Principles of inner ear sustained release following intratympanic administration

Wang, Xiaobo; Dellamary, Luis; Fernandez, Rayne; Ye, Qiang; LeBel, Carl; Piu, Fabrice

doi:10.1002/lary.21370

Cited by 65 publications

(69 citation statements)

References 20 publications

(17 reference statements)

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“…The intratympanic administration of OTO-104 has been extensively studied both nonclinically [Wang et al, 2009[Wang et al, , 2011aPiu et al, 2011] and clinically [Lambert et al, 2012] in various species. It was not associated with adverse effects at doses that achieved sustained inner ear exposure both locally in the ear as well as systemically in animal studies.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that dexamethasone formulated using a poloxamer hydrogel provides lasting exposure in the inner ear of guinea pigs and sheep for weeks to months with a single intratympanic injection [Wang et al, 2009[Wang et al, , 2011a. A proprietary otic formulation, OTO-104, was well tolerated locally and systemically in extensive toxicology studies conducted in guinea pigs .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…Other potential round window delivery systems that could be evaluated in this fashion include poloxamer (40,41), as well as other aqueous solution-based systems (37,42). In addition, other approaches that directly introduce compounds into perilymph, whether through the round window or through a cochleostomy, may also be studied.…”

Section: Discussionmentioning

confidence: 99%

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea

2016

Otology &Amp; Neurotology

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Hypothesis-Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity.Background-Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we utilize a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by ABR and DPOAEs.

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“…Such results are consistent with the short residence time of dexamethasone in the inner ear compartment when administered as a solution intratympanically. In guinea pigs, a DSP solution is cleared rapidly, with drug levels in the perilymph lasting for about 12 h [Wang et al, 2009[Wang et al, , 2011a. Therefore, the therapeutic potential of dexamethasone is best achieved when the drug can remain present in the inner ear compartment for extended periods of time.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, a dexamethasone solution is cleared rapidly from the middle ear down the Eustachian tube, with drug levels in the perilymph lasting for about 12 h in guinea pigs [Wang et al, 2009[Wang et al, , 2011a. In the clinic, inconsistent clinical responses are commonly observed due to variable and limited exposure with aqueous solutions [Bird et al, 2007[Bird et al, , 2011.…”

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confidence: 99%

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

Harrop-Jones

Wang²,

Fernandez

et al. 2016

Audiol Neurotol

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The otoprotective effects of OTO-104 were investigated following both acute and chronic administration of cisplatin. The acute administration of cisplatin to guinea pigs resulted in profound hearing loss (70-80 dB SPL) across all frequencies tested. A single intratympanic injection of 6% OTO-104, but not of lower doses, almost completely protected against cisplatin ototoxicity. In contrast, a dexamethasone solution administered under the same experimental conditions offered no otoprotection. OTO-104 was also very effective in protecting against the progressive hearing loss observed with the chronic administration of cisplatin (3 injections at a weekly interval). The otoprotection was found to be dependent upon the activation of dexamethasone-dependent classical nuclear receptor pathways.

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Principles of inner ear sustained release following intratympanic administration

Abstract: The inner ear pharmacokinetic profile of drugs administered intratympanically is not only highly dependent upon the nature of the vehicle but also upon the physicochemical properties of the drug delivered.

Cited by 65 publications

References 20 publications

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

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

Non-Ototoxic Local Delivery of Bisphosphonate to the Mammalian Cochlea

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

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