Introduction





“Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine.” These plant-based traditional medicine systems continue to play an essential role in health care, with about 80% of the world’s inhabitants relying mainly on traditional medicines for their primary health care. Plant products also have an important role in the health care systems of the remaining 20%, who reside in developed countries. About 25% of prescription drugs dispensed from community pharmacies in the United States from 1959 to 1980 contained plant extracts or active principles derived from higher plants.

At least 119 chemical substances derived from 90 plant species are important drugs currently in use. Of these 119 drugs, 74% were discovered as a result of research directed at the isolation of active compounds from plants used in traditional medicine.18 Based on 1991 sales, half of the leading pharmaceuticals were either derived from natural products or contained a pharmacopoeia that was based on natural products (O’Neill MJ, Lewis JA. 1993). In 1993, 57% of the top 150 brand-name products prescribed contained at least one major active compound, or were derived or patterned after compounds, reflecting biological diversity (Grifo F. et al. 1997). Many researchers have discussed the importance of medicinal plants as sources of new therapeutic agents (Cragg GM, Newman DJ. 2001) and others have effectively focused on the potential of specific chemical classes (e.g., alkaloids) in drug discovery. Recent research continues to validate an ethnobotanically targeted approach to the initial discovery of pharmaceuticals (Lewis W.H. 1999). Still others estimate that of about 375 total drugs of pharmaceutical significance in the rain forests of the world, only one-eighth have been discovered. Assessing the worth to humanity of drugs already known and used might be even more relevant. Subsequently, Cinchona bark has been used since the seventeenth century. In 1820, when Caventou and Pelletier identified its active alkaloid quinine, and later quinidine, along with their analogs, isomers, semi synthetics, and synthetics to treat malaria, heart conditions, and other ailments, sales escalated. Worldwide use of these drugs against malaria and arrhythmia generated untold wealth, relieved much suffering, and saved millions of lives. Further, use of the antimalarial drugs led to the successful habitation of vast areas of tropical to warm temperate regions, making possible new opportunities for progress and riches. Sales of these drugs to the present time amount to an astounding net figure in the tens, if not hundreds, of billions of dollars.

Medical Ethnobotany Indigenous peoples use a wide range of plants therapeutically to maintain their health. There is great promise for new drug discoveries based on traditional plant uses (Lewis W.H, Elvin-Lewis M.P. 1995). To be allowed to use this knowledge, researchers must recognize that both intangible resources (knowledge) and tangible resources (genetic material) are being provided. In 1992, the United Nations Convention on Biological Diversity confirmed the rights of source nations over the genetic materials found within their boundaries. That convention also required that local and indigenous knowledge, practices, and innovations be protected and recognized (Lewis W.H. 2000). Before conducting ethnobotanical research, it is essential to obtain agreements among all parties, addressing prior informed consent, confidentiality, ownership of intellectual property and tangible biological materials, collecting area scope, conservation of medicinal plants and habitats, responsibilities of parties, benefit sharing, compensation due parties at all stages of research, development, and commercialization, and supplier of materials. Appropriate models exist for guidance in developing collaborative agreements, so that the discovery of new natural products.





A number of phytochemicals (castanospermine, calanolides, prostratin) are potentially useful in the treatment of human autoimmune deficiency syndrome (AIDS). Cell modifiers of plants that act as mutagens, teratogens, lectins, or mitogens are described. Antimutagenic compounds have important potential roles in cancer chemoprevention. Indeed, the greatest advancement in cancer therapeutics in the last quarter of a century has been the incorporation of compounds and analogs isolated from plants sources and their semi synthetic derivatives.





Many texts and monographs have been studied carefully in selecting the examples of plants useful, harmful, and enjoyable to humans. From these works we have gleaned what our forefathers learned the hard way and passed on to us. They performed experiments over thousands of years by trial and error, and we, with broader insight and scientific expertise, have a much greater opportunity to utilize these data than any who preceded us. Valuable data, however, are not always recorded. It behooves us to study the practices of indigenous populations before they are lost, through either human indifference or our relentless ability to change and destroy the vegetation around us. We hope that this book will stimulate those interested in Ethnobotany and human welfare to look closely and seriously at the field data awaiting our scrutiny.



Natural products and their derivatives represent more than 50% of the drugs in clinical use in the world (Cowan, 1999, Sofowora, 1984). One of the paramount reasons for pursuing natural products chemistry resides in the actual or potential pharmacological activity to be found in alkaloids, terpenoids, coumarins, flavonoids, lignans and the like. Since the advent of antibiotics in the 1950’s, the use of plant derivatives as a source of antimicrobials has been virtually non-existent (Cowan, 1999). Antimicrobial plant extracts have been recognized as a future source of new antimicrobials in the event of the current downturn in the pace at which these are being derived from microorganisms. The public is also becoming more aware of problems with overprescription and misuse of traditional antibiotics (Cowan, 1999). Resistance to anti-microbial agents is recognized at present as a major global public health problem. Infective diseases account for approximately one-half of all deaths in countries in tropical regions. In industrialized nations, despite the progress made in the understanding of microorganisms and their control, incidents of epidemics due to drug resistant microorganisms and the emergence of hitherto unknown disease causing microbes, pose enormous public health concerns (Iwu et al; 1999). The number of resistant strains of microbial pathogens is also growing since penicillin resistance and multiresistant pneumococci caused a major problem in South African hospitals in 1977 (Berkowitz, 1995). Berkowitz, (1995) referred to the emergence of drug resistant bacteria as a medical catastrophe. Leggiadro (1995) stated that effective regimens might not be available to treat some enterococci isolates and that it is critically important to develop new antimicrobial compounds for these and other organisms before we enter the post antibiotic era. The cost of drugs is a sizable proportion of total health expenditure in most developing countries. In some of these countries, drug related expenses account for up to 30-50% of the total cost of health care (Sofowora, 1984). This situation is becoming increasingly unbearable to many nations including South Africa. The World Health Organization (WHO), have observed that up to 80% of the rural populace in the developing countries depend on herbal or alternative medicine and requested member countries to explore safe indigenous medicines for their national health care (Sofowora, 1984).



Plants have served as a source of new pharmaceutical products and inexpensive starting materials for the synthesis of some known drugs. Components with medicinal properties from plants play an important role in conventional Western medicine. In 1984, at least 25% of the Western medicine issued in the US and Canada were derived from or modeled after plant natural products and 119 secondary metabolites were used globally as drugs (Farnsworth, 1994). It has been estimated that 14-28% of higher plant species are used medically. Only 15% of all angiosperms have been investigated chemically and 74% of pharmaceutically active plant derived components were discovered after following up on ethnomedical use of the plant (Farnsworth, 1991). The traditions of collecting, processing and applying plant and plant-based medications have been handed down from generation to generation. In many African countries, traditional medicines, with medicinal plants as their most important components, are sold in marketplaces or prescribed by traditional healers (without accurate dose value) in their homes (Herdberg and Staugard, 1989). Because of this strong dependence on plants as medicines, it is important to study their safety and efficacy (Farnsworth, 1994). The value of ethnomedicine and traditional pharmacology is nowadays gaining increasing recognition in modern medicine because the search for new potential medicinal plants is frequently based on an ethno-medicinal basis. In the ethno-pharmacological approach, local knowledge about the potential uses of the plants is very useful as compared to the random approach where indigenous knowledge is not taken into consideration. Compounds inhibiting microorganisms, such as benzoin and emetine have been isolated from plants (Cox, 1994). It is possible that antimicrobial compounds from plants may inhibit bacteria by a different mechanism than the presently used antibiotics and may have clinical value in the treatment of resistant microbial strains. For this reason, it is therefore important to investigate plants as alternative sources of anti-microbial compounds. Preliminary work done on the southern African members of the section Hypocrateropsis (Eloff, 1999a) indicated that most of the members of this section had substantial antibacterial activity against Gram-positive and Gram-negative bacteria. Bioautography studies indicated that members of the section Hypocrateropsis have different antibacterial compounds from members of other sections. Substantial antibacterial activity of some species further motivated this study. Fossils of plants date back as early as 3.2 billion years ago. These plants provided the foundation upon which animal life and later, human life were based on. They provide bodybuilding food and calories as well as vitamins essential for metabolic regulation. Plants also yield active principles employed as medicines [Shultes, 1992] Fossils of plants date back as early as 3.2 billion years ago. These plants provided the foundation upon which animal life and later, human life were based on. They provide bodybuilding food and calories as well as vitamins essential for metabolic regulation. Plants also yield active principles employed as medicines [Shultes, 1992].

Finding healing powers in plants is an ancient idea. Hundreds, if not thousands, of indigenous plants have been used by people on all continents as poultices and infusions dating back to prehistory. There is evidence of Neanderthals, living 60 000 years ago in present-day Iraq, using hollyhock (Alcea rosea L.), which is still in ethnomedicinal use around the world today [Cowan, 1999]. The Bible offers descriptions of at least 30 healing plants of which frankincense (Boswellia sacra L.) and myrrh (Commiphora myrrha L.) were employed as mouthwashes due to their reported antiseptic properties. The fall of ancient civilizations resulted in the destruction or loss of much of the documentation of plant pharmaceuticals but many cultures continued in the excavation of the older works as well as building upon them. Native Americans were reported to have used 1625 species of plants as food while 2564 found use as drugs, while the Europeans started turning towards botanicals when treatment in the 1800s became dangerous and ineffective [Cowa n, 1999]. Today some 1500 species of medicinal and aromatic plants are widely used in Albania, Bulgaria, Croatia, France, Germany, Hungary, Spain, Turkey and the United Kingdom [Hoareau, 1999].



Screening of antimicrobial plants for new pharmaceuticals

Plants are the oldest source of pharmacologically active compounds, and have provided humankind with many medically useful compounds for centuries (Cordell, 1981). Today it is estimated that more than two thirds of the world’s population relies on plant derived drugs; some 7000 medicinal compounds used in the Western pharmacopoeia are derived from plants (Caufield, 1991). In the USA approximately 25% of all prescription drugs used contain one or more bioactive compounds derived from vascular plants (Farnsworth&Morris, 1976; Farnsworth, 1984). Thus, phytochemical screening of plants species, especially of ethnopharmaceutical use, will provide valuable baseline information in the search for new pharmaceuticals. Yet fewer than 10% of the world’s plant species have been examined for the presence of bioactive compounds (Myers, 1984). Hence screening of antimicrobial plants for new agents poses an enormous challenge and are important especially with the emergence of drug resistant disease strains. During the past 10 years there has been a substantial resurgence of interest and pursuit of natural products discovery and development, both in the public and private sectors. Explanation for this, possibly transient or at least cyclical revival, might include: the increasingly sophisticated science that can be brought to bear on the discovery and development processes (Meyer and Afolaya n, 1995) and the very real threat of the disappearance of the biodiversity essential for such research. It has only been in the past two decades or so that interest in higher plant antimicrobial agents has been reawakened world wide, and the literature in this area is becoming substantial (Mistscher et al., 1984)



1.5 Preformed antimicrobial compounds and plant defense against microbial attack

Plants produce a diverse array of secondary metabolites, many of which have antimicrobial activity. Some of these compounds are constitutive, existing in healthy plants in their biologically active forms. Others such as cyanogenic glycosides and glucosinolates occur as inactive precursors and are activated in response to tissue damage or pathogen attack. This activation often involves plant enzymes, which are released as a result of breakdown in cell integrity. Compounds belonging to the latter category are still regarded as constitutive because they are immediately derived from pre-existing constituents. Mansfield (1983) and Van Etten et al., (1995) have proposed the term ‘phytoanticipin’ to distinguish these preformed antimicrobial compounds from phytoalexins, which are synthesized from remote precursors in response to pathogen attack, probably as a result of de novo synthesis of enzymes. In recent year s, studies of plant disease resistance mechanisms have tended to focus on phytoalexin biosynthesis and other active responses triggered after pathogen attack (Hammond-Lassack&Jones, 1996). In contrast, preformed inhibitory compounds have received relatively little attention, despite the fact that these plant antibiotics are likely to represent one of the first chemical barriers to potential pathogens.



1.6 Phytoalexins (postinfectional agents)

There have been numerous attempts to associate natural variation in levels of preformed inhibitors in plants with resistance to particular pathogens, but they have failed to reveal any positive correlation. However, whereas preformed inhibitors may be effective against a broad spectrum of potential pathogens, successful pathogens are likely to be able to circumvent the affects of these antibiotics by avoiding them altogether or by tolerating or detoxifying them (Schonbeck & Schlosse r, 1976; Fry & Myer s, 1981; Van Etten et al., 1995). The biology associated with these classes, [the constitutive (preinfective) agents and the phytoalexins (postinfectional agents)] is strikingly similar, and in some cases, the same compound is a constitutive agent in some species and a phytoalexin in others (Osbourn, 1996). Phytoalexins are antimicrobial compounds that are either not present or are present only in very small quantities in uninfected plants (Van Etten et al., 1995). After microbial invasion, however, enzymes, which catalyse the formation of phytoalexins that are toxic to the invading organism, become activated. In plants, phytoalexin production and field resistance to infection is often a consequence of this feature of their biosynthetic machinery. Also, the quantity of phytoalexins is often very small even in infected plants when compared with the amount of constitutive agents.



1.7 Efficacy of traditionally used plants

The search for natural products to cure diseases represents an area of great interest in which plants have been the most important source. In South African traditional medicine, the use of plants is a widespread practice, and the persistence in the use of medicinal plants among people of urban and rural communities in South Africa could be considered as evidence of their efficacy (Meyer and Afolayan, 1996). Although there is an important local ethnobotanical bibliography describing the most frequently used plants in the treatment of conditions consistent with sepsis and other diseases, there are very few experimental studies, which validate the therapeutic properties of these plants.





MAJOR GROUPS OF ANTIMICROBIAL COMPOUNDS FROM PLANTS



Plants have an almost limitless ability to synthesize aromatic substances, most of which are phenols or their oxygen-substituted derivatives (Geissman, T. A. 1963). Most are secondary metabolites, of which at least 12,000 have been isolated, a number estimated to be less than 10% of the total (Schultes, R. E. 1978). In many cases, these substances serve as plant defense mechanisms against predation by microorganisms, insects, and herbivores. Some, such as terpenoids, give plants their odors; others (quinones and tannins) are responsible for plant pigment. Many compounds are responsible for plant flavor (e.g., the terpenoid capsaicin from chili peppers), and some of the same herbs and spices used by humans to season food yield useful medicinal compounds.



Phenolics and Polyphenols

Simple phenols and phenolic acids are some of the simplest bioactive phytochemicals consist of a single substituted phenolic ring. Cinnamic and caffeic acids are common representatives of a wide group of phenylpropane-derived compounds that are in the highest oxidation state (Fig. 1).

The common herbs tarragon and thyme both contain caffeic acid, which is effective against viruses (Wild, R. (ed.). 1994), bacteria (Brantner, A.et al 1996), and fungi (Duke, J. A. 1985). Catechol and pyrogallol both are hydroxylated phenols, shown to be toxic to microorganisms. Catechol has two OH groups, and pyrogallol has three. The site(s) and number of hydroxyl groups on the phenol group are thought to be related to their relative toxicity to microorganisms, with evidence that increased hydroxylation results in increased toxicity (Geissman, T. A. 1963). In addition, some authors have found that more highly oxidized phenols are more inhibitory (Scalbert, A. 1991). The mechanisms thought to be responsible for phenolic toxicity to microorganisms include enzyme inhibition by the oxidized compounds, possibly through reaction with sulfhydryl groups or through more nonspecific interactions with the proteins (Mason, T. et. al, 1987).

Phenolic compounds possessing a C3 side chain at a lower level of oxidation and containing no oxygen are classified as essential oils and often cited as antimicrobial as well. Eugenol is a well-characterized representative found in clove oil (Fig. 1). Eugenol is considered bacteriostatic against both fungi (Duke, J. A. 1985) and bacteria (Thomson, W. A. R. (ed.). 1978).



Quinones.

Quinones are aromatic rings with 2 ketone substitutions (Fig.1). They are ubiquitous in nature and are characteristically highly reactive. These compounds, being colored, are responsible for the browning reaction in cut or injured fruits and vegetables and are an intermediate in the melanin synthesis pathway in human skin (Schmidt, H. 1988). Their presence in henna gives that material its dyeing properties (Fessenden, R. J., and J. S. Fessenden. 1982). The switch between diphenol (or hydroquinone) and diketone (or quinone) occurs easily through oxidation and reduction reactions. The individual redox potential of the particular quinone-hydroquinone pair is very important in many biological systems, witness the role of ubiquinone (coenzyme Q) in mammalian electron transport systems. Vitamin K is a complex naphthoquinone. Its antihemorrhagic activity may be related to its ease of oxidation in body tissues (Harris, R. S.1963). Hydroxylated amino acids may be made into quinones in the presence of suitable enzymes, such as a polyphenoloxidase (Vamos-Vigyazo, L. 1981).

In addition to providing a source of stable free radicals, quinones are known to complex irreversibly with nucleophilic amino acids in proteins (Stern, J. L. et.al, 1996), often leading to inactivation of the protein and loss of function. For that reason, the potential range of quinone antimicrobial effects is great. Probable targets in the microbial cell are surface-exposed adhesins, cell wall polypeptides, and membrane-bound enzymes. Quinones may also render substrates unavailable to the microorganism. As with all plant-derived antimicrobials, the possible toxic effects of quinones must be thoroughly examined. Kazmi et al (Kazmi, M. H, et al. 1994) described an anthraquinone from Cassia italica, a Pakistani tree, which was bacteriostatic for Bacillus anthracis, Corynebacterium pseudodiphthericum, and Pseudomonas aeruginosaand bactericidal forPseudomonas pseudomalliae. Hypericin, an anthraquinone from St. John’s wort (Hypericum perforatum), has received much attention in the popular press lately as an antidepressant, and Duke reported in 1985 that it had general antimicrobial properties (Duke, J. A. 1985).



Flavones, flavonoids, and flavonols.

Flavones are phenolic structures containing one carbonyl group (as opposed to the two carbonyls in quinones) (Fig. 1). The addition of a 3-hydroxyl group yields a flavonol (Fessenden, R. J., and J. S. Fessenden. 1982). Flavonoids are also hydroxylated phenolic substances but occur as a C6-C3unit linked to an aromatic ring. Since they are known to be synthesized by plants in response to microbial infection (Dixon, R. A. et al.1983), it should not be surprising that they have been found in vitro to be effective antimicrobial substances against a wide array of microorganisms. Their activity is probably due to their ability to complex with extra cellular and soluble proteins and to complex with bacterial cell walls, as described above for quinones. More lipophilic flavonoids may also disrupt microbial membranes (Tsuchiya, H, et al 1996). Catechins, the most reduced form of the C3 unit in flavonoid compounds, deserve special mention. These flavonoids have been extensively researched due to their occurrence in oolong green teas. It was noticed some time ago that teas exerted antimicrobial activity and that they contain a mixture of catechin compounds. These compounds inhibited in vitro Vibrio cholerae, Streptococcus mutans (Tsuchiya, H. et al. 1994), Shigella (Vijaya, K., et al. 1995), and other bacteria and microorganisms



Flavonoid compounds exhibit inhibitory effects against multiple viruses. Numerous studies have documented the effectiveness of flavonoids such as swertifrancheside (Pengsuparp, T, et al. 1995), glycyrrhizin (from licorice), and chrysin (Critchfield, J. W., S. T. Butera, and T. M. Folks. 1996) against HIV.An isoflavone found in a West African legume, alpinumisoflavone, prevents schistosomal infection when applied topically (Perrett, S., P. J. Whitfield, L. Sanderson, and A. Bartlett. 1995). Phloretin, found in certain serovars of apples, may have activity against a variety of microorganisms (Hunter, M. D., and L. A. Hull. 1993). Galangin (3,5,7-trihydroxyflavone), derived from the perennial herb Helichrysum aureonitens, seems to be a particularly useful compound, since it has shown activity against a wide range of gram-positive bacteria as well as fungi and viruses, in particular HSV-1 and coxsackie B virus type 1 (Meyer, J. J. M, et al. 1997.). Delineation of the possible mechanism of action of flavones and flavonoids is hampered by conflicting findings. Flavonoids lacking hydroxyl groups on their-rings are more active against microorganisms than are those with the OH groups; this finding supports the idea that their microbial target is the membrane. Lipophilic compounds would be more disruptive of this structure. However, several authors have also found the opposite effect; i.e., the more hydroxylation, the greater the antimicrobial activity (Sato, M., et al. 1996). This latter finding reflects the similar result for simple phenolics (see above). It is safe to say that there is no clear predictability for the degree of hydroxylation and toxicity to microorganisms.



Tannins.

“Tannin” is a general descriptive name for a group of polymeric phenolic substances capable of tanning leather or precipitating gelatin from solution, a property known as astringency. Their molecular weights range from 500 to 3,000 (87), and they are found in almost every plant part: bark, wood, leaves, fruits, and roots (Scalbert, A. 1991). They are divided into two groups, hydrolyzable and condensed tannins. Hydrolyzable tannins are based on gallic acid, usually as multiple esters with D-glucose, while the more numerous condensed tannins (often called proanthocyanidins) are derived from flavonoid monomers (Fig. 1). Tannins may be formed by condensations of flavan derivatives that have been transported to woody tissues of plants. Alternatively, tannins may be formed by polymerization of quinone units (Geissman, T. A. 1963). This group of compounds has received a great deal of attention in recent years, since it was suggested that the consumption of tannin-containing beverages, especially green teas and red wines, can cure or prevent a variety of ills (Serafini, M., et al. 1994).

Many human physiological activities, such as stimulation of phagocytic cells, host-mediated tumor activity, and a wide range of anti-infective actions, have been assigned to tannins. One of their molecular actions is to complex with proteins through so-called nonspecific forces such as hydrogen bonding and hydrophobic effects, as well as by covalent bond formation (Stern, J. L, et al. 1996.). Thus, their mode of antimicrobial action, as described in the section on quinones, may be related to their ability to inactivate microbial adhesins, enzymes, cell envelope transport proteins, etc. The antimicrobial significance of this particular activity has not been explored. There is also evidence for direct inactivation of microorganisms: low tannin concentrations modify the morphology of germ tubes of Crinipellis perniciosa. Tannins in plants inhibit insect growth (Schultz, J. C.1988) and disrupt digestive events in ruminal animals. Scalbert (Scalbert, A. 1991) reviewed the antimicrobial properties of tannins in 1991. He listed 33 studies that had documented the inhibitory activities of tannins up to that point. According to these studies, tannins can be toxic to filamentous fungi, yeasts, and bacteria. Condensed tannins have been determined to bind cell walls of ruminal bacteria, preventing growth and protease activity. Although this is still speculative, tannins are considered at least partially responsible for the antibiotic activity of methanolic extracts of the bark of Terminalia alata found in Nepal (Taylor, R. S. L., et al. 1996.). This activity was enhanced by UV light activation (320 to 400 nm at 5 W/m2 for 2 h). At least two studies have shown tannins to be inhibitory to viral reverse transcriptases (Nonaka, G.I. et al 1990).



Coumarins.

Coumarins are phenolic substances made of fused benzene and-pyrone rings. They are responsible for the characteristic odor of hay. As of 1996, at least 1,300 had been identified. Their fame has come mainly from their antithrombotic, anti-inflammatory, and vasodilatory activities (Namba, T., et al.1988). Warfarin is a particularly well-known coumarin which is used both as an oral anticoagulant and, interestingly, as a rodenticide (Keating, G. J., and R. O’Kennedy. 1997). It may also have antiviral effects (Berkada, B. 1978). Coumarins are known to be highly toxic in rodents and therefore are treated with caution by the medical community. However, recent studies have shown a “pronounced species-dependent metabolism” (Weinmann, I. 1997), so that many in vivo animal studies cannot be extrapolated to humans. It appears that toxic coumarin derivatives may be safely excreted in the urine in humans (Weinmann, I. 1997). Several other coumarins have antimicrobial properties. R. D. Thornes, working at the Boston Lying-In Hospital in 1954, sought an agent to treat vaginal candidiasis in his pregnant patients. Coumarin was found in vitro to inhibit Candida albicans. (During subsequent in vivo tests on rabbits, the coumarin-spiked water supply was inadvertently given to all the animals in the research facility and was discovered to be a potent contraceptive agent when breeding programs started to fail (Thornes, R. D. 1997) As a group, coumarins have been found to stimulate macrophages, which could have an indirect negative effect on infections. More specifically, coumarin has been used to prevent recurrences of cold sores caused by HSV-1 in humans (Berkada, B. 1978). Hydroxycinnamic acids, related to coumarins, seem to be inhibitory to gram-positive bacteria (Fernandez, M. A., M. D. Garcia, and M. T. Saenz. 1996.). Also, phytoalexins, which are hydroxylated derivatives of coumarins, are produced in carrots in response to fungal infection and can be presumed to have antifungal activity (Hoult, J. R. S., and M. Paya. 1996). General antimicrobial activity was documented in woodruff (Galium odoratum) extracts (Thomson, W. A. R. (ed.). 1978). All in all, data about specific antibiotic properties of coumarins are scarce, although many reports give reason to believe that some utility may reside in these phytochemicals (Scheel, L. D. 1972). Further research is warranted.



Terpenoids and Essential Oils

The fragrance of plants is carried in the so-called Quinta essentia, or essential oil fraction. These oils are secondary metabolites that are highly enriched in compounds based on an isoprene structure (Fig. 1). They are called terpenes, their general chemical structure is C10 H16, and they occur as diterpenes, triterpenes, and tetraterpenes (C20, C 30, and C40), as well as hemiterpenes (C5) and sesquiterpenes (C15). When the compounds contain additional elements, usually oxygen, they are termed terpenoids.

Terpenoids are synthesized from acetate units, and as such they share their origins with fatty acids. They differ from fatty acids in that they contain extensive branching and are cyclized. Examples of common terpenoids are methanol and camphor (monoterpenes) and farnesol and artemisin (sesquiterpenoids). Artemisin and its derivative-arteether, also known by the name qinghaosu, find current use as antimalarials (Vishwakarma, R. A. 1990). In 1985, the steering committee of the scientific working group of the World Health Organization decided to develop the latter drug as a treatment for cerebral malaria.

Terpenenes or terpenoids are active against bacteria (Tassou, C. C.,t al.1995, Taylor, R. S. L, et al. 1996.) fungi (Rao, K. V., et al. 1993. Suresh, B., et al.1997, Taylor, R. S. L, et al. 1996), viruses (74, 86, 173, 212, 246), and protozoa (Vishwakarma, R. A. 1990). In 1977, it was reported that 60% of essential oil derivatives examined to date were inhibitory to fungi while 30% inhibited bacteria (Chaurasia, S. C., and K. K. Vyas. 1977). The triterpenoid betulinic acid is just one of several terpenoids (see below) which have been shown to inhibit HIV. The mechanism of action of terpenes is not fully understood but is speculated to involve membrane disruption by the lipophilic compounds. Accordingly, Mendoza (Mendoza et al. 1997) found that increasing the hydrophilicity of kaurene diterpenoids by addition of a methyl group drastically reduced their antimicrobial activity. Food scientists have found the terpenoids present in essential oils of plants to be useful in the control of Listeria monocytogenes. Oil of basil, a commercially available herbal, was found to be as effective as 125-ppm chlorine in disinfecting lettuce leaves (Wan, J., A. Wilcock, and M. J. Coventry. 1998).



A terpenoid constituent, capsaicin, has a wide range of biological activities in humans, affecting the nervous, cardiovascular, and digestive systems (Virus, R. M., and G. F. Gebhart. 1979) as well as finding use as an analgesic. Although possibly detrimental to the human gastric mucosa, capsaicin is also bactericidal to Helicobacter pylori (Jones, N. L., S. Shabib, and P. M. Sherman.1997). Another hot-tasting diterpene, aframodial, from a Cameroonian spice, is a broad-spectrum antifungal (Ayafor, J. F., M. H. K. Tchuendem, and B. Nyasse. 1994). The ethanol-soluble fraction of purple prairie clover yields a terpenoid called petalostemumol, which showed excellent activity against Bacillus subtilis and Staphylococcus aureus and lesser activity against gram-negative bacteria as well as Candida albicans (Hufford, C. D., et al. 1993). Two diterpenes isolated by Batista et al. (Batista, O, et al. 1994) were found to be more democratic; they worked well against Staphylococcus aureus, V. cholerae, P. aeruginosa, and Candida spp. When it was observed that residents of Mali used the bark of a tree called Ptelopsis suberosa for the treatment of gastric ulcers, investigators tested terpenoid-containing fractions in 10 rats before and after the rats had ulcers chemically induced. They found that the terpenoids prevented the formation of ulcers and diminished the severity of existent ulcers.

Whether this activity was due to antimicrobial action or to protection of the gastric mucosa is not clear. Kadota et al. (Kadota, S.,et al. 1997) found that trichorabdal A, a diterpene from a Japanese herb, could directly inhibit H. pylori.



Alkaloids

Heterocyclic nitrogen compounds are called alkaloids. The first medically useful example of an alkaloid was morphine, isolated in 1805 from the opium poppy Papaver somniferum (Fessenden, R. J., and J. S. Fessenden. 1982); the name morphine comes from the Greek Morpheus, god of dreams. Codeine and heroin are both derivatives of morphine. Diterpenoid alkaloids, commonly isolated from the plants of the Ranunculaceae, or buttercup family, are commonly found to have antimicrobial properties (Omulokoli, E., B. Khan, and S. C. Chhabra. 1997). Solamargine, a glycoalkaloid from the berries of Solanum khasianum, and other alkaloids may be useful against HIV infection as well as intestinal infections associated with AIDS (Sethi, M. L. 1979). While alkaloids have been found to have microbiocidal effects, the major antidiarrheal effect is probably due to their effects on transit time in the small intestine.

Berberine is an important representative of the alkaloid group. It is potentially effective against trypanosomes and plasmodia (Omulokoli, E., B. Khan, and S. C. Chhabra. 1997). The mechanism of action of highly aromatic planar quaternary alkaloids such as berberine and harmane is attributed to their ability to intercalate with DNA (Phillipson, J. D., and M. J. O’Neill. 1987).



Lectins and Polypeptides

Peptides, which are inhibitory to microorganisms, were first reported in 1942 (Balls, A. K., et al. 1942). They are often positively charged and contain disulfide bonds. Their mechanism of action may be the formation of ion channels in the microbial membrane (Zhang, Y., and K. Lewis. 1997) or competitive inhibition of adhesion of microbial proteins to host polysaccharide receptors (Sharon, N., and I. Ofek. 1986). Recent interest has been focused mostly on studying anti-HIV peptides and lectins, but the inhibition of bacteria and fungi by these macromolecules, such as that from the herbaceous Amaranthus, has long been known. Thionins are peptides commonly found in barley and wheat and consist of 47 amino acid residues (Mendez, E., et al. 1990). Which are toxic to yeasts and gram-negative and gram-positive bacteria. Thionins AX1 and AX2 from sugar beet are active against fungi but not bacteria (Kragh, K. M., et al. 1995). Fabatin, a newly identified 47-residue peptide from fava beans, appears to be structurally related to-thionins from grains and inhibits E. coli, P. aeruginosa, and Enterococcus hirae but not Candida or Saccharomyces (Zhang, Y., and K. Lewis. 1997).The larger lectin molecules, which include mannose-specific lectins from several plants, MAP30 from bitter melon (Lee-Huang, S., et al 1995), GAP31 from Gelonium multiflorum8), and jacalin (Favero, J., et al. 1993), are inhibitory to viral proliferation (HIV, cytomegalovirus), probably by inhibiting viral interaction with critical host cell components. It is worth emphasizing that molecules and compounds such as these whose mode of action may be to inhibit adhesion will not be detected by using most general plant antimicrobial screening protocols, even with the bioassay-guided fractionation procedures (Rinehart, K. L., et al. 1990) used by natural-products chemists..



Mixtures

The chewing stick is widely used in African countries as an oral hygiene aid (in place of a toothbrush) (Norton, M. R., and M. Addy. 1989). Chewing sticks come from different species of plants, and within one stick the chemically active component may be heterogeneous. Crude extracts of one species used for this purpose, Serindeia werneckei, inhibited the periodontal pathogens Porphyromonas gingivalis and Bacteroides melaninogenicus in vitro

(Rotimi, V. O., et al. 1988). Whether these compounds, long utilized in developing countries, might find use in the Western world is not yet known. Papaya (Carica papaya) yields a milky sap, often called latex, which is a complex mixture of chemicals. Chief among them is papain, a well-known proteolytic enzyme (Oliver-Bever, B. 1986). An alkaloid, carpaine, is also present (Burdick, E. M. 1971). Terpenoids are also present and may contribute to its antimicrobial properties (Thomson, W. A. R. (ed.). 1978). Osato et al. (168) found the latex to be bacteriostatic to B. subtilis, Enterobacter cloacae, E. coli, Salmonella typhi, Staphylococcus aureus, and Proteus vulgaris. Ayurveda is a type of healing craft practiced in India but not unknown in the United States. Ayurvedic practitioners rely on plant extracts, both “pure” single-plant preparations and mixed formulations. The preparations have lyrical names, such as Ashwagandha (Withania somnifera root) (Dhuley, J.1998), Cauvery 100 (a mixture) (Manonmani, S., et al. 1995), and Livo-vet (Kumar, O., and B. Singh. 1992). These preparations are used to treat animals as well as humans. In addition to their antimicrobial activities, they have been found to have antidiarrheal (Manonmani, S., et al. 1991), immunomodulatory (Manonmani, S., et al. 1995), anticancer, and psychotropic (Shah, L., et al. 1997) properties. In vivo studies of Abana, an Ayurvedic formulation, found a slight reduction in experimentally induced cardiac arrhythmias in dogs (Gautam, C. S., et al. 1993). Two microorganisms against which Ayurvedic preparations have activity are Aspergillus spp. and Propionibacterium acnes (Paranjpe, P., and P. H. Kulkarni. 1995). (The aspergillosis study was performed with mice in vivo, and it is therefore impossible to determine whether the effects are due to the stimulation of macrophage activity in the whole animal rather than to direct antimicrobial effects.) The toxicity of Ayurvedic preparations has been the subject of some speculation, especially since some of them include metals. Propolis is a crude extract of the balsam of various trees; it is often called bee glue, since honeybees gather it from the trees. Its chemical composition is very complex: like the latexes described above, terpenoids are present, as well as flavonoids, benzoic acids and esters, and substituted phenolic acids and esters (Amoros, M., et al. 1992). Synthetic cinnamic acids, identical to those from propolis, were found to inhibit hemagglutination activity of influenza virus (Serkedjieva, J., and N. Manolova. 1992). Amoros et al. found that propolis was active against an acyclovir-resistant mutant of HSV-1, adeno virus type 2, vesicular stomatitis virus, and poliovirus. Mixtures of chemicals, such as are found in latex and propolis, may act synergistically. While the flavone and flavonol components were active in isolation against HSV-1, multiple flavonoids incubated simultaneously with the virus were more effective than single chemicals, a possible explanation of why propolis is more effective than its individual compounds (Amoros, M., et al. 1992). Of course, mixtures are more likely to contain toxic constituents, and they must be thoroughly investigated and standardized before approved for use on a large-scale basis in the West.



Other Compounds

Many phytochemicals not mentioned above have been found to exert antimicrobial properties. This review has attempted to focus on reports of chemicals that are found in multiple instances to be active. It should be mentioned, however, that there are reports of antimicrobial properties associated with polyamines, isothiocyanates (Iwu, M. M., et al. 1991), thiosulfinates (Tada, M., et al 1988), and glucosides (Murakami, A., et al.1992, Rucker, G., et al .1992.). Polyacetylenes deserve special mention. Estevez-Braun et al. isolated a C17polyacetylene compound from Bupleurum salici- folium, a plant native to the Canary Islands. The compound, 8S-heptadeca-2(Z),9(Z)-diene-4,6-diyne-1,8-diol, was inhibitory to S. aureus and B. subtilis but not to gram-negative bacteria or yeasts (Estevez-Braun, A., et al. 1994). Acetylene compounds and flavonoids from plants traditionally used in Brazil for treatment of malaria fever and liver disorders have also been associated with anti- malarial activity (29).

Much has been written about the antimicrobial effects of cranberry juice. Historically, women have been told to drink the juice in order to prevent and even cure urinary tract infec- tions. In the early 1990s, researchers found that the monosac- charide fructose present in cranberry and blueberry juices competitively inhibited the adsorption of pathogenic E. coli to urinary tract epithelial cells, acting as an analogue for mannose (252). Clinical studies have borne out the protective effects of cranberry juice (17). Many fruits contain fructose, however, and researchers are now seeking a second active compound from cranberry juice that contributes to the antimicrobial properties of this juice (252).







Natural products have been used to elucidate physiological processes and even define them, hence the naming of ‘nicotinic’ and ‘muscarinic’ receptors and even more recently ‘endorphins’ from ‘endogenous morphines’. Natural products are the basis of many standard drugs used in modern medicine and are so widely used that even some members of the medical profession are not aware of their plant origin. Some of the newer pharmacological tools such as colforsin (an adenyl cyclase stimulator), ginkgolide B (a specific platel et activating factor (PAF) antagonist) and phorbolesters that activate proteinkinase C, are at the forefront of biochemical research and are obtainable only from plant sources [Williamson, 1996].

Although medicinal plants may not always lead to the discovery of novel compounds which may be employed in the treatment or cure of disease, plants may give valuable insight into the pathology of diseased conditions or the disturbed human mind. Hallucinogenic plants have been thought to transport the mind to realms of ethereal wonder and some were even considered to be gods. It is only recently, the past twenty years, that modern westernized societies have realized the significance of these plants in shaping the history of primitive and even advanced cultures. Some of these plants contain chemicals capable of inducing visual, auditory, tactile, olfactory and gustatory hallucinations or causing artificial psychoses and the question is whether a thorough understanding of the chemical composition of these drugs may lead to discovery of new drugs for the treatment of psychiatric conditions. As a result of the complexity of the human brain and central nervous system, psychiatry has not developed as rapidly as other fields of medicine, mainly due to the lack of adequate tools, therefore these drugs may provide the necessary pharmacological tools for the discovery of more appropriate and effective drugs [Shultes, 1992].







2.1.4 Current developments



The rationale for studying plants as traditional medicines is that 80% of 5200 million people live in less developed countries. The WHO estimates that 80% of these people rely almost exclusively on traditional medicine for their primary health care needs. Since medicinal plants are the ‘backbone” of traditional medicine, this means that more than 3300 million people utilize medicinal plants on a regular basis. [Farnsworth, 1994].



It cannot be denied that higher plants have yielded many useful drugs to alleviate the medical problems facing the World’s population. In 1985, Farnsworth identified 119 secondary metabolites isolated from higher plants that were being used globally as drugs [Farnsworth, 1990]. About 75% of these drugs have the same or related uses as the plant from which they were discovered. These 119 useful drugs are still obtained commercially for the most part by extraction from only about 90 species of plants. With more than 250,000 species of higher plants more useful drugs remain to be discovered.



There is a great demand and potential for medicinal plant research as shown by the growing market in medicinal herbs. They are high in value, low in shipping volume, popular with the public interested in natural products and strong competitors for synthetic drugs developed at high costs. In 1980 the consumer paid about $ 8.0 billion for prescription drugs in which the active principles were derived from plants [Farnsworth & Morris, 1976, Farnsworth 1982b]. Dollar values from 1994 also provide strong support: $6.5 billion in Europe, $2.1 billion in Japan, $2.3 billion in the rest of Asia and $1.5 billion in North America. It is estimated that medicinal plants are therefore a $12 billion market and expected to increase for another 10 or 20 years [http://www.bizjournals]. In spite of this, not a single pharmaceutical manufacturer in the United States had a serious research program designed to discover new drugs from the plant kingdom at that stage [Farnsworth, 1984].



In developed countries, the cost of taking a drug from the discovery stage to the market place can exceed $50 million and span a period of several years. The industry is therefore reluctant to invest in the development of any drug when its investment cannot be recovered. Failure of many programs to produce useful drugs after several years of intensive effort and millions of dollars, signals to many that plants are an uninteresting source of useful drugs [Farnsworth, 1984]. In spite of the widespread usage of plants and plant products, there is often no evidence to support their use. No clear rationale is proposed for most product use over the traditional beliefs and superstition and therefore a scientific explanation is warranted.





Plants have served as a source of new pharmaceutical products and inexpensive starting materials for the synthesis of many known drugs. Natural products and their derivatives represent more than 50% of the drugs in clinical use in the world (Cowan, 1999, Sofowora, 1984) (Table 2-2). Although the first chemical substance to be isolated from plants was benzoic acid in 1560, the search for useful drugs of known structures did not begin until 1804 when morphine was separated from Papaver somniferum L. (Pium). Since then many drugs from higher plants have been discovered, but less than 100 with defined structures are in common use. Less than half of these (Table 2- 1) are accepted as useful drugs in industrialized countries (Farnsworth, 1984). Considering the great number of chemicals that have been derived from plants as medicine, scientific evaluation of plants used traditionally for the treatment of bacterial infection seems to be a logical step of exploiting the anti-microbial compounds, which may be present in plants. Plant-based anti-microbials represent a vast untapped source of medicines with enormous therapeutic potential (Cowan, 1999). They are supposedly effective in treatment of infectious diseases while simultaneously mitigating many of the side effects that are often associated with synthetic anti-microbials (Iwu et al., 1999)





Herbal medicines are the synthesis of therapeutic experiences of generations of practicing physicians of indigenous systems of medicine for over hundreds of years while nutraceuticals are nutritionally or medicinally enhanced foods with health benefits of recent origin and marketed in developed countries. The marketing of the former under the category of the latter is unethical. Herbal medicines are also in great demand in the developed world for primary health care because of their efficacy, safety and lesser side effects. They also offer therapeutics for age-related disorders like memory loss, osteoporosis, immune disorders, etc. for which no modern medicine is available. India despite its rich traditional knowledge, heritage of herbal medicines and large biodiversity has a dismal share of the world market due to export of crude extracts and drugs. WHO too has not systematically evaluated traditional medicines despite the fact that it is used for primary health care by about 80% of the world population? However, in 1991 WHO developed guidelines for the assessment of herbal medicine. Suggestions for herbal medicine standardization are outlined. The scenario and perceptions of herbal medicine are discussed. HERBAL medicine is still the mainstay of about 75–80% of the world population, mainly in the developing countries, for primary health care because of better cultural acceptability, better compatibility with the human body and lesser side effects. However, the last few years have seen a major increase in their use in the developed world. In Germany and France, many herbs and herbal extracts are used as prescription drugs and their sales in the countries of European Union were around $ 6 billion in 1991 and may be over $ 20 billion now. In USA, herbal drugs are currently sold in health food stores with a turnover of about $ 4 billion in 1996, which is anticipated to double by the turn of the century1. In India, the herbal drug market is about $ one billion and the export of plant-based crude drugs is around $ 80 million2. Herbal medicines also find market as nutraceuticals (health foods) whose current market is estimated at about $ 80–250 billion in USA and also in Europe3.





Nutraceuticals

This is a term of recent origin (1979) and comprises nutritionally or medicinally enhanced foods with health benefits3. These include engineered grain; cereals supplemented with vitamins or minerals or genetically manipulated soybean and canola oil without trans fatty acids, etc. Many pharma and biotech companies have moved into this area since it does not involve regulatory clearances and offers large markets. These companies have extended the term nutraceutical to include pure compounds of natural origin like lovastatin (a lipid lowering agent from red rice yeast), docosahexaenoic acid (a cardiovascular stimulant from algae), sterols, curcumin (from plants), etc. Likewise herbal preparations are being marketed as nutraceuticals or health foods and even the minimum standards lay down by WHO are not followed. It is pertinent to mention that herbal medicines are therapeutics of the indigenous/traditional systems of medicine and it is unethical to classify them as health foods. The regulatory agencies should, therefore, step in to prevent such misuse of natural products/herbal medicines as was done by US-FDA by banning the dietary supplement cholestin (i.e. lovastatin).

Nutraceuticals are in great demand in the developed world particularly USA and Japan. Nutraceutical market in USA alone is about $ 80–250 billion, with a similar market size in Europe and Japanese sales worth $ 1.5 billion3. Such huge markets have arisen because of the Dietary Supplement Health Education Act passed by USA in 1994, which permits unprecedented claims to be made about food or the dietary supplement’s ability about health benefits including prevention and treatment of diseases. This act has motivated pharma to include not only compounds isolated from fauna and flora but also herbal medicines as nutraceuticals, which is unfortunate. The developing countries also see this as a good opportunity and are marketing such products.

As per available records, the herbal medicine market in 1991 in the countries of the European Union was about $ 6 billion (may be over $ 20 billion now), with Germany accounting for $ 3 billion, France $ 1.6 billion and Italy $ 0.6 billion3. Incidentally in Germany and France, herbal extracts are sold as prescription drugs and are covered by national health insurance. In 1996, the US herbal medicine market was about $ 4 billion and with the current growth rate may be more than double by the turn of century. Thus a reasonable guesstimate for current herbal medicine market worldwide may be around $ 30–60 billion. The Indian herbal drug market is about $ one billion and the export of herbal crude extracts is about $ 80 million (Table 1). The 10 best-selling herbal medicines in developed countries1 are given in Table 2. The sales of these drugs account for almost 50% of the herbal medicine market. These drugs have been well standardized and some of them namely echinacea, garlic, gingko, ginseng and saw palmetto are supported with mode of action and clinical studies. Amongst the developed countries Germany holds the lead and has published individual monographs on therapeutic benefits of more than 300 herbs. In developing countries, China has compiled/generated data on over 800 medicinal plants and exports large amounts of herbal drugs. India has prepared only a few monographs and its exports are dismal. Why herbal medicine? Herbal medicines are being used by about 80% of the world population primarily in the developing countries for primary health care. They have stood the test of time for their safety, efficacy, cultural acceptability and lesser side effects. The chemical constituents present in them are a part of the physiological functions of living flora and hence they are believed to have better compatibility with the human body. Ancient literature also mentions herbal medicines for age-related diseases namely memory loss, osteoporosis, diabetic wounds, immune and liver disorders, etc. for which no modern medicine or only palliative therapy is available. These drugs are made from renewable resources of raw materials by ecofriendly processes and will bring economic prosperity to the masses growing these raw materials.



Herbal medicine scenario in India

The turnover of herbal medicines in India as over-the-counter products, ethical and classical formulations and home remedies of Ayurveda, Unani and Siddha systems of medicine is about $ 1 billion with a meagre export of about $ 80 million. Psyllium seeds and husk, castor oil and opium extract alone account for 60% of the exports. 80% of the exports to developed countries are of crude drugs and not finished formulations leading to low revenue for the country. Thus the export of herbal medicines from India is Table 1. India is sitting on a gold mine of well-recorded and well-practiced knowledge of traditional herbal medicine. But, unlike China, India has not been able to capitalize on this herbal wealth by promoting its use in the developed world despite their renewed interest in herbal medicines. This can be achieved by judicious product identification based on diseases found in the developed world for which no medicine or only palliative therapy is available; such herbal medicines will find speedy access into those countries. Backward integration from market demands will pay rich dividends. Strategically, India should enter through those plant-based medicines that are already well accepted in Europe, USA and Japan. Simultaneously, it should identify those herbs (medicinal plants), which are time-tested and dispensed all over in India.

The basic requirements for gaining entry into developed countries include:

(i) Well-documented traditional use,

(ii) Single plant medicines,

(iii) Medicinal plants free from pesticides, heavy metals, etc.,

(iv) Standardization based on chemical and activity profile, and

(v) Safety and stability. However, mode of action studies in animals and efficacy in human will also be supportive.

Such scientifically generated data will project herbal medicine in a proper perspective and help in sustained global market. The World Health Organization (WHO) has recently defined traditional medicine (including herbal drugs) as comprising therapeutic practices that have been in existence, often for hundreds of years, before the development and spread of modern medicine and are still in use today. Or say, traditional medicine is the synthesis of therapeutic experience of generations of practicing physicians of indigenous systems of medicine. The traditional preparations comprise medicinal plants, minerals, organic matter, etc. Herbal drugs constitute only those traditional medicines that primarily use medicinal plant preparations for therapy. The earliest recorded evidence of their use in Indian, Chinese, Egyptian, Greek, Roman and Syrian texts dates back to about 5000 years. The classical Indian texts include Rigveda, Atherveda, Charak Samhita and Sushruta Samhita. The herbal medicines/traditional medicaments have, therefore, been derived from rich traditions of ancient civilizations and scientific heritage.





Table 6. Medicinal plants being imported in India

Botanical name Native name

Cuscuta epithymum Aftimum vilaiyti

Glycyrrhiza glabra Mullathi

Lavendula stoechas Ustukhudus

Operculina turpethum Turbud

Pimpinella anisum Anise fruit

Smilax china Chobchini

Smilax ornata Ushba

Thymus vulgaris Hasha

Source: BCIL2.GENERAL ARTICLES

CURRENT SCIENCE, VOL. 78, NO. 1, 10 JANUARY 2000 39



Table 3. Frequency of occurrence of medicinal plants in herbal

formulations in India

Common name Botanical name

No. of herbal

formulations

Triphala Terminalia chebula 219

Terminalia belerica

Emblica officinalis

Yashtimadhu Glycyrrhiza glabra 141

Pipali Piper longum 135

Vasaka Adhatoda vasica 110

Ashwagandha Withania somnifera 109

Mastak (Motha) Cyperus rotundus 102

Gulacha Tinospora cordifolia 88

Daruharidra Berberis aristata 65

Gokshura Tribulus terrestris 65

Kutaja Holarrhena antidysenterica 59

Punarnava Boerhavia diffusa 52

Source: BCIL2.GENERAL ARTICLES

CURRENT SCIENCE, VOL. 78, NO. 1, 10 JANUARY 2000 37





Table 4. Major Indian medicinal plants used in three indigenous

systems of medicine

Botanical name Sanskrit name

Abies webbiana Taleespatra

Achyranthes aspera Apamarga

Acorus calamus Vacha

Aloe sp. Kumari

Andrographis paniculata Bhoonimba (Kalmeg)

Asparagus adscendens Mushali

Asparagus racemosus Shatavari

Bauhinia variegata Kachnar

Bergenia ligulata Pashan bheda

Boerhavia diffusa Punarnava

Centella asiatica Mandukparni

Clerodendrum serratum Bharangi

Convolvulus pluricaulis Shankhapushpi

Crataeva nurvala Varuna

Dioscorea bulbifera Vidarikand

Embelia ribes Vidanga

Gymnemma sylvestre Madhunashni

Hedychium spicatum Shathi

Holarrhena antidysenterica Kutaja

Mesua ferrea Nagkesar

Nardostachys jatamansi Jatamansi

Ocimum sp. Tulsi

Phyllanthus amarus Bhumyamalika

Phyllanthus emblica Amalika (Amla)

Picrorhiza kurrooa Kutki

Piper longum Pippali

Pluchea lanceolata Rasna

Psoralea corylifolia Bakuchi

Rubia cordifolia Manjistha

Saraca indica Ashoka

Saussurea lappa Kushtha

Sida sp. Bala

Symplocos racemosa Lodhra

Terminalia arjuna Arjuna

Terminalia chebula Haritaki (Harad)

Tinospora cordifolia Guduchi

Tribulus terrestris Gokshura

Valeriana jatamansi Tagar

Vitex negundo Nirgundi

Withania somnifera Ashwagandha

Source: BCIL2.



Table 5. Medicinal plants being exported from India

Botanical name Part of the plant

Aconitum species

(other than heterophyllum)

Root

Acorus calamus Rhizome

Adhatoda vasica Whole plant

Berberis aristata Root

Cassia angustifolia Leaf and pod

Colchicum luteum Rhizome and seed

Hedychium spicatum Rhizome

Heracleum candicans Rhizome

Inula racemosa Rhizome

Juglans regia Bark

Juniperus communis Fruit

Juniperus macropoda Fruit

Picrorhiza kurrooa Root

Plantago ovata Seed and husk

Podophyllum emodi Rhizome

Punica granatum Flower, root and bark

Rauvolfia serpentina Root

Rheum emodi Rhizome

Saussurea lappa Rhizome

Swertia chirayita Whole plant

Valeriana jatamansi Rhizome

Zingiber officinale Rhizome







































Market size of herbal medicines.

Country Drug sales in

US $ (billion)

Europe (1991)

Germany 3.0

France 1.6

Italy 0.6

Others 0.8

Europe (1996) ~ 10.0

USA (1996) 4.0

India (1996) 1.0

Other countries (1996) 5.0

All countries (1998) ~ 30.0–60.0



Table 2. Ten best-selling herbal medicines in USA

Drug Botanical name

Market rank

as per sale

Echinacea Echinacea species 1

Garlic Allium sativum 2

Goldenseal Hydrastis canadensis 3

Ginseng Panax species 4

Ginko Ginko biloba 5

Saw palmeto Serenoa repens 6

Aloe gel Aloe barbadensis 7

Ephedra Ephedra species 8

Eleuthero Eleutherococcus senticosus 9

Cranberry Vaccinium macrocarpon 10



negligible despite the fact that the country has a rich traditional knowledge and heritage of herbal medicine. Considering the huge herbal medicine and nutraceutical market in developed countries, India should reconsider exporting crude herbal drugs.

Three of the 10 most widely selling herbal medicines in developed countries, namely preparation of Allium sativum, Aloe barbadensis and Panax species are available in India (Table 2). India is the largest grower of Psyllium (Plantago ovata) and Senna (Cassia senna) plants and one of the largest growers of Castor (Ricinus communis) plant. These are also exported in large amounts and yet our market share is dismal because of export of crude extracts/drugs. Twenty other plants are commonly exported as crude drugs worth $ 8 million. Five of these, namely Glycyrrhiza glabra, Commiphora mukul, Plantago ovata, Aloe barbadensis and Azadirachta indica are even used in modern medicine. The plants Glycyrrhiza glabra, Piper longum, Adhatoda vasica, Withania somnifera, Cyperus rotundus, Tinospora cordifolia, Berberis aristata, Tribulus terristris, Holarrhena antidysenterica and Boerhavia diffusa have been used in 52 to 141 herbal formulations and triphala (Terminalia chebula, Terminalia belerica and Embelica officinalis) alone have been used in 219 formulations (Table 3). In spite of this, efforts have not been made to preserve their germ-plasm from different localities, identification of active plants vis-à-vis climatic zone and development of agro technologies for their organized farming and use as authentic materials in herbal medicines for better economic gains.

India is one of the 12-mega biodiversity centers having over 45,000 plant species. Its diversity is unmatched due to the presence of 16 different agro climatic zones, 10 vegetative zones and 15 biotic provinces. The country has 15,000–18,000 flowering plants, 23,000 fungi, 2500 algae, 1600 lichens, 1800 bryophytes and 30 million microorganisms. India also has equivalent to 3/4 of its land exclusive economic zone in the ocean harboring a large variety of flora and fauna, many of them with therapeutic properties. About 1500 plants with medicinal uses are mentioned in ancient texts and around 800 plants have been used in traditional medicine; the most widely used plants are given in Table 4. Tables 5 and 6 give the names of medicinal plants exported and imported in India, respectively. The major traditional sector pharmas, namely Himalaya, Zandu, Dabur, Hamdard, Maharishi, etc. and modern sector pharmas, namely Ranbaxy, Lupin, Allembic, etc. are standardizing their herbal formulations by chroma tography techniques like TLC/HPLC finger printing, etc. There are about 7000 firms in the small-scale sector manufacturing traditional medicines with or without standardization. However, none of the pharma has standardized herbal medicines using active compounds as markers linked with confirmation of bioactivity of herbal drugs in experimental animal models.



Role of WHO in herbal medicine

Two decades ago, WHO referred to traditional health systems (including herbal medicine) as ‘holistic’ – ‘that of viewing man in his totality within a wide ecological spectrum, and of emphasizing the view that ill health or disease is brought about by an imbalance or disequilibrium of man in his total ecological system and not only by the causative agent and pathologenic evolution’ (WHO6), probably implying that the indigenous system drugs (including herbal medicine) restore the imbalance or disequilibrium leading to the cure of ill health or disease. Such an attitude sent signals that WHO as an organization has failed to provide leadership to establish traditional systems of medicine that provide health care to about 80% of the world population. However, it helped the inclusion of proven traditional remedies in national drug policies and regulatory approvals by developing countries. The World Health Assembly continued the debate and adopted a resolution (WHA 42.43) in 1989 that herbal medicine is of great importance to the health of individuals and communities. The redefined definition of traditional medicine thus issued in the early nineties is given vide supra (see herbal medicine). Consequently, in 1991 WHO developed guidelines for the assessment of herbal medicine7, and the 6th International Conference of Drug Regulatory Authorities held at Ottawa in the same year ratified the same.



The salient features of WHO guidelines are:

• Quality assessment: Crude plant material; preparation; finished product.

• Stability: Shelf life

• Safety assessment: Documentation of safety based on experience or/and; Toxicology studies.

• Assessment of efficacy: Documented evidence of traditional use or/and; Activity determination (animals, human).



Herbal medicine standardization in indigenous/traditional systems of medicine, the drugs is primarily dispensed as water decoction or ethanolic extract. Fresh plant parts, juice or crude powder are a rarity rather than a rule. Thus medicinal plant parts should be authentic and free from harmful materials like pesticides, heavy metals, microbial or radioactive contamination, etc. The medicinal plant is subjected to a single solvent extraction once or repeatedly, or water decoction or as described in ancient texts. The extract should then be checked for indicated biological activity in an experimental animal model(s). The bioactive extract should be standardized on the basis of active principle or major compound(s) along with fingerprints. The next important step is stabilization of the bioactive extract with a minimum shelf life of over a year. The stabilized bioactive extract should undergo regulatory or limited safety studies in animals.



Determination of the probable mode of action will explain the therapeutic profile. The safe and stable herbal extract may be marketed if its therapeutic use is well documented in indigenous systems of medicine, as also viewed by WHO. A limited clinical tribal to establish its therapeutic potential would promote clinical use. The herbal medicines developed in this mode should be dispensed as prescription drugs or even OTC products depending upon disease consideration and under no circumstances as health foods or nutraceuticals.