Accumulation of drugs on inner ear melanin. Therapeutic and ototoxic mechanisms.
The aim of this study was to obtain more information about the possible role of melanin in the hearing process and to investigate the ototoxic and therapeutic effects of certain drugs with known affinity to this pigment. In order to obtain hearing threshold curves, young albino and pigmented guinea pigs were tested by N1-electrocochleography. There were no significant differences between the curves for the two strains, indicating that melanin has no major influence on the hearing process in young guinea pigs under normal conditions at thresholds. The acute and long-term ototoxic effect of kanamycin, an aminoglycoside antibiotic capable of accumulating on melanin in vitro, was studied in albino and pigmented guinea pigs by electrophysiological and morphological methods. In the highest dose used, 200 mg/kg/day, kanamycin caused significantly more damage in the pigmented guinea pigs than in the albino ones. To elucidate the possible role of melanin affinity in pharmacological treatment of tinnitus and the site of action of lidocaine and tocainide, nine patients with disabling tinnitus were treated with lidocaine, QX-572 (a quaternary derivative of lidocaine which does not readily penetrate the blood-brain barrier) and tocainide (an amine analogue of lidocaine which can be taken orally). In six patients all three substances had a beneficial effect, but in the remaining three patients none of them produced any response. Autoradiographic studies in rats, both in vivo and in vitro, showed that all three substances accumulated on inner ear melanin. Auditory brainstem-evoked responses (ABRs) were measured in 10 healthy male subjects after single-dose injections of the respective drugs, in doses normally reducing tinnitus in sensitive patients. Neither drug produced any significant change in ABR. The results of these studies support a hypothesis that accumulation of drugs on inner ear melanin can constitute both an ototoxic and a therapeutic mechanism.
D000328:Adult; D000779:Anesthetics, Local / Q000627:therapeutic use*; D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects; D002986:Clinical Trials as Topic; D004311:Double-Blind Method; D007758:Ear, Inner / Q000187:drug effects*; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects; D006801:Humans; D007612:Kanamycin / Q000633:toxicity*; D008012:Lidocaine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D051381:Rats; D014012:Tinnitus / Q000188:drug therapy*; D016677:Tocainide
D000779:Anesthetics, Local; D008543:Melanins; D016677:Tocainide; D007612:Kanamycin; D008012:Lidocaine; C006110:carcainium chloride