HUMAN NEUTROPHIL BACTERICIDAL PERMEABILITY-INCREASING PROTEIN REDUCESMORTALITY-RATE FROM ENDOTOXIN CHALLENGE - A PLACEBO-CONTROLLED STUDY

Objectives: To study the toxicology and pharmacology of the endotoxin- neutralizing agent, bactericidal/permeability-increasing protein. Desi gn: Prospective, randomized, placebo-controlled laboratory study. Sett ing: Academic research laboratory. Subjects: CD-1 mice (n = 259); Spra gue Dawley rats (n = 26); New Zealand White rabbits (n = 19). Interven tions: Pharmacokinetics of intravenously injected bactericidal/permeab ility-increasing protein was assessed in mice. Toxicology was tested i n mice and rats. Efficacy of intravenously administered bactericidal/p ermeabihty-increasing protein as an endotoxin-neutralizing agent was t ested in mice, rats, and rabbits. Measurements and Main Results: Admin istration of a single 10-mg/kg bolus injection of bactericidal/permeab ility-increasing protein resulted in no alterations in hematologic, re nal, or hepatic function, activity level, or weight gain in animals ob served over a 7-day study period. A single bolus injection (10 mg/kg) of bactericidal/permeability-increasing protein protected 15 of 16 mic e from a lethal endotoxin challenge (mortality rate 1/16 [6.25%]) comp ared with a 100% (16/16) mortality rate in the saline-treated controls (p < .001). Bactericidal/permeability-increasing protein administered up to 1 hr after endotoxin provided significant protection against le thal endotoxin challenge. Furthermore, bactericidal/permeability-incre asing protein reduced the induration and dermal necrosis observed in t he localized dermal Shwartzman reaction. Conclusions: Bactericidal/per meability-increasing protein is a potent antiendotoxin that neutralize s endotoxin in vivo and prevents mortality in animal models of lethal endotoxemia.