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.
Huntingdon Research Centre Ltd., Cambridgeshire, England.
W N
WN
Hooks
K A
KA
Colman
C
C
Gopinath
F
F
Inage
M
M
Kato
S
S
Takayama
D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005123:Eye / Q000187:drug effects; D005260:Female; D008297:Male; D009752:Nutritional Status; D009929:Organ Size / Q000187:drug effects; D011619:Psychotropic Drugs / Q000097:blood / Q000633:toxicity* / Q000652:urine; D011760:Pyrrolidinones / Q000097:blood / Q000633:toxicity* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
D011619:Psychotropic Drugs; D011760:Pyrrolidinones; C058876:nefiracetam