Intratympanic Diltiazem-Chitosan Hydrogel as an Otoprotectant Against Cisplatin-Induced Ototoxicity in a Mouse Model

Naples, James G.; Ruckenstein, Michael J.; Singh, Jarnail; Cox, Brandon C.; Li, Daqing

doi:10.1097/mao.0000000000002417

Cited by 10 publications

(12 citation statements)

References 55 publications

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“…In an epidemiologic study, women taking CCB medications were found to have, on average, 12 dB better hearing than those not on a CCB (43). In vitro and in vivo results revealed that CCB treatment is protective in cisplatin-induced ototoxicity (10)(11)(12). Based on the preclinical findings, L-Type calcium channel blockade could be a potential therapeutic target for SNHL.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro and in vivo results show that CCB treatment is protective in cisplatin-induced ototoxicity (10)(11)(12). In vivo mouse models revealed, following cisplatin injection, intratympanic diltiazem administration reduced click-evoked auditory brainstem response (ABR) threshold shifts compared with control, highlighting potential therapy for cisplatin-induced ototoxicity (11,12). Further, a clinical study showed that patients treated with a combination of nimodipine, and a steroid had improved recovery from idiopathic sudden sensorineural hearing loss compared with steroid use alone (13).…”

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confidence: 99%

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Calcium Channel Blockers and the Risk of Sensorineural Hearing Loss

Sutton

Magagnoli

Cummings

et al. 2021

Otology &Amp; Neurotology

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Objective: To evaluate calcium channel blockers as a potential prophylactic agent for sensorineural hearing loss (SNHL). Patients: We used a retrospective cohort of US veterans treated by the Veteran's Affairs healthcare system. Patients were included in the study if 1) they were diagnosed with high blood pressure; 2) had no previous diagnosis of SNHL; 3) were prescribed a calcium channel blocker after diagnosis or as a control cohort, patients who had no antihypertensive medication use. Intervention: Patients were categorized into mutually exclusive cohorts by their antihypertensive medication exposure: calcium channel blocker exposed and no antihypertensive medication exposure. Main Outcome Measure: Incident SNHL was defined as an inpatient or outpatient record with diagnosis codes international classification of diseases (ICD)-9-CM 389.1 or ICD-10-CM H90, H90.41, H90.42, H90.A21, H90.A22. An audiology or otolaryngology clinic visit was required for patients with an outpatient diagnosis of SNHL.Results: A total of 1,338,409 patients met the inclusion criteria consisting of 292,981 patients with CCBs (25,614 with verapamil and 267,367 with other CCBs) and 1,045,428 patients with no antihypertensive medication. On average, patients were middle-aged, White men with a body mass index (BMI) of 30þ. Cox proportional hazards model estimates from propensity score matched data revealed CCB users had a 23.6% decreased risk of SNHL compared with those with no antihypertensive medication use (hazard ratios [HR] ¼ 0.764; 95% confidence interval ¼ [0.752-0.777]). Conclusion: This analysis found evidence supporting the theory that calcium channel blockers might be a potential prophylactic agent for sensorineural hearing loss. Additional research is warranted.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Calcium Channel Blockers and the Risk of Sensorineural Hearing Loss

Sutton

Magagnoli

Cummings

et al. 2021

Otology &Amp; Neurotology

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“…OTO-104(poloxamer hydrogel containing dexamethasone) provides a sustained-exposure to dexamethasone and alleviates cisplatin-induced ototoxicity ( Fernandez et al., 2016 ). A Diltiazem (calcium-channel blocker)-loaded chitosan-glycerophosphate (CGP) hydrogel has been used as a vehicle to provide controlled and sustained delivery to the inner ear ( Naples et al., 2020 ). In addition, hydrogel itself can be cross-linked with functional reagents, such as genipin or STS, with potential therapeutic effect ( Videhult Pierre et al., 2019 ; Yuksel Aslier et al., 2019 ).…”

Section: Strategies To Combat Cisplatin-induced Ototoxicitymentioning

confidence: 99%

Current Strategies to Combat Cisplatin-Induced Ototoxicity

Chen

et al. 2020

Front. Pharmacol.

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Cisplatin is widely used for the treatment of a number of solid malignant tumors. However, ototoxicity induced by cisplatin is an obstacle to effective treatment of tumors. The basis for this toxicity has not been fully elucidated. It is generally accepted that hearing loss is due to excessive production of reactive oxygen species by cells of the cochlea. In addition, recent data suggest that inflammation may trigger inner ear cell death through endoplasmic reticulum stress, autophagy, and necroptosis, which induce apoptosis. Strategies have been extensively explored by which to prevent, alleviate, and treat cisplatin-induced ototoxicity, which minimize interference with antitumor activity. Of these strategies, none have been approved by the Federal Drug Administration, although several preclinical studies have been promising. This review highlights recent strategies that reduce cisplatin-induced ototoxicity. The focus of this review is to identify candidate agents as novel molecular targets, drug administration routes, delivery systems, and dosage schedules. Animal models of cisplatin ototoxicity are described that have been used to evaluate drug efficacy and side effect prevention. Finally, clinical reports of otoprotection in patients treated with cisplatin are highlighted. For the future, high-quality studies are required to provide reliable data regarding the safety and effectiveness of pharmacological interventions that reduce cisplatin-induced ototoxicity.

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“…Unfortunately, cisplatin HL is difficult to reproduce in a mouse model, as important systemic toxicity generally arises before the onset of mild to moderate ototoxicity. Current mouse models to study ototoxic adverse effects of cisplatin consist of intraperitoneal (IP) cisplatin injection of a single high dose (e.g., Parham, 2011 ; Naples et al, 2020 ) or lower doses in a repeated fashion ( Breglio et al, 2017 ; Fernandez et al, 2019 ; DeBacker et al, 2020 ). However, in such models, strong toxicity and animal distress are observed, including important weight loss and ataxia, raising important and prohibitive ethical concerns.…”

Section: Introductionmentioning

confidence: 99%

Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

Nacher-Soler

Lenglet

Coelho

et al. 2021

Front. Cell. Neurosci.

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Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.

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Intratympanic Diltiazem-Chitosan Hydrogel as an Otoprotectant Against Cisplatin-Induced Ototoxicity in a Mouse Model

Cited by 10 publications

References 55 publications

Calcium Channel Blockers and the Risk of Sensorineural Hearing Loss

Calcium Channel Blockers and the Risk of Sensorineural Hearing Loss

Current Strategies to Combat Cisplatin-Induced Ototoxicity

Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

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