Intratympanic Gentamicin Injection in Ménière’s Disease: Our Ten Years’ Experience and Outcomes

Objective: The aim of our study is to evaluate the effectiveness of intratympanic gentamicin injection (ITG) on vertigo control with reduced doses and its hearing effects. Materials and Method: The study was conducted at Otolaryngology Department of AORN “S.G. Moscati” between January 2005 and January 2015 on 72 patients with disabling unilateral Meniere’s disease. We use 0.2-0.3 mL of gentamicin sulfate at a concentration of 40mg/ml, injected into the affected ear through the posterior-inferior quadrant of the tympanic membrane. The procedure was carried out for three following days. Main outcome measures: vertigo control and hearing threshold changes after ITG treatment. Results: In 98.6% of the patients(n=71) the ITG produced the full remission of the vertiginous symptoms. In 91.6% of cases(n=66) a single treatment (three consequent injections) was sufficient to control vertigo, in 5.5% of cases(n=4) two treatments were necessary to control vertigo and in 1.3% of patients(n=1) three treatments were necessary to control vertigo. In no case we have had hearing loss after ITG procedure. The pre-treatment pure tone average was 48db. The post-treatment pure tone average was 49.2db. This difference was no statistical difference. Conclusion: In this study we reported high vertigo control, long follow-up and no case of significant hearing worsening. We consider the three injections in the following three days with low doses of gentamicin a safe and valid treatment for Meniere’s disease.

Progress in the mechanisms and preventive measures of cisplatin-induced ototoxicity / 国际儿科学杂志

Cisplatin is a broad-spectrum and highly effective chemotherapeutic agent, with a dose-dependent therapeutic effect.Unfortunately, high-does therapy is limited by ototoxicity, nephrotoxicity and neurotoxicity.Ototoxicity is a common and serious complication after cisplatin chemotherapy, which has greatly debilitating effect on patients′ quality of life.Currently, there are no FDA-approved drugs available to prevent cisplatin-induced hearing loss.In recent years, domestic and international studies on cisplatin-induced ototoxicity have revealed many new mechanisms and therapeutic targets.Many candidate agents have shown good hearing protection.Moreover, local drug delivery methods are being optimized, promising for further translations to clinical applications.

Effect of Spirulina on Cochlea Histopathological Changes in Wistar Rats Induced by Kanamicin

@#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.

Protective effect of creatine on amikacin-induced ototoxicity / Efeito protetor da creatina na ototoxicidade induzida por amicacina

Abstract 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 2 g/kg once daily via gastric gavage for 21 days. The amikacin group received amikacin at a dose of 600 mg/kg by intramuscular injections once daily for 21 days. The amikacin + creatine monohydrate group received intramuscular injections of amikacin (600 mg/kg) once daily for 21 days and creatine monohydrate (2 g/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.

Resumo Introdução Os aminoglicosídeos são amplamente conhecidos por seus efeitos colaterais ototóxicos. No entanto, eles são antibióticos potentes usados no tratamento de doenças potencialmente fatais devido à atual preocupação com a resistência aos antimicrobianos. Nossa hipótese é que os suplementos de creatina, aos quais atribui-se um efeito benéfico sobre o sistema de defesa antioxidante mitocondrial e manutenção da homeostase energética ideal, possam melhorar os efeitos colaterais ototóxicos. Objetivo Investigar os efeitos protetores da creatina mono-hidratada contra a ototoxicidade induzida pela amicacina em ratos em um modelo experimental animal com o uso das emissões otoacústicas por produto de distorção e o potencial evocado auditivo de tronco encefálico. Método Vinte ratos saudáveis foram divididos em quatro grupos (5 ratos em cada): o grupo controle, o grupo creatina mono-hidratada, o grupo amicacina e o grupo amicacina + creatina mono-hidratada. O grupo creatina mono-hidratada recebeu creatina na dose de 2 g / kg uma vez ao dia por gavagem gástrica por 21 dias. O grupo amicacina recebeu amicacina na dose de 600 mg/kg por injeção intramuscular uma vez ao dia por 21 dias. O grupo amicacina + creatina mono-hidratada recebeu injeções intramusculares de amicacina (600 mg/kg) uma vez ao dia por 21 dias e creatina mono-hidratada (2 g/kg) uma vez ao dia por gavagem gástrica por 21 dias. O grupo controle nada recebeu. As medidas de emissões otoacústicas por produto de distorção e potencial evocado auditivo de tronco encefálico foram feitas em todos os ratos nos dias 0, 7, e 21. Resultados Em relação aos valores do potencial evocado auditivo de tronco encefálico, foi observado aumento significante dos limiares auditivos no grupo amicacina no 21° dia (p < 0,001). O grupo amicacina + creatina mono-hidratada apresentou níveis significantemente mais baixos de limiares auditivos de potencial evocado auditivo de tronco encefálico no dia 21 em comparação com o grupo amicacina (p < 0,001). Além disso, o grupo controle e o grupo amicacina + creatina mono-hidratada não diferiram significantemente em relação aos limiares de potencial evocado auditivo de tronco encefálico no 21° dia de tratamento (p > 0,05). Quando comparamos os valores de emissões otoacústicas por produto de distorção, não houve diferença significante entre os grupos amicacina e amicacina + creatina mono-hidratada no 7° dia (p > 0,05). No entanto, valores significantemente mais altos de emissões otoacústicas por produto de distorção foram observados no grupo amicacina + creatina mono-hidratada no 21° dia em comparação com o grupo amicacina p < 0,001). Conclusão O tratamento com creatina mono-hidratada protege contra a ototoxicidade da amicacina quando administrado em dose suficiente e por um período de tempo adequado.

Antioxidant Effect of Curcumin on the Prevention of Oxidative Damage to the Cochlea in an Ototoxic Rat Model Based on Malondialdehyde Expression

Abstract Introduction Aminoglycoside, as an antimicrobial medication, also has side-effects on the inner ears, bringing about hearing disorders. Curcumin has been proven to be a strong scavenger against various reactive oxygen species (ROS), and the increase in ROS production is considered to play an important role in the process of hearing disorder. Objective To prove that curcumin is an effective antioxidant to prevent cochlear damage based on malondialdehyde (MDA) expression. Methods The present research used 32 Rattus norvegicus, of the Wistar lineage, randomly divided into 8 groups: negative control, ototoxic control (a single dose of 40 mg/ml of gentamicin via intratympanic injection), 2 groups submitted to ototoxic control + curcumin treatment (100 mg/kg, 200 mg/kg), 2 groups who iunderwent ototoxic control + curcumin treatment for 7 days, and two groups submitted to curcumin treatment as prevention for 3 days + ototoxic induction. Results The results showed that the lowest dosage of curcumin (100 mg/kg) could decrease MDA expression on the cochlear fibroblastic wall of the ototoxic model; however using greater doses of curcumin (200 mg/kg) for 7 days would provide a better effect. Curcumin could also significantly decrease MDA expression when it was administered during the preototoxic exposure. Conclusion Curcumin can be used as a therapy for ototoxic prevention based on the decrease in MDA expression.

The Ototoxicity of Chloroquine and Hydroxychloroquine: A Systematic Review

Abstract Introduction Chloroquine and hydroxychloroquine are antimalarial drugs widely used in the treatment of rheumatic diseases. With the global pandemic caused by the new coronavirus, there was an increase in the prescription of these drugs, which led to a major concern regarding their ototoxic effects. Objectives The objective of the present study was to assess existing scientific evidence about the toxic effects of chloroquine and hydroxychloroquine on the peripheral and/or central auditory system. Data Synthesis A systematic literature review was performed by searching the PubMed (Medline), Scopus, Web of Science, LILACS, and SciELO electronic databases, in a search of articles that fullfiled the predefined inclusion and exclusion criteria. The review was conducted in three phases and, in all of them, analyses were performed by two independent researchers. Disagreements were discussed with a third researcher until a consensus was reached. A total of 437 articles were found and 8 were included in this review. Seven of the included studies reported hearing loss in their samples and presented a diagnostic hypothesis of ototoxicity induced by chloroquine or hydroxychloroquine. The most common type of hearing loss was sensorineural, with varying laterality and degrees of severity. The most frequently used audiological test was pure tone audiometry, and only two studies assessed brainstem evoked responses. Conclusion The scientific evidence compiled in this research showed that chloroquine and hydroxychloroquine have an ototoxic effect in the peripheral auditory system. These drugs can cause cochlear damage, including changes in the stria vascularis and lesions in sensory hair cells.

The effect of genistein on cisplatin induced ototoxicity and oxidative stress / Efeito da genisteína na ototoxicidade induzida pela cisplatina e estresse oxidativo

Abstract Highlights Cisplatin is an antineoplastic agent used malignant diseases. Cisplatin ototoxicity is generally bilateral, irreversible, and progressive. Genistein is a phytoestrogen. Genistein functions as antioxidant and cell cycle inhibitor by inhibiting DNA topoisomerase. Genistein showed positive effects on ototoxicity with its antioxidant. 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.

Resumo DESTAQUES A cisplatina é um agente antineoplásico usado em lesões malignas. A ototoxicidade da cisplatina é geralmente bilateral, irreversível e progressiva. A genisteína é um fitoestrógeno. A genisteína funciona como antioxidante e inibidor do ciclo celular ao inibir a topoisomerase do DNA. A genisteína apresentou efeitos positivos sobre a ototoxicidade com seu efeito antioxidante. Objetivo A cisplatina é um agente antineoplásico usado em adultos e crianças para o tratamento de diversas lesões malignas. Pode causar ototoxicidade irreversível. A genisteína é um fitoestrógeno que funciona como antioxidante e inibidor do ciclo celular ao inibir as enzimas DNA topoisomerase e tirosina-quinase. O efeito protetor da genisteína na prevenção da ototoxicidade induzida pela cisplatina e os níveis de estresse oxidativo foram investigados. Método Trinta e dois ratos Sprague Dawley foram usados em 4 grupos (controle, cisplatina, cisplatina + genisteína, genisteína). As medidas das emissões otoacústicas por produto de distorção foram tomadas nos dias 1, 2 e 5 do protocolo do teste. Foram medidos os níveis séricos de malondialdeído, superóxido dismutase, catalase, glutationa peroxidase, estado antioxidante total, estado oxidante total e índice de estresse oxidativo. Resultados A audição do grupo cisplatina + genisteína foi melhor do que a do grupo cisplatina. Enquanto os parâmetros malondialdeído, estado oxidante total e índice de estresse oxidativo diminuíram significantemente no grupo cisplatina + genisteína em comparação com o grupo cisplatina, o superóxido dismutase mostrou aumento significantemente (p < 0,05). Conclusão A genisteína apresentou efeitos positivos contra a ototoxicidade com seu efeito antioxidante. Nível de evidência Nível 3.

Ototoxic effects of antineoplastic drugs: a systematic review / Efeitos ototóxicos dos medicamentos antineoplásicos: uma revisão sistemática

Abstract 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.

Resumo Introdução Os quimioterápicos à base de cisplatina desempenham papel importante no tratamento do câncer em diversos níveis e são os agentes ototóxicos mais citados quando analisadas evidências científicas. Objetivo Apresentar evidências científicas com base em revisão sistemática da literatura (PRISMA), com o intuito de sistematizar informações sobre os efeitos ototóxicos do uso de medicamentos antineoplásicos. Método Para a seleção dos estudos foi usada a combinação baseada no Medical Subject Heading Terms (MeSH). Foram usadas as bases de dados Medline (Pubmed), Lilacs, SciELO, Scopus, Web of Science e Bireme, sem restrição de idioma, período e localização. Foi feita avaliação da qualidade dos artigos, na qual se incluíam artigos com nota mínima 6 na escala modificada da literatura. Os desenhos dos estudos selecionados foram do tipo descritivo, coorte e transversal, os quais estavam relacionados com o objetivo da pesquisa. Resultados Três artigos foram admitidos para esta revisão sistemática. A ototoxicidade causada pela cisplatina isoladamente variou de 45% a 83,3%, enquanto a causada pelo uso associado com a carboplatina variou de 16,6% a 75%. Verificou-se uma variação significativa nas doses cumulativas desses antineoplásicos, tanto no uso isolado quanto em combinação. Alterações auditivas, principalmente em altas frequências, foram evidenciadas após finalização do tratamento. Conclusão Alterações auditivas após o uso de medicamentos antineoplásicos à base de platina foram constatadas, porém verificou-se uma importante heterogeneidade quanto à frequência da ototoxicidade e a dose cumulativa das drogas usadas.

Ototoxicity of an association of insecticides compounds containing dichlorvos and cypermethrin in Wistar rats

ABSTRACT Purpose: to evaluate possible ototoxicity secondary to exposure to a combination of pesticides (dichlorvos and cypermethrin based insecticides). Methods: the Wistar rats were divided into 3 groups (12 animals per group): control (water), positive control for hearing damage (cisplatin) and experimental (exposed to dichlorvos and cypermethrin). The amplitude of distortion product otoacoustic emissions was assessed before and after the exposure. Systemic toxicity signs were also evaluated (clinical signs, weight gain and plasma cholinesterase). Wilcoxon test analyzed the post-exposure amplitudes compared to pre-exposure and Kruskal Wallis following Dunn's post hoc tests analyzed the amplitudes' variation. Normally distributed variables were evaluated by Student's t test. Results: body weight and plasma cholinesterase values were similar comparing the pre and post exposure in the experimental group. The control group did not manifest significant amplitude reduction of otoacoustic emissions between the pre and post evaluation. In the group exposed to cisplatin there was a significant reduction in amplitudes at 12 kHz on the right (p = 0.006; Wilcoxon) and 4 kHz on the left (p = 0.032; Wilcoxon). In the group exposed to pesticides, there was a significant reduction in the right ear at 4 kHz (p = 0.034; Wilcoxon) and 8 kHz (p = 0.019; Wilcoxon) and in the left ear at 4 kHz (p = 0.007; Wilcoxon), 6 kHz (p = 0.023; Wilcoxon), 8 kHz (p = 0.045; Wilcoxon) and 12 kHz (p = 0.028; Wilcoxon). Conclusion: there was ototoxicity in the experimental group, without a relevant systemic toxicity.

Astaxanthine attenuates cisplatin ototoxicity in vitro and protects against cisplatin-induced hearing loss in vivo

Astaxanthine (AST) has important biological activities including antioxidant and anti-inflammatory effects that could alleviate neurological and heart diseases, but its role in the prevention of cisplatin-induced hearing loss (CIHL) is not yet well understood. In our study, a steady interaction between AST and the E3 ligase adapter Kelch-like ECH-associated protein 1, a predominant repressor of nuclear factor erythroid 2-related factor 2 (NRF2), was performed and tested via computer molecular docking and dynamics. AST protected against cisplatin-induced ototoxicity via NRF2 mediated pathway using quantitative PCR and Western blotting. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential revealed that AST reduced ROS overexpression and mitochondrial dysfunction. Moreover, AST exerted anti-apoptosis effects in mouse cochlear explants using immunofluorescence staining and HEI-OC1 cell lines using quantitative PCR and Western blotting. Finally, AST combined with poloxamer was injected into the middle ear through the tympanum, and the protection against CIHL was evaluated using the acoustic brain stem test and immunofluorescent staining in adult mice. Our results suggest that AST reduced ROS overexpression, mitochondrial dysfunction, and apoptosis via NRF2-mediated pathway in cisplatin-exposed HEI-OC1 cell lines and mouse cochlear explants, finally promoting cell survival. Our study demonstrates that AST is a candidate therapeutic agent for CIHL.

Los acúfenos de Miguel Ángel y su relación con la toxicología / Miguel Ángel's tinnitus and its relation to toxicology

Resumen El Plomo ha tenido una estrecha relación con el mundo artístico pictórico a través de los pigmentos utilizados por los artistas durante milenios. El íntimo contacto con sustancias químicas potencialmente peligrosas para la salud, casi siempre sin medidas de higiene y seguridad laboral, ha desarrollado en muchos casos, enfermedades laborales en estos artistas, a veces sospechadas y en otros casos, más que confirmadas. En el presente trabajo se analiza la historia de vida laboral de Miguel Angel Buonarroti, de quien se tiene registro suficiente como para establecer un nexo causal con exposición laboral al Plomo.

Abstract Lead has shown a close relationship with the fine arts'world through the pigments used by artists for thousand of years. Close contact with potentially dangerous chemical substances for health, almost always without occupational hygiene and safety measures, has produced, in many cases, occupational illnesses in these artists, sometimes suspected and in other cases, more than confirmed. In the present work, the history of Miguel Angel Buonarroti's working life is analyzed, since there is sufficient record to establish a causal link with occupational exposure to Lead.

Rol protector de N-acetilcisteína en la ototoxicidad inducida por cisplatino en pacientes con cáncer de cabeza y cuello. Ensayo clínico controlado aleatorizado

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

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.

Effects of Toluene on the Development of the Inner Ear and Lateral Line Sensory System of Zebrafish / 生物医学与环境科学（英文）

Objective@#The aim of this study was to explore the ototoxicity of toluene in the early development of zebrafish embryos/larvae.@*Methods@#Zebrafish were utilized to explore the ototoxicity of toluene. Locomotion analysis, immunofluorescence, and qPCR were used to understand the phenotypes and molecular mechanisms of toluene ototoxicity.@*Results@#The results demonstrated that at 2 mmol/L, toluene induced zebrafish larvae death at 120 hours post fertilization (hpf) at a rate of 25.79% and inhibited the rate of hatching at 72 hpf. Furthermore, toluene exposure inhibited the distance travelled and average swimming velocity of zebrafish larvae while increasing the frequency of movements. As shown by fluorescence staining of hair cells, toluene inhibited the formation of lateral line neuromasts and middle line 1 (Ml @*Conclusion@#This study indicated that toluene may affect the development of both the inner ear and lateral line systems in zebrafish, while the lateral line system may be more sensitive to toluene than the inner ear.

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.

Chloroquine and COVID-19: Should We Care about Ototoxicity?

Abstract Introduction Severe acute respiratory syndrome coronavirus 2 was first described in December 2019 in China leading to a Public Health Emergency of International Concern. It was named by the World Health Organization as Coronavirus Disease 2019 (COVID-19), and it garnered unprecedented attention from public health researchers around the world, and studies analyzing chloroquine and hydroxychloroquine as a possible therapy have arisen in the last 2 months. Objective To review the literature and describe updated facts about the ototoxicity of chloroquine and hydroxychloroquine, an important side effect that can be present in patients with COVID-19 treated with these drugs. Data Synthesis The most typical treatment regimen is 5 days of hydroxychloroquine at daily doses of 400 to 600 mg. There is no randomized clinical trial that can prove so far the efficacy of this medication, and few studies have evaluated adverse events potentially linked to their use in patients with COVID-19. While there is no concrete evidence on the incidence of ototoxicity using chloroquine in the short term, we need to consider that, as a pandemic disease, millions of patients with COVID-19 may receive this treatment, and ototoxicity can be a possible adverse event. Conclusion Despite the urgent global situation caused by the COVID-19, the risk of irreversible hearing loss may outweigh the unproven benefit of using hydroxychloroquine or chloroquine, especially in patients with mild forms of COVID-19, who may be cured with supportive treatment. The potential hearing loss that can be caused by these medications may advise against their use in COVID-19 patients.

A study of effect of aminoglycoside therapy on auditory brainstem evoked responses in preterm and term neonates

Background: Aminoglycosides are widely used drugs in neonates with associated ototoxic side effects, that can be diagnosed with auditory brainstem evoked responses, which is the recommended screening technique in neonatal intensive care unit infants.  This study was conducted to evaluate the effect of aminoglycoside therapy on auditory brainstem evoked responses in term and preterm neonates.Methods: A cross-sectional case control study. Two groups of 26 term and 22 preterm neonates who received aminoglycosides, with no other known risk factors for ototoxicity, were compared with suitable matched control group of 10 neonates in each. ABER was done after at least 5 days of aminoglycoside therapy and results were compared to suitable matched controls.Results: Mean latency of wave I in term neonates at 90 dB and 60 dB and mean interwave latencies of I-V waves in preterm neonates at 30 dB was higher in study group and statistically significant. No statistically significant difference in any of ABER parameters was observed in any group, at all other intensities.Conclusions: Wave I latency was prolonged in study group of term neonates at two intensities which indicates effect of aminoglycoside therapy on distal portion of acoustic nerve. But as there were no such findings at other intensities in term study group and in preterm study group and moreover no other ABER abnormalities were observed, it was concluded that the aminoglycoside therapy has low potential for ototoxicity. Authors support the ABER screening for early detection of hearing abnormalities, and recommend study on larger group of neonates and meta-analysis for final conclusion for evidence-based recommendations to use aminoglycosides in neonates, in view of audiometric and neurological abnormalities.

Hearing function of gold miners with and without a history of tuberculosis treatment: a retrospective data review / Função auditiva de garimpeiros com e sem história de tratamento de tuberculose: uma revisão retrospectiva dos dados

Abstract Introduction: South Africa has a high prevalence of co-existing tuberculosis and HIV. As ototoxicity linked to the treatments for these conditions occurs with concomitant exposure to other ear toxins such as hazardous noise exposure, it is important to investigate the combination impact of these toxins. Limited published evidence exists on the co-occurrence of these conditions within this population. Objectives: The objective of this study was to compare the hearing function of gold miners with (treatment group) and without (non-treatment group) the history of tuberculosis treatment, in order to determine which group had increased risk of noise induced hearing loss. Furthermore, possible influence of age and HIV in these two groups was examined. Methods: A retrospective record review of 102 miners' audiological records, divided into two groups, was conducted, with data analyzed both qualitatively and quantitatively. Results: Findings suggest that gold miners with a history of tuberculosis treatment have worse hearing thresholds in the high frequencies when compared to those without this history; with evidence of a noise induced hearing loss notch at 6000 Hz in both groups. Pearson's correlations showed values between 0 and 0.3 (0 and −0.3) which are indicative of a weak positive (negative) correlation between HIV and hearing loss, as well as between hearing loss and age in this population. Conclusions: Current findings highlight the importance of strategic hearing conservation programs, including ototoxicity monitoring, and the possible use of oto-protective/chemo-protective agents in this population.

Resumo Introdução: A África do Sul apresenta uma alta prevalência de coinfecção de tuberculose e HIV. Como a ototoxicidade associada aos tratamentos para essas condições é observada na exposição concomitante a outros agentes ototóxicos, como a exposição a ruídos perigosos, é importante investigar o impacto da combinação desses agentes. São poucas as evidências publicadas sobre a co-ocorrência dessas condições nessa população. Objetivo: Comparar a função auditiva de garimpeiros com (grupo tratamento) e sem (grupo sem tratamento) história de tratamento de tuberculose, a fim de determinar que grupo apresentava maior risco de perda auditiva induzida por ruído. Além disso, avaliou-se a possível influência da idade e do HIV nesses dois grupos. Método: Os registros audiológicos de 102 garimpeiros, divididos em dois grupos, foram revisados de forma retrospectiva; os dados foram qualitativa e quantitativamente analisados. Resultados: Os achados indicam os garimpeiros com histórico de tratamento de tuberculose apresentam piores limiares auditivos nas altas frequências quando comparados àqueles sem esse histórico; em ambos os grupos, observou-se perda auditiva induzida por ruído com entalhe audiométrico a 6.000 Hz. As correlações de Pearson mostraram valores entre 0 e 0,3 (0 e -0,3), que são indicativos de uma fraca correlação positiva (negativa) entre o HIV e a perda auditiva, bem como entre a perda auditiva e a idade nessa população. Conclusões: Os resultados atuais destacam a importância de programas estratégicos de conservação auditiva, inclusive monitoramento de ototoxicidade, e o possível uso de agentes oto-/quimioprotetores nessa população.

Terapia vestibular en vestibulopatía bilateral por gentamicina: reporte de un caso y revisión de la literatura / Vestibular therapy in a case of gentamicin-induced vestibulopathy: case report and literature revision

La vestibulopatía bilateral es poco frecuente, se caracteriza principalmente por inestabilidad al caminar o al estar de pie, visión borrosa inducida por el movimiento u oscilopsia al caminar o al realizar movimientos rápidos de la cabeza o del cuerpo, empeoramiento de la estabilidad en la oscuridad o terrenos irregulares, reducción de los síntomas al estar en condiciones estáticas, ganancia del reflejo vestíbulo-ocular angular reducida de forma bilateral, entre otros. Existen múltiples causas. Dentro de las causas identificables, se describen principalmente medicamentos ototóxicos, meningitis y enfermedad de Ménière. Se presenta el caso de una paciente de 64 años diagnosticada con vestibulopatía bilateral posterior a tratamiento intramuscular con gentamicina por sobreinfección bacteriana cutánea de las manos. La evaluación vestibular complementada con videonistagmografía y prueba de impulso cefálico asistida por video confirman el diagnóstico y se inicia tratamiento con rehabilitación vestibular enfocada en promover la compensación central a través de estrategias de sustitución principalmente; además de habituación y adaptación vestibular, favoreciendo la estabilización de la mirada, mantención del equilibrio, control postural, marcha y reducción de los síntomas.

Bilateral vestibulopathy is infrequent, and it is characterized mostly by unstable walking or when standing, blurred vision induced by movement, or oscillopsia when walking or performing fast movements; worsening of the stability in darkness or uneven ground, but with lack of symptoms in static conditions. Other symptoms may include bilateral reduction of the oculo-vestibular reflex. Among the identifiable causes, there is the use of ototoxic medication, meningitis, Ménière's disease, although it can be idiopathic or have a neurological cause. We hereby describe the case of a 64-year-old woman, diagnosed with bilateral vestibulopathy secondary to intramuscular treatment with gentamicin due to a bacterial hand infection. Vestibular assessment was complemented with video-nystagmography and video head impulse test which confirmed the diagnosis, and therapy was started with vestibular rehabilitation focused on promoting central compensation mainly, through substitution strategies. Also, habituation exercise and vestibular adaptation strategies were used, thus promoting sight stabilization, balance maintenance, postural control, walking, and reduction of the symptoms.

Protective effect of N-acetylcysteine against cisplatin ototoxicity in rats: a study with hearing tests and scanning electron microscopy / Efeito protetor da N-acetilcisteína na ototoxicidade por cisplatina em ratos: um estudo com testes auditivos e microscopia eletrônica de varredura

Abstract Introduction Ototoxicity is a health problem appearing after powerful treatments in serious health conditions. It is sometimes inevitable when treatment of the serious disease is required. Cisplatin is an antineoplastic agent which was investigated previously to reveal increased nitrogen and reactive oxygen radicals that damages hair cells, resulting in ototoxicity. N-acetylcysteine, previously shown to decrease ototoxicity caused by different agents, is known to be a powerful in vitro antioxidant. Probably N-acetylcysteine, in addition to its antioxidant effect, blocks a cascade where reactive oxygen species result in apoptosis in the cochlea. Objectives The possible preventive effect of N-acetylcysteine in cisplatin ototoxicity was studied with auditory brain stem responses, otoacoustic emissions, and histopathological investigation of the cochlea in a scanning electron microscopy. Methods This study was conducted on 21 Wistar Albino rats in four groups. 1 mL/kg/day three times in total intraperitoneal (i.p.) Saline (n = 5), 500 mg/kg/day i.p. three times in total N-acetylcysteine (n = 5), i.p. 15 mg/kg cisplatin alone (single dose) (n = 5) and i.p. 15 mg/kg cisplatin plus 500 mg/kg/day N-acetylcysteine (n = 6) were administered. The rats were anesthetized to study the hearing tests before and after the experiment. The rats were sacrificed to investigate the cochleas by scanning electron microscopy. Results Auditory brain stem responses and otoacoustic emissions values were attenuated in the cisplatin group. The group that received N-acetylcysteine in addition to cisplatin had better auditory brain stem responses thresholds and otoacoustic emissions. The samples obtained from the cisplatin group showed surface irregularities, degeneration areas, and total or partial severe stereocilia losses. The changes were milder in the cisplatin + N-acetylcysteine group. Conclusion Cisplatin ototoxicity can be detected by auditory brain stem responses and otoacoustic emissions testing in rats. N-acetylcysteine may protect the cochlear cells from histopathological changes. We concluded that N-acetylcysteine given 4 h after cisplatin injection has a potential otoprotective effect against cisplatin ototoxicity. which suggests it could be used in clinical trials.

Resumo Introdução A ototoxicidade é um problema que pode ocorrer após certos tipos de tratamentos para condições graves de saúde. Às vezes é inevitável quando o tratamento da doença é necessário. A cisplatina é um agente antineoplásico cujo uso em pesquisas anteriores demonstrou aumentar os radicais livres de nitrogênio e espécies reativas de oxigênio que danificam as células ciliadas e resultam em ototoxicidade. Por outro lado, a N-acetilcisteína, que já demonstrou diminuir a ototoxicidade causada por diferentes agentes, é conhecida por ser um potente antioxidante in vitro. Provavelmente a N-acetilcisteína, além de seu efeito antioxidante, bloqueia uma cascata onde espécies reativas de oxigênio resultam em apoptose na cóclea. Objetivos Estudar o possível efeito preventivo da N-acetilcisteína na ototoxicidade por cisplatina por meio de potencial evocado auditivo de tronco encefálico, emissões otoacústicas e investigação histopatológica da cóclea por microscopia eletrônica de varredura. Método Este estudo foi realizado em 21 ratos albinos Wistar, separados em quatro grupos. Foram administrados: 1 mL/kg/dia intraperitoneal (i.p.) de solução salina (n = 5), três vezes no total; 500 mg/kg/dia i.p. de N-acetilcisteína (n = 5), três vezes no total; 15 mg/kg i.p. (dose única) somente de cisplatina (n = 5) e 15 mg/kg i.p. de cisplatina e 500 mg/kg/dia i.p. de N-acetilcisteína (n = 6). Os ratos foram anestesiados para estudo dos testes auditivos antes e depois do experimento. Os ratos foram sacrificados para investigação da cóclea por microscopia eletrônica de varredura. Resultados Os potenciais evocados auditivos de tronco encefálico e os valores das emissões otoacústicas estavam atenuados no grupo cisplatina. O grupo que recebeu N-acetilcisteína além da cisplatina apresentou melhores limiares de respostas auditivas do tronco encefálico e emissões otoacústicas. As amostras obtidas do grupo cisplatina apresentaram irregularidades de superfície, áreas de degeneração, com perdas graves totais ou parciais de estereocílios. As alterações foram mais leves no grupo cisplatina + N-acetilcisteína. Conclusão A ototoxicidade por cisplatina pode ser detectada por meio de potenciais evocados auditivos de tronco encefálico e pelo teste de emissões otoacústicas em ratos. A N-acetilcisteína pode proteger as células cocleares contra alterações histopatológicas. Concluímos que a N-acetilcisteína administrada 4 horas após a injeção de cisplatina tem potencial efeito otoprotetor contra a ototoxicidade por cisplatina e pode ser utilizada em ensaios clínicos.