Pathophysiological studies on canine renal papillary necrosis induced by nefiracetam   :   Nefiracetamにより誘発されたイヌ腎乳頭壊死の病態生理学的研究 

作成者 土屋, 由美
作成者の別表記 Tsuchiya, Yoshimi
キーワード等 renal papillary mecrosis, prostaglandin, clusterin, tissue kallikrein, 腎乳頭壊死, プロスタグランジン, クラステリン, 組織カリクレイン
日本十進分類法 (NDC) 490
内容 学位:千大院医薬博甲第医薬7号
抄録:The occurrence of RPN seen only in dogs after repeated oral administration of nefiracetam at a relatively high dose is due to inhibition of renal PG synthesis by the nefiracetam metabolite M-18. In the present study, analyses of urinary proteins and renal mRNA expression were carried out to investigate the possible existence of a specific protein expressing characteristics of RPN evoked by nefiracetam. In the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of urinary proteins from male dogs given nefiracetam at 300mg/kg/day over weeks 5 to 11, a protein of around 40 kD, which was not seen in the control urine, and protein of around 30 kD emerged in distinct bands. Consequently, clusterin precursor was identified in the former band, and tissue kallikrein precursor was recognized in the latter band by liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS). By quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis with renal morphological aspects, individual findings showed that renal clusterin mRNA was increased in certain dogs showing severe renal injuries, and renal tissue kallikrein also increased presumably related to hemodynamics. These results demonstrate that changes in renal clusterin mRNA may reflect the progression or severity of RPN, whereas upregulation of tissue kallikrein mRNA may play a subsequently compensating role in the prevention of RPN. Effects of nefiracetam, a neurotransmission enhancer, on renal biochemistry and morphology with toxicokinetic disposition were investigated in both in vivo and in vitro systems. In the in vivo studies with rats, dogs, and monkeys, only the dog exhibited RPN.…

コンテンツの種類 博士論文 Doctoral Thesis
DCMI資源タイプ text
ファイル形式 application/pdf
言語 英語

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