RESUMEN
CONCLUSION: Combination therapy corticosteroids plus an oral antioxidant L-N-acetylcysteine (LNAC) was associated with improved hearing over corticosteroids alone, particularly at the 6-month follow-up and at high frequencies (i.e. 4000 Hz). This is the first report of a beneficial effect of LNAC in sudden idiopathic sensorineural hearing loss (SISNHL). OBJECTIVE: To determine the association between antioxidant treatment and functional outcomes in SISNHL. METHODS: This was a case-control study of adult patients with SISNHL, treated with oral prednisone plus intratympanic dexamethasone either alone or in combination with LNAC. The outcome measure was change in pure-tone thresholds at 500-4000 Hz. Hearing recovery was also recorded as the percentage of subjects with final pure-tone threshold average (PTA) within 50% of the difference between the initial value of the affected ear and the value of the unaffected ear. Comparisons were made between combination (corticosteroids plus LNAC) and single (no LNAC use) therapy groups. RESULTS: At 6 months, the mean PTA improvements were 26.1 dB and 15.1 dB for the combination and single therapy groups, respectively (p = 0.046). Higher gains at 4000 Hz were noted with LNAC use. The percentage of patients with at least 50% recovery was 63% and 35% for the combination and single therapy groups, respectively (p = 0.0319).
Asunto(s)
Acetilcisteína/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Adolescente , Adulto , Anciano , Dexametasona/uso terapéutico , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Pruebas Auditivas , Humanos , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Estudios Retrospectivos , Adulto JovenRESUMEN
One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review.
Asunto(s)
Corticoesteroides/uso terapéutico , Antioxidantes/administración & dosificación , Muerte Celular/efectos de los fármacos , Enfermedades Cocleares/tratamiento farmacológico , Células Ciliadas Auditivas/efectos de los fármacos , Pérdida Auditiva/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Inhibidores de Caspasas , Enfermedades Cocleares/complicaciones , Enfermedades Cocleares/patología , Sistemas de Liberación de Medicamentos/métodos , Células Ciliadas Auditivas/patología , Pérdida Auditiva/prevención & control , Humanos , Inflamación/complicaciones , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Modelos Biológicos , Fármacos Neuroprotectores/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
HYPOTHESIS: Dexamethasone (DXM) protects hearing against trauma-induced loss. MATERIALS: in vivo: A guinea pig model of electrode induced trauma (EIT)-induced hearing loss was used to locally deliver dexamethasone. In vitro: TNF-α-challenged organ of Corti explants treated with DXM or polymer-eluted DXM +/- PI3K/Akt/PkB/NFkB inhibitors were used for hair cells count and gene expression studies. RESULTS: in vivo: local DXM treatment of EIT-animals prevents trauma-induced loss of ABR thresholds that occurs in EIT-animals and EIT-animals treated with the carrier solution (i.e., AP), and prevented loss of auditory hair cells. In vitro: DXM and polymer-eluted DXM were equally effective in protecting hair cells from ototoxic levels of TNF-α Inhibitor treated explants demonstrated that DXM treatment requires both Akt/PKB and NFkB signalling for otoprotection. DXM treatment of explants showed up regulation of anti-apoptosis related genes (i.e., Bcl-2, Bcl-xl) and down regulation of pro-apoptosis related genes (i.e., Bax, TNFR-1). CONCLUSIONS: DXM exert its otoprotective action by activation of cell signal molecules (e.g., NFkB) that alter the expression of anti- and pro-apoptosis genes.