Current Opinion in Investigational Drugs

2 Current Opinion in Investigational Drugs 2006 Vol 7 No 1
predicted to become a major challenge for healthcare providers,
especially as the currently asymptomatic carriers of this virus
may develop hepatocellular carcinoma. Furthermore, the death
rate due to HCV infection is predicted to triple in the next ten to
20 years. Current treatment protocols involve either the
administration of interferon (IFN)α or its pegylated form alone
or in combination with ribavirin (RBV). IFNα causes
neuropsychiatric adverse effects and anemia is the most
common side effect of RBV. In addition, the response rate for
both therapeutic approaches is < 50%. Thus, the identification
of new and effective drugs for the treatment of HCV infection is
critical. These researchers previously identified a novel
compound, N 3,5'-cyclo-4-(β-D-ribofuranosyl)-vic-triazolo[4,5b]pyridin-5-one
(CRTP), which exhibited moderate anti-HCV
activity in a subgenomic RNA replicon system. In an effort to
discover more potent anti-HCV agents, a series of 6- and 7substituted
derivatives of CRTP were synthesized. In this
study, different 5-thiono, 6-halo, 7-alkylamino and 7-methyl
analogs of CRTP were synthesized and their anti-HCV activity
and cytotoxicity evaluated. Some of the newly synthesized
compounds exhibited 8- to 40-fold more potent anti-HCV
activity than that of CRTP.
Findings CRTP was initially synthesized from 1-(2,3,5-tri-Obenzoyl-β-D-ribofuranosyl)-5-nitropyridin-2-one
using either
a five-step traditional synthetic method or a one-pot
synthetic method. Further synthetic procedures involving
CRTP resulted in 5-thiono, 6-chloro/bromo, 7-amino or 7alkylamino
analogs. The 7-methyl analog of CRTP was
prepared using a different methodology. The synthesized
compounds were tested for their ability to inhibit HCV RNA
in a subgenomic replicon Huh-7 cell line. Cytotoxicity was
determined using an MTS assay. Among the compounds
tested, the 5-thiono, 6-chloro, 6-bromo, 7-amino, 7methylamino
and 7-methyl analogs exhibited more potent
anti-HCV activity than CRTP, with the 6-chloro and 6-bromo
analogs being the most potent. This study suggests a direct
correlation between the anti-HCV activity and the
cytotoxicity of these compounds.
Endocrine & metabolics
Selected by Mariano J Elices (PharmaMar USA, Cambridge,
MA, USA)
Normal fasting plasma glucose levels and type 2
diabetes in young men.
Tirosh A, Shai I, Tekes-Manova D, Israeli E, Pereg D, Shochat
T, Kochba I, Rudich A; Israeli Diabetes Research Group
(Medical Corps Headquarters, Tel-Hashomer, Israel).
N Engl J Med (2005) 353(14):1454-1462.
• Significance Science textbooks generally list the range of
fasting plasma glucose values for healthy individuals
(normoglycemic) as being 70 to 110 mg/dl. However, in
2003, an expert committee at the American Diabetes
Association (ADA) revised this long-held view and
suggested that fasting blood glucose levels of 101 to 109
mg/dl represent impairment of glucose metabolism and
thus pose a risk for the development of type 2 diabetes. In
general, the incidence of type 2 diabetes has increased in
developed countries, including among younger members of
the population that have traditionally not been considered to
be at risk; thus it is of significant value to uncover risk
factors for this illness.
Findings In order to address which risk factors contribute to
the development of type 2 diabetes, the investigators examined
a computerized database that was established in 1992 to
capture data from the MELANY (MEtabolic, Lifestyle, And
Nutrition assessment in Young adults) trial. This trial was
conducted among military personnel over 25 years of age in
Israel who received periodic examinations every three to five
years. At the time of their periodic visit, each individual gave a
blood sample after a 14-h fasting period, and received a medical
examination; a detailed questionnaire was also completed by
each individual. The primary endpoint of the study was a new
diagnosis of type 2 diabetes during the trial (based on criteria
outlined by the ADA expert committee) which involved the
recording of two fasting plasma glucose levels of at least 126
mg/dl. Of 13,163 male individuals with fasting blood glucose
levels of ≤ 100 mg/dl, there were 208 new cases of type 2
diabetes (ie, a 1.6% incidence) spanning an average of 5.7 years
of follow-up. Multivariate models showed that males with
fasting blood glucose at the high end of the normal range (91 to
99 mg/dl), combined with serum triglyceride levels of ≥ 150
mg/dl, had an 8.23-fold higher risk of developing type 2
diabetes compared with individuals with fasting plasma
glucose and serum triglyceride levels of ≤ 86 and < 150 mg/dl,
respectively. In a similar manner, hazard ratios revealed a 8.29fold
higher risk of developing type 2 diabetes in obese men
(body mass index ≥ 30) even when they had a normal, albeit
high, fasting blood glucose (91 to 99 mg/dl), compared with
control individuals with fasting plasma glucose levels and a
body mass index of ≤ 86 mg/dl and < 25, respectively. These
data strongly suggest that normoglycemic individuals with
either serum triglyceride levels > 150 mg/dl or exhibiting
relative obesity (ie, body mass index ≥ 30) are at an increased
risk of developing type 2 diabetes later in life. From a healthcare
standpoint, these findings expose a host of opportunities in
diagnostic, preventive and therapeutic areas in type 2 diabetes.
Oncological
Selected by Robert E Hurst (Oklahoma University Health
Sciences Center, OK, USA)
A potential synergistic anticancer effect of paclitaxel
and amifostine on endometrial cancer.
Dai D, Holmes AM, Nguyen T, Davies S, Theele DP,
Verschraegen C, Leslie KK (University of New Mexico Health
Sciences Center, Albuquerque, NM, USA).
Cancer Res (2005) 65(20):9517-9524.
• Significance Although the prognosis for endometrial cancer
is generally good, advanced or recurrent cases have a poor
prognosis, with chemotherapy offering mostly palliative
therapy. Amifostine has been proven to protect normal cells
against a number of chemotherapeutic agents, including
paclitaxel. Amifostine not only allows the administration of
higher doses of paclitaxel but, in this study, the drug also had a
direct effect on endometrial cancer cells, and acted
synergistically with paclitaxel. Thus, combination therapy
with these two drugs may be more effective than paclitaxel
alone.