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Introduction: Due to the growing burden of disease in South Africa, encompassing conditions such as tuberculosis, human immunodeficiency virus, and cancer, the holistic management of affected patients incorporating ototoxicity monitoring is a necessity. However, ototoxicity monitoring in developing countries may be limited due to a lack of resources and inadequate healthcare facilities. Subsequently, the use of tele-audiology may be a revolutionary technique with the potential to provide audiology services to under-served populations with limited access. Methods: The study aimed to describe the use of tele-audiology services in ototoxicity monitoring through a scoping review of English peer-reviewed articles from June 2009 to June 2020. Seventeen articles were purposively selected from the following databases: PubMed, Science Direct, Taylor and Francis Online, WorldCat, and Google Scholar. Data was extracted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram and results were analyzed using deductive thematic analysis. Results and discussion: While a minority of the studies indicated that the cost of implementation and network connectivity within a South African context pose as barriers, most researchers reported that tele-audiology provides a reliable, time-efficient, cost-effective, and easily accessible alternative for ototoxicity monitoring. Hardware including the WAHTS, KUDUwave, and OtoID, along with software such as the TabSINT, Otocalc, uHear, and the hearTest, have proven to be useful for ototoxicity monitoring. A need for further investigations regarding the feasibility of tele-audiology implementation in South Africa is evident. Despite this, it provides audiologists with an opportunity to offer contact-less services during COVID-19, thus, confirming its versatility as an augmentative method for ototoxicity monitoring. [ABSTRACT FROM AUTHOR]

Systemic poisoning related to cobalt–chromium total hip arthroplasty can affect multiple organs. In the otolaryngologic area the most frequent symptoms are tinnitus and hearing loss. In this report, we describe 2 patients with cobalt-containing hip prostheses who presented with otologic symptoms. The first case describes a patient with an extremely high cobalt blood level, which we believe may be one of the highest reported to date, after replacing a broken ceramic-on-ceramic prosthesis with a metal-on-metal prosthesis. This patient suffered all known complications associated with cobalt poisoning and survived. The second case, a female patient with a left resurfacing metal-on-metal prothesis, presented with bilateral continuous high-pitched tinnitus that started 8 months after surgery. Orthopedic surgeons and otologists should be vigilant for cobalt-induced ototoxicity in patients with metal-on-metal total hip prostheses. [ABSTRACT FROM AUTHOR]

Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin. [ABSTRACT FROM AUTHOR]

Ferroptosis, characterized by iron‐dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin‐induced ototoxicity. Existing research has suggested that in cisplatin‐mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4‐Octyl itaconate (4‐OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti‐inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4‐OI on cisplatin‐induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI‐OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH‐DA. Real‐time PCR quantified inflammatory cytokines TNF‐α, IL‐6 and IL‐1β. Network Pharmacology and RNA sequencing (RNA‐seq) analysis of the potential mechanism of 4‐OI resistance to cisplatin‐induced ferroptosis. The expressions of ferroptosis‐related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO‐1, GCLC and NQO1) were tested by real‐time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin‐induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4‐OI exhibited anti‐inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin‐induced cell loss. In the present study, we show that 4‐OI inhibits cisplatin‐induced ferroptosis possibly through activation of the NRF2/HO‐1 signalling pathway, thereby exerting a protective effect against cisplatin‐induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin‐induced hearing loss. [ABSTRACT FROM AUTHOR]

Background: Pakistan ranks fourth among the 22 high-burden countries for multidrug-resistant tuberculosis (MDR-TB). The rising incidence of MDR-TB highlights the need for effective treatment programs, as the clinical management of MDR-TB involves prolonged multidrug regimens that frequently result in adverse events (Aes). Objective: This study aims to determine the frequency of treatment-related adverse events among patients enrolled in MDR-TB treatment. Methodology: We conducted a retrospective case series study involving patients enrolled for MDR-TB treatment from January 2014 to April 2015 at the Programmatic Management of Drug-Resistant TB (PMDT) unit of Lady Reading Hospital (LRH) in Peshawar, Pakistan. Patient data were recorded in an Electronic Nominal Record System (ENRS). Statistical analysis was performed using SPSS software, with subjective data assessed through the Chi-Square test and quantitative data analyzed using Student's t-test. Both univariate and multivariate regression models were employed to explore the relationship between medication-related adverse reactions and treatment outcomes, setting a significance threshold at p < 0.05. Results: The study included 411 MDR-TB patients undergoing treatment. Of these, 360 patients were analyzed, comprising 212 (51.6%) males and 148 (36%) females, predominantly aged between 15-44 and 45-64 years. The most frequently reported side effects were psychiatric symptoms (67%), gastrointestinal issues (58.5%), ototoxicity (49.5%), and arthralgia/arthritis (48.7%). Psychiatric symptoms affected 241 (67%) patients, with 91 (25.3%) experiencing major adverse events. In contrast, 150 (41.6%) cases of adverse events were classified as non-serious and managed through additional medications or dosage adjustments. Conclusion: Adverse events are common among MDR-TB patients treated at PMDT-LRH Peshawar. Younger patients and those with cavitary lung disease should be monitored closely for the development of adverse events to enhance patient safety and treatment efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation of drug-drug interactions that might impact ototoxicity would facilitate design of safer multidrug regimens and mitigate unsafe polypharmacy by flagging combinations that potentially cause adverse interactions for monitoring. They may also identify protective agents that antagonize ototoxic injury. Methods: To address this need, we have developed a novel workflow that we call Parallelized Evaluation of Protection and Injury for Toxicity Assessment (PEPITA), which empowers high-throughput, semi-automated quantification of ototoxicity and otoprotection in zebrafish larvae via microscopy. We used PEPITA and confocal microscopy to characterize in vivo the consequences of drug-drug interactions on ototoxic drug uptake and cellular damage of zebrafish lateral line hair cells. Results and discussion: By applying PEPITA to measure ototoxic drug interaction outcomes, we discovered antagonistic interactions between macrolide and aminoglycoside antibiotics that confer protection against aminoglycosideinduced damage to lateral line hair cells in zebrafish larvae. Co-administration of either azithromycin or erythromycin in zebrafish protected against damage from a broad panel of aminoglycosides, at least in part via inhibiting drug uptake into hair cells via a mechanism independent from hair cell mechanotransduction. Conversely, combining macrolides with aminoglycosides in bacterial inhibition assays does not show antagonism of antimicrobial efficacy. The proof-of-concept otoprotective antagonism suggests that combinatorial interventions can potentially be developed to protect against other forms of toxicity without hindering on-target drug efficacy. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors (CCS) exposed to platinum chemotherapy are at an increased risk of developing hearing loss and reporting decreased quality of life (QOL). This study compared two QOL measures; one developed for children with hearing loss, The Hearing Environments and Refection on Quality of Life (HEAR-QL), and one validated in CCS, the Patient-Reported Outcomes Measurement Information System (PROMIS), to assess their ability to evaluate QOL deficits in this population. Methods: Subject eligibility were restricted to CCS exposed to platinum-based chemotherapy but who were free of known risk factors for cognitive impairment, (non-central nervous system tumor, no cranial radiation, or intrathecal chemotherapy). Participants had to be between 8-17 years, have completed anti-cancer therapy for at least 6 months, and have an audiogram within 1 year, Participants completed the HEAR-QL-26 (7-12 years) or the HEAR-QL-28 (13-18 years) and the PROMIS. Independent samples and/or one sample T-tests were utilized to compare participants with normal hearing and hearing loss, and to compare outcome measures to normative HEAR-QL and PROMIS data. Non-parametric correlations were utilized to evaluate the relationship between QOL and demographic and medical variables, and QOL and severity of hearing loss. Results: Fifty-four CCS were evaluable. The mean age was 12.0 years. Twenty-eight participants (51.9%) received cisplatin, 30 (55.6%) carboplatin, and 4 (7.4%) received both. Twenty participants (37%) demonstrated hearing loss. Participants with hearing loss scored significantly lower on the HEAR-QL than those with normal hearing (mean: 70.3, SD: 21.7, vs mean: 88.0, SD: 9.3, p =.004 for the HEAR-QL-26; mean: 84.7, SD: 10.2 vs mean: 94.8, SD: 3.4, p =.040 for the HEARQL-28). Participants with normal hearing scored significantly lower on the HEARQL-26 than the normative mean (mean: 88, SD: 9.3, normative mean: 98, SD: 5, p =.000). The PROMIS failed to identify any differences in QOL between participants based on hearing status, or when compared to the normative mean. Conclusion: The HEAR-QL was more sensitive than the PROMIS in identifying QOL deficits in CCS at risk for hearing loss. The HEAR-QL should be considered in studies seeking to improve the QOL of CCS with hearing loss. [ABSTRACT FROM AUTHOR]

Objective: The impact of acquiring hearing loss might be exacerbated during adolescence, as this normal transition from childhood to adulthood is characterised by identity construction and social intensity. This study aimed to describe the lived experiences of South African adolescents with acquired hearing loss following aminoglycoside treatment for multidrug resistant tuberculosis. Design: The study adopted a descriptive phenomenological design and indepth, semi-structured interviews were conducted in English, isiZulu and Afrikaans. The data was managed and analysed according to a modified version of Hycner's framework. Study sample: Six participants aged 16-24 years with bilateral, mild to profound hearing loss acquired from aminoglycoside treatment were recruited from two South African provinces. Results: Three themes emerged which created a triple burden for participants. They endured socio-economic hardship encompassing limited economic and emotional support. Participants battled the consequences of life-threatening MDR-TB including illness, hospitalisation, stigma, and other challenges. Finally, participants were left with life-changing hearing loss. Conclusion: The findings indicate the necessity of holistic management of adolescents with aminoglycoside-related acquired hearing loss and serves as motivation to improve ototoxic monitoring practices and patient uptake of monitoring services and calls for the cessation, or at least cautious use, of aminoglycosides. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gentamicin is a commonly used medication in NICUs. It is known to have ototoxic & nephrotoxic side effects. To date there is no consensus about dosing regimen in different institutions. Our study aims to evaluate the Neofax® dosing regimen for gentamicin in neonatal early onset sepsis in relation to trough level before the second dose and its association with the incidence of gentamicin side effects, namely hearing impairment/loss and acute kidney injury. METHODS: Retrospective chart review of newborns admitted to Tawam hospital NICU (June 2019–May 2020) who received gentamicin for early onset sepsis (≤72 hours old). Trough levels before the second dose at 24,36 and 48 hours were reviewed (≥1 mg/L is high). Excluded patients with renal risk factors. Side effects (hearing impairment, acute renal injury) were also assessed. RESULTS: Total of 265 infants were included, among whom 149 patients received gentamicin at 24 hours interval, 99 at 36 and 17 at 48 hours interval. Trough level was high in 76% (P = 0.022), 65% (P = 0.127), and 53% (P = 0.108) of patients who received gentamicin at 24, 36, and 48 hours, respectively. Hearing screening was normal in 99.2% of patients, while 2 patients failed the test (Both with normal trough levels). No patients in our study developed renal injury related to gentamicin use. CONCLUSION: Neofax® gentamicin dosing often results in high trough levels, especially in late preterm/term infants. This study found no correlation between high trough levels and hearing impairment upon discharge or acute kidney injury. Further studies with larger sample size are recommended. [ABSTRACT FROM AUTHOR]

Purpose: Persons with cystic fibrosis (PwCF) are at high risk for ototoxicity due to the routine use of intravenous aminoglycoside (IV-AG) antibiotics in respiratory infection management. Additionally, factors that contribute to ototoxicity-related symptom development and severity in PwCF are unknown. Given the increased risk of ototoxicity in people with diabetes, we explored the association between cystic fibrosis--related diabetes (CFRD) and self-reported ototoxicity symptoms (tinnitus and vestibular problems) in PwCF treated with aminoglycosides. Method: PwCF (N = 39; 25 females, 14 males; Mage = 30.1 years, SD = 10.3) were recruited from the Cystic Fibrosis Care Center at Oregon Health & Science University. Patients completed the validated questionnaires to ascertain their experiences with ototoxicity-related symptoms of tinnitus and balance function. The diagnosis of CFRD, including oral glucose tolerance testing (OGTT), insulin treatment, hemoglobin A1c, and cumulative IV-AG treatment history, was obtained through a medical chart review. Participants were classified into three groups based on their medical diagnoses via OGTT: normal glucose tolerance (NGT; control; n = 16), abnormal glucose tolerance (AGT; n = 9), and CFRD (n = 14). Participants in each group were further classified based on survey outcomes for ototoxicity-related symptoms. Results: There was a trend toward a higher proportion of patients with CFRD reporting tinnitus compared to the AGT and NGT groups, but did not meet statistical significance (§² = 2.24, p = .13). Approximately, 43% of patients with CFRD reported experiencing clinically significant tinnitus lasting > 3 min compared to 11% in the AGT group and 13% in the NGT group (§² = 3.751, p = .05). Cumulative IV-AG exposure tended to be higher in CFRD compared to other groups. High balance function was generally reported in all groups. Conclusions: Patients with CFRD have greater ototoxicity-related symptoms. Further investigation of the relationship between CF-related comorbidities and the risk of developing ototoxicity-related symptoms is warranted to improve the detection and management of ototoxicity in PwCF. [ABSTRACT FROM AUTHOR]

Introduction: Streptomycin and kanamycin are aminoglycosides that are toxic to the cochlea vestibular system, can causing hearing loss. This antibiotic is used for the treatment of tuberculosis and its ototoxicity occurs in 20% of tuberculosis patients. Spirulina is a cyanobacterial species that is used as a dietary supplement and contains phycocyanin compounds that function as antioxidants and anti-inflammatory. The aim of this study was to determine the effect of spirulina on histopathological changes in the cochlea in Wistar rats after kanamycin induction. Methods: this study is a form of posttest-only controlled group design research with a sample of 24 wistar rats divided into 4 groups, namely negative control group, positive control group, treatment group 1 and treatment group 2. Observations of the study took place in November-December 2021. Histopathological measurements in hair cells, macrophages and cochlear vasculature. The analysis used non-parametric Kruskal-Wallis and post-hoc Mann-Whitney tests. Results: There were more hair cell damage, macrophage cell count, and significant vascular dilatation in the kanamycin group than in the without kanamycin group with the value p=0.001. There was significantly less number of hair cell damage in the kanamycin group with spirulina at a dose of 1000 mg than in the kanamycin group with spirulina at a dose of 400 mg p=0.045. Conclusion: There was a significant effect on the administration of spirulina on histopathological changes in the cochlea of rats. [ABSTRACT FROM AUTHOR]

Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the impact of polystyrene nanoplastics on auditory organs remains unknown. Here, our results showed that polystyrene nanoplastics entered the cochlea of mice, HEI-OC1 cells, and lateral line hair cells of zebrafish, causing cellular injury and increasing apoptosis. Additionally, we found that exposure to polystyrene nanoplastics resulted in a significant elevation in the auditory brainstem response thresholds, a loss of auditory sensory hair cells, stereocilia degeneration and a decrease in expression of Claudin-5 and Occludin proteins at the blood-lymphatic barrier in mice. We also observed a significant decrease in the acoustic alarm response of zebrafish after exposure to polystyrene nanoplastics. Mechanistic analysis revealed that polystyrene nanoplastics induced up-regulation of the Nrf2/HO-1 pathway, increased levels of malondialdehyde, and decreased superoxide dismutase and catalase levels in cochlea and HEI-OC1 cells. Furthermore, we observed that the expression of ferroptosis-related indicators GPX4 and SLC7A11 decreased as well as increased expression of ACLS4 in cochlea and HEI-OC1 cells. This study also revealed that polystyrene nanoplastics exposure led to increased expression of the inflammatory factors TNF-α, IL-1β and COX2 in cochlea and HEI-OC1 cells. Further research found that the cell apoptosis, ferroptosis and inflammatory reactions induced by polystyrene nanoplastics in HEI-OC1 cells was reversed through the pretreatment with N-acetylcysteine, a reactive oxygen species inhibitor. Overall, our study first discovered and systematically revealed the ototoxicity of polystyrene nanoplastics and its underlying mechanism. [ABSTRACT FROM AUTHOR]

Abstract Cisplatin is an antineoplastic medicine used in the treatment for various types of cancer. Among its side effects is ototoxicity, which may result in a bilateral and irreversible hearing loss. The ototoxic effect in the pediatric population has a bigger impact as it compromises language acquisition. The discovery of drugs with otoprotective effects and the optimal way to administer them have become significant challenges in minimizing the impact of cisplatin regarding auditory function. The objective was to understand otoprotective drugs and their relevance in the preventive treatment to cisplatin-induced ototoxicity in childhood. An integrative review was conducted by consulting databases including PubMed, Bireme, MedLine, LILACS, SciELO, and ClinicalTrials.gov. The search strategy was performed by crossing descriptors (DeCS and MeSH) and free terms. Studies published in English, Spanish, and Portuguese were selected, with no publication year restrictions. Subsequently, articles were selected according to inclusion and exclusion criteria. A total of 736 articles were found in PubMed, 431 in Bireme, 425 in MedLine, 6 in LILACS, 0 in SciELO, and 4 in ClinicalTrials.gov. After document analysis, 12 articles were selected for full analysis. Evidence was found for 8 substances with potential otoprotective effects when used with cisplatin, which tend to minimize the impact of cisplatin regarding auditory function. The substances found were: Amifostine, Dexamethasone, Genistein, Ginkgo Biloba, Lycopene, N-acetylcysteine, Polydatin also Sodium Thiosulfate. In general, these drugs are applied before, during, or after cisplatin infusion, depending on the chosen drug, via intravenous, oral, or transtympanic injections, acting as antioxidant therapy. The biochemical effects of these substances are relevant to their potential otoprotective properties, including the inactivation of oxygen free radicals and electrophilic platinum species. The use of these substances can reduce ototoxicity, decreasing cisplatin-induced hearing loss and improving the confort of life, especially for children.

BackgroundAminoglycosides, such as Streptomycin, are cheap, potent antibiotics widely used Sub-Saharan Africa. However, aminoglycosides are the commonest cause of ototoxicity. The limited prospective epidemiological studies on aminoglycoside ototoxicity from Sub-Saharan Africa motivated this study to provide epidemiological information on Streptomycin-induced ototoxicity, identify risk factors and predictors of ototoxicity.MethodA longitudinal study of 153 adults receiving Streptomycin-based anti-tuberculous drugs was done. All participants underwent extended frequency audiometry and had normal hearing thresholds at baseline. Hearing thresholds were assessed weekly for 2 months, then monthly for the subsequent 6 months. Ototoxicity was determined using the ASHA criteria. Descriptive statistics were used to analyze socio-demographic variables. Ototoxicity incidence rate was calculated, and Kaplan–Meier estimate used to determine cumulative probability of ototoxicity. Chi-square test was done to determine parameters associated with ototoxicity and Cox regression models were used to choose the predictors of ototoxicity.ResultsAge of participants was 41.43 ± 12.66 years, with a male-to-female ratio of 1:0.6. Ototoxicity was found in 34.6% of the participants, giving an incidence of 17.26 per 1,000-person-week. The mean onset time to ototoxicity was 28.0 ± 0.47 weeks. By 28th week, risk of developing ototoxicity for respondents below 40 years of age was 0.29, and for those above 40 years was 0.77. At the end of the follow-up period, the overall probability of developing ototoxicity in the study population was 0.74. A significant difference in onset of ototoxicity was found between the age groups: the longest onset was seen in

Abstract Objectives Cisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin‐induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug‐induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin‐induced Schwann cell injury and investigates the ability of the antioxidant N‐acetylcysteine to promote Schwann cell viability. A local delivery system of drug‐eluting microparticles was then fabricated, characterized, and investigated for bioactivity. Methods RSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC50). In subsequent experiments, RSC96 cells were co‐treated with cisplatin and both resuspended or eluted N‐acetylcysteine. Cell viability was assessed with the CCK8 assay. Results The LC50 dose of cisplatin was determined to be 3.76 μM (p = 2.2 x 10−16). When co‐dosed with cisplatin and a therapeutic concentration of resuspended or eluted N‐acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone. Conclusion RSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N‐acetylcysteine improved cell viability and mitigated this injury. N‐acetylcysteine was packaged into microparticles and eluted N‐acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin‐induced ototoxicity. Level of Evidence N/A Laryngoscope, 2023.

Substance abuse is a rare but known cause of sensorineural hearing loss (SNHL). We report a case of acute SNHL in a 28-year-old man following an overdose of methamphetamine and incidental ingestion of fentanyl. On initial encounter, he had moderate-to-severe hearing loss in the right ear and severe-to-profound hearing loss in the left ear in addition to acute kidney injury, liver failure, and lactic acidosis. The patient was treated with a two-week course of high-dose steroids and expressed a subjective improvement in hearing. This case highlights the importance of auditory testing following a drug overdose and is one of the only documented cases of hearing loss following methamphetamine use in recent years. There is a paucity of literature regarding the mechanism causing acute SNHL secondary to methamphetamines. Proposed etiologies include neurotransmitter depletion or reduced cochlear blood flow as possible causes of ototoxicity. [ABSTRACT FROM AUTHOR]

Ototoxicity refers to the adverse effects of substances on auditory or vestibular functions. This study examines the evidence of ototoxicity’s association with exposure to common environmental pollutants, as documented in toxicological profiles by the Agency for Toxic Substances and Disease Registry. Our aim was to evaluate whether the evidence supports modifying the charting of ototoxic effects in the summary tables of these toxicological profiles and providing a guide for scientists to access these data. Health outcomes of interest included hearing loss, vestibular effects, cochlear lesions, tonal alterations, cellular damage, and ototoxicity-related outcomes (neurological, nephrotoxic, hepatic, and developmental effects). We obtained ototoxicity information for 62 substances. Hearing-related effects were reported, along with neurological effects. Overall, 26 profiles reported strong evidence of ototoxicity, including 13 substances previously designated as ototoxic by other health and safety agencies. Commonly studied outcomes included hearing loss, damage to ear anatomy, and auditory dysfunction. Vestibular dysfunction and tinnitus are rarely studied. Our findings highlight the lack of conclusive evidence of ototoxic properties for many substances, especially for pesticides and herbicides. This review supports charting the evidence of ototoxicity separately in toxicological profiles’ summary tables. Improving the communication of ototoxicity-related health effects might impact their recognition and prompt further research. A stronger evidence base could support improved prevention efforts in terms of serious health outcomes.

AIM: To study whether glycyrrhizic acid (GL) can resist the ototoxicity of cisplatin( CDDP) in mice and its molecular mechanism. METHODS： Male C57BL/6J mice were divided into 5 groups： control group, DMSO(5%) group, CDDP(4 mg/kg) group, CDDP+low-dose(50 mg/kg) GL group, and CDDP+high-dose(100 mg/kg) GL group(n=14) . Auditory brainstem response(ABR) was used to detect hearing changes of mice. HE staining was used to observe the morphological change of cochlear stria vascular in mice. Evans blue(EB) staining was used to observe the per meability change of the blood-labyrinth barrier (BLB) . Immunohistochemical technique was used to detect the expression and distribution of adhesion protein VE-cadherin and tight junction protein ZO-1 on the cochlear stria. ELISA assay and immunofluorescence technology were employed to detect the expression of tumor necrosis factor-α( TNF-α) and interleu kin-1β( 1L-1β) . RESULTS： In CDDP group, ABR waveforms of all frequencies were disturbed, the hearing threshold was significantly increased, and I wave latency was prolonged (P<0. 05) . In CDDP+GL group, ABR waveforms of various frequencies were well differentiated, the hearing threshold was significantly decreased, and the latency of I-wave was shortened(P<0. 01) . The disordered morphology and more vacuoles in the stria vascularis were observed by HE staining in CDDP group. The GL alleviated CDDP-induced damage in the stria vascularis. In EB staining, CDDP caused an increase in per meability of BLB(P<0. 01), which was improved by GL treatment (P<0. 01) . Immunohistochemical results showed that the expression of VE-cadherin and ZO-1 in CDDP group were decreased (P<0. 01), which was restored in CDDP+GL group(P<0. 01) . The ELISA and immunofluorescence results showed that the expression of IL-1β and TNF-α was increased after CDDP treatment(P<0. 01), which was restored in CDDP+GL group(P<0. 01) . CONCLUSION: The GL alleviates CDDP-induced hearing loss in mice by inhibiting CDDP-induced inflammation and reducing the permeability of BLB. [ABSTRACT FROM AUTHOR]

Aim: Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown. Methods: Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK‐8 assay was conducted for assessing cell viability in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin‐treated neonatal mouse cochlear explants, while TUJ‐1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase‐3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K‐AKT signaling effectors. Results: Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin‐treated HEI‐OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin‐induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase‐3 and activated PI3K‐AKT signaling in cisplatin‐injured HEI‐OC1 cells. Conclusion: CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin‐associated hearing loss. [ABSTRACT FROM AUTHOR]

Purpose: Ototoxic medications and chemical agents in the workplace can put individuals' hearing and vestibular health at risk for permanent injury. Proactive ototoxicity management (OtoM) strategies aim to minimize exposure, avoid onset of symptoms, provide ongoing monitoring, and manage auditory and vestibular changes as the clinical needs of the patient evolve. During a 2021 American Speech-Language-Hearing Association Special Interest Groups Open House, members of the International Ototoxicity Management Group discussed how best to integrate OtoM into routine clinical practice, what tools to use, and what special considerations need to be understood to best support patients and their families. Here, we have summarized their viewpoints to encourage widespread adoption of improved OtoM services for at-risk individuals. Conclusions: The field of audiology needs to move to a place where we better understand the full extent of ototoxicity and can agree on expanding minimum guidelines that can be implemented more universally to mitigate, detect, and manage the damage from ototoxic exposures. Only recently has our field seen a therapeutic drug that can protect against ototoxicity; however, the population served is restricted only to children receiving treatment for nonmetastatic carcinoma. This is hopefully just the beginning of future therapeutic interventions to come, but, in the meantime, ototoxicity resulting from other medications in different patient populations and chemical agents persists. [ABSTRACT FROM AUTHOR]

Gentamicin (GM) is one of the commonly used antibiotics in the aminoglycoside class but is ototoxic, which constantly impacts the quality of human life. Pyrroloquinoline quinone (PQQ) as a redox cofactor produced by bacteria was found in soil and foods that exert an antioxidant and redox modulator. It is well documented that the PQQ can alleviate inflammatory responses and cytotoxicity. However, our understanding of PQQ in ototoxicity remains unclear. We reported that PQQ could protect against GM‐induced ototoxicity in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells in vitro. To evaluate reactive oxygen species (ROS) production and mitochondrial function, ROS and JC‐1 staining, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) measurements in living cells, mitochondrial dynamics analysis was performed. GM‐mediated damage was performed by reducing the production of ROS and inhibiting mitochondria biogenesis and dynamics. PQQ ameliorated the cellular oxidative stress and recovered mitochondrial membrane potential, facilitating the recovery of mitochondrial biogenesis and dynamics. Our in vitro findings improve our understanding of the GM‐induced ototoxicity with therapeutic implications for PQQ. Gentamicin (GM), a commonly used antibiotic, is often associated with ototoxicity. PQQ exhibits neuroprotective, cardiovascular, and anti‐tumor effects as potent antioxidants. We found that PQQ protected HEI‐OC1 cells in vitro from gentamicin‐induced ototoxicity. Additionally, PQQ enhanced mitochondrial depolarization and reduced ROS levels while preventing the decline of mitochondrial basal respiration and respiratory capacity, thereby improving mitochondrial dynamic impairments. Our in vitro findings enhance our understanding of the ototoxicity caused by genetically modified organisms and have potential therapeutic implications for PQQ. [ABSTRACT FROM AUTHOR]

It is widely recognized that platinum‐based chemotherapy, particularly cisplatin therapy, can cause ototoxicity. At present, there are no Food and Drug Administration‐approved drugs to prevent or alleviate ototoxicity. Ototoxicity is generally believed to be caused by excessive reactive oxygen species production in the inner ear. Accordingly, a variety of antioxidants have been developed to protect against ototoxicity. To improve the efficiency of drug delivery to the cochlea, here, we synthesized simple and easy‐to‐obtain glutathione carbon dots (GSH CDs) with ultra‐small dimensions. The experimental results revealed that the GSH CDs have strong free‐radical scavenging activity and can restore mitochondrial function, maintain hair cell stability, and protect hair cells from cisplatin‐induced oxidative stress. Thus, GSH CDs may serve as a new therapeutic agent for preventing cisplatin‐induced ototoxicity. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) were formerly known as mere byproducts of metabolism with damaging effects on cellular structures. The discovery and description of NADPH oxidases (Nox) as a whole enzyme family that only produce this harmful group of molecules was surprising. After intensive research, seven Nox isoforms were discovered, described and extensively studied. Among them, the NADPH oxidase 3 is the perhaps most underrated Nox isoform, since it was firstly discovered in the inner ear. This stigma of Nox3 as "being only expressed in the inner ear" was also used by me several times. Therefore, the question arose whether this sentence is still valid or even usable. To this end, this review solely focuses on Nox3 and summarizes its discovery, the structural components, the activating and regulating factors, the expression in cells, tissues and organs, as well as the beneficial and detrimental effects of Nox3-mediated ROS production on body functions. Furthermore, the involvement of Nox3-derived ROS in diseases progression and, accordingly, as a potential target for disease treatment, will be discussed. [ABSTRACT FROM AUTHOR]

Aminoglycosides are commonly used for the treatment of life-threatening bacterial infections, however, aminoglycosides may cause irreversible hearing loss with a long-term clinical therapy. The mechanism and prevention of the ototoxicity of aminoglycosides are still limited although amounts of studies explored widely. Specifically, advancements in programmed cell death (PCD) provide more new perspectives. This review summarizes the general signal pathways in programmed cell death, including apoptosis, autophagy, and ferroptosis, as well as the mechanisms of aminoglycoside-induced ototoxicity. Additionally, novel interventions, especially gene therapy strategies, are also investigated for the prevention or treatment of aminoglycoside-induced hearing loss with prospective clinical applications. [ABSTRACT FROM AUTHOR]

Our study investigated the embryo-ototoxic effects of deodorant2 (DA2) on zebrafish embryos, which serve as valuable model organisms due to genetic and physiological similarities to humans. We focused on understanding DA2's impact on zebrafish hair cells, which are vital for sensory perception and balance regulation. DA2, provided by the Ministry of Environment, Republic of Korea, was used at 460 μg/mL in dimethyl sulfoxide (DMSO), with a 0.43% DMSO solvent control group. Three experiments, each using 10 zebrafish specimens from each group, showed an initial 13% hair cell count reduction in the DA2-exposed group. Subsequent experiments demonstrated reductions of 37% and 22%, each with one mortality case. Statistical analysis revealed a significant 24% hair cell count reduction in the DA2-exposed group. We also assessed DA2's impact on zebrafish behavior. Although not statistically significant, differences in distances traveled (0.33–0.39, 95% confidence interval: −0.46–1.1, p = 0.2033) and latencies (−0.016–0.018, 95% confidence interval: −0.052–0.021, p = 0.1917) hinted at negative effects. These results highlight DA2's ototoxic properties affecting zebrafish auditory systems and behavior. Further investigation into DA2's effects on aquatic organisms and potential mitigation strategies are essential. These findings contribute to understanding DA2's safety profile, benefiting aquatic ecosystems and human health assessments. [ABSTRACT FROM AUTHOR]

Exposure to loud noise or chemical agents may cause hearing disorders such as tinnitus and recruitment, known as an increase in the perception of loudness in addition to hearing loss. Our study aims to evaluate the hearing abilities of hairdressers exposed to noise and chemical agents in the working environment. The study included one hundred hairdressers and one hundred participants who do not work as hairdressers or are nonworkers. The participants' demographic characteristics, working conditions, and auditory complaints were questioned, and each participant completed the Speech, Spatial, and Qualities of Hearing Scale (SSQ). A statistically significant difference was found between the two groups in speech perception, spatial perception, hearing quality, and general SSQ scores. Hairdressers' SSQ scores were significantly lower in all sub-dimensions and general scale scores (p < 0.001). The auditory complaints of the hairdressers and the low SSQ scores indicate that exposure to noise and chemical agents affects the hairdressers' hearing system. [ABSTRACT FROM AUTHOR]

• In the cochlea, sound detection highly relies on the extracellular matrix (ECM) integrity, and hereditary deafness in humans is caused by mutations in numerous ECM-related genes. • Cochlear matrisome plays an active role during the development of the hearing organ and the establishment of its unique architecture. • Cochlear matrisome changes with ageing and in response to cochlear insults, such as noise exposure, ototoxic drug administration and insertion of cochlear implants. • ECM remodeling exerts protective functions or improves tissue repair after injury but may also exacerbate cochlear damage. Deciphering the role of individual ECM components and regulators might provide valuable therapeutic targets for hearing preservation. The extracellular matrix (ECM) consists in a complex meshwork of collagens, glycoproteins, and proteoglycans, which serves a scaffolding function and provides viscoelastic properties to the tissues. ECM acts as a biomechanical support, and actively participates in cell signaling to induce tissular changes in response to environmental forces and soluble cues. Given the remarkable complexity of the inner ear architecture, its exquisite structure-function relationship, and the importance of vibration-induced stimulation of its sensory cells, ECM is instrumental to hearing. Many factors of the matrisome are involved in cochlea development, function and maintenance, as evidenced by the variety of ECM proteins associated with hereditary deafness. This review describes the structural and functional ECM components in the auditory organ and how they are modulated over time and following injury. [ABSTRACT FROM AUTHOR]

To better characterize the frequency and patterns of hearing dysfunction in patients who have received teprotumumab to treat thyroid eye disease. Noncomparative case series. Patients who underwent audiology testing before and after completion of teprotumumab infusions. A review of patients who underwent audiology testing before and after completion of teprotumumab infusions was carried out. Additional audiogram testing during treatment was included when available. Hearing function was analyzed using audiogram data measuring threshold hearing levels at specific frequencies. Basic demographic data as well as information regarding otologic symptoms also were obtained and analyzed. Hearing loss demonstrated by a significant change in decibel hearing thresholds or that meets criteria for ototoxicity. Twenty-two patients (44 ears) were included in the study, with baseline and most recent audiology testing after treatment ranging from 84 days before to 496 days after treatment. Fifteen patients (30 ears) also underwent testing during treatment starting after the second infusion up until the day of, but before, the eighth infusion. Hearing loss after treatment met criteria for ototoxicity in 17 of the 44 ears (38.6%), with 11 of the 22 patients (50.0%) meeting criteria in at least 1 ear. The pure-tone average decibel hearing levels (HLs) across all 44 ears demonstrated hearing loss after treatment (P = 0.0029), specifically at high (P = 0.0008) and middle frequencies (P = 0.0042), but not at low frequencies (P = 0.8344). Patients who were older also were more likely to experience hearing loss after treatment (P = 0.0048). Audiometric data demonstrate that teprotumumab influences hearing function, most significantly at higher frequencies and in older patients. Audiometric testing is critical for counseling patients regarding teprotumumab treatment. A protocol for monitoring hearing during treatment is needed to detect and manage hearing changes associated with teprotumumab use. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Each year over half a million people experience permanent hearing loss caused by treatment with therapeutic drugs with ototoxic side effects. There is a major unmet clinical need for therapies that protect against this hearing loss without reducing the therapeutic efficacy of these lifesaving drugs. At least 17 clinical trials evaluating 10 therapeutics are currently underway for therapies aimed at preventing aminoglycoside- and/or cisplatin-induced ototoxicity. This review describes the preclinical and clinical development of each of these approaches, provides updates on the status of ongoing trials, and highlights the importance of appropriate outcome measures in trial design and the value of reporting criteria in the dissemination of results. [ABSTRACT FROM AUTHOR]

Objectives: Ototoxicity is a common disabling side effect of platinum‐based chemotherapy. This study aimed to assess the evidence on the management of platinum‐induced ototoxicity in adult cancer patients. Methods: Four databases were searched up to 1 November 2022. Original studies were included if they reported on a pharmacologic or non‐pharmacologic intervention to prevent or treat platinum ototoxicity in adults. The articles' quality was assessed via two grading scales. Results: Nineteen randomised controlled trials and five quasi‐experimental studies with 1673 patients were analysed. Eleven interventions were identified, nine pharmacological and two non‐pharmacological. Six of the interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins and D‐methionine) showed mild benefits in preventing cisplatin‐induced ototoxicity. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed with a low risk of bias. The majority of studies inadequately documented intervention‐related adverse effects, thereby limiting safety conclusions. Conclusions: Current interventions have mild benefits in preventing cisplatin‐induced ototoxicity in adult cancer patients. Sodium thiosulphate is the most promising intervention as a preventive strategy. Rigorous, high‐quality research is warranted, encompassing an evaluation of all potential symptoms and innovative treatment modalities. [ABSTRACT FROM AUTHOR]

Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA 32 -HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway. Synthesis and schematic illustration of RHD gel for radiation-induced ototoxicity. (A) Schematic diagram of the synthesis of RHD gel. (B) Intratympanic injections of RHD gel. (C) Schematic diagram of animal experimentation. (D) Schematic diagram of RHD gel regulating ROS/mTOR signaling pathway for protecting against radiation-induced hearing loss. [Display omitted] • Intratympanic injection of hydrogel is a safe and effective way to deliver drugs. • RHD peptide gel may affect the mTOR pathway by decreasing ROS levels, protecting against radiation-induced ototoxicity. • RHD gel demonstrates biocompatibility and does not compromise the anti-tumor efficacy of radiotherapy. [ABSTRACT FROM AUTHOR]

The Kir4.1 channel, an inwardly rectifying potassium ion (K+) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K+ homeostasis in supporting cells, with K+ concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient. [ABSTRACT FROM AUTHOR]

Background: High‐dose carboplatin is an essential part of curative high‐dose chemotherapy (HDCT) for patients with previously treated germ cell tumors (GCTs). Although hearing loss (HL) is a known side effect of HDCT, data on its severity and characteristics are limited. Methods: Eligible patients received HDCT for GCTs from 1993 to 2017 and had audiograms before and after HDCT. HL severity was classified by American Speech‐Language‐Hearing Association criteria, and mean change in hearing threshold at each frequency (0.25–8 kHz) was estimated from pre‐ to post‐HDCT and between HDCT cycles. Results: Of 115 patients (median age, 32 years), 102 (89%) received three cycles of HDCT. Of 106 patients with normal hearing to mild HL in the speech frequencies (0.5–4 kHz) before HDCT, 70 (66%) developed moderate to profound HL in the speech frequencies after HDCT. Twenty‐five patients (22%) were recommended for hearing aids after HDCT. Patients with moderate to profound HL isolated to the higher frequencies (6–8 kHz) before HDCT were more likely to develop moderate to profound HL in the speech frequencies after HDCT (94% vs. 61%; p =.01) and to be recommended for hearing aids (39% vs. 18%; p =.05). Conclusions: HL was frequent after HDCT for GCTs, with most patients developing at least moderate HL in the speech frequencies and approximately one in five recommended for hearing aids. Moderate to profound HL isolated to high frequencies at baseline was predictive of more clinically significant hearing impairment after HDCT. Plain Language Summary: Some patients with germ cell tumors, the most common malignancy in adolescent and young adult men, are not cured with standard‐dose chemotherapy and require high‐dose chemotherapy (HDCT).Using detailed hearing assessments of patients receiving HDCT, we found that most patients developed significant hearing loss and that one in five needed hearing aids.Thus, strategies to reduce this side effect are urgently needed, and all patients receiving HDCT should have a hearing test after therapy. High‐dose carboplatin for relapsed or refractory germ cell tumors has a profound impact on patients' hearing. Strategies to reduce this ototoxicity are urgently needed, and management of patients receiving high‐dose carboplatin should include routine posttreatment audiometric assessment. [ABSTRACT FROM AUTHOR]

Cisplatin is a chemotherapeutic drug for the treatment of several solid tumors, whose use is limited by its nephrotoxicity, neurotoxicity, ototoxicity, and development of resistance. The toxicity is caused by DNA cross-linking, increase in reactive oxygen species and/or depletion of cell antioxidant defenses. The aim of the work was to study the effect of antioxidant compounds (Lisosan G, Taurisolo®) or hydrogen sulfide (H2S)-releasing compounds (erucin) in the auditory HEI-OC1 cell line treated with cisplatin. Cell viability was determined using the MTT assay. Caspase and sphingomyelinase activities were measured by fluorometric and colorimetric methods, respectively. Expression of transcription factors, apoptosis hallmarks and genes codifying for antioxidant response proteins were measured by Western blot and/or RT-qPCR. Lisosan G, Taurisolo® and erucin did not show protective effects. Sodium hydrosulfide (NaHS), a donor of H2S, increased the viability of cisplatin-treated cells and the transcription of heme oxygenase 1, superoxide dismutase 2, NAD(P)H quinone dehydrogenase type 1 and the catalytic subunit of glutamate-cysteine ligase and decreased reactive oxygen species (ROS), the Bax/Bcl2 ratio, caspase-3, caspase-8 and acid sphingomyelinase activity. Therefore, NaHS might counteract the cytotoxic effect of cisplatin by increasing the antioxidant response and by reducing ROS levels and caspase and acid sphingomyelinase activity. [ABSTRACT FROM AUTHOR]

Introduction: Aminoglycoside antibiotics such as gentamicin are bactericidal and effective against gram negative organisms and act synergistically against gram positive organisms, including S taphylococcus aureus. However, they have serious adverse effects such as nephrotoxicity and ototoxicity. Gentamicin ototoxicity may occur after a single dose and results in decreased vestibular function, which is frequently debilitating and often permanent. Objective: To emphasize the risk of gentamicin ototoxicity and suggest alternative antibiotics in penicillin-allergic patients undergoing surgery. Case Summary: We present a case of a woman with preexisting Meniere's Disease who received gentamicin 400 mg perioperatively for a sigmoidectomy due to a penicillin allergy listed in the patient's medical record. The patient developed severe ototoxicity preventing her from working or driving. Physical examination was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades. Vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior. Discussion: Gentamicin is indicated for surgical prophylaxis when a patient has a true allergy to penicillins and cannot receive cephalosporins, though alternatives exist. True allergies include IgE-mediated illness (anaphylaxis, bronchospasm, or urticaria 30-60 minutes after administration) or exfoliative reactions (Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis). The authors encourage more prudent use of gentamicin, especially in patients susceptible for debilitating otologic insults, and offer recommendations for alternative agents prior to using gentamicin. [ABSTRACT FROM AUTHOR]

Background and Aims: Cisplatin is currently one of the most widely used anticancer drugs in the world. However, its clinical usefulness has frequently been limited by severe side effects, such as nephrotoxicity, ototoxicity and neurotoxicity. Therefore, platinum(II) oxalato complexes with substitute imidazole or benzimidazole carrier ligands were synthesized and their cytotoxic effects were investigated against non-small cell lung cancer (H1299) and human colon adenocarcinoma (CaCo-2), and mouse fibroblast cells lines (L929). Methods: Four platinum(II) complexes, [Pt(L1-L4)2(oxalate)] were synthesized and characterized by FT-IR, 1H NMR and elemental analyses. The MTT method was used to determine the potential antiproliferative effect of synthesized platinum(II) complexes and positive controls. Results: In this study, the cytotoxic activity of platinum(II) complexes against tested cell lines was assessed, with moderate IC50 values. According to IC50 values, Complex 5 with 2-ethylbenzimidazole ligand was found to be the most active complex against H1299 and CaCo-2 cell lines. In general, the compounds are also promising drug candidates for H1299 cell lines with very low activity against the CaCo-2 cell lines. Conclusion: Further modification and development of Complex 4 and 5 derivatives and in vitro cytotoxic activity studies against different cancer cell lines may lead to the emergence of new anticancer agents in the near future. [ABSTRACT FROM AUTHOR]

Cisplatin-based therapies are standard-of-care for advanced-stage head and neck squamous cell carcinoma (HNSCC). Treatment regimens include 3 weeks of high-dose bolus cisplatin or 6–7 weeks of low-dose weekly cisplatin, both with concurrent radiation. The effects of cisplatin dosage on swallowing function warrant further study. A 237-patient cohort treated for HNSCC at a single center were studied retrospectively. Gastrostomy tube dependence served as the primary endpoint. Secondary endpoints included weight changes, esophageal stricture, and lymphedema. The primary/secondary outcomes were not statistically significant; however, ototoxicity and renal toxicity were significantly higher in the high-dose group. These findings add insight into cisplatin dose-based functional outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICIs) are related to various immune-related adverse events (irAEs). However, the knowledge is limited with rare irAEs like hearing loss. Therefore, we evaluated the characteristics, presentation, and treatment of ICI-related hearing loss by reviewing the individual patient data from the previous studies. Methods: We conducted a systematic search of the Web of Science, PubMed, and Embase databases for studies published until 17 November 2022. The selected MeSH search terms were “hearing loss” OR “hearing impairment” OR “ototoxicity” OR “vestibular toxicity” OR “audiovestibular toxicity” AND “immune checkpoint inhibitor” OR “immunotherapy.” Results: A total of 38 patients were included. Melanoma was the most frequent diagnosis (73.7%). The median time from ICI initiation to hearing loss development was 3 months. The hearing impairment was secondary to bilateral sensorineural hearing loss (SNHL) in 24 (68.6%) patients, and at least one other irAE accompanied the hearing loss in 24 patients. Hearing loss significantly improved in 45.7% of the patients. The overall response rate and disease control rate were 67.6% and 85.3%, respectively. Conclusion: We observed that most cases of ICI-related hearing loss were reversible, observed in patients with melanoma, accompanied by other irAEs, and associated with a high response rate to ICIs. With the expanded use of ICIs in the earlier treatment lines and adjuvant settings, the number of survivors with ICI-related hearing loss is expected to increase. Further research is needed to define the true prevalence of ICI-related hearing loss, optimal diagnosis, and management. [ABSTRACT FROM AUTHOR]

Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3–5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 μM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity. [ABSTRACT FROM AUTHOR]

Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field – required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use – ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.

Introduction/Justification: Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy worldwide, with substantial morbidity and mortality. Cisplatin-based chemoradiotherapy is a standard treatment modality for most HNSCC patients, but it is associated with significant adverse effects, including ototoxicity. Glutathione S-transferase pi 1 (GSTP1) is a gene involved in the detoxification of cisplatin, and single nucleotide variants as GSTP1 c.313 A>G have been linked to differential susceptibility to ototoxicity in HNSCC patients under therapy. It is unknown, however, if genotyping selection could improve patient outcomes and reduce treatment costs. Objectives: This study aims to investigate the potential cost reduction of GSTP1 c.313 A>G genotyping in identifying HNSCC patients at risk of cisplatin-induced ototoxicity, with the goal of optimizing therapeutic decision-making and reducing the economic burden associated with audiological support interventions (ASIs). Materials and Methods: A decision analytic model was designed, where patients with low-risk genotypes (GSTP1 c.313 AA) would receive cisplatin, while those with high-risk (GSTP1 c.313 AG/GG) would hypothetically receive docetaxel. Transitional probabilities were then calculated using Metropolis-Hastings algorithm. Costs included genotyping, therapy, and ASIs provision. A probabilistic Markov model was developed to simulate the clinical and economic outcomes associated with GSTP1 genotyping in HNSCC patients receiving cisplatin-based chemoradiotherapy. Transition probabilities, treatment costs, and the probabilities of adverse events were incorporated into the model over a ten-year time horizon. Sensitivity analyses were conducted to assess the robustness of the results. Results: The median total cost per patient in the conventional arm was R$ 2,025.05 (credibility interval R$ 1,975.58 to R$ 2,047.75). Simulation results indicated that implementing genotyping could result in significant cost reductions in the first year, with savings ranging from R$ 92.53 to R$140.06 per patient, depending on the number of simultaneous genotyping tests performed (in this case, 3 and 5 samples, respectively). Over a ten-year period, cumulative cost savings of R$75,689.10 were projected for 250 patients, primarily attributed to decreased expenditures on ASIs and audiological support services. Conclusion: The analysis demonstrated that GSTP1 c.313 A>G genotyping has the potential to yield cost savings in the management of cisplatin-induced ototoxicity in HNSCC patients. Genotyping for GSTP1 polymorphisms represents a promising approach to identify HNSCC patients at increased risk of cisplatin-induced ototoxicity, allowing for personalized treatment strategies. These findings highlight the importance of integrating pharmacogenetic testing into clinical practice to enhance patient outcomes and healthcare resource utilization. Further research and implementation efforts are warranted to validate this strategy in routine HNSCC management.

Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs). Despite various strategies to combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed a gene therapy concept to protect cochlear cells from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used to ectopically express various antioxidant enzymes or anti-apoptotic proteins to enhance the cellular ROS scavenging or prevent apoptosis in affected cell types. In direct comparison, anti-apoptotic proteins mediated a stronger reduction in cytotoxicity than antioxidant enzymes. Importantly, overexpression of the most promising candidate, Bcl-xl, achieved an up to 2.5-fold reduction in cisplatin-induced cytotoxicity in HEI-OC1 cells, phoenix auditory neurons, and primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction in cochlear explants. Strikingly, in vivo application of the LV BCL-XL vector improved hearing and increased HC survival in cisplatin-treated mice. In conclusion, we have established a preclinical gene therapy approach to protect mice from cisplatin-induced ototoxicity that has the potential to be translated to clinical use in cancer patients.

Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin.

Introduction: Ototoxicity is a debilitating side effect of over 150 medications with diverse mechanisms of action, many of which could be taken concurrently to treat multiple conditions. Approaches for preclinical evaluation of drug-drug interactions that might impact ototoxicity would facilitate design of safer multi-drug regimens and mitigate unsafe polypharmacy by flagging combinations that potentially cause adverse interactions for monitoring. They may also identify protective agents that antagonize ototoxic injury.Methods: To address this need, we have developed a novel workflow that we call Parallelized Evaluation of Protection and Injury for Toxicity Assessment (PEPITA), which empowers high-throughput, semi-automated quantification of ototoxicity and otoprotection in zebrafish larvae via microscopy. We used PEPITA and confocal microscopy to characterize in vivo the consequences of drug-drug interactions on ototoxic drug uptake and cellular damage of zebrafish lateral line hair cells.Results and discussion: By applying PEPITA to measure ototoxic drug interaction outcomes, we discovered antagonistic interactions between macrolide and aminoglycoside antibiotics that confer protection against aminoglycoside-induced damage to lateral line hair cells in zebrafish larvae. Co-administration of either azithromycin or erythromycin in zebrafish protected against damage from a broad panel of aminoglycosides, at least in part via inhibiting drug uptake into hair cells via a mechanism independent from hair cell mechanotransduction. Conversely, combining macrolides with aminoglycosides in bacterial inhibition assays does not show antagonism of antimicrobial efficacy. The proof-of-concept otoprotective antagonism suggests that combinatorial interventions can potentially be developed to protect against other forms of toxicity without hindering on-target drug efficacy.

BackgroundChildhood cancer survivors (CCS) exposed to platinum chemotherapy are at an increased risk of developing hearing loss and reporting decreased quality of life (QOL). This study compared two QOL measures; one developed for children with hearing loss, The Hearing Environments and Refection on Quality of Life (HEAR-QL), and one validated in CCS, the Patient-Reported Outcomes Measurement Information System (PROMIS), to assess their ability to evaluate QOL deficits in this population.MethodsSubject eligibility were restricted to CCS exposed to platinum-based chemotherapy but who were free of known risk factors for cognitive impairment, (non-central nervous system tumor, no cranial radiation, or intrathecal chemotherapy). Participants had to be between 8-17 years, have completed anti-cancer therapy for at least 6 months, and have an audiogram within 1 year, Participants completed the HEAR-QL-26 (7-12 years) or the HEAR-QL-28 (13-18 years) and the PROMIS. Independent samples and/or one sample T-tests were utilized to compare participants with normal hearing and hearing loss, and to compare outcome measures to normative HEAR-QL and PROMIS data. Non-parametric correlations were utilized to evaluate the relationship between QOL and demographic and medical variables, and QOL and severity of hearing loss.ResultsFifty-four CCS were evaluable. The mean age was 12.0 years. Twenty-eight participants (51.9%) received cisplatin, 30 (55.6%) carboplatin, and 4 (7.4%) received both. Twenty participants (37%) demonstrated hearing loss. Participants with hearing loss scored significantly lower on the HEAR-QL than those with normal hearing (mean: 70.3, SD: 21.7, vs mean: 88.0, SD: 9.3, p =.004 for the HEAR-QL-26; mean: 84.7, SD: 10.2 vs mean: 94.8, SD: 3.4, p =.040 for the HEAR-QL-28). Participants with normal hearing scored significantly lower on the HEAR-QL-26 than the normative mean (mean: 88, SD: 9.3, normative mean: 98, SD: 5, p =.000). The PROMIS failed to identify any differences in QOL between participants based on hearing status, or when compared to the normative mean.ConclusionThe HEAR-QL was more sensitive than the PROMIS in identifying QOL deficits in CCS at risk for hearing loss. The HEAR-QL should be considered in studies seeking to improve the QOL of CCS with hearing loss.

Ototoxic drugs can result in hearing loss and tinnitus. Early detection of the ototoxic process can help minimize or prevent these consequences. The American Speech–Language–Hearing Association has provided guidelines for monitoring ototoxicity, whereas Italy has not yet implemented a national monitoring protocol. This study aims to assess the current state of ototoxicity monitoring in patients receiving cisplatin therapy. A self-administered survey has been used to gather information from oncologists, audiologists, and ENT specialists. The research was conducted at Santa Maria della Misericordia hospital in Perugia. Two questionnaires were administered, one to ENT/audiology specialists and another to oncology specialists. Both questionnaires were used to collect information on awareness of chemotherapy-induced ototoxicity. A comprehensive understanding of cisplatin-induced ototoxicity has been widely established (100%). The most commonly reported audiological symptoms by patients were hearing loss (100%) and tinnitus (87.5%). The majority of ENT and audiologists (93.8%) and oncologists (92.9%) expressed the need for a specific ototoxic monitoring program. However, they noted the absence of a well-defined ototoxicity monitoring protocol. A well-established and efficient ototoxic monitoring system facilitates early detection of ototoxic hearing loss and subsequent rehabilitation of inevitable hearing impairment.