The development of a therapeutic strategy to prevent aminoglycoside- induced hearing loss seems more urgent than ever. Millions of patients are treated annually in the US; worldwide, aminoglycosides are the most commonly used antibiotics. The problem is aggravated by the global resurgence of tuberculosis and the increased occurrence of resistant bacteria which necessitate multi-drug regimens including aminoglycosides. Given the 10 to 20 percent incidence of cochlear and vestibular disturbances associated with aminoglycoside treatment, this constitutes a major health problem in the US and abroad. The goal of the proposed research is to develop a rational protective treatment against aminoglycoside-ototoxicity. The anticipated studies are founded on exciting recent discoveries from this laboratory that allow the proposal of a mechanism of toxicity and a pharmacological means of protection. The first successful tests of the proposal of a mechanism of toxicity and a pharmacological means of protection. The first successful tests of the protective strategy have already been completed in guinea pig. The approach is based on the novel hypothesis that gentamicin can chelate iron. The iron-gentamicin complex catalyzes free-radical reactions which are toxic to the cell. These reactions can be inhibited by radical scavengers and, most dramatically, by iron chelators which attenuate gentamicin-induced hearing loss in guinea pigs in vivo. The goals of the proposal will be primarily accomplished by experiments on prevention or amelioration of aminoglycoside otoxicity in guinea pigs in vivo. In vitro and in vivo experiments will establish efficacious and safe combinations of iron chelators and scavengers. These goals are aided by structural and chemical analyses of the iron-aminoglycoside complexes which will improve our understanding of the underlying mechanisms and guide the development of protective strategies. These questions will be addressed with well-established biochemical, physiological, analytical and physicochemical techniques. The prevention or amelioration of adverse effects of aminoglycoside antibiotics will have far reaching implications for the continued but safe use of a family of drugs whose primary efficacy is unquestioned.
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