Effects of thromboxane A2 synthase inhibitors (CV-4151 and ozagrel), aspirin, and ticlopidine on the thrombosis caused by endothelial cell injury.
The antiplatelet and antithrombotic effects of CV-4151 (isbogrel), a potent selective thromboxane A2 (TXA2) synthase inhibitor, were compared with those of ozagrel (OKY-046), aspirin, and ticlopidine in rats. Two hours after oral administration, CV-4151, ozagrel and aspirin inhibited blood TXA2 generation with ID50 values of 0.04, 0.3 and 6.4 mg/kg, respectively. These values were similar to the oral ID50 values of CV-4151 (0.06 mg/kg), ozagrel (0.92 mg/kg) and aspirin (7.0 mg/kg) for arachidonic acid (AA)-induced platelet aggregation ex vivo. Two hours after p.o. administration, CV-4151 and ozagrel inhibited femoral vein platelet-rich thrombosis caused by endothelial injury with ID50 values of 2.46 and 13.7 mg/kg, respectively. However, aspirin (100 mg/kg, p.o.) only slightly inhibited the thrombosis. Ticlopidine (300 mg/kg, p.o.) slightly but significantly inhibited AA-induced and ADP-induced platelet aggregation, however, it potently inhibited the thrombosis. CV-4151 and ozagrel given by i.v. injection showed therapeutic effects on the thrombosis with ED50 values of 0.026 and 0.066 mg/kg, respectively. These values were similar to the i.v. ED50 values of CV-4151 (0.0056 mg/kg) and ozagrel (0.042 mg/kg) for blood TXA2 generation. However, aspirin (30 mg/kg, i.v.) only moderately reduced the thrombosis. CV-4151 (> 0.3 mg/kg, p.o.), ozagrel (> 3 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) all significantly prolonged tail bleeding time. Aspirin (100 mg/kg, p.o.) tended to prolong the bleeding time. The antiplatelet and antithrombotic effects of CV-4151 are more potent than those of ozagrel, aspirin and ticlopidine in rats. CV-4151 may therefore be a useful drug for the treatment of thrombotic diseases.
Terashita
Z
Z
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
Imura
Y
Y
Kawamura
M
M
Kato
K
K
Nishikawa
K
K
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001760:Bleeding Time; D004730:Endothelium, Vascular / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005268:Femoral Vein; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000188:drug therapy*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors; D013988:Ticlopidine / Q000494:pharmacology*
D005229:Fatty Acids, Monounsaturated; D008689:Methacrylates; D011725:Pyridines; D013931:Thromboxanes; D013930:Thromboxane-A Synthase; C045446:isbogrel; C034364:ozagrel; D013988:Ticlopidine; D001241:Aspirin