isbogrel and Thrombosis

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.

Topics: Animals; Aspirin; Bleeding Time; Endothelium, Vascular; Fatty Acids, Monounsaturated; Femoral Vein; Male; Methacrylates; Platelet Aggregation; Pyridines; Rats; Rats, Sprague-Dawley; Thrombosis; Thromboxane-A Synthase; Thromboxanes; Ticlopidine

This study was designed to clarify the mechanism of a reversal of the ischemia-induced decrease in adenosine triphosphate (ATP) in relation to the changes in liver blood flow. All vessels to the left and median lobes were occluded for 15 or 30 min and then reperfused for 15 or 30 min, respectively. Ischemia led to a significant decrease in the ATP level. ATP levels recovered fully after 30 min of reperfusion following 15 min of occlusion. However, a significantly low ATP level was observed even after 30 min of reperfusion following 30 min of occlusion. Premedication with CV-4151 (5 mg/kg, i.v.), a thromboxane A2 (TXA2) synthetase inhibitor, significantly improved the recovery of ATP levels after 30 min of reperfusion following 30 min of occlusion. Liver blood flow was restored fully immediately after reperfusion following 15 min of occlusion. In contrast a significantly low liver blood flow was observed after 30 min of reperfusion following 30 min of occlusion. Premedication with CV-4151 accelerated the recovery of liver blood flow after reperfusion. Morphological studies revealed that microthrombi were formed during ischemia, and CV-4151 mitigated the formation of microthrombi. These results indicate that the formation of microthrombi, which might be associated with TXA2 synthesis during ischemia, inhibited the restoration of liver blood flow, which might be responsible for the obstruction of the recovery of ATP.

Topics: Adenosine Triphosphate; Animals; Fatty Acids, Monounsaturated; Guanosine Triphosphate; Liver; Male; Pyridines; Rats; Rats, Inbred Strains; Reperfusion Injury; Thrombosis; Thromboxane-A Synthase

Topics: Animals; Coronary Disease; Dogs; Epoprostenol; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Pyridines; Rats; Thrombosis; Thromboxane B2; Thromboxane-A Synthase