Cisplatin and ototoxicity in childhood: the perspective of supporting otoprotective agentes.

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.

Self-reporting of hearing loss and tinnitus in the diagnosis of ototoxicity by meglumine antimoniate in patients treated for American tegumentary Leishmaniasis.

INTRODUCTION: American Tegumentary Leishmaniasis (ATL) treatment is based on pentavalent antimonials (Sb5+), but these drugs have been associated to several adverse effects. Hearing loss and tinnitus during treatment with meglumine antimoniate (MA) have already been reported. This study aimed to describe the usefulness of self-reporting of hearing loss and tinnitus in diagnosing MA-induced ototoxicity. METHODS: A prospective longitudinal study was conducted with 102 patients with parasitological diagnosis of ATL, treated with different MA schemes. The presence of clinical auditory toxicity was defined as the emergence or worsening of self-reporting hearing loss and/or tinnitus during monitoring. Measures of sensitivity, specificity, and the positive and negative predictive value of the patient's self-reporting of hearing loss and tinnitus in relation to the result of the audiometric test (considered the gold standard) were calculated. RESULTS: The age of the evaluated patients ranged from 15 to 81 years, with a median of 41 years, and most were male (73.5%). Seventy-five patients (73.5%) had cutaneous leishmaniasis and 27 (26.5%) mucosal leishmaniasis. Eighty-six patients (84.3%) received intramuscular (IM) treatment and 16 (15.7%) were treated with intralesional MA. During treatment, 18 (17,6%) had tinnitus and 7 (6,9%) had complaint of hearing loss. 53 (52%) patients had cochlear toxicity confirmed by tone threshold audiometry and high frequency audiometry, from which 60% received a dose of 20 mg Sb5+/kg/day (p = 0.015) and 96.2% were treated with IM MA (p = 0.001). Tinnitus has greater specificity and positive predictive value than hearing loss, with a low number of false positives, but with a high false negative value. CONCLUSION: Although the large number of false negatives suggests that self-report of hearing loss or tinnitus cannot be considered a good screening test for referring the patient to an audiometry, the low number of false positives suggests the need to value the patient's complaint for referral. Otherwise, this study reinforces the importance of audiological monitoring during treatment with MA, especially in those patients with self-reporting of hearing loss or tinnitus when treated with 20 mg Sb5+/kg/day via IM.

Zebrafish neuromast sensory system: Is it an emerging target to assess environmental pollution impacts?

Environmental pollution poses risks to ecosystems. Among these risks, one finds neurotoxicity and damage to the lateral line structures of fish, such as the neuromast and its hair cells. Zebrafish (Danio rerio) is recommended as model species to be used in ecotoxicological studies and environmental biomonitoring programs aimed at assessing several biomarkers, such as ototoxicity. However, little is known about the history of and knowledge gaps on zebrafish ototoxicity. Thus, the aim of the current study is to review data available in the scientific literature about using zebrafish as animal model to assess neuromast toxicity. It must be done by analyzing the history and publication category, world production, experimental design, developmental stages, chemical classes, neuromasts and hair cell visualization methods, and zebrafish strains. Based on the results, number, survival and fluorescence intensity of neuromasts, and their hair cells, were the parameters oftentimes used to assess ototoxicity in zebrafish. The wild AB strain was the most used one, and it was followed by Tübingen and transgenic strains with GFP markers. DASPEI was the fluorescent dye most often applied as method to visualize neuromasts, and it was followed by Yo-Pro-1 and GFP transgenic lines. Antibiotics, antitumorals, metals, nanoparticles and plant extracts were the most frequent classes of chemicals used in the analyzed studies. Overall, pollutants can harm zebrafish's mechanosensory system, as well as affect their behavior and survival. Results have shown that zebrafish is a suitable model system to assess ototoxicity induced by environmental pollution.

Prevention and treatment of cisplatin-induced ototoxicity in adults: A systematic review.

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.

Occupational Lead Exposure Ototoxicity Evaluated With Distortion-Product Otoacoustic Emissions.

OBJECTIVES: To evaluate the extent of hearing loss among pottery workers in Mexico exposed to lead. DESIGN: The authors conducted a cross-sectional study including 315 adult pottery workers. Auditory function was evaluated by air conduction pure-tone audiometry (pure-tone average) and distortion-product otoacoustic emission (DPOAE) levels (amplitude and signal-to-noise ratio). Lead exposure was assessed with a single blood sample test and classified as low, medium, and high according to blood lead tertiles. Logistic regression models were calculated for the association between blood lead levels, pure-tone average, and DPOAE records. RESULTS: Median (25th-75th) blood lead levels were 14 µg/dL (7.5-22.6 µg/dL). The audiometric pattern and DPOAE records were similar across blood lead levels groups in all frequencies, and no statistically significant differences were found. Adjusted logistic regression models showed no increase in the odds for hearing thresholds >25 dB (HL) and DPOAE absence associated with blood lead levels, and no dose-response pattern was observed ( p > 0.05). CONCLUSIONS: Given the results from this cross-sectional study, no association was found between blood lead levels and hearing loss assessed with DPOAE. Future longitudinal work should consider chronic lead exposure estimates among underrepresented populations, which can potentially inform safer work practices to minimize the risk of ototoxicity.

[Efficacy of intratympanic infiltration of N-acetyl cysteine in cisplatin ototoxicity]. / Eficacia de infiltración intratimpánica de N-acetilcisteína en ototoxicidad por cisplatino.

Introduction: Currently there is no approved preventive or therapeutic pharmacological treatment to treat ototoxicity caused by cisplatin. N-acetyl cysteine (NAC) is a safe and inexpensive antioxidant that has been studied as an otoprotective alternative. Objective: To describe the efficacy of intratympanic infiltration of NAC as prevention and treatment of ototoxicity induced in patients treated with cisplatin. Material and methods: Open, longitudinal, prospective, randomized clinical trial in cancer patients treated with cisplatin who met the inclusion criteria. Out of the sample of 22 patients, 11 underwent intratympanic NAC infiltration and 11 were taken as a control group. It was performed an audiometry at the beginning and one month after on all patients. Results: A sample of 22 patients with a mean age of 53 (±13) was collected. In our sample of 11 patients with infiltration in both ears, 1 ear showed improvement; on the other hand, in the control group that was not infiltrated, 4 showed an increase in hearing loss from mild to moderate in all 4 cases, 2 in the left ear and 2 in the right ear (Spearman's Rho = 0.93, p ≤ 0.001). Relative risk was of 1.22. Conclusions: An association can be observed that intratympanic NAC could become an alternative for the prevention and treatment of cisplatin-induced ototoxicity.

Introducción: actualmente no existe ningún tratamiento farmacológico preventivo o terapéutico aprobado para tratar la ototoxicidad causada por el cisplatino. La N-acetilcisteína (NAC) es un antioxidante seguro y de bajo costo que ha sido estudiado como una alternativa otoprotectora. Objetivo: describir la eficacia de la infiltración intratimpánica de la NAC como prevención y tratamiento de la ototoxicidad generada en pacientes tratados con cisplatino. Material y métodos: ensayo clínico abierto, longitudinal, prospectivo, aleatorizado, en pacientes con cáncer tratados con cisplatino que cumplieron con los criterios de inclusión. De la muestra de 22 pacientes a 11 se les infiltró NAC intratimpánica y 11 se tomaron como grupo control. Se les realizó audiometría inicial y un mes después a la totalidad de los pacientes. Resultados: se recabó una muestra de 22 pacientes con edad promedio de 53 (±13). En nuestra muestra de 11 pacientes con infiltración en ambos oídos, un oído mostró mejoría; por otro lado, en el grupo control que no fue infiltrado 4 mostraron aumento en la hipoacusia y pasaron del nivel leve al moderado en los 4 casos, 2 en el oído izquierdo y 2 en el oído derecho (Rho de Spearman = 0.93, p ≤ 0.001). El riesgo relativo fue de 1.22. Conclusión: se puede observar una asociación de que la NAC intratimpánica pudiera llegar a ser una alternativa para la prevención y el tratamiento de la ototoxicidad inducida por cisplatino.

Audiological follow-up in transplant patients treated with calcineurin immunosuppressants "Calcineurin inhibitors and Ototoxicity" / Seguimiento audiológico en pacientes trasplantados en tratamiento con inmunosupresores inhibidores de calcineurina

BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.

INTRODUCCIÓN: La ototoxicidad corresponde a un efecto secundario a agentes terapéuticos que se manifiesta como hipoacusia sensorioneural bilateral simétrica de frecuencias agudas. Se postulan posibles efectos ototóxicos de los inmunosupresores inhibidores de la calcineurina, pero hasta la fecha es aún incierto. El objetivo de este estudio fue evaluar los cambios audiológicos en pacientes trasplantados en tratamiento inmunosupresor con inhibidores de calcineurina. MATERIAL Y MÉTODO: Cohorte prospectiva. Se incluyeron pacientes adultos sometidos a trasplante hepático o renal tratados con inhibidores de calcineurina. Se realizó una evaluación otorrinolaringo-lógica pre-trasplante con audiometría tonal, emisiones otoacústicas por producto de distorsión y cuestionario Tinnitus Handicap Inventory. Se realizó una evaluación audiológica de seguimiento uno, tres y seis meses después del trasplante. Se compararon los umbrales auditivos antes y después del inicio del tratamiento inmunosupresor y se correlacionaron con las concentraciones plasmáticas de IC. RESULTADOS: Se incluyeron 17 pacientes, 59% hombres, con una mediana de edad de 54,7 años. La mediana de seguimiento fue 5,8 meses. Se observaron cambios en el promedio tonal puro en dos pacientes, los cuales no seguían un patrón audiométrico sugerente de ototoxicidad. Todos los pacientes recibieron Tacrolimus dentro del rango terapéutico durante el seguimiento. Tres pacientes diferentes excedieron el rango esperado una vez sin embargo, se corrigieron rápidamente y no se correlacionaron con cambios auditivos, puntaje de tinnitus o emisiones otoacústicas. DISCUSIÓN: Impresiona que Tacrolimus no se asocia a hipoacusia cuando los niveles están en rango terapéutico durante un período de seguimiento de seis meses post trasplante.

MATE1 expression in the cochlea and its potential involvement in cisplatin cellular uptake and ototoxicity.

BACKGROUND: Cisplatin appears to enter the cochlear cells through the organic cation transporter 2 (OCT2). There is recent evidence that multidrug and toxin extrusion protein 1 (MATE1) is involved in cisplatin-induced nephrotoxicity. Its presence and role in the ear are unknown. AIMS/OBJECTIVES: Evaluate the presence and localization of MATE1, and determine the localization of OCT2, in the cochlea. Evaluate cisplatin uptake with regard to MATE1 and OCT2 expression. MATERIAL AND METHODS: Murine cochlear explants and paraffin-embedded cochleae were evaluated with immunohistochemistry for OCT2 and MATE1. Explant cultures were also treated with Texas Red cisplatin to determine their cellular uptake. RESULTS: MATE1 is present in the cochlea. Most intense labeling of MATE1 and OCT2 was seen in the outer hair cells (OHCs) and pillar cells, respectively. Both transporters were observed in the spiral ganglion neurons and stria vascularis. Expression levels of OCT2 and MATE1 decreased following cisplatin exposure. Texas Red cisplatin staining was strong in OHCs and pillar cells. CONCLUSIONS AND SIGNIFICANCE: To the best of our knowledge, this is the first study demonstrating the presence and localization of MATE1 in the cochlea. OCT2 labeling was seen in pillar cells. Consistently, OHCs and pillar cells uptake Texas Red cisplatin.

Cisplatin-Induced Ototoxicity: A Concise Review of the Burden, Prevention, and Interception Strategies.

Cisplatin is a bedrock of cancer management and one of the most used chemotherapeutic agents in the treatment of germ cell, lung, bladder, ovarian, and head and neck cancers. Approximately 500,000 patients diagnosed annually with these cancer types in the United States could be candidates for treatment with cisplatin. There is a 5-fold increase in the risk of hearing impairment or ototoxicity with cisplatin, which can manifest as ringing in the ear (tinnitus), high-frequency hearing loss, and at late stages, a decreased ability to hear normal conversation. More than half of adult and pediatric patients with cancer treated with cisplatin developed hearing impairment with major impact on patients' health-related quality of life. A considerable evidence gap persists regarding the burden and effective prevention and interception strategies for cisplatin-induced ototoxicity, especially in adult patients with cancer. We conducted a review of the published literature to provide an update on the status of this important clinical challenge. We also surveyed practicing oncologists within our network of academic and community practices to gain a better understanding of how the published literature compares with real-world practice. Our review of the literature showed a lack of standardized guidelines for monitoring and treatment of cisplatin-induced ototoxicity, especially in the adult cancer patient population. Our survey of practicing oncologists mirrored the findings from the published literature with a heterogeneity of practice, which highlights the need for standardization.

Audiological follow-up in transplant patients treated with calcineurin immunosuppressants "Calcineurin inhibitors and Ototoxicity".

BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.

Pharmacological treatment with annexin A1-derived peptide protects against cisplatin-induced hearing loss.

Cisplatin is an antineoplastic agent widely used, and no effective treatments capable of preventing cisplatin-induced ototoxicity and neurotoxicity in humans have yet been identified. This study evaluated the effect of the anti-inflammatory annexin A1 (AnxA1)-derived peptide Ac2-26 in a cisplatin-induced ototoxicity model. Wistar rats received intraperitoneal injections of cisplatin (10 mg/kg/day) for 3 days to induce hearing loss, and Ac2-26 (1 mg/kg) was administered 15 min before cisplatin administration. Control animals received an equal volume of saline. Hearing thresholds were measured by distortion product otoacoustic emissions (DPOAE) before and after treatments. Pharmacological treatment with Ac2-26 protected against cisplatin-induced hearing loss, as evidenced by DPOAE results showing similar signal-noise ratios between the control and Ac2-26-treated groups. These otoprotective effects of Ac2-26 were associated with an increased number of ganglion neurons compared with the untreated cisplatin group. Additionally, Ac2-26 treatment produced reduced immunoreactivity on cleaved caspase 3 and phosphorylated ERK levels in the ganglion neurons, compared to the untreated group, supporting the neuroprotective effects of the Ac2-26. Our results suggest that Ac2-26 has a substantial otoprotective effect in this cisplatin-induced ototoxicity model mediated by neuroprotection and the regulation of the ERK pathway.

The effect of genistein on cisplatin induced ototoxicity and oxidative stress.

OBJECTIVE: Cisplatin is an antineoplastic agent used in adults and children for the treatment of various malignant diseases. It can cause irreversible ototoxicity. Genistein is a phytoestrogen. Genistein functions as an antioxidant and cell cycle inhibitor by inhibiting the DNA topoisomerase and tyrosine protein kinase enzymes. The protective effect of genistein in preventing cisplatin-induced ototoxicity and levels of the oxidative stress was investigated. METHODS: 32 Sprague Dawley rats were used in 4 groups (control, cisplatin, cisplatin + genistein, genistein). Otoacoustic emission measurements of the distortion product were performed on the 1st, 2nd and 5th days of the test protocol. Serum malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, total antioxidant status, total oxidant status and oxidative stress index measurements were made. RESULTS: The hearing of the cisplatin + genistein group was found to be better than that of the cisplatin group. While the malondialdehyde, total oxidant status and oxidative stress index parameters decreased significantly in the cisplatin + genistein group compared to the cisplatin group, superoxide dismutase increased significantly (p < 0.05). CONCLUSION: Genistein showed positive effects against ototoxicity with its antioxidant effect. LEVEL OF EVIDENCE: Level 3.

Protective effect of creatine on amikacin-induced ototoxicity.

INTRODUCTION: Aminoglycosides are widely known for their ototoxic side effects. Nevertheless, they are potent antibiotics used in the treatment of life-threatening conditions because of the current concern for antibiotic resistance. We hypothesized that creatine supplements which are believed to improve mitochondrial antioxidant defense system and maintain optimal energy homeostasis may improve the ototoxic side effects. OBJECTIVE: This study aimed to investigate the protective effects of creatine monohydrate against ototoxicity induced by amikacin in rats in an experimental animal model, using distortion product otoacoustic emissions and auditory brainstem response. METHODS: Twenty healthy rats were assigned to four groups (5 rats in each): the control group, the creatine monohydrate group, the amikacin group and the amikacin+creatine monohydrate group. The creatine monohydrate group received creatine at a dose of 2g/kg once daily via gastric gavage for 21 days. The amikacin group received amikacin at a dose of 600mg/kg by intramuscular injections once daily for 21 days. The amikacin+creatine monohydrate group received intramuscular injections of amikacin (600mg/kg) once daily for 21 days and creatine monohydrate (2g/kg) once daily via gastric gavage for 21 days. The control group received nothing. The distortion product otoacoustic emissions and auditory brainstem response measurements were performed on all rats on days 0, 7, 21. RESULTS: Regarding auditory brainstem response values, a significant increase in the auditory threshold was observed in the amikacin group on day 21 (p< 0.001). The amikacin+creatine monohydrate group showed significantly lower levels of auditory brainstem response auditory thresholds on day 21 in comparison to the amikacin group (p< 0.001). Additionally, the control group and the amikacin+creatine monohydrate group did not differ significantly with respect to auditory brainstem response thresholds on treatment day 21 (p> 0.05). When we compare distortion product otoacoustic emissions values, there was no significant difference between the amikacin and amikacin+creatine monohydrate groups on day 7 (p> 0.05), However significantly greater distortion product otoacoustic emissions values were observed in the amikacin+creatine monohydrate group on day 21 compared to the amikacin group (p< 0.001). CONCLUSION: Our findings demonstrate that creatine treatment protects against amikacin ototoxicity when given at a sufficient dose and for an adequate time period.

Ototoxic effects of antineoplastic drugs: a systematic review.

INTRODUCTION: Platinum-based chemotherapeutics play an important role in the treatment of cancer at different levels and are the most cited ototoxic agents when scientific evidence is analyzed. OBJECTIVE: To present scientific evidence based on a systematic literature review, PRISMA, in order to systematize information on the ototoxic effects of using antineoplastic drugs. METHODS: For the selection of studies, the combination based on the Medical Subject Heading Terms (MeSH) was used. The Medline (Pubmed), LILACS, SciELO, SCOPUS, WEB OF SCIENCE and BIREME databases were used, without restriction of language, period, and location. Evaluation of the quality of the articles was carried out, which included articles with a minimum score of 6 in the modified scale of the literature. The designs of the selected studies were descriptive, cohort, and cross-sectional, which were related to the research objective. RESULTS: Three articles were included in this systematic review. The ototoxicity caused by cisplatin alone varied from 45% to 83.3%, while that caused by the use associated with carboplatin varied from 16.6% to 75%. There was a significant variation in the cumulative doses of these antineoplastic agents, both in isolated and in combination. Auditory changes, especially at high frequencies, were evident after completion of treatment. CONCLUSION: Auditory changes after the use of platinum-based antineoplastic drugs were found, however, there was an important heterogeneity regarding the frequency of ototoxicity and the cumulative dose of the drugs used.

Perda auditiva em pacientes oncológicos usuários de AASI: impacto no reconhecimento de fala e na qualidade de vida / Hearing loss in cancer patients who use IHAs: Impact on speech recognition and on Quality of Life

INTRODUÇÃO: Tanto o câncer quanto a perda auditiva (PA) podem interferir na qualidade de vida, o primeiro por alterar a rotina e envolver um tratamento muitas vezes agressivo, e a segunda por interferir na comunicação interpessoal, podendo levar ao isolamento ou privação social. OBJETIVO: Analisar o impacto da PA na qualidade de vida e no reconhecimento de fala em pacientes submetidos a tratamento oncológico, usuários de aparelho de amplificação sonora individual (AASI). METODOLOGIA: Estudo prospectivo de corte transversal aprovado pelo comitê de ética da Instituição. Foram selecionados usuários de AASI acompanhados no Serviço Ambulatorial de Saúde Auditiva da Univali ­ SASA/Univali. Os participantes com registro de diagnóstico e tratamento de câncer foram alocados no grupo estudo (GE) e, aqueles sem histórico de câncer, pareados por idade e grau da PA, foram alocados no grupo controle (GC). Os dados quanto ao histórico do câncer, limiares audiométricos e uso do AASI foram coletados em prontuário. A aplicação de questionários de qualidade de vida e autoavaliação (SF-36, HHIA/HHIES e IOI-HA) e do teste de reconhecimento de sentenças no silêncio e no ruído foram coletados em visita de rotina para acompanhamento no serviço no período de setembro de 2019 a janeiro de 2022. Os dados coletados foram analisados no software SPSS v.25, sendo a comparação entre os grupos realizada por meio dos testes paramétricos e não paramétricos como Qui-quadrado, teste de Fisher, teste t para igualdade de médias ou U de Mann-Whitney para amostras independentes, adotando-se nível de significância de 5%. A correlação entre as variáveis foi analisada pelo teste de Spearman. RESULTADOS: A amostra contou com 30 participantes ­ 15 alocados no GE e 15 no GC. A idade média foi de 62,4 anos no GE e de 61,4 anos no GC, com distribuição semelhante quanto ao sexo. No GE todos os participantes apresentaram histórico de câncer prévio, sendo o tratamento predominante a quimio associada à radioterapia. Nos dois grupos predominou PA neurossensorial de grau moderado e configuração descendente, porém com diferença significante para o grau da PA à esquerda (p = 0,025). Não foram observadas diferenças significantes no reconhecimento de sentenças no silêncio e no ruído entre os grupos. A qualidade de vida mostrou diferença significante no Domínio aspectos sociais, sendo o grupo com pior desempenho o GE. O impacto da PA e o desempenho com o uso do AASI avaliados pelos questionários HHIA/HHIE-S e IOI-HA foi semelhante entre os grupos. Ao analisar a correlação entre as variáveis estudadas observou-se correlação positiva para o reconhecimento de fala no silêncio, handicap auditivo e fator 1 do questionário IOI-HA ("eu e meu AASI"), bem como houve correlação positiva para os Domínios capacidade funcional, dor, vitalidade e Índice do SF-36 com o questionário IOI-HA (fator 1 ou fator 2 ­ "eu e o resto do mundo"). CONCLUSÃO: Os dois grupos estudados apresentaram desempenhos semelhantes no reconhecimento de fala, na autopercepção do handicap auditivo e na qualidade de vida, salvo no Domínio aspectos sociais do questionário SF-36, que revelou maior impacto quando a díade câncer e perda auditiva estavam associadas (GE)

INTRODUCTION: Both cancer and hearing loss (HL) can interfere in Quality of Life: the former for changing the routine and often involving aggressive treatments and the latter for interfering in interpersonal communication, with the possibility of leading to social isolation or deprivation. OBJECTIVE: To analyze the impact of HL on Quality of Life and on speech recognition in patients undergoing cancer treatments and who use hearing aids (HAs). METHODOLOGY: Prospective and cross-sectional study approved by the Ethical committee of the Institution. Hearing aid users followed up at Univali Hearing Health Outpatient Service ­ SASA/Univali were selected. Participants with a record of cancer diagnosis and treatment were allocated to the study group (SG) and those without a history of cancer, matched by age and degree of HL, were allocated to the control group (CG). Data regarding cancer history, audiometric thresholds and HA use were collected from medical records. Quality of Life and self-assessment questionnaires (SF-36, HHIA/HHIES and IOI-HA) scores and sentences recognition in quiet and in noise were assessed in the routine monitoring visits at SASA/Univali. Data were analyzed in the SPSS software (version 25), initially testing data normality and comparing groups by means of the following parametric and non-parametric tests: Chi-square, Fisher's and t test for equality of means or through the Mann-Whitney U test for independent samples. The correlation between the variables was analyzed through Spearman's test, adopting a 5% significance level for all tests. RESULTS: The sample was composed by 30 participants, 15 allocated to the SG and 15 to the CG. Mean age in the SG and CG was 62.4 and 61.4 years old, respectively, with similar distribution regarding gender. All the SG participants had a previous cancer history, with combined chemotherapy and radiotherapy as predominant treatment. Sensorineural HL of moderate degree and descending configuration predominated in both groups, although with a statistically significant difference for HL degree in the left ear (p = 0.025). No statistically significant differences were observed in sentences recognition in quiet or noise. Quality of Life showed a statistically significant difference in the Social Aspects domain, with the SG presenting worse performance. The impact of HL and performance with IHA use evaluated through the HHIA/HHIE-S and IOIHA questionnaires were similar between the groups. When analyzing the correlation between the variables studied, a positive correlation was observed for speech recognition in the midst of silence, auditory handicap and factor 1 of the IOI-IHA questionnaire ("Me and my HA"), as well as a positive correlation for the Functional Ability, Pain and Vitality domains and the SF36 Index with the IOI-HA questionnaire (factor 1 or factor 2 ­ "Me and the rest of the world"). CONCLUSION: Both groups in this sample presented similar performance in speech recognition, self-perception of the auditory handicap and Quality of Life, except in the Social Aspects domain of the SF-36 questionnaire, suggesting higher impact when cancer and hearing loss were associated (SG).

Rol protector de N-acetilcisteína en la ototoxicidad inducida por cisplatino en pacientes con cáncer de cabeza y cuello. Ensayo clínico controlado aleatorizado / Protective role of N-acetylcisteine from cisplatin-induced ototoxicity in patients with head and neck cancer. A randomized, placebo controlled clinical trial

Resumen Introducción: La ototoxicidad por cisplatino es un evento muy frecuente y sus consecuencias producen mucho deterioro en los pacientes. El diagnóstico precoz es esencial, pues permitiría implementar apropiadamente estrategias para aminorar su efecto. Entre estas tenemos la N-acetilcisteína, un agente antioxidante que ha demostrado efecto otoprotector. Objetivo: Evaluar el rol otoprotector de N-acetilcisteína comparado con placebo, en pacientes con cáncer de cabeza y cuello tratados con cisplatino. Material y Método: Ensayo clínico aleatorizado, paralelo y controlado con placebo. Se incluyen pacientes con cáncer de cabeza y cuello que requieren tratamiento con cisplatino, dos ramas: un grupo control que recibe placebo y otro que recibe el fármaco. Se realizan audiometrías de altas frecuencias (6-16 kHz) antes, durante y una vez finalizado el tratamiento. Resultados: Se aleatorizaron 45 pacientes, 23 al grupo intervencional y 22 al grupo control. Se encontró una incidencia general de la ototoxicidad del 73%, un empeoramiento en relación con tiempo de medición, una detención y estabilización del efecto ototóxico en el grupo que recibió N-acetilcisteína, todas estas diferencias fueron significativas. Conclusión: La N-acetilcisteína no previene la ototoxicidad inducida por cisplatino, pero modifica su curso de instalación y progresión. No se registraron efectos adversos al uso del fármaco. El monitoreo audiológico precoz es esencial para identificar la ototoxicidad y ejercer acciones para modificar su curso y mejorar la calidad de vida.

Abstract Introduction: Cisplatin-induced ototoxicity is a very frequent event and its consequences can cause a lot of deterioration in patients. There are some strategies to reduce its effect, among these, N-acetylcysteine, an antioxidant agent, has shown otoprotective effect. Aim: To evaluate the effect of N-acetylcysteine on ototoxicity by chemotherapy-radiotherapy in patients with head and neck cancer, compared with placebo. Material and Method: Randomized, parallel design and placebo controlled clinical trial. Patients with head and neck cancer who require treatment with cisplatin were enrolled: a control group that receives a placebo and experimental group that receives the drug. High-frequency audiometries were performed before, during and after the treatment finalization. Results: Forty-five patients were randomized, 23 for the experimental group and 22 for control group. The investigators found an incidence of ototoxicity of 73%, a worsening in relation to the time of measurement and a stopping and stabilization of the ototoxic effect in the group that received N-acetylcysteine, all these differences were statistically significant. Conclusion: N-acetylcysteine does not prevent cisplatin-induced ototoxicity, but does modify its course of installation and progression. No adverse effects were registered in this trial. Early audiological monitoring is essential to identify ototoxicity and eventually modify its course and improve the quality of life.

Ototoxic effects of hydroxychloroquine.

OBJECTIVE: To present scientific evidence based on a systematic review of the literature (PRISMA), aiming to systematize evidence of the ototoxic effects of hydroxychloroquine (HCQ). METHODS: The studies were selected using a combination based on the Medical Subject Headings (MeSH). The databases searched were MEDLINE (PubMed), LILACS, SciELO, and BIREME, encompassing articles from January 2010 to May 2020, with no restrictions of language and place of publication. RESULTS: A total of 148 articles with the potential to be included were retrieved. Of these, two answered the research question, which consisted of seeking evidence of the ototoxic effects of hydroxychloroquine. These studies scored 11 in their quality assessment with the modified protocol by Pithon et al.13. CONCLUSIONS: The studies reported possible ototoxicity of HCQ. Audiovestibular changes, such as hearing loss, peripheral vestibular syndrome, and tinnitus were evidenced in patients submitted to HCQ. The improvement in the audiological examinations and the regression in the vestibular syndrome after stopping the treatment with HCQ are strong arguments in favor of the ototoxicity caused by this medication. However, there are still divergences about the relationship between ototoxic effects and the use of HCQ.

Ototoxic effects of hydroxychloroquine

SUMMARY OBJECTIVE To present scientific evidence based on a systematic review of the literature (PRISMA), aiming to systematize evidence of the ototoxic effects of hydroxychloroquine (HCQ). METHODS The studies were selected using a combination based on the Medical Subject Headings (MeSH). The databases searched were MEDLINE (PubMed), LILACS, SciELO, and BIREME, encompassing articles from January 2010 to May 2020, with no restrictions of language and place of publication. RESULTS A total of 148 articles with the potential to be included were retrieved. Of these, two answered the research question, which consisted of seeking evidence of the ototoxic effects of hydroxychloroquine. These studies scored 11 in their quality assessment with the modified protocol by Pithon et al.13. CONCLUSIONS The studies reported possible ototoxicity of HCQ. Audiovestibular changes, such as hearing loss, peripheral vestibular syndrome, and tinnitus were evidenced in patients submitted to HCQ. The improvement in the audiological examinations and the regression in the vestibular syndrome after stopping the treatment with HCQ are strong arguments in favor of the ototoxicity caused by this medication. However, there are still divergences about the relationship between ototoxic effects and the use of HCQ.

Ototoxicity of cypermethrin in Wistar rats / Ototoxicidade da cipermetrina em ratos Wistar

Abstract Introduction: This study presents the effect of cypermethrin on the cochlear function in Wistar rats post-subchronic inhalation exposure. Worldwide several pesticides are described as causing health disorders. Cypermethrin is currently one of the most commonly used, however, little is known about its harmful effects, especially related to hearing. Human studies have associated pesticides with hearing disorders, but they present limited conclusions due to the multiple factors to which the population is exposed, such as noise. Objective: Mimic human exposure to cypermethrin and to verify the effects on cochlear function. Methods: It is a subchronic inhalation animal study (6 weeks, 4 hours/day), using 36 male Wistar aged 60 day. Rats were randomly assigned into three groups: Control (12 rats exposed to inhalation of water); Positive Control for auditory lesion (12 rats administrated with 24 mg/kg intraperitoneal cisplatin); Experimental (12 rats exposed to inhalation of cypermethrin - 0.25 mg/L). Animals were evaluated by distortion product otoacoustic emissions pre- and post-exposure. Results: The frequencies of 8, 10 and 12 kHz in both ears (right p = 0.003; 0.004; 0.008 and left 0.003; 0.016; 0.005 respectively) and at frequencies 4 and 6 in the right ear (p = 0.007 and 0.015, respectively) in the animals exposed to cypermethrin resulted in reduction. Conclusion: Subchronic inhalation exposure to cypermethrin provided ototoxicity in rats.

Resumo Introdução: Este estudo apresenta o efeito da cipermetrina sobre a função coclear em ratos Wistar após exposição por inalação subcrônica. Em todo o mundo, vários pesticidas são descritos como causadores de distúrbios de saúde. A cipermetrina é atualmente um dos mais utilizados, porém pouco se conhece sobre seus efeitos deletérios, principalmente relacionados à audição. Estudos em humanos associaram pesticidas a alterações auditivas, mas apresentaram conclusões limitadas devido aos múltiplos fatores aos quais a população está exposta, como, por exemplo, o ruído. Objetivo: Mimetizar a exposição humana à cipermetrina e verificar os seus efeitos na função coclear. Método: Estudo de inalação subcrônica em animais (6 semanas, 4 horas/dia), 36 ratos machos Wistar com 60 dias. Os ratos foram distribuídos aleatoriamente em três grupos: controle (12 ratos expostos à inalação de água); controle positivo para lesão auditiva (12 ratos com administração de 24 mg/kg de cisplatina intraperitoneal); e experimental (12 ratos expostos a inalação de cipermetrina - 0,25 mg/L). Os animais foram avaliados por emissões otoacústicas por produto de distorção, pré e pós-exposição. Resultados: As frequências de 8, 10 e 12 kHz em ambas as orelhas (direita p = 0,003; 0,004; 0,008 e esquerda 0,003; 0,016; 0,005 respectivamente) e frequências 4 e 6 na orelha direita (p = 0,007 e 0,015, respectivamente) apresentaram redução nos animais expostos à cipermetrina. Conclusão: A exposição subcrônica por inalação à cipermetrina resultou em ototoxicidade em ratos.

Potential use of n-3 PUFAs to prevent oxidative stress-derived ototoxicity caused by platinum-based chemotherapy.

Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.