ENDOTHELIAL FUNCTION MODULATION AND CONTROL OF VASCULAR AND THROMBOTIC DISORDERS: EXPERIMENTAL RESULTS WITH A POLYDEOXY RIBONUCLEOTIDE AGENT DEFIBROTIDE

Abstract

Numerous approaches with single and multiple drugs modulating protease cascade, platelet function and blood viscosity and to reduce blood lipids to manage thrombotic processes have been tried. Defibrotide, a polydeoxyribonucleotide, (Mr =17,000) offers a new approach to vascular and related thrombotic processes as it acts via modulation of endothelial cell function. We have used a primate model (Macaca mulatta) to study the endogenous action of this agent after the oral (10-25 mg/kg) and intravenous (5-10 mg/kg) administration. This agent produced no effect on clotting tests and ex vivo laboratory findings but rather it elevated the t-PA (antigen and functional), protein C (antigen and functional), prostacyclin and decreased thromboxane, 01.2-antiplasmin (functional) and t-PA inhibitor (functional) in both studies. These observations suggest that Defibrotide modulates endothelial function. Hepatic isolation in rabbits totally blocked the antithrombotic actions of Defibrotide suggesting that this agent is converted into an active product endogenously. Pretreatment of Defibrotide with nucleases also resulted in a complete loss of its actions. Defibrotide produced dose dependent antithrombotic actions in animal models (rabbit venous stasis and rat vena caval ligation) after either intravenous or oral administration. Blood pressure, heart rate, respiration and kidney function were not altered by it. No effect on bleeding time was noted in any studies. Upon oral administration this drug produced pharmacologic action after 2 hours whereas after intravenous administration, the action peaked at 30 minutes. Defibrotide exhibited cytoprotective effects towards endothelial lining of the vascular smooth muscles characterized by microscopic studies. In summary Defibrotide is an endothelial support agent whose multicomponent actions are primarily mediated via the physical and functional modulation of the endothelial cells in the vascular system.