Medicinal Plants

Outline• Medicine in pre-scientific times

• Synthetic organic chemistry and medicine

• Alkaloids

• glycosides

• Foxglove (digoxin)

• Willow bark (aspirin)

• quinine

• Ephidrine

• Schizophrenia and resperine

• cancer treatment

• Chapter 19

Plants in Medicine• The idea of using plants for healing goes back to

very ancient prehistoric times in all cultures. – Neanderthal burial with useful medical plants from

60,000 years ago. Shanidar Cave in Iraq. Buried with 8 plant species, 7 of which have medicinal uses. (I note that skepticism is needed here: some researchers now think these plants (clumps of pollen, actually) were buried there by rodents long after the person died.)

– Otzi the Iceman, who died about 5200 years ago and was preserved in a glacier in northern Italy, carried two lumps of birch fungus, which can be used as both a laxative and an antibiotic. He had intestinal parasites.

– Some animals also seem to use plants as medicine

• Basic problem with archeological evidence: plant material decays easily, especially if it is edible.

Medicine in Early Civilizations

• Sumerian clay tablets with cures

• Egypt: Ebers papyrus (3500 years ago)

• Shen-nung, the Chinese emperor who also invented agriculture, wrote a book about medicinal herbs, which he tested on himself.

• Rig-veda in India

• Badianus manuscript is an illustrated guide to pre-Columbian Aztec herbal medicine. Translated into Spanish from native language by Badianus, but written by an Aztec healer of high repute.

• Hippocrates (400 BC) : ancient Greek healer. Medical doctors take the Hippocratic Oath. Western medicine was founded on his works.

• Dioscorides (100 AD) was a Roman who compiled De Materia Medica, which discusses 600 plants of medicinal value.

• Galen

• Avicenna (1050 AD) was a Persian whose Canon of Medicine built on Dioscorides’s work.

Herbals• The Renaissance in Europe was a revival of ancient

learning and intellectual activity, a turning away from uncritical acceptance of the Bible as the source of all knowledge. Roughly 1300-1650, starting in Italy and varying by region. The period between medieval times and modern times.

• Invention of the moveable type printing press in 1450 allowed wide dissemination of knowledge.

– A word for you (that won’t be on the test): incunabula: a book published before 1500.

• Many herbals, illustrated books describing plants and their uses, were published. Practical uses together with a lot of mysticism, superstition, and what we now consider pseudoscience: astrology for example.

• Doctors and other healers had gardens where they grew useful plants. Others were harvested from the wild.

Doctrine of Signatures• The Doctrine of Signatures (which is known to be false!) was popular in

these books: herbs that resemble parts of the body can be used to heal those parts.

– Liverwort, lungwort, bloodroot, snakeroot (healing snakebite), for example.

– Advocated by Paracelsus (1500 AD). But, the idea is found in many cultures.

• The idea: Since God created the world for us humans, He marked things with a sign (a signature) indicating their use.

– Also linked to this: the idea that the cure for every disease can be found near where the disease is common.

• The history of science is filled with counter-examples. We have to figure out the uses of plants and other objects by experiment and observation. How a plant looks is not related to how it will interact with the human body.

– That is, sometimes there is a correlation between how a plant looks and how it is used, but it isn’t a causal relationship. That is, you might find a plant useful for some purpose and then find an aspect of its appearance that helps you remember that use, but if you see a plant that you think resembles some part of the body, it probably won’t specifically affect that body part.

– You can think of the Doctrine of Signatures as a useful mnemonic device, but it isn’t a guide to how novel plants will work.

Some Examples

Hepatica leaves have 3 lobes,just like the liver

Snakeroot

Walnut: looks sort of likea brain!

Tomatoes are red and havefour chambers, just like the heart.

lungwort

Pre-Scientific Medicine• Across all cultures, healing the body was very mixed up with religious

belief. In the absence of an effective cure, prayer seemed like the only solution.

– It wasn’t clear what worked and what didn’t. Medicine was based on anecdotal evidence: I as a doctor tried such-and-such a cure, and it worked or it didn’t, and I change my opinions about what to use in a given situation based on this.

– Also, written works passed down from the ancients (such as Hippocrates) were given great weight.

• This led to medicinal recipes with many ingredients, most of which had no effect.

– And some of which were there just to produce drama: many patients felt that an effective cure had to make them vomit or otherwise go through an unpleasant physical experience to start the healing process.

• Many people get better from good nursing: keeping them warm and well fed and rested, and paying attention to their complaints. The body has great power to heal itself if given a chance.

– This led to medicines being given credit for cures they didn’t deserve.

Systems of Medicine• Our present system, scientific medicine, is only 200 years

old or so. There have been many other concepts in medicine, and there continue to be alternative systems of medicine. These other systems often contain concepts that are specifically denied or disproved by science.

• Hippocrates and the Four Humors: blood, phlegm, black bile, and yellow bile. The humors have properties of hot, cold, wet and dry. In disease, the humors get out of balance. The theory formed the basis of Western medicine until the 1850’s or so.

– We get words for personality traits like sanguine, phlegmatic, choleric, and bilious from this theory.

– This theory also encompasses the idea of the four elements: earth, air, fire, and water.

• Traditional Chinese medicine and Ayurveda (traditional Indian medicine) are also alternative theories of medicine that remain popular.

• Francis Bacon, an early scientific philosopher, said. ‘This is the foundation of all. We are not to imagine or suppose, but to discover, what nature does or may be made to do”.

Scientific Testing• The essence of the scientific method is the controlled

experiment: the subjects are divided into two groups, with one group given the experimental treatment and the other given a control treatment.

– The control treatment should be as similar to the experimental as possible, just missing the one element being tested.

– A useful refinement: double-blind experiments, where neither the patients nor the doctor knows who is getting the experimental treatment and who is getting the control. This avoids the placebo effect, where patients often get better even with a control treatment.

• Statistical analysis of the results is necessary, because random factors influence the results. An important feature of statistics: using enough subjects to get statistically significant results.

• Animal models for the disease are very useful: you can do more experiments without upsetting patients and their families.

– More recently, tissue culture cells and even simpler model systems can sometimes be used.

Statistical Analysis• Allows decision making based on math and not just speculation.

– A major fallacy that statistics is designed to reduce is basing conclusions on anecdotal evidence (one or a small number of observations that occurred to someone you know). Your brother-in-law’s cousin won the lottery while wearing a rabbit’s foot, so you now go out and get a rabbit’s foot too.

• common things to calculate from the data: mean (the average) and standard deviation.

– Many results fall into a bell-shaped curve. Standard deviation is the width of the curve: the points on the curve where 2/3 of all observations fall between. For example: a group of men has average (mean) height of 176 cm plus or minus 10 cm (176 10) means 2/3 of everyone was between 166 and 186 cm.

• Conclusions based on statistics take both the mean and the standard deviation into account: how much do the two groups overlap?

Active Principles

• A big idea from the early 1800’s: The reason that certain plants are effective against particular diseases is because they contain specific chemical compounds (the active principles) , with the rest of the plant material irrelevant.

– If you isolate (or synthesize) the active principle, you can control the dosage people are given and avoid giving them other plant compounds that might have bad side effects.

– In contrast, the amount a plant contains can vary with environmental conditions, age of the plant, the plant’s genetics, and many other factors.

– Also, it is possible to determine whether a given plant is actually effective, or which parts of mixtures are important.

• This concept led to people trying to extract the active principles from plants. For instance: which works better, soaking the plant material in cold water, hot water, alcohol, etc.? Which part of the plant produces the most active principle?

– Lots of help from alchemy, the precursor to modern chemistry.

Organic Chemistry• It was once thought that "organic" chemical compounds could only be

made by living organism: that's what "organic" means.

• The doctrine of Vitalism, which is now thought to be false: living organisms and their components are endowed with a "vital force" that is separate from their chemical reactions.– Nowadays we think of life as just a set of complex chemical reactions. I

wish to note, however, that so far no one has been able to create life in the laboratory.

• In 1828, Friedrich Wöhler synthesized urea (waste product from nitrogen in protein) from inorganic compounds. Followed by many others. Vitalism loses vitality: "The great tragedy of science, the slaying of a beautiful hypothesis by an ugly fact.", to quote Wöhler.

• We now believe that any chemical compound found in living organisms can be synthesized in the laboratory from simple precursors.– We don't necessarily know how to create some of the more complicated one,

but it isn't considered impossible.

• Organic compounds now just mean those containing carbon. A few exceptions like carbon dioxide are mostly for historical reasons.

More Organic Chemistry• Another big event: mauve dye synthesized accidentally,

while trying to make quinine. It's a big seller: suddenly there's money to be made in organic chemistry.

• In 1863, Friedrich Kekule describes how carbon bonds with other atoms: the structure of organic compounds becomes clear.– His breakthrough idea, how the 6 carbons in benzene link

into a ring, came to him in a dream.

• Synthesis in multiple step processes, separation techniques, analytical methods, lots of chance findings.

• Germany was the leader in this field.

• How this relates to medicinal plants: You can modify the structure of useful chemical compounds and sometimes make them more effective, or have fewer side effects, or more stable during storage, or other useful properties.

Medicinal Chemistry• The effect of organic chemistry and the scientific method:

useful compounds are still isolated from plants: taxol is a recent example. However, once isolated, attempts are made to synthesize them and modify them. – This helps avoid the supply of the plant from being cut off due

to disease or political or economic reasons.

– The Germans pioneered this philosophy of self-sufficiency in the 1800’s because they had poor access to the ocean trade routes and very few overseas colonies.

– Also, synthesizing an active principle from scratch proves that you really do understand its structure.

• It is worth considering whether the healing effect of a plant is due solely to a single active compound, with all others irrelevant. There are many cases where several compounds acted synergistically. And, healing is also helped by the placebo effect and also by careful individual attention from a healer. We are not just biological machines that respond uniformly to impersonal treatment.

Drug Discovery• Where do new medicinal drugs come from?

• More precisely: where do drug families come from, since once a useful pharmaceutical drug has been discovered, it gets modified in thousands of ways by chemists trying to improve it.

• In the past, two sources: compounds suggested by traditional herbal medicine, and serendipitous (random chance) discoveries.

• Today, rational drug design is becoming important: understanding of how the disease works and where it might be intervened with, coupled with knowledge of the physical structure of enzymes involved allows the design of completely new drug molecules.

• Also, combinatorial chemistry: start with a useful compound, make a large library of modified versions, then test them all against a target.

• The whole process of discovering and testing a new drug is very expensive and laborious: let's say $1 billion and 10 years to get from discovering a new drug to getting it on the market.

Active Principles in Plants• The value of plants as medicine come from specific chemical compounds

they contain. These compounds are secondary metabolites: not directly related to the plant’s ability to grow or reproduce.

• Secondary metabolites are probably present as a defense against infection by bacteria or fungi, or to prevent insects and other animals from eating them.– Some secondary metabolites inhibit other plant species: they poison the soil.

– Also, some are used to attract animals to help with pollination and seed dispersal: the scents of fruits and flowers, for example.

• Different species produce different secondary metabolites. Within plant families, the secondary metabolites are similar. For instance, the carrot family and mustard family.

• A 2001 study counted 122 compounds used in medicine that were derived from traditional herbal medicine. Of these, 80% were used for the purpose the herbalists said they were good for. Traditional herbal medicine is a very useful starting point for drug discovery. – It is thought that about 10,000 different plants have been used in herbal medicine

at some point in human history.

Major Groups of Secondary Metabolites

• Alkaloids. Many different compounds, found in many plants. They all contain nitrogen atoms, are alkaline (basic), and taste bitter. Structures vary widely.– Often affect the nervous system. Whether this is good or bad depends on

dosage and your point of view. For example, morphine.

• Glycosides. A sugar is attached to the active component. This makes them non-toxic until an enzyme removes the sugar, which happens in the digestive system.– Cyanogenic. Very simple: cyanide attached to a sugar. Remove the sugar

and release the poison: it stops the ability to make ATP.

– Steroid. Steroids have a particular ring structure and are used to make hormones in animals. Two main types:

• cardioactive (meaning that they affect your heart).

• Saponins are soapy and very toxic: they work especially well as fish poisons because they dissolve easily in water. The steroid found in yams (Dioscorea) is a saponin.

• ss

Some Glycosides

Malaria• Malaria is a disease native to Africa. It has probably evolved with

us for a very long time: closely related diseases affect chimpanzees, gorillas, and other mammals.

• Malaria is thought to killed more people than any other infectious disease. It kills between 1 and 3 million people a year, mostly young children in sub-Saharan Africa. – It is widespread in the tropics throughout the world, and it can be

found in temperate areas as well.

• Many Southern cities used to empty out in the summer as anyone with sufficient resources would leave town to avoid malaria, going to hill country or the seashore.

• Large effects on war. More soldiers died of disease (often malaria) than by violence until modern times. Nomads had less malaria than city dwellers, which gave them a big advantage.

• After malaria came to the New World, Native Americans had no resistance and many died of it. In contrast, Africans often had resistance, so they worked better as slaves.

Malaria Cases in 1996

Malaria as a Disease• The disease is caused by a single celled eukaryotic parasite

called Plasmodium falciparum, plus a few closely related species of Plasmodium. The parasites are highly adapted to humans and have several ways of evading the immune system and remaining dormant.

• The disease itself is cyclical: first you get chills, then a fever, then fever with sweats (cold-dry, hot-dry, hot-wet). Then, a feeling of complete exhaustion. At this point you either die or fall asleep for a while and wake up refreshed. Then the cycle starts again, with a 2-3 day period.

– The parasites live in red blood cells, and when they rupture the cells, the victim gets anemia and a heavy dose of toxic hemoglobin derivatives.

• Malaria can be a chronic recurring disease: many people never get rid of it, and it can start up again at any time.

• Other symptoms include severe headaches caused by intracranial pressure, renal failure (blackwater fever), anemia, enlarged spleen and enlarged liver.

Malaria and Mosquitoes• Malaria has long been associated with swamps. The

word “malaria” means “bad air” is Italian: it was thought that the disease was caused by the poisonous vapors of the stagnant water and rotting vegetation. This theory goes back to Hippocrates.

– Called ague in other places: mentioned several places in Shakespeare.

• In the 1850’s it was recognized that malaria was caused by a parasite spread by mosquitoes.

• An amusing wrong turn: in 1878, a bacterium was alleged to be the cause of malaria (the Germ Theory of Disease as the answer to all problems). The problem with this: bacteria are much easier to kill than eukaryotic parasites because as prokaryotes, the metabolism of bacteria differ in major ways from that of eukaryotes.

• The actual life cycle of the parasite was worked out n the late 1800’s and early 1900’s.

Malaria Life Cycle• The Plasmodium parasite needs to be in three

different locations to complete its life cycle. It undergoes several changes of form during the process.– Human liver. Shortly after the mosquito injects the

parasites, they migrate to the liver. Some of the parasites can remain dormant in liver cells for months or years, periodically releasing the next stage of parasites into the blood and causing a relapse of disease symptoms.

– Human red blood cells. After multiplying and changing their form in the liver, the parasites move into the red blood cells. They multiply and burst the blood cells, causing the disease symptoms.

– Mosquito’s gut. After a mosquito ingests infected blood, the parasites undergo sexual reproduction in its gut, and the resulting parasites migrate to the salivary gland.

– The cycle repeats when the mosquito bites a new host.

Malaria Prevention

• The most effective way to eliminate malaria has been to eliminate the mosquitoes that carry the parasite.

– Eliminating swamps and stagnant water has historically been the most effective method.

– The insecticide DDT was used very effectively from the 1940’s to the 1970’s. Unfortunately it is quite persistent in the environment and toxic to birds and other animals. Its used was banned for most purposes.

– Similarly, spraying stagnant water with kerosene was effective for control, but it kills the fish.

• Sleeping under insecticide-treated mosquito nets can be quite effective.

• Very little malaria in the US or Europe any more due to effective mosquito control measures.

Genetic Resistance to Malaria• Natural selection for malaria resistance has caused

the spread of several human genetic conditions that affect red blood cells.

– These conditions are otherwise very harmful.

• Sickle cell anemia is an alteration of hemoglobin that causes it to crystallize into long rods when oxygen gets low (while exercising, for example). This causes the blood cells to get distorted and kills the parasites. The mutation seems to have arisen at least 4 times independently in different parts of Africa, and once in India.

• Other hemoglobin diseases, called thallassemias, also protect against malaria. There are many forms, found in the Mediterranean region all the way across Asia to Indonesia.

• Several other diseases affecting the red blood cells also confer some malaria resistance and are found in the malaria belt.

Quinine• Quinine is an alkaloid found in the bark of the cinchona tree,

which grows in the Andes Mountains, mostly in Peru. It was used to reduce fever by the native peoples. 1630’s.

– The tree was named after the Countess of Chinchon by Linnaeus (who accidentally left out an h). She was the first known European user of the bark as a malaria treatment.. All other treatments had failed, so her physician decided to try a medicine obtained from local healers. (This story may be less than historically accurate).

• Quinine kills the malaria parasites in the blood. Since the parasites also live in the liver, quinine must be taken daily to prevent a relapse of the disease.

• The supply was controlled by Jesuit priests for a long time, and so the medicine was known as “Jesuit’s bark”.

– It worked very well in many cases, unlike all other malaria cures.

– However, some bark worked better than others, due to concentration differences n quinine. High altitude trees produced much more than sea level trees.

– Oliver Cromwell, an English revolutionary in the 1600’s, died of malaria rather than use a product associated with the Roman Catholics he hated.

More Quinine• Gathering the bark kills the trees, so demand started to far

outstrip supply. Quite expensive, and headed for extinction.

• In 1860, the British started growing cinchona in India and Sri Lanka (after stealing the seeds). Spread to Dutch Indonesia also.

• Quinine is quite bitter, which led to the development of the mixed drink the gin-and-tonic. This drink was developed by the British army in India during the 1700’s. It is used to flavor and dilute the alcohol in gin, and make its administration much more pleasant. Tonic water was originally a mixture of quinine and carbonated water, with sweeteners added to ease the bitterness. The juniper berry taste of gin complements the bitterness of the quinine.

• Cheap and plentiful quinine from India allowed Indians, Chinese, and Europeans to live many places they hadn’t beforehand.

Distribution of the 20 millionIndians living outside India

New World Quinine vs. Old World Malaria

• The oddity here: the cure for a disease was in a plant that didn’t grow anywhere near where the disease was. Is this just a chance event? What is the natural selection (scientific) reason why quinine existed in that bark? Just a general plant defense mechanism: it tastes bad? Is it just chance that it happened to fit a human problem very neatly? What did the American native people use it for, and why does it work for that, or why did they think it did?

– What about the possibility that malaria existed in the New World before Columbus? Evidence against it: no natural genetic resistance, with lots of it in the Old World. Also, Aztec and Mayan records don’t describe the disease in a way that anyone has been able to recognize.

– Used it for fever and a muscle relaxant

– The old doctrine that every disease has its cure somewhere in the vicinity. Probably comes from some ancient healer like Hippocrates or Galen. But, there is no reason to think its true. It describes a Universe that is set up for our purposes. In the world of Science, we don’t consider that a valid concept.

• There are undoubtedly many medically useful compounds in plants that have not been discovered yet: a good reason to maintain biodiversity.

Artemisinin

• Many anti-malarial drugs have been developed. Artemisinin is the active principle in the plant Artemisia annua (wormwood). This plant has been used in traditional Chinese medicine to treat fevers.– In the 1960’s, Chinese scientists tested 200

traditional medicines that had been used to treat malaria. Only this one worked.

– It also works against other blood parasites such as schistosomes (blood flukes).

• The drug has been modified by organic chemists to make it more stable and usable by the human metabolic system.

• Current work on malaria includes much effort to develop a vaccine. Unfortunately, the parasite is very good at evading the immune system.

Aspirin• Today, aspirin is probably the most widely used synthetic

drug. However, it originated in the plant world.

• The inner bark of willow trees, made into a tea, has been used for relief of pain, fever, and inflammation since ancient times. Hippocrates discussed in ancient Greece, and it is also mentioned in medical works from ancient Sumerian city of Ur in 3000 BC. Native American tribes also used it.

• The active ingredient in willow bark is salicylic acid. It is a plant hormone: it is released when the plant is wounded, and stimulates the cells to strengthen their cell walls and produce enzymes and other compounds to fight the infection.

– It also gets converted to a volatile form, methyl salicylate (which is Oil of Wintergreen). This compound induces pathogen defense mechanisms in nearby plants.

• Salicylic acid was extracted from willow bark in the early 1800’s.

More Aspirin• Salicylic acid is very irritating. It gets used today as a wart

remover! In low concentrations, it is used to exfoliate the skin (remove dead cells) and unclog pores. It also was very hard on the stomach, which limited its usefulness. However, salicylic acid was used as a painkiller in the middle 1800’s.

• In the 1890’s, chemists at Bayer Laboratories in Germany developed a derivative, acetyl salicylic acid, that was less harsh.

• It was marketed as aspirin.

• During World War 1, the Bayer patent on aspirin was voided in Britain, and “aspirin” became a term anyone could legally use.

• After the US entered World War 1, all of Bayer’s property was auctioned off, including even the name “Bayer Aspirin”. The Bayer company survived in Germany, and in 1994, they bought back the US rights to their own name for $1 billion.

How Aspirin Works

• Aspirin reduces the production of prostaglandins, by inhibiting the enzyme cyclooxygenase (COX). COX converts the fatty acid arachidonic acid into prostaglandins.

• Prostaglandins are molecules that act as local hormones, transmitting signals between cells. They are released from injured cells. They sensitize pain nerves so fire more easily, meaning that you feel more pain.

• They also raise the body’s internal temperature.

• Aspirin also inhibits blood clotting. It is often used in low doses to prevent heart attacks.

COX-2 Inhibitors• There are 2 forms of COX. Aspirin inhibits both of

them. But newer drugs inhibit just COX-2.

• COX-1 produces prostaglandins in the digestive system that protect it, while COX-2 produces prostaglandins responsible for pain and inflammation. Aspirin’s well known properties as a stomach irritant are due to its inhibiting COX-1 in addition to COX-2.

• Drugs inhibiting COX-2 only have been found. Vioxx and Celebrex became very popular drugs for treating arthritis and chronic pain. They are much easier on the stomach than aspirin is. However, they seem to cause an increase in blood clots and heart attacks. In light of this, Vioxx was taken off the market and use of Celebrex is greatly decreased.

Foxglove and Dropsy

• Foxglove (Digitalis purpurea) is an Old World plant, found in much of Europe, western Asia and northern Africa. It is a biennial. In the first year it makes a rosette of leaves close to the ground, and in the second year is grows a tall flower stalk. It is a common ornamental garden flower. All parts of it are quite poisonous!

– Long a part of many herbal cures

• Congestive heart failure (called dropsy in the old days) is a condition where the heart can’t pump enough blood to satisfy the body’s needs. It is a slowly progressing condition, not a sudden stopping of the heart.

– Symptoms: swelling of feet, ankles, and lungs due to fluid buildup, shortness of breath, general tiredness.

– Retention of fluid is called edema.

– Problem is, the heart can’t push the blood through the kidneys with enough force to get them to work properly in excreting all the water.

Digitalis as Herbal Medicine• William Withering was an English doctor in the 1700’s. He also wrote a book

about English plants. – Withering hated botany in college, but he fell in love with a woman who liked to paint flowers, and

while collecting them for her he became devoted to botany.

• He had a patient with very bad dropsy, who he expected to die within days. A few weeks later he returned, and she was alive and much healthier. He learned that she had used an herbal recipe “kept secret by an old woman in Shropshire” . It was very effective in relieving the symptoms of dropsy.

• There were 20 or more components to the recipe, but, after paying the herbalist a good sum of money, learned that foxglove was the important one.

– Other ingredients were present to induce vomiting and other side effects, which proved to the patient how strong the medicine was.

• He spent 10 years researching which part of the plant was most effective, when to harvest it, how to extract it, and what the optimum dose was.

• Previous dropsy treatment: puncture the tissues with a (non-sterile) scalpel, then stretch the patient over bedsprings and collect the fluid in buckets.

• Some doctors didn’t approve of foxglove as a treatment, since it had its origins in witchcraft. Also, many cases of overdose occurred (if a little bit is good, then a lot must be better!). Also, it didn’t cure other diseases that herbalists alleged it was good for

Digoxin

• The active chemical compounds in foxglove were isolated in the early 1900’s. They are several steroid glycosides, with the most active one being digoxin. It is still used in treating congestive heart failure.

• Digoxin increases the pumping force of the heart muscles. Too much can lead to a heart attack.

• Heart disease is the leading cause of death in the US. Dropsy was very common 200 years ago, but it is easily treated today.

Coumarin and Blood Clotting• Coumarin is a chemical compound that produces the smell of

freshly mown grass. It is used in the perfume industry, as a substitute for vanilla, and as a flavoring agent for tobacco.

• Coumarin can be converted into a powerful anti-coagulant by enzymes found in fungi.– The blood doesn’t clot, causing the victim to bleed to death.

• Origin: In the 1920’s, cows at Wisconsin dairy farms started bleeding to death after de-horning or castration, and some just spontaneously. A little observation showed that it occurred after that had eaten hay that had been made from sweet clover and was moldy. Non-moldy hay had no effect.

• Chemists at the University of Wisconsin developed an assay for blood clotting using rabbits, and after several years of effort, they isolated the active compound.

More Coumarin• Clover makes good silage: cows like the

way it tastes. Care must be taken to prevent fungal infection, which converts the sweet-smelling coumarin to the anti-coagulant dicoumarol.

• It proved to be useful for preventing blood clots, which can kill by blocking blood circulation in the heart or brain.

• Once dicoumarol was isolated, various chemical modifications were tried, and soon a much stronger one, warfarin, was created.

– Named for the Wisconsin Alumni research Foundation (WARF).

• Warfarin interferes with vitamin K, which is needed for blood clotting. The antidote to warfarin is large doses of vitamin K.

Warfarin• Warfarin is primarily used as rat poison. It is odorless

and tasteless, so rats will eat it when mixed with food. It usually takes several feedings to build up a lethal dose, so the rats don’t associate it with the food.

– Mice and rats are bad to have around. They eat and contaminate our food. They spread salmonella and other diseases through their feces, which get everywhere in an infested house. They gnaw wires, pipes and wooden structures. The fleas on rats carried (and in some places still carry) bubonic plague.

– By now, mice and rats have a lot of resistance to warfarin, so its use is declining.

• There is a theory that Jozef Stalin was killed by his successor Nikita Khrushchev using warfarin in 1953. Stalin was the head of the Communist Party in the Soviet Union, which made him the absolute ruler of that country,

– I find this a bit ironic: “a discrepancy between the expected result and actual results when enlivened by perverse appropriateness.”.

Ephedrine• Ephedrine is a stimulant and nasal decongestant. It is

chemically similar to amphetamines. It is an alkaloid derived from plants in the genus Ephedra, which (unlike almost all other plants we are examining) is a gymnosperm.

• It has long been used in traditional Chinese medicine to treat asthma and bronchitis.

• In sports, ephedrine is considered a performance-enhancing drug and is banned.

– A big reason why ephedrine is regulated: Baltimore Orioles pitcher Steve Bechler died in 2003 with ephedrine toxicity playing a “significant role”. He died of a heatstroke at the beginning of spring training in the hot weather of south Florida.

• The illegal dugs methamphetamine and MDMA (Ecstasy) can be made relatively easily from ephedrine and its close mimic pseudoephedrine (also found in plants). For this reason, most states regulate the amount you can buy.

– In Illinois you are required to show identification, give them your address, and you can only but 1 package a day.

Reserpine and Schizophrenia

• Snakeroot is the common name of several unrelated plants with long coiled roots. It fits the Doctrine of Signatures quite well, and so it has been used to treat snakebite in several different cultures.

• We are concerned here with Rauwolfia serpentina, the snakeroot that grows in India. It is also used in traditional Chinese medicine, and was discovered by the semi-legendary emperor Shen Nung. It was used as a general poison antidote, and as a tranquilizer and cure for insanity.

• In the 1950’s, the alkaloid reserpine was isolated from snakeroot. It acts as a sedative, and was used as a treatment for schizophrenia. It also lowered blood pressure

• Today, resperine is mostly used to combat high blood pressure. It causes the blood vessels to relax. However, other drugs have taken its place. Hypertension is a major medical issue, so much scientific effort goes into finding drugs to control it effectively. The sedative effects of reserpine are a strongly negative side effect for this use.

Schizophrenia

• About 1% of the US population has some form of schizophrenia. Most develop it between ages 16 and 30, and only rarely after age 45. It can be hard to recognize in younger people.

• “lose touch with reality”: – hallucinations (seeing or hearing things that aren’t there). Voices telling

you what to do, invisible fingers touching you, smelling odors no one else can detect. Hearing voices is the most common symptom.

– Delusions: false beliefs that cannot be changed by facts (especially if they are not common in your culture). People of television are speaking directly to you, radio waves are controlling your behavior, belief that you are a famous historical figure (like Napoleon), belief that others are plotting against you or trying to harm you.

– Movement disorders: agitated body movements, repeating the same motions over and over, walking oddly.

– “flat affect”: your face shows no emotion and you talk in a dull monotone

– Inability to plan, or sustain planned activities, or make decisions.

– inability to interact with others properly: speech is disconnected and makes no sense to others.

What Causes Schizophrenia?

• The actual cause isn’t clear, but both genetics and the environment play a role.

– Genetics: it “runs in families”. The risk in the general population is 1%, but it’s 10% if a sibling or parent has it, and 50% if an identical twin has it. However, no specific gene is known to cause schizophrenia, despite serious efforts to find one. It is a “complex genetic trait”: probably many genes contribute small amounts to your risk.

– Environment: possibly virus exposure or malnutrition before birth play a role (but no specific viruses have been identified). Trauma: child abuse and neglect seems to play a significant role in the development of some schizophrenia. Post-traumatic stress disorder and other adult traumas may also play a role. Hallucinogenic drugs such as LSD can trigger schizophrenia in people who are pre-disposed to get it.

– Marijuana use is high among schizophrenics, and tobacco use is also far above the general population, but this may be the result of self-medication and not causation. But, marijuana may increase the risk.

• No obvious differences in brain structure associated with schizophrenia. It is strictly a mental illness.

Treatment• Old days: jail, insane asylum, being treated as a witch or possessed by demons. Or,

occasionally treated as a saint communicating with God. • Pyschosurgery. The lobotomy involved destroying part of the frontal lobes of the

brain. It became very popular in the 1940’s, but in the 1950’s, psychoactive drugs were shown to be more effective and less damaging.

• Electroconvulsive therapy. Mostly used for chronic depression today.• Drug treatment. First generation drugs included reserpine and thorazine. Newer

drugs target the dopamine system in the brain.– They have some side effects like drowsiness and dizziness. Also, major weight gain and

an increased risk of diabetes.

– Long term use can result in “tardive dyskinesia”, which is uncontrollable muscle movements.

– If you stop taking the medication abruptly, relapse can occur. Many people stop taking them because they feel better and the side effects get intolerable. Drug treatment may need to be lifelong.

– Different people respond to different drugs in different ways: it is necessary to try several out to find the best one.

• Behavioral treatment: it is possible to develop mental skills to manage the disease: to ignore the voices in your head, to act normal even if you don’t feel normal, to rest the reality of your thoughts. Self-help groups and family education help a lot.

Saints, Demonic Possession, Insane Asylums

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Psychosurgery• The lobotomy (also called leucotomy) was invented by Portuguese

doctor Egas Moniz, who won a Nobel Prize for it in 1949. • The idea was to destroy the prefrontal cortex, or sever their

connection to the rest of the brain. It was meant to help cases of severe mental illness, at a time when there was no effective treatment. Psychotic people were simply confined to insane asylums before this.

– The prefrontal cortex the part of the brain immediately behind the eyes, which is involved with the executive function of the brain: predicting outcomes, differentiating between conflicting ideas, personality expression, decision making and social behavior.

• Walter Freeman, an American psychiatrist, simplified the procedure so it could be done in cheaply in a mental hospital. A thin instrument was placed under the eyelid and against the top of the eye socket. Then it was pounded through the thin bone into the brain with a mallet. The instrument was swept from side to side, severing the connections. Repeated on the other side.

• Approximately 40,000 lobotomies in the US in the 1940’s and early 1950’s. Freeman drove around in a “lobotomobile”, performing the surgery at mental hospitals. Stopped with the advent of drug therapy. Freeman lost his medical license after killing a patient.

Cancer Treatments

• Cancer is the uncontrolled division of cells that eventually overwhelm the normal functions of the body.

– Normal cells stop dividing in response to signals: wound healing, for example.

• Cancer always starts with a single cell. It takes 4 or 5 separate mutations to transform a cell to the cancerous state. It multiplies into a tumor.

• In addition to uncontrollable division, a growing tumor must attract new blood vessels to fed itself. Eventually, many tumors metastatize: pieces break off an move through the blood to new locations.

• Cancer treatments suffer from natural selection: if you kill almost all the tumor cells but leave a few resistant cells alive, they multiply and the tumor grows back, now resistant to the therapy you applied.

• Different cell types become cancerous in different ways, making a general cancer treatment difficult.

• However, most cancer treatments (chemotherapy and radiation therapy) focus on stopping cell division. Common side effects like nausea, joint pain and hair loss are due to cell division stopping in other tissues.

Vinca Alkaloids• The Madagascar periwinkle Catharanthus roseus (used

to be Vinca rosea) was used as a traditional Chinese remedy for diabetes. In the 1950’s it was tested scientifically, and it had little effect on diabetes. However, the scientists noticed that it suppressed bone marrow activity. This led to the finding that the lifespan of mice with leukemia was significantly prolonged by Vinca extracts. Vinca contains over 70 different alkaloids, but purification work isolated vincristine and vinblastine as the active agents.

• These drugs prevent cell division by binding to the mitotic spindle, the apparatus that pulls the chromosomes apart. It binds to the spindle proteins, preventing them from joining together.

• They are very useful in treating leukemia, which is cancer of the bone marrow cells that produce blood cells. It also helps with several other cancers.

Taxol• Taxol is an alkaloid derived from the Pacific yew (Taxus

brevifolia), a gymnosperm that grows in western North America.

• In the 1960’s, the National cancer Institute ran a large scale anticancer screening program. Most samples submitted were synthetic compounds, but there was also a program for screening natural products isolated from plants and fungi. Bark from the Pacific yew had some activity in a simple assay procedure.

• Testing in animals and then humans showed that it helped with lung cancer, breast cancer, and ovarian cancer, as well as Kaposi’s sarcoma (common in AIDS).

• Huge amounts of bark were harvested to purify the drug, increasing as it continued to show promise as a cancer treatment. It would be easy to drive the tree to extinction, since harvesting the bark kills the trees.

• It is now produced from a line of tissue culture cells deriveed from the Pacific yew. The cells make and secrete taxol, which is them purified.

• Taxol binds to the mitotic spindle and stabilizes the structure so it can’t be re-used. This prevents further cell division.

Mitosis (Cell Division)