Associate Professor in Herbal Medicines, School of Pharmacy, University of Auckland, Auckland, New Zealand
José M. Prieto Garcia MPharm PhD MRSC FLS FHEA
Lecturer in Pharmacognosy, Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, University of London, London, UK
Simon Gibbons FRSC FLS
Professor of Medicinal Phytochemistry, Research Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK
Elizabeth M. Williamson BSc (Pharm) PhD MRPharmS FLS
Emeritus Professor of Pharmacy, School of Pharmacy, University of Reading, UK
FOREWORDS BY
A. Douglas Kinghorn BPharm MSc PhD DSc FRPharmS FAAAS FAAPS FLS FSP
Professor and Jack L. Beal Chair of Natural Products Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
Mark Blumenthal BA ND (hon causa) PhD (hon causa)
Founder and Executive Director, American Botanical Council; Editor-in-Chief, HerbalGram and HerbClip; Founder and Director, ABC-AHP-NCNPR Botanical Adulterants Program, Austin, Texas, USA
The rights of Michael Heinrich, Joanne Barnes, Simon Gibbons and Elizabeth M. Williamson to be identified as authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.
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Notices
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Dedication vii
Foreword ix
A. Douglas Kinghorn
Foreword xi
Mark Blumenthal
Preface xv
PART A FUNDAMENTALS OF PHARMACOGNOSY 1
SECTION 1 PHYTOTHERAPY AND PHARMACOGNOSY
1. Importance of plants in modern pharmacy and medicine 4
2. Pharmacognosy and its history: people, plants and natural products 13
SECTION 2 BASIC PLANT BIOLOGY
3. General principles of botany: morphology and systematics 29
4. Families yielding important phytopharmaceuticals 37
5. Ethnobotany and ethnopharmacy 52
SECTION 3 NATURAL PRODUCT CHEMISTRY
6. Natural product chemistry 65
7. Methods in natural product analytical chemistry 105
8. Isolation and structure elucidation of natural products 121
9. Anticancer natural products 142
SECTION 4 MEDICINES AND NUTRACEUTICALS/BOTANICALS DERIVED FROM PLANT EXTRACTS
10. Production, quality control and standardization of herbal materials 162
11. The complex chemistry and pharmacology of herbal medicines 173
12. Toxicity of herbal constituents 179
SECTION 5 MEDICINAL PLANTS IN TRADITIONAL MEDICINE SYSTEMS, COMPLEMENTARY AND INTEGRATIVE MEDICINE
13. Overview of medicinal plants in healthcare systems 185
14. Characteristics of traditional medicine systems using herbal substances 190
15. Western herbal medicine 192
16. ‘Oriental’ and ‘Asian’ forms of traditional medicine 196
17. African, American and Oceanian traditional medicine using herbal preparations 210
18. Complementary/alternative or ‘integrative’ therapies involving use of plant substances 218
19. Herbal medicine interactions 228
PART B IMPORTANT NATURAL PRODUCTS AND PHYTOMEDICINES USED IN PHARMACY AND MEDICINE 233
20. The gastrointestinal and biliary system 235
21. The cardiovascular system 250
22. The respiratory system 259
23. The central nervous system 273
24. Infectious diseases 286
25. The endocrine system 295
26. The reproductive tract 306
27. The musculoskeletal system 309
28. The skin 318
29. The eye 326
30. Ear, nose and oropharynx 328
31. Weight loss supplements 331
32. Miscellaneous supportive therapies for stress, ageing, cancer and debility 334
Index 345
Dedication
To our families, for their unfailing support throughout the preparation of this book, and to our many colleagues around the world who are interested in medicinal plants/ethnopharmacology, pharmacognosy and phytotherapy.
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Foreword
Worldwide, drugs derived from organisms continue to be important for the treatment and prevention of many diseases. Pharmacognosy, which is defined in this book as ‘the science of biogenic or nature-derived pharmaceuticals and poisons’, has been an established pharmaceutical science taught in institutions of pharmacy education for well over a hundred years.
The subject area has changed considerably since its initiation, having metamorphosed from a largely descriptive botanical and mycological field in the late 19th and early 20th centuries, to having much more of a chemical and biological focus within approximately the last 60 years. Today, pharmacognosy embraces the scientific study of mainly small-molecule organic compounds from plants, animals and microbes, of both terrestrial and marine origin. It has been estimated that almost 50% of new drugs introduced into medicine in Western countries over the last 70 years were either obtained directly from an ever more diverse range of organisms, or were otherwise derived from natural products. Even in an age of biotechnology, computer chemistry and refinements in chemical synthesis, there continues to be a steady stream of new natural productderived drugs approved by the U.S. Food and Drug Administration. Most of the new natural productderived drugs that have reached the market over the last decade and a half have been obtained from terrestrial microbe sources, but there are several other examples of both higher plant and marine animal origin. In the United States, the first two examples of ‘botanical drug products’ (sinecatechins from green tea – Camellia sinensis (L.) Kuntze and crofelemer from Croton lechleri Müll. Arg.) have received official approval within the last 10 years. Natural products continue to be widely utilized as laboratory probes for many different targets to help better understand cellular processes.
Pharmacognosy has evolved relatively recently to include the topics of phytotherapy and nutraceuticals. Also, the teaching of pharmacognosy has become more relevant than previously over the last 20 years, as a result of a substantially increased use of herbal remedies (phytomedicines) by the public, particularly in Europe, North America and Australasia. If the United States is taken as an example, community pharmacists have to deal with the availability of a rather bewildering array of thousands of ‘botanical dietary supplement’ products, of which many were introduced soon after the passage of the Dietary Supplement Health and Education Act of 1994. There are now many publications in the biomedical literature describing the biological properties and mechanistic parameters of purified constituents of dietary supplements of natural origin. Therefore, societal interest in pharmacognosy is likely to increase in the future as the biochemical role of phytomedicines, nutraceuticals and drugs of natural origin in general becomes more clearly defined.
The third edition of this volume, Fundamentals of Pharmacognosy and Phytotherapy, by Michael Heinrich, Joanne Barnes, José Prieto Garcia, Simon Gibbons and Elizabeth Williamson, aims to provide a contemporary perspective of natural product drugs providing an introduction into this field. The book is organized into two major parts, ‘Fundamentals of pharmacognosy’ (Part A) and ‘Important natural products and phytomedicines in medicine and pharmacy’ (Part B). Part A is divided into five sections, dealing, in turn, with: the history and importance of pharmacognosy and phytotherapy in pharmacy and medicine; relevant principles of botany and ethnobotany; the chemistry and analysis of secondary metabolites of organisms pertinent to drug therapy; the characterization and standardization of phytomedicines and nutraceuticals; and the use of
A. DOUGLAS KINGHORN
medicinal plants in Oriental and South Asian systems of traditional medicine, as well as in Western complementary and alternative medicine. Part B provides coverage of the use of phytomedicines in various therapeutic categories, affecting, respectively: the gastrointestinal system and biliary system; the cardiovascular system; the respiratory system; the central nervous system; infectious diseases; the endocrine system (including effects on diabetes); the reproductive tract; the musculoskeletal system and bones; the skin; the eyes; the ears, nose and orthopharynx; weight loss supplements; and miscellaneous supportive therapies. Some of these categories are new for this third edition of the book.
This comprehensive pharmacognosy textbook integrates very effectively the various traditional elements of pharmacognosy and phytotherapy. The five talented coauthors have been successful in this endeavour in large part because they have contributed their collective and complementary technical expertise in several diverse areas, including ethnobotany and ethnopharmacology,
classical botanical pharmacognosy, natural product and analytical chemistry, phytochemistry, phytotherapy and clinical pharmacy.
This new edition may be confidently recommended for purchase by undergraduate and professional doctoral students in pharmacy, as well as beginning graduate students in programmes in the pharmaceutical sciences and related areas. It will also be of great interest for use in continuing education courses for pharmacists, dentists, nurses and physicians. In addition, all those with a scientific interest in herbalism and traditional medicine will find the content of value. The book will moreover serve as a reliable source of information on natural product drugs for the interested lay reader. The previous editions of Fundamentals of Pharmacognosy and Phytotherapy have proven to be very highly regarded by readers. This updated and partially reorganized volume will be especially warmly welcomed by educators of future pharmacists and of other healthcare professionals.
Foreword
Consumer interest in and use of herbs, teas, medicinal plants, phytomedicines, plant-derived ingredients and so-called ‘nutraceuticals’ has been growing worldwide over the past four decades. Scientific and clinical research on the chemistry, pharmacology, toxicology, and clinical applications of medicinal plants and related products is accelerating at a significant rate. The growth of publications on such research increased almost 700% in a 30-year period from 1977 to 2007, and if such growth in research publications were measured today (2017), the rate of the continued increase might be even higher.
Accordingly, the corresponding need for reliable professional educational materials on these increasingly popular natural products has never been more compelling.
Consumers continue to purchase and utilize herbs and medicinal plant products in growing numbers. They are regulated in a variety of ways, either as a form of food or as various types of medicines: dietary supplements in the US and food supplements in the European Union (EU), so-called Traditional Herbal Medicines in the EU, Natural Health Products in Canada, and other names for a wide spectrum of product formulations that are regulated under a variety of regulatory regimes.
Pharmacognosy is the study of drugs of natural origin, whether they are derived from plants, bacteria, fungi, or animals. Many modern drugs are derived directly from plants – a truism that is commonly known among pharmacists, physicians, researchers, and even many educated consumers. Classic examples include the still-employed cardiac drug digoxin (from the toxic foxglove plant, Digitalis purpurea and D. lanata), the anti-inflammatory drug colchicine (from the also toxic Mediterranean autumn crocus, Colchicum
autumnale) and the analgesic and anodyne opiates –codeine and morphine – from the opium poppy (Papaver somniferum). The latter (morphine) is the very first plant-based drug (isolated in 1804). In relatively rapid succession, in the early 19th century other plant-derived single-chemical entity drugs were isolated from their plant sources: strychnine (from Strychnos nux-vomica), the antimalarial quinine (from the South American cinchona bark, Cinchona officinalis), and numerous others, giving rise to the modern pharmaceutical industry.
In recent years there has been some debate among researchers as to whether the search for new pharmaceutical drugs from plants is a worthwhile endeavour. Chemists normally prefer the purity of single-chemical entity (SCE) drugs, whether natural or synthetic, and chemical synthesis has often been the preferred route of discovery, when appropriate, usually due to the lower cost and chemical simplicity of SCEs, i.e. when compared to the chemically complex botanical materials – roots, leaves, barks, flowers, seeds, etc., and their extracts.
Investigations into the long history of the use of medicinal plants in indigenous cultures – the sciences of ethnobotany and ethnopharmacology – has often produced excellent leads for the development of new medicines. Although now dated, the most-cited study of this process was published by the World Health Organization in 1979 in which 119 modern plantderived drugs were listed (including, of course, all those mentioned above). Not surprisingly, the modern applications of 74% of these drugs correlated directly with the traditional ethnobotanical uses of their source plants.
Lest anyone think that the ethnobotanical approach to drug discovery is an archaic and/or futile endeavour, one only need review the blockbuster news in
MARK BLUMENTHAL
the medical plant community in 2015 that Chinese researchers were granted the Nobel Prize in Physiology or Medicine for discovery of the highly successful antimalarial drug artemisinin, derived from the traditional Chinese herb quinghao (Artemisia annua, sometimes referred to as sweet wormwood). Traditional uses of this plant for reducing intermittent fevers led to its being investigated by Chinese scientists in the 1970s when seeking leads for the development of a new antimalarial drug.
Further interest is generated by the recent development and official United States government approval of two new plant-derived chemically complex medicines, a tannin-rich extract of green tea (Camellia sinensis) in an ointment for the topical treatment of human papilloma virus and an oligomeric proanthocyanidinrich extract of the exudate of the bark of a South American tree sangre de drago (Croton lechlerii, dragon’s blood) for symptomatic relief of diarrhoea in HIV/ AIDS patients on antiretroviral therapy. Approval of new chemically complex plant-derived medicines is probably inevitable and may constitute a new era in pharmacy and medicine.
Medicinal plants have played and will continue to play a significant role in the development of modern medicines, and will continue to be used by the public as self-selected medicines and supplements. Correspondingly, a growing number of licensed health professionals also recommend or prescribe medicinal plant-based supplements and related natural products.
Of particular interest is the increased consumer acceptance and use of herbs and medicinal plant products in industrialized nations. In the U S market, retail sales of herbs and other plant-based dietary supplements in 2015 reached almost US$7 billion – a new record for sales in the United States. These sales data do not reflect similar growth in other countries. This does not reflect the additional sales volume related to the use of herbal teas or the growing use of botanical ingredients in cosmetics and, more recently, in conventional foods, e.g. nutrition bars.
What should be immediately clear from examining a list of top-selling herbs (at least as it represents consumer demand in the United States) is the presence of many botanicals that have a long history of food use, either as spices and food flavourings and/or as conventional foods.
Popular spices such as turmeric root and rhizome (Curcuma longa), the top-selling supplement in the United States in the natural food store channel for the past 4 years, garlic (Allium sativum), ginger (Zingiber officinale), and red pepper (Capsicum annuum) are used
by consumers for a variety of traditional and clinically documented health benefits. Conventional foods, such as cranberry (Vaccinium macrocarpon), bilberry (Vaccinium myrtillus, an anthocyanin-rich type of blueberry), pomegranate (Punica granatum), soy (Glycine max), and/or their extracts have gained significant popularity as dietary supplements and phytomedicines in various countries, again based on the growing amount of clinical research demonstrating their obvious safety, as well as their activity/efficacy in published clinical trials.
This brings a relatively new spectrum of plants to the pharmacognosist for study of their chemistry, pharmacology, toxicology, and various ways that these substances in raw, dried, powdered form, or as extracts (and essential oils) can be formulated for optimal consumption by a growing consumer base interested in safe, effective, reliable natural products.
With the increased acceptance of the healthpromoting benefits of many food items, one can forecast that future pharmacognosy educational materials will recognize the field of nutritional biochemistry as an equally important area of research. The growing trend of ‘food as medicine’ is rife with opportunities for pharmacists, physicians, and dietitians/nutritionists to share vitally important information for the benefit of health consumers.
While consumer demand for natural health products continues to grow and the market responds with an almost dizzying array of natural products, one of the most important recent developments is the growing concern of botanical experts regarding the quality and identity of botanical raw materials, extracts, and essential oils.
Quality issues related to herbal ingredients have come under increased scrutiny due to increased reports of problems related to the first issue noted above, i.e. the adulteration of the raw materials, extracts, or essential oils with undisclosed lower-cost ingredients. While adulteration with another plant can be a result of accidental misidentification of the plant in the field or in processing and/or inadequate training of harvesting and processing personnel, reliable reports continue to confirm the highly lamentable practice of intentional adulteration of botanical materials used as ingredients in consumer products meant for health effects, e.g. dietary/food supplements. Adulterated botanical materials are also found in cosmetic products and other items for topical use.
There are generally two areas of concern when it comes to medicinal plant quality: (1) identity and authenticity, and (2) purity. With respect to the former,
the first priority in any effective quality-control system for herbs and medicinal plants is ensuring the proper identity of the raw plant material, whether it is to be used as simply raw material for a consumer product (e.g. a herbal tea or capsule), or whether it is to be used as the starting material for the creation of a botanical extract (made with one or more solvents) or distilled into an essential oil. The second priority of purity deals with ensuring that the raw material does not contain any excessive levels of other plant materials (pharmacopeias usually allow up to 2% of foreign organic material in herbal starting materials used for medicinal purposes), excessive levels of pesticides or other agricultural chemicals or excessive levels of heavy metals (often derived from soil or water), and that there is no microbial contamination.
Adulteration of foods, spices, botanical drugs, and medicinal products is not a recent phenomenon. Recent publications document the problem of substitution with undisclosed lower-cost materials and/or dilution with such ingredients going as far back as 2000 years, and probably even earlier. It was for this reason that the first pharmacopeia was initiated in the late 15th century – as a means to compile methods to ensure the proper botanical identity of herbal drugs and to detect known adulterants.
As a section of this book demonstrates, botanical authentication is a necessary first step in any robust and effective quality-control system used in the various areas of the supply chain and manufacturing in the botanical industry. Plant species identification and authentication is conducted using various techniques – macroscopic and organoleptic, microscopic, chemical and genetic. Industry and nonprofit groups
continually offer training programmes on these techniques in order to serve the increasingly specialized quality-control needs of the global botanical industry. Accordingly, there is a growing need in the burgeoning botanical industry for well-qualified technicians and scientists with adequate training in medicinal plant identity, authentication, and other means of appropriate qualification, e.g. botanists, pharmacognosists, natural product chemists, and others. This textbook presents as an excellent reference contributing to such education and training.
While earlier pharmacognosy texts tended to be organized on a phytochemical basis (e.g. alkaloids, glycosides, tannins, etc.), this text takes the rational approach of organizing the content based on a therapeutic and clinical basis – physiological systems upon which the natural medicines have their primary actions and uses (e.g. cardiovascular system, nervous system, digestive system, etc.). The authors, all experts in pharmacognosy, also provide essential and rational information for the appropriate use of medicinal plants in therapy, especially as practiced by licensed health professionals.
This book, the third edition of a work that has gained significant prominence and respect as a leading textbook, contains highly valuable and authoritative information for anyone who is a student of pharmacy and/ or pharmacognosy. It is also a valuable reference for industry quality-control personnel, herbalists, natural product researchers, and others in the health professionals who wish to learn about the growing popularity of herbs and medicinal plants and how natural botanical preparations can provide a growing range of safe and effective health benefits for consumers worldwide.
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Preface
In the last few decades, pharmacognosy (the study of drugs of natural origin) as an academic discipline, and its application in healthcare, has changed remarkably but still focuses on the quality of products and the development of new medicines Anagnostou and Heinrich, 2017. There has been a revival of interest in natural products as sources of new drugs, phytotherapy and herbal medicines highlighting the responsibilities of healthcare professionals. This has created the need to provide teaching and learning in these topics for students of pharmacy, medicine, nursing and other health professions, including medical herbalism. Knowledge about plant-derived medicinal products is essential in all areas of healthcare, not only because these forms of treatment are a popular healthcare choice (often used as self-medication) but because of the importance of them in many traditional medical systems globally. This text aims to provide a contemporary, therapeutics-oriented perspective on plants as medicines, as well as a general overview of the topic that non-specialist readers will find interesting and useful. This book is not a guide to treatment, rather, it is a textbook presenting the scientific principles and summarizing the traditional, preclinical and clinical evidence underpinning the use of herbaland other plant-derived medicines. The content has arisen, in part, from new lecture courses developed by the authors, as well as from developments in the analysis, evidence-based practice and regulation of herbal medicines. The book covers all fundamental aspects of pharmacognosy, as well as topics relating to the therapeutic use of plant drugs, known as phytotherapy. The text is unique in covering the subject of medicinal plants as an important element of contemporary healthcare, an approach that reflects the current public interest in it.
The book combines sections on the scientific study of plant drugs – phytochemistry, ethnopharmacy and botany – with descriptions of traditional medicine systems, such as Western medical herbalism, traditional Chinese medicine (TCM), and Ayurvedic medicine. For this edition, a new chapter covering the analysis of complex plant mixtures has been added (phytochemical analysis) and summaries of Australian Aboriginal medicine, Rongoā Māori (Aotearoa New Zealand), Kampo (Japan), Unani (India, Pakistan, Middle East), Jamu (Indonesia, Malaysia) and the traditional medicine of the Americas, have also been included. This new material is introduced and supported by a new overview of medicinal plants in healthcare systems. As in previous editions, a separate chapter covers ‘integrative’ or ‘complementary/alternative’ therapies, such as aromatherapy, homoeopathy and others, if it involves the use of plant-derived substances.
The fully revised and updated Part B continues to provide a comprehensive summary of the use of and evidence for herbal medicines and pure natural substances in different medical conditions, organized into therapeutic categories based on the British National Formulary (BNF) classification. Numerous medicinal plants and a new section on superfoods have been added. Natural product-derived drugs include those produced by biotechnology and from animal and microbial sources; these are vast and important subjects, so comprehensive coverage was not possible in this text.
Our intention is to equip the reader with the information and knowledge necessary to understand the role of natural products in the drug discovery process, and to enable the assessment of potential benefits and harms of plant-based medicines when advising patients who wish to use them. We aim to provide a
strong foundation in the scientific principles of plantderived drugs, focusing on their chemistry, with chemical structures where necessary and appropriate.
In this new edition, we have increased the references and further reading material in each section, so the reader can delve further into the subject, and consult the original work from which our information was taken. We thank all those who have contributed advice, suggestions and support, including our colleagues, both present and former, and the wider
Reference
Anagnostou, S., Heinrich, M., 2017. Pharmacognosy – from Pharmacographica to DNA-based techniques’? Planta Medica. doi.org/10.1055/s-0043–108999.
Pharmacognosiaceae. Finally, from our plant family to our own families, as ever, our deepest and warmest thanks are for you.
Last, but not least, Dr José Prieto Garcia has joined the team of authors.
Michael Heinrich
Joanne Barnes
José M. Prieto Garcia
Simon Gibbons
Elizabeth M. Williamson
PART A Fundamentals of pharmacognosy
Why are plants and their extracts still important in pharmacy and medicine? In 2015, the scientific importance of pharmacognosy and natural product research was highlighted globally. Prof. Youyou Tu (* 1930, China) was awarded the Nobel Prize in Physiology or Medicine ‘for her discoveries concerning a novel therapy against malaria’ and more specifically for the discovery and development of artemisinin, one of the most important antimalarial drugs we have today (Tu 2016) and to Prof. William C. Campbell (* 1930, Northern Ireland / USA) and Prof. Satoshi Ōmura (* 1935, Japan) ‘for their discoveries concerning a novel therapy against infections caused by roundworm parasites’. These two scientists led the development of avermectins, fungal metabolites from Streptomyces avermitilis and their derivatives (Campbell 1991, Ōmura and Shiomi 2007).
Historically, plants have yielded some of our most important drugs, but, with the great advances in medicinal chemistry of the last century, in many drug discovery programmes synthetic drugs superseded them as the main focus of research. However, the development of drugs using natural products as ‘lead’ molecules continues, and many plant-derived pure compounds (or natural products) are used in modern, conventional medicine; other compounds are potentially useful to humans or are of toxicological relevance.
There has also been a huge rise in the use of phytopharmaceuticals and herbal medicines in recent years, especially in North America, Europe and Australasia. Traditional medicine, which uses many plant remedies, remains an important (and in some cases, the only) form of treatment in many developing countries but is increasing throughout the world. People in many countries now want to cure minor health problems with something ‘natural’ and ageing populations have an increasing demand for
medicines and foods (‘nutraceuticals’) to help combat the symptoms and problems of ageing. This public demand is an enormous challenge for all health professionals, many of whom have little specialist knowledge of natural medicines.
This book is divided into two parts. The first part addresses the concepts that help in the understanding of the pharmacognostical basis of such medical products, including pharmaceutical, pharmacological, toxicological and phytochemical aspects. The second part is devoted to important plant-derived medicines, which are arranged in therapeutic categories.
Part A is devoted to the basic scientific principles underlying the use of medicinal plants, and the extracts and pure compounds (sometimes referred to as ‘natural products’) derived from them. This part is selective, and highlights those aspects most relevant to everyday practice. In the first chapter, a general introduction to the scientific field of pharmacognosy, and one of its main applications, phytotherapy, is given. Chapter 2 provides an overview of the historical development of plants in pharmacy and medicine, showing how the modern use of medicinal plants has evolved. In Chapters 3–5 the botanical basis of the discipline is summarized, covering classification and the use of plants by people with little or no access to modern medicine – known as ethnobotany and ethnopharmacy. Chapters 6–8 deal mainly with phytochemistry. Here, the types of compounds that may be present are discussed, together with their isolation and identification, using chromatographic and spectroscopic techniques. In Chapter 9 a very short overview of the process is given, from agricultural production or collection from the wild, to the processing of the pharmaceutical product or health-food supplement. Phytomedicines have particular attributes not encountered using synthetic drugs or single
compounds, in that the botanical drug or an extract derived from it may be combined with other herbal drugs or extracts. This may involve synergistic and other interactions; this is discussed in Chapter 10. Some ancient written traditions, such as Chinese and Ayurvedic medicine, have been passed on for centuries, and their practical use and philosophical basis are presented in Chapter 11. Chapter 12 looks at the complementary and alternative therapies that are currently popular in Europe, Australasia
and North America. These are non-science-based approaches to healing, to which pharmacists and members of the medical professions are now being more frequently exposed. More detailed information on these topics can be found in the further reading sections of each chapter. Due to lack of space, there is no section on biotechnology (e.g. fermentation and tissue culture), which is a more specialized area and of less relevance to practising pharmacists and medical doctors.
Section 1 Phytotherapy and pharmacognosy
SECTION CONTENTS
1. Importance of plants in modern pharmacy and medicine 4
2. Pharmacognosy and its history: people, plants and natural products 13
Chapter 1 Importance of plants in modern pharmacy and medicine
AIMS AND DEFINITIONS
This introductory textbook aims to provide a scientific basis for the use of plants in pharmacy (pharmacognosy) and also to describe the main characteristics of herbal medicines (herbal medicinal products, herbal remedies, phytomedicines) and their clinical use [herbal medicine (UK), Phytotherapy (Continental Europe)]. There is also an overview of some historical aspects of medicinal plants use by different societies (ethnobotany, ethnopharmacology) and on the role of plants in a variety of popular ‘nonscientific’ medical systems (traditional medicine).
Pharmacognosy (derived from pharmakon, ‘remedy’, and gignosco, ‘knowledge’) is the science of biogenic or nature-derived pharmaceuticals and poisons. It deals with all medicinal plants, including those yielding complex mixtures, which are used in the form of crude herbs (comminuted herbal substance) or extracts (phytotherapy), pure compounds such as morphine, and foods having additional health benefits only in the context of having preventive effects (nutraceuticals).
TYPES OF DRUGS DERIVED FROM PLANTS
HERBAL DRUGS, DERIVED FROM SPECIFIC PARTS OF A MEDICINAL PLANT
Botanical drugs that form the basis for herbal remedies or phytomedicines include, for example:
l The aerial parts of St John’s wort (Hypericum perforatum), used in the treatment of mild to moderate depression.
l The leaves of Ginkgo biloba, used for cognitive deficiencies (often in the elderly), including
impairment of memory and affective symptoms such as anxiety.
l The flower heads of chamomile (Chamomilla recutita), used for mild gastrointestinal complaints and as an anti-inflammatory agent.
l The leaves and pods of senna (Cassia spp.), used for constipation.
From the perspective of pharmacognosy and rational phytotherapy, such products lie alongside, and in some cases are, conventional pharmaceutical medicines. Herbal medicines are often considered to be part of complementary and alternative medicine (CAM), and the use of herbal medicinal products (HMPs) has increased alongside the increasing utilization of CAM across the developed world.
NATURAL PRODUCTS OR COMPOUNDS ISOLATED FROM NATURE
These are pure chemical entities, often used in the form of licensed medicines. They are sometimes produced synthetically and referred to as ‘nature identical’ (if that is the case), but were originally discovered from plant drugs. Examples include:
l Morphine, from opium poppy (Papaver somniferum), used as an analgesic.
l Digoxin and other digitalis glycosides, from foxglove (Digitalis spp.), used to treat heart failure.
l Taxol, from the Pacific yew (Taxus brevifolia), used as an anticancer treatment.
l Quinine, from Cinchona bark (Cinchona spp.), used in the treatment of malaria.
l Galanthamine from Galanthus and Leucojum species, used in the management of cognitive disorders.
NUTRACEUTICALS OR ‘FUNCTIONAL FOODS’
Many foods are known to have beneficial effects on health. Examples include:
l Garlic, ginger, turmeric and many other herbs and spices.
l Anthocyanin- or flavonoid-containing plants such as bilberries, cocoa and red wine.
l Carotenoid-containing plants such as tomatoes, carrots and many other vegetables.
USE OF HERBAL MEDICINES
Globally, the WHO (World Health Organization) now advocates universal health coverage and the integration of safe and effective traditional providers and complementary services into self-care practices and health service delivery, with a particular focus on herbal medicines. The use of these remedies is extensive, increasing and complex. In several surveys 20–33% of the UK’s population claimed to regularly use complementary and alternative medicine (CAM) alone or in addition to orthodox or conventional medicine and treatments. In the UK, usage is particularly frequent amongst those who are over-the-counter-medicines users. There is not, on the whole, a wide understanding of what herbal medicines are (or are not) (IPSOSMORI 2008). Healthcare professionals and students also commonly use such products. Forty-three percent of students at a University School of Pharmacy reported using at least one type of CAM during the last 12 months (Freymann et al 2006).
In the United States, approximately 38% of adults and approximately 12% of children are using some form of CAM (NIH/NCCAM). Kennedy et al (2008) showed that in the preceding 12 months about 38 million adults in the United States (18.9% of the population) used herbal medicines or supplements, but that only onethird revealed this use to their physician. Data for other regions are even more limited, but the usage of herbal medicines is widespread in countries like India, Indonesia, Australia and China, to name just a few.
In addition, market research data reveal high levels of expenditure on herbal medicines, although it is difficult to obtain precise figures for sales of such products since some are classed as food supplements and are sold through numerous outlets. For similar reasons, it is usually not possible to compare properly the estimates for expenditure on herbal medicines using different studies and in different countries. For
2009, it was estimated that the total value of the global market of herbal medicines was around $83 billion. In 2009 in the United States alone, consumers spent a total estimated $5 billion on herbal dietary supplements. In the UK in 2007, the market for herbal medicines was estimated to be almost £700 million, which, compared with many other European countries, is rather low. The European market for herbal supplements and herbal medicines is currently worth about $7.4 billion. Germany is the largest European market, with a 27% share, followed by France (24%), Italy (12%) and the UK (9%). The Indian healthcare market is valued at $7.3 billion, 60% of which is controlled by pharmaceutical drug manufacturers, while 30% is controlled by Ayurvedic medicine manufacturers, and the Chinese market is worth around $8 billion (Gruenwald 2008).
In most continental European countries, such phytomedicines are licensed medicinal products and are used under medical supervision. However, the widespread use of herbal medicines by the general public raises several important issues. Some of these relate to how individuals, whether consumers or healthcare professionals, perceive and use these preparations; other concerns relate to the quality, safety and efficacy of the herbal medicines themselves.
As part of the primary healthcare team, pharmacists, as well as nurses and general practitioners, need to be competent in advising consumers on the safe, effective and appropriate use of all medicines, including herbal medicines. Healthcare professionals also need to be aware that patients may be using products and making healthcare choices without their knowledge.
There are many reasons for the increased use of herbal medicines. These may range from the appeal of products from ‘nature’ and the perception that such products are ‘safe’ (or at least ‘safer’ than conventional medicines, which are often derogatorily referred to as ‘drugs’), to more complex reasons related to the philosophical views and religious beliefs of individuals.
In developed countries, most purchases of HMPs are made on a self-selection basis from pharmacies and health-food stores, as well as from supermarkets, by mail order and via the Internet. Normally, with the exception of pharmacists, there is no requirement for a trained healthcare professional to be available on the premises to provide information and advice and, in any case, most HMPs can be sold or supplied without the involvement of a healthcare professional. Several studies have confirmed that many individuals do not seek professional advice before purchasing or using such products, even when purchased from a pharmacy (Barnes et al 1998, Gulian et al 2002). Rather, consumers of HMPs
tend to rely on their own (usually limited) knowledge, or are guided by advice from friends and relatives or the popular media. Consumers who do seek professional advice (e.g. from their pharmacist or general practitioner) may find that they are not able to have their question(s) answered fully. In some cases this may be because the information simply is not available, but it is also recognized that, at present, many healthcare professionals are not adequately informed about herbal medicines, particularly with regard to their quality, safety and efficacy. This book attempts to redress that omission.
Herbal medicines are used for general health maintenance, as well as for treating disease and this includes serious conditions such as cancer, HIV/AIDS, multiple sclerosis, asthma, rheumatoid arthritis and osteoarthritis. Older patients, pregnant and breastfeeding women, and children also take HMPs, and this raises concerns because, as with conventional medicines, precautions need to be taken. For example, few medicines (whether conventional or herbal) have been established as safe for use during pregnancy and it is generally accepted that no medicine should be taken during pregnancy unless the benefit to the mother or foetus outweighs any possible risk to the foetus. Similarly, HMPs should be used with caution in children and the elderly, who, as with conventional medicines, differ from adults in their response, metabolism and clearance of drugs. The use of herbal medicines by patients who are already taking prescribed medicines is of particular concern as there is the potential for drug–herb interactions to occur. For example, important pharmacokinetic and pharmacodynamic interactions between St John’s wort (Hypericum perforatum L.) and certain conventional medicines have been documented (Williamson et al 2009) and mechanisms for such interactions have been identified. Generally, information on interactions between HMPs and conventional medicines is limited, although potential drug–herb interactions can sometimes be identified based on the known phytochemistry and pharmacological properties of the herbs involved.
These issues illustrate once more the need for healthcare professionals, and especially pharmacists, to be knowledgeable about HMPs, and professional bodies are increasingly mindful of their responsibilities regarding herbal medicines and have taken steps to address the issue. It is now recognized by the UK Committee on Safety of Medicines and the Medicines and Healthcare Products Regulatory Agency that pharmacists have an important role to play in pharmacovigilance regarding HMPs; this involves reporting suspected adverse reactions and disseminating information to patients and the public about safety concerns. Calls for healthcare profes-
sionals to be competent with regard to herbal medicines and other ‘complementary’ therapies are now coming from outside the professions.
In summary, the use of herbal products continues to be a popular healthcare choice among patients and the general public. Most pharmacies sell herbal medicines and it is likely that pharmacists will be asked for advice on such products or that they will have to consider other implications of herbal product use, such as interactions with conventional medicines. This book provides the scientific background to the use of plants as medicines.
SOME FUNDAMENTAL ASPECTS OF THE REGULATION OF HERBAL MEDICINES *
The regulation of herbal medicines is complex, varies greatly and is constantly changing. These diverse regulatory frameworks form an essential basis for the activities of all healthcare professionals and for research on such products. For example, in the UK, until recently Ginkgo biloba was considered a food and now is, as in other European countries, regulated as a traditional herbal medical product. It is a herbal medical product in Germany and a food supplement in the USA. In the UK echinacea may be a traditional herbal medical product or a food supplement or a registered medicine. It is classed as a dietary supplement in the USA and in general as a medicine in Germany. Therefore a brief and selective overview of the regulation of herbal medicines in key English-speaking countries is given here, excluding the regulation of the professions involved in their production, prescription and dispensing. We also include a short overview of the regulation of traditional Chinese medicines in the three key political entities where they are used widely: Hong Kong, People’s Republic of China and Taiwan.
UNITED KINGDOM
In essence today’s regulatory framework in the UK is very similar to those in other countries of the European Union (based on the regulation as of 2017). Historically, in the UK, many of the concerns regarding herbal medicinal products have arisen from the lack of regulation of such products. Consequently, such products lacked
*Acknowledgement: We gratefully acknowledge the input from many colleagues and their teams who provided information on the regulatory situation in individual countries: Eric Brand (TCM), Pulok Mukherjee (India), Hans Wohlmuth (Australia), Johannes v. Staden (South Africa) and Udoamaka Ezuruike (Nigeria).
evidence for acceptable standards for quality, safety and efficacy. A range of safety problems arose as a result of the use of unlicensed herbal preparations of inadequate pharmaceutical quality.
The basis for the current regulatory regime for the licensing of medicines in the UK is set out by the 1968 Medicines Act and other regulations that have arisen from the implementation of relevant European Commission legislation, namely Directive 65/65/EEC, now revised as Directive 2001/83/EC. Under this legislation, which has been in place since 2004, manufacturers of products, including herbal remedies, which are classed as medicinal products must hold a marketing authorization (MA, or product licence, PL) for that product unless it satisfies the criteria for exemption from the requirement for a MA. In essence, medicinal products are defined as those that are medicinal by presentation or (not and) by function. Manufacturers of products comprising new chemical entities, including isolated constituents from plant or other natural sources, are required to submit applications for MAs for those products, based on the full dossier of chemical, pharmaceutical, pharmacological, toxicological and clinical data.
Herbal products are available on the UK market as:
l Licensed herbal medicines.
l Traditional herbal medical products registered under the European ‘Traditional Herbal Medicinal Product Directive’ (THMPD)
l Herbal medicines exempt from licensing.
l Unlicensed herbal products, sold as food or dietary supplements.
l Prescription-only medicines (POM); these potentially hazardous plants may only be dispensed by order of a prescription by a registered doctor.
l Pharmacy-only medicines (P); certain others may only be supplied by a registered pharmacist, or may be subject to dose (but not duration of treatment) and route of administration restrictions.
Licensed herbal medicines
Most licensed herbal products in the UK were initially granted a product licence of right (PLR) because they were already on the market when the licensing system was introduced in the 1970s. When PLRs were reviewed, manufacturers of herbal products intended for use in minor self-limiting conditions were permitted to rely on bibliographic evidence to support efficacy and safety, rather than being required to carry out new controlled clinical trials. So, many licensed herbal
medicinal products have not necessarily undergone stringent testing. The ‘well-established use’ directive (99/83/EC) was intended to allow greater flexibility on the use of bibliographic data to demonstrate safety and efficacy, and it was hoped that this legislation would provide a regulatory framework for the many unlicensed herbal products on the market. Unfortunately, interpretations of the provisions of the directive vary between EU member states and this directive is not widely accepted in the UK.
Traditional herbal medical products
The Traditional Herbal Medicinal Products Directive (THMPD) 2004/24/EC (see http://www.mhra.gov .uk) is a regulatory process established to provide a mechanism whereby manufacturers of good-quality herbal medicines can register their products as medicinal products, and this allows them to make (restricted) medicinal claims on the packaging and the patient information leaflet (PIL):
l Evidence that a corresponding herbal product (i.e. one derived from the same botanical drug and prepared in a similar way) has been used traditionally for at least 30 years (15 years non-EU and 15 years in the EU, or more than 30 years in the EU).
l Bibliographic data on safety with an expert report.
l A quality dossier specifying how the company complies with the quality guidance requirements of the regulators.
l Details on the PIL, packaging, naming and labelling.
Products registered under this directive can only be used for minor, self-limiting conditions. Overall, it provides an assurance that the patient is receiving not only a good-quality product, but also more reliable advice on its use.
Unlicensed herbal medicines
HMPs still exempt from licensing are those ‘compounded and supplied by herbalists on their own recommendation’ [specified under Section 12(1) of the Medicines Act 1968] and those consisting solely of dried, crushed or comminuted (fragmented) plants. They must not contain any non-herbal ‘active’ ingredients and are sold under their botanical name and with no written recommendations for use [specified under Section 12(2) of the Medicines Act]. The exemptions
