Résumés
Résumé
Le traitement des maladies thrombotiques implique l’utilisation de substances antiplaquettaires, anti-coagulantes ou profibrinolytiques. L’action antiplaquettaire de l’aspirine est due à l’inhibition indirecte de la production du thromboxane A2 (TXA2), un puissant vasoconstricteur également activateur des plaquettes. Le terutroban (S 18886), quant à lui, agit plus spécifiquement comme antagoniste sélectif des récepteurs TP, les récepteurs du TXA2 qui, dans le système vasculaire, se trouvent sur les plaquettes, les cellules musculaires lisses et l’endothélium. Les études précliniques et cliniques effectuées avec le terutroban ont démontré ses effets antithrombotiques. Le but de cette revue est de résumer le rôle des récepteurs TP endothéliaux dans l’athérogenèse et de décrire les études qui, menées avec le terutroban, ont contribué à établir ce rôle. En effet, l’activation des récepteurs TP endothéliaux, en provoquant l’expression de molécules d’adhérence qui favorisent l’adhérence et l’infiltration de monocytes/macrophages dans la paroi artérielle, participe à la genèse de l’athérosclérose.
Summary
Treatment of thrombotic diseases implicates the use of anti-platelet agents, anti-coagulants and pro-fibrinolytic substances. Amongst the anti-platelet drugs, aspirin occupies a unique position. As soon as it became evident that the major action of aspirin is indirect blockade, through inhibition of cyclooxygenase (COX), of the production of thromboxane A2 (TXA2), a powerful vasoconstrictor and platelet activator, research for new anti-thrombotics that interact more specifically with the production and/or the action of TXA2 was started. Terutroban (S 18886) is a selective antagonist of TP receptors, the receptors for TXA2, that are present on platelets and on vascular smooth muscle cells, but also on endothelial cells. The role played by the platelet and smooth muscle cell TP receptors in thrombotic disease is well known, and preclinical and clinical studies with terutroban have illustrated the powerful antithrombotic effects of this agent. The implication of endothelial TP receptors in the development of atherosclerotic disease has only been examined during the past five years and studies with terutroban have been crucial for understanding the role of these endothelial receptors in cardiovascular physiopathology. The goal of the present review is to discuss the arguments in favour of the hypothesis suggesting that activation of endothelial TP receptors, by causing expression of adhesion molecules, favours adhesion and infiltration of monocytes/macrophages in the arterial wall, thereby stimulating the development of atherosclerosis. The review will also highlight the important contribution of the studies performed with terutroban in this research area. The triple activity (anti-thrombotic, anti-vasoconstrictor, anti-atherosclerotic) observed with terutroban in preclinical studies, stressed by the first results in clinical development, places terutroban as an innovative drug with a unique potential for treatment of cardiovascular disorders.
Parties annexes
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