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

Abstract

Summary. Platelet activation and thrombus formation play a critical role in the onset of acute coronary syndromes. Thromboxane A 2 (TxA 2 ) is among the different chemical modulators released by activated platelets. TxA 2 is considered one of the most powerful agonists for platelet activation. In addition, TxA 2 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 TxA 2 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 lg kg )1 day )1 were selected based on a previous platelet aggregation study. S 18886 shows a dosedependent 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.

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study

“…Terutroban is a selective TXA 2 / prostaglandin endoperoxide (TP) receptor antagonist with potent antithrombotic activity, as well as antiatherosclerotic and antivasoconstrictive properties [1]. The antithrombotic properties of terutroban have been investigated in animal models [2,3], including ex vivo models of thrombosis in a Badimon chamber [4]. Ex vivo experiments have also been performed in patients previously treated with aspirin for the primary or secondary prevention of ischemic stroke: in this setting, terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to the clopidogrel and aspirin combination [5].…”

Effect of the Thromboxane Prostaglandin Receptor Antagonist Terutroban on Arterial Thrombogenesis after Repeated Administration in Patients Treated for the Prevention of Ischemic Stroke

“…Terutroban is currently in development as an antiplatelet agent with a new mode of action and with additional antivasoconstrictive and antiatherosclerotic properties. Terutroban has potent antiplatelet activity, reportedly at least as effective in patients as aspirin [3], and its antithrombotic activity has been demonstrated in a porcine model of thrombosis [3]. …”

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

“…Notably, none of the antagonists that were developed for TPR has received approval by the Food and Drug Administration; and they face important shortcomings and limitations because of frequent administration, high doses, and high costs 18, 37, 38, 55, 56, 60. In contrast, much like our passive immunization studies,19, 47 we believe that active vaccination is likely to offer a promising approach for the treatment of thrombosis.…”