Transcript Medicinal Plants

Medicinal Plants
Plants have a far more complex chemistry than animals,
and secondary chemicals from plants have been
recognized for their medicinal value for at least 4,000
years.
The first pharmacopoeia, a list of herbal cures, was
Chinese, called the Pun-Tsao. Of similar age was the
poetry of the Indian Rig-Veda, which included herbal
medicines. As a medical practice, it is called Ayurvedic
medicine.
Only slightly newer was the Aztec collection of medical
knowledge, written in the Badianus Manuscript.
More recent, but better known, are the herbal remedies
described by Hippocrates around 400 BC and the
Greek-Roman military physician Dioscorides.
Some of the remedies they described (or derivatives
from them) are still in use today: Willow bark tea, which
contains salicin (the precursor of acetylsalicylic acid
[aspirin]) was prescribed for pain and headache, as well
as other gout and other ailments it may not alleviate.
By the middle ages, and particularly with the invention of
the printing press, a variety of herbals were published
with drawings and descriptions of plants useful as herbal
remedies, as well as the diseases they were useful in
treating.
One of the important early herbalists was Otto Brunfels.
He was a true Renaissance man, a priest, later a
Protestant, and an accurate observer. He published a
number of volumes of herbal medicines, including
Onomastikon medicinae, continens omnia nomina
herbarum, fruticum etc. (1534).
Not all herbals were as careful and accurate. Some were
based on astrology and other superstitions.
This was the time when the “Doctrine of Signatures” was
revived. If you don’t remember from an earlier lecture,
the doctrine of signatures claimed that plant form would
indicate function. One we saw before was mandrake
root, with the belief it would enhance virility.
The roots are supposed to
look like the torso and legs
of a man.
Another was bloodroot; its
red sap was used to treat
blood disorders.
From the opposite perspective, a significant amount of
the descriptive botany prior to Linnaeus came from the
work of physicians, and remember that Linnaeus was a
physician.
It was those physicians who described remedies using
herbals that led to many modern treatments. They
developed extracts from effective plants, and those
extracts are (though many are now synthesized, rather
than extracted) the basis of modern treatments.
Example 1: William Withering made the association
between a folk remedy of foxglove and its success in
treating congestive heart failure in 1775. He extracted
digitalis (the name from the plant species, Digitalis
purpurea) and established its use.
Digitalis contains a number of
cardiac glycosides, among which is
digoxin, which is the modern drug
administered. As a drug it increases
the strength of cardiac contraction
and tends to prevent arrythmia.
However, in excess it is toxic; it
causes nausea, anorexia and
vomiting. It has, as a result, been
sometimes abused as a weight loss drug.
William Withering is considered to be the
“father” of modern pharmaceutical
chemistry.
Example 2: Friedrich Serturner isolated morphine from
the opium poppy in 1805. He named the drug for the
Greek god of dreams, Morpheus.
This sap
contains the
morphine.
In 1874 a German chemist discovered that adding acetyl
groups caused the drug to dissolve in the fatty layers of
the brain far more rapidly, and thus bind more readily to
the opiate receptors. Binding leads to the physiological
responses. Those receptors also bind endorphins that
our bodies synthesize.
Example 3: In 1828 Henri Leroux extracted the active
ingredient in the inner bark of willow, Salix spp., which
had long been known for its pain-relieving properties.
Both Hippocrates and the Cherokee nation (as examples
themselves) used a willow bark tea to reduce pain and
fevers. Leroux named the extract salicin. An Italian
chemist, Raffaele Piria, discovered the reactions that
change salicin into salycilic acid.
Salicylic acid irritates the stomach. In 1853 Charles
Gerhardt neutralized the acidity (buffering) by turning
salycilic acid into acetylsalycilic acid. Gerhardt was not
interested in manufacturing. In 1897 a chemist named
Hoffman at Bayer, a German drug company, rediscovered Gerhardt’s work.
In 1899 Bayer registered the trademark name aspirin (a
– for the acetyl groups added, spir – for the plant genus
Spiraea, a meadowsweet, from which first extracts were
made, or possibly for Piria, and the
in – a common ending for drug names.
It was the same Hoffman who developed
heroin from morphine only 11 days after
(re)-discovering aspirin.
It is important to recognize that aspirin, though it began
with a plant extract, was the first synthetic drug, a
product of “modern chemistry”.
It remains the most widely used synthetic drug:
• In long term daily use (low dose), it is believed to
prevent or reduce the probability of heart attack
• it stimulates the immune system
• it suppresses prostaglandins and thromboxanes,
reducing pain, inflammation and fever
• it delays cataract formation
However, in children aspirin can interact with chicken
pox, leading to a serious disease – Reyes syndrome.
The advice is to use acetaminophen (Tylenol) for kids.
There are many more examples, but before looking at
some it’s important to recognize how large a fraction of
our medicines either are still extracted from plants or are
now synthesized, but were originally derived from plants.
At least 25% of all prescriptions have active ingredients
that are derived from plants. At least a similar fraction
contain active ingredients synthesized based on plant
extracts.
If we (somewhat loosely) include ingredients derived
from fungi (e.g. penicillin and the other –cillin antibiotics),
the fraction is far larger than 50%.
In addition, there is a huge market for herbal
‘supplements’ - ~$20 billion dollars/year.
The active ingredients in virtually all these plant-derived
medicines are either alkaloids or glycosides.
Alkaloids: are amine-containing molecules (the diagram
is of ephedrine) usually derived as secondary products
of amino acid metabolism.
The name (alkaloid) comes from their alkalinity and bitter
taste. Their most important effects are on the nervous
system, both physiologically and psychologically.
Animals and fungi also may produce alkaloids.
Important examples include caffeine, nicotine, morphine,
cocaine, quinine, atropine, scopolamine, mescaline,
theobromine, vincristine, vinblastine and ephedrine.
Note the –ine ending on al these names. We’ll return to
some of these in considering more examples of
medicines
A few don’t end in –ine: psilocybin, lysergic acid
Others are poisonous, e.g. strychnine and coniine.
Glycosides: get their collective name because the
active ingredient is attached to a sugar (-glyco). There
are 3 main categories: cyanogenic glycosides, cardiac
glycosides and saponins.
Cyanogenic glycosides release HCN when the linkage is
cleaved by digestive enzymes. HCN is toxic, therefore,
in general these glycosides have no medical application.
There is one controversial exception – laetrile, a cancer
treatment derived from peach pits, in which the HCN is
supposedly released only within cancerous cells.
Amygdalin is the most common cyanogenic glycoside,
present in almonds and the pits of cherries, peaches,
apricots, apples, crabapples, and plums. However,
remember the cyanogenic glycosides in cassava,
requiring special preparation before consumption.
Cardiac glycosides attach a steroid molecule to the
sugar. The steroid (and the effect of the glycoside)
varies. Digitalis is an example of a medically useful
cardiac glycoside, but many
others are toxic or fatal, e.g.
glycosides in oleander
(oleandrin and neriine) and
common milkweed.
These chemicals are generally believed to have evolved
as plant defenses against herbivores. A cardiac
glycoside is the best example of turning this around.
The glycoside in milkweed sap is taken up and
sequestered in sacs along the sides of the Monarch
butterfly caterpillar. It does not poison the caterpillar,
who then uses it as a defense against predators who
might eat it.
Within a very few minutes of eating a butterfly (or
caterpillar) raised on milkweed, the bluejay upchucks.
Saponin glycosides are mostly harmful, since they cause
red blood cell lysis. However, in low doses they are used
as expectorants (break up phlegm and make it possible
for you to cough it out). Liquorice contains a saponin
glycoside.
The name derives from their similarity in action to soaps,
and saponins are sometimes used as mild detergents.
That also explains how they cause cell lysis – by acting
like a detergent breaking up ‘fatty’ cell membranes.
Also, remember that the part attached to the sugar is a
steroid. Diosgenin from Dioscorea (true yam) was the
plant source for the first birth control pills.
There are a number of other glycosides that don’t fit into
the 3 groups that are of interest:
Arbutin – from common Bearberry (Arctostaphylos uvaursi) – known to Inuit and northern native cultures as a
urinary antiseptic
Steviol glycosides – from Stevia rebaudiana bertoni –
are natural sweeteners used in many cultures that are
40 – 300x ‘sweeter’ than sucrose
Anthraquinone glycosides – from Aloe vera – effectively
reduce pain, enhance healing, particularly from 1st
degree burns. This use dates back to ancient Egypt
Sinigrin and sinalbin – thiol (sulfur containing) glycosides
that are the flavor of black and white mustard
Now let’s go back to the alkaloids, and consider some
examples from the enormous variety…
1. Quinine – an alkaloid initially derived from a South
American genus, Cinchona. It is in the same family as
coffee. The Incas knew of its herbal benefits; they
apparently treated the wife of the Viceroy, the Countess
of Cinchon. Her recovery from the symptoms of malaria
led Linneaus to name the plant after her.
The bark of Cinchona was powdered to make the
treatment. During the 17th and 18th centuries the bark
became quite valuable and expensive. In 1820 Pierre
Pelletier and Joseph Cavetou isolated quinine from the
bark powder, and soon quinine replaced bark powder in
treatment.
However, large quantities were needed for extraction.
Plantations were established in India and Java, and a
high yield variety of Cinchona ledgeriana was developed
in Bolivia.
A synthetic drug with fewer side effects, chloroquine,
was developed in 1944 by American chemists
Woodward and Doering. Chloroquine replaced quinine
as the treatment of choice. Recently there has been a
return to quinine treatment because the organism most
frequently responsible for malaria, Plasmodium
falciparum, has become resistant to chloroquine.
R.B. Woodward
Nobel prize 1965
W. Doering
Quinine acts in two ways against the plasmodium: 1) It
kills the life stage called a merozoite in the bloodstream
and 2) it acts as a prophylactic, preventing the initial
infection of red blood cells.
Medicine hasn’t stood still since the evolution of
resistance. An alkaloid from Artemesia annua,
wormwood, a temperate weed, and synthetic derivatives
from it, are proving effective against resistant strains.
2. Treatment of schizophrenia using drugs has drawn
from 4000 year old Indian herbology to find snakeroot,
Rauwolfia serpentina, and an alkaloid within called
reserpine. This drug was only isolated from snakeroot
roots in 1952. It is an antipsychotic and antihypertensive.
It works by depleting monoamine neurotransmitters
(dopamine, norepinephrine, and serotonin).
Due to various side effects (nausea, vomiting, gastric
ulceration, depression), its use as an antipsychotic has
effectively ended. It is still used as an antihypertensive.
Even where it is not used, many other alkaloids used are
also derived from snakeroot.
3. Ephedrine is an alkaloid used in herbal medicine as a
decongestant. It is extracted from species in the genus
Ephedra. That use reaches back thousands of years in
China, where the regional species, Ephedra sinica, has
its own common name, Ma Huang.
However, ephedrine is not used as a decongestant
much in North America. Instead, it is used as a
metabolic stimulant, in weight loss drugs, and in body
sculpting. It is banned by the IOC and NCAA.
Why? Its physiological effects are similar to those of
amphetamines. Amphetamine and methamphetamine
are synthetic derivatives of ephedrine. It “turns on”
thermogenesis, the burning of calories (largely fat) to
produce heat, stimulates the heart (heart rate and blood
pressure), relaxes bronchial muscles permitting greater
air intake, and increases blood flow to muscles and
brain. That explains why it is banned, but you need to
know it is also dangerous. Its use can lead to (among
many effects) tachycardia, cardiac arrythmia,
hypertension, delusion and paranoia.
In various over-the-counter and prescription medicines,
pseudoephedrine has replaced ephedrine with fewer
side effects, though it, too, is banned in sports.
4. Therapeutic alkaloids in cancer treatment - blue
periwinkle, Catharanthus roseus, from Madagascar
contains alkaloids vinblastine and vincristine which
are very effective against leukemia and lymphoma.
vincristine
Vincristine works by binding to tubulin, a protein critical
in microtubule structure that, among other functions,
makes up the mitotic spindle. The cell division that
characterizes cancer is prevented.
The concentrations of these alkaloids is very low. Your
text tells you it takes 53 tons of leaves to make 100 g of
vincristine.
Vincristine is (carefully) injected intravenously in the
treatment of childhood leukemia, Hodgkin’s lymphoma,
and non-Hodgkin’s lymphoma as part of differing
chemotherapy regimes for each disease.
Vinblastine is used to treat both Hodgkin’s and nonHodgkin’s lymphomas.
Both vinca alkaloids were isolated by
Robert Noble and Charles Beer from
periwinkle. There are many other
potent alkaloids in this species,
though none are in wide therapeutic
use yet.
5. Taxol (paclitaxel) is yet another example of a drug
found ‘just in time’. Taxol is extracted from the bark of
the Pacific yew, Taxus brevifolia.
The Pacific yew grows naturally in the
old growth forests of the Pacific northwest of the U.S., British Columbia and
northward into southern Alaska.
Lumber companies harvesting
‘desirable’ trees from these forests
considered the yew to be a ‘junk’ tree,
and cut them only to clear cut areas for re-planting.
The drug yield is very small, and pacific yew grows very
slowly. It requires the yield of 6 100-year old trees to
treat one patient. The yew was on the edge of becoming
endangered. What to do?
The drug was spotted in yew bark in 1963 and only
isolated from yew bark in 1967 (by Monroe Wall and
Mansukh Wani) from samples of 30,000 plants (in the
case of the yew, needles, twigs, and bark) provided to
scan for anti-tumor activity in mice.
Taxol has a complicated structure, and lab synthesis is
still not possible. However, a number of alternate means
of production have been developed.
1. Taxol can be “semi-synthesized” using a much more
abundant chemical found in a number of other yews.
Cell culture has also been used to produce that
starting chemical, deacetylbaccatin.
2. Fermentation (combined with a little genetic
engineering) technology can be used to produce
taxol-like chemicals from actinobacteria, or paclitaxel
itself from Nodulisporium sylviforme culture.
3. Plant cell fermentation is now used to produce most
taxol using a specific callus tissue from Taxus. The
drug is extracted from the culture, separated by
chromatography, and purified by crystallization.
Taxol works in a way opposite to other anti-cancer drugs
mentioned thus far. Rather than preventing tubulin
organization into the spindle apparatus, taxol binds to
microtubules and ‘hyper’stabilizes their structure. You
can think of this as rigidly fixing the structure. Mitosis
can’t be completed (microtubules can’t disassemble),
nor a new cycle begun after that binding.
Taxol also causes cell death (apoptosis) by binding to
and blocking the activity of a protein, Bcl-2 (B cell
leukemia 2). That protein blocks apoptosis.
Paclitaxel is an effective treatment for lung, ovarian, and
breast cancer, and advanced forms of Karposi’s
sarcoma. A related taxoid drug, Taxotere, is now used to
treat drug-resistant and metastatic breast cancer.
6. A tree relative of tupelo, Camptotheca acuminata,
was the original source for a drug used to treat leukemia
and cancers of the liver and stomach in China as an
herbal therapy. The drug was/is camptothecin, an
alkaloid secondary chemical. Higher concentrations of
the same drug were found in the stem wood of
Nothopodytes foetida from western India.
It was Dr. Monroe Wall who ‘discovered’ the anti-cancer
properties of the tree’s bark and wood in 1958, and, with
others, isolated the drug from plant material in 1966. It
was tried on mice and on patients with gastro-intestinal
cancers in the early 1970’s, then stopped due to severe
side effects.
As a result, semi-synthetic derivatives with fewer side
effects were developed: topotecan (Hycamptin) is used
on metastatic ovarian cancer and small cell lung cancer.
Irinotecan (Camptosar) is used (with other drugs) in
treating colo-rectal cancer.
camptothecin
Camptothecin and its derivatives work differently. They
affect the function of an enzyme, topoisomerase I. This
enzyme normally cleaves DNA, unwinds it, then religates the DNA it cleaved. Once camptothecin is bound
to the enzyme, it can cleave but not re-ligate DNA. As a
result, there are numerous single strand breaks in the
DNA, and dividing cells can’t properly complete the
process.
There are many other anti-cancer drugs derived from
plant and bacterial sources. A complete review would
take more than an entire semester.
Herbal remedies are used in many other situations. Your
text has a short list in table 19.2. It also notes a caution:
licensing and extensive testing are required for
prescription and over-the-counter drugs, but as long as
an herbal is offered as a dietary supplement, all that is
required is that the product be safe, not necessarily
effective.
It is on that basis that ephedrine-containing and
comfrey-based products were banned, and warnings
required for some others.
We’ll concentrate on herbal products that seem to have
a proven usefulness…
St. John’s Wort, Hypericum perforatum, is now believed
to be a useful herbal remedy for depression.
It is also called Klamath weed, and is an invasive,
poisonous plant that causes photosensitivity when
consumed by some animals. It is ‘controlled’, in an
excellent example of biological control, by a beetle,
Chrysolina quadrigemina, that feeds on its leaves.
Simple physical removal doesn’t work well because it is
rhizomatous.
How you can recognize it –
black dots on the leaves.
Chrysolina quadrigemina
St. John’s wort has been used as an herbal medicine
since Greek times. Both the Greeks and Native
Americans used St.John’s wort for inducing abortion
and externally as an anti-inflammatory and antiseptic.
Today its use as an antidepressant seems to show
significant clinical effect against mild to moderate
depression, but to be ineffective against more severe
depression. It also apparently has fewer and less severe
side effects than many of the other medications used.
It may work in the same way as a number of commercial
medications as an SSRI (selective serotonin reuptake
inhibitor). If that is true, the likely active ingredient is
hyperforin.
Ginkgo biloba is an ancient tree usually placed with the
Coniferophyta, but sometimes off on its own in a group
called the Ginkgophyta. It’s really alone, as there is only
one species in the group. It is, without question, a
gymnosperm; its seeds are not protected within an
ovarian wall, as are the Angiosperms.
The Ginkgo is an ancient plant, with leaf fossils at least
270 million years old. After the Cretaceous it slowly
dwindled in abundance and distribution, until today the
only native distribution left is in central China.
Ginkgo has, however, been grown in many other places.
It is a dioecious species, and there is a fairly common
male cultivar called “Autumn Gold” that is widely grown
(even locally).
In China, an herbal tea of ginkgo has been used for
4,000 years to treat breathing problems (asthma,
bronchitis). In modern western medicine, flavenoids in
ginkgo extracts seem to have circulatory (improved
microcirculation) and nootropic effects (enhances
memory and brain function), as well as anti-oxidant
function.
The disease against which ginkgo shows promise is
Alzheimer’s dementia (along with other mild forms of
dementia). It works when used as a daily dietary
supplement, but you shouldn’t bother now. It seems to
have no material effect on young, healthy adults.
However, improved circulation also comes with a
negative side effect – it blocks PAF (platelet agregation
factor) and slows or prevents clotting. As a result, it is
contra-indicated for those who are taking aspirin as part
of a heart/circulation regime, pregnant women, and
those taking MAO (monoamine oxidase) inhibitors.
One last herbal, of personal interest to males at my age
– saw palmetto, Serenoa repens, as a dietary
supplement. Saw palmetto is a small palm, growing to
no more than 2 – 4m. Its leaves lead to a secondary
description as a ‘fan palm’. It is native to the
southeastern U.S.
An extract of the fruit of saw palmetto is suggested to
reduce a problem called BPH, benign prostate
hyperplasia.
The problem is very common, affecting 50% of men over
50 and 90% of men over 70. When the prostate
enlarges, it slowly squeezes on the urethra, and makes
urination more difficult.
The cause of the hyperplasia is dihydrotestosterone, a
product of testosterone metabolism (it is also involved in
producing male pattern baldness). The fruit extract of
saw palmetto inhibits 5--reductase, an enzyme that
converts testosterone to dihydrotestosterone, and
interferes with the binding of DHT to androgen receptors
in the prostate.
Saw palmetto extract has fewer side effects and works
for a larger percentage of sufferers than the usual,
synthetic medicine prescribed.
Since it is an herbal medicine, there is controversy about
the evidence that point to its usefulness.
A few other herbal/medicinal plants and their suggested
uses:
Echinacea purpurea – purple coneflower, a prairie plant;
suggested as an immune system stimulant that shortens
the length of the common cold
Valerian, from Valeriana offinalis, is an herbal sedative
and apparently useful against insomnia. It is native to
Europe and Asia, but has been introduced into North
America. Its mode of action is probably related to
interaction with GABA ( amino butyric acid), but the
mechanism is unknown. Extended use can lead to
addiction and withdrawal symptoms.
Ginseng (Panax spp.) is suggested to stimulate the
immune system, increase resistance to stress, and to
increase libido and sexual performance. Parts of that
may be supported by evidence of anti-oxidant activity;
parts are controversial. The active ingredients are
gensenosides (triterpene saponins).
Siberian ginseng is widely sold as an
herbal; it is not a Panax, rather it is
Eleutherococcus senticosus, and
instead of gensenosides it contains
eleutherosides.
In Asia they want American ginseng (P. quinquefolius),
and the wild plants have more of the desired chemical.
However, the wild plant is becoming very rare. Korean
beliefs are that American ginseng promotes ‘Eum’
energy (female), while Asian ginseng (red) promotes
‘Yang’ (male).
In North America, it seems Siberian ginseng sells better
than North American (Is this an example of “the grass is
always greener…”?)
Most of the North American ginseng is produced in
Ontario, British Columbia, and Wisconsin.