Intratympanic Versus Intravenous Delivery of Dexamethasone and Dexamethasone Sodium Phosphate to Cochlear Perilymph

Bird, Philip; Murray, D.; Zhang, Mei; Begg, Evan J.

doi:10.1097/mao.0b013e3182255933

Cited by 117 publications

(100 citation statements)

References 9 publications

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“…This pattern seems to suggest a lasting benefit -if the treatment effect was to wear off, it would do so more quickly than only after 3 months as small molecules such as the active substance of AM-101 tend to get cleared from the cochlea within a few days already [e.g. Chen et al, 2003;Salt, 2005;Bird et al, 2011]. The gradual improvement is most likely the result of adaptation processes within the auditory system [van de Heyning et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

Selecting Appropriate Dose Regimens for AM-101 in the Intratympanic Treatment of Acute Inner Ear Tinnitus

et al. 2015

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Inhibition of cochlear N-methyl-D-aspartate (NMDA) receptors with AM-101, a small molecule antagonist delivered by intratympanic injection, represents a novel approach to treat acute tinnitus triggered by glutamate excitotoxicity. An earlier double-blind, randomized, placebo-controlled phase II clinical trial (TACTT0) had demonstrated a significant and dose-dependent improvement in tinnitus triggered by acute acoustic trauma or otitis media from baseline to day 90. A second phase II trial (TACTT1) now sought to evaluate the most appropriate dose regimen for this treatment. Outcomes from the TACTT1 trial showed no significant difference in tinnitus improvement between a single-dose treatment and a dose regimen comprising three doses over 2 weeks. Taken together, three injections over 3 consecutive days showed the best results in the two phase II trials, suggesting that repeated and concentrated inhibition of cochlear NMDA receptors provides best treatment effects, while keeping the procedural impact on patients short.

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Section: Discussionmentioning

confidence: 99%

Selecting Appropriate Dose Regimens for AM-101 in the Intratympanic Treatment of Acute Inner Ear Tinnitus

et al. 2015

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“…This is consistent with a recently published prospective randomized clinical trial in patients suffering from sudden sensorineural hearing loss [Rauch et al, 2011], which demonstrated comparable therapeutic benefits between a 19-day course of orally administered prednisolone and a regimen of 4 intratympanic injections of methylprednisolone. However, it has been recognized that the systemic route to treat otic disorders is inadequate owing to poor inner ear absorption and significant risks of adverse effects [Bird et al, 2007[Bird et al, , 2011Rauch et al, 2011].…”

Section: Discussionmentioning

confidence: 99%

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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“…There have been numerous pharmacokinetic studies of locally-applied corticosteroids in animals (Nomura 1984;Parnes et al 1999;Chandrasekhar et al 2000;Bachmann et al 2001;Hahn et al 2006Hahn et al , 2012Liu et al 2006;Plontke et al 2008b;Yang et al 2008;Wang et al 2009;Borden et al 2011;Salt et al 2011a) and humans (Bird et al 2007;Bird et al 2011), but only a subset of these studies has been analyzed quantitatively to derive an elimination rate. Plontke and analyzed prednisoline data of Bachmann et al (2001) from guinea pigs and found it to be consistent with an elimination half-time from perilymph of 130 min.…”

Section: Introductionmentioning

confidence: 99%

Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

Salt

Hartsock

Gill

et al. 2012

JARO

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Perilymph pharmacokinetics was investigated by a novel approach, in which solutions containing drug or marker were injected from a pipette sealed into the perilymphatic space of the lateral semi-circular canal (LSCC). The cochlear aqueduct provides the outlet for fluid flow so this procedure allows almost the entire perilymph to be exchanged. After wait times of up to 4 h the injection pipette was removed and multiple, sequential samples of perilymph were collected from the LSCC. Fluid efflux at this site results from cerebrospinal fluid (CSF) entry into the basal turn of scala tympani (ST) so the samples allow drug levels from different locations in the ear to be defined. This method allows the rate of elimination of substances from the inner ear to be determined more reliably than with other delivery methods in which drug may only be applied to part of the ear. Results were compared for the markers trimethylphenylammonium (TMPA) and fluorescein and for the drug dexamethasone (Dex). For each substance, the concentration in fluid samples showed a progressive decrease as the delay time between injection and sampling was increased. This is consistent with the elimination of substance from the ear with time. The decline with time was slowest for fluorescein, was fastest for Dex, with TMPA at an intermediate rate. Simulations of the experiments showed that elimination occurred more rapidly from scala tympani (ST) than from scala vestibuli (SV). Calculated elimination half-times from ST averaged 54.1, 24.5 and 22.5 min for fluorescein, TMPA and Dex respectively and from SV 1730, 229 and 111 min respectively. The elimination of Dex from ST occurred considerably faster than previously appreciated. These pharmacokinetic parameters provide an important foundation for understanding of drug treatments of the inner ear.

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Intratympanic Versus Intravenous Delivery of Dexamethasone and Dexamethasone Sodium Phosphate to Cochlear Perilymph

Abstract: Administration of dexamethasone IT results in much higher perilymph concentrations and much lower plasma concentrations compared with IV administration.

Cited by 117 publications

References 9 publications

Selecting Appropriate Dose Regimens for AM-101 in the Intratympanic Treatment of Acute Inner Ear Tinnitus

Selecting Appropriate Dose Regimens for AM-101 in the Intratympanic Treatment of Acute Inner Ear Tinnitus

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

Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

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