Effective, selective and specific inhibition of COX-1 may overcome the 'aspirin paradox'

摘要

The central role that activated platelets play in the establishment and progression of arterial thrombosis can readily be appreciated from the major efforts pharmaceutical companies have devoted to the development and marketing of drugs that target platelet receptors and enzymes involved in governing platelet responses to agonists [1-3]. The net effects of the bi-directional interactions between platelets and endothelial cells probably determine whether hemostasis or thrombosis occurs in any given situation. During agonist-mediated platelet activation, platelets rapidly (i. e. within seconds of an agonist binding to its receptors) on platelets) secrete ADP and ATP (and other molecules) from their a-granules and platelet cyclooxygenase-1 (COX-1) initiates the synthesis of thromboxane A2 (TXA2) from platelet-derived arachidonate. These platelet-derived products collectively help to effectively propagate platelet responses to agonists that result in adhesion of platelets to thrombogenic surfaces and platelet aggregation thereon [4-6], While the endothelium provides a potential thrombogenic surface for platelet adhesion, the endothelium is also a primary site for synthetizing three important antithrombotic principles that acting together can minimize the adhesion of resting and activated platelets to the endothelium. The three antithrombotic agents are prostacyclin (PGI2) and nitric oxide (both synthesized in response to agonists) and the constitutively expressed endothelial CD39 (ADPase/ATPase or nucleoside triphos-phate diphosphate hydrolase or NDTase-1) [7j. PGI2 prevents and nitric oxide inhibits platelet responses to agonists whereas CD39 hydrolyses platelet-derived ADP and ATP thereby eliminating their ability to augment platelet responses to agonists [7-10].