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1439807132 herbal

  1. 1. © 2011 by Taylor & Francis Group, LLC
  2. 2. © 2011 by Taylor & Francis Group, LLC
  3. 3. OXIDATIVE STRESS AND DISEASE Series Editors Lester Packer, Ph.D. Enrique Cadenas, M.D., Ph.D. University of Southern California School of Pharmacy Los Angeles, California 1. Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases, edited by Luc Montagnier, René Olivier, and Catherine Pasquier 2. Understanding the Process of Aging: The Roles of Mitochondria, Free Radicals, and Antioxidants, edited by Enrique Cadenas and Lester Packer 3. Redox Regulation of Cell Signaling and Its Clinical Application, edited by Lester Packer and Junji Yodoi 4. Antioxidants in Diabetes Management, edited by Lester Packer, Peter Rösen, Hans J. Tritschler, George L. King, and Angelo Azzi 5. Free Radicals in Brain Pathophysiology, edited by Giuseppe Poli, Enrique Cadenas, and Lester Packer 6. Nutraceuticals in Health and Disease Prevention, edited by Klaus Krämer, Peter-Paul Hoppe, and Lester Packer 7. Environmental Stressors in Health and Disease, edited by Jürgen Fuchs and Lester Packer 8. Handbook of Antioxidants: Second Edition, Revised and Expanded, edited by Enrique Cadenas and Lester Packer 9. Flavonoids in Health and Disease: Second Edition, Revised and Expanded, edited by Catherine A. Rice-Evans and Lester Packer 10. Redox–Genome Interactions in Health and Disease, edited by Jürgen Fuchs, Maurizio Podda, and Lester Packer 11. Thiamine: Catalytic Mechanisms in Normal and Disease States, edited by Frank Jordan and Mulchand S. Patel 12. Phytochemicals in Health and Disease, edited by Yongping Bao and Roger Fenwick 13. Carotenoids in Health and Disease, edited by Norman I. Krinsky, Susan T. Mayne, and Helmut Sies 14. Herbal and Traditional Medicine: Molecular Aspects of Health, edited by Lester Packer, Choon Nam Ong, and Barry Halliwell© 2011 by Taylor & Francis Group, LLC
  4. 4. 15. Nutrients and Cell Signaling, edited by Janos Zempleni and Krishnamurti Dakshinamurti 16. Mitochondria in Health and Disease, edited by Carolyn D. Berdanier 17. Nutrigenomics, edited by Gerald Rimbach, Jürgen Fuchs, and Lester Packer 18. Oxidative Stress, Inflammation, and Health, edited by Young-Joon Surh and Lester Packer 19. Nitric Oxide, Cell Signaling, and Gene Expression, edited by Santiago Lamas and Enrique Cadenas 20. Resveratrol in Health and Disease, edited by Bharat B. Aggarwal and Shishir Shishodia 21. Oxidative Stress and Age-Related Neurodegeneration, edited by Yuan Luo and Lester Packer 22. Molecular Interventions in Lifestyle-Related Diseases, edited by Midori Hiramatsu, Toshikazu Yoshikawa, and Lester Packer 23. Oxidative Stress and Inflammatory Mechanisms in Obesity, Diabetes, and the Metabolic Syndrome, edited by Lester Packer and Helmut Sies 24. Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects, edited by Mulchand S. Patel and Lester Packer 25. Dietary Modulation of Cell Signaling Pathways, edited by Young-Joon Surh, Zigang Dong, Enrique Cadenas, and Lester Packer 26. Micronutrients and Brain Health, edited by Lester Packer, Helmut Sies, Manfred Eggersdorfer, and Enrique Cadenas 27. Adipose Tissue and Inflammation, edited by Atif B. Awad and Peter G. Bradford© 2011 by Taylor & Francis Group, LLC
  5. 5. © 2011 by Taylor & Francis Group, LLC
  6. 6. CRC PressTaylor & Francis Group6000 Broken Sound Parkway NW, Suite 300Boca Raton, FL 33487-2742© 2011 by Taylor and Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa businessNo claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 9 8 7 6 5 4 3 2 1International Standard Book Number: 978-1-4398-0713-2 (Hardback) is book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made topublish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materialsor the consequences of their use. e authors and publishers have attempted to trace the copyright holders of all material repro -duced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If anycopyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in anyform by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming,and recording, or in any information storage or retrieval system, without written permission from the publishers.For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copy-right.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have beengranted a photocopy license by the CCC, a separate system of payment has been arranged.Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identifica-tion and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Herbal medicine : biomolecular and clinical aspects / editors, Iris F.F. Benzie and Sissi Wachtel-Galor. -- 2nd ed. p. ; cm. -- (Oxidative stress and disease ; 28) Rev. ed. of: Herbal and traditional medicine / edited by Lester Packer, Choon Nam Ong, Barry Halliwell. c2004. Includes bibliographical references and index. Summary: “Responding to the increased popularity of herbal medicines and other forms of complementary or alternative medicine in countries around the world, this reference reviews and evaluates various safety, toxicity, and quality-control issues related to the use of traditional and herbal products for health maintenance and disease prevention and treatment. With over 3,550 current references, the book highlights the role of herbal medicine in national health care while providing case studies of widely used herbal remedies and their effects on human health and wellness and the need for the design and performance of methodologically sound clinical trials for the plethora of herbal medicines”--Provided by publisher. ISBN 978-1-4398-0713-2 (hardcover : alk. paper) 1. Herbs-- erapeutic use. 2. Herbs --Molecular aspects. 3. Traditional medicine. I. Benzie, Iris F. F. II. Wachtel-Galor, Sissi. III. Herbal and traditional medicine. IV. Series: Oxidative stress and disease ; 28. [DNLM: 1. Phytotherapy. 2. Plants, Medicinal. W1 OX626 v.28 2010 / WB 925] RM666.H33H458 2010 615’.321--dc22 2010042248Visit the Taylor & Francis Web site athttp://www.taylorandfrancis.comand the CRC Press Web site athttp://www.crcpress.com © 2011 by Taylor & Francis Group, LLC
  7. 7. ContentsSeries Preface ....................................................................................................................................ixForeword ...........................................................................................................................................xiPreface............................................................................................................................................ xiiiEditors .............................................................................................................................................. xvContributors ...................................................................................................................................xviiChapter 1 Herbal Medicine: An Introduction to Its History, Usage, Regulation, Current Trends, and Research Needs .......................................................1 Sissi Wachtel-Galor and Iris F. F. BenzieChapter 2 Antioxidants in Herbs and Spices: Roles in Oxidative Stress and Redox Signaling .................................................................................................. 11 Ingvild Paur, Monica H. Carlsen, Bente Lise Halvorsen, and Rune BlomhoffChapter 3 Evaluation of the Nutritional and Metabolic Effects of Aloe vera ............................. 37 Meika Foster, Duncan Hunter, and Samir SammanChapter 4 Bilberry (Vaccinium myrtillus L.) .............................................................................. 55 Wing-kwan Chu, Sabrina C. M. Cheung, Roxanna A. W. Lau, and Iris F. F. BenzieChapter 5 Cordyceps as an Herbal Drug .................................................................................... 73 Bao-qin Lin and Shao-ping LiChapter 6 Cranberry ................................................................................................................. 107 Catherine C. Neto and Joe A. VinsonChapter 7 The Amazing and Mighty Ginger ............................................................................ 131 Ann M. Bode and Zigang DongChapter 8 Biological Activities of Ginseng and Its Application to Human Health .................. 157 Jae Joon Wee, Kyeong Mee Park, and An-Sik ChungChapter 9 Ganoderma lucidum (Lingzhi or Reishi): A Medicinal Mushroom........................ 175 Sissi Wachtel-Galor, John Yuen, John A. Buswell, and Iris F. F. BenzieChapter 10 Pomegranate Ellagitannins ...................................................................................... 201 David Heber vii© 2011 by Taylor & Francis Group, LLC
  8. 8. viii ContentsChapter 11 Medical Attributes of St. John’s Wort (Hypericum perforatum).............................. 211 Kenneth M. Klemow, Andrew Bartlow, Justin Crawford, Neil Kocher, Jay Shah, and Michael RitsickChapter 12 Health Benefits of Tea .............................................................................................. 239 Mauro Serafini, Daniele Del Rio, Yao Denis N’Dri, Saverio Bettuzzi, and Ilaria PelusoChapter 13 Turmeric, the Golden Spice: From Traditional Medicine to Modern Medicine ...... 263 Sahdeo Prasad and Bharat B. AggarwalChapter 14 Biomolecular and Clinical Aspects of Chinese Wolfberry ..................................... 289 Peter Bucheli, Qiutao Gao, Robert Redgwell, Karine Vidal, Junkuan Wang, and Weiguo ZhangChapter 15 Botanical Phenolics and Neurodegeneration ........................................................... 315 Albert Y. Sun, Qun Wang, Agnes Simonyi, and Grace Y. SunChapter 16 Cardiovascular Disease ............................................................................................ 333 Richard Walden and Brian TomlinsonChapter 17 Herbs and Spices in Cancer Prevention and Treatment ........................................... 361 Christine M. Kaefer and John A. MilnerChapter 18 Herbal Treatment for Dermatologic Disorders......................................................... 383 Philip D. ShenefeltChapter 19 Diabetes and Herbal (Botanical) Medicine ..............................................................405 William T. Cefalu, Jaqueline M. Stephens, and David M. RibnickyChapter 20 Bioactive Components in Herbal Medicine: Experimental Approaches ................. 419 Foo-tim Chau, Kwok-pui Fung, Chi-man Koon, Kit-man Lau, Shui-yin Wei, and Ping-chung LeungChapter 21 Ethics of Using Herbal Medicine as Primary or Adjunct Treatment and Issues of Drug–Herb Interaction ....................................................................... 439 Lauren Girard and Sunita VohraChapter 22 Integration of Herbal Medicine into Evidence-Based Clinical Practice: Current Status and Issues ......................................................................................... 453 Anthony Lin Zhang, Charlie Changli Xue, and Harry H. S. Fong© 2011 by Taylor & Francis Group, LLC
  9. 9. Series PrefaceDuring evolution, oxygen—itself a free radical—was chosen as the terminal electron acceptorfor respiration; hence, the formation of oxygen-derived free radicals is a consequence of aerobicmetabolism. These oxygen-derived radicals are involved in oxidative damage to cell componentsinherent in several pathophysiological situations. Conversely, cells convene antioxidant mecha-nisms to counteract the effects of oxidants in either a highly specific manner (e.g., by superoxidedismutases) or a less-specific manner (e.g., through small molecules such as glutathione, vitamin E,and vitamin C). Oxidative stress, as defined classically, entails an imbalance between oxidants andantioxidants. However, the same free radicals that are generated during oxidative stress are pro-duced during normal metabolism and, as a corollary, are involved in both human health and diseaseby virtue of their involvement in the regulation of signal transduction and gene expression, activa-tion of receptors and nuclear transcription factors, antimicrobial and cytotoxic actions of immunesystem cells, and aging and age-related degenerative diseases. In recent years, research disciplines focusing on oxidative stress have increased our knowledgeof the importance of the cell redox status and the recognition of oxidative stress as a process withimplications for many pathophysiological states. From this multi- and interdisciplinary interest inoxidative stress emerges a concept that attests the vast consequences of the complex and dynamicinterplay of oxidants and antioxidants in cellular and tissue settings. Consequently, our view ofoxidative stress is both growing in scope and following new directions. Likewise, the term “reactiveoxygen species,” adopted at some stage to highlight nonradical/radical oxidants, now fails to reflectthe rich variety of other species in free-radical biology and medicine, encompassing nitrogen-,sulfur-, oxygen-, and carbon-centered radicals. These reactive species are involved in the redoxregulation of cell functions and, as a corollary, oxidative stress is increasingly viewed as a majorupstream component in cell-signaling cascades involved in inflammatory responses, stimulation ofcell adhesion molecules, and chemoattractant production and as an early component of age-relatedneurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, andamyotrophic lateral sclerosis. Hydrogen peroxide is probably the most important redox-signalingmolecule that, among others, can activate nuclear factor κB (NF-κB), NF-E2 related factor 2 (Nrf2),and other universal transcription factors, and that is involved in the redox regulation of insulin andmitogen-activated protein kinase (MAPK) signaling. These pleiotropic effects of hydrogen peroxideare largely accounted for by changes in the thiol/disulfide status of a cell, an important determi-nant of the cell’s redox status with clear involvement in adaptation, proliferation, differentiation,apoptosis, and necrosis. The identification of oxidants in the regulation of redox cell signaling and gene expression is asignificant breakthrough in the field of oxidative stress. The classical definition of oxidative stressas an imbalance between the production of oxidants and the occurrence of antioxidant defenses nowseems to provide a limited depiction of oxidative stress, although it emphasizes the significanceof cell redox status. Because individual signaling and control events occur through discrete redoxpathways rather than through global balances, a new definition of oxidative stress was advancedby Dean P. Jones as a disruption of redox signaling and control that recognizes the occurrence ofcompartmentalized cellular redox circuits. These concepts are anticipated to serve as platformsfor the development of tissue-specific therapeutics tailored to discrete, compartmentalized redoxcircuits. This, in essence, dictates the principles of drug development–guided knowledge of themechanisms of oxidative stress. Hence, successful interventions will take advantage of new knowl-edge of compartmentalized redox control and free-radical scavenging. ix© 2011 by Taylor & Francis Group, LLC
  10. 10. x Series Preface Virtually all diseases examined thus far involve free radicals. Although in most cases free radicalsare secondary to the disease process, in some instances causality is established for free radicals.Thus, there is a delicate balance between oxidants and antioxidants in health, and disease clearlyassociates with and in at least some cases is caused by loss of such balance. Their proper balanceis essential for ensuring healthy aging. Compelling support for the involvement of free radicals indisease development originates from epidemiological studies showing that enhanced antioxidantstatus is associated with reduced risk of several diseases. Of great significance is the role played bymicronutrients in modulation of cell signaling. This establishes a strong linking of diet, health, anddisease centered on the abilities of micronutrients to regulate redox cell signaling and modify geneexpression. Oxidative stress is an underlying factor in health and disease. In this series of books, the impor-tance of oxidative stress and diseases associated with organ systems is highlighted by exploring thescientific evidence and clinical applications of this knowledge. This series is intended for research-ers in basic biomedical sciences and for clinicians. The potential of such knowledge in facilitatinghealthy aging and disease prevention warrants further knowledge about how oxidants and anti-oxidants modulate cell and tissue functions. Lester Packer Enrique Cadenas© 2011 by Taylor & Francis Group, LLC
  11. 11. ForewordThis book, Herbal Medicine: Biomolecular and Clinical Aspects, Second Edition, edited by IrisF.  F. Benzie and Sissi Wachtel-Galor, reports updated information on some of the most widelyinvestigated traditional and herbal medicines, and establishes continuity with a previous book inthis series, Herbal and Traditional Medicine: Molecular Aspects of Health, edited by Lester Packer,Choon Nam Ong, and Barry Halliwell. This new edition is timely because there is unprecedentedinterest in understanding the molecular basis of the biological activity of traditional remedies—manyof which are derived from plants and herbs (phytomedicines) or from products that are availableas herbal supplements—and because such herbal supplements enjoy much popularity throughoutthe world. This popularity is the result of the recognition of alternative and complementary formsof medicine by governmental and nongovernmental changes; for example, the U.S. Public HealthService and the National Institutes of Health established the Office of Dietary Supplement and theNational Center for Complementary and Alternative Medicine (NCCAM), which seek to verifyhealth claims. Western and traditional medicines hold great promise once research and medicalpractice are appropriately coordinated. The number of herbal remedies recognized to date is staggering, and an extensive literature hasdocumented their existence and reported on their beneficial effects toward health and well-being,disease prevention, and disease treatment. Herbal Medicine: Biomolecular and Clinical Aspects,Second Edition selects some of the best-case scenarios and widely used and known herbal remediesto report on their effects on health in light of the current knowledge concerning their basic biologi-cal mechanisms of action. Coeditors Iris F. F. Benzie and Sissi Wachtel-Galor must be congratulatedfor their excellent effort. Lester Packer Enrique Cadenas xi© 2011 by Taylor & Francis Group, LLC
  12. 12. PrefaceHerbal medicine has been used throughout history and within every culture to prevent and treatdiseases. In any individual culture, the materials used were those that were available within thegeographical location and addressed local health concerns. With immigration and trade, culturaltraditions were exposed and often overwhelmed by modern scientific concepts and medical prac-tices. However, the mix and movement of cultures that began only fairly recently, along with mod-ern transportation, storage, and communication tools, brought an enormous increase in the generalavailability of herbs from different cultures and geographical areas. In a different culture, an herbwould often be used for its appearance, coloring, or taste rather than for any perceived health bene-fits. Indeed, some of the herbs discussed in this book, such as curcumin, garlic, and cumin, are oftenreferred to as “spices,” or regarded as simple, if somewhat exotic, ingredients of foods from farawaylands. Nonetheless, the long history and powerful reputation of many types of herbs, spices, andfungi are impressive. In this time of increasing need for effective, affordable health promotion andtreatment strategies for our aging populations and growing problems posed by new and antibiotic-resistant microbes, the history and reputation of herbal medicines must be examined in a rigorousand scientific way so that their biomolecular effects, if confirmed, can be translated into clini-cal benefit. Because of the strong associations among oxidative stress, aging, and disease, there isincreasing interest in the biomolecular effects of herbs, which may be related to antioxidant action. By biomolecular effects, we mean the measurable or observable changes (biomarkers) that occurin cells, animals, and human subjects, healthy or otherwise, under controlled conditions of treat-ment with an herb. Biomarkers reflect organ, cell, and organelle function or damage, and homeo-static control mechanisms. These are not limited to the genomic level, although this is a level onwhich interest and insight are growing, but include a wide range and variety of biochemical and“metabolomic” biomarkers, such as hemoglobin A1c (HbA1c) for glycemic control, plasma high-sensitivity C-reactive protein (hsCRP) for inflammation, the number and function of immune cells,plasma cholesterol and triglycerides for lipid balance, and biomarkers of liver and renal function. Inaddition, herbs contain many compounds with powerful antioxidant properties, and herb-inducedchanges in biomarkers that assess antioxidant status and oxidative stress, such as plasma ascorbicacid and lipid peroxides, antioxidant enzyme activity/induction, and oxidation-induced damage toDNA, are of interest in relation to the mechanisms of herbal protection. In cell-culture studies,direct cytotoxicity and protection, gene expression, protein synthesis, and transport mechanismscan be measured, and the morphology and growth of cells can be assessed. In animal studies, tumoroccurrence and size can be examined. By clinical effects, we mean the outcome of the biomoleculareffects in terms of human health preservation and restoration. This book focuses on presenting the current scientific evidence of biomolecular effects of selectedherbs in relation to clinical outcomes and therapy for promotion of human health. Although theterms “herb” and “herbal medicine” in traditional medicine are sometimes used in relation to ani-mal or insect parts, our use of the term is limited to plants and fungi. Also, whereas many herbalmedicines are made by mixing different herbs, the focus in this book is on single herbs. The herbsselected cover a wide range and include flowering herbs, leaves, and leaf exudate (St. John’s wort,tea, aloe vera), fruits and berries (pomegranate, cranberry, wolfberry, bilberry), roots and rhizomes(ginseng, ginger, and turmeric), and fungi (lingzhi and cordyceps). There is a chapter that focuseson the antioxidant properties and effects of herbs (Chapter 2), and other chapters shift the focusinto the clinical arena and the use of herbs in relation to cardiovascular disease, cancer, diabetes,skin disorders, and neurodegenerative disease. The ethics of using herbal medicine and its integra-tion into modern, evidence-based medicine are also discussed. Finally, the use of new technologies xiii© 2011 by Taylor & Francis Group, LLC
  13. 13. xiv Prefaceof mass spectrometry and chemometric fingerprinting in the authentication of herbs is presented.These technologies will bring a previously unknown level of quality control to the production ofherbal extracts. Currently, many commercially available herbal products are uncharacterized andof questionable quality or content. The composition of natural products such as herbs can varygreatly with season, growing conditions, preparation, and storage. However, there is also adultera-tion, contamination, and misidentification of herbs and herbal products. Improved quality controltechniques and processes for the identification of herbs and the establishment of characteristicchemical “fingerprints” for herbs and herbal medicines are badly needed. For well-designed clinical trials to be performed and for them to generate valid findings, herbsthat are safe and of consistent quality and composition are needed. For findings to be valid in termsof human health and disease, a wide and diverse range of biomarkers needs to be investigated incontrolled human trials. To translate the positive findings of science-based studies and clinical trialsinto action for health promotion, consumers need to be supplied with the same herbal products asthe ones shown to have these effects. Quality, consistency, and control are needed across all aspectsof production, testing, and promotion of herbal medicines; further, at the heart of ethically accept-able and responsible use of herbal medicines in modern health care, there must be science-basedevidence of biomolecular and clinical effects. In closing, we would like to express our sincere thanks to the authors who contributed theirexpertise and time to the production of this volume. Individually the authors are leaders in theirfield. Collectively they embody a truly international collection of wisdom and experience in thebiomolecular and clinical aspects of herbal medicine. We are honored to be in their company.MATLAB® is a registered trademark of The MathWorks, Inc. For product information, please contact: The MathWorks, Inc. 3 Apple Hill Drive Natick, MA 01760-2098 USA Tel: 508 647 7000 Fax: 508 647 7001 E-mail: info@mathworks.com Web: www.mathworks.com© 2011 by Taylor & Francis Group, LLC
  14. 14. Editors Dr. Iris F. F. Benzie is a chair professor of biomedical science in the Department of Health Technology and Informatics at the Hong Kong Polytechnic University, Hong Kong SAR, People’s Republic of China (http://www.polyu.edu.hk/hti). She has a doctorate in bio- medical science from the University of Ulster, United Kingdom, and a master’s degree in clinical and pathological science from the Chinese University of Hong Kong. She is a fellow of the Institute of Biomedical Science in the United Kingdom, a fellow of the Hong Kong Society of Clinical Chemistry, an accredited clinical biochem- ist, a chartered biologist, and a chartered scientist. Originally from Scotland, she has lived and worked in Hong Kong for many years. Her research interest is in the area of dietary antioxidants, herbs, andfunctional foods, and the role of antioxidants and oxidative stress in aging and chronic degenerativedisease using a biomarker approach. She has published over 100 scientific papers and book chapters,and she developed the patented ferric reducing ability of plasma (FRAP) assay, a widely used testfor measuring the total antioxidant/reducing power of foods, herbs, drugs, and biological fluids. Dr. Sissi Wachtel-Galor is a research fellow in the Department of Health Technology and Informatics at the Hong Kong Polytechnic University, Hong Kong SAR, People’s Republic of China. She has a bachelor’s degree in industrial engineering and a master’s degree in biotechnology from the Technion–Israel Institutes of Technology, Haifa, Israel. Dr. Wachtel-Galor received her PhD in biomedical sci- ences from the Hong Kong Polytechnic University, Hong Kong, where she was awarded the first distinguished thesis prize for her outstanding achievements. Dr. Wachtel-Galor was born in Italy, grew up in Israel, and has traveled and lived in the United States and in Asia. During her travels, she was introduced to different types of traditional and herbal medicine, which sparked her interest in her present research areas.Her research interests include herbal medicine with a focus on Chinese medicine, vegetarian diets,endogenous antioxidants, and antioxidants from dietary sources and their effects on inflammatorymechanisms. Her approach is to use biomarkers in the assessment of antioxidant status and oxidativestress, and she has extensive experience in both animal and human supplementation studies. xv© 2011 by Taylor & Francis Group, LLC
  15. 15. ContributorsBharat B. Aggarwal John A. BuswellCytokine Research Laboratory Institute of Edible FungiDepartment of Experimental Therapeutics Shanghai Academy of Agricultural SciencesThe University of Texas Shanghai, People’s Republic of Chinaand Monica H. CarlsenAnderson Cancer Center Department of NutritionHouston, Texas Institute of Basic Medical Sciences Faculty of MedicineAndrew Bartlow University of OsloDepartment of Biology Oslo, NorwayWilkes UniversityWilkes-Barre, Pennsylvania William T. Cefalu The Botanical Research CenterIris F. F. Benzie Pennington Biomedical Research CenterDepartment of Health Technology and Louisiana State University System Informatics Baton Rouge, LouisianaThe Hong Kong Polytechnic UniversityKowloon, Hong Kong, People’s Republic of and China Biotech Center Rutgers UniversitySaverio Bettuzzi New Brunswick, New JerseyDivision of BiochemistryDepartment of Experimental Medicine Foo-tim ChauUniversity of Parma Department of Applied Biology andParma, Italy Chemical Technology The Hong Kong Polytechnic UniversityRune Blomhoff Kowloon, Hong Kong, People’s RepublicDepartment of Nutrition of ChinaInstitute of Basic Medical SciencesFaculty of Medicine Sabrina C. M. CheungUniversity of Oslo Department of Health Technology andOslo, Norway Informatics The Hong Kong Polytechnic UniversityAnn M. Bode Kowloon, Hong Kong, People’s RepublicThe Hormel Institute of ChinaUniversity of MinnesotaAustin, Minnesota Wing-kwan Chu Department of Health Technology andPeter Bucheli InformaticsManufacturing Support Department The Hong Kong Polytechnic UniversityNestlé Product Technology Centre Kowloon, Hong Kong, People’s RepublicKonolfingen, Switzerland of China xvii© 2011 by Taylor & Francis Group, LLC
  16. 16. xviii ContributorsAn-Sik Chung David HeberDepartment of Biological Sciences Department of MedicineKorea Advanced Institute of Science and UCLA Center for Human Nutrition Technology David Geffen School of Medicine atDaejeon, Korea University of California Los Angeles, CaliforniaJustin CrawfordDepartment of Biology Duncan HunterWilkes University Discipline of Nutrition and MetabolismWilkes-Barre, Pennsylvania School of Molecular Bioscience University of SydneyZigang Dong Sydney, AustraliaThe Hormel InstituteUniversity of Minnesota Christine M. KaeferAustin, Minnesota Epidemiology and Genetics Research Program Division of Cancer Control and PopulationsHarry H. S. Fong SciencesUniversity of Illinois at Chicago National Cancer InstituteChicago, Illinois Rockville, Marylandand Kenneth M. KlemowThe Royal Melbourne Institute of Department of Biology Technology (RMIT) Wilkes UniversityMelbourne, Australia Wilkes-Barre, PennsylvaniaMeika Foster Neil KocherDiscipline of Nutrition and Metabolism Department of BiologySchool of Molecular Bioscience Wilkes UniversityUniversity of Sydney Wilkes-Barre, PennsylvaniaSydney, Australia Chi-man KoonKwok-pui Fung Institute of Chinese MedicineInstitute of Chinese Medicine The Chinese University of Hong KongThe Chinese University of Hong Kong Shatin, Hong Kong, People’s Republic of ChinaShatin, Hong Kong, People’s Republic of China Kit-man LauQiutao Gao Institute of Chinese MedicineNestlé Research Centre The Chinese University of Hong KongNestlé R&D Centre Beijing Ltd. Shatin, Hong Kong, People’s Republic of ChinaBeijing, People’s Republic of China Roxanna A. W. LauLauren Girard Department of Health Technology andCARE Program InformaticsDepartment of Pediatrics The Hong Kong Polytechnic UniversityFaculty of Medicine and Dentistry Kowloon, Hong Kong, People’s RepublicUniversity of Alberta of ChinaEdmonton, Alberta, Canada Ping-chung LeungBente Lise Halvorsen Institute of Chinese MedicineDepartment of Nutrition The Chinese University of Hong KongInstitute of Basic Medical Sciences Shatin, Hong Kong, People’s Republic of ChinaFaculty of MedicineUniversity of OsloOslo, Norway© 2011 by Taylor & Francis Group, LLC
  17. 17. Contributors xixShao-ping Li Robert RedgwellInstitute of Chinese Medical Sciences Food Science and Technology DepartmentUniversity of Macau Nestlé Research CentreMacao, People’s Republic of China Vers-chez-les-Blanc, Lausanne, SwitzerlandBao-qin Lin David M. RibnickyInstitute of Chinese Medical Sciences The Botanical Research CenterUniversity of Macau Pennington Biomedical Research CenterMacao, People’s Republic of China Louisiana State University System Baton Rouge, LouisianaJohn A. MilnerNutrional Science Research Group andDivision of Cancer Prevention Biotechnology CenterNational Cancer Institute Rutgers UniversityRockville, Maryland New Brunswick, New JerseyYao Denis N’Dri Daniele Del RioHuman Nutrition Unit Human Nutrition UnitDepartment of Public Health Department of Public HealthUniversity of Parma University of ParmaParma, Italy Parma, ItalyCatherine C. Neto Michael RitsickDepartment of Chemistry and Biochemistry Department of BiologyUniversity of Massachusetts–Dartmouth Wilkes UniversityNorth Dartmouth, Massachusetts Wilkes-Barre, PennsylvaniaKyeong Mee ParkDepartment of Oriental Medicine Samir SammanDaejon University Discipline of Nutrition and MetabolismDaejeon, South Korea School of Molecular Bioscience University of SydneyIngvild Paur Sydney, AustraliaDepartment of NutritionInstitute of Basic Medical Sciences Mauro SerafiniFaculty of Medicine Area of Nutrition SciencesUniversity of Oslo Antioxidant Research LaboratoryOslo, Norway Rome, ItalyIlaria Peluso Jay ShahArea of Nutrition Sciences Department of BiologyAntioxidant Research Laboratory Wilkes UniversityRome, Italy Wilkes-Barre, PennsylvaniaSahdeo Prasad Philip D. ShenefeltCytokine Research Laboratory Department of Dermatology andDepartment of Experimental Therapeutics Cutaneous SurgeryThe University of Texas College of MedicineAustin, Texas University of South Floridaand Tampa, FloridaAnderson Cancer CenterHouston, Texas© 2011 by Taylor & Francis Group, LLC
  18. 18. xx ContributorsAgnes Simonyi Sissi Wachtel-GalorDepartment of Biochemistry Department of Health Technology andUniversity of Missouri InformaticsColumbia, Missouri The Hong Kong Polytechnic University Kowloon, Hong Kong, People’s RepublicJaqueline M. Stephens of ChinaThe Botanical Research CenterPennington Biomedical Research Center Richard WaldenLouisiana State University System Centre for Clinical Pharmacology andBaton Rouge, Louisiana Therapeutics Division of Medicineand University College LondonBiotechnology CenterRutgers University Junkuan WangNew Brunswick, New Jersey Nestlé Research Centre Nestlé R&D Centre Beijing Ltd.Albert Y. Sun Beijing, People’s Republic of ChinaDepartment of Medical Pharmacology and Physiology and Department of Pathology and Qun Wang Anatomical Sciences Department of Medical PharmacologyUniversity of Missouri and PhysiologyColumbia, Missouri University of Missouri Columbia, MissouriGrace Y. SunDepartment of Pathology and Anatomical Jae Joon Wee Sciences and Department of Biochemistry KT&G Central Research InstituteUniversity of Missouri Daejeon, South KoreaColumbia, Missouri Shui-yin WeiBrian Tomlinson Department of Applied Biology and ChemicalDepartment of Medicine and Therapeutics TechnologyThe Chinese University of Hong Kong The Hong Kong Polytechnic UniversityShatin, Hong Kong, People’s Republic of China Kowloon, Hong Kong, People’s Republic of ChinaKarine VidalFood Immunology Department Charlie Changli XueNestlé Research Centre Discipline of Chinese MedicineVers-chez-les-Blanc School of Health SciencesLausanne, Switzerland RMIT University Melbourne, AustraliaJoe A. VinsonDepartment of Chemistry John YuenUniversity of Scranton Department of Health Technology andScranton, Pennsylvania Informatics The Hong Kong Polytechnic UniversitySunita Vohra Kowloon, Hong Kong, People’s RepublicCARE Program of ChinaDepartment of PediatricsFaculty of Medicine and DentistryUniversity of AlbertaEdmonton, Alberta, Canada© 2011 by Taylor & Francis Group, LLC
  19. 19. Contributors xxiAnthony Lin Zhang Weiguo ZhangDiscipline of Chinese Medicine Nestlé Research CentreSchool of Health Sciences Nestlé R&D Centre Beijing Ltd.RMIT University Beijing, People’s Republic of ChinaMelbourne, Australia© 2011 by Taylor & Francis Group, LLC
  20. 20. 1 Herbal MedicineIts History, An Introduction to Usage, Regulation, Current Trends, and Research Needs Sissi Wachtel-Galor and Iris F. F. BenzieCONTENTS1.1 Herbal Medicine: A Growing Field with a Long Tradition ...................................................... 11.2 Herbal Medicine and the Aging Population ............................................................................. 41.3 Herbal Medicines: Challenges and Regulations .......................................................................4 1.3.1 International Diversity and National Policies ............................................................... 5 1.3.2 Quality, Safety, and Scientific Evidence ....................................................................... 61.4 Research Needs.........................................................................................................................71.5 Conclusions ...............................................................................................................................8Acknowledgments.............................................................................................................................. 9References .......................................................................................................................................... 91.1  HERBAL MEDICINE: A GROWING FIELD WITH A LONG TRADITIONTraditional medicine is “the knowledge, skills and practices based on the theories, beliefs and expe-riences indigenous to different cultures, used in the maintenance of health and in the prevention,diagnosis, improvement or treatment of physical and mental illness” (World Health Organization,http://www.who.int/topics/traditional_medicine/en/). There are many different systems of tradi-tional medicine, and the philosophy and practices of each are influenced by the prevailing condi-tions, environment, and geographic area within which it first evolved (WHO 2005), however, acommon philosophy is a holistic approach to life, equilibrium of the mind, body, and the envi-ronment, and an emphasis on health rather than on disease. Generally, the focus is on the overallcondition of the individual, rather than on the particular ailment or disease from which the patientis suffering, and the use of herbs is a core part of all systems of traditional medicine (Engebretson2002; Conboy et al. 2007; Rishton 2008; Schmidt et al. 2008). Traditional Chinese medicine (TCM) is an important example of how ancient and accumulatedknowledge is applied in a holistic approach in present day health care. TCM has a history of morethan 3000 years (Xutian, Zhang, and Louise 2009). The book The Devine Farmer’s Classic ofHerbalism was compiled about 2000 years ago in China and is the oldest known herbal text in theworld, though the accumulated and methodically collected information on herbs has been devel-oped into various herbal pharmacopoeias and many monographs on individual herbs exist. Diagnosis and treatment are based on a holistic view of the patient and the patient’s symptoms,expressed in terms of the balance of yin and yang. Yin represents the earth, cold, and femininity,whereas yang represents the sky, heat, and masculinity. The actions of yin and yang influencethe interactions of the five elements composing the universe: metal, wood, water, fire, and earth. 1© 2011 by Taylor & Francis Group, LLC
  21. 21. 2 Herbal Medicine: Biomolecular and Clinical AspectsTCM practitioners seek to control the yin and yang levels through 12 meridians, which bring andchannel energy (Qi) through the body. TCM is a growing practice around the world and is usedfor promoting health as well as for preventing and curing diseases. TCM encompasses a range ofpractices, but herbal medicine is a core part (Engebretson 2002; Nestler 2002; Schmidt et al. 2008;Xutian, Zhang, and Louise 2009). Three of the top-selling botanical products, namely Ginkgobiloba, Allium sativum (garlic), and Panax ginseng, can be traced back to origins in TCM and aretoday used to treat various diseases (Li, Jiang, and Chen 2008; Xutian, Zhang, and Louise 2009). Over the past 100 years, the development and mass production of chemically synthesized drugshave revolutionized health care in most parts of the word. However, large sections of the populationin developing countries still rely on traditional practitioners and herbal medicines for their primarycare. In Africa up to 90% and in India 70% of the population depend on traditional medicine tohelp meet their health care needs. In China, traditional medicine accounts for around 40% of allhealth care delivered and more than 90% of general hospitals in China have units for traditionalmedicine (WHO 2005). However, use of traditional medicine is not limited to developing countries,and during the past two decades public interest in natural therapies has increased greatly in indus-trialized countries, with expanding use of ethnobotanicals. In the United States, in 2007, about38% of adults and 12% of children were using some form of traditional medicine (Ernst, Schmidt,and Wider 2005; Barnes, Bloom, and Nahin 2008). According to a survey by the National Centerfor Complementary and Alternative Medicine (Barnes, Bloom, and Nahin 2008), herbal therapyor the usage of natural products other than vitamins and minerals was the most commonly usedalternative medicine (18.9%) when all use of prayer was excluded. A survey conducted in HongKong in 2003 reported that 40% of the subjects surveyed showed marked faith in TCM comparedwith Western medicine (Chan et al. 2003). In a survey of 21,923 adults in the United States, 12.8%took at least one herbal supplement (Harrison et al. 2004) and in another survey (Qato et al. 2008),42% of respondents used dietary or nutritional supplements, with multivitamins and minerals mostcommonly used, followed by saw palmetto, flax, garlic, and Ginkgo, at the time of the interview. The most common reasons for using traditional medicine are that it is more affordable, moreclosely corresponds to the patient’s ideology, allays concerns about the adverse effects of chemi-cal (synthetic) medicines, satisfies a desire for more personalized health care, and allows greaterpublic access to health information. The major use of herbal medicines is for health promotionand therapy for chronic, as opposed to life-threatening, conditions. However, usage of traditionalremedies increases when conventional medicine is ineffective in the treatment of disease, such asin advanced cancer and in the face of new infectious diseases. Furthermore, traditional medicinesare widely perceived as natural and safe, that is, not toxic. This is not necessarily true, especiallywhen herbs are taken with prescription drugs, over-the-counter medications, or other herbs, as isvery common (Canter and Ernst 2004; Qato et al. 2008; Loya, Gonzalez-Stuart, and Rivera 2009;Cohen and Ernst 2010). Regardless of why an individual uses it, traditional medicine provides an important health careservice whether people have physical or financial access to allopathic medicine, and it is a flourish-ing global commercial enterprise (Engebretson 2002; Conboy et al. 2007; Evans et al. 2007). In1990, expenditure associated with “alternative” therapy in the United States was estimated to beUS$13.7 billion. This had doubled by the year 1997, with herbal medicines growing faster than anyother alternative therapy (Eisenberg et al. 1998). In Australia, Canada, and the United Kingdom,annual expenditure on traditional medicine is estimated to be US$80 million, US$1 billion, andUS$2.3 billion, respectively. These figures reflect the incorporation of herbal and other forms oftraditional medicine into many health care systems and its inclusion in the medical training of doc-tors in many parts of the developed world. The total commercial value of the ethnobotanicals market cannot be ignored. For example, in1995, the total turnover of nonprescription-bound herbal medicines in pharmacies was equal toalmost 30% of the total turnover of nonprescription-bound medicines in Germany, and in the UnitedStates, the annual retail sales of herbal products was estimated to be US$5.1 billion. In India,© 2011 by Taylor & Francis Group, LLC
  22. 22. Herbal Medicine 3herbal medicine is a common practice, and about 960 plant species are used by the Indian herbalindustry, of which 178 are of a high volume, exceeding 100 metric tons per year (Sahoo 2010). InChina, the total value of herbal medicine manufactured in 1995 reached 17.6 billion Chinese yuan(approximately US$2.5 billion; Eisenberg et al. 1998; WHO 2001). This trend has continued, andannual revenues in Western Europe reached US$5 billion in 2003–2004 (De Smet 2005). In China,sales of herbal products totaled US$14 billion in 2005, and revenue from herbal medicines in Brazilwas US$160 million in 2007 (World Health Organization; http://www.who.int/topics/traditional_medicine/en/). It is estimated that the annual worldwide market for these products approachedUS$60 billion (Tilburt and Kaptchuk 2008). Currently, herbs are applied to the treatment of chronic and acute conditions and various ail-ments and problems such as cardiovascular disease, prostate problems, depression, inflammation,and to boost the immune system, to name but a few. In China, in 2003, traditional herbal medi-cines played a prominent role in the strategy to contain and treat severe acute respiratory syndrome(SARS), and in Africa, a traditional herbal medicine, the Africa flower, has been used for decades totreat wasting symptoms associated with HIV (De Smet 2005; Tilburt and Kaptchuk 2008). Herbalmedicines are also very common in Europe, with Germany and France leading in over-the-countersales among European countries, and in most developed countries, one can find essential oils, herbalextracts, or herbal teas being sold in pharmacies with conventional drugs. Herbs and plants can be processed and can be taken in different ways and forms, and they includethe whole herb, teas, syrup, essential oils, ointments, salves, rubs, capsules, and tablets that contain aground or powdered form of a raw herb or its dried extract. Plants and herbs extract vary in the sol-vent used for extraction, temperature, and extraction time, and include alcoholic extracts (tinctures),vinegars (acetic acid extracts), hot water extract (tisanes), long-term boiled extract, usually roots orbark (decoctions), and cold infusion of plants (macerates). There is no standardization, and compo-nents of an herbal extract or a product are likely to vary significantly between batches and producers. Plants are rich in a variety of compounds. Many are secondary metabolites and include aro-matic substances, most of which are phenols or their oxygen-substituted derivatives such as tan-nins (Hartmann 2007; Jenke-Kodama, Müller, and Dittmann 2008). Many of these compoundshave antioxidant properties (see Chapter 2 on antioxidants in herbs and spices). Ethnobotanicals areimportant for pharmacological research and drug development, not only when plant constituentsare used directly as therapeutic agents, but also as starting materials for the synthesis of drugs oras models for pharmacologically active compounds (Li and Vederas 2009). About 200 years ago,the first pharmacologically active pure compound, morphine, was produced from opium extractedfrom seeds pods of the poppy Papaver somniferum. This discovery showed that drugs from plantscan be purified and administered in precise dosages regardless of the source or age of the material(Rousseaux and Schachter 2003; Hartmann 2007). This approach was enhanced by the discoveryof penicillin (Li and Vederas 2009). With this continued trend, products from plants and naturalsources (such as fungi and marine microorganisms) or analogs inspired by them have contributedgreatly to the commercial drug preparations today. Examples include antibiotics (e.g., penicillin,erythromycin); the cardiac stimulant digoxin from foxglove (Digitalis purpurea); salicylic acid, aprecursor of aspirin, derived from willow bark (Salix spp.); reserpine, an antipsychotic and antihy-pertensive drug from Rauwolfia spp.; and antimalarials such as quinine from Cinchona bark andlipid-lowering agents (e.g., lovastatin) from a fungus (Rishton 2008; Schmidt et al. 2008; Li andVederas 2009). Also, more than 60% of cancer therapeutics on the market or in testing are basedon natural products. Of 177 drugs approved worldwide for treatment of cancer, more than 70% arebased on natural products or mimetics, many of which are improved with combinatorial chemistry.Cancer therapeutics from plants include paclitaxel, isolated from the Pacific yew tree; camptothecin,derived from the Chinese “happy tree” Camptotheca acuminata and used to prepare irinotecanand topotecan; and combretastatin, derived from the South African bush willow (Brower 2008).It is also estimated that about 25% of the drugs prescribed worldwide are derived from plants, and121 such active compounds are in use (Sahoo et al. 2010). Between 2005 and 2007, 13 drugs derived© 2011 by Taylor & Francis Group, LLC
  23. 23. 4 Herbal Medicine: Biomolecular and Clinical Aspectsfrom natural products were approved in the United States. More than 100 natural product–baseddrugs are in clinical studies (Li and Vederas 2009), and of the total 252 drugs in the World HealthOrganization’s (WHO) essential medicine list, 11% are exclusively of plant origin (Sahoo et al.2010).1.2  HERBAL MEDICINE AND THE AGING POPULATIONAverage life expectancy at birth has increased from around 41 years in the early 1950s to approaching80 years in many developed countries. Consequently, the percentage of elderly people (65 years andabove) in our populations is increasing. The graying of our populations brings an increasing burdenof chronic age-related disease and dependency. Aging is associated with a progressive decline inphysiological function and an increased risk of pathological changes leading to cancer, cardiovascu-lar disease, dementia, diabetes, osteoporosis, and so on. Lifestyle factors such as nutrition or exerciseplay an important role in determining the quality and duration of healthy life and in the treatment ofchronic diseases (Bozzetti 2003; Benzie and Wachtel-Galor 2009, 2010). It is most likely that thereis no one cause of aging, and different theories of aging have been suggested over the years. Geneticfactors are undoubtedly important, but among all the metabolic theories of aging, the oxidative stresstheory is the most generally supported theory (Harman 1992; Beckman and Ames 1998). This theorypostulates that aging is caused by accumulation of irreversible, oxidation-induced damage (oxidativestress) resulting from the interaction of reactive oxygen species with the DNA, lipid, and proteincomponents of cells. However, even if the aging process itself is found to be unrelated to oxidativestress, highly prevalent chronic age-related diseases all have increased oxidative stress (Holmes,Bernstein, and Bernstein 1992; Beckman and Ames 1998; Finkel and Holbrook 2000; Rajah et al.2009). Antioxidants in herbs may contribute at least part of their reputed therapeutic effects (Balsanoand Alisi 2009; Tang and Halliwell 2010). With the growing popularity of herbal medicine, the “traditional” ways of identification and prep-aration of herbs need to be replaced with more accurate and reproducible methods (see Chapter 20)so as to ensure the quality, safety, and consistency of the product. Given the market value, poten-tial toxicity and increasing consumer demand, particularly in the sick and elderly members of ourpopulations, regulation of production and marketing of herbal supplements and medicines requireattention.1.3  HERBAL MEDICINES: CHALLENGES AND REGULATIONSWHO has recognized the important contribution of traditional medicine to provide essential care(World Health Organization, http://www.who.int/topics/traditional_medicine/en/). In 1989, the U.S.Congress established the Office of Alternative Medicine within the National Institutes of Health toencourage scientific research in the field of traditional medicine (http://nccam.nih.gov, last access:November 5, 2010), and the European Scientific Cooperative on Phytotherapy (ESCOP) was foundedin 1989 with the aim of advancing the scientific status and harmonization of phytomedicines at theEuropean level (www.escop.com, last access: November 5, 2010). This led to an increase in investmentin the evaluation of herbal medicines. In the United States, the National Center for Complementaryand Alternative Medicine at the National Institutes of Health spent approximately US$33 million onherbal medicines in the fiscal year 2005; in 2004, the National Canadian Institute committed nearlyUS$89 million for studying a range of traditional therapies. While this scale of investment is lowcompared to the total research and development expenses of the pharmaceutical industry, it neverthe-less reflects genuine public, industry, and governmental interest in this area (Li and Vederas 2009). With tremendous expansion in the interest in and use of traditional medicines worldwide, twomain areas of concern arise that bring major challenges. These are international diversity andnational policies regarding the regulation of the production and use of herbs (and other complemen-© 2011 by Taylor & Francis Group, LLC
  24. 24. Herbal Medicine 5tary medicines) and their quality, safety, and scientific evidence in relation to health claims (WHO2005; Sahoo et al. 2008).1.3.1  InternatIonal DIversIty anD natIonal PolIcIesThe diversity among countries with the long history and holistic approach of herbal medicinesmakes evaluating and regulating them very challenging. In addition, there are a great number ofdifferent herbs used. Legislative criteria to establish traditionally used herbal medicines as part ofapproved health care therapies faces several difficulties. In a survey conducted across 129 countries,WHO reported the following issues regarding herbal medicines: lack of research data, appropriatemechanisms for control of herbal medicines, education and training, expertise within the nationalhealth authorities and control agency, information sharing, safety monitoring, and methods to evalu-ate their safety and efficacy. The support needed from different countries includes informationsharing on regulatory issues, workshops on herbal medicines safety monitoring, general guidelineson research and evaluation of herbal medicines, provision of databases, herbal medicine regulationworkshops, and international meetings. National policies are the basis for defining the role of traditional medicines in national healthcare programs, ensuring that the necessary regulatory and legal mechanisms are established forpromoting and maintaining good practice, assuring the authenticity, safety, and efficacy of tradi-tional medicines and therapies, and providing equitable access to health care resources and theirresource information (WHO 2005). Another fundamental requirement is harmonization of the mar-ket for herbal medicines for industry, health professionals, and consumers (Mahady 2001). Herbalmedicines are generally sold as food supplements, but a common regulatory framework does notexist in different countries. As a result, information on clinical indications for their use, efficacy,and safety are influenced by the traditional experience available in each place. A brief outline of thelegislation in United States, Canada, and Europe is given in this section, and could be used to guidethe legal aspects of the herbal medicine industry in other countries. In the United States, under the Dietary Supplement Health and Education Act (DSHEA) of1994, any herb, botanical and natural concentrate, metabolite and constituent of extract, is classi-fied as a dietary supplement. Dietary supplements do not need approval from the Food and DrugAdministration (FDA) before they are marketed (FDA 2010). Under DSHEA, herbal medicines,which are classified as dietary supplements, are presumed safe, and the FDA does not have theauthority to require them to be approved for safety and efficacy before they enter the market,which is the case for drugs. This means that the manufacturer of the herbal medicine is responsi-ble for determining that the dietary supplements manufactured or distributed are indeed safe andthat any representations or claims made about them are sustained by adequate evidence to showthat they are not false or misleading. However, a dietary supplement manufacturer or distribu-tor of a supplement with a “new dietary ingredient,” that is, an ingredient that was not marketedin the United States before October 1994, may be required to go through premarket review forsafety data and other information. Also, all domestic and foreign companies that manufacturepackage labels or hold dietary supplements must follow the FDA’s current good manufacturingpractice (GMP) regulations, which outline procedures for ensuring the quality of supplementsintended for sale (FDA 2010; Gao 2010). Regarding contamination, the FDA has not issued anyregulations addressing safe or unsafe levels of contaminants in dietary supplements but has setcertain advisory levels in other foods (FDA 2010; Gao 2010). A product being sold as an herbalsupplement (dietary supplement) in the United States cannot suggest on its label or in any of itspackaging that it can diagnose, treat, prevent, or cure a specific disease or condition withoutspecific approval from the FDA. A claim also cannot suggest an effect on an abnormal conditionassociated with a natural state or process, such as aging (FDA 2010; Gao 2010). In Canada, herbal remedies must comply with the Natural Health Products Regulations (HealthCanada 2003). According to these regulations, all natural products require a product license before© 2011 by Taylor & Francis Group, LLC
  25. 25. 6 Herbal Medicine: Biomolecular and Clinical Aspectsthey can be sold in Canada. In order to be granted a license, detailed information on the medicinalingredients, source, potency, nonmedicinal ingredients, and recommended use needs to be fur-nished. Once a product has been granted a license, it will bear the license number and follow stan-dard labeling requirements to ensure that consumers can make informed choices. A site licenseis also needed for those who manufacture, pack, label, and import herbal medicines. In addition,GMPs must be employed to ensure product safety and quality. This requires that appropriate stan-dards and practices regarding the manufacture, storage, handling, and distribution of natural healthproducts be met. The GMPs are designed to be outcome based, ensuring safe and high-quality prod-ucts, while giving the flexibility to implement quality control systems appropriate to the product lineand business. Product license holders are required to monitor all adverse reactions associated withtheir product and report serious adverse reactions to the Canadian Department of Health. In Europe, the European Directive 2004/24/EC released in 2004 by the European Parliamentand  by the Council of Europe provides the guidelines for the use of herbal medicines (Calapai2008). The directive establishes that herbal medicines released on the market need authoriza-tion by the national regulatory authorities of each European country and that these products musthave a recognized level of safety and efficacy (Calapai 2008). The registration of herbal medici-nal products needs sufficient evidence for the medicinal use of the product throughout a periodof at  least 30 years in the European Union (EU), at least 15 years within the EU, and 15 yearselsewhere for products from outside the EU. With regard to the manufacturing of these productsand their quality, products must fulfill the same requirements as applications for a marketing autho-rization. Information is based on the availability of modern science–based public monographs inthe European Pharmacopeia and their equivalents developed by the pharmaceutical industry. Thestandards put forward allow not only to define the quality of products but also to eliminate harm-ful compounds, adulteration, and contamination. Within the EU, a number of committees wereset up to attempt and standardize the information and guidelines related to herbal medicines. Avariety of materials has been produced, such as monographs on herbs and preparations, guidelineson good agricultural and collection practice for starting materials of herbal origin, and guidelineson the standardization of applications and setting up pragmatic approaches for identification andquantitative determination of herbal preparations and their complex compositions (Routledge 2008;Vlietinck, Pieters, and Apers 2009).1.3.2  QualIty, safety, anD scIentIfIc evIDenceHerbal medicine has been commonly used over the years for treatment and prevention of diseasesand health promotion as well as for enhancement of the span and quality of life. However, thereis a lack of a systematic approach to assess their safety and effectiveness. The holistic approachto health care makes herbal medicine very attractive to many people, but it also makes scientificevaluation very challenging because so many factors must be taken into account. Herbal medicinesare in widespread use and although many believe herbal medicines are safe, they are often used incombination and are drawn from plant sources with their own variability in species, growing condi-tions, and biologically active constituents. Herbal extracts may be contaminated, adulterated, andmay contain toxic compounds. The quality control of herbal medicines has a direct impact on theirsafety and efficacy (Ernst, Schmidt, and Wider 2005; Ribnicky et al. 2008). But, there is little dataon the composition and quality of most herbal medicines not only due to lack of adequate policies orgovernment requirements but also due to a lack of adequate or accepted research methodology forevaluating traditional medicines (WHO 2001; Kantor 2009). In addition, there is very little researchon whole herbal mixtures because the drug approval process does not accommodate undifferentiatedmixtures of natural chemicals. To isolate each active ingredient from each herb would be immenselytime-consuming at a high cost, making it not cost-effective for manufacturers (Richter 2003). Another problem is that despite the popularity of botanical dietary and herbal supplements, someherbal products on the market are likely to be of low quality and suspect efficacy, even if the herb© 2011 by Taylor & Francis Group, LLC
  26. 26. Herbal Medicine 7has been shown to have an effect in controlled studies using high-quality product. There is a beliefthat herbs, as natural products, are inherently safe without side effects and that efficacy can beobtained over a wide range of doses. Although herbs may well have undesirable side effects, thereare no set “doses,” and herb–drug or herb–herb interactions are possible. A major hypothetical advantage of botanicals over conventional single-component drugs is thepresence of multiple active compounds that together can provide a potentiating effect that may notbe achievable by any single compound. This advantage presents a unique challenge for the sepa-ration and identification of active constituents. Compounds that are identified by activity-guidedfractionation must be tested in appropriate animal models to confirm in vivo activity. Ideally, thecomposition of the total botanical extract must be standardized and free of any potential hazards,and plants should be grown specifically for the production of botanical extracts under controlledconditions and originate from a characterized and uniform genetic source with a taxonomic recordof the genus, species, and cultivar or other additional identifiers. Records should be maintained forthe source of the seed, locations and conditions of cultivation, and exposure to possible chemicaltreatments such as pesticides. Because the environment can significantly affect phytochemical pro-files and the efficacy of the botanical end product, botanical extracts can vary from year to year andmay be significantly affected by temperature, drought, or flood as well as by geographic location.Therefore, biochemical profiling must be used to ensure that a consistent material is used to producea botanical. The concentration step can also be challenging, and the process to concentrate activecompounds to a sufficient level can negatively affect their solubility and bioavailability. Therefore,improving efficacy by increasing concentration can be counterproductive, and the use of solubiliz-ers and bioenhancers needs to be considered just as for drugs (Ribnicky et al. 2008). However, thereare major challenges to achieving this. Although in theory botanicals should be well characterized and herbal supplements should beproduced to the same quality standards as drugs, the situation in practice is very different from thatof a pure drug. Herbs contain multiple compounds, many of which may not be identified and oftenthere is no identifier component, and chemical fingerprinting is in its early stages and is lacking forvirtually all herbs (see Chapter 20). This makes standardization of botanicals difficult, althoughsome can be produced to contain a standardized amount of a key component or class of components,such as ginsenosides for ginseng products or anthocyanins for bilberry products (see chapter 4 onbilberry and chapter 8 on ginseng in this volume). However, even when such key compounds havebeen identified and a standard content is agreed or suggested, there is no guarantee that individualcommercial products will contain this. Another interesting point to consider is that herbal materials for commercial products are col-lected from wild plant populations and cultivated medicinal plants. The expanding herbal productmarket could drive overharvesting of plants and threaten biodiversity. Poorly managed collectionand cultivation practices could lead to the extinction of endangered plant species and the destructionof natural resources. It has been suggested that 15,000 of 50,000–70,000 medicinal plant speciesare threatened with extinction (Brower 2008). The efforts of the Botanic Gardens ConservationInternational are central to the preservation of both plant populations and knowledge on how toprepare and use herbs for medicinal purposes (Brower 2008; Li and Vederas 2009).1.4  RESEARCH NEEDSResearch needs in the field of herbal medicines are huge, but are balanced by the potential healthbenefits and the enormous size of the market. Research into the quality, safety, molecular effects,and clinical efficacy of the numerous herbs in common usage is needed. Newly emerging scientifictechniques and approaches, many of which are mentioned in this book, provide the required test-ing platform for this. Genomic testing and chemical fingerprinting techniques using hyphenatedtesting platforms are now available for definitive authentication and quality control of herbal prod-ucts. They should be regulated to be used to safeguard consumers, but questions of efficacy will© 2011 by Taylor & Francis Group, LLC
  27. 27. 8 Herbal Medicine: Biomolecular and Clinical Aspectsremain unless and until adequate amounts of scientific evidence accumulate from experimentaland controlled human trials (Giordano, Engebretson, and Garcia 2005; Evans 2008; Tilburt andKaptchuk 2008). Evidence for the potential protective effects of selected herbs is generally basedon experiments demonstrating a biological activity in a relevant in vitro bioassay or experimentsusing animal models. In some cases, this is supported by both epidemiological studies and a lim-ited number of intervention experiments in humans (WHO 2001). In general, international researchon traditional herbal medicines should be subject to the same ethical requirements as all researchrelated to human subjects, with the information shared between different countries. This shouldinclude collaborative partnership, social value, scientific validity, fair subject selection, favorablerisk-benefit ratio, independent review, informed consent, and respect for the subjects (Giordano,Engebretson, and Garcia 2005; Tiburt and Kaptchuk 2008). However, the logistics, time, and costof performing large, controlled human studies on the clinical effectiveness of an herb are prohibi-tive, especially if the focus is on health promotion. Therefore, there is an urgent need to developnew biomarkers that more clearly relate to health (and disease) outcomes. Predictor biomarkersand subtle but detectable signs of early cellular change that are mapped to the onset of specificdiseases are needed. Research is needed also to meet the challenges of identifying the active compounds in the plants,and there should be research-based evidence on whether whole herbs or extracted compounds arebetter. The issue of herb–herb and herb–drug interactions is also an important one that requiresincreased awareness and study, as polypharmacy and polyherbacy are common (Canter and Ernst2004; Qato et al. 2008; Loya, Gonzalez-Stuart, and Rivera 2009; Cohen and Ernst 2010). The useof new technologies, such as nanotechnology and novel emulsification methods, in the formulationof herbal products, will likely affect bioavailability and the efficacy of herbal components, and thisalso needs study. Smart screening methods and metabolic engineering offer exciting technologiesfor new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manip-ulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharma-ceutical agents (Li and Vederas 2009). This can lead to reinvestigation of some agents that failedearlier trials and can be restudied and redesigned using new technologies to determine whether theycan be modified for better efficacy and fewer side effects. For example, maytansine isolated in theearly 1970s from the Ethiopian plant Maytenus serrata, looked promising in preclinical testing butwas dropped in the early 1980s from further study when it did not translate into efficacy in clinicaltrials; later, scientists isolated related compounds, ansamitocins, from a microbial source. A deriva-tive of maytansine, DM1, has been conjugated with a monoclonal antibody and is now in trials forprostate cancer (Brower 2008).1.5  CONCLUSIONSPlants, herbs, and ethnobotanicals have been used since the early days of humankind and are stillused throughout the world for health promotion and treatment of disease. Plants and natural sourcesform the basis of today’s modern medicine and contribute largely to the commercial drug prepara-tions manufactured today. About 25% of drugs prescribed worldwide are derived from plants. Still,herbs, rather than drugs, are often used in health care. For some, herbal medicine is their preferredmethod of treatment. For others, herbs are used as adjunct therapy to conventional pharmaceuticals.However, in many developing societies, traditional medicine of which herbal medicine is a corepart is the only system of health care available or affordable. Regardless of the reason, those usingherbal medicines should be assured that the products they are buying are safe and contain what theyare supposed to, whether this is a particular herb or a particular amount of a specific herbal com-ponent. Consumers should also be given science-based information on dosage, contraindications,and efficacy. To achieve this, global harmonization of legislation is needed to guide the responsibleproduction and marketing of herbal medicines. If sufficient scientific evidence of benefit is available© 2011 by Taylor & Francis Group, LLC
  28. 28. Herbal Medicine 9for an herb, then such legislation should allow for this to be used appropriately to promote the use ofthat herb so that these benefits can be realized for the promotion of public health and the treatmentof disease.ACKNOWLEDGMENTSThe authors thank the Hong Kong Polytechnic University for funding this work.REFERENCESBalsano, C., and A. Alisi. 2009. Antioxidant effects of natural bioactive compounds. Curr Pharm Des 15:3063–73.Barnes, P. M., B. Bloom, and R. Nahin. 2008. Complementary and alternative medicine use among adults and children: United States, 2007. CDC National Health Statistics Report # 12. www.cdc.gov/nchs/data/nhsr/ nhsr012.pdf access date: 5 NovBeckman, K. B., and B. N. Ames. 1998. The free radical theory of ageing matures. Physiol Rev 78:47–81.Benzie, I. F. F., and S. Wachtel-Galor. 2009. Biomarkers in long-term vegetarian diets. Adv Clin Chem 47:170–208.Benzie, I. F., and S. Wachtel-Galor. 2010. Vegetarian diets and public health: Biomarker and redox connections. Antioxid Redox Signal 13(10):1575–91.Bozzetti, F. 2003. Nutritional issues in the care of the elderly patient. Crit Rev Oncol Hematol 48:113–21.Brower, V. 2008. Back to nature: Extinction of medicinal plants threatens drug discovery. J Natl Cancer Inst 100:838–9.Calapai, G. 2008. European legislation on herbal medicines: A look into the future. Drug Saf 31:428–31.Canter, P. H., and E. Ernst. 2004. Herbal supplement use by persons aged over 50 years in Britain: Frequently used herbs, concomitant use of herbs, nutritional supplements and prescription drugs, rate of informing doctors and potential for negative interactions. Drugs Aging 21:597–605.Chan, M. F., E. Mok, Y. S. , Wong, .ST. F. ,Tong, .FM. C. , Day, .CC. K. , Tang, .Kand D. H. Wong . .H2003. Attitudes of Hong Kong Chinese to traditional Chinese medicine and Western medicine: Survey and cluster analysis. Complement Ther Med 11(2):103–9.Cohen, P. A., and E. Ernst. 2010. Safety of herbal supplements: A guide for cardiologists. Cardiovasc Ther 28:246–53.Conboy, L., T. J. Kaptchuk, D. M. Eisenberg, B. Gottlieb, and D. Acevedo-Garcia. 2007. The relationship between social factors and attitudes toward conventional and CAM practitioners. Complement Ther Clin Pract 13:146–57.De Smet, P. 2005. Herbal medicine in Europe: Relaxing regulatory standards. N Engl J Med 352:1176–8.Eisenberg, D. M., R. B. Davis, S. L. Ettner, S. Appel, S. Wilkey, M. Van Rompay, and R. C. Kessler. 1998. Trends in alternative medicine use in the United States, 1990–1997: Results of a follow-up national survey. JAMA 280:1569–75.Engebretson, J. 2002. Culture and complementary therapies. Complement Ther Nurs Midwifery 8:177–84.Ernst, E., K. Schmidt, and B. Wider. 2005. CAM research in Britain: The last 10 years. Complement Ther Clin Pract 11:17–20.Evans, S. 2008. Changing the knowledge base in Western herbal medicine. Soc Sci Med 67:2098–106.Evans, M., A. Shaw, E. A. Thompson, S. Falk, P. Turton, T. Thompson, and D. Sharp. 2007. Decisions to use complementary and alternative medicine (CAM) by male cancer patients: Information-seeking roles and types of evidence used. BMC Complement Altern Med 7:25.Finkel, T., and N. J. Holbrook. 2000. Oxidants oxidative stress and the biology of ageing. Nature 408:239–47.Food and Drug Administration (FDA). 2010. Overview of dietary supplements. website: www.fda.gov/food/ dietarysupplements/consumerinformation (accessed November 5, 2010).Giordano, J., J. Engebretson, and M. K. Garcia. 2005. Challenges to complementary and alternative medical research: Focal issues influencing integration into a cancer care model. Integr Cancer Ther 4:210–8.Harman, D. 1992. Free radical theory of aging. Mutat Res 275:257–66.Harrison, R. A., D. Holt, D. J. Pattison, and P. J. Elton. 2004. Who and how many people are taking herbal supplements? A survey of 21,923 adults. Int J Vitam Nutr Res 74:183–6.Hartmann, T. 2007. From waste products to ecochemicals: Fifty years research of plant secondary metabolism. Phytochemical 68:2831–46.© 2011 by Taylor & Francis Group, LLC
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  30. 30. 2 Antioxidants in Herbs and Spices Roles in Oxidative Stress and Redox Signaling Ingvild Paur, Monica H. Carlsen, Bente Lise Halvorsen, and Rune BlomhoffCONTENTS2.1 Introduction ............................................................................................................................ 112.2 Reactive Oxygen Species: Complex Roles in Normal Physiology ......................................... 12 2.2.1 Role of Reactive Oxygen Species in Cell Signaling ................................................... 12 2.2.2 Production of Reactive Oxygen Species ..................................................................... 13 2.2.3 How Are Reactive Oxygen Species Perceived? .......................................................... 132.3 Examples of the Dual Roles of Reactive Oxygen Species in Pathologies .............................. 14 2.3.1 Reactive Oxygen Species in Rheumatoid Arthritis .................................................... 14 2.3.2 Exploitation of Reactive Oxygen Species Signaling by Cancer Cells to Survive and Grow ....................................................................................................... 14 2.3.3 Positive Role of Reactive Oxygen Species in Exercise ............................................... 142.4 Is There a Role of Dietary Antioxidants in Oxidative Stress?................................................ 152.5 Total Antioxidant Content of Foods and Drinks: Largest Density of Antioxidants Contained in Spices and Herbs ............................................................................................... 152.6 Total Amounts of Antioxidants in Herbs and Spices ............................................................. 172.7 Research Needs: Potential Health Effects of Dietary Antioxidants ....................................... 192.8 Conclusions ............................................................................................................................. 33References ........................................................................................................................................ 332.1  INTRODUCTIONHerbs and spices are traditionally defined as any part of a plant that is used in the diet for theiraromatic properties with no or low nutritional value (Davidson 1999; Hacskaylo 1996; Smith andWinder 1996). However, more recently, herbs and spices have been identified as sources of variousphytochemicals, many of which possess powerful antioxidant activity (Larson 1988; Velioglu et al.1998; Kähkönen et al. 1999; Dragland et al. 2003). Thus, herbs and spices may have a role in anti-oxidant defense and redox signaling. In the scientific and public literature, antioxidants and oxidative stress are very often presentedin a far too simple manner. First, reactive oxygen species (ROS) are lumped together as one func-tional entity. However, there are many different ROS that have separate and essential roles in normalphysiology and are required for a variety of normal processes. These physiological functions arenot overlapping, and the different ROS that exist cannot, in general, replace each other. DifferentROS are also strongly implicated in the etiology of diseases such as cancers, atherosclerosis, 11© 2011 by Taylor & Francis Group, LLC

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