Fibrinogen receptor antagonists

Abstract

Fibrinogen receptor antagonists represent a potential new form of antithrombotic therapy for the treatment or prevention of vascular complications including: myocardial infarct, unstable angina, stroke and complications during percutaneous transluminal angioplasty. They function by disrupting the fibrinogen - platelet glycoprotein llb-llla (GP llb-llla) interaction and are active inhibitors in vitro and in vivo of all platelet activating agents; however, aspirin, one current form of therapy, blocks only one pathway of platelet activation (thromboxane A₂ via cyclooxygenase). Initial clinical trials with the iv fibrinogen receptor antagonists, c7E3 (Centocor) and Integrelin (COR), demonstrate an enhanced efficacy over aspirin therapy in preventing vascular complications. Additional iv receptor antagonists (MK-0383, Merck; Ro 44-9883, Hoffmann LaRoche; SC-52012 Searle) are in Phase I clinical trials for similar indications. In animal models of an Ml, all of the above iv fibrinogen receptor antagonists have been used in combination therapy with a fibrinolytic agent (such as streptokinase, recombinant tissue plasminogen activator) and have prevented re-occlusion post-lysis. Several orally active fibrinogen receptor antagonists (SC-54684, Searle; L-703-014, Merck; GR 144,053, Glaxo; BIBU 104, Boehringer Ingleheim; DMP 728, DuPont Merck) designed for chronic adminstration to prevent a Mi or stroke and to treat unstable angina are in development. Clinical efficacy with the iv fibrinogen receptor antagonists has been demonstrated at 80% inhibition of ex vivo platelet aggregation and a percentage of receptors are available for maintaining haemostasis. Dosing regimens to achieve similar levels of inhibition may be required in chronic oral therapy to avoid potential side effects (bleeding events). Alternatively, dosing regimens are conceivable where the platelets would be 100% inhibited during high risk hours of the day, and sub-maximally inhibited during the remainder of the day to help maintain vascular haemostasis. The therapeutic index for this class of agent is still being determined.