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Article ; Online: Mechanisms of Ototoxicity and Otoprotection.

Steyger, Peter S

Otolaryngologic clinics of North America

2021 Volume 54, Issue 6, Page(s) 1101–1115

Abstract: Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of environmental exposures (eg, lead, cadmium, solvents). This article reviews the ... ...

Abstract	Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of environmental exposures (eg, lead, cadmium, solvents). This article reviews the fundamental mechanisms underlying ototoxicity by clinically relevant, hospital-prescribed medications (ie, aminoglycoside antibiotics or cisplatin, as illustrative examples). Also reviewed are current strategies to prevent prescribed medication-induced ototoxicity, with several clinical or candidate interventional strategies being discussed.
MeSH term(s)	Aminoglycosides/adverse effects ; Anti-Bacterial Agents/adverse effects ; Cisplatin/adverse effects ; Ear, Inner ; Humans ; Ototoxicity
Chemical Substances	Aminoglycosides ; Anti-Bacterial Agents ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2021-11-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	417489-6
ISSN	1557-8259 ; 0030-6665
ISSN (online)	1557-8259
ISSN	0030-6665
DOI	10.1016/j.otc.2021.08.007
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Article: Mechanisms Involved in Ototoxicity.

Steyger, Peter S

Seminars in hearing

2021 Volume 32, Issue 3, Page(s) 217–228

Abstract: The modern era of evidence-based ototoxicity emerged in the 1940s following the discovery of aminoglycosides and their ototoxic side effects. New classes of ototoxins have been identified in subsequent decades, notably loop diuretics, antineoplastic ... ...

Abstract	The modern era of evidence-based ototoxicity emerged in the 1940s following the discovery of aminoglycosides and their ototoxic side effects. New classes of ototoxins have been identified in subsequent decades, notably loop diuretics, antineoplastic drugs, and metal chelators. Ototoxic drugs are frequently nephrotoxic, as both organs regulate fluid and ion composition. The mechanisms of ototoxicity are as diverse as the pharmacological properties of each ototoxin, though the generation of toxic levels of reactive oxygen species appears to be a common denominator. As mechanisms of cytotoxicity for each ototoxin continue to be elucidated, a new frontier in ototoxicity is emerging: How do ototoxins cross the blood-labyrinth barrier that tightly regulates the composition of the inner ear fluids? Increased knowledge of the mechanisms by which systemic ototoxins are trafficked across the blood-labyrinth barrier into the inner ear is critical to developing new pharmacotherapeutic agents that target the blood-labyrinth barrier to prevent trafficking of ototoxic drugs and their cytotoxic sequelae.
Language	English
Publishing date	2021-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	604961-8
ISSN	1098-8955 ; 0734-0451
ISSN (online)	1098-8955
ISSN	0734-0451
DOI	10.1055/s-0031-1286616
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Article ; Online: Mechanisms of Aminoglycoside- and Cisplatin-Induced Ototoxicity.

Steyger, Peter S

American journal of audiology

2021 Volume 30, Issue 3S, Page(s) 887–900

Abstract: Purpose This review article summarizes our current understanding of the mechanisms underlying acquired hearing loss from hospital-prescribed medications that affects as many as 1 million people each year in Western Europe and North America. Yet, there ... ...

Abstract	Purpose This review article summarizes our current understanding of the mechanisms underlying acquired hearing loss from hospital-prescribed medications that affects as many as 1 million people each year in Western Europe and North America. Yet, there are currently no federally approved drugs to prevent or treat the debilitating and permanent hearing loss caused by the life-saving platinum-based anticancer drugs or the bactericidal aminoglycoside antibiotics. Hearing loss has long-term impacts on quality-of-life measures, especially in young children and older adults. This review article also highlights some of the current knowledge gaps regarding iatrogenic causes of hearing loss. Conclusion Further research is urgently needed to further refine clinical practice and better ameliorate iatrogenic drug-induced hearing loss.
MeSH term(s)	Aged ; Aminoglycosides/adverse effects ; Anti-Bacterial Agents/adverse effects ; Antineoplastic Agents/adverse effects ; Child ; Child, Preschool ; Cisplatin/adverse effects ; Humans ; Ototoxicity
Chemical Substances	Aminoglycosides ; Anti-Bacterial Agents ; Antineoplastic Agents ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2021-08-20
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1162315-9
ISSN	1558-9137 ; 1059-0889
ISSN (online)	1558-9137
ISSN	1059-0889
DOI	10.1044/2021_AJA-21-00006
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Article ; Online: Mechanisms and Impact of Aminoglycoside-Induced Vestibular Deficits.

Janky, Kristen / Steyger, Peter S

American journal of audiology

2023 Volume 32, Issue 3S, Page(s) 746–760

Abstract: Purpose: Acquired vestibulotoxicity from hospital-prescribed medications such as aminoglycoside antibiotics affects as many as 40,000 people each year in North America. However, there are no current federally approved drugs to prevent or treat the ... ...

Abstract	Purpose: Acquired vestibulotoxicity from hospital-prescribed medications such as aminoglycoside antibiotics affects as many as 40,000 people each year in North America. However, there are no current federally approved drugs to prevent or treat the debilitating and permanent loss of vestibular function caused by bactericidal aminoglycoside antibiotics. This review will cover our current understanding of the impact of, and mechanisms underlying, aminoglycoside-induced vestibulotoxicity and highlight the gaps in our knowledge that remain. Conclusions: Aminoglycoside-induced vestibular deficits have long-term impacts on patients across the lifespan. Additionally, the prevalence of aminoglycoside-induced vestibulotoxicity appears to be greater than cochleotoxicity. Thus, monitoring for vestibulotoxicity should be independent of auditory monitoring and encompass patients of all ages from young children to older adults before, during, and after aminoglycoside therapy.
MeSH term(s)	Child ; Humans ; Child, Preschool ; Aged ; Aminoglycosides/adverse effects ; Anti-Bacterial Agents/adverse effects ; Vestibule, Labyrinth
Chemical Substances	Aminoglycosides ; Anti-Bacterial Agents
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	1162315-9
ISSN	1558-9137 ; 1059-0889
ISSN (online)	1558-9137
ISSN	1059-0889
DOI	10.1044/2023_AJA-22-00199
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Book ; Online: Cellular Mechanisms of Ototoxicity

Zuo, Jian / Watts, Kelly / Esquivel, Carlos / Cunningham, Lisa / Steyger, Peter S.

2018

Abstract: The auditory perception of sounds (environmental, vocal or music) is one of the 5 principal senses consciously monitored by our brains, and is crucial for many human endeavors as well as quality of life. Loss of optimal performance in this principal ... ...

Abstract	The auditory perception of sounds (environmental, vocal or music) is one of the 5 principal senses consciously monitored by our brains, and is crucial for many human endeavors as well as quality of life. Loss of optimal performance in this principal sensory system leads to loss of effective communication and intimacy, as well as increased risk of isolation, depression, cognitive decline, and greater vulnerability to predators.The vestibular system ensures that individuals remain upright and effectively monitor their posture within their spatial surroundings, move effectively, and remain focused on visual targets during motion. The loss of vestibular sensitivity results in postural instability, falls, inability to observe the environment during motion, and a debilitating incapacity to function effectively.- The sensory cells for both auditory and vestibular systems are located within the inner ear of the temporal bulla.There are many causes of auditory and vestibular deficits, including congenital (or genetic) events, trauma, aging and loud sound exposures. Ototoxicity refers to damage of the auditory or vestibular structures or functions, as the result of exposure to certain pharmaceuticals, chemicals, and/or ionizing radiation exposure that damage the inner ear. Ototoxicity is a major contributor to acquired hearing loss and vestibular deficits, and is entirely preventable.In 2009, the United States Department of Defense initiated the Hearing Center of Excellence (HCE), headquartered in San Antonio, Texas, in response to the prevalence of acquired auditory and vestibular deficits in military and veteran populations.- The knowledge shared in this eBook supports the HCE's mandate to improve aural protection of military and civilian populations worldwide.The last few years have seen significant advances in understanding the cellular mechanisms underlying ototoxic drug-induced hearing loss and vestibular deficits. In this eBook, we present some of these advances and highlight gaps where further research is needed. Selected articles discuss candidate otoprotective agents that can ameliorate the effects of ototoxicity in the context of how they illustrate cellular mechanisms of ototoxicity. Our goal in illustrating these advances in mechanisms of ototoxicity is to accelerate the development of clinical therapies that prevent or reverse this debilitating disorder
Keywords	Science (General) ; Neurosciences. Biological psychiatry. Neuropsychiatry
Size	1 electronic resource (292 p.)
Publisher	Frontiers Media SA
Document type	Book ; Online
Note	English ; Open Access
HBZ-ID	HT020101798
ISBN	9782889454839 ; 2889454835
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article: Local Delivery of Therapeutics to the Cochlea Using Nanoparticles and Other Biomaterials.

Dash, Shreshtha / Zuo, Jian / Steyger, Peter S

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 9

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 ... ...

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 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.
Language	English
Publishing date	2022-09-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15091115
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Article ; Online: Aminoglycoside- and Cisplatin-Induced Ototoxicity: Mechanisms and Otoprotective Strategies.

Kros, Corné J / Steyger, Peter S

Cold Spring Harbor perspectives in medicine

2019 Volume 9, Issue 11

Abstract: Ototoxicity refers to damage of inner ear structures (i.e., the cochlea and vestibule) and their function (hearing and balance) following exposure to specific in-hospital medications (i.e., aminoglycoside antibiotics, platinum-based drugs), as well as a ... ...

Abstract	Ototoxicity refers to damage of inner ear structures (i.e., the cochlea and vestibule) and their function (hearing and balance) following exposure to specific in-hospital medications (i.e., aminoglycoside antibiotics, platinum-based drugs), as well as a variety of environmental or occupational exposures (e.g., metals and solvents). This review provides a narrative derived from relevant papers describing factors contributing to (or increasing the risk of) aminoglycoside and cisplatin-induced ototoxicity. We also review current strategies to protect against ototoxicity induced by these indispensable pharmacotherapeutic treatments for life-threatening infections and solid tumors. We end by highlighting several interventional strategies that are currently in development, as well as the diverse challenges that still need to be overcome to prevent drug-induced hearing loss.
MeSH term(s)	Aminoglycosides/adverse effects ; Aminoglycosides/therapeutic use ; Animals ; Anti-Bacterial Agents/adverse effects ; Anti-Bacterial Agents/therapeutic use ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/therapeutic use ; Cisplatin/adverse effects ; Cisplatin/therapeutic use ; Cochlea/drug effects ; Drug Discovery ; Hearing Loss/chemically induced ; Hearing Loss/prevention & control ; Humans ; Neoplasms/drug therapy ; Protective Agents/pharmacology
Chemical Substances	Aminoglycosides ; Anti-Bacterial Agents ; Antineoplastic Agents ; Protective Agents ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2019-11-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a033548
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Article ; Online: Reader response: Neurologic complications of coronavirus infections.

Steyger, Peter S / Kujawa, Sharon G / Shinobu, Leslie A

Neurology

2020 Volume 95, Issue 7, Page(s) 324

MeSH term(s)	Coronavirus Infections ; Humans ; Nervous System Diseases
Keywords	covid19
Language	English
Publishing date	2020-08-20
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000010229
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Article: Preferential Cochleotoxicity of Cisplatin.

Prayuenyong, Pattarawadee / Baguley, David M / Kros, Corné J / Steyger, Peter S

Frontiers in neuroscience

2021 Volume 15, Page(s) 695268

Abstract: Cisplatin-induced ototoxicity in humans is more predominant in the cochlea than in the vestibule. Neither definite nor substantial vestibular dysfunction after cisplatin treatment has been consistently reported in the current literature. Inner ear hair ... ...

Abstract	Cisplatin-induced ototoxicity in humans is more predominant in the cochlea than in the vestibule. Neither definite nor substantial vestibular dysfunction after cisplatin treatment has been consistently reported in the current literature. Inner ear hair cells seem to have intrinsic characteristics that make them susceptible to direct exposure to cisplatin. The existing literature suggests, however, that cisplatin might have different patterns of drug trafficking across the blood-labyrinth-barrier, or different degrees of cisplatin uptake to the hair cells in the cochlear and vestibular compartments. This review proposes an explanation for the preferential cochleotoxicity of cisplatin based on current evidence as well as the anatomy and physiology of the inner ear. The endocochlear potential, generated by the stria vascularis, acting as the driving force for hair cell mechanoelectrical transduction might also augment cisplatin entry into cochlear hair cells. Better understanding of the stria vascularis might shed new light on cochleotoxic mechanisms and inform the development of otoprotective interventions to moderate cisplatin associated ototoxicity.
Language	English
Publishing date	2021-07-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2021.695268
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Article ; Online: Hepatocyte growth factor mimetic confers protection from aminoglycoside-induced hair cell death in vitro.

Uribe, Phillip M / Hudson, Alexandria M / Lockard, Gavin / Jiang, Meiyan / Harding, Joseph / Steyger, Peter S / Coffin, Allison B

Hearing research

2023 Volume 434, Page(s) 108786

Abstract: Loss of sensory hair cells from exposure to certain licit drugs, such as aminoglycoside antibiotics, can result in permanent hearing damage. Exogenous application of the neurotrophic molecule hepatocyte growth factor (HGF) promotes neuronal cell survival ...

Abstract	Loss of sensory hair cells from exposure to certain licit drugs, such as aminoglycoside antibiotics, can result in permanent hearing damage. Exogenous application of the neurotrophic molecule hepatocyte growth factor (HGF) promotes neuronal cell survival in a variety of contexts, including protecting hair cells from aminoglycoside ototoxicity. HGF itself is not an ideal therapeutic due to a short half-life and limited blood-brain barrier permeability. MM-201 is a chemically stable, blood-brain barrier permeable, synthetic HGF mimetic that serves as a functional ligand to activate the HGF receptor and its downstream signaling cascade. We previously demonstrated that MM-201 robustly protects zebrafish lateral line hair cells from aminoglycoside ototoxicity. Here, we examined the ability of MM-201 to protect mammalian sensory hair cells from aminoglycoside damage to further evaluate MM-201's clinical potential. We found that MM-201 exhibited dose-dependent protection from neomycin and gentamicin ototoxicity in mature mouse utricular explants. MM-201's protection was reduced following inhibition of mTOR, a downstream target of HGF receptor activation, implicating the activation of endogenous intracellular substrates by MM-201 as critical for the observed protection. We then asked if MM-201 altered the bactericidal properties of aminoglycosides. Using either plate or liquid growth assays we found that MM-201 did not alter the bactericidal efficacy of aminoglycoside antibiotics at therapeutically relevant concentrations. We therefore assessed the protective capacity of MM-201 in an in vivo mouse model of kanamycin ototoxicity. In contrast to our in vitro data, MM-201 did not attenuate kanamycin ototoxicity in vivo. Further, we found that MM-201 was ototoxic to mice across the dose range tested here. These data suggest species- and tissue-specific differences in otoprotective capacity. Next generation HGF mimetics are in clinical trials for neurodegenerative diseases and show excellent safety profiles, but neither preclinical studies nor clinical trials have examined hearing loss as a potential consequence of pharmaceutical HGF activation. Further research is needed to determine the consequences of systemic MM-201 application on the auditory system.
MeSH term(s)	Mice ; Animals ; Aminoglycosides/toxicity ; Proto-Oncogene Proteins c-met/pharmacology ; Zebrafish ; Ototoxicity ; Hepatocyte Growth Factor/pharmacology ; Anti-Bacterial Agents/toxicity ; Cell Death ; Kanamycin/toxicity ; Mammals
Chemical Substances	Aminoglycosides ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Hepatocyte Growth Factor (67256-21-7) ; Anti-Bacterial Agents ; Kanamycin (59-01-8)
Language	English
Publishing date	2023-05-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	282629-x
ISSN	1878-5891 ; 0378-5955
ISSN (online)	1878-5891
ISSN	0378-5955
DOI	10.1016/j.heares.2023.108786
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