FASTING FOR 24H REVEALS LIVER MICROSTEATOSIS AFTER CONTINUOUS IV INFUSION OF MILACEMIDE IN THE RAT

Milacemide (2-n-pentylaminoacetamide) hydrochloride was administered b y continuous i.v. infusion for up to 7 days, at 300 and 600 mg/kg per day to male Sprague-Dawley rats. This was intended to provide high and sustained exposure to evaluate the effect of a preterminal 24-h fast on liver lipid content. Liver lipid content, as assessed by triglyceri de concentration and histopathology, was not different in saline contr ols or rats infused with up to 600 mg/kg per day for up to 7 days, whe n they had access to food up to sacrifice. When the rats were fasted f or 24 h before sacrifice, milacemide produced microsteatosis in the pe riportal and midzonal areas. The effect was significant after 2 days o f infusion at 600 mg/kg per day and increased in intensity with durati on of administration. After 7 days of infusion, at 600 mg/kg per day, liver triglycerides increased by more than 4-fold in rats fasted for t he last 24 h. No other differences from the controls were observed at light microscopy or in liver protein content and AST activity. Liver A LT activity was decreased by 28% and plasma ALT activity by 23%. Plasm a triglyceride levels were lowered by milacemide, in both fasted and f ed rats. This study demonstrates that fasting for 24 h triggers the de velopment of liver microsteatosis in rats exposed to milacemide. Fasti ng has been previously described to increase liver microsteatosis afte r administration of sodium valproate, 4-en valproate and pentenoic aci d in the rat. These findings might help to identify the mechanism of t he hepatic effects of milacemide. Such effects were not observed in th e regular animal toxicity studies conducted by the oral route. Some pa tients, however, presented evidence of liver dysfunction.