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AM-111 Reduces Hearing Loss in a Guinea Pig Model of Acute Labyrinthitis

Authors


  • This work was originally presented in poster format at the Association for Research in Otolaryngology, 30th Midwinter Meeting, Denver, Colorado, U.S.A., February 10–15, 2007.

    The lead and senior authors have no financial relationship with Auris Medical and do not stand to benefit from the publication of this research. Yannick Hondarrague is a contracted technician who has no ownership in the company. Thomas Meyer is the managing director of Auris Medical, which owns the license on AM-111. He reviewed the manuscript for accuracy but did not directly perform any of the experiments nor impose his interpretations on the results.

    Funding for the animals and the drug used in this study was provided by Auris Medical, Duedingen, Switzerland, under a Cooperative Research and Development Agreement with the Medical Research Service of the Department of Veterans Affairs. Gregory Barkdull received salary support from the National Institutes of Health under the Ruth L. Kirschstein National Research Service Award DC000028-16A1. Elizabeth Keithley received salary support from the Veterans Affairs Research Service. Yannick Hondarrague received salary support from Laboratoires Auris.

Abstract

Objectives/Hypothesis: This study investigated the otoprotective properties of AM-111, an inhibitor of c-Jun N-terminal kinase-mediated apoptosis and inflammation.

Study Design: A controlled, prospective animal study using a guinea pig model of acute labyrinthitis.

Methods: Acute labyrinthitis was generated by injection of antigen into the scala tympani of sensitized guinea pigs. Treatment groups received 100 μL of AM-111 at concentrations of 100 μmol/L, 10 μmol/L, and 1 μmol/L in a hyaluronic acid gel formulation delivered over the round window niche within 1 hour of antigen challenge. Cochlear function was monitored over 21 days with serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements followed by histologic analysis.

Results: The ABR results on day 21 demonstrated that untreated control ears for acute labyrinthitis had a mean hearing loss (HL) of 68 ± 12 dB. In contrast, ears treated with AM-111 (100 μmol/L) had a mean HL of 39 ± 31 dB. These two groups were statistically different (one-way analysis of variance, P = .03). Secondary outcomes, including DPOAE shift, inner hair cell survival, inflammatory cell counts, and spiral ganglion density, were also statistically significant in favor of an otoprotective effect of AM-111. Lower doses of AM-111 did not produce a statistically significant reduction in HL over controls.

Conclusion: AM-111 delivered over the round window membrane in a 100 μL hyaluronic acid formulation at a 100 μmol/L concentration immediately after induction of acute labyrinthitis in the guinea pig cochlea protects hearing, reduces hair cell loss, and reduces the number of inflammatory cells at 21 days after treatment.

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