Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in rats

A 52-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30, 100 and 300 mg/kg/d were selected for this study. Treatment-related findings were confined to the 300 mg/kg/d level and, to a lesser extent, the 100 and 30 mg/kg/d levels, with the investigations indicating the kidney as the main target organ for toxicity. The microscopic pathology examination of this organ showed papillary epithelial hyperplasia and/or collecting duct epithelial hyperplasia, with cortical scarring and occasional mineralisation in the papilla. Histopathological changes in the liver, centrilobullar hepatocyte enlargement (accompanied by fine vacuolation) and foci/areas of eosinophilic hepatocytes were considered to reflect the induction of drug-metabolising enzymes in the liver. Other tissues showing treatment-related findings included the salivary glands, urinary bladder, spleen, pancreas and adrenals. Additionally, other notable findings included (in the high dosage males only) a decline in body weight (from week 34), lower erythrocytic characteristics and slightly higher plasma urea nitrogen and alkaline phosphatase values. The results in this study, therefore, indicated that the non-toxic effect level was 10 mg/kg/d of nefiracetam.