Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker

Platelets play a major role in thrombus formation, as well as in the pathog enesis of atherothrombosis. Inhibition of platelet function is now emphasis ed more than ever for prevention and treatment of almost all vascular disea ses, since thrombosis is established as the key pathogenic event causing ac ute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicy lic acid (aspirin) has been shown to reduce the incidence of myocardial inf arction and stroke, its effect is weak and more effective antithrombotic ag ents are required to manage patients at high-risk for recurrent vascular ev ents. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represe nts a significant advance in interventional cardiology and treatment of acu te ischaemic syndromes. The past several years have seen the introduction o f many platelet GPIIb/IIIa blockers into the clinical arena targeting the u nique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen an d von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intraven ously have proven efficacious in mitigating arterial thrombosis in acute co ronary syndromes (unstable angina and non-ST-elevation myocardial infarctio n) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa block ers are being developed to provide additional benefits for primary and seco ndary prevention of thrombosis as chronic treatment, especially in high-ris k patients. Lotrafiban (SmithKline Beecham) is a member of the latest gener ation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III cl inical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-asp artic acid amino acid sequence. This sequence itself mimics the binding sit e of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa recept or. Preliminary results of the clinical trial APLAUD (antiplarelet useful d ose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic at tack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a wor ldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/II Ia receptor to avoid Vascular occlusion) is currently underway. In general, GPIlb/IIIa blockade seems clinically very promising. A number of unresolve d issues, however, remain to be elucidated.