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Xemilofiban is a GP IIB/IIIA
antagonist known as a Fiban; that inhibits platelet aggregation.
This particular drug is useful for indications similar to those
for Aggrastat®, Integrilin®, and ReoPro®, which are
all administered intravenously (IV). Xemilofiban and these alternatives
prevent local ischemia, heart attacks and other major adverse cardiac
events (MACE) due to platelet activation and aggregation that is
a result of percutaneous coronary intervention procedures. Xemilofiban
was developed as an oral formulation, giving it certain distinct
advantages over the IV alternatives.
Phase III clinical trials with more than 7,000 patients (See materials
about the EXCITE trials.). These trials attempted to gain market
approval for an oral course of treatment for six months. The FDA
did not grant market approval for this protocol because of insufficient
evidence of efficacy and concerns about safety over this long of
a period of treatment. The agency did suggest a resubmission for
a short period of treatment (2-4 days) around intervention procedures
such as angioplasties and stent placements. Pharmacia opted to shelve
the project, rather than move ahead with this reduced market opportunity.
Although the platelet
was once considered to be merely a passive participant in the coagulation
cascade, it is now recognized as an active synthesizer of humoral
factors that potentiate both clot formation and inflammation.
- For several decades,
antiplatelet therapy centered on the thromboxane pathway and its
inhibition by aspirin, and aspirin remains the background template
therapy for acute ischemic syndromes, as well as for secondary
- However, despite the
wealth of data that support the use of aspirin, and indeed the
data that suggest it should be more widely prescribed, aspirin
remains a suboptimal antiplatelet agent, as evidenced clinically
by the fact that even patients who are taking aspirin may nevertheless
sustain a thrombotic event. 5-40% incidence of aspirin resistance.
- Drugs have been developed
to improve on the template of aspirin therapy; the glycoprotein
IIb/IIIa inhibitors and the thienopyridines have been extensively
- Large individual variability
exists in response to clopidogrel, new data presented at the American
College of Cardiology 2003 Scientific Sessions suggests. The researchers,
led by Dr Wei Lau (University of Michigan Health System, Ann Arbor),
estimate that around 28% of people may not respond adequately
to the antiplatelet effects of the drug.
- The glycoprotein IIb/IIIa
receptor is an integrin found in high concentration on the platelet
membrane, and is often referred to as the final common pathway
of platelet aggregation. The evidence supporting the utility of
intravenous GPIIb/IIIa inhibition in percutaneous coronary intervention
is overwhelming. However, "platelet escape"
has been observed with ReoPro® under constant infusion.
- In contrast to the
favorable data obtained for the intravenous GPIIb/IIIa inhibitors,
results with oral GPIIb/IIIa inhibitors have been disappointing.
This showed that our understanding of GPIIb/IIIa inhibition was
not as deep as believed.
- Three major factors
appear to contribute to undesirable therapeutic effect from
oral or IV GP: paradoxical antagonist-induced platelet activation,
the level of platelet inhibition "platelet escape",
and local and system inflammation.
A critical issue
with the use of the Fibans, either oral or intravenous, is
the extent, duration and timing of platelet inhibition.
- Moderate levels
of platelet inhibition not only lack efficacy but, when prolonged,
are associated with a paradoxical increase in ischemic events
due to the unmasking of antagonist-induced prothrombic and
for the foreseeable future the use of ASA, heparin, (Low Molecular
Weight Heparin), thienopyridines and GPIIb/IIIa inhibitors will
be the standard of care in PCI with Stent, for the foreseeable
future. See Figure 1.
1 Current and Future therapeutic Scenario's
yellow are product innovators or market leaders. Axis describes
sites of activity or treatment scenario.
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