title: 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.
authors.affiliation: Department of Medicine, Sections of Cardiology and Critical Care, Rush Medical College, Chicago, Illinois, USA. Roy.d.goldfarb@umdnj.edu
authors.forename: Roy D
authors.initials: RD
authors.lastname: Goldfarb
authors.forename: John W
authors.initials: JW
authors.lastname: Ortegel
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parrillo
authors.forename: Sergio
authors.initials: S
authors.lastname: Zanotti-Cavazzoni
authors.forename: Larry C
authors.initials: LC
authors.lastname: Casey
authors.forename: R Phillip
authors.initials: RP
authors.lastname: Dellinger
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D006321:Heart / Q000502:physiology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology*; D034421:Sus scrofa; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014655:Vascular Resistance / Q000502:physiology
chemical_list: D000891:Anti-Infective Agents, Local; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate