A novel dual regulator of tumor necrosis factor-alpha and interleukin-10 protects mice from endotoxin-induced shock.
A pyrimidylpiperazine derivative, N-[1-(4-¿[4-(pyrimidin-2-yl)piperazin-1-yl]methyl¿phenyl)cycloprop yl] acetamide (Y-39041), is a dual cytokine regulator of tumor necrosis factor (TNF)-alpha and interleukin-10 production. Lipopolysaccharide-induced TNF-alpha release in BALB/c mice was inhibited by the oral treatment with the compound at 10-100 mg/kg (about 80% suppression) while interleukin-10 release was augmented (about 10-fold increase at 30 mg/kg). In addition, Y-39041 (30 mg/kg, p.o.) completely protected mice from lipopolysaccharide-induced death by the treatment before and after lipopolysaccharide injection. The finding that Y-39041 suppresses TNF-alpha production and stimulates interleukin-10 production at the same time provides new insights for the treatment of septic shock, rheumatoid arthritis and Crohn's diseases.
Fukuda
T
T
Research Laboratories, Yoshitomi Pharmaceutical Industries, 955 Koiwai, Yoshitomi-cho, Chikujo-gun, Fukuoka, Japan. fukuda_tetsuko@yoshitomi.co.jp
Sumichika
H
H
Murata
M
M
Hanano
T
T
Adachi
K
K
Hisadome
M
M
D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D004731:Endotoxins; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000081:Acetamides; D004731:Endotoxins; D008070:Lipopolysaccharides; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; C406663:Y 39041; D016753:Interleukin-10; C044101:endotoxin, Escherichia coli