TP Receptor Antagonism: A New Concept in Atherothrombosis and Stroke Prevention

Abstract

Conventional antiplatelet agents such as aspirin, ticlopidine, and clopidogrel are currently used in the prevention of cardiovascular and cerebrovascular events. However, side effects such as bleeding complications and gastrointestinal disorders and, in some patients, resistance have made the development of new agents desirable. Recently, thromboxane receptors (thromboxane and prostaglandin endoperoxide PGG₂-PGH₂ receptors) called TP receptors have received increasing attention. These receptors are membrane-bound G-coupled receptors found not only on platelets but also on macrophages, monocytes, vascular endothelial cells, and smooth muscle cells. Antagonists of TP receptors have advantages over aspirin as they not only block the effect of thromboxane A₂ on platelets, but also inhibit other ligands such as prostaglandin endoperoxides and isoprostanes. Given the distribution of TP receptors in platelets, in circulating inflammatory cells, in the vascular wall and in atherosclerotic plaques, they also inhibit the effects of thromboxane A₂ over TP receptors on vascular cells or in the plaque. Terutroban (Triplion® or S18886), a new oral specific TP receptor antagonist, has, aside from being an antithrombotic agent, important vascular properties. It improves endothelial function and has an antiatherosclerotic effect. The potential therapeutic applications of terutroban in the prevention of atherothrombosis, particularly in the cerebrovascular and cardiovascular fields including stroke and coronary artery disease, are based on a number of convincing experimental animal and clinical studies. A large trial is currently comparing the efficacy and safety of terutroban versus aspirin in secondary prevention of cardiovascular events in patients who have suffered a stroke or transient ischemic attack (PERFORM Study).

New Directions in Antiplatelet Therapy

“…TXA 2 pathway inhibitors include picotamide (a combined TXA 2 synthase inhibitor and TP receptor blocker), ridogrel (a combined TXA 2 synthase inhibitor and TP receptor blocker), ramatroban (a TP receptor inhibitor), NCX 4016 (a nitric oxidereleasing aspirin derivative), Si8886/terutroban (a TP receptor inhibitor), and EV-077 (a combined TXA 2 synthase inhibitor and TP receptor blocker). 59,60 Some of these agents have been tested in clinical settings. In a randomized trial of patients with diabetes mellitus and peripheral artery disease (PAD), picotamide reduced long term overall mortality, but not major cardiovascular events, compared with aspirin.…”

Diabetes and Antiplatelet Therapy in Acute Coronary Syndrome

“…Ezeknek további jelentőségük lehet a cukorbetegek thrombocytáinak célzott kezelésében. [149][150][151][152] Az aszpirinkezelés kiegészítése clopidogrellel vitathatatlan klinikai előnnyel jár akut coronariaszindróma, illetve PCI esetén (lásd a táblázatban), azonban továbbra is jelentős számban következnek be visszatérő cardiovascularis események. Egyre több bizonyíték szól amellett, hogy e korlátozott hatékonyság hátterében a válaszkészség egyéni variációi állnak, diabetes mellitusban szenvedő betegek esetében is.…”

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

“…To this end, TPR's clear role in normal hemostasis is supported by the finding that “patients” have a bleeding disorder as a result of a point mutation in the receptor protein 14, 15, 16. On the other hand, upregulated signaling through TPR has been implicated in the pathogenesis of multiple cardiovascular and thrombosis‐based diseases 17, 18, 19, 20. Consistent with this concept are clinical findings indicating that inhibition of platelet TXA 2 production provides therapy for thromboembolic diseases,21, 22, 23 which is the underlying rationale for the use of aspirin in such diseases 24, 25…”