Roy Dilip, Kulkarni Amol, Chaudhary Manu, Chaudhary Saransh, Payasi Anurag, Aggarwal Anmol
Venus Medicine Research Centre, Baddi 173205, Himachal Pradesh, India.
Antibiotics (Basel). 2021 Mar 28;10(4):359. doi: 10.3390/antibiotics10040359.
Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034_F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase ( < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034_F21, F24) and no appreciable damage was detected in the other two groups (VRP034_F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.
尽管多粘菌素B在治疗危及生命的革兰氏阴性菌感染中起着关键作用，但其临床应用因急性肾损伤风险而受到限制。作为应对措施，一种新型多粘菌素B制剂正在研发中，以减轻药物引起的肾损伤。在本研究中，我们使用大鼠肾损伤生物标志物，评估了该新型制剂的四种变体（VRP034_F21 - F24）与标准多粘菌素B相比的毒性。将斯普拉格-道利大鼠皮下注射多粘菌素B（对照组）或四种多粘菌素B制剂之一，剂量为25 mg/kg/天（人等效剂量：4 mg/kg/天），分四次给药，持续两天。在基线和第2天结束时采集血清样本，用于测定血清生物标志物。在第2天进行尸检，并采集肾脏进行组织病理学评估。在对照组中，与基线值相比，第2天所有生物标志物均出现统计学显著升高（<0.0001）[尿素：311%；肌酐：700%；KIM - 1：180%；胱抑素C：66%]，50%的动物在预定尸检前死亡（1只在第7次给药后死亡，2只在第8次给药后死亡）。相比之下，用新型制剂治疗的动物在任何生物标志物上均未出现显著升高，也未观察到死亡情况。对照组肾脏的组织病理学证实组织出现坏死变化，伴有充血和空泡化，而在两个制剂组（VRP034_F21、F24）中仅发现轻微的肾小管损伤，在另外两个组（VRP034_F22 - 23）中未检测到明显损伤。本研究中测试的新型多粘菌素B制剂显著降低了大鼠多粘菌素诱导的肾损伤风险。
