PHARMACOLOGICAL CHARACTERIZATION OF A NEW 4-AMIDINOPHENYL-ALANINE THROMBIN-INHIBITOR (CRC-220)

The new thrombin inhibitor CRC 220 was characterized in vivo for its a ntithrombotic effects. CRC 220 led to a dose-dependent prolongation of clotting parameters as determined in rats, rabbits, dogs, sheeps, pig s and monkeys. We evaluated the efficacy of CRC 220 to prevent thrombu s formation in arteries and in the microcirculation in different anima l models. In a rabbit model of tissue factor-induced coagulation activ ation, infusion of 0.5 mg/kg x h CRC 220 (3 hours) led to a significan t prevention of fibrinogen decrease. In a rat model of lethal LPS-indu ced DIC CRC 220 significantly prevented the mortality rate after a 4h- infusion of 0.75 mg/kg x h. Thrombin-induced platelet aggregation in r at lungs could be prevented by the i.v, bolus injection of CRC 220. A dose of 0.3 mg/kg leads to a reduction of more than 80% of platelet de position in the lung, significant inhibition was still observed 90 min utes after CRC 220 administration; at this time the inhibitor had alre ady been cleared from plasma. Arterial thrombosis was induced in rabbi ts by squeezing and stenosis of the A. carotis. The i.v. bolus adminis tration of CRC 220 dose-dependently prevented thrombus formation, an E D(50) of 0.03 mg/kg was calculated. This dose was associated with only a minor prolongation of aPTT.