Thromboxane Receptors Antagonists and/or Synthase Inhibitors
Atherothrombosis is the major cause of mortality and morbidity in Western countries. Several clinical conditions are characterized by increased incidence of cardiovascular events and enhanced thromboxane (TX)-dependent platelet activation. Enhanced TX generation may be explained by mechanisms relatively insensitive to aspirin. More potent drugs possibly overcoming aspirin efficacy may be desirable. Thromboxane synthase inhibitors (TXSI) and thromboxane receptor antagonists (TXRA) have the potential to prove more effective than aspirin due to their different mechanism of action along the pathway of TXA2. TXSI prevent the conversion of PGH2 to TXA2, reducing TXA2 synthesis mainly in platelets, whereas TXRA block the downstream consequences of TXA2 receptors (TP) activation.
TXA2 is a potent inducer of platelet activation through its interaction with TP on platelets. TP are activated not only by TXA2, but also by prostaglandin (PG) D2, PGE2, PGF2α, PGH2, PG endoperoxides (i.e., 20-HETE), and isoprostanes, all representing aspirin-insensitive mechanisms of TP activation. Moreover, TP are also expressed on several cell types such as macrophages or monocytes, and vascular endothelial cells, and exert antiatherosclerotic, antivasoconstrictive, and antithrombotic effects, depending on the cellular target.
Thus, targeting TP receptor, a common downstream pathway for both platelet and extraplatelet TXA2 as well as for endoperoxides and isoprostanes, may be a useful antiatherosclerotic and a more powerful antithrombotic intervention in clinical settings, such as diabetes mellitus, characterized by persistently enhanced thromboxane (TX)-dependent platelet activation through isoprostane formation and low-grade inflammation, leading to extraplatelet sources of TXA2. Among TXRA, terutroban is an orally active drug in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. Despite great expectations on this drug supported by a large body of preclinical and clinical evidence and pathophysiological rationale, the PERFORM trial failed to demonstrate the superiority of terutroban over aspirin in secondary prevention of cerebrovascular and cardiovascular events among ~20,000 patients with stroke. However, the clinical setting and the design of the study in which the drug has been challenged may explain, at least in part, this unexpected finding.
Drugs with dual action, such as dual TXS inhibitors/TP antagonist and dual COXIB/TP antagonists are currently in clinical development. The theoretical rationale for their benefit and the ongoing clinical studies are herein discussed.
KeywordsAntiplatelet therapy Atherothrombosis Ischemic stroke Platelet activation Thromboxane biosynthesis TP antagonists
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