The new
thrombin inhibitor
CRC 220 was characterized in vivo for its antithrombotic effects.
CRC 220 led to a dose-dependent prolongation of clotting parameters as determined in rats, rabbits, dogs, sheeps, pigs and monkeys. We evaluated the efficacy of
CRC 220 to prevent
thrombus formation in arteries and in the microcirculation in different animal models. In a rabbit model of
tissue factor-induced coagulation activation, infusion of 0.5 mg/kg x h
CRC 220 (3 hours) led to a significant prevention of
fibrinogen decrease. In a rat model of lethal LPS-induced
DIC CRC 220 significantly prevented the mortality rate after a 4h-infusion of 0.75 mg/kg x h.
Thrombin-induced platelet aggregation in rat 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 deposition in the lung, significant inhibition was still observed 90 minutes after
CRC 220 administration; at this time the inhibitor had already been cleared from plasma. Arterial
thrombosis was induced in rabbits by squeezing and
stenosis of the A. carotis. The i.v. bolus administration of
CRC 220 dose-dependently prevented
thrombus formation, an ED50 of 0.03 mg/kg was calculated. This dose was associated with only a minor prolongation of aPTT.