New Drug ClassesPlatelet GPIIb-IIIa blockers
Section snippets
αllbβ3the molecule
To understand the biology of GPIIb-IIIa blockers requires a brief consideration of the structure and function of their target. Of the many families of adhesion receptors, the integrins are among the largest; and αIIIbβ3 is one of the more than twenty integrins.4 All integrins are noncovalently linked α/β heterodimers (figure 1). The aminoacid sequence of αIIIbβ3 indicates that each subunit has a large extracellular domain, a single transmembrane region, and a short cytoplasmic tail. The αIIIb
αIIIbβ3 function
Under conditions of normal haemostasis, platelets circulate freely in the blood without interacting with the vessel wall or with each other. Vascular injury, such as rupture of an atherosclerotic plaque, perturbs the non-thrombogenic properties of the endothelium and exposes the subendothelial matrix, including collagens, fibronectins, laminin, and von Willebrand factor (vWF). These ground substances are recognised by adhesion receptors, notably GPIb-IX-V and GPVI and integrins α2β1, α5β1 and α6
αIIbβ3 antagonism
The participation of αIIIbβ3 in platelet aggregation, whatever the initiating event or agonist, provides the molecular logic for therapeutic blockade of this receptor. The feasibility of such blockade was demonstrated in the early 1980s by the development of peptides and antibodies that could interact with αIIIbβ3, block ligand binding to the receptor, and inhibit platelet aggregation.24 In theory, this blockade should not compromise platelet adhesion to the subendothelial matrix so that
Clinical efficacy
Over the past decade considerable experience with inhibition of αIIIbβ3 has been accrued in clinical trials. The results of 10 large, placebo-controlled randomised trials, superimposed on aspirin background therapy, are summarised in figure 4.30, 31, 32, 33, 34, 35, 36, 37, 38, 39 Four parenterally administered GPIIb-IIIa blockers (abciximab, eptifibatide, and tirofiban and lamifiban) have been tested in two different clinical indications–namely, percutaneous coronary intervention and the acute
Safety
In the early trials, GPIIb-IIIa blockade was associated with a significantly higher rate of bleeding complications30, 33 but this proved to be largely attributable to excessive and prolonged concurrent heparin administration. All of the later trials, incorporating reduced, weight-adjusted heparin regimens, have demonstrated no excess in major bleeding, as defined by need for transfusion or by a 5 g/dL or greater fall in haemòglobin.31, 32, 35, 36, 39 Importantly, there has been no excess in
Unresolved issues
Despite the impressive progress in our understanding of αIIIbβ3 and its role in platelet function and the promising entry of GPIIb-IIIa blockers into patient care, much remains to be learned. Critical questions are:
Precisely how do ligands and antagonists bind to αIIIbβ3 A three-dimensional structure of αIIIbβ3 is vital to our understanding of the receptor and to drug design.
How does αIIIbβ3 become activated and can specific activation events be targets for new antithrombotic drugs? Such
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2022, CellCitation Excerpt :However, despite emergence of new targets, including integrins αVβ6 and αVβ8 in fibrosis and immuno-oncology, there are no approved chronic (oral) small-molecule integrin antagonists. An intense pharmaceutical effort to develop oral antagonists of αIIbβ3 following the success of parenteral ligand mimetics (Scarborough and Gretler, 2000) was fueled by anticipation of “the dawn of a new era in antithrombotic therapy, the era of αIIbβ3 antagonism” (Topol et al., 1999). However, oral integrin antagonists (Chew et al., 2001; Topol et al., 2003), as well as longer-term dosing of parenteral inhibitors (Théroux et al., 1998), were beset with massive failure.
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