Direct Round Window Application of Gentamicin with Varying Delivery Vehicles: A Comparison of Ototoxicity

Sheppard, William M.; Wanamaker, Hayes H.; Pack, Adam K.; Yamamoto, Satoshi; Slepecky, Norma

doi:10.1016/j.otohns.2004.05.021

Cited by 33 publications

(41 citation statements)

References 17 publications

(37 reference statements)

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“…Other studies have reported the effectiveness of distinct biodegradable hydrogels for IT delivery of drugs such as gentamicin [Kelly et al, 1999;Sheppard et al, 2004], neurotrophins [Endo et al, 2005] and beclomethasone [Arnold et al, 2005]. In our study, an HAbased hydrogel containing thiol-modified HA and gelatin at a ratio of 9: 1 was used to deliver dexamethasone to the inner ear.…”

Section: Discussionmentioning

confidence: 98%

“…However, the efficiency of HA as a carrier agent for IT delivery appears to be dependent on the specific drug being delivered and on the gel composition [Kelly et al, 1999;Chandrasekhar et al, 2000;Sheppard et al, 2004;Endo et al, 2005;Tsuyoshi et al, 2005;Yildirim et al, 2005;Coleman et al, 2007;James et al, 2008;Saber et al, 2009]. In a guinea pig model, 1 h after IT treatment, perilymph levels of dexamethasone were 20% higher when used in the presence of HA (9.5 mg/ml) compared with dexamethasone alone [Chan-drasekhar et al, 2000].…”

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confidence: 99%

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Hyaluronic Acid Hydrogel Sustains the Delivery of Dexamethasone across the Round Window Membrane

Borden¹,

Saunders

Berryhill

et al. 2010

Audiol Neurotol

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Background: The use of intratympanic (IT) steroids for the treatment of inner ear disorders is promising, but the clinical challenges of prolonged middle ear drug application have proven burdensome, and a sustainable delivery system is yet to be developed. Method: In this study, a guinea pig model was used to determine if dexamethasone in combination with a hyaluronic-acid (HA)-based hydrogel is an efficient, stable and sustainable dexamethasone delivery system to the inner ear. For each animal, right and left middle ear bullae were randomly selected to be filled with dexamethasone alone or dexamethasone-HA (Dex-HA) gel. Perilymph samples were collected at different time points and dexamethasone levels were determined using an ELISA. Results: Dexamethasone was measurable in the perilymph samples up to 72 h after treatment. At 24 h after treatment, the perilymph dexamethasone concentrations were significantly higher (p = 0.01) in the ears treated with Dex-HA gel than in those treated with dexamethasone alone. While the perilymph dexamethasone concentration had decreased at 48 h after treatment with Dex-HA gel, the levels were still higher than those observed at 24 h in ears treated with dexamethasone alone. A high variability in dexamethasone concentration was observed between the samples, and the variability between matched ears receiving different treatments was remarkably lower than the variability within each treatment group, suggesting that individual parameters might play a major role in perilymph dexamethasone concentration. There was no statistically significant correlation between dexamethasone concentration and sex, weight or laterality. Conclusions: Our results show that the Dex-HA gel used in this study provides an effective and sustained dexamethasone release mechanism that might be utilized to treat conditions such as sudden sensorineural hearing loss. This could potentially reduce the morbidity and costs associated with IT treatment.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Hyaluronic Acid Hydrogel Sustains the Delivery of Dexamethasone across the Round Window Membrane

Borden¹,

Saunders

Berryhill

et al. 2010

Audiol Neurotol

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“…The total volume injected is likely to be a major factor in such observations. Hyaluronate gels applied to the middle ear space are reported to have no toxic effects (Engstrom et al, 1987,Laurent et al, 1992,Sheppard et al, 2004. Studies investigating the functional consequences of the RW injection protocol reported here are now ongoing.…”

Section: Discussionmentioning

confidence: 71%

Marker retention in the cochlea following injections through the round window membrane

et al. 2007

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Local delivery of drugs to the inner ear is increasingly being used in both clinical and experimental studies. Although direct injection of drugs into perilymph appears to be the most promising way of administering drugs quantitatively, no studies have yet demonstrated the pharmacokinetics in perilymph following direct injections. In this study, we have investigated the retention of substance in perilymph following a single injection into the basal turn of scala tympani (ST). The substance injected was a marker, trimethylphenylammonium (TMPA) that can be detected in low concentrations with ion-selective microelectrodes. Perilymph pharmacokinetics of TMPA was assessed using sequential apical sampling to obtain perilymph for analysis. The amount of TMPA retained in perilymph was compared for different injection and sampling protocols. TMPA concentrations measured in fluid samples were close to those predicted by simulations when the injection pipette was sealed into the bony wall of ST but were systematically lower when the injection pipette was inserted through the round window membrane (RWM). In the latter condition it was estimated that over 60% of the injected TMPA was lost due to leakage of perilymph around the injection pipette at a rate estimated to be 0.09 μL/min. The effects of leakage during and after injections through the RWM were dramatically reduced when the round window niche was filled with 1% sodium hyaluronate gel before penetrating the RWM with the injection pipette. The findings demonstrate that in order to perform quantitative drug injections into perilymph, even small rates of fluid leakage at the injection site must be controlled.

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“…This may be achieved by injecting viscous gel formulations, or by placing wicks, microcatheters [35] into, or close to, the round window niche. Gel-based formulations include hyaluronates [36], collagens [37], chitosans [38], fibrins [39], starch, celluloses, 6 elatin [40], poloxamers [41], and many others. Viscosity that is too high may also result in the formation of an air bubble on the RWM, thus preventing effective diffusion, or may temporarily impair the ossicular mobility.…”

Section: Discussionmentioning

confidence: 99%

Intratympanic Injections: An Unsolved Mystery

Parelkar¹,

Thorawade²,

Jagade³

et al. 2015

IJOHNS

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Aims: The aim of this study was to test the effectiveness of intratympanic dexamethasone injections as a treatment for severe disabling tinnitus and also observe its effect on hearing loss if any. Materials and Methods: Thirty patients with severe disabling tinnitus in the age group 20 to 60 years were selected and randomly assigned to receive intratympanic injections of a dexamethasone solution 4 mg/ml (0.5 ml) or isotonic saline (0.5 ml) solution under topical anaesthesia, once per week for 4 weeks using a zero degree endoscope. Improvement in tinnitus was assessed using a visual analog scale, considering 2-point improvement as significant and alteration in hearing if any was noted by pure tone audiometery before and after the therapy. Results: The improvement in tinnitus was not significant, with no alteration in audiometery reports. Conclusions: Intratympanic therapy is an attractive mode of treatment because of its highly targeted delivery, low concentration of the drugs required and a very good patient tolerance. Although there has been no breakthrough in intratympanic therapy for tinnitus or other otological conditions, accessibility to the inner ear through the semipermeable round window membrane holds many promises in the near future.

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Direct Round Window Application of Gentamicin with Varying Delivery Vehicles: A Comparison of Ototoxicity

Abstract: The fibrin/Gelfoam vehicle was the only delivery system to produce reliable damage. Ototoxic damage depended on the vehicle. We found no evidence for selective vestibular ototoxicity with gentamicin.

Cited by 33 publications

References 17 publications

Hyaluronic Acid Hydrogel Sustains the Delivery of Dexamethasone across the Round Window Membrane

Hyaluronic Acid Hydrogel Sustains the Delivery of Dexamethasone across the Round Window Membrane

Marker retention in the cochlea following injections through the round window membrane

Intratympanic Injections: An Unsolved Mystery

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