ABSTRACT

Colistin-induced nephrotoxicity (CIN) occurs in up to 60% of patients, and this has restricted its clinical use. In view of its efficacy amidst the rising challenge of infections caused by multidrug-resistant bacteria, current studies are focusing on ways to ameliorate colistin-induced nephrotoxicity. This study investigated treatment-time differences in colistin-induced nephrotoxicity in Wistar rats. A dose of 600,000 IU/Kg/day of colistimethate sodium (CMS) was administered to male Wistar rats to induce nephrotoxicity; the rats tolerated the higher dose for the treatment duration with higher mean values of serum creatinine, urea, and malondialdehyde compared to the group that received 450,000 IU/Kg/day CMS (p ≤ 0.05). Four groups (n = 8/group) of rats received intraperitoneal (i.p.) injections of 600,000 IU/Kg/day CMS each at four equally spaced circadian times (00:00, 06:00, 12:00, and 18:00 h) to determine the time of administration with least renal toxicity. Biomarkers of oxidative stress and renal toxicity were measured and kidney histology studied after the treatments. The results showed a 24-h pattern in nephrotoxicity from CIN, and that treatment during the activity time period (dark phase) caused lowest CIN. Histological findings supported this finding, with photomicrographs consistently showing more pronounced features of CIN in the groups treated during time frame that coincided with the rest phase in rats (12:00 and 18:00).

摘要

高达 60% 的患者发生多粘菌素诱导的肾毒性 (CIN)，这限制了其临床应用。鉴于其在多重耐药菌引起的感染挑战日益严峻的情况下的疗效，目前的研究重点是减轻粘菌素引起的肾毒性的方法。本研究调查了 Wistar 大鼠中粘菌素诱导的肾毒性的治疗时间差异。给雄性 Wistar 大鼠施用 600,000 IU/Kg/天的粘菌素钠（CMS）以诱导肾毒性；与接受 450,000 IU/Kg/天 CMS 的组相比，大鼠耐受更高剂量的治疗持续时间，血清肌酐、尿素和丙二醛的平均值更高（p ≤ 0.05）。四组 (n = 8/组) 的大鼠接受了 600 的腹膜内 (ip) 注射，000 IU/Kg/天 CMS，每个在四个等距的昼夜节律时间（00:00、06:00、12:00 和 18:00 h），以确定肾毒性最小的给药时间。治疗后测量氧化应激和肾毒性的生物标志物并研究肾脏组织学。结果显示 CIN 的肾毒性呈 24 小时模式，活动时间段（暗期）的治疗导致 CI​​N 最低。组织学发现支持这一发现，显微照片始终显示在与大鼠休息阶段（12:00 和 18:00）重合的时间范围内治疗的组中的 CIN 特征更明显。治疗后测量氧化应激和肾毒性的生物标志物并研究肾脏组织学。结果显示 CIN 的肾毒性呈 24 小时模式，活动时间段（暗期）的治疗导致 CI​​N 最低。组织学发现支持这一发现，显微照片始终显示在与大鼠休息阶段（12:00 和 18:00）重合的时间范围内治疗的组中的 CIN 特征更明显。治疗后测量氧化应激和肾毒性的生物标志物并研究肾脏组织学。结果显示 CIN 的肾毒性呈 24 小时模式，活动时间段（暗期）的治疗导致 CI​​N 最低。组织学发现支持这一发现，显微照片始终显示在与大鼠休息阶段（12:00 和 18:00）重合的时间范围内治疗的组中的 CIN 特征更明显。