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Effects of 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine on anticoagulation in mice and the inhibition of experimental thrombosis in rats.

Journal of cardiovascular pharmacology (2014-08-29)
Hai-Ling Yu, Feng Zhang, Tian Lan, Zhe-Shan Quan
ABSTRACT

: Thrombosis is a major complication that could be fatal in acute or chronic cardio-cerebral-vascular diseases. Therefore, the development of novel agents for anticlotting and the prevention of thrombosis and cardiovascular diseases are clinically significant. This study aimed to evaluate the anticoagulant and antithrombotic effects of 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine (Q808), a new phthalazine tetrazole derivative. Bleeding time, clotting time, and serum calcium ion (Ca) concentration were assessed in mice, whereas arteriovenous thrombus weight and plasma prothrombin time were evaluated in rats, and platelets Ca influx was determined in rabbit. Daily oral administration of Q808 at 25, 50, or 100 mg/kg for 3 days significantly delayed bleeding time and clotting time in mice compared with controls. Q808 administration at 50 mg/kg significantly reduced experimental thrombus weight by 62.6% and delayed plasma prothrombin time by 58.7% in rats, whereas 50 and 100 mg/kg of Q808 daily significantly increased serum Ca concentration in mice. Q808 at 0.2, 0.4, and 0.8 mg/mL significantly inhibited thrombin-induced Ca influx in rabbit platelets. Our results suggest that Q808 at 25-200 mg/kg daily exerts anticoagulant and antithrombotic effects, and its mechanisms of action may involve both the intrinsic and extrinsic coagulation pathways that inhibit certain coagulation factors and platelet functions.

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