Pharmacodynamic Properties of Antiplatelet Agents

Current Knowledge and Future Perspectives

Kallirroi I Kalantzi; Maria E Tsoumani; Ioannis A Goudevenos; Alexandros D Tselepis


Expert Rev Clin Pharmacol. 2012;5(3):319-336. 

In This Article

Thromboxane & Prostaglandin Endoperoxide Receptor Antagonists

TxA2 secreted from activated platelets binds to specific G-coupled receptors, the TP receptors (thromboxane and prostaglandin endoperoxide PGG2–PGH2 receptors), and serves as an agonist of these receptors. TP receptors are present in platelets, macrophages, monocytes, vascular endothelial cells and smooth muscle cells, and are abundantly expressed in atherosclerotic plaques.[116] Antagonism of TP receptors may inhibit platelet function and thrombosis, and also atherogenesis, by reducing vessel wall inflammation and proliferation induced by TP agonists TxA2, PG endoperoxides, and isoprostanes secreted by activated platelets, circulating monocytes and macrophages resident in the plaques.[117] Consequently, TP is an attractive target for the development of both anti-thrombotic and antiatherogenic agents.

Previous attempts to develop TP antagonists failed owing to poor pharmacodynamic properties, since persistent and complete platelet inhibition, as is afforded by aspirin, was not achieved with these compounds. Studies in animal models revealed that directly targeting the TP receptor may provide beneficial CV effects that are superior to those obtained by inhibiting COX-1.[118] In this regard, an orally available TP antagonist, terutroban (S-18886), inhibits TxA2-induced platelet aggregation and vasoconstriction, improves endothelial function and has an antiatherogenic effect. The potential therapeutic applications of terutroban in the prevention of atherothrombosis, particularly in stroke and coronary artery disease, are based on a number of experimental animal and clinical studies.[119,120] A pharmacokinetic/pharmacodynamic study was conducted in 30 patients with peripheral artery disease who were randomized to receive five different oral doses of terutroban (1, 2.5, 5, 10 or 30 mg) for 12 weeks. The pharmacokinetics of terutroban was linear, with peak plasma levels being reached between 30 min and 2 h with a half-life of 5.8–10 h. No significant accumulation of terutroban in plasma was observed after repeated dosing and there was a predictable relationship between the plasma drug concentration and the degree of platelet inhibition. Maximal inhibition of platelet aggregation was achieved within 1 h with all oral doses of terutroban, and this effect was maintained for at least 12 h. No major adverse events were observed after terutroban administration.[121] Despite the above promising data, the clinical development of terutroban was recently discontinued after an analysis in a Phase III PERFORM trial revealed that terutroban (30 mg/day) is unlikely to exhibit superiority versus low aspirin dose (100 mg/day) on reducing cerebrovascular and CV events in over than 19,000 patients with a recent history of cerebrovascular ischemia.[122] Other TP antagonists (GR 32191, ifetroban and sulotroban) had also disappointing results in Phase II and III clinical trials.[4] Consequently, despite the promising pathophysiological and pharmacodynamic data obtained using the TP antagonists, the clinical efficacy and safety of these agents still remains an issue for further investigation.


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