Examination of lesions in the urinary bladder and kidney of dogs induced by nefiracetam, a new nootropic agent.
Toxic lesions induced by nefiracetam, a nootropic drug, in the urinary bladder and kidney were examined by repeated oral administration of 300 mg/kg/day for 1, 2, 3, 4, or 11 wk to male and female beagle dogs. Each dog was sacrificed after each treatment period, and urinalysis and serum biochemistry were performed for surviving dogs at several time points. One male and 2 females died during week 10 or 11. Degeneration and desquamation of epithelial cells and edema and hemorrhage in the lamina propria were observed in the urinary bladder after 1 wk of treatment. These changes became severe as time progressed and were reflected in the clinical abnormalities of hematuria and increased protein excretion in urine. However, epithelial regeneration and hyperplasia were seen thereafter, and almost no change was seen in the urinary bladder after treatment for 11 wk. Instead of recovery as in the urinary bladder, the kidney showed epithelial degeneration and hyperplasia in the papilla and collecting duct and interstitial congestion and hemorrhage after treatment for 11 wk. Extensive hemorrhage and papillary necrosis were seen in animals that died during week 10 or 11 of dosing. These kidney changes were associated with increased urinary volume and decreased osmotic pressure. The lesions are thought to have a common etiopathogenesis and to be initiated by the epithelial damage with a time lag between expression of injury in the urinary bladder and the kidney.
Kashida
Y
Y
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Yoshida
M
M
Ishii
Y
Y
Nomura
M
M
Kato
M
M
D000818:Animals; D001774:Blood Chemical Analysis; D004285:Dogs; D005260:Female; D006417:Hematuria / Q000139:chemically induced; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D018697:Nootropic Agents / Q000633:toxicity*; D011760:Pyrrolidinones / Q000633:toxicity*; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D014556:Urine / Q000737:chemistry
D018697:Nootropic Agents; D011760:Pyrrolidinones; C058876:nefiracetam