Trease and Evans Pharmacognosy

Contents Preface ix

11. Plantcell andtissueculture;biological conversions; clonalpropagation j2

Contributors xi

12. Phytochemicalvariationwithin a species 80 Pqrt I Introducfion

13. Deteriorationof storeddrugs 9l I

l. Plantsin medicine:the originsof pharmacognosy 3 2. The scopeandpracticeof pharmacognosy 5 3. Plant nomenclatureand taxonomv 8 Pqrl2 The plont qnd onimql kingdoms os

sourcesof drugs

ll

4. Biologicalandgeographical sourcesof drugs 13 5. A taxonomicapproachto the studyof medicinalplantsandanimal-derived drugs 15 6. Pharmacologicalactivitiesof natural products 4I 7. Synergyin relationto the pharmacological actionof phytomedicinals 49 E. M. Williamszn

14. Quality control 95 Pqrt 4 Some currenl frends

107

15. Plant productsand High Throughput Screening 109 M. J. O'Neill, J. A. Lewis 16. Biologically activecompoundsfrom marine organisms 115 G. Blttnden 17. Traditionalplant medicinesas a sourceof new drugs 125 P. J. Houghton Pqrt 5

Phyrochemisrry 135 18. Generalmethodsassociatedwith the phytochemicalinvestigationof herbal products 137 19. Basicmetabolicpathwaysandthe origin of secondarymetabolites150

Port 3 Pqrt 6 Principlesrelqted to the commerciqt qnd relqted drugs of Phqrmqcopoeiol production, quolity qnd stqndqrdizqtion biologicol origin l7l of nolurql products 55 Introduction 173

8. Commercein crudedruss 5i R. Baker

20. Hydrocarbonsand derivatives 174

9. Productionofcrude drugs 6l

21. Carbohydrates 191

10. Plantgrowthregulators 6l

22. Phenolsand phenolicglycosides 214

Id..:e6Nif 23. Volatile oils and resins 253 24. Saponins,cardioactivedrugsand other steroids 289 25. Miscellaneousisoprenoids 315 26. Cy anageneticglycosides,glucosinolate compoundsand miscellaneous glycosides 321 27. Alkaloids

37. Aspectsof Asian medicineand its practicern the West 461 M. Aslam

38. Chineseherbsin the West 482 S. Y.Mills

39. Plantsin African traditional medicine-an overview 488 A. Sofowora

333

28. Tumour inhibitors from plants 394 P. M. Dewick 29. Antiprotozoalnatural products 401 C. W. Wright 30. An overview of drugs with antihepatotoxic and oral hypoglycaemic activities 414

Port 8 Nonmedicinol toxic plonts ond pesticides 497 40. Hallucinogenic, allergenic,teratogenicand other toxic plants 499 4L. Pesticidesof naturalorigin

509

3L. Vitamins and hormones 42I

33. Colouringandflavouringagents 435

Pcrrt9 Morphologicol qnd microscoPicql exqminqtion of drugs 513

34. Miscellaneousproducts 440

I n t r o d u c t i o n5 1 5

32. Antibacterial and antiviral drugs 429

Porl7 Plqnts in complementqry ond troditionql syslems of medicine 445 Introduction 441 35. Herbal medicine in Britain and Europe: regulation and practice 449 S. Y.Mills 36. Homoeopathicmedicine and aromatherapy 460 M. A. Healy, M. Aslam

42. Plant description,morphology and anatomy 516 43. Cell differentiation and ergasticcell contents 526 44. Techntquesin microscoPY 538 Index

549

E

Plonts in medicine: theorigins of phormocognosy

The universal role of plants in the treatment of diseaseis exemplified by their employment in all the major systemsof medicine irrespective of the underlying philosophical premise. As examples, we have Western medicine with origins in Mesopotamia and Egypt, the Unani (Islamic) and Ayurvedic (Hindu) systemscentred in western Asia and the Indian subcontinent and those of the Orient (China, Japan,Tibet, etc.). How and when such medicinal plants were first used is, in many cases, lost in pre-history, indeed animals, other than man, appear to have their own materia medica. Following the oral transmission of medical information came the use of writing (e.g. the Egyptian Papyrus Ebers c.1600 nc), baked clay tablets(some 660 cuneiform tablets c. 650 ec from Ashurbanipal's library at Nineveh, now in the British Museum, refer to drugs well-known today), parchments and manuscript herbals, printed herbals (invention of printing l44O AD), pharmacopoeias and other works of reference (ftrst London Pharmacopoeia, 1618; first British Pharmacopoeia 1864), and most recently electronic storage of data. Similar records exist for Chinese medicinal plants (texts from the 4th century ec), Ayurvedic medicine (Ayurveda 2500-600 nc) and Unani medicine (Kitab-Al-ShiJa, rhe Magnum Opus of Avicenna,980-1037 ao). In addition to the above recorded information there is a great wealth of knowledge concerning the medicinal, narcotic and other properties ofplants that is still ffansmitted orally from generationto generationby tribal societies,particularly those of tropical Africa, North and South America and the Pacific countries. These are areas containing the world's greatest number of plant species, not found elsewhere, and with the westernization of so many of the peoples of these zones there is a pressing needto record local knowledge before it is lost forever. In addition, with the extermination of plant species progressing at an alarming rate in certain regions, even before plants have been botanically recorded, much less studied chemically and pharmacologically, the need arises for increasedefforts directed towards the conservation of genepools. A complete understandingof medicinal plants involves a number of disciplinesincluding commerce,botany,horticulture, chemistry enzymology, genetics, quality control and pharmacology.Pharmacognosyis not any one of theseper sebut seeksto embracethem in a unified whole for the betterunderstandingand utilization of medicinal plants.Aperusal ofthe monographson crude drugs in a modem pharmacopoeiaat once illusfates the necessityfor a multidisciplinary approach.Unlike those who laid the foundations of pharmacognosy,no one person can now expectto be an expert in all areasand, asis illustratedin the next chapter, pharmacognosycan be independently approachedfrom a number of viewpoints. The word 'pharmacognosy'had its debut in the early 19th century to designatethe discipline related to medicinal plants; it is derived from the Greek pharmakon, 'a drug', and gignosco, 'to acquire a knowledge of' and, as recordedby Dr K. Ganzinger(Sci. Pharm.1982, 50, 351), the terms 'pharmacognosy' and 'pharmacodynamics' were probably first coined by JohannAdam Schmidt (1759-1809) in his hand-written manuscript Lehrbuch der Materia Medica, which was posthumously published in Vienna in 18I 1. Schmidt was, unril his death,professor at the medico-surgical JosephAcademy in Vienna; interestingly he was also Beethoven's physician. Shortly after the above publication, 'pharrnacognosy' appears again in 1815 in a small work by Chr. Aenotheus Seydler entitled Analecta Pharmacognostica. Pharmacognosyis closely related to botany and plant chemistry and, indeed, both originated from the eartier scientific studieson medicinal plants. As late as the beginning of the 20th century, the subject had developed mainly on the botanical side, being concemed with the description and identification of drugs, both in the whole state and in powdeq and with their history, commerce, collection, preparation and

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storage. Such branches of pharmacognosy are still of fundamental importance, particularly for pharmacopoeialidentification and quality control purposes, but rapid developments in other areas have enormously expandedthe subject. The use of modern isolation techniquesand pharmacologicaitesting proceduresmeansthat new plant drugs usually find their way into medicine as purified substancesrather than in the fbrm of galenical preparations.Preparationis usually confined to one or a few companieswho process all the raw material; thus, few pharmacists have occasion to handle dried Catharanthus roseils although they are familiar with formulations ofthe isolated alkaloids vinblastine and vincristine. For these new drugs it is important that the pharmacist, rather than being fully conversant with the macroscopical and histological charactersof the dried plant, is able to cary out the chromatographic and other proceduresnecessaryfor the identification and determination of purity of the preparation supplied. Similar remarks apply to such drugs as Rauwolfia, the modem preparationsof ergot, and the cardioactive and purgative drugs. When specific plants,including thoseusedin traditional medicine, suddenly become of interest to the world at large, the local wild sourcessoon become exhausted.This necessitates,as in the caseof Catharanthusroseus,Coleus forskohlii, Arnica montana and Taxus brevfolia, research into the cultivation or a.rtificial propagation by cell culture, etc., of such species.In order to avert the type of supply crisis that arose at the clinical trial stage with the anticancer drug taxol, isolated from 7. brevfolia, the US National Cancer Institute has initiated plans for future action when a similar situation again arises (see G. M. Cragg et al., J. Nat. Prod., 1993, 56, 165'7).

However, it has been repofied that as a result of demandfor the new drug galanthamine(qv) for the treatmentof Alzheimer's disease,the native sourceof Leucojum aestivumis now in danger. The use of single pure compounds,including synthetic drugs, is not without its limitations, and in recent years there has been an immenserevival in interestin the herbal and homoeopathicsystems of medicine, both of which rely heavily on plant sources,At the 9th Congress of the Italian Society of Pharmacognosy(1998) it was stated that the current return of phytotherapy was clearly reflected by the increased market of such products. In 1995 the latter, for Europe, reached a figure of $6 billion, with consumption for Germany $2.5 billion, France $1.6 billion and ltaly 600 million. In the US, where the use ofherbal products has never been as strong as in continental Europe, the increase in recent years has also been unprecedentedwith the market for all herb salesreaching a peak in 1998 approaching$700 million. Again, illustrating the same trend, the editor of Journal of Natural Products, 1999, writes that in response to the increasing prominence of herbal remedies, additional contributions describingscientific investigationsof a rigorous nature are welcomed. Undoubtedly, the plant kingdom still holds many speciesof plants containingsubstances of medicinalvalue which haveyet to be discovered; large numbers of plants are constantly being screenedfor their possiblepharmacological value (particularly for their anti-inflammatory, hypotensive, hypoglycaemic, amoebicidal, anti-fertility, cytotoxic, antibiotic and anti-Parkinsonismproperties). Pharmacognosistswith a multidisciplinary background are able to make valuable contributions to theserapidly developing fields of study.

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Thescopeond proctice of phormocognosy

Until relatively recently pharmacognosywas regarded, almost exclusively, as a subject in the pharmaceuticalcurriculum focused on those natural products employed in the allopathic system of medicine. Coincident with the increasing attractivenessof alternative (complementary) therapies and the tremendous range of herbal products now generally available to the public, regulatory requirements covering medicinal herbs are being introduced by many countries in order to control the quality ofthese products.Monographs are now available on a large number of such drugs giving descriptions,testsfor identity and purity and assaysof active constituents.These monographs are being compiled by a number of bodies (see below). In this respect recognition should be given to the pioneering production ofthe Brirlsh Herbal Pharmacopoeia, first produced in 1974with subsequenteditions, and a new one pending. Pharmacognosyis also important in those countries having their own systems of medicine in which plants are important components. Although pharmacognosyis principally concernedwith plant materials, there are a small number of animal products which are traditionally encompassedwithin the subject; these include such items as beeswax,gelatin, woolfat, vitamins, etc. Other natural products such as the antibiotics, hormones and others may or may not be involved, depending on the teaching practice of a particular institution. As is shown in Chapter 16 m4rine organisms,many of the animal kingdom, are receiving increasing attention. Materials having no pharmacological action which are of interest to pharmacognosistsare natural fibres, flavouring and suspendingagents,colourants,disintegrants,stabilizers and filtering and support media. Other areasthat have natural associations with the subject are poisonous and hallucinogenic plants, allergens,herbicides,insecticidesand yrolluscicides. Vegetabledrugs can be arrangetlfor study under the following headings.

t . Alphabetical. Either Latin or vernacular names may be used. This arrangement is employed fol dictionaries, pharmacopoeias, etc. Although suitable for quick referenceit gives no indication ofinterrelationshipsbetween drugs. 2. Taxonomic.On the basis ofan acceptedsystemofbotanical classification (Chapter 3), the drugs are arranged according to the plants from which they are obtained, in classes,orders, families, genera and species.It allows for a precise and ordered arrangement and accommodatesany drug without ambiguity. As the basic botanical knowledge of pharmacy studentsdecreasesover the years this system is becoming less popular for teaching purposes. Morphological. The drugs are divided into groups such as the following: leaves, flowers, fruits, seeds,herbs and entire organisms, woods, barks, rhizomes and roots (known as organized drugs), and dried latices, extracts, gums, resins, oils, fats and waxes (unorganized drugs). These groupings have some advantagesfor the practical study of crude drugs; the identification of powdered drugs (see Chapter 44) is often basedon micro-morphological characters. 4 . Pharmacological or Therapeutic. This classification involves the grouping of drugs according to the pharmacological action of their most important constituent or their therapeutic use. R. Pratt and H. W. Youngken Jr. were, in 1956, the first to use this approach for an English languagetextbook and now, with so many plant materials being screenedfor specific pharmacological activity, this type of listing is found increasingly in the literature. Its use is illustrated in Chapters28-32.However, it is important to appreciatethat the constituents of any one drug may fall into different pharmacological groups. Chemical or Biogenetic. The important constituents,e.g. alkaloids, glycosides, volatile oils, etc., or their biosynthetic pathways, form

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Until relatively recently pharmacognosywas regarded,almost exclusively, as a subjectin the pharmaceuticalcumiculumfocusedon those natural products employed in the allopathic system of medicine. Coincident with the increasingattractivenessof alternative(complementary)therapiesand the tremendousrange of herbal productsnow generally available to the public, regulatory requirementscovering medicinal herbs are being introducedby many countries in order to controlthe quality o1'theseproducts.Monographsarenow availablcon a largenurnberof suchdrugsgiving descriptions,testsfor identity and purity and assaysof active constituents.Thesemonographsare being compiled by a number of bodies(seebelow). In this respectrecognition shouldbe given to the pioneeringproductionof theBriti,shHerbal Phormacopoeia,first producedin 1974with subsequent editions,and a new one pending.Pharmacognosyis also importantin thosecountries having their own systemsof medicine in which plants are important components. Although pharmacognosyis principally concemedwith planrmaterials, there are a small number of animal productswhich are traditionally encompassedwithin the subject; these include such items as beeswax,gelatin,woolfat. vitamins,etc.Othernaturalproductssuchas the antibiotics, hormones and others may or may not be involved, dependingon the teaching practice of a particular institution.As is shown in Chapter l6 marine organisms,many of the animal kingdorn, are receiving increasingattention.Materials having no pharmacological actionwhich are of interestto pharmacognosists are natr.rral fibres, llavouring and suspendingagents.colourants.disintegrants,stabilizers ir:r.li" iiiilt;..,,r and filtering and supportmedia.Other areasthat have naturalassocia- ,t:tltiiut:ti : tions with the subjectare poisonousand haliucinogenicplants. aller- ititlu:itau itit.ti]illlrl: gens,herbicides,insecticidesand molluscicides. tit,lri1; Vegetabledrugscan be arrangedfor studyunderthe fbllowing head:tiiril rliiit ings. l . Alphabetical.Either Latin or vernacularnamesmay be used.This

arrangementis employed for dictionaries, pharmacopoeias,etc. Although suitablefbr quick referenceit gives no indicationof interrelationshipsbetweendrugs. Taronomic.On the basisof an acceptedsystemofbotanical classification (Chapter3), the drugs are arrangedaccordingto the plants from which they are obtained,in classes,orders,families, genera and species.It allows for a preciseand ordered arrangementand accommodatesany drug without ambiguity.As the basic botanical knowledgeof pharmacystudentsdecreases over the yearsthis system is becominglesspopuiarfor teachingpurposes. 3 . Morphological. The drugs are divided into groups such as the following: leaves.flowers, fruits, seeds,herbs and entire organisms. woods.barks,rhizomesand roots (known as organizeddrugs).and dried latices,extracts,gums, resins,oi1s,fats and waxes (unorganized drugs).Thesegroupingshave some advantagesfbr the practical study of crude drugs;the identitlcationof powdereddrr.rgs(see Chapterzlzl)is often basedon micro-morphologicalcharacters. 4 . PharmacoktgicaLor Therupeutic.This classificationinvolves the grouping of drugs accordingto the pharmacologicalaction of their most impoftant constituentor their therapeuticuse. R. Pratt and H. W YoungkenJr. were, in 1956.the first to use this approachfor an English languagetextbook and now. with so many plant materials being screenedfbr speciticpharmacologicalactivity.this type of listing is found increasinglyin the literature.Its use is illr-rstrated in Chapters28-32. However,it is importantto appreciatethat the constituentsof any one drug rnay fall into different pharmacological groups. Chemicalor Biogenetic.The importantconstituents,e.g. alkaloids. glycosides.volatile oils, etc., or their biosyntheticpathways.form

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INTRODUCTION As rnentioncdpreviously,a nllrnberof bodieshave implernented the basis of classificationof the drugs.This is a popular approach on ncdicinal herbs.The aint has is phytochernicallybiased. researchand publishednlonogrilphs when the teaching of pl.rarmacognosy Anbiguities alise when particulardrugs possess a numberof active been to sct standardsfix' cluality.etlicacy and sat'etyin order that the principlesbelongingto diflerent phiitochenricalgroups.as illustrat- many tl'aditionalherbs mcct legal requirernents.The follou'ing are of note: ed b1,liquorice.ginseng.r'aleliart.ctc. The sclremeis ernployedin drugs. Chaptels20 27 tbr anangin-tthe cstablishedphartnacopoeial 'I'hese 'nvet'c cleveloped German Commission E monographs. 'I'he *'ill fbllou'ing list of works. arrangedin the abcxe five gror.rps. fbr the Gelrnan FccleralHealth Authoritl' betwccn 1978-1994and andalsoproviclea usefullist oftcxtbooksandt'orks serveascxanrples involr,e32.1herbsused in Gelrnantladitionalmedicine.The monoof reftlence:tlroseno longer in print may be fbund in established graphs give sollrces.constitllentsand considerablcphannacological pharnracer,rticirl liblaries. They havc nou' beentranslatedinto English and clinicalintbrrnation. b1'theArnericiinBotanicalCtiuncilin 1999as tr single and pLrblishcd l. Alphobeticol a handbookfbr practiceon a sciBissetN G (cd). Wichtl N'l 1996Herbal cltr.rgs. u'ork. errtific basis.Meclphanr ScientificPublishcrs,StLtttgat'l r . l i t i s h H c r b a lM c d i c i n e B r a c l l e l ' PR ( e d ) 1 9 9 2B r i t i s hh e r b a lc o n t p c n d i u n B A s s o c i a t i o nB. o u r n e m o u t hU. K Press.London Vols I-II Blitish PhalmacopoeiaI 999. Pharrnaceutical B r i t i s hH c r b a lP h ; r r m a c o p o e1i a9 9 6 .B r i t i s hH e r b a lM e c l i c i n eA s s o c i a t i o t r . Exeter.UK Niartindale:the Extr-aPharmacopoeia.32nd ccln. | 999. PharntaccuticalPress. Londou l999 2-llNationalFornrr-rlary LinitedStatesPhamracopoeia Wren R Cl I988 Potter'sneu'c1'clopocidaol botanrcaldrugs and pfeparations. reuritten b1'WilliamsonE NI and Er'ansF J. C W Daniel Co. Safll'orr \\alden. UK Tl-re national pharmacopocias of niarry countries and the Europeau Pharmacopoeia; the relevant crude drug mono-qraphs of the latter are i r r c l u t l e tilr t t h e B l i t i r h P h r r t n l r c o p o e i r

2. Toxonomic . a r i s . 3r ' o l s . a s s o nP P a l i sR R . N I o l ' s eH 1 9 6 5 .1 9 6 7 .1 9 7I M a t i d r cr n d d i c a l eM ThornasH 1929 Handbuchdet'Phalmacie.Urban and Schu arzcnbcrg.Berlin. Band V 2 r'ols, Phannacogrtosr' . t he d n .B a i l l i i r e T i n d a l la n d T r e a s eG E , E r , a n sW C 1 9 7 2P h a r n a c o g n o s l l' O Casscll.London

3. Morphologicol f, .-1 !

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Mauclt'ich.Vienna.Vol I. Barks and Belger F Hanclbuchder Dt'ogenkunclc. f l o u ' e l s .1 9 . 1 9V: o l I I . L e a r e s .1 9 5 0 :V o l I I I . F f u i t sa n d u ' o o d s ,1 9 5 2 1V o l I V . Vol V. Roots. I 960r Vol Vl. Rcsinsetc and seeds.196.{:Vol Herbs. I 9-5,1: V I I . I n d e x .1 9 6 7 JacksonB P. Snou don D W I 990 Atlas o 1'nticrtrscopl'of nredicinalplants. culinar.vherbsand spices.BelhavenPrcss.l-ondon N'lortonJ F 1977Mixor medicinalplants:botany'.culturc and uses.Thomas. S p l i n g f i e l dI.L . U S A 5th edn. Churchill Livingstone. \\allis T E, I 967 Tertbook of Pharmacognosl'. l"ondon

Coopelativefbr Scier.rtific ESCOPmonographs. ESCOP(European Phytotherapy)is an alllliation of Europeanassociatioltswhich has ploducecl60 monographson helbal clrugs.pttblishedin loose-leaffbrm in six thscicr-rle s. harmonizingthe standaldsfbr thesedrugsthror-rghout thc Er.rlopeanUnion. Intbrrration is given on approved therapcutic uses, ancl unlike the ComrnissionE nono-graphs.plovidcs ref'elerrces. AHP monographs. The American Herbal Pharntacopoeiaplanned by the end of 2000.'nvithsorne30 to havepublishedI l- I 3 t.nonographs of American traditional more pending.Thele is naturally a selectiot-t herbs n'ith somc overlap l''ith thc European monographs.The as trncxamplethe St John'sWort monograph tleatmentis exhaustir,e: rvith ovcr publishedin HelbalGraml99T. No .l extendsto -i2 pa-ees andchemicalfbrmttlae. I50 ref'erences. colourphotographs WHO monographs. The World Health Organization published MerlicirutlPluttts irt 1999.It ttrtSeleL'tetl Volunre I of its MottogrtLplt.s contaiusstandardsfbr clualityof dlr.rgstogethelwith a thelapeuticsccin the tion: 3l plant species.the majcx'ityol u'hich at'ealso inclLrded Vcrlume2. containinga further29 rnonoabovelists.are consiclered. graphs.is cluelbr pLrblicationin 2000. is alsoproducUSPmonographs. The United StatesPharr-nacopocia all involving ing helbnl monographs.Elevcn har"ebeertpr"rblished. drugstteateclabove.and twelve more are expecteclduring 2000.

wishing to read ttliginnl resealchwill Current awareness. Str.rdents in this book and shouldlearnhow to find sin-rilar find rnar-ry ret'erences A, Libcrti t- E I 988 Natural ploduct nredicinc.G F Stickley. Del i\'lalclerosian As no onecanhopeto readall the scientificliteraonesfbl themselves. P h i l a d c l p h i aP. A . U S A specialior.rrnllsare clevotedto the publicationof ture that is pLrblished. PrattR, YoungkenH W. Jr 19-56Pharrlacognosy.2nd edn. Lippincott. P h i l a d e l p h i aP.A . U S A brief abstlacts from the oliginal papers. Such abstractsgive the Ross N4S F. Brain K R 1977An intfoductionto phytopharmacy.Pitnlall author's name.the sub.iectoi the rcscarch.the ref'elencencccssaryto N{edical.Tunbridge\\iells a blief outlineof the locatethe papelin the oliginaljoLrrnalanclusr-rally work it contains. Most phat'nracydepartntentlibraries contain 5. Chemicol phy'tochcrnistry'. medicinarlplants.Intefcept BnrnetonJ 1999Pharnracognos-v. Cltenitul Abstrrr't.r'and Biolo,gital Abstrccls,which in the appropriate Scicntific. N'ledicaland TechnicalPublications EVen st'. the :)':tetrllttr scctionscover all aleasof pharntaco-[nosy. Deu,ick P N{ I 997 \Iedicinal naturalproducts.a biosl'nthcticiipproach.John canilselfbe ofthe absuactsto covera broacllielclof intcrests searching W i l e y .C h i c h e s t e r lrtles and publicatictns as and such ClrcntittLl rnost tinre-consunrin-9. 6 t l r i n e g g e l E 1 9 9 9 P h a r m a k o g n o s i c P h y t o p h a r m a z i e . H i i n s eR l . S t i c h c rO . S t e CurrentCottentscan be usedto give a rrore rapidindicationof recent edn. Springer.Berlin (|ir C)t'ntrcnt1 bibRobbersJ E. SpeedicM K. Tl ler V E 1996 Pharmacognosyand pharmacoregularlyincludesa selected publications. Phltothenq1'Re.search b i o t e c h n o l o g lW ' . i l l i a m s& W i l k i n s .B a l t i m o r e lioglaphy relating to plant dlugs. Inlbrntatioti stot'ageanclretrieval is Tauchnitz.Leipz-iglttro editiort.s TschirchA Handbuchder Pl.tilrnako-unosic. occupiedby sucnow itself a scicnce.anc'la glanceat the shelf:space t oltnttt'strltto l 9-l-i1 tutd nunterou.s is sutlicierrtto indicatethatbetbre ceedingyearsof CftcrnlL:trlAb.strtLcts long. if not already'.manual searchesof the litcrature u'ill become With the increase in interest in rnedicinal plants world-wide there are Inevitablyit will bc necessalyto rely on inrpossiblylon-eprocedures. n o \ \ ' n r a n y p u b l i c a t i o n s c o \ ' e f i n g r c g i o n a l a l e a so f t h e g l o b e . T r e a t m e n t databasesfbr litelature scanniug.PltunnucogttostTitlesis a cornputcr of the plants in thcse wolks rna)' be on an1, of the abovc lines. Some researchpublicationsup to 1974 of phytochenrical abstl'act co\rerage cxamples are given fbllowing the Introduction to Paft VII.

4. Phormqcologicol or Theropeutic

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T H ES C O P EA N D P R A C T I COEF P H A R M A C O G N O S Y tl0 vols) producedundel the directionof Prof-essol N. Farnsr','or.th.as anv book can). Symposiall,hich cor,ervaLiolrsaspectsof pharnraI i n i ' " ' e r s i t y o f I l l i n o i s . S u b s e q u c n t l y .F a r n s w o r t h i n t r . o d u c e c lcognosyarc tiequently held in variouspartsofthe world and scientists \APRALERT. a NaturalProcluctDarabasewhich is rrainly. br.rtnor can easilvbecomeacquninted u'ith othershar,inglike interests. Often cntirely.post-ltl75and is vieu.'ed bv rrany as a logicaland inclispens- the infbn-r-ral discussionswhich invariably ariseat sr.rch meetingscanbe able collectiono1'pharmacognostic information.The NAPRALERT an extremelyuselulnteansof disseminating infbrmation.ln addition, database is availableon a schedulcd-fee basisft) scientists.industrial the lecturesplesentedat such nteetingsare often sr.rbsequentlv pubfirns. -qovemment agenciesand acadenticinstitutions. Among othcr lished in book fbrm. Modern comntunicationsystemsmake u'orlduselirl databaseshaving a reler,'ance to pharntaco-tnosy and published '"videcontactbetweenresealchers much sintpler. on the Web arc MEDLINE. conrpiledby the US NarionalLibrarl,of Now al'ailableto Westernscientists interestcd in orientalrnedicineis Medicineand EMBASE. producedby ExccrptitMedica. the qualtelly joumal Abstnrc:t.s o.l'CltineseMeditirrc, publishedby the S o m e j o u l r r a l s f o r e r a r - n p l e .P l r t r t t u M e d i t ; u . . l o u r n o l o f ' ChineseUniversityol HorrgKong. This givesabstractsin Englishof Ltltrtophunrrut'ologv Plntocltetnisn'y nnd Jountttl of' NtttunLl significantChineseresearch papersfrorn morethanonehundredscienPt'o(luLt.\-periodicallycolttuin reviL-\\s on \oll(. i.rs|ectof medicinal titic journalsnot feadilyar,ailable outsideChina. plants.Otlrel pcliodical publicationsappearingin bor-rndfbr-m are Usefirl dictionaliesto be lbund in most Unir.ersitylibrtrriesinclude devoteclto reviewson certainaspectsof plar-rtconstituclttsand are use- DicticrttLryof Organic Contpountlsconsisting of 7 r'olurnesand 10 ful fbr updating;ofien the rcr,ielvscor,eronly the adrrncesin I parti- sLrpplements (to 1992).Dittiotmry ol Alkaloitl.s12 r,olunies)(1989). culal tlc-lclsincethe pler,iousr,olunte.Examplesare NtfturtLl Product Dictionar-t o.f Tbrpertritls( 19911and Dit:tionurt' of Natuml pnxlucts Reports(six issuespcl vear) .andAlkaloitl.y(AcadenricPrcss).Books (1994) all publisheclbv Chapmanand Hall and also phttot'hemictrl thatarenot partofa seliesbut. like the above,rrultiauthorand dealing Dictiornrt': A Hundbookol Bioactit'eCompountls.frcmplutfi.t ( 1993), \\'ithccrtainspeciaiized areas(c.g.alkaloids.flavonoids.isoprenoids). publishedby Taylol and Francis.Sorneof thesemore expensivevolcorrtinuallyappearand generallvgive up-to-dateinfolmation (in so flr Lrmesare availableon CD-ROM.

z

IE BOTANICAT NOMENCTATURE Beforethe time of Linnaeus( 1707 1778)many plantswere known by a double Latin title; however,it is to this great Swedishbiologist that we owe the generaladoptionof the presentbinon-rialsystem.in which the flrst narrc dcnotcs the genus, while the second(specific) name denotesthe species.All specificnamesmay be written with small initial letters although tirmerly capitals were used where specieswere named after persons. Thus the species of Cinchona named after CharlesLedger,who broughtits seedsliorn Brazil in 1865.is now writtcn Clrrry'rono Ietlgerionaratherthan CinchonuLedgerianu. The specificname is usually chosento indicatesome striking characteristicof the plant fbr example.the hemlock with the spottedstem is namedConiunrntaculuturtt(.mutulutus.-d. -1u11. spotted).Sometimes the reasonfbr the name is not as obvious as in the examplejust mentioned.but onceit is discoveredit will serveas a reminderofa characteristicof the plant-fbr example,Stl c/rnos potatorum (potator,-oris, a drinker) bearsa namewhich is only intelligiblewhen it is known that the seedsof this speciesareusedin India lbr clearingwater. The modernrules governingthe terrninologyof plant taxonomy are laid down in the Internroioncl Codeof BotanicalNomenclature. Unlike the names of chernical substances,which are subject to changeswhich confolm to evolving systemsof nomenclature. systematic plant namesare strictly controlledby ruleswhich give precedence to that name used by the botanist who first described the species. Nevertheless, this seeminglystraightfbrwardapproachcan give rise to variousquilks in spelling.The following are threeexamplesinvolving rnedicinal plants Rauvolfia vis ir vis RauwoLfia;the former name was given to this Apocynaceousgenusby Plumier in 1703,honouringthe botanistLeonard Rauwolf. This spelling ovelsight causednuch contentionover the yearscentringon whetherPlumier's obvious intention shouldbe adoptedin the nameRaLntollia.Both spellingsarecommonly fbund but the rules dictate that Rauvolfia has priority. In anotherexample the downy thornapplemay be encounteredas eilher Datura innoria or Datttra irnxia. The fbrmer. as Datura irutoxia Miller. was used in 1768(Gurd.Dlo.. edn.8, Dutttru no. 5) and this spellingwas invariably employedfor some200 years:howeverin Miller's original description. the plant was characterizedas: 'Datura (lnoxitt) pericarpiisspinosis inoxiis ovatis propendentibusfoliis cordatis pubescentibus'(W. E. Saflbrd,J. \Wrsh.Acud. Sci.. 1921,11,173) and taxonomistsnow considerD. irro-rlaMiller to havepriolity. Both versionsarestill commonly encountered. A third exarnpleconcernsthe genusofthe cocaplantwhich may appearas Er1,1fup.ry1u^, or in older literature as Erythrox:-lon.

Plont nomencloture ondtoxonomy

3. i

r

SUBDIVISIONS OF THEPHYTA The branchesofthe genealogicaltreediffer so much in sizethat it is not easyto decidewhich are of equalsystematicimportance,and what one biologist may consideras a lamily anothermay regardas a subfamily. Similarly. the speciesof one botanistmay be the subspeciesor variety of another.The main hierarchicalsubdivisionsof a division. aranged according to Engler's scheme.may be illustrated by the lollowing exampleshowingthe systematicpositionof peppermint.

h !: I

l

BOTANICAT NOMENCLATURE8 SUBDIVISIONSOF THE PHYLA

8

BOTANICAT SYSTEMS OF CTASSIFICATION9 TAXONOMICCHARACTERS9 PTANTTAXONOMY CHEMICAT

ro

Division Class Subclass Order Suborder Family Subfamily Tribe

Anglospermae Dicotyledoneae Sympetalae Tubiflorae Velbenineae Labiatae (Lamiaceae) Stachydoideae Satureieae

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PLANTNOMENCLATURE AND TAXONOMY Genus Species Varieties

Mentha MenthapiperitaLinnaeus(Peppermint) Menthupiperita var.olrtcinalis Sole (White Peppermint) Menthupiperita var.vul,qari,s Sole(Black Peppermint)

It will be notedthat in pharn-racopoeias and in researchpublications botanicalnamesarefbllowed by the nar-nes of personsor their accepted (e.g.Linnaeusand Sole in the caseofpeppermintgiren abbreviations above).Theserefer to the botanistwho first describedthc speciesor variety.Studentsneednot attemptto memorizethesenames.and in the fbllowing pagesthey areusuallyomittedexceptin caseswheredif-fbrent botanicalnameshave at differenttimes beenappliedto the sameplant and thereis possibilityof confusion.The sourceof cloves,fbl example. is now usuallygiven asS,t';.r'glum aromaticltm(L.) Men. et Pen'y:prior to 1980 the B.P. used the name Eugetict <:ortophlllus (Spreng.) Sprague;other synonymswhich may be found in the older literatureale E. caryopltyllatzz Thunb. andE. urontuticc(L.) Baill. Worldwide,not all authorsof researchpapersusethe currentlyacceptednauteso cautionis necessaryand botanicalsollrcesshor-rld be checked.

BOTANICAT SYSTEMS OF CTASSIFICATION Before the widespreadacceptanceof the principle of evolution. biologists,being convincedof the lixity of speciesand lacking much of the infbrmationavailabletoday.confinedthemselvesto more or lessartificial methodsof classification,their systemsbeing fiequently basedon one or a f'ewcharactersinsteadof upon the organismas a whole. These earlier systemsare now mainly of historic interest.but certainof their f'eatures-for example.the large division of seed plants into monocotyledonsand dicotyledonsas used by John Ray (1628-1705) survive today. Linnaeus' Sper:lesPluttnrunt of 1753 is the starting point fbr the rnodeln nomenclatureof plants,althoughhis actual system of classificationis er.rtirelyartificial and of little signilicancetoday. The Prodrontu.r. startedby A. P de Candolle(1778-1841)and completedLrnderthe editorshipof his sonAlphonse( 1806-93).was a massive work of l7 volumes which prof'essedto be an accountof every flowering plant then known. The system of classificationenrployed was a modification and extension of that introduced earlier bv De Jussieu( I 748- I 836) and further demonstratedthe inadequacies of the Linnaean system which were then becorningapparent.Bentham and Hooker's GeneraPlattarum (1862-1883)was pattelnedon the de Candolles'work, eachgenr.rs bein-uredescribedfrom herbariumspecimensand not consistingof a restatementof earliel literature.Although largely artificial, it was convenientto retain this systernas a basisfor collectionssuchas the herbariaof Kew and the British Museurn. Durin-9the last 100 years a considerablenurnber of phylogenetic systemsof classificationhave beenpropounded:thesesystemsan'ange taxa (any groups used for classificationsuch as orders,families, genera, etc.) to indicate the possiblerelationshipof one taxon to another. Such systemsare clearly susceptibleto changewith increasingknowledge, and no final system acceptableto all taxonomistsis in sightl indeed,r-nanytaxonomistsare now more concernedwith the production of sound.workable pheneticsystems.A close examinationof the phylogeneticsystemsreveals that certain taxa lbrm precise group\. othershavelesswell-definedboundariesand other groupsare difllcult to accommodatephylogenetically.The work of Engler ( 182141930) in associationwith other German systematistsis still adheredto in this connection.Engler's scheme of classificationlargely embodied the fundamentalconceptsof Eichler ( 1839-87)and was exemplifiedin the 20-volume work (1887-891 Die natiirlichen Pflun:.enfimilien. by Engler and Prantl.Subsequentto this, thereappcaredmany editionsof Engler's Syllabusder P.flartsnftunilien.the eleventhby Engler and

Diels in 1936.The last versionof the S.t'11aDus. producedby Melchoir as two volumes,was publishedin 196:1;lhe plant lamiliesin Chapter Five of this textbook are anangedin this order.The imntediatepopularity of E,ngier'sworks was due to their applicabilityto plants of the whole world: they aflbrdeda meansof identifying all known genera.A modern replacementfbr this classical wolk is The Funilie.s uncl Generao.fVasculrLr Plants (.K. Kubitzki et a/. (eds)).So far three volumeshavebeenpublished.the lastin 1998. Obviously. large n'orks such as the erboveare not easily cornpiled and many taxonomistshar,'eproducedphylogeneticschcmesdirected at various levels of classificationwithout the completesystematicsof the Engler series.Of the schemes,those of Cronquist(1981) and Takhtajan (1959.)are generally similar whereasthat of Hutchinson (1992) differs in that the dicotyledonsare divided inro two large gfoups-those characterist.ically and primitively woody (Lignosae) and those chalactelisticallyand primitively herbaceous(Herbaceae). Theseschemesincorpolatedataoften not acccssibleto the earliertaxonomists:thus Cronquist,while emphasizin-e classicalrnorphoiogical charactersand following the strobilartheory ofAngiosperm evolution also takes account of micromorphological data (e.g. ernbryology and pollen structure),chemical data (e.g. secondarymetabolitesand serology)and the fbssil record.Dahl-eren's proposals(1983).which involve a taxonomic method telnreclcladistics.demorrstratethe distribLrtionof charactersand his cladogramsof the orders of An-tiospermscan be convenientlyused fbr illustratingthe occunence of secondarymetabolitesthroughoutthe hi-uherplants.

TAXONOMICGHARACTERS All plantspossesshundredsol'chalactersof a morphological.histological, embryological,selological.chenricaland geneticnaturewhich arc potentially availablefor building up a classificationof the plant kingdom. ln the artificial schemesthe charactersemployedwere those that experiencehad showncould be usedto producesuitablegroupsor taxa.The eventualscheme.into which could be insertednew plants as they were discoveredol in which any plant cor"rldeasily be traced. resembleda catalogLlewith a 'telephonedirectot'y' arangentent of plants in which the groupsof individualslisted togetherdid not necessarily haveany phylogeneticrelationship.but rnerelypossessed certain common f-eatures. Phylogeneticclassiflcations.wl-richendeavourto indicate the relationship of one taxon to another.imply the use of charactersthat are capableof showing suchrelationships.Becausesornegroupsof plants are firore primitive than othels on the evolLltionaryscale.certaincharacters will also be primitive. whereas other characterswill have evolvedfrom thenr.Thus, woody plantsaregenerallyregardedas more primitive than herbaceousones and flowers with f-ew parts more advanccdthan thosewith rrranyparts. The difliculties facing the ttronornist lre apprecieble.The appearance of a particular characterin celtain plants does nol necessarily imply a relationshipbetweenthcseplants.becauseat somc tinte in the past. under favourableconditions.whole groups ol unrelatedplanls could have undergonethis change(e.g. the developmentof fuscd corollas from polypetalousflowers; this is known a contergence). Altcrnatively.relatedplantsmay.in somc point of time. havestartcdto diverge in their characteristicsso that the modern phenotypesappear very dissimilar this is divergen<'e. Parallelism ret-ersto tl-resintilar evolution of charactersin related plants or related groups of plants. Having decidedwhich charactersare of value and how many can be used. the taxonomist then has to considel whether each character shouldbe eivenequalvalueor whethera 'wei-ghtin-q'system shouldbe employed. Compr.rtershave an obvious role in dealing with large

r

INTRODUCTION nLlmbelsof charactersappliedto thousandsof plants.not only tl'on'rthc aspectol stolagcand retrievalof infbrnration.but alsofbt'thc sciencc lole in of ttunteric'ulto.totlotit\'.which will probably'plal' an increasin-rr For a fuller discr-rssion of this subject thc dcveloprnentof systematics. the readeris referredto Hevwood'sPIurttTtt.rctrtorrn.

PTANTTAXONOMY CHEMICAT rnLlchattentionand has.attermany This subjecthasrecentll,attlactccl yeals,broughtthc plant cherristback to systematicbotany.The concept that plantscan be classifiedon the basisof their chemicalconstitucntsis not ne\\':lbl examplc.earlyu'orkersclassifiedthealgaeinto grccn.brou'nand fed fbrms.but it is only duringthe last;10yealsthat ha\reled to thc of isolationand characterization moderntechniclues of plant samples.Compared chemical scleeningof rnanl' thor-rsands with molphological chalacters.chemical constitucntsale often more preciselydefinablcanclcan be of more fundamentalsigniticancefbr classificationpurposes.Plant trxononrists.in generrtl.hold the view bc considareyct anothert1'peof charactct'to thntchcmicalcharactels thoscnscdtraditionally. but it cloesnot necessarill'fbleredalon-gside lou'that taxa constmctedon a purell chemicalbasis.if such wele possibleon the clataat pl'esentavailable.woulclnecessalilycoincicle u'ith thosearrivedat by classicalmethods. The characters cmployedin chemicaltaxonomyneedto be thoseof distributionin the plant kingdom.The presenceof sr.rch internrediale ubicpritouscompoundsas the essentialamino tcids and comfiton sugarsis oflittle diagnosticvalueand.at the othcrextreme.the occurof the large in the singlespeciesConrrlrttntLt'ulatun renceof ccrrriine Chalacters is alsoof little taxonomicsigniticance. farnilyUmbellif'elae n-roststudied in this connectionare therelbrc seconclaryrnetabolites (alkaloids.isoprenoids.flavorroids.characteristicglvcosides.etc.). pharmaceutical interest. manyof which areof established rretabolitesmay be subjecttcr Horvever,asdiscussedlater.sccondary' valiationin the living plant.dependingon environmental considerable and ontogeneticfictors. and more stablechemical characteristicsare of'fbled by those closely rssociatcd r.r'ithDNA composition of the species.Increasingly.it is becoming possibleto use DNA hyblidization. serolilxonomyand antino acid sequencingtechniquesfor taxoapplication(Y Mino rurrr1., nonic purposcs.One pharmaco-gnostical of the com1993.33.601) hasbccnthe deterrninatiott Pltrtoclternisn-r plesplctc amino acid sequenccof one of the iron sulphurf'en'edoxins suppollthe view that ent in .,irrieticsof Duturo stromoniunt.The lesr.rlts lbrms are valietiesof a singlespeciesand that the the r"'hiteand pr"u'ple tree datlrras(e.g.D. urboreal ale best regardedas constitutingone section of the gcnus Dcttura and not a separategents (ltlern.. ibitl.. andD..fitstu\991.37..129:1995.'13,I 186):work with D. querci.foliu r.,.rrr also sllggeststhat the amino acid sequencedependsnot on the applied but on the section.Similar studieswele subsequently species. (Y. Mino and K. YasudaPhytoc'lrctnisrrt' 1998,49, 163l). to P/rr'.ia1l.r A secondexample(H. Mizukamiet aL..Biril.Pharnt.BulL..1993.16. 3881shor.vsthat restrictionfi'agmentlcngth polymorphisrns(RFLPs) can be r.rsedas a sirnple and elficient method for distinguishing betweenDuboi.sictleiclthardtii,D. mtoporoide.sand the hybrid of the tu,o specics(RFLPs are producedby digestionof DNA with restriction species and vary in numbcrand sizeaccordingto -9enus. endonucleases

etc.) Ho$'e\,el'. the sanre,rrouptbrlnd (ihid.. 1993.16. 6ll) that the tcchniqucdiclnot clistinguish betweerr the variousgeoglaphical strains of tlre traditiona]Chrnesedrug Gleltniulittoruli.s(Unrbellif'erae) containirr-sdilferent furanocoumarincompositions but did so with B uplettrtrnt.fhlcutttrrt(iltid.. p. 279). The diff-erentiatior.r bctu'ccr-rsamplesof Parttn ginsertg (Oriental (Ar.nericarr ginscn-e). ginsen-u) P. Erirtqrte.fttliurr and adultelants can be clilficLrltbv conventionallncansand F. Ngan et ol. (Plrltochenti.str-t and difl'elentiation. 1999.50. 787) havereportedon the authentication one tl'ornanother.ol si.r speciesof Partu-rand also their adulterants. using RFLPs invol"'ingthe DNA scclucnccs in a sclcctcdlibosomal rcglon. DNA analysishasbeenuse'dto disRandomarnplifiedpoly'rnorphic of Melissao./.ficiuuli.s corlnron tin-suish betweenthe varioussubspecies market.Prcviously.sampleshavc bccn classion tl'rephalmaceutical fied accordingto the distributionpattcrnof compoundsprcscntin the lemonbalnroil (H.-T.Wolf r:ta1..PlantoMetlicu 1999.65.83). studiesof Acrirrrrgr.rmexudateshavedemonstrated Serotaxonorric testsin thechemota-ronomic anall,scs the r,alueof suchimrnunological (T. C. Balihvin at tl.. of these economically impoilant proc'lr.rcts Phvochemi.strt1990.50. 599). (in German) is that of A standardwork on chemotarxonomy Hegnauer(see.Further Reading):it contprisesI I volumespLrblished over neally :10years.A fbur-r'olumework in English is that ol Darnle-v it does not appearto have Gibbs. publishedin 1974;r-rnfbrtr.rnatell'. beenupdatecl. the P G. Waterman(Pht'rotlteni.itnl998. 49. 1175)hasdiscussed indicatir-rg tl-refactorswhich still currentstatusof chemosystematics. contributcto thc peripherallole of the subjectin taxonoury.

Further reoding Generql fqxonomy of cllssitlcation of flou'eringplants. A I 9EI An integfated s)'stern Cronquist Press. NewYork.USA Columbia L,niversrt-v E 195.1. 196.1. Sl,llabus der BnglelA.\{elchoirH. Werclelnrann r Bomtraeger, Berlin.Germanl'. 2 rols Pflanzentar.r.rilien. Gcbriide Arnolcl.Lontlon.UK Hevu'ood V H 1987Planttaxonoml'. 3rclecln.Edu'ard Longman. Harlo*.Esser.UK Holrncs S 1986Outlineof plantclassification. Alnold.London.UK 3rdecln.Edrvard Jeffre-v C 1989Biologicalnomcnclature. anclHall.London. UK MinelliA 1993. Biolo-lrical s)stematics. Chaprnan (ed of planttarononrv to thcprinciples SivalqrnV V 1991Introduction Llrir.ersitv Press. Carnblidge. UK RobsonN K P).2ndedn.Carnbridgc 2nclecln.Carnbticlge StaccC A I 991Planttrxonomyandbiosl'stcrratics. Unrversitl' Prcss.Camblidge, UK Chemicol tqxonomy of lloweringphnts.N4cGill GibbsR Darnley197;1 ChemotaKrnomy .1r'ols N'lontreal. Clanacla. UnilersityPress. Academic Press. Harborne J B, TurnerB L i 98.1.Plantchemosystelnatics. London. UK Recentadvanccs in thcchcmosrstcuratics of Harborne J B. WilliarnsC A 199,1 Phl"tocherrristry 37(1t: 3 I 8 theN4onocotyledons. Prcss. andscrotaxonotry. Acadcrnic Harvkes J G (cd) 1968Chemotaxononrv London. UK Bitkhliuscr. Basle. dcrPt'lanzcn. Hcgnaucr R 1962-l992Chemotaronomie VolsI-X Su'itzerhnd. M H I99;1.1996Chemotaxonouiic dct Pflanzen. He-enauer R. Hcgnauel parts1 ancl2 Birkhrir.rser. Basle.Switzerlancl. XIa andXIb. Legr.rminosae

3t:'S*

PART

2

The plqnt qnd qnimol kingdoms qs sourcesof drugs

d',-*

iJ A

"r* t

"t

E

Biologicol ond geogrophicol sources of drugs

GEOGRAPHICAT SOURCES 1 4

Culrenl estimatesof the numbelof specieso1'llowelingplantsran-ue between200 000 and250 000 in son"re 300 familiesand l0 500 genera. Despitea rapidlyexpandingIitelatureon phytochemisrry. only a small percentageof the total specieshas been examined chcrniczrlly.and thereis a lalge field fbl firtureresearch. However, rlrandid not requirethe modernrnethodsof invcstigation to collect fbr hirnselfa materiamedicaof plantswhich he often usedin conjunction with magictrl and other ritual plactices.SLrchfolk medicines natulallv varied accordingto the plants availablein a particular climatic area and can be slr.rdiedtoday in those rnore or less undisturbedplimitive socictieswhich still exist. It is interestingto reflect that suchcollectionsof herbalntedicinescompiledovel centuriesby trial and error,and plesurrablyusing the patientas thc experirnental animal throughout,ntllst sr.rrelycontain solne material worthy of furthel in',estigation and shouldnot be too readilydiscarded. Is it not also possiblethat thosematerialsproducin-tadlersercactions.one of the principal problernsin the introductionof new drugs, ntight also have beeneliminatedby sucha systemof developrrent'l In the currentsearchtbr new drugshaving.tor exanrple.antitumout or hypotcnsiveactivitythe plantsinvolved,unlike many of the more tladitionalmedicaments, very oftenshowno imrnediateindicationsof pharmacologicalactivity.Investigatorsarethus laced with the problem of making a systerratic investigationiront among the thctusandsof speciesstill unex:urined.One obvious line of approachis to startwith lblk medicinesof the world on the assumptionthat theserraterialshave alreadybeensubjected to somehumanscrcening. howcvercrude.and found acceptableto thoseculturesthat usethem. For many areasof the world. the plants used in folklore have beenadequatelyrecordedlbut for other regions-tbr example.in SouthArnerica.with its vastt-loraof potentially useful plants the art of lblk medicinein aburiginal societiesis in lapid declineowing to a chan-eing modeof lif'eof rhepeople. Ethnobotanistsare cun'ently fighting a battle againsttime to record suchintbrmation before.within a generationor so. it is lost and with it a possible short cut to some rnedicinally useful plant. However. the urgencyis well-recognizedand as describedin Chapter8. the biological and geographicalsourcesof many traditional plant relnediesare being actively researchedand documented.Much recordedintbrmation still requiressifting.An exampleof the employmentof a combination of literaturesurveysand data fiom other sourcesin the searchfbr new drugsis the US NationalCarrcerInstitute'sscreeningof thousands of plant extractsfor antineoplasticand cytotoxic activity. This undertaking involvesthe team-wolk of botanists.phytochenrists. pharrracologists and clinicians. In the absence of such sophisticated collaborat.iorr, rnuch useful researchby one discipline fails to be fbllowed throughto a r-rtilitarian conclusion. An inspectionofthe plant or plant-deriveddrugsinclLrdedin western phalmacopoeiasshowsthem to be composedof thosewhich hat'e sr.rrvived tiom Gleek and Roman eras.inclLrdrngsome spices.thosemore chalacteristicof our own flora (e.g. cligitalis)and introducedat a later date. other pharrlacologicallyactiie drugs (e.g. cinchona-quirrine -and ipecacuanha) addedas a resultof increasedtraveland colonial expansion,drugs (e.g.rauwollia reselpine)long usedin othel systems of medicinebut of rnore recenl introductioninto Westernnredicine. and finally. recently discoveredplant constituentsof therapeutic value (e.9. vinblastineand vincristine trom CathtLrunthu.s roseus)and those semisyntheticproducts(e.g. steloidalhormones)which depend on plant sourcesfor startin-ematerial. An examinationof the list of drugs derivedfrom natural sources.as included in any pharn-racopoeia, soon reveals that the majority are derivedfrom the Spermatophyta-the dominantseedbearingplantsof the land. Within the Spcrmatopl.ryta the numbel of speciesarrd the number of usefirl medicinal plants is divided unevenly between the

fE

T H EP T A N TA N D A N I M A LK I N G D O M SA S S O U R C E O S F DRUGS phyla Gyrnnospermae. which yields some usefuloils. resinsand the alkaloid ephedrine. and rhe Angiospermae.which is divided into Monocotyledons andDicotyledons(bothof theseproviciemany useful drugs but especiallythe Dicotyledons).Of the other divisions of the plant kingdom. the fun-siprovide a number of useful drugs,especially antibiotics.and are importantin pharmacyin a numberof other wavs. The algae are a sourceof a limited number of dr.ugs(e.g. agar and alginic acid), but the flll pharrracologicalimportanceof this large groupof aqr.ratic plantshasstill to be realized.At the nroment.lichens and mossescontribute littlc to nredicine and the Pteridophytesare pharmaceuticallybest-knownfbi' the taenicidalf'ernsand lycopodiurn. Land animalsprovide suchtraditionalpharmaceuticalmatedalsasgelatin. wool tat. beeswaxand cochineal,and are a sourceofhormones. vitaminsand scra.Among the rrany intportantphar.maceutical aspects of the Bacteriophytaare the production of antibiotics. their use in etl'ectingvarious chemical conversionsof added substratesand their employmentin -eeneticengineeringas. for example,in the pr.oduction of human insr.rlinand the transfilrmationof hi-eherplant cells by incorporationof part of thc DNA of a bacter-ial plastidinto the plant genorne.

Andes of South America, were most successfully introduced to Indonesia(particularly Java) and India. These becamerhe principal geographicalsourcesfor the bark and its alkaloids. Java f'ell to the Japanese in 1942and,as India normally consumesmost of its own quinine production,there was a great shortageof this vital alkaloid at a time when large armies were lighting in malarial areas.Expeditions searchedthe original SouthAmerican habitatsand wild treessupplied usefulbut inadequatequantities.Fortunately.very successfulsynthetic anti-malarialswere discoveredat this time and put into large-scaleproduction. However, 50 years on the malarial parasitehas, in certain areas.becomeextremelyresistantto thesedrugsand the useof quinine has again been invoked.There is also a steadydemandfor other cinchona alkaloids. and Zaire and other Aliican states,together with Guatemala.producemost of the world's bark. China has now emergedas a major producerof a number of quality medicinal plant products including coumarin, menthol and oils of eucalyptus.peppermint.spearmint,sassafrasand valerian in addition to its establishedlistings.Other changesevident from market reports include the acceptanceby the Europeanmarket of expensivehighquality Australian coriander.Guatemalaas the principal producerof cardamonsandPodophyllumemodifrom China. GEOGRAPHICAT SOURCES Many countriesproducelimited quantitiesof medicinal plants and spicesfbr domesticconsumptionand theseare not listed on the interTwo tactorswhich determinethe commercialgeographicalsourcesof a nationalmarket. dru-eare the suitabilityof the plant to a particularenvironmentand the Governmentalpolicies on the export of raw materialsmay af-tect economicfactorsassociatedwith the productionof a drug in a particu- geographicalsources.as when the Indian government limited the lar area. export of crr"rderauwolfia root, selling only the more highly priced Many plantsgrow equallywell in nunterouslocalitieshavingsimilar extract. Supplies of the root were subsequentlyobtained from climates;and aseconomicconditionschangein one area,so the collec- Thailand. Changes in the legal cultivation of medicinal opium in tion ol cultivationof a drlg plantmay move in accordance. Developing Turkey must eventr-rallyaffect the geographicalsource of the drug: countriesmay also stafi the cultivationofrledicinal plants.and in this thus,the opium poppy has beencultivatedin Tasmaniaon a largescale respectSouthAmerica. India and S.E. Asian countrieshave beenpar- in recentyearsbut political f'actorsare militating againstthe continuaticularly active. Cinnamon, traditionally produced in Sri Lanka, has tion ofthis source.Political considerationshave also led to changesin beenintroducedto the Seychellesas a commercialcrop. with so much the startingmaterialslbr corticosteroids.Up to 1970the sole intermesuccess that the planthas now becomea weed!Cinnamonalsogrows diate sourcematerialfbr the manufactureof contraceptivesteroidswas well in West Africa bLrtis not commercially utilized ther"e.It must be diosgeninderived from the Mexican yam. Then the Mexican governremembered.however.that a plant may _qrowwell in different situa- ment nationalizeddiosgeninproductionand increasedprices to above tions but fail to producethe sameconstituents(e.g.cinchonasgrowing thosefor total synthesis;as a result,in subsequentyearsmanufacturers at altitudeand in the plains).The cultivation of Duturtt stnmtoniumin have turned to other startingmaterialssuch as hecogenin(trom sisal), En-elandas a half-hardy annual has long become uneconomic and solasodine(.fromSoLanumspp.), microbiologicalproductsfrom chomuch material is now intported fionr easternEurope. Similarly. the lesterol,stigmasterol,sitosteroland squalene,and petroleumproducts. USA. which at one time utilizeddomesticsuppliesof the solanaceous The more recent emergenceof China as a producer of high-quality, drugs and digitalis. now obtains such raw materials fiom fbrmer low-priced diosgeninhas againchangedthe situation. Yugoslavia.Bulgaria and Hungary as well as fiom South America. National and international restrictions on the collection of wild During and after World War II, agar production was initiated around plants have also afTectedthe sourcesof some drugs; the Washington New Zealand.Australiaand SouthAflica. bLrtwith the re-emergence of Convention on InternationalTrade in EndangeredSpecies(CITES) the Japaneseindustrythesesourcesbecamelessimportant.Scarcityof placed all speciesof Aloe exceptA. rera on the pr.otectedlist without acaciafrom the Sudanprornptedthe exploitationof the Nigerian gum. warning;this causedproblemsin the marketingof aloesproducedfiom Pharmacopoeial oncecameexclusivelyfrom Jamaica:a decline the r.rsualspecies.Other medicinal plants which have recently been _uinger in productionin Jarnaicnarrda vastimprovementin the quality of some given CITES listing include Htdrasti.scanadensis(1997) and prLtnus Afiican -eingershas led to the use of these and Chineseginger on a africana ( 1998). large scale.Olllcial storax wzls once derived only from the Turkish A numberof the abovetactorshavegiven addedimpetusto research Lfuuidambarorienruli.s(e.-s.Us'Pfiom 185I ) but limited suppliesled on the applicationof cloning techniquesin cultivationand to the artifito the adrnissioninto many phalmacopoeiasof American storax.l. cial cultureof plant cells and organs(seeChapter12). stvrociflua (e.g. USP from l936). Similarly. a lasting shortageof Rio (Brazilian)ipecacuanha root hrs led to the widespreaduse of the Furtherreoding Artuso A I 997 Drugs of naturalorigin: economicand policy aspectsof discovCartagena.Nicaraguaand Panamavarieties,which areobtainablefiom ery. developmentand marketing.PharmaceuticalProductsPress. a mr.rchwidel areaof Southand CentralArnerica.With the exceptionof Binghampton.NY India. attemptsto cr.rltivatethe drug in other areas(e.g. Malaya) met J o u r n a l o f E t h n o p h a r m a c o l o g y , s p e c i a l i s s u e l 9 9 6 5 l ( l 3).Intellectualproperty with onl1,lirlited success.In contrast.the cinchonas,indigenousto the rights.naturally-derived bioactivecompoundsand resourceconser\xtiun

.;:--lr!F

A toxonomic opprooch to the studyof medicinql plonts ondonimoL

derived drugs

For classificationpurposesthe plant and anirnal kingdorns are each divided into a numberof phyla and in additionto the phyla. the classification includesgroupingsofgradually dirninishingsize,namelydivisions.classes,orders.subordersand families.According to the systent used,thesegroupingsmay, or may not. indicatephylogeneticrelationships. In this chapterthe principalplant lamilies of pharmaceuticalinterest are ananged accordingto the botanicalschene of Engler (q.v.).The chapter is divided into six parts: Thallophytes;Bryophytes and Pteridophytesl Gymnosperms: Angiosperrns (Dicotyledons): Angiosperms(Monocotyledons);The Animal Kingdom. At the beginning ofeach largetaxon ofplants a table is given to clarify the orders and tamilies involved.According to the botanicalsystemof classification considered,schemesvarry!as do the numbels of families. genera and speciescited within an order.

The old term 'thallophyte'includesthoseplantswhich are not ditTerentiated into root, stemand leaves.Englerdividesthem into l3 phyla. They includebacteria.algae,fungi and lichens.The positionsof the main families of pharmaceuticalinterestare indicatedbelow. l . -

r

- - ^ , , -

-

. - - :

- i : . -

- '

BACTERIAAND ALGAE

- . ' , . , i " i ' . " l : 1 . 1. .: , ' 1 . . , , ' . , ' 1

BACTERIOPHYTA

THATLOPHYTES r 5 BACTERIA AND ATGAE l 5 FUNGI t 6 LICHENS

r8

The bacteriaare unicellularorganisms,the great rnajorityof which rangein size fiom 0.75 to 8 ptm.They reproduceby binary fission. Most speciesof bacteriacontain no chlorophyll, althoughthere is one group whose nembers contain a chlorophyll-likepigrnentand photosynthesize. Recent researchhas revealedmuch more of the detailsofcellular structureand it has beenpossibleto distinguishin certain species,in no small detail, the various componentsof the cell. Forexample.in Escherichiacolithe cell wall consistsof afburlayer structure,the inner one being rigid. the three outer onesnonrigid. Within the three-1ayerwall structure lies a protoplast membraneenclosingthe cytoplasm.The protoplastmembraneacts as a pelmeability barrier to all but very large moleculesand contains enzymes concerned with respiration and the active transport of n'retabolities. Bacteriaexist in a numberof characteristicshapes,namely: 1. Rod-shapedor bacillaryfbrms (e.g.Clostridiumyyelchii,Escherichia coli andBacillussubtilis\.

BRYOPHYTES AND PTERIDOPHYTESr 8

r8 PTERIDOPHYTAr 8 BRYOPHYTA

GYMNOSPERMS 1 9 ANGIOSPERMS: DICOTYIE DONS 20 SUBCTASS ARCHICHTAMYDEAE2 l

Phyla

O rders

Familie,s

Bacteriophyta

Eubacteriales

Chrysophyta (Diatomeae)

Di scales Pennatales

Phaeophyta(Brown Algae)

Laminariales Fucales

Rhodophyta(Red Al-sae)

Gelidiales Gigartinales

Rhizobiaceae, Micrococcaceae Actinodiscaceae Fragilariaceae, Naviculariaceae Lamirrariaceae Fucaceae, Sargassaceae Gelidiaceae Gracilariaceae. Gigartinaceae

SUBCIASSSYMPETALAE 3 t ANGIOSPERMS: MONOCOTYTEDONS36 ANIMAT PRODUCTS 39

tE

T H EP L A N TA N D A N I M A LK I N G D O M SA S S O U R C E O S F DRUGS 2. Sphericaior coccal tbrnts. which can occur singly but ar.eusually tbund in characteristica-egregates-i.e.in chains(streptococci).in groups of two (diplococci).four.(tetracocci)or eight (sarcinae). Agglegates of iregr,rlarpatternaresaidto be of staphylococcal fbrm. -1.Twistedor spiriliarformsrvhich.if havinga sinsletwist. belongto the genr-rs VlDrio,.while thosewith rnorethan one twist belongto the genus5prru1ftlrr. zl. Blanched lbrms which sontetimes occur in the genus Myt ttbutteriunt.

PHAEOPHYTA!

IAMINAR|AIES

Lqminoriqceoe The brown algac are r.nainlv nrarine and vary fiom microscopic branchedfllanrentsto leatheryfiond-like fbrms up to 60 rn in length. They or",etheir brown colour to the carotenoidpignient fircoxanthin. Vn'hich rnasksthe otheIpiglnents. Many of the30 species<'tfLutttinuriuareusedin coastalclistricts lbr agricultural purposes. Thev areusedlbr the manulacture ofalginic acid ( q . r .t . n t a n n i t orln J i o t l i n c .

Other in-rportanlrnorphologicalf'eatures which are of value in classif,ving bacteriaare: (l) Thc possession of flagella.thread-likeprocesses FUCATES whosenurnberandpositionarcofieno1'diagnostic importance. (2) The PHAEOPHYTA: fbrnrationof capsr.rles consistingof polysaccharidernaterialwhich is of Fucqceqe ond Sorgossoceoe grcar impol'tancein relation to the imrnunologicalpropertiesof the Exarr-tplcs of theFucaceae (about30 spp.)andpelt,etia;and lu'cFur.u.r orgrnism.(3) The possession 'Ihese of endospores, which arehighly refr.act- of the Sargassaceae about250 speciesof Szligzls,varr. arecollected ir.'ebodiestbrrnedby certainspeciesunder what appearto be adverse on a l:Lrgescalein many partsof the wor.ldfbr the pr.oduction of alginic environmentalconditions.The position of the sporein relation to the acid and its derir,atives.The specieshave been n'ruchinvestigatedfbr rest of the cell is of diagnosticimportance.(:1)Pigrnentationl utuny biologicalfl'activepropefiies E resitulosu_i.tbr example.gives waterbacteriaarecirpableof claboratin_q corrplexcolouringmarrers. solubleextractsthat inhibit the activity of the HIV r.everse-tr.:rnscriptase Bacteriaare able to carr)' out a very wide r-angeof chemical reacenzynre. tions, some of which are usedlbr identificationand clifl'erentiation. in addition to fbrming the basisof n-ranyimportant industritrlptocesses. Bacterialactionis used.fbrcxarnple.in theproductionoir.,inegar. GEUDIAIES acet- RHODOPHYTA: onc. br.rtylalcohol. lactic acid and L-sorbose.Notable examplesof Gelidioceoe reactionswhich are useful fbr characterizingbacteriaar.ethe abilitl, to The red algaeale divided into I I or.dcr.s. The 3000 specicsare mainly fermentcarbohydratesu,ith the fbrmation of acidic and gaseousprodmarine and are particularly abundtrntin the tropics and subtropics. ucts:the abilityto digestplotein.as shou'nby gelatinlicluelactionl the Most are relativelysmall.'I'heirplastidscontain chlorophyll,the red productionof hydro-qensulphidcliom organicsulphr.rr compounds. pi-enrentphycoerythrin(usLrallyin sufTicientcluantityto mask the other Bacteriaare most important in medicine and pharmacyin the fblpl-qrrents). and sontetimcs the bluepignterrtphycocyanin. lowing respects:as disease-producirrg organisms(about l0% of bacImportant generaof thc Gelidiaceaeare Gelicliwn (about :10 spp.) teriaareprobablypathogenic): fbl producingantibiotics(Chapter32): alndPterot:latlia(5 spp.).Many of thesetrreusedin the preparationof lbr eflectingbiochemicalconversions; as agcnrsin the deterioration of agars(q.\'.). clude drugs and medicar-nents (Chaptcr l3)l in geneticengineering involving recombinantDNA (c.-e.the productionof hurnaninsLrlin). Bactcriiralso play a I'ital role in nature-tbr example,in the nitrogen RHODOPHYTA: GIGARTINAIES cycle atmosphericnitrogen is fixed by A:pnfiacter or. symbiotically. qnd Grocilorioceqe Gigortinoceoe by various speciesof RhizobiL.nn. Nitrosonttnnsis able to oxidize Grucilariu (100 spp.l is a sourceof agar.particular-lvG. lit.henoides. zrnrmoniato nitl'ite. while Nitr.tlbaclel.can oxidize nitrite to nitr.ate. found in the Indian Ocean. Ir-rthe GigartinaceaeChondrtts crispu.s Bacteri:rare important in sewagepurification. in the lening of fibres yiefds cara-eeen or Irish moss(q.v.):()igrtrtinu.stelluttt hasbeeninvessuchasjuteand flax, anclin the ripeninuofcheese. tigatedas a sourceol British agar.

CHRYSOPHYIA: DISCALES

FUNGI

Actinodiscoceqe The Chrysophytahasthreeclasses, oneof which is theBaciltar-iophyceae The fungi are saplophytic or parasitic r.nentbers of the Thallophyta. (Diatomeae). containingsome l0 000 speciesof diatom.They areunicelentirell'devoidof chlorophyll.The plantbody is madeup of filaments lular algac.havea silicaskeleton.iind showinfinitevarietvin shapeandin or hyphae,which to-eetherconstitutcthe mycelium. The hyphaentay the sculpturingof the cell wall. Thereare two main types:the subclass be aseptateand coenocytic. but arc ofien septate.the individual pennatae Centricae(in u'hich Discalesis one of the orders)and sr.rbclass segments beinguni-. bi- or multinucleate. In the fbrmationof fr.uiting (which inclLrdes the order Pennatales). The Cenhicaeare centricor.disbodies the hyphaernay becomewoven into densemassesof pser.rclocoid in shapeand -uencllllvma'ine. while the pennataeare pennateor palenchyma(e.g.the sclerotiumof elgot). naviculoicland rrorc olien occurin fiesh water. The plotoplastof fungalcellsconsistsof granularor reticulatecytoAn exampleof the larnily Actinodiscaceae is Aruchnoidi.scrr.r.. found plasn, which in older cells is ofien vacuolated.The nr.rcleus mav shor.v in Japaneseagar'(q.r,.)and other generaare fbund in cliatoniteor a delicatereticulunt and one ol' morc nr"rcleolior its contentsrral' be kieselgLrhr'(q.r,.). condensed into a chromatinbody.The cell wall in manyAr.chirnycctes and somePhycomycetes (Oornycetes) and in the )reasts consistsmainly ofcellulosc. but in other fungi eelluloseis rephceclby the nitrogenCHRYSOPHYTA: PENNATATES ous substance chitin. Frogilorioceoe qnd Nqviculqriqceqe Sexualand asexualreproductionoccur.The characteristicsporesof Species of thesetr,o fantiliesoccurin diatontiteandareillustrated in the sporophytcgenerationare known as oospores(pr.oducedendogenFig.3;1. L ously) or basidiospot'es(produceclexogenously).In the Fungi

..:l-,f##

A TAXONOMICAPPROACH TO THESTUDYOF MEDICINALPLANTS AND ANIMAL.DERIVED DRUGS Irrrpcrl'ecti the sporophytegenerationis missing.The fungi trlsoproJLrcesporcshaving no significancein the altelnationof the sener.rtions:they ale bolne on the gametophyte(Phycolrycetesand (nlsts and some Autobiisidio\scomycetes)or on the spot'ophy'te nr\ cctcs).Theseaccessory sporesofien takethe fbrrn of conidia.nonnrotilespores.hornecxtemallyon conidiophores. The Archinry'cetes arethe simplestfirngi.in which the myceliuntis lubscntol mdimentary.A ntemberof this group causeswilrt diseasein potirtoes.The tirllowing glorrpsand fiimilics are of pharrraceutical i nterest.

Clus.s

Orzler

f utnilie.s

Phyconycetes Ascomycetes

M ucotales Pr"otoascales Plectascales Sphaeriales CLivicipitales Polypolinales Agaricales

Mucolaceae Siiccharomycetaceiie Asper_qillaceae Hypocreaceae C lar,icipitrceae Polyporaceae Tricholometaceae Amanltaceae Agaflcaceae Phallinaceae Dematiaceae

Basidiornycctcs

Fun,qiImperfecti

Phallinales Moniliales

PHYCOMYC ETES: MUCORALES

E

CLAVICIPITATES Clovicipiioceoe Like otherAscomycetes. the ascospores areproducecl in I saeor.ascus. Genera of the Clar,icipitaceaeinclude Clat iceps ( 10 -spp.)and (100 spp.),See'Ergot'.C.purpureuand its lif-ehistory. Corth'ceps

BASIDIOMYCETES: POIYPORINAIES Polyporoceoe The Basidionrvcetes producebasidiospores. borne externallvon the sporemothercellor basiclium. They have septatemyceliawhich produce elaboratefi'uitin-g bodies(e.g. mushlooms).Somentembersare edible.otherspoisonous. T h e P o l y p o r a c e a ei n c l u d e s P o l t p o r u s , P o l t s t i c h u s , f o m e . ; . GanoclerntuandBoletus(200 spp.).PolvltorusrlJicinulis (white agaric) and P .fomenturiuswere fbnlerly nsed in nredicine.Cunodernct lucitlo has long beenused in Chinesernedicineand its biologically active triterpenoidshave attractedrecent attention.IJoletuseduli.sis edible.

AGARICALES Tricholometoceqe An orderof severaltamilies.of u'hichthe Tricholonteraceae conralns (q.r'.).Othcr Clitotybe(80 spp.),speciesof which producer.nuscarine fanrilies crf the order contain Strophurio, Psiloc:tbe and Conoctbe. (q.r'.)such as psilosinarrcl which producehallucinogenicsubstances psilocybin.

Mucorqceqe These fun-ei have an aseptate mycelium: members include Pltttoplttlrorain.festans, which causespotatobli-eht.In the Mucoraceae we haveMucor (40 spp.)and Rhippus (8 spp.),which are amongthe AGARICATES moulds associatedwith badll' stored fbod ploducts. Sonre R/l;o7;a.i Amqniloceqe speciesareusedindustriallyfor the saccharillcation of starchymaterial Thefarnilf inclr-rdes Amunita(-50-60spp.)andPluteus; Amanitutttusandfirr producingo-lacticacid fbm glucose:they areimpoltantin the caritr (t1y agalic ) and A. pdntherino contain rnuscarine (c1.v. ). microbiologicalconversions of steroids(q.r,.1.

ASCOMYCETES:PROTOASCALES

AGARICATES Agoricoceoe

Socchoromycetqceqe This family inc[tdes the common ntushroom.Agtu'itu.s cLuttpL',\tt.i\. This group includesthe yeasts.some 30 speciesof Sacchanttn'ces. The genusAgrtricus(P.sttlliotrr) containsabout30 species. Dlicd yeast(q.v.) is preparedfi'om a strainol S. cereyi.sicte. Amcntber of the lelated lamily Cr'-vptococcaceae ts Cantlitfu arrlrs.which producestorulayeast.a rich sourceof proteinsandvitamins. PHATLINATES

PTECTASCALES Aspergilloceoe In this oldcr the conidial sta-eeis more prominentthan the ascalstage. Penicilliurn(over'100 spp.)l,ieldsimpgrtantantibiotics(q.r'.)suchas penicillin and griseofirlvin:alsothe i rnmunosuppressant ntycophenolic acid.P. i.slcurclioorr fbrms emodin.Ar-nongthe 60 speciesof Aspergillu.; may bc noted A. orr:oe. r-rsedin the manufactureof soya saucc:A. prodLrcing the antibioticfumagillin; andA..flut'ttsproducine .fumigutu.s, allatoxin in poorly storedt'eedingmaterials.

SPHAERIATES Hypocreoceoe (10 spp.)produces Gibberelltt the plantgrowthregulators knownas gibbelellins. filstisolated tron G..fugikunrl. seeChapter: 8.

Phollinoceoe Theordercontains two families.ThePhallinaceae takesits namefrom ( l0 spp.). Plmllu.s Phnllu.s intputlitus is thestinkhorn.

FUNGIIMPERFECT: MONItIAtES Demqtiqceqe The Fungi lmperf-ectiis a group in which sexualsporeshave not been demonstrated.Some membersmav be Ascomyceteswhich have completely lost the ascusstage. The iamily Denratiaceaecontains Helmintho.sltorimn(150-200 spp.),a speciesof which. H. gruntiniutt't,.produces helminthosporin (q.v.).Another tamily of the group, the Tuberculariaceae. contains Fnsaritrrtt(65 spp.).f-usariutrt/irri will transfirrmdigitorigenininro digoxigenin. Fungal sporesale a common sourceof allergens.

T H EP L A NA T N DA N I M A LK I N G D O MASSS O U R C EOSF D R U G S surfacehas been skimmed off. soil may be excavatedin a very pure form. Sphagnummoss. consistingof a mixture of various speciesof Sphugntun,can be collectedin many parts of Britain. It rnay be used A lichenis a symbioticassociation ofan algaand a fungalpartner.Some. (enclosedin muslin bags)as arrabsor.bent dressingor compressedinto particularly in zrctic regions. are used as fbod. The deseft species sheets.making absorbentmattresses. Largequantitieswere usedin this Lectuutra esculentais regardedas the biblical manna.The 'oak moss' way in World War I. used as a llxative in pefumery is the lichen E',,entiaprunastri. Many The pharmacologically activeterpcnoids(sesquiterpenes, diterpenes) lichenscontainderivativesof orcinol. orcellic acid and lecanoricacidl and aromaticcompouncls of the bryophyteshavebeenwell studied.(For thesecompoundsare termeddepsidesand are phenolicacidsfbrmed by a review seeY Asakawa.Proc. Phttothem.Sot'.Eur.. 1990.29.369. the interactionof the carboxyl gloup of one molecule with the hydroxyl This volume (eds. H. D. Zinsmeisterand R. Mues). published by -eroupof another.A classof theseacidstenned depsidones(e.g.norstictic ClarendonPress.Oxford. alsoincludesa further28 review iu-ticlescol, andpsoromicacids)complexwith metalsandareprobablyresponsible for eringthe chemistryandchernicaltaxonomyof the Br-yophytes.) the ability of lichensto flourishon mineral-richsoilsincludingmine tailOf the many bryophyte orders. farnilies and genera.a few which ingsandto accumulate largequantitiesofmetals,suchascopper,zinc etc. have beensubjectsofrecent researchale listed below. Lichen dyes were formerly much used in the textile industry. Litmus. prodr.rced fl'orn certainlichens (e.g. Lecanora,Roccellu spp.) Clctss Order Genera by fermentation.is usedas an indicator. Icelandmoss. Cetroria islandiccr.has been used for disguisingthe Hepaticae Jungerrnaniinales Buzz,ania, SoIeno,stoma, tasteof nauseousmedicinesand with other species(e.g.Clarkmia spp.) Glntnonitrion, for thc treatnrentof cough.It containsthe very bitter depsidone.cetraric Diploph-,'Llunt acid. Many lichens have antibiotic propertiesas illustratedby usnic Jubulineales Luttulariu acid.fbund in Cladoniu and Usneaspp.(seeE. R. Conechdet al. 1998, Musci (336 spp.) Sphagnales Spltugrtunt Fitoteropia. 69, 1931'V. Marcano et al., J. Ethnoplnrmacolog,t 1999, Dicranales I)i crcur urrt t -52 spp.) 66, 343); 29 speciesoflcelandic lichenshaverecentlybeeninvestigated Funariales Funuriu(ll7spp.1 lor their cancer chernopreventiveand cytotoxic activity (K. Ing6lfsd6ttirer al., Pharm.8io1.,2000.38,313). It is possibleto isolateand grow the algaefrom lichens as suspension cultures(seeP Hdrmiiliet al., Fitoterapia, 1992,63.211). PTERIDOPHYTA The accompanyinglist indicatessomeof the families and generaof recentinterest. The Pteridophytaincludesthe Filices (ferns),Articulatae (horsetails) and Lycopsida(club mosses).They show an alternationof-renerations. the sporophytebeing the larger'.A few are of medicalimportance. Order Fttmih Genent Of the many families, subfamiliesand generathe following mav bc noted. Rocceliales Roccellaceae Roccella(3 I spp.) Lecanorales Pertusariaceae Pertusuria(608 spp.) Lecanotaceae Lecanora(1100spp.) Class Order Funtilt G e t t er a (800 spp.) Parmeliaceae ParmeLict Cetraria (62 spp..1 Filices Filicales Polypocliaceae Pohpodium(.abou| Usneaceae U,vrea(500 spp.) (dividedinto 50 spp.) Evemia (8 spp.) many subfanrilies)D rl opteris (about Alectorio (48 spp.) 1 5 0s p p . ) Caloplacales Caloplacaceae Culoplaca(,180spp.) Plerls (280 spp.) Teloschistaceae Xanthnria(21 spp.) Preridium(1 sp.1

LICHENS

Thesetwo phyla areof relativelysmall pharmaceuticalimportance,but h a re : o r r r cp h l t o e h e r n i c a r nl l e r e s t .

BRYOPHYTA The phylum is clir,idedinto two classes,Hepaticae(liverworts) and Musci (mosses).Both show alternationof generations.The more consplcuousgametophytegcnerationis a leat--likethallusin the liverworts and a leafy plant with a stem in the mosses.On the latter is borne the sporoph)le generation u ith sporangium. Peat.longusedasa domesticfuel.consistsofpartly decayedmosses and othel plants.In some areas(c.g. partsof lreland) depositsof bog moss(lar-uelyspeciesof Sphagnuntlare many feet thick. and after the

Articulatae Equisetales Equisetaceae Lycopsida Lycopodiales Lycopodiaceae

Ont'chium(6 spp.) Dennst0edtid (7i) spp.; AdiantLon(.abotl 200 spp.) Athyrimn(180 spp.) Asplenium(about700 spp.) Ecluisetunt(32 spp.) Lt'copodiunt(abouI .100spp.)

Male fern rhizome(q.v.) derivedfrom Drtopteris filir-mas is one of many fernscontainingphloroglucinolderivatives.The insect-rr-roulding hormonesor pterosinsarewidely distributedin f-ernsand attl-actconsiderableresearch. The dried sterilestemsof the horsetail. Ecluiseturn on)enseare used in herbal medicine and ale listed in rhe BHP. Pleparationsare used internally to treat inflammiition and mild infectior"rsof the genito-

A TAXONOMICAPPROACH TO THESTUDYOF MEDICINALPLANTS AND ANIMALDERIVED DRUGS ..:llrrr\ tract and externallyfbr wound healing,fracturesetc. There are .,;.p.rrcntl\'two chemotypesof the specieswith diffelent f'lavonoid -, 'nrpositions. Horsetailsgive a high mineralashcontainingconsider.:irlc'amountsof silica. Correct identificationof the herb is ir-nportant ..cause the relatedspeciesE. paLustreis poisonous. The sporesof lycopodium (.Lt'copodium clavattrm)are usedin quantitatire microscopy(q.v.)and to a limited extentin medicatedsnuffs. Ju:tin-9powdersand lubricants.As a dustingpowder for rubbergloves rt has beenknown to give rise to dermatitisand mild cautionhas been e'\pressedregardingits use as a lubricantnon-stickagentfor condoms rclative to a possiblecauseof granulomas.The lycopodium alkaloids have been extensivelystudied(for a review seeW. A. Ayer and L. S. Trifbnov,Alkaloids, 1991,45, 233). Bracken(Pteridium aquilinum) has been a recentcauseof concern o\\'ing to its carcinogenicpropertiesand known bovine poisoning.The useofthe young shootsfor culinary purposesis discouragedand avoidance of bracken sporesin the atmospheresuggested.The toxic con\tituent is ptaquiloside.an unstable glycoside of an illudane-type rrorsesquiterpene. Other similal compoundsare widely distributedin the genusPte.ridium.

ageing process,the leavesof the ginkgo tlee have been extensively investigated.For furtherdetailssee 'Diterpenoids'.

(ORCONTFERATES) coNTFERAE Pinoceqe All mernbersof the older are trees or shrubs:mostly evergreenwith needle-likeleaves:monoeciousol dioecious.Sporophyllsr.rsually in cones.Resinductsoccurin all parts. The Pinaceaeare trees,rarely shrubs.Important generaare: ADles (,50spp.).Pseudotsugu (7 spp.), Tsuga (l 5 spp.),P i cea (50 spp.).larn (11 spp.),Cedru,s (1spp.).andPinus(.10 100spp.).They areabundant in the northern hemisphereand extend southwaldsto Indonesiaand Central America. Apalt fiorr their great value as timber and papermaking material. many species (e.9. Pinus) yield oleoresin (see 'Colophony Resin and Crude Turpentine'). Other speciesare ADles balsttnea. yielding Canadabalsam: P.seudtxsugu taifolia (Douglas tir).: Picea ables (Norway spruce): and Lari.r eltropoelts(larch). The barks of larch and hen-rlockspr'r.rce ale tanningmatelials.Pirtusltirtea (the umbrellapine) produceslargeedible seeds(pignons).

CONIFERAE The division Gymnospermaecontainsmany fossil members.Of the I I ordersin the Engler classification,it is only necessaryto mentionfive ordels and l0 families: Orders

Families

Cycadales Ginkgoales Coniferae

Cycadaceae Ginkgoaceae Pinaceae,Taxodiaceae. Cupressaceae. Araucariaceae. Podocarpaceae, Cephalotaxaceae Taxaceae Ephedraceae

Taxales Gnetales

The gymnospermsare one of the two great divisions of the seedbearing plants or spermaphyta.They differ from the angiospermsin having ovuleswhich are not enclosedin an ovary.A perianthis absent exceptin the Gnetales.The seedsusually containone matureembryo with from two to 15 cotyledonsembeddedin endosperm.The wood is composedlargelyof tracheids,vesselsbeing absent.

CYCADALES Cycodoceoe The order containsonly l0 generaand about 100 species.The family Cycadaceaecontainsthe single genus C-vcas,with 20 species.A sago (not to be confusedwith that fiom certainpalms) is obtainedfrom the pith of C-r'ca.r circinttlis and C. revolula.

Tqxodiqceqe A snrall family of l0 genera. including Sequoitr, Turodiunt. Cr1'ptomerio,Tetraclini,;, Tain'aniuand Ctuutinghantiu'.| 6 species. The resin sandaracis produced in North Afiica and Spain fiorn Tetraclini,rarticuldtd. Some of the farnily contain antifungal diterpenes.othersalkaloids.

CONIFERAE €upressoceoe A family of 19 generaand 130 speciesol'treesand shrubs. Merrbersdifl'erfiom the Pinaceaein that the lear,esand cone-scales areusnallyoppositeor wholled andthe ovuleserect.The generainclude CttLlirris(16 spp.,Australasia),Thujn (5 spp..China, Japanand North (15-20 spp.),Chumaect'paris(7 spp.),Jwtiperus America). Cupressu,s (60 spp., northern hemisphere).Jtutilterus conrmutis yields juniper berriesand volatile oil (q.v.);J. virginicntu.the red cedal wood r.rsed lbr pencils:andJ. sabina,volatile oil ofsavin: J. oxt'cedrus,by destructive distillation.yields oil of cade,which was formerly much usedin veterinary wolk. This tar-like oil containscadineneand phenols. Various diterpenesand flavonoidsof the lamily havebeenstudied.

CONIFERAE Arqucqriqceoe Two generaand 38 speciesof trees.which sometimeshave pungent leaves. ArarLcaria( I8 spp.)providesuseful timbers; andAgathis (20 spp.), the resins known as copals ol animes. which are used fbr varnish. Manila copal is obtainedfiom the MalaysianAgathis alba; andkauri copal fromA. ctustralis.the kauri pine. in Austlalia and New Zealand. The best copals are usually those for.rndin the ground long aftel the treesare dead.

GINKGOALES Ginkgooceoe With theexceptionof Ginkgobiloba,themaidenhair-tree, theplantsof this orderare foundonly as fossils.In recentyears,owing to their increasing usefor thetreatment of variousdiseases associated with the

CONIFERAE Podocorpoceoe Six generaand 125speciesof treesand shrubs.The largestger-rus, (100spp.),extendsfrorntropicalto tcmperate Podocarpus zonesand

E

T H EP L A N TA N D A N I M A LK I N G D O M SA S S O U R C E O S F DRUGS vicldsvaluabletimbels.A chalacteristic chemictrlf eatureof this genus flowersmay be unisexr.ral (e.g.Salicaceae). bLrtaremoreusuallybisexis the widespreadoccurrcnceof nol'diterpene and bisnorditcrpene ual. The perianth may or may not be difl'erentiatedinto sepalsand clilnctones: thcsecompoundserhibit a r.'arietyof biologicalactivities petals.and the latter rnay be free fiom one anotheror-fused. ( s e cI . K u b oe t a l . . P l t y t o c h e n i s t r t ' . 1 9 9 2 . 3115.4 5 ) . The classificationadoptedin the fbllowing pagesis that of Engler. who divides the dicotyledonsinto two groups.the Archichlamydeae and Syrnpetalae.The Archichlamydeaeare further divided into 37 CONIFERAE ordersand about 226 farr-rilies and the Svmpetalaeinto I I ordersand Cepholotoxoceqe about63 f'amilies. A firnrili, of onc genus(.Caphuloto.rtrs) and scvcn speciesof treesancl The namesof the ordersterminatein '-ales'.subordersin '-neae'. shrubs(plum yews)fbund from thc easternHimalavasto Japan.Thev families usuallyin '-aceae'(Compositae. Gramineaeand Labiataeare havebeenintensivelvstudiedfirl thcir antiturnourconstituents andthe exceptions). and sometimes into subfamilies endingin '-oideae'. alkalcrids(harrin-qtonineand hor-r-roharringtonine) of C. hu rt.ingtoniu The Archichlamydeaecontain those families that in early editions haveshou'nconsiclerable promise(seeChapter28). rvereglouped under Monochlarnydeaeand Dialypetalae.The llowers have either no perianth or a perianththat is difl-erentiated into sepals TAXATES and petals. the latter being free. Engler's classificationof the Dicotyledonsis given in a somewhatabbreviatedfbrm below. Tqxoceoe

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An order of onlY one tanily. r"'hichincludesthe -genera Zi-rir,i( I 0 spp.). Psetrclota.ru.s, Torreta . Austrotu-ru s andAnertotu.rus. The common yew. Zl.ur.r'bcrct'trtu,produces valr-rablewood. The fruit hasa fleshyred aril.All partsofthe plantarevery poisonous. and cattleandholsescandie ver.vlapidly aftereatinsthe leaves and stems. In additionto alkaloids.a cyanosenetic glycosideandanrirnrnout a-eenr havebeenreportedin the genus. Ta.rrtsbrevirtilia(the Paciticyew). The bark of this speciesyieldsthe prorrisin-t anticancerdlug taxol. a nitro,eenous diterpene.Low yields fiom the bark and thc scarcityof rau'r.naterialleadingto damageto fbrests by. olien illegal.over-collectionharrpeledthe developmentof the drug. The ini estigationof alternatir.e sollrceshasnow led to tissuecultureproceduresfbr the procluction of taxolbr.rttheyieldsarestill low.A pronrising developmentinvolving a renevn,able sourcehas beenthe isolationof l0deacetylbaccatin frornthefreshneeclles of T.bucutu in up to 0.1%yield irndits chen"icalconversiorr to taxol. T.rrrcdia.7.. orspitktu andT.chinensi.r'areotherspeciesinvesligatedtbr taxancalkaloids.For firrtherreading seethe supplernent to issueNo. I of f'rroterzpia1993.vo|64.

FamiLt

Orclt'r'

SubclassArchichlamydeae Juglandales Salicales Fagales Urticales Proteales Santalales Polygonales Centrospermae

Cactales Magnoliales

GNETATES

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Ephedroceoe The order consistsof three families (Gnetaceae. Ephedraceacand WeL"r'itchiirceae). threegencraand aboLrt70-75 species. The Ephedraceae containsthe single genusEphedra (q.v.),about,10 speciesof shrubs.They occur in arid legions of thc subtropicsandtropics. Theil seed.with two cotyledons.is enclosedin a perianthwhich becomeswoocly.Variousspeciesyield the drug ephedra(q.v.) and the aLkaloidenhedrine.

Ranunculales Piperales Aristolochiales Guttif-erales Sarraceniales Papaverales

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The angiospern-rs or f-loweringplantsinclr.rde inorethan 250 000 species ol herbs.shrubsand trees.The sporophylls(stamensand carpels)ar.e usr.ralll, aranged with otherleaves(theperianth)to fbnn a 'flou'er'. The ovulcs are enclosedin a chamber(the ovary) fbrrnedfiom the carpels, anda stigmais providedfbr theleceptionand gernrinationof thepollcn. The en-rbryoplant containedin the seedhas one or two seedleavesor cotyledons.The woocl almost invariablycontainstrue vessels.Thc phylun-ris divicledinto rronocotyledonsand dicotylcdons. The dicotyledons are herbs. shrubs of trees, the seedsof which havetwo cotyledons.The leavesareusuallyreticulatelyveinedand the typical stem strLrctlrre is a ring of open vascularbundles.Unlike the monocotyledons,which typically have their floral parts in threes. drcotyledonousllowers are usually pentanerousor tetramerous.The

Rosales

Geraniales

Rutales

Sapindales

Myricaceae.Juglandaceae Salicaceae Betulaceae.Fagaceae Ulmaceae.Moraceae(including Cannabinaceae) and Urticaceae Proteaceae Olacaceae.Santalaceae. Loranthaceae Polygonaceae Phytolaccaceae. Caryophyllaceae. Chenopodiaceae Cactaceae Magnoliaceae.Winteraceae. Annonaceae.Eupomatiaceae. Myri sticaceae.Canellaceae. Schisandlaceae. Illiciaceae, M o n im i u e e a eC. a l v c u n l h a c e a e . Lauraceae,Hernandiaceae Ranunculaceae. Berberidaceae. Meni spermiiceae, Ny mphaeaceae Piperaceae Ari stolochiaceae Paeoniaceae. Dipterocarpaceae. Theaceae.Guttiferae S a n a c e n i a c e aNee. p e n l h a c e u e . Droseraceae Papaveraceae (including Fumariaceae). Capparaceae. Crr.rciferae H a m u m ei d l a c e a eC, r u : s ul l c e a e . Saxifragaceae. Rosaceae. Leguminosae,Krameriaceae Geraniaceae, Zygophyllaceae, Linaceae,Erythroxylaceae, Euphorbiaceae Rutaceae,Simaroubaceae. Burseraceae. Meliaceae, Malpighiaceae, Polygalaceae Anacardiaceae, Aceraceae. Sapindaceae. Hippocastanaceae

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A TAXONOMICAPPROACH TO THESTUDYOF MEDICINAT P LANTS ANDANIMAI.DERIVED DRUGS Familv \ubclass Archichlamydeae (continued) ('dIastrales Aquifoliaceae,Celastraceae, Rhumnales \ I a lv a l e s

Thr,melaeales \riolales

Cucurbitales Myrtiflorae

Umbellillorae

SubclassSympetalae Ericales Primulales Plumbaginales Ebenales Oleales Gentianales

Tubiflorae

Plantaginales Dipsacales Campanulales

Buxaceae Rhamnaceae, Vitaceae Elaeocarpaceae, Tiliaceae, Malr uceae.Bombacaceae, Sterculiaceae Thyrnelaeaceae. Elaeagnaceae Flacourtiaceae, Violaceae, Turneraceae, Passifloraceae, Cistaceae,Bixaceae, Tamaricaceae, Caricaceae Cucurbitaceae Lythraceae,Myrtaceae, Punicaceae,Rhizophoraceae, Combretaceae, Onagraceae Alangiaceae,Comaceae, Garryaceae, Araliaceae, Umbelliferae

morerecently,sedative; seeM. Girzuet al., pharm.Biot., 199g.36. 280.

SALICATES Sqlicqceqe The single family of the order containsonly two genera,Sall.r (500 spp.)and Populus(35 spp.).The dioeciousflowers are in catkins. Both generacontainphenolicglycosidessuchas fragilin, salicinand populin.Salicin,formerly usedin medicine,hasbeenreplacedby other drugs. Willow charcoal is the chief kind of wood charcoal used in Britain. osiers (sa1l-r:purpureaands. viminarrs)are used for basketmaking, and S. alba yar. caeruleais usedfor cricket_bats.Speciesof Populuscontainrafflnoseand stachyose.The dried winter buds of var_ ious speciesof poplar constituteBalm of GileadBud BIlp, andthe hive productpropolismay be derivedfrom poplar bud exudates.

FAGALES

Betuloceoe ond Fogoceoe Thesefamilies consistof monoecioustreesand shrubs.Their crassificatlon togetheris confirmedby similaritiesin constituents. The Betulaceaehastwo genera,Alnus (35 spp.) and,Betula (60 spp.). Ericaceae constituentsinclude many phenolicsubstances suchas myricetin. detMyrsinaceae,Primulaceae phinidin and ellagic acid; also terpenoidssuch as lupeol and betulin. Plumbaginaceae The wood of Betula alba is usedfor charcoal. Sapotaceae, Ebenaceae, The Fagaceaehas eight generaand about900 species.Fagus (10 Styracaceae spp.) includes the beech, F. sylvatictt, the nuts of which are Oleaceae expressedto yield o1l Castanea(12 spp.)includesthe sweetchest_ Loganiaceae,Gentianaceae, nuI, C. sath)a, which yields timber and a bark used for tannins. Menyanthaceae, Apocynaceae, Quercus(450 spp.)provides valuabletimber. Differe nt euercus spp. Asclepiadaceae, Rubiaceae containshikimic acid (a cyclitol), methyl salicylateand terpenoids. Polemoniaceae, Convolvulaceae, The cupules and unripe acorns of e. aegelop.s(valonia) are used in Boraginaceae, Verbenaceae, tanning. Q. ilex and Q. robur yield tanning barks and e. tinctoria, a Labiatae,Solanaceae, yellow dye. Q. suber affordsthe commonly usedcork, in an industry B uddlejaceae,Scrophulariaceae, worth (1987) some f 120 million p.a. to portugal's economy; Bignoniaceae,Acanthaceae, becausethere is no plannedre-afforestationthe industry now facesa Pedaliaceae, Gesneriaceae. decline. An extract of Q. stenophylla has been marketed for the Myoporaceae accelerationof the elimination of renal and urethral calculi. Turkish Plantaginaceae galls (q.v.), an important source of tannic acid, are vegetable Caprifoliaceae,Valerianaceae, growths formed on the young twigs of the dyer,s oak, e. infectoria, Dipsacaceae as a result of the activity of a gall-wasp. Similar galls are produced Campanulaceae (including on the English oak, Q. robur. Lobeliaceae),Compositae

URTICATES SUBCIASSARCHICHTAMYDEAE JUGTANDATES

Ulmoceoe, Moroceoe, Cqnnqbinqceoe, Urficqceqe The Cannabinaceae,originally included in the Moraceae. rs now regardedas a separatefamily.

Myricoceoe ond Juglondqceqe l. The Ulmaceaecontains 15 generaand 200 speciesof tropical or The order containsonly thesetwo small families. temperateshrubsand trees.Generainclude ILlmus(45 spp.),Celtis The Myricaceaehas three or four generaof trees and shrubswith (80 spp.) and Trema(30 spp.).Members contain no latex (distinc_ unisexual flowers. Some members contain volatile oil (e.e. Myricct tion from Moraceae).Mucilage is abundantin the barks of ulmus prrle.the bog myrrlel. rubra (.see'SlipperyElm Bark') and U. campesrris;raffinose and The Juglandaceaehas seven or eight genera and the best_known stachyoseoccur in Ulmus,an indole alkaloid occursin Celrls. speciesis the walnut,Juglansregla, which producestimber and edible 2. The Moraceae has about 53 genera and 1400 species.They are nurs.Juglans containsthe naphthoquinonejuglone, the sugarsraffi_ mainly tropical or subtropicalshrubsor treescontaininglatex. The noseand stachyose,flavonoidsand phenolicacids. fruit is often multiple, as in Flcr.rs,the fig. The large genusFlcas The leavesand pericarpof J. regia havelong beenusedasextractsin (about 800 spp.) includes trees and shrubs of very varied habit. traditional medicine and pharmacologicallydemonstratedto be anti_ These include F. benghalensls(banyan),F. elastica (indiarubber helmintic, antidiarrhoeal,antifungal, astringent,hypoglycaemicand, tree) and F. carica (common fig). The latex is often anthelmintic.

THEPLANTAND ANIMAL KINGDOMSA5 SOURCES OF DRUGS owing to the proteolyticenzymef icin. Another genusCastlllorz( l0 spp.), yields. from C. eLastica,Panama rubber or caoutchouc. Among other constituentsrcported in the tamily are cardenolides (in five genera)and pyridine alkaloids(in two genera).Speciesof Morus areusedin orientalmedicine. 3. The Cannabinaceae or Cannabidaceae consistsof the two genera Cannabis and Humulus comprising C. siliva (hemp), H. lupulus (common hop) (q.v.) and H. japonica (Japanesehop). The chemistry of theseplants is a justification for their separationfrom the Moraceae.Connabisproducesthe besthemp when grorvnin a temperateclimate,whilst the more activesamplesof Indian hemp (q.v.) are usually associatedwith warmer climates. 4. The Urticaceaehas45 generaand 550 species;tropicalor temperate herbs or undershrubswithout latex. Some genera have stinging hairs (e.g. Urtica, 50 species of stinging nettle), others lack such hairs (e.9. Pilea, Boehmeriaand Parietaria). Root extractsof the common stinging nettle are used in herbal medicine, often in combinationwith other species,for the treatmentof benignprostate hyperplasia.For a review with 78 referencessee E. Bombardelli and P Morazzoni, Fitoterapia 1997, 68,38'7.

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is a one-seeded,usually three-wingednut (e.g. dock and buckwheat). Anthocyaninpigmentsare common; also flavonesand flavonols-for example,buckwheat,Fagopyrumesculentum,is a commercialsource of rutin. Quinones (anthraquinones,phenanthraquinones, anthrones and dianthrones)are tbund in many speciesof Rheum. Rumer and Pol!-gonum.

CENTROSPERMAE

Phytoloccoceoe/ Coryophylloceoe, Chenopodioceoe The order contains13 lamilies which show a passagefrom the monochlamydeoustype of flower (e.g. Phytolaccaceaeand Chenopodiaceae) to the dichlamydeoustype of flower (e.g. Caryophyllaceae). Most tamilies ofthe order,exceptthe Caryophyllaceae,producecharacteristicbetacyaninand betaxanthinpigments.which indicateafTinity with the Cactales(the next order,below). The Phytolaccaceaeis a lamily of 12 genera and 100 species; herbs, shrubs and trees, found particularly in tropical America and S o u t hA f r i c a . P h . t t o l n c c ra3 5 s p p . t i n c l u d e sP h . t t o l a tttt ( u n e r iat n o (Poke root), the leaves and roots of which have been found as an adulterant of belladonna: its berries contain a dyestuff. The roots which contain saponinsare included inthe BHP (1983) for the treatPROTEATES ment of rheumatic diseases;the roots elaborateantihepatotoxicneolignans. Proleoceoe The Caryophyllaceaehas 70 generaand about 1750species,mostly The singlefamily of the order,the Proteaceae, contains62 generaand herbs, and is wide-spread. Genera include Saponarin, Stelluria, 1050 species.Shrubsand treesare particularlyabundantin Australia. Arenaria, Spergularia,Hentiariu, Silene, Lychnis, Gypsophila (125 New Zealand and South Africa. Many specieshave been examined spp.) and Dittnthus (300 spp.). Many of these plants are rich in chemically,and the constituentsreportedinclude cyanogeneticcomsaponins.The root of Saponariaofficinalis hasbeenincludedin many pounds, alkaloids, tannins,leucoanthocyanins, arbutin and the sugar pharmacopoeias. It containsabout 5% of saponinsand is widely used alcohol polygalitol. Genera include Protea (130 spp.), Grevillea, as a domesticdetergent. Persoonia,Hakea andKnightia, The Chenopodiaceae contains 102 generaand 1400 species;most grow naturally in soils containing much sait (halophytes).Genera include Beta (6 spp.'), Chenopodium (100-150 spp.), Salicornia. SANTATALES AtripLer and Anabasis.From the wild Beta vulgaris (sea-beet)have Olococeoe, Sqntqlqceqe, Loronthoceoe been derived garden beetroot, sugar-beetand the mangold-wurzel. The ordercontainssevenfamiliesof which only four needbe men- Chenopoditrmanthelminticumyields the anthelminticMexican tea or 'wormseed' tioned. and its oil of chenopodium(q.v.). The Olacaceaehas about27 generaand 250 species.Few have been examinedchemically.Acetylenic acidsoccur in OLaxstricta. The Santalaceae containsabout 30 generaand 400 species.Of the CACTALES genera,Santafun contains25 speciesandThesiumabout 325 species. Cqctqceqe Monoterpenesand sesquiterpenes occur in severalgenera.The plants The Cactaceaeis the only family of the order and containsfrom 50 to arehemiparasiticherbs.shrubsand small trees.Santalum. aLbumyields 150 genera and about 2000 species.The plants are xerophytesand, sandalwoodand sandalwoodoil (q.v.)and is rich in sesquiterpene alco- with possibly one exception,are all native to the Americas.They will hols. Australian sandalwoodand its oil are obtained fiom another not grow wherethereis vitually no rainfall, but thrive in desertswhere member of the family, Eucarya spicata. there is a reasonablerainfall even if rain occurs very infrequently. The Loranthaceaeis a fairly large family of 36 generaand 1300 Some cacti occur in rain forests,where they are often epiphytes(e.g. species.The genus Visr:an consistsof about 60 speciesof parasitic Epipb'llum). The majority are succulentand storewater in their stems. evergreenshrubs,which often containcyclitols. The dried aerialparts The plant body is usuallyglobularor cylindrical and bearswool, spines of the common mistletoe, Visctnnttlbum, which grows on apple and and flowers, buI rn Epiph,vllum the stems are flattened and consist of other treesare included in the BllP 1983and are usedfbr variouscir- jointed segments,which areoften mistakenfor leaves.Among the genculatory conditions.It containsglycoproteins(the mistletoe lectins), era are Epiphl,llum (21 spp.),Opuntict(250 spp.), Cephalocereus(48 polypeptides(viscotoxins),lignansetc. spp.'),Cereus (50 spp.) and Echinocereus(75 spp.). The leaves of Opuntia and Nopolea provide food for cochineal insects (q.v.). Opuntiaficus-indicct,the prickly-pear,is sometimesgrown as a hedge POTYGONALES but can become a troublesomeweed. Dried cactusllowers (Opuntia Polygonoceoe spp.)areusedas an astringentherbalremedy.Lophophoran'illiamsiiis This one-family order occupiesan isolatedposition. It has about 40 the plant producingpeyote,anhaloniumor 'mescalbuttons';it contains generaand 800 species,mostly herbs.About 29 speciesare indigenous mescaline(q.v.).Severalgeneracontainsimple isoquinolinealkaloids; to Britain. Generainclude Rheum (50 spp.),Rumex(about 180 spp.), cyanogeneticglycosidesare very rare or absent;most speciescontain The fiuit Fagopyrum(15 spp.),Coccoloba(150 spp.) andPoLt'gonum. abundantmucilage.

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A TAXONOMIC TOTHESTUDY APPROACH OFMEDTCTNAL ANDAN|MAr.-DER|VED DRUGS Ed PLANTS

ttAAGNOHAtES Mognolioceoe, Winferoceoe, Annonqceqe, Myristicoceoe, Conellqceoe, Schisondroceoe, llliciqceqe, Monimiqceoe, Louroceoe ond Hernondiqceoe fhis order contains22 families. i The MagnoliaceaecontainsI 2 generaand about230 species,which occur in both temperateand tropical regions. They are trees or shrubswith oil cells in the parenchyma.Generainclude Magnolia t 180 spp.),Michelia (50 spp.) and Liriodendron (l sp.),tulip tree. The remedial propertiesof L. tulipifera, which is reportedto contain alkaloids (e.g. dihydroglaucine) and sesquiterpenes,have been (Crellin,J.K. Pharm.J., 1988.240,29). assessed I The Winteraceaecomprises7 generaand 120 species.Drim.vswinterr (Winter's bark) has beenmuch usedfor its stimulantand tonic propertiesand a number of pharmacologicalinvestigationshave been reported in the literature. The bark contains volatile oil, sesquiterpenes, lactones,flavonoidsand,recentlyreported,polygo1998,62, dial derivatives(V. C. Filho et al., J. EthnopharmacoLogy 223). ,r. The Annonaceaecontains 120 genera and about 2100 species, which are found mainly in the tropical regions of the Old World. Genera include Uvaria (150 spp.), Xybpia (100-150 spp.), Monodora (20 spp.) and Annona (120 spp.). The seeds of Monodora myristica are usedlike nutmegs.Many membersof the family containalkaloidsmainly of the isoquinolinetype.The family is of importancein folk medicine. 1. The Myristicaceaeis a family of 18 generaand 300 species,which are mainly fbund in tropical Asia. Generainclude Myristica (120 spp.),Virola (60 spp.),Horsfieldia (80 spp.) and Knemtt (37 spp.). The flowers are dioeciousand consist of an inconspicuousthreelobedperianthwith 3-18 monadelphousstamensor a solitarycarpel containing a basal anatropousovule. The fruit is a fleshy drupe, which splitsalongboth dorsaland ventralsutures.The singleseedis more or lesscompletelyenvelopedin a lobed aril. The chemistryof the family has not beenthoroughlyinvestigated.Somespecies(see 'Nutmeg' 'Mace') and containvolatile oil and hallucinogenicsubstances. 5. The Canellaceae is a small family of five generaand l6 species; trees with gland-dotted leaves. Fruit is a berry. Genera include Canella, Cinnamodendronand Wttrburgia.Canella bark, a spice, is obtained from Canella alba, grown in the Bahamas and Florida. 6. The Schisandraceae comprisestwo generaand 47 speciesof climbing shrubs..lc/risandrahas25 species;lignansarecommonconstituents. -. The Illiciaceae,sometimesclassifiedunder Magnoliaceae,has the single genus llLicium (42 spp.), fbund in Asia, Atlantic North 'Star-aniseFruit and America and the West Indies.See Oil'. \. The Monimiaceaeincludes20 generaand 150 speciesof treesand shrubs. which often contain volatile oil and resin. In South America there are many traditional uses of plants of this family; G. G. Leitao et aL. (J. Ethnopharmacology1999,65, 87), have reviewed the pharmacology and chemistry. The genera include Hedycarya (25 spp.) and Peumus(one sp.). Peumusboldus has a hard wood, its bark yields a dye and its leavescontain the alkaloid boldine. L). The Lauraceaehas 32 generaand about 2000-2500 species.These are tropical or subtropical trees and shrubswith leathery,evergreen leaves;the flowers are usually bisexual(e.9. Cinnamomum),rarely unisexual(e.9. Laurus). The fruit is a bery or drupe. Alkaloids, volatile oils and fixed oils occur in manv species.Volatile oil cells

occur in the leavesand cortex.Generainclude Persea(150 spp.), Ocotea(.300400 spp.),Cinnttmomum(250 spp.),Anl&a (40 spp.), Litsea (400 spp.),Neolitserz(80 spp.),Lindera (100 spp.),Laarus (2 spp.) and Cry-ptocaryrz (200-250 spp.). The bark of Cnptocarl'a massoiayields an essentialoil that has a coconut-likearomaand is usedas a cosmeticadditive.e.g.in shampoos; C moschatagives the maceof Brazilian nutmeg.The bay laurel, lnurus nobilis, is the only European representativeof the family: 45 constituentsof the essentialoil have been identified, the principalone being I ,8-cineole.Otherconstituents of the leavesare glycosylatedfl avonoids,(-)-epicatechin,(+)-catechin,(+)-epigallocatechinand procyanidins.For recentresearchand other references see C. Fiorini et al., Phytochemistry1998,47,821. For drugs see 'Cinnamon bark','Cassiabark'and'Camphor'. 10. The Hernandiaceae has threegeneraand 54 species.Membersare tropicaltrees,shrubsor lianeswith oil cells. Speciesof Hernandia (24 spp.) contain tumour-inhibitingalkaloids and lignans including podophyllotoxin;they have been used in traditional Samoan medicine.

RANUNCULALES: Rqnunculqceqe, Berberidoceoe, Menispermqceqe qnd Nymphoeoceoe Of the sevenfamilies in this orderthe abovefour areof medicinalinterest.The families show a considerablevariety ofplant constituentsand alkaloids are very common. In the four named families the alkaloids are often basedon benzylisoquinoline,bisbenzylisoquinolineor aporphine. 1. The Ranunculaceae comprises59 generaandabout1900species. The plantsare mostly perennialherbswith a rhizomeor rootstock.They are well represented in Britain. Many members are poisonous. The flowers are bisexual,regular (e.g. Ranunculus)or zygomorphic (.e.g.Aconitum). The perianth is simple or differentiated into calyx and corolla. The stamensare numerousand free. The carpelsare usually numerous in the regular flowers or fewer in the zygomorphic ones.The fruit is an etaerioof achenesor follicles, or a berry. Genera includeHelleborus(20 spp.),Aconitum (300 spp.),Thalictrum(150 (400 spp.), spp.),Clematis(250 spp.),Actttea(lO spp.).Ranunculri.s Anemone(150 spp.),Delphinium (250 spp.).Adonis (20 spp.) and Hepatica ( I 0 spp.).The family has diversechemical constituentsand is of considerablephytochemicaland chemotaxonomicinterest.For basedon sizeand shape,fall into two disexample,the chromosomes, tinct groups, the Ranunculus type (R-type) and the Thalictrumtype (T-type). The glycoside ranunculin has been found only in plants of the R-type. This glycosidehydrolysesto protoanemonin,which is vesicantand accountsfor this property in many species.Isoquinolinederived alkaloids occur in Thalictrum, Aquilegia and H1;drastis; diterpene-derived alkaloidsin Delphinium andAconitum.Saponins, mainly triterpenoid, occur in Ranunculus, TroLlius, Clematis, Anemone and Thalictrum, cyanogeneticglycosidesrn RanuncuLus and Clematis; cardenolidesrn Adonis, bufodienolidestn Helleborus. Black helleborerhizome, from Helleborus niger, containsvery powerful cardiac glycosides but is now little used in medicine. Various aconite roots, containing highly toxic alkaloids (q.v.) have also lost much of their former popularity. Black Cohosh of the BI1P is the dried rhizome of Cimicfugtt racemosa:it containstriterpenoidglycosides structurally related to cycloartenol, also isoflavones including formononetin. The drug contains substanceswith endocrineactivity and is usedin herbal medicine to treat menopausaland other female disorders.and also variousrheumaticconditions.A numberof other

THEPLANTAND ANIMAL KINGDOMSAS SOURCES OF DRUGS species e.g. C. simple,r, are used in Chinese medicine (see, for example,A. Kussanoet al., Chem.Plnrm. Bull., 1999,47, I 175)and to date suchspecieshave beenmore thoroughly examinedchemically than C. racemosa.Recently,however,a new 9,19-cyclolanostanetype triterpenexyloside, and other known relatedxylosideshavebeen characterizedfrom the latter species(E. Bedir and I. A. Khan, Chem. Pharm. Bull.,2000, 48, 425; see also Y. Shao et al., J. Nat. Prod., 2000. 63, 905). The EuropeanC. foetida (bugbane)is a traditional vermin preventative. 2. The Berberidaceaehas 14 generaand about 575 species,they are perennialshrubsusually with spiny leaves.The flowers are hermaphrodite,regular and hypogynous.The perianth is difl'erentiated into calyx and corolla.The stamensare generallyin two whorls and the ovary is composedof one carpel. The fruit is a berry with one to numerousseeds.Generainclude Berberis(450 spp.).Mahonia (70 spp.),Epimeditun.Vancotteria andLeontice. The Berberidaceaecontains alkaloids of the benzylisoquinoline, bisbenzylisoquinolineand aporphine Iypes. Leontice contains an alkaloidal amine and quinolizidine. Lignans such as dehydropodophyllotoxinoccur; also triterpenoidsaponins.The root tubers ol Leonticeleontopetalumcontain saponinand alkaloidsand have been usedfor the treatmentof epilepsy.For other drugs see under 'Hydrastis','Podophyllum' and'IndianPodophyilum'. In some members of the lamily there is a close resemblanceto the Ranunculaceae. Hydrastis,lbr example,is sometimesplacedin the Ranunculaceaein the same tribe as the peony. There are also relationshipswith the Papaveraceae,narcotine being found in both families. 3. The Menispermaceaeis a family of 65 genera and 350 species; mainly tropical twining shrubs,herbs or trees.The plants usually have palmately lobed leaves and dioecious flowers. Anomalous stem structure is frequently found and abnormal secondarygrowth often takesplacein the roots (e.g.of Chondodendrontomentosum'), successive cambiabeing producedto give concentricrings of wood. The broad primary medullary rays found in the stem of Coscinium are a family characteristic. The fruit is a drupe the dorsal side of which developsmore rapidly than the ventral, as in the tish beny Anamirta cocculus.Thesecontainthe highly toxic substancepicro'Calumba' 'Curare'. toxin. For drugs see and The generainclude Chondodendron(8 spp.), Tiliacora (25 spp.), Triclisia (25 spp.),Anamirta (l sp.), Cosclnlun (8 spp.),Tinospora (40 spp.),Jateorhiza(2 spp.),Abuta (35 spp.),Cocculus(11 spp.), (30 spp.) Menispermum(3 spp.),Stephania(40 spp.),Cissctmpelcts and Cyclea(30 spp.). Alkaloids are impoftant constituentsof the family and have recently beenreviewed(J.M. Barbosa-Ftlhoet al., TheAlkaloids2000,54, 1). The authorsreport that in the period 1970-1997,1560 alkaloids have beencited in twenty-twodifferentclassesincludingbenzylisoquinoIines (604), aporphines(303), protoberberines(275) and other smaller citations. Saponinsare presentin many species.Cosciniumfenestra'tree tum ('false calumba', turmeric') stems are widely used in SE Asia and India for the heatmentof a variety of ailments.The principal alkaloid constituentsareberberineandjatrorrhizine. Stephaniapierrii (5. erecta) contains bisbenzylisoquinoline alkaloids and is used in Thai folk medicine as a musclerelaxant. Tinosporacordi.foliars used inAyurvedic medicineand a considerablenumberofpharmacological actions, including immunomodulatory have been demonstratedfor 'Calumba'and'Curare'. the drug.For otherdrugssee 4. The Nymphaeaceaeis a small family of about six generaand 70 species.Speciesof Nymphaea(waterJilies) are widely cultivated. The genera include Nymphaea (50 spp.), Nuphar (25 spp.), Nelumbo (2 spp.) and Ondinea.Alkaloids occur which resemble

thoseof other families of the order but the chemistryof the family requires further research.Nuphar ttariegatum rhizomes contain antibacterialtannins and have long been used in folk medicine, similarly Nymphaen spp..NeLumbon.ucifera(the sacredlotus) and Nymphaealotus (.thewhite lotus) were reveredin the ancientcivilizationsof India, China,Tibet and Egypt.

PIPERATES Piperoceoe Four families are includedin the Piperales;only the Piperaceaeis consideredhere. The Piperaceae(excludingthe Peperomiaceae) consistsoffour genera and about 2000 species.The plants are tropical, mostly climbing shrubsor lianes,with swollen nodesand fleshy spikesof flowers. The Ieavescontain oi1cells. The one-celledovary has a singlebasalovule and developsinto a berry.The seedscontainendospermand abundant perisperm.The four generaare Piper (3bofi 2000 spp.), Trianaeopiper (18 spp.),Ottonia (70 spp.) andPothonorpfte (10 spp.).In additionto the above,Engler includesin the Piperaceaethe Peperomiaceae with its four generaand about 1000 speciesof succulentherbs and subshrubs.AII but 5 of its speciesbelong to the genus Peperomia.The Piperaceaecontainsphenolic estersand ethers;pyrrolidine alkaloids; volatile oils and lignans.The peppers(q.v.) are widely usedas condiments. Cubebs,Piper cubeba,was formerly used in medicine but is now obsolescent. In the SouthPacific islandsan aqueousextractof the roots of P methysticum(kava-kava)is consumedas a dtual stimulant; large dosescauseintoxication.In herbalmedicinethe root is usedas a diuretic, stimulant and tonic. the active principles are pyrone derivatives (kava lactones);a piperidinealkaloid,pipermethysticine,hasalso beenisolated.

ARISTOTOCHIATES Aristolochioceoe The ordercomprisesthreefamilies,of which only the Aristolochiaceae is of importance. The Aristolochiaceaehas seven genera and about 500 species. Members occur in the tropics and warm temperatezones,excluding Australia.Most are herbsor climbing shrubs.Oil-secretingcells occur throughout the family, often forming transparent dots on the leaves. The principalgeneraareAristolochia(350 spp.)andAsarum(70 spp.). Constituentsof the family include alkaloids(aporphineand protoberberine), aristolochic acid, phenolic esters and ethers, volatile oils and flavonoids. Some species show tumour-inhibiting properties. Asarun europaeum,asarabacca root, was formerly used in European medicine.

GUTTIFERALES Pqeoniqceqe, Dipferocorpqceqe, Theoceoe, Guttiferoe Of the 16 families in the order.only the four aboveneedbe noted. 1. The Paeoniaceae containsthe single genusPaeoniawith 33 species which are perennial rhizomatous herbs, occasionally shrubby. Paeonia mosculais one of Britain's rarestwild plants;it grows on the island of Steep Holme, in the Bristol Channel, having been introduced there by monks in the 14th century for medicinal purposes.Peony root is important in Chinese medicine and the speciesused,P. lactiflora, has beenextensivelyinvestigated.It is a constituent of a herbal tea which, in the UK. has come into orominence for the treatment of children's eczema.The active anti-

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A TAXONOMICAPPROACH TO THESTUDYOF MEDICINALPLANTS AND ANIMAL-DERIVED DRUGS ::rllammatory ingredient appears to be paeonol, 2'-hydroxy- 1. The Papaveraceae is a family of 26 generaand about 300 species. -:'-nrethoxyacetophenone; other constituentsof the rhizome are The plantsare usuallyherbswith solitary,showy flowers of the flo:r()noterpenoidglycosidesone of which, paeoniflorin,is used as a ral formula K 2 - 3, C 2 + 2 or 2 + 4, A -, G (2 - *). The fruit is gen^r.is fbr the quality control of the drug by HPLC. erally a capsule,with numerous seeds,each containing a small - fhc- Dipterocarpaceae has 15 generaand about 580 species.Many embryo in an oily endosperm.Generainclude Platvstemon(abolt .,rc largetreesyielding usefui timbers.Oleoresinsare a characterof 60 spp.),Romnera(2 spp.),Eschscholtzia(10 spp.),Sanguinaritt(.1 :he thmily. Generainclude Dipterocarpus (76 spp.), Shorea (180 sp.), CheLidonian(1 sp.),Bocconia (10 spp.),Glaucium (25 spp.), 'lp.). Dr)-obalanops (.9 spp.) and Hopea (90 spp.). Products Meconopsis(43 spp.),Argemone(10 spp.)andPapaver(100 spp.). :rrcfude:gurjun balsam from Dipterocarpus turbinal,s; varnish All memberscontainlatex tissue.The latex is sometimesin vessels :c.ins trom speciesof.Sftorea,Hopea andBalanocarpus;an edible which accompanythe vascularsystem(e.g.in Papaver);sometimes irt rr hich can be usedinsteadof cocoabutterin chocolatemanufacin latex sacs (e.g. Sanguinaria).The family is rich in alkaloids. rure. fiom the nuts of Shorca macrophylla; and Borneo camphor, Some, such as the opium alkaloids (q.v.),are of great medicat and t rom D ryobalnnzp,ta romatica. economic importance. Eschscholtzia californica, used by the ' I'hc'Theaceae or Ternstroemiaceae consistsof 16 generaand about Californian Indians as a sedativeand now similarly prescribedin l,x) speciesof tropical and subtropicaltrees and shrubs.Genera Europe,has been validatedexperimentally.Mustard oil glycosides '.'.;lurJe Camellic (82 spp.)andTernstroemla(100 spp.).Among the appear to be absent from the family (compare Capparaceaeand -,rn\tituents are purine basesin Camellia, saponins,tannins and Cruciferae). ::r.-d oils. By far the most important plant commercially is 2. Fumariaceae.Includedin the Papaveraceae by Engler but now genr ttrtelliu sinensis,which yields tea and caffeine.The so-called'tea erally regardedas a separatefamily. It contains16 generaand about .:c-d oil' is an edible oil which is a possibleadulterantof the more 55 species:they contain a watery, not milky, juice. Isoquinoline :rpensive olive oil and is obtainedfrom Camellictsasanqa. alkaloidsare a featureof the family. Fumitory is usedfor liver dis- I hc'Guttiferaecontainsabout40 generaand 1000species.They are orders,seeChapter30. ::ccs. shrubsor lianes,exceptHypericl.rn,which is oiten treatedas 3. Capparaceae. A family of 30 generaand 650 species;usually trees -: :eptrote family, the Hypericaceae. The main genera are or shrubs,often xerophytic.The genusCapparis(250 spp.)includes Htpericum (400 spp.), Kielmeyera (20 spp.), Clusia (145 spp.), Capparis spinosa,the buds of which (capers)are used in flavourGtt rci n ia (400 spp.)andCalophylltua ( I I 2 spp.). Constituentsof rhe ing. Like the Cruciferae,the family has myrosin cells and mustardternily include resins,volatile oils, alkaloids,xanthonesand seed oil glycosidessuch as glucocapparin.The only alkaloid reportedis ,'ils. Products include resin from Caloph,vllumand gamboge, a pyrrolidine in two genera. Cardenolides,which occur in some ioloured gum resin, trom Garcinia. The edible fruit mangosteenis Cruciferae,havenot beenfound in the Capparaceae. zl. Cruciferae.A family of 375 generaand about 3200 species;herbs ,'btainedfrom Garcinia manpostanaand a few undershrubs.The inflorescenceis typically a raceme withoutbracts.The flowersareof thetype,K2 +2,C2 +2, A2 + 4, SARRACENIATES G(2). The stamensare tetradynamousand the ovary is divided into two loculi by a replum uniting the two parietalplacentas.The fruit Sorrqcenioceoe, Nepenfhoceoe, Droseroceoe is called a siliqua when elongated,as in the wallflower and mus.::c threesmall families of insectivorousplantsforming this order are tards; or silicula when almost as broad as long, as in shepherd's : nrinorpharmaceuticalinterest. purse and horseradish.The testas of the seeds often contain The Sarraceniaceae consistsof three generaand 17 speciesof pitmucilage. Genera include Brassica (about 30 spp.), Slnapis (10 -:'.1'r-plants. The Nepenthaceaehas two genera and 68 species,of spp.),Nasturtium(6 spp.),Lepidium (150 spp.),Hesperis(30 spp.), .,.:ich 67 belong to Nepenthes.Intheseplants,which occur mainly in Cheiranthus (10 spp.), Isatis (45 spp.), Erysimum (100 spp.), ::',pical Asia, the leaves are modified into pitchers, which attract Crambe(25 spp.) andLunariu (3 spp.).CultivatedBrassicaspecies ::.c'ctSby their colour and honey-like secretion.The Droseraceaehas include: B. nigra (black mustard); B. oleracea (cabbage,cauli: ,ur seneraand 105 species.Ofthese, 100 belongto Drosera,which is flower, broccoli, etc.); B. campestris,turnip; and B. napus,rape or -:nresentedin Britain by three sundews.In thesecommon bog-plants colza oil. Sinapis alba yields white mustard Nasturtium officinale, ::r!' leaves are covered with glandular hairs which trap and digest water cress;LepidiLLmsativum, garden cress;Isatis tinctoria, Ihe :r'ects.The Europeansundew,Drosera rotundifolia, has long been dyestuff woad, made by grinding and fermenting the leaves(for the ::rployed in folk medicine and has been included in some pharmasignificance of indoxyl derivatives in this connection see T. -,poeias (BHP 1983).In Italy it is an ingredientof a liqueur.It contains Kokubun et al., Phl,"tochemistry 1998,49, 19); Crambe maritimcL, ::rcnaphthoquinone plumbagone,which has antimicrobialactivity. the seakale. Many membersof the Cruciferaecontain mustard-oil glycosidesand in specialmyrosin cells containthe enzymesnecessary for their hydrolysis.Cardiacglycosidesoccur in some genera PAPAVERALES and the seedsusuallycontainmucilageand fixed oil. Popoveroceoe/ Fumqrioceoe, Cqppqroceoe, Cruciferqe ROSALES \n order of sevenfamilies, if the Fumariaceaeis separatedfiom the i'.ipaveraceae. The Papaveraceae belongsto the suborderPapaverineae Homomelidoceqe, Crqssuloceqe, Soxifrogqceqe, .,rJ the Capparaceae and Cruciferaeto the Capparineae. Someworkers Rosoceoe, Leguminosoe, Kromerioceoe :lgard the Papaveraceaeas related to the Ranunculalesand the The order Rosalesconsistsof l9 families divided into four suborders. t'.ipparineaeas derived from the Cistales.Chemical support for this The iamilies to be consideredfall into the subordersas follows: . rcri is that alkaloids of the Papaveraceae are relatedto those of the Hamamelidineae (Hamamelidaceae);Saxifragineae (Crassulaceae, R.rnunculaceae,and that thiogluconates are absent from the Saxifragaceae and Pittosporaceae); Rosineae (Rosaceae); i'rpaveraceaebut presentin the other two families. Leguminosineae (Leguminosae and Krameriaceae).The flowers are

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OF DRUGS THEPLANTAND ANIMAI KINGDOMSAS SOURCES usuallyhermaphrodite(rarelybisexualby abortion:e.g.koussoflowers from Bral,era');hypogynous.perigynousor epigynous.The sepalsand petals are usually free; stamensand carpelsfree or united.

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A family of 26 genen and 106 speciesof trees 1. Hamamelidaceae. and shrubs,chiefly subtropical.GeneraincludeHamamelis(6 spp.) and Liquidambar (6 spp.). Drugs (q.v.) include hamamelisleaves (Hamamelis virginiana), Levant storax (Liquidambar orientalis) and American storaxor sweetgum (L. s6raciflua). The family contains tannins, balsamic resins,phenolic acids and cyclitols; alkaloids are absent. 2. Crassulaceae. A family of 35 generaand I 500 species;many perennial xerophytes. Genera include Sedum (abort 600 spp.), Sempervivum(25 spp.) and Crassula(about300 spp.).An interesting chemical character of the family is the presence,often in large amounts,of isocitric acid;it was in this xerophyticlamily that a distinctive build-up of malic acid during the hoursof darknesswas first acid metabolism(CAM) given to noticedand the term crassulacean this particularadaptationof the photosyntheticcycle (seeChapter 19). The carbohydrate sedoheptulose occurs in both the and the Saxifragaceae. Cyanogeneticglycosidesand Crassulaceae cardiacglycosidesoccur in some species;tanninsare common but alkaloidsrare.Speciesof Sedumhavebeenusedmedicinallybut the family containsno importantdrugs. is a family of 30 generaand about 580 species; 3. The Saxifragaceae chiefly north temperateherbs.GeneraincludeSaxiJrage(370 spp.), AstiLbe and Ribes. The latter, sometimes separatedas the family includes such well-known fruits as the blackcurGrossulariaceae, rant, redcunant and gooseberry.These are rich in citric and malic acidsand in ascorbicacid.Black Cunant SyrLrpis usedmedicinally. containtanninsand saponins, Somemembersof the Saxifragaceae but alkaloidsare rare. 4. Rosaceae.A family which includes about 100 genera and 2000 speciesof herbs, shrubs and trees. The leaves are simple (e.g. Pntnus) or compound(e.g.Rosa).Considerablevariety existsin the flowers and fruits. There are no anatomicalfeaturescharacteristicof the family as a whole, and the various subfamiliesfrequentlyshow differences in stomatal arangement, origin of cork, etc. Genera (3 spp.),Malus include Spiraea(100 spp.),QuiLlaja(3 spp.), P1'"rus (35 spp.), .Sorbls (100 spp.), Kerria (1 sp.), Rubus (250 spp.), Potentilla (500 spp.), Geum (40 spp.), Alchemilla (250 spp.), Agrimonia (15 spp.),Poterium (25 spp.),Rosa (250 spp.),Prunus, including Laurocerasus (430 spp.) and Crataegus (200 spp.). Constituentsof the Rosaceaeinclude cyanogeneticglycosides, saponins,tannins, seed fats, sugar alcohols, cyclitols, terpenoids and mucilage; alkaloids and coumarins are rare. The secondary metabolites of the family have been the basis for a number of chemosystematicstudies(for such studiesinvolving hydrolysable tannins see T. Okuda et aL., Phytochemistry, 1992, 31, 3091). Impoftant products (q.v.) are oil of rose (Rosa damascena),rose hips (R. canina), wild cherry bark (Prunus serotina), almond oil hawthorn (Pruntrsamygdalus),quillaia bark (Quillaia saponaricL) (Crataegus oxycanthoides).Other products are cherry-laurel leaves (Prwttts laurocerasus'),quince seeds (Pyrus c1'donlc), prunes (Prwtus domestica),raspbery fruits and leaves(RaDasidaeus)and morello cherries(Prunuscerasus). 5. Leguminosae.This is the secondlargestfamily of flowering plants and contains600 generaand about l2 000 species.It includesmore important drugs than any other family. It is divided into three subfamilies-the Papilionaceae, the Mimosoideae and the containing,respectively,about 377, 40 and 133 Caesalpinoideae, genera.Importantcharactersand generain eachsubfamily are:

(1) Papilionaceae:Herbs, shrubsor trees; leaves simple or compound; flowers zygomorphic and papilionaceous(e.g. in broom); stamens 10, monadelphousor diadelphous; fruit a legume.GeneraincludeMyroxylon (2 spp.),Sophora(50 spp.), Crotalaria (550 spp.), Lupinus (200 spp.), C.vtisus(25-30 spp.), Ononis (75 spp.), Medicago (100 spp.), Melilotus (25 spp.'),Trfolium (300 spp.), Psoralea (130 spp.), IndigoJera (700 spp.),Astragalus(2000 spp.),Vicia (150 spp.),Lens (10 spp.), Lathyrus (130 spp.), Pisum (.6 spp.),Abrus (12 spp.), (10 spp.),Ery-thrina(100 spp.),Mucuna (120 spp.), GL1-cine P haseolus (200-240 spp.),A r ac his ( I 5 spp.), Tri g onell a (abotr 100 spp.), Butea (30 spp.), Derris (80 spp.), Lonchocarpus (150 spp.), Copaifera (25 spp.) and Er1-throphleum(17 spp.). Drugs (q.v.) from this subfamily are fenugreekseeds,calabar bean,tonco seed,liquorice root, denis, lonchocarpus,Tolu balsam, Pem balsam, arachis oil and tragacanthgum. Common British plants with poisonous properties include broom (C,yrisusscoparius),laburnum (Cytisus laburnum) and many speciesof Lupinus. Among economicproductsother than drugs may be mentionedsunnhemp (.Crotalariajuncea),lentils (lens esculents),peas(Pisun sotivum),soya bean (Glycine hispida), scarlet runner, French and Lima beans (Phaseolus spp.), groundnut (Arachis hypogaea) and copaiba oleoresin and copals (Copctfera spp.). Species of Indigofera, including L tinctoria, are a source of indigo (for biosynthesisof indigo see Z.-Q. Xia and M. H. Zenk, Phytochemistry, 1992, 31,

269s). (2) Mimosoideae: Most members of this subfamiiy are trees or shrubs;leavesusually bipinnate;flowers regular;calyx usually gamosepalous; stamensequalin numberto the petalsor twice as numerous; fruit a legume. Important genera are Mimosa (450-500 spp.) and Acacia (150-800 spp.). Productsinclude acaciagumsfromAcacia spp.,wattlebarksusedin tanningfrom Acacia spp.and volatile oil suchas oil of cassie(A.Jarnesiana), which are usedin perfumery. (3) Caesalpinoideae: Membersaretreesor shrubs;leavespinnateor bipinnate;flowers zygomorphic;typical floral formula K5, C5, A 5 + 5, G L Drugs derived from this subfamily are sennaleaves and pods,cassiapodsand tamarinds.Otherproductsarethe redwoods logwood, from HaematoxyLon,and sappanwood, from Caesalpinia;sassybark, from Ery-throphleumguineense,and carobbeansfrom Ceratoniasiliqua. Of the threesubfamilies,the Mimosoideaeand Caesalpinoideae are mostly tropicalplants,while the Papilionaceaeoccur in both tropical and temperate regions. Tannin sacs are common, The conparticularlyin the Mimosoideaeand Caesalpinoideae. stituentsof the Leguminosaeshow many similaritiesto thoseof the Rosaceae.Both contain cyanogeneticglycosides,saponins, tannins, mucilage and anthocyanins.Alkaloids, however, are common in the Leguminosaebut rarein the Rosaceae.For a discussionofthe chemotaxonomicrelevanceof seedpolysaccharides and flavonoids in the family see R. Hegnauerand R. J. Grayer-Barkmerjer,Phyrochem., 1993, 34, 3. An important work of referencefor the family is Phytochemical Dictionary of the Leguminosae,Vols I and 2 (1994), compiled by I. W. Southonand publishedby Chapmanand Hall, London. (4) Krameriaceae: This, often includedin the Leguminosae(q.v.),is a family of one genus, Krameria, and 20 species.They are shrubs or herbs found liom the southern USA to the Argentine. but two of the petals The flowers resemblethe Caesalpinoideae, are modified into glands and there are only three stamens.They containphlobatannins;see'Rhatany'.

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GERANIATES Geronioceo e, Zygophyllqceqe, Linoceoe, Eryf hroxyloceoe, Euphorbiqceoe . ::l order Geranialesconsistsof nine families. fhe Geraniaceaeconsistsof five generaand 750 species;mostly herbs.Members of the two large generalGeranium (2100spp.) and Pelurgonium(250 spp.) are popularly called 'geraniums'and the ;orrrmercialrose geraniumoil is obtainedfroma Pelargoniunt.The tamily containsvolatile oils which are widely used in perfumery: nroreresearchis neededon other constituents. - The Zygophyllaceaeis a family of 25 genera and 240 species; nrostlywoody perennials,tropical and subtropical.Generainclude (100 spp.), Tribulus (20 spp.), Guaiacum (6 spp.), 1,tgoph1:lLum Peganum(5 or 6 spp.) and Balanites(25 spp.).Peganumharmala .rtd Tribulusterrestrisare usedin Indian medicinelthe alkaloidsof the tbrmer (harmine, harmaline and derivatives)have been proJucedin hairy root cuituresand the saponinsof the latterhavebeen r'\tensively studied(seeY.-X. Xl et aL.,Phltochemistr,r1998, 49, 199). Some memberscontain alkaloids, steroidalsaponinsor lignans.For drugssee'GuaiacumResin'. : The Linaceaeis a lamily of l9 generaand about290 species;mostlr herbs or shrubs.About 230 of the speciesbelong to Linum. Constituentsof the family include cyanogeneticglycosides,fixed oils. mucilages,diterpenesand triterpenes.Flax and linseedand its ,ril (q.v.)are obtainedfrom Linum Ltsitatissimum. : The Erythroxylaceaeis closely relatedto the Linaceaeand comprises .ome thtee to four generawith E r!-thro.r-rLum pre-eminent(about 200 .pp). The other small genera including Nectaropetalwn are repre\entedby about l0 species.Ery-throxy-lunt spp.aredistributedwidely throughouttropical and subtropicalregions with large areasof diver'iflcation in South America and Madagascar.Alkaloids have been tirundin most speciesanalysedby modernmethods;theseareprincipally estersof the tropanetype togetherwith biosyntheticallyrelated hasessuch as hygrine, hygroline and cuscohygrine.Nicotine is of linrited occurrence,cocaine and cinnamoylcocaineappear to be restrictedto the cultivatedspeciesE. coca and E. novogranotense. The small treesor shrubsproducehard woods which constitutea rich \ource of diterpenoidcompounds.Quinonesand saponinsprobably contributeto the colour and durability of the wood. Phenoliccon\tituents in the form of aromatic acids such as cafteic and chlorogenicacids,and flavonoidsmay havechemosystematic impoftance. ' The Euphorbiaceaeis a large family of about 300 generaand 6000 or ntore species.Most members are treesor shrubs,a few herbs. Some renera (e.g. Euphorbia) are xerophytic. The flowers are unisexual rnd regularwith usually five perianthleaves;stamensmay be numerous and are free or united.The superiorovary ofthree calpels forms a trilocular capsule.Genera include Euphorbia (about 2000 spp.), Phyllanthus(about 550 spp.) Mallotus (2 spp.), Ricinus (1 sp.), Croton (150 spp.),Hevea (12 spp.),Jatropha (175 spp.),Manihot t 170spp.),Sapium(120 spp.),Poranthera(10 spp.),Securinega(25 .pp.),Aleurite,s(2 spp.)andHippomane(5 spp.).In additionto castor reedsand castoroil (q.v.), productsinclude the dye and taenicide kamala (from Mallotus philippinensis'); rubber, frorn species of Hevea, Manihot and Sapium; manihot or cassava starch, from llunihot esculentus(rzrllis);Chinesetallow, a fat, from Sapiumsebilerum, and a drying otl, from Aleurites moLuccana.Phyllanthus is a ri idespreadtropical genusand has beenmuch employed in traditional medicines. Minor drugs are croton oii, from Croton tigliunt, and cascarillabark, from C. cascariLlaand C. eleuteria.In somecasesthe lirtex is poisonousor irritant (e.g. that of Hippomane), and the resinous product 'euphorbium' was formerly much used as an

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antifbulingagentfor ships'hulls.Many speciescontainirritantor piscicidal substances.Some members such as cassavamay contain cyanogeneticglycosides.This plant, Manihot esculentus,occursin two varieties,sweetand bitter, only the latter yielding prussicacid. In addition to the constituentsalready mentioned, some members contain anthraquinones,triterpenoids, fatty acid epoxides, unsaturated fatty acids and antitumour agents.Alkaloids, when present,areusually of the aporphine,pyridine, indole, quinoline or tropanetypes. Latices from Euphorbitt specieshave widely varying biochemical propefiies with respectto their protein and carbohydrateproperties, the type and amountsof enzymespresent,and their haemagglutinar ing activities.For a review of the chemistry,taxonomy,and economic botanyofthe family, seeTheEuphorbiales,S. L. Jury,T. Reynolds, andD. F. Cutler (eds)( 1987),London,UK: AcademicPressandfor a review (293 refs) of the phytoconstituentsof Euphorbia spp. seeA. K. Singlaand K. Pathak,Fitoterpia 1990,61,483.

RUTATES Rutoceoe, Simorouboceoe, Burserqceoe, Melioceoe, Molpighioceqe, Polygoloceoe This order is closely allied to the Geraniales.The chief differenceis that in the Rutales the plants are mainly shrubs or trees. The flowers havea disc betweenthe androeciumand the gynaecium.Oil glandsare of generaloccurrence.The order contains 12 families and is divided into three suborders.Of the families mentionedabove,the Rutaceae, Simaroubaceae, Burseraceae andMeliaceaeall belongto the samesuborder. the Rutineae. l. Rutaceae.The family consistsof about 150 generaand 900 species; mainly shrubsand trees;distributedin both temperateand tropical countries,but particularlyabundantin SouthAfrica and Australia. Oil giandsare presentin the leavesand other parts.The flowers are usuallyin cymeswith 4-5 sepals,4-5 petals,8 or l0 stamensand a superiorovary.The fruits areof varioustypes,but in the orangesubfamily, the Aurantioideae,it is a hesperidium.Fruits include orange and lemon (q.v.), lime (.Citruslimetttt and C. medica var. acidtt), ciIron, bergamot, shaddock and grapefruit. There are 12 different speciesof Citrus. Other generainclude Zanthoxylum(20-30 spp.), Fagara (250 spp.), Choisya (6 spp.),Ruta (7 spp.),Dictamnus (6 spp.),Diosma (15 spp.),Galipea (13 spp.). Cttsparia (Angostura) (30 spp.), Ptelea (3 spp.), Toddalia (l sp.), Skimmia (7-8 spp.), Limonia(1 sp.),Aegle(3 spp.),Moniera (2 spp..),Haplophyllum(70 spp.),Teclea(30 spp.),Esenbeckia(38 spp.)andMurra,-a (12 spp.). Productsnot mentionedabove are buchu leaves (.Barosmaspp.); jaborandi leavesand their alkaloid, pilocarpine(Piktcarpus spp.); Japan pepper (Zantfutx,-lumpiperitum); elephantapple (Limonin acidi ssima); Braziiian angostura(Esenbeckiafeb rifu,ga);and angostura or cusparia (Galipea fficinalis). Speciesof Haplophtllum, Evodia, CLausena,Phellodendron, and ZanthoxyLumhave all been used in traditionai medicine. Bael fruits (Aegle marmelos)are an impofiant Ayurvedic medicine;they containcoumarins,flavonoids (rutin and marmesin)and a glucosylatedpropelargonidincontaining up to five units of pelargonidinwith immunomodulatoryactivity (A. M. Abeysekeraet al., Fitoterapia 1996,67,367). Prickly Ash bark ol the BHP is derived from Zanthoxylumclaya-hercalis;among other constituentsit containsalkaloids e.g. chelerythrineand nitidine, a lignan-asarininand an n-isobutyl polyeneamide.It is used as an antirheumatic.The bis-indolealkaloid yeuhchukenefrom Murraya panicuLatahas been studiedfor its anti-implantation,contraceptive activity; for informationon the uses,activity and phytochemistryof this species,togetherwith a report on the isolation of cinnamates

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T H EP L A NA T N DA N I M A LK I N G D O MA SSS O U R C EOSF D R U G S and coumarins from the leaves, see Atta-ur-Rahman et al., P hytochemist ry 1997,44,683. Constituentsof the Rutaceaeinclude a wide variety of alkaloids, volatile oils, rhamno-gh,rcosides, coumarins and terpenoids.Alkaioids include alkaloidal amines, imidazole, indole, isoquinoline,pyridine, pyruolidine,quinazoline and quinoline types.Many of the fruits are rich in citric and other acidsand in vitamin C. A tamily of 20 generaand about I 20 species;trop2, Simaroubaceae. ical and subtropical shrubs and trees. Members differ from the Rutaceaein not containingoil glands.Bitter principlesiue a characteristic of the family. Genera include Quassia (Simarouba) (40 spp.),Picrasma (Aeschrion')(6 spp.),Brucea (10 spp.),Souktmeu (10 spp.),Ailanthus (10 spp.), andPerriera (l sp.).Quassiawoods (q.v.) are used as bitters.Ailanthus glanduLosa,Tree of Heaven.is widely cultivated and its leaveshave been used to adulteratebelladonnaand mint. For a discussionof the quassinoidsof the lamily 'Quassia'. see Burseraceae. A family of about 16 generaand 500 species:tropical in north-eastAfrica, Arabia shrubsand trees.Many representatives and tropical America. The leaves, like the Rutaceae,are glanddotted.Oleoresincanalsare found in the phloem and sometimesin the pith. Genera include Commiphora (185 spp.), Bonvellia (24 spp.),Bursera (80 spp.), and Canaritutt(75 spp.).The best-known product of the family is myrrh (q.v.). Other productsare frankincense (Boswellia spp.), American elemi (.Bursera gummifer), Manila elemi and Javaalmond from Canariumluzonicum. Meliaceae.A family of 50 generaand about 1400 species:treesor shrubs.Someyield timber (e.g.mahoganyfromSwieteniamahagonl); others, seed oils. Generainclude Cedrela, Swietenia,Khat'tt, Carapa, Melia and Azadirachta. Azadirachta lndlczz(Neem) is an important Indian medicinal plant (q.v.); bark, leavesand seedsare used. Significant constituentsof the family are triterpenoidsand limonoids. 5. Malpighiaceae.A family of 60 generaand 800 species;shrubsor small trees.GeneraincludeMalpighia (35 spp.) andBanisteriopsis. Some membershave stinging hatrs.Banisteriop.rlscontainsindole alkaloids,and plantsmay be hallucinogenic. A family of 12 generaand about800 species,of which 6. Polygalaceae. in Britain by some600 speciesbelongto PoLvgala.Itis represented the milkwort, Po$gala vulgaris. Other genera are Mrtnnina, Securidaca and Carpoktbia. Senegaroot (q.v.) is obtained from the North American Polygala senega. Characteristic constituents are triterpenoid saponinsand,in Po\tgala, the sugaralcohol polygalitol. Methyl salicylateis commonto a numberof genera

speciesof Rftls yield Japaneselacquerand the fat knorvn as Japan wax. Mastic resin containstriterpenoidacidsand alcohols. Aceraceae.A family of trees and shrubs.In the genusAcer (100 spp.)is Acer .rrz ccharttm,which yields maple su-9ar. A tamily of about150generaand2000 species:tropical 3 . Sapindaceae. and subtropical.Generainclude Paullinia (180 spp.),Supindus(13 spp.),Curdiospermum(12 spp.'),Eriocoelunt,Blighia andRadlkoferu. The seedsof PuLilliniacupanLtaremade into a pasteand dried to form guarana;this contains cafl-eineand is used as a beverage.Sapindus saponoriahasbeenusedin Brazil and India asa soapand for the treat(q.v.) it containssaponinswith hederagenin ment of severaldiseases; as an aglycone.Constituentsof the family include saponins.cyanogeneticglycosides.cyclitols(e.g.shikimicacid);the seedfats contain a high proporlion of oleic acid.Alkaloids have beenleported in a f'ew species,includingcaffeineandtheobrominein Paulliia. A small family of only two genera and 15 4 . Hippocastanaceae. species;tropical treesand shrubsof southernAfrica. Aesculus(13 spp.) containsthe horse chestnut,A. hippocustanum.Its seedfat, like the Sapindaceae, containsa high proportion,about65-'707o,of oleic acid. Severalof the speciesexaminedcontainphenolicacids, coumarins,cyclitols and saponins;alkaloidsappearto be absent.

CETASTRATES Aquifolioceoe, Celqsfrqceqe, Buxoceqe An order of 13 families;treesand shrubswith simple leaves.

1. Aquifbliaceae.The holly family consistsof two generaand about 400 species,all but one of which belongto the genusl1er.Members are trees and shrubsfound in the temperateand tropical regions. Matd or Paraguaytea is obtained from lle.r paraguariensis and other productis cassina,the leavesof A similarcaffeine-containing species. Ilex cassine. Constituents reporled in the family include caffeine. theobromine,cyclitols (shikimic acid and inositol), triterpenesand triterpenoid saponins. 2. Celastraceae. A family of 55 generaand 850 species:tropical and temperatetrees and shrubs.Generainclude Euont'rltts (176 spp.). Celastrus(39 spp.), Cassine (40 spp.), MuytenLts(225 spp.;. Prionstemrna, Catha, Tripterl,giunt and Peripterygitt. Catha edulis yields the leavesknown as khat or Abyssiniantea:thesecontainthe The root bark of Euorrymus alkaloid cathine (norpseudoephedrine). containscardioactiveglycosidesand is includedin the atropLrrpureLts 811P.Constituentsof the family includealkaloidalamines,alkaloids of the pyridine and purine types,sugaralcohols(dulcitol),saponins, cardenolides,terpenoidsand substanceshaving antitumor.rractivity. 3. Buxaceae.A family of five generaand 100 speciesof tropical and temperate,usually evergreen,shrubs.The generaareBa-rrls(70 spp.), SAPINDATES and Notoburus (7 spp.), Sarcocolla (16-20 spp.), Pachv-,candra Simmondsia.Much researchhas beendone on the steroidalalkaloids Anqcqrdioceqe, Aceroceoe, Sopindqceqe, of the family, includingthe genusBrnus, somespeciesof which find Hippocostonqceqe usein traditionalmedicine;seeAtta-ur-Rahmanet aL.,J. Nat. Prod.. The Sapindalesconsistof 10 families. 1991, 60,976 fbr a study of '8. longifolia. Other constituentsinclude Afamily of60 generaand some600 species;main1. Anacardiaceae. phenolic acids and waxes. The seedsof ,Slnmondsittchinensisyreld ly tropical trees and shrubs.Generainclude MangiJern (40 spp.), the Iiquid wax, jojoba wax, which consistsof straightchain estersof Anacardium (15 spp.), Rhus (250 spp.), Pislacia (10 spp.), 20 1, 22:1,24:I fattyacids(q.v.)andalcohols. Toxicodendntn(15 spp.), Lannea (70 spp.), Cotinus (3 spp.) and Schinus(30 spp.).Productsinclude the mango,Mang(bra indica; cashewnut,Anacardiumoccidentale;sumacleaves,usedin dyeing RHAMNALES and tanning, Rhus coriaria; the Japanesewax tree, Thus sucRhqmnoceqe, Viloceoe cedanea; mastic resin, Pistacia lentiscus; and pistachio nuts, The order containsthreelamilies. Pistacia vera. The family containsdyeing and tanning materials, l. Rhamnaceae.A farnily of 59 genera and about 900 species: and phenolic compoundssome of which causedermatitis(e.g. the cosmopolitan,usually trees or shrubs. Genera include Rhttntntts vesicantconstituentsof the poison ivy. Rhustoxicodendron).Other

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A TAXONOMICAPPROACH TO THESTUDYOF MEDICINAL AND ANIMALDERIVED PLANTS DRUGS I I {) spp.),Zizyphus1I00 spp.),Scutia(9 spp.),Discaria(I0 spp.), (-rtl11p17,r1,rr, (17 spp.),Maesopsisand Hot,enia.British speciesare :he alder buckthorn,Rlumuutsalnus, and the buckthorn,Rhamnu.s arlturtit'ct.These,like R. purshiana,which producescascarabark, .()rrtainquinones.The edible fruts of Zizipltus.jujubct are known as Frenchjujubes and are used in traditional Chinesemedicine as a rlild sedative.The constituentsof the family include purgative .luinones (anthraquinones.anthranols and their glycosides).A1kaloidal peptidesoccur in some genera;also terpenoidsand triterpL'noidsaponins. - \ itaceae.The family contains about 65 spp. of Viri.s(vines). V. . iti.fertL producesgrapes,wine, raisinsand cunants.Therehas been ionsiderablerecentinterestin the beneficialefl-ectofred wine arisrng tiom its antioxidant properties with respect to low-density lipoprotein and protection against atherosclerosisand coronary heart disease;see E. N. Frankel and A. S. Meyer, Pharm. Biol., 1998.36(suppl.),14.The compoundsinvolvedincludeflavonoids, arrthocyanins,flavonols and phenolic acids. For a review of Vitis vitti.t'era with 108references.seeE. Bombardelli and P Morazzoni, f i t r t t c t " P1i .9l 9 56. 6 . 2 9 ' .

gum come from Sterculiaurens.As in the Malvaceae.mucilageis common;pr.rrinebasesoccur in Theobromaand Cola.

THYMELAEATES Thymeloeoceqe, Elqeqgnqceoe An order of five families. l. Thymelaeaceae.A family of 90 genera and 500 species;mostly temperateand tropical shrubs.Generainclude Gnidia (lO0 spp.), Daphne (70 spp.) and Pimelett(80 spp.).Some speciesof Daphne arepoisonousand containvesicantresins.The bark of Daphneme1ereum was formerly official; the floral fragranceis composedof about 957c s-(+)-linalool.Mucilage and coumarinscommon in the f a m i l l: a l k a l o i d a sbrent. 2. Elaeagnaceae.A family of three genera and about 50 species, inciuding Hippophae(3 spp.),Elaeagnus(45 spp.) andShepherdia (3 spp.).Amongthe constituentsare indole alkaloidsand cyclitols.

VIOLATES AAALVAIES Eloeocorpoceqe, Tilioceoe, Mqlvqceqe, Bombocqceqe, Sierculiqceqe \n order of sevenfamilies. Herbs, shrubsor trees;tropical and tem:'.irate.Many speciescontainmucilagelalkaloidsal'erare.

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Elaeocarpaceae. A family of 12 generaand 350 speciesof tropical and subtropicaltrees and shrubs.Chief generaElaeocarpus(200 :pp.) and Sloanea (120 spp.). Indolizidine alkaloids occur in Elueocarpus. I Tiliaceae.A family of 50 generaand some450 species;usuallytrees crrshrubs.Generainclude Corchorus( 100 spp.) and Tilia (50 spp.). Jute flbre is obtained from Corcltoruscapsulari.sand C. olitorius. Lime Tree Flower BHP, BP 2000 is the dried inllorescencesof Tilia plary'ph.t'll.os or T. cordata and is used for treatingrespirttory tract infectionsand as a nervine and tonic: constituentsinclude volatile oil (composedof over 90 cornponents),flavonoids and phenolic acids.The American lime yields phloem fibres, usedby gardeners under the name of 'bass'. Cardiac glycosidesare reported from Corchorus'.alkaloidsare absent. i Malvaceae.The family contains75 generaand about 1000 species of herbs,shrubsand trees;tropical and temperate.Generainclude ,llalva (.40 spp.), Goss1pium (20-41 spp., authorities differ), Hibist:us (300 spp.), Althaett (12 spp.), Pavonia (200 spp.) and Thespesia(15 spp.).The cottons,speciesof Gossl-pium,are imponant both ior their seedhairs and seedoil (q.v.).Marshmallow root, lromAlthaea o.fficinali.s, is usedas a demulcent(q.v.).The common hollyhock is Althaea rosea.Few specieshave been studiedchemically, but saponins,tannins.leucoanthocyanins and phenolicacids occur;typical alkaloidsappearto be absent. I. Bombacaceae. A small family of about20 generaand 180 speciesof tropical trees. Genera include Bombax (8 spp.), Ceiba and .\tlunsonia. Kapok, which consists of the lignified, silky hairs n hich line the fruits of various speciesof Bombax and Ceiba, has beenusedfor life-beltsand as a stuffing material. i Sterculiaceae. A tamily of 60 generaand 700 species;mainly tropical. Genera include Sterc'ulio(300 spp.), Theobroma(30 spp.), Cola (125 spp.) and Brachtchiton. Cocoa, oil of theobromaand chocolateare preparedfrom Theobromococao; kola or cola nuts corne from Cola vera and C. acuminata; and sterculiaor karaya

Flqcourtioceoe, Violoceqe, Turneroceqe, Pqssiflorqceqe, Cistoceqe, Bixoceoe, Tomoricoceoe, Coricqceqe An orderof 20 famiiies.It includesherbs,shrubsand trees;tropicaland temperate.Cyanogeneticglycosidesoccur in someof the families (e.g. Flacourtiaceae. Turneraceaeand Passifloraceae), but are absentfrom others(e.g.Violaceae). l. Flacourtiaceae.A family of 93 genera and over i000 species. Generainclude Ervthrospermurz(6 spp.),Htdnocarptrs (40 spp.), Flacourtia (15 spp.) and Homolium (200 spp.).The seedoils have beenparticularlystudied,as speciesof H y-dnocarpus containcyclic, unsaturatedacids which are bactericidaltowards the micrococcus of leprosy.Other constituentsof the family include cyanogenetic glycosides,tanninsand phenolic acids.Alkaloids reportedonly in one genus,Ryctnitt. 2. Violaceae.A family of22 generaand about900 species;cosmopolitan, herbsand shrubs.Generainclude Viola (500 spp.),H v-banthus (150 spp.) and Hymenanthertt(7 spp.).The pansy (Viola tricolor'), sweetviolet (V. odoruila')and dog violet (V c'anina)have beenused medicinally.They contain volatile oil and anthocyanin,flavonoid (rutin) and carotenoid pigments. Hybanthus ipecacuanha has occuned as an adulterantof genuineipecacuanha. 3. Turneraceae.A family of seven genera and i20 speciesof trees, shrubsand herbs. Turnera has 6 1 speciesand T. diffusa is the source of damianaleaves. 4. Passifloraceae. A family of l2 generaand 600 species;tropical and warm temperate;shrubsand trees,often climbers.The main genera are Passiflora (500 spp.),Adenia (92 spp.) and Tetrapathaea,Ihe latter a singlespeciesfrom New Zealand.Someof the fruits are edible (e.g. passion fruit, from Passiflora edulis). The dried aerial pafis of P. incarnata are a popular herbal sedative;they contain flavonoids and tracesof cyanogeneticglycosides,volatile oil and harmane-typealkaloids.Pharmacologicaltestshave supportedthe traditionalusage(R. Soulimaniet al., J. Ethnopharmacologl,1991, 5 7 . 1l ) . 5. Cistaceae.A family of eight generaand 200 species.Members are herbs and shrubs,particularlyfound on chalk or sand.The genera include Helianthemum(100 spp.),Cistus (.20spp.) and Halirnium. Speciesof Clsarsyield the oleo-gum resin ladanum,used in perfumery and for embalming.

A TAXONOMICAPPROACH TO THESTUDYOF MEDICINAL PLANTS AND ANIMAT-DERIVED DRUGS

I

i l{) spp.),ZiTplns (100 spp.),Scutio(9 spp.),Discaria(10 spp.), ( olutttbrina( l7 spp.).Maesopsisand Hoveria. British speciesare the alder buckthorn.Rhamrus al.nus,and the buckthorn,Rhamnus , utlturtica.These.like R. purshiana,which producescascarabark, J()ntainquinones.The edible truts of Ziziphus.jujttbttareknown as l'rcnch jujubes and are used in traditional Chinesemedicine as a rlild sedative.The constituentsof the family include purgative quinones (anthraquinones,anthranolsand their glycosides).Alkaloidal peptidesoccur in some generaialso terpenoidsand triterpenoidsaponins. Vitaceae.The family contains about 65 spp. of Vitls (vines). V. viti.feraprodtces grapes.wine. raisinsand cunants.Therehas been considerablerecentinterestin the benellcialefTectof red wine arisin_sfrom its antioxidant properties with respect to low-density lipoprotein and protection against atherosclerosisand coronary hcart diseaselsee E. N. Frankel and A. S. Meyer, Pharm. Biol., 1998,36(suppl.),1zl.The compoundsinvolvedincludeflavonoids, anthocyanins,flavonols and phenolic acids. For a review of Vitis rittifera with 108references,seeE. Bombardelli and P. Morazzoni, L itrttsl'p1a Iq95.66. 29 | .

MAIVAIES Eloeocorpoceqe, Tiliqceqe, Molvqceoe/ Bombococeoe, Sterculiqceqe \n order of sevenfamilies. Herbs. shrubsor trees:tropical and temIrrrate.Many speciescontainmucilage;alkaloidsarerare. l. Elaeocarpaceae. A family of I 2 generaand 350 speciesof tropical and subtropicaltrees and shrubs.Chief generaElaeocarpus(200 spp.) and Sloanea (120 spp.). Indolizidine alkaloids occur in Elueocarpus. l. Tiliaceae.Afamily of 50 generaand some450 species;usuallyffees crrshrubs.Generainclude Corchorus(100 spp.) and Tilia (50 spp.). Jute fibre is obtainedfrom Corchoruscapsularis and C. olitorius. of Tilia Lime Tree Flower BHP. BP 2000 is the dried inflorescences plattphy-llos or T. cordata and is used for treating respiratory tract int'ectionsand as a nervine and tonic: constituentsinclude volatile oil (composedof over 90 components).flavonoids and phenolic acids.The American lime yields phioem fibres. used by gardeners under the name of'bass'. Cardiac glycosidesare reported from Corchorus.alkaloidsare absent. .1. Malvaceae.The family contains75 generaand about 1000 species of herbs,shrubsand trees;tropical and temperate.Generainclude Malva (.40 spp.). Gossypium (2041 spp., authorities diff'er). Hibiscus (300 spp.), Althaea (12 spp.), Pavonia (200 spp.) and Thespesia(15 spp.).The cottons,speciesof Gossypium,areimportant both for their seedhairs and seedoil (q.v.).Marshmallow root, from AlthaeaolJicinulis,is usedas a demulcent(q.v.).The common hollyhock is Althaea rosea.Few specieshave been studiedchemand phenolic acids ically, but saponins,tannins,leucoanthocyanins occur;typical alkaloidsappearto be absent. -1. Bombacaceae. A small family of about20 generaand 180 speciesof tropical trees. Genera include Bombax (8 spp.), Ceiba and Adansonia. Kapok, which consists of the lignified, silky hairs which line the fruits of various speciesof Bombax and Ceiba,has beenusedfor lif'e-beltsand as a stuffing material. 5. Sterculiaceae. A family of 60 generaand 700 species;mainly tropical. Genera include Sterculia (300 spp.), Theobroma(30 spp.), Cola (.125spp.) and Brachtchiton. Cocoa, oil of theobromaand chocolateare preparedfrom Theobromacacao; kola or cola nuts come from Cola vera and C. acuminata; and sterculiaor karaya

lF

gum come from Sterculiauren.s.As in the Malvaceae,mucilageis common;purine basesoccur in Theobromaand Cola.

THYMETAEATES Thymeloeoceqe, Eloeqgnqceoe An order of five families. l. Thymelaeaceae.A family of 90 genera and 500 species;mostly temperateand tropical shrubs.Generainclude Cnldia (100 spp.), Daphne (70 spp.) and PimeLea(80 spp.).Some speciesof Daphne arepoisonousand containvesicantresins.The bark of Daphneme7.ereum was formerly official; the floral fragranceis composedof about95% s-(+)-linalool.Mucilageand coumarinscommonin the i a m i l y :a l k i r l o i dasb s e n l . 2. Elaeagnaceae.A family of three genera and about 50 species, including Hippophae(3 spp.),Elaeagnus(45 spp.) and Shepherdia (3 spp.).Among the constituentsare indole alkaloidsand cyclitols.

vtotAtEs Flocourtioceoe, Violoceoe, Turnerqceoe, Possifloroceoe, Cistoceqe, Bixoceoe, Tomoricoceoe, Coricoceoe An orderof 20 families.It includesherbs,shrubsandtrees;tropical and temperate.Cyanogeneticglycosidesoccur in someof the families (e.g. Flacourtiaceae. Turneraceaeand Passifloraceae), but are absentfrom others(e.g.Violaceae). l. Flacourtiaceae.A family of 93 genera and over 1000 species. Generainclude Erythrospermurr(6 spp.),Hy-dnocarpus(40 spp.), Flttcourtia (15 spp.) and Homalium (200 spp.).The seedoils have beenparticularlystudied,as speciesof Htdnocarpus containcyclic, unsaturatedacids which are bactericidaltowards the micrococcus of leprosy.Other constituentsof the tamily include cyanogenetic glycosides,tanninsand phenolic acids.Alkaloids reportedonly in one genus,Ryania. 2. Violaceae.A lamily of 22 generaand about900 species;cosmopolitan, herbsand shrubs.Generainclude Viola (500 spp.'),H)tbanthus (150 spp.) and Hymenanthera(1 spp.).The pansy(Vbh tricolttr), sweetviolet (V. odorata) and dog violet (V canina) have beenused medicinally.They contain volatile oi1 and anthocyanin,flavonoid (rutin) and carotenoid pigments. Hybanthus ipecacuanha has occurredas an adulterantof genuineipecacuanha. 3. Turneraceae.A family of seven generaand 120 speciesof trees, shrubsand herbs.Turnerahas61 speciesandT.dffisa is the source of damianaleaves. A family of 12 generaand 600 species;tropical and 4. Passit'loraceae. warm temperate;shrubsand trees,often climbers.The main genera are Passiflora (500 spp.),Adenia (92 spp.) and Tetrapathaea,the latter a singlespeciesfrom New Zealand.Someof the fiuits are edible (e.g. passion fruit, from PassiJktraedulis). The dried aerial parts of P. incarnata are a popular herbal sedative;they contain flavonoids and tracesof cyanogeneticglycosides,volatile oil and harmane-typealkaloids.Pharmacologicaltestshave supportedthe traditionalusage(R. Soulimaniet aL.,J. Ethnopharmacology1997, 5/- tt) .

5. Cistaceae.A family of eight generaand 200 species.Members are herbs and shrubs,particularlyfound on chalk or sand.The genera include Helianthemum(100 spp.),Cistus (20 spp.) and Halimium. Speciesof Cls/us yield the oleo-gum resin ladanum,used in perfumeryand for embalming.

@

T H EP L A NA T N DA N I M A LK I N G D O MASS S O U R C EOSF D R U G S

-,frii;r;ri:r 6. Bixaceae.This consistsof the single genusBlra with fbur species.

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Bixa orellancLis cultivated for the colouring matter of its seeds. 'annatto',is usedasan ediblecolourant,see This, underthe nameof Chapter33. 7 . Tamaricaceae.A family of four genera and 120 species;herbs and shrubs. Tamarlx (54 spp.) includes T. mannifera, a plant which when puncturedby scaleinsectsyields the mannaof the Bedouins. 8 . Caricaceae.A family of four genera and 55 species;small trees mainly found in tropical America and Afiica. Carica contatns 45 species,and Carica papaya (papaw) is cultivated for the milky juice which is the sourceof the proteolytic enzyme papain.

CUCURBITATES Cucurbitoceqe An order containing the single family Cucurbitaceae. A family of about 110 generaand 640 species;abundantin the tropics; mostly herbs climbing by tendrils, with abundantsap and very rapid growth. Flowers are generally unisexual, regular and pentamerous,exceptin the gynoecium,which is reducedto three.The fruit is the fleshy type seenin the cucumber.Most membershavebicollateralvascular bundles.Generainclude Cucurbita (5 spp.),Cucumis(25 spp.), Ecballium (l sp.), Citrulfus (3 spp.),Luffa (.6 spp.),Bry-onia(4 spp.) and Momordica (45 spp.), Cucurbita pepo rs vegetable marrow; C. maxima, great pumpkin; Cucumis melo, Ihe melon; C. salivu.r, the cucumber; Ecballium elcLterium,the squirting cucumber,yields the purgative elatertum; Citrullus colocynthis yields colocynth; C. lanatus, the water melon. The vascular network of the pericarp of L.ftl is used as a bath sponge(loofah). The fruits and seedsof L. acutangula contain saponins and are used in Ayurvedic medicine. Bryony root, from Bryonia dioica, was formerly used as a purgative and for the treatment of gout; it containssaponinsand sterols.Br1-oniaalba containsantituThe enzyme elaterasehydrolysesthe bitter glucomour substances. sides of the family to cucurbitacins and glucose.The cucurbitacins are triterpenoidbitter principlesnamedA to Q, and the compoundformeris cucurbitacin-E. ly known as cx,-elaterin

MYRTIFIORAE

guajavcLgives the edible fruit guava. Constituentsof the family other than volatile oils are leucoanthocyanins,cyclitols, tannins (e.g. in eucaiyptuskinos), phenolic acids and esters.Cyanogenetic glycosidesand alkaloidsarerare. Punicaceae.The family containsthe single genusPunictt with two species.The fruit rind of Punica granatum, lhe pomegranate, containstannin; in its stem and root bark tannin is accompaniedby the liquid alkaloids pelletierine and isopelleterine.Pelletierine tannatewas formerly official. A family of 16 generaand 120 species;often trees Rhizophoraceae. of mangrove habit. Rhizophora (7 spp.) yields the tanning material mangrovecutch. Afamily of 20 generaand 600 species;tropical and 5. Combretaceae. subtropicaltreesand shrubs;usually rich in tannin.Generainclude Terminalia(250 spp.),Combretum(250 spp.),Quisqualis(17 spp.) and Anogeissus(l I spp.). Myrobalans, the fruits of Terminalia chebula,arerich in tannin and areusedboth in tanningand in medicinel Combretum butlnrosuntyields a butter-like substance; and AnogeissusLatfolia yields the gum known as ghatti gum. A family of 21 generaand 640 species;temperateand 6. Onagraceae. tropical; mostly perennialherbs,but a few shrubsand trees.Genera include Fuchsia (100 spp.),Oenothera(80 spp.).Clarkia (36 spp.) and Epilobium (215 spp.). Many are cultivated for their flowers. Seeds of Oenothera spp. have become important as sourcesof evening primrose oil (q.v.). Various speciesof Epilobium e.g. E. angustfolium and E. hirsutun are used traditionally for the ffeatment of benign prostatehyperplasia;the active componentsappear to be two macrocyclicellagitanninsoenotheinA & B (B. Ducrey e/ al., Planta Medica 1997, 63, I I 1). Tanninsand a few cyanogenetic plantsarerecorded;alkaloidsare rare or absent.

UMBELTIFTORAE Arolioceoe, Cornoceqe/ Gorryoceoe, Alongioceoe, Umbelliferoe An order of seven families. A11. except the Umbellif'erae and Araliaceae,are small. Acetylenic compoundsoccur throughout the order.

l. Alangiaceae.A family of 2 genera and 20 species,of which 17 belong to A/an gium; rropical trees and shrubs.Alkaloids and triterpenoid saponinsoccur.A. Iamarkii is an Indian medicinalplant. A family of 12 generaand 100 species;treesand shrubs, 2. Cornaceae. rarely herbs.Generainclude Cornus(4 spp.) andAcuba (3 spp.). l. Lythraceae.A famiiy of 25 generaand 550 species;herbs, shrubs and trees. Genera include Rotala (50 spp.), Lythrum (35 spp.), 3. Garryaceae.Contains only Garrya, with 18 species.Shrubs containing alkaloids. Decodon (1 sp.), Lagerstroemia(35 spp.), Heimia (3 spp.) and lawsoneoccursin henna,the 4. Araliaceae.A family of 55 generaand 700 species;mainly tropical Lawsonia( I sp.).The naphthoquinone treesand shrubs,someclimbing (e.g.ivy). GeneraincludePanax (.8 leavesof lzwsonia inermis.Somespeciescontainalkaloids. spp.), Tetrapanc.r(l sp.), Aralia (.35 spp.), Hedera (15 spp.), of ever2. Myrtaceae.A family of about I 00 generaand 3000 species Cussonia (25 spp.), Pseudopanax(6 spp.), Fatsin (l sp.) and in Australia,the EastIndies greenshrubsand trees;well represented Sciadodendron(1 sp.).The best-knowndrug, which has beenused and tropical America. The family is divided into two subfamilies, for many centuries,is ginseng,from Panax schinseng(P. ginseng). the Myrtoideae (fruit a berry or drupe) and the Leptospermoideae Tetrapanaxpapt,rferum is the ricepaper tree, and Hedera helix the include Myrtoideae (fruit a loculicidal capsule). Genera of the common ivy. Resin passagesoccur in the tamily. Constituents Myrtus (100 spp.),Psidium (140 spp.),Pimenta (18 spp.),Eugenia include saponins,a few alkaloids,acetyleniccompoundsand diter(1000 spp.),Pseudocaryophyllusand Syzygium(Jambosa).To the penoidsand tritetpenoids. Leptospermoideae belong Eucalyptus (over 500 spp.), Leptospermum(50 spp.) andMelaleuca (about I 00 spp.).The large 5. Umbeltif'erae.The family contains about 275 genera and 2850 species.Most membersare herbswith furrowed stemsand hollow genusEucalyplzs has presentedtaxonomic problems and following internodes.Some are annuals(e.g. coriander),some biennials(e.g. a recentrevision for Flora of Australia the nine, previouslyestabhemlock) and some perennials(e.g. speciesof Ferula). The three lished, subgeneraare each afforded generic status.Many of the gensubfamiliesand main generaare as follows: (1) Hydrocotyloideae cloves era provide importantvolatile oils and spices-for example, Hrdrocot,nle(100 species);(2) Saniculoideaeincludes includes pimento. Psidium and (q.v.), cajuput oil oil, its oil eucalyptus and

Punicqceoe, Rhizophorqceqe, Lythroceoe, Myrtoceoe, Onogroceoe Combretqceoe, An order of 17 families.Many membersrich in tannins.

'.'-{ll*1

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A TAXONOMICAPPROACH TO THESTUDYOF MEDICINAL PLANTS AND ANIMAT-DERIVED DRUGS EnrLgium(230spp.),Aslrantia(10 spp.)andSanicLrLa (37 spp.);(3) ApioideaeincludesChaerophtllum(40 spp.),Coriandrum(2 spp.), Stnlrnium (8 spp.),Conium (4 spp.),Bupleurum(150 spp.).Apiln ll sp.), Petrctselinum(5 spp.). Carum (30 spp.), pimpinella (.150 spp.), Se.rell(80 spp.), Foeniculum (5 spp.), Oenanthe(40 spp.), Ligtrsticum (60 spp.), Angelica (80 spp.), Ferula (133 spp.), Peucedanum(120 spp.),Pastinaca(15 spp.),Laserpitium(35 spp.), Thap.s ia (6 spp.),Dtttrcus(60 spp.),Ammi ( I 0 spp.),H eracleum (70 spp.),Prangos(30 spp.)andAnethum(l sp.).The leavesareusually largeand havea sheathingbaseandmuch-dividedlamina.The flowers are small and arrangedin simpleor compoundumbels.Each has a five-lobed calyx, five petals,five stamens,and an inferior twocelledovary.The fruit is a cremocarp,which is frequentlycrowned with a stigma-bearingdisc known as the stylopodium.When ripe, the two mericarps separatefrom one another but frequently remain attachedto the simple or forked carpophorewhich lies between them. The line separatingthe two mericarpsis known as the commissure.Each mericarp containsa single seedwhich consistsof a largeendosperm,which has a small embryo embeddedin it nearthe apex.Five primary ridgescontainingfibrovascularbundlesrun from baseto apexin the pericarp,and secondaryridges sometimesalternate with these. Between the ridges are schizogenousoleoresin canalsknown as vittae. Members of the family differ in the number and arrangementof the vittae in eachmericarp,but six is common, four on the dorsalsurfaceandtwo on the commissural.Similar ducts occur in the stemand roots and in speciesof Ferula yield the oleogum resinsand asafbetida,ammoniacumand galbanum. The main umbelliferousfruits and their volatile oils used in pharmacy are fennel, Foeniculurn vulgare; caraway, Carum carvi; dill, .\rtethum graveolens; coriander, Coriandrum sativum; aniseed, Pimpinella anisum; and cumin, Cumminumcyminum.Bupleurumfalcetum roots contain oleanenesaponinsand are an important antihepatotoxic drug in oriental medicine. Msnaga, from Ammi visnaga, Among poisonousplants l ields khellin, a dimethoxyfuranochromone. of the family may be mentionedConium maculatum,the sponedhemlock, which containsthe alkaloid coniine; and Oenanthecrocata, the hemlock waterdropwort,which contains oenanthotoxin.Other wellknown plants of the family are celery, Apium graveolersl parsley, Petroselinumcrispum; parsnip,Pastinacasativa; and carrol,Daucus cttrota. Constituentsof the family, other than volatile oils and resins, include coumarins (e.g. umbelliferone), furocoumarins,chromonocoumarins, terpenes and sesquiterpenes, triterpenoid saponins and acetyleniccompounds.Alkaloids occur (e.g.coniine)but arerare.

spp.),Lyonia (30 spp.'), Arbulls (20 spp.) andArctosraphyios(71 spp.). In addition to the well-known gardenplants, the family includes the wintergreen,Gaultheriaprocumbens,which yields natural oil of wintergreen(now generallyreplacedby syntheticmethyl salicylate);and bearberry leaves from Arctostaphl-losuva-ursi, which contain the phenolic glycosidearbutin and are again official. The medicinalproperties of Var:ciniummyrtillus (bilbeny, blueberry, whortleberry) have been utilized since the Middle Ages and have recently beenreviewed (P. Morazzoni and E. Bombardelli, Fitoterapia 1996,67, 3). The family producesphenolicacids,phenolicglycosides(e.g.arbutin),aucubin glycosides,diterpenoids(grayanotoxin),triterpenoids(ursolic acid), cyclitols and leucoanthocyanins.A few species are cyanogenetic; saponinsare absent.

PRIMUTATES Myrsinoceoe, Primuloceoe An order of threefamilies. The Primulaceaeconsistsof 20 generaand about 1000 speciesof herbaceousperennialswith rhizomesor tubers.Especiallycommon in the north temperateregions. Many members are cultivated as garden plants. Genera include Primula (500 spp.), Cyclamen (15 spp.), Anagallis (31 spp.) and Dionysia (41 spp.). The dried flowers of Primula uerls (the cowslip) are used in herbal medicinefor insomnia and as a sedativein combinationwith otherherbs.The flowers areparticularly rich in flavonoids.Saponinsare presentin somespecies;also phenolicestersand ethers.Alkaloids appearto be absent.Anthocyanin pigmentsare common,but not betacyaninsor betaxanthins.

PTUMBAGINATES Plumboginoceoe The Plumbaginaceaeis the only family of the order, and contains l9 genera and about 775 species.Members are herbs or shrubs often found on seacoastsor salt steppes.GeneraincludePlunrbago( l2 spp.) and Ceratostigna. Roots of Plumbago spp. are used in traditional Indian medicine; immunosuppressiveand antitumour activities have beendemonstrated.Constituentsfound in the family include phenolic acids, tannins, anthocyanin pigments and naphthoquinones(e.g. plumbagin).

EBENATES Sopotoceoe, Ebenoceoe, Sfyrococeoe An order of sevenfamilies consistingmainly of treesand shrubs.

SUBCTASSSYTNPETATAE The Sympetalaederive their name fiom the fact that their petals are fused.The subclassconsistsof i I ordersand 63 families. the chief of which have alreadybeentabulated.

ERICATES Ericqceoe An order of five families, including the Pyrolaceae,Epacridaceaeand Ericaceae.Only the last family, the largest,will be described. Ericaceae.A family of about80 generaand 2000 species;pafticularly common on moors and peaty soils. Members are shrubsor small trees.The generainclude Rhododendron(500-600 spp.),Ledum (lO :pp.), Erica (over 500 spp.), Calluna (l sp.). Vaccinium(300-400 (49 spp.),Gaultheria (about 210 spp.),Pieris (lO spp.). Ga,1/ussacia

l. Sapotaceae. A family of some 35-75 ill-defined generaand about 800 species;most are tropical trees, often yielding good timber. Generainclude Mimusops (57 spp.),Madhuca (Bassia)(85 spp.), Achras (70 spp.),Pierreodendron(2 spp.),Palaquium (about 115 spp.)andBu4.'rospermum(l sp.).Latex sacsoccur in the leaves,and in the coftex, phloem and pith of the stems.Gutta-perchais the coagulatedlatex from speciesof Palaquium andpayena. The oily seedsof Burl^rospermum parkii are expressedto yield sheabutter which can be usedas an ointment and creambasefor topical applications.Constituentsinclude latex, seedfats, cyanogeneticglycosides,saponins,tannins,leucoanthocyanins, pyrrolizidine alkaloids and the cyclitol D-quercitol. 2. Ebenaceae. A family of threegeneraand about500 species;tropicai treesand shrubs.The chief genera areDiospt,ros(about 500 spp.) and Euclea (20 spp.). Varieties of ebony are obtained from DiospyrosebenumandEucleapseudebenus . In South-EastAsia the

E

OF DRUGS THT PHNT AND ANIMAL KINGDOMSAS SOURCES fresh unripe fruits of D. mollis have long been used as an anthelmintic (hookworms and tapeworms). Other speciesyield edible fruits, 'date-plums'.For recentphytochemicalresearchon the root- and stem-barksof Diospyros spp. involving the isolation of triterpenoids,diquinonesand napthoquinonesseeM. R. Khan and D. Timi, Fitoterapia 1999,70, 194; 209. Naphthoquinonesare a characteristicof the family. A family of 12 generaand 180 speciesof trees and 3. Styracaceae. shrubs.Generainclude S4rrax(130 spp.) and Halensia. Benzoins (q.v.) are obtainedfrom speciesof Sry^rax. Constituentsof the family include balsamicresins,phenolicacids,tanninsand the benzofuran egonol.

OtEAtES Oleoceqe The Oleaceaeis the only family of the order.It is widely distributed, andcontains29 generaand about600 species.GeneraincludeOlea (20 spp.), Forsythia (7 spp.), FraxintLs (70 spp.), Syringa (30 spp.), Osmanthus(15 spp.), Jasminum (300 spp.) and Ligustrum (.4V50 spp.). Many speciesare grown in Britain (e.g. Syringa vulgaris, lhe iilac). The manna of present-daycommerce is obtained by making incisions in the stem of the manna ash, Fraxinus ornus. Of great economic importanceis the olive, Olea europoea.In addition to olive oil (q.v.),the family producessugaralcohols(e.g.the mannitol of manna), saponins,tannins,coumarinsand iridoid glycosides.Alkaloids arerare.

GENTIANALES Menyonthoceoe, Logonioceoe, Gentionoceoe, Asclepiodoceoe, Rubioceqe Apocynoceoe, An order of sevenfamilies which is of medical and chemicalinterest. All the families contain alkaloids,but importantglycoside-containing generaalso occur. 1. Loganiaceae.A family of 18 generaand 500 species;trees,shrubs and herbs, some lianes. Genera include Strychnos (200 spp.), Logania (25 spp.), Gelsemium (2 spp.), Geniostoma (60 spp.), Anthocleista(14 spp.) and Gardneria (5 spp.).Nux vomica seeds (q.v.),the seedsof Slrycftnos nux-vomicc,arethe principalsourceof 'Curare') owes its strychnine and brucine; calabash-curare(see activity largely to Snl,chnosspecies.The family is rich in alkaloids of the indole and oxindole groups.Other constitutentsare the aucubin glycosideloganin,and iridoids. 2. Gentianaceae.A family of 80 generaand about 1000 species;herbs and a few shrubs widely distributed. The leaves are opposite and decussate.the corolia lobes are contofied in the bud and the axis shows bicollateral bundles and interxylary phloem. Genera include Gentiana (400 spp.),Exacum (.40spp.),Sebaca(100 spp.),Erythraea (.Centaurium)(30 spp.), Chironia (30 spp.), Swertia (100 spp.), Halenia (about 100 spp.)and Enicostema(3 or 4 spp.).Gentianroot (see 'Gentian'), from Gentianalutea, has long been usedin medicine. The herb of Swertia chirata (Chvetta) is describedtnthe BHP (1983);it is usedto stimulatethe appetitein anorexia.S.japonicats used in Japan as a stomachic;hairy root cultures produce xanthone derivatives, the secoiridoids amarogentin and amaroswerin, and phenylglucosides.Some members,on account of their bitter principles, are usedin liqueurs. The family containsalkaloids; iridoid glycosides;flavones,xanthonesand their glycosides;phenolic acids; tannins; and the trisaccharidegentianose. This small family of five generaand 33 speciesis 3. Menyanthaceae. It consistsof aquatic01 sometimesincluded in the Gentianaceae.

marsh herbs such as the British planl Menyanthes trifoliata, the it containsbitter principles but buckbean.Like the Gentianaceae, the leavesinsteadofbeing oppositeand decussateare alternate. 4 . Apocynaceae.A family of about250 generaand 2000 specieswhich Many membersare woody is closely allied to the Asclepiadaceae. climbers found in the tropics and subtropics.The only British speciesare the periwinkles, Vinca major and V.minor. Types of fruit are a pair of follicles, a berry, capsulesor two indehiscentmericarps. The plants contain latex in non-articulated,branched or unbranched laticifers. The vascular bundles are bicollateral. Important genera, arrangedunder two subfamilies, are as follows: Arduina-Carissa(35 spp.),Allamanda(15 spp.), A. Plumieroideae'. Landolphia (55 spp.), Carpodinus (50 spp.), Hancornia (1 sp.), Pleiocarpa (3 spp.), Plumeria (7 spp.), Alstonia (50 spp.), Aspidosperma (80 spp.), Rha4lta (2 spp.), Amsonia (25 spp.), Lochnera-Catharanthus (5 spp.), Vinca (.5spp.), Tabernaemontana (100 spp.), Voacanga(25 spp.),Alyxia (80 spp.),Rauwolfia (100 spp.),Ochrosia (30 spp.) and Cerbera (6 spp.); B. Apocynoideae: Echites (6 spp.), Dipladenia (30 spp.), Odontadenia (30 spp.), Mandevilla (114 spp.), Baissea (40 spp.), Funtumia (3 spp.), Apoctanum (7 spp.), Nerium (3 spp.), Strophanthus(60 spp.), Wrightia (23 spp.), Parsonia (100 spp.), Lyonsia (24 spp.) and Malouetia (25 spp.).Drugs include the Madagascaranperiwinkle, Catharanthus rosers (also known as Lochnera rosea and Vinca rosea); strophanthusseeds;rauwolfia roots; kurchi or holarrhena bark; alstonia barks; and aspidospermabarks. Many speciesof Landolphitt, Carpondinus and Hancornia yield rubber latex. [For a review (148 refs) of Rhazyastricta andR. orientalis,usedin Unani medicine, seeAtta-Ur-Rahmanet al., Fitoterapia, 1989, 60,291. For uses,chemistryand pharmacologyof Malouetia spp.(41 refs) seeN. G. Bisset,/. Ethnopharm,1992,36, 43.l Constituentsof the Plumieroideaeinciude a vast rangeof indoline alkaloids; over 500 rn Alstonia, Aspidospermum,Catharanthus, H unteria, P leiocarpa, Tabernaemontana,Rauwolfia and Voacanga. Steroidal alkaloids occur in Holarrhena and harman-type alkaloids in Amsonia and Aspidosperma. Cardioactive glycosides occur rn Acokanthera, Carissa andMelodinus and in Apocltanum,Nerium andStrophanthas.Other constituentsof the family are cyanogenetic glycosides,leucoanthocyanins,saponins,tannins,coumarins,phenolic acids, cyclitols and triterpenoids.Widely grown omamental plantsof the family includespeciesof Ansonia, Nerium (oleander), Vinca, Plumeria (frangipani), Thevetia (yellow oleander) and M andevilla (Chileanj asmine). A family of 130 generaand 2000 species;tropical Asclepiadaceae. and subtropicalshrubs,often twining, or perennialherbs.Genera include Asclepias(120 spp.), Tylophora(150 spp.),Xysmalobium (l sp.), Cryptostegia (2 spp.), Cynanchum,Marsdenia, Pergularia and Hemidesmrzs.The latex cells usually contain a latex rich in triterpenes.Other constituentsinclude: alkaloids of the indole, phenanthroindolizidineand pyridine groups; cardenolides;cyanogenetic glycosides;saponins,tannins,and cyclitols. Although the family yields no important drugs, many membersare used in folk medicine in their countriesof origin and others as arrow poisons. Among the better-known are Indian sarsaparilla,from Hemidesmus indicus, and condurango bark, from Marsdenia condurango. Cryptostegia grandiflora, the rubber vine or pink allamanda, contains poisonouscardenolideswith some therapeuticpotential; the plant, introduced to Australia as an ornamental, has become an aggressiveweed. 6 . Rubiaceae.A tamily of about500 generaand 6000 species,most of which are tropical treesand shrubs.A few membersare herbs growing in temperateclimates(e.g. speciesof Galium, such as the bed-

5;;i*41

A TAXONOMICAPPROACH TO THESTUDYOF MEDICINALPLANTS AND ANIMAL-DERIVED DRUGS \traws,goosegrass or cleaversofBritain). The first subfamilyis the subcontinentis used in a number of folk remedies:an alcoholic Cinchonoideae,the carpels of which bear numerous ovules and extractofthe plant hashypotensiveand bradycardiaceffects. nhich includes Oldenlandia (300 spp.), Condaminea (3 spp.), Anatomicalcharactersincludethe presenceof latexcells,bicollaterCinchona(40 spp.),Uncaria (60 spp.),Naaclea(35 spp.),Gardenia al bundlesand frequentlyabnormalvasculardevelopmentsuchas is r250 spp.) and Mitragyna (i2 spp.). The second subfamily, found in drugssuchasipomoeaandjalap (q.v.).Brazilian arrowroot Rubioideae,has only one ovule in eachloculus; it includesthe genis the starch obtained from the tubers of the sweet potato, Ipomoea era Coffea (40 spp.), Ixora (400 spp.), P(Netta (400 spp.), batatas. Many speciescontain hallucinogens(q.v.) such as ololiPsychotria(700 spp.),Cephadlis-Uragoga(.780spp.),Mitchella (2 uqui, from Rlvea corymbosa,and morning glory seeds,from species ;pp.), Asperula (200 spp.),Galium (400 spp.) andRubia (60 spp.). of lpomoea. The family containsindole, isoquinoline,pyrrolidine Productsinclude cinchonabarksand their alkaloidssuchas quinine and tropane alkaloids,purgative resins,phenolic acids and tritert q.v.),ipecacuanha root (see'Ipecacuanha'),catechu,from Uncaria penoid saponins.Pynolizidine alkaloidshave recentlybeenreportqambier,and coffee (q.v.),from Coffeaarabica and other species. ed in the family for the first time (seedsof 1. hederifolia). Pst'chotriaviridis is a componentof the hallucinogenicpreparation 3. Boraginaceae.A family of about 100 genera and 2000 species; avahuasca(q.v); other speciessuch as P. brachypoda and P. colmostly herbs,often perennial.Inflorescencea coiled cincinnus.The orota are constituents of traditional painkillers (M. B. Leal and flowers change colour during development. Genera include E. Elisabetsky,Int. J. Pharmacognosj-1996,34,267). Of the many Heliotropium (250 spp.), Cynoglossum(50-60 spp.), Symphytum other alkaloid-containingspecies may be mentioned mitragyna (25 spp.), Borago (3 spp.), Anchusa (50 spp.), Alkanna (25-30 leaves, from species of Mitragyna, and yohimbe bark, from spp.),Pulmonaria (i0 spp.) and Lithospermr.rn(60 spp.).Products Pansinystaliayohimbe. Alkaloids of the indole,oxindole,quinoline include speciesof Lithospermum,which have hormone activity; and purine types are common; anthraquinonesoccur in Morinda, alkanna or anchusaroot, from Alkanna tinctoria. which contains Rubia and Galium, and many have long been used as dyes (e.g. red colouring matters.Both the Lithospermum spectesandAlkanna madder, from Rubia tinctorum'). Anthocyanins occur in Cinchona; contain naphthoquinone derivatives. Formerly official were aucubin glycosides (e.g. asperulin), cyclitols (e.g. quinic acid), Cynoglossumfficinale (hound's tongue),Borago fficinale (borcoumarins,depsidesin Coffea; phlobatannins,catechins(e.g. in age) and Pulmonaria fficinale (lung-wort).The seedoil of borage Uncaria); diterpenoidsand triterpenoidsand iridoid glycosidesin is particularly rich in y-linolenic acid (q.v.) and the plant is now Genipa.Morinda reticuLatais interesting,as it accumulatesselenbeing cultivatedin Englandfor its oil. Naphthoquinones, the ureide ium and is very toxic;M. citrifulia, M. eLliptica andM. Lucidaare all allantoin,pyrrolizidine alkaloids,cyclitols, phenolicacids and tanemployed in traditional medicine, some anthraquinones(e.g. nins, occur in the family. Allantoin is particularly abundant in the alizarin-l-methyl-ether)have been shown to possessantifungal root of comfrey, Symphytumfficinale. The common occurrenceof properties(G. Rath et al., Int. J. Pharmacognosl1995,33, 107). pyrrolizidine alkaloids (Alkana, Borago, Cynoglossum, Heliotropium, Symphytum)has causedconcern regarding the herbal useof a numberof species. TUBIFTORAE 4. Verbenaceae. A family of about 100generaand 3000 species;herbs, shrubs and trees, many lianes. Genera include Tectona(3 spp.), Polemoniqceqe, Convolvuloceoe, Boroginoceoe, Lippia (220 spp.),Verbena(250 spp.),Callicarpa (140 spp.),Vitex Verbenoceoe, Lobiotoe, Solonoceoe, (250 spp.),Nyctanthes,Duranta and Stilbe.Teak is obtainedfrom Scrophulorioceoe/ Bignonioceoe, Aconthoceoe, Tectonagrandis; verbena oil from Lippia citriodora; and vervain, Pedolioceoe, Gesnerioceoe, Myoporqceqe formerly official, from Verbenaofficinalis. Viter agnus-castushas .{n order of six subordersand 26 families containing many important beenusedmedicinally in Europe at least sinceclassicalGreek and drugs.The families consideredbelow fall into the following suborders: Roman times and today is still availableas a herbalpreparationfor l. Convolvulineae:Polemoniaceae and Convolvulaceae. the treatment of female conditions relating to the premenstrualsyn1. Boraginineae:Boraginaceae. drome and the menopause. (For a report of recent research see -1. Verbenineae:Verbenaceaeand Labiatae. Pharm. J. 2001,265, 106.) By GC-MS 34 compoundshave been J. Solanineae:Solanaceae, Scrophulariaceae, Bignoniaceae, identified as componentsof the volatile oil, principaliy mono- and (Zeljan MaleSet al., Planta Medica 1998, 64,286). Acanthaceae, Pedaliaceae and Gesneriaceae. sesquiterpenes 5. Myopineae:Myoporaceae. Labdan diterpenes appear to be partialiy responsible for the dopaminergic activity of the fruits (E. Hoberg et al., Planta Medica Membersof thesefamilies are usuallyherbswith alternateor oppos2000, 66, 352). For an article on the drug seeP Houghton,Pharm. ite simple leaves.The flowers are generallybisexualand often zygoJ., 1994,253,'720.Among the constituentsfound in the family are morphic. They usually have two or four epipetalousstamensand a volatile oils, saponins,tannins,quinones,iridoids, piscicidal subbicarpellary superior ovary. stances;alkaloids appearto be rare. I . Polemoniaceae.A family of I 5 generaand 300 species;herbs which 5. Labiatae (Lamiaceae).A family of about 200 genera and 3300 are often cultivated as border plants. Generainclude PhLox(67 spp.) species;aromatic,annual or perennialherbs or undershrubs.The andPolemoniun (50 spp.).The chemistry of the family is imperfect family is well representedin the Mediterranean area and in Britain. ly known, but constituentsinclude saponinsand tannrns. The flowers are bisexual, zygomorphic, usually have the floral forl. Convolvulaceae.A family of about 55 genera and 1650 species. mula K(5), C(5), A4, G(2), and are arrangedin verticillasters.The Most are annual or perennial herbs, often with twining stems:a few corolla is bilabiate and the stamensdidynamous.With the exception shrubsand trees.Generainclude Convolvulus(250 spp.),Ipomoea of Rosmarinus,the generahave a gynobasic style and the four nut(500 spp.), Pharbitis-lpomoea, Argyreia (91 spp.) and Cuscuta lets have only a small surface of contact with one another. ( 170 spp.).The genusCuscutaconsistsof parasiteswhich aresomeRosemary also differs from most genera in having only two statimes placedin a separatefamily, the Cuscutaceae. Speciesofdodmens. The herbaceousmembersof the family have squarestems. der are parasitic on clover and on flax. C. reflexa found in the Indian The leavesand other aerialpartshave clothing hairs (seeFig. 43.4)

E

THEPLANTAND ANIMAL KINGDOMSAS SOURCES OF DRUGS and glandularhairs (Fig. 43.5), which secretethe volatile oil. The generaincludeAjuga (40 spp.),Teucrium(300 spp.),Rosmarinus(3 spp.),Scutellaria (300 spp.'),Lavandulc (28 spp.),Marrubium (40 spp.),Nepeta (250 spp.),Lamium (40-50 spp.),Ballota (35 spp.), Stnchl's(300 spp.),Salvia (700 spp.).Monnrda (12 spp.),Sature.ja (30 spp.),Origanum ( l5-20 spp.),Th.y-mus (300-,100spp.),Mentha (18 spp. and 13 hybrid spp;),Pogostemon(40 spp.),Ocimum (l5O spp.),Leonuru.s(14 spp.) andLeonotis(41 spp.).Many membersof the family are used as culinary or medicinal herbs, as sourcesof volatile oils and in some casesfor the preparationof constituents of the volatile oils such as menthol and thymol; chemicalracesare common. In addition to rosemary, lavender, peppermint and spearmint, described elsewhere, note pennyroyal (Mentha pulegium'), sweet marjoram (Ori ganum mctrjo rana), patchouli (.Pogostemon patchouli'y,melissa (Melissa fficinalis), germander (.Teucriumchamaedn,s),wood sage(7. scorodonia),wood betony (StachysfficinaLis), sage(Salvia fficinalis), sweetbasil (Ocimwn basilicum), holy basil (O. sanctum),savory (Saturejaspp.), horehotnd (Marrubium spp.) and hyssop (H1-ssopusofficinalis). Also Ihyme (Th,tmusvulgaris) andMonarda punclata, both of which are imporlant sourcesof thymol. In addition to the volatile oils, constituents of the family include diterpenoids and triterpenoids, saponins,a f'ewpyridine and pyrrolidine alkaloids,insect-moulting hormones,polyphenolsand tannins,iridoids and their glycosides, quinones,furanoids,cyclitols, coumarin, and the sugarsraffinose and stachyose. The family has been extensively researchedand the book Advancesin Labiate Science,R. M. Harley and T. Reynolds(eds), 1992,publishedby the Royal Botanic Gardens,Kew, contains38 conferencepaperscoveringall aspectsofthe family. Also from Kew comesthe Lamiales NewsLetter,from February 2000 renamedVitex, which provides a forum for discussionfor scientistsof all disciplines working on the Labiataeand Verbenaceae. (The Lamialesis an order of the Bentham-Hooker system of classification and includesthe abovetwo families.) 6. Solanaceae. A family of about90 generaandover 2000 species;tropical and temperate; herbs, shrubs or small trees. Genera include Nicandra (1 sp.),Lycium (80-90 spp.),Atopa (4 spp.),Hyoscyamus (20 spp.),Phy"salis(100 spp.), Capsicum(about 50 spp.),Solanum including L,-copersicon(1700 spp.),Mandragora (6 spp.),Datura (10 spp.), SoLandra(10 spp.), Cestrum (150 spp.),Nicotiana (66 spp.), Petunia (40 spp.), Salpiglossis(18 spp.), Schizanthus(15 spp.), Scopolia (6 spp.), Withania (10 spp.), Duboisia (2 spp.), Acnistus (50 spp.) and Fabiana (25 spp.). Only five speciesare indigenousto Britain but many others are cultivated. The indigenous ones are Datura stramonium, thomapple; Solanum dulcamara,bittersweetor woody nightshade;Solanumnigntm, black nightshade; Atropa belladonna, deadlynightshade;Hyoscyamusni ger, henbane. Among species commonly cultivated in England are Solanum tuberosum, potato; Solanum lycopersicum, tomato; Nicotiana tabacunt, tobacco; Phr-saLisalkekengi, Chinese lantem; Capsicum spp.,red and green peppers;Solanum p seudocapsicum, winter cherryt Lycium halimfoLium,Duke of Argyll's Tea-plant. The flowers are bisexual and seldom markedly zygomorphic, although the carpelsare placed obliquely (see Fig. 25.6D). They have the floral formula K(5), C(5), A'5, c(2). The ovary is typically bilocular,but frequentlybecomesfalsely three-to five-locular(e.g. Daturct). On the flowering branchesadnation of the leaves with their axillary branchesoften occursand the true origin of the partsis only made out by cutting sections.All membersof the family have intraxylary phloem which is often accompaniedby sclerenchymatous fibres.

Productsof the Solanaceaeinclude: stramoniumleaves:henbane leaves; belladonnaherb and root; capsicums;potato starch fiom Solanum tuberosum; mandrake, from Mandragora fficinarurn; duboisia,liom speciesof Duboisia which are usedfor the manufacture of ffopane alkaloids; scopolia leaves and roots, sourcesof tropanealkaloids;tobaccofrom Nlcotiana tabacunt,the wasteproducts of which are usedfor the extractionof the insecticidenicotine. The family containsa wide range of alkaloids which are of grear taxonomic interest.Types of alkaloid recordedare tropane,alkaloidal amine, indole, isoquinoline, purine, pyrazole, pyridine, pynolidine, quinazolizidine,steroid alkaioids and glycoalkaloids. Other constituentsinclude steroidal saponins, withanoiides, coumarins, cyclitols, pungent principles (e.g. in Capsicum). flavones,carotenoidsand anthraquinones in Fabiana. Buddlejaceae. A family of 6-10 generaare 150 spp.;principal genera areBuddl eja ( I 00 spp.) andN uxia (40 spp.). Although B uddlei a spp. have been used in traditional medicine in many parts of the world it was only relatively recently (e.g. P. J. Houghton, J. Nar. Prod., 1985,48, 1005) that detailedphytochemicalinvestigations were initiated.The genusproducesflavonoids,iridoids and acylated iridoid glycosides,sesquiterpenoids, phenylethanoids,lignans and saponins(saikosaponins).Until the isolation of saikosaponinsby Yamamotoet al. (.Chem.Pharm. Bull. 1991,39,2'764)rhesecompounds were known only in Bupleurum spp. (Umbelliferae). Apparently,the eating habits of some insectsindicate a similarity betweenBuddleia and the Scrophulariaceae. Scrophulariaceae. A tamily of 220 generaand about 3000 species; annualor perennialherbs or undershrubs,a few trees;some semiparasites. Members differ from the Solanaceaein that they have carpelsplaced in an anterior*posteriorplane, in the aestivationof the corolla and in not possessingbicollateralbundles.The flowers are usually zygomorphic and the stamens reduced to four. Anatomicai charactersinclude glandularhairs in which the headis divided by verticalwalls only, and the stomata,which are surrounded by three or more epidermalcells. Calcium oxalateis relatively rare; when present,it occursin small solitary crystals.Generaare Verbascum (306 spp.), Calceolaria (300-400 spp.), Linaria (150 spp.),Antirrhinum (42 spp.), Suophularia (about 300 spp.), Penstemon (250 spp.), Mimulus (100 spp.), Gratiola (20 spp.),Veronica(300 spp.),Digitelis (20-30 spp.),Isoplexis(4 spp.), Melamptrum (35 spp.), Euphrasia (200 spp.), Bartsia (30 spp.), Pedicularis (500 spp.'),Rhirunthr.rs(50 spp.), Odontitis (30 spp.), Chaenorrhinum(20 spp.'),Bacopa (100 spp.) and Gratiola (20 spp.).Important drugs are the leavesof Digitalis purpurea and D. lanata and their cardiac glycosides. Picrorhiza rhizome or 'Indian gentian' from Picrorhiza kurroa containsbiner iridoid glycosides;it is usedin India to treatliver ailments.Verbascumthapsus (mullein), commonly cited as an adulteranrof digitalis,is usedas a herbalmedicinein Europeand India, particularlyfor bronchialconditions.The four speciesof lsoplexls,formerly placedin the genus Digitalis, are found only in the Canary Islands and Madeira. Cardenolideswhich are mono- and diglucosidesonly (cf Digitalis), occur in both genera; the clonal propagation of I. canariensis has beendescribed(F. Schallerand W Kreis, Planta Medica 1996,62, zl50).Other constituentsof the family include: steroidaland triterpenoid saponins;cyanogeneticglycosidesin Linaria spp.;aucubin glycosides; naphthoquinonesand anthraquinones;aurones; iridoids.Alkaloids are not very comfilon, but monoterpenoid,quinazoline and quinolizidinetypesoccur in somespecies. Bignoniaceae.A family of about I 20 generaand 650 species;mainly tropical trees,shrubsor lianes; particularly abundantin Brazil. Genera include Jacaranda (50 spp.), Catalpa (11 spp.), Tecoma

s;r*2fr

A TAXONOMICAPPROACH TO THESTUDYOF MEDICINAT PLANTS AND ANIMAI.-DERIVED DRUGS ( l6 spp.).Mussatia (3 spp.),Amphicome(2 spp.),Kigelia (1 sp.) and Tecomella(1 sp.).Kigelia pinnata bark is used in traditional Nigerian medicine; it containsnaphthoquinoidsand iridoids and has beeninvestigatedfbr antibacterialactivity by p Houghton at King's College, London (Pharm. J., 1993,250, 848). Tecoma stens,a shrubwith bright yellow funnel-shapedflowers is found in British greenhouses; it containsmonoterpenealkaloids,seeA. p. Lins and J. D'A. Felicio, Phy,tochen,1993,34,876. In South America the leavesof Mussatiahtacinthina and other speciesare chewed alone or mixed with coca leaves for their sweetening, euphoric or medicinal effects.The above genera have received considerablephytochemicalattentionand constituentsofthe family include iridoids and iridoid glycosides, saponins, phenylpropanoids,tanninsand quinones;alkaloidsarerare. 10. Acanthaceae.A family of 250 generaand 2500 species.Shrubs and herbs, including some climbing plants and xerophytes. Abundant in the tropics but also found in the Mediterranean, Australia and the USA. Genera include Acanthus (50 spp.), Andrographis(20 spp.),Blepharis (100 spp.),Adhatoda (20 spp.) andBorLeria (230 spp.).The leavesof Adhatoduvaslcaareusedin India for the treatmentof cough and contain the atkaloid vascine (peganine);the antitussiveactivity has been demonstratedpharmacologically (J. N. Dhuley, J. Ethnopharmacolog,t1999, 67, 361). Andrographispaniculata (q.v.) is also an important Indian drug plant. In addition to alkaloids,the family containstannins, diterpenoids,cyanogeneticcompoundsand saponins. I l. Pedaliaceae. A small family of l2 generaand 50 species;tropical herbs,or rarely shrubs;mostly shoreor desertpiants.The genera include Harpagophytun (8 spp.),Pedalium (l sp.) and Sesamum (30 spp.).Sesamumindicum yields the fixed oil sesameor gingili o1l.Harpagophytumprocumbens(Devil's Claw) is found especially in the Kalahari desert and Namibian steppes.Its secondary tuberizedroots aremuch usedin traditionalmedicineand it is now includedin westernmedicine(q.v.).Other constituentsof the family includephenolicsand flavonoids. 12. Gesneriaceae. A family of 120 generaand 2000 species;mainly tropical and subtropicalherbs.The genus Streptocarpushas 132 species.Tannins,naphthoquinones, chalconesand anthraquinones but no alkaloidshavebeenreported. I 3. Myoporaceae.A family of threegeneraand some240 species.The gents Eremkophila (209 spp.) is entirely Australian and has been usedin aboriginalmedicine.Myoporum (c. 30 spp.)occursin the SW Pacific area and the monotypic Bontia is found only in the WestIndies.The family containsa strikingrangeof terpenoidsand also tannins,cyanogeneticglycosidesand furans. (For a review (150 refs) seeE. L. Ghisalberti,Phttochemistn-1994,35,7)

PTANTAGINALES Plontoginoceoe An order containingthe single family Plantaginaceae, which consists of three generaand abofi 270 species;annualor perennialherbs.All but four speciesbelongto the genusPlantago (plantains).The seedsof severalspeciesare usedin medicine;see 'Psyllium'.

DIPSACALES Coprifolioceoe, Volerionoceqe, Dipsococeoe An order of four families; includesherbs,shrubsand small trees. 1. Caprifbliaceae.A family of 12 generaand about450 species;mainly north temperate, herbs and small trees. Important genera are

Viburnum(200 spp.),Lonicera (200 spp.) andSambucus(40 spp.). British members include the common e1de4 Sambucus nigra; honeysuckles,species of Lonicera; the guelder-rose,Viburnum opulus. EIder flowers, usually in the form of an ointment, are used as a domestic remedy and are included in the Bp 2000. The root bark of black haw, Viburnum prunifolium, is official in the BHp (1996). Constituentsreported in the famity are valerianic acid (compareValerianaceae), aucubinglycosides,saponins,coumarins and cyanogeneticglycosides. 2. Valerianaceae. A family of I 3 generaand about360 species.Herbs, rarely shrubs. Genera include Valeriana (over 200 spp.), ValerianeI la (80 spp.),Centranthus ( I 2 spp.) andp atrina (20 spp.). The first three of thesegenera are representedin Britain. The flowers of Valeriana and Valerianella have three stamens. those of Centranthus only one. Centranthus ruber is the common red valerian. The valerian roots of commerce are derived from the European Valerianafficinalis (q.v.) and the Indian valerian,V.wallichii.The family contains esters yielding isovalerianic acid (compare Caprifoliaceae), alkaloids and iridoids; valepotriates are characteristic of the tribe Valerianeaebut are not found in the tribe patrinieae. 3. Dipsacaceae.A family of eight genera and about 150 species. Genera include Scabiosa (100 spp.), Knautia (50 spp.) and Dipsacus (15 spp.). The ripe flower-headsof Dipsacusfullorum (fuller's teasel)are still usedto a limited extent for raising nap on certain cloths. Constituentsreported for the family include aC-glycoside,a few alkaloids,and tannins.

CAMPANULATES Gomponuloceqe, Compositoe An order of eight families. In the families consideredbelow, the anthers are either in contact with one another or fused so as to form a tube into which the pollen is shed. The flowers are hermaphrodite or unisexualby suppression.Mainly herbs with latex vesselsor oil passages. 1. Campanulaceae. A family of about 70 genera and 2000 species. Tropical or subtropical herbs; a few trees or shrubs.The subfamily Campanuloideaecontains Campanula (about 300 spp.) and has regular flowers, generally with free anthers. The subfamily Lobelioideae(which has sometimesbeen consideredas a separate family, the Lobeliaceae) contains Lobelia (200-300 spp.). In this subfamily the flowers are zygomorphic and the anthers syngenesious.Family charactersinclude the presenceof latex vesselsand inulin. Of medicinal importanceis lobelia herb or Indian tobacco, Lo beIi a infl ata, which containsalkaloids (q.v.). Indian lobelia, from L. nicotaniaefolia, also contains lobeline. In addition to the constituentsalready mentioned, members of the family contain phenolic compounds, tannins and triterpenoid glycosides. The piperidine alkaloids found in the Lobelioideae have not beenfound in the other subfamilies, but they are not considered sufficiently significant to justify a separate family. 2. Compositae. The Compositae is the largest family of flowering plants and contains about 900 genera and some 13 000 species. Compared with some other large families such as the Leguminosae, the number of important economic products derived from it is relatively small. Chemical researchin recent years has increasedmedical interest in the family and we now have a better knowledge of many almost-discardedfolk remediesas well as hitherto uninvestigated plants. The latter include some having antitumour or antibacterial activity and others forming commercial sources of rubber latex. The two subfamilies and their main generaare as follows.

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(1) Tubuliflorae: In this subfamily latex vesselsare absent. but schizogenous oil ductsarecommon.The corollasof the disc-florets are nonligulate.Genera include Senecio (1300 spp.), Xanthium (30 spp.),Ambrosin (30-40 spp.), Zinnia (20 spp.), As the name indicates, monocotyledonshave an embryo with one Helianthus (1i0 spp.), Dahlia (21 spp.'), Helenium (40 cotyledon. Many members are herbs, usually with parallel-veined spp.), Tageres(50 spp.). Solidctgo(100 spp.), Bel/ls (1-5spp.), leaves.The stelehasscattered,closedvascularbundles;the flowers are Aster (500 spp.), Erigeron (200 spp.), Achillea (200 spp.), usuallytrimerous. As with the dicotyledonsa much abbreviatedform of Engler's clasAnthemis(200 spp.),Chn,santhemum(c.200 spp.),Matricaria (40 spp.),Tanacetum(50-60 spp.),A rtemisia(400 spp.),Blumea sification indicating the main orders and families of pharmaceutical (50 spp.), Inula (200 spp.). Doronicum (35 spp.). CalenduLa and phytochemicalinterestis given below. (20-30 spp.), Euparorium (1200 spp.), Arnica (32 spp.), Vernonia (600 spp.). Echinops (100 spp.), Carlina (20 spp.), Farnilies Orders Arctium (5 spp.), Carduus (100 spp.), Centaurea(600 spp.), (13 (70 spp.) and Gerbera spp.).Omitting the huge Carthanrus Liliif'lorae Liliaceae,Agavaceae.Amaryllidaceae. number of cultivatedgardenplants,note chamomileor Roman Hypoxidaceae,Dioscoreaceae, chamomileflowers, from Anthemis nobilis; Germanchamomile, Iridaceae Matrir:arin chamontilla; insect flowers, Chrysonthemum. Bromeliales Bromeliaceae cinerariffblium; wormseedor santonica,Artemisia cina; arnica Graminales Gramineae flowers and rhizome, Arnica monttzna; calendula tlowers, Principes PaImae Calendula ofJicinalis; yarrow herb, Achillett milLefoLium: Araceae,Lemnaceae Spathiflorae grindelia herb, Grindelia camporum: blessed thistle leaves, Cyperaceae Cyperales Cnic'usbenediclus;coltsfoot leaves,Ia.isi/agofafiara; wornMusaceae,Zingiberaceae,Cannaceae, Scitamineae wood herb, Artemisitt absinthitrm:pellitory or pyrethrum root, Marantaceae Anacycluspyrethrumt elecampaneroot, InLrlahelenium; Ngai Microspermae Orchidaceae camphor, frcm Blumea balsam.fera.The llorets of the saff-lower, Carthamustinctorius,areusedas dye and as a substitutefor saffron. Refined Sunflower OiI EP/BP is expressedfrom the seeds uHtFtoRAE relined. of HelianthusannuLtsand subsequently (2) Liguliflorae: In this subfamily latex vesselsare present but Liliqceqe, Agovoceoe, Hypoxidoceoe, volatile oil is rare.All the flowers haveligulate corollas.Genera Amoryllidoceqe, Dioscoreoceoe, lridoceoe include Cichorium (9 spp.),Crepis(200 spp.),Hieraciurn (over The order is divided into five suborders and 17 families. Some 1000spp.),Taraxacwn(60 spp.),Lttctuca(100 spp.),Scorzonera botanistsfavour further subdivision-for example, the separationliom ( I 50 spp.) andSonchus(50 spp.).Vegetablesobtainedfrom this the Liliaceae of Smilttr and Rrlscls into separate families, the group include lettuce,scorzoneraroot, chicory and endive. Of respectively. Smilaceaeand Ruscaceae members used medicinally may be noted dandeiion root, Many membersof the group areperennialherbshaving a bulb, corm Taraxacumo|ficinaLe;lactucarium or iettuce-opium,Loctuca or rhizome. The flowers are hermaphrodite.regular or zygomorphic, virosa; mouse-earhawkweed,Hi eraciumpiloseI La-which has andtypicallyhavethefloral fbrmulaP3 + 3,A3 + 3 or3 + 0. G(3).The antibiotic activity and has been used for the treatmentof Malta perianthis usually petaloid;the ovary superior(e.g.Liliaceae)or int'efever. Chicory root and dandelion root have been used,particu- rior (e.g.Iridaceae).Fruit a capsuleor berry. larly in war-time Europe, as adulterantsof or substitutesfor cof'fee. A Turkestan dandelion, Taraxacum ktk-sa,qhiz, has since I Liliaceae.Awidely distributedtamily ofabout 250 generaand 3700 species;mostly perennialherbswith a rhizome or bulb. The flowers 1936beenwidely cultivatedin the former USSR as a sourceof usuallyhave six stamensand a superior(rarely semi-inferior)ovary, rubber latex. with numerousanatropousovules attachedto axile placentas.The fruit is a loculicidal or septicidalcapsule,or a beny. As might be expectedfiom its size,the Compositaecontainsa wide Without troubling the readerwith the namesof subfamilies or tribes, variet-vof chemicalconstituentsand the literatureis enormous.Already the numbersinsertedbelow will indicatethe principal generawithin mentionedare the latex of the Ligulillorae and inulin which is often each: l. Vertrtrum(25 spp.), Gloriosa (5 spp.) and Colchicwn (.65 present in very large amounts (e.g. in dahlia tubers). Some of the (12spp.),Bowiea(2spp.), spp.);2. Herreria(8spp.):3.Asphodelus volatile oils fbund in the Tubuliflorae contain acetyleniccompounds. Funkia-Hosta (10 spp.), Kniphofia (75 spp.) and Aloe (about 330 Sesquiterpenes known as azulenesgive the blue colour to fieshly disspp.); 4. Gagea (70 spp.),Allium (450 spp.); 5. Lilitun (80 spp.), lactonesoccur tilled oil of chamomileand yarrow.Many sesquitetpene (85 spp.). TuLipa(lOO spp.); 6. Scl11a(80 spp.), Urginea Fritillaria (e.g. santonin), and are of varying types, including eudesmanolides (100 spp.),Ornirhogttltrm(150 spp.),Hyacinthus(30 spp.),Mu,scari germacranoiides. guaianolidesand pseudoguaianolides; someof these (60 spp.); 7. Asparagus (300 spp.). Pol-tgonatum(50 spp.), have cytotoxic activity. The toxic Senecio alkaloids derived from Convallaria (1 spp.), Trillium (30 spp.), Paris (20 spp.); 8. pyrrolizidine have been much researched.Some causeliver damage Ophiopogon(20 spp.); 9. Aletris (25 spp.); 10. Smilax (about 350 and are therefbredangerousto livestock. Alkaloids of the pyridine, 'Agavaceae'. spp.).For Yucca,Dracaena andAgaveseebelow r.rnder quinoline and diterpenoidtypes also occur in the family. Other conSome members of the family are cultivated for their flowers. stituentsinclude the insecticidalestersof pyrethrum(q.v.) triterpenoid Vegetablesinclude asparagus(Asparagus oflicinalis) and onion, saponinsofgrindelia, cyclitols.coumarinsand flavonols.Steviarebaugarlic, shallot,leek and chives (all from speciesof Allium). Drugs diana, a herb indigenousto Nofih EasternParaguay,is the sourceof include squill, sarsaparilla,veratrum, colchicum seed and corrn, stevioside,an ent-kaureneglycoside used as a sweetenerfor soft aloesand cevadillaseed.Garltc(Alliun sativum).an age-oldremedy drinks.etc.

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A TAXONOMICAPPROACH TO THESTUDYOF M'DICINAt PTANTS AND ANIMAL.DERIVED DRUGS frequently used for the treatment of colds, bronchitis, etc., has recentlyreceivedmuch attentionas a preventativeof heaft disease, as an antibioticand as an anticancerdrug. Many member"sof the family contain alkaloids, which are of the steroidal,isoquinolineor purine types. Other steroidalsubstances includesterols,cardenolides, bufadienolidesand steroidalsaponins. The amino acid azetidine-2-carboxylic acid occursin many genera and is also found in the Agavaceae.Other constituentsinclude quinones (benzoquinones,naphthoquinones,anthraquinonesand anthrones);flavonoids (anthocyaninsand flavonols); rhe y-pyrone chelidonicacid: cyanogeneticsubstances; and fructosan-typecarbohydrates.Somevolatile oils of the family haveantimicrobialproperties. Agavaceae.A family of 20 genera and 670 species.The genera (40 spp.).Agave (300 spp.),Cordyline(15 spp.), include YLLcca (150 spp.),Sansevieria(60 spp.),Phonnium (2 spp.), Drac:cteno Nolina (30 spp.) and Furcraeu (20 spp.).Dragon's blood is a dark red secretionfrom the leavesand trunkof Dracaena draco andD. t'innabctri;the tbrmer is a native of the Canary Islandsand Willis (A Dictionary of the Flowering Plants ttnd Ferns. I 985) citesa tree blown down in 1868.70ft high and 4-511in girth, rhat was supposedto be 6000 yearsold. Steroidalsaponinshave recently been reported as constituents of the resin (Y. Mimaki er al., Phytochemistn' 1999, 50. 805). D. cinnabari was the source of commercialSocotradragon'sblood, the flavonoids of which have beenstudied(M. Masaoudet al., Phytocltemisn.r 1995,38, 745; 751). The resin is traditionally used as an astringentin the treatment of diarrhoea;it alsohashaemostaticand antisepticpropefiies. Note that anotherdragon's blood is obtained from Daemonorops spp.(Palmae)(q.v). Steroidal saponins occur in species of Yucca,Agave and Furcraea; Sansevieria 7e-vlanicayields bow-string hemp and Furcraea giganteu Mauritius hemp. The leavesof Agrzuesisnlana yield the fibre sisalwhich is producedin largequantitiesin Central America and Kenya: the fermented sap of this plant forms the Mexican drink pulque. Speciesof Sansevieriaare common houseplants under the name of 'mother-in-law'stongue'. Alkaloids and cardenolidesappear to be absent from the family but the constituentsotherwiseclosely resemblethoseof the Liliaceae. 3 . Amaryllidaceae.A family of 85 genera and about 1100 species; mostly tropical or subtropical,and often xerophytes.Many have bulbs or rhizomes.Perianthpetaloid.A 3 + 3, G(-3).Fruit a loculicidal capsuleor berry.GeneraincludeGalotthus (20 spp.),Leuco.junt (l2spp.'1.Aman'llis (l sp;),Nerine(30 spp.),Puncratittm(15 spp.), Hy-menocttllis(50 spp.), Narcissus(60 spp.), Ungernia (6 spp.), Hippectstrurn(75 spp.) and Sternbergia(8 spp.).The tamily contains typesof alkaloid unlike thoseof any other family in the order. R. Darnley Glbbs (Chemotaxotlom)' of Flowering Plants,Yol.I, p. 148, 1914) lists nine groups of theseAmaryllidaceousalkaloids. One of these alkaloids, lycorine, has a marked fungicidal action; another,galanthamine.obtainedfrom Leucojumaestivumand other species.is a newly marketeddrug for the treatmentof Alzheimer's disease. Hypoxidaceae.A family of seven generaand 120 species.Herbs from a tuberousrhizome or conn. SeveralHypoxis spp.have found use in traditional medicine as anti-inflammatoryand anti-tumour drugs.A lipophilic extract is marketedin Germany,and the dried corm in South Africa, fbr treatmentof prostatehypertrophy.The genus containsphenolic glycosidesof the norlignan type (see M. Nicoletti et ul., J. Ethrtopharm.,1992,36.95). -5. Dioscoreaceae. A lamily of five generaand about 750 species; tropical or warm temperateclimbing herbs or shrubs.The plants

have fleshy tubers (called yams) or rhizomes. The leaves are often arow-shaped. Flowers dioecious.Fruit a capsuleor berry. The genera are Dioscorea (over 600 spp.), Tamus (5 spp.), Rajann (25 spp.), Stenomeris (2 spp.). Tamus commuLris,the black bryony, is exceptionalin that it grows in Europe.It is common in Englishhedgerowsand its scarletberriesarepoisonous;a number ofphenanthronederivativeshave been reportedfrom the rhizome as well as dioscin and gracillin (see R. Aquino, J. Nat. Prod. 1985, 48, 502,81i). The yams of Dioscorea batatas con' tain abundant starch and are important foodstuffs in the tropics. Steroidal saponinsare presentin many speciesof Dioscorea and Tamusandtheir extractionhas becomean important industry (see Chaprer24). 6. Iridaceae.A iamily of more than 60 generaand 800 species.Found in both tropical and temperateregions.Many perennialherbswith corm (e.g. Crctcus)or rhizome (e.g. lrls). Flowers hermaphrodite, regular or zygomorphic; P3 + 3 petaloid, ,A3, G(3). inferior (or rarely superior).The fiuit is a loculicidal capsulewith numerous seeds.The genera include Crocus (15 spp.),Romulea (90 spp.), Sis,-rinchium(100 spp.), Tritonia (55 spp.),Freesia (20 spp.) and lris (about 300 spp.). Products of this family are saff,ron,from Crocus sativus,and orris root, from speciesof 1rls. Constituents include quinones(naphthoquinones and anthraquinones), aromatic ketones (e.g. in lris), carotenoidpigments (e.g. in saffron), terpenoids (mono-, sesqui-,di-and tetraterpenoids),and flavonoids (anthocyanins,flavones,flavonolsand isoflavones).

BROMELIATES Bromelioceqe The Bromeliaceaeis the only family of the order and containsabout44 generaand 1400 species;mainly tropical and subtropical,xerophytes and epiphytes.Fruit a berry or capsule.Theseinterestingplants vary very much in size and habitat; many are grown as house-plantsor in greenhouses. Generainclude Bromelia (40 spp.) andAnanas (5 spp.). Ananas comosus(syn. A. sativus)is the pineapple,the juice of which containsbromelain,a protein-splittingenzymewhich can be usedas an adjunct in the treatment of trauma and oedema arising from surgery and for soft tissueinflammation.It is cited as an aid to digestionand recentstudies(Gut 1998,43,196) have suggestedit as a possiblecure for travellers' diarrhoea. The chemistry of the family requires much more study,but many speciescontain gums and mucilagesand there arereportsof tannins,phenolicacidsand flavonoids.

GRAMINATES Gromineqe An order of one family. The Gramineae contains about 620 genera and l0 000 species. Mostly herbswith fibrousroots;rarely shrubsor trees.Annuals,biennials and perennialsalmostuniversallydistributedandmany of greateconomic importance.Leavesalternate,with sheath;blade usually long and nalrow; veins normally parallel. Jnflorescenceof numerous spikelets, with scales.Flowers bisexual, protected by palea; stamensusually three;ovary unilocularwith one ovule.Fruit one-seeded, usuallya caryopsis (rarely a nut or berry). Some important genera are Bambusa (70 spp.), Arundinaria (150 spp.), Oryza (25 spp.), Arundo (12 spp.), Triticum (about 20 spp.), Agropyron (100-150 spp.), Hordeum (20 spp.),Secale(4 spp.),Avena (.'70spp.),Sorghum(60 spp.),Zett (l sp.), Saccharum(5 spp.)andAndropogon(113 spp.),Cymbopogon(60 spp.), Pfuilaris (20 spp.)andVetiveria(10 spp.).Productsincludebamboosof

THEPLANTAND ANIMAL KINGDOMSAS SOURCES OF DRUGS many difl'erent sizes, fiom speciesof Bambusa and ArundincLria, rtce from Oryz.asdlir,r, wheat from Triticum, barley from Hordeurn, rye from SecaLe,millet or guinea corn from Sorghumvulgare, maize or Indian com from Zea nnls and sugarcane from Sucr:harumoJJicinarum. The tribe Paniceae, which includes Andropogon, Cymbopogon and Vetiveria,is rich in volatile oils. These grassoils are relatively cheap and are much used in perfumery,especiallyfor scentingsoap.They includecitronellaoils, lemon-grassandpalmarosa(geranium)oils from speciesof Cymbopogon;oil of vetivertfromVetiveria zizanioides.The rootsofthe latterplant,khus-khus,are usedboth in perlumeryand as a drug and are alsowoven into fragranFsmellingmatsand f'ans. The Gramineaecontains a very wide range of constituentsbut a large proportionof the chemicalwork has been devotedto the abovementioned fbodstuffs, starches,sugar and volatile oils. Other constituentsinclude l1 difl'erentclassesof alkaloid (fbr details seeR. D. G1bbs, Chemotaxonom\ of Flon'ering Plants, MonIreal, Canada: McGill University Press),saponins,cyanogeneticsubstances, phenolic acids,flavonoidsand terpenoids.

sonouslatex, the poison being destroyedby heat.The generainclude Acorus (2 spp.), Arum (15 spp.), Monstera (50 spp.), Dracunculn, Amorphophallus and Cnptocoryne. Ca\amls or sweet l1ag rhizome is derivedfrom the pelennialherb Acorus calamus,which is widely distributed in damp situationsin Europe and North America. Arum, also known as lords and ladies,cuckoo-pintand wake robin, is Arummaculutum, a common hedgerowplant in England. lt and other speciesof Arum are poisonous;these plants contain amines and cyanogenetic compounds.Speciesof Monsteraareoften grown as house-plants. The rhizome ol Cryptocorvnespiralis is known as 'Indian ipecacuanha'. Amorphophalluscampanulunrsis the elephant-footyam. Many membersof the family arecyanogenetic.Alkaloids, eitherpyridine or indole types, are reported in a f'ew genera. Other constituents include saponins,tannins.phenolicacids,aminesand terpenoids.

CYPERATES

Cyperoceoe The order containsthe singlefamily. The Cyperaceaehas about 90 generaand 4000 species:widely disPRINCIPES tributedherbs.Generainclude Cl,perus(550 spp.),Scirpus(300 spp.) Polmoe and Carex (150-200 spp.).Formerly oflicial in a number of pharmaThe order containsthe singlefamily Palmae. copoeiaswere the rhizomesof Carex arenaria and Cr-perusrotundus. The Palmaehas 217 generaand about 2500 species.Wideiy distri- Papyrus, used in ancient times as paper, is derived from Cyperus buted in the tropics and subtropics.Mostly treeswith an unbranched pap)-rus.Like some members of the Gramineae.certain speciesof stem bearing a crown of large, often branched leaves.The flowers are Scirpus andAntpektdesmoseryeas host plants for speciesof Claviceps usually unisexualand regular,consistingof two trimerous whorls of and produce ergot-like sclerotia. Other lamily constituentsinclude small perianth leaves, six stamensand three superior carpels. The volatile oils, tannins,phenolicacids,flavonoidsand sesquiterpenoids. carpelsrnay be free or united and develop into a berry. drupe or nut. The seedscontaina very small embryo but abundantendosperm.Important generaare Pfutenir (17 spp.), Sabal (25 spp.').Copernicia (30 spp.), SCITAMINEAE Metroxt'lon (15 spp.), Calamus(375 spp.),Areca (54 spp.),Elaeis (2 Musoceoe, Zingiberoceqe, Cqnnoceqe, Morontoceoe spp.), Cocos (l sp.), Phytelephas(l-5 spp.). Serorcta (1 sp.) and An order of live families. (100 spp.). Of economic interest are the date palm, Dttemonorr.tps I . Musaceae.A family of two generaand 42 species,namelyMLrsa(35 Phoenix dactylfera; sago from the stemsof Metro.nlort rumpii and M. spp.)and Enseta(7 spp.).The plantsaregiant herbswith 'false'aerlaeve; raltan canes from speciesof CaLamus;areca or betel nuts from ial stemsand sheathedleavesarisingfrom a rhizone. Fruit a berry. Areca catechu;palm oil and palm kernel oil from Elaeis gLtineensis; Of economic importance are the fruits of Musa paradisiacu (plancoconut from Cocos nucifera; camaubawax from Copernicia cerifera. tain) and M. sapientum(banana),which are rich in starch.Manila The resin from speciesof Daemorutrop.igives the EastAsian dragon's hemp or abacais derived from Mustt re-rti1ls.Constituentsof the blood and this appears(1997) to be the only available commercial family include starchand fructosans,phenolicacids,anthocyanins, source; the constituentsinvestigatedare of flavonoid origin, some terpenoidsand sterols;only isolated examplesof alkaloids (alkaderived from 5-methoxyflavan-7-oland 5-methoxy-6-methylflavanloidal amine and an indole alkaloid)are reported. 7-o1.Isolatedcompoundshavebeennameddracoflavans(A. Arnone el al., J. Nat. Prod.,1991,60,971).The fruits of Serenoarepens(saw-pal- 2. Zingiberaceae.A family of about 49 genera and 1300 species. Perennialaromaticherbswith fleshy rhizomesand tuberousroots; metto) native to the SE coastal statesof North America are a popular flowers in racemes,headsor cymes. Perianth6-merous,the outer remedy for male impotence and are used in the treatment of the sympcalyx-like, the inner corolla-like.Two of the stamensmodified as a toms of benign prostatehyperplasia.Seedsof PhVelephas spp. (P petaloidlabellum.Fruit a loculicidal capsule.Seedwith perisperm. aequatorialisin Ecuador)are the basisof the vegetableivory industrv Genera include Curcuma (5 spp.), Alpinia (250 spp.), Zingiber (for a reportseeA. S. Barfod et al., Econ.Bot., 1990,44,293).In addi(80-90 spp.),Amomum (150 spp.),Elettaria (7 spp.),Aframomum tion to the fixed oil, carbohydratesand leaf wax mentioned above, the (50 spp.) andHedychium(50 spp.).Cosrls (150 spp.)is includedby family containssaponins,tannins,catechins,llavonoids,terpenoidsand Engler in the Zingiberaceae, but is sometimesseparatedasa distinct ketones.AlkaloidsoccurinAreca, but few havebeenfound in othergenfamily. Its main difference from the other genera listed is that its era.Steroidalsubstances occur(e.g.estronein the pollen of Pfutenix). aedal partsarenot aromatic.Productsof the family includeturmeric, the rhizomesof Curcumalonga; grnger,the rhizome of Zingiber SPATHIFTORAE officinale; cardamom fruits from Elettaria cardamomum; and Arqceqe grainsof paradise,the seedsof Aframomummelegueta.Volatileoiis The order consistsof two families. the Araceaeand the Lemnaceae. and pungentprinciplessuch as are found in ginger (q.v.) are a feaThe latter, which containsonly six generaand 30 speciesof aquatic ture of the family. Other constituentsinclude the colouring matters herbs,is of little importance. known as curcuminoids(see 'Turmeric'), tannins,phenolic acids, The Araceaehas I 15 generaand about2000 species;rnainlyherbsor leucoanthocyanins, flavonoids,ketonesand terpenoids.Only a few climbing shrubsand over 90Vctropical; many memberscontain poiisolatedexamplesof alkaloidshavebeenreported.

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A TAXONOMICAPPROACH TO THESTUDYOF MEDICINALPLANTS AND ANIMAL.DERIVED DRUGS 3. Cannaceae.This iamily containsonly the single genus Canna (55 B) which inhibit tumour promotion.As with the spongesthereis much spp.).The rhizome of Canna edulis yields the starch,Queensland cunent biochemicalinterestin this ohvlum. arTowroot. :1. Marantaceae.A family of 30 generaand zl00speciesof tropical herbaPTATYHEI.JYIINTHES ceous perennials.The genus Maranta (23 spp.) contains Maranta arundinacea,the rhizome of which yields WestIndian arowroor. (Flotworms)

MICROSPERMAE

ThisphylumincludestheTrematodes (theparasiticflukessuchasthe liverfluke andSchistosoma) andtheCestoda (tapeworms).

Orchidoceoe NEMATODA The order containsa singlefamily. The Orchidaceaeis one of the largestlamilies of llowering plants, (Roundworms) with some 735 genera, over 17 000 species and many hybrids. Someareparasitic in manandanimals. Cosmopolitanperennialherbs,some terrestrialbut many tropical epiphytes(e.9. Vanilla).The ovary is inferior and the fruit a capsule;seeds very small and light. GeneraincludeOrchis (35 spp.).Ctpripedium (50 MOTLUSCA spp.),Phalaenopsis(.35 spp.),Dendrobium (1400 spp.'),Liparis (250 Class Gastropoda includesthe snails,slugsand limpets. Some snails spp.),Malaxis (300 spp.), Vanda(60 spp.),Cry.ptosrr-lls (20 spp.) and are vectorsof parasitessuchas Sc/rlslosona. Vanilla(90 spp.).The glycosidesofvanilla, which producevanillin and Class Lamellibranchia includes scallops, mussels, oysters and other aromatic substancesby slow enzymic change,have long been clams. known. More recently, attention has been directed to the numerous Class Cephalopodaincludesthe squids,cuttlefishesand octopuses. alkaloids present in the family. Sorne of these are of an unusual Cuttlefish bone (from Sepia fficinalis) has been employed in dentiindolizidine type, others are derivatives of indole, pynolidine and liices and as an antacid. pyrrolizidine. Other constituents include phenolic acids, tannin, fl avonoids,coumarinsand teruenoids.

ANNE[IDA (Segmented \,vorms) Earthworms,lugworms and leeches(q.v.) belong to this phylum. The potent neurotoxlc agent nereistoxin is obtained from the Japanese As with the Plant Kingdom, animalsare classifiedinto Phyla, Classes, speciesLumbr i conereis heterop oda. Orders,Families,Generaand Species.Although the number of pharmacognosticalproductsderived from animal sourcesis limited there ARTHROPODA hasbeen,in recentyears,an immenseinterestin the chemistryof many marine creaturesas potential sourcesof drugs and biologically active A very large phylum of jointed animals including the crustaceans, materials.In this respectmuch researchhas beenpublishedon the sim- insectsand arachnids. pler marine organisms. Class Crustacea includes the shrimps, crabs, lobsters,centipedes Listed below are selectedanimal phyla which embracespeciesof and millipedes. Of little medicinal significance,neverthelessbrine interest (the many animal products used in traditional medicinesof shrimpsare being increasinglyused in place of higher animalsfor the Africa, India and the Orient are not included). preliminary testingof phytochemicalsfor toxicity. Class Insecta. Of the many ordersof this taxon the following have medicinalinterest:

PROTOZOA

Unicellular microorganisms including parasites causing malaria (Plasmodium), sleeping sickness (Trypanosonttt)and dysentery (Entamoeba). Some dinofl agellates (Pro ro cent r um, D in op ht si s) pr oducepolyethertoxins responsiblefor someshell-fishpoisoning.

PORIFERA (Sponges) Metabolites include bromophenols(antibacterialproperties),cyclic peroxides and peroxyketals (antimicrobial, ichthyotoxic, cytotoxic activities),modified sesquitetpenes (antimalarial,antifungal,antibacterial, anticanceractivities).Siliceousspongespiculesare often found in samplesof kieselguhrand agar(q.v.).

COETENTERATA (Jellflishes, seq onemones, corqls) ThesoftcoralPlexaLtahomomallais a rich sourceof prostaglandin ,{2 andSarcophyton glaucumcontainsditetpenoids(sarcophytols A and

(l) Order Anoplura (Lice): Commonly infest birds and mammals. Important from human standpointts Pediculushumanusencounteredas the body louse(.corporis)and the headlouse(capitis);itts a proven carrier of typhus fever and an indirect transmitter of relapsingfever. (2) Order Hemiptera (Bugs): The cochineal beetle (q.v.) is an lmportant colourant and shellacis a resinoussubstanceprepared from a secretion that encrusts the bodies of a scale insect Laccifer lacc'a. (3) Order Coleoptera(Beetles):Beetlesof the generaCantharis and Mylabris, known as blisteringbeetles,possessvesicantproperties and preparations of C. vesicatoria were at one time used in Westernmedicinein the form of plasters,collodionsetc. asrubefacientsand vesicants.Their use continuesin the traditionalmedicine of EasternAsia (R. W. Pemberton,J. Ethnopharmacology 1999,65, 181).A numberof small beetlesare importantinfestants ofstored drugs(seeChapter13). (4) Order Lepidoptera (Butterflies and moths): Some moths infest storeddrugs (seeChapter l3). Silk has been traditionally used in pharmacyin the form of oiled silk.

THEPLANTAND ANIMAL KINGDOMSAS SOURCES OT DRUGS (5) Order Hymenoptera (Ants, bees, wasps, etc.): Hive products derived from Apis mellifica include honey, beeswax, royal jelly and propolis (q.v.). (6) Order Diptera (Flies, gnats and midges): The successfuluse of maggotsin the treatmentof woundsinfectedwith antibiotic-resistant Staphylococcusaureus has received recent attention.Sterile larvae of the common greenbottleLucilia sericatc are used.For a report seePharm. J . 1999,262, 422. Class Arachnida. Arthropods with two divisions to the body (cephalothoraxand abdomen)including spiders,scorpionsand mites. Order Acarina (Mites): the common housemite(q.v.) is a causeof allergyin humans;other speciesinfest storeddrugs(seeChapter13).

CHORDATA The most important subphylum of the Chordata is the Vertebrata (Craniata)composedof all those animals with backbones;a number of classification schemes will be found in the literature and two major groupings often referred to as superclassesare the Pisces

(aquatic vertebrates)and the Tetrapoda(terrestrialvertebrates)each divided into four classes.The followins four classeshave medicinal significance: 1. Class Osteichthyes (Bony fish). Cod and halibut important for their liver oils which contain vitamins A and D and eicosaoentaenoic acid (dietary supplement). 2. ClassAmphibia (Frogsand toads).Dried and powderedtoadskins contain cardioactive principles and were used for the treatment of dropsy before the widespreadadoption of digitalis. 3 . Class Reptilia (Crocodiles,snakesand lizards).Snakevenomsare important products. 4 . Class Mammalia (Warm-blooded animals which suckle their young). Variouslydivided into subclasses, infraclassesand orders. SubclassEutheria embracesthe placental mammals, e.g. bats, rodents, carnivores, whales, ungulates and primates. Formerly important was the whale-product spermaceti but its collection is now illegal. Other pharmaceuticalsinclude lard, suet, wool fat, wool, gelatin, musk, catgut, insulin, hormones,blood and liver oroducts.vaccinesand sera.

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As indicated in Chapter 2, a val,id scheme for the study of medicinal plants and their products,and one which emphasizespharmaceutical '!, use, can be based on pharmacologicalaction. The scheme can be extended to include numerous plants which, although eliciting a --,."1i pharmacologicalresponse,arenot, for variedreasons,usedasdrugs.In i !, the latter categorywould be placed hundredsof alkaloid- and glyco4a side-containingplants. Somemajor pharmacologicalgroupingsinvolve drugswhich act on r d the nervous systems,heart and blood vessels,lungs, gastrointestinal tract,kidneys,liver, reproductiveorgans,skin and mucousmembranes. Other categoriesinclude hormones,vitamins and chemotherapeutic lr drugs used for the treatment of infections and malignant diseases. r.it Someplants(e.9.Papaver,ipecacuanhaand liquorice)containa range #i{ 1 , of compounds with differing pharmacologicalproperties. Oliver..'!i. Bever's classicalreview ("/. Ethnopharmacol.,1983, 7, 1) on West '9i African plants which act on the nervous system well illustratesthe problemsof constructinga purely pharmacologicalclassificationfor ! herbal materials. A system based on clinical usage may be more straightforward for the throughly-studied allopathic drugs used in ' 1 Westernmedicine but difficulties can arise for plants used in tradition. al medicinebecauseof the often numerousconditionsfor which anv '.1{i i""' one drug may be employed. I j

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The nervous systemcoordinatesand regulatesthe various voluntary and involuntary activitiesof the body and is convenientlyconsidered under two headings-the centralnervoussvstem(CNS) and the autonomic nervoussystem.The two are interlinked and somedrugs which affect the CNS may also produce reactions associatedwith the autonomic system.In the caseof otherswhich act via the autonomicsystem it is sometimesmore convenientto classifythem underother headings appropriateto the organsinvolved; thus,thoseproducingvasoconstriction or vasodilation may appearunder the considerationof the circulatory and respiratorysystems.

THENASATAND RESPIRATORY SYSTEMS 45 THELIVER 45 THEURINARYAND REPRODUCTIVE SYSTEMS 45 THESKIN AND MUCOUSMEMBRANES 45 ACTIONON SUGARMETABOTISM 46 AND ANTI.INFTAMMATORY STEROIDS DRUGS 46 NONSTEROI DAt ANTI.IN FTAMMATORY DRUGS 46 TREATMENT OF INFECTIONS 47 TREATMENT DISEASES 47 OF NAALIGNANT TREATMENT OF ALTERGIES47 THEIMIVTUNESYSTEM 47

vfTA ^tNs 48

THECENTRALNERVOUSSYSTEM The central nervous system comprisesthe brain (cerebrum,cerebellum, medulla oblongata)and the spinal cord. It coordinatesthe voluntary activities of the body and exhibits numerousinteractionswithin the system together with linkages to the autonomic system. Drugs involved with the CNS can be broadly classifiedaccordingto whether they have a general stimulatory or depressant action with further subdivisionregardingspecificactionssuchas anticonvulsantand psychopharmacologicalactivities.Some of the most useful natural drugs of the group arethe narcotic(opioid) analgesics;otherssuchasthe hallucinogenicdrugshave importantsociologicalimplications.SeeTable 6. I for a summary of drugs acting on the central nervous system.

THEAUTONOMTSNERVOUSSYSTEM The autonomic nervous system supplies the smooth muscle tissues and glandsofthe body.Its function is complex,involving gangliasituatedoutsidethe spinal cord; it is composedof two divisions,the sympathetic (thoracolumbaror adrenergic)division, which arises from the thoracic and lumbar regions; and the parasympathetic(craniosacral or cholinergic) division, originating in the brain and in the sacral region. In general,an increasein activity of the sympathetic systemgearsthe body for immediateaction (fight and flight), whereas stimulation of the parasympatheticor vagal systemproduceseffects

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OF DRUGS THEPLANTAND ANTMALKINGDOMSAS SOURCES

Toble 6.I

Drugs octing on the cenlrql neryous syslem.

Drugsoffecting mentolactivity Lysergicocid diethylomide Mescoline Connobis Purineboses(e.g.coffeine,theophylline, theobromine) Cocoine I

Ginkgo bilobo Ginseng Golonthqmine Hypericum Soge Reserpine Yohimbine Volerion,Possifloro

fromergotolkoloidsor by ortificiolculture Prepored by pcrtiolsynthesis Hollucinogenic. Hollucinogenic. Obtoinedfrompeyotecoctus contoinedin the resinof Cannobissotivo Hollucinogenic. Activeconstituents of beveroges-coffee,feo, cocoo,kolo, mst6 Stimulotementoloctivity;conslituents oddiction.Contoinedin the leoves One of fhe eorliesidrugsusedos o mentolstimulont.Produces ol Erghroxylumcoca lmprovesshorttermmemory porticulorlyin the elderly lmprovesmentolconcentrotion diseose of Alzheimer's olkoloidfor treofment Promising Amoryllidoceous Populorherbolremedyfor reliefof mild-moderotedepression memoryloss Revivedinferestin its usefor counterocting Depresses mentoloctivity.Usedin psychiohictreoiment.Obtoinedfrom Rouwolfiospp. reoctions ond effecton heortmusclerenderit o[ bul itsontiodrenoline Similoroctionlo reserpine of theApocynoceoe no clinicaluse.Foundin voriousspecies ond improvesleepquolity Sedotiveond hypnotic;oid sleeplessness

of the CNS in Anolepticdrugs(stimulonts odditionto ihe menlolstimulonts indicotedobove) Picrotoxin Lobeline Strychnine Comphor

Anolepticpreviouslyusedin the freotmentof borbiturotepoisoning.Obtoinedfrom berriesof Anomirtococculus Obtoined from Lobelioinflato Obtoinedlrom the seedsof Weok onolepiic;toxic dosesproducespinolconvulsions. Strychnos spp. comphoraond by synthesis Weok onoleptic.Obtoinedlrom Cinnamomum

of motor function Central depressants Troponeolkoloids(e.g.hyoscine, otropine,etc.) root Gelsemium Anolgesicdrugs Morphine Codeine

of Porkinson's diseose. Formerlythe only drugseffectivein the olleviotionof the symptoms ond deliriumtremens Usedin treotmenfof trovelsickness clinicollyowing to high toxicity.Golenicolpreporotionsoccosionollyusedos Rorely-employed oniisposmodics octionon lhe coughond respirotorycentres.The Effective for reliefof severepoin. Depressonl principololkoloidof opium Althoughlessoctivethonmorphineit is o muchsoferdrugfor thereliefof mildpoin ond for use os o cougnsuPpressonl

Many factors affect the complex regulation of the heart and the large group of drugswhich is known to possesscardiovascularactivity is not confinedto actionon the heartmuscleitself. Thus thosedrugspossessing antiarrhythmic, antihypetensive, antihyperlipidaemic,vasoconstrictor, vasodilator,blood anticoagulant,and platelet aggregation activitiesmust also be consideredin this group.As with other importis an activesearchin the plant kingdom for compounds ant areas.,there of new which may also serveaslead compoundsfor the semi-synthesis drugs.For sometherapeuticgroups,the lack of simplereliable screening techniquesis a problem. AND BTOOD THEHEART.CIRCULATION In a review (over 390 refs) E. L. Chisalberti et aL. (.seeFurther Reading)have iisted some447 speciesfrom 109 families having carIn developedcountries,coronary and associatedcirculatory diseases diovascularactivity,togetherwith a compilationof over 700 secondary now constitutethe principal causeof human mortality.Not surprising- plant metaboliteshaving suchactivity. ly, therefore,this is an areaof intensivetesearch,not entirely devoted to treatment, but also to the prevention of these diseases.With increasedpublic awarenessof the importanceof the latter. healthier Cordiooctive glycosides living focusedon diet, supplementaryfood factors,exercise,etc. has A considerablenumber of plants scatteredthroughoutthe plant kingtaken on a more important role, not least in the mind of the commercial dom contain C21or Cz+steroidalglycosideswhich exerta slowing and world where health food storesnow supply many dietary supplements strengtheningeffect on the failing heart. In Western medicine it is the and medicinal plant products which overlap the traditional pharma- glycosidesof variousDigitalis speciesthat are extensivelyemployed. The pharmacologicaleffectivenessof the cardioactiveglycosidesis ceuticalranqe.

more associatedwith those occurring during sleep and with energy conservation.Two important neurotransmittersubstancesof the autonomic nervous system are acetylcholine and noradrenalineand its which either mimic or antagonize derivatives;hence,other substances the action of either of these will produce a marked physiological response.Drugs acting on the autonomicnervoussystemare summarized in Table6.2.

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Toble 6.2

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Drugs octing on the outonomic nervous system.

AcetylcholineJike drugs Pilocorpine Arecoline Muscorine Physostigmine Antogoni stsof ocelylcholine Troponeesterqlkoloids(e.g.hyoscine, olropine)

Neuromusculor blockingogenls(e.g.tubocurorine) Gonglionblockingogents{e.g.tubocurorine in lorgedoses)(notclinicollyimportont)

Fromleovesol Pilocarpusmicrophyllus Fromseedso[ Arecacalechu FromAmonitospp.ond otherfungi A cholinesterose inhibitorfrom seedsof Physostigno venenosum

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AdrenalineJikedrugs Ephedrine

Fromstemsof Ephedrospp.; moinlysynthetic

Antogonistsof odrenoline Ergotolkoloids(e.g.ergotomine)

Fromsclerolioof C/ovicepsspp.

No rodrenoline d e pletion Reserpine

Hosontihypertensive effectresultingfromdilotionof heortond circuloloryvessels

Ophtholmic preporations Theeye, being underthe confrolof the outonomic nervoussystem,is offecfedby someof the drugs mentioned obove;theseincludeotropine,hyoscine, physostigmine ond pilocorpine.

dependenton both the aglyconesand the sugarattachments;the inherent activity residesin the aglycones,but the sugarsrendbr the compounds more soluble and increase the power of fixation of the glycosidesto the hearl muscle. The overall action of the digitalis glycosidesis complicatedby the numberof differenteffectsproduced.and their exactmode of actionon myocardialmusclein relationto currentviews on cardiacmusclephysiology is still an areaofinvestigation.Digitalis probably actsin competition with K ions for specificreceptorenzyme(ATPase)sitesin the cell membranesof cardiacmuscleand is particularlysuccessfulduring the depolarizationphaseof the muscle when there is an influx of Na+ ions. The clinical effect in cases of congestiveheart failure is to increasethe force of myocardial contraction (the positive inotropic effect)resultingin a completeemptyingof the ventricles.As a iesult of depressionof conductionin the bundleof His, the atrioventricularconduction time is increased,resultingin an extendedP-R interval on the electrocardiogram. Arising from their vaguseffects,the digitalisglycosidesare also usedto control supraventricular(atrial) cardiacarrhythmias. The diuretic action of digitalis, important in the treatmentof dropsy,arisesfrom the improved circulatoryeffect. However, fbllowing the introductionof saferdiureticsin the 1950s,diuretic therapyfor heart lailure has becomemuch more imporlant and in somecasescan replacedigitalis treatment. Among the many other plant generacontainingcardioactiveglycosidesrelatedto thoseof Digitalis, and usedsimilarly, areStrophanthus, Convallaria, Nerium, Thevetia and Erysimwn For a full account of thesedrugs seeChapter24

Antiorrhyrhmic drugs As mentioned above, the cardiac glycosidescan be used to control supraventricular (atrial) cardiac arrhythmias. There are a number of other drugs such as the alkaloid quinidine (obtainedfrom variouscinchona barks. q.v.) which act on both supraventricularand ventricular

arrhythmias.Quinidine is oflicial in most pharmacopoeias as its salts and finds prophylacticuse in recunentparoxysmaldysrhythmiassuch as affial fibrillation or flutter.Its therapeuticusefor the attemptedconversion of atrial librillation to sinus rhythm has now been largely replacedb1 electricalcardioversion.

Antihypertensive drugs The control of hypertensionis an imporlant element in the management of cardiovasculardisorders.Primary hypertension,as distinct from other specialfbrms which usually requirehospitalization,representsabout 907c of all casesranging from mild conditionswith the occasionalrise in blood pressureto thosewith severeunrelievedhigh pressure.Of the hypotensiveplant drugs rauwolfia and its principal alkaloid reserpinetogetherwith Venfirumextractswere recognizedin allopathic medicine in the early 1950s.However, a number of other plants regularly employed by Western herbal practitionersinclude mistletoe. Crataegus, Yarrow, Tilia and, Fagopt.runt. In Ayurvedic medicinePiper betle,Josminumsabac,Cardiospermumhalicacabum and Tribulus terrestris,used in the treatmentof hypertension,have beenshownto exhibit a high angiotensinconvertingenzymeinhibition suggesting a possible mechanism of action for these drugs (B. Somanadhanet al., J. Ethnophrtrmacology1999,65, 103). Plotelef octivofing foctor (PAF) ontogonists In the circulatorysystemthrombi may be causedon the arterialsideas a result of the adhesionof blood plateletsto one anotherand to the walls of the vessels.This platelet aggregationis triggered by the platelet activating factor which is releasedliom activatedbasophils. PAF from the rabbit was characterizedin the 1970sas a l-O-alkyl-2acetyl-sn-glyceryl-3-phosphorylcholine. A number of prostaglandins and thromboxanesarealso involved in the aggregationmechanismand thromboxane,A2which is synthesizedfrom arachidonicacid (q.v), is particularlypotent.In undamagedvesselsthromboxane'{2 is possibly

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THEPLANTAND ANIMAL KINGDOMSAS SOURCES OF DRUGS balancedby a prostaglandine.g. prostacyclinof the arterial intima which hasdeaggregation properties. For the secondarypreventionof cerebrovascularor cardiovascular disease,aspirin, which irreversibly acetylatesthe platelet enzyme cyclo-oxygenasehas been employedat dosagesof 300 mg daily with useful results.A large number of piants have been screenedfor antiPAF activity. One of the first natural products so identified was the neolignankadsurenoneobtainedfrom Piper futokadsurn,a plant long used in Chinese traditional medicine for allergy treatments.Other plants of traditional medicine reported to have anti-PAF activity include speciesof Forsythia,Arctium, Centipeda,Tussilago,P1-rola, Populus and Peucedanum.The active constituentsinclude lignans, sesquiterpenes, coumarins,pyrocatecholand salicyl alcohol. Extractsof the maidenhairtree,Ginkgobilobahaveprovedespeciaiiy interestingand are commerciallyavailablein Europe for the treatment of variouscirculatorydisorders. Certainfish oils (e.g.cod-liver,halibut-liver)once employedsolely for their vitamin contentshaverecentlyreceiveda resurgencein popularity as dietary supplements.One favourable responseis that they decreasethe ability of plateletsto aggregateby virtue of their high eicosapentaenoic acid content;this acid tendsto favour the biosynthesis of thromboxaneA3, a weakerstimulatorof plateletaggregationthan thromboxaneA.2. Drugs ocfing on blood yessels (Table 6.3) These drugs are essentially either vasoconstdctor or vasodilator substances but their action may originatein a variety of ways (direct, cenffal,peripheralor reflex). Some of the drugs (e.g. ergot,bronchodilators,diuretics),which are particularlyuseful in relation to specific systems,areclassifiedelsewhere.

Warfarin sodium is one of the most widely useddrugs.Plantsusedin herbal medicinewhich containcoumarinderivativesand possessantivitamin K activity include Meliktu.y officinalis, Galium aparine and Ltnandula offic inal is. Other anticoagulantsare heparin.which is given by injection, and hirudin, produced by the leech; hirudin, a polypeptideof 65 arnino acids,can alsobe obtainedfrom geneticallymodified Sctccharon4'ces.

Hypolipidoemicdrugs In recentyearsmuch prominencehas beengiven to the associationof high levels of blood cholesteroland plasmatriglycerideswith atherosclerosisand ischaemicheartdisease.Treatmentof hyperlipidaemiais preferablydietaryaccompaniedby other naturalregimes.Drug therapy is reservedfor the more intractableconditions.Naturalproductshaving a beneficial action include nicotinic acid (Chapter31) and those fish oils containinghigh quantitiesof to-3-marinetriglycerides.The latter involve eicosapentaenoic acid and docasahexaenoic acid which, when colnting from the methyl end,possessthe first doublebond at C-3. I'Qhesuggestedbeneficiatpropertiesof garlic (Altiunt sativum) for the treatmentof variouscardiovascularconditionsremain a subjectof extensiveinvestigation.With ref'erenceto hyperlipidaemicpatients, the majority of publisheddata suppoftsthe hypothesisthat garlic lowers serum total cholesteroland improves the lipid profile. There is a tendencytowardsreductionof low-densitylipoproteinand an increase in high-densitylipoprotein giving a more favourableHDL:LDL ratio. A reduction in the serum levels of total cholesterol. low-density lipoproteincholesteroltogetherwith a lowered atherogenicindex was observedwith mild hypercholesterolicpatients after a three-month courseof psyllium seeds(K. Sagawaet al., Biol. Phurm. Bull. 1998,

21,r84).

Orol onticoogulonts Thesecompoundsinhibit the clotting mechanismof the blood and are ACTIONON THEGASTROINTESTINAT TRACT of value in arterialthrombosis;they haveno effect on plateletaggregation. One group of active drugs constitutesthe 4-hydroxy-coumarins The gastrointestinaltract can be divided into threeregions-the upper which act by antagonizingthe effectsof vitamin K (seeChapter31). (mouth, stomach and upper pofiion of the duodenum),the middle

Ioble 6.3

Drugs ocfing on blood vessels.

Peripheral vo soconstrictor d rug s Ergotomine(torkote)from C/ovicepspurpureo Ergotoxine Ephedrine(synthetic ond from Ephedrospp.) Nicotine

Produces o direciconstrictor effectin vosculorsmoothmuscle;the reversqlof the dilotionof croniolvessels leodsto iis useol fheonsetof clossicol migroineottock Similorto ergotomine Prolonged ociionon bloodpressure-see olso'Autonomic NervousSystem' gonglio,ond by it Vosoconstrictor effectsorisefrom itsoctionon sympothetic promotingreleoseof vosopressin ond odrenoline

Cenlral vo soconstrictordrugs Mostof the drugs(e.g.picrotoxin)which stimulote the centrolnervoussystemolso stimulotethevosomotorcentrein the medullo,producingo risein blood pressure. Althoughot one time usedos respirolorystimulonts, thesedrugshovebeenlorgelyreplocedby mechonicoldevicesfor o*ificiolventilotion of therunos Vosodilotordrugs (onopiumolkoloid) Popoverine

Actsdirectlyon the bloodvessels by cousingreloxotion of smoothmuscle. An introvenous iniectionusedfor theheolment of pulmonory orteriolembolism Xonthinederivotives(coffeine,theobromine, theophylline) As popoverine;they olso hoveo centrolvosoconstrictor octioncounterocting the peripheroleffect.Also diurefic Ergotomine Adrenolineontogonist-see'AutonomicNervousSystem' Reserpine Vosodilototion is producedby o peripherolond centroloction(q.v.) Verotrumolkoloids{fromVerolrurn spp.} Brodycordio ond peripherol vosodilototion by sensilizotion of cordioc,oorticond corotidsinusbororeceotors

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PHARMACOLOGICAT ACTIVITIES OF NATURAT PRODUCTS , lo.,r'erhalf of the duodenr.rm to the ileocolic sphincter)and the lower icaecum,colon andrectum).It is the upperandthe lower portionsthat |rrc lnost susceptibleto disorderand are consequentlyassociatedwith thc greatestnumberof drLrgsfbr their treatment(seeTable6.zl).

Toble 6.4

THENASATAND RESPIRATORY SYSTEMS A largenumberof drugsof plant origin areto be found in this group.As infectionsof the respiratorytract are amongstthe most comrnonof illnesses,it is not surprisingthat thereare numerousproprietarypreparations lbr their ffeatment(Table6.5).

Drugs octing on lhe gosfrointestinol trocl.

Bitters Al one lime thesewere extensively usedin liquid medicoments lo stimulote oppetite.Thebitterconstituenls stimulote thegustoiorynervesin themouthond giveriselo on increose in thepsychicsecretion of gostriciuice.Extrocts of thefollowing drugshovebeenso employed: gention,quossio,columbo, cinchono(orquinine),nuxvomico(orstrychnine). Consideroble recentreseorch hosinvolvedthe investigotion of o numberof thesebittercompounds for otherpossibleusesie.g. thebittersof theSimorouboceoe os ontiiumour ond onfimoloriol ogents Anticholinergic drugs In thiscopocityhyoscineond hyoscyomine helpdisturbonces cousedby goskicmobilityond musclesposm porticulorly wilh someulcerpotients Emetics lpecocuonho preporotions, on orol odministrotion, hoveo deloyedemeticoctionproducedby irritotion of themucous (see'Expecloronts'). membrones Picrotoxin stimulotes thevomiting centrethroughitsgeneroleffecton the centrolnervoussystem Anti-emeticsGingerhos receivedscientificopprovolfor the prevention of thesymptoms of trovelsickness. Connobisoffords sickness reliefto potients undergoing chemotheropy. Corminolives Theseore oromoticsubstonces whichossisltheeructotion reflex;theirmodeof octionisobscure.Dilloil is usedfor thereliefof flotulence, especiolly in bobies.Otherplontsor oilsusedos corminotives includecorowoy,fennel,peppermjnt, thyme,nutmeg, colomus, pimento, ginger,clove,cinnomon, chomomile, motricorio. Cholkis usedos on ontocidond chorcoolos on odsorbent. Ulcertheropy Derivoiives of glycyrrhelinicocid (o triterpenoidof liquoriceroot)proveeffectivein the treofmentof pepticulcer. Deglycynhizinized liquoricehosolsobeenemployed. Oiher ontiulcer ogentsincludeolginicocid, morshmollow ond comfrey. Demulcents Thesesootheond orotectthe olimentorvtroctond overlopwith somemoteriols usedin ulcertheropy. lcelondmoss, orrisond elmbork moy be includedhere. Loxatives ond purgotives Purgotives moy be clossedoccordingto theirmodeof oction

THELIVER The liver. the principalorganof metabolismand excretion,is subjectto a nunber of diseaseswhich may be classedas liver cirrhosis (cell destructionand increasein librous tissue).acute or chronic hepatitis (inflammatory disease)and hepatitis (noninflammatoly condition). The most commondrug of plant origin usedin Westernmedicinefbr its antihepatotoxic propefiies is Sily-hunttnaricutum. In Indian and Oriental medicine many plants are so used. For a discussionof this field of currentinterestseeChaoter30.

THEURINARYAND REPRODUCTIVE SYSTEMS A numberof plant materialsareto be found in this _eroup; the examples given in Table6.6 are confinedto Westernusage.

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THESKIN AND MUCOUSMEMBRANES In addition to itcting as covering lbr the body, the skin perfbrms a number of other physiological functions. Drugs affecting the skin may be of an emollient nature or they may act as absorbents,astringents.irritants or antiseptics(seeTable 6.7). A nurnberof substances are easily absorbedthrough the skin; this fact is utilized in transdermal medicationbut mllst alsobe bornein mind with respectto \urious poisons.

Agor,psyllium ond ispoghulo Bron

Hydrophilic colloidswhich funciionos bulk-producing loxotives An indigeslible vegetoble fibrewhich obsorbswoterond providesbulk Senno(leoves ond fruit) Contoinsonthroquinone derivotives which ore hydrolysedin the bowel io stimulote Auerboch's plexusin thewoll Coscoro,rhuborb,oloes As senno Costoroil Contoinsglycerides whichon hydrolysis yieldriconoleic ocid, irritontto thesmollbowel Podophyllum resin, Drosticpurgotives,now little jolopresin,colocynth usedfor thispurpose. Theywere oftenprescribedwiih bellodonnoto reducegriping

Rectaland colonicdrugs Arochisoil, esculin,homomelis,pilewort ond bolsomof Peruore exomples of thisgroup;theyincludethose usedin supposiiories Anfidiorrhoeol drugs Morphineond codeineoct by increosing the smooihmuscletoneof thebowelond by reducingitsmobility. Commonlyprescribed with koolin

Toble 6.5 syslems.

Drugr ccfing on the nosol ond respirqbry

Aromoticinholations

Bronchodilotorsond nosoldecongestonts Expectoronts

Benzoin, cineole,eucolyptus oil, menthol pumilopineoil, bolsom ond peppermint, of Tolu,thymol,turpentine Ephedro,ephedrine, xonthines (theophylline) (insubemetic lpecocuonho doses),senego root,liquoricerool,squillbulb,tolu bolsom,pulmiliopineoil, lobelio, grindelio,ongelicorootond leof,storox, cocillqno,colisfoot,sweetviolet, bloodrool

Antiexpectoronts

a^..1^i^.

Cough depressonts

Morphine,codeine,noscopine, wild cherry

Demulcents

Morshmollow, verboscum, plontogo, lcelondmoss,honey

nrrnnina

E

AS SOURCES OF DRUGS IHE PLANT AND ANIMALKINGDOMS

Drugs octing on lhe urinory ond Toble 6.6 reproduclive systems.

Toble 6.7 Drugs used on the skin ond mucou6 membrcrnes.

Diuretics

Xonthine derivotives os presentin mony beveroges(teo,coffee,etc.)promotedilotion Digitolis of therenolmedullorybloodvessels. glycosides improvethefoilingheorlthereby ond glomerulor increosing renolperfusion originol filtrotion; hence,Withering's of infroduction of digitolisfor thetreotment dropsy.Thereis olsoo smollbut finiteeffecf of sodiumions on tubulorreobsorotion

Emollients ond demulcents Theseincludeo numberof vehicles usedin thepreporotion of ointments, creoms,lotions,etc.,ond includefixed oils {e.g.olive,orochis,coconut, theobromo),fots {wool-fot,lord},woxes spermoceti), of onimolorigin(beeswox, gums(ococio,kogoconlh)ond (psyllium, muciloges elmbork) Absorbents

chorcool Storch,olginotes,

Diureticsond urinory ontiseptics

Buchu,beorberry, iuniper,copoibo.These includedrugsusedfor the treotmentof cystitis ond urethrilis

Astringents

. o n n i oc c i d ) ,k r o m e r i o , T o n n i n(se . g T cotechu,golls,Aspidospermo, rind,kinos homomelis, pomegronote

Drugsocting on the uterus

Preporotions of ergotwere trodilionollyused in childbirihond thenlorgelyreplocedby lhe Administered isolotedolkoloidergomefrine. octionon os ifssoltsit hoso directstimulont the incidence theulerinemuscleond reduces hoemorrhoge. Ergotomine octs of postportum for obstehicuse similorlybul is nofsuitoble becouse of itsmorkedperipherol vosoconstrictor oction Blockhow is c uterinetonicond sedotive usedfor the prevenlionof miscorriogeond for dvsmenorrhoeo ofterchildbi*h Hydrostis is employedfor menorrhogio disorders ond othermenstruol Femole, Mole,gossypol{q.v.) see'Steroids'. plontshovebeen,ond ore Numerous being,testedfor ontifertiliiyoctivity

Counter-irritonts

copsicum, Comphor,furpentine, oconiie,methylsolicylote,mustordseed

Antiseptics

Tors,eucolyptus oil, thymeoil, eugenol, thymol,coiuput

Anti-inflommotoryogents

usedlocolly,motricorio, Corticosieroids ornico

Psoriosisond eczema treotment

ollonfoin, codeoil,evening Comfrey, primroseoil, chrysorobin , Lithospermum, sovin,myrrh,grindelio

Wound coverings

Typeof woundcovering(occlusive, is imporiont nonocclusive, hoemosiotic) in the heolingprocess. Seeolginotes, cotton,etc.

Oral controceptives

Mole impotence

(undercorefulmedicol Popoverine yohimbine(erectile dysfunction) supervision),

Benignprostote hyperplosioIBPH\

ore employed A numberof phytomedicinols (oftenos odmixtures) of to keot ihe symptoms withthe ossocioted BPH.Twometobolites ond conditionore dihydrotestosierone oestrogenwhich requiretwo enzymes ond oromotose)for their {5o+eductose in the body. ll hos beenshown,for synthesis someof the drugsused,thof theyore inhibitorsof thesetwo enzvmes.The followingexomplesore well-estoblished: Cucurbitopepo seeds(pumpkin),Epilobium ongustifolium ond otherspecies,Prunus africano lPygeun africanumlbork, Serenoo repensfruifs(sowpolmeito,sobol),Urlico dioicoond U. urensroot extrocts

ACTION ON SUGARMETABOLISftI Many plants have been used in traditional systems of medicine for the oral treatment of diabetes and it is particularly important that Western practitioners be aware of any patients already taking such medication. Among the plants so used are karela fruit (Momordica charantia), cumin fruit, ginseng, Teucrium oliverianum, neem (Azadirachta indica), onion, Aloe spp., Job's tears (Coix lachryma-jobi) and Galega officinalis. For a discussionof the current position on plant-derivedoral hypoglycaemic substancessee Chaoter30.

AN D ANTI.INFLAM'IilATORY STEROIDS DRUGS Two types of corticosteroidalhormoneare the glucocolticoids,which regulatecarbohydrateand protein metabolismand which also possess a stronganti-inflammatoryaction, and the mineralocorticoids,which influence the electrolyteand water balanceof the body. The clinical indicationsfor systemicffeatmentwith thesedrugs are complex, but include use in replacementtherapy,Addison's disease,reduction of lymphatic tissues(leukaemias),suppressionof lymphopoiesis(lymphomas) and as anti-inflammatory agents (a variety of conditions including rheumatoidarthritis,cerebraloedemaand raisedintracranial pressure). Thesehormonesare producednaturaliy in the adrenalcortex but a wide variety of semi-syntheticdrugs of this type is commonly in use. Theseare synthesizedusing plant steroidsas intermediates;diosgenin and hecogenin being the principal sources.To a lesser extent the steroidalalkaloids of the Solanaceaeare employed.There is a large world demandfor thesecompounds,pafticularly for the synthesisof oral contraceptives,and their distribution in nature and chemistry is consideredin more detail in Chaoter24.

NONSTEROIDAL ANTI' IN FI/AMMATORY DRUGS Aspirin, first synthesizedin 1853by Carl Gerhardt,is still one of the most widely-usedmild analgesicand nonsteroidalanti-inflammatory drugs(NSAID). It had its medicinalorigin in the salicylatesand glyco-

PHARMACOLOGICAL ACTIVITIES OF NATURAL PRODUCTS sidesof willow bark, long usedfor the treatmentof rheumaticdiseases, gout and painful conditionsof all types. In view of the universalrequirementfor NSAIDs very many plants havebeenutilized for the purposein traditionalmedicineand in recent yearsconsiderableresearcheffort has been expendedon their investigation. Enzymes have been used to detect anti-inflammatory activity of plants-galangin, a flavonoid of Alpinia olficinarum (Zingiberaceae; galangal rhizome) was found to be a cyclo-oxygenaseinhibitor. Lipoxygenase inhibitors are present in Spilanthes oleracea (a S. American plant of the Compositaeusedfor the treatmentof rheumatic disorders) and also rn Echinacea purpurea root, also Compositae, which containsa rangeof compoundsincluding isobutylamides. ln a review of plantsexhibiting anti-inflammatoryactivity Handa et al. (1992) cite that speciesof 96 generabelonging to 56 families are ascribedsuchactivity. In addition to the wide range of plants involved there is a similar diversity in the chemicalnatureof the active constituents.Flavonoids constituteone group widely associatedwith anti-infl'ammatoryactivity and are exemplifiedin Ihe BHP ( 1996)by the monographson Balm of Gilead Bud, Cimicifuga Rhizome, Equisetum, Jamaica Dogwood, Marigold, Matricaria Flowers,Meadowsweet,Poke Root, Red Clover Flower and Willow Bark. In the caseof an infusion of matricariaflowerc (Chamomilla recutita, German chamoqrile), used for its antiinflammatory action in the treatmentof acute gastritis, it has been shownby the mouse-eartestthat it is the flavonoidsandnot the volatile oils that are responsiblefor activity; however, for Calendula fficinalis the terpenoidswere found to be activeconstituents(seeAnon., Pharm. J., 1992,249, 474). With liquorice root (.Glycyrrhiz.aglabra) both the triterpenoidsaponinglycynhizin and the flavonoidshave,amongtheir other pharmacologicalactions,anti-inflammatoryactivity. Colchicine, an alkaloid of Colchicum autumnale, is the classical drug fbr the treatment of acute attack of gout. It may act by reducing the inflammatory responsecausedby depositsof urate crystalsin the joint and by reductionofphagocytosisofthe crystals.Its usehas been somewhatreplacedby allopurinol (inhibition ofxanthine oxidase)and by phenylbutazone.Guaiacumresin (q.v) is cited for the ffeatmentof chronicrheumaticconditionsand gout; it containsa mixture of lignans. The dried root of Harpagophl;tum procumbens (Devil's claw) (Pedaliaceae), hasrecentlyreceivedpopularattentionfor the treatment of painful rheumaticconditions;iridoid giycosides,e.g. harpagoside, are the characteristic constituents.The juice of Ananas comosus, the pineapple(Bromeliaceae)containsa mixture of at ieastfive proteolytic enzymescollectively called bromelin or bromelain.In Westernmedicine the enzymehas beenintroducedfor its ability to dissolvefibrin in conditionsof inflammatoryoedema. The action of ginkgolides (C2e terpenesfrom Ginkgo biloba) as potent antagonistsof plateletactivatingfactor has alreadybeen mentioned.

Tcble 6.8

Drug; u:td for the treqtrnent of infeclion!. , :

Antibiotics Mony higherplontspossess constituents hoving ontibocteriol properties; nonehosbeenutilizedclinicolly, moinly becouseof high toxicity.Mouldsond streplomyces ore the principol sources; seeChopler32 lor o considerotion of ontibocteriol ond onliviroldrugs Antimaloriols Untilthe odventof the synthetic oniimoloriols, quinine,isolotedfromthe bork of voriousCinchonospp., constiiuted the mosteffectiveogentfor thetreotment of molorio;it is stillusedin ThirdWorld countries ond is of someresurgenr importonce for combofingmoloriolorgonismsresistoni to other drugs.Artemisinin (Qinghooso), on unusuolsesquiterpene loclone, is the octiveconstiiuent of on oncientChinesedrug derivedfrom Artemisio annuo.ltis effectiveogoinsfchloroquineresistont stroins ol Plosmodiumvivox ond P.falciporumos well os qgoinstcerebrol molorio;seeChopter29 Amoebicides Emetine

Anthelminthics Extrociof molefern Sontonin

An olkoloidof ipecocuonho root,usedos itshydrochloride or bismuthiodide in the ireofmenl of omoebicdysentery. Completeerodicotion of thechronic infectionis difficultond combinedtheropy with otherdrugsis oftennecessory Fortopeworminfections Possesses o powerfuloctionin porolysinground-worms; olthoughonce extensively usedits high toxicityhos led to replocement by piperozine

Oil of Chenopodium

Likesontonin; if hosolsobeen extensively usedin hookwormdiseose but it givesvoriobleresulfs

Thymol

At one fime muchusedin hookworm treotment

Catharanthus andTaxusalkaloids) arein seneraluse.For a fullerdiscussionseechapter28.

IREATMENTOF AIIERGIES A largenumberof materialsgive rise to allergicconditionsin sensitive individuals.Extractscontainingspecificallergiesare availableas diagnostickits or for desensitization. Examplesof plant allergensaregrass, flower and treepollens,dried plantsand moulds(seeChapter40).

I}IE IMMUNE SYSTEfrI TREATMENT OF INFECTIONS For naturalproductsin this category,seeTable6.8.

The last 40 yearshavewitnesseda vast searchof the plant kingdom for substanceswith anticanceractivity; clinical trials are currently being conductedon a number of promising compoundsand others (e.g. the

Drugs aff'ectingthe immune system are termed immunomodulatory or adaptogenic.Somerepressthe systemand areofvalue in, for example, preventingrejectionof transplantedorgansand othersare stimulatory and can be usedto help combatviral infectionssuch asAIDS or assist in the treatment of cancer.Until relatively recently such herbal drugs were largely ignored by Westernorthodox medicine, although they have always featuredin traditional Chinese and Indian medicine in seekingto achievehomoestasiswith regardto bodily functions.Now, however,ginsengleadsthe marketin herbalsalesin Europeand the US andEchinaceaspp.,usedby native N. American Indians,ranks around

@

THEPLANTAND ANIMAL KINGDOMSAS SOURCES OF DRUGS fifth in the US herbmarket salesand is widely usedin Europe,with 800 Further recding preparationsbeing quotedas availablein Germany.For immunomodu- GhisalbertiE L, PennacchioM, AlexanderE 1998A review of drugshaving cardiovascular actrvity (nearb- 400 re/s). PharmaceuticalBiology 36(4): latorsof Chineseorigin seeL.-H. Zhang et al., PhvtotherapyResearch 231-219 1995,9, 315, and for Indian drugs seeA. A. Munganliwar et al., J. Handa S S, Chawla A S, SharmaA K 1992 Plants with anti-inflammatory Ethnopharmat'olo gy 1999,65, 125. activity (a review with 278 re;ferencesand 34 structuralformulae).

.:;nifu.}{s'

Fitoterapia63, 3 Wagner H (ed) 1999 Immunomodulatory agentsfrom plants. Birkhauser Verlag,Basle Williamson E M, Okpako D ! EvansF J (eds) i996 Pharmacologicalmerhods in phytotherapy research,Vol 1. Selection and pharmacological evaluation of plant material. John Wiley, Chichester

,1',...l:....:l',1.1:ll:.

Theseaccessorylbod substances are consideredin Chapter31

Yt'-

|

(

^

'

JynergyIn reotion

Some of the most popular and widely sold phytomedicines,such as those containing St John's wort, echinacea,ginkgo, garlic. kava and valerian. have considerablepharmacological and clinical evidence to supporttheir use,and synergyis generally assumedto play a p:Lrtin their medicinal effects. Attempts are rarely made to isolate a single constituentfrom theseextractsfor reasonswhich will be outlined later. and in Western medical herbalism. traditional Chinese medicine and Ayurveda,combinationsofherbs are fundamentalto their philosophy as well as being due to empirical observationsand historicalusage.This attitude to their formulation and use dilTerentiatesherbal products from conventionalmedicines,eventhosewhich containan isolatedplantconstituent.For example,pharmaceuticalscontaining ephedrine,cafTeineor evenpeppermint oil are rarely consideredas phytomedicinesdespitethe fact that they are obtained from plant sources.Valuable drugs such as digoxin, theVinca alkaloidsand taxol are alsonaturalproducts,but due to their h:ighpotency and toxicity the plants containing them have do not havesucha long historyof usageand haveneverbeenconsideredto be 'herbal medicines'.Modern herbalremediesareusuallyfound as whole or semi-purified exffacts and ideally should be standardizedlbr their activeconstituentswherepossibleto ensureclinical reproducibility.

to the phormocologicol octionof phytomedicinols

ll

.,1!.

,,t

.

WHAT 15SYNERGY? 'working Synergybroadly means together'and occurswhen the combined action of constituentsis greaterthan would be expectedfrom a considerationof individual contributions.In pharmacology,synergy has a specific definition, but the term is often misapplied to describe any kind of interactionbetweenconstituentsof a singleextract,as well as the componentsof a mixture of herbs. These interactionsmay involve a potentiationof therapeuticeffects,or an attenuationof toxicity or side-effects,within the preparation.Whether an effect is truly synergistic,or merely additive, is rarely establishedand evidenceto prove it conclusively is sparse.The opposite,antagonism.meaning 'working against',is much easierto define, being a reduction in the overall expectedeffect.Medical herbalistshaveoften insistedthat better resultsare obtainedwith whole plant exffactsratherthan with isolated compounds, for example the side-effects of ephedrine are not usually found with an extract of the herb Ephedra. If true synergy is occurring in phytomedicines,standardizationbecomes even more important, since the ratio between synergisticagentsis critical, and small changescan make resultsunpredictable.If combinationeffects are merely additive,changesin the ratio are lesscrucial. lt may therefore be useful to define synergypreciselybut routinely use the term 'polyvalent action' when the natureof the interactionis unclear.

E. M. Williamson

WHAT IS SYNERGY? 49 MEASURINGSYNERGY 49 DEMONSTRATING SYNERGYAND POIWAIENT ACTIONIN PHYTOMEDICINES 50 (r ). STNGLE ENHANCEMENT HERB OF ACTTVTTY EXTRACTS 5I (2). MULTTPTE ENHANCEMENT OF ACTTVTTY HERBEXTRACTS 52 SYNERGISTIC OTHERMISCETLANEOUS INTERACTIONS 53 ATTENUATION OF TOXICITY

coNctustoN

54

s3

]i,,.;ir ..; i!ll

.,..:il ',..r irtiltiri

:ltri riit. : -,t ,iait:,i ll,rii!1ir{lil

."

:i*,fir::lrl :r'l:. :;ll!;rrl

t*ir,:ti:i!9r ti:liitiEiiiui tiililtitt;3!t,ii!

MEASURINGSYNERGY Although the idea of synergyis easyto understand,the measurement of it is more problematic.It is fairly straightforwardto identify synergy when one of the agentsis inactive and a combinationof this with an active agentproducesan effect greaterthan that observedfor the active alone,but difficulties in measurementarisewhen more than one (and theremay easilybe several)areactive.The variousmethodsfor calculation are explainedthoroughlyby Berenbaum(see 'FurtherReading') andaresummarized belou'

'

- ,1.:ltii.,r

't.....

Summation of effects. Synergy is deemedpresent if the total effect of a combinationis greaterthan would be expectedfrom the sum of effects.This can be expressedmathematicallyas: E(da,db)=E(da)+E(db) where E = the observedeffect, and da and db are the dosesof agentsa andb.

::

fll

THEPLANT ANDANIMAL KINGDoMS As SoURCEs oF DRUGs Although the validity of this methodseemsevident.it actuallydepends upon the mechanismof action being similar for both agents,and a linearity of response.The method would be valid under theseconditions but they areunlikely to apply to complexherbalmixtures. Measurement of the effect of a fixed dose of one on the doseresponsecurve ofthe other. This methodalsoassumesa knowledge of the dose-response curve of each agent and a linearity of response, and would be almostimpossibiewith a herbalmixture. Comparison of the effect of a combination with that of each of its constituents. This methodwas originally suggestedby Gaddum (Pharmac'olog_r,, Oxford University Press,1940)and synergydeemedpresentif the effect of the combination was greaterthan that of each of the individual agents,(ie da,db> d a. and da,db> db). Although this method is independentof a knowledgeofthe mechanismof action.it can be shownto be flawed by consideringthe caseof a shamcombination(where a and b are the same agent and interaction is therefore impossible). Berenbaum quotes the following argument to demolish it effectively: if two men, working separately,can each cut down 10 trees in a day, but working togetherthey cut down I 5, the effect ofthe combinationcertainlyexceeds that of eachconstituentand would thereforefulfil Gaddum'smathematical criteria for synergy.In reality, this would be a nonsense. The isobole method. Although mathematicallythe most complicated, this is now consideredto be be the methodofchoice sinceit is independent of any knowledge of mechanismsand applies under most conditions.It makesno assumptionsaboutthe behaviourof eachagent and is applicableto multiple components,so can be applied to the analysis of effects in herbal mixtures. An isobole is an 'iso-effect' curve,in which a combinationof ingredients(da, db) is represented by a point on a graph,the axesofwhich arethe dose-axesofthe individual agents(Da and Db). If agentsdo not interact,the isobole(which is the line joining the points representingthe combination,to those on the dose-axesrepresentingthe individual dosesisoeffectivewith the combination) will be a straightline. If synergyis occurring,then smaller amountsare neededto producethe eff'ectand the isobole is said to be 'concave-up'. This is shown in the graph (Fig. 7.1) of actual results (Table 7.1) obtained from investigating synergy between the ginkgolideA and B. The oppositeappliesfor antagonism,producinga

14

12

E1 r- o

io *o

J c

.

0L

0

0.5

1.0 1.5 2.0 2.5 3.0 3.5 B (pM) Ginkgolide

4.0

Fig.7.l lsobolecurvefor 50% inhibition of GinkgolideA + B mixtures. (FromB Steinke. Chemisch-onolytische und Phormokologische Unfersuchungen von Pflonzlichen PAF-Antogonisten und Inhibitoren der Thrombozylenoggregotion. Thesis, MunichI 993, with permission.)

Toble 7.I The lC5s* vqlues of vqrious Ginkgolide A + B mixlures obtoined by on in vitto induced ploteler oggregqlion tesf.

mixture

3 :

2.40

t .

.) .)i

:3 :]0

quontityGinkgolide

B{cB)

lCso

GA:GB [tts/ ^l]

'.2

quontityGinkgolide

A {GAl

1.80 1.55 1.40

r.30

fus/ ml1

tttMl

[ps / nt]

[t'M]

l B0 |.47 0.90

4.41 3.60 2.21 1.27 0 .B 8 0.29

0.60 o.73 0.90 r.03 1.09 I.18

1.42 1.72 2.12 2.43 2.57 2.79

v.J I

0.36 0.12

n= 2-9 * lc5o = 50% Inhibition of GA + GB mixtures

'concave-down' isobole.It is possibleto have synergyat a pafiicular dosecombinationwith antagonismat a differentcombinationand this is reflected in the isobole. Other approachesto defining synergy are describedby Berenbaum,togetherwith examplesand proofs.

DEMONSTRAfl NG SYNERGYAND POLWATENT ACTIONIN PHYTOMEDICINES Proving synergy even within a single herbal extract would require fractionation ofthe extract,testingeachfraction, recombiningand testingthe whole again,and would alsonecessitate tesringpermutationsof the various fractionsto seehow eachis interactingwith the others.To complicate mattersfufther, herbalistsnormally usemixturesof extracts,and many are traditional combinationswhich are not intendedto targeta particularbiochemical system or enzyme (S. Y. Mills and K. Bone, Principles and Practice oJPh.ttotherapy',Churchill Livingstone, 2000), making evaluation of additive or synergisticeffects even more diflicult. Simple examples of this practicewould be the inclusion of laxative herbsin products usedfor haemorrhoids,or cholereticherbsin digestivepreparations.This is not synergy but more a way of approachingffeatment from several anglesconcurrently,and could be describedas 'polyvalent action', a term usedto include the variouseffectsofmultiple activeconstituentsacting in combination, in harmony and possibly in synergy, and therefore overcomes some of the problemsof defining the overall effect as synergistic where it could eveninclude antagonism,where that appliesto a reduction of undesirableeffects.As a preliminary step in looking for synergistic interactions,it is possibleto testthe effect of individual extractssingly and in combination, which will give an indication of synergy or antagonism althoughno real evidenceasto which compoundsareinteracting. In conventionalmedicineit is now common practiceto use several drugs to treat a singie complaint, such as in hypertension,psychoses and especiallycancer,and this applies even more to plant extracts, sincecombinationsare alreadypresentwithin the plant. There may be sound reasonsfor not isolating individual componentsin some herbs such as ginkgo, St John's wort and ginseng,becausethese are traditionally usedas standardized extractsfor which we havepositiveclinical data.Furtherexamplesaregiven in TableT.2. Otherreasonsfor not isolatingcompoundsinclude the situationwhen the active ingredients arenot fully known, or when they aresuspectedof beingunstable,such as with raspberry leaf. If their effects involve synergy the situation is even more complexand bioassay-ledfiactionation,the normal method

s Y N E R GrYN R E L A T T T OO NT H EP H A R M A C O L O G TACCATLT OO N Fp H y T O M E D t C t N A L S r

lable 7.2

Plontsfor which whole extrocts ore normolly used.

Reosonsfor not isolotingindividuol compoundsfrom extracts

Exomplesof herbol productsinvolved

Exhocts knownto contoino rongeof similoroctivecompounds, withwell documented clinicoloctivityfor wholeor semi-purified extroct

Aloe,Arnicq,Bilberry, Blockcohosh,Chomomile, Devil'sclow, Echinoceo, Essentiol oils,Feverfew, Ginger,Ginkgo,Koreonond Siberionginseng,Globeortichoke, Horsechestnuf, Liquorice, Senno ond olheronthroquinone loxotivedrugs,StJohn's wort,Volerion

Unsureof ocliveconstituenf(s) evenif somechemistryknown

Clivers,Chostetree,Fringetree,Howthorn,Kelp,Rospbenyleof, Possionflower,Nettle,Oots,Wild lettuceond monyoihers.

Aclivesknownor suspected to be unstoble

Gorlic,Ginger,Hops,Volerion

Synergyor onlogonism knownor suspecled

Artemisio onnuo,Connobis,Flovonoid confoining drugs,Ginkgo, Kovo,Liquorice, Rosemory, StJohn's wort,Sow polmefto, Volerionond monyothers.

used for identifying actives, and isolating lead compoundslbr drug development,must be usedwith cautioll sincethe existenceof interactions would render it useless(seeP. Houghton. Phl,tother.Res, 2000 14(O:419-123). The main activesofeven such an irnportantherb as the antidepressantSt. John'sworr (.Hypericumperforatum)are stil1underdiscussion, andeveniftrue synergyis occurring,it wouldbe unwiseto exclude,by over-purification,any constituentswhich may contributeto efficacy. There are numerousother herbsin the sameposition.where the phytochemistrymay be well documentedbut the actualcontributionof individual componentsto the overall eff'ect has not been ascertained. Examplesinclude hawthorn(.Crataegusoxl'cantha)as a caldiac tonic; the coneflower, Echinacea spp.. as an immunomodulator; hops (.Humulusluptilus')as a sedative;black cohosh (Cimifuga racemosu) and chasteberry(Vitex agnu,s-castus) as hormone-balancingagentsin women; saw palmetto(Serenoarepens)as an antionandrogenfor proprocumbens)as statichyperplasia,and Devil's claw (Hurpagopl't,*tttm an anti-inflammatoryagent.In othercases,the activesareunstable,and 'protection' of the herb or whole attemptsto remove them from the extractcould renderthem inactive.Here the obviousexamplesare garlic (ALliumsativutn)and valerian \.Valeriantrspp.tiGarlic is often formulated as a product containingthe precursoralliin. and the enzyme alliinase which in solution (i.e. in the stomach)liberatesthe active allicin and other unstable,but still active, decompositionproducts. This is not synergy,but efTectivelya drug delivery systeml-Interactionsin vivo may also occur between combinationswhich enhance or hinder therapeutic activity by affecting absorption, metabolismor excretion.Someof thesecan be seenin vitro. suchasthe complexingof plant polyphenolsand tanninswith many drugs,which This doesnot seemto be could theoreticallyreducetheir efTectiveness. a real problem, otherwisetea drinkers would find many of their prescribedmedicinesinactive. Other interactionswill only be seenclinically, suchas the efl'ectsof cytochromeP450 enzymeinductionwhich are only seenafter a pedod of treatment,as may happenwith concnrrent ingestionof grapefruitjuice. Examplesof synergyor polyvalent actiontakenfrom the literaturewill be dealt with accordingto whether they are thought to enhanceactivity or reduce toxicity.

ENHANCEMENT OF ACTIVITY(l). Single herb extrqcls

is likely that they work together.Recently synergyhas been demonstratedbetweenginkgolidesA and B using a plateletaggregationassay (seeTable 7.1 and Fig. 7.1). Ginkgo is usedfor two main indications: asthmaand cerebralinsufficiency.and thesecan be partly relatedto the differentconstituents.The ginkgolidesarediterpenesand areknown to be plateletactivatingfactor (PAF) antagonists.Numerousstudieshave shown that the ginkgolides antagonizemany of the effects of PAF, including bronchoconstriction,bronchial hyperresponsiveness, plateletaggregation,and allergicresponses. They may contributeto the efficacy of ginkgo in cerebralinsufficiency but their main benefit is probablyin inflammatorydisordersincluding asthma.Ginkgo flavones are also anti-inflarnmatory.the combinationbeing consideredadditive and possibly synergisticin effect as well as increasingblood circulation to the brain, and a total ginkgo extractactsas an antioxidantactivity in brain preparations.Clinical studieshave shown ginkgo to be effectivein improving cognitive function (U. Rigney et al., Ph\tother Res.1999,13 (5) 408-415) as well as the early stagesof dementia;the preparationusedbeing a total extractand notjust the flavonoids.This suggestsa polyvalentas well as synergisticactivity. Kovo Synergyhasbeenproposedas occuring in the effectsof the psychoactive herb kava, Piper ntethysticum,which is used traditionally in the South Pacific islandsand more recently elsewhereas a sedative,anxiolytic and mild hallucinogen.An extractof ground kava root and several isolatedknown sedativecompoundswere testedlbr their effects on the CNS, using a mousemodel of antagonizingclonic strychnineinduced convulsionsand death.The total kava extract was effective, and dihydromethysticin(DHM) determinedto be the most potentcomponent.A reconstitutedmixture of kawain, dihydrokawain,methysticin. dihydromethysticin,yangoninand dihydroyangonin,in the same ratio in which they were fbund in the crudeextract,was then testedand relatedto a potencysimilar to that of DHM. Howeverasthis compound representedonly 5% of the total extract, and the other constituents wereknown to be lesspotentthan DHM, the mixture wasconsideredto be synergistic.This was corroboratedwhen the anticonvulsantaction of yangonin and desmethoxyyangoninwas shown to be increased when given togetherwith otherkava constituents.Furtherdetailsof the complex pharmacologyof kava are availablein the review by Y. N. Singh and M. Blumentha\(HerbaLgrttm,1991, 39:33-56).

Ginkgo

Volerion

fbr their ginkgolide, Most Ginftgobiloba preparationsare standardized flavonoid and sesquiterpene content(for folmulae seeFig. 25.5), and althoughthesegroupsof compoundshave discretemodesof action,it

Severaldifferentcompounds(Fig. 25.2) presentin valerianhave sedative activity.The natureof any interactionsis not understood,but there is circumstantialevidencethat synergismis present.Holzl (pp 55-75

S F DRUGS T H EP L A N TA N D A N I M A LK I N G D O M SA S S O U R C E O

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timesthat expectedfrom a summationolthe individual components.It l' in'. Metlicinal and Arotnotic Plants-lndustrial Pro.files' Vtl is also possible that an unknown compound nray be involved' and Valerian.Harwood, 1997) has reported that an extract of ValeriancL Iruch furthertestingwould be needed.illustratingonce againthe diffiofticirutlisreducesglucoseconsumptionin areasofthe rat brain; howculties in proving synergy.Ginger is yet anotherexample of a cheneverindividuallyvaltrate.didrovaltrate,valerenicacidandvalerenone ically unsttrblelange of compoundsbeing responsiblelbr activity' and showednosuchelTectalthoughtheyareknowntobesedativeinother probably acting synergistically(S. M. Beckstlom-Sternbergand J A' biological systems.This may be an indicationthat synergismis occurHerbs and Edible Fungi I 994' Elsevier)' Duke, pp 210-223 in: STrrccs, ring(orbecausetheresearchelshavenotyetidentifiedtheactualconr. pound responsiblefbr this activity)

ENHANCEMENTOF ACTIVITY(2). Multiple herb

5t John's wort exlrqcls StJohn'swortisoneofthemostimportanthel.bsir-rclinicalusetoday. medicine typesof constituentare implicatedin its action TroditionolChinese Again several
r

SYNERGY IN RELATION TOTHEPHARMACOLOGICAL ACTIONOF PHYTOMEDICINALS n.ttle root. Urticu tlioictt. with pygeum bark, Pt'geurn africttnunt, \onretirneswith otherherbs.This cornbinationhasbeenshownto have :r nergisticactivity in an in vitro system.where its effect againstthe enzymesaromataseand 5-cx-reductase. which are irnplicatedin BHP, qcre tested.Nettle root extractalone was only efl'ectiveagainsteither enzyme at high concentrations.and pygeum bark. although more activeon 5-o-reductase,had only weak activitv againstaromatase. The combinationshoweda potencyequivalentto that of pygeurnbark on -5o-reductzrse. and aromatasewas significantlymore inhibitedby a mirture of the extracts than by each sepalately (R. Hartmann et al.. Plty'tonretlic ine. |996, 3/2: I 2 | - I 28). A mixture of lbur herbs used in Italy to aid digestion.known as Amaro MedicinaleGiuliani.is a classicexampleof herb con.rbining. The preparationhas beenshowr-rtcrbe not only clinically efl-ectivebut the mixture to be more eflicaceousthan the exll'acts.which were tested in pairsconsistingofgentian + rhubalb.and boldo + crscan, rgainst placebo.Althou-ehsynergywas not unequivocallyproven.the ingredients are certainly working together and a case can be made fbr the inclusion of each.Gentian,Gentiutu lutea, and lhubarb, Rheum spp.. both stimLrlategastricsecretion(at high dosesrhubarbis laxative.but in this preparationthe dose is low); boldo leaf. Petunusboltlu.s.ts reputed to increase bile f'low. and cascara, Rhantnus purshiuta, increasescolonic peristalsisby stimulatingthe myoentericplexus.The mixture was shown to increasepancreaticexocrine secretionand to accelerategastrointestinalmotility in humans,to a greaterextentthan the pairs of extractstested.It is therefbrethought to act as a digestive by stimulatingthe appetite,aiding gastric,pancreaticand biliary secretions, and enhancingcolonic transit (G. Blunetti et al.. pp 15-21 in Natural Drugs tutd the DigestiveTract. 1992.EMSI. Rome).

Stimulatin-sCOMplex) r'accines,where they enhancethe antibody responseto an antigen (R. Bomfbrd, Phttother. Re.i, 1988, 2: 159 16,1).At presentthey are rnore widely used in veterinarymedicine. It is likely that other saponin-containingdrugs have a similar effect as well as other.as yet not defined,synergisticactivity.

Drogon's blood The sap of Croton draconoitles and C. lechlerl, also known as Dragon'sblood becauseof its dark red viscousappearance. is usedtopically to aid wound healing.The healingqualitiesarerhoughtto be due to both physical and chemicalproperties.The occlusiveaction of the sap.which dries to tbrm a serni-perrneable covering,helps to prevent penetrationofpathogens.and within this protectivelayer the polyphenols act as antiseptics.Thc anti-inflamrnatoryand antioxidantcompoundsalso presentin the sap are thoughtto contributeto the healing and protective action (Z-P. Chen e/ al.. Pkmrtt Med., 1991, 60 -541-545).In this case.the plant extractis cleally polyvalentin action althoughprobably not exhibiting true synergy.

ATTENUATION OF TOXICITY

Liquorice Liquorice. Glvyrrhiz.a glabrct,is widely used for its antiulcer',antiinflammatory and antihepatotoxicproperties.One of its major constituents,the saponinglycyrrhizin (Fig. 24.12)exhibitsactivity in all of these areas.but so also do the flavones. isoflar,onesand chalcones. Glycyrrhizin is certainlyresponsiblefor the rnore seriousside-eff-ects relatedto its corticosteroid-like activity(suchas Cushing'ssyndrome) associatedwith ingestion of large amountsof liquorice.A small study on the bioavailabilityoi glycyrrhizin when given on its own or as part of a liquorice root extlact showed that absorptionof glycyrrhizin is OTHERMISCETTANEOUS SYNERGISTIC lower when taken as the extract than il given alone (G. CantelliINTERACTIONS Forti et al., Environ. Hedth Perspecr.,1994.102 (Suppl.9):65-68). Flovonoids Monitoring of blood and r.u'ine levels in volunteersafler ingestingglyIn addition to the involvement of flavonoids in the herbs mentioned cyrrhizin eitheraloneor as an equivalentdosein liquoricc showedsigpreviously.other examplesinclude that of the Chineseherb QLringhao, nificantly lower levelsin thosewho had takenthe extract.and although Artenti.siaannua. a source of the antirnalarialsesquiterpenelactone the samplesize was small. when a similar experimentwas caried out artemisinin.which is being usedas a templatefor the developmentof in rats the resultswere in agreement.The authorssuggestthat ditTerothercompoundssuchas artemether. J. D. Phillipson(Phltother Res-. encesaredue to an unspecifiedinteractiontaking placeduring intestin1999,13: l-7) reportedwork caried out by his group on the efTectof al absorption.In TCM. an extractmay be addedto a prescriptionpulely the other constituentsin an extractof the herb, where they discovered to attenllatethe side-eff-ects of another,and an example is the use that the llavonoids present,especiallycasticin and artemitin. sigrrifi- of liquorice as a detoxifier.Many Chinesephysiciansinsisr on using cantly enhancedthe in r''ilroantimalarialactivity of artemisininagainst liqr.roricein conjunctionwith aconiteroot and a preliminary study has Plasmodium.falcipttrLmr. Although not clinical evidence,it doesshow producedsomeevidenccto supportthis. When the amountof liquorice that the synelgisticactivity is not just a questionof enhancedabsorp- in a preparationcontainingfixed amountsof aconiteand gingerextract tion, excretion or bioavailability in vivo. Flavonoids are presentin rvas increased,a conespondingreduction in the amount of aconitine many phyton.redicines as well as lbods. and it is possiblethat they play which could be extracted fiom the decoction was observed (P. a role in clinical efficacy which could be synergisticin nature. In Miaorong and L. Jing, pp 28-30, Prrx'. 10rh Ann. Conf. Beijing Unit. anotherstudy. a seriesof con-rbinations of two flavonoids.including CltineseMed., 1996'1. This study indicatesthat the subjectof detoxifiamong others baicalein. genistein, naringenir-r.hespeletin and cation by use of liquorice deservesfurther attention,and it is quite quercetin,was assayedusing inhibition of ploliferation of a human probablethat many of the principlesof combinationsobservedin TCM breast cancer cell line, MDA-MB-435. Al1 combinationsexcept lbr will be fbund to be basedon similar nhenomena. narigeninand hesperetin,which are fairly closely chemically related. showed synergistic behaviour. with the most potent combinations Connobis being those which included quercetin(So et ttl., Nutr. Canc'er,1996, Althou_ghcannabisis generallytakenfbr its relaxantef-fbcts. it hasbeen 26: 161 181).This ofcourse has significantimplicationsfbr the effect known fbr many yearsthat tetrahydrocannabinol (THC), the main psyof diet as well astreatmentof illnesswith ohvtomedicines. choactiveingredient,can induce anxiety in a way not usually associated with the herb. For examplebatchesof cannabisresin from South Soponins Africa which naturally contain negligible amounts .of the nonSaponinsare surtactantswith biological activity so are likely to have psychoactivecannabidiol(CBD), have causeda psychoticreactionin modifying effects on other agents given concurrently. Quillaja users.It has since been verified that CBD can block the anxiety prosuponariu saponins ale used as adiuvants in ISCOM (lmmr.rno- voked by THC in a doLrble-blind procedureusing normal subjects,and

T H EP L A N TA N D A N I M A LK I N G D O M SA S S O U R C E O S F DRUGS the etl-ectwas considerecl to be a particularfbrm of antagonismbetween ratherthana generalblock ofTHC effects,sinceCBD thecannabinoids typicallyhad someactionswhich u'ereoppositcto thoseof TttC. bLrt not othcrs(Ztardi et ul. Pst'cltopharntucologt1982,76,245).Thcreare othcr indicationsthat CBD modifies the pharmacologyof THC and which support anecdotalreports by cannabisusers.This moditying efl'ectcor-rldbe i"eryimportantif anclwhen cannabisbecomesavailable fbr therapeuticuse and substantiates the theory that cannabisextrtrct may be rnore uselul in the tleatnrentof spasticit),and pain disordels would rendcrit unacceptable. thanTHC. whereanxietyas a side-eft-ect

coNcrusroN Therecan be no dor.rbtthat most herbsrely for their ef'fectson a variety ofconstituents andthe icleaof synergywithin andbetweenthemis also Whetherthey areactingin r 1r'u11 synergisticuay -sainingacceptance. ol by additive ef-tectsis not well documentedbut it is important.both for clevelopingmethodsof standardizationas rvell as to frLrtherour is also more knowledgcof mechanisms of action.Clinical evalLration diflicult without knowing the extent to which synerg,voccurs within the herbalpreparation.and it shouldbe further investigatedfbr all these to showthat synerreasons. In the meantimeevidenceis accunrulating gism doesoccurin extractsand mixturesand that we shouldcontinlle r sinto LlseouLwhole extlactswith confidence.ratherthan :rssruning gle chemicalentity is responsible which shouldbe cxtractedand used

alone.This has been describedrs the 'herbalshotgun'approachas 'silver opposedto the synthetic bullet'.It is hor.vever still vital to ensllre that extlactsare standardizedproperly tbr the activeprinciplesknown at the time and that any knoun srnergisticintt-'r'aetions are takeninto account.Synergy.however.aseviclcncccl in herbalrnedicine.may lend to ir-nprovedproductsn'ith incleasedefficacy.reducedtoxicity and in the caseof antibioticaction.lesslikely to leadto rniclobialresistance. The principlesapply to both plant-bnsecl and conventionalrnedicines. and althoughthis is an olclideairr naturalmedicine.it is relativelynew 'Cocktails'of rnedicines. lo conVentional chenrotherapeulic agentsare no.,vbeing usedto treatAIDS and cancerand historicallynanl' people. even if contrar'1' to rneclicaladvice.have alwaysinstinctivelypractisec'l polypharnracy.whetherherbalor not.

Furtherreoding Berenbaurr1\,1 1989What is s_vnelgl) PharmacologicalRer iews ,1I : 9-l l,l I Duke J A. Bogenschutz-Godu in M J 1999Thc syncrgl'principlc at u'or-kin p l a n t sp . a t h o , u e nisn.s e c t sh. e l b i l o r e sa n c h l u m a n s I. n : K a u l n r a n nP B . C s e k e L J. Warbel A. Dukc J A. BricnrannH L Natural proclnctsflom plants.CRC P r e s sB . o c aR a t o n .F L A . U S A . p p 1 8 3 - 2 0 5 lzacldoostM. RobinsonT 1987 S1'nergyand antaqonisnrin the phanracology o f a l k a l o r d apl l a n t s I. n : C r a k e rL E . S i m o nJ E ,( c d s )H e r b s .s p i c e sa n d nredicinalplants:rccctrtacllanccsin botirnt.horticu]tureanclpharnracology. . h o e n i r .A Z . U S A . V o l 2 . p p 1 3 7 l 5 l l O r r x P r e s sP W a g n e rH 1 9 9 9N c u ' t a r g o t si n t h e p h l t o p h a r m a c o l o goyf p l a n t s .I n : E r n s tE (ed) Herbal medicine.a conciseor,erviewlirr healthcareprofessionals Buttefworth Heinelnann.UK

E PART

3

Principlesrelqred to the commerciqlproducfion, quq lity ond sfqndordizslion of nqturql producls

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Commerce in crude drugs

HISTORICAT DEVETOPMENTS5 7 CURRENT ASPECTS 5 8 THEFUTURE 60

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CHANGING DEMANDS

Like almostall other basic commodities,the trade in crudedrugs is of great antiquity.The necessityibr goodsto be collected,graded,transported and distributedeffectively has rarely been consideredby the pharmacistas part of his or her remit and thus it has been left to the tradel or merchantto perfbrm this lessscientificbut by the sametoken importantgroup oftasks. The essentialsofthe tradeare still very much the sameas they were 10, 100 or 1000yearsago,though the speedand efficiency with which they can be performedhas improved exponentially with tirne. It is well within quite young living memory that one had to book a telephonecall to one's supplierin Brazil, China or India somehoursor perhapsa day in advance:now communicationsby fax, or increasingly popularly by e-rnail take moments to perfbrm, and repliescome with similar alacrity.

59

The absoluteorigins of the tradein crudedrugsareof courselost in the mists of time. One supposesthe first contract for the collection and supply of a drug with a third party in exchangelbr speciecame about when the physicianfound himself too busy to do this relatively menial task himself. The trust the physician had in the collector must have been remarkableas unadulterateddrug was essentialif only to avoid poisoningthe patient! Ref'erences from antiquity to the drug trade are rare, though somemural inscriptionsfrom Ancient Egypt dating back to 3000 ec evidenceknowiedgeof the effect of medicinal plants,and there are in the British Museum clay tabletsfrom the library of King Ashurbanipal (668-626 ec) of Assyria which evidencethat around 2500 ec the Sumerianshad a form of Herbal. By 660 ec around 250 drugs were recognizedby the Assyriansthemselves,some of which were actively cultivated.Hippocrates(f1.46'7Bc) was well acquainted with a variety of drugs (though it is improbablethat any of the works attributed to him are actually 'of his hand'). Theophrastus,like Alexanderthe Great,was a pupil of Aristotle, and latter becamechief of the Aristotelianschool.He listed some500 plantsknown to him, and distinguishedCinnamon from Cassia (an art which, apparently,is being lost in this day and age.at leastby somemanuf'acturers of foodstuffs!). It is instructive to note that the use of the Mercury's or Hermes' caduceus,nowadaysa widely understoodsymbol for medicine, was originally a symbol fbr commerce.Mohammed was said to be a spice trader,and at that time spice traderswere invariably also concernedwith crude drugs,particularlyas many productswere used for both culinary and medicinalpurposes,asthey aretoday.The adventures of all of the major explorers.such as Marco Polo, Columbus, Henry the Navigatorand the like were undertakenpartly with a view to the sourcingof botanicalcrude drugs.The establishmentof the great National Trading Companies,fbr instanceThe HonourableEast India Company, The Netherlands United East India Company and the DanishAsiatic Companywas undertakenwith a similar view. Prior to modern times. there was no real distinction between the Drug and Spice trades,and thus during London's developmentas an entrepot the Guiid of Pepperers of London (later the Grocers' Company)were chargedwith the overseeingof both trades.The fbundation of the East lndia Company in 1600placeda near monopoly in 'East the import of India Produce'into England,and it was from this that the modernGenelal Producetradeemerged. Initially in ad hoc form, and later by way of the lamous 'Coffee Houses', trade in drugs. even until the SecondWorld War, was conductedin the main by auction.The problemwas that the shippersat origin had no direct representationin the consumingcountries,and thus had to engagethe servicesof a broker.The usual format was for the goods,be theysent'on consignment'(i.e. sentspeculatively to London

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pRrNcrpLES pRoDUCTroN, pRoDUcTS RELATED To THEcoMMERcTAL ANDsTANDARDTzATToN euALrTy oF NATURAL in the reiisonable hopeola salc)or'ex stock'(beingthe propertyofthe importing merchant)to be put up for show priot to auction.The valious broking firms then attemptedto sell the merchandiseentrustedto them by pLrblic auction (the order in which the vtrrious brokers did so beingdecidedby lot) on the basisofthe -eoods placedon view in the r.varehouse or sarrrplesdrawn there and placedon view in the blokels' ofTices.Towardsthe end of the popularity of auctionsin London tiequentlvno. ol alnrostno. goodswele sold at the auction.the auctioneer"susual comment being'see you after'in order to be able tcr ne-qotiate betweenthe shipperand the potentialclrstomera mutually price. acceptable During the SecondWorld War when lines of communicationwith the variousori-tinswere disrLrpted. a certainamountof regulationwiis irnposcdby the gor,ernnrenl. which sau'an end to both the auctions and. due to licensingcontrols,the supply of goods to London on consignment.The trade then took a rrewfbrm: sampleswere displayedin 'I'he blokers' oflices lbl all to see. traders.blokersandbuyersmet in the (and sometimes Coln Exchangeand dealswere doneby word of mor"rth ir-rcovert wl-rispers) in the best traditionsof the trade.This niethod.by the 1960s with in-rprovir-rg communicationsand increasedvolumes. bccameimpracticaland the tradefinall)' took to conductingmost busin e : sh 1 r l p i e lt c l c c o m r n u n r c a t r o n . Obviously.whilst the tradeamongthe dealersandbrokerswas small and therelorealmost self'-regulating, littlc regulatoryinterferencewas reqr,rired.Horvever.the increasingnumbers of firms involved in the tradereqLrireda systen of settlingdisputesin an inexpensiveand swift lnanner.Thus in 1876the GeneralProduceBrokers'Associationof London was fblmed. This body performed a number of furrctions:a united voice to thoseoutsidethe trade.a meansofregulating the trade by meansof a systemof arbitrationand appealand a fbrum in which to voice concernsof interestto membersin general.The GPBA thrived initially, but sLrff-ered as time went on with variousgroupsof the trade fbrming their own Associations,leaving the GPBA with only the smaller partsof London CornmodityTrading as its remit. More recently broking as part of the London trade becameless relevant and the name was accordingly changed in 198I to the 'General Produce Associationof London' and finally in 1985 the name was again 'lntelnational cl-ranged, this time to the GenelalProduceAssociation'. to reflect the current true nature of the trade. Forms of contract are issuedby the Associationfol the r"rse of membersand others(it is probably true to say thatthe IGPAcontracts.termsand conditionsare those rnostgenerallyusedworld-wide). and thereis a thriving, and lelatively switi and inexpensivesysternof arbitrationand appeal.

ASPECTS CURRENT London's pre-eminenceas the drug-trading centre has diminished sonrervhatover the years.Whilst still Lrndeniably the largestmarketfbr' the trade in essentialoils and aromatic chemicals(a trade misnomer' tiequently nsed to denoteflavour trnd perfumerychemicalsand isolatessuchas menthol.camphor'.piperonal,vanillin and the like. be they naturalor synthetic).its role concerningcrudeherbsand botanicals (sr.rch asrhubarb.ipecacuanha andboldo, for instance)hasdecreasedto Hanrburg'sbenefit.andthe tradingof spiceshasmoved substantiallyto Rotterdarn.Nonetheless,when disputesneedto be settled,most e).es still invariablyturn to London in order to obtain a 'fair deal'. The North Arnericantradeis. asit alwayshasbeen.substantiallydiff'erent.Unlike most of WesternEurope.Canadaand the United States of Americaas well as being largeconsumersof crudedrugsare also largeprodr.rcers. Many pl'oductsregularly tradedin the Europeandrug markets emanatealnrost exclusir"elvfrom North America. There a

number of firms hold stocksof drr,rgs(many of native origin but not exclusively so) speculativell',being almost celtain that there will be demandfbr the productheld on their books in the near term. Glanted. there is a trend tou'ards thc European malket usagesof trade. but noncthelessconsumersin North America shouldbe thankful that due to this patternof br.rsiness it is still usuallypossibleto obtain materialsfor immediatedelivery fiom a trader'sstock.ratherthan waiting tbr shipment fiom oligin. There have recentlybeena number of companiesin the USA who have. lbr one reason or another.withdrawn fiorn the trade,andconsequentlythc NorthAn-rericanmarketis edging.however reluctantly,tolvardsthe Europeanmodel. Consumingpatternsin Europehavealsochanged.Therehas been substantialconsolidationof companiesconcernedwith crude and processedbotanrcaldrugs. particularlybLrtnot exclusivelywithin Gerrnany.to the extent that nowadays one large conglomerate, whilst not controllingthe business.hasgreatinfluence.A numberof recentclosuresand rationalizationhavecausedconcern.particularly on the part of consumingcompanies.What efl-ectall of this will eventr-rallvhave on the wor'ld markets for crude drugs has yet to be seen.but the curlent mood of the n'rarketcould rvell be describedas 'melancholic'. Tradenowadaysl-raschangedsubstantially.In relativelyrecenttimes many drugs r.vereimported speculativelywith a view to selling them 'afloat'(i.e. either oncc confln-nedthe goodswere aboardship) or fiom 'the spot' (i.e. with tl-rcgoods in storein a Eulopeanwarehouse,available fbl irmlediate delivery). With changingrequirernentsof biryers. be it eitherlor the quality ofthe goodsrequiredor with changingtrends in the particulardrugs used.this has becomelesscommon, and nowadaysit is more likely that a customerwill requestof a traderan offer lbr a specificquantityof crudedrug fbr shipmentfronr oligin and delivery afiel saf'earrival of shipment,be that in one delively or parts.either againsta sampleor (more rarely) a mr-rtuallyagreedlevel of quality. Whilst the customeris of courseat liberty to approachorigin direct lbr supplies.tht: ad\rantages of purchasingliom a traderare thoseof transf-erenceof risk. If the quality or condition of goods is sr.rchthat on arlival the goods are either of lower quality than that contractedor damagedin someway, or delir,eryis delayedbeyondthe agreedperiod, recoulse is to the local trader from whom one is far more likeiy to obtain settlementrathel than origin where satisfactionof a claim may be far more difficult or in some casesimpossibleto perfonn, due fbr instanceto local currencyregulations.Also if the traderconcernedsupplies the samematelial to various buyersit can fiequently be possible to re-arrangethe allocationson his book to provide the buyer with an 'emergency' delivery should production demands require this. In leturn lbr this servicethe tradel asks a small prernium over the price paid to origin and absoluteadherenceto the contract terms such as delively datesand termsof payment.for it is on this basisthat the price has beencalculatedand thus. by inf'erence,the margin. Margins in the crudedrug tradearecurrentlyprobablyassmall asthey haveeverbeen. For the customerto delay or cancelan order placed,or to delay payment once goodsare delivered.is unacceptableas would be the trader defaultin-e. deliveringgoodslate or of poor quality.A fallacy still holds in the consumerindustriesthatthe 'rapacious'trader makesvastsums fiom his livelihood.This may oncehavebeenthe case.centuriesrgo. but almost invariably nowadaysmargins are confined to low. single figure percentagelevels:representinga small fraction of thosethat the customer is usually making. This point cannot be overemphasized: contracts(which, atter all are basedon the conceptof'equity' or fairness)work both ways and,in London at leastthe old adage'Verbamea pacta'still holds with the traders:it must also do so with the customer. Is it reasonablethat if a traderhas purchaseda specilic product fbr a customer.for which he has no other potentialoutlet.he shor-rld without

;..yiff'-

C O M M E R C EI N C R U D ED R U G S . , ()Llr\cbe lequired not to cl(]llvcl'goodsbecauseof an erro| on the part : rhacustolner. or on a wl-rirl()f the customer'scustorner'l 'fhe qr,rcstion of quality fr.tlrrltl-retrader'spoint of r reu i: irrpr'or'l. Strongcompetitionat ol'iginhasseena -qcneral increasein quali. .r.ross the boarcl. Many goods are still traded on the olcl :,''efiptionssr-rch asthe 'Comr"non Round'or''Flat'gladesof Chinese 'Mossel ::rrburbor Bny'or' 'Port Elizabeth'aloesflom SouthAfl'ica. l , t n r i s a l w a y ss u l ' et h a t ' M o s s e B a y ' a l o e sw i l l p a s st h er e q u i r e m c n t s i the British Pharmacopoeia. whereas'Port Elizabeth'will rarely.if - . cr. do so. Nonetheless. lrore and nroretradingis being undeltaken :r the basisofpre-shipmentsantples.and shippersat origin teel hap.'rer to do so ltow thatthe *,ot'ld-widenetworksof cor.rrier sen ir:esare :r nl1gg.as a sampleo1'thespecificlot in cluestiorr can be on the desk t thc tradert.nvoor three days aftel it was dispatchedtrom origin. .,thcrthan the two or three weeks it used to take. or two or thlee rr{)llth\befbrethe adventof airntail.Some prodr-rcts are stiil traded ..n()nthe basisofoutturn analysis.therebeingdefineda n0rrinalcon.-'ntoi isolateupon which the price of the contractis calcr.rlated, a :rininrunrlevel below which the parcel is rejectable.and an agreed :\r.()-l'rta fonrula fbr adjustingthe irrvoicevalueonce the qLralityhas '.ecrrindependently established. Thc'r',orld from a commelcialpoint of view haschangeddrarnatical\ ()\er the pastlew yeals.Thc changein EastemEul'opeffom state..rpitalism(lcssnccurately comr.r-rurrism) to free-market economies has .:i.()changcdsupplypatternsti'om thesecountries.Fifieen yearsa-uoas . llil(lcf. ()llc hJd ()tlc ()t l\\(r \otttce CompiLnie\ lrr c()nlijel itt a couttl11.

Be it desirableor ot.herwise. therehas beena move over recentyears lor the goods to be extractedat ori-uinand the isolate rather than the bulk drLrgbeing shipped.At flrst glancethis has many advanta-ees for irll concerned:the lesstechnicaliydemandingwork is pelformedat ori-Qinwherelabor.rrand iacilities arelessexpensiveand wherelocal regulations as legards.say,elfluent are less stringent,which addsvalue to the goods and increasedfbreign exchangeearningsfbr the country of origin. It is of advantageto the trader as there are less fi.eight.wat.ehor.rsing and handlingcostsinvolvedand finally it givesthe customer an (at leastserni-)preparedproductwith which to work thus elirninating the erpensiveand laboriousinitial extlactionprocesses.However, this conceptis a double-edgedsword.One may be temptedto be a little more cLrrsoryas regardsquality control ofthe inward product.particularly atier a long run of -9oodexpcrience.If a parcelof materialis found to bc of inferior quality lbr whateverreason.the lossdue to this tendsto be the -Qreater as concentrationof the product leads frequently to the acquisitionof t-ewer.largel parcelsand (this being the most important) deprivesthe corrsumingcountryor,'ertime of the knowledgeand equipment with which to perform thc completeprocess.In relativelypeaceful times this last considerationma1' be irlelevant; but if lines of communicationwith the tladitional suppliersale disruptedby war or naturaldisaster', theneventhoughit would bc possibleto obtainthe raw rraterial fiou'r elsewherethis wor-rldbe of little use if the know-how and/or equiprrentrequiredtbf thc contpleteextractionprocessis lost. Comnrercially this is of little moment.but fbl thegreater-eoodit is vital not to losethe expcrtisethat hasbeenbuilt up over lnen; centuliesin the consumingcountliesfbl tr smallcostsar,ing.

...hc-reas now thereis a plethoraof suppliers. Rcliabilitl,haschangcdas .' ell: tbnr-rerlycontractswct'esacrosanctbut nowadaysattitu.lesare a rttlcrnorerelaxed.Further.in orderto increaseincome.commercially . .tluablecrudedrugsarebeingproducediu colrntrieswhich pre",ioLrsly CHANGINGDEMANDS :r.r!lnot doneso.Indiais an ercellentcasein point.This countryhadfor' rirn\ \rear\ beena large nett importer of ipccacuanharool (C. ucunri- The patternof demandis changing.Recentinroadsinto the market by ,;/(1 ) 1brbothinternalconsuutption anclre-exportof finishedalkaloids. 'Nutraceuticals'(bio-actiVeproductspresentedas'dietary supple(;r.rnted.thcrehas beena small local cr.rltivatictn of this material.but ments' or similar')have changedthe demand lbr various botanicals. :rc qLralityuntil recently had becn lelativelv poor. Ol'er thc past f'erv Productsof which one would have heard rarely some l0 or 20 years .:.rrs.however.Indiahasbeenableto ofl'eripecacuanha of high qual, ago are now objectsof daily discussion.The lack of licensingof these :r rnd at vely competitivelcr,'els.These developmentsall tenclto productsis a point of major concern.The majority of the botanicals :rtlucethe price of the drugsin question.Br-rtat what point doesthis inl'oh'ed are well documentedand every companythat the writer has ...'!()urcdeleteriousto the market?The answermust bc dilectly related come acrossto date has beenresponsibleand reputable.However.the ',' cconomics.Subsequent to the changesin EastcrnEuropethe prices relatively high malgins that theseprodr.rcts attractwhen ofl'eredto the ,1 \orne drugshar,cfallen consistently. Thus in a placewhere aspir- consumer with this cachet and the comparative lack of technical .,trrrns tbl pelsonalinconrearelising tast (not unreasonablv. considering expeltise neededto manufacturethe product tbr presentationto the :'.i\t historyandcurrentcircurnstances). thc incorrefiom theirproduce public could probablyin time attract(or perhapshas alreadyatrracted) . consistentlyfalling. Pelhapsdue to increasedcompcririon.or cou- r,rndesirable elementsinto the trade.with potentiallydisastrousconse.'r:elv fior.r.rf actorsat the point of consunrption.the plicc falls. The quences.Origins are off-eringprepaled extractsthat need little rnore :rtial eil'ectoflovn,erpricesis in the shortterrnfrequentlyto raisethe than r.r.rixing with an excipientand tabletingor filling into freely avail..Lrelin'of the prodr.rct delivered.with a vieu to securin-e the next order. able capsules.If nutraceuticals,originally and naturally the domain of ilrr\\e\'€t'. if low pricesaresr.rstained theneventuallythe qualityof the the chemist'sshop.the supen'narket or the health tbod storeappearat - r,,pslowlyfallsastheproduceris r"rnable to f'ertilizeor tendthecropto more unlikely venuessuch as open-airmarketsand car boot sales(as rL' r)ptimllm ler,'els.Adulteration either with admixed drug or mole this traderhas seen.on occasion)then the potentialproblemsmultiply. ..rhtlv vn,ithu,ater(i.e. incleasingthe moisturecontent)solnetimes It is almost inconceivablethat well,known brandedproducts rvithin .,kesplace.Finalli' the fatnteror coliectoris presented with the deci- theil statedshelf lif'e would errergeat thesesites,but -eivena substan-:r)nofeithel continuingthc cultivationofthe ploductin theabsence of tial price advantage1othe public. is it not reasonableto speculate.be it ''r,,fit or to changecrop in tavour of one that gives a return. In thc by accidentol desi_en tlrat any problem startingwith a retail outlet of r rr|stcrse sLrpplies of a drug could well ceasefbr lack of protit to the this type attachedto goods of questionableorigin woLrldreflect badly 'r{)ducerwhich.whentakenin thecontextof thepriceat which the fln- on the industry as a whole?Licensingboth ofthe ntanufacturerand the .hcdproductis retailedto thepublic.is alrrostinsignificant. lt may be retailer would minimize this risk. even i1 that licensing wele far less :r.rtthe readeris taken abackby what appcarsto be a hard-nosedtrad- stringentthan that requiled for dispensing.Coincidentally,and as an ,: nrakin-ea piea fbr a fair deal to the ploducer';tl-ris.however,is not the aside,at the time of writing H.M. Governmentissuedan urgent warn-.,.c. The writer would lar prel'erto have a steady.susttrinedbusiness ing regardingthe interactionsof St. John'swort. a common nlltraceut. cr an extendedperiodratherthan a phenomenalshorttrading 'boom' ical, with oral contraceptivesand HIV medication.It is probablyfair to .:r.1 thereafter be out of busrness. expectmore instancesof this type in the future.

E

PRINCIPLES RELATED TO THECOMMERCIALPRODUCTION,QUALITYAND STANDARDIZATION OF NATURALPRODUCTS A relatively new term that has entered the ntarket is 'organic'. Certainly, valerian root and senna pods are amon-qstthose organic pharmaceuticalproductsavailable.In spicesand herbstherehasbeena substantialdemandfbr materialsthat c.ury this cachet.At government and sr,rpra-government level therearein placeregulationson what mily be describedas 'organic'and many organizationsthat monitor prodlrcers, tradersand manufacturerswho handle materialsof this description. Botanical medicinesare perceivedby the public as a pref'erable alternativeto extensivelypreparedor syntheticmedicines.and thus in orderboth to presenta more 'green'imageand to steala marchover the competitor,the conceptof 'organic'productionof pharmaceuticalraw materialswill undoubtedlybecornemore widespread.The problem with this is the size of the martet itself. The cost of employing an inspectorfrom one of the Europeanor Amelican certilicationorganizittions could well be f1000 (USSI600) daily. [f a collectorof. say. yohimbe bark in WestAfrica who blings to market 1000kg per annum is to have his few treescertifiedas 'organic'(whichthey almostcertainly would be) it would cost some years' wofih of income to obtain that certiflcation.hnpractical,yet if the demandfor 'organic'yohirrbe bark were to becomecontnterciallyinterestin_e then a largecommercial concernworlld move in to fill the gap.to the greatdetlimentof that collector'slivelihood.And all because(in thewordsoia well-knowntrader in botanical raw materials): 'the paper's more important than the goods'. We in the West are por-rringvast sums of money into the less well developed parts of the world to enable people such as this hypotheticalcollector to make a reasonablelivin-g,but with the other hand are stoppinghim frorn profiting from our money and his eflblt by what amolrnts to little more than a chan-eein fashion. There also tbllows fiom this point a lLrther concern.Recentlythe sLrpplyof organic nutmeghasbeendiflicult. due to the lact that goodstiee of prohibited levels of aflatoxin could not be obtained. The inabilitv to use

modern techniquesof cultivation (due to the requirementsof the 'organically-rninded' consumer)by direct conseqLlence can causethe ploduction of inferior quality goods: thus one could well ponder.the sanity of paying a substantialpremium (three-tbldin some cases,and at times more) fbr goodswhich, when viewed objectively.are of relatively poor quality.

THEFUTURE In rny f'ewyearsin the tradeI haveseenthe total demiseof the telegram as a tradingtool. and telex is goin-qthe sameway. If the rate of change continuesas it is. by the time this appearsin print the lax will be considered a quaint, slow fbrm of communication. E-mail may well be superseded within a shorttime. The tools of the tradechange.but the methods and principles do not. Trade is based on mutual trr"rst.If the supply of a raw materialneedsto be guaranteed,then thereis only one possiblemethod of obtainin-ethat guaranteedsupply. and that is from one's pret-erredtrader.If the tradertiom whom you obtain yourraw materialssays that the goods will be deliveredat a certain time then,within the tenns of the contract.that traderwill move heavenand eafih to do so.just as the trader'spredecessors did 10, 50 or 100 years ago.Many is the time that I have listenedto the cornplaintthat, 'Origin haslet me down, I need5 tons of XYZ root next week'. If supportis not tbrthcoming in ordinary times. then where is the impetus on the trader's part to plovide supportto those who require it in difTicult tirnes? Perhtrpsaccounting and pr"rrchasingdepartmentsin manufacturing organizationsshouldcarefully considerthis questionwhen looking at the 2c/cor so saving they make (or more often appearto rnake)when purchasingdirect fiom origin. As an insurancepolicy. the tladeris very inexpensive.

EI The crucledrue $'hich re:rchesthe pharntacer-rtical manufactulinglinc r,villhavepassedthroLrgh vadousstages.all of lvhichinfluencethe nature and amountof activeconstituents prescnt.Theseaspectswill be conside r c d u n c l e rt h e h c a d i n g s ' E n r , ' i r o n m e n C t aol r r d i t i o n s ' . ' C r - r l t i v a t e d and Wild Plarrts'.'Collection'. 'Drying'. 'Stora-re'ancl 'European Regulations'.

Production of crude drugs

ENVIRONMENTAT CONDITIONS Plant growth and dcvclopmenl.and often thc nature and quantity o1' secondarymetabolites.are atl-ectcdby tentperatr-rre. rainlhll. aspect. lengthof day (inclLrding the qualityof Iight)and altitude.Suchef-tecrs have been studiedby glou,ingpalticularplantsin difttrent climrtic areasanc'l observingvariations. The lindingsof suchresearch ale illustratedby work on cannabisby El-Kheiret til. in 1986in n'hichsccdsof cannabis.grou,'nin En-elandand rich in CBD and dcvoid o1'THC..,vhen cultivatedirr Suclanstartedto produceTHC in the flrst generationand in the secondgcnerationcontainedup to 3.3% THC r.iith a furlher' dccrease(dorvnto 07c in some plantsl of CBD (scc 'Cirnnabis'fbr cxplanrlionof chemistry).However.it is rmpossiblcto controlall the variablesin sLrchexperiments.and speciallaboratorics(phl,totrons) have beenconstrLlcted in u'hich all the factols are indcpendentlvcontrollable.Even so. a rneanin-etr-rl erpressionof the rcsnltscan ofierr prcscntsorneclifficr-rlty. For-example. a particularfactorma!' leadto the developmcntof a srnallplant which. rvhcnanalvsedon a percentage drv weight basis.indicatcsa high ploportion of ntetabolite.even thoughthe olerall yield per plantcouldbe quite low. Conversely. certain nutricntsnravresultirrthe productionof lrrge plantsrvith a someu'hat low analyticalfigure tbr constituentson I percentagcdr,vrr'eight basis.but yield per plantrrrayexceecl thatofthe control. Temperoture Temperature is a majortactorcontrollingthe developntent and rretabolisrnof plants.Althoughcachspeciesliasbecorneaclaptecl to its orvn naluralenr,ilonment. plantsale freclr-rently able to exist in a corrsidet'able ran,seof temperature. Nlanl tropicnland subtropicalplantsu'ill glow in temperateregionscluring summel utouths.but lack fiost |esistance to withstandthe rvinter.In general.thc highesttenlperatllres are erperiencedncar the Equltor. br,rtas the tempcratllrefalls lbout 1"C fbr every200 rr of elevation.it is possiblein" sa1,. Jan'raica to liave a tropicalclimateon the coastand a tenrpet'ate one in the mountains. The annualvariationsin tenrperttuleirrL-ju\tar irnportantas thc tcntperatureof the hottestmonth.At Sin-eapore thc annualrangeof temperatureis as iittle as 1.5oC.whereasMoscou. with its lrot summers and cold wintcrs.has a rangeo1'29.3"C.In gencral.the fbr"ntation of volatileoils appearsto be enhancecl at hi-shertcnrperatlrres. althou-gh 'fhe very hot claysnray lead to an excessphysicnlloss of oil. mean optimum temperatuletbr nicotincproductionin NicotitutL/ |rr.irrr',r is 2 0 ' C ( l o w e ra t I l - 1 2 ' C a n da t 3 0 " C ) .S c v c r a al u t h o r sh a v ei r r d i c a t c d thattixed oils producecl at low ternperatures containfatty acids$'ith a highercontentof doublebondsthan thosefbmted at higherternpera-

ENVIRONMENTAL CONDITIONS 6 l

tlll'es.

CUTTIVATED AND WIID PLANTS 62

Roinfoll Thc in-rportanteff-ectsof raintall on \,egetatioumust be considcredin relationto the annualrainfall.its distributionthronghoutthe 1,ear.its effect on humidity and its cflbct coupledwith the I'ater-holding propertiesofthe soii. Variablcrcsnltshavebeenreportedlor tl-reproduction of volatileoils underdiff'elentconclitions of lainfall anclmav in some i n s t a n c c sb e c o u p l e c li v i t h t h e d e v e l o p n t c not 1 ' s l a n d u l a rh a i r s . Continuousrain can leaclto a loss ol watcr-solubie-subslances fioni

COLTECTION63 DRYING 64 STORAGE 65 EUROPEAN REGUTATIONS66

PRINCIPLES RELATED TO THECOAI1MERCIAL PRODUCTION,AUALITYAND STANDARDIZATION OF NATURALPRODUCTS lear,esandloots by leaching:this is known to apply to someplantsploducing alkaloids.glycosidesand evenvolatile oils. This could account fbr loll,yields of someactiveconstituents in uet seasons tiom plants whosegeneralcondition appearsto be good. (Tinnevelly senna)it has been shown that With Cas.rlaongustill)liLL short-termdroughtincreasesthe concentrationof sennosides A+B but in the longel term causesloss of leaf biomass(H. Ratnayakaet c1.. PlantaMedit u.1998.64. :l3ll). Doy-length ond rodiotion chorqcteristics Plantsi'rry much in both the amountand intensityof the light which they requile. In the rvilil statethe plant will be found where its shade reqnircmcntsare met. and undel cultivationsimilar shademust be plovidecl. In certain casesresezrrchhas shown that iight is a factor r"'hichhelpsto determinethe amountof glycosidesor alkaloidsproWith belladonna.stramonium r.nd Cinchona ledseriona fLtl\ dr-rcecl. sunslrinegivesa higl-rer contentof alkaloidsthan doesshade.At Gifsur-Yvetteerperimentsindicatedthat with Datura strailtortituut',tr. nttulu ).ongexposureto intenselight brought about a sharpincreasein h1'oscinecontentat the time of flowering. An important in viv'ctrcaction in the fbrmation ol thc antitumour alkaloids of Cctthttranthus roserr,ris exemplified by tl.redimerization of the indole alkaloids catharanthineand vindolinc leading to vinblastine;Hirara et ttl. (.PlrtntaMed.. 1993, 59, 46) demonstratedthat irradiation of intact plants with near ultraviolet light in the ran-ge290-380 nm (peak 370 nm) stimulatesthe synthesisof dirneric alkaloids.probably by inducing catharanthine oxidationas a tliggerrcaction.This observationhas supportfiom ln l'ilrc studies. It hasbeenshownthat underlong-dayconditionspeppermintleaves plants grown contain menthone.menthol and tracesof menthofur"an; undershort-dayconditionscontainmenthofuranas a major component a long photoperiodtbr young leaves of the volatile oil. Fr.rrtherrnore activates the reduction path\vay with conversion of menthone to Inethol.ln studieson the day-night changesin the relative concentrasr'lveslrl.s and other species tions of volatilesfiom flowers of Nicoticutct a rrarked increase(about tenfbld) in aronraticcornpoundsincluding benzyl alcohol was detected at night. whereas no increase in the volatiies(e.g.linalool, caryoph-vllene) originatingfi'om the mevalonic acid pathway(q.r'.)was noted(J. H. I-oughrinet al., Phytochem.,1990, 29.2113\. metabolitesis The daily variation in the proportion of secondeLry plobably light-controlledand is discr-rssed more fully under 'Collection Times'. Many plants initiate flowers oniy in certain day-lengths,and uhere flowering is essentialthis lactor must be carefully considered before plantingin a new region. Presenceor absenceof light. together u ith u avelenqthl'ange.havea markedeffecton the secondarymetabolite prodr-rction of someplantsin tissuecr.rlture. Thc t1'peof radiationwhich plantsreceiveis alsoimportant.With Ocirrtttntbtt.silicum. C. B. Johnsonet ttl (Pltl'tochemistrt'.1999.51. har e fbund. in relationto herbsraisedurrderglassand leceiv507). in-qno UV-B radiation.that supplementary UV-B ladiationincreases lcvcls of both the phenyl-plopanoidsand terpenoidsof the ieaves. Flavonoiclsand anthocvaninsare also known to be int'luenced by UV-B radiation.Depletior-r of the ozonelayer and the consequent elfect of incleasedradirtion at the earth'ssurf'acehasbeena topic of much recentspeculation.Concerningmedicinalplants.R. Karouson et ul. (.Pltvtotlterttistr.t'. 1998, 49, 2273) r'aisedtwo chemotypes of Mentlta .;1tit'utuuhich were subjected to increased UV-B radiationequivalentto a l5% ozone depletionover Patras,Greece. ln one chemotypeessentialoil production was stimulatedby the treatmentwhile a similar non-significanttlend was noted with the other.

Altifude The coconutpalm needsa maritime climate and the sugarcaneis a lowland plant. Conversely, tea. cocoa, coff-ee,medicinal rhubarb, tragacanthand cinchonarequireelevation.In the caseof Cinchona succ'irubrathe plantsgrow well at low levelsbut producepractically no alkaloids. The bitter constituentsof Gentiana lrilea increasewith altitude. whereas the alkaloids of Aconitum napellus and Lobelia influta and the oil content of thyme and peppermint decrease.Other oil-producing plants may reach a maximum at certain altitudes. Pyrethrum -eivesthe best yields of f-lower-headsand pyrethrins at high altitudes on, or near, the Equator. It is therefore produced in East Afiica and north-west South America. However. vegetative growth is more lush under irrigated conditions at lower altitude, so the propagationfarms (fbr the vegetativemultiplicationof plants) are, in Ecuador.situatedat lower levels than the final commercial farms.

AND WIID PLANTS CUTTIVATED Certain drugs are now obtained almost exciusively frorn cultivated plants. These include cardamoms.Indian hemp, ginger, and peppermint and spearmintfbr oil production. Others include Ceylon cinnamon, linseed.fennel.cinchonaand opium. In other casesboth wild and cultivatedplants are used.Someplantshave beencultivatedfrom time immemorial (e.g. l1ax, opium poppy and coca). Others are now grown becausesuppliesof the wild plantsareinsufficientto meetthe demand or because,owing to sparsedistribution or inaccessibility, collectionis difficult. Cultivation is essentialin the case of drugs such as Indian hemp and opium, which are subject to govemment control. and recently for thosewild plants in dangerof over-exploitation and which have now been given CITES (q.v.) listing. In many casescultivationis advisablebecauseof the improvedquality of the drug which it is possibleto produce.The improvementmay be due to the following. (1) The power to confine collectionsto species,varietiesor hybrids which havethe desiredphytochemicalcharacters(e.g.aconite.cinnamon.f'ennel.cinchona,Labiatedrugsand valerian). (2) The better developmentof the plants owing to improved conditions of the soil. pruning.and the control of insectpests,fungi, etc. (3) The better facilities for treatmentafter collection. For example, drying at a correcttemperaturein the casesof digitalis,colchicum, belladonnaand valerian,and the peelingof cinnamonand ginger. For successin cultivation it is necessaryto study the conditions under which the plant flourishesin the wild stateand reproducethese conditionsor improve on them. Small changesin ecology can aff'ect plant products;thus,satisfactoryrubbertreesgrow wild in the Amazon basin but cleared areasconvertedto rubber olantationshave been a lailure.

Soils Dil}'erent plant speciesvary enormously in their soil and nutritive requirements.and this aspecthas receivedconsiderableattentionwith medicinalplants.Threeimportantbasiccharacteristics of soilsaretheir physical.chemicaland microbiologicalproperties. Variationsin particle sizeresult in diff-erentsoils rangingfiom clay, via sand.to gravel.Particlesizeis one factor influencingwater-holding capacity, and some plants (e.g. Althaea o.fficinalisl which produce rnucilage as a water-retainingmaterial contain less mucilage when grown on soil with a high moisture content. Although particular specieshavetheir own soil pH tolerances(Daturu strarnrntitutt6.O-8.2,

P R O D U C T I OO N F C R U D ED R U G S .\lujorana hortensis5.6-6.4), no markedinfluenceof pH value within the tolerancerange has been demonstratedfor essentialoils (.Mentha piperita) and alkaloids(D. stramonium).All plantsrequirecalcium for their normal nutrition but plants known as caliphobousplants (e.g. Pirtttspinuster and Digitalis purpurea) cannot be grown on chalky :oils, probablyowing to the alkalinity.In other casesdifferentvarieties of the same speciesmay grow on dilTerentsoils. For example, in Derbyshire,UK, Valerianafficinttlis var. sambucifollais common on the coal measures,but avoids the limestone,where it is replacedby \'hIeriana officinalis v ar.mikanii. The eff-ectof nitrogen-containingnutrientson alkaloid production has received considerable study (solanaceousdrugs including .\'icotiana,opium); generally nitrogen fertilizers increasethe size of the plantsand the amountsof alkaloidsproducedbut, as indicatedelserihere, the method of expressingthe results of such experimentsis irnpofiant.The effectsof nitrogen on glycosideand essentialoil contentsappearvariable;presumablyin thesecasesthe final result arises fiom the generaleffect of nitrogenon the plant'smetabolism.Nitrogen t'eftilizationhas been shown to increasethe silymarin content of the tiuits of Sl/1bum marianurngrown on reclaimedground.The eft'ectof potassiumon alkaloid production shows no consistenttrend, but an interestingexampleis the increasein putrescineproductionin barley grown on a potassium-deficientmedium, where it is possiblethat the organicbasehas beenformed to act as a substitutefor potassiumions. It has long been maintainedthat trace amountsof manganeseare necessaryfor the successfulproductionof Digitttlis pLrrpureaand more recentlyit was shown that a regimen of manganeseand molybdenum teedingover the two yearsof developmenlof D. grandiJloragives significant increasesin glycosideyield. Little work appearsto have beenperformedon the microbiology of .oil with respectto secondarymetabolism;Hardman and Petropoulos rPluntaMed.,1975,27,53) studiedthe responseof Trigonella.foenum,4roecum(potential source of diosgenin) to field inoculation with Rhiz,obium meliloti,210l in their attemptto establishthis speciesas a temperatecrop. Soil bacteriaof the genusAgnhacteriwn are finding rpplication in the productionof'hairy root'cultures (q.v.). Propogotion from seeds To ensuresuccessthe seedsmust be collectedwhen perfectly ripe. If not plantedimmediately,they shouldnormally be storedin a cooi and drv place and must not be kiln-dried. Some seedssuch as cinnamon. .oca and nutmegsrapidly losetheir power of germinationif allowed to Jry or if storedfor quite shortperiods.Long storageof all seedsusuallr much decreases the percentagewhich germinate. Although seedsare naturally sown at the seasonwhen they ripen, it ir frequentlymore convenient,especiallyin the caseofthe lesshardy crotic species,to defer sowing until the spring. In some cases,howL-\er, immediatesowing of the fresh seedis advisable.For example,it hasbeenshown that ifthe seedsof Colchicumautumnaleare air-dried L'\'enfor a few days,only about5clogerminatein I year and somemay not germinatefor 5 years; whereasif sown as soon as the capsules Jehisce,30Vc will germinatein the first year. In some instances,as ttirh Datura ferox and foxglove. seeds may remain viable in the ground for many years before germinating.With Er-t'throxylumcoca tnd E. novogranatensethe seeds stored at ,l'C for 24 days gave, respectively,297c and 07o germination (8.L. Johnson,PLantaMed., I989, 55, 691). Seedsmay, if slow germinating,be soakedin water or .r 0.27csolution of gibberellicacid for 48 h befbre sowing; more drastic methods,such as soakingin sulphuric acid in the caseofhenbane .eeds,or partial removal of the testaby meansof a file or grindstone, tave also been recommended.With lpontoea purgu Qalap')scailficaiion of the seedshas been the secret of successin obtainins 957c

E

germinationin eightdays (A. Linajeset al., EconomicBotuny,1994, 48, 84). Time of seed-sowingmay afTectthe active constituents,as illustrated by Cl'tamomillarecutita-for 17 cultivars investigatedmost gave a significantlyhigher yield of oil if they were spring-sownrarher than autumn-sownand the oil compositionalso varied (O. Gasicet ul., . i l R e s .1, 9 9 1 , 3 . 2 9 5t.h r o u g hC h e mA J. EssO . bs.116,37955). Propogofion by vegetolive meqns The following examplesof vegetativepropagationmay be mentioned. ( 1) By thedevelopment of bulbs(e.g.squill);conas(e.g.colchicum); tubers(e.9. jalapand aconite).or rhizomes(e.g.ginger). (2) By dit'isior?,a term usually applied to the separationof a plant which has a number of aerial stemsor buds, into separateparts eachhaving roots and a growing point. This methodmay be used lbr althaea.rhubarb,gentianand male f'ern. (.31By runnersor offsets(e.g.chamomileand the mints). (41 By suckersor stolons(e.g.liquorice and valerian). (5) By cuttings or portions of the plant severedfrom the plant and capableof developingroots. Successby this method has been extendedto a large number of plants by the use of rooting hormones(seeChapterl0) and by the employmentof mist propagation. Cuttings may be employed for the propagationof mints, lavender,rosemary,duboisias,tree daturas.coca and vanilla, to mention but a few. (6) By lay'eir.A layer is a branchor shootwhich is inducedto develop roots befbre it is compietely severedlrom the parent plant. This is doneby partly interruptingthe fbod supplyby meansof a cut or ligatureand embeddingthe part.Alternatively the slit portion of the branchis enclosedin moist peat.surroundedby moss, and the whole enclosedin polythene.This methodhas beenused successfullyfor the propagationof cascara. (7) By grafting and budding. Grafting is an operationin which two cut surt'aces,usually of different but closely related plants, are placedso as to unite and grow together.The rootedplant is called the s/ock and the portion cut ofTthe scion or gruft. ln Guatemala young Cinchonaledgerianascionsare graftedon Cinchonasuccirubra root-stocks.eventuallygiving a treewhich producesbark rich in the alkaloid quinidine. Grafting of female scions of Myristica.fragruns on male stocks may be used to increasethe proportionof fruitbearing treesin the plantation.The methodhas beenused considerablyin phytochemicalresearchto study sites of synthesisof metabolitesetc.Budding consistsof the introduction of a piece of bark bearing a bud into a suitablecavity or Tshapedslit madein the bark of the stock.Budding is largely used for Cilrus species,selectedstrainsof sweetorange,fbr example, being buddedon sour stocks. (8) By Jbrmentation.Thisprocessappliesparticularlyto the production of moulds and bacteria,and is extensivelyusedin the manufacture of antibiotics, lysergic acid derivatives and some vitamins. (9) By inocularlon.Specific to ergot whereby the sporesof the fungus are artificially culturedand injectedinto the rye headsby special machines. (10) By cell cuhure followed by difl'erentiationlseeChapter I l.

i':,i:]ii.]i,,]ii:iiii]''i.i..,i]

.l.::.oiiicn]6N..].::.']'.'..''....'..''.' Drugs may be collected from wiid or cultivated plants, and the task may be undertakenby casual.unskilled native labour (e.g. ipecacuan-

PRINCIPLES RELATED TO THECOMMERCIAT PRODUCTION,QUALITYAND STANDARDIZATION OF NATURALPRODUCTS ha) or by skilled workers in a highly scientific manner.(e.g. digitalis. belladonna and cinchona).In the USA the explosivedemandfor some herbs has led to concernover wholesaleuncontrolledcollection. socalled wildcrafting. resultin_u in the or.'er-harvesting of such planfs as Panax quinqueJblium. Polt'gula .tettego. Ecltinat.ea spp. and Cimicifilga racenloso (black cohosh). Elsewhere Prunus afi-it'anrr (pygeumbark) found fiom Nigeria ro Madagascar.RtrulrolJiuserpentina frorn India, and Turnera di.ffusct(.daniana)from Mexico are other e x a m p l eor f o r e r - e x p l o i t n t i o n . A strategyfbr the sr.rstained halvestingof Cumptothecaucuntintttu (Nyssaceae). the sourceof the anticancerdrug camptothecin.has been describedby R. M. Vincenter al.. (J. Nut.Prod.. 1997.60.618).The alkaloid is accumulatedin young leavesand by their repeatedremoval axillarv bud outgrowth is stimulatedgiving an increasedhlrvestable amountof camptothecinin a non-destructivemanner. The seasonat which eachdrug is collectedis usuallya matterofconsiderableimpoftance.as the amount.and sometimesthe nature.of the activeconstituentsis not constantthrou-ehor.rt the 1'ear.This applies.tbr example,to thecollectionof podophyllum.ephedra.rhubalb.wild cher-r.v and aconite.Rhubarbis repor-ted to containno anthraquinone derir,atives in winter but anthranolswhich.on the arrivalof wamer weather.areconvertedby oxidatiorrinto anthraquinones: also the contentsof C-glycosides,O-glycosidesandfreeanthraquinones in thede.,'eloping shootsand leavesof R/ralutuspurshiunafluctuatemarkedlythroughoutthc yeal-. The age of the plant is also of considerableimporttrnceand governs not only the total quantity of active constituentsproducedbr.rtalso the relative proportionsof the componentsof the active mixtur.e.A f'ew examplesaregiven in Table9. I br-rtsomeontogeneticr,'ariatjono1'constituentsmustexistfor all plants. Thereis increasingevidencethat the contpositionof a nr-rmberof secondaryplantmetabolitesvariesappreciablythroughouttheday andnieht. In some cases-fbr example.rvith digitalis and the tropanealkaloidcontainingplantswhich havebeenextensivelystudied-the evidencehas beensomewhatconllictingit-rthis respect.However.this may be largell,' due to the methodsof analysisemployed:thus, throughoutthe day the overaliamountof alkaloidor elycosidemay not charrgeto any extentbut there may be an interconversionof the variousalkaloidsor glycosides present.Daily variationsof the alkaloidsof the poppy,hemlock.lupin. broom, the solauraceous plants and ergot havebeenrepofted,alsowith the steroidalalkaloidsof industrialshoots'of SolanLunluc.irtiuturt?. the cardiac glycosidesof Digitalis purlttuea andD. lanatu. the simptephenolic glycosidesof Saln andthe volatileoil contentof PlnasandSah'la. Generally speaking.leavesare collectedas the flowers are beginning to open. flowers just before they are fully expanded.and underground organsas the aerial partsdie down. Leaves.llowers and fl-uits shouldnot be collectedwhen coveredwith dew or rain. Any which are discolouredor attackedby insectsor slugs should be rejected.Even with hand-picking.it is difiicult, certainlyexpensive.ro ger leaves. flowers or fiuits entirely free fiom other parts of the plant. In cases suchas sennaleafanddigitalisthe ofTlcialmonographs allon'a certain percentageof stalksto be presentor a limited amountol 'foreign matter'(fbr delinition.seeBP. fP and Chapterl4). Similar.ly. with roors and rhizomesa celtain amountof aerial stem is olien coliectediurd is permittedin the caseof senegaroot. The harvestingof umbellif-erous fmits resemblesthat of wheat. Reaping machinesare used. and the plants. after drf ing in shocks. are threshed to separatethe fruits. Specialmachinesale usedto harvestergot and lavenderflowers (illustrationswill be fbund in earlier editions).Barks are usually collected after a period of darrp weather,as they then separatemost readily fi-om the wood. For the collectionof -enms.gum resins,etc..dry weatheris obviouslyindicatedanclcare shouldbe taken to excludevegetable debrisas firr as possible.

Unclelgroundorgans must be fl'eed tiorn soil. Shaking the dru-e befbre.during and after dryin-u.or brushingit. rnaybe suflicientto separatea sandysoil. but in the caseof a clay or other hcavy soil rvashing is necessaly.For example,valelian collectedliont the wild is washed in the streamson the banks of which it usually grows. Before drying, any wormy or diseasedrhizomesor roots shouldbe rejected.Thoseof small size are ofien replanted.In certaincasesthe rootletsare cut off; rhr.rbarb. ginger and malshmalloware usually peeled.All largeorgans, such as calumbaroot and inr-rlarhizorne,shouldbe sliced to tacilitate drying. Befbre gentianroot is dried. it is made into heapsand allowecl to f-ermcnt.Seedssuch as nux vomica and cocoa.which are extracted lionr mucila-tinor.rs fiuits. ale rvashedfiee fiom pLrlpbeforedrying.

DRYING If enzymicactionis to be encouraged. slow drying at a moderatetemperatureis necessary. Examplesof this will befbund under'OrrisRhizome'. 'Vanilla Pods','CocoaSecds'and'GentianRoot'. If enzymicactionis not desired,dlying shoLrlcl takeplaceassoonaspossibleatier collection. Dlugs containingvolatileoils ale liableto losetheir aromaif not driedor if the oil is not distilledfrom them immediately.and all moist dmgs are liable to developmould. For thesereasons.drying apparatusand stills shor-rld be situatedas nearto the growing plantsaspossible.This hasthe furtheradvantagethat freightageis much reduced.as many tiesh dru-qs containa considerable amounl(60-90%) of water. The dr.rationo1'thedrying processvariesfrom a f'ewhours to many weeks.and in the caseof open-airdlying dependsvery lar.gelyon the weather.In sr-ritable climatesopen-airdlying is usedfbr such drugs as clove.colocynth.cardamorrr andcinnamon.Even in warnt anddry climrtes arrangementshave to be made fbr getting the drug under the cover of shedsor tarpaulinsat night or during wet lveather.For drying in sheclsthe drugs may be suspcndedin bundlesfi'om the roof. threaded on strings.as in the caseof Chineserhubarb,or. more comntonly, placedon traysmadcof sackingot'tinnedwire-netting.Papersspread on a wooden framework are also used. palticularly for fr.uits 1'rom rvhichit is desiredto collectthe seeds. Drying by artificial heat is more rapid than open-airdrying and is often rrecessary in tropicalcountries(e.g.WestAfiica. wherethe humiditv is very high. and Hondurastbr drf in-ecardamomfruits). In Europe continllous belt driers are used fbr large crops such as digitalis. Altemativelyheatmay be appliedby meansof opentires (e.g.nutmegs). siovesor hot-waterpipes.In all drying shedstheremust be a spaceofat leastl-5cm betweensr-rperirrposed trays.andair must circulatefreell'. H. N. ElSohly er a!. (Plcnru Metlictt. 1997.63. 83) have studiedthe ef}'ectof drying conditions on the taxane content ol' Tarus needles. Whenthelengthofdrying extendedup to l0 and 15 daysasin a shadehouseor in the laboratorythe recoveryof taxaneswas adver.sely afTected. Drying in a tobaccobarn. -{recnhouseor oven, and freeze-drying was generallvsatisfactor)'fortaxol and cephalomannine recoveriesbut the recoveriesfbr lO-deacctvltaxoland 10-deacetylbaccatin III were only 75-807cof thoseexpectcd. Rapid drying helps flowers and leavesto retain their colour and aromaticdrugs their aroma.but the temperatu|eused in each case must be governedby the constituentsand thc physicalnatureof the dru-e.As a generalrule. leaves.herbs irnd flowers may be dried betrveen20 and '10'C. and balks and roots between30 and 65"C. In the casesof colchicumcorm and di-qitalisleaf it will be notedrhatthe BPC and BP specify the temperaturesat which drying is to be done. For rural tropical areas.solar dryers have some distinct advantages over conventionalartiflcial heat dryers and have beenintroducedinto somecountnes.

PRODUCTION FC R U D D ERUGS

Toble 9.I

Exomples of the ontogeneric voriqrion of some metobolites.

Exomple Volotileoils Mentho piperito M. spicoto Cloves Coriondumsotivum Achilleamillefoltum

Lourusnobilis Volerionaofficinolis Cinnomomum comphoro Diterpenes Taxusbaccato Connobinoids Connobissotiva Cordiooctive glycosides Digitolispurpureo D. lonato Cyonogenetic glycosides Linum u sitotissimumseeds Sferoidol sopogenins Agovesp. Yuccosp. Dioscoreotokoro Alkoloids Popaversomniferum Doturosfromonium Duboisiomyoporoides

Ontogenetic variotion

Relotively highproportion of pulegonein youngplonts:replocedby menthone ond mentholos leovesmoture Progression frompredominonce of corvonein youngplontsto dihydrocorvone in olderones Contoinobovt| 4-21% of oil; mother'blown'clovescontoinvery liitleoil Morked_ chongesin oil composition ot the beginningof floweringond fruiiing Duringflowering,monoterpenes 1,8-cineole} predominote in oilifrom leovesond flowers.Oil {principolly obtoinedduringthevegetotive periodcontoinsprincipolly (92%)withgermocrone sesquiterpenes D the moior comoonent Highestyield:end of August{Portugol), .luly(Chino),Spring(lsroel), coincidingwirhhighesilevelof l,B
lpomoeovio/oceoseeds Steroidol olkoloids Solonum dulcomoro lr uits Solosodine contentfluctuoles duringmoturotion of fruit;tomotidenol predominote ond solodulcidine eveniuolly Cihusglycosides ond limonoidsLimonin ond noringinlevelsin gropefruit follos fruitmotures Furonocoumorins Ammivisnogo Unripefruitsrichestin bothkhellinond visnogin Tonnins Liquidomborformosono seosonoble voriotionof hydrolysoble leoftonnis.mosiropidchongesin thespring Vonillin Vanillaplonifolia Highestroteof vonillinbiosynlhesis occursB monthsofterflowerpollinotion

Exactly how far dlying is to be carr.iedis a matter.for. practical erperience.If leavesand other delicatestructuresare overdried.they becomevery brittle and tend to break in transit.Drugs such as aloes rnd opium may requirelurther drying aftel importation.

STORAGE The lar-ue-scale stora-se of drugs is a considerableundertaking.Except in a f'ew cases,such as cascal'abark, long storage,although ofien unavoidable"is not to be recommended.DrugssuchasIndianhemp and .lrsaparilla deteriorateevenwhen carefr-lllystored.It hasbeenreported

that the contentof taxol in Taxusbttctuta leavesand extractsstoredat room temperature lbr one year decreasedby 3040Va and j0-807a respectively;storagein a freezerand out of direct sunlightproducedno adversedeterioration(B. Das et ul., Plunta Medicct,1998,64,96). Similarly the alkamides of the popular immunostimulant herb Echinatea pLtry)ureadecreaserapidly on storage;N. B. peny e/ a1. (PlcuttaMedica, 2000, 66. -54)have shown thar althoughdrying has liule efl'ecton the quantity of alkamides,storagefbr 64 weeksat 2,lo produces an 80% loss,anda significantlossevenat - I 8 o.Drugs storedin the usual contiliners-sacks. bales, wooden cases,cardboardboxes and paper bags-reabsorb about 10 l2c/c or more of moisture. They are then termed 'air-dry'. Plastic sackswill effectively seal the contents.The

PRINCIPLES RELATED TO THECOMMERCIALPRODUCTION, OUALITYAND STANDARDIZATION OF NATURALPRODUCTS

t I

pemissible moisturecontentsof starch,acaciagum and otherswill be found in the BP and EuropeanPharmacopoeizz. The combinede11'ects of moistureandtemperature water-condenon humidity andthe subsequent sation when the temperaturefalls, must be consideredin drug storage. Drugs such as digitalis and Indian hemp should never be allowed to becorneair-dry or they lose a considerablepart oftheir activity.They may be kept in sealedcontainerswith a dehydratingagent.For largequantities thebottom of a casemay be filled with quicklimeand separated from the drug by a perfbratedgrid or sacking.If the lime becomesmoist, it should berenewed.Volatileoils shouldbe storedin sealed.well-filledcontainers in a cool,dark place.Similarremarksapplyto fixed oils,parlicularlycodliver oil. In the latter casethe air in the containersis sometimesreplaced by an inert gas. Air-dry drugs are aiways susceptibleto the attack of insects and other pests, so they should be examined frequently during storageand any showing mould or worminessshouldbe rejected. In order to reducetrndesirablemicrobial contaminationand to prevent the developmentof other living organisms,some plant materials may requiresterilizationbeforestorage.

To ensurethat satisfactory standardsfor the growing and primary processing of medicinal and aromatic (culinary) herbs are achieved throughout the European Union 'Guidelines for Good Agricultural Practice of Medicinal and Aromatic Plants' was issued as a final Europeanversion in August 1998. It covers seedsand propagation, cultivation. harvesting,primary processing,packaging, storageand transport, personnel and facilities, documentation, education and quality assurance.Details can be found in ICMAP News, No 6, April 1999 (ICMAP = InternationalCouncil for Medicinal and Aromatic Plants).

Furtherreoding Hayward M D, Bosamtrk N O, RomagosaI (eds) 1994Plant breeding.principlesand prospects.Chapmanand Hall, London Hornok L (ed) 1992Cultivation and processingof medicinalplants.J. Wiley and Sons.Chichester,UK

@ ..,ru1ilMt :uat'1149!'i

ripllr

The growth and developmentof plants is regulatedby a nunrberof chemical substanceswhich together exert a complex interaetion to meet the needsof the plant. Five groups of plant hormonesare well established: they arethe auxins,gibberellins. cytokinins,abscisicacid and its derivatives.and ethylene.Thesesubsttincesare of wide distribution and may, in fact, occur in all higher plants.They are spccific in their action, are active in very low concentlations"and regulatecell enlargement,cell di vi sion. cell dif'fbrentiation. or-Qanogenesis. senescence and dormancl'.Their action is probably sequential.Other hormonesconcernedwith flower fbrmation and reproduction.but as yet uncharacterized have also been envisaged.The essentialrole of thcse substances is illustratedby cell andtissuccultures:without the addition of suitablehormonesno developmentor cell division occurs. The eft'ectsofthese very activesubstances on the productionofsecondplantscontainingur ary metabolites.pafticulally with a view to prodr.rcin-e enhancedproportion of active constituent, are of interest to phamaIn sr.rch cognosists. studiesthe mannelin which the resultsarerecordedis all-inpoftant.particularlyas the lreatmentmay alsoinf-lr.rence the sizeof the testplantcomparedwith the controls.For commercialpurposesyield pel hectaleis an obviouscriterion,whereasfor biosyntheticstutlies1'reld per plarrtor per centfreshweight rnaybe of more significance.For final drug evaluationpercentdly weightis themostlikely requirement. In spiteofthe earll'enthusiasm fbr resealchon drugenhrncernent b1 the use of hormonesappliedto medicinal field crops.very little in the way of useful practicalapplicationemergcd;the rcsultsu'ere.hower-er, of interest and selectedexamolesof this older work continue to be retuined in thi\ chilpter.

.,t:iililii''''lrriirllil litrnal tliri:

tiiti:r t{itu

ti;tt;t, t{:i{1u1

u{11t uutalrt t:.{iul uit'uitla t;tlJf irililrl:l ritlt:tlt; .iiutrr uiiilt!l , . :: tri:it!:il

Plont growth regulotors

t.,

,,;,:.'

''.,. ,AuxrNs :

:

These growth-promotin-9substanceswere first studied in 193I by Dutch workers who isolatedtwo growth-regulatingacids (auxin-aand auxin-b,obtainedfiom humanurine and cerealproducts,respectively). They subsequentlynoted that thesehad similar propertiesto indole3-acetic acid (lAA). the compound now consideredto be the major' auxin of plants. and fbund particularly in actively grouing tissues. Severalsimilar acids. potential precursorsof indoleaceticacid. have also been r"eportedas natural products:they include indoleacetaldehyde, indoleacetonitrileand indolepyruvicacid.Thesecompoundsand IAA are all derived,rn the plants,fiom trypbphan. Typical effects of auxins are cell elongationgiving an increasein stern length. inhibition of root growtl-r,adventitiousroot production and fruirsetting in the absenceof pollination.A numberof widely used synthetic auxins include indole-3-butyric acid. naphthalene-1-acetic acid (NAA) and 2,zl-dichlorophenoxyacetic acid (2.4-D).

(Y-T-CH2.cooH \,,/\N/ H lndole-3-aceticacid

o-cH2cooH

AUXTNS 67

I

GIBBERETTINS 68

4-\-cl

V

CEtt DIVISIONHORMONES: CYTOKININS 69

I

GROWTHINHIBITORS 70

cl

ETHYTENE 7 l

acid 2,4-Dichlorophenoxyac€tic

I I

ASTOI'l I j\! t11':qSf Ty

I tIERARY& t N F O i i ; * r r i l i O N S f RVICE t s

Il

PRINCIPLE RS E L A T ETDO T H EC O M M E R C I APL R O D U C T I O NQ,U A L I T Y AND STANDARDIZATION OF NATURAL PRODUCTS ln the plant.oxidativedegladationof IAA to sive a numberof prodGIBBERETLINS ucts is controlledby IAA oxidasc.Sone substancessuch as the orthodiphenols(e._s.cafl'eic and chlorogenic acids and qr.rercetin) inhibit the actionol'the enzyrneand. hence.stimulategrowth therr- This group of plant growth re-qulatorswas discoveled by Japanese 'bakanae'(foolish seedlings) disease of selves.Conr,elsely. r-nonophcnols suchas7.r-courllric acidpromotcthe rvorkersin connectionwith the actionof IAAoxidase anclso inhibit gr'o$'th.IAA rnayalsobc conjr"r- rice. In this. the afl'ectedplantsbecomeexcessivclytall and are r"rnable gatedin the plantrvithasparticacid.-llutamicacid,-qlycine, sugarsand to supportthcmseh'es;through a combinationof the resulting weakthey eventuallydie. The causativeorgantsm cvclitols:suchbound lbrnrsnrayrepresent a detoxicationmechanisnr nessand parasitedan-rage g i kuroi. and in I 926 Kurosawafound that of the discaset s GibbereILa.fu or are inactivc stora-{cforms of the hormone. The main practicalusesof auxinsare (1) in low conceutratir)ns to extl'actsof the fungr-rscould initiate the disease symptoms when appliedto healthyrice plants.Sorrrel0 yearslater.Yabutaand Hayashi accelelatethe looting of woody and herbaceor.rs cuttin-us and (2) in higher concentrations to act as selectileherbicidesor weed-killers. isolatecla crystallinesampleof the active material which they called 'gibberellin'. Pleoccupationwith the auxinsby westernplant physioloPlacccllbr 2.1h in a l:-500000 solutionof NAA. cuttin_ss r.villsubsequenth'clevelop roots.This inclucles cuttingsfiom treessuchas holly. -qists.the existenceof languagebarrielsand the adventof World War II of these which lr'ele fbrmelly i'er'1'diflicultto plopagatcin this way and had to meant thrit a firrthel l0 yearselapsedbefore the sigr-rificance groupsin Britain, outsideJapan.In the 19-50s be raisedtl'onrseedor bl grafiing. Sirnilarly.indolc--3-butyric acid was findingswasappreciated successful vith CiuL:lututL cuttin-qs. savin-q solne2 or 3 yearscompared the USA and Japanfurther investigatedthesecompounds.which were uith grou'th fl'ornseed.Sirnilarresultshave beenobtainedwith cr-rt- shown to har,eamazingefl'ectswhen appliedto plants.lt soonbecame tingsof Curicu,Cuft?a,Pirtt.ts and otherspecies. ln biogeneticstudies. apparentthat a range of gibberellinswas involved. and they are now use has been lnade of auxins to induce rclot forrnation on isolated distinguishedas GA1. GA2, GA3, etc. GA-,. comntonly ref'erredto as leavessuclras thoseof Nicotitutttandl)uturu species. Auxins usedin gibbcrellic acid and ploduced commercially by fungal cultivation. is suitableconcentration(usuallystlongerthan when usedfbr rooting probably the best-knownof the serics:its structurewas finally detercuttings)selectivelydestroysome speciesof plant and leaveothcrs nrined in 1959. The tirst good indications that gibberellinsactually mol'eor lessunaff'ected. They have.therefore,a very irnportantrole as existedin higher plants came with West and Phinney'sobservationin 1956 that the liquid endospermof the wild cucumber (.Echinocytis selectiveweed-killersin horticr.rltr-rre Thus 2.,1-Dis arrdagricultr.rre. particularlytoxic to clicot,vlcdonous plantsr"'hile.in suitableconcentra- rrtucrocur;ta)was particularlyrich in substancespossessinggibtion. lraving little efl'ecton nonocotyledons.It can. therefbrc.be used berellin-like activity and Radley's reporl of a substancefi'om peaacidon paperchromatograrns. Finally" to destroysuchdicotyledonous weedsas dandelionand plantaintion-r shootsbehavinglike -eibbelellic isolatedcrystallineGA1 fiom Phaseolus glass lirwns. (N.B. Certain carbi.urateiLnd urea derivativeshar,e an in 1958MacMillanand SLrter By 1980,58 gibberellinsr'vereknown of which abouthalf oppositeef'l'ectand can be usedto destroygrassu'ithout seliousinjury' rnultif'lorLts. were derivedfiom the Gibberellafungus and half fiorn higher plants. to clicotyledonous clops.) GA117was charactelized from fern gametophytes in 1998(C. Wynne Thele have beenscr,eralrcpol'tson the ellects of anxins on the fbret al.. Plrttochenti.stn'. 1998.49. 1837).Of thesemany GAs rnostare mationol secondary metabolites on medicinalplants. Seedlingsar-rdyoung plantsol-Mentlrupiperitu,uhen treatedwith either deiid-enclrnetabolitesor are intennediatesin the fbrrnation ol only a lirnitednumberhavehormonalactivityp€r derir':rtives of NAA, gave in the mitture plilnts an increasedyield activecompoLrnds: (30-50%) of oil which itself contained4.5-L).0%more mentholthan sa. It is now consideredpossiblethat thesc substancesare pre\ent in tl-recontrols.The study of the efl'ectsof auxins on alkaloid fblrnation nrost.if not all, plants. Gibberellinsare synthesizedin leavesand they acculnulateirr relalras concentratedprincipalll' on the tropane alkaloids ol Duturu species. Molphologicalchanges in theplantswereobserved(2.4-D,fbr tively lalge quantitiesin the imrnatureseedsand fiuits of someplants. exarnple.producedabnorrnaland bizalrefbrms of D. ,stnrntoniurn: an The most dramaticef-fbctof gibberellinscan be seenby their applicarncreasein tlichome production.palticularlf in branchednonglandr"rlar tion to short-nodeplants for example.thoseplantsproducingrosettes lbrmsl smoothfiuits as distinct f'romtl-rosewith spinesland a prolifer- of leaves (Digitulis. Htoscl'antus)-when bolting and flowering is ation of vasculartissue).Genclall.v.wolkcls tbr-rndno markedel-lecton induced; also. dr','alfvalieties of many plants. when treatedwith the alkaloidproductionor on the type of alkaloidsprocLrcecl, althougha horrrone, -qrowto the sameheight as taller varieties.Other irnportant of various Russirnpaperrecoldsthatwith thornapplearrdscopoliatissuecultures aclionsof the gibbelellinsarethe initiationof the synthesis a stimulatingef1'ect on alkaloid production\\'ilsobtainedwith NAA ancl hydrolyticand proteolyticenzymesLrponwhich seedgerminationand seedlingestablishment depencl. an inhibiting effect '"vith 2..1-D: sirnilal resr-rltswere reportecilbr The growtl.retfectof gibberellir.rs arisesby cell elongationin the subIlarnrolfiu :erytentinutissuc cultules r.vith thesc fivo horrnones.An increasedalkaloid production has been repolted fbl submcrgedcul- apical neristem region where young internodesare developin-e.The efttcts of gibberellins and auxins appear complernentarv,the fLrll tules o1'certrinelgd strainswhen tleatedu,ith variousauxins(lAAl NAA: l.'1-D: inckrlepropionic acid: indole butl'ric acidl. r'n,heleas stirrr.rlationof elongatronby eithel hormonenecessitatingan adequate unplcdictablcirregularclurntitrtiveand qurlitativeell'ectson ergoline presenceof the other'. As with auxins,gibberellinsappealalso to occur in plarrtsin deactialkaloicl ploduction were observed with the same hormones in Ilsottroctr.Rllcrr and Argt'reia (Conl'olvulaceae)suspensioncultures. vatecltbmrs: thus. f3-D-glucopyranosylesters of GAl. GA*, GA8. Erpelimentscalriedout in Hungalyinvoh.'ingthc injcctionof IAA into GA-j7and GAjg ale known. As such they rlray servea depot function. poppy'capsulesI anclf davsatter tlowerirrgploduceda relativelyelon- The glucosylesterof GA3 has beenpreparedin severallaboratories. The biogeneticpathwaysof the gibberellinsappearto be similar in alkaloidcontent.In stud-tatedcapsulelbrm rncl.in general.a reducecl ies on anthlacluiuoncproduction b1' cell suspcnsior.r cultures of both higher plantsand Gibberelh. They ariseat the Crq geranylgeranyl level of the isoplenoidr.nevalorric acid pathway(q.v.) Morittdu citriloliu. Zc-nkanclco-u'orkershave shown that cells grown pyrophosphate with cyclizations the C2s tctlacyclic diterpernoid entkauin the presenceof NAA havea substantial productiorr anthlaquinone -eiving but thoseu ith l.-l-D assoleauxindo not.IAA appears to haveno benc- renoic acid. which by a rnultistep ring contraction furnishes the GAtrficial eflecton the productionof sennosides in Ca,rslautgustifoliu. -eibbanering system as exemplilied by the key intern.rediate

PLANTGROWTH REGULATORS been publishedon the efTectsof the hormoneon the morphology and alkaloid contentof treatedplants.H_r,osr.r.omu.s niger is a perennialand the hormoneeffectsincludedstemelongationgiving a two- to threefbld increasein height: a spindly and vine-like growrh; slightly chlororic and narrow leaves;a more rapid onset of flowering; increasesin the stcrndry weights but decreasesin the dry weights of leaves.tops and Gibberellic acid (CA3) roots.The overall yield of alkaloidsin the treatedplants was reduced by about a half and the concentrationof alkaloidsin variousmorphological parts ranged fi'om 13 to 81c/cof that of the controls,with the stemsshowingthe greatestteduction.Subsequentexperimentsshowed that with belladonna.increasedalkaloid yields could be obtainedby adjustingthe doseof GA treanr-rent to favoul overallgrowth in the older plant. Similar resultshavebeenreportedwilh Daturutspp..plants showing GA12aldehyde. Key diversification point for synthesisof GA s the predictablernorphologicaleff'ectsand giving a reducedalkaloid yield. The efl'ectswere not transmittedto the second-generation plants. With NicoticuttttabucnntandDuboisiu hybrids,treatmentagaingavea aldehyde.Severalpathwaysdiverge fiom GA1,-aldehydeto give the generallyreducedalkaloidcontentaccontpaniedby characteristicrnorknown 90 or so gibberellins.All GAs have either the ent-gibberellane phologicalel1'ects. (C19 GAs) (loss of C-20) tC,e GAs) or the ent-20-norgibberellane Other alkaloid-containingplants which have been subjectedto GA carbon skeleton.Both types are rnodified by the position and number treatmentinch-rdeCathnranthusftrJetl.r(generallya lowering of alkao1'OH groups.oxidationstateof C-18 and C-20. lactonefbrrnation. loid contentand somechangein the relative proportionof vinblastine presenceand position of double bonds on ring A, epoxide fbrmation, to other alkaloids');Rauu,olJia.\erpentinu(loweringof alkaloidconcenthe presenceof a carboxylgroup and hydrationof the C I 6-C 17 double tration in the roots,the e1I'ectincreasingwith dose):andTltea sinensis bond. (slight differencein cafl'einecontentof leaves).It worlld appear,thereThe gibberellinshave beenusedto treat rnany plants which contain fore. that with the alkaloid-containingplantsso tar tested.the substanusetul secondarymetabolites.A sumnraryof someof the findings, fbr tial internodal growth produced by GA is oflset by a lower ovelall difterentgroups,is given below. acculnulationof alkaloid. Volotile oils ond ierpenoids Early wolk involving GA treatmentof volatile oil-containing plants n'as corrcernedwith resultantchangesin morphologicalcharactersin generasuchas Citru,s,Eucoh'ptusandFoericulum.GA sprayingof the llowers of Huntulus Lupulusadvancedthe maturity of the hops by 10 days and gave a more evenly developedcrop. Although the conesof treatedf1owerswere more subjectto wind burn than normal.their yield rvasincreasedby about407c.The cr-resincontentof the hops,on which theil commercia]value depends.however.was l.Sclccomparedrvith l0.2Vc for the controlsl the volatile oil corrposition also difl'ered. Several studies have becn made of the ef}'ectsof GA treatment on Mentha piperitu. The detailedresultsvary, but the generalresult is a loweling of the oil content (possibly by reduction of the number of slandularhairs)with little changein the oi1composition.In contrastto the above,Kaul and Kapoor havereportedlavourably on the GA tt'eatrrent of ChenopodituttambrosioitlesandAnethunt.spp. with respectto rolatile oil content.The tbnner affordeda 33% increasein volatile oil with no appreciablechange in ascaridoie content. Wilh AnethLun grttvectlens specificdosesof GA increasedthe oil contentby up to 50% and with A. sol rr (Indiandill) by up to 30%.At the lower dosesof GA trcatmenttherewas no significantchangein the can'onecontentof the oil, but at higher concentl'ations thel'eappealedto be a slight increase over the (then)official limit (53%. BP 1958).With FoenicLrlum vulgare and Cctriandrumsatiyturt Gjerstad found that tblial spral's of 100 palts/I 06 GA, apptiedbi-weekly.gave a diff-erence in caulinelength of 200-3007cbut no dit-ferenccs were detectedin yield of fiuits and quantity andquaiityof volatileoil.

Glycosides In 1959 Sayedand Beal reportedthe efl'ectsof the daili,'GA rreatment of first-year rosetteDlgrtalis purpurea plants. Flowering occurredin the first year with treatedplantsand the leavesbecamelongerand more linear.with an increasein dly weight.An increasein cardioactiveglycosideswas obtained but no incteasein the digitoxose content was observed.Sinrilar experimentsby Burton and Sciuchettiin 1961 involving weekly treatmentsof D. lanuta produced similar results, with 'bolting' afterrhetwelfth week.The total glycosideper shootof the treatedplantswas considerablyincreasedin the first 8 weeks.and at harvest time showedabout 30cloincreasewith the lowcr doseof hormone (10 ptgweek r), and a 507cdecrease with the higher(50 prgweek-l).The authors concluded that the effect of the treatment of glycoside productioncorrelatedmore closely with thc growth responsethan with the e1l-ect on carbohydratefbrmation.With both leaf and root cultures Lui and Staba (1981) found GA to have a positive eff-ecton the productionof digoxin. Applicationof GAto Cassiaangustifoliu(Bhatiaetal.,PlantaMed.. 1978.34.437)appeared to redllcethe sennoside contentofthe leaves at all concentrationsused.but slightly increasedthe dry weight of the shoot.

Fixed oils Gjerstad obtaineclcastor plants (.Ricinuscomntttnis)five times the hei-ehtof controls as a result of GA treatment.No significant differenceswere observedregardingthe quantity and quality of the fixed oil of the seed.

Alkoloids The seeds ol the tropanc alkaloid-producingspeciesol Atropct. CELIDIVISIONHORMONES:CYTOKININS Ht'oscyarttus tnd Dttturtt often exhibit protracteddormancyor en'atic GA treatmentof the seedscan be r.rsed to assistin obtain- Auxins and gibberellinsare concernedlargely with cell enlargement: _uermination; ing unifolm -eelminationiind total cmergence.Considerablework has and although they influence cell-multiplication processes,there are

@

OF NATURALPRODUCTS RELATED TO THECOMMERCIATPRODUCTION,QUALITYAND STANDARDIZATION PRINCIPLES other substanceswhich have a more specific efTecton cell division (cytokinesis).The activity of the latteris not only confinedto cell division in a tissueper se; they also regulatethe patternand frequencyof organ productionas well as position and shape.They have an inhibiThe plesenceof such compoundshas been tory effect on senescence. suspectedfor many years, the German botanist Haberlandtin 1913 having noted that phloem tissuescontainedwater-solublesubstances cells of woundcapableof promoting cell division in parenchymatous ed potato tubers.It was not until many yearslater (1954) that Miller, working at Wisconsinon tissuecultures,discoveredthat agedor autoclaved DNA from herring sperm stimulatedcell division. This active degradationproductwas calledkinetin and in 1955was identifiedas 6furfulylaminopurine (6-furfuryladenine).Kinetin itself has not been isolatedfrom plants,but in 1964,atler the indication of cytokinins in liquid endospermof the coconut and in extractsof maize embryos at the milky stage,an active substancenamed zeatin was isolatedfrom the latter source.Like most other cytokinins,it is a 6-substitutedade1)-aminopurine.It nine derivative, 6-(4-hydroxy-3-methylbut-2-eny has sincebeenshown to be associatedin maize with zeatinriboside(1 B-o-ribofuranose)and with a phosphateester of this compound.The hormonecomplex has been detectedin the cambial region of various and dihydrozeatinare examplesof woody plants.lsopentenyladenine cytokinin isolatedfrom other sources;many more have been detected but not identified.The sidechainof cytokininsis of isoprenoidorigin.

NH-Cl{a-c-

l N

-

f"-f' -cl-l o

r\ t

=*^li) Kinetin

Cytokinins have been much employed in tissue culture work, in which they are usedto promotethe formation of adventitiousbuds and shoots from undifl'erentiatedcells. In cell cultures, they have been shown to promote the biosynthesisof berberine(Thalictrum minus), condensedtannins(Onobrychis viccfo lia')andrhodoxanthin(Rlclnus). A limited study only has been made of the efTectsof cytokinins on secondarymetabolismin intact plants. Concerningplants producing tropanealkaloids.Ambroseand Sciuchettihavecomparedthe actionof . Plantsreceivedweekly dosesof kinetin and GA on Datura meteloides 25 pg kinetin; in relationto the controlsthe following differenceswere noted: Kinetin treatment

Gibberellicacid treatment

Shorterand bushierplants Decreasedgrowth No changein alkaloid contentin plant organs Delayedresponse

Taller and spindly plants Increasedgrowth Decreasedalkaloid production Rapid response

ment was that in field plantsit led to a delayin the usualseasonalfall in alkaloid content(February-April in Australia),thus permitting an economically useful,extendedcollectionperiod.Shahet al. (1990) reported favourableincreasesin growth and alkaloid yield with Hrosct,amus muticustreatedwith kinetin (50 p.p.m.). Verzdr-Petri injected benzyladenineand kinetin separatelyinto developingpoppy capsules:the effectswere similar to thoseobserved with auxins.Leavesof the coffee plant after kinetin treatmentdeveloped a transientincreaseof up to 107cin their caffeine content.The effect was transitoryand passedafter 6-12 days.With Cassiacrngustifolia plants low concentrations of hormone were found to increase slightly the sennosidecontent and to favour an increasein the dry weight of shoots.

NH.cHr-q":i"*t

cH2oH ryA-\ \^-/

H

Zeatin

GROWTHINHIB|rOR5 Natural growth inhibitors are presentin plants and affect bud opening, seedgerminationand developmentof dormancy.One such substance, abscisic acid [3-methyl-5-(1-hydroxy-4-oxo-2,6.6-trimethyl-2-cycloacidl was isolated and charhexane-1-y 1)-cis,trans-2,4-pentadienoic acterizedin 1965;it has also beenisolatedfrom the ftrngusCenospora rosicola. The structuralsimilarity of abscisicacid (ABA) to the carotenoids prompted researchon the relationshipof these two groups of comthat somexanthophylls,parpoundsand it hasnow beendemonstrated ticularly violaxanthin,producea germinationinhibitor on exposureto 'apoin supportof an indirect light. Evidencehas now accumr-rlated carotenoid'pathwayfor ABA biosynthesis,the most likely precleavage precursorsbeing 9'-cis-neoxanthinand 9-cls-violaxanthinwhich fracture acrossthe I 1,12 (1 1'J2) doublebond to producexanthoxinwhich in plant tissuesis readily transfbrmedinto ABA (seeA. D. Parry and R. 815).However,it is alsopossiblethat Horgan,Phytochem.,1991.30, level of the MVA ABA arisesfrom farnesolat the C15sesquiterpenoid pathway (q.v.).The theoreticalpostulationinvolves a number of s