Junctional Modulation of Round Window Membrane Enhances Dexamethasone Uptake into the Inner Ear and Recovery after NIHL.

Delivery of substances into the inner ear via local routes is increasingly being used in clinical treatment. Studies have focused on methods to increase permeability through the round window membrane (RWM) and enhance drug diffusion into the inner ear. However, the clinical applications of those methods have been unclear and few studies have investigated the efficacy of methods in an inner ear injury model. Here, we employed the medium chain fatty acid caprate, a biologically safe, clinically applicable substance, to modulate tight junctions of the RWM. Intratympanic treatment of sodium caprate (SC) induced transient, but wider, gaps in intercellular spaces of the RWM epithelial layer and enhanced the perilymph and cochlear concentrations/uptake of dexamethasone. Importantly, dexamethasone co-administered with SC led to significantly more rapid recovery from noise-induced hearing loss at 4 and 8 kHz, compared with the dexamethasone-only group. Taken together, our data indicate that junctional modulation of the RWM by SC enhances dexamethasone uptake into the inner ear, thereby hastening the recovery of hearing sensitivity after noise trauma.

Evaluation of the blood-perilymph barrier in ears with endolymphatic hydrops.

BACKGROUND: Otological diseases including Meniere's disease (MD) involve endolymphatic hydrops (EH), which can be visualized by magnetic resonance imaging (MRI) with gadolinium contrast agents, but the temporal changes of contrast in the inner ear have not been evaluated. OBJECTIVES: We investigated the permeability of the blood-perilymph barrier (BPB) in ears with EH to evaluate the severity of the inner ear disturbances. MATERIALS AND METHODS: The study included 32 ears from 16 patients with EH or related diseases who underwent MRI. The permeability of the BPB was assessed by the signal-intensity ratio (SIR) at four-time points: before and at 10 min, 4 h, and 24 h after administration of gadolinium for assessing EH. RESULTS: Cochlear EH was found in 25 of the 32 ears, and vestibular EH in 11. The rate of EH was significantly higher in symptomatic ears; however, the existence of EH was not related to SIR values. Nevertheless, SIR values in the basal turn were significantly higher 4 and 24 h after injection of gadolinium in patients aged ≥50 years. CONCLUSION AND SIGNIFICANCE: Higher SIR values observed in older patients with EH indicate severe disturbances of the BPB in the cochlea, which may account for intractable inner ear disturbances in older patients.

An LCMS-based untargeted metabolomics protocol for cochlear perilymph: highlighting metabolic effects of hydrogen gas on the inner ear of noise exposed Guinea pigs.

INTRODUCTION: Noise-induced hearing loss (NIHL) is an increasing problem in society and accounts for a third of all cases of acquired hearing loss. NIHL is caused by formation of reactive oxygen species (ROS) in the cochlea causing oxidative stress. Hydrogen gas (H2) can alleviate the damage caused by oxidative stress and can be easily administered through inhalation. OBJECTIVES: To present a protocol for untargeted metabolomics of guinea pig perilymph and investigate the effect of H2 administration on the perilymph metabolome of noise exposed guinea pigs. METHODS: The left ear of guinea pigs were exposed to hazardous impulse noise only (Noise, n = 10), noise and H2 (Noise + H2, n = 10), only H2 (H2, n = 4), or untreated (Control, n = 2). Scala tympani perilymph was sampled from the cochlea of both ears. The polar component of the perilymph metabolome was analyzed using a HILIC-UHPLC-Q-TOF-MS-based untargeted metabolomics protocol. Multivariate data analysis (MVDA) was performed separately for the exposed- and unexposed ear. RESULTS: MVDA allowed separation of groups Noise and Noise + H2 in both the exposed and unexposed ear and yielded 15 metabolites with differentiating relative abundances. Seven were found in both exposed and unexposed ear data and included two osmoprotectants. Eight metabolites were unique to the unexposed ear and included a number of short-chain acylcarnitines. CONCLUSIONS: A HILIC-UHPLC-Q-TOF-MS-based protocol for untargeted metabolomics of perilymph is presented and shown to be fit-for-purpose. We found a clear difference in the perilymph metabolome of noise exposed guinea pigs with and without H2 treatment.

Gentamicin delivery to the inner ear: Does endolymphatic hydrops matter?

INTRODUCTION: Middle ear application of gentamicin is a common medical treatment for uncontrolled Ménière's disease. The objective of the study was to evaluate the impact of endolymphatic hydrops on inner ear delivery. METHODS: Perilymph gentamicin concentrations and correlation with endolymphatic hydrops in an animal model were assessed. A group of 24 guinea pigs was submitted to surgical obstruction of the endolymphatic sac and duct of the right ear. Gentamicin was applied either to the right ear's round window niche or through a transtympanic injection. Perilymph specimens were collected at different times. Histologic morphometry was used to evaluate both turn-specific and overall hydrops degree. RESULTS: In animals with endolymphatic hydrops, lower concentrations of gentamicin were observed after 20 or 120 minutes of exposure and in both types of administration, when compared to controls. This difference reached statistical significance in the round window niche application group (Mann-Whitney, p = 0,007). A negative correlation between perilymphatic gentamicin concentration and hydrops degree could be observed in both groups, after 120 minutes of exposure (Spearman correlation, round window niche p<0,001; TT p = 0,005). CONCLUSIONS: The study indicates that the endolymphatic hydrops degree has a negative interference on the delivery of gentamicin into the inner ear following middle ear application.

A Polymer-Based Extended Release System for Stable, Long-term Intracochlear Drug Delivery.

OBJECTIVE: Investigate a new polymer-based drug coating suitability for safe intracochlear delivery and ability to maintain long-term physiologically active levels of the corticosteroid fluticasone propionate. STUDY DESIGN: In vitro dissolution study to evaluate release profiles of polymer-coated drug particles and in vivo studies using a guinea pig model to measure perilymph drug concentrations at specific time points after implantation with polymer-coated drug particles and evaluate their effect on hearing function. METHODS: Polymer-coated fluticasone propionate (FP) particles were surgically implanted in guinea pigs through the round window membrane into the cochlear scala tympani. In the pilot study, pre- and post-op hearing thresholds were conducted on days 7, 14, and 42. In a second study, post-op hearing thresholds were conducted on days 90, 120, and 180. Perilymph drug concentrations were measured on the same time points. RESULTS: In 15 of 16 animals from day 7 through day 90, drug levels were within the targeted range, with no initial burst release detected. Drug was present in all animals on day 90 and was detected in some animals at 120 and 180 days. Hearing was tested and compared with non-implanted ears. Very good hearing preservation was observed in ears implanted with intracochlear particles when compared with contralateral ears. CONCLUSIONS: The polymer-based extended release system is effective in providing long-term, stable drug delivery for at least 90 days with good hearing outcomes. The results of this study support the potential for achieving long-term drug delivery with a single intracochlear administration.

Mannitol and the blood-labyrinth barrier.

BACKGROUND: Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol. STUDY DESIGN: Controlled animal research project. METHODS: Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post-infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point. RESULTS: Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood. CONCLUSIONS: Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph.

Ultra-high-field (9.4 T) MRI Analysis of Contrast Agent Transport Across the Blood-Perilymph Barrier and Intrastrial Fluid-Blood Barrier in the Mouse Inner Ear.

HYPOTHESIS: Effective paramagnetic contrast agent for the penetration of the perilymphatic spaces of the scala tympani, scala vestibuli, and scala media of the mouse inner ear can be determined using intravenous injection of various gadolinium (Gd) complexes and ultra-high-field magnetic resonance imaging (MRI) at 9.4 Tesla. BACKGROUND: A number of contrast agents have been explored in experimental high-field MRI to determine the most effective Gd complex for ideal signal-to-noise ratio and maximal visualization of the in vivo mammalian inner ear in analyzing the temporal and spatial parameters involved in drug penetration of the blood-perilymph barrier and intrastrial fluid-blood barrier in the mouse model using MRI. METHODS: Gadoteric acid (Dotarem), Gadobutrol (Gadovist), Gadodiamide (Omniscan), Gadopent acid (Magnevist), and Mangafodipir (Teslascan) were administered intravenously using the tail vein of 60 Balb/C mice. High-resolution T1 images of drug penetration were acquired with a horizontal 9.4 T Agilent magnet after intravenously injection. Signal intensity was used as a metric of temporal and spatial parameters of drug delivery and penetration of the perilymphatic and endolymphatic spaces. RESULTS: ANOVA analysis of the area under the curve of intensity enhancement in perilymph revealed a significant difference (p < 0.05) in the scalae uptake using different contrast agents (F (3,25) = 3.54, p = 0.029). The Gadoteric acid complex Dotarem was found to be the most effective Gd compound in terms of rapid, morphological enhancement for analysis of the temporal, and spatial distribution in the perilymphatic space of the inner ear. CONCLUSION: Gadoteric acid (Dotarem) demonstrated efficacy as a contrast agent for enhanced visualization of the perilymphatic spaces of the inner ear labyrinthine in the mouse, including the scala tympani and scala vestibuli of the cochlea, and the semicircular canals of the vestibular apparatus. These findings may inform the clinical application of Gd compounds in patients with inner ear fluid disorders and vertigo.

Ear Cubes for local controlled drug delivery to the inner ear.

A new type of advanced drug delivery systems is proposed: Miniaturized implants, which can be placed into tiny holes drilled into (or close to) the oval window. They consist of two parts: 1) A cylinder, which is inserted into the hole crossing the oval window. The cylinder (being longer than the depth of the hole) is partly located within the inner ear and surrounded by perilymph. This provides direct access to the target site, and at the same time assures implant fixation. 2) A cuboid, which is located in the middle ear, serving as a drug reservoir. One side of the cuboid is in direct contact with the oval window. Drug release into the cochlea occurs by diffusion through the cylindrical part of the Ear Cubes and by diffusion from the cuboid into and through the oval window. High precision molds were used to prepare two differently sized Ear Cubes by injection molding. The miniaturized implants were based on silicone and loaded with different amounts of dexamethasone (10 to 30 % w/w). The systems were thoroughly characterized before and upon exposure to artificial perilymph at 37°C. Importantly, drug release can effectively be controlled and sustained during long time periods (up to several years). Furthermore, the implants did not swell or erode to a noteworthy extent during the observation period. Drug diffusion through the polymeric matrix, together with limited dexamethasone solubility effects, seem to control the resulting drug release kinetics, which can roughly be estimated using mathematical equations derived from Fick's second law. Importantly, the proposed Ear Cubes are likely to provide much more reliable local long term drug delivery to the inner ear compared to liquid or semi-solid dosage forms administered into the middle ear, due to a more secured fixation. Furthermore, they require less invasive surgeries and can accommodate higher drug amounts compared to intracochlear implants. Thus, they offer the potential to open up new horizons for innovative therapeutic strategies to treat inner ear diseases and disorders.

Intracochlear Drug Injections through the Round Window Membrane: Measures to Improve Drug Retention.

The goal of this study was to develop an appropriate methodology to apply drugs quantitatively to the perilymph of the ear. Intratympanic applications of drugs to the inner ear often result in variable drug levels in the perilymph and can only be used for molecules that readily permeate the round window (RW) membrane. Direct intracochlear and intralabyrinthine application procedures for drugs, genes or cell-based therapies bypass the tight boundaries at the RW, oval window, otic capsule and the blood-labyrinth barrier. However, perforations can release inner ear pressure, allowing cerebrospinal fluid (CSF) to enter through the cochlear aqueduct, displacing the injected drug solution into the middle ear. Two markers, fluorescein or fluorescein isothiocyanate-labeled dextran, were used to quantify how much of an injected substance was retained in the cochlear perilymph following an intracochlear injection. We evaluated whether procedures to mitigate fluid leaks improved marker retention in perilymph. Almost all procedures to reduce volume efflux, including the use of gel for internal sealing and glue for external sealing of the injection site, resulted in improved retention of the marker in perilymph. Adhesive on the RW membrane effectively prevented leaks but also influenced fluid exchange between CSF and perilymph. We conclude that drugs can be delivered to the ear in a consistent, quantitative manner using intracochlear injections if care is taken to control the fluid leaks that result from cochlear perforation.

Intrauterine Lipopolysaccharide-Induced Chorioamnionitis in a Sheep: Does It Affect the Auditory System?

BACKGROUND: Fetal exposure to in utero inflammation such as chorioamnionitis is related to central nervous system injury. We hypothesized that chorioamnionitis can provoke inflammatory changes in the perilymph and alter hearing outcome. METHODS: Pregnant ewes were randomized into 2 groups: intrauterine injection with lipopolysaccharide (LPS; n = 19) or saline (n = 21). In the first experiment, fetal perilymph samples were taken for cytokine analysis. In the second experiment, consecutive bone-conducted auditory brain stem responses were obtained from 1 to 7 months after birth. RESULTS: Perilymph samples showed a significant elevation in interleukin 8 in the LPS group. Auditory brain stem response analysis demonstrated higher response thresholds and a prolongation of absolute peak V and interpeak intervals I to V and III to V in the LPS group compared to sham treatment. CONCLUSION: Our study confirms the hypothesis that an intrauterine inflammation by LPS can result in a fetal perilymphatic inflammatory response and functional impaired hearing outcomes after birth in a sheep model.

A novel chitosan-hydrogel-based nanoparticle delivery system for local inner ear application.

HYPOTHESIS: A chitosan-hydrogel-based nanoparticle (nanohydrogel) delivery system can be used to deliver therapeutic biomaterials across the round window membrane (RWM) into the inner ear in a mouse model. BACKGROUND: Delivering therapies to the inner ear has always been a challenge for the otolaryngologist. Advances in biomedical nanotechnology, increased understanding of the RWM diffusion properties, and discovery of novel therapeutic targets and agents, have all sparked interest in the controlled local delivery of drugs and biomaterials to the inner ear using nanoparticles (NPs). METHODS: Fluorescently-labeled liposomal NPs were constructed and loaded into a chitosan-based hydrogel to form a nanohydrogel, and in vitro studies were performed to evaluate its properties and release kinetics. Furthermore, the nanohydrogel was applied to the RWM of mice, and perilymph and morphologic analysis were performed to assess the NP delivery and distribution within the inner ear. RESULTS: NPs with an average diameter of 160 nm were obtained. In vitro experiments showed that liposomal NPs can persist under physiologic conditions for at least two weeks without significant degradation and that the nanohydrogel can carry and release these NPs in a controlled and sustained manner. In vivo findings demonstrated that the nanohydrogel can deliver intact nanoparticles into the perilymphatic system and reach cellular structures in the scala media of the inner ear of our mouse model. CONCLUSION: Our study suggests that the nanohydrogel system has great potential to deliver therapeutics in a controlled and sustained manner from the middle ear to the inner ear without altering inner ear structures.

Micro CT visualization of silver nanoparticles in the middle and inner ear of rat and transportation pathway after transtympanic injection.

BACKGROUND: Silver nanoparticles (Ag NPs) displayed strong activities in anti-bacterial, anti-viral, and anti-fungal studies and were reportedly efficient in treating otitis media. Information on distribution of AgNPs in different compartments of the ear is lacking. OBJECTIVE: To detect distribution of Ag NPs in the middle and inner ear and transportation pathways after transtympanic injection. METHODS: Contrast effect of Ag NPs in the micro CT imaging was assessed in a phantom. AgNPs at various concentrations (1.85 mM, 37.1 mM, and 370.7 mM) were administered to rat middle ear using transtympanic injection and cadaver heads were imaged using micro CT at several time points. RESULTS: The lowest concentration of Ag NPs that could be visualized using micro CT was 37.1 mM. No difference was observed between the solvents, deionized H2O and saline. Ag NPs at 37.1 mM were visible in the middle ear on 7 d post-administration. Ag NPs at 370.7 mM generated signals in the middle ear, ossicular chain, round window membrane, oval window, scala tympani, and Eustachian tube for both 4 h and 24 h time points. A gradient distribution of Ag NPs from the middle ear to the inner ear was detected. The pathways for Ag NPs to be transported from the middle ear into the inner ear are round and oval windows. CONCLUSION: This study provided the imaging evidence that Ag NPs are able to access the inner ear in a dose-dependent manner after intratympanic administration, which is relevant to design the delivery concentration in the future clinic application in order to avoid adverse inner ear effect.

Cochlear pharmacokinetics of cisplatin: an in vivo study in the guinea pig.

OBJECTIVES/HYPOTHESIS: Cisplatin produces toxic lesions to outer hair cells (OHCs) in the cochlear base but not in the apex. The objective of this study was to compare the pharmacokinetic profile of cisplatin in scala tympani (ST) perilymph in the cochlear base and apex, respectively. STUDY DESIGN: In vivo animal study. METHODS: Forty-seven guinea pigs were given an intravenous bolus injection of an ototoxic dose of cisplatin. Ten to 240 minutes after cisplatin was given, blood, cerebrospinal fluid (CSF), and ST perilymph were aspirated within the same target time. ST perilymph was aspirated from the basal turn and from the apex of the cochlea by two different sampling techniques. Liquid chromatography with postcolumn derivatization was used for quantitative determination of the parent drug. RESULTS: Ten minutes after administration, the concentration of cisplatin in ST perilymph was 4-fold higher in the basal turn of the cochlea than in the apex. At 30 minutes, the drug concentrations did not differ. At 60 minutes, the level of cisplatin in ST perilymph and blood UF was equivalent. The perilymph-blood ratio increased thereafter with time. CONCLUSION: The pharmacokinetic findings of an early high concentration of cisplatin in the base of the cochlea and delayed elimination of cisplatin from ST perilymph compared to blood might correlate to the cisplatin-induced loss of OHCs in the base of the cochlea.

In vivo electrochemical monitoring of the change of cochlear perilymph ascorbate during salicylate-induced tinnitus.

As one of the most important neurochemicals in biological systems, ascorbate plays vital roles in many physiological and pathological processes. In order to understand the roles of ascorbate in the pathological process of tinnitus, this study demonstrates an in vivo method for real time monitoring of the changes of ascorbate level in the cochlear perilymph of guinea pigs during the acute period of tinnitus induced by local microinfusion of salicylate with carbon fiber microelectrodes (CFMEs) modified with multiwalled carbon nanotubes (MWNTs). To accomplish in vivo electrochemical monitoring of ascorbate in the microenvironment of the cochlear perilymph, the MWNT-modified CFME is used as working electrode, a microsized Ag/AgCl is used as reference electrode, and Pt wire is used as counter electrode. Three electrodes are combined together around a capillary to form integrated capillary-electrodes. The integrated capillary-electrode is carefully implanted into the cochlear perilymph of guinea pigs and used both for externally microinfusing of salicylate into the cochlear perilymph and for real time monitoring of the change of ascorbate levels. The in vivo voltammetric method based on the integrated capillary-electrodes possesses a high selectivity and a good linearity for ascorbate determination in the cochlear perilymph of guinea pigs. With such a method, the basal level of cochlear perilymph ascorbate is determined to be 45.0 ± 5.1 µM (n = 6). The microinfusion of 10 mM salicylate (1 µL/min, 5 min) into the cochlear decreases the ascorbate level to 28 ± 10% of the basal level (n = 6) with a statistical significance (P < 0.05), implying that the decrease in ascorbate level in the cochlear may be associated with salicylate-induced tinnitus. This study essentially offers a new method for in vivo monitoring of the cochlear perilymph ascorbate following the salicylate-induced tinnitus and can thus be useful for investigation on chemical essences involved in tinnitus.

Electrophysiological monitoring of hearing function during cochlear perilymphatic perfusions.

CONCLUSION: The cochlear perilymphatic perfusion produces, by itself, significant effects in the cochlear physiology that could be associated with the surgical procedure. These effects need to be well characterized to allow a reliable quantification of the effects of the experimental agent being tested. OBJECTIVES: The study focused on the accurate description of the electrophysiological effects on the cochlear potential recordings of perilymphatic perfusions. METHODS: Two successive cochlear perilymphatic perfusions were carried out. The first used artificial perilymph. The second used artificial perilymph alone or a kainic acid (KA) solution in artificial perilymph. The compound action potential of the auditory nerve (CAP-AN) was recorded: (1) before the first perfusion, (2) after the first perfusion and (3) after the second perfusion, and compared between groups. RESULTS: The first intracochlear perfusion with artificial perilymph produced significant effects in the CAP-AN that could be related to the surgical procedure. These effects were analysed separately from the effects produced by the KA. In particular, the KA administered intracochlearly produced a significant increase in the latency and a decrease in the amplitude of the CAP-AN N1 wave compared with the controls that were perfused twice with artificial perilymph.

Estimation of gadolinium-induced T1-shortening with measurement of simple signal intensity ratio between the cochlea and brain parenchyma on 3D-FLAIR: correlation with T1 measurement by TI scout sequence.

PURPOSE: T(1)-shortening of labyrinthine fluid on 3-dimensional fluid-attenuated inversion recovery (3D-FLAIR) has been reported in many inner ear disorders. Although semi-quantitative assessment by simple signal intensity ratio between cochlear fluid and brain tissue has been tried, its feasibility using a multi-channel phased-array head coil with an inherently inhomogenous sensitivity distribution has not been fully evaluated. We evaluated the feasibility of measuring simple signal intensity ratio by correlating rapid T(1) measurements using an inversion time (TI) scout sequence. MATERIALS AND METHODS: We evaluated 10 patients with Meniere's disease and 4 patients with sudden deafness. Nine of the patients with Meniere's disease received a unilateral intratympanic injection of Gd-DTPA; the tenth patient received bilateral injections. The 4 patients with sudden deafness received a double-dose intravenous injection. Magnetic resonance (MR) images were obtained 24 hours after intratympanic injections and 4 hours after intravenous injections at 3 tesla using a 32-channel head coil. We measured the ratio (CM ratio) between the signal intensity of the perilymph in the cochlea (C) and that of the medulla oblongata (M) and correlated it with the null-point inversion time (TI(null)) obtained with the TI scout sequence. The TI scout consisted of 85 images obtained with TI values between 132.5 and 3087.5 ms at increments of 37.5 ms. RESULTS: The correlation coefficient between TI(null) and the natural logarithm of the CM ratio was -0.88 (P<0.01). There was significant negative linear correlation. CONCLUSIONS: Measurement of the simple signal intensity ratio between the cochlea and the medulla can be used for semi-quantitative analysis of 3D-FLAIR. The results of this study may facilitate clinical research of inner-ear disease using 3D-FLAIR.

Dose-dependent sustained release of dexamethasone in inner ear cochlear fluids using a novel local delivery approach.

The thermo-reversible triblock copolymer poloxamer 407 was investigated as a drug delivery vehicle for micronized dexamethasone into the middle and inner ears of guinea pigs. The study characterized the gelation and in vitro release kinetics of poloxamer formulations. In vivo, the pharmacokinetic profile of formulations containing varying concentrations of poloxamer and dexamethasone was examined following intratympanic administration. Significant drug levels within the perilymph were observed for at least 10 days, while systemic exposure was minimal. The sustained-release kinetics profile could be significantly modulated by varying the concentrations of both poloxamer and dexamethasone. Assessment of auditory function revealed a small transient shift in hearing threshold, most probably of conductive nature, which resolved itself within a week. No significant histological changes of the round window membrane or cochlea could be noted. Poloxamer 407 thus represents an effective and safe delivery system to achieve sustained release of dexamethasone to the inner ear.

Development of a microfluidics-based intracochlear drug delivery device.

BACKGROUND: Direct delivery of drugs and other agents into the inner ear will be important for many emerging therapies, including the treatment of degenerative disorders and guiding regeneration. METHODS: We have taken a microfluidics/MEMS (MicroElectroMechanical Systems) technology approach to develop a fully implantable reciprocating inner-ear drug-delivery system capable of timed and sequenced delivery of agents directly into perilymph of the cochlea. Iterations of the device were tested in guinea pigs to determine the flow characteristics required for safe and effective delivery. For these tests, we used the glutamate receptor blocker DNQX, which alters auditory nerve responses but not cochlear distortion product otoacoustic emissions. RESULTS: We have demonstrated safe and effective delivery of agents into the scala tympani. Equilibration of the drug in the basal turn occurs rapidly (within tens of minutes) and is dependent on reciprocating flow parameters. CONCLUSION: We have described a prototype system for the direct delivery of drugs to the inner ear that has the potential to be a fully implantable means for safe and effective treatment of hearing loss and other diseases.

Endolymphatic hydrops and therapeutic effects are visualized in 'atypical' Meniere's disease.

A 53-year-old male with fluctuating low frequency sensorineural hearing loss and tinnitus, but without vertigo, was evaluated by MRI obtained by intratympanic injection of a gadolinium-based contrast agent (GBCA) before and after the administration of isosorbide. The endolymphatic hydrops was semi-quantitatively evaluated by a 3.0-T MR scanner. For quantification, the affected side/contralateral side ratios were calculated. A gadodiamide (a kind of GBCA)-enhanced space surrounding the endolymph in the affected side with a 0.50 ratio (which may have represented endolymphatic hydrops) improved after isosorbide therapy to a 0.98 ratio. Thus, endolymphatic hydrops was demonstrated in a patient with 'atypical' Meniere's disease (MD), suggesting that at least some atypical MD may share similar etiology with, and therefore be a continuum of, MD. Also, therapeutic effects could be visualized by using MRI. Therefore, MRI-based diagnosis of MD-related disease will be a powerful tool not only because of its precision but also its usefulness for therapeutic evaluation.

Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity.

BACKGROUND: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained. METHODS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided. RESULTS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics. CONCLUSION: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.