Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.
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http://dx.doi.org/10.1038/s41401-019-0342-5 | DOI Listing |
J Med Case Rep
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Department of Medical Oncology, La Fe University and Polytechnic Hospital, Valencia, Spain.
Eur J Med Chem
January 2025
Inner Mongolia University Research Center for Glycochemistry of Characteristic Medicinal Resources, College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, 010021, China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France; Fuyang Institute & School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311422, Zhejiang, China; Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, Hainan, 571158, China. Electronic address:
Cancer is one of the most aggressive diseases known to humanity, characterized by low survival rates and poor prognoses. Currently, platinum-based anticancer drugs and traditional photosensitizers used in photodynamic therapy (PDT) are the most widely employed treatment modalities. However, the platinum-based medications, particularly cisplatin, the most commonly used agent, have several drawbacks.
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October 2024
Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Pediatr Blood Cancer
January 2025
Department of Nephrology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
Purpose: Platinum-based chemotherapy is a mainstay of treatment for many childhood cancers but is associated with acute nephrotoxicity and long-term ototoxicity. There is emerging evidence of long-term renal complications. This study aimed to assess the prevalence of chronic kidney disease (CKD) in children treated with platinum chemotherapy (cisplatin and carboplatin) and identify potential risk factors for the development of CKD.
View Article and Find Full Text PDFJ Pharm Pharmacol
January 2025
Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India.
Objectives: Platinum-based anticancer chemotherapy (PAC) represents a cornerstone in cancer treatment, retaining its status as the gold standard therapy. However, PAC's efficacy is countered by significant toxicities, such as nephrotoxicity, ototoxicity, and neurotoxicity. Recent studies have linked these toxicities to ferroptosis, characterized by iron accumulation, reactive oxygen species generation, and lipid peroxidation.
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