"It is only 8 o'clock in the morning and it looks like it could be a long day here at the Restawhile Nursing Home. I just checked in on Mrs. Lopez who had been diagnosed with Hodgkin's disease. She seems to be doing quite well after her final round of a combination chemotherapeutic regimen including the drug vincristine. Her doctors said that there is a complete response in 70% of the patients who are treated with the combination of drugs she received. I had better go check on Mr. Pauls who is suffering from congestive heart failure. I need to make sure that he has taken his digitalis. Sometimes he tries to skip a dose, but I am not sure why. Oh, no, I forgot to check the CDC website to see if I need to get a prescription for an analog of quinine before my trip to Costa Rica! I can't remember if malaria is a threat there or not? Better get on the Internet later today. Sure feels like I might have a headache coming on with all of this work to do! Let me grab two aspirin from this bottle before I start my day of work here at Restawhile."
Four widely used modern drugs are mentioned in the scenario above, and the four drugs all have very different uses and biochemical activity. What all four drugs have in common is that in some way they are derived from natural plant materials. Vincristine and vinblastine, known as the Vinca alkaloids, are isolated from the Madagascar periwinkle plant, Catharanthus roseus. These drugs are the best known plant-derived anticancer drugs (Cragg and Boyd, 1996). These drugs are effective because they interfere with the formation of the spindle fibers in actively mitotic cells. Digitalis is the Latin name of the plants of the foxglove genus that William Withering identified in 1775 as being extremely effective in curing what was known at that time as dropsy. Dropsy patients suffered from retention of fluid that was alleviated by the administration of foxglove extracts. Currently, powdered foxglove leaf is still administered in tablet or capsule form to increase the force of heart contractions and therefore allow more time to rest between contractions. The story behind the discovery of quinine may be as much folklore as fact. A Spanish legend holds that a Spanish soldier invading the Inca Empire of Peru was suffering from malaria. As luck would have it, he drank the dark-brown water in a pool in which Cinchona trees (quinine trees) had fallen. After awakening from his nap, he discovered that his fever had subsided due to the "tea" from the tea bark. Whether or not the story is totally true, it is clear that the discovery of the bitter tasting quinine was important to the health of many, including the U.S. troops in Africa and the South Pacific during World War II as well as others who traveled and lived in malarial areas, which at one time included Washington, St. Louis, London, and Rome. And the history of the relatively inexpensive aspirin found in almost every home in the United States can be traced back to Filipendula ulmaria (Rosaceae), which is referred to as Spirea ulmaria in older literature. Long known as a medicinal plant to treat pain and fevers and as an antiseptic, the chemical salicylic acid was isolated from the flower buds in 1899. At that time the Bayer Company began to market acetylsalicylic acid, a synthetic derivative. They named this product "aspirin" and derived the name from the "a" in acetyl and the "spirin" from Spirea. Although we reach for a bottle of aspirin when pain strikes, the ancient Greeks and North American Indians gathered a piece of bark from a plant in the willow genus Salix to relieve their pain since members of the Salicaceae family also produce salicylic acid.
Today most of our over-the-counter and prescription medications arrive at our home in a convenient tablet or capsule form, packaged nicely in a transportable container with an accurate dosage noted on the container. It is easy for us to lose sight of the fact that it has not always been that way in the United States and it is not that way in all other countries of the world. We have a history of interest in phytochemicals. Crude vegetable drugs were the dominant therapy until the time of World War II; however, change was on the horizon. During the late nineteenth century, Western medicine, or "scientific medicine", which relies heavily on chemical analysis of drugs, synthesis of drugs, surgical innovations and medical research, began to supersede the folk and learned medicine that had been gathered and traded between cultures since the time of the Ancient Egyptians (Root-Bernstein, 1998). Development of synthetic chemistry in the 1930's reduced our reliance on the natural world. The 1940's ushered in the discovery and development of fermentation and synthetic organic chemistry. During the 1960's and 1970's pharmaceutical firms incorporated techniques from molecular biology and computer-assisted drug design and moved away from any interest in folk knowledge of medicinal plants. Today that pendulum is swinging back to an interest at many levels in the value of traditional medicine and folklore. No longer are traditional healers, called shamans, referred to as "witch doctors" and dismissed as unimportant in the healing process. There is currently a rising recognition of the value of centuries of experience and historical knowledge gathered by indigenous cultures with medicinal plants. For many conditions, traditional medicine is effective, less expensive, more widely available and more culturally accepted than Western medicine. For example, Martin, the local healer in the small Mexican village of Ajoya treats his young paralyzed patient with horrible bedsores the size of small fists with a paste made of honey and sugar. While the first thought might be to scoff at this simplistic folk remedy, it is important to realize that the underlying science is the osmotic power of the mixture and the ability to create a hypertonic environment that is inhospitable to the growth of bacteria. Also, there is increasing research evidence that the sugar-based treatments may create an effective and painless form of debridement of the wounds, which removes dead tissue and sterilizes the wound through other biochemical actions of other components of honey. In a culture where hard cash is difficult to come by, it is easier for a local healer to acquire honey and sugar than it is to acquire tubes of antibiotics and other appropriate dressings. And Martin's patient was completely healed and pain-free in six weeks. (Root-Bernstein, 1998).
A renewed interest in ethnobotany
Pliny the Elder (circa A.D. 77) said, "nature distributed medicine everywhere". Plants do not have the ability to fight or flee from a predator, so they evolved chemical defenses, which humans have recognized and harvested to enhance the survival of the human species. Norman Farnsworth of the University of Illinois estimates that 89 plant-derived drugs currently prescribed in the industrialized world were discovered by studying folk knowledge (Balick, 1996). However, less than one-half of 1% of all flowering plant species in the world have ever been studied for potential pharmacological activity (Balick, 1996). Ethnobotany is the field of study that analyzes the results of the indigenous manipulations of plant materials together with the cultural context in which the plants are used (Balick, 1996). The work of ethnobotanists focuses on many plant uses, such as palms for thatch roofs, timber for boats, fibers for cordage, and plants appropriate for use in producing textile products and plant dyes. These studies pale though in comparison to the study of the use of plants for food and medicine. According to Michael Balick (1996), the ideal ethnobotanist is a "combination of anthropologist, archaeologist, botanist, chemist, psychologist, ecologist, explorer, folklorist, pharmacologist and diplomat". Since ethnobotanists must live for extended periods of time with indigenous people (people who follow traditional, nonindustrial lifestyles in areas that they have occupied for generations) a strong sense of adventure probably is also important. Ethnobotany requires an interdisciplinary approach to understand the connections between people in a human society and the plants in their environment. Probably the most important personal characteristic of an ethnobotanist is the ability to secure and maintain the trust of the people of a society being studied, especially the traditional healers and the elders of the society.
There are two major approaches for the "discovery" of plant derived pharmaceuticals. The first approach is the random approach. In this approach, a large number of plants are collected and screened for biochemical activity. Generally, there is a low success rate from the random collection process although the discovery of the drug taxol, currently used in some cases of breast and ovarian cancer, was discovered through this method. The second major approach is the targeted approach, and the ethnobotanical drug discovery process is one form of the targeted approach. In an ethnobotanical drug discovery process the plants used by traditional healers are eventually formulated into a medicine used in a clinical setting. History shows that a targeted, ethnobotanical approach is more likely to succeed than random screening.
The modern ethnobotanical drug discovery programs include the following processes:
á Folk knowledge of a plant's possible therapeutic activity accumulates in the indigenous culture
á A healer uses the plant for his or her patients
á The healer communicates the knowledge about this plant to a formally trained scientist
á The scientist collects and identifies the plant. Generally, one to two kilograms of plant parts are collected in the field. The plant parts are either dried or placed in a preservative.
á The scientist will test extracts of the plant with a bioassay protocol to look for the desired pharmacological activity. To produce the extracts, plants are macerated, placed in a solvent and shaken for 24 hours. The solvent will be removed in an evaporator and the plant extract will be freeze-dried. Generally, only 0.5 to 1 gram of crude extract will be produced from every one to two kilogram sample.
á The scientist will isolate a pure compound by using the bioassay to trace the source of the activity in the plant extract.
á The scientist will determine the structure of the pure substance (Balick, 1996)
Once the pure substance has been identified, it is now possible to calibrate appropriate dosage, perform clinical trials and perhaps move the drug into commercial development.
The science of modern drug development
Efforts for developing new pharmaceuticals have generally focused on one of the following five approaches: (McChesney, 1996)
1. A derivation from existing agents (example: isolating just the intermediate metabolite that is valuable for the response desired and reformulating, repackaging and renaming the drug)
2. Synthesis of additional analogs of existing agents
3. Use of combination therapy of existing agents with other drugs (examples include AIDS "cocktails" and cancer chemotherapy combinations)
4. Improvement of delivery of existing agents to the target site
5. Discovery of new prototype pharmaceutical agents
James D. McChesney of the Research Institute of Pharmaceutical Sciences, School of Pharmacy, the University of Mississippi points out
"Éthere is an urgent need for the development of totally new prototype agents that do not share the same toxicities, cross-resistance, or mechanism of action as existing agents. Natural products have, in the past, provided a rich source of such prototype bioactive compounds, and it is essential that the search for new drugs pursue this route. The major advantage of this approach is the likelihood of identifying new prototype drugs with quite different chemical structures and mechanisms of action and, hence, lower likelihood of similar toxicities and cross-resistance. Clearly, the higher plants represent a bountiful source of new prototypic bioactive agents that must be examined." (McChesney, 1996)
Developing new drugs is not a cheap, quick nor a sure thing. It is estimated that it takes evaluation of more than 10,000 chemical substances to develop one lead. Direct clinical costs for a single drug are estimated to be 24 million dollars, but the average total cost of successfully bringing a drug to market is more likely somewhere between 100 million and 225 million dollars due to the high cost of funding the research of the failures. "Evaluation of new natural products of plant origin holds significant promise of lowering present-day drug discovery and development costs" (McChesney, 1996).
Linking to conservation practices
James D. McChesney reminds us that "it is important to recognize that biological diversity is an outward evidence of chemical diversity" (McChesney, 1996). What has long been known is that the zone of greatest biological diversity (the number of species present in a given ecosystem and the population size of each species relative to the others) is found in the tropics. In fact some ecologists use the term "hyperdiversity" to describe the abundance of species found in tropical moist forests (Kricher, 1997). Costa Rica has long been recognized as a repository of biological diversity. About 4% of the total number of species on earth claim Costa Rica as home. As tropical habitats are clear-cut for lumber or converted inappropriately for agriculture, species diversity can be lost. There are many estimates for how much we are losing and how fast we are losing it, but more importantly is the idea that there are discussions about new arguments and practices to counter this inappropriate conversion of tropical moist forests. One argument is the recognition of the chemical diversity of the plants found in the tropical ecosystems. Only scientists who specialized in the region originally recognized the potential pharmaceutical wealth of the tropical forests (Reid et al., 1996). This has now become a mainstream argument for biodiversity conservation, which translates into tropical habitat conservation.
New Models for Development
Tropical ecosystems provide more than just a reserve of chemical diversity for pharmaceuticals. Current trends in health and fitness contribute to a growing market for natural personal care products, such as soaps, shampoos and lotions. Rainforest products also appeal to our "global awareness" and a desire to use our purchasing power to take a public policy position. A good example of this is the purchase of "shade-grown" coffee, which helps maintain habitat for migrating songbirds. However, it is easier to attract most peoples' attention if you can assure them that there are still hidden treasures in the rainforest that could cure the most feared diseases - cancer, heart-disease and AIDS. Also, a country such as Costa Rica can attract funding dollars for programs such as pharmaceutical research. One paradigm for new models for conservation can include the concept of extractive reserves.
The conservation concept of extractive reserves recognizes that tropical ecosystems should be viewed as depositories of botanical and cultural diversity. Areas of tropical rain forest can be set aside for continuous harvesting of renewable forest products. These extractive reserves are a model for using resources and providing acceptable benefits to all parties involved while protecting the resource from degradation. This is in contrast to traditional strategies that create reserves essentially free from human disturbances, but do not necessarily provide economic opportunities for indigenous communities in the immediate area. The sustainable harvest of non-timber forest products, such as rubber, cacao (chocolate), nuts, fruits, fibers, oils and medicinal plants can help reconcile economic development and environmental conservation. This new model for development becomes valuable as the useful flora of isolated communities is recognized as products of global interest. By using the model of extractive reserves, such as has been done in Brazil and the Programme for Belize, communities have a direct stake and interest in conserving the environment. In order to work, extractive reserve models must include education of the local communities on the value of the resources and the value of sustainable management, especially where poverty persists (Elizabetsky, 1996). The extractive reserve model is an attempt to balance the needs of indigenous communities for hard cash in a global economy with the need for conservation of habitat for flora and fauna. While the extractive reserve model still needs additional research, the model is valuable because not only does it help preserve biological diversity of plants, animals and microorganisms, but it also halts the loss of indigenous knowledge systems. In an extractive reserve in Brazil, Elizabetsky (1996) reports that the women from the reserve knew the uses for 150 different species of plants. We must recognize that formal academic systems are only one route for transmitting knowledge. Conservation efforts should not focus just on maintaining plant, animal and soil microorganism species, but they must also focus on retaining and rescuing traditional knowledge by helping communities forge links with research and commercial institutions to cope with the impacts of globalization. There is a need to demonstrate that what can be harvested from the rainforest is worth more than the value of simply cutting down the trees for lumber usage.
It is impossible to carry out research for pharmaceuticals if the habitat disappears before projects can be completed. Destruction of tropical ecosystems is extensive in much of Central America. The rate of destruction may be as great as 123.5 acres every hour (Nader and Rojas, 1996). Mark Plotkin (2000) points out that no major medical compound has ever been developed from an eastern Brazilian rain forest plant. He feels that it is because indigenous tribes were obliterated before any ethnobotanical studies were ever conducted with the indigenous people. In order to win the race for time, Costa Rica has set aside 25% of its territory as protected land and has become proactive in prospecting the sustainable use of its biodiversity. (Nader and Rojas, 1996).
In 1989 the Instituto Nacional de Biodiversidad de Costa Rica (INBio) was founded by government decree. INBio is a private, non-profit association that has as its primary objective to conserve the nation's biodiversity by forming collaborative agreements with other private and governmental efforts. INBio's approach is "Save-Know-Use", and has led them to sign an agreement with Merck Pharmaceuticals, the world's largest pharmaceutical firm, to provide Merck with plant, insect and environmental samples for research. In return for initial processing and extracting of samples, Merck agreed to contribute one million dollars to INBio as well as $130,000 worth of laboratory equipment (Levine, 1992). Royalties will be paid to INBio if Merck successfully develops a pharmaceutical product from a sample provided by INBio. Monies from royalties and a portion of the initial $1 million are to be used to support conservation programs in Costa Rica.
Collaborative agreements have continued to expand. INBio signed an agreement with Recombinant Bio Catalysis, Inc. The focus of this project is to supply industry with new catalysts derived from microorganisms along with helping INBio scientists acquire expertise in recombinant DNA research.
The reality is that logging a forest for its lumber supply is money in the bank for a cash starved country that is struggling to overcome poverty and play a role in the new global economy. Cash starved countries with tropical resources must find economically beneficial alternatives to deforestation. Conservation efforts must focus on agreements or alliances that provide a profitable alternative to resource exploitation. Also, developed countries cannot continue to view tropical ecosystems and indigenous populations as resources to be exploited. Agreements and alliances must respect the local culture and be collaborative agreements that benefit the indigenous populations both through economic and educational opportunities. A global recognition of the great chemical diversity of the rainforest may be one ticket for the survival train.
Balick, M.J. and Cox, P. A. (1996). Plants, People and Culture: The Science of Ethnobotany. New York: Scientific American Library.
Brito, A.R.M.S. and Brito A. A. (1996). Medicinal Plant Research in Brazil: Data from Regional and National Meetings. In M. J. Balick, E.Elisabetsky, S. A. Laird, (Eds.), Medicinal Resources of the Tropical Forest, (pp. 386-401). New York: Columbia University Press.
Cragg, G.M. and Boyd, M. R. (1996). Drug Discovery and Development at the National Cancer Institute: The Role of Natural Products of Plant Origin. In M. J. Balick, E.Elisabetsky, S. A. Laird, (Eds.), Medicinal Resources of the Tropical Forest, (pp. 101-136). New York: Columbia University Press.
Elisabetsky, E. (1996). Community Ethnobotany: Setting Foundations for an Informed Decision on Trading Rain Forest Resources. In M. J. Balick, E.Elisabetsky, S. A. Laird, (Eds.), Medicinal Resources of the Tropical Forest, (pp. 402-407). New York: Columbia University Press.
Kricher, J. (1997). A Neotropical Companion. New Jersey: Princeton University Press.
Levine, K. ((1992, November 23). Merck's search for drugs no threat to rain forest. Drug Topics, 136, 37.
McChesney, J. D. (1996) Biological Diversity, Chemical Diversity, and the Search for New Pharmaceuticals. In M. J. Balick, E.Elisabetsky, S. A. Laird, (Eds.), Medicinal Resources of the Tropical Forest, (pp. 11-18). New York: Columbia University Press.
Nader, W. and Rojas, M. (1996, April 1). Gene Prospecting for Sustainable Use of the Biodiversity in Costa Rica. Genetic Engineering News, 16, 35.
Plotkin, M.J. (2000). Medicine Quest: In Search of Nature's Healing Secrets. New York: Viking Penguin.
Reid, W.V., Laird, S. A. Meyer, C. A., Gamez, R, Sittenfeld, A, Janzen, D, Gollin, M. A., Juma, C. (1996). Biodiversity Prospecting. In M. J. Balick, E.Elisabetsky, S. A. Laird, (Eds.), Medicinal Resources of the Tropical Forest, (pp. 142-173). New York: Columbia University Press.
Root-Bernstein, R. and M. (1998). Honey, Mud, Maggots, and Other Medical Marvels: The Science Behind Folk Remedies and Old Wives' Tales. Boston: A Mariner Book by Houghton Mifflin Company.
Sittenfeld, A., (1996). Tropical Medicinal Plant Conservation and Development Projects: The Case of the Costa Rican National Institute of Biodiversity (INBio). In M. J. Balick, E.Elisabetsky, S. A. Laird, (Eds.), Medicinal Resources of the Tropical Forest, (pp. 334-340). New York: Columbia University Press.
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