Otoprotective Agents Research Articles

Evaluating calcium channel blockers and bisphosphonates as otoprotective agents in cochlear implantation hearing preservation candidates

Objectives Evaluate potential effects of calcium channel blockers (CCB) and bisphosphonates (BP) on residual hearing following cochlear implantation. Methods Medications of 303 adult hearing preservation (HP) candidates (low frequency pure tone average [LFPTA] of 125, 250, and 500 Hz ≤80 dB HL) were reviewed. Postimplantation LFPTA of patients taking CCBs and BPs were compared to controls matched by age and preimplantation LFPTA. Results Twenty-six HP candidates were taking a CCB (N = 14) or bisphosphonate (N = 12) at implantation. Median follow-up was 1.37 years (range 0.22–4.64y). Among subjects with initial HP, 29% (N = 2 of 7) CCB users compared to 50% (N = 2 of 4) controls subsequently lost residual hearing 3–6 months later (OR = 0.40, 95% CI = 0.04–4.32, p = 0.58). None of the four BP patients with initial HP experienced delayed loss compared to 50% (N = 2 of 4) controls with initial HP (OR = 0.00, 95% CI = 0.00–1.95, P = 0.43). Two CCB and one BP patients improved to a LFPTA <80 dB HL following initial unaided thresholds that suggested loss of residual hearing. Discussion There were no significant differences in the odds of delayed loss of residual hearing with CCBs or BPs. Conclusion Further investigation into potential otoprotective adjuvants for maintaining residual hearing following initial successful hearing preservation is warranted, with larger cohorts and additional CCB/BP agents.

Cisplatin-induced ototoxicity: a novel approach to an ancient problem.

With the scarcity of pharmacological otoprotective agents against cisplatin-induced ototoxicity (CIO), researchers find themselves compelled to look at and navigate all possible strategies to identify ways to prevent CIO. One of these promising strategies is pharmacogenomic implementation. This strategy aims for identifying and detecting high-risk genetic variants to tailor cisplatin therapy to reach the best survival outcomes with the least risk of ototoxicity.

Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model.

The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear. Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents. RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N -acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined. The estimated 50% lethal concentration dose for gentamicin was 805.6 μM, which was 46-fold higher than that for cisplatin (17.5 μM). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% ( p < 0.001) increase in cell viability when compared with cisplatin alone. However, this protective effect was not consistent across all trials. NAC was encapsulated into a PLGA microparticle and elution plateaued at 5 days. When dosed at their respective therapeutic ranges, cisplatin is more likely than gentamicin to induce damage to the Schwann cell model. Although NAC demonstrates an uncertain role in protecting against cisplatin-induced Schwann cell cytotoxicity, this study establishes a method to screen for other otoprotective medications to encapsulate into a tunable microparticle for localized drug delivery.

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it.

Sodium thiosulfate as cisplatin otoprotectant in children: The challenge of when to use it.

Hair cell toxicology: With the help of a little fish.

Hearing or balance loss are disabling conditions that have a serious impact in those suffering them, especially when they appear in children. Their ultimate cause is frequently the loss of function of mechanosensory hair cells in the inner ear. Hair cells can be damaged by environmental insults, like noise or chemical agents, known as ototoxins. Two of the most common ototoxins are life-saving medications: cisplatin against solid tumors, and aminoglycoside antibiotics to treat infections. However, due to their localization inside the temporal bone, hair cells are difficult to study in mammals. As an alternative animal model, zebrafish larvae have hair cells similar to those in mammals, some of which are located in a fish specific organ on the surface of the skin, the lateral line. This makes them easy to observe in vivo and readily accessible for ototoxins or otoprotective substances. These features have made possible advances in the study of the mechanisms mediating ototoxicity or identifying new potential ototoxins. Most importantly, the small size of the zebrafish larvae has allowed screening thousands of molecules searching for otoprotective agents in a scale that would be highly impractical in rodent models. The positive hits found can then start the long road to reach clinical settings to prevent hearing or balance loss.

Pericytes of Stria Vascularis Are Targets of Cisplatin-Induced Ototoxicity: New Insights into the Molecular Mechanisms Involved in Blood-Labyrinth Barrier Breakdown.

The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing loss. In this study, cell viability, proliferation rate, cytotoxicity and reactive oxygen species production were evaluated. The protein content of phospho-extracellular signal-regulated kinases (ERK) 1/2, total ERK 1/2, phospho-cytosolic phospholipase A2 (cPLA2), total cPLA2 and cyclooxygenase 2 (COX-2) and the release of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) from BCPs were analyzed. Finally, the protective effect of platelet-derived growth factor (PDGF-BB) on BCPs treated with cisplatin was investigated. Cisplatin reduced viability and proliferation, activated ERK 1/2, cPLA2 and COX-2 expression and increased PGE2 and VEGF release; these effects were reversed by Dexamethasone. The presence of PDGF-BB during the treatment with cisplatin significantly increased the proliferation rate. No studies on cell regeneration in ear tissue evaluated the effect of the PDGF/Dex combination. The aim of this study was to investigate the effects of cisplatin on cochlear pericytes and propose new otoprotective agents aimed at preventing the reduction of their vitality and thus maintaining the BLB structure.

Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss

Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t = 0) were given mannitol at either t = 0, t = 6 or t = 0,6 h. Another group of rats were treated with cisplatin with mannitol at 0 h and NAC/STS with and without mannitol at 6 h. Concurrent mannitol (t = 0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t = 6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t = 0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t = 6) was better than NAC/STS (t = 6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t = 6 h reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t = 0 h), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.

An Overview of Nanoparticle Drug Delivery for Ototoxin and Noise Mediated Hearing Loss Treatment

Abstract: Efficient delivery of therapeutic material to target site of the inner ear is considered as the most challenging process due to their poor blood flow and inaccessibility sensitivity towards chemical stimuli, inability of drug to be delivered as well. Novel nanoparticlebased drug transport approaches have emerged for overcoming the restriction associated with inner ear therapeutic material delivery. The main focus of this article is to highlight the potential benefits, pre-clinical level otoprotective effect of different types of NPs based payload delivery strategies in mitigating sensorineural hearing impairment resulting from medication (cisplatin and antibiotic treatment) and noise exposure. This review converses about advantage of nanocarrier assisted targeted cell specific inner ear drug delivery approach and demonstrates that targeted NPs delivery systems have the capability to be utilized as vehicle to transport therapeutic materials into the OHCs within the cochlea in controlled and sustained way and maximize following therapeutic effects. Efficacy of systemic and minimally invasive intratympanic and RWM approach for delivering steroids/ genetic material to the inner ear has also been compared in this article. Understanding the importance (design, formulation, cochlear biocompatibility and cell specific binding efficiency of NPs, mechanistic pathways, route of delivery, positive therapeutic outcomes) and hitches (adverse effects after treatment, negative therapeutic outcome) of currently available NPs based drug delivery systems offer new opportunity to develop best treatment methods for sensorineural hearing dysfunction. Keywords: Nanocarriers, Otoprotective agents, Sensorineural heating loss, Ototoxicity, Noise trauma, Ototoxin.

The audiogram: Detection of pure-tone stimuli in ototoxicity monitoring and assessments of investigational medicines for the inner ear.

Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided.

Current Concepts and Future Trends in Increasing the Benefits of Cochlear Implantation: A Narrative Review.

Hearing loss is the most common neurosensory disorder, and with the constant increase in etiological factors, combined with early detection protocols, numbers will continue to rise. Cochlear implantation has become the gold standard for patients with severe hearing loss, and interest has shifted from implantation principles to the preservation of residual hearing following the procedure itself. As the audiological criteria for cochlear implant eligibility have expanded to include patients with good residual hearing, more attention is focused on complementary development of otoprotective agents, electrode design, and surgical approaches. The focus of this review is current aspects of preserving residual hearing through a summary of recent trends regarding surgical and pharmacological fundamentals. Subsequently, the assessment of new pharmacological options, novel bioactive molecules (neurotrophins, growth factors, etc.), nanoparticles, stem cells, and gene therapy are discussed.

A combinatorial approach to protect sensory tissue against cisplatin-induced ototoxicity

Sensorineural Hearing Loss (SNHL) is a highly prevalent disorder involving permanent damage or loss to the inner ear's mechano-sensory hair cells and nerve fibers. Major contributing causes are ototoxic drugs, loud noises, and aging. Drug-induced hearing loss (DIHL), affects over 25% of patients treated with common therapeutics such as aminoglycoside antibiotics, loop diuretics or chemotherapeutics. A commonly used chemotherapeutic agent, cisplatin, is very effective for treating malignant tumors, but results in a majority of patients experiencing irreversible hearing loss and/or tinnitus. Additionally, since there is currently no FDA-approved treatments for SNHL, attenuation of ototoxicity is a major area of investigation in oncology, otolaryngology and hearing research. Several potential otoprotective agents have been investigated at the clinical trial stage, but none have progressed to a full FDA-approval. In this study, we investigated a combinatorial approach comprised of an antioxidant, a p53 inhibitor and a neurotrophin, as a multifactorial otoprotective treatment for cisplatin exposure. In vitro, HEI-OC1 cells, an immortalized organ of Corti epithelial cell line, pre-treated with this biotherapeutic cocktail had significantly reduced cisplatin-induced cell death, DNA fragmentation, and apoptotic activation. In an ex vivo study, rat pup D2-D3 organ of Corti explants, significant protection against cisplatin-based hair cell and neuronal loss was achieved by delivery of the same combinatorial pretreatment. Interestingly, the hair cell protection was localized to the basal and middle regions of the organ of Corti. Together, these findings highlight a novel approach to attenuate cisplatin ototoxicity and potentially prevent DIHL by addressing biological mechanisms of cisplatin ototoxicity.

Long-Term Incidence and Predictors of Significant Hearing Loss Requiring Hearing Assistive Devices Among Childhood Cancer Survivors: A Population-Based Study.

Hearing loss is a significant late effect among childhood cancer survivors. Recent guidelines note insufficient evidence to quantify its natural history or risk associated with specific exposures. We examined the long-term incidence and predictors of hearing loss requiring hearing amplification devices (HADs) using population-based health care data. In Ontario, Canada, HAD costs are subsidized by the Assistive Devices Program (ADP). Ontario children < 18 years of age at cancer diagnosis between 1987 and 2016 were identified and linked to ADP claims. Cumulative HAD incidence was compared between cases and matched controls. Patient, disease, and treatment predictors of HAD were examined. We identified 11,842 cases and 59,210 controls. Cases were at higher risk for HAD (hazard ratio [HR], 12.8; 95% CI, 9.8 to 16.7; P < .001). The cumulative incidence of HAD among survivors was 2.1% (95% CI, 1.7% to 2.5%) at 20 years and 6.4% (95% CI, 2.8% to 12.1%) at 30 years post-diagnosis. The 30-year incidence was highest in neuroblastoma (10.7%; 95% CI, 3.8% to 21.7%) and hepatoblastoma (16.2%; 95% CI, 8.6% to 26.0%) survivors. Predictors of HAD in multivariable analyses included age 0-4 years at diagnosis (v 5-9 years; HR, 2.2; 95% CI, 1.4-3.3; P < .001). Relative to no cisplatin exposure, patients receiving < 200 mg/m2 were not at greater risk, unlike those receiving higher cumulative doses. Relative to no cranial or facial radiation, those who had received ≤ 32.00 Gy were at no higher risk, unlike those who had received > 32.00 Gy. Carboplatin exposure was not associated with HAD. Childhood cancer survivors are at elevated risk for requiring HAD, which continues to increase between 20 and 30 years after diagnosis. Thresholds of cisplatin and radiation exposure exist, above which risk substantially increases. Prolonged monitoring and trials of otoprotective agents are warranted in high-risk populations.

Astaxanthin-loaded polymer-lipid hybrid nanoparticles (ATX-LPN): assessment of potential otoprotective effects

BackgroundOtotoxicity is one of the major side effects of platinum-based chemotherapy, especially cisplatin therapy. To date, no FDA approved agents to alleviate or prevent this ototoxicity are available. However, ototoxicity is generally believed to be produced by excessive generation of reactive oxygen species (ROS) in the inner ear, thus leading to the development of various antioxidants, which act as otoprotective agents. Astaxanthin (ATX) is an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies, owing to its unique antioxidant capacity.Methods and resultsIn this study, we aimed to evaluate the potential antioxidant properties of ATX in the inner ear by using the HEI-OC1 cell line, zebrafish, and guinea pigs. Because ATX has poor solubility and cannot pass through round window membranes (RWM), we established lipid-polymer hybrid nanoparticles (LPN) for loading ATX. The LPN enabled ATX to penetrate RWM and maintain concentrations in the perilymph in the inner ear for 24 h after a single injection. ATX-LPN were found to have favorable biocompatibility and to strongly affect cisplatin-induced generation of ROS, on the basis of DCFHDA staining in HEI-OC1 cells. JC-1 and MitoTracker Green staining suggested that ATX-LPN successfully reversed the decrease in mitochondrial membrane potential induced by cisplatin in vitro and rescued cells from early stages of apoptosis, as demonstrated by FACS stained with Annexin V-FITC/PI. Moreover, ATX-LPN successfully attenuated OHC losses in cultured organ of Corti and animal models (zebrafish and guinea pigs) in vivo. In investigating the protective mechanism of ATX-LPN, we found that ATX-LPN decreased the expression of pro-apoptotic proteins (caspase 3/9 and cytochrome-c) and increased expression of the anti-apoptotic protein Bcl-2. In addition, the activation of JNK induced by CDDP was up-regulated and then decreased after the administration of ATX-LPN, while P38 stayed unchanged.ConclusionsTo best of our knowledge, this is first study concluded that ATX-LPN as a new therapeutic agent for the prevention of cisplatin-induced ototoxicity.

Use of the guinea pig in studies on the development and prevention of acquired sensorineural hearing loss, with an emphasis on noise.

Guinea pigs have been used in diverse studies to better understand acquired hearing loss induced by noise and ototoxic drugs. The guinea pig has its best hearing at slightly higher frequencies relative to humans, but its hearing is more similar to humans than the rat or mouse. Like other rodents, it is more vulnerable to noise injury than the human or nonhuman primate models. There is a wealth of information on auditory function and vulnerability of the inner ear to diverse insults in the guinea pig. With respect to the assessment of potential otoprotective agents, guinea pigs are also docile animals that are relatively easy to dose via systemic injections or gavage. Of interest, the cochlea and the round window are easily accessible, notably for direct cochlear therapy, as in the chinchilla, making the guinea pig a most relevant and suitable model for hearing. This article reviews the use of the guinea pig in basic auditory research, provides detailed discussion of its use in studies on noise injury and other injuries leading to acquired sensorineural hearing loss, and lists some therapeutics assessed in these laboratory animal models to prevent acquired sensorineural hearing loss.

The efficacy of statins as otoprotective agents: A systematic review.

This systematic review examined current literature, summarised research findings and identified research gaps regarding the efficacy of statins on audiological outcomes. Systematic search of electronic databases and grey literature was performed. Eligibility criteria were the study of a statin drug with report of audiological outcomes such as hearing, tinnitus or balance in either human or animal studies. Data extraction and quality assessment were performed by two independently researchers. The characteristics of the study and research findings were collated and summarised. A narrative synthesis was conducted. Meta-analysis was not possible due to heterogeneity of the included studies. Analysis of searches yielded 17 studies meeting the criteria. Included studies had variable drug type and dosage, outcome measures and associated inner ear conditions. Most animal experiments showed promising audiological outcomes after statin treatment, demonstrated by the results of auditory brainstem response, distortion product otoacoustic emissions and inner ear histology. However, no clear effect can be discerned in human trials due to the mixed results, and heterogeneity in research methodology and quality. Audiological outcomes were not always correlated with cholesterol levels. Statins remain a potential candidate as otoprotective agents which warrant further investigation.

Incidence and predictors of significant hearing loss requiring hearing assistive devices among childhood cancer survivors: A population-based study.

10055 Background: Though hearing loss is a significant late effect among childhood cancer survivors, recent guidelines note insufficient evidence to quantify natural history or risk associated with specific exposures. We examined the long-term incidence and predictors of hearing loss requiring hearing amplification devices (HAD) using population-based healthcare data. Methods: In Ontario, Canada, HAD costs are subsidized by the provincial Assistive Devices Program (ADP). Ontario children age &lt;18 years at cancer diagnosis between 1987-2016 were identified using a pediatric cancer registry and linked to ADP claims. The cumulative incidence of HAD use was compared between cases and matched controls. Patient, disease, and treatment predictors of HAD were examined. Results: We identified 11,842 cases and 59,210 matched controls. Cases were at higher risk of HAD [hazard ratio (HR) 12.8, 95% confidence interval (95CI) 9.8-16.7; p&lt;0.001]. The cumulative incidence of HAD among survivors was 2.1% (95CI 1.7-2.5%) at 20-years and 6.4% (95CI 2.8-12.1%) at 30-years. 30-year incidence was highest in survivors of neuroblastoma (10.7%, 95CI 3.8-21.7%) and hepatoblastoma (16.2%, 95CI 8.6-26.0%). Predictors of HAD in multivariable analyses included age 0-4 years at diagnosis (vs. 5-9 years, HR 2.2, 95CI 1.4-3.3; p&lt;0.001). Relative to no cisplatin exposure, patients receiving 1-200mg/m2 were not at greater risk, unlike those receiving higher cumulative doses (Table). Relative to no radiation, those receiving ≤32Gy were at no higher risk, unlike while those receiving &gt;32Gy. Carboplatin exposure was not associated with HAD. Conclusions: Childhood cancer survivors are at elevated risk of requiring HAD which continues to rise between 20 and 30 years from diagnosis. Thresholds of cisplatin and radiation exposure exist above which risk substantially increases. Prolonged monitoring and trials of otoprotective agents are warranted in high-risk populations. [Table: see text]

Structure Characterization and Otoprotective Effects of a New Endophytic Exopolysaccharide from Saffron.

Saffron, a kind of rare medicinal herb with antioxidant, antitumor, and anti-inflammatory activities, is the dry stigma of Crocus sativus L. A new water-soluble endophytic exopolysaccharide (EPS-2) was isolated from saffron by anion exchange chromatography and gel filtration. The chemical structure was characterized by FT-IR, GC-MS, and 1D and 2D-NMR spectra, indicating that EPS-2 has a main backbone of (1→2)-linked α-d-Manp, (1→2, 4)-linked α-d-Manp, (1→4)-linked α-d-Xylp, (1→2, 3, 5)-linked β-d-Araf, (1→6)- linked α-d-Glcp with α-d-Glcp-(1→ and α-d-Galp-(1→ as sidegroups. Furthermore, EPS-2 significantly attenuated gentamicin-induced cell damage in cultured HEI-OC1 cells and increased cell survival in zebrafish model. The results suggested that EPS-2 could protect cochlear hair cells from ototoxicity exposure. This study could provide new insights for studies on the pharmacological mechanisms of endophytic exopolysaccharides from saffron as otoprotective agents

Genetic susceptibility to aminoglycoside ototoxicity

IntroductionAminoglycosides are a well-known clinically relevant antibiotic family used to treat bacterial infections in humans and animals and can produce toxic side effects. Aminoglycoside-induced hearing loss (HL) has been shown to have a genetic susceptibility. Mitochondrial DNA mutations have been implicated in inherited and acquired hearing impairment. ObjectiveLiterature review of genetic mutations associated with aminoglycoside-induced ototoxicity. MethodsPubMed was accessed from 1993 to 2017 using the search terms “aminoglycoside, genetic, ototoxicity, hearing loss”. Exclusion criteria consisted of a literature in a language other than English, uncompleted or ongoing studies, literature with non-hearing related diseases, literature on ototoxicity due to cisplatin/carboplatin based chemotherapy, literature on ototoxicity from loop diuretics, animal studies, literature studying oto-protective agents, and literature without documented aminoglycoside exposure. Results108 articles were originally identified, and 25 articles were included in our review. Mitochondrial 12S rRNA mutations were identified in all 25 studies in a total of 220 patients. Eight studies identified A1555G mutation as primary genetic factor underlying HL in cases of aminoglycoside-induced ototoxicity. The next most common mutation identified was C1494T. DiscussionMitochondrial 12s rRNA mutation A1555G was present in American, Chinese, Arab-Israeli, Spanish and Mongolian ethnicities. All mutations leading to aminoglycoside ototoxicity were mitochondrial mutations. ConclusionsConsideration of preexisting genetic defects may be valuable in treatments involving aminoglycosides. In particular populations such as those of Chinese origin, clinicians should continue to consider the increased susceptibility to aminoglycosides.

Prevention of cisplatin-induced hearing loss in children: Informing the design of future clinical trials.

Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin‐induced hearing loss (CIHL) is a common, clinically significant side effect with life‐long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Children’s Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well‐informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research.

Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity.

The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could interfere with the chemotherapeutic efficacy of the primary drugs. This is especially true for the drug cisplatin, whose anticancer actions are attenuated by antioxidants which provide adequate protection against hearing loss. Other current or potential otoprotective agents could pose a similar problem, if administered systemically. The application of various biologicals or protective agents directly to the cochlea would allow for high levels of these agents locally with limited systemic side effects. In this report, we demonstrate a trans-tympanic method of delivery of various drugs or biological reagents to the cochlea, which should enhance basic science research on the cochlea and provide a simple way of directing the use of otoprotective agents in the clinics. This report details a method of trans-tympanic drug delivery and provides examples of how this technique has been used successfully in experimental animals to treat cisplatin ototoxicity.