PHARMACOLOGICAL PROPERTIES OF CY-216 AND OF ITS ACLM AND BCLM COMPONENTS IN THE RABBIT

This study compares some in vivo pharmacological properties of CY 216 and of its ACLM and BCLM components having a molecular weight above an d below 5.4 kDa respectively. The anti-factor Xa/antithrombin ratio of these compounds determined in a rabbit plasma system were 2.5 and 1.2 for CY 216 and ACLM respectively while BCLM was devoid of anti-thromb in effect. After bolus intravenous injection, continuous infusion and subcutaneous administration, the clearances of anti-factor Xa activity generated by ACLM were, on the average, 2 and 1.5 times higher than t hose generated by BCLM and CY 216 respectively. The clearances of the anti-thrombin activity were comparable for CY 216 and ACLM, and higher than those of the antifactor Xa activity. The duration of the antithr ombotic effect was investigated in the Wessler model after a single su bcutaneous injection of 1000 anti-factor Xa units of one of the compou nds. Using thromboplastin as thrombogenic stimulus, the most efficient agent was ACLM and the antithrombotic activity was essentially correl ated to the circulating anti-thrombin activity. Using human serum as t hrombogenic stimulus, ACLM and BCLM were more efficient than CY 216 an d the antithrombotic activity was mainly correlated to the anti-factor Xa activity. The ability of the 3 compounds to inhibit venous thrombo sis growth was compared: they were found equipotent and the antithromb otic effect was independent of the anti-thrombin activity. The prohaem orrhagic properties were compared in the rabbit ear model. The activit y of the 3 compounds were comparable and significantly less prohaemorr hagic than unfractionated heparin. These results suggest that the haem orrhagic potential of unfractionated heparin and of LMWH is independen t of the anti-thrombin and anticoagulant activity, but related to the molecular weight. These observations indicate that factor Xa inhibitio n is a valuable target to prevent and to treat venous thrombosis and t hat the anti-factor Xa activity of a low molecular weight heparin (LMW H) largely contributes to its antithrombotic effect.