Trends in Pharmac&gicd Sciences

May Em2

Is there a place for ethnopharmacology

in our time? !Scientists like Rudolf BuchlGm. Thomas Fraser and Rudolf Kobert devoted a great patt of their active life to the study of tlvz pharmacological effects of natural products. During the time of exploration and coloniaJiim, they had access to a mul- titudeofctudedrugs. fn fact. oneofthebest surveys of these drugs was written during this time by Hattwich’. It is to men like these that we owe many of the drugs we use today.

It is questionable if any of these pm ni- nent research workers can be tegatded as ethnopharmacologists in the modem sense. Truly, they spent decades investigating ethnobotanical materials and their active principles, but they dii not carry out f=ld studies among different ethnic groups, nor dii they in all cases tealize the utmost impxtance of authenticating plant and dntg materials. Whereas, at that time, it took months for drkd leaves to arrive in Eutope for analysis. it is now possibk to take a full) equipped floating labnratoty up the Ama ran. not only for studks of accurately ides tif& fresh botanical material. but ako for the analysis of active components in blood.

Jntemstinttiuhtionaldrugsisthusnot new but has been spuned in recent ye_;s By

methodolo~$cal advances in phytochemis Uy. a growing mtmber of emal studies, and an upsurge of interest in tenewabk msoumes and axlitional medicii.

TIE observaIion. idemiRcaunn. descrip tionandexperbmxUinveatigatkaofthe ingredients and the effects of indigenous drugs is a tndy intetdisciphnary fkld of research. The term e-logy has been used loosely to desctibe this fteW’. but so far little attempt has been mde to define the aims and scope of this disciplii. Ethnopharmacological research is based on botany, pharmacology and chemistry. but other disciplines have made vital contribu lions. Based on these considerations. we have recently def& ethqhannacology as ‘the intetdisciplintuy scientitir expl- bon of biilogically active agents traditionally emplovcd ot observed by mat?.Thisstudyoftmditionaldtugsisnot meanttorukocateatetumtotheuseof llksetemedksintheiiaboligiiform. nor !o exploit tmditional medicine.

The objectives of ethnopharmarology

aJrtorescueanddoclmlemmnImpon;ml cultunl heritage before it is Iosf. and to investigate and evaluate the qnts cm ployed.

Field obserwtions and dewip01~~ of tk use and effecta of traditional remcdtc5. botanical ukntification and phytochemird and pharmacological studies. are all within rk scope of &qham~ology. It is essential. houfever. that anthropologists inktested in ethn@amu+cology seek COR tact and colhtboration with rrp3ts in botany, t hemistty and pharmacology. That such a tr.ultidisciplinaq approach prrunts ad&d ir;ivantages is not dwavs nAzcd. Even ia ant times an a~thn~polqist can give a tktaikd dertiption of an .+&i~aa poison &eal without hutherinp 3thv11 the cbemicd composition ot the poisonott drink WA or even its plant origin. Indeed tenuuitohk in a time that bvours teamwork and the cnvolvement of many diriplincs!

Ihe Gst successful nultidisciplin;u) snack CPU an ethnopharmrological ptob lem w% initiated by tk French naturalist. Lescheunth & la Tour. in 1803. He CDL lected sr @es of an armw poison in Java. as well a.9 detailed. titst-hand information ftomthenativesaboutthccngredientsand pteparatton. In Fmncc. a specimen of the major plant ingtedient was stud&l by the boumist Jussieu who identified it as a Sf7~~Jttto.r specks. Leschenault then gave tbr poison to Magendii and Raffenau de Lilk. who studied the effects in hens. tab

982,

bits. dogs and a hnrse. They observed vi* Alt~gh they have ken used with only lent c~nvulsiom. asphyxia and death in 5 moderate success, the recommendation of a min and discovered that the chief action mixture of pyridinium and tropane was on the spinal cord. This finding is a alkaloids is a striking parallel to the native landmafk in p~~yn~ics, since it use of chemically similar c0n~lxma.s.

rppnesents the frst time that the action of a Aqueous decoctions of ~l~e~~a~d~ poimn was shown to act on a specitic ujjittis are traditionally used to accelerate organ. A decade later the alkaloid responrt childbirth by the Lulua population in Zaire.

ibk for these symptoms. strychnine, was In his capacity as medical missionary

isolated by Pelletier and Caventou. Thus, Lmznts Gran observed increased uterine we have here for the first time an interdisci- activity in woman receiving: these pre- plinary study starting with fieldwork lxmitions’. ffe also isolated semtonin from among natives and continuing with botany, the plant. However, the usual dccoction pharmacology and the isolation of the from about 100 g of dried plant would not active pincipk. Later on this was followed give a higher total intake than about 2 mg of by the i~~ti~n of strychnine into semtonin, and since serotonin is rapidly clinical medicine. destroyed when taken orally it could have

The identification ob‘ medicinal plants no action. In in vim experiments with iscs. and other traditional drugs is of course a lated organs, Gran showed that ihe crucial point, and good e~~~ increased uterine contractions produced by c&gicai research can only be based on the water extract also persisted after treat- properly prepared voucher specimens, ment with methysergide. Therefote carefully authenticated by experts. There another, or several other compounds(s). aie many examples in the past, however. of mast be the active principle(s). In his p~~~~ts neglecting this point. oniy R-h. which is a fine example of mod- to find that their results are diffhlt to em e~n[~~ology. Gran went on to repeat. Wherever possible, phytacbemical i&ate the active principles and found studies un medkinal plants should be fol- oxytocic peptides. lowed by a careful search for the biological Most traditional drugs are admiitered activities of rhe compounds isolated. When as mixtures of many co~~nts. aad with biologically active principles have been today’s knowledge of the many possible found, the findings must be interpreted in interactions between drugs, and between the light of the traditional use. food and drugs. ethnopharmacological

It is impossible, however. IO establish a research must deal with this aspect too.

dose-effect ~lation~ip unless the 0~~ Additive. synergistic, or ~~~t~ drug prepatations (water infusioas etc.) are effects are all possible. Various admixtures analysed and evaluated chemically and have also been shown to affect the phaimacologicall~s. As a result we must, binavailability of pharmacologically active in et.hnopla?nr~acological research, have principles. proper ~pfmg and analysis method% and We believe that ~~:~olog~ studies this necessity mquires close rckoperation of tmditional medicinal agents should he by pharmacologists. with anthropologists initiated prior to or in parallel withchemicai and ethnobotanisls on the one hand and research and should guide the isolation of sp&alists in chemical aaalysis on the active principles. Field observations of other. A recent example fmrn our depart traditional therapies and the w ment of this approach is 5u6&i~ cological effects in humans should be myoporoides. used by the natives of New carried out by trained pharmacologists, and Cakdonia as an antidote in ciguatera fish when interesting activity is fouML. control- poisoning. Since a water infusion ol ledexperiments should be initiati. Duboiria ~~OP~?O~S is used for the treatment of CigtUtera poisoning, such an Band modern infusion was pmpared and the alkaloid COB tncdicine tent quantitaud. The infusion contains a Recent surveys have shown that the per- pnvesful mixtun: of nic&ne and centage ofnatural products in the modem =Jp@kmine. &pared in the trt~%ional drug ~n~urn is cottsiderable. esti way, two mo1&fu9s would equal roughly !nates varying fmm 35 to 50%. Almost 50 mg of nicotine and 20 mg of cveryclassofdrug includesa model sbuc- sfopolamine. The potential of this prepara- tune derived from nature, exhibiting the ticminthtaeatmem of ciguaterapoisoning ~L%IIx- evident when modern knowledge

classic4 e&Is of that spxcifk phsnna

of tlrc! poisoning was examined. Based on coiogical category. A gtcal number of

h vine experiments with the toxin, two these natural pmducts have come to us from thescientifi study ofremediistraditionally

wel&tavn anticholinesterase antidotes employed by various cultures. Most of have been su&%ested: atropine and them ate plant-derived, and pilo~arpine, pyridiium aldoxime methiodii. ~stine+ emetine, ~~~~,

Plnltts cdIeeled iit tmtd#m In.4 PhmlP useil t@tlrf E‘utcef ty.9 Attlhelminks 29.2 Fish pnisons 38.6 Ptnnts puiwnuur 10 mutt .w.o Amnv poisons 52.2

*I~wtwr shw b ~~ni~cunt idiots &Fee1 in rrpritnentaI tuttw syrtems INatiomtl Cattwr In& we. F~~hesda. M;Yyland). Wmm Ref. 9.)

digitoxin, qlUte. atmpine and reserpine are a few wel~k~wn exampl&.

Evidently, the ethnopharmacological impulse to modem medicine can lead to many novel useful drugs, but modern and traditional u.ses may be entirely different. For example, the plant material studied at the National Cancer institute’ (Bethesda, Maryland) has been collected at random, but the analysis performed by Spjut and Rrdue (summarized in Table 1) shows that if ~tit~or screening had been guided by the knowledge of medicinal folklore and poisonous plants. the yield of active species would have been greatly incn%seds. In this study, plants were classifEd as ‘active’ tegatdless of tumor system oc whether the results weta obtained from in viva or fit vim studies. Tbt validity of the data in Table 1 should therefore be further ana lysed. Another example is the antileukemic activity of vincristine from Caf~ara~t~~ mvw which was found when the plant was investigated br:ause of its folk use as a diabetes remedy.

It is generally accepted that ergot has constituted a gold-mine for finding therapeutically active components (natur- ally occurring or malifti chemically) against many different diseases. It is by no means inconceivable that the cannabiioids may play a similar role in the future. Derivatives am already being tested for var- ious purposes in clinical medicine.

m above data seem to support the con- clusion that traditional medicine is a general, nowerful soutce of biological activity,

The Beld of mediiinal plants is far fmttt exhausted. The flora of Ihe Amazon has hean estimated at 73,ooO species. During 30 years of ethnobotanical and ethnopku- macological mseatch in this area, Schultes has collected Iran on the use of ever 1300 species as poisons, narcotics or ‘medicines’. This, and many other treasure&urs of human knowledge am W~f~~~O~~~UP~ chalknge= *@.

TIPS - May IW2

The ultimate aim of ethnopharmacology is tbz validation (or invalifMon) of these traditional pepsrations. c&r thnntgh the isolation of active substances or thmugh pharmacological findings. The inform&n gattuIE+d about indigenous drugs will per- mit a feedback to traditional medicine. Harmful practicescan be discouraged, such as the use of pkmts containing tumor- pmducing pynolizidii alkaloids. Know- ledge of active consciluents in indigenous

drugs may lead lo substantial impro- menls in traditional therapy. In mcent years. WHO has emphasii the impor- lance of scientific investigations into indigenous herbal mediiines. Many Third World countries lode upon native medicinal plants as possible additions to the

WHO list of ‘essential drugs’. once theii value has been clinically proven.

Ethnopharmacology is not just a science of tk past utilizing an out-m&d appmach. It still constitutes a ScientifK backbone in the development of active tbapeutics based upon traditional me& i&e of various ethnic ~JWPL Although noI highly esteemed at the moment, it is a challenge to m&m pharmxologists.

BO HOLhlSlEJX. JAN G. BRLIHN

Reading list I Hanwich. C. (1911) Drr mcnwk/i&n

Cenursmi~te/. Tawhniu. Lclpzq 2 Ehnn. D. ii.. Holmwd~. B. and Kline. N. S.

feds) (1967) Efhnophwmwdo~ic Smmh Jw Psychoucriw Drugs. U.S. 00~1. Rnring Otlii. Washingtm. D.C.. Publk Hrullh Swvicr P&l. No. 1645 (rqwinmi hy Raven Pnxs. New Vmk. 1979)

3 !-khultes. R. E. ml Swam. T. (19761 in 7k Rrwnf Owmiwry nJ Natund Prodwa. Includ- ing Tobacco: Pmerdinp oJrhr Sword Phihp

Morris Scirm~ Sympusium (Fina. N. J.. 4.1. pp. 13.3..171. New Vwk

4 Bwhn, 1. G. and Holmsledl. 8. 1” Nmmd Pro. ducts as M&&a/ Agrrtu (Rcinhud. E. anal Beat. J. I... 4s). PP. 4OS-830. Hipphates Vw- Ia& SwJrn

5 MaIon. hi H. (1977) in Nrw NawaJ J’nxfwis and Plmu Dogs with Pharmucolo~icul. b&g- it-al or 7Ywmpetuic Acriv&v (Wagner. H. rwi WoltT. P.. cds). PP. 2343. Spinger. Berth

Some of the pharmacological actions of aminopyridines have been known for many years. but it is mainly since the relati\cly nxent IL= of camimlpylidine hydnlchklr- ide as an anticunre agent by Bulgarian anaesthetists (panicularly D. Paskov and E. Stojanov) that t&e substances have been studied in considerable detail. Such is the wide-ad interest in their actions by membrane biilogists. pharmxologists. and clinicians. especially anxsthetists, that it was cxmsidered appmptiate to assess the present state of knowledge at an intema- tional symposium held in Paris in July 1981 and organized by Lechat (Paris). Thesleff (Lund) and l3owman (Glasgow). The symposium. the full pmceediigs of which are shortly to be published by Pergamon Ress. look thf. form of a satc!btc sym posium of the 8th lntemational Congress of Phanrmlogy. Much of the early work on this class of compounds was camed out by Fastier and his colleagues in New Zealand. and so it was gtatifying to find Professor Fred Fastier present at tk Pans sqm posium. and still active in the field.

In addition to their anticurare action, aminopmines pmduce a vide variety of other effects. Thus. in venebtates and invettebrates they have been shown to facilitate hansmission at synapses (both excitatory and inhibitory) in the brain and spinal cord. and at autonomic ganglia and neumeffector junctions. including as Anne Bowman and .1. S. Gillespie have rhoun. the non-adnmcrgic. noschnlinrrgic. non- purinergic junctions in the bovine tvtractor pnis m&e. Even the release of cenain hormones (pnrlactin. calcitonin. pamthor. mane) from endtxrine cells ma> be incnxsed by +aminopyridute. as descrihrui in Paris b! Sand and his c+ worker. Aminopyridlnes habc also h-en fixmd to affect conduction In excitable membmnes. lo increaw muscle contractil- ity. and lo facilitate transmission at ekctri- tally transmitting ephaptic jtmclions in the qhtl cotd of ttu frog. For a brief review, B R article by Thesleff ( 19800) may be LIVI- s rlted. Most work has been done on ti , .~musular junction in skebtal muscle.

siwe it is tk effect of +aminop)ndine ;il this site that is the mam one to hare heen cnplonedclinlcally.

Tk pyridine nitrogen of 44111uh~ pyridine has a PKa value of 9.? Y) thal al body pH valtux about9l3% ol the mokxukr arepmtonatedtoformth? InonocatLrn. -Ilk- charge on the cationic form 8% d&cahzed. the extremes being repmznted b> the IU~ forms on rhe right of the react1011 belou

Molg6. Lundh 2nd Thcskff *howed that when the pH of tht mlution tUihin_g an LXX

lated nerve-muscle pcepamtinn i\: rdwd. thr potency of amimp~lv.Xinrs in facdtt.n- ing transmw.ion is increasexl. r\n mceaw in pH a~ppreaes th: protonawn of hminopyxdine w thal morr mzlecuk~ then eGt m tk norbionized lipa&wlublc form (i.e. the aboce Z(IUXIOII IS smiical tlr thr left). In this form the tnolt~uks u0uh.i be better abk to pxetmte the hpti of cell membranes. so that the effecl of pH II+ constitute evidence ihat thr alte oi acnon I\ inttacwllular. Modifkalion of rw3celluliu pH has httle effect on mtrxellular pH. w that once m the s?h4 most of the r.&cules would again become pnuonstd. suggesting that the monocattlanic ii~mls .ue the 3ct1vc species 0we the\ haw redkal

lhea sik dadion.

AF first shonn b) Lenwpnun .uxi Lccha In I%-. and subsequently ~nntirmed tr) numerous workers. +aminop~ridme th.llC tates neuromuscular tmnsmisrion h! increaGng the rrlezw of x~t~lzholme evoked by nerve impulses. II ir .&wad of

anticholinestemse activily . lk dug exerts

its action on tk n+asc pnwzs~ \\ithoul

making more acutykholint’ awluhlr ior &asc. Thus. for example. II dwz not

ithxwie IL m&iliL;ltion of nxnsmincr-