Kobayashi H, Ohi H, Kawashima Y
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine.
Nihon Sanka Fujinka Gakkai Zasshi. 1989 Jun;41(6):683-7.
The present study was performed to evaluate the mechanism of the protective effect of urinastatin (US) against cisplatin (CDDP) induced nephrotoxicity. We measured consecutively the change in the creatinine clearance (Ccr) level, urinary arylamidase (AA) activity, and urinary gamma-glutamyl transpeptidase (gamma-GTP) activity as the indices of nephrotoxicity. These drugs such as US (10,000 U/kg, 3h: group 1), gabexate mesilate (2mg/kg/h, 4h: group 2), and aprotinin (5,000 U/kg/h, 4h: group 3) as protease inhibitors, and dopamine HCl (0.3mg/kg/h, 4h: group 4) for the increase in renal blood flow were used with the hydration of 15 ml/kg/h during 4 hours of experiments on rabbits. The change in the Ccr value after the intravenous administration of CDDP indicated that the level in groups 3, 4 decreased significantly at one day after the administration of CDDP. On the other hand, there was little significant increase in urinary AA activity and/or urinary gamma-GTP activity in group 1, while a transitional increase was observed in groups 2, 3, and 4, among which the highest level was found in group 4. These results are attributed to the protective action of US against CDDP mainly in the inhibition of the lysosomal enzyme released by the destruction of lysosomes in the proximal tubule cells of the kidney.
本研究旨在评估乌司他丁（US）对顺铂（CDDP）诱导的肾毒性的保护作用机制。我们连续测量肌酐清除率（Ccr）水平、尿芳基酰胺酶（AA）活性和尿γ-谷氨酰转肽酶（γ-GTP）活性的变化，以此作为肾毒性指标。在对家兔进行的4小时实验中，使用了这些药物，如作为蛋白酶抑制剂的US（10000 U/kg，3小时：第1组）、甲磺酸加贝酯（2mg/kg/h，4小时：第2组）和抑肽酶（5000 U/kg/h，4小时：第3组），以及用于增加肾血流量的盐酸多巴胺（0.3mg/kg/h，4小时：第4组），同时以15 ml/kg/h的速度进行4小时的补液。静脉注射CDDP后Ccr值的变化表明，第3组和第4组在注射CDDP一天后水平显著下降。另一方面，第1组尿AA活性和/或尿γ-GTP活性几乎没有显著增加，而第2组、第3组和第4组则出现短暂增加，其中第4组增加水平最高。这些结果归因于US对CDDP的保护作用，主要是抑制肾近端小管细胞溶酶体破坏释放的溶酶体酶。
