Issue Date: June 27, 2011
Plant Medicines Key to Global Health
On the London Underground, passengers are advised to “mind the gap” to avoid falling into the space between the train and the platform. Drug discovery has its own famous, and famously widening, gap—that between research investment and approved drugs.
Perhaps even more important is another void lurking in the process of creating new drugs: a vast gap in drug accessibility. This chasm exists between developed and developing economies, as well as between rich and poor within developed nations like the U.S.
The majority of the world’s population has limited or no access to many existing drugs. What’s more, scant attention is afforded drug discovery for most of the top killers in developing countries, such as HIV/AIDS, lower respiratory infections, diarrhea, hepatitis C, childhood diseases, malaria, and tuberculosis (TB).
Traditional plant-based medicines are the only treatments available for much of the world. And these herbal supplements often lack quality and evidence for safety and efficacy.
One of the missions for the International Year of Chemistry should be to close these gaps in drug accessibility and quality. Chemistry and biology remain the basis for drug discovery and development. But what will provide the moral compass in global health care for the next 20 to 30 years? Which diseases will have marketed drugs, and how much will they cost? Will industry focus on developing medicinal agents for the whole world? If not, which stakeholders will participate financially and scientifically in discovering and developing drugs for the majority of the world’s people? Chemistry can play a wise, compassionate, and sustainable role in bridging these gaps in global health.
Several paradigm shifts are necessary to supply quality medicinal agents to an expanding global population of 7.1 billion, possibly rising to 10 billion by 2035, according to some estimates. The first is to think of all medicines, whether natural or synthetic, as essential, sustainable commodities. Whether prescription products, over-the-counter medicines, or plant-based drugs, they should be synthesized or sourced in a manner that makes them as sustainable as possible. As the global population expands, it is critical that access to drugs for future generations is not jeopardized by resource depletion.
That means developing strategies in which the reagents for synthetic drug processes are sustainable. For chiral processes, one example is to explore in depth the replacement of heavy-metal catalysts or expensive chiral reagents with cheap, renewable reagents from common plant materials such as cassava, coconut juice, sugarcane, and carrots. Nature already carries out many chemical transformations with high regio- and stereospecificity. This substrate specificity should be explored.
This shift also means evaluating how plant-based medicines affect ecosystems. Overharvesting can impact critical resources. At least 85% of medicinal plants sold are collected indiscriminately from the field; consequently, many essential medicinal plants are threatened. (Biodivers. Conserv., DOI: 10.1023/B:BIOC.0000021333.23413.42). As a result, the sustainability of medicinal plants has become essential to long-term health care strategies. The long-term stability of medicinal plant activity is one aspect of sustainability; another is the tremendous waste of plant resources through inefficient extraction techniques. Reducing usage while maintaining health benefits is an important strategy. Chemical analysis of the extract and residue is critical to determine whether active components remain unextracted. Analysis can also correlate chemical identity with biological response.
A second paradigm shift is to change the focus of drug discovery to attend to the developing world’s disease needs.
For the majority of people in the world, chemistry has played a minimal role in providing or improving their medicinal agents. Global pharmaceutical investment is skewed toward the financial rewards of the wealthiest markets; at least 90% of R&D funding is spent on the health issues of less than 10% of the global population, and only 20 of the 1,556 new chemical entities marketed globally in the period 1975–2004 were for either tropical diseases or TB (J. Nat. Prod., DOI: 10.1021/np068054v ). As a result, many major diseases in the world desperately need a drug pipeline. Funding for discovery research on these diseases is inadequate by several billion dollars per year.
Some progress is being made. Without expecting a return on investment, a small number of pharmaceutical companies have established drug discovery partnerships, focused primarily on vaccine development for malaria and TB. Novartis and GlaxoSmithKline, for example, have established partnerships to conduct research on neglected diseases (C&EN, Nov. 9, 2009, page 16).
However, these partnerships between companies and nonprofit organizations are typically in the developed world, and the research is conducted mostly there. It is time for a global commitment to bring developing countries into the drug discovery research process.
New international initiatives for natural product drug discovery should develop a more structured, well-funded, broader approach that reflects evidence-based traditional medicines. Innovative collaborations and partnerships must form across the developed-developing world divide and among developing countries. Such collaborations can provide local infrastructure, information systems, people, and most important, funding and long-term commitments in order to promote local and regional drug discovery initiatives using indigenous knowledge. Programs must also build commercial capacity and develop appropriate protections for intellectual property rights. Many questions remain: Who owns the intellectual property rights? Is it the sovereign country of origin (usually in a low- or middle-income country) or the developer of the invention (often in the developed world)? Is sharing the rights to the invention a win-win solution?
A third paradigm shift is to improve the fundamental quality control of traditional and plant-based medicines. For millennia, cultures around the world used a slow-throughput process of trial and error to develop a local, natural-resources-based tradition of ethnomedicine. Today, these systems of traditional medicine provide the drug supply for more than 4.5 billion people (). For many people, little has changed in their drug delivery system in 4,000 years. Their main or only access to medicinal agents remains a local market, a shaman, a hakim, or other herbal practitioner.
In some middle- and low-income countries, governments, academic institutions, and corporations are already using local resources and indigenous knowledge to discover new drugs for global diseases and to validate the safety and efficacy of traditional medicines.
For instance, in China, large government investments in such efforts are a central component of national health care policy. Development of research and industrial production facilities is a high priority. In the modern quality-control laboratories of one major company, a dedicated ultraperformance liquid chromatography system examines each batch of each traditional medicine product for active constituents. Tight quality control will ensure regulatory acceptance in future global marketing of evidence-based traditional Chinese medicine products.
Currently though, quality control of plant-based medicines is a global issue. Back in Chicago, at my local health food store, 15
This is a deplorable hole in the health care system, when at least half of the population in the U.S. takes botanical dietary supplements in addition to over-the-counter and prescription products, fully expecting that such medicine will “work” (National Center for Health Statistics Data Brief, April 2011, No. 61).
Patients have the right to expect safety and efficacy in dietary supplements as a result of a strong evidence base, in which natural product and analytical chemistry are essential core components. Fortunately, there has been tremendous progress in the sciences behind traditional medicine and dietary supplements, so opportunities to improve the situation are available. Adequate funding and regulatory incentives are absent, however.
Definitions and regulations for traditional medicines and dietary supplements typically begin (and often end) with a botanical analysis of the plant material. However, health benefits do not accrue from the name of a plant. Instead, evidence-based traditional medicine must rest on appropriate, contemporary science-based regulations. It must also receive support from information systems, botany, chemistry, and biology, including the application of appropriate biotechnologies and well-designed clinical studies.
Many sciences must come together to enable this paradigm shift in quality control. Pharmacognosy, the study of biologically active natural products, can bring a fully integrated, highly collaborative focus to these studies. The global implementation of regulatory and scientific foundations for traditional medicines and dietary supplements would transform health care for all.
Information management must play a major role in the paradigm shift. Ethnomedical information, including that in the public domain, is exceptionally scattered, making it difficult to compare global plant use and to track research results. Collating and evaluating locally generated data are important activities that are ongoing. But an accessible, global compilation of traditional medicine that embraces the contemporary botanical, chemical, biological, and clinical aspects of plants would be an exceptionally valuable resource for government agencies, scientists, industry, practitioners, and patients.
Clinical information must also be accessible, transparent, and public, even (especially!) when clinical trials give negative results. All trials on traditional medicines and dietary supplements should be registered online at clinicaltrials.gov, and comply with the CONSORT standards—an evidence-based, minimum set of recommendations for reporting. It should no longer be acceptable that ineffective agents are marketed with health claims if these have been clinically disproven, even if the agents are safe; the patient expects efficacy, after all.
The laboratory sciences must play important roles, too. Using the correct part of the correct plant is not an adequate botanical standard for scientific studies on traditional medicines or dietary supplements. Considering otherwise may be a fatal and fundamental flaw; it is a prime reason why variable results currently come from repeated testing of plant extracts in different laboratories. As a plant’s metabolism changes—for instance with age, time of year, or location—its chemical profile changes. Consequently, the plant’s biological and therapeutic effects will change in a nonpredictable, nonreproducible manner.
Only when such medicines and supplements are defined in a botanically and chemically consistent manner does it become appropriate to explore the in vivo and in vitro effects, the pharmacokinetics, the formulation, the mechanism of action of metabolites, and the efficacy of traditional medicines and dietary supplements.
Achieving this standard of botanical and chemical identification requires DNA-based plant analysis and natural-product-based analytical chemistry. The “bar coding” of medicinal plants to quickly, easily, and reliably distinguish species on the basis of one or two short genetic sequences has become a very active research area, particularly in China. For traditional medicines, it will become a standard for botanical quality control and an integral aspect of regulatory control.
Concurrently, metabolomics is providing a vivid demonstration that a single plant species and part will show significant chemical diversity based on external and genetic factors. Combining bar coding and metabolomics will transform the fundamental definition of a plant as a traditional medicine or dietary supplement and assist in ensuring both safety and efficacy.
In addition to identifying the active components of medicinal plants, science—particularly chemistry—must help protect patients from contamination and adulteration of traditional medicines and dietary supplements. Contaminants may include pesticides, heavy metals, microbial species, and radiation, while adulterants may include other plant materials with similar biological effects, or synthetic drugs. Aware of these issues, some companies in Asia are ramping up sophisticated analytical chemistry to analyze more than 150 potential contaminants and adulterants in their products.
Biologically, microarray assays and genome profiling of the effects of traditional medicine extracts are delineating the functions of an individual plant extract and its components. Such knowledge permits rationalization of the use of a medicinal plant and suggests biological methods for quality control to augment botanical and chemical controls.
Still unclear, however, are the nonscientific strategies, including sharing of the financial investments, necessary to bring traditional medicines and dietary supplements to a higher level of quality and standardization, ensuring safety and a healthful outcome.
The modern study of medicinal plants extends beyond quality control into drug discovery. Identifying and developing individual agents from effective traditional medicines are being pursued very aggressively in several countries. Standardized plant preparations based on traditional medicines are also in advanced clinical development. Researchers are searching for synergistic effects of plant products with other plant medicines to enhance effectiveness, mirroring the philosophies of multiple-medicine regimens for cancer and HIV/AIDS.
Personalized plant-based medicines may evolve from deconstruction of the diverse functional roles of multiple components within complex ethnomedicines. The process of deconstruction asks important questions: Are all of the plants in a 20-plant prescription biologically necessary? Are there ways to improve the concentration of the effective ingredients, standardize the dose, and maintain safety? Would different extraction techniques lead to higher yields of active ingredients?
Studying how traditional medicines modulate human genes, individually and as complex mixtures, is important mechanistically and could lead to prescribing “designer” traditional medicines based on an individual’s genetic makeup. Traditional medicine, with a heavy investment in contemporary science and technology, is rapidly becoming very nontraditional.
An important outcome of these studies will be that in most parts of the world, a plethora of new, effective products derived from traditional medicines will be available. Some of these products will be in direct competition with the single-agent synthetic modalities of the developed world. Beyond the scientific questions, economic and regulatory ones will remain: What are the global implications for traditional medicines demonstrated to be safe, effective, and sustainable? Where will they be marketed and how will they be regulated? What disease-related health claims, based in science and on standardized clinical trials, will be allowed? Will they provide a reliable source of medication that can bridge the gap in access to drugs for the majority of the world’s population?
Developing the evidence base for traditional medicine requires openness to the role that chemistry—specifically, natural product chemistry and analytical chemistry—must play in redefining health care for the majority of people. A commitment to initiate dialogues for more extensive collaboration and development would constitute a major achievement for global health in this International Year of Chemistry.
Despite the essential role in global health care that traditional medicine and the natural product sciences must have for the majority, the influence of professional scientific groups in public policy has, to date, been minimal. To enable progress in medicinal agents, that paradigm also has to change. In some parts of the world, constructive steps are being taken. For instance, the Japanese Liaison of Oriental Medicine brings together Japan’s major scientific societies dedicated to traditional medicine. The group uses its expertise to assist the government directly, providing advice and opinion, representing the government at international meetings, and proposing areas for future R&D.
In North America and Europe, there is a need for similar groups from natural product, chemical, and biological societies to assist government scientists and regulators. Such cooperation would enable scientifically sound choices with respect to establishing an evidence base for the quality, safety, and efficacy of traditional medicines and dietary supplements being sold globally and online.
Rationalizing traditional medicine to focus on products that are scientifically demonstrated to be safe and effective is an enormous task and will take many years to plan, fund, develop, and implement. Yet for most of the world, there is little choice.
With enhanced global collaboration and leadership, the International Year of Chemistry can begin to change the paradigms of traditional medicine and dietary supplements. The outcome would be a major transformation in health care for practitioners and patients who would be ensured access to products that provide health benefits with minimal risk. With wisdom and compassion, chemistry can “mind the gap” by helping make it smaller!
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