Transcript Plants Used to Treat Heart Disease

Statin Drugs
Cholesterol lowering
drugs
Individual level risk factors for
cardiovascular disease
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High Blood Pressure
High Blood Cholesterol
Tobacco Use
Physical inactivity
Poor nutrition
Obesity
Diabetes
High Cholesterol Profile
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19% of Americans ages 20-74 have high
serum cholesterol
Mean level 203 mg/dl
Most prevalent among White, non-Hispanic
females
Least prevalent among Black males
Cholesterol
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What is cholesterol?
Cholesterol production is controlled by a
feedback mechanism in which cholesterol
inhibits the enzyme b-hydroxy-b-methylglutarylCoA reductase (HMG Co-A reductase).
By inhibiting this enzyme, the conversion of
HMG-CoA to mevalonic acid is stopped
Cholesterol synthesis
Cholesterol
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Cholesterol transport by lipoproteins
Low Density Lipoproteins – LDL transports
cholesterol throughout body – Bad cholesterol
High Density Lipoproteins- HDL removes
excess cholesterol and carries it back to liver
for degradation
Lipoproteins
Statin Drugs
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Cholesterol-lowering drugs originally isolated from
fungi
All terpenes
Six statins are currently prescribed by physicians
Three of these (pravastatin, simvastatin, and
lovastatin) are derived by fermentation of the
fungus Aspergillus terreus, while three (fluvastatin,
atorvastatin, rosuvastatin) are synthetics
Statin Drugs
Chemical Name
Brand Name in
U.S.
Production Method
Pravastatin(G?)
Pravachol
Fermentation - modified
Simvastatin(G?)
Zocor
Fermentation - modified
Lovastatin (G)
Mevacor
Fermentation
Fluvastatin
Lescol
Synthetic
Atorvastatin
Lipitor
Synthetic
Rosuvastatin
Crestor
Synthetic
Cerivastatin
Baycol
Synthetic - no longer
available
Statins
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Statins drugs act as inhibitors to HMG-CoA
Reductase
Can reduce blood cholesterol levels up to 60%
They specifically lower LDL cholesterol levels
and even produce some increases in HDL
cholesterol levels.
The cholesterol reduction significantly reduces
a patient's risk of heart disease
Discovery of statins
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Some drugs available but not effective
In 1971,Endo and Kuroda (Sankyo Pharmaceuticals
in Japan) began search for better drugs
Cholesterol pathway known and they wanted to find
a HMG-CoA reductase inhibitor – looked for a
microorganism – screened over 6000
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Two (3rd later) cmpds identified - one was from Penicillium
citrinum - named mevastatin
In 1976 isolated and crystallized
Clinical trials started in 1978 and quickly stopped because of
animal tumors
Mevastatin (compactin)
Lovastatin (Mevacor)
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Meanwhile Merck pharmaceuticals isolated a
related cmpd - lovastatin from the fungus
Aspergillus terreus
Sankyo gets credit as co-discovering this cmpd
By 1980, clinical trials began and they were
completed in 1986
FDA approved Aug 1987
Lovastatin (Mevacor)
Other Statins - Type I
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Meanwhile Sankyo and Bristol-Myers Squibb were
entering clinical trials on another statin - pravastatin
(Pravachol) - approved Oct 1991
Soon after Merck came out with a second statin simvastatin (Zocor) - approved Dec 91
Simvastatin produced by chemical modification
Simvastatin is approximately twice as potent as
pravastatin and lovastatin
Monascus another source of lovastatin (red yeast rice)
Simvastin and Pravastatin
Synthetics
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Soon several synthetics joined the group of
natural statins - called Type II statins
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fluvastatin (Lescol)
atorvastatin (Lipitor)
rusovastatin (Crestor)
cerivastatin (Baycol) - FDA approval withdrawn
Fluvastatin and Atorvastatin
Cerivastatin and Rosuvastatin
Mode of Action
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Statins bind to the active site of HGM-CoA
reductase - competitive inhibitor with much
high affinity for binding the HGM-CoA
In compensation for the inhibition, cells in
liver begin to produce more HMG Co-A
But they also produce more LDL receptors
Since the liver is responsible for removing
LDL’s from plasma by the LDL receptors,
blood cholesterol levels fall dramatically
More on mode of action
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Statins do more than bind to active site - they also
seem to change the active site and this makes these
drugs very effective and specific
Synthetic statins (Type II) are larger molecules and
form more interactions with the active site and appear
to be better inhibitors
Potential for newer drugs as well because there is
another binding site right by the active where NADP
binds and it may be possible to develop new statins
that will bind both places
Benefits of statin drugs
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Prevent strokes
Reduce coronary artery inflammation
Affect blood vessel growth
Some immune system expression
Reduce risk of osteoporosis
Reduce the risk of colon cancer when combined with
non-steroid anti-inflammatory drugs
Reduce risk of Alzheimer’s Disease
Reduce MS symptoms
Sales of Statin Drugs - $15.5 billion
•
Lipitor (atorvastatin)*
$3.7b (2003 – $7.8b)
•
Zocor (simvastatin)*
$2.2b (2003 - $5.5b)
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Pravachol (pravastatin)
$1.2b
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Baycol (cerivastatin)
$0.2b
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Lescol (fluvastatin)
$0.2b
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Mevacor (lovastatin)
$0.2b
*Two top selling drugs in US – Liptor also top selling in world
Effect of Statin Use on Population
Percent of Population with High Cholesterol
33.3
28.6
27.8
-9
4
19
88
-8
0
19
76
-7
4
71
19
60
-6
2
19.7
19
%
40
30
20
10
0
Side Effects
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Side effects include muscle pain and elevated
liver enzymes.
In August 2001, Bayer Pharmaceuticals
voluntarily withdrew Baycol (cerivastatin)
following the deaths of 31 patients in the U.S.
over a four year period
Baycol recall
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The deaths resulted from rhabdomyolysis,
which destroys muscle cells and causes
severe muscle pain
Hundreds of non-fatal cases of rhabdomyolysis
also reported in the US
Although this condition is a side effect of all
statin drugs, it is exceedingly rare in the six
approved statins and the health benefits clearly
outweigh the slight risk
Side effects
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The side effects may be exacerbated by
interactions with other drugs
A number of the Baycol deaths were patients
also taking gemfibrozil (another class of
cholesterol lowering drugs)
Grapefruit juice also increases the side effects
In the pipeline
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New cholesterol lowering drugs being
developed
Glabridin - found in the roots of licorice and
anise plants
Appears to inhibit the oxidation of LDL
cholesterol, which is a factor in the build-up of
arterial plaque
Reserpine
Antihypertensive drug
Snakeroot, Rauwolfia
serpentina
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“Doctrine of signatures"
Standard treatment in
Ayuvedic medicine
Root used for treating
snakebites, insect
stings, and even
mental illness
Search for
schizophrenia
treatment
Rauwolfia serpentina and reserpine
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In 1952 the alkaloid reserpine was isolated
from the roots
Valuable tranquilizer - side effect was a
reduction in blood pressure
Today, this is actually the principal application
of reserpine, as a treatment for hypertension
What is high blood pressure?
Reserpine mode of action
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Acts on nervous system
Inhibits normal sympathetic activity by decreasing
the storage of catecholamines (especially
norepinephrine) at the pre-synaptic, CNS, and
peripheral neurons
Binds to the storage vesicles, causing
catecholamines to leak into the synapse so that
they are not available for release when the presynaptic neuron is stimulated.
Serotonin storage also affected
Mode of action
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These actions result in a reduction in both
cardiac output and peripheral vascular
resistance
As a result heart rate decreases and blood
pressure decreases