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Frontiers in Neurology 2020
PubMed: 33193062
DOI: 10.3389/fneur.2020.593917 -
Frontiers in Neurology 2021Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of... (Review)
Review
Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of drugs is rarely assessed in pre-clinical drug development or during clinical trials, so this debilitating side-effect is often discovered as patients begin to report hearing loss. Furthermore, drug-induced ototoxicity in adults, and particularly in elderly patients, may go unrecognized due to hearing loss from a variety of etiologies because of a lack of baseline assessments immediately prior to novel therapeutic treatment. During the current pandemic, there is an intense effort to identify new drugs or repurpose FDA-approved drugs to treat COVID-19. Several potential COVID-19 therapeutics are known ototoxins, including chloroquine (CQ) and lopinavir-ritonavir, demonstrating the necessity to identify ototoxic potential in existing and novel medicines. Furthermore, several factors are emerging as potentiators of ototoxicity, such as inflammation (a hallmark of COVID-19), genetic polymorphisms, and ototoxic synergy with co-therapeutics, increasing the necessity to evaluate a drug's potential to induce ototoxicity under varying conditions. Here, we review the potential of COVID-19 therapies to induce ototoxicity and factors that may compound their ototoxic effects. We then discuss two models for rapidly detecting the potential for ototoxicity: mammalian auditory cell lines and the larval zebrafish lateral line. These models offer considerable value for pre-clinical drug development, including development of COVID-19 therapies. Finally, we show the validity of screening for ototoxic potential using a computational model that compares structural similarity of compounds of interest with a database of known ototoxins and non-ototoxins. Preclinical screening at , and levels can provide an earlier indication of the potential for ototoxicity and identify the subset of candidate therapeutics for treating COVID-19 that need to be monitored for ototoxicity as for other widely-used clinical therapeutics, like aminoglycosides and cisplatin.
PubMed: 34489859
DOI: 10.3389/fneur.2021.725566 -
Journal of Cancer Survivorship :... Feb 2023Ototoxicity is considered a dose-limiting side effect of some chemotherapies. Hearing loss, in particular, can have significant implications for the quality of life for... (Review)
Review
PURPOSE
Ototoxicity is considered a dose-limiting side effect of some chemotherapies. Hearing loss, in particular, can have significant implications for the quality of life for cancer survivors. Here, we review therapeutic approaches to mitigating ototoxicity related to chemotherapy.
METHODS
Literature review.
CONCLUSIONS
Numerous otoprotection strategies are undergoing active investigation. However, numerous challenges exist to confer adequate protection while retaining the anti-cancer efficacy of the chemotherapy.
IMPLICATIONS FOR CANCER SURVIVORS
Ototoxicity can have significant implications for cancer survivors, notably those receiving cisplatin. Clinical translation of multiple otoprotection approaches will aid in limiting these consequences.
Topics: Humans; Antineoplastic Agents; Ototoxicity; Quality of Life; Cancer Survivors; Cisplatin
PubMed: 36637631
DOI: 10.1007/s11764-022-01317-6 -
Archives of Toxicology Aug 2021Vestibular hair cells are mechanosensory receptors that are capable of detecting changes in head position and thereby allow animals to maintain their posture and... (Review)
Review
Vestibular hair cells are mechanosensory receptors that are capable of detecting changes in head position and thereby allow animals to maintain their posture and coordinate their movement. Vestibular hair cells are susceptible to ototoxic drugs, aging, and genetic factors that can lead to permanent vestibular dysfunction. Vestibular dysfunction mainly results from the injury of hair cells, which are located in the vestibular sensory epithelium. This review summarizes the mechanisms of different factors causing vestibular hair cell damage and therapeutic strategies to protect vestibular hair cells.
Topics: Aging; Animals; Epithelium; Hair Cells, Vestibular; Humans; Ototoxicity; Vestibular Diseases
PubMed: 33983457
DOI: 10.1007/s00204-021-03067-3 -
Biomedicine & Pharmacotherapy =... Sep 2023Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side...
Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.
Topics: Antineoplastic Agents; Ferroptosis; Iron; NF-E2-Related Factor 2; Ototoxicity; Oxaliplatin; Reactive Oxygen Species; Animals; Mice; Cell Line
PubMed: 37523980
DOI: 10.1016/j.biopha.2023.115248 -
Frontiers in Neurology 2021This review summarizes current knowledge about the occurrence of hearing and balance disorders after antimalarial drugs treatment. It also examines the clinical... (Review)
Review
This review summarizes current knowledge about the occurrence of hearing and balance disorders after antimalarial drugs treatment. It also examines the clinical applications of antimalarials, their mechanisms behind this ototoxicity and how it can be monitored. It includes studies with larger numbers of patients and those in which auditory function was assessed using audiological tests. Some antimalarials have been repurposed for other conditions like autoimmune disorders, rheumatic diseases, some viral diseases and cancers. While old antimalarial drugs, such as quinoline derivatives, are known to demonstrate ototoxicity, a number of new synthetic antimalarial agents particularly artemisinin derivatives, demonstrate unknown ototoxicity. Adverse audiovestibular effects vary depending on the medication itself, its dose and route of administration, as well as the drug combination, treated disease and individual predispositions of the patient. Dizziness was commonly reported, while vestibular symptoms, hearing loss and tinnitus were observed much less frequently, and most of these symptoms were reversible. As early identification of ototoxic hearing loss is critical to introducing possible alternative treatments with less ototoxic medications, therefore monitoring systems of those drugs ototoxic side effects are much needed.
PubMed: 33959089
DOI: 10.3389/fneur.2021.661740 -
Biochemical Pharmacology Mar 2022Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of...
Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors, but its side effects limit its application. Ototoxicity, a major adverse effect of cisplatin, causes irreversible sensorineural hearing loss. Unfortunately, there are no effective approaches to protect against this damage. Autophagy has been shown to exert beneficial effects in various diseases models. However, the role of autophagy in cisplatin-induced ototoxicity has been not well elucidated. In this study, we aimed to investigate whether the novel autophagy activator trehalose could prevent cisplatin-induced damage in the auditory cell line HEI-OC1 and mouse cochlear explants and to further explore its mechanisms. Our data demonstrated that trehalose alleviated cisplatin-induced hair cell (HC) damage by inhibiting apoptosis, attenuating oxidative stress and rescuing mitochondrial dysfunction. Additionally, trehalose significantly enhanced autophagy levels in HCs, and inhibiting autophagy with 3-methyladenine (3-MA) abolished these protective effects. Mechanistically, we showed that the effect of trehalose was attributed to increased nuclear translocation of transcription factor EB (TFEB), and this effect could be mimicked by TFEB overexpression and inhibited by TFEB gene silencing or treatment with cyclosporin A (CsA), a calcineurin inhibitor. Taken together, our findings suggest that trehalose and autophagy play a role in protecting against cisplatin-induced ototoxicity and that pharmacological enhancement of TFEB-mediated autophagy is a potential treatment for cisplatin-induced damage in cochlear HCs and HEI-OC1 cells.
Topics: Animals; Antineoplastic Agents; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line; Cisplatin; Hair Cells, Auditory; Mice; Mice, Inbred C57BL; Ototoxicity; Trehalose
PubMed: 34971589
DOI: 10.1016/j.bcp.2021.114904 -
The Turkish Journal of Pediatrics 2022Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity....
BACKGROUND
Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity. Several risk factors for cisplatininduced ototoxicity have been reported, including race and age. This study aimed to evaluate the incidence of ototoxicity and its long-term outcome in Thai pediatric solid-tumor patients receiving cisplatin and to determine the risk factors associated with hearing impairment.
METHODS
A retrospective study was conducted in solid-tumor patients < 15 years old from 2007 to 2019 at Siriraj Hospital, Bangkok, Thailand. Hearing was evaluated by an audiogram and/or auditory steady-state response and the impairment was graded according to the Common Terminology Criteria for Adverse Events version 5. Grade 2 and above was considered significant hearing loss.
RESULTS
In total, the hearing of 47 patients was evaluated. At the end of treatment, hearing impairment and significant hearing loss were found in 66% and 48.9% of patients, respectively. A high median cumulative cisplatin dose was significantly associated with worse hearing impairment (p = 0.039) and a more progressive grading of ototoxicity (p = 0.005). A risk factor for significant hearing loss was a cumulative dose ≥400 mg/m2 (p = 0.014). All 9 patients who received a cumulative dose > 600 mg/m2 and 5 patients who received aminoglycoside developed significant hearing loss. One patient had progressive hearing impairment at 8 months after the end of treatment and 1 patient developed grade 3 ototoxicity which required a hearing aid after bone marrow transplantation. The latter patient received a total cisplatin dose of 708.2 mg/m < sup > 2 < /sup > and carboplatin 1400 mg/m < sup > 2 < /sup > .
CONCLUSIONS
The incidence of hearing impairment in pediatric patients receiving cisplatin is high. Regular hearing evaluation is essential for the early detection of ototoxicity. Long-term follow-up is recommended, especially in patients who have a combination of other risk factors for hearing loss.
Topics: Adolescent; Antineoplastic Agents; Child; Cisplatin; Hearing; Hearing Loss; Humans; Neoplasms; Ototoxicity; Retrospective Studies; Thailand
PubMed: 35899566
DOI: 10.24953/turkjped.2021.5012 -
Neurobiology of Disease Jul 2023Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases...
Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin-Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7-/- mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.
Topics: Animals; Mice; Aminoglycosides; Receptors, Purinergic P2X7; Ototoxicity; Anti-Bacterial Agents; Neomycin; Hair Cells, Auditory; Cochlea; Adenosine Triphosphate
PubMed: 37263384
DOI: 10.1016/j.nbd.2023.106176 -
Brazilian Journal of Otorhinolaryngology 2022Platinum-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... (Review)
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.
Topics: Antineoplastic Agents; Cisplatin; Cross-Sectional Studies; Hearing Loss; Humans; Ototoxicity
PubMed: 33757754
DOI: 10.1016/j.bjorl.2021.02.008