Hirulog effect in rat endotoxin shock.
Hirulog is a thrombin catalytic site inhibitor which exhibits specificity for the anionic binding exosite of alpha thrombin. Here, we have evaluated the effect of Hirulog (1, 5 and 10 mg/kg, 30 min pretreatment) in a rat model of endotoxemia. Intravenous injection of lipopolysaccharide from E. coli (25 mg/kg; serotype 0127:B8) caused decreases in blood pressure which were significantly reduced (about 60%) in animals pretreated with Hirulog. Rat survival to endotoxin was significantly increased in Hirulog pretreated group (5 and 10 mg/kg) up to 24 hours. Hirulog at the dose of 10 mg/kg inhibited both endotoxin-induced leukopenia at 30 and 60 minute points and thrombocytopenia at 30 minute point but not at 90 and 120 minute points. Fibrinogen levels were significantly reduced after 2 hours following endotoxin administration. Pretreatment with Hirulog (5-10 mg/kg i.v.) 30 min prior to administration of endotoxin prevented changes in fibrinogen plasma levels. These results demonstrate that Hirulog-induced inhibition of thrombin is effective in reducing toxic and lethal effects of endotoxin.
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D005340:Fibrinogen / Q000187:drug effects / Q000378:metabolism; D006629:Hirudins / Q000031:analogs & derivatives* / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy; D007970:Leukopenia / Q000139:chemically induced / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy*; D013917:Thrombin / Q000037:antagonists & inhibitors; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy; D014115:Toxemia / Q000097:blood
D000991:Antithrombins; D006629:Hirudins; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005340:Fibrinogen; D013917:Thrombin; C074619:bivalirudin