Antithrombotic effects of S 18886, a novel orally active thromboxane A2 receptor antagonist

Abstract

Platelet activation and thrombus formation play a critical role in the onset of acute coronary syndromes. Thromboxane A2 (TxA2) is among the different chemical modulators released by activated platelets. TxA2 is considered one of the most powerful agonists for platelet activation. In addition, TxA2 exerts a vasoconstrictor effect by serving as an agonist of the thromboxane receptor (TP) on the vascular smooth muscle cell membranes. The putative effect of TxA2 on thrombosis is demonstrated by the clinical effectiveness of acetylsalicylic acid (ASA) in the prevention of acute coronary syndromes. Among the clinically used antiplatelet agents, clopidogrel has shown to be slightly more effective than ASA in the prevention of atherothrombotic events in patients with peripheral arterial disease, and is one of the most widely used after aspirin. The aims of the study were to study the antithrombotic effects of escalating doses of the TP-receptor antagonist, S 18886 and to compare its effects with those achieved by the administration of ASA (5 mg kg-1 day-1), and clopidogrel (3 mg kg-1 day-1). The study was undertaken at high and low shear rate conditions using the Badimon perfusion chamber in a porcine model. Antithrombotic effects were assessed as changes on platelet and fibrin(ogen) deposition. The doses of 30 and 100 micro g kg-1 day-1 were selected based on a previous platelet aggregation study. S 18886 shows a dose-dependent antithrombotic response. The dose of S-100 develops similar antithrombotic effects to those of clopidogrel and superior to those of aspirin. The antithrombotic effects were statistically significant at both studied shear rate conditions. Therefore, the orally active TP-receptor antagonist, S 18886, appears to be a new and effective agent to prevent atherothrombotic complications.