Human neutrophil bactericidal/permeability-increasing protein reduces mortality rate from endotoxin challenge: a placebo-controlled study.
OBJECTIVE
To study the toxicology and pharmacology of the endotoxin-neutralizing agent, bactericidal/permeability-increasing protein.


METHODS
Prospective, randomized, placebo-controlled laboratory study.


METHODS
Academic research laboratory.


METHODS
CD-1 mice (n = 259); Sprague Dawley rats (n = 26); New Zealand White rabbits (n = 19).


METHODS
Pharmacokinetics of intravenously injected bactericidal/permeability-increasing protein was assessed in mice. Toxicology was tested in mice and rats. Efficacy of intravenously administered bactericidal/permeability-increasing protein as an endotoxin-neutralizing agent was tested in mice, rats, and rabbits.


RESULTS
Administration of a single 10-mg/kg bolus injection of bactericidal/permeability-increasing protein resulted in no alterations in hematologic, renal, or hepatic function, activity level, or weight gain in animals observed over a 7-day study period. A single bolus injection (10 mg/kg) of bactericidal/permeability-increasing protein protected 15 of 16 mice from a lethal endotoxin challenge (mortality rate 1/16 [6.25%]) compared 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 lethal endotoxin challenge. Furthermore, bactericidal/permeability-increasing protein reduced the induration and dermal necrosis observed in the localized dermal Shwartzman reaction.


CONCLUSIONS
Bactericidal/permeability-increasing protein is a potent antiendotoxin that neutralizes endotoxin in vivo and prevents mortality in animal models of lethal endotoxemia.
Fisher
C J
CJ
Cleveland Clinic Foundation, OH.
Marra
M N
MN
Palardy
J E
JE
Marchbanks
C R
CR
Scott
R W
RW
Opal
S M
SM
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004731:Endotoxins / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008050:Lipid A / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D011817:Rabbits; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D004731:Endotoxins; D008050:Lipid A; D008565:Membrane Proteins; C021623:bactericidal permeability increasing protein