Pharmacological rescue of noise induced hearing loss using N-acetylcysteine and acetyl-L-carnitine.

Despite the use of hearing protection devices (HPDs) and engineering changes designed to improve workspaces, noise-induced hearing loss continues to be one of the most common and expensive disabilities in the US military. Many service members suffer acoustic trauma due to improper use of HPDs, sound levels exceeding the protective capacity of the HPDs, or by unexpected, injurious exposures. In these cases, there is no definitive treatment for the hearing loss. This study investigated the use of the pharmacological agents N-acetylcysteine and acetyl-L-carnitine after acoustic trauma to treat cochlear injury. N-Acetylcysteine is an antioxidant and acetyl-L-carnitine a compound that maintains mitochondrial bio-energy and integrity. N-Acetylcysteine and acetyl-L-carnitine, respectively, significantly reduced permanent threshold shifts and hair cell loss compared to saline-treated animals when given 1 and 4 h post-noise exposure. It may be possible to obtain a greater therapeutic effect using these agents in combination or at higher doses or for a longer period of time to address the secondary oxidative events occurring 7-10 days after acute noise exposure.

Microdose gentamicin administration via the round window microcatheter: results in patients with Meniere's disease.

Transtympanic gentamicin is becoming increasingly popular in the treatment of Meniere's disease. In this report we examine our experience with the use of microdose gentamicin via the Round Window Microcatheter for the treatment of Meniere's disease. Thirty-six patients were treated with gentamicin administration via the Round Window Microcatheter between July 1997 and August 2000. The patients all underwent 10 days of continuous treatment with a total dose of 2.4-3.75 mg of gentamicin (10 mg/ml). All patients had extensive pre-, intra-, and post-therapy auditory and vestibular testing. In this group, vertigo was eliminated in 89% of the patients, and tinnitus and pressure were significantly reduced in over 60% of the patients. Only one patient suffered a significant hearing loss and, most importantly, in all but one patient vestibular function was improved or normalized after treatment. Round Window Microcatheter-administered microdose gentamicin is an exciting new treatment for Meniere's disease. Preliminary results indicate that vertigo can be controlled without a significant reduction in cochlear or vestibular function in most patients. These results suggest that this therapy may be acting at a non-hair cell site. Our results are compared to the published literature examining transtympanic injection. In addition, the underlying science supporting this type of treatment is examined.

R-phenylisopropyladenosine attenuates noise-induced hearing loss in the chinchilla.

Reactive oxygen species, which are cytotoxic to living tissues, are thought to be partly responsible for noise-induced hearing loss. In this study R-phenylisopropyladenosine (R-PIA), a stable non-hydrolyzable adenosine analogue which has been found effective in upregulating antioxidant enzyme activity levels, was topologically applied to the round window of the right ears of chinchillas. Physiological saline was applied to the round window of the left ears (control). The animals were then exposed to a 4 kHz octave band noise at 105 dB SPL for 4 h. Inferior colliculus evoked potential thresholds and distortion product otoacoustic emissions (DPOAE) were measured and hair cell damage was documented. The mean threshold shifts immediately after the noise exposure were 70-90 dB at frequencies between 2 and 16 kHz. There were no significant differences in threshold shifts at this point between the R-PIA-treated and control ears. By 4 days after noise exposure, however, the R-PIA-treated ears showed 20-30 dB more recovery than saline-treated ears at frequencies between 4 and 16 kHz. More importantly, threshold measurements made 20 days after noise exposure showed 10-15 dB less permanent threshold shifts in R-PIA-treated ears. The amplitudes of DPOAE also recovered to a greater extent and outer hair cell losses were less severe in the R-PIA-treated ears. The results suggest that administration of R-PIA facilitates the recovery process of the outer hair cell after noise exposure.

Changes in cochlear antioxidant enzyme activity after sound conditioning and noise exposure in the chinchilla.

Exposure to low level noise prior to a high level exposure reduces noise-induced hearing loss in mammals. This phenomenon is known as sound conditioning or 'toughening'. Reactive oxygen intermediates have been implicated in noise-induced cochlear damage. To evaluate if in situ antioxidant processes may play a role in the toughening phenomenon initiated by low level noise exposure we analyzed glutathione reductase, gamma-glutamyl cysteine synthetase, and catalase in stria vascularis and organ of Corti fractions from cochleae of chinchillas exposed to a sound conditioning paradigm. Chinchillas were either (A) kept in quiet cages (control), (B) exposed to conditioning noise of a 0.5 kHz octave band (90 dB for 6 h/day for 10 days), (C) exposed to high level noise (105 dB for 4 h) or (D) exposed to conditioning noise (B) followed by exposure to the higher level noise (C). Each of the noise exposure conditions (B, C, D) induced changes in the levels of these three antioxidant enzymes. The enzyme-specific activity data for the four subject groups support the following two hypotheses. (1) Changes in glutathione reductase, gamma-glutamyl cysteine synthetase, and catalase play a role in attenuating hearing loss associated with sound conditioning followed by high level noise. (2) Hair cells in the organ of Corti are protected from noise-induced damage by increasing stria vascularis levels of catalase, a hydrogen peroxide scavenging enzyme, and of enzymes involved in maintaining glutathione in the reduced state. The model formulated by these hypotheses suggests that agents that protect or augment the glutathione system in the cochlea may be protective against noise-induced hearing loss.

Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla.

The effects of a combination of two antioxidant compounds were studied in a chinchilla model of noise-induced hearing loss. After obtaining baseline hearing thresholds using inferior colliculus evoked potentials, chinchillas were exposed for 6 h to octave band noise centered at 4 kHz (105 dB SPL). Post-noise thresholds were obtained 1 h after the noise exposure, and then animals received either saline or salicylate and N-L-acetylcysteine combination. Another group received antioxidant treatment 1 h prior to noise. Hearing was tested at 1, 2 and 3 weeks post-noise. Subsequently, the cochleae were harvested, and cytocochleograms were prepared. There was a 20-40 dB SPL threshold shift at 3 weeks for tested controls. Permanent threshold shifts (PTS) were significantly reduced (P<0.05) to approximately 10 dB for the pre-treatment group at week 3. The PTS for the post-treatment group at week 3 was similar to the pre-treatment group at 1 and 2 kHz (0-10 dB) but was intermediate between the control and pre-treatment groups at 4 and 8 kHz (23 dB). Animals pre-treated with antioxidant had a significant reduction in hair cell loss but those post-treated with antioxidant had no protection from hair cell loss. These findings demonstrate the feasibility of reduction of noise-induced hearing loss using clinically available antioxidant compounds.

Use of the round window microcatheter in the treatment of Meniere's disease.

OBJECTIVES/HYPOTHESIS: Transtympanic gentamicin is an increasingly popular treatment for Meniere's disease. The present report examines the 2-year follow-up of our first 27 patients with Meniere's disease treated with the use of microdose gentamicin through the Round Window Microcatheter. We applied the 1995 American Academy of Otolaryngology-Head and Neck Surgery criteria to this patient group to analyze the results of treatment. STUDY DESIGN: This study is an evaluation of consecutive patients with predetermined data collection on each patient. METHODS: Patients with confirmed Meniere's disease underwent placement of the Round Window Microcatheter, which was filled with 10 mg/mL gentamicin, after placement into the round window niche was confirmed. Ten milligrams per milliliter of gentamicin was injected into the catheter by hand on two occasions after device placement in the first several patients. The remaining patients had continuous infusion of 10 mg/mL gentamicin at 1microL/h for the next 10 days. The catheter was removed 10 days after placement. All patients underwent an extensive set of hearing and vestibular tests on several occasions before, during, and after treatment. RESULTS: In the patients in the study, vertigo was eliminated in 92.6%, with 3.7% of patients (1/27) demonstrating a mild permanent threshold shift in hearing. Tinnitus and pressure were significantly reduced in more than 65% of patients. Only one patient demonstrated a reduction of vestibular function after treatment. CONCLUSIONS: Results of this study on this group of patients indicate that vertigo can be controlled in the long term using microdose gentamicin without a significant reduction in cochlear or vestibular function in most of the patients in our series. Our results are compared with the published literature examining transtympanic injection. In addition, the underlying science supporting this type of treatment is examined.

Transtympanic versus sustained-release administration of gentamicin: kinetics, morphology, and function.

OBJECTIVES/HYPOTHESIS: Transtympanic gentamicin therapy has become a popular treatment modality for Meniere's disease, but questions regarding the ideal dose of medicine, the best administration paradigm, and the safest treatment end-point remain unanswered. The goal of this study is to examine the inner ear kinetics of transtympanic gentamicin and compare this with the kinetics of sustained-release delivery in a basic science model. In addition, we plan to examine the relationship of these kinetics curves to the effect of the two treatment modalities on inner ear function and morphology. It is hoped that this analysis will help clinicians to better apply local medical therapy to the ear. STUDY DESIGN: The study is a basic science project designed to examine perilymph gentamicin concentrations, hearing results, and inner ear morphology in an animal model. METHODS: Gentamicin was applied to the right ear of chinchillas either through a transtympanic approach or in a sustained-release device. The left ear remained untreated as an internal control. At set time points the animals' hearing and balance function was studied and the perilymph was harvested, after which the animal was killed and preserved for histological evaluation. Kinetics curves were constructed for each of the two treatment paradigms and compared with histological and functional outcomes. RESULTS: The two groups yielded dramatically different kinetics curves. The transtympanic curve had a high peak level at 24 hours with rapid fall-off and almost total elimination by 48 hours, whereas the sustained-release curve was characterized by a long, flat plateau phase with a peak that was approximately one-third that of the transtympanic curve. In addition, the variability seen in perilymph concentrations was significantly higher in the transtympanic group than in the sustained-release group. Immunohistochemical analysis using antibodies against cleaved caspase-3 and cleaved caspase-7 demonstrated early damage in the spiral ganglion of both groups, before any obvious morphological change in the hair cells. The staining was significantly more dense in animals with transtympanic delivery. Cochlear and vestibular hair cell damage was seen at late time points in animals from both groups. Hearing loss (HL) progressed in an orderly fashion in the sustained-release group of animals, with no HL seen in the early time points and universal significant threshold shifts present by 72 hours. In the transtympanic group, the HL was more variable, with significant threshold shifts occurring as early as 4 hours after treatment, but with some animals demonstrating preserved hearing at the 72-hour time point. All animals demonstrated profound HL at the 6-day time point. CONCLUSIONS: There is a significant difference in the shape and variability of the perilymph kinetics curve when comparing sustained-release delivery to transtympanic delivery of gentamicin. High early peak levels of gentamicin seen with transtympanic therapy may have a profound effect on the spiral ganglion and produce early HL before obvious hair cell damage. Sustained delivery of gentamicin produces universal HL at 72 hours. The reliability of sustained-release delivery to the ear reduces functional and morphological variations between animals.

Dematiaceous fungal sinusitis.

Six cases of dematiaceous fungal sinusitis are reported, together with a review of 33 other cases collated from a review of the English literature. The sinusitis was more often unilateral vs. bilateral. A characteristic serpiginous hyperdense intrasinus opacification, as well as sinus expansion with bone erosion, was often seen on CT scan. MRI scan showed lucent sinus cavities on T1 and T2 weighting. A comparison of surgical treatment vs. surgery with systemic antifungal therapy revealed decreased recurrence and complication statistics in the combined therapy group. There was a trend toward increased recurrence/persistence and complications associated with invasive histologic findings and only surgical treatment, but not statistically significant. At the present time, we recommend comprehensive surgical treatment followed by systemic antifungal therapy, though clinical judgment and individualization should occur. Future studies are planned to further define the disease entity and its therapy.

Targeted topical steroid therapy in sudden sensorineural hearing loss.

OBJECTIVE: To treat patients with sudden sensorineural hearing loss (SSNL) who failed oral prednisone therapy by using a round window membrane (RWM) microcatheter. This topical delivery strategy sought to improve effectiveness of steroid treatment to the inner ear by targeting drug delivery to the RWM. STUDY DESIGN: Nonrandomized prospective design. SETTING: Tertiary care facility. PATIENTS: Six patients with severe unilateral SSHL, five of whom were refractory to a course of oral steroid therapy treated within 6 weeks of SSHL and three additional patients treated more than 6 weeks after SSHL. INTERVENTION: Therapeutic use of RWM catheter. MAIN OUTCOME MEASURES: Pure-tone averages (PTAs) and word identification scores (WIS). RESULTS: Five of the six patients treated within 6 weeks of SSHL improved their WIS. Of the six, four returned to baseline hearing, one recovered hearing that could benefit by hearing amplification, and one regained moderate improvement in PTA but not WIS. CONCLUSION: Targeted topical steroid administration avoids the significant systemic side effects of oral steroids and may offer more effective dosing than simple transtympanic injection of medicine. Although these findings are preliminary, it is possible that after further study, targeted drug delivery may be a useful technique to consider in patients with severe to profound hearing loss that have failed all other management options.

Morphologic changes in the inner ear of Chinchilla laniger after middle ear administration of gentamicin in a sustained-release vehicle.

The use of transtympanic gentamicin has become a popular method of treating Meniere's disease; nevertheless, many questions still remain regarding this therapy. Until investigators can control the exact amount of medicine that is administered to the ear and have an understanding of the kinetics of gentamicin, therapy will continue to rely on empirical data. Previously we described the use of a fibrin-based sustained-release vehicle impregnated with gentamicin in the middle ears of chinchillas. With this model a kinetics curve of gentamicin was defined. The inner ears of these animals were submitted for immunohistochemical and histologic analysis. We discuss the ultrastructural changes seen and correlate this to our kinetics data. We also examine measurement of hair cell damage with heat shock protein levels. By better understanding the actions of gentamicin in this animal model, we hope to facilitate safer use of intratympanic medicines in our patient population.

Therapeutic effects of orally administrated antioxidant drugs on acute noise-induced hearing loss.

OBJECTIVE: The objective of this study was to investigate the dose-dependent therapeutic effect of the orally administrated antioxidant drugs [4-hydroxy alpha-phenyl-tert-butylnitrone (4-OHPBN) and N-acetyl-L-cysteine (NAC)] on acute noise-induced hearing loss because oral administration is the most commonly used method of drug administration due to its convenience, safety, and economical efficiency. METHODS: Thirty chinchilla were exposed to a 105 dB octave band noise centered at 4 kHz for 6 h and randomly assigned to a control group (saline only) and three experimental groups [4-OHPBN (10 mg/kg) plus NAC (20 mg/kg), 4-OHPBN (20 mg/kg) plus NAC (50 mg/kg), and 4-OHPBN (50 mg/kg) plus NAC (100 mg/kg)]. The drugs were orally administrated beginning 4 h after noise exposure and then administered twice daily for the next 2 days. Permanent auditory brainstem response threshold shifts, distortion product otoacoustic emission threshold shifts, and the percentage of missing outer hair cell were determined. RESULTS: The oral administration significantly reduced permanent hearing threshold shift, distortion product otoacoustic emission threshold shift, and the percentage of missing outer hair cell in a dose-dependent manner. DISCUSSION: This result demonstrates that orally administered drugs can treat acute noise-induced hearing loss in a dose-dependent manner. This suggests that oral administration was effective in treating acute noise-induced hearing loss as in intraperitoneal administration.

Use of organotypic cultures of Corti's organ to study the protective effects of antioxidant molecules on cisplatin-induced damage of auditory hair cells.

HYPOTHESIS: Cisplatin causes the generation of reactive oxygen species (ROS), which interferes with the antioxidant defense system of Corti's organ and results in damage to the hair cells. BACKGROUND: Cisplatin is a widely used chemotherapeutic agent with the dose-limiting side effect of ototoxicity. Evidence is accumulating that cisplatin interferes with the antioxidant defense system of Corti's organ. METHODS: Organotypic explants of P-3 rat organ of Corti were the in vitro model system. Presence of intact auditory hair cells and stereocilia bundle integrity was assayed by phalloidin-FITC staining. Fluorescent dye probes detected H2O2 and intracellular thiol [e.g., glutathione (GSH)]. Spectrophotometric analysis determined antioxidant enzyme levels. RESULTS: There was a rapid dose-dependent cisplatin cytotoxicity in the explants after 48 h of exposure. An accumulation of H2O2 and a reduction of GSH levels were observed within cisplatin-exposed hair cells. L-buthionine sulfoximine, an inhibitor of GSH formation, enhanced cisplatin ototoxicity, whereas N6-(2-phenylisopropyl) adenosine, an adenosine agonist, elevated antioxidant enzyme levels and ameliorated cisplatin toxicity. The following molecules protected hair cells from cisplatin-induced damage: GSH; glutathione diethyl ester (GSHe); ebselen (EBS); 4-methylthiobenzoic acid (MTBA); and D-methionine (D-MET). EBS, MTBA, and D-MET in vitro protection correlates with in vivo protection in rats. CONCLUSIONS: Organotypic culture of Corti's organ has been validated as a model for studying cisplatin toxicity and for screening otoprotective molecules. Some of the events that contribute to cisplatin's ability to damage auditory hair cells are generation of ROS (e.g., H2O2), depletion of intracellular GSH, and interference with antioxidant enzymes within the cochlea. Agents that bolster the cochlea's antioxidant system can prevent cisplatin destruction of auditory hair cells. Identified protective agents may prove to be clinically useful in limiting or completely protecting from cisplatin ototoxicity.

Growth factor treatment enhances vestibular hair cell renewal and results in improved vestibular function.

The vestibules of adult guinea pigs were lesioned with gentamicin and then treated with perilymphatic infusion of either of two growth factor mixtures (i.e., GF I or GF II). GF I contained transforming growth factor alpha (TGFalpha), insulin-like growth factor type one (IGF-1), and retinoic acid (RA), whereas GF II contained those three factors and brain-derived neurotrophic factor. Treatment with GF I significantly enhanced vestibular hair cell renewal in ototoxin-damaged utricles and the maturation of stereociliary bundle morphology. The addition of brain-derived neurotrophic factor to the GF II infusion mixture resulted in the return of type 1 vestibular hair cells in ototoxin-damaged cristae, and improved vestibular function. These results suggest that growth factor therapy may be an effective treatment for balance disorders that are the result of hair cell dysfunction and/or loss.