In this article, we will discuss Defibrotide Sodium (Mechanism of Action). So, let’s get started.
Mechanism of Action
The mechanism of action of defibrotide sodium has not been fully elucidated. In vitro, defibrotide sodium enhances
the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide sodium increased tissue plasminogen activator (t-PA) and thrombomodulin expression, and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion.
At a dose 2.4 times the maximum recommended dose, Defibrotide sodium does not prolong the QTc interval to any clinically relevant extent.
Plasma concentrations of PAI-1 were assessed on an exploratory basis as a potential pharmacodynamic marker for efficacy in Study 2. PAI-1 is an inhibitor of t-PA and therefore of fibrinolysis. Mean PAI-1 levels on Days 7 and 14 were lower than those at baseline in patients with complete response (CR) and in those who were alive at Day+100, but this trend did not reach statistical significance. There were no statistically significant differences in mean PAI-1 levels by treatment or outcome.