TAKEDA-143242 Increased Survival Via Reduced Cytokines in Porcine Peritonitis

Abstract

TAKEDA-143242 (TAK-242) is a small molecule shown to inhibit lipopolysaccharide-induced intracellular signaling and inflammation. In vitro studies demonstrated that TAK-242 can prevent release of TNF-α, IL-1β, and IL-6 from activated macrophages of several species, including pigs. This study tested the hypothesis that TAK-242 would protect pigs from lethal gram-negative peritonitis via an anti-cytokine mechanism. A validated model of porcine gram-negative peritonitis, which employs chronically inplantated cardiac transducers and aortic and pulmonary artery catheters, was used. Pigs were pretreated with TAK-242 or its vehicle via a blinding procedure prior to intraperitoneal implantation of an LD(90) dose of E. coli 0111:B4 in a fibrin clot. Ten pigs were treated with TAK-242 and nine with its vehicle. All ten TAK-242 treated pigs survived, while three of the nine vehicle treated pigs survived (P = 0.01 χ(2) test). Pulmonary artery pressure increased markedly in vehicle pigs, and this elevation was significantly (two-way ANOVA) obviated in TAK-242 treated group. Circulating levels of cytokines in vehicle treated pigs showed increased expression (3930 ± 1770 at 1 h, 1007 ± 400 TNF-α at 2 h; 719 ± 308 of IL-1β at 2-6 h; 33000 ± 1000 of IL-6 at 2-4 h [pg/mL, mean ± SEM]). Peak circulating levels of these cytokines were significantly reduced by pretreatment with TAK-242 (<25 pg/mL TNF-α ; <100 pg/mL IL-1β; 0-1700 pg/mL IL-6, peak values). This study found that pretreatment with TAK-242 yielded significantly positive survival benefit in a lethal sepsis model that was associated with improved cardiovascular status and suppressed cytokine release.