Transcript Medicinal Plants

Medicinal Plants
Outline
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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
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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.
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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
lungwort
Hepatica leaves have 3 lobes,
just like the liver
Walnut: looks sort of like
a brain!
Tomatoes are red and have
four chambers, just like
the heart.
Snakeroot
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
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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.
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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
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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.
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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.
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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
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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.
• s
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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
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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.
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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.
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Very little malaria in the US or Europe any more due
to effective mosquito control measures.
Genetic Resistance to Malaria
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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.
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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
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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).
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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 million
Indians 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
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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
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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
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William Withering was an English doctor in the 1700’s. He also wrote a book
about English plants.
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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.
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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.
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 sweetsmelling 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
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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
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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.
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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
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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.
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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
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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)