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Drug-mediated ototoxicity and tinnitus: alleviation with melatonin.
Reiter RJ, Tan DX, Korkmaz A, Fuentes-Broto L.
Source
Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Texas USA. [email]reiter@uthscsa.edu[/email].
Abstract
This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage.
http://www.ncbi.nlm.nih.gov/pubmed/21673362
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full textquote:
TINNITUS: REDUCTION BY MELATONIN
Tinnitus is the perception of sound when it is otherwise externally quiet. It occurs as a result of a variety of conditions including allergies, a consequence of medications (e.g., aspirin) or a congenital defect and may accompany natural hearing loss that is observed during aging. Tinnitus is often caused by noiseinduced hearing impairment (71). When the health care professional can actually hear a sound emanating from the ear of a patient, it is referred to as objective tinnitus (72). Conversely, where no noise can be perceived by anyone other than the patient, it is referred to as subjective tinnitus (73). Interest in the potential use of melatonin to minimize tinnitus was initiated by observation of Rosenberg et al. (74) who found that melatonin, taken at a dose of 3 mg daily for 30 days, caused a perceptible reduction in tinnitus. The improvement was most obvious in patients with bilateral, as opposed to unilateral, tinnitus and in those whose sleep was disturbed because of tinnitus. Melatonin is also a sleep promoting agent, however, which may have reduced the perception of tinnitus. Due to their results, the authors suggested that melatonin should be included in the armamentarium of drugs useful in treating subjective tinnitus. A double-blind, placebo-controlled prospective study also showed that melatonin alleviated subjective tinnitus (75). In this study, melatonin (3 mg daily) was compared with the D2 dopamine receptor antagonist, sulpiride (50 mg daily), or combined with it with tinnitus perception being subjectively graded by the patients; the duration of treatment was 30 days. Using the subjective rating scale, sulpiride reduced tinnitus by 56%, melatonin lowered it by 40% and the combined treatment caused an 81% drop in subjective tinnitus. The visual analogue scale evaluation also indicated that the combination of drugs also was the best treatment to reduce tinnitus perception. In this study it was surmised that melatonin’s efficacy in limiting the perception of tinnitus stemmed from its ability to reduce the response to dopamine, possibly by inhibiting the release of the tissue biogenic amine which may be mediated by central-type benzodiazepine receptors (76). While Lopez-Gonzalez and coworkers (75) provide a logical flow diagram to illustrate how melatonin may impact tinnitus via a dopaminergic mechanism, the paper provides no direct support for this hypothesis. Similar findings using a combination of melatonin and sulodexide were observed in terms of reducing tinnitus. In the 34 patients receiving this treatment, the combination of drugs improved the quality of life and reduced the subjective evaluation of the severity of tinnitus (77). Sulodexide, a glycosaminoglycan, was used because of its ability to enhance the blood flow in the labyrinthine microcirculation. In a study that lacked a placebo-treated control group, melatonin also seemingly reduced the subjective interpretation of the severity of tinnitus in patients as assessed using the Tinnitus Handicap Inventory (78). In the same report, the effect of melatonin on sleep was estimated. As with the presumed reduction in tinnitus, melatonin also improved sleep quality as evaluated using the Pittsburgh Sleep Quality Index. There seemed to be some association between the improvements in sleep and tinnitus. The authors of this report feel melatonin may be a safe treatment for tinnitus, particularly in patients where the tinnitus is so severe it disturbs sleep.