Facility for Anti-Infective Drug Development and Innovation, Drug Delivery, Disposition, and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Antimicrob Agents Chemother. 2011 Sep;55(9):4044-9. doi: 10.1128/AAC.00328-11. Epub 2011 Jun 27.
Colistin-induced nephrotoxicity is a dose-limiting adverse effect when colistin is used against Gram-negative pathogens. This study examined the nephroprotective effect of melatonin against colistin in rats. Rats (n = 7 per group) were treated intravenously twice daily with saline, colistin (at increasing doses from 0.5 to 4.0 mg/kg), melatonin (5 mg/kg), or both melatonin and colistin for 7 days. The severity of renal alteration was examined both biochemically and histologically. The effect of coadministration of melatonin on colistin pharmacokinetics was investigated. Significantly lower urinary N-acetyl-β-d-glucosaminidase excretion was observed from day 1 in the colistin-melatonin group compared to the colistin group (P < 0.0001). Plasma creatinine increased significantly (P = 0.023) only in the colistin group on day 6. Significant histological abnormalities (P < 0.0001) were detected only in the kidneys of the colistin group. Melatonin altered colistin pharmacokinetics; the total body clearance in the colistin-melatonin group (1.82 ± 0.26 ml/min/kg) was lower than in the colistin group (4.28 ± 0.93 ml/min/kg). This is the first study demonstrating the protective effect of melatonin against colistin-induced nephrotoxicity, which indicates that colistin-induced nephrotoxicity is mediated through oxidative stress. It also highlights the potential of coadministering an antioxidant to widen the therapeutic window of this very important last-line antibiotic.
黏菌素引起的肾毒性是黏菌素对抗革兰氏阴性病原体时的剂量限制不良反应。本研究探讨了褪黑素对大鼠黏菌素肾毒性的保护作用。大鼠（每组 7 只）每天静脉注射两次生理盐水、黏菌素（剂量从 0.5 至 4.0mg/kg 递增）、褪黑素（5mg/kg）或褪黑素和黏菌素联合治疗 7 天。分别从生化和组织学两个方面检查肾脏损伤的严重程度。还研究了同时给予褪黑素对黏菌素药代动力学的影响。与黏菌素组相比，黏菌素-褪黑素组在第 1 天的尿 N-乙酰-β-D-氨基葡萄糖苷酶排泄量明显较低（P<0.0001）。仅在第 6 天，黏菌素组的血浆肌酐显著升高（P=0.023）。仅在黏菌素组的肾脏中发现明显的组织学异常（P<0.0001）。褪黑素改变了黏菌素的药代动力学；黏菌素-褪黑素组的全身清除率（1.82±0.26ml/min/kg）低于黏菌素组（4.28±0.93ml/min/kg）。这是第一项表明褪黑素对黏菌素诱导的肾毒性具有保护作用的研究，这表明黏菌素诱导的肾毒性是通过氧化应激介导的。它还强调了同时给予抗氧化剂以扩大这种非常重要的最后一线抗生素的治疗窗的潜力。
