Importance of plants in modern pharmacy and medicine

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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 uses [herbal medicine (UK), phytotherapy (Continental Europe)]. There is also an overview of some of the historical aspects of medicinal plant use in different societies (ethnobotany, ethnopharmacology) and of the role of plants in a variety of popular ‘non-scientific’ medical systems (traditional medicine).

Pharmacognosy (derived from Greek 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 which form the basis for herbal remedies or phytomedicines include, for example:

• the herb of St John’s wort (Hypericum perforatum), used in the treatment of mild to moderate depression

• the leaves of Ginkgo biloba, used for cognitive deficiencies (often in the elderly), including impairment of memory and affective symptoms such as anxiety

• the flower heads of chamomile (Chamomilla recutita), used for mild gastrointestinal complaints and as an anti-inflammatory agent

• 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) and of CAM has increased 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:

• morphine, from opium poppy (Papaver somniferum), used as an analgesic

• digoxin and other digitalis glycosides, from foxglove (Digitalis spp.), used to treat heart failure

• taxol, from the Pacific yew (Taxus brevifolia), used as an anticancer treatment

• quinine, from Cinchona bark (Cinchona spp.), used in the treatment of malaria

• 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:

• garlic, ginger, turmeric and many other herbs and spices

• anthocyanin- or flavonoid-containing plants such as bilberries, cocoa and red wine

• carotenoid-containing plants such as tomatoes, carrots and many other vegetables.

Use of herbal medicines

The use of these remedies is extensive, increasing and complex. In several surveys 20–33% of the UK population claimed to regularly use 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) (IPSOS-MORI 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 US (18.9% of the population) used herbal medicines or supplements, but that only one-third 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 is estimated that the total value of the global market in herbal medicines was around $83 billion. In 2009 in the USA alone consumers spent an estimated total of $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; the Chinese market comes in at around $8 billion.

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 of the products and healthcare choices that patients are making, often 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. In any case, most HMPs can be sold or supplied without the involvement of a healthcare professional and 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 he or she is not able to answer their question(s) 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.

HMPs are used for general health maintenance, as well as for treating diseases, including 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 fetus outweighs any possible risk to the fetus. Similarly, HMPs should be used with caution in children and the elderly, who, as with conventional medicines, differ from adults in their response to, and 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) 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 with regard to HMPs; this involves reporting suspected adverse reactions and disseminating information to patients and the public about safety concerns. Calls for healthcare professionals 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 a medicine in Germany. Therefore here a brief and selective overview of the regulation of herbal medicines in key English-speaking countries is given, excluding the regulation of the professions involved in their production, prescription and dispensing.

United kingdom

In essence, today’s regulatory framework in the UK, is very similar to the ones in other countries of the European Union. 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 evidence for acceptable standards for quality, safety and efficacy. A range of safety problems occurred 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 which 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, 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:

• licensed herbal medicines

• traditional herbal medical products registered under the European ‘Traditional Herbal Medicinal Product Directive’ (THMPD)

• herbal medicines exempt from licensing

• unlicensed herbal products, sold as food or dietary supplements

• prescription-only medicines (POM); these potentially hazardous plants may only be dispensed by order of a prescription by a registered doctor

• 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 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 make (restricted) medicinal claims on the packaging and the patient information leaflet (PIL). Examples of the types of information that may be displayed are given here:

• 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).

• Bibliographic data on safety with an expert report.

• A quality dossier specifying how the company complies with the quality guidance requirements of the regulators.

• Details on the patient information leaflet (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 were initially intended to give herbalists the flexibility to prepare remedies for their patients, although, at present, there is no statutory regulation of herbalists in the UK (this is under review).

Traditional medicines used by ethnic groups include Traditional Chinese Medicines (TCM) and Ayurvedic medicines. These products are subject to the same legislation as are ‘Western’ herbal medicines. Some toxic species, like Aristolochia sp., are banned. There still remain problems associated with some imported medicines: in addition to containing non-herbal ingredients such as animal parts and/or minerals, some manufactured (‘patent’) ‘herbal’ products have been found to contain conventional drugs which may have POM status in the UK (e.g. dexamethasone and glibenclamide) or which are banned. Non-herbal active ingredients of any type (chemically synthesized, animal products) cannot legally be included in herbal remedies, and inclusion of drugs with POM status represents an additional infringement of European and US legislation. Some ingredients, such as certain species of plants, are also restricted under the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES).

Australia

In Australia, Western herbal medicine is one of the most popular forms of CAM and a range of ethnic medicines, especially TCM, are increasingly becoming popular. All medicines, including herbal and other complementary medicines, are covered by the Therapeutic Goods Act (1989) and regulated by a federal agency, the Therapeutic Goods Administration (TGA, http://www.tga.gov.au/). A statutory expert committee, the Advisory Committee on Complementary Medicines (formerly the Complementary Medicines Evaluation Committee) provides the TGA with advice on the regulation of complementary medicines. The Australian regulatory guidelines for complementary medicines ( http://www.tga.gov.au/docs/html/argcm.htm) provide information to help producers and distributors of complementary medicines to meet their obligations under therapeutic goods legislation.

Australia adopts a two-tiered, risk-based approach to the regulation of all medicines. Low-risk medicines, including most herbal and complementary medicines, are included in the Australian Register of Therapeutic Goods (ARTG) as listed medicines and identified by a unique AUST L number of the label. Medicines deemed to be of higher risk are entered on the register as registered medicines and identified by an AUST R number. While registered medicines undergo full pre-market safety and efficacy evaluation, listed medicines are not evaluated for efficacy, but product sponsors must hold evidence to support the claims they make about the product. Random and targeted post-market audits of this evidence are carried out by the regulator. Indications and claims for listed medicines are limited to health maintenance, health enhancement or non-serious, self-limiting conditions and may be supported by evidence from traditional use or scientific evidence. Both listed and registered medicines must be made to pharmaceutical GMP standards, and herbal ingredients must conform to the relevant BP (AH thu EurPhar) monograph, if one exists.

Medicines extemporaneously compounded for a specific patient following consultation are exempt from inclusion on the ARTG; this allows herbalists and other practitioners to compound individualized formulae for their patients.

Canada

In Canada herbal medicines are classified as ‘natural health products’ which require a product licence before they can be marketed. The relevant agency is ‘Health Canada’. Since 2004 this is regulated in the The Natural Health Products Regulations. The system is intended to find an equilibrium between openness towards various health paradigms (e.g. Traditional Chinese Medicine, Ayurveda, Western traditional herbalism, etc.) and scientific rigor. Hence, specific health claims are allowed on the basis of a variable evidence base that becomes more stringent with the severity of the condition treated with a product. A manufacturer has to submit detailed information on the product to Health Canada, including: medicinal ingredients, source, potency, non-medicinal ingredients and recommended use(s). Once a product has been assessed and granted market authorization by Health Canada, the product label will bear an eight digit product licence number preceded by the distinct letters NPN (Natural Product Number), or, in the case of a homeopathic medicine, by the letters DIN-HM (Homeopathic Medicine Number).

This number on the label will inform consumers that the product license application has been reviewed and approved by Health Canada to meet the standards in terms of safety, efficacy and quality. GMPs (Good Manufacturing Practices) must be guaranteed in the products production in order to ensure the product’s quality and thus its safety. In addition the system requires that all Canadian producers and importers of natural health products are licensed.

Similar to the UK, an Adverse Reaction Reporting System for natural health products is in place and is used to warn the public (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/index-eng.php).

India

India has an ancient heritage of traditional medicine (see Chapter 12) with a well-recorded and widely practised knowledge of herbal medicine. The Department of Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homoeopathy (AYUSH) within the Ministry of Health & Family Welfare focuses on its regulation and on the improvement of standards in the areas of quality control and standardization of drugs, the availability of raw material, research and development, education/training of professionals, and a wider outreach with regard to these traditional medical systems.

The Traditional Herbal Medicines Act, 2006 regulates the sale of the traditional herbal medicines which are marketed without any licence and control on the basis of being from ancient texts. According to the Act every retailer or seller of traditional herbal medicines needs to have a licence to sell traditional herbal medicines from the Authority. Every manufacturer of traditional herbal medicine needs to work under the principles of GMP and has to list the ingredients of each medicine on the packing of the medicine along with their accurate quantity. Side effects and warning of contraindications need to be stated on the package. Pharmacopoeia Committees have been established to develop quality standards for the main groups of therapeutically relevant drugs of Ayurveda, Unani, Siddha and homoeopathy (Mukherjee et al 2007).

The Indian Government also established an independent body – the ‘National Medicinal Plants Board’ under the Ministry of Health and Family Welfare. It is responsible for co-ordinating all matters relating to the development of medicinal plants, including policies and strategies for conservation, proper harvesting, cost-effective cultivation and marketing of raw material in order to protect, sustain and develop this sector. Uniquely, the Indian government has established programmes for the documentation of traditional Indian knowledge, which is already available in public domain. The political goal is to safeguard the sovereignty of this traditional knowledge and to protect it from being misused in patenting on non-patentable inventions. The Traditional Knowledge Digital Library (TKDL) is an original proprietary database, which is fully protected under national and international laws of Intellectual Property Rights and is maintained and developed by the government. TKDL also allows automatic conversion of information from Sanskrit into various languages. The information includes names of plants, Ayurvedic description of diseases under their modern names and therapeutic formulations (Mukherjee et al 2007).

United states of america (USA)

In the USA, herbal medicines are generally regulated as ‘dietary supplements’. The US Food and Drug Administration (FDA, www.fda.gov/Food/DietarySupplements/) is in charge of these comparatively loose regulations (http://nccam.nih.gov/health/supplements/wiseuse.htm). Some key characteristics stand out:

• Prior to marketing, dietary supplements do not have to be assessed for safety and effectiveness. Limited therapeutic claims may be made, e.g. that a dietary supplement addresses a nutrient deficiency, supports health, or is linked to a particular body function (e.g. immunity). However, this requires supportive prior research. Such a claim must be followed by the words ‘This statement has not been evaluated by the U.S. Food and Drug Administration (FDA). This product is not intended to diagnose, treat, cure, or prevent any disease.’

• Since 2008 ‘Good manufacturing practices’ (GMPs) is expected in order to ensure that dietary supplements are processed consistently and meet quality standards.

• Once a dietary supplement is on the market, the FDA monitors the claims made and the product’s safety. If inappropriate claims are made the manufacturer receives a warning letter or is required to remove the product from the marketplace. If a product is found to be unsafe, the FDA takes similar action against the manufacturer and/or distributor.

References

Barnes J., Mills S.Y., Abbot N.C., et al. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br. J. Clin. Pharmacol.. 1998;45:496-500.

Freymann H., Rennie T., Bates I., Nebel S., Heinrich M. Knowledge and use of herbal medical products and other CAM among British undergraduate pharmacy students. Pharm. World Sci.. 2006;27:13-18.

Gulian C., Barnes J., Francis S.A., et al. Types and preferred sources of information concerning herbal medicinal products: face-to-face interviews with users of herbal medicinal products. International Journal of Pharmaceutical Practice. 2002;10(Suppl.):R33.

IPSOS – Mori. Public perceptions of herbal medicines general public qualitative & quantitative research. London, UK: IPSOS-Mori; 2008.

Kennedy J., Wang C.C., Wu C.H. Patient disclosure about herb and supplement use among adults in the US. Evid. Based Complement. Alternat. Med.. 2008;5:451-456.

Williamson E.M., Driver S., Baxter K., editors. Stockley’s herbal medicines. London: Interactions Pharmaceutical Press, 2009.

Further reading

Barnes J., Phillipson J.D., Anderson L.A. Herbal medicines. A guide for healthcare professionals, third ed. London: Pharmaceutical Press; 2009.

Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Berlin: Springer-Verlag; 1995.

Cavaliere C., Rea P., Lynch M.E., Blumenthal M. Herbal supplement sales rise in all channels in 2009. HerbalGram. 2010;86:82-85.

Evans W.C. Trease and Evans’s pharmacognosy, sixteenth ed. London: WB Saunders; 2009.

Hänsel R., Sticher O., editors. Pharmakognosie – phytopharmazie. Berlin: Springer, 2010.

McEwen J. What does TGA approval of medicines mean? Australian Prescriber. 2004;27:156-158.

Mills S., Bone K. Phytotherapy. Principles and practice. London: Churchill Livingstone; 2000.

Mukherjee P.K., Venkatesh M., Kumar V. An overview on the development in regulation and control of medicinal and aromatic plants in the Indian system of medicine. Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas (BLACPMA). 2007;6:129-136.

Robbers J.E., Speedie M.K., Tyler V.E. Pharmacognosy and pharmacobiotechnology. Baltimore: Williams & Wilkins; 1996.

Ross I. Medicinal plants of the world. Totawa, NJ: Humana Press, 1999;vol. I.

Ross I. Medicinal plants of the world. Totawa, NJ: Humana Press, 2000;vol. II.

Schulz V., Haensel R., Tyler V. Rational phytotherapy. Berlin: Springer-Verlag; 1998.

Thomas K.J., Nicholl J.P., Coleman P. Use and expenditure on complementary medicine in England: a population based survey. Complement Ther. Med.. 2001;9:2-11.

Williamson E. Potter’s herbal cyclopedia. Saffron Walden: CW Daniels; 2003.

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