1. Medicinal Plants Reading: Textbook, Chapter 11
On Thursday we will take up discussion of how plants have been used medicinally.

2. Margarine – made from fats
- originally from animal fats
- white in color, so yellow dye added to create appearance of butter
Advantage: Stores better than butter
Dairy Industry – fought against use of margarine
- Taxes
Regulations against sale; against use of dyes
Wisconsin – prohibited sale of colored margarine– Repealed 1967; + heavy tax on uncolored (white) margarine (people would buy and mix their own coloring agent)

3. Quiz

4. Quiz
Name two of the four major vegetable oil crops.
Name a medicinal plant, and tell what medicine is obtained from it and a disease it is used to treat
What does soap have to do with vegetable oil?

5. History - Highlights Fig. 11.2, p. 263
2500 BC – Sumerian use of opium poppy
The Romans were very pragmatic in their accomplishments, building a network of roads to unite their kingdom and establishing a standing army to keep the peace. Their interest in medicinal plants was driven by the wish to keep their troops healthy and in action. A Roman physician of Greek origin, Dioscorides, compiled a list of medicinal plants that was to serve for centuries as the ultimate word on herbal medicine.

6. History - Highlights Fig. 11.2, p. 263
2500 BC – Sumerian use of opium poppy
1770 BC – Code of Hammurabi in Babylon – mentions plants
The Romans were very pragmatic in their accomplishments, building a network of roads to unite their kingdom and establishing a standing army to keep the peace. Their interest in medicinal plants was driven by the wish to keep their troops healthy and in action. A Roman physician of Greek origin, Dioscorides, compiled a list of medicinal plants that was to serve for centuries as the ultimate word on herbal medicine.

7. History - Highlights Fig. 11.2, p. 263
2500 BC – Sumerian use of opium poppy
1770 BC – Code of Hammurabi in Babylon – mentions plants
1550 BC – Ebers papyrus in Egypt – 700+ medicinal formulas
The Romans were very pragmatic in their accomplishments, building a network of roads to unite their kingdom and establishing a standing army to keep the peace. Their interest in medicinal plants was driven by the wish to keep their troops healthy and in action. A Roman physician of Greek origin, Dioscorides, compiled a list of medicinal plants that was to serve for centuries as the ultimate word on herbal medicine.

8. History - Highlights Fig. 11.2, p. 263
2500 BC – Sumerian use of opium poppy
1770 BC – Code of Hammurabi in Babylon – mentions plants
1550 BC – Ebers papyrus in Egypt – 700+ medicinal formulas
400 BC – Hippocrates (Greece) – “Father of Medicine”
300 BC – Theophrastus, Botanical Gardens in Athens
The Romans were very pragmatic in their accomplishments, building a network of roads to unite their kingdom and establishing a standing army to keep the peace. Their interest in medicinal plants was driven by the wish to keep their troops healthy and in action. A Roman physician of Greek origin, Dioscorides, compiled a list of medicinal plants that was to serve for centuries as the ultimate word on herbal medicine.

9. History - Highlights Fig. 11.2, p. 263
2500 BC – Sumerian use of opium poppy
1770 BC – Code of Hammurabi in Babylon – mentions plants
1550 BC – Ebers papyrus in Egypt – 700+ medicinal formulas
400 BC – Hippocrates (Greece) – “Father of Medicine”
300 BC – Theophrastus, Botanical Gardens in Athens
77 AD – Dioscorides, De Materia Medica
The Romans were very pragmatic in their accomplishments, building a network of roads to unite their kingdom and establishing a standing army to keep the peace. Their interest in medicinal plants was driven by the wish to keep their troops healthy and in action. A Roman physician of Greek origin, Dioscorides, compiled a list of medicinal plants that was to serve for centuries as the ultimate word on herbal medicine.

10. History - Highlights Fig. 11.2, p. 263
2500 BC – Sumerian use of opium poppy
1770 BC – Code of Hammurabi in Babylon – mentions plants
1550 BC – Ebers papyrus in Egypt – 700+ medicinal formulas
400 BC – Hippocrates (Greece) – “Father of Medicine”
300 BC – Theophrastus, Botanical Gardens in Athens
77 AD – Dioscorides, De Materia Medica
The use of plants as medicines dates to antiquity. We know from studying contemporary cultures that people following a hunter-gatherer lifestyle tend to develop a very good knowledge of the plants of their region and to learn through experimentation about many of the useful ones. The first written records of plant medicines date back to as long as 4500 years ago during the time of the Sumerian culture. The Code of Hammurabi mentions plants in a medicinal context, and the Egyptians became relatively sophisticated in the practices of traditional medicine, including the use of many plants. A Greek, Hippocrates, took a systematic approach to recording information about medical treatments, and is regarded as the Father of Medicine. Another Greek, Theophraastus, gathered together a large garden of plants in Athens, primarily ones with medicinal applications. The Romans were very pragmatic in their accomplishments, building a network of roads to unite their kingdom and establishing a standing army to keep the peace. Their interest in medicinal plants was driven by the wish to keep their troops healthy and in action. A Roman physician of Greek origin, Dioscorides, compiled a list of medicinal plants that was to serve for centuries as the ultimate word on herbal medicine.

11. History – Highlights II
1500 AD – Age of herbalism, Paracelsus – Doctrine of Signatures
Plants have been an important source of medicines. Recent innovations have seen the adoption of scientific approaches to medicine, and the ability of biochemists to synthesize and in some cases produce variant compounds that are better drugs compared to medicines formerly derived from plants. Most recently there has been a counter-culture movement back toward “traditional” approaches to medicine.

12. History – Highlights II
1500 AD – Age of herbalism, Paracelsus – Doctrine of Signatures
1775 AD – Dr. William Withering – Foxglove extracts
Plants have been an important source of medicines. Recent innovations have seen the adoption of scientific approaches to medicine, and the ability of biochemists to synthesize and in some cases produce variant compounds that are better drugs compared to medicines formerly derived from plants. Most recently there has been a counter-culture movement back toward “traditional” approaches to medicine.

13. History – Highlights II
1500 AD – Age of herbalism, Paracelsus – Doctrine of Signatures
1775 AD – Dr. William Withering – Foxglove extracts
1900 AD – Half of drugs in U.S. Pharmacopeia still derived directly from plants
Plants have been an important source of medicines. Recent innovations have seen the adoption of scientific approaches to medicine, and the ability of biochemists to synthesize and in some cases produce variant compounds that are better drugs compared to medicines formerly derived from plants. Most recently there has been a counter-culture movement back toward “traditional” approaches to medicine.

14. History – Highlights II
1500 AD – Age of herbalism, Paracelsus – Doctrine of Signatures
1775 AD – Dr. William Withering – Foxglove extracts
1900 AD – Half of drugs in U.S. Pharmacopeia still derived directly from plants
1900s – advent of “scientific medicine”
Plants have been an important source of medicines. Recent innovations have seen the adoption of scientific approaches to medicine, and the ability of biochemists to synthesize and in some cases produce variant compounds that are better drugs compared to medicines formerly derived from plants. Most recently there has been a counter-culture movement back toward “traditional” approaches to medicine.

15. History – Highlights II
1500 AD – Age of herbalism, Paracelsus – Doctrine of Signatures
1775 AD – Dr. William Withering – Foxglove extracts
1900 AD – Half of drugs in U.S. Pharmacopeia still derived directly from plants
1900s – advent of “scientific medicine”
2000 – Alternative medicine; concern for biodiversity
During the latter stages of the Medieval period, there was burst of interest in the application of plants in medicinal contexts. Some innovative ideas were developed that must be considered in the context of the time to be fully appreciated. One is the Doctrine of Signatures, enumerated by the famous herbalist Paracelsus among others. This held that, since everything was created by a Divine Being, and was created specifically for the use of people, then the creator would have left some sign as to how people were to use the plant – thus research into plants and their properties consisted of looking for the proper “sign” – a plant part shaped like a liver would indicate it would be good for heart disease; one shaped like a heart would be good for heart disease etc. The ultimate was a plant with parts shaped like an entire human body – this would cure everything and thus be a panacea, or cure-all (in fact the genus name for one such plant, the underground parts of which vaguely suggest the human form, is Panax, the common name is ginseng. In empirical practice, however, it was slowly determined that few plants lived up to their suggested structures. An important advance was made in 1775 when Dr. William Withering in Great Britain followed up on established folk medicine and showed that foxglove extracts were in fact effective in treating heart disease (this drug, digitalin, and ones similar in chemical structure to it are still utilized today). Plants have been an important source of medicines. Recent innovations have seen the adoption of scientific approaches to medicine, and the ability of biochemists to synthesize and in some cases produce variant compounds that are better drugs compared to medicines formerly derived from plants. Most recently there has been a counter-culture movement back toward “traditional” approaches to medicine.

16. Plant-Derived Medicines
Major Classes of Compounds:
Steroids
Plant-derived medicines include a variety of types of chemical compounds, but two classes of compounds, steroids and alkaloids, are particularly important.

17. Plant-Derived Medicines
Major Classes of Compounds:
Steroids
Alkaloids
Plant-derived medicines include a variety of types of chemical compounds, but two classes of compounds, steroids and alkaloids, are particularly important.

18. Plant-Derived Medicines
Major Classes of Compounds:
Steroids
Alkaloids
Useful terms:
“Secondary Compound”
“Glycoside”
Plant-derived medicines include a variety of types of chemical compounds, but two classes of compounds, steroids and alkaloids, are particularly important. Two terms that are frequently encountered when discussing compounds from plants listed. The term “secondary compound” dates from early biochemical investigations into the functioning of organisms. The compounds that were essential for a plant to function (e.g. chlorophyll, ATP, glucose) are termed “primary compounds”, and are found in all plants. Compounds that occur in some plants, but are not essential for function, are called secondary compounds. For many years biochemists considered many of these compounds to be metabolic byproducts or waste products – a convenient place for a plant, which is not capable of excretion, to put unneeded chemicals. Continuing studies have not documented uses, often defensive ones, for many of these compounds. A glycoside denotes any compound that has one or more sugars attached to it. As we have seen with cyanogenic glycosides and glucosinolates, attaching a sugar is a way to render a toxic compound innocuous, and the sugar can also help in the transport or storage of the compound within the plant.

19. Steroids - Chemistry
Fig. 11.5, p. 271

20. Steroids - Chemistry Fig. 11.5, p. 271
Steroids are organic compounds that include a specific type of basic structure that consists of 3 6-membered rings (e.g., containing 6 carbon atoms each) and a fourth ring that contains 5 carbons. Different steroids exist based on added chemical substituents at various positions of the molecule. For example, the structure of a common and important steroid, cholesterol, is shown. Cholesterol is produced only by animals.

21. Steroids - Chemistry
A wide variety of steroids occur in nature, and quite a number of them have important functions. For example, ergasterol (upper left) is the precursor to vitamin D. Cortisone (upper right) has significant anti-inflammatory effects in people, and anabolic steroids such as methandrostanolone (middle left) have been used and misused to help to add muscle tissue to athletes. Some steroids function in people as sex hormones, for instance testosterone (middle right) and beta-Oestradiol (bottom left)

22. Alkaloids - Chemistry
Organic compound, with N, usually in ring structure
Fig. 11.7, p. 272

23. Alkaloids - Chemistry
Organic compound, with N, usually in ring structure
Physiologically active on vertebrate nervous systems
Fig. 11.7, p. 272

24. Alkaloids - Chemistry
Organic compound, with N, usually in ring structure
Physiologically active on vertebrate nervous systems
 Diverse class of compounds
Fig. 11.7, p. 272

25. Alkaloids - Chemistry
Organic compound, with N, usually in ring structure
Physiologically active on vertebrate nervous systems
 Diverse class of compounds
Fig. 11.7, p. 272
Allkaloids are a large group of chemical compounds that are produced by various biochemical pathways. They are defined by relatively general properties, including their activities on vertebrate nervous systems. Plants produce a large number of alkaloids, many of which have important applications. Coniine and strychnine (upper left and lower right) are two highly poisonous compounds. Nicotine is one of the most poisonous chemicals known (we will discuss this compound in more detail later). Being poisonous can be a double-edged sword, however. Reserpine and vinblastine are two alkaloids that are poisonous in large quantities but have been determined to be highly effective medicines when used at the proper concentrations and conditions.

26. Examples of Plant Medicines
Fig , p. 276
1900 – over half of drugs in U.S. Pharmacopeia from plants
2001 – about 25% of drugs in U.S. Pharmacopeia from plants, but many synthetic compounds are based on plant-produced structures, or start with plant materials
Anasthetics, analgesics, heart medicines, laxatives, muscle relaxants etc.
At one time plants were a major source of medicines for doctors. That has changed as biochemistry and molecular biology have moved ahead, but even in 2001 about ¼ of the drugs listed as being efficaceous by the U.S. Pharmacopeia were derived from plants, and many more compounds that we now synthesize either start with plant materials or recreate a compound that was originally isolated from a plant.

27. Chaulmoogra Oil - Hydnocarpus
Leprosy – bacterial disease, affects sensitive individuals
Chaulmoogra oil – first effective treatment
Active ingredient – seed oil
Now replaced with antibiotics
Chaulmoogra oil is no longer used in medicine, but before the development of antibiotics it provided the first effective treatment to the disease called leprosy. Leprosy is a bacterial disease in which the cartilage of the victim is attacked and destroyed. The disfigurement that is produced is horrible – the nose and ears are made of cartilage, and the joints may also be slowly but progressively destroyed.
Fig. 11.8, p. 273

28. Malaria - Cinchona Fig. 11.9, p. 274 Malaria – caused by protozoan
Cinchona = “Jesuit’s Bark”
Malaria is the most widespread infectious disease in the world, and it causes millions of deaths each year as well as disabling disease in many more. The disease is caused by a protozoan (actually at least 4 different, related species) and it is spread by mosquitos. Control can be achieved by suppressing the mosquito vector, or by treating the disease medicinally. The medicine quinine was the first effective treatment, and it was obtained from extracting the bark of a shrub from the Andes Mountain region, Cinchona officinalis. The history of how the plant came to be used is a colorful one. It acquired the name “Jesuits Bark” because the missionaries of this Catholic Order were instrumental in learning about this plant from native American healers. Later, a prominent protestant politician in England, Oliver Cromwell, refused to take the medicine because of its association with the Jesuits, and he perished from malaria.

29. Cinchona - “bark of Peru”; ”yellow bark”
About 40 species - Andean area of South America
“Stolen” by British, Dutch
Although there are some 40 species in the genus, Cinchona officinalis is the only one that produces high levels of quinine. Because quinine was for a long time the only known, effective treatment against this terrible disease, it became a valuable commodity for the Andean countries, particularly Peru and Ecuador, where it was gathered from the wild. Later, the British and the Dutch, seeking a better source of the drug for their tropical colonies in Asia, arranged to smuggle seeds of the species out of Peru against this express wishes of the Peruvian government. The plantations that were established in the Far East from these seed sources lowered dramatically the price for quinine, to the benefit of poor Indian workers but to the extreme detriment to the economy of Peru. The European countries justified their illegal action on the basis that it served for the benefit of mankind.
Native
Grown

30. Salix - Aspirin
Hippocrates (Greece) – used willow bark to treat pain

31. Salix - Aspirin Hippocrates (Greece) – used willow bark to treat pain
1897 – Bayer Co. (Germany) Chemist – synthesizes, names aspirin

32. Salix - Aspirin Hippocrates (Greece) – used willow bark to treat pain
1897 – Bayer Co. (Germany) Chemist – synthesizes, names aspirin
The drug called aspirin has a long history, although not under this name. The famous Greek physician Hippocrates used an extract from willow bark to treat pain, and this formed part of the medicine kit of Europeans. Willow bark contains a compound called Salicin (from Salix, the genus of willows) which is mildly effective against pain. A similar compound, methyl salicylate, occurs in others plants, included the wintergreen. Either compound can be treated chemical to produce salicylic acid, and adding an additional acetyl group gives the compound called acetylsalicylic acid, which is even more effective as a pain medication than either natural product. A German chemist working for the Bayer Company developed the first commercial synthesis of this compound, and he proposed the name aspirin for it. Although originally a trade name, it became accepted as the common name for this compound. Aspirin is one of several compounds that are called non-steroidal antiinflammatory compounds (NSAIDs), which are highly useful in treating both pain and inflammation.

33. Dioscorea steroids
Wild Yam – convenient source for steroidal saponins which can be converted into synthetic hormones for use in contraceptives
Fig , p. 277
The species of yam have been found to be a convenient source for the starting material to synthesize the hormones which form the basis of chemical contraceptives (the “Pill”). Although chemists can synthesize many substances from simple starting compounds, the complicated structure of steroidal hormones has defied an economical solution. A chemist, George Rosenkranz, realized that the process of making human steroidal hormones such as progesterone could be reached using the chemicals produced by yams as a starting material. His ideas were initially rejected by the American company he was working for, and he ended up relocating to Mexico and starting a highly profitable industry there.

34. Papaver Alkaloids Fig. 11.6, p. 279
A chemically distinctive set of alkaloids, the papaverines, characterizes members of the poppy family, Papaveraceae. These compounds are highly effective in the treatment of pain, but they have also proven to be problematic because people become physiologically addicted to them, and care must be taken in treatment to avoid addiction. They are also problematic because they are abused. The compounds occur in a type of liquid called latex which is stored in special ducts called laticifers within parts of the poppy plants. Although they occur in various places, it is the developing fruit (“seed pod”) which is the commercial source for them. In the poppy plant these compounds occur in mixtures, and a crude preparation of these is called opium. A major and useful compound is morphine, which is highly effective in blocking pain. Chemists seeking to modify morphine with the goal of producing a more effective pain medicine were the first to synthesize heroin, which they named in the hope that it would prove to be a “heroic” drug. Unfortunately, heroin is even more highly addictive than morphine and is not used medicinally, but it has become a widely abused drug. Codeine is another opiate, that has only a slight chemical difference from either morphine or heroin (note the substituent on the upper left in each molecule - hydroxy in morphine; acetyl in heroine; methyl in codeine), and it is both less effective in treating pain than morphine (but still quite effective) and also less addictive (but still addictive). The Papaver alkaloids have been both a great benefit and a scourge to people.

35. Catharanthus – poster child for plant-derived medicines
Fig , p. 282
Effective drugs vs. lymphomas (Hodgkin’s disease)
A real success story in modern medicine is provided by the development of effective anticancer drugs from the tropical plant Madagascar Periwinkle – Catharanthus roseus. This plant, endemic to Madagascar, has provided a pair of chemically similar drugs which effectively treat a type of cancer of the lymph system called Hodgkin’s disease. The chemical structure of these compounds is relatively complicated, and provides an example where plants are capable of syntheses that still challenge biochemists. The prospect that other tropical plants may sequester compounds that are effective in treating human diseases is a convincing and widely cited argument for preservation of our native biota. Because of the huge amounts of money that can be made (drug companies are always on the lookout for diseases such as cancers that afflict relatively wealthy people who live long enough to be at high risk of acquiring them, and are willing to pay large amounts for their health), considerable effort has been spent on “bioprospecting” – searching for new drugs in tropical areas.

36. average to develop a new drug in U.S. - $231 million/12 years
New Drug Development
average to develop a new drug in U.S. - $231 million/12 years
-> many not developed, if patent protection not available, or if market not assured
Comparison:
Germany - "reasonable certainty" of safety and effectiveness
U.S "absolute proof"
-> some modern herbal preparations coming from Europe, sold as dietary supplements in U.S.
Examples: St. John's Wort, Echinacea, Gingko
The development of new drug products is not, however, either cheap or easy. There are hundreds of thousands of plants that could be screen, each potentially containing many chemicals, and the process of screening these for effectiveness against human diseases is a daunting task. One shortcut is to look to folk medicine for plants that may be particularly promising as medicines. In some cases, however, this is not productive for commercial uses because patent protection may not be available if a use has already been established. A few standard screens have been developed, but the process is arduous and compounds may be overlooked for a variety of reasons. Once a promising drug is developed, there is still a long and expensive process to bring it to market. This is particularly difficult in the U.S. where there must be absolute proof that it is both (1) safe and (2) effective as a treatment. A number of plant products that seem promising have not been developed as medicines, and they are often sold as herbal supplements, rather than as medicines. These include items such as St. John’s Wort (for depression), Echinacea (to treat the common cold) and Ginkgo (to boost the memory). Without a company to pay for it, testing the plants for effectiveness has been slow, but recently studies have been released that cast doubts on whether any of these are really effective in their purported uses.

37. Looking for new drugs - General parameters:
1 in 10,000 chemicals screened -> new drug product
Development of new drug in U.S years/$231 million (average)
Many drugs/diseases - not pursued because of lack of profitability
A variety of factors come together to make the search for new drugs a difficult undertaking. On average, only a few of the many chemicals extracted from plants will be the source of a new drug. A company wishing to play in this game must have deep pockets, because it takes many years and lots of investment to bring the possibility of a profit. Many drugs and many diseases are not pursued because they may not have the potential to ever be profitable.

38. Development of Phy 906 – Phytoceutica Herbal medicine
Based on Chinese Traditional Medicine
Mixture of herbs: scutellaria (skullcap), glycyrrhiza (licorice), ziziphus (jujube), Paeonia (peony)
Application: treat nausea and pain associated with cancer chemotherapy regimes
Initial results: not only effective against side effects, but also appears to increase efficacy of chemotherapy for certain cancers
A potential new approach to screening and developing medications is exemplified by the development of an adjunct to chemotherapy called Phy The start-up company, Phytoceutica, utilized traditional Chinese herbal medicine as an inspiration to search for medically useful compounds. They have developed a preparation made from a combination of 4 herbs that appears to have the potential to treat symptoms such as nausea and pain that are side effects of anti-cancer chemotherapies. Their initial results suggest that, in addition to be effective for the side effects, the preparation may also increase the efficacy of the main treatment through two routes: (1) higher levels of the anti-cancer drug may be used because the side effects are tolerated; (2) physiological differences induced by the herbal treatment increase the effectiveness of the chemotherapy in eliminating cancer cells. The company is applying modern technologies, including advanced types of chromatography as well as gene chips, to monitor the quality of the preparation and its physiological effects.

39. Problems in Development of Rain Forest Drugs International Agreements
(1) Discovery
- by pharmaceutical companies
- preceded by traditional healers
Who discovered/Who should benefit financially?
(2) Ownership - seeds, genes, chemicals
cycle:
Gene poor country, has scientific expertise
-> Gene rich country, has genetic diversity but lacks science
-> development of chemical by gene poor country
-> now sell back to gene rich/economically poor country
In addition to the scientific and economic challenges, development of new drugs from tropical plants also brings in a host of political and ethical issues.

40. Tuesday Lecture – Psychoactive and Poisonous Plants
Reading: Textbook, Chapter 12
In the next lecture we will take up discussion of plants that have psychoactive effects on people; these are all poisonous in large amounts. We will extend our discussion to consider a few other plants that are poisonous.