Protection against hepatic injury by a novel spiropiperidine derivative

Abstract

The evaluation of a novel hepatoprotective agent, Y-8845 (8-(2-dimethylaminoethyl)-3-oxo-4-phenyl-1-thia-4,8-diazaspiro [4,5]decane dihydrochloride monohydrate), against carbon tetrachloride (CCl 4)- and endotoxin-induced acute and chronic hepatic injury was carried out in rats. This compound, in a dose-dependent way, markedly reduced the increases in serum transaminase activities, the extent of liver cell necrosis, and the delay in indocyanine green (ICG) disappearance produced by a single toxic dosage of CCl 4. This protective effect was observed even at doses of Y-8845 lower than 10 mg/kg po. It was also shown to protect the liver against injury induced by endotoxin. Furthermore, in the chronic liver injury induced by repeated administrations of CCl 4 for 12 weeks, significant reductions of the increases in serum enzyme activities, liver fibrosis, and liver enlargement, and improvement in the ICG retention rate, were recognized in the Y-8845-treated groups at 10 mg/kg po or less. These findings indicate that this new agent has a remarkable protective effect, and possibly a therapeutic effect on liver injury.