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Pharmaceuticals
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Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies
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Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 20736

Special Issue Editors

Prof. Peter S. Steyger

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Guest Editor
Translational Hearing Center, Biomedical Sciences, Creighton University, Omaha, NE, USA
Interests: ototoxicity; cochleotoxicity; aminoglycosides; inflammatory responses; blood–labyrinth barrier; drug screening; drug delivery; pharmacokinetics and pharmacodynamics of ototoxic and otoprotection drugs; ex vivo and in vivo animal models for testing hearing
Prof. Dr. Sonia M. Rocha-Sanchez

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Co-Guest Editor
Department of Oral Biology, Creighton University, Omaha, NE, USA
Interests: hair cell regeneration; cell cycle manipulation; regenerative strategies; otoprotection; ototoxicity; drug screening; drug development; pharmacological interventions
Dr. E. Jeffrey North

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Co-Guest Editor
Department of Pharmacy Sciences, Creighton University, Omaha, NE, USA
Interests: ototoxicity; otoprotective strategies; antimicrobials; medicinal chemistry; drug discovery/development; pharmacokinetics
Dr. Tal Teitz

E-Mail Website
Co-Guest Editor
Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, USA
Interests: hearing loss; chemotherapy- and noise-induced hearing loss; drug screenings; drug development; repurposing drugs for hearing protection; drug delivery; combination therapies; anti-apoptotic drugs including kinase inhibitors; anti-cancer and anti-inflammatory agents; ex vivo and in vivo models for testing hearing; cellular mechanisms of otoprotection; role of the supporting cells in otoprotection

Special Issue Information

Dear Colleagues,

Cells within the inner ear are protected by the blood–labyrinth barrier (BLB; endothelial cells of the inner ear vasculature) and by the epithelial cells lining the endolymphatic duct. In homeostatic conditions, this strict permeability barrier is required to maintain the electrophysiological environment that enables sensitive auditory and vestibular functions. However, in circumstances that require therapeutic interventions for otoprotection or repair of inner ear structures, the permeability of the BLB becomes a significant challenge. For example, while clinically essential, yet cochleotoxic and vestibulotoxic, aminoglycosides and cisplatin readily cross the BLB, but other compounds intended to maintain or protect the inner ear may be unable to do so. Furthermore, preclinical models that facilitate the discovery of otoprotective compounds and mimic the medical settings in which ototoxicity occurs to validate and optimize candidate ototprotective compounds are critically required. For this special issue, we invite original research and review manuscripts in two broad categories:

(i) Mechanisms of ototoxicity, including but not limited to transport of ototoxins across the blood–labyrinth barrier, including anatomy and physiology; paracellular, expression, and kinetics of drug-permeant ion channels and transporters for uptake and elimination of ototoxins, pharmacokinetics and pharmacodynamics within the inner ear, inner ear intracellular signalling pathways, development of preclinical of clinical settings where ototoxicity is prevalent, modulation by comorbidities (e.g., aging, inflammation, injury, ischemia, neurodegenerative disease, noise trauma), genetic polymorphisms, and dysfunction;

(ii) Strategies for otoprotection, including but not limited to drug discovery, drug screening, drug–response curves, dosage strategies, local and systemic drug delivery and clearance of otoprotective compounds from the inner ear, balance of drug toxicities to therapeutic benefits, challenges related to the delivery of gene therapies, nanotechnologies, biologics, or small molecules, drug repurposing, structure–activity relationships in developing and testing otoprotective drugs, preclinical models for testing efficacy of otoprotective drugs in clinically relevant settings, and role of supporting cells in otoprotection of sensory hair cells.

Ultimately, all manuscripts should focus on the translational aspects of developing drugs, other genetic and biomedical strategies for preserving sensory hair cells within the inner ear with putative high clinical/translational impact, and/or the cellular mechanism(s) by which these drugs/strategies work during/after exposure to ototoxic drugs. All manuscripts should also discuss gaps in knowledge for that specific topic that need to be addressed.

Prof. Peter S. Steyger
Prof. Sonia M. Rocha-Sanchez
Dr. E. Jeffrey North
Dr. Tal Teitz

Guest Editors

Keywords

  • Ototoxicity
  • Cochleotoxicity
  • Vestibulotoxicity
  • Ototoxins
  • Aminoglycosides
  • Cisplatin
  • Noise
  • Inflammatory responses
  • Otoprotective compounds
  • Blood–labyrinth barrier
  • Blood–labyrinth barrier permeability
  • Drug delivery to the inner ear
  • Drug screening
  • Drug development
  • Repurposing drugs
  • Anti-cancer drugs
  • Animal models for testing ototoxicity
  • Sensory cells of the inner ear
  • Supporting cells of the inner ear

Published Papers (7 papers)

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Research

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13 pages, 2978 KiB  
Article
An In Vitro Model for Characterization of Drug Permeability across the Tympanic Membrane
by Joachim G. S. Veit, Bhaskar Birru, Ruby Singh, Elizabeth M. Arrigali and Monica A. Serban
Pharmaceuticals 2022, 15(9), 1114; https://doi.org/10.3390/ph15091114 - 07 Sep 2022
Cited by 3 | Viewed by 2982
Abstract
Otic disorders, such as otitis media and hearing loss, affect a substantial portion of the global population. Despite this, oto-therapeutics, in particular those intended to treat hearing loss, have seen limited development and innovation. A significant factor to this is likely a result [...] Read more.
Otic disorders, such as otitis media and hearing loss, affect a substantial portion of the global population. Despite this, oto-therapeutics, in particular those intended to treat hearing loss, have seen limited development and innovation. A significant factor to this is likely a result of the inherent costs and complexities of drug discovery and development. With in vitro 3D tissue models seeing increased utility for the rapid, high-throughput screening of drug candidates, it stands to reason that the field of otology could greatly benefit from such innovations. In this study, we propose and describe an in vitro 3D model, designed using a physiologically based approach, which we suggest can be used to estimate drug permeability across human tympanic membranes (TM). We characterize the permeability properties of several template drugs in this model under various growth and storage conditions. The availability of such cost-effective, rapid, high-throughput screening tools should allow for increased innovation and the discovery of novel drug candidates over the currently used animal models. In the context of this TM permeation model, it may promote the development of topical drugs and formulations that can non-invasively traverse the TM and provide tissue-targeted drug delivery as an alternative to systemic treatment, an objective which has seen limited study until present. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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14 pages, 15488 KiB  
Article
Development and Characterization of an In Vitro Round Window Membrane Model for Drug Permeability Evaluations
by Ruby Singh, Bhaskar Birru, Joachim G. S. Veit, Elizabeth M. Arrigali and Monica A. Serban
Pharmaceuticals 2022, 15(9), 1105; https://doi.org/10.3390/ph15091105 - 05 Sep 2022
Cited by 5 | Viewed by 2603
Abstract
Hearing loss and balance disorders are highly common disorders, and the development of effective oto-therapeutics remains an area of intense research. Drug development and screening in the hearing research field heavily rely on the use of preclinical models with often ambiguous translational relevance. [...] Read more.
Hearing loss and balance disorders are highly common disorders, and the development of effective oto-therapeutics remains an area of intense research. Drug development and screening in the hearing research field heavily rely on the use of preclinical models with often ambiguous translational relevance. This often leads to failed advancement in the market of effective therapeutics. In this context, especially for inner ear-specific pathologies, the availability of an in vitro, physiologically relevant, round window membrane (RWM) model could enable rapid, high-throughput screening of potential topical drugs for inner ear and cochlear dysfunctions and could help accelerate the advancement to clinic and market of more viable drug candidates. In this study, we report the development and evaluation of an in vitro model that mimics the native RWM tissue morphology and microenvironment as shown via immunostaining and histological analyses. The developed three-dimensional (3D) in vitro model was additionally assessed for barrier integrity by transepithelial electrical resistance, and the permeability of lipophilic and hydrophilic drugs was determined. Our collective findings suggest that this in vitro model could serve as a tool for rapid development and screening of topically deliverable oto-therapeutics. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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11 pages, 6499 KiB  
Article
An Evaluation of the Drug Permeability Properties of Human Cadaveric In Situ Tympanic and Round Window Membranes
by Joachim G. S. Veit, Bhaskar Birru, Yong Wang, Ruby Singh, Elizabeth M. Arrigali, Ryan Park, Briggs Miller, Matthew A. Firpo, Albert H. Park and Monica A. Serban
Pharmaceuticals 2022, 15(9), 1037; https://doi.org/10.3390/ph15091037 - 23 Aug 2022
Cited by 9 | Viewed by 2191
Abstract
It is estimated that hearing loss currently affects more than 1.5 billion people, or approximately 20% of the global population; however, presently, there are no Food and Drug Administration-approved therapeutics or prophylactics for this condition. While continued research on the development of otoprotective [...] Read more.
It is estimated that hearing loss currently affects more than 1.5 billion people, or approximately 20% of the global population; however, presently, there are no Food and Drug Administration-approved therapeutics or prophylactics for this condition. While continued research on the development of otoprotective drugs to target this clear unmet need is an obvious path, there are numerous challenges to translating promising therapeutic candidates into human clinical testing. The screening of promising drug candidates relies exclusively on preclinical models. Current models do not permit the rapid high-throughput screening of promising drug candidates, and their relevance to clinical scenarios is often ambiguous. With the current study, we seek to understand the drug permeability properties of the cadaveric tympanic and round window membranes with the goal of generating knowledge that could inform the design and/or evaluation of in vitro organotypic models. The development of such models could enable the early high-throughput screening of topical therapeutic candidates and should address some of the limitations of currently used animal models. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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13 pages, 2897 KiB  
Communication
Encapsulation of Alpha-Lipoic Acid in Functional Hybrid Liposomes: Promising Tool for the Reduction of Cisplatin-Induced Ototoxicity
by Manuela Curcio, Giuseppe Cirillo, Rosario Amato, Lorenzo Guidotti, Diana Amantea, Michele De Luca, Fiore Pasquale Nicoletta, Francesca Iemma and Mercedes Garcia-Gil
Pharmaceuticals 2022, 15(4), 394; https://doi.org/10.3390/ph15040394 - 24 Mar 2022
Cited by 7 | Viewed by 2335
Abstract
In this study, in order to address the drawback of cisplatin (CDDP)-induced ototoxicity, we propose a straightforward strategy based on the delivery of a sulfur-based antioxidant, such as lipoic acid (LA), to HEI-OC1 cells. To this aim, hybrid liposomes (LA@PCGC) with a spherical [...] Read more.
In this study, in order to address the drawback of cisplatin (CDDP)-induced ototoxicity, we propose a straightforward strategy based on the delivery of a sulfur-based antioxidant, such as lipoic acid (LA), to HEI-OC1 cells. To this aim, hybrid liposomes (LA@PCGC) with a spherical shape and a mean diameter of 25 nm were obtained by direct sonication of LA, phosphatidylcholine and a gelatin-curcumin conjugate in a physiological buffer. LA@PCGC were found to be stable over time, were quickly (i.e., by 1 h) taken up by HEI-OC1 cells, and guaranteed strong retention of the bioactive molecule, since LA release was less than 20%, even after 100 h. Cell viability studies showed the efficiency of LA@PCGC for stabilizing the protective activity of LA. Curcumin residues within the functional liposomes were indeed able to maintain the biological activity of LA, significantly improving (up to 2.19-fold) the viability of HEI-OC1 cells treated with 5 μM CDDP. Finally, LA@PCGC was incorporated within an alginate-based injectable hydrogel carrier to create a formulation with physical chemical features suitable for potential ear applications. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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10 pages, 3423 KiB  
Article
Association between Statin Use and Sensorineural Hearing Loss in Type 2 Diabetic Patients: A Hospital-Based Study
by Hye-Won Han, Jeong Yee, Yoon-Hee Park and Hye-Sun Gwak
Pharmaceuticals 2021, 14(11), 1076; https://doi.org/10.3390/ph14111076 - 25 Oct 2021
Cited by 2 | Viewed by 3779
Abstract
Statins have emerged as protective agents against sensorineural hearing loss (SNHL) associated with dyslipidemia, but the effects of statins on SNHL are not consistent. The purpose of this study was to investigate the association between statin use and the risk of SNHL using [...] Read more.
Statins have emerged as protective agents against sensorineural hearing loss (SNHL) associated with dyslipidemia, but the effects of statins on SNHL are not consistent. The purpose of this study was to investigate the association between statin use and the risk of SNHL using a hospital cohort. This nested case-control study included type 2 diabetic patients over the age of 18 years without a history of hearing loss. Of these, 1379 patients newly diagnosed with SNHL or tinnitus were classified as cases, and 5512 patients matched to the cases based on age, sex, and index year were classified as controls. Chi-squared tests were used to compare categorical variables between the two groups. Odds ratios (ORs) and adjusted odds ratios (AOR) were calculated from univariate and multivariable unconditional logistic regression analyses, respectively. There was a significant difference in the prevalence of statin use between the cases and controls (53.7% vs. 61.2%, respectively; p < 0.001). The use of statins in type 2 diabetic patients significantly reduced the risk of SNHL or tinnitus by 24.8% (95% CI 14.2–34.1%, p < 0.001) after controlling for confounders. Similar results were found for the association between statin use and SNHL (AOR = 0.706; 95% CI 0.616–0.811, p < 0.001). The protective effects of statins against SNHL were consistent regardless of age and sex. The use of statins for type 2 diabetic patients was significantly associated with a reduced risk of SNHL, regardless of age and sex. Further studies are needed, especially large cohort studies, to evaluate the long-term protective effects of statins. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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Review

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20 pages, 1534 KiB  
Review
Local Delivery of Therapeutics to the Cochlea Using Nanoparticles and Other Biomaterials
by Shreshtha Dash, Jian Zuo and Peter S. Steyger
Pharmaceuticals 2022, 15(9), 1115; https://doi.org/10.3390/ph15091115 - 07 Sep 2022
Cited by 4 | Viewed by 3761
Abstract
Hearing loss negatively impacts the well-being of millions of people worldwide. Systemic delivery of ototherapeutics has limited efficacy due to severe systemic side effects and the presence of the blood–labyrinth barrier that selectively limits or enables transfer of molecules between plasma and inner [...] Read more.
Hearing loss negatively impacts the well-being of millions of people worldwide. Systemic delivery of ototherapeutics has limited efficacy due to severe systemic side effects and the presence of the blood–labyrinth barrier that selectively limits or enables transfer of molecules between plasma and inner ear tissues and fluids. Local drug delivery into the middle and inner ear would be preferable for many newly emerging classes of drugs. Although the cochlea is a challenging target for drug delivery, recent technologies could provide a safe and efficacious delivery of ototherapeutics. Local drug delivery routes include topical delivery via the external auditory meatus, retroauricular, transtympanic, and intracochlear delivery. Many new drug delivery systems specifically for the inner ear are under development or undergoing clinical studies. Future studies into these systems may provide a means for extended delivery of drugs to preserve or restore hearing in patients with hearing disorders. This review outlines the anatomy of the (inner) ear, describes the various local delivery systems and routes, and various quantification methodologies to determine the pharmacokinetics of the drugs in the inner ear. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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14 pages, 444 KiB  
Review
Nitrative Stress and Auditory Dysfunction
by Monazza Shahab and Samson Jamesdaniel
Pharmaceuticals 2022, 15(6), 649; https://doi.org/10.3390/ph15060649 - 24 May 2022
Cited by 2 | Viewed by 1761
Abstract
Nitrative stress is increasingly recognized as a critical mediator of apoptotic cell death in many pathological conditions. The accumulation of nitric oxide along with superoxide radicals leads to the generation of peroxynitrite that can eventually result in the nitration of susceptible proteins. Nitrotyrosine [...] Read more.
Nitrative stress is increasingly recognized as a critical mediator of apoptotic cell death in many pathological conditions. The accumulation of nitric oxide along with superoxide radicals leads to the generation of peroxynitrite that can eventually result in the nitration of susceptible proteins. Nitrotyrosine is widely used as a biomarker of nitrative stress and indicates oxidative damage to proteins. Ototoxic insults, such as exposure to noise and ototoxic drugs, enhance the generation of 3-nitrotyrosine in different cell types in the cochlea. Nitrated proteins can disrupt critical signaling pathways and eventually lead to apoptosis and loss of sensory receptor cells in the cochlea. Accumulating evidence shows that selective targeting of nitrative stress attenuates cellular damage. Anti-nitrative compounds, such as peroxynitrite decomposition catalysts and inducible nitric oxide synthase inhibitors, prevent nitrative stress-mediated auditory damage. However, the role of nitrative stress in acquired hearing loss and its potential significance as a promising interventional target is yet to be fully characterized. This review provides an overview of nitrative stress mechanisms, the induction of nitrative stress in the auditory tissue after ototoxic insults, and the therapeutic value of targeting nitrative stress for mitigating auditory dysfunction. Full article
(This article belongs to the Special Issue Drug-induced Ototoxicity: Mechanisms and Otoprotective Strategies)
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