Reproductive toxicity studies of the new cognition-enhancing agent nefiracetam in rats and rabbits.
The reproductive toxicity of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7) was investigated in rats and rabbits. Nefiracetam was administered orally for 9 weeks or more until successful copulation to male rats at doses of up to 480 mg/kg/d. Female rats were treated with nefiracetam at the same doses for more than 2 weeks prior to and in the early stages of pregnancy. No adverse effects on fertility were noted at any dose level. Nefiracetam elicited no evidence of teratogenicity when administered during the fetal organogenesis period to pregnant rats at doses of up to 1000 mg/kg/d, or to pregnant rabbits at doses of up to 270 mg/kg/d. Rat fetuses in the 1000 mg/kg group exhibited decreased body weights, delayed ossification and an increased incidence of skeletal variations such as cervical ribs and shortening of the 13th ribs. Decreased body weight gain and decreased food intake were also noted in rat dams of the 1000 mg/kg group. Nefiracetam showed no adverse effects on postnatal development, behavior or reproductive performance of rat offspring, except for decreased body weight gain in the 1000 mg/kg group. Rabbit fetuses in the 270 mg/kg group exhibited increased skeletal variations, mainly presence of the 13th ribs. Decreased body weight gain and decreased food intake were also noted in rabbit dams of the 270 mg/kg group. In a perinatal and postnatal toxicity study in rats using doses of up to 500 mg/kg, decreased food intakes were noted in dams of the 500 mg/kg group.(ABSTRACT TRUNCATED AT 250 WORDS)
Watanabe
T
T
Drug Safety Research Center, Developmental Research Laboratories, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Matsuhashi
K
K
Shimada
M
M
Harada
S
S
Tawara
K
K
Takayama
S
S
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011619:Psychotropic Drugs / Q000633:toxicity*; D011760:Pyrrolidinones / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects
D011619:Psychotropic Drugs; D011760:Pyrrolidinones; C058876:nefiracetam