I. Definition
    Plants used for healing purposes.

II. Uses of Medicinal Plants.  Medicinal plants can:

1. be used intact to make a tea, or poultice, etc.  This is the pattern in herbal and traditional medicine. An advantage of using the intact plant is that several different components in the plant may act together (synergistically) to produce the desired effect; 
   
2. serve as the source of a drug that is extracted and purified from the plant.  This is the typical situation in Western medicine. Advantages of extracting the drugs – dose is more easily controlled; sale of the product is also controlled (via patents); 
   
3. serve as the starting material for the synthesis of other drugs (i.e., Mexican yam, periwinkle), or 
   
4. serve as the model of the synthesis of novel new drugs.

III. Importance of herbal medicines
    Medicinal plants are a very important component of the US. Pharmacopoeia. For example, between 1959-1973, 25% of all prescription drugs in US contained one or more substances from plants as the active ingredient. In 1973, approximately 1.03 billion dollars was spent on these drugs. Interestingly, in 1974 the American pharmaceutical industry spent one billion dollars on research, yet only 200,000 for research on drug plants.

IV. Pharmacognosy
    Study of medicines obtained from plants

V. Brief History of Medicinal Plants

• Western medicine originates with the Greeks.
  • Hippocrates (460-377 BC) - Founder of medicine
  • Aristotle - was a great natural historian
  • Theophrastus (372-287 BC) - Founder of botany, described many plants
  • Pliny (43-70 AD) - major compendium of natural history
  • Dioscorides (40-90 AD) - De Materia Medica - encyclopedia of medicinal plants that was major gospel of plant medicine form hundreds of years. Information was accepted probably cuz of: (a) series of wars; (b) Black Death; (c) hi infant mortality (60%). During this time, monasteries were pockets of scholarship. They produced herbals, but mostly copied faithfully info from past. Fortunately the Arabs (i.e., Avicenna) filled the intellectual void. The trend wasn't reversed until the printing press made information available outside of monasteries and the advent of the Renaissance.
    
• Gerard’s Herbal
  
• Herbal medicine eventually gave way to more scientific studies. From the Greek notion that pure reason could answer any question, empirical studies developed.
   
• Herbal medicines in other cultures. Herbs are very important components of medicine in other cultures (i.e., Chinese medicine; Indian Ayurvedic medicine; native North American Indians).

VI. Drug Discovery - or, how did our ancestors learn which plants were useful for medicinal purposes?

VII.  Drug Discovery in the 21st Century
    In general, there is a modern prejudice against herbal drugs/medicines.  This is partly the result of our love of new technology and our cultural prejudices (i.e, "witch doctor").  Fortunately, this is changing for a variety of reasons:  (a) concerns over loss of global biodiversity; (b) increased cultural sensitivity; (c) new tools in the laboratory to help in the screening process; and (d) better incentives (i.e., economic, social, political, other).  The general steps for identifying medicinal plants is:

A.  Identify Potential Medicinal Plants

1. Random Approach - plants are selected more-or-less at random.  Taxol, used to treat breast cancer, was discovered this way.
   
2. Targeted Search - plants with "promising" activity are screened for activity.  Plants are selected on the basis of:  (a) Phylogeny - plants related to those with known medicinal activity are studied; and (b) cultural pre-screen - plants known to be used medicinally by indigenous cultures are studied.  This latter method can be accomplished by checking the literature for reports of plants used by people; studying the herbarium for information about medicinal plants; or visiting and conducting studies of other cultures.  This is one of the jobs of an "ethnobotanist."  Richard Evans Schultes (see Public Folder for obituary) and Mark Plotkin are good examples of ethnobotanists who have extensively studied the medicinal (and other plants) of South American natives. Good ones, like Plotkin and Schultes, must know the language of the people, must develop a working relationship, understand the culture, obtain direct exposure to the culture (participant observer, not just an objective observer), recreated experiences. 

B.  Botanical Investigations
    As much as possible is learned about the plant.  It is collected and  voucher specimens are preserved (in a herbarium).  Appropriate permissions must first be obtained and the ethnobotanist must negotiate an equitable return for the country/people involved.

C.  Screening for Biologically Activity
    The plant is extracted and the extract is tested for biological activity with a bioassay.  A bioassay is a test that examines the effect of a test chemical on a living system.  There are many bioassays.  We will perform two bioassays in lab using brine shrimp and the bacterium, Escherischia coli.  The use of animals is now avoided.

D. Chemically Analyze the Extract
    If the extract shows biological activity in the screening tests, the extract is fractionated (separated into individuals components) and then each fraction is tested for activity to isolate and identify the active ingredient(s).

E.  Synthesis
    Once the biodynamic chemical has been isolated and identified, it will be synthesize so that enough will be available for further testing and use.  In some cases, the chemical cannot be synthesized, so it must be extracted from a natural source, or 

F.  Clinical Trials
    Phase I - Toxicity Studies; Phase II - Efficacy in Small Groups; Phase III - Large scale study, double blind.

VII. Survey of Select Medicinal Plants – we will study several medicinal plants.  As we consider each plant, we will focus on five major concepts:

1. Folk Use & History - how was the plant used by native/indigenous people?  Is it still used this way?  
2. Scientific Discovery - how did knowledge of the medicine come to the attention of scientists (ethnobotanists)?
3. Botanical Explorations - what do we know about the plant?  where does it grow?  What parts are used? etc.
4. Physiological Action of the Plant - what is the action of the plant on humans?
5. Chemical Explorations - what are the active ingredients?  what kind of molecules are they?  how do they act?

VIII. Foxglove (Digitalis purpurea)  (not on exam)

Folk Use/History
    Used by an old woman from Shropshire to treat dropsy - which is caused by an accumulation of fluid (lungs, abdomen, extremities), which in turn, is due to a failure of heart to pump properly. One of the components of her mixture was foxglove.

Scientific Discovery
    William Withering learned about this folk remedy plant about 1775. He was an English country doctor and good botanist.

Botanical Explorations
    This plant is a biennial in the Snapdragon family (Scrophulariaceae). It had been listed in Gerard’s herbal as a powerful medicinal plant.

Physiological Activity
    Withering found it successful in treating dropsy. Published account of his studies. One problem was with dosage. Amount varied with season, etc.

Chemical Explorations
    Foxglove provides about 30 different steroidal glycosides including digoxin & digitonin. These chemicals are powerful heart drugs. Stimulate heart muscle. Slows rate of heart beat and increases the strength of each beat. Not yet commercially synthesized - still extracted from foxglove leaves.

IX. Snakeroot (Rauwolfia serpentina)  (not on exam)

Folk Use/History
    Used for centuries in India to treat snakebite because of the snakelike appearance of root. Also used to cure "madness", put child to sleep (cure insomnia) and treat anxiety.

Scientific Discovery
    Ignored for years; slowly accepted and studied.

Botanical Explorations
    Named and identified in eighteenth century.

Physiology & Chemistry
    In 1930's, Indian chemists isolated molecules, relatively inactive. Another student showed powder had hypnotic effect and lowered blood pressure. In 1949 two chemists at CIBA in Basel isolated reserpine and found it had strong activity. Alkaloid. Blocks neurotransmitter, acts on hypothalamus.

X. Aspirin

Folk Use/History
    The bark of the willow has long been used as a pain reliever by Greeks as well as native Americans - independent discoveries.

Scientific Discovery
    Important plant in Gerard's herbal.

Botanical Explorations
    Found in willow (Salix), meadowsweet (Spiraea or Filipendula ulmaria) and wintergreen.

Physiological Explorations
    Early studies by Rev Edmund Stone found the bark was good for fever and chills. Effects - anti-inflammatory, antipyretic (reduces fever); analgesic (reduces pain). Major effect by suppressing the release of prostaglandins that are released by injured cells (also stimulated by other hormones). Also shown to reduce risk of heart attack/stroke due to its ability to suppress aggregation of blood platelets that could form blood clots.

Chemistry
    French & German chemists worked on isolating active ingredients. In 1828 isolated salicin (a glycoside of salicylic acid). Lead to the lab synthesis of salicylic acid. In 1898 Felix Hoffmann at Bayer Co. learned about a derivative - acetylsalicylic acid - more effective, fewer side effects (stomach irritation). Named it aspirin (a = acetylsalicylic acid; spirin = Spirea).

XI. Fever Bark Tree (Cinchona sp.)  (not on exam)

Folk Use/History/Scientific Discovery
    Used to treat malaria.  This disease has probably killed more people than all wars and plagues and Black Death. Even today, there is a very high rate of death. Caused by protozoan parasite (Plasmodium) transmitted by a mosquito. People didn't originally know the cause, thought it was caused by bad air (mal aria, Italian).  Killed thousands during the Civil War, as far north as St. Louis, and even Minnesota. The fall of Rome and Greece were due in part to malaria. During WWII, one half of all troops suffered from malaria.

    Used by Peruvian Indians to treat fevers. Gave plant the name quina

    Discovered during the conquest of the Incan Empire in the late 16th and early 17th century. Spanish legends indicate a soldier suffering from malaria drank from a pool of brown water at base of quinine tree. Another Spanish legend suggests that Indians noted sick animals drinking water from the brown tepid pools.

     Word of Cinchona reached Europe in 1630's by Jesuits. Worked great. But, physicians were wary of using it because: (a) it was new; (b) sponsored by the Jesuits - feared it was a plot by Catholics to kill Protestants. For example, Oliver Cromwell died rather than being "Jesuited to death".

    Robert Talbor, apothecary, used quinine in a secret remedy to cure malaria. Cured the Royal family (Charles II) also the ailing son of Louis XIV. He was knighted. He was rather clever because he belittled Peruvian bark, but kept his recipe a secret until his death. His recipe included rose leaves, lemon juice, cinchona bark.

    Struggle for bark in the 1800's. S. America wanted to keep its monopoly. Prohibited export. Tried to smuggle seeds/cuttings. Quinine was critical to British and Dutch in colonies in India. Sent men to SA to obtain but failed. Finally Charles Ledger, an Australian, convinced an Indian, Manuel Incra, to collect seeds from a high-yielding tree. He did, was discovered, and killed. Ledger sent seeds to London which did not want them because a previous batch was low in quality. The Dutch bought one pound of seeds for the equivalent of $20. High quality, became basis of huge industry. By 1930 Dutch plantations produced 22 million pounds - 97% of world's quinine.

    In 1940 Germans seized entire European repository when it captured Amsterdam. When Japanese conquered Indonesia in 1942, US & allies with quinine. Small plantation in Philippines soon fell, too. Last allied plane to leave carried 4 million seeds flown to Maryland to germinate and planted in Costa Rica. Little hope could mature fast enough. More Americans died from malaria than fighting.

    Botanist Raymond Fosberg was dispatched to the Andes to find bark. He collected 12.5 million pounds. Learned about biology of Cinchona but never found original high yielding species.

    Synthetics lacked efficacy, unpleasant side effects (nausea, diarrhea and yellowing of skin).

    WWII stopped flow to Allied countries. Japanese invasion of Dutch East Indies in 1942 captures. Then in 1944 synthesized , but expensive.

Botanical Explorations
    There are about 40 species of Cinchona. lots of varieties and produce varying amounts of active ingredients. They grow on the slopes of the Andes high in the rain forest. Use bark. In coffee family (Rubiaceae). Linnaeus named after Countess of Cinchon, wife of the Viceroy of Peru. Legend suggests that she has was miraculously cured in 1638 by the bark.

Physiological Activity
    In 1820 isolated alkaloid quinine by French chemists M. Pelletier and Joseph Caventou.

Chemistry
    Quinine active ingredient.

XII. Medicinal Plant Quickies

1. Mexican yams (Dioscorea sp). 
       The tubers are collected and processed to extract diosgenin and steroidal materials. Processed to provide precursors for birth control pills and other steroids. Mimics the effect of progesterone in preventing ovulation.
   
2. Ginseng (Panax quinquefolia) - extremely important in Chinese medicine.  Taproot used as a general tonic.  Root human-like appearance.  Perhaps responsible (i.e., Doctrine of Signatures).  Commands high price, collected to near extinction.  (not on exam)
   
3. Rosy periwinkle (Cantharanthus roseus) - used to treat leukemia, Hodgkin's.  Discovered from a healer's claims that it was useful against diabetes.  Produces a variety of alkaloids including vinblastine and vincristine.  Lily Co. discovered in screenings. (not on exam)
   
4. Ginkgo (Ginkgo biloba) - deciduous gymnosperm.  treat senility, memory loss. (not on exam)
   
5. Echinacea - infections, boost immune system  (not on exam)
   

XIII.  Animals and Medicinal Plants  (not on exam)
    Humans weren't the first to use plants for medicine - other animals do, too.  Zoopharmacognosy, first reported in 1987 by Eloy Rodriquez and Richard Wrangham.  Wooly spider monkeys in Brazil eat fruits of the "Monkey Ear" plant to enhance fertility.  This plant has since been shown to be rich in the steroid stigmasterol.  Bears chew the roots of Ligusticum porteri (Carrot Family) and smear it on their fur.  Contains coumarins that act as flea and tick repellent.  Chimps eat Aspilia and Vernonia (both Sunflower family) for infections and upset stomachs.

References

• Lispke, Michael.  1994.  Animal Heal Thyself.  National Wildlife.  Dec/Jan, pp 46 -49.
• Plotkin, Mark.  2000.  Medicine Quest:  In Search of Nature's Healing Secrets.  Viking, Penguin, Putman, NY.