Aminoglycosides (AG) such as amikacin are commonly used in cystic fibrosis patients with opportunistic pulmonary infections including multi-drug resistant mycobacterium tuberculous and ...non-tuberculous mycobacterium. Unfortunately, this class of drugs is known to cause peripheral damage to the cochlea leading to hearing loss that can fluctuate and become permanent over time or multiple exposures. However, whether amikacin can lead to central auditory dysfunction like hyperacusis (increased sensitivity to sound) or tinnitus (perception of sound in the absence of acoustic stimulation) is not well described in the literature. Thus, an animal model needs to be developed that documents these side effects in order to develop therapeutic solutions to reduce AG-induced auditory dysfunction. Here we present pioneer work in mice which demonstrates that amikacin can lead to fluctuating behavioral evidence of hyperacusis and tinnitus as assessed by the acoustic startle reflex. Additionally, electrophysiological assessments of hearing via auditory brainstem response demonstrate increased central activity in the auditory brainstem. These data together suggest that peripheral AG-induced dysfunction can lead to central hyperactivity and possible behavioral manifestations of hyperacusis and tinnitus. Importantly, we demonstrate that ebselen, a novel investigational drug that acts as both an antioxidant and anti-inflammatory, can mitigate AG-induced hyperacusis.
Learn about new strategies and novel compounds that are currently in preclinical and clinical development for the prevention and treatment of noise induced hearing loss, the largest neurosensory ...market you've never heard of.
Noise-induced hearing loss (NIHL) is the leading occupational disease and a major contributor to the development of age-related hearing loss. The pharmacological prevention and treatment of NIHL has been under preclinical investigation for the past 20 years. Promising treatments have now been identified and entered into clinical development. Within the next five years, safe and effective drugs could be approved as the first generation of otoprotectants. This review covers strategies that are under investigation for NIHL. Drugs that effectively prevent and treat NIHL will have a significant impact on medical costs, disability compensation and several issues affecting the quality of life.
Aminoglycosides (AG) antibiotics are a common treatment for recurrent infections in cystic fibrosis (CF) patients. AGs are highly ototoxic, resulting in a range of auditory dysfunctions. It was ...recently shown that the acoustic startle reflex (ASR) can assess behavioral evidence of hyperacusis and tinnitus in an amikacin cochleotoxicity mouse model. The goal of this study was to establish if tobramycin treatment led to similar changes in ASR behavior and to establish whether ebselen can prevent the development of these maladaptive neuroplastic symptoms. CBA/Ca mice were divided into three groups: Group 1 served as a control and did not receive tobramycin or ebselen, Group 2 received tobramycin (200 mg/kg/s.c.) and the vehicle (DMSO/saline/i.p.) daily for 14 continuous days, and Group 3 received the same dose/schedule of tobramycin as Group 2 and ebselen at (20 mg/kg/i.p.). Auditory brainstem response (ABR) and ASR hearing assessments were collected at baseline and 2, 6, 10, 14, and 18 weeks from the start of treatment. ASR tests included input/output (I/O) functions which assess general hearing and hyperacusis, and Gap-induced prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus. At 18 weeks, histologic analysis showed predominantly normal appearing hair cells and spiral ganglion neuron (SGN) synapses. Following 14 days of tobramycin injections, 16 kHz thresholds increased from baseline and fluctuated over the 18-week recovery period. I/O functions revealed exaggerated startle response magnitudes in 50% of mice over the same period. Gap detection deficits, representing behavioral evidence of tinnitus, were observed in a smaller subset (36%) of animals. Interestingly, increases in ABR wave III/wave I amplitude ratios were observed. These tobramycin data corroborate previous findings that AGs can result in hearing dysfunctions. We show that a 14-day course of tobramycin treatment can cause similar levels of hearing loss and tinnitus, when compared to a 14-day course of amikacin, but less hyperacusis. Evidence suggests that tinnitus and hyperacusis might be common side effects of AG antibiotics.
Cisplatin ototoxicity has been associated with the generation of toxic levels of reactive oxygen species (ROS) which can lead to injury or loss of outer hair cells in the organ of Corti, damage to ...the stria vascularis, and loss of spiral ganglion cells, resulting in permanent hearing loss. In an attempt to reduce the formation of ROS and to bolster the innate oxidative stress defenses of the cochlea, we tested individual and combined formulations of allopurinol, a xanthine oxidase inhibitor, and ebselen, a glutathione peroxidase mimic. We used an acute cisplatin toxicity rat model (16 mg/kg i.p.) to analyze allopurinol and ebselen alone and in combination for their ability to reduce cisplatin associated hearing loss and nephrotoxicity. The results from our studies indicate that a combined formulation of ebselen and allopurinol affords significant protection to the cochlea and kidney from cisplatin toxicity. In the cochlea, protection is dependent on the preservation of outer hair cell number, while in the kidney, protection is associated with the preservation of proximal tubular epithelia. Further evaluation of the chemoprotective effects of ebselen and allopurinol on cisplatin side effects in the presence of tumor appears warranted.
•Ebselen is the first investigational new drug to advance to Phase 3 in Meniere's Disease.•Ebselen was shown to be effective in a Phase 2 involving Noise-Induced Hearing Loss.•Ongoing studies in ...ototoxicity and other neuroinflammatory diseases show early efficacy.•Future studies will test if ebselen can mitigate central auditory dysfunction.
The global impact of hearing loss and related auditory dysfunction including tinnitus and hyperacusis on human health is significant and growing. A substantial body of literature has found that these hearing diseases and disorders result from significant number of genetic variations and molecular mechanisms. Investigational new drugs have been tested and several approved drugs have been repurposed in clinical trials, but no therapeutics for any auditory related indication have been FDA approved. A unique investigational new drug called ebselen (SPI-1005), that is anti-inflammatory and neuroprotective, has been shown to reduce noise-induced and aminoglycoside-induced hearing loss in animals. Multiple phase 2 clinical trials have demonstrated the safety and efficacy of SPI-1005 treatment in Meniere's disease and acute noise-induced hearing loss. SPI-1005 is currently being tested to prevent and treat tobramycin-induced ototoxicity in cystic fibrosis patients with acute lung infections. This review summarizes the published and presented data involving SPI-1005 and other drugs being tested to prevent or treat sensorineural hearing loss. Additionally, recent clinical data showing the relationship between pure tone audiometry and words-in-noise test results in a Meniere's disease are presented, which may have larger implications for the field of hearing research.
To review basic and clinical findings relevant to defining temporary (TTS) and permanent (PTS) threshold shifts and their sequelae.
Relevant scientific literature and government definitions were ...broadly reviewed.
The definitions and characteristics of TTS and PTS were assessed and recent advances that expand our knowledge of the extent, nature, and consequences of noise-induced hearing loss were reviewed.
Exposure to intense sound can produce TTS, acute changes in hearing sensitivity that recover over time, or PTS, a loss that does not recover to preexposure levels. In general, a threshold shift ≥10 dB at 2, 3, and 4 kHz is required for reporting purposes in human studies. The high-frequency regions of the cochlea are most sensitive to noise damage. Resonance of the ear canal also results in a frequency region of high-noise sensitivity at 4 to 6 kHz. A primary noise target is the cochlear hair cell. Although the mechanisms that underlie such hair cell damage remain unclear, there is evidence to support a role for reactive oxygen species, stress pathway signaling, and apoptosis. Another target is the synapse between the hair cell and the primary afferent neurons. Large numbers of these synapses and their neurons can be lost after noise, even though hearing thresholds may return to normal. This affects auditory processing and detection of signals in noise. The consequences of TTS and PTS include significant deficits in communication that can impact performance of military duties or obtaining/retaining civilian employment. Tinnitus and exacerbation of posttraumatic stress disorder are also potential sequelae.
Noise-induced hearing loss is a leading cause of occupational and recreational injury and disease, and a major determinant of age-related hearing loss. No therapeutic agent has been approved for the ...prevention or treatment of this disorder. In animal models, glutathione peroxidase 1 (GPx1) activity is reduced after acute noise exposure. Ebselen, a novel GPx1 mimic, has been shown to reduce both temporary and permanent noise-induced hearing loss in preclinical studies. We assessed the safety and efficacy of ebselen for the prevention of noise-induced hearing loss in young adults in a phase 2 clinical trial.
In this single-centre, randomised, double-blind, placebo-controlled phase 2 trial, healthy adults aged 18–31 years were randomly assigned (1:1:1:1) at the University of Florida (Gainsville, FL, USA) to receive ebselen 200 mg, 400 mg, or 600 mg, or placebo orally twice daily for 4 days, beginning 2 days before a calibrated sound challenge (4 h of pre-recorded music delivered by insert earphones). Randomisation was done with an allocation sequence generated by an independent third party. The primary outcome was mean temporary threshold shift (TTS) at 4 kHz measured 15 min after the calibrated sound challenge by pure tone audiometry; a reduction of 50% in an ebselen dose group compared with the placebo group was judged to be clinically relevant. All participants who received the calibrated sound challenge and at least one dose of study drug were included in the efficacy analysis. All randomly assigned patients were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT01444846.
Between Jan 11, 2013, and March 24, 2014, 83 participants were enrolled and randomly assigned to receive ebselen 200 mg (n=22), 400 mg (n=20), or 600 mg (n=21), or placebo (n=20). Two participants in the 200 mg ebselen group were discontinued from the study before the calibrated sound challenge because they no longer met the inclusion criteria; these participants were excluded from the efficacy analysis. Mean TTS at 4 kHz was 1·32 dB (SE 0·91) in the 400 mg ebselen group compared with 4·07 dB (0·90) in the placebo group, representing a significant reduction of 68% (difference −2·75 dB, 95% CI −4·54 to −0·97; p=0·0025). Compared with placebo, TTS at 4 kHz was non-significantly reduced by 21% in the 200 mg ebselen group (3·23 dB SE 0·91 vs 4·07 dB 0·90 in the placebo group; difference −0·84 dB, 95% CI −2·63 to 0·94; p=0·3542) and by 7% in the 600 mg ebselen group (3·81 dB 0·90 vs 4·07 dB 0·90 in the placebo group; difference −0·27, 95% CI −2·03 to 1·50; p=0·7659). Ebselen treatment was well tolerated across all doses and no significant differences were seen in any haematological, serum chemistry, or radiological assessments between the ebselen groups and the placebo group.
Treatment with ebselen was safe and effective at a dose of 400 mg twice daily in preventing a noise-induced TTS. These data lend support to a role of GPx1 activity in acute noise-induced hearing loss.
Sound Pharmaceuticals.
Objectives/Hypothesis: Ebselen, a glutathione peroxidase mimic, is a candidate compound for the prevention of noise‐induced hearing loss.
Study Design: Single‐blinded, placebo‐controlled study.
...Methods: Methods included single and repeated noise exposures on F‐344 female rats given oral or injected ebselen or vehicle before and after noise, evoked auditory brainstem responses using click and pure‐tone stimuli, light and fluorescence microscopy of cochleae stained with 4′,6‐Diamidino‐2‐phenylindole (DAPI) and fluorescein isothiocyanate–phalloidin, and statistical power determined by ANOVA.
Results: Auditory brainstem response indicated that ebselen provided significant protection from both temporary and permanent threshold shifts following single and repeated noise exposure. On average, three times more outer hair cells were lost in control versus ebselen‐treated animals.
Conclusion: Ebselen reduces noise‐induced hearing loss in rats.
The chemoprotective effects of combined ebselen and allopurinol in breast (MTLn3) and ovarian (NuTu-19) cancer models using a repeated cisplatin dosing schedule (6 mg/kg i.p.x3 weeks) were studied. ...Otoprotection was evaluated using auditory evoked brainstem response (ABR) to determine threshold and latency shifts, and outer hair cell counts. Nephroprotection was analyzed by serological markers blood urea nitrogen (BUN) and creatinine and histological evaluation. Myelotoxicity was quantified using cytological counts for platelets and changes in hematocrit. Hepatotoxicity was determined by changes in the serological markers amino alanine transferase (ALT) and aspartate amino transferase. Significant chemoprotective effects were observed for multiple organ systems including oto- (ABR threshold shifts for click and 24-kHz stimuli, p<0.05, 8 and 16 kHz, p<0.01, MTLn3 group; hair cell counts, p<0.05 both groups), nephro- (BUN and creatinine, p<0.01), myelo- (platelet p<0.05, hematocrit p<0.05) and hepatotoxicity (ALT p<0.05) in rats receiving oral ebselen and allopurinol. Importantly, the anti-tumor activity of cisplatin was not compromised. On the contrary, improved mortality, morbidity and outcome were observed in the ovarian cancer model. This combined oral formulation of ebselen and allopurinol is an attractive candidate for clinical evaluation.
Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding ...adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.
•Presymptomatic antioxidant treatment prevents loss of parvalbumin in NVHL rats•Antioxidant treatment prevents altered prefrontal electrophysiology in NVHL rats•Prepulse inhibition deficits are prevented by antioxidants
Cabungcal et al. show that antioxidant treatment during juvenile and adolescent stages prevents the onset of electrophysiological and behavioral deficits in a developmental model for schizophrenia. The reversal of adolescent-onset deficits suggests redox modulation is a potential target for early intervention.
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