Additive effects of a bradykinin antagonist, NPC 17761, and a leumedin, NPC 15669, on survival in animal models of sepsis.
The effects of coadministration of NPC 17761 (D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Hype (transthiophenyl)-Oic-Arg), a potent bradykinin antagonist, and NPC 15669 (N-[9H-(2,7-dimethylfluoren-9-yl-methoxy)carbonyl]-L-leucine), a leukocyte recruitment inhibitor, were examined in rodent models of experimental shock. In mice, ED50 doses of NPC 17761 (0.12 mg/kg) and NPC 15669 (4 mg/kg), administered together, increased survival (83%) and inhibited leukopenia (60% at 4 h) in response to a lethal dose of endotoxin. In rats, independent administration of NPC 15669 (10 mg/kg, i.v. bolus) or NPC 17761 (0.1 mg/kg/h, 4 h) did not significantly increase survival (36 +/- 4 and 46 +/- 9 h, respectively) versus controls (27 +/- 1 h). However, co-treatment essentially "cured" (survival > 1 week) all septic animals, suggesting synergistic effects of the two agents.
Otterbein
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Scios Nova Inc., Baltimore, MD 21224.
Lowe
V C
VC
Kyle
D J
DJ
Noronha-Blob
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L
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065168:Bradykinin Receptor Antagonists; D004195:Disease Models, Animal; D004357:Drug Synergism; D004731:Endotoxins / Q000633:toxicity; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010538:Peritonitis / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy*; D015996:Survival Rate
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D004731:Endotoxins; C071244:N-(9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl)leucine; C083947:NPC 17761; D007930:Leucine; D001920:Bradykinin