52-WEEK ORAL TOXICITY STUDY OF THE NEW COGNITION-ENHANCING AGENT NEFIRACETAM IN RATS

A 52-week toxicity study by oral gavage administration was performed i n Sprague-Dawley rats with nefiracetam (N-(2,6-dimethylphenyl)-2-(2-ox o-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 an d to a lesser extent, the 100 and 30 mg/kg/d levels, with the investig ations indicating the kidney as the main target organ for toxicity. Th e microscopic pathology examination of this organ showed papillary epi thelial hyperplasia and/or collecting duct epithelial hyperplasia, wit h cortical scarring and occasional mineralisation in the papilla. Hist opathological changes in the liver, centrilobullar hepatocyte enlargem ent (accompanied by fine vacuolation) foci/areas of eosinophilic hepat ocytes 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 a drenals. Additionally, other notable findings included (in the high do sage males only) a decline in body, weight (from week 34), lower eryth rocytic characteristics and slightly higher plasma urea nitrogen and a lkaline phosphatase values. The results in this study, therefore, indi cated that the non-toxic effect level was 10 mg/kg/d of nefiracetam.