Y-40138, a multiple cytokine production modulator, protects against D-galactosamine and lipopolysaccharide-induced hepatitis.

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs are associated with tumor necrosis factor (TNF) production. D-Galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure. In this model, TNF-alpha plays a central role in the pathogenesis of D-GalN/LPS-induced liver injury in mice. Y-40138, N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl inhibits TNF-alpha and augments interleukin (IL)-10 production in LPS-injected mice in plasma. In the present study, we examined the effect of Y-40138 on D-GalN/LPS-induced hepatitis. Y-40138 (10mg/kg, i.v.) significantly suppressed TNF-alpha and monocyte chemoattractant protein-1 (MCP-1) production and augmented IL-10 production in plasma. In addition, Y-40138 significantly inhibited TNF-alpha production induced by direct interaction between human T lymphocytes and macrophages. Y-40138 suppressed plasma alanine transaminase (ALT) elevation and improved survival rate in D-GalN/LPS-injected mice, and it is suggested that the protective effect of Y-40138 on hepatitis may be mediated by inhibition of TNF-alpha and MCP-1, and/or augmentation of IL-10. This compound is expected to be a new candidate for treatment of cytokine and/or chemokine-related liver diseases such as alcoholic hepatitis.

Treatment with Y-40138, a multiple cytokine production modulator, inhibits lipopolysaccharide- or tumour necrosis factor-alpha-induced production of pro-inflammatory cytokines and augments interleukin-10.

N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide . HCl (Y-40138) suppresses liver injury in concanavalin A- and D-galactosamine/lipopolysaccharide (LPS)-induced mouse hepatitis models. However, the mechanism of action of Y-40138 has not been fully investigated. In this study, we examined the effect of Y-40138 on cytokine production in mice. Cytokine production was induced by intraperitoneal injection of LPS (0.5 mg kg(-1)) or intravenous injection of recombinant mouse tumour necrosis factor (TNF)-alpha (10 mug mouse(-1)) in BALB/c mice. TNF-alpha and interleukin (IL)-10 reached maximum levels 1.5 h after the LPS injection. IL-12 and interferon-sigma (IFN-sigma) reached maximum levels 3 to 9 h after the injection. When Y-40138 was orally administered 30 min prior to the injection, it inhibited TNF-alpha, IL-12 and IFN-sigma production and augmented IL-10 production. Y-40138 also inhibited IL-12 production and augmented IL-10 production in TNF-alpha-stimulated mice. In IL-10 knockout mice, Y-40138 inhibited TNF-alpha and IL-12 production 1.5 h after the LPS injection but not after 3 h or later, unlike in wild mice. In addition, TNF-alpha production was inhibited by Y-40138 at concentrations that could not augment IL-10 production. These data suggest that Y-40138 modulates pro-inflammatory cytokine production by both IL-10-dependent and -independent mechanisms.

Therapeutic administration of Y-40138, a multiple cytokine modulator, inhibits concanavalin A-induced hepatitis in mice.

Concanavalin A-induced hepatitis is often used as a model of liver injury. In this model, plasma tumor necrosis factor-alpha (TNF-alpha) level increased in concanavalin A-injected mice. Prophylactic treatment with Y-40138, N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide.HCl, significantly suppressed the increase in plasma TNF-alpha level. In this study, we compared the effect of Y-40138 with those of pentoxifylline and anti-TNF-alpha antibody on concanavalin A-induced hepatitis. Prophylactic treatment with pentoxifylline, anti-TNF-alpha antibody and Y-40138 reduced plasma alanine aminotransferase level. Therapeutic treatment with Y-40138 significantly reduced plasma alanine aminotransferase level, but pentoxifylline and anti-TNF-alpha antibody did not. Therapeutic treatment with Y-40138 significantly reduced plasma interferon-gamma (IFN-gamma) and monokine induced by interferon-gamma levels. From these results, Y-40138 may be expected as a new class of therapeutic drug for treatment of TNF-alpha, IFN-gamma and/or chemokine-related liver diseases such as alcoholic liver disease.

Combination benefit of a pyrimidylpiperazine derivative (Y-40138) and methotrexate in arthritic rats.

Anti-tumor necrosis factor-alpha (TNFalpha) antibody in combination with methotrexate dramatically decreases joint destruction in rheumatoid arthritis. The aim of this study was to examine combined treatment with N-[1-(4-([4-(pyrimidin-2-yl)piperazin-1-yl]methyl)phenyl)cyclopropyl] acetamide HCl (Y-40138) and methotrexate in rat adjuvant-induced arthritis. The increase in hindpaw volume and joint destruction was suppressed by single therapeutic administration (days 15-20) of Y-40138 (30 mg/kg, p.o.), but not by prophylactic administration (days 1-9). However, arthritic progression was suppressed by single prophylactic administration of methotrexate (0.3 mg/kg, p.o.), but not by therapeutic administration. Combined administration (days 10-20) of Y-40138 (0.3-1 mg/kg) and methotrexate (0.03 mg/kg) synergistically suppressed the increase in hindpaw volume and joint destruction. We concluded that Y-40138 in combination with methotrexate synergistically suppressed arthritic progression. These data suggest that combined treatment with Y-40138 and methotrexate may increase efficacy of therapy for rheumatoid arthritis.