● Introduction 97 ● Garlic 97 ● Ginseng 98 ● Ginkgo biloba 99 ● Echinacea 99 ● Soy 99 CHAPTER 17 ALTERNATIVE MEDICINES: HERBALS AND NUTRACEUTICALS INTRODUCTION ‘Alternative’ therapies (i.e. alternative to licensed products of proven quality, safety and efficacy) span a huge range from frank charlatanry (e.g. products based on unscientific postulates, composed of diluent or of snake oil), through physical therapies such as massage and aroma therapies which certainly please (‘placebo’ means ‘I will please’) and do a great deal less harm than some conventional therapies (e.g. surgery, chemotherapy), through to herbal medications with undoubted pharmacological activity and the potential to cause desired or adverse effects, albeit less predictably than the licensed products that have been derived from them in the past and will no doubt be so derived in the future. Medicine takes an empirical, evidence-based view of therapeutics and, if supported by sufficiently convincing evidence, alternative therapies can enter the mainstream of licensed products. Overall, efforts to test homeopathic products have been negative (Ernst, 2002) and it has been argued that no more resource should be wasted on testing products on the lunatic fringe, even when they come with royal endorsement and (disgracefully) public funding. Here we focus on herbal and nutraceutical products that may cause pharmacological effects. Herbal remedies include dietary supplements (any product other than tobacco intended for ingestion as a supplement to the diet, including vitamins, minerals, anti-oxidants – Chapter 35 – and herbal products), phytomedicines (the use of plants or plants components to achieve a therapeutic effect/outcome) and botanical medicines (botanical supplements used as medicine). The recent increase in the use of herbal remedies by normal healthy humans, as well as patients, is likely to be multifactorial and related to: (1) patient dissatisfaction with conventional medicine; (2) patient desire to take more control of their medical treatment; and (3) philosophical/cultural bias. In the USA, approximately one-third of the population used some form of complementary or alternative medicine (the majority consuming herbal products) in the past 12 months. At a clinical ● Saw palmetto 100 ● St John’s wort 100 ● Glucosamine 101 ● Miscellaneous herbs recently found to be toxic or meriting their withdrawal from the market 101 therapeutic level, it is disconcerting that 15–20 million Americans regularly take herbal remedies, while concomitantly receiving modern prescription drugs, implying a significant risk for herb–drug interactions. In Scotland, some 12% of general practitioners and 60% of general practices prescribe homeopathic medicines! Herbal remedies are particularly used by certain groups of patients, notably HIV and cancer patients. The stereotypical user is a well-educated, career professional, white female. From a therapeutic perspective, many concerns arise from the easy and widespread availability, lack of manufacturing or regulatory oversight, potential adulteration and contamination of these herbal products. Furthermore, there is often little or no rigorous clinical trial evidence for efficacy and only anecdotes about toxicity. Many patients who are highly attuned to potential harms of conventional drugs (such as digoxin, a high quality drug derived historically from extracts of dried foxglove of variable quality and potency) fail to recognize that current herbals have as great or greater potential toxicities, often putting their faith in the ‘naturalness’ of the herbal product as an assurance of safety. This chapter briefly reviews the most commonly used herbals (on the basis of sales, Table 17.1) from a therapeutic perspective and addresses some of the recently identified problems caused by these agents. GARLIC Garlic has been used as a culinary spice and medicinal herb for thousands of years. One active compound in garlic is allicin, and this is produced along with many additional sulphur compounds by the action of the enzyme allinase when fresh garlic is crushed or chewed. Initial clinical trials suggested the potential of garlic to lower serum cholesterol and triglyceride, but a recent trial has shown limited to no benefit. Garlic has been advocated to treat many conditions, ranging from many cardiovascular diseases, e.g. atherosclerosis including peripheral vascular disease, hypertension, lipid disorders and sickle
98 ALTERNATIVE MEDICINES: HERBALS AND NUTRACEUTICALS cell anaemia. Garlic can alter blood coagulability by decreasing platelet aggregation and increasing fibrinolysis. Adverse effects The adverse effects of garlic use involve gastro-intestinal symptoms including halitosis, dyspepsia, flatulence and heartburn. Other reported adverse effects include headache, haematoma and contact dermatitis. Drug interactions Garlic inhibits many drug-metabolizing (CYP450) enzymes in vitro, but induces CYP450s when administered chronically in vivo (reminiscent of many anticonvulsant drugs – Chapter 22 – as well as ethanol). Clinical studies using probe-drug cocktails have shown that garlic has no significant effect on the activity of CYP1A2 (caffeine), CYP2D6 (debrisoquine, dextromethorphan) and CYP3A4 (alprazolam, midazolam). Clinical studies suggest that garlic significantly decreases the bioavailability of saquinavir and ritonavir. These HIV protease inhibitors are not only metabolized by CYP3A4, but are also substrates for P-glycoprotein. The clinical importance of these interactions is uncertain, but potentially appreciable. GINSENG Table 17.1: Most commonly used herbal products based on dollar sales Product Plant Intended condition to Annual sales in be used for USA ($ millions) Garlic Allium sativum Hyperlipidaemia– hypercholesterolaemia 34.5 Ginkgo Ginkgo biloba Dementia and claudication 33.0 Echinacea Echinacea purpurea Prevention of common cold 32.5 Soy Glycine max Symptoms of menopause 28.0 Saw palmetto Serenoa repens Prostatic hypertrophy 23.0 Ginseng Panax ginseng Fatigue 22.0 St John’s wort Hypericum perforatum Depression (mild) 15.0 Black cohosh Actaea racemosa Menopausal symptoms 12.3 Cranberry Vaccinia macrocarpon Cystitis and UTI 12.0 Valerian Valeriana officinalis Stress and sleeplessness 8.0 Milk thistle Silybum marianum Hepatitis and cirrhosis 7.5 Evening primrose Oenothera biennis Premenstrual symptoms 6.0 Bilberry Vaccinia myrtillus Diabetic retinopathy 3.5 Grape seed Vitis vinifera Allergic rhinitis 3 UTI: urinary tract infection There are several types of ginseng (Siberian, Asian, American and Japanese), the most common type used in herbal preparations being the Asian variety (Panax ginseng). In humans, ginseng has been suggested to be a sedative-hypnotic, an aphrodisiac, an antidepressant and a diuretic, and therapeutic benefits have been claimed for many indications (see below). Its pharmacologic properties include actions as a phytoestrogen, suggesting that its use, as with soy supplementation, could be disadvantageous in women with oestrogen-sensitive cancers (e.g. breast or endometrium). The active component of ginseng, ginsenoside, inhibits cAMP phosphodiesterase and monamine oxidase. These properties may partly explain purported central nervous system (CNS) stimulant actions of ginseng (though not sedative/hypnotic effects), potential modulation of the immune system and increase of glycogen storage. However, possible efficacy of ginseng in improving physical or psychomotor performance, cognitive function, immune function, diabetes mellitus and herpes simplex type 2 infections is not established beyond reasonable doubt. Adverse effects The adverse effects of ginseng are primarily CNS effects – agitation, irritability, insomnia and headache. Others noted include hypertension and mastalgia. Drug interactions In vitro evidence suggests that ginseng extracts inhibit CYP3A4 in human hepatocytes. These in vitro data are consistent with study data during an 18-day course of ginseng where it significantly increased the peak plasma concentration of nifedipine, a CYP3A4 substrate, in healthy volunteers. As with other herbs (e.g. echinacea), substantial variability in ginsenoside content has been reported among commercially available ginseng preparations, indicating that clinically significant effects on the pharmacokinetics of drugs that are metabolized by CYP3A4 could be highly variable between batches.