ARTEMISIA Medicinal and Aromatic Plants - Industrial Profiles Individual volumes in this series provide both industry and academia with in-depth coverage of one major medicinal or aromatic plant of industrial importance. Edited by Dr Roland Hardman Volume 1 Valerian edited by Peter J. Houghton Volume 2 Perilla edited by He-Ci Yu, Kenichi Kosuna and Megumi Haga Volume 3 POPPY edited by Jeno Bernith Volume 4 Cannabis edited by David T. Brown Volume 5 Neem H.S. Puri Volume 6 Ergot edited by Vladimir Kren and Ladislav Cvak Volume 7 Caraway edited by fiva NCmeth Volume 8 Saffron edited by Moshe Negbi Volume 9 Tea Tree edited by Ian Southwall Volume 10 Basil edited by Hiltunen and Holm Volume 11 Fenugreek edited by Georgios Petropoulos Volume 12 Ginkgo biloba edited by Teris A. Van Beek Volume 13 Black Pepper Piper Nigrum edited by P.N. Ravindran Volume 14 Sage edited by Spriadon E. Kintzios Volume 15 Ginseng edited by W.E. Court Volume 16 Mistletoe - The Genus Viscum edited by A. Biissing Volume 17 Tea - Bioactivity and Therapeutic Potential edited by Yong-su Zhen Volume 18 Artemisia edited by Colin W. Wright ARTEMISIA Edited by Colin W. Wright The School of Pharmacy University of Bradford UK London and New York First published 2002 by Taylor & Francis 11 New Fetter Lane, London EC4P 4EE Simultaneously published in the USA and Canada by Taylor & Francis Inc, 29 West 35th Street, New York, NY 10001 Taylor & Francis is an imprint of the Taylor & Francis Group O 2002 Taylor & Francis All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Every effort has been made to ensure that the advice and information in this book is true and accurate at the time of going to press. However, neither the publisher nor the authors can accept any legal responsibility or liability for any errors or omissions that may be made. In the case of drug administration, any medical procedure or the use of technical equipment mentioned within this book, you are strongly advised to consult the manufacturer's guidelines. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book has been requested ISBN 0-415-27212-2 CONTENTS Preface to the series vii Preface ix Contributors xi 1. Introduction to the Genus 1 Marco Mucciarelli and Massimo Maffei 2. Analysis and Quality Control of Commerical Artemisia Species H.J. Woerdenbag and N. Pras 3. Artemisia absinthium Stanley G. Deans and Alan I. Kennedy 4. Artemisia dracunculus Stanley G. Deans and Elisabeth ].M. Simpson 5. Artemisia herba-alba Peter Proksch 6. Ethnobothany, Phytochemistry and BiologicalPPharmacological Activities of Artemisia ludoviciana ssp. Mexicana (Estafiate) Michael Heinrich 7. Artemisia pallens R. N. Kulkarni 8. Artemisia vulgaris Peter A. Linley 9. Artemisia Species in Traditional Chinese Medicine and the Discovery of Artemisinin Hongwen Yu and Shouming Zhong 10. Cultivation of Artemisia annua L. John C. Laughlin, G.N. Heazlewood and B.M. Beattie 11. Variation and Heritability of Artemisinin Content in Artemisia annua L. Nicholas Delabays, Charly Darbellay and Nicole Galland 12. Phytochemistry of Artemisia annua and the Development of Artemisinin-Derived Antimalarial Agents Rajendra S. Bhakuni, Dharam C. Jain and Ram P. Sharma vi CONTENTS 13. The Mode of Action of Artemisinin and its Derivatives Colin W; Wright and David C. Warhurst 14. The Clinical Use of Artemisinin and its Derivatives in the Treatment 289 of Malaria Polrat Wilairatana and Sornchai Looareesuwan 15. Regulation of the Quality and Use of Artemisinin and its Derivatives 309 Penelope Phillips-Howard Index 323 PREFACE TO THE SERIES There is increasing interest in industry, academia and the health sciences in medici- nal and aromatic plants. In passing from plant production to the eventual product used by the public, many sciences are involved. This series brings together informa- tion which is currently scattered through an ever increasing number of journals. Each volume gives an in-depth look at one plant genus, about which an area special- ist has assembled information ranging from the production of the plant to market trends and quality control. Many industries are involved such as forestry, agriculture, chemical, food, flavour, beverage, pharmaceutical, cosmetic and fragrance. The plant raw materials are roots, rhizomes, bulbs, leaves, stems, barks, wood, flowers, fruits and seeds. These yield gums, resins, essential (volatile) oils, fixed oils, waxes, juices, extracts and spices for medicinal and aromatic purposes. All these commodities are traded world- wide. A dealer's market report for an item may say "Drought in the country of origin has forced up prices". Natural products do not mean safe products and account of this has to be taken by the above industries, which are subject to regulation. For example, a number of plants which are approved for use in medicine must not be used in cosmetic products. The assessment of "safe" to use starts with the harvested plant material which has to comply with an official monograph. This may require absence of, or prescribed limits of, radioactive material, heavy metals, aflatoxin, pesticide residue, as well as the required level of active principle. This analytical control is costly and tends to exclude small batches of plant material. Large scale contracted mechanised cultivation with designated seed or plantlets is now preferable. Today, plant selection is not only for the yield of active principle, but for the plant's ability to overcome disease, climatic stress and the hazards caused by mankind. Such methods as in vitro fertilisation, meristem cultures, and somatic embryogenesis are used. The transfer of sections of DNA is giving rise to controversy in the case of some end-uses of the plant material. Some suppliers of plant raw material are now able to certify that they are supplying organically-farmed medicinal plants, herbs and spices. The Economic Union directive (CVOIEU No 2092191) details the specifications for the obligatory quality controls to be carried out at all stages of production and processing of organic products. Fascinating plant folklore and ethnopharmacology leads to medicinal potential. Examples are the muscle relaxants based on the arrow poison, curare, from species of Chondrodendron, and the antimalarials derived from species of Cinchona and Artemisia. The methods of detection of pharmacological activity have become increasingly reliable and specific, frequently involving enzymes in bioassays and avoiding the use of laboratory animals. By using bioassay linked fractionation of crude plant juices or extracts, compounds can be specifically targeted which, for vii ... v111 PREFACE TO THE SERIES example, inhibit blood platelet aggregation, or have antitumour, or antiviral, or any other required activity. With the assistance of robotic devices, all the members of a genus may be readily screened. However, the plant material must be fully authenti- cated by a specialist. The medicinal traditions of ancient civilisations such as those of China and India have a large armamentarium of plants in their pharmacopoeias which are used throughout South East Asia. A similar situation exists in Africa and South America. Thus, a very high percentage of the World's population relies on medicinal and aro- matic plants for their medicine. Western medicine is also responding. Already in Germany all medical practitioners have to pass an examination in phytotherapy before being allowed to practise. It is noticeable that throughout Europe and the USA, medical, pharmacy and health related schools are increasingly offering training in phytotherapy. Multinational pharmaceutical companies have become less enamoured of the single compound magic bullet cure. The high costs of such ventures and the endless competition from me too compounds from rival companies often discourage the attempt. Independent phytomedicine companies have been very strong in Germany. However, by the end of 1995, eleven (almost all) had been acquired by the multina- tional pharmaceutical firms, acknowledging the lay public's growing demand for phytomedicines in the Western World. The business of dietary supplement in the Western World has expanded from the Health Store to the pharmacy. Alternative medicine includes plant based products. Appropriate measures to ensure the quality, safety and efficacy of these either already exist or are being answered by greater legislative control by such bodies as the Food and Drug Administration of the USA and the recently created European Agency for the Evaluation of Medicinal Products, based in London. In the USA, the Dietary Supplement and Health Education Act of 1994 recognised the class of phytotherapeutic agents derived from medicinal and aromatic plants. Furthermore, under public pressure, the US Congress set up an Office of Alternative Medicine and this office in 1994 assisted the filing of several Investigational New Drug (IND) applications, required for clinical trials of some Chinese herbal preparations. The significance of these applications was that each Chinese prepara- tion involved several plants and yet was handled as a single IND. A demonstration of the contribution to efficacy, of each ingredient of each plant, was not required. This was a major step forward towards more sensible regulations in regard to phytomedicines. My thanks are due to the staff of Harwood Academic Publishers who have made this series possible and especially to the volume editors and their chapter contribu- tors for the authoritative information. Roland Hardman PREFACE The genus Artemisia comprises some 400 species including a number which are important for their medicinal properties. Chief among these is A. annua, the source of the antimalarial drug artemisinin. According to a legend, in the 5th century B.C. the city of Selinus in Sicily was delivered from a plague thought to be malaria and this event was commemorated by the minting of a coin. The obverse of the Selinus coin (figure la), shows a chariot driven by Artemis representing the women of the city who suffered severely from the fever accompanied by her brother Apollo, who, as the god of healing is firing arrows to destroy the plague (McGregor, 1996). The reverse of the Selinus coin (figure lb), also includes Artemis and Apollo represented as a cockerel and a bull respectively while the central figure is the river god Selinus representing Empedocles, a student of Pythagoras who is reputed to have delivered the city from the fever by cleansing the surrounding marshes. Although this interpre- tation of the reverse of the coin is not generally accepted by modern scholars, the association of Artemis with Artemisia (= plant sacred to Artemis) and with the deliv- erance of Selinus from malaria is fascinating. The herb A. annua has been used in China for thousands of years to treat fevers and the isolation of artemisinin in 1971, a highly potent antimalarial agent has proved to be of considerable importance as malaria parasites are increasingly devel- oping resistance to established antimalarial drugs. Artemisinin is unusual in that the molecule contains a peroxide group which is rarely found in nature although another example is the explosive compound ascaridole, the major constituent of la Figure 1 The Selinus coin. The British Museum
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