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Drugs used in non-orthodox medicine
P.A.G.M. de Smet and A.G. Vulto
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Drugs used in non-orthodox medicine
INTRODUCTION In a previous volume (SEDA-9,418) the opinion was expressed that, because of parallels between the biochemical pathways in man and animals on the one hand and those in plants on the other hand, carefully planned research efforts should result in the development of new, powerful and valuable therapeutic compounds derived from plants. Based on ethnotherapeutic criteria or folkloric considerations and phylogenetic and taxonomic relationships, several research programs in the pharmaceutical industry are concentrating on the selection of attractive candidates for the isolation of active principles that could be used as a basis for further drug development. This approach should prove fruitful in two ways: the original leads stem from traditional medicine and traditional medicine will obtain objective information on the pharmacological and toxicological properties of indigenous preparations. The growing interest in this research strategy is demonstrated by a number of papers in the journal Trends in Pharmacological Sciences on the traditional Materia Medica of Asian countries (1-4). In one of these articles, Dohadwalla (4) describes the successful results obtained with two products in the Hoechst research laboratories in Bombay, India. In a search for antihypertensive compounds a proaporphine alkaloid, stepharine, was isolated from the plant Stephania glabra (Menispermaceae). Because of side effects observed in beagle dogs (fluid retention and swelling of the extremities), a program was initiated which resulted in the synthetic compound, trequinsin. This drug lowers the blood pressure by acting on peripheral vessels and it is also a potent inhibitor of ADP-induced platelet aggregation in vitro; the compound is now at the stage of Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 ElsevierSciencePublishers B.V., 1987
human clinical trials. A second example is forskolin, isolated from the plant Coleus forskohlii (Labiatae). This compound has peripheral vasodilatory properties, possesses positive inotropic activity, and is also a potent inhibitor of human platelet aggregation. It has a unique mode of action, namely activation of adenylate cyclase with a consequent rise in cAMP levels. A number of derivatives has been produced, but none has shown potencies greater than forskolin in enzyme stimulation. Thus, the optimal structural requirements for activity are similar to those of the natural product.
Ipecac syrup and myopathy Most clinical reports o f adverse reactions to herbal medicines relate to isolated cases, which have had no or little impact on current practice. Once in a while, however, such reports build up to a cluster o f evidence for unexpected toxicity, thus requiring a re-evaluation o f the regulatory status o f the herbal medicine. A notable example o f the latter,,category is the recent stream o f papers describing severe myopathy and even death in patients with a major eating disorder, who had misused syrup o f ipecac to induce vomiting after binge eating (5"). According to the latest United States Pharmacopeia, syrup o f ipecac is prepared from the powdered dried rhizome and roots o f Cephaelis acuminata and contains 1.23-1.57 mg o f ethersoluble ipecac alkaloids per milliliter. These alkaloids consist o f at least 90% emetine and cephaeline, with the latter constituting 1-2 times the amount o f the former (6). Much lower alkaloidal concentrations may be found in ipecac syrups outside the United States (7). In the United States, syrup o f ipecac is considered to be the oral emetic o f choice in accidental poisoning. When used as such, serious adverse effects are usually absent (5, 8, 9). However, the syrup has gained popularity among patients with anorexia nervosa or bulimia ner-
Drugs used in non-orthodox medicine Chapter50 rosa who may use it for prolonged periods as a cheap andfreely available means for self-induced emesis after food consumption. Such unapproved practices may lead to substantial body levels of emetine (lOt), not only because the very slow elimination rate of emetine will lead to accumulation (11, 12), but also because the regular use of ipecac may reduce its reliability as an emetic so that the ipecac alkaloids remain available for absorption (10 r 13c). The neuromuscular toxicity of emetine is wellknown. Principal clinical manifestations are weakness, aching, tenderness, and stiffness o f the skeletal muscles, particularly those of the neck and extremities (11). The exact mechanisms responsible for this muscular dysfunction remain to be established. According to one prevailing opinion, emetine does not block neuromuscular transmission, but may exert a direct effect on the muscle fiber at a subcellular level, e.g. by affecting protein synthesis and/or mitochondrial oxidative phosphorylation (13-15). At least 7 cases of myopathy following ipecac misuse have already been described in detail (13c', 14c, 16c, 17c, 18c, 19", 20c), and preliminary epidemiological data suggest that additional reports are likely to follow (21). In the reported cases the length of time for which ipecac syrup had been misused on a regular basis ranged from 1 month (20) or even less (18, 19) to several years (13, 14). In all except I patient, who died from cardiac complications (18, 19), the muscle weakness markedly improved after the withdrawal of ipecac. However, 1 patient who had misused ipecac for years still showed mild residual weakness after 5 months (14) and electromyographic findings in another case of prolonged misuse were still abnor~nal 6 months after discontinuation (13). Muscle biopsies have revealed a t~redominance of type I fibers, a slight decrease in the average diameter of muscle fibers, and isolated necrotic granular basophilic fibers (13). A point of interest is that ipecac misusers may also have a history of abusing laxatives (16, 19). These drugs are capable o f producing a hypokalemic form o f muscular weakness that can be differentiated from emetine-induced myopathy by muscle biopsy (22). Some other effects observed in ipecac misusers include lethargy (16), erythema (17), dysphagia (18) and ECG abnormalities, with T-wave changes being the most prominent (13, 16). Emetine is a well-recognized cardiotoxic agent (11, 8). Although myocardial cellular damage is generally regarded as the main cardiotoxic effect (23), it remains to be clarified whether this
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underlies the cardiotoxic manifestations of therapeutic doses (24R). A recent ultrastructural study of rabbits treated with emetine revealed both myocardial and neural lesions (23), and beta-blockade was recently reported to protect rabbits against emetine-induced T-wave changes
(25). One ipecac misuser with myopathic symptoms showed a sinus tachycardia, which wus followed by severe hypotension, ventricular tachycardia, and death. Autopsy revealed inflammation of the visceral pericardium as well as hyperemia and scattered focal hyalinization of the myocardium (18, 19). Fatal cardiovascular complications, this time without an apparent weakness of the extremities, were also observed in another ipecac misuser. Microscopic examination of the heart showed diffuse interstitial edema with focal connective tissue proliferation, but actual fiber necrosis was not present. Emetine, as measured by fluorescence spectrophotometry, was recoveredfrom the liver (14.0 l~g/g), the kidney (7.4 #g/g) and various body fluids (lower concentrations). Based on these figures, the total body amount at the time of death was estimated to be 100 mg (10). Other publications suggest that ipecac syrup may have claimed additional victims in the anorectic and bulimic population. According to the lay press, substantial emetine levels were discovered postmortem in the late pop singer Karen Carpenter, who had been known to suffer from periods of binge eating (21, 26). Also, the misuse of ipecac could have been a contributing factor to the recently described death of yet another patient with anorexia nervosa (27, 28). It should be noted, however, that eating disorders themselves are associated with cardiac changes and death (16, 27, 29) so that the existence of a causal relationship between ipecac misuse and a fatal cardiac syndrome is not generally accepted (30). Discussions on the systemic toxicity of ipecac tend to focus on the constituent, emetine (8, 10, 13, 14, 20). However, the principal alkaloid in ipecac syrup is cephaeline rather than emetine (6) and there is ample evidence from studies on intact animals and isolated animal tissues that the former alkaloid shares the toxic potential of the latter (31-34). It is therefore to be hoped that future papers on ipecac poisoning will differentiate explicitly between emetine, cephaeline and any metabolites, when toxicological effects are discussed. This differentiation should also be made when body levels are reported, since a selective assay method for emetine and cephaeline is now available (35).
424 Growing concern that anorectic and bulimic individuals will misuse syrup o f ipecac made questionable its availability in the United States as a non-prescription item. At the time of writing this review, this matter was still under discussion (5"). Some health-care professionals, notably physicians treating patients with an eating disorder, have suggested that because the syrup presents such a danger it should be reclassified as a prescription-only product (18, 36). The opposite opinion was expressed by staff members of poison control centers, among others, who argued that ipecac syrup is the oral emetic of choice for poisoning, especially in young children, and that its reclassification would decrease its immediate availability in cases of poisoning, increase its costs and cause concern about safety among physicians and the lay public (5, 37, 38). The American Medical Association decided to support the latter view (9), and the Food and Drug Administration also seemed inclined to take this attitude (5). An intermediate point of view was that the syrup should be distributed by pharmacists only (5, 36). Note added in proof A recent editorial in The British Medical Journal questions whether ipecac syrup really prevents drug absorption and systemic toxicity in a reliable way (93).
HERBAL REMEDIES (SED-IO,890; SEDA-9, 421; SEDA-IO, 433) In the period covered by this review, the orthodox medical literature has not devoted much attention to the fact that herbal remedies are nowadays much in demand by the general public. In contrast, several pharmaceutical journals have promoted the idea that pharmacists should be more properly educated in this field so that they can resume their central role in supplying herbal remedies, thereby improving quality control and providing guidance on efficacy and safety (39-42). As a logical consequence, the Canadian Pharmaceutical Journal started a well-referenced series on popular medicinal herbs, such as licorice (43), chilli pepper (44), valerian (45), mistletoe (46) and evening primrose (47). With respect to valerian, it might be useful to add that the reputed sedative activity of the valepotriates in this plant could not be convincingly demonstrated in recent animal studies (48). The American Medical Association has published a useful and authoritative Handbook of Poisonous and Injurious Plants (49).
Chapter 50 P.A.G.M. de Smet and A.G. Vulto Although this publication does not specifically address the question of the toxicity of herbal remedies, it does provide a wealth of concise, up-to-date information about the toxicity of almost 150 genera and species occurring in the northern part of the western hemisphere. With respect to botanical medicines, a lengthy general survey of unwanted effects has appeared in the Italian literature (50~). Also, H/insel (51) has provided information about the toxicity of some hundred common ingredients of herbal teas. More specific publications have reinforced several of the arguments that underly the current professional concern about the safety of herbal medicines: (a) Incorrect identification of serf-collected plant material can result in serious poisoning A herbal tea prepared from foxglove leaves, which had been mistaken for comfrey leaves, has induced yet another case of digitalis toxicity (52c). Infusions of inadvertently collected A tractylis gummifera roots produced hepatic and renal injuries in 5 Spanish patients, one of whom died from hepatic failure and a massive gastrointestinal hemorrhage (53cR). (b) Inadequate quality control of herbal medicines leads to the selling of inferior products In a Belgian investigation of 3 different kinds of herbal products (laxative mixtures, peppermint products and lime-tree products), a majority of the samples studied were of poor quality. Samples of laxative mixtures contained ingredients without laxative action, constipating herbs or fibrous material (which is ineffective when used as a tea). The peppermint and lime-tree products originated largely from an inferior species. Many, samples were contaminated with pathogenic bacteria of fecal origin and the legal limits concerning the presence of insecticide residues were frequently surpassed. A deplorable finding was that pharmacists had not put their pharmacognostic training into practice: products sold by these professionals were no better than those obtained from other vendors (54c). An analytical search for pesticidal contaminants in crude drugs was also performed by Kwon et al (55). In a study of 3 drugs from South Korea (ginseng root, Angelica root and Cnidium rhizome), these investigators not only recovered trace amounts of hexachlorcyclohexanes and heptachlorepoxide, but also demonstrated the presence of the fungicide compound quintozen in the ginseng root in a concentration exceeding the minimally acceptable amount. Although the authors themselves are not worried by this fact, since they feel that the safety of the compound is such that problems in
Drugs used in non-orthodox medicine Chapter 50 man are not to be expected, their findings illustrate the need for screening the degree of contamination of crude drugs with pesticides on a regular basis. (c) Elusive ingredients of herbal remedies may lead to unforeseen reactions Anticholinergic poisoning occurred following the consumption of a burdock root tea commercially available in the United States. Just as in a previously reported case (SEDA-3, 387), chemical analysis of the original preparation revealed the inexplicable presence of atropine (56c). Another unexpected constituent of tea products on the U.S. market was the psychostimulating alkaloid, cocaine (see below). (d) Inappropriate uses of herbal drugs may substantially increase their potential risk as a health hazard Flagrant examples in the period reviewed were cases of overconsumption of ipecac syrup (see above) or a herbal laxative product (see below) by patients with eating disorders. (e) The persistent call for natural products may stimulate the return of herbal remedies that have become obsolete in official medicine because of their inefficacy and/or adverse reaction profile An example of this danger was the reintroduction of local treatment with laurel oil (see below). (f) Insufficient evaluation of tile therapeutic value and harmlessness of newly marketed herbal remedies continues to he a problem In West Germany, a parenteral product of Dionaea muscipula had to be withdrawn from the market within a few years because of serious allergic reactions (see below). In the Netherlands, an oriental medicinal pill called 'Chien Pu Wan' was introduced as a food supplement without proper documentation of the chemistry, pharmacology and toxicology of its 21 different ingredients (57R). Unproven claims about the therapeutic usefulness of the product included chronic conditions like rheumatic disorders, thus potentially exposing the user to long-term risks. It was particularly distressing that no information was available about the level o f aristolochic acids in the pill, because one of the declared ingredients was Aristolochiafangchi, which is reported to contain these compounds (58, 59). A mixture of aristolochic acids was so highly carcinogenic in rats that the West German health authorities decided to ban all Aristolochia products, including homeopathic dilutions up to D10 (60, 61R). To counterbalance all these data, the literature has also provided a nice example of
425 the fact that suspected adverse reactions to medicinal plants should be evaluated as carefully as those to chemical drugs: Eun and Lee (62cr) observed 4 cases of contact dermatitis due to a commercial ointment with an extract of the leaves and stems of Centella asiatica. This extract, which contains madecassic acid, asiatic acid and asiaticoside, has been widely used in Korea for wound healing and for the prevention of cicatrization. Patch testing of the 4 patients and of 63 controls with the individual components suggested that topical reactions to the ointment are due mainly to the presence of propylene glycol. According to the authors, a true allergic reaction to the active components remained unproven. Cnca leaf tea Siegel et al (63 c) have drawn attention to certain tea bags, known as 'Health Inca Tea' and 'Mate de Coca', that are being promoted in the United States as natural stimulants without caffeine. Although these products have been available for only a few years, total sales in grocery and health-food stores and through mail orders are already estimated at 1.5 million tea bags. Botanical examination of several samples revealed the presence of 1 or 2 commonly cultivated South American coca varieties. Chemical analysis did not show any evidence of decocainization: an average amount of about 5 mg of cocaine per tea bag o f 1 gram was within the range of concentrations that are normally found in coca leaves - a surprising finding, since only decocainlzed coca leaf products are legal in the United States. When users follow package directions and merely drink a few cups per day, their daily intake of cocaine remains low and seems to result only in some mild stimulation, mood elevation and increased heart rate. In contrast to a once commonly held belief, cocaine does produce profound pharmacological effects, such as intense euphoria, when high doses are given orally (64). One user of the coca leaf tea bags experienced severe agitation, tachycardia, perspiration and elevated blood pressure persisting for 2 hours, after drinking an infusion of 80 bags (63c). Apparently overconsumption, leading to ill effects and abuse, constitutes a potential risk of coca tea leaf products that reinforces the legislation against their availability. Dionaea muscipula A few years ago, the expressed sap of the fly-catching plant Dionaea muscipula was in-
426 troduced on the West German market as a herbal oncolytic in the form of Carnivora* ampoules and oral drops. This therapy was not derived from folk medicine and may have arisen from the idea that the carnivorous properties of the herb could be extended from insect tissues to human tumors. Despite a considerable lack of scientific data about the constituents, efficacy and safety of the Carnivora* dosage forms, they became available with the proviso that they were to be used only in patients who had failed to respond to all kinds of conventional anticancer treatment. Sensational success stories in the lay press subsequently promoted sales to as much as 20,000 packages per month (65, 66). In an open study of incurable cancer patients, Carnivora* therapy consistently failed to reduce tumors to less than half of their original mass. Furthermore, intramuscular administration frequently produced shivers and fever, and produced an anaphylactic shock in 2 out of 44 patients (67c, 68~). Evidence that peptide structures may be present (65) provides a tentative but plausible explanation for these reactions. The West German Federal Health Office responded to the findings with a prohibition of the sale of Carnivora* ampoules. The oral product was not instantly banned from the market, but the manufacturer was asked to present a controlled clinical trial demonstrating the efficacy and safety of Carnivora* drops before the end of 1988. In the meantime, the product information should warn against its use in pregnancy and should list reddening of the face, headache, dyspnea, nausea and vomiting as adverse effects (69). Feverfew One of the rare traditional remedies of Western society that was recently subjected not only to several non-clinical studies, but also to a formal clinical trial, is the asteraceous herb feverfew (Tanacetum parthenium, also known as Pyrethrum parthenium or Chrysanthemum parthenium). Its raw leaves and tablets prepared from them are widely used in the United Kingdom for the self-treatment of conditions such as arthritis and migraine (70, 71). In-vitro effects of feverfew extracts include interference with arachidonic acid metabolism (71, 72) and inhibition of the secretory activity of polymorphonuclear leukocytes and blood platelets (73). A recent double-blind trial has suggested that the herb provides an effective prophylactic treatment for migraine (74), but the design of
Chapter 50 P.A.G.M. de Smet and A.G. Vulto the trial did not go unchallenged (75). As the patients entering the study were already on feverfew (either stopping active treatment or not), further investigations in patients who have not yet received the plant are still warranted. Feverfew is rich in allergenic sesquiterpene lactones, a principal one being parthenolide. It is therefore not surprising that contact dermatitis may occur (74, 76c, 77c). The most common adverse reaction reported so far by migraine patients is ulceration of the mouth. A more widespread inflammation of the oral mucosa and tongue, often accompanied by swelling of the lips and sometimes by loss of taste, may also be observed. Chronic toxicity studies are not yet available (74r). Herbal laxatives Certain dangerous laxatives of natural origin, such as podophyllum, have been superseded by less toxic alternatives in orthodox medicine. However, they may still be incorporated in alternative medicines, which are sold by so-called health food shops without proper counselling on uses and side effects. The potential dangers of these products are highlighted by a case of prolonged poisoning due to an overdose of laxative tablets containing podophyllin, aloin, rheum and senna (78c): A 20-year-oldfemale was admitted to hospital with abdominal pain, diarrhea and vomiting as initial symptoms. Her history included the regular misuse of Triad Herb~tl Laxative tablets (15mg podophyllin, 30 mg aloin, 20 mg rheum and 40 rag senna) as a means of controlling her weight. Half-a-day before hospitalization, she had ingested a large overdose of these tablets. The patient appeared agitated and confused and became comatose within 12 hours after examination. She developed decorticate posturing and spasms of the limbs that changed into hypotonicity after her transfer to an intensive care unit. Her ECG showed abnormalities. The comatose state persisted for 5 days and was followed by drowsiness and confusion for a further 10 days. A tracheostomy was performed. It was removed after 19 days in hospital, but memory impairment and slow mentation remained. Gross weakness in the extremities made it impossible for her to stand or sit unaided, and nerve conduction studies 2 weeks after admission revealed a diffuse sensorimotor neuropathy. After 3 months, the patient was walking with elbow crutches and she was discharged from hospital. She was still suffering from impaired sensory modalities in hands and feet and from severe muscle weakness about the ankles. Two months later, her personality had apparently become normal, but the
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Drugs used in non-orthodox medicine Chapter 50
sensory impairment persisted and she still needed foot calipers and a walking-stick. The prolonged neurological symptoms in this patient are so characteristic o f podophyllum poisoning (79cR) that they were presumably caused by the podophyllin component of the herbal product. Laurel oil
Laurel oil is an unctuous mixture of fixed oil and essential oil, obtained by pressing the fresh berries of Laurus nobilis. Due to its potent sensitizing properties, which had already been described at the beginning of the present century, this product has become rather obsolete in orthodox medicine. So long as a public predilection for natural remedies persists, however, laurel oil may continue to produce allergic reactions. Hausen (80cr) described 2 German cases, where unauthorized external self-treatment resulted in expanding contact dermatitis within 10-14 days, without producing any therapeutic effect: A 53-year-old woman applied undiluted laurel oil twice daily to her left thigh because of a lipoma. When small vesicles and itching arose after 14 days of treatment, she stopped the application, but her symptoms increased over the next days. A vesicularbullous dermatitis and swelling of tlae left thigh developed and were followed by reactions extending to the right thigh, upper abdomen and forearms. Subsequent corticosteroid therapy gradually provided relief, but small foci remained on her thigh for weeks. After the patient had recovered from this primary incident, she suffered from similar reactions after the use of certain cosmetic products (bath mixture, toothpaste, shampoo), foodstuffs (sauerkraut, mixed pickles) and a drug (antihemorrhoidal suppository containing camomile oil). Chemical investigations of the applied laurel oil in combination with epicutaneous testing of the patient revealed that the sensitizing principles were sesquiterpene lactones with an ~t-methylenegroup (costunolid, dehydrocostuslaetone, eremanthin) and that the patient was cross-allergic to other plants containing related compounds, such as feverfew and camomile. A deplorable detail of the case-report by Hausen is that both patients had taken the suggestion to use laurel oil from a healthinsurance magazine. H O M E O P A T H I C MEDICINES "SED-IO, 897) Homeopathic remedies are generally considered to be free from side effects. In previous
volumes attention was given to adulteration of herbal and homeopathic medicines (SED-10, 890). Now another case of adulteration of a 'homeopathic' cure for asthma has been reported (81). The drug, Dumcap (Duzcap Pharmacy, Khoprapar, Karachi, Pakistan), is labelled to contain 'nux vomica, arsenic album, Blatta orientalis, and stramoni folic' (strychnine, arsenic trioxide, cockroach extract, and stramonium leaves). Chemical analysis showed the presence of prednisolone (4 mg in each capsule) and betamethasone (quantity not specified). Although no side effects were mentioned in this report, they are likely to occur, especially since the drug is also recommended for children. Although not marketed outside Pakistan, the manufacturer distributes the drug by mail to the United States, Western Europe, and the F a r East. APHRODISIACS Yohimbine (SED-IO,
903)
Although yohimbine has a long-standing reputation as an aphrodisiac, the value of this indole alkaloid as a sexual stimulant requires further study (82, 83). Tablets containing 1/12 grain (about 5 mg) of yohimbine hydrochloride are available in the United States under the brand names Yohimex and Yocon, the latter product with the enticing annotation that it may have activity as an aphrodisiac (84). The pharmacology of yohimbine has been reviewed comprehensively by Goldberg and Robertson (85R). The compound appears to act predominantly as an antagonist of presynaptic %-adrenoceptors and thereby counteracts inhibition of noradrenaline release. Principal adverse effects in man are emotional arousal and a rise in blood pressure and heart rate. There is clinical evidence that these emotional and autonomic responses may be markedly influenced by other drugs, e.g. potentiation by chlorpromazine and attenuation by amobarbital or reserpine. Another influential factor might be the route of administration: a comparison of results obtained in different studies would seem to suggest that intravenous injection may produce a more dramatic pressure response than oral ingestion (85). However, the validity of this impression remains to be established in a study comparing both ways of administration in the same subjects. The anxiogenic potential of yohimbine is
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Chapter 50 P.A.G.M. de Smet and A.G. Vulto
highlighted by two recent case-reports. Price et al (86c) administered the drug to 55 patients with a major depression, 39 patients with agoraphobia and panic disorder, and 20 normal subjects. Three of the 7 depressive patients with a bipolar diathesis reacted to an oral challenge dose of 10-20 mg with manic-like symptoms, compared with no cases among the 48 patients with unipolar depression or among the other two test groups. Linden et al (87c) described an acute dissociative reaction in a 16year-old girl who had ingested a street drug called yo-yo, which could be identified as yohimbine. Subsequent symptoms included anxiety, hypertension and tachycardia. The reaction resolved spontaneously but lasted for about 36 hours.
milk and eggs conducted by the U.S. Department of Agriculture and the U.S Food and Drug Administration. In addition, the lack of areolar pigmentation, which was a characteristic in previously reported estrogen-induced tbelarche, makes it again unlikely that an estrogen intoxicant is responsible. A casecontrol study of premature thelarche is now being conducted. In conclusion, it is doubted that the reported cases of precocious sexual development represent an epidemic, and environmental estrogens appear not to play a significant role in the development of precocious sexual development.
Precocious sexual development (SEDA-8, 445)
Several papers have been published dealing with serious side effects of immunoaugmentive therapy, including thymus gland extracts, aristolochic acid, Carnivora | (see above) and cell suspensions. A review has appeared in German (90R), and more specifically one of the forms of immunoaugmentive therapy (IAT) has been criticized recently by Curr et al (91).* This alternative unapproved cancer treatment is based on the theory that a cancer patient's defective immune system can be augmented to control tumor growth by the intramuscular injection of 4 so-called specific immune serum protein fractions: (a) blocking protein, (b) tumor antibody, (c) tumor complement, and (d) deblocking protein. These fractions are variously derived from necrotic tumors and the pooled blood of cancer patients and healthy donors. 'Stabilization' of the immune 'gystem requires 4-6 weeks, after which patients return home with a supply of serum and a therapy schedule. The treatment was offered until recently at the Immunology Researching Center in Freeport, Bahamas. By 1985 the clinic had treated over 3000 people (at an average treatment cycle cost of $10,000). In 1978, the Pan-American Health Organization visited the center and concluded that the treatment offered was without scientific rationale. As no objective and consistent treatment effects had been made, closure of the clinic was recommended. Analysis by the National Cancer Institute (U.S.A.) revealed that all of the treatment materials were dilute
In a previous volume we payed attention to the increase in the incidence of precocious sexual development in children from the early age of 6 months up to 8 years in Puerto Rico as reported repeatedly by Dr. Carmen Saenz de Rodriguez and her colleagues. It was hypothesized that the occurrence of residual estrogens and environmental estrogen-like compounds may have contributed to this phenomenon (e.g. zearalenone and one of its derivatives zcaralenol, both secondary metabolites of Fusarium spp., a common soil microfungus). It appears that zearalenone has been isolated from the blood of some of these patients. Also, in 29% of 326 children with premature thelarche whose blood samples were analysed, circulating total estrogens were said to be above normal (88). In a detailed and well-documented editorial most of the findings and conclusions of Dr. Saenz are seriously questioned (89). It is stated that ~-zearal_enol should not be confused with ~-zearan_alol (Zeranol, a growth promotor in meat production). These two compounds are not biologically interconvertible. A second comment regards the epidemiological reliability of the phenomenon: the true incidence of precocious development in Puerto Rico has not been established. Further, since comparative data are lacking, it is questioned if the reported cases are epidemic or normal. According to the anonymous author, Dr. Saenz and colleagues go well beyond the established facts in suggesting that estrogen exposure is due to residues, particularly zeranol, in meat, milk and poultry. No support for this suggestion has emerged from numerous analyses of Puerto Rican meat,
I M M U N O A U G M E N T I V E THERAPY
*It is important to distinguish the 'alternative' approaches to immunoaugmentation from the cautious scientific approaches dealt with in Chapter 39 of these volumes (Ed.).
Drugs used in non-orthodox medicine Chapter 50 blood proteins (predominantly albumin). Moreover, a number of the materials was uniformly contaminated with bacteria (Pseudomonas, Corynebacterium, staphylococci, Bacillus, Propionibacteriurn, and Achromobacter species). Samples screened for hepatitis B all disclosed surface antigen or anticore antibody or both and several cases of hepatitis B in IAT patients without other risk factors have been documented. Other documented side effects of IAT are abscess formation at injection sites On 4 cases Nocardia asteroides was isolated). In addition to treating cancer patients, the center offers treatment to patients with the acquired immunodeficiency syndrome (AIDS). Analysis of treatment samples from such patients revealed, in addition to uniform hepatitis B contamination, antibodies to human T-cell lymphotropic virus type III (HTLV-III or HIV) in 37 of 72 samples. From one sample viable HIV-virus could be isolated! Consequently, these reagents are potentially capable of transmitting AIDS and many patients will have been exposed to HIV. It may take years to know the extent of the damage caused by this treatment.
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Cell therapy Although not promoted as immunoaugmentive therapy, cell therapy is closely related (SED-10,903). It is reported that a patient developed disseminated encephalomyelitis after a second course of Niehans-Siecacel Suspension for back pain (92c). This preparation contains freeze-dried cells taken from sheep fetuses. After a 10 day treatment course the patient showed clear-cut inflammation (localization not specified) and chills. In 3 weeks time she started to develop signs of neurological derangement, which increased with time. These symptoms developed in a short time to a disseminated encephalomyelitis, which was treated with high doses of prednisolone. The neurological symptoms subsided only slowly and partially. After 20 weeks there was still a visual defect and a disturbance of the pyramidal tract, and also a decreased control over the anal sphincter. The clinical picture resembles that of a postviral or post-vaccination encephalomyelitis. Although it is clear that the dangers encountered at a time when fresh-cell therapy was popular have decreased, they have not disappeared.
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12. Schwartz DE, Herrero J (1965) Comparative pharmacokinetic studies of dehydroemetine and emetine in guinea pigs using spectro-fluorometric and radiometric methods. Am. J. Trop. Med. Hyg., 14, 78. 13. Palmer EP, Guay AT (1985) Reversible myopathy secondary to abuse of ipecac in patients with major eating disorders. N. Engl. J. Med., 313, 1457. 14. Mateer JE, FarreU BJ, Chou SSM, Gutmann L (1985) Reversible ipecac myopathy. Arch. Neurol., 42, 188. 15. SugieH, Russin R, Verity MA (1984) Emetine myopathy: two case reports with pathobioehemical analysis. Muscle Nerve, 7, 54. 16. Brotman MC, Forbath N, Garfinkel PE, Humphrey JG (1981) Myopathy due to ipecac syrup poisoning in a patient with anorexia nervosa. Can. Med. Assoc. J., 125, 453. 17. Bennett HS, Spiro AJ. Pollack MA, Zucker P (1982) Ipecac-induced myopathy simulating dermatomyositis. Neurology, 32, 91. 18. Friedman EJ (1984) Death from ipecac intoxication in a patient with anorexia nervosa. Am. J. Psychiatry, 141, 702. 19. Romig RA (1984) The potential toxicity of ipecac. Am. J. Psychiatry, 141, 1639. 20. Moldawsky RJ (1985) Myopathy and ipecac abuse in a bulimic patient. Psychosomatics, 26, 448. 21. Pope Jr HG, Hudson JI, Nixon RA, Herridge
430 PL (1986) The epidemiology of ipecac abuse. N. Eng. J. Med., 314, 245. 22. Lane RJM, Routledge PA (1983) Drug-induced neurological disorders. Drugs, 26, 124. 23. Yusuf Khan M, Haider B, Thind IS (1983) Emetine-induced cardiomyopathy in rabbits. J. Submicrosc. Cytol., 15, 495. 24. Yang WCT, Dubick M (1980) Mechanism of emetine cardiotoxicity. Pharmacol. Ther., 10, 15. 25. Mittal SR, Mathur AK, Sharma SK (1984) Protective effect of metoprolol on emetine induced T wave changes in animals. Int. J. Cardiol., 6, 82. 26. Murphy DH (1985) Anatomy of ipecac misuse: three case studies. Am. Pharm. (Non-Sci. ed.), 25, 480. 27. Isner JM, Roberts WC, Heymsfield SB, Yager J (1985) Anorexia nervosa and sudden death. Ann. Intern. Med., 102, 49. 28. Romig RA (1985) Anorexia nervosa, ipecac, and sudden death. Ann. Intern. Med., 103, 641. 29. Ferguson JM (1985) Bulimia" a potentially fatal syndrome. Psychosomatics, 26, 252. 30. Isner JM (1986) Effects of ipecac on the heart. N. Eng. J. Med., 314, 1253. 31. Wild RB (1895) The pharmacology of the ipecacuanha alkaloids. Lancet, 2, 1274. 32. Waiters AL, Koch EW (1917) Pharmacological studies of the ipecac alkaloids and some synthetic derivatives of cephaeline. I. Studies on toxicity. J. Pharmacol. Exp. Ther., 10, 73. 33. Epstein D (1932) The actions of emetine and cephaeline on the circulation, uterus and intestine. Q. J. Pharm. Pharmaeol., 5, 21. 34. Boyd EM, Knight LM (1964) The expectorant action of cephaeline, emetine and 2-dehydroemefine. J. Pharm. Pharmacol., 16, 118. 35. Moran DM, Crouch DJ, Finkle BS (1984) Absorption of ipecac alkaloids in emergency patients. Ann. Emerg. Med., 13, 1100. 36. Anonymous (1985) Schlegel on 'Today' show: change labelling, restrict sale. ,4m Pharm., (NonSci. ed.), 25, 483. 37. Troutman WG, Reed MT, Jones LA (1985) Ipecac: education, not restriction, needed. Am. Pharm., (Non-Sci. ed.), 25, 652. 38. Hull BL (1985) Ipecac on prescription7 Am. J. Psychiatry, 142, 141. 39. Corrigan D (1985) Educating the pharmacist about herbal medicines. Pharm. Int., 6, 22. 40. Chandler RF (1985) Traditional remedies still valued in modern pharmacy. Can. Pharm. J., 118, 419. 41. Anderson LA, Phillipson JD (1986) Herbal medicine, education and the pharmacist. Pharm. J., 236, 303. 42. Zwaving JH (1986) Fytotherapie en fytotherapeutica. Pharm. Weekbl., 121, 390. 43. Chandler RF (1985) Licorice, more than just a flavour. Can. Pharm. J., 118, 421. 44. Locock RA (1985) Capsicum. Can. Pharm. J., 118, 517. 45. B61iveau J (1986) Valeriana oflicinalis. Can. Pharm. J., 119, 25.
Chapter 50 P.A.G.M. de Smet and A.G. Vulto 46. Locock RA (1986) Mistletoe. Can. Pharm. J., 119, 125. 47. Briggs CJ (1986) Evening primrose, la belle de nuit, the king's cureall. Can. Pharm. J., 119, 249. 48. Hazelhoff B (1984) Phytochemical and Pharmacological Aspects of Valerian Compounds, p 51. Thesis, University of Groningen: 49. Lampe KF, McCann MA (1985) AMA Handbook of Poisonous and Injurious Plants. American Medical Association, Chicago, IL. 50. Fossati C, Fanzio G (1985) Effetti collaterali indesiderati e tossici delle piante medicinali. Clin. Ter., 112, 249. 51. H/insel R 0985) Teedrogen. In: Roth HJ (Ed), Pharmazeutisches Taschenbuch, p. 347. Wissenschaftlicbe Verlagsgesellschaft, Stuttgart. 52. Bain RJI (1985) Accidental digitalis poisoning due to drinking herbal tea. Br. Med. J., 290, 1624. 53. Caravaca Magarifios F, Cubero Gomez J J, Arrobas Vaca M e t al (1985) Afectaci6n renal y hepatica en la intoxicaci6n por Atractylis gummifera. Nefrologia, 5, 205. 54. Ulmann RM (1985) Wie wiedt er in de kruidenhof? Pharm. Weekbl., 120, 482. 55. Kwon SK, Dicke W, Thier H-P (1986) Peztizidriickst/inde in drei Drogen aus Siidkorea. Planta Med., 155. 56. Rhoads PM, Tong TG, Banner Jr W, Anderson R (1985) Anticholinergic poisonings associated with commercial burdock root tea. Clin. Toxicol., 22, 581. 57. De Smet PAGM (1986) 'Chien Pu Wan' pillen. Pharm. Weekbl., 121, 437. 58. Mix DB, Guinaudeau H, Shamma M (1982) The aristolochic acids and aristolactams. J. Nat. Prod., 45, 657. 59. Xu LZ (1984) Comparison of the chemical constituents of Aristolochia moupinensis and Aristolochia fangchi. Chang Yao Tung Pao, 9(5), 14. 60. Anonymous (1981) Zum Zulassungswiderruf Aristolochias/iure-haltigerFer tigarzneimittel. Pharm. Ztg, 126, ]'373. 61. Hagemann U, Grase R, Thiele A, Bass R, Sch6nh6fer PS (1982) Probleme der Arzneimittelsicberheit: Aristolochiasfiure. Miinch. Med. Wochenschr., 124, 611. 62. Eun HC, Lee AY (1985) Contact dermatitis due to Madecassol. Contact Derm., 13, 310. 63. Siegel RK, Elsohly MA, Plowman T et al (1986) Cocaine in herbal tea. J. Am. Med. Assoc., 255, 40. 64. Van Dyke C, Jatlow P, Ungerer J e t al (1978) Oral cocaine: plasma concentrations and central effects. Sci, 200, 211. 65. Anonymous (1985) Kurzbewertung des Phytotherapeutikums Carnivora zur Behandlung maligner Tumoren. Arznei-Telegramm, No. 7, 51. 66. Anonymous (1986) Nachschau: Einschr/inkungen/Vertriebsstop fiir Carnivora/Carnivora VF. Arznei- Telegramm, No. 1, 6. 67. Stadler HW, Dietzel U, Saner R (1985) Erfahrungen mit einem "Onkophytotherapeutikum'. Dtsch. Med. Wochenschr., 110, 1184.
Drugs used in non-orthodox medicine
Chapter 50
68. Dietzel U, Sauer R, Reichardt U (1985) Erfahrungen mit Carnivora. Fortschr. Med., 103, 760. 69. Anonymous (1986) Carnivora | - Massnahmen des Bundesgesundheitsamtes. Pharm. Ztg, 131, 109. 70. Berry MI (1984) Feveffew faces the future. Pharm. J. 232, 611. 71. Anonymous (1985) Feverfew - a new drug or an old wives' remedy? Lancet, 1, 1084. 72. Capasso F (1986) The effect of an aqueous extract of Tanacetum parthenium L. on arachidonic acid metabolism by rat peritoneal leucocytes. J. Pharm. Pharmacol., 38, 71. 73. Heptinstall S, WiUiamson L, White A, Mitchell JRA (1985) Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet, 1, 1071. 74. Johnson ES, Kadam NP, Hylands DM, Hylands PJ (1985) Efficacy of feverfew as prophylactic treatment of migraine. Br. Med. J., 291, 569. 75. Waller PC, Ramsay LE (1985) Efficacy of feverfew as prophylactic treatment of migraine. Br. Med. J., 291, 1128. 76. Vickers HR (1950) Contact dermatitis. Contact Derm., 164, 226. 77. Mitchell JC, Geissman TA, Dupuis G, Towers GHN (1971) Allegic contact dermatitis caused by Artemisia and Chrysanthemum species: the role of sesquiterpene lactones. J. Invest. Dermatol., 56, 98. 78. Dobb GJ, Edis RH (1984) Coma and neuropathy after ingestion of herbal laxative containing podophyllin. Med. J. Aust., 140, 495. 79. Cassidy DE, Drewry J, Fanning JP (1982) Podophyllum toxicity: a report ofta fatal case and a review of the literature. Clin. Toxicol., 19, 35. 80. Hausen BM (1985) Lorbeer-Allergie: Ursache, Wirkung und Folgen der iiussedichen Anwendung eines sogenannten Naturheilmittels. Dtsch. Med. Wochenschr., 110, 634.
431 81. Morice A (1986) Adulterated 'homoeopathic' cure for asthma. Lancet, 1, 862. 82. Young FE, Heckler MM (1985) Aphrodisiac drug products for over-the-counter human use. Fed. Regist., 50, 2168. 83. Buffum J (1985) Pharmacosexology update: yohimbine and sexual function. J. Psyehoact. Drugs, 17, 131. 84. Barnhart ER (Ed) (1986) Physicians" Desk Reference, 40th ed, pp 985, 1310. Medical Economics Co., Oradell. 85. Goldberg MR, Robertson D (1983) Yohimbine: a pharmacological probe for study of the alphaz-adrenoreceptor. Pharmacol. Rev 35, 143. 86. Price LH, Charney DS, Heninger GR (1984) Three cases of manic symptoms following yohimbine administration. Am. J. Psychiatry, 141, 1267. 87. Linden CH, Vellman WP, Rumack B (1985) Yohimbine: a new street drug. Ann. Emerg. Med., 4, 1002. 88. Saenz de Rodriguez CA (1984) Environmental hormone contamination in Puerto Rico. N. Engl. J. Med., 310, 1741. 89. Anonymous (1986) Precocious development in Puerto Rican children. Lancet, 1, 721. 90. Anonymous (1986) Immunstimulation Chance oder Gefahr? Arzneitelegramm, No. 8, 70. 91. Curt GA, Katterhagen G, Mahaney FX (1986) Immunoaugmentive therapy, a primer on the perils of unproved treatments. J. Am. Med. Assoc., 255, 505. 92. Seyfert S, Zynda B, Fuchs C et al (1985) Dissiminierte Enzephalomyelitis nach SiccazellInjektion. Dtsch. .~rztebl., 41, 2984. 93. Vale JA, Meredith TJ, Proudfoot AT (1986) Syrup of ipecacuanha: is it really useful? Br. Med. J., 293, 1321.
50
Drugs used in non-orthodox medicine
INTRODUCTION In a previous volume (SEDA-9,418) the opinion was expressed that, because of parallels between the biochemical pathways in man and animals on the one hand and those in plants on the other hand, carefully planned research efforts should result in the development of new, powerful and valuable therapeutic compounds derived from plants. Based on ethnotherapeutic criteria or folkloric considerations and phylogenetic and taxonomic relationships, several research programs in the pharmaceutical industry are concentrating on the selection of attractive candidates for the isolation of active principles that could be used as a basis for further drug development. This approach should prove fruitful in two ways: the original leads stem from traditional medicine and traditional medicine will obtain objective information on the pharmacological and toxicological properties of indigenous preparations. The growing interest in this research strategy is demonstrated by a number of papers in the journal Trends in Pharmacological Sciences on the traditional Materia Medica of Asian countries (1-4). In one of these articles, Dohadwalla (4) describes the successful results obtained with two products in the Hoechst research laboratories in Bombay, India. In a search for antihypertensive compounds a proaporphine alkaloid, stepharine, was isolated from the plant Stephania glabra (Menispermaceae). Because of side effects observed in beagle dogs (fluid retention and swelling of the extremities), a program was initiated which resulted in the synthetic compound, trequinsin. This drug lowers the blood pressure by acting on peripheral vessels and it is also a potent inhibitor of ADP-induced platelet aggregation in vitro; the compound is now at the stage of Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 ElsevierSciencePublishers B.V., 1987
human clinical trials. A second example is forskolin, isolated from the plant Coleus forskohlii (Labiatae). This compound has peripheral vasodilatory properties, possesses positive inotropic activity, and is also a potent inhibitor of human platelet aggregation. It has a unique mode of action, namely activation of adenylate cyclase with a consequent rise in cAMP levels. A number of derivatives has been produced, but none has shown potencies greater than forskolin in enzyme stimulation. Thus, the optimal structural requirements for activity are similar to those of the natural product.
Ipecac syrup and myopathy Most clinical reports o f adverse reactions to herbal medicines relate to isolated cases, which have had no or little impact on current practice. Once in a while, however, such reports build up to a cluster o f evidence for unexpected toxicity, thus requiring a re-evaluation o f the regulatory status o f the herbal medicine. A notable example o f the latter,,category is the recent stream o f papers describing severe myopathy and even death in patients with a major eating disorder, who had misused syrup o f ipecac to induce vomiting after binge eating (5"). According to the latest United States Pharmacopeia, syrup o f ipecac is prepared from the powdered dried rhizome and roots o f Cephaelis acuminata and contains 1.23-1.57 mg o f ethersoluble ipecac alkaloids per milliliter. These alkaloids consist o f at least 90% emetine and cephaeline, with the latter constituting 1-2 times the amount o f the former (6). Much lower alkaloidal concentrations may be found in ipecac syrups outside the United States (7). In the United States, syrup o f ipecac is considered to be the oral emetic o f choice in accidental poisoning. When used as such, serious adverse effects are usually absent (5, 8, 9). However, the syrup has gained popularity among patients with anorexia nervosa or bulimia ner-
Drugs used in non-orthodox medicine Chapter50 rosa who may use it for prolonged periods as a cheap andfreely available means for self-induced emesis after food consumption. Such unapproved practices may lead to substantial body levels of emetine (lOt), not only because the very slow elimination rate of emetine will lead to accumulation (11, 12), but also because the regular use of ipecac may reduce its reliability as an emetic so that the ipecac alkaloids remain available for absorption (10 r 13c). The neuromuscular toxicity of emetine is wellknown. Principal clinical manifestations are weakness, aching, tenderness, and stiffness o f the skeletal muscles, particularly those of the neck and extremities (11). The exact mechanisms responsible for this muscular dysfunction remain to be established. According to one prevailing opinion, emetine does not block neuromuscular transmission, but may exert a direct effect on the muscle fiber at a subcellular level, e.g. by affecting protein synthesis and/or mitochondrial oxidative phosphorylation (13-15). At least 7 cases of myopathy following ipecac misuse have already been described in detail (13c', 14c, 16c, 17c, 18c, 19", 20c), and preliminary epidemiological data suggest that additional reports are likely to follow (21). In the reported cases the length of time for which ipecac syrup had been misused on a regular basis ranged from 1 month (20) or even less (18, 19) to several years (13, 14). In all except I patient, who died from cardiac complications (18, 19), the muscle weakness markedly improved after the withdrawal of ipecac. However, 1 patient who had misused ipecac for years still showed mild residual weakness after 5 months (14) and electromyographic findings in another case of prolonged misuse were still abnor~nal 6 months after discontinuation (13). Muscle biopsies have revealed a t~redominance of type I fibers, a slight decrease in the average diameter of muscle fibers, and isolated necrotic granular basophilic fibers (13). A point of interest is that ipecac misusers may also have a history of abusing laxatives (16, 19). These drugs are capable o f producing a hypokalemic form o f muscular weakness that can be differentiated from emetine-induced myopathy by muscle biopsy (22). Some other effects observed in ipecac misusers include lethargy (16), erythema (17), dysphagia (18) and ECG abnormalities, with T-wave changes being the most prominent (13, 16). Emetine is a well-recognized cardiotoxic agent (11, 8). Although myocardial cellular damage is generally regarded as the main cardiotoxic effect (23), it remains to be clarified whether this
423
underlies the cardiotoxic manifestations of therapeutic doses (24R). A recent ultrastructural study of rabbits treated with emetine revealed both myocardial and neural lesions (23), and beta-blockade was recently reported to protect rabbits against emetine-induced T-wave changes
(25). One ipecac misuser with myopathic symptoms showed a sinus tachycardia, which wus followed by severe hypotension, ventricular tachycardia, and death. Autopsy revealed inflammation of the visceral pericardium as well as hyperemia and scattered focal hyalinization of the myocardium (18, 19). Fatal cardiovascular complications, this time without an apparent weakness of the extremities, were also observed in another ipecac misuser. Microscopic examination of the heart showed diffuse interstitial edema with focal connective tissue proliferation, but actual fiber necrosis was not present. Emetine, as measured by fluorescence spectrophotometry, was recoveredfrom the liver (14.0 l~g/g), the kidney (7.4 #g/g) and various body fluids (lower concentrations). Based on these figures, the total body amount at the time of death was estimated to be 100 mg (10). Other publications suggest that ipecac syrup may have claimed additional victims in the anorectic and bulimic population. According to the lay press, substantial emetine levels were discovered postmortem in the late pop singer Karen Carpenter, who had been known to suffer from periods of binge eating (21, 26). Also, the misuse of ipecac could have been a contributing factor to the recently described death of yet another patient with anorexia nervosa (27, 28). It should be noted, however, that eating disorders themselves are associated with cardiac changes and death (16, 27, 29) so that the existence of a causal relationship between ipecac misuse and a fatal cardiac syndrome is not generally accepted (30). Discussions on the systemic toxicity of ipecac tend to focus on the constituent, emetine (8, 10, 13, 14, 20). However, the principal alkaloid in ipecac syrup is cephaeline rather than emetine (6) and there is ample evidence from studies on intact animals and isolated animal tissues that the former alkaloid shares the toxic potential of the latter (31-34). It is therefore to be hoped that future papers on ipecac poisoning will differentiate explicitly between emetine, cephaeline and any metabolites, when toxicological effects are discussed. This differentiation should also be made when body levels are reported, since a selective assay method for emetine and cephaeline is now available (35).
424 Growing concern that anorectic and bulimic individuals will misuse syrup o f ipecac made questionable its availability in the United States as a non-prescription item. At the time of writing this review, this matter was still under discussion (5"). Some health-care professionals, notably physicians treating patients with an eating disorder, have suggested that because the syrup presents such a danger it should be reclassified as a prescription-only product (18, 36). The opposite opinion was expressed by staff members of poison control centers, among others, who argued that ipecac syrup is the oral emetic of choice for poisoning, especially in young children, and that its reclassification would decrease its immediate availability in cases of poisoning, increase its costs and cause concern about safety among physicians and the lay public (5, 37, 38). The American Medical Association decided to support the latter view (9), and the Food and Drug Administration also seemed inclined to take this attitude (5). An intermediate point of view was that the syrup should be distributed by pharmacists only (5, 36). Note added in proof A recent editorial in The British Medical Journal questions whether ipecac syrup really prevents drug absorption and systemic toxicity in a reliable way (93).
HERBAL REMEDIES (SED-IO,890; SEDA-9, 421; SEDA-IO, 433) In the period covered by this review, the orthodox medical literature has not devoted much attention to the fact that herbal remedies are nowadays much in demand by the general public. In contrast, several pharmaceutical journals have promoted the idea that pharmacists should be more properly educated in this field so that they can resume their central role in supplying herbal remedies, thereby improving quality control and providing guidance on efficacy and safety (39-42). As a logical consequence, the Canadian Pharmaceutical Journal started a well-referenced series on popular medicinal herbs, such as licorice (43), chilli pepper (44), valerian (45), mistletoe (46) and evening primrose (47). With respect to valerian, it might be useful to add that the reputed sedative activity of the valepotriates in this plant could not be convincingly demonstrated in recent animal studies (48). The American Medical Association has published a useful and authoritative Handbook of Poisonous and Injurious Plants (49).
Chapter 50 P.A.G.M. de Smet and A.G. Vulto Although this publication does not specifically address the question of the toxicity of herbal remedies, it does provide a wealth of concise, up-to-date information about the toxicity of almost 150 genera and species occurring in the northern part of the western hemisphere. With respect to botanical medicines, a lengthy general survey of unwanted effects has appeared in the Italian literature (50~). Also, H/insel (51) has provided information about the toxicity of some hundred common ingredients of herbal teas. More specific publications have reinforced several of the arguments that underly the current professional concern about the safety of herbal medicines: (a) Incorrect identification of serf-collected plant material can result in serious poisoning A herbal tea prepared from foxglove leaves, which had been mistaken for comfrey leaves, has induced yet another case of digitalis toxicity (52c). Infusions of inadvertently collected A tractylis gummifera roots produced hepatic and renal injuries in 5 Spanish patients, one of whom died from hepatic failure and a massive gastrointestinal hemorrhage (53cR). (b) Inadequate quality control of herbal medicines leads to the selling of inferior products In a Belgian investigation of 3 different kinds of herbal products (laxative mixtures, peppermint products and lime-tree products), a majority of the samples studied were of poor quality. Samples of laxative mixtures contained ingredients without laxative action, constipating herbs or fibrous material (which is ineffective when used as a tea). The peppermint and lime-tree products originated largely from an inferior species. Many, samples were contaminated with pathogenic bacteria of fecal origin and the legal limits concerning the presence of insecticide residues were frequently surpassed. A deplorable finding was that pharmacists had not put their pharmacognostic training into practice: products sold by these professionals were no better than those obtained from other vendors (54c). An analytical search for pesticidal contaminants in crude drugs was also performed by Kwon et al (55). In a study of 3 drugs from South Korea (ginseng root, Angelica root and Cnidium rhizome), these investigators not only recovered trace amounts of hexachlorcyclohexanes and heptachlorepoxide, but also demonstrated the presence of the fungicide compound quintozen in the ginseng root in a concentration exceeding the minimally acceptable amount. Although the authors themselves are not worried by this fact, since they feel that the safety of the compound is such that problems in
Drugs used in non-orthodox medicine Chapter 50 man are not to be expected, their findings illustrate the need for screening the degree of contamination of crude drugs with pesticides on a regular basis. (c) Elusive ingredients of herbal remedies may lead to unforeseen reactions Anticholinergic poisoning occurred following the consumption of a burdock root tea commercially available in the United States. Just as in a previously reported case (SEDA-3, 387), chemical analysis of the original preparation revealed the inexplicable presence of atropine (56c). Another unexpected constituent of tea products on the U.S. market was the psychostimulating alkaloid, cocaine (see below). (d) Inappropriate uses of herbal drugs may substantially increase their potential risk as a health hazard Flagrant examples in the period reviewed were cases of overconsumption of ipecac syrup (see above) or a herbal laxative product (see below) by patients with eating disorders. (e) The persistent call for natural products may stimulate the return of herbal remedies that have become obsolete in official medicine because of their inefficacy and/or adverse reaction profile An example of this danger was the reintroduction of local treatment with laurel oil (see below). (f) Insufficient evaluation of tile therapeutic value and harmlessness of newly marketed herbal remedies continues to he a problem In West Germany, a parenteral product of Dionaea muscipula had to be withdrawn from the market within a few years because of serious allergic reactions (see below). In the Netherlands, an oriental medicinal pill called 'Chien Pu Wan' was introduced as a food supplement without proper documentation of the chemistry, pharmacology and toxicology of its 21 different ingredients (57R). Unproven claims about the therapeutic usefulness of the product included chronic conditions like rheumatic disorders, thus potentially exposing the user to long-term risks. It was particularly distressing that no information was available about the level o f aristolochic acids in the pill, because one of the declared ingredients was Aristolochiafangchi, which is reported to contain these compounds (58, 59). A mixture of aristolochic acids was so highly carcinogenic in rats that the West German health authorities decided to ban all Aristolochia products, including homeopathic dilutions up to D10 (60, 61R). To counterbalance all these data, the literature has also provided a nice example of
425 the fact that suspected adverse reactions to medicinal plants should be evaluated as carefully as those to chemical drugs: Eun and Lee (62cr) observed 4 cases of contact dermatitis due to a commercial ointment with an extract of the leaves and stems of Centella asiatica. This extract, which contains madecassic acid, asiatic acid and asiaticoside, has been widely used in Korea for wound healing and for the prevention of cicatrization. Patch testing of the 4 patients and of 63 controls with the individual components suggested that topical reactions to the ointment are due mainly to the presence of propylene glycol. According to the authors, a true allergic reaction to the active components remained unproven. Cnca leaf tea Siegel et al (63 c) have drawn attention to certain tea bags, known as 'Health Inca Tea' and 'Mate de Coca', that are being promoted in the United States as natural stimulants without caffeine. Although these products have been available for only a few years, total sales in grocery and health-food stores and through mail orders are already estimated at 1.5 million tea bags. Botanical examination of several samples revealed the presence of 1 or 2 commonly cultivated South American coca varieties. Chemical analysis did not show any evidence of decocainization: an average amount of about 5 mg of cocaine per tea bag o f 1 gram was within the range of concentrations that are normally found in coca leaves - a surprising finding, since only decocainlzed coca leaf products are legal in the United States. When users follow package directions and merely drink a few cups per day, their daily intake of cocaine remains low and seems to result only in some mild stimulation, mood elevation and increased heart rate. In contrast to a once commonly held belief, cocaine does produce profound pharmacological effects, such as intense euphoria, when high doses are given orally (64). One user of the coca leaf tea bags experienced severe agitation, tachycardia, perspiration and elevated blood pressure persisting for 2 hours, after drinking an infusion of 80 bags (63c). Apparently overconsumption, leading to ill effects and abuse, constitutes a potential risk of coca tea leaf products that reinforces the legislation against their availability. Dionaea muscipula A few years ago, the expressed sap of the fly-catching plant Dionaea muscipula was in-
426 troduced on the West German market as a herbal oncolytic in the form of Carnivora* ampoules and oral drops. This therapy was not derived from folk medicine and may have arisen from the idea that the carnivorous properties of the herb could be extended from insect tissues to human tumors. Despite a considerable lack of scientific data about the constituents, efficacy and safety of the Carnivora* dosage forms, they became available with the proviso that they were to be used only in patients who had failed to respond to all kinds of conventional anticancer treatment. Sensational success stories in the lay press subsequently promoted sales to as much as 20,000 packages per month (65, 66). In an open study of incurable cancer patients, Carnivora* therapy consistently failed to reduce tumors to less than half of their original mass. Furthermore, intramuscular administration frequently produced shivers and fever, and produced an anaphylactic shock in 2 out of 44 patients (67c, 68~). Evidence that peptide structures may be present (65) provides a tentative but plausible explanation for these reactions. The West German Federal Health Office responded to the findings with a prohibition of the sale of Carnivora* ampoules. The oral product was not instantly banned from the market, but the manufacturer was asked to present a controlled clinical trial demonstrating the efficacy and safety of Carnivora* drops before the end of 1988. In the meantime, the product information should warn against its use in pregnancy and should list reddening of the face, headache, dyspnea, nausea and vomiting as adverse effects (69). Feverfew One of the rare traditional remedies of Western society that was recently subjected not only to several non-clinical studies, but also to a formal clinical trial, is the asteraceous herb feverfew (Tanacetum parthenium, also known as Pyrethrum parthenium or Chrysanthemum parthenium). Its raw leaves and tablets prepared from them are widely used in the United Kingdom for the self-treatment of conditions such as arthritis and migraine (70, 71). In-vitro effects of feverfew extracts include interference with arachidonic acid metabolism (71, 72) and inhibition of the secretory activity of polymorphonuclear leukocytes and blood platelets (73). A recent double-blind trial has suggested that the herb provides an effective prophylactic treatment for migraine (74), but the design of
Chapter 50 P.A.G.M. de Smet and A.G. Vulto the trial did not go unchallenged (75). As the patients entering the study were already on feverfew (either stopping active treatment or not), further investigations in patients who have not yet received the plant are still warranted. Feverfew is rich in allergenic sesquiterpene lactones, a principal one being parthenolide. It is therefore not surprising that contact dermatitis may occur (74, 76c, 77c). The most common adverse reaction reported so far by migraine patients is ulceration of the mouth. A more widespread inflammation of the oral mucosa and tongue, often accompanied by swelling of the lips and sometimes by loss of taste, may also be observed. Chronic toxicity studies are not yet available (74r). Herbal laxatives Certain dangerous laxatives of natural origin, such as podophyllum, have been superseded by less toxic alternatives in orthodox medicine. However, they may still be incorporated in alternative medicines, which are sold by so-called health food shops without proper counselling on uses and side effects. The potential dangers of these products are highlighted by a case of prolonged poisoning due to an overdose of laxative tablets containing podophyllin, aloin, rheum and senna (78c): A 20-year-oldfemale was admitted to hospital with abdominal pain, diarrhea and vomiting as initial symptoms. Her history included the regular misuse of Triad Herb~tl Laxative tablets (15mg podophyllin, 30 mg aloin, 20 mg rheum and 40 rag senna) as a means of controlling her weight. Half-a-day before hospitalization, she had ingested a large overdose of these tablets. The patient appeared agitated and confused and became comatose within 12 hours after examination. She developed decorticate posturing and spasms of the limbs that changed into hypotonicity after her transfer to an intensive care unit. Her ECG showed abnormalities. The comatose state persisted for 5 days and was followed by drowsiness and confusion for a further 10 days. A tracheostomy was performed. It was removed after 19 days in hospital, but memory impairment and slow mentation remained. Gross weakness in the extremities made it impossible for her to stand or sit unaided, and nerve conduction studies 2 weeks after admission revealed a diffuse sensorimotor neuropathy. After 3 months, the patient was walking with elbow crutches and she was discharged from hospital. She was still suffering from impaired sensory modalities in hands and feet and from severe muscle weakness about the ankles. Two months later, her personality had apparently become normal, but the
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Drugs used in non-orthodox medicine Chapter 50
sensory impairment persisted and she still needed foot calipers and a walking-stick. The prolonged neurological symptoms in this patient are so characteristic o f podophyllum poisoning (79cR) that they were presumably caused by the podophyllin component of the herbal product. Laurel oil
Laurel oil is an unctuous mixture of fixed oil and essential oil, obtained by pressing the fresh berries of Laurus nobilis. Due to its potent sensitizing properties, which had already been described at the beginning of the present century, this product has become rather obsolete in orthodox medicine. So long as a public predilection for natural remedies persists, however, laurel oil may continue to produce allergic reactions. Hausen (80cr) described 2 German cases, where unauthorized external self-treatment resulted in expanding contact dermatitis within 10-14 days, without producing any therapeutic effect: A 53-year-old woman applied undiluted laurel oil twice daily to her left thigh because of a lipoma. When small vesicles and itching arose after 14 days of treatment, she stopped the application, but her symptoms increased over the next days. A vesicularbullous dermatitis and swelling of tlae left thigh developed and were followed by reactions extending to the right thigh, upper abdomen and forearms. Subsequent corticosteroid therapy gradually provided relief, but small foci remained on her thigh for weeks. After the patient had recovered from this primary incident, she suffered from similar reactions after the use of certain cosmetic products (bath mixture, toothpaste, shampoo), foodstuffs (sauerkraut, mixed pickles) and a drug (antihemorrhoidal suppository containing camomile oil). Chemical investigations of the applied laurel oil in combination with epicutaneous testing of the patient revealed that the sensitizing principles were sesquiterpene lactones with an ~t-methylenegroup (costunolid, dehydrocostuslaetone, eremanthin) and that the patient was cross-allergic to other plants containing related compounds, such as feverfew and camomile. A deplorable detail of the case-report by Hausen is that both patients had taken the suggestion to use laurel oil from a healthinsurance magazine. H O M E O P A T H I C MEDICINES "SED-IO, 897) Homeopathic remedies are generally considered to be free from side effects. In previous
volumes attention was given to adulteration of herbal and homeopathic medicines (SED-10, 890). Now another case of adulteration of a 'homeopathic' cure for asthma has been reported (81). The drug, Dumcap (Duzcap Pharmacy, Khoprapar, Karachi, Pakistan), is labelled to contain 'nux vomica, arsenic album, Blatta orientalis, and stramoni folic' (strychnine, arsenic trioxide, cockroach extract, and stramonium leaves). Chemical analysis showed the presence of prednisolone (4 mg in each capsule) and betamethasone (quantity not specified). Although no side effects were mentioned in this report, they are likely to occur, especially since the drug is also recommended for children. Although not marketed outside Pakistan, the manufacturer distributes the drug by mail to the United States, Western Europe, and the F a r East. APHRODISIACS Yohimbine (SED-IO,
903)
Although yohimbine has a long-standing reputation as an aphrodisiac, the value of this indole alkaloid as a sexual stimulant requires further study (82, 83). Tablets containing 1/12 grain (about 5 mg) of yohimbine hydrochloride are available in the United States under the brand names Yohimex and Yocon, the latter product with the enticing annotation that it may have activity as an aphrodisiac (84). The pharmacology of yohimbine has been reviewed comprehensively by Goldberg and Robertson (85R). The compound appears to act predominantly as an antagonist of presynaptic %-adrenoceptors and thereby counteracts inhibition of noradrenaline release. Principal adverse effects in man are emotional arousal and a rise in blood pressure and heart rate. There is clinical evidence that these emotional and autonomic responses may be markedly influenced by other drugs, e.g. potentiation by chlorpromazine and attenuation by amobarbital or reserpine. Another influential factor might be the route of administration: a comparison of results obtained in different studies would seem to suggest that intravenous injection may produce a more dramatic pressure response than oral ingestion (85). However, the validity of this impression remains to be established in a study comparing both ways of administration in the same subjects. The anxiogenic potential of yohimbine is
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Chapter 50 P.A.G.M. de Smet and A.G. Vulto
highlighted by two recent case-reports. Price et al (86c) administered the drug to 55 patients with a major depression, 39 patients with agoraphobia and panic disorder, and 20 normal subjects. Three of the 7 depressive patients with a bipolar diathesis reacted to an oral challenge dose of 10-20 mg with manic-like symptoms, compared with no cases among the 48 patients with unipolar depression or among the other two test groups. Linden et al (87c) described an acute dissociative reaction in a 16year-old girl who had ingested a street drug called yo-yo, which could be identified as yohimbine. Subsequent symptoms included anxiety, hypertension and tachycardia. The reaction resolved spontaneously but lasted for about 36 hours.
milk and eggs conducted by the U.S. Department of Agriculture and the U.S Food and Drug Administration. In addition, the lack of areolar pigmentation, which was a characteristic in previously reported estrogen-induced tbelarche, makes it again unlikely that an estrogen intoxicant is responsible. A casecontrol study of premature thelarche is now being conducted. In conclusion, it is doubted that the reported cases of precocious sexual development represent an epidemic, and environmental estrogens appear not to play a significant role in the development of precocious sexual development.
Precocious sexual development (SEDA-8, 445)
Several papers have been published dealing with serious side effects of immunoaugmentive therapy, including thymus gland extracts, aristolochic acid, Carnivora | (see above) and cell suspensions. A review has appeared in German (90R), and more specifically one of the forms of immunoaugmentive therapy (IAT) has been criticized recently by Curr et al (91).* This alternative unapproved cancer treatment is based on the theory that a cancer patient's defective immune system can be augmented to control tumor growth by the intramuscular injection of 4 so-called specific immune serum protein fractions: (a) blocking protein, (b) tumor antibody, (c) tumor complement, and (d) deblocking protein. These fractions are variously derived from necrotic tumors and the pooled blood of cancer patients and healthy donors. 'Stabilization' of the immune 'gystem requires 4-6 weeks, after which patients return home with a supply of serum and a therapy schedule. The treatment was offered until recently at the Immunology Researching Center in Freeport, Bahamas. By 1985 the clinic had treated over 3000 people (at an average treatment cycle cost of $10,000). In 1978, the Pan-American Health Organization visited the center and concluded that the treatment offered was without scientific rationale. As no objective and consistent treatment effects had been made, closure of the clinic was recommended. Analysis by the National Cancer Institute (U.S.A.) revealed that all of the treatment materials were dilute
In a previous volume we payed attention to the increase in the incidence of precocious sexual development in children from the early age of 6 months up to 8 years in Puerto Rico as reported repeatedly by Dr. Carmen Saenz de Rodriguez and her colleagues. It was hypothesized that the occurrence of residual estrogens and environmental estrogen-like compounds may have contributed to this phenomenon (e.g. zearalenone and one of its derivatives zcaralenol, both secondary metabolites of Fusarium spp., a common soil microfungus). It appears that zearalenone has been isolated from the blood of some of these patients. Also, in 29% of 326 children with premature thelarche whose blood samples were analysed, circulating total estrogens were said to be above normal (88). In a detailed and well-documented editorial most of the findings and conclusions of Dr. Saenz are seriously questioned (89). It is stated that ~-zearal_enol should not be confused with ~-zearan_alol (Zeranol, a growth promotor in meat production). These two compounds are not biologically interconvertible. A second comment regards the epidemiological reliability of the phenomenon: the true incidence of precocious development in Puerto Rico has not been established. Further, since comparative data are lacking, it is questioned if the reported cases are epidemic or normal. According to the anonymous author, Dr. Saenz and colleagues go well beyond the established facts in suggesting that estrogen exposure is due to residues, particularly zeranol, in meat, milk and poultry. No support for this suggestion has emerged from numerous analyses of Puerto Rican meat,
I M M U N O A U G M E N T I V E THERAPY
*It is important to distinguish the 'alternative' approaches to immunoaugmentation from the cautious scientific approaches dealt with in Chapter 39 of these volumes (Ed.).
Drugs used in non-orthodox medicine Chapter 50 blood proteins (predominantly albumin). Moreover, a number of the materials was uniformly contaminated with bacteria (Pseudomonas, Corynebacterium, staphylococci, Bacillus, Propionibacteriurn, and Achromobacter species). Samples screened for hepatitis B all disclosed surface antigen or anticore antibody or both and several cases of hepatitis B in IAT patients without other risk factors have been documented. Other documented side effects of IAT are abscess formation at injection sites On 4 cases Nocardia asteroides was isolated). In addition to treating cancer patients, the center offers treatment to patients with the acquired immunodeficiency syndrome (AIDS). Analysis of treatment samples from such patients revealed, in addition to uniform hepatitis B contamination, antibodies to human T-cell lymphotropic virus type III (HTLV-III or HIV) in 37 of 72 samples. From one sample viable HIV-virus could be isolated! Consequently, these reagents are potentially capable of transmitting AIDS and many patients will have been exposed to HIV. It may take years to know the extent of the damage caused by this treatment.
429
Cell therapy Although not promoted as immunoaugmentive therapy, cell therapy is closely related (SED-10,903). It is reported that a patient developed disseminated encephalomyelitis after a second course of Niehans-Siecacel Suspension for back pain (92c). This preparation contains freeze-dried cells taken from sheep fetuses. After a 10 day treatment course the patient showed clear-cut inflammation (localization not specified) and chills. In 3 weeks time she started to develop signs of neurological derangement, which increased with time. These symptoms developed in a short time to a disseminated encephalomyelitis, which was treated with high doses of prednisolone. The neurological symptoms subsided only slowly and partially. After 20 weeks there was still a visual defect and a disturbance of the pyramidal tract, and also a decreased control over the anal sphincter. The clinical picture resembles that of a postviral or post-vaccination encephalomyelitis. Although it is clear that the dangers encountered at a time when fresh-cell therapy was popular have decreased, they have not disappeared.
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