Ibuprofen improves survival from endotoxic shock in the rat.
During endotoxemia, there is a significant increase in arachidonic acid-derived metabolites. To test the hypothesis that one or more of these metabolites play a significant role in the pathogenesis of endotoxic shock we investigated the therapeutic efficacy of varying doses of ibuprofen, a cyclooxygenase inhibitor, on the pathophysiologic sequelae of endotoxic shock in the Long-Evans rat, induced by S. enteritidis endotoxin (20 mg/kg). Pretreatment with ibuprofen (1-3.75 mg/kg) produced an optimal survival rate of 80% compared to only 11% in the vehicle-treated group. Doses of 0.1, 0.5 and 30 mg/kg of ibuprofen also significantly (P < .05) improved survival over nontreated shocked controls. Plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha(PGF1 alpha) levels rose from < 200 pg/ml to 2207 +/- 282 (N = 16) and 840 +/- 59 (N = 8), respectively, within 30 min after injection. The rise in plasma thromboxane B2 and 6-keto-PGF1 alpha levels was reduced with ibuprofen (3.75 and 30 mg/kg) to < 200 pg/ml. Ibuprofen (3.75 and 30 mg/kg) reduced thrombin-induced in vitro platelet thromboxane B2 synthesis by 95 and 99%, respectively. The severity of coagulopathies as reflected by elevations in serum fibrogen/fibrin degradation products and lysosomal integrity were likewise significantly reduced (40%) with ibuprofen (3.75 mg/kg) pretreatment. These results are consistent with the hypothesis that arachidonic acid metabolites play a significant early role in the pathogenesis of endotoxic shock. Our observations suggest potential benefits from agents which inhibit fatty acid cyclooxygenase.
D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005966:Glucuronidase / Q000097:blood; D007052:Ibuprofen / Q000627:therapeutic use*; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D011460:Prostaglandins F / Q000032:analysis; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy*; D013929:Thromboxane B2 / Q000032:analysis
D005338:Fibrin Fibrinogen Degradation Products; D011460:Prostaglandins F; D013929:Thromboxane B2; D000135:Acid Phosphatase; D005966:Glucuronidase; D007052:Ibuprofen