PROTECTION FROM GENTAMICIN OTOTOXICITY BY IRON CHELATORS IN GUINEA-PIG IN-VIVO

This study details the prevention of gentamicin-induced hearing loss i n guinea pig in vivo. The approach is based on our recent demonstratio ns of a redox-active gentamicin-iron complex in vitro and partial atte nuation of gentamicin-induced hearing loss by the iron chelators defer oxamine and 2,3-dihydroxybenzoate. In our study, guinea pigs receiving injections of gentamicin (120 mg/kg body weight daily x 19 days) deve loped a progressive threshold shift reaching 50 to 70 dB at 18 kHz. Co ncurrent treatment with different doses of 2,3-dihydroxybenzoate (30-3 00 mg/kg/day) reduced the threshold shift: to 25 to 15 dB. Coinjection of gentamicin with dihydroxybenzoate (100 mg/kg/day) plus mannitol (1 5 mg/kg/day) yielded complete functional and morphological protection from gentamicin ototoxicity although partial protection was observed w ith combinations of dihydroxybenzoate and deferoxamine. Dihydroxybenzo ate also attenuated gentamicin-induced vestibular toxicity. The iron c helators and radical scavengers affected neither serum levels nor the antimicrobial efficacy of gentamicin against Escherichia coil. These r esults 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 b e promising therapeutic agents to reduce aminoglycoside ototoxicity.