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Early Pathophysiological Features in Canine Renal Papillary Necrosis Induced by Nefiracetam

¹ Drug Safety Research Laboratory
² Technology Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
³ Department of Toxicology and Environmental Health, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

Correspondence: Address correspondence to: Yoshimi Tsuchiya, Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13, Kita-kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan; e-mail:tsuchgtc{at}daiichipharm.co.jp

To ascertain the early pathophysiological features in canine renal papillary necrosis (RPN) caused by the neurotransmission enhancer nefiracetam, male beagle dogs were orally administered nefiracetam at 300 mg/kg/day for 4 to 7 weeks in comparison with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), at 50 mg/kg/day for 5 weeks. During the dosing period, the animals were periodically subjected to laboratory tests, light-microscopic, immunohistochemical, and electron-microscopic examinations and/or cyclooxygenase (COX)-2 mRNA analysis. In laboratory tests, a decrease in urinary osmotic pressure and increases in urine volume and urinary lactate dehydrogenase (LDH) level were early biomarkers for detecting RPN. Light-microscopically, nefiracetam revealed epithelial swelling and degeneration in the papillary ducts in week 7, while ibuprofen displayed degeneration and necrosis in the papillary interstitium in week 5. In immunohistochemical staining with COX-2 antibody, nefiracetam elicited a positive reaction within interstitial cells around the affected epithelial cells in the papillary ducts (upper papilla) in week 7, and ibuprofen positively reacted within interstitial cells adjacent to the degenerative and/or necrotic lesions in week 5. Ultrastructurally, nefiracetam exhibited reductions of intracellular interdigitation and infoldings of epithelial cells in the papillary ducts, whereas ibuprofen showed no changes in the identical portions. Thus, the early morphological change in the papilla brought about by nefiracetam was quite different from that elicited by ibuprofen. By the renal papillary COX-2 mRNA expression analysis, nefiracetam exceedingly decreased its expression in week 4, but markedly increased it in week 7, suggesting an induction of COX-2 mRNA by renal papillary lesions. These results demonstrate that the epithelial cell in the papillary ducts is the primary target site for the onset of RPN evoked by nefiracetam.

Key Words: Renal papillary necrosis • dog • nefiracetam • ibuprofen • cyclooxygenase-2

Abbreviations: RPN, renal papillary necrosis • NSAIDs, nonsteroidal anti-inflammatory drugs • COX, cyclooxygenase • PG, prostaglandin

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