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.
Fukuda
Tetsuko
T
Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan. Fukuda.Tetsuko@mf.m-pharma.co.jp
Mogami
Akira
A
Hisadome
Masao
M
Komatsu
Hirotsugu
H
D000081:Acetamides / Q000008:administration & dosage / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D019743:Chemokines, CXC / Q000097:blood; D003208:Concanavalin A / Q000009:adverse effects*; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D010431:Pentoxifylline / Q000008:administration & dosage / Q000627:therapeutic use; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011292:Premedication; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
D000081:Acetamides; D000906:Antibodies; D019743:Chemokines, CXC; D016207:Cytokines; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; C406663:Y 39041; D003208:Concanavalin A; D007371:Interferon-gamma; D000410:Alanine Transaminase; D010431:Pentoxifylline