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 pentoxitylline 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. (c) 2005 Elsevier B.V. All rights reserved.