Medicinal plants in therapy* - WHO

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Bulletin of the World Health Organization, 63 (6): 965-981 (1985) © World Health Organization 1985

Medicinal plants in therapy*

NORMAN R. FARNSWORTH,' OLAYIWOLA AKERELE,2 AUDREY S. BINGEL,3DJAJA D. SOEJARTO,4 & ZHENGANG GuO5

One of the prerequisites for the success ofprimary health care is the availabilityand use ofsuitable drugs. Plants have always been a common source ofmedicaments,either in the form of traditional preparations or as pure active principles. It is thusreasonable for decision-makers to identify locally available plants or plant extractsthat could usefully be added to the national list of drugs, or that could even replacesome pharmaceutical preparations that need to be purchased and imported. Thisupdate article presents a list of plant-derived drugs, with the names of the plantsources, and their actions or uses in therapy.

Since most medicinal plants occur naturally in a large number of countries, a plant ofpotential importance in one country may well have been studied by scientists elsewhere.Considerable time and effort could be saved if their findings could be made available to allinterested people. Pooled information is especially critical when it comes to drugs, as avalue judgement on the safety or efficacy of a particular drug can rarely be based on theresults of a single study. In contrast, a combination of information indicating that aspecific plant has been used in a local health care system for centuries, together withefficacy and toxicity data published by several groups of scientists, can help in decidingwhether it should be considered acceptable for medicinal use (1).No accurate data are available to assess the value and extent of the use of plants or of

active principles derived from them in the health care systems of countries. WHO hasestimated that perhaps 807o of the more than 4000 million inhabitants of the world rely

A French translation of this article will appear in a later issue of the Bulletin.Research Professor of Pharmacognosy and Director, WHO Collaborating Centre for Traditional Medicine, College of

Pharmacy, Health Sciences Center, University of Illinois, 833 South Wood Street, Chicago, IL 60680, USA. Requests for reprintsshould be sent to this author.

2 Programme Manager, Traditional Medicine, World Health Organization, Geneva, Switzerland.3 Professor of Pharmacology, Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy,

Health Sciences Center, University of Illinois.4 Associate Professor of Pharmacognosy, Program for Collaborative Research in the Pharmaceutical Sciences, College of

Pharmacy, Health Sciences Center, University of Illinois and Honorary Research Associate, Department of Botany, FieldMuseum of Natural History, Chicago, IL, USA.

5 Research Associate in Traditional Medicine, Lanzhou Medical College, Lanzhou Gansu, People's Republic of China.

460 -965-

N. R. FARNSWORTH ET AL.

chiefly on traditional medicines for their primary health care needs, and it can safely bepresumed that a major part of traditional therapy involves the use of plant extracts or theiractive principles.

In the developed countries, too, plant-derived drugs may be of importance. In the USA,for example, 25% of all prescriptions dispensed from community pharmacies from 1959 to1980 contained plant extracts or active principles prepared from higher plants. This figuredid not vary by more than ± 1.0% in any of the 22 years surveyed (2, 3), and in 1980consumers in the USA paid more than $8000 million for prescriptions containing activeprinciples obtained from plants (4). Despite this, virtually no interest is shown by pharma-ceutical companies in the USA in investigating plants as sources of new drugs. Industrialinterest in exploiting plants for this purpose is almost exclusively found in China andJapan. Clearly, the pathway is open for scientists in developing countries to organize andimplement interdisciplinary research programmes for the further utilization of thesenatural sources of drugs. These sources are usually available in abundance and can providesafe, stable, standardized, and effective galenical products for use in primary health care orcan lead to the discovery of new biologically active plant-derived principles that may becandidates for use as drugs. However, before considering how such programmes can beimplemented, we must examine whether plants are a logical starting-point for drugdevelopment programmes.

MEDICINAL PLANTS IN THERAPY

Secondary plant principles in primary health care

The drugs listed in Annex 1 have been, or are currently, obtained from plants. As manyexamples as possible have been included of plant-derived drugs of known chemicalcomposition that are used in various countries in primary health care or that are recognizedas valuable drugs in widespread (i.e., non-prescription) use. For this purpose we have reliedprimarily on recent pharmacopoeias of selected countries, on the current clinical literature,and on personal knowledge of drug use in various countries.A few of the drugs are simple synthetic modifications of naturally obtained substances.

In some cases, the natural product is now replaced by a commercially synthesized product.Annex 1 shows that there are at least 119 distinct chemical substances derived from plantsthat can be considered as important drugs currently in use in one or more countries. InAnnex 2 these drugs are classified according to therapeutic category in order to highlightthe broad range of uses for which plant principles can be employed. Altogether, about 62therapeutic categories can be distinguished. From Annex 3 it can be seen that these drugsare primarily obtained from only about 91 species of plants. Most of these plants could beadapted for cultivation and use in almost every country. Research is nevertheless requiredto determine whether the useful active principle could be produced by plants cultivated inan alien habitat. The economics of cultivating such plants and obtaining their activeprinciples has also to be carefully considered.

Correlation between the use of plants in traditional medicine and of the drugs obtainedfrom them

One of the major approaches in developing new drugs from plants is to examine the usesclaimed for a traditional preparation. Although investigators involved in the developmentof drugs from natural products usually argue that there is a close relationship between atraditional preparation and a drug obtained from the same plant, data supporting suchclaims have not been presented. However, an attempt has been made to present in Annex 1

966A


a correlation between the traditional uses of some plants with the pharmacological actionof the isolated drug for 119 substances extracted from plant sources. Although our studiesare incomplete at present, we believe that the three levels of correlation indicated in Annex1 are reasonably accurate. The correlations were established as follows:

(1) If there was positive proof of a correlation, based on a study of the ethnomedical usesof plants and a knowledge of the actions of the chemical substances extracted from them,this was designated as "yes".

(2) If there was some correlation between the use of a traditional plant preparation andthe use of substances derived from it or a related plant, we considered this as a positivecorrelation and indicated it as "indirect". For example, Digitalis lanata Ehrh. has not beenfound to be used in traditional medicine as a diuretic or for the treatment of congestiveheart failure or dropsy, uses that are related to cardiotonic activity. However, the isolationof several drugs from D. lanata (acetyldigoxin, deslanoside, digoxin, lanatosides A, B andC) that are currently used as cardiotonic agents was due to the known usefulness ofD.purpurea L. as a cardiotonic agent. Chemical studies on D. lanata were thereforeinitiated with the possibility of finding cardiotonic agents, even though D. lanata itself wasnot used in this manner. Similarly, the "indirect" discovery of tubocurarine was based on astudy of Chondodendron tomentosum R. & P. and other plants used as arrow poisons byIndians from various cultures; study of the paralysis of the skeletal muscles of birds inflight and of running animals by arrows dipped in "curare" products led to the discoveryof tubocurarine. Altogether, 10 plant sources are designated in Annex 1 with an "indirect"correlation.

(3) Thirty-one plant-derived drugs were found for which no correlation could be foundbetween their use as drugs and the traditional uses of the plants from which they wereobtained (Annex 1). However, more careful study of the older literature may reveal somerelationship.

Of the 119 plant-derived drugs listed in Annex 1, 88 (74%0) were discovered as a result ofchemical studies to isolate the active substances responsible for the use of the originalplants in traditional medicine.

Approach to the study of plants used in traditional medicine

Annex 1 shows that a fairly high percentage of useful plant-derived drugs werediscovered as a result of scientific follow-up of well-known plants used in traditionalmedicine, and it can be concluded that this is a good approach for discovering other usefuldrugs from plants. In contrast, other approaches, such as phytochemical screening,massive biological screening of randomly collected plants, and phytochemical examinationof plants with the aim of identifying new chemical compounds have not proved to be veryhelpful in discovering new drugs.

However, there are two fundamental questions that must be considered before oneinitiates research on plants used in traditional medicine. Is it desirable to put in effort todiscover pure compounds in the hope of using them as drugs per se or is it preferable to goon using traditional preparations and make no attempt to identify the active principles?

For the majority of developing countries, the cost of imported drugs on a large scale isalmost prohibitive. On the other hand, these countries have an enormous wealth ofinformation on medicinal plants, which are not only cheap and abundant but alsoculturally acceptable. Furthermore, most developing countries have neither a well-organized pharmaceutical industry nor the manufacturing capacity to isolate largequantities of active principles from plants should they be discovered. Thus, programmesfor this kind of drug development in these countries have to be well planned and

967


coordinated (within the country), and they may be carried out in stages as illustrated in Fig.1. This flow chart focuses on the initial need to produce safe and effective galenicalproducts but includes the long-term objective of discovering the active principles. Theseprogrammes could eventually lead to the development of a pharmaceutical industry in thecountry.

Critics of the use of galenical products rather than pure active constituents shouldconsider the following simplified example, which illustrates the value of galenical prepara-tions. A chemically standardized tincture ofA tropa belladonna for use in treating stomachulcers has a therapeutic efficacy at least equivalent to that of a standard dose of atropinesulfate (the major active principle of A. belladonna). The plant itself can be cultivatedeasily in almost any country and the manufacture of a stable, standardized tincture wouldrequire little in the way of hard currency, which would be needed to import tablets ofatropine sulfate. Other similar examples of efficacious galenical preparations that could bepromoted in developing countries can be identified from the information presented inAnnex 1. There is therefore much in favour of establishing programmes for producingstandardized and safe galenical traditional preparations for potential use in primary healthcare, as shown in Fig. 1, with the eventual aim of discovering their active principles.Even if the active principles have not yet been identified in some of the plants used in

traditional medicine, historical evidence of the value of such plants could result in usefulpreparations, provided they are safe. Evaluation of safety should therefore be a primeconsideration, even at the expense of establishing efficacy of the preparation.

WHO 851626

Fig 1. Flow chart of sequence for the study of plants used in traditional medicine.

968


Simplified pharmacological pre-screening of plant extracts

One point that should be noted about the biological activity data on plant extractsreported in the literature is the difficulty of reproducing many of the results. In general, themore sophisticated the bioassay, the lower the chance of being able to reproduce the data,but the reason for this remains elusive. Many of the reports on the pharmacological testingof crude plant extracts have been published by investigators working in laboratories indeveloping countries. One explanation might therefore be that laboratory animals in somedeveloping countries are undernourished and thus respond biochemically in a differentway from animals that have a better nutritional intake. It is also possible that low-gradelaboratory animal infections, especially parasitic infestations, which may not manifestthemselves visibly, could cause animals to respond abnormally to the action of drugs. Theinability to reproduce experiments involving the biological evaluation of plant extracts hasalso been attributed to variation in the chemical constituents due to the age of the plants,the time of year or season when they were collected, or the geographical area where theywere collected. Although chemical variation in plants is well known, we are unaware ofreliable experimental data indicating that this is the reason for the inability to reproduce thebiological effects of plant extracts.

Scientists are generally reluctant to accept data on the effects of crude plant extracts inhumans or in intact animals unless an explanation of the reported effects is also given.Conversely, data from mechanistic studies (usually in vitro) on crude plant extracts rarelyattract much interest in the absence of evidence demonstrating the effects in an intactanimal or human subject.

In most developing countries, chemical and botanical expertise is usually readilyavailable but experienced pharmacologists are rare. If trained pharmacologists are in shortsupply or if they are not interested in collaborative efforts to discover new drugs fromplants, it is feasible for chemists to set up and implement certain in vitro bioassays (some-times referred to as "pre-screens") or cell-culture systems that can provide valuableinformation. Similarly, pharmacologists may find it more convenient and economical tostudy drug effects in vitro as an alternative to using intact laboratory animals in theirresearch. There are sufficient bioassay techniques described in the literature to enablealmost any biological activity of interest to be studied without using intact animals. Indeed,there is a worldwide trend to avoid experimenting on intact animals in the early stages ofdrug development. Some of the "pre-screens" rely on chemical or biochemical expertiserather than on pharmacological knowledge and training and hence should be managed bychemists. A few of these bioassays are listed in Annex 4.Most of the "pre-screens" indicated in Annex 4 can be performed using relatively simple

equipment. Virtually all assays can be conducted using tissue culture equipment, a CO2-incubator, an inverted microscope, a sterile hood, a cell counter, water baths, dry airincubators, an autoclave, a recording spectrophotometer, and a liquid scintillationcounter. However, many of the in vitro "pre-screens" can be effectively carried outwithout some or all of this equipment. Thus, the chemist who does not have collaboratingbiologists could set up one or more bioassays that facilitate the isolation of biologicallyactive molecules. These compounds are usually likely to be chemically complex and possessnovel structures that are interesting from the scientific point of view.The "pre-screens" listed in Annex 4 have all been successfully employed for the

biological evaluation of crude extracts and may need only slight modification to adaptthem to laboratories where conditions are not the best. The information provided in thecited references should be adequate to set up the bioassay systems, as well as to facilitate anunderstanding of the basic principles involved.

969

970 N. R. FARNSWORTH ET AL.

CONCLUSION

Scientists in developing countries are entering an era in which plants can be expected tooccupy a prominent position in the list of national priorities. This type of drug researchcould lead to industrial development in the country where the discoveries are made. Thesource of starting materials is normally abundant and readily available since in mostdeveloping countries the flora remains virtually unexploited, and we believe that over thenext two decades many useful drugs will be isolated from plants. The majority of thesediscoveries should and will be made by enthusiastic, energetic, and highly motivatedscientists in developing countries.

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Annex 2

Therapeutic indications of plant-derived drugs

Therapeutic indication Drug Therapeutic indication Drug

Abortifacient

Analgesic

Analeptic

Antiarrhythmic

Anticholinergic

Antidepressant

Antiemetic

Antigout

Antihepatotoxic

Antihypertensive

Anti-inflammatory

Antioxidant

Anti-Parkinsonism

Antipyretic

Antitussive

Aphrodisiac

Astringent

Bronchodilator

Capillary fragility

Cardiotonic

TrichosanthinYuanhuacineYuanhuadine

BorneolCodeineMorphineRotundineSalicin( ±)-Tetrahydropalmatine

Picrotoxin

Quinidine

AnisodamineAnisodineAtropineHyoscyamine

Glaziovine

A9-Tetrahydrocannabinol

Colchicine

Silymarin

DeserpidineProtoveratrines A & BRescinnamineReserpineRhomitoxinTetrandrine

AescinBorneolBromelain

Nordihydroguaiaretic acid

L-Dopa

BorneolHemsleyadinPalmatineQuinine

BergeninCodeineGlaucineNoscapineRorifone

Yohimbine

Hydrastine

KhellinTheophylline

HesperidinRutin

AcetyidigoxinAdonisideConvallatoxinDeslanosideDigitalinDigitoxinDigoxinGitalinLanatosides A,B,COuabainScillarin A

Cerebral stimulant

Chemotherapy:Anthelmintic

Antiamoebic

Antiascaris

Antidysentery

AntifungalAntimalarialAntitumour

Choleretic

Cholinesterase inhibitor

Circulatory disorders

CNS stimulant

Condylomata acuminata

Decrease ocular tension

Dental plaque inhibition

Detoxicant

Diuretic

Emetic

Expectorant

Haemostatic

Insecticide

Laxative

Leukoderma

Local anaesthetic

Male contraceptive

Oxytocic

Parasympathomimetic

Piscicide

Vincamine

AgrimopholArecolineQuisqualic acidEmetineGlaucarubinKainic acidSantoninAesculetinAndrographolideBerberineHemsleyadinNeoandrographolideThymolQuinineColchiceine amideColchicineDemecolcineEtoposideMonocrotalineTeniposide eVinblastineVincristine

CurcuminCynarin

GalanthaminePhysostigmine

Ajmalicine

CaffeineStrychnine

Podophyllotoxin

A9-Tetrahydrocannabinol

Sanguinarine

Palmatine

TheobromineTheophylline

Emetine

Pinitol

(+ )-CatechinHydrastine

Nicotine

DanthronSennosides A & B

Xanthotoxin

Cocaine

Gossypol

PachycarpineSparteineVasicine

Pilocarpine

RotenoneaSynthetic modification of a natural product.

978


Annex 2: continued

Therapeutic indication Drug Therapeutic indication Drug

Proteolytic

Respiratory stimulant

Rubefacient

ScabicideSedative

Skeletal muscle relaxant

Smoking deterrent

Smooth muscle relaxant

BromelainChymopapainPapainoa-Lobeline

Allyl isothiocyanateCamphorMentholMethyl salicylateBenzyl benzoate

RotundineScopolamine( ± )-TetrahydropalmatineValepotriatesAnabasineCissampelineTubocurarinea-LobelinePapaverine

Sweetener

Sympathomimetic

Tranquillizer

VasodilatorVitiligoVulnerary

GlycyrrhizinPhyllodulcinStevioside

EphedrinePseudoephedrinePseudoephedrine, nor-

DeserpidineKawainRescinnamineReserpineRhomitoxinRotundine(± )-TetrahydropalmatineTheobromineXanthotoxin

AllantoinAsiaticoside

Annex 3

Plants used in traditional medicine and the drugsderived from them

Plant' Drug

Adhatoda vasica VasicineAdonis vernalis AdonisideAesculus hippocastanum AescinAgrimonia eupatoria AgrimopholAmmi majus XanthotoxinAmmi visnaga KhellinAnabasis aphylla AnabasineAnanas comosus BromelainAnamirta cocculus PicrotoxinAndrographis paniculata Andrographolide

NeoandrographolideAnisodus tanguticus Anisodamine

AnisodineAreca catechu ArecolineArdisia japonica BergeninArtemisia maritima SantoninAtropa belladonna AtropineBerberis vulgaris BerberineBrassica nigra Allyl isothiocyanateCamellia sinensis Caffeine

TheophyllineCannabis sativa A9-TetrahydrocannabinolCarica papaya Chymopapain

Papain

See Annex 1 for plant authority names.

Plant Drug

Cassia acutifolia

Cassia angustifoliaCassia species

Catharanthus roseus

Centella asiatica

Cephaelis ipecacuanhaChondodendron tomentosumCinchona ledgeriana

Cinnamomum camphoraCissampelos pareiraCitrus species

Colchicum autumnale

Convallaria majalisCoptis japonicaCorydalis ambiguaCrotalaria sessiliflora

Curcuma longaCynara scolymusCytisus scopariusDaphne genkwa

Sennosides A & B

Sennosides A & BDanthronVinblastineVincristine

Asiaticoside

Emetine

TubocurarineQuinidineQuinine

CamphorCissampelineHesperidinRutin

Colchiceine amideColchicineDemecolcineConvallatoxinPalmatine

± )-TetrahydropalmatineMonocrotalineCurcumin

Cynarin

SparteineYuanhuacineYuanhuadine

Annex 3: continued on next page

979


Annex 3: continued

Plant Drug

Datura metel

Digenia simplex

Digitalis lanata

Digitalis purpurea

Ephedra sinica

Erythroxylum coca

Fraxinus rhynchophylla

Gaultheria procumbens

Glaucium flavum

Glycyrrhiza glabra

Gossypium species

Hemsleya amabilis

Hydrangea macrophyllavar. thunbergii

Hydrastis canadensis

Hyoscyamus niger

Larrea divaricata

Lobelia inflata

Lonchocarpus nicou

Lycoris squamigeraMentha species

Mucuna deeringiana

Nicotiana tabacum

Ocotea glazioviiPapaver somniferum

Pausinystalia yohimba

Scopolamine

Kainic acid

AcetyldigoxinDeslanosideDigoxinLanatosides A, B, C

DigitalinDigitoxinGitalin

EphedrinePseudoephedrinePseudoephedrine, nor-

Cocaine

Plant

Physostigma venenosum

Pilocarpus jaborandi

Piper methysticum

Podophyllum peltatum

Potentilla fragarioides

Quisqualis indica

Rauvolfia canescens

Rauvolfia serpentina

Aesculetin Rhododendron molle

Methyl salicylate Rorippa indica

Glaucine Salix alba

Glycyrrhizin Sanguinaria canadensis

Gossypol Silybum marianum

Hemsleyadin Simarouba glauca

Sophora pachycarpaPhyllodulcin Stephania sinicaHydrastine Stephania tetrandraHyoscyamine Stevia rebaudianaNordihydroguaiaretic acid

Strophanthus gratus

ai-LobelineStrychnos nux-vomica

RotenoneTheobroma cacao

Galanthamine Thymus vulgaris

MentholTrichosanthes kirilowii

L-Dopa

Nicotine Urginea maritimaNicotine

Valeriana officinalisGlaziovine

Veratrum albumCodeineMorphine Vinca minorNoscapine Several plants

Papaverine

Yohimbine

Drug

Physostigmine

Pilocarpine

Kawain

Etoposide"PodophyllotoxinTeniposide b

(+ )-Catechin

Quisqualic acid

Deserpidine

AjmalicineRescinnamineReserpine

Rhomitoxin

Rorifone

Salicin

Sanguinarine

SilymarinGlaucarubin

Pachycarpine

Rotundine

Tetrandrine

Stevioside

Ouabain

StrychnineTheobromine

Thymol

Trichosanthin

Scillarin A

Valepotriates

Protoveratrines A & B

Vincamine

AllantoinBenzyl benzoateBorneolPinitol

b Synthetic modification of a natural product.

980

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Medicinal plants in therapy* - WHO

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Transcript of Medicinal plants in therapy* - WHO