Affiliation:
1. Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
Abstract
Polymyxin B, a relatively toxic antibiotic, has potent endotoxin-neutralizing properties that may be beneficial as adjunctive therapy in gram-negative sepsis. Polymyxin B nonapeptide (deacylated polymyxin B) is devoid of antibiotic activity but retains the capacity to disorganize the outer membrane of gram-negative bacteria. To evaluate the potential therapeutic usefulness of this derivative, we produced purified polymyxin B nonapeptide, tested its in vivo toxicity in animals, and evaluated its in vitro antiendotoxin activity. Effectiveness as an antiendotoxin agent was assessed by examining the ability of polymyxin B nonapeptide to block the enhanced release of toxic oxygen radicals induced by lipopolysaccharide in human neutrophils (priming). In vivo, at doses of 1.5 and 3.0 mg/kg, polymyxin B nonapeptide did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were observed with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concentration-dependent manner, but the parent compound, polymyxin B, was 63 times more effective on a weight basis. The inhibitory activity of both compounds, however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. We conclude that polymyxin B nonapeptide is less toxic than polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compound. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. The findings suggest that these compounds block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference51 articles.
1. Armitage P. 1971. Statistical methods in medical research p. 44450. John Wiley & Sons Inc. New York.
2. Studies on tuberculin fever. III. Mechanisms involved in the release of endogenous pyrogen in vitro;Atkins E. C.;J. Exp. Med.,1965
3. Biological defence mechanism. The production by leukocytes of superoxide, a potent bactericidal agent;Babior B. M.;J. Clin. Invest.,1973
4. Inhibition of the biologic effects of endotoxin on neutrophils by polymyxin B sulfate;Bannatyne R. M.;J. Infect. Dis.,1977
5. Analysis of 1186 episodes of gram-negative bacteremia in non-university hospitals: the effects of antimicrobial therapy;Bryan C. S.;Rev. Infect. Dis.,1983
Cited by
142 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献