Traditional Chinese Medicine

41 Traditional Chinese Medicine

Problems and Drawbacks

Barry Halliwell National University of Singapore

Singapore, Republic of Singapore

I. INTRODUCTION Traditional Chinese medicine (TCM) is one of a range of complementary

treatments that are widely used in Asia, but are also becomingly increasingly popular in Western countries. This popularity is growing even in countries such as England where conventional medical treatment is free to the end-user, whereas TCM rarely is (1). Annual sales of herbal remedies in the United States exceed US$350 million (2) and the global market for all herbal and homoeopathic remedies has been estimated at over US$4 billion in the United States, over US$6 billion in Europe (3), and over US$2 billion in Asia (4). TCM encompasses several different treatments, including acupuncture, mox- ibustion, medicinal food, herbs, traditional massage, and qigong, but I will concern myself here only with herbal therapies. These ‘‘natural’’ remedies are widely perceived as safer than pharmaceutical company drugs, more ‘‘natu- ral,’’ ‘‘gentle,’’ and less likely to cause side effects. In fact, just because a product is natural does not mean it is safe: examples of plant-produced toxins include cyanide (5), many carcinogens, a prime example being the powerful carcinogen aflatoxin (6), digitalis, ergot, and belladonna. Indeed the use of

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selected plant extracts to eliminate enemies and induce abortion has been widespread throughout the centuries. In general also, the more effective a drug, the more side effects might be predicted. Thus by reasoning from first principles, the safest medicine might be homoeopathic, although its effective- ness is as yet uncertain.

Despite the rising popularity of TCM and the setting up of a Center for Alternative Medicine (CAM) at the prestigious National Institutes of Health in the United States, TCM is still regarded skeptically by the Western medical profession, because in general its effectiveness has not been proved by rigorous clinical trials. However, the same is true for several commonly used medical and surgical procedures, and the impact of some ‘‘trial-confirmed’’ procedures such as chemotherapy on the patient’s quality of life can be devastating (7). The fact that TCM practitioners often tailor treatment (or claim to do this) to each patient makes it difficult to do conventional controlled clinical trials. However there is growing evidence that conventional treatments developed for, for example, white European or American men (on whom the majority of published trials have been done) are not optimal for other races (8).

In approaching the area of TCM, there seem to be several different standpoints taken by various parties:

1. Accept TCM as a ‘‘given,’’ known to be effective and useful,

popularize it and set up courses to teach it in the West

2. Take a skeptical view and attempt to used evidence-based medicine to establish whether or not TCM is effective

3. Take TCM that are thought to be effective for a particular condition and use conventional pharmacology to isolate effective ingredients. For example, the cholinesterase inhibitor huperzine was isolated from a plant thought to improve memory (9). The antimalarial artemisinin was evolved from Artemisia annua, an ancient Chinese herb (quinghao) used to treat fevers (10). Plants have been the origin of some of our most helpful medicines, including taxol, vincristine, aspirin, and morphine.

However, several other key issues must be addressed (Table 1), most of them focused around the issue of quality control. To quote Lee (1), ‘‘As TCM

is winning support, it must demonstrate that its products are both safe and of high quality . . . and safe from contaminants.’’ This is rarely the case today. Indeed the U.S. Alpha–National Association Newsletter recommends, ‘‘Don’t use herbal remedies for serious illnesses, don’t give herbs to children and don’t use them if you are pregnant or trying to get pregnant. Also, tell your doctor about all products that you take.’’

Let us examine these issues in turn.

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T ABLE 1 Problems with TCM Toxicity of the product (just because it is natural does not mean it is safe).

Is it what it is supposed to be? Often no established quality control tests. When established tests exist, they are rarely simple to use. Variable potency (part of plant, stage in growth cycle, time of year, year to

year, different soil composition in different areas). Contamination with toxins (microbial, chemical, e.g., pesticides, metal from containers, elements from soil, e.g., selenium). Deliberate adulteration. Deterioration on storage. Perception of safety encourages excessive use. Coprescription of several products, possibility of interactions with other TCM

ingredients or conventional drugs. Placental transport, excretion into breast milk, possible teratogenicity. Toxicity to growing children?

II. PROBLEM 1: THE PRODUCT IS TOXIC As Paracelsus said, ‘‘The right dose differentiates a poison from a remedy.’’

For example, the balance of clinical evidence favors the view that Hypericum perforatum (St. John’s Wort) is effective in treating mild to moderate depression (2,3), although not all studies support this (11). Its mechanism of action appears to involve monoamine oxidase inhibition (2) and so excessive doses, or coadministration with synthetic MAO inhibitor antide- pressants, are likely to cause side effects. Absinthe was a popular emerald green liqueur in the nineteenth and early-twentieth centuries in Europe, but was eventually banned because of its dose-dependent and progressive toxic- ity, due to constituents of the wormwood oil used to make it (12). Wormwood extracts were used in antiquity to kill intestinal worms, and are still used now for gastrointestinal and liver problems in some countries (12,13).

Several problems have arisen with various herbal products that induce hepatotoxicity. Herbal teas from germander (Teucrium chamaedrys) have been widely used throughout antiquity, but several cases of germander- induced hepatitis with periportal inflammation and centrilobular necrosis associated with consumption of capsules containing germander extract led to the banning of all germander products in France (14). Jin bu huan (JBH) has been used in TCM as a sedative, analgesic, and decongestant, but chronic consumption of some products can cause hepatotoxicity (14). One problem is that a variety of herbs are marketed as JBH, although the offending one was labeled as an extract of Polygala chinensis (14). Indeed it is common in TCM for one name to apply to a group of botanically unrelated materials. Other

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organ damage can also occur. In Taiwan, consumption of extracts from leaves of Sauropus androgynus as a slimming aid produced lung damage resembling bronchiolitis obliterans (15). Whereas hepatotoxicity often resolves on dis- continuing the offending product (14), the lung damage induced by S. androgynus appeared to be permanent (15).

The gallbladders of animals are used in TCM in some countries, but bile constituents can be variably toxic: the grass carp bile appears especially so and cases of human hemolysis and renal failure have been reported (16). On a related topic, a case of parasitic infestation after consumption of snake bile and blood has occurred (17).

III. PROBLEM 2: THE PRODUCT IS NOT WHAT IT IS SUPPOSED TO BE

The essential basic requirement for any herbal product is that the correct plant(s) are used. Even then there can be differences: the chemical composi- tion of plants varies enormously depending on developmental stage, soil composition, amount of water and sunlight, etc. (Table 1). Nevertheless, occasionally the wrong plant is used and sometimes the same name in TCM can encompass several different plants (see above). Two patients consuming a range of herbal products ‘‘to cleanse the body’’ presented with digitalis poisoning, due to the use of Digitalis lanata instead of plantain in the formulation. Investigation revealed that approximately 2700 kg of this product had been imported into the United States, and only vigorous action by the Food and Drug Administration in recalling supplies prevented more problems (18).

In Belgium, over 40 patients consuming products allegedly containing the Chinese herbs Stephania tetrandra and Magnolia officinalis developed interstitial fibrosis and progressive renal failure. Chemical analysis revealed that a nephrotoxic herb, Aristolochia fangchi, had, apparently accidentally, been substituted for S. tetrandra. Aristolochia species contain powerful carcinogens and indeed patients with the above ‘‘Chinese herb nephropathy’’ are at high risk of urothelial carcinoma (19). Cases have also been reported in England and a local British newspaper (20) commented: ‘‘There are now more than 3000 clinics prescribing 400 unlicensed Chinese herbal treatments and no-one really knows what’s being prescribed.’’

Ginkgo biloba leaf extract is widely consumed to improve mental function (11), but of 14 products tested by the Hong Kong Consumer Council, none of them met the specifications recommended by the World Health Organization (WHO). Eleven had insufficient active ingredients overall, and 13 had an excess content of gingkolic acid (21). In the United

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States, analysis of commercial ginseng preparations showed that 25% contained no ginseng at all (22).

In fact, authentication of the starting plant material is a key problem. Detailed reference standards (e.g., herbarium-authenticated specimens, de- scriptive illustrated monographs) are not available for the majority of plants used in TCM. DNA fingerprinting of plant material may make some contribution, but once powders and extracts have been generated it becomes difficult. NMR-, HPLC-, and LC-MS-based analysis of chemical composi- tion is a valuable tool, as illustrated by its use in the digitalis poisoning cases (18), examination of the authenticity of Ginkgo and ginseng preparations (21,22), identification of toxic components of grass carp bile (16), and investigation of JBH-induced hepatotoxicity (14). However, in the frequent absence of official standards and given the natural variation in chemical composition of even the same plant at different times (Table 1), the use of analytical techniques can be limited. Examples of their value include the HPLC method specified by the British Pharmacopeia for the evaluation of the active constituents of licorice (22), a common ingredient in herbal prepara- tions. Much more work is yet to be done.

IV. PROBLEM 3: THE PRODUCT MAY HAVE DETERIORATED OR BECOME CONTAMINATED

A pharmaceutical product is described as stable if it meets the five elements of stability: physical, chemical, microbial, toxicological, and therapeutic. Many natural compounds readily oxidize and degrade, giving products with differ- ent properties. For example, the carotenoids h-carotene and lycopene may have antioxidant properties as intact molecules, yet their degradation prod- ucts can be cytotoxic in cell cultures (23). Flavonoids and other plant polyphenolics are also easily oxidizable (24). Plant materials contain enzymes that affect their constituents; for example, the difference between green tea and black tea is the inactivation of an enzyme that oxidizes phenols during the preparation of the former but not the latter (25). Drying of plant material can cause loss of thermolabile constituents and further loss can occur on storage, especially if storage conditions are moist or too hot. However, shelf lives of TCM are rarely given on the packaging.

Microbial contamination from soil and during handling of plants, or bacterial and fungal infection during storage, is a potential problem. Plant materials are especially susceptible because of their organic nature, being good substrates for bacterial/fungal growth, especially if the moisture level in the environment is high. Aflatoxins are among the noxious products that can be generated (6,26). Medicinal plant materials can also contain pes- ticide residues (27) and sometimes toxic elements from the soil including

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arsenic, cadmium, and selenium (11,28,29). Metals can also be introduced during processing, e.g., by the preparation of medicines in lead containers (28,29).

V. PROBLEM 4: THE PRODUCT MAY HAVE BEEN DELIBERATELY ADULTERATED

The deliberate addition of compounds to herbal preparations is an even more worrisome problem. Adulterants include phenylbutazone, indomethacin, dexamethasone, prednisolone, acetaminophen, fenfluramine, and aminopy- rine (11,22,30). Phenylbutazone can cause severe agranulocytosis, which is why its use as a drug is now very limited, but several cases of damage by herbs containing it as an adulterant have been reported (22,31,32). In 2002 in Singapore the Health Sciences Authority identified phenylbutazone in the herbal remedy serbuk jarem (encok), used to treat rheumatism and ‘‘body aches.’’ In England, herbal creams prescribed by TCM practitioners to treat facial and other eczema were analyzed and eight were found to be adulterated with dexamethasone, in some cases at a level that should not be used on the face (33). Yet another example is PC-SPES (see below).

VI. PROBLEM 5: THE PRODUCTS MAY PRODUCE HARM BY INTERACTING WITH EACH OTHER OR WITH PHARMACEUTICALS TAKEN CONCURRENTLY

TCM prescriptions may contain multiple different products whose ingre- dients can interact with each other in unexpected ways, or can influence the effects of Western drugs taken concurrently. TCM is often used by subjects with chronic diseases, who are likely to take Western drugs at the same time. For example, PC-SPES is allegedly a combination of eight herbs sometimes used by patients with prostate cancer. It was found to have potent oestrogenic activity (34). Coadministration of PC-SPES with estrogens might thus cause overdose problems, and PC-SPES in high doses may itself produce side effects such as breast tenderness and loss of libido (34). PC-SPES was banned in 2002 in the United States after chemical analysis showed it to be adulterated with diethylstilbestrol (a known carcinogen) indomethacin and warfarin (35). The action of St. John’s wort in inhibiting monoamine oxidase can potentiate the effects of serotonin-reuptake inhibitors (3,36). It also induces hepatic enzymes, accelerating the clearance of several drugs including theophylline, cyclosporin, and warfarin and decreasing their plasma levels (36). Garlic extracts affect the metabolism of paracetamol and warfarin, and kava can interact with drugs used in the treatment of Parkinson’s disease (3). The Lancet recently discussed the need for surgeons to monitor intake of herbal

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products and to recommend that ingestion of such products as ginseng, kava, St. John’s wort, and valerian should stop several days before surgery (37). It is well known that grapefruit juice contains agents that inhibit intestinal cytochrome P450 (CYP3A4) and result in higher blood levels of certain drugs (e.g., amiodarone, cyclosporin, benzodiazepines, nifedipine, lovastatin, saquinavir), possibly to a toxic level (38). It seems likely that many similar phenomena involving ingredients in TCM remain to be discovered.

VII. CONCLUSION: THE WAY FORWARD The data reviewed above show that TCM cannot at present be taken as an

acceptable given body of knowledge. Practitioners need to be licensed and subject to quality control checks on their prescriptions to deter adulteration. They should participate in national or international adverse-event-reporting networks. They should be monitored by a disciplinary body. Better monitor- ing of prescribed and ‘‘over-the-counter’’ TCM products for adulterants and contaminants is needed. Products should be registered and evidence that the manufacturer complies with GMP should be available. The labels should specify the composition of the product, both active and ‘‘inactive’’ ingre- dients, the supplier, and the country of origin. Data on stability should be obtained and used to provide ‘‘sell by’’ and ‘‘use by’’ dates. Much more work needs to go into genetic and chemical methods to identify and quality-control TCM, and standards need to be established. Finally, the public needs to be educated to be prudent in what they take, not to overdose, to buy from reputable suppliers, to patronize only licensed TCM practitioners, and to alert their doctors to any TCM that they are taking. The use of TCM in infants, pregnant women, and nursing mothers cannot be considered safe, since present data are insufficient to establish or rule out teratogenic actions or adverse effects on children. Work to address some of the above problems is already underway (4,39–42).

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