The aim of these interdisciplinary studies is the elucidation of biochemical mechanisms underlying aminoglycoside-induced hearing loss. Specifically, we wish to describe the molecular events leading to inner ear damage; to establish structure-toxicity relationships and develop in-vitro tests for ototoxicity; and to define conditions of reversibility or amelioration of toxic effects. The work is based on previously obtained results and begins with the hypothesis that these antibiotics bind to polyphosphoinositide lipids, displace calcium, and disturb membrane structure and function. The studies will combine biochemical, physicochemical, electrophysiological, and morphological techniques. The interaction of aminoglycosides with phosphatidylinositol bisphosphate is quantitated by physicochemical measurements, e.g., with monomolecular lipid films, differential scanning calorimetry or permeability changes of liposomes. Structurally modified drugs are tested as to their lipid binding and their effect on cochlear microphonics and action potentials in perilymphatic perfusions in order to determine those sites on the antibiotic that are involved in its ototoxic action. Drug/lipid interactions in monolayers will also be investigated for their usefulness as an in-vitro correlate of drug ototoxicity. Pharmacokinetic studies will determine the distribution of preferentially cochleotoxic and vestibulotoxic aminoglycosides in the inner ear and this will be compared to phosphoinositide content in these structures. Reversibility of gentamicin-induced hearing loss, previously established in cochlear perfusions, will be explored after systemic injection of the drug. The proposed studies should expand our understanding of the biochemical mechanisms underlying aminoglycoside ototoxicity and provide guidance for drug modification and amelioration of toxic effects.
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