The mechanism of anti-thrombotic, thrombolytic and fibrinolytic actions of camonagrel--a new thromboxane synthase inhibitor.
So far pharmacological consequences of inhibition of thromboxane A2 (TXA2) synthase by imidazole derivatives (e.g., camonagrel or dazoxiben) were linked to suppression of platelet activity. Here we report that in patients with peripheral atherosclerosis or in cats with extracorporeal thrombogenesis treatment with camonagrel is associated with activation of fibrinolysis or thrombolysis. These phenomena seem to be related to the camonagrel-induced shift in metabolism of prostaglandin endoperoxides from TXA2 to prostacyclin (PGI2), although in an in vitro model the involvement of the L-arginine/nitric oxide pathway cannot be excluded. In cats camonagrel (10 mg/kg i.v.) produced not only a fall in TXB2 but also a rise in 6-keto-PGF1 alpha and no change in cyclic-GMP plasma levels. This points to PGI2 rather than to nitric oxide as an in vivo mediator of camonagrel-induced thrombolysis. The crucial role of endogenous PGI2 in the thrombolytic response to camonagrel in cats was evidenced by its blockade following pretreatment of animals with a megadose of aspirin (50 mg/kg i.v.) and lack of any effect on pretreatment with L-NAME (100 micrograms/kg/min, i.v.). Obviously TXA2 synthase inhibitors (e.g., camonagrel) and cyclo-oxygenase inhibitors (e.g., aspirin) antagonize each other in their anti-thrombotic actions and must not be administered at the same time. Furthermore, in patients camonagrel (800 mg orally) suppressed TXA2 generation by 99.5% and doubled the plasma level of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Gryglewski
R J
RJ
Department of Pharmacology, Jagiellonian University, Medical College, Cracow, Poland.
Szczeklik
A
A
Korbut
R
R
Swies
J
J
Musiał
J
J
Krzanowski
M
M
Maga
P
P
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D001780:Blood Coagulation Tests; D002415:Cats; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D013927:Thrombosis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D013928:Thromboxane A2 / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D018608:Ultrasonography, Doppler / Q000187:drug effects
D007093:Imidazoles; C029166:dazoxiben; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase