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

A 52-week toxicity study by oral administration (capsule) was performe d in beagle dogs with nefiracetam (N-(2,6- dimethylphenyl)-2-(2-oxo-1- pyrrolidinyl) aceamide, DM-9384, CAS 77191-36-7), a new cognition-enha ncing agent, as a part of a safety evaluation program. Dosages of 0 (c ontrol), 10, 30 and 90 mg/kg/ d were selected for this study Treatment -related findings were confined to the 90 mg/kg/d level and indicated the kidney and the testis as the main target organs for toxicity. Sign s of systemic toxicity, as indicated by the laboratory investigations, were not apparent until the second half of the study and included the principal findings of higher urea nitrogen, and creatinine, with high er urinary volumes and corresponding lower specific gravity, osmolarit y and protein values. The microscopic pathology examination showed var ious changes at the renal papilla, collecting ducts, and medullary and cortical scarring. This examination also revealed decreased spermatog enesis in the testes, with associated decreased numbers/absence of spe rmatozoa in the epididymides. At the 30 mg/kg/d level, the minor micro scopic pathology changes seen in the kidneys of one male animal were c onsidered to be of equivocal toxicological importance There were no tr eatment-related findings at the low dosage level (10 mg/kg/d) and, the refore, this level was considered as the non-toxic effect level of nef iracetam.