Therapeutic efficacy of the polymyxin-like peptide ranalexin in an experimental model of endotoxemia

Background. A rat model was used to investigate the efficacy of a polycationic peptide, the polymyxin-like ranalexin, in the prevention of lethality in a rat model of septic shock. The effect of ranalexin was compared with those of polymyxin B and imipenem. Methods. Adult male Wistar rats (weight range: 250-300 g) were used for all the experiments. The study included five groups: an uninfected control group C-0, an untreated control group C-1, and three drug-treated groups that received 1 mg/kg ranalexin (group 2), 20 mg/kg imipenem (group 3), and 3 mg/kg polymyxin B (group 4). Rats, with the exception of the uninfected control group (C-0), were given an intraperitoneal injection of 2 x 10(10) colony-forming units of Escherichia coli. Each group included 15 animals. Bacterial growth in abdominal exudate and plasma; endotoxin and tumor necrosis factor alpha (TNF-alpha) concentrations in plasma, and mortality were evaluated. Results. Results were evaluated 48 h after inoculation. Ranalexin, imipenem, and polymyxin B significantly reduced the lethality (survival was 93.3, 80.0, and 93.3%, respectively) and the growth of E. coli both in abdominal fluid and plasma compared with saline treatment. Ranalexin showed higher antimicrobial activity than polymyxin B and imipenem and, at the same time, exhibited an antiendotoxin activity similar to that of polymyxin B (less than or equal to0.015 EU/mL). Finally, ranalexin and polymyxin B significantly reduced plasma TNF-alpha levels (less than or equal to4 pg/mL). Conclusion. Monodose ranalexin treatment prevents bacterial growth, endotoxemia, and mortality in rats with septic shock. (C) 2001 Academic Press.