ANTITHROMBOTIC ACTIONS OF A SULFOMUCOPOLYSACCHARIDE MIXTURE (ATERIOD) IN ANIMAL MODELS

Ateriod obtained from beef mucosal lining is a sulfomuco-polysaccharide mixture of various glycosaminoglycans which contains derma tans, heparatans and traces of heparin. It has been used in the treatment ofatherosclerosis and related vaso-oclusive disorders. Ateriod is standardized in terms of its lipoprotein lipase activation actions. Ateriod contains signfi-cant in vitro anticoagulant and antiprotease (anti-factor Xa and anti-factor Ila) activities as measured by clot-based and chromr ogenic substrate methods. However, this in vitro activity is 7-10 times lesser than heparin. In order to study the antithrombotic actions of this agent in subcutaneous, intravenous and oral routes, we utilized a rabbit stasis thrombosis model with a prothrombin complex concentrate/Russell's viper venom thrombogenic challenge and prolonged stasis. The apparent ED50 for the antithrombotic action were found to be: IV (75-100 ug/ kg), SC (0.8-1.3 mg/kg) and oral (20-30 mg/kg). In both the IV- and SC studies, sustained anticoagulant and antiprotease actions were evident. The observed antithrombotic actions did not relate to the anti-factor IIa or anti-factor Xa actions. Pretreatment of Ateriod with equigravimetric amounts of protamine and platelet factor 4 did not neutralize the antithrombotic actions of this agent in the rabbit model. In a primate (Macaca mulatta) model of pharmacokinetics, ex vivo analysis following subcutaneously administered Ateriod showed sustained anticoagulant and antiprotease effects. The time course of the subcutaneously administered Ateriod was markedly different than heparin and a low molecular weight heparin. Treated animals were shown to resist induced hypercoagulability following injection of homologous serum as measured by FPA generation for extended periods. These studies suggest that Ateriod produces a strong antithrombotic action and that it has highly sustained pharmacokinetics. The antithrombotic activity appears to be primarily mediated via non-antithrombin - HI dependent events which may be related to heparin cofactor II and vascular/ cellular modifications.