Phytochemistry Letters 4 (2011) 391398

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Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol

Phytochemistry and traditional medicine A revolution in process

Geoffrey A. Cordell *
Natural Products Inc., 9447 Hamlin Ave, Evanston, IL 60203, USA

A R T I C L E I N F O

A B S T R A C T

Article history: Received 16 May 2011 Accepted 20 May 2011 Available online 2 June 2011 Keywords: Phytochemistry Traditional medicine New strategies Integrated technologies Safety and efcacy Health care

Selected contemporary aspects of the inextricable link between phytochemistry and traditional medicine are discussed. New technologies, including plant barcoding and principal component analysis, are being deployed in the development of strategies to provide an evidence base for the quality, safety and efcacy of traditional medicines, as a route to improved health care. The role of phytochemistry in underpinning this evolving evidence base is explored. 2011 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

1. Introduction It is widely considered that the birth of phytochemistry was the isolation of tartaric acid from grapes in 1769 by the Swedish chemist Carl Wilhelm Scheele, although Marggraf had isolated sucrose from sugar beets 22 years earlier. The seeds (arcanum) of biological activity in medicinal plants to which Theophrastus Bombastus von Hohenheim (Paracelsus) referred in the 15th century, we now call molecules. It was the therapeutic properties of these plants, disclosed by diverse cultures over the millennia, which formed the basis of health care the world over. In early part of the 19th century, one of the challenges was to study these active principles. The place to start the investigation was obvious; the most powerful, and probably the most notorious, traditional medicine on Earth, opium, Papaver somniferum L. The power of opium was legendary. Now, for the rst time, the curiosity was unbearable. Some primitive tools to investigate what was inside the plant were available, and some investigators had the courage to test the isolated material on themselves; the pharmacist apprentice rner did just that with opium, isolating morphine. Frederich Sertu A dramatic period of exploration followed, resulting in the

Abbreviations: AFLP, amplied fragment length polymorphism; CBOL, consortium on barcoding of life; CITES, convention on international trade in endangered species; GPS, global positioning system; HPLCMS, high performance liquid chromatographymass spectrometry; ISSR, inter-simple sequence repeat; IUPAC, international union of pure and applied chemistry; NAPRALERT, natural products alert; NMR, nuclear magnetic resonance; PCA, principal component analysis; RAPD, random amplied polymorphic DNA; WHO, World Health Organization. * Corresponding author. Tel.: +1 847 903 1886. E-mail address: pharmacog@gmail.com.

isolation of the main active ingredients of the most famous traditional medicines of the time, strychnine, emetine, piperine, caffeine, quinine, colchicine, and, in 1826, coniine. proposed the linking of carbon atoms in After August Kekule 1858, curiosity shifted to elucidation of the structures of these isolated biological agents. Were they similar in structure, were they different, what atoms did they contain, how were those atoms arranged? How many of these compounds were, as Louis Pasteur had determined for tartaric acid, chiral? Was there a relationship between the structures of the compounds and their biological effect? Many questions, too few answers; for the questions, though straightforward for a simple alkaloid such as coniine, were signicantly more challenging for strychnine, whose structure took 127 years of degradative organic chemistry to elucidate. Now, strychnine, in all its structural glory, could be deduced de novo through modern 2D nuclear magnetic resonance (NMR) spectroscopic techniques in an afternoon perhaps. This discussion is offered to make two important points. Firstly, that phytochemistry and traditional medicine are inextricably linked; indeed that it was curiosity about one which led to the development of the other. Secondly, that the technologies now available make it possible to determine the secondary metabolic prole of a plant, at a given point in time, rapidly and in signicant detail, and, albeit in a limited manner, correlate that information with biological activity. Plants are stunning chemical factories, and chemotaxonomy has provided some broad, albeit substantially incomplete, assessments regarding the distribution of various structural classes of secondary metabolites, such as alkaloids, quassinoids, avonoids, betalains, etc. For example, one would not expect to nd a monoterpene indole alkaloid, such as vindoline, in a plant in the

1874-3900/$ see front matter 2011 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.phytol.2011.05.005

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family Amaryllidaceae, or the Asteraceae, or the Solanaceae, extensive in number and as chemically diverse as those plant families are. However, the period of analyzing plants on that basis, solely for chemotaxonomic purposes, is now largely over. Huge gaps in knowledge remain. For example, it was pointed out (Cordell et al., 2001) that there are over 153 plant families which have never been investigated for the presence of alkaloids, and 35 plant families for which alkaloids have been detected and from which no alkaloids have ever been isolated. Some gaps may subsequently be lled, in part, as genetic information accrues regarding which plants possess which genes for which biosynthetic pathways, even though those secondary metabolic pathways may not always be expressed. It is the chemical prole, and the potential chemical prole, which is of considerable signicance in terms of biological outcomes and regulatory standardization for a medicinal plant. It is also important to recognize one, neglected, concept in the chemotaxonomic assessment of the chemical prole of a plant. As a digital photograph is a photographic moment in time, so the determination of the chemical constituents in a dried plant material is, assuming no degradation of metabolites, a phytochemical moment in the dynamic metabolic prole of that plant. It is not a denitive assessment of the secondary metabolite capacity of that plant; a perspective to be mentioned subsequently. A broad revolution in phytochemistry is strengthening its relevancy through the application of powerful new technologies, and is restoring and enhancing the original link between phytochemistry and traditional medicine. By the end of this brief contribution, at least one aspect of the new raison detre for phytochemistry at the very forefront of the rapidly evolving evidence base of traditional medicine, should be evident. 2. The changing face of traditional medicine The World Health Organization (WHO) (Anonymous, 2002) denes traditional medicine as . . .health practices, approaches, knowledge and beliefs incorporating plant, animal and mineral based medicines, spiritual therapies, manual techniques and exercises, applied singularly or in combination to treat, diagnose and prevent illness or maintain well-being. For much of the world, traditional medicine has changed little in the last 4000 years (Cordell, 2007, 2008, 2009, in press-a, in press-b; Cordell and Colvard, 2005, 2007). At the same time, for at least 4.5 billion people on Earth, plant-based traditional medicine is their dominant, or perhaps only, form of accessible primary health care (Payyappallimana, 2010). It represents part of the enormous health care divide in the world between North and South. The issues are substantial and disturbing, but unfortunately cannot be discussed in this context, other than to indicate the vast gulf in infrastructure for studying traditional medicines that exists between the North and the South (Boutayeb, 2007). Many countries of the world now understand that their health care needs as far as drugs are concerned, both for local and global diseases, will not be provided by the dominant pharmaceutical companies (Boutayeb, 2007; Campaign, 2010; Jarvis, 2010; Newman & Cragg, 2007). Those companies are seeking alternative strategies which reduce the scope of investment of their research and drug discovery operations (Jarvis, 2010; Mullin, 2010). Some countries, such as India, have developed local capacity to produce at least some of the organic chemicals needed for generic pharmaceutical products (Tremblay, 2010), once they are no longer patent protected. Some countries, for example South Africa, have begun to look at their locally available traditional medicines with a view to drug discovery. Other countries, for example China, are developing traditional medicines as a means to drug discovery and to raise the quality of the plant product acquired by the patient as part of the global expansion of traditional Chinese medicine which is

now underway. Populations all over the world in lower-income countries though may only have access to local traditional medicines based on plant materials as their critical source of primary health care. In the past ten years, a signicant shift has occurred in the strategic approach to traditional medicine, although that development is not yet fully recognized, or well funded. In some ways, the revolution began with the publication of the WHO Traditional Medicine Strategy 20022005 (Anonymous, 2002). This seminal document elucidated a four-part strategy to improve traditional medicine on a global basis. Development of guidelines for safety, efcacy and quality was regarded as a fundamental requirement in order to establish a solid evidence base for traditional medicine. Much has changed in the years since that document was prepared, and numerous new strategies are now evolving (Cordell, 2008, 2009, in press-a, in press-b). The International Union of Pure and Applied Chemistry (IUPAC) has published a series of protocols on safety, efcacy, standardization, and documentation of herbal medicine in which aspects of phytochemistry and analytical chemistry feature, and in which strategies for quality control are discussed in detail (Mosihuzzaman and Choudhary, 2008). If fully implemented, these strategies from the World Health Organization (WHO) and IUPAC, will raise the scepter of traditional medicine from its rather jaundiced view in the eyes of most of modern medicine regulators and practitioners. To understand that perspective, it is important to be aware of the goals for traditional medicine. One of the recognized goals is to be included as an integral aspect of a health system and for patients to be covered by health insurance for their use of traditional medicine products (and practices). That role in health care requires a strong evidence base, one which will assure safety and efcacy for both patients and practitioners founded on reproducible quality. Phytochemistry is at the very core of that assurance. So, with some notable exceptions, why isnt traditional medicine included as an integral aspect in most health systems now? Until certain myths associated with traditional medicines are dispelled, and a scientically and technologically sound evidence base is developed, little progress towards acceptance will be achieved at the government policy and health professional levels. Access to quality health care is a human right within Article 25 of the Universal Declaration of Human Rights of the United Nations (Anonymous, 1948). If traditional medicine is to fulll its crucial role in global health, the long-standing, well-entrenched myths must be busted and solid pillars of science and technology erected to underpin the evidence base required for acceptability in the health system of a country. In recent articles (Cordell, 2007, 2008, 2009, in press-a), and more specically in a book chapter (Cordell, in press-b), the author has begun to outline a selection of some new strategies which will contribute to enhancing the evidence base for traditional medicine. These strategies concern how national policies and regulations are formulated with respect to establishing standards for the quality of safe and effective traditional medicine products and practices; how research capacity on traditional medicine can be built; how the safe and effective use of traditional medicine can be promoted; and how there can be enhanced communication and cooperation within traditional medicine and with other medical practices. A selection of these strategies, all of which involve phytochemistry and the analysis of plant secondary metabolic proles, as an integral aspect of their development, implementation, and application, includes:  Develop policies, regulatory criteria, and technical guidelines which would provide and assure the continued availability of quality, safe, and effective traditional medicine products and practices based on the results of evidence-based research, and

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which could support inclusion in health care systems, insurance programs, and on essential medicine lists. Promote the harmonization of policies and regulations related to traditional medicine between nations, and encourage the development of international standards for terminology in traditional medicine. Develop professional advisory groups to enhance the understanding of traditional medicine by government ofcials, the media, the public, industry, and health care professionals, in order to improve communication regarding policy, regulatory, scientic, social, and economic issues relating to traditional medicine. Establish and implement regulatory standards for pesticides, herbicides, insecticides, heavy metals, microbial contamination, and adulteration with synthetic and natural compounds in traditional medicines and related products. Develop funded programs for government, academic institutions, and the private sector to conduct evidence-based research (botanical, chemical, biological and clinical), establish national centers of research excellence in traditional medicine, and enhance the infrastructure (personnel and facilities) for those research programs. Develop national and international evidence-based research programs using natural resources on: (i) local diseases for which the medicines are not available, are expensive, or have a poor risk prole, (ii) known or emerging global diseases for which there is no known locally available effective medicine, and (iii) diseases for which there is signicant resistance to existing therapeutic agents. Develop regulatory criteria and sponsor programs for the education and registration of practitioners of traditional medicine. Develop resource inventory and conservation programs to assure the sustainability of important natural health materials. Initiate funding programs from governments and global foundations to develop globally accessible databases on all aspects of traditional medicine.

3. Phytochemistry an expanded role in traditional medicine Founded on appropriate regulations and sustainability, the scientic and technological pillars of traditional medicine are: (i) information systems, (ii) botany, (iii) phytochemistry, and (iv) biology, including biotechnology (Cordell, 2007, 2008, 2009, in press-a, in press-b). While these sciences are pillars, they must also be the interweaving threads which in consort form a strong scientic link which transforms the plant in the eld to the product being taken as a medicine by the patient. 3.1. Information systems All over the world, for hundreds of years, indigenous communities have collected and passed on the results of their ultra-slow throughput clinical screening of plants for their ability to prevent and treat disease states. The last 200 years has witnessed major efforts to accrue and collate this ethnomedical information, through the preservation of the ancient texts, annotations on herbarium specimens, the publication of surveys of medicinal plant use, and in some instances, most notably the Natural Products Alert (NAPRALERT) data base (Loub et al., 1985), the computerized storage of ethnomedical information. As research institutes in countries around the world begin to evaluate scientically their traditional medicine systems, these local and global information resources are critical. From an evidentiary perspective, if the same part of the same plant has been used for the same purpose in several different systems of indigenous medicine, the priority of that plant for scientic study may be raised. Unfortunately, the vast amount of ethnomedical information in the public domain is highly scattered, making such comparisons difcult to accomplish. A centralized compilation on a global basis, for example through WHO, would provide an extremely valuable and highly signicant global health care resource for governments, scientists, industry, practitioners and the public. One of the most important aspects of access to information systems which report details of past basic, applied, and clinical research on traditional medicines is that valid research is not repeated. While it may well be necessary to repeat certain experiments in the course of a complete study of the safety and efcacy of a traditional medicine, there are too many studies underway which are duplicative, sometimes even within the same country. That is wasteful of limited nancial and personnel resources, and indicates the need for more coordinated and considered approaches. Critical in the initial development of hypotheses for traditional medicine is the ability to analyze the existing data, and to make decisions regarding priorities for experimentation. 3.2. Botany Safe and effective plant-based traditional medicine begins by relying on the acquisition and use of the correct part of an appropriately identied plant. Recent developments in DNA-based technologies as applied to plants indicate that the denition of a medicinal plant from a quality control perspective necessitates a new scientic approach (Cordell, in press-a, in press-b) beyond morphological examination and simple chemical tests (Trease and Evans, 1972). These attributes are commonly used in dening a plant in pharmacopoeial compilations, and although some forms of chemical proling have been introduced as a part of standardization in the European Pharmacopoeia, DNA techniques will surely supplant those denitions in the very near future. Although these DNA techniques, such as random amplied polymorphic DNA (RAPD), amplied fragment length polymorphism (AFLP), and inter-simple sequence repeat (ISSR) analysis

There is somewhat of a chicken and egg situation to certain of these initiatives; which is rst, the regulation or the science? For sound public policy which can be implemented and monitored, the science must take precedence, and the regulatory standards follow. It would discredit traditional medicine for there to be a regulation regarding a quality standard for which there was no applicable technology. Regulations are static, however, and should evolve as the quality and capacity of the science and technology is enhanced in a country. Standards for quality, safety, and efcacy are a rolling continuum for which regulations should develop over a 515 year period. However, before that can be accomplished there are those four myths associated with traditional medicine (and with phytotherapeuticals) which need to be addressed. Fortunately, there are four pillars, synergistic with, and underpinned by, appropriate regulations and sustainable access, which can form the scientic basis of a new strategic approach to traditional medicine quality control and good therapeutic outcomes in which phytochemistry is a critical component (Cordell, 2009, in press-a, in press-b). The myths to be dispelled are that traditional medicinal plants are: (i) safe and effective based on historical use, (ii) that traditional medicines are already regulated, (iii) that using the correct plant (and plant part) is an adequate quality control standard, and iv) that the biological activity is consistently reproducible and is diminished in older plant material. It is critical, at several different levels, for these myths, which result in unfettered health claims and inappropriate assumptions, to be resolved through scientic experimentation.

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have been used to study genetic variation in medicinal plants (Heubl, 2010; Behera et al., 2008), attention has now turned to the development and application of DNA barcoding (CBOL Plant Working Group, 2009), as one facet of the Consortium for the Barcoding of Life (CBOL). Barcoding has already demonstrated utility for the identication of several medicinal plant species in the genera Aconitum (He et al., 2010), Astragalus (Guo et al., 2010), Curcuma (Cao et al., 2010), Dendrobium (Yao et al., 2009; Asahina et al., 2010), Hypericum (Howard et al., 2009), Panax (Zuo et al., 2011), and Phyllanthus (Srirama et al., 2010), as well as plants in the families Asteraceae (Gao et al., 2010b), Caprifoliaceae (Liu et al., 2010), Euphorbiaceae (Pang et al., 2010), Fabaceae (Gao et al., 2010a, 2011), Huperziaceae (Shao et al., 2010), Polygonaceae (Song et al., 2009), and Rutaceae (Luo et al., 2010). The distinctions between several pteridophyte genera have also been studied (Ma et al., 2010). There is signicant experimentation underway to discover which DNA fragments are best to use for species identication, with efforts concentrating on the ITS2 (Chen et al., 2010; Gao et al., 2010a,b; Guo et al., 2010; Liu et al., 2010; Luo et al., 2010; Pang et al., 2010), matK (Asahina et al., 2010; Gao et al., 2011) and trnHpasbA (He et al., 2010; Ma et al., 2010; Shao et al., 2010; Song et al., 2009; Yao et al., 2009) genes. Reliability rates, the ability to make positive medicinal plant identication at the genus and species level, is typically very high (close to 100%) for the former, and in the range of 7696% for the latter. In an overview of their work, Chen and co-workers (2010), using seven DNA barcodes (psbA-trnH, matK, rbcL, rpoC1, ycf5, ITS2 and ITS), and based on results from 6600 plant samples from 753 genera and 4800 species, found that the discrimination ability of the ITS2 barcode gave a 92.7% successful identication rate, concluding that this could potentially used for the identication of medicinal plants. A database has been established for about 1000 plants which are mentioned in the Chinese Pharmacopoeia and the American Herbal Pharmacopoeia (Lou et al., 2010). One of the potential future developments is that the barcoding technique could be incorporated into highly automated, hand-held devices which could provide extremely rapid, in-eld plant identication (Newmaster et al., 2009). 3.3. Phytochemistry A particular plant has a diverse set of genes for secondary metabolic production which, at this juncture, are rather uncontrollable and unpredictable. At the same time, the total capability and capacity to produce secondary metabolites of various structure types is not known for any plant. This is why, for example, changing either intrinsic or extrinsic factors (soil pH, altitude, moisture, light, temperature, stress, fertilizer, etc.), or placing a plant into tissue culture, typically produces a new, and sometimes unexpected, secondary metabolic prole. It is a reason why plant recollections frequently fail to yield plant material with the anticipated biological activity, and was a primary reason why pharmaceutical companies withdrew plant extracts from large scale screening programs. The discovery of drugs from plants was, for many years, conducted on the basis of the magic bullet theory, paralleling that of synthetic drugs. However, in practice, a plant may contain several, closely-related metabolites with quite similar activities (Silva et al., 2001). These factors (compound variation and metabolite complexity) were discussed for many years in the context of how to analyze a traditional medicine. Now, a completely new perspective on secondary metabolite proling has emerged with the introduction of metabolomics (Verpoorte et al., 2005, 2007; Heinrich, 2008; Okada et al., 2010); dened as both the qualitative and quantitative analysis of all the metabolites in an organism. The technique typically employs

multivariate analysis of the proton NMR spectra of crude extracts, and the principal component analysis (PCA) of the low molecular weight secondary metabolites (Verpoorte et al., 2007), although hyphenated mass spectrometric techniques can also be used (Tanaka et al., 2008; Xie et al., 2008; Okada et al., 2009). Heinrich (2008) summarized some of the initial studies that were conducted on medicinal plants, and another overview has also appeared (Okada et al., 2010). More recent work has extended the utility to distinctions being made between ve Panax species (Xie et al., 2008), four Ephedra species (Okada et al., 2009), and de rich et al., 2010), placing 43 samples three Echinacea species (Fre of Astragalus into four groups (Tanaka et al., 2008), characterizing tinctures of herbal products directly (Politi et al., 2009), and distinguishing between samples of Rhodiola rosea from three different locations (Ioset et al., 2011). A study of the Mexican plant Galphimia glauca is of interest because it correlates the analysis of plant collection from six sites with an active principle through in vivo testing (Cardoso-Taketa et al., 2008). This very important technique is dramatically and rapidly changing the approaches which can be applied to traditional medicine standardization. It is demonstrating that species identication can be made, that batches of the same plant from different sources can be readily distinguished, and that manufacturing processes can be discerned. The maturity of a particular plant part can also be discerned (Shuib et al., 2011). In addition, within a plant species, well-dened chemical races are shown to occur, wherein plants grown under slightly different conditions cluster into groups when their metabolic prole is analyzed by NMR spectroscopy (Maulidiani et al., in press). When chemical races occur in the instance of a medicinal plant, one can expect that the biological prole for each of the chemical races will also be different, with only one of them providing the anticipated, full benecial pharmacological effect. Consequently, a combined approach of botanical barcoding and PCA analysis will, in the near future, become an essential aspect for dening a protocol for medicinal plant authentication (Cordell, in press-a, in press-b). This is the core of the revolution in process that is underway. One might consider that scenario would adequately address the issue of plant identication for a traditional medicine; unfortunately, it does not, quite. Specic individual clones of plants can demonstrate signicant (at least four-fold) differences in concentration of a major medicinal metabolite during a yearly growth cycle, even in controlled culture conditions (Stanilova et al., 2010). Since this variation is possible for the desired active ingredients, in theory, the same could be true for potential toxic metabolites. The consequence is that both, or either, safety and efcacy could be modulated from a dened standard during the course a year of plant development. Consequently, a therapeutic outcome based on a prescribed measure of dried plant material or extract cannot be categorically assured without quantitative phytochemical analysis on a lot-to-lot basis. 3.4. Biology The observed biological effects of a medicinal plant are the consequence of the interplay of a certain concentration of the numerous biologically active constituents produced by the plant at a given point in time. This point may seem almost redundantly obvious. However, it is this precise point which is overlooked when the dening regulations for traditional medicines and phytotherapeuticals stop at the level of the plant part, or perhaps with an internal marker compound. In the absence of a biological parameter for the extract which is directly, or perhaps indirectly, related to the anticipated preventive or therapeutic outcome, there can be no assured health care benet. Why would a patient take a

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traditional medicine, phytotherapeutical, or dietary supplement without that assurance? One of the great challenges for traditional medicine quality control is therefore to create, over time, a series of evolving standards which inter-relate botany, phytochemistry, and biology, and which can be used to dene and standardize a traditional medicine with the assured outcomes of safety and efcacy. There is an additional important link between phytochemistry and biological evaluation (in vitro, in vivo, and clinical) which needs to be restated. For a biological test to have any validity, the nature of the material being evaluated needs to be carefully dened. It is unethical to give an animal or a human a compound or extract of unknown character. Many papers are published where a material is extracted from a plant, or a compound is purchased (maybe to be used as a control), and there is no stated determination of the chemical nature of the materials or their purity (in the case of the compound). Phytochemical analysis is therefore needed for all materials being evaluated, test materials and controls, in order to establish their nature, and hence the fundamental validity and reproducibility of the experiments. Dereplication techniques were initiated, using paper chromatography, at the time when pharmaceutical companies were seeking new antibiotic scaffolds. Over time, chemical and biological aspects of dereplication evolved, and eventually these strategies were integrated (Cordell and Shin, 1999) into a high performance liquid chromatographymass spectrometry (HPLC MS) system where the stream could be split and samples for chemical and biological analysis could be collected in 96-well plates in the same time frame. At the time, this technique was used to search for novel anticancer agents in plant extracts (Cordell et al., 1997). In terms of traditional medicine quality control, the further development of such techniques could prove critical in providing a correlation between specic active constituents in an extract and their biological activity, if the appropriate assays are employed. 3.5. Integrated technologies pharmacognosy in a suitcase In several previous articles (Cordell, 2007, 2008, 2009, in pressa, in press-b), the author has discussed the concept of initiating quality control for traditional medicine in the eld. A number of options are available (Cordell, in press-a), including various hyperspectral and remote-sensing techniques (Baranska and Schulz, 2009) for studying alkaloids (Urlaub et al., 1998), opium (Schulz et al., 2004), and cocaine (Carter et al., 2000; Ryder et al., 2000). A more attractive strategy would be a more consolidated approach, in which a series of nanotechnology-based devices are integrated into a highly-portable system which would provide botanical authentication, preliminary phytochemical analysis for critical constituents, and biological evaluation without any intermediate isolation steps. Extensions to such a system could also be used for the purposes of in-eld drug discovery programs looking for new single agent or dened poly-constituent drugs. Imagine the possibility of going to the eld and directly determining the identication of a plant through DNA barcoding, and subsequently its chemical and biological potential, without the wasteful strategy of collecting many plants (or many specimens of the same plant) and conducting laboratory analysis. The necessary peripheral technologies of solar powered batteries, global positioning systems (GPS), data base systems for botanical barcoding, ethnomedical, chemical, and biological information systems are available or in development. Also available are miniextraction systems [possibly using functionalized hollow bers (Li et al., 2010)], hand-held Raman laser detection systems, minimass spectrometers, and nanobiotechnological systems. What is needed is the development of the suitcase to embrace those

technologies. In other words, the enhanced software packages which can link the various outputs, access the various on-line databases, and integrate the datasets to provide a coherent and reasonably rapid response in the eld. Even more dramatic would be the development of non-invasive systems which could monitor the complex metabolite production of key compounds in real time. Rather than the phytochemical moment, a picture of secondary metabolite production in an instant, such an approach would constitute a phytochemical epic, the Cecil B. DeMille version of secondary metabolite analysis, the phytochemists dream movie. 3.6. Sustainability There is an inevitable intersection of traditional medicine, biodiversity, and public health when degradation of biodiversity impacts the critical resources for maintaining health (Alves and Rosa, 2007). Aspects of the necessity for the development of sustainable approaches for the provision of medicinal plants in the future have been discussed previously (Cordell, 2007, 2008, 2009, in press-a, in press-b). Eighty-ve percent or more of medicinal plants sold around the world are collected indiscriminately from the eld (Akerele et al., 1991; Chaudhuri, 2007; Hamilton, 2004; Roberson, 2011; Ved et al., 1998). Already, many medicinal plants are under threat or have disappeared. Although the actual number of medicinal plants on the Convention and International Trade in Endangered Species (CITES) list of 28,000 threatened plant species is not known (Anonymous, 2011), one can imagine that it is several thousand, since statistically, at least 6% of all plants have a documented medicinal use (Cordell and Colvard, 2005). In addition to the obvious strategy of cultivation of a species (Hamilton, 2004; Pinheiro, 1997; Sumelong, 2010), there are several other strategies which might be used for developing sustainable, alternative traditional medicinal plant resources. These include: plant part substitution from the same plant or from a plant in the same genus, particularly if the plant part used is non-sustainable such as the bark, root or rhizome. Politi et al. (2004) have described a metabolomics approach to study substitution of the roots (used traditionally) of Vismia guineensis by the leaves. Seeking similar active compounds in related plants is also an option. One signicant complication of these approaches is that safety and efcacy will need to be re-assessed, since the overall phytochemical prole of the plant part will have changed dramatically compared with that used traditionally. A more subtle aspect of sustainability relates to the use of multicomponent plant regimens, where up to twenty plants may be involved. Such mixtures are a phytochemical analysis nightmare with respect to metabolite standardization. The question is whether, in order to achieve the desired biological and therapeutic effects, all of the component plants are necessary, or whether some can be eliminated, so that the product is safe, effective, and more sustainable. The stability of medicinal plant activity or the toxicity prole (and which compounds are responsible for altering that prole) is also an aspect of sustainability. For example, if a plant material (in whatever form) has no loss of activity and no change in toxicity prole after ve years, it can still be marketed. This reduces the need to access additional plant material. In the future, such studies will be of critical importance in order to maintain important medicinal plant supplies more efciently. Speaking of efciency, there is currently a vast amount of traditional medicinal plant waste being produced on a daily basis all over the world. In most traditional medicine systems, and for many remedies taken orally, the plant material is extracted once with hot water under various conditions. The ltered decoction is then either given to the patient or lyophilized for inclusion in a capsule or tablet. The marc, the residual plant material, is used for fertilizer, sent to a landll, or in some instances, used as animal

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fodder. The signicant assumption is made that all of the constituents responsible for the biological activity are completely water-soluble and are being effectively extracted. The remaining, water-insoluble, chemical constituents in the marc, their biological activity, and the potential of utilizing this material as a medicinal plant resource do not appear to have been explored, in spite of the environmental need for optimal use of the acquired medicinal plant material. 3.7. Quality control Quality control for traditional medicine begins in the eld and ends with a safe and effective product being delivered to the patient, followed by post-marketing pharmacovigilance. It is an evolutionary process. The World Health Organization has recognized this, and developed a series of guidelines to assist nations develop their strategies for the quality control of herbal medicines (Anonymous, 1996a,b, 1998, 2005), and for conducting research on traditional medicines (Anonymous, 2000). The implementation of Good Agricultural and Collection Practices (Anonymous, 2003), Good Laboratory Practices (Code of Federal Regulations, 1978), Good Manufacturing Practices (Anonymous, 1996a, 2005) and Good Clinical Practices (International Conference on Harmonization, 2002) should, at a minimum, come together to develop successful processes for developing a high-quality, herbal product over time. Phytochemistry has an important and indispensable role in the implementation of each of those steps. Each requires knowing what is in the plant in terms of constituents, knowing what is happening to those constituents during the processing of the plant, and assuring appropriate analyses when materials are being tested biologically, and eventually delivered to the patient in a nished product. In addition, there are serious concerns being expressed all over the world with respect to contamination and adulteration of traditional medicines. Contaminants may include various pesticides, herbicides, insecticides, heavy metals (arsenic, cadmium, lead, and mercury), microbial species, radiation, etc., and adulterants may include other (perhaps cheaper) plant materials with similar biological effects or synthetic drugs. One company in China is monitoring each batch of their traditional medicine products for over 190 possible contaminants. Some of these contaminants have been identied for controlling herbal medications in the European Union (Mosihuzzaman and Choudhary, 2008). 3.8. Other considerations for phytochemistry and traditional medicine Several previous articles have discussed the need for phytochemistry to have a larger voice in traditional medicine at the government level (Cordell, 2008, 2009, in press-a, in press-b). If the expectation is that traditional medicine use will likely increase globally as the population moves beyond 8 billion people (probably by 2020), then well-delineated strategies will be needed by the health systems of many countries of the world to assure the most effective use of available traditional medicine plant material. Phytochemists should be involved in developing the strategic thinking necessary to accomplish this aspect of quality health care. In addition, the development, promulgation, and enforcement of regulatory standards for traditional medicines in order to assist governments and regulatory agencies assure an appropriately benecial product is an important role for phytochemists. Finally, phytochemistry has a very important role in public awareness and professional education with respect to traditional medicine, phytotherapeuticals and dietary supplements. There are many companies who project false or misleading claims with respect to the phytochemical aspects and the biological signi-

cance of their products. Phytochemists have the responsibility, as content experts, to expose these misstatements and to correct impressions so that patients and health professionals are appropriately informed. The role for phytochemistry in health professions education is also clear, in the high-income and in the middle- and low-income worlds. The interface between traditional medicine and other forms of medicine will overlap for many patients around the world. As a consequence, health professionals, physicians, dentists, pharmacists, and nurses, all need to be aware of the potential benets and the potential risks of these products, and the nature of the sciences necessary to be applied for the delivery of a quality, safe and efcacious product. 4. Conclusions Phytochemistry has a long-standing, intimate relationship with traditional medicine lasting over 200 years. That relationship is now undergoing a revolution in practice as new technologies for botanical authentication, phytochemical analysis, and biological determination are employed for the development of new strategies to improve the quality control of medicinal plants. Through interaction with botany and biological evaluation, phytochemistry has a major role to play in many aspects of assuring safe and effective traditional medicines for most of the people of the world. This brief overview has highlighted some of those potential areas for contributing to the enhancement of global health care in the future. Phytochemists should continue to coalesce their strategic objectives and collaborate with scientists and clinicians across several disciplines for the advancement of traditional medicine and take full advantage of the technologies that are now available. References
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