I Mohamed, A Shuid, B Borhanuddin, N Fozi
drug development, herbal medicine, phytomedicine, phytotherapy
I Mohamed, A Shuid, B Borhanuddin, N Fozi. The Application of Phytomedicine in Modern Drug Development. The Internet Journal of Herbal and Plant Medicine. 2012 Volume 1 Number 2.
List of Abbreviations
Phytomedicine or the use of herbal medicine with therapeutics properties has been around since the dawn of human civilisation. Sheng-Nongs Herbal Book, one of the earliest sources of folk knowledge on the use of herbs in China, dated back to 3000 B.C. and included knowledge of 365 plants, animals and minerals useful as medication1. A phytopharmaceutical preparation or herbal medicine is any manufactured medicine obtained exclusively from plants, either in the crude state or as pharmaceutical formulation2. Although the industrial revolution and the development of organic chemistry resulted in a preference for synthetic products, World Health Organisation (WHO) reports that between 70% and 95% of citizens in a majority of developing countries still rely on traditional medicine as their primary source of medication3. The role of herbal medicine started to decline after the 1960s as vast quantities of resources and money were used to promote synthetic medication. Besides this, advances in the human genome, increase knowledge of the structure and function of proteins and the notion that synthetic drugs are safer with fewer side effects (which does not necessarily be true) also contributed to the rise in the popularity of synthetic drugs. However, these advancements have several major constraints. The large number of possible new drug targets has already outgrown the number of existing compounds that could potentially serve as drug candidates and the field of chemistry has limitation when it comes to synthesising new drug structures.
In the last decade, herbal medicine has seen some form of revival, advancing at a greater pace in community acceptance of their therapeutics effects. This field is bringing forward new lead drug discoveries as well as safe and efficacious plant-based medicines. In turn, this leads to growing number of sales of commercialised medicinal herbs and most importantly, growing number of pharmaceutical companies that involve in the research and development of plants as a source for modern medicine. What chemists have been desperately seeking, Mother Nature has already plenty of stock. This review tries to expound on the importance of herbal medicine in modern drug development by highlighting salient topics from the history of herbal medicine and examining its roles in modern drug development. In addition, this review discusses the challenges and future of herbal medicine in modern medical practice.
A Short History of Herbal Medicine
Traditional medical practice remains the largest healthcare system in the world. The Hindu Kush Himalayas (Afghanistan, Bangladesh, Bhutan, China, India, Nepal and Pakistan) host the four largest traditional medicinal systems in the world, comprising of Ayurvedic medicine, Chinese medicine, Tibetan medicine and Unani medicine1. Ayurveda remains one of the most ancient traditional medicine systems and is still widely practiced in India, Sri Lanka and other countries with 400 000 registered Ayurvedic practitioners in India alone. Atharvaveda (around 1200 B.C.), Charak Samhita and Sushrut Samhita (1000-500 B.C.) are the main literatures that give detailed description of over 700 herbs4. Currently, over 1000 plants form the Ayurvedic Pharmacopoeia. In China, herbal medicine continued it expansion from Sheng-Nongs Herbal Book (around 3000 B.C.) to the current updated inventory of medicinal plants used in Traditional Chinese Medicine (TCM) that includes 11 146 species of herbs/plants of which 492 species are cultivated and the remaining wild plants. Both the Ayurvedic and Chinese Traditional Medicine systems date back to ancient time, with an ever-expanding knowledge of plant properties and their medicinal qualities that were preserved in ancient texts. This body of knowledge has been constantly updated and passed down to newer generations in revised versions, while preserving its originality and values. Currently, only China has a frequently updated inventory of traditional medicines used, with India starting to initiate similar efforts. The Chinese government is one of the most active governments in the world in promoting the use of traditional medicine and integrating it with allopathic, conventional medicine.
Appearing later than its Oriental counterparts, the Western version of herbal medicine began at the cradle of Western civilisation in Ancient Greece around the fifth century B.C. with the influence of accumulated medical knowledge from Egypt, Persia and Babylon5. During the first century A.D., Dioscorides produced an influential herbal medicine text called De Materia Medica, which became a standard reference for Western practitioners for the next 1,500 years. Curiously, this book also included information on herbal remedies that had been used in Ayurvedic medicine for centuries. Around the same period, Galen of Pergamum formulated 130 antidotes and medicinal preparations (also known as galenicals) that may include up to 100 herbs and other substances. The complexity involved in preparing these intricate medicinal prescriptions gave rise to the Galenic system that saw physicians as the ultimate authority in health care. It was around this time that traditional herbalists, with their “simple” remedies, began to be ousted from the mainstream medical system in Medieval Europe. Nevertheless, the knowledge of traditional herbal medicine was preserved by Catholic monks throughout the Middle Ages, with its practitioners still existing outside the mainstream system. Around the eighth century A.D., Western herbal medicine began to be influenced by the herbal knowledge of Arab physicians who conducted extensive research on medicinal herbs found in Europe, Persia, India and the Far East. Later, with the discovery of the Americas in the fifteenth century A.D., a variety of the New World medicinal plants became available to Europeans. Among the ancient knowledge of herbal medicine that came from the New World, the significant ones came from the Mexican traditional medicine, which combined the knowledge of four indigenous groups – Maya, Nahua, Zapotec and Mixe as well as the Inca civilisation6. Medicinal plants continued to be the main source of products used for maintenance of health in Western conventional medicine until the nineteenth century when Friedrich Wohler accidentally synthesised urea in 18287. This first organic synthesis in human history ushered the age of synthetic compound. For the next 100 years, synthetic drugs became the mainstay of Western conventional medicine, with phytomedicine pushed into the shadows.
Current Categories of Herbal Medicine
The term “herbal medicine” is fraught with misconceptions that stems from the diversity of its approaches. According to Ernst8, herbal medicine can be categorised into three general groupings, namely phytotherapy, over-the-counter (OTC) herbal medicine and traditional herbalism. Among these, phytotherapy is the one that adheres to scientific methodology and generates reasonably sound data9. Based on the principles of phytotherapy, a herb contains a number of pharmacologically active compounds that should be seen as a single unit. The whole extract can be standardised and clinically tested for a distinct clinical condition. This prominent feature differentiates phytotherapy from conventional pharmacotherapy, which generally favours the more reductionist approach. Aside from this, phytotherapy strongly abides by the principles of pharmacotherapy that requires knowledge and skills for medical diagnosis and identification of suitable treatment8. OTC herbal medicine however lacked in scientific evidence10, in terms of efficacy and safety11. In a similar note, traditional herbalism is rooted in beliefs that have been long abandoned by the rest of medicine8. Not beholden to the conventional disease categories, traditional herbalists would typically prescribe an individualised concoction of several plant extracts based on the characteristics of each individual patient12. A systematic review by Guo
Current Usage, Issues and Roles
The majority population of the developing world relies on traditional herbal medicine as the primary source of treatment for illnesses3. The issue of compliance with traditional medicines varies according to local beliefs and socio-cultural status, and is less reliant on the efficacy of the traditional medicine. This may result in a disadvantage towards users of traditional medicines because patients may continue with treatment even though medicine is not efficacious and vice versa due to personal and population beliefs.’
Approximately 25% of drugs prescribed worldwide came from plants, with 121 such active compounds being in current use2. There are 252 drugs considered as basic and essential by the WHO, of which 11% are exclusively of plant origin, while the majority of synthetic drugs also have plant precursors. In 1997, world market for over-the-counter phytomedicinal products was USD 10 billion with an annual growth of 6.5%14. In 2003, growth was well over expectation with sales exceeding USD 65 billion, with USD 9 billion in Europe alone4. China and India have already a well-established herbal medicine industry, while Germany lead the developed countries with 54% of phytomedicinal products being sold as medical prescriptions that were covered by health insurance15. Plants can be used as therapeutic resources in several ways - herbal teas or other home remedies, crude extracts and extraction with purification to isolate an active compound. Among the examples of drugs obtained from plants are reserpine from
As mentioned earlier, interest in herbal medicine as a path to drug development increased greatly in the early 1980s7. This could be due to the inefficiency of conventional medicine (e.g. cytotoxicity, side effects and ineffectiveness of synthetic drugs), abusive and incorrect use of synthetic drugs and most importantly, the high cost involved in conventional medicine and the fact that a large percentage of the world’s population does not have access to conventional pharmacological treatment2. With the limitations of synthetic chemistry, there also arises the need to find new medicines to combat the emergence of multi-resistant pathogens7, as well as to manage a whole range of chronic and difficult-to-treat diseases such as cancer, diabetes and AIDS. Natural products offer unmatched structural variety and their usefulness can be extended by probing biological pathways4. Large pharmaceutical companies now have specific departments dedicated to the study of new drugs from natural resources. Even though it was once thought that focusing on herbal medicine could provide a swifter and more economical approach to drug discovery3, however the reality is actually a bit disheartening. Research and development of therapeutics materials from plant origin is an arduous task and involve high cost. Each new drug requires an investment of around USD 100-360 million and a minimum of 10 years of work, with only 1 in 10,000 tested compounds being considered promising2. However, this pales in comparison with a newly developed synthetic drug, where the development cost would reach USD 800 million16, which is more than the gross national product of some countries. The cost effectiveness of modern drug development originating from phytomedicine is now increasingly being accepted with big pharmaceutical companies investing greatly2.
Methods of Phytomedicine Research
Modern natural drugs chemistry actually began with the work of Serturner, who first isolated morphine from opium poppy
One of the methods of selecting potential plants for drug development is to decide on a well-defined pharmacological activity and perform a randomised search for this activity among plant extracts, resulting in active species to be considered for further study. At one point of time, the concept of high-throughput screening (HTS) became the paradigm of lead discovery of novel bioactive phytocompounds19. HTS allows a researcher to efficiently conduct hundreds of experiments simultaneously via a combination of modern robotics and other specialised laboratory hardware. It applies a forceful method to collect a large amount of experimental observations about the reaction of phytocompounds towards the exposure of various chemical compounds in a relatively short time. However, results of HTS in producing synthetic anti-cancer drug have been less than promising20. The National Cancer Institute (NCI) in the USA has tested more than 50 000 plant samples for anti-HIV activity and 33,000 samples for anti-tumour activity2. It should be reminded that these plants were not screened for other pharmacological activities. Through HTS, several plant products have been identified for the production of new anti-cancer drugs, which include the vinca alkaloids, the taxanes and camptothecins derived from
The most common method of plant-based drug identification and selection remains with careful observation of the use of herbal medicine in the folk medicine of various cultures, which includes analysing traditional ethnobotanical documentation and inventories2. This is sometimes referred as the “reverse pharmacology path” because clinical experiences, observation and available data from human use are utilised as the starting-point, instead of being the end-point, in conventional drug research. The information gathered can be extremely useful for the study of individual phytocompounds, with the determination of best extraction method by observing the traditional preparation procedure of individual plants, as well as the identification of pharmacological activity by observing the traditional formulation used, its route of administration and doses2. Examples of the application of the reverse pharmacology include the anti-malarial drug quinine, which had its origin in the royal households of the South American Incas. Another is tubocurarine, a muscle relaxant originating from curare in the plant species
We would now examine one example of herbal medicine detailing its role in modern drug development with the reverse pharmacology approach. Qian Ceng Ta, a Chinese herbal medicine that is prepared from the moss
Ahmad et al. 30identified at least five major limitations in the development of herbal medicine: (i) the reproducibility of biological activity of herbal extracts; (ii) its toxicity and adverse effects; (iii) its adulteration and contamination; (iv) herb–drug interactions issues; and (v) standardisation issues. We shall now briefly examine each of these limitations.
Reproducibility of biological activity of herbal medicine
One of the most problematic issues faced by the field of phytomedicine is the high failure rate to reproduce the biological activity of individual herbal extracts after the success of initial screening process. Over 40% of plant extracts found actually lack this reproducibility31. This failure in re-sampled and re-extracted batches points towards the variation of biochemical profiles of plants harvested at different times and locations, as well the existence of unique variation in the same type of plant. The different methods of extraction and detection of biological activities in laboratories may also contribute to this lack of reproducibility. Wide variations in chemical composition of herbal medicine require careful chemical analysis to ensure consistency. Conflicting reports of efficacy could be due to this difference in consistency. Additionally, the synergistic interactions between the varieties of phytocompounds in each individual extract may also influence its activity and efficacy. The desired pharmacological effect may not be caused by a single phytocompound but by a combination of phytocompounds resulting in pharmacodynamic synergism. This is seen in
Toxicity and adverse effects of herbal medicine
There is a predominant myth in society that medicinal herbs or plants are much safer than conventional pharmaceuticals due to its “natural” origin. This cannot be further than the truth! Like all other medicines, there is a specific dosage threshold for each herbal medicine to be efficacious as well as to be toxic. There have been reports in the literature 32, 33 that many herbal medicine preparations are potentially toxic and some are even carcinogenic. For example, aristolochic acid derived from
Adulteration and contamination of herbal medicine
Herbal medicine may become adulterated and contaminated in countries that are lax in their purity control regulation. This may cause significant medical problems, especially in children37,38. For example, a review found 13 reports of heavy metal poisoning among children who consumed herbal medicine in Singapore, Hong Kong, the USA, the UK and the UAE from 1975 to 200238. A recent cross-sectional study among 13,504 adults in the USA showed that women using herbal supplements (including Ayurvedic or traditional Chinese medicine herbs, St. John’s Wort, and “other” herbs) had blood lead levels that were 10% higher than women non-users, although these increased levels were not seen among men39.
Herb–drug interactions issues
Not surprisingly, the pharmacokinetic profile of administered conventional pharmaceuticals can be changed by the usage of herbal medicine40. These interactions may potentiate or antagonize the absorption and metabolism of drugs, as well as cause adverse effects like allergy41. However, it is worthy of note that herbal medicine has the lowest level (7.6%) of reported adverse effects compared to other modes of complementary and alternative medicine42.
Herbal medicine standardisation issues
Herbal medicine rarely meet the standard of standardisation, which is partially due to the scarcity of scientific information about the acting pharmacological principles of the extracted phytocompounds and the fact that the plants are not cultivated under controlled condition30. The significant variability in content and quality of commercialised herbal products is the result of variability in the content and concentration of phytocompounds within the extract as well as the different extraction and processing techniques employed by different producers36.
Aside from the limitations discussed above, among the problems faced from plant-based drug development is the issue of eco-sustainability. Taxol, an anti-tumour agent, is isolated from the bark of
The Future of Herbal Medicine
What does the future hold in store for herbal medicine? Socio-cultural and economical problems, lack of well-planned and integrated strategies, as well as poor access to scientific information must be dealt with in order to fully utilise the available resources for the modern concept of drug development. It is important to encourage more ethnobotanical studies among indigenous people before their way of life or they themselves disappear25. Besides this, the problem of patents, intellectual property and rights of the native population where the phytomedicine knowledge originated should be addressed adequately. This native population is often found to be in need of better care, but they do not usually benefit from sharing their knowledge to the rest of the so-called “modern world”. It is curious to note that drug companies generate more than USD 100 million each year from the sale of drugs from natural compounds, without returning profits to the countries where the compounds were found44. Protecting and compensating local groups for their indigenous knowledge as well as providing access to modern medicine should be seen as a reasonable expectation from the conventional pharmaceutical or herbal medicine companies that stand to benefit greatly from this “collaboration”. Meanwhile, it is unfortunate that current herbal medicine companies are still mainly small businesses and as a result, products sold are of inferior quality and frequently mixed with contaminants and sometimes toxin. Professional links must be forged between these businesses, the government, large pharmaceutical companies, academic institution and the local community to continue the expansion and development of herbal medicine in the right direction. This will promote the rational and responsible exploitation of biodiversity as a source of chemical compounds that can be used for developing new drugs. For example, the International Cooperative Biodiversity Group (ICBG) program, which is currently based in Peru, has been established to form interdisciplinary collaboration between universities, research institutions, government and pharmaceutical companies25. In China, Yunnan Institute of Tropical Botany (YITB) has collaborated with Yamanouchi Pharmaceutical of Japan, resulting in the development of seven patents from 1988 to 19911. Similar programs should be encouraged worldwide.
Besides this, the improvement of drugs found in nature is now possible by organic chemistry, gene amplification and recombinant procedures, high-throughput screening, gene chip technology, or chemosystemics25. Through these methods, now there are new local anaesthetics derived from cocaine without its original dangerous effects 45 and there is also chloroquine that is less toxic than quinine4.
The golden field of herbal medicine must be explored and harvested to the fullest in order for the mainstream medical field to progress further. The great new discoveries promised by the budding field of modern phytomedicine are just too tempting to be resisted by those who respect the dynamic of scientific progress. Be it in the jungle or in a dusty monastery, some traditional herbal knowledge can be seen as a gift from the past to those in the future, who should refine this knowledge using the state-of-the-art methods. Indeed, the future of phytomedicine in modern drug development looks very promising, as long as scientists keep a curious and objective mind, without prejudice towards the concept of “herbal medicine”.