U.S., approximately 2 million 

patients develop hospital-acquired infections (HAIs). Overall, 23.8 % to 50% of patients 

with hospital-acquired bloodstream infections and 14.8% to 71% of patients with 

hospital-acquired pneumonia die. The cost associated with each HAI is: $558 to $593 for 



70

each urinary tract infection, $2,734 for each surgical site infection, $3,061 to $40,000 for 

each bloodstream infection, and $4,947 for each pneumonia. 

20. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, 

extra costs, and attributable mortality. 

Pittet D, Tarara D, Wenzel RP. 

JAMA 1994 May 25;271(20):1598-601. 

The results of this study show that the incidence of hospital-related bloodstream 

infections in the Surgical Intensive Care Unit (SICU) of a tertiary hospital is 2.67%. 

Mortality rates in patients with this complication are 50% versus 15% in matched 

controls. Length of stay in the hospital and in the SICU increases significantly in patients 

with bloodstream infection compared to controls (54 vs. 30 days and 15 days vs. 7 days, 

respectively). The cost attributable to this complication was estimated at approximately 

$40,000 per survivor. 

21. Prolongation of hospital stay and extra costs due to hospital-acquired infection in a 

neonatal unit. 

Leroyer A, et al. 

J Hosp Infect 1997 Jan;35(1):37-45. 

The results of this study indicate that the incidence of hospital-acquired infections (HAIs) 

in a neonatology unit ias 5.5%. For each HAI, the mean extra length of stay per patient is 

5.2 days and the mean extra cost per patient $10,440. 

22. Costs of treating simple nosocomial urinary tract infection. 

Rutledge KA, McDonald HP Jr. 

Urology 1985 Jul;26(1 Suppl):24-6. 

The results of this study show that the annual national cost of hospital-acquired urinary 

tract infections is $1.8 billion (1985 values). 

23. Infections in the hospitalized elderly. 

Gingrich D. 

Hosp Physician 1990 Jan;26(1):35-8. 

The results of this study show that hospital-acquired infections in the elderly are 

associated with high mortality rates and with health care costs of $4 billion per year 

(1990 values). 



71

24. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a 

pediatric medicaid population 

Berman S; Byrns PJ; Bondy J; Smith PJ; Lezotte D. 

Pediatrics, 100(4):585-92 1997 Oct. 

This study evaluated the pattern of antibiotic prescribing in a sample population of 

12,381 children with middle ear infection. This condition is the most frequent reason for 

prescribing antibiotics to children in the U.S., even though several studies have shown 

that they are no better than placebo in the management of children and infants with 

middle ear infections. The results of the study show that in 1991 and 1992, low-cost 

antibiotics accounted for 67% of the total antibiotic fills and for 21% of the total costs. 

High-cost antibiotics, on the other hand, accounted for 30% of the fills and for 77% of the 

total costs. The more expensive antibiotics had the same efficacy and were associated 

with a slightly higher incidence of adverse reactions compared to the less expensive ones. 

These data indicate that just switching choice of antibiotic in patients with middle ear 

infection could save almost two-thirds of the cost of antibiotic treatment without 

interfering with patient outcome. 

25. Errors in the treatment of tuberculosis in Baltimore. 

Rao SN, Mookerjee AL, Obasanjo OO, Chaisson RE. 

Chest 2000 Mar;117(3):734-7. 

The results of this study show that private physicians often treat tuberculosis (TB) 

incorrectly, favoring the development of acquired drug resistance and multidrug resistant 

TB. The study was conducted on 110 patients diagnosed with TB in the city of Baltimore 

between 1994 and 1995. Almost 40% of patients treated by a private physician were 

prescribed the wrong treatment regimen, compared to 5% of those treated at the 

Baltimore City Health Department's Tuberculosis Clinic. Inappropriate management 

consisting of low-doses antibiotics and short treatment courses is an important cause of 

treatment failure and acquired antibiotic resistance. The authors estimated the costs of 

salvage of inadequate treatment at $180,000 per patient. 

26. "Routine" preoperative studies. Which studies in which patients? 

Marcello PW, Roberts PL. 

Surg Clin North Am 1996 Feb;76(1):11-23 

This article highlights that 60% of routine tests conducted on patients in preparation of 

their surgery are unnecessary and add an extra $18 billion to the annual health care bill. 

In addition, unnecessary tests cause harm resulting from complications associated with 



72

the testing procedure, or with the unnecessary treatment of patients who receive a false 

positive test result. 

27. Unnecessary preoperative investigations: evaluation and cost analysis. 

Allison JG; Bromley HR. 

Am Surg, 62(8):686-9 1996 Aug. 

The results of this study indicate that two-thirds of the tests patients undergo in 

preparation of their surgery are unnecessary. The study evaluated prospectively the 

appropriateness of pre-operative testing in 60 randomly selected ambulatory surgery 

patients. Only one-third of tests had clinical indications and was therefore deemed 

appropriate. The cost of inappropriate tests was estimated at $47 to $80 per patient. The 

authors emphasize the need of changing obsolete practices. 

28. Extraimmunization Among US Children. 

Feikema SM et al. 

JAMA 2000;283:1311-1317. 

The results of this study show that in the U.S., every year approximately 900,000 children 

aged 19-36 months (one fifth of all U.S. children in that age group) receive at least an 

extra immunization, leading to an excess cost of $26.5 billion. The investigators surveyed 

parents of 32,742 children and obtained information from 22,806 of them through their 

health care provider. They found that 21% of them had received at least one extra 

vaccination. Extra doses of vaccine, in addition to adding discomfort and stress to the 

baby, are associated with an increased risk of adverse reactions. The risk of adverse 

reactions is particularly high with extra doses of the diphtheria-tetanus vaccine, and there 

is evidence showing that extra doses of these vaccines can cause serious side effects. In 

addition extra immunizations add extra costs and labor to the health care system. This 

study estimated this excess cost at $26.5 billions. This estimate, however, is conservative, 

since it does not take in account the costs associated with vaccine handling and 

distribution, parent's travel time, treatment for adverse effects, or other indirect costs. 

29. Cost-Utility Analysis of Screening Intervals for Diabetic Retinopathy in Patients With 

Type 2 Diabetes Mellitus. 

Vijan S; Hofer TP; Hayward RA. 

JAMA 2000;283:889-896. 

The results of this study show that screening for eye disease every other year or every 

three years can be as effective as screening annually to prevent blindness in patients with 

type 2 diabetes and no signs of eye deterioration. Current guidelines recommend yearly 

eye examination for diabetic patients on the basis of cost-effectiveness analyses 



73

demonstrating an economic benefit associated with this practice. The authors of the study 

used a computer model to assess the costs and effectiveness of yearly versus extended 

screening intervals. The results of the study indicate that a high-risk diabetic patient aged 

45 years with poor glycemic control is expected to gain 21 days of sight by attending 

screening visits annually, rather than every third year. On the other hand, a 65-year old 

low-risk diabetic patient with moderately well glycemic control is expected to gain 3 

days of sight by undergoing screening annually, rather than every third year. Screening 

low-risk patients annually rather than every other year results in an additional cost of 

$123,580 for each year of quality life gained. These estimates show that annual eye 

screening produces little benefits in low-risk diabetic patients, while substantially 

increasing health care costs. The authors emphasize that current guidelines calling for 

yearly screening in patients with type 2 diabetes should be re-evaluated, and 

recommendations should be tailored to patients clinical status. 

30. Costs of poison-related hospitalizations at an urban teaching hospital for children. 

Woolf A; Wieler J; Greenes D. 

Arch Pediatr Adolesc Med, 151(7):719-23 1997 Jul. 

The results of this study show that poison-related admissions to a single pediatric facility 

account for 0.9% of all pediatric hospital admissions and are associated with an estimated 

annual cost of $1 million. Acetaminophen, lead and antidepressants are the substances 

most frequently involved in poisoning. 

31. Economic outcomes of a targeted intervention program: the costs of treating allergic 

rhinitis patients. 

Santos R, Cifaldi M, Gregory C, Seitz P. 

Am J Manag Care 1999 Apr;5(4 Suppl):S225-34. 

The results of this study, conducted on a cohort of 7,936 patients with symptoms of 

allergic rhinitis, show that each year one managed care provider (Lovelace Health 

Systems) spends approximately $2 million for the symptomatic treatment of this 

condition. 

32. Cost effectiveness of low-molecular weight heparin versus warfarin following hip 

replacement surgery. 

Saunders ME; Grant RE. 

J Natl Med Assoc, 90(11):677-80 1998 Nov. 

This study compared the cost-efficacy of low-molecular-weight (LMW) heparin versus 

warfarin use for the prophylaxis of deep vein thrombosis and pulmonary embolism 



74

following hip-replacement surgery. Use of LMW heparin was associated with a saving of 

$1,253 per patient and with a 0% versus 3% incidence of thrombo-embolic events, 

compared to warfarin. These data indicate that switching to LMW heparin could 

significantly cut health care costs and improve patient outcome. 

33. Cost-effectiveness of routine radiation therapy following conservative surgery for 

early-stage breast cancer. 

Hayman JA; Hillner BE; Harris JR; Weeks JC. 

J Clin Oncol, 16(3):1022-9 1998 Mar. 

The results of this study show that in women aged 60 and older, radiation therapy after 

conservative surgery for early stage breast cancer adds nothing in terms of life 

expectancy while increasing the cost of therapy by $9,800 per patient. 

34. Escalating costs for cancer chemotherapy. 

Nyman JV; Dorr RT; Hall GR. 

Am J Hosp Pharm, 38(8):1151-4 1981 Aug. 

The results of this study indicate that the annual cost of antineoplastic drugs for one 

hospital rose from $10,156 in 1973-1974 to $296,914 in 1979-1980, these amounts 

consisting of 5.74% and 16.74% of the hospital total drug budget, respectively. This 

increase was not justified by patient load, inflation, or amount of medication prescribed. 

35. The costs of cancer care in the United States: implications for action. 

Schuette HL; Tucker TC; Brown ML; Potosky AL; Samuel T. 

Oncology (Huntingt), 9(11 Suppl):19-22 1995 Nov. 

This article emphasizes that the annual direct and indirect costs of cancer care are in the 

range of $100 billion, indicating the need to shift the costs toward more effective 

measures such as prevention. 

36. Comprehensive discharge planning and home follow-up of hospitalized elders: a 

randomized clinical trial. 

Naylor MD, Brooten D, Campbell R, Jacobsen BS, Mezey MD, Pauly MV, Schwartz JS. 

JAMA 1999 Feb 17;281(7):613-20. 

This randomized study evaluated the outcome of a comprehensive discharge planning 

and home follow-up intervention program conducted by nurses from two urban hospitals 



75

on a cohort of elderly patients at risk for hospital readmissions. Twenty-four weeks after 

discharge, patients in the intervention group, compared to those in the control group, 

showed decreased rate of hospital admissions (37% vs. 20%), decreased rate of multiple 

hospital readmissions (6.2% vs. 14.5%) and reduced length of hospital stay when readmitted 

(1.5 days vs. 4 days). Total Medicare reimbursement costs were about $0.6 

million in the intervention group versus $1.2 million in the control group. These data 

indicate that preventive intervention in high-risk patients results in a 50% reduction in 

health care costs and in improved patient outcome. 

37. Cost-effectiveness of colon cancer screening. 

Lieberman D. 

Am J Gastroenterol, 86(12):1789-94 1991 Dec. 

This study evaluated the cost-effectiveness of two different methods of colon cancer 

screening: sigmoidoscopy from age 50 with yearly testing for fecal occult blood (as 

recommended by the American Cancer Society) and colonoscopy. The cost of preventing 

one death from colon cancer was estimated to be $444,133 with sigmoidoscopy and 

$347,214 with colonoscopy. 

38. Clinical and economic impact of oral ciprofloxacin as follow-up to parenteral 

antibiotics. 

Grasela TH Jr; et al. 

DICP, 25(7-8):857-62 1991 Jul-Aug. 

This study, conducted on a sample population of 766 patients initially treated with 

parenteral antibiotics for respiratory tract (RTI), skin or skin structure (SSS), bone or 

joint (BJI), and urinary tract infections (UTI) for a median of 4, 6, 6, and 7.5 days, 

respectively, shows that switching to oral antibiotic therapy shortened hospital stay and 

saved in drugs and hospitalization costs a total of $980,246. 

39. Cost and morbidity associated with antibiotic prophylaxis in the ICU. 

Namias N; Harvill S; Ball S; McKenney MG; Salomone JP; Civetta JM. 

J Am Coll Surg, 188(3):225-30 1999 Mar. 

This study evaluated prospectively data on prophylactic antibiotic (PA) treatment in 

patients admitted to the Surgical Intensive Care Unit of a teaching hospital over a 19month 

period, to determine physicians' compliance to current guidelines recommending 

cessation of PA at 24 hours. In 61% of patients, PA therapy was continued beyond 24 

hours. Patients receiving PA for more than 4 days had higher rates of bacteremias and 



76

line infections, compared to those with shorter antibiotic course. The cost of 

inappropriate antibiotic treatment in this patient population was estimated at $44,893. 

40. Antimicrobial prophylaxis in surgical patients. 

Crossley K, Gardner LC. 

JAMA 1981 Feb 20;245(7):722-6. 

This study evaluated use of prophylactic antibiotics (PA) in a cohort of 1,021 surgical 

patients from 27 different hospitals. Only 41% of patients received PA in the four hours 

before surgery, and in one-third of patients PA continued for more than 72 hours. 

Reducing the time of PA treatment would save 18% to 50% of the total cost of 

perioperative antibiotic prophylaxis. 

41. Surveillance of the use of antibiotic prophylaxis in surgery. 

Finkelstein R, Reinhertz G, Embom A. 

Isr J Med Sci 1996 Nov;32(11):1093-7. 

This study evaluated implementation of prophylactic antibiotic (PA) treatment two years 

after updated recommendations on its use were made available throughout the surgical 

wards of an Israeli hospital. In certain types of surgery, PA was prescribed systematically 

without indications for its use. In almost 50% of patients the first dose of PA therapy was 

not given at the appropriate timing; PA administration extended over the recommended 

24 hours in 21% of cases and frequently consisted of unstandardized regimens. These 

data indicate high rates of inappropriate PA treatment. This phenomenon results in extra 

health care costs and contributes to the worldwide increase in antibiotic resistance. 

42. Surgical infections and prophylactic antibiotics: 341 consecutive cases of gallbladder 

surgery in the era of laparoscopic surgery. 

Garcia N, Kapur S, McClane J, Davis JM. 

J Laparoendosc Adv Surg Tech A 1997 Jun;7(3):157-62. 

This study evaluated the appropriateness of prophylactic antibiotic (PA) treatment in a 

cohort of 341 consecutive patients admitted to the hospital for laparoscopic and open 

cholecystectomy. In 63.2% of cases PA was administered inappropriately. Seventy-three 

percent of patients received a large-spectrum antibiotic when a cheaper and narrower 

spectrum agent would have been adequate. 



77

43. Oral versus intravenous antibiotics for community acquired lower respiratory tract 

infection in a general hospital: open, randomised controlled trial. 

Chan R; Hemeryck L; O'Regan M; Clancy L; Feely J. 

BMJ, 310(6991):1360-2 1995 May 27. 

The results of this study, conducted on a cohort of 541 patients admitted to the hospital 

over a 1-year period for lower respiratory tract infections who had no immune system 

depression or severe infection, show that treatment with oral antibiotics is equally 

effective to intravenous antibiotic therapy as to patient clinical outcome and mortality, 

and is associated with reduced hospital length of stay. The authors estimated that if the 

800 patients admitted every year to the hospital would be treated routinely with oral 

rather than intravenous antibiotics, the hospital could save approximately 176,000 pounds 

per year, and patients would benefit from early discharge. 

44. Early transition to oral antibiotic therapy for community-acquired pneumonia: 

duration of therapy, clinical outcomes, and cost analysis. 

Omidvari K; de Boisblanc BP; Karam G; Nelson S; Haponik E; Summer W. 

Respir Med, 92(8):1032-9 1998 Aug. 

This randomized study evaluated the therapeutic efficacy and costs of conventional 7-day 

treatment with intravenous (IV) antibiotics for community-acquired pneumonia versus 

abbreviated 2-day course of IV antibiotics followed by oral antibiotics. Clinical course, 

cure rates and survival were similar in the two treatment groups. Oral therapy was 

associated with shorter hospital stay (7.3 versus 9.71 days) and reduced overall costs of 

care ($2953 vs. $5002 per patient). 

45. Oral versus initial intravenous therapy for urinary tract infections in young febrile 

children. 

Hoberman A, Wald ER, Hickey RW, Baskin M, Charron M, Majd M, et al. 

Pediatrics 1999 Jul;104(1 Pt 1):79-86. 

This randomized study evaluated the cost and efficacy of outpatient oral versus inpatient 

intravenous antibiotic therapy in the treatment of children 1 to 24 months old with febrile 

urinary tract infection. Oral therapy was judged to be as safe and effective as intravenous 

therapy, and its use was associated with an over 50% reduction in overall costs ($1473 

per patient for oral therapy versus $3577 for intravenous therapy). 

46. The cost of antibiotics in treating upper respiratory tract infections in a medicaid 

population. 



78

Mainous AG 3rd; Hueston WJ. 

Arch Fam Med, 7(1):45-9 1998 Jan-Feb. 

Antibiotic therapy for nonspecific upper respiratory tract infections (URIs) is 

nonindicated and ineffective, and increases the occurrence of antibiotic-resistant 

pathogens. This study evaluated antibiotic prescribing practices for URIs in a sample 

population of 50,000 Medicaid recipients. Antibiotics were prescribed in 60% of 

outpatient visits and in 48% of emergency department episodes. In 23% and 9% of the 

outpatient and emergency department visits, respectively, a prescription for 

antihistamines was filled. These data indicate that contrary to published guidelines, 

physicians routinely prescribe antibiotics in over 50% of patients with upper respiratory 

infections, resulting in significant extra health care costs and in the favoring of the spread 

of antibiotic-resistant bacterial strains. 

47. Antibiotic administration in patients undergoing common surgical procedures in a 

community teaching hospital: the chaos continues. 

Gorecki P, Schein M, Rucinski JC, Wise L. 

World J Surg. 1999 May;23(5):429-32. 

This study evaluated the appropriateness of antibiotic treatment in a randomly selected 

sample of 211 patients undergoing elective (132 patients) or emergency (79 patients) 

surgery in a teaching hospital during 1996. Seventy-four percent of patients received 

inappropriate antibiotic treatment. The total cost of prolonged antibiotic treatment for this 

cohort was estimated at $18,533. 

48. Decrease in expenditures and selected nosocomial infections following 

implementation of an antimicrobial-prescribing improvement program. 

Frank MO, Batteiger BE, Sorensen SJ, Hartstein AI, Carr JA, McComb JS, et al. 

Clin Perform Qual Health Care 1997 Oct-Dec;5(4):180-8 

The results of this study show that implementation of an antimicrobial-prescribing 

improvement program in an academic medical center was associated with a substantial 

reduction in antibiotic use, which translated in cost savings of $390,000 in 1994 alone, 

compared to the costs prior to program implementation. In addition, decreased use of 

antimicrobial agents was associated with an over 50% reduction in the rate of several 

hospital-acquired infections. 

49. Government orders inquiry as price of generic drugs soars. 

Jones, J. 

BMJ 1999;319:1151 ( 30 October ). 



79

This article reports on the recent sharp increase in the price of generic drugs in UK. In 

1999 for example, the price of common drugs such as amoxicillin, furosemide, and 

thyroxine, was 4-8 times higher than in 1998. This rise could result in extra annual health 

care expenses of $320 million. 

MALNUTRITION – 30 Studies 

1. Prevalence of malnutrition in general medical patients. 

Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J. 

JAMA 1976 Apr 12;235(15):1567-70. 

This study shows that in 1976, the prevalence of malnutrition in hospitalized patients of 

the general wards of an urban teaching hospital, was 44% or greater. Thirty-four percent 

of patients had levels of lymphopenia likely to be associated with reduced cellular 

immunity. 

2. Incidence and recognition of malnutrition in hospital. 

McWhirter JP, Pennington CR. 

BMJ 1994 Apr 9;308(6934):945-8. 

This 1994 study shows that 40% of patients admitted to an acute teaching hospital were 

malnourished, and in 78% of them nutritional status further deteriorated during hospital 

stay. In addition, two thirds of all patients lost weight during hospital stay. 

3. In 1995 a correlation between malnutrition and poor outcome in critically ill patients 

still exists. 

Giner M, Laviano A, Meguid MM, Gleason JR. 

Nutrition 1996 Jan;12(1):23-9. 

This study shows that 43% of 129 patients admitted to the intensive care unit of a 

hospital, were malnourished. Length of hospital stay, complications and number of deaths 

were greater in malnourished compared to well-nourished patients, and malnourished 

patients with less severe illnesses had worse clinical outcomes than sicker, wellnourished 

patients. The study also showed that malnutrition in patients who underwent 

surgery developed mainly during their preoperative stay in general medicine wards. 



80

4. In-hospital malnutrition: indications of postoperative evolution. 

Farré Rovira R, Frasquet Pons I, Ibor Pica JF. 

Nutr Hosp, 13(3):130-7 1998 May-Jun. 

This study shows that, after admission to the hospital, the number of patients with below- 

normal levels of serum albumin doubles, and the number of those with below-normal 

levels of body weight and body mass index, triplicates. Nutritional status worsens as 

length of hospital stay increases. 

5. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. 

Sullivan DH, Sun S, Walls RC. 

JAMA 1999 Jun 2;281(21):2013-9. 

This study evaluated whether hospitalized patients receive adequate nutritional intake 

during hospital stay and whether eventual nutritional deficits translate in increased 

mortality rates. The results of the study, conducted on 497 elderly patients during a 4year 

period, showed that 21% of patients consumed less than 50% of their estimated 

maintenance energy requirements, and this was partly due to the fact that patients were 

frequently ordered to eat nothing by mouth but did not receive nutritional 

supplementation by other routes. Patients with low energy intake were 8 times more 

likely to die while being in the hospital and 3 times more likely to die within 90 days, 

compared to patients with normal energy intake. These findings indicate that during their 

hospital stay, elderly patients often receive largely inadequate nutrient intake -a practice 

that seems associated with a significant negative impact on their overall survival. 

6. Malnutrition and clinical outcomes: the case for medical nutrition therapy. 

Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. 

J Am Diet Assoc 1996 Apr;96(4):361-6, 369. 

This article reports on the results of several studies conducted on over 1,327 patients, 

indicating that 40% to 55% of hospitalized patients are either malnourished or at risk for 

malnutrition, and 12% of them are severely malnourished. Postoperative complications 

and mortality occur 2-3 times more often, and hospital costs are 35% to 75% higher, in 

malnourished compared to well-nourished patients. 

7. Prevalence of malnutrition in nonsurgical hospitalized patients and its association with 

disease complications. 

Naber TH, et al. 

Am J Clin Nutr 1997 Nov;66(5):1232-9. 



81

The results of this study, conducted on 155 patients admitted to the internal medicine 

ward of a hospital, show that the prevalence of malnutrition in this cohort, according to 

the Maastricht Index (which evaluates ideal weight together with prealbumin, albumin, 

and lymphocytes levels) was 62%. Rates of complications were 3 times higher in 

malnourished versus well-nourished patients. 

8. The relationship between clinical assessments of nutritional status and adverse 

outcomes in older hospitalized medical patients. 

Covinsky KE, Martin GE, Beyth RJ, Justice AC, Sehgal AR, Landefeld CS. 

J Am Geriatr Soc 1999 May;47(5):532-8. 

This study evaluated the nutritional status of 369 patients aged 70 years or more admitted 

to a general ward of a tertiary care hospital, and found that 60% of them were well 

nourished, 25% were moderately malnourished, and 16% were severely malnourished. 

After controlling for severity of disease, presence of coexisting diseases, and functional 

status on admission, the researchers showed that severely malnourished patients were 2.8 

times more likely to die and 3.2 times more likely to be admitted to a nursing home 

within a year of discharge, compared to well nourished patients. 

9. Protein-energy undernutrition and the risk of mortality within six years of hospital 

discharge. 

Sullivan DH, Walls RC. 

J Am Coll Nutr 1998 Dec;17(6):571-8. 

The results of this study show that protein-energy malnutrition is the single strongest 

predictor of long-term mortality in elderly individuals discharged from the hospital. In 

the study, 322 elderly patients were followed for 6 years after being discharged from the 

hospital to evaluate the effects that nutritional status had on their long-term survival. 

Patients were defined as being at risk for malnutrition if they had serum albumin levels 

below 3.0 g/dL or body mass index below 19. Being at risk for malnutrition was the 

strongest predictor of death in the following 6 years. A diagnosis of congestive heart 

failure, being discharged to a health care facility, age and marital status were not as 

strongly associated with mortality as protein-energy malnutrition. 

10. Economic impact of malnutrition: a model system for hospitalized patients. 

Reilly JJ Jr, Hull SF, Albert N, Waller A, Bringardener S. 

JPEN J Parenter Enteral Nutr 1988 Jul-Aug;12(4):371-6. 

This retrospective study, conducted on 771 individuals admitted to two acute care 

hospitals, shows that the rate of likelihood of malnutrition was 59% in medical wards and 



82

48% in surgical wards. Rates of minor and major complications were 2.6 and 3.4 times 

higher, respectively, in patients with likelihood of malnutrition compared to those 

without it. Likelihood of malnutrition was associated with a 3.8-fold increased risk of 

death. Suspected malnutrition was also associated with increased length of hospital stay 

and increased excess average costs of $1738 to $3557 per patient. The impact of a 

nutritional intervention program could not be assessed, because too few patients had 

received it. 

11. High-quality nutritional interventions reduce costs. 

Smith PE, Smith AE. 

Healthc Financ Manage 1997 Aug;51(8):66-9. 

This article reports on the results of a survey of 19 hospitals indicating that length of 

hospital stay decreases by approximately 2 days in patients who receive optimal 

nutritional care. The survey also revealed that only 7.5% of patients at risk for 

malnutrition receive optimal nutritional intervention, and this omission results in an 

increased cost of $1.064 per patient at risk of malnutrition. 

12. Relationship of nutritional status to length of stay, hospital costs, and discharge status 

of patients hospitalized in the medicine service. 

Chima CS, Barco K, Dewitt ML, Maeda M, Teran JC, Mullen KD. 

J Am Diet Assoc 1997 Sep;97(9):975-8. 

This study, conducted on all 173 individuals admitted to three medicine units during a 1month 

period, shows that those who, upon admission, were classified as being at risk for 

malnutrition, had, compared to patients not a risk of malnutrition, higher hospital length 

of stay (6 days vs. 4 days), higher hospitalization costs ($6,196 vs. $4,563), and higher 

home health care needs, even if 91% of them received nutrition intervention during 

hospitalization. 

13. The five-year evolution of a malnutrition treatment program in a community hospital. 

Brugler L, DiPrinzio MJ, Bernstein L. 

Jt Comm J Qual Improv 1999 Apr;25(4):191-206. 

This study shows that implementation of a malnutrition treatment program in a 395-bed 

community hospital in Delaware, resulted in reduction of average patient length of stay 

from 10.8 to 8.2 days, in decrease of incidence of major complications from 75.3% to 

17.5%, and in reduction of 30-day hospital re-admission rates from 16.5% to 7.15. 



83

14. Effect of malnutrition after acute stroke on clinical outcome. 

Dávalos A, et al. 

Stroke, 27(6):1028-32 1996 Jun. 

This study, conducted on a cohort of 104 patients with acute stroke, shows that the 

number of individuals with malnutrition increased from 16.3% at admission to 26.4% 

after a week in the hospital. Malnourished patients had increased incidence of infections 

and bedsores. In addition, patients with malnutrition after a week of hospitalization had a 

3.5-fold increased risk of poor outcome, regardless of their age and nutritional status at 

admission. 

15. Influence of nutritional status on clinical outcome after acute stroke. 

Gariballa SE, Parker SG, Taub N, Castleden CM. 

Am J Clin Nutr 1998 Aug;68(2):275-81. 

This study shows that the nutritional status of patients admitted to the hospital over a 15month 

study period for acute stroke, deteriorated significantly during hospital stay. 

Malnutrition was significantly associated with increased risk of infections and poor 

functional outcome, and was a strong predictor of mortality in the 3 months after the 

stroke. 

16. Clinical significance of preoperative nutritional status in 215 noncancer patients. 

Warnold I, Lundholm K. 

Ann Surg 1984 Mar;199(3):299-305. 

The results of this study, conducted on 215 patients hospitalized for surgery, show that 

those with low nutritional status had a two-fold increase in rates of post-operative 

complications and in length of hospital stay, compared to those with normal nutritional 

status. The difference in rate of complications was particularly evident for major 

complications, which occurred in 31% of undernourished patients, compared to 9% of 

well-nourished subjects. 

17. Outcomes of undernutrition in patients in the community with cancer or 

cardiovascular disease. 

Edington J, Winter PD, Coles SJ, Gale CR, Martyn CN. 

Proc Nutr Soc 1999 Aug;58(3):655-61. 

The results of this study indicate that even low levels of malnutrition are associated with 

significantly increased rates of morbidity and mortality in individuals with cancer or 

cardiovascular diseases. In the study, conducted on 10,128 individuals aged 18 and older 



84

with a diagnosis of cancer or cardiovascular disease, those with body mass index (BMI) 

levels below 20 kg/m2 had higher rates of physician consultations and higher rates of 

death, compared to those with higher levels of BMI. Poor nutritional status was strongly 

associated with increased risk of hospitalization in patients with cardiovascular disease. 

18. Impact of body mass index and albumin on morbidity and mortality after cardiac 

surgery. 

Engelman DT, et al. 

J Thorac Cardiovasc Surg 1999 Nov;118(5):866-73. 

The results of this study indicate that patients with albumin levels below 2.5 g/dL and 

body mass index below 20 kg/m2 undergoing cardiac bypass surgery have significantly 

higher rates of post-operative morbidity and mortality, compared to those with normal 

values of both parameters. 

19. Nutritional status is a prognostic factor for survival in ALS patients. 

Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. 

Neurology 1999 Sep 22;53(5):1059-63. 

The results of this study show that patients with amyotrophic lateral sclerosis (ALS) with 

malnutrition have a 7.7-fold increased risk of death, compared to well-nourished patients, 

independently of neurological scores and type of ALS. The authors recommend increased 

surveillance of nutritional status in patients with this disease. 

20. The impact of nutritional status on the outcome of lung volume reduction surgery: a 


Mazolewski P, Turner JF, Baker M, Kurtz T, Little AG. 

Chest 1999 Sep;116(3):693-6. 

The results of this study indicate that patients with end stage emphysema and with belownormal 

levels of body mass index (BMI) undergoing lung surgery have significantly 

increased post-operative morbidity and length of hospital stay, compared to patients with 

normal levels of BMI. This study shows that body mass index value is a good indicator of 

nutritional status and a simple way to screen individuals at risk of nutritional deficiencies. 

The authors suggest that correction of nutritional deficiencies may translate in lower rates 

of hospital morbidity, length of stay, and health care costs in this group of patients. 



85

21. Malnutrition in childhood lymphoblastic leukemia: a predictor of early mortality 

during the induction-to-remission phase of the treatment. 

Mejia-Arangure JM, et al. 

Arch Med Res 1999 Mar-Apr;30(2):150-3. 

The results of this study show that malnourished children undergoing chemotherapy for 

acute lymphoblastic leukemia (ALL) have a 2.6-fold increased risk of death, compared to 

well-nourished children. The risk of mortality increases with increased severity of 

nutritional deficit. 

22. Disability is associated with malnutrition in institutionalized elderly people. 

The I.R.A. Study. Istituto di Riposo per Anziani. 

Romagnoni F, et al. 

Aging (Milano) 1999 Jun;11(3):194-9. 

The results of this study indicate that disability in elderly patients is strongly associated 

with the presence of anthropometric and plasma measurements indicative of malnutrition. 

This association exists independently of age, gender, and presence of coexisting illness or 

other confounding factors. The authors highlight the importance of correcting nutritional 

imbalances in the management of elderly disabled patients. 

23. Body mass index and mortality among older people living in the community. 

Landi F, et al. 

J Am Geriatr Soc 1999 Sep;47(9):1072-6. 

The results of this study show that elderly individuals living in the community who have 

body mass index (BMI) levels below 22 Kg/m2 (a sign of malnutrition) have a 20% 

increased risk of being dependent in one or more Activities of Daily Living and a 15% 

increased risk of death, compared to individuals with normal BMI levels. 

FOLLOWING IS A SERIES OF STUDY SHOWING THE EFFECTS OF 

NUTRITIONAL SUPPLEMENTATION ON MORBIDITY AND MORTALITY. 

24. Dietary supplementation in elderly patients with fractured neck of the femur. 

Delmi M, Rapin CH, Bengoa JM, Delmas PD, Vasey H, Bonjour JP. 

Lancet 1990 Apr 28;335(8696):1013-6. 



86

The results of this study show that elderly patients hospitalized with a fracture of the neck 

of the femur who underwent nutritional supplementation had approximately half the rates 

of complications and death, compared to those who did not receive dietary 

supplementation. The study was conducted on 59 elderly patients who were randomly 

assigned to receive daily for an average of 32 days an oral nutritional supplement (27 

patients), or no supplementation (32 patients). Most patients had nutritional deficiencies 

upon admission. Outcome was favorable in 56% of supplemented patients, compared to 

13% of those not supplemented. In the supplemented group, 44% of patients experienced 

complications or death, compared to 87% of patients in the non-supplemented group. 

These differences persisted 6 months after the occurrence of the fracture. Average length 

of hospital stay was 24 days in the supplemented group, and 40 days in the nonsupplemented 

group. These findings indicate that daily oral supplementation cuts length 

of hospital stay and rates of complications and death by half, in elderly patients with 

fractured neck of the femur. 

25. Effect of vitamin and trace-element supplementation on immune responses and 

infection in elderly subjects. 

Chandra RK. 

Lancet 1992 Nov 7;340(8828):1124-7. 

The results of this study show that supplementation with modest physiological amounts 

of nutrients improves immune status and significantly reduces rates of infections in 

elderly individuals. The study was conducted on 96 healthy elderly subjects who were 

randomized to receive a nutritional supplement containing vitamins and trace elements or 

a placebo pill. After 12 months, immune function was improved, compared to baseline 

values, in individuals who had received nutritional supplementation, but not in those 

receiving placebo. In addition, those who received the supplement, spent considerable 

less time being ill from infectious diseases, compared to control subjects who received 

placebo (23 days versus 48 day per year). These findings indicate that a simple nutritional 

supplement is efficacious in improving immune status and significantly decreasing rates 

of infections in elderly individuals. 

26. Vitamin C depletion and pressure sores in elderly patients with femoral neck fracture. 

Goode HF, Burns E, Walker BE. 

BMJ 1992 Oct 17;305(6859):925-7. 

The results of this study show that vitamin C concentration in elderly patients 

hospitalized with fractured neck of the femur who developed pressure ulcers is 

approximately half that of patients who did not develop this complication, indicating that 

vitamin C depletion may be an important factor in the etiology of pressure ulcers in the 

elderly. 



87

27. Impact of trace elements and vitamin supplementation on immunity and infections in 

institutionalized elderly patients: a randomized controlled trial. 

MIN. VIT. AOX. geriatric network. 

Girodon F, et al. 

Arch Intern Med 1999 Apr 12;159(7):748-54. 

The results of this double-blind, placebo-controlled study conducted on 725 

institutionalized patients aged 65 and older, show that supplementation with zinc and 

selenium is associated with a significant reduction of the incidence of respiratory tract 

infections. 

28. The clinical effects of vitamin C supplementation in elderly hospitalised patients with 

acute respiratory infections. 

Hunt C, Chakravorty NK, Annan G, Habibzadeh N, Schorah CJ. 

Int J Vitam Nutr Res 1994;64(3):212-9. 

The results of this randomized, double-blind, placebo controlled trial show that elderly 

patients admitted to the hospital for acute respiratory infections who receive daily 

supplementation of 200 mg of vitamin C, had significantly improved disease course, 

compared to those who received placebo. The positive effects of vitamin C 

supplementation were particularly evident in patients who were most severely ill, and 

who often had very low levels of the vitamin on admission. 

29. Routine protein energy supplementation in adults: systematic review. 

Potter, J et al. 

BMJ 1998;317:495-501. 

This study reviewed 30 randomized trial conducted on 2,062 patients, evaluating the 

impact of routine oral and enteral nutritional supplementation on survival in adult 

hospitalized patients. Patients who received nutritional supplementation showed 

significant improvements in body weight and mid-arm muscle circumference, and had an 

overall 36% increased rate of survival, compared to untreated patients. These findings 

indicate that protein calorie supplementation improves nutritional status in adults and 

significantly lowers fatality rates. 

30. Care of dying patients in hospital. 

Mills M, Davies HT, Macrae WA. 

BMJ 1994 Sep 3;309(6954):583-6. 



88

This study assessed the level of care received by dying patients in 13 wards of four large 

university hospitals in Scotland and concluded that patients basic needs before dying 

were left unmet: thirst remained unquenched, oral hygiene was poor, eating was not 

encouraged. Contact with patients by nurses and doctors was minimal and patient 

isolation increased as death advanced. Over half of the patients remained conscious until 

shortly before death. 

MEDICAL ERRORS & ADVERSE DRUG REACTIONS – 76 Studies 

1. Epidemiology of medical error. 

Weingart, SN. et al. 

BMJ 2000;320:774-777 ( 18 March ). 

This article presents a review of current available information on the incidence and nature 

of medical errors in U.S. hospitals. Medical errors have been estimated to kill 48,000- 

98,000 Americans each year, and to injure an additional 1 million. These data, however, 

are likely to significantly underestimate the real extent of the problem, since they only 

refer to hospital patients, and are not inclusive of errors occurring in nursing homes and 

other health care settings. In addition, the methods used by investigators to identify 

adverse medical events can significantly affect the estimates of their prevalence. In a 

landmark study conducted by the University of Harvard, for example, where the 

researchers used a stringent definition of error, it was calculated that 3.7% of hospitalized 

patients experienced an adverse event, which was caused by errors -and was therefore 

preventable- in two-thirds of cases. In another study, where errors were detected through 

a computerized model, the incidence of adverse drug reactions in hospitalized patients 

was estimated to be 1.7%. On the other hand, when Bates and colleagues determined the 

incidence of adverse drug reactions by reviewing patients' medical charts and by 

conducting interviews with physicians, they found that 6.5% of hospitalized patients 

developed an adverse drug reaction, and another 5.5% developed a potential adverse drug 

reaction; these events were found to be caused by errors in 28% of cases. Furthermore, 

when trained observers who visited a general surgery unit where asked to evaluate the 

rate of adverse events, they reported that almost 50% of patients experienced an adverse 

event, which was serious in 18% of cases. Little research has been conducted on the 

extent of medical error outside hospital settings. One study revealed that drug-related 

complications occur in 18% of outpatients. Another study calculated that every year 

treatment-related complications result in 116 million additional physicians visits, 76 

million prescriptions, 17 million emergency department visits, 8 million hospital 

admissions, 3 million long-term care facility admissions, and 200,000 additional deaths, 

for a cost of $76.6 billion. These data indicate that the extent of injury caused by 

preventable errors occurring in health care settings is enormous, and the real dimension 

of the problem is largely unknown. 



89

2. Reporting and preventing medical mishaps: lessons from non-medical near miss 

reporting systems. 

Barach, P. and Small S. 

BMJ 2000;320:759-763 ( 18 March ). 

This article reports on some of the data that emerged from the results of two studies 

conducted by the Institute of Medicine showing that, every year, approximately 100,000 

patients die needlessly in the hospital as a result of errors in medical management, and 

many more are injured. These data, already alarming, become even more preoccupying 

when considering that, as the article highlights, 50%-96% of adverse events are not 

reported. These data indicate that preventable deaths from errors in medical management 

have reached endemic proportions, and that the extent of the injury is largely 

underestimated. 

3. To Err Is Human: Building a Safer Health System. 

Kohn L., Corrigan J., and Donaldson M., Editors; Committee on Quality of Health Care 

in America, Institute of Medicine. 

http://www.iom.edu 

The Institute of Medicine (IOM) committee released a report on November 29, 1999 on 

medical errors in U.S. hospitals. A medical error was defined as "the failure to complete a 

planned action as intended or the use of a wrong plan to achieve an aim". The report 

presented the results from two large studies revealing that medical errors occurring in the 

hospital kill an estimated 44,000 (based on one study) or 98,000 (based on the second 

study) Americans each year. These estimates do not include errors that may arise in 

settings other than the hospital such as outpatient clinics, retail pharmacies, nursing 

homes, home care, and day-surgery clinics. Even considering only the most conservative 

figure (44,000 deaths per year), medical errors would be the eight leading cause of death, 

killing more people than breast cancer, AIDS or traffic accidents. The yearly cost 

resulting from such errors has been estimated at approximately $9 billion. Many of these 

errors are avoidable, and the IOM called for a 50% reduction in errors over the next 5 

years. According to the report, systems designed to ensure public safety are over a decade 

behind in the health care industry compared to other high-risk industries. 

4. Reducing errors in medicine. 

Leape LL. 

BMJ 1999;319:136-137 ( 17 July ). 

This article reports on previous studies demonstrating that injuries from medical care 

occur in 3.7% to 6.7% of hospital admissions, and are fatal in 13.6% of cases. Over half 

of these injuries are preventable. From these data it is deduced that, in the U.S., more 

than 120,000 individuals die each year while in the hospital from errors that are 



90

avoidable. The cost of a preventable medication error has been estimated at 

approximately $4,700 per event. 

5. Medication-prescribing errors in a teaching hospital. A 9-year experience. 

Lesar TS, Lomaestro BM, Pohl H. 

Arch Intern Med, 157(14):1569-76 1997 Jul 28. 

In this study 11,186 medication-prescribing errors with a potential for adverse patient 

outcome were detected and averted by a staff pharmacist of a teaching hospital over a 9year 

period. The number of detected errors increased from 522 in the year 1987 to 2115 

in 1995, with a significant increased rate of errors per order written, per admission and 

per patient/day. 

6. Factors related to errors in medication prescribing. 

Lesar TS, Briceland L, Stein DS. 

JAMA, 277(4):312-7 1997 Jan 22-29. 

In this study, conducted on a 631-bed tertiary care teaching hospital, 2103 errors with a 

potential for adverse patient consequences were detected and averted over a 1-year 

period. Overall, the rate of errors was 3.99 per 1000 written orders. 

7. Medication prescribing errors in a teaching hospital. 

Lesar TS, Briceland LL, Delcoure K, Parmalee JC, Masta-Gornic V, Pohl H. 

JAMA, 263(17):2329-34 1990 May 2. 

In this study, conducted in a tertiary care teaching hospital, researchers detected and 

averted a rate of 3.13 medication-prescribing errors per 1000 physicians' written orders. 

In 58% of cases, the errors had a potential for adverse patient consequences. 

8. A look into the nature and causes of human errors in the intensive care unit. 

Donchin Y, Gopher D, Olin M, Badihi Y, Biesky M, Sprung CL, Pizov R, Cotev S. 

Crit Care Med, 23(2):294-300 1995 Feb. 

In this study, an estimated 1.7 errors per patient per day were detected in the intensive 

care unit (ICU) of a teaching hospital. For the whole ICU, an average of two severe or 

potentially detrimental errors occurred each day. 



91

9. Relationship between medication errors and adverse drug events. 

Bates DW, Boyle DL, Vander Vliet MB, Schneider J, Leape L. 

J Gen Intern Med 1995 Apr;10(4):199-205. 

This study evaluated the frequency of medication errors in a sample population of 379 

consecutive patients admitted to an urban tertiary care hospital. On average, 0.3 

medication errors per patient occurred each day, with half of these errors consisting of 

missing doses. About 1% of the medication errors resulted in adverse drug events. 

10. A computer alert system to prevent injury from adverse drug events: development and 

evaluation in a community teaching hospital. 

Raschke RA, et al. 

JAMA 1998 Oct 21;280(15):1317-20. 

In this study, a computer alert system was used in a 650-bed university hospital to 

identify prescription errors with the potential of causing adverse drug events. Errors with 

such potential were detected at a rate of 64 per 1000 admissions and were unrecognized 

by physicians prior to notification in 44% of cases. 

11. Improving prescribing patterns for the elderly through an online drug utilization 

review intervention: a system linking the physician, pharmacist, and computer. 

Monane M, Matthias DM, Nagle BA, Kelly MA. 

JAMA 1998 Oct 14;280(14):1249-52. 

In this study, a computer alert system was used to evaluate the appropriateness of 

medications prescribing in a cohort of 23,269 elderly patients. Overall, the system fired 

43,007 alerts for suboptimal medication. In 56% of cases, a pharmacist was able to notify 

the alert to a physician. Of the notified alerts, 24% resulted in change to a more 

appropriate drug. 

12. Inappropriate medication is a major cause of adverse drug reactions in elderly 

patients. 

Lindley CM, et al. 

Age Ageing 1992 Jul;21(4):294-300. 

This study evaluated the rate of prescribing of drugs with absolute contraindications or 

unnecessary, in a sample population of 416 elderly patients consecutively admitted to a 

teaching hospital. On admission, 11.5% of patients were receiving drugs with absolute 

contraindications, and 27% were receiving drugs that were unnecessary. Adverse drug 

reactions (ADRs) occurred in 27% of patients on medication, and half of these reactions 



92

were due to drugs with absolute contraindications or unnecessary. ADRs were the cause 

of hospital admission in 6.3% of patients, and were due to inappropriate prescribing (and 

were therefore avoidable) in half of the cases. 

13. Inappropriate medication prescribing for the elderly by office-based physicians. 

Aparasu RR, Fliginger SE. 

Ann Pharmacother 1997 Jul-Aug;31(7-8):823-9. 

The results of this study show that in 1992, 7.6% of individuals aged 65 and greater 

received at least 1 of 20 medications that should never be prescribed to the elderly, by 

their office-based doctor. The authors emphasize how the high rates of inappropriate 

prescribing by office-based doctor raises concerns on the quality of care they deliver. 

14. Inappropriate drug prescriptions for elderly residents of board and care facilities. 

Spore DL, Mor V, Larrat P, Hawes C, Hiris J. 

Am J Public Health 1997 Mar;87(3):404-9. 

The results of this study indicate that a minimum of 20% to 25% of elderly individuals 

living in board and care facilities receive at least one inappropriate medication (a drug 

that should be entirely avoided in this age group). 

15. Prescription of contraindicated and interacting drugs in elderly patients admitted to 

hospital. 

Gosney M, et al. 

Lancet 1984 Sep 8;2(8402):564-7. 

The results of this study, conducted on 573 elderly patients admitted to a teaching 

hospital, show that overall, 3.2% of the prescriptions they received before, during, or 

after hospital stay, were for drugs that were either contraindicated or that interacted 

adversely with other drugs. Overall, almost 24% of patients received a contraindicated or 

interacting drug. Approximately 84% of the inappropriate prescriptions were either 

preventable or probably preventable. 

16. Do too many cooks spoil the broth? Multiple physician involvement in medical 

management of elderly patients and potentially inappropriate drug combinations. 

Tamblyn RM; McLeod PJ; Abrahamowicz M; Laprise R. 

CMAJ, 154(8):1177-84 1996 Apr 15. 



93

This study shows that the prevalence of a potentially inappropriate drug combination 

(PIDC) in a population of elderly Medicare patients ranged from 4% to 20.3%. The 

greater the number of physician involved in patient care, the higher the risk of PIDC. 

17. A database analysis of potentially inappropriate drug use in an elderly medicaid 

population. 

Piecoro LT, Browning SR, Prince TS, Ranz TT, Scutchfield FD. 

Pharmacotherapy 2000 Feb;20(2):221-8. 

The results of this study, conducted on 64,832 elderly individuals, show that 27% of them 

had been prescribed at least one inappropriate medication. The rate of irrational 

prescribing was higher in nursing home residents (33%) than in outpatients (24%). 

ADVERSE DRUG REACTIONS AND ADVERSE EVENTS 

18. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of 

prospective studies. 

Lazarou J, Pomeranz BH, Corey PN. 

JAMA 1998 Apr 15;279(15):1200-5. 

This study analyzed 39 prospective U.S. studies to determine the incidence of serious and 

fatal adverse drug reactions (ADRs). Serious ADRs were defined as those requiring 

hospitalization or resulting in permanent damage. Only ADRs requiring hospital 

admission or occurring in the hospital were included in the analysis. Overall, the 

incidence of serious ADRs was 6.7 per 100 patients and that of fatal ADRs was 0.32 per 

100 patients. Extrapolation of these data to the entire U.S. population revealed that in 

1994 alone, over 2.2 million patients experienced a serious ADR and 106,000 died from 

this complication. These figures place ADRs between the fourth and sixth leading cause 

of death in the U.S. These are conservative estimates, since they don't take in 

consideration possible ADRs, errors in drug administration, patient non-compliance, 

overdose, drug abuse, therapeutic failures and injuries and deaths occurring in nursing 

home patients. 

19. Drug-related emergency department visits and hospital admissions. 

Prince BS, Goetz CM, Rihn TL, Olsky M. 

Am J Hosp Pharm 1992 Jul;49(7):1696-700. 



94

This study evaluated the prevalence of different drug-related illnesses in patients visiting 

the emergency department or admitted to the hospital at one institution during a 4-month 

period. Drug-related illnesses were found to account for 3% of emergency visits and 

resulted in hospital admission in approximately 1/4 of cases. Of interest, adverse drug 

reactions were not the most common type of drug-related illnesses. Overdose or abuse 

accounted for 35% of drug-related complications, followed by noncompliance (28%), 

adverse drug reactions (28%), toxicity (8%), and drug interaction (1%). 

20. The role of medication noncompliance and adverse drug reactions in hospitalizations 

of the elderly. 

Col N; Fanale JE; Kronholm P. 

Arch Intern Med, 150(4):841-5 1990 Apr. 

The results of this study, conducted on 315 elderly patients consecutively admitted to the 

hospital, show that in 28.2% of them, the cause of hospitalization was related to the 

medication they were taking, and was due to noncompliance with treatment in 11.4% of 

cases, and to adverse drug reactions in another 16.8%. 

21. Drug-related hospital admissions. 

Nelson KM, et al. 

Pharmacotherapy 1996 Jul-Aug;16(4):701-7. 

The results of this study indicate that 73 (16%) of 452 consecutive admissions to a 

hospital were for drug-related problems. Approximately 55% were due to drug failure, 

33% to adverse drug reactions and 12% to drug overdose. About half of the drug-related 

admissions were preventable. 

22. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. 

Singh G. 

Am J Med, 105(1B):31S-38S 1998 Jul 27. 

This study shows that each year, approximately 107,000 individuals are hospitalized for 

gastrointestinal (GI) complications derived from nonsteroidal anti-inflammatory drug 

(NSAID) use and that, among arthritis patients alone, at least 16,500 die as a 

consequence of NSAID use. These are conservative estimates, since they don't take into 

account gastrointestinal complications occurring in patients taking over-the-counter 

NSAIDs. If we consider that every year, in the U.S., there are over 70 million 

prescriptions written for NSAIDs, and over 30 billion tablets are sold over-the-counter, 

the number of injuries and death caused by only one type of adverse event related to 

NSAID use -gastrointestinal complications- reaches staggering figures. 



95

23. Incidence and types of preventable adverse events in elderly patients: population 

based review of medical records. 

Thomas, EJ. and Brennan TA. 

BMJ 2000;320:741-744 ( 18 March ). 

The results of this study show that hospitalized elderly patients have almost twice the risk 

of developing preventable adverse reactions, compared to younger patients. The study, 

conducted on 13 Utah' and 15 Colorado' hospitals, found that the incidence of adverse 

events leading to prolongation of hospital stay, disability or death in patients younger 

than 64 years of age is 2.8%, while that of patients aged 65 years or more is 5.3%. The 

incidence of preventable adverse events is 1.6% in younger patients and 3.0% in older 

ones, indicating that almost half of the adverse events that occur in hospitalized patients 

are preventable. Elderly patients, compared to younger ones, experience significantly 

higher rates of preventable adverse drug reactions, adverse events due to medical 

procedures, and falls. These data are likely to significantly underestimate the real 

incidence of adverse events in hospitalized patients, since adverse events were evaluated 

through medical chart documentation (where the occurrence of an adverse event is often 

not documented), the evaluation was performed by nurses and general practitioners (and 

not by specialists), their judgment of an adverse event was not always consistent, the 

study evaluated only adverse events that prolonged hospital stay or resulted in disability 

or death, and was conducted on hospitals that were not randomly selected. With this said, 

death due to preventable adverse events in hospitalized patients, still ranks at least as the 

8th cause of mortality in the U.S. 

24. Medication-related visits to the emergency department: a prospective study. 

Tafreshi MJ, Melby MJ, Kaback KR, Nord TC. 

Ann Pharmacother 1999 Dec;33(12):1252-7. 

The results of this study show that 28% of visits to the emergency room are related to 

medications. In the study, one physician and pharmacists evaluated prospectively the 

percentage of visits to the emergency room that were due to medications in a sample of 

253 consecutive patients. In 71 patients (28.1%) the cause of the visit was due to 

medications, either in the form of adverse drug reaction, or of overprescribing. Over twothirds 

of the reactions were judged to be preventable. Cardiovascular medications were 

the most frequent class of drugs implicated. The cost for each preventable drug-related 

visit was estimated at $1444. The article emphasizes that the high rate of drug-related 

visits found in the study is accounted for by the study design (prospective, observational 

study) and by the presence of drug experts in determining the presence of treatment- 

complications. 



96

25. Drug Complications in Outpatients. 

Gandhi TK, Burstin HR, Cook EF, Puopolo AL, Haas JS, Brennan TA, Bates DW. 

J Gen Intern Med. 2000 Mar;15(3):149-154. 

The results of this study show that almost 1 out of 5 patients who take prescription drugs 

experience a treatment-related complication. The study was conducted on 2,248 

randomly chosen patients from 11 ambulatory clinics in Massachusetts. Patient 

interviews and medical chart reviews were conducted to determine the frequency of drugrelated 

adverse reactions. Eighteen percent of patients reported complications from 

treatment, but only one-sixth of these adverse reactions were reported in the medical 

chart. Approximately 50% of patients who experienced an adverse reaction sought 

medical attention as a consequence of it, and 5% of them were hospitalized. These figures 

show that drug-related complications occur significantly more often than reported in 

patients' medical charts, leading to extensive utilization of the health care resources and 

patients' dissatisfaction with quality of care. This study is particularly important because 

presents rates of adverse drug reactions in outpatient settings, where most of the 

medications are given, and because reveals how the vast majority of adverse reactions are 

unreported. 

26. Adverse drug events in elderly patients receiving home health services following 

hospital discharge. 

Gray SL, Mahoney JE, Blough DK. 

Ann Pharmacother 1999 Nov;33(11):1147-53. 

The results of this study show that 20% of elderly individuals who are discharged after 

hospitalization on medications, experience drug-related adverse effects. The study was 

conducted on 256 individuals aged 65 or more, who were hospitalized for medical illness 

and who received, upon discharge, home health nursing services. Twenty-percent of them 

reported at least one adverse effect from treatment, which involved the gastrointestinal 

system in approximately one third of cases and the central nervous system in another 

third. Women and individuals with low cognition were particularly at risk of 

experiencing treatment-related adverse events. 

27. Incidence of adverse events and negligence in hospitalized patients. Results of the 

Harvard Medical Practice Study I. 

Brennan TA, et al. 

N Engl J Med 1991 Feb 7;324(6):370-6. 

This study evaluated the extent of injuries caused by medical management in a random 

population of over 30,000 patients hospitalized in the state of New York. Treatmentrelated 

injuries occurred in 3.7% of patients and were due to negligence in over a quarter 

of them. They led to disability lasting less than 6 months in 70% of patients, to permanent 



97

disability in 2.6% of cases, and to death in 13.6% of cases. Extrapolation of these data for 

the whole state of New York showed that in 1984, medical management in the state of 

New York alone injured approximately 100,000 patients, with 27,000 of these injuries 

being due to negligence. Elderly patients were particularly at risk of adverse reactions 

due to negligent care. When these data were later further analyzed (Leape et al. Qual Rev 

Bull 1993 May;19(5):144-9.), it was shown that two-thirds of the injuries was due to 

errors, and was therefore potentially preventable. 

28. Computerized surveillance of adverse drug reactions in hospital: implementation. 

Levy M, et al. 

Eur J Clin Pharmacol 1999 Jan;54(11):887-92. 

The results of this study, conducted on a sample population of 199 consecutive patients 

admitted to the medical ward of a hospital, indicate that adverse drug reactions (ADRs) 

were present in 32% of patients and were the cause of hospitalization in 9% of cases. 

Twenty-seven percent of ADRs were defined as serious. 

29. Incidence of adverse drug events and potential adverse drug events. Implications for 

prevention. ADE Prevention Study Group. 

Bates DW, et al. 

JAMA 1995 Jul 5;274(1):29-34. 

The results of this study, conducted on 4031 hospitalized patients from 11 different units 

of two tertiary care hospitals, show that the incidence of adverse drug events (ADEs) and 

potential ADEs in this cohort was 6.5% and 5.5%, respectively. One percent of all ADE 

were fatal, 12% life-threatening, 30% serious, and 57% significant. Forty-two percent of 

the serious and life-threatening ADEs were preventable. 

30. Incidence of adverse drug reactions in adult medical inpatients. 

Bowman L, Carlstedt BC, and Black CD. 

Can J Hosp Pharm 1994 Oct;47(5):209-16. 

This study estimated that 23.1% of patients admitted to the internal medicine ward of a 

hospital experience an adverse drug reaction (ADR). Length of hospital stay doubled 

in patients with ADR, compared to those without this complication. The severity of 

ADRs in this study was less than previously reported, with 10% of all ADRs judged to be 

severe, 53% moderate, and 36% mild. 



98

31. Adverse drug reaction-related hospitalizations of nursing facility patients: a 4-year 

study. 

Cooper JW. 

South Med J 1999 May;92(5):485-90. 

The results of this study indicate that one every 6-7 nursing home residents is 

hospitalized for adverse drug reactions (ADRs). The drugs more commonly involved in 

ADR-related hospitalizations are NSAIDs, psychotropic drugs (for inducing falls), 

digoxin and insulin. In the sample population evaluated in this study, 10% of patients 

experienced recurrent hospitalization for the same problem. The risk of being 

hospitalized increased with the number of medications that nursing home patients 

received. 

32. Iatrogenic complications in high-risk, elderly patients. 

Lefevre F, Feinglass J, Potts S, Soglin L, Yarnold P, Martin GJ, Webster JR. 

Arch Intern Med 1992 Oct;152(10):2074-80. 

This study evaluated the medical records of 120 elderly patients admitted to a large 

university hospital for congestive heart failure, acute myocardial infarction, or 

pneumonia, and found that in 58.3% of them, a minimum of one iatrogenic complication 

occurred. The complication was judged to be potentially preventable in 35.8% of 

patients. 

33. Adverse drug events in high risk older outpatients. 

Hanlon JT, et al. 

J Am Geriatr Soc 1997 Aug;45(8):945-8. 

This study evaluated the frequency of adverse drug events (ADEs) in a cohort of 167 

elderly ambulatory patients taking more than 5 scheduled medications. Fifty-eight 

patients (35%) reported 80 ADEs that were textbook confirmed, of which 95% were 

predictable. Eleven percent of patients with ADEs were hospitalized, 10% required an 

emergency room visit and 63% a physician consultation. 

34. Adverse drug events in hospitalized elderly. 

Gray SL, Sager M, Lestico MR, Jalaluddin M. 

J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M59-63. 

The results of this study, conducted on a cohort of 157 patients aged 70 and over 

consecutively admitted to the hospital, show that 14.6% of them experienced adverse 

drug reactions (ADRs), that were potentially preventable in half the cases. Upon 



99

discharge, 50% of patients with ADRs experienced a decline in one or more activities of 

daily living, compared to 24% of patients without ADRs. 

35. Adverse drug reactions in an elderly outpatient population. 

Schneider JK, Mion LC, Frengley JD. 

Am J Hosp Pharm 1992 Jan;49(1):90-6. 

This study, conducted on a cohort of 463 elderly outpatients, documented 107 adverse 

drug reactions (ADRs) that occurred in 97 (21%) individuals and caused the 

hospitalization of 12 of them. Attendance to a geriatric clinic, use of potentially 

dangerous drug combinations, and use of drugs requiring laboratory monitoring were all 

associated with an increased risk of experiencing ADRs. 

36. Hospital characteristics associated with adverse events and substandard care. 

Brennan TA, et al. 

JAMA 1991 Jun 26;265(24):3265-9. 

This study evaluated 31,000 medical charts from 51 randomly selected NY hospitals, and 

found that the incidence of patient injuries due to medical treatment varied from 0.2% to 

7.9% (mean 3.2%). Rates of adverse events were significantly higher in primary teaching 

hospitals (4.1%) compared to rural hospitals (1%). The percentage of adverse events due 

to negligence varied from 1 to 60% (mean 25%) and was significantly lower in teaching 

hospitals (10.7%) and significantly higher in hospital with a predominance of minority 

patients. 

37. Physician characteristics and prescribing for elderly people in New Brunswick: 

relation to patient outcomes. 

Davidson W; Molloy DW; Bédard M. 

CMAJ, 152(8):1227-34 1995 Apr 15. 

This study examined whether mortality and morbidity rates in a community of elderly 

patients in New Brunswick could be associated with any physician' personal, 

professional, or practice characteristic. The results of the study revealed that general 

practitioners with higher patients' mortality rates were more likely to be males, prescribed 

more drugs, had larger practices, saw more patients and billed more per year compared to 

doctors with lower mortality rates. In addition, the study found higher rates of hip 

fractures in patients of doctors who prescribed more frequently antihypertensives, 

bronchodilators, cholesterol-lowering agents, gastrointestinal drugs and non-steroidal 

antiinflammatory drugs, who had larger practices, and who billed more per year. 



100

38. An alternative strategy for studying adverse events in medical care. 

Andrews LB, Stocking C, Krizek T, Gottlieb L, Krizek C, Vargish T, Siegler M. 

Lancet 1997 Feb 1;349(9048):309-13. 

This study shows that the frequency of adverse drug reactions (ADRs) reported in 

medical records may not be a real representation of the actual rate at which these events 

occur. When trained observers recorded all ADRs discussed at clinical meetings, the 

actual incidence of serious ADRs among a study group of 1047 patients was 17.7%. With 

each day of hospital stay, the risk of experiencing an adverse event increased by 6%. 

39. The incident reporting system does not detect adverse drug events: a problem for 

quality improvement. 

Cullen DJ, Bates DW, Small SD, Cooper JB, Nemeskal AR, Leape LL. 

Jt Comm J Qual Improv 1995 Oct;21(10):541-8. 

The results of this study show that adverse drug events (ADEs) occurring in hospitalized 

patients are rarely reported to the hospital's quality assurance program. In particular, of 

the 55 ADEs that were detected during the study period, only 3 (6%) had been reported to 

the incident reporting system, even though 26 of them were serious or life threatening. 

Fifteen of the ADEs detected were considered preventable. These findings indicate that 

studies based on data gathered from voluntary reporting of adverse events may be 

underestimating the incidence of these complications by as much as 94%. 

40. Reporting of adverse drug reactions by hospital doctors and the response to 

intervention. 

McGettigan P, Golden J, Conroy RM, Arthur N, Feely J. 

Br J Clin Pharmacol 1997 Jul;44(1):98-100. 

The results of this study indicate that in Ireland only 45% of doctors from 118 hospitals 

had ever reported adverse drug reactions (ADRs). When reporting cards were made 

readily available by placing them inside the patient admission chart and doctors were 

regularly reminded to report ADRs, the frequency of reports increased by 5 times over a 

3-month period. However, the rate of reports declined rapidly after discontinuation of 

verbal reminders. 

41. Underreporting of suspected adverse drug reactions to newly marketed ("black 

triangle") drugs in general practice: observational study. 



101

Martin,M, et al. 

BMJ 1998;317:119-120 ( 11 July ). 

The results of this study show that physicians report only 9% of suspected adverse 

reactions to newly marketed drugs to the Committee on safety of Medicines. Although 

the highest rate of reporting was for serious adverse drug reactions, still only 32% of 

serious unlabelled reactions (those that are not listed in the accompanying drug 

information sheet) and 11% of serious labeled reactions were submitted to the 

Committee. These data indicate that the large majority of serious adverse drug reactions 

go unreported. 

42. Adverse drug reactions in a hospital general medical unit meriting notification to the 

Committee on Safety of Medicines. 

Smith CC, et al. 

Br J Clin Pharmacol 1996 Oct;42(4):423-9. 

The results of this study show that suspected adverse drug reactions (ADRs) occur in 

6.8% of patients admitted to the hospital and are responsible for the hospitalization in 3/4 

of cases. Only 6.3% of adverse drug reactions that, according to current guidelines, 

should have been notified to the Committee on Safety of Medicines had been actually 

submitted. The majority of unreported ADRs were for those that caused hospital 

admissions and involved mostly well-known complications to commonly used drugs. 

43. Differences in perceived and presented adverse drug reactions in general practice. 

Ottervanger JP, Valkenburg HA, Grobbee DE, Stricker BH. 

J Clin Epidemiol 1998 Sep;51(9):795-9. 

This study indicates that patients experience significantly more adverse drug reactions 

(ADRs) than what their physicians are aware of. ADRs to sumatriptan were evaluated 

through a questionnaire sent to physicians and their patients. To avoid bias, no specific 

reactions were listed in the questionnaire. The most frequent ADRs reported by patients' 

physicians were: dizziness (1.7%), nausea or vomiting (1.5%) drowsiness or sedation 

(1.4%) and chest pain (1.3%). Patients on the other hand reported dizziness (8.1%), chest 

pain (7.9%), paraesthesia (11.7%), and feeling of heaviness (8%). The authors conclude 

that post-marketing studies that utilize data from physicians could significantly 

underestimate the real incidence of adverse drug reactions. 

44. Postmarketing surveillance and adverse drug reactions: current perspectives and 

future needs. 



102

Brewer T, Colditz GA. 

JAMA 1999 Mar 3;281(9):824-9. 

This article illustrates how spontaneous reporting of adverse drug reactions (ADRs) is not 

a reliable indicator of the true occurrence of these events. Spontaneous reporting leaves 

potentially important ADRs undetected, since it cannot adequately assess the incidence of 

events occurring separated in time from treatment initiation, or consisting of symptoms 

occurring also in individuals not exposed to the drug. 

45. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs 

in general practice in England: analysis of 48 cohort studies. 

Martin RM, Biswas PN, Freemantle SN, Pearce GL, Mann RD. 

Br J Clin Pharmacol 1998 Nov;46(5):505-11. 

The results of this study, conducted on a cohort of over 510,000 patients, show that 

women have a 60% increased risk of developing an adverse drug reactions compared to 

men. Interestingly, the majority of clinical trials are conducted on men. 

46. Adverse drug events in hospitalized patients. A comparison of doctors, nurses and 

patients as sources of reports. 

van den Bemt PM, et al. 

Eur J Clin Pharmacol 1999 Apr;55(2):155-8. 

The results of this study, conducted on a sample population of 620 hospitalized patients, 

indicate that adverse drug events (ADEs) occur in 29% of patients. Serious ADEs 

comprised 26% of all ADEs reported by doctors, and were detected three-times as 

frequently by doctors than by their patients. Adverse reactions to new drugs, on the other 

hand, were reported more frequently by patients than by their doctors. 

47. Retrospective analysis of the frequency and recognition of adverse drug reactions by 

means of automatically recorded laboratory signals. 

Tegeder I, et al. 

Br J Clin Pharmacol 1999 May;47(5):557-564. 

This study evaluated retrospectively the incidence of adverse drug reactions in 

hospitalized patients through an automatic system (ALS) that fired signals every time 

laboratory results revealed abnormalities potentially indicative of an adverse drug 

reaction (ADR). Eighteen of 98 signals that were alerted were considered as probable 

ADRs after reviewing laboratory results and patients' charts. In two-thirds of the cases, 



103

the attending physician was not aware that an adverse drug reaction had occurred, even 

though 80% of the reactions were considered predictable. 

48. The nosocomial component of medical care. 

A prospective study on the amount, spectrum and costs of medical disturbances in a 

department of infectious diseases. 

Jorup-Ronstrom C, Britton S. 

Scand J Infect Dis Suppl 1982;36:150-6. 

The results of this study, conducted on a cohort of 1271 patients admitted to the 

infectious disease department of a hospital, show that 11% of the admissions were due to 

complications to previous medical treatment while 27% of patients developed adverse 

reactions during hospitalization. Overall, the cost for medical care-related adverse events 

accounted for 17% of the total department costs. 

49. Visits to office-based physicians in the United States for medication-related 

morbidity. 

Aparasu RR. 

J Am Pharm Assoc (Wash) 1999 May-Jun;39(3):332-7. 

This study indicates that in 1995, approximately 2 million outpatients visits occurred 

because of medication side effects, and the majority of these visits resulted in a scheduled 

follow-up visit. The drugs most frequently involved were hormones and synthetic 

substitutes (13%), followed by antibiotics (11.5%) and cardiovascular drugs (9%). These 

data indicate that adverse drug reactions leading to consultation of an office-based 

physician result in significant utilization of health care resources. 

50. Adverse reactions to antibiotic drugs: the present scope of the problem in outpatient 

care and possibilities for improvement. 

Hemminki E. 

Int J Health Serv 1981;11(2):283-301. 

This article shows that in 1974, in the U.S., physicians wrote an average of 1 antibiotic 

prescription for each inhabitant. Antibiotic-related adverse drug reactions (ADRs) and 

serious ADRs, occurred in 7.6% and 1.4% of the population, respectively. If antibiotics 

had been prescribed only when necessary, two-thirds of ADRs would have been 

prevented; if the drug of choice had been prescribed, 37% of ADRs would have been 

prevented. If the antibiotic of choice had been prescribed only when necessary, four fifth 

of all ADRs would have been avoided. 



104

51. Errors in the treatment of tuberculosis in Baltimore. 

Rao SN, Mookerjee AL, Obasanjo OO, Chaisson RE. 

Chest 2000 Mar;117(3):734-7. 

The results of this study show that private physicians often treat tuberculosis (TB) 

incorrectly, favoring the development of acquired drug resistance and multidrug resistant 

TB. The study was conducted on 110 patients diagnosed with TB in the city of Baltimore 

between 1994 and 1995. Almost 40% of patients treated by private physicians were 

prescribed the wrong treatment regimen, compared to 5% of those treated at the 

Baltimore City Health Department's Tuberculosis Clinic. Inappropriate management 

consisting of low-doses antibiotics and short treatment courses is an important cause of 

treatment failure and acquired antibiotic resistance. The authors estimated the costs of 

salvage of inadequate treatment at $180,000 per patient. 

52. Complications of care in a medical intensive care unit. 

Rubins HB, Moskowitz MA. 

J Gen Intern Med 1990 Mar-Apr;5(2):104-9. 

The results of this study indicate that 14% of patients admitted to a medical intensive care 

unit of a teaching hospital develop a complication from treatment. Patients with 

complications tend to be older and more severely ill, and have longer hospital stay and 

higher mortality rates, compared to those with uncomplicated course (67% vs. 27%). The 

authors conclude that since mortality rates in these patients exceeded significantly the 

expected mortality rate of 46%, it is conceivable that complications of care in the MICU 

independently contribute to in-hospital mortality. 

53. Acute renal failure: clinical outcome and causes of death. 

Barretti P; Soares VA. 

Ren Fail, 19(2):253-7 1997 Mar. 

This study shows that the incidence of acute renal failure (ARF) in hospitalized patients 

is 4.9/1000 patients. Over 46% of patients who develop ARF die. Nephrotoxic drugs are 

the main cause of ARF in 21% of cases. 

54. Incidence and characteristics of preventable iatrogenic cardiac arrests. 

Bedell SE, et al. 

JAMA 1991 Jun 5;265(21):2815-20. 



105

The results of this study, conducted on all patients hospitalized during a one-year period 

at Boston's Beth Israel Hospital, show that 28 (14%) of the 203 cardiac arrests suffered 

by patients had a iatrogenic cause (e.g. medications, medical procedures, or failure to 

detect warning signs). Sixty-one percent of patients with iatrogenic cardiac arrest died. 

Approximately 10% of all arrests were due to preventable physicians' errors (lack of 

attention to patients' history, to findings of physical examination, and to laboratory 

results). 

55. Iatrogenic congestive heart failure in older adults: clinical course and prognosis. 

Rich MW, et al. 

J Am Geriatr Soc 1996 Jun;44(6):638-43. 

This study shows that in 7% of patients aged 70 years or older hospitalized with heart 

failure the cause is iatrogenic, e.g. the heart failure is induced by medications, by 

excessive administration of fluids or by a complication of a medical procedure. In this 

study, in-hospital and one-year mortality rates in patients with iatrogenic heart failure 

were 32% and 68%, respectively, compared to 9% and 39% in noniatrogenic patients. 

Iatrogenic vs. noniatrogenic heart failure was associated with a 2.5-fold higher risk of 

death. 

56. Consumption of NSAIDs and the development of congestive heart failure in elderly 

patients: an underrecognized public health problem. 

Page J, Henry D. 

Arch Intern Med 2000 Mar 27;160(6):777-84. 

The results of this study indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are 

an important cause of hospitalization for congestive heart failure (CHF) in individuals 

with or without a history of heart disease. The study was conducted on 365 patients 

hospitalized for heart failure and 658 controls. Individuals who used NSAIDs in the 

previous week had a 2-fold increased risk of hospitalization for CHF, compared to nonusers. 

In patients with a history of heart disease, use of NSAIDs was associated with a 

10-fold increased risk of hospitalization for CHF. The risk increased with increasing 

doses of NSAIDs taken in the previous week, and was greater with NSAIDs of long 

versus short half-life. The authors concluded that NSAIDs could account for 

approximately 20% of hospitalizations for congestive heart failure. Heart failure affects 

approximately 4.6 million Americans and this condition represent the most common 

hospital discharge diagnosis among patients older than 65 years. If this association is 

casual, as the dose-response relation suggests, cardiovascular morbidity due to NSAIDs 

would surpass gastro-intestinal NSAID-related morbidity, which alone is responsible for 

a minimum of 105,000 hospitalizations and 16,500 deaths occurring each year in the U.S. 

The economic and health consequences of these findings are staggering. 



106

57. Hospitalizations with adverse events caused by digitalis therapy among elderly 

Medicare beneficiaries. 

Warren JL, McBean AM, Hass SL, Babish JD. 

Arch Intern Med 1994 Jul 11;154(13):1482-7. 

This study indicates that in 1987, more than 3 million Medicare recipients were taking 

digitalis. During a seven-year study period, among this cohort, 202,011 patients were 

hospitalized because of adverse reactions to digitalis. This means that, every year, for 

every 1,000 individuals taking digitalis, 8.53 are hospitalized for adverse drug reactions 

to the drug. 

58. Contribution of adverse drug reaction to admission rates in an acute psychiatric ward. 

Hermesh H, et al. 

Acta Psychiatr Scand 1985 Jul;72(1):104-10. 

The results of this study show that 7.5% of all admission to an acute psychiatric ward, are 

due to adverse drug reactions. The elderly are particularly at risk of experiencing drugrelated 


59. Adverse drug reactions (ADRs) in patients with HIV infection. A prospective study. 

Gonzalez-Martin G, et al. 

Int J Clin Pharmacol Ther 1999 Jan;37(1):34-40. 

In this study, the frequency of adverse drug reactions (ADRs) evaluated in a cohort of 50 

ambulatory patients with HIV infection was 32%. In 18.5% of patients ADRs were 

severe and in 70.4% moderate. Trimethroprim-sulfamethoxazole and zidovudine were the 

most frequent cause of ADRs. Withdrawal of the responsible drug was required in 50% 

of cases. 

60. Survey of drug-related deaths in Victoria. 

Coleridge J; Cameron PA; Drummer OH; McNeil JJ. 

Med J Aust, 157(7):459-62 1992 Oct 5. 

This study evaluated the cause of death in a sample of 231 drug-related deaths reported in 

Victoria. The primary cause of death was attributed to heroin and morphine in 35% of 

cases and to prescription drugs in 47% of cases. Tricyclic antidepressants and 

benzodiazepines were responsible for 14% and 6.5% of deaths, respectively. The mode of 

death was unclear in most cases and could have been other than suicide. 



107

61. The manner of death among fatalities where dextropropoxyphene caused or 

contributed to death. 

Jonasson B; Jonasson U; Saldeen T. 

Forensic Sci Int, 96(2-3):181-7 1998 Sep 28. 

In this study, blood sample analyses from 23,691 deceased individuals were evaluated for 

presence of dextropropoxyphene (DXP), one of the most frequently prescribed painmedication 

in Sweden. DXP was found in 1782 samples (7.5%) and was the cause of 

death in 54% of these cases. 

62. Deaths related to iodinated contrast media reported spontaneously to the U.S. Food 

and Drug Administration, 1978-1994 

Effect of the availability of low-osmolality contrast media. 

Spring DB; Bettmann MA; Barkan HE. 

Radiology, 204(2):333-7 1997 Aug. 

This study evaluated the number of iodinated contrast medium-related deaths reported to 

the U.S. Food and Drug Administration Spontaneous Reporting System from 1967 to 

1994. Over a thousand deaths were reported during that period, 855 of which occurred 

after 1978. There was a 42% increase in deaths each year from 1987 to 1994 mostly 

associated with use of nonionic contrast media. 

63. Reports of 355 transfusion-associated deaths: 1976 through 1985. 

Sazama K. 

Transfusion, 30(7):583-90 1990 Sep. 

This study describes 256 blood transfusion-related deaths reported to the Food and Drug 

Administration from 1976 to 1985. Fifty-one percent of these deaths were due to 

transfusion of incompatible blood products. 

64. Autologous donation error rates in Canada. 

Goldman M, Remy-Prince S, Trepanier A, Decary F. 

Transfusion 1997 May;37(5):523-7. 

This study shows that although use of autologous blood transfusions should eliminate 

certain risks associated with transfusions, the possibility of errors, mainly clerical, is still 

high, with a detected rate of 1 error for every 149 units transfused. 



108

65. Wristband identification error reporting in 712 hospitals. 

A College of American Pathologists' Q-Probes study of quality issues in transfusion 

practice. 

Renner SW, Howanitz PJ, Bachner P. 

Arch Pathol Lab Med 1993 Jun;117(6):573-7. 

Wristband identification of patients is essential to prevent incompatible blood 

transfusions. This study detected wristband identification errors in 2.2% of patients from 

712 hospitals. Absent wristband was the error most frequently encountered, followed by 

multiple wristbands with different information, incomplete, erroneous and illegible data, 

and patient wearing another patient' wristband. 

ADVERSE DRUG REACTIONS AND ERRORS IN CHILDREN 

66. Drug utilization and reported adverse reactions in hospitalized children. 

Mitchell AA, Goldman P, Shapiro S, Slone D. 

Am J Epidemiol 1979 Aug;110(2):196-204. 

This study estimated the frequency of adverse clinical events in a cohort of 1669 

hospitalized children at 45.7%. Approximately 17% of the adverse events were drugrelated. 

67. A prospective study of adverse drug reactions as a cause of admission to a paediatric 

hospital. 

Martinez-Mir I, et al. 

Br J Clin Pharmacol 1996 Sep;42(3):319-24. 

The results of this study indicate that 4.3% of 512 consecutive hospital admissions of 

children 1 to 24 months old were probably drug-related. Respiratory drugs, antibiotics, 

drugs active on the central nervous system and dermatological drugs were the agents 

most frequently involved. 

68. A prospective study of adverse drug reactions in hospitalized children. 

Martinez-Mir I, Garcia-Lopez M, Palop V, Ferrer JM, Rubio E, Morales-Olivas FJ. 

Br J Clin Pharmacol 1999 Jun;47(6):681-8. 



109

The results of this study, conducted on a cohort of 512 consecutive pediatric patients 1 to 

24 months old admitted to the medical ward of a hospital, show that the incidence of 

adverse drug reactions (ADRs) in this study group was 16.6%. Girls had a 66% higher 

risk of ADRs. Antibiotics and vaccines were the most frequent cause of ADRs (41.5%). 

69. Adverse drug reactions (ADRs) in hospitalized pediatric patients. A prospective 

study. Gonzalez-Martin G, Caroca CM, Paris E.Int J Clin Pharmacol Ther 1998 

Oct;36(10):530-3. 

The results of this study show that 13.7% of children admitted to the hospital develop an 

adverse drug reaction (ADR). Ninety-three percent of the ADRs were dose-dependent. 

Twenty-eight percent were severe and 51% were moderate. Causality assessment 

determined that 54% of ADRs were probable and 32% possible. 

70. Medication errors in paediatric practice: insights from a continuous quality 

improvement approach. 

Wilson DG; et al. 

Eur J Pediatr, 157(9):769-74 1998 Sep. 

In this prospective study, a multidisciplinary committee evaluated over a 2-year period 

the incidence of medication errors in pediatric patients. The committee detected 411 

errors that occurred in 682 children. Sixty-eight percent of errors were averted prior to 

drug administration, 24 errors with potential for serious patient adverse reactions were 

not detected in advance and caused overt clinical consequences in 4 cases. 

71. Errors by paediatric residents in calculating drug doses. 

Rowe C; Koren T; Koren G. 

Arch Dis Child, 79(1):56-8 1998 Jul. 

This article shows that a significant number of physicians specializing in childcare 

prescribe the wrong dose of medication to infants and children. This finding is important, 

since inappropriate dosage in this age group may be associated with significant morbidity 

and mortality. Approximately 10% of residents who participated in this study committed 

a 10-fold dosage error, which may be life threatening. 

72. Prevalence of feeding tube placement errors & associated risk factors in children. 

Ellett ML; Maahs J; Forsee S. 

MCN Am J Matern Child Nurs, 23(5):234-9 1998 Sep-Oct. 



110

The results of this study, conducted on a cohort of 201 hospitalized children who had an 

enteral tube inserted, show that in approximately 14% of them the feeding tube was 

misplaced (e.g. the tip of the tube was in the esophagus and in the intestine when it was 

meant to be in the stomach, or in the esophagus and stomach when it was meant to be in 

the intestine). 

SURGICAL COMPLICATIONS 

73. The nature of adverse events in hospitalized patients. 

Results of the Harvard Medical Practice Study II. 

Leape LL, et al. 

N Engl J Med 1991 Feb 7;324(6):377-84. 

This study analyzed the medical records of 30,195 randomly selected in-hospital patients 

and found that the incidence of patient injuries due to medical treatment was 3.7%. Fortyeight 

percent of events were due to surgical procedures, 19% to drug-related 

complications, 14% to wound infections, and 13% due to technical complications. 

74. Proportion of hospital deaths associated with adverse events. 

Garcia-Martin M, et al. 

J Clin Epidemiol 1997 Dec;50(12):1319-26. 

This study shows that 56% of hospital deaths secondary to adverse events are due to 

surgical complications and 22% are due to hospital-related infections. 

75. The incidence and nature of surgical adverse events in Colorado and Utah in 1992. 

Gawande AA, Thomas EJ, Zinner MJ, Brennan TA. 

Surgery 1999 Jul;126(1):66-75. 

This study evaluated the medical records of 15,000 patients hospitalized in Utah and 

Colorado, and found that the incidence of surgical adverse events in this cohort was 

3.0%. Fifty-four percent of surgical adverse events were preventable and this type of 

complication accounted for 12.2% of all hospital deaths occurring in Utah and Colorado. 



111

76. Are in-hospital deaths and long stay markers for errors in surgery? 

Troëng T; Janzon L. 

Qual Assur Health Care, 2(2):149-59 1990. 

In this study, surgical errors were found in the care of 23% of patients who died in the 

hospital during a 1-year study period, in 10% of those who had a long hospital stay, and 

in 3% of those referred to other departments. 

NURSING HOME PROTOCOL 

THE SOLUTION 

The problems of malnutrition and dehydration are due in particular to the institutional 

food provided by vendors who have used RDA’s which have been shown to be: a) 

insufficient and b) grossly inadequate for people who have compromised immune 

systems and multiple nutritional deficiencies. 

We offer a detailed examination of the scientific literature citing actual therapeutic 

dosages in relation to the category of illnesses that affect a nursing home population. 

We conclude, after reviewing thousands of scientific articles and using data from test 

groups of 300 individuals, most of whom are in senior citizen age groups, that nutrition 

and exercise, as presented in this proposed protocol, play a key role in the health and 

well-being of senior citizens. 

7 

In January, 1997, 300 seniors were enrolled in a "Reverse the Aging Process Study" that 

ran for 18 months. Sixty-five people completed the study; 235 became controls. This was 

a lifestyle modification study that measured changes in blood chemistry, weight, physical 

dimensions, physical appearance, memory, energy levels, sleep patterns, bowel 

movements, night time urination, muscle strength, digestion, olfactory senses, visual 

senses, tactile senses, skin texture, hair texture, and stress levels. 

The results of the study showed that of the 65 participants that completed 

the study: 

1. 52% had lower cholesterol and triglyceride levels 

2. 68% had increased DHEA levels 

3. 78% had a significant improvement in their fat to muscle ratio 

4. 90% had an increase in bowel movements 

5. 92% had a decreased need for sleep 

6. 95% had increased energy levels 

7. 97% had lowered stress levels 

Additional data from numerical diaries kept by participants reflected 

subjective data, citing improvements in overall quality of life. 

We propose that this protocol would benefit the vast majority of people in 



112

nursing homes and hospices. We offer the anecdotal case history of Harry Biele as an 

example of our protocol. Harry is a 90 year-old man who just 10 years ago had chronic 

sinusitis, asthma, arthritis, enlarged prostate, a precancerous lower bowel and main 

coronary artery blockage. He is now a marathoner living life to its fullest. His 

cardiologist has taken him off his heart medication, including beta blockers, and his 

general practitioner has taken him off his asthma inhalers. He is not an exception. Harry 

is an example of someone who has taken positive action toward his own health. He 

improved his nutrition by applying a protocol similar to this one. Exercise became part of 

Harry’s daily ritual. He now appears to be closer to 70 than 90. 

NURSING HOME INTERVENTION PROTOCOL 

The nursing home intervention protocol consists of a) diet, b) supplementation, c) 

exercise. 

DIET 

1. Intake of animal protein should be reduced (1 x week) and consumption of cold-water 

fish should be increased (3 x week). 

2. Additional protein should be derived from whole grains, legumes and seeds. If needed 

a protein powder supplement may be used. 

3. The diet should provide 40-50 grams of fiber a day. 

4. At least one (preferably 3) serving of a cruciferous vegetable should 

be provided daily: Brussell sprouts, broccoli, cabbage, or cauliflower. 

5. 1-2 glasses of dark green leafy vegetable juices/day. The juice should also include 1inch 

length of ginger, aloe concentrate and protein powder (optional). 

6. 1/2-1 gallon of water ingested/day. 

7. Caffeine, soda, white sugar, and refined white flour products should 

be reduced to a minimum. For optimal results, they should be 

eliminated completely. 

8. Olive oil should be used for cooking purposes. 

9. Supplements should be taken with meals in divided doses where noted. 

Following the description of the supplement protocol there are detailed peer 

review journal articles of human studies and trials demonstrating the 

efficacy and suggested dosages of vitamins, nutrients, and herbs. 



113

Vitamins, Nutrients & Herbal Supplements 

9 

SEE TABLES 

Physical Exercise 

It is no secret anymore: exercise is a very important element in the overall health of 

people of all ages. However, as we age our tendons shrink and our muscle mass 

decreases. So in order to keep the body as youthful as possible, muscle mass needs to be 

retained, and if possible, increased. Tendons need to be stretched. So as we get older we 

actually need more exercise and longer stretching. All forms of exercise should be 

preceded with a thorough stretching routine. Stretching will elongate and strengthen the 

tendons and get the muscles warmed up and ready for movement. Senior citizens in 

general will take a longer time to warm up. 

Some exercises that are recommended for senior citizens are: fast walking, low impact 

aerobics, weight lifting, Yoga (for stretching), treadmill and the stair climbing machine. 

All exercises that are not too impacting on the joints are beneficial. 

We learned in our Reversing the Aging Process Study that most of the participants and 

100% of the controls were not exercising properly. They were not doing enough exercise 

and not exercising with enough intensity. 

Our exercise protocol is modified specifically for senior citizens: 

a) Build up gradually to 45 minutes/day of aerobic activity. 

b) Take the pulse during a workout to maintain the target heart rate. A 

heart rate monitor is very useful and can be purchased at any local sports 

store. Generally, the target heart rate is determined by taking 220, 

subtracting your age (this is the maximal heart rate), and then multiplying 

the result by 50%-60%. Therefore, an 81 year-old person would have a rate 

of 220 minus 81 times 50%-60%, or 70 to 83 beats per minute. After a few 

months of training, increase to 70% of the maximal heart rate. 

c) As well as aerobic exercise, do weight training 3 times per week. 

Vitamins, Nutrients & Herbal 

Supplements 

Suggested 

Dosages 

Dosages Based on Peer- 

Review Journal Articles** 

B Complex 50 mg 10-200 mg 

B6 25-75 mg 50-200 mg 

Folic Acid 400 mcg 2.5-35 mg 

B12 100 mcg 1,000 mcg-3 mg 



114

Choline 500 mg 500 mg-16,000 mg 

Vitamin E 400-800 IU 30-4,800 mg 

L-Methionine 500 mg 2,000-10,000 mg 

Vitamin C 2,000-15,000 mg 30-17,000 mg 

Silybum Marianum 50 mg 140-600 mg 

Garlic 500 mg 4xday 3,000-10,000 mg 

Evening Primrose Oil 500 mg 2xday 3,000-6,000 mg 

Fish oil lipids 1,000 mg 2,600-24,000 mg 

Ginkgo Biloba 60-120 mg 50-600 mg 

Lecithin/Choline 5 gm 0.500 gm-16 gm 

N-Acetyl Cysteine 500-1,000 mg 300 mg-42,000 mg 

DHEA 25 mg 30-500 mg 

DMAE 200 mg 

Phosphatidyl serine 200 mg 3xday 50-800 mg 

Acetyl L-Carnitine 500 mg 2xday 1,000-3,000 mg 

Co-enzyme Q-10 100-300 mg 30-390 mg 

Calcium/Magnesium 800-1,400 mg 1,000-1,400 mg (Ca++) 

Niacin 100-500 mg 500-3,000 mg 

Glutathione 500-1,000 mg 2,500-5,000 mg 

Curcumine 250 mg 500 mg 

Alpha Lipoic Acid 200 mg 100-600 mg 

Melatonin 5 mg 0.3-75 mg 

Pregnenolone 10 mg 70 mg (based on 70 kg male) 

Precursors to growth Hormone 

Arginine 1,000 mg 4,000-35,000 mg 

Ornithine 1,000 mg 10,000-18,000 mg 

Glutamine 1,000 mg 1,500-4,000 mg 

TMG-Betaine 500 mg 6,000-20,000 mg 

Linoleic acid (Conjugated FA) 500 mg 

Herbs for Cleansing 

Apple pectin 25-50 mg 8,500-20,000 mg 

Bee Pollen 25-50 mg 

Burdock root 25-50 mg 

Chrysanthemum 25-50 mg 

Dandelion root 25-50 mg 

Hibiscus 25-50 mg 

Kelp 25-50 mg 

Oregano 25-50 mg 

Peppermint 25-50 mg Enteric-coated capsules 

Psyllium 25-50 mg 3,400-15,000 mg 

Red clover 25-50 mg 100 mg (Coumarin) 

Vitamin and Mineral Indexes 

Nutrients Recommended 

Adult Intake 

Source of 

Recommended 



115

Intake 

Therapeutic Intake Range 

based on Peer-Review 

Journals** 

Vitamin A 5,000 IU USRDA* 

Vitamin D 400 IU USRDA 

Vitamin E 30 IU USRDA 30-2,800mg 

12 

Vitamin C 60 mg RDA* 30-17,000mg 

Thiamin (B1) 1.5 mg USRDA 10-200mg 

Riboflavin (B2) 1.7 mg USRDA 10-400mg 

Niacin (B3) 

(nicotinamide) 

20 mg USRDA 500-3,000mg 

Pyridoxine (B6) 2.0 mg RDA 50-200mg 

Folacin 0.4 mg USRDA .02mg-35mg Folic acid 

Biotin 0.3 mg USRDA 

Pantothenic acid 

(B5) 10 mg USRDA 

Calcium 1,200 mg RDA 1,000-1,400mg 

Phosphorus 1,200 mg RDA 

Magnesium 400 mg USRDA 

Iron 18 mg USRDA 

Zinc 15 mg USRDA 

Copper 3 mg ESAADDI* 

Fluoride 4 mg ESAADDI 

Iodine 0.15 mg USRDA 

Selenium 0.2 mg ESAADDI 

*RDA-Recommended Dietary Allowances; USRDA-United States Recommended Daily 

Allowances; ESAADDI-Estimated Safe and Adequate Daily Dietary Intakes. 

Shils, et al. 1994. Modern Nutrition in Health and Disease, Eighth Edition Volume 2. Lea 

& Febiger, p. 1582. 

**The therapeutic doses are based on Peer-Review Journals with a focus on human trials 

and studies. These articles are cited within the proposal. Please refer to the Reference 

Section for details. 

All senior citizens and baby boomers can improve their health. This is the 

scientific literature that justifies the use of recommended supplements in 

this protocol. Applying this protocol can play an important role in anyone’s 

life. 

Peer-Review Journal References for Vitamins, Nutrients and Herbs 

B-Complex 

B1 

Alzheimer's disease 



116

Gold M, Hauser RA, Chen MF. Plasma thiamine deficiency associated with 

Alzheimer's disease but not Parkinson's disease. Metab Brain Dis. 1998 

Mar;13(1):43-53. 

Mimori, Y. et al. 1966. Thiamine therapy in Alzheimer's disease. Metab Brain 

Disease, 11(1), Mar., 89-94. 

Dose: 100mg/day, 12 weeks 

Cardiovascular/Coronary Heart Disease 

Ito M, Tanabe Y, Suzuki K, Kumakura M, Aizawa Y. Shoshin beriberi with 

vasospastic angina pectoris possible mechanism of mid-ventricular obstruction: possible 

mechanism of mid-ventricular obstruction. Circ J. 2002Nov;66(11):1070-2. 

Shimon, I. et al. 1995. Improved left ventricular function after thiamine 

supplementation in patients with congestive heart failure receiving longterm 

Furosemide therapy. Am J Med, 98(5), 485-490. 

Dose: 200mg day 

Freye and Hartung, E. 1982. The Potential use of thiamine in patients with 

cardiac insufficiency. Acta Vitamino Enzymol, 4(4), 285-290. 

Dose: 50mg/kg 

Epilepsy 

Naito E, Ito M, Yokota I, Saijo T, Chen S, Maehara M, Kuroda Y. Concomitant 

administration of sodium dichloroacetate and thiamine in west syndrome 

caused by thiamine-responsive pyruvate dehydrogenase complex 

deficiency. J Neurol Sci. 1999 Dec 1;171(1):56-9. 

Botez, M. I. et al. 1993. Thiamine and folate treatment of chronic epileptic 

patients: A controlled study with the Wechsler IQ scale. Epilepsy Res, 

16(2), Oct., 157-163. 

Fatigue 

Heap LC, Peters TJ, Wessely S. Vitamin B status in patients with chronic 

fatigue syndrome. J R Soc Med. 1999 Apr;92(4):183-5. 

Suzuki, M. and Itokawa, Y. 1996. Effects of thiamine supplementation on 

exercise-induced fatigue, Metabolic Pr Brain Dis., 11(1), Mar., 95-106. 

Febrile Lymphadenopathy 

Lonsdale D. Recurrent febrile lymphadenopathy treated with large doses of 

vitamin B1: report of two cases. Dev Pharmacol Ther. 1980;1(4):254-64. 

Lonsdale, D. 1980. Recurrent febrile lymphadenopathy treated with large 

doses of vitamin B1: Report of two cases. Dev Pharmacol Ther., 1(4), 254- 

264. 



117

General 

Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T. Thiamine treatment 

in psychiatry and neurology. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20. 

Meador, K. J. et al. 1993. Evidence for a clinical cholinergic effect of highdose 

thiamine. Ann Neurol, 34(5), Nov., 724-726. 

Smidt, L. J. et al. 1991. Influence of thiamin supplementation on the health 

and general well-being of an elderly Irish population with marginal thiamin 

deficiency. J Gereontology, 46(1), Jan., M16-22. 

Dose: 10mg/day 

Lactic Acidosis 

McComsey GA, Lederman MM. High doses of riboflavin and thiamine may 

help in secondary prevention of hyperlactatemia. AIDS Read. 2002 

May;12(5):222-4. 

Klein, G. et al. 1990. [Life-threatening lactic acidosis during total parenteral 

nutrition. Successful therapy with thiamine]. Dtsch Med Wochenschr, 

115(7), Feb., 254-256. 

Dose: 400mg 

Liver Disease 

Levy S, Herve C, Delacoux E, Erlinger S. Thiamine deficiency in hepatitis C 

virus and alcohol-related liver diseases. Dig Dis Sci. 2002 Mar;47(3):543-8. 

15 

Hassan, R. et al. 1991. Effect of thiamine on glucose utilization in hepatic 

cirrhosis. J Gastroenterology Hepatology, 6(1), Jan.-Feb., 59-60. 

Dose: 50 mg/day for 30 days 

Rossouw, J. E. et al. 1978. Red blood cell transketolase activity and the 

effect of thiamine supplementation in patients with chronic liver disease. 

Scandinavian J Gastroenterology, 13(2), 133-138. 

Dose: 200 mg/day 

Seasonal Ataxia 

Nishimune T, Watanabe Y, Okazaki H, Akai H. Thiamin is decomposed due to 

Anaphe spp. entomophagy in seasonal ataxia patients in Nigeria. J Nutr. 

2000 Jun;130(6):1625-8. 

Adamolekun, B. et al. 1994. A double-blind, placebo-controlled study of the 

efficacy of thiamine hydrochloride in a seasonal ataxia in Nigerians. 

Neurology, 44(3 Pt 1), Mar., 549-551. 



118

Surgical Stress 

Vinogradov, V. V. et al. 1981. [Thiamine prevention of the corticosteroid 

reaction after surgery]. Probl Endokrinol, 27(3), May-June, 11-16. 

Dose: IV administration of 0.12 g one day and 1.5-2 hours prior to surgery 

B2 

Congenital Methaemoglobinaemia 

Svecova D, Bohmer D. Congenital and acquired methemoglobinemia and its 

therapy. Cas Lek Cesk. 1998 Mar 23;137(6):168-70. 

Hirano, M. et al. 1981. Congenital methaemoglobinaemia due to NADH 

methaemoglobin reductase deficiency: Successful treatment with oral 

riboflavin. British J Haematology, 47(3), Mar., 353-359. 


Depression 

Tolmunen T, Voutilainen S, Hintikka J, Rissanen T, Tanskanen A, Viinamaki H, 

Kaplan GA, Salonen JT. Dietary folate and depressive symptoms are 

associated in middle-aged Finnish men. J Nutr. 2003 Oct;133(10):3233-6. 

Bell, I. R. et al. 1992. Brief communication. Vitamin B1, B2, and B6 

augmentation of tricyclic antidepressant treatment in geriatric depression 

with cognitive dysfunction. J Am Coll Nutr., 11(2), Apr., 159-163. 

Dose: 10mg B1, B2 and B6 each with antidepressants 

Migraine 

Mauskop A. Alternative therapies in headache. Is there a role? Med Clin 

North Am. 2001 Jul;85(4):1077-84. 

Schoenen, J. et al. 1994. High-dose riboflavin as a prophylactic treatment of 

migraine: Results of an open pilot study. Cephalalgia, 14(5), Oct., 328-329. 

Dose: 400mg for at least 3 months 

Sickle Cell Disease 

Ajayi OA, George BO, Ipadeola T. Clinical trial of riboflavin in sickle cell 

disease. East Afr Med J. 1993 Jul;70(7):418-21. 

Ajayi, O. A. et al. 1993. Clinical trial of riboflavin in sickle cell disease. East 

African Med J, 70(7), 418-421. 

Dose: 5mg 2x/day for 8 weeks 

B6 

Anemia 

Shoolingin-Jordan PM, Al-Daihan S, Alexeev D, Baxter RL, Bottomley SS, Kahari 

ID, Roy I, Sarwar M, Sawyer L, Wang SF. 5-Aminolevulinic acid synthase: 

mechanism, mutations and medicine. Biochim Biophys Acta. 2003 Apr 

11;1647(1-2):361-6. 

Toriyama, T. et al. 1993. Effects of high-dose vitamin B6 therapy on 



119

microcytic and hypochromic anemia in hemodialysis patients. Nippon 

Jinzo Gakkai Shi 35(8), Aug., 975-980. 

Dose: 180mg for 20 weeks 

Asthma 

Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail". Altern Med 

Rev. 2002 Oct;7(5):389-403. 

Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak 

WJ. The effect of a subnormal vitamin B-6 status on homocysteine 

metabolism. J Clin Invest. 1996 Jul 1;98(1):177-84. 

Collipp, P. J. et al. 1975. Pyridoxine treatment of childhood bronchial asthma. Ann 

Allergy 35(2), Aug., 93-97.Dose: 200mg/day 


Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteinelowering 

therapy with folic acid, vitamin B12, and vitamin B6 on clinical 

outcome after percutaneous coronary intervention: the Swiss Heart study: 

a randomized controlled trial. JAMA. 2002 Aug 28;288(8):973-9. 

Van den Berg, M. et al. 1994. Combined vitamin B6 plus folic acid therapy in 

young patients with arteriosclerosis and hyperhomocysteinemia. J 

Vascular Surg. 20(6), Dec., 933-940. 

Dose: 250mg for 6 weeks 

Ellis, J. M. and McCully, K. S. 1995. Prevention of myocardial infarction by 

vitamin B6. Res Commun Mol Pathol Pharmac 89(2) Aug., 208-220. 

Carpal Tunnel Syndrome 

Holm G, Moody LE. Carpal tunnel syndrome: current theory, treatment, 

and the use of B6. J Am Acad Nurse Pract. 2003 Jan;15(1):18-22. 

Ellis, J. et al. 1979. Clinical results of a cross-over treatment with 

pyridoxine and placebo of the Carpal Tunnel Syndrome. Am J Clin Nutr 

32(10), Oct., 2040-2046. 


Kasdan, M. L. and Janes, C. 1987. Carpal Tunnel Syndrome and vitamin B6. 

Plastic Reconstructive Surgery 79(3), Mar., 456-462. 


Stransky, M. et al. 1989. Treatment of Carpal Tunnel Syndrome with vitamin 



120

B6: A double-blind study. Southern Med J 82(7), July, 841-842. 

Ellis, J. M. 1987. Treatment of Carpal Tunnel Syndrome with vitamin B6. 

Southern Med J 80(7), July, 882-884. 

Dose: 100mg to 200mg/day for 12 weeks 

Guzman, F. J. L. et al. 1989. Carpal Tunnel Syndrome and vitamin B6. Klin 

Wochenschr, 67(1), Jan. 4, 38-41. 

Dose: 150mg/day for 3 months 

Ellis, J. et al. 1981. Therapy with vitamin B6 with and without surgery for 

treatment of patients having the Idiopathic Carpal Tunnel Syndrome. Res 

Commun Pathol Pharmacol 33(2) Aug., 331-344. 

Diabetes 

Okada M, Shibuya M, Yamamoto E, Murakami Y. Effect of diabetes on vitamin 

B6 requirement in experimental animals. Diabetes Obes Metab. 1999 

Jul;1(4):221-5. 

Bennink, H. J. and Schreurs, W. H. 1975. Improvement of oral glucose 

tolerance in gestational diabetes by pyridoxine. Br Med J 3(5974), 13-15. 

Immune Function 

Grimble RF. Effect of antioxidative vitamins on immune function with 

clinical applications. Int J Vitam Nutr Res. 1997;67(5):312-20. 

Casciato, D. A. et al. 1984. Immunologic abnormalities in hemodialysis 

patients: Improvement after pyridoxine therapy. Nephron 38(1), 9-16. 

Dose: 50mg/day for 3-5 weeks 

Primary Hyperoxaluria 

van Woerden CS, Groothoff JW, Wanders RJ, Davin JC, Wijburg FA. Primary 

hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol 

Dial Transplant. 2003 Feb;18(2):273-9. 

Milliner, D. S. et al. 1994. Results of long-term treatment with 

orthophosphate and pyridoxine in patients with primary 

hyperoxaluria. NEJM. 331(23), Dec. 8, 1553-1558. 

B12 

Anemia 

de Lonlay P, Fenneteau O, Touati G, Mignot C, Billette de Villemeur T, Rabier D, 

Blanche S, Ogier de Baulny H, Saudubray JM. Hematologic manifestations of 

inborn errors of metabolism. Arch Pediatr. 2002 Aug;9(8):822-35. 



121

Samson, D. et al. 1977. Reversal of ineffective erythropoiesis in pernicious 

anaemia following vitamin B12 therapy. Br J Haematology 35(2), Feb., 217- 

224. 

Kafetz, K. 1985. Immunoglobulin deficiency responding to vitamin B12 in 

two elderly patients with megaloblastic anaemia. Postgrad Med J 61(722), 

Dec., 1065-1056. 

Kubota, K. et al. 1987. Restoration of decreased suppressor cells by 

vitamin B12 therapy in a patient with pernicious anemia. Am J Hematol 

24(2), Feb., 221-223. 

Kubota, K. et al. 1992. Restoration of abnormally high CD4/CD8 ratio and 

low natural killer cell activity by vitamin B12 therapy in a patient with postgastrectomy 

megaloblastic anemia. Internal Med 31(1), Jan., 125-126. 

Apthae 

Wray, D. et al. 1975. Recurrent aphthae: Treatment with vitamin B12, folic 

acid, and iron. British Med J 2(5969), May 31, 490-493. 

Bronchial Squamous Metaplasia 

Heimburger, D. C> et al. 1988. Improvement in bronchial squamous 

metaplasia in smokers treated with folate and vitamin B12. Report of a 

preliminary randomized, double-blind intervention trial. JAMA 259(10), Mar. 

11, 1525-1530. 

Dose: 500mcg for 4 months 

Dementia 

Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are 

decreased in late-onset AD patients. J Neural Transm. 2001;108(1):93-9. 

Regland, B. et al. 1991. Vitamin B12-induced reduction of platelet 

monoamine oxidase activity in patients with dementia and pernicious 

anaemia. Eur Arch Psychiatry Clin Neurosci 240(4-5), 288-291. 

General 

Tschop M, Folwaczny C, Schindlbeck N, Loeschke K. Megaloblastic anemia due 

to inadequate nutrition. Dtsch Med Wochenschr. 1997 Jun 20;122(25-26):820-4. 

Newbold, H. L. 1989. Vitamin B-12: Placebo or neglected therapeutic tool? 

Med Hypothesis, 28(3), May, 155-164. 

Hepatitis 

Mathe G, Morette C, Hallard M, Pontiggia P, Blanquet D, Hage F. Viral and 

20 

immunologic follow up of 4 to 9 years of AIDS treatments by quadruple 



122

combinations of virostatics including integrase inhibitors applied in short 

sequences differing by drug rotation. Acta Pharmacol Sin. 2002 Jan;23(1):1-15. 

Iwarson, S. and Lindberg, J. 1977. Coenzyme-B12 therapy in acute viral 

hepatitis. Scandinavian J Infectious Dis 9(2), 157-158. 

Komar, I. V. 1982. [Use of vitamin B12 in the combined therapy of viral 

hepatitis]. Vopr Pitan (1), Feb., 26-29. 

Dose: 100mcg every other day 

Imerslund-Grasbeck Syndrome 

Salameh, M. M. et al. 1991. Reversal of severe neurological abnormalities 

after vitamin B12 replacement in the Imerslund-Grasbeck Syndrome. J 

Neurology 238(6), Sept., 349-350. 

Methylmalonic Acidemia 

Gordon, B. A. and Carson, R. A. 1976. Methylmalonic acidemia controlled 

with oral administration of vitamin B12. Canadian Med Assoc J 115(3), Aug. 

7, 233-236. 

Dose: Continuous intramuscular supplements in doses of 1 mg on 

alternate days followed by 15 mg/day taken orally 

Multiple Sclerosis 

Kira, J. et al. 1994. Vitamin B12 metabolism and massive-dose methyl 

vitamin B12 therapy in Japanese patients with multiple sclerosis. Internal 

Med 33(2), Feb., 82-86. 

Dose: 60mg/day for 6 months 

Sleep 

Honma, K. et al. 1992. Effects of vitamin B12 on plasma melatonin rhythm 

in humans: Increased light sensitivity phase-advances the Circadian 

Clock? Experentia 48(4), Aug. 15, 716-720. 

Dose: 3mg/day 

Ohta, T. et al. 1991. Treatment of persistent sleep-wake schedule disorders 

in adolescents with methylcobalamin (vitamin B12). Sleep 14(5), Oct., 414- 

418. 

Dose: 3,000mcg/day 

Okawa, M. et al. 1990. Vitamin B12 treatment for sleep-wake rhythm 

disorders. Sleep 13(1), Feb., 15-23. 

Dose: 1.5 mg /day tid 

Vitiligo 

Montes, L. F. et al. 1992. Folic acid and vitamin B12 in vitiligo: A nutritional 

approach. Cutis 50(1), July, 39-42. 



123

Choline/Lecithin 

Head Injury 

Dempsey RJ, Raghavendra Rao VL. Cytidinediphosphocholine treatment to 

decrease traumatic brain injury-induced hippocampal neuronal death, 

cortical contusion volume, and neurological dysfunction in rats. J Neurosurg. 

2003 Apr;98(4):867-73. 

Levin, H. S. 1991. Treatment of postconcussional symptoms with CDPcholine. 

J Neurol Sci 103 Suppl, July, S39-S42. 

Dose: 1 gm of CDP-choline 

Maldonado, V. C. et al. 1991. Effects of CDP-choline on the recovery of 

patients with head injury. J. Neurol Sci 103 Suppl, July, S15-S18. 

Hemiplegia 

Hazama T, Hasegawa T, Ueda S, Sakuma A. Evaluation of the effect of CDPcholine 

on poststroke hemiplegia employing a double-blind controlled 

trial. Assessed by a new rating scale for recovery in hemiplegia. Int J 

Neurosci. 1980;11(3):211-25. 

Hazama, T. et al. 1980. Evaluation of the effect of CDP-choline on 

poststroke hemiplegia employing a double-blind controlled trial. Assessed 

by a rating scale for recovery in hemiplegia. Int J Neurosci 11(3), 211-215. 

Dose: ranging from 250-1000 mg over an 8 week period 

Hepatic Steatosis 

Oliveira CP, da Costa Gayotto LC, Tatai C, Della Bina BI, Janiszewski M, Lima ES, 

Abdalla DS, Lopasso FP, Laurindo FR, Laudanna AA. Oxidative stress in the 

pathogenesis of nonalcoholic fatty liver disease, in rats fed with a cholinedeficient 

diet. J Cell Mol Med. 2002 Jul-Sep;6(3):399-406. 

Buchman, A. L. et al. 1995. Choline deficiency: A cause of hepatic steatosis 

during parenteral nutrition that can be reversed with intravenous choline 

supplementation. Hepatology 22(5), Nov., 1399-1403. 

Dose: 1-4 g choline chloride over a period of 4 weeks 

Neurological Function 

Uteshev VV, Meyer EM, Papke RL. Regulation of neuronal function by 

choline and 4OH-GTS-21 through alpha 7 nicotinic receptors. J 

Neurophysiol. 2003 Apr;89(4):1797-806. Epub 2002 Dec 04 

Fernandez, R. L. 1983. Efficacy and safety of oral CDP-choline. Drug 

surveillance study in 2817 cases. Arzeimittelforschung 33(7A), 1073-1080. 

Dose: 6 ml/day mean dose of CDP-choline 



124

Seizures 

Yang Y, Liu Z, Cermak JM, Tandon P, Sarkisian MR, Stafstrom CE, Neill JC, 

Blusztajn JK, Holmes GL. Protective effects of prenatal choline 

supplementation on seizure-induced memory impairment. J Neurosci. 2000 

Nov 15;20(22):RC109. 

McNamara, J. O. et al. 1980. Effects of oral choline on human complex 

partial seizures. Neurology 30(12), 1334-1336. 

Dose: 12-16 g/day 

Stroke 

Rao AM, Hatcher JF, Dempsey RJ. CDP-choline: neuroprotection in transient 

forebrain ischemia of gerbils. J Neurosci Res. 1999 Dec 1;58(5):697-705. 

Tazaki, Y. et al. 1988. Treatment of acute cerebral infarction with a choline 

precursor in a multicenter double-blind placebo-controlled study. Stroke 

19(2), Feb., 211-216. 

Dose: 1000 mg iv CDP-choline/day for 14 days 

Tardive Dyskinesia 

Tammenmaa IA, McGrath JJ, Sailas E, Soares-Weiser K. Cholinergic 

medication for neuroleptic-induced tardive dyskinesia. Cochrane Database 

Syst Rev. 2002;(3):CD000207. 

Gelenberg, A. J. et al. 1979. Choline and lecithin in the treatment of tardive 

dyskinesia: Preliminary results from a pilot study. Am J Psychiatry 136(6), 

June, 772-776. 

Growdon, . H. et al. 1977. Oral choline administration to patients with 

tardive dyskinesia. NEJM 297(10), Sept. 8, 524-527. 

Arranz, J. and Ganoza, G. 1983. Treatment of chronic dyskinesia with CDPcholine. 

Arzneimittelforschung 33(&a), 1071-1073. 

Dose: 500-1200 mg CDP-choline/day 

Nasrallah, H. A. et al. 1984. Variable clinical response to choline in tardive 

dyskinesia. Psychol Med 14(3), Aug., 697-700. 

Folic acid 

Anemia 

Agarwal KN, Gomber S, Bisht H, Som M. Anemia prophylaxis in adolescent 

school girls by weekly or daily iron-folate supplementation. Indian Pediatr. 

2003 Apr;40(4):296-301. 



125

Rahpael, J. C. et al. 1975. [Myelopathy and macrocytic anemia associated 

with a folate deficiency. Cure by folic acid]. Ann Med Interne 126(5), May, 

339-348. 

Arthritis 

Endresen GK, Husby G. Folate supplementation during methotrexate 

treatment of patients with rheumatoid arthritis. An update and proposals 

for guidelines. Scand J Rheumatol. 2001;30(3):129-34. 

Morgan, S. L. et al. 1994. Supplementation with folic acid during 

methotrexate therapy for rheumatoid arthritis. A double-blind, placebocontrolled 

trial. Annals Intern Med 121(11), Dec. 1, 833-841. 

Dose: 5mg or 27.5 mg at weekly doses 

Morgan, S. L. et al. 1990. The effect of folic acid supplementation on the 

toxicity of lowdose methotrexate in patients with rheumatoid arthritis. 

Arthritis Rheum 33(1), Jan., 9-18. 

Dose: 1mg folic acid/day 

Flynn, M. A. et al. 1994. The effect of folate and cobalamin on osteoarthritic 

hands. J American Colle Nutr 13(4), Aug., 351-356. 

Dose: 6400mcg folate/day 

Cancer 

Bajetta E, Celio L, Buzzoni R, Ferrari L, Marchiano A, Martinetti A, Longarini R, 

Becerra C, Ilardi C, John W. Phase II study of pemetrexed disodium (Alimta) 

administered with oral folic acid in patients with advanced gastric cancer. 

Ann Oncol. 2003 Oct;14(10):1543-8. 

Saito, M. et al. 1994. Chemoprevention effects on bronchial squamous 

metaplasia by folate and vitamin B12 in heavy smokers. Chest 106(2), Aug., 

496-499. 

Jennings, E. 1995. Folic acid as a cancer-preventing agent. Med 

Hypotheses 45(3), Sept., 297-303. 


Das UN. Folic acid says NO to vascular diseases. Nutrition. 2003 Jul-Aug;19(7- 

8):686-92. 

Landgren, F. et al. 1995. Plasma homocysteine in acute myocardial 

infarction: Homocysteine-lowering effect of folic acid. J Intern Med 237(4), 

Apr., 381-388. 



126

Dose: 2.5mg or 10mg over a 6 week period 

van den Berg, M. et al. 1994. Combined vitamin B6 plus folic acid therapy in 

young patients with arteriosclerosis and hyperhomocysteinemia. J 

Vascular Surgery 20(6), Dec., 933-940. 

Dose: 5mg folic acid/day 

Morrison, H. I. et al. 1996. Serum folate and risk of fatal coronary heart 

disease. JAMA 275(24), June 26, 1893-1896. 

Wilcken, D. E. et al. 1988. Folic acid lowers elevated plasma homocysteine 

in chronic renal insufficiency: Possible implications for prevention of 

vascular disease. Metabolism 37(7), July, 697-701. 

Dose: 5mg folic acid/day for average of 15 days 

Arnadottir, M. et al. 1993. The effect of high-dose pyridoxine and folic acid 

supplementation on serum lipid and plasma homocysteine concentrations 

in dialysis patients. Clinical J Nephrol 40(4), Oct., 236-240. 

Dose: 5mg/day 

Cervical Dysplasia 

Thomson SW, Heimburger DC, Cornwell PE, Turner ME, Sauberlich HE, Fox LM, 

25 

Butterworth CE. Correlates of total plasma homocysteine: folic acid, copper, 

and cervical dysplasia. Nutrition. 2000 Jun;16(6):411-6. 

Butterworth, Jr. C. E. 1982. Improvement of cervical dysplasia associated 

with folic acid therapy in users of oral contraceptives. Am J Clin Nutr, 35(1) 

Jan., 73-82. 

Dose: 10mg folic acid/day for 3 months 

Fragile X Syndrome 

Strom CM, Brusca RM, Pizzi WJ. Double-blind, placebo-controlled crossover 

study of folinic acid (Leucovorin for the treatment of fragile X syndrome. 

Am J Med Genet. 1992 Nov 15;44(5):676-82. 

Brown, W. T. et al. Folic acid therapy in the Fragile X Syndrome. Am. J Med 

Genetics 17(1), Jan., 289-297. 

Hagerman, R. J. et al. 1986. Oral folic acid versus placebo in the treatment 

of males with the Fragile X Syndrome. Am. J Med Genetics 23(1-2), Jan.- 

Feb., 241-262. 


Lejeune, J. et al. 1984. [Trial of folic acid treatment in Fragile X Syndrome] 



127

Ann Genet 27(4), 230-232. 

Dose: 0.5 mg/kg per day of folic acid 

Gingival Health 

Munoz CA, Kiger RD, Stephens JA, Kim J, Wilson AC. Effects of a nutritional 

supplement on periodontal status. Compend Contin Educ Dent. 2001 

May;22(5):425-8, 430, 432 passim; quiz 440. 

Vogel, R. I. et al. 1976. The effect of folic acid on gingival health. J 

Periodontology 47(11), Nov., 667-668. 

Dose: 4mg/day for 30 days 

Homocystinuria 

Ashfield-Watt PA, Moat SJ, Doshi SN, McDowell IF. Folate, homocysteine, 

endothelial function and cardiovascular disease. What is the link? Biomed 

Pharmacother. 2001 Oct;55(8):425-33. 

Takenaka, T. et al. 1993. [Effect of folic acid for treatment of homocystinuria 

due to 5,10-methylenetetrahydrofolate reductase deficiency]. Rinsho 

Shinkeigaku 33(11), Nov., 1140-1145. 

Dose: 400mcg/day of folic acid over approx 70 days 

Kidney Damage 

Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, Scott-Douglas 

N. Oral vitamin B(12) and high-dose folic acid in hemodialysis patients 

with hyper-homocyst(e)inemia. Kidney Int. 2001 Mar;59(3):1103-9. 

Chauveau, P. et al. 1996. Long-term folic acid (but not pyridoxine) 

supplementation lowers elevated plasma homocysteine level in chronic 

renal failure. Miner Electrolyte Metab 22(1-3), 106-109. 

Dose: 10mg/day folate for 3 months 

Lithium Prophylaxis 

McKeon P, Shelley R, O'Regan S, O'Broin J. Serum and red cell folate and 

affective morbidity in lithium prophylaxis. Acta Psychiatr Scand. 1991 

Mar;83(3):199-201. 

Coppen, A. et al. 1986. Folic acid enhances lithium prophylaxis. J Affective 

Disorders 10(1), Jan.-Feb., 9-13. 

Dose: 200mcg/day folic acid 

Multiple Sclerosis 

Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 



128

1996 Dec;54(12):382-90. 

Kanevskaia, S. A. et al. 1990. [Folic acid in the combined treatment of 

patients with disseminated sclerosis and chronic gastritis] Vrach Delo (4), 

Apr. 96-97. 

Dose: 200-300mcg/day 

Zinc Absorption 

Tavares E, Carreras O, Gomez-Tubio A, Murillo D, Murillo ML. Effects of folic 

acid and amino acids supplementation on zinc intestinal absorption in the 

progeny of ethanol-treated rats. J Physiol Biochem. 2000 Sep;56(3):247-56. 

Milne, D. B. et al. 1984. Effect of oral folic acid supplements on zinc, 

copper, and iron absorption and excretion. Am J Clin Nutr 39(4), Apr., 535- 

539. 

Dose: 400mcg folic acid every other day for 16 weeks 

Niacin 

General 

Talpur N, Echard BW, Yasmin T, Bagchi D, Preuss HG. Effects of niacin-bound 

chromium, Maitake mushroom fraction SX and (-)-hydroxycitric acid on 

the metabolic syndrome in aged diabetic Zucker fatty rats. Mol Cell 

Biochem. 2003 Oct;252(1-2):369-77. 

Chojnowska-Jezierska, J,. and Adamska-Dyniewska, H. 1998. Efficacy and 

safety of one-year treatment with slow-release nicotinic acid. Monitoring of 

drug concentration in serum. Int J Clin Pharmacol Ther, 36(6), Jun., 326- 

332. 

Dose: 1.5 g/d (2 months), and subsequently 2-3 g/d (10 months), on average 

2.13 g/d. During the treatment with 2.0 g/d dose. 

Hoogerbrugge, N. et al. 1998. The additional effects of acipimox to 

simvastatin in the treatment of combined hyperlipidaemia. J Intern Med, 

243(5) May, 151-156. 

Dose: Acipimox in a daily dose of 3 X 250 mg for 12 weeks. 

Brown, B. G. et al. 1998. Lipid altering or antioxidant vitamins for patients 

with coronary disease and very low HDL cholesterol? The HDLAtherosclerosis 

Treatment Study Design. Can J Cardiol, Suppl A, Apr. 14, 

6A-13A. 

Chojnowska-Jezierska, J. and Adamska-Dyniewska, H. 1997. [Prolonged 

treatment with slow release nicotinic acid in patients with type II 



129

hyperlipidemia]. Pol Arch Med Wewn, 98(11) Nov., 391-399 

Dose: one-year therapy with slow-release nicotinic acid 

McKenney, J.M. et al. 1998. A randomized trial of the effects of atorvastatin 

and niacin in patients with combined hyperlipidemia or isolated 

hypertriglyceridemia. Collaborative Atorvastatin Study Group. Am J Med, 

104(2) Feb., 137-143 

Dose: immediate-release niacin 1 g 3x/day for 12 weeks 

Brown, B. G. et al. 1998. Use of niacin, statins, and resins in patients with 

combined hyperlipidemia. Am J Cardiol, 81(4A) Feb. 26, 52B-59B 

Fagerberg, B. et al. 1998. Mortality rates in treated hypertensive men with 

additional risk factors are high but can be reduced: a randomized 

intervention study. Am J Hypertens, 11(1 Pt 1) Jan., 14-22. 

Kukharchuk, V. V. et al. 1997. [The effect of long-term Enduracin 

monotherapy on the clinical and biochemical status of patients with 

ischemic heart disease]. Ter Arkh, 69(9), 41-45 

Dose: enduracin in a dose 1500 mg/day. 

Brown, B. G. et al. 1997. Moderate dose, three-drug therapy with niacin, 

lovastatin, and colestipol to reduce low-density lipoprotein cholesterol 

Dose: 30mg/day Vitamin C 

Okamoto, K et al. 1992. [The relationship between dietary ascorbic acid 

intake and serum lipid concentration in the aged.] Nippon Ronen Igakkai 

Zasshi 29(12), Dec., 908-911. 

Cheraskin, E. 1994. Chronologic versus biologic age. J Advancement Med 

7(1), Spring, 31-41. 

Dose: 100mg-200mg/day Vitamin C 

Cheraskin, E. 1993. Vitamin C, cancer and aging. Age 16, 55-58. 

Delafuente, J. C. et al. 1986. Immunologic modulation by vitamin C in 

elderly. Int J Immunopharmacol 8(2), 205-211. 

Alcohol Toxicity 

Sivaram AG, Suresh MV, Indira M. Combined effect of ascorbic acid and 

selenium supplementation on alcohol-induced oxidative stress in guinea 

pigs. Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):397-401 

Susick, R. L. and Zannoni, V. G. 1987. Effect of ascorbic acid on the 

consequences of acute alcohol consumption in humans. Clin Pharmacol 

Ther, 41(5), May, 502-509. 

Dose: 0.95gm/kg body weight over 2.5 hours for 2 weeks 

Wickramasinghe, S. N. and Hasan, R. 1994. In vivo effects of Vitamin C on 

the cytotoxicity of post-ethanol serum. Biochem Pharmacol, 48(3), Aug. 3, 

621-624. 

Dose: 1gm/day for 3 days 

Chen, M. F. et al. 1990. Effect of ascorbic acid on plasma alcohol clearance. 

J Am Coll Nutr, 9(3), June, 185-189. 

Arthritis 

Jensen NH. Reduced pain from osteoarthritis in hip joint or knee joint 

during treatment with calcium ascorbate. A randomized, placebocontrolled 

cross-over trial in general practice. Ugeskr Laeger. 2003 Jun 

16;165(25):2563-6.s 

Oldroyd, K. G. and Dawes, P. T. 1985. Clinically significant vitamin C 

deficiency in rheumatoid arthritis. British J Rheumatology 24(4) Nov, 362- 

363. 

Davis, R. H. et al. 1990. Vitamin C influence of localized adjuvant arthritis. J 

American Podiatry Med Assoc 80(8) Aug, 414-418. 



131

Dose: 150mg/kg of subcutaneous Vitamin C for 20 days 

Asthma 

Kongerud J, Crissman K, Hatch G, Alexis N. Ascorbic acid is decreased in 

induced sputum of mild asthmatics. Inhal Toxicol. 2003 Feb;15(2):101-9. 

Hatch, G. E. 1995. Asthma, inhaled oxidants, and dietary antioxidants. 

American J Clin Nutr 61(3 Suppl), Mar, 625S-630S. 

Anderson, R. et al. 1980. The effect of ascorbate on cellular humoral 

immunity in asthmatic children. South African Med J 58(24) Dec 13, 974- 

977. 

Dose: 1g ascorbic single daily dose for a 6-month period 

Anah, C. O. et al. 1980. High dose ascorbic acid in Nigerian asthmatics. 

Trop Geogr Med 32(2) June, 132-137. 

Dose: 1g of ascorbic acid daily 

Rozanov, E. M. et al. 1987. [Vitamin PP and C allowances and their 

correction in the treatment of bronchial asthma patients.] Vopr Pitan (6):21- 

4, Nov-Dec, 21-24. 

Dose: 275-300 mg of Vitamin C 

Cancer 

Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line 

chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003 

Apr;22(2):118-23. 

Block, G. et al. 1991. Epidemiologic evidence regarding vitamin C and 

cancer. Am J Clin Nutr 54(6 Suppl) Dec., 1310S-1314S. 

Herrero, R. et al. A case-control study of nutrient status and invasive 

cervical cancer: I. Dietary indicators. Am J Epi 134(11), Dec. 1, 1335-1346. 

Stahelin, H. B. et al. Plasma antioxidant vitamins and subsequent cancer 

mortality in the 12-year follow-up of the prospective based study. Am J Epi 

133(8), Apr. 15, 766-775. 

Knekt, P et al. 1991. Dietary antioxidants and the risk of lung cancer. Am J 

Epi 134(5), Sept. 1, 471-479. 

Trizna, Z. et al. 1991. Effects of N-acetyl-L-cysteine and ascorbic acid on 

mutagen-induced chromosomal sensitivity in patients with head and neck 

cancers. Am J Surgery 162(4), Oct., 294-298. 



132

Ferraroni, M et al. 1994. Selected micronutrient intake and the risk of 

colorectal cancer. British J Cancer 70(6), Dec., 1150-1155. 

Shibata, A. et al. 1992. Intake of vegetables, fruits, beta-carotene, vitamin C 

and vitamin supplements and cancer incidence among the elderly: A 

prospective study. British J Cancer 66(4) Oct., 673-679. 

Bussey, H. J. et al. A randomized trial of ascorbic acid in polyposis coli. 

Cancer 50(7) Oct. 1, 1434-1439. 

Dose: 3g/day of ascorbic acid for 9 months 

Fontham, E. T. et al. 1988. Dietary vitamins A and C and lung cancer risk in 

Louisiana. Cancer 62(10), Nov. 15, 2267-2273. 

Park, C. H. et al. 1980. Growth suppression of human leukemic cells in vitro 

by L-ascorbic acid. Cancer Res 40(4), 1062-1065. 

Kaugars, G. et al. 1993. Serum and tissue antioxidant levels in 

supplemented patients with premalignant oral lesions (meeting abstract). 

FASEB J 7(4), A519. 

Dose: 1000mg Vitamin C for 9 months 

Sobala, G. M. et al. 1989. Ascorbic acid in the human stomach. 

Gastroenterology 97(2) Aug., 357-363. 

Paganelli, G. M. et al. 1992. Effect of vitamin A, C, and E supplementation 

on rectal cell proliferation in patients with colorectal adenomas. J National 

Cancer Inst. 84(1) Jan. 1, 47-51. 

Brock, K. E. et al. Nutrients in diet and plasma and risk of in situ cervical 

cancer. J National Cancer Inst. 80(8) June 15, 580-585. 

Potter, J. D. and McMichael, A. J. 1986. Diet and cancer of the colon and 

rectum: A case-control study. J National Cancer Inst. 76(4) Apr., 557-569. 

Moffat, L. et al. 1983. High dose ascorbate therapy and cancer. NFCR 

Cancer Res Assoc Symp. (2), 243-256. 

Dose: 2.5 g Vitamin C 4x/day 

Kaugars, G. et al. 1993. The role of antioxidants in the treatment of oral 

leukoplakia. CCPC-93: Second Int Cancer Chemo Prevention Conf. Berlin, 

Germany, Apr. 28-30, 65. 

Dose: 1000mg/day of ascorbic acid for 9 months 

Greco, A. M. et al. 1982. Study of blood vitamin C in lung and bladder 

cancer patients before and after treatment with ascorbic acid: A preliminary 

report. Acta Vitaminol Enzymol 4(1-2), 155-162. 



133

Dose: 5g/day 

Glatthaar, B. E. et al. The role of ascorbic acid in carcinogenesis. Adv Exp 

Med Biol 206, 357-377. 

Chen, L H. et al. 1988. Vitamin C, vitamin E and cancer. Anticancer Res 8(4), 

July-Aug., 739-748. 

Garcia-Alejo Hernandez, R. et al. 1989. [Radioprotective effect of ascorbic 

acid on oral structures in patients with cancer of the head and neck]. Av 

odontoestomatol 5(7), Sept., 469-472. 

La Vecchia, C. et al. Selected micronutrient intake and the risk of gastric 

cancer. Cancer Epidemiol Biomarkers Prev. 3(5) July-Aug., 393-398. 

Dyke, G. W. et al. Effect of vitamin C supplementation on gastric mucosal 

DNA damage. Carcinogenesis 15(2), 291-295. 

Slattery, M. L. et al. 1990. Dietary vitamins A, C, and E and selenium as risk 

factors for cervical cancer. Epidemiology 1(1), Jan., 8-15. 

Reed, P. I. et al. 1991. Effect of ascorbic acid on the intragastric 

environment in patients at increased risk of developing gastric cancer. 

IARC Sci Publ. (105), 139-142. 

Nomura, A. M. et al. 1991. Dietary factors in cancer of the lower urinary 

tract. Int. J Cancer 48(2), May 10, 199-205. 

Verreault, R. et al. 1989. A case-control study of diet and invasive cervical 

cancer. Int J Cancer 43(6), June 15, 1050-1054. 

Cameron, E. 1982. Vitamin C and cancer: An overview. Int J Vitamin Nutr 

Res Suppl 23, 115-127. 

Murata,, A. et al. 1982. Prolongation of survival times of terminal cancer 

patients by administration of large doses of ascorbate. Int J Vitamin Nutr 

Res Suppl 23, 103-113. 

Waddell, . R. and Germer, R. E. 1980. Indomethacin and ascorbate inhibit 

desmoid tumors. J Surg Oncol 15(1), 85-90. 

Ghosh, J and Das, S. 1995. Evaluation of vitamin A and C status in normal 

and malignant conditions and their possible role in cancer prevention. 

Japanese J Cancer Res 76(12) Dec., 1174-1178. 

Cameron, E. and Campbell, A. 1991. Innovation vs. quality control: An 

'Unpublishable' clinical trial on supplemental ascorbate in incurable 



134

cancer. Med Hyp 36(3), Nov., 185-189. 

Jaffey, M. Vitamin C and cancer: Examination of the value of eleven trial 

results using broad inductive reasoning. Med Hyp 8(1), 49-84. 

Dose: 10g/day Vitamin C 

Campbell, A. et al. 1991. Reticulum cell sarcoma: Two complete 

spontaneous' regressions in response to high-dose ascorbic acid therapy. 

A report on subsequent progress. Oncology 48(6), 495-497. 

Kaminski, M. and Boal, R. 1992. An effect of ascorbate acid on delayedonset 

muscle soreness. Pain 50(3), Sept., 317-321. 

Raushenbakh, M. O. et al. [Effect of ascorbic acid on formation and 

leukemogenic activity of p-hydroxyphenyllactic acid]. Probl Gematol 

Pereliv Krovi 27(7), 3-6. 

Dose: 8g/day over 8-10 days before chemotherapy 

Stahelin, H. B. 1989. [Vitamins and cancer: Results of a Basel study]. Soz 

Praventivmed 34(2), 75-77. 

Gorozhanskaia. E. G. et al. [The role of ascorbic acid in the combined 

preoperative preparation of cancer patients]. Vopr Onkol 35(4), 436-441. 

Dose: 1.5g/day of ascorbic acid for 7 days. 

Baikova, V. N. et al. 1982. [The effect of large doses of ascorbic acid on 

tyrosine metabolism and hemoblastosis course in children]. Vopr Onkol 

28(9), 28-34. 

Dose: 100mg/kg/day. 

Yuan, J. M. et al. 1995. Diet and breast cancer in Shanghai and Tianjin, 

China. British J Cancer 71, 1353-1358. 

Howe, G. R. et al. 1990. Dietary factors and the risk of breast cancer: 

Combined analysis of 12 case-controlled studies. J National Cancer Inst. 

82, 561-569. 

VanEenwyk, J. 1993. The role of vitamins in the development of cervical 

cancer. The Nutrition Report. 11(1), Jan., 1-8. 

Amburgey, C. F. et al. 1993. Undernutrition as a risk factor for cervical 

intraepithelial neoplasia: A case control analysis. Nutrition and Cancer 

20(1), 51-60. 


Mak S, Newton GE. Vitamin C augments the inotropic response to 



135

dobutamine in humans with normal left ventricular function. Circulation. 

2001 Feb 13;103(6):826-30. 

Salonen, J. T. et al. 1991. Effects of antioxidant supplementation on platelet 

function: A randomized pair-matched, placebo-controlled, double-blind trial in men 

with low antioxidant status. Am J Clin Nutr. 53(5), May, 1222-1229. 

Dose: 600mg of ascorbic acid/day. 

Trout, D. L. 1991. Vitamin C and cardiovascular risk factors. Am J Clin Nutr 

53(1 Suppl), Jan., 322S-325S. 

34 

Sisto, T. et al. 1995. Pretreatment with antioxidants and allopurinol 

diminishes cardiac onset events in coronary artery bypass grafting. Ann 

Thorac Surg 59(6) June, 1519-1523. 

Khaw, K. T. and Woodhouse, P. 1988. Interrelation of vitamin C, infection, 

haemostatic factors and cardiovascular disease. British Med J 310(6994), 

June 17, 1559-1563. 

Dose: 60mg. 

Brox, A. G. et al. 1988. Treatment of idiopathic thrombocytopenic purpura 

with ascorbate. British J Haematology 70(3) Nov., 341-344. 

Singh, R. B. et al. 1995. Effect of antioxidant-rich foods on plasma ascorbic 

acid, cardiac enzyme, and lipid peroxide levels in patients hospitalized with 

acute myocardial infarction. J Am Dietetic Assoc. 95(7), July, 775-780. 

Singh, R. B. et al. 1994. Plasma levels of antioxidant vitamins and oxidative 

stress in patients with acute myocardial infarction. Acta Cardiol 49(5), 441- 

452. 

Riemersma. R. A. et al. 1989. Low plasma vitamins E and C. Increased risk 

of angina in Scottish men. Annals NY Academy Sci. 570, 291-295. 

Gey, K. F. et al. 1987. Relationship of plasma level of vitamin C to mortality 

from ischemic heart disease. Annals NY Academy Sci. 498, 110-123. 

Cordova, C, et al. 1982. Influence of ascorbic acid on platelet aggregation in 

vitro and in vivo. Atherosclerosis 41(1), Jan., 15-19. 

Dose: 2g of ascorbic acid. 

Bordia, A. K. 1980. The effect of vitamin C on blood lipids, fibrinolytic 

activity and platelet adhesiveness in patients with coronary artery disease. 

Atherosclerosis 35(2), Feb., 181-187. 

Dose: 2g/day Vitamin C. 



136

Li, C. C. 1990. [Changes on creatine phosphokinase and malondialdehyde 

in the serum and clinical use of large doses of vitamin C following open 

heart surgery]. Chung Hua Wai Ko Tsa Chih 28(1) Jan., 16-17, 60-61. 

Dose: 250mg/kg Vitamin C prior to heart surgery. 

Bordia, A. and Verma, S. K. 1985. Effect of vitamin C on platelet 

adhesiveness and platelet aggregation in coronary artery disease patients. 

Clinical Cardiology 8(10) Oct.., 552-554. 

Dose: 1g and 1 g every 8 hours over 10 days. 

Yoshioka, M. et al. 1984. Inverse association of serum ascorbic acid level 

and blood pressure or rate of hypertension in male adults aged 30-39 

years. Int J Vitamin Nutr Res. 54(4), 343-347. 

Simon, J. A. 1992. Vitamin C and cardiovascular disease: A review. J Am 

Coll Nutr. 11(2) Apr., 107-125. 

Mostafa, S. et al. 1989. Beneficial effects of vitamin C on risk factors of 

cardiovascular diseases. J Egyptian Public health Assoc. 64(1-2), 123-133. 

Dose: 500mg/day of Vitamin C. 

Fujimura, I. et al. [Correlation between hypercholesterolemia and vitamin C 

deficient diet]. Rev Hosp Clin Fac Med Sao Paulo 46(1), Jan.-Feb., 14-18. 

Dobson, H. M. et al. 1984. The effect of ascorbic acid on the seasonal 

variations in serum cholesterol levels. Scottish Med J 29(3) July, 176-182. 

Dose: 1g of ascorbic acid for 2 months. 

Gey, K. F. et al. [Essential antioxidants in cardiovascular diseases-Lessons 

for Europe]. Ther Umsch 51(7) July, 475-482. 

Dingchao, H. et al. 1994. The protective effects of high-dose ascorbic acid 

on myocardium against reperfusion injury after cardiopulmonary bypass. 

Thorac Cardiovasc Surg 42(5) Oct., 276-278. 

Dose: 250 mg/kg. 

Cataracts 

Serum ascorbic acid and other correlates of self-reported cataract among 

older Americans. 

Simon JA, Hudes ES. Serum ascorbic acid and other correlates of selfreported 

cataract among older Americans. J Clin Epidemiol. 1999 

Dec;52(12):1207-11. 

Jacques, P. F. and Chylack Jr., L. T. Epidemiologic evidence of a role for 

the antioxidant vitamins and carotenoids in cataract prevention. Am J Clin 



137

Nutr 53(1 Suppl) Jan., 352S-355S. 

Robertson, J. M. et al. 1991. A possible role for vitamins C and E in cataract 

prevention. Am J Clin Nutr. 53(1 Suppl), Jan., 346S-351S. 

Jacques, P. F. et al. 1988. Antioxidant status in persons with and without 

senile cataract. Arch Ophthalmol 106(3)m Mar., 337-340. 

Gerster, H. 1989. Antioxidant vitamins in cataract prevention. Z 

Ernahrungswiss. 28(1), Mar., 56-75. 

Cervical Dysplasia 

Ho GY, Palan PR, Basu J, Romney SL, Kadish AS, Mikhail M, Wassertheil-Smoller 

S, Runowicz C, Burk RD. Viral characteristics of human papillomavirus 

infection and antioxidant levels as risk factors for cervical dysplasia. Int J 

Cancer. 1998 Nov 23;78(5):594-9. 

Wassertheil-Smoller, S. et al. 1981. Dietary Vitamin C and uterine cervical 

Dysplasia. Am J Epi, 114(5), No., 714-724. 

Romney, S. L. et al. 1985. Plasma Vitamin C and uterine cervical dysplasia. 

Am J Obstetrics Gynecology, 151(7), Apr. 1, 976-980. 

Common Cold 

Van Straten M, Josling P. Preventing the common cold with a vitamin C 

supplement: a double-blind, placebo-controlled survey. Adv Ther. 2002 May- 

Jun;19(3):151-9. 

Hemila, H. 1994. Does Vitamin C alleviate the symptoms of the common 

cold?-A review of current evidence. Scandanavian J Infect Dis, 26(1), 1-6. 

Dose: 1g Vitamin C. 

Diabetes 

Krawczuk-Rybak M, Peczynska J, Urban M. Usefulness of antioxidant vitamin 

supplementation in children and adolescents with newly diagnosed 

diabetes mellitus type. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 

1999;5(1):11-20. 

Johnson, C. S. and Yen, M. F. 1994. Megadose of vitamin C delays insulin 

response to a glucose challenge in normoglycemic adults. Am J Clin Nutr 

60(5), Nov., 735-738. 

Dose: 2g/day for 2 weeks. 

Paolisso, G. et al. 1994. Plasma vitamin C affects glucose homeostasis in 

healthy subjects and in non-insulin-dependent diabetics. Am J Physiol 



138

266(2 Pt 1), Feb., E261-268. 

Davie, S. J. et al. Effect of vitamin C on glycosylation of proteins. Diabetes 

41(2), Feb., 167-173. 

Dose: 1g/day of Vitamin C for 3 months. 

Vinson, J. A. et al. 1989. In vitro and in vivo reduction of erythrocyte 

sorbitol by ascorbic acid. Diabetes 38(8), Aug., 1036-1041. 

Dose: 500mg/day for 2 weeks. 

Yue, D. K. et al. 1990. Abnormalities of ascorbic acid metabolism and 

diabetic control: Differences between diabetic patients and diabetic rats. 

Diabetes Res Clin Pract. 9(3) July, 239-244. 

Kodama, M. et al. 1993. Diabetes mellitus is controlled by vitamin C 

treatment. In vivo 7(6A), Nov.-Dec., 535-350. 

Cunningham, J. J. et al. 1994. Vitamin C: An aldose reductase inhibitor that 

normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus. J 

Am Coll Nutr. 13(4), Aug., 344-350. 

Dose: 100-600mg/day of Vitamin C for 58 days. 

Cunningham, J. J. et al. Reduced mononuclear leukocyte ascorbic acid 

content in adults with insulin-dependent diabetes mellitus consuming 

adequate dietary vitamin C. Metabolism 40, 146-149. 

Fatigue 

Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ, 

Powell JR. Prolonged vitamin C supplementation and recovery from 

demanding exercise. Int J Sport Nutr Exerc Metab. 2001 Dec;11(4):466-81. 

Cheraskin, E. et al. 1976. Daily Vitamin C consumption and fatigability. J 

Am Geriatric Soc., 24(3), 136-137. 

Glaucoma 

Filina AA, Sporova NA. Effect of lipoic acid on tyrosine metabolism in 

patients with open-angle glaucoma. Vestn Oftalmol. 1991 May-Jun;107(3):19-21. 

Jampel, H. D. 1990. Ascorbic acid is cytotoxic to dividing human Tenon's 

capsule fibroblasts: A possible contributing factor in glaucoma filtration 

surgery success. Arch Ophthalmol. 108(9) Sept., 1323-1325. 

Glutathione Deficiency 

Lenton KJ, Sane AT, Therriault H, Cantin AM, Payette H, Wagner JR. Vitamin C 

augments lymphocyte glutathione in subjects with ascorbate deficiency. Am 

J Clin Nutr. 2003 Jan;77(1):189-95. 



139

Jain, A. et al. 1994. Effect of ascorbate or N-acetylcysteine treatment in a 

patient with hereditary glutathione synthetase deficiency. J Pediatrics, 

124(2), Feb., 229-233. 

Dose: 0.7 mmol/kg/day for 1-2 weeks. 

Herpes 

Hovi T, Hirvimies A, Stenvik M, Vuola E, Pippuri R. Topical treatment of 

recurrent mucocutaneous herpes with ascorbic acid-containing solution. 

Antiviral Res. 1995 Jun;27(3):263-70. 

Fitzherbert, J. 1979. Genital herpes and zinc. Med J Aust, 1, 399. 

Dose: 250mg Vitamin C 2x/day 

Terezhalmy, G. T. et al. 1978. The use of water-soluble bioflavonoidascorbic 

acid complex in the treatment of recurrent herpes labialis. Oral 

Surgery, 45, 56-62. 

Dose: 200mg Vitamin C for 3-5 times/day for 3 days beginning after onset 

of symptoms. 

Immune enhancement 

Heuser G, Vojdani A. Enhancement of natural killer cell activity and T and 

B cell function by buffered vitamin C in patients exposed to toxic 

chemicals: the role of protein kinase-C. Immunopharmacol Immunotoxicol. 1997 

Aug;19(3):291-312. 

Anderson, R. et al. 1980. The effects of increasing weekly doses of 

ascorbate on certain cellular and humoral immune functions in normal 

volunteers. Am J Clin Nutr. 33(1) Jan., 71-76. 

Dose: 2-3g/day. 

Penn, N. D. et al. 1991. The effect of dietary supplementation with vitamins 

A, C and E on cell-mediated immune function in elderly long-stay patients: 

A randomized controlled trial. Age Ageing 20(3) May, 169-174. 

Kodama, M. et al. 1994. Autoimmune disease and allergy are controlled by 

vitamin C treatment. In vivo 8(2), Nar.-Apr., 251-257. 

Delafuente, J. C. et al. 1986. Immunologic modulation by vitamin C in the 

elderly. Int J Immunopharmacol 8(2), 205-211. 


Menopause 

Vihtamaki T, Parantainen J, Koivisto AM, Metsa-Ketela T, Tuimala R. Oral 



140

ascorbic acid increases plasma oestradiol during postmenopausal hormone 

replacement therapy. Maturitas. 2002 Jun 25;42(2):129-35. 

Horoschak, A. 1959. Nocturnal leg cramps, easy bruisability and epistaxis 

in menopausal patients: Treated with Hesperidin and ascorbic acid. 

Delaware State Med J. 19-22. 

Dose: 200mg of Vitamin C following each meal and at bedtime for 2 weeks 

plus another 100mg of both 4x/day for 4 weeks. 

Neutrophil Dysfunction 

Demertzis S, Scherer M, Langer F, Dwenger A, Hausen B, Schafers HJ. Ascorbic 

acid for amelioration of reperfusion injury in a lung autotransplantation 

model in sheep. Ann Thorac Surg. 2000 Nov;70(5):1684-9. 

Rebora, A. et al. 1980. Neutrophil dysfunction and repeated infections: 

Influence of levamisole and ascorbic avid. British J Dermatology, 102(1), 

Jan., 49-56. 

Levy, R. and Schlaeffer, F. 1993. Successful treatment of a patient with 

recurrent furunculosis by Vitamin C: Improvement of clinical course and of 

impaired neutrophil functions. Int J Dermatology, 32(11), Nov., 832-834. 

Dose: 500mg/day of Vitamin C for 30 days. 

Obesity 

Harnroongroj T, Jintaridhi P, Vudhivai N, Pongpaew P, Tungtrongchitr R, Phonrat 

B, Changbumrung S, Schelp FP. B vitamins, vitamin C and hematological 

measurements in overweight and obese Thais in Bangkok. J Med Assoc Thai. 

2002 Jan;85(1):17-25. 

Naylor, G. J. et al. 1985. A double blind placebo controlled trial of ascorbic 

acid in obesity. Nutr Health, 4(1), 25-28. 


Paget's Disease 

Basu TK, Smethurst M, Gillett MB, Donaldson D, Jordan SJ, Williams DC, Hicklin 

JA. Acta Vitaminol Enzymol. 1978;32(1-4):45-9. Ascorbic acid therapy for the 

relief of bone pain in Paget's disease. 

Smethurst, M. et al. 1981. Combined therapy with ascorbic acid and 

calcitonin for the relief of bone pain in Paget's disease. Acta Vitaminol 

Enzymol, 3(1), 8-11. 



141

Pancreatitis 

Shishlov VI. The status of ascorbate oxidation-reduction system of blood in 

patients with chronic pancreatitis throughout parenteral nutrition. Klin 

Khir. 1999;(10):7-9. 

Bonham MJ, Abu-Zidan FM, Simovic MO, Sluis KB, Wilkinson A, Winterbourn 

CC, Windsor JA. Early ascorbic acid depletion is related to the severity of 

acute pancreatitis. Br J Surg. 1999 Oct;86(10):1296-301. 

Scott, P. et al. 1993. Vitamin C status in patients with acute pancreatitis. 

British J Surgery, 80(6), June, 750-754. 

Parkinson's disease 

Martin A, Youdim K, Szprengiel A, Shukitt-Hale B, Joseph J. Roles of vitamins E 

and C on neurodegenerative diseases and cognitive performance. Nutr Rev. 

2002 Oct;60(10 Pt 1):308-26. 

Fahn, S. 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in 

early Parkinson's disease. Annals Neurology 32 Suppl., S128-S132. 

Reilly, D. K. et al. 1983. On-off effects in Parkinson's disease: A controlled 

investigation of ascorbic acid therapy. Advanc Neurol 37, 51-60. 

Linazasoro, G. and Gorospe, A. [Treatment of complicated Parkinson 

disease with a solution of levodopa-carbidopa and ascorbic acid]. 

Neurologia 10(6) June-July, 220-223. 

Yapa, S. C. 1992. Detection of subclinical ascorbate deficiency in early 

Parkinson's Disease. Public Health 106(5) Sept., 393-395. 

Periodontal Disease 

Lowe G, Woodward M, Rumley A, Morrison C, Tunstall-Pedoe H, Stephen K. 

Total tooth loss and prevalent cardiovascular disease in men and women: 

possible roles of citrus fruit consumption, vitamin C, and inflammatory 

and thrombotic variables. J Clin Epidemiol. 2003 Jul;56(7):694-700. 

Leggott, P. J. et al. 1991. Effects of ascorbic acid depletion and 

supplementation of periodontal health and subgingival microflora in 

humans. J Dental Res, 70(12), Dec., 1531-1536. 

Leggott, P. J. et al. 1986. The effect of controlled ascorbic acid depletion 

and supplementation on periodontal health. J Periodonotal, 57(8), Aug., 

480-485. 

Respiration 

Kelly Y, Sacker A, Marmot M. Nutrition and respiratory health in adults: 

41 



142

findings from the health survey for Scotland. Eur Respir J. 2003 Apr;21(4):664- 

71. 

Lee MH, Shiau SY. Increase of dietary vitamin C improves haemocyte 

respiratory burst response and growth of juvenile grass shrimp, Penaeus 

monodon, fed with high dietary copper. Fish Shellfish Immunol. 2003 

Apr;14(4):305-15. 

Peters, E. M. et al. 1993. Vitamin C supplementation reduces the incidence 

of postrace symptoms of upper-respiratory-tract infection in ultramarathon 

runners. Am J Clin Nutr. (2) Feb., 170-174. 

Dose: 600mg/day Vitamin C. 

Mohsenin, V. 1987. Effect of vitamin C on NO2-induced airway 

hyperresponsiveness in normal subjects: A randomized double-blind 

experiment. Am Rev Resp Dis 136(6), Dec., 1408-1411. 

Dose: 500mg 4x/day of ascorbic acid for 3 days. 

Bucca, C. et al. 1990. Effect of vitamin C on histamine bronchial 

responsiveness of patients with allergic rhinitis. Ann Allergy 65(4), Oct., 

311-314. 

Dose: 2g of Vitamin C. 

Bucca, C. et al. 1989. Effects of vitamin C on airway responsiveness to 

inhaled histamine in heavy smokers. European Respir J 2(3), Mar., 229-233. 

Dose: 2g of Vitamin C. 

Schizophrenia 

Rachkauskas GS. The efficacy of enterosorption and a combination of 

antioxidants in schizophrenics. Lik Sprava. 1998 Jun;(4):122-4. 

Sandyk, R. and Kanofsky, J. D. 1993. Vitamin C in the treatment of 

schizophrenia. Int J Neuroscience, 68(1-2), Jan., 67-71. 

Sickle Cell Anemia 

Jaja SI, Ikotun AR, Gbenebitse S, Temiye EO. Blood pressure, hematologic and 

erythrocyte fragility changes in children suffering from sickle cell anemia 

following ascorbic acid supplementation. J Trop Pediatr. 2002 Dec;48(6):366-70. 

42 

Jain, S. K. et al. 1985. Reduced levels of plasma ascorbic acid (Vitamin C) 

in sickle cell disease patients: Its possible role in the oxidant damage to 

sickle cells in vivo. Clin Chim Acta, 149(2-3), July 15, 257-161. 

Smoking Cessation 

Dietrich M, Block G, Hudes M, Morrow JD, Norkus EP, Traber MG, Cross CE, 

Packer L. Antioxidant supplementation decreases lipid peroxidation 

biomarker F(2)-isoprostanes in plasma of smokers. Cancer Epidemiol 

Biomarkers Prev. 2002 Jan;11(1):7-13. 

Levin, E. D. et al. 1993. Clinical trials using ascorbic acid aerosal to aid 

smoking cessation. Drug Alcohol Depend, 33(3), Oct., 211-223. 

Stroke 

Kurl S, Tuomainen TP, Laukkanen JA, Nyyssonen K, Lakka T, Sivenius J, Salonen 

JT. Plasma vitamin C modifies the association between hypertension and 

risk of stroke. Stroke. 2002 Jun;33(6):1568-73. 

Gale, C. R. et al. 1995. Vitamin C and risk of death from stroke and coronary 



143

heart disease in cohort of elderly people. British Med J 310(6994) June 17, 

1563-1566. 

Tetanus 

Jahan, J. K. et al. 1985. Effect of ascorbic acid in the treatment of tetanus. 

Bangladesh Med Res Council Bull, 10(1), June, 24-28. 

Dose: 1000 mg/day iv 

Wound healing 

Jagetia GC, Rajanikant GK, Rao SK. Evaluation of the effect of ascorbic acid 

treatment on wound healing in mice exposed to different doses of 

fractionated gamma radiation. Radiat Res. 2003 Mar;159(3):371-80. 

Ringsdorf Jr., W. M. and Cheraskin, E. 1982. Vitamin C and human wound 

healing. Oral Surg Med Oral Pathol 53(3) Mar., 231-236. 

Dose: 500-3000mg/day. 

Goode, H. F. et al. 1992. Vitamin C depletion and pressure sores in elderly 

patients with femoral neck fractures. British Med J 305(6859) Oct. 17, 925- 

927. 

Vitamin E 

43 

Abetalipoproteinemia 

Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of 

combined vitamin A and E treatment for the prevention of retinal 

degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia 

patients. Eye. 2001 Aug;15(Pt 4):525-30. 

Illingworth, D. R. et al. 1980. Abetalipoprotein. Report of two cases and 

review of therapy. Arch Neurol 37(10), Oct., 659-662. 

Bishara, S. et al. 1982. Combined Vitamin A and therapy prevents retinal 

electrophysiological deterioration in abetalipoprotein. British J 

Ophthalmology 66(12), Dec., 767-770. 

Muller, D. P. et al. 1983. Vitamin E and neurological function: 

Abetalipoproteinaemia and other disorders of fat absorption. Ciba Found 

Symp 101, 106-121. 

Hegele, R. A. and Angel, A. 1985. Arrest of neuropathy and myopathy in 

abetalipoproteinemia with high-dose Vitamin E therapy. Canadian Med 

Assoc J 132(1), Jan., 1, 41-44. 

Dose: 3200mg/day over 7 years. 

Aging 

Polidori MC. Antioxidant micronutrients in the prevention of age-related 

diseases. J Postgrad Med. 2003 Jul-Sep;49(3):229-35. 

Courtiere, A. et al. 1989. [Lipid peroxidation in aged patients. Influence of 

an antioxidant combination (vitamin C-vitamin E-rutin)]. Therapie 44(1) 

Jan.-Feb., 13-17. 


Sano M. Noncholinergic treatment options for Alzheimer's disease. J Clin 

Psychiatry. 2003;64 Suppl 9:23-8. 

Klatte ET, Scharre DW, Nagaraja HN, Davis RA, Beversdorf DQ. Combination 

therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis 



144

Assoc Disord. 2003 Apr-Jun;17(2):113-6. 

Adams, Jr., J. D. et al. 1991. Alzheimer's and Parkinson's Disease. Brain 

levels of glutathione, glutathione disulfide, and Vitamin E. Mol Chem 

Neuropathol. 14(3), June, 213-226. 

Anemia 

44 

Juan-Salles C, Prats N, Resendes A, Domingo M, Hilton D, Ruiz JM, Garner MM, 

Valls X, Marco AJ. Anemia, myopathy, and pansteatitis in vitamin Edeficient 

captive marmosets (Callithrix spp.). Vet Pathol. 2003 Sep;40(5):540-7. 

Ono, K. 1985. Effects of large dose of Vitamin E supplementation on 

anemia in hemodialysis patients. Nephron, 40(4), 440-445. 

Dose: 600mg/day for 30 days. 

Arthritis 

Can C, Cinar MG, Kosay S, Evinc A. Vascular endothelial dysfunction 

associated with elevated serum homocysteine levels in rat adjuvant 

arthritis: effect of vitamin E administration. Life Sci. 2002 Jun 14;71(4):401-10. 

Honkanen, V. E. et al. 1990. Serum cholesterol and Vitamins A and E in 

juvenile chronic arthritis. Clin Exp Pheumatol 8(2), Mar.-Apr., 187-191. 

Honkanen, V. E. et al. 1989. Vitamins A and E, retinol binding protein and 

zinc in Rheumatoid Arthritis. Clin Exp Pheumatol 7(5), Sept.-Oct., 465-469. 

Ataxia 

Roubertie A, Biolsi B, Rivier F, Humbertclaude V, Cheminal R, Echenne B. Ataxia 

with vitamin E deficiency and severe dystonia: report of a case. Brain Dev. 

2003 Sep;25(6):442-5. 

Rayner, R. J. et al. 1993. Isolated Vitamin E deficiency and progressive ataxia. Arch Dis 

Child 69(5), Nov., 602-603. 

Brain injury 

Ikeda Y, Mochizuki Y, Nakamura Y, Dohi K, Matsumoto H, Jimbo H, Hayashi M, 

Matsumoto K, Yoshikawa T, Murase H, Sato K. Protective effect of a novel 

vitamin E derivative on experimental traumatic brain edema in rats-- 

preliminary study. Acta Neurochir Suppl. 2000;76:343-5. 

Dzandzhgava, T. G. and Shakarishvili, R. R. 1991. [Effect of alphatocopherol 

and selenium on the activity of antioxidant enzymes and level of 

lipid peroxidation products in erythrocytes of patients with cerebral 

ischemia]. Vopr Med Khim 37(5), Sept.-Oct. 79-82. 

Cancer 

Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype 

for selective antitumour activity. Br J Cancer. 2003 Nov 17;89(10):1822-6. 

45 

Zu K, Ip C. Synergy between selenium and vitamin E in apoptosis induction 

is associated with activation of distinctive initiator caspases in human 

prostate cancer cells. Cancer Res. 2003 Oct 15;63(20):6988-95. 

Kneky, P. et al. 1991. Vitamin E and cancer prevention. Am J Clin Nutr 53(1 

Suppl), Jan., 283S-286S. 

Kneky, R. et al. 1988. Serum Vitamin E and risk of cancer among Finnish 

men during a 10-year follow-up. Am J Epidemiology 127(1), Jan., 28-41. 



145

Knekt, P. et al. 1991. Dietary antioxidants and the risk of lung cancer. Am J 

Epidemiology 134(5), Sept. 1, 471-479. 

Garewal, H. S. and Schantz, S. 1995. Emerging role of beta-carotene and 

antioxidant nutrients in prevention of oral cancer. Arch Otalaryngol Head 

Neck Surg 121(2), Feb., 141-144. 

Wald, N. J. et al. 1984. Plasma retinol, beta-carotene and Vitamin E levels in 

relation to the future risk of breast cancer. British J Cancer 49(3), Mar., 321- 

324. 

Wald, N. J. et al. 1987. Serum Vitamin E and subsequent risk of cancer. 

British J Cancer 56(1), July, 69-72. 

Salonen, J. T. et al. 1985. Risk of cancer in relation to serum concentrations 

of selenium and Vitamins A and E: Matched case-control analysis of 

prospective data. British Med J 290(6466), Feb. 9, 417-420. 

London, R. S. et al. 1981. Endocrine parameters and alpha-tocopherol 

therapy of patients with mammary dysplasia. Cancer Res 41(9 Pt 2), Sept., 

3811-3813. 

Dose: 600 units/day. 

Taylor, P. R. et al. 1994. Prevention of esophageal cancer: The nutrition 

intervention trials in Linxian, China: Linxian nutrition intervention trials 

study group. Cancer Res. 54(7 Suppl), April 1, 2029s-2031s. 

Dose: 30-60IU/day for 5.25 years. 

Bostick, R. M. et al. 1993. Reduced risk of colon cancer with high intake of 

Vitamin E: The Iowa Women's Health Study. Cancer Res 53(18), Sept. 15, 

4230-4237. 

Zheng, W. et al. 1993. Serum micronutrients and the subsequent risk of oral 

and pharyngeal cancer. Cancer Res 53(4) Feb. 15, 795-798. 

Menkes, M. J. 1986. Vitamin A, E, Selenium and risk of lung cancer. 

Dissertation Abstracts Int. 46(11), 3807. 

46 

Longnecker, M. P. et al. 1992. Serum alpha-tocopherol concentration in 

relation to subsequent colorectal cancer: Pooled data from five cohorts. J 

National Cancer Inst. 84(6), Mar. 18, 430-435. 

Menkes, M. S. et al. 1986. Serum beta-carotene, Vitamins A and E, 

selenium, and the risk of lung cancer. NEJM 315(20), Nov. 13, 1250-1254. 

Wei, Q. et al. 1993. Vitamin supplementation has a protective effect on 

basal cell carcinoma. Am Soc Preventive Oncology, 17th Annual Meeting, 

Mar. 20-23, Tuscon, AR. 

Does: greater than 100 IU/day. 

Knekt, P. 1993. Vitamin E and smoking and the risk of lung cancer. Annals 

NY Acad Sci. 686, May 28, 280-287. 

London, S. J. et al. 1992. Carotenoids, retinol, and Vitamin E and risk of 

proliferative benign breast disease and breast cancer. Cancer Causes 

Control 3(6), Nov., 503-512. 

Benner, S. F. et al. 1994. Reduction in oral mucosa micronuclei frequency 

following alpha-tocopherol treatment of oral leukoplakia. Cancer Epidemiol 

Biomarkers Prev. 3(1), Jan.-Feb., 73-76. 



146

Dose: 400 IU. 

de Vries, N. and Snow, G. B. 1990. Relationships of Vitamins A and E and 

beta-carotene serum levels to head and neck cancer patients with and 

without second primary tumors. Eur Arch Otorhinolaryngol 247(6), 368-370. 

Garewal, H. 1982. Chemoprevention of oral cancer: Beta-carotene and 

Vitamin E in leukoplakia. European J Cell Biology 28(1), Aug., 92-97. 

Knekt, P. et al. 1988. Serum Vitamin E, serum selenium and the risk of 

gastrointestinal cancer. Int J Cancer 42(6), Dec. 15, 846-850. 

Knekt, P. 1988. Serum Vitamin E level and risk of female cancers. Int J 

Epidemiology 17(2), June, 281-286. 

Prasad, K. N. and Edwards-Prasad, J. 1992. Vitamin E and cancer 

prevention: Recent advances and future potentials. J Am College Nutr. 

11(5), Oct. 487-500. 

Torun, M. et al. 1995. Serum Vitamin E level in patients with breast cancer. 

J Clin Pharm Ther., 20(3), June, 173-178. 

Lockwood, K. et al. ?. Apparent partial remission of breast cancer in 'high 

risk' patients supplemented with nutritional antioxidants, essential fatty 

acids and coenzyme Q10. Mol Aspects Med., 15(Suppl), 231-240. 

Dose: 2500 IU. 

Palan, R. R. et al. 1991. Plasma levels of antioxidant beta-carotene and 

alpha-tocopherol in uterine cervix dysplasias and cancer. Nutr Cancer 

15(1), 13-20. 

LeGardeur, B. Y. et al. 1990. A case-control study of serum Vitamins A, E, 

and C in lung cancer patients. Nutr Cancer 14(2), 133-140. 

Wadleigh, R. et al. 1990. Vitamin E in the treatment of chemotherapyinduced 

mucosisitis. Proceedings Annual Meeting Am Soc Clin 

Oncologists 9, A1237. 

Dose: 400 mg/ml applied to lesions for 1 week. 

Dimery, I. et al. 1992. Reduction in toxicity of high dose 13-CIS-Retinoic 

acid (13-CRA) with alpha-tocopherol. Proc Annual Meeting Am Soc Clin 

Oncologists 11, A399. 

Dose: 800, 1200, 1600, 2000 IU/day 4 week cycle. 

Sukolinskii, V. N. and Morozkina, T. S. 1989. [Prevention of postoperative 

complications in patients with stomach cancer using an antioxidant 

complex]. Vopr Onkol 35 (10), 1242-1245. 

Gorozhanskaia, E. G. et al. 1995. [The role of alpha-tocopherol and retinol 

in correcting disorders of lipid peroxidation in patients with malignant liver 

neoplasms]. Vopr Onkol 41(1), 47-51. 

Dose: 600 mg for 7 days prior to surgery. 

Cardiovascular/Coronary heart disease 

Salonen, J. T. et al. 1991. Effects of antioxidant supplementation on platelet 

function: A randomized pair-matched, placebo-controlled, double-blind trial 

in men with low antioxidant status. Am J Clin Nutr 53(5) May, 1222-1229. 

Dose: 300 mg/day for 5 months. 

Bellizz, M. C. et al. 1994. Vitamin E and coronary heart disease: The 



147

European paradox. Eur J Clin Nutr. 48(11), Nov., 822-831. 

Dose: 1 capsule of palmvitee/day for 30 days. 

Tan, D. T. et al. 1991. Effect of a palm-oil-vitamin E concentrate on the 

serum and lipoprotein lipids in humans. Am J Clin Nutr. 53(4 Suppl), Apr. 

1027S-1030S. 

Qureshi, A. A. et al. 1991. Lowering of serum cholesterol in 

hypercholesterolemic humans by tocopherols (Palmvitee). Am J Clin Nutr. 

53(4 Suppl), Apr. 1021S-1026S. 

Dose: 200 mg palmvitee capsules/day or 200mg gamma-tocotrienol/day for 

4 weeks. 

48 

Paolisso, G. et al. 1995. Chronic intake of pharmacological doses of 

Vitamin E might be useful in the therapy of elderly patients with coronary 

heart disease. Am J Clin Nutr. 61(4), Apr., 848-852. 


Brown, K. M. et al. 1994. Vitamin E supplementation suppresses indexes of 

lipid peroxidation and platelet counts in blood of smokers and nonsmokers 

but plasma lipoprotein concentrations remain unchanged. Am J Clin Nutr. 

60(3), Sept., 383-387. 

Dose: 280 mg/day for 10 weeks. 

Steiner, M. et al. 1995. Vitamin E plus aspirin compared with aspirin alone 

in patients with transient ischemic attacks. Am J Clin Nutr 62(6 Suppl), 

Dec., 1381S-1384S. 

Dose: 400 IU/day for up to 2 years. 

Chan, A. C. et al. 1986. Transitory stimulation of human platelet 12- 

lipoxygenase by Vitamin E supplementation . Am J Clin Nutr. 44(2), Aug., 

278-282. 

400 IU/day of either D- or DL- alpha-tocopherol for 4 weeks. 

Guetta, V. et al. 1995. Effect of combined 17 beta-estradiol and Vitamin E on 

low-density lipoprotein oxidation in postmenopausal women. Am J Clin 

Cardiology 75(17), June 15, 1274-1276. 

Knekt, P. et al. 1994. Antioxidant vitamin intake and coronary mortality in a 

longitudinal population study. Am J Epidemiology. 139(12), June 15, 1180- 

1189. 

Sisto, T. et al. 1995. Pretreatment with antioxidants and Allopurinol 

diminishes cardiac onset events in coronary artery bypass grafting. Ann 

Thorac Surg, 59(6), June, 1519-1523. 

Princen, H. M. et al. 1992. Supplementation with Vitamin E but not betacarotene 

in vivo protects low density lipoprotein from lipid peroxidation in 

vitro: Effect of cigarette smoking. Arteriosclerosis Thrombosis 12(5), May, 

554-562. 

Dose: 100 IU/day of DL-alpha-tocopherol. 

Reaven, P. D. and Witzum, J. L. 1993. Comparisons of supplementation of 

RRR-alpha-tocopherol and racemic alpha-tocopherol in humans. Effects on 

lipid levels and lipoprotein susceptibility to oxidation. Arterioscler Thromb 

13 (4), Apr., 601-608. 



148

Reaven, P. D. et al. 1993. Effect of dietary antioxidant combinations in 

humans: Protection of LDL by vitamin E but not by beta-carotene. 

Arterioscler Thromb 13(4), Apr., 590-600. 

49 

Kritchevsky, S. B. et al. Dietary antioxidants and carotid artery wall 

thickness: The ARIC study. Atherosclerosis risk in communities study. 

Circulation 92(8), Oct. 15, 2142-2150. 

Jialal, I. and Grundy, S. M. 1993. Effect of combined supplementation with 

alpha-tocopherol, ascorbate, and beta-carotene on low-density lipoprotein 

oxidation. Circulation 88(6), Dec., 2780-2786. 

Dose: 800 IU/day. 

Luoma, P. V. et al. 1995. High serum alpha-tocopherol, albumin, selenium 

and cholesterol, and low mortality from coronary heart disease in Northern 

Finland. J Internal Med 237(1), Jan., 49-54. 

Haglund, O. et al. 1991. The effects of fish oil on triglycerides, cholesterol, 

fibrinogen and malondialehyde in humans supplemented with Vitamin E. J 

Nutr. 121(2), Feb., 165-169. 

Hodis, H. N. et al. 1995. Serial coronary angiographic evidence that 

antioxidant Vitamin intake reduces progression of coronary artery 

atherosclerosis. JAMA 273(23), June 21, 1849-1854. 

Dose: 100 IU/day or more. 

Fuenmayor, A. J. et al. Vitamin E and ventricular fibrillation threshold in 

myocardial ischemia. Japanese Circulation J 53(10), Oct., 1229-1232. 

Riemersma, R. A. et al. 1991. Risk of angina pectoris and plasma 

concentrations of Vitamins A, C, and E and Carotene. Lancet 337(8732), 

Jan. 5, 1-5. 

Kardinaal, A. F. et al. Antioxidants in adipose tissue and risk of myocardial 

infarction: The EURAMIC study. Lancet 342(8884), Dec. 4, 1379-1384. 

Rimm, E. B. et al. 1993. Vitamin E consumption and the risk of coronary 

heart disease in men. NEJM 328(20), May 20, 1450-1456. 

Dose: 60 IU/day or more. 

Stampfer, M. J. et al. 1993. Vitamin E consumption and the risk of coronary 

disease in women. NEJM 328(20), May 20, 1444-1449. 

Singh, R. B. et al. 1994. Diet, antioxidant vitamins, oxidative stress and risk 

of coronary artery disease: The Peerzada prospective study. Acta Cardiol 

49(5), 453-467. 

Knight, J. A. et al. 1993. The effect of Vitamins C and E on lipid peroxidation 

in stored erythrocytes. Ann Clin Lab Sci 23(1), Jan.-Feb., 51-56. 

Postaire, E. et al. 1995. Increase of singlet oxygen protection of 

erythrocytes by Vitamin E, Vitamin C, and beta-carotene intakes. Biochem 

Mol Biol Int 35(2) Feb., 371-374. 

50 

Dose: 15 mg/day for 15 days. 

Kleijnen, J. et al. 1989. Vitamin E and cardiovascular disease. European J 

Clin Pharmacol 37(6), 541-544. 

Gey, K. F. 1989. Inverse correlation of Vitamin E and ischemic heart 



149

disease. Int J Vitamin Nutr Res Suppl 30, 224-231. 

Dmoszynska-Giannopoulou, A. et al. 1987. Alpha-tocopherol: Effect of 

sulphinpyrazone and alpha-tocopherol on platelet activation and function 

in haemodialysed patients. Int Urol Nephrol 22(6), 561-566. 

Cloarec, M. J. et al. Alpha-tocopherol: Effect on plasma lipoproteins in 

hypercholesterolemic patients. Israeli J Med Sci 23(8), Aug., 869-872. 

Dose: 500 IU/day for 3 months. 

Rifici, V. A. and Khachadurian, A. K. 1993. Dietary supplementation with 

Vitamins C and E inhibits in vitro oxidation of lipoproteins. J Am Coll Nutr 

12(6), Dec., 631-637. 


Lenzhofer, R. et al. 1983. Acute cardian toxicity in patients after 

Doxorubucin treatment and the effect of combined tocopherol and 

Nifedipine pretreatment. J Cancer Res Clin Oncol 106(2), 143-147. 

Yukawa, S. et al. 1992. Prevention of aortic calcification in patients on 

hemodialysis by long-term administration of Vitamin E. J Nutr Sci 

Vitaminol. Spec No:187-90. 


Gey, K. F. et al. 1994. [Essential antioxidants on cardiovascular diseases- 

Lessons for Europe]. Ther Unsch 51(7), July, 475-482. 

Dose: 100 mg/day. 

Steiner, M. 1993. Effect of alpha-tocopherol administration on platelet 

function in man. Thromb Haemost 49(2), Apr. 28, 73-77. 

Dose: 400-1200 IU/day over 6 weeks. 

Cataracts 

Mathew JP, Thomas VC, Thomas I. Selenite cataract and its attenuation by 

vitamin E in Wistar rats. Indian J Ophthalmol. 2003 Jun;51(2):161-70. 

Jacques, P. F. et al. 1988. Antioxidants status in persons with and without 

senile cataract. Arch Ophthalmol 106(3), Mar., 337-340. 

51 

Knekt, P. et al. 1992. Serum antioxidant Vitamins and risk of cataract. 

British Med J 305(6866), Dec. 5, 1392-1394. 

Robertson, J. M. et al. 1989. Vitamin E intake and risk of cataracts in 

humans. Ann NY Acad Sci 570, 372-382. 

Cystic Fibrosis 

Winklhofer-Roob BM, Rock E, Ribalta J, Shmerling DH, Roob JM. Effects of 

vitamin E and carotenoid status on oxidative stress in health and disease. 

Evidence obtained from human intervention studies. Mol Aspects Med. 2003 

Dec;24(6):391-402. 

Sitrin, M. D. et al. 1987. Vitamin E deficiency and neurologic disease in 

adults with cystic fibrosis. Annals Int Med, 107(1), July, 51-54. 

Sung, J. H. et al. 1980. Axonal dystrophy in the gracile nucleus in 

congenital biliary atresia and cystic fibrosis (mucoviscidosis): Beneficial 

effect of Vitamin E therapy. J Neuropathol Exp Neurol, 39(5), Sept., 584-597. 

Cynamon, H. A. et al. 1988. Effect of Vitamin E deficiency on neurologic 

function in patients with cystic fibrosis. J Pediatrics, 113(4), Oct., 637-640. 



150

Elias, E. et al. 1981. Association of spinocerebellar disorders with cystic 

fibrosis or chronic childhood cholestasis and very low serum Vitamin E. 

Lancet, 2(8259), Dec. 12, 1319-1321. 

James. D. R. et al. 1991. Increased susceptibility to peroxide-induced 

haemolysis with normal Vitamin E concentrations in cystic fibrosis. Clin 

Chim Acta, 204(1-3), Dec. 31, 279-290. 

Diabetes 

Hirnerova E, Krahulec B, Strbova L, Stecova A, Dekret J, Hajovska A. Effect of 

vitamin E therapy on progression of diabetic nephropathy. Vnitr Lek. 2003 

Jul;49(7):529-34. 

Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, 

Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin 

M, Ippolito E, Bavera P. Evaluation of the local effects of vitamin E (EMousse) 

on free radicals in diabetic microangiopathy: a randomized, 

controlled trial. Angiology. 2003 Jul-Aug;54(4):415-21. 

Colette, C. et al. 1988. Platelet function in Type I diabetes: Effects of 

supplementation with large doses of Vitamin E. Am J Clin Nutr 47(2), Feb., 

256-261. 

Dose: 1 gm/day for 35 days. 

Paolisso, G. et al. Pharmacologic doses of Vitamin E improve insulin action 

in healthy subjects and non-insulin-dependent diabetic patients. Am J Clin 

Nutr 57(5), May, 650-656. 


Salonen, J. T. et al. 1995. Increased risk of non-insulin dependent Diabetes 

Mellitus at low plasma Vitamin E concentrations: A four year follow-up 

study in men. British Med J 311(7013), Oct. 28, 1124-1127. 

Karpen, C. W. et al. 1984. Interrelation of platelet Vitamin E and 

thromboxane synthesis in type I Diabetes Mellitus. Diabetes, 33(3), Mar., 

239-243. 

Watanabe, J. et al. 1984. Effect of Vitamin E on platelet aggregation in 

Diabetes Mellitus. Thromb Haemost, 51(3), July 29, 3130316. 

Karpen, C. W. et al. 1985. Production of 12-hydroyeicosatetraenoic acid and 

Vitamin E status in platelets from type I human diabetic subjects. Diabetes 

34(6), June, 526-531. 

Caballero, B. 1993. Vitamin E improves the action of insulin. Nutr Rev, 

51(11), Nov., 339-340. 

Kunisaki, M. et al. 1990. Effects of Vitamin E administration on platelet 

function in Diabetes Mellitus. Diabetes Res, 14(1), May, 37-42. 


Dmoszynska-Giannopoulou, A. et al. 1989. [Effect of Vitamin E on the 

function of blood platelets in patients with Diabetes Mellitus], Pol Tyg Lek, 

44(21-22), May 22-29, 496-498. 



151


Dzhavad-zade, M. D. et al. 1992. [Disorders of pulmonary hemodynamics in 

patients with Diabetic Nephroangiopathy and its correction with 

antioxidants], Probl Endokrinol, 38(2), Mar.-Apr., 20-22. 

Dose: 8 mcg/kg/day for 2 weeks. 

Mamedgasanov, R. M. and Rakhmani, S. A. [Dynamics of lipid peroxidation 

in patients with noninsulin-dependent Diabetes Mellitus], Probl Endokrinol, 

35(1), Jan.-Feb., 19-21. 

Balabolkin, M. I. et al. 1994. [Effect of high doses of tocopherol on the 

process of lipid peroxidation and insulin secretion in patients with noninsulin- 

dependent Diabetes Mellitus], Probl Endokrinol, 40(3), May-June, 

10-12. 

Dose: 600-1200 mg/day. 

Kuznetsov, N. S. et al. 1993. [The use of antioxidants (alpha-tocopherol 

acetate) in the treatment of Diabetes Mellitus], Probl Endokrinol, 39(2), 

Mar.-Apr., 9-11. 


Watanabe, J. et al. 1984. Effect of Vitamin E in platelet aggregation in 

Diabetes Mellitus. Tohoku J Exp Med, 143(2), June, 161-169. 

Splavskii, O. I. 1982. [Effectiveness of Vitamin E in the combined therapy of 

the hepatobiliary system lesions in Diabetes Mellitus]. Vopr Pitan, (6), Nov.- 

Dec., 36-39. 

Gerster, H. et al. 1993. Prevention of platelet dysfunction by Vitamin E in 

diabetic athersclerosis. Z Ernahrungswiss 32(4), Dec., 243-261. 

Disseminated Granuloma Anulare 

Burg G. Disseminated granuloma anulare: therapy with vitamin E 

topically. Dermatology. 1992;184(4):308-9. 

Goldstein RK, Zillikens D, Miller K, Elsner P, Burg G. Local treatment of 

disseminated granuloma anulare with a vitamin E emulsion. Hautarzt. 1991 

Mar;42(3):176-8. 

Epilepsy 

Oztas B, Kilic S, Dural E, Ispir T. Influence of antioxidants on the blood-brain 

barrier permeability during epileptic seizures. J Neurosci Res. 2001 Nov 

15;66(4):674-8. 

Ogunmekan, A. O. and Hwang, P. A. 1989. A randomized, double-blind, 

placebo-controlled, clinical trial of D-alpha-tocopherol acetate (Vitamin E), 

as Add-on therapy, for epilepsy in children. Epilepsia, 30(1), Jan.-Feb., 84- 

89. 

Kovalenko, V. M. et al. 1984. [Alpha-tocopherol in the complex treatment of 



152

several forms of epilepsy]. Zh Nevropatol Psikhiatr, 84(6), 892-897. 


Megrabian, A. A. et al. 1986. [Use of lithium carbonate and Vitamin E in the 

complex treatment of epileptics]. Zh Nevropatol Psikhiatr, 86(9), 1407-1410. 

Gastrointestinal Disease 

Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot 

WJ, Dong ZW, Mark SD. Prospective study of serum vitamin E levels and 

esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. 

Beno, I. et al. 1994. The activity of Cu/Zn-superoxide dismutase and 

catalase of gastric mucosa in chronic gastritis, and the effect of alphatocopherol. 

Bratisl Lek Listy, 95(1), Jan., 9-14. 

Feher, J. and Pronai, L. 1993. [Role of free radical scavengers in 

gastrointestinal diseases], Orv Hetil, 34(13), Mar. 28, 693-696. 

General 

Bidoli E, Bosetti C, La Vecchia C, Levi F, Parpinel M, Talamini R, Negri E, Maso 

LD, Franceschi S. Micronutrients and laryngeal cancer risk in Italy and 

Switzerland: a case-control study. Cancer Causes Control. 2003 Jun;14(5):477-84 

Johnson KA, Bernard MA, Funderburg K. Vitamin nutrition in older adults. 

Clin Geriatr Med. 2002 Nov;18(4):773-99. 

Wartanowicz, W. et al. 1984. The effect of alpha-tocopherol and ascorbic 

acid on the serum lipid peroxide level in elderly people. Anna Nutr Metab, 

28(3), 186-191. 


Regnault, C. et al. 1993. Influence of beta carotene,, Vitamin E, and Vitamin 

C on endogenous antioxidant defenses in erythrocytes. Ann Pharmacother, 

27(11), Nov., 1349-1350. 

Denzlinger, C. et al. 1995. Modulation of the endogenous leukotriene 

production by fish oil and Vitamin E. J Lipid Mediat Cell Signal, 11(2), Mar., 

119-132. 


Hearing loss 

Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in 

treatment of idiopathic sudden hearing loss. Otol Neurotol. 2003 Jul;24(4):572- 

5. 

Romeo, G. 1985. The therapeutic effect of Vitamins a and E in 

neurosensory hearing loss. Acta Vitaminol Enzymol, 7 Suppl, 85-92. 

Romeo, G. and Giorgetti, M. 1985. [Therapeutic effects of Vitamin A 

associated with Vitamin E in perceptual hearing loss], Acta Vitaminol 

Enzymol, 7(1-2), 139-143. 

Hemodialysis 

Badiou S, Cristol JP, Morena M, Bosc JY, Carbonneau MA, Dupuy AM, Descomps 

B, Canaud B. Vitamin E supplementation increases LDL resistance to ex 



153

vivo oxidation in hemodialysis patients. Int J Vitam Nutr Res. 2003 Jul;73(4):290- 

6. 

Giardini, O. et al. 1984. Effects of alpha-tocopherol administration on red 

blood cell membrane lipid peroxidation in hemodialysis patients. Clin 

Nephrol, 21(3), Mar., 174-177. 

Hemolysis 

Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, Movilli E, Cancarini 

GC, De Marinis S, D'Avolio G, Broccoli R, Manganoni A, Albertin A, Di Lorenzo D. 

Effects of a vitamin E-bonded membrane and of glutathione on anemia 

and erythropoietin requirements in hemodialysis patients. J Nephrol. 2002 

Sep-Oct;15(5):558-64. 

Prussick, R. et al. 1992. The protective effect of Vitamin E on the hemolysis 

associated with dapsone treatment in patients with dermatitis 

herpetiformis. Arch Dermatol, 128(2)Feb., 210-213. 

Dose: 800 IU/day for 4 weeks. 

Hafez, M, et al. 1986. Improved erythrocyte survival with combined vitamin 

E and selenium therapy in children with glucose-6-phosphate 

dehydrogenase deficiency and mild chronic hemolysis. J Pediatrics, 108(4), 

Apr., 558-561. 

Dose: 800 IU/day for 2 months. 

Corash, L. et al. 1980. Reduced chronic hemolysis during high-dose 

Vitamin E administration in Mediterranean-type glucose-6-phosphate 

dehydrogenase deficiency. New England J Med, 303(8), Aug. 12, 416-420. 

Yalcin, A. S. et al. 1989. The effect of Vitamin E therapy on plasma and 

erythrocyte lipid peroxidation in chronic hemodialysis patients. Clin Chim 

Acta, 185(1), Oct. 31, 109-112. 

Dose: 300 mg/day for 1 month. 

Hepatitis 

Xu M, Hou J, Wu Y, Ling Y. Study on the modulation of the inflammatory 

response in mouse hepatic vasculitis with sodium selenite and vitamin E 

antioxidants. Zhonghua Bing Li Xue Za Zhi. 2000 Aug;29(4):279-83. 

Han, Y. C. 1993. [Study of anti-lipid peroxidation of Vitamin E in human 

body]. Chung Hua Yu Fang I Hsueh Tsa Chih, 27(3), May, 132-134. 

Dose: 200 mg/day after 10 days. 


Ortuno J, Esteban MA, Meseguer J. High dietary intake of alpha-tocopherol 

acetate enhances the non-specific immune response of gilthead seabream 

(Sparus aurata L.). Fish Shellfish Immunol. 2000 May;10(4):293-307. 

Meydani, S. N. et al. 1990. Vitamin E supplementation enhances cellmediated 

immunity in healthy elderly subjects. Am J Clin Nutr, 52(3), Sept., 

557-563. 


Kowdley, K. V. et al. 1992. Vitamin E deficiency and impaired cellular 



154

immunity related to intestinal fat malabsorption. Gastroenterology 102(6), 

June, 2139-2142. 

Penn, N. D. et al. 1991. The effect of dietary supplementation with Vitamins 

A, C and E on cell-mediated immune function in elderly long-stay patients: 

A randomized controlled trial. Age Ageing, 20(3), May, 169-174. 

Taccone-Gallucci, M. et al. 1986. Vitamin E supplementation in 

hemodialysis patients: Effects on peripheral blood mononuclear cells lipid 

peroxidation and immune response. Clin Nephrol, 25(2), Feb., 81-86. 

Gaidova, O. S. et al. 1990. [The immunomodulating properties of Vitamin E 

in surgery involving artificial circulation], Grud serdechnososudistaia Khir, 

(12), Dec., 30-33. 

Dose: 40 mg/kg 3.5 hours prior to open heart surgery. 

Kidney disease/Damage 

Saran R, Novak JE, Desai A, Abdulhayoglu E, Warren JS, Bustami R, Handelman 

GJ, Barbato D, Weitzel W, D'Alecy LG, Rajagopalan S. Impact of vitamin E on 

plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease 

(CKD): a pilot study. Nephrol Dial Transplant. 2003 Nov;18(11):2415-20. 

Bilenko, M. V. et al. 1983. [Use of antioxidants to prevent damage during 

acute ischemia and reperfusion of the kidneys], Biull Eksp Biol Med, 96(9), 

Sept., 8-11. 

Leg cramps 

Roca AO, Jarjoura D, Blend D, Cugino A, Rutecki GW, Nuchikat PS, Whittier FC. 

Dialysis leg cramps. Efficacy of quinine versus vitamin E. ASAIO J. 1992 Jul- 

Sep;38(3):M481-5. 

Roca, A. O. et al. 1992. Dialysis leg cramps: Efficacy of quinine versus 

Vitamin E. ASAIO J, 38(3), July-Sept., M481-485. 


Mucositis 

Lopez I, Goudou C, Ribrag V, Sauvage C, Hazebroucq G, Dreyfus F. Treatment 

of mucositis with vitamin E during administration of neutropenic 

antineoplastic agents. Ann Med Interne (Paris). 1994;145(6):405-8. 

Wadleigh, R. G. et al. 1992. Vitamin E in the treatment of chemotherapyinduced 

Mucositis. Am J Med. 92(5) May, 481-484. 

Myotonic dystrophy 

Backman E, Henriksson KG. Effect of sodium selenite and vitamin E 

treatment in myotonic dystrophy. J Intern Med. 1990 Dec;228(6):577-81. 

Orndahl, G. et al. 1986. Myotonic dystrophy treated with selenium and 

Vitamin E. Acta Med Scand, 219(4), 407-414. 

Dose: 600 mg Vitamin E. 

Neurological function 



155

Yargicoglu P, Yaras N, Agar A, Gumuslu S, Bilmen S, Ozkaya G. The effect of 

vitamin E on stress-induced changes in visual evoked potentials (VEPs) in 

rats exposed to different experimental stress models. Acta Ophthalmol Scand. 

2003 Apr;81(2):181-7. 

Muller, D. P. et al. 1983. Vitamin E and neurological function. Lancet 

1(8318), Jan. 29, 225-228. 

Muller, D. P. 1986. Vitamin E-Its role in neurological function. Postgraduate 

Med J, 62(724), Feb., 107-112. 

Lloyd, B. W. and Dubowitz, V. 1992. Progressive neurological disorders 

associated with obstructive jaundice and Vitamin E deficiency. 

Neuropediactrics, 13(3), Aug., 155-157. 

Davidai, G. et al. 1986. Hypovitaminosis E induced neuropathy in exocrine 

pancreatic failure. Arch Dis Child, 61(9), Sept., 901-903. 

Palmucci, L. et al. 1988. Neuropathy secondary to Vitamin E deficiency in 

acquired in acquired intestinal malabsorption. Italian J Neurol Sci, 9(6), 

Dec., 599-602. 

Neutrophil 

Hou J, Wu Y, Ling Y. Modulation of the inflammatory response through 

complement-neutrophil activation feedback mechanism with selenium and 

vitamin E. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2000 Dec;22(6):580-4. 

Chai, J. et al. 1995. [Protective effects of Vitamin E on impaired neutrophil 

phagocytic function in patients with severe burn]. Chung Hua Cheng Hsing 

Shao Shang Wai Ko Tsa Chih, 11(1), Jan., 32-35. 

Osteoarthritis 

Kaiki G, Tsuji H, Yonezawa T, Sekido H, Takano T, Yamashita S, Hirano N, Sano 

A. Osteoarthrosis induced by intra-articular hydrogen peroxide injection 

and running load. J Orthop Res. 1990 Sep;8(5):731-40. 

Blankenhorn, G. 1986. [Clinical effectiveness of Spondyvit (vitamin E) in 

activated arthroses: A multicenter placebo-controlled double-blind study], 

Z Orthop, 124(3), May-June, 340-343. 


Scherak, O. et al. 1990. [High dose Vitamin E therapy in patients with 

activated arthrosis], Z Rheumatol, 49(6), Nov.-Dec., 369-373. 


Machtey, I. and Ouaknine, L. 1978. Tocopherol in osteoarthritis: A 



156

controlled pilot study. J Am Geriatric Soc, 26(7), July, 328-330. 



Fariss MW, Zhang JG. Vitamin E therapy in Parkinson's disease. Toxicology. 

2003 Jul 15;189(1-2):129-46. 

Fahn, S. 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in 

early Parkinson's disease. Ann Neurol, 32(Suppl), S128-S132. 

Dexter, D. T. et al. 1994. Nigrostriatal function in Vitamin E deficiency: 

Clinical, experimental, and positron emission tomographic studies. Ann 

Neurol, 35(3), Mar., 298-303. 

Peripheral neuropathy 

Lagueny A. Metabolic and nutritional neuropathies. Rev Prat. 2000 Apr 

1;50(7):731-5. 

Traber, M. G. et al. 1987. Lack of tocopherol in peripheral nerves of vitamin 

E-deficient patients with peripheral neuropathy. NEJM, 317(5), July 30, 262- 

265. 

Physical Performance 

Asha Devi S, Prathima S, Subramanyam MV. Dietary vitamin E and physical 

exercise: I. Altered endurance capacity and plasma lipid profile in ageing 

rats. Exp Gerontol. 2003 Mar;38(3):285-90. 

Simon-Schnass, I. and Pabst, H. 1988. Influence of Vitamin E on physical 

performance. Int J Vitam Nutr Res, 58(1), 49-54. 

Dose: 2x200 mg dl-alpha-tocopherol acetate for 10 weeks. 

Pulmonary health 

Wang S, Sun NN, Zhang J, Watson RR, Witten ML. Immunomodulatory effects 

of high-dose alpha-tocopherol acetate on mice subjected to sidestream 

cigarette smoke. Toxicology. 2002 Jun 14;175(1-3):235-45. 

Mohsenin, V. 1991. 1991. Lipid peroxidation and antielastase activity in the 

lung under oxidant stress: Role of antioxidant defenses. J Appl Physiology, 

70(4), Apr., 1456-1462. 

Respiration 

Rocksen D, Ekstrand-Hammarstrom B, Johansson L, Bucht A. Vitamin E 

reduces transendothelial migration of neutrophils and prevents lung 

injury in endotoxin-induced airway inflammation. Am J Respir Cell Mol Biol. 

2003 Feb;28(2):199-207. 



157

Richards, G. et al. 1990. Investigations of the effects of oral administration 

of Vitamin E and beta-carotene on the chemiluminescence responses and 

the frequency of sister chromatid exchanges in circulating leukocytes from 

cigarette smokers. Am Rev Respiratory Dis, 142(3), Sept., 648-654. 

Dose: 900 IU for 6 weeks. 

Skopinska-Rozewska, E. et al. 1987. The effect of Vitamin E treatment on 

the incidence of OKT+4 lymphocytes in the peripheral blood of children 

with chronic respiratory tract infections. Archives Immunol Ther Exp, 35(2), 

207-210. 

Short Bowel Syndrome 

Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am 

Fam Physician. 1997 Jan;55(1):197-201. 

Howard, L. et al. 1982. Reversible neurological symptoms caused by 

Vitamin E deficiency in a patient with short bowel syndrome. Am J Clin 

Nutr, 36(6), Dec., 1243-1249. 

Traber, M. G. et al. 1994. Efficacy of water-soluble Vitamin E in the 

treatment of Vitamin E malabsorption in short-bowel syndrome. Am J Clin 

Nutr, 59(6), June, 1270-1274. 

Smoking 

Dyer AR, Elliott P, Stamler J, Chan Q, Ueshima H, Zhou BF; INTERMAP 

Research Group. Dietary intake in male and female smokers, ex-smokers, 

and never smokers: the INTERMAP study. J Hum Hypertens. 2003 

Sep;17(9):641-54. 

Pacht, E. R. et al. 1986. Deficiency of Vitamin E in the alveolar fluid of 

cigarette smokers: Influence on alveolar macrophage cytotoxicity. J Clin 

Invest 77(3), Mar., 789-796. 

Hoshino, E. et al. 1990. Vitamin E suppresses increased lipid peroxidation 

in cigarette smokers. J Parenteral Enteral Nutr, 14(3), May-June, 300-305. 


Spinocerebeller dysfunction 

Brin, M. F. et al. 1985. Blind loop syndrome, Vitamin E malabsorption, and 

spinocerebellar degeneration. Neurology, 35(3), Mar., 338-342. 

Spondylosis 

Mahmud, Z. and Ali, S. M. 1992. Role of Vitamin A and E in spondylosis. 

Bangladesh Med Res Counc Bull, 18(1), Apr., 47-59. 


Steatorrhoea 

Rovner AJ, Schall JI, Jawad AF, Piccoli DA, Stallings VA, Mulberg AE, Zemel BS. 

Rethinking growth failure in Alagille syndrome: the role of dietary intake 



158

and steatorrhea. J Pediatr Gastroenterol Nutr. 2002 Oct;35(4):495-502. 

Evans, D. J. et al. 1995. Symptomatic Vitamin E deficiency diagnosed after 

histological recognition of myometrial lipofuscinosis. Lancet 346(8974), 

Aug. 26, 545-546. 

Stress 

Banerjee AK, Mandal A, Chanda D, Chakraborti S. Oxidant, antioxidant and 

physical exercise. Mol Cell Biochem. 2003 Nov;253(1-2):307-12. 

Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U, Iuliano L. Vitamin E 

Supplementation in Patients With Carotid Atherosclerosis. Reversal of 

Altered Oxidative Stress Status in Plasma But Not in Plaque. Arterioscler 

Thromb Vasc Biol. 2003 Oct 30. 

Meydani, M. et al. 1992. Vitamin E requirement in relation to dietary fish oil 

and oxidative stress in elderly. EXS, 62, 411-418. 

Rokitzki, L. et al. 1994. Alpha-tocopherol supplementation in racing cyclists 

during extreme endurance training. Int J Sport Nutr, 4(3), Sept., 253-264. 

Hartmann, A. et al. 1995. Vitamin E prevents exercise-induced DNA 

damage. Mutation Res, 346(4), Apr., 195-202. 


Tardive Dyskinesia 

Michael N, Sourgens H, Arolt V, Erfurth A. Severe tardive dyskinesia in 

affective disorders: treatment with vitamin E and C. Neuropsychobiology. 

2002;46 Suppl 1:28-30. 

Egan, M. F. et al. 1992. Treatment of Tardive Dyskinesia with Vitamin E. Am 

J Psychiatry, 149(6), June, 773-777. 


Elkashef, A. M. et al. 1990. Vitamin E in the treatment of Tardive Dyskinesia. 

Am J Psychiatry 147(4), Apr., 505-506. 

Dabiri, L. M. et al. 1994. Effectiveness of Vitamin E for treatment of longterm 

Tardive Dyskinesia. Am J Psychiatry, 151(6), June, 925-926. 

Adler, L. A. et al. 1993. Vitamin E treatment of Tardive Dyskinesia. Am J 

Psychiatry, 150(9), Sept., 1405-1407. 

Dose: 1600 IU/day for 8-12 weeks. 

Bischot, L. et al. 1993. Vitamin E in extrapyramidal disorders. Pharm World 

Sci 15(4), Aug. 20, 1993, 146-150. 


Adler, L. A. et al. 1993. Vitamin E in Tardive Dyskinesia: Time course of 

effect after placebo substitution. Psychopharmacol Bull, 29(3), 371-374. 

Lohr, J. B. et al. 1988. Vitamin E in the treatment of Tardive Dyskinesia: The 

possible involvement of free radical mechanisms. Schizophrenia Bull, 

14(2), 291-296. 



159

Thyroid Dysfunction 

Mano T, Iwase K, Hayashi R, Hayakawa N, Uchimura K, Makino M, Nagata M, 

Sawai Y, Oda N, Hamada M, Aono T, Nakai A, Nagasaka A, Itoh M. Vitamin E 

and coenzyme Q concentrations in the thyroid tissues of patients with 

various thyroid disorders. Am J Med Sci. 1998 Apr;315(4):230-2. 

Venditti P, De Leo T, Di Meo S. Vitamin E administration attenuates the 

triiodothyronine-induced modification of heart electrical activity in the rat. J 

Exp Biol. 1997 Mar;200 ( Pt 5):909-14. 

Krishnamurthy, S. and Prasanna, D. 1984. Serum Vitamin E and lipid 

peroxides in malnutrition, hyper and hypothyroidism. Acta Vitaminol 

Exzymol, 6(1), 17-21. 

Danis, I. et al. 1990. [Vitamin E and malondialdehyde in the blood serum of 

thyrotoxicosis patients]. Probl Endokrinol, 36(5), Sept.-Oct. 21-24. 

Tuberculosis 

Plit ML, Theron AJ, Fickl H, van Rensburg CE, Pendel S, Anderson R. Influence 

of antimicrobial chemotherapy and smoking status on the plasma 

concentrations of vitamin C, vitamin E, beta-carotene, acute phase 

reactants, iron and lipid peroxides in patients with pulmonary 

tuberculosis. Int J Tuberc Lung Dis. 1998 Jul;2(7):590-6. 

Gur'eva, I. G. et al. [Antioxidants-Effective pathogenic agents in the 

combined therapy of Pulmonary Tuberculosis]. Ter Arkh 59(7), 72-74. 

Ulcerative colitis 

Sato K, Kanazawa A, Ota N, Nakamura T, Fujimoto K. Dietary supplementation 

of catechins and alpha-tocopherol accelerates the healing of 

trinitrobenzene sulfonic acid-induced ulcerative colitis in rats. 

J Nutr Sci Vitaminol (Tokyo). 1998 Dec;44(6):769-78. 

Bennet, J. D. 1986. Use of alpha-tocopherylquinone in the treatment of 

ulcerative colitis. Gut, 27(6), June, 695-697. 

Dose: 3 gm/day. 

Vitiligo 

Potapenko AY, Kyagova AA. The application of antioxidants in investigations 

and optimization of photochemotherapy. Membr Cell Biol. 1998;12(2):269-78. 

Koshevenko, I. 1989. [Alpha-tocopherol in the combined treatment of 

Vitiligo]. Vestn Dermatol Venerol, (10), 70-72. 



160

Wound healing 

Susaman N, Yalcin S, Ilhan N, Ozercan IH, Kaygusuz I, Karlidag T, Gok U. The 

effect of vitamin E on histopathologic healing and lipid peroxidation levels 

in experimentally induced traumatic tympanic membrane perforations. 

Kulak Burun Bogaz Ihtis Derg. 2003 Mar;10(3):87-92. 

Haberal, M. et al. 1988. The effects of Vitamin E on immune regulations 

after thermal injury. Burns Incl Therm Injuries, 14(5) Oct., 388-393. 

Yellow Nail Syndrome 

Tosti A, Piraccini BM, Iorizzo M. Systemic itraconazole in the yellow nail 

syndrome. Br J Dermatol. 2002 Jun;146(6):1064-7. 

Williams, H. C. et al. 1991. Successful use of topical Vitamin E solution in the 

treatment of nail changes in Yellow Nail Syndrome. Arch Dermatol, 127(7), July, 

1023-1028. 

Omega fatty acids 

Arthritis 

Rennie KL, Hughes J, Lang R, Jebb SA. Nutritional management of 

rheumatoid arthritis: a review of the evidence. J Hum Nutr Diet. 2003 

Apr;16(2):97-109. 

64 

Kremer, J. M. 1991. Clinical studies of Omega-3 fatty acid supplementation 

in patients who have Rheumatoid arthritis. Rheum Dis Clin North Am, 17(2) 

May, 391-402. 

Geusens, P. et al. 1994. Long-term effect of Omega-3 fatty acid 

supplementation in active Rheumatoid Arthritis. A 12-month, double-blind, 

controlled study. Arthritis Rheum 37(6), June, 824-829. 

Dose: 2.6 gm/day for 12 months. 

Cancer 

Dewailly E, Mulvad G, Sloth Pedersen H, Hansen JC, Behrendt N, Hart Hansen JP. 

Inuit are protected against prostate cancer. Cancer Epidemiol Biomarkers Prev. 

2003 Sep;12(9):926-7. 

Kemen, M. et al. 1995 Early postoperative enteral nutrition with arginineomega- 

3 fatty acids and ribonucleic acid-supplemented diet versus 

placebo in cancer patients: An immunologic evaluation of impact. Crit Care 

med 23(4), Apr., 652-659. 

Anti, M. et al. 1992. Effect of omega-3 fatty acids on rectal mucosal cell 

proliferation in subjects at risk for colon cancer. Gastroenterology, 103(3) 

Sept., 883-891. 

Dose: 4 g EPA, 3.6 g DHA for 12 weeks. 




161

Lee KW, Lip GY. The role of omega-3 fatty acids in the secondary 

prevention of cardiovascular disease. QJM. 2003 Jul;96(7):465-80. 

Levine, P. H. et al. 1989. Dietary supplementation with Omega-3 fatty acids 

prolongs platelet survival in hyperlipidemic patients with atherosclerosis. 

Arch Intern Med 149(5) May, 1113-1116. 

Illingworth, D. R. et al. 1984. Inhibition of low density lipoprotein synthesis 

by dietary omega-3 fatty acids in humans. Arteriosclerosis. Arch Intern 

Med, 4(3), May-June, 270-275. 

Dose: 24 gm/day for 4 weeks. 

Harris, W. S. et al. 1984. Dietary omega-3 fatty acids prevent carbohydrateinduced 

hypertriglyceridemia. Metabolism, 33(11), Nov., 1016-1019. 

d'Ivernois, C. et al. [Potential value of omega-3 polyunsaturated fatty acids 

in the prevention of atherosclerosis and cardiovascular diseases], Arch Mal 

Coeur Vaiss, 85(6), June, 899-904. 

65 

Lox, C. D. 1990. The effects of dietary marine fish oils (Omega-3 fatty acids) 

on coagulation profiles in men. Gen Pharmacol, 21(2), 241-246. 

Dose: 900 mg over a period of 30 days. 

Engler, M. B. 1994. Vascular effects of omega-3 fatty acids: Possible 

therapeutic mechanisms in cardiovascular disease. J Cardiovascular Nurs, 

8(3) Apr., 53-67. 

Lungershausen, Y. K. et al. 1994. Reduction of blood pressure and plasma 

triglycerides by omega-3 fatty acids in treated hypertensives. J 

Hypertension, 12(9), Sept., 1041-1045. 

Diabetes 

Christopher CL, Mathuram LN, Genitta G, Cyrus I, Jaya Sundar S. Omega-3 

polyunsaturated fatty acids inhibit the accumulation of PAS-positive 

material in the myocardium of STZ-diabetic wistar rats. Int J Cardiol. 2003 

Apr;88(2-3):183-90. 

Landgraf-Leurs, M. M. et al. 1990. Pilot study on omega-3 fatty acids in type 

I Diabetes Mellitus. Diabetes, 39(3), Mar., 369-375. 

Dose: 5.4 gm EPA, 2.3 gm DHA. 

Popp-Snijders, C. et al. 1987. Dietary supplementation of omega-3 

polyunsaturated fatty acids improves insulin sensitivity in non-insulindependent 

diabetes. Diabetes Res, 4(3), Mar., 141-147. 

Dose: EPA and DHA 3 gm for 8 weeks. 

Evening Primrose Oil 

Arthritis 

Belch JJ, Hill A. Evening primrose oil and borage oil in rheumatologic 

conditions. Am J Clin Nutr. 2000 Jan;71(1 Suppl):352S-6S. 

Jantti, J. et al. 1989. Evening primrose oil in rheumatoid arthritis: Changes 

in serum lipids and fatty acids. Ann Rheum Disease, 48(2), Feb., 1240127. 

Dose: 20 ml evening primrose oil (EPO) containing 9% of gamma-linolenic 



162

acid for 12 weeks. 

Brzeski, M. et al. 1991. Evening primrose oil in patients with rheumatoid 

arthritis and side-effects of non-steroidal anti-inflammatory drugs. British J 

Rhheumatology, 30(5), Oct., 370-372. 

Dose: 6 gm/day 

66 

Eczema 

Ashcroft DM, Po AL. Herbal remedies: issues in licensing and economic 

evaluation. Pharmacoeconomics. 1999 Oct;16(4):321-8. 

Schlin-Karrila, M. et al. Evening primrose oil in the treatment of atopic 

eczema: Effect on clinical status, plasma phospholipid fatty acids and 

circulating blood prostaglandins. British J Dermatology, 117(1), July, 11-19. 

Biagi, P. L. et al. 1988. A long-term study on the use of evening primrose oil 

(Efamol) in atopic children. Drugs Exp Clin Res, 14(4), 285-290. 

Diabetes 

Uccella, R. et al. [Action of evening primrose oil on cardiovascular risk 

factors in insulin-dependent diabetics]. Clin Ter, 129(5), June 15, 381-388. 


Schlin-Karrila, M. et al. Evening primrose oil in the treatment of atopic 

eczema: Effect on clinical status, plasma phospholipid fatty acids and 

circulating blood prostaglandins. British J Dermatology, 117(1), July, 11-19. 

Biagi, P. L. et al. 1988. A long-term study on the use of evening primrose oil 

(Efamol) in atopic children. Drugs Exp Clin Res, 14(4), 285-290. 

Diabetes 

Uccella, R. et al. [Action of evening primrose oil on cardiovascular risk 

factors in insulin-dependent diabetics]. Clin Ter, 129(5), June 15, 381-388. 


Takahashi, R. et al. 1993. Evening primrose oil and fish oil in non-insulindependent- 

diabetes. Prostaglandins Leukot Essent Fatt Acids, 49(2), Aug., 

569-571. 

Dose: 4gm/day for 4 weeks. 

DMAE 

Hemiballismus-hemichorea 

Jameson, H. D. et al. 1977. Hemiballismus-hemichorea treated with 

dimethylaminoethanol. Dis Nerv Syst 38(11) Nov., 931-932 

Phosphatidyl serine 


Shea TB. Phospholipids alter tau conformation, phosphorylation, 



163

proteolysis, and association with microtubules: implication for tau 

function under normal and degenerative conditions. J Neurosci Res. 1997 Oct 

1;50(1):114-22. 

Heiss, W. D. et al. 1994. Long-term effects of phosphatidylserine, pyritinol, 

and cognitive training in Alzheimer's Disease. A neuropsychological, EEG, 

and PET investigation. Dementia, 5(2), Mar.-Apr., 88-98. 


Engel, R. R. et al. 1992. Double-blind cross-over study of 

phosphatidylserine vs. placebo in patients with early dementia of the 

Alzheimer type. Eur Neuropsychopharmacol 2(2), June, 1992, 149-155. 


Crook, T. et al. 1992. Effects of phosphatidylserine in Alzheimer's disease. 

Psychopharmacol Bull, 28(1), 61-66. 


Brain Function 

Mitoma J, Kasama T, Furuya S, Hirabayashi Y. Occurrence of an unusual 

phospholipid, phosphatidyl-L-threonine, in cultured hippocampal 

neurons. Exogenous L-serine is required for the synthesis of neuronal 

phosphatidyl-L-serine and sphingolipids. J Biol Chem. 1998 Jul 

31;273(31):19363-6. 

Lombardi, G. F. 1989. [Pharmacological treatment with phosphatidyl serine 

of 40 ambulatory patients with senile dementia syndrome]. Minerva Med 

80(6), June, 599-602. 

Crook, T. H. et al. 1991. Effects of phosphatidylserine in the age-associated 

memory impairment. Neurology 41(5), May, 644-649. 

Dose: 100 mg for 12 weeks. 

Delwaide, P. J. et al. 1986. Double-blind randomized controlled study of 

phosphatidylserine in senile demented patients. Acta Neurol Scand, 73(2) 

Feb., 136-140. 

Dose: 3x100 mg. 

Maggioni, M. et al. (1990). Effects of phosphatidylserine therapy in geriatric 

patients with depressive disorders. Acta Psychiatr Scand, 81(3), Mar., 265- 

270. 


Cenacchi, T. t al. 1993. Cognitive decline in elderly: A double-blind, 

placebo-controlled multicenter study on efficacy of phosphatidylserine 

administration. Aging 5(2), Apr., 123-133. 



164


Sakai, M. et al. 1996. Pharmacological effect of phosphatidylserine 

enzymatically synthesized from soybean lecithin on brain functions in 

rodents. J Nutr Sci Vitaminol 42(1), Feb., 47-54. 


Epilepsy 

Loeb, C. et al. 1987. Preliminary evaluation of the effect of GABA and 

phosphatidylserine in epileptic patients. Epilepsy Res, 1(3), May, 209-212. 


Finfgeld, E. W. et al. 1989. Double-blind study with phosphatidylserine (PS) 

in Parkinsonian patients with senile dementia of Alzheimer's type. Prog 

Clin Biol Res, 1235-1246. 

Schizophrenia 

Tachik, K. H. et al. 1986. Phosphatidyleserine inhibition of monoamine 

oxidase in platelets of schizophrenics. Biol Psychiatry 21(1), Jan., 59-68. 

Stress 

Sohi KK, Mittal N, Hundal MK, Khanduja KL. Gallic acid, an antioxidant, 

exhibits antiapoptotic potential in normal human lymphocytes: A Bcl-2 

independent mechanism. J Nutr Sci Vitaminol (Tokyo). 2003 Aug;49(4):221-7. 

Monteleone, P. et al. 1992. Blunting by chronic phosphatidylserine 

administration of the stress-induced activation of the hypothalamopituitary- 

adrenal axis in healthy men. European J Clin Pharmacol 42(4), 

385-388. 


Monteleone, P. et al. 1990. Effects of phosphatidylserine on the 

neuroendocrine response to physical stress in humans. 

Neuroendocrinology, 52(3), 243-248. 

Dose: 50 and 75 mg/day. 

Calcium 

Calcium Pancreatitis 

Kaur, N. et al. 1996. Chronic calcific pancreatitis associated with 

osteomalacia and secondary hyperparathyroidism. Indian J 

Gastroenterology 15(4) Oct., 147-148. 

Calcium absorption 



165

Harvey, J. A. et al. 1990. Superior calcium absorption from calcium citrate 

than calcium carbonate using external forearm counting. J Am Coll Nutr, 

9(6), Dec., 583-587. 

Cancer 

Kim JA, Kang YS, Lee YS. Role of Ca2+-activated Cl- channels in the 

mechanism of apoptosis induced by cyclosporin A in a human hepatoma 

cell line. Biochem Biophys Res Commun. 2003 Sep 19;309(2):291-7. 

Duris, I. et al. Calcium chemoprevention in colorectal cancer. 

Hepatogastroenterology, 43(7), Jan.-Feb., 152-154. 

Dental health 

Krall EA, Wehler C, Garcia RI, Harris SS, Dawson-Hughes B. Calcium and 

vitamin D supplements reduce tooth loss in the elderly. Am J Med. 2001 Oct 

15;111(6):452-6. 

Gupta, S. K. et al. 1994. Reversal of clinical and dental fluorosis. Indian 

Pediatr, Apr., 439-443. 


Hip fracture 

Dawson-Hughes B. Calcium and protein in bone health. Proc Nutr Soc. 2003 

May;62(2):505-9. 

Meunier, P. 1996. Prevention of hip fractures by correcting calcium and 

Vitamin D insufficiencies in elderly people. Scand J Rheumatology, 

103(Suppl), 75-78. 

Dose: 1.2 gm/day for a 3 year study. 

Hypertension 

Liao XD, Tang AH, Chen Q, Jin HJ, Wu CH, Chen LY, Wang SQ. Role of Ca2+ 

signaling in initiation of stretch-induced apoptosis in neonatal heart cells. 

Biochem Biophys Res Commun. 2003 Oct 17;310(2):405-11. 

Wimalawansa, S. J. 1993. Antihypertensive effects of oral calcium 

supplementation may be mediated through the potent vasodilator CGRP. 

Am J Hypertension, 6(12), Dec., 996-1002. 

Dose: 1.4 gm/day. 

Osteoporosis 

Koo WW, Warren L. Calcium and bone health in infants. Neonatal Netw. 2003 

Sep-Oct;22(5):23-37. 

Adachi, J. D. et al. 1996. Vitamin D and calcium in the prevention of 

corticosteroid induced osteoporosis: A 3 year follow-up. J Rheumatology 

23(6), June, 995-1000. 

Dose:1000 mg/day. 

Leyes-Vence, M. et al. 1996. Transient osteoporosis of the hip. Presentation 

of a case and literature review. Acta Orthop Belg, 62(1), Mar., 56-59. 



166

Prince, R. et al. 1995. The effects of calcium supplementation (milk powder 

of tablets) and exercise on bone density in postmodern women. J Bone 

Mineral Res 10(7), July, 1068-1075. 

Dose: 1 gm/night over a period of 2 years. 

Haines, C. J. et al. 1995. Calcium supplementation and bone mineral 

density in postmenopausal women using estrogen replacement therapy. 

Bone 16(5), may, 529-531. 

Warady, B. D. 1994. Effects of nutritional supplementation and bone 

mineral status of children with Rheumatic diseases receiving corticosteroid 

therapy. J Rheumatology, 21(3), mar., 530-535. 

Vestibulitis 

Metts JF. Vulvodynia and vulvar vestibulitis: challenges in diagnosis and 

management. 

Am Fam Physician. 1999 Mar 15;59(6):1547-56, 1561-2. 

Solomons, C. C. et al. 1991. Calcium citrate of vulvar vestibulitis. A case 

report. J Reproductive Med, 36(12), Dec., 879-882. 

Magnesium 

Gastrointestinal Problems 

Witham CL, Stull CL. Metabolic responses of chronically starved horses to 

refeeding with three isoenergetic diets. J Am Vet Med Assoc. 1998 Mar 

1;212(5):691-6. 

Zartarian M, Perez JP, Gelas B, Thomas JL. Comparative study of the shortterm 

acceptability and tolerance of a new oral formulation of magnesium 

(TX 1341) and a reference magnesium. J Gynecol Obstet Biol Reprod (Paris). 

1997;26(2):182-6. 

Sue, Y. J. et al. 1994. Efficacy of magnesium citrate cathartic in pediatric 

toxic ingestions. Ann Emerg Med, 24(4), Oct., 709-712. 

Acetyl L-Carnitine 


Scapagnini G, Ravagna A, Bella R, Colombrita C, Pennisi G, Calvani M, Alkon D, 

Calabrese V. Long-term ethanol administration enhances age-dependent 

modulation of redox state in brain and peripheral organs of rat: protection 

by acetyl carnitine. Int J Tissue React. 2002;24(3):89-96. 

Cipolli, C. and Chiari, G. 1990. [Effects of L-acetylcarnitine on mental 

deterioration in the aged: Initial results]. Clin Ter, 132(6Suppl), Mar. 31, 479- 

510. 



167


Salvioli, G. and Neri, M. 1994. L-acetylcarnitine treatment of mental decline 

in the elderly. Drugs Exp Clin Res, 20(4), 169-176. 


Bella, R. et al. 1990. Effect of acetyle-L-carnitine on geriatric patients 

suffering from dysthymic disorders. Int J Clin Pharmacol Res, 10(6), 355- 

360. 

Dose: 3 gm/day for 30-60 days. 

Passeri, M. et al. 1990. Acetyl-L-carnitine in the treatment of mildly 

demented elderly patients. Int J Clin Pharmacol Res, 101(1-2), 75-79. 

Dose: 2 gm/day for 3 months. 

Franceschi, C. et al. 1990. Immunological parameters in aging: Studies on 

natural immunomodulatory substances. Int J Clin Pharmacology Res 10(1- 

2), 53-57. 

Alcoholism 

Calabrese V, Scapagnini G, Latteri S, Colombrita C, Ravagna A, Catalano C, 

Pennisi G, Calvani M, Butterfield DA. Long-term ethanol administration 

enhances age-dependent modulation of redox state in different brain 

regions in the rat: protection by acetyl carnitine. Int J Tissue React. 

2002;24(3):97-104. 

Tempesta, E. et al. 1990. Role of acetyl-L-carnitine in the treatment of 

cognitive deficit in chronic alcoholism. Int J Clin Pharmacology Res, 10(1- 

2), 101-107. 


Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-carnitine in 

Alzheimer's disease patients unresponsive to acetylcholinesterase 

inhibitors. Curr Med Res Opin. 2003;19(4):350-3. 

Sano, M. et al. 1992. Double-blind parallel design pilot study of acetyl 

levocarnitine in patients with Alzheimer's disease. Arch Neurol, 49(11), 

Nov., 1137-1141. 

Dose: 2.5 gm/day for 3 months. 

Spagnoli, A. et al. 1991. Long-term acetyl-L-carnitine treatment in 

Alzheimer's disease. Neurology, 41(11), Nov., 1726-1732. 

Rai, G. et al. 1990. Double-blind, placebo controlled study of acetyl-Lcarnitine 

in patients with Alzheimer's dementia. Curr Med Res Opin, 11(10), 

638-647. 

Dose: 2 gm/day for 24 weeks. 

Parnetti, L. et al. 1992. Pharmacokinetics of IV and oral acetyl-L-carnitine in 

a multiple dose regimen in patients with senile dementia of Alzheimer type. 



168

European J Clin Pharmacology, 42(1), 89-93. 

Pettegrew, J. W. et al. 1995. Clinical and neurochemical effects of acetyl-Lcarnitine 

in Alzheimer's disease. Neurobiol Aging, 16(1), Jan.-Feb., 1-4. 

Amenorrhea 

Genazzani, A. D. et al. 1991. Acetyl-L-carnitine as possible drug in the 

treatment of hypothalamic amenorrhea. Acta Obstet Gynecol Scand, 70(6), 

487-492. 



Adembri, C. et al. 1994. Ischemia-reperfusion of human skeletal muscle 

during aortoiliac surgery: Effects of acetylcarnitine. Histol Histopathol, 9(4), 

Oct., 683-690. 

Dose:3 mg/day iv prior to surgery. 

Dementia 

Kidd PM. A review of nutrients and botanicals in the integrative 

management of cognitive dysfunction. Altern Med Rev. 1999 Jun;4(3):144-61. 

Sinforiani, E. et al. 1990. Neuropsychological changes in demented patients 

treated with acetyl-L-carnitine. Int J Clin Pharmacology Res 10(1-2), 69-74. 

Bonavita, E. 1986. Study of the efficacy and tolerability of L-acetylcarnitine 

therapy in the senile brain. Int J Clin Pharmacol Ther Toxicol, 24(9), Sept., 

511-516. 

Dose: 1,000 mg/day. 

Depression 

Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam 

K, McClure RJ. 31P-MRS study of acetyl-L-carnitine treatment in geriatric 

depression: preliminary results. Bipolar Disord. 2002 Feb;4(1):61-6. 

Garzya, G. et al. 1990. Evaluation of the effects of L-acetylcarnitine on 

senile patients suffering from depression. Drugs Exp Clin Res, 16(2), 101-1- 

6. 


Neurological function 

Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, Wood PA, Franken P. 

Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations 

during sleep. Nat Genet. 2003 Jul;34(3):320-5. 

De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment 

of diabetic neuropathy. A long-term, randomised, double-blind, placebocontrolled 

study. Drugs R D. 2002;3(4):223-31. 



169

Mezzina, C. et al. 1992. Idiopathic facial paralysis: New therapeutic 

prospects with acetyl-L-carnitine. Int J Clin Pharmacology Res, 12(5-6), 

299-304. 


Mazzocchio, R. et al. 1990. Enhancement of recurrent inhibition by 

intravenous administration of L-acetylcarnitine in spastic patients. J Neurol 

Neurosurg Psychiatry, 53(4), Apr., 321-326. 


Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's 

disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-8. 

Kidd PM. Parkinson's disease as multifactorial oxidative 

neurodegeneration: implications for integrative management. Altern Med 

Rev. 2000 Dec;5(6):502-29. 

Puca, F. M. et al. 1990. Clinical pharmodynamics of acetyl-L-carnitine in 

patients with Parkinson's disease. Int J Clin Pharmacol Res, 10(1-2), 139- 

143. 

Dose: 1 or 2 gm/day for 7 days. 

Stroke 

Lolic MM, Fiskum G, Rosenthal RE. Neuroprotective effects of acetyl-Lcarnitine 

after stroke in rats. Ann Emerg Med. 1997 Jun;29(6):758-65. 

Arrigo, A. et al. 1990. Effects of acetyl-L-carnitine on reaction times in 

patients with cerebrovascular insufficiency. Int J Clin Pharmacol Res, 10(1- 

2), 133-137. 

Postiglione, A. et al. 1990. Cerebral blood flow in patients with chronic 

cerebrovascular disease: Effect of acetyl-L-carnitine. Int J Clin 

Pharmacology Res, 10(1-2), 129-132. 

Dose: 1.5 gm iv. 

Rosadini, G. et al. 1990. Acute effects of acetyl-L-carnitine on regional 

cerebral blood flow in patients with brain ischaemia. Int J Clin Pharmacol 

Res, 10(1-2), 123-128. 

Dose: 1,500 mg iv. 

Postiglione, A. et al. 1991. Effect of acute administration of L-acetyl 

carnitine on cerebral blood flow in patients with chronic cerebral infarct. 

Pharmacology Res.23(3), Apr., 241-246. 

Dose: 1.5 gm iv. 

Co-enzyme Q-10 

Cancer 



170

Palan PR, Mikhail MS, Shaban DW, Romney SL. Plasma concentrations of 

coenzyme Q10 and tocopherols in cervical intraepithelial neoplasia and 

cervical cancer. Eur J Cancer Prev. 2003 Aug;12(4):321-6. 

Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line 

chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003 

Apr;22(2):118-23. 

Lockwood, K. et al. 1995. Progress therapy on breast cancer with Vitamin 

Q10 and the regression of metastases. Biochem Biophys Res Commun, 

212(1), July 6, 172-177. 

Dose: 390 mg/day for 3-5 years. 

Lockwood, K. et al. 1994. Partial and complete regression of breast cancer 

in patients in relation to dosage of coenzyme Q10, Biochem Biophys Res 

Commun, 199(3), Mar. 30, 1504-1508. 

Dose: 390 mg/day after 1 month tumor no longer palpable, after 2 months 

mammagrophy indicated no tumor. 

Tsubaki, K. et al. 1984. [Investigation of the preventive effect of CoQ10 

against the side-effects of anthracycline antineoplastic agents], Gan To 

Kagaku Ryoho, 11(7) July, 1420-1427. 

Dose: 1 mg/kg/day iv. 

Okuma, K. et al. 1983. [Protective effect of coenzyme Q10 in cardiotoxicity 

induced by adriamycin], Gan To Kagaku Ryoho, 11(3), Mar., 502-508. 


Kamikawa, T. et al. 1985. Effects of coenzyme Q10 on exercise tolerance in 

chronic stable angina pectoris. Am J Cardiology, 56(4), Aug. 1, 1985, 247- 

251. 


Tanaka, J. et al. 1983. Coenzyme Q10: The prophylactic effect on low 

cardiac output following cardiac valve replacement. Annals Thoraci Surg. 

33(2), Feb., 145-151. 

Dose: 30-60 mg/day orally for 6 days. 

76 

Chello, M. et al. 1994. Protection by Coenzyme Q10 from myocardial 

reperfusion injury during coronary artery bypass grafting. Annals Thoracic 

Surg. 58(5), Nov., 1427-1432. 

Dose:150 mg/day for 7 days before surgery. 

Chen, Y. F. et al. 1994. Effectiveness of coenzyme Q10 in myocardial 

preservation during hypothermic cardioplegic arrest. J Thoracic 

Cardiovascular Surg. 107(1), Jan., 242-247. 



171

Greenberg, S. M. and Frishman, W. H. 1988. Coenzyme Q10: A new drug for 

myocardial ischemia? Med Clin North America, 72(1), Jan., 243-258. 

Nishikawa, Y. et al. 1989. Long-term coenzyme Q10 therapy for a 

mitochondrial encephalomyopathy with cytochrome C oxidase deficiency: 

A 31P NMR study. Neurology, 39(3), Mar., 399-403. 

Ogasahara, S. et al. 1985. Improvement of abnormal pyruvate metabolism 

and cardia conduction defect with coenzyme Q10 in Kearns-Sayre 

syndrome, Neurology, 35(3), Mar., 372-373. 

Dose: 60-120 mg/day for 3 months. 

Folkers, K. et al. 1992. Therapy with coenzyme Q10 of patients in heart 

failure who are eligible of ineligible for a transplant. Biochem Biophys Res 

Commun, 182(1) Jan. 15, 247-253. 

Sunamori, M. et al. 1991. Clinical experience of coenzyme Q10 to enhance 

intraoperative myocardial protection in coronary artery revascularization, 

Cardiovasc Drugs Ther, 5 Suppl 2, Mar., 297-300. 

Dose: pretreatment with 5mg/kg iv. 

Baggio, E. et al. 1993. Italian multicenter study of the safety and efficacy of 

coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The 

CoQ10 drug surveillance investigators. Clin Investigations, 71(8 Suppl), 

S145-149. 

Dose: 50-100 mg/day for 3 months. 

Langsjoen, P. H. et al. 1993. Isolated diastolic dysfunction of the 

myocardium and its response to CoQ10 treatment. Clin Investigations, 71(8 

Suppl), S140-144. 

Morisco, C. et al. 1993. Effect of coenzyme Q10 therapy in patients with 

congestive heart failure: A long-term multicenter randomized study. Clin 

Investigations, 71(8 Suppl), S134-146. 

Dose: 2 mg/kg/day for 1 year. 

Lampertico, M. and Conis, S. 1993. Italian multicenter study on the efficacy 

and safety of coenzyme Q10 as adjuvant therapy in heart failure. Clin 

Investigations, 71(8 Suppl), S129-S133. 


Mortensen, S. A. 1993. Perspectives on therapy of cardiovascular diseases 

with coenzyme Q10 (Ubiquinonq). Clin Investigations, 71(8 Suppl), S116- 

S123. 

Mortensen, S. A. et al. 1985. Long-term coenzyme Q10 therapy: A major 

advance in the management of resistant myocardial failure. Drugs Exp Clin 

Res, 11(8), 581-593. 


Langsjoen. P. H. et al. 1985. Effective treatment with coenzyme Q10 of 

patients with chronic myocardial disease. Drugs Exp Clin Res, 11(8), 577- 



172

579. 

Oda, T. 1985. Effect of coenzyme Q10 on stress-induced cardiac 

dysfunction in paediatric patients with mitral valve prolapse: A study by 

stress echocardiography. Drugs Exp Clin Res, 11(8), 557-576. 

Dose: 3-3.4 mg/day. 

Suzuki, H. et al. 1984. Cardiac performance and coenzyme Q10 levels in 

thyroid disorders. Endocrinol Japan, 31(6), Dec., 755-761. 

Kato, T. et al. 1990. Reduction in blood viscosity by treatment with 

coenzyme Q10 in patients with ischemic heart disease. Int J Clin Pharmacol 

Ther Toxicol, 28(3), Mar., 123-126. 


Manzoli, U. et al. 1990. Coenzyme Q10 in dilated cardiomyopathy. Int J 

Tissue React 12(3), 173-178. 

Dose: 100 mg/day orally. 

Langsjoen, P. H. et al. 1990. A six-year clinical study of therapy of 

cardiomyopathy with coenzyme Q10. Int J Tissue React, 12(3), 168-171. 

Langsjoen, P. H. et al. 1990. Pronounced increase of survival of patients 

with cardiomyopathy when treated with coenzyme Q10 and conventional 

therapy. Int J Tissue React, 12(3), 163-168. 

Diabetes 

Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme 

Q(10) improves endothelial dysfunction of the brachial artery in Type II 

diabetes mellitus. Diabetologia. 2002 Mar;45(3):420-6. 

Suzuki, Y. et al. 1995. A case of Diabetic amyotrophy associated with 3243 

mitochondrial tRNA(leu: UUR) Mutation and successful therapy with 

coenzyme Q10, Endocr J, 42(2), Apr., 141-145. 


Folkers, K. et al. 1993. The activities of coenzyme Q10 and vitamin B6 for 

immune responses. Biochem Biophys Res Commun, 193(1), May 28, 88-92. 

Lung disease 

Gazdik F, Gvozdjakova A, Nadvornikova R, Repicka L, Jahnova E, Kucharska J, 

Pijak MR, Gazdikova K. Decreased levels of coenzyme Q(10) in patients with 

bronchial asthma. Allergy. 2002 Sep;57(9):811-4. 

Fujimoto, S. et al. 1993. Effects of coenzyme Q10 administration on 

pulmonary function and exercise performance in patients with chronic lung 

diseases. Clin Investigations, 71(8 Suppl), S126-S166. 




173

Muscular Injury 

Folkers, K. and Simonsen, R. 1995. Two successful double-blind trials with 

coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic 

atrophies. Biochim Biophys Acta, 127(1), May 24, 281-286. 

Glutathione 


Cruz R, Almaguer Melian W, Bergado Rosado JA. Glutathione in cognitive 

function and neurodegeneration. Rev Neurol. 2003 May 1-15;36(9):877-86. 

Julius, M. et al. 1994. Glutathione and morbidity in a community-based 

sample of elderly. J Clin Epi, 47(9), Sept., 1021-1026. 

Cancer 

Kaufmann Y, Kornbluth J, Feng Z, Fahr M, Schaefer RF, Klimberg VS. Effect of 

glutamine on the initiation and promotion phases of DMBA-induced 

mammary tumor development. JPEN J Parenter Enteral Nutr. 2003 Nov- 

Dec;27(6):411-8. 

Flagg, E. W. et al. 1994. Dietary glutathione intake and the risk of oral and 

pharyngeal cancer. Am J Epi, 139(5), Mar. 1, 453-465. 

Cascinu, S. et al. 1995. Neuroprotective effect of reduced glutathione on 

cisplatin-based chemotherapy in advanced gastric cancer: A randomized 

double-blind placebo-controlled trial. J Clin Oncology, 13(1), Jan., 26-32. 

Bowman, A. et al. 1994. Effect of adding glutathione (GSH) to cisplatin 

(CDDP) in the treatment of stage I-IV ovarian cancer. British J Cancer, 

71(Suppl 24), 14. 

Dose: 3 gm/m2 for 21 days. 

Spatti, G. B. et al. 1990. Cisplatin with minimal hydration and glutathione 

protection in the treatment of ovarian carcinoma. Anticancer Res, 10(5B), 

1425-1456. 

Dose: 2.5-5 gm in 100-200 ml of normal saline over 15 minutes iv. 

Dalhoff, K. et al. 1992. Glutathione treatment of hepatocellular carcinoma. 

Liver, 12(5), Oct., 341-343. 


Trickler, D. et al. 1993. Inhibition of oral carcinogenesis by glutathione. Nutr 

Cancer, 20(2), 139-144. 



174

Smyth, J. et al. 1995. Glutathione improves the therapeutic index of 

cisplatin and quality of life for patients with ovarian cancer. Proceedings 

Annual Meeting Am Soc Clin Oncologists, 14, A761. 

Cataracts 

Reddy VN, Giblin FJ, Lin LR, Dang L, Unakar NJ, Musch DC, Boyle DL, 

Takemoto LJ, Ho YS, Knoernschild T, Juenemann A, Lutjen-Drecoll E. 

Glutathione peroxidase-1 deficiency leads to increased nuclear light 

scattering, membrane damage, and cataract formation in gene-knockout 

mice. Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3247-55. 

Sternberg Jr., P. 1993. Protection of retinal pigment epithelium from 

oxidative injury by glutathione and precursors. Invest Ophthalmol Vis Sci, 

34(13), Dec., 3661-3668. 

Gastric injury 

Yajima N, Hiraishi H, Yamaguchi N, Ishida M, Shimada T, Terano A. 

Monochloramine-induced cytolysis to cultured rat gastric mucosal cells: 

role of glutathione and iron in protection and injury. J Lab Clin Med. 1999 

Oct;134(4):372-7. 

Loguericio, C. et al. 1953. Glutathione prevents ethanol induced gastric 

mucosal damage and depletion of sulfydryl compounds in humans. Gut, 

34(2), Feb., 161-165. 

Liver damage 

Grattagliano I, Lauterburg BH, Portincasa P, Caruso ML, Vendemiale G, Valentini 

AM, Palmieri VO, Palasciano G. Mitochondrial glutathione content 

determines the rate of liver regeneration after partial hepatectomy in eu- 

and hypothyroid rats. 

J Hepatol. 2003 Oct;39(4):571-9. 

Nardi, E. A. et al. 1991. [High-dose reduced glutathione in the therapy of 

alcoholic hepatopathy]. Clin Ter, 136(1), Jan. 15, 47-51. 

Dentico, P. et al. 1995. [Glutathione in the treatment of chronic fatty liver 

diseases], Recenti Prog Med, 86(7-8), July-Aug., 290-293. 

N-Acetyl-Cysteine 

Adult respiratory distress syndrome 

Davreux CJ, Soric I, Nathens AB, Watson RW, McGilvray ID, Suntres ZE, Shek 

PN, Rotstein OD. N-acetyl cysteine attenuates acute lung injury in the rat. 

Shock. 1997 Dec;8(6):432-8. 

Laurent, T. et al. 1996. Oxidant-antioxidant balance in granulocytes during 

ARDS. Effect of N-acetylcysteine. Chest, 109(1), Jan., 163-166. 

Bernard, G. R. 1990. Potential of N-acetylcysteine as treatment for the Adult 

Respiratory Distress Syndrome. European Resp J Suppl, 11 Oct., 496s- 



175

498s. 

Cardiovascuar/Coronary heart disease 

Reinhart, K. et al. 1995. N-acetylcysteine preserves oxygen consumption 

and gastric mucosal pH during hyperoxic ventilation. Am J Resp Critical 

Care Med, 151(3 Pt 1), Mar., 773-779. 

Dose: 150 mg/kg-1. 

Boesgaard, S. et al. 1992. Preventive administration of intravenous Nacetylcysteine 

and development of tolerance to isosorbide dinitrate in 

patients with angina pectoris. Circulatio, 85(1), Jan., 143-149. 

Dose: 2 gm NAC over 15 minutes iv. 

Horowitz, J. D. et al. 1993. Potentiation of the cardiovascular effects of 

nitroglycerin by N-acetylcysteine. Circulation, 68(6), Dec., 1247-1253. 

Dose: 100 mg/kg of NAC iv. 

Arstall, M. A. et al. 1995. N-acetylcysteine in combination with nitroglycerin 

and streptokinase for the treatment of evolving acute myocardial infarction. 

Safety and biochemical effects. Circulation, 92(10), Nov. 15, 2855-2862. 

Dose: 15 gm iv NAC. 

Boesgaard, S. et al. 1994. Altered peripheral vasodilator profile of 

nitroglycerin during long-term infusion of N-acetylcysteine. J Am Coll 

Cardiology, 23(1), Jan., 163-169. 

Dose: 2 gm iv NAC followed by 5 mg/kg per hour on human veins. 

Spies, C. et al. 1996. [Effect of prophylactically administered Nacetylcysteine 

on clinical indicators for tissue oxygenation during 

hyperoxic ventilation in cardiac risk patients], Anaesthesist, 45(4), Apr., 

343-350. 

Dose: 150 mg/kg NAC. 

Horowitz, J. D. et al. 1990. Nitroglycerine/N-acetylecysteine in the 

management of unstable angina pectoris. European Heart J, 9(Suppl A) 

Jan., 95-100. 

Dose: 5 gm 6 hourly iv. 

Svendsen, J. H. et al. 1989. N-acetylcysteine modifies the acute effects of 

isosorbide-5-mononitrate in angina pectoris patients. Pharmacol, 13(2), 

Feb., 320-323. 

Andersen, L. W. et al. 1995. The role of N-acetylcysteine administration on 

the oxidative response of neutrophils during cardiopulmonary bypass. 

Perfusion, 10(1), 21-26. 

Dose: bolus of 100 mg/kg of NAC followed by a continuous infusion of 20 

mg/kg. 



176

Chronic Bronchitis 

Jaber R. Respiratory and allergic diseases: from upper respiratory tract 

infections to asthma. Prim Care. 2002 Jun;29(2):231-61. 

Rasmussen, J. B. and Glennow, C. 1988. Reduction in days of illness after 

long-term treatment with N-acetylcysteine controlled-release tablets in 

patients with chronic bronchitis. European Respir J, 1(4), Apr., 351-355. 

Dose: 300 mg bid. 

82 

Gerards, H. H. and Vits, U. 1991. [Therapy of bronchitis. Successful singledosage 

treatment with N-acetylcysteine, results of an administration 

surveillance study in 3,076 patients]. Fortschr Med, 109(34), Nov. 30, 707- 

710. 

Dose: 600 mg/kg. 

Boner, A. L. et al. 1984. A combination of cefuroxine and N-acetyl-cysteine 

for the treatment of maxillary sinusitis in children with respiratory allergy. 

Int J Clin Pharmacol Ther Toxicol, 22(9), Sept, 511-514. 

Dose: 15-25 mg/kg/day over a 10 day period. 

Santagelo, G. et al. 1985. A combination of Cefuroxime and N-acetylcysteine 

for the treatment of lower respiratory tract infections in children. 

Int J Clin Pharmacol Ther Toxicol, 23(5), May, 279-281. 

General 

Simkeviciene V, Straukas J, Uleckiene S. N-acetil-l-cysteine and 2-amino-2- 

thiiazoline N-acetyl-l-cysteinate as a possible cancer chemopreventive 

agents in murine models. Acta Biol Hung. 2002;53(3):293-8. 

Smilkstein, M. J. et al. 1991. Acetaminophen overdose: A 48-hour 

intravenous N-acetylcysteine treatment protocol. Annals Emergency Med., 

20(10), Oct., 1058-1063. 

Dose: (12) 70 mg/kg dose every 4 hours and a loading dose of 140mg/kg. 

Lund, M. E. et al. 1984. Treatment of acute methylmercury ingestion by 

hemodialysis with N-acetylcysteine (Mucomyst) infusion and 2,3- 

dimercaptopropane sulfonate. J Toxicol Clin Yoxicol, 22(1), July, 31-49. 

Jensen, T. et al. 1988. Effect of oral N-acetylcyteine administration on 

human blood neutrophil and monocyte function. APMIS, 96(1), Jan., 62-67. 

Dose: 400 mg oral dose. 

De Groote, J. and Van Steenbergen, W. 1995. Paracetamol intoxication and 

N-acetyl-cysteine treatment. Acta Gastroenterol Belg, 58(3-4), May-Aug., 

326-334. 

Todisco, T. et al. 1985. Effect of N-acetylcysteine in subjects with slow 

pulmonary mucociliary clearance. European J Respir Diseases Suppl, 139, 

136-141. 

Dose: 0.6 gm/day. 

83 

Beckett, G. J. et al. 1990. Intravenous N-acetylcysteine, hepatoxicity and 



177

plasma glutathione S-transferase in patients with Paracetamol overdosage. 

Hum Exp Toxicol, 9(3) May, 183-186. 

Brahm, J. et al. 1992. [Paracetamol overdose: A new form of suicide in 

Chile and the value of N-acetylcysteine administration]. Rev Med Chil, 

120(4), Apr., 427-499. 

Glutathione deficiency 

Boulares AH, Contreras FJ, Espinoza LA, Smulson ME. Roles of oxidative stress 

and glutathione depletion in JP-8 jet fuel-induced apoptosis in rat lung 

epithelial cells. Toxicol Appl Pharmacol. 2002 Apr 15;180(2):92-9. 

Jan, A. et al. 1994. Effect of ascorbate or N-acetylcysteine treatment in a 

patient with hereditary glutathione synthetase deficiency. J Pediatrics, 

124(2), Feb., 229-233. 

Martensson, J. et al. 1989. A therapeutic trial with N-acetylcysteine in 

subjects with hereditary glutathione synthetase deficiency (5- 

oxoprolinuria), J Inherist Metab Dis, 12(2), 120-130. 

Dose: 15 mg/kg/day. 

Hepatitis 

Neri S, Ierna D, Antoci S, Campanile E, D'Amico RA, Noto R. Association of 

alpha-interferon and acetyl cysteine in patients with chronic C hepatitis. 

Panminerva Med. 2000 Sep;42(3):187-92. 

Hepatitis viral load correlates to glutathione levels. Posit Health News. 1998 

Fall;(No 17):14-5. 

Hansen, R. M. et al. 1991. Gold induced hepatitis and pure red cell aplasia. 

Complete recovery after corticosteroid and N-acetylcysteine therapy. J 

Pheumatology, 18(8), Aug., 1251-1253. 

Liver damage 

Neal R, Matthews RH, Lutz P, Ercal N. Antioxidant role of N-acetyl cysteine 

isomers following high dose irradiation. Free Radic Biol Med. 2003 Mar 

15;34(6):689-95. 

Bromley, P. N. et al. 1995. Effects of intraoperative N-acetylcysteine on 

orthotopic liver transplantation. British J Anaesth, 75(3), Sept., 352-354. 

Oh, T. E. and Shenfield, G. M. 1980. Intravenous N-acetylcysteine for 

Paracetamol poisoning. Med J Australia, 1(13), June 28, 664-665. 

Lung damage 

Rahman Q, Abidi P, Afaq F, Schiffmann D, Mossman BT, Kamp DW, Athar M. 

Glutathione redox system in oxidative lung injury. Crit Rev Toxicol. 1999 

Nov;29(6):543-68. 

Meyer, A. et al. 1995. Intravenous N-acetylcysteine and lung glutathione of 

patients with pulmonary fibrosis and normals. Am J Respiratory Crit Care 



178

Med, 152(3), Sept., 1055-1060. 

Dose: 1.8 gm. 

Suter, P. M. et al. 1994. N-acetylcysteine enhances recovery from acute 

lung injury in man. A randomized, double-blind, placebo-controlled clinical 

study. Chest, 105(1), Jan., 190-194. 

Dose: 40 mg/kg/day iv over a period of 72 hours. 

Eklund, A. et al. 1988. Oral N-acetylcysteine reduces selected humoral 

markers of inflammatory cell activity in BAL fluid from healthy smokers: 

Correlation to effects on cellular variables. European Respir J, 1(9), Oct., 

832-838. 

Dose: 200 mg tid over an 8 week period. 

Linden, M. et al. 1988. Effects of oral N-acetylecysteine on cell content and 

macrophage function in bronchoalveolar lavage from healthy smokers. 

European Respiratory J, 1(7), July, 645-650. 


Muscle fatigue 

Khawli FA, Reid MB. N-acetylcysteine depresses contractile function and 

inhibits fatigue of diaphragm in vitro. J Appl Physiol. 1994 Jul;77(1):317-24. 

Reid, M. B. et al. 1994. N-acetylcysteine inhibits muscle fatigue in humans. 

J Clin Investigations, 94(6), Dec., 2468-2474. 

Dose: pretreatment with 150 mg/kg. 

Sjogren's Syndrome 

Walters, M. T. et al. 1986. A double-blind, cross-over, study of oral Nacetylcysteine 

in Sjogren's syndrome. Scandanavian J Pheumatol Suppl, 

61, 253-258. 

Alpha Lipoic acid 

Diabetes 

Gouty S, Regalia J, Cai F, Helke CJ. Alpha-Lipoic acid treatment prevents the 

diabetes-induced attenuation of the afferent limb of the baroreceptor 

reflex in rats. Auton Neurosci. 2003 Oct 31;108(1-2):32-44. 

Kahler, W. et al. 1993. Diabetes Mellitus-A free radical-associated disease. 

Results of adjuvant supplementation. Z. Gesante Inn Med, 48(5), May, 223- 

232. 


Jacob, S. et al. 1995. Enhancement of glucose disposal in patients with 

type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung, 45(8), Aug., 

872-874. 



179

Dose: 1000 mg. 

Ziegler, D. et al. 1995. Treatment of symptomatic diabetic peripheral 

neuropathy with anti-oxidant alpha-lipoic acid. A 3-week multicentre 

randomized controlled trial. Diabetologia, 38(12), Dec., 1425-1433. 

Dose: 600 mg/day over a 3 week period. 

Klein, W. 1975. [Treatment of diabetic neuropathy with oral alpha-lipoic 

acid]. MMW Munch Med Wochenschr, 117(22), May 30, 957-958. 

Dose: 2x50 mg or 2x100 mg/day. 

General 

Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF. Lipoic acid improves 

survival in transgenic mouse models of Huntington's disease. Neuroreport. 

2001 Oct 29;12(15):3371-3. 

Mottley C, Mason RP. Sulfur-centered radical formation from the 

antioxidant dihydrolipoic acid. J Biol Chem. 2001 Nov 16;276(46):42677-83. Epub 

2001 Sep 06 

Barbirolli, B. et al. 1995. Lipoic (thiotic) acid increases brain energy 

availability and skeletal muscle performance as shown by an in vivo 31PMRS 

in a patient with mitochondrial cytopathy. J Neurology, 242(7), July, 

472-477. 

Dose: 600 mg/day for 1 month. 

Glaucoma 

Head KA. Natural therapies for ocular disorders, part two: cataracts and 

glaucoma. Altern Med Rev. 2001 Apr;6(2):141-66. 

Filina, A. A. et al. 1995. Lipoic acid as a means of metabolic therapy of 

open-angle glaucoma. Vestn Oftalmol, 111(4), Oct.-Dec., 6-8. 

Dose: 0.15 gm/day for 1 month. 

DHEA 


Kamel HK. Sarcopenia and aging. Nutr Rev. 2003 May;61(5 Pt 1):157-67. 

Ponholzer A, Plas E, Schatzl G, Jungwirth A, Madersbacher S; Austrian Society of 

Urology. Association of DHEA-S and estradiol serum levels to symptoms of 

aging men. Aging Male. 2002 Dec;5(4):233-8. 

Yen, S. S. et al. 1995. Replacement of DHEA in aging men and women. 

Potential remedial effects. Ann NY Acad Sci, 774, Dec. 29, 128-142. 



180


Leowattana W. DHEA(S): the fountain of youth. J Med Assoc Thai. 2001 Oct;84 

Suppl 2:S605-12. 

Hillen T, Lun A, Reischies FM, Borchelt M, Steinhagen-Thiessen E, Schaub RT. 

DHEA-S plasma levels and incidence of Alzheimer's disease. Biol Psychiatry. 

2000 Jan 15;47(2):161-3. 

Yanase, T. et al. 1996. Serum dehyfroepiandrosterone (DHEA) and DHEAsulfate 

(DHEA-S) in Alzheimer's Disease and in cerebrovascular dementia. 

Endocr J, 43(1), Feb., 119-123. 

Cognitive function 

Harris DS, Wolkowitz OM, Reus VI. Movement disorder, memory, psychiatric 

symptoms and serum DHEA levels in schizophrenic and schizoaffective 

patients. World J Biol Psychiatry. 2001 Apr;2(2):99-102. 

Friess, E. et al. 1995. DHEA administration increases rapid eye movement 

sleep and EEG power in the Sigma frequency range. Am J Physiol, 268(1 Pt 

1), Jan., E107-13. 

Dose: 500 mg oral dose. 

87 

Depression 

Goodyer IM, Herbert J, Tamplin A. Psychoendocrine antecedents of persistent 

first-episode major depression in adolescents: a community-based 

longitudinal enquiry. Psychol Med. 2003 May;33(4):601-10. 

Wolkowitz, O. M. et al. 1997. Dehydroepiandrosterone (DHEA) treatment of 

depression. Biol Psychiatry, 41(3), Feb. 1, 311-318. 

Dose: 30-90 mg/day for 4 weeks. 

General 

Netherton C, Goodyer I, Tamplin A, Herbert J. Salivary cortisol and 

dehydroepiandrosterone in relation to puberty and gender. 

Psychoneuroendocrinology. 2004 Feb;29(2):125-40. 

Khorram, O. 1996. DHEA: A hormone with multiple effects. Curr Opin 

Obstet Gynecol, 8(5), Oct., 351-354. 

Lupus 

Chang DM, Lan JL, Lin HY, Luo SF. Dehydroepiandrosterone treatment of 

women with mild-to-moderate systemic lupus erythematosus: a 

multicenter randomized, double-blind, placebo-controlled trial. Arthritis 

Rheum. 2002 Nov;46(11):2924-7. 

Van Vollenhoven, R. F. and McGuire, J. L. 1996. Studies of 

dehydroepiandrosterone (DHEA) as a therapeutic agent in systemic lupus 

erythematosus. Ann Med Interne, 147(4), 290-296. 



181

Melatonin 

Cancer 

Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ. Melatonin 

and cell death: differential actions on apoptosis in normal and cancer cells. 

Cell Mol Life Sci. 2003 Jul;60(7):1407-26. 

Lissoni, P. et al. 1992. Biological and clinical results of a 

neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin 

as a first line treatment in advanced non-small cell lung cancer. British J 

Cancer, 66(1), July, 155-158. 


Lissoni, P. et al. 1995. Modulation of cancer endocrine therapy by 

melatonin: A phase II study of Taxoifen plus melatonin in metastatic breast 

cancer patients progressing under Tamoxifen alone. British J Cancer, 

71(4), Apr., 854-856. 


Neri, B. et al. 1994. Modulation of human lymphoblastoid interferon activity 

by melatonin in metastatic renal cell carcinoma: A phase II study. Cancer, 

73(12), June 15, 3015-3019. 


Lissoni, P. et al 1994. A randomized study with the pineal hormone 

melatonin versus supportive care alone in patients with brain metastases 

due to solid neoplasms. Cancer, 73(3), Feb 1, 699-701. 

Lissoni, P. et al. 1989. Endocrine and immune effects of melatonin therapy 

in metastic cancer patients. European J Cancer Clin Oncol, 25(5), May, 789- 

795. 

Dose: 20 mg/day intramuscular, followed with 10mg/day in patients 

experiencing remission. 

Viviani, S. et al. 1990. Preliminary studies on melatonin in the treatment of 

Myelodysplastic Syndromes following cancer chemotherapy. J Pineal Res, 

8(4), 347-354. 


Gonzalez, R. et al. 1991. Melatonin therapy of advanced human malignant 

melanoma. Melanoma Res, 1(4), Nov.-Dec., 237-243. 

Dose: daily oral dose of 5 mg/m2 to 700mg/m2 after 5 weeks. 

Lissoni, P. et al. 1991. Clinical results with pineal hormone melatonin in 

advanced cancer resistant to standard antitumor therapies. Oncology, 

48(6), 448-450. 

Dose: 20 mg/day followed with 10mg/day orally. 

Jet Lag 



182

Beaumont M, Batejat D, Pierard C, Van Beers P, Denis JB, Coste O, Doireau P, 

Chauffard F, French J, Lagarde D. CAFFEINE OR MELATONIN EFFECTS 

ON SLEEP AND SLEEPINESS AFTER RAPID EASTWARD 

TRANSMERIDIAN TRAVEL. J Appl Physiol. 2003 Sep 5. 

Petri, K. et al. 1989. Effect of melatonin of jet lag after long haul flights. 

BMJ, 298(6675), Mar. 18, 705-707. 

Dose: 5 mg 3 days prior to flight. 

Petrie, K. et al. A double-blind trial of melatonin as a treatment for jet lag in 

internatinal cabin crew. Biological Psychiatry, 33(7), Apr. 1, 526-530. 

Dose: 5 mg 3 days prior to flight. 

Sleep 

Turk J. Melatonin supplementation for severe and intractable sleep 

disturbance in young people with genetically determined developmental 

disabilities: short review and commentary. J Med Genet. 2003 Nov;40(11):793- 

6. 

Palm, L. et al. 1991. Correction of non-24-hour sleep/wake cycle by 

melatonin in a blind retarded boy. Ann Neurol, 29(3), Mar., 336-339. 

Zhdanova, I. V. et al. 1995. Sleep-inducing effects of low doses of melatonin 

ingested in the evening. Clin Pharmacol Therapy, 57(5), 552-558. 

Dose: 0.3 or 1.0 mg at 6, 8 or 9PM. 

Dahlitz, M. et al. 1991. Delayed sleep phase syndrome response to 

melatonin. Lancet, 337(8750), May 11, 1121-1124. 

Dose: 5 mg for 4 weeks. 

Garfinkel, D. et al. 1995. Improvement of sleep quality in elderly people by 

controlled-release melatonin. Lancet, 346(8974), Aug. 26, 541-544. 

Dose: 2 mg/night for 3 weeks. 

Etzioni, A. et al. 1996. Melatonin replacement corrects sleep disturbances 

in a child with pineal tumor. Neurology, 46(1), Jan, 261-263. 

Dose: 3 mg/night for 2 weeks. 

MacFarlane, J. G. et al. 1991. The effects of exogenous melatonin on the 

total sleep time and daytime alertness of chronic insomniacs: A preliminary 

study. Biological Psychiatry, 30(4), Aug. 15, 371-376. 

Dose: 75 mg per os/night. 

Folkard, S. et al. 1993. Can melatonin improve shift workers' tolerance of 

the night shift? Some preliminary findings. Chronobiol Int, 10(5), Oct., 315- 

320. 

Dose: 5 mg/night. 

Jan, J. E. et al. 1994. The treatment of sleep disorders with melatonin. Dev 

Med Child Neurol, 36(2), Feb., 970107. 

Dose: 2-10 mg. 



183

Waldhauser, F. et al. 1990. Sleep laboratory investigations on hypnotic 

properties of melatonin. Psychopharmacology, 100(2), 222-226. 

Tzischinsky, O. and Lavie, P. 1994. Melatonin possesses time-dependent 

hypnotic effects. Sleep, 17(7), Oct., 638-645. 

Dose: 5 mg. 

Haimov, I. et al. 1995. Melatonin replacement therapy of elderly insomniacs. 

Sleep, 18(7), Sept., 598-603. 

Dose: 2 mg/night for 7 consecutive days. 1 mg of sustained-release. 

Vision 

Scher J, Wankiewicz E, Brown GM, Fujieda H. MT(1) melatonin receptor in 

the human retina: expression and localization. Invest Ophthalmol Vis Sci. 2002 

Mar;43(3):889-97. 

Samples, J. R. et al. 1988. Effect of melatonin on intraocular pressure. 

Current Eye Res 7(7), July, 649-653. 

Pregnenolone 

Kamei H, Noda Y, Nabeshima T, Yamada K. Effects of sigma receptor ligands 

on psychiatric disorders. Nihon Shinkei Seishin Yakurigaku Zasshi. 2003 

Oct;23(5):187-96. 

Araneo, B. A. et al. 1995. Dehydroepiandrosterone reduces progressive 

dermal ischemia caused by 

thermal&127;&127;&127;&127;&127;&127;&127;&127;&127; injury. J Surg 

Res, 59(2) Aug., 250-262 

Dose: Subcutaneous administration of DHEA at approximately 1 mg/kg/day 

achieved optimal protection against the&127; development of progressive 

dermal ischemia. 

Arginine 

Cancer 

Bonafe M, Ceccarelli C, Farabegoli F, Santini D, Taffurelli M, Barbi C, Marzi E, 

Trapassi C, Storci G, Olivieri F, Franceschi C. Retention of the p53 codon 72 

arginine allele is associated with a reduction of disease-free and overall 

survival in arginine/proline heterozygous breast cancer patients. Clin Cancer 

Res. 2003 Oct 15;9(13):4860-4. 

Brittenden, J. et al. 1994. L-arginine stimulates host defenses in patients 

with breast cancer. Surgery, 115(2), Feb., 205-212. 



Tousoulis D, Davies GJ, Tentolouris C, Crake T, Goumas G, Stefanadis C, 

Toutouzas P. Effects of L-arginine on flow mediated dilatation induced by 



184

atrial pacing in diseased epicardial coronary arteries. Heart. 2003 

May;89(5):531-4. 

Rector, T. S. et al. 1996. Randomized, double-blind, placebo controlled 

study of supplemental oral L-arginine in patients with heart failure. 

Circulation, 93(12), June 15, 2135-2141. 

Dose: 5.6 to 12.6 gm/day over 6 weeks. 

Koifman, B. et al. 1995. Improvement of cardiac performance by 

intravenous infusion of L-arginine in patients with moderate congestive 

heart failure. J Am Coll Cardiol, 26(5), Nov. 1, 1251-1256. 

Dose: 20 gm iv. 

Clarkson, P. et al. 1996. Oral L-arginine improves endothelium-dependent 

dilation in hypercholesterolemic young adults. J Clin Investigation, 97(8), 

Apr. 15, 1989-1994. 

Dose: 7 gm 3x/day over 4 weeks. 

McCaffrey, M. J. et al. 1995. Effect of L-arginine infusion on infants with 

persistent pulmonary hypertension on the newborn. Biol Neonate, 6794), 

240-243. 

Dose: 500 mg/kg infused over 30 minutes. 

Hishikawa, K. et al. 1992. L-arginine as a antihypertensive agent. J 

Cardiovascular Pharmacol, 20(suppl 12), S196-S197. 

Kilbourn, R. G. et al. 1995. NG-methyl-L-arginine, an inhibitor of nitric oxide 

synthase, reverses interleukin-2-induced hypotension. Crit Care Med, 23(6), 

June, 1018-1024. 

Dose: 12 mg/kg followed by 4mg/kg every 4 hours. 

General 

Huang ZH, Lin HW, Li Z, Feng HM, Sun YG, Zhang QG. L-arginine decreases 

P-selectin expression in traumatic shock. Di Yi Jun Yi Da Xue Xue Bao. 2003 

Aug;23(8):777-80. 

Pittari, A. M. et al. 1993. Therapy with arginine chlorohydrate in children 

with short constitutional stature. Minerva Pediatr, 45(1-2), Jan.-Feb., 61-65. 


Hepatitis 

Rizzo, S. 1986. Clinical trial with arginine tidiacicate in symptomatic chronic 

persistent hepatitis. Int J Clin Pharmacol Res, 6(3), 225-230. 

Dose: 80 ml of 10% L-arginine HCL daily per os over 6 months. 

Pain 

Harima, A. et al. 1991. Analgesic effect of L-arginine in patients with 

persistent pain. European Neuropsychopharmacol, 1(4), Dec., 529-533. 

Dose: iv 10% solution, 300ml (30g)/patient over a 60-70 minute period. 

Wound healimg 



185

Lu, S. L. 1993. Effect of arginine supplementation on T-lymphocyte function 

in burn patients. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 

9(5), Sept., 368-371. 

Ornithine 


Virgili M, Necchi D, Scherini E, Contestabile A. Increase of the ornithine 

decarboxylase/polyamine system and transglutaminase upregulation in the 

spinal cord of aged rats. Neurosci Lett. 2001 Aug 17;309(1):62-6. 

Brocker, P. et al. 1994. A two-centre, randomized, double-blind trial or 

ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects, 

Age Ageing, 23(4), July, 303-306. 


Cancer 

Sandgren S, Belting M. Suramin selectively inhibits carcinoma cell growth 

that is dependent on extracellular polyamines. Anticancer Res. 2003 Mar- 

Apr;23(2B):1223-8. 

Dunzendorfer, U. 1981. Alpha-difluoromethyornithine (alpha DFMO) and 

phenoxybenzamine hydrochloride in the treatment of chronic nonsuppurative 

prostatitis. Arzneimittelforschung, 31(2), 382-385. 

Dose: 18 gm/day over 1 month. 

Alberts, D. S. et al. 1996. Positive randomized, double blinded, placebo 

controlled study of topical difluoromethyl ornithine (DFMO) in the 

chemoprevention of skin cancer. Proc Annual Meeting Am Soc Clin 

Oncology, 15, A342. 

Dose: 10% w/w topical solution of DFMO applied for 6 months. 

Encephalopathy 

Nicolaides P, Liebsch D, Dale N, Leonard J, Surtees R. Neurological outcome of 

patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. 2002 

Jan;86(1):54-6. 

Herlong, H. F. et al. 1980. The use of ornithine salts of branched-chain 

ketoacids in portal-systemic encephalopathy. Ann Intern Med, 93(4), Oct., 

545-550. 

Dose: 34 mmol/day over 7-10 days. 

Surgical Trauma 

Yin L. Effects on the normalization of amino acids in metabolic support for 

trauma surgical patients Zhonghua Wai Ke Za Zhi. 1992 Nov;30(11):659-62, 699. 

Wernerman, J. et al. 1989. Glutamine and ornithine-alpha-ketoglutarate but 

not branched-chain amino acids reduce the loss of muscle glutamine after 

surgical trauma. Metabolism, 38(8 Suppl 1), Aug., 63-66. 



186

Glutamine 

Cancer 

Todorova VK, Harms SA, Luo S, Kaufmann Y, Babb KB, Klimberg VS. Oral 

glutamine (AES-14) supplementation inhibits PI-3k/Akt signaling in 

experimental breast cancer. JPEN J Parenter Enteral Nutr. 2003 Nov- 

Dec;27(6):404-10. 

94 

Skubitz, K. M. and Anderson, P. M. 1996. Oral glutamine to prevent 

chemotherapy induced stomatitis: A pilot study. J Lab Clin Med, 127(2), 

Feb., 223-228. 

Dose: 4 gm swish and swallow. 


Khogali SE, Pringle SD, Weryk BV, Rennie MJ. Is glutamine beneficial in 

ischemic heart disease? Nutrition. 2002 Feb;18(2):123-6. 

Svedjeholm, R. et al. 1995. Glutamate and high-dose glucose-insulinpotassium 

(GIK) in the treatment of severe cardiac failure after cardiac 

operations. Ann Thirac Surg, 59(2 Suppl), Feb., S23-S30. 

General 

Zhu M, Tang D, Zhao X, Cao J, Wei J, Chen Y, Xiao L, Sun Q. Impact of 

glutamine of gut permeability and clinical prognosis on the aging patients 

undergoing gastric-intestinal operation. Zhongguo Yi Xue Ke Xue Yuan Xue 

Bao. 2000 Oct;22(5):425-7. 

Castell, L. M. et al. 1996. Does glutamine have a role in reducing infections 

in athletes? Eur J Appl Physiol, 73(5), 488-490. 

Liver damage 

Dhar A, Kujath S, Van Way CW 3rd. Glutamine administration during total 

parenteral nutrition protects liver adenosine nucleotides during and after 

subsequent hemorrhagic shock. JPEN J Parenter Enteral Nutr. 2003 Jul- 

Aug;27(4):246-51. 

Santagati, G. et al. 1978. [Glutamic acid gamma-ethyl ester in high doses in 

the treatment of high blood ammonia levels in severe hepatic failure]. 

Minerva Med, 69(20), Apr. 28, 1367-1374. 

Neurotoxicity 

Hasegawa K, Mizutani Y, Kuramoto H, Nagao S, Masuyama H, Hongo A, Kodama 

J, Yoshinouchi M, Hiramatsu Y, Kudo T, Okuda H. The effect of L-Glutamine 

and Shakuyaku-Kanzo-to for paclitaxel-induced myalgia/arthralgia. Gan To 

Kagaku Ryoho. 2002 Apr;29(4):569-74. 

Cooper AJ. Role of glutamine in cerebral nitrogen metabolism and 

ammonia neurotoxicity. Ment Retard Dev Disabil Res Rev. 2001;7(4):280-6. 

95 

Jackson, D. V. et al. 1988. Amelioration of vincristine neurotoxicity by 

glutamic acid. Am J Med. 84(6), June, 1016-1022. 


Short Bowel Syndrome 

Wilmore DW. Indications for specific therapy in the rehabilitation of 



187

patients with the short-bowel syndrome. Best Pract Res Clin Gastroenterol. 2003 

Dec;17(6):895-906. 

Byrne, T. A. et al. 1995. A new treatment for patients with short-bowel 

syndrome. Growth hormone, glutamine, and a modified diet. Annals Surg, 

222(3), Sept., 243-254. 

Tinnitus 

Ehrenberger, K. and Brix, R. 1983. Glutamic acid and glutamic acid 

diethylester in tinnitus treatment. Acta Otolaryngol, 95(5-6), May-June, 599- 

605. 

Wound injury 

MacKay D, Miller AL. Nutritional support for wound healing. Altern Med Rev. 

2003 Nov;8(4):359-377. 

Yan, R. et al. 1995. Early enteral feeding and supplement of glutamine 

prevent occurence of stress ulcer following severe thermal injury. Chung 

Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 11(3), May, 189-192. 

L-Methionine 

Hepatitis 

Gazarian KG, Gening LV, Gazarian TG. L-Homoserine: a novel excreted 

metabolic marker of hepatitis B abnormally produced in liver from 

methionine. Med Hypotheses. 2002 Apr;58(4):279-83. 

Cho MK, Kim SG. Enhanced expression of rat hepatic microsomal epoxide 

hydrolase by methylthiazole in conjunction with liver injury. Toxicology. 

2000 May 5;146(2-3):111-22. 

Windsor, J. A. and Wynne-Jones, G. 1988. Halothane hepatitis and prompt 

resolution with methionine therapy: Case report. New Zealand Med J 

101(851), Aug. 10, 502-503. 

96 

Neuropathy 

Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, 

dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry. 

1998 Jul;65(1):23-8. 

Stacy, C. B. et al. 1992. Methionine in the treatment of nitrous-oxideinduced 

neuropathy and myeloneuropathy. J Neurol, 239(7), Aug., 401-403. 

Paracetamol Poisoning 

Wallace KP, Center SA, Hickford FH, Warner KL, Smith S. S-adenosyl-Lmethionine 

(SAMe) for the treatment of acetaminophen toxicity in a dog. J 

Am Anim Hosp Assoc. 2002 May-Jun;38(3):246-54. 

Vale, J. A. et al. 1981. Treatment of acetaminophen poisoning. The use of 

oral methionine. Arch Intern Med, 141(3 Spec No), Feb. 23, 394-396. 

Crome, P. et al. 1976. Oral methionine in the treatment of severe 

Paracetamol (Acetaminophen) overdose. Lancet, 2(7990), Oct. 6, 829-830. 

Dose: 2-5 gm every 4 hours up to a total of 10g beginning within 10 hours 

of overdose. 

Breen, K. J. et al. 1982. Paracetamol self-poisoning: Diagnosis, 

management, and outcome. Med J Australia, 1(2), Jan. 23, 77-79. 

Trimethyl glycine Betaine 



188

Dry Mouth 

Soderling, E. et al. 1998. Betaine-containing toothpaste relieves subjective 

symptoms of dry mouth. Acta Odontol Scand, 56(2) Apr., 65-69 

Dose: Betaine-containing toothpaste. 

Homocystinuria 

Montero Brens C, Dalmau Serra J, Cabello Tomas ML, Garcia Gomez AM, Rodes 

Monegal M, Vilaseca Busca A. Homocystinuria: effectiveness of the treatment 

with pyridoxine, folic acid, and betaine. An Esp Pediatr. 1993 Jul;39(1):37-41. 

Wilcken, D. E. et al. 1985. Homocystinuria due to cystathionine betasynthase 

deficiency--the effects of betaine treatment in pyridoxineresponsive 

patients. Metabolism, 34(12) Dec., 1115-1121 

Dose: Betaine (trimethylglycine) 6 g/d. 

97 

Wendel, U. and Bremer, H. J. 1984. Betaine in the treatment of 

homocystinuria die to 5,10-methylenetetrahydrofolate reductase deficiency. 

Europ J Pediatrics 142(2), June, 147-150. 

Dose: 15-20 gm/day. 

Aloe 


Agarwal, O. P. 1985. Prevention of atheromaous heart disease. Angiology, 

36(8), Aug., 485-492. 

Constipation 

Odes, H. A. and Madar, Z. 1991. A double-blind trial of a celandin, Aloe vera 

and psyllium laxative preparation in adult patients with constipation. 

Digestion, 49(2), 65-71. 

Diabetes 

Abdullah KM, Abdullah A, Johnson ML, Bilski JJ, Petry K, Redmer DA, Reynolds 

LP, Grazul-Bilska AT. Effects of Aloe vera on gap junctional intercellular 

communication and proliferation of human diabetic and nondiabetic skin 

fibroblasts. J Altern Complement Med. 2003 Oct;9(5):711-8. 

Ghannam, N. et al. 1986. The antidiabetic activity of aloes: Preliminary 

clinical and experimental observations. Hormone Res, 24(4), 288-294. 

Dose: 1/2 tsp/day for 4-14 weeks. 

Ghannam, N. et al. 1986. The antidiabetic activity of aloes. Hormone Res, 

24, 288-294. 

Dose: 1/2 tsp 4x/day for 14 weeks. 

Skin Damage 

Strickland FM, Pelley RP, Kripke ML. Prevention of ultraviolet radiationinduced 

suppression of contact and delayed hypersensitivity by Aloe 

barbadensis gel extract. J Invest Dermatol. 1994 Feb;102(2):197-204. 

Syed, T. A. et al. 1996. Management of psoriasis with aloe vera extract in a 

hydrophilic cream: A placebo-controlled, double-blind study. Trop Med Int 

Health, 1(4), Aug., 505-509. 

Dose: 0.5% Aloe vera extract in a hydrophilic cream. 

98 

Wound Healing 



189

Muller MJ, Hollyoak MA, Moaveni Z, Brown TL, Herndon DN, Heggers JP. 

Retardation of wound healing by silver sulfadiazine is reversed by Aloe 

vera and nystatin. Burns. 2003 Dec;29(8):834-6. 

Fulton Jr., J. E. The stimulation of postdermabrasion wound healing with 

stabilized aloe vera gel-polyethylene oxide dressing. J Dermatol Surg 

Oncology, 16(5), may, 460-467. 

Dose: stabilized Aloe vera. 

Visuthiokosol, V. et al. 1995. Effect of aloe vera gel to healing of burn 

wound a clinical and histologic study. J Med Assoc Thailand, 78(8), Aug., 

403-409. 

Dose: Aloe vera gel. 

Apple Pectin 

Acute Intestinal Infections 

Potievskii, E. G. et al. 1994. [Experimental and clinical studies of the effect 

of pectin on the causative agents of acute intestinal infections]. Zh 

Mikrobiol Epidemiol Immunobiol, Suppl 1 Aug., 106-109 

Dose: 5% pectin solution. 

Diarrhea 

Potievskii EG, Shavakhabov ShSh, Bondarenko VM, Ashubaeva ZD. 

Experimental and clinical studies of the effect of pectin on the causative 

agents of acute intestinal infections. Zh Mikrobiol Epidemiol Immunobiol. 1994 

Aug-Sep;Suppl 1:106-9. 

de la Motte, S. et al. 1997. [Double-blind comparison of an apple pectinchamomile 

extract preparation with placebo in children with diarrhea]. 

Arzneimittelforschung, 47(11) Nov., 1247-1249 

Dose: Apple pectin and chamomille. 

Hypercholesterolemia 

Biesenbach, G. et al. 1993. [The lipid lowering effect of a new guar-pectin 

fiber mixture in type II diabetic patients with hypercholesterolemia]. Leber 

Magen Darm, 23(5) Sept., 204. 

Dose: 1 package of 17 gm with about 5.9 gm water-soluble fiber) dissolved 

in 250 ml water for the next 9 weeks: during the first 3 weeks 2 portions per 

99 

day, the next 3 weeks twice 1/2 portion and the last 3 weeks one 1/2 portion 

daily. The fiber mixture had to been consumed 30 minutes before taking a 

main meal. 

Pirich, C. et al. 1992. [Lowering cholesterol with Anticholest--a high fiber 

guar-apple pectin drink]. Wien Klin Wochenschr, 104(11):314-316. 

Dose: (group 1) at dosages of 1 cup (17 gm) every second day, or 

(group 2) of 1 cup a day or (group 3) of 2 cups a day. 

Hyperlipidemia 

Biesenbach G, Grafinger P, Janko P, Kaiser W, Stuby U, Moser E. The lipid 

lowering effect of a new guar-pectin fiber mixture in type II diabetic 

patients with hypercholesterolemia. Leber Magen Darm. 1993 Sep;23(5):204, 

207-9. 

Grudeva-Popova, J. and Sirakova, I. 1998. Effect of pectin on some 



190

electrolytes and trace elements in patients with hyperlipoproteinemia. Folia 

Med (Plovdiv), 40(1):41-45 

Dose: 15 gm/day high-esterified pectin for 3 months. 

Grudeva-Popova, J. et al. 1997. Application of soluble dietary fibres in 

treatment of hyperlipoproteinemias. Folia Med (Plovdiv), 39(1), 39-43. 

Satiety 

Tiwary, C. M. et al. 1997. Effect of pectin on satiety in healthy US Army 

adults. J Am Coll Nutr, 16(5) Oct., 423-428 

Dose: 5, 10, 15, 20g 

Bee Pollen 

Climacteric Symptoms 

Szanto, E. et al. 1994. [Placebo-controlled study of melbrosia in treatment 

of climacteric symptoms]. Wien Med Wochenschr, 144(7):130-133. 

Memory Function 

Iversen, T. et al. 1997. The effect of Nao Li Su on memory functions and 

blood chemistry in elderly people. J Ethnopharmacol, 56(2) Apr., 109-116. 

Memory Function 

100 

Iarosh, A. A. 1990. [Changes in the immunological reactivity of patients 

with disseminated sclerosis treated by prednisolone and the preparation 

Proper-Myl]. 

Syringomyelia 

Ludianskii, E. A. 1991. [The use of apiotherapy and radon baths in treating 

syringomyelia]. Zh Nevropatol Psikhiatr Im S Korsakova, 91(3), 102-103. 

Chrysanthemum 

Lee JS, Kim HJ, Lee YS. A new anti-HIV flavonoid glucuronide from 

Chrysanthemum morifolium. Planta Med. 2003 Sep;69(9):859-61. 

Urzua A, Mendoza L. Antibacterial activity of fresh flower heads of 

Chrysantemum coronarium. Fitoterapia. 2003 Sep;74(6):606-8. 

Yu, X. Y. 1993. [A prospective clinical study on reversion of 200 

precancerous patients with hua-sheng-ping]. Chung Kuo Chung Hsi I Chieh 

Ho Tsa Chih 13(3) Mar., 147-149 

Zhou , Y. L. 1987. [Chrysanthemum morifolium in the treatment of 

hypertension]. Chung Hsi I Chieh Ho Tsa Chih, 7(1) Jan., 18-20. 

Cruciferous vegetables 

Cancer 

Jackson SJ, Singletary KW. Sulforaphane: a naturally occurring mammary 

carcinoma mitotic inhibitor which disrupts tubulin polymerization. 

Carcinogenesis. 2003 Oct 24. 

Yuan, &127; J. M. et al. 1998. Cruciferous vegetables in relation to renal cell 

carcinoma. Int J Cancer, 77(2) Jul. 17, 211-216. 

Rosen, C. A. 1998. &127;Preliminary results of the use of indole-3-carbinol 

for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg, 

118(6) Jun., 810-815. 

&127;&127;&127;Dose: oral indole-3-carbinol and had a minimum follow-up 

of 8 months and a mean follow-up of 14.6 months. 



191

DeMarini, D. M. et al. 1997. Pilot study of free and conjugated urinary 

mutagenicity during consumption of pan-fried meats: possible modulation 

by cruciferous vegetables, glutathione S-transferase-M1, and Nacetyltransferase- 

2. Mutat Res, 381(1) Nov. 19, 83-96. 

101 

Dose: Ingestion of cruciferous vegetables. 

Witte, J. S. et al. 1996. Relation of vegetable, fruit, and grain consumption 

to colorectal adenomatous&127; polyps. Am J Epidemiol, 144(11) Dec. 1, 

1015-1025. 

Steinmetz, K. A. and&127; Potter, J. D. 1996. Vegetables, fruit, and cancer 

prevention: a review. J Am Diet Assoc, 96(10) Oct, &127;1027-1039. 

General 

Nagle CM, Purdie DM, Webb PM, Green A, Harvey PW, Bain CJ. Dietary 

influences on survival after ovarian cancer. Int J Cancer. 2003 Aug 

20;106(2):264-9. 

Michnovicz, J. J. et al. 1997. Changes in levels of urinary estrogen 

metabolites after oral indole-3-carbinol&127; treatment in humans. J Natl 

Cancer Inst, 89(10) May 21, 718-723. 

Dose: Oral ingestion of 13C (6-7 mg/kg/day. Men received for &127;1 week, 

women received for 2 months. 

Chen, L. et al. 1996. Decrease of plasma and urinary oxidative metabolites 

of acetaminophen after consumption of watercress by human volunteers. 

Clin Pharmacol Ther, 60(6) Dec., 651-660. 

Dose: Watercress homogenates (50 gm). 

Smokers 

Caicoya M. Lung cancer and vegetable consumption in Asturias, Spain. A 

case control study. Med Clin (Barc). 2002 Jul 13;119(6):206-10. 

Seow A, Poh WT, Teh M, Eng P, Wang YT, Tan WC, Chia KS, Yu MC, Lee HP. 

Diet, reproductive factors and lung cancer risk among Chinese women in 

Singapore: evidence for a protective effect of soy in nonsmokers. Int J 

Cancer. 2002 Jan 20;97(3):365-71. 

Hecht SS, Chung FL, Richie JP Jr, Akerkar SA, Borukhova A, Skowronski L, 

Carmella SG. Effects of watercress consumption on metabolism of a 

tobacco-specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers 

Prev. 1995 Dec;4(8):877-84. 

Taioli, E. et al. 1997. Effects of indole-3-carbinol on the metabolism of 4- 

(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers. Cancer Epidemiol 

Biomarkers Prev, 6(7) Jul., 517-522. 

Dose: 400 mg of I3C on 5 consecutive days and maintained constant 

smoking habits during this period. 

102 

Curcumine (Turmeric) 

Anti-inflammatory Effects 

Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory 

actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(2- 

3):113-9. 



192

Satoskar, R. R. et al. 1986. Evaluation of anti-inflammatory property of 

curcumin (Diferuloyl Methane) in patients with postoperative inflammation. 

Int J Clin Pharmacol Ther Toxicol, 24(12), Dec., 651-654. 

Cancer 

Zhang H, Yang L, Liu S, Ren L. Study on active constituents of traditional 

Chinese medicine reversing multidrug resistance of tumor cells in vitro. 

Zhong Yao Cai. 2001 Sep;24(9):655-7. 

Polasa, K. et al. 1992. Effect of turmeric on urinary mutagens in smokers. 

Mutagenesis, 7(2), Mar., 107-109. 

Kuttan, R. et al. 1987. Turmeric and curcumin as topical agents in cancer 

therapy. Tumori, 73(1), Feb. 28, 29-31. 


Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory 

actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(2- 

3):113-9. 

Soni, K. B. and Kuttan, R. 1992. Effect of oral curcumin administration on 

serum peroxides and cholesterol levels in human volunteers. Indian J 

Physiol Pharmacol, 36(4), Oct., 273-275. 


Dandelion Root 

Chronic Colitis 

Chakurski, I. et al.&127; 1981. [Treatment of chronic colitis with an herbal 

combination of Taraxacum officinale, Hipericum perforatum, Melissa 

officinaliss, Calendula officinalis and Foeniculum vulgare]. Vutr Boles, 

20(6), 51-54. 

Garlic 

103 

Cancer 

Das S. Garlic - A Natural Source of Cancer Preventive Compounds. Asian 

Pac J Cancer Prev. 2002;3(4):305-311. 

You, W. C. et al. 1989. Allium vegetables and reduced risk of stomach 

cancer. J National Cancer Inst, 81(2), Jan. 18, 162-164. 


Li G, Shi Z, Jia H, Ju J, Wang X, Xia Z, Qin L, Ge C, Xu Y, Cheng L, Chen P, Yuan 

G. A clinical investigation on garlicin injectio for treatment of unstable 

angina pectoris and its actions on plasma endothelin and blood sugar 

levels. J Tradit Chin Med. 2000 Dec;20(4):243-6. 

Bordia A, Verma SK, Srivastava KC. Effect of garlic on platelet aggregation in 

humans: a study in healthy subjects and patients with coronary artery 

disease. Prostaglandins Leukot Essent Fatty Acids. 1996 Sep;55(3):201-5. 

Gadkari, J. V. and Joshi, V. D. 1991. Effect of ingestion of raw garlic on 

serum cholesterol level, clotting time and fibrinolytic activity in normal 

subjects. J Postgrad Med, 37(3), July, 128-131. 


Bordia, A. 1981. Effect of garlic on blood lipids in patients with coronary 

heart disease. Am J Clin Nutr, 34(10), Oct., 2100-2103. 



193

Jain, A. K. et al. 1993. Can garlic reduce levels of serum lipids? A 

controlled clinical study. Am J Med, 94(6), June, 632-635. 

Dose: 300 mg 3x/day. 

Warhafsky, S. et al. 1993. Effect of garlic on total serum cholesterol. A 

meta-analysis. Annals Int Med, 119(7 Pt 1), Oct. 1, 599-605. 

Vorberg, G. and Schneider, B. 1990. Therapy with garlic: Results of a 

placebo-controlled, double-blind study. British J Clin Pract Symp Suppl, 69, 

Aug., 7-11. 

Dose: 900 mg garlic powder for 4 months. 

Auer, W. et al. 1990. Hypertension and hyperlipidaemia: Garlic helps in mild 

cases. British J Clin Pract Symp Suppl, 69, Aug., 3-6. 

McMahon, F. G. and Vargas, R. 1993. Can garlic lower blood pressure? A 

pilot study. Pharmacotherapy, 13(4), July-Aug., 406-407. 

104 

Dose: 1.3% allicin at 2400mg. 

Ali, M. and Thomson, M. 1995. Consumption of a garlic clove a day could 

be beneficial in preventing thrombosis. Prostaglandins Leukot Essent Fatty 

Acids, 53(3), Sept., 211-212. 

Dose: 1 fresh clove of garlic/day for 16 weeks. 

Kieswetter, H. et al. 1993. Effect of garlic on platelet aggregation in patients 

with increased risk of juvenile ischaemic attack. European J Pharmacology, 

45(333-336. 

Dose: 800 mg powdered garlic over 4 weeks. 

Silagy, C. A. and Neil, A. W. 1994. A meta-analysis of this effect of garlic on 

blood pressure. J Hypertension, 12, 463-468. 

Dose: 600-900 mg/day of dried garlic powder for 12 weeks. 

Hepatopulmonary Syndrome 

Abrams GA, Fallon MB. Treatment of hepatopulmonary syndrome with 

Allium sativum L. (garlic): a pilot trial. J Clin Gastroenterol. 1998 Oct;27(3):232- 

5. 

Caldwell, S. H. et al. 1992. Ancient remedies revisited: Does Allium Sativum 

palliate the hepatopulmonary syndrome? J Clin Gastroenterology, 15(3), 

Oct., 248-250. 

Meningitis 

Shen J, Davis LE, Wallace JM, Cai Y, Lawson LD. Enhanced diallyl trisulfide 

has in vitro synergy with amphotericin B against Cryptococcus 

neoformans. Planta Med. 1996 Oct;62(5):415-8. 

Davis LE, Shen J, Royer RE. In vitro synergism of concentrated Allium 

sativum extract and amphotericin B against Cryptococcus neoformans. 

Planta Med. 1994 Dec;60(6):546-9. 

Davis, L. E. et al. 1990. Anitfungal activity in human cerebrospinal fluid and 

plasma after intravenous administration of Allium Sativum. Antimicrob 

Agents Chemother, 34(4), Apr., 651-653. 

Gingko Biloba 


Topic B, Tani E, Tsiakitzis K, Kourounakis PN, Dere E, Hasenohrl RU, Hacker R, 



194

105 

Mattern CM, Huston JP. Enhanced maze performance and reduced oxidative 

stress by combined extracts of zingiber officinale and ginkgo biloba in the 

aged rat. Neurobiol Aging. 2002 Jan-Feb;23(1):135-43. 

Taillandier, J. et al. 1986. [Treatment of cerebral aging disorders with Ginko 

Biloba extract. A longitudinal multicenter double-blind drug vs. placebo 

study]. Presse Med, 15(31), Sept. 25, 1583-1587. 

Allard, M. 1986. [Treatment of the disorders of aging with Ginko Biloba 

extract. From pharmacology to clinical medicine]. Presse Med, 15(31), Sept. 

25, 1540, 1545. 

Anti-Clastogenic Effects 

Emerit, I. et al. 1995. Clastogenic factors in the plasma of Chernobyl 

accident recovery workers: Anticlastogenic effect of Gingko Biloba extract. 

Radiat Res, 144(2), Nov., 198-205. 


Brain Function/ Injury 

Siddique MS, Eddeb F, Mantle D, Mendelow AD. Extracts of Ginkgo biloba and 

Panax ginseng protect brain proteins from free radical induced oxidative 

damage in vitro. Acta Neurochir Suppl. 2000;76:87-90. 

Hofferberth, B. 1989. [The effect of Ginko Biloba extract on 

neurophysiological and psychometric measurement results in patients with 

psychotic organic brain syndrome. A double-blind study against placebo]. 

Arzneimittelforschung, 39(8), Aug., 918-922. 


Hopfenmuller, W. 1994. [Evidence for a therapeutic effect of Ginko Biloba 

special extract. Meta-analysis of 11 clinical studies in patients with 

cerebrovascular insufficiency in old age]. Arzneimittelforschung, 44(9), 

Sept., 1005-1013. 


Gessner, B. et al. 1985. Study of the long-term action of a Ginkgo Biloba 

extract on vigilance and mental performance as determined by means of 

quantitative pharmaco-EEg and psychometric measurements. 

Arzneimittelforschung, 35(9), 1459-1465. 


Kleijnen, J. and Knipschild, P. 1992. Ginkgo Biloba for cerebral 

insufficiency. British J Clin Pharmacology, 34(4), Oct., 352-358. 

106 

Dose: 120 mg/day for 4-6 weeks. 

Allain, H. et al 1993. Effect of two doses of Ginkgo Biloba extract (EGb 761) 

on the dual coding test in elderly subjects. Clin Ther, 15(3), may-June, 549- 

558. 

Dose: 320 or 600 mg. 

Rai, G. S. et al. 1991. A double-blind, placebo controlled study of Gingko 

Biloba extract ('tanakan') in elderly outpatients with mild to moderate 

memory impairment. Curr Med Res Opin, 12(6), 350-355. 

Dose: 120 mg/day at 12 and 24 weeks. 



195

Grassel, E. 1992. [Effect of Ginkgo-biloba extract on mental performance: 

Double-blind study using computerized measurement conditions in 

patients with cerebral insufficiency]. Fortschr Med, 110(5), Feb. 20, 73-76. 

Eckmann, F. 1990. [Cerebral insufficiency-Treatment with Gingko-biloba 

extract. Time of onset of effect in a double-blind study with 60 inpatients]. 

Fortschr Med, 108(29), Oct. 10, 557-560. 


Gerhardt, G. et al. 1990. [Drug therapy of disorders of cerebral 

performance: Randomized comparative study of dihydroergotoxine and 

Ginkgo Biloba extract]. Fortschr Med, 108(19), June 30, 384-388. 

Subhan, Z. and Hindmarch, I. 1984. The psychopharmacological effects of 

Ginkgo Biloba extract in normal healthy volunteers. Int J Clin 

Pharmacology Res, 4(2), 89-93. 

Dose: 120, 240, or 600 mg/day. 

Raabe, A. et al. 1991. [Therapeutic follow-up using automatic perimetry in 

chronic cerebroretinal ischemia in elderly patients. prospective doubleblind 

study with graduated dose Ginkgo Biloba treatment (EGb 761), Klin 

Monatsbl Augenheilkd, 199(6), Dec., 432-438. 


Lebuisson, D. A. et al. 1986. [Treatment of senile macular degeneration with 

Ginkgo Biloba extract. A preliminary double-blind drug vs. placebo study]. 

Presse Med, 15(31), Sept. 25, 1556-1558. 

Funfgeld, E. W. 1989. A natural and broad spectrum nootropic substance 

for treatment of SDAT-the Ginkgo Biloba extract. Prog Clin Biol Res, 317, 

1247-1260. 


Mahady GB. Ginkgo biloba for the prevention and treatment of 

107 

cardiovascular disease: a review of the literature. J Cardiovasc Nurs. 2002 

Jul;16(4):21-32. 

Schneider, B. 1992. [Ginkgo biloba extract in peripheral arterial diseases. 

Meat-analysis of controlled clinical studies]. Arzneimittelforschung, 42(4), 

Apr., 428-436. 

Jung, F. et al. 1990. Effect of Ginkgo Biloba on fluidity of blood and 

peripheral microcirculation in volunteers. Arzneimittelforschung, 40(5), 

May, 589-593. 

Bauer, U. 1984. 6-month double-blind randomised clinical trial of Ginkgo 

Biloba extract versus placebo in two parallel groups in patients suffering 

from peripheral arterial insufficiency. Arzneimittelforschung, 34(6), 716-720. 

Schaffler, K. and Reeh, P. W. 1985. [Double blind study of the hypoxia 

protective effect of a standardized Ginkgo Biloba preparation after repeated 

administration in healthy subjects]. Arzneimittelforschung, 35(8), 1283- 

1286. 

Witte, S. et al. 1992. [Improvement of hemorheology with Ginkgo Biloba 

extract. Decreasing a cardiovascular risk factor]. Fortschr Med, 110(13), 

May 10m 247-250. 



196


Koltringer, P. et al. 1993. [Hemorheologic effects of Ginkgo Biloba extract 

EFb 671. Dose-dependent effect of EGb 761 on microcirculation and 

visoelasticity of blood]. Fortschr Med, 111(10), Apr. 10, 170-172. 

Dose: single injection of 50, 100, 150, 200 mg. 

Bauer, U. 1986. [Ginkgo Biloba extract in the treatment of arteriopathy of 

the lower extremities. A 65-week trial]. Presse Med, 15(31), Sept. 25, 1546- 

1549. 

Koltringer, P. et al. 1989. [Microcirculation in parenteral Ginkgo Biloba 

extract therapy]. Wien Klin Wochenschr, 101(6), Mar. 17, 198-200. 

Claudication 

Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent 

claudication: a meta-analysis of randomized trials. Am J Med. 2000 

Mar;108(4):276-81. 

Erns, E. 1996. [Ginkgo Biloba in treatment of intermittent claudication. A 

systematic research based on controlled studies in the literature]. Fortschr 

Med, 114(8), Mar. 20, 85-87. 

Drabaek, H. et al. 1986. [The effect of Ginkgo Biloba extract in patients with 

intermittent claudication]. Ugeskr Laeger, 158(27), July 1, 3928-3931. 

108 


Diabetes 

Fitzl G, Welt K, Wassilew G, Clemens N, Penka K, Mukke N. The influence of 

hypoxia on the myocardium of experimentally diabetic rats with and 

without protection by Ginkgo biloba extract. III: Ultrastructural 

investigations on mitochondria. Exp Toxicol Pathol. 2001 Feb;52(6):557-68. 

Lanthony, P. and Cosson, J. P. 1988. [The course of color vision in early 

diabetic retinopathy treated with Ginkgo Biloba extract. A preliminary 

double-blind versus placebo study]. J Fr Ophtalmol, 11(10), 671-674. 

Edema 

Westman J, Drieu K, Sharma HS. Antioxidant compounds EGB-761 and BN- 

520 21 attenuate heat shock protein (HSP 72 kD) response, edema and cell 

changes following hyperthermic brain injury. An experimental study using 

immunohistochemistry in the rat. Amino Acids. 2000;19(1):339-50. 

Lagrue, G. et al. [Idiopathic cyclic edema. The role of capillary 

hyperpermeability and its correction by Ginkgo Biloba extract]. Presse 

Med, 15(31), Sept. 25, 1550-1553. 

General 

Schulz V. Ginkgo extract or cholinesterase inhibitors in patients with 

dementia: what clinical trials and guidelines fail to consider. Phytomedicine. 

2003;10 Suppl 4:74-9. 

Lagrue, G. et al. 1986. [Recurrent shock with monoclonal gammopathy. 

Treatment in the acute and chronic phases with oral and parenteral Ginkgo 

Biloba extract]. Presse Med, 15(31), Sept. 25, 1554-1555. 

Hearing Loss 

Hoffman, F. et al. 1994. [Ginkgo extract EGb 761 )tenobin)/HAES versus 



197

Naftidrofuryl (Dusodril)/HAES. A randomized study of therapy of sudden 

deafness]. Laryngorhinootologie, 73(3), Mar., 149-152. 

Dubreuil, C. 1986. [Therapeutic trial in acute cochlear deafness. A 

comparative study of Ginkgo Biloba extract and Nicergoline]. Presse Med, 

15(31), Sept. 25, 1559-1561. 

Hepatitis 

109 

Li, W. et al. [Preliminary study of early fibrosis of chronic hepatitis B 

treated with Ginkgo Biloba composita]. Chung Kuo Chung Hsi I Chieh Ho 

Tsa Chih, 15(10) Oct., 593-595. 

Neuropathy 

Yoshikawa T, Naito Y, Kondo M. Ginkgo biloba leaf extract: review of 

biological actions and clinical applications. Antioxid Redox Signal. 1999 

Winter;1(4):469-80. 

Koltringer, P. et al. 1989. [Ginkgo Biloba extract and folic acid in the 

therapy of changes caused by autonomic neuropathy]. Acta Med Austriaca, 

16(2), 35-37. 

Dose; 87.5 mg for 4 days. 

Tinnitus 

Morgenstern C, Biermann E. The efficacy of Ginkgo special extract EGb 761 

in patients with tinnitus. Int J Clin Pharmacol Ther. 2002 May;40(5):188-97. 

Meyer, B. 1986. [Multicenter randomized double-blind drug vs. placebo 

study of the treatment of Tinnitus with Ginkgo Biloba extract]. Presse med, 

15(31), Sept. 25, 1562-1564. 

Vertigo 

Cesarani A, Meloni F, Alpini D, Barozzi S, Verderio L, Boscani PF. Ginkgo biloba 

(EGb 761) in the treatment of equilibrium disorders. Adv Ther. 1998 Sep- 

Oct;15(5):291-304. 

Haguenaauer, J. P. et al. 1986. [Treatment of equilibrium disorders with 

Ginkgo Biloba extract. A multicenter double-blind drug vs. placebo study]. 

Presse Med, 15(310, Sept. 25, 1569-1572. 

Hibiscus 

Renal Stone Disease 

Kirdpon, S. et al. 1994. Changes in urinary chemical composition in healthy 

volunteers after consuming roselle (Hibiscus sabdariffa Linn.) juice. J Med 

Assoc Thai, 77(6) Jun., 314-321. 

Dose: Roselle juice consumption, 16 gm/day. 

Peppermint 

110 

General 

Hiki N, Kurosaka H, Tatsutomi Y, Shimoyama S, Tsuji E, Kojima J, Shimizu N, 

Ono H, Hirooka T, Noguchi C, Mafune K, Kaminishi M. Peppermint oil reduces 

gastric spasm during upper endoscopy: a randomized, double-blind, 

double-dummy controlled trial. Gastrointest Endosc. 2003 Apr;57(4):475-82. 

Spirling LI, Daniels IR. Botanical perspectives on health peppermint: more 

than just an after-dinner mint. J R Soc Health. 2001 Mar;121(1):62-3. 



198

Gobel, H. et al. 1994. Effect of peppermint and eucalyptus oil preparations 

on neurophysiological and experimental algesimetric headache 

parameters. Cephalalgia, 14(3), June, 228-234. 

Irritable Bowel Syndrome 

Gaby AR. Treatment with enteric-coated peppermint oil reduced smallintestinal 

bacterial overgrowth in a patient with irritable bowel syndrome. 

Altern Med Rev. 2003 Feb;8(1):3. 

Logan AC, Beaulne TM. The treatment of small intestinal bacterial 

overgrowth with enteric-coated peppermint oil: a case report. Altern Med 

Rev. 2002 Oct;7(5):410-7. 

Treating irritable bowel syndrome with peppermint oil. British Med J, Oct. 6, 

835-836. 

Dose: Peppermint oil in enteric-coated capsules. 

Ulcers 

Meyer, J. et al. 1945. Action of oil of peppermint on the secretion and 

motility of the stomach in man. Arch Int Med, 56,88-97. 

Psyllium 

Jenkins DJ, Kendall CW, Marchie A, Jenkins AL, Connelly PW, Jones PJ, Vuksan 

V. The Garden of Eden--plant based diets, the genetic drive to conserve 

cholesterol and its implications for heart disease in the 21st century. Comp 

Biochem Physiol A Mol Integr Physiol. 2003 Sep;136(1):141-51 

Sierra M, Garcia JJ, Fernandez N, Diez MJ, Calle AP. Therapeutic effects of 

psyllium in type 2 diabetic patients. Eur J Clin Nutr. 2002 Sep;56(9):830-42. 

111 

Zumarraga, L. et al. 1997. Absence of gaseous symptoms during ingestion 

of commercial fibre preparations. Aliment Pharmacol Ther, 11(6) Dec., 

1067-1072. 

Dose: Psyllium 3.4 gm. 

McRorie, J. W. et al. 1998. Psyllium is superior to docusate sodium for 

treatment of chronic constipation. Aliment Pharmacol Ther, 12(5) May, 491- 

497. 

Dose: Psyllium (5.1 gm b.d.). 

Moran, S. et al. 1997. [Effects of fiber administration in the prevention of 

gallstones in obese patients on a reducing diet. A clinical trial]. Rev 

Gastroenterol Mex, 62(4) Oct., 266-272. 

Dose: Psyllium 15 gm. 

Rigaud, D. et al. 1998. Effect of psyllium on gastric emptying, hunger 

feeling and food intake in normal volunteers: a double blind study. Eur J 

Clin Nutr, 52(4) Apr., 239-245. 

Dose: Psyllium 7.4 gm. 

Segawa, K. et al. 1998. Cholesterol-lowering effects of psyllium seed 

associated with urea metabolism. Biol Pharm Bull, 21(2) Feb., &127;184- 

187. 

Davidson, M. H. et al. 1998. Long-term effects of consuming foods 

containing psyllium seed husk on serum lipids in subjects with 

hypercholesterolemia. Am J Clin Nutr, 67(3) Mar., 367-376. 



199

Dose: Psyllium seed 0, 3.4, 6.8, or 10.2 gm for 24 weeks. 

Washington, N. et al. 1998. Moderation of lactulose-induced diarrhea by 

psyllium: Effects on motility and fermentation. Am J Clin Nutr, 67(2) Feb., 

317-321. 

Dose: Psyllium 3.5 gm 3x/day. 

Olson, B. H. et al. 1997. Psyllium-enriched cereals lower blood total 

cholesterol and LDL cholesterol, but not HDL cholesterol, in 

hypercholesterolemic adults: results of a meta-analysis. J Nutr, 127(10) 

Oct., 1973-1980. 

Dose: 3 gm soluble fiber/day. 

Red Clover 

Cancer 

112 

Rock E, DeMichele A. Nutritional approaches to late toxicities of adjuvant 

chemotherapy in breast cancer survivors. 

J Nutr. 2003 Nov;133(11 Suppl 1):3785S-3793S. 

Katz AE. Flavonoid and botanical approaches to prostate health. J Altern 

Complement Med. 2002 Dec;8(6):813-21. 

Jarred RA, Keikha M, Dowling C, McPherson SJ, Clare AM, Husband AJ, 

Pedersen JS, Frydenberg M, Risbridger GP. Induction of apoptosis in low to 

moderate-grade human prostate carcinoma by red clover-derived dietary 

isoflavones. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1689-96. 

Marshal, M. E. et al. 1987. Treatment of metastatic renal cell carcinoma with 

coumarin (1,2-benzopyrone) and cimetide: A pilot study. J Clin Oncology, 

5f(6), June, 862-866. 

Dose:100 mg/day coumarin. 

Silybum Marianum (Milk Thistle) 

Alcohol Abuse 

Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for the 

treatment of liver disease: a systematic review and meta-analysis. Am J Med. 

2002 Oct 15;113(6):506-15. 

Fintelmann, V. 1970. [Zur therapie der fettleber mit silymarin]. 

Therapiewoche, 20, 1055. 

Cirrhosis 

Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver 

diseases. Drugs. 2001;61(14):2035-63. 

Ferenci, P. et al. 1989. Randomized controlled trial of silymarin treatment in 

patients with cirrhosis of the liver. J Hepatol,&127; 9(1) Jul., 105-113. 

Dose:140 mg silymarin 3x/day. 

Diabetes 

Savickiene N, Dagilyte A, Lukosius A, Zitkevicius V. Importance of biologically 

active components and plants in the prevention of complications of 

diabetes mellitus. Medicina (Kaunas). 2002;38(10):970-5. 

113 

Velussi, M. 1997 et al. Long-term (12 months) treatment with an anti-oxidant 

drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need 



200

and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol, 26(4) 

Apr., 871-879. 

Dose: 600 mg silymarin/day. 

Zhang. J. Q. et al. 1993. [Effects of silybin on red blood cell sorbitol and 

nerve conduction velocity in diabetic patients]. Chung Kuo Chung Hsi I 

Chieh Ho Tsa Chih, 13(12) Dec., 725-726. 

Dose: Silybin 231 mg/day for 4 weeks. 

Geller, L. I. et al. 1993. [Treatment of fatty hepatosis in diabetics]. Probl 

Endokrinol (Mosk), 39(5) Sept., 20-22. 

Drug Abuse 

Carrescia, O. et al. 1980. Silymarin in the prevention of hepatic damage by 

psychopharmacologic drugs. Experimental premises and clinical 

evaluation. Clin Ter, 95, 157. 

Hepatitis 

Giese LA. Milk thistle and the treatment of hepatitis. Gastroenterol Nurs. 2001 

Mar-Apr;24(2):95-7. 

Buzzelli, G. et al. 1993. A pilot study on the liver protective effect of 

silybinphosphatidylcholine 

complex (IdB1016) in chronic active hepatitis. Int J 

Clin Pharmacol Ther Toxicol, 31(9), Sept., 456-460. 

Dose: 240 mg silybin bid. 

Liver damage 

Schumann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G. Silibinin 

protects mice from T cell-dependent liver injury. J Hepatol. 2003 

Sep;39(3):333-40. 

Bromley, P. N. et al. 1995. Effects of intraoperative N-acetylcysteine on orthotopic liver 

transplantation. British J Anaesth, 75(3), Sept., 352-354. 

Oh, T. E. and Shenfield, G. M. 1980. Intravenous N-acetylcysteine for Paracetamol 

poisoning. Med J Australia, 1(13), June 28, 664-665. 

Lung damage 

Meyer, A. et al. 1995. Intravenous N-acetylcysteine and lung glutathione of patients with 

pulmonary fibrosis and normals. Am J Respiratory Crit Care Med, 152(3), Sept., 1055- 

1060. 

114 

Dose: 1.8 gm. 

Suter, P. M. et al. 1994. N-acetylcysteine enhances recovery from acute lung injury in 

man. 

A randomized, double-blind, placebo-controlled clinical study. Chest, 105(1), Jan., 190- 

194. 

Dose: 40 mg/kg/day iv over a period of 72 hours. 

Eklund, A. et al. 1988. Oral N-acetylcysteine reduces selected humoral markers of 

inflammatory cell activity in BAL fluid from healthy smokers: Correlation to effects on 

cellular variables. European Respir J, 1(9), Oct., 832-838. 


Linden, M. et al. 1988. Effects of oral N-acetylecysteine on cell content and macrophage 

function in bronchoalveolar lavage from healthy smokers. European Respiratory J, 1(7), 



201

July, 645-650. 


Muscle fatigue 

Reid, M. B. et al. 1994. N-acetylcysteine inhibits muscle fatigue in humans. J Clin 

Investigations, 94(6), Dec., 2468-2474. 

Dose: pretreatment with 150 mg/kg. 

Sjogren's Syndrome 

Walters, M. T. et al. 1986. A double-blind, cross-over, study of oral N-acetylcysteine in 

Sjogren's syndrome. Scandanavian J Pheumatol Suppl, 61, 253-258. 

115 

Vitamin B1 – 120 Studies 

1. J Neurol Neurosurg Psychiatry. 2003 May;74(5):674-6. 

Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: 

impaired physiological nerve conduction due to thiamine deficiency? 

Ishibashi S, Yokota T, Shiojiri T, Matunaga T, Tanaka H, Nishina K, Hirota H, Inaba A, 

Yamada M, Kanda T, Mizusawa H. 

Japan 

2. J Clin Pharm Ther. 2003 Feb;28(1):47-51. Effect of intravenous infusions of thiamine 

on the disposition kinetics of thiamine and its pyrophosphate. Drewe J, Delco F, Kissel T, 

Beglinger C. 

Switzerland 

3. Ke ZJ, DeGiorgio LA, Volpe BT et al. Reversal of thiamine deficiency-induced 

neurodegeneration. J Neuropathol Exp Neurol 2003 Feb;62(2):195-207. 

4. Anti-obesity effects of a mixture of thiamin, arginine, caffeine, and citric acid in noninsulin 

dependent diabetic KK mice. Muroyama K, Murosaki S, Yamamoto Y, Odaka H, 

Chung HC, Miyoshi M. J Nutr Sci Vitaminol (Tokyo). 2003 Feb;49(1):56-63. 

PMID: 12882397 

5. Anaesthesiol Reanim. 2003;28(1):13-20. 



202

Can alcoholic withdrawal delirium be prevented? Hensel M, Kox WJ. 

6. Cardiology. 2003;99(4):177-81. 

Dietary intake of various nutrients in older patients with congestive heart failure. Gorelik 

O, Almoznino-Sarafian D, Feder I, Wachsman O, Alon I, Litvinjuk V, Roshovsky M, 

Modai D, Cohen N. 

7. Eur J Clin Nutr. 2002 Dec;56(12):1162-8. 

Changes in the intake of vitamins and minerals by men and women with hyperlipidemia 

and overweight during dietetic treatment. Grzybek A, Klosiewicz-Latoszek L, Targosz U. 

8. Psychiatr Genet. 2002 Dec;12(4):217-24. 

Individual susceptibility to Wernicke-Korsakoff syndrome and alcoholism-induced 

cognitive deficit: impaired thiamine utilization found in alcoholics and alcohol abusers. 

Heap LC, Pratt OE, Ward RJ, Waller S, Thomson AD, Shaw GK, Peters TJ. 

9. Alcohol Alcohol. 2002 Nov-Dec;37(6):513-21. 

The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's 

encephalopathy in the accident and Emergency Department Thomson AD, Cook CC, 

Touquet R, Henry JA; Royal College of Physicians, London. 

10. Bras Cardiol. 2002 Nov;79(5):454. 

Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy 

taking diuretics. da Cunha S, Albanesi Filho FM, da Cunha Bastos VL, Antelo DS, Souza 

MM. 

11. Circ J. 2002 Nov;66(11):1070-2. 

Shoshin beriberi with vasospastic angina pectoris possible mechanism of mid-ventricular 

obstruction: possible mechanism of mid-ventricular obstruction. Ito M, Tanabe Y, Suzuki 

K, Kumakura M, Aizawa Y. 

Japan 

12. Mol Genet. 2002 Nov 1;11(23):2951-60. 

Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter 

Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. 

Oishi K, Hofmann S, Diaz GA, Brown T, Manwani D, Ng L, Young R, Vlassara H, 



203

Ioannou YA, Forrest D, Gelb BD. 

13. Biochim Biophys Acta. 2002 Oct 9;1588(1):79-84. 

Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a 

point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. 

Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y, Kitamura S, Takada E, Horii Y, 

Kuroda Y. 

14. Nutr Rev. 2002 Sep;60(9):277-80. 

Acute versus marginal deficiencies of nutrients. 

Carpenter KJ.. 

15. Ann Neurol. 2002 Aug;52(2):195-204. 

Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo. 

Sheline CT, Choi EH, Kim-Han JS, Dugan LL, Choi DW. 

16. AIDS Read. 2002 May;12(5):222-4. 

High doses of riboflavin and thiamine may help in secondary prevention of 

hyperlactatemia. 

McComsey GA, Lederman MM. 

17. Med Sci Monit. 2002 May;8(5):CR357-63. 

Alcohol consumption and the risk of colorectal cancer at low levels of micronutrient 

intake. 

Jedrychowski W, Steindorf K, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig J, 

Penar A. 

18. Neurochem Int. 2002 May;40(6):493-504 

Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. 

Gibson GE, Zhang H. 

19. Obstet Gynecol. 2002 May;99(5 Pt 2):875-7. 

Hyperemesis gravidarum complicated by Wernicke's encephalopathy. 

Spruill SC, Kuller JA. 

20. Proc Nutr Soc. 2002 May;61(2):251-7. 

Meeting the challenges of micronutrient deficiencies in emergency-affected populations. 

Weise Prinzo Z, de Benoist B. 



204

21. Dig Dis Sci. 2002 Mar;47(3):543-8. 

Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases. 

Levy S, Herve C, Delacoux E, Erlinger S. 

22. Int J Geriatr Psychiatry. 2002 Feb;17(2):189-92. 

Using thiamine to reduce post-ECT confusion. 

Linton CR, Reynolds MT, Warner NJ. 

23. J Am Coll Nutr. 2002 Feb;21(1):33-7. 

Vitamin profile of 563 gravidas during trimesters of pregnancy. 

Baker H, DeAngelis B, Holland B, Gittens-Williams L, Barrett T Jr.. 

24. Gastric Cancer. 2002;5(2):77-82. 

Reduced thiamine (vitamin B1) levels following gastrectomy for gastric cancer. 

Iwase K, Higaki J, Yoon HE, Mikata S, Miyazaki M, Kamiike W. 

25. J Nutr Health Aging. 2002;6(4):237-42. 

Dietary intake analysis in institutionalized elderly: a focus on nutrient density. 

Dror Y, Berner YN, Stern F, Polyak Z. 


Reduced serum concentrations of riboflavine and ascorbic acid, and blood thiamine 

pyrophosphate and pyridoxal-5-phosphate in geriatric patients with and without pressure 

sores. 

Selvaag E, Bohmer T, Benkestock K. 

27. Medicina (B Aires). 2002;62(4):331-4. 

Acute cardiovascular beriberi (shoshin-beriberi). 

Lopez Gaston OD, Malvino ER, McLoughlin D, Osatnik J, Chavez Zambrano MA, Pino 

C. 

28. Rocz Panstw Zakl Hig. 2002;53(3):243-52. 

Changes in vitamins intake in overweight and obese adults after low-energy diets 

Pachocka L, Klosiewicz-Latoszek L. 

29. Sci Total Environ. 2001 Dec 17;281(1-3):177-82. 

Lead poisoning in Indian silver refiners. 

Tandon SK, Chatterjee M, Bhargava A, Shukla V, Bihari V. 



205

30. Am J Clin Nutr. 2001 Dec;74(6):808-13. 

Postpartum thiamine deficiency in a Karen displaced population. 

McGready R, Simpson JA, Cho T, Dubowitz L, Changbumrung S, Bohm V, Munger RG, 

Sauberlich HE, White NJ, Nosten F. 

31. J Nutr Sci Vitaminol (Tokyo). 2001 Dec;47(6):385-6. 

Cooperation of divalent ions and thiamin diphosphate in regulation of the function of pig 

heart pyruvate dehydrogenase complex. 

Czerniecki J, Czygier M. 

32. Mech Ageing Dev. 2001 Dec;123(1):21-7. 

Co-culture with astrocytes or microglia protects metabolically impaired neurons. 

Park LC, Zhang H, Gibson GE. 

33. Psychiatry Res. 2001 Nov 5;108(1):49-55. 

Serial MRI and (1)H-MRS of Wernicke's encephalopathy: report of a case with 

remarkable cerebellar lesions on MRI. 

Murata T, Fujito T, Kimura H, Omori M, Itoh H, Wada Y. 

34. Am J Kidney Dis. 2001 Nov;38(5):941-7. 

Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal 

dialysis patients. 

Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. 

35. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):453-6. 

Wernicke's encephalopathy due to hyperemesis gravidarum: an under-recognised 

condition. 

Togay-Isikay C, Yigit A, Mutluer N. 

36. Harefuah. 2001 Nov;140(11):1062-7, 1117. 

Micronutrient (vitamins and minerals) supplementation for the elderly, suggested by a 

special committee nominated by Ministry of Health 

Dror Y, Stern F, Berner YN, Kaufmann NA, Berry E, Maaravi Y, Altman H, Cohen A, 

Leventhal A, Kaluski DN. 

37. Surgery. 2001 Nov;130(5):851-8. 

Thiamine reverses hyperglycemia-induced dysfunction in cultured endothelial cells. 

Ascher E, Gade PV, Hingorani A, Puthukkeril S, Kallakuri S, Scheinman M, Jacob T. 



206

38. J Hum Nutr Diet. 2001 Oct;14(5):365-70. 

Riboflavin deficiency in cystic fibrosis: three case reports. 

McCabe H. 

39. Am J Physiol Cell Physiol. 2001 Sep;281(3):C786-92. 

Mechanism of thiamine uptake by human jejunal brush-border membrane vesicles. 

Dudeja PK, Tyagi S, Kavilaveettil RJ, Gill R, Said HM. 

40. J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):357-62. 

Postgastrectomy polyneuropathy with thiamine deficiency. 

Koike H, Misu K, Hattori N, Ito S, Ichimura M, Ito H, Hirayama M, Nagamatsu M, 

Sasaki I, Sobue G. 

41. Wei Sheng Yan Jiu. 2001 Sep;30(5):273-5. 

Effect of multi-micronutrient on heat adaptation and its probable mechanism. 

Guo J, Zhao F, Qiu L, Li X. 

42. Eur J Biochem. 2001 Aug;268(15):4177-82. 

The effect of thiamine supplementation on tumour proliferation. A metabolic control 

analysis study. 

Comin-Anduix B, Boren J, Martinez S, Moro C, Centelles JJ, Trebukhina R, Petushok N, 

Lee WN, Boros LG, Cascante M. 

43. Life Sci. 2001 Jul 27;69(10):1181-91. 

Characteristics of depressive behavior induced by feeding thiamine-deficient diet in mice. 

Nakagawasai O, Tadano T, Hozumi S, Taniguchi R, Tan-No K, Esashi A, Niijima F, 

Kisara K. 

44. Am J Ophthalmol. 2001 Jul;132(1):19-26. 

Use of vitamin supplements and cataract: the Blue Mountains Eye Study. 

Kuzniarz M, Mitchell P, Cumming RG, Flood VM. 

45. Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G144-50. 

Mechanism of thiamine uptake by human colonocytes: studies with cultured colonic 



207

epithelial cell line NCM460. 

Said HM, Ortiz A, Subramanian VS, Neufeld EJ, Moyer MP, Dudeja PK. 

46. Eur J Pharmacol. 2001 Jun 15;421(3):157-64. 

B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models 

of nociception in mice. 

Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM. 

47. Br J Nutr. 2001 Jun;85(6):741-8. 

Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy 

epidemic. 

Arnaud J, Fleites-Mestre P, Chassagne M, Verdura T, Garcia Garcia I, Hernandez- 

Fernandez T, Gautier H, Favier A, Perez-Cristia R, Barnouin J. 

France/Cuba 

48. Int J STD AIDS. 2001 Jun;12(6):407-9. 

Severe lactic acidosis and thiamine administration in an HIV-infected patient on 

HAART. 

Arici C, Tebaldi A, Quinzan GP, Maggiolo F, Ripamonti D, Suter F. 

49. Aquat Toxicol. 2001 May;52(3-4):229-39. 

The use of thiamine and thiamine antagonists to investigate the etiology of early 

mortality syndrome in lake trout (Salvelinus namaycush). 

Fitzsimons JD, Vandenbyllaardt L, Brown SB. 

50. Mt Sinai J Med. 2001 May;68(3):216-8. 

Wernicke's encephalopathy in a non-alcoholic man: case report and brief review. 

Munir A, Hussain SA, Sondhi D, Ameh J, Rosner F. 

51. J Biochem (Tokyo). 2001 Apr;129(4):543-9. 

Suppression of the accumulation of triosephosphates and increased formation of 

methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro. 

Thornalley PJ, Jahan I, Ng R. 



208

52. Nutrition. 2001 Apr;17(4):351-2. 

Severe metabolic acidosis and heart failure due to thiamine deficiency. 

Ozawa H, Homma Y, Arisawa H, Fukuuchi F, Handa S. 

53. Am J Gastroenterol. 2001 Mar;96(3):864-8. 

Thiamine treatment of chronic hepatitis B infection. 

Wallace AE, Weeks WB. 

54. Public Health. 2001 Mar;115(2):133-8. 

Relationships between dietary intake and cognitive function level in Korean elderly 

people. 

Lee L, Kang SA, Lee HO, Lee BH, Park JS, Kim JH, Jung IK, Park YJ, Lee JE. 

55. Rev Med Liege. 2001 Mar;56(3):155-8. 

Shoshin beriberi: myth or reality? 

Masset C, Lancellotti P, Nkoghe D. 

56. Ukr Biokhim Zh. 2001 Mar-Apr;73(2):51-6. 

Interaction of rat brain thiamine kinase with thiamine and its derivatives 

Pylypchuk Siu, Parkhomenko IuM, Protasova ZS, Vovk AI, Donchenko HV. 

57. Brain Research. 2001 Feb 16;892(1):218-27. 

Glucose induced IEG expression in the thiamin-deficient rat brain. 

Zimitat C, Nixon PF. 

Australia 

58. Can J Neurol Sci. 2001 Feb;28(1):89-92. 

Wernicke’s encephalopathy following gastroplasty for morbid obesity. 

Toth C, Voll C. 

59. Alcohol Clin Exp Res. 2001 Jan;25(1):112-6. 

Thiamin treatment and working memory function of alcohol-dependent people: 

preliminary findings. 

Ambrose ML, Bowden SC, Whelan G. 

60. Ann Nutr Metab. 2001;45(4):175-80. 

Nutritional disorders among workers in North China during national turmoil. 

Lee BY, Thurmon TF. 



209

61. Behav Neurol. 2001-2002;13(3-4):89-94. 

Wernicke-Korsakoff syndrome following small bowel obstruction. 

Deb S, Law-Min R, Fearnley D. 

62. Blood Cells Mol Dis. 2001 Jan-Feb;27(1):135-8. 

Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity 

thiamine transport. 

Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP. 

63. Br J Nutr. 2001 Jan;85(1):49-58. 

Longitudinal vitamin and homocysteine levels in normal pregnancy. 

Cikot RJ, Steegers-Theunissen RP, Thomas CM, de Boo TM, Merkus HM, Steegers EA. 

64. J Int Med Res. 2001 Jan-Feb;29(1):37-40. 

Cardiac beriberi among illegal mainland Chinese immigrants. 

Chen KT, Chiou ST, Chang YC, Pan WH, Twu SJ. 

China 

65. Rev Environ Health. 2001 Jul-Sep;16(3):213-22. 

Risk of colorectal cancer from alcohol consumption at lower vitamin intakes. A hospitalbased 

case-control study in Poland. 

Jedrychowski W, Steindorf K, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig J, 

Penar A. 

Poland 

66. J Am Coll Cardiol. 2001 Jun 1;37(7):1765-74. 

Chronic heart failure and micronutrients. 

Witte KK, Clark AL, Cleland JG. 

UK 

67. Molecular mechanisms of thiamine utilization. 

Singleton CK, Martin PR. 

USA 

68. J Clin Anesth. 2001 May;13(3):230-8. 

Early recognition of acute cardiovascular beriberi by interpretation of hemodynamics 

Gabrielli A, Caruso L, Stacpoole PW. 

USA.. 



210

69. Behav Brain Res. 2001 Mar 15;119(2):167-77. 

Aging potentiates the acute and chronic neurological symptoms of pyrithiamine-induced 

thiamine deficiency in the rodent. 

Pitkin SR, Savage LM. 

USA 

70. Clin Nephrol. 2001 Mar;55(3):248-53. 

Central and extrapontine myelinolysis in a patient in spite of a careful correction of 

hyponatremia. 

Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin IM. 

Belgium 

71. J Am Med Dir Assoc. 2001 Mar-Apr;2(2):71-5. 

Wernicke's Encephalopathy: The Subacute Setting as Safety Net. 

Buxbaum RC, Yurkofsky M. 

USA 

72. Pediatr Radiol. 2001 Mar;31(3):167-8. 

Wernicke's encephalopathy in a child: case report and MR findings. 

Coe M, Carfagnini F, Tani G, Ambrosetto P. 

Italy 

73. Am J Kidney Dis. 2001 Feb;37(2):427-30. 

Chorea induced by thiamine deficiency in hemodialysis patients. 

Hung SC, Hung SH, Tarng DC, Yang WC, Huang TP. 

China 

74. J Magn Reson Imaging. 2001 Feb;13(2):163-6. 

In vivo and in vitro proton NMR spectroscopic studies of thiamine-deficient rat brains. 

Lee H, Holburn GE, Price RR. 

USA 

75. Ann Fr Anesth Reanim. 2001 Jan;20(1):40-3. 



211

Postoperative encephalopathies: thiamine deficiency, an unrecognized etiology 

S, Andrianjatovo JJ, Dubau B, Winnock S, Maurette P. 

France 

76. Ann Hematol. 1999 Feb;78(2):105-7. 

Downbeat nystagmus caused by thiamine deficiency: an unusual presentation of CNS 

localization of large cell anaplastic CD 30-positive non-Hodgkin's lymphoma. 

Mulder AH, Raemaekers JM, Boerman RH, Mattijssen V. 

Netherlands 

77. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20. 

Thiamine treatment in psychiatry and neurology 

Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T. 

Garmany 

78. Eur J Paediatr Neurol. 2000;4(3):115-7. 

Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive 

pyruvate dehydrogenase deficiency. 

Di Rocco M, Lamba LD, Minniti G, Caruso U, Naito E. 

Italy 

ANIMAL RESEARCH 

79. Brain Res Bull. 2000 Jan 1;51(1):47-55. 

Immunohistochemical estimation of rat brain somatostatin on avoidance learning 

impairment induced by thiamine deficiency. 

Nakagawasai O, Tadano T, Niijima F, Tan-No K, Kisara K. 

Japan. 

80. Ann Vasc Surg. 2000 Jan;14(1):37-43. 

Thiamine (Vitamin B1) protects against glucose- and insulin-mediated proliferation of 

human infragenicular arterial smooth muscle cells. 

Avena R, Arora S, Carmody BJ, Cosby K, Sidawy AN. 

USA 

81. Acta Haematol. 2000;102(3):157-9. 

Graft failure of autologous peripheral blood stem cell transplantation due to acute 



212

metabolic acidosis associated with total parenteral nutrition in a patient with relapsed 

breast cancer. 

Sawada M, Tsurumi H, Hara T, Goto H, Yamada T, Oyama M, Moriwaki H. 

Japan. 

82. Nihon Arukoru Yakubutsu Igakkai Zasshi. 2000 Feb;35(1):19-27. 

Alcohol intake and nutrition. 

Itokawa Y. 

Japan 

83. Presse Med. 2000 Feb 12;29(5):240-1. 

Right heart failure caused by thiamine deficiency (cardiac beriberi)] 

Akpan T, Peschard S, Brinkane AH, Bergheul S, Leroy-Terquem E, Levy R. 

France 

84. J Neurochem. 2000 Jan;74(1):114-24. 

Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell 

death in culture. 

Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. 

USA 


Diuretic use: a risk for subclinical thiamine deficiency in elderly patients. 

Suter PM, Haller J, Hany A, Vetter W. 

Switzerland 

86. Neurol Neurochir Pol. 2000;34 Suppl 8:59-66. 

Disturbances of glucose metabolism in epilepsy and other neurodegenerative diseases 

Szutowicz A, Jankowska A, Tomaszewicz M. 

Poland 

87. No To Shinkei. 2000 Jan;52(1):59-63. 

A case of Wernicke-Korsakoff syndrome with dramatic improvement in consciousness 

immediately after intravenous infusion of thiamine 

Kikuchi A, Chida K, Misu T, Okita N, Nomura H, Konno H, Takase S, Takeda A, 



213

Itoyama Y. 

Japan 

88. Acta Neuropathol (Berl). 1999 Dec;98(6):614-21. 

Changes in serotonergic neurons in the brain of pyrithiamine-induced acute thiaminedeficient 

mice. 

Matsushita H, Takeuchi Y, Kosaka K, Fushiki S, Kawata M, Sawada T. 

Japan 

89. Clin Nutr. 1999 Dec;18(6):375-8. 

Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase 

activity and thiamin pyrophosphate effect. 

Muri RM, Von Overbeck J, Furrer J, Ballmer PE. 

Switzerland. 

90. Endocr J. 1999 Dec;46(6):787-93. 

Gestational thyrotoxicosis with acute Wernicke encephalopathy: a case report. 

Ohmori N, Tushima T, Sekine Y, Sato K, Shibagaki Y, Ijuchi S, Akano K. 

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91. Am Fam Physician. 1999 Oct 1;60(5):1468-76. 

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2. Trace amine deficit in depressive illness: the phenylalanine connexion. 

Acta Psychiatrica Scandinavica 61(Suppl. 280):29-39, 1980 

3. Phenylalanine levels in endogenous psychoses. 

Psychiatrie, Neurologie und Medizinische Psychologie 32(10):631-633, 1980 

4. Evaluation of the relative potency of individual competing amino acids to tryptophan 

transport in endogenously depressed patients. 

Psychiatry Research 3(2):141-150, 1980 

5. Amino acids in mental illness. 



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Neuropisiquiatria (Buenos Aires) 8(1):60-64, 1977 

7. Theoretical and therapeutic potential of indoleamine precursors in affective disorders. 

Neuropsychobiology (Basel) 3(4):199-233, 1977 

8. Phenylethylamine and glucose in true depression. 

Journal of Orthomolecular Psychiatry (Regina) 5(3):199-202, 1976 

9. Therapeutic action of D-phenylalanine in Parkinson's disease. 

Arzneimittel-Forschung (Aulendorf) 26(4):577-579, 1976 

10. Effects of D-phenylalanine on clinical picture and phenethylaminuria in depression. 

Biological Psychiatry 10(2):235-239, 1975 

11. Phenylalanine for endogenous depression. 

Joof Orthomolecular Psychiatry (Regina) 3(2):80-81, 1974 

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G. Bounous1, J Molson2 

2. Anticancer Research 15: 2643-2650, 1995 

The Use of a Whey Protein Concentrate in the Treatment of Patients with metastatic 

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RENEE S. KENNEDY1, GEORGE P. KONOK1, GUSTAVO BOUNOUS2, SYLVAIN 

BARUCHEL3 and TIMOTHY D.G. LEE4 

3. Clin Invest Med, 16: 204-209, 1993 

Whey Proteins As A Food Supplement In HIV-Seropositive Individuals 

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The Biological Activity Of Undenatured Dietary Whey Proteins: Role Of Glutathione. 

G. Bounous, P. Gold 

5. Cancer Letters, 57: 91-94, 1991 

Whey Proteins In Cancer Prevention 

G. Bounous*, G. Batist** and P. Gold*** 

6. Tumor Biol 11: 129-136, 1990 

Dietary Milk Proteins Inhibit the Development of Dimethylhydrazine-Induced 

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R. Papenburga, G. Bounousa, D. Fleiszera, P. Goldb 


The Influence Of Dietary Whey Protein On Tissue 

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Gustavo Bounous, Francine Gervais,Victor Amer, Gerald Batist, and Phil Gold. 


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G. Bounous, G. Batist, P. Gold 

9. Clinical and Investigative Medicine, Vol. 11,.No. 4,.pp 271-278,. 1988. 

The Immunoenhancing Property Of Dietary Whey 

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Gustavo Bounous, Patricia A.L. Kongshavn, and Phil Gold. 

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G. Bounous, R. Papenburg, P.A.L Kongshavn, P. Gold, and D. Fleiszer. 

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Mechanism Of Altered B-Cell Response Induced By Changes 

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G. Bounous, N. Shenouda,* P.A.L. Kongshavn† and D.G. Osmond* 

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Differential Effect of Dietary Protein Type on the B-Cell and 

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Gustavo Bounous and Patricia A.L. Kongshavn. 

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14. Minerva Dietol Gastroenterol 35(4): 241-5, 1989 

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15. Oxidative Stress, Cell Activation and Viral infection C. Pasquier et al. (eds) 1994 

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Influence Of Dietary Proteins On The Immune System Of Mice. 

17. The Journal of Infectious Diseases, 144: 281, 1981 

Influence Of Dietary Lactalbumin Hydrolysate On The Immune System Of Mice And 

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G. Bounous, M.M. Stevenson*, P.A.L. Kongshavn. 

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LC Lands, MD, PhD*†, VL Grey, PhD†‡, AA Smountas, BSc. 

19. Accepted for publication in “Chest” 

Treatment Of Obstructive Airway Disease With A Cysteine Donor Protein Supplement: 

A Case Report 

Bryce Lothian, MD, Vijaylaxmi Grey, PhD, R. John Kimoff, MD, Larry Lands, MD, 

PhD. 

20. PR514 

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21. Anticancer Research 20: 4785-4792, 2000. 

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22. Accepted for publication in Nutrition and Cancer, Vol 38, Issue #2 

Enhancing Effect of Patented Whey Protein Isolate 

(IMMUNOCAL) on the Cytotoxicity of Anti-cancer Drug 

Wayne Y. Tsai, Wen-Huei Chang, Ching-Hsein Chen, and Fung-Jou Lu 

Department of Biochemistry, College of Medicine National Taiwan University, Taipei, 

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56. Novi AM. Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced 

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L-Taurine – 94 Studies 

1. Arzneimittelforschung. 1993 Mar;43(3):308-12. 

Effects on heart membranes after taurine treatment in rabbits with congestive heart 

failure. 

Elizarova EP, Orlova TR, Medvedeva NV. 

2. Jpn Circ J. 1992 Jan;56(1):95-9. 

Usefulness of taurine in chronic congestive heart failure and its prospective application. 

Azuma J, Sawamura A, Awata N. 

Third Department of Internal Medicine, Osaka University Medical School, Japan. 

3. Kardiologiia. 1991 Jun;31(6):77-80. (Animal Study) 

[Use of taurine in the treatment of experimental congestive heart failure] 

[Article in Russian] 

Orlova TsR, Elizarova EP, Ryff IM, Fetisova NI, Mit'kina LI. 

4. Am Heart J. 1986 Dec;112(6):1278-84. (Animal Study) 

Beneficial effect of taurine in rabbits with chronic congestive heart failure. 

Takihara K, Azuma J, Awata N, Ohta H, Hamaguchi T, Sawamura A, Tanaka Y, 

Kishimoto S, Sperelakis N. 

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Hasegawa H, Yamagami T, Ishiyama T, et al. 

6. Res Commun Chem Pathol Pharmacol. 1984 Aug;45(2):261-70. (Animal Study) 

Beneficial effect of taurine on congestive heart failure induced by chronic aortic 

regurgitation in rabbits. 

Azuma J, Takihara K, Awata N, Ohta H, Sawamura A, Harada H, Kishimoto S. 

7. Clin Ther. 1983;5(4):398-408. 

Therapy of congestive heart failure with orally administered taurine. 

Azuma J, Hasegawa H, Sawamura A, Awata N, Ogura K, Harada H, Yamamura Y, 

Kishimoto S. 

8. Physiol Chem Phys. 1977;9(3):259-63. (Animal Study) 

A relation between myocardial taurine contest and pulmonary wedge pressure in dogs 

with heart failure. 

Newman WH, Frangakis CJ, Grosso DS, Bressler R. 

9. Amino Acids. 2002;23(4):381-93. 

Treatment of hypertension with oral taurine: experimental and clinical studies. 

Militante JD, Lombardini JB. 

Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, 

Texas, USA. 

10. Poult Sci. 2001 Nov;80(11):1607-18. (Animal Study) 

Taurine, cardiopulmonary hemodynamics, and pulmonary hypertension syndrome in 

broilers. 

Ruiz-Feria CA, Wideman RF Jr. 

Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. 

cruizfe@hotmail.com 

11. Amino Acids. 2000;19(3-4):643-65. (Animal Study) 



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Effects of high salt diets and taurine on the development of hypertension in the strokeprone 

spontaneously hypertensive rat. 

Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. 

Department of Pharmacodynamics, College of Pharmacy, University of Florida, 

Gainesville 32610, USA. dawson@cop.health.ufl.edu 







13. Hypertens Res. 2000 May;23(3):277-84. 

Oral taurine supplementation prevents the development of ethanol-induced hypertension 

in rats. 

Harada H, Kitazaki K, Tsujino T, Watari Y, Iwata S, Nonaka H, Hayashi T, Takeshita T, 

Morimoto K, Yokoyama M. 

First Department of Internal Medicine, Kobe University School of Medicine, Japan. 

14. Can J Physiol Pharmacol. 1999 Oct;77(10):749-54. (Animal Study) 

Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, 

an animal model of insulin resistance. 

Anuradha CV, Balakrishnan SD. 

Department of Biochemistry, Annamalai University, Annamalai Nagar, Tamil Nadu, 

India. 


Plasma taurine levels in broilers with pulmonary hypertension syndrome induced by 

unilateral pulmonary artery occlusion. 

Ruiz-Feria CA, Beers KW, Kidd MT, Wideman RF Jr. 



251


cruizfe@comp.uark.edu 

16. J Hypertens. 1994 Jun;12(6):653-61. (Animal Study) 

Taurine amplifies renal kallikrein and prevents salt-induced hypertension in Dahl rats. 

Ideishi M, Miura S, Sakai T, Sasaguri M, Misumi Y, Arakawa K. 

Department of Internal Medicine, Fukuoka University School of Medicine, Japan. 

17. Cardiovasc Res. 1988 May;22(5):351-8. (Animal Study) 

Retardation of the development of hypertension in DOCA salt rats by taurine supplement. 

Inoue A, Takahashi H, Lee LC, Sasaki S, Kohno Y, Takeda K, Yoshimura M, Nakagawa 

M. 

2nd Department of Medicine, Kyoto Prefectural University of Medicine, Japan. 

18. Hypertension. 1987 Oct;10(4):383-9. 

Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats. 

Abe M, Shibata K, Matsuda T, Furukawa T. 

Department of Pharmacology, School of Medicine, Fukuoka University, Japan. 

19. Jpn Heart J. 1983 Jan;24(1):91-102. 

Decrease of urinary taurine in essential hypertension. 

Kohashi N, Katori R. 

20. Amino Acids. 2002;22(1):27-38. 

Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats. 

Nandhini AT, Anuradha CV. 

Department of Biochemistry, Faculty of Science, Annamalai University, Tamil Nadu, 

India. 

21. Drug Chem Toxicol. 2001 Nov;24(4):429-37. 



252

Protective role of vitamin E, 2-deoxy-D-glucose, and taurine on perchloroethylene 

induced alterations in ATPases. 

Ebrahim AS, Babu E, Thirunavukkarasu C, Sakthisekaran D. 

Department of Medical Biochemistry, Dr. ALM Post-Graduate Institute of Basic Medical 

Sciences, University of Madras, Taramani, Chennai 600113, India. 

22. Diabetes. 2003 Feb;52(2):499-505. (Animal Study) 

Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage 

in long-term experimental diabetes. 

Odetti P, Pesce C, Traverso N, Menini S, Maineri EP, Cosso L, Valentini S, Patriarca S, 

Cottalasso D, Marinari UM, Pronzato MA. 

Department of Internal Medicine, University of Genova, Italy. 

23. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46. 

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Hansen SH. 

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35. Sugano M, Tsujita A, Yamasaki M, et al. Conjugated linoleic acid modulates tissue 

levels of chemical mediators and immunoglobulins in rats. Lipids 1998;33:521–27. 

36. Nicolosi RJ, Rogers EJ, Kritchevsky D, et al. Dietary conjugated linoleic acid reduces 

plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters. 

Artery 1997;22:266–77. 

37. Lee KN, Kritchevsky D, Pariza MW, et al. Conjugated linoleic acid and 

atherosclerosis in rabbits. Atherosclerosis 1994;108:19–25. 

38. Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated 

linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. 

Biochem Biophys Res Commun 1998;244:678–82. 

39. Herbel BK, McGuire MK, McGuire MA, et al. Safflower oil consumption does not 

increase plasma conjugated linoleic acid concentrations in humans. Am J Clin Nutr 

1998;67:332–37. 

40. Thom E. A pilot study with the aim of studying the efficacy and tolerability of 

Tonalin CLA on the body composition in humans. Medstat Research Ltd., Lillestrom, 

Norway, July 1997[unpublished]. 

41. Banni S, Angioni E, Stefania M, et al. Conjugated linoleic acid and oxidative stress. J 

Am Oil Chem Soc. 1998; 75:261-267. 

42. Belury MA. Conjugated linoleate: a polyunsaturated fatty acid with unique 

chemopreventive properties. Nutr Rev. 1995; 53:83-89. 



309

43. Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of linoleic acid and 

conjugated linoleic acid on human prostate cancer in SCID mice. Anticanc Res. 1998; 

18:833-38. 

44. de Deckere EA, van Amelsvoort JM, Mc Neill GP, Jones P. Effects of conjugated 

linoleic acid (CLA) isomers on lipid levels and peroxisome proliferation in the hamster. 

Br J Nutr. 1999; 82:309-17. 

45. Gavino VC, Gavino G, Leblanc MJ, Tuchweber B. An isomeric mixture of 

conjugated linoleic acids but not pure cis-9, trans-11-octadecadienoic acid affects body 

weight gain and plasma lipids in hamsters. J Nutr. 2000; 130:27-29. 

46. Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated 

linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. 

Biochem Biophys Res Commun. 1998; 244:678-682. 

47. Lee KN, Pariza MW, Ntambi JM. Conjugated linoleic acid decreases hepatic 

stearoyl-CoA desaturase mRNA expression. Biochem Biophys Res Commun. 1998; 

248:817-821. 

48. McCarty MF. Downregulaton of macrophage activation by PPAR gamma suggests a 

role for conjugated linoleic acid in prevention of Alzheimer's disease. J Med Food. 1998; 

1:217-226. 

49. Moya-Camarena SY, Belury MA. Species differences in the metabolism and 

regulation of gene expression by conjugated linoleic acid. Nutr Rev. 1999; 57:336-340. 

50. Ostrowski E, Muralitharan M, Cross RF. Dietary conjugated linoleic acids increase 

lean tissue and decrease fat deposition in growing pigs. J Nutr. 1999; 129:2037-2042. 

51. Pariza MW, Park Y, Cook ME. Mechanisms of action of conjugated linoleic acid: 

evidence and speculation. Proc Soc Exp Biol Med. 2000; 223: 8-13. 

52. Pariza MW, Parks Y, Cook ME. Conjugated linoleic acid and the control of cancer 

and obesity. Toxicol Sci. 1999; 51 (2 Suppl):107-110. 

53. Pariza MW, Park Y, Kim S, et al. Mechanism of body fat reduction by conjugated 

linoleic acid. FASEB J. 1997; 11:A139. 

54. Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid on body 

composition in mice. Lipids. 1997; 32:853-858. 

55. van den Berg JJ, Cook NE, Tribble DL. Reinvestigation of the antioxidant properties 

of conjugated linoleic acid. Lipids. 1995; 30:599-605. 



310

56. Yurawecz MP, Mossoba MM, Kramer JKG, Pariza MW, Nelson GJ, eds. Advances in 

Conjugated Linoleic Acid Research. Volume 1. Champaign, IL: AOCS Press; 1999. 

Linolenic Acid – 10 Studies 

1. Botha JH, Robinson KM, Leary WP. The response of human carcinoma cell lines to 

gamma-linolenic acid with special reference to the effects of agents which influence 

prostaglandin and thromboxane syntheses. Prostaglandins Leukot Med. 1985; 19:63-77. 

2. de Antueno R, Elliot M, Ells G, et al. In vivo and in vitro biotransformation of the 

lithium salt of gamma-linolenic acid by three human carcinomas. Br J Cancer. 1997; 

75:1812-1818. 

3. Fearon KC, Falconer JS, Ross JA, et al. An open-label phase I/II dose escalation study 

of the treatment of pancreatic cancer using lithium gammalinolenate. Anticancer Res. 

1996; 16; 867-874. 

4. Ferguson PJ. Synergistic cytotoxicity between gamma-linolenic acid and the flavonoid 

naringenin against a human oral squamous carcinoma cell line (Meeting abstract). Proc 

Annu Meet Am Assoc Cancer Res. 1997; 38:A2148. 

5. Ilc K, Ferrero JM, Fischel JL, et al. Cytotoxic effects of two gamma linolenic salts 

(lithium gammalinolenate or meglumine gammalinolenate) alone or associated with a 

nitrosourea: an experimental study on human glioblastoma cell lines. Anticancer Drugs. 

1999; 10:413-417. 

6. Kairemo KJ, Jekunen AP, Korppi-Tommola ET, Pyrhonen SO. The effect of lithium 

gamma-linolenate therapy of pancreatic cancer on perfusion in liver and pancreatic 

tissues. Pancreas. 1998; 16:105-106. 

7. Kinchington D, Randall S, Winther M, Horrobin D. Lithium gamma-linolenateinduced 

cytotoxicity against cells chronically infected with HIV-1. FEBS Lett. 1993; 

330:219-221. 

8. Ravichandran D, Cooper A, Johnson CD. Effect of lithium gamma-linoenate on the 

growth of experimental human pancreatic carcinoma. Br J Surg. 1998; 85:1201-1205. 

9. Ravichandran D, Cooper A, Johnson CD. Growth inhibitory effect of lithium 

gammalinolenate on pancreatic cancer cell lines: the influence of albumin and iron. Eur J 

Cancer. 1998; 34:188-192. 



311

10. Seegers JC, Lotterling ML, Panzer A, et al. Comparative anti-mitotic effects of 

lithium gamma-linolenate, gamma-linolenic acid and arachidonic acid, on transformed 

and embryonic dells. Prostaglandins Leukot Essent Fatty Acids. 1998; 59:285-291. 

Caprylic Acid - 9 Studies 

1. Abate MA, Moore TL. Monooctanin use for gallstone dissolution. Drug Intell Clin 

Pharm. 1985; 19:708-713. 

2. Kabara JJ. Fatty acids and derivatives as antimicrobial agents. In: Kabara JJ, ed. The 

Pharmacological Effect of Lipids I. Champaign, IL: American Oil Chemists' Society; 

1978; 1-14. 

3. Wyss O, Ludwig BJ, Joiner RR. The fungistatic and fungicidal action of fatty acids 

and related compounds. Arch Biochem. 1943;7,415. 

4. Effect of Caprylic Acid on Performance and Mortality of Growing Rabbits.Skřivanová 

V., M. Marounek: Effect of Caprylic Acid on Performance and Mortality of Growing 

Rabbits. Acta Vet. Brno 71, 2002: 435-439. 

5. Enig MG. Lauric Oils as Antimicrobial Agents: Theory of Effect, Scientific Rationale, 

and Dietary Application as Adjunct Nutritional Support for HIV-Infected Individuals. in 

Watson R ed. Food and Nutrients in AIDS. CRC Press. Florida, pp81-97. 1999. 

6. Isaacs CE, Kim KS and Thormar H. Inactivation of Enveloped Viruses in Human 

Bodily Fluids by Purified Lipids. Annal NY Acad Sci. 724: 457. 1994. 

7. Sadeghi S et al. Dietary Lipids Modify the Cytokine Response to Bacterial 

Lipopolysaccharide in Mice. Immunology. 96(3): 404-10. 1999. 

8. J Dairy Sci. 2005 Oct;88(10):3488-95. Antibacterial effect of caprylic acid and 

monocaprylin on major bacterial mastitis pathogens. Nair MK, Joy J, Vasudevan P, 

Hinckley L, Hoagland TA, Venkitanarayanan KS. Department of Animal Science, Unit 

4040, University of Connecticut, Storrs 06269, USA. 

9. Final report of the safety assessment for Caprylic/Capric Triglyceride.Anonymous 

J ENV PATH TOX Vol:4, 4 (1980) pp 105-20. 

Glycerophosphorylcholine – 11 Studies 



312

1. Pflügers Archiv European Journal of Physiology (Historical Archive). 

Publisher: Springer-Verlag GmbH. ISSN: 0031-6768 (Paper) 1432-2013 (Online) 

DOI: 10.1007/BF00583795. Issue: Volume 409, Numbers 4-5. Date:August 1987. 

Pages: 411 - 415 

2. Transport Processes, Metabolism and Endocrinology; Kidney, Gastrointestinal Tract, 

and Exocrine Glands. Role and regulation of glycerophosphorylcholine in rat renal 

papilla. Gabriele Wirthensohn, Franz-X. Beck and Walter G. Guder. Biochim Biophys 

Acta. 1993 Jul 25;1150(1):25-34.Metabolism of the 'organic osmolyte' 

glycerophosphorylcholine in isolated rat inner medullary collecting duct cells. II. 

Regulation by extracellular osmolality. Bauernschmitt HG, Kinne RK. 

3. Biochim Biophys Acta. 1985 Jan 9;833(1):111-8. 1-O-alkyl-2-acyl-sn-glycero-3phosphorylcholine 

is the precursor of platelet-activating factor in stimulated rabbit 

platelets. Evidence for an alkylacetyl-glycerophosphorylcholine cycle. Touqui L, 

Jacquemin C, Dumarey C, Vargaftig BB. 

4. Biochim Biophys Acta. 1982 Mar 12;710(3):370-6. Phosphatidylcholine of blood 

lipoprotein is the precursor of glycerophosphorylcholine found in seminal plasma. 

Hammerstedt RH, Rowan WA. 

5. Med Biol. 1985;63(2):81-7. Impaired glycerophosphorylcholine synthesis in 

murine muscular dystrophy. Infante JP. 

6. FEBS Lett. 1985 Jul 8;186(2):205-10. Defective synthesis of 

glycerophosphorylcholine in murine muscular dystrophy; the primary molecular 

lesion? Infante JP. 

7. Dev Neurosci. 1989;11(1):26-9. Regional and developmental estimations of 

glycerophosphorylcholine phosphodiesterase activities in rat brain. Kanfer JN, 

McCartney DG. 

8. J Parasitol. 1995 Jun;81(3):335-40. Glycerophosphorylcholine, a component of 

both Ascaris suum muscle and Caenorhabditis elegans. Arevalo JI, Saz HJ, 

Nowak T, Larry JP. 



313

9. Kidney Cell Survival in High Tonicity - osmotic regulation of GPC: choline 

phosphodiesterase.Handler J.S. 1 ; Kwon H.M. Comparative Biochemistry and 

Physiology -- Part A: Physiology, Volume 117, Number 3, July 1997, pp. 301- 

306(6). Elsevier Science. 

10. Glycerophosphorylcholine phosphocholine phosphodiesterase activity in cultured 

oligodendrocytes, astrocytes, and central nervous tissue of dysmyelinating rodent 

mutants. J. Yuan, D. G. McCartney, M. Monge, A. Espinosa de Los Monteros, B. 

Zalc, J. de Vellis, J. N. Kanfer. Journal of Neuroscience Research. Volume 31, 

Issue 1, 1992. Pages 68-74 

Phosphatidylserine – 13 Studies 

1. Amaducc L, SMID Group. Phosphatidylserine in the treatment of Alzheimer's disease. 

Results of a multicenter study. Psychopharmacol Bull. 1988; 24:130-134. 

2. Baer E, Maurukas J. Phosphatidyl serine. J Biol Chem. 1955; 212:25-38. 

3. Blokland A, Honig W, Brouns F, Jolles J. Cognition-enhancing properties of 

subchronic phosphatidylserine (PS) treatment in middle-aged rats: comparison of bovine 

cortex PS with eggs PS and soybean PS. Nutr. 1999; 15: 778-783. 

4. Casamenti F, Scali C, Pepeu G. Phosphatidylserine reverses the age-development 

decrease in cortical acetylcholine release: a microdialysis study. Eur J Pharmac. 1991; 

194:11-16. 

5. Crook T, Petrie W, Wells C, et al. Effects of phosphatidylserine in Alzheimer's 

disease. Psychopharmacol Bull. 1992; 28:61-66. 

6. Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in ageassociated 

memory impairment. Neurol. 1991; 41:644-649. 

7. Folch J. Brain cephalin, a mixture of phosphatides. Separation from it of phosphatidyl 

serine, phosphatidyl ethanolamine, and a fraction containing an inositol phosphatide. J 

Biol Chem. 1942; 146:35-41. 

8. Monteleleone P, Maj M, Reinat L, et al. Blunting by chronic phosphatidylserine 

administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis 

in healthy men. Eur J Pharmacol. 1992; 41:385-388. 



314

9. Nunzi MG, Milan F, Guidolin D, Toffano G. Dendritic spine loss in hippocampus of 

aged rats. Effect of brain phosphatidylserine. Neurobiol Aging. 1987; 8:501-510. 

10. Pepeu G, Marconcini Pepeu I, Amaducc L. A review of phosphatidylserine 

pharmacological and clinical effects. Is phosphatidylserine a drug for the ageing brain? 

Pharmacol Res. 1996; 33:73-80. 

11. Phosphatidylserine- a novel pharmacological approach to brain ageing. Clin Trials J. 

1987; 24:1-130. 

12. Villardita C, Grioli S, Salmeri G, et al. Multicentre clinical trial of brain 

phophatidylserine in elderly patients with intellectual deterioration. Clinic Trials J. 1987; 

24:84-93. 

13. Zanott A, Valzelli L, Toffano G. Chronic phosphatidylserine treatment improves 

spatial memory and passive avoidance in aged rats. Psychopharmacol. 1989; 99:316-321. 

Pregenolone -23 Studies 

1. Sahelian, Ray, M.D. Pregnenolone: Nature's Feel Good Hormone. (Garden City Park, 

New York: Avery Publishing Group, 1997), 57. 

2. Roberts, E. (1995) "Pregnenolone-From Selye to Alzheimer and a Model of the 

Pregnenolone Sulfate Binding Binding Site on the GABAA Receptor," Biochemical 

Pharmacology 49:1 (1995): 1-16. 

3. Regelson, William, M.D., and Carol Colman, The Super-Hormone Promise: Nature's 

Antidote to Aging. (New York: Pocket Books, 1996), 79. 

4. Young, D. Gary, Pregnenolone: A Radical New Approach to Health, Longevity, and 

Emotional Well-Being. (Salem, Utah: Essential Science Publishing, 2000), 21. 

5. Lee, John R., M.D. "Natural" vs. "Synthetic" Hormones, A Question of Semantics. (3 

July 1998). 

6. Flood, et al., "Memory-enhancing effects in male mice of pregnenolone and steroids 

metabolically derived from it." Proc Natl Acad Sci USA, (Mar 1, 1992): 1567-71. 

7. Mathis, C, et al., "The neurosteroid pregnenolone sulfate blocks NMDA antagonistinduced 

deficits in a passive avoidance memory task." Psychopharmacology (Berl). (Oct. 

1993): 201-6. 



315

8. Flood JF, et al., "Age related decrease of plasma testosterone in SAMPX mice: 

replacement improved age related impairment of learning and memory." Physiol Behav 

(Apr 1995): 669-73. 

9. Rebel, P et al., "Biosynthesis and assay of neurosteroid in rats and mice: functional 

correlates." J Steroid Biochem Mol Biol, (June 1995), 355-60. 

10. George, MS et al., "CSF neuroactive steroids in affective disorders: pregnenolone. 

progesterone, and DBI." Biol Psychiatry, (May 1994), 775-80. 

11. Guth et al.. "Key role for pregnenolone in combination therapy that promotes 

recovery after spinal cord injury." Proc Natl Acad Sci USA (Dec 6, 1994), 12308-12. 

12. Shiraki M1 et al., "The effect of estrogen and sex steroids and thyroid hormone 

preparation on bone mineral density in senile osteoporosis--a comparative study of the 

effect of 1 alphahydroxycholecalciferol on senile osteoporosis." Nippon Naibunpi Gakkai 

Zasshi (Feb 199 1)84-95. 

13. Sahelian, Ray, MD, pregnenolone: A Practical Guide Melatonin/DHEA Research. 

14. 1. Akwa Y, Young J, Kabbadj K, et al. Neurosteroids: biosynthesis, metabolism and 

function of pregnenolone and dehydroepiandrosterone in the brain. J Steroid Biochem 

Mol Biol. 1991;40(1-3):71-81. 

15. Havlikova H, Hill M, Hampl R, Starka L. Sex- and age-related changes in 

epitestosterone in relation to pregnenolone sulfate and testosterone in normal subjects. J 

Clin Endocrinol Metab. 2002 May;87(5):2225-31. 

16. Araghiniknam M, Chung S, Nelson-White T, Eskelson C, Watson RR. Antioxidant 

activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sci. 

1996;59(11):L147-57. 

17. Darnaudery M, Pallares M, Piazza PV, Le Moal M, Mayo W. The neurosteroid 

pregnenolone sulfate infused into the medial septum nucleus increases hippocampal 

acetylcholine and spatial memory in rats. Brain Res. 2002 Oct 4;951(2):237-42. 

18. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis 

and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):103- 

14. 

19. Jaliffa CO, Howard S, Hoijman E, et al. Effect of neurosteroids on the retinal 

gabaergic system and electroretinographic activity in the golden hamster. J Neurochem. 

2005 Jul 11. 

20. Roberts E. Pregneolone—from Selye to Alzheimer and a model of the pregnenolone 

sulfate binding site on the GABAA receptor. Biochem Pharmacol. 1995 Jan 6;49(1):1-16. 



316

21. McGavack TH, Chevalley J, Weissberg J. The use of delta 5-pregnenolone in various 

clinical disorders. J Clin Endocrinol Metab. 1951 Jun;11(6):559-77. 

22. Dzugan SA, Arnold SR. Hypercholesterolemia treatment: a new hypothesis or just an 

accident? Med Hypotheses. 2002 Dec;59(6):751-6. 

23.George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM. CSF 

neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol 

Psychiatry. 1994 May 15;35(10):775-80. 

Benfotiamine – 32 Studies 

1. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in 

treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. 

2. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of 

hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 

Mar;9(3):294-9. Epub 2003 Feb 18. 

3. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of 

hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 

Mar;9(3):294-9. 

4. 1. Bitsch R, Wolf M, Möller J. Bioavailability assessment of the lipophilic 

benfotiamine as compared to a water-soluble thiamin derivative. Ann Nutr Metab 

1991;35(2):292-6. 

5. Schreeb KH, Freudenthaler S, Vormfelde SV, et al. Comparative bioavailability of two 

vitamin B1 preparations: benfotiamine and thiamine mononitrate. Eur J Clin Pharmacol 

1997; 52(4):319-20. 

6. Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J 

Clin Pharmacol Ther 1996;34(2):47-50. 

7. Frank T, Bitsch R, Maiwald J, Stein G. High thiamine diphosphate concentrations in 

erythrocytes can be achieved in dialysis patients by oral administration of benfontiamine. 

Eur J Clin Pharmacol. 2000;56(3):251-7. 



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8. Pike RL, Brown ML. Nutrition, An Integrated Approach, 3rd Ed. New 

York:MacMillan; 1986:467. 

9. Hammes H-P, Du X, Edlestein D, et al. Benfotiamine blocks three major pathways of 

hyperglycemic damage and prevents experimental diabetic neuropathy. Nat Med 

2003;9(3):294-99. 

10. Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human 

collagen in diabetes mellitus. Proc Natl Acad Sci 1984;81(2):583-7. 

11. Brownlee M. The pathological implications of protein glycation. Clin Invest Med 

1995;18(4):275-81. 

12. Pomero F, Molinar Min A, La Selva M, et al. Benfotiamine is similar to thiamine in 

correcting endothelial cell defects induced by high glucose. Acta Diabetol 

2001;38(3):135-8. 

13. Stracke H, Hammes HP, Werkman D, et al. Efficacy of benfotiamine versus thiamine 

on function and glycation products of peripheral nerves in diabetic rats. Exp Clin 

Endocrinol Diabetes 2001;109(6):300-6. 

14. Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic 

nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003;52(8):2110-20. 

15. Bergfeld R, MatsumaraT, Du X, Brownlee M. Benfotiamin prevents the 

consequences of hyperglycemia induced mitochondrial overproduction of reactive 

oxygen specifies and experimental diabetic neuropathy (Abstract) Diabetologia 2001; 

44(Suppl1):A39. 

16. 1996 Feb; 34(2): 47-50. Loew D. “Pharmacokinetics of thiamine derivatives 

especially of Benfotiamine.” Int J Clin Pharmacol Ther. 

17. Stracke H, Lindemann A, Federlin K. “A Benfotiamine-vitamin B combination in 

treatment of diabetic polyneuropathy.” Exp Clin Endocrinol Diabetes 1996; 104(4): 311- 

6. 

18. Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes HP. “Benfotiamine 

inhibits intracellular formation of advanced glycation endproducts in vivo.” Diabetes. 

2000 May; 49(Suppl1): A143 (P583). 



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19. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, 

Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. “Benfotiamine 

blocks three major pathways of hyperglycemic damage and prevents experimental 

diabetic retinopathy.” Nat Med. 2003 Mar; 9(3): 294-9. 

20. Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P. “Effectiveness 

of different Benfotiamine dosage regimens in the treatment of painful diabetic 

neuropathy.” Arzneimittelforschung. 1999 Mar; 49(3): 220-4. 

21. Koltai MZ. “Prevention of cardiac autonomic neuropathy in dogs with 

Benfotiamine.” In Gries FA, Federlin K. “Benfotiamine in the Therapy of 

Polyneuropathy.” New York: Georg Thieme Verlag, 1998; 45-9. 

22. Ann N Y Acad Sci. 2005 Jun;1043:784-92. Inhibitors of advanced glycation end 

product formation and neurovascular dysfunction in experimental diabetes. Cameron NE, 

Gibson TM, Nangle MR, Cotter MA. School of Medical Sciences, Institute of Medical 

Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. 

n.e.cameron@abdn.ac.uk 

23. High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma 

protein in streptozotocin-induced diabetic rats. Karachalias N, Babaei-Jadidi R, Kupich 

C, Ahmed N, Thornalley PJ.Department of Biological Sciences, University of Essex, 

Wivenhoe Park, Colchester, Essex CO4 3SQ, UK. thorp@essex.ac.uk. 

24. Curr Drug Targets. 2005 Jun;6(4):453-74. The role of AGEs and AGE inhibitors in 

diabetic cardiovascular disease. Thomas MC, Baynes JW, Thorpe SR, Cooper ME. 

25. Clin Lab. 2005;51(5-6):257-73. Mutations in the transketolase-like gene TKTL1: 

clinical implications for neurodegenerative diseases, diabetes and cancer. Coy JF, 

Dressler D, Wilde J, Schubert P.R-Biopharm AG, Landwehrstrasse 54, 64293 Darmstadt, 

Germany. j.coy@r-biopharm.de 

26. Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7. Erratum in: Int J Clin Pharmacol 

Ther. 2005 Jun;43(6):304. Benfotiamine in the treatment of diabetic polyneuropathy--a 

three-week randomized, controlled pilot study (BEDIP study). Haupt E, Ledermann H, 

Kopcke W. Saale-Klinik, Bad Kissingen, Lindenfels, Germany. BfA.Saaleklinik@tonline.de 

27. Diabetologia. 2004 Dec;47(12):2235-46. Epub 2004 Dec 11. High-dose thiamine 

therapy counters dyslipidaemia in streptozotocin-induced diabetic rats.Babaei-Jadidi R, 

Karachalias N, Kupich C, Ahmed N, Thornalley PJ.Department of Biological Sciences, 

University of Essex, Wivenhoe Park, Colchester, Essex, CO4 3SQ, UK. 

28. Diabetes Metab Res Rev. 2004 Jul-Aug;20(4):330-6. Thiamine and benfotiamine 

prevent increased apoptosis in endothelial cells and pericytes cultured in high glucose. 



319

Beltramo E, Berrone E, Buttiglieri S, Porta M. Department of Internal Medicine, 

University of Turin, Italy. elena.beltramo@unito.it 

29. Diabetes. 2003 Aug;52(8):2110-20. Prevention of incipient diabetic nephropathy by 

high-dose thiamine and benfotiamine. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah 

S, Thornalley PJ. Department of Biological Sciences, University of Essex, Central 

Campus, Wivenhoe Park, Colchester, Essex, UK. 

30. Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18. Benfotiamine blocks three major 

pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. 

Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, 

Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Medical 

Clinic V, School of Clinical Medicine, Mannheim, Germany. 

31. Eksp Klin Farmakol. 2002 Jul-Aug;65(4):37-41. [The immunometaboic effects of 

benfotiamine and riboxine on hemolytic anemia] [Article in Russian] Uteshev BS, 

Lazareva GA, Prokopenko LG.Pharmacology Department, State Medical University, ul. 

Ostrovityanova 1, Moscow, 117437 Russia. 

32. MMW Fortschr Med. 2001 Apr 19;143(16):53. [Chronic alcohol abuse. Benfotiamine 

in alcohol damage is a must] [Article in German] Ayazpoor U. 

SUPER ANTIOXIDANTS 

Vitamin A – 41 STUDIES 

1. Groff JL. Advanced Nutrition and Human Metabolism. 2nd ed. St Paul: West 

Publishing; 1995. 

2. Ross AC. Vitamin A and retinoids. In: Shils M, ed. Nutrition in Health and Disease. 

9th ed. Baltimore: Williams & Wilkins; 1999:305-327. 

3. Semba RD. The role of vitamin A and related retinoids in immune function. Nutr Rev. 

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Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:329-346. 

5. McCullough, F. et al. The effect of vitamin A on epithelial integrity. Proceedings of 

the Nutrition Society. 1999; volume 58: pages 289-293. (PubMed) 

6. Olson JA. Vitamin A. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 

7th ed. Washington D.C.: ILSI Press; 1996:109-118. 

7. Lynch SR. Interaction of iron with other nutrients. Nutr Rev. 1997;55(4):102-110. 

(PubMed) 

8. Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999. 

9. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. 

2000;71(4):878-884. (PubMed) 

10. Christian P, West KP, Jr. Interactions between zinc and vitamin A: an update. Am J 

Clin Nutr. 1998;68(2 Suppl):435S-441S. (PubMed) 

11. Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with 

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L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, 

Griffin M, Ippolito E, Bavera P. 

Evaluation of the local effects of vitamin E (E-Mousse) on free radicals in 

diabetic microangiopathy: a randomized, controlled trial. 

Angiology. 2003 Jul-Aug;54(4):415-21. 

PMID: 12934761 

62. Jessup JV, Horne C, Yarandi H, Quindry J. 

The effects of endurance exercise and vitamin E on oxidative stress in the 

elderly. 

Biol Res Nurs. 2003 Jul;5(1):47-55. 

PMID: 12886670 

63. Canbaz S, Duran E, Ege T, Sunar H, Cikirikcioglu M, Acipayam M. 

The effects of intracoronary administration of vitamin E on myocardial 

ischemia-reperfusion injury during coronary artery surgery. 

Thorac Cardiovasc Surg. 2003 Apr;51(2):57-61. 

PMID: 12730811 

64. Manson JE, Bassuk SS, Stampfer MJ. 

Does vitamin E supplementation prevent cardiovascular events? 

J Womens Health (Larchmt). 2003 Mar;12(2):123-36. Review. 

PMID: 12741415 

65. Chang CW, Chu G, Hinz BJ, Greve MD. 

Current use of dietary supplementation in patients with age-related macular 

degeneration. 

Can J Ophthalmol. 2003 Feb;38(1):27-32. 

PMID: 12608514 

66. Letur-Konirsch H, Delanian S. 

Successful pregnancies after combined pentoxifylline-tocopherol treatment in 

women with premature ovarian failure who are resistant to hormone replacement 

therapy. 

Fertil Steril. 2003 Feb;79(2):439-41. 

PMID: 12568863 



333

67. Olanow CW. 

Dietary vitamin E and Parkinson's disease: something to chew on. 

Lancet Neurol. 2003 Feb;2(2):74. 

PMID: 12849259 

68. Martin A. 

Antioxidant vitamins E and C and risk of Alzheimer's disease. 

Nutr Rev. 2003 Feb;61(2):69-73. Review. 

PMID: 12674439 

69. Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, 

Takata J, Karube Y, Fujiwara M. 

Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral 

infarction in mice. 

Neurosci Lett. 2003 Jan 30;337(1):56-60. 

PMID: 12524170 

70. Rehim WM, Sharaf IA, Hishmat M, el-Toukhy MA, Rawash NA, Fouad HN. 

Antioxidant capacity in Fasciola hepatica patients before and after treatment 

with triclabendazole alone or in combination with ascorbic acid (vitamin C) and 

tocofersolan (vitamin E). 

Arzneimittelforschung. 2003;53(3):214-20. 

PMID: 12705178 

71. Brockes C, Buchli C, Locher R, Koch J, Vetter W. 

Vitamin E prevents extensive lipid peroxidation in patients with hypertension. 

Br J Biomed Sci. 2003;60(1):5-8. 

PMID: 12680623 

72. Lin Y, Huang R, Santanam N, Liu YG, Parthasarathy S, Huang RP. 

Profiling of human cytokines in healthy individuals with vitamin E 

supplementation by antibody array. 

Cancer Lett. 2002 Dec 10;187(1-2):17-24. 

PMID: 12359346 

73. Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, 

Corazza D, Meduri R. 

[Photodynamic therapy for age related macular degeneration with and without 

antioxidants] 

Can J Ophthalmol. 2002 Dec;37(7):399-404. French. 

PMID: 12518724 

74. Malafa MP, Fokum FD, Smith L, Louis A. 

Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E 

succinate. 



334

Ann Surg Oncol. 2002 Dec;9(10):1023-32. 

PMID: 12464597 

75. Ghosh D, Das UB, Misro M. 

Protective role of alpha-tocopherol-succinate (provitamin-E) in 

cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a 

correlative approach to oxidative stress. 

Free Radic Res. 2002 Nov;36(11):1209-18. 

PMID: 12592673 

76. Liu L, Meydani M. 

Combined vitamin C and E supplementation retards early progression of 

arteriosclerosis in heart transplant patients. 

Nutr Rev. 2002 Nov;60(11):368-71. Review. 

PMID: 12462519 

77. Boshtam M, Rafiei M, Sadeghi K, Sarraf-Zadegan N. 

Vitamin E can reduce blood pressure in mild hypertensives. 

Int J Vitam Nutr Res. 2002 Oct;72(5):309-14. 

PMID: 12463106 

78. Jialal I, Devaraj S, Venugopal SK. 

Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha 

tocopherol therapy. 

Free Radic Res. 2002 Dec;36(12):1331-6. Review. 

PMID: 12607825 

Vitamin B6 - 28 STUDIES 

1. Leklem JE. Vitamin B-6. In: Machlin L, ed. Handbook of Vitamins. New York: 

Marcel Decker Inc; 1991:341-378. 

2. Leklem JE. Vitamin B-6. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in 

Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:413-422. 

3. Hansen CM, Leklem JE, Miller LT. Vitamin B-6 status of women with a constant 

intake of vitamin B-6 changes with three levels of dietary protein. J Nutr. 

1996;126(7):1891-1901. (PubMed) 

4. Food and Nutrition Board, Institute of Medicine. Vitamin B6. Dietary Reference 




335

Biotin, and Choline. Washington D.C.: National Academy Press; 1998:150-195. 

(National Academy Press) 

5. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of 

plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing 

folic acid intakes. JAMA. 1995;274(13):1049-1057. (PubMed) 

6. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and 

supplements in relation to risk of coronary heart disease among women. JAMA. 

1998;279(5):359-364. (PubMed) 

7. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart 

disease incidence in relation to fasting total homocysteine, related genetic 

polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. 

Circulation. 1998;98(3):204-210. (PubMed) 

8. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. 

Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 

1994;124(10):1927-1933. (PubMed) 

9. Meydani SN, Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff 

SN. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte 

proliferation in elderly adults. Am J Clin Nutr. 1991;53(5):1275-1280. (PubMed) 

10. Talbott MC, Miller LT, Kerkvliet NI. Pyridoxine supplementation: effect on 

lymphocyte responses in elderly persons. Am J Clin Nutr. 1987;46(4):659- 

664. (PubMed) 

11. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and 

neurocognitive function in the elderly. Am J Clin Nutr. 2000;71(2):614S-620S. 

(PubMed) 

12. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, 

folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J 

Clin Nutr. 1996;63(3):306-314. (PubMed) 

13. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and 

the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845. (PubMed) 

14. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake 

of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155(6):1847- 


15. Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr. 1999;81(1):7-20 

(PubMed) 



336

16. Villegas-Salas E, Ponce de Leon R, Juarez-Perez MA, Grubb GS. Effect of vitamin 

B6 on the side effects of a low-dose combined oral contraceptive. Contraception. 

1997;55(4):245-248. (PubMed) 

17. Kleijnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of the 

premenstrual syndrome--a review. Br J Obstet Gynaecol. 1990;97(9):847-852. (PubMed) 

18. Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM. Efficacy of vitamin B-6 

in the treatment of premenstrual syndrome: systematic review. Bmj. 

1999;318(7195):1375-1381. (PubMed) 

19. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of 

pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 

1995;173(3 Pt 1):881-884. (PubMed) 

20. Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for 

nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. 

Obstet Gynecol. 1991;78(1):33-36. (PubMed) 

21. Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. 

Cochrane Database Syst Rev. 2002(1):CD000145. (PubMed) 

22. Ellis JM, Kishi T, Azuma J, Folkers K. Vitamin B6 deficiency in patients with a 

clinical syndrome including the carpal tunnel defect. Biochemical and clinical response to 

therapy with pyridoxine. Res Commun Chem Pathol Pharmacol. 1976;13(4):743-757. 

(PubMed) 

23. Ellis J, Folkers K, Watanabe T, et al. Clinical results of a cross-over treatment with 

pyridoxine and placebo of the carpal tunnel syndrome. Am J Clin Nutr. 

1979;32(10):2040-2046. (PubMed) 

24. Keniston RC, Nathan PA, Leklem JE, Lockwood RS. Vitamin B6, vitamin C, and 

carpal tunnel syndrome. A cross-sectional study of 441 adults. J Occup Environ Med. 

1997;39(10):949-959. (PubMed) 

25. Spooner GR, Desai HB, Angel JF, Reeder BA, Donat JR. Using pyridoxine to treat 

carpal tunnel syndrome. Randomized control trial. Can Fam Physician. 1993;39:2122- 



Economics Company, Inc; 2001 

27. Hansen CM, Shultz TD, Kwak HK, Memon HS, Leklem JE. Assessment of vitamin 

B-6 status in young women consuming a controlled diet containing four levels of vitamin 

B-6 provides an estimated average requirement and recommended dietary allowance. J 

Nutr. 2001;131(6):1777-1786. (PubMed) 



337

28. Kretsch MJ, Sauberlich HE, Skala JH, Johnson HL. Vitamin B-6 requirement and 

status assessment: young women fed a depletion diet followed by a plant- or animalprotein 

diet with graded amounts of vitamin B-6. Am J Clin Nutr. 1995;61(5):1091-1101. 

(PubMed) 

29. Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B- 

6 requirements of elderly men and women. J Nutr. 1991;121(7):1062-1074. (PubMed). 

Magnesium - 86 Studies 

1. Bucca C, Rolla G. 

Nebulised magnesium in asthma: the right solution for an old remedy? 

Lancet. 2003 Jun 21;361(9375):2095-6. 

PMID: 12826427 

2. Jian W, Su L, Yiwu L. 

The effects of magnesium prime solution on magnesium levels and potassium loss in 

open heart surgery. 

Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. 

PMID: 12760983 

3. Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. 

Neuroprotection in transient focal cerebral ischemia by combination drug therapy and 

mild hypothermia: comparison with customary therapeutic regimen. 

Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. 

PMID: 12730554 

4. Geleijnse JM, Grobbee DE. 

Nutrition and health—hypertension. 

Ned Tijdschr Geneeskd. 2003 May 24;147(21):996-1000. 

PMID: 12811968 

5. Suresh S, Lozono S, Hall SC. 

Large-dose intravenous methotrexate-induced cutaneous toxicity: can oral 

magnesium oxide reduce pain? 

Anesth Analg. 2003 May;96(5):1413-4, table of contents. 

PMID: 12707144 

6. Sigman-Grant M, Warland R, Hsieh G. 

Selected lower-fat foods positively impact nutrient quality in diets of 

free-living Americans. 

J Am Diet Assoc. 2003 May;103(5):570-6. 

PMID: 12728214 



338

7.Haupt H, Scheibe F, Mazurek B. 

Therapeutic efficacy of magnesium in acoustic trauma in the guinea pig. 

ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. 

PMID: 12925813 

8. Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. 

The behavioral effects of magnesium therapy on recovery of function following bilateral 

anterior medial cortex lesions in the rat. 

Brain Res Bull. 2003 Apr 15;60(1-2):105-14. 

PMID: 12725898 

9. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, 

Komiya T, Okamura M, Kim S, Iwao H, Miura K. 

Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A 

nephrotoxicity: role in beneficial effects of magnesium supplementation. 

Transplantation. 2003 Apr 15;75(7):1040-4. 

PMID: 12698095 

10. Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. 

Summary measure of dietary musculoskeletal nutrient (calcium, vitamin D, 

magnesium, and phosphorus) intakes is associated with lower-extremity physical 

performance in homebound elderly men and women. 

Am J Clin Nutr. 2003 Apr;77(4):847-56. 

PMID: 12663282 

11. Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. 

Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) 

nephrotoxicity in rats. 

Clin Nephrol. 2003 Apr;59(4):267-72. 

PMID: 12708566 

12. Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. 

Development of ionized hypomagnesemia is associated with higher mortality rates. 

Crit Care Med. 2003 Apr;31(4):1082-7. 

PMID: 12682476 

13. Ilich JZ, Brownbill RA, Tamborini L. 

Bone and nutrition in elderly women: protein, energy, and calcium as main 

determinants of bone mineral density. 

Eur J Clin Nutr. 2003 Apr;57(4):554-65. 

PMID: 12700617 

14. Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider 

M, Chachashvily S, Averbukh Z, Golik A, Chen-Levy Z, Modai D. 

Serum magnesium aberrations in furosemide (frusemide) treated patients with 

congestive heart failure: pathophysiological correlates and prognostic 



339

evaluation. 

Heart. 2003 Apr;89(4):411-6. 

PMID: 12639869 

15. Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, Most- 

Windhauser MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research 

Group. 

Food group sources of nutrients in the dietary patterns of the DASH-Sodium trial. 

J Am Diet Assoc. 2003 Apr;103(4):488-96. 

PMID: 12669013 

16. Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami 

H. 

Woman with postpartum ventricular tachycardia and hypomagnesemia. 

J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. 

PMID: 12755529 

17. Singhi SC, Singh J, Prasad R. 

Hypo- and hypermagnesemia in an Indian Pediatric Intensive Care Unit. 

J Trop Pediatr. 2003 Apr;49(2):99-103. 

PMID: 12729292 

18. van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. 

Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. 

Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for 

long term treatment. 

PMID: 12632115 

19. Higgins JC. 

The 'crashing astimatic.' 

Am Fam Physician. 2003 Mar 1;67(5):997-1004. 

PMID: 12643359 

20. Roy SR, Milgrom H. 

Managing outpatient asthma exacerbations. 

Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. 

PMID: 12562559 

21. Cappell MS. 

Gastric and duodenal ulcers during pregnancy. 

Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. 

PMID: 12635419 

22. Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. 

Marfan syndrome, magnesium status and medical prevention of cardiovascular 

complications by hemodynamic treatments and antisense gene therapy. 



340

Magnes Res. 2003 Mar;16(1):59-64. 

PMID: 12735484 

23. Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. 

Pharmacotherapy. 2003 Mar;23(3):296-300. 

Effects of intravenous magnesium sulfate on the QT interval in patients 

receiving ibutilide. 

PMID: 12627926 

24. Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. 

Recenti Prog Med. 2003 Mar;94(3):136-41. 

Etiopathogenesis and clinical aspects of nephrolithiasis--at present. 

PMID: 12677782 

25. Touyz RM. 

Role of magnesium in the pathogenesis of hypertension. 

Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. 

PMID: 12537992 

26. Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. 

Effect of intra-operative magnesium sulphate on pain relief and patient comfort after 

major lumbar orthopaedic surgery. 

Anaesthesia. 2003 Feb;58(2):131-5. 

PMID: 12562408 

27. Pamnani MB, Bryant HJ, Clough DL, Schooley JF. 

Increased dietary potassium and magnesium attenuate experimental volume 

dependent hypertension possibly through endogenous sodium-potassium pump 

inhibitor. 

Clin Exp Hypertens. 2003 Feb;25(2):103-15. 

PMID: 12611422 

28. Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, Malinowska- 

Polubiec A, Romejko E. 

Calcium-phosphorus-magnesium homeostasis in pregnant women after renal 

transplantation. 

Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. 

PMID: 12566182 

29. Hata M, Miyao M, Mizuno Y. 

Osteoporosis as a lifestyle-related disease. 

Nippon Rinsho. 2003 Feb;61(2):305-13. 

PMID: 12638226 

30. Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. 

Magnesium reduces free radical concentration and preserves left ventricular 



341

function after direct current shocks. 

Resuscitation. 2003 Feb;56(2):199-206. 

PMID: 12589995 

31. Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. 

A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. 

N Engl J Med. 2003 Jan 23;348(4):304-11. 

PMID: 12540643 

32. Vink R, O'Connor CA, Nimmo AJ, Heath DL. 

Magnesium attenuates persistent functional deficits following diffuse traumatic brain 

injury in rats. 


PMID: 12493598 

33. Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, 

Efrati S, Weissgarten J. 

Cell-associated magnesium and QT dispersion in hemodialysis patients. 

Am J Kidney Dis. 2003 Jan;41(1):196-202. 

PMID: 12500237 

34. Meram I, Balat O, Tamer L, Ugur MG. 

Trace elements and vitamin levels in menopausal women receiving hormone 

replacement therapy. 

Clin Exp Obstet Gynecol. 2003;30(1):32-4. 

PMID: 12731741 

35. Duley L, Gulmezoglu AM, Henderson-Smart DJ. 

Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. 

Cochrane Database Syst Rev. 2003;(2):CD000025. 

PMID: 12804383 

36. Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. 

Adenosine triphosphate-magnesium chloride: relevance for intensive care. 

Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. 

PMID: 12528016 

37. Margolin A, Kantak K, Copenhaver M, Avants SK. 

A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit 

cocaine and opiate use in methadone-maintained patients. 

J Addict Dis. 2003;22(2):49-61. 

PMID: 12703668 

38. Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. 

Associations of lifestyle factors with bone mineral density among male 



342

university students in Japan. 

J Epidemiol. 2003 Jan;13(1):48-55. 

PMID: 12587613 

39. Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. 

Therapeutics indications and prognosis of eclampsia at Dakar University 

Teaching Hospital. 

J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. 

PMID: 12773926 

40. Darvish D. 

Magnesium may help patients with recessive hereditary inclusion body 

myopathy, a pathological review. 

Med Hypotheses. 2003 Jan;60(1):94-101. 

PMID: 12450772 

41. Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. 

A case of urolithiasis associated with short bowel syndrome. 

Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. 

PMID: 12638204 

42. Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. 

The use of magnesium to prevent laryngospasm after tonsillectomy and 

adenoidectomy: a preliminary study. 

Paediatr Anaesth. 2003 Jan;13(1):43-7. 

PMID: 12535038 

43. Byrd RP Jr, Roy TM. 

Magnesium: its proven and potential clinical significance. 

South Med J. 2003 Jan;96(1):104. 

PMID: 12602735 

44.: Kidd PM. 

Autism, an extreme challenge to integrative medicine. Part 2: medical 

management. 

Altern Med Rev. 2002 Dec;7(6):472-99. 

PMID: 12495373 

45. Carlin Schooley M, Franz KB. 

Magnesium deficiency during pregnancy in rats increases systolic blood 

pressure and plasma nitrite. 

Am J Hypertens. 2002 Dec;15(12):1081-6. 

PMID: 12460704 

46. Imazu M. 

Hypertension and insulin disorders. 



343

Curr Hypertens Rep. 2002 Dec;4(6):477-82. 

PMID: 12419178 

47. Grzybek A, Klosiewicz-Latoszek L, Targosz U. 

Changes in the intake of vitamins and minerals by men and women with 

hyperlipidemia and overweight during dietetic treatment. 

Eur J Clin Nutr. 2002 Dec;56(12):1162-8. 

PMID: 12494300 

48. Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. 

Optimisation of colon cleansing prior to computed tomographic 

colonography. 

JBR-BTR. 2002 Dec;85(6):289-96. 

PMID: 12553658 

49. Bhatia R, Prabhakar S, Grover VK. 

Tetanus. 

Neurol India. 2002 Dec;50(4):398-407. 

PMID: 12577086 

50. Murck H. 

Magnesium and affective disorders. 

Nutr Neurosci. 2002 Dec;5(6):375-89. 

PMID: 12509067 

51. Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, 

Togari H. 

Nitric oxide further attenuates pulmonary hypertension in 

magnesium-treated piglets. 

Pediatr Int. 2002 Dec;44(6):670-4. 

PMID: 12421268 

52. Minami T, Adachi T, Fukuda K. 

An effective use of magnesium sulfate for intraoperative management of 

laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. 

Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. 

PMID: 12401602 

53. Nakatani T, Asai T. 

Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity. 

Hinyokika Kiyo. 2002 Nov;48(11):699-705. 

PMID: 12512145 

54. Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, 

Russell E, Cotton DB. 

The effect of intrapartum magnesium sulfate therapy on fetal cardiac 



344

troponin I levels at delivery. 

J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. 

PMID: 12607765 

55. Unachak K, Louthrenoo O, Katanyuwong K. 

Primary hypomagnesemia in Thai infants: a case report with 7 years 

follow-up and review of literature. 

J Med Assoc Thai. 2002 Nov;85(11):1226-31. 

PMID: 12546321 

56. Berger R, Garnier Y, Jensen A. 

Perinatal brain damage: underlying mechanisms and neuroprotective 

strategies. 

J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. 

PMID: 12445595 

57. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. 

New migraine preventive options: an update with pathophysiological 

considerations. 

Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 

Feb 17. 

PMID: 12612763 

58. Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. 

Acid-base and electrolyte disturbances in patients with hypercalcemia. 

South Med J. 2002 Nov;95(11):1280-7. 

PMID: 12539994 

59. Rao GN. 

Diet and kidney diseases in rats. 

Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. 

PMID: 12512864 

60. Anderson RA. 

A complementary approach to urolithiasis prevention. 

World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. 

PMID: 12522585 

61. Paskitti M, Reid KH. 

Use of an adenosine triphosphate-based 'cocktail' early in reperfusion 

substantially improves brain protein synthesis after global ischemia in 

rats. 

Neurosci Lett. 2002 Oct 18;331(3):147-50. 

PMID: 12383918 



345

62. Gaby AR. 

Intravenous nutrient therapy: the "Myers' cocktail". 

Altern Med Rev. 2002 Oct;7(5):389-403. 

PMID: 12410623 

63.Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. 

Correction of ionized plasma magnesium during cardiopulmonary bypass 

reduces the risk of postoperative cardiac arrhythmia. 

Anesth Analg. 2002 Oct;95(4):828-34, table of contents. 

PMID: 12351253 

64. Davis GK, Homer CS, Brown MA. 

Hypertension in pregnancy: do consensus statements make a difference? 

Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. 

PMID: 12403283 

65. Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, 

Fujinaga H, Minami H; Kansai Magnesium Study Group. 

Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. 

Pediatr Int. 2002 Oct;44(5):505-9. 

PMID: 12225549 

66. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao 

T, Okamura M, Kim S, Iwao H, Miura K. 

Magnesium supplementation prevents experimental chronic cyclosporine a 

nephrotoxicity via renin-angiotensin system independent mechanism. 

Transplantation. 2002 Sep 27;74(6):784-91. 

PMID: 12364856 

67. Plasma exchange in severe postpartum HELLP syndrome. 

Forster JG, Peltonen S, Kaaja R, Lampinen K, Pettila V. 

Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. 

PMID: 12190795 

68. Kantas E, Cetin A, Kaya T, Cetin M. 

Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: 

pregnant human and rat. 

Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. 

PMID: 12225296 

69. Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. 

The use of magnesium sulfate to prevent pain on injection of propofol. 

Anesth Analg. 2002 Sep;95(3):606-8, table of contents. 

PMID: 12198045 



346

70. Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. 

Intrathecal magnesium prolongs fentanyl analgesia: a prospective, 

randomized, controlled trial. 


PMID: 12198056 

71. Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, 

Ghini AS, Chiariello L. 

Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery 

bypass grafting. 

Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. 

PMID: 12238830 

72. Tramer MR, Glynn CJ. 

Magnesium Bier's block for treatment of chronic limb pain: a randomised, 

double-blind, cross-over study. 

Pain. 2002 Sep;99(1-2):235-41. 

PMID: 12237201 

73. Patrick L. 

Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. 

Treatment approaches using vitamin E, magnesium, and 

betaine. 

Altern Med Rev. 2002 Aug;7(4):276-91. 

PMID: 12197781 

74. Attygalle D, Rodrigo N. 

Magnesium as first line therapy in the management of tetanus: a 

prospective study of 40 patients. 

Anaesthesia. 2002 Aug;57(8):811-7. 

PMID: 12133096 

75. Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, 

Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study 

Group. 

IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized 

controlled trial. 

Chest. 2002 Aug;122(2):489-97. 

PMID: 12171821 

76. Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. 

Effect of formulation variables on the floating properties of gastric floating drug delivery 

system. 

Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. 

PMID: 12236064 



347

77. van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, 

Tulleken CA, Nicolay K. 

Role of magnesium in the reduction of ischemic depolarization and lesion volume after 

experimental subarachnoid hemorrhage. 

J Neurosurg. 2002 Aug;97(2):416-22. 

PMID: 12186471 

78. Garcia MC, Byrd RP Jr, Roy TM. 

Lethal iatrogenic hypermagnesemia. 

Tenn Med. 2002 Aug;95(8):334-6. 

PMID: 12174756 

79. Patel S, Martinez-Ripoll M, Blundell TL, Albert A. 

J Mol Biol. 2002 Jul 26;320(5):1087-94. 

Structural enzymology of Li(+)-sensitive/Mg(2+)-dependent phosphatases. 

PMID: 12126627 

80. Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. 

Combined systemic administration of morphine and magnesium sulfate attenuates painrelated 

behavior in mononeuropathic rats. 

Brain Res. 2002 Jul 5;943(1):101-4. 

PMID: 12088843 

81. Dagdelen S, Toraman F, Karabulut H, Alhan C. 

The value of P dispersion on predicting atrial fibrillation after coronary artery bypass 

surgery: effect of magnesium on P dispersion. 

Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. 

PMID: 12167181 

82. Streetman DD, Bhatt-Mehta V, Johnson CE. 

Management of acute, severe asthma in children. 

Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. 

PMID: 12086560 

83. Kaye P, O'Sullivan I. 

The role of magnesium in the emergency department. 

Emerg Med J. 2002 Jul;19(4):288-91. 

PMID: 12101132 

84. Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; 

Japan-China Cooperative Study Group: Chongqing Project. 

Diet-related factors, educational levels and blood pressure in a Chinese 

population sample: findings from the Japan-China Cooperative Research 

Project. 

Hypertens Res. 2002 Jul;25(4):559-64. 

PMID: 12358141 



348

85. Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. 

Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver 

cirrhosis -- relation to spironolactone. 

J Intern Med. 2002 Jul;252(1):56-63. 

PMID: 12074739 

86. Malluche HH, Mawad H. 

Management of hyperphosphataemia of chronic kidney disease: lessons from the past and 

future directions. 

Nephrol Dial Transplant. 2002 Jul;17(7):1170-5. 

PMID: 12105237 

Zinc – 50 STUDIES 

1: Nowak G, Szewczyk B, Wieronska JM, Branski P, Palucha A, Pilc A, Sadlik K, 

Piekoszewski W. 

Antidepressant-like effects of acute and chronic treatment with zinc in forced 

swim test and olfactory bulbectomy model in rats. 

Brain Res Bull. 2003 Jul 15;61(2):159-64. 

PMID: 12832002 

2: Lambert JC, Zhou Z, Wang L, Song Z, McClain CJ, Kang YJ. 

Prevention of alterations in intestinal permeability is involved in zinc 

inhibition of acute ethanol-induced liver damage in mice. 

J Pharmacol Exp Ther. 2003 Jun;305(3):880-6. Epub 2003 Mar 06. 

PMID: 12626662 

3: Roldan S, Winkel EG, Herrera D, Sanz M, Van Winkelhoff AJ. 

The effects of a new mouthrinse containing chlorhexidine, cetylpyridinium 

chloride and zinc lactate on the microflora of oral halitosis patients: a 

dual-centre, double-blind placebo-controlled study. 

J Clin Periodontol. 2003 May;30(5):427-34. 

PMID: 12716335 

4: Winkel EG, Roldan S, Van Winkelhoff AJ, Herrera D, Sanz M. 

Clinical effects of a new mouthrinse containing chlorhexidine, cetylpyridinium 

chloride and zinc-lactate on oral halitosis. A dual-center, double-blind 

placebo-controlled study. 

J Clin Periodontol. 2003 Apr;30(4):300-6. 

PMID: 12694427 

5: Orbak R, Cicek Y, Tezel A, Dogru Y. 



349

Effects of zinc treatment in patients with recurrent aphthous stomatitis. 

Dent Mater J. 2003 Mar;22(1):21-9. 

PMID: 12790293 

6: Mossad SB. 

Effect of zincum gluconicum nasal gel on the duration and symptom severity of 

the common cold in otherwise healthy adults. 

QJM. 2003 Jan;96(1):35-43. 

PMID: 12509647 

7: McElroy BH, Miller SP. 

Effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) against the common 

cold in school-aged subjects: a retrospective chart review. 

Am J Ther. 2002 Nov-Dec;9(6):472-5. 

PMID: 12424502 

8: Nowak G, Szewczyk B. 

Mechanisms contributing to antidepressant zinc actions. 

Pol J Pharmacol. 2002 Nov-Dec;54(6):587-92. Review. 

PMID: 12866713 

9: Putt MS, Yu D, Kohut BE. 

Inhibition of calculus formation by dentifrice formulations containing 

essential oils and zinc. 

Am J Dent. 2002 Oct;15(5):335-8. 

PMID: 12537346 

10: Rostan EF, DeBuys HV, Madey DL, Pinnell SR. 

Evidence supporting zinc as an important antioxidant for skin. 

Int J Dermatol. 2002 Sep;41(9):606-11. Review. 

PMID: 12358835 

11: Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, Sommerfelt H, Bhan 

MK. 

Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 

years: randomised controlled trial in an urban slum. 

BMJ. 2002 Jun 8;324(7350):1358. 

PMID: 12052800 

12: Oken E, Duggan C. 

Update on micronutrients: iron and zinc. 

Curr Opin Pediatr. 2002 Jun;14(3):350-3. Review. 

PMID: 12011679 

13: Cho YH, Lee SJ, Lee JY, Kim SW, Lee CB, Lee WY, Yoon MS. 

Antibacterial effect of intraprostatic zinc injection in a rat model of chronic 



350

acterial prostatitis. 

Int J Antimicrob Agents. 2002 Jun;19(6):576-82. 

PMID: 12135851 

14: Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, Sommerfelt H, Bhan 

MK. 

Substantial reduction in severe diarrheal morbidity by daily zinc 

supplementation in young north Indian children. 

Pediatrics. 2002 Jun;109(6):e86. 

PMID: 12042580 

15: Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, Ulvik RJ, 

Molbak K, Bhan MK, Sommerfelt H. 

Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young 

children. 

Pediatrics. 2002 May;109(5):898-903. 

PMID: 11986453 

16: Lowe NM, Lowe NM, Fraser WD, Jackson MJ. 

Is there a potential therapeutic value of copper and zinc for osteoporosis? 

Proc Nutr Soc. 2002 May;61(2):181-5. Review. 

PMID: 12133199 

17: Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, Dolmans WM, 

Schlebusch H, van der Meer JW. 

A double-blind, placebo-controlled study of vitamin A and zinc supplementation 

in persons with tuberculosis in Indonesia: effects on clinical response and 

nutritional status. 


PMID: 11916759 

18: Afonne OJ, Orisakwe OE, Obi E, Dioka CE, Ndubuka GI. 

Nephrotoxic actions of low-dose mercury in mice: protection by zinc. 

Arch Environ Health. 2002 Mar-Apr;57(2):98-102. 

PMID: 12194165 

19: Hwang IK, Go VL, Harris DM, Yip I, Song MK. 

Effects of arachidonic acid plus zinc on glucose disposal in genetically 

diabetic (ob/ob) mice. 

Diabetes Obes Metab. 2002 Mar;4(2):124-31. 

PMID: 11940110 

20: Su JC, Birmingham CL. 

Zinc supplementation in the treatment of anorexia nervosa. 

Eat Weight Disord. 2002 Mar;7(1):20-2. Review. 

PMID: 11930982 



351

21: Tsocheva-Gaitandjieva NT, Gabrashanska MP, Tepavitcharova S. 

Trace element levels in the liver of rats with acute and chronic fascioliasis and after 

treatment with zinc-copper hydroxochloride mixed crystals. 

J Helminthol. 2002 Mar;76(1):87-90. 

PMID: 12018202 

22: Zemel BS, Kawchak DA, Fung EB, Ohene-Frempong K, Stallings VA. 

Effect of zinc supplementation on growth and body composition in children with 

sickle cell disease. 

Am J Clin Nutr. 2002 Feb;75(2):300-7. 

PMID: 11815322 

23: Yoshida S, Tomita H. 

A case of Cronkhite-Canada syndrome whose major complaint, taste disturbance, 

was improved by zinc therapy. 

Acta Otolaryngol Suppl. 2002;(546):154-8. 

PMID: 12132614 

24: Rahman MM, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. 

Synergistic effect of zinc and vitamin A on the biochemical indexes of vitamin 

A nutrition in children. 

Am J Clin Nutr. 2002 Jan;75(1):92-8. 

PMID: 11756065 

25: Prasad AS, Kucuk O. 

Zinc in cancer prevention. 

Cancer Metastasis Rev. 2002;21(3-4):291-5. Review. 

PMID: 12549767 

26: Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, 

Tsuji T. 

Effects of zinc deficiency/zinc supplementation on ammonia metabolism in 

patients with decompensated liver cirrhosis. 

Acta Med Okayama. 2001 Dec;55(6):349-55. 

PMID: 11779097 

27: Jampol LM, Ferris FL 3rd. 

Antioxidants and zinc to prevent progression of age-related macular 

degeneration. 

JAMA. 2001 Nov 21;286(19):2466-8. No abstract available. 

PMID: 11759670 

28: Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. 

Effects of iron and zinc supplementation in Indonesian infants on micronutrient 

status and growth. 



352

J Nutr. 2001 Nov;131(11):2860-5. 

PMID: 11694609 

29: Fong LY, Nguyen VT, Farber JL. 

Esophageal cancer prevention in zinc-deficient rats: rapid induction of 

apoptosis by replenishing zinc. 

J Natl Cancer Inst. 2001 Oct 17;93(20):1525-33. 

PMID: 11604475 

30: Takagi H, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, Kakizaki S, 

Hashimoto Y, Matsumoto T, Kojima A, Takezawa J, Suzuki K, Sato S, Mori M. 

Zinc supplementation enhances the response to interferon therapy in patients 

with chronic hepatitis C. 

J Viral Hepat. 2001 Sep;8(5):367-71. 

PMID: 11555194 

31: Christian P, Khatry SK, Yamini S, Stallings R, LeClerq SC, Shrestha SR, 

Pradhan EK, West KP Jr. 

Zinc supplementation might potentiate the effect of vitamin A in restoring 

night vision in pregnant Nepalese women. 

Am J Clin Nutr. 2001 Jun;73(6):1045-51. 

PMID: 11382658 

32: Najda J, Stella-Holowiecka B, Machalski M. 

Low-dose zinc administration as an effective Wilson's disease treatment. 

Biol Trace Elem Res. 2001 Jun;80(3):281-4. 

PMID: 11508632 

33: Iitaka M, Kakinuma S, Fujimaki S, Oosuga I, Fujita T, Yamanaka K, Wada S, 

Katayama S. 

Induction of apoptosis and necrosis by zinc in human thyroid cancer cell lines. 

J Endocrinol. 2001 May;169(2):417-24. 

PMID: 11312158 

34: Yang HM, Chai JK, Guo ZR. 

[Effect of improved topical agents on healing time of deep second-degree burn 

wound] 

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2001 May;15(3):162-4. Chinese. 

PMID: 11393958 

35: Khatun UH, Malek MA, Black RE, Sarkar NR, Wahed MA, Fuchs G, Roy SK. 

A randomized controlled clinical trial of zinc, vitamin A or both in 

undernourished children with persistent diarrhea in Bangladesh. 

Acta Paediatr. 2001 Apr;90(4):376-80. 

PMID: 11332926 



353

36: Yoshikawa Y, Ueda E, Miyake H, Sakurai H, Kojima Y. 

Insulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing 

effect in KK-A(y) mice with type 2 diabetes mellitus. 

Biochem Biophys Res Commun. 2001 Mar16;281(5):1190-3. 

PMID: 11243860 

37: Hotz C, Brown KH. 

Identifying populations at risk of zinc deficiency: the use of supplementation 

trials. 

Nutr Rev. 2001 Mar;59(3 Pt 1):80-4. Review. 

PMID: 11330625 

38: Ho E, Quan N, Tsai YH, Lai W, Bray TM. 

Dietary zinc supplementation inhibits NFkappaB activation and protects against 

chemically induced diabetes in CD1 mice. 

Exp Biol Med (Maywood). 2001 Feb;226(2):103-11. 

PMID: 11446433 

39: Dreno B, Moyse D, Alirezai M, Amblard P, Auffret N, Beylot C, Bodokh I, 

Chivot M, Daniel F, Humbert P, Meynadier J, Poli F; Acne Research and Study 

Group. 

Multicenter randomized comparative double-blind controlled clinical trial of 

the safety and efficacy of zinc gluconate versus minocycline hydrochloride in 

the treatment of inflammatory acne vulgaris. 

Dermatology. 2001;203(2):135-40. 

PMID: 11586012 

40: Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A, Khatun F, 

Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A. 

Therapeutic effects of oral zinc in acute and persistent diarrhea in children 

in developing countries: pooled analysis of randomized controlled trials. 

Am J Clin Nutr. 2000 Dec;72(6):1516-22. 

PMID: 11101480 

41: Saple DG, Ravichandran G, Desai A. 

Evaluation of safety and efficacy of ketoconazole 2% and zinc pyrithione 1% 

shampoo in patients with moderate to severe dandruff--a postmarketing study. 

J Indian Med Assoc. 2000 Dec;98(12):810-1. 

PMID: 11394481 

42: Hirt M, Nobel S, Barron E. 

Zinc nasal gel for the treatment of common cold symptoms: a double-blind, 

placebo-controlled trial. 

Ear Nose Throat J. 2000 Oct;79(10):778-80, 782. 

PMID: 11055098 



354

43: Sayeg Porto MA, Oliveira HP, Cunha AJ, Miranda G, Guimaraes MM, Oliveira 

WA, dos Santos DM. 

Linear growth and zinc supplementation in children with short stature. 

J Pediatr Endocrinol Metab. 2000 Sep-Oct;13(8):1121-8. 

PMID: 11085191 

44: Umeta M, West CE, Haidar J, Deurenberg P, Hautvast JG. 

Zinc supplementation and stunted infants in Ethiopia: a randomised controlled 

trial. 

Lancet. 2000 Jun 10;355(9220):2021-6. 

PMID: 10885352 

45: Goel A, Chauhan DP, Dhawan DK. 

Protective effects of zinc in chlorpyrifos induced hepatotoxicity: a 

biochemical and trace elemental study. 

Biol Trace Elem Res. 2000 May;74(2):171-83. 

PMID: 11051590 

46: Mocchegiani E, Muzzioli M. 

Therapeutic application of zinc in human immunodeficiency virus against 

opportunistic infections. 

J Nutr. 2000 May;130(5S Suppl):1424S-31S. Review. 

PMID: 10801955 

47: Williams DR. 

Chemical speciation applied to bio-inorganic chemistry. 

J Inorg Biochem. 2000 Apr;79(1-4):275-83. Review. 

PMID: 10830878 

48: Tahmaz L, Gokalp A, Kibar Y, Kocak I, Yalcin O, Ozercan Y. 

Effect of hypothyroidism on the testes in mature rats and treatment with 

levothyroxine and zinc. 

Andrologia. 2000 Mar;32(2):85-9. 

PMID: 10755190 

49: Cacic M, Percl M, Jadresin O, Kolacek S. 

[The role of zinc in the initial treatment of Wilson's disease in children] 

Lijec Vjesn. 2000 Mar;122(3-4):77-81. Serbo-Croatian (Roman). 

PMID: 10932534 

50: Penland JG. 

Behavioral data and methodology issues in studies of zinc nutrition in humans. 

J Nutr. 2000 Feb;130(2S Suppl):361S-364S. Review. 

PMID: 10721907 



355

Selenium – 50 STUDIES 

1: Santamaria A, Salvatierra-Sanchez R, Vazquez-Roman B, Santiago-Lopez D, 

Villeda-Hernandez J, Galvan-Arzate S, Jimenez-Capdeville ME, Ali SF. 

Protective effects of the antioxidant selenium on quinolinic acid-induced 

neurotoxicity in rats: in vitro and in vivo studies. 

J Neurochem. 2003 Jul;86(2):479-88. 

PMID: 12871589 

2: Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, 

Zghal K, Fki H, Damak J, Bahloul A. 

Sperm oxidative stress and the effect of an oral vitamin E and selenium 

supplement on semen quality in infertile men. 

Arch Androl. 2003 Mar-Apr;49(2):83-94. 

PMID: 12623744 

3: Di Leo MA, Ghirlanda G, Gentiloni Silveri N, Giardina B, Franconi F, Santini 

SA. 

Potential therapeutic effect of antioxidants in experimental diabetic retina: a 

comparison between chronic taurine and vitamin E plus selenium supplementations. 

Free Radic Res. 2003 Mar;37(3):323-30. 

PMID: 12688428 

4: Xu J, Yang F, Chen L, Hu Y, Hu Q. 

Effect of selenium on increasing the antioxidant activity of tea leaves 

harvested during the early spring tea producing season. 

J Agric Food Chem. 2003 Feb 12;51(4):1081-4. 

PMID: 12568576 

5: Kalinina EP, Zhuravskaia NS, Tsyvkina GI, Koziavina NV. 

[Correction of immune disorders with neoselenium in patients with chronic 

bronchitis] 

Klin Med (Mosk). 2003;81(3):43-6. Russian. 

PMID: 12698851 

6: Chow CK, Hong CB. 

Dietary vitamin E and selenium and toxicity of nitrite and nitrate. 

Toxicology. 2002 Nov 15;180(2):195-207. Review. 

PMID: 12324194 

7: El-Bayoumy K, Richie JP Jr, Boyiri T, Komninou D, Prokopczyk B, Trushin N, 

Kleinman W, Cox J, Pittman B, Colosimo S. 

Influence of selenium-enriched yeast supplementation on biomarkers of oxidative 

damage and hormone status in healthy adult males: a clinical pilot study. 

Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1459-65. 

PMID: 12433727 



356

8: Burbano X, Miguez-Burbano MJ, McCollister K, Zhang G, Rodriguez A, Ruiz P, 

Lecusay R, Shor-Posner G. 

Impact of a selenium chemoprevention clinical trial on hospital admissions of 

HIV-infected participants. 

HIV Clin Trials. 2002 Nov-Dec;3(6):483-91. 

PMID: 12501132 

9: Zuberbuehler CA, Messikommer RE, Wenk C. 

Choice feeding of selenium-deficient laying hens affects diet selection, 

selenium intake and body weight. 

J Nutr. 2002 Nov;132(11):3411-7. 

PMID: 12421860 

10: Arai T, Magori E, Morimoto Y. 

Changes in activities of enzymes in erythrocytes from ddY mice supplemented 

with dietary selenium. 

Exp Anim. 2002 Oct;51(5):517-9. 

PMID: 12451715 

11: Shor-Posner G, Lecusay R, Morales G, Campa A, Miguez-Burbano MJ. 

Neuroprotection in HIV-positive drug users: implications for antioxidant 

therapy. 

J Acquir Immune Defic Syndr. 2002 Oct 1;31 Suppl 2:S84-8. Review. 

PMID: 12394787 

12: Dylewski ML, Mastro AM, Picciano MF. 

Maternal selenium nutrition and neonatal immune system development. 

Biol Neonate. 2002 Aug;82(2):122-7. 

PMID: 12169835 

13: Holben DH, Smith AM, Ilich JZ, Landoll JD, Holcomb JP, Matkovic V. 

Selenium intakes, absorption, retention, and status in adolescent girls. 

J Am Diet Assoc. 2002 Aug;102(8):1082-7. 

PMID: 12171452 

14: Hintze KJ, Lardy GP, Marchello MJ, Finley JW. 

Selenium accumulation in beef: effect of dietary selenium and geographical area 

of animal origin. 

J Agric Food Chem. 2002 Jul 3;50(14):3938-42. 

PMID: 12083862 

15: Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF Jr, Slate EH, Fischbach 

LA, Marshall JR, Clark LC. 

Baseline characteristics and the effect of selenium supplementation on cancer 

incidence in a randomized clinical trial: a summary report of the Nutritional 

Prevention of Cancer Trial. 



357

Cancer Epidemiol Biomarkers Prev. 2002 Jul;11(7):630-9. 

PMID: 12101110 

16: Popova NV. 

Perinatal selenium exposure decreases spontaneous liver tumorogenesis in CBA 

mice. 

Cancer Lett. 2002 May 8;179(1):39-42. 

PMID: 11880180 

17: Murphy J, Hannon EM, Kiely M, Flynn A, Cashman KD. 

Selenium intakes in 18-64-y-old Irish adults. 

Eur J Clin Nutr. 2002 May;56(5):402-8. 

PMID: 12001010 

18: Gierus M, Schwarz FJ, Kirchgessner M. 

Selenium supplementation and selenium status of dairy cows fed diets based on 

grass, grass silage or maize silage. 

J Anim Physiol Anim Nutr (Berl). 2002 Apr;86(3-4):74-82. 

PMID: 11972675 

19: Gartner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. 

Selenium supplementation in patients with autoimmune thyroiditis decreases 

thyroid peroxidase antibodies concentrations. 

J Clin Endocrinol Metab. 2002 Apr;87(4):1687-91. 

PMID: 11932302 

20: Mehta U, Kang BP, Bansal G, Bansal MP. 

Studies of apoptosis and bcl-2 in experimental atherosclerosis in rabbit and 

influence of selenium supplementation. 

Gen Physiol Biophys. 2002 Mar;21(1):15-29. 

PMID: 12168721 

21: Kurz B, Jost B, Schunke M. 

Dietary vitamins and selenium diminish the development of mechanically induced 

osteoarthritis and increase the expression of antioxidative enzymes in the knee 

joint of STR/1N mice. 

Osteoarthritis Cartilage. 2002 Feb;10(2):119-26. 

PMID: 11869071 

22: Huang K, Yang S. 

Inhibitory effect of selenium on Cryptosporidium parvum infection in vitro and 

in vivo. 

Biol Trace Elem Res. 2002 Winter;90(1-3):261-72. 

PMID: 12666840 



358

23: Gazdik F, Horvathova M, Gazdikova K, Jahnova E. 

The influence of selenium supplementation on the immunity of 

corticoid-dependent asthmatics. 

Bratisl Lek Listy. 2002;103(1):17-21. 

PMID: 12061081 

24: Gazdik F, Kadrabova J, Gazdikova K. 

Decreased consumption of corticosteroids after selenium supplementation in 

corticoid-dependent asthmatics. 

Bratisl Lek Listy. 2002;103(1):22-5. 

PMID: 12061082 

25: Sepulveda RT, Zhang J, Watson RR. 

Selenium supplementation decreases coxsackievirus heart disease during murine 

AIDS. 

Cardiovasc Toxicol. 2002;2(1):53-61. 

PMID: 12189280 

26: Miyazaki Y, Koyama H, Nojiri M, Suzuki S. 

Relationship of dietary intake of fish and non-fish selenium to serum lipids in 

Japanese rural coastal community. 

J Trace Elem Med Biol. 2002;16(2):83-90. 

PMID: 12195730 

27: Muller AS, Pallauf J, Most E. 

Parameters of dietary selenium and vitamin E deficiency in growing rabbits. 

J Trace Elem Med Biol. 2002;16(1):47-55. 

PMID: 11878752 

28: de Lorgeril M, Salen P, Accominotti M, Cadau M, Steghens JP, Boucher F, de 

Leiris J. 

Dietary and blood antioxidants in patients with chronic heart failure. Insights 

into the potential importance of selenium in heart failure. 

Eur J Heart Fail. 2001 Dec;3(6):661-9. 

PMID: 11738217 

29: Sjunnesson H, Sturegard E, Willen R, Wadstrom T. 

High intake of selenium, beta-carotene, and vitamins A, C, and E reduces growth 

of Helicobacter pylori in the guinea pig. 

Comp Med. 2001 Oct;51(5):418-23. 

PMID: 11924801 

30: Kang BP, Mehta U, Bansal MP. 

Selenium supplementation protects from high fat diet-induced atherogenesis in 

rats: role of mitogen stimulated lymphocytes and macrophage NO production. 



359

Indian J Exp Biol. 2001 Aug;39(8):793-7. 

PMID: 12018582 

31: Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G. 

Adverse health effects of selenium in humans. 

Rev Environ Health. 2001 Jul-Sep;16(4):233-51. Review. 

PMID: 12041880 

32: Zhang ZW, Shimbo S, Qu JB, Watanabe T, Nakatsuka H, Matsuda-Inoguchi N, 

Higashikawa K, Ikeda M. 

Dietary selenium intake of Chinese adult women in the 1990s. 

Biol Trace Elem Res. 2001 May;80(2):125-38. 

PMID: 11437178 

33: Combs GF Jr. 

Selenium in global food systems. 

Br J Nutr. 2001 May;85(5):517-47. Review. 

PMID: 11348568 

34: Finley JW, Ip C, Lisk DJ, Davis CD, Hintze KJ, Whanger PD. 

Cancer-protective properties of high-selenium broccoli. 

J Agric Food Chem. 2001 May;49(5):2679-83. 

PMID: 11368655 

35: Federico A, Iodice P, Federico P, Del Rio A, Mellone MC, Catalano G, 

Federico P. 

Effects of selenium and zinc supplementation on nutritional status in patients 

with cancer of digestive tract. 


PMID: 11360134 

36: Chanoine JP, Neve J, Wu S, Vanderpas J, Bourdoux P. 

Selenium decreases thyroglobulin concentrations but does not affect the 

increased thyroxine-to-triiodothyronine ratio in children with congenital 

hypothyroidism. 

J Clin Endocrinol Metab. 2001 Mar;86(3):1160-3. 

PMID: 11238502 

37: Naziroglu M, Cay M. 

Protective role of intraperitoneally administered vitamin E and selenium on the 

antioxidative defense mechanisms in rats with diabetes induced by 

streptozotocin. 

Biol Trace Elem Res. 2001 Feb;79(2):149-59. 

PMID: 11330521 



360

38: Kiremidjian-Schumacher L, Roy M. 

Effect of selenium on the immunocompetence of patients with head and neck 

cancer and on adoptive immunotherapy of early and established lesions. 

Biofactors. 2001;14(1-4):161-8. Review. 

PMID: 11568453 

39: Gartner R, Albrich W, Angstwurm MW. 

The effect of a selenium supplementation on the outcome of patients with severe 

systemic inflammation, burn and trauma. 


PMID: 11568457 

40: Abdollahi M, Rahmat-Jirdeh N, Soltaninejad K. 

Protection by selenium of lead-acetate-induced alterations on rat submandibular 

gland function. 

Hum Exp Toxicol. 2001 Jan;20(1):28-33. 

PMID: 11339622 

41: Berger MM, Reymond MJ, Shenkin A, Rey F, Wardle C, Cayeux C, Schindler C, 

Chiolero RL. 

Influence of selenium supplements on the post-traumatic alterations of the 

thyroid axis: a placebo-controlled trial. 

Intensive Care Med. 2001 Jan;27(1):91-100. 

PMID: 11280679 

42: Combs GF Jr. 

Impact of selenium and cancer-prevention findings on the nutrition-health 

paradigm. 

Nutr Cancer. 2001;40(1):6-11. Review. 

PMID: 11799925 

43: Kim YS, Milner J. 

Molecular targets for selenium in cancer prevention. 

Nutr Cancer. 2001;40(1):50-4. Review. 

PMID: 11799923 

44: Francescato HD, Costa RS, Rodrigues Camargo SM, Zanetti MA, Lavrador MA, 

Bianchi MD. 

Effect of oral selenium administration on cisplatin-induced nephrotoxicity in 

rats. 

Pharmacol Res. 2001 Jan;43(1):77-82. 

PMID: 11207069 

45: Tutel'ian VA, Khotimchenko SA. 

[Selenium as an essential and deficient factor in the nutrition of Russian 

population] 



361

Vestn Ross Akad Med Nauk. 2001;(6):31-4. Russian. 

PMID: 11517874 

46: Shakhovskaia AK, Gmoshinskii IV, Vasil'ev AV, Loranskaia TI, Ovchinnikova 

IV, Orlova LA, Mazo VK. 

[Use of organic forms of selenium in nutrition of patients with 

gastrointestinal diseases] 

Vopr Pitan. 2001;70(3):22-4. Russian. 

PMID: 11517685 

47: Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris 

JS, Comstock GW. 

Association between alpha-tocopherol, gamma-tocopherol, selenium, and 

subsequent prostate cancer. 

J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. 

PMID: 11121464 

48: Djujic IS, Jozanov-Stankov ON, Milovac M, Jankovic V, Djermanovic V. 

Bioavailability and possible benefits of wheat intake naturally enriched with 

selenium and its products. 

Biol Trace Elem Res. 2000 Dec;77(3):273-85. 

PMID: 11204469 

49: Sieja K. 

Protective role of selenium against the toxicity of multi-drug chemotherapy in 

patients with ovarian cancer. 

Pharmazie. 2000 Dec;55(12):958-9. No abstract available. 

PMID: 11189880 

50: McKenzie RC. 

Selenium, ultraviolet radiation and the skin. 

Clin Exp Dermatol. 2000 Nov;25(8):631-6. Review. 

PMID: 11167979 

Copper – 60 Studies 

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effects on blood copper enzyme activities and indicators of cardiovascular disease risk. 

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Epidemiol. 2000;151(12):1182-1188. (PubMed) 

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24. Heresi G, Castillo-Duran C, Munoz C, Arevalo M, Schlesinger L. Phagocytosis and 

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25. Kelley DS, Daudu PA, Taylor PC, Mackey BE, Turnlund JR. Effects of low-copper diets on 

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26. Conlan D, Korula R, Tallentire D. Serum copper levels in elderly patients with femoral-neck 

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28. Baker A, Harvey L, Majask-Newman G, Fairweather-Tait S, Flynn A, Cashman K. Effect of 

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29. Baker A, Turley E, Bonham MP, et al. No effect of copper supplementation on biochemical 

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30. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics 

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34. Br J Nutr. 2003 Jul;90(1):161-8. 

Adaptive responses in men fed low- and high-copper diets. 

Majsak-Newman G, Dainty JR, Lewis DJ, Langford NJ, Crews HM, Fairweather-Tait SJ. 

PMID: 12844388 

35. Eur J Clin Nutr. 2003 May;57(5):706-12. 

Copper and zinc intake and serum levels in patients with juvenile rheumatoid arthritis. 

Silverio Amancio OM, Alves Chaud DM, Yanaguibashi G, Esteves Hilario MO. 

PMID: 12771972 

36. J Dairy Sci. 2003 Apr;86(4):1240-9. 

Role of dietary copper in enhancing resistance to Escherichia coli mastitis. 

Scaletti RW, Trammell DS, Smith BA, Harmon RJ. 

PMID: 12741549 

37. Contraception. 2003 Feb;67(2):161-3. 

Human spermatozoa motility analysis in a Ringer's solution containing cupric ions. 

Araya R, Gomez-Mora H, Vera R, Bastidas JM. 

PMID: 12586326 

38. J Nutr. 2003 Feb;133(2):522-7. 

Low dietary copper increases fecal free radical production, fecal water alkaline 

phosphatase activity and cytotoxicity in healthy men. 

Davis CD. 

PMID: 12566494 

39. J Nutr. 2002 Oct;132(10):3142-5. 

The timing of perinatal copper deficiency in mice influences offspring survival. 

Prohaska JR, Brokate B. 

PMID: 12368408 

40. Am J Clin Nutr. 2002 Sep;76(3):687-8; author reply 688. 

Extra dietary copper inhibits LDL oxidation. 

Klevay LM. 

PMID: 12198019 

41. Vet Rec. 2002 Jul 13;151(2):50-3. 

Effects of copper supplementation on the copper status of peripartum beef cows and their 

calves. 

Enjalbert F, Lebreton P, Salat O, Meschy F, Schelcher F. 

PMID: 12148603 

42. Ceska Slov Farm. 2002 Jul;51(4):205-7. 

Anti-inflammatory activity of (o-cresotinate) copper and zinc aquacomplexes 

Sokolik J, Tumova I, Blahova M, Bernathova M, Svec P. 

PMID: 12183910 



365

43. J Anim Sci. 2002 Jul;80(7):1999-2005. 

Effects of dietary copper on the expression of lipogenic genes and metabolic hormones in 

steers. 

Lee SH, Engle TE, Hossner KL. 

PMID: 12162670 

44. J Nutr. 2002 May;132(5):1018-25. 

Dietary copper affects azoxymethane-induced intestinal tumor formation and protein 

kinase C isozyme protein and mRNA expression in colon of rats. 

Davis CD, Johnson WT. 

PMID: 11983831 

45. Proc Nutr Soc. 2002 May;61(2):181-5. 

Is there a potential therapeutic value of copper and zinc for osteoporosis? 

Lowe NM, Lowe NM, Fraser WD, Jackson MJ. 

PMID: 12133199 

46. Bull Exp Biol Med. 2002 Apr;133(4):334-5. 

Protective effect of copper-rutin complex in animals with experimental epilepsy. 

Tsaryuk VV, Potapovich AI, Kostyuk VA. 

PMID: 12124637 

47. J Nutr. 2002 Feb;132(2):190-6. 

Skeletal unloading and dietary copper depletion are detrimental to bone quality of mature 

rats. 

Smith BJ, King JB, Lucas EA, Akhter MP, Arjmandi BH, Stoecker BJ. 

PMID: 11823577 

48. Trop Anim Health Prod. 2002 Feb;34(1):75-80. 

A possible association between dietary intake of copper, zinc and phosphate and delayed 

puberty in heifers in Sudan. 

Ahmed MM, Fadlalla IM, Barri ME. 

PMID: 11887424 

49. J Exp Biol. 2002 Jan;205(Pt 2):279-90. 

Copper metabolism in actively growing rainbow trout (Oncorhynchus mykiss): 

interactions between dietary and waterborne copper uptake. 

Kamunde C, Grosell M, Higgs D, Wood CM. 

PMID: 11821494 

50. Nutrition. 2001 Sep;17(9):701-8. 

Low dietary zinc alters indices of copper function and status in postmenopausal women. 

Milne DB, Davis CD, Nielsen FH. 

PMID: 11527655 



366

51. J Nutr. 2001 Aug;131(8):2171-6. 

A longitudinal investigation of aggregate oral intake of copper. 

Pang Y, MacIntosh DL, Ryan PB. 

PMID: 11481413 

52. J Anim Physiol Anim Nutr (Berl). 2001 Feb;85(1-2):29-37. 

The lowering effect of high copper intake on selenium retention in weanling rats depends 

on the selenium concentration of the diet. 

Yu S, Beynen AC. 

PMID: 11686770 

53. Gig Sanit. 2001 Jan-Feb;(1):54-7. 

Providing athletes with trace elements during intensive exercise 

Nasolodin VV, Gladkikh IP, Meshcheriakov SI. 

PMID: 11236477 

54. Biol Trace Elem Res. 2000 Dec;77(3):241-9. 

Effect of dietary copper on selenium toxicity in Fischer 344 rats. 

Tatum L, Shankar P, Boylan LM, Spallholz JE. 

PMID: 11204466 

55. J Nutr. 2000 Nov;130(11):2838-43. 

Zinc and copper intakes and their major food sources for older adults in the 1994-96 

continuing survey of food intakes by individuals (CSFII). 

Ma J, Betts NM. 

PMID: 11053529 

56. Cancer Lett. 2000 Oct 16;159(1):57-62. 

Inadequate dietary copper increases tumorigenesis in the Min mouse. 

Davis CD, Newman S. 

PMID: 10974406 

57. Inflamm Res. 2000 May;49(5):214-23. 

Nutritional supplementation with copper in the rat. I. Effects on adjuvant arthritis 

development and on some in vivo- and ex vivo-markers of blood neutrophils. 

Milanino R, Marrella M, Crivellente F, Benoni G, Cuzzolin L. 

PMID: 10893044 

58. Nippon Ronen Igakkai Zasshi. 2000 Apr;37(4):304-8. 

Copper supplement with cocoa for copper deficiency in patients with long-term enteral 

nutrition 

Wakugami K, Suenaga H, Egashira A, Taira T, Tokashiki T, Yamazaki T, Maehara A, 

Uechi K. 

PMID: 10917028 



367

59. Proc Soc Exp Biol Med. 2000 Mar;223(3):282-7. 

Alterations in hypertrophic gene expression by dietary copper restriction in mouse heart. 

Kang YJ, Wu H, Saari JT. 

PMID: 10719841 

60. Ann Nutr Metab. 2000;44(3):129-34. 

Plasma copper concentration as marker of copper intake from food. 

Konig JS, Elmadfa I. 

PMID: 11053900 

Quercetin – 20 STUDIES 

1. Pharmacology. 2003 Oct;69(2):59-67. Protective Effect of Flavonoids against Aging- 

and Lipopolysaccharide-Induced Cognitive Impairment in Mice. Patil CS, Singh VP, 

Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Pharmacology Division, University 

Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 

2. Clin Pharmacokinet. 2003;42(5):437-59. Clinical pharmacokinetics of antioxidants and 

their impact on systemic oxidative stress. Schwedhelm E, Maas R, Troost R, Boger RH. 

Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology Unit, 

University Hospital of Hamburg-Eppendorf, Hamburg, Germany. schwedhelm@ukehamburg.de 

3. Neurobiol Aging. 2002 Sep-Oct;23(5):891-97. Natural extracts as possible protective 

agents of brain aging. Bastianetto S, Quirion R. Department of Psychiatry and 

Pharmacology and Therapeutics, Douglas Hospital Research Centre, McGill University, 

6875 LaSalle Boulevard, Verdun, Que, Canada H4H 1R3. 

4. Mol Biol Cell. 2002 Jul;13(7):2502-17. Expression of caveolin-1 induces premature 

cellular senescence in primary cultures of murine fibroblasts. Volonte D, Zhang K, 

Lisanti MP, Galbiati F. Department of Pharmacology, University of Pittsburgh School of 

Medicine, Pittsburgh, Pennsylvania 15261, USA. 

5. Mech Ageing Dev. 2000 Dec 20;121(1-3):217-30. Antioxidants may contribute in the 

fight against ageing: an in vitro model. Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar 

P, Powell JR. Molecular Physiology, Unilever Research Laboratory Colworth, 

Sharnbrook, Bedford MK44 1LQ, UK. 

6. Eur J Clin Nutr. 2000 May;54(5):415-7. Quercetin intake and the incidence of 

cerebrovascular disease. Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, 



368

Hakkinen S, Aromaa A, Reunanen A. National Public Health Institute, Helsinki, Finland. 

paul.knekt@ktl.fi 

7. Free Radic Biol Med. 1997;22(4):669-78. Quercetin protects cutaneous tissueassociated 

cell types including sensory neurons from oxidative stress induced by 

glutathione depletion: cooperative effects of ascorbic acid. Skaper SD, Fabris M, Ferrari 

V, Dalle Carbonare M, Leon A. Researchlife S.c.p.A., Castelfranco Veneto, Italy. 

8. Exp Gerontol. 1982;17(3):213-7. Quercetin, flavonoids and the life-span of mice. 

Jones E, Hughes RE. 

9. Biochem Pharmacol. 1992 Mar 17;43(6):1167-79. Effects of flavonoids on immune 

and inflammatory cell functions. Middleton E Jr, Kandaswami C. Department of 

Medicine, State University of New York, Buffalo 14203. 

10. Lancet. 1993 Oct 23;342(8878):1007-11. Dietary antioxidant flavonoids and risk of 

coronary heart disease: the Zutphen Elderly Study. Hertog MG, Feskens EJ, Hollman PC, 

Katan MB, Kromhout D. National Institute of Public Health and Environment Protection, 

Bilthoven, Netherlands. 

11. Surgery. 2002 Feb;131(2):198-204. Quercetin inhibits human vascular smooth muscle 

cell proliferation and migration. Alcocer F, Whitley D, Salazar-Gonzalez JF, Jordan WD, 

Sellers MT, Eckhoff DE, Suzuki K, Macrae C, Bland KI. Department of Surgery, 

University of Alabama at Birmingham, 35294-0007, USA. 

12. Res Commun Chem Pathol Pharmacol. 1992 Nov;78(2):211-8. Changes in the 

xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney subjected to ischemiareperfusion 

stress: preventive effect of some flavonoids. Sanhueza J, Valdes J, Campos 

R, Garrido A, Valenzuela A. Unidad de Bioquimica Farmacologica y Lipidos, INTA, 

Universidad de Chile, Santiago. 

13. Methods Find Exp Clin Pharmacol. 2001 May;23(4):175-81. Quercetin, a 

bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine 

in rats. Satyanarayana PS, Singh D, Chopra K. Pharmacology Division, University 

Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 

14. Free Radic Biol Med. 2002 Jul 1;33(1):63-70. Quercetin metabolism in the lens: role 

in inhibition of hydrogen peroxide induced cataract. Cornish KM, Williamson G, 

Sanderson J. School of Biological Sciences, University of East Anglia, Norwich, Norfolk, 

UK. 

15. Zhongguo Yao Li Xue Bao. 1999 May;20(5):426-30. Quercetin decreased heart rate 

and cardiomyocyte Ca2+ oscillation frequency in rats and prevented cardiac hypertrophy 

in mice. Wang Y, Wang HY, Yuan ZK, Zhao XN, Wang JX, Zhang ZX. School of 

Medicine, State Key Laboratory of Coordination Chemistry, Nanjing University, China. 



369

16. Preferential requirement for protein tyrosine phosphatase activity in the 12-Otetradecanoylphorbol-13-acetate-induced 

differentiation of human colon cancer cells. 

Kuo ML, Huang TS, Lin JK. Institute of Toxicology, College of Medicine, National 

Taiwan University, Taipei. Biochem Pharmacol; 50(8):1217-22 1995 

17. Effect of Quercitrin on acute and chronic experimental colitis in the rat De Medina 

F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A. F.S. De Medina, Department of 

Pharmacology, School of Pharmacy, University of Granada, 18071 Granada Spain 

Journal of Pharmacology and Experimental Therapeutics (USA) , 1996, 278/2 (771-779) 

18. Inhibition of human breast cancer cell proliferation and delay of mammary 

tumorigenesis by flavonoids and citrus juices So FV, Guthrie N, Chambers AF, Moussa 

M, Carroll KK. Department of Pharmacology and Toxicology, University of Western 

Ontario, London, Canada. Nutrition and Cancer (USA) , 1996, 26/2 (167 181) 

19. Gitika B, Sai Ram M, Sharma SK, Ilavazhagan G, Banerjee PK. 

Quercetin protects C6 glial cells from oxidative stress induced by tertiarybutylhydroperoxide. 

Free Radic Res. 2006 Jan;40(1):95-102. 

PMID: 16298764 

20. Yang JH, Hsia TC, Kuo HM, Lee Chao PD, Chou CC, Wei YH, Chung JG. 

Inhibition of Lung Cancer Cell Growth by Quercetin Glucuronides via G2/M Arrest and 

Induction of Apoptosis. 

Drug Metab Dispos. 2005 Nov 9; [Epub ahead of print] 

PMID: 16280456 [PubMed - as supplied by publisher] 

Astaxanthin – 20 STUDIES 

1. Mol Cells. 2003 Aug 31;16(1):97-105. 

Astaxanthin inhibits nitric oxide production and inflammatory gene expression by 

suppressing I(kappa)B kinase-dependent NF-kappaB activation. 

Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, Han JA, Yim SV, Chang K, Kwon 

YG, Lee SK, Kim YM. 

Vascular System Research Center and Department of Molecular and Cellular 

Biochemistry, Kangwon National University Biology, Chunchon 200-701, Korea. 

2. Biochem Biophys Res Commun. 2003 Aug 1;307(3):704-12. 



370

Direct superoxide anion scavenging by a disodium disuccinate astaxanthin derivative: 

Relative efficacy of individual stereoisomers versus the statistical mixture of 

stereoisomers by electron paramagnetic resonance imaging. 

Cardounel AJ, Dumitrescu C, Zweier JL, Lockwood SF. 

Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210- 

1252, USA. 

3. Eur J Pharm Sci. 2003 Jul;19(4):299-304. 

Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by 

incorporation of lipid based formulations. 

Mercke Odeberg J, Lignell A, Pettersson A, Hoglund P. 

Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, 

Sweden. johanna.odeberg@klinfarm.lu.se 

4. J Med Food. 2003 Spring;6(1):51-6. 

Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: a randomized 

clinical trial. 

Spiller GA, Dewell A. 

Health Research and Studies Center, Los Altos, CA 94023, USA. spiller@sphere.org 

5. Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2694-701. 

Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. 

Ohgami K, Shiratori K, Kotake S, Nishida T, Mizuki N, Yazawa K, Ohno S. 

Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate 

School of Medicine, Sapporo, Japan. kohgami@med.hokudai.ac.jp 

6. Trends Biotechnol. 2003 May;21(5):210-6. 

Haematococcus astaxanthin: applications for human health and nutrition. 

Guerin M, Huntley ME, Olaizola M. 

Mera Pharmaceuticals Inc., 73-4460 Queen Kaahumanu Hwy, Suite 110, Kailua-Kona, 

96740, Hawaii, USA 

7. Redox Rep. 2002;7(5):290-3. 



371

Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. 

Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. 

First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 

8. J Pharm Sci. 2003 Apr;92(4):922-6. 

Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-beta, betacarotene-4,4'-dione) 

by Captisol (sulfobutyl ether beta-cyclodextrin). 

Lockwood SF, O'Malley S, Mosher GL. 

Hawaii Biotech, Inc., 99-193 Aiea Heights Drive, Suite 200, Aiea, Hawaii 96701, USA. 

slockwood@hibiotech.com 

9. Antioxid Redox Signal. 2003 Feb;5(1):139-44. 

Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. 

Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T, Toyokuni S, Oka S, 

Yasuhara M, Yoshikawa T. 

Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602-0841. 

10. Comp Biochem Physiol C Toxicol Pharmacol. 2002 Nov;133(3):443-51. 

Astaxanthin and canthaxanthin do not induce liver or kidney xenobiotic-metabolizing 

enzymes in rainbow trout (Oncorhynchus mykiss Walbaum). 

Page GI, Davies SJ. 

Fish Nutrition Unit, Department of Biological Sciences, University of Plymouth, Drake 

Circus, Plymouth PL4 8AA, UK. pagegi@mapleleaf.ca 

11. J Dermatol Sci. 2002 Oct;30(1):73-84. 

Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in 

culture. 

Lyons NM, O'Brien NM. 

Department of Food Science, Food Technology and Nutrition, University College Cork, 

Cork, Ireland. nob@ucc.ie 

12. Life Sci. 2002 Apr 21;70(21):2509-20. 



372

Contribution of the antioxidative property of astaxanthin to its protective effect on the 

promotion of cancer metastasis in mice treated with restraint stress. 

Kurihara H, Koda H, Asami S, Kiso Y, Tanaka T. 

Institute for Health Care Science, Suntory Ltd., 1-1-1 Wakayamadai, Shimamoto-cho, 

Mishima-gun, Osaka 618-8503, Japan. Hiroshi_Kurihara@suntory.co.jp 

13. Arch Toxicol. 2002 Jan;75(11-12):665-75. 

Metabolism and CYP-inducer properties of astaxanthin in man and primary human 

hepatocytes. 

Kistler A, Liechti H, Pichard L, Wolz E, Oesterhelt G, Hayes A, Maurel P. 

Vitamins and Fine Chemicals, Human Nutrition and Health, F. Hoffmann-La Roche Ltd, 

Basel, Switzerland. kistlera@bluewin.ch 

14. J Reprod Fertil Suppl. 2001;57:331-4. 

Effect of supplementation with the antioxidant astaxanthin on reproduction, pre-weaning 

growth performance of kits and daily milk intake in mink. 

Hansen KB, Tauson AH, Inborr J. 

Department of Animal Science and Animal Health, Royal Veterinary and Agricultural 

University, Gronnegardsvej 3, 1870 Frederiksberg C, Denmark. 

15. Biochem Biophys Res Commun. 2001 Oct 19;288(1):225-32. 

Astaxanthin and peridinin inhibit oxidative damage in Fe(2+)-loaded liposomes: 

scavenging oxyradicals or changing membrane permeability? 

Barros MP, Pinto E, Colepicolo P, Pedersen M. 

Department of Botany, Stockholm University, SE-10691 Stockholm, Sweden. 

mpbarros@botan.su.se 

16. J Atheroscler Thromb. 2000;7(4):216-22. 

Inhibition of low-density lipoprotein oxidation by astaxanthin. 

Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W, Kamiyama M, 

Itakura H, Yamamoto S, Kondo K. 

National Institute of Health and Nutrition, Tokyo, Japan. 



373

17. Methods Find Exp Clin Pharmacol. 2001 Mar;23(2):79-84. 

Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes 

in the liver of CCl4-treated rats. 

Kang JO, Kim SJ, Kim H. 

Department of Food and Nutrition, College of Human Ecology, Seoul National 

University, Korea. 

18. Biochim Biophys Acta. 2001 Jun 6;1512(2):251-8. 

Efficient radical trapping at the surface and inside the phospholipid membrane is 

responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. 

Goto S, Kogure K, Abe K, Kimata Y, Kitahama K, Yamashita E, Terada H. 

Faculty of Pharmaceutical Sciences, University of Tokushima, Japan. 

Kogure@ph.tokushima-u.ac.jp 

19. 0955-2863. 2000 Oct;11(10):482-490. 

Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma 

lipoproteins of men after single dose administration of astaxanthin(1). 

Osterlie M, Bjerkeng B, Liaaen-Jensen S. 

HIST, Department of Food Science, N-7004, Trondheim, Norway 

20. Antimicrob Agents Chemother. 2000 Sep;44(9):2452-7. 

Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in 

BALB/cA mice. 

Wang X, Willen R, Wadstrom T. 

Department of Infectious Diseases and Medical Microbiology, University of Lund, 

Sweden. 

L-Carnosine - 28 Studies 

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3. Stadtman ER, Levine RL. Protein oxidation. Ann NY Acad Sci. 2000; 899:191-208. 

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in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovascular 

Research. 1998; 37(3):586-600. 

5. Munch G, Schinzel R, Loske C, et al. Alzheimer's disease-synergistic effects of 

glucose deficit, oxidative stress and advanced glycation endproducts. Journal of Neural 

Transmission. 1998; 105(4-5):439-61. 

6. Hipkiss AR, Michaelis J, Syrris P. Non-enzymatic glycosylation of the dipeptide Lcarnosine, 

a potential anti-protein-cross-linking agent. FEBS Lett. 1995; 371(1):81-5. 

7. Munch G, Mayer S, Michaelis J, et al. Influence of advanced glycation end-products 

and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. 

Biochim Biophys Acta. 1997; 1360(1):17-29. 

8. Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated 

modifications. Biochem Biophys Res Commun. 1998; 248(1):28-32. 

9. Brownson C, Hipkiss AR. Carnosine reacts with a glycated protein. Free Radic Biol 

Med. 2000; 28(10):1564-70. 

10. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against 

malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci 

Lett. 1997; 238(3):135-8. 

11. Boldyrev AA, Stvolinsky SL, Tyulina OV, et al. Biochemical and physiological 

evidence that carnosine is an endogenous neuroprotector against free radicals. Cell Mol 

Neurobiol. 1997; 17(2):259-71. 

12. Hipkiss AR, Preston JE, Himsworth DT, et al. Pluripotent protective effects of 

carnosine, a naturally occurring dipeptide. Ann NY Acad Sci. 1998; 854:37-53. 

13. McFarland GA, Holliday R. Retardation of the senescence of cultured human diploid 

fibroblasts by carnosine. Exp Cell Res. 1994; 212(2):167-75. 

14. McFarland GA, Holliday R. Further evidence for the rejuvenating effects of the 

dipeptide L-carnosine on cultured human diploid fibroblasts. Exp Gerontol. 1999; 

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375

15. Yuneva MO, Bulygina ER, Gallant SC, et al. Effect of carnosine on age-induced 

changes in senescence-accelerated mice. J Anti-Aging Med. 1999; 2(4):337-42. 

16. Horning MS, Blakemore LJ, Trombley PQ. Endogenous mechanisms of 

neuroprotection: role of zinc, copper, and carnosine. Brain Res. 2000; 852(1):56-61. 

17. Huang X, Cuajungco MP, Atwood CS, et al. Cu(II) potentiation of alzheimer Ab 

neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal 

reduction. J Biol Chem. 1999; 274(52):37111-6. 

18. Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer Ab by 

Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998; 

273(21):12817-26. 

19. Cherny RA, Legg JT, McLean CA, et al. Aqueous dissolution of Alzheimer's disease 

Ab amyloid deposits by biometal depletion. J Biol Chem. 1999; 274(33):23223-8. 

20. Gulyaeva NV. Superoxide-scavenging activity of carnosine in the presence of copper 

and zinc ions. Biochemistry (Moscow). 1987; 52(7 Part 2):1051-4. 

21. de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to 

normal aging. Gerontology. 1997; 43(1-2):26-43. 

22. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against 

malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci 

Lett. 1997; 238(3):135-8. 

23. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for 

therapy. Pharmacol Ther. 1999; 81(3):163-221. 

24. Boldyrev A, Song R, Lawrence D, et al. Carnosine protects against excitotoxic cell 

death independently of effects on reactive oxygen species. Neuroscience. 1999; 

94(2):571-7. 

25. Stvolinsky SL, Kukley ML, Dobrota D, et al. Carnosine: an endogenous 

neuroprotector in the ischemic brain. Cell Mol Neurobiol. 1999; 19(1):45-56. 

26. Nagai K, Suda T, Kawasaki K, et al. Action of carnosine and beta-alanine on wound 

healing. Surgery. 1986;100(5):815-21. 

27. Vizioli MR, Blumen G, Almeida OP, et al. Effects of carnosine on the development 

of rat sponge-induced granulation tissue. II. Histoautoradiographic observations on 

collagen biosynthesis. Cell Mol Biol. 1983; 29(1):1-9. 

28. Ikeda D, Wada S, Yoneda C, et al. Carnosine stimulates vimentin expression in 

cultured rat fibroblasts. Cell Struct Funct. 1999; 24(2):79-87. 



376

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3: Belakbir, A., Ruiz, J.M., and Romero, L.; Yield and fruit quality of pepper (Capsicum 

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5: Bien, J.G., Brown, E.D., and Smith, J.C.; Determination of individual carotenoids in 

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isomerization in food systems. J. Food Sci. 44: 84-86 (1979). 

9: Brady, W.E., Mares-Perlman, J.A., Bowen, R. and Stacewicz-Sapuntzakis, M.; Human 

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10: Britton, G.; "Carotenoids: Spectroscopy," 1B: pp, 57. Birkhauser Verlag, Boston, 

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11: Bushway, R.J.; Separation of carotenoids in fruits and vegetables by high 

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12: Cano, M, P., Ancos, B., Lobo, G., Monreal, M., and De-Ancos, B.; Effects of 

freezing and canning of papaya slices on their carotenoid composition. Z. Lebensmittel 

Unters. Forsch. 202(4): 279-284 (1996). 



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14: Choo, YM., Yap, S.C., Ooi, C.X., Ma, A.X., Goh, S.H., and Ong, S.H.; Recovered oil 

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JAOCS 73: 599-602 (1996). 

15: Clinton, S.K., Emenhiser, C., Schwartz, S.J., Bostwick, D.G., Williams, A.W., 

Moore, B.J., and Erdman, J.W.; Cis-trans lycopene isomers, carotenoids, and retinol in 

the human prostate. Cancer Epidemiol. Biomarkers Prev. 5: 823-833 (1996). 

16: Clinton, S.K.; Lycopene: Chemistry. biology, and implications for human health and 

disease. Nutr. Rev. 56(2): 35-51 (1998). 

17: Colditz, G.A., Branch, L,G., and Lipnick, R.J.; Increased green and yellow vegetable 

intake and lowered cancer deaths in an elderly population. Am. Clin. Nutr. 41: 32-36 

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19: Cole, E.R., and Kapur, N.S.; The stability of lycopene. I. Degradation by oxygen. J. 

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20: Cook-Mozaffari, P.J., Azordegan, F., and Day, N.E.; Oseophageal cancer studies in 

the Caspian Litoral of Iran: Results of a case-control study. Brit. J. Cancer 39: 292-309 

(1979). 

21: Countryman, C., Bankson, D., Collins, S., Man, B., and Lin, W.; Lycopene inhibits 

the growth of the HL-60 promyelocylic leukemia cell line. Clin. Chem. 37:1056 (1991). 

22: Craft, N.E.; Carotenoid reversed-phase high-performance liquid chromatography 

methods: Reference compendium. Meth. Enzymol. 213: 185-205 (1992). 

23: Crouzet, J., and Kanasawud, P.; . Formation of volatile compounds by thermal 

degradation of carotenoids. Meth. Enzymol. 213: 54-62 (1992). 

24: Davies, B.H.; Carotenoids, In "Chemistry and Biochemistry of Plant Pigments," Vol. 

2, 2nd ed., ed. T.W. Goodwin, pp. 38-165. Academic Press, New York (1976). 

25: Di Mascio, P., Kaiser, S., and Sies, H.; Lycopene as the most efficient biological 

carotenoid singlet oxygen quencher. Arch. Biochem. Biophys. 274: 532-538 (1989). 

26: Diaz, M.N., Frei, B., Vita, J.A., and Keaney, J.F.; Antioxidants and atherosclerotic 

heart disease. New Eng. J. Med. 337: 408-416 (1997).. 



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27: Duggar, B.M.; Lycopersicon: The red pigment of the tomato and the effects of 

conditions on its development. Washington Univ. Stud., 1: 22-45 (1913). 

28: Duke, J.A. and Beckstrom-Stemberg, S.M.; Plants containing lycopene. 

Phytochemical database. USDA NCI Carotencid Food Composition Database. Agric. 

Res, Service, U.S. Dept. of Agriculture, Beltsville, Md. (1998). 

29: Duke, J.A.; "Handbook of Phytochemical Constituents of GRAS Herbs and Other 

Economic Plants." CRC Press, Boca Raton, Fla.(1992). 

30: Emenhiser, C., Sander, L.C., and Schwartz, S J.; Capabilitry of a polymeric C30 

stationary phase to resolve cis-trans carotenoid isomers in reversed-phase liquid 

chromatography J. Chromatog A 707: 205 216 (1995). 

31: Emenhiser, C., Simunovic, N, Sander, L. C., and Schwartz, S.J.; Separation of 

geometric isomers in biological extracts using a polymeric C 30 column in reversedphase 

liquid chromatography. J. Agric. Food Chem. 44: 3887-3893 (1996). 

32: Epler, K,S., Sander, L.G, Ziegler, R.G., Wise, S.A., and Craft, N.E.; Evaluation of 

reversed-phase liquid chromatographic columns for recovery and selectivity ofselected 

carotenoids. J. Chromatog. 595: 89-101 (1992). 

33: Ferruzzi, M.G., Sander, L.C., Rock, C.L., and Schwartz. S J.; Carotenoid 

determination in biological microsamples using liquid chromatography with a 

coulometric electrochemical array detector. Anal. Biochem. 256: 74-81 (1998). 

34: Forman. M.R., et.al.; The correlation between two dietary assessments of carotenoid 

intake and plasma Garotenoid concentrations: Application of a carotenoid food 

composition database. Am. J. Clin, Nutr 58: 519-24 (1993). 

35: Franceschi, S., Bidoli, E., La Vecchia, G., Talamini, R., D'Avanzo, B., and Negri, E.; 

Tomatoes and risk of digestive-tract cancers. Intl. J. Cancer 59(2): 181-184 ( 1994). 

36: Gartner, C., Stahl, W, and Sies, H.; Lycopene is more bioavailable from tomato paste 

than from fresh tomatoes, Am. J. Clin. Nutr. 66: 116-122 (1997). 

37: Gester, H.; The potential role of lycopene for human health. J. Am. Col. Nutr. 16(2): 

109-126 (1997). 

38: Giovannucci, E. L., Ascherio, A., Rimm, E. B., Stampfer, M.J., Colditz, G.A., and 

Willett, W.C.; Intake of carotenoids and retinol in relationship to risk of prostate cancer. 

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39: Godoy, H.T. and Rodriguez-Amaya, D.B.; Changes in individual carotenoids on 

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41: Ha, T.K.K., Saffar, N., Talwar, D., Cooney, J., Simpson, K., O'-Reilly D., and Lean, 

M.E.J.; Abnormal antioxidant vitamin and carotenoid status in chronic renal failure. 

Q.J.M. 89: 765-769 (1996). 

42: Harborne, J.B. and Baxter, H.; "Phytochemical Dictionary. A Handbook of Bioactive 

Compounds from Plants," Taylor & Frost, London (1983). 

43: Henry, L,K., Catignani, G.L., and Schwartz, S.J.; Oxidative degradation kinetics of 

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44: Jarvinen, R,, Knekt, P., Seppanen, R., and Teppo, L.; Diet and breast cancer risk in a 

cohort of Finnish women. Cancer Lett. 114: 251-253 (1997). 

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50: Khachik, F., et.al.; Effect of food preparation on qualitative and quantitative 

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Rosemary Leaf Powder - 20 STUDIES 

1. Chemical composition, plant genetic differences, antimicrobial and antifungal activity 

investigation of the essential oil of Rosmarinus officinalis L. 

J Agric Food Chem. 2004 Jun 2;52(11):3530-5. 

2. Effects of a novel gaseous antioxidative system containing a rosemary extract on the 

oxidation induced by nitrogen dioxide and ultraviolet radiation. 

Biosci Biotechnol Biochem. 2004 Apr;68(4):781-6.. 



380

3. Carnosic acid, a component of rosemary (Rosmarinus officinalis L.), promotes 

synthesis of nerve growth factor in T98G human glioblastoma cells. 

Biol Pharm Bull. 2003 Nov;26(11):1620-2. 

4. Antioxidant activities of rosemary, sage, and sumac extracts and their combinations on 

stability of natural peanut oil. 

J Med Food. 2003 Fall;6(3):267-70. 

5. Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development 

of leaves, flowers, stems, and roots of Rosmarinus officinalis. Antioxidant activity. 


6. Quantitative determination of phenolic diterpenes in rosemary extracts. Aspects of 

accurate quantification. 

J Chromatogr A. 2003 May 2;995(1-2):119-25. 

7. Aromas of rosemary and lavender essential oils differentially affect cognition and 

mood in healthy adults. 

Int J Neurosci. 2003 Jan;113(1):15-38. 

8. Suppressive effects of rosmarinic acid on mesangioproliferative glomerulonephritis in 

rats. 

Nephron. 2002 Dec;92(4):898-904. 

9. Carnosic acid inhibits proliferation and augments differentiation of human leukemic 

cells induced by 1,25-dihydroxyvitamin D3 and retinoic acid. 

Nutr Cancer. 2001;41(1-2):135-44. 

10. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase 

through down-regulating nuclear factor-kappaB in mouse macrophages. 

Carcinogenesis. 2002 Jun;23(6):983-91. 

11. Evaluation of the effectiveness of Rosmarinus officinalis (Lamiaceae) in the 

alleviation of carbon tetrachloride-induced acute hepatotoxicity in the rat. 

J Ethnopharmacol. 2002 Jul;81(2):145-54. 



381

12. Rosemary-stimulated reduction of DNA strand breaks and FPG-sensitive sites in 

mammalian cells treated with H2O2 or visible light-excited Methylene Blue. 

Cancer Lett. 2002 Mar 28;177(2):145-53. 

13. Antioxidant properties of phenolic diterpenes from Rosmarinus officinalis. 

Acta Pharmacol Sin. 2001 Dec;22(12):1094-8. 

14. Carnosol-induced apoptosis and downregulation of Bcl-2 in B-lineage leukemia cells. 

Cancer Lett. 2001 Sep 10;170(1):33-9. 

15. Chemistry and antioxidative factors in rosemary and sage. 

Biofactors. 2000;13(1-4):161-6. 

16. Inhibitory effects of rosmarinic acid on the proliferation of cultured murine mesangial 

cells. 

Nephrol Dial Transplant. 2000 Aug;15(8):1140-5. 

17. Allied studies on the effect of Rosmarinus officinalis L. on experimental 

hepatotoxicity and mutagenesis. 

Int J Food Sci Nutr. 1999 Nov;50(6):413-27. 

18. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic 

potentials. 

Indian J Exp Biol. 1999 Feb;37(2):124-30. 

19. Flavonoids in Rosmarinus officinalis leaves. 

Phytochemistry. 1994 Nov;37(5):1463-6. 

20. Rosmarinic Acid Research 

Rosmarinic acid. 

Institut fur Pharmazeutische Biologie, Philipps-Universitat Marburg, Deutschhausstr. 

Marburg, Germany. 



382

Tocotrienols – 40 STUDIES 

1. J Gerontol A Biol Sci Med Sci 2000 Jun;55(6):B280-5 

Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. 

Adachi H, Ishii N. 

Life Science Research Center, Lion Corporation, Kanagawa, Japan. hadachi@lion.co.jp 

2. N Engl J Med 1993 May 20;328(20):1450-6 

Vitamin E consumption and the risk of coronary heart disease in men. 

Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. 

Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115. 

3. N Engl J Med 1993 May 20;328(20):1444-9 

Vitamin E consumption and the risk of coronary disease in women. 

Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. 

Channing Laboratory, Boston, MA 02115. 

4. Lancet 1996 Mar 23;347(9004):781-6 

Randomised controlled trial of vitamin E in patients with coronary disease: 

Cambridge Heart Antioxidant Study (CHAOS) 

Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. 

Department of Medicine, Cambridge University. 

5. JAMA 2001 Mar 7;285(9):1178-82 

Effects of vitamin E on lipid peroxidation in healthy persons. 

Meagher EA, Barry OP, Lawson JA, Rokach J, FitzGerald GA. 

Center for Experimental Therapeutics, 811 Biomedical Research Bldg II/III, 

University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104-6160, USA. 

6. JAMA 1995 Jun 21;273(23):1849-54 

Serial coronary angiographic evidence that antioxidant vitamin intake reduces 

progression of coronary artery atherosclerosis. 

Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. 

Atherosclerosis Research Unit, University of Southern California School of Medicine, 

Los Angeles 90033, USA. 

7. Eur Heart J 2001 Jan;22(2):103-4 

Clinical, public health, and research implications of the Heart Outcomes 

Prevention Evaluation (HOPE) Study. 

Yusuf S. 

8. Am J Clin Nutr 1996 Mar;63(3):377-85 

Inverse relation between the concentration of low-density-lipoprotein vitamin E and 



383

severity of coronary artery disease. 

Regnstrom J, Nilsson J, Moldeus P, Strom K, Bavenholm P, Tornvall P, Hamsten A. 

Department of Medicine, the King Gustaf V Research Institute, Karolinska Hospital, 

Stockholm, Sweden. 

9. N Engl J Med 1996 May 2;334(18):1156-62 

Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal 

women. 

Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. 

Division of Epidemiology, University of Minnesota School of Public Health, 

Minneapolis 55454-1015, USA. 

10. Am J Epidemiol 1994 Jun 15;139(12):1180-9 

Antioxidant vitamin intake and coronary mortality in a longitudinal population study. 

Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. 

Social Insurance Institution, Helsinki, Finland. 

11. Sources And Consumption Of Antioxidants In The Diet 

Bieri J G 

J Am Oil Chem Soc 61 (12). 1984. 1917-1918. 1984 

12. J Nutr 1985 Jun;115(6):807-13 

Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. 

Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. 

13. J Intern Med 1996 Feb;239(2):111-7 

Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease 

patients. 

Ohrvall M, Sundlof G, Vessby B. 

Department of Geriatrics, University of Uppsala, Sweden. 

14. Proc Natl Acad Sci U S A 1997 Apr 1;94(7):3217-22 

Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements 

alpha-tocopherol: physiological implications. 

Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. 

Division of Biochemistry and Molecular Biology, University of California, Berkeley 

94720, USA. 

15. Proc Natl Acad Sci U S A 1993 Mar 1;90(5):1771-5 

Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol. 

Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ. 

Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813. 

16. J Gerontol A Biol Sci Med Sci 2000 Jun;55(6):B280-5 

Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. 

Adachi H, Ishii N. 



384

Life Science Research Center, Lion Corporation, Kanagawa, Japan. 

hadachi@lion.co.jp 

17. Lipids 1995 Dec;30(12):1179-83 

Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. 

Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML. 

Kenneth L. Jordan Research Group, Montclair, New Jersey 07042, USA. 

18. J Biol Chem 1993 May 25;268(15):11230-8 

Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional 

suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. 

Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. 

Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research 

Institute, Princeton, New Jersey 08543. 

19. Am J Clin Nutr 1991 Apr;53(4 Suppl):1021S-1026S 

Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols 

(palmvitee). 

Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, 

Ong A, Peterson DM, et al. 

Advanced Medical Research, Madison, WI 53719. 

20. Novel tocotrienols of rice bran modulate cardiovascular disease risk parameters of 

hypercholesterolomic humans 

Qureshi A.A.; Bradlow B.A.; Salser W.A.; Brace L.D. Dr. A.A. Qureshi, Advance 

Medical Research, 8251 Raymond Road, Madison, WI 53719 United States 

Journal of Nutritional Biochemistry ( J. NUTR. BIOCHEM. ) ( United States ) 1997 , 8/5 

(290-298) 

21. N Engl J Med 1990 Nov 8;323(19):1289-98 

Regression of coronary artery disease as a result of intensive lipid-lowering therapy in 

men with high levels of apolipoprotein B. 

Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, 

Fitzpatrick VF, Dodge HT. 

Department of Medicine, University of Washington School of Medicine, Seattle. 

22. N Engl J Med 1983 Aug 18;309(7):385-9 

Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease. 

Maciejko JJ, Holmes DR, Kottke BA, Zinsmeister AR, Dinh DM, Mao SJ. 

23. Br Heart J 1988 Nov;60(5):397-403 

High prevalence of hypertriglyceridaemia and apolipoprotein abnormalities in coronary 

artery disease. 

Barbir M, Wile D, Trayner I, Aber VR, Thompson GR. 

Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, 

London. 



385

24. Proc Natl Acad Sci U S A 2000 Oct 10;97(21):11494-9 

Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit 

cyclooxygenase activity in macrophages and epithelial cells. 

Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. 

Division of Biochemistry and Molecular Biology, University of California, 

Berkeley, CA 94720, USA. 

25. J Am Coll Cardiol 1999 Oct;34(4):1208-15 

Differential effects of alpha- and gamma-tocopherol on low-density lipoprotein 

oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis. 

Saldeen T, Li D, Mehta JL. 

Department of Forensic Medicine, University of Uppsala, Sweden. 

. 

26. J Nutr Biochem 2001 Jun;12(6):318-329 

Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on 

lipid parameters in hypercholesterolemic humans. 

Qureshi AA, Sami SA, Salser WA, Khan FA. 

Advanced Medical Research, 8251 Raymond Road, 53719, Madison, WI, USA 

27. Lipids 1993 Dec;28(12):1113-8 

gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed 

atherogenic diets. 

Watkins T, Lenz P, Gapor A, Struck M, Tomeo A, Bierenbaum M. 

Kenneth L. Jordan Heart Fund, Montclair, New Jersey 07042. 

28. J Nutr 2001 Jan;131(1):161S-163S 

Vitamin E: mechanisms of action as tumor cell growth inhibitors. 

Kline K, Yu W, Sanders BG. 

Division of Nutrition and. School of Biological Sciences, The University of Texas at 

Austin, Austin, TX 78712, USA. k.kline@mail.utexas.edu 

29. J Nutr 1994 May;124(5):607-14 

The chemoprevention of cancer by mevalonate-derived constituents of fruits and 

vegetables. 

Elson CE, Yu SG. 

Department of Nutritional Sciences, University of Wisconsin, Madison 53706-1571. 

30. J Nutr 1999 Apr;129(4):804-13 

Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by 

isoprenoids. 

Mo H, Elson CE. 

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 

53706, USA. 



386

31. J Nutr 1997 May;127(5):668-74 

Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. 

He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. 

Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA. 

32. Nutr Cancer 1992;18(1):1-29 

Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. 

Block G, Patterson B, Subar A. 

Dept. of Social and Administrative Health Sciences, School of Public Health, 

University of California, Berkeley 94720. 

33. Proc Soc Exp Biol Med 1999 Sep;221(4):294-311 

Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer. 

Elson CE, Peffley DM, Hentosh P, Mo H. 

Department of Nutritional Sciences, College of Agricultural and Life Sciences, 

University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. 

34. J Nutr 1995 Jun;125(6 Suppl):1666S-1672S 

Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in 

cancer and cardiovascular disease. 

Elson CE. 

Department of Nutritional Sciences, University of Wisconsin-Madison 53706, USA. 

35. Nutrition 1993 May-Jun;9(3):229-32 

Long-term administration of tocotrienols and tumor-marker enzyme activities during 

hepatocarcinogenesis in rats. 

Rahmat A, Ngah WZ, Shamaan NA, Gapor A, Abdul Kadir K. 

Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, 

Jalan Raja Muda Abdul Aziz, Kuala Lumpur. 

36. Comp Biochem Physiol C 1993 Sep;106(1):237-40 

Glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured rat 

hepatocytes treated with tocotrienol and tocopherol. 

Ong FB, Wan Ngah WZ, Shamaan NA, Md Top AG, Marzuki A, Khalid AK. 

Jabatan Biokimia, Fakulti Perubatan, Universiti Kebangsaan Malaysia, Jalan Raja Muda 

Abdul Aziz, Kuala, Lumpur. 

37. J Nutr 1997 May;127(5):668-74 

Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. 

He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. 

Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA. 

38. Lipids 1995 Dec;30(12):1139-43 



387

Effect of tocotrienols on the growth of a human breast cancer cell line in culture. 

Nesaretnam K, Guthrie N, Chambers AF, Carroll KK. 

Palm Oil Research Institute of Malaysia, Kuala Lumpur, Malaysia. 

39. Lipids 1998 May;33(5):461-9 

Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen 

receptor status. 

Nesaretnam K, Stephen R, Dils R, Darbre P. 

Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, The 

University of Reading, Whiteknights, England. sarnesar@porim.gov.my 

40. Int J Food Sci Nutr 2000;51 Suppl:S95-103 

Tocotrienols inhibit growth of ZR-75-1 breast cancer cells. 

Nesaretnam K, Dorasamy S, Darbre PD. 

Palm Oil Research Institute of Malaysia, PO Box 10620, Kuala Lumpur 50720, Malaysia. 

Raspberry Leaf Powder - 10 Studies 

1. Han C, Ding H, Casto B, Stoner GD, D'Ambrosio SM. 

Inhibition of the growth of premalignant and malignant human oral cell lines by extracts 

and components of black raspberries. 

Nutr Cancer. 2005;51(2):207-17. 

PMID: 15860443 

2. Huang C, Huang Y, Li J, Hu W, Aziz R, Tang MS, Sun N, Cassady J, Stoner GD. 

Inhibition of benzo(a)pyrene diol-epoxide-induced transactivation of activated protein 1 

and nuclear factor kappaB by black raspberry extracts. 

Cancer Res. 2002 Dec 1;62(23):6857-63. 

PMID: 124608993. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, 

Stoner GD, Klaunig JE 

3. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig 

JE. Inhibition of cellular transformation by berry extracts. 

Carcinogenesis. 2001 Feb;22(2):351-6. Erratum in: Carcinogenesis 2001 May;22(5):831- 

3. PMID: 11181460 

4. J Agric Food Chem. 2005 Jul 27;53(15):5922-31. 

Preclinical evaluation of rapeseed, raspberry, and pine bark phenolics for health related 

effects. 



388

Vuorela S, Kreander K, Karonen M, Nieminen R, Hamalainen M, Galkin A, Laitinen L, 

Salminen JP, Moilanen E, Pihlaja K, Vuorela H, Vuorela P, Heinonen M. 

5. Viljanen K, Kylli P, Kivikari R, Heinonen M. 

Inhibition of protein and lipid oxidation in liposomes by berry phenolics. 

J Agric Food Chem. 2004 Dec 1;52(24):7419-24. 

PMID: 15563229 

6. Vuorela S, Salminen H, Makela M, Kivikari R, Karonen M, Heinonen M. 

Effect of plant phenolics on protein and lipid oxidation in cooked pork meat patties. 

J Agric Food Chem. 2005 Nov 2;53(22):8492-7. 

PMID: 16248543 

7. Puupponen-Pimia R, Nohynek L, Hartmann-Schmidlin S, Kahkonen M, Heinonen M, 

Maatta-Riihinen K, Oksman-Caldentey KM. 

Berry phenolics selectively inhibit the growth of intestinal pathogens. 

J Appl Microbiol. 2005;98(4):991-1000. 

PMID: 15752346 

8. Puupponen-Pimia R, Nohynek L, Meier C, Kahkonen M, Heinonen M, Hopia A, 

Oksman-Caldentey KM. 

Antimicrobial properties of phenolic compounds from berries. 

J Appl Microbiol. 2001 Apr;90(4):494-507. 

PMID: 11309059 

9. Puupponen-Pimia R, Nohynek L, Alakomi HL, Oksman-Caldentey KM. 

Bioactive berry compounds-novel tools against human pathogens. 

Appl Microbiol Biotechnol. 2005 Apr;67(1):8-18. Epub 2004 Dec 2. Review. 

PMID: 15578177 

10. Viljanen K, Kylli P, Kivikari R, Heinonen M. 

Inhibition of protein and lipid oxidation in liposomes by berry phenolics. 

J Agric Food Chem. 2004 Dec 1;52(24):7419-24. 

PMID: 15563229 

Citrus Bioflavonoids – 11 STUDIES 

1. Tirkey N, Pilkhwal S, Kuhad A, Chopra K. 

Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon 

tetrachloride in rat liver and kidney. 

BMC Pharmacol. 2005 Jan 31;5(1):2. 

PMID: 15683547 

2. Garg A, Garg S, Zaneveld LJ, Singla AK. 



389

Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. 

Phytother Res. 2001 Dec;15(8):655-69. Review. 

PMID: 11746857 

3. Emim JA, Oliveira AB, Lapa AJ. 

Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, 

hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. 

J Pharm Pharmacol. 1994 Feb;46(2):118-22. 

PMID: 8021799 

4. WILLIAMS HL, HEDGECOCK LD. 

Citrus bioflavonoid, ascorbic acid and the B Vitamins in treatment of certain types of 

neurosensory deafness: preliminary report. 

Mayo Clin Proc. 1962 Aug 29;37:474-83. No abstract available. 

PMID: 14007172 

5. MARTIN WC. 

Treatment of capillary fragility with soluble citrus bioflavonoid complex. 

Int Rec Med Gen Pract Clin. 1955 Feb;168(2):66-9. No abstract available. 

PMID: 14353570 

6. Treatment of capillary fragility with soluble citrus bioflavonoid complex. 

Int Rec Med Gen Pract Clin. 1955 Feb;168(2):66-9. No abstract available. 

PMID: 14353570 

7. Emim JA, Oliveira AB, Lapa AJ. 

Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, 

hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. 

J Pharm Pharmacol. 1994 Feb;46(2):118-22. 

PMID: 8021799 

8. WILLIAMS HL, HEDGECOCK LD. 

Citrus bioflavonoid, ascorbic acid and the B Vitamins in treatment of certain types of 

neurosensory deafness: preliminary report. 

Mayo Clin Proc. 1962 Aug 29;37:474-83. No abstract available. 

PMID: 14007172 

9. FABRICANT ND. 

Therapeutic failure of citrus bioflavonoids in the common cold and nasal allergy. 

Eye Ear Nose Throat Mon. 1956 Nov;35(11):717-9. No abstract available. 

PMID: 13365639 

10. MACON WL Jr. 

Citrus bioflavonoids in the treatment of the common cold. 

Ind Med Surg. 1956 Nov;25(11):525-7. No abstract available. 

PMID: 13366468 



390

11. MENKIN V. 

Anti-inflammatory activity of some water-soluble bioflavonoids. 

Am J Physiol. 1959 Jun;196(6):1205-10. No abstract available. 

PMID: 13661342 

Rutin – 16 STUDIES 

1. Anon: Natural Medicines Comprehensive Database, 4 th ed. Therapeutic Research 

Faculty, Stockton, CA; 2002. 

2. Wijayanegara H, Mose JC, Achmad L et al: A clinical trial of hydroxyethylrutosides in 

the treatment of haemorrhoids of pregnancy. J Int Med Res 1992; 20(1):54-60. 

3. De Jongste AB, Jonker JJ, Huisman MV et al: A double-blind three center clinical trial 

on the short-term efficacy of O-(B-hydroxyethyl)-rutosides in patients with postthrombotic 

syndrome. Thromb Haemost 1989; 62(3):826-829. 

4. Bergqvist D, Hallbook T, Lindblad B et al: A double-blind trial of O-(Bhydroxyethyl)-rutoside 

in patients with chronic venous insufficiency. VASA 1981; 

10(3):253-260. 

5. Mann RJ: A double-blind trial of O.B-hydroxyethyl rutosides for stasis leg ulcers. Br J 

Clin Pract 1981; 35(2):79-81. 

6. Partial reversal by rutin and quercetin of impaired cardiac function in streptozotocininduced 

diabetic rats. 

Can J Physiol Pharmacol. 2005 Apr;83(4):343-355. 

7. Effect of rutin on total antioxidant status of rats exposed to cigarette smoke. 

Pharmacol Rep. 2005 Jan-Feb;57(1):84-9. 

8. Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements 

(quercetin, curcumin, silymarin, ginseng and rutin). 

Carcinogenesis. 2005 Apr 14; 

9. Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodiuminduced 

experimental colitis in mice: attenuation of pro-inflammatory gene expression. 



391

Biochem Pharmacol. 2005 Feb 1;69(3):395-406. 

10. [Inhibitory effect of quercetin, rutin and puerarin on HDL oxidation induced by 

Cu2+] Sichuan Da Xue Xue Bao Yi Xue Ban. 2004 Nov;35(6):836-8. 

11. [Effect of hesperidin and rutin on oxidative modification of high density lipoprotein 

in vitro] 

12. Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol 

quercetin, in human platelets. 


13. The modulating effects of quercetin and rutin on the mitomycin C induced DNA 

damage. 

Toxicol Lett. 2004 Jun 15;151(1):143-9. 

14. Synergistic inhibition of low-density lipoprotein oxidation by rutin, gamma-terpinene, 

and ascorbic acid. 

Phytomedicine. 2004 Feb;11(2-3):105-13. 

15. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation 

study. 

Eur J Clin Nutr. 2000 Oct;54(10):774-82. 

16. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung 

epithelium during the adult respiratory distress syndrome. 

Shock. 2000 Jan;13(1):14-8. 

Billberry - 17 Studies 

FILED ACCORDING TO CONDITION OR FUNCTION 

Anti-angiogenic 

1. Free Radic Res. 2002 Sep;36(9):1023-31. 

Anti-angiogenic property of edible berries. 

Roy S, Khanna S, Alessio HM, Vider J, Bagchi D, Bagchi M, Sen CK. 

Laboratory of Molecular Medicine, Department of Surgery, 512 Heart and Lung 



392

Research Institute, Ohio State University Medical Center, 473 W. 12th Avenue, 

Columbus, OH 43210, USA. 

Cancer 

2. J Agric Food Chem. 2003 Jan 1;51(1):68-75. 

Induction of apoptosis in cancer cells by Bilberry (Vaccinium myrtillus) and the 

anthocyanins. 

Katsube N, Iwashita K, Tsushida T, Yamaki K, Kobori M. 

Fruit Processing Research Center, AOHATA Corporation, Takehara, Hiroshima 

729-2392, Japan. 

3. J Agric Food Chem. 2003 Sep 24;51(20):5867-5870. 

Resveratrol in Raw and Baked Blueberries and Bilberries. 

Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, Van Breemen RB. 

Food and Nutritional Science Division, California State University, Long Beach, 

Long Beach, California 90840; Department of Chemistry, University of Illinois at 

Chicago, Chicago, Illinois 60607; and Department of Medicinal Chemistry and 

Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois 

60612. 

4. Planta Med. 1996 Jun;62(3):212-6. 

In vitro anticancer activity of fruit extracts from Vaccinium species. 

Bomser J, Madhavi DL, Singletary K, Smith MA. 

Department of Food Science and Human Nutrition, University of Illinois, Urbana 

61801, USA. 

Capillary support 

5. Pharmacol Res. 1995 Mar-Apr;31(3-4):183-7. (Animal Study) 

Effect of Vaccinium myrtillus anthocyanosides on ischaemia reperfusion injury in 

hamster cheek pouch microcirculation. 

Bertuglia S, Malandrino S, Colantuoni A. 

CNR Institute of Clinical Physiology, Pisa, Italy. 

6. Arzneimittelforschung. 1976;26(5):832-5. (Animal Study) 

Studies on Vaccinium myrtillus anthocyanosides. II. Aspects of anthocyanins 

pharmacokinetics in the rat. 

Lietti A, Forni G. 



393

7. Arzneimittelforschung. 1976;26(5):829-32. 

Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and 

antiinflammatory activity. 

Lietti A, Cristoni A, Picci M. 

Connective tissue 

8. Klin Monatsbl Augenheilkd. 1996 Dec;209(6):368-72. 

[Effect of anthocyanins on human connective tissue metabolism in the human] 

[Article in German] 

Boniface R, Robert AM. 

Labor fur Bindegewebsbiochemie, Medizinische Fakultat, Universitat Paris, Val de 

Marne. 

Dyslipidaemiae 

9. Thromb Res. 1996 Dec 1;84(5):311-22. (Animal Study) 

Novel lipid-lowering properties of Vaccinium myrtillus L. leaves, a traditional 

antidiabetic treatment, in several models of rat dyslipidaemia: a comparison 

with ciprofibrate. 

Cignarella A, Nastasi M, Cavalli E, Puglisi L. 

Institute of Pharmacological Sciences, University of Milano, Italy. 

Chronic Fatigue Syndrome 

10. Altern Med Rev. 2001 Oct;6(5):450-9. 

Chronic fatigue syndrome: oxidative stress and dietary modifications. 

Logan AC, Wong C. 

CFS/FM Integrative Care Centre, Toronto, ON, Canada. alancloganND@excite.com 

Cardiocascular and EYE 

11. Curr Mol Med. 2003 Mar;3(2):149-59. 



394

Potential mechanisms of cancer chemoprevention by anthocyanins. 

Hou DX. 

Department of Biochemical Science and Technology, Faculty of Agriculture, 

Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan. 

hou@chem.agri.kagoshima-u.ac.jp 

EYE 

12. J Biol Chem. 2003 May 16;278(20):18207-13. Epub 2003 Mar 19. 

A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other 

antioxidants inhibit A2E-epoxide formation. 

Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S, Itagaki Y, Nakanishi 

K. Department of Ophthalmology and Chemistry, Columbia University, New York, New 

York 10028, USA. jrs88@columbia.edu 

13. Altern Med Rev. 2001 Apr;6(2):141-66. 

Natural therapies for ocular disorders, part two: cataracts and glaucoma. 

Head KA. 

Thorne Research, Inc., P.O. Box 25, Dover, ID 83825,USA. kathi@thorne.com 

Ulcer 

14. Arzneimittelforschung. 1988 May;38(5):686-90. (Animal Study) 

Antiulcer activity of an anthocyanidin from Vaccinium myrtillus. 

Magistretti MJ, Conti M, Cristoni A. 

Research and Development Laboratories, Inverni della Beffa S.p.A., Milan, Italy. 

Bilberry High in Quercetin 

15. Eur J Clin Nutr. 2003 Jan;57(1):37-42. 

Consumption of black currants, lingonberries and bilberries increases serum 

quercetin concentrations. 

Erlund I, Marniemi J, Hakala P, Alfthan G, Meririnne E, Aro A. 

Biomarker Laboratory, National Public Health Institute, Helsinki, Finland. 

iris.erlund@ktl.fi 

16. J Agric Food Chem. 2000 Jul;48(7):2960-5. 

Influence of domestic processing and storage on flavonol contents in berries. 



395

Hakkinen SH, Karenlampi SO, Mykkanen HM, Torronen AR. 

Department of Clinical Nutrition, Department of Physiology, University of 

Kuopio, PO box 1627, FIN-70211 Kuopio, Finland. 

RNA 

17. Mol Biotechnol. 2001 Oct;19(2):201-3. 

Isolation of high quality RNA from bilberry (Vaccinium myrtillus L.) fruit. 

Jaakola L, Pirttila AM, Halonen M, Hohtola A. 

Department of Biology, University of Oulu, P.O. Box 3000, FIN-90014 Oulu, 

Finland. Laura.Jaakola@oulu.fi 

Red Wine Concentrate – 14 STUDIES 

1. Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial 

cells via extracellular signal-regulated kinase inhibition. 

Chem Biol Interact. 2005 Jan 15;151(2):143-9. King RE, Kent KD, Bomser JA. 

Department of Food Science and Technology, Ohio State University, Columbus, OH 

2. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 

Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Aggarwal BB, Bhardwaj A, Aggarwal 

RS, Seeram NP, Shishodia S, Takada Y. Cytokine Research Laboratory, Department of 

Bioimmunotherapy, The University of Texas M. D. 

3. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and 

antitumor effects on neuroblastoma in mice. 

Surgery. 2004 Jul;136(1):57-66. 

4. Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular 

Mechanisms. 

Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4 

5. Identification of a p53-dependent pathway in the induction of apoptosis of human 

breast cancer cells by the natural product, resveratrol. 

Laux MT, Aregullin M, College of Veterinary Medicine, Cornell University, Ithaca, NY, 

USA. 



396

J Altern Complement Med. 2004 Apr;10(2):235-9. 

6. Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of 

p53 in human neuroblastoma. 

Anticancer Res. 2004 Mar-Apr;24(2B):987-98. 

7. Resveratrol in raw and baked blueberries and bilberries. 

J Agric Food Chem. 2003 Sep 24;51(20):5867-70. 

Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. 

Food and Nutritional Science Division, California State University-Long Beach, CA 

90840 

8. Wine and tumors: study of resveratrol. 

Drugs Exp Clin Res. 2003;29(5-6):257-61. 

dependent antiproliferative and antiapoptotic action on DHL-4 cells. These results 

confirm resveratrol's potential therapeutic role on tumors. 

9. Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in 

cardiomyocytes: protection against oxidative and electrophilic injury. 

Cao Z, Li Y. St. John's University College of Pharmacy and Allied Health Professions, 

Jamaica, NY 

Eur J Pharmacol. 2004 Apr 5;489(1-2):39-48. 

10. Modulation of androgen receptor-dependent transcription by resveratrol and genistein 

in prostate cancer cells. 

Gao S, Liu GZ, Wang Z. 

The University of Texas M. D. Anderson Cancer Center, Houston, Texas . 

Prostate. 2004 May 1;59(2):214-25. 

11. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. 

Clin Cancer Res. 2004 Mar 15;10(6):2190-202. 

12. Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in 

rat hippocampal neurons: involvement of protein kinase C. 

Br J Pharmacol. 2004 Mar;141(6):997-1005. 



397

13. Resveratrol in raw and baked blueberries and bilberries. 

J Agric Food Chem. 2003 Sep 24;51(20):5867-70. 

Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. 

Food and Nutritional Science Division, California State University-Long Beach, CA 

90840 

14. Resveratrol protects myocardial ischemia-reperfusion injury through both NOdependent 

and NO-independent mechanisms. 

Free Radic Biol Med. 2004 Mar 15;36(6):774-81. 

Grape Skin Extract – 48 STUDIES 

1. Rosenkranz S, Knirel D, Dietrich H, Flesch M, Erdmann E, Bohm M. Inhibition of the 

PDGF receptor by red wine flavonoids provides a molecular explanation for the “French 

paradox”. FASEB J. 2002 Dec;16(14):1958-60. 

2. Criqui MH, Ringel BL. Does diet or alcohol explain the French paradox? Lancet. 1994 

Dec 24-31;344(8939-8940):1719-23. 

3. Burr ML. Explaining the French paradox. JR Soc Health. 1995 Aug;115(4):217-9. 

4. Lavayssiere R, Cabee A. MRI in France: the French paradox. J Magn Reson Imaging. 

2001 Apr;13(4):528-33. 

5. Mar MH, Zeisel SH. Betaine in wine: answer to the French paradox? Med Hypotheses. 

1999 Nov;53(5):383-5. 

6. De Beer D, Joubert E, Gelderblom W, Manley M. Antioxidant activity of South 

African red and white cultivar wines: free radical scavenging. J Agric Food Chem. 2003 

Feb 12;51(4):902-9. 

7. Cui J, Tosaki A, Cordis GA, et al. Cardioprotective abilities of white wine. Ann NY 

Acad Sci. 2002 May;957:308-16. 

8. Bertelli AA, Migliori M, Panichi V, et al. Oxidative stress and inflammatory reaction 

modulation by white wine. Ann NY Acad Sci. 2002 May;957:295-301. 

9. Ariga T. The antioxidative function, preventive action on disease and utilization of 

proanthocyanidins. Biofactors. 2004 21(1-4):197-201. 

10. Bagchi D, Garg A, Krohn RL, et al. Protective effects of grape seed 

proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid 



398

peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice. Gen 

Pharmacol. 1998 May;30(5):771-6. 

11. Ye X, Krohn RL, Liu W, et al. The cytotoxic effects of a novel IH636 grape seed 

proanthocyanidin extract on cultured human cancer cells. Mol Cell Biochem. 1999 

Jun;196(1-2):99-108. 

12.. Deshane J, Chaves L, Sarkikonda KV, et al. Proteomics analysis of rat brain protein 

modulations by grape seed extract. J Agric Food Chem. 2004 Dec 29;52(26):7872-83. 

13.. Rababah TM, Hettiarachchy NS, Horax R. Total phenolics and antioxidant activities 

of fenugreek, green tea, black tea, grape seed, ginger, rosemary, gotu kola and ginkgo 

extracts, vitamin E and tert-butylhydroquinone. J Agric Food Chem. 2004 Aug 

11;52(16):5183-6. 

14. Shi J, Yu J, Pohorly JE, Kakuda Y. Polyphenolics in grape seeds–biochemistry and 

functionality. J Med Food. 2003 Winter;6(4):291-9. 

15. Hagerman A, Riedl K, Jones GA, et al. High molecular weight plant polyphenolics 

(tannins) as biological antioxidants. J Agric Food Chem. 1998 46:1887-92. 

16. Natella F, Belelli F, Gentili V, Ursini F, Scaccini C. Grape seed proanthocyanidins 

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46. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to 

oxidation in heavy smokers. 

Vigna GB. University of Ferrara, Ferrara, Italy. 

Metabolism. 2003 Oct;52(10):1250-7. 

47. Polyphenolics in grape seeds-biochemistry and functionality. 

J Med Food. 2003 Winter;6(4):291-9. 

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China Green Tea Leaf Powder - 100 Studies 

1. J Agric Food Chem. 2003 Oct 22;51(22):6627-34. 

A Combination of Tea (Camellia senensis) Catechins Is Required for Optimal Inhibition 

of Induced CYP1A Expression by Green Tea Extract. 

Williams SN, Pickwell GV, Quattrochi LC. Department of Medicine, Section of Medical 

Toxicology, University of Colorado Health Sciences Center, Denver, Colorado 80262. 

2. Biochem Biophys Res Commun. 2003 Oct 24;310(3):715-719. 

Suppression of Helicobacter pylori-induced gastritis by green tea extract in Mongolian 

gerbils. 

Matsubara S, Shibata H, Ishikawa F, Yokokura T, Takahashi M, Sugimura T, 

Wakabayashi K. 

Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1- 

1, Tsukiji 5-chome, Chuo-ku, 104-0045, Tokyo, Japan 

3. Cell Mol Life Sci. 2003 Aug;60(8):1760-3. 

Green tea epigallocatechin-3-gallate is an inhibitor of mammalian histidine 

decarboxylase. 

Rodriguez-Caso C, Rodriguez-Agudo D, Sanchez-Jimenez F, Medina MA. 



402

Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of 

Malaga, Malaga, Spain. 

4. Eur J Cancer Prev. 2003 Oct;12(5):391-5. 

Effects of green tea on carcinogen-induced hepatic CYP1As in C57BL/6 mice. 

Yang M, Yoshikawa M, Arashidani K, Kawamoto T. 

Department of Preventive Medicine/Cancer Research Institute, Seoul National University 

College of Medicine, 28 Yongon-Dong Chongno-Gu, 110-799 Seoul, Korea. 

5. Eur J Cancer Prev. 2003 Oct;12(5):383-90. 

Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical 

lesions. 

Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, Bae SM, Lee IP. 

Department of Obstetrics and Gynaecology. 

6. Phytomedicine. 2003;10(6-7):517-22. 

Hydroxyl radical and hypochlorous acid scavenging activity of small centaury 

(Centaurium erythraea) infusion. A comparative study with green tea (Camellia sinensis). 

Valentao P, Fernandes E, Carvalho F, Andrade PB, Seabra RM, Bastos ML. 

CEQUP/Servico de Farmacognosia, Faculdade de Farmacia, Universidade do Porto, 

Porto, Portugal. 

7. Phytomedicine. 2003;10(6-7):494-8. 

Enhancement of neutral endopeptidase activity in SK-N-SH cells by green tea extract. 

Melzig MF, Janka M. 

Institut fur Pharmazie, Freie Universitat Berlin, Germany. melzig@zedat.fu-berlin.de 

8. Br J Pharmacol. 2003 Oct;140(3):487-499. Epub 2003 Aug 26. 

Interactions of androgens, green tea catechins and the antiandrogen flutamide with the 

external glucose-binding site of the human erythrocyte glucose transporter GLUT1. 

Naftalin RJ, Afzal I, Cunningham P, Halai M, Ross C, Salleh N, Milligan SR. 

New Hunt's House, King's College London, Guys Campus, London SE1 1UL. 



403

9. Clin Cancer Res. 2003 Aug 15;9(9):3312-9. 

Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration 

of epigallocatechin gallate and polyphenon E in healthy individuals. 

Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts 

DS. 

Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA. 

10. Clin Exp Allergy. 2003 Sep;33(9):1252-5. 

Green tea-induced asthma: relationship between immunological reactivity, specific and 

non-specific bronchial responsiveness. 

Shirai T, Reshad K, Yoshitomi A, Chida K, Nakamura H, Taniguchi M. 

Department of Internal Medicine, Fujinomiya City General Hospital, Fujinomiya, Japan. 

fmyhsp@lilac.ocn.ne.jp 

11. J Pharmacol Exp Ther. 2003 Oct;307(1):230-6. Epub 2003 Sep 03. 

Green tea polyphenol causes differential oxidative environments in tumor versus normal 

epithelial cells. 

Yamamoto T, Hsu S, Lewis J, Wataha J, Dickinson D, Singh B, Bollag WB, Lockwood 

P, Ueta E, Osaki T, Schuster G. 

Kochi Medical School, Japan. 

12. Biol Pharm Bull. 2003 Sep;26(9):1235-8. 

Inhibitory effect of green tea polyphenols on membrane-type 1 matrix metalloproteinase, 

MT1-MMP. 

Oku N, Matsukawa M, Yamakawa S, Asai T, Yahara S, Hashimoto F, Akizawa T. 

Department of Medical Biochemistry and COE Program in the 21st Century, University 

of Shizuoka, School of Pharmaceutical Sciences. 

13. Sichuan Da Xue Xue Bao Yi Xue Ban. 2003 Apr;34(2):303-5. 

[Protective effects of green tea on mice with the irradiating damage induced by gammaray][Article 

in Chinese] 

Wang Z, Zeng L, Xiao Y, Lu S, Gao X. 



404

Department of Nutrition and Food Hygiene, West China School of Public Health, 

Sichuan University, Chengdu 610041, China. 

14. Int J Cancer. 2003 Oct 10;106(6):871-8. 

Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of 

VE-cadherin phosphorylation and inactivation of Akt molecule. 

Tang FY, Nguyen N, Meydani M. 

Vascular Biology Laboratory, JM USDA-Human Nutrition Research Center on Aging at 

Tufts University, Boston, MA 02111, USA. 

15. J Urol. 2003 Sep;170(3):773-6. 

Inhibition of bladder tumor growth by the green tea derivative epigallocatechin-3-gallate. 

Kemberling JK, Hampton JA, Keck RW, Gomez MA, Selman SH. 

Department of Urology, Medical College of Ohio, 3065 Arlington Avenue, Dowling Hall 

2170, Toledo, OH 43614-5807, USA. 

16. J Neurochem. 2003 Sep;86(5):1189-200. 

Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human 

neuroblastoma SH-SY5Y cells. 

Zhang Y, Zhao B. 

Laboratory of Visual Information Processing, Institute of Biophysics, Academia Sinica, 

15 Datun Road, Chaoyang District, Beijing 100101, China. 

17. Brain Res Bull. 2003 Aug 30;61(4):399-406. 

Effects of delayed administration of (-)-epigallocatechin gallate, a green tea polyphenol 

on the changes in polyamine levels and neuronal damage after transient forebrain 

ischemia in gerbils. 

Lee SY, Kim CY, Lee JJ, Jung JG, Lee SR. 

Department of Pharmacology, Kyungpook National University, 700-422 Taegu, South 

Korea. 

18. Recent Results Cancer Res. 2003;163:165-71; discussion 264-6. 



405

Chemoprevention of nonmelanoma skin cancer: experience with a polyphenol from green 

tea. 

Linden KG, Carpenter PM, McLaren CE, Barr RJ, Hite P, Sun JD, Li KT, Viner JL, 

Meyskens FL. 

Department of Dermatology, University of California, Irvine, 101 The City Drive, 

Orange, CA 92868, USA. 

19. FASEB J. 2003 Oct;17(13):1913-5. Epub 2003 Aug 01. 

Dual mechanisms of green tea extract (EGCG)-induced cell survival in human epidermal 

keratinocytes. 

Chung JH, Han JH, Hwang EJ, Seo JY, Cho KH, Kim KH, Youn JI, Eun HC. 

Department of Dermatology, Seoul National University College of Medicine, and 

Laboratory of Cutaneous Aging Research, Clinical Research Institute, Seoul National 

University Hospital, Seoul, Korea. 

20. Biochem Biophys Res Commun. 2003 Aug 15;308(1):64-7. 

Effect of green tea polyphenols on angiogenesis induced by an angiogenin-like protein. 

Maiti TK, Chatterjee J, Dasgupta S. Department of Chemistry, Indian Institute of 

Technology, Kharagpur 721302, West Bengal, India. 

21. Eur J Epidemiol. 2003;18(5):401-5. 

Relation of coffee, green tea, and caffeine intake to gallstone disease in middle-aged 

Japanese men. 

Ishizuk H, Eguchi H, Oda T, Ogawa S, Nakagawa K, Honjo S, Kono S. 

Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, 

Fukuoka, Japan. 

22. Nutr Cancer. 2003;45(2):226-35. 

Catechin content of 18 teas and a green tea extract supplement correlates with the 

antioxidant capacity. 

Henning SM, Fajardo-Lira C, Lee HW, Youssefian AA, Go VL, Heber D. 

UCLA Center for Human Nutrition, School of Medicine, Warren Hall 14-166, 900 

Veteran Avenue, Los Angeles, CA 90095, USA. shenning@mednet.ucla.edu 



406

23. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 May;37(3):171-3. 

[Study on the protective effect of green tea on gastric, liver and esophageal cancers] 

[Article in Chinese] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Jiang QW, Yu 

SZ.School of Public Health, Fudan University, Shanghai 200032, China. 

24. Drugs Aging. 2003;20(10):711-21. 

Potential therapeutic properties of green tea polyphenols in Parkinson's disease. 

Pan T, Jankovic J, Le W. 

Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. 

25. Curr Drug Targets Immune Endocr Metabol Disord. 2003 Sep;3(3):234-42. 

Skin photoprotection by green tea: antioxidant and immunomodulatory effects. 

Katiyar SK. 

Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 

35294, USA. skatiyar@uab.edu 

26. Chem Res Toxicol. 2003 Jul;16(7):865-72. 

Identification of potential aryl hydrocarbon receptor antagonists in green tea. 

Palermo CM, Hernando JI, Dertinger SD, Kende AS, Gasiewicz TA. 

Department of Environmental Medicine, University of Rochester, Rochester, New York 

14642, USA. 

27. Life Sci. 2003 Aug 8;73(12):1479-89. 

Action of green tea catechin on bone metabolic disorder in chronic cadmium-poisoned 

rats. 

Choi JH, Rhee IK, Park KY, Park KY, Kim JK, Rhee SJ. 

Department of Food Science and Nutrition, Catholic University of Daegu, 712-702, 

South Korea. 

28. Ann N Y Acad Sci. 2003 May;993:351-61; discussion 387-93. 

Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, Rapomorphine, 

green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin. 



407

Weinreb O, Mandel S, Youdim MB. 

Eve Topf, Haifa, Israel. 

29. Life Sci. 2003 Aug 1;73(11):1383-92. 

Stimulatory effect of oral administration of green tea and caffeine on locomotor activity 

in SKH-1 mice. 

Michna L, Lu YP, Lou YR, Wagner GC, Conney AH. 

Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey and 

The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical 

School, Piscataway, NJ, USA. 

30. Life Sci. 2003 Jul 25;73(10):1299-313. 

Green tea extract inhibits angiogenesis of human umbilical vein endothelial cells through 

reduction of expression of VEGF receptors. 

Kojima-Yuasa A, Hua JJ, Kennedy DO, Matsui-Yuasa I. 

Department of Food and Human Health Sciences, Graduate School of Human Life 

Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, 

Japan. kojma@life.osaka-cu.ac.jp 

31. Int J Cancer. 2003 Sep 10;106(4):574-9. 

Green tea and risk of breast cancer in Asian Americans. 

Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC. 

Department of Preventive Medicine, University of Southern California, Keck School of 

Medicine, Los Angeles, CA, USA. annawu@hsc.usc.edu 

32. J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S. 

Molecular targets for green tea in prostate cancer prevention. Adhami VM, Ahmad N, 

Mukhtar H. 

Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 

33. FEBS Lett. 2003 Jul 10;546(2-3):265-70. 

Complex effects of different green tea catechins on human platelets. 



408

Lill G, Voit S, Schror K, Weber AA. 

Institut fur Pharmakologie und Klinische Pharmakologie, Universitatsklinikum 

Dusseldorf, Moorenstr 5, D-40225 Dusseldorf, Germany. 

34. Arch Intern Med. 2003 Jun 23;163(12):1448-53. 

Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized 


Maron DJ, Lu GP, Cai NS, Wu ZG, Li YH, Chen H, Zhu JQ, Jin XJ, Wouters BC, Zhao 

J. 

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, 

Tennessee 37232, USA. david.maron@vanderbilt.edu 

35. Anticancer Res. 2003 Mar-Apr;23(2B):1533-9. 

Green tea polyphenol targets the mitochondria in tumor cells inducing caspase 3dependent 

apoptosis. 

Hsu S, Lewis J, Singh B, Schoenlein P, Osaki T, Athar M, Porter AG, Schuster G. 

Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443. 

Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 

36. Zhonghua Liu Xing Bing Xue Za Zhi. 2003 Mar;24(3):192-5. 

[A case-control study on drinking green tea and decreasing risk of cancers in the 

alimentary canal among cigarette smokers and alcohol drinkers] 


Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Chen CW, Wei GR, Zhou XM, Jiang 

QW, Yu SZ. 

School of Public Health, Fudan University, Shanghai 200032, China. 

37. Arch Dermatol Res. 2003 Jul;295(3):112-6. Epub 2003 Jun 13. 

Comparative effects of polyphenols from green tea (EGCG) and soybean (genistein) on 

VEGF and IL-8 release from normal human keratinocytes stimulated with the 

proinflammatory cytokine TNFalpha. 

Trompezinski S, Denis A, Schmitt D, Viac J. 



409

INSERM U 346, Clinique Dermatologique, Hopital E. Herriot, 69437 Lyon, France. 

38. Carcinogenesis. 2003 Jun;24(6):1105-9. Epub 2003 Apr 24. 

Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, 

on diethylnitrosamine-induced hepato- and cholangiocarcinogenesis in mice by green tea 

infusion. 

Umemura T, Kai S, Hasegawa R, Kanki K, Kitamura Y, Nishikawa A, Hirose M. 

Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, 

Setagaya-ku, Tokyo 158-8501, Japan. umemura@nihs.go.jp 

39. DNA Cell Biol. 2003 Mar;22(3):217-24. 

A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer 

cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. 

Ahn WS, Huh SW, Bae SM, Lee IP, Lee JM, Namkoong SE, Kim CK, Sin JI. 

Department of Obstetrics and Gynecology, College of Medicine, The Catholic University 

of Korea, Seoul, Korea. 

40. J Biochem (Tokyo). 2003 May;133(5):571-6. 

Inhibitory effects of green tea catechins on the activity of human matrix 

metalloproteinase 7 (matrilysin). 

Oneda H, Shiihara M, Inouye K. 

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto 

University, Sakyo-ku, Kyoto 606-8502, Japan. 

41. Nutrition. 2003 Jun;19(6):536-40. 

Effect of green tea in the prevention and reversal of fasting-induced intestinal mucosal 

damage. 

Asfar S, Abdeen S, Dashti H, Khoursheed M, Al-Sayer H, Mathew T, Al-Bader A. 

Department of Surgery, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 

13110, Kuwait. sami@hsc.kuniv.edu.kw 

42. Carcinogenesis. 2003 May;24(5):927-36. 



410

Treatment of green tea polyphenols in hydrophilic cream prevents UVB-induced 

oxidation of lipids and proteins, depletion of antioxidant enzymes and phosphorylation of 

MAPK proteins in SKH-1 hairless mouse skin. 

Vayalil PK, Elmets CA, Katiyar SK. 

Department of Dermatology, University of Alabama at Birmingham, 1670 University 

Blvd, Volker Hall 557, 35294, USA. 

43. Exp Mol Med. 2003 Apr 30;35(2):136-9. 

Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced 

pancreatic beta-cell damage. 

Han MK. 

Department of Microbiology, Chonbuk National University Medical School and Institute 

for Medical Sciences, Jeonju 560-756, Korea. 

44. Oral Microbiol Immunol. 2003 Jun;18(3):192-5. 

Inhibitory effects of green tea catechins on protein tyrosine phosphatase in Prevotella 

intermedia. 

Okamoto M, Leung KP, Ansai T, Sugimoto A, Maeda N. 

Department of Oral Bacteriology, Tsurumi University School of Dental Medicine, 

Yokohama, Japan. 

45. Phytother Res. 2003 May;17(5):566-7. 

Superoxide dismutase activity enhanced by green tea inhibits lipid accumulation in 3T3- 

L1 cells. 

Mori M, Hasegawa N. 

Department of Food and Nutrition, Nagoya Bunri College, Nagoya, Japan. 


Powdered green tea has antilipogenic effect on Zucker rats fed a high-fat diet. 

Hasegawa N, Yamda N, Mori M. 

Department of Food and Nutrition, Nagoya Bunri College, Nagoya, Japan. 

hsgwn@nagoya-bunri.ac.jp 



411

47. J Agric Food Chem. 2003 May 21;51(11):3379-81. 

Effect of selenium on the yield and quality of green tea leaves harvested in early spring. 

Hu Q, Xu J, Pang G. 

Laboratory of Food Processing and Quality Control, College of Food Science and 

Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of 

China. 

48. Antiviral Res. 2003 Apr;58(2):167-73. 

Inhibition of adenovirus infection and adenain by green tea catechins. 

Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S. 

Departement de Microbiologie et d'Infectiologie, Faculte de Medecine, Universite de 

Sherbrooke, Que, Sherbrooke, Canada J1H 5N4. joseph.weber@usherbrooke.ca 

49. Arch Pharm Res. 2003 Mar;26(3):214-23. 

Comparison of green tea extract and epigallocatechin gallate on blood pressure and 

contractile responses of vascular smooth muscle of rats. 

Lim DY, Lee ES, Park HG, Kim BC, Hong SP, Lee EB. 

Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501- 

759, Korea. dylim@chosun.ac.kr 

50. Phytother Res. 2003 Apr;17(4):358-63. 

DNA degradation by water extract of green tea in the presence of copper ions: 

implications for anticancer properties. 

Malik A, Azam S, Hadi N, Hadi SM. 

Department of Biochemistry, Faculty of Life Science, AMU, Aligarh, India. 

51. Thromb Haemost. 2003 May;89(5):866-74. 

Green tea epigallocatechin-3-gallate inhibits platelet signalling pathways triggered by 

both proteolytic and non-proteolytic agonists. 

Deana R, Turetta L, Donella-Deana A, Dona M, Maria Brunati A, De Michiel L, Garbisa 

S. 



412

Department of Biological Chemistry and Institute of the Neuroscience of the Italian 

National Research Council (CNR), University of Padova, Italy, E-mail: 

arianna.donella@unipd.it 

52. J Immunol. 2003 Apr 15;170(8):4335-41. 

Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, 

and pulmonary fibrosis. 

Dona M, Dell'Aica I, Calabrese F, Benelli R, Morini M, Albini A, Garbisa S. 

Department of Experimental Biomedical Sciences, Medical School of Padova, Padova, 

Italy. 

53. Curr Med Chem Anti-Canc Agents. 2002 Jul;2(4):441-63. 

Green tea catechins as novel antitumor and antiangiogenic compounds. 

Demeule M, Michaud-Levesque J, Annabi B, Gingras D, Boivin D, Jodoin J, Lamy S, 

Bertrand Y, Beliveau R. 

Laboratoire de Medecine Moleculaire, UQAM-Hocric;pital Sainte-Justine, Montreal, 

Canada. 

54. Kidney Int. 2003 May;63(5):1785-90. 

Effect of green tea extract on cardiac hypertrophy following 5/6 nephrectomy in the rat. 

Priyadarshi S, Valentine B, Han C, Fedorova OV, Bagrov AY, Liu J, Periyasamy SM, 

Kennedy D, Malhotra D, Xie Z, Shapiro JI. 

The Department of Medicine, Medical College of Ohio, Toledo, Ohio 43614, USA. 

55. Phytother Res. 2003 Mar;17(3):206-9. 

Protective effect of green tea polyphenol (-)-epigallocatechin gallate and other 

antioxidants on lipid peroxidation in gerbil brain homogenates. 

Lee SR, Im KJ, Suh SI, Jung JG. 

Department of Pharmacology, School of Medicine and Brain Research Institute, 

Keimyung University, Taegu, South Korea. srlee@dsmc.or.kr 

56. FASEB J. 2003 May;17(8):952-4. Epub 2003 Mar 28. 



413

Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of 

nonamyloidogenic soluble precursor protein by green tea polyphenol (-)epigallocatechin-3-gallate. 

Levites Y, Amit T, Mandel S, Youdim MB. 

Eve Topf and USA National Parkinson Foundation, Centers of Excellence for 

Neurodegenerative Diseases Research, Technion Faculty of Medicine, Haifa, Israel. 

57. J Agric Food Chem. 2003 Apr 9;51(8):2421-5. 

Influence of green tea polyphenol in rats with arginine-induced renal failure. 

Yokozawa T, Cho EJ, Nakagawa T. 

Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 

Sugitani, Toyama 930-0194, Japan. yokozawa@ms.toyama-mpu.ac.jp 

58. J Pharmacol Exp Ther. 2003 Jul;306(1):29-34. Epub 2003 Mar 27. 

Green tea polyphenols induce differentiation and proliferation in epidermal keratinocytes. 

Hsu S, Bollag WB, Lewis J, Huang Q, Singh B, Sharawy M, Yamamoto T, Schuster G. 

Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443. 


59. Mutat Res. 2003 Feb-Mar;523-524:33-41. 

Anticlastogenic, antigenotoxic and apoptotic activity of epigallocatechin gallate: a green 

tea polyphenol. 

Roy M, Chakrabarty S, Sinha D, Bhattacharya RK, Siddiqi M. 

Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National 

Cancer Institute, 37 SP Mukherjee Road, Kolkata 700 026, India. 

60. Cancer. 2003 Mar 15;97(6):1442-6. 

A phase II trial of green tea in the treatment of patients with androgen independent 

metastatic prostate carcinoma. 

Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P, Tan W, Fitch TR, 

Rowland KM, Young CY, Flynn PJ. 



414

Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. 

jatoi.aminah@mayo.edu 

61. Int J Urol. 2003 Mar;10(3):160-6. 

Preventive effects of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine 

in rat by green tea leaves. 

Sato D, Matsushima M. 

Second Department of Urology, Toho University of Medicine, Tokyo, Japan. 

sai2uro@oha.toho-u.ac.jp 

62. J Biomed Sci. 2003 Mar-Apr;10(2):219-27. 

Green Tea Constituent (-)-Epigallocatechin-3-Gallate Inhibits Hep G2 Cell Proliferation 

and Induces Apoptosis through p53-Dependent and Fas-Mediated Pathways. 

Kuo PL, Lin CC. 

Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, 

Taiwan, ROC. 

63. Oncogene. 2003 Feb 20;22(7):1035-44. 

Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human 

epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate. 

Afaq F, Adhami VM, Ahmad N, Mukhtar H. 

Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 

64. FASEB J. 2003 Apr;17(6):702-4. Epub 2003 Feb 05. 

Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating 

vascular smooth muscle cells via activation of p53. 

Hofmann CS, Sonenshein GE. 

Department of Biochemistry, Boston University School of Medicine, Massachusetts 

02118, USA. 

65. Yan Ke Xue Bao. 2000 Sep;16(3):194-8. 

Growth inhibition, induction of apoptosis by green tea constituent (-)-epigallocatechin-3gallate 

in cultured rabbit lens epithelial cells. 



415

Huang W, Li S, Zeng J, Liu Y, Wu M, Zhang M. 

Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Sciences, Guangzhou 

510060, China. 

66. Anticancer Res. 2002 Nov-Dec;22(6C):4115-20. 

Induction of p57 is required for cell survival when exposed to green tea polyphenols. 

Hsu S, Yu FS, Lewis J, Singh B, Borke J, Osaki T, Athar M, Schuster G. 

Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443, 


67. J Biochem Mol Biol. 2003 Jan 31;36(1):66-77. 

Signal transduction pathways: targets for green and black tea polyphenols. 

Park AM, Dong Z. 

The Hormel Institute, University of Minnesota, Austin, MN 55912, USA. 

68. Clin Exp Pharmacol Physiol. 2003 Jan-Feb;30(1-2):88-95. 

Green tea catechins evoke a phasic contraction in rat aorta via H2O2-mediated multiplesignalling 

pathways. 

Shen JZ, Zheng XF, Wei EQ, Kwan CY. 

Department of Pharmacology, School of Medicine, Zhejiang University, Hubin Campus, 

Hangzhou, People's Republic of China. 

69. Anticancer Res. 2002 Nov-Dec;22(6A):3373-8. 

Induction of apoptosis by the green tea flavonol (-)-epigallocatechin-3-gallate in human 

endothelial ECV 304 cells. 

Yoo HG, Shin BA, Park JC, Kim HS, Kim WJ, Chay KO, Ahn BW, Park RK, Ellis LM, 

Jung YD. 

Chonnam University Research Institute of Medical Sciences, Chonnam National 

University Medical School, Kwangju, Korea. 

70. Cancer Detect Prev. 2002;26(6):411-8. 



416

Modification of lung cancer susceptibility by green tea extract as measured by the comet 

assay. 

Zhang H, Spitz MR, Tomlinson GE, Schabath MB, Minna JD, Wu X. 

Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center 

Box 189 1515 Holcombe Blvd, Houston, TX 77030, USA 

71. Biol Pharm Bull. 2002 Dec;25(12):1513-8. 

Neuroprotective effects of the green tea components theanine and catechins. 

Kakuda T. 

Central Research Institute, Itoen, Ltd, Shuzuoka, Japan. 

72. Life Sci. 2003 Jan 17;72(9):1073-83. 

Effects of green tea polyphenols on dopamine uptake and on MPP+ -induced dopamine 

neuron injury. 

Pan T, Fei J, Zhou X, Jankovic J, Le W. 

Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 

77030, USA. 

73. Asia Pac J Clin Nutr. 2002;11(4):292-7. 

Effect of green tea catechin on arachidonic acid cascade in chronic cadmium-poisoned 

rats. 

Choi JH, Chang HW, Rhee SJ. 

Department of Food Science and Nutrition, Catholic University of Daegu, Kyongsan-si, 

Korea. 

74. Antivir Chem Chemother. 2002 Jul;13(4):223-9. 

Antiviral properties of prodelphinidin B-2 3'-O-gallate from green tea leaf. 

Cheng HY, Lin CC, Lin TC. 

Graduate Institute of Pharmaceutical Science, College of Pharmacy, Kaohsiung Medical 

University, Kaohsiung, Taiwan, Republic of China. 

75. Atherosclerosis. 2003 Jan;166(1):23-30. 



417

Green tea catechins inhibit the cultured smooth muscle cell invasion through the 

basement barrier. 

Maeda K, Kuzuya M, Cheng XW, Asai T, Kanda S, Tamaya-Mori N, Sasaki T, Shibata 

T, Iguchi A. 

76. J Periodontal Res. 2002 Dec;37(6):433-8. 

Improvement of periodontal status by green tea catechin using a local delivery system: a 

clinical pilot study. 

Hirasawa M, Takada K, Makimura M, Otake S. 

Department of Microbiology, Nihon University School of Dentistry at Matsudo, 

Matsudo, Chiba Japan. masahira@mascat.nihon-u.ac.jp 

77. Breast Cancer Res Treat. 2002 Dec;76(3):195-201. 

(-)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells 

but not of their normal counterparts. 

Vergote D, Cren-Olive C, Chopin V, Toillon RA, Rolando C, Hondermarck H, Le 

Bourhis X. 

Laboratoire de Biologic du Developpement (UPRES-EA 1033), Universite des Sciences 

et Technologies de Lille, Villeneuve d'Ascq, France. 

78. Yakugaku Zasshi. 2002 Nov;122(11):995-9. 

[Glutamate transporter mediated increase of antitumor activity by theanine, an amino acid 

in green tea] 

[Article in Japanese] 

Sadzuka Y, Yamashita Y, Kishimoto S, Fukushima S, Takeuchi Y, Sonobe T. 

University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. sadzuka@u-shizuokaken.ac.jp 

79. Int J Cancer. 2002 Dec 10;102(5):439-44. 

The green tea polyphenol, epigallocatechin-3-gallate, protects against the oxidative 

cellular and genotoxic damage of UVA radiation. 

Tobi SE, Gilbert M, Paul N, McMillan TJ. 



418

Department of Biological Sciences, Institute of Environmental and Natural Sciences, 

Lancaster University, Lancaster, United Kingdom. 

80. Int J Oncol. 2002 Dec;21(6):1307-15. 

Bioactivity of well-defined green tea extracts in multicellular tumor spheroids. 

Mueller-Klieser W, Schreiber-Klais S, Walenta S, Kreuter MH. 

Institute of Physiology and Pathophysiology, Johannes Gutenberg-University Mainz, 

55099 Mainz, Germany. wolfgang.mueller-klieser@uni-mainz.de 

81. Life Sci. 2002 Dec 6;72(3):257-68. 

Anti-proliferative and differentiation-inducing activities of the green tea catechin 

epigallocatechin-3-gallate (EGCG) on the human eosinophilic leukemia EoL-1 cell line. 

Lung HL, Ip WK, Wong CK, Mak NK, Chen ZY, Leung KN. 

Department of Biochemistry, The Chinese University of Hong Kong, Shatin, China. 

82. Chem Phys Lipids. 2002 Dec;120(1-2):109-17. 

Antioxidant effects of green tea polyphenols on free radical initiated peroxidation of rat 

liver microsomes. 

Cai YJ, Ma LP, Hou LF, Zhou B, Yang L, Liu ZL. 

National Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu 730000, 

Lanzhou, People's Republic of China 

83. Food Chem Toxicol. 2002 Dec;40(12):1745-50. 

Direct scavenging of nitric oxide and superoxide by green tea. 

Nakagawa T, Yokozawa T. 

Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 

Sugitani, Japan. 

84. J Ethnopharmacol. 2002 Nov;83(1-2):109-16. 

Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress 

in experimental diabetes. 

M C S, K S, Kuttan R. 



419

Amala Cancer Research Centre, Amala Nagar,Trichur 680 553, Kerala, India. 

85. Zhonghua Yu Fang Yi Xue Za Zhi. 2002 Jul;36(4):243-6. 

[Green tea extracts protected against carbon tetrachloride-induced chronic liver damage 

and cirrhosis] 


Xiao J, Lu R, Shen X, Wu M. 

Department of Hutyition and Food Hygiene, School of Health, Fudan University, 

Shanghai 200032, China. 

86. Cancer Lett. 2002 Dec 15;188(1-2):163-70. 

Lack of inhibitory effects of green tea catechins in 1,2-dimetylhydrazine-induced rat 

intestinal carcinogenesis model: comparison of the different formulations, administration 

routes and doses. 

Hirose M, Yamaguchi T, Mizoguchi Y, Akagi K, Futakuchi M, Shirai T. 

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, 

Setagaya-ku, 158-8501, Tokyo, Japan. m-hirose@nihs.go.jp 

87. Cancer Lett. 2002 Dec 15;188(1-2):9-13. 

Green tea: cancer preventive beverage and/or drug. 

Fujiki H, Suganuma M, Imai K, Nakachi K. 

Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri 

University, Yamashiro-cho, 770-8514, Tokushima, Japan. hfujiki@ph.bunri-u.ac.jp 

88. Amino Acids. 2002;22(2):131-43. 

The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG). 

Wang YC, Bachrach U. 

Department of Molecular Biology, Hebrew University-Hadassah Medical School, 

Jerusalem, Israel. 

89. Mol Med. 2002 Jul;8(7):382-92. 

Synthetic analogs of green tea polyphenols as proteasome inhibitors. 



420

Smith DM, Wang Z, Kazi A, Li LH, Chan TH, Dou QP. 

Drug Discovery Program, H Lee Moffitt Cancer Center & Research Institute, 

Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, 

College of Medicine,University of South Florida, Tampa, FL 33612-9497, USA. 

90. Neurotoxicology. 2002 Sep;23(3):289-300. 

Differential modulation of growth and glutathione metabolism in cultured rat astrocytes 

by 4-hydroxynonenal and green tea polyphenol, epigallocatechin-3-gallate. 

Ahmed I, John A, Vijayasarathy C, Robin MA, Raza H. 

Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al 

Ain, United Arab Emirates. 

91. Drug Metab Dispos. 2002 Nov;30(11):1246-9. 

Contribution of presystemic hepatic extraction to the low oral bioavailability of green tea 

catechins in rats. 

Cai Y, Anavy ND, Chow HH. 

College of Pharmacy, University of Arizona, Tucson, Arizona 85724, USA. 

92. Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1):1025-32. 

Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3gallate 

by humans: formation of different metabolites and individual variability. 

Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S, Lambert G, Mohr S, Yang 

CS. 

Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of 

New Jersey, Piscataway, New Jersey 08854-8020, USA. 

93. Free Radic Biol Med. 2002 Oct 15;33(8):1097-105. 

Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity 

and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. 

Ahmed S, Rahman A, Hasnain A, Lalonde M, Goldberg VM, Haqqi TM. 

Department of Orthopedics, Case Western Reserve University, Cleveland, OH 44106- 

4946, USA. 



421

94. Ophthalmic Res. 2002 Jul-Aug;34(4):258-63. 

Green tea (Camellia sinensis) protects against selenite-induced oxidative stress in 

experimental cataractogenesis. 

Gupta SK, Halder N, Srivastava S, Trivedi D, Joshi S, Varma SD. 

Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, 

New Delhi, India. skgup@hotmail.com 

95. Inflammation. 2002 Oct;26(5):233-41. 

A green tea-derived polyphenol, epigallocatechin-3-gallate, inhibits IkappaB kinase 

activation and IL-8 gene expression in respiratory epithelium. 

Chen PC, Wheeler DS, Malhotra V, Odoms K, Denenberg AG, Wong HR. 

Division of Critical Care Medicine, Children's Hospital Medical Center and Children's 

Hospital Research Foundation, Cincinnati, OH 45244, USA. 

96. Biochem Biophys Res Commun. 2002 Sep 20;297(2):412-8. 

Elevation of P-glycoprotein function by a catechin in green tea. 

Wang EJ, Barecki-Roach M, Johnson WW. 

Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, 

NJ 07848, USA. 

97. Asia Pac J Clin Nutr. 2002;11(3):232-6. 

Effects of green tea catechin on prostaglandin synthesis of renal glomerular and renal 

dysfunction in streptozotocin-induced diabetic rats. 

Rhee SJ, Kim MJ, Kwag OG. 

Department of Food Science and Nutrition, Catholic University of Daegu, Gyungsan-si, 

Gyungbuk, Korea. sjrhee@cataegu.ac.kr 

98. Biol Pharm Bull. 2002 Sep;25(9):1238-40. 

Activity-guided fractionation of green tea extract with antiproliferative activity against 

human stomach cancer cells. 

Kinjo J, Nagao T, Tanaka T, Nonaka G, Okawa M, Nohara T, Okabe H. 



422

kinjojun@fukuoka-u.ac.jp 

99. Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G957-64. 

Prevention of hepatic ischemia-reperfusion injury by green tea extract. 

Zhong Z, Froh M, Connor HD, Li X, Conzelmann LO, Mason RP, Lemasters JJ, 

Thurman RG. 

Department of Cell and Developmental Biology, University of North Carolina at Chapel 

Hill, 27599, USA. 

100. Mutat Res. 2002 Sep;512(1):37-65. 

Comparative antimutagenic and anticlastogenic effects of green tea and black tea: a 

review. 

Gupta S, Saha B, Giri AK. 

Division of Human Genetics and Genomics, Indian Institute of Chemical Biology, 4 Raja 

S. C. Mullick Road, Jadavpur, Calcutta 700 032, India. 

Reduced L-Glutathione - 13 CITATIONS 

1: Kaposzta Z, Clifton A, Molloy J, Martin JF, Markus HS. 

S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty. 

Circulation. 2002 Dec 10;106(24):3057-62. 

PMID: 12473551 

2: Fraternale A, Casabianca A, Orlandi C, Cerasi A, Chiarantini L, Brandi G, Magnani 

M. 

Macrophage protection by addition of glutathione (GSH)-loaded erythrocytes to AZT and 

DDI in a murine AIDS model. 

Antiviral Res. 2002 Dec;56(3):263-72. 

PMID: 12406509 

3: Knight TR, Ho YS, Farhood A, Jaeschke H. 

Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: 

protection by glutathione. 

J Pharmacol Exp Ther. 2002 Nov;303(2):468-75. 

PMID: 12388625 



423

4: Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, Movilli E, Cancarini 

GC, De Marinis S, D'Avolio G, Broccoli R, Manganoni A, Albertin A, Di Lorenzo D. 

Effects of a vitamin E-bonded membrane and of glutathione on anemia and 

erythropoietin requirements in hemodialysis patients. 

J Nephrol. 2002 Sep-Oct;15(5):558-64. 

PMID: 12455724 

5: Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, 

Ubiali E, Catalano G. 

Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in 

advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. 

J Clin Oncol. 2002 Aug 15;20(16):3478-83. 

PMID: 12177109 

6: Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. 

Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and 

pain-free walking distance in patients with peripheral obstructive arterial disease: a 

randomized, double-blind, placebo-controlled trial. 

Mayo Clin Proc. 2002 Aug;77(8):754-9. 

PMID: 12173710 

7: Ueno Y, Kizaki M, Nakagiri R, Kamiya T, Sumi H, Osawa T. 

Dietary glutathione protects rats from diabetic nephropathy and neuropathy. 

J Nutr. 2002 May;132(5):897-900. 

PMID: 11983810 

8: Gao F, Yao CL, Gao E, Mo QZ, Yan WL, McLaughlin R, Lopez BL, Christopher TA, 

Ma XL. 

Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion 

injury. 

J Pharmacol Exp Ther. 2002 May;301(2):543-50. 

PMID: 11961055 

9: Inal ME, Akgun A, Kahraman A. 

Radioprotective effects of exogenous glutathione against whole-body gamma-ray 

irradiation: age- and gender-related changes in malondialdehyde levels, superoxide 

dismutase and catalase activities in rat liver. 

Methods Find Exp Clin Pharmacol. 2002 May;24(4):209-12. 

PMID: 12092007 

10: Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B. 

Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis. 

Am J Respir Crit Care Med. 2002 Apr 1;165(7):922-6. 

PMID: 11934715 



424

11: Kaposzta Z, Martin JF, Markus HS. 

Switching off embolization from symptomatic carotid plaque using S-nitrosoglutathione. 

Circulation. 2002 Mar 26;105(12):1480-4. 

PMID: 11914258 

12: Ortolani O, Conti A, De Gaudio AR, Moraldi E, Novelli GP. 

[Glutathione and N-acetylcysteine in the prevention of free-radical damage in the initial 

phase of septic shock] 

Recenti Prog Med. 2002 Feb;93(2):125-9. Italian. 

PMID: 11887346 

13: Amer MA. 

Modulation of age-related biochemical changes and oxidative stress by vitamin C and 

glutathione supplementation in old rats. 

Ann Nutr Metab. 2002;46(5):165-8. 

PMID: 12378038 

L-Cysteine – 22 STUDIES 

1. Neurosci Lett. 2003 Jul 31;346(1-2):97-100. 

L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain 

kynurenic acid production via selective interference with kynurenine aminotransferase II. 

Kocki T, Luchowski P, Luchowska E, Wielosz M, Turski WA, Urbanska EM. 

Department of Pharmacology and Toxicology, Medical University, Jaczewskiego 8, 20- 

090 Lublin, Poland. 

2. Biochem Biophys Res Commun. 2003 May 23;305(1):94-100. 

L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell 

proliferation and activation. 

Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okita K. 

Pharmaceuticals Research Laboratories, Ajinomoto Co, Inc, 1-1, Suzuki-cho, Kawasakiku, 

Kawasaki 210-8681, Japan. 

3. Proc Nutr Soc. 2000 Nov;59(4):595-600. 

Glutathione and immune function. 

Droge W, Breitkreutz R. 



425

Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer 

Feld 280, D-69120 Heidelberg, Germany. W.Droege@dkfz-heidelberg.de 

4. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):72-8. 

gamma-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake by 

HepG2 cells, a human hepatoma cell line. 

Wang W, Clarkson TW, Ballatori N. Department of Environmental Medicine, University 

of Rochester School of Medicine, Rochester, New York 14642, USA. 

5. Amino Acids. 2000;18(4):319-27. 

Polyamines and thiols in the cytoprotective effect of L-cysteine and L-methionine on 

carbon tetrachloride-induced hepatotoxicity. 

Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I. 

Department of Food and Nutrition, Faculty of Human Life Science, Osaka City 

University, Osaka, Japan. 

6. Z Naturforsch [C]. 2000 Mar-Apr;55(3-4):271-7. 

Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition 

induced by free radicals. 

Tsakiris S, Angelogianni P, Schulpis KH, Behrakis P. Department of Experimental 

Physiology, University of Athens, Medical School, Greece. stsakir@cc.uoa.gr 

7. Comp Biochem Physiol B Biochem Mol Biol. 1997 Feb;116(2):223-6. 

L-cysteine metabolism in guinea pig and rat tissues. 

Wrobel M, Ubuka T, Yao WB, Abe T. Department of Biochemistry, Okayama University 

Medical School, Japan. 

8. Gross A, Hack V, Stahl-Hennig C, Droge W. AIDS Res Hum Retroviruses. 1996 Nov 

20;12(17):1639-41. 

Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels 

in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIVinfected 

rhesus macaques. 

9. Biochem Pharmacol. 1996 May 3;51(9):1111-6. 



426

Maintenance of hepatic glutathione homeostasis and prevention of acetaminopheninduced 

cataract in mice by L-cysteine prodrugs. 

Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT. Department of Ophthalmology, 

University of Minnesota, Minneapolis, USA. 

10. Jpn J Physiol. 1995;45(5):771-83. 

The central effect of L-cysteine on cardiovascular system of the conscious rat. 

Takemoto Y. Department of Physiology, Hiroshima University School of Medicine, 

Minami-ku, Japan. 

11. FASEB J. 1994 Nov;8(14):1131-8. 

Functions of glutathione and glutathione disulfide in immunology and immunopathology. 

Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmunder 

H. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, 

Germany. 

12. Pharmacology. 1993;46(2):61-5. 

Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with 

N-acetyL-cysteine. 

Droge W. Division of Immunochemistry, Deutsches Krebsforschungszentrum, 

Heidelberg, BRD. 

13. Biochem Pharmacol. 1992 Jul 7;44(1):129-35. 

Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. 

Richie JP Jr, Lang CA, Chen TS. American Health Foundation, Valhalla, NY 10595. 

14. Biochem Pharmacol. 1992 Feb 4;43(3):483-8. 

Cysteine isopropylester protects against paracetamol-induced toxicity. 

Butterworth M, Upshall DG, Smith LL, Cohen GM. Toxicology Unit, School of 

Pharmacy, University of London, U.K. 

15. Blood. 1992 Sep 1;80(5):1247-53. 

Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg-Gly-Aspsulfoxide 

(G4120) in a hamster platelet-rich femoral vein thrombosis model. 



427

Imura Y, Stassen JM, Bunting S, Stockmans F, Collen D. Center for Thrombosis and 

Vascular Research, University of Leuven, Belgium. 

16. Jpn J Cancer Res. 1989 Feb;80(2):182-7. 

Enhanced antitumor effect of 5'-deoxy-5-fluorouridine by oral administration with Lcysteine. 

Iigo M, Nakajima Y, Araki E, Hoshi A. Chemotherapy Division, National Cancer Center 

Research Institute, Tokyo. 

17. Am Rev Respir Dis. 1985 Nov;132(5):1049-54. Investigation of the protective effects 

of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative 

inactivation of human alpha-1-protease inhibitor in vitro. Theron A, Anderson R. 

18. J Biol Chem. 1984 May 10;259(9):5606-11. Free radical metabolites of L-cysteine 

oxidation. Harman LS, Mottley C, Mason RP. 

19. Hum Genet. 1979;50(1):51-7. 

Chromosomal breakage in Crohn's disease: anticlastogenic effect of D-penicillamine and 

L-cysteine. 

Emerit I, Emerit J, Levy A, Keck M. 

20. Biol Trace Elem Res. 2000 Jul;76(1):19-30. 

Study of the effect of the administration of Cd(II), cysteine, methionine, and Cd(II) 

together with cysteine or methionine on the conversion of xanthine dehydrogenase 

into xanthine oxidase. 

Esteves AC, Felcman J. Department of Chemistry, Pontificia Universidade Catolica 

do Rio de Janeiro, Rio de Janeiro, Brazil. 

21. J Infect Dis. 2000 Sep;182 Suppl 1:S81-4. 

Regulation of cysteine-rich intestinal protein, a zinc finger protein, by mediators of 

the immune response. 

Cousins RJ, Lanningham-Foster L. 

Food Science and Human Nutrition Department, Center for Nutritional Sciences, 

University of Florida, Gainesville, FL 32611-0370, USA. 

22. Am J Med. 1991 Sep 30;91(3C):140S-144S. 



428

Modulation of lymphocyte functions and immune responses by cysteine and cysteine 

derivatives. 

Droge W, Eck HP, Gmunder H, 

Mihm S. Division of Immunochemistry, Deutsches Krebsforschungszentrum, 

Heidelberg, F.R.G. 

Coenzyme Q10 – 43 STUDIES 

1: Muller T, Buttner T, Gholipour AF, Kuhn W. 

Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with 

Parkinson's disease. 

Neurosci Lett. 2003 May 8;341(3):201-4. 

PMID: 12697283 [PubMed - indexed for MEDLINE] 

2: Elshershari H, Ozer S, Ozkutlu S, Ozme S. 

Potential usefulness of coenzyme Q10 in the treatment of idiopathic dilated 

cardiomyopathy in children. 

Int J Cardiol. 2003 Mar;88(1):101-2. 


3: Beal MF. 

Bioenergetic approaches for neuroprotection in Parkinson's disease. 

Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-8. Review. 


4: Lu WL, Zhang Q, Lee HS, Zhou TY, Sun HD, Zhang DW, Zheng L, Lee M, Wong 

SM. 

Total coenzyme Q10 concentrations in Asian men following multiple oral 50-mg doses 

administered as coenzyme Q10 sustained release tablets or regular tablets. 

Biol Pharm Bull. 2003 Jan;26(1):52-5. 


5: Van Maldergem L, Trijbels F, DiMauro S, Sindelar PJ, Musumeci O, Janssen A, 

Delberghe X, Martin JJ, Gillerot Y. 

Coenzyme Q-responsive Leigh's encephalopathy in two sisters. 

Ann Neurol. 2002 Dec;52(6):750-4. 


6: Ramadan LA, Abd-Allah AR, Aly HA, Saad-el-Din AA. 

Testicular toxicity effects of magnetic field exposure and prophylactic role of coenzyme 

Q10 and L-carnitine in mice. 



429

Pharmacol Res. 2002 Oct;46(4):363-70. 


7: Turunen M, Wehlin L, Sjoberg M, Lundahl J, Dallner G, Brismar K, Sindelar PJ. 

beta2-Integrin and lipid modifications indicate a non-antioxidant mechanism for the antiatherogenic 

effect of dietary coenzyme Q10. 

Biochem Biophys Res Commun. 2002 Aug 16;296(2):255-60. 


8: Sarter B. 

Coenzyme Q10 and cardiovascular disease: a review. 

J Cardiovasc Nurs. 2002 Jul;16(4):9-20. Review. 


9: Koryagin AS, Krylova EV, Luk'yanova LD. 

Effect of ubiquinone-10 on the blood system in rats exposed to radiation. 

Bull Exp Biol Med. 2002 Jun;133(6):562-4. 


10: Lamson DW, Plaza SM. 

Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. 

Altern Med Rev. 2002 Apr;7(2):94-111. Review. 


11: Beal MF. 

Coenzyme Q10 as a possible treatment for neurodegenerative diseases. 

Free Radic Res. 2002 Apr;36(4):455-60. Review. 


12: Rozen TD, Oshinsky ML, Gebeline CA, Bradley KC, Young WB, Shechter AL, 

Silberstein SD. 

Open label trial of coenzyme Q10 as a migraine preventive. 

Cephalalgia. 2002 Mar;22(2):137-41. 


13: Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. 

Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II 


Diabetologia. 2002 Mar;45(3):420-6. 


14: Lister RE. 

An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined with 

Ginkgo biloba extract in fibromyalgia syndrome. 

J Int Med Res. 2002 Mar-Apr;30(2):195-9. 




430

15: Huang CC, Kuo HC, Chu CC, Kao LY. 

Rapid visual recovery after coenzyme q10 treatment of leber hereditary optic neuropathy. 

J Neuroophthalmol. 2002 Mar;22(1):66. 


16: Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, 

Beal MF. 

Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of 

Huntington's disease. 

J Neurosci. 2002 Mar 1;22(5):1592-9. 


17: Brancato R, Fiore T, Papucci L, Schiavone N, Formigli L, Orlandini SZ, Gobbi PG, 

Carones F, Donnini M, Lapucci A, Capaccioli S. 

Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent keratocyte 

apoptosis after excimer laser photoablation in rabbits. 

J Refract Surg. 2002 Mar-Apr;18(2):135-9. 


18: Schilling G, Coonfield ML, Ross CA, Borchelt DR. 

Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a 

Huntington's disease transgenic mouse model. 

Neurosci Lett. 2001 Nov 27;315(3):149-53. 


19: Burke BE, Neuenschwander R, Olson RD. 

Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic 

hypertension. 

South Med J. 2001 Nov;94(11):1112-7. 


20: Di Giovanni S, Mirabella M, Spinazzola A, Crociani P, Silvestri G, Broccolini A, 

Tonali P, Di Mauro S, Servidei S. 

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 

deficiency. 

Neurology. 2001 Aug 14;57(3):515-8. 


21: Tran MT, Mitchell TM, Kennedy DT, Giles JT. 

Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. 

Pharmacotherapy. 2001 Jul;21(7):797-806. Review. 


22: [No authors listed] 

Extra co-enzyme Q10 for statin-users? 



431

Treatmentupdate. 2001 Jun;13(2):4-7. 


23: Gazdikova K, Gvozdjakova A, Kucharska J, Spustova V, Braunova Z, Dzurik R. 

[Effect of coenzyme Q10 in patients with kidney diseases] 

Cas Lek Cesk. 2001 May 24;140(10):307-10. Slovak. 


24: Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. 

Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis 

in apolipoprotein E gene knockout mice. 

Arterioscler Thromb Vasc Biol. 2001 Apr;21(4):585-93. 


25: Rauchova H, Lenaz G. 

[Coenzyme Q and its therapeutic use] 

Ceska Slov Farm. 2001 Mar;50(2):78-82. Review. Czech. 


26: Piotrowski P, Wierzbicka K, Smialek M. 

Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia 

treated with antioxidants. 

Folia Neuropathol. 2001;39(3):147-54. 


27: Rauscher FM, Sanders RA, Watkins JB 3rd. 

Effects of coenzyme Q10 treatment on antioxidant pathways in normal and 

streptozotocin-induced diabetic rats. 

J Biochem Mol Toxicol. 2001;15(1):41-6. 


28: Shinkai T, Nakashima M, Ohmori O, Terao T, Nakamura J, Hiramatsu N, Hashiguchi 

H, Tsuji S. 

Coenzyme Q10 improves psychiatric symptoms in adult-onset mitochondrial myopathy, 

encephalopathy, lactic acidosis and stroke-like episodes: a case report. 

Aust N Z J Psychiatry. 2000 Dec;34(6):1034-5. 


29: Choi C, Sunwoo IN, Kim HS, Kim DI. 

Transient improvement of pyruvate metabolism after coenzyme Q therapy in Kearns- 

Sayre syndrome: MRS study. 

Yonsei Med J. 2000 Oct;41(5):676-9. 


30: Kaikkonen J, Nyyssonen K, Tomasi A, Iannone A, Tuomainen TP, Porkkala-Sarataho 

E, Salonen JT. 



432

Antioxidative efficacy of parallel and combined supplementation with coenzyme Q10 

and d-alpha-tocopherol in mildly hypercholesterolemic subjects: a randomized placebocontrolled 

clinical study. 

Free Radic Res. 2000 Sep;33(3):329-40. 


31: Rotig A, Appelkvist EL, Geromel V, Chretien D, Kadhom N, Edery P, Lebideau M, 

Dallner G, Munnich A, Ernster L, Rustin P. 

Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme 

Q10 deficiency. 

Lancet. 2000 Jul 29;356(9227):391-5. 


32: Raitakari OT, McCredie RJ, Witting P, Griffiths KA, Letters J, Sullivan D, Stocker 

R, Celermajer DS. 

Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance 

endothelial function in hypercholesterolemic young adults. 

Free Radic Biol Med. 2000 Apr 1;28(7):1100-5. 


33: Liou CW, Huang CC, Lin TK, Tsai JL, Wei YH. 

Correction of pancreatic beta-cell dysfunction with coenzyme Q(10) in a patient with 

mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome and 


Eur Neurol. 2000;43(1):54-5. 


34: Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. 

Coenzyme Q10 in health and disease. 

Eur J Clin Nutr. 1999 Oct;53(10):764-70. Review. 


35: Svensson M, Malm C, Tonkonogi M, Ekblom B, Sjodin B, Sahlin K. 

Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism 

during high-intensity exercise. 

Int J Sport Nutr. 1999 Jun;9(2):166-80. 


36: Abe K, Matsuo Y, Kadekawa J, Inoue S, Yanagihara T. 

Effect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic 

acidosis, and stroke-like episodes (MELAS): evaluation by noninvasive tissue oximetry. 

J Neurol Sci. 1999 Jan 1;162(1):65-8. 


37: Piotrowski P, Ostrowski RP, Pankowska T, Smialek M. 

[The effect of coenzyme Q10 on lactate acidosis at the beginning of experimental 



433

cerebral ischemia in rats after the use of endothelin 1 (preliminary results)] 

Neurol Neurochir Pol. 1998 Nov-Dec;32(6):1397-404. Polish. 


38: Rowland MA, Nagley P, Linnane AW, Rosenfeldt FL. 

Coenzyme Q10 treatment improves the tolerance of the senescent myocardium to pacing 

stress in the rat. 

Cardiovasc Res. 1998 Oct;40(1):165-73. 


39: Palomaki A, Malminiemi K, Solakivi T, Malminiemi O. 

Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex 

vivo. 

J Lipid Res. 1998 Jul;39(7):1430-7. 


40: Singh RB, Niaz MA, Rastogi V, Rastogi SS. 

Coenzyme Q in cardiovascular disease. 

J Assoc Physicians India. 1998 Mar;46(3):299-306. Review. 


41: Lund EL, Quistorff B, Spang-Thomsen M, Kristjansen PE. 

Effect of radiation therapy on small-cell lung cancer is reduced by ubiquinone intake. 

Folia Microbiol (Praha). 1998;43(5):505-6. 


42: Ostrowski RP, Piotrowski P, Pankowska T, Smialek M. 

Evaluation of morphological changes after treatment with coenzyme Q10 (CoQ10) in 

endothelin-1 induced experimental ischemia in the rat. 

Folia Neuropathol. 1998;36(3):185-8. 


43: Dlugosz A, Sawicka E. 

The chemoprotective effect of coenzyme Q on lipids in the paint and lacquer industry 

workers. 

Int J Occup Med Environ Health. 1998;11(2):153-63. 


N-Acetylcysteine (NAC) - 40 STUDIES 



434

1. Hum Exp Toxicol. 2003 Aug;22(8):453-8. 

Successful treatment of acetaminophen overdose associated with hepatic failure. 

Pajoumand A, Jalali N, Abdollahi M, Shadnia S. Poison Centre, 

Loghman-Hakim Hospital, Faculty of Medicine, Shaheed-Beheshti University of 

Medical Science, Tehran, Iran. 

2. Klin Med (Mosk). 2003;81(4):58-60. 

[Safety of paracetamol as a representative of nonprescription analgetics-antipyretics] 


Makar'iants ML. 

3. Hepatology. 2002 Apr;35(4):876-82. 

Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. 

Schmidt LE, Dalhoff K, Poulsen HE. 

Departments of Hepatology and Clinical Pharmacology, Rigshospitalet, University 

Hospital, Copenhagen, Denmark. lars.schmidt@dadlnet.dk 

4. Exp Toxicol Pathol. 2002 Feb;53(6):489-500. 

Acetaminophen hepatotoxicity and mechanisms of its protection by N-acetylcysteine: a 

study of Hep3B cells. 

Manov I, Hirsh M, Iancu TC. 

Pediatric Research and Electron Microscopy Unit, Bruce Rappaport Faculty of Medicine, 

Technion-Israel Institute of Technology, Haifa, Israel. 

5. J Ocul Pharmacol Ther 1998 Aug;14(4):345-55 

Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and 

N-acetylcysteine. 

Zhao C, Shichi H. 

Department of Ophthalmology, Kresge Eye Institute, Wayne State University School of 

Medicine, Detroit, Michigan, USA. 



435

6. Metabolic activation and paracetamol hepatotoxicity - An update on the management 

of paracetamol (acetaminophen) poisoning. 

Chan T.Y.K.; Critchley J.A.J.H.; Chan J.C.N.; Tomlinson B. 

Department of Clinical Pharmacology, Chinese University of Hong Kong, Prince of 

Wales Hospital,Shatin Hong Kong Journal of the Hong Kong Medical Association (J. 

HONG KONG MED. ASSOC. ) (Hong Kong) 1994, 46/1 (87-92) 

7. Intravenous N-acetylcysteine, hepatotoxicity and plasma glutathione S-transferase in 

patients with paracetamol overdosage. 

Beckett GJ; Donovan JW; Hussey AJ; Proudfoot AT; Prescott LF 

University Department of Clinical Chemistry, Royal Infirmary, Edinburgh, Scotland, UK. 

Human & experimental toxicology (ENGLAND) May 1990, 9 (3) p183-6, 

8. A comparison of the protective effects of N-acetyl-cysteine and Scarboxymethylcysteine 

against paracetamol-induced hepatotoxicity. 

Ioannides C; Hall DE; Mulder DE; Steele CM; Spickett J; Delaforge M; 

Parke DV Toxicology (NETHERLANDS) Nov 1983, 28 (4) p313-21, 

9. Cimetidine protects against acetaminophen toxicity. 

Jackson J.E. 

Sect. Clin. Pharmacol., Dept. Pharmacol., Univ. Arizona Health Sci. Cent., 

Tucson, AZ 85724 United States Life Sciences ( LIFE SCI. ) (United Kingdom) 1982, 

31/1 (31-35) 

10. Effects of aspirin and acetaminophen on the liver. 

Zimmerman H.J. George Washington Univ. Med. Cent. 

Washington, D.C. 20037 United States Archives of Internal Medicine ( ARCH. INTERN. 

MED. ) (United States) 1981, 141/3 (333-342) 

11. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. 

Prescott L.F.; Park J.; Ballantyne A.; et al. 

Reg. Poisoning Treatm. Cent., Roy. Infirm., Edinburgh United Kingdom Lancet ( 

LANCET ) (United Kingdom) 1977, 2/8035 (432-434) 



436

12. The disposition and kinetics of intravenous N-acetylcysteine in patients with 

paracetamol overdosage 

Prescott L.F.; Donovan J.W.; Jarvie D.R.; Proudfoot A.T. 

University Department of Clinical Pharmacology, Royal Infirmary, Edinburgh EH3 97W 

United Kingdom European Journal of Clinical Pharmacology ( EUR. J. CLIN. 

PHARMACOL. ) ( Germany) 1989, 37/5 (501-506) 

13. Acetaminophen hepatotoxicity and malnutrition. 

Newman T.J.; Bargman G.J. 

Dept. Ped., Univ. Wisconsin Hosp., Madison, Wis. 53706 United States American 

Journal of Gastroenterology ( AM. J. GASTROENTEROL. ) (United States) 1979, 72/6 

(647-650) 

ALCOHOL 

14. Protective effect of N-acetylcysteine on rat liver cell membrane during methanol 

intoxication. 

Dobrzynska I, Skrzydlewska E, Kasacka I, Figaszewski Z. 

Institute of Chemistry, University in Bialystok, Poland. 

J Pharm Pharmacol. 2000 May;52(5):547-52 

ALS 

15. Neurobiol Dis. 2003 Aug;13(3):213-21. 

Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated 

with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. 

Beretta S, Sala G, Mattavelli L, Ceresa C, Casciati A, Ferri A, Carri MT, Ferrarese C. 

Department of Neuroscience and Biomedical Technologies, University of Milano- 

Bicocca, San Gerardo Hospital, via Donizetti, 106, 20052, Monza (MI), Italy. 

16. Neurochem Int. 2001 Aug;39(2):141-9. 

Glutathione elevation and its protective role in acrolein-induced protein damage in 

synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative 

disease. 



437

Pocernich CB, Cardin AL, Racine CL, Lauderback CM, Butterfield DA. Department of 

Chemistry, 125 Chemistry-Physics Building, University of Kentucky, Lexington, KY 

40506, USA. 

17. J Neurochem. 2001 Jan;76(1):224-33. 

N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell 

cytotoxicity: effects on beta-amyloid secretion and tau phosphorylation. 

Olivieri G, Baysang G, Meier F, Muller-Spahn F, Stahelin HB, Brockhaus M, Brack C. 

Neurobiology Laboratory, Psychiatric University Hospital, Basel, Switzerland. 

gianfranco.olivieri@pukbasel.ch 

18. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal 

model of familial amyotrophic lateral sclerosis. 

Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI. 

Neurology Service, Massachusetts General Hospital and Harvard Medical School, 

Boston, USA. Neuroreport 2000 Aug 3;11(11):2491-3 

19. Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-Lcysteine. 

Henderson JT, Javaheri M, Kopko S, Roder JC. 

Samuel Lunenfeld Research Institute, Program in Development and Fetal Health, Mount 

Sinai Hospital, Toronto, Ontario, Canada. J Neurosci 1996 Dec 1;16(23):7574-82 

CANCER 

20. Cancer Res. 2003 Jun 15;63(12):3413-7. 

2-Deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is 

mediated via disruptions in thiol metabolism. 

Lin X, Zhang F, Bradbury CM, Kaushal A, Li L, Spitz DR, Aft RL, Gius D. 

Section of Cancer Biology, Mallinckrodt Institute of Radiology, Washington University 

School of Medicine, St. Louis, Missouri, USA. 

21. Int J Biol Markers. 2003 Jan-Mar;18(1):70-4. 

Antiangiogenic activity of chemopreventive drugs. 



438

Pfeffer U, Ferrari N, Morini M, Benelli R, Noonan DM, Albini A. Laboratory of 

Molecular Oncology, National Cancer Research Institute, Genoa, Italy. 

ulrich.pfeffer@istge.it 

22. J Environ Pathol Toxicol Oncol. 2003;22(1):17-28. 

Reactive oxygen species, antioxidant mechanisms, and serum cytokine levels in cancer 

patients: impact of an antioxidant treatment. 

Mantovani G, Maccio A, Madeddu C, Mura L, Massa E, Gramignano G, Lusso MR, 

Murgia V, Camboni P, Ferreli L. 

Department of Medical Oncology, University of Cagliari, Cagliari, Italy. 

mantovan@pacs.unica.it 

23. Cell Mol Life Sci. 2003 Jan;60(1):6-20. 

Molecular mechanisms of N-acetylcysteine actions. 

Zafarullah M, Li WQ, Sylvester J, Ahmad M. 

Departement de Medecine, Centre de Recherche du Centre Hospitalier de l'Universite de 

Montreal, Lab. K-5255 Mailloux, Hopital Notre-Dame du CHUM, 1560 Sherbrooke est, 

Montreal, Quebec H2L 4M1, Canada. Muhammad.Zafarullah@umontreal.ca 

24. Toxicol Pathol. 2003 Jan-Feb;31(1):39-51. 

Slowing tumorigenic progression in TRAMP mice and prostatic carcinoma cell lines 

using natural anti-oxidant from spinach, NAO--a comparative study of three antioxidants. 

Nyska A, Suttie A, Bakshi S, Lomnitski L, Grossman S, Bergman M, Ben-Shaul V, 

Crocket P, Haseman JK, Moser G, Goldsworthy TL, Maronpot RR. 

Laboratory of Experimental Pathology, National Institute of Environmental Health 

Sciences (NIEHS), Research Triangle Park, North Carolina 27709, USA. 

nyska@niehs.nih.gov 

25. Toxicol Lett. 2003 Mar 3;138(3):243-51. 

Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta 

effect and protection by N-acetylcysteine. 

Malaplate-Armand C, Ferrari L, Masson C, Siest G, Batt AM. Centre du Medicament, 

Inserm U525, Faculte de Pharmacie, Universite Henri Poincare Nancy I, 30 rue Lionnois, 

54000 Nancy, France. 



439

26. J Neurooncol. 2002 Jan;56(2):109-17. 

Mitogen activated protein kinase activation and oxidant signaling in astrocytoma cells. 

Kuruganti PA, Wurster RD, Lucchesi PA. Neuroscience Program, Department of 

Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA. 

pkuruganti@yahoo.com 

27. Ann N Y Acad Sci. 2002 Nov;973:555-8. 

Type I insulin-like growth factor receptor expression on colorectal adenocarcinoma cell 

lines is decreased in response to the chemopreventive agent N-acetyl-l-cysteine. 

Kelly RG, Nally K, Shanahan F, O'Connell J. Department of Medicine, University 

College Cork, Ireland. 

28. Nutr Cancer. 2002;43(1):59-66. 

Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor 

multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) transgenic 

mice but has no impact on malignant progression. 

Martin KR, Saulnier MJ, Kari FW, Barrett JC, French JE. 

Transgenic Carcinogenesis Unit, Laboratory of Environmental Carcinogenesis and 

Mutagenesis, National Institute of Environmental Health Sciences, National Institutes of 

Health, Research Triangle Park, NC 27709, USA. krm12@psu.edu 

29. Acta Biol Hung. 2002;53(3):293-8. 

N-acetil-l-cysteine and 2-amino-2-thiiazoline N-acetyl-l-cysteinate as a possible cancer 

chemopreventive agents in murine models. 

Simkeviciene V, Straukas J, Uleckiene S. Institute of Biochemistry, Vilnius, Lithuania. 

vitalija@bchi.lt 

30. J Nutr. 2002 Aug;132(8):2151-6. N-acetylcysteine, vitamin C and vitamin E diminish 

homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. 

Huang RF, Huang SM, Lin BS, Hung CY, Lu HT. 

Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, 

ROC. rweifen@mails.fju.edu.tw 

31. J Urol. 2002 Aug;168(2):780-5. 



440

N-acetylcysteine augments the cellular redox changes and cytotoxic activity of 

internalized mycobacterium bovis in human bladder cancer cells. 

Pook SH, Esuvaranathan K, Mahendran R. 

Department of Surgery, National University of Singapore, Singapore. 

32. Carcinogenesis. 2002 Jun;23(6):993-1001. 

Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma 

development in a murine model by N-acetylcysteine. 

Seril DN, Liao J, Ho KL, Yang CS, Yang GY. 

Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical 

Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, 

NJ 08854-8020, USA. 

33. Oncol Rep. 2002 Jul-Aug;9(4):887-96. 

Phase II study of subcutaneously administered interleukin-2 in combination with 

medroxyprogesterone acetate and antioxidant agents as maintenance treatment in 

advanced cancer responders to previous chemotherapy. 

Mantovani G, Maccio A, Madeddu C, Mulas C, Massa E, Astara G, Ferreli L, Mudu MC, 

Gramignano G, Murgia V, Lusso MR, Mocci M, Cardia A, Mura L. 

Department of Medical Oncology, University of Cagliari, Italy. mantovan@pacs.unica.it 

An open, non-randomized phase II study was carried out including patients with 

34. Int J Cancer. 2002 Apr 1;98(4):493-7. 

Effects of N-acetylcysteine in an esophageal carcinogenesis model in rats treated with 

diethylnitrosamine and diethyldithiocarbamate. 

Balansky RM, Ganchev G, D'Agostini F, De Flora S. 

National Center of Oncology, Sofia, Bulgaria. 

35. Cancer Epidemiol Biomarkers Prev. 2002 Feb;11(2):167-75. 

Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in 

smokers. 



441

Van Schooten FJ, Nia AB, De Flora S, D'Agostini F, Izzotti A, Camoirano A, Balm AJ, 

Dallinga JW, Bast A, Haenen GR, Van't Veer L, Baas P, Sakai H, Van Zandwijk N. 

Department of Health Risk Analysis and Toxicology, Maastricht University, The 

Netherlands. 

36. Cancer Res. 2002 Jan 1;62(1):2-7. 

Inhibition of benzo(a)pyrene-induced lung tumorigenesis in A/J mice by dietary Nacetylcysteine 

conjugates of benzyl and phenethyl isothiocyanates during the 

postinitiation phase is associated with activation of mitogen-activated protein kinases and 

p53 activity and induction of apoptosis. 

Yang YM, Conaway CC, Chiao JW, Wang CX, Amin S, Whysner J, Dai W, Reinhardt J, 

Chung FL. 

Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, 

Valhalla, New York 10595, USA. 

37. FASEB J. 2002 Jan;16(1):2-14. 

Angioprevention': angiogenesis is a common and key target for cancer chemopreventive 

agents. 

Tosetti F, Ferrari N, De Flora S, Albini A. 

Molecular Biology Laboratory, National Cancer Research Institute (IST), Genova, Italy. 

38. Cancer Res. 2001 Nov 15;61(22):8171-8. 

Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral 

N-acetylcysteine. 

Albini A, Morini M, D'Agostini F, Ferrari N, Campelli F, Arena G, Noonan DM, Pesce 

C, De Flora S. 

National Institute for Cancer Research (IST), c/o Advanced Biotechnology Center, Largo 

R. Benzi 10, I-16132 Genoa, Italy. albini@vega.cba.unige.it 

39. Biogerontology. 2001;2(1):55-60. 

N-Acetyl-L-Cystein downregulates beta-amyloid precursor protein gene transcription in 

human neuroblastoma cells. 

Studer R, Baysang G, Brack C. 



442

Laboratory of Molecular Gerontology, Basel University, Psychiatric University Clinic, 

Switzerland. Rolf.Studer@Actelion.Com 

40. Cancer Res. 2001 Nov 1;61(21):7868-74. 

Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant 

against bone marrow toxicity after intracarotid administration of alkylators, with or 

without glutathione depletion in a rat model. 

Neuwelt EA, Pagel MA, Hasler BP, Deloughery TG, Muldoon LL. 

Alpha Lipoic Acid – 20 STUDIES 

1. Endocr Rev. 2002 Oct;23(5):599-622. 

Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 

diabetes. 

Evans JL, Goldfine ID, Maddux BA, Grodsky GM. 

University of California at San Francisco, San Francisco, California 94143, USA. 

jevansphd@earthlink.net 

2. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10. 

Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct 

interaction with DNA. Lee HA, Hughes DA. 

Immunology Group, Nutrition and Consumer Science Division, Institute of Food 

Research, Norwich Research Park, Colney, Norwich, Norfolk NR4 7UA, UK. 

3. FASEB J. 2001 Nov;15(13):2423-32. 

Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion 

molecule expression in human aortic endothelial cells. 

Zhang WJ, Frei B. 

Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA. 

4. Drug Metab Rev. 1998 May;30(2):245-75. 

alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal 

transduction and protects against oxidative injury. 

Packer L. 

Department of Molecular and Cell Biology, University of California, Berkeley 94720- 

3200, USA. 



443

5. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1709-15. 

Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. 

Suzuki YJ, Aggarwal BB, Packer L. 

Department of Molecular & Cell Biology, University of California, Berkeley 94720. 

AGING 

6. J Alzheimers Dis. 2003 Jun;5(3):229-39. 

Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha 

lipoic acid. 

Lovell MA, Xie C, Xiong S, Markesbery WR. 

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. 


Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse hippocampal 

HT22 cells. 

Pirlich M, Kiok K, Sandig G, Lochs H, Grune T. 

Department of Gastroenterology and Hepatology, University Hospital Charite, 

Humboldt-University Berlin, Schumannstr. 20/21, 10098, Berlin, Germany. 

8. Neurosci Lett. 2002 Mar 15;321(1-2):100-4. 

Beneficial effects of alpha-lipoic acid plus vitamin E on neurological deficit, reactive 

gliosis and neuronal remodeling in the penumbra of the ischemic rat brain. 

Gonzalez-Perez O, Gonzalez-Castaneda RE, Huerta M, Luquin S, Gomez-Pinedo U, 

Sanchez-Almaraz E, Navarro-Ruiz A, Garcia-Estrada J. 

Division de Neurociencias, Centro de Investigacion Biomedica de Occidente (CIBO) del 

Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Guadalajara Jalisco 

44340, Mexico. 

9. Free Radic Biol Med. 1997;22(1-2):359-78. 

Neuroprotection by the metabolic antioxidant alpha-lipoic acid. 

Packer L, Tritschler HJ, Wessel K. 


3200, USA. 

CATARACTS 

10. Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):44-50. 

Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gammalinolenic 

acid conjugate. 

Borenshtein D, Ofri R, Werman M, Stark A, Tritschler HJ, Moeller W, Madar Z. 

Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew 

University of Jerusalem, Rehovot 76100, Israel. 

11. Biochem Mol Biol Int. 1998 Oct;46(3):585-95. 

Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione 



444

concentrations in lens in model diabetic cataractogenesis. 

Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. 

Department of Biochemistry, University of Western Ontario, London, Canada. 

12. Biochem Biophys Res Commun. 1996 Apr 16;221(2):422-9. 

Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract 

formation in newborn rats. 

Maitra I, Serbinova E, Tritschler HJ, Packer L. 

Department of Molecular and Cell Biology, University of California, Berkeley, 94720- 

3200, USA. 


Modelling cortical cataractogenesis 17: in vitro effect of a-lipoic acid on glucose-induced 

lens membrane damage, a model of diabetic cataractogenesis. 

Kilic F, Handelman GJ, Serbinova E, Packer L, Trevithick JR. 

Dept. of Biochemistry, University of Western Ontario, London, Canada. 

DIABETES 

14. Vnitr Lek. 2002 Jun;48(6):534-41. 

[Autonomic neuropathy in diabetics, treatment possibilities] [Article in Czech] 

Lacigova S, Rusavy Z, Cechurova D, Jankovec Z, Zourek M. I. 

interni klinika Fakultni nemocnice, Plzen. 

15. Diabetes Metab Res Rev. 2002 May-Jun;18(3):176-84. 

Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment 

perspectives. 

van Dam PS. 

Department of Internal Medicine and Endocrinology, University Medical Center, Utrecht, 

The Netherlands. P.S.vanDam@digd.azu.nl 

16. Endocr Pract. 2002 Jan-Feb;8(1):29-35. 

Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlledrelease 

formulation of alpha-lipoic acid. 

Evans JL, Heymann CJ, Goldfine ID, Gavin LA. 

Northern California Diabetes Institute, Seton Medical Center, Dale City, CA 94015, 

USA. 

16. Nutrition. 2001 Oct;17(10):888-95. 

Molecular aspects of lipoic acid in the prevention of diabetes complications. 

Packer L, Kraemer K, Rimbach G. 

Department of Molecular Pharmacology and Toxicology, School of Pharmacy, 

University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90098-9121, 

USA. packerresearch@aol.com 



445

17. J Am Coll Nutr. 2001 Oct;20(5 Suppl):363S-369S; discussion 381S-383S. 

Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes. 

Ruhe RC, McDonald RB. 

Department of Nutrition, University of California, Davis 95616-8669, USA. 

18. Metabolism. 2001 Aug;50(8):868-75. 

The effects of treatment with alpha-lipoic acid or evening primrose oil on vascular 

hemostatic and lipid risk factors, blood flow, and peripheral nerve conduction in the 

streptozotocin-diabetic rat. 

Ford I, Cotter MA, Cameron NE, Greaves M. 

Departments of Medicine & Therapeutics, University of Aberdeen, Aberdeen, Scotland. 

19. Diabetes Technol Ther. 2000 Autumn;2(3):401-13. 

Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in 

patients with type 2 diabetes. 

Evans JL, Goldfine ID. 

Medical Research Institute, San Bruno, California 94066, USA. jevans@lipoic.com 

20. Free Radic Biol Med. 2001 Jul 1;31(1):53-61. 

Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric 

oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative 

stress. 

Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. 

Universitatsklinikum Hamburg-Eppendorf Klinik und Poliklinik fur Innere Medizin, 

Abteilung Kardiologie, Hamburg, Germany. heitzer@uke.uni-hamburg.de 

Superroxide Dismutase – 51 STUDIES 

1. Cai Q, Shu XO, Wen W, et al. Genetic polymorphism in the manganese superoxide 

dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai 

Breast Cancer Study. Breast Cancer Res. 2004;6(6):R647-R55. 

2. Ough M, Lewis A, Zhang Y, et al. Inhibition of cell growth by overexpression of 

manganese superoxide dismutase (MnSOD) in human pancreatic carcinoma. Free Radic 

Res. 2004 Nov;38(11):1223-33. 

3. Manju V, Balasubramanian V, Nalini N. Oxidative stress and tumor markers in 

cervical cancer patients. J Biochem Mol Biol Biophys. 2002 Dec;6(6):387-90. 

4. Lund-Olesen K. Etiology of multiple sclerosis: role of superoxide dismutase. Med 

Hypotheses. 2000 Feb;54(2):321-2. 



446

5. Choi J, Rees HD, Weintraub ST, et al. Oxidative modifications and aggregation of 

Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol 

Chem. 2005 Mar 25;280(12):11648-55. 

6. Hattori N. Etiology and pathogenesis of Parkinsonâ€s disease: from mitochondrial 

dysfunctions to familial Parkinsonâ€s disease. Rinsho Shinkeigaku. 2004 Apr;44(4- 

5):241-62. 

7. Ueda K, Ogata M. Levels of erythrocyte superoxide dismutase activity in Japanese 

people. Acta Med Okayama. 1978 Dec;32(6):393-7. 

8. Cutler RG. Antioxidants and longevity of mammalian species. Basic Life Sci. 

1985;35:15-73. 

9. Cutler RG. Antioxidants and aging. Am J Clin Nutr. 1991 Jan;53(1 Suppl):373S-9S. 

10. Life Extension-sponsored study #1. Changes in serum levels of superoxide dismutase 

and catalase in humans after dietary SODzymeâ„¢ supplementation. 

11. Knight JA. Free radicals: their history and current status in aging and disease. Ann 

Clin Lab Sci. 1998 Nov-Dec; 28(6):331-46. 

12. Reedy EA. The discovery of retrolental fibroplasia and the role of oxygen: a historical 

review, 1942-1956. Neonatal Netw. 2004 Mar;23(2):31-8. 

13. Huang H, Manton KG. The role of oxidative damage in mitochondria during aging: a 

review. Front Biosci. 2004 May 1;91100-17. 

14. Inoue M, Sato EF, Nishikawa M, et al. Mitochondrial generation of reactive oxygen 

species and its role in aerobic life. Curr Med Chem. 2003 Dec;10(23):2495-505. 

15. Ahsan H, Ali A, Ali R. Oxygen free radicals and systemic autoimmunity. Clin Exp 

Immunol. 2003 Mar;131(3):398-404. 

16. Allen RG, Tresini M. Oxidative stress and gene regulation. Free Radic Biol Med. 

2000 Feb 1;28(3):463-99. 

17. Kashiwagi K, Shinkai T, Kajii E, Kashiwagi A. The effects of reactive oxygen 

species on amphibian aging. Comp Biochem Physiol C Toxicol Pharmacol. 2005 

Feb;140(2):197-205. 

18. Lishnevskaia VL. The role of free radicals oxidation in the deterioration of 

haemovascular homeostasis in aging. Adv Gerontol. 2004;13:52-7. 

19. Karatas F, Ozates I, Canatan H, et al. Antioxidant status & lipid peroxidation in 

patients with rheumatoid arthritis. Indian J Med Res. 2003 Oct;118:178-81. 



447

20. Mazzetti I, Grigolo B, Pulsatelli L, et al. Differential roles of nitric oxide and oxygen 

radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis. Clin Sci 

(Lond). 2001 Dec;101(6):593-9. 

21. Bagis S, Tamer L, Sahin G, et al. Free radicals and antioxidants in primary 

fibromyalgia: an oxidative stress disorder? Rheumatol Int. 2005 Apr;25(3):188-90. 

22.Abou-Seif MA, Youssef AA. Evaluation of some biochemical changes in diabetic 

patients. Clin Chim Acta. 2004 Aug 16;346(2):161-70. 

23. Cai Q, Shu XO, Wen W, et al. Genetic polymorphism in the manganese superoxide 

dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai 

Breast Cancer Study. Breast Cancer Res. 2004;6(6):R647-R55. 

24. Ough M, Lewis A, Zhang Y, et al. Inhibition of cell growth by overexpression of 

manganese superoxide dismutase (MnSOD) in human pancreatic carcinoma. Free Radic 

Res. 2004 Nov;38(11):1223-33. 

25. Manju V, Balasubramanian V, Nalini N. Oxidative stress and tumor markers in 

cervical cancer patients. J Biochem Mol Biol Biophys. 2002 Dec;6(6):387-90. 

26. Lund-Olesen K. Etiology of multiple sclerosis: role of superoxide dismutase. Med 

Hypotheses. 2000 Feb;54(2):321-2. 

27. Choi J, Rees HD, Weintraub ST, et al. Oxidative modifications and aggregation of 

Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol 

Chem. 2005 Mar 25;280(12):11648-55. 

28. Hattori N. Etiology and pathogenesis of Parkinson’s disease: from mitochondrial 

dysfunctions to familial Parkinson’s disease. Rinsho Shinkeigaku. 2004 Apr;44(4-5):241- 

62. 

29. Ueda K, Ogata M. Levels of erythrocyte superoxide dismutase activity in Japanese 

people. Acta Med Okayama. 1978 Dec;32(6):393-7. 

30. Cutler RG. Antioxidants and longevity of mammalian species. Basic Life Sci. 

1985;35:15-73. 

31. Cutler RG. Antioxidants and aging. Am J Clin Nutr. 1991 Jan;53(1 Suppl):373S-9S. 

32. Life Extension-sponsored study #1. Changes in serum levels of superoxide dismutase 

and catalase in humans after dietary SODzyme supplementation. 

33. Bauerova K, Bezek A. Role of reactive oxygen and nitrogen species in 

etiopathologenesis of rheumatoid arthritis. Gen Physiol Biophys. 1999 Oct;18 Spec 

No:15-20. 



448

34. Hadjigogos K. The role of free radicals in the pathogenesis of rheumatoid arthritis. 

Panminerva Med. 2003 Mar;45(1):7-13. 

35. Life Extension-sponsored study #2. Effects of oral SODzyme administration on 

pain scores in human subjects with arthritis. 

36. Bijlsma JW, van de Putte LB. Non-steroidal anti-inflammatory agents (NSAID’s) 

with lesser side effects by selective inhibition of cyclo-oxygenase-2. Ned Tijdschr 

Geneeskd. 1998 Aug 1;142(31):1762-5. 

37. Bjarnason I, Zanelli G, Smith T, et al. The pathogenesis and consequence of nonsteroidal 

anti-inflammatory drug induced small intestinal inflammation in man. Scand J 

Rheumatol Suppl. 1987;64:55-62. 

38. Lazzaroni M, Bianchi PG. Gastrointestinal side effects of traditional non-steroidal 

anti-inflammatory drugs and new formulations. Aliment Pharmacol Ther. 2004 Jul;20 

Suppl 248-58. 

39. Beaugerie L, Thiefin G. Gastrointestinal complications related to NSAIDs. 

Gastroenterol Clin Biol. 2004 Apr;28 Spec No 3C62-C72. 

40. Rudic RD, Brinster D, Cheng Y, et al. COX-2 derived prostacyclin modulates 

vascular remodeling. Circ Res. 2005 May 19. 

41. Evensen S, Spigset O, Slordal L. COX-2 inhibitors—one step forward and two steps 

back. Tidsskr Nor Laegeforen. 2005 Apr 7;125(7):875-8. 

42. Meier P, Meyer zu SA, Burnier M. Selective COX-2 inhibitors and cardiovascular 

risk. Rev Med Suisse. 2005 Feb 23;1(8):543-50. 

43. Vouldoukis I, Conti M, Krauss P, et al. Supplementation with gliadin-combined plant 

superoxide dismutase extract promotes antioxidant defences and protects against 

oxidative stress. Phytother Res. 2004 Dec;18(12):957-62. 

44. Vouldoukis I, Lacan D, Kamate C, et al. Antioxidant and anti-inflammatory 

properties of a Cucumis melo LC. extract rich in superoxide dismutase activity. J 

Ethnopharmacol. 2004 Sep;94(1):67-75. 

45. Flohe L. Superoxide dismutase for therapeutic use: clinical experience, dead ends and 

hopes. Mol Cell Biochem. 1988 Dec;84(2):123-31. 

46. Muth CM, Glenz Y, Klaus M, et al. Influence of an orally effective SOD on 

hyperbaric oxygen-related cell damage. Free Radic Res. 2004 Sep;38(9):927-32. 

47. Dolegowska B, Chlubek D. Isoprostanes—new possibility of the oxidative stress 

estimation. Przegl Lek. 2004;61(12):1410-4. 



449

48.Caruso C, Lio D, Cavallone L, Francheschi C. Aging, longevity, inflammation, and 

cancer. Ann NY Acad Sci. 2004 Dec;1028:1-13. 

49. Kortekangas P, Peltola O, Toivanen A, Aro HT. Synovial fliud L-lactic acid in acute 

arthritis of the adult knee joint. Scand J Rheumatol. 1995;24(2):98-101. 

50. Kong Y, et al. korea Cancer Center Hospital. (2004) Influence of an orally effective 

superoxide dismutase (GliSODin®) on strenuous exercise-induced changes of blood 

antioxidant enzymes and plasma lactate. Poster presentation at the AACC, July 2004. 

51. Chenal H, Davit-Spraul A, Legrand J, et al. Restored antioxidant circulating 

capacities in west African AIDS patients receiving an antioxidant nutraceutical Cucumis 

melo extract rich in Superoxide dismutase activity (GliSODin®). [Submitted for 

publication.] 

Taurine - 20 STUDIES 

Congestive Heart Failure 

1. Arzneimittelforschung. 1993 Mar;43(3):308-12. (Animal Study) 

Effects on heart membranes after taurine treatment in rabbits with congestive heart 

failure. 

Elizarova EP, Orlova TR, Medvedeva NV. 

Russian Academy of Medical Science, Cardiology Research Center, Moscow. 

2. Jpn Circ J. 1992 Jan;56(1):95-9. 

Usefulness of taurine in chronic congestive heart failure and its prospective application. 

Azuma J, Sawamura A, Awata N. 

Third Department of Internal Medicine, Osaka University Medical School, Japan. 

3. Kardiologiia. 1991 Jun;31(6):77-80. (Animal Study) 

[Use of taurine in the treatment of experimental congestive heart failure] 


Orlova TsR, Elizarova EP, Ryff IM, Fetisova NI, Mit'kina LI. 



450

4. Am Heart J. 1986 Dec;112(6):1278-84. (Animal Study) 

Beneficial effect of taurine in rabbits with chronic congestive heart failure. 

Takihara K, Azuma J, Awata N, Ohta H, Hamaguchi T, Sawamura A, Tanaka Y, 

Kishimoto S, Sperelakis N. 

5. Clin Cardiol. 1985 May;8(5):276-82. 

Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial. 

Azuma J, Sawamura A, Awata N, Ohta H, Hamaguchi T, Harada H, Takihara K, 

Hasegawa H, Yamagami T, Ishiyama T, et al. 

6. Res Commun Chem Pathol Pharmacol. 1984 Aug;45(2):261-70. (Animal Study) 

Beneficial effect of taurine on congestive heart failure induced by chronic aortic 

regurgitation in rabbits. 

Azuma J, Takihara K, Awata N, Ohta H, Sawamura A, Harada H, Kishimoto S. 

7. Clin Ther. 1983;5(4):398-408. 

Therapy of congestive heart failure with orally administered taurine. 

Azuma J, Hasegawa H, Sawamura A, Awata N, Ogura K, Harada H, Yamamura Y, 

Kishimoto S. 

8. Physiol Chem Phys. 1977;9(3):259-63. (Animal Study) 

A relation between myocardial taurine contest and pulmonary wedge pressure in dogs 

with heart failure. 

Newman WH, Frangakis CJ, Grosso DS, Bressler R. 

Hypertension 

9. Amino Acids. 2002;23(4):381-93. 

Treatment of hypertension with oral taurine: experimental and clinical studies. 

Militante JD, Lombardini JB. 

Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, 

Texas, USA. 



451


Taurine, cardiopulmonary hemodynamics, and pulmonary hypertension syndrome in 

broilers. 

Ruiz-Feria CA, Wideman RF Jr. 


cruizfe@hotmail.com 













13. Hypertens Res. 2000 May;23(3):277-84. 

Oral taurine supplementation prevents the development of ethanol-induced hypertension 

in rats. 

Harada H, Kitazaki K, Tsujino T, Watari Y, Iwata S, Nonaka H, Hayashi T, Takeshita T, 

Morimoto K, Yokoyama M. 

First Department of Internal Medicine, Kobe University School of Medicine, Japan. 

14. Can J Physiol Pharmacol. 1999 Oct;77(10):749-54. (Animal Study) 

Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, 

an animal model of insulin resistance. 

Anuradha CV, Balakrishnan SD. 



452

Department of Biochemistry, Annamalai University, Annamalai Nagar, Tamil Nadu, 

India. 


Plasma taurine levels in broilers with pulmonary hypertension syndrome induced by 

unilateral pulmonary artery occlusion. 

Ruiz-Feria CA, Beers KW, Kidd MT, Wideman RF Jr. 


cruizfe@comp.uark.edu 

16. J Hypertens. 1994 Jun;12(6):653-61. (Animal Study) 

Taurine amplifies renal kallikrein and prevents salt-induced hypertension in Dahl rats. 

Ideishi M, Miura S, Sakai T, Sasaguri M, Misumi Y, Arakawa K. 

Department of Internal Medicine, Fukuoka University School of Medicine, Japan. 

17. Cardiovasc Res. 1988 May;22(5):351-8. (Animal Study) 

Retardation of the development of hypertension in DOCA salt rats by taurine supplement. 

Inoue A, Takahashi H, Lee LC, Sasaki S, Kohno Y, Takeda K, Yoshimura M, Nakagawa 

M. 

2nd Department of Medicine, Kyoto Prefectural University of Medicine, Japan. 

18. Hypertension. 1987 Oct;10(4):383-9. 

Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats. 

Abe M, Shibata K, Matsuda T, Furukawa T. 

Department of Pharmacology, School of Medicine, Fukuoka University, Japan. 

19. Jpn Heart J. 1983 Jan;24(1):91-102. 

Decrease of urinary taurine in essential hypertension. 

Kohashi N, Katori R. 



453

Glucose Metabolism 

20. Amino Acids. 2002;22(1):27-38. 

Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats. 

Nandhini AT, Anuradha CV. 

Department of Biochemistry, Faculty of Science, Annamalai University, Tamil Nadu, 

India. 

Pycnogenol – 20 STUDIES 

1. J Sex Marital Ther. 2003 May-Jun;29(3):207-13. 

Treatment of erectile dysfunction with pycnogenol and L-arginine. 

Stanislavov R, Nikolova V. 

Seminological Laboratory SBALAG, Maichin Dom, Sofia, Bulgaria. rstanik@abv.bg 

2. Phytother Res. 2003 Jun;17(6):671-4. 

Pycnogenol prevents haemolytic injury in G6PD deficient human erythrocytes. 

Sharma SC, Sharma S, Gulati OP. 

Department of Pharmacology and Therapeutics, Trinity College, Dublin-2 Ireland. 

ssharma@tcd.ie 

3. J Biochem Mol Toxicol. 2003;17(3):193-9. 

Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic 

rats. 

Maritim A, Dene BA, Sanders RA, Watkins JB 3rd. 

Moi University Faculty of Health Sciences, Eldoret, Kenya. 

4. J Med Food. 2001 Winter;4(4):201-209. 



454

Pycnogenol((R)) in the Management of Asthma. 

Hosseini S, Pishnamazi S, Sadrzadeh SM, Farid F, Farid R, Watson RR. 

College of Public Health and School of Medicine, The University of Arizona, 1501 N. 

Campbell Ave., Tucson, AZ 85724. 

5. Phytother Res. 2003 Jan;17(1):66-9. 

Pycnogenol inhibits the release of histamine from mast cells. 

Sharma SC, Sharma S, Gulati OP. 

Department of Pharmacology and Therapeutics, Trinity College, Dublin-2, Ireland. 

ssharma@tcd.ie 

6. J Am Diet Assoc. 2003 Jan;103(1):67-72. 

Pycnogenol does not impact the antioxidant or vitamin C status of healthy young adults. 

Silliman K, Parry J, Kirk LL, Prior RL. 

Department of Biological Sciences (Program in Nutrition and Food Science), 

California State University, Chico 95929, USA. 

7. Int Ophthalmol. 2001;24(3):161-71. 

Pycnogenol for diabetic retinopathy. A review. 

Schonlau F, Rohdewald P. 

Institute of Pharmaceutical Chemistry, Westfalische Wilhelms Universitat Munster, 

Germany. 

8. Phytother Res. 2002 Sep;16(6):567-71. 

Treatment of melasma with Pycnogenol. 



455

Ni Z, Mu Y, Gulati O. 

Beijing PHT Nutriment Science Technology Development Co. Ltd, Xiyuan Hospital of 

China Academy of Traditional Chinese Medicine, Institute of Food Safety Control and 

Inspection, Ministry of Public Health, Beijing, P R China. 

9. Phytomedicine. 2002 Jul;9(5):414-8. 

Effect of PYCNOGENOL on the toxicity of heart, bone marrow and immune organs as 

induced by antitumor drugs. 

Feng WH, Wei HL, Liu GT. 

Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union of 

Medical College, Beijing, People's Republic of China. 

10. Phytomedicine. 2002 Jul;9(5):410-3. 

PYCNOGENOL chewing gum minimizes gingival bleeding and plaque formation. 

Kimbrough C, Chun M, dela Roca G, Lau BH. 

School of Dentistry, Loma Linda University, California, USA. 

11. J Atten Disord. 2002 Sep;6(2):49-60. 

An experimental comparison of Pycnogenol and methylphenidate in adults with 

Attention-Deficit/Hyperactivity Disorder (ADHD). 

Tenenbaum S, Paull JC, Sparrow EP, Dodd DK, Green L. 

The Attention Deficit Center in St. Louis 63141, MO. 

12. Growth Horm IGF Res. 2002 Feb;12(1):34-40. 

Kyolic and Pycnogenol increase human growth hormone secretion in 

genetically-engineered keratinocytes. 

Buz'Zard AR, Peng Q, Lau BH. 

Department of Microbiology and Molecular Genetics, School of Medicine, Loma Linda 

University, Loma Linda, CA 92350, USA. 



456

13. Brain Res Mol Brain Res. 2002 Jul 15;104(1):55-65. 

Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis. 

Peng QL, Buz'Zard AR, Lau BH. 

Department of Microbiology and Molecular Genetics, School of Medicine, Loma Linda 

University, Loma Linda, CA 92350, USA. 

14. Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68. 

A review of the French maritime pine bark extract (Pycnogenol), a herbal medication 

with a diverse clinical pharmacology. 

Rohdewald P. 

Institute Pharmaceutical Chemistry, Westfalische Wilhelms-Universitat Munster, 

Germany. rohdewa@uni-muenster.de 

15. Phytother Res. 2002 Mar;16 Suppl 1:S1-5. 

Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. 

Koch R. 

Wolfsschlucht 6a, 34117 Kassel, Germany. 

16. Phytother Res. 2001 Dec;15(8):698-704. 

Pycnogenol efficacy in the treatment of systemic lupus erythematosus patients. 

Stefanescu M, Matache C, Onu A, Tanaseanu S, Dragomir C, Constantinescu I, Schonlau 

F, Rohdewald P, Szegli G. 

Department of Immunology, Cantacuzino Institute, Splaiul Independentei 103, 

Bucharest, Romania. 


Treatment of vascular retinopathies with Pycnogenol. 

Spadea L, Balestrazzi E. 



457

Dipartimento di Discipline Chirurgiche, Cattedra di Clinica Oculistica, Facolta di 

Medicina e Chirurgia, Via Vetoio, Coppito 2, L'Aquila, Italy. 

18. Free Radic Biol Med. 2000 Jan 15;28(2):219-27. 

Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to 

human keratinocytes by inhibiting inducible ICAM-1 expression. 

Bito T, Roy S, Sen CK, Packer L. 


3200, USA. 

19. J Agric Food Chem. 2000 Nov;48(11):5630-9. 

Enzyme inhibition and protein-binding action of the procyanidin-rich french maritime 

pine bark extract, pycnogenol: effect on xanthine oxidase. 

Moini H, Guo Q, Packer L. 

Department of Molecular and Cell Biology, 251 Life Sciences Addition, University of 

California at Berkeley, Berkeley, California 94720-3200, USA. 

20. Phytomedicine. 2000 Oct;7(5):383-8. 

PYCNOGENOL in chronic venous insufficiency. 

Petrassi C, Mastromarino A, Spartera C. 

Cattedra e Scuola di Specializzazione in Chirurgia Vascolare, Dipartimento di Scienze 

Chirurgiche, Universita degli Studi di L'Aquila, Italy. chirvasc@cc.univaq.it 

Licorice Root – 21 STUDIES 

1. Armanini D, Bonanni G, Palermo M. Reduction of serum testosterone in men by 

licorice. N Engl J Med 1999 Oct 7;341(15):1158 

2. Bergner P. Adverse effects anecdotes. Medical Herbalism. 1998:10(4):15 



458

3. Blumenthal, M [editor] The Complete German Commission E Monographs: 

Therapeutic Guide to Herbal Medicines. Austin, Texas: American Botanical Council, 

1998 

4. Budavari, S. [editor]. The Merck Index. Eleventh Edition. Rahway, New Jersey, 1989 

5. De Klerk, G.J., Nieuwenhuis M.G., Beutler J.J. Hypokalemia and hypertension 

associated with use of liquorice flavoured chewing gum. BMJ 1997;314:731 (8 March) 

6. Sakamoto K, Wakabayashi K Inhibitory effect of glycyrrhetinic acid on testosterone 

production in rat gonads. Endocrinol Jpn 1988 Apr;35(2):333-42 

7. Takahashi K, Yoshino K, Shirai T, Nishigaki A, Araki Y, Kitao M. Effect of a 

traditional herbal medicine (shakuyaku-kanzo-to) on testosterone secretion in patients 

with polycystic ovary syndrome detected by ultrasound. Nippon Sanka Fujinka Gakkai 

Zasshi 1988 Jun;40(6):789-92 

8. Takeuchi T, Nishii O, Okamura T, Yaginuma T. Effect of paeoniflorin, glycyrrhizin 

and glycyrrhetic acid on ovarian androgen production. Am J Chin Med 1991;19(1):73-8 

9. Werbach M, and Murray M. Botanical Influences in Illness: A Sourcebook of Clinical 

Research. Tarzana, California: Third Line Press, 2000 

10. Yaginuma T, Izumi R, Yasui H, Arai T, Kawabata M Effect of traditional herbal 

medicine on serum testosterone levels and its induction of regular ovulation in 

hyperandrogenic and oligomenorrheic women [Article in Japanese]. Nippon Sanka 

Fujinka Gakkai Zasshi 1982 Jul;34(7):939-44 

11. Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in 

chronic hepatitis C patients. Cancer. 1997;79(8):1494-1500. 

12. Blumenthal M, ed. The Complete German Commission E Monographs: Therapeutic 

Guide to Herbal Medicines. Austin, Tx: American Botanical Council; 1998. 

13. Davis EA, Morris DJ. Medicinal uses of licorice through the millennia: good and 

plenty of it. Mol Cell Endocrinol. 1991;78:1-6. 

14. Edwards CR. Lessons from licorice. N Engl J Med. 1991;325:1242-1243. 

15. Fu Y, Hsieh TC, Guo J, Kunicki J, Lee MY. Darzynkiewicz Z. Wu JM. 

Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), 

causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. 

Biochemical & Biophysical Research Communications. 322(1):263-70, 2004 



459

16. Guide to Medicinal and Aromatic Plants. Licorice Review. Purdue University. 

Available at: http://www.hort.purdue.edu/newcrop/med-aro/factsheets/LICORICE.html. 

Accessed August 24, 2005. 

17. Memorial Sloan-Kettering Cancer Center. Licorice. Available at: 

http://www.mskcc.org/mskcc/html/11571.cfm?RecordID=416&tab=HC. Accessed 

August 25, 2005 

18. Miyake K, Tango T, Ota Y, et al. Efficacy of stronger neo-minophagen C compared 

between two doses administered three times a week on patients with chronic viral 

hepatitis. J Gastroenterol Hepatol. 2002 Nov;17(11):1198-204. 

19. Suzuki F, Schmitt DA, Utsunomiya T, et al. Stimulation of host resistance against 

tumors by glycyrrhizin, an active component of licorice roots. In Vivo. 1992;6:589-596. 

20. Tamir S, Eizenberg M, Somjen D, et al. Estrogenic and antiproliferative properties of 

glabridin from licorice in human breast cancer cells.Cancer Research. 60(20):5704-9, 

2000 

21. Wang ZY, Nixon DW. Licorice and cancer. Nutrition & Cancer. 39(1):1-11, 2001. 

BroccolI Stem - 26 STUDIES 

1. Beecher C. Cancer preventive properties of varieties of Brassica oleracea: a review. 

Am J Clin Nutr 1994;59(Suppl):1166S-70S. 

2. Ensminger AH, Esminger M. K. J. e. al. Food for Health: A Nutrition Encyclopedia. 

Clovis, California: Pegus Press; 1986. 

3. Fahey JW, Haristoy X, Dolan PM et al. Sulforaphane inhibits extracellular, 

intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents 

benzopyrene-induced stomach tumors. Proc Natl Acad Sci USA 2002 May 

28;99(11):7610-5. 

4. Fahey JW, Zhang Y, Talalay P. Broccoli sprouts: an exceptionally rich source of 

inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci 

1997;94:10367-72. 

5. Gao X, Dinkova-Kostova AT, Talalay P. Powerful and prolonged protection of human 

retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative 

damage: the indirect antioxidant effects of sulforaphane. Proc Natl Acad Sci USA 2001 

Dec 18;98(26):15221-6. 



460

6. Huxley RR, Neil HAW. The relation between dietary flavonol intake and coronary 

heart disease mortality: a meta-analysis of prospective cohort studies,. European Journal 

of Clinical Nutrition (2003) 57, 904-908. 

7. Jackson SJ, Singletary KW. Sulforaphane inhibits human mcf-7 mammary cancer cell 

mitotic progression and tubulin polymerization. J Nutr. 2004 Sep;134(9):2229-36. 

8. Johnson IT. Vegetables yield anticancer chemical. Institute of Food Research, News 

Release, May 10, 2004. http://www.ifr.ac.uk . 

9. Kawamori T, Tanaka T, Ohnishi M, et al. Chemoprevention of azoxymethane-induced 

colon carcinogenesis by dietary feeding of S-methyl methane thiosulfonate in male F344 

rats. Cancer Res 1995 Sep 15;55(18):4053-8. 

10. Kurilich AC, Tsau GJ, Brown A, et al. Carotene, tocopherol, and ascorbate contents 

in subspecies of Brassica oleracea. J Agric Food Chem 1999 Apr;47(4):1576-81. 

11. Kushad MM, Brown AF, Kurilich AC, et al. Variation of glucosinolates in vegetable 

crops of Brassica oleracea. J Agric Food Chem 1999 Apr;47(4):1541-8. 

12. McKillop DJ, Pentieva K, Daly D, McPartlin JM, Hughes J, Strain JJ, Scott JM, 

McNulty H. The effect of different cooking methods on folate retention in various foods 

that are amongst the major contributors to folate intake in the UK diet. Br J Nutr. 2002 

Dec;88(6):681-8. 

13. Meng Q, Goldberg ID, Rosen EM, Fan S. Inhibitory effects of Indole-3-carbinol on 

invasion and migration in human breast cancer cells. Breast Cancer Res Treat 2000 

Sep;63(2):147-52. 

14. Misiewicz I, Skupinska K, Kasprzycka-Guttman T. Sulforaphane and 2-oxohexyl 

isothiocyanate induce cell growth arrest and apoptosis in L-1210 leukemia and ME-18 

melanoma cells. . Oncol Rep. 2003 Nov-Dec;10(6):2045-50. 

15. Nestle M. Broccoli sprouts as inducers of carcinogen-detoxifying enzyme systems: 

clinical, dietary, and policy implications. Proc Natl Acad Sci USA 1997 Oct 

14;94(21):11149-51. 

16. Nutrition Action Healthletter. Nutrition Action Healthletter. Dec 1999. Volume 26, 

Number 10. 

17. Pattison DJ, Silman AJ, Goodson NJ, Lunt M, Bunn D, Luben R, Welch A, Bingham 

S, Khaw KT, Day N, Symmons DP. Vitamin C and the risk of developing inflammatory 

polyarthritis: prospective nested case-control study. Ann Rheum Dis. 2004 Jul;63(7):843- 

7. 



461

18. Stoewsand GS. Bioactive organosulfur phytochemicals in Brassica oleracea 

vegetables-- a review. Food Chem Toxicol 1995 Jun;33(6):537-43. 

19. Thimmulappa RK, Mai KH, Srisuma S et al. Identification of Nrf2-regulated genes 

induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. 

Cancer Res 2002 Sep 15;62(18):5196-5203. 

20. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the 

premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premestrual 

syndrome study group. Am J Obstet Gynecol 1998;179(2): 444-52. 

21. Vallejo F, Tomás-Barberán F A, García-Viguera C. Phenolic compounds content in 

edible parts of broccoli inflorescences after domestic cooking. J Sci Food Agric, 2003 

Volume 83(14). 

22. Wood, Rebecca. The Whole Foods Encyclopedia. New York, NY: Prentice-Hall 

Press; 1988. 

23. Wu L, Ashraf MH, Facci M, Wang R, Paterson PG, Ferrie A, Juurlink BH. Dietary 

approach to attenuate oxidative stress, hypertension, and inflammation in the 

cardiovascular system. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7094-9. Epub 

2004 Apr 21. 

24. Yurtsever E, Yardimci KT. The in vivo effect of a Brassica oleracea var. capitata 

extract on Ehrlich ascites tumors of MUS musculus BALB/C mice. Drug Metabol Drug 

Interact 1999;15(2-3):215-22. 

25. Zhang J, Hsu B A JC, Kinseth B A MA, Bjeldanes LF, Firestone GL. . Indole-3carbinol 

induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in 

human LNCaP prostate carcinoma cells. Cancer. 2003 Dec 1;98(11):2511-20. 

26. Zhang Y, Kensler TW, Cho CG, et al. Anticarcinogenic activities of sulforaphane and 

structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 1994 

Apr 12;91(8):3147-50. 

Lutein - 21 STUDIES 

1. Bungard RA, Ruban AV, Hibberd JM, Press MC, Horton P, Scoles JD. Unusual 

carotenoid composition and a new type of xanthophylls cycle in plants. Proc Natl Acad 

Sci USA. 1999 Feb 2;96(3):1135-9. 



462

2. Bernstein PS, Zhao DY, Sharifzadeh M, Ermakov IV, Gellerman W. Resonance 

Raman measurement of macular carotenoids in the living human eye. Arch Biochem 

Biophys. 2004 Oct 15;430(2):163- 9. 

3. Johnson EJ, Hammond BR, Yeum KJ, et al. Relation among serum and tissue con- 

centrations of lutein and zeaxanthin and macular pigment density. Am J Clin Nutr. 2000 

Jun;71(6):1555-62. 

4. Alves-Rodrigues A, Shao A. The science behind lutein. Toxicol Lett. 2004 Apr 

15;150(1):57-83. 

5. Berendschot TT, Broekmans WM, Klopping-Ketelaars IA, Kardinaal AF, Van Poppel 

F, Van Norren D. Lens aging in relation to nutritional determinants and possible risk 

factors for age-related cataract. Arch Opthalmol. 2002 Dec;120(12):1732-7. 

6. Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, 

supplementation improves visual function in patients with age-related cataracts: a 2-y 

double-blind, placebo-controlled pilot study. Nutrition. 2003 Jan;19(1):21-4. 

7. Mitchell P, Smith W, Cumming RG, Flood V, Rochtchina E, Wang JJ. Nutritional fac- 

tors in the development of age-related eye disease. Asia Pac J Clin Nutr. 2003;12 

Suppl:S5. 

8. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized 

trial of lutein and antioxidant supplementation in the intervention of atrophic age-related 

macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplement Trial). 

Optometry. 2004 Apr;75(4):216-30. 

9. Dagnelie G, Zorge IS, McDonald TM. Lutein improves visual function in some 

patients with retinal degeneration: a pilot study via the Internet. Optometry. 2000 

Mar;71(3):147-64. 

10. Nishino H, Murakosh M, Ii T, et al. Carotenoids in cancer chemoprevention. Cancer 

Metastasis Rev. 2002;21(3-4):257-64. 

11. Yeum KJ, Ahn SH, Rupp de Paiva SA, Lee-Kim YC, Krinsky NI, Russell RM. 

Correlation between carotenoid concentrations in serum and normal breast adipose 

tissue of women with benign breast tumor or breast cancer. J Nutr. 1998 

Nov;128(11):1920-6. 

12. Tonioli P, Van Kappel AL, Akhmedkhanov A, et al. Serum carotenoids and breast 

cancer. Am J Epidemiol. 2001 Jun 15;153(12):1142-7. 

13. Slattery ML, Benson J, Curtin K, Ma KN, Schaeffer D, Potter JD. Carotenoids and 

colon cancer. Am J Clin Nutr. 2000 Feb;71(2):575-82. 



463

14. Roodenburg AJ, Leenen R, van het Hof KH, Westrate JA, Tijburg LB. Amount of fat 

in the diet affects bioavailability of lutein esters but not of alpha-carotene, beta-carotene, 

and vitamin E in humans. Am J Clin Nutr. 2000 May;71(5):1187-93. 

15. Pratt S. Dietary prevention of age-related macular degeneration. J Am Optom Assoc. 

1999 Jan;70(1):39-47. 

16. Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and 

risk of cataract extraction in US men. Am J Clin Nutr. 1999 Oct;70(4):517-24. 

17. Chung HY, Rasmussen HM, Johnson EJ. Lutein bioavailability is higher from lutein- 

enriched eggs than from supplements or spinach in men. J Nutr. 2004 Aug;134(8):1887- 

93. 

18. Le Marchand L, Hankin JH, Bach F, et al. An ecological study of diet and lung cancer 

in the South Pacific. Int J Cancer. 1995 Sep 27;63(1):18-23. 

19. Kruger CL, Murphy M, DeFreitas Z, Pfannkuch F, Heimbach J. An innovative 

approach to the determination of safety for a dietary ingredient derived from a new 

source: case study using a crystalline lutein product. Food Chem Toxicol . 2002 

Nov;40(11):1535-49. 

20. Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance, and interac- 

tions between lutein and beta-carotene when administered to human adults in separate 

or combined oral doses. Am J Clin Nutr. 1995 Sep;62(3):604-10. 

21. Koonsvitsky BP, Berry DA, Jones MB, et al. Olestra affects serum concentrations of 

alpha-tocopherol and carotenoids but not vitamin D or vitamin K status in free-living 

subjects. J Nutr. 1997 Aug;127(8 Suppl):1636S-5S. 

Cabbage Leaf – 10 STUDIES 

1. Tadi K, Chang Y, Ashok BT, Chen Y, Moscatello A, Schaefer SD, Schantz SP, 

Policastro AJ, Geliebter J, Tiwari RK. 

3,3'-Diindolylmethane, a cruciferous vegetable derived synthetic anti-proliferative 

compound in thyroid disease. 

Biochem Biophys Res Commun. 2005 Nov 25;337(3):1019-25. Epub 2005 Oct 3. 

PMID: 16219298 

2. Suzui M, Inamine M, Kaneshiro T, Morioka T, Yoshimi N, Suzuki R, Kohno H, 

Tanaka T. 



464

Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the 

tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. 

Int J Oncol. 2005 Nov;27(5):1391-9. 

PMID: 16211236 

3. Tilton SC, Givan SA, Pereira CB, Bailey GS, Williams DE. 

Toxicogenomic Profiling of the Hepatic Tumor Promoters Indole-3-Carbinol, 17{beta}estradiol 

and {beta}-naphthoflavone in Rainbow Trout. 

Toxicol Sci. 2005 Sep 28; [Epub ahead of print] 

PMID: 16192472 

4. Brew CT, Aronchik I, Hsu JC, Sheen JH, Dickson RB, Bjeldanes LF, Firestone GL. 

Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to 

stabilize p53 and induce G1 arrest of human mammary epithelial cells. 

Int J Cancer. 2005 Sep 8; [Epub ahead of print] 

PMID: 16152627 

5. D'Agostini F, Izzotti A, Balansky RM, Bennicelli C, Flora SD. 

Modulation of apoptosis by cancer chemopreventive agents. 

Mutat Res. 2005 Dec 11;591(1-2):173-86. Epub 2005 Aug 30. 

PMID: 16137721 

6. Manson MM. 

Inhibition of survival signalling by dietary polyphenols and indole-3-carbinol. 

Eur J Cancer. 2005 Sep;41(13):1842-53. 

PMID: 16087329 

7. Izzotti A, Bagnasco M, Cartiglia C, Longobardi M, Camoirano A, Tampa E, Lubet 

RA, De Flora S. 

Modulation of multigene expression and proteome profiles by chemopreventive agents. 

Mutat Res. 2005 Dec 11;591(1-2):212-23. Epub 2005 Aug 3. 

PMID: 16083920 

8. Aggarwal BB, Ichikawa H. 



465

Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 

Cell Cycle. 2005 Sep;4(9):1201-15. Epub 2005 Sep 6. 

PMID: 16082211 

9. Crowell JA, Page JG, Levine BS, Tomlinson MJ, Hebert CD. 

Indole-3-carbinol, but not its major digestive product 3,3'-diindolylmethane, induces 

reversible hepatocyte hypertrophy and cytochromes P450. 

Toxicol Appl Pharmacol. 2005 Jul 22; [Epub ahead of print] 

PMID: 16043203 

10. Wu HT, Lin SH, Chen YH. 

Inhibition of cell proliferation and in vitro markers of angiogenesis by indole-3-carbinol, 

a major indole metabolite present in cruciferous vegetables. 

J Agric Food Chem. 2005 Jun 29;53(13):5164-9. 

PMID: 15969492 

Carrot Root - 11 STUDIES 

1. Baybutt RC, Hu L, Molteni A. Vitamin A deficiency injures lung and liver 

parenchyma and impairs function of rat type II pneumocytes. J Nutr. 2000 

May;130(5):1159-65. 

2. Ensminger AH, Esminger M. K. J. e. al. Food for Health: A Nutrition Encyclopedia. 

Clovis, California: Pegus Press; 1986. 

3. Gaziano JM, Manson JE, Branch LG, et al. A prospective study of consumption of 

carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. 

Ann. Epidemiol. 1995; 5:255-260. 

4. Harris RA, Key TJ, Silcocks PB, et al. A case-controlled study of dietary carotene in 

men with lung cancer and in men with other epithelial cancers. Nutrition and 

Cancer(1991)15:63-68. 

5. Kobaek-Larsen M, Christensen LP, Vach W, Ritskes-Hoitinga J, Brandt K. Inhibitory 

Effects of Feeding with Carrots or (-)-Falcarinol on Development of Azoxymethane- 



466

Induced Preneoplastic Lesions in the Rat Colon. J Agric Food Chem. 2005 Mar 

9;53(5):1823-1827. 

6. Kritchevsky SB. beta-Carotene, carotenoids and the prevention of coronary heart 

disease. J Nutr 1999 Jan;129(1):5-8. 

7. Li T, Molteni A, Latkovich P, Castellani W, Baybutt RC. Vitamin A depletion induced 

by cigarette smoke is associated with the development of emphysema in rats. J Nutr. 

2003 Aug;133(8):2629-34. 

8. Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of 

lung cancer in 2 prospective US cohorts. Am J Clin Nutr(2000)Oct;72(4):990-7. 

9. Suzuki K, Ito Y, Nakamura S et al. Relationship between serum carotenoids and 

hyperglycemia: a population- based cross-sectional study. J Epidemiol 2002 

Sep;12(5):357-66. 

10. Wald NJ, Thompson SG, Densem JW, et al. Serum beta-carotene and subsequent risk 

of cancer: results from the BUPA study. British Journal of Cancer(1988)57:428-33. 

11. Ylonen K, Alfthan G, Groop, L et al. Dietary intakes and plasma concentrations of 

carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of 

type 2 diabetes: the Botnia Dietary Study. Am J Clin Nutr. 2003 Jun; 77(6):1434-41. 

Milk Thistle Leaf - 27 STUDIES 

1. Biosci Biotechnol Biochem. 2003;67(9):1857-1863. (Animal Study) 

Suppression of Ethanol and Lipopolysaccharide-induced Liver Injury by Extracts of 

Hydrangeae Dulcis Folium in Rats. 

Hashizume E, Nakagiri R, Shirai A, Kayahashi S, Yasushi S, Kamiya T. 

Kyowa Hakko Kogyo Co., LTD. 

2. Toxicon. 2003 Sep;42(4):339-49. 

Cytotoxic fungi-an overview. 

Karlson-Stiber C, Persson H. 



467

Swedish Poisons Information Centre, Karolinska Sjukhuset, S-171 76, Stockholm, 

Sweden 

3. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Sep 5;794(2):303-10. 

Application of liquid chromatography-electrospray ionization-ion trap mass spectrometry 

to investigate the metabolism of silibinin in human liver microsomes. 

Gunaratna C, Zhang T. 

Bioanalytical Systems, Inc., West Lafayette, IN 47906, USA. prema@bioanalytical.com 

4. J Hepatol. 2003 Sep;39(3):333-40. (Animal Study) 

Silibinin protects mice from T cell-dependent liver injury( small star, filled ). 

Schumann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G. 

Institute of Experimental and Clinical Pharmacology and Toxicology, University of 

Erlangen-Nuremberg, Fahrstrasse 17, DE-91054, Erlangen, Germany 

5. Alcohol Alcohol. 2003 Sep-Oct;38(5):411-4. 

Primary human hepatocytes are protected against prolonged and repeated exposure to 

ethanol by silibinin-dihemisuccinate. 

van Pelt JF, Verslype C, Crabbe T, Zaman Z, Fevery J. 

Department of Liver and Pancreatic Diseases, University Hospital Gasthuisberg, Catholic 

University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. 

Jos.vanPelt@med.kuleuven.ac.be 

6. Arzneimittelforschung. 2003;53(6):420-7. 

Preparation and pharmacological evaluation of silibinin liposomes. 

Maheshwari H, Agarwal R, Patil C, Katare OP. 

University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 

7. J Pharm Belg. 2003;58(1):28-31. 

[St. Mary's Thistle: an overview] 

[Article in French] 



468

Laekeman G, De Coster S, De Meyer K. 

K.U.Leuven. 

8. Phytother Res. 2002 Nov;16(7):632-8. 

Effect of silybin and its congeners on human liver microsomal cytochrome P450 

activities. 

Zuber R, Modriansky M, Dvorak Z, Rohovsky P, Ulrichova J, Simanek V, Anzenbacher 

P. 

Faculty of Chemical Technology, University of Pardubice, Nam. Cs. Legii 565, 532 10 

Pardubice, Czech Republic. 

9. Planta Med. 2002 Aug;68(8):676-9. (Animal Study) 

Physiological responses to a natural antioxidant flavonoid mixture, silymarin, in BALB/c 

mice: I induction of transforming growth factor beta1 and c-myc in liver with marginal 

effects on other genes. 

He Q, Osuchowski MF, Johnson VJ, Sharma RP. 

Department of Physiology and Pharmacology, College of Veterinary Medicine, The 

University of Georgia, Athens, GA 30602-7389, USA. 

10. Tidsskr Nor Laegeforen. 2002 Mar 20;122(8):777-80. 

[Serious mushroom poisoning by Cortinarius and Amanita virosa] 

[Article in Norwegian] 

Svendsen BS, Gjellestad A, Eivindson G, Berentsen G, Jacobsen D. 

Giftinformasjonssentralen Postboks 8189 Dep 0034 Oslo. b.j.s.svendsen@giftinfo.no 

11. Drugs. 2001;61(14):2035-63. 

The use of silymarin in the treatment of liver diseases. 

Saller R, Meier R, Brignoli R. 

Abteilung Naturheilkunde, University Hospital Zurich, Switzerland. 

12. Am Fam Physician. 2001 Nov 1;64(9):1555-60. 



469

Erratum in: Am Fam Physician 2002 Jun 15;65(12):2438. 

Comment in: Am Fam Physician. 2001 Nov 1;64(9):1515-6. 

Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications 

and supplements, diet and exercise. 

Riley TR 3rd, Bhatti AM. 

Pennsylvania State University College of Medicine, Hershey, USA. triley@psu.edu 

13. Am J Gastroenterol. 2001 Nov;96(11):3195-8. 

Comment in: Am J Gastroenterol. 2002 May;97(5):1272-3. 

Mushroom poisoning--from diarrhea to liver transplantation. 

Broussard CN, Aggarwal A, Lacey SR, Post AB, Gramlich T, Henderson JM, Younossi 

ZM. 

Department of Gastroenterology, The Cleveland Clinic Foundation, Ohio, USA. 

14. Eksp Klin Farmakol. 2001 Jul-Aug;64(4):53-5. 

[Effect of Silybum marianum oil and legalon on lipid peroxidation and liver antioxidant 

systems in rats intoxicated with carbon tetrachloride] 


Batakov EA. 

Pharmacology Department, General Surgery Department, Samara State Medical 

University, Chapaevskaya ul. 89, Samara, 443099 Russia. 

15. Effect of silibinin and vitamin E on restoration of cellular immune response after 

partial hepatectomy. 

Horvath ME, Gonzalez-Cabello R, Blazovics A, van der Looij M, Barta I, Muzes G, 

Gergely P, Feher J. 

Second Department of Medicine, Semmelweis University, Szentkiralyi str. 46, H-1088 

Budapest, Hungary. 

16. Hepatology. 2001 Aug;34(2):329-39. (Animal Study) 



470

Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: a study in vivo 

and in isolated hepatocyte couplets. 

Crocenzi FA, Sanchez Pozzi EJ, Pellegrino JM, Favre CO, Rodriguez Garay EA, Mottino 

AD, Coleman R, Roma MG. 

Instituto de Fisiologia Experimental (IFISE)-Facultad de Ciencias Bioquimicas y 

Farmaceuticas (CONICET - U.N.R.), Rosario, Argentina. 

17. Vopr Pitan. 2000;69(5):20-3. 

[Effects of bioflavonoids on the toxicity of T-toxin in rats. A biochemical study] 


Kravchenko LV, Avren'eva LI, Tutel'ian VA. 

The enrichment of a diet of rats by flavonoids of milk thistle, Silybum marianum, 

reduced toxicity of T-2 toxin and was accompanied by reduction of a degree of change of 

total and nonsedimentable activity of lysosomal enzymes and microsomal xenobiotic 

metabolizing enzymes. 

18. Drug Metab Dispos. 2000 Nov;28(11):1270-3. 

Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine 

diphosphoglucuronosyl transferase in human hepatocyte cultures. 

Venkataramanan R, Ramachandran V, Komoroski BJ, Zhang S, Schiff PL, Strom SC. 

Department of Pharmaceutical Sciences School of Pharmacy, Pennsylvania, USA. 

rv+@pitt.edu 

19. Ther Apher. 2000 Aug;4(4):303-7. 

Treatment of Amanita phalloides poisoning: I. Retrospective evaluation of 

plasmapheresis in 21 patients. 

Jander S, Bischoff J. 

Medizinische Klinik, Klinikum Ernst von Bergmann Potsdam, Germany. 

20. Pharmacol Toxicol. 2000 Jun;86(6):250-6. 

Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. 



471

Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, Bocker RH, Beckurts KT, Lang W, 

Hunz M, Fuhr U. 

Institute for Pharmacology, Clinical Pharmacology, University of Koln, Germany. 

21. 27. Am J Gastroenterol. 1998 Feb;93(2):139-43. 

Comment in: Am J Gastroenterol. 1999 Feb;94(2):545-6. 

Milk thistle (Silybum marianum) for the therapy of liver disease. 

Flora K, Hahn M, Rosen H, Benner K. 

Division of Gastroenterology, Oregon Health Sciences University, Portland 97201-3098, 

USA. 

22. Arzneimittelforschung. 1997 Dec;47(12):1383-7. (Animal Study) 

Effects of silibinin and of a synthetic analogue on isolated rat hepatic stellate cells and 

myofibroblasts. 

Fuchs EC, Weyhenmeyer R, Weiner OH. 

Department of Clinical Chemistry, Philipps-Universitat, Koln, Germany. 

23. Hepatology. 1997 Sep;26(3):643-9. (Animal Study) 

Comment in: Hepatology. 2001 Feb;33(2):483-4. 

Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary 

to complete bile duct obliteration in rats. 

Boigk G, Stroedter L, Herbst H, Waldschmidt J, Riecken EO, Schuppan D. 

24. Am Fam Physician. 1997 Apr;55(5):1797-800, 1805-9, 1811-2. 

Mushroom poisoning. 

McPartland JM, Vilgalys RJ, Cubeta MA. 

Michigan State University College of Osteopathic Medicine, East Lansing, USA. 

25. Minerva Anestesiol. 1996 May;62(5):187-93. 

[Silibinin and acute poisoning with Amanita phalloides] 



472

[Article in Italian] 

Carducci R, Armellino MF, Volpe C, Basile G, Caso N, Apicella A, Basile V. 

Cattedra di Tossicologia Ospedale A. Cardarelli, Universita degli Studi di Napoli 

Federico II. 

26. Hepatology. 1996 Apr;23(4):749-54. (Animal Study) 

Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties 

of silibinin. 

Dehmlow C, Erhard J, de Groot H. 

Institut fur Physiologische Chemie, Universitatsklinikum, Essen, Germany. 

27. Life Sci. 1996;58(18):1591-600. 

Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by 

silibinin in human cells. 

Dehmlow C, Murawski N, de Groot H. 

Institut fur Physiologische Chemie, Universitatsklinikum, Essen, Germany. 

Bromelain – 49 STUDIES 

1. Rowan AD, Buttle DJ, Barrett AJ. The cysteine proteinases of the pineapple plant. 

Biochem J 1990;266:869-875. 

2. Taussig SJ, Nieper HA. Bromelain: its use in prevention and treatment of 

cardiovascular disease, present status. J IAPM 1979;6:139-151. 

3. Harrach T, Eckert K, Schulze-Forster K, et al. Isolation and partial characterization of 

basic proteinases from stem bromelain. J Protein Chem 1995;14:41-52. 

4. Jeung A. Encyclopedeia of Common Natural Ingredients Used in Foods, Drugs, and 

Cosmetics. New York, NY: John Wiley & Sons;1980:74-76. 



473

5. White RR, Crawley FE, Vellini M, et al. Bioavailability of 125I bromelain after oral 

administration to rats. Biopharm Drug Dispos 1988;9:397-403. 

6. Heinicke RM, Van der Wal M, Yokoyama MM. Effect of bromelain on human platelet 

aggrega tion. Experientia 1972;28:844-845. 

7. Morita AH, Uchida DA, Taussig SJ. Chromato graphic fractionation and 

characterization of the active platelet aggregation inhibitory factor from bromelain. Arch 

Inter Phar Ther 1979;239:340-350. 

8. Livio M, Bertoni MP, De Gaetano G, et al. Effect of bromelain on fibrinogen level, 

prothrombin complex factors and platelet aggregation in the rat - A preliminary report. 

Drugs Expt Clin Res 1978;4:49-53. 

9. De-Giuli M, Pirotta F. Bromelain: interaction with some protease inhibitors and rabbit 

specific antiserum. Drugs Exp Clin Res 1978;4:21-23. 

10. Inoue K, Motonaga A, Dainaka J, et al. Effect of etodolac on prostaglandin E2 

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Nutrients That Have Demonstrated The Ability To Slow Down the 

Rate at Which We Age 

Acetyl-L-Carnitine - 49 ABSTRACTS 

ACETYL-L-CARNITINE: 50 RESEARCH ABSTRACTS 

1_ Ophthalmologica. 2003 SepOct;217(5):3517. 

Mitotropic compounds for the treatment of agerelated macular degeneration. The 

metabolic approach and a pilot study. 

Feher J, Papale A, Mannino G, Gualdi L, Balacco Gabrieli C. 

Ophthalmic Neuroscience Program, Institute of Ophthalmology, University of Rome 

La Sapienza, Rome, Italy. 

Recent histopathologic studies have shown that mitochondria and peroxisomes of the 

retinal pigment epithelium may play a central role in the pathophysiology of agerelated 

macular degeneration (AMD). We supposed that compounds which improve 

mitochondrial functions (mitotropic compounds) may show beneficial effects in 

preventing AMD. Fourteen patients affected by early AMD were treated with a mixture 

containing acetylLcarnitine (ALC), polyunsaturated fatty acids 

(PUFAs), coenzyme Q10 (CoQ10) and vitamin E, while an equal number of age and 

sexmatched patients affected by early AMD were treated with vitamin E only. 

Recovery time after macular photostress, foveal sensitivity and mean defect in 

the visual field as well as blood lipid levels were recorded at the beginning 

and after 3, 6, 9, 12 and 24 months of followup. In the treated group, all the 

visual functions showed slight improvement which was evident after 3 months of 

treatment and remained nearly stationary by the end of 24 months. The same tests in the 

control group showed slow worsening. The divergence between treated and control 

groups became more marked with time, but the difference was not significant at any time 

of the followup. These findings suggest that the blend of ALC, PUFA, CoQ10 and 

vitamin E may improve retinal functions in early AMD. 



477

2_ Int J Tissue React. 2002;24(3):8996. 

Longterm ethanol administration enhances agedependent modulation of redox 

state in brain and peripheral organs of rat: protection by acetyl carnitine. 

Scapagnini G, Ravagna A, Bella R, Colombrita C, Pennisi G, Calvani M, Alkon D, 

Calabrese V. Blanchette Rockefeller Neurosciences Institute, West Virginia University, 

Rockville, USA. 

Evidence is accumulating that intermediates of oxygen reduction may be 

associated with the development of alcoholic disease. Free radicalinduced 

perturbation of the oxidant/antioxidant balance in the cell is widely recognized 

as the main causative factor of agerelated disorders. In the present study we 

investigated the effects of 20 months of ethanol consumption on the antioxidant 

defense system in different rat organs compared with normal aging in the absence and 

presence of treatment with Lacetyl carnitine. We demonstrate that aged rats underwent 

significant perturbation of the antioxidant defense system, as indicated by depletion of 

reduced glutathione (GSH) content, increased oxidized GSH, free radicalinduced 

luminescence associated with increased hydroxynonenal content and decreased GSH 

reductase activity. These modifications, observed particularly in brain and liver compared 

with other organs, were enhanced by longterm alcohol exposure and, interestingly, were 

significantly reduced with acetyl carnitine supplements. Our results indicate that 

decreased GSH reductase activity and thiol depletion are important factors in effecting a 

pathogenic role for oxidative stress in aging and in all situations in which agecorrelated 

and oxidantinduced changes occur, such as in alcoholism. Administration of acetyl 

carnitine greatly reduces these metabolic abnormalities. Our findings support its 

pharmacological potential in the management of alcoholic disturbances. 

3_ Brain Res. 2002 Dec 13;957(2):22330. 

Reversal of biochemical and behavioral parameters of brain aging by melatonin 

and acetyl Lcarnitine. Sharman EH, Vaziri ND, Ni Z, Sharman KG, Bondy SC. 

Center for Occupational and Environmental Health, Department of Community and 

Environmental Medicine, University of California Irvine, Irvine, CA 926971825, USA. 

The potential utility of dietary supplementation in order to prevent some of the 

oxidative and inflammatory changes occurring in the brain with age, has been 

studied. The cerebral cortex of 27monthold male B6C3F1 mice had elevated 

levels of nitric oxide synthase 1 (EC 1.14.13.39) (nNOS) and peptide 

nitrotyrosine relative to cortices of younger (4monthold) animals. After 

25monthold mice received basal diet together with 300 mg/l acetyl Lcarnitine 

in the drinking water for 8 weeks, these levels were fully restored to those 

found in younger animals. A partial restoration was found when old animals 

received basal diet supplemented with 200 ppm melatonin in the diet. Levels of 

mRNA (messenger RNA) for nNOS were unchanged following these treatments 

implying translational regulation of nNOS activity. Behavioral indices indicative of 

exploratory behavior were also depressed in aged animals. Dietary 

supplementation with melatonin or acetyl Lcarnitine partially reversed these 



478

changes. These findings suggest that dietary supplementation cannot merely 

arrest but indeed reverse some agerelated increases in markers of oxidative and 

inflammatory events occurring with the cortex. 

4_ Ann N Y Acad Sci. 2002 Apr;959:491507. 

Mitochondrial decay in the aging rat heart: evidence for improvement by dietary 

supplementation with acetylLcarnitine and/or lipoic acid. 

Hagen TM, Moreau R, Suh JH, Visioli F. 

Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State 

University, Corvallis, Oregon 97331, USA. 

Mitochondrial decay has been postulated to be a significant underlying part of 

the aging process. Decline in mitochondrial function may lead to cellular energy 

deficits, especially in times of greater energy demand, and compromise vital 

ATPdependent cellular operations, including detoxification, repair systems, DNA 

replication, and osmotic balance. Mitochondrial decay may also lead to enhanced 

oxidant production and thus render the cell more prone to oxidative insult. In 

particular, the heart may be especially susceptible to mitochondrial dysfunction 

due to myocardial dependency on betaoxidation of fatty acids for energy and the 

postmitotic nature of cardiac myocytes, which would allow for greater 

accumulation of mitochondrial mutations and deletions. Thus, maintenance of 

mitochondrial function may be important to maintain overall myocardial function. 

Herein, we review the major agerelated changes that occur to mitochondria in 

the aging heart and the evidence that two such supplements, acetyllcarnitine 

(ALCAR) and (R)alphalipoic acid, may improve myocardial bioenergetics and 

lower the increased oxidative stress associated with aging. We and others have 

shown that feeding old rats ALCAR reverses the agerelated decline in carnitine 

levels and improves mitochondrial betaoxidation in a number of tissues studied. 

However, ALCAR supplementation does not appear to reverse the agerelated 

decline in cardiac antioxidant status and thus may not substantially alter 

indices of oxidative stress. Lipoic acid, a potent thiol antioxidant and 

mitochondrial metabolite, appears to increase low molecular weight antioxidant 

status and thereby decreases ageassociated oxidative insult. Thus, ALCAR along 

with lipoic acid may be effective supplemental regimens to maintain myocardial 

function. 

5_ Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):187681. 

Ageassociated mitochondrial oxidative decay: improvement of carnitine 

acetyltransferase substratebinding affinity and activity in brain by feeding 

old rats acetylL carnitine and/or Ralpha lipoic acid. 

Liu J, Killilea DW, Ames BN. 



We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a 

key mitochondrial enzyme for fuel utilization, is due to decreased binding 



479

affinity for substrate and whether this substrate, fed to old rats, restores CAT 

activity. The kinetics of CAT were analyzed by using the brains of young and old 

rats and of old rats supplemented for 7 weeks with the CAT substrate 

acetyllcarnitine (ALCAR) and/or the mitochondrial antioxidant precursor 

Ralphalipoic acid (LA). Old rats, compared with young rats, showed a decrease 

in CAT activity and in CATbinding affinity for both substrates, ALCAR and CoA. 

Feeding ALCAR or ALCAR plus LA to old rats significantly restored CATbinding 

affinity for ALCAR and CoA, and CAT activity. To explore the underlying 

mechanism, lipid peroxidation and total iron and copper levels were assayed; all 

increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid 

peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of 

youngrat brain with Fe(II) caused loss of CAT activity and binding affinity. In 

vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not 

alter binding affinity. However, in vitro treatment of CAT with the lipid 

peroxidation products malondialdehyde or 4hydroxynonenal caused a decrease in 

CATbinding affinity and activity, thus mimicking agerelated change. 

Preincubation of CAT with ALCAR or CoA prevented malondialdehydeinduced 

dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites 

can ameliorate oxidative damage, enzyme activity, substratebinding affinity, 

and mitochondrial dysfunction. 

6_ Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):18705. 

Feeding acetylLcarnitine and lipoic acid to old rats significantly improves 

metabolic function while decreasing oxidative stress. 

Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew 

JC, Ames BN. 


University, Corvallis, OR 97331, USA. 

Mitochondrialsupported bioenergetics decline and oxidative stress increases 

during aging. To address whether the dietary addition of acetyllcarnitine 

[ALCAR, 1.5% (wt/vol) in the drinking water] and/or (R)alphalipoic acid [LA, 

0.5% (wt/wt) in the chow] improved these endpoints, young (24 mo) and old 

(2428 mo) F344 rats were supplemented for up to 1 mo before death and 

hepatocyte isolation. ALCAR+LA partially reversed the agerelated decline in 

average mitochondrial membrane potential and significantly increased (P = 0.02) 

hepatocellular O(2) consumption, indicating that mitochondrialsupported 

cellular metabolism was markedly improved by this feeding regimen. ALCAR+LA also 

increased ambulatory activity in both young and old rats; moreover, the 

improvement was significantly greater (P = 0.03) in old versus young animals and also 

greater when compared with old rats fed ALCAR or LA alone. To determine whether 

ALCAR+LA also affected indices of oxidative stress, ascorbic acid and markers of lipid 

peroxidation (malondialdehyde) were monitored. The 

hepatocellular ascorbate level markedly declined with age (P = 0.003) but was 

restored to the level seen in young rats when ALCAR+LA was given. The level of 

malondialdehyde, which was significantly higher (P = 0.0001) in old versus young rats, 



480

also declined after ALCAR+LA supplementation and was not significantly different from 

that of young unsupplemented rats. Feeding ALCAR in combination with LA increased 

metabolism and lowered oxidative stress more than either compound alone. 

7_ Neurochem Res. 2000 Mar;25(3):3959. 

Effect of longterm feeding with acetylLcarnitine on the agerelated changes 

in rat brain lipid composition: a study by 31P NMR spectroscopy. 

Aureli T, Di Cocco ME, Capuani G, Ricciolini R, Manetti C, Miccheli A, Conti F. 

Department of Biochemistry, SigmaTau Labs, Pomezia, Italy. 

Changes in brain lipid composition have been determined in 24 monthsold Fischer rats 

with respect to 6 monthsold ones. The cerebral levels of sphingomyelin and cholesterol 

were found to be significantly increased in aged rats, whereas the amount of 

phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, 

phosphatidylinositol, and phosphatidic acid appear to be unaffected by aging. Longterm 

feeding with acetylLcarnitine was able to reduce the agedependent increase of both 

sphingomyelin and cholesterol cerebral levels with no effect on the other measured 

phospholipids. These findings shown that changes in membrane lipid metabolism and/or 

composition represent one of the alterations occurring in rat brain with aging, and that 

longterm feeding with acetylLcarnitine can be useful in normalizing these agedependent 

disturbances. 

8_ Am J Otol. 2000 Mar;21(2):1617. 

Biologic activity of mitochondrial metabolites on aging and agerelated hearing 

loss. Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS. 

Department of Otolaryngology Head & Neck Surgery, Henry Ford Health System, 

Detroit, Michigan 48323, USA. 

HYPOTHESIS: Compounds that upregulate mitochondrial function in an aging model 

will improve hearing and reduce some of the effects of aging. BACKGROUND: Reactive 

oxygen metabolites (ROM) are known products of oxidative metabolism and are 

continuously generated in vivo. More than 100 human clinical conditions have been 

associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, 

heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and 

cause extensive DNA, cellular, and tissue damage. Specific deletions within the 

mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. 

These deletions are the result of chronic exposure to ROM. When enough mtDNA 

damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis 

of the mitochondrial clock theory of aging, also known as the membrane hypothesis of 

aging. Nutritional compounds have been identified that enhance mitochondrial function 

and reverse several agerelated processes. It is the purpose of this article to describe the 

effects of two mitochondrial metabolites, alphalipoic acid and acetyl Lcarnitine, on the 

preservation of agerelated hearing loss. METHODS:Twentyone Fischer rats, aged 24 

months, were divided into three groups: acetyl1carnitine, alphalipoic acid, and control. 

The subjects were orally supplemented with either a placebo or one of the two nutritional 

compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline 



481

and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were 

obtained to assess for mtDNA mutations. RESULTS: The control group demonstrated an 

expected ageassociated threshold deterioration of 3 to 7 dB in the 6week study. The 

treated subjects experienced a delay in progression of hearing loss. Acetyl1carnitine 

improved auditory thresholds during the same time period (p

highly limited, nutritional and botanical therapies are available which have 

proven degrees of efficacy and generally favorable benefittorisk profiles. 

This review covers five such therapies: phosphatidylserine (PS), 

acetyllcarnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa 

monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through 

doubleblind trials for improving memory, learning, concentration, word recall, 

and mood in middleaged and elderly subjects with dementia or agerelated 

cognitive decline. PS has an excellent benefittorisk profile. ALC is an 

energizer and metabolic cofactor which also benefits various cognitive functions 

in the middleaged and elderly, but with a slightly less favorable 

benefittorisk profile. Vinpocetine, found in the lesser periwinkle Vinca 

minor, is an excellent vasodilator and cerebral metabolic enhancer with proven 

benefits for vascularbased cognitive dysfunction. Two metaanalyses of GbE 

demonstrate the best preparations offer limited benefits for vascular 

insufficiencies and even more limited benefits for Alzheimer's, while 

"commodity" GbE products offer little benefit, if any at all. GbE (and probably 

also vinpocetine) is incompatible with bloodthinning drugs. Bacopa is an 

Ayurvedic botanical with apparent antianxiety, antifatigue, and 

memorystrengthening effects. These five substances offer interesting 

contributions to a personalized approach for restoring cognitive function, 

perhaps eventually in conjunction with the judicious application of growth 

factors. 

11_ Mech Ageing Dev. 1995 Nov 3;85(1):3753. 

Age and traumadependent modifications of neuromuscular junction and skeletal 

muscle structure in the rat. Effects of longterm treatment with 

AcetylLCarnitine. 

De Angelis C, Scarfo C, Falcinelli M, Perna E, Ramacci MT, Angelucci L. 

Department of Morphometry and Histology, Institute for Research on Senescence, 

Rome, Italy. 

The influence of ageing and crushing of the sciatic nerve on the morphology of 

the neuromuscular junction (NMJ) and on the muscle fiber composition were 

studied in the rat soleus muscle using histochemical techniques associated with 

image analysis. The influence of a 6month treatment with AcetylLCarnitine 

(ALCAR, 150 mg/kg/day) on the age and crushingdependent changes of the NMJ and 

on agerelated modifications of the muscle fiber composition was assessed as 

well. In control old and injured young rats a loss of complexity of the NMJ was 

observed. Treatment with ALCAR resulted in an increased endplate complexity both 

in old rats and in young rats injured by crushing, in comparison with respective 

controls. The structure of the rat soleus muscle changes with increasing age. 

Modification mainly consists in a type II fiber atrophy, and in the alteration 

of the peculiar mosaic organization of the soleus muscle fibers. In 

ALCARtreated old rats, the morphology of the soleus muscle fibers was similar 

to that observed in adult animals. These findings suggest that treatment with 

ALCAR has a beneficial effect on NMJ and on muscle fiber structure in ageing or 



483

after nerve crushing. The possible mechanism of action of this 'trophic' effect 

of ALCARtreatment is discussed. 

12_ Mech Ageing Dev. 1995 Oct 13;84(2):10312. 

Carnitineacylcarnitine translocase activity in cardiac mitochondria from aged 

rats: the effect of acetylLcarnitine. 

Paradies G, Ruggiero FM, Petrosillo G, Gadaleta MN, Quagliariello E. 

Department of Biochemistry and Molecular Biology, University of Bari, Italy. 

Agerelated changes in mitochondrial fatty acids metabolism may underlie the 

progressive decline in cardiac function. The effect of aging and acute treatment 

with acetylLcarnitine on fatty acids oxidation and on carnitineacylcarnitine 

translocase activity in rat heart mitochondria was studied. Rates of 

palmitoylcarnitine supported respiration as well as carnitinecarnitine and 

carnitinepalmitoylcarnitine exchange reactions were all depressed (approx. 35%) 

in heart mitochondria from aged rats. These effects were almost completely 

reversed following treatment of aged rats with acetylLcarnitine. Heart 

mitochondrial cardiolipin content was significantly reduced (approx. 38%) in 

aged rats. Treatment of aged rats with acetylLcarnitine restored the level of 

cardiolipin to that of young rats. It is suggested that acetylLcarnitine is 

able to reverse agerelated decrement in mitochondrial carnitineacylcarnitine 

exchange activity by restoring the normal cardiolipin content. 

13_ J Gerontol A Biol Sci Med Sci. 1995 Jul;50(4):B23236. 

AcetylLCarnitine: chronic treatment improves spatial acquisition in a new 

environment in aged rats. 

Caprioli A, Markowska AL, Olton DS. 

Institute for Research on Senescence, Sigma Tau, Rome, Italy. 

Chronic AcetylLCarnitine (ALCAR) treatment prevents some agerelated memory 

impairment. The present experiment examined the effects of aging and ALCAR in 

Fischer 344 rats on retention of spatial discrimination test in a familiar 

environment (FE), and on the acquisition of a spatial discrimination in a novel 

environment (NE). Rats 18 months or 3 months old were trained with a new 

procedure to assess spatial discrimination in the Morris water maze. Performance 

during acquisition in FE was used to assign each old rat to one of two classes: 

Good Performers (GP) and Poor Performers (PP) based on their swim time to reach 

the platform. The old rats displayed heterogeneous performance and a spatial 

discrimination deficit. Chronic ALCAR treatment enhanced spatial acquisition in 

the NE of rats with agerelated behavioral impairments and had a slight effect 

on retention of the spatial discrimination in the FE. 

14_ Neurochem Res. 1994 Jul;19(7):7958. 

Agedependent loss of NMDA receptors in hippocampus, striatum, and frontal 

cortex of the rat: prevention by acetylLcarnitine. 

Castornia M, Ambrosini AM, Pacific L, Ramacci MT, Angelucci L. 



484

Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Italy. 

Acute i.p. administration of AcetylLCarnitine (ALCAR), a component of several 

biological systems, has been found to modify spontaneous and evoked 

electrocortical activity in young rats, and, in the old rats, to improve 

learning ability and to increase the number of NMDA receptors in the whole 

brain. The present study was aimed at ascertaining the effect of chronic 

treatment with ALCAR added to drinking water on agerelated changes in the 

different brain areas of rats. In twentyfourmonthold rats, ALCAR treatment 

for six months significantly impeded the decline in the number of NMDA receptors 

within the hippocampus, the frontal cortex and the striatum compared to the 

adult animal. This finding thus confirms the previously reported positive effect 

of ALCAR on the brain NMDA receptor system. 

15_ Ann N Y Acad Sci. 1993 Sep 24;695:3246. 

AcetylLcarnitine and Alzheimer's disease: pharmacological considerations 

beyond the cholinergic sphere. 

Carta A, Calvani M, Bravi D, Bhuachalla SN. 

SigmaTau Pharmaceuticals, Department of Scientific Affairs, Gaithersburg, 

Maryland 20878. 

Since ALCAR and Lcarnitine are "shuttles" of long chain fatty acids between the 

cytosol and the mitochondria to undergo betaoxidation, they play an essential 

role in energy production and in clearing toxic accumulations of fatty acids in 

the mitochondria. ALCAR has been considered of potential use in senile dementia 

of the Alzheimer type (SDAT) because of its ability to serve as a precursor for 

acetylcholine. However, pharmacological studies with ALCAR in animals have 

demonstrated its facility to maximize energy production and promote cellular 

membrane stability, particularly its ability to restore membranal changes that 

are agerelated. Since recent investigations have implicated abnormal energy 

processing leading to cell death, and severitydependent membrane disruption in 

the pathology of Alzheimer's disease, we speculate that the beneficial effects 

associated with ALCAR administration in Alzheimer patients are due not only to 

its cholinergic properties, but also to its ability to support physiological 

cellular functioning at the mitochondrial level. This hypothetical mechanism of 

action is discussed with respect to compelling supportive animal studies and 

recent observations of significant decrease of carnitine acetyltransferase (the 

catalyst of Lcarnitine acylation to acetylLcarnitine) in autopsied Alzheimer 

brains. 

16_ Physiol Behav. 1992 Jul;52(1):1857. 

Active avoidance learning in old rats chronically treated with levocarnitine 

acetyl. 

Ghirardi O, Caprioli A, Milano S, Giuliani A, Ramacci MT, Angelucci L. 

Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Rome, Italy. 



485

The aging laboratory animal is recognized as a suitable experimental model for 

the investigation on drugs potentially able to retard the agedependent decline 

in cognitive functions. There is robust evidence that levocarnitine acetyl 

(ALCAR), the acetyl derivative of carnitine, when administered chronically, 

prevents some agerelated deficits of the central nervous system, mainly at the 

hippocampal level. On the basis of this evidence and because learning of active 

avoidance was demonstrated to become impaired with age, we decided to 

investigate the effect of ALCAR in rats. For statistical evaluation of results, 

the Cluster Analysis technique was chosen. This procedure pointed out the great 

heterogeneity of the old population and allowed the classification of the 

animals into homogeneous groups according to their response pattern. The effect 

of ALCAR was evident in the higher number of treated old animals yielding escape 

responses, indicating that ALCAR can preserve, at least partially, learning and 

memory from the natural decay occurring with age. 

17_ Int J Clin Pharmacol Res. 1992;12(56):25362. 

Morphological and electrophysiological changes of peripheral nervemuscle unit 

in the aged rat prevented by levocarnitine acetyl. 

Scarfo C, Falcinelli M, Pacifici L, Bellucci A, Reda E, De Angelis C, Ramacci 

MT, Angelucci L. 

Institute for Research on Senescence, Sigma Tau S.p.A. Pomezia, Rome, Italy. 

The effects of levocarnitine acetyl on structure and function of the sciatic 

nerve and neuromuscular junctions of the soleus and extensor digitorum longus 

muscles were studied in the aged rat. To that end, neuromuscular conduction 

velocity (NMCV) was measured in vivo and morphological and morphometric 

evaluations were performed. Treatment with levocarnitine acetyl, 150 mg/kg day 

for six months, restored NMCV values to the levels measured in the young rat; 

significantly reduced the number of degenerating elements; and increased the 

number of myelinated fibres having normal structural features. In the soleus and 

extensor digitorum longus muscles, levocarnitine acetyl increased the complexity 

of neuromuscular junctions. These experimental findings suggest a neurotrophic 

action of levocarnitine acetyl on the peripheral nervous system that might have 

therapeutical applications in agerelated peripheral nerve changes. 

18_ J Neurosci Res. 1991 Nov;30(3):5559. 

Effect of acetylLcarnitine on the dopaminergic system in aging brain. 

Sershen H, Harsing LG Jr, BanaySchwartz M, Hashim A, Ramacci MT, Lajtha A. 

Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 

Orangeburg, New York 10962. 

We studied the effect of acetylLcarnitine (ALCAR) on dopamine release and the 

effect of longterm acetylLcarnitine treatment on agerelated changes in 

striatal dopamine receptors and brain amino acid levels. In striatal tissue that 

had been incubated with [3H]dopamine, acetylLcarnitine increased the release 

of [3H]dopamine evoked by electrical stimulation. In striatal tissue from aged 



486

mice administered acetylLcarnitine for 3 months, the release of [3H]dopamine 

evoked by electrical stimulation was higher than that of its aged control; the 

release after a second stimulation was similar in the two groups. There was a 

significant decline in the number of D1 striatal dopamine receptors with age. 

The Bmax was 51% lower in 1.5yearold mice than in 4monthold animals. 

Administration of acetylLcarnitine for 3 months diminished the reduction in 

the binding of [3H]SCH23390. [3H]Spiperone binding to D2 receptors was not 

decreased with age and was not affected by acetylLcarnitine treatment. 

Agerelated decreases in levels of several amino acids were observed in several 

brain regions. AcetylLcarnitine lessened the reduction in the level of taurine 

only in the striatum. The findings confirm the multiple effects of 

acetylLcarnitine in brain, and suggest that its administration can have a 

positive effect on agerelated changes in the dopaminergic system. 

19_ Brain Res Dev Brain Res. 1991 Apr 24;59(2):22130. 

AcetylLcarnitine enhances the response of PC12 cells to nerve growth factor. 

Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR, 

PerezPolo JR. 

Department of Human Biological Chemistry and Genetics, University of Texas 

Medical Branch, Galveston 77550. 

We have demonstrated that treatment of rat pheochromocytoma (PC12) cells with 

acetylLcarnitine (ALCAR) stimulates the synthesis of nerve growth factor 

receptors (NGFR). ALCAR has also been reported to prevent some agerelated 

impairments of the central nervous system (CNS). In particular, ALCAR reduces 

the loss of NGFR in the hippocampus and basal forebrain of aged rodents. On 

these bases, a study on the effect of NGF on the PC12 cells was carried out to 

ascertain whether ALCAR induction of NGFR resulted in an enhancement of NGF 

action. Treatment of PC12 cells for 6 days with ALCAR (10 mM) stimulated 

[125I]NGF PC12 cell uptake, consistent with increased NGFR levels. Also, neurite 

outgrowth elicited in PC12 cells by NGF (100 ng/ml) was greatly augmented by 

ALCAR pretreatment. When PC12 cells were treated with 10 mM ALCAR and then 

exposed to NGF (1 ng/ml), an NGF concentration that is insufficient to elicit 

neurite outgrowth under these conditions, there was an ALCAR effect on neurite 

outgrowth. The concentration of NGF necessary for survival of serumdeprived 

PC12 cells was 100fold lower for ALCARtreated cells as compared to controls. 

The minimal effective dose of ALCAR here was between 0.1 and 0.5 mM. This is 

similar to the reported minimal concentration of ALCAR that stimulates the 

synthesis of NGFR in these cells. The data here presented indicate that one 

mechanism by which ALCAR rescues aged neurons may be by increasing their 

responsiveness to neuronotrophic factors in the CNS. 

20_ Neurobiol Aging. 1990 SepOct;11(5):4918. 

Acetyl1carnitine. 1: Effects on mortality, pathology and sensorymotor 

performance in aging rats. 

Markowska AL, Ingram DK, Barnes CA, Spangler EL, Lemken VJ, Kametani H, Yee W, 



487

Olton DS. 

Department of Psychology, University of Colorado, Boulder 80309. 

Three different test sites assessed the effects of acetyl1carnitine (AC) on 

agerelated changes in general health, sensorymotor skills, learning, and 

memory. Two groups of rats began the experiments at 16 months of age. One group 

(OLDAC) was given AC, 75 mg/kg/day, beginning at 16 months. The other group 

(OLDCON) was treated identically except it was not given the drug. Beginning at 

22 months of age, these rats and a group of young (34 months old) rats (YGCON) 

were given a series of sensorymotor tasks. AC decreased mortality, and had no 

reliable effect on body weight, fluid intake, or the general health of the rats. 

These data indicate that a chronic dose of AC does not interfere with food and 

water intake, and may increase longevity. An agerelated decline of performance 

occurred in most of the sensorymotor tasks; locomotor activity was reduced in a 

novel environment and in a runwheel, and the ability to prevent falling was 

reduced in tests on a taut wire, rotorod, inclined screen, and several types of 

elevated bridges. An agerelated decline of performance did not occur in 

grooming, or in the latency to initiate several different behaviors. AC had no 

effect on performance in any sensorymotor task. These data indicate that the 

improvements produced by AC in some tests of spatial memory may be due to the 

effects of AC on cognitive abilities rather than on sensorymotor skills. 

21_ Neurochem Res. 1990 Jun;15(6):597601. 

AcetylLcarnitine as a precursor of acetylcholine. 

White HL, Scates PW. 

Division of Pharmacology, Wellcome Research Laboratories, Research Triangle 

Park, North Carolina 27709. 

Synthesis of [3H]acetylcholine from [3H]acetylLcarnitine was demonstrated in 

vitro by coupling the enzyme systems choline acetyltransferase and carnitine 

acetyltransferase. Likewise, both [3H] and [14C] labeled acetylcholine were 

produced when [3H]acetylLcarnitine and D[U14C] glucose were incubated with 

synaptosomal membrane preparations from rat brain. Transfer of the acetyl moiety 

from acetylLcarnitine to acetylcholine was dependent on concentration of 

acetylLcarnitine and required the presence of coenzyme A, which is normally 

produced as an inhibitory product of choline acetyltransferase. These results 

provide further evidence for a role of mitochondrial carnitine acetyltransferase 

in facilitating transfer of acetyl groups across mitochondrial membranes, thus 

regulating the availability in the cytoplasm of acetylCoA, a substrate of 

choline acetyltransferase. They are also consistent with a possible utility of 

acetylLcarnitine in the treatment of agerelated cholinergic deficits. 


Dietary acetylLcarnitine improves spatial behaviour of old rats. 

Markowska AL, Olton DS. 

Department of Psychology, Johns Hopkins University, Baltimore, Maryland. 



488

AcetylLcarnitine was given to aging rats to determine the extent to which it 

changed agerelated impairments in several different behaviours. One group of 

rats was given acetylLcarnitine, 80 mg/day, beginning at 16 months of age. A 

second group of rats was housed and treated identically, except that no drug was 

administered. At 22 months of age, both groups of rats began a series of 

behavioural tests, along with a group of young rats, four months of age. The 

tests included: place learning on a circular platform, probe reversal of place 

learning on a circular platform, two choice simultaneous spatial discrimination 

in the stem of a Tmaze spatial alternation in the arms of a Tmaze, and 

sensorymotor behaviour (initiation of walking, turning in an alley, walking on 

a square, round, and rectangular bridge, turning on an inclined grid, holding on 

to a wire, lightdark preference). The tasks varied in their sensitivity to 

agerelated impairments. These data indicate that longterm therapy with 

acetylLcarnitine attenuates certain agerelated cognitive deficits and may 

have a beneficial effect on longevity. 


Peroxidative stress and cerebral aging. 

Fariello RG. 

Department Neurological Sciences, RushPresbyterian St. Lukes Medical Center, 

Chicago, Illinois. 

In order to test the hypothesis that cerebral nuclei showing agerelated 

neuronal depletion would also show signs of vulnerability in their free radical 

scavenger systems and accumulation of the compounds resulting from peroxidation, 

the regional levels of a number of compounds were measured in mouse brains. With 

the exception of the tocopherols all the antioxidants had lower concentrations 

in the Substantia nigra which showed the most severe neuronal depletion with 

age. AcetylLcarnitine is being investigated as a determinant of neuronal 

longevity. 

24_ J Neurosci Res. 1989 Aug;23(4):4626. 

AcetylLcarnitine reduces the agedependent loss of glucocorticoid receptors in 

the rat hippocampus: an autoradiographic study. 

Patacchioli FR, Amenta F, Ramacci MT, Taglialatela G, Maccari S, Angelucci L. 

Institute of Pharmacology II, Medical Faculty, University of Rome, La Sapienza, 

Italy. 

Brain autoradiography in adrenalectomized rats injected with 3Hcorticosterone 2 

hr before sacrifice was used to study the effect of aging and longterm 

acetyllcarnitine treatment on the hippocampal glucocorticoid receptor. 

Densitometric analysis of silver grains in individual nerve cells of the 

hippocampus showed that pyramidal neurones of the CA1 field and granular cells 

of the dentate gyrus are richest in 3Hcorticosterone binding sites, whereas 

pyramidal neurons of the CA3 field have the lowest number of binding sites. 



489

There was a significant decline in the number of glucocorticoid receptors within 

the various hippocampal areas, both as the total number of 3Hcorticosterone 

binding sites and as the number per single pyramidal or granule neuron 

associated with aging and perhaps due to loss of adrenocorticoidcompetent 

neurons. The dentate gyrus and the CA1 region were mostly affected by the 

agedependent decrease in glucocorticoid receptors of the hippocampus. 

Twentyeightmonthold rats, treated with acetyllcarnitine for 7 months, 

showed a significantly higher number of 3Hcorticosterone binding sites within 

the various hippocampal regions examined than did agematched controls. The CA1 

and the dentate gyrus were the regions most susceptible to amelioration by 

acetyllcarnitine treatment. These findings suggest a positive effect of 

acetyllcarnitine treatment on agerelated changes which occur in the 

hippocampus. 

25_ Neurochem Res. 1988 Oct;13(10):90916. 

Action of Lacetylcarnitine on agedependent modifications of mitochondrial 

membrane proteins from rat cerebellum. 

Villa RF, Turpeenoja L, Benzi G, Giuffrida Stella AM. 

Institute of Pharmacology, Faculty of Science, University of Pavia, Italy. 

Protein patterns of mitochondrial outer membrane, inner membrane, and matrix 

from nonsynaptic (free) mitochondria from rat cerebellum at different ages (4, 

8, 12, 16, 20, and 24 months) were analyzed by gel electrophoresis. Acute 

Lacetylcarnitine treatment was performed by a single i.p. injection (100 mg/kg 

body weight) of the substance 60 min before the sacrifice of the animals. 

Different agedependent changes were obtained for the proteins of the three 

fractions. The amount of some protein subunits increased and/or decreased after 

drug treatment. In particular, protein composition of the inner mitochondrial 

membrane showed significant agerelated modifications. This result probably 

indicates differences in protein synthesis and/or turnover rates in the various 

mitochondrial compartments during aging. Acute Lacetylcarnitine treatment 

caused: a high increase in the amount of one inner membrane protein with Mw 16 

kDa, at all the ages studied; a decrease in the amount of many other inner 

membrane proteins; modifications of some matrix proteins. Our results show that 

in vivo administration of Lacetylcarnitine affects mainly the inner membrane 

protein composition of cerebellar mitochondria. 


Nerve growth factor binding in aged rat central nervous system: effect of 

acetylLcarnitine. 

Angelucci L, Ramacci MT, Taglialatela G, Hulsebosch C, Morgan B, WerrbachPerez 

K, PerezPolo R. 

Department of Pharmacology, University of Rome, Italy. 

The nerve growth factor protein (NGF) has been demonstrated to affect neuronal 

development and maintenance of the differentiated state in certain neurons of 



490

the peripheral and central nervous system (CNS) of mammals. In the CNS, NGF has 

sparing effects on cholinergic neurons of the rodent basal forebrain (BF) 

following lesions where it selectively induces choline acetyltransferase (ChAT). 

NGF also induces ChAT in the areas to which BF provides afferents. In aged rats, 

there is a reduction in the NGFbinding capacity of sympathetic ganglia. Here, 

we wish to report that there is a decrease in the NGFbinding capacity of the 

hippocampus and basal forebrain of aged (26monthold) rats as compared to 

4monthold controls but no change in NGF binding in cerebellum. In all 

instances, equilibrium binding dissociation constants did not differ 

significantly. Treatment of rats with acetylLcarnitine, reported to improve 

cognitive performance of aged rats, ameliorates these agerelated deficits. 

27_ Exp Brain Res. 2002 Jul;145(2):1829. Epub 2002 May 04. 

Systemic acetylLcarnitine eliminates sensory neuronal loss after peripheral 

axotomy: a new clinical approach in the management of peripheral nerve trauma. 

Hart AM, Wiberg M, Youle M, Terenghi G. 

University Department of Surgery, BlondMcIndoe Centre, Royal Free & University 

College Medical School, London, UK. 

Several hundred thousand peripheral nerve injuries occur each year in Europe 

alone. Largely due to the death of around 40% of primary sensory neurons, 

sensory outcome remains disappointingly poor despite considerable advances in 

surgical technique; yet no clinical therapies currently exist to prevent this 

neuronal death. Acetyl Lcarnitine (ALCAR) is a physiological peptide with 

roles in mitochondrial bioenergetic function, which may also increase binding of 

nerve growth factor by sensory neurons. Following unilateral sciatic nerve 

transection, adult rats received either one of two doses of ALCAR or sham, or no 

treatment. Either 2 weeks or 2 months later, L4 and L5 dorsal root ganglia were 

harvested bilaterally, in accordance with the Animal (Scientific Procedures) Act 

1986. Neuronal death was quantified with a combination of TUNEL [TdT (terminal 

deoxyribonucleotidyl transferase) uptake nick end labelling] and neuron counts 

obtained using the optical disector technique. Sham treatment had no effect upon 

neuronal death. ALCAR treatment caused a large reduction in the number of 

TUNELpositive neurons 2 weeks after axotomy (sham treatment 33/group; lowdose 

ALCAR 6/group, P=0.132; highdose ALCAR 3/group, P

28_ Drug Saf. 1998 Dec;19(6):48194. 

Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and 

management. 

Moyle GJ, Sadler M. 

Kobler Clinic, Chelsea and Westminster Hospital, London, England. 

Distal symmetrical peripheral neuropathy is a common adverse experience in 

persons with HIV infection. This condition, which presents as a pain, numbness. 

burning and/or dysaethesia initially in the feet, is often multifactorial in 

its origin. Nucleoside analogue reverse transcriptase inhibitors represent an 

important contributor to peripheral neuropathy. Specifically, around 10% of 

patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients 

may have to discontinue therapy with these agents due to neuropathy. Prompt 

withdrawal of these therapies enables gradual resolution of signs and symptoms 

in most patients, although a period of symptom intensification may occur shortly 

after withdrawal. Risk factors for developing peripheral neuropathy during 

nucleoside analogue therapy include low CD4+ cell count (

forebrain of treated animals, especially in the intermediate performance group. 

These results suggest a performancedependent effect of ALCAR and a nonlinear 

relationship between NGF levels and learning ability in aged rats. 

30_ Neurochem Res. 1997 Mar;22(3):25765. 

AcetylLcarnitine arginine amide prevents beta 2535induced neurotoxicity in 

cerebellar granule cells. 

Scorziello A, Meucci O, Calvani M, Schettini G. 

Institute of Pharmacology, School of Medicine, University of Genova, Italia. 

Cerebellar granule cells (CGC) at different stages of maturation in vitro (1 or 

6 DIV), were treated with beta 2535 and acetylLcarnitine arginine amide 

(ST857) in presence of 25 mM KCl in the culture medium, and neuronal viability 

was assessed. Three days of treatment slightly modified the survival of 1 

DIVtreated cells, which degenerate and die five days later betaamyloid 

matching. Similarly, a significative neurotoxic effect was observed on 6 DIV 

treatedcells after 5 days of exposure to the peptide, while the death occurred 

within 8 days. ST857 coincubated with beta 2535 was able to rescue neurons from beta 

2535induced neurotoxicity. We also studied the changes in Ca2+ 

homeostasis following glutamate stimulation, in control and betaamyloid treated 

single cells, either in presence or in absence of ST857. beta 2535 did not 

affect basal [Ca2+]i, while modified glutamateinduced [Ca2+]i increase, causing 

a sustained plateau phase of [Ca2+]i, that persisted after the removal of the 

agonist. ST857 pretreatment completely reverted this effect suggesting that, in 

CGC chronically treated with beta 2535, ST857 could protect the cells by 

neurotoxic insults of the peptide likely interfering with the cellular 

mechanisms involved in the control of Ca2+ homeostasis. 

31_ Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11733. 

Effects of acetylLcarnitine treatment and stress exposure on the nerve growth 

factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. 

Foreman PJ, PerezPolo JR, Angelucci L, Ramacci MT, Taglialatela G. 

Institute for Research on Senescence Sigma Tau, Pomezia, Italy. 

1. There is growing evidence that the nerve growth factor protein (NGF), a 

neurotrophic factor for peripheral and central nervous system (CNS) neurons, may play a 

role in the modulation of the hypothalamopituitaryadrenocortical axis 

(HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this 

reduction is prevented by treatment with AcetylLCarnitine (ALCAR), a chemical 

substance able to prevent some degenerative events associated with aging. 2. The authors 

studied the effect of cold stress on the lowaffinity NGF receptor 

(p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats 

chronically treated with ALCAR. 3. The present results show that ALCAR abolished the 



493

ageassociated reduction of p75NGFR mRNA levels in the basal forebrain of old animals, 

but did not affect the response to stress stimuli. 4. Also, 

treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old 

animals at levels almost identical to those observed in young control animals. 

5. These results suggest a neuroprotective effect for ALCAR on central 

cholinergic neurons exerted at the level of transcription of p75NGFR. The 

restoration of p75NGFR levels could increase trophic support by NGF of these CNS 

cholinergic neurons which are implicated in degenerative events associated with aging. 

32_ Neurochem Res. 1995 Jan;20(1):19. 

Neurite outgrowth in PC12 cells stimulated by acetylLcarnitine arginine amide. 

Taglialatela G, Navarra D, Olivi A, Ramacci MT, WerrbachPerez K, PerezPolo JR, 

Angelucci L. 

Institute for Research on Senescence SigmaTau, Pomezia, Italy. 

Senescence of the central nervous system is characterized by a progressive loss 

of neurons that can result in physiological and behavioral impairments. 

Reduction in the levels of central neurotrophic factors or of neurotrophin 

receptors may be one of the causes of the onset of these degenerative events. 

Thus, a proper therapeutic approach would be to increase support to degenerating 

neurons with trophic factors or to stimulate endogenous neurotrophic activity. 

Here we report that acetylLcarnitine arginine amide (ST857) is able to 

stimulate neurite outgrowth in rat pheochromocytoma PC12 cells in a manner 

similar to that elicited by nerve growth factor (NGF). Neurite induction by 

ST857 requires de novo mRNA synthesis and is independent of the action of 

several common trophic factors. The integrity of the molecular structure of 

ST857 is essential for its activity, as the single moieties of the molecule 

have no effect on PC12 cells, whether they are tested separately or together. 

Also, minor chemical modifications of ST857, such as the presence of the 

arginine moiety at a position other than the amino one, completely abolish its 

neuritogenic effect. Lastly, the presence of ST857 in the culture medium 

competes with the high affinity NGF binding in a dose dependent fashion. These 

results, although preliminary, are suggestive of a possible role for ST857 in 

the development of therapeutic strategies to counteract degenerative diseases of 

the CNS. 

33_ Int J Dev Neurosci. 1995 Feb;13(1):139. 

AcetylLcarnitine restores choline acetyltransferase activity in the 

hippocampus of rats with partial unilateral fimbriafornix transection. 

Piovesan P, Quatrini G, Pacifici L, Taglialatela G, Angelucci L. 

Institute for Research on Senescence, SigmaTau, Pomezia, Italy. 

Transection of the fimbriafornix bundle in adult rats results in degeneration 

of the septohippocampal cholinergic pathway, reminiscent of that occurring in 

aging as well as Alzheimer disease. We report here a study of the effect of a 

treatment with acetylLcarnitine (ALCAR) in threemonthold Fischer 344 rats 



494

earing a partial unilateral fimbriafornix transection. ALCAR is known to 

ameliorate some morphological and functional disturbances in the aged central 

nervous system (CNS). We used choline acetyltransferase (ChAT) and acetyl 

cholinesterase (AChE) as markers of central cholinergic function, and nerve 

growth factor (NGF) levels as indicative of the trophic regulation of the 

medioseptal cholinergic system. ChAT and AChE activities were significantly 

reduced in the hippocampus (HIPP) ipsilateral to the lesion as compared to the 

contralateral one, while no changes were observed in the septum (SPT), nucleus 

basalis magnocellularis (NBM) or frontal cortex (FCX). ALCAR treatment restored 

ChAT activity in the ipsilateral HIPP, while AChE levels were not different from 

those of untreated animals, and did not affect NGF content in either SPT or 

HIPP. 

34_ Neurol Res. 1995 Oct;17(5):3736. 

Effects of levoacetylcarnitine on second motoneuron survival after axotomy. 

Fernandez E, Pallini R, Tamburrini G, Lauretti L, Tancredi A, La Marca F. 

Department of Neurosurgery, Catholic University Medical School, Rome, Italy. 

Little is known about factors that regulate the survival of cranial motoneurons 

which project to peripheral targets. Various neurotrophic factors of central and 

peripheral origin have been isolated. In this study, we examined thirteen 

newborn Wistar rats to determine the effects of acetylLcarnitine treatment on 

the survival of motoneurons within the facial nucleus after transection of the 

facial nerve. AcetylLcarnitine was administered for 7 days in seven rats after 

nerve transection, while saline solution was injected in 6 rats used as 

controls. Both the motoneuron number and the motoneuron diameter were 

significantly higher in the facial nucleus of the rats treated with 

acetylLcarnitine than in the facial nucleus of the control rats. The results 

obtained suggest that acetylLcarnitine can rescue a substantial number of 

facial motoneurons from axotomyinduced cell death. Compared to neurotrophic 

factors, because of its simple molecular structure, acetylLcarnitine permits a 

safe oral and parenteral administration. It is suggested that acetylLcarnitine 

could be considered for use as a therapeutic agent in neurodegenerative 

disorders. 

35_ J Pharmacol Exp Ther. 1995 Jul;274(1):43743. 

Developmental deficiency of the cholinergic system in congenitally 

hyperammonemic spf mice: effect of acetylLcarnitine. 

Ratnakumari L, Qureshi IA, Maysinger D, Butterworth RF. 

Division of Medical Genetics, SainteJustine Hospital, Montreal, Quebec, Canada. 

The sparsefur (spf) mutant mouse has an Xlinked deficiency of hepatic 

ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal 

period similar to that seen in human patients. We studied the effect of 

congenital hyperammonemia on the development of cerebral cholinergic parameters 

such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and 



495

highaffinity choline uptake (HACU) in spf mice. The serum ammonia levels of spf 

mutant mice were significantly elevated after weaning compared with control 

animals. ChAT activity levels started decreasing in mutant spf mice from the age 

of 30 days (i.e., immediately after weaning); it reached significantly lower 

levels in the adult animals. HACU was consistently lower (P < .01) in spf/Y mice 

compared with controls up to the adult stage. However, there were no marked 

changes in the activity of AChE between control and hyperammonemic spf mice. The 

levels of betaNGF, which is essential for cholinergic differentiation and 

function, were significantly lower in different brain regions of adult mutant 

mice compared with normal controls. A treatment of spf/spf breeding females with 

acetylLcarnitine, at a dose of 1.5 mM in drinking water, starting from day 1 

of conception, resulted in a significant restoration of ChAT activity levels in 

some brain regions of the spf/Y offspring. The betaNGF levels were also 

significantly elevated after supplementation with ALCAR in mutant mice compared with 

untreated mutant mice. These data are suggestive of a neurotrophic property of ALCAR 

during cholinergic deficiency caused by congenital hyperammonemia. 

36_ Int J Dev Neurosci. 1995 Feb;13(1):139. 

AcetylLcarnitine restores choline acetyltransferase activity in the 

hippocampus of rats with partial unilateral fimbriafornix transection. 

Piovesan P, Quatrini G, Pacifici L, Taglialatela G, Angelucci L. 

Institute for Research on Senescence, SigmaTau, Pomezia, Italy. 

Transection of the fimbriafornix bundle in adult rats results in degeneration 

of the septohippocampal cholinergic pathway, reminiscent of that occurring in 

aging as well as Alzheimer disease. We report here a study of the effect of a 

treatment with acetylLcarnitine (ALCAR) in threemonthold Fischer 344 rats 

bearing a partial unilateral fimbriafornix transection. ALCAR is known to 

ameliorate some morphological and functional disturbances in the aged central 

nervous system (CNS). We used choline acetyltransferase (ChAT) and acetyl 

cholinesterase (AChE) as markers of central cholinergic function, and nerve 

growth factor (NGF) levels as indicative of the trophic regulation of the 

medioseptal cholinergic system. ChAT and AChE activities were significantly 

reduced in the hippocampus (HIPP) ipsilateral to the lesion as compared to the 

contralateral one, while no changes were observed in the septum (SPT), nucleus 

basalis magnocellularis (NBM) or frontal cortex (FCX). ALCAR treatment restored 

ChAT activity in the ipsilateral HIPP, while AChE levels were not different from 

those of untreated animals, and did not affect NGF content in either SPT or 

HIPP. 

37_ Neurochem Res. 1995 Jan;20(1):19. 

Neurite outgrowth in PC12 cells stimulated by acetylLcarnitine arginine amide. 

Taglialatela G, Navarra D, Olivi A, Ramacci MT, WerrbachPerez K, PerezPolo JR, 

Angelucci L. 




496

Senescence of the central nervous system is characterized by a progressive loss 

of neurons that can result in physiological and behavioral impairments. 

Reduction in the levels of central neurotrophic factors or of neurotrophin 

receptors may be one of the causes of the onset of these degenerative events. 

Thus, a proper therapeutic approach would be to increase support to degenerating 

neurons with trophic factors or to stimulate endogenous neurotrophic activity. 

Here we report that acetylLcarnitine arginine amide (ST857) is able to 

stimulate neurite outgrowth in rat pheochromocytoma PC12 cells in a manner 

similar to that elicited by nerve growth factor (NGF). Neurite induction by 

ST857 requires de novo mRNA synthesis and is independent of the action of 

several common trophic factors. The integrity of the molecular structure of 

ST857 is essential for its activity, as the single moieties of the molecule 

have no effect on PC12 cells, whether they are tested separately or together. 

Also, minor chemical modifications of ST857, such as the presence of the 

arginine moiety at a position other than the amino one, completely abolish its 

neuritogenic effect. Lastly, the presence of ST857 in the culture medium 

competes with the high affinity NGF binding in a dose dependent fashion. These 

results, although preliminary, are suggestive of a possible role for ST857 in 

the development of therapeutic strategies to counteract degenerative diseases of 

the CNS. 

38_ Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11733. 

Effects of acetylLcarnitine treatment and stress exposure on the nerve growth 

factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. 

Foreman PJ, PerezPolo JR, Angelucci L, Ramacci MT, Taglialatela G. 

005AInstitute for Research on Senescence Sigma Tau, Pomezia, Italy. 

1. There is growing evidence that the nerve growth factor protein (NGF), a 

neurotrophic factor for peripheral and central nervous system (CNS) neurons, may 

play a role in the modulation of the hypothalamopituitaryadrenocortical axis 

(HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this 

reduction is prevented by treatment with AcetylLCarnitine (ALCAR), a chemical 

substance able to prevent some degenerative events associated with aging. 2. The 

authors studied the effect of cold stress on the lowaffinity NGF receptor 

(p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats 

chronically treated with ALCAR. 3. The present results show that ALCAR abolished 

the ageassociated reduction of p75NGFR mRNA levels in the basal forebrain of 

old animals, but did not affect the response to stress stimuli. 4. Also, 

treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old 

animals at levels almost identical to those observed in young control animals. 

5. These results suggest a neuroprotective effect for ALCAR on central 

cholinergic neurons exerted at the level of transcription of p75NGFR. The 

restoration of p75NGFR levels could increase trophic support by NGF of these CNS 

cholinergic neurons which are implicated in degenerative events associated with 

aging. 



497

39_ Neurobiol Aging. 1995 JanFeb;16(1):14. 

Clinical and neurochemical effects of acetylLcarnitine in Alzheimer's disease. 

Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ. 

Department of Psychiatry, Western Psychiatric Institute and Clinic, University 

of Pittsburgh, School of Medicine, PA 15213, USA. 

In a doubleblind, placebo study, acetylLcarnitine was administered to 7 

probable Alzheimer's disease patients who were then compared by clinical and 31P 

magnetic resonance spectroscopic measures to 5 placebotreated probable AD 

patients and 21 agematched healthy controls over the course of 1 year. Compared 

to AD patients on placebo, acetylLcarnitinetreated patients showed 

significantly less deterioration in their MiniMental Status and Alzheimer's 

Disease Assessment Scale test scores. Furthermore, the decrease in 

phosphomonoester levels observed in both the acetylLcarnitine and placebo AD 

groups at entry was normalized in the acetylLcarnitinetreated but not in the 

placebotreated patients. Similar normalization of highenergy phosphate levels 

was observed in the acetylLcarnitinetreated but not in the placebotreated 

patients. This is the first direct in vivo demonstration of a beneficial effect 

of a drug on both clinical and CNS neurochemical parameters in AD. 

40_ Brain Res. 1995 Mar 13;674(1):1426. 

Spatial discrimination learning and choline acetyltransferase activity in 

streptozotocintreated rats: effects of chronic treatment with acetylLcarnitine. 

Prickaerts J, Blokland A, Honig W, Meng F, Jolles J. 

Department of Psychiatry and Neuropsychology, University of Limburg, Maastricht, 

The Netherlands. 

Treatment of rats with i.c.v. injected streptozotocin (STREP) may provide a 

relevant model of neurodegeneration that is induced by a decrease in the central 

metabolism of glucose. AcetylLcarnitine (ALCAR) enhances the utilization of 

alternative energy sources and by such a mechanism of action ALCAR could 

antagonize the effects of STREP treatment. In this study the effects of chronic 

treatment with ALCAR were evaluated on spatial discrimination learning in the 

Morris task and choline acetyltransferase (ChAT) activity of middleaged 

STREPtreated rats. Chronic treatment with ALCAR attenuated both the 

STREPinduced impairment in spatial bias and the decrease in hippocampal ChAT 

activity. These findings indicate that ALCAR treatment has a neuroprotective 

effect, although further studies are needed to characterize the mechanism of 

action of ALCAR in this model. 

41_ Brain Res. 1994 Jan 7;633(12):7782. 

AcetylLcarnitine treatment increases choline acetyltransferase activity and 

NGF levels in the CNS of adult rats following total fimbriafornix transection. 

Piovesan P, Pacifici L, Taglialatela G, Ramacci MT, Angelucci L. 




498

Transection of the fimbriafornix in adult rats is a useful model for producing 

impairments of cholinergic activity in the hippocampus (HIPP) and atrophy of the 

medial septum cholinergic perikarya, similar to those observed during 

senescence, that are possibly due to the lack of nerve growth factor (NGF) 

retrogradely transported from the hippocampus. In our investigation we used 

choline acetyltransferase (ChAT) as an index of cholinergic activity in HIPP, 

frontal cortex (FCX), septum and nucleus basalis magnocellularis (NBM) along 

with measurements of NGF levels in the HIPP. Threemonthold rats with 

unilateral total fimbria transection received acetylLcarnitine (ALCAR) (150 

mg/kg/day) in drinking water for 1 week before and 4 weeks after the lesion). 

ALCAR is a substance known to ameliorate some morphological and functional 

disturbances in the aging central nervous system (CNS). ChAT activity in septum 

and FCX, and NGF levels in HIPP were significantly increased in the treated 

group, compared with untreated control groups, while no changes were found in 

the NBM. On the other hand, a similar ALCAR treatment in unoperated animals 

induced an increase in ChAT activity in FCX but not in septum nor in NBM. These 

data are suggestive of a neurotrophic property of ALCAR exerted on those central 

cholinergic pathways typically damaged by aging. 

42_ Exp Gerontol. 1994 JanFeb;29(1):5566. 

AcetylLcarnitine treatment increases nerve growth factor levels and choline 

acetyltransferase activity in the central nervous system of aged rats. 

Taglialatela G, Navarra D, Cruciani R, Ramacci MT, Alema GS, Angelucci L. 


The hypothesis that some neurodegenerative events associated with ageing of the 

central nervous system (CNS) may be due to a lack of neurotrophic support to 

neurons is suggestive of a possible reparative pharmacological strategy intended 

to enhance the activity of endogenous neurotrophic agents. Here we report that 

treatment with acetyllcarnitine (ALCAR), a substance which has been shown to 

prevent some impairments of the aged CNS in experimental animals as well as in 

patients, is able to increase the levels and utilization of nerve growth factor 

(NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be 

attained when ALCAR is given either for long or short periods to senescent 

animals of various ages, thus indicating a direct effect of the substance on the 

NGF system which is independent of the actual degenerative stage of the neurons. 

Furthermore, longterm treatment with ALCAR completely prevents the loss of 

choline acetyltransferase (ChAT) activity in the CNS of aged rats, suggesting 

that ALCAR may rescue cholinergic pathways from ageassociated degeneration due to 

lack of retrogradely transported NGF. 

43_ Life Sci. 1994;54(17):120514. 

AcetylLcarnitine affects aged brain receptorial system in rodents. 

Castorina M, Ferraris L. 

Institute for Research on Senescence, SigmaTau, Pomezia, Rome, Italy. 



499

AcetylLcarnitine (ALCAR), the acetyl ester of carnitine, is regarded as a 

compound of considerable interest because of its capacity to counteract several 

physiological and pathological modifications typical of brain ageing processes. 

In particular, it has been demonstrated that ALCAR can counteract the 

agedependent reduction of several receptors in the central nervous system of 

rodents, such as the NMDA receptorial system, the Nerve Growth Factor (NGF) 

receptors, those of glucocorticoids, neurotransmitters and others, thereby 

enhancing the efficiency of synaptic transmission, which is considerably slowed 

down by ageing. The present review thus postulates the importance of ALCAR 

administration in preserving and/or facilitating the functionality of 

carnitines, the concentrations of which are diminished in the brain of old 

animals. 

44_ Biochem Pharmacol. 1992 Aug 4;44(3):57785. 

Stimulation of nerve growth factor receptors in PC12 by acetylLcarnitine. 


PerezPolo JR. 



AcetylLcarnitine (ALCAR) prevents some deficits associated with aging in the 

central nervous system (CNS), such as the agedrelated reduction of nerve growth 

factor (NGF) binding. The aim of this study was to ascertain whether ALCAR could 

affect the expression of an NGF receptor (p75NGFR). Treatment of PC12 cells with 

ALCAR increased equilibrium binding of 125INGF. ALCAR treatment also increased 

the amount of immunoprecipitable p75NGFR from PC12 cells. Lastly, the level of 

p75NGFR messenger RNA (mRNA) in PC12 was increased following ALCAR 

treatment. These results are in agreement with the hypothesis that there is a direct action 

of ALCAR on p75NGFR expression in aged rodent CNS. 

45_ Int J Dev Neurosci. 1992 Aug;10(4):3219. 

Culture of dorsal root ganglion neurons from aged rats: effects of acetylLcarnitine and 

NGF. 

Manfridi A, Forloni GL, ArrigoniMartelli E, Mancia M. 

Institute of Human Physiology II, University of Milan, Italy. 

In vitro neuronal preparations are used to study the action mechanism of 

substances which are active in normal and pathological brain aging. One major 

concern with in vitro assays is that the use of embryonic or adult neurons may 

hamper an appreciation of the relevance of these substances on aged nervous 

tissue. In the present study for the first time cultures of aged dorsal root 

ganglia from 24monthsold rats were maintained in vitro up to 2 weeks. This 

model was used to investigate the neurotrophic/neuroprotective action of nerve 

growth factor and acetylLcarnitine. A large population of aged dorsal root 

ganglia neurons was responsive to nerve growth factor (100 ng/ml). Nerve growth 

factor induced an increase of initial rate of axonal regeneration and influenced 



500

the survival time of these neurons. AcetylLcarnitine (250 microM) did not 

affect the axonal regeneration but substantially attenuated the rate of neuronal 

mortality. A significant difference was evident between the 

acetylLcarnitinetreated and the untreated neurons from the first cell 

counting (day 3 in culture). After 2 weeks the number of aged neurons treated 

with acetylLcarnitine was almost double that of the controls. The effects of 

acetylLcarnitine on aged DRG neurons potentially explain the positive effects 

in clinical and in vivo experimental studies. 

46_ Brain Res Dev Brain Res. 1991 Apr 24;59(2):22130. 

AcetylLcarnitine enhances the response of PC12 cells to nerve growth factor. 


PerezPolo JR. 



We have demonstrated that treatment of rat pheochromocytoma (PC12) cells with 

acetylLcarnitine (ALCAR) stimulates the synthesis of nerve growth factor 

receptors (NGFR). ALCAR has also been reported to prevent some agerelated 

impairments of the central nervous system (CNS). In particular, ALCAR reduces 

the loss of NGFR in the hippocampus and basal forebrain of aged rodents. On 

these bases, a study on the effect of NGF on the PC12 cells was carried out to 

ascertain whether ALCAR induction of NGFR resulted in an enhancement of NGF 

action. Treatment of PC12 cells for 6 days with ALCAR (10 mM) stimulated 

[125I]NGF PC12 cell uptake, consistent with increased NGFR levels. Also, neurite 

outgrowth elicited in PC12 cells by NGF (100 ng/ml) was greatly augmented by 

ALCAR pretreatment. When PC12 cells were treated with 10 mM ALCAR and then 

exposed to NGF (1 ng/ml), an NGF concentration that is insufficient to elicit 

neurite outgrowth under these conditions, there was an ALCAR effect on neurite 

outgrowth. The concentration of NGF necessary for survival of serumdeprived 

PC12 cells was 100fold lower for ALCARtreated cells as compared to controls. 

The minimal effective dose of ALCAR here was between 0.1 and 0.5 mM. This is 

similar to the reported minimal concentration of ALCAR that stimulates the 

synthesis of NGFR in these cells. The data here presented indicate that one 

mechanism by which ALCAR rescues aged neurons may be by increasing their 

responsiveness to neuronotrophic factors in the CNS. 

47_ Int J Dev Neurosci. 1991;9(1):3946. 

Effect of acetylLcarnitine on forebrain cholinergic neurons of developing rats. 

De Simone R, Ramacci MT, Aloe L. 

Institute of Neurobiology, C.N.R., Rome, Italy. 

It has been shown that the endogenous compound, acetylLcarnitine (ALCAR), acts 

in the brain as a metabolic cofactor in the synthesis of acetylcholine. In these 

studies, ALCAR was injected into the brain of developing rats every other day 

for the first three weeks after birth in order to assess its effect on forebrain 



501

cholinergic neurons. The results showed that intracerebroventricular (icv) 

administration of ALCAR causes an increase of choline acetyltransferase (ChAT) 

activity and of nerve growth factor receptor expression in the striatum. 

Biological assays of brain tissues revealed that the level of nerve growth 

factor (NGF) in the hippocampus also increases. The ability of brain cholinergic 

tissues to respond to exogenous administration of ALCAR is discussed. 

48_ J Neurosci Res. 1990 Mar;25(3):3315. 

125Ibetanerve growth factor binding is reduced in rat brain after stress exposure. 

Taglialatela G, Angelucci L, Ramacci MT, Foreman PJ, PerezPolo JR. 



In the central nervous system (CNS), the presence of nerve growth factor (NGF) 

and its receptor, NGFR, in cholinergic neurons has been demonstrated. In this 

study we report that, after exposure to stress, there was a reduction in total 

binding of NGF in the hippocampus and basal forebrain of 3.5monthold rats 

without significant changes in the frontal cortex or cerebellum. Chronic 

treatment with acetyllcarnitine (ALCAR), that prevents some agerelated 

impairments of CNS, for 1.5 months, decreased NGF binding in hippocampus and 

basal forebrain but abolished the stressrelated reduction of NGF binding 

observed in the hippocampus of untreated rats. 


Nerve growth factor binding in aged rat central nervous system: effect of 

acetylLcarnitine. 

Angelucci L, Ramacci MT, Taglialatela G, Hulsebosch C, Morgan B, WerrbachPerez 

K, PerezPolo R. 

Department of Pharmacology, University of Rome, Italy. 

The nerve growth factor protein (NGF) has been demonstrated to affect neuronal 

development and maintenance of the differentiated state in certain neurons of 

the peripheral and central nervous system (CNS) of mammals. In the CNS, NGF has 

sparing effects on cholinergic neurons of the rodent basal forebrain (BF) 

following lesions where it selectively induces choline acetyltransferase (ChAT). 

NGF also induces ChAT in the areas to which BF provides afferents. In aged rats, 

there is a reduction in the NGFbinding capacity of sympathetic ganglia. Here, 

we wish to report that there is a decrease in the NGFbinding capacity of the 

hippocampus and basal forebrain of aged (26monthold) rats as compared to 

4monthold controls but no change in NGF binding in cerebellum. In all 

instances, equilibrium binding dissociation constants did not differ 

significantly. Treatment of rats with acetylLcarnitine, reported to improve 

cognitive performance of aged rats, ameliorates these agerelated deficits. 



502

Alpha Lipoic Acid - 70 ABSTRACTS 

ALPHA LIPOIC ACID: 70 RESEARCH ABSTRACTS 

1. Endocr Rev. 2002 Oct;23(5):599-622. 

Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 

diabetes. 

Evans JL, Goldfine ID, Maddux BA, Grodsky GM. 

University of California at San Francisco, San Francisco, California 94143, USA. 

jevansphd@earthlink.net 

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, 

vascular endothelium, and kidney arise from chronic elevations of glucose and 

possibly other metabolites including free fatty acids (FFA). Recent evidence 

suggests that common stress-activated signaling pathways such as nuclear 

factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein 

kinases underlie the development of these late diabetic complications. In 

addition, in type 2 diabetes, there is evidence that the activation of these 

same stress pathways by glucose and possibly FFA leads to both insulin 

resistance and impaired insulin secretion. Thus, we propose a unifying 

hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear 

factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein 

kinases stress pathways, along with the activation of the advanced glycosy ation endproducts/receptor 

for advanced glycosylation end-products, protein kinase C, and sorbitol 

stress pathways, plays a key role in causing late complications in type 1 and type 2 

diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. 

Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine 

suggest that new strategies may become available to treat these conditions. 

2. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10. 

Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by 

direct interaction with DNA. 

Lee HA, Hughes DA. 

Immunology Group, Nutrition and Consumer Science Division, Institute of Food 

Research, Norwich Research Park, Colney, Norwich, Norfolk NR4 7UA, UK. 

The constitutive activity of the redox-sensitive transcription factor, 

NF-kappaB, which regulates the production of many inflammatory cytokines and 

adhesion molecules, appears to be up-regulated in an age-associated manner and it is 

thought this might contribute to the increased incidence of chronic 



503

inflammatory conditions observed with increasing age. As some antioxidants have 

demonstrated protective effects against rheumatoid arthritis, we are 

investigating the effects of vitamin E, vitamin C and alpha-lipoic acid (ALA) on 

NF-kappaB activity and on the expression of intracellular adhesion molecule 

(ICAM)-1. MonoMac6 cells (a human monocytic cell line) stimulated with tumour 

necrosis factor-alpha (TNF-alpha) were treated with antioxidants at 

physiological achievable levels and ICAM-1 mRNA levels investigated. Both 

vitamin E and vitamin C had no effect on ICAM-1 expression at the doses used, 

but ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent 

manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced NFkappaB 

activity in these cells in a dose-dependent manner. Addition of ALA to the 

binding reaction of nuclear extract with DNA prior to gel-shift analysis showed that it 

caused inhibition at this level. These initial results suggest that antioxidant modulation of 

monocyte activity might have potential benefits in inhibiting the dysregulated activity of 

redox-sensitive transcription factors that occurs with increasing age. 

3. FASEB J. 2001 Nov;15(13):2423-32. 

Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion 

molecule expression in human aortic endothelial cells. 

Zhang WJ, Frei B. 

Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA. 

Endothelial activation and monocyte adhesion are initiating steps in 

atherogenesis thought to be caused in part by oxidative stress. The metabolic 

thiol antioxidant alpha-lipoic acid has been suggested to be of therapeutic 

value in pathologies associated with redox imbalances. We investigated the role 

of (R)-alpha-lipoic acid (LA) vs. glutathione and ascorbic acid in tumor 

necrosis factor alpha (TNF-alpha) -induced adhesion molecule expression and 

nuclear factor kappaB (NF-kappaB) signaling in human aortic endothelial cells 

(HAEC). Preincubation of HAEC for 48 h with LA (0.05-1 mmol/l) dose-dependently 

inhibited TNF-alpha (10 U/ml) -induced adhesion of human monocytic THP-1 cells, as 

well as mRNA and protein expression of E-selectin, vascular cell adhesion molecule 1 

and intercellular adhesion molecule 1. LA also strongly inhibited TNF-alpha-induced 

mRNA expression of monocyte chemoattractant protein-1 but did not affect expression of 

TNF-alpha receptor 1. Furthermore, LA dose-dependently inhibited TNF-alphainduced 

IkappaB kinase activation, subsequent degradation of IkappaB, the 

cytoplasmic NF-kappaB inhibitor, and nuclear translocation of NF-kappaB. In 

contrast, TNF-alpha-induced NF-kappaB activation and adhesion molecule expression 

were not affected by ascorbic acid or by manipulating cellular glutathione status with l-2oxo-4-thiazolidinecarboxylic 

acid, N-acetyl-l-cysteine, or d,l-buthionine-S,Rsulfoximine. 

Our data show that clinically relevant concentrations of LA, but neither 

vitamin C nor glutathione, inhibit adhesion molecule expression in HAEC and monocyte 

adhesion by inhibiting the IkappaB/NF-kappaB signaling pathway at the level, or 

upstream, of IkappaB kinase. 

4. Drug Metab Rev. 1998 May;30(2):245-75. 



504

alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal 

transduction and protects against oxidative injury. 

Packer L. 

Department of Molecular and Cell Biology, University of California, Berkeley 

94720-3200, USA. 

Although the metabolic role of alpha-lipoic acid has been known for over 40 

years, it is only recently that its effects when supplied exogenously have 

become known. Exogenous alpha-lipoic acid is reduced intracellularly by at least 

two and possibly three enzymes, and through the actions of its reduced form, it 

influences a number of cell process. These include direct radical scavenging, 

recycling of other antioxidants, accelerating GSH synthesis, and modulating 

transcription factor activity, especially that of NF-kappa B (Fig. 12). These 

mechanisms may account for the sometimes dramatic effects of alpha-lipoic acid 

in oxidative stress conditions (e.g., brain ischemia-reperfusion), and point the 

way toward its therapeutic use. 

5. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1709-15. 

Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T 

cells. 

Suzuki YJ, Aggarwal BB, Packer L. 

Department of Molecular & Cell Biology, University of California, Berkeley 

94720. 

Acquired immunodeficiency syndrome (AIDS) results from infection with a human 

immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV 

proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and 

this transcriptional activator appears to regulate HIV activation. Recent 

findings suggest an involvement of reactive oxygen species (ROS) in signal 

transduction pathways leading to NF-kappa B activation. The present study was 

based on reports that antioxidants which eliminate ROS should block the 

activation of NF-kappa B and subsequently HIV transcription, and thus 

antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T 

cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, alpha-lipoic acid, 

prior to the stimulation of cells was found to inhibit NF-kappa B activation 

induced by tumor necrosis factor-alpha (25 ng/ml) or by phorbol 12-myristate 

13-acetate (50 ng/ml). The inhibitory action of alpha-lipoic acid was found to 

be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was 

required for N-acetylcysteine. These results indicate that alpha-lipoic acid may be 

effective in AIDS therapeutics. 

AGING 

6. J Alzheimers Dis. 2003 Jun;5(3):229-39. 

Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha 

lipoic acid. 



505

Lovell MA, Xie C, Xiong S, Markesbery WR. 

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. 

Current evidence supports the role of oxidative stress in the pathogenesis of neuron 

degeneration in Alzheimer's disease (AD). alpha-Lipoic acid (LA), an essential 

cofactor in mitochondrial dehydrogenase reactions, functions as an antioxidant and 

reduces oxidative stress in aged animals. Here, we describe the effects of LA and its 

reduced form, dihydrolipoic acid (DHLA), in neuron cultures treated with amyloid betapeptide 

(Abeta 25-35) and iron/hydrogen peroxide (Fe/H_2O_2). Pretreatment of 

dissociated primary hippocampal cultures with LA significantly protected against Abeta 

and Fe/H_2O_2toxicity. In contrast, concomitant treatment of cultures with LA and 

Fe/H_2O_2 significantly potentiated the toxicity. Decreased cell survival in cultures 

treated concomitantly with LA and Fe/H_2O_2 correlated with increased free radical 

production measured by dichlorofluorescein fluorescence. Treatment of cortical neurons 

with DHLA significantly protected glucose-transport against Fe/H_2O_2 or betamediated 

decreases although treatment with LA did not provide protection. These data 

suggest that DHLA, the reduced form of LA, significantly protects against both Abetaand 

Fe/H_2O_2 mediated toxicity. The data also suggest that concomitant exposure to LA 

and Fe/H_2O_2 significantly potentiates the oxidative stress. Overall, these data suggest 

that the oxidation state of LA is critical to its function and that in the absence of studies 

of LA/DHLA equilibria 

in human brain the use of LA as an antioxidant in disorders where there is increased Fe 

such as AD is of questionable efficacy. 


Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse 

hippocampal HT22 cells. 

Pirlich M, Kiok K, Sandig G, Lochs H, Grune T. 

Department of Gastroenterology and Hepatology, University Hospital Charite, 

Humboldt-University Berlin, Schumannstr. 20/21, 10098, Berlin, Germany. 

Oxidative stress is involved in a number of neurological disorders, including 

the neurotoxic effects of ethanol. Recent studies have described a 

neuroprotective potential of alpha-lipoic acid (LC) in several models of 

neuronal cell death related to oxidative stress. We tested the hypothesis that 

LC could be effective in preventing ethanol-induced neurotoxicity employing the 

clonal hippocampa cell line HT22. A 24 h incubation with ethanol 100-600 mM 

caused a dose-dependent loss of cell viability and a significant increase of the 

overall intracellular protein oxidation. Coincubation with LC 0.1 mM resulted in 

a significant decrease of ethanol-related neurotoxicity and a complete 

prevention of the ethanol-induced intracellular protein oxidation. These results 

indicate that the radical scavenging properties of LC are effective to 

ameliorate ethanol-induced neurotoxicity. 

8. Neurosci Lett. 2002 Mar 15;321(1-2):100-4. 

Beneficial effects of alpha-lipoic acid plus vitamin E on neurological deficit, 



506

eactive gliosis and neuronal remodeling in the penumbra of the ischemic rat 

brain. 

Gonzalez-Perez O, Gonzalez-Castaneda RE, Huerta M, Luquin S, Gomez-Pinedo U, 

Sanchez-Almaraz E, Navarro-Ruiz A, Garcia-Estrada J. 

Division de Neurociencias, Centro de Investigacion Biomedica de Occidente (CIBO) del 

Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Guadalajara 

Jalisco 44340, Mexico. 

During cerebral ischemia-reperfusion, the enhanced production of oxygen-derived free 

radicals contributes to neuronal death. The antioxidants alpha-lipoic acid and vitamin E 

have shown synergistic effects against lipid peroxidation by 

oxidant radicals in several pathological conditions. A thromboembolic stroke 

model in rats was used to analyze the effects of this mixture under two oral 

treatments: intensive and prophylactic. Neurological functions, glial reactivity 

and neuronal remodeling were assessed after experimental infarction. 

Neurological recovery was only found in the prophylactic group, and both 

antioxidant schemes produced down-regulation of astrocytic and microglial 

reactivity, as well as higher neuronal remodeling in the penumbra area, as 

compared with controls. The beneficial effects of this antioxidant mixture 

suggest that it may be valuable for the treatment of cerebral ischemia in 

humans. 

9. Free Radic Biol Med. 1997;22(1-2):359-78. 




94720-3200, USA. 

Reactive oxygen species are thought to be involved in a number of types of acute and 

chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant 

alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric 

acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed 

from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced 

in cells and tissues to 

dihydrolipoate, which is also exported to the extracellular medium; hence, 

protection is afforded to both intracellular and extracellular environments. 

Both alpha-lipoate and especially dihydrolipoate have been shown to be potent 

antioxidants, to regenerate through redox cycling other antioxidants like 

vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it 

would seem an ideal substance in the treatment of oxidative brain and neural 

disorders involving free radical processes. Examination of current research 

reveals protective effects of these compounds in cerebral ischemia-reperfusion, 

excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and 

diabetic neuropathy, inborn errors of metabolism, and other causes of acute or 

chronic damage to brain or neural tissue. Very few neuropharmacological intervention 

strategies are currently available for the treatment of stroke and numerous other brain 



507

disorders involving free radical injury. We propose that the various metabolic antioxidant 

properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and 

neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other 

tissues. The most important thiol antioxidant, glutathione, cannot be directly 

administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary 

human studies indicate that alpha-lipoate may be effective in numerous 

neurodegenerative disorders. 

CATARACT 

10. Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):44-50. 

Cataract development in diabetic sand rats treated with alpha-lipoic acid and 

its gamma-linolenic acid conjugate. 




BACKGROUND: Diabetes commonly leads to long-term complications such as cataract. 

This study investigated the effects of alpha-lipoic acid (LPA) and its 

gamma-linolenic acid (GLA) conjugate on cataract development in diabetic sand 

rats. METHODS: Two separate experiments were conducted. In Experiment 1, sand rats 

were fed a "high-energy" diet (70% starch), an acute model of Type 2 

diabetes, and injected with LPA. In Experiment 2, the animals received a 

"medium-energy" diet (59% starch), a chronic diabetic model, and were intubated 

with LPA or its GLA conjugate. Throughout the experiments, blood glucose levels 

and cataract development were measured. At the termination of the experiments, 

lens aldose reductase (AR) activity and lenticular reduced glutathione (GSH) 

levels were analyzed. RESULTS: LPA injection significantly inhibited cataract 

development and reduced blood glucose levels in rats fed the "high-energy" diet. 

Lens AR activity tended to be lower, while lenticular GSH levels increased. In 

sand rats fed a "medium-energy" diet (59% starch), LPA intubation had no effect 

on blood glucose levels and cataract development but GSH levels were increased. In 

contrast, sand rats intubated with GLA conjugate showed the highest blood glucose levels 

and accelerated cataract development. The conjugate treatment also decreased lenticular 

GSH content. CONCLUSIONS: The hypoglycemic effects of LPA are beneficial in the 

prevention of acute symptoms of Type 2 diabetes. It remains to be shown that the 

antioxidant activity of LPA is responsible for prevention or inhibition of cataract 

progression in sand rats. Copyright 2000 John Wiley & Sons, Ltd. 


Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on 

glutathione concentrations in lens in model diabetic cataractogenesis. 

Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. 

Department of Biochemistry, University of Western Ontario, London, Canada. 



508

In previous studies stereospecific protection against lens opacity was 

consistent with specific reduction of R-alpha-lipoic acid(R-alpha-LA) in 

mitochondria of the vulnerable cells at the lens equator where the first 

globular degeneration is seen in glucose cataract. In this study two further 

possible explanations of this effect were investigated: (1) increased glucose 

uptake by the lens, leading to increased glycolysis and release of lactate into 

the incubation medium and/or (2) maintenance of glutathione levels by the 

R-alpha-LA. The data did not support 1, but was consistent with 2, after 24 hr 

incubation. The concentrations of glutathione in normal lenses or lenses 

incubated with R- or racemic alpha-LA were not significantly different, but the 

concentration of glutathione in lenses incubated with S-alpha-LA was 

significantly lower than the R-alpha-LA-incubated lenses. 

12. Biochem Biophys Res Commun. 1996 Apr 16;221(2):422-9. 

Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced 

cataract formation in newborn rats. 

Maitra I, Serbinova E, Tritschler HJ, Packer L. 

Department of Molecular and Cell Biology, University of California, Berkeley, 

94720-3200, USA. 

This study revealed a marked stereospecificity in the prevention of buthionine 

sulfoximine-induced cataract, and in the protection of lens antioxidants, in 

newborn rats by alpha-lipoate, R- and racemic alpha-lipoate decreased cataract 

formation from 100% (buthionine sulfoximine only) to 55% (buthionine sulfoximine + 

R-alpha-lipoic acid) and 40% (buthionine sulfoximine + rac-alpha-lipoic acid) (p

glucose-induced lens membrane damage, a model of diabetic cataractogenesis. 

Kilic F, Handelman GJ, Serbinova E, Packer L, Trevithick JR. 

Dept. of Biochemistry, University of Western Ontario, London, Canada. 

The effect of R, S, and racemic forms of a-lipoic acid was tested on the 

formation of opacity in normal rat lenses incubated with 55.6 mM glucose, as a 

model for in vivo diabetic cataractogenesis. Control lenses, incubated 8 days 

with 5.56 mM glucose, did not develop opacities. Formation of lens opacities in 

vitro was correlated with lactate dehydrogenase (LDH) leakage into the 

incubation medium. Opacity formation and LDH leakage, resulting from incubation in 

medium containing 55.6 mM glucose to model diabetes, were both suppressed by the 

addition of 1 mM R-lipoic acid. Addition of 1 mM racemic lipoic acid reduces these 

damaging effects to the lens by one-half, while S-lipoic acid potentiated LDH leakage, 

consistent with the hypothesis that R-lipoic acid is the active form. Although HPLC 

analysis demonstrated that both stereoisomers of lipoic acid were reduced to 

dihydrolipoate at comparable rates by the intact lens, the mitochondrial lipoamide 

dehydrogenase system is highly specific for reduction of exogenous R-lipoic to 

dihydrolipoic acid. Therefore, stereospecific protection against this opacity is consistent 

with specific reduction of R-lipoic acid in mitochondria of the vulnerable cells at the lens 

equator where the first 

globular degeneration is seen in glucose cataract. 

____________________________________________________________ 

DIABETES 

14. Vnitr Lek. 2002 Jun;48(6):534-41. 

[Autonomic neuropathy in diabetics, treatment possibilities] [Article in Czech] 

Lacigova S, Rusavy Z, Cechurova D, Jankovec Z, Zourek M. 

I. interni klinika Fakultni nemocnice, Plzen. 

Diabetic neuropathy is a chronic complication of diabetes. It involves 

non-inflammatory damage of the function and structure of peripheral nerves by 

metabolic vascular pathogenic processes. In case of affection of vegetative 

nerves (small non-myelinated C fibres) autonomic neuropathy develops. It is a 

relatively frequent form of neuropathy which remains for a long time without 

clinical symptoms and therefore is rarely diagnosed and treated. Manifestations 

of the affection are encountered in all organs which are supplied by vegetative 

nerves. The presence of this complication of diabetes is signalized by 

tachycardia at rest, deterioration of gastric evacuation, diabetic diarrhoea or 

constipation, erectile dysfunction, impaired function of the sweat glans or 

impaired pupillary reaction. The advanced form involves the danger of latent 

myocardial ischaemia, serious postural hypotension and sudden death. It 

increases significantly the mortality of the affected patients. Similarly as the 

treatment of other complication of diabetes, treatment of autonomic neuropathy 

is difficult. The objective of the present paper is to review contemporary 



510

therapeutic possibilities. An essential prerequisite remain efforts to achieve 

optimal compensation. The authors draw attention to the effect of alpha-lipoic 

acid which exerts a positive effect not only on subjective symptoms but also on 

the objective finding. The other mentioned drugs are used either only 

experimentally or for purely symptomatic treatment. 

15. Diabetes Metab Res Rev. 2002 May-Jun;18(3):176-84. 

Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and 

treatment perspectives. 

van Dam PS. 

Department of Internal Medicine and Endocrinology, University Medical Center, 

Utrecht, The Netherlands. P.S.vanDam@digd.azu.nl 

Increased oxidative stress is a mechanism that probably plays a major role in 

the development of diabetic complications, including peripheral neuropathy. This 

review summarises recent data from in vitro and in vivo studies that have been 

performed both to understand this aspect of the pathophysiology of diabetic 

neuropathy and to develop therapeutic modalities for its prevention or 

treatment. Extensive animal studies have demonstrated that oxidative stress may 

be a final common pathway in the development of diabetic neuropathy, and that 

antioxidants can prevent or reverse hyperglycaemia-induced nerve dysfunction. 

Most probably, the effects of antioxidants are mediated by correction of 

nutritive blood flow, although direct effects on endoneurial oxidative state are 

not excluded. In a limited number of clinical studies, antioxidant drugs 

including alpha-lipoic acid and vitamin E were found to reduce neuropathic 

symptoms or to correct nerve conduction velocity. These data are promising, and 

additional larger studies with alpha-lipoic acid are currently being performed. 

Copyright 2002 John Wiley & Sons, Ltd. 

Endocr Pract. 2002 Jan-Feb;8(1):29-35. 

Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, 

controlled-release formulation of alpha-lipoic acid. 

Evans JL, Heymann CJ, Goldfine ID, Gavin LA. 

Northern California Diabetes Institute, Seton Medical Center, Dale City, CA 

94015, USA. 

OBJECTIVE: To determine the pharmacokinetics, safety, and tolerability of a 

novel, controlled-release oral formulation of alpha-lipoic acid (LA) and to 

investigate whether sustaining the concentration of LA in plasma would have a 

beneficial effect on glycemic control in patients with type 2 diabetes. METHODS: 

For the pharmacokinetic study, a single, 600-mg dose of either 

controlled-release LA (CRLA) or quick-release LA (QRLA) was administered orally to 

12 normal human subjects. The plasma profile of LA was determined for 24 hours after 

administration of the dose,and pharmacokinetic analyses were 

performed. For the safety and tolerability study, 21 patients with type 2 

diabetes were given 900 mg of CRLA daily for 6 weeks, followed by 1,200 mg of 



511

CRLA daily for an additional 6 weeks. Active treatment was followed by a 3-week 

washout period. Throughout the study, patients continued to take their prestudy 

antidiabetic medications, which included metformin (Glucophage), sulfonylureas 

(Amaryl, glyburide, and Glucotrol), acarbose (Precose), troglitazone (Rezulin), 

and insulin (either as monotherapy or in combination). CRLA was evaluated for 

safety and tolerability as well as for effects on glycemic control. RESULTS: The 

Tmax (time to maximal plasma concentration) of LA administered as CRLA was 1.25 

hours and was approximately 2.5-fold longer in comparison with the Tmax for QRLA 

(Tn,5X = 0.5 hour; P

Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes. 

Ruhe RC, McDonald RB. 

Department of Nutrition, University of California, Davis 95616-8669, USA. 

Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), is 

increasingly common throughout the world. The World Health Organization has 

predicted that between 1997 and 2025, the number of diabetics will double from 

143 million to about 300 million. The incidence of NIDDM is highest in 

economically developed nations, particularly the U.S., where approximately 6.5% 

of the population (17 million people) have either diagnosed or undiagnosed 

diabetes. The two most important factors contributing to the development of 

NIDDM are obesity and physical inactivity. The leading cause of mortality and 

morbidity in people with NIDDM is cardiovascular disease caused by macro- and 

microvascular degeneration. Current therapies for NIDDM focus primarily on 

weight reduction. Indeed, several investigations indicate that 65% to 75% of 

cases of diabetes in Caucasians could be avoided if individuals in this subgroup 

did not exceed their ideal weight. The success of this approach has been, at 

best, modest. An alternate approach to the control of Type 2 diabetes is to 

arrest the progress of the pathology until a cure has been found. To this end, 

some investigators suggest that dietary antioxidants may be of value. Several 

studies in humans and laboratory animals with NIDDM indicate that vitamin E and 

lipoic acid supplements lessen the impact of oxidative damage caused by 

dysregulation of glucose metabolism. In this brief review, we discuss the incidence, 

etiology, and current therapies for NIDDM and further explore the usefulness of dietary 

antioxidants in treating this disorder. 

18. Metabolism. 2001 Aug;50(8):868-75. 

The effects of treatment with alpha-lipoic acid or evening primrose oil on 

vascular hemostatic and lipid risk factors, blood flow, and peripheral nerve 

conduction in the streptozotocin-diabetic rat. 

Ford I, Cotter MA, Cameron NE, Greaves M. 

Departments of Medicine & Therapeutics, University of Aberdeen, Aberdeen, 

Scotland. 

Oxidative stress and defective fatty acid metabolism in diabetes may lead to 

impaired nerve perfusion and contribute to the development of peripheral 

neuropathy. We studied the effects of 2-week treatments with evening primrose 

oil (EPO; n = 16) or the antioxidant alpha-lipoic acid (ALA; n = 16) on 

endoneurial blood flow, nerve conduction parameters, lipids, coagulation, and 

endothelial factors, in rats with streptozotocin-induced diabetes. Compared with 

their nondiabetic littermates, untreated diabetic rats had impaired sciatic 

motor and saphenous sensory nerve-conduction velocity (NCV; P

EPO effectively corrected the deficits in NCV and endoneurial blood flow. ALA was 

associated with marked and statistically significant decreases in 

fibrinogen, factor VII, vWF, and triglycerides (P

occlusion plethysmography, we examined the effects of lipoic acid (0.2 mM) and 

ascorbic acid (1 and 10 mM) on forearm blood flow responses to acetylcholine, 

sodium nitroprusside and concomitant infusion of the NO-inhibitor, 

N(G)-monomethyl-L-arginine, in 39 diabetic patients and 11 control subjects. 

Plasma levels of antioxidants and parameters of lipid peroxidation were measured and 

correlated to endothelial function tests. Lipoic acid improved NO-mediated vasodilation 

in diabetic patients, but not in controls. NO-mediated vasodilation was improved by 

ascorbic acid at 10 mM, but not 1 mM. Improvements of endothelial function by ascorbic 

acid and lipoic acid were closely related. The beneficial effects of lipoic acid were 

positively related to plasma levels of malondialdehyde and inversely related to levels 

of ubiquinol-10. These findings support the concept that oxidative stress contributes 

to endothelial dysfunction and suggest a therapeutic potential of lipoic acid 

particularly in patients with imbalance between increased oxidative stress and 

depleted antioxidant defense. 

21. Diabetes Res Clin Pract. 2001 Jun;52(3):175-83. 

Effect of alpha-lipoic acid on the progression of endothelial cell damage and 

albuminuria in patients with diabetes mellitus: an exploratory study. 

Morcos M, Borcea V, Isermann B, Gehrke S, Ehret T, Henkels M, Schiekofer S, 

Hofmann M, Amiral J, Tritschler H, Ziegler R, Wahl P, Nawroth PP. 

Department of Internal Medicine I, University of Heidelberg, Bergheimerstr. 58, 

69115 Heidelberg, Germany. michael_morcos@med.uni-heidelberg.de 

Oxidative stress plays a central role in the pathogenesis and progression of 

late microangiopathic complications (diabetic nephropathy) in diabetes mellitus. 

Previous studies suggested that treatment of diabetic patients with the 

antioxidant alpha-lipoic acid reduce oxidative stress and urinary albumin 

excretion. In this prospective, open and non-randomized study, the effect of 

alpha-lipoic acid on the progression of endothelial cell damage and the course 

of diabetic nephropathy, as assessed by measurement of plasma thrombomodulin and 

urinary albumin concentration (UAC), was evaluated in 84 patients with diabetes mellitus 

over 18 months. Forty-nine patients (34 with Type 1 diabetes, 15 with Type 2 diabetes) 

had no antioxidant treatment and served as a control group. Thirty-five patients (20 with 

Type 1 diabetes, 15 with Type 2 diabetes) were treated with 600 mg alpha-lipoic acid per 

day. Only patients with an urinary albumin concentration

antioxidant drugs. A placebo-controlled study is needed. 

22. Bull Exp Biol Med. 2000 Oct;130(10):986-90. 

The function of endogenous protective systems in patients with insulin-dependent 

diabetes mellitus and polyneuropathy: effect of antioxidant therapy. 

Strokov IA, Manukhina EB, Bakhtina LY, Malyshev IY, Zoloev GK, Kazikhanova SI, 

Ametov AS. 

Department of Endocrinology and Diabetology, Russian Medical Academy of 

Postgraduate Education, Moscow. 

alpha-Lipoic acid is a very efficient antioxidants for the treatment and 

prevention of diabetic neuropathy. The aim of the present study was to evaluate 

the function of nitric oxide (NO) and stress proteins (HSP72) in 

insulin-dependent diabetes complicated by polyneuropathy and possible 

contribution of these systems to the therapeutic effects of alpha-lipoic acid. 

Plasma content of nitrites and nitrates in diabetic patients was almost 2-fold 

below the normal. The treatment with alpha-lipoic acid completely normalized the 

plasma content of these stable NO metabolites. The majority of patients had also 

low level of HSP72. Positive clinical effects of alpha-lipoic acid were 

accompanied by normalization of HSP72 synthesis. Thus, activation of the NO and HSP 

protective systems is involved in the therapeutic effect of alpha-lipoic 

acid in diabetic patients (type 1 diabetes mellitus) with polyneuropathy. 

23. Free Radic Biol Med. 2000 Dec;29(11):1122-8. 

Lipoic acid decreases lipid peroxidation and protein glycosylation and increases 

(Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-treated human 

erythrocytes. 

Jain SK, Lim G. 

Department of Pediatrics, Louisiana State University Health Sciences Center, 

Shreveport, LA 71130, USA. sjain@lsuhsc.edu 

Lipoic acid supplementation has been found to be beneficial in preventing 

neurovascular abnormalities in diabetic neuropathy. Insufficient (Na(+) + 

K(+))-ATPase activity has been suggested as a contributing factor in the 

development of diabetic neuropathy. This study was undertaken to test the 

hypothesis that lipoic acid reduces lipid peroxidation and glycosylation and can 

increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high 

glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with 

normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid 

(mixture of S and R sterioisomers) in a shaking water bath at 37 degrees C for 24 h. 

There was a significant stimulation of glucose consumption by RBC in the presence of 

lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly 

lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC 

exposed to high glucose concentrations. High glucose treatment significantly lowered 

the activities of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. Lipoic acid 

addition significantly blocked the reduction in activities of (Na(+) + K(+))- and Ca(++)- 



516

ATPases in high glucose-treated RBC. There were no differences in lipid peroxidation, 

GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity levels in normal glucose-treated 

RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and 

protein glycosylation, and increase (Na(+) + K(+))- and Ca(++)-ATPase activities in 

high-glucose exposed RBC, which provides a potential mechanism by which lipoic 

acid may delay or inhibit the development of neuropathy in diabetes. 

24. Med Hypotheses. 2000 Dec;55(6):510-2. 

Alpha lipoic acid: a novel treatment for depression. 

Salazar MR. 

Amherst College, Amherst, Massachusetts, USA. 

Insulin resistance has been associated with people diagnosed with depression. 

Conversely, it has also been documented that diabetics have an increased risk of 

depression. Evidence suggests that insulin activity plays a role in serotonergic 

activity by increasing the influx of tryptophan into the brain. This increased 

influx of tryptophan has been shown to result in an increase in serotonin 

synthesis. In accordance with the serotonin theory of depression, it may be 

possible to treat depression by increasing insulin activity. The antioxidant 

alpha lipoic acid has been shown to increase insulin sensitivity and is used to 

treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be 

clinically tested as an adjunct treatment for depression. Copyright 2000 

Harcourt Publishers Ltd. 

25. Wien Klin Wochenschr. 2000 Jul 28;112(14):610-6. 

Therapeutic potential of glutathione. 

Exner R, Wessner B, Manhart N, Roth E. 

Department of Surgery, University of Vienna, Austria. 

Reactive oxygen species, formed in various biochemical reactions, are normally 

scavenged by antioxidants. Glutathione in its reduced form (GSH) is the most 

powerful intracellular antioxidant, and the ratio of reduced to oxidised 

glutathione (GSH:GSSG) serves as a representative marker of the antioxidative 

capacity of the cell. Several clinical conditions are associated with reduced 

GSH levels which as a consequence can result in a lowered cellular redox 

potential. GSH and the redox potential of the cell are components of the cell 

signaling system influencing the translocation of the transcription factor NF 

kappa B which regulates the synthesis of cytokines and adhesion molecules. 

Therefore, one possibility to protect cells from damage caused by reactive 

oxygen species is to restore the intracellular glutathione levels. Cellular GSH 

concentration can be influenced by exogenous administration of GSH (as 

intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such 

as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid). The 

modulation of GSH metabolism might present a useful adjuvant therapy in many 



517

pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung 

processes, coronary disease, cancer and immunodeficiency states. 

26. Exp Clin Endocrinol Diabetes. 2000;108(3):168-74. 

Effects of alpha-lipoic acid on microcirculation in patients with peripheral 

diabetic neuropathy. 

Haak E, Usadel KH, Kusterer K, Amini P, Frommeyer R, Tritschler HJ, Haak T. 

Medical Department I, Center of Internal Medicine, University Hospital, 

Frankfurt, Germany. E.Haak@em.uni-frankfurt.de 

Diabetic polyneuropathy is a serious complication in patients with diabetes 

mellitus. In addition to the maintenance of a sufficient metabolic control, 

alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) is known to have beneficial 

effects on diabetic polyneuropathy although the exact mechanism by which ALA 

exerts its effect is unknown. In order to study the effect of ALA on 

microcirculation in patients with diabetes mellitus and peripheral neuropathy 

one group of patients (4 female, 4 male, age 60+/-3 years, diabetes duration 

19+/-4 years, BMI 24.8+/-1.3 kg/m2) received 1200 mg ALA orally per day over 6 

weeks (trial 1). A second group of patients (5 female, 4 male, age 65+/-3 years, 

diabetes duration 14+/-4 years, BMI 23.6+/-0.7 kg/m2) was studied before and 

after they had received 600 mg ALA or placebo intravenously over 15 minutes in 

order to investigate whether ALA has an acute effect on microcirculation (trial 

2). Patients were investigated by nailfold video-capillaroscopy. Capillary blood 

cell velocity was examined at rest and during postreactive hyperemia (occlusion 

of the wrist for 2 minutes, 200 mmHg) which is a parameter of the perfusion 

reserve on demand. The oral therapy with ALA resulted in a significant decrease 

in the time to peak capillary blood cell velocity (tpCBV) during postocclusive 

hyperemia (trial 1: 12.6+/-3.1 vs 35.4+/-10.9 s, p

associated with oxidative stress. Lipid peroxidation of nerve membranes has been 

suggested as a mechanism by which peripheral nerve ischemia and hypoxia could cause 

neuropathy. Lipoic acid (LA) is a powerful inhibitor of iron-dependent lipid peroxidation 

and reactive oxygen species. The treatment of diabetic peripheral and cardiac autonomic 

neuropathy with LA is based on good clinical and experimental evidence. MATERIALS 

AND METHODS: To investigate the magnitude of the oxidative stress, serum 

ceruloplasmin (Cp) and lipid peroxide (Lp) levels were measured in 10 patients with 

diabetic neuropathy, before and 70 days after treatment with single dose of 600 mg 

LA/day. For other 12 healthy age- and sex-matched control subjects the serum Cp and Lp 

levels were evaluated. RESULTS: Our results show that hyperglycemia is a factor for an 

increase in serum ceruloplasmin in patients with diabetic neuropathy compared to healthy 

subjects (p < 0.0001). High serum ceruloplasmin (Cp) level in patients with diabetes may 

be related to antioxidant defense. The treatment of diabetic neuropathy with LA does not 

affect significantly the serum Cp activity. The serum Lp levels after LA administration 

were significantly lower (p < 0.005) than those before treatment. CONCLUSIONS: The 

antioxidant therapy with LA improves and may prevent diabetic neuropathy. This 

improvement is associated with a reduction in the indexes of lipid peroxidation. 

Oxidative stress appears to be primarily due to the processes of nerve ischemia and 

hyperglycemia autooxidation. 

28. Diabet Med. 1999 Dec;16(12):1040-3. 

Effects of 3-week oral treatment with the antioxidant thioctic acid 

(alpha-lipoic acid) in symptomatic diabetic polyneuropathy. 

Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schutte K, Nehrdich D, 

Tritschler HJ, Mehnert H, Ziegler D. 

Deutsches Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, 

Dusseldorf, Germany. 

AIMS: To evaluate the efficacy and safety of short-term oral treatment with the 

antioxidant thioctic acid (TA) on neuropathic symptoms and deficits in patients 

with Type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: Patients 

were randomly assigned to oral treatment with 600 mg of TA t.i.d. (n = 12) or placebo (n 

= 12) for 3 weeks. Neuropathic symptoms (pain, burning, 

paraesthesiae, and numbness) in the feet were scored at weekly intervals and 

summarized as a Total Symptom Score (TSS). The Hamburg Pain Adjective List 

(HPAL) and the Neuropathy Disability Score (NDS) were assessed at baseline and day 

19. RESULTS: At baseline the TSS, HPAL, and NDS were not significantly different 

between the groups. The TSS in the foot decreased from baseline to day 19 by -3.75 +/- 

1.88 points (-47%) in the TA group and by -1.94 +/- 1.50 points (-24%) in the placebo 

group (P= 0.021 for TA vs. placebo). The total HPAL score decreased from baseline to 

day 19 by -2.20 +/- 1.65 points (-60%) in the TA group and by -0.96 +/- 1.32 points (- 

29%) in the placebo group (P = 0.072 for TA vs. placebo). The NDS decreased by -0.27 

+/- 0.47 points in the TA group, whereas it slightly increased by +0.18 +/- 0.4 points in 

the placebo group (P = 0.025 for TA vs. placebo). No differences between the groups 

were noted regarding the rates of adverse events. CONCLUSIONS: These preliminary 

findings indicate that oral treatment with 600 mg of TA t.i.d. for 3 weeks may improve 



519

symptoms and deficits resulting from polyneuropathy in Type 2 diabetic patients, without 

causing significant adverse reactions. 

29. Biofactors. 1999;10(2-3):157-67. 

The role of oxidative stress and NF-kappaB activation in late diabetic 


Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP. 

Medizinische Klinik I der Universitat Heidelberg, Germany. 

A common endpoint of hyperglycemia dependent cellular changes is the generation of 

reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. 

Therefore, oxidative stress is supposed to play an important role in the development of 

late diabetic complications. Formation of advanced glycation end products (AGE's) due 

to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied 

by oxidative, radical-generating reactions and thus represents a major source for oxygen 

free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular 

function by binding to several binding sites including the receptor for AGE's, RAGE. 

Binding of AGE's (and other ligands) to RAGE results in generation of intracellular 

oxidative stress and subsequent activation of the redox-sensitive transcription factor NFkappaB 

in vitro and in vivo. Consistently, activation of NF-kappaB in 

diabetic patients correlates with the quality of glycemic control and can be 

reduced by treatment with the antioxidant alpha-lipoic acid. The development of 

techniques allowing for a tissue culture independent measurement of NF-kappaB 

activation in patients with diabetes mellitus gives insights into the molecular 

mechanisms linking diabetes mellitus and hyperglycemia with formation of 

advanced glycated endproducts and generation of oxidative stress finally 

resulting in oxidative stress mediated cellular activation. 


Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: 

current evidence from clinical trials. 

Ziegler D, Reljanovic M, Mehnert H, Gries FA. 

Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, 

Germany. dan.ziegler@dfi.uni-duesseldorf.de 

Diabetic neuropathy represents a major health problem, as it is responsible for 

substantial morbidity, increased mortality, and impaired quality of life. 

Near-normoglycaemia is now generally accepted as the primary approach to 

prevention of diabetic neuropathy, but is not achievable in a considerable 

number of patients. In the past two decades several medical treatments that 

exert their effects despite hyperglycaemia have been derived from the 

experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been 

designed to improve or slow the progression of the neuropathic process and are being 

evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) 

which is available in Germany, none of these drugs is 

currently available in clinical practice. Here we review the current evidence 



520

from the clinical trials that assessed the therapeutic efficacy and safety of 

thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been 

completed using different study designs, durations of treatment, doses, sample 

sizes, and patient populations. Within this variety of clinical trials, those 

with beneficial effects of thioctic acid on either neuropathic symptoms and 

deficits due to polyneuropathy or reduced heart rate variability resulting from 

cardiac autonomic neuropathy used doses of at least 600 mg per day. The 

following conclusions can be drawn from the recent controlled clinical trials. 

1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day 

appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot 

study of 1800 mg per day given orally indicates that the therapeutic effect may 

be independent of the route of administration, but this needs to be confirmed in 

a larger sample size. 2.) The effect on symptoms is accompanied by an 

improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to 

reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) 

Preliminary data over 2 years indicate possible long-term improvement in motor 

and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing 

surveillance studies have revealed a highly favourable safety profile of the 

drug. Based on these findings, a pivotal long-term multicenter trial of oral 

treatment with thioctic acid (NATHAN I Study) is being conducted in North 

America and Europe aimed at slowing the progression of diabetic polyneuropathy 

using a clinically meaningful and reliable primary outcome measure that combines 

clinical and neurophysiological assessment. 

31. Free Radic Biol Med. 1999 Aug;27(3-4):309-14. 

Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in 

patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. 

Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, 

Dietze GJ, Rett K. 

Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl and City 

Hospital, Baden-Baden, Germany. snjacob@med.uni-tuebingen.de 

Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger 

was shown to enhance glucose transport and utilization in different experimental 

and animal models. Clinical studies described an increase of insulin sensitivity 

after acute and short-term (10 d) parenteral administration of ALA. The effects 

of a 4-week oral treatment with alpha-lipoic acid were evaluated in a 

placebo-controlled, multicenter pilot study to determine see whether oral 

treatment also improves insulin sensitivity. Seventy-four patients with type-2 

diabetes were randomized to either placebo (n = 19); or active treatment in 

various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or 

thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp 

was done on days 0 (pre) and 29 (post). In this explorative study, analysis was 

done according to the number of subjects showing an improvement of insulin 

sensitivity after treatment. Furthermore, the effects of active vs. placebo 

treatment on insulin sensitivity was compared. All four groups were comparable 



521

and had a similar degree of hyperglycemia and insulin sensitivity at baseline. 

When compared to placebo, significantly more subjects had an increase in 

insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As 

there was no dose effect seen in the three different alpha-lipoic acid groups, 

all subjects receiving ALA were combined in the "active" group and then compared to 

placebo. This revealed significantly different changes in MCR after treatment (+27% vs. 

placebo; p < .01). This placebo-controlled explorative study confirms previous 

observations of an increase of insulin sensitivity in type-2 diabetes after acute and 

chronic intravenous administration of ALA. The results suggest that oral administration 

of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The 

encouraging findings of this pilot trial need 

to be substantiated by further investigations. 

32. Free Radic Biol Med. 1999 Jun;26(11-12):1495-500. 

alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor 

glycemic control and albuminuria. 

Borcea V, Nourooz-Zadeh J, Wolff SP, Klevesath M, Hofmann M, Urich H, Wahl P, 

Ziegler R, Tritschler H, Halliwell B, Nawroth PP. 

Department of Internal Medicine I, University of Heidelberg, Germany. 

In the present cross-sectional study, the influence of alpha-lipoic acid on 

markers of oxidative stress, assessed by measurement of plasma lipid 

hydroperoxides (ROOHs), and on the balance between oxidative stress and 

antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol), was 

examined in 107 patients with diabetes 

mellitus. Patients receiving alpha-lipoic acid (600 mg/day for > 3 months) had 

significant lower ROOHs and a lower ROOH/(alpha-tocopherol/cholesterol) ratio 

than those without alpha-lipoic acid treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/- 

3.22 mumol/l; p < .0001] and [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 

vs. 2.16 +/- 1.17; p < 0.0001]. In addition, the influence of glycemic control 

and albuminuria on ROOHs and on the ratio of ROOH/(alpha-tocopherol/cholesterol) 

was examined in the presence and absence of alpha-lipoic acid treatment. Patients were 

subdivided into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) 

and (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither poor 

glycemic control, nor the presence of micro- or macroalbuminuria prevented the 

antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression analysis, 

alpha-lipoic acid was found to be the only factor significantly predicting low ROOHs and 

a low ratio of ROOH/(alpha-tocopherol/cholesterol). These data provide evidence that 

treatment with alpha-lipoic acid improves significantly the imbalance between increased 

oxidative stress and depleted antioxidant defence even in patients with poor glycemic 

control and albuminuria. 

33. Microvasc Res. 1999 Jul;58(1):28-34. 

The effect of alpha-lipoic acid on the neurovascular reflex arc in patients with 

diabetic neuropathy assessed by capillary microscopy. 

Haak ES, Usadel KH, Kohleisen M, Yilmaz A, Kusterer K, Haak T. 



522

Center of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, 

D-60590, Germany. 

Patients with diabetic polyneuropathy are known to have an impaired 

neurovascular reflex arc compared to healthy controls. This is seen in a delayed 

decrease in microcirculation of the ipsilateral hand after cooling of the 

contralateral hand. The aim of this pilot study was to investigate whether 

intravenous alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) therapy might be 

able to improve this impaired neurovascular reflex arc in patients with diabetic 

neuropathy. In addition, clinical effects were evaluated with the aid of the 

neuropathy symptom score (NSS) and the neuropathy disability score (NDS). Ten 

patients with diabetes mellitus and polyneuropathy (5 females, 5 males, 2 

smokers, 5 IDDM, 5 NIDDM, body mass index 26.1 +/- 1.0 kg/m2, age 58.3 +/- 9.5 

years, diabetes duration 15.7 +/- 11.2 years, Hb A1c 6.8 +/- 0.3%) were 

investigated by nail-fold capillaroscopy after contralateral cooling before and 

after intravenous therapy with 600 mg alpha-lipoic acid per day over 3 weeks. 

Cardiac autonomic neuropathy was excluded by beat-to-beat variation analysis. 

Symptoms of diabetic neuropathy were evaluated before and after therapy with the aid of 

the NSS and NDS. Capillary blood cell velocity (CBV) of the hand was 

determined before, during, and for the following 30 min after cooling (3 min at 

15 degrees C) of the contralateral hand. Blood pressure, heart rate, and local 

skin temperature were monitored at 2-min intervals. ALA therapy resulted in a 

significant improvement of the microcirculatory response to cooling, as seen by 

an immediate decrease in CBV of 12. 3% (P < 0.02 vs before treatment), which was 

absent before therapy. Blood pressure, heart rate, and local skin temperature were not 

different between investigations. There was a significant improvement of the NSS after 

therapy (5.4 +/- 1.1 vs 8.6 +/- 1.1 points, P < 0.01). These results demonstrate that 

intravenous therapy with ALA has a positive influence on the impaired neurovascular 

reflex arc in patients with diabetic neuropathy. Copyright 1999 Academic Press. 

34. Diabetes Care. 1999 Feb;22(2):280-7. 

alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and 

improves glucose effectiveness in lean and obese patients with type 2 diabetes. 

Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, 

Tritschler HJ, Cobelli C, Usadel KH. 

Department of Internal Medicine, J.W. Goethe-University, Frankfurt, Germany. 

OBJECTIVE: We examined the effect of lipoic acid (LA), a cofactor of the 

pyruvate dehydrogenase complex (PDH), on insulin sensitivity (SI) and glucose 

effectiveness (SG) and on serum lactate and pyruvate levels after oral glucose 

tolerance tests (OGTTs) and modified frequently sampled intravenous glucose 

tolerance tests (FSIGTTs) in lean (n = 10) and obese (n = 10) patients with type 

2 diabetes. RESEARCH DESIGN AND METHODS: FSIGTT data were analyzed by 

minimal modeling technique to determine SI and SG before and after oral treatment (600 

mg, twice a day, for 4 weeks). Serum lactate and pyruvate levels of diabetic patients after 



523

glucose loading were compared with those of lean (n = 10) and obese (n = 10) healthy 

control subjects in which SI and SG were also determined from FSIGTT data. 

RESULTS: Fasting lactate and pyruvate levels were significantly increased in patients 

with type 2 diabetes. These metabolites did not exceed elevated fasting concentrations 

after glucose loading in lean 

patients with type 2 diabetes. However, a twofold increase of lactate and 

pyruvate levels was measured in obese diabetic patients. LA treatment was 

associated with increased SG in both diabetic groups (lean 1.28 +/- 0.14 to 1.93 

+/- 0.13; obese 1.07 +/- 0.11 to 1.53 +/- 0.08 x 10(-2) min-1, P < 0.05). Higher 

SI and lower fasting glucose were measured in lean diabetic patients only (P < 

0.05). Lactate and pyruvate before and after glucose loading were approximately 

45% lower in lean and obese diabetic patients after LA treatment. CONCLUSIONS: 

Treatment of lean and obese diabetic patients with LA prevents 

hyperglycemia-induced increments of serum lactate and pyruvate levels and 

increases SG. 

35. Diabetologia. 1999 Feb;42(2):222-32. 

Peripheral blood mononuclear cells isolated from patients with diabetic 

nephropathy show increased activation of the oxidative-stress sensitive 

transcription factor NF-kappaB. 

Hofmann MA, Schiekofer S, Isermann B, Kanitz M, Henkels M, Joswig M, Treusch A, 

Morcos M, Weiss T, Borcea V, Abdel Khalek AK, Amiral J, Tritschler H, Ritz E, Wahl 

P, Ziegler R, Bierhaus A, Nawroth PP. 

Department of Medicine, University of Heidelberg, Germany. 

Increased oxidative stress and subsequent activation of the transcription factor 

NF-kappaB has been linked to the development of late diabetic complications. To 

determine whether oxidative stress dependent NF-kappaB activation is evident in 

patients with diabetic nephropathy we used an Electrophoretic Mobility Shift 

Assay based semiquantitative detection system which enabled us to determine 

NF-kappaB activation in ex vivo isolated peripheral blood mononuclear cells. We 

examined 33 patients with diabetes mellitus (Type I and Type II). Patients with 

diabetic nephropathy showed higher NF-kappaB binding activity in Electrophoretic 

Mobility Shift Assays and stronger immunohistological staining for activated NFkappaBp65 

than patients without renal complications. NF-kappaB binding activity 

correlated with the degree of albuminuria (r = 0.316) and with 

thrombomodulin plasma concentrations (r = 0.33), indicative for albuminuria 

associated endothelial dysfunction. In a 3 day intervention study in which 600 

mg of the antioxidant thioctic acid (alpha-lipoic acid) per day were given to 

nine patients with diabetic nephropathy oxidative stress in plasma samples was 

decreased by 48% and NF-kappaB binding activity in ex vivo isolated peripheral 

blood mononuclear cells by 38%. In conclusion, activation of the transcription 

factor NF-kappaB in ex vivo isolated peripheral blood mononuclear cells of 

patients with diabetes mellitus correlates with the degree of diabetic 

nephropathy. NF-kappaB activation is at least in part dependent on oxidative 

stress since thioctic acid (alpha-lipoic acid) reduced NF-kappaB binding 



524

activity. 

36. Diabetes Metab. 1998 Nov;24 Suppl 3:79-83. 

Future prevention and treatment of diabetic neuropathy. 

Tomlinson DR. 

Department of Pharmacology, Queen Mary and Westfield College, London, UK. 

d.tomlinson@qmw.ac.uk 

This review orders the likely components of the pathogenesis of diabetic 

neuropathy into vertical (temporal) and horizontal dimensions. It is argued that 

the effects of hyperglycaemia are transduced to neuronal dysfunction via at 

least three secondary biochemical disturbances--the sorbitol (polyol) pathway, 

non-enzymatic glycation of proteins and oxidative stress--and that there are 

clear interactions between them. Because of these interactions, interference 

with one of these biochemical transducers could either worsen or attenuate the 

effects of the others. Examples of these alternatives are given. It is suggested 

that the prime goal for pharmacological intervention should be a combined attack 

on all three sources of disturbance. Interventions further on in the sequence of 

pathogenesis are also considered, and the arguments for the use of neurotrophic 

factors are persuasive because of their selectivity for different neuronal 

phenotypes, even though side-effects may be inevitable. Finally, a novel 

conjugate of gamma-linolenic acid and alpha-lipoic acid is considered as an 

agent with the potential to correct effects arising from more than one pathway 

of disorder in experimental diabetic neuropathy. The preliminary results with 

this agent have been encouraging. 

37. Diabetes Care. 1998 Aug;21(8):1310-6. 

Insufficient glycemic control increases nuclear factor-kappa B binding activity 

in peripheral blood mononuclear cells isolated from patients with type 1 

diabetes. 

Hofmann MA, Schiekofer S, Kanitz M, Klevesath MS, Joswig M, Lee V, Morcos M, 

Tritschler H, Ziegler R, Wahl P, Bierhaus A, Nawroth PP. 

Department of Medicine, University of Heidelberg, Germany. 

OBJECTIVE: The redox-sensitive transcription factor nuclear factor-kappa B 

(NF-kappa B) is believed to contribute to late diabetic complications. It is 

unknown whether NF-kappa B is influenced by glycemic control. RESEARCH DESIGN 

AND METHODS: To determine whether NF-kappa B is activated in patients with 

insufficient glycemic control (HbA1c > 10%), we developed a tissue 

culture-independent electrophoretic mobility shift assay (EMSA)-based 

semiquantitative detection system that allowed us to determine NF-kappa B 

activation in ex vivo-isolated peripheral blood mononuclear cells (PBMCs). We 

included 43 patients with type 1 diabetes in this cross-sectional study. 10 of 

those received the antioxidant thioctic acid (600 mg/day p.o.) for 2 weeks. 

RESULTS: Monocytes of patients with HbA1c levels > 10% demonstrated 

significantly higher NF-kappa B binding activity in an EMSA and a stronger 



525

NF-kappa B staining in immunohistochemistry than monocytes of patients with 

HbA1c levels of 6-8%. The increase in NF-kappa B activation correlated with an 

increase in plasmatic markers of lipid peroxidation. Treatment with the 

antioxidant thioctic acid decreased NF-kappa B binding activity. CONCLUSIONS: 

Hyperglycemia induces activation of the transcription factor NF-kappa B in ex 

vivo-isolated PBMCs of patients with type 1 diabetes. NF-kappa B activation is 

at least partially dependent on oxidative stress, since the antioxidant thioctic 

acid significantly lowered the extent of NF-kappa B binding activity. 

38. Diabetes. 1997 Sep;46(9):1481-90. 

Advanced glycation end product-induced activation of NF-kappaB is suppressed by 

alpha-lipoic acid in cultured endothelial cells. 

Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, 

Berentshtein E, Tritschler H, Muller M, Wahl P, Ziegler R, Nawroth PP. 

Department of Internal Medicine, University of Heidelberg, Germany. 

Depletion of cellular antioxidant defense mechanisms and the generation of 

oxygen free radicals by advanced glycation end products (AGEs) have been 

proposed to play a major role in the pathogenesis of diabetic vascular 

complications. Here we demonstrate that incubation of cultured bovine aortic 

endothelial cells (BAECs) with AGE albumin (500 nmol/l) resulted in the 

impairment of reduced glutathione (GSH) and ascorbic acid levels. As a 

consequence, increased cellular oxidative stress led to the activation of the 

transcription factor NF-kappaB and thus promoted the upregulation of various 

NF-kappaB-controlled genes, including endothelial tissue factor. Supplementation of 

the cellular antioxidative defense with the natural occurring antioxidant alphalipoic 

acid before AGE albumin induction completely prevented the AGE albumindependent 

depletion of reduced glutathione and ascorbic acid. Electrophoretic 

mobility shift assays (EMSAs) revealed that AGE albumin-mediated NF-kappaB 

activation was also reduced in a time- and dose-dependent manner as long as alpha-lipoic 

acid was added at least 30 min before AGE albumin stimulation. Inhibition was not due 

to physical interactions with protein DNA binding, since alpha-lipoic acid, directly 

included into the binding reaction, did not prevent binding activity of recombinant NFkappaB. 

Western blots further demonstrated that alpha-lipoic acid inhibited the release 

and translocation of NF-kappaB from the cytoplasm into the nucleus. As a consequence, 

alpha-lipoic acid reduced AGE albumin-induced NF-kappaB mediated transcription and 

expression of endothelial genes relevant in diabetes, such as tissue factor and endothelin- 

1. Thus, supplementation of cellular antioxidative defense mechanisms by 

extracellularly administered alpha-lipoic acid reduces AGE albumin-induced 

endothelial dysfunction in vitro. 

39. Diabetes. 1997 Sep;46 Suppl 2:S62-6. 

Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic 

neuropathy. 

Ziegler D, Gries FA. 

Diabetes Research Institute at the Heinrich Heine University, Dusseldorf, 



526

Germany. 

Antioxidant treatment has been shown to prevent nerve dysfunction in 

experimental diabetes, providing a rationale for a potential therapeutic value 

in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic 

acid) were studied in two multicenter, randomized, double-blind 

placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy 

Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were 

randomly assigned to treatment with intravenous infusion of alpha-lipoic acid 

using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. 

The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet 

decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. 

Each of the four individual symptom scores was significantly lower in ALA 600 than in 

PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List 

(HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC 

after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, 

patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate 

variability were randomly assigned to treatment with a daily oral dose of 800 mg alphalipoic 

acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters 

of heart rate 

variability at rest were significantly improved in ALA compared with placebo. A 

trend toward a favorable effect of ALA was noted for the remaining two indexes. 

In both studies, no significant adverse events were observed. In conclusion, 

intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe 

and effective in reducing symptoms of diabetic peripheral neuropathy, and oral 

treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in 

NIDDM. 

40. Diabetes. 1997 Sep;46 Suppl 2:S38-42. 

The roles of oxidative stress and antioxidant treatment in experimental diabetic 

neuropathy. 

Low PA, Nickander KK, Tritschler HJ. 

Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 

55905, USA. 

Oxidative stress is present in the diabetic state. Our work has focused on its 

presence in peripheral nerves. Antioxidant enzymes are reduced in peripheral 

nerves and are further reduced in diabetic nerves. That lipid peroxidation will 

cause neuropathy is supported by evidence of the development of neuropathy de 

novo when normal nerves are rendered alpha-tocopherol deficient and by the 

augmentation of the conduction deficit in diabetic nerves subjected to this 

insult. Oxidative stress appears to be primarily due to the processes of nerve 

ischemia and hyperglycemia auto-oxidation. The indexes of oxidative stress 

include an increase in nerve, dorsal root, and sympathetic ganglia lipid 

hydroperoxides and conjugated dienes. The most reliable and sensitive index, 

however, is a reduction in reduced glutathione. Experimental diabetic neuropathy 



527

esults in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root 

ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation 

causes mitochondrial DNA mutations that increase reduced oxygen species, causing 

further damage to mitochondrial respiratory chain and function and resulting in a sensory 

neuropathy. Alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in 

vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50, and 100 

mg/kg administered intraperitoneally in preventing the biochemical, electrophysiological, 

and nerve blood flow deficits in the peripheral nerves of experimental diabetic 

neuropathy. Alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve 

conduction and nerve blood flow and biochemical abnormalities (reductions in reduced 

glutathione and lipid peroxidation). The nerve blood flow deficit was 50% (P < 0.001). 

Supplementation dose-dependently prevented the deficit; at the highest concentration, 

nerve blood flow was not different from that of control nerves. Digital nerve conduction 

underwent a dose-dependent improvement at 1 month (P < 0.05). By 3 months, all treated 

groups had lost their deficit. The antioxidant drug is potentially efficacious for human 

diabetic sensory neuropathy. 

41. Metabolism. 1997 Jul;46(7):763-8. 

Lipoic acid reduces glycemia and increases muscle GLUT4 content in 

streptozotocin-diabetic rats. 

Khamaisi M, Potashnik R, Tirosh A, Demshchak E, Rudich A, Tritschler H, Wessel K, 

Bashan N. 

Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion 

University of the Negev, Beer Sheva, Israel. 

Alpha lipoic acid (lipoate [LA]), a cofactor of alpha-ketodehydrogenase, 

exhibits unique antioxidant properties. Recent studies suggest a direct effect 

of LA on glucose metabolism in both human and experimental diabetes. This study 

examines the possibility that LA positively affects glucose homeostasis in 

streptozotocin (STZ)-induced diabetic rats by altering skeletal muscle glucose 

utilization. Blood glucose concentration in STZ-diabetic rats following 10 days 

of intraperitoneal (i.p.) injection of LA 30 mg/kg was reduced compared with 

that in vehicle-treated diabetic rats (495 +/- 131 v 641 +/- 125 mg/dL in fed 

state, P = .003, and 189 +/- 48 v 341 +/- 36 mg/dL after 12-hour fast, P = 

.001). No effect of LA on plasma insulin was observed. Gastrocnemius muscle 

crude membrane GLUT4 protein was elevated both in control and in diabetic rats 

treated with LA by 1.5- and 2.8-fold, respectively, without significant changes 

in GLUT4 mRNA levels. Gastrocnemius lactic acid was increased in diabetic rats 

(19.9 +/- 5.5 v 10.4 +/- 2.8 mumol/g muscle, P < .05 v nondiabetic rats), and 

was normal in LA-treated diabetic rats (9.1 +/- 5.0 mumol/g muscle). 

Insulin-stimulated 2-deoxyglucose (2 DG) uptake into isolated soleus muscle was 

reduced in diabetic rats compared with the control group (474 +/- 15 v 568 +/- 

52 pmol/mg muscle 30 min, respectively, P = .05). LA treatment prevented this 

reduction, resulting in insulin-stimulated glucose uptake comparable to that of 

nondiabetic animals. These results suggest that daily LA treatment may reduce 

blood glucose concentrations in STZ-diabetic rats by enhancing muscle GLUT4 



528

protein content and by increasing muscle glucose utilization. 

42. Diabetes Care. 1997 Mar;20(3):369-73. 

Comment in: 

Diabetes Care. 1997 Dec;20(12):1918-20. 

Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic 

neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial 

(DEKAN Study). Deutsche Kardiale Autonome Neuropathie. 

Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. 


Germany. 

OBJECTIVE: To evaluate the efficacy and safety of oral treatment with the 

antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic 

neuropathy (CAN), assessed by heart rate variability (HRV). RESEARCH DESIGN 

AND METHODS: In a randomized, double-blind placebo-controlled multicenter trial 

(Deutsche Kardiale Autonome Neuropathie [DEKAN] Study), NIDDM patients with 

reduced HRV were randomly assigned to treatment with daily oral dose of 800 mgALA 

(n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the 

coefficient of variation (CV), root mean square successive difference (RMSSD), and 

spectral power in the low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15- 

0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed. 

RESULTS: Seventeen patients dropped out of the study (ALA n = 10; placebo n = 7). 

Mean blood pressure and HbA1 levels did not differ between the groups at baseline and 

during the study, but heart rate at baseline was higher in the group treated with ALA (P < 

0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) [median 

(minimum-maximum)] in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) 

in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band 

increased by 0.06 bpm2 (-0. 09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (- 

0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend 

toward a favorable effect of ALA versus placebo for the CV and HF band power 

spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo). The changes in cardiovascular 

autonomic symptoms did not differ significantly between the groups during the period 

studied. No differences between the groups were noted regarding the rates of adverse 

events. CONCLUSIONS: These findings suggest that treatment with ALA using a welltolerated 

oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM 

patients. 

43. Biochem Pharmacol. 1997 Feb 7;53(3):393-9. 

Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. 

Mechanisms and implications for diabetes and ischemic injury. 

Roy S, Sen CK, Tritschler HJ, Packer L. 


94720-3200, U.S.A. sashwati@violet.berkeley.edu 

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated 



529

with respect to its influence on cellular reducing equivalent homeostasis. The 

requirement of NADH and NADPH as cofactors in the cellular reduction of 

alpha-lipoic acid to dihydrolipoate has been reported in various cells and 

tissues. However, there is no direct evidence describing the influence of such 

reduction of alpha-lipoate on the levels of cellular reducing equivalents and 

homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell 

line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular 

NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this 

effect was relatively less and slower compared with that of NADH. A 

concentration-dependent increase in glucose uptake was observed in Wurzburg 

cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ 

and in lactate/pyruvate ratios were observed in alpha-lipoate-treated cells. 

Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate 

may have direct implications in diabetes, ischemia-reperfusion injury, and other 

pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive 

oxygen species) imbalances are considered as major factors contributing to metabolic 

disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH 

levels in the cell by utilizing it as a co-factor for its 

own reduction process, whereas in oxidative stress both alpha-lipoate and its 

reduced form, dihydrolipoate, may protect by direct scavenging of free radicals 

and recycling other antioxidants from their oxidized forms. 

44, Free Radic Biol Med. 1997;22(1-2):359-78. 




94720-3200, USA. 

Reactive oxygen species are thought to be involved in a number of types of acute and 

chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant 

alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric 

acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed 

from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced 

in cells and tissues to 

dihydrolipoate, which is also exported to the extracellular medium; hence, 

protection is afforded to both intracellular and extracellular environments. 

Both alpha-lipoate and especially dihydrolipoate have been shown to be potent 

antioxidants, to regenerate through redox cycling other antioxidants like 

vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it 

would seem an ideal substance in the treatment of oxidative brain and neural 

disorders involving free radical processes. Examination of current research 

reveals protective effects of these compounds in cerebral ischemia-reperfusion, 

excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and 

diabetic neuropathy, inborn errors of metabolism, and other causes of acute or 

chronic damage to brain or neural tissue. Very few neuropharmacological 



530

intervention strategies are currently available for the treatment of stroke and 

numerous other brain disorders involving free radical injury. We propose that 

the various metabolic antioxidant properties of alpha-lipoate relate to its 

possible therapeutic roles in a variety of brain and neuronal tissue 

pathologies: thiols are central to antioxidant defense in brain and other 

tissues. The most important thiol antioxidant, glutathione, cannot be directly 

administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human 

studies indicate that alpha-lipoate may be effective in numerous neurodegenerative 

disorders. 


Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after 

repeated parenteral administration of thioctic acid. 

Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. 

Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl, Germany. 

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of 

Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to 

improve insulin sensitivity. Thioctic acid (TA), a naturally occurring compound, 

was shown to enhance glucose utilization in various experimental models after 

acute and chronic administration. It also increased insulin-stimulated glucose 

disposal in patients with NIDDM after acute administration. This pilot study was 

initiated to see whether this compound also augments glucose disposal in humans after 

repeated treatment. Twenty patients with NIDDM received TA (500 mg/ 500 ml NaCl, 

0.9%) as daily infusions over a period of ten days. A hyperinsulinaemic, isoglycaemic 

glucose-clamp was done on day 0 and day 11. Parenteral administration of TA resulted in 

a significant increase of insulin-stimulated glucose-disposal by about 30% (metabolic 

clearance rate for glucose, 2.5 +/- 0.3 vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivityindex: 

3.5 +/- 0.5 vs. 4.7 +/- 0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test). 

There were no changes in fasting plasma levels for glucose or insulin; this can be 

explained, however, by the short period of treatment and observation. This is the first 

clinical study to show that a ten day administration of TA is able to improve resistance of 

insulin-stimulated glucose disposal in NIDDM. Experimental data suggest several 

mechanisms in the mode of action. As the present investigation was an 

uncontrolled pilot trial, the encouraging results call for controlled studies to 

further elucidate the clinical relevance of the findings and the mode of action 

of this compound. 

46. Diabetologia. 1995 Dec;38(12):1425-33. 

Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant 

alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN 

Study). 

Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. 


Germany. 



531

Anti-oxidant treatment has been shown to prevent nerve dysfunction in 

experimental diabetes mellitus, thus providing a rationale of potential 

therapeutic value for diabetic patients. The effects of the anti-oxidant 

alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, 

randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic 

Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with 

symptomatic peripheral neuropathy who were randomly assigned to treatment with 

intravenous infusion of alpha-lipoic acid using three doses (1200, 600, or 100 mg ALA) 

or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) 

were scored at baseline and at each visit (days 2-5, 8-12, and 15-19) prior to infusion. In 

addition, the Hamburg Pain Adjective List, a multidimensional specific pain 

questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at 

baseline and day 19. According to the 

protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the 

feet decreased from baseline to day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in 

ALA 1200, -5.0 +/- 4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 

100, and -2.6 +/- 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 

600 vs PLAC: p < 0.001). The response rates after 19 days, defined as an improvement in 

the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 

65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p = 0.002). The total scale 

of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as 

compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 

32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These 

findings substantiate that intravenous treatment with alpha-lipoic acid using a dose of 600 

mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral 

neuropathy, without causing significant adverse reactions. 

47. Arzneimittelforschung. 1995 Aug;45(8):872-4. 

Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic 

acid. 

Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, 

Augustin HJ, Dietze GJ. 

Department of Internal Medicine, City Hospital, Baden-Baden, Germany. 


Type II diabetes (NIDDM); therefore pharmacological interventions should aim to 

improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, 

ALA), a natural occurring compound frequently used for treatment of diabetic 

polyneuropathy, enhances glucose utilization in various experimental models. To 

see whether this compound also augments insulin mediated glucose disposal in 

NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) 

or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups 

were comparable in age, body-mass index and duration of diabetes and had a 

similar degree of insulin resistance at baseline. Acute parenteral 

administration of ALA resulted in a significant increase of insulin-stimulated 

glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% 



532

(3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control 

group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 

ml/kg/min = post). This is the first clinical study to show that alpha-lipoic 

acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of 

ALA and its potential use as an antihyperglycemic agent require further 

investigation. 

________________________________________________________________ 

AGE-RELATED 

48. Eur Neuropsychopharmacol. 2003 Aug;13(4):241-7. 

Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of 

cognitive impairment in rats. 

Sharma M, Gupta YK. 

Neuropharmacology Laboratory, Department of Pharmacology, All India Institute of 

Medical Sciences, New Delhi 110029, India. 

In the present study, the effect of alpha lipoic acid, a potent free radical 

scavenger, was investigated against the intracerebroventricular streptozotocin 

model of cognitive impairment in rats, which is characterized by a progressive 

deterioration of memory, cerebral glucose and energy metabolism, and oxidative 

stress. Wistar rats were injected with intracerebroventricular streptozotocin 

bilaterally. The rats were treated chronically with alpha lipoic acid (50, 100 

and 200 mg/kg) orally for 21 days starting from day 1 of streptozotocin 

injection in separate groups. The learning and memory behavior was evaluated and the 

rats were sacrificed for estimation of oxidative stress. The 

intracerebroventricular streptozotocin rats treated with alpha lipoic acid (200 

mg/kg, p.o.) showed significantly less cognitive impairment as compared to the 

vehicle treated rats. There was also an insignificant increase in oxidative 

stress in the alpha lipoic acid treated groups. The study demonstrated the 

effectiveness of alpha lipoic acid in preventing cognitive impairment and 

oxidative stress induced by intracerebroventricular streptozotocin and its 

potential in dementia associated with age and age related neurodegenerative 

disorders where oxidative stress is involved such as Alzheimer's disease. 

49. J Neurochem. 2003 Mar;84(5):1173-83. 

The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory 

impairment and brain oxidative stress in aged SAMP8 mice. 

Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, 

Morley JE. 

Geriatric Research Education and Clinical Center (GRECC), VA Medical Center 

(151/JC), 915 N. Grand Boulevard, St. Louis, MO 63109, USA. farrsa52@aol.com 

Oxidative stress may play a crucial role in age-related neurodegenerative 

disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid 

(LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the 



533

SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and 

severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in 

comparison with 4-month-old mice, had increased levels of protein carbonyls (an index 

of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in 

the weakly immobilized/strongly immobilized 

(W/S) ratio of the protein-specific spin label MAL-6 (an index of 

oxidation-induced conformational changes in synaptosomal membrane proteins). 

Chronic administration of either LA or NAC improved cognition of 12-month-old 

SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press 

appetitive task without inducing non-specific effects on motor activity, 

motivation to avoid shock, or body weight. These effects probably occurred 

directly within the brain, as NAC crossed the blood-brain barrier and 

accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA 

reversed all three indexes of oxidative stress. These results support the 

hypothesis that oxidative stress can lead to cognitive dysfunction and provide 

evidence for a therapeutic role for antioxidants. 

50. Exp Gerontol. 2002 Dec;37(12):1489-94. 

Neurochemical changes related to ageing in the rat brain and the effect of 

DL-alpha-lipoic acid. 

Arivazhagan P, Panneerselvam C. 

Department of Medical Biochemistry, Dr AL Mudaliar Post Graduate Institute of 

Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, 

India. 

Age-related impairments of cognitive and motor function have been linked to a 

number of deleterious morphological and functional changes involving different 

areas of the brain. Loss of neurotransmitters, their receptors and 

responsiveness to neurotransmitters are key manifestations of neurological 

ageing and age-related disorders. In the present investigation we have evaluated 

the effect of DL-alpha-lipoic acid on neurotransmitters in discrete brain 

regions of young and aged rats. The levels of neurotransmitters were found to be 

lowered in aged rats. Moreover, DL-alpha-lipoic acid treated aged rats showed a 

increase in the status of dopamine, serotonin and norepinephrine. The results of 

this study provide evidence that DL-alpha-lipoic acid (a potent antioxidant) 

treatment can improve neurotransmitters during ageing. Hence, it can be 

concluded that DL-alpha-lipoic acid act as a potent neuromodulator in the brain 

of aged rats. 

51. Ann N Y Acad Sci. 2002 Apr;959:508-16. 

Can antioxidant diet supplementation protect against age-related mitochondrial 

damage? 

Miquel J. 

Department of Biotechnology, University of Alicante, E-03080 Alicante, Spain. 

Harman's free radical theory of aging and our electron-microscopic finding of an 



534

age-related mitochondrial degeneration in the somatic tissues of the insect 

Drosophila melanogaster as well as in the fixed postmitotic Leydig and Sertoli 

cells of the mouse testis led us to propose a mitochondrial theory of aging, 

according to which metazoan senescence may be linked to oxygen stress-injury to the 

genome and membranes of the mitochondria of somatic differentiated cells. These 

concepts attract a great deal of attention, since, according to recent 

work, the mitochondrial damage caused by reactive oxygen species (ROS) and 

concomitant decline in ATP synthesis seem to play a key role not only in aging, 

but also in the fundamental cellular process of apoptosis. Although diet 

supplementation with antioxidants has not been able to increase consistently the 

species-characteristic maximum life span, it results in significant extension of 

the mean life span of laboratory animals. Moreover, diets containing high levels 

of antioxidants such as vitamins C and E seem able to reduce the risk of 

suffering age-related immune dysfunctions and arteriosclerosis. Presently, the 

focus of age-related antioxidant research is on compounds, such as deprenyl, 

coenzyme Q10, alpha-lipoic acid, and the glutathione-precursors thioproline and 

N-acetylcysteine, which may be able to neutralize the ROS at their sites of 

production in the mitochondria. Diet supplementation with these antioxidants may 

protect the mitochondria against respiration-linked oxygen stress, with 

preservation of the genomic and structural integrity of these energy-producing 

organelles and concomitant increase in functional life span. 


Mitochondrial decay in the aging rat heart: evidence for improvement by dietary 

supplementation with acetyl-L-carnitine and/or lipoic acid. 

Hagen TM, Moreau R, Suh JH, Visioli F. 


University, Corvallis, Oregon 97331, USA. tory.hagen@orst.edu 

Mitochondrial decay has been postulated to be a significant underlying part of 

the aging process. Decline in mitochondrial function may lead to cellular energy 

deficits, especially in times of greater energy demand, and compromise vital 

ATP-dependent cellular operations, including detoxification, repair systems, DNA 

replication, and osmotic balance. Mitochondrial decay may also lead to enhanced 

oxidant production and thus render the cell more prone to oxidative insult. In 

particular, the heart may be especially susceptible to mitochondrial dysfunction 

due to myocardial dependency on beta-oxidation of fatty acids for energy and the 

postmitotic nature of cardiac myocytes, which would allow for greater 

accumulation of mitochondrial mutations and deletions. Thus, maintenance of 

mitochondrial function may be important to maintain overall myocardial function. 

Herein, we review the major age-related changes that occur to mitochondria in 

the aging heart and the evidence that two such supplements, acetyl-l-carnitine 

(ALCAR) and (R)-alpha-lipoic acid, may improve myocardial bioenergetics and 

lower the increased oxidative stress associated with aging. We and others have 

shown that feeding old rats ALCAR reverses the age-related decline in carnitine 

levels and improves mitochondrial beta-oxidation in a number of tissues studied. 



535

However, ALCAR supplementation does not appear to reverse the age-related 

decline in cardiac antioxidant status and thus may not substantially alter 

indices of oxidative stress. Lipoic acid, a potent thiol antioxidant and 

mitochondrial metabolite, appears to increase low molecular weight antioxidant 

status and thereby decreases age-associated oxidative insult. Thus, ALCAR along with 

lipoic acid may be effective supplemental regimens to maintain myocardial function. 

53. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1876-81. 

Erratum in: 

Proc Natl Acad Sci U S A 2002 May 14;99(10):7184. 

Age-associated mitochondrial oxidative decay: improvement of carnitine 

acetyltransferase substrate-binding affinity and activity in brain by feeding 

old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. 

Liu J, Killilea DW, Ames BN. 



We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a 

key mitochondrial enzyme for fuel utilization, is due to decreased binding 

affinity for substrate and whether this substrate, fed to old rats, restores CAT 

activity. The kinetics of CAT were analyzed by using the brains of young and old 

rats and of old rats supplemented for 7 weeks with the CAT substrate 

acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor 

R-alpha-lipoic acid (LA). Old rats, compared with young rats, showed a decrease 

in CAT activity and in CAT-binding affinity for both substrates, ALCAR and CoA. 

Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding 

affinity for ALCAR and CoA, and CAT activity. To explore the underlying 

mechanism, lipid peroxidation and total iron and copper levels were assayed; all 

increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid 

peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of 

young-rat brain with Fe(II) caused loss of CAT activity and binding affinity. In 

vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not 

alter binding affinity. However, in vitro treatment of CAT with the lipid 

peroxidation products malondialdehyde or 4-hydroxy-nonenal caused a decrease in CATbinding 

affinity and activity, thus mimicking age-related change. 

Preincubation of CAT with ALCAR or CoA prevented malondialdehyde-induced 

dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites 

can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, 

and mitochondrial dysfunction. 

54. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5. 

Erratum in: 

Proc Natl Acad Sci U S A 2002 May 14;99(10):7184. 

Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves 

metabolic function while decreasing oxidative stress. 



536

Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, 

Ames BN. 


University, Corvallis, OR 97331, USA. 

Mitochondrial-supported bioenergetics decline and oxidative stress increases 

during aging. To address whether the dietary addition of acetyl-l-carnitine 

[ALCAR, 1.5% (wt/vol) in the drinking water] and/or (R)-alpha-lipoic acid [LA, 

0.5% (wt/wt) in the chow] improved these endpoints, young (2-4 mo) and old 

(24-28 mo) F344 rats were supplemented for up to 1 mo before death and 

hepatocyte isolation. ALCAR+LA partially reversed the age-related decline in 

average mitochondrial membrane potential and significantly increased (P = 0.02) 

hepatocellular O(2) consumption, indicating that mitochondrial-supported 

cellular metabolism was markedly improved by this feeding regimen. ALCAR+LA also 

increased ambulatory activity in both young and old rats; moreover, the 

improvement was significantly greater (P = 0.03) in old versus young animals and 

also greater when compared with old rats fed ALCAR or LA alone. To determine 

whether ALCAR+LA also affected indices of oxidative stress, ascorbic acid and 

markers of lipid peroxidation (malondialdehyde) were monitored. The 

hepatocellular ascorbate level markedly declined with age (P = 0.003) but was 

restored to the level seen in young rats when ALCAR+LA was given. The level of 

malondialdehyde, which was significantly higher (P = 0.0001) in old versus young 

rats, also declined after ALCAR+LA supplementation and was not significantly 

different from that of young unsupplemented rats. Feeding ALCAR in combination with 

LA increased metabolism and lowered oxidative stress more than either compound alone. 

55. Exp Gerontol. 2001 Dec;37(1):81-7. 

Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats. 

Arivazhagan P, Ramanathan K, Panneerselvam C. 

Department of Medical Biochemistry, Dr AL Mudaliar Post Graduate Institute of 

Basic Medical Sciences, University of Madras, Taramani Campus, 600 113, Chennai, 

India. palaniarivu@yahoo.com 

Ageing is characterized by a failure to maintain homeostasis under conditions of 

physiological stress, with an increasing susceptibility to disease and death. 

The accumulation of errors committed by faulty biochemical reactions over a vast 

period generates the cumulative effect observed during ageing. The most notable 

among the effects of ageing are the age-related disorders where free radicals 

are the major cause. When the level of free radicals increases because of diet, 

lifestyle, environment or other influences, it results in subsequent reduction 

of antioxidants. Reduced glutathione is one of the most fascinating molecules 

virtually present in all animal cells in often quite higher concentrations. An 

essential mechanism that accounts for most of the metabolic and cell regulatory 

properties of glutathione is the thiol disulfide exchange equilibria. We 

evaluated the age-associated alterations in glutathione dependent enzymes, 

glutathione and hydroxyl radicals in young and aged rats with respect to lipoate 



537

supplementation. In aged rats, activities of glutathione peroxidase, glutathione 

reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase and the 

level of glutathione were low, whereas the level of hydroxyl radical was 

higher than in the young ones. Administration of DL-alpha-lipoic acid, a thiol 

antioxidant intraperitoneally to the aged rats, led to a time-dependent 

reduction in hydroxyl radicals and elevation in the activities/level of 

glutathione systems. Hence it can be suggested that lipoate, a dithiol prevents the 

oxidation of reduced glutathione and protects its related enzymes from peroxidative 

damage. 

56. FASEB J. 2001 Mar;15(3):700-6. 

Oxidative stress in the aging rat heart is reversed by dietary supplementation 

with (R)-(alpha)-lipoic acid. 

Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM. 

Linus Pauling Institute, Department of Biochemistry, Oregon State University, 

Corvallis, Oregon 97331, USA. 

Oxidative stress has been implicated as a causal factor in the aging process of 

the heart and other tissues. To determine the extent of age-related myocardial 

oxidative stress, oxidant production, antioxidant status, and oxidative DNA 

damage were measured in hearts of young (2 months) and old (28 months) male 

Fischer 344 rats. Cardiac myocytes isolated from old rats showed a nearly 

threefold increase in the rate of oxidant production compared to young rats, as 

measured by the rates of 2,7-dichlorofluorescin diacetate oxidation. 

Determination of myocardial antioxidant status revealed a significant twofold 

decline in the levels of ascorbic acid (P = 0.03), but not alpha-tocopherol. A 

significant age-related increase (P = 0.05) in steady-state levels of oxidative 

DNA damage was observed, as monitored by 8-oxo-2'-deoxyguanosine levels. To 

investigate whether dietary supplementation with (R)-alpha-lipoic acid (LA) was 

effective at reducing oxidative stress, young and old rats were fed an AIN-93M diet with 

or without 0.2% (w/w) LA for 2 wk before death. Cardiac myocytes from old, LAsupplemented 

rats exhibited a markedly lower rate of oxidant production that was no 

longer significantly different from that in cells from 

unsupplemented, young rats. Lipoic acid supplementation also restored myocardial 

ascorbic acid levels and reduced oxidative DNA damage. Our data indicate that the 

aging rat heart is under increased mitochondrial-induced oxidative stress, which is 

significantly attenuated by lipoic acid supplementation. 

57. Antioxid Redox Signal. 2000 Fall;2(3):473-83. 

(R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of 

hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. 

Hagen TM, Vinarsky V, Wehr CM, Ames BN. 

Department of Molecular and Cell Biology, University of California at Berkeley 

94720, USA. 

Hepatocytes were isolated from young (3-5 months) and old (24-28 months) rats 



538

and incubated with various concentrations of tert-butylhydroperoxide (t-BuOOH). 

The t-BuOOH concentration that killed 50% of cells (LC50) in 2 hr declined 

nearly two-fold from 721 +/- 32 microM in cells from young rats to 391 +/- 31 

microM in cells from old rats. This increased sensitivity of hepatocytes from 

old rats may be due, in part, to changes in glutathione (GSH) levels, because 

total cellular and mitochondrial GSH were 37.7% and 58.3% lower, respectively, 

compared to cells from young rats. Cells from old animals were incubated with 

either (R)- or (S)-lipoic acid (100 microM) for 30 min prior to the addition of 

300 microM t-BuOOH. The physiologically relevant (R)-form, a coenzyme in 

mitochondria, as opposed to the (S)-form significantly protected hepatocytes 

against t-BuOOH toxicity. Dietary supplementation of (R)-lipoic acid [0.5% 

(wt/wt)] for 2 weeks also completely reversed the age-related decline in 

hepatocellular GSH levels and the increased vulnerability to t-BuOOH as well. An 

identical supplemental diet fed to young rats did not enhance the resistance to 

t-BuOOH, indicating that antioxidant protection was already optimal in young 

rats. Thus, this study shows that cells from old animals are more susceptible to 

oxidant insult and (R)-lipoic acid, after reduction to an antioxidant in the 

mitochondria, effectively reverses this age-related increase in oxidant 

vulnerability. 

58. Am J Otol. 2000 Mar;21(2):161-7. 

Biologic activity of mitochondrial metabolites on aging and age-related hearing 

loss. 

Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS. 

Department of Otolaryngology Head & Neck Surgery, Henry Ford Health System, 

Detroit, Michigan 48323, USA. 

HYPOTHESIS: Compounds that upregulate mitochondrial function in an aging model 

will improve hearing and reduce some of the effects of aging. BACKGROUND: Reactive 

oxygen metabolites (ROM) are known products of oxidative metabolism and are 

continuously generated in vivo. More than 100 human clinical conditions have been 

associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, 

heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and 

cause extensive DNA, cellular, and tissue damage. Specific deletions within the 

mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. 

These deletions are the result of chronic exposure to ROM. When enough mtDNA 

damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis 

of the mitochondrial clock theory of aging, also known as the membrane hypothesis of 

aging. Nutritional compounds have been identified that enhance mitochondrial function 

and reverse several age-related processes. It is the purpose of this article to describe the 

effects of two mitochondrial metabolites, alpha-lipoic acid and 

acetyl L-carnitine, on the preservation of age-related hearing loss. METHODS: 

Twenty-one Fischer rats, aged 24 months, were divided into three groups: 

acetyl-1-carnitine, alpha-lipoic acid, and control. The subjects were orally 

supplemented with either a placebo or one of the two nutritional compounds for 6 

weeks. Auditory brainstem response testing was used to obtain baseline and 



539

posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues 

were obtained to assess for mtDNA mutations. RESULTS: The control group 

demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in 

the 6-week study. The treated subjects experienced a delay in progression of 

hearing loss. Acetyl-1-carnitine improved auditory thresholds during the same 

time period (p

old rats to determine its efficacy in reversing the decline in metabolism seen 

with age. Young (3 to 5 months) and old (24 to 26 months) rats were fed an 

AIN-93M diet with or without (R)-lipoic acid (0.5% w/w) for 2 wk, killed, and 

their liver parenchymal cells were isolated. Hepatocytes from untreated old rats 

vs. young controls had significantly lower oxygen consumption (P

Department of Internal Medicine, City Hospital, Baden-Baden, Germany. 

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II 

diabetes (NIDDM); therefore pharmacological interventions should aim to improve 

insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural 

occurring compound frequently used for treatment of diabetic polyneuropathy, enhances 

glucose utilization in various experimental models. To see whether this compound also 

augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA 

(1000 mg/Thioctacid/500 ml NaCl, n = 7) 

or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were 

comparable in age, body-mass index and duration of diabetes and had a similar degree of 

insulin resistance at baseline. Acute parenteral administration of ALA resulted in a 

significant increase of insulin-stimulated glucose disposal; metabolic clearance rate 

(MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p 

< 0.05), whereas the control group did 

not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This 

is the first clinical study to show that alpha-lipoic acid increases insulin stimulated 

glucose disposal in NIDDM. The mode of action of ALA and its potential use as an 

antihyperglycemic agent require further investigation. 

63. Diabetes 1996 Aug;45(8):1024-9 

The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose 

metabolism in insulin-resistant rat skeletal muscle. 

Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ. 

Department of Physiology, University of Arizona College of Medicine, Tucson, USA. 

Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese 

Zucker (fa/fa) rat--an animal model of muscle insulin resistance--was used to test whether 

acute (100 mg/kg body wt for 1 h) and chronic (5-100 mg/kg for 10 days) parenteral 

treatments with a racemic mixture of the antioxidant alpha-lipoic acid (ALA) could 

improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport 

activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and 

glucose oxidation were determined in the isolated epitrochlearis muscles in the absence 

or presence of insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake, glycogen 

synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese 

rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic 

treatments (30 mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P < 

0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from 

the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both 

insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was 

associated with a significantly greater (21%) in vivo muscle glycogen concentration. 

These adaptive responses after chronic ALA administration were also associated with 

significantly lower (15-17%) plasma levels of insulin and free fatty acids. No significant 

effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase 

and citrate synthase were observed. Collectively, these findings indicate that parenteral 

administration of the antioxidant ALA significantly enhances the capacity of the insulin- 



542

stimulatable glucose transport system and of both oxidative and nonoxidative pathways 

of glucose metabolism in insulin-resistant rat skeletal muscle. 

64. Am J Physiol 1997 Jul;273(1 Pt 1):E185-91 

Differential effects of lipoic acid stereoisomers on glucose metabolism in 

insulin-resistant skeletal muscle. 

Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. 

Department of Physiology, University of Arizona, Tucson 85721-0093, USA. 

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulinstimulated 

glucose metabolism in insulin-resistant humans and animals. We determined 

the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose 

metabolism in skeletal muscle of an animal model of insulin resistance, 

hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated 

intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 

mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2- 

DG) uptake], glycogen synthesis, and glucose oxidation were determined in the 

epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)- 

ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA 

had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced 

plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese 

animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. 

Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, 

whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)- 

ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 

33% enhancement of insulin-stimulated glucose oxidation. No significant increase in 

these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) 

protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% 

of obese control with S-(-)-ALA 

treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances 

insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism 

in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more 

effective than the S-(-) enantiomer. 

65. Free Radic Biol Med 2000 Dec;29(11):1122-8 

Lipoic acid decreases lipid peroxidation and protein glycosylation and increases (Na(+) + 

K(+))- and Ca(++)-ATPase activities in high glucose-treated human erythrocytes. 

Jain SK, Lim G. 

Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, 

LA 71130, USA. sjain@lsuhsc.edu 

Lipoic acid supplementation has been found to be beneficial in preventing neurovascular 

abnormalities in diabetic neuropathy. Insufficient (Na(+) + K(+))-ATPase activity has 

been suggested as a contributing factor in the development of diabetic neuropathy. This 

study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and 



543

glycosylation and can increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high 

glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with 

normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid 

(mixture of S and R sterioisomers) in a shaking water bath at 37 degrees C for 24 h. 

There was a significant stimulation of glucose consumption by RBC in the presence of 

lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly 

lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed 

to high glucose concentrations. High glucose treatment significantly 

lowered the activities of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. 

Lipoic acid addition significantly blocked the reduction in activities of (Na(+) + K(+))- 

and Ca(++)-ATPases in high glucose- treated RBC. There were no differences in lipid 

peroxidation, GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity levels in normal 

glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid 

peroxidation and protein glycosylation, and increase (Na(+) + K(+))- and Ca(++)-ATPase 

activities in high-glucose exposed RBC, which provides a potential mechanism by which 

lipoic acid may delay or inhibit the development of neuropathy in diabetes. 

66. Free Radic Biol Med 1999 Aug;27(3-4):309-14 

Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in 

patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. 

Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, 

Dietze GJ, Rett K. 

Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl and City 

Hospital, Baden-Baden, Germany. snjacob@med.uni-tuebingen.de 

Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger 

was shown to enhance glucose transport and utilization in different experimental 

and animal models. Clinical studies described an increase of insulin sensitivity 

after acute and short-term (10 d) parenteral administration of ALA. The effects 

of a 4-week oral treatment with alpha-lipoic acid were evaluated in a 

placebo-controlled, multicenter pilot study to determine see whether oral 

treatment also improves insulin sensitivity. Seventy-four patients with type-2 

diabetes were randomized to either placebo (n = 19); or active treatment in 

various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or 

thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp 

was done on days 0 (pre) and 29 (post). In this explorative study, analysis was 

done according to the number of subjects showing an improvement of insulin 

sensitivity after treatment. Furthermore, the effects of active vs. placebo 

treatment on insulin sensitivity was compared. All four groups were comparable 

and had a similar degree of hyperglycemia and insulin sensitivity at baseline. 

When compared to placebo, significantly more subjects had an increase in 

insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As 

there was no dose effect seen in the three different alpha-lipoic acid groups, 

all subjects receiving ALA were combined in the "active" group and then compared 

to placebo. This revealed significantly different changes in MCR after treatment 

(+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms 



544

previous observations of an increase of insulin sensitivity in type-2 diabetes 

after acute and chronic intravenous administration of ALA. The results suggest 

that oral administration of alpha-lipoic acid can improve insulin sensitivity in 

patients with type-2 diabetes. The encouraging findings of this pilot trial need 

to be substantiated by further investigations. 

67. Diabetes Care 1999 Feb;22(2):280-7 

alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations 

and improves glucose effectiveness in lean and obese patients with type 2 

diabetes. 

Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, 

Tritschler HJ, Cobelli C, Usadel KH. 

Department of Internal Medicine, J.W. Goethe-University, Frankfurt, Germany. 

OBJECTIVE: We examined the effect of lipoic acid (LA), a cofactor of the 

pyruvate dehydrogenase complex (PDH), on insulin sensitivity (SI) and glucose 

effectiveness (SG) and on serum lactate and pyruvate levels after oral glucose 

tolerance tests (OGTTs) and modified frequently sampled intravenous glucose 

tolerance tests (FSIGTTs) in lean (n = 10) and obese (n = 10) patients with type 

2 diabetes. RESEARCH DESIGN AND METHODS: FSIGTT data were analyzed by minimal 

modeling technique to determine SI and SG before and after oral treatment (600 mg, twice a day, 

for 4 weeks). Serum lactate and pyruvate levels of diabetic 

patients after glucose loading were compared with those of lean (n = 10) and 

obese (n = 10) healthy control subjects in which SI and SG were also determined 

from FSIGTT data. RESULTS: Fasting lactate and pyruvate levels were 

significantly increased in patients with type 2 diabetes. These metabolites did 

not exceed elevated fasting concentrations after glucose loading in lean 

patients with type 2 diabetes. However, a twofold increase of lactate and 

pyruvate levels was measured in obese diabetic patients. LA treatment was 

associated with increased SG in both diabetic groups (lean 1.28 +/- 0.14 to 1.93 

+/- 0.13; obese 1.07 +/- 0.11 to 1.53 +/- 0.08 x 10(-2) min-1, P < 0.05). Higher 

SI and lower fasting glucose were measured in lean diabetic patients only (P < 

0.05). Lactate and pyruvate before and after glucose loading were approximately 

45% lower in lean and obese diabetic patients after LA treatment. CONCLUSIONS: 

Treatment of lean and obese diabetic patients with LA prevents 

hyperglycemia-induced increments of serum lactate and pyruvate levels and 

increases SG. 

68. Exp Clin Endocrinol Diabetes 1996;104(3):284-8 

Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after 

repeated parenteral administration of thioctic acid. 

Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. 

Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl, Germany. 




545

Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to 

improve insulin sensitivity. Thioctic acid (TA), a naturally occurring compound, 

was shown to enhance glucose utilization in various experimental models after 

acute and chronic administration. It also increased insulin-stimulated glucose 

disposal in patients with NIDDM after acute administration. This pilot study was 

initiated to see whether this compound also augments glucose disposal in humans 

after repeated treatment. Twenty patients with NIDDM received TA (500 mg/ 500 ml 

NaCl, 0.9%) as daily infusions over a period of ten days. A hyperinsulinaemic, 

isoglycaemic glucose-clamp was done on day 0 and day 11. Parenteral 

administration of TA resulted in a significant increase of insulin-stimulated 

glucose-disposal by about 30% (metabolic clearance rate for glucose, 2.5 +/- 0.3 

vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivity-index: 3.5 +/- 0.5 vs. 4.7 +/- 

0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test). There were no changes in 

fasting plasma levels for glucose or insulin; this can be explained, however, by 

the short period of treatment and observation. This is the first clinical study 

to show that a ten day administration of TA is able to improve resistance of 

insulin-stimulated glucose disposal in NIDDM. Experimental data suggest several 

mechanisms in the mode of action. As the present investigation was an 

uncontrolled pilot trial, the encouraging results call for controlled studies to 

further elucidate the clinical relevance of the findings and the mode of action 

of this compound. 

69. Protection against oxidative stress-induced insulin resistance in rat L6 

muscle cells by mircomolar concentrations of alpha-lipoic acid. 

Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL. 

Diabetes Research Laboratory, Mount Zion Hospital, San Francisco, California 94143-1616, USA. 

bmaddux@itsa.ucsf.edu 

Diabetes. 2001 Feb;50(2):404-10. 

Free Full Text Article Here 

http://diabetes.diabetesjournals.org/cgi/content/full/50/2/404 

In diabetic patients, alpha-lipoic acid (LA) improves skeletal muscle glucose transport, resulting in 

increased glucose disposal; however, the molecular mechanism of action of LA is presently unknown. We 

studied the effects of LA on basal and insulin-stimulated glucose transport in cultured rat L6 muscle cells 

that overexpress GLUT4. When 2-deoxy-D-glucose uptake was measured in these cells, they were more 

sensitive and responsive to insulin than wild-type L6 cells. LA, at concentrations < or = 1 mmol/l, had only 

small effects on glucose transport in cells not exposed to oxidative stress. When cells were exposed to 

glucose 

oxidase and glucose to generate H2O2 and cause oxidative stress, there was a marked decrease in insulinstimulated 

glucose transport. Pretreatment with LA over the concentration range of 10-1,000 pmol/l 

protected the insulin effect from inhibition by H2O2. Both the R and S isomers of LA were equally 

effective. In addition, oxidative stress caused a significant decrease (approximately 50%) in reduced 

glutathione concentration, along with the rapid activation of the stress-sensitive p38 mitogen-activated 

protein kinase. Pretreatment with LA prevented both of these events, coincident with protecting insulin 

action. These studies 

indicate that in muscle, the major site of insulin-stimulated glucose disposal, one important effect of LA on 

the insulin-signaling cascade is to protect cells from oxidative stress-induced insulin resistance. 

70. Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma-linolenic 

acid conjugate. 




546



Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):44-50. 

BACKGROUND: Diabetes commonly leads to long-term complications such as cataract. This study 

investigated the effects of alpha-lipoic acid (LPA) and its 

gamma-linolenic acid (GLA) conjugate on cataract development in diabetic sand 

rats. METHODS: Two separate experiments were conducted. In Experiment 1, sand rats were fed a "highenergy" 

diet (70% starch), an acute model of Type 2 

diabetes, and injected with LPA. In Experiment 2, the animals received a 

"medium-energy" diet (59% starch), a chronic diabetic model, and were intubated 

with LPA or its GLA conjugate. Throughout the experiments, blood glucose levels 

and cataract development were measured. At the termination of the experiments, 

lens aldose reductase (AR) activity and lenticular reduced glutathione (GSH) 

levels were analyzed. RESULTS: LPA injection significantly inhibited cataract 

development and reduced blood glucose levels in rats fed the "high-energy" diet. 

Lens AR activity tended to be lower, while lenticular GSH levels increased. In 

sand rats fed a "medium-energy" diet (59% starch), LPA intubation had no effect 

on blood glucose levels and cataract development but GSH levels were increased. In contrast, sand rats 

intubated with GLA conjugate showed the highest blood glucose levels and accelerated cataract 

development. The conjugate treatment also decreased lenticular GSH content. CONCLUSIONS: The 

hypoglycemic effects of LPA are beneficial in the prevention of acute symptoms of Type 2 diabetes. 

It remains to be shown that the antioxidant activity of LPA is responsible for prevention or inhibition of 

cataract progression in sand rats. Copyright 2000 John Wiley & Sons, Ltd. 

Mixed Tocopherols - 398 Studies 

1. Am J Clin Nutr. 2005 Feb;81(2):508-14. 

Relation of the tocopherol forms to incident Alzheimer disease and to cognitive 

change. 

Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, Scherr PA. 

Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL 

60612, USA. martha_c_morris@rush.edu 

BACKGROUND: High intake of vitamin E from food (tocopherol), but not from 

supplements (which usually contain alpha-tocopherol), is inversely associated with 

Alzheimer disease. OBJECTIVE: We examined whether food intakes of vitamin E, 

alpha-tocopherol equivalents (a measure of the relative biologic activity of tocopherols 

and tocotrienols), or individual tocopherols would protect against incident Alzheimer 

disease and cognitive decline over 6 y in participants of the Chicago Health and Aging 

Project. DESIGN: The 1993-2002 study of community residents aged >or=65 y included 

the administration of 4 cognitive tests and clinical evaluations for Alzheimer disease. 

Dietary assessment was by food-frequency questionnaire. RESULTS: Tocopherol intake 

from food was related to the 4-y incidence of Alzheimer disease determined by logistic 

regression in 1041 participants who were clinically evaluated (n=162 incident cases) and 

to change in a global cognitive score determined by mixed models in 3718 participants. 



547

Higher intakes of vitamin E (relative risk: 0.74 per 5 mg/d increase; 95% CI: 0.62, 0.88) 

and alpha-tocopherol equivalents (relative risk: 0.56 per 5 mg/d increase; 95% CI: 0.32, 

0.98) were associated with a reduced incidence of Alzheimer disease in separate 

multiple-adjusted models that included intakes of saturated and trans fats and 

docosahexaenoic acid. alpha- and gamma-Tocopherol had independent associations. In 

separate mixed models, a slower rate of cognitive decline was associated with intakes of 

vitamin E, alpha-tocopherol equivalents, and alpha- and gamma-tocopherols. 

CONCLUSION: The results suggest that various tocopherol forms rather than alpha- 

tocopherol alone may be important in the vitamin E protective association with 

Alzheimer disease. 


2. Am J Clin Nutr. 2003 Apr;77(4):975-84. 

High-dose antioxidant supplements and cognitive function in community-dwelling 

elderly women. 

Grodstein F, Chen J, Willett WC. 

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, 

Harvard Medical School, Boston, MA 02115, USA. 

fran.grodstein@channing.harvard.edu 

BACKGROUND: telephone tests of cognitive function [Telephone Interview of 

Cognitive Status (TICS), delayed recall of the TICS 10-word list, immediate and delayed 

recall of a short paragraph, a test of verbal fluency, and a digit span backwards test] were 

administered to the women, who were 70-79 y of age at that time. We used linear and 

logistic regression models to calculate multivariate-adjusted mean differences in test 

scores and relative risks of a low score for specific supplement users compared with 

nonusers. RESULTS: Long-term, current users of vitamin E with vitamin C had 

significantly better mean performance, as judged by a global score that combined 

individual test scores, than did women who had never used vitamin E or C (P = 0.03); 

there was a trend for increasingly higher mean scores with increasing durations of use (P 

= 0.04). These associations were strongest among women with low dietary intakes of 

alpha-tocopherol. Benefits were less consistent for women taking vitamin E alone, with 

no evidence of higher scores with longer durations of use. Use of specific vitamin C 

supplements alone had little relation to performance on our cognitive tests. 

CONCLUSION: The use of specific vitamin E supplements, but not specific vitamin C 

supplements, may be related to modest cognitive benefits in older women. 


3. JAMA. 2002 Jun 26;287(24):3223-9. 

Dietary intake of antioxidants and risk of Alzheimer disease. 

Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, 



548

Breteler MM. 

Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR 

Rotterdam, The Netherlands. 

CONTEXT: Laboratory findings have suggested that oxidative stress may contribute to 

the pathogenesis of Alzheimer disease. Therefore, the risk of Alzheimer disease might be 

reduced by intake of antioxidants that counteract the detrimental effects of oxidative 

stress. OBJECTIVE: To determine whether dietary intake of antioxidants is related to 

risk of Alzheimer disease. DESIGN AND SETTING: The Rotterdam Study, a 

population-based, prospective cohort study conducted in the Netherlands. 

PARTICIPANTS: A total of 5395 participants who, at baseline (1990-1993), were aged 

at least 55 years, free of dementia, and noninstitutionalized and had reliable dietary 

assessment. Participants were reexamined in 1993-1994 and 1997-1999 and were 

continuously monitored for incident dementia. MAIN OUTCOME MEASURES: 

Incidence of Alzheimer disease, based on Diagnostic and Statistical Manual of Mental 

Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of 

Neurological and Communicative Disorders and Stroke and Alzheimer Disease and 

Related Disorders Association (NINCDS-ADRDA) criteria, associated with dietary 

intake of beta carotene, flavonoids, vitamin C, and vitamin E. RESULTS: After a mean 

follow-up of 6 years, 197 participants developed dementia, of whom 146 had Alzheimer 

disease. When adjustments were made for age, sex, baseline Mini-Mental State 

Examination score, alcohol intake, education, smoking habits, pack-years of smoking, 

body mass index, total energy intake, presence of carotid plaques, and use of 

antioxidative supplements, high intake of vitamin C and vitamin E was associated with 

lower risk of Alzheimer disease (rate ratios [RRs] per 1-SD increase in intake were 0.82 

[95% confidence interval [CI], 0.68-0.99] and 0.82 [95% CI, 0.66-1.00], respectively). 

Among current smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 

0.37-1.14] and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake of 

beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95% CI, 0.31- 

0.96]). The associations did not vary by education or apolipoprotein E genotype. 

CONCLUSION: High dietary intake of vitamin C and vitamin E may lower the risk of 

Alzheimer disease. 

4. Arch Neurol. 2002 Jul;59(7):1125-32. 

Vitamin E and cognitive decline in older persons. 

Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. 

Department of Preventive medicine, Rush Institute for Healthy Aging, Rush- 

Presbyterian-St Luke's Medical Center, 1645 W Jackson, Suite 675, Chicago, IL 60612, 

USA. mmorris@rush.edu 

BACKGROUND: Previous studies raise the possibility that antioxidants protect against 

neurodegenerative diseases. OBJECTIVE: To examine whether intake of antioxidant 

nutrients, including vitamin E, vitamin C, and carotene, is associated with reduced 



549

cognitive decline with age. DESIGN: Longitudinal population-based study conducted 

from September 17, 1993, to November 20, 2000, with an average follow-up of 3.2 years. 

PATIENTS: The patients were 2889 community residents, aged 65 to 102 years, who 

completed a food frequency questionnaire, on average 18 months after baseline. MAIN 

OUTCOME MEASURE: Cognitive change as measured by 4 tests (the East Boston 

Memory Test, which tests immediate and delayed recall; the Mini-Mental State 

Examination; and the Symbol Digit Modalities Test) at baseline and 3 years for all 

participants, and at 6 months for 288 randomly selected participants. RESULTS: We used 

random-effects models to estimate nutrient effects on individual change in the average 

score of the 4 cognitive tests. The cognitive score declined on average by 5.0 x 10(-2) 

standardized units per year. There was a 36% reduction in the rate of decline among 

persons in the highest quintile of total vitamin E intake (-4.3 x 10(-2) standardized units 

per year) compared with those in the lowest quintile (-6.7 x 10(-2) standardized units per 

year) (P =.05), in a model adjusted for age, race, sex, educational level, current smoking, 

alcohol consumption, total calorie (energy) intake, and total intakes of vitamin C, 

carotene, and vitamin A. We also observed a reduced decline with higher vitamin E 

intake from foods (P =.03 for trend). There was little evidence of association with vitamin 

C or carotene intake. CONCLUSION: Vitamin E intake, from foods or supplements, is 

associated with less cognitive decline with age. 

5. Mixed Tocopherols (Vitamin E) 

1: Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, 

Mark SD. 

Prospective study of serum vitamin E levels and esophageal and gastric cancers. 

J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. 

PMID: 13130117 

2: Engler MM, Engler MB, Malloy MJ, Chiu EY, Schloetter MC, Paul SM, Stuehlinger M, Lin KY, Cooke 

JP, Morrow JD, Ridker PM, Rifai N, Miller E, Witztum JL, Mietus-Snyder M. 

Antioxidant vitamins C and E improve endothelial function in children with 

hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial. 

Circulation. 2003 Sep 2;108(9):1059-63. Epub 2003 Aug 11. 

PMID: 12912807 

3: Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. 

Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. 

Hepatology. 2003 Aug;38(2):413-9. 

PMID: 12883485 

4: Miller RR Jr, Olson BM, Rorick N, Wittingen AL, Bullock M. 

Embryonic exposure to exogenous alpha- and gamma-tocopherol partially attenuates ethanol-induced 

changes in brain morphology and brain membrane fatty acid composition. 

Nutr Neurosci. 2003 Aug;6(4):201-12. 

PMID: 12887137 

5: Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert 

P; ATBC Study Group. 



550

Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a 

postintervention follow-up. JAMA. 2003 Jul 23;290(4):476-85. 

PMID: 12876090 

6: Fariss MW, Zhang JG. 

Vitamin E therapy in Parkinson's disease. 

Toxicology. 2003 Jul 15;189(1-2):129-46. Review. 

PMID: 12821288 

7: Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen 

L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, 

Griffin M, Ippolito E, Bavera P. 

Evaluation of the local effects of vitamin E (E-Mousse) on free radicals in 

diabetic microangiopathy: a randomized, controlled trial. 

Angiology. 2003 Jul-Aug;54(4):415-21. 

PMID: 12934761 

8: Pathak A, Roth P, Piscitelli J, Johnson L. 

Effects of vitamin E supplementation during erythropoietin treatment of the 

anaemia of prematurity. 

Arch Dis Child Fetal Neonatal Ed. 2003 Jul;88(4):F324-8. 

PMID: 12819167 

9: Jessup JV, Horne C, Yarandi H, Quindry J. 

The effects of endurance exercise and vitamin E on oxidative stress in the 

elderly. 

Biol Res Nurs. 2003 Jul;5(1):47-55. 

PMID: 12886670 

10: Peluzio MC, Miguel E Jr, Drumond TC, Cesar GC, Santiago HC, Teixeira MM, 

Vieira EC, Arantes RM, Alvarez-Leite JI. 

Monocyte chemoattractant protein-1 involvement in the alpha-tocopherol-induced 

reduction of atherosclerotic lesions in apolipoprotein E knockout mice. 

Br J Nutr. 2003 Jul;90(1):3-11. 

PMID: 12844369 

11: Ahmed J, Zaman MM, Ali K. 

Antioxidant vitamins improves hemoglobin level in children with group a beta 

hemolytic streptococcal infection. 

Mymensingh Med J. 2003 Jul;12(2):120-3. 

PMID: 12894046 

12: Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. 

Antioxidants in treatment of idiopathic sudden hearing loss. 

Otol Neurotol. 2003 Jul;24(4):572-5. 

PMID: 12851547 

13: Hirnerova E, Krahulec B, Strbova L, Stecova A, Dekret J, Hajovska A. 

[Effect of vitamin E therapy on progression of diabetic nephropathy] 

Vnitr Lek. 2003 Jul;49(7):529-34. Slovak. 

PMID: 12931434 

14: Ylonen K, Alfthan G, Groop L, Saloranta C, Aro A, Virtanen SM. 

Dietary intakes and plasma concentrations of carotenoids and tocopherols in 



551

elation to glucose metabolism in subjects at high risk of type 2 diabetes: the 

Botnia Dietary Study. 


PMID: 12791620 

15: Mathew JP, Thomas VC, Thomas I. 

Selenite cataract and its attenuation by vitamin E in Wistar rats. 

Indian J Ophthalmol. 2003 Jun;51(2):161-70. 

PMID: 12831147 

16: Lin JY, Selim MA, Shea CR, Grichnik JM, Omar MM, Monteiro-Riviere NA, 

Pinnell SR. 

UV photoprotection by combination topical antioxidants vitamin C and vitamin E. 

J Am Acad Dermatol. 2003 Jun;48(6):866-74. 

PMID: 12789176 

17: Botsoglou NA, Govaris A, Botsoglou EN, Grigoropoulou SH, Papageorgiou G. 

Antioxidant activity of dietary oregano essential oil and alpha-tocopheryl 

acetate supplementation in long-term frozen stored turkey meat. 

J Agric Food Chem. 2003 May 7;51(10):2930-6. 

PMID: 12720373 

18: Bilgihan A, Bilgihan K, Yis O, Sezer C, Akyol G, Hasanreisoglu B. 

Effects of topical vitamin E on corneal superoxide dismutase, glutathione 

peroxidase activities and polymorphonuclear leucocyte infiltration after 

photorefractive keratectomy. 

Acta Ophthalmol Scand. 2003 Apr;81(2):177-80. 

PMID: 12752058 

19: Stone WL, LeClair I, Ponder T, Baggs G, Reis BB. 

Infants discriminate between natural and synthetic vitamin E. 


PMID: 12663289 

20: Prieto Castro RM, Leva Vallejo ME, Regueiro Lopez JC, Anglada Curado FJ, 

Alvarez Kindelan J, Requena Tapia MJ. 

Combined treatment with vitamin E and colchicine in the early stages of 

Peyronie's disease. 

BJU Int. 2003 Apr;91(6):522-4. 

PMID: 12656907 

21: Fujikawa A, Gong H, Amemiya T. 

Vitamin E prevents changes in the cornea and conjunctiva due to vitamin A 

deficiency. 

Graefes Arch Clin Exp Ophthalmol. 2003 Apr;241(4):287-97. Epub 2003 Mar 15. 

PMID: 12719990 

22: Bruunsgaard H, Poulsen HE, Pedersen BK, Nyyssonen K, Kaikkonen J, Salonen 

JT. 

Long-term combined supplementations with alpha-tocopherol and vitamin C have no 

detectable anti-inflammatory effects in healthy men. 

J Nutr. 2003 Apr;133(4):1170-3. 

PMID: 12672938 



552

23: Canbaz S, Duran E, Ege T, Sunar H, Cikirikcioglu M, Acipayam M. 

The effects of intracoronary administration of vitamin E on myocardial 

ischemia-reperfusion injury during coronary artery surgery. 

Thorac Cardiovasc Surg. 2003 Apr;51(2):57-61. 

PMID: 12730811 

24: Yousef MI, Abdallah GA, Kamel KI. 

Effect of ascorbic acid and Vitamin E supplementation on semen quality and 

biochemical parameters of male rabbits. 

Anim Reprod Sci. 2003 Mar 20;76(1-2):99-111. 

PMID: 12559724 

25: Kogure K, Manabe S, Hama S, Tokumura A, Fukuzawa K. 

Potentiation of anti-cancer effect by intravenous administration of vesiculated 

alpha-tocopheryl hemisuccinate on mouse melanoma in vivo. 

Cancer Lett. 2003 Mar 20;192(1):19-24. 

PMID: 12637149 

26: Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, 

Zghal K, Fki H, Damak J, Bahloul A. 

Sperm oxidative stress and the effect of an oral vitamin E and selenium 

supplement on semen quality in infertile men. 

Arch Androl. 2003 Mar-Apr;49(2):83-94. 

PMID: 12623744 

27: Morinobu T, Yoshikawa S, Hamamura K, Tamai H. 

Measurement of vitamin E metabolites by high-performance liquid chromatography 

during high-dose administration of alpha-tocopherol. 

Eur J Clin Nutr. 2003 Mar;57(3):410-4. 

PMID: 12627176 

28: Shang F, Lu M, Dudek E, Reddan J, Taylor A. 

Vitamin C and vitamin E restore the resistance of GSH-depleted lens cells to 

H2O2. 

Free Radic Biol Med. 2003 Mar 1;34(5):521-30. 

PMID: 12614841 

29: Di Leo MA, Ghirlanda G, Gentiloni Silveri N, Giardina B, Franconi F, 

Santini SA. 

Potential therapeutic effect of antioxidants in experimental diabetic retina: a 

comparison between chronic taurine and vitamin E plus selenium supplementations. 


PMID: 12688428 

30: Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio 

A, Leonetti C, Jandolo B, Cognetti F, Bove L. 

Neuroprotective effect of vitamin E supplementation in patients treated with 

cisplatin chemotherapy. 

J Clin Oncol. 2003 Mar 1;21(5):927-31. 

PMID: 12610195 

31: Rangarajan M, Zatz JL. 

Effect of formulation on the topical delivery of alpha-tocopherol. 



553

J Cosmet Sci. 2003 Mar-Apr;54(2):161-74. 

PMID: 12715093 

32: Manson JE, Bassuk SS, Stampfer MJ. 

Does vitamin E supplementation prevent cardiovascular events? 

J Womens Health (Larchmt). 2003 Mar;12(2):123-36. Review. 

PMID: 12741415 

33: Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, 

Rissanen TH, Tuomainen TP, Valkonen VP, Ristonmaa U, Lakka HM, Vanharanta M, 

Salonen JT, Poulsen HE; Antioxidant Supplementation in Atherosclerosis 

Prevention Study. 

Six-year effect of combined vitamin C and E supplementation on atherosclerotic 

progression: the Antioxidant Supplementation in Atherosclerosis Prevention 

(ASAP) Study. 

Circulation. 2003 Feb 25;107(7):947-53. 

PMID: 12600905 

34: Cyrus T, Yao Y, Rokach J, Tang LX, Pratico D. 

Vitamin E reduces progression of atherosclerosis in low-density lipoprotein 

receptor-deficient mice with established vascular lesions. 

Circulation. 2003 Feb 4;107(4):521-3. 

PMID: 12566360 

35: Aghdassi E, Wendland BE, Steinhart AH, Wolman SL, Jeejeebhoy K, Allard JP. 

Antioxidant vitamin supplementation in Crohn's disease decreases oxidative 

stress. a randomized controlled trial. 

Am J Gastroenterol. 2003 Feb;98(2):348-53. 

PMID: 12591053 

36: Chang CW, Chu G, Hinz BJ, Greve MD. 

Current use of dietary supplementation in patients with age-related macular 

degeneration. 

Can J Ophthalmol. 2003 Feb;38(1):27-32. 

PMID: 12608514 

37: Letur-Konirsch H, Delanian S. 

Successful pregnancies after combined pentoxifylline-tocopherol treatment in 

women with premature ovarian failure who are resistant to hormone replacement 

therapy. 

Fertil Steril. 2003 Feb;79(2):439-41. 

PMID: 12568863 

38: Ortuno J, Esteban MA, Meseguer J. 

The effect of dietary intake of vitamins C and E on the stress response of 

gilthead seabream (Sparus aurata L.). 

Fish Shellfish Immunol. 2003 Feb;14(2):145-56. 

PMID: 12526878 

39: Bae JH, Schwemmer M, Lee IK, Lee HJ, Park KR, Kim KY, Bassenge E. 

Postprandial hypertriglyceridemia-induced endothelial dysfunction in healthy 

subjects is independent of lipid oxidation. 

Int J Cardiol. 2003 Feb;87(2-3):259-67. 

PMID: 12559548 



554

40: Abubakar MG, Taylor A, Ferns GA. 

Aluminium administration is associated with enhanced hepatic oxidant stress 

that may be offset by dietary vitamin E in the rat. 

Int J Exp Pathol. 2003 Feb;84(1):49-54. 

PMID: 12694486 

41: Olanow CW. 

Dietary vitamin E and Parkinson's disease: something to chew on. 

Lancet Neurol. 2003 Feb;2(2):74. 

PMID: 12849259 

42: Martin A. 

Antioxidant vitamins E and C and risk of Alzheimer's disease. 

Nutr Rev. 2003 Feb;61(2):69-73. Review. 

PMID: 12674439 

43: Bulger EM, Maier RV. 

An argument for Vitamin E supplementation in the management of systemic 

inflammatory response syndrome. 

Shock. 2003 Feb;19(2):99-103. Review. 

PMID: 12578114 

44: Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, 

Takata J, Karube Y, Fujiwara M. 

Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral 

infarction in mice. 


PMID: 12524170 

45: Rehim WM, Sharaf IA, Hishmat M, el-Toukhy MA, Rawash NA, Fouad HN. 

Antioxidant capacity in Fasciola hepatica patients before and after treatment 

with triclabendazole alone or in combination with ascorbic acid (vitamin C) and 

tocofersolan (vitamin E). 


PMID: 12705178 

46: Brockes C, Buchli C, Locher R, Koch J, Vetter W. 

Vitamin E prevents extensive lipid peroxidation in patients with hypertension. 

Br J Biomed Sci. 2003;60(1):5-8. 

PMID: 12680623 

47: Lohr JB, Kuczenski R, Niculescu AB. 

Oxidative mechanisms and tardive dyskinesia. 

CNS Drugs. 2003;17(1):47-62. Review. 

PMID: 12467492 

48: Yap SP, Yuen KH, Lim AB. 

Influence of route of administration on the absorption and disposition of 

alpha-, gamma- and delta-tocotrienols in rats. 

J Pharm Pharmacol. 2003 Jan;55(1):53-8. 

PMID: 12625867 

49: Olmedilla B, Granado F, Blanco I, Vaquero M. 

Lutein, but not alpha-tocopherol, supplementation improves visual function in 



555

patients with age-related cataracts: a 2-y double-blind, placebo-controlled 

pilot study. 

Nutrition. 2003 Jan;19(1):21-4. 

PMID: 12507634 

50: Falsini B, Piccardi M, Iarossi G, Fadda A, Merendino E, Valentini P. 

Influence of short-term antioxidant supplementation on macular function in 

age-related maculopathy: a pilot study including electrophysiologic assessment. 

Ophthalmology. 2003 Jan;110(1):51-60; discussion 61. 

PMID: 12511345 

51: Lin Y, Huang R, Santanam N, Liu YG, Parthasarathy S, Huang RP. 

Profiling of human cytokines in healthy individuals with vitamin E 

supplementation by antibody array. 

Cancer Lett. 2002 Dec 10;187(1-2):17-24. 

PMID: 12359346 

52: Kogure K, Hama S, Manabe S, Tokumura A, Fukuzawa K. 

High cytotoxicity of alpha-tocopheryl hemisuccinate to cancer cells is due to 

failure of their antioxidative defense systems. 

Cancer Lett. 2002 Dec 5;186(2):151-6. 

PMID: 12213284 

53: Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, 

Rodriguez C, Calle EE, Thun MJ. 

Vitamin C and vitamin E supplement use and bladder cancer mortality in a large 

cohort of US men and women. 

Am J Epidemiol. 2002 Dec 1;156(11):1002-10. 

PMID: 12446256 

54: Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella 

F, Garcia I, Maier RV. 

Randomized, prospective trial of antioxidant supplementation in critically ill 

surgical patients. 

Ann Surg. 2002 Dec;236(6):814-22. 

PMID: 12454520 

55: Malafa MP, Fokum FD, Smith L, Louis A. 


succinate. 


PMID: 12464597 

56: Peponis V, Papathanasiou M, Kapranou A, Magkou C, Tyligada A, Melidonis A, 

Drosos T, Sitaras NM. 

Protective role of oral antioxidant supplementation in ocular surface of 

diabetic patients. 

Br J Ophthalmol. 2002 Dec;86(12):1369-73. 

PMID: 12446368 

57: Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, 

Corazza D, Meduri R. 


antioxidants] 



556


PMID: 12518724 

58: Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ, Bell RA; The Insulin 

Resistance and Atherosclerosis Study (IRAS). 

Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The 

Insulin Resistance and Atherosclerosis Study (IRAS). 

Diabetes Care. 2002 Dec;25(12):2172-7. 

PMID: 12453956 

59: Jialal I, Devaraj S, Venugopal SK. 




PMID: 12607825 

60: Jaarin K, Gapor MT, Nafeeza MI, Fauzee AM. 

Effect of various doses of palm vitamin E and tocopherol on aspirin-induced 

gastric lesions in rats. 

Int J Exp Pathol. 2002 Dec;83(6):295-302. 

PMID: 12657138 

61: Ringseis R, Eder K. 

Insufficient dietary vitamin e increases the concentration of 

7beta-hydroxycholesterol in tissues of rats fed salmon oil. 

J Nutr. 2002 Dec;132(12):3732-5. 

PMID: 12468614 

62: Wan Nazaimoon WM, Khalid BA. 

Tocotrienols-rich diet decreases advanced glycosylation end-products in 

non-diabetic rats and improves glycemic control in streptozotocin-induced 


Malays J Pathol. 2002 Dec;24(2):77-82. 

PMID: 12887164 

63: Vasdev S, Gill V, Parai S, Longerich L, Gadag V. 

Dietary vitamin E and C supplementation prevents fructose induced hypertension 

in rats. 

Mol Cell Biochem. 2002 Dec;241(1-2):107-14. 

PMID: 12482032 

64: Sahin K, Sahin N, Onderci M. 

Vitamin E supplementation can alleviate negative effects of heat stress on egg 

production, egg quality, digestibility of nutrients and egg yolk mineral 

concentrations of Japanese quails. 

Res Vet Sci. 2002 Dec;73(3):307-12. 

PMID: 12443690 




PMID: 12324194 



557

66: Kolb E, Seehawer J. 

[Significance and application of vitamin E in broilers and laying hens, 

especially during supplementation with fish oil] 

Berl Munch Tierarztl Wochenschr. 2002 Nov-Dec;115(11-12):458-64. Review. German. 

PMID: 12481654 

67: Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, 

Rodriguez C, Calle EE, Thun MJ. 

Vitamin C and vitamin E supplement use and bladder cancer mortality in a large 

cohort of US men and women. 

Am J Epidemiol. 2002 Dec 1;156(11):1002-10. 

PMID: 12446256 

68: Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella 

F, Garcia I, Maier RV. 

Randomized, prospective trial of antioxidant supplementation in critically ill 

surgical patients. 

Ann Surg. 2002 Dec;236(6):814-22. 

PMID: 12454520 

69: Malafa MP, Fokum FD, Smith L, Louis A. 


succinate. 


PMID: 12464597 

70: Peponis V, Papathanasiou M, Kapranou A, Magkou C, Tyligada A, Melidonis A, 

Drosos T, Sitaras NM. 

Protective role of oral antioxidant supplementation in ocular surface of 


Br J Ophthalmol. 2002 Dec;86(12):1369-73. 

PMID: 12446368 

71: Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, Corazza 

D, Meduri R. 


antioxidants] 


PMID: 12518724 

72: Jialal I, Devaraj S, Venugopal SK. 




PMID: 12607825 

73: Jaarin K, Gapor MT, Nafeeza MI, Fauzee AM. 

Effect of various doses of palm vitamin E and tocopherol on aspirin-induced 

gastric lesions in rats. 

Int J Exp Pathol. 2002 Dec;83(6):295-302. 

PMID: 12657138 

74: Ringseis R, Eder K. 

Insufficient dietary vitamin e increases the concentration of 



558

7beta-hydroxycholesterol in tissues of rats fed salmon oil. 

J Nutr. 2002 Dec;132(12):3732-5. 

PMID: 12468614 

75: Wan Nazaimoon WM, Khalid BA. 

Tocotrienols-rich diet decreases advanced glycosylation end-products in 

non-diabetic rats and improves glycemic control in streptozotocin-induced 


Malays J Pathol. 2002 Dec;24(2):77-82. 

PMID: 12887164 

76: Vasdev S, Gill V, Parai S, Longerich L, Gadag V. 

Dietary vitamin E and C supplementation prevents fructose induced hypertension 

in rats. 

Mol Cell Biochem. 2002 Dec;241(1-2):107-14. 

PMID: 12482032 

77: Sahin K, Sahin N, Onderci M. 

Vitamin E supplementation can alleviate negative effects of heat stress on egg 

production, egg quality, digestibility of nutrients and egg yolk mineral 

concentrations of Japanese quails. 

Res Vet Sci. 2002 Dec;73(3):307-12. 

PMID: 12443690 

78: Castellini C, Lattaioli P, Bosco AD, Beghelli D. 

Effect of supranutritional level of dietary alpha-tocopheryl acetate and 

selenium on rabbit semen. 

Theriogenology. 2002 Dec;58(9):1723-32. 

PMID: 12472142 

79: Wu K, Li Y, Zhao Y, Shan YJ, Xia W, Yu WP, Zhao L. 

Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in 

human gastric cancer SGC-7901 cells. 

World J Gastroenterol. 2002 Dec;8(6):982-6. 

PMID: 12439910 




PMID: 12324194 

81: Kolb E, Seehawer J. 

[Significance and application of vitamin E in broilers and laying hens, 

especially during supplementation with fish oil] 

Berl Munch Tierarztl Wochenschr. 2002 Nov-Dec;115(11-12):458-64. Review. German. 

PMID: 12481654 

82: Wu K, Willett WC, Chan JM, Fuchs CS, Colditz GA, Rimm EB, Giovannucci EL. 

A prospective study on supplemental vitamin e intake and risk of colon cancer 

in women and men. 


PMID: 12433706 



559

83: Ghosh D, Das UB, Misro M. 

Protective role of alpha-tocopherol-succinate (provitamin-E) in 

cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a 

correlative approach to oxidative stress. 

Free Radic Res. 2002 Nov;36(11):1209-18. 

PMID: 12592673 

84: Roongpraiwan R, Suthutvoravut U, Feungpean B, Phuapradit P. 

Effect of oral vitamin E supplementation in children with cholestasis. 

J Med Assoc Thai. 2002 Nov;85 Suppl 4:S1199-205. 

PMID: 12549795 

85: Liu L, Meydani M. 

Combined vitamin C and E supplementation retards early progression of 

arteriosclerosis in heart transplant patients. 

Nutr Rev. 2002 Nov;60(11):368-71. Review. 

PMID: 12462519 

86: Stohs SJ, Ohia S, Bagchi D. 

Naphthalene toxicity and antioxidant nutrients. 

Toxicology. 2002 Oct 30;180(1):97-105. Review. 

PMID: 12324202 

87: Kuriyama K, Shimizu T, Horiguchi T, Watabe M, Abe Y. 

Vitamin E ointment at high dose levels suppresses contact dermatitis in rats by 

stabilizing keratinocytes. 

Inflamm Res. 2002 Oct;51(10):483-9. 

PMID: 12477076 

88: Boshtam M, Rafiei M, Sadeghi K, Sarraf-Zadegan N. 

Vitamin E can reduce blood pressure in mild hypertensives. 

Int J Vitam Nutr Res. 2002 Oct;72(5):309-14. 

PMID: 12463106 

89: Bozkurt AK. 

Alpha-tocopherol (Vitamin E) and iloprost attenuate reperfusion injury in 

skeletal muscle ischemia/reperfusion injury. 

J Cardiovasc Surg (Torino). 2002 Oct;43(5):693-6. 

PMID: 12386586 

90: Chao JT, Gapor A, Theriault A. 

Inhibitory effect of delta-tocotrienol, a HMG CoA reductase inhibitor, on 

monocyte-endothelial cell adhesion. 

J Nutr Sci Vitaminol (Tokyo). 2002 Oct;48(5):332-7. 

PMID: 12656204 

91: Soybir N, Soybir G, Lice H, Dolay K, Ozseker A, Koksoy F. 

The effects of desferrioxamin and vitamin E as supplements to antibiotics in 

the treatment of peritonitis in rats. 

J R Coll Surg Edinb. 2002 Oct;47(5):700-4. 

PMID: 12463711 

92: Frenoux JM, Noirot B, Prost ED, Madani S, Blond JP, Belleville JL, Prost 

JL. 



560

Very high alpha-tocopherol diet diminishes oxidative stress and 

hypercoagulation in hypertensive rats but not in normotensive rats. 

Med Sci Monit. 2002 Oct;8(10):BR401-7. 

PMID: 12388913 

93: Senatore M, Nicoletti A, Rizzuto G. 

Is the bioreactivity of vitamin-E-modified dialyzer an expression of increased 

plasmatic vitamin E concentration? 

Nephron. 2002 Oct;92(2):487-9. 

PMID: 12218339 

94: Martin A, Youdim K, Szprengiel A, Shukitt-Hale B, Joseph J. 

Roles of vitamins E and C on neurodegenerative diseases and cognitive 

performance. 

Nutr Rev. 2002 Oct;60(10 Pt 1):308-26. Review. 

PMID: 12392148 

95: Zhao Y, Wu K, Xia W, Shan YJ, Wu LJ, Yu WP. 

The effects of vitamin E succinate on the expression of c-jun gene and protein 

in human gastric cancer SGC-7901 cells. 

World J Gastroenterol. 2002 Oct;8(5):782-6. 

PMID: 12378615 

96: Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang 

J, Selzer RH, Azen SP; VEAPS Research Group. 

Alpha-tocopherol supplementation in healthy individuals reduces low-density 

lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis 

Prevention Study (VEAPS). 

Circulation. 2002 Sep 17;106(12):1453-9. 

PMID: 12234947 

97: Huang HY, Appel LJ, Croft KD, Miller ER 3rd, Mori TA, Puddey IB. 

Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a 

randomized controlled trial. 

Am J Clin Nutr. 2002 Sep;76(3):549-55. 

PMID: 12197998 

98: Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ, Charnock-Jones DS, 

Mallet A, Poston L. 

Vitamin C and E supplementation in women at risk of preeclampsia is associated 

with changes in indices of oxidative stress and placental function. 

Am J Obstet Gynecol. 2002 Sep;187(3):777-84. 

PMID: 12237663 

99: Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, Tellez-Rojo MM, Moreno-Macias 

H, Reyes-Ruiz NI, del Rio-Navarro BE, Ruiz-Navarro MX, Hatch G, Slade R, 

Hernandez-Avila M. 

Antioxidant supplementation and lung functions among children with asthma 

exposed to high levels of air pollutants. 

Am J Respir Crit Care Med. 2002 Sep 1;166(5):703-9. 

PMID: 12204869 

100: Harris A, Devaraj S, Jialal I. 

Oxidative stress, alpha-tocopherol therapy, and atherosclerosis. 



561

Curr Atheroscler Rep. 2002 Sep;4(5):373-80. Review. 

PMID: 12162937 

101: Velasquez-Pereira J, Arechiga CF, McDowell LR, Hansen PJ, Chenoweth PJ, 

Calhoun MC, Risco CA, Batra TR, Williams SN, Wilkinson NS. 

Effects of gossypol from cottonseed meal and dietary vitamin E on the 

reproductive characteristics of superovulated beef heifers. 

J Anim Sci. 2002 Sep;80(9):2485-92. 

PMID: 12350026 

102: Kessler M, Ubeaud G, Walter T, Sturm F, Jung L. 

Free radical scavenging and skin penetration of troxerutin and vitamin 

derivatives. 

J Dermatolog Treat. 2002 Sep;13(3):133-41. 

PMID: 12227877 

103: Pasantes-Morales H, Quiroz H, Quesada O. 

Treatment with taurine, diltiazem, and vitamin E retards the progressive visual 

field reduction in retinitis pigmentosa: a 3-year follow-up study. 

Metab Brain Dis. 2002 Sep;17(3):183-97. 

PMID: 12322788 

104: Reis EA, Zugno AI, Franzon R, Tagliari B, Matte C, Lammers ML, Netto CA, 

Wyse AT. 

Pretreatment with vitamins E and C prevent the impairment of memory caused by 

homocysteine administration in rats. 

Metab Brain Dis. 2002 Sep;17(3):211-7. 

PMID: 12322790 

105: Barnett KT, Fokum FD, Malafa MP. 

Vitamin E succinate inhibits colon cancer liver metastases. 

J Surg Res. 2002 Aug;106(2):292-8. 

PMID: 12175981 

106: Akazawa A, Nishikawa K, Suzuki K, Asano R, Kumadaki I, Satoh H, Hagiwara K, 

Shin SJ, Yano T. 

Induction of apoptosis in a human breast cancer cell overexpressing ErbB-2 

receptor by alpha-tocopheryloxybutyric acid. 

Jpn J Pharmacol. 2002 Aug;89(4):417-21. 

PMID: 12233821 

107: Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. 

Vitamin E and cognitive decline in older persons. 

Arch Neurol. 2002 Jul;59(7):1125-32. 

PMID: 12117360 

108: Morton LW, Ward NC, Croft KD, Puddey IB. 

Evidence for the nitration of gamma-tocopherol in vivo: 

5-nitro-gamma-tocopherol is elevated in the plasma of subjects with coronary 

heart disease. 

Biochem J. 2002 Jun 15;364(Pt 3):625-8. 

PMID: 11960550 



562

109: Malmberg KJ, Lenkei R, Petersson M, Ohlum T, Ichihara F, Glimelius B, 

Frodin JE, Masucci G, Kiessling R. 

A short-term dietary supplementation of high doses of vitamin E increases T 

helper 1 cytokine production in patients with advanced colorectal cancer. 

Clin Cancer Res. 2002 Jun;8(6):1772-8. 

PMID: 12060616 

110: Desideri G, Croce G, Marinucci MC, Masci PG, Stati M, Valeri L, Santucci A, 

Ferri C. 

Prolonged, low dose alpha-tocopherol therapy counteracts intercellular cell 

adhesion molecule-1 activation. 

Clin Chim Acta. 2002 Jun;320(1-2):5-9. 

PMID: 11983194 

111: Radosavac D, Graf P, Polidori MC, Sies H, Stahl W. 

Tocopherol metabolites 2, 5, 7, 

8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2, 7, 

8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) in human serum 

after a single dose of natural vitamin E. 

Eur J Nutr. 2002 Jun;41(3):119-24. 

PMID: 12111049 

112: Masaki H, Okano Y, Ochiai Y, Obayashi K, Akamatsu H, Sakurai H. 

alpha-tocopherol increases the intracellular glutathione level in HaCaT 

keratinocytes. 

Free Radic Res. 2002 Jun;36(6):705-9. 

PMID: 12180196 

113: Desideri G, Marinucci MC, Tomassoni G, Masci PG, Santucci A, Ferri C. 

Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and 

von Willebrand factor levels and increases nitric oxide concentrations in 

hypercholesterolemic patients. 

J Clin Endocrinol Metab. 2002 Jun;87(6):2940-5. 

PMID: 12050277 

114: LeBlanc SJ, Duffield TF, Leslie KE, Bateman KG, TenHag J, Walton JS, 

Johnson WH. 

The effect of prepartum injection of vitamin E on health in transition dairy 

cows. 

J Dairy Sci. 2002 Jun;85(6):1416-26. 

PMID: 12146472 

115: Rajagopalan R, Wani K, Huilgol NG, Kagiya TV, Nair CK. 

Inhibition of gamma-radiation induced DNA damage in plasmid pBR322 by TMG, a 

water-soluble derivative of vitamin E. 

J Radiat Res (Tokyo). 2002 Jun;43(2):153-9. 

PMID: 12238329 

116: Sagach VF, Scrosati M, Fielding J, Rossoni G, Galli C, Visioli F. 

The water-soluble vitamin E analogue Trolox protects against 

ischaemia/reperfusion damage in vitro and ex vivo. A comparison with vitamin E. 

Pharmacol Res. 2002 Jun;45(6):435-9. 

PMID: 12162942 



563

117: Neuzil J. 

Alpha-tocopheryl succinate epitomizes a compound with a shift in biological 

activity due to pro-vitamin-to-vitamin conversion. 

Biochem Biophys Res Commun. 2002 May 24;293(5):1309-13. Review. 

PMID: 12054655 

118: Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. 

Combined treatment by pentoxifylline and tocopherol for recipient women with a 

thin endometrium enrolled in an oocyte donation programme. 

Hum Reprod. 2002 May;17(5):1249-53. 

PMID: 11980747 

119: Mydlik M, Derzsiova K, Racz O, Sipulova A, Boldizsar J, Lovasova E, 

Hribikova M. 

Vitamin E as an antioxidant agent in CAPD patients. 

Int J Artif Organs. 2002 May;25(5):373-8. 

PMID: 12074333 

120: Cuppini R, Ciaroni S, Cecchini T, Ambrogini P, Ferri P, Cuppini C, Ninfali 

P, Del Grande P. 

Tocopherols enhance neurogenesis in dentate gyrus of adult rats. 

Int J Vitam Nutr Res. 2002 May;72(3):170-6. 

PMID: 12098885 

121: Hatfield PG, Robinson BL, Minikhiem DL, Kott RW, Roth NI, Daniels JT, 

Swenson CK. 

Serum alpha-tocopherol and immune function in yearling ewes supplemented with 

zinc and vitamin E. 

J Anim Sci. 2002 May;80(5):1329-34. 

PMID: 12019622 

122: Ikeda S, Tohyama T, Yamashita K. 

Dietary sesame seed and its lignans inhibit 2,7,8-trimethyl- 

2(2'-carboxyethyl)-6-hydroxychroman excretion into urine of rats fed 

gamma-tocopherol. 

J Nutr. 2002 May;132(5):961-6. 

PMID: 11983822 

123: Mune M, Otani H, Yukawa S. 

Effects of antioxidants on kidney disease. 

Mech Ageing Dev. 2002 Apr 30;123(8):1041-6. 

PMID: 12044953 

124: Mu L, Feng SS. 

Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction 

technique for fabrication of polymeric nanospheres for controlled release of 

paclitaxel (Taxol). 

J Control Release. 2002 Apr 23;80(1-3):129-44. 

PMID: 11943393 

125: Park S, Choi SB. 

Effects of alpha-tocopherol supplementation and continuous subcutaneous insulin 

infusion on oxidative stress in Korean patients with type 2 diabetes. 



564


PMID: 11916760 

126: Neuzil J, Kagedal K, Andera L, Weber C, Brunk UT. 

Vitamin E analogs: a new class of multiple action agents with anti-neoplastic 

and anti-atherogenic activity. 

Apoptosis. 2002 Apr;7(2):179-87. Review. 

PMID: 11865203 

127: Smith KJ, Norwood C, Skelton H. 

Treatment of disseminated granuloma annulare with a 5-lipoxygenase inhibitor 

and vitamin E. 

Br J Dermatol. 2002 Apr;146(4):667-70. 

PMID: 11966702 

128: Bolisetty S, Naidoo D, Lui K, Koh TH, Watson D, Whitehall J. 

Antenatal supplementation of antioxidant vitamins to reduce the oxidative 

stress at delivery--a pilot study. 

Early Hum Dev. 2002 Apr;67(1-2):47-53. 

PMID: 11893435 

129: Rivera JD, Duff GC, Galyean ML, Walker DA, Nunnery GA. 

Effects of supplemental vitamin E on performance, health, and humoral immune 

response of beef cattle. 

J Anim Sci. 2002 Apr;80(4):933-41. 

PMID: 12002330 

130: Kamiyama S, Howlader ZH, Ito M, Komai M, Furukawa Y. 

Effect of deficiency of vitamins C and/or E on lipoprotein metabolism in 

osteogenic disorder Shionogi rat, a strain unable to synthesize ascorbic acid. 

J Nutr Sci Vitaminol (Tokyo). 2002 Apr;48(2):95-101. 

PMID: 12171442 

131: Pinelli A, Trivulzio S, Tomasoni L, Bertolini B, Pinelli G. 

High-dose vitamin E lowers urine porphyrin levels in patients affected by 

porphyria cutanea tarda. 

Pharmacol Res. 2002 Apr;45(4):355-9. 

PMID: 12030801 

132: Ciocoiu M, Badescu M, Paduraru I, Colev-Luca V. 

[Platelet adhesion and antioxidant therapy in experimental stress] 

Rev Med Chir Soc Med Nat Iasi. 2002 Apr-Jun;107(2):331-3. Romanian. 

PMID: 12638285 

133: Fang JC, Kinlay S, Beltrame J, Hikiti H, Wainstein M, Behrendt D, Suh J, 

Frei B, Mudge GH, Selwyn AP, Ganz P. 

Effect of vitamins C and E on progression of transplant-associated 

arteriosclerosis: a randomised trial. 

Lancet. 2002 Mar 30;359(9312):1108-13. 

PMID: 11943259 

134: Neuzil J, Zhao M, Ostermann G, Sticha M, Gellert N, Weber C, Eaton JW, 

Brunk UT. 

Alpha-tocopheryl succinate, an agent with in vivo anti-tumour activity, induces 



565

apoptosis by causing lysosomal instability. 

Biochem J. 2002 Mar 15;362(Pt 3):709-15. 

PMID: 11879199 

135: Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, Korinek V, Sattler 

W, Ucker DS, Terman A, Schroder A, Erl W, Brunk UT, Coffey RJ, Weber C, Neuzil 

J. 

Vitamin E succinate is a potent novel antineoplastic agent with high 

selectivity and cooperativity with tumor necrosis factor-related 

apoptosis-inducing ligand (Apo2 ligand) in vivo. 

Clin Cancer Res. 2002 Mar;8(3):863-9. 

PMID: 11895920 

136: Devaraj S, Chan AV Jr, Jialal I. 

alpha-Tocopherol supplementation decreases plasminogen activator inhibitor-1 

and P-selectin levels in type 2 diabetic patients. 

Diabetes Care. 2002 Mar;25(3):524-9. 

PMID: 11874941 

137: Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. 

Evaluation of dietary intake of vitamin E in the treatment of atopic 

dermatitis: a study of the clinical course and evaluation of the immunoglobulin 

E serum levels. 

Int J Dermatol. 2002 Mar;41(3):146-50. 

PMID: 12010339 

138: Sahin K, Kucuk O, Sahin N, Sari M. 

Effects of vitamin C and vitamin E on lipid peroxidation status, serum hormone, 

metabolite, and mineral concentrations of Japanese quails reared under heat 

stress (34 degrees C). 

Int J Vitam Nutr Res. 2002 Mar;72(2):91-100. 

PMID: 11944200 

139: Tabet N, Mantle D, Walker Z, Orrell M. 

Endogenous antioxidant activities in relation to concurrent vitamins A, C, and 

E intake in dementia. 

Int Psychogeriatr. 2002 Mar;14(1):7-15. 

PMID: 12094909 

140: Moreira I, Mahan DC. 

Effect of dietary levels of vitamin E (all-rac-tocopheryl acetate) with or 

without added fat on weanling pig performance and tissue alpha-tocopherol 

concentration. 

J Anim Sci. 2002 Mar;80(3):663-9. 

PMID: 11890402 

141: Brancato R, Fiore T, Papucci L, Schiavone N, Formigli L, Orlandini SZ, 

Gobbi PG, Carones F, Donnini M, Lapucci A, Capaccioli S. 

Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent 

keratocyte apoptosis after excimer laser photoablation in rabbits. 

J Refract Surg. 2002 Mar-Apr;18(2):135-9. 

PMID: 11934201 



566

142: Tauler P, Aguilo A, Fuentespina E, Tur JA, Pons A. 

Diet supplementation with vitamin E, vitamin C and beta-carotene cocktail 

enhances basal neutrophil antioxidant enzymes in athletes. 

Pflugers Arch. 2002 Mar;443(5-6):791-7. Epub 2002 Jan 31. 

PMID: 11889577 

143: Harper L, Nuttall SL, Martin U, Savage CO. 

Adjuvant treatment of patients with antineutrophil cytoplasmic 

antibody-associated vasculitis with vitamins E and C reduces superoxide 

production by neutrophils. 

Rheumatology (Oxford). 2002 Mar;41(3):274-8. 

PMID: 11934963 

144: Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. 

Vitamin E oxidation in human atherosclerotic lesions. 

Circ Res. 2002 Feb 22;90(3):333-9. 

PMID: 11861423 

145: Isler M, Delibas N, Guclu M, Gultekin F, Sutcu R, Bahceci M, Kosar A. 

Superoxide dismutase and glutathione peroxidase in erythrocytes of patients 

with iron deficiency anemia: effects of different treatment modalities. 

Croat Med J. 2002 Feb;43(1):16-9. 

PMID: 11828552 

146: Dimakakos PB, Kotsis T, Kondi-Pafiti A, Katsenis K, Doufas A, Chondros K, 

Kouskouni E. 

Oxygen free radicals in abdominal aortic surgery. An experimental study. 

J Cardiovasc Surg (Torino). 2002 Feb;43(1):77-82. 

PMID: 11803334 

147: Morinobu T, Ban R, Yoshikawa S, Murata T, Tamai H. 

The safety of high-dose vitamin E supplementation in healthy Japanese male 

adults. 

J Nutr Sci Vitaminol (Tokyo). 2002 Feb;48(1):6-9. 

PMID: 12026191 

148: Jones KH, Liu JJ, Roehm JS, Eckel JJ, Eckel TT, Stickrath CR, Triola CA, 

Jiang Z, Bartoli GM, Cornwell DG. 

Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and 

multidrug-resistant cancer cells. 

Lipids. 2002 Feb;37(2):173-84. 

PMID: 11908909 

149: Chylack LT Jr, Brown NP, Bron A, Hurst M, Kopcke W, Thien U, Schalch W. 

The Roche European American Cataract Trial (REACT): a randomized clinical trial 

to investigate the efficacy of an oral antioxidant micronutrient mixture to slow 

progression of age-related cataract. 

Ophthalmic Epidemiol. 2002 Feb;9(1):49-80. 

PMID: 11815895 

150: van Winden SC, Kuiper R. 

[Congenital white muscle disease in a Belgian blue calf] 

Tijdschr Diergeneeskd. 2002 Feb 1;127(3):74-7. Dutch. 

PMID: 11858038 



567

151: Fleshner NE. 

Vitamin E and prostate cancer. 

Urol Clin North Am. 2002 Feb;29(1):107-13, ix. Review. 

PMID: 12109337 

152: Wu K, Zhao Y, Liu BH, Li Y, Liu F, Guo J, Yu WP. 

RRR-alpha-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell 

growth by inducing apoptosis and DNA synthesis arrest. 

World J Gastroenterol. 2002 Feb;8(1):26-30. 

PMID: 11833065 

153: Mireles-Rocha H, Galindo I, Huerta M, Trujillo-Hernandez B, Elizalde A, 

Cortes-Franco R. 

UVB photoprotection with antioxidants: effects of oral therapy with 

d-alpha-tocopherol and ascorbic acid on the minimal erythema dose. 

Acta Derm Venereol. 2002;82(1):21-4. 

PMID: 12013192 

154: Sarlos P, Molnar A, Kokai M, Gabor G, Ratky J. 

Comparative evaluation of the effect of antioxidants in the conservation of ram 

semen. 

Acta Vet Hung. 2002;50(2):235-45. 

PMID: 12113179 

155: Raederstorff D, Elste V, Aebischer C, Weber P. 

Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid 

profile in hamsters. 

Ann Nutr Metab. 2002;46(1):17-23. 

PMID: 11914511 

156: Woodson K, Triantos S, Hartman T, Taylor PR, Virtamo J, Albanes D. 

Long-term alpha-tocopherol supplementation is associated with lower serum 

vascular endothelial growth factor levels. 

Anticancer Res. 2002 Jan-Feb;22(1A):375-8. 

PMID: 12017317 

157: Nafeeza MI, Fauzee AM, Kamsiah J, Gapor MT. 

Comparative effects of a tocotrienol-rich fraction and tocopherol in 

aspirin-induced gastric lesions in rats. 

Asia Pac J Clin Nutr. 2002;11(4):309-13. 

PMID: 12495264 

158: Theriault A, Chao JT, Gapor A, Chao JT, Gapor A. 

Tocotrienol is the most effective vitamin E for reducing endothelial expression 

of adhesion molecules and adhesion to monocytes. 

Atherosclerosis. 2002 Jan;160(1):21-30. Erratum in: Atherosclerosis. 

2002;164(2):389.. 

PMID: 11755919 

159: Stone WL, Papas AM, LeClair IO, Qui M, Ponder T. 

The influence of dietary iron and tocopherols on oxidative stress and ras-p21 

levels in the colon. 

Cancer Detect Prev. 2002;26(1):78-84. 

PMID: 12088207 



568

160: Vaney N, Chouhan S, Bhatia MS, Tandon OP. 

Event related evoked potentials in dementia: role of vitamin E. 

Indian J Physiol Pharmacol. 2002 Jan;46(1):61-8. 

PMID: 12024959 

161: Avdeeva MG, Moisova DL, Gorodin VN, Kostomarov AM, Zotov SV, Cherniavskaia 

OV. 

[The role glucose-6-phosphate dehydrogenase in pathogenesis of anemia in 

leptospirosis] 

Klin Med (Mosk). 2002;80(6):42-4. Russian. 

PMID: 12138802 

162: Cornwell DG, Williams MV, Wani AA, Wani G, Shen E, Jones KH. 

Mutagenicity of tocopheryl quinones: evolutionary advantage of selective 

accumulation of dietary alpha-tocopherol. 

Nutr Cancer. 2002;43(1):111-8. 

PMID: 12467142 

163: Slamenova D, Chalupa I, Robichova S, Gabelova A, Farkasova T, Hrusovska L, 

Bacova G, Sebova L, Eckl P, Bresgen N, Zeitheim P, Schneider P, Wsolova L, 

Barancokova M, Kazimirova A, Navarova J, Bezek S. 

Effect of dietary intake of vitamin A or E on the level of DNA damage, 

chromosomal aberrations, and micronuclei induced in freshly isolated rat 

hepatocytes by different carcinogens. 

Nutr Cancer. 2002;42(1):117-24. 

PMID: 12235643 

164: Haqqani AS, Sandhu JK, Birnboim HC. 

Dietary vitamin E affects neutrophil distribution and genetic instability in 

murine Mutatect tumors. 

Nutr Cancer. 2002;42(1):105-11. 

PMID: 12235641 

165: Nagyova A, Mongiellova V, Krivosikova Z, Blazicek P, Spustova V, Gajdos M, 

Dzurik R. 

Serum ex vivo lipoprotein oxidizability in patients with ischemic heart disease 

supplemented with vitamin E. 

Physiol Res. 2002;51(5):457-64. 

PMID: 12470198 

166: Saral Y, Uyar B, Ayar A, Naziroglu M. 

Protective effects of topical alpha-tocopherol acetate on UVB irradiation in 

guinea pigs: importance of free radicals. 

Physiol Res. 2002;51(3):285-90. 

PMID: 12234121 

167: Jachec W, Tomasik A, Tarnawski R, Chwalinska E. 

Evidence of oxidative stress in the renal cortex of diabetic rats: favourable 

effect of vitamin E. 

Scand J Clin Lab Invest. 2002;62(1):81-8. 

PMID: 12002418 

168: Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. 

Vitamin E inhibits melanoma growth in mice. 



569

Surgery. 2002 Jan;131(1):85-91. 

PMID: 11812968 

169: Zhang JG, Nicholls-Grzemski FA, Tirmenstein MA, Fariss MW. 

Vitamin E succinate protects hepatocytes against the toxic effect of reactive 

oxygen species generated at mitochondrial complexes I and III by alkylating 

agents. 

Chem Biol Interact. 2001 Dec 21;138(3):267-84. 

PMID: 11714483 

170: Schnell JW, Anderson RA, Stegner JE, Schindler SP, Weinberg RB. 

Effects of a high polyunsaturated fat diet and vitamin E supplementation on 

high-density lipoprotein oxidation in humans. 

Atherosclerosis. 2001 Dec;159(2):459-66. 

PMID: 11730827 

171: Peluzio MC, Homem AP, Cesar GC, Azevedo GS, Amorim R, Cara DC, Saliba H, 

Vieira EC, Arantes RE, Alvarez-Leite J. 

Influences of alpha-tocopherol on cholesterol metabolism and fatty streak 

development in apolipoprotein E-deficient mice fed an atherogenic diet. 

Braz J Med Biol Res. 2001 Dec;34(12):1539-45. 

PMID: 11717706 

172: Sylvester PW, McIntyre BS, Gapor A, Briski KP. 

Vitamin E inhibition of normal mammary epithelial cell growth is associated 

with a reduction in protein kinase C(alpha) activation. 

Cell Prolif. 2001 Dec;34(6):347-57. 

PMID: 11736999 

173: Kumar B, Cole WC, Prasad KN. 

Alpha tocopheryl succinate, retinoic acid and polar carotenoids enhanced the 

growth-inhibitory effect of a cholesterol-lowering drug on immortalized and 

transformed nerve cells in culture. 

J Am Coll Nutr. 2001 Dec;20(6):628-36. 

PMID: 11771679 

174: Cornelli U, Terranova R, Luca S, Cornelli M, Alberti A. 

Bioavailability and antioxidant activity of some food supplements in men and 

women using the D-Roms test as a marker of oxidative stress. 

J Nutr. 2001 Dec;131(12):3208-11. 

PMID: 11739867 

175: Shimizu K, Kondo R, Sakai K, Takeda N, Nagahata T, Oniki T. 

Novel vitamin E derivative with 4-substituted resorcinol moiety has both 

antioxidant and tyrosinase inhibitory properties. 

Lipids. 2001 Dec;36(12):1321-6. 

PMID: 11834083 


Dietary supplements reduce risk of vision loss from age-related macular 

degeneration. 

Optom Vis Sci. 2001 Dec;78(12):856. 

PMID: 11780662 



570

177: Bang OS, Park JH, Kang SS. 

Activation of PKC but not of ERK is required for vitamin E-succinate-induced 

apoptosis of HL-60 cells. 

Biochem Biophys Res Commun. 2001 Nov 9;288(4):789-97. 

PMID: 11688977 

178: Bidoli E, La Vecchia C, Talamini R, Negri E, Parpinel M, Conti E, Montella 

M, Carbone MA, Franceschi S. 

Micronutrients and ovarian cancer: a case-control study in Italy. 

Ann Oncol. 2001 Nov;12(11):1589-93. 

PMID: 11822759 

179: Bidoli E, La Vecchia C, Talamini R, Negri E, Parpinel M, Conti E, Montella 

M, Carbone MA, Franceschi S. 

Micronutrients and ovarian cancer: a case-control study in Italy. 

Ann Oncol. 2001 Nov;12(11):1589-93. 

PMID: 11822759 

180: Zaluska WT, Ksiazek A, Roliski J. 

Effect of vitamin E modified cellulose membrane on human lymphocyte, monocyte, 

and granulocyte CD11b/CD18 adhesion molecule expression during hemodialysis. 

ASAIO J. 2001 Nov-Dec;47(6):619-22. 

PMID: 11730199 

181: Ziaei S, Faghihzadeh S, Sohrabvand F, Lamyian M, Emamgholy T. 

A randomised placebo-controlled trial to determine the effect of vitamin E in 

treatment of primary dysmenorrhoea. 

BJOG. 2001 Nov;108(11):1181-3. 

PMID: 11762659 

182: Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P. 

Flavonol and flavone intake and the risk of cancer in male smokers (Finland). 

Cancer Causes Control. 2001 Nov;12(9):789-96. 

PMID: 11714106 

183: Ikeda S, Toyoshima K, Yamashita K. 

Dietary sesame seeds elevate alpha- and gamma-tocotrienol concentrations in 

skin and adipose tissue of rats fed the tocotrienol-rich fraction extracted from 

palm oil. 

J Nutr. 2001 Nov;131(11):2892-7. 

PMID: 11694614 

184: Pehrson B, Holmgren N, Trafikowska U. 

The influence of parenterally administered alpha-tocopheryl acetate to sows on 

the vitamin E status of the sows and suckling piglets and piglets after weaning. 

J Vet Med A Physiol Pathol Clin Med. 2001 Nov;48(9):569-75. 

PMID: 11765814 

185: Bayes B, Pastor MC, Bonal J, Junca J, Romero R. 

Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and 

vitamin E. 

Nephrol Dial Transplant. 2001 Nov;16(11):2172-5. 

PMID: 11682663 



571

186: Grau A, Guardiola F, Grimpa S, Barroeta AC, Codony R. 

Oxidative stability of dark chicken meat through frozen storage: influence of 

dietary fat and alpha-tocopherol and ascorbic acid supplementation. 

Poult Sci. 2001 Nov;80(11):1630-42. 

PMID: 11732681 

187: Leshchinsky TV, Klasing KC. 

Relationship between the level of dietary vitamin E and the immune response of 

broiler chickens. 

Poult Sci. 2001 Nov;80(11):1590-9. 

PMID: 11732676 

188: Rao MV, Sharma PS. 

Protective effect of vitamin E against mercuric chloride reproductive toxicity 

in male mice. 

Reprod Toxicol. 2001 Nov-Dec;15(6):705-12. 

PMID: 11738524 

189: Soltani-Frisk S, Gronowitz E, Andersson H, Strandvik B. 

Water-miscible tocopherol is not superior to fat-soluble preparation for 

vitamin E absorption in cystic fibrosis. 

Acta Paediatr. 2001 Oct;90(10):1112-5. 

PMID: 11697419 

190: Age-Related Eye Disease Study Research Group. 

A randomized, placebo-controlled, clinical trial of high-dose supplementation 

with vitamins C and E, beta carotene, and zinc for age-related macular 

degeneration and vision loss: AREDS report no. 8. 

Arch Ophthalmol. 2001 Oct;119(10):1417-36. 

PMID: 11594942 

191: Iuliano L, Micheletta F, Maranghi M, Frati G, Diczfalusy U, Violi F. 

Bioavailability of vitamin E as function of food intake in healthy subjects: 

effects on plasma peroxide-scavenging activity and cholesterol-oxidation 

products. 

Arterioscler Thromb Vasc Biol. 2001 Oct;21(10):E34-7. 

PMID: 11597949 

192: Limaye LS, Kale VP. 

Cryopreservation of human hematopoietic cells with membrane stabilizers and 

bioantioxidants as additives in the conventional freezing medium. 

J Hematother Stem Cell Res. 2001 Oct;10(5):709-18. 

PMID: 11672518 

193: Qureshi AA, Salser WA, Parmar R, Emeson EE. 

Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 

ApoE-deficient mice. 

J Nutr. 2001 Oct;131(10):2606-18. 

PMID: 11584079 

194: Lee L, Kang SA, Lee HO, Lee BH, Jung IK, Lee JE, Hoe YS. 

Effect of supplementation of vitamin E and vitamin C on brain 

acetylcholinesterase activity and neurotransmitter levels in rats treated with 

scopolamine, an inducer of dementia. 



572


PMID: 11814146 

195: Tidow-Kebritchi S, Mobarhan S. 

Effects of diets containing fish oil and vitamin E on rheumatoid arthritis. 

Nutr Rev. 2001 Oct;59(10):335-8. Review. 

PMID: 11669239 

196: Muscari A, Bastagi L, Poggiopollini G, Tomassetti V, Massarelli G, Boni P, 

Puddu P. 

Short term effect of atorvastatin and vitamin E on serum levels of C3, a 

sensitive marker of the risk of myocardial infarction in men. 

Cardiovasc Drugs Ther. 2001 Sep;15(5):453-8. 

PMID: 11855664 

197: Gaede P, Poulsen HE, Parving HH, Pedersen O. 

Double-blind, randomised study of the effect of combined treatment with vitamin 

C and E on albuminuria in Type 2 diabetic patients. 

Diabet Med. 2001 Sep;18(9):756-60. 

PMID: 11606175 

198: Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I, Ben Hamida M, 

Kayden H, Mebazaa R, Hentati F. 

Effect of vitamin E supplementation in patients with ataxia with vitamin E 

deficiency. 

Eur J Neurol. 2001 Sep;8(5):477-81. 

PMID: 11554913 

199: Lyons NM, Woods JA, O'Brien NM. 

alpha-Tocopherol, but not gamma-tocopherol inhibits 7 

beta-hydroxycholesterol-induced apoptosis in human U937 cells. 


PMID: 11697131 

200: Toyokuni S, Masumizu T, Ozeki M, Kondo S, Hiroyasu M, Kohno M, Hiai H. 

An electron spin resonance study on alkylperoxyl radical in thin-sliced renal 

tissues from ferric nitrilotriacetate-treated rats: the effect of 

alpha-tocopherol feeding. 


PMID: 11697123 

201: Kakizaki S, Takagi H, Fukusato T, Toyoda M, Horiguchi N, Sato K, Takayama 

H, Nagamine T, Mori M. 

Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth 

factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine. 

Int J Vitam Nutr Res. 2001 Sep;71(5):261-7. 

PMID: 11725690 

202: Stulak JM, Lerman A, Porcel MR, Caccitolo JA, Romero JC, Schaff HV, Napoli 

C, Lerman LO. 

Renal vascular function in hypercholesterolemia is preserved by chronic 

antioxidant supplementation. 

J Am Soc Nephrol. 2001 Sep;12(9):1882-91. 

PMID: 11518781 



573

203: Zhang WR, Hayashi T, Sasaki C, Sato K, Nagano I, Manabe Y, Abe K. 

Attenuation of oxidative DNA damage with a novel antioxidant EPC-K1 in rat 

brain neuronal cells after transient middle cerebral artery occlusion. 

Neurol Res. 2001 Sep;23(6):676-80. 

PMID: 11547942 

204: Shen CT, Wang NK. 

Antioxidants may mitigate the deterioration of coronary arteritis in patients 

with Kawasaki disease unresponsive to high-dose intravenous gamma-globulin. 

Pediatr Cardiol. 2001 Sep-Oct;22(5):419-22. 

PMID: 11526424 

205: Zhao BQ, Suzuki Y, Kondo K, Ikeda Y, Umemura K. 

Combination of a free radical scavenger and heparin reduces cerebral hemorrhage 

after heparin treatment in a rabbit middle cerebral artery occlusion model. 

Stroke. 2001 Sep;32(9):2157-63. 

PMID: 11546911 

206: Fariss MW, Nicholls-Grzemski FA, Tirmenstein MA, Zhang JG. 

Enhanced antioxidant and cytoprotective abilities of vitamin E succinate is 

associated with a rapid uptake advantage in rat hepatocytes and mitochondria. 

Free Radic Biol Med. 2001 Aug 15;31(4):530-41. 

PMID: 11498286 

207: Alleva R, Tomasetti M, Andera L, Gellert N, Borghi B, Weber C, Murphy MP, 

Neuzil J. 

Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing 

mitochondrial antioxidant protection. 

FEBS Lett. 2001 Aug 10;503(1):46-50. 

PMID: 11513852 

208: Hayes K, Pronczuk A, Perlman D. 

Vitamin E in fortified cow milk uniquely enriches human plasma lipoproteins. 

Am J Clin Nutr. 2001 Aug;74(2):211-8. 

PMID: 11470723 

209: Gupta RC, Milatovic D, Dettbarn WD. 

Nitric oxide modulates high-energy phosphates in brain regions of rats 

intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by 

N-tert-butyl-alpha-phenylnitrone or vitamin E. 

Arch Toxicol. 2001 Aug;75(6):346-56. 

PMID: 11570692 

210: Bauersachs J, Fleming I, Fraccarollo D, Busse R, Ertl G. 

Prevention of endothelial dysfunction in heart failure by vitamin E: 

attenuation of vascular superoxide anion formation and increase in soluble 

guanylyl cyclase expression. 

Cardiovasc Res. 2001 Aug 1;51(2):344-50. 

PMID: 11470474 

211: Gokkusu C, Palanduz S, Ademoglu E, Tamer S. 

Oxidant and antioxidant systems in niddm patients: influence of vitamin E 

supplementation. 



574

Endocr Res. 2001 Aug;27(3):377-86. 

PMID: 11678585 

212: Montero D, Tort L, Robaina L, Vergara JM, Izquierdo MS. 

Low vitamin E in diet reduces stress resistance of gilthead seabream (Sparus 

aurata) juveniles. 

Fish Shellfish Immunol. 2001 Aug;11(6):473-90. 

PMID: 11556478 

213: Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C, Muller-Thomsen T, Beisiegel U. 

Influence of vitamin E and C supplementation on lipoprotein oxidation in 

patients with Alzheimer's disease. 

Free Radic Biol Med. 2001 Aug 1;31(3):345-54. 

PMID: 11461772 

214: Klipstein-Grobusch K, den Breeijen JH, Grobbee DE, Boeing H, Hofman A, 

Witteman JC. 

Dietary antioxidants and peripheral arterial disease : the Rotterdam Study. 

Am J Epidemiol. 2001 Jul 15;154(2):145-9. 

PMID: 11447047 

215: Scott KC, Hill RC, Lewis DD, Boning AJ Jr, Sundstrom DA. 

Effect of alpha-tocopheryl acetate supplementation on vitamin E concentrations 

in Greyhounds before and after a race. 

Am J Vet Res. 2001 Jul;62(7):1118-20. 

PMID: 11453489 

216: Soltys K, Dikdan G, Koneru B. 

Oxidative stress in fatty livers of obese Zucker rats: rapid amelioration and 

improved tolerance to warm ischemia with tocopherol. 

Hepatology. 2001 Jul;34(1):13-8. 

PMID: 11431728 

217: Gonzalez R, Sanchez de Medina F, Galvez J, Rodriguez-Cabezas ME, Duarte J, 

Zarzuelo A. 

Dietary vitamin E supplementation protects the rat large intestine from 

experimental inflammation. 

Int J Vitam Nutr Res. 2001 Jul;71(4):243-50. 

PMID: 11582860 

218: Roeber DL, Belk KE, Tatum JD, Wilson JW, Smith GC. 

Effects of three levels of alpha-tocopheryl acetate supplementation to feedlot 

cattle on performance of beef cuts during retail display. 

J Anim Sci. 2001 Jul;79(7):1814-20. 

PMID: 11465368 

219: Khajehdehi P, Mojerlou M, Behzadi S, Rais-Jalali GA. 

A randomized, double-blind, placebo-controlled trial of supplementary vitamins 

E, C and their combination for treatment of haemodialysis cramps. 


PMID: 11427639 



575

220: Ruiz JA, Guerrero L, Arnau J, Guardia MD, Esteve-Garcia E. 

Descriptive sensory analysis of meat from broilers fed diets containing vitamin 

E or beta-carotene as antioxidants and different supplemental fats. 

Poult Sci. 2001 Jul;80(7):976-82. 

PMID: 11469665 

221: Manzella D, Barbieri M, Ragno E, Paolisso G. 

Chronic administration of pharmacologic doses of vitamin E improves the cardiac 

autonomic nervous system in patients with type 2 diabetes. 


PMID: 11382659 

222: Bass RT 2nd, Swecker WS Jr, Eversole DE. 

Effects of oral vitamin E supplementation during late gestation in beef cattle 

that calved in late winter and late summer. 

Am J Vet Res. 2001 Jun;62(6):921-7. 

PMID: 11400851 

223: Cederberg J, Siman CM, Eriksson UJ. 

Combined treatment with vitamin E and vitamin C decreases oxidative stress and 

improves fetal outcome in experimental diabetic pregnancy. 

Pediatr Res. 2001 Jun;49(6):755-62. 

PMID: 11385134 

224: Yano T, Yano Y, Yajima S, Kumadaki I, Ichikawa T, Otani S, Hagiwara K. 

The suppression of ornithine decarboxylase expression and cell proliferation at 

the promotion stage of lung tumorigenesis in mice by alpha-tocopheryloxybutyric 

acid. 

Biochem Pharmacol. 2001 May 1;61(9):1177-81. 

PMID: 11301052 

225: Vetrugno M, Maino A, Cardia G, Quaranta GM, Cardia L. 

A randomised, double masked, clinical trial of high dose vitamin A and vitamin 

E supplementation after photorefractive keratectomy. 

Br J Ophthalmol. 2001 May;85(5):537-9. 

PMID: 11316710 

226: Tesoriere L, D'Arpa D, Butera D, Allegra M, Renda D, Maggio A, Bongiorno A, 

Livrea MA. 

Oral supplements of vitamin E improve measures of oxidative stress in plasma 

and reduce oxidative damage to LDL and erythrocytes in beta-thalassemia 

intermedia patients. 

Free Radic Res. 2001 May;34(5):529-40. 

PMID: 11378535 

227: Musaev MU, Mavlianov IR. 

[Effect of tocopherol acetate, indomethacin and dexamethasone on some indices 

of local lung defense in rheumatoid arthritis] 

Lik Sprava. 2001 May-Jun;(3):110-3. Russian. 

PMID: 11559995 

228: Gille L, Staniek K, Nohl H. 

Effects of tocopheryl quinone on the heart: model experiments with xanthine 

oxidase, heart mitochondria, and isolated perfused rat hearts. 



576

Free Radic Biol Med. 2001 Apr 15;30(8):865-76. 

PMID: 11295529 

229: Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, 

Albanes D. 

Dietary and other methyl-group availability factors and pancreatic cancer risk 

in a cohort of male smokers. 

Am J Epidemiol. 2001 Apr 1;153(7):680-7. 

PMID: 11282796 

230: Kennedy M, Bruninga K, Mutlu EA, Losurdo J, Choudhary S, Keshavarzian A. 

Successful and sustained treatment of chronic radiation proctitis with 

antioxidant vitamins E and C. 

Am J Gastroenterol. 2001 Apr;96(4):1080-4. 

PMID: 11316150 

231: Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, 

Stocker R. 

Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits 

atherosclerosis in apolipoprotein E gene knockout mice. 

Arterioscler Thromb Vasc Biol. 2001 Apr;21(4):585-93. 

PMID: 11304477 

232: Cataldi A, Gasbarro V, Viaggi R, Soverini R, Gresta E, Mascoli F. 

[Effectiveness of the combination of alpha tocopherol, rutin, melilotus, and 

centella asiatica in the treatment of patients with chronic venous 

insufficiency] 

Minerva Cardioangiol. 2001 Apr;49(2):159-63. Italian. 

PMID: 11292962 

233: Morelli S, Sgreccia A, Bernardo ML, Gurgo Di Castelmenardo A, Petrilli AC, 

De Leva R, Nuccio F, Calvieri S. 

Systemic sclerosis (scleroderma). A case of recovery of cardiomyopathy after 

vitamin E treatment. 

Minerva Cardioangiol. 2001 Apr;49(2):127-30. English, Italian. 

PMID: 11292956 

234: Galobart J, Barroeta AC, Baucells MD, Codony R, Ternes W. 

Effect of dietary supplementation with rosemary extract and alpha-tocopheryl 

acetate on lipid oxidation in eggs enriched with omega3-fatty acids. 

Poult Sci. 2001 Apr;80(4):460-7. 

PMID: 11297285 

235: Altavilla D, Saitta A, Cucinotta D, Galeano M, Deodato B, Colonna M, Torre 

V, Russo G, Sardella A, Urna G, Campo GM, Cavallari V, Squadrito G, Squadrito F. 

Inhibition of lipid peroxidation restores impaired vascular endothelial growth 

factor expression and stimulates wound healing and angiogenesis in the 

genetically diabetic mouse. 

Diabetes. 2001 Mar;50(3):667-74. 

PMID: 11246889 

236: Horton JW, White DJ, Maass DL, Hybki DP, Haudek S, Giroir B. 

Antioxidant vitamin therapy alters burn trauma-mediated cardiac NF-kappaB 



577

activation and cardiomyocyte cytokine secretion. 

J Trauma. 2001 Mar;50(3):397-406; discussion 407-8. 

PMID: 11265018 

237: Roghani M, Behzadi G. 

Neuroprotective effect of vitamin E on the early model of Parkinson's disease 

in rat: behavioral and histochemical evidence. 

Brain Res. 2001 Feb 16;892(1):211-7. 

PMID: 11172767 

238: Ishige K, Schubert D, Sagara Y. 

Flavonoids protect neuronal cells from oxidative stress by three distinct 

mechanisms. 

Free Radic Biol Med. 2001 Feb 15;30(4):433-46. 

PMID: 11182299 

239: Andreone P, Fiorino S, Cursaro C, Gramenzi A, Margotti M, Di Giammarino L, 

Biselli M, Miniero R, Gasbarrini G, Bernardi M. 

Vitamin E as treatment for chronic hepatitis B: results of a randomized 

controlled pilot trial. 

Antiviral Res. 2001 Feb;49(2):75-81. 

PMID: 11248360 

240: Naziroglu M, Cay M. 

Protective role of intraperitoneally administered vitamin E and selenium on the 

antioxidative defense mechanisms in rats with diabetes induced by 

streptozotocin. 

Biol Trace Elem Res. 2001 Feb;79(2):149-59. 

PMID: 11330521 

241: Orbe J, Rodriguez JA, Calvo A, Grau A, Belzunce MS, Martinez-Caro D, Paramo 

JA. 

Vitamins C and E attenuate plasminogen activator inhibitor-1 (PAI-1) expression 

in a hypercholesterolemic porcine model of angioplasty. 

Cardiovasc Res. 2001 Feb 1;49(2):484-92. 

PMID: 11164859 

242: Jialal I, Traber M, Devaraj S. 

Is there a vitamin E paradox? 

Curr Opin Lipidol. 2001 Feb;12(1):49-53. Review. 

PMID: 11176203 

243: Neuzil J, Weber T, Schroder A, Lu M, Ostermann G, Gellert N, Mayne GC, 

Olejnicka B, Negre-Salvayre A, Sticha M, Coffey RJ, Weber C. 

Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular 

pathways and structural requirements. 

FASEB J. 2001 Feb;15(2):403-15. 

PMID: 11156956 

244: Lopez Bote CJ, Isabel B, Flores JM. 

Effect of dietary linoleic acid concentration and vitamin E supplementation on 

cell desquamation and susceptibility to oxidative damage of pig jejunal mucosa. 

J Anim Physiol Anim Nutr (Berl). 2001 Feb;85(1-2):22-8. 

PMID: 11686769 



578

245: Gupta R, Singhal S, Goyle A, Sharma VN. 

Antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree-bark 

powder: a randomised placebo-controlled trial. 

J Assoc Physicians India. 2001 Feb;49:231-5. 

PMID: 11225136 

246: Meydani M. 

Vitamin E and atherosclerosis: beyond prevention of LDL oxidation. 

J Nutr. 2001 Feb;131(2):366S-8S. Review. 

PMID: 11160562 

247: Packer L, Weber SU, Rimbach G. 

Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. 


PMID: 11160563 

248: Freedman JE, Keaney JF Jr. 

Vitamin E inhibition of platelet aggregation is independent of antioxidant 

activity. 


PMID: 11160564 

249: Qureshi AA, Peterson DM, Hasler-Rapacz JO, Rapacz J. 

Novel tocotrienols of rice bran suppress cholesterogenesis in hereditary 

hypercholesterolemic swine. 

J Nutr. 2001 Feb;131(2):223-30. 

PMID: 11160537 

250: Galli F, Varga Z, Balla J, Ferraro B, Canestrari F, Floridi A, Kakuk G, 

Buoncristiani U. 

Vitamin E, lipid profile, and peroxidation in hemodialysis patients. 

Kidney Int Suppl. 2001 Feb;78:S148-54. 

PMID: 11169001 

251: Mydlik M, Derzsiova K, Racz O, Sipulova A, Lovasova E, Petrovicova J. 

A modified dialyzer with vitamin E and antioxidant defense parameters. 

Kidney Int Suppl. 2001 Feb;78:S144-7. 

PMID: 11169000 

252: Wu K, Shan YJ, Zhao Y, Yu JW, Liu BH. 

Inhibitory effects of RRR-alpha-tocopheryl succinate on benzo(a)pyrene 

(B(a)P)-induced forestomach carcinogenesis in female mice. 

World J Gastroenterol. 2001 Feb;7(1):60-5. 

PMID: 11819734 

253: Chen R, Tunstall-Pedoe H, Bolton-Smith C, Hannah MK, Morrison C. 

Association of dietary antioxidants and waist circumference with pulmonary 

function and airway obstruction. 

Am J Epidemiol. 2001 Jan 15;153(2):157-63. 

PMID: 11159161 

254: Neuzil J, Weber T, Gellert N, Weber C. 

Selective cancer cell killing by alpha-tocopheryl succinate. 



579

Br J Cancer. 2001 Jan 5;84(1):87-9. 

PMID: 11139318 

255: Helmy M, Shohayeb M, Helmy MH, el-Bassiouni EA. 

Antioxidants as adjuvant therapy in rheumatoid disease. A preliminary study. 


PMID: 11367869 

256: Yam D, Peled A, Shinitzky M. 

Suppression of tumor growth and metastasis by dietary fish oil combined with 

vitamins E and C and cisplatin. 

Cancer Chemother Pharmacol. 2001;47(1):34-40. 

PMID: 11221959 

257: Hirvonen T, Pietinen P, Virtanen M, Ovaskainen ML, Hakkinen S, Albanes D, 

Virtamo J. 

Intake of flavonols and flavones and risk of coronary heart disease in male 

smokers. 

Epidemiology. 2001 Jan;12(1):62-7. 

PMID: 11138821 

258: Fischer M, Wohlrab J, Marsch W. 

Crux medicorum ulcerated radiation-induced fibrosis - successful therapy with 

pentoxifylline and vitamin E. 

Eur J Dermatol. 2001 Jan-Feb;11(1):38-40. 

PMID: 11174136 

259: Kaul N, Devaraj S, Jialal I. 

Alpha-tocopherol and atherosclerosis. 

Exp Biol Med (Maywood). 2001 Jan;226(1):5-12. Review. 

PMID: 11368238 

260: Bron D, Asmis R. 

Vitamin E and the prevention of atherosclerosis. 

Int J Vitam Nutr Res. 2001 Jan;71(1):18-24. Review. 

PMID: 11276917 

261: Preuss HG, Marcusen C, Regan J, Klimberg IW, Welebir TA, Jones WA. 

Randomized trial of a combination of natural products (cernitin, saw palmetto, 

B-sitosterol, vitamin E) on symptoms of benign prostatic hyperplasia (BPH). 

Int Urol Nephrol. 2001;33(2):217-25. 

PMID: 12092634 

262: Rose AT, McFadden DW. 

Alpha-tocopherol succinate inhibits growth of gastric cancer cells in vitro. 

J Surg Res. 2001 Jan;95(1):19-22. 

PMID: 11120630 

263: Cooney RV, Custer LJ, Okinaka L, Franke AA. 

Effects of dietary sesame seeds on plasma tocopherol levels. 

Nutr Cancer. 2001;39(1):66-71. 

PMID: 11588904 



580

264: Cinar MG, Ulker S, Alper G, Evinc A. 

Effect of dietary vitamin E supplementation on vascular reactivity of thoracic 

aorta in streptozotocin-diabetic rats. 

Pharmacology. 2001 Jan;62(1):56-64. 

PMID: 11150923 

265: Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, 

Taylor PR, Barrett MJ, Albanes D. 

Effects of long-term alpha-tocopherol supplementation on serum hormones in 

older men. 

Prostate. 2001 Jan 1;46(1):33-8. 

PMID: 11170129 

266: Neuzil J, Weber T, Terman A, Weber C, Brunk UT. 

Vitamin E analogues as inducers of apoptosis: implications for their potential 

antineoplastic role. 

Redox Rep. 2001;6(3):143-51. Review. 

PMID: 11523588 

267: Parkhomets' VP, Silonov SB, Donchenko HV. 

[Effect of alpha-tocopherol, tocopheryl quinone and other complexes with 

tocopherol-binding proteins on the activity of enzymes metabolizing arachidonic 

acid] 

Ukr Biokhim Zh. 2001 Jan-Feb;73(1):43-7. Ukrainian. 

PMID: 11599425 

268: Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris 

JS, Comstock GW. 

Association between alpha-tocopherol, gamma-tocopherol, selenium, and 

subsequent prostate cancer. 

J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. 

PMID: 11121464 

269: Preiser JC, Van Gossum A, Berre J, Vincent JL, Carpentier Y. 

Enteral feeding with a solution enriched with antioxidant vitamins A, C, and E 

enhances the resistance to oxidative stress. 

Crit Care Med. 2000 Dec;28(12):3828-32. 

PMID: 11153621 

270: Title LM, Cummings PM, Giddens K, Nassar BA. 

Oral glucose loading acutely attenuates endothelium-dependent vasodilation in 

healthy adults without diabetes: an effect prevented by vitamins C and E. 

J Am Coll Cardiol. 2000 Dec;36(7):2185-91. 

PMID: 11127459 

272: Baldi A, Savoini G, Pinotti L, Monfardini E, Cheli F, Dell'Orto V. 

Effects of vitamin E and different energy sources on vitamin E status, milk 

quality and reproduction in transition cows. 

J Vet Med A Physiol Pathol Clin Med. 2000 Dec;47(10):599-608. 

PMID: 11199208 

272: Schuelke M, Finckh B, Sistermans EA, Ausems MG, Hubner C, von Moers A. 

Ataxia with vitamin E deficiency: biochemical effects of malcompliance with 

vitamin E therapy. 



581

Neurology. 2000 Nov 28;55(10):1584-6. 

PMID: 11094124 

273: Fogarty A, Lewis S, Weiss S, Britton J. 

Dietary vitamin E, IgE concentrations, and atopy. 

Lancet. 2000 Nov 4;356(9241):1573-4. 

PMID: 11075775 

274: Engelen W, Keenoy BM, Vertommen J, De Leeuw I. 

Effects of long-term supplementation with moderate pharmacologic doses of 

vitamin E are saturable and reversible in patients with type 1 diabetes. 

Am J Clin Nutr. 2000 Nov;72(5):1142-9. 

PMID: 11063441 

275: Mares-Perlman JA, Lyle BJ, Klein R, Fisher AI, Brady WE, VandenLangenberg 

GM, Trabulsi JN, Palta M. 

Vitamin supplement use and incident cataracts in a population-based study. 

Arch Ophthalmol. 2000 Nov;118(11):1556-63. 

PMID: 11074813 

276: Yano T, Yajima S, Hagiwara K, Kumadaki I, Yano Y, Otani S, Uchida M, 

Ichikawa T. 

Vitamin E inhibits cell proliferation and the activation of extracellular 

signal-regulated kinase during the promotion phase of lung tumorigenesis 

irrespective of antioxidative effect. 

Carcinogenesis. 2000 Nov;21(11):2129-33. 

PMID: 11062179 

277: Vlasov AP, Tarasova TV, Sudakova GIu, Ashirov RS, Kil'diushov AN, 

Dubovskaia TN, Rubtsov OIu, Lazareva OA. 

[Effect of antioxidants on endotoxicosis in experimental peritonitis] 

Eksp Klin Farmakol. 2000 Nov-Dec;63(6):58-61. Russian. 

PMID: 11202515 

278: Salonen JT, Nyyssonen K, Salonen R, Lakka HM, Kaikkonen J, 

Porkkala-Sarataho E, Voutilainen S, Lakka TA, Rissanen T, Leskinen L, Tuomainen 

TP, Valkonen VP, Ristonmaa U, Poulsen HE. 

Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a 

randomized trial of the effect of vitamins E and C on 3-year progression of 

carotid atherosclerosis. 

J Intern Med. 2000 Nov;248(5):377-86. 

PMID: 11123502 

279: Delvin EE, Salle BL, Reygrobellet B, Mellier G, Claris O. 

Vitamin A and E supplementation in breast-fed newborns. 

J Pediatr Gastroenterol Nutr. 2000 Nov;31(5):562-5. 

PMID: 11144444 

280: Devaraj S, Jialal I. 

Alpha tocopherol supplementation decreases serum C-reactive protein and 

monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. 

Free Radic Biol Med. 2000 Oct 15;29(8):790-2. 

PMID: 11053781 



582

281: Al Deeb S, Al Moutaery K, Arshaduddin M, Tariq M. 

Vitamin E decreases valproic acid induced neural tube defects in mice. 


PMID: 11018306 

282: Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, 

Weissgarten Y, Brunner D, Fainaru M, Green MS. 

Secondary prevention with antioxidants of cardiovascular disease in endstage 

renal disease (SPACE): randomised placebo-controlled trial. 

Lancet. 2000 Oct 7;356(9237):1213-8. 

PMID: 11072938 

283: Yamamoto S, Tamai H, Ishisaka R, Kanno T, Arita K, Kobuchi H, Utsumi K. 

Mechanism of alpha-tocopheryl succinate-induced apoptosis of promyelocytic 

leukemia cells. 

Free Radic Res. 2000 Oct;33(4):407-18. 

PMID: 11022849 

284: Andres D, Alvarez AM, Diez-Fernandez C, Zaragoza A, Cascales M. 

HSP70 induction by cyclosporine A in cultured rat hepatocytes: effect of 

vitamin E succinate. 

J Hepatol. 2000 Oct;33(4):570-9. 

PMID: 11059862 

285: Pearce KA, Boosalis MG, Yeager B. 

Update on vitamin supplements for the prevention of coronary disease and 

stroke. 

Am Fam Physician. 2000 Sep 15;62(6):1359-66. Review. 

PMID: 11011864 

286: Huraib S, Tanimu D, Shaheen F, Hejaili F, Giles C, Pagayon V. 

Effect of vitamin-E-modified dialysers on dialyser clotting, erythropoietin and 

heparin dosage: a comparative crossover study. 

Am J Nephrol. 2000 Sep-Oct;20(5):364-8. 

PMID: 11092992 

287: Jain SK, McVie R, Smith T. 

Vitamin E supplementation restores glutathione and malondialdehyde to normal 

concentrations in erythrocytes of type 1 diabetic children. 

Diabetes Care. 2000 Sep;23(9):1389-94. 

PMID: 10977039 

288: Woodson K, Stewart C, Barrett M, Bhat NK, Virtamo J, Taylor PR, Albanes D. 

Effect of vitamin intervention on the relationship between GSTM1, smoking, and 

lung cancer risk among male smokers. 


PMID: 10566550 

289: Pignatelli P, Pulcinelli FM, Lenti L, Gazzaniga PP, Violi F. 

Vitamin E inhibits collagen-induced platelet activation by blunting hydrogen 

peroxide. 

Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2542-7. 

PMID: 10521385 



583

290: Barbagallo M, Dominguez LJ, Tagliamonte MR, Resnick LM, Paolisso G. 

Effects of vitamin E and glutathione on glucose metabolism: role of magnesium. 

Hypertension. 1999 Oct;34(4 Pt 2):1002-6. 

PMID: 10523398 

291: Steiner M. 

Vitamin E, a modifier of platelet function: rationale and use in cardiovascular 

and cerebrovascular disease. 

Nutr Rev. 1999 Oct;57(10):306-9. 

PMID: 10575906 

292: Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, Parmar K, Bewley 

SJ, Shennan AH, Steer PJ, Poston L. 

Effect of antioxidants on the occurrence of pre-eclampsia in women at increased 

risk: a randomised trial. 

Lancet. 1999 Sep 4;354(9181):810-6. 

PMID: 10485722 

293: Bursell SE, King GL. 

Can protein kinase C inhibition and vitamin E prevent the development of 

diabetic vascular complications? 

Diabetes Res Clin Pract. 1999 Sep;45(2-3):169-82. Review. 

PMID: 10588370 

294: Inal M, Kanbak G, Sen S, Akyuz F, Sunal E. 

Antioxidant status and lipid peroxidation in hemodialysis patients undergoing 

erythropoietin and erythropoietin-vitamin E combined therapy. 


PMID: 10499778 

295: Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, 

Laffel L, King GL. 

High-dose vitamin E supplementation normalizes retinal blood flow and 

creatinine clearance in patients with type 1 diabetes. 

Diabetes Care. 1999 Aug;22(8):1245-51. 

PMID: 10480765 

296: Salasche SJ, Lebwohl M. 

Clinical pearl: vitamin E (alpha-tocopherol), 800 IU daily, may reduce retinoid 

toxicity. 

J Am Acad Dermatol. 1999 Aug;41(2 Pt 1):260. 

PMID: 10426898 

297: Farrag EK. 

Interaction between supplemented selenium and/or vitamin E and Mn, Zn, Fe, and 

Cu in Schistosoma infected mice. 

J Egypt Soc Parasitol. 1999 Aug;29(2):517-29. 

PMID: 10605502 

298: Hoffman RM, Garewal HS. 

Alpha-tocopherol supplementation for men with existing coronary artery disease: 

a feasibility study. 

Prev Med. 1999 Aug;29(2):112-8. Erratum in: Prev Med 2000 Jan;30(1):80. 

PMID: 10446037 



584

299: Fighera MR, Queiroz CM, Stracke MP, Brauer MC, Gonzalez-Rodriguez LL, 

Frussa-Filho R, Wajner M, de Mello CF. 

Ascorbic acid and alpha-tocopherol attenuate methylmalonic acid-induced 

convulsions. 

Neuroreport. 1999 Jul 13;10(10):2039-43. 

PMID: 10424671 

300: van Dam PS, Bravenboer B, van Asbeck BS, Marx JJ, Gispen WH. 

High rat food vitamin E content improves nerve function in 

streptozotocin-diabetic rats. 

Eur J Pharmacol. 1999 Jul 9;376(3):217-22. 

PMID: 10448879 

301: Zheng K, Adjei AA, Shinjo M, Shinjo S, Todoriki H, Ariizumi M. 

Effect of dietary vitamin E supplementation on murine nasal allergy. 

Am J Med Sci. 1999 Jul;318(1):49-54. 

PMID: 10408761 

302: Carrasquedo F, Glanc M, Fraga CG. 

Tissue damage in acute myocardial infarction: selective protection by vitamin 

E. 

Free Radic Biol Med. 1999 Jun;26(11-12):1587-90. 

PMID: 10401625 

303: Velasquez-Pereira J, Risco CA, McDowell LR, Staples CR, Prichard D, 

Chenoweth PJ, Martin FG, Williams SN, Rojas LX, Calhoun MC, Wilkinson NS. 

Long-term effects of feeding gossypol and vitamin E to dairy calves. 

J Dairy Sci. 1999 Jun;82(6):1240-51. 

PMID: 10386310 

304: Gorgun M, Erdogan D, Abban G, Turkozkan N, Elbeg S. 

Effect of vitamin E on adriamycin- induced nephrotoxicity at the 

ultrastructural level in guinea pigs. 

Nephron. 1999 Jun;82(2):155-63. 

PMID: 10364708 

305: Ferro D, Basili S, Pratico D, Iuliano L, FitzGerald GA, Violi F. 

Vitamin E reduces monocyte tissue factor expression in cirrhotic patients. 

Blood. 1999 May 1;93(9):2945-50. 

PMID: 10216089 

306: Behl C. 

Vitamin E and other antioxidants in neuroprotection. 

Int J Vitam Nutr Res. 1999 May;69(3):213-9. 

PMID: 10389030 

307: Kugiyama K, Motoyama T, Doi H, Kawano H, Hirai N, Soejima H, Miyao Y, 

Takazoe K, Moriyama Y, Mizuno Y, Tsunoda R, Ogawa H, Sakamoto T, Sugiyama S, 

Yasue H. 

Improvement of endothelial vasomotor dysfunction by treatment with 

alpha-tocopherol in patients with high remnant lipoproteins levels. 

J Am Coll Cardiol. 1999 May;33(6):1512-8. 

PMID: 10334416 



585

308: Bennett RT, Mazzaccaro RJ, Chopra N, Melman A, Franco I. 

Suppression of renal inflammation with vitamins A and E in ascending 

pyelonephritis in rats. 

J Urol. 1999 May;161(5):1681-4. 

PMID: 10210439 

309: Naito Y, Yoshikawa T, Matsuyama K, Yagi N, Kasai K, Sugimoto N, Masui Y, 

Yoshida N, Kondo M. 

Effect of vitamin E in gastric mucosal injury induced by ischaemia-reperfusion 

in nitric oxide-depleted rats. 

Aliment Pharmacol Ther. 1999 Apr;13(4):553-9. 

PMID: 10215742 

310: Vogel R. 

Antioxidants are useful in preventing cardiovascular disease: a debate. Pro 

antioxidants. 

Can J Cardiol. 1999 Apr;15 Suppl B:23B-25B. 

PMID: 10350680 

311: Canturk Z, Canturk NZ, Ozbilim G, Yenisey C. 

Experimental cirrhosis of the liver and cytoprotective effects of alpha 

tocopherol. 

East Afr Med J. 1999 Apr;76(4):223-7. 

PMID: 10442105 

312: Chugh SN, Kakkar R, Kalra S, Sharma A. 

An evaluation of oxidative stress in diabetes mellitus during uncontrolled and 

controlled state and after vitamin E supplementation. 

J Assoc Physicians India. 1999 Apr;47(4):380-3. 

PMID: 10778519 

313: Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson 

JE, Hankinson SE, Willett WC. 

Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. 

J Natl Cancer Inst. 1999 Mar 17;91(6):547-56. 

PMID: 10088626 

314: Yasuda S, Watanabe S, Kobayashi T, Hata N, Misawa Y, Utsumi H, Okuyama H. 

Dietary docosahexaenoic acid enhances ferric nitrilotriacetate-induced 

oxidative damage in mice but not when additional alpha-tocopherol is 

supplemented. 


PMID: 10711790 

315: Lefaix JL, Delanian S, Vozenin MC, Leplat JJ, Tricaud Y, Martin M. 

Striking regression of subcutaneous fibrosis induced by high doses of gamma 

rays using a combination of pentoxifylline and alpha-tocopherol: an experimental 

study. 

Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):839-47. 

PMID: 10098440 

316: Morgante M, Beghelli D, Pauselli M, Dall'Ara P, Capuccella M, Ranucci S. 

Effect of administration of vitamin E and selenium during the dry period on 

mammary health and milk cell counts in dairy ewes. 



586

J Dairy Sci. 1999 Mar;82(3):623-31. 

PMID: 10194683 

317: Venditti P, Masullo P, Di Meo S, Agnisola C. 

Protection against ischemia-reperfusion induced oxidative stress by vitamin E 

treatment. 

Arch Physiol Biochem. 1999 Feb;107(1):27-34. 

PMID: 10455556 

318: Avunduk AM, Yardimci S, Avunduk MC, Kurnaz L, Aydin A, Kockar MC, Delibasi 

T, Dayanir V. 

Prevention of lens damage associated with cigarette smoke exposure in rats by 

alpha-tocopherol (vitamin E) treatment. 

Invest Ophthalmol Vis Sci. 1999 Feb;40(2):537-41. 

PMID: 9950617 

319: Palace VP, Hill MF, Farahmand F, Singal PK. 

Mobilization of antioxidant vitamin pools and hemodynamic function after 

myocardial infarction. 

Circulation. 1999 Jan 5-12;99(1):121-6. 

PMID: 9884388 

320: Seth RK, Kharb S. 

Protective function of alpha-tocopherol against the process of cataractogenesis 

in humans. 

Ann Nutr Metab. 1999;43(5):286-9. 

PMID: 10749028 

321: Sharma N, Desigan B, Ghosh S, Sanyal SN, Ganguly NK, Majumdar S. 

Effect of antioxidant vitamin E as a protective factor in experimental 

atherosclerosis in rhesus monkeys. 

Ann Nutr Metab. 1999;43(3):181-90. 

PMID: 10545674 

322: Melhus H, Michaelsson K, Holmberg L, Wolk A, Ljunghall S. 

Smoking, antioxidant vitamins, and the risk of hip fracture. 

J Bone Miner Res. 1999 Jan;14(1):129-35. 

PMID: 9893075 

323: Daneyemez M, Kurt E, Cosar A, Yuce E, Ide T. 

Methylprednisolone and vitamin E therapy in perinatal hypoxic-ischemic brain 

damage in rats. 

Neuroscience. 1999;92(2):693-7. 

PMID: 10408617 

324: Landmark K. 

[Vitamin E is beneficial for the immune system in the elderly] 

Tidsskr Nor Laegeforen. 1998 Nov 20;118(28):4403-4. Review. Norwegian. 

PMID: 9889616 

325: Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Tsunoda R, 

Moriyama Y, Miyao Y, Yoshimura M, Ogawa H, Yasue H. 

Vitamin E administration improves impairment of endothelium-dependent 

vasodilation in patients with coronary spastic angina. 



587

J Am Coll Cardiol. 1998 Nov 15;32(6):1672-9. 

PMID: 9822095 

326: Tutuncu NB, Bayraktar M, Varli K. 

Reversal of defective nerve conduction with vitamin E supplementation in type 2 

diabetes: a preliminary study. 

Diabetes Care. 1998 Nov;21(11):1915-8. 

PMID: 9802743 

327: Hahn S, Kuemmerle NB, Chan W, Hisano S, Saborio P, Krieg RJ Jr, Chan JC. 

Glomerulosclerosis in the remnant kidney rat is modulated by dietary 

alpha-tocopherol. 

J Am Soc Nephrol. 1998 Nov;9(11):2089-95. 

PMID: 9808095 

328: Nugent D, Newton H, Gallivan L, Gosden RG. 

Protective effect of vitamin E on ischaemia-reperfusion injury in ovarian 

grafts. 

J Reprod Fertil. 1998 Nov;114(2):341-6. 

PMID: 10070363 

329: Rosen P, Du X, Tschope D. 

Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: 

prevention by alpha-tocopherol? 

Mol Cell Biochem. 1998 Nov;188(1-2):103-11. Review. 

PMID: 9823016 

330: Ribeiro Jorge PA, Neyra LC, Ozaki RM, de Almeida E. 

Improvement in the endothelium-dependent relaxation in hypercholesterolemic 

rabbits treated with vitamin E. 

Atherosclerosis. 1998 Oct;140(2):333-9. 

PMID: 9862276 

331: Campbell MH, Miller JK. 

Effect of supplemental dietary vitamin E and zinc on reproductive performance 

of dairy cows and heifers fed excess iron. 

J Dairy Sci. 1998 Oct;81(10):2693-9. 

PMID: 9812274 

332: Webel DM, Mahan DC, Johnson RW, Baker DH. 

Pretreatment of young pigs with vitamin E attenuates the elevation in plasma 

interleukin-6 and cortisol caused by a challenge dose of lipopolysaccharide. 

J Nutr. 1998 Oct;128(10):1657-60. 

PMID: 9772132 

333: Chan AC. 

Vitamin E and atherosclerosis. 

J Nutr. 1998 Oct;128(10):1593-6. Review. 

PMID: 9772122 

334: Fedoruk AS, Gozhenko AI, Rogovyi IuE. 

[The protective action of alpha-tocopherol on kidney function and lipid 

peroxidation in acute hemic hypoxia] 



588

Patol Fiziol Eksp Ter. 1998 Oct-Dec;(4):35-8. Russian. 

PMID: 9951303 

335: Pizarro M, Lissi E, Reyes J, Holmgren J. 

[Duchenne muscular dystrophy. Effects of vitamin E administration on urinary 

luminescence] 

Rev Med Chil. 1998 Oct;126(10):1165-72. Spanish. 

PMID: 10030087 

336: Konopacka M, Widel M, Rzeszowska-Wolny J. 

Modifying effect of vitamins C, E and beta-carotene against gamma-ray-induced 

DNA damage in mouse cells. 

Mutat Res. 1998 Sep 11;417(2-3):85-94. 

PMID: 9733928 

337: Allard JP, Aghdassi E, Chau J, Tam C, Kovacs CM, Salit IE, Walmsley SL. 

Effects of vitamin E and C supplementation on oxidative stress and viral load 

in HIV-infected subjects. 

AIDS. 1998 Sep 10;12(13):1653-9. 

PMID: 9764785 

338: Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS, Evans 

DA. 

Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. 

Alzheimer Dis Assoc Disord. 1998 Sep;12(3):121-6. 

PMID: 9772012 

339: Barak Y, Swartz M, Shamir E, Stein D, Weizman A. 

Vitamin E (alpha-tocopherol) in the treatment of tardive dyskinesia: a 

statistical meta-analysis. 

Ann Clin Psychiatry. 1998 Sep;10(3):101-5. 

PMID: 9781472 

340: Green D, O'Driscoll G, Rankin JM, Maiorana AJ, Taylor RR. 

Beneficial effect of vitamin E administration on nitric oxide function in 

subjects with hypercholesterolaemia. 

Clin Sci (Lond). 1998 Sep;95(3):361-7. 

PMID: 9730857 

341: Jain SK, Krueger KS, McVie R, Jaramillo JJ, Palmer M, Smith T. 

Relationship of blood thromboxane-B2 (TxB2) with lipid peroxides and effect of 

vitamin E and placebo supplementation on TxB2 and lipid peroxide levels in type 

1 diabetic patients. 

Diabetes Care. 1998 Sep;21(9):1511-6. 

PMID: 9727900 

342: Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, 

Weidinger F. 

Additional benefit of vitamin E supplementation to simvastatin therapy on 

vasoreactivity of the brachial artery of hypercholesterolemic men. 

J Am Coll Cardiol. 1998 Sep;32(3):711-6. 

PMID: 9741516 



589

343: Weiss WP. 

Requirements of fat-soluble vitamins for dairy cows: a review. 

J Dairy Sci. 1998 Sep;81(9):2493-501. Review. 

PMID: 9785241 

344: Davey PJ, Schulz M, Gliksman M, Dobson M, Aristides M, Stephens NG. 

Cost-effectiveness of vitamin E therapy in the treatment of patients with 

angiographically proven coronary narrowing (CHAOS trial). Cambridge Heart 

Antioxidant Study. 

Am J Cardiol. 1998 Aug 15;82(4):414-7. 

PMID: 9723625 

345: Meydani SN, Meydani M, Blumberg JB, Leka LS, Pedrosa M, Diamond R, Schaefer 

EJ. 

Assessment of the safety of supplementation with different amounts of vitamin E 

in healthy older adults. 

Am J Clin Nutr. 1998 Aug;68(2):311-8. 

PMID: 9701188 

346: Steinberg FM, Chait A. 

Antioxidant vitamin supplementation and lipid peroxidation in smokers. 

Am J Clin Nutr. 1998 Aug;68(2):319-27. Erratum in: Am J Clin Nutr 1999 

Jun;69(6):1293. 

PMID: 9701189 

347: Delanian S. 

Striking regression of radiation-induced fibrosis by a combination of 

pentoxifylline and tocopherol. 

Br J Radiol. 1998 Aug;71(848):892-4. 

PMID: 9828807 

348: Inan C, Kilinc K, Kotiloglu E, Akman HO, Kilic I, Michl J. 

Antioxidant therapy of cobalt and vitamin E in hemosiderosis. 

J Lab Clin Med. 1998 Aug;132(2):157-65. 

PMID: 9708577 

349: Wittenborg A, Petersen G, Lorkowski G, Brabant T. 

[Effectiveness of vitamin E in comparison with diclofenac sodium in treatment 

of patients with chronic polyarthritis] 

Z Rheumatol. 1998 Aug;57(4):215-21. German. 

PMID: 9782602 

350: Sangha O, Stucki G. 

[Vitamin E in therapy of rheumatic diseases] 

Z Rheumatol. 1998 Aug;57(4):207-14. Review. German. 

PMID: 9782601 

351: Bartfay WJ, Hou D, Brittenham GM, Bartfay E, Sole MJ, Lehotay D, Liu PP. 

The synergistic effects of vitamin E and selenium in iron-overloaded mouse 

hearts. 

Can J Cardiol. 1998 Jul;14(7):937-41. Review. 

PMID: 9706279 



590

352: Cinar MG, Can C, Ulker S, Gok S, Coker C, Soykan N, Kosay S, Evinc A. 

Effect of vitamin E on vascular responses of thoracic aorta in rat experimental 

arthritis. 

Gen Pharmacol. 1998 Jul;31(1):149-53. 

PMID: 9595294 

353: Sajjad SH. 

Vitamin E in the treatment of tardive dyskinesia: a preliminary study over 7 

months at different doses. 

Int Clin Psychopharmacol. 1998 Jul;13(4):147-55. 

PMID: 9727725 

354: Feldmann M, Jachens G, Holtershinken M, Scholz H. 

[Effects of a selenium/vitamin E substitution on the development of newborn 

calves on selenium-deficient farms] 

Tierarztl Prax Ausg G Grosstiere Nutztiere. 1998 Jul;26(4):200-4. German. 

PMID: 9710921 

355: Vatassery GT, Fahn S, Kuskowski MA. 

Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP 

study. Parkinson Study Group. 

Neurology. 1998 Jun;50(6):1900-2. 

PMID: 9633757 

356: Halliday GM, Yuen KS, Bestak R, Barnetson RS. 

Sunscreens and vitamin E provide some protection to the skin immune system from 

solar-simulated UV radiation. 

Australas J Dermatol. 1998 May;39(2):71-5. Review. 

PMID: 9611373 

357: Berrocal MC, Bujan J, Jurado F, Abeger A. 

Vitamin E improves the uptake of unsaturated soya lecithin liposomes by human 

fibroblasts in vitro. 

J Microencapsul. 1998 May-Jun;15(3):347-59. 

PMID: 9608397 

358: Adhirai M, Selvam R. 

Effect of cyclosporin on liver antioxidants and the protective role of vitamin 

E in hyperoxaluria in rats. 

J Pharm Pharmacol. 1998 May;50(5):501-5. 

PMID: 9643443 

359: de la Fuente M, Ferrandez MD, Burgos MS, Soler A, Prieto A, Miquel J. 

Immune function in aged women is improved by ingestion of vitamins C and E. 

Can J Physiol Pharmacol. 1998 Apr;76(4):373-80. 

PMID: 9795745 

360: Yoshida WB, Alasio T, Mazziotta R, Qin F, Kashani M, Lee S, Dardik H, 

Becker R. 

Effect of alpha-tocopherol, taurine and selenium on the attenuation of 

ischemia/reperfusion injury of splanchnic organs. 

Cardiovasc Surg. 1998 Apr;6(2):178-87. Erratum in: Cardiovasc Surg 1998 

Dec;6(6):682. 

PMID: 9610832 



591

361: Suntres ZE, Shek PN. 

Prophylaxis against lipopolysaccharide-induced acute lung injury by 

alpha-tocopherol liposomes. 


PMID: 9559611 

362: Kott RW, Thomas VM, Hatfield PG, Evans T, Davis KC. 

Effects of dietary vitamin E supplementation during late pregnancy on lamb 

mortality and ewe productivity. 

J Am Vet Med Assoc. 1998 Apr 1;212(7):997-1000. 

PMID: 9540871 

363: Ikarashi Y, Tsuchiya T, Nakamura A, Beppu M, Kikugawa K. 

Effect of vitamin E on contact sensitization responses induced by 

2,4-dinitrochlorobenzene in mice. 

J Nutr Sci Vitaminol (Tokyo). 1998 Apr;44(2):225-36. 

PMID: 9675703 

364: Tong WM, Wang F. 

Alterations in rat pancreatic islet beta cells induced by Keshan disease 

pathogenic factors: protective action of selenium and vitamin E. 

Metabolism. 1998 Apr;47(4):415-9. 

PMID: 9550538 

365: Bonn D. 

Vitamin E may reduce prostate-cancer incidence. 

Lancet. 1998 Mar 28;351(9107):961. 

PMID: 9734953 

366: Kolaja KL, Xu Y, Walborg EF Jr, Stevenson DE, Klaunig JE. 

Vitamin E modulation of dieldrin-induced hepatic focal lesion growth in mice. 

J Toxicol Environ Health A. 1998 Mar 27;53(6):479-92. 

PMID: 9537283 

367: Smigel K. 

Vitamin E reduces prostate cancer rates in Finnish trial: U.S. considers 

follow-up. 


PMID: 9521161 

368: Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, 

Haapakoski J, Malila N, Rautalahti M, Ripatti S, Maenpaa H, Teerenhovi L, Koss 

L, Virolainen M, Edwards BK. 

Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: 

incidence and mortality in a controlled trial. 


PMID: 9521168 

369: Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. 

[Randomized, double-blind, placebo-controlled study of supplemental vitamin E 

on attenuation of the development of nitrate tolerance] 

J Cardiol. 1998 Mar;31(3):173-81. Japanese. 

PMID: 9557281 



592

370: Mutaku JF, Many MC, Colin I, Denef JF, van den Hove MF. 

Antigoitrogenic effect of combined supplementation with dl-alpha-tocopherol, 

ascorbic acid and beta-carotene and of dl-alpha-tocopherol alone in the rat. 

J Endocrinol. 1998 Mar;156(3):551-61. 

PMID: 9582512 

371: Wolf R, Wolf D, Ruocco V. 

Vitamin E: the radical protector. 

J Eur Acad Dermatol Venereol. 1998 Mar;10(2):103-17. Review. 

PMID: 9553906 

372: Chan W, Krieg RJ Jr, Norkus EP, Chan JC. 

alpha-Tocopherol reduces proteinuria, oxidative stress, and expression of 

transforming growth factor beta 1 in IgA nephropathy in the rat. 

Mol Genet Metab. 1998 Mar;63(3):224-9. 

PMID: 9608545 

373: Lopez-Torres M, Thiele JJ, Shindo Y, Han D, Packer L. 

Topical application of alpha-tocopherol modulates the antioxidant network and 

diminishes ultraviolet-induced oxidative damage in murine skin. 

Br J Dermatol. 1998 Feb;138(2):207-15. 

PMID: 9602862 

374: Canturk NZ, Canturk Z, Utkan NZ, Yenisey C, Ozbilim G, Yildirir C, Yalman Y. 

Cytoprotective effects of alpha tocopherol against liver injury induced by 

extrahepatic biliary obstruction. 

East Afr Med J. 1998 Feb;75(2):77-80. 

PMID: 9640827 

375: Brown KM, Morrice PC, Duthie GG. 

Erythrocyte membrane fatty acid composition of smokers and non-smokers: effects 

of vitamin E supplementation. 

Eur J Clin Nutr. 1998 Feb;52(2):145-50. 

PMID: 9505161 

376: Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR, Fidler P, 

Stella PJ, Swan DK, Vaught NL, Novotny P. 

Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. 

J Clin Oncol. 1998 Feb;16(2):495-500. 

PMID: 9469333 

377: Mitchinson M. 

Long-term alpha tocopherol may yet prolong life. 

BMJ. 1998 Jan 24;316(7127):308. 

PMID: 9472536 

378: Fuller CJ, Huet BA, Jialal I. 

Effects of increasing doses of alpha-tocopherol in providing protection of 

low-density lipoprotein from oxidation. 

Am J Cardiol. 1998 Jan 15;81(2):231-3. 

PMID: 9591910 



593

379: Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos F. 

Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore 

immunodeficiency and prolong survival for severely ill patients with generalized 

malignancy: a randomized control trial. 

Cancer. 1998 Jan 15;82(2):395-402. 

PMID: 9445198 

380: Bekyarova G, Yankova T, Kozarev I. 

Combined application of alpha-tocopherol and FC-43 perfluorocarbon emulsion 

suppresses early postburn lipid peroxidation and improves deformability of 

erythrocytes. 

Acta Chir Plast. 1998;40(1):17-21. 

PMID: 9640804 

381: Bekyarova G, Yankova T. 

alpha-Tocopherol and reduced glutathione deficiency and decreased deformability 

of erythrocytes after thermal skin injury. 

Acta Physiol Pharmacol Bulg. 1998;23(2):55-9. 

PMID: 10347621 

382: Personelle J, Bolivar de Souza Pinto E, Ruiz RO. 

Injection of vitamin A acid, vitamin E, and vitamin C for treatment of tissue 

necrosis. 

Aesthetic Plast Surg. 1998 Jan-Feb;22(1):58-64. 

PMID: 9456357 

383: Cartier R, Bouchard D. 

[The beneficial effect of natural antioxidants on the endothelial function of 

regenerated endothelium] 

Ann Chir. 1998;52(8):827-33. French. 

PMID: 9846436 

384: Thurich T, Bereiter-Hahn J, Schneider M, Zimmer G. 

Cardioprotective effects of dihydrolipoic acid and tocopherol in right heart 

hypertrophy during oxidative stress. 

Arzneimittelforschung. 1998 Jan;48(1):13-21. 

PMID: 9522025 

385: Gey KF. 

Vitamins E plus C and interacting conutrients required for optimal health. A 

critical and constructive review of epidemiology and supplementation data 

regarding cardiovascular disease and cancer. 


PMID: 9523035 

386: Koya D, Haneda M, Kikkawa R, King GL. 

d-alpha-tocopherol treatment prevents glomerular dysfunctions in diabetic rats 

through inhibition of protein kinase C-diacylglycerol pathway. 

Biofactors. 1998;7(1-2):69-76. 

PMID: 9523030 

387: Kunisaki M, Bursell SE, Umeda F, Nawata H, King GL. 

Prevention of diabetes-induced abnormal retinal blood flow by treatment with 

d-alpha-tocopherol. 



594

Biofactors. 1998;7(1-2):55-67. 

PMID: 9523029 

388: Suzukawa M, Ayaori M, Shige H, Hisada T, Ishikawa T, Nakamura H. 

Effect of supplementation with vitamin E on LDL oxidizability and prevention of 

atherosclerosis. 


PMID: 9523028 

389: Surai P, Kostjuk I, Wishart G, Macpherson A, Speake B, Noble R, Ionov I, 

Kutz E. 

Effect of vitamin E and selenium supplementation of cockerel diets on 

glutathione peroxidase activity and lipid peroxidation susceptibility in sperm, 

testes, and liver. 

Biol Trace Elem Res. 1998 Summer;64(1-3):119-32. 

PMID: 9845467 

390: Brown DJ, Goodman J. 

A review of vitamins A, C, and E and their relationship to cardiovascular 

disease. 

Clin Excell Nurse Pract. 1998 Jan;2(1):10-22. Review. 

PMID: 12675072 

391: Walker MK, Vergely C, Lecour S, Abadie C, Maupoil V, Rochette L. 

Vitamin E analogues reduce the incidence of ventricular fibrillations and 

scavenge free radicals. 

Fundam Clin Pharmacol. 1998;12(2):164-72. 

PMID: 9565770 

392: Haklar G, Sirikci O, Ozer NK, Yalcin AS. 

Measurement of reactive oxygen species by chemiluminescence in diet-induced 

atherosclerosis: protective roles of vitamin E and probucol on different radical 

species. 

Int J Clin Lab Res. 1998;28(2):122-6. 

PMID: 9689555 

393: Eberlein-Konig B, Placzek M, Przybilla B. 

Protective effect against sunburn of combined systemic ascorbic acid (vitamin 

C) and d-alpha-tocopherol (vitamin E). 

J Am Acad Dermatol. 1998 Jan;38(1):45-8. 

PMID: 9448204 

394: Sobajic SS, Mihailovic MB, Miric MO. 

The effects of selenium deficiency, dietary selenium, and vitamin E 

supplementation on the oxidative status of pig liver. 

J Environ Pathol Toxicol Oncol. 1998;17(3-4):265-70. 

PMID: 9726800 

395: Dursun SM, Oluboka OJ, Devarajan S, Kutcher SP. 

High-dose vitamin E plus vitamin B6 treatment of risperidone-related 

neuroleptic malignant syndrome. 

J Psychopharmacol. 1998;12(2):220-1. 

PMID: 9694035 



595

396: Lee KT, Tsai LY, Sheen PC. 

Effect of vitamin E, topical hypothermia and steroid on ischemic liver in rats. 

Kaohsiung J Med Sci. 1998 Jan;14(1):6-12. 

PMID: 9519683 

397: Sieradzki E, Olejarz E, Strauss K, Marzec A, Mieszkowska M, Kaluzny J. 

[The effect of selenium and vitamin E on the healing process of experimental 

corneal lesions in the eye of the rabbit] 

Klin Oczna. 1998;100(2):85-8. Polish. 

PMID: 9695542 

398: McBride JM, Kraemer WJ, Triplett-McBride T, Sebastianelli W. 

Effect of resistance exercise on free radical production. 

Med Sci Sports Exerc. 1998 Jan;30(1):67-72. 

PMID: 9475646 

Glycerylphosphorylcholine – 4 Studies 

1. Mech Ageing Dev 2001 Nov;122(16):2025-40 

Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with 

probable senile dementia of Alzheimer’s type. 

A multicentre, randomized, controlled study compared the efficacy of l-alpha-glyceryl-phosphorylcholine 

(alpha GPC) and ST200 (acetyl-l-carnitine) among 126 patients with probable senile dementia of 

Alzheimer’s type (SDAT) of mild to moderate degree. Efficacy was evaluated by means of behavioural 

scales and psychometric tests. The results showed significant improvements in most neuropsychological 

parameters in the alpha GPC recipients. Improvements also occurred in the ST200 recipients but to a lesser 

extent. Tolerability was good in both groups. These positive findings require replication in larger, doubleblind, 

longitudinal studies coupling clinical and biological determinations. 

2. Drugs Aging 1993 Mar-Apr;3(2):159-64 

Alpha-glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An 

Italian multicenter clinical trial. 

The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to 

provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been 

tested in a clinical open multicenter trial on 2,044 patients suffering from recent stroke or transient 

ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days 

and orally at the dose of 400 mg tid during the following five months after the first phase. The evaluation of 

the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug 

administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS) and the 



596

Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean 

increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end 

of the five month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 

(p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, 

reaching the “normality” score at the 3rd month assessment. The GDS score at the end of the trial 

corresponded to “no cognitive decline” or “forgetfulness” in 71% of the patients. Adverse events were 

complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The 

most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and 

headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients 

with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability. 

Ann N Y Acad Sci 1994 Jun 30;717:253-69 

3. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an 

analysis of published clinical data. 

This paper has reviewed the documentation on the clinical efficacy of choline alphoscerate, a cholinergic 

precursor, considered as a centrally acting parasympathomimetic drug in dementia disorders and in acute 

cerebrovascular disease. Thirteen published clinical trials, examining in total 4,054 patients, have evaluated 

the use of choline alphoscerate in various forms of dementia disorders of degenerative, vascular or 

combined origin, such as senile dementia of the Alzheimer’s type (SDAT) or vascular dementia (VaD) and 

in acute cerebrovascular diseases, such as transitory ischemic attack (TIA) and stroke. Analysis has 

assessed the design of each study, in particular with respect to experimental design, number of cases, 

duration of treatment and tests used to evaluate drug clinical efficacy. Most of the 10 studies performed in 

dementia disorders were controlled trials versus a reference drug or placebo. Overall, 1,570 patients were 

assessed in these studies, 854 of which in controlled trials. As detected by validated and appropriate tests, 

such as Mini Mental State Evaluation (MMSE) in SDAT and Sandoz Clinical Assessment Geriatric 

(SCAG) in VaD, administration of choline alphoscerate significantly improved patient clinical condition. 

Clinical results obtained with choline alphoscerate were superior or equivalent to those observed in control 

groups under active treatment and superior to the results observed in placebo groups. Analysis stresses the 

clear internal consistency of clinical data gathered by different experimental situations on the drug effect, 

especially with regard to the cognitive symptoms (memory, attention) characterizing the clinical picture of 

adult-onset dementia disorders. The therapeutic usefulness of choline alphoscerate in relieving cognitive 

symptoms of chronic cerebral deterioration differentiates this drug from cholinergic precursors used in the 

past, such as choline and lecithin. Three uncontrolled trials were performed with choline alphoscerate in 

acute cerebrovascular stroke and TIA, totaling 2,484 patients. The results of these trials suggest that this 

drug might favor functional recovery of patients with cerebral stroke and should be confirmed in future 

investigations aimed at establishing the efficacy of the drug in achieving functional recovery of patients 

with acute cerebrovascular disease. 

Mech Ageing Dev 2001 Nov;122(16):2041-55 

4. Behavioral effects of L-alpha-glycerylphosphorylcholine: influence on cognitive 

mechanisms in the rat. 

The phosphorylcholine precursor, L-alpha-glycerylphosphorylcholine (alpha-GPC), was injected at the 

dose of 100 mg/kg/day for 20 days to aged male rats of the Sprague-Dawley strain, 24 months old, showing 

a deficit of learning and memory capacity. The drug was also administered to rats with amnesia induced 

pharmacologically with bilateral injections of kainic acid into the nucleus basalis magnocellularis (NBM). 

Learning and memory capacity of the animals, studied with tests of active and passive avoidance behavior, 

was improved after treatment with alpha-GPC in all experimental groups. These results indicate that this 

drug affects cognitive mechanisms in the rat through an involvement of central neurotransmission. 



597

Pharmacol Biochem Behav 1992 Feb;41(2):445-8 

Carnosine - 47 ABSTRACTS 

CARNOSINE: 47 RESEARCH ABSTRACTS 

1. Bull Exp Biol Med. 2003 Feb;135(2):130-2. 

Protective effect of carnosine on Cu,Zn-superoxide dismutase during impaired 

oxidative metabolism in the brain in vivo. 

Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev AA. 

Institute of Neurology, Russian Academy of Medical Sciences, Moscow. 

sls@bio.inevro.msk.ru 

Natural hydrophilic antioxidant carnosine protects cerebral cytosolic 

Cu,Zn-superoxide dismutase (SOD) under conditions of oxidative stress in various 

in vivo models: short-term hypobaric hypoxia in rats and accumulation of 

age-related changes in senescence-accelerated mice (SAMP). Administration of 

carnosine preventing Cu,Zn-SOD inactivation reduced mortality in rats and 

prolonged average life span in SAMP-mice. 

2. Bull Exp Biol Med. 2002 Jun;133(6):559-61. 

Effect of carnosine on Drosophila melanogaster lifespan. 

Yuneva AO, Kramarenko GG, Vetreshchak TV, Gallant S, Boldyrev AA. 

M. V. Lomonosov Moscow State University, Moscow. 

A positive dose-dependent effect of carnosine (beta-alanyl-L-histidine) on the 

lifespan of male Drosophila melanogaster flies was shown. The mean lifespan of 

male flies receiving 200 mg/liter carnosine approached that of females. At the 

same time carnosine had no effect on the lifespan of female flies. This positive 

effect of carnosine probably reflects its protective action against age-related 

accumulation of free radicals and did not depend on carnosine metabolism in the 

body. Addition of 200 mg/liter histidine and beta-alanine (separately or in 

combination) had no effect on the mean lifespan of flies. 


AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? 

Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G. 

Physiological Chemistry I, Biocenter, University of Wurzburg, Germany. 



598

In Alzheimer's disease, age-related cellular changes such as compromised energy 

production and increased radical formation are worsened by the presence of AGEs 

as additional, AD specific stress factors. Intracellular AGEs (most likely 

derived from methylglyoxal) crosslink cytoskeletal proteins and render them 

insoluble. These aggregates inhibit cellular functions including transport 

processes and contribute to neuronal dysfunction and death. Extracellular AGEs, 

which accumulate in ageing tissue (but most prominently on long-lived protein 

deposits like the senile plaques) exert chronic oxidative stress on neurons. In 

addition, they activate glial cells to produce free radicals (superoxide and NO) 

and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit the formation 

of AGEs by specific chemical mechanisms (AGE-inhibitors), including 

aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the 

development of (AGE-mediated) diabetic complications. Assuming that 'carbonyl 

stress' contributes significantly to the progression of Alzheimer's disease, 

AGE-inhibitors might also become interesting novel therapeutic drugs for 

treatment of AD. 

4. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4765-9. 

Age-related losses of cognitive function and motor skills in mice are associated 

with oxidative protein damage in the brain. 

Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. 

Department of Pharmacology, University of North Texas Health Science Center, 

Fort Worth, 76107, USA. 

The hypothesis that age-associated impairment of cognitive and motor functions 

is due to oxidative molecular damage was tested in the mouse. In a blind study, 

senescent mice (aged 22 months) were subjected to a battery of behavioral tests 

for motor and cognitive functions and subsequently assayed for oxidative 

molecular damage as assessed by protein carbonyl concentration in different 

regions of the brain. The degree of age-related impairment in each mouse was 

determined by comparison to a reference group of young mice (aged 4 months) 

tested concurrently on the behavioral battery. The age-related loss of ability 

to perform a spatial swim maze task was found to be positively correlated with 

oxidative molecular damage in the cerebral cortex, whereas age-related loss of 

motor coordination was correlated with oxidative molecular damage within the 

cerebellum. These results support the view that oxidative stress is a causal 

factor in brain senescence. Furthermore, the findings suggest that age-related 

declines of cognitive and motor performance progress independently, and involve 

oxidative molecular damage within different regions of the brain. 

5. J Histochem Cytochem. 1998 Jun;46(6):731-5. 

Cytochemical demonstration of oxidative damage in Alzheimer disease by 

immunochemical enhancement of the carbonyl reaction with 

2,4-dinitrophenylhydrazine. 

Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF, Kowall N, Perry G. 



599

Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, 

USA. 

Formation of carbonyls derived from lipids, proteins, carbohydrates, and nucleic 

acids is common during oxidative stress. For example, metal-catalyzed, 

"site-specific" oxidation of several amino acid side-chains produces aldehydes 

or ketones, and peroxidation of lipids generates reactive aldehydes such as 

malondialdehyde and hydroxynonenal. Here, using in situ 

2,4-dinitrophenylhydrazine labeling linked to an antibody system, we describe a 

highly sensitive and specific cytochemical technique to specifically localize 

biomacromolecule-bound carbonyl reactivity. When this technique was applied to 

tissues from cases of Alzheimer disease, in which oxidative events including 

lipoperoxidative, glycoxidative, and other oxidative protein modifications have 

been reported, we detected free carbonyls not only in the disease-related 

intraneuronal lesions but also in other neurons. In marked contrast, free 

carbonyls were not found in neurons or glia in age-matched control cases. 

Importantly, this assay was highly specific for detecting disease-related 

oxidative damage because the site of oxidative damage can be assessed in the 

midst of concurrent age-related increases in free carbonyls in vascular basement 

membrane that would contaminate biochemical samples subjected to bulk analysis. 

These findings demonstrate that oxidative imbalance and stress are key elements 

in the pathogenesis of Alzheimer disease. 

6. Carnosine prevents activation of free-radical lipid oxidation during stress. 

Gulyaeva NV, Dupin AM, Levshina IP. 

Bull Exp Biol Med. 1989; 107(2):148-152. 

No abstract available. 

Neurosci Lett. 1998 Feb 13;242(2):105-8. 

Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: 

protection by carnosine, homocarnosine and beta-alanine. 

Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN. 

Institute of Gerontology, King's College London, UK. j.preston@kcl.ac.uk 

The effect of a truncated form of the neurotoxin beta-amyloid peptide (A 

beta25-35) on rat brain vascular endothelial cells (RBE4 cells) was studied in 

cell culture. Toxic effects of the peptide were seen at 200 microg/ml A beta 

using a mitochondrial dehydrogenase activity (MTT) reduction assay, lactate 

dehydrogenase release and glucose consumption. Cell damage could be prevented 

completely at 200 microg/ml A beta and partially at 300 microg/ml A beta, by the 

dipeptide carnosine. Carnosine is a naturally occurring dipeptide found at high 

levels in brain tissue and innervated muscle of mammals including humans. Agents 

which share properties similar to carnosine, such as beta-alanine, 

homocarnosine, the anti-glycating agent aminoguanidine, and the antioxidant 

superoxide dismutase (SOD), also partially rescued cells, although not as 

effectively as carnosine. We postulate that the mechanism of carnosine 

protection lies in its anti-glycating and antioxidant activities, both of which 

are implicated in neuronal and endothelial cell damage during Alzheimer's 



600

disease. Carnosine may therefore be a useful therapeutic agent. 

7. FEBS Lett. 1995 Aug 28;371(1):81-5. 

Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential 

anti-protein-cross-linking agent. 

Hipkiss AR, Michaelis J, Syrris P. 

Division of Biomolecular Engineering, CSIRO, North Ryde, NSW, Australia. 

The dipeptide carnosine (beta-alanyl-L-histidine) was readily glycosylated 

non-enzymatically upon incubation with the sugars glucose, galactose, 

deoxyribose and the triose dihydroxyacetone. Carnosine inhibited glycation of 

actyl-Lys-His-amide by dihydroxyacetone and it protected alpha-crystallin, 

superoxide dismutase and catalise against glycation and cross-linking mediated 

by ribose, deoxyribose, dihydroxyacetone, dihydroxyacetone phosphate and 

fructose. Unlike certain glycated amino acids, glycated carnosine was 

non-mutagenic. The potential biological and therapeutic significance of these 

observations are discussed. 

8. Biochim Biophys Acta. 1997 Feb 27;1360(1):17-29. 

Influence of advanced glycation end-products and AGE-inhibitors on 

nucleation-dependent polymerization of beta-amyloid peptide. 

Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, 

Schinzel R, Cunningham AM. 

Theodor-Boveri-Institute (Biocenter), Wurzburg, Germany. 

muench@biozentrum.uni-wuerzburg.de 

Nucleation-dependent polymerization of beta-amyloid peptide, the major component 

of plaques in patients with Alzheimer's disease, is significantly accelerated by 

crosslinking through Advanced Glycation End-products (AGEs) in vitro. During the 

polymerization process, both nucleus formation and aggregate growth are 

accelerated by AGE-mediated crosslinking. Formation of the AGE-crosslinked 

amyloid peptide aggregates could be attenuated by the AGE-inhibitors Tenilsetam, 

aminoguanidine and carnosine. These experimental data, and clinical studies, 

reporting a marked improvement in cognition and memory in Alzheimer's disease 

patients after Tenilsetam treatment, suggest that AGEs might play an important 

role in the etiology or progression of the disease. Thus AGE-inhibitors may 

generally 

9. Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32. 

Carnosine protects proteins against methylglyoxal-mediated modifications. 

Hipkiss AR, Chana H. 

Molecular Biology and Biophysics Group, King's College London, United Kingdom. 

alan.hipkiss@kcl.ac.uk 

Methylglyoxal (MG) (pyruvaldehyde) is an endogenous metabolite which is present 

in increased concentrations in diabetics and implicated in formation of advanced 



601

glycosylation end-products (AGEs) and secondary diabetic complications. 

Carnosine (beta-alanyl-L-histidine) is normally present in long-lived tissues at 

concentrations up to 20 mM in humans. Previous studies showed that carnosine can 

protect proteins against aldehyde-containing cross-linking agents such as aldose 

and ketose hexose and triose sugars, and malon-dialdehyde, the lipid 

peroxidation product. Here we examine whether carnosine can protect protein 

exposed to MG. Our results show that carnosine readily reacts with MG thereby 

inhibiting MG-mediated protein modification as revealed electrophoretically. We 

also investigated whether carnosine could intervene when proteins were exposed 

to an MG-induced AGE (i.e. lysine incubated with MG). Our results show that 

carnosine can inhibit protein modification induced by a lysine-MG-AGE; this 

suggests a second intervention site for carnosine and emphasizes its potential 

as a possible non-toxic modulator of diabetic complications. 

10. Free Radic Biol Med. 2000 May 15;28(10):1564-70. 

Carnosine reacts with a glycated protein. 

Brownson C, Hipkiss AR. 

Division of Biomolecular Science, GKT School of Biomedical Sciences, King's 

College London, Guy's Campus, London Bridge, London, UK. 

Oxidation and glycation induce formation of carbonyl (CO) groups in proteins, a 

characteristic of cellular aging. The dipeptide carnosine 

(beta-alanyl-L-histidine) is often found in long-lived mammalian tissues at 

relatively high concentrations (up to 20 mM). Previous studies show that 

carnosine reacts with low-molecular-weight aldehydes and ketones. We examine 

here the ability of carnosine to react with ovalbumin CO groups generated by 

treatment of the protein with methylglyoxal (MG). Incubation of MG-treated 

protein with carnosine accelerated a slow decline in CO groups as measured by 

dinitrophenylhydrazine reactivity. Incubation of [(14)C]-carnosine with 

MG-treated ovalbumin resulted in a radiolabeled precipitate on addition of 

trichloroacetic acid (TCA); this was not observed with control, untreated 

protein. The presence of lysine or N-(alpha)-acetylglycyl-lysine methyl ester 

caused a decrease in the TCA-precipitable radiolabel. Carnosine also inhibited 

cross-linking of the MG-treated ovalbumin to lysine and normal, untreated 

alpha-crystallin. We conclude that carnosine can react with protein CO groups 

(termed "carnosinylation") and thereby modulate their deleterious interaction 

with other polypeptides. It is proposed that, should similar reactions occur 

intracellularly, then carnosine's known "anti-aging" actions might, at least 

partially, be explained by the dipeptide facilitating the inactivation/removal 

of deleterious proteins bearing carbonyl groups. 

11.Neurosci Lett. 1997 Dec 5;238(3):135-8. 

Protective effects of carnosine against malondialdehyde-induced toxicity towards 

cultured rat brain endothelial cells. 

Hipkiss AR, Preston JE, Himswoth DT, Worthington VC, Abbot NJ. 

Molecular Biology and Biophysics Group, King's College London, Strand, UK. 



602

Malondialdehyde (MDA) is a deleterious end-product of lipid peroxidation. The 

naturally-occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in 

brain and innervated tissues at concentrations up to 20 mM. Recent studies have 

shown that carnosine can protect proteins against cross-linking mediated by 

aldehyde-containing sugars and glycolytic intermediates. Here we have 

investigated whether carnosine is protective against malondialdehyde-induced 

protein damage and cellular toxicity. The results show that carnosine can (1) 

protect cultured rat brain endothelial cells against MDA-induced toxicity and 

(2) inhibit MDA-induced protein modification (formation of cross-links and 

carbonyl groups). 

12. Cell Mol Neurobiol. 1997 Apr;17(2):259-71. 

Biochemical and physiological evidence that carnosine is an endogenous 

neuroprotector against free radicals. 

Boldyrev AA, Stvolinsky SL, Tyulina OV, Koshelev VB, Hori N, Carpenter DO. 

M. V. Lomonosov Moscow State University, Moscow, Russia. 

1. Carnosine, anserine, and homocarnosine are endogenous dipeptides concentrated 

in brain and muscle whose biological functions remain in doubt. 2. We have 

tested the hypothesis that these compounds function as endogenous protective 

substances against molecular and cellular damage from free radicals, using two 

isolated enzyme systems and two models of ischemic brain injury. Carnosine and 

homocarnosine are both effective in activating brain Na, K-ATPase measured under 

optimal conditions and in reducing the loss of its activity caused by incubation 

with hydrogen peroxide. 3. In contrast, all three endogenous dipeptides cause a 

reduction in the activity of brain tyrosine hydroxylase, an enzyme activated by 

free radicals. In hippocampal brain slices subjected to ischemia, carnosine 

increased the time to loss of excitability. 4. In in vivo experiments on rats 

under experimental hypobaric hypoxia, carnosine increased the time to loss of 

ability to stand and breath and decreased the time to recovery. 5. These actions 

are explicable by effects of carnosine and related compounds which neutralize 

free radicals, particularly hydroxyl radicals. In all experiments the effective 

concentration of carnosine was comparable to or lower than those found in brain. 

These observations provide further support for the conclusion that protection 

against free radical damage is a major role of carnosine, anserine, and 

homocarnosine. 

13. Ann N Y Acad Sci. 1998 Nov 20;854:37-53. 

Pluripotent protective effects of carnosine, a naturally occurring dipeptide. 

Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis J, 

Lawrence J, Mateen A, Allende L, Eagles PA, Abbott NJ. 

Molecular Biology and Biophysics Group, King's College London, Strand, United 

Kingdom. alan.hipkiss@kcl.ac.uk 

Carnosine is a naturally occurring dipeptide (beta-alanyl-L-histidine) found in 



603

ain, innervated tissues, and the lens at concentrations up to 20 mM in humans. 

In 1994 it was shown that carnosine could delay senescence of cultured human 

fibroblasts. Evidence will be presented to suggest that carnosine, in addition 

to antioxidant and oxygen free-radical scavenging activities, also reacts with 

deleterious aldehydes to protect susceptible macromolecules. Our studies show 

that, in vitro, carnosine inhibits nonenzymic glycosylation and cross-linking of 

proteins induced by reactive aldehydes (aldose and ketose sugars, certain triose 

glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation 

product). Additionally we show that carnosine inhibits formation of MDA-induced 

protein-associated advanced glycosylation end products (AGEs) and formation of 

DNA-protein cross-links induced by acetaldehyde and formaldehyde. At the 

cellular level 20 mM carnosine protected cultured human fibroblasts and 

lymphocytes, CHO cells, and cultured rat brain endothelial cells against the 

toxic effects of formaldehyde, acetaldehyde and MDA, and AGEs formed by a 

lysine/deoxyribose mixture. Interestingly, carnosine protected cultured rat 

brain endothelial cells against amyloid peptide toxicity. We propose that 

carnosine (which is remarkably nontoxic) or related structures should be 

explored for possible intervention in pathologies that involve deleterious 

aldehydes, for example, secondary diabetic complications, inflammatory 

phenomena, alcoholic liver disease, and possibly Alzheimer's disease. 

14. Exp Cell Res. 1994 Jun;212(2):167-75. 

Retardation of the senescence of cultured human diploid fibroblasts by 

carnosine. 

McFarland GA, Holliday R. 

CSIRO Division of Biomolecular Engineering, Sydney Laboratory, NSW, Australia. 

We have examined the effects of the naturally occurring dipeptide carnosine 

(beta-alanyl-L-histidine) on the growth, morphology, and lifespan of cultured 

human diploid fibroblasts. With human foreskin cells, HFF-1, and fetal lung 

cells, MRC-5, we have shown that carnosine at high concentrations (20-50 mM) in 

standard medium retards senescence and rejuvenates senescent cultures. These 

late-passage cultures preserve a nonsenescent morphology in the presence of 

carnosine, in comparison to the senescent morphology first described by Hayflick 

and Moorhead. Transfer of these late-passage cells in medium containing 

carnosine to unsupplemented normal medium results in the appearance of the 

senescent phenotype. The serial subculture of cells in the presence of carnosine 

does not prevent the Hayflick limit to growth, although the lifespan in 

population doublings as well as chronological age is often increased. This 

effect is obscured by the normal variability of human fibroblast lifespans, 

which we have confirmed. Transfer of cells approaching senescence in normal 

medium to medium supplemented with carnosine rejuvenates the cells but the 

extension in lifespan is variable. Neither D-carnosine, 

(beta-alanyl-D-histidine), homocarnosine, anserine, nor beta-alanine had the 

same effects as carnosine on human fibroblasts. Carnosine is an antioxidant, but 



604

it is more likely that it preserves cellular integrity by its effects on protein 

metabolism. 

15. Exp Gerontol. 1999 Jan;34(1):35-45. 

Further evidence for the rejuvenating effects of the dipeptide L-carnosine on 

cultured human diploid fibroblasts. 

McFarland GA, Holliday R. 

CSIRO Division of Molecular Science, Sydney Laboratory, North Ryde, Australia. 

We have confirmed and extended previous results on the beneficial effects of 

L-carnosine on growth, morphology, and longevity of cultured human fibroblasts, 

strains MRC-5 and HFF-1. We have shown that late-passage HFF-1 cells retain a 

juvenile appearance in medium containing 50 mM carnosine, and revert to a 

senescent phenotype when carnosine is removed. Switching cells between medium 

with and without carnosine also switches their phenotype from senescent to 

juvenile, and the reverse. The exact calculation of fibroblast lifespans in 

population doublings (PDs) depends on the proportion of inoculated cells that 

attach to their substrate and the final yield of cells in each subculture. We 

have shown that carnosine does not affect cell attachment, but does increase 

longevity in PDs. However, the plating efficiency of MRC-5 cells seeded at low 

density is strongly increased in young and senescent cells by carnosine, as 

shown by the growth of individual colonies. We have also demonstrated that very 

late-passage MRC-5 cells (with weekly change of medium without subculture) 

remain attached to their substrate much longer in medium containing carnosine in 

comparison to control cultures, and also retain a much more normal phenotype. 

Carnosine is a naturally occurring dipeptide present at high concentration in a 

range of human tissues. We suggest it has an important role in cellular 

homeostasis and maintenance. 

Biosci Rep. 1999 Dec;19(6):581-7. 

16. Carnosine, the protective, anti-aging peptide. 

Boldyrev AA, Gallant SC, Sukhich GT. 

Center for Molecular Medicine, Department of Biochemistry, Biological Faculty, 

MV Lomonosov, Moscow State University, Vorobjovy Gory, Russia. 

aab@1.biocenter.bio.msu.ru 

Carnosine attenuates the development of senile features when used as a 

supplement to a standard diet of senescence accelerated mice (SAM). Its effect 

is apparent on physical and behavioral parameters and on average life span. 

Carnosine has a similar effect on mice of the control strain, but this is less 

pronounced due to the non-accelerated character of their senescence processes. 

17. Effect of carnosine on age-induced changes in senescence-accelerated mice 

Yuneva M.O.; Bulygina E.R.; Gallant S.C.; Kramarenko G.G.; Stvolinsky S.L.; 



605

Semyonova M.L.; Boldyrev A.A. 

Prof. A.A. Boldyrev, Department of Biochemistry, School of Biology, Moscow State 

University, Vorobjovy Gory, 119899 Moscow Russian Federation 

Author Email: aab@1.biocenter.bio.msu.ru 

Journal of Anti-Aging Medicine ( J. ANTI-AGING MED. ) ( United States ) 1999 , 2/4 

(337-342) 

The effect of carnosine on the life span and several brain biochemical characteristics in 

senescence-accelerated mice-prone 1 (SAMP1) was investigated. A 50% survival rate of 

animals treated with carnosine increased by 20% as compared to controls. Moreover, the 

number of animals that lived to an old age significantly increased. The effect of carnosine 

on life span was accompanied by a decrease in the level of 2'-tiobarbituric acid reactive 

substances (TBARS), monoamine oxidase b (MAO b), and Na/K-ATPase activity. There 

was also an increase in glutamate binding to N-methyl-D-aspartate receptors. These 

observations are consistent with the conclusion that carnosine increases life span and 

quality of life by diminishing production of lipid peroxides and reducing the influence of 

reactive oxygen species (ROS) on membrane proteins. 

18. Salganik R.I.; Dikalova A.; Dikalov S.; La D.; Bulygina E.; Stvolinsky S.; Boldyrev 

A. 

Dr. R.I. Salganik, 2217B, McGavran-Greenberg Hall, School of Public Health, 

University of North Carolina, Chapel Hill, NC 27599 United States 

Author Email: rsalganik@unc.edu 

Journal of Anti-Aging Medicine ( J. ANTI-AGING MED. ) ( United States ) 2001 , 4/1 

(49-54) 

Impairment of long-term memory is characteristic of aging and some neurodegenerative 

diseases associated with the increased generation of reactive oxygen species (ROS). An 

inbred OXYS rat strain was developed from Wistar rats with an inherited overproduction 

of ROS, manifesting impairment of long-term memory and oxidative damage of cell 

structures and functions. A highly inbred OYXR strain harboring oxidative patterns close 

to normal Wistar rats served as a control. Alterations of brain neurochemical functions in 

OXYS rats and the possibility of protecting them with different antioxidants were 

studied. Assaying the oxidative DNA lesion, 8-hydroxydeoxyguanine (8-OHdG), and 

lipid peroxidation-induced etheno-DNA adducts in rat liver DNA indicated a high 

oxidative stress in OXYS rats. We found that the Na/K-ATPase activity, N-methyl-Daspartate 

(NMDA) receptors, and the integrity of sulfhydryl (SH) groups, parameters 

associated with memory-related neurochemical mechanisms, were altered in OXYS rat 

brains compared to that of control OXYR rats. Protection of neurochemical functions was 

investigated by long-term treatment of OXYS rats with different antioxidants, namely, 

2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene; BHT), 2,6-dimethyl-3hydroxypyridine 

(emoxipine), and beta-alanyl-L-histidine (carnosine). We determined 

that BHT protected rat brains from the oxidative alteration of Na/K-ATPase but did not 

protect NMDA receptors and SH groups. Emoxipine protected rat brain from oxidative 



606

impairment of SH group, but did not protect NMDA receptors and Na/K-ATPase. 

Carnosine protected from oxidative impairment rat brain NMDA receptors, Na/K- 

ATPase, and protein SH groups. 

19. Biochemistry (Mosc). 2000 Jul;65(7):807-16. 

Interactions between carnosine and zinc and copper: implications for 

neuromodulation and neuroprotection. 

Trombley PQ, Horning MS, Blakemore LJ. 

Biomedical Research Facility, Department of Biological Science, Florida State 

University, Tallahassee, Florida 32306-4340, USA. trombley@neuro.fsu.edu. 

This review examines interactions in the mammalian central nervous system (CNS) 

between carnosine and the endogenous transition metals zinc and copper. Although 

the relationship between these substances may be applicable to other brain 

regions, the focus is on the olfactory system where these substances may have 

special significance. Carnosine is not only highly concentrated in the olfactory 

system, but it is also contained in neurons (in contrast to glia cells in most 

of the brain) and has many features of a neurotransmitter. Whereas the function 

of carnosine in the CNS is not well understood, we review evidence that suggests 

that it may act as both a neuromodulator and a neuroprotective agent. Although 

zinc and/or copper are found in many neuronal pathways in the brain, the 

concentrations of zinc and copper in the olfactory bulb (the target of afferent 

input from sensory neurons in the nose) are among the highest in the CNS. 

Included in the multitude of physiological roles that zinc and copper play in 

the CNS is modulation of neuronal excitability. However, zinc and copper also 

have been implicated in a variety of neurologic conditions including Alzheimer's 

disease, Parkinson's disease, stroke, and seizures. Here we review the 

modulatory effects that carnosine can have on zinc and copper's abilities to 

influence neuronal excitability and to exert neurotoxic effects in the olfactory 

system. Other aspects of carnosine in the CNS are reviewed elsewhere in this 

issue. 

20. Brain Res. 2000 Jan 3;852(1):56-61. 

Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. 

Horning MS, Blakemore LJ, Trombley PQ. 

Biomedical Research Facility, Department of Biological Science, Florida State 

University, Tallahassee 32306-4340, USA. horning@neuro.fsu.edu 

Zinc and copper are endogenous transition metals that can be synaptically 

released during neuronal activity. Synaptically released zinc and copper 

probably function to modulate neuronal excitability under normal conditions. 

However, zinc and copper also can be neurotoxic, and it has been proposed that 

they may contribute to the neuropathology associated with a variety of 

conditions, such as Alzheimer's disease, stroke, and seizures. Recently, we 

demonstrated that carnosine, a dipeptide expressed in glial cells throughout the 

brain as well as in neuronal pathways of the visual and olfactory systems, can 



607

modulate the effects of zinc and copper on neuronal excitability. This result 

led us to hypothesize that carnosine may modulate the neurotoxic effects of zinc 

and copper as well. Our results demonstrate that carnosine can rescue neurons 

from zinc- and copper-mediated neurotoxicity and suggest that one function of 

carnosine may be as an endogenous neuroprotective agent. 

21. Neuroscience. 1999;94(2):571-7. 

Carnosine protects against excitotoxic cell death independently of effects on 

reactive oxygen species. 

Boldyrev A, Song R, Lawrence D, Carpenter DO. 

International Center for Biotechnology and Center for Molecular Medicine, MV 

Lomonosov Moscow State University, Department of Biochemistry, School of 

Biology, Russia. 

The role of carnosine, N-acetylcarnosine and homocarnosine as scavengers of 

reactive oxygen species and protectors against neuronal cell death secondary to 

excitotoxic concentrations of kainate and N-methyl-D-aspartate was studied using 

acutely dissociated cerebellar granule cell neurons and flow cytometry. We find 

that carnosine, N-acetylcarnosine and homocarnosine at physiological 

concentrations are all potent in suppressing fluorescence of 

2',7'-dichlorofluorescein, which reacts with intracellularly generated reactive 

oxygen species. However, only carnosine in the same concentration range was 

effective in preventing apoptotic neuronal cell death, studied using a 

combination of the DNA binding dye, propidium iodide, and a fluorescent 

derivative of the phosphatidylserine-binding dye, Annexin-V. Our results 

indicate that carnosine and related compounds are effective scavengers of 

reactive oxygen species generated by activation of ionotropic glutamate 

receptors, but that this action does not prevent excitotoxic cell death. Some 

other process which is sensitive to carnosine but not the related compounds is a 

critical factor in cell death. These observations indicate that at least in this 

system reactive oxygen species generation is not a major contributor to 

excitotoxic neuronal cell death. 

22. Cell Mol Neurobiol. 1999 Feb;19(1):45-56. 

Carnosine: an endogenous neuroprotector in the ischemic brain. 

Stvolinsky SL, Kukley ML, Dobrota D, Matejovicova M, Tkac I, Boldyrev AA. 

Institute of Neurology, Russian Academy of Medical Sciences, Moscow, Russia. 

1. The biological effects of carnosine, a natural hydrophilic neuropeptide, on 

the reactive oxygen species (ROS) pathological generation are reviewed. 2. We 

describe direct antioxidant action observed in the in vitro experiments. 3. 

Carnosine was found to effect metabolism indirectly. These effects are reflected 

in ROS turnover regulation and lipid peroxidation (LPO) processes. 4. During 

brain ischemia carnosine acts as a neuroprotector, contributing to better 

cerebral blood flow restoration, electroencephalography (EEG) normalization, 

decreased lactate accumulation, and enzymatic protection against ROS. 5. The 



608

data presented demonstrate that carnosine is a specific regulator of essential 

metabolic pathways in neurons supporting brain homeostasis under unfavorable 

conditions. 

23. Surgery. 1986 Nov;100(5):815-21. 

Action of carnosine and beta-alanine on wound healing. 

Nagai K, Suda T, Kawasaki K, Mathuura S. 

In rats treat-given hydrocortisone to suppress healing, tensile strength of the 

skin at the site of an incision wound was significantly higher in rats locally 

treated with carnosine than in untreated animals. Similar effects on the tensile 

strength of the skin were observed by the administration of beta-alanine and 

histidine, but not of beta-alanine alone. Exogenous carnosine was degraded in 

the body by carnosinase and histidine decarboxylase to yield histamine. Since 

beta-alanine, the other degradation product of carnosine, was found to stimulate 

the biosynthesis of nucleic acids and collagen, histamine derived from carnosine 

is considered to have enhanced the process of wound healing by stimulating 

effusion at the initial stage of inflammation. Thus, the enhancement by 

carnosine of wound healing may be ascribed to stimulation of early effusion by 

histamine and of collagen biosynthesis by beta-alanine. The wound-healing 

effects of carnosine were further demonstrated by the observation that carnosine 

significantly increased granulation suppressed by cortisone, mitomycin C, 

5-fluorouracil, and bleomycin. 

24. Nippon Seirigaku Zasshi. 1986;48(11):735-40. 

[Immuno-enhancing actions of carnosine and homocarnosine] [Article in Japanese] 

Nagai K, Suda T. 

Immuno-enhancing actions of carnosine, beta-alanine, homocarnosine, and 

gamma-aminobutyric acid were studied in ddY mice by evaluating plaque-forming 

cell reaction against sheep red blood cells. Animals were administered the test 

agents in prior to, or simultaneously with, various treatments that are known to 

reduce immune function such as administration of the anti-tumor agents, 

mitomycin C and 5-fluorouracil, immunosuppressant cyclophosphamide, 

antiinflammatory agent hydrocortisone, or cancer implantation and 

gamma-irradiation. Experiments were performed also in aged mice with reduced 

immune function. The administration of these drugs showed non-specific 

immuno-enhancing effects under all conditions examined and on all cell groups 

that may have been affected by these immunosuppressive stimulus. 


[Antineoplastic effects of carnosine and beta-alanine--physiological 

considerations of its antineoplastic effects] [Article in Japanese] 


Antineoplastic effects of carnosine (CAR) and beta-alanine (ALA), were examined 



609

in vivo using ddY mice implanted with the solid tumor Sarcoma-180. The sarcoma 

was treated with trypsin, 10(5) cells were implanted subcutaneously in the back 

of the animals, and CAR and ALA were administered subcutaneously 2 cm from the 

implantation site starting on the next day. The animals treated with ALA alone 

showed prolongation of survival to a T/C value of 132%; the growth of the tumor 

was inhibited and mortality reduced in those treated with CAR alone. Regression 

of the tumor was observed in the animals treated with either drug. The effects 

of these agents were enhanced when administered in combination with the 

non-specific active immuno-enhancing agent OK-432. More than half the animals 

treated with CAR and OK-432 survived the observation period (T/C greater than 

218%), and survival was prolonged in those treated with ALA and OK-432 to a T/C 

value of 132%. The agents also showed potent antineoplastic effects on 

Sarcoma-180 when the tumor had been attenuated in vivo with mitomycin C (MMC). 


[Immunoregulative effects of homocarnosine and gamma-aminobuthyric acid] [Article 

in Japanese] 


The effects of homocarnosine and GABA on antibody production (PFC reaction) and 

cellular immunity (delayed hypersensitivity reaction, DHR) were examined in 

vivo. In mice treated with these agents, PFC reaction to 2 X 10(7) SRBC was 

enhanced but that to 1 X 10(9) SRBC was suppressed; moreover, immunoreaction was 

reduced in immature mice (2-2.5 weeks old) but was increased in aged mice (30 

weeks old or above). These agents had optimal doses on the PFC reaction in mice 

given 1 X 10(8) SRBC and DHR, and induced recovery of immunofunction suppressed 

by the administration of MMC. 


[Immunoregulative effects of carnosine and beta-alanine] [Article in Japanese] 


Physiological factors involved in immunity and tissue repair with regulate 

homeostasis, a physiological function of the connective tissue, are as yet 

unidentified. We earlier detected the granulation-promoting action of carnosine, 

and reported on the acceleration of tissue repair in experimental as well as 

clinical studies. In that study, immunoregulatory effects of carnosine and 

beta-alanine were examined by the plaque-forming cell (PFC) count and delayed 

hypersensitivity reaction (DHR). The PFC value increased in mice pretreated with 

these agents. In these mice, PFC reaction to 2 X 10(7) SRBC was enhanced but 

that to 1 X 10(9) SRBC was suppressed. The agents also suppressed excess 

immunoreaction in immature mice but increased weakened immunoreaction in aged 

animals. Furthermore, the agents had the optimal doses for the enhancement of 

both PFC reaction to 1 X 10(8) SRBC and DHR to 1% picryl chloride. They also 

induced recovery of immunofunction suppressed by the administration of MMC. 



610

Carnosine and beta-alanine exerts immunoregulatory effects by activating both T 

and B cells. Our observations indicated that the agents not only promote tissue 

repair but also help maintain homeostasis and accelerate spontaneous healing. 

28. Effects of carnosine on the development of rat sponge-induced granulation tissue. II. 

Histoautoradiographic observations on collagen biosynthesis. 

Vizioli MR, Blumen G, Almeida OP, et al. 

Cell Mol Biol. 1983; 29(1):1-9. 

No abstract available. 

29. Cell Struct Funct. 1999 Apr;24(2):79-87. 

Carnosine stimulates vimentin expression in cultured rat fibroblasts. 

Ikeda D, Wada S, Yoneda C, Abe H, Watabe S. 

Laboratory of Aquatic Molecular Biology and Biotechnology, Graduate School of 

Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Japan. 

Two-dimensional electrophoretic gel profiles were compared between rat 3Y1 

fibroblasts cultured in the presence and absence of 30 mM L-carnosine 

(beta-alanyl-L-histidine) for one week without any replenishment of medium. 

While a number of cellular proteins changed their expression levels by the 

addition of carnosine, we identified one of the most prominently varied proteins 

as vimentin. Immunoblot analysis with anti-vimentin antibody demonstrated that 

the vimentin levels increased about 2-fold after one-week culture in the 

presence of carnosine. We also confirmed that the increase of vimentin 

expression was dependent on the concentration of carnosine added to the medium. 

Moreover, when cultured cells were stained with anti-vimentin antibody and 

observed by light microscopy, most cells grown in the presence of carnosine were 

found to have markedly developed vimentin filaments. The increase of vimentin 

expression was also observed by adding with carnosine related dipeptides, 

N-acetylcarnosine and anserine. 

30. Cell Mol Life Sci. 2000 May;57(5):747-53. 

A possible new role for the anti-ageing peptide carnosine. 

Hipkiss AR, Brownson C. 

Biomolecular Sciences Division, GKT School of Biomedical Sciences, King's 

College London, UK. alan.hipkiss@kcl.ac.uk 

The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) is found 

in surprisingly large amounts in long-lived tissues and can delay ageing in 

cultured human fibroblasts. Carnosine has been regarded largely as an 

anti-oxidant and free radical scavenger. More recently, an anti-glycating 

potential has been discovered whereby carnosine can react with 

low-molecular-weight compounds that bear carbonyl groups (aldehydes and 

ketones). Carbonyl groups, arising mostly from the attack of reactive oxygen 

species and low-molecular-weight aldehydes and ketones, accumulate on proteins 



611

during ageing. Here we propose, with supporting evidence, that carnosine can 

react with protein carbonyl groups to produce protein-carbonyl-carnosine adducts 

('carnosinylated' proteins). The various possible cellular fates of the 

carnosinylated proteins are discussed. These proposals may help explain 

anti-ageing actions of carnosine and its presence in non-mitotic cells of 

long-lived mammals. 


Carnosine reacts with protein carbonyl groups: another possible role for the 

anti-ageing peptide? 

Hipkiss AR, Brownson C. 

Biomolecular Sciences Division, GKT School of Biomedical Sciences, King's 

College London, Guy's Campus London Bridge, London EC1 1UL, UK. 


Carnosine (beta-alanyl-L-histidine) can delay senescence and provoke cellular 

rejuvenation in cultured human fibroblasts. The mechanisms by which such a 

simple molecule induces these effects is not known despite carnosine's well 

documented anti-oxidant and oxygen free-radical scavenging activities. Carbonyl 

groups are generated on proteins post-synthetically by the action of reactive 

oxygen species and glycating agents and their accumulation is a major 

biochemical manifestation of ageing. We suggest that, in addition to the 

prophylactic actions of carnosine, it may also directly participate in the 

inactivation/disposal of aged proteins possibly by direct reaction with the 

carbonyl groups on proteins. The possible fates of these 'carnosinylated' 

proteins including the formation of inert lipofuscin, proteolysis via the 

proteasome system and exocytosis following interaction with receptors are also 

discussed. The proposal may point to a hitherto unrecognised mechanism by which 

cells/organisms normally defend themselves against protein carbonyls. 

CARNOSINE AND GLYCATION 

32. Mech Ageing Dev 2001 Sep 15;122(13):1431-45 

Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein 

carbonyl groups. 

Hipkiss AR, Brownson C, Carrier MJ. 

Division of Biomolecular Sciences, GKT School of Biomedical Sciences, King's 

College London, Guy's Campus, London Bridge, London SE1 1UL, UK. 


Carnosine (beta-alanyl-L-histidine) is a physiological dipeptide which can delay 

ageing and rejuvenate senescent cultured human fibroblasts. Carnosine's 

anti-oxidant, free radical- and metal ion-scavenging activities cannot 

adequately explain these effects. Previous studies showed that carnosine reacts 

with small carbonyl compounds (aldehydes and ketones) and protects 



612

macromolecules against their cross-linking actions. Ageing is associated with 

accumulation of carbonyl groups on proteins. We consider here whether carnosine reacts 

with protein carbonyl groups. Our evidence indicates that carnosine can react nonenzymically 

with protein carbonyl groups, a process termed 'carnosinylation'. We 

propose that similar reactions could occur in cultured fibroblasts and in vivo. A 

preliminary experiment suggesting that carnosine is effective in vivo is presented; it 

suppressed diabetes-associated increase in blood pressure in fructose-fed rats, an 

observation consistent with carnosine's anti-glycating actions. We speculate that: (i) 

carnosine's apparent anti-ageing actions result, partly, from its ability to react with 

carbonyl groups on 

glycated/oxidised proteins and other molecules; (ii) this reaction, termed 

'carnosinylation,' inhibits cross-linking of glycoxidised proteins to normal 

macromolecules; and (iii) carnosinylation could affect the fate of glycoxidised 

polypeptides. 

33. Biochemistry (Mosc) 2000 Jul;65(7):771-8 

Carnosine and protein carbonyl groups: a possible relationship. 

Hipkiss AR. 

Division of Biomolecular Sciences, GKT School of Biomedical Sciences, King's 

College London, London SE1 1UL, UK. alan.hipkiss@kcl.ac.uk. 

Carnosine has been shown to react with low-molecular-weight aldehydes and 

ketones and has been proposed as a naturally occurring anti-glycating agent. It 

is suggested here that carnosine can also react with ("carnosinylate") proteins 

bearing carbonyl groups, and evidence supporting this idea is presented. 

Accumulation of protein carbonyl groups is associated with cellular ageing 

resulting from the effects of reactive oxygen species, reducing sugars, and 

other reactive aldehydes and ketones. Carnosine has been shown to delay 

senescence and promote formation of a more juvenile phenotype in cultured human 

fibroblasts. It is speculated that carnosine may intracellularly suppress the deleterious 

effects of protein carbonyls by reacting with them to form 

protein-carbonyl-carnosine adducts, i.e., "carnosinylated" proteins. Various 

fates of the carnosinylated proteins are discussed including formation of inert 

lipofuscin and proteolysis via proteosome and RAGE activities. It is proposed 

that the anti-ageing and rejuvenating effects of carnosine are more readily 

explainable by its ability to react with protein carbonyls than its 

well-documented antioxidant activity. 

34. Neurosci Lett 1998 Feb 13;242(2):105-8 

Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: 

protection by carnosine, homocarnosine and beta-alanine. 



The effect of a truncated form of the neurotoxin beta-amyloid peptide (A 

beta25-35) on rat brain vascular endothelial cells (RBE4 cells) was studied in 



613

cell culture. Toxic effects of the peptide were seen at 200 microg/ml A beta 

using a mitochondrial dehydrogenase activity (MTT) reduction assay, lactate 

dehydrogenase release and glucose consumption. Cell damage could be prevented 

completely at 200 microg/ml A beta and partially at 300 microg/ml A beta, by the 

dipeptide carnosine. Carnosine is a naturally occurring dipeptide found at high levels in 

brain tissue and innervated muscle of mammals including humans. Agents which share 

properties similar to carnosine, such as beta-alanine, homocarnosine, the anti-glycating 

agent aminoguanidine, and the antioxidant superoxide dismutase (SOD), also partially 

rescued cells, although not as effectively as carnosine. We postulate that the mechanism 

of carnosine 

protection lies in its anti-glycating and antioxidant activities, both of which 

are implicated in neuronal and endothelial cell damage during Alzheimer's 

disease. Carnosine may therefore be a useful therapeutic agent. 

35. Biochemistry (Mosc) 1997 Oct;62(10):1119-23 

Change in the functional properties of actin by its glycation in vitro. 

Kuleva NV, Kovalenko ZS. 

Department of Biochemistry, School of Biology and Soil Sciences, St. Petersburg 

State University, Universitetskaya Naberezhnaya 7/9, Vasil'evskii Ostrov, St. 

Petersburg, Russia. 

The influence of glycation (non-enzymatic glycosylation) on structural and 

functional properties of actin of rabbit skeletal muscle and the effects of the 

natural anti-glycating dipeptide carnosine were studied. Glucose (0.5 M), 

fructose (0.5 M), and glyceraldehyde (0.05 M) were used as glycating agents. 

Marked changes in the structural and functional properties were observed in the 

presence of glyceraldehyde when high-molecular-weight components appear. This was 

followed by a decrease in the ability of actin to activate myosin ATPase, to polymerize, 

and to inhibit DNase I. In the presence of 0.05 M carnosine, the 

quantity of high-molecular-weight products decreased and myosin ATPase 

activation was retained. Since muscle tissue contains millimolar quantities of 

carnosine, glycation of actin associated with changes in its properties is 

evidently more likely to occur in non-muscle cells. 

CARNOSINE AND DEGENERATIVE 

36. Biochim Biophys Acta. 2000 Dec 15;1524(2-3):162-70. 

Enhanced oxidative damage by the familial amyotrophic lateral 

sclerosis-associated Cu,Zn-superoxide dismutase mutants. 

Kang JH, Eum WS. 

Department of Genetic Engineering, Division of Natural Sciences, Chongju 

University, 360-764, Chongju, South Korea. jhkang@chongiu.ac.kr 

Some cases of familial amyotrophic lateral sclerosis (FALS), a degenerative 

disorder of motor neurons, is associated with mutation in the Cu,Zn-superoxide 



614

dismutase (SOD) gene SOD1. The purified FALS mutant and wild-type Cu,Zn-SODs 

expressed in Escherichia coli cells have identical dismutation activity whereas 

the hydroxyl radical formation of FALS mutants was enhanced relative to that of 

the wild-type enzyme. These higher free radical-generating activities of mutants 

facilitated the release of copper ions from their own molecules. The reaction of 

the mutants with hydrogen peroxide enhanced DNA strand breaks and lipid 

peroxidation. The results suggested that the enhanced oxidative damage of 

macromolecules is mediated in the Cu,Zn-SOD mutants and hydrogen peroxide system 

via the generation of hydroxyl radicals by a combination of the higher free 

radical-generating activities of mutants and a Fenton-like reaction of copper 

ions released from oxidatively damaged Cu,Zn-SODs. Carnosine has been proposed 

to act as antioxidant in vivo. We investigated whether carnosine could protect 

the oxidative damage induced by FALS mutants. Carnosine effectively inhibited 

the DNA cleavage and lipid peroxidation. These results suggest that the higher 

free radical-generating function of FALS mutants can lead to increased oxidative 

damage of macromolecules which further implicates free radical-mediated motor 

neuronal injury in the pathogenesis of FALS and carnosine may be explored as 

potential therapeutic agents for FALS patients. 

GLYCATION AND CARNOSINE SEARCH 

37. Life Sci. 2003 Apr 25;72(23):2603-16. 

The polyamines spermine and spermidine protect proteins from structural and 

functional damage by AGE precursors: a new role for old molecules? 

Gugliucci A, Menini T. 

Biochemistry Laboratory, Division of Basic Medical Sciences, Touro University, 

College of Osteopathic Medicine, 1310 Johnson Lane, Mare Island, Vallejo, CA 

94592, USA. agugliuc@touro.edu 

Due to the importance of glycation in the genesis of diabetic complications, an 

intense search for synthetic new antiglycation agents is ongoing. However, a 

somewhat neglected avenue is the search for endogenous compounds that may 

inhibit the process and be a source of protodrugs. Based on their ubiquity, 

their polycationic nature, their essential role in growth, their relatively high 

concentrations in tissues, and their high concentrations in sperm, we 

hypothesized that polyamines inhibit glycation and that might be one of their so 

far elusive functions. In this study we demonstrate a potent antiglycation 

effect of physiological concentrations of the polyamines spermine and 

spermidine. We employed two approaches: in the first, we monitored structural 

changes on histones and ubiquitin in which polyamines inhibit glycation-induced 

dimer and polymer formation. In the second we monitored functional impairment of 

catalytic activity of antithrombin III and plasminogen. Protection is afforded 

against glycation by hexoses, trioses and dicarbonyls AGE precursors and is 

comparable to those of aminoguanidine and carnosine. 

38. Biochem Biophys Res Commun. 2003 Jan 3;300(1):75-80. 



615

Carnosine promotes the heat denaturation of glycated protein. 

Yeargans GS, Seidler NW. 

Department of Biochemistry, University of Health Sciences, 1750 Independence 

Avenue, Kansas City, MO 64106-1453, USA. 

Glycation alters protein structure and decreases biological activity. Glycated 

proteins, which accumulate in affected tissue, are reliable markers of disease. 

Carnosine, which prevents glycation, may also play a role in the disposal of 

glycated protein. Carnosinylation tags glycated proteins for cell removal. Since 

thermostability determines cell turnover of proteins, the present study examined 

carnosine's effect on thermal denaturation of glycated protein using cytosolic 

aspartate aminotransferase (cAAT). Glycated cAAT (500 microM glyceraldehyde for 

72h at 37 degrees C) increased the T(0.5) (temperature at which 50% denaturation 

occurs) and the Gibbs free energy barrier (DeltaG) for denaturation. The 

enthalpy of denaturation (DeltaH) for glycated cAAT was also higher than that 

for unmodified cAAT, suggesting that glycation changes the water accessible 

surface. Carnosine enhanced the thermal unfolding of glycated cAAT as evidenced 

by a decreased T(0.5) and a lowered Gibbs free energy barrier. Additionally, 

carnosine decreased the enthalpy of denaturation, suggesting that carnosine may 

promote hydration during heat denaturation of glycated protein. 

39. Life Sci. 2002 Mar 1;70(15):1789-99. 

Effects of thermal denaturation on protein glycation. 

Seidler NW, Yeargans GS. 

Department of Biochemistry, University of Health Sciences, Kansas City, MO 

64106, USA. nseidler@uhs.edu 

Protein denaturation occurs at sites of inflammation. We hypothesized that 

denatured protein may provide a more susceptible target for glycation, which is 

a known mediator of inflammation. We examined the effects of thermal 

denaturation on the susceptibility of protein glycation using glyceraldehyde 

3-phosphate dehydrogenase (GAPDH) and aspartate aminotransferase (AAT) as our 

target proteins. GAPDH and AAT are ubiquitous proteins that exhibited very 

different thermal stabilities. Glycating agents, methylglyoxal (MG) and 

glyceraldehyde (Glyc), caused an increase in the formation of advanced glycation 

endproducts (AGEs) in native and denatured GAPDH and AAT. The effects of the 

glycating agents were more pronounced with the denatured proteins. In addition 

to nitroblue tetrazolium (NBT)- reactivity, our measured endpoints were 

absorbance (lambda = 365 nm) and fluorescence (lambda(ex) = 370 nm; lambda(em) = 

470 nm) properties that are typically associated with protein glycation. We also 

looked at carnosine's ability to prevent glycation of native and denatured 

protein. Carnosine, an endogenous histidine dipeptide, exhibits 

anti-inflammatory activity presumably due to its anti-oxidant and anti-glycation 

properties. Carnosine prevented Glyc-induced AGE formation in both native and 

denatured AAT suggesting that carnosine's anti-inflammatory activity may be due 

in part to carnosine's ability to prevent glycation of denatured protein. 



616


Reaction of carnosine with aged proteins: another protective process? 

Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A. 

GKT School of Biomedical Sciences, King's College London, Guy's Campus, London 

Bridge, London SE1 1UL, United Kingdom. alan.hipkiss@kcl.ac.uk 

Cellular aging is often associated with an increase in protein carbonyl groups 

arising from oxidation- and glycation-related phenomena and suppressed 

proteasome activity. These "aged" polypeptides may either be degraded by 20S 

proteasomes or cross-link to form structures intractable to proteolysis and 

inhibitory to proteasome activity. Carnosine (beta-alanyl-l-histidine) is 

present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues 

in many animals, especially long-lived species. Carnosine can delay senescence 

in cultured human fibroblasts and reverse the senescent phenotype, restoring a 

more juvenile appearance. As better antioxidants/free-radical scavengers than 

carnosine do not demonstrate these antisenescent effects, additional properties 

of carnosine must contribute to its antisenescent activity. Having shown that 

carnosine can react with protein carbonyls, thereby generating "carnosinylated" 

polypeptides using model systems, we propose that similar adducts are generated 

in senescent cells exposed to carnosine. Polypeptide-carnosine adducts have been 

recently detected in beef products that are relatively rich in carnosine, and 

carnosine's reaction with carbonyl functions generated during amino acid 

deamidation has also been described. Growth of cultured human fibroblasts with 

carnosine stimulated proteolysis of long-labeled proteins as the cells 

approached their "Hayflick limit," consistent with the idea that carnosine 

ameliorates the senescence-associated proteolytic decline. We also find that 

carnosine suppresses induction of heme-oxygenase-1 activity following exposure 

of human endothelial cells to a glycated protein. The antisenescent activity of 

the spin-trap agent alpha-phenyl-N-t-butylnitrone (PBN) towards cultured human 

fibroblasts resides in N-t-butyl-hydroxylamine, its hydrolysis product. As 

hydroxylamines are reactive towards aldehydes and ketones, the antisenescent 

activity of N-t-butyl-hydroxylamine and other hydroxylamines may be mediated, at 

least in part, by reactivity towards macromolecular carbonyls, analogous to that 

proposed for carnosine. 

41. Biosci Biotechnol Biochem. 2002 Jan;66(1):36-43. 

Effect of carnosine and related compounds on the inactivation of human 

Cu,Zn-superoxide dismutase by modification of fructose and glycolaldehyde. 

Ukeda H, Hasegawa Y, Harada Y, Sawamura M. 

Department of Bioresources Science, Faculty of Agriculture, Kochi University, 

Nankoku, Japan. hukeda@cc.kochi-u.ac.jp 

Glycolaldehyde, an intermediate of the Maillard reaction, and fructose, which is 

mainly derived from the polyol pathway, rapidly inactivate human 

Cu,Zn-superoxide dismutase (SOD) at the physiological concentration. We employed 



617

this inactivation with these carbonyl compounds as a model glycation reaction to 

investigate whether carnosine and its related compounds could protect the enzyme 

from inactivation. Of eight derivatives examined, histidine, Gly-His, carnosine 

and Ala-His inhibited the inactivation of the enzyme by fructose (p

concentrations, the chelating activity of AGE inhibitors and AGE-breakers may 

contribute to their inhibition of AGE formation and protection against 

development of diabetic complications. 

43. Free Radic Biol Med. 2000 May 15;28(10):1564-70. 

Carnosine reacts with a glycated protein. 


Division of Biomolecular Science, GKT School of Biomedical Sciences, King's 

College London, Guy's Campus, London Bridge, London, UK. 

Oxidation and glycation induce formation of carbonyl (CO) groups in proteins, a 

characteristic of cellular aging. The dipeptide carnosine 

(beta-alanyl-L-histidine) is often found in long-lived mammalian tissues at 

relatively high concentrations (up to 20 mM). Previous studies show that 

carnosine reacts with low-molecular-weight aldehydes and ketones. We examine 

here the ability of carnosine to react with ovalbumin CO groups generated by 

treatment of the protein with methylglyoxal (MG). Incubation of MG-treated 

protein with carnosine accelerated a slow decline in CO groups as measured by 

dinitrophenylhydrazine reactivity. Incubation of [(14)C]-carnosine with 

MG-treated ovalbumin resulted in a radiolabeled precipitate on addition of 

trichloroacetic acid (TCA); this was not observed with control, untreated 

protein. The presence of lysine or N-(alpha)-acetylglycyl-lysine methyl ester 

caused a decrease in the TCA-precipitable radiolabel. Carnosine also inhibited 

cross-linking of the MG-treated ovalbumin to lysine and normal, untreated 

alpha-crystallin. We conclude that carnosine can react with protein CO groups 

(termed "carnosinylation") and thereby modulate their deleterious interaction 

with other polypeptides. It is proposed that, should similar reactions occur 

intracellularly, then carnosine's known "anti-aging" actions might, at least 

partially, be explained by the dipeptide facilitating the inactivation/removal 

of deleterious proteins bearing carbonyl groups. 

44. J Biochem Mol Toxicol. 2000;14(4):215-20. 

Carnosine prevents the glycation-induced changes in electrophoretic mobility of 

aspartate aminotransferase. 

Seidler NW. 

University of Health Sciences, Department of Biochemistry, Kansas City, MO 

64106-1453, USA. NSEIDLER@fac1.uhs.edu 

Carbohydrate-derived aldehydes cause irreversible loss of protein function via 

glycation. We previously observed that glyceraldehyde 3-phosphate (Glyc3P) 

abolishes the enzyme activity of cardiac aspartate aminotransferase (cAAT). We 

also examined the protective effects of carnosine against Glyc3P-induced loss of 

enzyme activity. The present study looked at carnosine's prevention of 

Glyc3P-induced change in protein structure. Purified cAAT (2 mg protein/mL) was 

incubated with various concentrations of carnosine (1-20 mM) in the presence of 

Glyc3P (500 microM) for 4 days at 37 degrees C. Following incubation, samples 



619

were analyzed by SDS-polyacrylamide gel electrophoresis. Carnosine showed 

prevention of protein modification at carnosine-to-Glyc3P ratios of 10:1 or 

greater. There was a progressive loss of the unmodified cAAT protein band as 

Glyc3P concentration was increased. Additionally, the gel position of the 

Glyc3P-modified cAAT protein varied over time. The apparent molecular weight 

(MWapp) of the Glyc3P-modified cAAT protein that formed after 1 day at 37 

degrees C (500 microM) was greater than its MWapp after 2 days, suggesting that 

a chemical rearrangement of the initial adduct occurs. These observations 

support the hypothesis that carnosine is an antiglycation agent and that its 

mechanism of action involves prevention of protein modification. 

45. Tsitologiia. 2000;42(1):66-71. 

[Nonenzymatic glycosylation of and oxidative damage to actin in vitro and in 

vivo] [Article in Russian] 

Kuleva NV, Zalesova ZS. 

St. Petersburg State University. 

A study was made the influence exerted by non-enzymatic glycosylation 

(glycation) and oxidative destruction on structural and functional parameters of 

actin (free NH2-groups, advanced glycation end product and bityrosine 

cross-linking content, DNase inhibition by G-actin and myosin Mg(2+)-ATPase 

activation by F-actin). The functional properties of actin were shown to change 

under high molecular weight product formation and oxidative destruction: the 

extent of DNAase I inhibition decreases (from 70 to 40%) and the extent of 

myosin Mg(2+)-ATPase decreases (by 40%). Carnosine prevents actin oligomer 

formation and oxidative destruction which favours preservation of the protein 

functional properties. 

46. Arch Toxicol. 1999 Aug;73(6):307-9. 

Carnosine prevents glyceraldehyde 3-phosphate-mediated inhibition of aspartate 

aminotransferase. 

Swearengin TA, Fitzgerald C, Seidler NW. 

Department of Biochemistry, University of Health Sciences, 1750 Independence 

Boulevard, Kansas City, MO 64106-1453, USA. 

Post-mitotic tissues, such as the heart, exhibit high concentrations (20 mM) of 

carnosine (beta-alanyl-l-histidine). Carnosine may have aldehyde scavenging 

properties. We tested this hypothesis by examining its protective effects 

against inhibition of enzyme activity by glyceraldehyde 3-phosphate (Glyc3P). 

Glyc3P is a potentially toxic triose; Glyc3P inhibits the cardiac aspartate 

aminotransferase (cAAT) by non-enzymatic glycosylation (or glycation) of the 

protein. cAAT requires pyridoxal 5-phosphate (PyP) for catalysis. We observed 

that carnosine (20 mM) completely prevents the inhibition of cAAT activity by 

Glyc3P (5 mM) after brief incubation (30 min at 37 degrees C). After a prolonged 

incubation (3.25 h) of cAAT with Glyc3P (0.5 mM) at 37 degrees C, the protection 

by carnosine (20 mM) persisted but PyP availability was affected. In the absence 



620

of PyP from the assay medium, cAAT activities (plus Glyc3P) were 95 +/- 18.2 

micromol/min per mg protein (mean +/- SD), minus carnosine and 100 +/- 2.4, plus 

carnosine; control activity was 172 +/- 3.9. When PyP (1.0 microM) was included 

in the assay medium, cAAT activities (plus Glyc3P) were 93 +/- 14.8, minus 

carnosine and 151 +/- 16.8, plus carnosine, P < 0. 001; control activity was 180 

+/- 17.7. These data, which showed carnosine moderating the effects of both 

Glyc3P and PyP, suggest that carnosine may be an endogenous aldehyde scavenger. 

47. Int J Biochem Cell Biol. 1998 Aug;30(8):863-8. 

Carnosine, a protective, anti-ageing peptide? 

Hipkiss AR. 


Carnosine (beta-alanyl-L-histidine) has protective functions additional to 

anti-oxidant and free-radical scavenging roles. It extends cultured human 

fibroblast life-span, kills transformed cells, protects cells against aldehydes 

and an amyloid peptide fragment and inhibits, in vitro, protein glycation 

(formation of cross-links, carbonyl groups and AGEs) and DNA/protein 

cross-linking. Carnosine is an aldehyde scavenger, a likely lipofuscin (age 

pigment) precursor and possible modulator of diabetic complications, 

atherosclerosis and Alzheimer's disease. 

Magnesium - 570 CITATIONS 

1: Zausinger S, Scholler K, Plesnila N, Schmid-Elsaesser R. 

Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in 

rats. Stroke. 2003 Sep;34(9):2246-51. Epub 2003 Jul 31. 

PMID: 12893947 

2: Dube L, Granry JC. 

The therapeutic use of magnesium in anesthesiology, intensive care and emergency 

medicine: a review. 

Can J Anaesth. 2003 Aug-Sep;50(7):732-46. 

PMID: 12944451 

3: Sibai BM. 

Diagnosis and management of gestational hypertension and preeclampsia. 

Obstet Gynecol. 2003 Jul;102(1):181-92. 

PMID: 12850627 

4: Hughes R, Goldkorn A, Masoli M, Weatherall M, Burgess C, Beasley R. 



621

Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in 

treatment of severe asthma in adults: randomised placebo-controlled trial. 

Lancet. 2003 Jun 21;361(9375):2114-7. 

PMID: 12826434 

5: Bucca C, Rolla G. 


Lancet. 2003 Jun 21;361(9375):2095-6. 

PMID: 12826427 

6: Jian W, Su L, Yiwu L. 

The effects of magnesium prime solution on magnesium levels and potassium loss in 

open heart surgery. 

Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. 

PMID: 12760983 

7: Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. 

Neuroprotection in transient focal cerebral ischemia by combination drug therapy and 

mild hypothermia: comparison with customary therapeutic regimen. 

Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. 

PMID: 12730554 

8: Geleijnse JM, Grobbee DE. 

Nutrition and health—hypertension. 


PMID: 12811968 

9: Suresh S, Lozono S, Hall SC. 



Anesth Analg. 2003 May;96(5):1413-4, table of contents. 

PMID: 12707144 

10: Sigman-Grant M, Warland R, Hsieh G. 



J Am Diet Assoc. 2003 May;103(5):570-6. 

PMID: 12728214 

11: Haupt H, Scheibe F, Mazurek B. 


ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. 

PMID: 12925813 

12: Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. 



622

The behavioral effects of magnesium therapy on recovery of function following bilateral 

anterior medial cortex lesions in the rat. 

Brain Res Bull. 2003 Apr 15;60(1-2):105-14. 

PMID: 12725898 

13: Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, 

Komiya T, Okamura M, Kim S, Iwao H, Miura K. 



Transplantation. 2003 Apr 15;75(7):1040-4. 

PMID: 12698095 

14: Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. 





PMID: 12663282 

15: Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. 

Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) 

nephrotoxicity in rats. 

Clin Nephrol. 2003 Apr;59(4):267-72. 

PMID: 12708566 

16: Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. 



PMID: 12682476 

17: Ilich JZ, Brownbill RA, Tamborini L. 




PMID: 12700617 

18: Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider 




evaluation. 

Heart. 2003 Apr;89(4):411-6. 

PMID: 12639869 



623

19: Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, Most- 

Windhauser MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research 

Group. 

Food group sources of nutrients in the dietary patterns of the DASH-Sodium trial. 

J Am Diet Assoc. 2003 Apr;103(4):488-96. 

PMID: 12669013 

20: Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami 

H. 


J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. 

PMID: 12755529 

21: Singhi SC, Singh J, Prasad R. 


J Trop Pediatr. 2003 Apr;49(2):99-103. 

PMID: 12729292 

22: van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. 

Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. 

Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for 

long term treatment. 

PMID: 12632115 

23: Higgins JC. 

The 'crashing astimatic.' 

Am Fam Physician. 2003 Mar 1;67(5):997-1004. 

PMID: 12643359 

24: Roy SR, Milgrom H. 


Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. 

PMID: 12562559 

25: Cappell MS. 


Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. 

PMID: 12635419 

26: Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. 



Magnes Res. 2003 Mar;16(1):59-64. 

PMID: 12735484 

27: Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. 



624

Pharmacotherapy. 2003 Mar;23(3):296-300. 



PMID: 12627926 

28: Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. 

Recenti Prog Med. 2003 Mar;94(3):136-41. 

Etiopathogenesis and clinical aspects of nephrolithiasis--at present. 

PMID: 12677782 

29: Touyz RM. 


Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. 

PMID: 12537992 

30: Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. 

Effect of intra-operative magnesium sulphate on pain relief and patient comfort after 

major lumbar orthopaedic surgery. 

Anaesthesia. 2003 Feb;58(2):131-5. 

PMID: 12562408 

31: Pamnani MB, Bryant HJ, Clough DL, Schooley JF. 



inhibitor. 

Clin Exp Hypertens. 2003 Feb;25(2):103-15. 

PMID: 12611422 

32: Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, Malinowska- 

Polubiec A, Romejko E. 



Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. 

PMID: 12566182 

33: Hata M, Miyao M, Mizuno Y. 

Osteoporosis as a lifestyle-related disease. 

Nippon Rinsho. 2003 Feb;61(2):305-13. 

PMID: 12638226 

34: Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. 



Resuscitation. 2003 Feb;56(2):199-206. 

PMID: 12589995 



625

35: Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. 


N Engl J Med. 2003 Jan 23;348(4):304-11. 

PMID: 12540643 

36: Vink R, O'Connor CA, Nimmo AJ, Heath DL. 

Magnesium attenuates persistent functional deficits following diffuse traumatic brain 

injury in rats. 


PMID: 12493598 

37: Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, 

Efrati S, Weissgarten J. 


Am J Kidney Dis. 2003 Jan;41(1):196-202. 

PMID: 12500237 

38: Meram I, Balat O, Tamer L, Ugur MG. 



Clin Exp Obstet Gynecol. 2003;30(1):32-4. 

PMID: 12731741 

39: Duley L, Gulmezoglu AM, Henderson-Smart DJ. 


Cochrane Database Syst Rev. 2003;(2):CD000025. 

PMID: 12804383 

40: Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. 


Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. 

PMID: 12528016 

41: Margolin A, Kantak K, Copenhaver M, Avants SK. 

A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit 

cocaine and opiate use in methadone-maintained patients. 

J Addict Dis. 2003;22(2):49-61. 

PMID: 12703668 

42: Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. 



J Epidemiol. 2003 Jan;13(1):48-55. 

PMID: 12587613 



626

43: Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. 

Therapeutics indications and prognosis of eclampsia at Dakar University 

Teaching Hospital. 

J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. 

PMID: 12773926 

44: Darvish D. 

Magnesium may help patients with recessive hereditary inclusion body 

myopathy, a pathological review. 

Med Hypotheses. 2003 Jan;60(1):94-101. 

PMID: 12450772 

45: Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. 

A case of urolithiasis associated with short bowel syndrome. 

Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. 

PMID: 12638204 

46: Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. 



Paediatr Anaesth. 2003 Jan;13(1):43-7. 

PMID: 12535038 

47: Byrd RP Jr, Roy TM. 


South Med J. 2003 Jan;96(1):104. 

PMID: 12602735 

48: Kidd PM. 


management. 

Altern Med Rev. 2002 Dec;7(6):472-99. 

PMID: 12495373 

49: Carlin Schooley M, Franz KB. 

Magnesium deficiency during pregnancy in rats increases systolic blood 

pressure and plasma nitrite. 

Am J Hypertens. 2002 Dec;15(12):1081-6. 

PMID: 12460704 

50: Imazu M. 


Curr Hypertens Rep. 2002 Dec;4(6):477-82. 

PMID: 12419178 

51: Grzybek A, Klosiewicz-Latoszek L, Targosz U. 



627



Eur J Clin Nutr. 2002 Dec;56(12):1162-8. 

PMID: 12494300 

52: Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. 

Optimisation of colon cleansing prior to computed tomographic 

colonography. 

JBR-BTR. 2002 Dec;85(6):289-96. 

PMID: 12553658 

53: Bhatia R, Prabhakar S, Grover VK. 

Tetanus. 

Neurol India. 2002 Dec;50(4):398-407. 

PMID: 12577086 

54: Murck H. 


Nutr Neurosci. 2002 Dec;5(6):375-89. 

PMID: 12509067 

55: Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, 

Togari H. 

Nitric oxide further attenuates pulmonary hypertension in 

magnesium-treated piglets. 

Pediatr Int. 2002 Dec;44(6):670-4. 

PMID: 12421268 

56: Minami T, Adachi T, Fukuda K. 



Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. 

PMID: 12401602 

57: Nakatani T, Asai T. 

Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity. 

Hinyokika Kiyo. 2002 Nov;48(11):699-705. 

PMID: 12512145 

58: Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, 

Russell E, Cotton DB. 

The effect of intrapartum magnesium sulfate therapy on fetal cardiac 

troponin I levels at delivery. 

J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. 

PMID: 12607765 



628

59: Unachak K, Louthrenoo O, Katanyuwong K. 

Primary hypomagnesemia in Thai infants: a case report with 7 years 

follow-up and review of literature. 

J Med Assoc Thai. 2002 Nov;85(11):1226-31. 

PMID: 12546321 

60: Berger R, Garnier Y, Jensen A. 

Perinatal brain damage: underlying mechanisms and neuroprotective 

strategies. 

J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. 

PMID: 12445595 

61: Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. 



Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 

Feb 17. 

PMID: 12612763 

62: Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. 


South Med J. 2002 Nov;95(11):1280-7. 

PMID: 12539994 

63: Rao GN. 


Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. 

PMID: 12512864 

64: Anderson RA. 


World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. 

PMID: 12522585 

65: Paskitti M, Reid KH. 


substantially improves brain protein synthesis after global ischemia in 

rats. 


PMID: 12383918 

66: Gaby AR. 


Altern Med Rev. 2002 Oct;7(5):389-403. 

PMID: 12410623 



629

67: Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. 

Correction of ionized plasma magnesium during cardiopulmonary bypass 

reduces the risk of postoperative cardiac arrhythmia. 

Anesth Analg. 2002 Oct;95(4):828-34, table of contents. 

PMID: 12351253 

68: Davis GK, Homer CS, Brown MA. 


Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. 

PMID: 12403283 

69: Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, 

Fujinaga H, Minami H; Kansai Magnesium Study Group. 

Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. 

Pediatr Int. 2002 Oct;44(5):505-9. 

PMID: 12225549 

70: Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao 




Transplantation. 2002 Sep 27;74(6):784-91. 

PMID: 12364856 

71: Plasma exchange in severe postpartum HELLP syndrome. 


Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. 

PMID: 12190795 

72: Kantas E, Cetin A, Kaya T, Cetin M. 

Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: 

pregnant human and rat. 

Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. 

PMID: 12225296 

73: Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. 



PMID: 12198045 

74: Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. 

Intrathecal magnesium prolongs fentanyl analgesia: a prospective, 

randomized, controlled trial. 


PMID: 12198056 



630

75: Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, 

Ghini AS, Chiariello L. 

Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery 

bypass grafting. 

Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. 

PMID: 12238830 

76: Tramer MR, Glynn CJ. 



Pain. 2002 Sep;99(1-2):235-41. 

PMID: 12237201 

77: Patrick L. 

Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. 

Treatment approaches using vitamin E, magnesium, and 

betaine. 

Altern Med Rev. 2002 Aug;7(4):276-91. 

PMID: 12197781 

78: Attygalle D, Rodrigo N. 

Magnesium as first line therapy in the management of tetanus: a 

prospective study of 40 patients. 

Anaesthesia. 2002 Aug;57(8):811-7. 

PMID: 12133096 

79: Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, 

Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study 

Group. 

IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized 


Chest. 2002 Aug;122(2):489-97. 

PMID: 12171821 

80: Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. 

Effect of formulation variables on the floating properties of gastric floating drug delivery 

system. 

Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. 

PMID: 12236064 

81: van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, 

Tulleken CA, Nicolay K. 

Role of magnesium in the reduction of ischemic depolarization and lesion volume after 

experimental subarachnoid hemorrhage. 

J Neurosurg. 2002 Aug;97(2):416-22. 

PMID: 12186471 



631

82: Garcia MC, Byrd RP Jr, Roy TM. 


Tenn Med. 2002 Aug;95(8):334-6. 

PMID: 12174756 

83: Patel S, Martinez-Ripoll M, Blundell TL, Albert A. 

J Mol Biol. 2002 Jul 26;320(5):1087-94. 


PMID: 12126627 

84: Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. 

Combined systemic administration of morphine and magnesium sulfate attenuates painrelated 

behavior in mononeuropathic rats. 

Brain Res. 2002 Jul 5;943(1):101-4. 

PMID: 12088843 

85: Dagdelen S, Toraman F, Karabulut H, Alhan C. 

The value of P dispersion on predicting atrial fibrillation after coronary artery bypass 

surgery: effect of magnesium on P dispersion. 

Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. 

PMID: 12167181 

86: Streetman DD, Bhatt-Mehta V, Johnson CE. 


Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. 

PMID: 12086560 

87: Kaye P, O'Sullivan I. 


Emerg Med J. 2002 Jul;19(4):288-91. 

PMID: 12101132 

88: Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; 



population sample: findings from the Japan-China Cooperative Research 

Project. 

Hypertens Res. 2002 Jul;25(4):559-64. 

PMID: 12358141 

89: Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. 

Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver 

cirrhosis -- relation to spironolactone. 

J Intern Med. 2002 Jul;252(1):56-63. 

PMID: 12074739 



632

90: Malluche HH, Mawad H. 

Management of hyperphosphataemia of chronic kidney disease: lessons from the past and 

future directions. 


PMID: 12105237 

91: Gordin A, Goldenberg D, Golz A, Netzer A, Joachims HZ. 

Magnesium: a new therapy for idiopathic sudden sensorineural hearing 

loss. 

Otol Neurotol. 2002 Jul;23(4):447-51. 

PMID: 12170143 

92. Ozkaya O, Kalman S, Bakkaloglu S, Buyan N, Soylemezoglu O. 

Cyclosporine-associated facial paralysis in a child with renal 

transplant. 

Pediatr Nephrol. 2002 Jul;17(7):544-6. Epub 2002 Jun 18. 

PMID: 12172772 

93: Guh JY, Chen HC, Chuang HY, Huang SC, Chien LC, Lai YH. 

Risk factors and risk for mortality of mild hypoparathyroidism in hemodialysis patients. 

Am J Kidney Dis. 2002 Jun;39(6):1245-54. 

PMID: 12046038 

94: Gohda T, Shou I, Fukui M, Funabiki K, Horikoshi S, Shirato I, Tomino Y. 

Parathyroid hormone gene polymorphism and secondary hyperparathyroidism 

in hemodialysis patients. 

Am J Kidney Dis. 2002 Jun;39(6):1255-60. 

PMID: 12046039 

95: Lozo E, Riecke K, Schwabe R, Vormann J, Stahlmann R. 

Synergistic effect of ofloxacin and magnesium deficiency on joint 

cartilage in immature rats. 

Antimicrob Agents Chemother. 2002 Jun;46(6):1755-9. 

PMID: 12019086 

96: Bigal ME, Bordini CA, Speciali JG. 

Efficacy of three drugs in the treatment of migrainous aura: a 

randomized placebo-controlled study. 

Arq Neuropsiquiatr. 2002 Jun;60(2-B):406-9. 

PMID: 12131941 

97: Petridou E, Zavras AI, Lefatzis D, Dessypris N, Laskaris G, Dokianakis 

G, Segas J, Douglas CW, Diehl SR, Trichopoulos D. 

The role of diet and specific micronutrients in the etiology of oral 

carcinoma. 



633

Cancer. 2002 Jun 1;94(11):2981-8. 

PMID: 12115387 

98: Matsusaka T, Hasebe N, Jin YT, Kawabe J, Kikuchi K. 

Magnesium reduces myocardial infarct size via enhancement of adenosine 

mechanism in rabbits. 

Cardiovasc Res. 2002 Jun;54(3):568-75. 

PMID: 12031702 

99: Bigal ME, Bordini CA, Tepper SJ, Speciali JG. 

Intravenous magnesium sulphate in the acute treatment of migraine 

without aura and migraine with aura. A randomized, double-blind, placebo-controlled 

study. 

Cephalalgia. 2002 Jun;22(5):345-53. 

PMID: 12110110 

100: Advanced life support drugs: do they really work? 

Nolan JP, De Latorre FJ, Steen PA, Chamberlain DA, Bossaert LL. 

Curr Opin Crit Care. 2002 Jun;8(3):212-8. 

PMID: 12386499 

101: Morimatsu H, Uchino S, Bellomo R, Ronco C. 

Continuous veno-venous hemodiafiltration or hemofiltration: impact on 

calcium, phosphate and magnesium concentrations. 

Int J Artif Organs. 2002 Jun;25(6):512-9. 

PMID: 12117290 

102: Cho MS, Lee KS, Lee YK, Ma SK, Ko JH, Kim SW, Kim NH, Choi KC. 

Relationship between the serum parathyroid hormone and magnesium levels in 

continuous ambulatory peritoneal dialysis (CAPD) patients using 

low-magnesium peritoneal dialysate. 

Korean J Intern Med. 2002 Jun;17(2):114-21. 

PMID: 12164088 

103: Magpie Trial Collaboration Group. 

Do women with pre-eclampsia, and their babies, benefit from magnesium 

sulphate? The Magpie Trial: a randomised placebo-controlled trial. 

Lancet. 2002 Jun 1;359(9321):1877-90. 

PMID: 12057549 

104: Karapinar K, Ulus AT, Kaplan S, Tutun U, Saritas A, Aksoyek A, Apaydn N, 

Saritas Z, Katircioglu SF. 

Mg++SO4 treatment improves the hemodynamics following the acute 

myocardial ischemia and reperfusion. 

Panminerva Med. 2002 Jun;44(2):129-33. 

PMID: 12032431 



634

105: Hoane MR, Barth TM. 

The window of opportunity for administration of magnesium therapy 

following focal brain injury is 24 h but is task dependent in the rat. 

Physiol Behav. 2002 Jun 1;76(2):271-80. 

PMID: 12044600 

106: Sidani M, Campbell J. 

Gynecology: select topics. 

Prim Care. 2002 Jun;29(2):297-321, vi. 

PMID: 12391713 

107: Jaber R. 

Respiratory and allergic diseases: from upper respiratory tract 

infections to asthma. 

Prim Care. 2002 Jun;29(2):231-61. 

PMID: 12391710 

108: van der Sijs IH, Ho-Dac-Pannekeet MM. 

The treatment of hypomagnesemia. 


PMID: 12051060 

109: Pharmacokinetics of ionized versus total magnesium in subjects with 

preterm labor and preeclampsia 

Taber EB, Tan L, Chao CR, Beall MH, Ross MG 

Am J Obstet Gynecol. 2002 May;186(5):1017-21. 

PMID: 12015530 

110: Baghdadli A, Gonnier V, Aussilloux C. 

Encephale. 2002 May-Jun;28(3 Pt 1):248-54. 

Review of psychopharmacological treatments in adolescents and adults with autistic 

disorders. 

PMID: 12091786 

111: Chia RY, Hughes RS, Morgan MK. 

Magnesium: a useful adjunct in the prevention of cerebral vasospasm following 

aneurysmal subarachnoid haemorrhage. 

J Clin Neurosci. 2002 May;9(3):279-81. 

PMID: 12093134 

112: Lukaski HC, Nielsen FH. 

Dietary magnesium depletion affects metabolic responses during submaximal exercise in 

postmenopausal women. 

J Nutr. 2002 May;132(5):930-5. 

PMID: 11983816 



635

113: Toll J, Erb H, Birnbaum N, Schermerhorn T. 

Prevalence and incidence of serum magnesium abnormalities in 

hospitalized cats. 

J Vet Intern Med. 2002 May-Jun;16(3):217-21. 

PMID: 12041648 

114: Lees KR. 

Management of acute stroke. 

Lancet Neurol. 2002 May;1(1):41-50. 

PMID: 12849544 

115: Roffe C, Sills S, Crome P, Jones P. 

Randomised, cross-over, placebo controlled trial of magnesium citrate in 

the treatment of chronic persistent leg cramps. 

Med Sci Monit. 2002 May;8(5):CR326-30. 

PMID: 12011773 

116: Stoll ML, Listman JA. 

Nephrolithiasis in a neonate with transient renal wasting of calcium and 

magnesium. 

Pediatr Nephrol. 2002 May;17(5):386-9. 

PMID: 12042901 

117: Rukshin V, Shah PK, Cercek B, Finkelstein A, Tsang V, Kaul S. 

Comparative antithrombotic effects of magnesium sulfate and the platelet 

glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in a canine 

model of stent thrombosis. Circulation. 2002 Apr 23;105(16):1970-5. 

PMID: 11997285 

118: Dorsch NW. 

Therapeutic approaches to vasospasm in subarachnoid hemorrhage. 

Curr Opin Crit Care. 2002 Apr;8(2):128-33. 

PMID: 12386513 

119: van der Heyden JJ, Standley CA. 

Maternal-fetal effects of magnesium sulfate on serum osmolality in 

pre-eclampsia. 

J Matern Fetal Neonatal Med. 2002 Apr;11(4):270-4. 

PMID: 12375684 

120: Gulliksson H, AuBuchon JP, Vesterinen M, Sandgren P, Larsson S, Pickard 

CA, Herschel I, Roger J, Tracy JE, Langweiler M; Biomedical Excellence for 

Safer Transfusion Working Party of the International Society of Blood 

Transfusion. Storage of platelets in additive solutions: a pilot in vitro study of the effects 

of potassium and magnesium. 



636

Vox Sang. 2002 Apr;82(3):131-6. 

PMID: 11952987 

1: Stroke. 2003 Sep;34(9):2246-51. Epub 2003 Jul 31. 

Combination drug therapy and mild hypothermia after transient focal cerebral 

ischemia in rats. 

Zausinger S, Scholler K, Plesnila N, Schmid-Elsaesser R. 

PMID: 12893947 

2: Can J Anaesth. 2003 Aug-Sep;50(7):732-46. 

The therapeutic use of magnesium in anesthesiology, intensive care and emergency 

medicine: a review: [L'usage therapeutique du magnesium en anesthesiologie, 

reanimation et medecine d'urgence]. 

Dube L, Granry JC. 

PMID: 12944451 

3: Obstet Gynecol. 2003 Jul;102(1):181-92. 

Diagnosis and management of gestational hypertension and preeclampsia. 

Sibai BM. 

PMID: 12850627 

4: Lancet. 2003 Jun 21;361(9375):2114-7. 

Comment in: 

Lancet. 2003 Jun 21;361(9375):2095-6. 

Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in 

treatment of severe asthma in adults: randomised placebo-controlled trial. 

Hughes R, Goldkorn A, Masoli M, Weatherall M, Burgess C, Beasley R. 

PMID: 12826434 

5: Lancet. 2003 Jun 21;361(9375):2095-6. 

Comment on: 



637

Lancet. 2003 Jun 21;361(9375):2114-7. 


Bucca C, Rolla G. 

PMID: 12826427 

6: Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. 

The effects of magnesium prime solution on magnesium levels and potassium loss 

in open heart surgery. 

Jian W, Su L, Yiwu L. 

PMID: 12760983 

7: Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. 

Neuroprotection in transient focal cerebral ischemia by combination drug therapy 

and mild hypothermia: comparison with customary therapeutic regimen. 

Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. 

PMID: 12730554 

8: Ned Tijdschr Geneeskd. 2003 May 24;147(21):996-1000. 

[Nutrition and health--hypertension] 

[Article in Dutch] 

Geleijnse JM, Grobbee DE. 

PMID: 12811968 

9: Anesth Analg. 2003 May;96(5):1413-4, table of contents. 



Suresh S, Lozono S, Hall SC. 

PMID: 12707144 

10: J Am Diet Assoc. 2003 May;103(5):570-6. 



638



Sigman-Grant M, Warland R, Hsieh G. 

PMID: 12728214 

11: ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. 


Haupt H, Scheibe F, Mazurek B. 

PMID: 12925813 

12: Brain Res Bull. 2003 Apr 15;60(1-2):105-14. 

The behavioral effects of magnesium therapy on recovery of function following 

bilateral anterior medial cortex lesions in the rat. 

Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. 

PMID: 12725898 

13: Transplantation. 2003 Apr 15;75(7):1040-4. 



Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya 


PMID: 12698095 

14: Am J Clin Nutr. 2003 Apr;77(4):847-56. 




Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. 

PMID: 12663282 

15: Clin Nephrol. 2003 Apr;59(4):267-72. 



639

Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine 

(ddI) nephrotoxicity in rats. 

Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. 

PMID: 12708566 

16: Crit Care Med. 2003 Apr;31(4):1082-7. 


Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. 

PMID: 12682476 

17: Eur J Clin Nutr. 2003 Apr;57(4):554-65. 



Ilich JZ, Brownbill RA, Tamborini L. 

PMID: 12700617 

18: Heart. 2003 Apr;89(4):411-6. 



evaluation. 

Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider 


PMID: 12639869 

19: J Am Diet Assoc. 2003 Apr;103(4):488-96. 

Food group sources of nutrients in the dietary patterns of the DASH-Sodium 

trial. 

Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, Most- 

Windhauser 

MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research Group. 

PMID: 12669013 



640

20: J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. 


Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami 

H. 

PMID: 12755529 

21: J Trop Pediatr. 2003 Apr;49(2):99-103. 


Singhi SC, Singh J, Prasad R. 

PMID: 12729292 

22: Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. 

Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study 

for long term treatment. 

van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. 

PMID: 12632115 

23: Am Fam Physician. 2003 Mar 1;67(5):997-1004. 

The 'crashing astimatic.'. 

Higgins JC. 

PMID: 12643359 

24: Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. 


Roy SR, Milgrom H. 

PMID: 12562559 

25: Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. 




641

Cappell MS. 

PMID: 12635419 

26: Magnes Res. 2003 Mar;16(1):59-64. 



Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. 

PMID: 12735484 

27: Pharmacotherapy. 2003 Mar;23(3):296-300. 



Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. 

PMID: 12627926 

28: Recenti Prog Med. 2003 Mar;94(3):136-41. 

[Etiopathogenesis and clinical aspects of nephrolithiasis--at present] 

Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. 

PMID: 12677782 

29: Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. 


Touyz RM. 

PMID: 12537992 

30: Anaesthesia. 2003 Feb;58(2):131-5. 

Effect of intra-operative magnesium sulphate on pain relief and patient comfort 

after major lumbar orthopaedic surgery. 

Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. 



642

PMID: 12562408 

31: Clin Exp Hypertens. 2003 Feb;25(2):103-15. 



inhibitor. 

Pamnani MB, Bryant HJ, Clough DL, Schooley JF. 

PMID: 12611422 

32: Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. 



Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, Malinowska-Polubiec 

A, Romejko E. 

PMID: 12566182 

33: Nippon Rinsho. 2003 Feb;61(2):305-13. 

[Osteoporosis as a lifestyle-related disease] 

Hata M, Miyao M, Mizuno Y. 

PMID: 12638226 

34: Resuscitation. 2003 Feb;56(2):199-206. 



Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. 

PMID: 12589995 

35: N Engl J Med. 2003 Jan 23;348(4):304-11. 


Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. 

PMID: 12540643 



643

36: Neurosci Lett. 2003 Jan 9;336(1):41-4. 

Magnesium attenuates persistent functional deficits following diffuse traumatic 

brain injury in rats. 

Vink R, O'Connor CA, Nimmo AJ, Heath DL. 

PMID: 12493598 

37: Am J Kidney Dis. 2003 Jan;41(1):196-202. 


Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, Efrati 

S, Weissgarten J. 

PMID: 12500237 

38: Clin Exp Obstet Gynecol. 2003;30(1):32-4. 



Meram I, Balat O, Tamer L, Ugur MG. 

PMID: 12731741 

39: Cochrane Database Syst Rev. 2003;(2):CD000025. 


Duley L, Gulmezoglu AM, Henderson-Smart DJ. 

PMID: 12804383 

40: Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. 


Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. 

PMID: 12528016 

41: J Addict Dis. 2003;22(2):49-61. 



644

A preliminary, controlled investigation of magnesium L-aspartate hydrochloride 

for illicit cocaine and opiate use in methadone-maintained patients. 

Margolin A, Kantak K, Copenhaver M, Avants SK. 

PMID: 12703668 

42: J Epidemiol. 2003 Jan;13(1):48-55. 



Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. 

PMID: 12587613 

43: J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. 

[Therapeutics indications and prognosis of eclampsia at Dakar University 

Teaching Hospital] 

Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. 

PMID: 12773926 

44: Med Hypotheses. 2003 Jan;60(1):94-101. 

Magnesium may help patients with recessive hereditary inclusion body myopathy, a 

pathological review. 

Darvish D. 

PMID: 12450772 

45: Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. 

[A case of urolithiasis associated with short bowel syndrome] 

Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. 

PMID: 12638204 

46: Paediatr Anaesth. 2003 Jan;13(1):43-7. 





645

Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. 

PMID: 12535038 

47: South Med J. 2003 Jan;96(1):104. 


Byrd RP Jr, Roy TM. 

PMID: 12602735 

48: Altern Med Rev. 2002 Dec;7(6):472-99. 


management. 

Kidd PM. 

PMID: 12495373 

49: Am J Hypertens. 2002 Dec;15(12):1081-6. 

Magnesium deficiency during pregnancy in rats increases systolic blood pressure 

and plasma nitrite. 

Carlin Schooley M, Franz KB. 

PMID: 12460704 

50: Curr Hypertens Rep. 2002 Dec;4(6):477-82. 


Imazu M. 

PMID: 12419178 

51: Eur J Clin Nutr. 2002 Dec;56(12):1162-8. 



Grzybek A, Klosiewicz-Latoszek L, Targosz U. 



646

PMID: 12494300 

52: JBR-BTR. 2002 Dec;85(6):289-96. 

Optimisation of colon cleansing prior to computed tomographic colonography. 

Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. 

PMID: 12553658 

53: Neurol India. 2002 Dec;50(4):398-407. 

Tetanus. 

Bhatia R, Prabhakar S, Grover VK. 

PMID: 12577086 

54: Nutr Neurosci. 2002 Dec;5(6):375-89. 


Murck H. 

PMID: 12509067 

55: Pediatr Int. 2002 Dec;44(6):670-4. 

Nitric oxide further attenuates pulmonary hypertension in magnesium-treated 

piglets. 

Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, Togari H. 

PMID: 12421268 

56: Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. 



Minami T, Adachi T, Fukuda K. 

PMID: 12401602 

57: Hinyokika Kiyo. 2002 Nov;48(11):699-705. 



647

[Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity] 

Nakatani T, Asai T. 

PMID: 12512145 

58: J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. 

The effect of intrapartum magnesium sulfate therapy on fetal cardiac troponin I 

levels at delivery. 

Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, Russell E, 

Cotton DB. 

PMID: 12607765 

59: J Med Assoc Thai. 2002 Nov;85(11):1226-31. 

Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and 

review of literature. 

Unachak K, Louthrenoo O, Katanyuwong K. 

PMID: 12546321 

60: J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. 

Perinatal brain damage: underlying mechanisms and neuroprotective strategies. 

Berger R, Garnier Y, Jensen A. 

PMID: 12445595 

61: Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 Feb 

17. 



Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. 

PMID: 12612763 

62: South Med J. 2002 Nov;95(11):1280-7. 




648

Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. 

PMID: 12539994 

63: Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. 


Rao GN. 

PMID: 12512864 

64: World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. 


Anderson RA. 

PMID: 12522585 

65: Neurosci Lett. 2002 Oct 18;331(3):147-50. 


substantially improves brain protein synthesis after global ischemia in rats. 

Paskitti M, Reid KH. 

PMID: 12383918 

66: Altern Med Rev. 2002 Oct;7(5):389-403. 


Gaby AR. 

PMID: 12410623 

67: Anesth Analg. 2002 Oct;95(4):828-34, table of contents. 

Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the 

risk of postoperative cardiac arrhythmia. 

Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. 

PMID: 12351253 



649

68: Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. 


Davis GK, Homer CS, Brown MA. 

PMID: 12403283 

69: Pediatr Int. 2002 Oct;44(5):505-9. 

Randomized controlled trial of magnesium sulfate infusion for severe birth 

asphyxia. 

Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, Fujinaga H, 

Minami H; Kansai Magnesium Study Group. 

PMID: 12225549 

70: Transplantation. 2002 Sep 27;74(6):784-91. 



Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, 

Okamura M, Kim S, Iwao H, Miura K. 

PMID: 12364856 

71: Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. 

Plasma exchange in severe postpartum HELLP syndrome. 


PMID: 12190795 

72: Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. 

Effect of magnesium sulfate, isradipine, and ritodrine on contractions of 

myometrium: pregnant human and rat. 

Kantas E, Cetin A, Kaya T, Cetin M. 

PMID: 12225296 



650

73: Anesth Analg. 2002 Sep;95(3):606-8, table of contents. 


Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. 

PMID: 12198045 


Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, 


Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. 

PMID: 12198056 

75: Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. 

Combination of sotalol and magnesium prevents atrial fibrillation after coronary 

artery bypass grafting. 

Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, Ghini AS, 

Chiariello L. 

PMID: 12238830 

76: Pain. 2002 Sep;99(1-2):235-41. 



Tramer MR, Glynn CJ. 

PMID: 12237201 

77: Altern Med Rev. 2002 Aug;7(4):276-91. 

Nonalcoholic fatty liver disease: relationship to insulin sensitivity and 

oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. 

Patrick L. 

PMID: 12197781 

78: Anaesthesia. 2002 Aug;57(8):811-7. 



651

Magnesium as first line therapy in the management of tetanus: a prospective study 

of 40 patients. 

Attygalle D, Rodrigo N. 

PMID: 12133096 

79: Chest. 2002 Aug;122(2):489-97. 

IV magnesium sulfate in the treatment of acute severe asthma: a multicenter 

randomized controlled trial. 

Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, 

Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study Group. 

PMID: 12171821 

80: Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. 

Effect of formulation variables on the floating properties of gastric floating 

drug delivery system. 

Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. 

PMID: 12236064 

81: J Neurosurg. 2002 Aug;97(2):416-22. 

Role of magnesium in the reduction of ischemic depolarization and lesion volume 

after experimental subarachnoid hemorrhage. 

van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, Tulleken 

CA, Nicolay K. 

PMID: 12186471 

82: Tenn Med. 2002 Aug;95(8):334-6. 


Garcia MC, Byrd RP Jr, Roy TM. 

PMID: 12174756 

83: J Mol Biol. 2002 Jul 26;320(5):1087-94. 



652


Patel S, Martinez-Ripoll M, Blundell TL, Albert A. 

PMID: 12126627 

84: Brain Res. 2002 Jul 5;943(1):101-4. 

Combined systemic administration of morphine and magnesium sulfate attenuates 

pain-related behavior in mononeuropathic rats. 

Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. 

PMID: 12088843 

85: Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. 

The value of P dispersion on predicting atrial fibrillation after coronary 

artery bypass surgery: effect of magnesium on P dispersion. 

Dagdelen S, Toraman F, Karabulut H, Alhan C. 

PMID: 12167181 

86: Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. 


Streetman DD, Bhatt-Mehta V, Johnson CE. 

PMID: 12086560 

87: Emerg Med J. 2002 Jul;19(4):288-91. 


Kaye P, O'Sullivan I. 

PMID: 12101132 

88: Hypertens Res. 2002 Jul;25(4):559-64. 


population sample: findings from the Japan-China Cooperative Research Project. 



653

Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; 


PMID: 12358141 

89: J Intern Med. 2002 Jul;252(1):56-63. 

Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic 

liver cirrhosis -- relation to spironolactone. 

Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. 

PMID: 12074739 

90: Nephrol Dial Transplant. 2002 Jul;17(7):1170-5. 

Management of hyperphosphataemia of chronic kidney disease: lessons from the 

past and future directions. 

Malluche HH, Mawad H. 

PMID: 12105237 

91: Otol Neurotol. 2002 Jul;23(4):447-51. 

Magnesium: a new therapy for idiopathic sudden sensorineural hearing loss. 

Gordin A, Goldenberg D, Golz A, Netzer A, Joachims HZ. 

PMID: 12170143 

92. Pediatr Nephrol. 2002 Jul;17(7):544-6. Epub 2002 Jun 18. 

Cyclosporine-associated facial paralysis in a child with renal transplant. 

Ozkaya O, Kalman S, Bakkaloglu S, Buyan N, Soylemezoglu O. 

PMID: 12172772 

93: Am J Kidney Dis. 2002 Jun;39(6):1245-54. 

Risk factors and risk for mortality of mild hypoparathyroidism in hemodialysis 

patients. 

Guh JY, Chen HC, Chuang HY, Huang SC, Chien LC, Lai YH. 



654

PMID: 12046038 

94: Am J Kidney Dis. 2002 Jun;39(6):1255-60. 

Parathyroid hormone gene polymorphism and secondary hyperparathyroidism in 

hemodialysis patients. 

Gohda T, Shou I, Fukui M, Funabiki K, Horikoshi S, Shirato I, Tomino Y. 

PMID: 12046039 

95: Antimicrob Agents Chemother. 2002 Jun;46(6):1755-9. 

Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in 

immature rats. 

Lozo E, Riecke K, Schwabe R, Vormann J, Stahlmann R. 

PMID: 12019086 

96: Arq Neuropsiquiatr. 2002 Jun;60(2-B):406-9. 

[Efficacy of three drugs in the treatment of migrainous aura: a randomized 

placebo-controlled study] 

Bigal ME, Bordini CA, Speciali JG. 

PMID: 12131941 

97: Cancer. 2002 Jun 1;94(11):2981-8. 

The role of diet and specific micronutrients in the etiology of oral carcinoma. 

Petridou E, Zavras AI, Lefatzis D, Dessypris N, Laskaris G, Dokianakis G, Segas 

J, Douglas CW, Diehl SR, Trichopoulos D. 

PMID: 12115387 

98: Cardiovasc Res. 2002 Jun;54(3):568-75. 

Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism 

in rabbits. 

Matsusaka T, Hasebe N, Jin YT, Kawabe J, Kikuchi K. 

PMID: 12031702 



655

99: Cephalalgia. 2002 Jun;22(5):345-53. 

Intravenous magnesium sulphate in the acute treatment of migraine without aura 

and migraine with aura. A randomized, double-blind, placebo-controlled study. 

Bigal ME, Bordini CA, Tepper SJ, Speciali JG. 

PMID: 12110110 

100: Curr Opin Crit Care. 2002 Jun;8(3):212-8. 

Advanced life support drugs: do they really work? 

Nolan JP, De Latorre FJ, Steen PA, Chamberlain DA, Bossaert LL. 

PMID: 12386499 

101: Int J Artif Organs. 2002 Jun;25(6):512-9. 

Continuous veno-venous hemodiafiltration or hemofiltration: impact on calcium, 

phosphate and magnesium concentrations. 

Morimatsu H, Uchino S, Bellomo R, Ronco C. 

PMID: 12117290 

102: Korean J Intern Med. 2002 Jun;17(2):114-21. 

Relationship between the serum parathyroid hormone and magnesium levels in 

continuous ambulatory peritoneal dialysis (CAPD) patients using low-magnesium 

peritoneal dialysate. 

Cho MS, Lee KS, Lee YK, Ma SK, Ko JH, Kim SW, Kim NH, Choi KC. 

PMID: 12164088 

103: Lancet. 2002 Jun 1;359(9321):1877-90. 

Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? 

The Magpie Trial: a randomised placebo-controlled trial. 

Magpie Trial Collaboration Group. 

PMID: 12057549 



656

104: Panminerva Med. 2002 Jun;44(2):129-33. 

Mg++SO4 treatment improves the hemodynamics following the acute myocardial 

ischemia and reperfusion. 

Karapinar K, Ulus AT, Kaplan S, Tutun U, Saritas A, Aksoyek A, Apaydn N, Saritas 

Z, Katircioglu SF. 

PMID: 12032431 

105: Physiol Behav. 2002 Jun 1;76(2):271-80. 

The window of opportunity for administration of magnesium therapy following 

focal brain injury is 24 h but is task dependent in the rat. 

Hoane MR, Barth TM. 

PMID: 12044600 

106: Prim Care. 2002 Jun;29(2):297-321, vi. 

Gynecology: select topics. 

Sidani M, Campbell J. 

PMID: 12391713 

107: Prim Care. 2002 Jun;29(2):231-61. 

Respiratory and allergic diseases: from upper respiratory tract infections to 

asthma. 

Jaber R. 

PMID: 12391710 


[The treatment of hypomagnesemia] 

van der Sijs IH, Ho-Dac-Pannekeet MM. 

PMID: 12051060 

109: Am J Obstet Gynecol. 2002 May;186(5):1017-21. 



657

Pharmacokinetics of ionized versus total magnesium in subjects with preterm 

labor and preeclampsia. 

Taber EB, Tan L, Chao CR, Beall MH, Ross MG. 

PMID: 12015530 

110: Encephale. 2002 May-Jun;28(3 Pt 1):248-54. 

[Review of psychopharmacological treatments in adolescents and adults with 

autistic disorders] 

Baghdadli A, Gonnier V, Aussilloux C. 

PMID: 12091786 

111: J Clin Neurosci. 2002 May;9(3):279-81. 

Magnesium: a useful adjunct in the prevention of cerebral vasospasm following 

aneurysmal subarachnoid haemorrhage. 

Chia RY, Hughes RS, Morgan MK. 

PMID: 12093134 

112: J Nutr. 2002 May;132(5):930-5. 

Dietary magnesium depletion affects metabolic responses during submaximal 

exercise in postmenopausal women. 

Lukaski HC, Nielsen FH. 

PMID: 11983816 

113: J Vet Intern Med. 2002 May-Jun;16(3):217-21. 

Prevalence and incidence of serum magnesium abnormalities in hospitalized cats. 

Toll J, Erb H, Birnbaum N, Schermerhorn T. 

PMID: 12041648 

114: Lancet Neurol. 2002 May;1(1):41-50. 

Management of acute stroke. 



658

Lees KR. 

PMID: 12849544 

115: Med Sci Monit. 2002 May;8(5):CR326-30. 

Randomised, cross-over, placebo controlled trial of magnesium citrate in the 

treatment of chronic persistent leg cramps. 

Roffe C, Sills S, Crome P, Jones P. 

PMID: 12011773 

116: Pediatr Nephrol. 2002 May;17(5):386-9. 

Nephrolithiasis in a neonate with transient renal wasting of calcium and 

magnesium. 

Stoll ML, Listman JA. 

PMID: 12042901 

117: Circulation. 2002 Apr 23;105(16):1970-5. 

Comparative antithrombotic effects of magnesium sulfate and the platelet 

glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in a canine model of 

stent thrombosis. 

Rukshin V, Shah PK, Cercek B, Finkelstein A, Tsang V, Kaul S. 

PMID: 11997285 

118: Curr Opin Crit Care. 2002 Apr;8(2):128-33. 

Therapeutic approaches to vasospasm in subarachnoid hemorrhage. 

Dorsch NW. 

PMID: 12386513 

119: J Matern Fetal Neonatal Med. 2002 Apr;11(4):270-4. 

Maternal-fetal effects of magnesium sulfate on serum osmolality in 

pre-eclampsia. 

van der Heyden JJ, Standley CA. 



659

PMID: 12375684 

120: Vox Sang. 2002 Apr;82(3):131-6. 

Storage of platelets in additive solutions: a pilot in vitro study of the 

effects of potassium and magnesium. 

Gulliksson H, AuBuchon JP, Vesterinen M, Sandgren P, Larsson S, Pickard CA, 

Herschel I, Roger J, Tracy JE, Langweiler M; Biomedical Excellence for Safer 

Transfusion Working Party of the International Society of Blood Transfusion. 

PMID: 11952987 

121: Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. 

Neuroprotection in transient focal cerebral ischemia by combination drug therapy 

and mild hypothermia: comparison with customary therapeutic regimen. 

Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. 

PMID: 12730554 

122: Brain Res Bull. 2003 Apr 15;60(1-2):105-14. 

The behavioral effects of magnesium therapy on recovery of function following 

bilateral anterior medial cortex lesions in the rat. 

Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. 

PMID: 12725898 

123: Transplantation. 2003 Apr 15;75(7):1040-4. 



Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya 


PMID: 12698095 

124: Am J Cardiol. 2003 Mar 1;91(5):517-21. 

Effects of oral magnesium therapy on exercise tolerance, exercise-induced chest 

pain, and quality of life in patients with coronary artery disease. 

Shechter M, Bairey Merz CN, Stuehlinger HG, Slany J, Pachinger O, Rabinowitz B. 

PMID: 12615252 

125: Clin Exp Hypertens. 2003 Feb;25(2):103-15. 



inhibitor. 

Pamnani MB, Bryant HJ, Clough DL, Schooley JF. 

PMID: 12611422 



660

126: Med Hypotheses. 2003 Jan;60(1):94-101. 

Magnesium may help patients with recessive hereditary inclusion body myopathy, a 

pathological review. 

Darvish D. 

PMID: 12450772 

127: Paediatr Anaesth. 2003 Jan;13(1):43-7. 



Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. 

Department of Anaesthesia, Inonu University School of Medicine, Turkey. 

PMID: 12535038 

128: South Med J. 2003 Jan;96(1):104. 


Byrd RP Jr, Roy TM. 

PMID: 12602735 

129: Brain Res. 2002 Nov 15;955(1-2):133-7. 

Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in 

hypoxia-ischemia. 

Turkyilmaz C, Turkyilmaz Z, Atalay Y, Soylemezoglu F, Celasun B. 

PMID: 12419529 

130: Transplantation. 2002 Sep 27;74(6):784-91. 



Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, 

Okamura M, Kim S, Iwao H, Miura K. 

PMID: 12364856 


Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, 


Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. 

PMID: 12198056 

132: Am J Hypertens. 2002 Aug;15(8):691-6. 

The effect of magnesium supplementation on blood pressure: a meta-analysis of 

randomized clinical trials. 

Jee SH, Miller ER 3rd, Guallar E, Singh VK, Appel LJ, Klag MJ. 

PMID: 12160191 

133: Thorac Cardiovasc Surg. 2002 Aug;50(4):208-15. 

Initial reperfusion with magnesium after cardioplegic arrest attenuates 

myocardial reperfusion injury. 



661

Fuchs F, Messmer K, Kuppe H, Habazettl H. 

PMID: 12165870 

134: Cardiovasc Res. 2002 Jun;54(3):568-75. 

Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism 

in rabbits. 

Matsusaka T, Hasebe N, Jin YT, Kawabe J, Kikuchi K. 

PMID: 12031702 

135: Physiol Behav. 2002 Jun 1;76(2):271-80. 

The window of opportunity for administration of magnesium therapy following 

focal brain injury is 24 h but is task dependent in the rat. 


PMID: 12044600 


[The treatment of hypomagnesemia] 

van der Sijs IH, Ho-Dac-Pannekeet MM. 

PMID: 12051060 

137: Eur J Pharmacol. 2002 May 10;442(3):241-50. 

Dietary Mg(2+) supplementation restores impaired vasoactive responses in 

isolated rat aorta induced by chronic ethanol consumption. 

Brown RA, Ilg KJ, Chen AF, Ren J. 

PMID: 12065078 

138: Eur J Clin Nutr. 2002 May;56(5):409-14. 

Dietary magnesium intake in type 2 diabetes. 

Walti MK, Zimmermann MB, Spinas GA, Jacob S, Hurrell RF. 

PMID: 12001011 

139: J Nutr. 2002 May;132(5):930-5. 

Dietary magnesium depletion affects metabolic responses during submaximal 

exercise in postmenopausal women. 

Lukaski HC, Nielsen FH. 

PMID: 11983816 

140: Am J Clin Nutr. 2002 Mar;75(3):550-4. 

Low dietary magnesium increases supraventricular ectopy. 

Klevay LM, Milne DB. 

PMID: 11864862 

141: Magnes Res. 2002 Mar;15(1-2):27-36. 

Therapeutic effect of parenteral magnesium on noise-induced hearing loss in the 

guinea pig. 

Scheibe F, Haupt H, Ising H, Cherny L. 



662

PMID: 12030420 

142: Med Hypotheses. 2002 Mar;58(3):213-20. 

Unexpected benefit of sorbitol placebo in Mg intervention study of premenstrual 

symptoms: implications for choice of placebo in RCTs. 

Walker AF, De Souza MC, Marakis G, Robinson PA, Morris AP, Bolland KM. 

PMID: 12018972 

143: Ann Pharmacother. 2002 Feb;36(2):255-60. 

High-dose oral magnesium treatment of chronic, intractable erythromelalgia. 

Cohen JS. 

PMID: 11847944 

144: Am J Epidemiol. 2002 Jan 15;155(2):125-31. 

Dietary magnesium, potassium, sodium, and children's lung function. 

Gilliland FD, Berhane KT, Li YF, Kim DH, Margolis HG. 

PMID: 11790675 

145: Am J Hypertens. 2002 Jan;15(1 Pt 1):10-5. 

Magnesium infusion improves endothelium-dependent vasodilation in the human 

forearm. 

Haenni A, Johansson K, Lind L, Lithell H. 

PMID: 11824853 

146: Ann Thorac Surg. 2002 Jan;73(1):112-8. 

Magnesium-supplemented warm blood cardioplegia in patients undergoing coronary 

artery revascularization. 

Yeatman M, Caputo M, Narayan P, Lotto AA, Ascione R, Bryan AJ, Angelini GD. 

PMID: 11833996 

147: Asia Pac J Clin Nutr. 2002;11(4):268-73. 

Impact of supplementary high calcium milk with additional magnesium on 

parathyroid hormone and biochemical markers of bone turnover in postmenopausal 

women. 

Green JH, Booth C, Bunning R. 

PMID: 12495258 

148: J Nutr Health Aging. 2002;6(2):147-53. 

Magnesium and trace elements in the elderly: intake, status and recommendations. 

Vaquero MP. 

PMID: 12166371 

149: Pediatr Cardiol. 2002 Jan-Feb;23(1):41-8. Epub 2002 Feb 19. 

Studies of magnesium in congenital long QT syndrome. 

Hoshino K, Ogawa K, Hishitani T, Kitazawa R. 

PMID: 11922507 



663

150: Prog Cardiovasc Dis. 2002 Jan-Feb;44(4):267-74. 

The importance of effect mechanism in the design and interpretation of clinical 

trials: the role of magnesium in acute myocardial infarction. 

Woods KL, Abrams K. 

PMID: 12007082 

151: Metabolism. 2001 Dec;50(12):1409-17. 

Magnesium reduces insulin-stimulated glucose uptake and serum lipid 

concentrations in type 1 diabetes. 

Djurhuus MS, Klitgaard NA, Pedersen KK, Blaabjerg O, Altura BM, Altura BT, 

Henriksen JE. 

PMID: 11735085 

152: South Med J. 2001 Dec;94(12):1195-201. 


Fox C, Ramsoomair D, Carter C. 

PMID: 11811859 

153: Arch Cardiol Mex. 2001 Oct-Dec;71(4):335-44. 

[Magnesium in the treatment of acute myocardial infarction. Review and 

controversies] 

Juarez U, Antman EM. 

PMID: 11806038 

154: Magnes Res. 2001 Sep;14(3):173-9. 

Mechanisms of action of the anti-atherogenic effect of magnesium: lessons from a 

mouse model. 

Sherer Y, Bitzur R, Cohen H, Shaish A, Varon D, Shoenfeld Y, Harats D. 

PMID: 11599549 

155: Magnes Res. 2001 Sep;14(3):211-6. 

Dietary intakes of Mg, Ca and P with whole-day food rations from Cracovie, Lodz, 

Olsztyn and Poznan, Poland. 

Skibniewska KA. 

PMID: 11599554 

156: J Nutr. 2001 Jul;131(7):1875-8. 

Dairy food consumption, blood pressure and stroke. 

Massey LK. 

PMID: 11435500 

157: Ann N Y Acad Sci. 2001 Jun;939:271-82. 

Non-pharmacologic (physiologic) neuroprotection in the treatment of brain 

ischemia. 

Auer RN. 



664

PMID: 11462780 

158: Blood Coagul Fibrinolysis. 2001 Jun;12(4):223-8. 

Intravenous magnesium does not influence the activity of the coagulation 

cascade. 

Ravn HB, Lassen JF, Bergenhem N, Kristensen AT. 

PMID: 11460004 

159: Nutr Metab Cardiovasc Dis. 2001 Jun;11(3):158-67. 

Diet enrichment with calcium and magnesium enhances the cholesterol-lowering 

effect of plant sterols in obese Zucker rats. 

Vaskonen T, Mervaala E, Seppanen-Laakso T, Karppanen H. 

PMID: 11590991 

160: Indian J Pediatr. 2001 May;68(5):417-9. 

Neuronal protection with magnesium. 

Gathwala G. 

PMID: 11407156 

161: Magnes Res. 2001 Mar;14(1-2):51-63. 

The behavioral and anatomical effects of MgCl2 therapy in an electrolytic lesion 

model of cortical injury in the rat. 


PMID: 11300622 

162: Cerebrovasc Dis. 2001;11(1):44-50. 

Effect of nicardipine and magnesiumon cerebral infarction - brain surface 

perfusion technique. 

Mikami C, Suzuki M, Tsuiki K, Ogawa A. 

PMID: 11173793 

163: CNS Drugs. 2001;15(12):921-30. 

Magnesium for neuroprotection in ischaemic stroke: rationale for use and 

evidence of effectiveness. 

Muir KW. 

PMID: 11735612 

164: Crit Care Clin. 2001 Jan;17(1):155-73, viii. 

Hypomagnesemic disorders. 

Dacey MJ. 

PMID: 11219227 

165: J Nutr Health Aging. 2001;5(4):253-5. 

Dietary intake of calcium, magnesium and phosphorus in an elderly population 

using duplicate diet sampling vs food composition tables. 

Moreno-Torres R, Ruiz-Lopez MD, Artacho R, Oliva P, Baena F, Baro L, Lopez C. 



665

PMID: 11753488 

166: Magnes Res. 2000 Dec;13(4):233-7. 

Effect of magnesium on fibrin formation from lower molecular weight (LMW) 

fibrinogen. 

Lipinski B, Lipinska I. 

PMID: 11153893 

167: Magnes Res. 2000 Dec;13(4):275-84. 

Beneficial antithrombotic effects of the association of pharmacological oral 

magnesium therapy with aspirin in coronary heart disease patients. 

Shechter M, Merz CN, Paul-Labrador M, Meisel SR, Rude RK, Molloy MD, Dwyer JH, 

Shah PK, Kaul S. 

PMID: 11153897 

168: Magnes Res. 2000 Dec;13(4):265-73. 

Cerebral palsy and experimental hypoxia-induced perinatal brain injury: is 

magnesium protective? 

Oorschot DE. 

PMID: 11153896 

169: Magnes Res. 2000 Dec;13(4):249-64. 

Long-term excessive magnesium supplementation is deleterious whereas suboptimal 

supply is beneficial for bones in rats. 

Riond JL, Hartmann P, Steiner P, Ursprung R, Wanner M, Forrer R, Spichiger UE, 

Thomsen JS, Mosekilde L. 

PMID: 11153895 

170: Circulation. 2000 Nov 7;102(19):2353-8. 

Oral magnesium therapy improves endothelial function in patients with coronary 

artery disease. 

Shechter M, Sharir M, Labrador MJ, Forrester J, Silver B, Bairey Merz CN. 

PMID: 11067788 

171: Eur J Neurol. 2000 Nov;7(6):741-4. 

The effect of magnesium oral therapy on spasticity in a patient with multiple 

sclerosis. 

Rossier P, van Erven S, Wade DT. 

PMID: 11136367 

172: J Cardiothorac Vasc Anesth. 2000 Oct;14(5):524-30. 

Postoperative atrial tachyarrhythmias in patients undergoing coronary artery 

bypass graft surgery without cardiopulmonary bypass: a role for intraoperative 

magnesium supplementation. 

Maslow AD, Regan MM, Heindle S, Panzica P, Cohn WE, Johnson RG. 

PMID: 11052432 



666

173: Magnes Res. 2000 Sep;13(3):197-203. 

Are low magnesium levels in type 1 diabetes associated with electromyographical 

signs of polyneuropathy? 

Engelen W, Bouten A, De Leeuw I, De Block C. 

PMID: 11008927 

174: Med Hypotheses. 2000 Sep;55(3):263-5. 

Magnesium and potassium supplementation in the prevention of diabetic vascular 

disease. 

Whang R, Sims G. 

PMID: 10985921 

175: J Acoust Soc Am. 2000 Jul;108(1):453-6. 

The role of magnesium in the susceptibility of soldiers to noise-induced hearing 

loss. 

Walden BE, Henselman LW, Morris ER. 

PMID: 10923909 

176: Neuroepidemiology. 2000 Jul-Aug;19(4):210-6. 

Dietary intake of calcium, magnesium and antioxidants in relation to risk of 

amyotrophic lateral sclerosis. 

Longnecker MP, Kamel F, Umbach DM, Munsat TL, Shefner JM, Lansdell LW, Sandler 

DP. 

PMID: 10859501 

177: Thromb Res. 2000 Jul 1;99(1):61-9. 

Intravenously and topically applied magnesium in the prevention of arterial 

thrombosis. 

Toft G, Ravn HB, Hjortdal VE. 

PMID: 10904104 

178: J Am Coll Nutr. 2000 Jun;19(3):374-82. 

Magnesium status and parameters of the oxidant-antioxidant balance in patients 

with chronic fatigue: effects of supplementation with magnesium. 

Manuel y Keenoy B, Moorkens G, Vertommen J, Noe M, Neve J, De Leeuw I. 

PMID: 10872900 

179: Psychopharmacology (Berl). 2000 Jun;150(2):220-5. 

The effects of an oral multivitamin combination with calcium, magnesium, and 

zinc on psychological well-being in healthy young male volunteers: a 

double-blind placebo-controlled trial. 

Carroll D, Ring C, Suter M, Willemsen G. 

PMID: 10907676 

180: Med Pregl. 2000 May-Jun;53(5-6):319-24. 



667

[Magnesium in cardiology] 

Topalov V, Kovacevic D, Topalov A, Kovacevic D. 

PMID: 11089379 

181: Am Heart J. 2000 Apr;139(4):703. 

Benefits of magnesium in acute myocardial infarction: timing is crucial. 

Gyamlani G, Parikh C, Kulkarni AG. 

PMID: 10740162 

182: J Womens Health Gend Based Med. 2000 Mar;9(2):131-9. 

A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 

50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: a 

randomized, double-blind, crossover study. 

De Souza MC, Walker AF, Robinson PA, Bolland K. 

PMID: 10746516 

183: Pathobiology. 2000 Mar-Apr;68(2):93-8. 

Suppression of atherogenesis in female low-density lipoprotein receptor knockout 

mice following magnesium fortification of drinking water: the importance of 

diet. 

Sherer Y, Shoenfeld Y, Shaish A, Levkovitz H, Bitzur R, Harats D. 

PMID: 10878506 

184: Psychiatry Res. 2000 Feb 14;93(1):83-7. 

Magnesium oxide augmentation of verapamil maintenance therapy in mania. 

Giannini AJ, Nakoneczie AM, Melemis SM, Ventresco J, Condon M. 

PMID: 10699232 

185: Eur Arch Otorhinolaryngol. 2000;257(7):355-61. 

Preventive magnesium supplement reduces ischemia-induced hearing loss and blood 

viscosity in the guinea pig. 

Scheibe F, Haupt H, Vlastos GA. 

PMID: 11052244 

186: Gynecol Obstet Invest. 2000;49(4):231-5. 

Comparison of magnesium and methyldopa for the control of blood pressure in 

pregnancies complicated with hypertension. 

Rudnicki M, Frolich A, Pilsgaard K, Nyrnberg L, Moller M, Sanchez M, 

Fischer-Rasmussen W. 

PMID: 10828704 

187: J Intern Med. 2000 Jan;247(1):78-86. 

Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects 

of magnesium supplementation. 

Ceremuzynski L, Gebalska J, Wolk R, Makowska E. 

PMID: 10672134 



668

188: Wien Med Wochenschr. 2000;150(15-16):335-41. 

Interrelationship of magnesium and congestive heart failure. 

Seelig MS. 

PMID: 11105329 


[Magnesium in coronary artery disease--is there evidence?] 

Kiss K, Stuhlinger HG, Glogar HD, Smetana R. 

PMID: 11105327 


[Significance of magnesium in cardiac arrhythmias] 

Stuhlinger HG, Kiss K, Smetana R. 

PMID: 11105328 


The role of magnesium as antithrombotic therapy. 

Shechter M. 

PMID: 11105330 

192: J Hum Hypertens. 1999 Nov;13(11):777-80. 

Effect of a mineral salt diet on 24-h blood pressure monitoring in elderly 

hypertensive patients. 

Katz A, Rosenthal T, Maoz C, Peleg E, Zeidenstein R, Levi Y. 

PMID: 10578223 

193: J Neurosci Res. 1999 Nov 1;58(3):442-8. 

Mexiletine and magnesium independently, but not combined, protect against 

permanent focal cerebral ischemia in Wistar rats. 

Lee EJ, Ayoub IA, Harris FB, Hassan M, Ogilvy CS, Maynard KI. 

PMID: 10518118 

194: Panteleeva GP, Bondar' VV, Krasnikova NI, Raiushkin VA. 

[Cerebrolysin and magnesium-B6 in the treatment of side effects of psychotropic 

drugs] 

Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(1):37-41. Russian. 

PMID: 11530457 

195: Kawasaki T, Itoh K, Kawasaki M. 

Reduction in blood pressure with a sodium-reduced, potassium- and 

magnesium-enriched mineral salt in subjects with mild essential hypertension. 

Hypertens Res. 1998 Dec;21(4):235-43. 

PMID: 9877516 

196: Durlach J, Bac P, Bara M, Guiet-Bara A. 



669

Is the pharmacological use of intravenous magnesium before preterm 

cerebroprotective or deleterious for premature infants? Possible importance of 

the use of magnesium sulphate. 

Magnes Res. 1998 Dec;11(4):323-5. Review. 

PMID: 9884990 

197: van den Broek FA, Beynen AC. 

The influence of dietary phosphorus and magnesium concentrations on the calcium 

content of heart and kidneys of DBA/2 and NMRI mice. 

Lab Anim. 1998 Oct;32(4):483-91. 

PMID: 9807763 

198: Ascherio A, Rimm EB, Hernan MA, Giovannucci EL, Kawachi I, Stampfer MJ, 

Willett WC. 

Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US 

men. 

Circulation. 1998 Sep 22;98(12):1198-204. 

PMID: 9743511 

199: Ram L, Schonewille JT, Martens H, Van't Klooster AT, Beynen AC. 

Magnesium absorption by wethers fed potassium bicarbonate in combination with 

different dietary magnesium concentrations. 

J Dairy Sci. 1998 Sep;81(9):2485-92. 

PMID: 9785240 

200: Fonseca FA, Paiva TB, Silva EG, Ihara SS, Kasinski N, Martinez TL, Filho EE. 

Dietary magnesium improves endothelial dependent relaxation of balloon injured 

arteries in rats. 

Atherosclerosis. 1998 Aug;139(2):237-42. 

PMID: 9712329 

201: Zorbas YG, Kakurin AG, Kuznetsov NK, Federov MA, Yaroshenko YY. 

Magnesium loading effect on magnesium deficiency in endurance-trained subjects 

during prolonged restriction of muscular activity. 

Biol Trace Elem Res. 1998 Aug;63(2):149-66. 

PMID: 9823441 

202: Kawano Y, Matsuoka H, Takishita S, Omae T. 

Effects of magnesium supplementation in hypertensive patients: assessment by 

office, home, and ambulatory blood pressures. 

Hypertension. 1998 Aug;32(2):260-5. 

PMID: 9719052 

203: Garcia LA, Dejong SC, Martin SM, Smith RS, Buettner GR, Kerber RE. 

Magnesium reduces free radicals in an in vivo coronary occlusion-reperfusion 



670

model. 

J Am Coll Cardiol. 1998 Aug;32(2):536-9. 

PMID: 9708488 

204: Dimai HP, Porta S, Wirnsberger G, Lindschinger M, Pamperl I, Dobnig H, 

Wilders-Truschnig M, Lau KH. 

Daily oral magnesium supplementation suppresses bone turnover in young adult 

males. 

J Clin Endocrinol Metab. 1998 Aug;83(8):2742-8. 

PMID: 9709941 

205: Hornyak M, Voderholzer U, Hohagen F, Berger M, Riemann D. 

Magnesium therapy for periodic leg movements-related insomnia and restless legs 

syndrome: an open pilot study. 

Sleep. 1998 Aug 1;21(5):501-5. 

PMID: 9703590 

206: Ramirez JE, Alvarez EG, Montano M, Shen Y, Zinn RA. 

Influence of dietary magnesium level on growth-performance and metabolic 

responses of Holstein steers to laidlomycin propionate. 

J Anim Sci. 1998 Jul;76(7):1753-9. 

PMID: 9690629 

207: Serebruany VL, Atar D, Dalesandro MR, O'Connor CM, Gurbel PA. 

Changes in hemostasis after parenteral magnesium in myocardial 

ischemia-reperfusion: from animal studies to clinical trials. 

Magnes Res. 1998 Jun;11(2):133-40. Review. 

PMID: 9675757 

208: Seelig MS, Elin RJ, Antman EM. 

Magnesium in acute myocardial infarction: still an open question. 

Can J Cardiol. 1998 May;14(5):745-9. Review. 

PMID: 9627532 

209: Lima Mde L, Cruz T, Pousada JC, Rodrigues LE, Barbosa K, Cangucu V. 

The effect of magnesium supplementation in increasing doses on the control of 

type 2 diabetes. 

Diabetes Care. 1998 May;21(5):682-6. 

PMID: 9589224 

210: Ahn EK, Bai SJ, Cho BJ, Shin YS. 

The infusion rate of mivacurium and its spontaneous neuromuscular recovery in 

magnesium-treated parturients. 

Anesth Analg. 1998 Mar;86(3):523-6. 

PMID: 9495406 



671

211: Ichikawa S. 

[Magnesium and calcium changes in serum and atrial muscle caused by open heart 

surgery and the effect of preoperative oral magnesium administration] 

Jpn J Thorac Cardiovasc Surg. 1998 Mar;46(3):287-98. Japanese. 

PMID: 9584479 

212: Muir KW. 

New experimental and clinical data on the efficacy of pharmacological magnesium 

infusions in cerebral infarcts. 

Magnes Res. 1998 Mar;11(1):43-56. Review. 

PMID: 9595548 

213: Schindler R, Thoni H, Classen HG. 

The role of magnesium in the generation and therapy of benign muscle cramps. 

Combined in-vivo/in-vitro studies on rat phrenic nerve-diaphragm preparations. 

Arzneimittelforschung. 1998 Feb;48(2):161-6. 

PMID: 9541727 

214: Yang CY, Cheng MF, Tsai SS, Hsieh YL. 

Calcium, magnesium, and nitrate in drinking water and gastric cancer mortality. 

Jpn J Cancer Res. 1998 Feb;89(2):124-30. 

PMID: 9548438 

215: McCord JK, Borzak S, Davis T, Gheorghiade M. 

Usefulness of intravenous magnesium for multifocal atrial tachycardia in 

patients with chronic obstructive pulmonary disease. 

Am J Cardiol. 1998 Jan 1;81(1):91-3. 

PMID: 9462615 

216: Ford ES. 

Race, education, and dietary cations: findings from the Third National Health 

And Nutrition Examination Survey. 

Ethn Dis. 1998 Winter;8(1):10-20. 

PMID: 9595243 

217: Harari M, Barzillai R, Shani J. 

Magnesium in the management of asthma: critical review of acute and chronic 

treatments, and Deutsches Medizinisches Zentrum's (DMZ's) clinical experience at 

the Dead Sea. 

J Asthma. 1998;35(7):525-36. Review. 

PMID: 9777879 

218: Bren A, Kmetec A, Kveder R, Kaplan-Pavlovcic S. 

Magnesium hydrogen carbonate natural mineral water enriched with K(+)-citrate 

and vitamin B6 improves urinary abnormalities in patients with calcium oxalate 

nephrolithiasis. 



672

Urol Int. 1998;60(2):105-7. 

PMID: 9563149 

219: Ravn HB, Kristensen SD, Hjortdal VE, Thygesen K, Husted SE. 

Early administration of intravenous magnesium inhibits arterial thrombus 

formation. 

Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3620-5. 

PMID: 9437213 

220: Galan P, Preziosi P, Durlach V, Valeix P, Ribas L, Bouzid D, Favier A, 

Hercberg S. 

Dietary magnesium intake in a French adult population. 

Magnes Res. 1997 Dec;10(4):321-8. 

PMID: 9513928 

221: Kummerow FA, Mahfouz M, Zhou Q. 

Cholesterol metabolism in human umbilical arterial endothelial cells cultured 

in low magnesium media. 


PMID: 9513931 

222: Itoh K, Kawasaka T, Nakamura M. 

The effects of high oral magnesium supplementation on blood pressure, serum 

lipids and related variables in apparently healthy Japanese subjects. 

Br J Nutr. 1997 Nov;78(5):737-50. 

PMID: 9389897 

223: Iannello S, Prestipino M, Cavalleri A, Spina S, Belfiore F. 

[Precordial discomfort and ECG changes of repolarization associated with 

hypomagnesemia in a young women following colectomy for diffuse colonic 

lipomatosis] 

Minerva Cardioangiol. 1997 Nov;45(11):581-6. Review. Italian. 

PMID: 9549292 

224: Faintuch JJ, Menezes MS. 

[Magnesium and myocardial infarction. Brazilian aspects] 

Rev Hosp Clin Fac Med Sao Paulo. 1997 Nov-Dec;52(6):333-6. Review. Portuguese. 

PMID: 9629745 

225: Hill J, Micklewright A, Lewis S, Britton J. 

Investigation of the effect of short-term change in dietary magnesium intake in 

asthma. 

Eur Respir J. 1997 Oct;10(10):2225-9. 

PMID: 9387944 

226: De Franceschi L, Bachir D, Galacteros F, Tchernia G, Cynober T, Alper S, 



673

Platt O, Beuzard Y, Brugnara C. 

Oral magnesium supplements reduce erythrocyte dehydration in patients with 

sickle cell disease. 

J Clin Invest. 1997 Oct 1;100(7):1847-52. 

PMID: 9312186 

227: Chugh SN, Kolley T, Kakkar R, Chugh K, Sharma A. 

A critical evaluation of anti-peroxidant effect of intravenous magnesium in 

acute aluminium phosphide poisoning. 

Magnes Res. 1997 Sep;10(3):225-30. 

PMID: 9483483 

228: Sasaki R, Hirota K, Nakamaru K, Masuda A, Satone T, Ito Y. 

[Influence of fluid replacement on serum magnesium concentration and proper 

magnesium supplementation during general anesthesia] 

Masui. 1997 Sep;46(9):1179-85. Japanese. 

PMID: 9311207 

229: Altura BM, Gebrewold A, Zhang A, Altura BT, Gupta RK. 

Short-term reduction in dietary intake of magnesium causes deficits in brain 

intracellular free Mg2+ and [H+]i but not high-energy phosphates as observed by 

in vivo 31P-NMR. 

Biochim Biophys Acta. 1997 Aug 21;1358(1):1-5. 

PMID: 9296515 

230: De Franceschi L, Brugnara C, Beuzard Y. 

Dietary magnesium supplementation ameliorates anemia in a mouse model of 

beta-thalassemia. 

Blood. 1997 Aug 1;90(3):1283-90. 

PMID: 9242563 

231: Haberl R. 

[Medicamentous anti-arrhythmia therapy. Is oral adjuvant therapy with 

electrolytes of value?] 

Herz. 1997 Jun;22 Suppl 1:77-80. Review. German. 

PMID: 9333595 

232: Zehender M, Meinertz T, Just H. 

[Magnesium deficiency and magnesium substitution. Effect on ventricular cardiac 

arrhythmias of various etiology] 


PMID: 9333593 

233: Vester EG. 

[Clinico-electrophysiologic effects of magnesium, especially in 

supraventricular tachycardia] 



674


PMID: 9333591 

234: McCully JD, Levitsky S. 

Mechanisms of in vitro cardioprotective action of magnesium on the aging 

myocardium. 


PMID: 9368237 

235: Soldatovic D, Vujanovic D, Matovic V, Plamenac Z. 

Compared effects of high oral Mg supplements and of EDTA chelating agent on 

chronic lead intoxication in rabbits. 

Magnes Res. 1997 Jun;10(2):127-33. 

PMID: 9368233 

236: Starobrat-Hermelin B, Kozielec T. 

The effects of magnesium physiological supplementation on hyperactivity in 

children with attention deficit hyperactivity disorder (ADHD). Positive response 

to magnesium oral loading test. 

Magnes Res. 1997 Jun;10(2):149-56. 

PMID: 9368236 

237: Zehender M, Meinertz T, Faber T, Caspary A, Jeron A, Bremm K, Just H. 

Antiarrhythmic effects of increasing the daily intake of magnesium and 

potassium in patients with frequent ventricular arrhythmias. Magnesium in 

Cardiac Arrhythmias (MAGICA) Investigators. 

J Am Coll Cardiol. 1997 Apr;29(5):1028-34. 

PMID: 9120155 

238: Lichodziejewska B, Klos J, Rezler J, Grudzka K, Dluzniewska M, Budaj A, 

Ceremuzynski L. 

Clinical symptoms of mitral valve prolapse are related to hypomagnesemia and 

attenuated by magnesium supplementation. 

Am J Cardiol. 1997 Mar 15;79(6):768-72. 

PMID: 9070556 

239: Mervaala EM, Pere AK, Lindgren L, Laakso J, Teravainen TL, Karjala K, 

Vapaatalo H, Ahonen J, Karppanen H. 

Effects of dietary sodium and magnesium on cyclosporin A-induced hypertension 

and nephrotoxicity in spontaneously hypertensive rats. 

Hypertension. 1997 Mar;29(3):822-7. 

PMID: 9052902 

240: Matkovics B, Kiss I, Kiss SA. 

The activation by magnesium treatment of anti-oxidants eliminating the oxygen 

free radicals in Drosophila melanogaster in vivo. 



675

Magnes Res. 1997 Mar;10(1):33-8. 

PMID: 9339836 

241: Nilsson CG, Lagerlof H. 

[Forced fibrinolysis causes damage to the myocardium. Magnesium therapy is 

considerate in myocardial infarction] 

Lakartidningen. 1997 Jan 15;94(3):148-50. Review. Swedish. 

PMID: 9053633 

242: Davis M, Perry RH, Mendelow AD. 

The effect of non-competitive N-methyl-D-aspartate receptor antagonism on 

cerebral oedema and cerebral infarct size in the aging ischaemic brain. 

Acta Neurochir Suppl (Wien). 1997;70:30-3. 

PMID: 9416269 

243: Bar-Dayan Y, Shoenfeld Y. 

Magnesium fortification of water. A possible step forward in preventive 

medicine? 

Ann Med Interne (Paris). 1997;148(6):440-4. Review. 

PMID: 9538378 

244: Alavalkama K. 

[Who forgot magnesium] 

Duodecim. 1997;113(8):767. Finnish. 

PMID: 11466877 

245: Mervaala E. 

[Magnesium, an electrolyte worth noticing] 

Duodecim. 1997;113(2):97-8. Finnish. 

PMID: 11370049 

246: Marx A, Neutra RR. 

Magnesium in drinking water and ischemic heart disease. 

Epidemiol Rev. 1997;19(2):258-72. Review. 

PMID: 9494787 

247: Lopez Martinez J, Sanchez Castilla M, Garcia de Lorenzo y Mateos A, 

Culebras Fernandez JM. 

[Magnesium: metabolism and requirements] 

Nutr Hosp. 1997 Jan-Feb;12(1):4-14. Review. Spanish. 

PMID: 9147537 

248: Benzer W. 

[Significance of supraphysiologic administration of magnesium after myocardial 

infarct] 

Wien Klin Wochenschr Suppl. 1997;2:38-41. Review. German. 



676

PMID: 9340922 

249: Sanjuliani AF, de Abreu Fagundes VG, Francischetti EA. 

Effects of magnesium on blood pressure and intracellular ion levels of 

Brazilian hypertensive patients. 

Int J Cardiol. 1996 Oct 11;56(2):177-83. 

PMID: 8894790 

250: Kolev ST, Leman P, Kite GC, Stevenson PC, Shaw D, Murray VS. 

Toxicity following accidental ingestion of Aconitum containing Chinese remedy. 

Hum Exp Toxicol. 1996 Oct;15(10):839-42. 

PMID: 8906434 

251: Kimura Y, Murase M, Nagata Y. 

Change in glucose homeostasis in rats by long-term magnesium-deficient diet. 


PMID: 8981248 

252: Gawaz M. 

[Antithrombocytic effectiveness of magnesium] 

Fortschr Med. 1996 Sep 20;114(26):329-32. Review. German. 

PMID: 8999005 

253: Shils ME, Rude RK. 

Deliberations and evaluations of the approaches, endpoints and paradigms for 

magnesium dietary recommendations. 

J Nutr. 1996 Sep;126(9 Suppl):2398S-2403S. 

PMID: 8811804 

254: Arsenian MA, New PS, Cafasso CM. 

Safety, tolerability, and efficacy of a 

glucose-insulin-potassium-magnesium-carnitine solution in acute myocardial 

infarction. 

Am J Cardiol. 1996 Aug 15;78(4):477-9. 

PMID: 8752197 

255: Gilleran G, O'Leary M, Bartlett WA, Vinall H, Jones AF, Dodson PM. 

Effects of dietary sodium substitution with potassium and magnesium in 

hypertensive type II diabetics: a randomised blind controlled parallel study. 

J Hum Hypertens. 1996 Aug;10(8):517-21. 

PMID: 8895035 

256: Peikert A, Wilimzig C, Kohne-Volland R. 

Prophylaxis of migraine with oral magnesium: results from a prospective, 

multi-center, placebo-controlled and double-blind randomized study. 

Cephalalgia. 1996 Jun;16(4):257-63. 



677

PMID: 8792038 

257: Geleijnse JM, Witteman JC, den Breeijen JH, Hofman A, de Jong PT, Pols HA, 

Grobbee DE. 

Dietary electrolyte intake and blood pressure in older subjects: the Rotterdam 

Study. 

J Hypertens. 1996 Jun;14(6):737-41. 

PMID: 8793696 

258: Ravn HB, Vissinger H, Kristensen SD, Wennmalm A, Thygesen K, Husted SE. 

Magnesium inhibits platelet activity--an infusion study in healthy volunteers. 

Thromb Haemost. 1996 Jun;75(6):939-44. 

PMID: 8822590 

259: Roth A, Kornowski R, Agmon Y, Vardinon N, Sheps D, Graph E, Burke M, 

Laniado 

S, Yust I. 

High-dose intravenous magnesium attenuates complement consumption after acute 

myocardial infarction treated by streptokinase. 

Eur Heart J. 1996 May;17(5):709-14. 

PMID: 8737101 

260: Singh RB, Singh NK, Niaz MA, Sharma JP. 

Effect of treatment with magnesium and potassium on mortality and reinfarction 

rate of patients with suspected acute myocardial infarction. 

Int J Clin Pharmacol Ther. 1996 May;34(5):219-25. 

PMID: 8738859 

261: Dietch D, Wilson A, Thomas A. 

Magnesium is underused in acute atrial fibrillation. 

BMJ. 1996 Apr 27;312(7038):1101. 

PMID: 8616439 

262: Navas FJ, Cordova A. 

Effect of magnesium supplementation and training on magnesium tissue 

distribution in rats. 

Biol Trace Elem Res. 1996 Summer;53(1-3):137-45. Erratum in: Biol Trace Elem Res 

1996 Oct-Nov;55(1-2):213. 

PMID: 8862744 

263: Martyka Z, Kotela I, Blady-Kotela A. 

[Clinical use of magnesium] 

Przegl Lek. 1996;53(3):155-8. Review. Polish. 

PMID: 8754371 

264: Meinertz T. 



678

[Magnesium: current studies--critical evaluation--consequences] 

Z Kardiol. 1996;85 Suppl 6:147-51. Review. German. 

PMID: 9064959 

265: Zehender M. 

[Magnesium as an anti-arrhythmic therapy principle in supraventricular and 

ventricular cardiac arrhythmias] 


PMID: 9064958 

266: Beuckelmann DJ. 

[Value of magnesium in acute myocardial infarct] 


PMID: 9064957 

267: Van Leer EM, Seidell JC, Kromhout D. 

Dietary calcium, potassium, magnesium and blood pressure in the Netherlands. 

Int J Epidemiol. 1995 Dec;24(6):1117-23. 

PMID: 8824852 

268: Sueta CA, Patterson JH, Adams KF Jr. 

Antiarrhythmic action of pharmacological administration of magnesium in heart 

failure: a critical review of new data. 


PMID: 8861138 

269: Herzog WR, Schlossberg ML, MacMurdy KS, Edenbaum LR, Gerber MJ, Vogel 

RA, 

Serebruany VL. 

Timing of magnesium therapy affects experimental infarct size. 

Circulation. 1995 Nov 1;92(9):2622-6. 

PMID: 7586365 

270: Seelig MS. 

ISIS 4: clinical controversy regarding magnesium infusion, thrombolytic 

therapy, and acute myocardial infarction. 

Nutr Rev. 1995 Sep;53(9):261-4. Review. 

PMID: 8577409 

271: Landmark K, Abdelnoor M. 

[Magnesium therapy in acute myocardial infarction. New points of view] 

Tidsskr Nor Laegeforen. 1995 Aug 10;115(18):2268-70. Review. Norwegian. 

PMID: 7652726 

272: Dahle LO, Berg G, Hammar M, Hurtig M, Larsson L. 

The effect of oral magnesium substitution on pregnancy-induced leg cramps. 



679

Am J Obstet Gynecol. 1995 Jul;173(1):175-80. 

PMID: 7631676 

273: Leor J, Kloner RA. 

An experimental model examining the role of magnesium in the therapy of acute 


Am J Cardiol. 1995 Jun 15;75(17):1292-3. 

PMID: 7778564 

274: Lonnerdal B. 

Magnesium nutrition of infants. 

Magnes Res. 1995 Mar;8(1):99-105. Review. 

PMID: 7669512 

275: Bac P, Pages N, Herrenknecht C, Teste JF. 

Inhibition of mouse-killing behaviour in magnesium-deficient rats: effect of 

pharmacological doses of magnesium pidolate, magnesium aspartate, magnesium 

lactate, magnesium gluconate and magnesium chloride. 

Magnes Res. 1995 Mar;8(1):37-45. 

PMID: 7669506 

276: Sojka JE, Weaver CM. 

Magnesium supplementation and osteoporosis. 

Nutr Rev. 1995 Mar;53(3):71-4. Review. 

PMID: 7770187 

277: Eibl NL, Kopp HP, Nowak HR, Schnack CJ, Hopmeier PG, Schernthaner G. 

Hypomagnesemia in type II diabetes: effect of a 3-month replacement therapy. 

Diabetes Care. 1995 Feb;18(2):188-92. 

PMID: 7729296 

278: Drybanska-Kalita A. 

[Effect of various methods of supplementing magnesium on health status of 

children under special care] 

Ann Acad Med Stetin. 1995;41:211-9. Polish. 

PMID: 8615546 

279: Henrotte JG, Aymard N, Allix M, Boulu RG. 

Effect of pyridoxine and magnesium on stress-induced gastric ulcers in mice 

selected for low or high blood magnesium levels. 

Ann Nutr Metab. 1995;39(5):285-90. 

PMID: 8585697 

280: Salem M, Kasinski N, Munoz R, Chernow B. 

Progressive magnesium deficiency increases mortality from endotoxin challenge: 

protective effects of acute magnesium replacement therapy. 



680

Crit Care Med. 1995 Jan;23(1):108-18. 

PMID: 8001362 

281: Heesch CM, Eichhorn EJ. 

Magnesium in acute myocardial infarction. 

Ann Emerg Med. 1994 Dec;24(6):1154-60. Review. 

PMID: 7978600 

282: Bubeck J, Haussecker H, Disch G, Spatling L, Classen HG. 

Potentiation of magnesium-deficiency-induced foetotoxicity by concomitant iron 

deficiency and its prevention by adequate supply via drinking water. 

Magnes Res. 1994 Dec;7(3-4):245-54. 

PMID: 7786687 

283: Colonna F, Giorgi R, Ciana G, Benettoni A. 

[Efficacy of magnesium in a case of neonatal pulmonary hypertension refractory 

to the usual therapies] 

Minerva Pediatr. 1994 Dec;46(12):553-5. Italian. 

PMID: 7731416 

284: Atar D, Serebruany V, Poulton J, Godard J, Schneider A, Herzog WR. 

Effects of magnesium supplementation in a porcine model of myocardial ischemia 

and reperfusion. 

J Cardiovasc Pharmacol. 1994 Oct;24(4):603-11. 

PMID: 7528843 

285: Schmitt HJ, Barth GR, Thierauf P. 

Neuronal protection by intraischemic brain perfusion: an electron microscopy 

study in the rat. 

J Neurosurg Anesthesiol. 1994 Oct;6(4):265-74. 

PMID: 8000201 

286: Spisak V. 

[Treatment of acute myocardial infarct with magnesium] 

Vnitr Lek. 1994 Oct;40(10):649-53. Slovak. 

PMID: 7810083 

287: Roth A, Eshchar Y, Keren G, Kerbel S, Harsat A, Villa Y, Laniado S, Miller 

HI. 

Effect of magnesium on restenosis after percutaneous transluminal coronary 

angioplasty: a clinical and angiographic evaluation in a randomized patient 

population. A pilot study. The Ichilov Magnesium Study Group. 

Eur Heart J. 1994 Sep;15(9):1164-73. 

PMID: 7982415 

288: Geleijnse JM, Witteman JC, Bak AA, den Breeijen JH, Grobbee DE. 



681

Reduction in blood pressure with a low sodium, high potassium, high magnesium 

salt in older subjects with mild to moderate hypertension. 

BMJ. 1994 Aug 13;309(6952):436-40. 

PMID: 7920126 

289: Shils ME, Rude RK. 

Deliberations and evaluations of the approaches, endpoints and paradigms for 

magnesium dietary recommendations. 

J Nutr. 1996 Sep;126(9 Suppl):2398S-2403S. 

PMID: 8811804 

290: Dorup I, Skajaa K, Thybo NK. 

[Oral magnesium supplementation to patients receiving diuretics--normalization 

of magnesium, potassium and sodium, and potassium pumps in the skeletal muscles] 

Ugeskr Laeger. 1994 Jul 4;156(27):4007-10, 4013. Danish. 

PMID: 8066894 

291: Balon TW, Jasman A, Scott S, Meehan WP, Rude RK, Nadler JL. 

Dietary magnesium prevents fructose-induced insulin insensitivity in rats. 

Hypertension. 1994 Jun;23(6 Pt 2):1036-9. 

PMID: 8206589 

292: Paolisso G, Scheen A, Cozzolino D, Di Maro G, Varricchio M, D'Onofrio F, 

Lefebvre PJ. 

Changes in glucose turnover parameters and improvement of glucose oxidation 

after 4-week magnesium administration in elderly noninsulin-dependent (type II) 


J Clin Endocrinol Metab. 1994 Jun;78(6):1510-4. 

PMID: 8200955 

293: Lasserre B, Spoerri M, Moullet V, Theubet MP. 

Should magnesium therapy be considered for the treatment of coronary heart 

disease? II. Epidemiological evidence in outpatients with and without coronary 

heart disease. 

Magnes Res. 1994 Jun;7(2):145-53. 

PMID: 7999529 

294: Kurita T. 

Antiarrhythmic effect of parenteral magnesium on ventricular tachycardia 

associated with long QT syndrome. 


PMID: 7999530 

295: Weiss M, Lasserre B. 

Should magnesium therapy be considered for the treatment of coronary heart 

disease? I. A critical appraisal of current facts and hypotheses. 



682


PMID: 7999528 

296: Thomas J, Tomb E, Thomas E, Faure G. 

Migraine treatment by oral magnesium intake and correction of the irritation of 

buccofacial and cervical muscles as a side effect of mandibular imbalance. 

Magnes Res. 1994 Jun;7(2):123-7. 

PMID: 7999526 

297: Rob PM, Lebeau A, Schmid H, Sack K, Classen HG. 

Cyclosporin induces magnesium deficiency in rats and thereby aggravates its own 

nephrotoxicity: benefit of magnesium supplementation. 

Transplant Proc. 1994 Jun;26(3):1736-7. 

PMID: 8030111 

298: Olerich MA, Rude RK. 

Should we supplement magnesium in critically ill patients? 

New Horiz. 1994 May;2(2):186-92. Review. 

PMID: 7922443 

299: Singh RB, Rastogi SS, Ghosh S, Niaz MA. 

Dietary and serum magnesium levels in patients with acute myocardial 

infarction, coronary artery disease and noncardiac diagnoses. 

J Am Coll Nutr. 1994 Apr;13(2):139-43. 

PMID: 8006295 

300: Orlov MV, Brodsky MA, Douban S. 

A review of magnesium, acute myocardial infarction and arrhythmia. 

J Am Coll Nutr. 1994 Apr;13(2):127-32. Review. 

PMID: 8006293 

301: Casthely PA, Yoganathan T, Komer C, Kelly M. 

Magnesium and arrhythmias after coronary artery bypass surgery. 

J Cardiothorac Vasc Anesth. 1994 Apr;8(2):188-91. 

PMID: 7515706 

302: Williams JM, Hammad A, Cottington EC, Harchelroad FC. 

Intravenous magnesium in the treatment of hydrofluoric acid burns in rats. 

Ann Emerg Med. 1994 Mar;23(3):464-9. 

PMID: 8135420 

303: Rahman MI, Chagoury ME. 

Selections from current literature: magnesium, myocardial infarction and 

meta-analysis. 

Fam Pract. 1994 Mar;11(1):96-101. 

PMID: 8034161 



683

304: Howard JM, Davies S, Hunnisett A. 

Red cell magnesium and glutathione peroxidase in infertile women--effects of 

oral supplementation with magnesium and selenium. 

Magnes Res. 1994 Mar;7(1):49-57. 

PMID: 8054261 

305: Corica F, Allegra A, Di Benedetto A, Giacobbe MS, Romano G, Cucinotta D, 

Buemi M, Ceruso D. 

Effects of oral magnesium supplementation on plasma lipid concentrations in 

patients with non-insulin-dependent diabetes mellitus. 

Magnes Res. 1994 Mar;7(1):43-7. 

PMID: 8054260 

306: Hampton EM, Whang DD, Whang R. 

Intravenous magnesium therapy in acute myocardial infarction. 

Ann Pharmacother. 1994 Feb;28(2):212-9. Review. 

PMID: 8173140 

307: Sueta CA, Clarke SW, Dunlap SH, Jensen L, Blauwet MB, Koch G, Patterson JH, 

Adams KF Jr. 

Effect of acute magnesium administration on the frequency of ventricular 

arrhythmia in patients with heart failure. 

Circulation. 1994 Feb;89(2):660-6. 

PMID: 7508827 

308: Simko F. 

Pathophysiological aspects of the protective effect of magnesium in myocardial 

infarction (review). 

Acta Med Hung. 1994;50(1-2):55-64. Review. 

PMID: 7638042 

309: McLean RM. 

Magnesium and its therapeutic uses: a review. 

Am J Med. 1994 Jan;96(1):63-76. Review. 

PMID: 8304365 

310: Retta TM, Afre GM, Randall OS. 

Dietary management of blood pressure. 

J Assoc Acad Minor Phys. 1994;5(4):147-51. Review. 

PMID: 7812082 

311: Takahashi S, Okada K, Yanai M. 

Magnesium and parathyroid hormone changes to magnesium-free dialysate in 

continuous ambulatory peritoneal dialysis patients. 

Perit Dial Int. 1994;14(1):75-8. 



684

PMID: 8312420 

312: Hix CD. 

Magnesium in congestive heart failure, acute myocardial infarction and 

dysrhythmias. 

J Cardiovasc Nurs. 1993 Oct;8(1):19-31. Review. 

PMID: 8106895 

313: Miturzynska-Stryjecka H, Bielak G. 

[Beneficial effects of magnesium salts used in acute myocardial infarction] 

Wiad Lek. 1993 Oct;46(19-20):766-9. Review. Polish. 

PMID: 7975622 

314: Stella PR, Kan G. 

[Magnesium: a promising addition to the therapy in acute myocardial infarct] 

Ned Tijdschr Geneeskd. 1993 Sep 25;137(39):1958-61. Review. Dutch. 

PMID: 8413703 

315: Teo KK, Yusuf S. 

Role of magnesium in reducing mortality in acute myocardial infarction. A 

review of the evidence. 

Drugs. 1993 Sep;46(3):347-59. Review. 

PMID: 7693427 

316: Mass H, Santoni F, Pirazzi B. 

On the use of parenteral magnesium salts in the treatment of acute ischaemic 

heart disease: a brief review. 

Magnes Res. 1993 Sep;6(3):275-89. Review. 

PMID: 8292502 

317: Driessens FC. 

[Prevention of osteoporosis and pathological calcifications] 

Ned Tijdschr Tandheelkd. 1993 Sep;100(9):412, 413-4. Dutch. 

PMID: 11917878 

318: Scheller S, Krol W, Skirmuntt K, Zydowicz G, Shani J. 

Antitumoral effect of bleomycin+dolomite combination treatment, in mice bearing 

Ehrlich ascites carcinoma. 

Z Naturforsch [C]. 1993 Sep-Oct;48(9-10):818-20. 

PMID: 7504493 

319: Shaheen BE, Cornish LA. 

Magnesium in the treatment of acute myocardial infarction. 

Clin Pharm. 1993 Aug;12(8):588-96. Review. 

PMID: 8222523 



685

320: Heimburger DC. 

Marked resistance of normal subjects to tube-feeding-induced diarrhea: the role 

of magnesium. 

JPEN J Parenter Enteral Nutr. 1993 Jul-Aug;17(4):394. 

PMID: 8271368 

321: Soldatovic D, Matovic V, Vujanovic D. 

Prophylactic effect of high magnesium intake in rabbits exposed to prolonged 

lead intoxication. 

Magnes Res. 1993 Jun;6(2):145-8. 

PMID: 8274359 

322: Gullestad L, Birkeland K, Molstad P, Hoyer MM, Vanberg P, Kjekshus J. 

The effect of magnesium versus verapamil on supraventricular arrhythmias. 

Clin Cardiol. 1993 May;16(5):429-34. 

PMID: 8504578 

323: Matz R. 

Magnesium: deficiencies and therapeutic uses. 

Hosp Pract (Off Ed). 1993 Apr 30;28(4A):79-82, 85-7, 91-2. 

PMID: 8473371 

324: Kummerow FA, Wasowicz E, Smith T, Yoss NL, Thiel J. 

Plasma lipid physical properties in swine fed margarine or butter in relation 

to dietary magnesium intake. 

J Am Coll Nutr. 1993 Apr;12(2):125-32. 

PMID: 8463511 

325: Luo SQ, Plowman MC, Hopfer SM, Sunderman FW Jr. 

Mg(2+)-deprivation enhances and Mg(2+)-supplementation diminishes the 

embryotoxic and teratogenic effects of Ni2+, Co2+, Zn2+, and Cd2+ for frog 

embryos in the FETAX assay. 

Ann Clin Lab Sci. 1993 Mar-Apr;23(2):121-9. 

PMID: 8457141 

326: Rudnicki PM, Frolich A, Fischer-Rasmussen W. 

[Magnesium therapy in pregnancy-induced hypertension and pre-eclampsia] 

Ugeskr Laeger. 1993 Feb 15;155(7):460-3. Review. Danish. 

PMID: 8465449 

327: Dorup I, Skajaa K, Thybo NK. 

Oral magnesium supplementation restores the concentrations of magnesium, 

potassium and sodium-potassium pumps in skeletal muscle of patients receiving 

diuretic treatment. 

J Intern Med. 1993 Feb;233(2):117-23. 

PMID: 8381850 



686

328: Lichodziejewska B, Klos J. 

[Magnesium in cardiology. Instant success of an undervalued ion] 

Kardiol Pol. 1993 Feb;38(2):126-30. Review. Polish. 

PMID: 8230983 

329: Moesgaard B, Larsen IE, Quistorff B, Therkelsen I, Christensen VG, 

Jorgensen PF. 

Effect of dietary magnesium on post mortem phosphocreatine utilization in 

skeletal muscle of swine: a non-invasive study using 31P-NMR spectroscopy. 

Acta Vet Scand. 1993;34(4):397-404. 

PMID: 8147293 

330: Widman L, Wester PO, Stegmayr BK, Wirell M. 

The dose-dependent reduction in blood pressure through administration of 

magnesium. A double blind placebo controlled cross-over study. 

Am J Hypertens. 1993 Jan;6(1):41-5. 

PMID: 8427660 

331: Spatling L. 

[Magnesium in obstetrics and gynecology] 

Gynakol Geburtshilfliche Rundsch. 1993;33(2):85-91. Review. German. 

PMID: 8400911 

332: Joachims Z, Netzer A, Ising H, Rebentisch E, Attias J, Weisz G, Gunther T. 

Oral magnesium supplementation as prophylaxis for noise-induced hearing loss: 

results of a double blind field study. 

Schriftenr Ver Wasser Boden Lufthyg. 1993;88:503-16. English, German. 

PMID: 8460390 

333: Orita H, Fukasawa M, Hirooka S, Minowa T, Uchino H, Washio M. 

Prevention of postischemic reperfusion injury: the improvement of myocardial 

tissue blood flow after ischemia by terminal nicorandil-Mg cardioplegia. 

Surg Today. 1993;23(4):344-9. 

PMID: 8318789 

334: England MR, Gordon G, Salem M, Chernow B. 

Magnesium administration and dysrhythmias after cardiac surgery. A 

placebo-controlled, double-blind, randomized trial. 

JAMA. 1992 Nov 4;268(17):2395-402. 

PMID: 1404796 

335: Haga H. 

Effects of dietary magnesium supplementation on diurnal variations of blood 

pressure and plasma Na+, K(+)-ATPase activity in essential hypertension. 

Jpn Heart J. 1992 Nov;33(6):785-800. 



687

PMID: 1338597 

336: Chau AC, Gabert HA, Miller JM Jr. 

A prospective comparison of terbutaline and magnesium for tocolysis. 

Obstet Gynecol. 1992 Nov;80(5):847-51. 

PMID: 1407926 

337: Gullestad L, Dolva LO, Soyland E, Manger AT, Falch D, Kjekshus J. 

Oral magnesium supplementation improves metabolic variables and muscle strength 

in alcoholics. 

Alcohol Clin Exp Res. 1992 Oct;16(5):986-90. 

PMID: 1443440 

338: Paolisso G, Di Maro G, Cozzolino D, Salvatore T, D'Amore A, Lama D, 

Varricchio M, D'Onofrio F. 

Chronic magnesium administration enhances oxidative glucose metabolism in 

thiazide treated hypertensive patients. 

Am J Hypertens. 1992 Oct;5(10):681-6. 

PMID: 1418829 

339: Horner SM. 

Efficacy of intravenous magnesium in acute myocardial infarction in reducing 

arrhythmias and mortality. Meta-analysis of magnesium in acute myocardial 

infarction. 

Circulation. 1992 Sep;86(3):774-9. 

PMID: 1387591 

340: Facchinetti F, Battaglia C, Benatti R, Borella P, Genazzani AR. 

Oral magnesium supplementation improves fetal circulation. 

Magnes Res. 1992 Sep;5(3):179-81. 

PMID: 1467155 

341: Martin M, Diaz-Rubio E, Casado A, Lopez Vega JM, Sastre J, Almenarez J. 

Intravenous and oral magnesium supplementations in the prophylaxis of 

cisplatin-induced hypomagnesemia. Results of a controlled trial. 

Am J Clin Oncol. 1992 Aug;15(4):348-51. 

PMID: 1514533 

342: Luo L, Tong JM, Huang JC. 

Effects of dietary chloride and magnesium on the incidence of tibial 

dyschondroplasia in chickens fed on Chinese practical diets. 

Br Poult Sci. 1992 Jul;33(3):603-11. 

PMID: 1643524 

343: Paolisso G, Sgambato S, Gambardella A, Pizza G, Tesauro P, Varricchio M, 

D'Onofrio F. 



688

Daily magnesium supplements improve glucose handling in elderly subjects. 


PMID: 1595589 

344: Brilla LR, Haley TF. 

Effect of magnesium supplementation on strength training in humans. 

J Am Coll Nutr. 1992 Jun;11(3):326-9. 

PMID: 1619184 

345: del Castillo Rueda A, Recarte Garcia-Andrade C, Torres Segovia FJ. 

[Magnesium: therapeutic usefulness in emergency situations] 

An Med Interna. 1992 May;9(5):246-50. Review. Spanish. 

PMID: 1504208 

346: Holecek V, Holecek T. 

[New findings on the clinical significance of magnesium] 

Cas Lek Cesk. 1992 Mar 4;131(4):101-3. Review. Czech. 

PMID: 1581935 

347: McIntosh TK. 

Pharmacologic strategies in the treatment of experimental brain injury. 

J Neurotrauma. 1992 Mar;9 Suppl 1:S201-9. Review. 

PMID: 1588609 

348: Landmark K, Urdal P. 

[Magnesium therapy in acute myocardial infarction] 

Tidsskr Nor Laegeforen. 1992 Feb 10;112(4):495-7. Review. Norwegian. 

PMID: 1553701 

349: Hsieh ST, Sano H, Saito K, Kubota Y, Yokoyama M. 

Magnesium supplementation prevents the development of alcohol-induced 

hypertension. 

Hypertension. 1992 Feb;19(2):175-82. 

PMID: 1737652 

350: Teo KK, Yusuf S, Collins R, Held PH, Peto R. 

Effects of intravenous magnesium in suspected acute myocardial infarction: 

overview of randomised trials. 

BMJ. 1991 Dec 14;303(6816):1499-503. 

PMID: 1838289 

351: Koo WW, Tsang RC. 

Mineral requirements of low-birth-weight infants. 

J Am Coll Nutr. 1991 Oct;10(5):474-86. Review. 

PMID: 1955624 



689

352: Birch RF, Lake CL. 

Pro: magnesium is a valuable therapy in the cardiac surgical patient. 

J Cardiothorac Vasc Anesth. 1991 Oct;5(5):518-21. Review. 

PMID: 1932660 

353: Touyz RM. 

Magnesium supplementation as an adjuvant to synthetic calcium channel 

antagonists in the treatment of hypertension. 

Med Hypotheses. 1991 Oct;36(2):140-1. 

PMID: 1664038 

354: Facchinetti F, Borella P, Sances G, Fioroni L, Nappi RE, Genazzani AR. 

Oral magnesium successfully relieves premenstrual mood changes. 

Obstet Gynecol. 1991 Aug;78(2):177-81. 

PMID: 2067759 

355: Leor J, Harman M, Rabinowitz B, Mozes B. 

Giant U waves and associated ventricular tachycardia complicating astemizole 

overdose: successful therapy with intravenous magnesium. 

Am J Med. 1991 Jul;91(1):94-7. 

PMID: 1677532 

356: Singh RB, Rastogi SS, Mani UV, Seth J, Devi L. 

Does dietary magnesium modulate blood lipids? 

Biol Trace Elem Res. 1991 Jul;30(1):59-64. 

PMID: 1718369 

357: Finlayson DC. 

Magnesium: its time has come. 

J Cardiothorac Vasc Anesth. 1991 Jun;5(3):199-200. 

PMID: 1863737 

358: Davydenko NV, Vasilenko IG. 

[Magnesium level in food rations and the prevalence of ischemic heart disease 

among the population] 

Gig Sanit. 1991 May;(5):44-6. Russian. 

PMID: 1916337 

359: Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. 

Magnesium prophylaxis of menstrual migraine: effects on intracellular 

magnesium. 

Headache. 1991 May;31(5):298-301. 

PMID: 1860787 

360: Saggese G, Federico G, Bertelloni S, Baroncelli GI, Calisti L. 



690

Hypomagnesemia and the parathyroid hormone-vitamin D endocrine system in 

children with insulin-dependent diabetes mellitus: effects of magnesium 

administration. 

J Pediatr. 1991 Feb;118(2):220-5. 

PMID: 1993948 

361: Rudnicki M, Frolich A, Rasmussen WF, McNair P. 

The effect of magnesium on maternal blood pressure in pregnancy-induced 

hypertension. A randomized double-blind placebo-controlled trial. 

Acta Obstet Gynecol Scand. 1991;70(6):445-50. 

PMID: 1763608 

362: Steidl L, Ditmar R. 

Treatment of soft tissue calcifications with magnesium. 

Acta Univ Palacki Olomuc Fac Med. 1991;130:273-87. 

PMID: 1838878 

363: Gullestad L, Oystein Dolva L, Birkeland K, Falch D, Fagertun H, Kjekshus J. 

Oral versus intravenous magnesium supplementation in patients with magnesium 

deficiency. 

Magnes Trace Elem. 1991-92;10(1):11-6. 

PMID: 1814318 

364: Mathew R, Altura BM. 

The role of magnesium in lung diseases: asthma, allergy and pulmonary 

hypertension. 

Magnes Trace Elem. 1991-92;10(2-4):220-8. Review. 

PMID: 1844555 

365: Rudnicki M, Frolich A, Fischer-Rasmussen W. 

Magnesium supplement in pregnancy-induced hypertension: effects on maternal and 

neonatal magnesium and calcium homeostasis. 

Miner Electrolyte Metab. 1991;17(6):399-403. 

PMID: 1823392 

366: Itokawa Y. 

Cardiovascular disease and magnesium: epidemiological and experimental data. 

Proc Finn Dent Soc. 1991;87(4):651-7. Review. 

PMID: 1775493 

367: Ogata H, Izumo Y. 

[Mortality reduction in mice administered a single abundant dose of zinc, 

manganese or magnesium after irradiation by gamma-rays at sublethal doses] 

Radioisotopes. 1990 Dec;39(12):573-6. Japanese. 

PMID: 2290996 



691

368: Donoghue DJ, Krueger WF, Donoghue AM, Byrd JA, Ali DH, el Halawani ME. 

Magnesium-aspartate-hydrochloride reduces weight loss in heat-stressed laying 

hens. 

Poult Sci. 1990 Nov;69(11):1862-8. 

PMID: 2087447 

369: Netten PM, de Mulder PH, Theeuwes AG, Willems JL, Kohler BE, Wagener DT. 

Intravenous magnesium supplementation during cisdiammine-dichloroplatinum 

administration prevents hypomagnesemia. 

Ann Oncol. 1990 Sep;1(5):369-72. 

PMID: 1702009 

370: Seelig MS. 

Increased need for magnesium with the use of combined oestrogen and calcium for 

osteoporosis treatment. 


PMID: 2132751 

371: Ogawa Y, Yamaguchi K, Morozumi M. 

Effects of magnesium salts in preventing experimental oxalate urolithiasis in 

rats. 

J Urol. 1990 Aug;144(2 Pt 1):385-9. 

PMID: 2374212 

372: Mathew R, Gloster ES, Altura BT, Altura BM. 

Pulmonary vasculature in monocrotaline-induced hypertensive rats on magnesium 

therapy. 

Microcirc Endothelium Lymphatics. 1990 Aug-Oct;6(4-5):267-83. 

PMID: 2149161 

373: Hara A, Matsumura H, Abiko Y. 

Beneficial effect of magnesium on the isolated perfused rat heart during 

reperfusion after ischaemia: comparison between pre-ischaemic and post-ischaemic 

administration of magnesium. 

Naunyn Schmiedebergs Arch Pharmacol. 1990 Jul;342(1):100-6. 

PMID: 2402298 

374: Keren A, Tzivoni D. 

Magnesium therapy in ventricular arrhythmias. 

Pacing Clin Electrophysiol. 1990 Jul;13(7):937-45. Review. 

PMID: 1695751 

375: Iseri LT. 

Role of magnesium in cardiac tachyarrhythmias. 

Am J Cardiol. 1990 Jun 19;65(23):47K-50K. 



692

PMID: 2353670 

376: Tzivoni D, Keren A. 

Suppression of ventricular arrhythmias by magnesium. 

Am J Cardiol. 1990 Jun 1;65(20):1397-9. Review. 

PMID: 2188497 

377: Demory JE, Firmin JM, Parot P. 

[The value of magnesium pyrrolidone carboxylate in true cervix dystocia. A 

double blind versus placebo study] 

Rev Fr Gynecol Obstet. 1990 Jun;85(6):413-6. French. 

PMID: 2389112 

378: Wu HW, Wen JX, Qu GR. 

[Changes in fluorine metabolism during the treatment with calcium-magnesium 

preparation in 60 cases of endemic fluorosis] 

Zhonghua Nei Ke Za Zhi. 1990 Jun;29(6):357-9, 383. Chinese. 

PMID: 2269037 

379: Abraham GE, Grewal H. 

A total dietary program emphasizing magnesium instead of calcium. Effect on the 

mineral density of calcaneous bone in postmenopausal women on hormonal therapy. 

J Reprod Med. 1990 May;35(5):503-7. 

PMID: 2352244 

380: Fontana-Klaiber H, Hogg B. 

[Therapeutic effects of magnesium in dysmenorrhea] 

Schweiz Rundsch Med Prax. 1990 Apr 17;79(16):491-4. German. 

PMID: 2349410 

381: Classen HG, Nowitzki S. 

[The clinical importance of magnesium. 2. The indications for supplementation 

and therapy] 

Fortschr Med. 1990 Apr 10;108(10):198-200. Review. German. 

PMID: 2187780 

382: Huang QF, Gebrewold A, Altura BT, Altura BM. 

Cocaine-induced cerebral vascular damage can be ameliorated by Mg2+ in rat 

brain. 

Neurosci Lett. 1990 Feb 5;109(1-2):113-6. 

PMID: 2314626 

383: Bacon JA, Bell MC, Miller JK, Ramsey N, Mueller FJ. 

Effect of magnesium administration route on plasma minerals in Holstein calves 

receiving either adequate or insufficient magnesium in their diets. 

J Dairy Sci. 1990 Feb;73(2):470-3. 



693

PMID: 2329207 

384: Singh RB. 

Effect of dietary magnesium supplementation in the prevention of coronary heart 

disease and sudden cardiac death. 

Magnes Trace Elem. 1990;9(3):143-51. 

PMID: 2248695 

385: Huang QF, Gebrewold A, Altura BT, Altura BM. 

Mg2+ protects against PCP-induced cerebrovasospasms and vascular damage in rat 

brain. 


PMID: 2158788 

386: Singh RB, Rastogi SS, Sharma VK, Saharia RB, Kulshretha SK. 

Can dietary magnesium modulate lipoprotein metabolism? 


PMID: 2130823 

387: Abraham AS. 

Treatment of patients with acute myocardial infarction with intravenous 

magnesium. 

Magnes Trace Elem. 1990;9(4):177-85. Review. 

PMID: 2095160 

388: Ising H, Rebentisch E, Bertschat F, Gunther T. 

Correlations between ventricular arrhythmias and electrolyte disturbances after acute 



PMID: 2095164 

389: Singh RB, Sircar AR, Rastogi SS, Garg V. 

Magnesium and potassium administration in acute myocardial infarction. 


PMID: 2095163 

390: Chouinard G, Beauclair L, Geiser R, Etienne P. 

A pilot study of magnesium aspartate hydrochloride (Magnesiocard) as a mood 

stabilizer for rapid cycling bipolar affective disorder patients. 

Prog Neuropsychopharmacol Biol Psychiatry. 1990;14(2):171-80. 

PMID: 2309035 

391: Ploceniak C. 

[Bruxism and magnesium, my clinical experiences since 1980] 

Rev Stomatol Chir Maxillofac. 1990;91 Suppl 1:127. French. 

PMID: 2130443 



694

392: Martineau J, Barthelemy C, Roux S, Garreau B, Lelord G. 

Electrophysiological effects of fenfluramine or combined vitamin B6 and 

magnesium on children with autistic behaviour. 

Dev Med Child Neurol. 1989 Dec;31(6):721-7. 

PMID: 2599266 

393: Hauser SP, Braun PH. 

[Intravenous magnesium administration in bronchial asthma] 

Schweiz Med Wochenschr. 1989 Nov 18;119(46):1633-5. German. 

PMID: 2609133 

394: Laubach HE. 

Effect of dietary magnesium on Ascaris suum infections of mice. 

Biochem Med Metab Biol. 1989 Oct;42(2):95-104. 

PMID: 2789853 

395: Chiossi M, Rosati U, Renna S, Lattere M, De Santis L. 

[Theophylline poisoning in childhood: depurative therapy using a combination of 

activated charcoal and a saline cathartic] 

Minerva Pediatr. 1989 Oct;41(10):535-7. Italian. 

PMID: 2615728 

396: Inui K, Kobayashi M, Orita H, Shimanuki T, Kohno M, Fukasawa M, Abe K, 

Kuraoka S, Washio M. 

[Effect of magnesium containing cardioplegic solution on the cases of extended 

aortic cross clamping] 

Rinsho Kyobu Geka. 1989 Oct;9(5):468-71. Japanese. 

PMID: 9301958 

397: Grases F, Genestar C, Conte A, March P, Costa-Bauza A. 

Inhibitory effect of pyrophosphate, citrate, magnesium and chondroitin sulphate 

in calcium oxalate urolithiasis. 

Br J Urol. 1989 Sep;64(3):235-7. 

PMID: 2553195 

398: Kinnunen O, Salokannel J. 

Comparison of the effects of magnesium hydroxide and a bulk laxative on lipids, 

carbohydrates, vitamins A and E, and minerals in geriatric hospital patients in 

the treatment of constipation. 

J Int Med Res. 1989 Sep-Oct;17(5):442-54. 

PMID: 2553511 

399: Durlach J. 

Recommended dietary amounts of magnesium: Mg RDA. 




695

PMID: 2701269 

400: Mletzko R, Jung W, Manz M, Kamradt T, Vogel F, Luderitz B. 

[Arrhythmogenic effect of flecainide--treatment with i.v. magnesium] 

Z Kardiol. 1989 Sep;78(9):602-6. German. 

PMID: 2510412 

401: Paolisso G, Passariello N, Pizza G, Marrazzo G, Giunta R, Sgambato S, 

Varricchio M, D'Onofrio F. 

Dietary magnesium supplements improve B-cell response to glucose and arginine 

in elderly non-insulin dependent diabetic subjects. 

Acta Endocrinol (Copenh). 1989 Jul;121(1):16-20. 

PMID: 2662695 

402: Ditmar R, Steidl L. 

[The importance of magnesium in orthopedics. VI. The importance of magnesium in 

the treatment of ectopic calcification and ossification] 

Acta Chir Orthop Traumatol Cech. 1989 Jun;56(3):190-200. Czech. 

PMID: 2502888 

403: Calvani M. 

[Magnesium and hypomagnesemia in childhood] 

Recenti Prog Med. 1989 Jun;80(6):338-43. Review. Italian. 

PMID: 2672198 

404: Green SM, Naftel J. 

Antiarrhythmic efficacy of magnesium in the setting of life-threatening digoxin 

toxicity. 

Am J Emerg Med. 1989 May;7(3):347-8. 

PMID: 2712905 

405: Rasmussen HS, Aurup P, Goldstein K, McNair P, Mortensen PB, Larsen OG, 

Lawaetz H. 

Influence of magnesium substitution therapy on blood lipid composition in 

patients with ischemic heart disease. A double-blind, placebo controlled study. 

Arch Intern Med. 1989 May;149(5):1050-3. 

PMID: 2719498 

406: Roden DM. 

Magnesium treatment of ventricular arrhythmias. 

Am J Cardiol. 1989 Apr 18;63(14):43G-46G. Review. 

PMID: 2650516 

407: Nowson CA, Morgan TO. 

Magnesium supplementation in mild hypertensive patients on a moderately low 

sodium diet. 



696

Clin Exp Pharmacol Physiol. 1989 Apr;16(4):299-302. 

PMID: 2663263 

408: Pastorfide GB, Gorgonio NM, Ganzon AR, Alberto RM. 

Zinc chloride spray--magnesium hydroxide ointment dual topical regimen in the 

treatment of obstetric and gynecologic incisional wounds. 

Clin Ther. 1989 Mar-Apr;11(2):258-63. 

PMID: 2660997 

409: Kohvakka A, Luurila O, Gordin A, Sundberg S. 

Comparison of potassium alone and potassium-magnesium supplementation in 

patients with heart failure using hydrochlorothiazide. 

Magnesium. 1989;8(2):71-6. 

PMID: 2755214 

410: Rasmussen HS. 

Clinical intervention studies on magnesium in myocardial infarction. 

Magnesium. 1989;8(5-6):316-25. Review. 

PMID: 2693849 

411: Iseri LT, Allen BJ, Brodsky MA. 

Magnesium therapy of cardiac arrhythmias in critical-care medicine. 


PMID: 2693848 

412: Mathew R, Altura BT, Altura BM. 

Strain differences in pulmonary hypertensive response to monocrotaline alkaloid 

and the beneficial effect of oral magnesium treatment. 

Magnesium. 1989;8(2):110-6. 

PMID: 2526910 

413: Chaudry IH. 

ATP-MgCl2 and liver blood flow following shock and ischemia. 

Prog Clin Biol Res. 1989;299:19-31. Review. 

PMID: 2657790 

414: Seifert B, Wagler P, Dartsch S, Schmidt U, Nieder J. 

[Magnesium--a new therapeutic alternative in primary dysmenorrhea] 

Zentralbl Gynakol. 1989;111(11):755-60. German. 

PMID: 2675496 

415: Keren A, Dorian P, Davy JM, Opie LH. 

Effects of magnesium on ischemic and reperfusion arrhythmias in the rat heart 

and electrophysiologic effects of hypermagnesemia in the anesthetized dog. 

Cardiovasc Drugs Ther. 1988 Dec;2(5):637-45. 

PMID: 3154638 



697

416: Rasmussen HS, Larsen OG, Meier K, Larsen J. 

Hemodynamic effects of intravenously administered magnesium on patients with 

ischemic heart disease. 

Clin Cardiol. 1988 Dec;11(12):824-8. 

PMID: 3233812 

417: Mathew R, Gloster ES, Altura BT, Altura BM. 

Magnesium aspartate hydrochloride attenuates monocrotaline-induced pulmonary 

artery hypertension in rats. 

Clin Sci (Lond). 1988 Dec;75(6):661-7. 

PMID: 2974771 

418: Pinkham CS, Kubena KS. 

Consequences of low dietary magnesium and high dietary calcium on pregnancy 

outcome and tissue mineralization in rats. 

Magnes Res. 1988 Dec;1(3-4):147-53. 

PMID: 3275202 

419: Kovacs L, Molnar BG, Huhn E, Bodis L. 

[Magnesium substitution in pregnancy. A prospective, randomized double-blind 

study] 

Geburtshilfe Frauenheilkd. 1988 Aug;48(8):595-600. German. 

PMID: 3063587 

420: Rasmussen HS. 

Justification for intravenous magnesium therapy in acute myocardial infarction. 

Magnes Res. 1988 Jul;1(1-2):59-73. Review. 

PMID: 3079204 

421: Rasmussen HS, Gronbaek M, Cintin C, Balslov S, Norregard P, McNair P. 

One-year death rate in 270 patients with suspected acute myocardial infarction, 

initially treated with intravenous magnesium or placebo. 

Clin Cardiol. 1988 Jun;11(6):377-81. 

PMID: 3396238 

422: Hallson PC, Rose GA. 

Reduction of the urinary risk factors of urolithiasis with magnesium and 

tartrate mixture: a new treatment. 

Br J Urol. 1988 May;61(5):382-4. 

PMID: 3395794 

423: Moser PB, Reynolds RD, Acharya S, Howard MP, Andon MB. 

Calcium and magnesium dietary intakes and plasma and milk concentrations of 

Nepalese lactating women. 




698

PMID: 3354499 

424: Dyckner T, Wester PO, Widman L. 

Effects of peroral magnesium on plasma and skeletal muscle electrolytes in 

patients on long-term diuretic therapy. 

Int J Cardiol. 1988 Apr;19(1):81-7. 

PMID: 3372076 

425: Spatling L, Spatling G. 

Magnesium supplementation in pregnancy. A double-blind study. 

Br J Obstet Gynaecol. 1988 Feb;95(2):120-5. 

PMID: 3349001 

426: Oster JR, Epstein M. 

Management of magnesium depletion. 

Am J Nephrol. 1988;8(5):349-54. Review. 

PMID: 3071142 

427: Mathew R, Altura BM. 

Magnesium and the lungs. 

Magnesium. 1988;7(4):173-87. Review. 

PMID: 3072451 

428: Sjogren A, Floren CH, Nilsson A. 

Oral administration of magnesium hydroxide to subjects with insulin-dependent 

diabetes mellitus: effects on magnesium and potassium levels and on insulin 

requirements. 

Magnesium. 1988;7(3):117-22. 

PMID: 3054347 

429: Critelli G, Reale A. 

[Magnesium and cardiac arrhythmias. Revived interest for an old substance] 

Cardiologia. 1987 Sep;32(9):989-98. Review. Italian. 

PMID: 3319159 

430: Rasmussen HS, Suenson M, McNair P, Norregard P, Balslev S. 

Magnesium infusion reduces the incidence of arrhythmias in acute myocardial 

infarction. A double-blind placebo-controlled study. 

Clin Cardiol. 1987 Jun;10(6):351-6. 

PMID: 3297445 

431: Floriot C, Delacour JL, Bourscheid D, Wagschal G, Daoudal P, Ory JP, Guyon 

B. 

[Value of magnesium chloride in supraventricular paroxysmal tachycardia and 

tachycardia caused by auricular fibrillation] 

Presse Med. 1987 May 9;16(17):829. French. 



699

PMID: 2954105 

432: Abraham AS, Rosenmann D, Kramer M, Balkin J, Zion MM, Farbstien H, Eylath 

U. 

Magnesium in the prevention of lethal arrhythmias in acute myocardial 

infarction. 

Arch Intern Med. 1987 Apr;147(4):753-5. 

PMID: 3548627 

433: Joffres MR, Reed DM, Yano K. 

Relationship of magnesium intake and other dietary factors to blood pressure: 

the Honolulu heart study. 

Am J Clin Nutr. 1987 Feb;45(2):469-75. 

PMID: 3812346 

434: Martin RW, Gaddy DK, Martin JN Jr, Lucas JA, Wiser WL, Morrison JC. 

Tocolysis with oral magnesium. 

Am J Obstet Gynecol. 1987 Feb;156(2):433-4. 

PMID: 3826180 

435: Penev I, Marinov B, Ruseva R, Vlasova D. 

[Importance of magnesium in preventing late pregnancy toxicoses (pre-eclampsia) 

(preliminary report)] 

Akush Ginekol (Sofiia). 1987;26(4):31-4. Bulgarian. 

PMID: 3674320 

436: Kinnunen O, Salokannel J. 

Constipation in elderly long-stay patients: its treatment by magnesium 

hydroxide and bulk-laxative. 

Ann Clin Res. 1987;19(5):321-3. 

PMID: 3126699 

437: Classen HG, Fischer G, Marx J, Schimatschek H, Schmid C, Stein C. 

Prevention of stress-induced damage in experimental animals and livestock by 

monomagnesium-L-aspartate hydrochloride. 

Magnesium. 1987;6(1):34-9. 

PMID: 3821173 

438: Breuer J, Moniz C, Baldwin D, Parsons V. 

The effects of zero magnesium dialysate and magnesium supplements on ionised 

calcium concentration in patients on regular dialysis treatment. 

Nephrol Dial Transplant. 1987;2(5):347-50. 

PMID: 3122112 

439: Roujouleh H, Lavaud S, Toupance O, Melin JP, Chanard J. 

[Magnesium hydroxide treatment of hyperphosphatemia in chronic hemodialysis 



700

patients with an aluminum overload] 

Nephrologie. 1987;8(2):45-50. French. 

PMID: 3614505 

440: Goldberg P, Fleming MC, Picard EH. 

Multiple sclerosis: decreased relapse rate through dietary supplementation with 

calcium, magnesium and vitamin D. 

Med Hypotheses. 1986 Oct;21(2):193-200. 

PMID: 3537648 

441: Bradley RJ. 

Calcium or magnesium concentration affects the severity of 

organophosphate-induced neuromuscular block. 

Eur J Pharmacol. 1986 Aug 15;127(3):275-8. 

PMID: 3019732 

442: Willox JC, McAllister EJ, Sangster G, Kaye SB. 

Effects of magnesium supplementation in testicular cancer patients receiving 

cis-platin: a randomised trial. 

Br J Cancer. 1986 Jul;54(1):19-23. 

PMID: 3524645 

443: Luthringer C, Berthelot A. 

[Dietary magnesium and mineralocorticoid DOCA-salt hypertension in the rat. 

Effect on the metabolism of sodium and magnesium] 

Arch Mal Coeur Vaiss. 1986 Jun;79(6):871-4. French. 

PMID: 3099703 

444: O'Donovan R, Baldwin D, Hammer M, Moniz C, Parsons V. 

Substitution of aluminium salts by magnesium salts in control of dialysis 

hyperphosphataemia. 

Lancet. 1986 Apr 19;1(8486):880-2. 

PMID: 2870354 

445: Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. 

Intravenous magnesium in acute myocardial infarction. 

Lancet. 1986 Feb 1;1(8475):234-6. 

PMID: 2868254 

446: Laban E, Charbon GA. 

Magnesium and cardiac arrhythmias: nutrient or drug? 

J Am Coll Nutr. 1986;5(6):521-32. Review. 

PMID: 3537078 

447: Fehlinger R, Mielke U, Fauk D, Seidel K. 

Rheographic indications for reduced cerebral vasoconstriction after oral 



701

magnesium medication in tetanic patients, a double-blind, placebo-controlled 

trial. 

Magnesium. 1986;5(2):60-5. 

PMID: 3713254 

448: Iseri LT. 

Magnesium and cardiac arrhythmias. 


PMID: 3523053 

449: Marier JR. 

Magnesium content of the food supply in the modern-day world. 

Magnesium. 1986;5(1):1-8. Review. 

PMID: 3515057 

450: Rude RK, Adams JS, Ryzen E, Endres DB, Niimi H, Horst RL, Haddad JG Jr, 

Singer FR. 

Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium 

deficiency. 

J Clin Endocrinol Metab. 1985 Nov;61(5):933-40. 

PMID: 3840173 

451: Clemens MG, McDonagh PF, Chaudry IH, Baue AE. 

Hepatic microcirculatory failure after ischemia and reperfusion: improvement 

with ATP-MgCl2 treatment. 

Am J Physiol. 1985 Jun;248(6 Pt 2):H804-11. 

PMID: 3923842 

452: Fuss M, Cogan E, Gillet C, Karmali R, Geurts J, Bergans A, Brauman H, 

Bouillon R, Corvilain J. 

Magnesium administration reverses the hypocalcaemia secondary to 

hypomagnesaemia despite low circulating levels of 25-hydroxyvitamin D and 

1,25-dihydroxy vitamin D. 

Clin Endocrinol (Oxf). 1985 Jun;22(6):807-15. 

PMID: 3874724 

453: Martineau J, Barthelemy C, Garreau B, Lelord G. 

Vitamin B6, magnesium, and combined B6-Mg: therapeutic effects in childhood 

autism. 

Biol Psychiatry. 1985 May;20(5):467-78. 

PMID: 3886023 

454: Delhumeau A, Victor J, Granry JC, Monrigal JP, Chapillon M, Cavellat M. 

[Anti-arrhythmia effects of magnesium salts. 4 cases] 

Presse Med. 1985 Mar 16;14(11):629-32. French. 

PMID: 3157950 



702

455: O'Sullivan G, Sear JW, Bullingham RE, Carrie LE. 

The effect of magnesium trisilicate mixture, metoclopramide and ranitidine on 

gastric pH, volume and serum gastrin. 

Anaesthesia. 1985 Mar;40(3):246-53. 

PMID: 2986474 

456: Hirasawa H, Soeda K, Ohtake Y, Oda S, Kobayashi S, Odaka M, Sato H. 

Effects of ATP-MgCl2 and ATP-Na2 administration on renal function and cellular 

metabolism following renal ischemia. 

Circ Shock. 1985;16(4):337-46. 

PMID: 3836026 

457: Morgan KJ, Stampley GL, Zabik ME, Fischer DR. 

Magnesium and calcium dietary intakes of the U.S. population. 

J Am Coll Nutr. 1985;4(2):195-206. 

PMID: 4019942 

458: Corby DG, McCullen AH, Chadwick EW, Decker WJ. 

Effect of orally administered magnesium hydroxide in experimental iron 

intoxication. 

J Toxicol Clin Toxicol. 1985-86;23(7-8):489-99. 

PMID: 3831376 

459: Cohen L, Kitzes R. 

Early radiation-induced proctosigmoiditis responds to magnesium therapy. 

Magnesium. 1985;4(1):16-9. 

PMID: 4033202 

460: Marier JR, Neri LC. 

Quantifying the role of magnesium in the interrelationship between human 

mortality/morbidity and water hardness. 

Magnesium. 1985;4(2-3):53-9. 

PMID: 4046646 

461: Conradt A, Weidinger H, Algayer H. 

Magnesium therapy decreased the rate of intrauterine fetal retardation, 

premature rupture of membranes and premature delivery in risk pregnancies 

treated with betamimetics. 

Magnesium. 1985;4(1):20-8. 

PMID: 2863425 

462: Pignide L, Hersch R. 

[Efficacy and limits of magnesium therapy in extrasystole] 

Magnesium. 1985;4(5-6):272-9. French. 

PMID: 2422503 



703

463: Ulmann A, Hadj S, Lacour B, Bourdeau A, Bader C. 

Renal magnesium and phosphate wastage in a patient with hypercalciuria and 

nephrocalcinosis: effect of oral phosphorus and magnesium supplements. 

Nephron. 1985;40(1):83-7. 

PMID: 4000339 

464: Lakshmanan FL, Rao RB, Kim WW, Kelsay JL. 

Magnesium intakes, balances, and blood levels of adults consuming self-selected 

diets. 

Am J Clin Nutr. 1984 Dec;40(6 Suppl):1380-9. 

PMID: 6507359 

465: Jonas C, Etienne T, Barthelemy C, Jouve J, Mariotte N. 

[Clinical and biochemical value of Magnesium + vitamin B6 combination in the 

treatment of residual autism in adults] 

Therapie. 1984 Nov-Dec;39(6):661-9. French. 

PMID: 6397868 

466: Reynolds CK, Bell MC, Sims MH. 

Changes in plasma, red blood cell and cerebrospinal fluid mineral 

concentrations in calves during magnesium depletion followed by repletion with 

rectally infused magnesium chloride. 

J Nutr. 1984 Jul;114(7):1334-41. 

PMID: 6737093 

467: Vacanti FX, Ames A 3rd. 

Mild hypothermia and Mg++ protect against irreversible damage during CNS 

ischemia. 

Stroke. 1984 Jul-Aug;15(4):695-98. 

PMID: 6464063 

468: Lewis LD, Morris ML Jr. 

Treatment and prevention of feline struvite urolithiasis. 

Vet Clin North Am Small Anim Pract. 1984 May;14(3):649-60. Review. 

PMID: 6377667 

469: Mills BJ, Broghamer WL, Higgins PJ, Lindeman RD. 

Inhibition of tumor growth by magnesium depletion of rats. 

J Nutr. 1984 Apr;114(4):739-45. 

PMID: 6716176 


[Reduced frequency of gestoses in beta-mimetic treated risk pregnancies with 

added magnesium therapy] 

Geburtshilfe Frauenheilkd. 1984 Feb;44(2):118-23. German. 



704

PMID: 6564044 

471: Schaumann E, Bergmann W. 

[Magnesium, an essential factor in the pathogenesis and therapy of diseases of 

civilization] 

Z Gesamte Hyg. 1984 Feb;30(2):84-7. German. 

PMID: 6711060 

472: Johansson BW. 

Magnesium infusion in decompensated hypomagnesemic patients. 

Acta Pharmacol Toxicol (Copenh). 1984;54 Suppl 1:125-8. 

PMID: 6711328 

473: Suau A, Dominguez Martin A, Ferrando Cucarella J, Juncosa Iglesias L, Munoz 

Benitez J, Nieto Calvet M, Perez Gieb J, Perez Mota A, Pineda Garcia A, 

Rodriguez Sanchez E, et al. 

Treatment of gastric pyrosis with almagate in patients with and without 

endoscopically demonstrable duodenal ulcer. A multicentre clinical trial. 

Arzneimittelforschung. 1984;34(10A):1380-3. 

PMID: 6548926 

474: Llupia J, Lumachi B, Beckett PR, Roberts DJ. 

Protective action of almagate against bile-facilitated gastric ulceration in 

the pylorus-ligated (Shay) rat. 

Arzneimittelforschung. 1984;34(10A):1373-5. 

PMID: 6548924 


[Additional magnesium therapy in tocolysis: clinico-chemical monitoring 

parameters] 

Geburtshilfe Frauenheilkd. 1984 Jan;44(1):19-24. German. 

PMID: 6559720 

476: Karppanen H, Tanskanen A, Tuomilehto J, Puska P, Vuori J, Jantti V, 

Seppanen ML. 

Safety and effects of potassium- and magnesium-containing low sodium salt 

mixtures. 

J Cardiovasc Pharmacol. 1984;6 Suppl 1:S236-43. 

PMID: 6204148 

477: Dyckner T, Wester PO. 

Intra-/extracellular shifts of potassium after the administration of Mg in 

patients with cardiovascular diseases. 

Magnesium. 1984;3(4-6):339-45. 

PMID: 6536841 



705

478: Luoma H, Koskinen M, Tuomisto J, Collan Y. 

Reduction of the lethality and the nephrocalcinotic effect of single fluoride 

doses by magnesium in rats. 

Magnesium. 1984;3(2):81-7. 

PMID: 6503359 

479: Moe BH. 

On the therapeutic mechanism of Mg2+ in digitoxic arrhythmias and the role of 

cardiac glycosides in Mg depletion. 

Magnesium. 1984;3(1):8-20. 

PMID: 6482510 

480: Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. 

Magnesium therapy in acute myocardial infarction--a double-blind study. 

Magnesium. 1984;3(4-6):346-52. 

PMID: 6399346 

481: Cohen L, Laor A, Kitzes R. 

Reversible retinal vasospasm in magnesium-treated hypertension despite no 

significant change in blood pressure. 

Magnesium. 1984;3(3):159-63. 

PMID: 6392763 

482: Buck DR, Bales J. 

Maternal dietary magnesium effects on lactation success and on milk yield and 

composition in the rat. 

J Nutr. 1983 Dec;113(12):2421-31. 

PMID: 6655508 

483: Marie PJ, Travers R, Delvin EE. 

Influence of magnesium supplementation on bone turnover in the normal young 

mouse. 

Calcif Tissue Int. 1983 Sep;35(6):755-61. 

PMID: 6652550 


[Reduction of low weight birth, premature amniotic rupture and premature labor 

following additional magnesium therapy in high risk pregnancy treated with beta 

mimetics and cerclage] 

Geburtshilfe Frauenheilkd. 1983 Jun;43(6):355-62. German. 

PMID: 6554207 

485: Atteh JO, Leeson S. 

Influence of increasing the calcium and magnesium content of the drinking water 

on performance and bone and plasma minerals of broiler chickens. 



706

Poult Sci. 1983 May;62(5):869-74. 

PMID: 6878125 


[The importance of betamimetics and magnesium for the outcome of pregnancy: I. 

Reduction of intrauterine growth retardation, premature rupture of membranes and 

premature birth after supplemental magnesium therapy] 

Z Geburtshilfe Perinatol. 1983 May-Jun;187(3):127-37. Review. German. 

PMID: 6137118 

487: Malestein A. 

[Does the supply of magnesium affect the feed intake in ruminants?] 

Tijdschr Diergeneeskd. 1983 Mar 15;108(6):250-3. Dutch. 

PMID: 6573812 

488: Berthelot A, Esposito J. 

Effects of dietary magnesium on the development of hypertension in the 


J Am Coll Nutr. 1983;2(4):343-53. 

PMID: 6317730 

489: Bartl W, Riss P. 

[Pathophysiology and therapy of magnesium deficiency in pregnancy] 

Z Geburtshilfe Perinatol. 1982 Nov-Dec;186(6):335-7. German. 

PMID: 6891868 

490: Salducci J, Planche D. 

[A therapeutic trial in patients with spasmophilia] 

Sem Hop. 1982 Oct 7;58(36):2097-100. French. 

PMID: 6294844 

491: Harwood EJ. 

The influence of dietary magnesium on reduction of nephrocalcinosis in rats fed 

purified diet. 

Lab Anim. 1982 Oct;16(4):314-8. 

PMID: 7176523 

492: Luoma AR, Koskinen M, Olkkonen H, Luoma H. 

Caries reduction in rats through F + Mg supplementation of dietary sucrose with 

observations on bone mineral density and soft and hard tissue minerals. 

Scand J Dent Res. 1982 Oct;90(5):345-53. 

PMID: 6960464 

493: Wischnik A, Mendler N, Schroll A, Heimisch W, Weidenbach A. 

[The cardiac hazard of tocolysis and antagonizing possibilities. II. 

Communication: protection of the myocardium by means of substitution of 



707

magnesium] 

Geburtshilfe Frauenheilkd. 1982 Jul;42(7):537-42. German. 

PMID: 6922076 

494: Lelord G, Callaway E, Muh JP. 

Clinical and biological effects of high doses of vitamin B6 and magnesium on 

autistic children. 

Acta Vitaminol Enzymol. 1982;4(1-2):27-44. 

PMID: 7124567 

495: Chaudry IH, Kupper TS, Schleck S, Clemens MG, Baue AE. 

Impairment of reticuloendothelial function following thermal injury and its 

restoration with ATP-MgCl2 administration. 

Circ Shock. 1982;9(3):297-305. 

PMID: 7094221 


Magnesium treatment of diuretic-induced hyponatremia with a preliminary report 

of a new aldosterone-antagonist. 

J Am Coll Nutr. 1982;1(2):149-53. 

PMID: 7185847 

497: Johansson G, Backman U, Danielson BG, Fellstrom B, Ljunghall S, Wikstrom B. 

Effects of magnesium hydroxide in renal stone disease. 

J Am Coll Nutr. 1982;1(2):179-85. 

PMID: 6764473 

498: Guillot AP, Hood VL, Runge CF, Gennari FJ. 

The use of magnesium-containing phosphate binders in patients with end-stage 

renal disease on maintenance hemodialysis. 

Nephron. 1982;30(2):114-7. 

PMID: 7099318 

499: Gullner HG, Gill JR Jr, Bartter FC. 

Correction of hypokalemia by magnesium repletion in familial hypokalemic 

alkalosis with tubulopathy. 

Am J Med. 1981 Oct;71(4):578-82. 

PMID: 7025624 

500: Harris JC, Rumack BH, Bregman DJ. 

Comparative efficacy of injectable calcium and magnesium salts in the therapy 

of hydrofluoric acid burns. 

Clin Toxicol. 1981 Sep;18(9):1027-32. 

PMID: 7318388 

501: Stromme JH, Steen-Johnsen J, Harnaes K, Hofstad F, Brandtzaeg P. 



708

Familial hypomagnesemia--a follow-up examination of three patients after 9 to 

12 years of treatment. 

Pediatr Res. 1981 Aug;15(8):1134-9. 

PMID: 7267188 

502: Krasner BS, Girdwood R, Smith H. 

The effect of slow releasing oral magnesium chloride on the QTc interval of the 

electrocardiogram during open heart surgery. 

Can Anaesth Soc J. 1981 Jul;28(4):329-33. 

PMID: 7260710 

503: Gurvich DB, Korovina NA. 

[Effect of a magnesium-enriched diet on electrolyte metabolism and oxalate 

excretion in kidney diseases in children] 

Vopr Pitan. 1981 Jul-Aug;(4):27-30. Russian. 

PMID: 7293102 

504: Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B, Callaway E. 

Effects of pyridoxine and magnesium on autistic symptoms--initial observations. 

J Autism Dev Disord. 1981 Jun;11(2):219-30. 

PMID: 6765503 


Effects of magnesium infusions in diuretic induced hyponatraemia. 

Lancet. 1981 Mar 14;1(8220 Pt 1):585-6. 

PMID: 6110822 


[Oral magnesium therapy in cases of preterm labour (author's transl)] 

Geburtshilfe Frauenheilkd. 1981 Feb;41(2):101-2. German. 

PMID: 6908857 

507: Singh RB, Singh VP, Cameron EA. 

Magnesium in atherosclerotic cardiovascular disease and sudden death. 

Acta Cardiol. 1981;36(6):411-29. 

PMID: 6977957 

508: Karppanen H. 

Epidemiological studies on the relationship between magnesium intake and 

cardiovascular diseases. 

Artery. 1981;9(3):190-9. 

PMID: 7305668 

509: Mesmer M, Fischer G, Classen HG. 

[Inhibition of stress reactions by magnesium. Beneficial effects of parenteral 

magnesium therapy on the development of stress ulcers in rats (author's transl)] 



709

Arzneimittelforschung. 1981;31(2):389-91. German. 

PMID: 7194659 

510: Knox D, Cowey CB, Adron JW. 

Studies on the nutrition of salmonid fish. The magnesium requirement of rainbow 

trout (Salmo gairdneri). 

Br J Nutr. 1981 Jan;45(1):137-48. 

PMID: 7470429 

511: Brundig P, Berg W, Schneider HJ. 

The influence of magnesium chloride on blood and urine parameters in calcium 

oxalate stone patients. 

Eur Urol. 1981;7(2):97-9. 

PMID: 7461010 

512: Main AN, Morgan RJ, Russell RI, Hall MJ, MacKenzie JF, Shenkin A, Fell GS. 

Mg deficiency in chronic inflammatory bowel disease and requirements during 

intravenous nutrition. 

JPEN J Parenter Enteral Nutr. 1981 Jan-Feb;5(1):15-9. 

PMID: 6785467 

513: Cobden I, McMahon MJ, Dixon MF, Axon AT. 

Double-blind clinical, endoscopic and histological comparison of 

hydrotalcite/dimethicone suspension and magnesium hydroxide/aluminum hydroxide 

suspension in the treatment of symptomatic gastritis. 

Pharmatherapeutica. 1981;2(9):607-12. 

PMID: 7267678 

514: Bac P. 

[Audiogenic seizure in the mouse according to strain and sex: the effect of the 

magnesium ration and neuromediators] 

Reprod Nutr Dev. 1981;21(3):429-40. French. 

PMID: 6130580 

515: Horn B. 

Magnesium-it's about time. 

West J Med. 1981 Jan;134(1):72-3. 

PMID: 7210668 

516: Johansson G, Backman U, Danielson BG, Fellstrom B, Ljunghall S, Wikstrom B. 

Biochemical and clinical effects of the prophylactic treatment of renal calcium 

stones with magnesium hydroxide. 

J Urol. 1980 Dec;124(6):770-4. 

PMID: 7441826 

517: Landahl S, Graffner C, Jagenburg R, Lundborg P, Steen B. 



710

Prevalence and treatment of hypomagnesemia in the elderly studies in a 

representative in 70-year-old population and in geriatric patients. 

Aktuelle Gerontol. 1980 Sep;10(9):397-402. 

PMID: 6110376 

518: Siegel NJ, Glazier WB, Chaudry IH, Gaudio KM, Lytton B, Baue AE, Kashgarian 

M. 

Enhanced recovery from acute renal failure by the postischemic infusin of 

adenine nucleotides and magnesium chloride in rats. 

Kidney Int. 1980 Mar;17(3):338-49. 

PMID: 7401453 

519: Binswanger U, Schiffl H, Huggler M, Becker C. 

1,25 dihydroxycholecalciferol treatment of uraemic rats after high magnesium 

feeding. 

Proc Eur Dial Transplant Assoc. 1980;17:563-8. 

PMID: 6894642 

520: Maksimovich IaB, Gaidenko AI, Aksel'rod LB, Malakhova OP. 

[Mechanism of the anti-arrhythmia action of potassium and magnesium 

nicotinates] 

Farmakol Toksikol. 1979 Sep-Oct;42(5):501-4. Russian. 

PMID: 488322 

521: Brautbar N, Lee DB, Coburn JW, Kleeman CR. 

Influence of dietary magnesium in experimental phosphate depletion: bone and 

soft tissue mineral changes. 

Am J Physiol. 1979 Aug;237(2):E152-7. 

PMID: 464091 

522: Chaudry IH, Hirasawa H, Baue AE. 

Impairment of reticuloendothelial system function with sepsis and its 

improvement with ATP-MgCl2 plus glucose administration. 

Adv Shock Res. 1979;2:153-62. 

PMID: 262800 

523: Menotti A, Signoretti P. 

[Characteristics of drinking water and coronary heart disease. An 

epidemiological experience (author's transl)] 

G Ital Cardiol. 1979;9(7):674-7. Italian. 

PMID: 540698 

524: Hirasawa H, Ohkawa M, Odaka M, Sato H. 

Improved survival, RES function, and ICG test with ATP-MgCl2 following hepatic 

ischemia. 

Surg Forum. 1979;30:158-60. 



711

PMID: 538581 

525: Wiberg JJ, Turner GG, Nuttall FQ. 

Effect of phosphate or magnesium cathartics on serum calcium: observations in 

normocalcemic patients. 

Arch Intern Med. 1978 Jul;138(7):1114-6. 

PMID: 666471 

526: Binet P, Miocque M, Pechery C, Roux M, Rinjard P. 

[Comparative corrective effect of magnesium 2-pyrrolidone carboxylate and 

magnesium chloride on skin and hematological disorders in experimental magnesium 

deficiency in the rat] 

Therapie. 1978 Jul-Aug;33(4):491-500. French. 

PMID: 734628 

527: Hirasawa H, Chaundry IH, Baue AE. 

Improved hepatic function and survival with adenosine triphosphate-magnesium 

chloride after hepatic ischemia. 

Surgery. 1978 Jun;83(6):655-62. 

PMID: 644458 

528: Moore MJ, Flink EB. 

Magnesium deficiency as a cause of serious arrhythmias. 

Arch Intern Med. 1978 May;138(5):825-6. 

PMID: 646549 

529: Borges LF, Gucer G. 

Effect of magnesium on epileptic foci. 

Epilepsia. 1978 Feb;19(1):81-91. 

PMID: 414910 

530: Holdsworth JD. 

A fresh look at magnesium trisilicate. 

J Int Med Res. 1978;6 Suppl 1:70-6. 

PMID: 35427 

531: Lytton B, Glazier WB, Chaudry IH, Baue AE. 

The use of adenosine triphosphate with magnesium chloride in the treatment of 

post ischemic renal injury. 

Trans Am Assoc Genitourin Surg. 1978;70:145-8. 

PMID: 753014 

532: Schneider HJ, Hesse A, Berg W, Kirsten J, Nickel H. 

[Animal-experiment studies on the effect of magnesium and vitamin B 6 on 

calcium-oxalate nephrolithiasis] 

Z Urol Nephrol. 1977 Jun;70(6):419-27. German. 



712

PMID: 906678 

533: Jorgensen I, Schjelderup-Mathiesen PM. 

[Magnesium--an alternative in treatment resistant tachyarrhythmias] 

Tidsskr Nor Laegeforen. 1977 May 30;97(15):770-769. Norwegian. 

PMID: 867390 

534: Bletry O, Certin M, Herreman G, Wechsler B, Godeau P. 

[Hypokalemia and hypomagnesemia in a cirrhotic patient. Correction of metabolic 

disorders by magnesium] 

Sem Hop. 1977 May 23;53(20):1175-8. French. 

PMID: 198892 

535: Berthelot A, Miss-Pages C, Gairard A. 

[Calcium metabolism and mineralocorticoid-induced hypertension: effects of 

parathormone and exogenous thyrocalcitonin and of variations in dietary calcium 

and magnesium] 

C R Seances Soc Biol Fil. 1977;171(5):1101-6. French. 

PMID: 146554 

536: Freeman JB, Wittine MF. 

Magnesium requirements are increased during total parenteral nutrition. 

Surg Forum. 1977;28:61-2. 

PMID: 103228 

537: Hutchinson BR. 

Preoperative magnesium trisilicate in infants. 

Anaesth Intensive Care. 1976 Aug;4(3):192-5. 

PMID: 9840 

538: Anast C, David L, Winnacker J, Glass R, Baskin W, Brubaker L, Burns T. 

Serum calcitonin-lowering effect of magnesium in patients with medullary 

carcinoma of the thyroid. 

J Clin Invest. 1975 Dec;56(6):1615-21. 

PMID: 1202087 

539: Hadlich M, Kolb E. 

[Calcium, magnesium, phosphorus, chloride and glucose in the blood of cattle 

following intravenous infusion of solutions with various calcium and magnesium 

concentration aimed at improving the treatment of hypomagnesemia] 

Arch Exp Veterinarmed. 1975 Jun;29(3):379-95. German. 

PMID: 1190966 

540: Pointillart A, Meslin JC. 

[Effect of dietary magnesium levels on cardiac lesions in rats fed a diet rich 

in rapeseed oil] 



713

Nutr Metab. 1975;19(1-2):10-9. French. 

PMID: 1226266 

541: Catto GR, MacLeod M, Pelc B, Kodicek E. 

The investigation and treatment of renal osteodystrophy. 

Proc Eur Dial Transplant Assoc. 1975;11:473-80. 

PMID: 1197272 

542: Slezak J, Tribulova N. 

Morphological changes after combined administration of isoproterenol and 

K+,Mg2+-aspartate as a physiological Ca2+ antagonist. 

Recent Adv Stud Cardiac Struct Metab. 1975;6:75-84. 

PMID: 1197902 

543: Janke J, Fleckenstein A, Hein B, Leder O, Sigel H. 

Prevention of myocardial Ca overload and necrotization by Mg and K salts or 

acidosis. 


PMID: 743 

544: Classen HG, Marquardt P, Spath M, Ebel H, Schumacher KA. 

Improvement by chlorine of the intestinal absorption of inorganic and organic 

Mg compounds and of their protective effect against adrenergic cardiopathy. 


PMID: 128076 

545: Ghani MF, Smith JR. 

The effectiveness of magnesium chloride in the treatment of ventricular 

tachyarrhythmias due to digitalis intoxication. 

Am Heart J. 1974 Nov;88(5):621-6. 

PMID: 4419576 

546: Izawa H, Imura M, Kuroda M, Takeda R. 

Proceedings: Effect of magnesium on secondary hyperparathyroidism in chronic 

hemodialysis: a case with soft tissue calcification improved by high Mg 

dialysate. 

Calcif Tissue Res. 1974;15(2):162. 

PMID: 4844404 

547: Levin MP, Yearwood LL, Carpenter WN. 

The desensitizing effect of calcium hydroxide and magnesium hydroxide on 

hypersensitive dentin. 

Oral Surg Oral Med Oral Pathol. 1973 May;35(5):741-6. 

PMID: 4573138 

548: Rosler A, Rabinowitz D. 



714

Magnesium-induced reversal of vitamin-D resistance in hypoparathyroidism. 

Lancet. 1973 Apr 14;1(7807):803-4. 

PMID: 4121224 

549: Prikryl P. 

[Positive therapeutic effect of K-Mg asparaginate in Prinzmetal's angina 

pectoris and Adams-Stokes syndrome] 

Cas Lek Cesk. 1973 Feb;112(6):186. Czech. 

PMID: 4726977 

550: Szelenyi I. 

Magnesium and its significance in cardiovascular and gastro-intestinal 

disorders. 

World Rev Nutr Diet. 1973;17:189-224. Review. 

PMID: 4570425 

551: Ringenbach MG. 

[Decrease in transfusion reactions by the use of magnesium thiosulfate] 

Bord Med. 1972 Dec;5(20):2743-6. French. 

PMID: 4660157 

552: Fernandez PC, Kovnat PJ. 

Metabolic acidosis reversed by the combination of magnesium hydroxide and a 

cation-exchange resin. 

N Engl J Med. 1972 Jan 6;286(1):23-4. 

PMID: 5006921 

553: Tokumaru M, Takaoka A, Inoue H, Tateichi K. 

[Effective treatment of tetany in a newborn infant by combined administration 

of magnesium and calcium] 

Nippon Shonika Gakkai Zasshi. 1971 Oct;75(10):913-6. Japanese. 

PMID: 5169738 

554: Wenzel E. 

[The therapeutic effect of kavain and magnesium orotate on traumatic and 

vascular brain lesions] 

Wien Med Wochenschr. 1971 Mar 20;121(12):226-36. German. 

PMID: 5556378 

555: Casucci N, Girardi F, Argentieri R, Venezia L. 

[On a case of grave disorders of cardiac rhythm caused by hyper-potassemia, in 

a patient in hemodialytic therapy, controlled with Mg ascorbate] 

Minerva Nefrol. 1970 Nov-Dec;17(6):208-12. Italian. 

PMID: 5516057 

556: Villanyi P, Votin J, Rahlfs V. 



715

[Arteriosclerosis, myocardial infarct and blood lipids, their therapeutic 

modification by magnesium orotate] 

Wien Med Wochenschr. 1970 Jan 31;120(5):76-83. German. 

PMID: 5513887 

557: Golber LM, Anan'eva KA, Kandror VI, Kriukova IV, Negovskaia AV. 

[The importance of magnesium in preventing myocardial metabolic disorders in 

thyrotoxicosis] 

Biull Eksp Biol Med. 1969 Mar;67(3):23-6. Russian. 

PMID: 5821450 

558: Stein DG, Brink JJ. 

Prevention of retrograde amnesia by injection of magnesium pemoline in 

dimethylsulfoxide. 

Psychopharmacologia. 1969;14(3):240-7. 

PMID: 5389242 

559: Szulc EJ. 

[Clinical studies on the therapeutic effect of potassium-magnesium aspartate in 

coronary disease] 

Wiad Lek. 1968 Sep 1;21(17):1509-14. Polish. 

PMID: 4882478 

560: Combes-Hamelle A, Stelian Y. 

[Value of magnesium bromoglutamate syrup for problems of behavior and 

psychomotor development of the child] 

Ann Pediatr (Paris). 1968 Aug-Sep;15(8):585-6. French. 

PMID: 5685048 

561: Bertharion G. 

[Magnesium lactate used as protective agent against hyperoxemia convulsions in 

white rats] 

J Physiol (Paris). 1968;60 Suppl 2:348. French. 

PMID: 5734904 


Magnesium--its nutritional and pharmacologic effects. 

Med Lett Drugs Ther. 1967 Nov 17;9(23):93-4. 

PMID: 6054465 

563: Atlan D, Regis H, Gastaut H. 

Treatment of spasmophilia in the adult by magnesium lactate. 

Electroencephalogr Clin Neurophysiol. 1967 Oct;23(4):388. 

PMID: 4167803 



716

564: Reichertz PL, Noell G, Hemmati A. 

[Therapy of disorders of myocardial metabolism with potassium-magnesium 

aspartate] 

Med Welt. 1967 Sep 23;38:2236-43. German. 

PMID: 5614953 

565: Atlan D, Regis H, Gastaut H. 

[Treatment of spasmophilia of the adult by magnesium lactate] 

Rev Neurol (Paris). 1967 Jul;117(1):170-7. French. 

PMID: 4863462 

566: de Alencastro GG, da Fonseca JP. 

[Therapy of sickle cell anemia by alkalies and magnesium salts. Presentation of 

a case] 

Hospital (Rio J). 1967 Jun;71(6):1771-4. Portuguese. 

PMID: 5304212 

567: Durlach J. 

[The physiologic role of magnesium. Phlebothrombotic disease due to magnesium 

deficiency] 

Coeur Med Interne. 1967 Apr;6(2):213-32. French. 

PMID: 5618969 

568: Guerrier Y. 

[Magnesium lactate in the treatment of pharyngo-laryngeal paresthesia] 

J Fr Otorhinolaryngol Audiophonol Chir Maxillofac. 1967 Apr;16(4):289-90. 

French. 

PMID: 4241457 

569: Kwitko ML, Wener J, Simon MA, Pintar K. 

The inhibition of iris lipidosis in rabbits with oral magnesium. 

Can J Ophthalmol. 1966 Jul;1(3):240-8. 

PMID: 5914355 

570: Dumont M. 

[Treatment of uterine pain in pregnancy with magnesium lactate] 

Lyon Med. 1965 May 23;213(21):1571-82. French. 

PMID: 5828798 



717

Quercetin - 30 ABSTRACTS 

1. Pharmacology. 2003 Oct;69(2):59-67. Protective Effect of Flavonoids against Aging- 

and Lipopolysaccharide-Induced 

Cognitive Impairment in Mice.Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, 

Kulkarni SK. 

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab 

University, Chandigarh, India. 

Flavonoids, naturally occurring polyphenolic compounds, are known to inhibitboth 

lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha and interleukin 6 release 

which modulate the proinflammatory molecules that have been reported in many 

progressive neurodegenerative disorders, including Alzheimer's disease (AD), viral and 

bacterial meningitis, AIDS dementia complex,and stroke. The present experiments were 

performed to study the possible effects of exogenously administered flavonoids 

(apigenin-7-glucoside and quercetin) on the cognitive performance in aged and LPStreated 

mice (an animal model for AD) using passive avoidance and elevated plus-maze 

tasks. Aged and LPS-treated mice showed poor retention of memory in step-through 

passive avoidance and in plus-maze tasks. Chronic administration of the flavonoids 

apigenin-7-glucoside (5-20 mg/kg i.p.) and quercetin (25-100 mg/kg i.p.) dose 

dependently reversed the age-induced and LPS-induced retention deficits in both test 

paradigms. However, flavonoids after chronic administration in young mice did not show 

any improvement of memory retention in both paradigms. Apigenin-7-glucoside showed 

more efficacy as compared with quercetin in both models that may be probably due to its 

greater efficacy to inhibit cyclooxygenase-2 and inducible nitric oxide synthase. Chronic 

treatment with flavonoids did not alter the locomotor activity in both young and aged 

mice; however, aged mice showed improvement of performance on Rota-Rod test. The 

results showed that chronic treatment with flavonoids reverses cognitive deficits in aged 

and LPS-intoxicated mice which suggests that modulation of cyclooxygenase-2 and 

inducible nitric synthase by flavonoids may be important in the prevention of memory 

deficits, one of the symptoms related to AD. Copyright 2003 S. Karger AG, Basel 

2. Clin Pharmacokinet. 2003;42(5):437-59. 

Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative 

stress. 

Schwedhelm E, Maas R, Troost R, Boger RH. 

Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology Unit, 

University Hospital of Hamburg-Eppendorf, Hamburg, Germany. 

schwedhelm@uke-hamburg.de 

Dietary antioxidants play a major role in maintaining the homeostasis of the 

oxidative balance. They are believed to protect humans from disease and aging. 

Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and other 



718

micronutrients such as carotenoids, polyphenols and selenium have been evaluated as 

antioxidant constituents in the human diet. This article addresses data provided from 

clinical trials, highlighting the clinical pharmacokinetics of 

vitamin C, vitamin E, beta-carotene, lycopene, lutein, quercetin, rutin, 

catechins and selenium. The bioavailability of vitamin C is dose-dependent. 

Saturation of transport occurs with dosages of 200-400 mg/day. Vitamin C is not 

protein-bound and is eliminated with an elimination half-life (t((1/2))) of 10 

hours. In Western populations plasma vitamin C concentrations range from 54-91 

micro mol/L. Serum alpha- and gamma-tocopherol range from 21 micro mol/L (North 

America) to 27 micro mol/L (Europe) and from 3.1 micro mol/L to 1.5 micro mol/L, 

respectively. alpha-Tocopherol is the most abundant tocopherol in human tissue. The 

bioavailability of all-rac-alpha-tocopherol is estimated to be 50% of R,R,R-alphatocopherol. 

The hepatic alpha-tocopherol transfer protein 

(alpha-TTP) together with the tocopherol-associated proteins (TAP) are 

responsbile for the endogenous accumulation of natural alpha-tocopherol. 

Elimination of alpha-tocopherol takes several days with a t((1/2)) of 81 and 73 

hours for R,R,R-alpha-tocopherol and all-rac-alpha-tocopherol, respectively. The 

t((1/2)) of tocotrienols is short, ranging from 3.8-4.4 hours for gamma- and 

alpha-tocotrienol, respectively. gamma-Tocopherol is degraded to 2, 7, 

8-trimethyl-2-(beta-carboxyl)-6-hyrdoxychroman by the liver prior to renal 

elimination. Blood serum carotenoids in Western populations range from 0.28-0.52 micro 

mol/L for beta-carotene, from 0.2-0.28 for lutein, and from 0.29-0.60 for lycopene. Alltrans-carotenoids 

have a better bioavailability than the 

9-cis-forms. Elimination of carotenoids takes several days with a t((1/2)) of 

5-7 and 2-3 days for beta-carotene and lycopene, respectively. The bioconversion of betacarotene 

to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg 

dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols 

such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to 

plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl 

moieties. The t((1/2)) ranges from 12-19 hours. The bioavailabillity of catechins is low 

and they are eliminated with a t((1/2)) of 2-4 hours. Catechins are degraded to several 

gamma-valerolactone derivatives and phase II conjugates have also been identified. Only 

limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been 

reported to date. 

3. Neurobiol Aging. 2002 Sep-Oct;23(5):891-97. 

Natural extracts as possible protective agents of brain aging. 

Bastianetto S, Quirion R. 

Department of Psychiatry and Pharmacology and Therapeutics, Douglas Hospital 

Research Centre, McGill University, 6875 LaSalle Boulevard, Verdun, Que, Canada 

H4H 1R3. 

A growing number of studies suggest that natural extracts and phytochemicals 

have a positive impact on brain aging. We examined the potential of the Ginkgo 



719

iloba extract EGb 761 and red wine-derived constituents on cell death produced 

by beta-amyloid (Abeta) peptides and oxidative stress, with respect to their 

possible deleterious role in age-related neurological disorders. We found that 

EGb 761, possibly through the antioxidant properties of its flavonoids, was able 

to protect hippocampal cells against toxic effects induced by Abeta peptides. 

Moreover, we showed that an exposure of rat hippocampal cells to the nitric 

oxide (NO) donor sodium nitroprusside (SNP) resulted in a decrease in cell 

survival and increase in reactive oxygen species (ROS) accumulation. However, 

EGb 761 and red wine-derived polyphenols protected against these events, due to their 

antioxidant activities, and their ability to block SNP-stimulated activity 

of protein kinase C (PKC). Taken together, these results support the hypothesis that 

dietary intake of natural substances may be beneficial in normal aging of the brain. 

Copyright 2002 Elsevier Science Inc. 

4. Mol Biol Cell. 2002 Jul;13(7):2502-17. 

Expression of caveolin-1 induces premature cellular senescence in primary 

cultures of murine fibroblasts. 

Volonte D, Zhang K, Lisanti MP, Galbiati F. 

Department of Pharmacology, University of Pittsburgh School of Medicine, 

Pittsburgh, Pennsylvania 15261, USA. 

Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the 

principal structural component of caveolae in vivo. Several lines of evidence 

are consistent with the idea that caveolin-1 functions as a "transformation 

suppressor" protein. In fact, caveolin-1 mRNA and protein expression are lost or 

reduced during cell transformation by activated oncogenes. Interestingly, the 

human caveolin-1 gene is localized to a suspected tumor suppressor locus 

(7q31.1). We have previously demonstrated that overexpression of caveolin-1 

arrests mouse embryonic fibroblasts in the G(0)/G(1) phase of the cell cycle 

through activation of a p53/p21-dependent pathway, indicating a role of 

caveolin-1 in mediating growth arrest. However, it remains unknown whether 

overexpression of caveolin-1 promotes cellular senescence in vivo. Here, we 

demonstrate that mouse embryonic fibroblasts transgenically overexpressing 

caveolin-1 show: 1) a reduced proliferative lifespan; 2) senescence-like cell 

morphology; and 3) a senescence-associated increase in beta-galactosidase 

activity. These results indicate for the first time that the expression of 

caveolin-1 in vivo is sufficient to promote and maintain the senescent 

phenotype. Subcytotoxic oxidative stress is known to induce premature senescence in 

diploid fibroblasts. Interestingly, we show that subcytotoxic level of 

hydrogen peroxide induces premature senescence in NIH 3T3 cells and increases 

endogenous caveolin-1 expression. Importantly, quercetin and vitamin E, two antioxidant 

agents, successfully prevent the premature senescent phenotype and the up-regulation of 

caveolin-1 induced by hydrogen peroxide. Also, we demonstrate that hydrogen peroxide 

alone, but not in combination with quercetin, stimulates the caveolin-1 promoter activity. 

Interestingly, premature senescence induced by hydrogen peroxide is greatly reduced in 



720

NIH 3T3 cells harboring antisense caveolin-1. Importantly, induction of premature 

senescence is recovered when caveolin-1 levels are restored. Taken together, these results 

clearly indicate a central role for caveolin-1 in promoting cellular senescence and they 

suggest the hypothesis that premature senescence may represent a tumor suppressor 

function mediated by caveolin-1 in vivo. 

5. Mech Ageing Dev. 2000 Dec 20;121(1-3):217-30. 

Antioxidants may contribute in the fight against ageing: an in vitro model. 

Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR. 

Molecular Physiology, Unilever Research Laboratory Colworth, Sharnbrook, Bedford 

MK44 1LQ, UK. 

Elderly humans have altered cellular redox levels and dysregulated immune 

responses, both of which are key events underlying the progression of chronic 

degenerative diseases of ageing, such as atherosclerosis and Alzeimer's disease. Poorly 

maintained cellular redox levels lead to elevated activation of nuclear transcription 

factors such as NFkB and AP-1. These factors are co-ordinately responsible for a huge 

range of extracellular signalling molecules responsible for inflammation, tissue 

remodelling, oncogenesis and apoptosis, progessess that orchestrate many of the 

degenerative processess associated with ageing. It is now clear that levels of endogenous 

anti-oxidants such as GSH decrease with age. This study aimed to investigate the 

potential of exogenous anti-oxidants to influence inflammatory responses and the ageing 

process itself. We investigated the potential of the dietary antioxidant, quercetin, to 

reverse the age related influences of GSH depletion and oxidative stress using in vitro 

human umbilical vein endothelial cells (HUVEC) and human skin fibroblast (HSF) cell 

models. Oxidative stress-induced inflammatory responses were investigated in a GSH 

depletion and a Phorbol 12-myristate 13-acetate (PMA)-induced stress model. As 

measured with a sensitive HPLC fluorescence method, GSH in HUVEC was depleted by 

the addition of L-buthionine-[S,R]-sulfoxiniine (BSO), a gamma-glutamylcysteine 

synthetase inhibitor, to the culture medium at a concentration of 0.25 mM. Time course 

studies revealed that the GSH half-life was 4.6 h in HUVEC. GSH depletion by BSO for 

24 h led to a slight increase in intracellular adhesion molecule – 1 (ICAM1) expression 

and prostaglandin E2 (PGE2) secretion in both types of cells. However, GSH depletion 

markedly enhanced PMA-induced ICAM and PGE2 production in HUVEC. Responses 

were progressively elevated following prolonged BSO treatment. Inhibition studies 

showed that 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a protein kinase C 

(PKC) inhibitor, not only abolished most of PMA-induced ICAM-1 expression and 

PGE2, production, but also eliminated GSH depletion-enhanced PMA stimulation. This 

enhancement was also inhibited by supplementation with quercetin. The results clearly 

demonstrate that GSH depletion increased the susceptibility of vascular endothelial cells 

and fibroblasts to oxidative stress associated inflammatory stimuli. This increased in vitro 

susceptibility may be extrapolated to the in vivo situation of ageing, providing a useful 

model to study the influence of micronutrients on the ageing process. In conclusion, these 

data suggest that dietary antioxidants could play a significant role in the reduction of 

inflammatory responses. 



721

6. Eur J Clin Nutr. 2000 May;54(5):415-7. 

Quercetin intake and the incidence of cerebrovascular disease. 

Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Hakkinen S, Aromaa A, 

Reunanen A. 

National Public Health Institute, Helsinki, Finland. paul.knekt@ktl.fi 

OBJECTIVE: To study the relation between intake of the antioxidant flavonoid 

quercetin and subsequent incidence of cerebrovascular disease (CVA). DESIGN: A 

cohort study carried out among 9208 Finnish men and women 15 y or more of age and 

initially free from cardiovascular disease. During a 28 y follow-up period in 1967-1994, a 

total of 824 cases with CVA were diagnosed. METHODS: Food consumption data were 

collected using a dietary history interview method covering the total habitual diet during 

the previous year. RESULTS: Quercetin intake was not associated with CVA incidence. 

The relative risk of CVA adjusted for age, serum cholesterol, body mass index, smoking, 

hypertension, diabetes, geographical area, occupation and intake of beta-carotene, 

vitamin E, vitamin C, fibre, various fatty acids, and energy between the highest and 

lowest quartiles of quercetin intake was 0.99 (95% confidence interval (CI)=0.71-1.38) 

for men and 0.85 (CI=0.60-1.21) for women. In contrast, apples, the major source of 

quercetin in the study population, showed a significant inverse associationn both in men 

and women, mainly due to an association with thrombotic or embolic stroke. The relative 

risks of thrombotic stroke after further adjustment for quercetin intake were 0.59 

(CI=0.35-0.99; P=0.45) and 0.61 (CI=0.33-1.12: P for trend=0.02) for men and women, 

respectively. CONCLUSIONS: The results suggest that the intake of apples is related to a 

decreased risk of thrombotic stroke. This association apparently is not due to the presence 

of the antioxidant flavonoid quercetin. 

7. Free Radic Biol Med. 1997;22(4):669-78. 

Quercetin protects cutaneous tissue-associated cell types including sensory 

neurons from oxidative stress induced by glutathione depletion: cooperative 

effects of ascorbic acid. 

Skaper SD, Fabris M, Ferrari V, Dalle Carbonare M, Leon A. 

Researchlife S.c.p.A., Castelfranco Veneto, Italy. 

Oxidation reactions are essential biological reactions necessary for the 

formation of high-energy compounds used to fuel metabolic processes, but can be 

injurious to cells when produced in excess. Cutaneous tissue is especially 

susceptible to damage mediated by reactive oxygen species and low-density 

lipoprotein oxidation, triggered by dysmetabolic diseases, inflammation, 

environmental factors, or aging. Here we have examined the ability of the 

flavonoid quercetin to protect cutaneous tissue-associated cell types from 

injury induced by oxidative stress, and possible cooperative effects of ascorbic 

acid. Human skin fibroblasts, keratinocytes, and endothelial cells were cultured 

in the presence of buthionine sulfoximine (BSO), an irreversible inhibitor of 



722

glutathione (GSH) synthesis. Depletion of intracellular levels of GSH leads to 

an accumulation of cellular peroxides and eventual cell death. Quercetin 

concentration-dependently (EC50: 30-40 microM) reduced oxidative injury of BSO to all 

cell types, and was also effective when first added after BSO washout. 

BSO caused marked decreases in the intracellular level of GSH, which remained 

depressed in quercetin-protected cells. Ascorbic acid, while by itself not 

cytoprotective synergized with quercetin, lowered the quercetin EC50 and 

prolonged the window for cytoprotection. The related flavonoids rutin and 

dihydroquercetin also decreased BSO-induced injury to dermal fibroblasts, albeit 

less efficaciously so than quercetin. The cytoprotective effect of rutin, but 

not that of dihydroquercetin, was enhanced in the presence of ascorbic acid. 

Further, quercetin rescued sensory ganglion neurons from death provoked by GSH 

depletion. Direct oxidative injury to this last cell type has not been 

previously demonstrated. The results show that flavonoids are broadly protective for 

cutaneous tissue-type cell populations subjected to a chronic intracellular form of 

oxidative stress. Quercetin in particular, paired with ascorbic acid, may be of therapeutic 

benefit in protecting neurovasculature structures in skin from oxidative damage. 

8. Exp Gerontol. 1982;17(3):213-7. 

Quercetin, flavonoids and the life-span of mice. 

Jones E, Hughes RE. 

A dietary supplement of 0.1% quercetin significantly reduced the life span of 

mice. The effect was predominantly on the 'shorter living' males. A blackcurrant 

juice extract, containing a mixture of flavonoids in addition to quercetin, 

prolonged significantly the life span of the 'older dying' females. The 

significance of these results vis-a-vis aging mechanisms and the dietary intake 

of quercetin is discussed. 

9. Biochem Pharmacol. 1992 Mar 17;43(6):1167-79. 

Effects of flavonoids on immune and inflammatory cell functions. 

Middleton E Jr, Kandaswami C. 

Department of Medicine, State University of New York, Buffalo 14203. 

No doubt can remain that the flavonoids have profound effects on the function of 

immune and inflammatory cells as determined by a large number and variety of in vitro 

and some in vivo observations. That these ubiquitous dietary chemicals may have 

significant in vivo effects on homeostasis within the immune system and on the behavior 

of secondary cell systems comprising the inflammatory response seems highly likely but 

more work is required to strengthen this hypothesis. Ample evidence indicates that 

selected flavonoids, depending on structure, can affect (usually inhibit) secretory 

processes, mitogenesis, and cell-cell interactions including possible effects on adhesion 

molecule expression and function. The possible action of flavonoids on the function of 

cytoskeletal elements is suggested by their effects on secretory processes. Moreover, 



723

evidence indicates that certain flavonoids may affect gene expression and the elaboration 

and effects of cytokines and cytokine receptors. How all of these effects are mediated is 

not yet clear but one important mechanism may be the capacity of flavonoids to stimulate 

or inhibit protein phosphorylation and thereby regulate cell function. Perhaps the 

counterbalancing effect of cellular protein tyrosine phosphatases will also be found to be 

affected by flavonoids. Some flavonoid effects can certainly be attributed to their 

recognized antioxidant and radical scavenging properties. A potential mechanism of 

action that requires scrutiny, particularly in relation to enzyme inhibition, is the redox 

activity of appropriately configured flavonoids. Finally, in a number of 

cell systems it seems that resting cells are not affected significantly by flavonoids but 

once a cell becomes activated by a physiological stimulus a flavonoid-sensitive substance 

is generated and interaction of flavonoids with that substance dramatically alters the 

outcome of the activation process. 

10. Thromb Res. 1991 Oct 1;64(1):91-100. 

Inhibition of platelet aggregation by some flavonoids. 

Tzeng SH, Ko WC, Ko FN, Teng CM. 

Department of Pharmacology, Taipei Medical College, Taiwan. 

The inhibitory effects of five flavonoids on the aggregation and secretion of 

platelets were studied. These flavonoids inhibited markedly platelet aggregation 

and ATP release of rabbit platelets induced by arachidonic acid or collagen, and 

slightly those by platelet-activating factor. ADP-induced platelet aggregation 

was also suppressed by myricetin, fisetin and quercetin. The IC50 on arachidonic 

acid-induced platelet aggregation was: fisetin, 22 microM; kaempferol, 20 

microM; quercetin, 13 microM; morin, 150 microM less than IC50 less than 300 

microM. The thromboxane B2 formations were also inhibited by flavonoids in 

platelets challenged with arachidonic acid. Fisetin, kaempferol, morin and 

quercetin antagonized the aggregation of washed platelets induced by U46619, a 

thromboxane A2/prostaglandin endoperoxides mimetic receptor agonist. In human 

platelet-rich plasma, quercetin prevented the secondary aggregation and blocked 

ATP release from platelets induced by epinephrine or ADP. These results 

demonstrate that the major antiplatelet effect of flavonoids tested may be due 

to both the inhibition of thromboxane formation and thromboxane receptor 

antagonism. 

11. Am J Clin Nutr. 2000 Nov;72(5):1150-5. 

Erratum in: 

Am J Clin Nutr 2001 Feb;73(2):360. 

The flavonoids quercetin and catechin synergistically inhibit platelet function 

by antagonizing the intracellular production of hydrogen peroxide. 

Pignatelli P, Pulcinelli FM, Celestini A, Lenti L, Ghiselli A, Gazzaniga PP, 

Violi F. 

Department of Experimental Medicine and Pathology, Institute of 1st Clinical 



724

Medicine, University La Sapienza, National Institute for Nutrition, Rome, Italy. 

gazzaniga@uniroma1.it 

BACKGROUND: Epidemiologic studies have shown an inverse relation between 

moderate consumption of red wine and cardiovascular disease. Studies have shown 

that red wine and its component flavonoids inhibit in vivo platelet activation, 

but the underlying mechanism has not yet been identified. OBJECTIVE: Because we 

showed previously that collagen-induced platelet aggregation is associated with 

a burst of hydrogen peroxide, which in turn contributes to stimulating the 

phospholipase C pathway, the aim of this study was to investigate whether 

flavonoids synergize in inhibiting platelet function and interfere with platelet 

function by virtue of their antioxidant effect. DESIGN: We tested the effect of 

2 flavonoids, quercetin and catechin, on collagen-induced platelet aggregation 

and hydrogen peroxide and on platelet adhesion to collagen. RESULTS: Catechin 

(50-100 micromol/L) and quercetin (10-20 micromol/L) inhibited collagen-induced 

platelet aggregation and platelet adhesion to collagen. The combination of 25 

micromol catechin/L and 5 micromol quercetin/L, neither of which had any effect 

on platelet function when used alone, significantly inhibited collagen-induced 

platelet aggregation and platelet adhesion to collagen. Such a combination 

strongly inhibited collagen-induced hydrogen peroxide production, calcium 

mobilization, and 1,3,4-inositol triphosphate formation. CONCLUSIONS: These data 

indicate that flavonoids inhibit platelet function by blunting hydrogen peroxide 

production and, in turn, phospholipase C activation and suggest that the 

synergism among flavonoids could contribute to an understanding of the relation 

between the moderate consumption of red wine and the decreased risk of 

cardiovascular disease. 

12. Lancet. 1993 Oct 23;342(8878):1007-11. 

Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen 

Elderly Study. 

Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. 

National Institute of Public Health and Environment Protection, Bilthoven, 

Netherlands. 

Flavonoids are polyphenolic antioxidants naturally present in vegetables, 

fruits, and beverages such as tea and wine. In vitro, flavonoids inhibit 

oxidation of low-density lipoprotein and reduce thrombotic tendency, but their 

effects on atherosclerotic complications in human beings are unknown. We 

measured the content in various foods of the flavonoids quercetin, kaempferol, 

myricetin, apigenin, and luteolin. We then assessed the flavonoid intake of 805 

men aged 65-84 years in 1985 by a cross-check dietary history; the men were then 

followed up for 5 years. Mean baseline flavonoid intake was 25.9 mg daily. The 

major sources of intake were tea (61%), onions (13%), and apples (10%). Between 

1985 and 1990, 43 men died of coronary heart disease. Fatal or non-fatal 

myocardial infarction occurred in 38 of 693 men with no history of myocardial 



725

infarction at baseline. Flavonoid intake (analysed in tertiles) was 

significantly inversely associated with mortality from coronary heart disease (p 

for trend = 0.015) and showed an inverse relation with incidence of myocardial 

infarction, which was of borderline significance (p for trend = 0.08). The 

relative risk of coronary heart disease mortality in the highest versus the 

lowest tertile of flavonoid intake was 0.42 (95% CI 0.20-0.88). After adjustment 

for age, body-mass index, smoking, serum total and high-density-lipoprotein 

cholesterol, blood pressure, physical activity, coffee consumption, and intake 

of energy, vitamin C, vitamin E, beta-carotene, and dietary fibre, the risk was 

still significant (0.32 [0.15-0.71]). Intakes of tea, onions, and apples were 

also inversely related to coronary heart disease mortality, but these 

associations were weaker. Flavonoids in regularly consumed foods may reduce the 

risk of death from coronary heart disease in elderly men. 

13. Arch Intern Med. 1996 Mar 25;156(6):637-42. 

Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the Zutphen 

study. 

Keli SO, Hertog MG, Feskens EJ, Kromhout D. 

Department of Chronic Disease and Environmental Epidemiology, National Institute 

of Public Health and Environmental Protection, Bilthoven, The Netherlands. 

BACKGROUND: Epidemiological studies suggested that consumption of fruit and 

vegetables may protect against stroke. The hypothesis that dietary antioxidant 

vitamins and flavonoids account for this observation is investigated in a 

prospective study. METHODS: A cohort of 552 men aged 50 to 69 years was examined 

in 1970 and followed up for 15 years. Mean nutrient and food intake was 

calculated from cross-check dietary histories taken in 1960, 1965, and 1970. The 

association between antioxidants, selected foods, and stroke incidence was 

assessed by Cox proportional hazards regression analysis. Adjustment was made 

for confounding by age, systolic blood pressure, serum cholesterol, cigarette 

smoking, energy intake, and consumption of fish and alcohol. RESULTS: Forty-two 

cases of first fatal or nonfatal stroke were documented. Dietary flavonoids 

(mainly quercetin) were inversely associated with stroke incidence after 

adjustment for potential confounders, including antioxidant vitamins. The 

relative risk (RR) of the highest vs the lowest quartile of flavonoid intake ( > 

or = 28.6 mg/d vs

14. Surgery. 2002 Feb;131(2):198-204. 

Quercetin inhibits human vascular smooth muscle cell proliferation and migration. 

Alcocer F, Whitley D, Salazar-Gonzalez JF, Jordan WD, Sellers MT, Eckhoff DE, 

Suzuki K, Macrae C, Bland KI. 

Department of Surgery, University of Alabama at Birmingham, 35294-0007, USA. 

BACKGROUND: The French paradox has been associated with regular intake of red 

wine, which is enriched with flavonoids. Quercetin, a flavonoid present in the 

human diet, exerts cardiovascular protection through its antioxidant properties. 

We hypothesized that the beneficial effect of quercetin also could be related to 

the inhibition of vascular smooth muscle cell proliferation and migration. 

METHODS: Human aortic smooth muscle cells (AoSMC) were grown in culture in the 

presence of serum. Quercetin inhibited the serum-induced proliferation of AoSMC. 

This inhibition was dose-dependent and not attributed to toxicity. Cell cycle 

analysis revealed that quercetin arrested AoSMC in the G(0)/G(1) phase. The 

effect of quercetin on AoSMC migration was examined using explant migration and 

Transwell migration assays. Quercetin significantly decreased migration in both 

assays in a consistent manner. Finally, Western blot analysis of AoSMC exposed 

to quercetin demonstrated a significant reduction in the activation of 

mitogen-activated protein kinase, a signaling pathway associated with the 

migration of vascular smooth muscle cells. CONCLUSIONS: Quercetin inhibits the 

proliferation and migration of AoSMC, concomitant with inhibition of 

mitogen-activated protein kinase phosphorylation. These findings provide new 

insights and a rationale for the potential use of quercetin in the prophylaxis 

of cardiovascular diseases. 

15. Mol Pharmacol. 2001 Oct;60(4):656-65. 

Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun 

N-terminal kinase activation by angiotensin II in cultured rat aortic smooth 

muscle cells. 

Yoshizumi M, Tsuchiya K, Kirima K, Kyaw M, Suzaki Y, Tamaki T. 

Department of Pharmacology, The University of Tokushima School of Medicine, 

Tokushima, Japan. yoshizu@basic.med.tokushima-u.ac.jp 

Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, 

which results in various cardiovascular diseases. Ang II-induced cellular events 

have been implicated, in part, in the activation of mitogen-activated protein 

(MAP) kinases. Although it has been proposed that daily intake of bioflavonoids 

belonging to polyphenols reduces the incidence of ischemic heart diseases (known 

as "French paradox"), the precise mechanisms of efficacy have not been 

elucidated. Thus, we hypothesized that bioflavonoids may affect Ang II-induced 

MAP kinase activation in cultured rat aortic smooth muscle cells (RASMC). Our 

findings showed that Ang II stimulated rapid and significant activation of 

extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), 

and p38 in RASMC. Ang II-induced JNK activation was inhibited by 



727

3,3',4',5,7-pentahydroxyflavone (quercetin), a major bioflavonoid in foods of 

plant origin, whereas ERK1/2 and p38 activation by Ang II were not affected by 

quercetin. Ang II caused a rapid tyrosine phosphorylation of Src homology and 

collagen (Shc), which was inhibited by quercetin. Quercetin also inhibited Ang 

II-induced Shc.p85 association and subsequent activation of phosphatidylinositol 

3-kinase (PI3-K)/Akt pathway in RASMC. Furthermore, LY294002, a PI3-K inhibitor 

and a quercetin derivative, inhibited Ang II-induced JNK activation as well as 

Akt phosphorylation. Finally, Ang II-induced [(3)H]leucine incorporation was 

abolished by both quercetin and LY294002. These findings suggest that the 

preventing effect of quercetin on Ang II-induced VSMC hypertrophy are 

attributable, in part, to its inhibitory effect on Shc- and PI3-K-dependent JNK 

activation in VSMC. Thus, inhibition of JNK by quercetin may imply its 

usefulness for the treatment of cardiovascular diseases relevant to VSMC growth. 

16. Br J Pharmacol. 2001 May;133(1):117-24. 

Antihypertensive effects of the flavonoid quercetin in spontaneously 

hypertensive rats. 

Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo A, 

Tamargo J. 

Department of Pharmacology, School of Pharmacy, University of Granada, 18071 

Granada, Spain. 

1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin 

for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto 

rats (WKY) were analysed. 2. Quercetin induced a significant reduction in 

systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and 

heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight 

index and the kidney weight index in vehicle-treated SHR were significantly 

greater than in control WKY and these parameters were significantly reduced in 

quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 

4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside 

or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the 

endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, 

P

treatment with quercetin. 

Brookes PS, Digerness SB, Parks DA, Darley-Usmar V. 

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 

35294-2180, USA. brookes@uab.edu 

Polyphenolic compounds present in red wines, such as the flavonol quercetin, are 

thought capable of cardioprotection through mechanisms not yet clearly defined. 

It has been established that mitochondria play a critical role in myocardial 

recovery from ischemia-reperfusion (I-R) damage, and in vitro experiments 

indicate that quercetin can exert a variety of direct effects on mitochondrial 

function. The effects of quercetin at concentrations typically found in 1-2 

glasses of red wine on cardiac I-R and mitochondrial function in vivo are not 

known. Quercetin was administered to rats (0.033 mg/kg per day by gavage for 4 

d). Isolated Langendorff perfused hearts were subjected to I-R, and cardiac 

functional parameters determined both before and after I-R. Mitochondria were 

isolated from post-I-R hearts and their function assessed. Compared to an 

untreated control group, quercetin treatment significantly decreased the 

impairment of cardiac function following I-R. This protective effect was 

associated with improved mitochondrial function after I-R. These results 

indicate that oral low dose quercetin is cardioprotective, possibly via a 

mechanism involving protection of mitochondrial function during I-R. 

18. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9052-7. 

The NF-kappa B signal transduction pathway in aortic endothelial cells is primed 

for activation in regions predisposed to atherosclerotic lesion formation. 

Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. 

Department of Laboratory Medicine and Pathobiology, University of Toronto, 

Toronto General Research Institute, Toronto, Ontario, M5G 2C4, Canada. 

Atherosclerotic lesions form at distinct sites in the arterial tree, suggesting that 

hemodynamic forces influence the initiation of atherogenesis. If NF-kappaB plays a role 

in atherogenesis, then the activation of this signal transduction pathway in arterial 

endothelium should show topographic variation. The expression of NF-kappaB/IkappaB 

components and NF-kappaB activation was evaluated by specific antibody staining, en 

face confocal microscopy, and image analysis of endothelium in regions of mouse 

proximal aorta with high and low probability (HP and LP) for atherosclerotic lesion 

development. In control C57BL/6 mice, expression levels of p65, IkappaBalpha, and 

IkappaBbeta were 5- to 18-fold higher in the HP region, yet NF-kappaB was activated in 

a minority of endothelial cells. This suggested that NF-kappaB signal transduction was 

primed for activation in HP regions on encountering an activation stimulus. 

Lipopolysaccharide treatment or feeding low-density lipoprotein receptor knockout mice 

an atherogenic diet resulted in NF-kappaB activation and up-regulated expression of NFkappaB-inducible 

genes predominantly in HP region endothelium. Preferential regional 

activation of endothelial NF-kappaB by systemic stimuli, including 



729

hypercholesterolemia, may contribute to the localization of atherosclerotic lesions at sites 

with high steady-state expression levels of NF-kappaB/IkappaB components. 

19. Clin Exp Allergy. 2000 Apr;30(4):501-8. 

Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator 

release from human cultured mast cells. 

Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. 

Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan. 

BACKGROUND: Flavonoids have a variety of activities including anti-allergic 

activities, and are known to inhibit histamine release from human basophils and murine 

mast cells. OBJECTIVE: The effects of luteolin, a flavone, on the immunoglobulin (Ig) 

E-mediated allergic mediator release from human cultured mast cells (HCMCs) were 

investigated and compared with those of baicalein and quercetin. METHODS: HCMCs 

were sensitized with IgE, and then treated with flavonoids before challenge with 

antihuman IgE. The amount of released mediators was determined as was mobilization of 

intracellular Ca2+ concentration, protein kinase C (PKC) translocation and 

phosphorylation of intracellular proteins were detected after anti-IgE stimulation. 

RESULTS: Luteolin, baicalein and quercetin inhibited the release of histamine, 

leukotrienes (LTs), prostaglandin D2 (PGD2), and granulocyte macrophage-colony 

stimulating factor (GM-CSF) from HCMC in a concentration-dependent manner. 

Additionally, the three flavonoids inhibited A23187-induced histamine release. As 

concerns Ca2+ signalling, luteolin and quercetin inhibited Ca2+ influx strongly, although 

baicalein did slightly. With regard to PKC signalling, luteolin and quercetin inhibited 

PKC translocation and PKC activity strongly, although baicalein did slightly. The 

suppression of Ca2+ and PKC signallings might contribute to the inhibition of mediator 

release. The activation of extracellular signal-regulated kinases (ERKs) and c-Jun NH2terminal 

kinase (JNK), that were activated just before the release of LTs and PGD2 and 

GM-CSF mRNA expression in IgE-mediated signal transduction events, were clearly 

suppressed by luteolin and quercetin. In contrast, the flavonoids did not affect the 

activation of p38 mitogen-activated protein kinase (p38 MAPK) pathway. 

CONCLUSION: These results indicate that luteolin is a potent inhibitor of human mast 

cell activation through the inhibition of Ca2+ influx and PKC activation. 

20. Res Commun Chem Pathol Pharmacol. 1992 Nov;78(2):211-8. 

Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney 

subjected to ischemia-reperfusion stress: preventive effect of some flavonoids. 

Sanhueza J, Valdes J, Campos R, Garrido A, Valenzuela A. 

Unidad de Bioquimica Farmacologica y Lipidos, INTA, Universidad de Chile, 

Santiago. 

The enzyme xanthine oxidase has been implicated in the tissue oxidative injury 

after ischemia-reperfusion. This enzyme, which is a source of oxygen free 

radicals, is formed from a dehydrogenase form during ischemia. The ratio 



730

dehydrogenase/oxidase of rat kidney homogenates decreases during the ischemia 

and the reperfusion. Two flavonoids, quercetin and silybin, characterized as 

free radical scavengers, exert a protective effect preventing the decrease in 

the dehydrogenase/oxidase ratio observed during ischemia-reperfusion. The 

mechanism of this effect and the role of flavonoids in the ischemia-reperfusion 

tissue damage is discussed. 

21. Methods Find Exp Clin Pharmacol. 2001 May;23(4):175-81. 

Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by 

cyclosporine in rats. 

Satyanarayana PS, Singh D, Chopra K. 

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab 

University, Chandigarh, India. 

Nephrotoxicity is the most common and clinically important side effect of cyclosporine 

(CsA). Recent evidence suggests that reactive oxygen species (ROS) play an important 

role in CsA nephrotoxicity. This study was designed to demonstrate the role of oxidative 

stress and its relation to renal dysfunction and to investigate the effects of quercetin, a 

bioflavonoid with antioxidant properties, in CsA-induced nephrotoxicity. Quercetin (0.5 

and 2.0 mg/kg i.p.) was administered 24 h before and concurrently with CsA (20 mg/kg 

s.c.) for 21 days. Tissue lipid peroxidation was measured as thiobarbituric acid reacting 

substances (TBARS). Renal function was assessed by estimating plasma creatinine, 

blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological 

alterations were assessed histopathologically. Pretreatment with CsA (20 mg/kg 

s.c.) for 21 days produced elevated levels of TBARS and deteriorated renal function as 

assessed by increased plasma creatinine, BUN and decreased creatinine and urea 

clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed 

severe striped interstitial fibrosis, arteriopathy, glomerular basement thickening, tubular 

vacuolization and hyaline casts. Quercetin (2 mg/kg) markedly reduced elevated levels of 

TBARS and significantly attenuated renal dysfunction and morphological changes in 

CsA-treated rats. It is likely that quercetin, due to its antioxidant properties, prevented 

CsA-induced ROS and consequently CsA nephrotoxicity. These results clearly 

demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction, and 

also point to the therapeutic potential of the natural antioxidant quercetin in CsA-induced 

nephrotoxicity. 

22. Free Radic Biol Med. 2002 Jul 1;33(1):63-70. 

Quercetin metabolism in the lens: role in inhibition of hydrogen peroxide 

induced cataract. 

Cornish KM, Williamson G, Sanderson J. 

School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK. 

Oxidative stress is implicated in the initiation of maturity onset cataract. Quercetin, a 

major flavonol in the diet, inhibits lens opacification in a lens organ culture oxidative 



731

model of cataract. The aim of this research was to investigate the metabolism of quercetin 

in the lens and show how its metabolism affects the ability to prevent oxidation-induced 

opacity. The LOCH model (Free Radical Biology & Medicine 26:639; 1999) was 

employed, using rat lenses to investigate the effects of quercetin and metabolites on 

hydrogen peroxide-induced opacification. High-performance liquid chromatography 

analysis showed that the intact rat lens is capable of converting quercetin aglycone to 3'- 

O-methyl quercetin (isorhamnetin). Over a 6 h culture period no further metabolism of 

the 3'-O-methyl quercetin occurred. Loss of quercetin in the lens was accounted for by 

the increase in 3'-O-methyl quercetin. Incubation with 

3,5-dinitrocatechol (10 microM), a catechol-O-methyltransferase (COMT) inhibitor, 

prevented the conversion of quercetin to 3'-O-methyl quercetin. The presence of both 

membrane-bound and soluble COMT was confirmed by immunoblotting. The results 

demonstrate that in the rat lens COMT methylates quercetin and that the product 

accumulates within the lens. Quercetin (10 microM) and 3'-O-methyl quercetin (10 

microM) both inhibited hydrogen peroxide- (500 microM) induced sodium and calcium 

influx and lens opacification. Incubation of lenses with quercetin in the presence of 

COMT inhibitor revealed that the efficacy of quercetin is not dependent on its 

metabolism to 3'-O-methyl quercetin. The results indicate dietary quercetin and 

metabolites are active in inhibiting oxidative damage in the lens and thus could play a 

role in prevention of cataract formation. 

23. Free Radic Biol Med. 1999 Sep;27(5-6):683-94. 

Structure-activity relationships of quercetin in antagonizing hydrogen 

peroxide-induced calcium dysregulation in PC12 cells. 

Wang H, Joseph JA. 

Jean Mayer United States Department of Agriculture Human Nutrition Research 

Center on Aging at Tufts University, Boston, MA 02111, USA. 

wang_us@hnrc.tufts.edu 

Oxidative stress can induce neurotoxic insults by increasing intracellular 

calcium (Ca2+), which has been implicated in various neurodegenerative diseases 

in aging. Previously, we showed that hydrogen peroxide induced calcium 

dysregulation in PC12 cells, as evidenced by (i) an increase in calcium 

baselines, (ii) a decrease in depolarization-induced calcium influx, and (iii) a 

failure to recover the Ca2+ levels. In the present experiments, we investigated 

whether a dietary flavonoid, quercetin, can antagonize the effects of hydrogen 

peroxide in the same cell model. We also investigated the possible 

structure-activity relationships of quercetin by comparing the results with four 

other flavonoids, each having a slightly different structure from quercetin. Our 

results indicated that two structural components, including (i) 3', 4'-hydroxyl 

(OH) groups in the B ring and (ii) a 2,3-double bond in conjugation with a 4-oxo 

group in the C ring, along with the polyphenolic structures were crucial for the 

protection. These structural components are found in quercetin, and this 

compound was also the most efficacious in reducing both the H2O2-induced Ca2+ 

dysregulation in cells and oxidative stress assessed via the dichlorofluorescein 



732

assay. Collectively, these data indicated that the particular polyphenolic 

structural components of quercetin provided its strong antioxidant property of 

protecting cells against H2O2-induced oxidative stress and calcium 

dysregulation. 

24. Zhongguo Yao Li Xue Bao. 1999 May;20(5):426-30. 

Quercetin decreased heart rate and cardiomyocyte Ca2+ oscillation frequency in 

rats and prevented cardiac hypertrophy in mice. 

Wang Y, Wang HY, Yuan ZK, Zhao XN, Wang JX, Zhang ZX. 

School of Medicine, State Key Laboratory of Coordination Chemistry, Nanjing 

University, China. 

AIM: To study the effects of quercetin (Que) on myocardial excitation-contraction 

coupling and cardiac remodeling. METHODS: Left ventricles and femoral arteries of rats 

were cannulated for hemodynamic recording. Mouse cardiac hypertrophy was induced by 

abdominal aortic coarctation (AAC). Cultured myocardial cells in neonatal rats were 

loaded with Fura 2-AM. The intracellular calcium ([Ca2+]i) and spontaneous [Ca2+]i 

oscillations ([Ca2+]i-SO) were tested by AR-CM-MIC cation measurement system. 

RESULTS: Que 3 or 25 mg.kg-1 i.v. in rats decreased heart rate from (420 +/- 19) to 

(390 +/- 15) and (314 +/- 18) beat.min-1, respectively, companied with very modest 

changes in both left ventricular pressures (LVP) and its differential dpLV/dtmax. Que 10, 

50, 250 mumol.L-1 concentration-dependently slowed the frequency of [Ca2+]i-SO in 

cultured myocardial cells from (26 +/- 4) to (25 +/- 3), (18 +/- 4), and (12 +/- 3) 

time.min-1, respectively, but did not change their resting [Ca2+]i or amplitudes of 

[Ca2+]i-SO. Similarly, the increases in frequency of [Ca2+]i-SO caused by either 

isoproterenol (Iso) or ouabain (Oua) were prevented by Que 100 mumol.L-1, while the 

simultaneous increases in amplitude of [Ca2+]i-SO remained. Besides, [Ca2+]i rises 

excited by angiotensin II (Ang II) but not high [K+]o were prevented by Que 100 

mumol.L-1. Daily administration of Que 120 mg.kg-1 i.g. for 5 d markedly prevented the 

cardiac hypertrophy in AAC mice, without effects on the ventricular mass to body weight 

ratio (VM/BW) in sham-operated mice. CONCLUSION: Quercetin decreased myocardial 

[Ca2+]i-oscillation frequency and prevented cardiac remodeling, but had no direct effect 

on cardiac excitation-contraction coupling. 

25. Zhongguo Yao Li Xue Bao. 1995 May;16(3):223-6. 

Effects of quercetin on aggregation and intracellular free calcium of platelets. 

Xiao D, Gu ZL, Bai JP, Wang Z. 

Department of Pharmacology, Suzhou Medical College, China. 

AIM: To study the effects of Que on the intraplatelet free calcium concentration 

and the effects of calcium on the inhibition of platelet aggregation by Que. 

METHODS: Using Quin-2 fluorescence technique. RESULTS: Que inhibited the 

platelet aggregation and the rise of [Ca2+]i induced by thrombin in platelets. 

The values of IC50 and 95% confidence interval were 146.2 (92.4 - 231.3) and 



733

78.5 (49.5 - 124.4) mumol.L-1, respectively. The inhibitory effects of Que on 

platelet aggregation induced by thrombin were reduced by adding calcium to the 

medium, and Que had no effect on thrombin-induced internal Ca2+ release from 

dense tubular system. CONCLUSION: The inhibitory effects of Que on aggregation 

and the rise of [Ca2+]i in platelets was mainly due to an inhibition of Ca2+ 

influx. 

26. Antiproliferative potency of structurally distinct dietary flavonoids on human colon 

cancer cells 

Kuo SM. 

Nutrition Program, State University of New York at Buffalo, 14214, USA. 

smkuo@acsu.buffalo.edu 

Cancer Letters (Ireland), 1996, 110/1-2 (41-48) 

Dietary flavonoids are known to be antiproliferative and may play an important role in 

cancer chemoprevention, especially cancers of the gastrointestinal tract, because of a 

direct contact with food. This study was designed to compare the antiproliferative 

potency of several structurally distinct dietary flavonoids in colon cancer cells, Caco-2 

and HT-29, and in rat nontransformed intestinal crypt cells, IEC-6. Flavonoids varied 

significantly in their antiproliferative potency depending on the structural features but the 

observations were consistent among the three cell lines studied. Of the two most potent 

flavonoids, quercetin and genistein, the effect was found to be dose-dependent and 

chromatin condensation, an indication of apoptosis, was noticed. Quercetin was found to 

distribute throughout the cell with higher amounts in the perinuclear and nucleoli areas. 

The lack of specific cell membrane enrichment by quercetin was consistent with its lack 

of effect on the transepithelial resistance. While several flavonoids including quercetin 

were found to be unstable, the chemical instability did not correlate with the 

antiproliferative potency, although it may contribute to the antiproliferative effect. 

27. Preferential requirement for protein tyrosine phosphatase activity in the 12-Otetradecanoylphorbol-13-acetate-induced 

differentiation of human colon cancer cells. 

Kuo ML, Huang TS, Lin JK. 

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei. 

Biochem Pharmacol; 50(8):1217-22 1995 

Some lines of colon cancer cells are forced to undergo differentiation by 12-Otetradecanoylphorbol-13-acetate 

(TPA). The increases in activities of both protein 

tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) have been reported to be 

associated with the TPA-induced differentiation of HL-60 leukemia cells. In the present 

study, a 2-fold increase in PTP activity was observed in SW620 human colon cancer cells 

after 30 min of TPA treatment; a maximal level (4- to 5-fold) was reached at 60 min and 

continued for more than 6 hr. In addition, two TPA-induced differentiated characteristics, 

morphological alteration and release of cellular surface proteoglycan, were effectively 

blocked by PTP inhibitors, such as sodium orthovanadate (50 microM), zinc chloride 

(100 microM), and iodoacetate (250 microM), but not by the protein serine/threonine 

phosphatase inhibitor okadaic acid (20 nM). On the other hand, although TPA induced a 



734

transient slight increase in PTK activity (1.4-fold) at 60 min, four PTK inhibitors 

(genistein, herbimycin A, tyrphostin-23 and quercetin) had different effects on the TPAinduced 

release of cell surface proteoglycan. Genistein (60 microM) potentiated this 

process, but in contrast, quercetin (45 microM) could partially inhibit the TPA effect. 

Taken together, these observations suggest that both PTP and PTK activities were 

increased in SW620 cells in response to TPA; however, the activation of PTP seems to be 

preferentially required for the TPA-induced differentiation of SW620 human. 

28. Effect of Quercitrin on acute and chronic experimental colitis in the rat 

De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A. 

F.S. De Medina, Department of Pharmacology, School of Pharmacy, 

University of Granada, 18071 Granada Spain 

Journal of Pharmacology and Experimental Therapeutics (USA) , 1996, 278/2 

(771-779) 

Quercitrin was tested for acute and chronic anti-inflammatory activity in 

trinitrobenzenesulfonic acid-induced rat colitis. The inflammatory status 

was evaluated by myeloperoxidase, alkaline phosphatase and total 

glutathione levels, leukotriene B4 synthesis, in vivo colonic fluid 

absorption, macroscopical damage and occurrence of diarrhea and adhesions. 

Treatment with 1 or 5 mg/kg of quercitrin by the oral route reduced 

myeloperoxidase and alkaline phosphatase levels, preserved normal fluid 

absorption, counteracted glutathione depletion and ameliorated colonic 

damage at 2 days. Increasing or lowering the dose of the flavonoid resulted 

in marked loss of effect. The acute anti-inflammatory effect of quercitrin 

is unrelated to impairment of neutrophil function or lipoxygenase 

inhibition, and it may be caused by mucosal protection or enhancement of 

mucosal repair secondary to increased defense against oxidative insult 

and/or preservation of normal colonic absorptive function. When tested in 

chronic colitis (2 and 4 weeks), quercitrin treatment (1 or 5 mg/kg . day) 

decreased colonic damage score and the incidence of diarrhea, and 

normalized the colonic fluid transport. All other parameters were 

unaffected. The chronic effect of the flavonoid is apparently related to 

its action on colonic absorption, although it can be partly secondary to 

its acute beneficial effect. 

29. Inhibition of human breast cancer cell proliferation and delay of mammary 

tumorigenesis by flavonoids and citrus juices 

So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. 

Department of Pharmacology and Toxicology, University of Western Ontario, London, 

Canada. 

Nutrition and Cancer (USA) , 1996, 26/2 (167-181) 



735

Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, 

respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and 

quercetin, were tested singly and in one-to-one nd growth of a human breast carcinoma 

cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited 

by 50% (IC50), based on incorporation of (3H)thymidine, varied from 5.9 to 140 

microg/ml for the single flavonoids, with the most potent being baicalein. IC50 

values for the one-to-one combinations ranged from 4. 7 microg/ml (quercetin + 

hespererin, quercetin + naringenin) to 22.5 microg/ml (naringenin + hespererin). All 

the flavonoids showed low cytotoxicity (>500 microg/ml for 50% cell death). 

Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These 

compounds, as well as grapefruit and orange juice concentrates, were tested for 

their ability to inhibit development of mammary tumors induced by 

7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats. Two 

experiments were conducted in which groups of 21 rats were fed a semipurified diet 

containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at 

approximately 50 days of age while in diestrus. One week later, individual groups were 

given double- strength grapefruit juice or orange juice or fed naringin or naringenin at 

levels comparable to that provided by the grapefruit juice; in the second experiment, 

the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, 

rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in 

both experiments tumor development was delayed in the groups given orange 

juice or fed the naringin-supplemented diet compared with the other three groups. 

Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat 

variable in the different groups, rats given orange juice had a smaller tumor burden 

than controls, although they grew better than any of the other groups. These experiments 

provide evidence of anticancer properties of orange juice and indicate that citrus 

flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, 

especially when paired with quercetin, which is widely distributed in other foods. 

30. Quercetin glycosides inhibit lipoxygenase-induced LDL oxidation 

Inhibition of mammalian 15-lipoxygenase-dependent lipid peroxidation 

in low-density lipoprotein by quercetin and quercetin monoglucosides. 

Luiz da Silva E, Tsushida T, Terao J. 

National Food Research Institute, Ministry of Agriculture, Forestry, and Fisheries, 

Ibaraki, Japan. 

Arch Biochem Biophys. 1998 Jan 15;349(2):313-20. 

Lipoxygenase is suggested to be involved in the early event of atherosclerosis by 

inducing plasma low-density lipoprotein (LDL) oxidation in the subendothelial space of 

the arterial wall. Since flavonoids such as quercetin are recognized as lipoxygenase 

inhibitors and they occur mainly in the glycoside form, we assessed the effect of 

quercetin and its glycosides (quercetin 3-O-beta-glucopyranoside, Q3G; quercetin 4'- 

O-beta-glucopyranoside, Q4'G; quercetin 7-O-beta-glucopyranoside, Q7G) on rabbit 

reticulocyte 15-lipoxygenase (15-LOX)-induced human LDL lipid peroxidation and 



736

compared it with the inhibition obtained by ascorbic acid and alpha-tocopherol, the main 

water-soluble and lipid-soluble antioxidants in blood plasma, respectively. Quercetin 

inhibited the formation of cholesteryl ester hydroperoxides (CE-OOH) and endogenous 

alpha-tocopherol consumption effectively throughout the incubation period of 6 h. 

Ascorbic acid exhibited an effective inhibition only in the initial stage and LDL 

preloaded with fivefold alpha-tocopherol did not affect the formation of CE-OOH 

compared with the native LDL. CE-OOH formation was inhibited by both quercetin and 

quercetin monoglucosides in a concentration-dependent manner. Quercetin, Q3G, and 

Q7G exhibited a higher inhibitory effect than Q4'G (IC50: 0.3-0.5 microM for quercetin, 

Q3G, and Q7G and 1.2 microM for Q4'G). While endogenous alpha-tocopherol was 

completely depleted after 2 h of LDL oxidation, quercetin, Q7G, and Q3G prevented the 

consumption of alpha-tocopherol. Quercetin and its monoglucosides were also exhausted 

during the LDL oxidation. These results indicate that quercetin glycosides as well as its 

aglycone are capable of inhibiting lipoxygenase-induced LDL oxidation more efficiently 

than ascorbic acid and alpha-tocopherol. 

L-Carnosine - 15 Studies 

1. Bull Exp Biol Med. 2003 Feb;135(2):130-2. 

Protective effect of carnosine on Cu,Zn-superoxide dismutase during impaired oxidative metabolism in the 

brain in vivo. 

Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev AA. 

Institute of Neurology, Russian Academy of Medical Sciences, Moscow. sls@bio.inevro.msk.ru 

2. Bull Exp Biol Med. 2002 Jun;133(6):559-61. Effect of carnosine on Drosophila melanogaster lifespan. 

Yuneva AO, Kramarenko GG, Vetreshchak TV, Gallant S, Boldyrev AA. M. V. Lomonosov 

Moscow State University, Moscow. 

3. Biogerontology. 2001;2(1):19-34. AGES in brain ageing: AGE-inhibitors as neuroprotective and antidementia 

drugs? 

Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G. 

Physiological Chemistry I, Biocenter, University of Wurzburg, Germany. 

4. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4765-9. Age-related losses of cognitive function and 

motor skills in mice are associated with oxidative protein damage in the brain. 

Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. 

Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, 76107, USA. 



737

5. J Histochem Cytochem. 1998 Jun;46(6):731-5. Cytochemical demonstration of oxidative damage in 

Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4dinitrophenylhydrazine. 

Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF, Kowall N, Perry G. Institute of Pathology, Case 

Western Reserve University, Cleveland, Ohio 44106, USA. 

6. Neurosci Lett. 1998 Feb 13;242(2):105-8. Toxic effects of beta-amyloid(25-35) on immortalised rat 

brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. 



7. FEBS Lett. 1995 Aug 28;371(1):81-5. Non-enzymatic glycosylation of the dipeptide L-carnosine, a 

potential anti-protein-cross-linking agent. 

Hipkiss AR, Michaelis J, Syrris P. 

Division of Biomolecular Engineering, CSIRO, North Ryde, NSW, Australia. 

8. Biochim Biophys Acta. 1997 Feb 27;1360(1):17-29. Influence of advanced glycation end-products and 

AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. 

Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham 

AM. 

Theodor-Boveri-Institute (Biocenter), Wurzburg, Germany. muench@biozentrum.uni-wuerzburg.de 

9. Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32. Carnosine protects proteins against 

methylglyoxal-mediated modifications. 

Hipkiss AR, Chana H. 

Molecular Biology and Biophysics Group, King's College London, United Kingdom. 


10. Free Radic Biol Med. 2000 May 15;28(10):1564-70. Carnosine reacts with a glycated protein. 


Division of Biomolecular Science, GKT School of Biomedical Sciences, King's College London, Guy's 

Campus, London Bridge, London, UK. 

11.Neurosci Lett. 1997 Dec 5;238(3):135-8. Protective effects of carnosine against malondialdehydeinduced 

toxicity towards cultured rat brain endothelial cells. 

Hipkiss AR, Preston JE, Himswoth DT, Worthington VC, Abbot NJ. 




738

12. Cell Mol Neurobiol. 1997 Apr;17(2):259-71. Biochemical and physiological evidence that carnosine 

is an endogenous neuroprotector against free radicals. Boldyrev AA, Stvolinsky SL, Tyulina OV, Koshelev 

VB, Hori N, Carpenter DO. M. V. Lomonosov Moscow State University, Moscow, Russia. 

13. Ann N Y Acad Sci. 1998 Nov 20;854:37-53. Pluripotent protective effects of carnosine, a naturally 

occurring dipeptide. 

Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis J, Lawrence J, Mateen A, 

Allende L, Eagles PA, Abbott NJ. 

Molecular Biology and Biophysics Group, King's College London, Strand, United Kingdom. 


14. Exp Cell Res. 1994 Jun;212(2):167-75. Retardation of the senescence of cultured human diploid 

fibroblasts by carnosine. McFarland GA, Holliday R. 

CSIRO Division of Biomolecular Engineering, Sydney Laboratory, NSW, Australia. 

15. Exp Gerontol. 1999 Jan;34(1):35-45. Further evidence for the rejuvenating effects of the dipeptide Lcarnosine 

on cultured human diploid fibroblasts. McFarland GA, Holliday R. CSIRO Division of 

Molecular Science, Sydney Laboratory, North Ryde, Australia. 

Cayenne – 267 Studies 

1. Allison DB, Fontaine KR, Heshka S, Mentore JL, Heymsfield SB. Alternative 

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2. Attal N. Chronic neuropathic pain: mechanisms and treatment [Review]. Clin J Pain 

2000;16(3 Suppl):S118-30. 

3. Bouraoui A, Toumi A, Mustapha HB, et al. Effects of capsicum fruit on theophylline 

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4. Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine: Expanded Commission 

E Monographs. Newton, MA: Integrative Medicine Communications; 2000:52-56. 

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6. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a 

double-blind trial. Clin Ther. 1991;13(3):383-395. 

7. Egger G, Cameron-Smith D, Stanton R. The effectiveness of popular, non-prescription 

weight loss supplements. Medical Journal of Australia. 1999;171(11-12):604-608. 



739

8. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin 

cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol. 

1997;15(8):2974-2980. 

9. Fusco BM, Giacovazzo M. Peppers and pain. The promise of capsaicin. Drugs. 

1997;53(6):909-914. 

10. Fusco BM, Marabini S, Maggi CA, Fiore G, Geppetti P. Preventative effect of 

repeated nasal applications of capsaicin in cluster headache. Pain. 1994;59(3):321-325 

11. Gallo R, Cozzani E, Guarrera M. Sensitization to pepper (Capsicum annuum) in a 

latex-allergic patient. Contact Dermatitis. 1997;37(1):36-37. 

12. Hakas JF Jr. Topical capsaicin induces cough in patient receiving ACE inhibitor. Ann 

Allergy. 1990;65:322. 

13. Hautkappe M, Roizen MF, Toledano A, Roth S, Jeffries JA, Ostermeier AM. Review 

of the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction. 

[Review]. Clin J Pain. 1998;14(2):97-106. 

14. Jensen PG, Larson JR. Management of painful diabetic neuropathy [Review]. Drugs 

Aging. 2001;18(10):737-749. 

15. Kang JY, Yeoh KG, Chia HP, Lee HP, Chia YW, Guan R, Yap I. Chili--protective 

factor against peptic ulcer? Dig Dis Sci. 1995;40(3):576-9 

16. Kenney JK, Jamjian C, Wheeler MM. Prevention and management of pain associated 

with Herpes zoster. Journal of Pharmaceutical Care in Pain and Symptom Control. 

1999;7(3):7-26. 

17. Nicholas JJ. Physical modalities in rheumatological rehabilitation. Archives of 

Physical and Medical Rehabilitation. 1994;75(9):994-1001. 

18. Paice JA, Ferrens CE, Lashley FR, Shott S, Vizgirda V, Pitrak D. Topical capsaicin in 

the management of HIV-associated peripheral neuropathy. J Pain Symtom Manage. 

2000;19(1):45-52. 

19. Petersen KL, Fields HL, Brennum J, Sandroni P, Rowbotham MC. Capsaicin evoked 

pain and allodynia in post-herpetic neuralgia. Pain. 2000;88:125-133. 

20. Rains C, Bryson HM. Topical Capsaicin. A review of its pharmacological properties 

and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and 

osteoarthritis. Drugs and Aging. 1998;7(4):317-328. 

21. Robbins W. Clinical applications of capsaicinoids [Review]. Clin J Pain. 2000;16(2 

Suppl):S86-89. 



740

22. Rosenstein ED. Topical agents in the treatment of rheumatic disorders. Rheum Dis 

Clin North Am. 1999;25(4):899-913. 

23. Stander S, Luger T, Metze D. Treatment of prurigo nodularis with topical capsaicin. 

J Am Acad Dermatol. 2001;44(3):471-478. 

24. Stankus SJ, Dlugopolski M, Packer D. Management of herpes zoster (shingles) and 

postherpetic neuralgia. [Review]. Am Fam Physician. 2000;61(8):2437-44, 2447-2448. 

25. Volmink J, Lancaster T, Gray S, Silagy C. Treatments for postherpetic neuralgia--a 

systematic review of randomized controlled trials. Fam Pract. 1996;13(1):84-91. 

25. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced 

gastroduodenal mucosal injury in humans. Dig Dis Sci. 1995;40:580–583. 

26. Yoshioka M, St-Pierre S, Suzuki M, Tremblay A. Effects of red pepper added to 

high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in 

Japanese women. Br J Nutr. 1998;80(6):503-510. 

27. Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. Eur J Clin 

Pharmacol. 1994;46:517-522. 

Phosphatidylserine – 19 Studies 

1. Palmieri, G., et al., Double-blind controlled trial of phosphatidylserine in patients with 

senile mental deterioration. Clin. Trials J. 1987;24:73-83. 

2. Delwaide PJ, et al. Double-blind randomized controlled study of phosphatidylserine in 

senile demented patients. Acta Neurol Scand 1986 Feb;73(2):136-40. 

3. Crook TH, et al. Effects of phosphatidylserine in age-associated memory impairment. 

Neurology 1991 May;41(5):644-649. 

4. Cenacchi T, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled 

multicenter study on efficacy of phosphatidylserine administration. Aging (Milano) 1993 

Apr;5(2):123-33. 

5. Funfgeld EW, et al. Double-blind study with phosphatidylserine (PS) in parkinsonian 

patients with senile dementia of Alzheimer's type (SDAT). Prog Clin Biol Res 

1989;317:1235-46. 

6. (no authors listed) Phosphatidylserine in the treatment of clinically diagnosed 

Alzheimer's disease. The SMID Group. J Neural Transm Suppl 1987;24:287-92. 

7. Amenta F, et al. Treatment of cognitive dysfunction associated with Alzheimer's 

disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? 



741

Mech Ageing Dev 2001 Nov;122(16):2025-40. 

8. Heiss WD, et al. Activation PET as an instrument to determine therapeutic efficacy in 

Alzheimer's disease. Ann N Y Acad Sci 1993 Sep 24;695:327-31. 

9. Crook T, et al. Effects of Phosphatidylserine in Alzheimer's Disease. Psychopharmacol 

Bull 1992;28(1):61-66. 

10. Engel RR, Double-blind cross-over study of phosphatidylserine vs. placebo in 

patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 1992 

Jun;2(2):149-55. 

11. Maggioni M, et al. Effects of Phosphatidylserine Therapy in Geriatric Patients With 

Depressive Disorders. Acta Psychiatr Scand 1990;81:265-270. 

12. Monteleone P, et al. Blunting by chronic phosphatidylserine administration of the 

stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J 

Clin Pharmacol 1992;42(4):385-388. 

13. Monteleone P, et al. Effects of phosphatidylserine on the neuroendocrine response to 

physical stress in humans. Neuroendocrinology 1990 Sep;52(3):243-8. 

14. Benton D, et al. The influence of phosphatidylserine supplementation on mood and 

heart rate when faced with an acute stressor. Nutr Neurosci 2001;4(3):169-78. 

15. Gindin, J., et al. 1990, Effect of Soy Lecithin Phosphatidylserine (PS) Treatment on 

Daily Functioning and Self-Reported General Condition in Patients with Alzheimer's 

Disease, The Geriatric Institute of Education and Research Kaplan Medical Centre, 

Rehovot, and Hadassah Medical School, Hebrew University of Jerusalem, Israel. 

16. Sakai M, et al. Pharmacological effects of phosphatidylserine enzymatically 

synthesized from soybean lecithin on brain functions in rodents. J Nutr Sci Vitaminol 

(Tokyo) 1996 Feb;42(1):47-54. 

17. Schreiber S, et al. An open trial of plant-source derived phosphatidylserine for 

treatment of age-related cognitive decline. Isr J Psychiatry Relat Sci 2000;37(4):302-7. 

18. Suzuki S, et al. Oral administration of soybean lecithin transphosphatidylated 

phosphatidylserine improves memory impairment in aged rats. J Nutr 2001 

Nov;131(11):2951-6. 

19. Van den Besselaar AM. Phosphatidylethanolamine and phosphatidylserine 

synergistically promote heparin's anticoagulant effect. Blood Coagul Fibrinolysis 

1995;6:239-244. 



742

Ginkgo Biloba Leaf Powder – 25 Studies 

1. Blumenthal M, ed. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical 

Council; 2003 

2. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine. Expanded 

Commission E Monographs. 1st ed. Newton, MA: Integrative Medicine 

Communications; 2000. 

3. Cooper R. Gin(kgo) and tonic—with a twist! J Altern Complement Med. 2003 

Oct;9(5):599-601. 

4. Cieza A, Maier P, Poppel E. Effects of Gink- go biloba on mental functioning in 

healthy volunteers. Arch Med Res. 2003 Sep;34(5):373-81. 

5. Trick L, Boyle J, Hindmarch I. The effects of Ginkgo biloba extract (LI 1370) 

supplementation and discontinuation on activities of daily living and mood in free living 

older volunteers. Phytother Res. 2004 Jul;18(7):531-7. 

6. Smith JV, Luo Y. Studies on molecular mechanisms of Ginkgo biloba extract. Appl 

Microbiol Biotechnol. 2004 May;64(4):465-72. 

7. McKenna DJ, Jones K, Hughes K. Efficacy, safety, and use of ginkgo biloba in clinical 

and preclinical applications. Altern Ther Health Med. 2001 Sep;7(5):70-90. 

8. Davies JA, Johns L, Jones FA. Effects of bilobalide on cerebral amino acid neurotransmission. 

Pharmacopsychiatry. 2003 Jun;36 Suppl 1S84-8. 

9. Auguet M, Delaflotte S, Hellegouarch A, Clostre F. Pharmacological bases of the 

vascular impact of Ginkgo biloba extract. Presse Med. 1986 Sep 25;15(31):1524-28. 

10. Yoshikawa T, Naito Y, Kondo M. Ginkgo biloba leaf extract: review of biological 

actions and clinical applications. Antioxid Redox Signal. 1999;1(4):469-80. 

11. Huang SY, Jeng C, Kao SC, Yu JJ, Liu DZ. Improved haemorrheological properties 

by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with 

retinopathy. Clin Nutr. 2004 Aug;23(4):615-21. 

12. Evans JG, Wilcock G, Birks J. Evidence-based pharmacotherapy of Alzheimer’s 

disease. Int J Neuropsychopharmacol. 2004 Sep;7(3):351-69. 

13. Kurz A, Van Baelen B. Ginkgo biloba compared with cholinesterase inhibitors in 

the treatment of dementia: a review based on meta-analyses by the cochrane 

collaboration. Dement Geriatr Cogn Disord. 2004;18(2):217-26. 



743

14. Jacoby D, Mohler ER, III. Drug treatment of intermittent claudication. Drugs. 

2004;64(15):1657-70. 

15. Horsch S, Walther C. Ginkgo biloba special extract EGb 761 in the treatment of 

peripheral arterial occlusive disease (PAOD)—a review based on randomized, controlled 

studies. Int J Clin Pharmacol Ther. 2004 Feb;42(2):63-72. 

16. McKay D. Nutrients and botanicals for erectile dysfunction: examining the 

evidence. Altern Med Rev. 2004 Mar;9(1):4-16. 

17. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J 

Sex Marital Ther. 1998 Apr;24(2):139-43. 

18. Chao JC, Hung HC, Chen SH, Fang CL. Effects of Ginkgo biloba extract on 

cytoprotective factors in rats with duodenal ulcer. World J Gastroenterol. 2004 Feb 

15;10(4):560-6. 

19. Abdel-Salam OM, Baiuomy AR, El batran S, Arbid MS. Evaluation of the antiinflammatory, 

anti-nociceptive and gastric effects of Ginkgo biloba in the rat. Pharmacol 

Res. 2004 Feb;49(2):133-42. 

20. Colciaghi F, Borroni B, Zimmermann M, et al. Amyloid precursor protein 

metabolism is regulated toward alpha-secretase pathway by Ginkgo biloba extracts. 

Neurobiol Dis. 2004 Jul;16(2):454-60. 

21. Antagonistic effects of extract from leaves of Ginkgo biloba on glutamate neurotoxicity. 

Zhu L Wu J Liao H Gao J Zhao XN Zhang ZX 

Acta Pharmacol Sin 1997 JUL;18(4):344 

Zhu L, Nanjing Univ, Sch Med, Nanjing 210093, PEOPLES R CHINA 

22. Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats. 

Jastreboff PJ Zhou ST Jastreboff MM Kwapisz U Gryczynska U 

Audiol Neuro Otol 1997 JUL-AUG;2(4):197-212 

Jastreboff PJ, Univ Maryland, Sch Med, Dept Surg, Tinnitus & Hyperacusis Ctr, 10 S Pine St, Mstf Bldg, 

RM 436, Baltimore,MD 21201 USA 

23. Phospholipid breakdown and choline release under hypoxic conditions: Inhibition by bilobalide, a 

constituent of Ginkgo biloba. 

Klein J Chatterjee SS Loffelholz K 

Brain Res 1997 MAY 2;755(2):347-350 

Klein J, Univ Mainz, Dept Pharmacol, Obere Zahlbacher Str 67, D 55101 Mainz, GERMANY 

24. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to 

moderate primary degenerative dementia of the Alzheimer type or multi- infarct dementia (Reprinted f rom 

Pharmacopsychiat, vol 29, pg 47-56, 1996). 

Kanowski S Herrmann WM Stephan K Wierich W Horr R 



744

Phytomedicine 1997 MAR;4(1):3-13 

Kanowski S, Free Univ Berlin, Klinikum Benjamin Franklin, ABT Gerontopsychiat, Dept Gerontopsychiat, 

D 14050 Berlin, GERMANY 

25. Effect of Ginkgo biloba extract (EGb 761) on the vasospastic response of mouse cutaneous arterioles to 

platelet activation. 

Stucker O Pons C Duverger JP Drieu K DArbigny P 

Int J Microcirc Clin Exp 1997 MAR-APR;17(2):61-66 

Stucker O, Cerom, 155 Rue Faubourg St Denis, F 75010 Paris, FRANCE 

Linoleic Acid – 29 Studies 

1. Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources 

Ip C.; Scimeca J.A.; Thompson H.J. 

Department of Surgical Oncology, Roswell Park Center Institute, Elm and Carlton 

Streets, Buffalo, NY 14263 USA 

CANCER (USA) , 1994, 74/3 (1050-1054) 

2. Conjugated linoleic acid and atherosclerosis in rabbits 

Lee K.N.; Kritchevsky D.; Pariza M.W. 

Food Research Institute, Dept. Food Microbiology/Toxicology, University of Wisconsin- 

Madison, 1925 Willow Drive, Madison, WI 53706 USA 

Atherosclerosis (Ireland), 1994, 108/1 (19-25) 


conventional but not germ-free rats fed linoleic acid 

Chin S.F.; Storkson J.M.; Liu W.; Albright K.J.; Pariza M.W. 

Food Microbiology/Toxicology Dept., 

Food Research Institute, University of Wisconsin, Madison, WI 53706 USA 

J. NUTR. (USA) , 1994, 124/5 (694-701) 


the in vitro growth of human cancer cells 

Shultz TD; Chew BP; Seaman WR; Luedecke LO 

Cancer Lett (NETHERLANDS) Apr 15 1992, 63 (2) p125-33, 


of the mammary gland in the rat 

Ip C; Singh M; Thompson HJ; Scimeca JA 

Cancer Res (UNITED STATES) Mar 1 1994, 54 (5) p1212-5, 



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of the mammary gland in the rat 

CANCER RES. (USA) , 1994, 54/5 (1212-1215) 

7. Effect of cheddar cheese consumption on plasma conjugated linoleic acid 

concentrations in men 

NUTR. RES. (USA) , 1994, 14/3 (373-386) 

8. Differential stimulatory and inhibitory responses of human MCF-7 breast cancer cells 

to linoleic acid and conjugated linoleic acid in culture 

ANTICANCER RES. (Greece) , 1992, 12/6 B (2143-2145) 

pronounced (8 - 81%) than LA. These in vitro results suggest that CLA is cytotoxic to 

MCF-7 cells. 


the in vitro growth of human cancer cells 

CANCER LETT. (Ireland) , 1992, 63/2 (125-133) 

10. Inhibition of Listeria monocytogenes by fatty acids and monoglycerides 

APPL. ENVIRON. MICROBIOL. (USA) , 1992, 58/2 (624-629) 

11. Recognition of cervical neoplasia by the estimation of a free-radical reaction product 

(octadeca-9,11-dienoic acid) in exfoliated cells 

CLIN. CHIM. ACTA (NETHERLANDS) , 1987, 163/2 (149-152) 

12. Feeding conjugated linoleic acid to animals partially overcomes catabolic responses 

due to endotoxin injection 

BIOCHEM. BIOPHYS. RES. COMMUN. (USA) , 1994, 198/3 (1107-1112) 


conventional but not germ-free rats fed linoleic acid 

J. NUTR. (USA) , 1994, 124/5 (694-701) 

14. Conjugated linoleic acid and atherosclerosis in rabbits 

ATHEROSCLEROSIS (Ireland) , 1994, 108/1 (19-25) 

15. Conjugated linoleic acid is a growth factor for rats as shown by enhanced weight gain 

and improved feed efficiency 

J. NUTR. (USA) , 1994, 124/12 (2344-2349) 

16. Cows' milk fat components as potential anticarcinogenic agents 

Journal of Nutrition (USA) , 1997, 127/6 (1055-1060) 

17. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in 

adult and neonatal rat ventricular myocytes 



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Proceedings of the National Academy of Sciences of the United States of America (USA) , 

1997, 94/8 (4182-4187) 

18. Effects of dietary conjugated linoleic acid on lymphocyte function and growth of 

mammary tumors in mice 


19. Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells 

in SCID mice 


20. Lymphatic recovery, tissue distribution, and metabolic effects of conjugated lioleic 

acid in rats 

Journal of Nutritional Biochemistry (USA) , 1997, 8/1 (38-43) 

21. Proliferative responses of normal human mammary and MCF-7 breast cancer cells to 

linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture 


22. Conjugated linoleic acid modulates hepatic lipid composition in mice 

Lipids (USA) , 1997, 32/2 (199-204) 

23. Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion 


24. The efficacy of conjugated linoleic acid in mammary cancer prevention is 

independent of the level or type of fat in the diet 

Carcinogenesis (United Kingdom) , 1996, 17/5 (1045-1050) 

25. Dietary modifiers of carcinogenesis 

Environmental Health Perspectives (USA) , 1995, 103/SUPPL. 8 (177-184) 

26. Effects of C18 fatty acid isomers on DNA synthesis in hepatoma and breast cancer 

cells 

Anticancer Research (Greece) , 1995, 15/5 B (2017-2021) 

27. Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer 

prevention 


28. The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline 

quinone as nonessential dietary antioxidants 

Nutrition Reviews (USA) , 1995, 53/3 (49-58) 



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29. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic 

atharosclerosis in hypercholasterolemic hamsters 

Artery (USA) , 1997, 22/5 (266-277) 

Inositol – 6 Studies 

1. Can intervention in inositol phosphate signalling pathways improve therapy for cystic fibrosis? 

Expert Opin Ther Targets. 2005 Dec;9(6):1307-17. 

PMID: 16300477 

2. 1. Levine J, Barak Y, Gonzalves M, et al. Double-blind, controlled trial of inositol treatment of 

depression. Am J Psychiatry 1995;152:792–4. 

3. Levine J, Barak Y, Kofman O, Belmaker RH. Follow-up and relapse analysis of an inositol study of 

depression. Isr J Psychiatry Relat Sci 1995;32:14–21. 

4. Benjamin J, Levine J, Fux M, et al. Double-blind, placebo-controlled, crossover trial of 

inositol treatment for panic disorder. Am J Psychiatry 1995;152:1084–6. 

5. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive 

disorder. Am J Psychiatry 1996;153:1219–21. 

6. Colodny L, Hoffman RL. Inositol—Clinical applications for exogenous use. Altern 

Med Rev 1998;3:432–47. 



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