A Novel Anti-Thrombotic Heparinoid (ORG 10172) Devoid Of Bleeding Inducing Capacity: A Survey Of Its Pharmacological Properties In Experimental Models In Rats

The pharmacological profile of a heparinoid (Org 10172) was assessed In experimental thrombosis and bleeding models In rats. Org 10172 Inhibited thrombus formation In arteriovenous shunts dose dependently (ID₅₀=5 mg/kg i.v.); heparin USP had an ID₅₀ of 0,4 mg/kg I.v. in the same model. Taking the effective dose ratio of the compounds into account both Org 10172 and heparin USP similarly reduced the ¹²⁵I-fibrin content In thrombi; Org 10172 however affected less the ⁵¹Cr-labeled platelet content in the thrombi than heparin USP.

Heparin USP progressively prolonged bleeding at doses of 1 mg/kg i.v. and higher, whereas Org 10172 showed no increase in bleeding over a dose range of 50-200 mg/kg i.v. The benefit (anti-thrombotic)/risk (bleeding) ratio is at least 20-fold higher than for heparin USP.

In vitro Org 10172 did not Inhibit the collagen-Induced release of serotonin from platelets, in contrast to heparin USP. Org 10172 was at least 500 times less active In enhancing the thrombin-AT III Interaction than heparin USP, it showed a very small increase In APTT and had about 6% of the factor X_a- inhibiting activity of heparin USP. The improved profile of the drug may be attributed to these quite different effects on blood platelet function and the coagulation pathway.