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Professor of pharmacognosy, University of Angers (France) School of Pharmacy
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Pharmacognosy
Phytochemistry Medicinal Plants
© TECHNIQUE & DOCUMENTATION, 1999
ISBN : 2-7430-0316-2 (2nd edition, 1999)
(reprint, 2001) ISBN : 2-7430-0028-7 (1st edition, 1995) Originally published in French as: Pharmacognosies phytochimie, plantes medicinales (3rd edition, 1999) by Technique & Documentation/Editions medicales internationales
© INTERCEPT Ltd, 1999
ISBN : 1-898298-63-7 (2nd edition, 1999)
(reprint, 2001) ISBN : 1-898298-13.-0 (1st edition, 1995)
All rights reserved. No part of this publication may be reproduced, stored in retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of the publisher or the Centre francais d'exploitation du droit de copie (20, rue des Grands-Augustins - 75006 Paris, France). Exceptions are allowed in respect of reproduction exclusively intended for the private use of the person making the copy and not intended for collective use, or for analysis and short extracts justified by the scientific or informative character of the publication in which they are included (Law dated July 1, 1992 - art. L 122-4 and L 122-5 and Penal Code art. 425).
2nd edition
Translated by Caroline K. Hatton
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Also available:
Toxic Plants Dangerous to Humans and Animals J. Bruneton, 1999
Insects and forests: the role and diversity of insects in the R. Dajoz, 1999
Illustrations. This book was illustrated by Annie Bruneton, after the foSl>
Berg, O.C. and Schmidt, C.F. (1893-1902). At/asderofficinei/en Pflanzen, 4 volumes, Verlag von Arthur Felix Leipzig: (p. 22, 54, 74, 84, 94, 114, 132, 140, 182, 232, 244, 256, 268, 286, 300, 320, 354, 392, 416, 426, 432, 446, 454, 468, 486. 500, 514, 522, 534, 542, 556, 566, 574, 586, 594, 606, 612, 618, 644, 666, 690, 712. 720, 728. 744, 762, 774, 792, 812, 816, 820, 828, 848, 858, 900, 912, 930, 950, 960, 976, 984, 1002, 1012, 1030, 1044, 1048, 1060, 1070, 1082). Chaumeton, F.P. (1814 -> 1818). Flore medicate, 6 volumes, C.L.F. Panckoucke, Paris, (vol. 3 -> 6 with the collaboration of Chamberet and Poiret; illustrations by E. Panckoucke and PJ.F. Turpin); (p. 10, 104,154, 198. 206, 212, 280, 332, 338, 382, 550, 644, 678, 840, 866, 884, 924). Lamarck. J.B. de Monet, chevalier de (1791 -»). Tableau encyclopedique et mithodique des trois regnes de la nature, Panckoucke, Paris; (p. 956).
Cover photography:  Papaver rhoeas l. (Papaveraceae) by Annie BRUNETON
In the four years since the publication of the first English edition of "Pharmacognosy Phytochemistry, Medicinal Plants", the level of interest in plants with potential health benefits has not dropped, quite the contraiy. _
The therapeutic armamentarium has been augmented, in particular with antimalarial and anticancer compounds that are semisynthetic, but would not exist without the plants that produce their precursors. The future will tell the real impact of these recent additions; the knowledge of the novel mechanism of action of three of them opens new and hopeful research avenues. Novel natural substances have demonstrated potential as antiretroviral agents in experimental conditions. Others that were long known could SOOT help improve the symptoms of Alzheimer's senile dementia.
The market for herbal medicines has evolved dynamically. Quantitatively, th Europeans are believed to have spent nearly six billion U.S. dollars in 1995 on plan based pharmaceuticals *. Qualitatively, the release of certain new drugs on the mark has made quite a sensation. Again, the future will tell—/ hope—if the excitement that tht generate is clinically justified.
Consumers, who want to see risk minimized in many domains, are becomin increasingly interested in prevention. This is probably why they are interested in foe quality and in plants, for the micronutrlents that they contribute to the daily food intak Pharmacognosy cannot ignore this facet of the knowledge of plants. It has a mission i participate in wellness education at the grass-roots level because of the potential impa* on public health.
These multiple changes and the accumulation of new data have led to delaying n further the distribution of an updated and expanded version of "Pharmacognos-Phytochemistry, Medicinal Plants ".
The second edition was revised in the same spirit as that in which the previous one wc I written, but not all facets of the knowledge of plants were treated in the same fashior
some were developed, others simply maintained. The same is true for the monograph. The phytochemical generalities are among the portions that were not expanded: it did nc seem desirable to go beyond a general overview—structural or metabolic—of the principc categories of secondary metabolites. In contrast, special attention was devoted to th
biological activity of plants and their constituents, and to the extent that information could be found and used, to clinical data. The approved indications for plants are systematically mentioned for the quasi totality of the species listed in the annex of the French Explanatory Note on "plant-based medicines" ["Medicaments a base de plantes", Les cahiers de I'Agence du medicament, 1998]. It seemed useful to cite, as much as possible, and while awaiting a much-needed European harmonization, the data on plant use as it is presented in the German Commission E monographs. As indicated above, a non negligible place was granted to plant metabolites whose consumption is thought to have an impact on the incidence of certain disorders, particularly cardiovascular disease and cancer.
For the bibliography, I made the choice not to systematically reference all the data: although this would be required for a monograph, perhaps it is not in a general text, considering its breadth and its primary purpose, which is pedagogical. The principle of selecting recent and representative articles and books to list at the end of each chapter was maintained. The vast majority of the selected references were published between 1993 and 1998.
Once more, I am at a loss for words to express my deep gratitude to Michel Lebceuffor his thankless labor, meticulously reading the manuscript, and most of all, for his observations, always pertinent. I give special thanks to Helene Guinaudeau, Gilbert Fournier, and Jean-Frangois Verbist, who provided useful advice on specific points. I also wish to thank Daniele Pioletfor her relentless hunt for spelling and typographical errors.
December 1998
I am especially grateful to Caroline K. Hatton, Ph.D., who provided the translation of the original manuscript with uncommon diligence, efficiency, and competence, and whose pertinent comments gave me food for thought, and to Cindy Angerhofer, Ph.D. (Director of Research and Product Development, Tom's of Maine), who devoted substantial time to reviewing the translation.
July 1999
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Introduction to the 2nd edition (1993)
The concept of phytochemistry is easy to understand, but that of pharmacognosy undoubtedly requires definition and commentary. The phrase "medicinal plants" also deserves a few comments. There is no point in proceeding any further without a good grasp of the meaning of the words which define the scope of this work.
Etymologically,p/ia77wac0gn0S'j> is the knowledge (from the Greek gnosis) of poisons (pharmacon). Note that pharmacon not only means poison, but also medication... the difference lies in the dose. Thus one might legitimately think that pharmacognosy treats all drug-like substances: that is not the case. Pharmacognosy limits its field of investigation to natural starting materials: it is simply the descendant of "materia medica *", a discipline which, since Dioscorides's treatise by that name, and until the birth of synthetic chemistry, dealt with mineral, animal, and plant starting materials, in other words all of the materials available to prepare remedies, since no others were known!
As time passed, mineral substances lost their appeal. Those that are still in use are now covered as well-defined substances, just like synthetic organic substances and in the same texts. Is pharmacognosy, then, the study of starting materials of plant or animal origin intended for therapeutic use? In fact, a number of French experts and many foreign authors—the former through their lectures, the latter through their writings—treat hormones, enzymes, but also substances elaborated by micro-organisms. Some do not hesitate to include biotechnology and genetic engineering.
Under these conditions, pharmacognosy is the study of starting materials and substances intended for therapeutics, and of biological origin, in other words obtained from plants, animals, or by fermentation from micro-organisms.
Although I gladly abide by this definition, this writing will survey a field of applications both narrower and less restrictive. Is this a paradox? No. The field is narrower because it is limited only to plants and to products arising from plants *. It is less restrictive because it is not limited to the sole criterion of therapeutic use: starting materials for the synthesis of drugs, hallucinogenic plants, manufacturing aids, food additives, plants or components for cosmetology, or insecticides of plant origin must be included. The pharmacist—who is not the only one who should be concerned—musí
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know useful plants, and must also know toxic plants: therefore, these appear prominently in this book. Nature stimulates the creativity of chemists: synthetic analogs, when available, will be mentioned without being fully developed.
Beyond the definition of pharmacognosy, it is important to emphasize what many consider, and they are absolutely correct, one of its major assets: its multidisciplinary character. In pharmacognosy, to study a plant is: to define its identity; to describe its morphology and anatomy; to know its origin and production methods; to appreciate their impact on the plant quality; to determine its chemical composition and the factors that may affect it; to know the structure, physico-chemical properties, and pharmacological activity of the active principles; and, this is a crucial goal, to identify the variables which objectively reflect quality and to develop the methods to control it; finally, to come to grips with all the problems linked to the optimal utilization of plants and plant products: indications, contraindications, side effects, and drug interactions. As noted by V. E. Tyler et al. pharmacognosy is "an applied science that deals with the biologic, biochemical, and economic features of natural drugs and their constituents".
To know plants and their uses is also—and this applies mostly to phytotherapy—to be aware of the limits and the dangers of what must be at times no more than a "placebotherapy", but is never completely innocuous: the intoxications reported in 1992 show, if need be, that "natural" does not always rhyme with innocuous. As stated by P. Delaveau, medicinal plants, also known in French as simples, are in reality exceptionally complex.
Medicinal Plant. The noun is common, the adjective is commonplace, and their juxtaposition introduces a concept that is not always easy to define. A plant is said to be medicinal when "at least one part possesses therapeutic properties". It may be listed in the French or in other Pharmacopoeias, although this may be true for plants that are of use to pharmacy without being medicinal. In France, a plant not listed in the Pharmacopoeia can be a drug, even if it is not considered a medicinal plant: the only requirement is to present it as having curing or preventive properties for diseases (article 512 of the French public health code. Many medicinal plants are only medicinal (for example the foxglove, used for its leaves), but many are not just medicinal: thyme and other Lamiaceae are herbs as well as medicinal plants, the artichoke is an edible vegetable, as well as a medicinal plant. If these examples are straightforward—the in vitro spasmolytic properties of the infusion of thyme are well known, and the fact that it is the artichoke leaf that is medicinal and the inflorescence receptacle that is edible is well known—things are sometimes less clear: what about the onion? What about tea? What about nutmeg? The onion is an edible vegetable *, but do the inhibitory properties toward cyclo-oxygenase of its sulfur-containing compounds make it a medicinal plant? Tea is one of the beverages most widely consumed worldwide, and everybody knows the effects of caffeine: isn't tea also a medicinal plant? Nutmeg is a spice, but is it known in every country that it can be a hallucinogen? And that the neolignans that have been isolated from it are not without pharmacological interest? The French Pharmacopoeia does note that "plants with medicinal properties can also have dietary or culinary uses or also be used in the preparation of refreshing beverages".
These digressions are not aimed at arriving at a precise definition of the concept of medicinal plant: they simply lead to the question of the scope of the present text. First of
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all I shall cover drugs, in other words "starting materials from which pharmacists prepare medications *" (Littre, 1870). Here, the limits are clear: any plant or plant substance used to prepare a medication must be described. Many of these plants and substances are
.j the subject of a monograph in the 10th edition of the French Pharmacopoeia, and this
facilitated my selection. Other plants and substances, described in previous editions or in other national pharmacopoeias, will complete this first list.
What about "medicinal plants" (in the sense of the term accepted by the public at large)? For several years now, the fad for natural therapies has thrust these plants into the limelight. The fact that magistral preparations are no longer covered by the French national health care program or Social Security has not shaken the trust (not always justified) that some still have in them. Although the pace of publication of books on this
j topic has slowed down a little, bookstores continue to offer recipe books which—to cite
P. Delaveau once more—are like old furniture: "too many replicas and not enough authenticity". Need I add that the compilation of errors leads to gross inaccuracies? Under these conditions, it is fully justified to bring to students and professionals the essentials of the information currently available on these plants, even if this raises more questions than it provides answers.
So I shall treat these plants. Very well. But which plants? To select some and
\ eliminate others implicitly grants some value to the former and expresses a doubt about
the others! While reserving the right to critically review the activities attributed to a plant, my first step will be to adopt the selection—which it would have been better to debate— made by the experts nominated by the French Ministry of Health and of Social Affairs, a choice materialized in 1990 by a list of 174 drugs in the Annex of the French Herbal Remedies, Notice to Applicants for Marketing Authorization. The whole list? No. For several of the plants, there is nearly no scientific literature and for a small number, I have simply not found sufficient information to justify describing them. Overall, relevance does not appear to have been a priority...
In the field of plants as in other fields, it is constructive to look elsewhere: French practices, no matter how clever, are not the whole story. For the key drugs, the question is virtually superfluous: naturally occurring cardiac glycosides or anticholinergics are recognized everywhere, and at most there are marketing differences. For the other plants, one enters the fascinating field of the traditional medicines: one could devote an ¥ encyclopedia to this. Therefore I shall cite only a few examples, chosen mainly as a
function of the true pharmacological potential of the substances contained in the plants. To look elsewhere is also to look to the future: I will introduce a few examples of plants which may some day make a significant contribution to the therapeutic arsenal.
Of course, pharmacognosy has its prerequisites: I will assume that the reader is somewhat familiar with the language of botany, fluent in organic and analytical i chemistry, and has mastered the fundamentals of pharmacology. To assist the reader—
and as reflected by the third term in the title: Phytochemistry—I will grant a place ol honor to the presentation of the compounds involved in the activity of the plants. The knowledge of their structure and of their behavior is fundamental. It is the underpinning required to understand the nature and details of the quality control methods, to rationalize the extraction procedures, sometimes to envision the pharmacological activity, and often
contents
to predict the pharmacokinetics and bioavailability: it is also a prelude to synthesis, whether this is dictated by the need for freedom from the constraints of an erratic supply, or the desire to design more efficacious structural analogs, or, "like the reason to climb Mount Everest, by the challenge in itself (R. Mechoulam). These are challenges which constantly expand the horizons of organic chemistry. To study molecular structures is also to understand their origins. The knowledge of the biosynthetic mechanisms guides the hypotheses of the structure elucidator, and inspires the chemist to propose biomimetic syntheses. The more we add to knowledge, the more we are fascinated: a handful of elementary synthons react together to form edifices as complex as they are innumerable. Our awe and wonder before this synthetic cornucopia can only be greater given our virtually complete lack of knowledge of the biological role of these substances. For now, the biosynthetic origin suggests an outline in four parts: primary metabolism products, phenolics (acetates and shikimates), terpenes and steroids, and alkaloids.
Was it necessary to add a fifth part to this work? Was a general introduction really necessary? Yes, probably. But this was a tall challenge. What about covering the production and marketing of medicinal plants? Publication in a periodical is more appropriate than a book in a field which sometimes evolves rapidly, and not only as a function of climatic constraints (consider the market changes induced by political upheavals in eastern and southeastern Europe). What about detailing the origin of the plants? Comparing the harvesting of wild plants with cultivation? Other texts have dealt with this, so there is no need to recopy them. As far as the production and optimization techniques are concerned, they follow the general principles of any agricultural production (with one difference in that the active principle is the criterion by which to select a medicinal plant): the scientific literature on this topic is abundant.
The question which remains (among others) is that of plant quality control. Not so many years ago, the morphologic and anatomical examination of the drugs, together with a few color reactions, was often the essential element of the assay. Back then, it was justified to refer the reader to specialized texts, or to introduce basic concepts in plant anatomy. Today, the chromatographic techniques (TLC, GC, HPLC) permit rapid qualitative and quantitative quality control, and the most sophisticated techniques allow the detection of the most subtle falsifications (for example, NMR of isotopomers). Under these conditions, the only reasonable solution is to refer the reader to analytical chemistry books and periodicals*... and add reminders that before implementing complicated methods, verifying the identity of a sample (morphology, microscopy) is a common sense step which may save time and... money!
Pharmacognosy, Phytochemistry, Medicinal Plants. I shall attempt to provide information to the reader in these specialized fields. In addition, for the reader who wants more, I shall list selected references. To prepare this text, I reviewed more than three thousand references, therefore a selection was in order. This choice, somewhat arbitrary, was made in favor of books, reviews of general interest, more recent and more specialized articles as long as they provided a sufficient introductory or retrospective bibliography. Hopefully, these elements will enable the reader to rapidly and efficiently build a database on the topic of interest [...].
Foreword..................................................................................................................................v
Introduction to the 2nd edition...............................................................................................vii
Contents...................................................................................................................................xi
Abbreviations.........................................................................................................................xii
Part 1 Compounds of Primary Metabolism.......................................................................1
Carbohydrates..................................................................................................................3
Introduction, 3 . Monosaccharides, 7. Oligosaccharides, 27. Polysaccharides, 35 .
from microorganisms and fungi, 39 . Algae Polysaccharides, 45 . Homogeneous
Polysaccharides, 65. Heterogeneous Polysaccharides, 81 Lipids...........................................................................................................................123
Plant Lipids: Generalities, 123 . Vegetable oils, 137. Alkyne derivatives, 169 Amino Acids and Peptides, Proteins and Enzymes.....................................................183
Amino Acids Which are not Constituents of Proteins, 185 . Cyanogenic Glycosides,
189. Glucosinolates, 199. Betalains, 213. Protein Sweeteners, 215. Lectins, 217.
Enzymes, 221
Part 2 Phenolics. Shikimates, Acetates............................................................................225
Shikimates - Phenylpropane Derivative-containing Drugs.........................................233
Generalities, 227. Phenols and Phenolic Acids, 239 . Coumarins, 263 . Lignans, Neolignans, 279. Drugs Containing Phenylpropane Chain Elongation Derivatives, 295. Flavonoids, 309 . Anthocyanins, 355 . Tannins, 369
Polyketides...................................................................................................................405
Quinones, 409. Orcinols and Phloroglucinols, (Cannabis, 445)
Part 3 Terpenoids and Steroids........................................................................................461
Introduction 463 . Monoterpenes, 473 . Sesquiterpenes, 479 . Essential Oils, 483 . Oleoresins, 579. Iridoids, 589 . Pyrethrins, 613 . Sesquiterpenoid Lactones, 619 . Diterpenes, 637. Triterpenes, 661 . Saponins, 671 . Cardiac Glycosides, 721 . Other Steroids, Other Triterpenes, 751. Carotenoids, 769
Part 4 Alkaloids.................................................................................................................781
Generalities..................................................................................................................783
Alkaloids Derived from Ornithine and Lysine............................................................801
Tropane Alkaloids, 805 . Pyrrolizidine Alkaloids, 833 . Quinolizidine Alkaloids 849. Indolizidine Alkaloids, 855. Piperidine Alkaloids, 859
Alkaloids derived from Nicotinic Acid.......................................................................86"
Alkaloids Derived from Phenylalanine and Tyrosine.................................................87-5
Phenethylamines, 879. Simple Isoquinolines, 887. Benzyltetrahydroisoquinolines, 88'j (Curares, 899; Morphinan Alkaloids, 925) . Phenethylisoquinolines, 949 Amaryllidaceae Alkaloids, 957. Monoterpenoid Isoquinolines, 961
Alkaloids Derived from Tryptophan...........................................................................96%
Tryptamines, ß-Carboline Alkaloids, 969 . Esere, 975 . Ergoline Alkaloids, 97^ (Ergot of Rye, 983) . Monoterpenoid Indole Alkaloids, 999 (Apocynaceae, 1016 Cinchonas, 1029)
Alkaloids Derived from Anthranilic Acid.................................................................104^
Alkaloids Derived from Histidine.............................................................................104r
Terpenoid Alkaloids..................................................................................................104^
Alkaloids with Miscellaneous Structures..................................................................106'*-
Purine Bases..............................................................................................................107
ABBREVIATIONS GC-MS
GPP
ADI acceptable daily intake GSH
ADP adenosine diphosphate \ HDL
AFNOR Association Frangaise de NORmalisation HFCS
= French Association for Standardization HHDP
AIDS acquired immune deficiency syndrome HIV
ALAT alanine aminotransferase HPLC
ANDEM Agence nationale pour ie developpement de I' evaluation medicale ie-
= French national agency for the development of medical evaluation IM
AOCS American Oil Chemists Society INN
APRIA Association pour la Promotion Industrie Agriculture INRA
AST aspartate aminotransferase IP
ATP adenosine triphosphate IPP
auct. auctorum (of authors) IR
A-V atrium-ventricle ISO
AZT 3'-azido-3'-deoxythymidine IUD
B.C. before Christ IV
BHT butylated hydroxytoluene LD50
BHP British Herbal Pharmacopoeia i LDL
BP British Pharmacopoeia LH
BP boiling point LPP
CNRS Centre National de la Recherche Scientifique LSD
= French National Research Council MAM
CNS central nervous system MAO
CoA coenzyme A MMDA
CSP Code de la Sante Publique = French Public Health Code NADP(H)
cv. cultivar ', NF
DAB Deutsches Arzneibuch = German Pharmacopoeia NMR
DCCC droplet counter current chromatography NSAID
DE dextrose equivalent OSB
DE degree of esterification PAF
DHHDP dehydrohexahydroxydiphenic acid PEG
DM degree of methylation PEP
DMAPP dimethylallylpyrophosphate P-P-
DNA deoxyribonucleic acid PPm
ECG electrocardiogram PUVA
EEG electroencephalogram RNA
e.g. exempli gratia (for example) SC
et al. et allii (and other authors) SF.TTA
Eur. id. code European identification code for food colorings and additives
Eur. Ph. European Pharmacopoeia SP-
ex after spp.
FAB-MS fast atom bombardment-mass spectrometry ; subsp.
FAO Food and Agriculture Organization /'>,-     a.    ,./  . „,.. /,,,     ,/ THC
FDA Food and Drug Administration »       (J 1
FPP farnesyl pyrophosphate l> (- ■-i-'i i£ •- c,a., ci-yomtUtjr-,/>K-fm"v^\> TPA
French Expl. Note French Explanatory Note .„,-/>/,,   , „ .'. ' UDP
Br PI-, P«»n/-1i Dk.,m.m„™™ I TV
gas chromatography-mass spectrometry
geranyl pyrophosphate
reduced glutathione
high density lipoproteins
high fructose corn syrup
hexahydroxydiphenic acid
human immunodeficiency virus
high pressure liquid chromatography
id est (that is)
intramuscular (route)
international non-proprietary name
Institut National de la Recherche Agronomique
intraperitoneal (route)
isopentenyl pyrophosphate
infra-red
International Organization for Standardization term
intra-uterine device
intravenous (route)
lethal dose 50
low density lipoproteins
luteinizing hormone
linalyl pyrophosphate
lysergic satire didthylamide
methylazoxymefhanol
monoamine oxidase
3-methoxy-4,5-methylenedioxyamphetamine nicotinamide dinucleotide phosphate (reduced) Norme Frangaise = French standard nuclear magnetic resonance non-steroidal anti-inflammatory drug
o-succinylbenzoic acid = 4-(2'-carboxyphenyl)-4-oxobutanoic acid
platelet activating factor
polyethylene glycol
phosphoenolpyruvate
pro parte (in part)
part per million
psoralen + 320-400 nm UVA radiation treatment ribonucleic acid subcutaneous (route)
Societe d'Exploitation Industrielle des Tabacs et Allumettes = French manufacturer of tobacco products and matches species
various species in the genus
subspecies
tetrahydrocannabinol
thin-layer chromatography
12-O-tetradecanoylphorbol-13-acetate
uridine diphosphate