defibrotide and Shock

Defibrotide (DEF), a compound previously found to stimulate vascular prostacyclin (PGI2) formation, has been investigated in an experimental model of septic shock. Anesthetized pigs were subjected to i.v. infusion of lipid A (1.5 mg/kg per hr for 4 hr). DEF (50 mg/kg per hr) or vehicle were infused i.v. throughout the experiments, starting 1 hr prior to lipid A. Two out of 7 pigs receiving vehicle survived lipid A infusion for 4 hr, whereas 6 out of 7 DEF treated animals survived this period (P less than 0.05). DEF delayed the shock-induced depression of platelet count and preserved platelet secretory function (collagen-induced ATP-secretion). DEF increased plasma PGI2 by 45% (P less than 0.05) during lipid A infusion and tended to reduce thromboxane levels. DEF did not change eicosanoid formation in sham-shock pigs (n = 4 per group). In vivo treatment with DEF significantly increased the stimulatory effect of bradykinin (1 microM) and arachidonic acid (100 microM) on PGI2 formation ex vivo of mesenteric and iliac artery segments. The improvement of survival in lipid A-induced shock by DEF may be related to an enhancement of vascular PGI2 generation, potentially due to a reduction of shock-induced platelet activation and microcirculatory dysfunction.

Topics: Animals; Arachidonic Acid; Blood Platelets; Bradykinin; Disease Models, Animal; Drug Synergism; Epoprostenol; Lipid A; Platelet Count; Polydeoxyribonucleotides; Shock; Survival Rate; Swine; Thromboxane A2

To further clarify the protective mechanism(s) of defibrotide in splanchnic artery occlusion (SAO) shock, we observed the effect of defibrotide on polymorphonuclear leukocyte (PMN) accumulation in the intestinal tissue, gastric lysosomal hydrolases and endothelial function of the ischemia-reperfused superior mesenteric artery (SMA). Pentobarbital anesthetized rats were subjected to occlusion of both the celiac and superior mesenteric arteries for 90 min followed by 2 h reperfusion. The rats receiving only the vehicle for defibrotide exhibited a marked increase in intestinal myeloperoxidase (MPO) activity and a significant endothelial dysfunction manifested by the loss of endothelium-dependent vasorelaxation. Only 2 of 6 rats (33%) survived 2 h of reperfusion. In contrast, those rats treated with defibrotide exhibited significantly attenuated PMN accumulation in intestinal tissue, enhanced endothelium-dependent vasorelaxation in SMA rings, prolonged survival time and increased survival rate to 6 of 7 (i.e., 86%). However, addition of defibrotide in vitro had no direct effect on LTB4 activated PMN adherence to vascular endothelium. Moreover, defibrotide preserved gastric lysosomal membranes in vitro. These results indicate that the protective effect of intravenous administration of defibrotide on SAO shock may be related to its endothelial preserving effect reducing PMN adherence and protection of endothelial and lysosomal membrane integrity.

Topics: Animals; Fibrinolytic Agents; Ileum; Male; Mesenteric Vascular Occlusion; Neutrophils; Peroxidase; Polydeoxyribonucleotides; Rats; Rats, Inbred Strains; Reperfusion; Shock

Defibrotide stimulates PGI2 production and exerts significant antithrombotic, fibrinolytic and plasminogen-activating activities. We studied its effects in splanchnic artery occlusion (SAO) shock in rats. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion usually resulting in death 90-120 minutes after releasing the clamps. Defibrotide 910 mg/kg +25 mg/kg/h) treated SAO shock rats maintained higher post-reperfusion mean arterial blood pressure compared to those receiving only the vehicle (0.9% NaCl). SAO shock rats treated with defibrotide exhibited lower plasma activities of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and myocardial depressant factor (p less than 0.02 from vehicle) as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). All SAO shock rats treated with defibrotide survived the entire 120 post-release period compared with only a 42% survival rate for rats receiving only the vehicle (p less than 0.02). These results suggest a remarkable protective effect of defibrotide in SAO shock.

Topics: Animals; Blood Pressure; Cathepsin D; Fibrinolytic Agents; Male; Mesenteric Vascular Occlusion; Myocardial Depressant Factor; Polydeoxyribonucleotides; Rats; Rats, Inbred Strains; Shock; Splanchnic Circulation