Testicular toxicity induced in dogs by nefiracetam, a neutrotransmission enhancer.
To investigate mechanisms of the testicular toxicity of nefiracetam and to find sensitive parameters to predict the toxicity, male beagle dogs were orally administered 180 or 300 mg/kg per day of the drug once and for 1 and 4 weeks. Time-course changes in serum and/or testicular hormone levels and semen parameters, and testicular morphology were examined. The testicular testosterone level was decreased 4 h after single administration of nefiracetam at 300 mg/kg per day, but the progesterone level showed no change at that time. The serum testosterone level was decreased after single, 1-week or 2-week treatment. In contrast, the serum estradiol level was increased from 1- to 4-week treatment. No changes in serum LH, FSH and inhibin B levels were observed throughout the experimental period. Decreased sperm motility and increased number of malformed sperms were first observed in semen after 4-week treatment. Histopathological examination of the testis revealed moderate and severe seminiferous atrophy with multinucleated giant cell formation at 180 and 300 mg/kg per day, respectively, after 4-week treatment, but not 1-week treatment. These results show that nefiracetam decreases testicular testosterone level in dogs following single oral administration of a high dose, and induces severe morphologic changes after 4-week treatment. This reduction is shown to be a sensitive parameter to detect the toxicity, and is suggested to be induced by the impaired conversion of progesterone to testosterone in Leydig cells.
Shimomura
Kazuhiro
K
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co, Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. shimop7x@daiichipharm.co.jp
Shimada
Makoto
M
Hagiwara
Miyoko
M
Harada
Shigeo
S
Kato
Michiyuki
M
Furuhama
Kazuhisa
K
D000818:Animals; D004285:Dogs; D004958:Estradiol / Q000097:blood; D006728:Hormones / Q000097:blood; D008297:Male; D018697:Nootropic Agents / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011374:Progesterone / Q000097:blood; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011760:Pyrrolidinones / Q000633:toxicity*; D012661:Semen / Q000166:cytology / Q000187:drug effects; D013081:Sperm Motility / Q000187:drug effects; D013733:Testicular Diseases / Q000139:chemically induced* / Q000473:pathology; D013737:Testis / Q000187:drug effects / Q000473:pathology; D013739:Testosterone / Q000097:blood
D006728:Hormones; D018697:Nootropic Agents; D011760:Pyrrolidinones; C058876:nefiracetam; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol