HIRULOG EFFECT IN RAT ENDOTOXIN-SHOCK

Hirulog(TM) is a thrombin catalytic site inhibitor which exhibits spec ificity for the anionic binding exosite of alpha thrombin. Here, we ha ve evaluated the effect of Hirulog(TM) (1, 5 and 10 mg/kg, 30 min pret reatment) in a rat model of endotoxemia. Intravenous injection of lipo polysaccharide from E. coli (25 mg/kg; serotype 0127:B8) caused decrea ses in blood pressure which were significantly reduced (about 60%) in animals pretreated with Hirulog(TM). Rat survival to endotoxin was sig nificantly increased in Hirulog(TM) pretreated group (5 and 10 mg/kg) up to 24 hours. Hirulog(TM) at the dose of 10 mg/kg inhibited both end otoxin-induced leukopenia at 30 and 60 minute points and thrombocytope nia at 30 minute point but not at 90 and 120 minute points. Fibrinogen levels were significantly reduced after 2 hours following endotoxin a dministration. Pretreatment with Hirulog(TM) (5-10 mg/kg i.v.) 30 min prior to administration of endotoxin prevented changes in fibrinogen p lasma levels. These results demonstrate that Hirulog (TM)-induced inhi bition of thrombin is effective in reducing toxic and lethal effects o f endotoxin.