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 cognition-enhancing agent, was examined in ddY mice, SD rats and beagle dogs. The LD50 values of nefiracetam were 2005 mg/kg for male mice and 1940 mg/kg for female mice, 1182 mg/kg for male rats and 1408 mg/kg for female 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 side or back and loss of righting reflex, considered to be caused by depression of the central nervous system. Pathologically, no remarkable change associated with nefiracetam administration was observed in any species. 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, and of the metabolites (M-3 and M-11) by intravenous injection in male ddY mice. LD50 values of the 3-Me and 4-Me forms were 1399 and 1534 mg/kg, respectively. Clinical signs in mice treated with these by-products were similar to those caused by nefiracetam. The other compounds induced no toxic signs or death up to the highest dose (2000 mg/kg) used.
Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
T
T
Sugawara
M
M
Kato
K
K
Furuhama
F
F
Inage
N
N
Suzuki
S
S
Takayama
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004285:Dogs; D004340:Drug Contamination; D005260:Female; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000633:toxicity*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011619:Psychotropic Drugs; D011760:Pyrrolidinones; C058876:nefiracetam