Drugs used in non-orthodox medicine

P.A.G.M. de Smet and A.G. Vulto

50

Drugs used in non-orthodox medicine

HERBAL REMEDIES (SED-IO, 890; SEDA-9, 421; SEDA-IO, 433; SEDA-11, 422) In the period covered by this Annual, numerous publications on phytotherapy have appeared. There were several papers on herbal medicine in general (1R-5 R) as well as various specific articles, e.g. on ginseng (6 R, 7R), comfrey (8 R) and garlic (9 R, 10R). A significant clinical report on the latter plant noted that a commercial dried garlic pill failed to show any beneficial effect on blood lipids, apolipoproteins, and blood coagulation parameters in patients with hyperlipoproteinemia (llC). There were also new textbooks, some of them limited to a certain geographical area, such as The People's Republic of China (12 R, 13R) and West Africa (14R), others providing a more general view (15 R, 16R). The Journal of Ethnopharmacology started to reproduce abstracts of ethnopharmacological papers on a regular basis (17r Perhaps even more relevant was an editorial in the same journal inviting scientists to respond if they were interested in the creation of an International Society for Ethnopharmacology (18c). New and revised handbooks on herbal toxicology have been published (19 R, 20 R, 21 r, 22 R) and the unwanted effects of plant-derived products have been reviewed in various journals (5 r, 23 r, 24r, 25R--28R). One of these papers challenged an otten-recited case of mistletoe being the suspected cause of hepatitis (SEDA-6,418): it seems that the product accused of causing this unwanted effect did not contain mistletoe, even though its label declared that it was present (5). One other article reported that West German doctors and pharmacists have established a 'Network of Mutual Information', which can be used to report suspected cases of herbal toxicity. It referred to various reported cases, viz. a fatal hypo-

Side Effectsof DrugsAnnual 12 M.N.G. Dukes and L. Beeley,editors 9 Elsevier SciencePublishers B.V., 1988

volemic shock with cardiac arrest following the use of sennosides and the development of perilous allergic reactions with laryngeal edema and dyspnea a few minutes after injecting a preparation from expressed Echinacea sap (28c). Unfortunately, the article provided insufficient details to assess the relevance of these reports. More specific papers dealt with the safety profiles of Sanguinaria (29 R) and linseed (30R), with allergic and respiratory reactions to psyllium (31R), with hyperthyroidism during use of sea kelp (32c), and also with cutaneous reactions to Arnica (33R), kava-kava (34c) and Dictamnus albus (35c), and to a product called 'Golden Health Blood Purifying Tablets' said to contain extracts of red clover, burdock, queen's delight, poke root, prickly ash, sassafras bark, and Passiflora (36c).

Post-Chernobyl contamination of herbal products In April, 1986, the nuclear reactor accident at Chernobyl shook the world. One of the direct consequences of this tragic disaster was concern about the fall-out exposure of agricultural products, Understandably, questions were also raised about the safety of medicinal herbs and their preparations, which prompted a unique series of Austrian and West German studies (37c-40c). These investigations have shown that the degree of radioactive contamination varied considerably with habitat, plant species, time of harvesting and extraction procedure. A study of medicinal plants cultivated in the Austrian Steiermark area showed the following variations in JJ4Cs and 137Cs levels (37c): a. Levels of Melissa leaf samples collected on May 10 in different places ranged from 744 to as high as 40,000 Bq/kg. b. Levels of a peppermint leaf sample and a Melissa leaf sample harvested in the same place on May 10 were 3145 Bq/kg and 16,687 Bq/kg, respectively. c. The sJ4Cs/ t3ZCs contamination of Viola tricolor samples gathered in one place declined from 22,896 Bq/kgfor the first crop (on May 15) to less

Drugs used in non-orthodox medicine Chapter 50 than 385 Bq/kg for the second crop (on June 25). d. An infusion and a tincture made from the same sample of Melissa leaves had retained only 23 % and 11%, respectively, of the 134Cs/~37Cs Radioactivity measured in the original crude material. A tincture from other Melissa leaves showed a recovery of 8 %, whereas less than 1% of original activity could be retrieved from essential oils that had been prepared from this second sample by distillation or by n-pentane extraction. The results also suggested that crude drugs consisting of leaves were more prone to contamination than those consisting of flowers, presumably because the flowers had not yet developedfully at the time of thefall-out (37r Large variations in the level and extractability of 134Cs/137Cs radioactivity were also observed in a German investigation of medicinal herbs collected in Bavaria (39c). Individual levels rangedfrom no contamination at all in a Salvia sample to 16,454 Bq]kg in a sample of lavender. The recovery of radioactivity from teas preparedfrom contaminated herbs varied from 6 % for Equisetum arvense to 100% in the case of Hypericum perforatum. To put the results of radioactivity determinations in perspective, a realistic upper limit was needed, beyond which the safety of a herb could no longer be guaranteed. The only official figures available were the maximum allowable ~~4Csff 37Cs concentrations of 370 Bq/kg for milk and 600 Bq/kg for other foodstuffs, as determined by the European Economic Community (EEC). A West German expert committee questioned whether it was appropriate to transfer such values for fresh foods without further ado to dried ingredients for medicinal teas, which were likely to be taken in smaller amounts and over a shorter period of time (41R). However, practicing pharmacists were right to point out that patients may use quite large quantities of medicinal teas (42c), and the committeefailed to come up with alternative threshold values (4IS). For want of something better and to prevent herbs that surpassed the legal limit for foodstuffs from being sold in pharmacies, the Central Laboratory of German Pharmacists decided to retain the EEC limit of 600 Bq/kg. It calculated that herbs satisfying this upper value were unlikely to represent a health risk: even if the crude drug were to contain 600 Bq/kg and all this radioactivity could be extracted, the contamination of one liter of tea preparedfrom 15 g would still be less than lO Bq/l, which is much lower than the upper limit of 370 Bq/l established for milk. The daily use of one liter of tea would then result in an exposure of about 6 mrem per year, whereas natural radiation already provides an annual dose of 200-500 mrem (40c). In the second half of 1986, the Central Labo-

403 ratory of German Pharmacists purchased samples of almost 50 different medicinal herbs on the West German market. None of these samples showed an activity of 600 Bq/kg or more. However, additional testing revealed values of up to 3100 Bq/kg in foreign samples, thus demonstrating the need for systematic quality control (40c). This need was also illustrated by the announcement of a West German firm that it was unable to supply certain herbs because they surpassed the EEC limit (43c), and it becomes even more compelling& evident when the extremefigures sometimes found in other studies are considered (see above).

Herbal remedies: sources of concern

As in Annual 11 (p. 424), we should like to illustrate some of the arguments underlying concern about the safety of herbal medicines with case reports and studies published in the review period. Improved quality control is still needed to prevent the use of inferior or adulterated herbal products West German pharmacists and their

Central Laboratory found evidence that some batches of frangula bark had an unacceptably high anthron content (44c). This is usually a sign of insufficient storage, since anthrone glycosides present in the fresh bark are known to be converted into anthraquinone derivatives during storage. As the fresh bark can produce nausea and vomiting, it should not be used until it has been stored for at least I year (44c, 45R). Also in West Germany, warnings against the adulteration of a Sri Lankan herbal drug with corticosteroids had to be renewed. It was found that this product, originally named 'Amborum special-F', was imported under a variety of other names (e.g., Formula Nr. 9, Hautwaschmittel Cureall-6, Kayankal forte, Asforte, Herbal Tea Syrup, Natural Herbs Tea Syrup) so as to delude the customs officers (46c). Adulteration of a diet pill with thyroid hormones, which resulted in several cases of thyrotoxicosis, has been reported from the United States (47c). Unreliable consumer information continues to be a substantial problem In an elegant paper on the United States situation, Tyler (3R) recalls

that most plant drugs sold in his country do not have any claim of efficacy on the label or package insert, because the Food and Drug Administration can confiscate the product if such a claim is not satisfactorily proven. To fill

404 the resulting information gap, health food stores provide a vast assortment of booklets and pamphlets on herbal medicines, most of which are written for one purpose only: the selling of products. Thus, these sources tend to advocate all the allegedly good features of herbs, even if that means the reiteration of uncritical or outdated information, while the potential dangers are minimized, purposely or out of ignorance. Tyler adds that people selling herbal preparations view his own book The Honest Herbal, which critically reviews herbs for lay readers, as being too conservative and that they refuse to handle it in their stores. Exuberant literature advocating the virtues of herbal medicines is also flourishing in Europe. Ranking high in raising unrealistic hopes was Health from the Pharmacy of God by Maria Treben, which sold over 600,000 copies in West Germany and Austria. It suggested inter alia that every internal or external malignant tumor can be selftreated with Equisetum. Corrigan (5) rightly classifies such information as nonsense. In a general discussion on the risks of alternative cancer treatments, Jungi (48 r) points out that besides the possibility of side effects due directly to the non-orthodox remedy, there are also indirect risks, such as depriving patients of potentially successful orthodox treatment and the provocation of guilt and anxiety. However, such scientific scepticism has not prevented a second book by Treben on the wondrous qualities of Medicinal Plants from the Garden of God from being recently published (49~ Unfortunately, it may be impossible to take any legal action against an unjustifiable promise of therapeutic potential, especially when it is cleverly hidden between the lines. Under the significant title 'Profiteers from Misery', a Dutch medical journal has warned against advertisements inviting AIDS patients to participate in a study on the efficacy of a herbal potion in their disease. The comment complained that legal action against such malpractice could only be undertaken after an offense had been committed (50c). There is still an alarming lack of scientific data about the possibility of drug interactions between herbal remedies and orthodox products An African research group has compared the disposition of oral antipyrine in 20 healthy volunteers with that in 12 patients who were chronically on herbs. Although we only have an abstract of this study (51r which leaves many questions unanswered, the results are too interesting to be disregarded: both groups had a

Chapter 50 P.A.G.M. de Smet and A.G. Vulto similar volume of distribution, but the total clearance was substantially higher in the group on herbs than in the control group: 92 + 10 versus 51 + 6.5 ml/min. Correspondingly, the half-life in the herb users was much shorter than that in the healthy subjects: 7.5 + 2.6 versus 12.3 + 1.5 hours. Orthodox practitioners have insufficient knowledge to be able to advise their patients about herbal medicine The knowledge of British general practitioners about various alternative forms of treatment was assessed in a questionnaire study. Out of 145 doctors, 38% had received some training in complementary medicine. Herbal medicine turned out to be the least understood: only 5% claimed more than a poor knowledge of this subject, compared with 21-23% for homeopathy, spiritual healing and acupuncture, 33~o for hypnosis, and 55% for spinal manipulation (52c). In an African interview study, about 90 % of 50 indigenous healers were aware that some of their herbal remedies were toxic. In contrast, only 5% of a group of health assistants replied that some traditional remedies had toxic effects (53c). While herbal healers and consumers may readily recognize gross symptoms of acute toxicity, they are likely to miss more subtle effects, such as mutagenic, carcinogenic and teratogenic activity This well-known concern again became topical following new reports on the mutagenic activity of herbal remedies and their constituents in the SalmoneUa/mammafian microsome assay (see Special Review below). Although the health authorities in some countries have prepared or have taken regulatory steps to improve control of the quality and product data of herbal remedies, other countries are lagging behind considerably in legislative action on plant medicines As phytotherapeutic preparations continue to proliferate as natural alternatives to synthetic drugs, governmental agencies are becoming increasingly forced to consider whether they should establish legislative guidelines for the marketing of herbal products. The Canadian authorities accepted this challenge by asking an expert committee for advice on these matters. The committee produced a bulky report (54x), in which it presented various general recommendations, such as the development of a Canadian reference source along the lines of the British Herbal Pharmacopoeia. The committee distinguished 4 different categories of herbs and botanical preparations: (I) un-

Drugs used in non-orthodox medicine Chapter 50 acceptable for use in or as foods; (II) generally acceptable as foods; (III) acceptable as foods under specified conditions; and (IV) generally used for medicinal purposes. The committee Table 1. Herbs and botanical preparations recommended for addition to the section of Canadian Food and Drug Regulations. which covers forbidden food adulterants (54R) American false pennyroyal oil (Hedeoma pulegioides) American mandrake (Podophyllum peltatum) American mistletoe (Phoradendron peltatum ameri-

calla) Autumn crocus/meadow saffron (Colchicum autumnale) Berries (Bryonia alba, B. dioica) Betel nuts (Areca catechu) Calamus (Acorus calamus) Some studies suggestthat the constituent ~-asarone may be carcinogenic (56); further investigation suggested on current inclusion in the section covering food adulterants (54) Canadian hemp (Apocynum cannabinum) Castor beans (Ricinus communis) Climbing nightshade ( Solanum dulcamara) Croton (Croton tiglium) Daphne/mezereum (Daphne species) Devil pepper (Rauwolfia species) Contains reserpine, and in excess can cause hypotension (56) Dog's bane (Apocynum androsaemifolium) European mandrake (Mandragora offlcinarum) European mistletoe berries (Viscum album) European pennyroyal oil (Mentha pulegium) Florida arrowroot seeds (Zamia integrifolia) Foxglove (Digitalis purpurea) Protracted use can adversely affect the liver (56) Henbane (Hyoscyamus niger) Horsechestnut (Aesculus hippocastanum) Ignatius beans Jimsonweed (Datura stramonium) High atropine content makes it potentially dangerous (56) Lantana (Lantana camara) Levant cotton (Gossypiumherbaceum) Contains the male contraceptive gossypol; possibility of permanent sterility, and cases of inflammation of the vas deferens (56) Mushroom (Amanita species) Narcissus (Narcissus pseudonarcissus) Red pokeweed (Phytolacca americana) Spanish arrowroot (Maranta malaccensis) Strophanthus kombe Tansy oil (Tanacetum vulgare) Thuja ( Thuja occidentalis) White cohosh or baneberry (Actea species) White poppy seeds (Papaver somniferum, 1". dubium, P. hybridus, P. argemone) Yellowjessamine (Gelsemium sempervirens and other species) Yohimbe ( Corynanthe yohimbe)

405 identified 37 herbs and botanical preparations as Category I agents and recommended their addition to the section of the Canadian Food and Drug Regulations, which covers forbidden food adulterants (Table 1). It also provided a list of another 11 plants requiring further review with regard to their acceptability as foodstuffs (Table2). For Category III, the committee recommended the development of cautionary labdling statements (in particular with reference to avoidance during pregnancy) to specify the conditions under which it would he acceptable to market the herbs and botanical preparations in this category as foods. This general recommendation was accompanied by a short list of 11 potential candidates for cautionary labelling (Table 3). Surprisingly, neither the Table 2. Plants requMng further review with respect to their acceptability as foodstuffs in Canada (54R) Bloodroot Calabar beans Celandine Coltsfoot Contains small amounts of hepatotoxie alkaloids (56) Comfrey Contains bepatotoxic alkaloids (56) Euphorbia Heliotrope Liferoot Contains a toxic alkaloid (56) Levant wormwood Ragwort Sassafras Contains safrole, a suspected carcinogen (56)

Table 3. Potential candidates for cautionary labelling in Canada, with particular reference to avoidance during pregnancy (54a) Barberry Contains potentially hypotensive alkaloids (56) Dong quai Contains coumarin derivatives (56) Goldenseal Lily-of-the-valley Lobdia Oregano No problems if used normally in cooking, but a concentrated dose of oregano oil a c t s a s a gastrointestinal irritant, causing contractions which may stimulate uterine contractions (56) Parsley oil Pigweed oil Savin oil Uva ursi Yarrow

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Chapter 50 P.A.G.M. de Smet and A.G. Vulto

original report nor a condensed version in the quality of their products and that the operative Canadian PharmaceuacalJoarnal (55 r ) provided Dutch Food Act already offered legal possidetails on the scientific basis of the committee's bilities to counteract the marketing of very classifications. In contrast, a comment in the noxious herbs (63c). A logical consequence of a Canadian medical press (56 R) unveiled some of reluctant attitude on the part of governmental the committee's arguments, which are repro- health officers is the dra~ing of non-official regulations by private organizations. For induced here in Tables 1-3. The Canadian initiative gives us the op- stance, the Royal Dutch Association for the portunity to outline an earlier, but equally inter- Advancement of Pharmacy has estabfished a esting, development in the Federal Republic of working group for the preparation of a forGermany, which has not yet been discussed in mulary ofphytotherapeutics (64c). The Pharmathese volumes (57-59). Under the Second ceutical Society of Ireland and the Irish PharFederal Drug Act in that country, all herbal maceutical Union are setting up a joint working drugs have to be submitted to a benefit/risk party to consider the area of herbal medicines evaluation. To perform this tremendous task, and the role of the pharmacist (65). Likewise, the Federal Health Office set up a special com- the Association of Danish Proprietor Pharmamittee of experts who are rightly attempting to cists has made an agreement with the Danish canalize rather than dam up the green wave Health Product Association to evaluate the sweeping over their country. The results have quality of herbal products offered to consumers been set down in monographs, which serve as a by pharmacies (66c). The results of this process scientific touchstone when a marketing licenee can be found in a loose-leaf 'Naturmedicinis applied for a new botanical medicine and katalog' of evaluated product monographs when the licences of already-existing products (67r). To those primarily interested in the unhave to be renewed. When the committee wanted effects of herbal drugs, this catalog does started, it first tackled the most familiar reme- not contain much useful information. dies with mild pharmacological activity, for Although such initiatives on the part of which admission criteria could be established pharmaceutical organizations are commendawithout much difficulty. How that the review ble, we seriously doubt whether their impact process is being expanded to include other will be so great that they can abolish the need herbs, however, it is becoming increasingly dif- for legal regulations, since most herbal remedies ficult to pronounce a verdict of admissibility in are nowadays sold outside pharmacies. all cases. For instance, the committee recently proposed banning Vinca minor (the perennial periwinkle) and its preparations from the West Mutagenicity of herbal remedies German market (60~) since there is no adequate proof of therapeutic usefulness, while there is G~ggelmann and Schimmer (68r have assessed evidence from an animal study to suggest that the mutagenic potential of commercial plant exthe periwinkle may induce transient hemato- tracts and tincturespurchased from a West German logical changes such as leukocytopenia and firm for Salmonella strains TA 98 and TA 100 with lymphocytopenia (61c). It should be noted that and without the addition of a metabolizing S9-fracthe monographs of the committee deal only with tion. Out of 46 samples prepared from 23 different efficacy and potential harmfulness and do not medicinal plants, 15 samples showed a positive provide criteria for quality control. The latter response. A small increase of 2--4 times the number can be found in so-called 'Standardzulassangen' of spontaneous revertants was observedfor extracts (62R), for which another committee of the of Angelica, Arnica, Betula, Centaurium and Federal Health Office is responsible. Humulus lupulus and for tincture of Gentiana. Many other countries lag behind in establish- Tinctures of Crataegus and Hypericum produced a ing a strict governmental policy on the safety larger increase of more than 10 times the control and quality control of herbal medicines. The value. Additional testing of commercial combinaDutch Secretary of State for Welfare, Public tion products containing Crataegus or Hypericum Health and Culture declared early in 1987 that revealed that the presence of other plants markedly he had no intention of proposing a law on influenced the mutagenic response. A preparation medicinal herbs, since he considered it of Hypericum and 5 other plants produced haO'the extremely difficult to submit the production and response seen with 10mg Hypericum per plate composition of such herbs to legislative rules. without $9 mix, even though it provided 30 mg He felt that the producers of botanical medi- Hypericum per plate. However, another Hypericum cines should guarantee of their own accord the preparation with 11 additional plants produced

Drugs used in non-orthodox medicine Chapter 50

407

almost twice the response of 10 mg Hypericum, that it is: a convenient short-term screening method, although only 5 mg per plate was present. The which can be used to corroborate the results of cause of these discrepancies remains to be estabcarcinogeniciry studies and to show the most lished. promising subjects offuture research. Care should On the one hand, such data should not be used be taken, however, to avoid false-negative results to cry 'wolf with regard to phytotherapeutic drugs. because of insufficient solubiliO, or bactericidal Positive mutagenicity results in bacteria are not to effects or because transformation processes in vivo be taken as proof of carcinogenic rislcs in man, us (such as hydrolysis) are not adequately reproduced (74R, 75R, 82R-84"~). there are obvious differences in final outcome, organism, type of exposure, pharmacokinetic handA princ~val issue is, of course, how the carcinoling, etc. Added to these universal arguments are genic potential of a crude drug should be evaluated specific pharmacognostic points. First, it may be in terms of public health, after it has reacted posithat a report on the mutagenicity of medicinal plant tively in initial bacterial mutagenicity screening. parts merely states that the tested materials were Obviously, it would be uneconomical to demand purchased through commercial channels. When that any herbal remedy should be submitted to there is not even a hint about the verification of the chronic mammalian carcinogenicity testing as soon botanical origin or about the phytochemical and as mutagenic properties have been demonstrated. microbiological quality of the samples, it seems Instead, a more realistic approach to risk assessdifficult to exclude the possibility of falsification or ment is to establish whether a herbal product is also the presence of contaminants, such as aflatoxins positive in other simple genotoxicity assays. An (69 c) or pesticides. Second, extrapolation of data essential pharmacognostic step will be to identify on an isolated constituent or plant extract to all the constituents responsible for the mutagenic preparations from that plant is hazardous. For response. An elegant isolation procedure is fracinstance, Morimoto et ai (70oR)found substantial tionated extraction on guidance of the same bacdifferences in mutagenic activity when testing terial assay as that in which the crude drug gave a aqueous and methanolic extracts of the same positive reaction (85 r162 Once the responsible Japanese crude drugs. Also, Andersen and Jensen agents have been isolated and identified, it becomes (71 r showed a mutagenic effect of pure menthone possible to characterize their intrinsic mutagenic in some Salmonella strains, whereas peppermint activity and to explain the effects of modifying oil, containing so much menthone that it was parameters such as other constituents, extraction expected to have mutagenic properties, failed to processes and storage conditions. Chemical identifiproduce a positive response in their study. An even cation will also permit a literature search for phytomore compelling example is that the Oriental drug chemical, therapeutic and toxicological information Bupleuri radix was not only reported as mutagenic on the constituents and their closely related deriva(70r and non-mutagenic (72c) in Salmonella/ tives. mammalian microsome testing, but also as having Apart from the usual principles that can be antimutagenic activity in this assay (73r Thus, applied to assess the risk of mutagenic chemicals, there are both general and specific reasons for the following pragmatic question may be he~vful in avoiding any unnecessary alarm. the case of mutagenic herbal remedies: To what On the other hand, however, mutagenicity data extent do herbal mutagens occur in the human diet ? on herbal extracts and naturally occurring Among the most common phenolic compounds in compounds cannot be dismissed lightheartedly on vascular plants are the flavonoids, quercetin and the basis of their subclinical nature. A fair majority kaempferol. These natural agents have been repeatof the substances and products which have been edly demonstrated to have substantial mutagenic identified so far as animal or human carcinogens activity and show little difference in potency. Their show positive responses in bacterial mutagenicity glycosides are present in various everyday assays (74R, 75R). Herbal remedies and their con- foodstuffs and beverages, such as fruit jams, coffee stituents do not collectively escape this general and tea. Although inactive, these glycosides may trend. On the contrary, several medicinal plants become mutagenic upon acid, enzymatic or bacand plant constituents with suspected or proven terial hydrolysis (83R. 88 c, 89r For instance, carcinogenic properties, such as black pepper (76r quercetin, kaempferol and the more weakly muta]3-asarone (77c), pyrrolizidine alkaloids (78c), genic flavonoid myricetin were found to be the safrol (79c), allyl isothiocyanate (80c), and major determinants of the mutagenic effect of comaristolochic acids (81 c) are all mutagenic in bac- mon Japanese tea infusions which had been pretreated with human intestinal bacteria (89c). One teria. Hence, bacterial mutagenicity testing of crude of these infusions yielded a total amount of approxidrugs should be taken precisely for the scientific tool mately 10-15 t~g/ml of quercetin and kaempferol

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Chapter 50 P.A.G.M. de Srnet and A.G. Vulto

following bacterial hydrolysis, so each cup of 200 ml (77cj. It is well-established, however, that the might contain up to 0.2-0.3 mg of these mutagenic fl-asarone content of the rhizome and of calamus oil flavonoids. Any risk assessment of a mutagenic varies considerably according to the origin o f the herbal remedy should therefore take into account sample: in contrast to the triploid and tetraploid the fact that the observed mutagenicity may be due plants from the Old World, the diploid North to constituents also found in the normal diet. To American variety is devoid of fl-asarone (93R). This show the importance of this principle, we will apply phytochemical difference becomes appealing it to the results of Gi~ggelmann and Schimmer (see because of a recent report stating that the spasmolyabove}. These investigators suggested that the muta- tic activity of fl-asarone-free calamus oil, as genic effects of Hypericum perforatum and some of measured in the isolated guinea-pig ileum, is the other plants they tested could be due to the superior to that of calamus oil with a low content of presence of flavonoids (68cR}. Let us suppose that fl-asarone, while fl-asarone;rich oil does not show this suspicion will be experimentally confirmed. The any spasmolytic activity at all (94c). Since calamus flavonoid content of Hypericum perforatum has is used primarily as a stomachicum and carminabeen estimated at 28 mg/g of quercetin glycosides tive, products with negligible amounts o f fl-asarone (90c}, corresponding with 16 mg/g of quercetin, so should thus be preferred to products with a subthat the usual dose of 2 g for one cup of herbal tea stantial fl-asarone content. (45 R) could result maximally in an exposure to Unfortunately, it is not always possible to come 32 mg of quercetin. This figure differs by only one up with a simple phytochemical guideline. Let us order of magnitude from the figure calculated for consider the recent finding that the valepotriates in the Japanese tea infusion. In other words, it would valerian exhibit mutagenic activity for Salmonella be rather ambivalent to worry about the mutagenic strain TAIO0 and for two Escherichia coli strains dangers of Hypericum perforatum flavonoids while in the presence of a metabolic activation system drinking a cup of ordinary tea. Instead, the present (95c). As has already been mentioned previously toxicological and regulatory status of food flavo- (SEDA-11,424), evidence is accumulating that holds should be judiciously applied to flavonoid- any sedative activity which valerian may possess containing medicinal plants. Mammalian studies does not lie in its valepotriates (96c}. In other performed so far to detect carcinogenic activity of words, it would be prudent to prefer valerian prepaquercetin have produced equivocal results. Accord- rations without valepotriates to commercial proingly, legislative measures have not as yet been ducts which are guaranteed to contain a fixed taken against the food flavonoids (91R}. As long as amount of these constituents. At first sight, tradithis situation remains unchanged, it would be over- tional aqueous and ethanolic extracts would seem reactive to issue strong warnings against the use of to be safer, since valepotriates are labile substances those herbal remedies which owe their mutagenicity which are largely destroyed during the usual extracto quercetin and/or related compounds. tion procedures (97c}. However, additional investiWhile flavonoid activity seems a likely cause for gations on the mutagenicity of valepotriates have some of the mutagenic effects observed by shown that their decomposition products, baldrinal G6ggelmann and Schimmer, not all of their results and homobaldrinal, are already mutagenic without should be explained in this way. In the case of metabolic activation (98c}. Since these degradation Gentiana, for instance, the responsible agents products are said to be present in traditional appear to be the trace constituents, gentisin and extracts (45 R}, such preparations may not represent isogentisin (85c). These yellow pigments belong to a viable alternative to the commercial drugs with a the chemical class of xanthone derivatives. Interest- standardized valepotriate content. ingly, a recent series of Japanese studies has shown For the majority of herbal remedies, scientific that the mutagenic capacity of the Oriental folk evaluation of genotoxicity and carcinogenicity still medicine Swertia japonica is also attributable to has a long way to go before a realistic risk assessmembers of this class (86 c, 92c). Such data ment can be made. In view of the enormous upsurge emphasize that each medicinal plant with muta- of phytotherapeutic healing in the western world genic effects should be properly evaluated instead of and the significant role that medicinal plants will assuming that its mutagenicity will be due to con- continue to play in developing countries, research in stituents also occurring in common foodstuffs. this area should undoubtedly be intensified. Another pragmatic question to be asked in the A good example is the mutagenicity of the natural risk assessment of mutagenic herbal remedies is anthranoid derivatives, which has attracted conwhether the therapeutic potential and the mutagenic siderable attention in recent years. Compared to activity reside in the same constituents. The muta- the flavonoids, these compounds are much less genicity and carcinogenicity o f calamus prepara- ubiquitous in the human diet, so a mutagenic effect tions are both attn'buted to the constituent fl-asarone cannot be so readily submerged in the background

Drugs used in non-orthodox medicine Chapter 50 activity offoods and beverages. They occur primarily in laxative plants such as aloe, cascara sagrada, medicinal rhubarb and senna in the form of free anthraquinones, anthrones, dianthrones and/or O- and C-glycosides derived from these substances (83R). Mutagenicity data on these naturally occurring laxatives are summarized in Table 4. Although metabolic activation may be required, all tested monomeric aglycones exhibit mutagenicity for Salmonella strains TA 1537 and TA 2637. As is also the case with flavonoid glycosides, the O-glycosides can become mutagenic as well after pretreatment with enzymes. In contrast, the dimeric O-glycoside sennoside A was not found to be mutagenic in vitro, but this negative finding does not necessarily exclude the possibility of in-vivo transformation into mutagenic metabolites (I 05 R). At present, little would seem to be known about the carcinogenicity of the herbal anthranoid laxatives with mutagenic and promutagenic potentiaL It would be sensible, however, to evaluate their genotoxic and carcinogenic properties, since the closely related synthetic agent dantron ( = 1,8-dihydroxyanthraquinone) shows a similar Salmonella mutagenicity profile (83 R, 99 c, 101 c, 102 c) and has just been reported to induce tumors in rodents at a dietary exposure level of 0 . 2 - 1 % per day (106 c, 107c). Although a 'no effect'dose was not estimated so that the actual risk of dantron remained quite obscure, the findings were taken as a reason for urging the British supplier to restrict its use (t08c), and dantron products were withdrawn from the West German market (109~). Such measures might easily lead to the replacement of dantron by a

409 herbal anthranoid product. However, if one suspects that a health hazard of dantron cannot be excluded, one needs to know to what extent such a switch might lead from the frying-pan into the fire. So long as the actual risk of a mutagenic remedy still awaits experimental evaluation, one's attitude will inevitably continue to depend on non-experimental and therefore refutable grounds. A crucial point wouM seem to be to what extent one is prepared to give such medicines the benefit of the doubt. Some will believe in the innocence of natural medicines, so long as their guilt has not been definitely proven, while others may feel that it is always better to avoid products of unproven safety, even if this implies being overcautious. I f one is inclined to choose the former, common sense dictates that one should weigh all the data on a herbal drug on the same pair of scales: when there are only in-vitro data on the therapeutic potential and mutagenicity of a herbal medicine, it would be short-sighted to accept theformer without hesitation as evidence of clinical usefulness and to dismiss the latter at the same time as being clinically irrelevant. We ourselves believe that information about mutagenicity, even when the actual risk is still unclear, should become an integral part of teaching patients that natural products are not benign by definition (110", 111R). A major reason why many people prefer drugs of natural origin to synthetic chemicals is the widespread notion that the latter category will inflict serious adverse reactions, including carcinogenic effects. It would be quite ironical then, if someone with a general fear of the carcinogenicity of synthetic drugs were unknowingly

Table 4. Mutagenicity of some naturally occurring laxatives in the Salmonella/mammalian microsome assay Salmonella tester strains*

Ref no.

TA 98 TA 100

TA 1535 TA 1538

TA 1537

TA 2637

Monomeric aglycones Aloe-emodin Chrysophanol Emodin Physcion Rhein

0 0 0 0 0

0 0 0 0 0

+ + (**) +/+(**) + / + (**) +

nt +( * * ) +(**) nt nt

83,99,100 83,99,101 99,101,102,103 83,100 83

Monomeric O-glycosides Emodin- 1-monoglycoside Franguloside

0 0

0 0

+ (***) + (**)/+ (***)

nt nt

83,1 O0 83,100,104

Monomeric C-glycosides Aloin

0

0

0

nt

83,99,100

Dimeric O-glycosides Sennoside A

0

nt

nt

0

101

* 0 = no or questionablemutagenic activity; + = significantmutagenic activity;** mammalian microsomal activation requiredfor mutagenicity: *** pretreatment with glycosidases requiredfor mutagenici~ ; nt = not tested.

410

Chapter 50 P.A.G.M. de Smet and A.G. Vulto

to substitute a safe orthodox agent for a herbal product which might have carcinogenic properties. I f consumers are to be informed about the mutagenic potential of certain herbal remedies, the principal question is, of course, which practical advice should be offered to them, so long as the carcinogenic risk still has to be assessed. Here we endorse the view of H~nsel (112 R) that medicinal teas should be used onlyfor a limited period so long as data on their long-term toxicity are virtually lacking. Especially when a herbal remedy shows mutagenicity not attributable to common dietary constituents and when its therapeutic benefit remains to be proven, use in excessive quantities or for prolonged periods should be actively discouraged.

Propolis allergy (I13r

cR, 116")

Propolis (bee glue) is a resinous compound produced by bees from substances forming the protective cover of plants. These compounds can have antibacterial, antimycotic, waterrepellant and insulating properties. Bees collect these protective substances and mix them with wax for use as a kind of cement for sealing up crevices in their hives. Bees show some preference for propolis of the poplar tree which is known to be a potent hypersensitivity inducer. Hypersensitivity reactions among beekeepers and forestry workers are not uncommon. It has been suggested that hypersensitivityto beeswax is due to traces of propolis found in the wax (113c). Like many products of natural origin, propolis is advocated for treatment of skin diseases and as a cosmetic. It is used both locally and orally. Due to increased use, many reports have appeared in the specialized literature (Contact Dermatitis) in recent years on the allergic reactions caused by propolis. The composition of propolis varies, depending on its geographic origin, and comprises resins and balms (50 %), waxes (30 %), aromatic oils (10%), pollen (5%) and minerals, cinnamon-like compounds, coumarins, terpenoids, glycosides, colorants and flavonoids. About 5070 of patients who are allergic to propolis are also allergic to balsam of Peru, a potent sensitizer (SED-10, 258). Propolis is available under different trade names (e.g. Api Kompleks) and also as a generic product (I 0 70 in petrolatum or lanolin). Due to its potent sensitizing properties, use ofpropolis should be discouraged, especially since it appears to have no obvious therapeutic advantages.

ACUPUNCTURE (SED-IO, 898; SEDA-9. 420) Brattberg (117 c) has investigated in more detail one of the potential adverse effects of acupuncture: drowsiness. She wondered, in particular, if patients might become a traffic hazard when driving home after acupuncture treatment. The study group consisted of 122 patients (48 men and 74 women; average age 51 years, range 15-76 years), who were all treated for some kind of pain (migraine, tension headache, pain localized in the extremities, etc.). On average, 8 treatments were given per patient at weekly intervals. The degree of drowsiness was registered immediately following acupuncture treatment, on arriving home, the same evening, and the day after. At the followingvisit the nurse or doctor completed the questionnaire. Sixtyeight patients (567o)were moderately drowsyimmediately following the treatment and/or upon arrival home, and 35 patients (2970) were even excessively drowsy shortly after acupuncture. The general impression was that patients react most strongly after the first or second acupuncture treatment, but there were also patients who were unaffected at first but who became drowsy later in the course of treatment. No relation was found between the result of treatment and the degree of drowsiness. It does not therefore seem possible to predict with any certainty which patients willbecome drowsy followingacupuncture or when in the course of treatment such an effect might appear. The author discusses 3 potential mechanisms to explain the drowsiness: a fall in blood pressure, a fall in blood sugar, and the release of 'endogenous opiates'. Although a fall in blood pressure or blood sugar level could not be excluded for all patients, it was not observed in the patients who were controlled for these factors. She therefore suggests that the drowsiness might be due to the release of endorphins in the majority of cases. It should be realized that Brattberg has merely performed an uncontrolled study of subjective patient experiences which still requires confirmation by properly controlled research on the influence of acupuncture on objectively measurable parameters. It would be unwise from the viewpoint of traffic safety, however, to ignore her results because of their inconclusive nature. As long as reliable evidence to the contrary is lacking, it would be prudent to take into account the possibility that acupuncture may represent a tral~c hazard by pointing out to patients that their driving ability might be adversely affected shortly after a session of acupuncture treatment. Dundee et al (118 c) carried out a study to investigate the potential usefulness of acupunc-

Drugs used in non-orthodox medicine

Chapter 50

ture as an antiemetic for perioperative vomiting. Interestingly, such vomiting is often due to the use ofopioids before or during anesthesia, while the effects of acupuncture are usually attributed to the endogenous release of opioid peptides. The acupuncture procedure was used in addition to opioid premedication in fit women (aged 16-60 years) who were to undergo minor gynecological operations. The opioids used were either the partial antagonist meptazinol (100 nag i.m., 50 patients) or nalbuphine (10rag, 75patients), a kappa-agonist and partial g-type receptor antagonist. For each treatment there was a control group of patients who did not receive the acupuncture treatment or who received 'dummy' acupuncture. The authors report less vomiting in the groups who received 'active' acupuncture treatment. According to the authors, there were no side effects attributable to acupuncture, although the occurrence of a non-anatomically distributed feeling of heaviness, numbness or tightness (chi) was interpreted as a correct positioning of the acupuncture needle. In The Lancet two controlled studies on the efficacy of acupuncture for exercise-induced asthma (119 r ) and disabling breathlessness (120 r ) were published, together with an editorial (121r). Under the strictly controlled conditions of these trials no side effects were observed among 12 adults and 19 children. One child suffered from transient nausea in relation to acupuncture. Nevertheless it is stated in the editorial that acupuncture is not entirely innocuous.

SOLVENT S N I F F I N G Previously, we discussed the use of volatile inhalants as a sexual or motor stimulant (SED-10,903) (a topic which has also been touched on in the section of these volumes dealing with social drugs and drugs of addiction). Related to this is the inhalation of solvents to induce mental stimulation or euphoria ('glue sniffing'). The deliberate inhalation of volatile substances, usually halogenated or unsubstituted hydrocarbons, to obtain a 'high' is becoming increasingly fashionable among teenage boys. This is not only shown by the number of papers devoted to this subject, but also by the number of cases which have been systematically collected by Anderson e t a l (122c). These authors report on 282 deaths from solvent abuse during 1971-1983 in the United Kingdom, 80 of which occurred in 1983. Solvents in glues (mostly toluene) were associated

411

with just over a quarter of deaths. Toxicological analysis of intoxications with volatile substances other than glue solvents yielded most frequently 1,1,l-trichloroethane, followed by trichloroethylene, chloroform, carbon tetrachloride and toluene. Propellants and solvents in aerosols were also implicated. As mechanisms or causes of death, trauma accounted for 11 ~o of deaths. Twenty-one percent of the subjects were found with a plastic bag over the head and in 18% there was evidence of inhaled stomach contents. In these cases it was not certain whether death occurred from asphyxia or was caused primarily by direct toxic effects of the substance itself, as was assumed for the remaining 5 1 ~ . Recently, the same authors (123 R) reported on trends in mortality in the period 1981-1985. In this period 385 deaths were analyzed: there was a steady increase from year to year (from 41 in 1981 to 116 in 1985). In 7 4 ~ the victims were under 20 years of age (17~ between 10 and 14 years old). Trauma in these cases can be caused by agitation secondary to inhalation, which may cause running and banging, followed by sudden death (124c). It had previously been suggested in 1970 that volatile hydrocarbons might sensitize the heart to the arrhythmogenic effects of endogenous catecholamines. There is now much evidence to support this hypothesis (125R). Firstly, solvent abuse has been followed by documented ventricular fibrillation (126c). Secondly, sudden death related to solvent abuse has occurred often in circumstances associated with intense cardiac sympathetic stimulation, e.g., physical exertion, particularly running, and various forms of autoerotic behavior. And thirdly, the hypothesis was proven to hold true in animal experiments. Hypoxia, hypokalemia and alcohol may all increase the risk of arrhythmia after solvent abuse. The relative toxicity of the many chemicals inhaled is not known and their effects on the heart are probably caused by non-specific physicochemical actions and seem to occur at doses similar to those that affect the CNS. This implies that any sniffer who obtains a 'high' also runs the risk of developing an arrhythmia, particularly if combined with physical exertion. There is now also evidence that chronic exposure to halogenated hydrocarbons may lead to dilated cardiomyopathy (127 r 128c). Direct (reversible) respiratory arrest after acute inhalation of adhesive containing toluene has also been documented (129 c) and as no distinctive features at necropsy are evident, this probably accounts for the rarity of respiratory depression as a post-mortem diagnosis in solvent

412 abusers. Another symptom of solvent abuse can be epilepsy or encephalopathy, as was shown by Allister et al (130c), who found high concentrations of toluene (14.5/zg/g tissue) in the brain of a chronic 15-year-old toluene abuser, Renal damage has also been implicated in several reports on glue sniffing. Intentional gasoline inhalation is a subset of solvent inhalation with similarities in its social, economic and behavioral correlates. Exposure to fumes of gasoline is common and its odor, often perceived as pleasant, may induce abuse in children and adolescents. Inhalation at concentrations of 1% causes dizziness and drunkenness within 5 minutes. Ten to 15 breaths have

Chapter 50 P.A.G.M. de Smet and A.G. Vulto

been reported to be sufficient to induce the desired effects. A review on the history, toxicology, diagnosis, complications and treatment of this specific substance abuse behavior has been published by Fortenberry (131R).

ACKNOWLEDGMENTS We would like to thank Prof. Dr. Rudolf Hansel, Prof. Dr. Heinz Schilcher, Dr. Konstantin Keller and Dr. Desmond Corrigan for their valuable communications.

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Drugs used in non-orthodox medicine

Chapter 50

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