PHAR1101 Study Guide - Quiz Guide: Myofibril, Alois Alzheimer, Maraviroc
PHAR 1101 E-TUTE – CHELSEA GRAY
E-Tutorial 1: Finding New Medicines in Nature:
• The main reason we study pharmacology is to see where the medicines we use today come from and what they do for us
• Human societies have acquired long standing knowledge of medicinal plants for thousands of years
• With advances in chemistry in the 19th century, the active constituents of the medicinal properties of these plants were extracted, leading to new
drugs
Whats the Big Idea?
1. Observation of a plants biological effects
2. Historical or cultural records of medicinal plant usage
3. Preparation of plant extracts for research use
4. Fractionation of the complex mixture into separate constituents
5. Identification of individual molecules in each plant extract fraction
6. The molecules of interest are tested for pharmacological and toxic properties in lab animals or other processes
7. Promising and safe molecules are then tested in human patients that may suffer from a particular problem or may even be completely healthy
8. Molecules that make it through animal and human testing and that are being used for human use need to be approved by regulatory agencies
9. If all goes to plan, new medications are available for use in human patients
Artemisinin → Plant-Derived Antimalarial Drug:
• Tu Youyou → Won the 2015 Nobel prize in medicine alongside two of his colleagues, lead researching in project
, a scientific program of Peoples Army China to protect their troops
against malaria
• He was guided by two ancient handbooks of traditional Chinese medicine that
lead to him successfully extracting Artemisinin from Artemisia annua leaves
(1967)
• This plant had long been used by Chinese doctors to treat fevers
• Resulted in effective anti-malarial medications
Some Key Definitions:
• Bioactive Substance → a plant derived substance or chemical, that upon
entering the body will produce a desirable physiological change e.g. analgesics
dull the perception of pain, lower blood pressure or improve an individuals
mood (humans have long used bioactive plants as medicines)
➢ Morphine → the opium poppy has been used long since ancient
times to treat strong pain, in 1806, the discover of its bioactive
substance named the drug morphine after Morpheus the Greek
god of dreams
➢ Aspirin → the leaves and bark of Willow trees have long been
used to treat mild pain, in the 19th century, extraction of willows
bioactive constituent salicylate soon lead to semisynthetic
analgesic aspirin
• Bioprospecting → the scientific search for effective bioactives in nature, around 20-30% of current medicines
can be traced to natural origins (many are chemically altered → semisynthetic), the search has been very
successful → many come from plants but other natural findings have come from frogs (skin secretions that
contain peptides used for pain relief or antibiotic properties), cone shells (the toxins released by cone shells
developed the drug Ziconotide – approved in 2004 for pain releif), sea sponges (stationary marine creatures that
are a rich source of bioactives that may one day be used in finding treatments for cancer, infections and
inflammation) and microorganisms (antibiotics were discovered from bacteria and fungi → ongoing work focuses
on extremophiles that include microorganisms growing in tougher environments)
Issues and limitations in Bioprospecting:
• Human impact → when a new drug is discovered by using indigenous medical knowledge, care is needed to minimize negative impacts of
harvesting on tribal populations while also ensuring a return of royalties and other benefits
• Environmental impact → the ecological consequences of harvesting drug-containing plants required careful consideration if the plant is
endangered (e.g. pacific yew, the source of the anticancer drug Taxol)
• Toxicity → unfortunately, some bioactive substances can cause toxicity or harm in humans. This is especially a problem with drugs obtained
from animal venoms (sea cones, etc.)
• Bio piracy → this occurs when scientists or companies collect plant or other natural materials without concern for the human or environmental
impact of their actions (e.g. when reef species such as corals are removes excessively)
Why do Plants Make Bioactives?
1. Growth regulators → Some botanical chemicals act as growth regulators, which influence the speed at which a plant grows new roots, stems or
leaves
2. Pest Deterrents → some plants make chemicals to act as natural insecticides or to make their leaves taste bad to pests or predators
3. Natural Sun-blocks → similar to titanium dioxide in sunscreen lotions, some plant chemicals absorb UV rays to protect leaves from solar
radiation
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PHAR 1101 E-TUTE – CHELSEA GRAY
Some Plant Derived Drugs:
• Warfarin (anticoagulant) → used for prevention of stroke which was made from sweet clover that was introduced to the US from Europe
• Colchicine → used for gout (A painful inflammatory disease) which is made from the extraction of Autumn Crocus
• Atropine → used in ophthalmology and eye surgery and extracted from Bella Donna
• Digoxin → cardiac stimulant (used for heart failure), was extracted from digitalis commonly known as fox-glove
• Quinine → used for malaria, extracted from Cinchona
• L-dopa → used for individuals with Parkinsons disease neurodegenerative condition, extracted originally from the velvet bean
• Taxol → anti-cancer drug, originally extracted from the pacific yew tree
• Morphine → powerful pain reliever, still extracted to this day from the opium poppy
Colchicine → Example 1:
• Famous bioactive medicine that is used in the treatment of
gout (a very painful inflammatory disease)
• Dioscorides (50-90 AD) → a famous doctor from the Greco
–Roman world, specialized in the healing uses of plants. Each
chapter in his De Materia Medica describes the preparation and use of particular plant derived drugs
• Autumn Crocus → this pretty flower grows widely in Europe and blooms in Autumn, Dioscorides recommended using its bulbs to treat gout
patients
• Gout → a painful inflammatory condition that involves sharp pain and tissue swelling, its symptoms strikes suddenly and involve deposition of
urate crystals within the joints (toes, ankles, wrist, fingers, etc.)
• Uric Acid → this substance forms in the body via the metabolism of purines (components of DNA), some purines are also found in food (e.g. liver
and beer), most uric acid dissolves in blood and is eliminated in urine, however high levels form in gout sufferers
• Colchicine → two French chemists extracted this drug from Autumn Crocus in 1820, it has powerful effects on dividing cells (anti-mitotic) and is
quite toxic, but when used correctly, it often provides effective gout relief
Warfarin → Example 2:
• Widely effective and used plant-derived drug
• Warfarin stories begin in the s with a US epidemic of cow poisoning → a farmer in Wisconsin talked to a scientist/doctor and presented a
bucket of un-clotted cow blood to him
• 1900 → the toxic grassland weed called sweet clover entered the US from Europe
• 1901 → Karl Paul Link is born
• 1920 → outbreaks of fatal cow poisoning due to mouldy sweet clover across the USA
• 1932 → Un-clotted cows blood is presented to Dr. Link a biochemist in Wisconsin
• 1941 → Dr. Link finally extracts purified dicoumaroul from mouldy sweet clover
• 1948 → Dr. Link makes warfarin – a safer blood thinning (anticoagulant) drug suitable for humans
• Warfarin uses:
➢ Used as a blood thinner to prevent blood clots
➢ Depending on where they form, blood clots can cause two types of medical emergencies → strokes (occurs when a blood clot block
blood vessels that supply the brain with oxygen, causing a serious loss of function) or heart attacks (occurs when a blood clot
blocks blood vessels that supply the heart muscle with oxygen and rich blood, causing a life threatening situation)
➢ Warfarin helps reduce the risk of strokes and heart attacks in at-risk patients, but the rug is very toxic and must be carefully
monitored
Tutorial 2: Drug Discovery by Disease Model Testing:
• Where do drugs come from? → DISEASE MODEL TESTING PERSPECTIVE
• As they learned more about disease, scientists created animal models which show the same symptoms as humans
• Scientists began testing chemicals for their effectiveness as drugs in such disease models
• This approach soon led to new drugs
Whats the big idea?
• Possess an animal that is affected by a disease that a human may have → e.g. bacterial disease
• The animal is then administered to see if the drugs work or not and improve the state of the animal
• Compound A (ineffective): lacks antibacterial properties → therefore the animal remains sick → not a potential new drug and can be discarded
• Compound B (effective): may be suitable for further drug development as the animal has improved in its condition → needs to be further
developed to be able to be used in humans
Key Features of this approach:
1. Observant researchers → this approach needs scientists who assess the effectiveness with which molecules prevent disease in animals, so
long as they find a drug that works, they can figure out how it works later
2. Compound library → for this strategy to succeed, scientists must test many molecules as potential drugs, the total set of test chemicals is
called a compound library
3. Animal Model → this approach requires a good animal model – i.e. mice, rats or other species who show similar disease symptoms to those
experienced by humans, the mice may have some type of cancer (e.g. colon tumors) or infectious disease
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PHAR 1101 E-TUTE – CHELSEA GRAY
Classic Example 1: Salvarsan:
• First success in the discovery of new drugs → Salvarsan for the treatment of syphilis (and STI)
• Syphilis: contagious sexually transmitted disease that has long plagues humanity, it has affected many famous people – including dictators
(napoleon and Hitler), writers (Oscar Wild) and gangsters (alcapone)
• Syphilis stages → usually begins with painless skin lesions near the genitals soon after infection, these can disappear for a few months to be
followed by the secondary phase of syphilis involving rashes on the hands, feet and other sites, patients also experience fever and fatigue during
this period. The disease can then lie dormant for decades before returning with a vengeance! → The final tertiary stage involved paralysis, weight
loss, brain damage (dementia) and blindness!
• Syphilis is caused by a nasty bacterium called Treponema pallidum
• For thousands of years, humans had no way to kill this bug, and it took a heavy toll on society
• That is why the discovery of Salvarsan by Paul Ehrlich was a major advance!
• Paul Ehrlich → the inventor of Salvarsan: in 1887, this famous German scientist became a professor
at Charitè hospital in Berlin. He was interested in biological stains → coloured dye molecules that
accumulate in tissues within the body → he was unpaid due to his Jewish background and found a cure
for diphtheria (bacterial disease → nose and throat). He began
conducting experiments in rabbits to see what happened to these
dye molecules in the bodies. (e said WUNDERBAR! – I saw that
dyes accumulated in the animals internal body organs, I
wondered if toxic arsenic molecules could accumulate in tissues
infected by the syphilis bacterium, they may act as magic bullets
without harming the host!
• Steps in the discovery of Salvarsan:
1. Arsenic (As) is a toxic metal that is quite common in
the Earths crust
2. Arsenic (As) also exists in compound form (next to its
metallic form), which includes many inorganic and
organic forms. Chemists began making many organic
arsenicals in the early 20th century
3. In Berlin, Ehrlich established an animal model involving rabbits infected with the syphilis
bacterium. He then began testing hundreds of organic arsenic compounds
4. After testing 605 arsenic compounds, Erhlich finally discovered compound 606 which treated
syphilis infections. This was marketed as Salvarsan → the first modern antibiotic
5. Further testing led to neosalvarsan → a better drug with fewer side effects. Thanks to these
drugs, European syphilis cases fell by % in years. Ehrlichs magic bullet idea proved true!
Classic Example 2: Prontosil:
• Inspired by the work of Ehrlich, another testing breakthrough involved a German group led by Gerhard
Domagk who invented the sulfonamides
• The forerunner of this antibiotic class – Prontosil – was discovered via testing in bacterium-infected mice
• The discovery of this medication had many ups and downs and many spontaneous events
• Josef Klarer: a chemist at IG Farben in Germany, begins making hundreds of coloured compounds known as
azo dyes
• Gerhard Domagk: Chief of the bacteriology lab at )G Farben begins testing Klarers azo dyes for
antibacterial properties/effects. Domagk finds one molecule – Prontosil – is very effective against
streptococcus infections in mice → streptococcus bacteria are a major cause of infection in humans
• Fearing that Prontosil is too toxic for humans, Domagk refuses to test in human patients
• Domagks year old daughter becomes sick after pricking her finger on an un-sterilised needle
• The daughter, Hildegarde grows sicker after the infection spreads to her lymph nodes and also causing severe blood poisoning due to there not
being any antibiotics available. As her condition situation declines, her doctors recommend amputation of her arm
• With Hildegarde near death, Domagk administers a large dose of Prontosil to his child
• After the drug was administered, (ildegards fever subsides and her condition improves, she walks out of hospital just 2 days after being
administered Prontosil
• Domagk strangely waited several years before publishing his work, and omitted the story of his daughter!
• Progress on Prontosil is hampered by an odd side effect, as a colourful dye, it turned patients skin a bright orangey-pink colour! – Like a lobster!
• In 1935, researchers find that Prontosils antibacterial effect is due to a colourless metabolite in the human body!
• These discoveries led to the sulfonamides, a broad class of antibiotics that slow down bacterial growth by starving them of folic acid (they now
face major resistance problems)! But back in their time, Prontosil was a major breakthrough!
Issues with the approach:
• Poor model: due to inherent biological differences between humans and animals, some animal models are better than others. Over-reliance on a
poor model might mislead researchers into drawing false conclusions about a potential drug. Some researchers are trying to overcome these
limitations by developing humanised mice that carry human genes, but these approached remain to be proven
• Disease complexity: some human diseases are complex and nearly impossible to reproduce in animals. This means animal-based testing is more
handy for some diseases than others
• Ethical Factors: animal based drug testing can raise ethical issues, especially when the disease symptoms cause the animal suffering or when the
drugs are necessarily toxic (e.g. some anti-cancer drugs)
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Document Summary
The main reason we study pharmacology is to see where the medicines we use today come from and what they do for us. Identification of individual molecules in each plant extract fraction. The molecules of interest are tested for pharmacological and toxic properties in lab animals or other processes. If all goes to plan, new medications are available for use in human patients. Tu youyou won the 2015 nobel prize in medicine alongside two of his colleagues, lead researching in project. Artemisinin plant-derived antimalarial drug: (cid:887)(cid:884)(cid:885), a scientific program of people(cid:495)s army (cid:523)china(cid:524) to protect their troops against malaria. He was guided by two ancient handbooks of traditional chinese medicine that lead to him successfully extracting artemisinin from artemisia annua leaves (1967) This plant had long been used by chinese doctors to treat fevers. Morphine the opium poppy has been used long since ancient substance named the drug (cid:494)morphine(cid:495) after morpheus the greek.
