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Saw-scaled vipers (Echis carinatus), also known as "carpet"
vipers, live in areas of sandy soil and rock outcroppings in Africa, India
and parts of the Middle East. They are grey or brownish in colour, patterned
on the body with brownish blotches, a wavy white stripe, and a dark cross
on their heads. When aroused, they coil and twist, rubbing their serrated
scales against each other to create a sound similar to that of a saw cutting
wood and it is this characteristic noise that gave its name. This is usually
a warning prior to fast leaping strikes to defend itself. Saw-scaled vipers
are quick to strike, and their venom is highly toxic to humans 28. Echis carinatus is probably the world's deadliest
snake, based on documented deaths, especially in Sri Lanka 29.
The deaths of nearly fifty people per million from snakebite occur there
each year, 29 many bleeding uncontrollably to their
death when bitten due to the anticoagulant nature of certain peptides within
the venom 28.
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Echis
carinatus |
Although many venomous snakes contain anticoagulant toxins in their venom,
echistatin isolated from the venom of Echis carinatus, was chosen for development
because it is particularly potent and simplistic in structure, which also
made it easier to replicate in the laboratory.
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Merck Research Laboratories then investigated the specific protein regions
of the toxin that produced the inhibitory effect and removed the regions
toxic to patients. This lead to the development of tirofiban (marketed as
Aggrastat), a small, organic molecule that mimics a portion of the natural
protein found in the venom of the saw-scaled viper. Like the original venom
constituent, tirofiban inhibits platelet aggregation in clotting by blocking
glycoprotein (GP) IIb/IIIa receptors on their surfaces 28.
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GP IIb/IIIa receptors are the attachment sites for fibrinogen, which
promotes platelet aggregation. In unstable angina, years of cholesterol
build up on the walls of coronary arteries suddenly results in their rupture.
This induces platelets to surround the area and form a clot. However, as
this increases in size and blocks arterial blood flow to the heart, myocardial
infarction can result.
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Aggrastat
Therefore tirofiban, which prevents/reduces
the formation of this clot, was found to reduce the risk of ischaemic events
during the 48hr infusion period of unstable angina patients, as well as
decrease mortality, in the PRISM trial (PRISM
Study Investigators, 1998). The PRISM-PLUS trial showed that the benefit
of using tirofiban with aspirin and heparin compared to heparin alone was
also still evident after 6 months. If used with just aspirin it lead to
increased mortality at 7 days (from myocardial infarction) , demonstrating
that heparin was necessary to co-administer. (PRISM-PLUS
Study Investigators, 1998) However, this may have been due to higher
risk patients being used than in the PRISM trial. (Chesebro
et al, eds, 1998; Ramsay, ed, 1998)
The future of Aggrastat looks very promising
and the recent clinical trials, though still ongoing, suggest that it will
have an important part to play in the treatment of heart conditions. It
is a potent inhibitor of platelet aggregation in clotting and shows how
useful animal toxins can be in the development of today's new drugs. |
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