PROFIBRINOLYTIC ACTIVITY OF DEFIBROTIDE IS PTOSTACYCLIN-INDEFENDEMT

The profibrinolytic, antithrombotic and thrombolytic activities of Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, have been previously described. Defibrotide is also able to promote the generation and release into the circulation of prostacyclin and of plasminogen activator factor (tPA) from vascular walls. These two last activities, i.e., PGI2 and tPA stimulation, could be of importance in the profibrinolytic activity of Defibrotide. In an attempt to clarify the profibrinolytic mechanism/s of Defibrotide, the role of PGI2 generation in this activity was investigated in rabbits in which the cycloxygenase pathway was blocked with Indcmethacin. Male rabbits were treated with Indcmethacin, 10 ng/Kg, i.v., 20 minutes or 2 hours before Defibrotide administration. Defibrotide was injected i.v. into rabbits at two dose levels (16 or 64 rrg/Kg). Rabbits treated with Defibrotide only were used as controls. The profibrinolytic activity was evaluated measuring the lysed area of normal human fibrin plates induced by euglobulin fraction obtained from plasma. Results are reported in the Table.Indomethacin (Indo) administered 20 min (*) or 2h (**) before Defibrotide.AN3VA: N.S. vs. Vehicle + D 12.5 or D 50 ng/Kg i.v.; P< 0.01 vs. basal.The results reported here demonstrate that the profibrinolytic activity of Defibrotide is independent of PGI2 generation: Indcmethacin pro treatment was unable to suppress or to reduce the fibrinolytic response of the rabbit to Defibrotide.