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Evaluation of Herbal Medicinal Products
Evaluation of Herbal
Medicinal Products
Perspectives on quality, safety and efficacy

Edited by
Pulok K Mukherjee
Director, School of Natural Product Studies, Jadavpur University, Kolkata, India

Peter J Houghton
Emeritus Professor in Pharmacognosy, Pharmaceutical Sciences Division, King’s College London,
London, UK

London • Chicago
Published by the Pharmaceutical Press
An imprint of RPS Publishing

1 Lambeth High Street, London SE1 7JN, UK

100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA

© Pharmaceutical Press 2009

is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain

First published 2009

Typeset by J&L Composition, Scarborough, North Yorkshire

Printed in Great Britain by Cromwell Press Group, Trowbridge

ISBN 978 0 85369 751 0

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, without the prior written permission of the copyright holder.

The publisher makes no representation, express or implied, with regard to the accuracy of the information
contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that
may be made.

The right of Pulok K Mukherjee and Peter J Houghton to be identified as the editors of this work has been
asserted by them in accordance with the Copyright, Designs and Patents Act, 1988.

A catalogue record for this book is available from the British Library
Contents

Preface viii
Contributors ix
Glossary xiii

Part 1 Overview of various types of traditional medicine 1

1 The worldwide phenomenon of increased use of herbal products:

opportunities and threats 3

2 Developing herbal medicinal products with quality, safety and efficacy:

from field to bedside, with particular reference to the situation in India 13

3 Natural remedies from Turkey: perspectives of safety and efficacy 28

4 Traditional Chinese medicines: the challenge of acceptance by

Western medicine 42

5 Traditional Chinese medicines: evaluation of botanical extracts and

dietary supplements 62

6 Synergy and polyvalence: paradigms to explain the activity of herbal products 85

7 From clinical evidence to mechanism of action: the development of

standardised phytomedicines 95

Part 2 Pharmacological evaluation for some therapeutic areas 105

8 Herbal medicines for functional gastrointestinal disorders: study

methods for quality, safety and efficacy 107

9 Therapy and prevention of hepatocellular carcinoma using herbal drugs 122

vi | Contents

10 Testing of herbal products used to treat infections 133

11 Natural products research in Helicobacter pylori infections 149

12 Evaluation of the efficacy of herbal medicinal products used to treat

cardiovascular diseases 160

13 Herbal medicinal products as antiangiogenic agents: perspectives

and evaluation 174

14 Herbs affecting the central nervous system 187

15 Herbs used to treat respiratory conditions other than infections 203

16 Immunomodulatory herbal medicinal products: establishing standards

and activity, with particular reference to herbs used in Ayurveda 215

17 Tests on Indian and Peruvian medicinal plants used for wound healing 228

18 Evidence of the efficacy of herbal medicinal products used for conditions

associated with inflammation 243

19 Tests for antioxidant activity and their relevance to herbal medicinal products 261

20 Herbal medicinal products affecting memory and cognitive disorders 282

21 Evaluation of herbal medicinal products against herpes virus diseases 295

22 Herbal medicinal products for tinnitus: perspectives and evaluation 314

23 Traditional herbs for healthcare – turmeric: a case history 322

24 Safety and efficacy of Hachimi-jio-gan: a Chinese preparation to

counteract oxidative damage 340

Part 3 Product development 357

25 Essential oils in the treatment of skin diseases: aspects of efficacy

and toxicology 359

26 Shelf-life of herbal remedies: challenges and approaches 369

 Contents | vii

Part 4 Evaluation of quality and safety 381

27 Authentication and quality assessment of botanicals and botanical

products used in clinical research 383

28 Quality control of Chinese herbal drugs 393

29 Clinical trials as signposts to efficacy 426

30 Toxicological evaluation of herbal medicines: approaches and perspectives 444

31 Safety evaluation of herbal medicines 457

Index 479
Preface

It would be impossible in one book to cover every However, we hope that this collection of articles
possible aspect of the evaluation of herbal medicinal gives a sufficient overview of approaches to the eval-
products. Apart from the large number of plant uation of herbal medicinal products to enable others
species used throughout the world for medicinal to produce similar articles to make the picture more
purposes, there are many disease states, geographical complete.
regions and cultural considerations. Our aim is to improve the level of understanding
Consequently, some will be disappointed that a of the various avenues that are needed to provide a
topic has not been included, which they think impor- fully rounded evaluation of these materials, so that
tant, while others will think that a particular they can be used with greater confidence, because
geographical area, disease state or analytical method of improved quality and an increasing scientifically
has been overemphasised or neglected! sound evidence base.
We make no pretence of claiming that this
volume is comprehensive, and recognise that there Pulok K Mukherjee
are many interesting and exciting developments in Peter J Houghton
analytical approaches and biological studies which
are barely mentioned.
Contributors

Bolanle A Adeniyi Cees J Beukelman

Departments of Pharmacy Practice, and Medicinal Section Medicinal Chemistry and Chemical Biology,
Chemistry and Pharmacognosy, UIC PAHO/WHO Department of Pharmaceutical Sciences, Faculty of
Collaborating Center for Traditional Medicine, Sciences, Utrecht University, Utrecht, The Netherlands
and b PhytoGeniX BV, Utrecht, The Netherlands
University of Illinois at Chicago, College of Pharmacy,
833 South Wood Street, Chicago, IL 60612, USA Sujit K Bhattacharya
ICMR Virus Unit, I D & B G Hospital Campus,
O P Agarwal
Beliaghata, Kolkata 700 010, India
Indian Council of Medical Research, Ansari Nagar,
New Delhi 110 029, India Tuhin Kanti Biswas
J B Roy State Ayurvedic Medical College and
K F H Nazeer Ahmed Hospital, 170–172, Raja Dinendra Street, Kolkata
School of Natural Product Studies, Department of 700 004, India
Pharmaceutical Technology, Jadavpur University,
Shrabana Chakrabarti
Kolkata 700 032, India
S N Pradhan Centre for Neurosciences, University of
Stanley O Aniagu Calcutta, 244B Acharya J C Bose Road, Kolkata 700
020, India
Molecular Pathobiology Group, School of
Biosciences, University of Birmingham, Birmingham, Sekhar Chakraborty
UK ICMR Virus Unit, I D & B G Hospital Campus,
Beliaghata, Kolkata 700 010, India
Rudolf Bauer
Institute of Pharmaceutical Sciences, Department of Debprasad Chattopadhyay
Pharmacognosy, Universitätsplatz 4/1, 8010 Graz, ICMR Virus Unit, I D & B G Hospital Campus,
Austria Beliaghata, Kolkata 700 010, India

Ezra Bejar Raymond Cooper

Herbalife International, Century City, CA 90067, PhytoScience Inc, PO Box 1935, Los Altos CA
94023, USA
USA
Larry H Danziger
Albert J J van den Berg
Departments of Pharmacy Practice, and Medicinal
Section Medicinal Chemistry and Chemical Biology, Chemistry and Pharmacognosy, UIC PAHO/WHO
Department of Pharmaceutical Sciences, Faculty of Collaborating Center for Traditional Medicine,
Sciences, Utrecht University, Utrecht, The Netherlands University of Illinois at Chicago, College of Pharmacy,
and b PhytoGeniX BV, Utrecht, The Netherlands 833 South Wood Street, Chicago, IL 60612, USA
x | Contributors

Cynthia L Darlington K B Harikumar

Department of Pharmacology and Toxicology, Amala Cancer Research Centre, Thrissur 680 555,
School of Medical Sciences, University of Otago Kerala, India
Medical School, Dunedin, New Zealand
P J Houghton
Sonali Das Department of Pharmacy, King’s College London,
ICMR Virus Unit, I D & B G Hospital Campus, Franklin Wilkins Building, 150 Stamford Street,
Beliaghata, Kolkata 700 010, India London SE1 9NH, UK

Rajendra M Dobriyal Tianan Jiang

Herbal Research Labs, Hindustan Unilever Research Life Extension Inc, 1100 West Commercial Boulevard,
Center, 64 Main Road, Whitefield, Bangalore 560 Fort Lauderdale, FL 33309, USA
066, India
Ki Sung Kang
Brian J Doyle Institute of Natural Medicine, University of Toyama,
Departments of Pharmacy Practice, and Medicinal 2630 Sugitani, Toyama, 930-0194, Japan
Chemistry and Pharmacognosy, UIC PAHO/WHO
Collaborating Center for Traditional Medicine, David O Kennedy
University of Illinois at Chicago, College of Pharmacy, Brain, Performance and Nutrition Research Centre,
833 South Wood Street, Chicago, IL 60612, USA Northumbria University, Newcastle upon Tyne NE1
8ST, UK
Cristobal Fraga
Department of Physiology, University of Santiago de Arif-ullah Khan
Compostela, Spain Natural Product Research Division, Department
of Biological and Biomedical Sciences, Aga Khan
A Gantait University, Karachi 74800, Pakistan
School of Natural Product Studies, Department of
Pharmaceutical Technology, Jadavpur University, Burt H Kroes
Kolkata 700 032, India Medicinal Chemistry and Chemical Biology Section,
Department of Pharmaceutical Sciences, Faculty of
Anwarul Hassan Gilani Sciences, Utrecht University, Utrecht, The Netherlands
Natural Product Research Division, Department of
Biological and Biomedical Sciences, Aga Khan N Satheesh Kumar
University, Karachi 74800, Pakistan School of Natural Product Studies, Department of
Pharmaceutical Technology, Jadavpur University,
R Govindarajan Kolkata 700 032, India
National Botanical Research Institute, Rana Pratap
Marg, Lucknow 226 001, India V Kumar
School of Natural Product Studies, Department of
Wandee Gritsanapan Pharmaceutical Technology, Jadavpur University,
Department of Pharmacognosy, Faculty of Pharmacy, Kolkata 700 032, India
Mahidol University, 447 Sri-Ayuthaya Road,
Ratchatevi, Bangkok 10400, Thailand Ramadasan Kuttan
Amala Cancer Research Centre, Thrissur 680 555,
S Bart A Halkes Kerala, India
Section Medicinal Chemistry and Chemical Biology,
Department of Pharmaceutical Sciences, Faculty of
Sciences, Utrecht University, Utrecht, The Netherlands
and b PhytoGeniX BV, Utrecht, The Netherlands
 Contributors | xi

Talash Anne Likimani Lara O Orafidiya

Herbalife International, Century City, CA 90067, Department of Pharmaceutics, Obafemi Awolowo
USA University, Ile-Ife, Nigeria

Chang-Xiao Liu Srikanta Pandit

Tianjin Institute of Pharmaceutical Research, Tianjin J B Roy State Ayurvedic Medical College and Hospital,
300193, China Kolkata 700 004, India

Tracie Locklear Alexander G Panossian

Departments of Pharmacy Practice, and Medicinal Swedish Herbal Institute Research and Development,
Chemistry and Pharmacognosy, UIC PAHO/WHO Gothenburg, Sweden
Collaborating Center for Traditional Medicine,
University of Illinois at Chicago, College of Pharmacy, Bhushan Patwardhan
833 South Wood Street, Chicago, IL 60612, USA Interdisciplinary School of Health Sciences, University
of Pune, Pune, India
Gail B Mahady
Departments of Pharmacy Practice, and Medicinal Roman Perez-Fernández
Chemistry and Pharmacognosy, UIC PAHO/WHO Department of Physiology, University of Santiago de
Collaborating Center for Traditional Medicine,
Compostela, Spain
University of Illinois at Chicago, College of Pharmacy,
833 South Wood Street, Chicago, IL 60612, USA Werayut Pothitirat
Mohua Maulik Department of Pharmacognosy, Faculty of Pharmacy,
Mahidol University, 447 Sri-Ayuthaya Road,
Indian Council of Medical Research, New Delhi,
Ratchatevi, Bangkok 10400, Thailand
India
K C Preethi
Subir Kumar Maulik
Amala Cancer Research Centre, Thissur 680 555,
Department of Pharmacology, All India Institute of
Kerala, India
Medical Sciences, New Delhi, India
P Pushpangadan
Royce Mohan
Amity Institute for Herbal and Biotech Products
Departments of Ophthalmology & Visual Science
Development, Mannamoola, Peroorkada, Trivandrum-
and Pharmaceutical Sciences, Angiogenesis Discovery
5, Kerala, India
Research, Lexington, KY 40536-0305, USA

Kakali Mukherjee Gulam Nabi Qazi

School of Natural Product Studies, Department of Hamdard University, Hamdard Nagar, New Delhi,
Pharmaceutical Technology, Jadavpur University, India
Kolkata 700 032, India
Sujay Rai
Pulok K Mukherjee School of Natural Product Studies, Department of
School of Natural Product Studies, Department of Pharmaceutical Technology, Jadavpur University,
Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India
Kolkata 700 032, India
Vietla S Rao
DB Anantha Narayana Department of Physiology and Pharmacology,
Herbal Research Labs, Hindustan Unilever Research Faculty of Medicine, Federal University of Ceara,
Center, 64, Main Road, Whitefield, Bangalore 560 Rua Cel Nunes de Melo-1127, Porangabussu;
066, India Fortaleza, CE, Brazil
xii | Contributors

José-Luis Ríos Eva M Vigo

Departament de Farmacologia, Facultat de Farmàcia, Department of Physiology, University of Santiago de
Universitat de Valància, Spain Compostela, Spain

B P Saha A Wahile
School of Natural Product Studies, Department of School of Natural Product Studies, Department of
Pharmaceutical Technology, Jadavpur University, Pharmaceutical Technology, Jadavpur University,
Kolkata 700 032, India Kolkata 700 032, India

Kumar N Satheesh
Eva M Wenzig
School of Natural Product Studies, Department of
Institute of Pharmaceutical Sciences, Department of
Pharmaceutical Technology, Jadavpur University, Pharmacognosy, Universitätsplatz 4/1, 8010 Graz,
Kolkata 700 032, India Austria

Samuel Seoane Jenneke A Wijbenga

Department of Physiology, University of Santiago de Scientific Institute Dutch Pharmacists, The Hague,
Compostela, Spain The Netherlands

Christine M Slover Georg C Wikman

Departments of Pharmacy Practice, and Medicinal Swedish Herbal Institute Research and Development,
Chemistry and Pharmacognosy, UIC PAHO/WHO Gothenburg, Sweden
Collaborating Center for Traditional Medicine,
University of Illinois at Chicago, College of Pharmacy, Edwin van den Worm
833 South Wood Street, Chicago, IL 60612, USA Section Medicinal Chemistry and Chemical Biology,
Department of Pharmaceutical Sciences, Faculty of
Paul F Smith Sciences, Utrecht University, Utrecht, The Netherlands
Dept. of Pharmacology and Toxicology, School of
Medical Sciences, University of Otago Medical
Pei-Gen Xiao
School, Dunedin, New Zealand Institute of Medicinal Plants, Chinese Academy of
Medical Science, Beijing, 100094, China
Nai-Ning Song
Noriko Yamabe
Tianjin Institute of Pharmaceutical Research, Tianjin
Institute of Natural Medicine, University of Toyama,
300193, China
2630 Sugitani, Toyama, 930-0194, Japan
Roy Upton
Erdem Yesilada
Registered Herbalist, Executive Director, American
Yeditepe University, Faculty of Pharmacy, Kayisdagi,
Herbal Pharmacopoeia, Scotts Valley, CA, USA
34755 Istanbul, Turkey
Ashok Vaidya Takako Yokozawa
ICMR Advanced Centre of Reverse Pharmacology, Institute of Natural Medicine, University of Toyama,
MRC-KHS, Vile Parle, Mumbai, India 2630 Sugitani, Toyama, 930-0194, Japan

M Venkatesh Yiwen Zheng

School of Natural Product Studies, Department of Department of Pharmacology and Toxicology,
Pharmaceutical Technology, Jadavpur University, School of Medical Sciences, University of Otago
Kolkata 700 032, India Medical School, Dunedin, New Zealand
Glossary

Adverse drug reaction (ADR) In the pre-approval effects of an investigational product(s), and/or to
clinical experience with a new medicinal product or identify any adverse reactions to an investigational
its new usages, particularly as the therapeutic dose(s) product(s), and/or to study absorption, distribution,
may not be established, all noxious and unintended metabolism, and excretion of an investigational
responses to a medicinal product related to any dose product(s) with the object of ascertaining its safety
should be considered adverse drug reactions. The and/or efficacy. The terms ‘clinical trial’ and ‘clinical
phrase ‘responses to a medicinal product’ means that study’ are synonymous.
a causal relationship between a medicinal product
and an adverse event is at least a reasonable possi- Dietary supplement A product taken by mouth that
bility, i.e., the relationship cannot be ruled out. contains a ‘dietary ingredient’ intended to supplement
the diet. The ‘dietary ingredients’ in these products
Adverse event (AE) An AE is any untoward medical may include: vitamins, minerals, herbs or other botan-
occurrence in a patient or clinical investigation icals, amino acids, and substances such as enzymes,
subject who has been administered a pharmaceutical organ tissues, glandulars, and metabolites. Dietary
product but which does not necessarily have a causal supplements can also be extracts or concentrates, and
relationship with this treatment. An AE can therefore may be found in many forms such as tablets, capsules,
be any unfavourable and unintended sign (including soft gels, gel caps, liquids, or powders. They can also
an abnormal laboratory finding), symptom, or be in other forms (such as a bar) but if they are, infor-
disease temporally associated with the use of a mation on their label must not represent the product
medicinal (investigational) product, whether or not as a conventional food or as a sole item of a meal or
related to the medicinal (investigational) product diet.
(see the ICH guidance for Clinical Safety Data
Management: definitions and standards for expedited Directive 99/83/EEC on ‘well-established use’ The
reporting, E2A, 1994). Directive permitted the use of bibliographic refer-
ences in place of pharmacological and toxicological
Botanicals Plant-based or -derived ingredients. Any
testing of HMPs and the results of clinical trials
product that is made from plants or herbs. Botanicals
for products that have already been on sale in the
are obtained from plant material and may include
European Union as a medicinal product, for not
leaves, roots, bark and/or seeds. The plant material is
less than 10 years. Volume 2A of the Notice to
typically processed by milling and/or extraction to
Applicants clarifies the legal background of biblio-
produce the botanical dietary ingredient, aroma,
graphic applications as follows: ‘Where the
herbal medicinal product or traditional herbal
constituent or constituents of the medicinal product
medicine.
have a well-established medicinal use, with recog-
Clinical trial/study Any investigation in human nised efficacy and an acceptable level of safety,
subjects intended to discover or verify the clinical demonstrated by detailed references to published
pharmacological, and/or other pharmacodynamic literature’.
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