THE HISTORY OF HERBAL MEDICINE
The use of natural products as medicinal agents presumably predates the earliest recorded history as the earliest humans used various, but specific plants to treat illness. Records from as early as 2700 B.C. from China, traced to the Emperor Shen Nong, indicate the usefulness of plants for treating diseases, and some archaeological discoveries trace the use of herbal medicine in China, much earlier.
The Ebers papyrus, written in about 1550 B.C., includes many of the plants used in Egyptian medicine. Theophrastus (370-285 BC) began the scientific classification of plants, and Dioscorides De Materia Medica (77 AD) reported the uses, medicinal and otherwise, of over 600 plants. Ibn al-Baitar (1197-1248) listed over 1400 drugs and medicinal plants in his Corpus of Simples. In Europe, after the tenth century, much of the medicinal lore was based in the church, particularly the monastic orders, but by the 1500's, after the invention of the printing press, herbals available to the general public were popular, particularly in England. By the late 1700's, studies like William Withering's "An Account of the Foxglove and its Medicinal Uses" (1785) began to appear. These were based on case histories and described specific doses and gave administration indications for herbal remedies.
In the United States, before the advent of specific pharmaceuticals, herbal medicine was relied upon to treat many illnesses. Development of drugs based on natural products has had a long history in the United States, and in 1991, almost half of the best selling drugs were natural products or derivatives of natural products. There has recently been a resurgence of interest in herbal remedies, and a Reuters/Zogby poll in 2000 showed that 40% of people in the U.S. had tried herbal remedies. In 1998, the U.S. market for natural supplements was over $12 billion in sales and increasing by as much as 10% per year. Herbs such as St. John's Wort, ginkgo, echinacea, and ginseng are among the most popular herbs. In 1999, echinacea was reported to make up 38% of the
U.S. market, with ginkgo a close second at 34%. The efficacy of these herbs is being investigated in many laboratories, and efforts are also being made to isolate and identify any active constituents.
Natural products, as the term implies, are those chemical compounds derived from living organisms, plants, animals, insects, and the study of natural products is the investigation of their structure, formation, use, and purpose in the organism. Drugs derived from natural products are usually secondary metabolites and their derivatives, and today those must be pure and highly characterized compounds. Until the late 1800's, organic chemistry was almost exclusively the study and use of natural products. The purpose of these compounds in the organisms and their formation was little understood or investigated, primarily due to the lack of appropriate techniques and structural theory. The natural products that were studied and used tended to be the compounds that occurred in the largest amounts, mostly in plants, and were most easily isolated in a pure, or sometimes not very pure, form by techniques such as simple distillation, steam distillation, or extraction with acid or base. Originally teas or decoctions (aqueous extracts) or tinctures or elixirs (alcoholic extracts) were used to prepare and administer herbal remedies - these were usually the starting points for isolation work. We now employ different solvents, e.g., ethanol to extract, hexane to concentrate non-polar constituents, methanol to concentrate polar constituents, and modern isolation techniques include all types of chromatography, often guided by bioassays, to isolate the active compounds or analyze the full spectrum concentrated extracts.
Up until the 1950's, the structures of natural products, when determined, were determined by degradative techniques, and a structure was not proven until the compound had been synthesized in an unambiguous manner. Stereochemistry was not often determined. Now, structures are elucidated primarily by spectroscopic techniques, and the stereochemistry is an important feature of the structure.
The treatment of diseases with pure isolated pharmaceutical agents is a relatively modern phenomenon. However, as European explorers and merchants spread out to the Western and Eastern parts of the world, some of the benefits they would bring back were newly discovered pharmaceutical preparations of natural origin. One of the earliest success stories in developing a drug from a natural product was aspirin. The Ebers papyrus indicates the use of willow leaves as an anitpyretic treatment, and early English herbals also recommend the use of teas made from willow bark for this use. Following on these folk treatments, chemists and pharmacists began to isolate the compounds responsible for the remedy. Among the earliest pure compounds discovered was salicin, isolated from the bark of the white willow, Salix alba, in 1825-26. It was subsequently converted to salicylic acid via hydrolysis and oxidation, and proved so successful as an antipyretic (fever reducing) that it was actively manufactured and used worldwide. The use of salicylic acid, however, often led to severe gastrointestinal toxicity. This was overcome when Felix Hoffmann of Bayer Company converted salicylic acid into acetylsalicylic acid (ASA) via acetylation. Bayer then began marketing ASA under the trade name aspirin in 1899. Today, aspirin is still the most widely used analgesic and antipyretic drug in the world.
Many of the earliest isolated pure compounds with biological activity were alkaloids. This was due to the ease of isolation. The nitrogen generally makes the compound basic and the compound exists in the plant as a salt. Thus, alkaloids are often extracted with water or mild acid and then recovered as crystalline material by treatment with base.
Prior to approximately 300 years ago, malaria was the scourge of Europe, likely having been introduced through the Middle East. Malaria is caused by protozoa of the genus Plasmodium, contained as spores in the gut of the Anopheles mosquitos, which then spreads the spores to humans when it bites. As the Spanish and Portugese explorers began to colonize South America, they discovered a cure for malaria known to the native Indians. This was the bark of the Cinchona trees. The use of Cinchona bark to treat malaria was first reported in Europe in 1633, and the first bark reached Rome about 12 years later. Teas made from the bark cured people suffering from malaria, one of the major scourges in
Europe at the time, and the bark became known as Jesuit's bark. Because of the philosophical differences between Protestants and Catholics, many Protestants refused to be treated with the bark. One of the most prominent Protestants of the time, Oliver Cromwell, reportedly died of malaria because of this stubbornness.
Isolated originally from Cinchona succirubra, quinine is one of 31 alkaloids with related structures, and the principal antimalarial compound, in the plant. (Alkaloids have been defined in various ways, but one definition comes fairly close to actuality. An alkaloid is a plant-derived compound that is toxic or physiologically active, contains a nitrogen in a heterocyclic ring, is basic, has a complex structure, and is of limited distribution in the plant kingdom.) Malaria is still a major problem throughout the world, and, although synthetic antimalarial drugs largely supplanted quinine as the treatment for malaria during World War II, quinine is often once again the drug of choice as strains of malaria have become resistant to the synthetic drugs. However, the search for other antimalarial drugs from natural sources has also continued. Qinghaosu (artemisinin), isolated from Qing Hao (Artemisia annua), an herb traditionally used in Chinese medicine for treating intestinal parasites, Malaria, and other febrile diseases, has been proved to be the most effective "last resource" treatment against Malaria. Qinghaosu (artemisinin) also shows powerful action agains a wide range of cancer cells.
Among the most famous of the alkaloids are the Solanaceae or tropane alkaloids. Plants containing these alkaloids have been used throughout recorded history as poisons, but many of the alkaloids do have valuable pharmaceutical properties. Atropine, the racemic form of hyoscyamine, comes from Atropa belladonna (deadly nightshade) and is used to dilate the pupils of the eye. Atropine is also a CNS stimulant and is used as a treatment for nerve gas poisoning. Scopolamine, another member of this class is used as a treatment for motion sickness. Cocaine, from Erythroxylum coca, is closely related in structure, is also a CNS stimulant, and has been used as a topical anesthetic in opthamology. It is also a drug of abuse. Cocaine was found in very small amounts in the original Coca-Cola formula, but was not the main concern of the USDA at the time. Caffeine was considered to be the major problem with the drink. Datura stramonium (Jimsonweed), a plant found in Virginia contains similar compounds.
The ergot alkaloids come from a fungus, Claviceps purpurea, which is a parasite on rye and wheat. The ergot alkaloids are responsible for ergotism (St. Anthony's fire), which manifests itself as gangrenous ergotism, resulting in loss of limbs, or convulsive ergotism, resulting in hallucinations. In both cases, death usually follows and outbreaks of ergotism caused 11,000 deaths in
Russia as late as 1926. Today the problem is recognized and controlled. Some of the ergot alkaloids have been used to treat migraine headaches and sexual disorders in clinical applications. The most famous of these alkaloids is lysergic acid diethylamide, LSD, a powerful hallucinogen that is a synthetic derivative of the natural products. Similar alkaloids, particularly ergine, are also found in Mexican morning glories, such as Ipomeoa tricolor.
The morphine alkaloids derived from the opium poppy, Papaver somniferum, are powerful pain relievers and narcotics. The narcotic activity of P. somniferum was noted on Sumerian tablets in 3500 B.C., making it one of the oldest drugs known. Opium is the dried latex of the seed heads of P. somniferum, and has been used as an analgesic (eliminates or relieves pain) and narcotic (induces sleep or drowsiness) in preparations such as laudanum and paregoric. Morphine is the principal alkaloid and was first isolated between 1803 and 1806. It was widely used for pain relief beginning in the 1830's, but was also recognized as being addictive. In an attempt to make morphine less addictive, Bayer chemists acetylated the hydroxyl groups to produce diacetylmorphine. This was marketed as a non-addictive pain reliever under the trade name Heroin for about two years in the early 1900's, until it was recognized to be more addictive than morphine. Other derivatives of morphine have been developed and found use as opiate antagonists or as animal tranquilizers.
Vincristine and Visblastin, some of the most potent antileukemic drugs in use today, was isolated from Chan Chun Hua (Catharanthus roseus), an herb traditionally used in Chinese Medicine for treatment of lung tumors and lymphomas, and also for its astringent, diuretic, and cough suppressant effects. Because of better pharmacological efficacy, these complex structure medicines are still isolated from the plant Chan Chun Hua (Catharanthus roseus, also sometimes known as Madagascan periwinkle) rather than prepared by synthesis. Vincristine (leurocristine, VCR) is most effective in treating childhood leukemias and non-Hodgkin's lymphomas, where vinblastine (vincaleukoblastine, VLB) is used to treat Hodgkin's disease.
Topoisomerase I (Topo-I) is a major target for anticancer drug discovery and design. As a result, Topo-I inhibitors constitute an important class of the current anticancer drugs. To date, all of the Topo-I inhibitors that have been clinically evaluated are analogues of Campothecin, and extract from Xishu tree (Campotheca Acuminata), a Chinese herbal medicine traditionally used to treat tumors, has shown significan antitumor activity in lung, ovarian, breast, pancreas, and stomach cancers. Etoposide and Teniposide which derived from Ba Jiao Lian (Podophyllum), an herb long used in Traditional Chinese Medicine for its antitumor effect, is now commonly prescribed as a conventional cancer treatment in the West.
Recent progress on the study of anticancer drugs originating from plants in China is further reviewed here. Guided by the experience of traditional Chinese medicine, several new drugs have been found. Indirubin from Ban Lan Gen or Da Qin Ye (Indigofera tinctoria) is useful for the treatment of some forms of leukemia. Studies indicate that ginsenoside Rh2 is an inducer of cell differentiation in melanoma B-16 cells in vitro. Pharmacological studies have demonstrated that curcumin from Curcuma longa is an antimutagen as well as an antipromotor for cancer. Daidzein and acetyl boswellic acid have been shown to be effective inducers of cell differentiation in HL-60 cells. Guided by the chemotaxonomic principle of plants, harringtonine and homoharringtonine isolated from Cephalotaxus hainanesis have exhibited significant antileukemia activity and are widely used in clinics in China. Taxol, isolated from Taxus chinensis (Taxus brevifolia ) also known as Pacific yew tree in North America, is one of the most well-known anti-cancer drug. Taxol acts to stabilize the mitotic apparatus in cells, causing them to act as normal cells rather than undergo rapid transformation as they do in cancer.
Since one of the major problems with taxol, as with many other natural products used as drugs, is solubility in aqueous systems, much effort has been devoted to finding a more soluble form. Taxotere (docetaxel) was prepared by the French firm, Rhone-Poulenc, and has similar activity to taxol (paclitaxel), but slightly better solubility. Other researchers have tried to add a group to the 2'-OH which would increase the solubility and then be removed in vivo. These are mostly esters with a salt incorporated to increase the water solubility. Other investigators have modified the C-13 side chain ester and added functionality at C-14 to increase the oral bioavailability. These modified taxoids are still at early stages of testing, but illustrate the principles of development of second generation drugs. In these circumstances, the SAR studies have been used to guide the modification of the natural product to maintain or improve the activity while adjusting the physical properties. The continuous search for new anticancer drugs from plants will be a fruitful frontier in cancer treatment and chemoprevention.
Menthol, a monoterpene (10 carbons) isolated from various mints, is a topical pain reliever and antipuretic (relieves itching). Plants in the mint family have been used for medicinal purposes since before 2000 BC, but menthol was not isolated until 1771. Thujone, another monoterpene, is the toxic agent found in Artemisia absinthium (wormwood) from which the liqueur, absinthe, is made. Borneol and camphor are two common monoterpenes. Borneol, derivatives are used clinically in China as a male contraceptive.
Steroids are modified triterpenes. They are probably most familiar from their role as hormones, i.e., androgens such as testosterone and estrogens such as progesterone steroids, such as cortisone, are most often used as anti-inflammatory agents, but many have other uses such as in birth control pills. Prior to 1943, most steroids were obtained from natural sources. For example, progesterone could only be isolated in quantities of 20 mg from 625 kg of pig ovaries. The large numbers of commercially and medicinally valuable steroids available today have been made possible by the semi-synthetic preparation of progesterone from diosgenin. This process, known as the Marker process, was developed in the early 1940's by Russell Marker, a rather colorful character, who left his position of professor of chemistry at PennState to pursue this project in Mexico. Marker collected Mexican yams in bandit country, processed the yams to isolate the diosgenin, and then converted the diosgenin into ca. 3 kg of pure progesterone at a cost of $8 per gram. He and a Mexican pharmacist then formed a company which later became the major pharmaceutical company, Syntex.
Camphor is used as a counterirritant, anesthetic, expectorant, and antipruritic, among many other uses. Digitalis, called a cardiac glycoside, is a heart drug from the powdered leaves of Digitalis purpurea, also known as foxglove. Excessive use of digitalis has been known to produce xanthopsia (yellow vision). Related steroids, e.g., bufotoxin isolated from Bufo marinus (the cane toad), are actually more toxic than useful. The cane toad also produces bufotenine, a substance close in structure to dimethyltryptamine and the hallucinogenic alkaloids of ergot.
Star Anise is the unusual, almost ripe, dried, star-shaped multiple fruit of a small oriental tree (Illicium Verum Hooker F.), which is a member of the magnolia family (Magnoliaceae). Star Anise has been used in oriental cooking for thousands of years as it's pungent, liquorice-like flavour, and it was introduced into Europe in the 17th Century where it was used in baked goods and in the making of fruit jams. More famously it was used as one of the main flavourings of the liqueurs Pernod an Anisette. In fact, Star Anise have been used in Chinese medicine for centuries, instead of normal used to flavour ingredients, it also have been widely used pharm and include the treatment of indigestion, stomach ache, colic in babies, and even facial paralysis, in recently years, scientists also have found that star anise has possible cancer-fighting properties, some cancer treatments showed "promising activity" against lung cancer cells.
Today, Star Anise is the world's only weapon against bird Flu (Avian Flu), as it is the chief source a shikimic acid, a vital ingredient of the antiviral drug that can reduce the severity of flu symptoms. In fact, the vital ingredients of shikimic Acid is extracted from the seeds of star anise, then it is converted to epoxide in a process requiring three chemical steps carried out at low temperature on seven separate sites, the most dangerous part of the process involves the conversion of epoxide into azide in a reaction that produces highly explosive material, at the last, the crystal stands ingredients named "Oseltamivir" could get through vaccum dryer, which the role active ingredient of Tamiful, the only drug the world has which may reduce the severity of Bird Flu(Avian Flu).
SUGGESTED READING:
John Mann, Murder, Magic and Medicine, Oxford
University Press, 1994.
Varro E. Tyler, Lynn R. Brady, and James E. Robbers, Pharmacognosy, 8th edition, Lea & Febiger, 1981.
Murray Goodman and Frank Morehouse, Organic Molecules in Action, Gordon and Breach, 1973.
Lonnelle Aikman, Nature's Healing Arts - From Folk Medicine to Modern Drugs, National Geographic Society, 1977.
Iwao Ojima, Pierre-Yves Bounaud, and Ralph J. Bernacki, "Designing taxanes to treat multidrug-resistant tumors," Modern Drug Discovery, May/June, 1999, pp. 45-52.
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