THE MECHANISM OF ANTITHROMBOTIC, THROMBOL YTIC AND FIBRINOLYTIC ACTIONS OF CAMONAGREL - A NEW THROMBOXANE SYNTHASE INHIBITOR

So far pharmacological consequences of inhibition of thromboxane A(2) (TXA(2)) synthase by imidazole derivatives (e.g., camonagrel or dazoxi ben) were linked to suppression of platelet activity. Here we report t hat in patients with peripheral atherosclerosis or in cats with extrac orporeal thrombogenesis treatment with camonagrel is associated with a ctivation of fibrinolysis or thrombolysis. These phenomena seem to be related to the camonagrel-induced shift in metabolism of prostaglandin endoperoxides from TXA(2) to prostacyclin (PGI(2)), although in an in vitro model the involvement of the L-arginine/nitric oxide pathway ca nnot be excluded. In cats camonagrel (10 mg/kg i.v.) produced not only a fall in TXB(2) but also a rise in 6-keto-PGF(1 alpha), and no chang e in cyclic-GMP plasma levels. This points to PGI(2) rather than to ni tric oxide as an in vivo mediator of camonagrel-induced thrombolysis. The crucial role of endogenous PGI(2) in the thrombolytic response to camonagrel in cats was evidenced by its blockade following pretreatmen t of animals with a megadose of aspirin (50 mg/kg i.v.) and lack of an y effect on pretreatment with L-NAME (100 mu g/kg/min, i.v.). Obviousl y TXA(2) synthase inhibitors (e.g., camonagrel) and cyclo-oxygenase in hibitors (e.g., aspirin) antagonize each other in their anti-thromboti c actions and must not be administered at the same time. Furthermore, in patients camonagrel (800 mg orally) suppressed TXA(2) generation by 99.5% and doubled the plasma level of 6-keto-PGF(1 alpha). This was a ccompanied by lowering of PAI-1 antigen concentration and a rise in pl asma t-PA activity. Euglobulin clot lysis time (ECLT) was also shorten ed. In conclusion, in men and cats camonagrel activates fibrinolysis a nd thrombolysis through the release of endogenous PGI(2).