Song B B, Anderson D J, Schacht J
Kresge Hearing Research Institute, University of Michigan, Ann Arbor 48109-0506, USA.
J Pharmacol Exp Ther. 1997 Jul;282(1):369-77.
This study details the prevention of gentamicin-induced hearing loss in guinea pig in vivo. The approach is based on our recent demonstrations of a redox-active gentamicin-iron complex in vitro and partial attenuation of gentamicin-induced hearing loss by the iron chelators deferoxamine and 2,3-dihydroxybenzoate. In our study, guinea pigs receiving injections of gentamicin (120 mg/kg body weight daily x 19 days) developed a progressive threshold shift reaching 50 to 70 dB at 18 kHz. Concurrent treatment with different doses of 2,3-dihydroxybenzoate (30-300 mg/kg/day) reduced the threshold shift to 25 to 15 dB. Coinjection of gentamicin with dihydroxybenzoate (100 mg/kg/day) plus mannitol (15 mg/kg/day) yielded complete functional and morphological protection from gentamicin ototoxicity although partial protection was observed with combinations of dihydroxybenzoate and deferoxamine. Dihydroxybenzoate also attenuated gentamicin-induced vestibular toxicity. The iron chelators and radical scavengers affected neither serum levels nor the antimicrobial efficacy of gentamicin against Escherichia coli. These results confirm that iron and free radicals play a crucial role in the toxic side effects of gentamicin. Furthermore, they suggest that iron chelators, which are well-established drugs in clinical therapy, may be promising therapeutic agents to reduce aminoglycoside ototoxicity.
本研究详细阐述了豚鼠体内庆大霉素所致听力损失的预防方法。该方法基于我们近期在体外证实的具有氧化还原活性的庆大霉素 - 铁复合物，以及铁螯合剂去铁胺和2,3 - 二羟基苯甲酸对庆大霉素所致听力损失的部分减轻作用。在我们的研究中，接受庆大霉素注射（每日120 mg/kg体重，共19天）的豚鼠在18 kHz处出现渐进性阈值偏移，达到50至70 dB。同时用不同剂量的2,3 - 二羟基苯甲酸（30 - 300 mg/kg/天）进行治疗可将阈值偏移降低至25至15 dB。将庆大霉素与二羟基苯甲酸（100 mg/kg/天）加甘露醇（15 mg/kg/天）共同注射，可对庆大霉素耳毒性产生完全的功能和形态学保护，尽管二羟基苯甲酸与去铁胺联合使用时仅观察到部分保护作用。二羟基苯甲酸还减轻了庆大霉素所致的前庭毒性。铁螯合剂和自由基清除剂对庆大霉素的血清水平及对大肠杆菌的抗菌效力均无影响。这些结果证实铁和自由基在庆大霉素的毒副作用中起关键作用。此外，它们表明在临床治疗中已确立的铁螯合剂可能是减少氨基糖苷类耳毒性的有前景的治疗药物。
