fr-167653 and Acute-Disease

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-1 and TNF-alpha possess overlapping and synergetic activities inducing the production in cascade of other cytokines, adhesion molecules, arachidonic acid metabolites, as well as activating immune and non-immune cells. FR167653 (C24H18FN5O2-H2SO4-H2O) is a newly synthesized organic compound with a potent inhibitory effect on IL-1beta and TNF-alpha production. We hypothesized that the suppression of IL-1 and TNF-alpha induced by FR167653 could effectively attenuate experimentally induced colonic damage.. Colonic lesions were induced in male Sprague-Dawley rats (250-300 g) by intrarectal instillation of 4% acetic acid. The effect of FR167653 administration at 1.0, 1.5, 2.5 mg/kg per 6 h subcutaneously on acetic acid-induced colonic damage was assessed. The lesion area, microscopic findings, colonic and serum levels of TNF-alpha and IL-1beta were also evaluated.. Treatment with FR167653 at 1.5 and 2.5 mg/kg per 6 h was able to ameliorate the gross macroscopic appearance of colonic lesions significantly, as well as ameliorate the lesion area induced by acetic acid. Colonic mucosal TNF-alpha and IL-1beta levels of rats treated with FR167653 showed significant decrease in a dose-dependent fashion compared with the control group. In the same manner, serum TNF-alpha of rats treated with FR167653 was significantly lower than that of respective controls.. Subcutaneous administration of FR167653 was able to ameliorate the acute changes induced by acetic acid instillation in a dose-dependent manner. This is the first report to evaluate the dual inhibition of the production of IL-1 and TNF-alpha, offered by FR167653, in acute experimental colitis. Further studies are necessary to evaluate FR167653's efficacy and safety on long-term conditions.

Topics: Acetic Acid; Acute Disease; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Disease Models, Animal; Interleukin-1; Male; Molecular Structure; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

This study was designed to evaluate the possible role of cytokines (IL-1 and TNF-alpha) in the pathogenesis of acute pancreatitis in the early stage of the disease and to evaluate the protective effect of the cytokine suppressive agent, FR167653, against pancreatic injuries. Acute pancreatitis was induced in rats by closed duodenal loop. However, the free passage for the gastrointestinal contents was maintained by inserting the tube into the duodenum. In this model, the survival rate was significantly decreased as compared with the control sham-operated rats at 48 h after induction of pancreatitis. Marked hyperamylasemia and a significant increase in pancreatic water and trypsin contents were observed at 24 h after induction of pancreatitis. Pancreatic subcellular redistribution of lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. However, treatment with FR167653 at a dose of 1.5 mg/kg (four times, every 6 h after induction of pancreatitis) significantly prevented all these pancreatic injuries, improving the survival rate. These results indicate that cytokines such as IL-1 and TNF-alpha may be involved in the pathogenesis of acute pancreatitis in the early stage of the disease, and that a cytokine-suppressive agent might be of therapeutic value for the treatment of acute pancreatitis.

Topics: Acute Disease; Animals; Cathepsin B; Duodenum; Interleukin-1; Lysosomes; Male; Pancreatitis; Pyrazoles; Pyridines; Rats; Rats, Wistar; Survival Rate; Time Factors; Tumor Necrosis Factor-alpha