SINGLE-DOSE TOXICITY STUDY OF THE NEW COGNITION-ENHANCING AGENT NEFIRACETAM IN MICE, RATS AND DOGS

Single oral dose toxicity of nefiracetam (N-(2,6-dimethylphenyl)-2- (2 -oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognit ion-enhancing agent, was examined in ddY mice, SD rats and beagle dogs The LD(50) values of nefiracetam were 2005 mg/kg for male mice and 19 40 mg/kg for female mice, 1182 mg/kg for male mts and 1408 mg/kg for f emale rats and more than 500 mg/kg for beagle dogs. Common toxic signs in all species were a decrease in locomotor activity, lying on the si de or back and loss of righting reflex, considered to be caused by dep ression of the central nervous system. Pathologically, no remarkable c hange associated with nefiracetam administration was observed in any s pecies. In addition, toxicities of the decomposition product (D-2) and by-products (Bis, 3-Me and 4-Me) of nefiracetam were examined by oral administration, anti of the metabolites (M-3 and M-11) by intravenous injection in male ddY mice LD(50) values of the 3-Me and 4-Me forms w ere 1399 and 1534 mg/ kg, respectively. Clinical signs in mice treated with these by-products were similar to those caused by nefiracetam. T he other compounds induced no toxic signs or death up to the highest c lose (2000 mg/kg) used.