Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial.

Background: Noise-induced hearing loss is a leading cause of occupational and recreational injury and disease, and a major determinant of age-related hearing loss. No therapeutic agent has been approved for the prevention or treatment of this disorder. In animal models, glutathione peroxidase 1 (GPx1) activity is reduced after acute noise exposure.

Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome.

Perrault syndrome is a genetically heterogeneous recessive disorder characterized by ovarian dysgenesis and sensorineural hearing loss. In a nonconsanguineous family with five affected siblings, linkage analysis and genomic sequencing revealed the genetic basis of Perrault syndrome to be compound heterozygosity for mutations in the mitochondrial histidyl tRNA synthetase HARS2 at two highly conserved amino acids, L200V and V368L. The nucleotide substitution creating HARS2 p.

Ebselen treatment reduces noise induced hearing loss via the mimicry and induction of glutathione peroxidase.

Previous studies indicate that noise induced hearing loss (NIHL) involves a decrease in glutathione peroxidase (GPx) activity and a subsequent loss of outer hair cells (OHC). However, the cellular localization of this GPx decrease and the link to OHC loss are still poorly understood. In this report, we examined the cellular localization of GPx (GPx1, GPx 3 and GPx 4) in F-344 rat before and after noise exposure and after oral treatment with ebselen, a small molecule mimic of GPx activity.

Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss.

In a large consanguineous Palestinian kindred, we previously mapped DFNB28--a locus associated with recessively inherited, prelingual, profound sensorineural hearing impairment--to chromosome 22q13.1. We report here that mutations in a novel 218-kDa isoform of TRIOBP (TRIO and filamentous actin [F-actin] binding protein) are associated with DFNB28 hearing loss in a total of nine Palestinian families.

Compounds for the prevention and treatment of noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is the leading occupational disease and a major contributor to the development of age-related hearing loss. The pharmacological prevention and treatment of NIHL has been under preclinical investigation for the past 20 years. Promising treatments have now been identified and entered into clinical development.

Combined oral delivery of ebselen and allopurinol reduces multiple cisplatin toxicities in rat breast and ovarian cancer models while enhancing anti-tumor activity.

The chemoprotective effects of combined ebselen and allopurinol in breast (MTLn3) and ovarian (NuTu-19) cancer models using a repeated cisplatin dosing schedule (6 mg/kg i.p.x3 weeks) were studied.

Reduction of acute cisplatin ototoxicity and nephrotoxicity in rats by oral administration of allopurinol and ebselen.

Cisplatin ototoxicity has been associated with the generation of toxic levels of reactive oxygen species (ROS) which can lead to injury or loss of outer hair cells in the organ of Corti, damage to the stria vascularis, and loss of spiral ganglion cells, resulting in permanent hearing loss. In an attempt to reduce the formation of ROS and to bolster the innate oxidative stress defenses of the cochlea, we tested individual and combined formulations of allopurinol, a xanthine oxidase inhibitor, and ebselen, a glutathione peroxidase mimic. We used an acute cisplatin toxicity rat model (16 mg/kg i.

Ebselen-mediated protection from single and repeated noise exposure in rat.

Objectives/hypothesis: Ebselen, a glutathione peroxidase mimic, is a candidate compound for the prevention of noise-induced hearing loss.

Study Design: Single-blinded, placebo-controlled study.

Methods: Methods included single and repeated noise exposures on F-344 female rats given oral or injected ebselen or vehicle before and after noise, evoked auditory brainstem responses using click and pure-tone stimuli, light and fluorescence microscopy of cochleae stained with 4',6-Diamidino-2-phenylindole (DAPI) and fluorescein isothiocyanate-phalloidin, and statistical power determined by ANOVA.

Comparison of SPE and fast LC to eliminate mass spectrometric matrix effects from microsomal incubation products.

Twenty-seven highly diversified pharmaceutical compounds were used as a test set to evaluate matrix effects from microsomal media on LC/MS analyses. The individual effects of Tris buffer, NADPH and microsomes on ESI response were investigated. Direct flow injection MS/MS analysis, using no sample preparation or HPLC separation, gave an average of 2.