The Sustained-Exposure Dexamethasone Formulation OTO-104 Offers Effective Protection against Noise-Induced Hearing Loss

Abstract

The otoprotective effects of OTO-104 were investigated both prior to and following acute acoustic trauma. Guinea pigs received a single intratympanic injection of OTO-104 and were assessed in a model of acute acoustic trauma. Doses of at least 2.0% OTO-104 offered significant protection against hearing loss induced by noise exposure when administered 1 day prior to trauma and up to 3 days thereafter. Otoprotection remained effective even with higher degrees of trauma. In contrast, the administration of a dexamethasone sodium phosphate solution did not protect against noise-induced hearing loss. Activation of the classical nuclear glucocorticoid and mineralocorticoid receptor pathways was required for otoprotection by OTO-104. The sustained exposure properties of OTO-104 were also superior to a steroid solution.

Resolution of Cochlear Inflammation: Novel Target for Preventing or Ameliorating Drug-, Noise- and Age-related Hearing Loss

“…Similarly, it was found that an anti-IL-6-receptor antibody protected mice from NRHL (Wakabayashi et al, 2010). The anti-inflammatory and pro-resolution glucocorticoid dexamethasone (DEXA), delivered to the round window membrane, has also been shown to reduce hearing loss in patients after noise exposure (Zhou et al, 2013; Harrop-Jones et al, 2016). …”

Evaluation of Sustained-Release Steroid Hydrogels in a Guinea Pig Model for Noise-Induced Hearing Loss

“…We opted for the use of a 6% Dex hydrogel, because such hydrogels have been reported to be well tolerated and effective drug delivery systems for the treatment of noise-induced hearing loss and cisplatin ototoxicity in guinea pigs Harrop-Jones et al, 2016;Piu et al, 2011]. TAAC concentrations of 6 and 30% were chosen to allow both, the comparison of hydrogels with a comparable glucocorticoid concentration and of glucocorticoid doses which are comparable according to their systemic efficacy .…”

“…Nevertheless, in future studies the use of very high intratympanic glucocorticoid concentrations should be critically evaluated with respect to its risk-benefit ratio. The timing of glucocorticoid therapy emerged as important factor for its efficacy in various publications [Chang et al, 2009;Harrop-Jones et al, 2016;Honeder et al, 2016]. Glucocorticoid treatment before the actual insult to the inner ear results in better otoprotection in different trauma models including cochlear implantation and noiseinduced hearing loss Honeder et al, 2016].…”

“…While preparatory intratympanic treatment is feasible in situations like cochlear implantation surgery, this is not the case in the setting of noise-induced hearing loss. In such cases, timely and durative glucocorticoid application is necessary to generate sufficient drug concentrations in the inner ear and appears to be more effective than delayed application [Chi et al, 2011;Harrop-Jones et al, 2016;Muller et al, 2017].…”

“…Based on these results, our group tested the pharmacokinetic properties and tolerability of a TAAC-loaded POX407 hydrogel and proposed it as a promising vehicle for sustained high-dose inner ear glucocorticoid delivery Honeder et al, 2014]. Otoprotective effects of Dex-loaded POX407 hydrogels were reported in models for cochlear implantation electrode insertion trauma, noise-induced hearing loss as well as acute and chronic cisplatin ototoxicity Harrop-Jones et al, 2016;Honeder et al, 2016].…”