It was the best of times, it was the worst of times,
it was the age of wisdom, it was the age of foolishness,
it was the epoch of belief, it was the epoch of incredulity,
it was the season of Light, it was the season of Darkness,
it was the spring of how, it was the winter of despair.
These comments thoroughly and accurately portray the situation in the United States today regarding healing herbs and phytomedicinals as well as pure chemical entities isolated from drug plants. To understand why this contradictory condition prevails, we need to review briefly the history of drug research.
HISTORY OF DRUG RESEARCH
The empirical search for agents to cure disease probably began with the earliest stirrings of thought and reason in the brains of humanoid creatures -- the forerunners of Homo sapiens. It centered on the kingdom because of the widespread abundance of numerous species, some of which, having been tried for food, were rejected, probably for reasons of unpalatability, but were found nevertheless to exert interesting physiological effects on those who consumed them. Coffee beans (Coffea spp.) and tea leaves [Camellia sinensis (L.) O. Kuntzel produced stimulation; opium poppy latex (Papaver somniferum L.) caused a dulling of pain sensations; cinchona bark (Cinchona spp.) cured intermittent fever; ergot [Claviceps purpurea (Fr.) Tul.] resulted in abortion; deadly nightshade (Atropa belladonna L.), in proper dose, stopped intestinal spasms: digitalis (Digitalis purpurea L.) cured dropsy (cardiac edema); and on and on. Gradually, human beings developed a medicinal armamentarium of vast scope, and most of the drugs came from plants.
Over the years, scientists have speculated as to just why it is that plants produce such a wide variety of secondary chemical constituents that are of no obvious use to them but that are so significant to humans. In considering the answer to this question, one must be especially careful to avoid teleological thought because, lacking any vestige of a central nervous system, plants cannot be endowed with purpose. However, the Cherokee Indians were not bothered by teleology when they opined that one of the objectives of plants was to cure the various diseases inflicted on humans by animals in retaliation for the hunting and killing of various animal species by people.
When I was a graduate student, we were taught that secondary plant constituents were basically the result of metabolic errors and were a kind of waste product that simply accumulated in the organism which had no excretory mechanism. In recent times, scientists have tended to believe that these constituents confer survival value on the plant through their unpalatability or toxicity. Such compounds would be analogous to physical structures, such as thorns, in preventing, or at least deterring, consumption of the plant by animals.
I have often pondered this theory after watching a slug consume with impunity a deadly amanita mushroom [Amanita phalloides (Fr.) Secr.], with its lethal (to humans) peptide toxins, and must confess that I am not totally convinced it is correct. At least it does not tell the whole story. Time does not permit their detailed consideration here; but at least six theories, each of them reasonable to some degree, have been proposed to account for the existence of various secondary plant constituents. Probably there is some truth in each of them. Certainly, no single theory provides the total explanation encompassing all of them. Besides, what is important here is the fact that many such compounds do possess interesting physiological activities in animals that render them useful as drugs.
Some of the tales relating to the discovery of these plant medicines are fascinating, and on hearing a few of them, it is easy to see why some of us decided to devote our professional lives to pharmacognosy or medical botany.
Humankind has always found it difficult to face reality, and plants have long provided a variety of temporary escape mechanisms ranging from alcohol to opium. Even the naked aboriginals of Australia had their pituri, a scopolamine-containing species of Dubosia that was chewed to increase endurance so necessary in a vast land deficient in both food and water Also, the Chukchee and Koryaks of the Siberian wastes and the Kamchatka Peninsula found a beautiful mushroom, the fly agaric [Amanita muscaria (Fr.) Hook.], that they consumed as an intoxicant. Because the active principle was concentrated in the urine, the poor tribesmen who could not afford the mushroom collected the urine of those more fortunate individuals who could and then drank it to obtain the same effect.
According to Greek legend, the Christmas rose, black hellebore (Helleborus niger L.), was popularized as a medicine after Melampus, a physician in the Greek district of Argos, cured King Proetus' daughters of madness by administering it, or a related species, to them.
Aconite (Aconitum napellus L.) first gained notoriety as an arrow poison in ancient China and was subsequently used as such in India and even in Europe (Gaul). American Indians dipped their harpoon tips in an extract of aconite before whaling expeditions.
To be perfectly truthful, no one really knows how or when cinchona (Cinchona spp.) bark was discovered to be a useful treatment for intermittent fever (malaria). The story I like best is the fevered native drinking from a pool of stagnant water into which a cinchona tree had fallen. On the other hand, a few authorities believe malaria did not even exist in the Western Hemisphere until after 1492. I believe they are wrong, but you may believe what you wish.
Podophyllum (Podophyllum peltatum L.), or mayapple, was employed by the American Indians as an emetic, a cathartic, and an escharotic. The latter property is now most valued, podophyllum resin being employed externally in the treatment of venereal warts and similar papillomas.
The reputations of some medicinal plants have changed markedly over the years. Originally known as wild nard some 2,000 years ago, the herb now called valerian (Valeriana officinalis L.) serves as an excellent example. Today, we view it as a malodorous root with tranquilizing or sedative properties. In the sixteenth century, its odor was thought to be very pleasing, and it was highly valued as a flavor for food. Further, it was employed then as a stimulant, not as a depressant.
These kinds of stories of empirical drug discovery are just a sampling, but the examples given are sufficient to explain the process. The important thing to remember is that, by means of superstition, folklore, and, most of all simple testing, humans were able to determine the physiological action of a large number of plant species, and many of them were used for medicinal purposes.
Then, in the nineteenth century, came the realization that it would be desirable, in many cases, to concentrate and more or less standardize the activity in these crude vegetable materials. The fluid extract was born, prepared by macerating and extracting (percolating) the drug with a (usually) hydroalcoholic solvent or menstruum. The next logical step was the actual isolation and purification of the active principles, a very complicated process with the equipment then available. Because of their chemical and physical properties, which made them easy to purify, alkaloids were the first type of principles studied, beginning with the isolation of morphine by the German pharmacist Serturner in 1806. Other types of compounds had to wait well into the twentieth century until the development of various types of chromatography and electrophoresis made it possible to separate them from accompanying active constituents as well as inactive plant material.
Isolation and utilization of pure chemical constituents had several advantages. Doses of potent compounds could be administered with great precision. Also, undesirable constituents, such as astringent tannins, could be eliminated, rendering the consumption of tannin-rich drugs, such as cinchona bark, much more pleasant. But problems also arose. Some plant materials contain a large number of active principles -- opium is a good example -- and purification may eliminate certain useful ones. Besides, in some cases, the isolation and purification of specific constituents is simply not necessary. It would be a waste of time and money to purify such herbal remedies as peppermint, peppermint oil (Mentha x piperira L.), or cascara (Rhamnus purshiana DC.). In some cases, the identity of the active principle(s) remains unknown. Valerian is an example. I view this as a sad commentary on the priorities established by twentieth-century scientists.
THE NEED FOR PHYTOMEDICINALS
So, it appears that within the realm of medicine there remains a legitimate need for various dosage forms of plant drugs in addition to the pure chemical principles isolated from them. These range from teas (technically, infusions) prepared from the coarsely comminuted (pulverized) vegetable material to hydroalcoholic tinctures or fluid extracts in which 10 ml normally represents 1 to 10 g of starting material. Variations exist of each of these so-called galenicals -- named for the second-century Greek physician Galen who originated some of them. Extracts of potent drugs are often standardized by chemical or biological means to assure uniform potency.
Another popular dosage form is prepared simply by encapsulating finely powdered herbs. Alternatively, compressed tablets containing them may be produced. Modifications here include enteric coating to ensure the release of active constituents in the duodenum rather than the stomach. This is of considerable importance with acid-labile active constituents such as alliinase, the allicin-releasing enzyme in garlic (Allium sativum L.). In modern parlance, these infusions, galenicals, and encapsulated or tableted herbs are all known as phytomedicinals.
PROBLEMS WITH PHYTOMEDICINALS IN THE UNITED STATES
How many plant drugs are there which may be used safely and effectively as phytomedicinals? In Germany, where Commission E of the German Federal Health Agency has been studying plant drugs since 1978, about 200 different ones are now recommended out of a total of about 300 that have been examined. However, in that country, phytomedicinals are frequently prescribed by physicians who learn their virtues in the standard medical education programs. In the United States, this information is not included in medical curriculums, so most phytomedicinals are self-selected by the patient. Because it would be utter folly to self-diagnose and self-treat a cardiac ailment, such as angina, some of the European preparations, in this case hawthorn (Crataegus spp.), cannot be recommended in the United States. Consequently, the number of useful phytomedicinals in this country at present is probably closer to 125.
I have purposely not used the term OTC drugs to describe these preparations because in the United States most of these remedies are not legally classified as drugs. Instead, herbs and phytomedicinals are technically dietary supplements. In a few cases, they are food additives: but in all cases, they are foods, not drugs. The reasons for this are both economic and political. The kind of effort required here to prove a chemical entity safe and effective as a drug is extremely expensive. A figure of $350 million is now commonly quoted. Because the FDA views phytomedicinals as being composed of scores of chemical entities and requires each to be evaluated independently, the cost of obtaining the necessary proof is obviously prohibitive. This is particularly true in the case of popular folk medicines with a long history of use for which patent protection and resulting market exclusivity is, at best, problematic. This does not allow research costs to be recovered, so the necessary res earch is not carried out.
The regulatory situation just described has caused natural drugs to fall into a state in the United States that is characterized by the lines in my opening quotation. It is the best of times because consumers display an enormous interest in herbal medicine. It is the worst of times because that interest is not shared by pharmaceutical companies, physicians, or the government. It is the spring of hope because consumers usually prevail here; it is the winter of despair because that has not yet happened. With respect to self-selected phytomedicinals, the season of darkness presently prevails.
It is too early to tell how the recently passed Dietary Supplement Health and Education Act of 1994 will affect the present situation. Although it permits the marketing of herbs, per se, with literature-derived information, it does not permit drug claims for them. Moreover, phytomedicinals as well as combination products are excluded from the Act's provisions. A commission on labeling is to be established with a report due in two years. Also, the Office of Dietary Supplements will be established in the National Institutes of Health with a $5 million budget. Finally, the government must now assume the burden of proof that an herb is unsafe. One certain effect of the legislation is increased funding for the legal profession.
NEW CHEMICAL ENTITLES FROM PLANTS
The situation is not greatly improved when one considers plants as sources of specific chemical entities used as approved drugs. Although no survey has been conducted for more than a quarter century, analysis of 1.05 billion prescriptions in 1967 showed that about 25% were for drugs containing higher plant principles. The largest single category (9.94% of all prescriptions) consisted of various hormones, not isolated from plant material per se but prepared by semisynthesis from plant-derived precursors. The so-called birth control pills are prominent examples. Similar situations existed for the analgesics, which included mostly chemical modifications or imitations of the opium poppy alkaloids morphine and codeine. The point is that relatively few unmodified higher plant constituents were widely used in medicine in 1967, and the situation has changed little in the interim.
During the last 35 years or so, only three entirely new chemical compounds that have attained approved-drug status have been isolated from higher plants. All are antineoplastic agents. The first was vinblastine, isolated by Noble et al. from Catharanthus roseus G. Don in 1958, and the second was vincristine (leurocristine), isolated by Svoboda from the same plant in 1961. The third, taxol, was first obtained by Wall and colleagues from Taxus brevifolia Nutt. in 1971, but some 20 years were to pass before FDA gave approval of its use in the treatment of ovarian cancer. These very limited successes belie the intensive search efforts made during the period when the programs of the National Cancer Institute alone screened about 40,000 species for antitumor activity. Nevertheless, studies by ethnobotanists and others continue apace in many remote areas of the world in an effort to identify exotic plants with little-known physiological activities that may yield patentable constituents or models.
A considerable number of these efforts are sponsored by major pharmaceutical companies both in the United States and abroad. Exploration is currently proceeding in Brazil, Costa Rica, China, Mexico, and even Samoa, to name just a few areas. Some promising leads have already been reported in both the scientific and the popular press.
The modern-day plant-drug hunters are following in illustrious footsteps. During his 14 years of exploration on the northwest Amazon and in the Andes (1849-1863), Richard Spruce developed a particular interest in various indegenous narcotics and stimulants, including coca (Erythroxlum spp.) and guarana (Paullinia cupana H.B.K.), and also in the cinchona tree. Another Englishman, Charles Ledger, was responsible for smuggling viable seeds of the true calisaya tree (Cinchona calisaya Wedd.) out of Bolivia in 1865. The irony of this feat is that when the seeds were offered for sale to the government of British India, purchase was declined. Dutch authorities were more perceptive, and, by 1874, more than two million high-grade cinchona trees were being cultivated in Java, much to the financial advantage of citizens of the Netherlands.
The greatest of the American pharmacist plant-drug explorers was Henry Hurd Rusby, dean and professor of materia medica at the Columbia University College of Pharmacy, Rusby carried out extensive explorations in the jungles of South America between the 1880's and 1920's. He was initially commissioned by Parke, Davis and Company in 1885, primarily to obtain a large supply of coca leaves in Bolivia and to ship it back to the United States. He did collect some 20,000 lbs. of leaf, but it could not be shipped as a result of a revolution in Colombia, so Parke, Davis wired him to return home. He did so, but went the long way around by crossing the Andes and going down the Amazon to the State of Para on the east coast of Brazil. Needless to say, Rusby's experiences during this 1885-1887 period were numerous. They are related in exciting detail in his book Jungle Memories, published in 1933.
During this expedition, Rusby collected 45,000 plant specimens, many of which were new to science. Only one, however, proved to be a commercially useful phytomedicinal. It was cocillana, the bark of Guarea rusbyii (Britton) Rusby, a nauseant-expectorant that was once a popular ingredient in cough syrups. Although it received official recognition in The National Formulary from 1916 to 1926, its medicinal use has now been discontinued. The potential toxicity and precision dosage required of cocillana and other nauseant-expectorants has greatly restricted their use in modern medical practice.
A LESSON FROM ARROW POISONS
Various arrow poisons prepared by several South American Indian tribes and known as curare were first brought to Europe by Sir Walter Raleigh in 1595: however, it was not until 1856 that Claude Bernard described curare's physiologic activity as a skeletal muscle relaxant. Some 40 years later, in 1898, Boehm isolated the active principle tubocurarine from a sample of unknown botanic origin. Much later, in the mid-twentieth century, King isolated tubocurarine from curare prepared from a known species. Chondodendron tomentosum Ruiz and Pav., and confirmed the structure as a quaternary ammonium compound. Both tubocurarine chloride and a more potent methyl analogue, metocurine iodide, are official in the USP and are commonly employed as nondeplorizing muscle relaxants. Such agents tend not to induce random contraction (fibrillation) of the muscle fiber and are quite selective for nonrespiratory muscle.
It is instructive to compare curare of the South American natives with the arrow poison employed by the inhabitants of tropical Africa. Since such poisons were once widely used in both areas, it is only natural to assume that they would be prepared from similar plants with similar active constituents. This is not the case. African poisons are basically made from species of Strophanthus, usually S. kombé. Oliver or S. hispidus DC. These plants rely on the presence of cardiac glycosides similar to those found in digitalis for their deadly effects, which are initially cardiac arrhythmia followed by standstill. This is a very different mechanism than that of curare poisoning, which kills by paralyzing the respiratory muscles.
It was mentioned earlier that the arrow poison used in ancient China and in India was neither curare nor strophanthus, but aconite. Although its toxic constituents are alkaloids, not glycoside, the effects produced are more reminiscent of those induced by strophanthus than by curare. The heart first becomes arrhythmic and then ceases to beat. Drug-plant hunters must not assume that different plants used for the same purpose have similar constituents or physiological mechanisms of action. Each species must be carefully studied as an individual entity.
DRUG DISCOVERY IN THE FUTURE
The future of drug discovery does not lie in the search for new traditional drugs in the rainforest, the screening of their extracts for various physiological activities, and the isolation of active chemical constituents or prototypes that can be made effective by semisynthesis. The future also does not lie in the random screening of newly synthesized organic chemicals in the hope that one will cure cancer or prevent the rejection of a transplanted liver. No, the future lies, as molecular biologists are prone to remind us, in the identity of the nature of receptor sites on or within cells in the brain or in other organs or tissues and the customized synthesis of agents that will occupy those sites to promote some desirable effect or to prevent an undesirable one.
However, contrary to that oft-repeated phrase, "The future is now," in drug discovery at least, the future is not yet here. It will come, but it will come slowly and in pieces, not all at once. So, until the day when genetic engineering developments can be made with sufficient ease to permit the marketing of its products at affordable costs, or the day when all those receptor sites are known and appropriately fitting drugs can be synthesized with ease, we must rely on the classic empirical methods for the discovery of new drugs. Certainly the plant kingdom is a tried and true source. If we are able to curb the naturally rapacious nature of an ever-expanding human population, perhaps a considerable number of those useful species may be examined scientifically and clinically before being trampled, burned, or plowed into extinction. There are certain to be some good, new drugs out there remaining to be discovered, but to find them has become a race against time.
PLANT PRESERVATION -- A NECESSITY AND AN OBLIGATION
John Riddle tells us that one of the first drug plants to be rendered extinct in the ancient world was silphium, a birth-control agent highly valued by the ancient Romans. Its employment as a contraceptive was so widespread that this difficult-to-cultivate plant no longer existed in the Mediterranean area, or anywhere else, after the third century A.D. This paradox serves as an important lesson to all who seek to improve the destiny of human beings by making use of materials from the kingdom of the plants.
In advancing our own cause, we must be ever mindful not to destroy that which helps us to advance. Plants have been faithful servants to humans from the beginning of time. Isn't it about time for us to express our thanks by helping plants to continue to occupy their rightful place in the world -- a world in which botanicals existed long before Homo sapiens?
If we don't, humanity will be the big loser!
1. Raison d'être of Secondary Plant Constituents
D. H. Williams, M. J. Stone, P. R. Houck, and S. K. Rahman: "Why Are Secondary Medatolites (Natural Products) Biosynthesized?" Journal of Natural Products 52: 1189-1208 (1989).
2. Plant Drug Discovery
F. A. Flückiger and D. Hanbury: Pharmacographia: A History of Drugs, Macmillan and Co., London, 1879, 803 pp.
M. L. Duran-Reynals: The Fever Bark Tree, Doubleday & Company, Inc., Garden City, New York, 1946, 2 7 5 pp.
J. Jaramillo-Arango: The Conquest of Malaria, William Heinemann, London, 1950, 125 pp.
M. B. Kreig: Green Medicine, Rand McNally & Company, Chicago, 1964, 462 pp.
J. U. Lloyd: Origin and History of All the Pharmacopeial Vegetable Drugs, Chemicals and Preparations, Caxton Press, Cincinnati, 1921, 449 pp.
N. Taylor: Plant Drugs That Changed the World, Dodd, Mead & Company, New York, 1965, 275 pp.
V. E. Tyler: "Medicinal Plant Research: 1953-1987," Planta Medica 1988: 95-100 (1988).
V. E. Tyler: "Natural Products and Medicine," HerbalGram No. 28: 40-45 (1993).
3. Herbal Regulation in the United States and Europe
V. E. Tyler: Herbs of Choice: The Therapeutic Use of Phytomedicinals, Pharmaceutical Products Press, Binghamton, New York, 1994, 209 pp.
V. E. Tyler: "Phytomedicines in Western Europe: Potential Impact on Herbal Medicine in the United States," in Human Medicinal Agents from Plants, A.D. Kinghorn and M.F. Balandrin, eds., ACS Symposium Series 534, American Chemical Society, Washington, D.C., 1993, pp. 25-37. Reprinted in HerbalGram No. 30: 24-30, 67-68 (1994).
4. Plant Drug Hunters on the Amazon
R. Spruce: Notes of a Botanist on the Amazon & Andes, Vols. 1 and 2, Johnson Reprint Corporation, New York, 1970, 518 and 542 pp.
H. H. Rusby: Jungle Memories, Whittlesey House, New York, 1933, 388 pp.
5. The Future of Phytomedicinals
V. E. Tyler: "Plant Drugs in the Twenty-first Century," Economic Botany 40: 279-288 (1986). Reprinted in HerbalGram No. 11: 6-11 (1987) and as Classic Botanical Reprint No. 207.
6. Plant Preservation
J. M. Riddle, J. W. Estes, and J. C. Russell: "Ever Since Eve...Birth Control in the Ancient World," Archaeology 47(2): 30-35 (1994).
Article copyright American Botanical Council.
By Varro E. Tyler