Medicinal Plants

Medicinal Plants Simpson and Ogorzaly: pp. 262 – 285 Levetin and McMahon: pp. 15 – 17, 330 – 349 Pre-History – The first “doctors”, or healers, were probably those members of society that possessed an extensive knowledge of their local flora (i.e. all plants growing in a particular region). Today we call these people medicine men or shamans. Evidence that these people were our first doctors comes from research by ethnobotanists working with indigenous groups. e.g. the late Richard Evans Schultes and his student, Mark Plotkin. Ancient History – oldest known documentation of medicinal plants comes from the Ancient Sumerians, although involved in mathematics and sciences, they attribute human illness to supernatural sources; recorded plant remedies on a clay tablet dated at ~2500 B.C. The Code of Hammurabi, written under the direction of the King of Babylon also mentions use medicinal plants like henbane and licorice. Pen Tsao – a pharmacopoeia, or book containing an official list of medicines, is complied under the direction of Emperor Shen-nung of China ~ 2500 B.C. Desribes use of 365 medicinal plants including opium, ephedra, hemp, and chaulmoogra. Ebers Papyrus – dated ~ 1500 B.C. from Egypt – documents preparation of 700 remedies made from such plants as mandrake, aloe, castor, and hemp Rig Veda – earliest Hindu text from Ancient India, dated ~ 1500 B.C. (at latest), verses include mention of numerous medicinal plants including snakeroot (Rauwolfia serpentina). Text provides foundation of Ayurveda, an Indian system of healing that includes at least 1500 plant-derived medicines in its pharmacopoeia Western Tradition of Medicinal Plants and the Roots of Pharmacology (i.e. the science of drugs) Hippocrates (460-377 B.C) – considered the Father of Medicine (modern-day physicians take Hippocratic oath), breaks with earlier tradition in his belief that human illnesses have natural sources; particularly in his notion that illness is caused by an imbalance of the four bodily humors Theophrastus (371-287 B.C.) – student of Plato And Aristotle, considered the Father of Botany, wrote Historia Plantarum that included directions for the collection, preparation, and use of 600 medicinal plant species Dioscorides (1st century A.D.) Greek physician who works with Roman (Nero’s) army – writes De Materia Medica, a 5- volume pharmacopoeia, that includes 1000 simple remedies prepared from 600 different plant species. Although, it includes a lot of false information, it does document the use of willow bark to relieve pain associated with gout. Medieval Europe – European Christianity discourages practice of medicine based on rational science, replaces it with dogmatic explanations of medical phenomena. De Materia Medica remains standard medical text until Renaissance. In other parts of world, however, progress in medicine is made. e.g .Chinese update Pen Tsao; Arabs translate Greek texts and build hospitals in Baghdad; Avicenna (980-1037), Persian physician writes Canon of Medicine Renaissance – with overall renewal of intellectual activity in Europe in 15th century and invention of the printing press, Age of Herbals begins. Herbals are books that include illustrations of useful plants. Authors of these herbals were predominantly German botanists who had spent some time in monasteries: Otto Brunfels (1464-1534), Hieronymus Bock (1498-1554). Leonard Fuchs (1501-1566), and Valerius Cordus (1515-1544). Pararcelsus – (1493-1541) – proponent of the Doctrine of Signatures, which is the notion that God placed plants on the planet for use by humans and indicated their use to humans with signs e.g. lobed appearance of liverwort indicates its use in liver ailments, red sap of bloodwort signifies its use for blood disorders 17th and 18th centuries – waning use of herbals coincides with advance of scientific method for testing hypotheses. This led to a better understanding of the human physiology and therefore the mechanisms by which medicines acted on the human body. e.g William Withering – English physician publishes his work on the treatment of dropsy with foxglove (Digitalis purpurea) in 1775. Dropsy is the retention of fluid in lungs, gut, and extremities caused by congestive heart failure. Although Withering suspected that the active components of foxglove influence heart rates, he could never conclusively draw the connection between heart failure and dropsy. We now know that congestive heart failure is caused by reduced force of heart contractions, which causes stagnation of blood through veins, which, in turn, causes accumulation of fluid. We also now know that the active components in foxglove strengthen the force of heart contractions by slowing contraction rates.  19th Century – advancements in chemistry lead to isolation and extraction of active components of medicinal plants. e.g. salicin isolated from willow (Salix spp.) in1828 leads to development of acetylsalicylic acid, or aspirin, a related compound with less side-effects, by Felix Hoffman of the Bayer Company in 1898. 20th Century – further scientific advancement leads to increased use of synthetic drugs and decreased use of medicines derived from plants. e.g. development of drugs by the rational drug design model. However, 25% of all prescription medicines contain plant chemicals and an even greater proportion contains synthetic analogues of plant chemicals. In addition, 75% of the world’s human population depends on folk and herbal remedies as medicine. Also, rate at which a drug can be designed as opposed to discovered in a new product may not differ greatly so, many drug companies are have once again turned to natural sources of medicine. Finally, Westerners are turning to herbal alternatives to conventional medicines. Chemistry – The bioactivity of medicinal plants is generally attributed to their secondary chemistry. Remember, these are called “secondary” compounds because they have no known functions in primary physiological processes like photosynthesis and respiration. Many classes of secondary compounds are found in medicinal plants but we will focus on two: alkaloids and steroidal glycosides. Alkaloids – chemically diverse (heterogeneous) group; contain nitrogen, which are usually found in rings (although there are exceptions where the nitrogen atoms are not included in the rings - e.g. ephedrine); usually bitter substances, which can be attributed to their alkaline, or basic, pH. Other examples include quinine, morphine, cocaine, reserpine, and nicotine. Steroidal glycosides – contain a steroid molecule and sugar molecules. The steroid molecules are the same as those found in animal hormones produced by the pituitary glands, adrenal glands, and sex organs. These compounds, however, do not seem to have any function in plants. Examples include cardiac glycosides, so-called because they affect heart function, like digitoxin, as well as, sapogenins, so-called because they foam like soap when mixed with water, like diosgenin. Natural History of Medicinal Plants Why do plants produce these compounds with medicinal properties? Was Paracelsus correct when he proclaimed that these plants were placed here by God to heal humans? Or do they also provide functions in the plants themselves? Plant biochemists and physiologists of the early twentieth century assumed that plant secondary compounds were metabolic waste products – the botanical equivalents of urea found in animal urine. But, a growing body of evidence over the last 40 – 50 years strongly suggests that many plant secondary chemicals have evolved as adaptations to herbivores and pathogens. For example, nicotine, an alkaloid produced by Nicotiana spp., deters foliar herbivory by the tobacco hornworm (Manduca sexta) However, certain herbivores have been able to not only overcome these chemical defenses in plants but, further, are able to sequester these chemicals and use them as defense against their predators. e.g. larvae (i.e. caterpillars) of monarch butterflies (Danaus plexippus) are able to ingest and store the cardiac glycosides of milkweeds (Asclepias spp.), their host plant, which then make them unpalatable to birds (e.g. blue jays, Cyanocitta cristata bromia). This process of constant adaptation and counteradaptation whereby plants and their herbivores are selecting each other’s traits is an example of coevolution. The chemicals that plants use against herbivores and pathogens are usually considered to fit into 1 of 2 categories: toxins and digestibilty-reducers. Toxins usually occur in relatively small concentrations in plant tissue and poison or interfere with the development of its targets; e.g. alkaloids and steroidal glycosides. Digestibility-reducers occur in relatively large concentrations in plant tissue and do not necessarily harm herbivores but make plant tissue unpalatable to herbivores; e.g. tannins. The plant secondary chemicals that convey medicinal value top plants generally fit into the toxin category. More examples of medicinal plants: Mexican Yam – Dioscorea spp. (Dioscoreaceae) - In late 1930s discovered that it contains diosgenin, a sapogenin, which is extracted from its tubers - used as starting chemical in the synthesis of birth control pills and of cortisone and hydrocortisone - tubers can weigh between 20 and 30 lbs. By 1950s, it becomes major source of precursors for these drugs this is a cheaper source for the synthesis of these products than other sources like the bile acids found in urine of cattle Snakeroot – Rauwolfia serpentina (Apocynaceae) - small shrub native to tropical forests of India, Sri Lanka, and Indonesia - Important plant in the pharmacopoeia of Ayurvedic medicine for past 4000 years - Because the roots resembled the shape of snakes, it was used as a remedy for snakebites. In addition, it was used to treat mental illness. Teas made from infusions of the root seemed to have a sedative effect and were even used to induce meditative states - In 1952, reserpine, an alkaloid was isolated form its roots - By 1957, 1500 paper on the use of snakeroot for schizophrenia and other mental illnesses were published  revolutionized treatment of mental illness in replacing heretofore used treatments such as electric shock therapy and lobotomies - The bioactivity of snakeroot stems from its ability to block neurotransmitters (norepinephrine) that transmit nerve signals between the parasympathetic nervous system and the heart and blood vessels  This causes a dilation/relaxation of blood vessels Therefore, it lowers blood pressure - Consequently, snakeroot was also used to treat hypertension - In 1954, because of fear that snakeroot may be over-harvested to extinction, India imposes an embargo on its export  leads to exploration of close relatives around the world  Rauwolfia vomitoria, native to west Africa where it was used as a sedative, becomes major source of reserpine. Also 2 new world species are used as sources of Rauwolfia alkaloids: R. canescens and R. tetraphylla Jesuit’s Bark – Cinchona officinalis and other Cinchona spp. (Rubiaceae) - in mid-17th century, Jesuits in South America adopt a remedy for malaria used by natives – infusions of bark called quina quina, meaning “bark of barks”, by Indians steeped in water - Jesuits report new of a cure for malaria back to Europe but because the Jesuits were so disliked, they were not believed - Malaria – comes from Italian mal’aria meaning “bad air” because it was attributed breathing bad air near swamps. Malaria has been killing people since antiquity as recorded by ancient Greeks and Egyptians. Killed more soldiers in WWI than enemy fire and currently claims about a million lives a year. - Malaria caused by 4 species of Plasmodium, single-celled protozoan organisms that are carried to humans by female mosquitoes of the genus Anapheles - Plasmodium is a parasite that completes its life cycle in the blood of its host causing fever, chills, anemia, and enlargement of the spleen. One species in particular, Plasmodium falciparum can casue seizures, convulsions, coma and death if not treated. - Jesuit’s Bark finally accepted by Europeans in 1681 - Quinine kills Plasmodium during one of its life stages in the blood of the host - - - In 1820, quinine is isolated from bark. 1 of 4 anti-malarial alkaloids produced by plant, out of 36 total alkaloids found in Cinchona Concentration of quinine and related alkaloids differs greatly among the 40 species of Cinchona, as well as, among populations of a given species  Dutch identify a high-yielding species, Cinchona ledgeriana, with help of an Indian near Lake Titicaca in Bolivia  establish plantations in Java  Europe and US are cut off from supplies in Indonesia by Japanese during WWII  leads to development of synthetic quinine, which leads to development of semisynthetic analogues of quinine that are now commonly used However, many strains of Plasmodium have become resistant to synthetic drugs so attention has once again returned to natural quinine, which seems to retain its resistance to new strains Also, note that quinine is a cumulative drug meaning that it accumulates in the blood, which can cause cinchonism, characterized by nausea, skin rashes, headaches, and diarrhea Dietary Supplement Health and Education Act (DSHEA) – signed by President Clinton and enacted by Congress in 1994 – expanded the definition of “dietary supplement”, which formerly referred to vitamins and minerals, to include herbs Because these herbs are now considered “dietary supplements”, they do not require the extensive testing and clinical trials to which prescription and over-the-counter the drugs are subject Herbal products are $4 billion/year industry and account for 20% of dietary supplement industry Some popular herbal supplements include St. John’s Wort (Hypericum perforatum, Clusiaceae), native to Europe, documented by Hippocrates and Dioscorides, currently used by European physicians in treatment of depression Saw Palmetto (Serenoa repens, Arecaceae/Palmae), native to coastal plain of SE US, fruits eaten by indigenous peoples of this region, used to treat Benign Prostate Enlargement (BPE), less side-effects than finasteride, a drug prescribed for BPE Issues with DSHEA: Drug interactions need to be studied – St. Johns’ Wort may block effects of prescribed drugs like warfarin, an anticoagulant, and birth control pills. Ginkgo biloba, used to increase blood flow to the brain may exacerbate anticoagulant effects of coumadin and aspirin and thus induce bleeding Ma Huang, Ephedra sinica, used by Chinese as a bronchodilator in treatment of asthma, bronchitis, etc. Ephedrine and other related alkaloids produced by the plant have amphetamine –like properties and were thus included in diet and workout pills, which are attributed to numerous deaths. Food and Drug Administration (FDA) bans drug effective April, 2004.