Anti-GPIIb/IIIa Drugs: Current Strategies and Future Directions

Abstract

SummaryThree platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been approved as adjunctive therapy to decrease the ischemic complications of percutaneous coronary interventions (PCI) and/or unstable angina. They include the chimeric murine/human monoclonal antibody 7E3 Fab fragment (abciximab), a cyclic heptapeptide based on the KGD amino acid sequence (eptifibatide), and a nonpeptide mimetic of the RGD sequence (tirofiban). The agents are very effective in providing both short-term and long-term benefit after PCI, and one agent has also demonstrated a progressive long-term mortality benefit. The long-term mortality benefit is highly cost-effective when compared to other medical interventions. The benefits in treating unstable angina without PCI are less dramatic and robust, with some agents providing no benefit. Severe thrombocytopenia is an infrequent, but potentially serious, complication of therapy with all of the agents. The risk of major bleeding is increased only minimally or not at all by the drugs. Currently, a number of new indications for GPIIb/IIIa antagonists are under study, including acute myocardial infarction (± thrombolytic therapy, ± PCI) and stroke. In addition to their impact on improving outcome, the results of clinical trials with these agents provide crucial insights into the contribution of GPIIb/IIIa-mediated platelet function in the pathophysiology of thrombotic vascular disease.

Cyclic arginine-glycine-aspartic acid peptide inhibits macrophage infiltration of the kidney and carotid artery lesions in apo-E-deficient mice

“…Our findings extend the previous usage of RGD peptides in blocking cell-to-matrix adhesion, inhibiting angiogenesis and platelet aggregation, and as probes for imaging of vascular injury (4,6,10,21,23) and raise the possibility of their therapeutic applicability in suppressing monocytic infiltration of the vascular wall, the prerequisite for the formation of atherosclerotic plaque, especially in the vessels with intimal injury and in renal microcirculation. Therefore, our observation on the potency of cRGD peptide in inhibiting monocyte-endothelial cell interaction makes this nontoxic and nonimmunogenic compound an attractive alternative to the neutralizing antibodies.…”

Recent insights on biochemical and molecular basis for developing antihaemostatic agents: A review

“…Based on these structural data, tirofiban, a tyrosine analog, was developed. Tirofiban has been tested in several clinical trials in the treatment of non-ST -elevation myocardial ischemia (11). It has reduced the death rate, new myocardial ischemia, or refractory, ischemia during the 48-hour infusion period largely as a result of reduction in recurrent ischemia.…”

“…Further, patients who received the combination of tirofiban and heparin had reduced 30-day mortality and recurrent ischemia. Several other oral compounds were developed for clinical use including lamifiban, xemilofiban and fradafiban (11). However, despite the potential advantage of sustained glycoprotein lib/Ilia blockade and the ease of oral administration, initial results with oral agents were disappointing and these agents had an adverse impact on myocardial infarction and death(13).…”

“…Eptifibatide: Eptifibatide, a disulfide-linked cyclic peptide, is a short acting and reversible inhibitor of platelet aggregation (11 ). Eptifibatide contains a lysineglycine-aspartic acid sequence similar to that found in the snake venom, barbourin.…”

“…Thromboxane synthase is an enzyme responsible for platelets aggregation and selective inhibitors against Abciximab: Abciximab is derived from a murine monoclonal antibody that binds glycoprotein Ilbtllla and prevents adhesive ligands from binding to the activated receptor (11). It is a potent inhibitor of platelet aggregation.…”