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Pharmacognosy-I Dr. Wafaa M.A. AlShakh Hamed • Reference text: • Trease and Evans Pharmacognosy; (Latest edition). • Robbers JE, Speedie MK, Tyler VE (Eds.); Pharmacognosy and Pharmacobiotechnology; latest edition. General Introduction • Pharmacognosy is the study of those natural substances, principally plants that find use in medicine. • Pharmacognosy: derived from the Greek, pharmakon a drug and gnosis in knowledge . • Pharmacognosy: may be defined as a science that deals with the biological, biochemical, and economic feature of natural drugs and their constituents. It is study of drugs that originate in the plant and animal kingdoms. Introduction to Pharmacognosy • • • • • A brief history of natural products in medicine Value of natural drug products Production of natural drug products The role of natural products in drug discovery General principles of botany: morphology and systematics I. The history of natural products in medicine • A great proportion of the natural products used as drugs • The study of drugs used by traditional healers is an important object of pharmacognostical research • Sumerians and Akkadians (3rd millennium BC) The 18th century, Pharmacognosy • Linnaeus (naming and classifying plants) • At the end of the 18th century, crude drugs were still being used as powders, simple extracts, or tinctures The era of pure compounds (In 1803, a new era in the history of medicine) • Isolation of morphine from opium • Strychnine (1817) • Quinine and caffeine (1820) • Nicotine (1828) • Atropine (1833) • Cocaine (1855) • In the 19th century, the chemical structures of many of the isolated compounds were determined • In the 20th century, the discovery of important drugs from the animal kingdom, particularly hormones and vitamins. microorganisms have become a very important source of drugs The knowledge of naturally occurring drugs was transmitted by: •Orally. • In written form as papyri. •On packed clay tablet. •Parchments. •Printed herbal. •Pharmacopeias and other works. •Recently by computerized information. Definitions • Pharmacognosy is the study of those natural substances, principally plants that find use in medicine. • Pharmacognosy: It is the science of biogenic or nature-derived pharmaceuticals and poisons Crude drugs: It is used for those natural products such as plants or part of plants, extracts and exudates which are not pure compounds Definitions • Crude :Mean any product that has not been advanced of improved in condition , by shredding , grinding , chipping , crushing , distilling or by any other process except what is essential to its proper patching and to the preventing of decay or deterioration during manufacture. • Drugs :Means those pure substances whether they are natural or synthetic which have therapeutic or medicinal properties and chiefly used as medicine or as an ingredient in medicine . • Definitions • Crude drugs are used infrequently as therapeutic agents; more often their chief principals are separated by various means and are employed in a more specific manner. These principles are known as Derivatives or extractive and whether the extractive is a single substance or mixture of substances, it is considered the chief constituent of drug. The active principle are obtained by Extraction which removes only those substances that can dissolved in the liquid or mixture ( solvent ) and the insoluble portion remains, known as Marc. • Ethnobotany: It is a broad term referring to the study of plants by humans • Ethnomedicine: It refers to the use of plants by humans as medicine • Traditional medicine: It is the sum total of all non-mainstream medical practices, usually excluding so called “western” medicine • Natural products: they can be 1. Entire organism (plant, animal, organism) 2. Part of an organism (a leaf or flower of a plant, an isolated gland or other organ of an animal) 3. An extract or an exudate of an organism 4. Isolated pure compounds Types of drugs derived from plants 1. Herbal drugs, derived from specific parts of a medicinal plant 2. Compounds isolated from nature 3. Nutraceuticals, or “functional foods” Pharmacognosy mainly concerned with : • Naturally occurring substance that have medicinal action. • Natural and synthetic fibers and the surgical dressings. • Pharmacognosy includes the study of other materials used in pharmacy as flavoring agents, suspending agents, disintegrants and other ingredients . • Other fields which have naturally association are those of poisonous and hallucinogenic plants, the raw material for production of oral contraceptives, allergens, and insecticides . • Pharmacognosy closely related to both botany and chemistry , so the beginning of the present century Pharmacognosy has developed mainly on the botanical side which concerned with the descriptions and identification of drugs both in the whole state and powder, and with their , history , commerce , collection , preparation and storage. • Concerned with the elucidation of the biogenetic pathway for the formation of medically active secondary metabolites of plants . • Dealing with the chromatography and other procedure for identification and determination of drugs. Geographical source or habitat We have 3 sources : • Indigenous plant: Those growing in their native countries e.g. Aconitum – napellus is native to central and southern Europe. • Naturalized: e.g. Datura stramonium which introduced into USA from Europe some introducing by birds or ocean current or by man end animal . • Cultivated: e.g. cinchona in America and Indonesia which cultivated by man. Official drugs : The official drugs are natural substances which recognized and included 1- Dried leaves of Mint plants and their active constituents ( Menthone , Menthol , methyl acetate …) these compounds are used to treat some stomach & intestinal diseases . 2- Whole plant Catharanthus and their active constituents (Vincristin and vinblastin ) these compounds are used in treating Cancer diseases . 3- The juice or extract of un ripped fruit of poppy plants (Papaver sp.) and its active constituents as ( Morphine ) used as narcotic analgesics . 4- Caffeine from the seeds of Coffee plants & theophylline from leaves of tea plants are used as stimulants . Some drugs are natural preparations , that are included in the official Pharmacopoeia , but they are not found in the current issues , because those drugs by the time are being have toxic effects ex: 1- Colchicum plant which used in treating a gout disease . 2- Khat plant which used in Yamane country to decrease sensation of fatigue and hungry. Non – official drugs : Such kind of drugs are never appear in official pharmacopoeia . So in general speaking a crude drug may have official or unofficial status official title of crude drug it appears in pharmacopoeia or other official reference books & are given both in English & Latin . while non official drugs are never appear in pharmacopoeia . Commerce in Drugs • The commercial origin of a drug refers to its production and its channels of trade . • Drugs frequently bear a geographic name indicating the country or region in which they are collected .These names don’t necessarily reflect the area where the plant grows. • Drugs are collected in all parts of the world. The Mediterranean region yield more drugs than any other region in the world but India, central Europe and America yield numerous and valuable drugs. • Neither the scientific name of the plant nor the commercial name of them is necessarily an indication of the true habitat of drug plants . II. Value of natural products • Compounds from natural sources play four significant roles in modern medicine: 1. They provide a number of extremely useful drugs that are difficult, if not impossible, to produce commercially by synthetic means. These include such diverse groups of compounds as the alkaloids of the opium poppy, of ergot, and of solanaceous plants; cardiotonic glycosides of digitalis, most of the antibiotics and all of the serums, vaccines and related products. II. Value of natural products 2. Natural sources also supply basic compounds that may be modified slightly to render them more effective or less toxic. • example the numerous variations of the morphine molecule. 3. Their utility as prototypes or models for synthetic drugs possessing physiologic activities similar to the originals H3C COOH COOH COOH Ibuprofen H3 C HO O O Salicylic Acid Aspirin CH3 CH3 4. Some natural products contain compounds that demonstrate little or no activity themselves but which can be modified by chemical or biological methods to produce potent drugs not easily obtained by other methods Baccatin III Taxol Preparation of Drugs for commercial market: • • • • • 1- Collection 2- Harvesting 3- Drying 4- Garbling 5- packaging, storage and preservation . Collection For proper collection we must notice: • Collection of drugs from cultivated plant always ensures a true natural sources and reliable product. But it differ incase of collection of wild plant . • Carelessness or ignorance some part of the collected plant can result incomplete or partial substitution special increase of difficulty to collect or natural source was scarce. • The proper time of collection is important because the nature and quantity of constituents vary greatly in some species according to the season. The most advantageous collection time is when the part of the plant that constitutes the drug is highest in its content of active principles and when the material will dry to give the maximum quality and appearance . Harvesting The mode of harvesting varies with each drug. Some drugs may be collected by hand labor, however when the cost of labor is an important factor, the use of mechanical devices is often more successful in economic production of the drug. But some drugs, the skillful selection of plant parts is important factor (as in case of digitalis). Drying • The drying of the plant material by removing sufficient moisture were : • Ensure good keeping qualities . • Prevent molding . • Prevent the action of enzymes . • Prevent the action of bacteria . • Prevent chemical and other changes. Drying • • • • The benefit of drying will : Fix the constituents. Facilitate grinding and milling . Converts the drug into a more convenient form for commercial handling. Successful drying involves two main Principles : • Control of temperature. • Regulation of air flow. • The plant material can be dried either by the sun or by the use of artificial heat. But with some natural products, such as vanilla fermentation or sweating will occurs which will change the constituents, so such drugs require special drying processes, usually called curing. Garbling • Garbling consists of the removal of extraneous matter. Such as other parts of the plant, dirt and added adulterants. This step is done during collection, but also should carried out after the drug was dried and before packaging. Garbling may be done by mechanical means in some case, but its usually semiskilled operation. Storage of crude drugs • There are great differences in the stability of crude drugs because of slow enzymic changes in the constituents. • Drugs containing glycosides and esters are usually less stable than those containing alkaloids. • Drugs with essential oils deteriorate rather quickly through evaporation, oxidation and polymerization of the substances constituting the essential oil. • Tannins on the other hand, have an almost unlimited durability. Packaging, storage and preservation : • It is important to choose the type of packaging that provides a good protection to the drugs . • Usually leaves and herbs material are baled with power balers into a solid compact mass that are sewn into a burlap cover . • Drug that are likely to deteriorate from absorbed moisture (e . g . Digitalis, ergot )are packed in moisture proof cans. Gums, resins and extracts are shipped in barrels and boxes. Proper storage and preservation are important factors in maintaining a high degree of quality of the drug. • Hard–packed bales, barks and resinous drugs usually absorb little moisture. But leaf herb and root drugs that are not well packed tend to absorb moisture which reaches 10 – 30 % the weight of the drug. • Excessive moisture not only increases the weight of the drug, thus reducing the percentage of active constituents, but also favors enzymatic activity and facilitates fungal growth. • Light adversely affects drugs that are highly colored rendering them unattractive and possible causing undesirable changes in constituents. The oxygen of the air increases oxidation of the constituents of drugs, especially when enzyme oxidase is present. Therefore, the warehouse should be cool, dark and well ventilated with dry air. III. Production of natural drug products 1. Collection (wild) 2. Cultivation (commercial), collection, harvesting, drying, garbling, packaging, storage and preservation e.g. ginseng, ginkgo, peppermint 3. Fermentation (Recombinant DNA technology or Genetically engineered drugs) 4. Cell-culture techniques 5. Microbial transformation 6. Biologics (prepared from the blood of animals) IV. The role of natural products in drug discovery 1. Combinatorial chemistry 2. High-throughput screening of natural products 3. Combinatorial biosynthesis 4. Ethnopharmacology V. General principles of botany: morphology and systematics • How to define a pharmaceutical plant-derived drug from the botanical point of view ? a botanical drug is a product that is either: Derived from a plant and transformed into a drug by drying certain plant parts, or sometimes the whole plant, or 1. Obtained from a plant, but no longer retains the structure of the plant or its organs and contains a complex mixture of biogenic compounds (e.g. fatty and essential oils, gums, resins, balms) • isolated pure natural products are thus not “botanical drugs”, but rather chemically defined drugs derived from nature. the following plant organs are the most important, with the Latin name that is used, for example in international trade, in parentheses: 1. Aerial parts or herb (herba) 2. Leaf (folia) 3. Flower (flos) 4. Fruit (fructus) 5. Bark (cortex) 6. Root (radix) 7. Rhizome (rhizoma) 8. Bulb (bulbus) • The large majority of botanical drugs in current use are derived from leaves or aerial parts. • A plant-derived drug should be defined not only in terms of the species from which it is obtained but also the plant part that is used to produce the dried product. Thus, a drug is considered to be adulterated if the wrong plant parts are included (e.g. aerial parts instead of leaves) Taxonomy • It is the science of naming organisms and their correct integration into the existing system of nomenclature • The names of species are given in binomial form: the first part of the name indicates the wider taxonomic group, the genus; the second part of the name is the species. Papaver somniferum L. • Species: somniferum, here meaning ‘sleepproducing’ • Genus: Papaver (a group of species, in this case poppies, which are closely related) • Family: Papaveraceae (a group of genera sharing certain traits) • L.: indicates the botanist who provided the scientific description of the species assigned the botanical name first and who Morphology of higher plants 1. Flower • It is the essential reproductive organ of a plant. • For an inexperienced observer, two characteristics of a flower are particularly noteworthy: the size and the color • Although the flowers are of great botanical importance, they are only a minor source of drugs used in phytotherapy or pharmacy e.g. chamomile, Matricaria recutita L. (Asteraceae ) 2. Fruit and seed • The lower plants, such as algae, mosses and ferns, do not produce seeds Gymnosperm and Angiosperm • Gymnosperm: they are characterized by seeds that are not covered by a secondary outer protective layer, but only by the testa – the seed’s outer layer • Angiosperm: the seeds are covered with a specialized organ (the carpels) which in turn develop into the pericarp. • Drugs from the fruit thus have to be derived from an angiosperm species • Fruits and seeds have yielded important phytotherapeutic products, including: Fruit Caraway, Carum carvi L. (Umbelliferae) Seed (white) mustard, Sinapis alba L. (Brassicaceae) 3. Leaves • The function of the leaves, as collectors of the sun’s energy and its assimilation, results in their typical general anatomy with a petiole (stem) and a lamina (blade) • A key characteristic of a species is the way in which the leaves are arranged on the stem, they may be: 1. Alternate 2. Distichously 3. Opposite 4. Decussate 5. Whorled • The form and size of leaves are essential characteristics e.g. oval, oblong, obovate, rounded, linear, lanceolate, elliptic, spatulate, cordate, hastate or tendril • The margin of the leaf is another characteristic feature e.g. entire, serrate, dentate, sinuate, ciliate or spinose • Numerous drugs contain leaf material as the main component. e.g. Atropa belladonna L. (Solanaceae) 4. Bark • The bark as an outer protective layer frequently accumulates biologically active substances e.g. Red cinchona, Cinchona succirubra L. (Rubiaceae) • No stem-derived drug is currently of major importance 5. Rhizome and root drugs • Underground organs of only a few species have yielded pharmaceutically important drugs e.g. 1. Sarsaparilla, Smilax regelii (Smilacaceae) 2. Korean ginseng, Panax ginseng (Araliaceae) 6. The bulbs and exudates 1. Garlic, Allium sativum L. (Liliaceae) 2. Aloe vera L. (Asphodelaceae) Animal drugs: • Animal drugs production from wild or domesticated animals. Wild animal (whale, must deer) or fished (cod and halibut) when drugs consist of insects. Either collected from wild insect (cantharides) or cultivate them by furnish the insect with food and shelter maintain optimum condition for their propagation (honeybee) . • Drugs such as lanolin and milk products as wells as hormones , endocrine products and some enzymes , are obtained from domesticated hogs, sheep or cattle , the slaughter house is the usual source of glandular products of enzymes. • Processing and purification of the animal drugs vary with the individual drug. Evaluation of drugs: • To evaluate drugs mean to identify it and to determine its quality and purity. • The identity of a drug can be established by its actual collection form a plant or animal that has been identified, another method of identification is the comparison of a representative unknown sample to a published description of the drug and the authentic sample. • Quality refers to the value of the drug i.e. the count of medicinal principles or active constituents present e.g. carbohydrate, glycosides, tannins, lipids, oils, steroids, alkaloids …etc.) A high grade of quality in a drug is of primary, and effort should be made to obtain and maintain this high quality. The evaluation of a drug involves a number of methods that may be classified as follows • • • • • Organoleptic. Microscopic. Biologic or pharmacologic. Chemical. Physical 1. Organoleptic: refers to evaluation by means of organs of sense and include the macroscopic of the drug, its odor, test, occasionally the sound or snap of the fracture, and the fell of the drug to touch. 2. Microscopic characteristics are important. 3. Pharmacologic activity of certain drugs have been applied to their evaluation and standardization. Assay on living animals as well as on intact organs often indicate the strength of the drug or its preparations , when living organism are used the assay are called bioassays. 4. Chemical methods of evaluation crude drugs and their products are widely and they were represents the best methods of determining the official potency. 5. Physical: the application of typical physical constants to crude is rare, but physical constants are extensively applied to the active principles drugs. Such as alkaloids, volatile oils, fixed oils and others. Classification of Drugs: • Drugs may be classified according to: 1. Alphabetical: Using either Latin or English names, the drugs are arranged alphabetical order. 2. Taxonomic: The drugs are arranged according to the plants from which they were obtained in phyla, orders, families, genera and species. 3. Morphological : Here the drugs are divided into groups such as the : leaves , flowers, fruits , seeds , herbs and entire organism , woods , barks rhizomes and roots ( organized drugs ) dried lattices , extracts gums, resins, oils , fats and waxes ( unorganized drugs ). 4. Pharmacological or therapeutic: Grouping the drug according to the pharmacological action of their most important constituent or their therapeutic uses. 5. Chemical or Biogenetic: Here the drugs the divide into groups according to their most important constituents. E.g. alkaloids, glycosides, volatile oils …..etc. or according to the biosynthetic path ways by which the active constituents are produced. • Each of the methods of classification has advantages and disadvantages. Chemistry of drugs: • The living organism may be considered a biosynthetic laboratory not only for chemical compounds ( carbohydrate , proteins , fats ) that are utilized as food by humans but also for a number of compounds ( glycosides , alkaloids , terpenes….) that exert a physiological effect. • These chemical compounds give plant and animal drugs their therapeutic properties. Drugs are used as such in their crude form or they may be extracted. The resulting principals being employed as a medicinal agents and they are called active constituents. • These active constituent are differentiated from inert constituents (cellulose, lignin suberin, and cutin in addition, starch, albumin, coloring matters and other substances) which also occur in plant and animal drugs. • Often the presence of inert substances may affect the absorbability or potency of the active constituents. To remove the undesirable effects of inert matter in the crude drug or its preparation, active principle are extracted, crystallized and purified for better therapeutic uses. • Active constituent may be divided into two classes: • pharmacologically active • and Pharmaceutically active. • Pharmacologically active which are responsible for the therapeutic activity of drug, either single or mixture of principles (e.g. of single: sugars, starch, plant acids, enzyme, glycosides, steroids, alkaloids, proteins, hormones and vitamins). The mixture: e.g. volatile oils, fats waxes , fixed oil, resins, oleoresins, oleo gum resins and balsams. • Pharmaceutical active constituent those which are used in pharmacy as diluents, disintegrants and other ingredients. • The secondary active constituents of plant drugs are influenced by 3 principle factors: • heredity ( genetic composition ) • Ontogeny (stage of development). • Environment. 1. Genetic effect induces both quantitative and qualitative changes. • Plants of the same species that resemble one another closely inform and structure may be quite different in genetic composition. This often results distinct differences in chemical composition, particularly with references to secondary constituents. Such plants are said to belong to different chemical races, e.g. papaver somniferum contain alkaloid, Morphine while papaver rhoeas have no morphine alkaloid Content. 2. Ontogeny plays a significant role in the nature of the active constituent found in medicinal plants. It might be expected that concentration of secondary metabolites increase with the age of plant. It is not generally appreciated that the identity of these constituent may also vary according to the stage of development. The cannabidiol alkaloid content of cannabis sativa reaches a peak early in the growing season then begins to decline, when this decline occur , the concentration of tetrahydrocannabinol alk. begins to increase and continues increasing until the plant approach maturity. In the opium poppy, papaver somniferum the morphine contents of the capsules is highest within 2-3 weeks after flowering and if these poppy is harvested early, codeine are predominate on the other hand, if harvesting was delayed the morphine decomposed. 3. Environmental factors : Can produce variation in secondary constituents include soil, climate and method of cultivation, for example, many alkaloid containing plants accumulate higher concentrations of such constituents in moist than in arid lands. This may actually related to the soil which is usually poor in nitrogen sources which are usually required for a good yield of alkaloids. • really this is not necessarily the case with volatile oil bearing plants, excess nitrogen was not necessarily cause an increase in the their yields. New bioassays: • In fractionating extracts, to determine the identity of the active constituent, we need simple bioassay procedures. • Researchers have reported success with a simple bioassay utilizing brine shrimp. The eggs of this creature are available in the dry state from pet shops where they are stocked as food for tropical fish, after hatching in a brine solution. The shrimp are exposed to different concentration of the test material, LC50 (median lethal concentration) value in mg is calculated. It has been determined that the activities of a broad range of compounds are manifested as toxic to the shrimp. The method is rapid, reliable, and inexpensive and may be applied in house by chemists, botanists or others. For these reasons, it has been successfully utilized in several studies involving the screening of large numbers of plant species for compounds with useful biologic or pharmacologic activities. • Another procedure is potato-disc. This involve observation for the inhibition of crown gall tumors, induced potato disc by Agrobaterium tumefaciens and using various plant extracts or constituents, being screened in a preliminary fashion for their anti cancer potential . • Results have been encouraging and have correlated statistically with other more elaborated and costly cell culture procedures, at least for certain kinds of antitumor activity. Old fashioned pregnancy test, involved injecting the patients urine into a rabbit and then sacrificing the animal to examine the condition of its ovaries. While now a day women suspecting pregnancy simply dips a plastic strip bearing certain monoclonal antibodies into a urine specimen and look for color change. New analytical methods: • Our analytical capabilities also will be improved because of their complex nature of plants and difficulty to fractionate for the purpose of isolation and identification of active constituents. • Certain experiment done by using selective solvent extraction as out lined by Dragendroff in the 1880, gave away in this century to adsorption chromatography , which in turn take way to ion exchange , paper partition and thin layer technique before developing into high pressure liquid chromatography (HPLC) and gas chromatography Coupled with mass spectrometry, this last methodology has been extremely useful. So called multiple stage mass spectrometry has now come upon the hope identification and quantitation of nanogram quantities, of active constituents in tissue sample approximating 1 mg without prior extraction or purification. • Other powerful techniques for structural determination of complex plant constituent include X ray crystallography and nuclear magnetic resonance (NMR) spectroscopy in its several variation. • It is evident the further study in all of those techniques couple with some unexpected new developments, will lead to the ultimate (black box ). A few milligrams of plant tissue placed in one side will be converted into a print out, listing all the constituent interest and their concentration in sample. Culture Techniques: • One of the present problems in producing plant drugs is securing adequate amounts of the proper material. Collection in quantity of properly identified sometimes scarce, wild growing plants scarce wild growing plants is becoming increasingly difficult; the difficulty will be over come in these years by a plant culture methodology. • Present limitation of plant cell culture techniques include: • Slow growth. • Expensive media. • Tendency to store desired metabolites in the tissues rather than to exert them into the media, where they are easily recovered. • Such producing is now economically feasible only when the compounds produced are both costly and unique as plant products. • Some compounds produced in high yields in such cultures include diosgenin glycoside from the plant discorea and serpentine alk. from catharanthus roseus . • Techniques will be greatly improved as a result of new information regarding factors influencing the formation of secondary plant constituents. • Research has shown pharmaceutically desirable secondary metabolites natural are phytoalexins, which synthesized only when the plants are subject to physical, chemical, microbiological, or fungal damage. • Example: gossypol in Gospium arboreum, increase yield of these compounds resulted from the addition of heat. The yield of other constituents like codeine and morphine in the plant papaver somniferum cell suspension culture are greatly improved by similar methods. • Numerous studies which done have shown have that stress conditions in plant cell suspension culture , such as interaction with an appropriate pathogen , can induce the formation of secondary constituent increase that such constituent are not produced in quantity under normal conditions. • This approach is currently employed commercially in production of quinine. • Alternative methods will be developed for plant unable to accumulate large cell masses in terminate time in such cases isolation and immobilization; of enzyme of intact plant cells seem reasonable. • Another approach to alter the slow growth rate in plant cell – suspension culture is to transfer plant genes, which code for the enzymes catalyzing the desired biosynthetic reactions, into a bacterial or fungal cell. • Many gene products are required to products desired secondary metabolites. • We hope in the future that the manipulation of plant cells, plant genes and plant enzymes rather than the plant themselves should provide us with useful medicinal agents . New plant drugs : for healing some types of diseases • a new drugs which useful to help diseases which still remain not cures : these diseases are : 1. Viral diseases such as herpes (genitals, simplex and zoster) AIDS, and cancers. 2. Diseases of unknown etiology, including arthritis, some cancers and muscular dystrophy . 3. Self inflicted diseases such as alcoholism drug dependency, smoking and stress. 4. Genetic diseases, ranging from cystic fibrosis and hemophilia to sickle – cell disease. • In addition improve drugs need to be developed for 1.The control of symptoms such as pain. 2.Treatment of elevated cholesterol level , diabetis and hypertension. 3.General susceptibility to disease of various kinds . 4. Infections and non infections diseases • In recent years, the concept of immunotherapy (stimulation of the body to develop and improve its own defenses) has developed from a very promising filed of drug therapy. • Another area in which plant principles are exhibiting considerable promise is that of hepatoprotective drugs. Such agents are urgently needed not only to protect the liver from infections such as viral hepatitis but also to help and prevent damage form ingested toxins ranging from amotoxin to ethyl alcohol. • Silymarin, a mixture of flavonolignans obtained from the seeds of the plant silybium marianum which is currently marketed in Europe and used for these purposes with success .