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Objective: The use of glucocorticoids for secondary (salvage/rescue) therapy of idiopathic sudden hearing loss (ISSHL), including controlled and uncontrolled studies with intratympanic injections or continuous, catheter mediated applications, were evaluated by means of a meta-analysis in an attempt to define optimal local drug delivery protocols for ISSHL., Study Design: A total of 30 studies with 33 treatment groups between January 2000 and June 2014 were selected based on sufficiently detailed description of application protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time drug remained in the middle ear, and on the specific timing of injections. Various factors were compared with hearing outcome, including baseline data, individual parameters of the application protocols, calculated peak concentration (Cmax), and total dose (area under the curve, AUC)., Results: There was no dependence of hearing outcome on individual parameters of the application protocol, Cmax or AUC. Hearing gain and final hearing thresholds were independent of treatment delay., Conclusion: Based on the available data from uncontrolled and controlled randomized and non-randomized studies no clear recommendation can be made so far for a specific application protocol for either primary or secondary (salvage) intratympanic steroid treatment in patients with ISSHL. For meta-analyses, change in pure tone average (PTA) may not be an adequate outcome parameter to assess effectiveness of the intervention especially with inhomogeneity of patient populations. Final PTA might provide a better outcome parameter.

Cochlear implants have been widely used for patients with profound hearing loss and partial deafness. Residual low-frequency hearing, however, may deteriorate due to insertion trauma and tissue response around the electrode array. The present study investigated in vitro and in vivo release of dexamethasone from silicone used for cochlear implant electrode carriers. The in vitro experiment involved an apparatus simulating the inner ear fluid environment in humans. Release from two sizes of silicone films (200 µm × 1 mm × 10 mm and 500 µm × 1 mm × 10 mm), each loaded with 2 % dexamethasone, and was measured for 24 weeks. In the in vivo experiment, silicone rods loaded with 2 or 10 % dexamethasone, respectively, were implanted into the scala tympani of guinea pigs. Perilymph concentrations were measured during the first week after implantation. The results showed that dexamethasone was released from the silicone in a sustained manner. After a burst release, perilymph concentration was similar for silicone incorporated with 2 and 10 % dexamethasone, respectively. The similar pharmacokinetic profile was found in the in vitro experiment. The period of sustained drug delivery was maintained for 20 weeks in vitro and for 1 week in vivo. The results of the present study suggest that drugs like dexamethasone are released in a controlled manner from silicon electrode carriers of cochlear implants. Further studies will identify optimal release profiles for the use with cochlear implants to improve their safety and long-term performance.

Objective: To evaluate the feasibility and hearing outcome of a biocompatible degradable dexamethasone releasing implant for continuous drug delivery to the round window membrane in patients with idiopathic sudden sensorineural hearing loss (ISSHL) and insufficient recovery after systemic high dose glucocorticoid therapy., Patients: Five patients with profound or moderate-to-severe hearing loss after systemic high-dose prednisolone for ISSHL received local salvage therapy with a controlled release dexamethasone implant in the middle ear., Intervention: Pieces of a sterile rod shaped poly(D,L-lactide-co-glycolide) PLGA polymer matrix containing a total of 0.7 mg dexamethasone, which is approved for intravitreal use were implanted into the round window niche., Main Outcome Measure(s): Intraoperative handling and feasibility and hearing recovery as measured by change in pure tone threshold, final word recognition score, and categories of improvement were evaluated., Results: The implants were surgically placed without major difficulties. The mean hearing threshold significantly improved at follow up by 31 ± 31 dB HL (from 94 ± 27 to 63 ± 36 dB HL; p < 0.05). Two of five patients recovered completely. One patient showed partial hearing recovery with serviceable hearing., Conclusion: Although no drugs are currently approved for local therapy of inner ear disorders, there is increasing evidence that intratympanic glucocorticoids are effective as salvage therapy in ISSHL. The present study has shown encouraging results with a biodegradable polymer delivery system, demonstrating the translation of preclinical studies with controlled drug delivery into clinical practice.

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.

Hypothesis: To determine whether intracochlearly applied dexamethasone will lead to better control of drug levels, higher peak concentrations, and lower base-to-apex concentration gradients in the scala tympani (ST) of the guinea pig than after intratympanic (round window [RW]) application., Background: Local application of drugs to the RW results in substantial variation of intracochlear drug levels and significant base-to-apex concentration gradients in ST., Methods: Two microliters of dexamethasone-phosphate (10 mg/ml) were injected into ST either through the RW membrane, which was covered with 1% sodium hyaluronate gel or through a cochleostomy with a fluid tight seal of the micropipette. Perilymph was sequentially sampled from the apex at a single time point for each animal, at 20, 80, or 200 min after the injection ended. Results were mathematically interpreted by means of an established computer model and compared with previous experiments performed by our group with the same experimental techniques but using intratympanic applications., Results: Single intracochlear injections of 20 minutes resulted in approximately 10 times higher peak concentrations (on average) than 2 to 3 hours of intratympanic application to the RW niche. Intracochlear drug levels were less variable and could be measured for over 220 minutes. Concentration gradients along the scala tympani were less pronounced. The remaining variability in intracochlear drug levels was attributable to perilymph and drug leak from the injection site., Conclusion: With significantly higher, less variable drug levels and smaller base-to-apex concentration gradients, intracochlear applications have advantages to intratympanic injections. For further development of this technique, it is of importance to control leaks of perilymph and drug from the injection site and to evaluate its clinical feasibility and associated risks.

Objectives: To study the safety and efficacy of continuous intratympanic dexamethasone-phosphate (Dex-P) for severe to profound sudden idiopathic sensorineural hearing (ISSHL) or sudden idiopathic anacusis after failure of systemic therapy., Study Design: Randomized, double-blind, placebo controlled multicenter trial., Methods: Patients with ISSHL and insufficient recovery (mean 4PTA = 97 dB HL) after systemic high dose glucocorticoid therapy received either Dex-P (4 mg/ml) or placebo (NaCl 0.9%) continuously applied for 14 days into the round window niche via a temporarily implanted catheter. For ethical reasons, intratympanic treatment was continued with Dex-P in all patients for another 14 days after the placebo-controlled study period. According to a two-step adaptive study design an interim analysis was performed after inclusion of 23 patients., Results: Intention-to-treat analysis for the primary outcome criterion (4PTA: 0.5-3 kHz) during the placebo controlled study period (14 days) showed an average hearing improvement in the treatment group of 13.9 dB (SD: 21.3) and in the placebo group of 5.4 dB (SD: 10.4). This difference in hearing improvement between the two groups (mean: 8.4 dB, SD: 17.0, 95% CI: -7.1-24.1) was statistically not significant (p = .26). Of the secondary outcome parameters, the largest benefit of local salvage therapy was found for maximum speech discrimination with an improvement of 24.4% (SD: 32.0) in the treatment and 4.5% (SD: 7.6) in the placebo group (p = 0.07). After a 3 month follow-up period (i.e. after all patients received intratympanic Dex-P) hearing improvement in the two groups was very similar. No serious adverse events were observed. Sample size calculation after the interim analysis resulted in stopping of the trial., Conclusions: The tendency toward better hearing improvement in the treatment group, the rather conservative inclusion criteria, the limited placebo-controlled observation period and the absence of serious adverse events supports further investigation local inner ear drug delivery as a first or second line treatment option for ISSHL.

Hypothesis: Local application of dexamethasone-21-dihydrogen-phosphate (Dex-P) to the round window (RW) membrane of guinea pigs produces a substantial basal-apical concentration gradient in scala tympani (ST) perilymph., Background: In recent years, intratympanically applied glucocorticoids are increasingly being used for the treatment of inner ear disease. Although measurements of intracochlear concentrations after RW application exist, there is limited information on the distribution of these drugs in the inner ear fluids. It has been predicted from computer simulations that substantial concentration gradients will occur after RW application, with lower concentrations expected in apical turns. Concentration gradients of other substances along the cochlea have recently been confirmed using a sequential apical sampling method to obtain perilymph., Methods: Dexamethasone-21-dihydrogen-phosphate (10 mg/ml) was administered to the RW membrane of guinea pigs (n = 9) in vivo for 2 to 3 hours. Perilymph was then collected using a protocol in which 10 samples, each of approximately 1 mul, were taken sequentially from the cochlear apex into capillary tubes. Dexamethasone-21-dihydrogen-phosphate concentration of the samples was analyzed by high-performance liquid chromatography. Interpretation of sample data using a finite element model allowed the longitudinal gradients of Dex-P in ST to be quantified., Results: The Dex-P content of the first sample in each experiment (dominated by perilymph from apical regions) was substantially lower than that of the third and fourth sample (dominated by basal turn perilymph). These findings qualitatively demonstrated the existence of a concentration gradient along ST. After detailed analysis of the measured sample concentrations using an established finite element computer model, the mean basal-apical concentration gradient was estimated to be 17,000. Both absolute concentrations of Dex-P in ST and the basal-apical gradients were found to vary substantially., Conclusion: The existence of substantial basal-apical concentration gradients of Dex-P in ST perilymph were demonstrated experimentally. If the variability in peak concentration and gradient is also present under clinical conditions, this may contribute to the heterogeneity of outcome that is observed after intratympanic application of glucocorticoids for various inner ear diseases.

Before new drugs for the treatment of inner ear disorders can be studied in controlled clinical trials, it is important that their pharmacokinetics be established in inner ear fluids. Microdialysis allows drug levels to be measured in perilymph without the volume disturbances and potential cerebrospinal fluid contamination associated with fluid sampling. The aims of this study were to show: (i) that despite low recovery rates from miniature dialysis probes, significant amounts of drug are removed from small fluid compartments, (ii) that dialysis sampling artifacts can be accounted for using computer simulations and (iii) that microdialysis allows quantification of the entry rates through the round window membrane (RWM) into scala tympani (ST). Initial experiments used microdialysis probes in small compartments in vitro containing sodium fluorescein. Stable concentrations were observed in large compartments (1000 microl) but significant concentration declines were observed in smaller compartments (100, 10 and 5.6 microl) comparable to the size of the inner ear. Computer simulations of these experiments closely approximated the experimental data. In in vivo experiments, sodium fluorescein 10 mg/ml and dexamethasone-dihydrogen-phosphate disodium salt 8 mg/ml were simultaneously applied to the RWM of guinea pigs. Perilymph concentration in the basal turn of ST was monitored using microdialysis. The fluorescein concentration reached after 200 min application (585+/-527 microg/ml) was approximately twice that of dexamethasone phosphate (291+/-369 microg/ml). Substantial variation in concentrations was found between animals by approximately a factor of 34 for fluorescein and at least 41 for dexamethasone phosphate. This is, to a large extent, thought to be the result of the RWM permeability varying in different animals. It was not caused by substance analysis variations, because two different analytic methods were used and the concentration ratio between the two substances remained nearly constant across the experiments and because differences were apparent for the repeated samples obtained in each animal. Interpretation of the results using computer simulations allowed RWM permeability to be quantified. It also demonstrated, however, that cochlear clearance values could not be reliably obtained with microdialysis because of the significant contribution of dialysis to clearance. The observed interanimal variation, e.g., in RWM permeability, is likely to be clinically relevant to the local application of drugs in patients.

Background: Systemic glucocorticoids are commonly used for primary therapy of idiopathic sudden sensorineural hearing loss (ISSNHL). However, the comparative effectiveness and risk profiles of high-dose over lower-dose regimens remain unknown. Methods: We randomly assigned patients with sudden hearing loss of greater than or equal to 50 dB within 7 days from onset to receive either 5 days of high-dose intravenous prednisolone at 250 mg/d (HD-Pred), 5 days of high-dose oral dexamethasone at 40 mg/d (HD-Dex), or, as a control, 5 days of oral prednisolone (Pred-Control) at 60 mg/d followed by 5 days of tapering doses. The primary outcome was the change in hearing threshold (pure tone average) in the three most affected contiguous frequencies from baseline to day 30. Secondary outcomes included speech understanding, tinnitus, communication competence, quality of life, hypertension, and insulin resistance. Results: A total of 325 patients were randomly assigned. Mean change in 3PTAmost affected hearing threshold from baseline to 30 days was 34.2 dB (95% CI, 28.4 to 40.0) in the HD-Pred group, 41.4 dB (95% CI, 35.6 to 47.2) in the HD-Dex group, and 41.0 dB (95% CI, 35.2 to 46.8) in the Pred-Control group (P=0.09 for analysis of variance). There were more adverse events related to trial medication in the HD-Pred (n=73) and HD-Dex (n=76) groups than in the Pred-Control group (n=46). Conclusions: Systemic high-dose glucocorticoid therapy was not superior to a lower-dose regimen in patients with ISSNHL, and it was associated with a higher risk of side effects. (Funded by the Federal Ministry of Education and Research [BMBF]; EudraCT number, 2015-002602-36.) [ABSTRACT FROM AUTHOR]

Glucocorticoids are used intra-operatively in cochlear implant surgeries to reduce the inflammatory reaction caused by insertion trauma and the foreign body response against the electrode carrier after cochlear implantation. To prevent higher systemic concentrations of glucocorticoids that might cause undesirable systemic side effects, the drug should be applied locally. Since rapid clearance of glucocorticoids occurs in the inner ear fluid spaces, sustained application is supposedly more effective in suppressing foreign body and tissue reactions and in preserving neuronal structures. Embedding of the glucocorticoid dexamethasone into the cochlear implant electrode carrier and its continuous release may solve this problem. The aim of the present study was to examine how dexamethasone concentrations in the electrode carrier influence drug levels in the perilymph at different time points. Silicone rods were implanted through a cochleostomy into the basal turn of the scala tympani of guinea pigs. The silicone rods were loaded homogeneously with 0.1, 1, and 10% concentrations of dexamethasone. After implantation, dexamethasone concentrations in perilymph and cochlear tissue were measured at several time points over a period of up to 7 weeks. The kinetic was concentration-dependent and showed an initial burst release in the 10%- and the 1%-dexamethasone-loaded electrode carrier dummies. The 10%-loaded electrode carrier resulted in a more elevated and longer lasting burst release than the 1%-loaded carrier. Following this initial burst release phase, sustained dexamethasone levels of about 60 and 100 ng/ml were observed in the perilymph for the 1 and 10% loaded rods, respectively, during the remainder of the observation time. The 0.1% loaded carrier dummy achieved very low perilymph drug levels of about 0.5 ng/ml. The cochlear tissue drug concentration shows a similar dynamic to the perilymph drug concentration, but only reaches about 0.005–0.05% of the perilymph drug concentration. Dexamethasone can be released from silicone electrode carrier dummies in a controlled and sustained way over a period of several weeks, leading to constant drug concentrations in the scala tympani perilymph. No accumulation of dexamethasone was observed in the cochlear tissue. In consideration of experimental studies using similar drug depots and investigating physiological effects, an effective dose range between 50 and 100 ng/ml after burst release is suggested for the CI insertion trauma model. [ABSTRACT FROM AUTHOR]

Abstract Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration. Highlights • Quantitative pharmacokinetic studies of the inner ear allow drug therapies to be compared. • Molecular properties determine how readily drugs pass through membranous boundaries of the ear. • The properties of dexamethasone-phosphate make it unsuitable as a therapy for hearing disorders. [ABSTRACT FROM AUTHOR]