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Drugs used in non-orthodox medicine
A.G. Vulto and H. Buurma
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Drugs used in non-orthodox medicine
INTRODUCTION If one considers the parallels between the biochemical pathways in man and animals on the one hand and those in plants on the other, one might have expected a far more elaborate range of drugs derived from the plant kingdom to be available than actually exists. Less than 100 plant-derived drugs of defined structure are in common use today throughout the world and of these less than half are more or less accepted as useful drugs in industrialized countries. Nevertheless, those which have been accepted are widely used. In the United States, the consumer paid during 1980 about 8.0 billion dollars for prescription drugs in which the active principles are still obtained from plants (1R). About 40% of all medicines produced in the Soviet Union are of natural origin; for cardiovascular agents the percentage is even higher (70%), with quinine and digitalis obviously leading the way. Many secondary plant constituents play a prominent role unrivalled by any synthetic compound in sophisticated pharmacological experiments. Because of the vast variety of plant life in the world, it is only to be expected that research in this field must in time produce, directly or after chemical modification, new powerful and valuable compounds that can be used to treat diseases. A lead to such investigations can be found by observing the medical traditions in developing countries, where as many as two-thirds of the population rely on plants as sources of drugs. Important contributions to such studies are to be found in Side Effects o f Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page (transactional system) $0.20 per article per page (licensing system)
the Journal of Ethnopharmacology, which recently entered its tenth volume. Another important development is the establishment of research and treatment centers devoted to traditional medicine in about 20 African countries. In Sri Lanka, the traditional medicine course at the Ayurveda College was recently extended to include the elements of pharmacology, therapeutics, and surgical emergencies. Several well-funded screening programs have been set up to provide facilities for testing a great number of natural compounds. For instance, UNESCO is supporting cooperation between local investigators and researchers within established laboratories in screening potential antiparasitic drugs (2). It is hoped that, by doing so, traditional medical remedies hitherto restricted to isolated areas will eventually benefit all mankind. It is noteworthy that the scientific community of the industrialized countries is well aware of its responsibilities, as can been seen from the number of meetings and conferences devoted to this topic. A concise overview is available in the Proceedings of the 20th Alfred Benzon Symposium, held in 1983 in Copenhagen and published under the title Natural Products and Drug Development (3R). There is a wealth of information available on the chemical nature of plant constituents, in many cases collected in past decennia, but most of these compounds have never been tested in a pharmacological model to evaluate their effects in a physiological system. Unfortunately, this is still the case in some areas of research, as is clear from several papers delivered at the Alfred Benzon Symposium. It is surprising to see to what length researchers go to establish with the most advanced techniques the three-dimensional structure of secondary metabolites isolated from plant material but without any attempt to evaluate the biological potential of such a compound (examples of this can be found in
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ReL 3). If there is a lead, such as an indigenous use of a certain plant material, setting up tests for biological activity would not be too difficult although there are certainly limitations for simply equipped laboratories. A good example is the work on gossypol derivatives (see below). Meanwhile, the debate on the contribution of 'alternative' medicine to health care in Western countries goes on without really addressing the main question: Why do some patients prefer an alternative healer to a conventional physician? Complications must arise with patients who consult both conventional and alternative health-care providers, which can result in ample opportunity for interference between the one treatment and the other. It is therefore justifiable to pay serious attention to reports on both the positive and negative effects of treatments instituted by alternative healers or at the initiative of the patient himself. It is hoped that this Chapter on remedies used in non-orthodox medicine will contribute to a more general understanding of this rather neglected area. This neglect is partly caused by the fact that in most countries there is no official legal status for alternative medicines; as a consequence, systematic toxicological data on such medicines are hardly available. While many alternative remedies can be of some benefit, several practices may lead to side effects which are easily overlooked. Because of the nature of this series, we shall have to concentrate on such side effects. A short review of this topic appeared recently in Canada (4). Next to many books on pharmacognosy, an important standard work has now been published that specifically deals with practical therapeutics (including side effects) employing material of herbal origin (5R).
oriented health-care organization, better suited for cities in industrialized countries than to areas where patients sometimes have to walk for days to reach such facilities. It appears that 'integration' has become the watchword of the 1980s (6). In the following sections we discuss from the Ayurvedic tradition the use of Kutaja and from the Chinese that of Red Jewel Paste.
Drugs used in non-orthodox medicine
TRADITIONAL MEDICINE IN DEVELOPING COUNTRIES It is obvious that a change has taken place in the attitudes of the medical c o m m u n i t y towards traditional medicine and its practitioners. It has become clear that it may be far more effective to use the existing infrastructure of traditional medicine to introduce the principles of hygiene and basic health maintenance than to try to convert an exisiting system to a Western-
Ayurvedic medicine 'Ayurveda' is the name of the ancient medical system of India where it is supposed to have been practised since before 1000 B.C. and it was the topic of a special review in the 1983 Annual (SEDA-7, 462). After the preparation of that short overview, a detailed monograph by N. Nath Pal was published (7). It deals predominantly with the philosophical and practical backgrounds of the Ayurvedic tradition and how this is embedded in the whole culture of the areas where it is practised. The problems with which researchers of the Ayurvedic tradition are confronted are clearly indicated in this review: in more than 70 textbooks on Ayurvedic medicine, some of them several centuries old, about 800 single drugs and some 200 compound drugs are described. However, if one also considers the different modes of preparation, the n u m b e r of Ayurvedic drug formulations is estimated to be in the region of some 23,000. Of this large number, about 2000 are in popular use and more generally available. In 1940, the Drug and Cosmetics Act authorized in India a series of 54 books on Ayurveda providing descriptions of the formulae in accordance with which Ayurvedic drugs are required to be processed and manufactured. Now, the Ayurvedic Pharmacopoeia Committee is compiling a standard Ayurvedic Formulary and Pharmacopoeia, to bring about more uniformity. The first volume of the Ayurvedic Formulary describes some 450 preparations most widely used in state hospitals in India. Steps are being taken to establish an Ayurvedic Drug Research Centre for the testing and standardization of drugs used according to the Ayurvedic tradition. The importance of Ayurveda in Sri Lanka will be clear from the fact that for a population of about 14 million people there are some 5000 doctors trained in so-called 'Western' medicine and approximately 10,000
420 Ayurvedics, of whom about half work fulltime. 'The merits or otherwise of its treatments have not been thoroughly investigated but as the main health care problems continue to be a need for effective sanitation and pure water its overall effect must be to the good.' (6)
Kutaja Chaturvedi and Singh reported their findings on the side effects of Kutaja, an Ayurvedic drug used in amebiasis and giardiasis (8c). The drug contains the bark powder of Holarrhena antidysenterica (Apocynaceae) and was given to 12 inpatients, in daily doses of 4 g for 15 days (in 3 divided doses). One patient was treated with 6 g a day. Four of these patients complained of adverse reactions, the nature of which was variable. The reported side effects are: burning sensation
in the head, abdomen and feet, dryness of the mouth, nausea, flatulence and constipation, and a n u m b e r of side effects related to the central nervous system such as agitation, nervousness, fatique and insomnia. Two patients had vertigo. In 1 case (in which the patient took 6 g a day) syncope occurred because of an acute hypotensive state. After recovery and supportive treatment, a rechallenge with Kutaja was given, again with a dramatic drop in blood pressure (to 84/54 mmHg); treatment was then discontinued. Another patient developed a gradual decline of blood pressure till the 9th day of treatment after which it persisted at 100/60 mmHg (falling from 124/86 mmHg at the beginning of treatment). The authors state that after cessation of the use of Kutaja the blood pressure returned to normal levels (126/92 mmHg) within 2 days. Based upon a literature source the authors suggested that conessine, an alkaloid constituent of Kutaja, was the major cause of the subjective symptoms. It is known that this alkaloid is likely to produce such symptoms in doses of some 500 mg a day or more. It is also pointed out that some other Ayurvedic drugs such as Bhallataka (based on Semicarpus annacardium), Aconite (Aconitum ferox) and Sarpagandha (Rauwolfia serpentina) produce side effects; the latter are also of course known in the West.
Chapter50 A.G. Vulto and H. Buurma Priapism due to traditional remedies Several indigenous treatments such as cantharides and yohimbine are known to cause priapism, a persistent, painful erection of the penis usually unrelated to sexual stimulation or desire although the onset may be initiated b y sexual stimuli. Rathore (9) reported 4 cases of priapism, one of which was caused by ingestion of an indigenous medicine for its supposed action as an aphrodisiac. Most peculiar was the finding that this patient improved after treatment with other indigenous remedies. Unfortunately, the composition of the causative preparation was not mentioned.
Red Jewel Paste Appendectomy is, in most cases, the accepted treatment for appendicitis. However, in China a preparation called 'Red Jewel Paste', consisting of 23 traditional Chinese medicines, is used as a non-operative external therapy for appendicitis (10c). In a report on 500 cases the side effects were intestinal hyperperistalsis in most patients, mild diarrhea (ca. 11%), local dermatitis (ca. 4%), local itching sensations (ca. 11%) and urticaria (ca. 2%). The paste, whose composition is not revealed, is applied locally under occlusion on the patient's fight lower quadrant. In the case of severe abdominal pain, analgesics or sedatives are available for the patients. However, antimicrobial treatment other than the paste is not allowed. It is suggested that Red Jewel Paste is a strong inhibitor of some pathogenic bacteria (such as Staphylococcus aureus, Pneumococcus, /~-hemolytic streptococcus and enterococcus). It is mainly effective in soothing the pain and tenderness that accompanies appendicitis. In almost all the chronic cases, surgical treatment was necessary. About half of the acute cases had an appendectomy some time later. In less then 10% of the cases was there no relapse over a 10-year follow-up period.
ACUPUNCTURE (SED-I O, 898) It is beyond doubt that some forms of acupuncture, when properly employed in
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susceptible individuals, can diminish the experience of pain. However, the objective clinical value of acupuncture in the treatment of pain (the best-investigated reason for treatment with acupuncture) is still controversial (11, 12) and requires controlled studies for a better understanding (13). Even designing such studies seems however to be a problem which is difficult to overcome: the choice of control- or placebo treatment is not easy. A placebo treatment such as 'random needling' may have a response rate as high as 40% (13). Besides difficulties with the validation of this technique there is also the risk of side effects induced by acupuncture treatment (SED-10, 898). Kropp and H~'ssler reviewed the occurrence o f pneumothorax after acupuncture in the thoracic region (14c). They describe in some detail 2 cases in which more or less typical symptoms appeared within 10 minutes after insertion of the needles. The pneumothorax itself developed more slowly after an onset with chest pain, persistent coughing and heavy breathing. It may take some days before it is possible to establish a definite diagnosis. The major cause of this side effect is too deep an insertion of the needles. In lean adults, the surface of the lungs can be as little as 2 cm below the surface of the skin. These authors suggest that this side effect is highly underreported, possibly because the spontaneous resorption of small amounts of air or liquid from the pleural cavity limits the urge of the patient to consult a physician for this condition. They advise limiting the depth of needle injection in the thoracic region to 0 . 5 - 1 . 0 cm in order to avoid this possibly serious complication.
properties and its supposed bile-stimulating action. Both herbal preparations are highly toxic. The U.S. F o o d and Drug Administration has designated several herbs as unsafe for inclusion in food, beverages and drugs. These are hsted in Table 1. That the use of these herbs can result in serious side effects is illustrated by a recent case.report by Hogan III (16 C).
HERBAL REMEDIES (SED-I O, 890) Herbs unsafe to use in foods, beverages or drugs. It is possible to find poisonous herbs included in 'natural' medicines and dietary aids. An article in American Pharmacy (15 R) mentioned the introduction of a dietary aid containing mandrake (PodophyIlum peltatum) (see Ref. 5, p. 250) and pokeroot (Phytolacca americana) (SEDA-5, 433). Phytolacca has emetic, purgative and mildly narcotic properties and mandrake was probably included for its strong laxative
A 25-year-old woman consulted her gynecologist because of abnormal menstrual bleeding. On pelvic examination a small mass was palpated; subsequent laparoscopy revealed a small amount of endometriosis. The mass effect was thought to result from an unusually placed ovary. After discharge from hospital her complaints persisted. Three weeks later at a re-evaluation, she was found to have an elevated prothrombin time of 53.4 seconds and an activated partial thrombophstin time of 70 seconds (40 seconds is about the normal reading), indicating disturbed coagulation. A wide variety of physical and laboratory examinations was then undertaken. The physical examinations disclosed essentially no abnormalities (apart from erosive gastritis, which was thought to be secondary to aspirin ingestion). Because the patient strongly denied taking coumarin-type drugs, quantitative clotting factor levels were obtained. Factor VII was 8% of normal, Factor IX 3%, Factor X 6%, and Factor V 61%. She was given parenteral vitamin K 1 and her prothrombin time and activated partial thromboplastin time rapidly returned to normal. At this point in her evaluation, further important information was elicited.. She had been accustomed to eating only 'natural' foods and she had accumulated stocks of about 40 herbs for use in various tonics and remedies. She had been drinking large amounts of a 'seasonal tonic' herbal tea for approximately 2 months before seeking hematological consultation. The recipe for this tea is found in Table 2. The patient related that she had consumed the equivalent of 20 pots of this tea in a period of 2 weeks, while drinking somewhat lesser quantities before and after that period. Her problems probably only started later, because she had increased her intake of tea in an attempt to lose weight. In commenting on this case the author relates the 3 coumarin-containing herbs in this mixture to the patient's coagulation defect: tonka beans (contains 1-3% coumarins by weight) (see also Table 1), melitot and sweet woodruff. However, the concomitant use of dextropropoxyphene napsylate plus acetaminophen (paracetamol) and the intake of a fairly large dose of vitamin A and perhaps even the intake of bromelains (to mention just some of the 'supplements' she was taking) may have enhanced the effect caused by the herbal preparation. Bromelains is a proteolytic enzyme derived from pineapple
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Table I. Herbs that should not be used in foods, beverages or drugs* Botanical name of plant source: common names
Remarks
Botanical name of plant source: common names
Remarks
Arnica montana Arnica; Arnica flowers; wolf's bane; leopard's bane; mountain tobacco; Flores arnicae
Aqueous and alcoholic extracts of the plant contain choline, plus 2 unidentified substances that affect the heart and vascular systems; Arnica, an active irritant, can produce violent toxic gastroenteritis, nervous disturbances, change in pulse rate, intense muscular weakness, collapse, and death
Conium maeulatum Hemlock; Conium; poison hemlock; spotted hemlock; spotted parsley; St. Bennet's herb; spotted cowbane; fool's parsley
Contains the poisonous alkaloid coniine and 4 other closely related alkaloids; often confused with water hemlock (Cicuta maculata); not to be confused with hemlock, hemlock spruce etc. (Tsuga canaden sis)
Hyoscyamus niger Henbane; Hyoscyamus; black henbane; hog's bean; poison tobacco; devil's eye
Contains the alkaloids hyoscyamine, hyoscine (scopolamine) and atropine; a poisonous plant
Exagonium purga, Ipomoea jalapa and Ipomoea purga Jalap root; jalap; Ture jalap; jalapa; Vera Cruz jalap; High John root; (possible also known as High John the Conqueror, John Conqueror, St. John the Conqueror root, Hi John Conqueror)
A large twining vine of Mexico, this plant has undergone many name changes; the drug is a powerful drastic cathartic; purgative powers of jalap reside in its resin; in overdoses, jalap may produce dangerous hypercatharsis
Datura stramonium Jimson weed; Datura; Stramonium; apple of Peru; Jamestown weed; thornapple; tolguacha
Contains the alkaloids atropine, hyoscyamine and scopolamine; illegal drug for non-prescription use; a poisonous plant
Convallaria majalis Lily of the valley; Convallaria; May lily
Contains the toxic cardiac glycosides convallatoxin, convallarin and convallamarin; poisonous plant
Lobelia inflata Lobelia; Indian tobacco; wild tobacco; asthma weed; emetic weed
A poisonous plant that contains the alkaloid lobeline plus a number of other pyridine alkaloids; overdoses of the plant or extracts of the leaves or fruits produce vomiting, sweating, pain, paralysis, depressed temperatures, rapid but feeble pulse, collapse, coma and death
Atropa belladonna Belladonna; deadly nightshade
Poisonous plant that contains the toxic solanaceous alkaloids hyoscyamine, atropine and hyoscine
Solanum dulcamara Bittersweet twigs; dulcamara; bittersweet; woody nightshade; climbing nightshade
Poisonous; contains the toxic glycoalkaloid solanine, also solanidine and dulcamarin
Sanguinaris canadensis Bloodroot; Sanguinaria; red puccoon
Contains the poisonous alkaloid sanguinarine and other alkaloids
Cytisus scoparius Broom-tops; scoparius spartium; Scotch broom; Irish broom; broom
Contains toxic sparteine, isosparteine and other alkaloids, also hydroxytyramine
Aesculus hippoeasteranum Buckeyes; Aesculus; horse chestnut
Contains a toxic coumarin glycoside, aesculin (esculin); a poisonous plant
Acorus calamus Calamus; sweet flag; sweet root; sweet cane; sweet cinnamon
Oil of calamus, Jammu variety, is a carcinogen (causes cancer); FDA regulations prohibit marketing of calamus as a food or food additive
Hefiotropium europaeum Heliotrope
A poisonous plant; it contains alkaloids that produce liver damage; not to be confused with garden heliotrope (Faleriana officinalis)
* Adapted from the FDA Consumer, October, 1983, and reprinted by courtesy of the Editors of American Pharmacy ,(15 R).
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Table 1 (continued) Botanical nam e of plant source: common names
Remarks
Mandragora officinarum The plant is a poisonous narcotic similar in its Mandrake; Mandragora; European mandrake properties to belladonna; contains the alkaloids hyoscyamine, scopolamine and mandragorine
Podophyllum peltatum Mandrake; May apple; PodophyHum; American mandrake; devil's apple;
A poisonous plant, it contains podophyllotoxin, a complex polycyclic substance, and umbrella plant; vegetable other constituents calomel; wild lemon; vegetable mercury
Phoradendron flavescens and Viscum flavescens Mistletoe; Viscum; American mistletoe Phoradendron juniperinum Mistletoe; Viscum; Juniper mistletoe Viscum album Mistletoe; Viscum; European mistletoe
Poisonous; contains the toxic pressor amines #phenylethylamine and tyramine
Violent purgative
Diptezyx odorata, Coumarouna odorata,
Active constituent of seed is coumarin; dietary feeding of coumarin to rats and dogs causes extensive liver damage, growth retardation, and testicular atrophy; FDA regulations prohibit marketing of coumarin as food or food additive
Dipteryx oppositifolia, and Coumarouna
oppositifofia Tonka bean; tonco bean; tonquin bean
Euonymus atropurpureus The poisonous principle Wahoo bark; has not been comEuonymus; burning bush; pletely identified; laxawahoo tive
Poisonous; contains the toxic pressor amines •-phenylethylamine and tyramine
(also called snakeroot, richweed)
Vinea major and Vinea minor Periwinkle; Vinca;
Contains pharmacologically active, toxic alkaloids such as vinblastine and vincristine that have cytotoxic and neurological actions and can injure the liver and kidneys
Hypericum; klamath weed; goatweed
Euonymus europaeus Spindle-tree
Eupatorium rugosum, E. ogeratoides and E. urticaefolium White snakeroot
Contains a purgative resin. In addition, morning glory seeds contain amides of lysergic acid but with a potency much less than that of LSD
Hypericum perforatum St. Johnswort;
Remarks
May be poisonous; little is known about its properties
Ipomoea purpurea Morning glory
greater periwinkle; lesser periwinkle
Botanical name of plant source: common names
A primary photosensitizer for cattle, sheep, horses and goats; contains hypericin, a fluorescent pigment, as a photosensitizing substance
Artemisia absinthium Wormwood; Absinthium; absinth; absinthe; madderwort; wermuth; mugwort; mingwort; warmot; Magenkraut; Herba absinthii
Poisonous plant; contains a toxic, unsaturated alcohol called tremetol combined with a resin acid; causes 'trembles' in cattle and other livestock; milk sickness is produced in humans by ingestion of milk, butter and possibly meat from animals poisoned by this plant Contains a volatile oil (oil of wormwood) that is an active narcotic poison; oil of wormwood is used to flavor absinthe, an alcoholic liqueur illegal in U.S.A. because its use can damage the nervous system and cause dental deterioration
Corynanthe yohimbi and Contains the toxic Pausinystalia yohimbe alkaloid yohimbine Yohimbe; yohimbi (quebrachine) and other alkaloids
424 Table 2 Recipe for 'seasonal tonic' (makes 10 pots of tea) 89 lb tonka beans* (ground) in 10 oz of 151-proof rum 2 oz melltot* 3 oz woodruff* 2 oz black pekoe tea 89 oz grated lemon peel 1/2lb grated orange peel 1 oz powdered hawthorn berries 1 oz hawthorn flowers 1 oz lobelia 3 sticks cinnamon 1 whole ginger root, minced *contains natural coumarins. and it is one of the many drugs reported to potentiate the effects of anticoagulants. The patient had been told by a friend that this enzyme would . remove fatty deposits from her hips.
Psyllium seeds (Plantago ovata, Plantago afra and Plantago arenaria) PsyUium seeds, as a w h o l e (several sources), b u t m o r e o f t e n t h e d r y h y d r o p h i l i c outer layer (husk, only obtainable from Plantago ovata), are t h e m a j o r c o n s t i t u e n t s of several b u l k laxatives in c o m m o n use in the United States and Europe. Adverse r e a c t i o n s are few a n d are m a i n l y r e l a t e d t o i n h a l a t i o n o f P l a n t a g o dust d u r i n g t h e p r o d u c t i o n o f t h e husks. T h e m a i n adverse r e a c t i o n s in t h e s e cases are r e s p i r a t o r y s y m p t o m s s u c h as r h i n i t i s a n d b r o n c h o s p a s m . Preparations containing Plantago are generally available w i t h o u t p r e s c r i p t i o n . In 2 r e c e n t case-reports, p r o b a b l y rare b u t serious side effects were revealed.
Agha et al (17 C) report a case in which a 23year~ld woman was admitted to hospital with a 2-week history of increasing midabdominal pain accompanied by nausea and vomiting, which had begun 2 days before admission. In the last week she had only 2 brown, gum-like bowel movements on the day of admission. She had a 6-year history of constipation which she treated with laxatives and recently with unrefined Psyllium seed husks. An abdominal radiograph revealed a large collection of material with curvillnear lucencies and a somewhat 'whorled' appearance occupying the upper abdomen and extending to the right iliac fossa. A diagnosis of a gastric or duodenal bezoar was suggested. Upper gastrointestinal examination using 4 oz of Hypaque (sodium diatrizoate) re-
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vealed a distended stomach with complete gastric outlet obstruction secondary to extrinsic compression. Because of the marked tenderness and the gastric outlet obstruction, the patient was taken to the operating room where a right colonic bezoar was found to be displacing and compressing the gastric antrum. Since the bowel was viable, the bezoar was broken up by hand and milked into the left colon. Postoperative cleansing enemas eventually cleared the colon. After 6 months the patient had recovered and was no longer using laxative preparations. In the discussion, the authors classify this type of bezoar as a mixed medication-induced phytobezoar. Phytobezoars are composed of fibrous matter such as skin, seeds and fibers from vegetables and fruits. Medication-induced bezoars may occasionally obstruct the gastrointestinal tract by virtue of their physical properties and location in the body. Examples of the latter are hygroscopic b u r laxatives, cholestyramine (SED-10, 823), non-abscrbable antacids, and vitamin C tablets. Most bezoars are situated in the stomach, whereas a primary colonic bezoar is extremely rare. In this case chronic constipation, heavy vegetable pulp ingestion, and bulk hygroscopic laxatives contribnted to the development of the colonic bezoar. Suhonen et al (18 c) describe in a second casereport a 33-year-old nurse seeking aid at hospital because of a generalized urticarial rash after taking 10 ml of granulated Psyllium laxative (Aqiolax). In hospital the symptoms were aggravated during the subsequent hour after admission: at first there was slight dyspnea, profuse diarrhea, and a lowered blood pressure of 80/55 mmHg; thereafter loss of consciousness occurred with an unmeasurable blood pressure. Complete recovery was secured with intravenous corticosteroids and plasma expanders, followed by oral prednisone for 5 days. Two months later, hypersensitivity to Psyllium was demonstrated by skin tests (scratch chamber technique on the dorsal skin). The other 12 components of the Aqiolax product gave negative results. The whole laxative product gave a strong wealing reaction (25 mm diameter) and Plantago ovata powder a somewhat smaller weal (10 mm) in 20 minutes. The histamine reference gave a 6 mm weal. With radioallergosorbent tests (RAST) both the laxative product and Plantago ovata gave strongly (maximum) positive scores. The presence of specific serum IgE antibodies was established, explaining the immediate hypersensitivity reaction after intake of the preparation. The total serum IgE of the woman was 130 U/ml (reference range: 0 - 1 1 0 U/ml). In their discussion the authors mention 2 poss~le means of sensitization. Firstly, the nurse had on several occasions handled Psyllium laxatives while administering drugs to geriatric patients. Secondly, she had taken Aqiolax for constipation for several weeks. The sudden onset of symptoms followed ingestion of a dose after a l-week pause in treatment.
Drugs used in non-orthodox medicine Chapter50 The hypersensitivity seen in this patient is rare and unusually strong compared to the symptoms of rhinitis and asthma that have previously been reported in the literature. They suggest the need to include a warning for hypersensitivity in the package insert.
Serenoa repens (American dwarf palm) The hexane extract of the fruit of the American dwarf palm tree Serenoa repens B. has been shown to have antiandrogenic properties, partly through a direct action at the level of the androgen receptor and also by inhibiting the enzyme, testosterone5a-reductase. The extract is commercially available in France as Permixon. Benign prostatic hyperplasia - an enlargement of the prostate - is a result of accumulation of dihydrotestosterone in the prostate. To date, the use of androgen receptor antagonists in the treatment of this disorder has been complicated by the side effects of antiandrogens. Champault et al (19 c) carried out a placebo-controlled doubleblind study to investigate the efficacy of the hexane extract P A l 0 9 in prostatic hyperplasia in 110 outpatients. The active treatment group received 320 mg/d (divided over 2 doses) of the tiposterolic extract. Not only did these authors report a significant improvement in the treatment group over the placebo group, but they also stated that the number of side effects reported in the treatment group was half that of the placebo group. All side effects were minor (e.g. headache). In addition, standard blood chemistry measurements showed no alteration. The effect of the extract is in all probability dependent on the availability of fl-sitosterin-3-D-glycoside, a compound that has been shown to have estrogen-like activity in animal models. The glycoside has a higher bioavailability due to greater hydrophilicity than the free /3-sitosterin. This fl-sitosterin (which is also present in significant amounts in crude cottonseed oil) has been shown to have beneficial effects in prostate adenomas when taken in a dose of 50 mg/d for 38 weeks. If an estrogen is indeed responsible, reports of estrogen-type side effects may in due course be expected.
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Licorice (SED-1 O, 895) Glycyrrhizinic acid, one of the constituents of licorice ( 9 - 1 2 % of dry weight), is a compound containing a steroidal structure (coupled with 2 molecules of glucuronic acid) and which has mineralocorticoid activity. It may, if taken in sufficient quantities, cause pseudo(hyper)aldosteronism with expansion of extracellular fluid volume, hypertension, hypokalemia and depression
of the renin-angiotensin-aldosterone system. Another effect can be amenorrhea and hyperprolactinemia due to competition with sex steroids for metabolizing liver enzymes. In the previous Annual (SEDA-8, 444), based on a letter to the Editor of The Lancet, we reported a case of pseudoaldosteronism due to the consumption of a non-alcoholic 'pastis' flavored with licorice. 'Pastis' is a French beverage based on aniseed oil. The case-report has been published in detail elsewhere (20 c). Corsi et al (21 c ) report the case of a 35year-old man who started eating licorice in quantities of 2 0 - 4 0 grams daily after having given up smoking. After 2 years, muscle weakness developed with accompanying hypertension and the clinical signs of an acute myopathy (albeit with some atypical features). Plasma aldosterone, renin and potassium levels were much lower than the normal range found in healthy individuals. After withdrawal of the licorice and the implementation of a high-potassium plus low-sodium diet, the patient recovered completely within 20 days. Based on an electron-microscopic study of the muscle tissue of this patient, the authors suggest that glycyrrhizinic acid may have a direct toxic effect on muscle fibers.
MISCELLANEOUS Gossypol (SED-1 O, 899) Gossypol is a yellowish phenohc compound occurring naturally in certain species of cotton plants of the Malvaciae family, mostly in the seeds and root bark. At one time, gossypol was considered to be only a toxic waste in the processing of cottonseed products. Before the discovery of the anti-
426 fertility action of gossypol, the compound was thought to be the active principle of cotton root bark, a Chinese folk medicine for the treatment of chronic bronchitis and cough. Based on this hypothesis, several clinical trials were carried out in bronchitic patients (22). Investigations of the mode of action and the toxicology of the c o m p o u n d are complicated by the fact that gossypol can exist in 3 tautomeric forms and that there are 2 optical isomers (23). Initially, gossypol was only isolated from the Gossypium species as a racemate, but the (+)-isomer has now been isolated from Thespesia populnea and also from the Gossypium species. However, it is the ( - ) - e n a n t i o m e r that possesses the antifertility action of this compound. It may well be that pure ( - ) - g o s s y p o l has a greater efficacy/toxicity ratio than the racemate that has been used in all studies published up to the present (24). It is claimed that in man at appropriate doses (20 mg daffy by m o u t h for 2 months and a maintenance dose of 50 rag/w) the drug has an antifertility efficacy of 9 5 99.07% (22 c , 25). Sperm motility is decreased as early as the second week of administration. Most of the reported side effects are reversible and generally mild, mainly including decrease or increase in appetite, fatigue, dryness o f the mouth, diarrhea, slight elevation o f SGPT and a tendency to sleepiness. Individual cases experienced depression of serum potassium levels, slight edema of the eyelid, and apparently decreased libido (and impotence). The drop in serum potassium levels is a major reason for concern, although it can be counteracted by supplementation of the diet with potassium. The overall occurrence of hypokalemic paralysis is about 1%, but it can increase to 5% depending on the average daffy intake of potassium. A second reason for concern is the inconsistent recovery o f fertility after cessation of gossypol treatment: about 10% of a group of volunteers remained azo-ospermic 6 months to 4.5 years post-regimen, indicating the possibility of irreversibility of fertility. A predisposing factor for this irreversibility was a treatment period of 2 years or more. This was confirmed in studies where the pattern of exfoliation of cells in human semen was investigated. The cell t y p e in semen that was most prominently exfoliated at the time of drug withdrawal appeared to be an indicator
Chapter50 A. G. Vulto and H. Buurma of the chance of recovery of fertility. Chances were lowest with the appearance of exfoliated spermatogonia (coinciding with an increased irreversible fertility after 2 or more years of treatment). There are pronounced differences among experimental species and strains in their sensitivity to both the anti-fertility and the toxicological action of gossypol. Hamsters appear to be the most sensitive species for the anti-fertility effect; rabbits and mice show toxic effects at dose levels that hardly affect fertility, Much more work will have to be performed on the toxicology of this compound before it can be accepted widely as a male contraceptive. The narrow gap between effective and toxic doses in animals with distinct species and strain differences will certainly complicate such studies, as will the complexity and reactivity of the molecule, resulting in photosensitivity and instability (23). Some of the reported effects of gossypol (22) found in animal studies both in vivo and in vitro are: a. lengthening of pentobarbital sleeping time and inhibition of gluthathione Stransferase activity, indicating a harmful influence on detoxification mechanisms (SEDA-6,423); b. degeneration o f skeletal muscle mitoehondria, depression of catechol-O-methyltransferase activity, blockade of neuromuscular transmission and lowering of cholinertie responses in vitro; c. decrease in calcium absorption and lowering of low-density lipoprotein level in blood; d. interferon induction, antitumor, antimicrobial and antiviral activities under experimental conditions. Apart from its direct toxicity and the problem of inconstant reversibility of fertility, there remains the question of longterm toxicity and possible genetic damage. Early Chinese reports indicated an absence of genetic damage (22, 26c), although this may need re-evaluation in the light of more recent findings (27c). Because the high proportion of artificial abortions of fetuses conceived after cessation of gossypol treatment, human data are unsatisfactory. In rats, the ratio of dead fetuses to the number of implantation sites was significantly higher in gossypol-treated animals (20 rag/ kg/d for 4 weeks, mating with females
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between 37 and 50 days post-treatment). Between 57 and 60 days post-treatment this difference no longer reached statistical significance. These results suggest that gossypol can directly damage the genetic material: once the sperm produced in the absence of gossypol is ejaculated, no abnormalities are any longer apparent. Regarding longterm effects, it is worrying that in testicular biopsy specimens from sterile men with a history of using crude cottonseed oil, Leydig cells were reduced in numbers and showed early signs of degeneration. Experiments in rats also showed changes in the morphology of Leydig ceils. Results from human studies are however inconsistent. It is becoming less and less likely that gossypol as it is now will ever be widely used as a male contraceptive all over the world. Elucidation of the mechanism of action and of the toxicological effects may provide the basis for the development of less toxic analogs (23) which could eventually lead to a male contraceptive pill. Another possible development is a more careful investigation of the dose-response relationships of the compound. Most studies have been aimed at producing azo-ospermia, but recent work shows that at far lower doses, with accordingly fewer side effects and possibly also fewer long-term problems, the fertilizing capacity of spermatozoa is sufficiently reduced to maintain a state of infertility.
knowledge of) azarcon and greta, a survey was started in Los Angeles County and in Colorado in 1982. In 1983 investigations in other states with migrant populations such as Arizona, New Mexico and Texas were started. In Los Angeles County, familiarity with the substances among the 545 households systematically selected was greatest amongst Mexican-Hispanics. Approximately onefourth of the Mexican-Hispanic families were familiar with one or both preparations and an estimated 7.2%-12.1% admitted prior use from 'years ago' to within the past month. Since investigators noticed a reluctance to admit the use of the remedies, the incidence of ingestion might have been greater than the results of the survey indicated. The Colorado survey among Texas farmworkers showed that 7 of 100 migrant children under 12 years of age had been treated with the compounds. Apparently, these remedies are most usually administered to infants and children for gastrointestinal illness. This age group is most susceptible in terms of clinical impact and the capacity to absorb lead (see also SEDA-6, 420 and SEDA-8, 445). The U.S. and Mexican health authorities have initiated recalls of the substances, which were until recently freely available at herb shops and 'health' (!) food stores and from folk healers on both sides of the Mexican-American border. Major media efforts publicizing the dangers of azarcon and greta have been directed at Hispanic communities in California. Another minority-group in the United States with significant exposure to and poisoning from lead are Hmong refugees from northern Laos (29). In the United States there is an estimated population of 50,000 and they live spread out over the country with concentrations in Fresno, Stockton, San Diego and St Paul. During a routine screening of children in 1983 by the St Paul, Minnesota, Division of Public Health, 35 children were found to have lead intoxication. Of these, 24 were Hmong children. One source of lead poisoning appeared to be a Hmong folk remedy used for treating infants and children with fever and rashes. In only 1 case, described by the authors, could a sample of the folk remedy be obtained. The remedy, generally referred to as pay-loo-ah, consists of red and orange powders, the composition and source of which vary and thus a more exact des-
Drugs used in non-orthodox medicine
Lead poisoning after ingestion of folk remedies In a case-report followed by an editorial note (28) the fairly widespread use in villages near the Mexican-American border of 2 folk remedies azarcon (lead tetroxide) and greta (lead oxide) is described and discussed. Greta and azarcon are fine powders with total lead content varying from 70% to more than 90%. According to the editorial note, the first cases of lead poisoning associated with the Mexican folk remedy azarcon were identified in Los Angeles and Colorado in the summer of 1981. Since that time, 9 additional confirmed cases associated with the ingestion of azarcon or the related remedy, greta, have been reported in California. Moreover, 5 cases have been reported from Michigan and Wisconsin. To investigate the exposure to (and the
428 cription of the material remains difficult. The one sample that was analyzed contained 8% lead. The U.S. Food and Drug Administration confirmed that 2 samples of other folk remedies obtained from this community contained lead (1% and 90%) while 3 contained arsenic (70-80%). The products investigated were in wide spread use and easily available through local Asian food stores or Hmong peddlers. Clearly, appropriate health education is necessary to avoid further occurrence of heavy metal poisoning among the Hmong community. Alcohol (SED-I O, 905) Ethanol and isopropanol are found as active ingredients in oral, parenteral and topical (including inhalational) prescription and non-prescription drug products. Although alcohol is primarily used for its solvent properties to help solubilize other drugs, it also possesses several concentrationdependent pharmacological actions, including sedative, carminative, cooling, antipyretic, rubefacient, cleansing and antiseptic properties. Concentrations of 40% or more may be found in some oral preparations, thus resulting in patients consuming as much as 30 ml of pure ethanol during the course of the day. A concise compilation of nearly 300 alcohol-containing prescription and non-prescription drugs in Canada is
Chapter50
A. G. Vulto and H. Buurma
presented by Parker and Baiilie (30). A similar list compiled for the Federal Republic of Germany contains almost 1500 preparations, including 50 parenteral drugs (31). Such lists should become available in every country in order to make it possible to counsel patients with alcohol problems, patients with liver disease, epileptic patients, patients with brain damage, children and pregnant women. Besides these risk-groups, patients taking all kinds of drugs may experience a change in drug effect due to u n k n o w n concomitant alcohol consumption. Alternatively, the use of certain antibiotics such as cefoperazon, cefoxitin and lamoxactam may trigger disulfiram-like reactions due to unexpected alcohol intake. A number of drugs are also known to potentiate the effects of alcohol on the central nervous system (varying from sulfonylurea drugs to drugs such as phentolamine and tolazoline) (30). Unfortunately, the presence of ethanol or the concentration is not always mentioned on the label.
ACKNOWLEDGMENTS We wish to thank Dr. Chris Fowler and Dr. Yie Shang-mian for their helpful and stimulating discussions during the preparation of the manuscript.
REFERENCES 1. Farnsworth NR (1984) The role of medicinal plants in drug development. In: KrogsgaardLarsen P e t al (Eds), Natural Products and Drug Development, p 17. Munksgaard, Copenhagen. 2. Burger A, Crabb~ P (1984) Screening programme of new compounds from developing countries. Trends PharmaeoL ScL, 11, 2. 3. Krogsgaard-Larsen P, B~gger Christensen S, Kofod H (Eds) (1984) Natural Products and Drug Development. Proceedings. Alfred Benzon Symposium 20, Copenhagen, August, 1983. Munksgaard, Copenhagen. 4. Lisowski F (1983) Herbal and unconventional remedies in the elderly. Can. Pharm. J., 116, 135. 5. H~nsel R, Haas H (1984) Therapie mit Phytopharmaka. Springer-Verlag,Berlin. 6. Varnam MA (1982) Respect for traditional medicine. Br. Med. J., 285, 1737. 7. N~.th Pal SM (1982) Drug and its action according to Ayurveda. Prog. Drug Res., 26, 55. 8. Chaturvedi GN, Singh KP (1983) Side effects
of a traditional indigenous drug - Kutaja (Holarrhena antidysenterica), lndian J. Physiol. Pharmacol., 255. 9. Rathore AH (1983) Priapism: a report of 4 cases. J. Pak. Med. Assoc., 33, 208. 10. Baoming Q (1983) A study on the mechanism and indications in treatment of acute appendicitis by Red Jewel Paste. J. Abdom. Surg., 25, 61. 11. Skrabanek P (1984) Acupuncture and the age of unreason. Lancet, 1, 1169. 12. Mendelson G, Robson J (1984) Br. Med. J., 288, 1999 (Correspondence). 13. Lewith GT (1984) Can we assess the effects of acupuncture? Br. Med. J., 288, 1475. 14. Kropp R, I-I~ssler R (1983) Akzidenteller Pneumothorax nach Injektionen und Akupunktur im Thoraxbereich. Med. Welt, 34, 1143. 15. Anonymous (1984) Herbs hazardous to your health. Am. Pharm., NS24, 120. 16. Hogan III RP (1983)Hemorrhagic diathesis caused by drinking an herbal tea. J. Am. Med.
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Assoc., 249, 2679. 17. Agha FP, Nostrant TT, Fiddian-Green RG (1984) ~3iant colonic bezoar': a medication bezoar due to Psyllium seed husks. Am. J. Gastroenterol., 79,319. 18. Suhonen R, Kantola I, Bj6rksten F (1983) Anaphylactic shock due to ingestion of Psyllium laxative. Allergy, 38, 363. 19. Champault G, Patel JC, Bonnard AM (1984) A double blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia, Br. J. Clin. Pharmacol., 18, 461. 20. Trono D, Cereda JM, Favre L (1983) Pseudosyndrome de Conn par intoxication au pastis sans alcool. Schweiz. Med. lr 113, 1092. 21. Corsi FM, Galgani S, Gasparini C et al (1983) Acute hypokalemic myopathy due to chronic licorice ingestion: report of a case. ltal. J. Neurol. ScL, 4, 493, 22. Qian S-Z, Wang Z-G (1984) Gossypol: apotential antifertility agent for males. Ann. Rev. Pharmacol. Toxicol., 24, 329. 23. Fong HHS (1984) Current status ofgo~ypol, zoapatanol and other plant-derived fertility regulating agents. In: Krogsgaard-Larsen P e t al (Eds), Natural Products and Drug Development, p 355. Munksgaard, Copenhagen. 24. Editorial (1984) Gossypol prospects. Lancet,
1, 1108. 25. Anonymous (1984)F.uture aspects of contraception. Lancet, 2, 703. 26. Tsui Y-C, Creasy MR, Hult~n MA (1983) The effect of the male contraceptive agent gossypol on hyman lymphocytes in vitro: traditional chromosome breakage, micronuclei, sister chromatid exchange, and cell kinetics. Z Med. Genet., 20, 81. 27. Nordenskj61d M, Lambert B (1984)Gossypol induces DNA strand breaks in human fibroblasts and sister chromatid exchanges in human lymphocytes in vitro. J. Med. Genet., 21, 129. 28. Sankury T et al (1983) Lead poisening from Mexican folk remedies - California. J. Am. Med. Assoc., 250, 3149. 29. Levitt C et al (1983) Folk remedy-associated lead poisoning in Hmong children. J. Am. Med. Assoc., 250, 3149. 30. Parker WA, Baillie GR (1983) Alcohol conraining pharmaceuticals. Can. Pharm. J., 116, 231. 31. Gr6bler A, Kotwas J (1983) Alkoholgehalt von Arzneimittein. In: Becker W, Moebius UM (Eds), Transparenztelegramm, p 48. A.T.I. Arzneimittelinformation Berlin GmbH. Berlin (West).
50
Drugs used in non-orthodox medicine
INTRODUCTION If one considers the parallels between the biochemical pathways in man and animals on the one hand and those in plants on the other, one might have expected a far more elaborate range of drugs derived from the plant kingdom to be available than actually exists. Less than 100 plant-derived drugs of defined structure are in common use today throughout the world and of these less than half are more or less accepted as useful drugs in industrialized countries. Nevertheless, those which have been accepted are widely used. In the United States, the consumer paid during 1980 about 8.0 billion dollars for prescription drugs in which the active principles are still obtained from plants (1R). About 40% of all medicines produced in the Soviet Union are of natural origin; for cardiovascular agents the percentage is even higher (70%), with quinine and digitalis obviously leading the way. Many secondary plant constituents play a prominent role unrivalled by any synthetic compound in sophisticated pharmacological experiments. Because of the vast variety of plant life in the world, it is only to be expected that research in this field must in time produce, directly or after chemical modification, new powerful and valuable compounds that can be used to treat diseases. A lead to such investigations can be found by observing the medical traditions in developing countries, where as many as two-thirds of the population rely on plants as sources of drugs. Important contributions to such studies are to be found in Side Effects o f Drugs Annual 9 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1985 ISBN 0 444 90394 1 $0.85 per article per page (transactional system) $0.20 per article per page (licensing system)
the Journal of Ethnopharmacology, which recently entered its tenth volume. Another important development is the establishment of research and treatment centers devoted to traditional medicine in about 20 African countries. In Sri Lanka, the traditional medicine course at the Ayurveda College was recently extended to include the elements of pharmacology, therapeutics, and surgical emergencies. Several well-funded screening programs have been set up to provide facilities for testing a great number of natural compounds. For instance, UNESCO is supporting cooperation between local investigators and researchers within established laboratories in screening potential antiparasitic drugs (2). It is hoped that, by doing so, traditional medical remedies hitherto restricted to isolated areas will eventually benefit all mankind. It is noteworthy that the scientific community of the industrialized countries is well aware of its responsibilities, as can been seen from the number of meetings and conferences devoted to this topic. A concise overview is available in the Proceedings of the 20th Alfred Benzon Symposium, held in 1983 in Copenhagen and published under the title Natural Products and Drug Development (3R). There is a wealth of information available on the chemical nature of plant constituents, in many cases collected in past decennia, but most of these compounds have never been tested in a pharmacological model to evaluate their effects in a physiological system. Unfortunately, this is still the case in some areas of research, as is clear from several papers delivered at the Alfred Benzon Symposium. It is surprising to see to what length researchers go to establish with the most advanced techniques the three-dimensional structure of secondary metabolites isolated from plant material but without any attempt to evaluate the biological potential of such a compound (examples of this can be found in
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ReL 3). If there is a lead, such as an indigenous use of a certain plant material, setting up tests for biological activity would not be too difficult although there are certainly limitations for simply equipped laboratories. A good example is the work on gossypol derivatives (see below). Meanwhile, the debate on the contribution of 'alternative' medicine to health care in Western countries goes on without really addressing the main question: Why do some patients prefer an alternative healer to a conventional physician? Complications must arise with patients who consult both conventional and alternative health-care providers, which can result in ample opportunity for interference between the one treatment and the other. It is therefore justifiable to pay serious attention to reports on both the positive and negative effects of treatments instituted by alternative healers or at the initiative of the patient himself. It is hoped that this Chapter on remedies used in non-orthodox medicine will contribute to a more general understanding of this rather neglected area. This neglect is partly caused by the fact that in most countries there is no official legal status for alternative medicines; as a consequence, systematic toxicological data on such medicines are hardly available. While many alternative remedies can be of some benefit, several practices may lead to side effects which are easily overlooked. Because of the nature of this series, we shall have to concentrate on such side effects. A short review of this topic appeared recently in Canada (4). Next to many books on pharmacognosy, an important standard work has now been published that specifically deals with practical therapeutics (including side effects) employing material of herbal origin (5R).
oriented health-care organization, better suited for cities in industrialized countries than to areas where patients sometimes have to walk for days to reach such facilities. It appears that 'integration' has become the watchword of the 1980s (6). In the following sections we discuss from the Ayurvedic tradition the use of Kutaja and from the Chinese that of Red Jewel Paste.
Drugs used in non-orthodox medicine
TRADITIONAL MEDICINE IN DEVELOPING COUNTRIES It is obvious that a change has taken place in the attitudes of the medical c o m m u n i t y towards traditional medicine and its practitioners. It has become clear that it may be far more effective to use the existing infrastructure of traditional medicine to introduce the principles of hygiene and basic health maintenance than to try to convert an exisiting system to a Western-
Ayurvedic medicine 'Ayurveda' is the name of the ancient medical system of India where it is supposed to have been practised since before 1000 B.C. and it was the topic of a special review in the 1983 Annual (SEDA-7, 462). After the preparation of that short overview, a detailed monograph by N. Nath Pal was published (7). It deals predominantly with the philosophical and practical backgrounds of the Ayurvedic tradition and how this is embedded in the whole culture of the areas where it is practised. The problems with which researchers of the Ayurvedic tradition are confronted are clearly indicated in this review: in more than 70 textbooks on Ayurvedic medicine, some of them several centuries old, about 800 single drugs and some 200 compound drugs are described. However, if one also considers the different modes of preparation, the n u m b e r of Ayurvedic drug formulations is estimated to be in the region of some 23,000. Of this large number, about 2000 are in popular use and more generally available. In 1940, the Drug and Cosmetics Act authorized in India a series of 54 books on Ayurveda providing descriptions of the formulae in accordance with which Ayurvedic drugs are required to be processed and manufactured. Now, the Ayurvedic Pharmacopoeia Committee is compiling a standard Ayurvedic Formulary and Pharmacopoeia, to bring about more uniformity. The first volume of the Ayurvedic Formulary describes some 450 preparations most widely used in state hospitals in India. Steps are being taken to establish an Ayurvedic Drug Research Centre for the testing and standardization of drugs used according to the Ayurvedic tradition. The importance of Ayurveda in Sri Lanka will be clear from the fact that for a population of about 14 million people there are some 5000 doctors trained in so-called 'Western' medicine and approximately 10,000
420 Ayurvedics, of whom about half work fulltime. 'The merits or otherwise of its treatments have not been thoroughly investigated but as the main health care problems continue to be a need for effective sanitation and pure water its overall effect must be to the good.' (6)
Kutaja Chaturvedi and Singh reported their findings on the side effects of Kutaja, an Ayurvedic drug used in amebiasis and giardiasis (8c). The drug contains the bark powder of Holarrhena antidysenterica (Apocynaceae) and was given to 12 inpatients, in daily doses of 4 g for 15 days (in 3 divided doses). One patient was treated with 6 g a day. Four of these patients complained of adverse reactions, the nature of which was variable. The reported side effects are: burning sensation
in the head, abdomen and feet, dryness of the mouth, nausea, flatulence and constipation, and a n u m b e r of side effects related to the central nervous system such as agitation, nervousness, fatique and insomnia. Two patients had vertigo. In 1 case (in which the patient took 6 g a day) syncope occurred because of an acute hypotensive state. After recovery and supportive treatment, a rechallenge with Kutaja was given, again with a dramatic drop in blood pressure (to 84/54 mmHg); treatment was then discontinued. Another patient developed a gradual decline of blood pressure till the 9th day of treatment after which it persisted at 100/60 mmHg (falling from 124/86 mmHg at the beginning of treatment). The authors state that after cessation of the use of Kutaja the blood pressure returned to normal levels (126/92 mmHg) within 2 days. Based upon a literature source the authors suggested that conessine, an alkaloid constituent of Kutaja, was the major cause of the subjective symptoms. It is known that this alkaloid is likely to produce such symptoms in doses of some 500 mg a day or more. It is also pointed out that some other Ayurvedic drugs such as Bhallataka (based on Semicarpus annacardium), Aconite (Aconitum ferox) and Sarpagandha (Rauwolfia serpentina) produce side effects; the latter are also of course known in the West.
Chapter50 A.G. Vulto and H. Buurma Priapism due to traditional remedies Several indigenous treatments such as cantharides and yohimbine are known to cause priapism, a persistent, painful erection of the penis usually unrelated to sexual stimulation or desire although the onset may be initiated b y sexual stimuli. Rathore (9) reported 4 cases of priapism, one of which was caused by ingestion of an indigenous medicine for its supposed action as an aphrodisiac. Most peculiar was the finding that this patient improved after treatment with other indigenous remedies. Unfortunately, the composition of the causative preparation was not mentioned.
Red Jewel Paste Appendectomy is, in most cases, the accepted treatment for appendicitis. However, in China a preparation called 'Red Jewel Paste', consisting of 23 traditional Chinese medicines, is used as a non-operative external therapy for appendicitis (10c). In a report on 500 cases the side effects were intestinal hyperperistalsis in most patients, mild diarrhea (ca. 11%), local dermatitis (ca. 4%), local itching sensations (ca. 11%) and urticaria (ca. 2%). The paste, whose composition is not revealed, is applied locally under occlusion on the patient's fight lower quadrant. In the case of severe abdominal pain, analgesics or sedatives are available for the patients. However, antimicrobial treatment other than the paste is not allowed. It is suggested that Red Jewel Paste is a strong inhibitor of some pathogenic bacteria (such as Staphylococcus aureus, Pneumococcus, /~-hemolytic streptococcus and enterococcus). It is mainly effective in soothing the pain and tenderness that accompanies appendicitis. In almost all the chronic cases, surgical treatment was necessary. About half of the acute cases had an appendectomy some time later. In less then 10% of the cases was there no relapse over a 10-year follow-up period.
ACUPUNCTURE (SED-I O, 898) It is beyond doubt that some forms of acupuncture, when properly employed in
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susceptible individuals, can diminish the experience of pain. However, the objective clinical value of acupuncture in the treatment of pain (the best-investigated reason for treatment with acupuncture) is still controversial (11, 12) and requires controlled studies for a better understanding (13). Even designing such studies seems however to be a problem which is difficult to overcome: the choice of control- or placebo treatment is not easy. A placebo treatment such as 'random needling' may have a response rate as high as 40% (13). Besides difficulties with the validation of this technique there is also the risk of side effects induced by acupuncture treatment (SED-10, 898). Kropp and H~'ssler reviewed the occurrence o f pneumothorax after acupuncture in the thoracic region (14c). They describe in some detail 2 cases in which more or less typical symptoms appeared within 10 minutes after insertion of the needles. The pneumothorax itself developed more slowly after an onset with chest pain, persistent coughing and heavy breathing. It may take some days before it is possible to establish a definite diagnosis. The major cause of this side effect is too deep an insertion of the needles. In lean adults, the surface of the lungs can be as little as 2 cm below the surface of the skin. These authors suggest that this side effect is highly underreported, possibly because the spontaneous resorption of small amounts of air or liquid from the pleural cavity limits the urge of the patient to consult a physician for this condition. They advise limiting the depth of needle injection in the thoracic region to 0 . 5 - 1 . 0 cm in order to avoid this possibly serious complication.
properties and its supposed bile-stimulating action. Both herbal preparations are highly toxic. The U.S. F o o d and Drug Administration has designated several herbs as unsafe for inclusion in food, beverages and drugs. These are hsted in Table 1. That the use of these herbs can result in serious side effects is illustrated by a recent case.report by Hogan III (16 C).
HERBAL REMEDIES (SED-I O, 890) Herbs unsafe to use in foods, beverages or drugs. It is possible to find poisonous herbs included in 'natural' medicines and dietary aids. An article in American Pharmacy (15 R) mentioned the introduction of a dietary aid containing mandrake (PodophyIlum peltatum) (see Ref. 5, p. 250) and pokeroot (Phytolacca americana) (SEDA-5, 433). Phytolacca has emetic, purgative and mildly narcotic properties and mandrake was probably included for its strong laxative
A 25-year-old woman consulted her gynecologist because of abnormal menstrual bleeding. On pelvic examination a small mass was palpated; subsequent laparoscopy revealed a small amount of endometriosis. The mass effect was thought to result from an unusually placed ovary. After discharge from hospital her complaints persisted. Three weeks later at a re-evaluation, she was found to have an elevated prothrombin time of 53.4 seconds and an activated partial thrombophstin time of 70 seconds (40 seconds is about the normal reading), indicating disturbed coagulation. A wide variety of physical and laboratory examinations was then undertaken. The physical examinations disclosed essentially no abnormalities (apart from erosive gastritis, which was thought to be secondary to aspirin ingestion). Because the patient strongly denied taking coumarin-type drugs, quantitative clotting factor levels were obtained. Factor VII was 8% of normal, Factor IX 3%, Factor X 6%, and Factor V 61%. She was given parenteral vitamin K 1 and her prothrombin time and activated partial thromboplastin time rapidly returned to normal. At this point in her evaluation, further important information was elicited.. She had been accustomed to eating only 'natural' foods and she had accumulated stocks of about 40 herbs for use in various tonics and remedies. She had been drinking large amounts of a 'seasonal tonic' herbal tea for approximately 2 months before seeking hematological consultation. The recipe for this tea is found in Table 2. The patient related that she had consumed the equivalent of 20 pots of this tea in a period of 2 weeks, while drinking somewhat lesser quantities before and after that period. Her problems probably only started later, because she had increased her intake of tea in an attempt to lose weight. In commenting on this case the author relates the 3 coumarin-containing herbs in this mixture to the patient's coagulation defect: tonka beans (contains 1-3% coumarins by weight) (see also Table 1), melitot and sweet woodruff. However, the concomitant use of dextropropoxyphene napsylate plus acetaminophen (paracetamol) and the intake of a fairly large dose of vitamin A and perhaps even the intake of bromelains (to mention just some of the 'supplements' she was taking) may have enhanced the effect caused by the herbal preparation. Bromelains is a proteolytic enzyme derived from pineapple
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Table I. Herbs that should not be used in foods, beverages or drugs* Botanical name of plant source: common names
Remarks
Botanical name of plant source: common names
Remarks
Arnica montana Arnica; Arnica flowers; wolf's bane; leopard's bane; mountain tobacco; Flores arnicae
Aqueous and alcoholic extracts of the plant contain choline, plus 2 unidentified substances that affect the heart and vascular systems; Arnica, an active irritant, can produce violent toxic gastroenteritis, nervous disturbances, change in pulse rate, intense muscular weakness, collapse, and death
Conium maeulatum Hemlock; Conium; poison hemlock; spotted hemlock; spotted parsley; St. Bennet's herb; spotted cowbane; fool's parsley
Contains the poisonous alkaloid coniine and 4 other closely related alkaloids; often confused with water hemlock (Cicuta maculata); not to be confused with hemlock, hemlock spruce etc. (Tsuga canaden sis)
Hyoscyamus niger Henbane; Hyoscyamus; black henbane; hog's bean; poison tobacco; devil's eye
Contains the alkaloids hyoscyamine, hyoscine (scopolamine) and atropine; a poisonous plant
Exagonium purga, Ipomoea jalapa and Ipomoea purga Jalap root; jalap; Ture jalap; jalapa; Vera Cruz jalap; High John root; (possible also known as High John the Conqueror, John Conqueror, St. John the Conqueror root, Hi John Conqueror)
A large twining vine of Mexico, this plant has undergone many name changes; the drug is a powerful drastic cathartic; purgative powers of jalap reside in its resin; in overdoses, jalap may produce dangerous hypercatharsis
Datura stramonium Jimson weed; Datura; Stramonium; apple of Peru; Jamestown weed; thornapple; tolguacha
Contains the alkaloids atropine, hyoscyamine and scopolamine; illegal drug for non-prescription use; a poisonous plant
Convallaria majalis Lily of the valley; Convallaria; May lily
Contains the toxic cardiac glycosides convallatoxin, convallarin and convallamarin; poisonous plant
Lobelia inflata Lobelia; Indian tobacco; wild tobacco; asthma weed; emetic weed
A poisonous plant that contains the alkaloid lobeline plus a number of other pyridine alkaloids; overdoses of the plant or extracts of the leaves or fruits produce vomiting, sweating, pain, paralysis, depressed temperatures, rapid but feeble pulse, collapse, coma and death
Atropa belladonna Belladonna; deadly nightshade
Poisonous plant that contains the toxic solanaceous alkaloids hyoscyamine, atropine and hyoscine
Solanum dulcamara Bittersweet twigs; dulcamara; bittersweet; woody nightshade; climbing nightshade
Poisonous; contains the toxic glycoalkaloid solanine, also solanidine and dulcamarin
Sanguinaris canadensis Bloodroot; Sanguinaria; red puccoon
Contains the poisonous alkaloid sanguinarine and other alkaloids
Cytisus scoparius Broom-tops; scoparius spartium; Scotch broom; Irish broom; broom
Contains toxic sparteine, isosparteine and other alkaloids, also hydroxytyramine
Aesculus hippoeasteranum Buckeyes; Aesculus; horse chestnut
Contains a toxic coumarin glycoside, aesculin (esculin); a poisonous plant
Acorus calamus Calamus; sweet flag; sweet root; sweet cane; sweet cinnamon
Oil of calamus, Jammu variety, is a carcinogen (causes cancer); FDA regulations prohibit marketing of calamus as a food or food additive
Hefiotropium europaeum Heliotrope
A poisonous plant; it contains alkaloids that produce liver damage; not to be confused with garden heliotrope (Faleriana officinalis)
* Adapted from the FDA Consumer, October, 1983, and reprinted by courtesy of the Editors of American Pharmacy ,(15 R).
Drugs used in non-orthodox medicine
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Table 1 (continued) Botanical nam e of plant source: common names
Remarks
Mandragora officinarum The plant is a poisonous narcotic similar in its Mandrake; Mandragora; European mandrake properties to belladonna; contains the alkaloids hyoscyamine, scopolamine and mandragorine
Podophyllum peltatum Mandrake; May apple; PodophyHum; American mandrake; devil's apple;
A poisonous plant, it contains podophyllotoxin, a complex polycyclic substance, and umbrella plant; vegetable other constituents calomel; wild lemon; vegetable mercury
Phoradendron flavescens and Viscum flavescens Mistletoe; Viscum; American mistletoe Phoradendron juniperinum Mistletoe; Viscum; Juniper mistletoe Viscum album Mistletoe; Viscum; European mistletoe
Poisonous; contains the toxic pressor amines #phenylethylamine and tyramine
Violent purgative
Diptezyx odorata, Coumarouna odorata,
Active constituent of seed is coumarin; dietary feeding of coumarin to rats and dogs causes extensive liver damage, growth retardation, and testicular atrophy; FDA regulations prohibit marketing of coumarin as food or food additive
Dipteryx oppositifolia, and Coumarouna
oppositifofia Tonka bean; tonco bean; tonquin bean
Euonymus atropurpureus The poisonous principle Wahoo bark; has not been comEuonymus; burning bush; pletely identified; laxawahoo tive
Poisonous; contains the toxic pressor amines •-phenylethylamine and tyramine
(also called snakeroot, richweed)
Vinea major and Vinea minor Periwinkle; Vinca;
Contains pharmacologically active, toxic alkaloids such as vinblastine and vincristine that have cytotoxic and neurological actions and can injure the liver and kidneys
Hypericum; klamath weed; goatweed
Euonymus europaeus Spindle-tree
Eupatorium rugosum, E. ogeratoides and E. urticaefolium White snakeroot
Contains a purgative resin. In addition, morning glory seeds contain amides of lysergic acid but with a potency much less than that of LSD
Hypericum perforatum St. Johnswort;
Remarks
May be poisonous; little is known about its properties
Ipomoea purpurea Morning glory
greater periwinkle; lesser periwinkle
Botanical name of plant source: common names
A primary photosensitizer for cattle, sheep, horses and goats; contains hypericin, a fluorescent pigment, as a photosensitizing substance
Artemisia absinthium Wormwood; Absinthium; absinth; absinthe; madderwort; wermuth; mugwort; mingwort; warmot; Magenkraut; Herba absinthii
Poisonous plant; contains a toxic, unsaturated alcohol called tremetol combined with a resin acid; causes 'trembles' in cattle and other livestock; milk sickness is produced in humans by ingestion of milk, butter and possibly meat from animals poisoned by this plant Contains a volatile oil (oil of wormwood) that is an active narcotic poison; oil of wormwood is used to flavor absinthe, an alcoholic liqueur illegal in U.S.A. because its use can damage the nervous system and cause dental deterioration
Corynanthe yohimbi and Contains the toxic Pausinystalia yohimbe alkaloid yohimbine Yohimbe; yohimbi (quebrachine) and other alkaloids
424 Table 2 Recipe for 'seasonal tonic' (makes 10 pots of tea) 89 lb tonka beans* (ground) in 10 oz of 151-proof rum 2 oz melltot* 3 oz woodruff* 2 oz black pekoe tea 89 oz grated lemon peel 1/2lb grated orange peel 1 oz powdered hawthorn berries 1 oz hawthorn flowers 1 oz lobelia 3 sticks cinnamon 1 whole ginger root, minced *contains natural coumarins. and it is one of the many drugs reported to potentiate the effects of anticoagulants. The patient had been told by a friend that this enzyme would . remove fatty deposits from her hips.
Psyllium seeds (Plantago ovata, Plantago afra and Plantago arenaria) PsyUium seeds, as a w h o l e (several sources), b u t m o r e o f t e n t h e d r y h y d r o p h i l i c outer layer (husk, only obtainable from Plantago ovata), are t h e m a j o r c o n s t i t u e n t s of several b u l k laxatives in c o m m o n use in the United States and Europe. Adverse r e a c t i o n s are few a n d are m a i n l y r e l a t e d t o i n h a l a t i o n o f P l a n t a g o dust d u r i n g t h e p r o d u c t i o n o f t h e husks. T h e m a i n adverse r e a c t i o n s in t h e s e cases are r e s p i r a t o r y s y m p t o m s s u c h as r h i n i t i s a n d b r o n c h o s p a s m . Preparations containing Plantago are generally available w i t h o u t p r e s c r i p t i o n . In 2 r e c e n t case-reports, p r o b a b l y rare b u t serious side effects were revealed.
Agha et al (17 C) report a case in which a 23year~ld woman was admitted to hospital with a 2-week history of increasing midabdominal pain accompanied by nausea and vomiting, which had begun 2 days before admission. In the last week she had only 2 brown, gum-like bowel movements on the day of admission. She had a 6-year history of constipation which she treated with laxatives and recently with unrefined Psyllium seed husks. An abdominal radiograph revealed a large collection of material with curvillnear lucencies and a somewhat 'whorled' appearance occupying the upper abdomen and extending to the right iliac fossa. A diagnosis of a gastric or duodenal bezoar was suggested. Upper gastrointestinal examination using 4 oz of Hypaque (sodium diatrizoate) re-
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A.G. Vulto and H. Buurma
vealed a distended stomach with complete gastric outlet obstruction secondary to extrinsic compression. Because of the marked tenderness and the gastric outlet obstruction, the patient was taken to the operating room where a right colonic bezoar was found to be displacing and compressing the gastric antrum. Since the bowel was viable, the bezoar was broken up by hand and milked into the left colon. Postoperative cleansing enemas eventually cleared the colon. After 6 months the patient had recovered and was no longer using laxative preparations. In the discussion, the authors classify this type of bezoar as a mixed medication-induced phytobezoar. Phytobezoars are composed of fibrous matter such as skin, seeds and fibers from vegetables and fruits. Medication-induced bezoars may occasionally obstruct the gastrointestinal tract by virtue of their physical properties and location in the body. Examples of the latter are hygroscopic b u r laxatives, cholestyramine (SED-10, 823), non-abscrbable antacids, and vitamin C tablets. Most bezoars are situated in the stomach, whereas a primary colonic bezoar is extremely rare. In this case chronic constipation, heavy vegetable pulp ingestion, and bulk hygroscopic laxatives contribnted to the development of the colonic bezoar. Suhonen et al (18 c) describe in a second casereport a 33-year-old nurse seeking aid at hospital because of a generalized urticarial rash after taking 10 ml of granulated Psyllium laxative (Aqiolax). In hospital the symptoms were aggravated during the subsequent hour after admission: at first there was slight dyspnea, profuse diarrhea, and a lowered blood pressure of 80/55 mmHg; thereafter loss of consciousness occurred with an unmeasurable blood pressure. Complete recovery was secured with intravenous corticosteroids and plasma expanders, followed by oral prednisone for 5 days. Two months later, hypersensitivity to Psyllium was demonstrated by skin tests (scratch chamber technique on the dorsal skin). The other 12 components of the Aqiolax product gave negative results. The whole laxative product gave a strong wealing reaction (25 mm diameter) and Plantago ovata powder a somewhat smaller weal (10 mm) in 20 minutes. The histamine reference gave a 6 mm weal. With radioallergosorbent tests (RAST) both the laxative product and Plantago ovata gave strongly (maximum) positive scores. The presence of specific serum IgE antibodies was established, explaining the immediate hypersensitivity reaction after intake of the preparation. The total serum IgE of the woman was 130 U/ml (reference range: 0 - 1 1 0 U/ml). In their discussion the authors mention 2 poss~le means of sensitization. Firstly, the nurse had on several occasions handled Psyllium laxatives while administering drugs to geriatric patients. Secondly, she had taken Aqiolax for constipation for several weeks. The sudden onset of symptoms followed ingestion of a dose after a l-week pause in treatment.
Drugs used in non-orthodox medicine Chapter50 The hypersensitivity seen in this patient is rare and unusually strong compared to the symptoms of rhinitis and asthma that have previously been reported in the literature. They suggest the need to include a warning for hypersensitivity in the package insert.
Serenoa repens (American dwarf palm) The hexane extract of the fruit of the American dwarf palm tree Serenoa repens B. has been shown to have antiandrogenic properties, partly through a direct action at the level of the androgen receptor and also by inhibiting the enzyme, testosterone5a-reductase. The extract is commercially available in France as Permixon. Benign prostatic hyperplasia - an enlargement of the prostate - is a result of accumulation of dihydrotestosterone in the prostate. To date, the use of androgen receptor antagonists in the treatment of this disorder has been complicated by the side effects of antiandrogens. Champault et al (19 c) carried out a placebo-controlled doubleblind study to investigate the efficacy of the hexane extract P A l 0 9 in prostatic hyperplasia in 110 outpatients. The active treatment group received 320 mg/d (divided over 2 doses) of the tiposterolic extract. Not only did these authors report a significant improvement in the treatment group over the placebo group, but they also stated that the number of side effects reported in the treatment group was half that of the placebo group. All side effects were minor (e.g. headache). In addition, standard blood chemistry measurements showed no alteration. The effect of the extract is in all probability dependent on the availability of fl-sitosterin-3-D-glycoside, a compound that has been shown to have estrogen-like activity in animal models. The glycoside has a higher bioavailability due to greater hydrophilicity than the free /3-sitosterin. This fl-sitosterin (which is also present in significant amounts in crude cottonseed oil) has been shown to have beneficial effects in prostate adenomas when taken in a dose of 50 mg/d for 38 weeks. If an estrogen is indeed responsible, reports of estrogen-type side effects may in due course be expected.
425
Licorice (SED-1 O, 895) Glycyrrhizinic acid, one of the constituents of licorice ( 9 - 1 2 % of dry weight), is a compound containing a steroidal structure (coupled with 2 molecules of glucuronic acid) and which has mineralocorticoid activity. It may, if taken in sufficient quantities, cause pseudo(hyper)aldosteronism with expansion of extracellular fluid volume, hypertension, hypokalemia and depression
of the renin-angiotensin-aldosterone system. Another effect can be amenorrhea and hyperprolactinemia due to competition with sex steroids for metabolizing liver enzymes. In the previous Annual (SEDA-8, 444), based on a letter to the Editor of The Lancet, we reported a case of pseudoaldosteronism due to the consumption of a non-alcoholic 'pastis' flavored with licorice. 'Pastis' is a French beverage based on aniseed oil. The case-report has been published in detail elsewhere (20 c). Corsi et al (21 c ) report the case of a 35year-old man who started eating licorice in quantities of 2 0 - 4 0 grams daily after having given up smoking. After 2 years, muscle weakness developed with accompanying hypertension and the clinical signs of an acute myopathy (albeit with some atypical features). Plasma aldosterone, renin and potassium levels were much lower than the normal range found in healthy individuals. After withdrawal of the licorice and the implementation of a high-potassium plus low-sodium diet, the patient recovered completely within 20 days. Based on an electron-microscopic study of the muscle tissue of this patient, the authors suggest that glycyrrhizinic acid may have a direct toxic effect on muscle fibers.
MISCELLANEOUS Gossypol (SED-1 O, 899) Gossypol is a yellowish phenohc compound occurring naturally in certain species of cotton plants of the Malvaciae family, mostly in the seeds and root bark. At one time, gossypol was considered to be only a toxic waste in the processing of cottonseed products. Before the discovery of the anti-
426 fertility action of gossypol, the compound was thought to be the active principle of cotton root bark, a Chinese folk medicine for the treatment of chronic bronchitis and cough. Based on this hypothesis, several clinical trials were carried out in bronchitic patients (22). Investigations of the mode of action and the toxicology of the c o m p o u n d are complicated by the fact that gossypol can exist in 3 tautomeric forms and that there are 2 optical isomers (23). Initially, gossypol was only isolated from the Gossypium species as a racemate, but the (+)-isomer has now been isolated from Thespesia populnea and also from the Gossypium species. However, it is the ( - ) - e n a n t i o m e r that possesses the antifertility action of this compound. It may well be that pure ( - ) - g o s s y p o l has a greater efficacy/toxicity ratio than the racemate that has been used in all studies published up to the present (24). It is claimed that in man at appropriate doses (20 mg daffy by m o u t h for 2 months and a maintenance dose of 50 rag/w) the drug has an antifertility efficacy of 9 5 99.07% (22 c , 25). Sperm motility is decreased as early as the second week of administration. Most of the reported side effects are reversible and generally mild, mainly including decrease or increase in appetite, fatigue, dryness o f the mouth, diarrhea, slight elevation o f SGPT and a tendency to sleepiness. Individual cases experienced depression of serum potassium levels, slight edema of the eyelid, and apparently decreased libido (and impotence). The drop in serum potassium levels is a major reason for concern, although it can be counteracted by supplementation of the diet with potassium. The overall occurrence of hypokalemic paralysis is about 1%, but it can increase to 5% depending on the average daffy intake of potassium. A second reason for concern is the inconsistent recovery o f fertility after cessation of gossypol treatment: about 10% of a group of volunteers remained azo-ospermic 6 months to 4.5 years post-regimen, indicating the possibility of irreversibility of fertility. A predisposing factor for this irreversibility was a treatment period of 2 years or more. This was confirmed in studies where the pattern of exfoliation of cells in human semen was investigated. The cell t y p e in semen that was most prominently exfoliated at the time of drug withdrawal appeared to be an indicator
Chapter50 A. G. Vulto and H. Buurma of the chance of recovery of fertility. Chances were lowest with the appearance of exfoliated spermatogonia (coinciding with an increased irreversible fertility after 2 or more years of treatment). There are pronounced differences among experimental species and strains in their sensitivity to both the anti-fertility and the toxicological action of gossypol. Hamsters appear to be the most sensitive species for the anti-fertility effect; rabbits and mice show toxic effects at dose levels that hardly affect fertility, Much more work will have to be performed on the toxicology of this compound before it can be accepted widely as a male contraceptive. The narrow gap between effective and toxic doses in animals with distinct species and strain differences will certainly complicate such studies, as will the complexity and reactivity of the molecule, resulting in photosensitivity and instability (23). Some of the reported effects of gossypol (22) found in animal studies both in vivo and in vitro are: a. lengthening of pentobarbital sleeping time and inhibition of gluthathione Stransferase activity, indicating a harmful influence on detoxification mechanisms (SEDA-6,423); b. degeneration o f skeletal muscle mitoehondria, depression of catechol-O-methyltransferase activity, blockade of neuromuscular transmission and lowering of cholinertie responses in vitro; c. decrease in calcium absorption and lowering of low-density lipoprotein level in blood; d. interferon induction, antitumor, antimicrobial and antiviral activities under experimental conditions. Apart from its direct toxicity and the problem of inconstant reversibility of fertility, there remains the question of longterm toxicity and possible genetic damage. Early Chinese reports indicated an absence of genetic damage (22, 26c), although this may need re-evaluation in the light of more recent findings (27c). Because the high proportion of artificial abortions of fetuses conceived after cessation of gossypol treatment, human data are unsatisfactory. In rats, the ratio of dead fetuses to the number of implantation sites was significantly higher in gossypol-treated animals (20 rag/ kg/d for 4 weeks, mating with females
Chapter 50
427
between 37 and 50 days post-treatment). Between 57 and 60 days post-treatment this difference no longer reached statistical significance. These results suggest that gossypol can directly damage the genetic material: once the sperm produced in the absence of gossypol is ejaculated, no abnormalities are any longer apparent. Regarding longterm effects, it is worrying that in testicular biopsy specimens from sterile men with a history of using crude cottonseed oil, Leydig cells were reduced in numbers and showed early signs of degeneration. Experiments in rats also showed changes in the morphology of Leydig ceils. Results from human studies are however inconsistent. It is becoming less and less likely that gossypol as it is now will ever be widely used as a male contraceptive all over the world. Elucidation of the mechanism of action and of the toxicological effects may provide the basis for the development of less toxic analogs (23) which could eventually lead to a male contraceptive pill. Another possible development is a more careful investigation of the dose-response relationships of the compound. Most studies have been aimed at producing azo-ospermia, but recent work shows that at far lower doses, with accordingly fewer side effects and possibly also fewer long-term problems, the fertilizing capacity of spermatozoa is sufficiently reduced to maintain a state of infertility.
knowledge of) azarcon and greta, a survey was started in Los Angeles County and in Colorado in 1982. In 1983 investigations in other states with migrant populations such as Arizona, New Mexico and Texas were started. In Los Angeles County, familiarity with the substances among the 545 households systematically selected was greatest amongst Mexican-Hispanics. Approximately onefourth of the Mexican-Hispanic families were familiar with one or both preparations and an estimated 7.2%-12.1% admitted prior use from 'years ago' to within the past month. Since investigators noticed a reluctance to admit the use of the remedies, the incidence of ingestion might have been greater than the results of the survey indicated. The Colorado survey among Texas farmworkers showed that 7 of 100 migrant children under 12 years of age had been treated with the compounds. Apparently, these remedies are most usually administered to infants and children for gastrointestinal illness. This age group is most susceptible in terms of clinical impact and the capacity to absorb lead (see also SEDA-6, 420 and SEDA-8, 445). The U.S. and Mexican health authorities have initiated recalls of the substances, which were until recently freely available at herb shops and 'health' (!) food stores and from folk healers on both sides of the Mexican-American border. Major media efforts publicizing the dangers of azarcon and greta have been directed at Hispanic communities in California. Another minority-group in the United States with significant exposure to and poisoning from lead are Hmong refugees from northern Laos (29). In the United States there is an estimated population of 50,000 and they live spread out over the country with concentrations in Fresno, Stockton, San Diego and St Paul. During a routine screening of children in 1983 by the St Paul, Minnesota, Division of Public Health, 35 children were found to have lead intoxication. Of these, 24 were Hmong children. One source of lead poisoning appeared to be a Hmong folk remedy used for treating infants and children with fever and rashes. In only 1 case, described by the authors, could a sample of the folk remedy be obtained. The remedy, generally referred to as pay-loo-ah, consists of red and orange powders, the composition and source of which vary and thus a more exact des-
Drugs used in non-orthodox medicine
Lead poisoning after ingestion of folk remedies In a case-report followed by an editorial note (28) the fairly widespread use in villages near the Mexican-American border of 2 folk remedies azarcon (lead tetroxide) and greta (lead oxide) is described and discussed. Greta and azarcon are fine powders with total lead content varying from 70% to more than 90%. According to the editorial note, the first cases of lead poisoning associated with the Mexican folk remedy azarcon were identified in Los Angeles and Colorado in the summer of 1981. Since that time, 9 additional confirmed cases associated with the ingestion of azarcon or the related remedy, greta, have been reported in California. Moreover, 5 cases have been reported from Michigan and Wisconsin. To investigate the exposure to (and the
428 cription of the material remains difficult. The one sample that was analyzed contained 8% lead. The U.S. Food and Drug Administration confirmed that 2 samples of other folk remedies obtained from this community contained lead (1% and 90%) while 3 contained arsenic (70-80%). The products investigated were in wide spread use and easily available through local Asian food stores or Hmong peddlers. Clearly, appropriate health education is necessary to avoid further occurrence of heavy metal poisoning among the Hmong community. Alcohol (SED-I O, 905) Ethanol and isopropanol are found as active ingredients in oral, parenteral and topical (including inhalational) prescription and non-prescription drug products. Although alcohol is primarily used for its solvent properties to help solubilize other drugs, it also possesses several concentrationdependent pharmacological actions, including sedative, carminative, cooling, antipyretic, rubefacient, cleansing and antiseptic properties. Concentrations of 40% or more may be found in some oral preparations, thus resulting in patients consuming as much as 30 ml of pure ethanol during the course of the day. A concise compilation of nearly 300 alcohol-containing prescription and non-prescription drugs in Canada is
Chapter50
A. G. Vulto and H. Buurma
presented by Parker and Baiilie (30). A similar list compiled for the Federal Republic of Germany contains almost 1500 preparations, including 50 parenteral drugs (31). Such lists should become available in every country in order to make it possible to counsel patients with alcohol problems, patients with liver disease, epileptic patients, patients with brain damage, children and pregnant women. Besides these risk-groups, patients taking all kinds of drugs may experience a change in drug effect due to u n k n o w n concomitant alcohol consumption. Alternatively, the use of certain antibiotics such as cefoperazon, cefoxitin and lamoxactam may trigger disulfiram-like reactions due to unexpected alcohol intake. A number of drugs are also known to potentiate the effects of alcohol on the central nervous system (varying from sulfonylurea drugs to drugs such as phentolamine and tolazoline) (30). Unfortunately, the presence of ethanol or the concentration is not always mentioned on the label.
ACKNOWLEDGMENTS We wish to thank Dr. Chris Fowler and Dr. Yie Shang-mian for their helpful and stimulating discussions during the preparation of the manuscript.
REFERENCES 1. Farnsworth NR (1984) The role of medicinal plants in drug development. In: KrogsgaardLarsen P e t al (Eds), Natural Products and Drug Development, p 17. Munksgaard, Copenhagen. 2. Burger A, Crabb~ P (1984) Screening programme of new compounds from developing countries. Trends PharmaeoL ScL, 11, 2. 3. Krogsgaard-Larsen P, B~gger Christensen S, Kofod H (Eds) (1984) Natural Products and Drug Development. Proceedings. Alfred Benzon Symposium 20, Copenhagen, August, 1983. Munksgaard, Copenhagen. 4. Lisowski F (1983) Herbal and unconventional remedies in the elderly. Can. Pharm. J., 116, 135. 5. H~nsel R, Haas H (1984) Therapie mit Phytopharmaka. Springer-Verlag,Berlin. 6. Varnam MA (1982) Respect for traditional medicine. Br. Med. J., 285, 1737. 7. N~.th Pal SM (1982) Drug and its action according to Ayurveda. Prog. Drug Res., 26, 55. 8. Chaturvedi GN, Singh KP (1983) Side effects
of a traditional indigenous drug - Kutaja (Holarrhena antidysenterica), lndian J. Physiol. Pharmacol., 255. 9. Rathore AH (1983) Priapism: a report of 4 cases. J. Pak. Med. Assoc., 33, 208. 10. Baoming Q (1983) A study on the mechanism and indications in treatment of acute appendicitis by Red Jewel Paste. J. Abdom. Surg., 25, 61. 11. Skrabanek P (1984) Acupuncture and the age of unreason. Lancet, 1, 1169. 12. Mendelson G, Robson J (1984) Br. Med. J., 288, 1999 (Correspondence). 13. Lewith GT (1984) Can we assess the effects of acupuncture? Br. Med. J., 288, 1475. 14. Kropp R, I-I~ssler R (1983) Akzidenteller Pneumothorax nach Injektionen und Akupunktur im Thoraxbereich. Med. Welt, 34, 1143. 15. Anonymous (1984) Herbs hazardous to your health. Am. Pharm., NS24, 120. 16. Hogan III RP (1983)Hemorrhagic diathesis caused by drinking an herbal tea. J. Am. Med.
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Assoc., 249, 2679. 17. Agha FP, Nostrant TT, Fiddian-Green RG (1984) ~3iant colonic bezoar': a medication bezoar due to Psyllium seed husks. Am. J. Gastroenterol., 79,319. 18. Suhonen R, Kantola I, Bj6rksten F (1983) Anaphylactic shock due to ingestion of Psyllium laxative. Allergy, 38, 363. 19. Champault G, Patel JC, Bonnard AM (1984) A double blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia, Br. J. Clin. Pharmacol., 18, 461. 20. Trono D, Cereda JM, Favre L (1983) Pseudosyndrome de Conn par intoxication au pastis sans alcool. Schweiz. Med. lr 113, 1092. 21. Corsi FM, Galgani S, Gasparini C et al (1983) Acute hypokalemic myopathy due to chronic licorice ingestion: report of a case. ltal. J. Neurol. ScL, 4, 493, 22. Qian S-Z, Wang Z-G (1984) Gossypol: apotential antifertility agent for males. Ann. Rev. Pharmacol. Toxicol., 24, 329. 23. Fong HHS (1984) Current status ofgo~ypol, zoapatanol and other plant-derived fertility regulating agents. In: Krogsgaard-Larsen P e t al (Eds), Natural Products and Drug Development, p 355. Munksgaard, Copenhagen. 24. Editorial (1984) Gossypol prospects. Lancet,
1, 1108. 25. Anonymous (1984)F.uture aspects of contraception. Lancet, 2, 703. 26. Tsui Y-C, Creasy MR, Hult~n MA (1983) The effect of the male contraceptive agent gossypol on hyman lymphocytes in vitro: traditional chromosome breakage, micronuclei, sister chromatid exchange, and cell kinetics. Z Med. Genet., 20, 81. 27. Nordenskj61d M, Lambert B (1984)Gossypol induces DNA strand breaks in human fibroblasts and sister chromatid exchanges in human lymphocytes in vitro. J. Med. Genet., 21, 129. 28. Sankury T et al (1983) Lead poisening from Mexican folk remedies - California. J. Am. Med. Assoc., 250, 3149. 29. Levitt C et al (1983) Folk remedy-associated lead poisoning in Hmong children. J. Am. Med. Assoc., 250, 3149. 30. Parker WA, Baillie GR (1983) Alcohol conraining pharmaceuticals. Can. Pharm. J., 116, 231. 31. Gr6bler A, Kotwas J (1983) Alkoholgehalt von Arzneimittein. In: Becker W, Moebius UM (Eds), Transparenztelegramm, p 48. A.T.I. Arzneimittelinformation Berlin GmbH. Berlin (West).