Protection against hepatic injury by a novel spiropiperidine derivative

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 (CCl4)- 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 CCl4. 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 CCl4 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.