Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats
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 ass...
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MDPI AG
2021-03-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/4/359 |
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| author | Dilip Roy Amol Kulkarni Manu Chaudhary Saransh Chaudhary Anurag Payasi Anmol Aggarwal |
| author_facet | Dilip Roy Amol Kulkarni Manu Chaudhary Saransh Chaudhary Anurag Payasi Anmol Aggarwal |
| author_sort | Dilip Roy |
| collection | DOAJ |
| description | 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 (<i>p</i> < 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. |
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| language | English |
| last_indexed | 2024-03-10T12:49:02Z |
| publishDate | 2021-03-01 |
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| series | Antibiotics |
| spelling | doaj.art-19562091854a4ff584d165a6da220e382023-11-21T13:10:46ZengMDPI AGAntibiotics2079-63822021-03-0110435910.3390/antibiotics10040359Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in RatsDilip Roy0Amol Kulkarni1Manu Chaudhary2Saransh Chaudhary3Anurag Payasi4Anmol Aggarwal5Venus Medicine Research Centre, Baddi 173205, Himachal Pradesh, IndiaVenus Medicine Research Centre, Baddi 173205, Himachal Pradesh, IndiaVenus Medicine Research Centre, Baddi 173205, Himachal Pradesh, IndiaVenus Medicine Research Centre, Baddi 173205, Himachal Pradesh, IndiaVenus Medicine Research Centre, Baddi 173205, Himachal Pradesh, IndiaVenus Medicine Research Centre, Baddi 173205, Himachal Pradesh, IndiaDespite 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 (<i>p</i> < 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.https://www.mdpi.com/2079-6382/10/4/359drug-induced kidney injurypolymyxin Bacute kidney injuryKIM-1nephrotoxicitycystatin-C |
| spellingShingle | Dilip Roy Amol Kulkarni Manu Chaudhary Saransh Chaudhary Anurag Payasi Anmol Aggarwal Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats Antibiotics drug-induced kidney injury polymyxin B acute kidney injury KIM-1 nephrotoxicity cystatin-C |
| title | Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats |
| title_full | Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats |
| title_fullStr | Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats |
| title_full_unstemmed | Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats |
| title_short | Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats |
| title_sort | polymyxin b induced kidney injury assessment of a novel formulation of polymyxin b vrp 034 in rats |
| topic | drug-induced kidney injury polymyxin B acute kidney injury KIM-1 nephrotoxicity cystatin-C |
| url | https://www.mdpi.com/2079-6382/10/4/359 |
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