Antithrombotic effects in a rat model of aspirin-insensitive arterial thrombosis of desethyl KBT-3022, the main active metabolite of a new antiplatelet agent, KBT-3022

Abstract

The antithrombotic effect of desethyl KBT-3022, which is the main active metabolite of the new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl] pyrrol-1-ylacetate; a cyclooxygenase inhibitor), was determined using a photochemically induced arterial thrombosis model in the rat femoral artery. Pretreatment with desethyl KBT-3022 (0.1, 0.3 and 1 mg/kg, i.v.) prolonged the time required to achieve thrombotic occlusion in the femoral artery and inhibited collagen-induced platelet aggregation in whole blood ex vivo, each in a dose-dependent manner. In all 6 rats used, particularly at the highest dose (1 mg/kg, i.v.) tested, cyclic variations in blood flow were hardly ever observed and complete cessation of blood flow did not occur during the 30-min observation time. BM-13505 (1, 3 and 10 mg/kg, i.v.), a thromboxane A2 receptor antagonist, also prolonged the time to occlusion, but cyclic variations in blood flow did occur. On the other hand, aspirin (10 and 30 mg/kg, i.v.) had little effect in terms of preventing thrombosis, although it inhibited collagen-induced platelet aggregation to the same extent as did desethyl KBT-3022. Desethyl KBT-3022 inhibited the thrombin-induced aggregation of washed platelets in a concentration-dependent manner (1-40 microM), whereas aspirin and BM-13505 did not. These findings suggest that the potent antithrombotic effect of desethyl KBT-3022 may be attributable in part to its additional ability to inhibit thrombin-induced platelet aggregation. Accordingly, thromboxane A2 and thrombin may be important thrombotic mediators in this rat model.

Potential adverse interaction between aspirin and Lisinopril in hypertensive rats

“…had little effect in terms of preventing photochemically induced arterial thrombosis in the rat femoral artery. 20 A synergistic effect of ticlopidine/ASA association was demonstrated with regard to ADP and collagen-induced platelet aggregation and also in experimental models including silk thread-induced thrombosis where a total inhibition of thrombosis formation was observed at highest dosage of ticlopidine and ASA tested (i.e., 100 /100 mg/kg p.o.). 21 Kalkman et al 22 carefully selected and validated the dose of 25 mg/kg per day ASA which caused marked inhibition of thromboxane production in rats but did not interfere with prostacyclin production reflecting the aims of low-dose ASA treatment in man.…”

Inhibitors of platelet signal transduction as anti-aggregatory drugs

“…At higher concentrations inhibition of cAMP phosphodiesterase and release of phosphatidic acid is observed [132]. The metabolite desethyl KBT-3022 was also able to inhibit ASA insensitive thrombosis in a photochemically-induced rat thrombosis model [133] and serotonin secretion more potently than ticlopidine [131]. In experimental models of aortic thrombosis KBT-3022 proved superior to ASA and ticlopidine regarding inhibition of thrombus formation, while in stasis-induced venous thrombosis models KBT-3022 failed to inhibit thrombosis [134].…”