Permanent and transient effects of locally delivered n-acetyl cysteine in a guinea pig model of cochlear implantation

The University of Melbourne, Australia.
Hearing research (Impact Factor: 2.97). 10/2009; 259(1-2):24-30. DOI: 10.1016/j.heares.2009.08.010
Source: PubMed


Protection of residual hearing after cochlear implant surgery can improve the speech and music perception of cochlear implant recipients, particularly in the presence of background noise. Surgical trauma and chronic inflammation are thought to be responsible for a significant proportion of residual hearing loss after surgery. Local delivery of the anti-oxidant precursor n-acetyl cysteine (NAC) to the cochlea via round window 30min prior to surgery, increased the level of residual hearing at 24-32kHz 4weeks post surgery compared to controls. The hearing protection was found in the basal turn near the site of implantation. Coincidentally, the basal turn was also the location that sustained the greatest hearing loss. As well as protecting residual hearing, NAC-treated animals demonstrated a reduction in the chronic inflammatory changes associated with implantation. While these findings indicate that anti-oxidant therapy can be used to reduce the hearing loss associated with surgical trauma, the local delivery of NAC was associated with a transient increase in hearing thresholds, and osseoneogenesis was seen in a greater number of NAC-treated animals. These side-effects would limit its clinical use through local cochlear administration. However, it is not known yet whether these effects would also be produced by other anti-oxidants, or ameliorated by using a different route of administration.

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    • "In addition, the formation of oxygen free radicals is hypothesised as a major cause of noise-induced hearing loss [104, 121]. Importantly, numerous studies have demonstrated that the application of various antioxidants, including n-acetyl cysteine, glutathione, resveratrol, and superoxide dismutase, can protect the auditory system from the degenerative effects of ototoxin- or noise-induced hearing loss [122–127]. Interestingly, therapeutic agents used for other clinical conditions, such as rasagiline, a monoamine oxidase type B inhibitor that is FDA-approved for use in Parkinson's disease, and metformin, an anti-diabetic drug, have also been demonstrated to attenuate hearing loss following ototoxin exposure [128, 129]. Clinical application of antioxidants for protection in the inner ear is also being developed: a molecule known as as SPI-1005, which induces glutathione peroxidase and reduces reactive oxygen species, is currently undergoing Phase II clinical trials [110]. "
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    ABSTRACT: Cochlear implants have provided hearing to hundreds of thousands of profoundly deaf people around the world. Recently, the eligibility criteria for cochlear implantation have been relaxed to include individuals who have some useful residual hearing. These recipients receive inputs from both electric and acoustic stimulation (EAS). Implant recipients who can combine these hearing modalities demonstrate pronounced benefit in speech perception, listening in background noise, and music appreciation over implant recipients that rely on electrical stimulation alone. The mechanisms bestowing this benefit are unknown, but it is likely that interaction of the electric and acoustic signals in the auditory pathway plays a role. Protection of residual hearing both during and following cochlear implantation is critical for EAS. A number of surgical refinements have been implemented to protect residual hearing, and the development of hearing-protective drug and gene therapies is promising for EAS recipients.This review outlines the current field of EAS, with a focus on interactions that are observed between these modalities in animal models. It also outlines current trends in EAS surgery and gives an overview of the drug and gene therapies that are clinically translatable and may one day provide protection of residual hearing for cochlear implant recipients.
    BioMed Research International 09/2014; 2014(Article ID 350504):17 pages. DOI:10.1155/2014/350504 · 3.17 Impact Factor
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    • "Similar inflammatory effects were found on the external and middle ear of guinea pigs treated with 4% intratympanic NAC [12]. In a guinea pig cochlear implant model [23], although preservation of residual hearing was found in the basal turn as well as a reduction in the chronic inflammatory response associated with cochlear implantation, a transient increase in hearing thresholds and osseoneogenesis was also found in animals treated with topical 4% NAC [23]. Topical 0.6% NAC after myringotomy in a guinea pig model showed significant otorrhea in the NAC treated group associated with reduced healing of the tympanic membrane post-myringotomy; 40% had persistent TM perforations in the NAC treated group versus 100% closure of perforations in the control group [24]. "
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    ABSTRACT: Background: The safety and efficacy of Ciprodex® has been demonstrated for treatment of chronic suppurative otitis media (CSOM). However, symptoms fail to resolve in 9-15% of patients. The objective of this study is to evaluate the efficacy of N-acetylcysteine (NAC) on S. aureus, and planktonic and sessile (biofilm forming) P. aeruginosa in vitro using clinical isolates from patients with CSOM. Methods: 1) Stability was assessed using liquid chromatography-mass spectrometry for each component in a prepared mixture of Ciprodex® and NAC over 15 days. Sterility was assessed by measuring bacterial growth on a blood agar plate. Efficacy was assessed using a disc diffusion method by inoculating plates with S. aureus ATCC 29513 and P. aeruginosa ATCC 27853, and measuring the clearance zone.2) Fifteen P. aeruginosa strains were isolated from patients with CSOM and tested in vitro using the bioFILM PA™ antimicrobial susceptibility assay. Treatment solutions included Ciprodex® & ciprofloxacin +/- NAC, and NAC alone (0.25%, 0.5% & 1.25%). Results: 1) NAC combined with Ciprodex® demonstrated stability, sterility, and efficacy over a two-week period2) P. aeruginosa strains in the sessile (33%-40%) and planktonic (13%) state demonstrated resistance to Ciprodex® and ciprofloxacin. When NAC ≥0.5% was used in isolation or as an adjunct to either of these medications, no resistance was found in the sessile or planktonic state among all 15 strains. Conclusion: 1) Ciprodex® combined with NAC has a shelf life of at least two weeks given the documented preservation of stability, sterility, and clinical efficacy of the mixed compounds.2) P. aeruginosa strains demonstrated resistance to both Ciprodex® and ciprofloxacin. NAC ≥0.5% overcomes issues with resistance and shows promise in the treatment of CSOM.
    Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale 07/2014; 43(1):20. DOI:10.1186/1916-0216-43-20 · 0.89 Impact Factor
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    • "Our study employed dexamethasone as a rescue agent. Administration of dexamethasone has been well documented in the attenuation of hair cell apoptosis in animal models, particularly in guinea pig models of apoptosis [13,14]. Himano demonstrated that local administration of dexamethasone directly to the inner ear preceding aminoglycoside administration attenuated hair cell loss. "
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    ABSTRACT: To investigate the effect of timing of dexamethasone administration on auditory hair cell survival following an ototoxic insult with kanamycin and furosemide.Study design: Controlled experimental study.Setting: Translational Science Experimental Laboratory. 5-6 week old CBA/CaJ mice, divided into 6 groups, were injected with kanamycin (1 mg/g SC) followed by furosemide (0.5 mg/g IP). Dexamethasone (0.1 mg/g IP) was injected at either 1 hour prior to insult, +1 hr, +6 hr, +12 hr, or +72 hr post insult. Temporal bones harvested on day 7 underwent Organ of Corti dissection. Immunohistochemical staining was performed using antibodies to myosin 7a, phalloidin, and TO-PRO. Hair cell counts demonstrate a uniform ototoxicity model with total loss of outer hair cells (OHCs) and near-total loss of inner hair cells (IHCs). The group pre-treated with dexamethasone showed a statistically significant improvement in counts compared to controls (p = 0.004). Counts from the other experimental groups given dexamethasone after the insult were highly variable but demonstrated some apical and middle turn inner hair cell survival. Treatment of systemic dexamethasone prior to ototoxic insult attenuates hair cell loss in a reliable, novel, ototoxicity model using kanamycin and furosemide in CBA/CaJ mice. Dosing with dexamethasone following ototoxic insult shows promising yet variable response in hair cell survival.
    Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale 04/2014; 43(1):12. DOI:10.1186/1916-0216-43-12 · 0.89 Impact Factor
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