Efficacy of S-2441, a synthetic oligopeptide, in a rat model for gram-negative bacteremia.
In vitro effects of S-2441, H-D-Pro-Phe-Arg-NH-Heptyl, include potent anti-bradykinin activity and broad-spectrum inhibition of serine proteases involved in the coagulation cascade. In this study, rats infused with 7.8 X 10(8) viable Escherichia coli were treated either with saline (group A) or with intravenous (0.1 mg) and intraperitoneal (0.4 mg) doses of S-2441 (group B). Survival rates for groups A and B were 68% and 98%, at 12 hours (P less than 0.001), and 37% and 73% at 24 hours (P less than 0.001), respectively. Hematologic studies revealed that S-2441 significantly inhibited E. coli-induced prolongation of prothrombin time and partial thromboplastin time as well as a rapid decrease in the values of factor X, anti-thrombin III, and fibrinogen. In addition, S-2441 attenuated E. coli-induced hypoglycemia and a marked reduction of serum complement level. Ultrastructural evaluation of the liver demonstrated that S-2441 prevented the development of extensive sinusosoidal microthrombosis and hepatocellular necrosis. The results indicate that S-2441 affords protection in lethal gram-negative bacteremia owing in part to attenuation of disseminated intravascular coagulation and complement-mediated reactions. The findings are consistent with the concept that S-2441 and related oligopeptides modulate serine protease-mediated responses involving inhibition of active enzymes with competitive antagonism of pharmcologically active products formed during the activation of coagulation, fibrinolytic, kallikrein, and complement systems.
D000818:Animals; D001779:Blood Coagulation Factors / Q000378:metabolism; D001780:Blood Coagulation Tests; D001786:Blood Glucose / Q000378:metabolism; D001920:Bradykinin / Q000037:antagonists & inhibitors; D003165:Complement System Proteins / Q000378:metabolism; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D009336:Necrosis; D009842:Oligopeptides / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D001779:Blood Coagulation Factors; D001786:Blood Glucose; D009842:Oligopeptides; C041399:prolyl-phenylalanyl-N-heptylargininamide; D003165:Complement System Proteins; D001920:Bradykinin