Iron chelators protect from aminoglycoside-induced cochleo- and vestibulo-toxicity.
The attenuation of gentamicin-induced hearing loss by iron chelators and radical scavengers has recently been demonstrated in guinea pig in vivo. The present study investigated whether this protective treatment is effective against hearing loss and vestibular damage caused by other aminoglycosides. In a direct comparison, dihydroxybenzoate was chosen over deferoxamine because of its more effective action against gentamicin-induced hearing loss. Guinea pigs received daily injections of kanamycin (250 mg/kg/d) or streptomycin (300 mg/kg/d) for 23 d to induce severe cochlear or vestibular toxicity, respectively. Kanamycin injections resulted in a progressive threshold shift of 60 to 80 dB at 18 kHz, while streptomycin injections induced only a small threshold shift. In contrast, streptomycin abolished almost all vestibular responses. Coinjection of aminoglycosides with a mixture of dihydroxybenzoate (100 mg/kg/d) and mannitol (30 mg/kg/d) significantly attenuated kanamycin-induced hearing loss and protected against streptomycin-induced vestibulotoxicity. DHB/mannitol did not affect serum levels or the antibacterial efficacy of either aminoglycoside. This study supports the idea that iron and free radicals play a critical role in the toxic side effects of aminoglycoside antibiotics. Furthermore, the previously proposed therapeutic protection is not limited to gentamicin but applicable to other aminoglycosides as well.
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Kresge Hearing Research Institute, University of Michigan, Ann Arbor 48109-0506, USA.
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Schacht
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D000617:Aminoglycosides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects*; D003404:Creatinine / Q000097:blood; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology; D004334:Drug Administration Schedule; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005839:Gentamicins / Q000008:administration & dosage / Q000633:toxicity; D006168:Guinea Pigs; D062385:Hydroxybenzoates / Q000008:administration & dosage / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007612:Kanamycin / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity; D008297:Male; D008353:Mannitol / Q000008:administration & dosage / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D012027:Reflex, Vestibulo-Ocular / Q000187:drug effects; D012709:Serum Albumin / Q000032:analysis; D013307:Streptomycin / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity; D014722:Vestibule, Labyrinth / Q000187:drug effects*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D016166:Free Radical Scavengers; D005839:Gentamicins; D062385:Hydroxybenzoates; D007502:Iron Chelating Agents; D012709:Serum Albumin; D008353:Mannitol; D007612:Kanamycin; C009135:2,3-dihydroxybenzoic acid; D003404:Creatinine; D003676:Deferoxamine; D013307:Streptomycin