International Journal of Audiology

ISSN: 1499-2027 (Print) 1708-8186 (Online) Journal homepage: https://www.tandfonline.com/loi/iija20

Protection for medication-induced hearing loss:

the state of the science

Tanisha L. Hammill & Kathleen C. Campbell

To cite this article: Tanisha L. Hammill & Kathleen C. Campbell (2018) Protection for medication-
induced hearing loss: the state of the science, International Journal of Audiology, 57:sup4, S87-
S95, DOI: 10.1080/14992027.2018.1455114

To link to this article: https://doi.org/10.1080/14992027.2018.1455114

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INTERNATIONAL JOURNAL OF AUDIOLOGY
2018, VOL. 57, NO. S4, S87–S95
https://doi.org/10.1080/14992027.2018.1455114

REVIEW ARTICLE

Protection for medication-induced hearing loss: the state of the science

Tanisha L. Hammilla,b and Kathleen C. Campbellc
a
Department of Defense Hearing, Center of Excellence, JBSA Lackland, TX, USA; bZcore Business Solutions, LLC, Round Rock, TX, USA;
c
Department of Medical Microbiology, Immunology and Cell Biology, School of Medicine, Southern Illinois University, Springfield, IL, USA

ABSTRACT ARTICLE HISTORY

Objective: This review will summarise the current state of development of pharmaceutical interventions Received 16 March 2017
(prevention or treatment) for medication-induced ototoxicity. Revised 2 March 2018
Design: Currently published literature was reviewed using PubMed and ClinicalTrials.gov to summarise Accepted 8 March 2018
the current state of the science. Details on the stage of development in the market pipeline are provided,
KEYWORDS
along with evidence for clinical safety and efficacy reported. Ototoxicity; hearing loss;
Study sample: This review includes reports from 44 articles and clinical trial reports regarding agents in pharmaceutical; drugs;
clinical or preclinical trials, having reached approved Investigational New Drug status with the Federal treatment; prevention
Drug Administration.
Results: Vitamins and antioxidants are the most common agents currently evaluated for drug-induced
ototoxicity intervention by targeting the oxidative stress pathway that leads to cochlear cell death and
hearing loss. However, other strategies, including steroid treatment and reduction of ototoxic properties
of the primary drugs, are discussed.
Conclusions: Retention of hearing during and after a life threatening illness is a major quality-of-life issue
for patients receiving ototoxic drugs and their families. The agents discussed herein, while not mature
enough at this point, offer great promise towards that goal. This review will provide a knowledge base
for hearing providers to inquiries about such options from patients and interdisciplinary care teams alike.

Abbreviations: ACE Mg: vitamin A (beta carotene), C and E combined with magnesium; Acu-Qter: coen-
zyme Q10 terclatrate and Acuval 400; D-met, D-methionine: DPOAE, Distortion Product Otoacoustic
Emission; FDA: Food and Drug Administration; GSH: Glutathione; NAC: N-acetylcysteine; PPI: proton pump
inhibitor; Q-ter: soluble formulation of coenzyme Q10; ROS: reactive oxygen species; SPI-1005: ebselen;
STS: sodium thiosulphate

Introduction ototoxicity). For detailed evidence of the ototoxic properties of

The term “ototoxic” can be used to refer to any source of non-
mechanical damage to the ear, including several medications,
many solvents, some heavy metals, and possibly select asphyx-
iants (Johnson and Morata 2010) yet ototoxicity is most often
used in the context of clinical, medication-induced hearing loss
or vestibular dysfunction. The field of pharmaceutical interven-
tions for noise-induced hearing loss (NIHL), a condition which
is also largely a result of toxic metabolic cochlear changes, is
worthy of its own review. As such, and coupled with the paucity
of research into any treatment modalities for other ototoxic inju-
ries, this review focuses on the current state of the science for
preventing or treating ototoxicity as most often seen in the clin-
ical setting: induced by medications. While physicians are ultim-
ately responsible for pharmaceutical treatment decisions, this
review aims to inform the audiologist as an interdisciplinary
partner and trusted provider in patient care.
The two most common types of ototoxic drugs are (1) can-
cer-fighting agents, namely platinum-based chemotherapy drugs
such as cisplatin and carboplatin, and (2) intravenously adminis-
tered antibiotics, including aminoglycosides and the glycopeptide
vancomycin (reported to exacerbate aminoglycoside-induced
these agents, see reviews by Campbell et al. (2003), and Campbell
and Fox (2016). A basic summary of the ototoxic mechanisms
of action theorised to cause hearing impairments and
vestibular dysfunction is provided below (also see reviews in
Campbell 2007).
Apoptosis, or cell death, is an essential process for the health
of all aerobic forms of life (beings with cell respiration reliant
upon oxygen). It removes aged or damaged cells, often to clear
the way for new development. In the human inner ear, the latter
is unfortunately not the case, as mammals cannot regenerate
cochlear tissue. Reactive oxygen species (ROS) often serve as the
catalyst for the apoptotic pathway. At the inter-cellular level,
mitochondria most often create ROS as a by-product of electron
transfer. However, various oxidative stressors can trigger the pro-
duction of excessive ROS, and can produce a type of ROS called
free radicals which have an unpaired electron. To return to
homeostasis, the free radical will take an electron from surround-
ing molecules which, in excess, can damage vital cell membrane
lipids and proteins by “stealing” their electron. This triggers cell
death through either the extrinsic death receptor pathway or the

CONTACT Tanisha L. Hammill tanishahammill@gmail.com Department of Defense Hearing Center of Excellence, 2200 Bergquist Drive, Suite 1, JBSA Lackland,
TX 78236, USA
This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In
accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.
This is an Open Access article that has been identified as being free of known restrictions under copyright law, including all related and neighboring rights (https://creativecommons.org/
publicdomain/mark/1.0/). You can copy, modify, distribute and perform the work, even for commercial purposes, all without asking permission.
S88 T. L. HAMMILL AND K. C. CAMPBELL
intrinsic mitochondrial pathway (for more detail see Wang and
Puel 2008 or Jin and El-Deiry 2005).
Glutathione (GSH) is a potent natural intracellular antioxidant,
an ROS scavenger, an anti-apoptotic agent, and has been shown to
protect the cochlea from noise and ototoxic damage (Kopke et al.
1997, 1999; Yamasoba et al. 1998); GSH is one of the auditory sys-
tem’s strongest inherent defence mechanisms and a common target
for intervention approaches. While GSH and other intrinsic defen-
ces normally keep the apoptotic process in balance and protect
against pathologic ROS over-production, this intrinsic system can
become overwhelmed during excessive ROS production secondary
to a toxic exposure. If ROS production exceeds inherent or supple-
mented antioxidant detoxification capabilities and triggers intra-
cochlear cell death pathways, cell death can occur, reducing audi-
tory and/or vestibular functionality. Given the hypothesis that
most ototoxic agents initiate damaging oxidative stress, approaches
for the prevention of ototoxicity-induced auditory sensory loss
include targets all along the cell death cascade. These targets
include: prevention of ROS initiation; neutralising the damage
inflicted by ROS-created free radicals, most notably to the cell
membrane lipids; or blocking the subsequent triggers of intrinsic
or extrinsic apoptosis prior to cell death (Huang et al. 2000).
Protective interventions for each ototoxin are considered with
the unique mechanisms of ototoxic action of the drug in mind, tak-
ing care not to decrease the therapeutic efficacy of the drug for its
intended, often life-saving, purpose. Interventions found to limit
the ototoxin’s therapeutic efficacy or further potentiate ototoxic
effects cannot be considered (Oishi, Kendall, and Schacht 2014).
Common ototoxic medications
Cisplatin is one of the most effective tools against many solid
tumour cancer types (Stewart 1999; de Castria et al. 2013).
Unfortunately, like most chemotherapeutic agents, cisplatin has a
high incidence of side effects, including ototoxicity that can be
seen in nearly all patients treated with higher-dose regimens
(Rybak et al. 2007). The cochlea sustains damage to the outer and
inner hair cells as well as supporting spiral ganglion and stria vas-
cularis cells (Campbell and Fox 2016). The primary mechanism of
action in each of these areas is thought to be the production of
inter-cellular ROS, which can trigger the metabolic apoptotic
pathway (Rybak et al. 2007; Jamesdaniel, Rathinam, and Neumann
2016). Therefore, antioxidant approaches have been widely
attempted to prevent apoptosis at the formative stage of ROS
development (thus preventing all downstream processes in the cell
death cascade) with the ultimate aim to prevent hearing loss.
Aminoglycosides (most commonly tobramycin, gentamicin,
amikacin, and kanamycin) are a class of antibiotics approved for
treatment of potentially life-threatening infections, especially
those caused by gram-negative bacteria, including bacterial endo-
carditis, peritonitis, and line sepsis (Gilbert 2005). While nephro-
toxic side effects are generally reversible, severe ototoxic damage
most often is not, which can lead to permanent hearing loss, ves-
tibular dysfunction, or both (Lerner et al. 1986).
Design and study sample
Currently published literature was reviewed using PubMed and
ClinicalTrials.gov to summarise the current state of the science
using compiled search terms developed with the assistance of a
medical librarian to include any clinical trials to prevent or treat
drug-induced ototoxicity with a chemical agent (Table 1). Of the
1343 articles returned on PubMed, 34 articles were determined to
be pharmaceutical interventions (prevention or treatment) for
drug-induced ototoxicity. Similarly, the ClinicalTrials.gov disease/
condition search was for “hearing loss” with “ototoxic OR
ototoxicity” added and searched with other advanced search crite-
ria left open to all options. Of the 18 trials returned in the search,
10 were added to the 34 PubMed articles for evaluation and dis-
cussion. Details on the stage of development in the market pipeline
are summarised below as available, as are the targeted mechanisms
of action and evidence for clinical safety and efficacy reported.
Agents in or approved for clinical investigations to
mitigate medication-induced ototoxicity (see Table 2)
Antioxidants and vitamins
Vitamins with magnesium
To date, animal work using vitamins A (specifically, beta caro-
tene, the precursor to vitamin A), C, and E, combined with mag-
nesium (ACE Mg) for otoprotection seems promising (Le Prell,
Hughes, and Miller 2007). Clinical trials have only occurred for
NIHL where results have not demonstrated efficacy (Le Prell
et al. 2011; Kil et al. 2017), but pre-clinical work suggests that
this combination may reduce aminoglycoside-induced ototoxicity
(Le Prell et al. 2014). This combination cannot be safely used in
smokers because beta carotene may increase the risk of lung can-
cer (Omenn 1998, 2007) and may be problematic in individuals
with gastric disorders because of the Mg content. Thus, even if
successful in clinical trials, ACE Mg may be contraindicated in
several patient populations. However, a 2016 study by Villani
et al. suggests that vitamin E alone may provide protection
against cisplatin-induced ototoxicity. More research is needed to
confirm these preliminary findings and better understand the
effects of antioxidant vitamins on the auditory system.
Ebselen (SPI-1005)
Either as a single agent (Rybak et al. 2000) or in combination with
allopurinol (Lynch et al. 2005a, 2005b), the anti-inflammatory,
anti-oxidant, GSH-mimic ebselen demonstrated some pre-clinical
efficacy in reducing cisplatin-induced ototoxicity. Conversely,
Lorito et al. (2011) did not find significant cisplatin otoprotection
with ebselen, so results are inconsistent. Ebselen was shown to pre-
vent free radical stresses in cochlear explants, thus preventing the
ROS damage and subsequent apoptotic death typically seen as a
result of cisplatin treatment (Kim et al. 2009). Guinea pig studies
have also demonstrated ebselen protection from gentamicin-
induced ototoxicity, suggesting that protection may extend across
multiple ototoxic agents (Takumida, Popa, and Anniko 1999).
Two clinical trials to evaluate ebselen for ototoxicity protection
are approaching recruitment and enrolment: a phase II study tar-
geting platinum chemotherapy ototoxicity treatment (Kil 2016a),
and a phase I/II study for the prevention and treatment of amino-
glycoside-induced ototoxicity (Kil 2016b). Lynch and Kil (2009)
previously published a phase I safety study that demonstrated a
good safety profile for ebselen in an NIHL population.
N-acetylcysteine (NAC)
Bock et al. first reported in 1983 that N-acetylcysteine (NAC), a
glutathione precursor, exacerbated aminoglycoside-induced hear-
ing loss in the guinea pig model. NAC investigations conducted
since then have demonstrated protection from aminoglycoside-
induced ototoxicity in several human studies (Kocyigit 2011;
Tokgoz et al. 2011). A systematic review with meta-analysis per-
formed by Kranzer and colleagues (Kranzer et al. 2015)
 INTERNATIONAL JOURNAL OF AUDIOLOGY 89

Table 1. List of search terms developed with the assistance of a medical librarian to extract and review any clinical trials to prevent or treat drug-induced ototoxicity
with a chemical agent in currently published literature.
1 Hearing loss[mesh:noexp] OR deafness[mesh:noexp] OR hearing loss, bilateral[mesh:noexp] OR hearing loss, conductive[mesh:noexp] OR hearing
loss, functional[mesh:noexp] OR hearing loss, high-frequency[mesh:noexp] OR hearing loss, mixed conductive-sensorineural[mesh:noexp] OR
hearing loss, sensorineural[mesh:noexp] OR hearing loss, central[mesh:noexp] OR hearing loss, noise-induced[mesh:noexp] OR hearing loss,
sudden[mesh:noexp] OR hearing loss, unilateral/OR (deaf[tiab] OR deafness[tiab] OR hearing loss[tiab])
2 Ear[mesh:noexp] OR ear, middle[mesh:noexp] OR ear, inner[mesh:noexp] OR cochlea[mesh:noexp] OR basilar membrane[mesh:noexp] OR cochlear
aqueduct[mesh:noexp] OR cochlear duct[mesh:noexp] OR “organ of corti”[mesh:noexp] OR hair cells, auditory[mesh:noexp] OR hair cells, audi-
tory, inner[mesh:noexp] OR hair cells, auditory, outer[mesh:noexp] OR labyrinth supporting cells[mesh:noexp] OR round window, ear[mesh:-
noexp] OR scala tympani[mesh:noexp] OR scala vestibuli[mesh:noexp] OR spiral ganglion[mesh:noexp] OR spiral lamina[mesh:noexp] OR
“spiral ligament of cochlea”/
3 (Ear[tiab] OR cochlea[tiab])
4 # 1 OR #2 OR #3
5 Cell death[mesh:noexp] OR apoptosis/
6 (Cell death[tiab] OR apopto[tiab])
7 #5 OR #6
8 #4 AND #7
9 Anibiotic[tiab] OR aminoglycoside[tiab] OR cisplatin[tiab] OR carboplain[tiab] OR plantinum[tiab] OR tobramycin[tiab] OR gentamicin[tiab] OR
amikacin[tiab] OR kanamycin[tiab]
10 Ototoxicity[tiab] OR ototoxic[tiab]
11 #9 OR #10
12 #4 AND #11
13 #8 AND #11
14 #12 OR #13
15 “4,5-dihydro-1-(3-(trifluoromethyl)phenyl)-1h-pyrazol-3-amine”[mesh:noexp] OR adalimumab[mesh:noexp] OR adapalene, benzoyl peroxide drug
combination[mesh:noexp] OR adapalene[mesh:noexp] OR algestone acetophenide[mesh:noexp] OR ampyrone[mesh:noexp] OR anti-inflamma-
tory agents, non-steroidal[mesh:noexp] OR anti-inflammatory agents[mesh:noexp] OR antioxidants[mesh:noexp] OR antipyrine[mesh:noexp] OR
apazone[mesh:noexp] OR aspirin[mesh:noexp] OR beclomethasone[mesh:noexp] OR benzydamine[mesh:noexp] OR betamethasone valerate[-
mesh:noexp] OR betamethasone[mesh:noexp] OR budesonide[mesh:noexp] OR bufexamac[mesh:noexp] OR celecoxib[mesh:noexp] OR clobeta-
sol[mesh:noexp] OR clofazimine[mesh:noexp] OR clonixin[mesh:noexp] OR corticosterone[mesh:noexp] OR cortisone[mesh:noexp] OR
curcumin[mesh:noexp] OR cyclooxygenase 2 inhibitors[mesh:noexp] OR cyclooxygenase inhibitors[mesh:noexp] OR desonide[mesh:noexp] OR
desoximetasone[mesh:noexp] OR dexamethasone isonicotinate[mesh:noexp] OR dexamethasone[mesh:noexp] OR diclofenac[mesh:noexp] OR
diflucortolone[mesh:noexp] OR diflunisal[mesh:noexp] OR dipyrone[mesh:noexp] OR epirizole[mesh:noexp] OR etanercept[mesh:noexp] OR eto-
dolac[mesh:noexp] OR fenoprofen[mesh:noexp] OR feprazone[mesh:noexp] OR fludrocortisone[mesh:noexp] OR flufenamic acid[mesh:noexp]
OR flumethasone[mesh:noexp] OR fluocinolone acetonide[mesh:noexp] OR fluocinonide[mesh:noexp] OR fluocortolone[mesh:noexp] OR fluoro-
metholone[mesh:noexp] OR fluprednisolone[mesh:noexp] OR flurandrenolone[mesh:noexp] OR flurbiprofen[mesh:noexp] OR fluticasone[mesh:-
noexp] OR glycyrrhetinic acid[mesh:noexp] OR glycyrrhizic acid[mesh:noexp] OR halcinonide[mesh:noexp] OR heparinoids[mesh:noexp] OR
hydrocortisone[mesh:noexp] OR ibuprofen[mesh:noexp] OR indomethacin[mesh:noexp] OR indoprofen[mesh:noexp] OR ketoprofen[mesh:-
noexp] OR ketorolac tromethamine[mesh:noexp] OR ketorolac[mesh:noexp] OR meclofenamic acid[mesh:noexp] OR mefenamic acid[mesh:-
noexp] OR mesalamine[mesh:noexp] OR methylprednisolone hemisuccinate[mesh:noexp] OR methylprednisolone[mesh:noexp] OR
mometasone furoate[mesh:noexp] OR naproxen[mesh:noexp] OR nedocromil[mesh:noexp] OR niflumic acid[mesh:noexp] OR olopatadine
hydrochloride[mesh:noexp] OR oxyphenbutazone[mesh:noexp] OR paramethasone[mesh:noexp] OR phenylbutazone[mesh:noexp] OR piroxi-
cam[mesh:noexp] OR prednisolone[mesh:noexp] OR prednisone[mesh:noexp] OR salicylates[mesh:noexp] OR sodium salicylate[mesh:noexp] OR
steroids[mesh:noexp] OR sulfasalazine[mesh:noexp] OR sulindac[mesh:noexp] OR suprofen[mesh:noexp] OR tilorone[mesh:noexp] OR tolmetin[-
mesh:noexp] OR triamcinolone acetonide[mesh:noexp] OR triamcinolone[mesh:noexp]
14 adalimumab[tiab] OR adapalene[tiab] OR algestone acetophenide[tiab] OR ampyrone[tiab] OR anti-inflammatory agents[tiab] OR antioxi-
dants [tiab] OR antipyrine[tiab] OR apazone[tiab] OR aspirin[tiab] OR beclomethasone[tiab] OR benzydamine[tiab] OR betamethasone[tiab] OR
budesonide[tiab] OR bufexamac[tiab] OR celecoxib[tiab] OR clobetasol[tiab] OR clofazimine[tiab] OR clonixin[tiab] OR corticosterone[tiab] OR
cortisone[tiab] OR curcumin[tiab] OR cyclooxygenase 2 inhibitor[tiab] OR cyclooxygenase inhibitor[tiab] OR desonide[tiab] OR desoximetaso-
ne[tiab] OR dexamethasone[tiab] OR diclofenac[tiab] OR diflucortolone[tiab] OR diflunisal[tiab] OR dipyrone[tiab] OR epirizole[tiab] OR etaner-
cept[tiab] OR etodolac[tiab] OR fenoprofen[tiab] OR feprazone[tiab] OR fludrocortisone[tiab] OR flufenamic acid[tiab] OR flumethasone[tiab]
OR fluocinolone acetonide[tiab] OR fluocinonide[tiab] OR fluocortolone[tiab] OR fluorometholone[tiab] OR fluprednisolone[tiab] OR flurandre-
nolone[tiab] OR flurbiprofen[tiab] OR fluticasone[tiab] OR glycyrrhetinic acid[tiab] OR glycyrrhizic acid[tiab] OR halcinonide[tiab] OR heparin-
oid[tiab] OR hydrocortisone[tiab] OR ibuprofen[tiab] OR indomethacin[tiab] OR indoprofen[tiab] OR ketoprofen[tiab] OR ketorolac
tromethamine[tiab] OR ketorolac[tiab] OR meclofenamic acid[tiab] OR mefenamic acid[tiab] OR mesalamine[tiab] OR methylprednisolone[tiab]
OR mometasone furoate[tiab] OR naproxen[tiab] OR nedocromil[tiab] OR niflumic acid[tiab] OR olopatadine hydrochloride[tiab] OR oxyphen-
butazone[tiab] OR paramethasone[tiab] OR phenylbutazone[tiab] OR piroxicam[tiab] OR prednisolone[tiab] OR prednisone[tiab] OR salicyla-
te[tiab] OR steroid[tiab] OR sulfasalazine[tiab] OR sulindac[tiab] OR suprofen[tiab] OR tilorone[tiab] OR tolmetin[tiab] OR triamcinolone[tiab]
16 Acetaminophen[tiab] OR adalimumab[tiab] OR adapalene[tiab] OR algestone acetophenide[tiab] OR ampyrone[tiab] OR anti-inflammatory agent-
s[tiab] OR antioxidants [tiab] OR antipyrine[tiab] OR apazone[tiab] OR aspirin[tiab] OR beclomethasone[tiab] OR benzydamine[tiab] OR beta-
methasone[tiab] OR budesonide[tiab] OR bufexamac[tiab] OR celecoxib[tiab] OR clobetasol[tiab] OR clofazimine[tiab] OR clonixin[tiab] OR
corticosterone[tiab] OR cortisone[tiab] OR curcumin[tiab] OR cyclooxygenase 2 inhibitor[tiab] OR cyclooxygenase inhibitor[tiab] OR desoni-
de[tiab] OR desoximetasone[tiab] OR dexamethasone[tiab] OR diclofenac[tiab] OR diflucortolone[tiab] OR diflunisal[tiab] OR dipyrone[tiab] OR
epirizole[tiab] OR etanercept[tiab] OR etodolac[tiab] OR fenoprofen[tiab] OR feprazone[tiab] OR fludrocortisone[tiab] OR flufenamic acid[tiab]
OR flumethasone[tiab] OR fluocinolone acetonide[tiab] OR fluocinonide[tiab] OR fluocortolone[tiab] OR fluorometholone[tiab] OR fluprednisolo-
ne[tiab] OR flurandrenolone[tiab] OR flurbiprofen[tiab] OR fluticasone[tiab] OR glycyrrhetinic acid[tiab] OR glycyrrhizic acid[tiab] OR halcinoni-
de[tiab] OR heparinoid[tiab] OR hydrocortisone[tiab] OR ibuprofen[tiab] OR indomethacin[tiab] OR indoprofen[tiab] OR ketoprofen[tiab] OR
ketorolac tromethamine[tiab] OR ketorolac[tiab] OR meclofenamic acid[tiab] OR mefenamic acid[tiab] OR mesalamine[tiab] OR methylpredniso-
lone[tiab] OR mometasone furoate[tiab] OR naproxen[tiab] OR nedocromil[tiab] OR niflumic acid[tiab] OR olopatadine hydrochloride[tiab] OR
oxyphenbutazone[tiab] OR paramethasone[tiab] OR phenylbutazone[tiab] OR piroxicam[tiab] OR prednisolone[tiab] OR prednisone[tiab] OR sal-
icylate[tiab] OR steroid[tiab] OR sulfasalazine[tiab] OR sulindac[tiab] OR suprofen[tiab] OR tilorone[tiab] OR tolmetin[tiab] OR
triamcinolone[tiab]
17 “24,25-dihydroxyvitamin d 3”[mesh:noexp] OR “25-hydroxyvitamin d 2”[mesh:noexp] OR acetylcarnitine[mesh:noexp] OR acetylcysteine[mesh:noexp]
OR alpha-tocopherol[mesh:noexp] OR ascorbic acid[mesh:noexp] OR beta carotene[mesh:noexp] OR beta-tocopherol[mesh:noexp] OR biotin[mesh:-
noexp] OR calcifediol[mesh:noexp] OR calcitriol[mesh:noexp] OR carnitine[mesh:noexp] OR cholecalciferol[mesh:noexp] OR cobamides[mesh:noexp]
OR cod liver oil[mesh:noexp] OR dehydroascorbic acid[mesh:noexp] OR dihydrotachysterol[mesh:noexp] OR dihydroxycholecalciferols[mesh:noexp]
(continued)
S90 T. L. HAMMILL AND K. C. CAMPBELL

OR ergocalciferols[mesh:noexp] OR flavin mononucleotide[mesh:noexp] OR folic acid[mesh:noexp] OR formyltetrahydrofolates[mesh:noexp] OR fur-

sultiamin[mesh:noexp] OR gamma-tocopherol[mesh:noexp] OR hydroxocobalamin[mesh:noexp] OR hydroxycholecalciferols[mesh:noexp] OR inositol
1,4,5-trisphosphate[mesh:noexp] OR inositol phosphates[mesh:noexp] OR inositol[mesh:noexp] OR leucovorin[mesh:noexp] OR magnesium[mesh:-
noexp] OR niacin[mesh:noexp] OR niacinamide[mesh:noexp] OR nicorandil[mesh:noexp] OR nicotinic acids[mesh:noexp] OR palmitoylcarnitine[-
mesh:noexp] OR palmitoylcarnitine[mesh:noexp] OR panax notoginseng[mesh:noexp] OR panax[mesh:noexp] OR pantothenic acid[mesh:noexp]
OR phytic acid[mesh:noexp] OR pteroylpolyglutamic acids[mesh:noexp] OR pyridoxal phosphate[mesh:noexp] OR pyridoxal[mesh:noexp] OR pyri-
doxamine[mesh:noexp] OR pyridoxine[mesh:noexp] OR riboflavin[mesh:noexp] OR superoxide dismutase[mesh:noexp] OR tetrahydrofolates[mesh:-
noexp] OR thiamine monophosphate[mesh:noexp] OR thiamine pyrophosphate[mesh:noexp] OR thiamine triphosphate[mesh:noexp] OR
thiamine[mesh:noexp] OR thioctic acid[mesh:noexp] OR tocopherols[mesh:noexp] OR tocotrienols[mesh:noexp] OR tocotrienols[mesh:noexp] OR
vitamin a[mesh:noexp] OR vitamin b 12[mesh:noexp] OR vitamin b 6[mesh:noexp] OR vitamin b complex[mesh:noexp] OR vitamin d[mesh:noexp]
OR vitamin e[mesh:noexp] OR vitamin k 1[mesh:noexp] OR vitamin k 2[mesh:noexp] OR vitamin k 3[mesh:noexp] OR vitamin k[mesh:noexp] OR
vitamin u[mesh:noexp] OR vitamins[mesh:noexp] OR xanthopterin[mesh:noexp]
18 “24,25-dihydroxyvitamin d 3”[tiab] OR “25-hydroxyvitamin d 2”[tiab] OR ginseng[tiab] OR acetylcarnitine[tiab] OR acetylcysteine[tiab] OR acetyl-l-
carnitine[tiab] OR alpha-tocopherol[tiab] OR anti-apoptotic[tiab] OR ascorbic acid[tiab] OR Astragaloside[tiab] OR beta carotene[tiab] OR beta-
tocopherol[tiab] OR biotin[tiab] OR calcifediol[tiab] OR calcitriol[tiab] OR carnitine[tiab] OR cholecalciferol[tiab] OR cobamides[tiab] OR cod
liver oil[tiab] OR dehydroascorbic acid[tiab] OR dihydrotachysterol[tiab] OR dihydroxycholecalciferols[tiab] OR ergocalciferols[tiab] OR flavin
mononucleotide[tiab] OR folic acid[tiab] OR formyltetrahydrofolates[tiab] OR fursultiamin[tiab] OR gamma-tocopherol[tiab] OR gene expression
inhibitor[tiab] OR hydroxocobalamin[tiab] OR hydroxycholecalciferols[tiab] OR inositol 1,4,5-trisphosphate[tiab] OR inositol phosphates[tiab] OR
inositol[tiab] OR leucovorin[tiab] OR magnesium[tiab] OR neuron regulation[tiab] OR niacin[tiab] OR niacinamide[tiab] OR nicorandil[tiab] OR
nicotinic acids[tiab] OR palmitoylcarnitine[tiab] OR palmitoylcarnitine[tiab] OR panax notoginseng[tiab] OR panax[tiab] OR pantothenic acid[-
tiab] OR peptide[tiab] OR phytic acid[tiab] OR pteroylpolyglutamic acids[tiab] OR pyridoxal phosphate[tiab] OR pyridoxal[tiab] OR pyridoxami-
ne[tiab] OR pyridoxine[tiab] OR riboflavin[tiab] OR ROS scavenger[tiab] OR Src Inhibitor[tiab] OR superoxide dismutase[tiab] OR
tetrahydrofolates[tiab] OR thiamine monophosphate[tiab] OR thiamine pyrophosphate[tiab] OR thiamine triphosphate[tiab] OR thiamine[tiab]
OR thioctic acid[tiab] OR TLR signalling modulator[tiab] OR tocopherols[tiab] OR tocotrienols[tiab] OR tocotrienols[tiab] OR vitamin a[tiab] OR
vitamin b 12[tiab] OR vitamin b 6[tiab] OR vitamin b complex[tiab] OR vitamin d[tiab] OR vitamin e[tiab] OR vitamin k 1[tiab] OR vitamin k
2[tiab] OR vitamin k 3[tiab] OR vitamin k[tiab] OR vitamin u[tiab] OR vitamins[tiab] OR xanthopterin[tiab]
19 3-hydroxyanthranilic acid[mesh:noexp] OR allopurinol[mesh:noexp] OR antioxidants[mesh:noexp] OR bilirubin[mesh:noexp] OR butylated hydrox-
yanisole[mesh:noexp] OR butylated hydroxytoluene[mesh:noexp] OR canthaxanthin[mesh:noexp] OR carotenoids[mesh:noexp] OR catalase[-
mesh:noexp] OR dimethyl sulfoxide[mesh:noexp] OR ergothioneine[mesh:noexp] OR free radical scavengers[mesh:noexp] OR grape seed
extract[mesh:noexp] OR masoprocol[mesh:noexp] OR melatonin[mesh:noexp] OR nitric oxide[mesh:noexp] OR pentoxifylline[mesh:noexp] OR
probucol[mesh:noexp] OR propyl gallate[mesh:noexp] OR pyrogallol[mesh:noexp] OR quercetin[mesh:noexp] OR selenic acid[mesh:noexp] OR
silymarin[mesh:noexp] OR superoxide dismutase[mesh:noexp] OR uric acid[mesh:noexp] OR zeta carotene[mesh:noexp]
20 3-hydroxyanthranilic acid[tiab] OR allopurinol[tiab] OR antioxidant[tiab] OR bilirubin[tiab] OR butylated hydroxyanisole[tiab] OR butylated
hydroxytoluene[tiab] OR canthaxanthin[tiab] OR carotenoid[tiab] OR catalase[tiab] OR dimethyl sulfoxide[tiab] OR ergothioneine[tiab] OR free
radical scavenger[tiab] OR grape seed extract[tiab] OR masoprocol[tiab] OR melatonin[tiab] OR nitric oxide[tiab] OR pentoxifylline[tiab] OR
probucol[tiab] OR propyl gallate[tiab] OR pyrogallol[tiab] OR quercetin[tiab] OR selenic acid[tiab] OR silymarin[tiab] OR superoxide dismutase[-
tiab] OR uric acid[tiab] OR zeta carotene[tiab]
21 “Lymphocyte specific protein tyrosine kinase p56(lck)”[mesh:noexp] OR “oncogene protein pp60(v-src)”[mesh:noexp] OR “proto-oncogene pro-
teins pp60(c-src)”[mesh:noexp] OR cell-penetrating peptides[mesh:noexp] OR glutathione peroxidase[mesh:noexp] OR glutathione[mesh:noexp]
OR hydroxyl radical[mesh:noexp] OR hypochlorous acid[mesh:noexp] OR jnk mitogen-activated protein kinases[mesh:noexp] OR mitogen-acti-
vated protein kinase 10[mesh:noexp] OR mitogen-activated protein kinase 8[mesh:noexp] OR mitogen-activated protein kinase 9[mesh:noexp]
OR peptides[mesh:noexp] OR peroxides[mesh:noexp] OR proto-oncogene proteins c-fyn[mesh:noexp] OR proto-oncogene proteins c-hck[mesh:-
noexp] OR proto-oncogene proteins c-yes[mesh:noexp] OR reactive oxygen species[mesh:noexp] OR singlet oxygen[mesh:noexp] OR src-family
kinases[mesh:noexp] OR toll-like receptor 1[mesh:noexp] OR toll-like receptor 10[mesh:noexp] OR toll-like receptor 2[mesh:noexp] OR toll-like
receptor 3[mesh:noexp] OR toll-like receptor 4[mesh:noexp] OR toll-like receptor 5[mesh:noexp] OR toll-like receptor 6[mesh:noexp] OR toll-
like receptor 7[mesh:noexp] OR toll-like receptor 8[mesh:noexp] OR toll-like receptor 9[mesh:noexp] OR toll-like receptors[mesh:noexp]
22 Carbamathione[tiab] OR glutathione peroxidase[tiab] OR glutathione[tiab] OR hydroxyl radical[tiab] OR hypochlorous acid[tiab] OR jnk inhibi-
tor[tiab] OR kinase[tiab] OR oncogene protein[tiab] OR peptide[tiab] OR peroxide[tiab] OR reactive oxygen species[tiab] OR ROS scaven-
ger[tiab] OR singlet oxygen[tiab] OR toll-like receptor[tiab]
23 “Coenzyme Q10”[tiab] OR Q10[tiab] OR methionine OR “sodium thiosulphate”[tiab] OR ebselen[tiab] OR Ginko[tiab] OR amifostine[tiab] OR
pantoprazole[tiab]
24 #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 or #23
25 #14 AND #24
26 “Clinical Trial” [PT:NoExp] OR “clinical trial, phase i”[pt] OR “clinical trial, phase ii”[pt] OR “clinical trial, phase iii”[pt] OR “clinical trial, phase iv”[pt]
OR “controlled clinical trial”[pt] OR “multicenter study”[pt] OR “randomized controlled trial”[pt] OR “Clinical Trials as Topic”[mesh:noexp] OR
“clinical trials, phase i as topic”[MeSH Terms:noexp] OR “clinical trials, phase ii as topic”[MeSH Terms:noexp] OR “clinical trials, phase iii as
topic”[MeSH Terms:noexp] OR “clinical trials, phase iv as topic”[MeSH Terms:noexp] OR “controlled clinical trials as topic”[MeSH Terms:noexp]
OR “randomized controlled trials as topic”[MeSH Terms:noexp] OR “early termination of clinical trials”[MeSH Terms:noexp] OR “multicenter
studies as topic”[MeSH Terms:noexp] OR “Double-Blind Method”[Mesh] OR ((randomised[TIAB] OR randomized[TIAB]) AND (trial[TIAB] OR trial-
s[tiab])) OR ((single[TIAB] OR double[TIAB] OR doubled[TIAB] OR triple[TIAB] OR tripled[TIAB] OR treble[TIAB] OR treble[TIAB]) AND
(blind[TIAB] OR mask[TIAB])) OR (“4 arm”[tiab] OR “four arm”[tiab])
27 #25 AND #26
28 #27 AND english[la]
Pharmaceutical interventions for drug-induced ototoxicity in clinical trials search terms.

summarised the evidence for the safety and otoprotective effect
of NAC when co-administered with aminoglycosides and did
support otoprotective effects, but with side effects of abdominal
pain, nausea, vomiting, diarrhoea, and arthralgia increased
1.4–2.2 times. The authors noted that further well-controlled
clinical trials are needed. Transtympanic NAC has provided
mixed results in two clinical trials to reduce cisplatin-induced
ototoxicity: Yoo et al. (2014) found no statistically significant
otoprotection, while Riga et al. (2013) reported statistically
significant protection only for 8000 Hz using the patient’s oppos-
ite ear as a control.
D-methionine (D-met)
Thus far, D-methionine (D-met) has been in clinical trials for noise-
induced and cisplatin-induced hearing loss and radiation-induced
oral mucositis. A phase I study was published showing a favourable
safety profile (Hamstra et al. 2010). However, pre-clinical work has
also demonstrated efficacy in protection from aminoglycoside-
 INTERNATIONAL JOURNAL OF AUDIOLOGY 91

Table 2. Summary of agents investigated for prevention or treatment of medication-induced ototoxicity in clinical trials to date (in bold font), including other pertin-
ent pre-clinical targets for ototoxic damage (not in bold font).
Investigated agent Ototoxicity injury-inducing target(s) ClinicalTrial(s).gov identifier Evidence for safety and efficacy
Alpha-lipoic acid – Aminoglycosides NCT00477607 Conlon et al. (1999), Rybak, Whitworth, and
– Carboplatin Somani (1999), Husain et al. (2005) and
– Cisplatin Martin (2014)
Amifostine – Cisplatin NCT00003269 Duval and Daniel (2012), Hensley et al. (2009)
and Mason (1999).
Co-enzyme Q10 – Cisplatin NCT02353650 Fetoni et al. (2012), Astolfi et al. (2016) and
– Gentamicin Rabau (2015)
– Tinnitus
D-methionine (D-met) – Amikacin NCT00427102 Hamstra et al. (2010), Sha and Schacht (2000),
– Carboplatin Fox et al. (2016), Campbell et al. (1996,
– Cisplatin 1999, 2007, 2009, 2016), Lockwood et al.
– Gentamicin (2000), Cloven et al. (2000) and Korver
– Kanamycin et al. (2002)
– Noise
– Platinum
– Tobramycin
Ebselen (SPI-1005) – Cisplatin or – Carboplatin NCT01451853 Rybak et al. (2000), Lorito et al. (2011), Kim
– Gentamicin NCT02819856 et al. (2009), Takumida, Popa, and Anniko
– Noise (1999), Lynch and Kil (2009) and Kil
– Platinum – Tobramycin et al. (2017)
Ginkgo Biloba – Aminoglycosides NCT01139281 Le Bars and Kastelan (2000), McKenna, Jones,
– Noise and Hughes (2001), Cakil et al. (2012), Dias
et al. (2015), Dias (2010), Huang, Whitworth,
and Rybak (2007), Finkler et al. (2012),
Fukaya and Kanno, (1999) and Ma
et al. (2015)
N-acetylcysteine (NAC) – Aminoglycosides NCT01271088 Bock et al. (1983), Kramer et al. (2006),
– Cisplatin Kocyigit (2011), Tokgoz et al. (2011), Kranzer
– Noise et al. (2015), Yoo et al. (2014) and Riga
et al. (2013)
Pantoprazole – Cisplatin NCT01848457 Balis (2016), Huang et al. (2013) and Luciani
et al. (2004)
Salicylate (aspirin) – Gentamicin None found Crabb et al. (2017), Chen et al. (2007) and Sha,
Qiu, and Schacht (2006)
SENS-401 – Cisplatin None found Petremann et al. (2017)
Sodium thiosulphate – Cisplatin NCT02281006 Otto et al. (1988), Neuwelt et al. (1996), Meyer
– Gentamicin NCT00716976 (2016), Muldoon et al. (2000), Harned et al.
– Noise (2008), Freyer et al. (2017), Pouyatos et al.
(2007) and Hochman et al. (2006)
Steroids – Cisplatin NCT01372904 € et al. (2016), Waissbluth et al. (2013), Sun
Ozel
– Gentamicin et al. (2016), Marshak et al. (2014) and
– Noise Marshak (2015)
Vitamins with magnesium – Aminoglycosides None found Le Prell, Hughes, and Miller (2007), Le Prell
– Cisplatin – Noise et al. (2014), Omenn (1998, 2007) and
Villani et al. (2016)
NIHL clinical trials were included where they are the only study design for cochlear protection to date but () their corresponding ClinicalTrials.gov NCT numbers
were not included.

induced ototoxicity, where D-met protected against gentamicin-
induced (Sha and Schacht 2000), amikacin-induced (Campbell et al.
2007), tobramycin-induced (Fox et al. 2016), and kanamycin-
induced (Campbell et al. 2016) hearing loss without antimicrobial
interference either in vitro or in vivo (Sha and Schacht 2000; Fox
et al. 2016). Multiple pre-clinical studies have demonstrated D-met
protection from cisplatin- and carboplatin-induced hearing loss
(Campbell et al. 1996, 1999, 2007; Lockwood et al. 2000) as well as
in one unpublished clinical trial (Campbell et al. 2009).
Cloven et al. (2000) also showed no antitumor interference for
cisplatin treatment from D-met. Nonetheless, to avoid risk of anti-
tumor interference, D-met can be applied directly to the round
window as a potential otoprotectant (Korver et al. 2002), although
this application technique precludes possible protection of other
systems such as the kidney or neural system.
Coenzyme Q10
Coenzyme Q10 is currently being tested in a clinical trial at the
University of Antwerp in Belgium to determine its effects on
tinnitus characteristics in patients with chronic tinnitus (Rabau
2015). Two pre-clinical studies have suggested that this antioxi-
dant may also have efficacy in ameliorating drug-induced ototox-
icity. Fetoni et al. (2012) demonstrated that Q-ter, a soluble
formulation of coenzyme Q10, significantly reduced gentamicin-
induced auditory evoked response threshold shift and prevented
cochlear outer hair cell loss in albino guinea pigs. Astolfi et al.
(2016) reported that a solution of coenzyme Q10 terclatrate and
Acuval 400, a multivitamin supplement containing antioxidant
agents and minerals (Acu-Qter), prevented cisplatin-induced
threshold shifts in rats. Thus, this agent may have potential to
prevent or treat several auditory disorders.
Alpha-lipoic acid
The antioxidant alpha-lipoic acid was first reported as a protect-
ive agent for aminoglycoside-induced ototoxicity by Conlon et al.
(1999). Later reports confirmed otoprotection from cisplatin-
induced (Rybak, Whitworth, and Somani 1999a, 1999b) and car-
boplatin-induced (Husain et al. 2005) hearing loss in pre-clinical
S92 T. L. HAMMILL AND K. C. CAMPBELL
studies. There is one completed clinical trial listed on
ClinicialTrials.gov for protection against cisplatin (Martin 2014).
To date, no clinical trial results for alpha-lipoic acid and ototo-
toxicity have been published.
Sodium thiosulphate (STS)
For decades the powerful antioxidant sodium thiosulphate (STS;
a common antidote to cyanide poisoning) has also shown effi-
cacy to protect against cisplatin-induced ototoxicity (Otto et al.
1988; Neuwelt et al. 1996). Yet, STS may diminish the cancer
fighting properties of the chemotherapy as a cisplatin neutraliser
(Jones, Basinger, and Holscher 1991; Church et al. 1995). Several
strategies have been employed in an attempt to use STS to
reduce cisplatin-induced ototoxicity without reducing antitumor
efficacy. Because STS is typically administered parenterally,
injected into the blood stream either by intravenous or intra-
arterial administration, and because it has been shown to mark-
edly interfere with cisplatin treatment efficacy, one clinical trial is
currently investigating the efficacy of a local STS application via
trans-tympanic injections of a STS-hyaluronate gel prior to cis-
platin treatments to prevent cisplatin-induced ototoxicity in head
and neck cancer patients (Meyer 2016). Another approach has
been to delay the STS administration by several hours after the
cisplatin administration in an attempt to allow tumour kill to
first occur prior to administration for the later occurrence of oto-
toxicity (Muldoon et al. 2000; Harned et al. 2008). A phase III
study which investigated the effects of STS on cisplatin-induced
hearing loss in a paediatric population did report a significant
reduction in cisplatin-induced hearing loss but reduced both
overall survival and event-free (morbidity- or complication-free)
survival in children with metastatic disease (Freyer 2008). For
children with localised disease, event-free survival and overall
survival were reduced, but not significantly. Interestingly, STS
has been tested for protection from NIHL (Pouyatos et al. 2007)
and gentamicin-induced hearing loss (Hochman et al. 2006) and
did not provide protection for either purpose in those studies.
Ginkgo biloba
With a well-established safety profile and known antioxidant
properties (Le Bars and Kastelan 2000; McKenna, Jones, and
Hughes 2001), ginkgo biloba has been examined for prevention
of hearing loss in animal model experiments and human trials
(Fukaya and Kanno 1999; Huang, Whitworth, and Rybak 2007;
Dias 2010; Cakil et al. 2012; Finkler et al. 2012; Dias et al. 2015;
Ma et al. 2015). However, results from these studies have shown
weak evidence of efficacy to date. Coupled with results from
Miman et al. (2002) that ginkgo biloba may actually potentiate
aminoglycoside-induced ototoxicity, further controlled trials are
warranted before it can be considered as a viable over-the-coun-
ter recommendation.
Other approaches
Amifostine
Multiple clinical trials have been conducted using amifostine, a
potent free-radical scavenger, to prevent cisplatin-induced oto-
toxicity but they have not demonstrated significant protection or
reduction of cisplatin-induced hearing loss, including conducting
a meta-analysis across multiple clinical trials (Duval and Daniel
2012). Currently, amifostine is not recommended for either
otoprotection or neuroprotection by the American Society of
Clinical Oncology 2008 Clinical Practice Guideline Update Use
of Chemotherapy and Radiation Therapy Protectants (Hensley
et al. 2009). The efficacy of amifostine is included in one active
clinical trial as a secondary endpoint on ClinicalTrials.gov with-
out results available (Mason 1999).
Steroids
Steroids are commonly used for the treatment of several inner
ear diseases and injuries. Dexamethasone and methylpredniso-
lone, with known anti-ROS activity including the ability to
increase inherent cochlear ROS defences, have been explored in
animal models as protective agents to reduce cisplatin-induced
ototoxicity. These steroids have successfully demonstrated poten-
tial therapeutic benefits through both histological and functional
measures, though intra-tympanic delivery seemed to deliver bet-
ter results than systemic administration (Waissbluth et al. 2013;
€
Ozel et al. 2016; Sun et al. 2016). Only one human study (phase
IV) was found in which 34 patients were recruited to receive
0.7 ml of dexamethasone phosphate, 10 mg/ml, injected unilat-
erally to the middle ear to prevent ototoxicity (Marshak et al.
2014). While only 15 participants completed the trial due to mor-
bidity or change in chemotherapy regimen, there was a statistic-
ally significant protective effect on hearing. Specifically, less
hearing loss and outer hair cell dysfunction were observed in the
treated group compared to controls at 6000 Hz in pure tone
audiometric results and distortion-product otoacoustic emissions
(DPOAE) f2 range results in the 4000–8000 Hz range, respectively
(Marshak 2015). While additional studies have been conducted in
NIHL, further controlled trials are needed across steroids, deliv-
ery methods, and patient populations for ototoxicity.
Pantoprazole
An ongoing clinical trial at the Children's Hospital of
Philadelphia is investigating Pantoprazole, a proton pump inhibi-
tor (PPI; Balis 2016). No results are currently published, but
bench research has suggested that pantoprazole may sensitise
tumour cells to cisplatin treatment, perhaps reducing the amount
of cisplatin required for treatment (Luciani et al. 2004; Huang
et al. 2013). Therefore, one method of reducing ototoxicity may
be by reducing the level of the ototoxin while retaining efficacy,
rather than directly modifying the mechanism of ototoxic action.
Salicylate
Salicylate has been studied in animal models for both NIHL
treatment (Yamashita et al. 2005; Coleman et al. 2010) as well as
ototoxicity prevention (Sha and Schacht 1999; see review in
Rybak et al. 2007), yet it is also well known for causing ototox-
icity (see Stypulkowski’s review and mechanisms of action paper
for more information, Stypulkowski 1990). Two clinical trials
have been conducted to determine if the right combination of
“enough, but not too much” can be determined to produce an
ototoxicity protection strategy against gentamicin (Sha, Qiu, and
Schacht 2006; Chen et al. 2007). These studies did show signifi-
cant reduction in hearing loss in the treatment groups, no nega-
tive impacts to gentamicin therapy, but notable gastric side
effects (gastric bleeding), which is a known risk factor for aspirin
treatment paradigms (Sha, Qiu, and Schacht 2006). Additionally,
a phase II study of the efficacy of salicylate in reduction of

cisplatin-induced ototoxicity did not yield oto-protective results,
although it was well tolerated (Crabb et al. 2017). As such, use of
salicylate requires more research to determine the safety profile
and optimised dosing for each ototoxic insult.
Discussion and conclusions
The number of agents in or approaching clinical trials for pro-
tecting against drug-induced ototoxicity is encouraging. The food
and drug administration (FDA) drug approval process is neces-
sarily careful, expensive, and arduous. However, promising pre-
clinical and clinical trials suggest one or more effective otopro-
tective agents will receive FDA approval for clinical use in the
not-too-distant future. Moreover, many of the current test agents
have shown protection against both chemotherapy- and amino-
glycoside-induced hearing loss in pre-clinical studies, some with
data demonstrating full retention of therapeutic efficacy.
Drug development pipelines for the prevention or treatment
of medicine-induced ototoxic hearing loss must be considered in
relation to several important factors, including: (a) the primary
condition for which the patient is being treated; (b) the interac-
tions ototoxicity-mediating drugs may have on those conditions
and/or treatments; (c) population characteristics (e.g. age or sex);
(d) delivery methods required to reach full efficacy potential for
the proposed mechanism of action; (e) risk-benefit trade-offs for
efficacious dosing schedules and patient tolerance, and (f) FDA
requirements for approval. For the latter, it is important to
understand the differences between an exempt (e.g. nutraceutical
agents available at health food stores) versus over-the-counter
versus prescription-only designation, what that means to patients
and their interdisciplinary care teams, as well as the sort of edu-
cation and communication about those products that may need
to be addressed.
Retention of hearing during and after a life-threatening illness
is a major quality of life issue for patients receiving ototoxic
drugs and their families. Communication impediment during
and after a major lifetime stressor (like illness) can delay progress
of treatment and recovery. The goal of patient care is always to
extend life duration but also to retain full life capabilities and
enjoyment. Certainly hearing is a major factor of the latter, and
the agents discussed herein, while not mature enough at this
point, offer great promise towards that goal.
Acknowledgements
The authors would like to thank the special issue editorial committee
for inviting this article into the “Ototoxicity: Special Topics in
Clinical Monitoring” collection. Additionally, the support and
encouragement of the DOD Hearing Center of Excellence (HCE)
and the HCE Pharmaceutical Interventions for Hearing Loss (PIHL)
Working Group which brought this edition about. Finally, the
authors would like to acknowledge and thank Melanie Halford for
her copy-editing support and Mrs. Nicole Larionova for her support
with the literature search.
Disclosure statement
The authors have no financial interests to disclose. Dr. Campbell’s
previous financial interest in D-methionine has since dissolved.
INTERNATIONAL JOURNAL OF AUDIOLOGY 93
References
Astolfi, L., E. Simoni, F. Valente, S. Ghiselli, S. Hatzopoulos, M. Chicca, and
A. Martini. 2016. “Coenzyme Q10 Plus Multivitamin Treatment Prevents
Cisplatin Ototoxicity in Rats.” PLoS One 11 (9): e0162106. doi:10.1371/
journal.pone.0162106.
Balis, F.M. 2016. Pilot Study to Prevent Nephrotoxicity of High-dose
Methotrexate by Prolonging the Infusion Duration and Prevent
Nephrotoxicity and Ototoxicity of Cisplatin with Pantoprazole in
Children, Adolescents and Young Adults with Osteosarcoma. https://clini-
caltrials.gov (Identification No. NCT01848457).
Bock, G.R., G.K. Yates, J.J. Miller, P. Moorjani. 1983. “Effects of N-acetylcys-
teine on Kanamycin Ototoxicity in the Guinea Pig.” Hearing Research 9
(3): 255–262. doi:10.1016/0378-5955(83)90030-8.
Cakil, B., F.S. Basar, S. Atmaca, S.K. Cengel, A. Tekat, Y. Tanyeri. 2012. “The
Protective Effect of Ginkgo Biloba Extract Against Experimental Cisplatin
Ototoxicity: Animal Research Using Distortion Product Otoacoustic
Emissions.” Journal of Laryngology & Otology 126 (11): 1097–1101.
doi:10.1017/S0022215112002046.
Campbell, K.C.M., ed. Pharmacology and Ototoxicity for Audiologists. Clifton
Park, NY: Thompson Delmar Learning.
Campbell, K.C.M., and D. Fox. 2016. “Cisplatin-Induced Hearing Loss in
Translational Research.” In Audiology, Neurotology, and the Hearing
Sciences, edited by Le Prell, Lobarinas, Popper, Fay, 141–164. Springer,
Cham: Springer Publishers.
Campbell, K.C.M., E. Kelly, N. Targovnik, L. Hughes, C. Van Saders, A.B.
Gottlieb, M.B. Dorr, and A. Leighton. 2003. “Audiologic Monitoring for
Potential Ototoxicity in a Phase I Clinical Trial of a New Glycopeptide
Antibiotic.” Journal of the American Academy of Audiology 14 (3):
157–168; quiz 170–171. doi:10.3109/14992027.2010.540722.
Campbell, K.C.M., S.M. Martin, R.P. Meech, T.L. Hargrove, S.J. Verhulst, and
D.J. Fox. 2016. “D-methionine (D-met) Significantly Reduces Kanamycin-
Induced Ototoxicity in Pigmented Guinea Pigs.” International Journal of
Audiology 55 (5): 273–278. doi:10.3109/14992027.2016.1143980.
Campbell, K.C.M., R.P. Meech, J.J. Klemens, M.T. Gerberi, S.S.W. Dyrstad,
D.L. Larsen, D.L. Mitchell, et al. 2007.” Prevention of Noise- and Drug-
induced Hearing Loss with D-Methionine.” Hearing Research 226 (1–2):
92–103. doi:10.1016/j.heares.2006.11.012.
Campbell, K.C.M., R.P. Meech, L.P. Rybak, L.F. Hughes. 1999. “D-
Methionine Protects Against Cisplatin Damage to the Stria Vascularis.”
Hearing Research 138 (1–2): 13–28. doi:10.1016/S0378-5955(99)00142-2.
Campbell, K.C.M., R. Nayar, S. Borgonha, L.F. Hughes, A. Rehemtulla,
B. Ross, and P. Sunkara. 2009. “Oral D-methionine (MRX-1024)
Significantly Protects Against Cisplatin-Induced Hearing Loss: A Phase II
Study in Humans.” Abstracts of the Association for Research in
Otolaryngology, 32: 7.
Campbell, K.C.M., L.P. Rybak, R.P. Meech, and L. Hughes. 1996. “D-
Methionine Provides Excellent Protection from Cisplatin Ototoxicity in
the Rat.” Hearing Research 102 (1–2): 90–98. doi:10.1016/S0378-
5955(96)00152-9.
Chen, Y., W.G. Huang, D.J. Zha, J.H. Qiu, J.L. Wang, S.H. Sha, and J.
Schacht. 2007. “Aspirin Attenuates Gentamicin Ototoxicity: from the
Laboratory to the Clinic.” Hearing Research 226 (1–2): 178–182.
doi:10.1016/j.heares.2006.05.008.
Church, M.W., J.A. Kaltenbach, B.W. Blakley, D.L. Burgio. 1995. “The
Comparative Effects of Sodium Thiosulfate, Diethyldithiocarbamate,
Fosfomycin and WR-2721 on Ameliorating Cisplatin-Induced Ototoxicity.”
Hearing Research 86 (1–2): 195–203. doi:10.1016/0378-5955(95)00066-D.
Cloven, N.G., A. Re, M.T. McHale, R.A. Burger, P.J. DiSaia, G.S. Rose, K.C.
Campbell, and H. Fan. 2000. “Evaluation of D-methionine as a
Cytoprotectant in Cisplatin Treatment of an Animal Model for Ovarian
Cancer.” Anticancer Research 20 (6B): 4205–4209. doi:10.1016/
j.phrs.2008.01.001.
Coleman, J., X. Huang, J. Liu, R. Kopke, and R. Jackson. 2010. “Dosing Study
on the Effectiveness of Salicylate/N-Acetylcysteine for Prevention of
Noise-Induced Hearing Loss.” Noise & Health 12 (48): 159.
Conlon, B.J., J.M. Aran, J.P. Erre, and D.W. Smith. 1999. “Attenuation of
Aminoglycoside-Induced Cochlear Damage with the Metabolic
Antioxidant Alpha-Lipoic Acid.” Hearing Research 128 (1–2): 40–44.
doi:10.1016/S0378-5955(98)00195-6.
Crabb, S.J., K. Martin, J. Abab, I. Ratcliffe, R. Thornton, B. Lineton, M. Ellis,
et al. 2017. “COAST (Cisplatin Ototoxicity Attenuated by Aspirin Trial):
A Phase II Double-Blind, Randomized Controlled Trial to Establish if
Aspirin Reduces Cisplatin Induced Hearing-Loss.” European Journal of
Cancer 87: 75–83. doi:10.1016/j.ejca.2017.09.033.
de Castria, T.B., E.M. da Silva, A.F. Gois, and R. Riera. 2013. “Cisplatin
Versus Carboplatin in Combination with Third-Generation Drugs for
S94 T. L. HAMMILL AND K. C. CAMPBELL
Advanced Non-small Cell Lung Cancer.” Cochrane Library 16 (8):
CD009256. doi:10.1002/14651858.CD009256.pub2.
Dias, M.A. 2010. The protective effect of Ginkgo biloba extract on cisplatin-
induced ototoxicity in humans. https://clinicaltrials.gov (Identification No.
NCT01139281).
Dias, M.A., A.L. Sampaio, A.R. Venosa, A. Meneses Ede, and C.A. Oliveira.
2015. “The Chemopreventive Effect of Ginkgo Biloba Extract 761 Against
Cisplatin Ototoxicity: A Pilot Study.” International Tinnitus Journal 19 (2):
12–19. doi:10.5935/0946-5448.20150003.
Duval, M., and S.J. Daniel. 2012. “Meta-Analysis of the Efficacy of Amifostine
in the Prevention of Cisplatin Ototoxicity.” Journal of Otolaryngology –
Head & Neck Surgery 41 (5): 309–315.
Fetoni, A.R., S.L. Eramo, R. Rolesi, D. Troiani, and G. Paludetti. 2012.
“Antioxidant Treatment with Coenzyme Q-ter in Prevention of
Gentamycin Ototoxicity in An Animal Model.” Acta Otorhinolaryngologica
Italica 32 (2): 103–110.
Finkler, A.D., A. Ferreira da Silveira, G. Munaro, and C.D. Zanrosso. 2012.
“Otoprotection in Guinea Pigs Exposed to Pesticides and Ginkgo Biloba.”
Brazilian Journal of Otorhinolaryngology 78 (3): 122–128. doi:10.1590/
S1808-86942012000300020.
Fox, D.J., M.D. Cooper, C.A. Speil, M.H. Roberts, S.C. Yanik, R.P. Meech,
T.L. Hargrove, S.J. Verhulst, L.P. Rybak, and K.C. Campbell. 2016. “D-
Methionine Reduces Tobramycin-Induced Ototoxicity Without
Antimicrobial Interference in Animal Models.” Journal of Cystic Fibrosis
15 (4): 518–530. doi:10.1016/j.jcf.2015.06.005.
Freyer, D.R. 2008. Sodium Thiosulfate in Preventing Hearing Loss in Young
Patients Receiving Cisplatin for Newly Diagnosed Germ Cell Tumor,
Hepatoblastoma, Medulloblastoma, Neuroblastoma, Osteosarcoma, or
Other Malignancy. https://clinicaltrials.gov (Identification No.
NCT00716976).
Freyer, D.R., L. Chen, M.D. Krailo, K. Knight, D. Villaluna, B. Bliss, B.H.
Pollock, et al. 2017. “Effects of Sodium Thiosulfate Versus Observation on
Development of Cisplatin-Induced Hearing Loss in Children with Cancer
(ACCL0431): A Multicentre, Randomised, Controlled, Open-Label,
Phase 3 Trial.” Lancet Oncology 18 (1): 63–74. doi:10.1016/S1470-
2045(16)30625-8.
Fukaya, H., and H. Kanno. 1999. “Experimental Studies of the Protective
Effect of Ginkgo Biloba Extract (GBE) on Cisplatin-Induced Toxicity in
Rats.” Nihon Jibiinkoka Gakkai Kaiho 102 (7): 907–917. [Japanese].
doi:10.3950/jibiinkoka.102.907.
Gilbert, D. 2005. “Aminoglycosides.” In Principles and Practice of Infectious
Diseases: Sixth Edition, edited by Mandell, Bennett, Dolin, 328–356. New
York: Churchill Livingstone.
Hamstra, D.A., A. Eisbruch, M.U. Naidu, G.V. Ramana, P. Sunkara, K.C.
Campbell, B.D. Ross, and A. Rehemtulla. 2010. “Pharmacokinetic Analysis
and Phase 1 Study of MRX-1024 in Patients Treated with Radiation
Therapy With or Without Cisplatinum for Head and Neck Cancer.”
Clinical Cancer Research 16 (9): 266–276. doi:10.1158/1078-0432.CCR-09-
3318.
Harned, T.M., O. Kalous, A. Neuwelt, J. Loera, L. Ji, P. Iovine, R. Sposto,
E.A. Neuwelt, and C.P. Reynolds. 2008.” Sodium Thiosulfate Administered
Six Hours After Cisplatin Does Not Compromise Antineuroblastoma
Activity.” Clinical Cancer Research 14 (2): 533–540. doi:10.1158/1078-
0432.CCR-06-2289.
Hensley, M.L., K.L. Hagerty, T. Kewalramani, D.M. Green, N.J. Meropol,
T.H. Wasserman, G.I. Cohen, et al. 2009. “American Society of Clinical
Oncology 2008 Clinical Practice Guideline Update: Use of Chemotherapy
and Radiation Therapy Protectants.” Journal of Clinical Oncology 27 (1):
127–145. doi:10.1200/JCO.2008.17.2627.
Hochman, J., B.W. Blakley, M. Wellman, and L. Blakley. 2006. “Prevention of
Aminoglycoside-Induced Sensorineural Hearing Loss.” Journal of
Otolaryngology 35 (3): 153–156.
Huang, S., M. Chen, X. Ding, X. Zhang, and X. Zou. 2013. “Proton Pump
Inhibitor Selectively Suppresses Proliferation and Restores the
Chemosensitivity of Gastric Cancer Cells by Inhibiting STAT3 Signaling
Pathway.” International Immunopharmacology 17 (3): 585–592.
doi:10.1016/j.intimp.2013.07.021.
Huang, T., A.G. Cheng, H. Stupak, W. Liu, A. Kim, H. Staecker, P.P.
Lefebvre, et al. 2000. “Oxidative Stress-Induced Apoptosis of Cochlear
Sensory Cells: Otoprotective Strategies.” International Journal of
Developmental Neuroscience 18 (2–3): 259–270. doi:10.1016/S0736-
5748(99)00094-5.
Huang, X., C.A. Whitworth, and L.P. Rybak. 2007. “Ginkgo Biloba Extract
(EGb 761) Protects Against Cisplatin-Induced Ototoxicity in Rats.”
Otology & Neurotology 28 (6): 828–833. doi:10.1097/
MAO.0b013e3180430163.
Husain, K., C. Whitworth, S.M. Somani, and L.P. Rybak. 2005. “Partial
Protection by Lipoic Acid Against Carboplantin-Induced Ototoxicity in
Rats.” Biomedical and Environmental Sciences 18 (3): 198–206.
Jamesdaniel, S., R. Rathinam, and W.L. Neumann. 2016. “Targeting Nitrative
Stress for Attenuating Cisplatin-Induced Downregulation of Cochlear LIM
Domain only 4 and Ototoxicity.” Redox Biology 10: 257–265. doi:10.1016/
j.redox.2016.10.016.
Jin, Z., and W.S. El-Deiry. 2005. “Overview of Cell Death Signaling
Pathways.” Cancer Biology & Therapy 4 (2): 139–163.
Johnson, A.-C., and T. Morata. 2010. “Occupational Exposure to Chemicals
and Hearing Impairment.” Nordic Expert Group for Criteria
Documentation of Health Risks from Chemicals 44 (4): 1–190.
Jones, M.M., M.A. Basinger, and M.A. Holscher. 1991. “Relative Effectiveness
of Some Compounds for the Control of Cisplatin-Induced
Nephrotoxicity.” Toxicology 68 (3): 227–247. doi:10.1016/0300-
483X(91)90072-9.
Kil, J. 2016a. Safety and Efficacy Study of SPI-1005 for Prevention of
Chemotherapy Induced Hearing Loss. https://clinicaltrials.gov
(Identification No. NCT01451853).
Kil, J. 2016b. SPI-1005 for Prevention and Treatment of Aminoglycoside
Induced Ototoxicity. https://clinicaltrials.gov (Identification No.
NCT02819856).
Kil, J., E. Lobarinas, C. Spankovich, S.K. Griffiths, P.J. Antonelli, E.D. Lynch,
and C.G. Le Prell. 2017. “Safety and Efficacy of Ebselen for the Prevention
of Noise-Induced Hearing Loss: A Randomised, Double-Blind, Placebo-
Controlled, Phase 2 Trial.” Lancet 390 (10098): 969–979. doi:10.1016/
S0140-6736(17)31791-9.
Kim, S.J., C. Park, A.L. Han, M.J. Youn, J.H. Lee, Y. Kim, E.S. Kim, et al.
2009. “Ebselen Attenuates Cisplatin-Induced ROS Generation Through
Nrf2 Activation in Auditory Cells.” Hearing Research 251 (1–2): 70–82.
doi:10.1016/j.heares.2009.03.003.
Kocyigit, I. 2011. Protective Effect of N-acetylcysteine Against Ototoxicity.
https://clinicaltrials.gov (Identification No. NCT01271088).
Kopke, R.D., W. Liu, R. Gabaizadeh, A. Jacono, J. Feghali, D. Spray, P.
Garcia, H. Steinman, B. Malgrange, R.J. Ruben, and L. Rybak. 1997. “Use
of Organotypic Cultures of Corti's Organ to Study the Protective Effects of
Antioxidant Molecules on Cisplatin-Induced Damage of Auditory Hair
Cells.” American Journal of Otolaryngology 18 (5): 559–571.
Kopke, R., K.A. Allen, D. Henderson, M. Hoffer, D.M. Frenz, and T. Van De
Water. 1999. “A Radical Demise: Toxins and Trauma Share Common
Pathways in Hair Cell Death.” Annals of the New York Academy of
Sciences 884 (1): 171–191. doi:10.1111/j.1749-6632.1999.tb08641.x.
Korver, K.D., L.P. Rybak, C. Whitworth, and K.C. Campbell. 2002. “Round
Window Application of D-Methionine Provides Complete Cisplatin
Otoprotection.” Otolaryngology – Head and Neck Surgery 126: 683–689.
doi:10.1067/mhn.2002.125299.
Kramer, S., L. Dreisbach, J. Lockwood, K. Baldwin, R. Kopke, S. Scranton,
and M. O'Leary. 2006. “Efficacy of the Antioxidant N-Acetylcysteine
(NAC) in Protecting Ears Exposed to Loud Music.” Journal of the
American Academy of Audiology 17(4): 265–278. doi:10.3766/jaaa.17.4.5.
Kranzer, K., W.F. Elamin, H. Cox, J.A. Seddon, N. Ford, and F. Drobniewski.
2015. “A Systematic Review and Meta-Analysis of the Efficacy and Safety
of N-Acetylcysteine in Preventing Aminoglycoside-Induced Ototoxicity:
Implications for the Treatment of Multidrug-Resistant TB.” Thorax 70
(11): 1070–1077. doi:10.1136/thoraxjnl-2015-207245.
Le Bars, P.L., and J. Kastelan. 2000. “Efficacy and Safety of a Ginkgo Biloba
Extract.” Public Health Nutrion 3 (4A): 495–499.
Le Prell, C.G., L.F. Hughes, and J.M. Miller. 2007. “Free Radical Scavengers
Vitamins A, C, and E Plus Magnesium Reduce Noise Trauma.” Free
Radical Biology and Medicine 42 (9): 1454–1463. doi:10.1016/
j.freeradbiomed.2007.02.008.
Le Prell, C.G., A.C. Johnson, A.C. Lindblad, Å., Skj€ onsberg, M. Ulfendahl, K.
Guire, G.E. Green, K.C.M. Campbell, and J.M. Miller. 2011. “Increased
Vitamin Plasma Levels in Swedish Military Personnel Treated with
Nutrients Prior to Automatic Weapon Training. Noise and Health 13 (55):
432. doi:10.4103/1463-1741.90317.
Le Prell, C.G., C. Ojano-Dirain, E.W. Rudnick, M.A. Nelson, S.J. DeRemer,
D.M. Prieskorn, and J.M. Miller. 2014. “Assessment of Nutrient
Supplement to Reduce Gentamicin-Induced Ototoxicity.” Journal of the
Association for Research in Otolaryngology 15 (3): 375–393. doi:10.1007/
s10162-014-0448-x.
Lerner, S.A., B.A. Schmitt, R. Seligsohn, and G.J. Matz. 1986. “Comparative
Study of Ototoxicity and Nephrotoxicity in Patients Randomly Assigned
to Treatment with Amikacin or Gentamicin.” American Journal of
Medicine 80 (6B): 98–104. doi:10.1016/0002-9343(86)90486-9.
Lockwood, D.S., D.L. Ding, J. Wang, and R.J. Salvi. 2000. “D-Methionine
Attenuates Inner Hair Cell Loss in Carboplatin-Treated Chinchillas.”
Audiology and Neurotology 5 (5): 263–266. doi:10.1159/000013890.

Lorito, G., S. Hatzopoulos, G. Laurell, K.C.M. Campbell, J. Petruccelli, P.
Giordano, K. Kochanek, et al. 2011. “Dose-Dependent Protection on
Cisplatin-Induced Ototoxicity – An Electrophysiological Study on the
Effect of Three Antioxidants in the Sprague–Dawley Rat Animal Model.”
Medical Science Monitor 17 (8): BR179–BR186. doi:10.12659/MSM.881894.
Luciani, F., M. Spada, A. De Milito, A. Molinari, L. Rivoltini, A. Montinaro,
M. Marra, et al. 2004. “Effect of Proton Pump Inhibitor Pretreatment on
Resistance of Solid Tumors to Cytotoxic Drugs.” Journal of the National
Cancer Institute 96 (22): 1702–1713. doi:10.1093/jnci/djh305.
Lynch, E.D., R. Gu, C. Pierce, and J. Kil. 2005a. “Combined Oral Delivery of
Ebselen and Allopurinol Reduces Multiple Cisplatin Toxicities in Rat
Breast and Ovarian Cancer Models While Enhancing Anti-tumor
Activity.” Anticancer Drugs 16 (5): 569–579. doi:10.1097/00001813-
200506000-00013.
Lynch, E.D., R. Gu, C. Pierce, and J. Kil. 2005b. “Reduction of Acute
Cisplatin Ototoxicity and Nephrotoxicity in Rats by Oral Administration
of Allopurinol and Ebselen.” Hearing Research 201 (1–2): 81–89.
doi:10.1016/j.heares.2004.08.002.
Lynch, E.D., and J. Kil. 2009. “Development of Ebselen, A Glutathione
Peroxidase Mimis, for the Prevention and Treatment of Noise-Induced
Hearing Loss.” Seminars in Hearing 30 (1): 47–55. doi:10.1055/s-0028-
1111106.
Ma, W., J. Hu, Y. Cheng, J. Wang, X. Zhang, and M. Xu. 2015. “Ginkgolide
B Protects Against Cisplatin-Induced Ototoxicity: Enhancement of
Akt–Nrf2–HO-1 Signaling and Reduction of NADPH Oxidase.” Cancer
Chemotherapy and Pharmacology 75: 949–959. doi:10.1007/s00280-015-
2716-9.
Marshak, T.M., M. Steiner, M. Kaminer, L. Levy, and A., Shupak. 2014.
“Prevention of Cisplatin-Induced Hearing Loss by Intratympanic
Dexamethasone: A Randomized Controlled Study.” Otolaryngology – Head
and Neck Surgery 150 (6): 983–990. doi:10.1177/0194599814524894.
Marshak, T.M. 2015. Prevention of cisplatin-induced hearing loss by intra-
tympanic dexamethasone treatment. https://clinicaltrials.gov (Identification
No. NCT01372904).
Martin, D.L. 2014. Alpha-lipoic acid in preventing hearing loss in cancer
patients undergoing treatment with cisplatin. https://clinicaltrials.gov
(Identification No. NCT00477607).
Mason, J.R. 1999. Amifostine Followed by High Dose Chemotherapy in
Treating Patients With Hematologic Cancer or Solid Tumors. https://clini-
caltrials.gov (Identification No. NCT 00003269).
McKenna, D.J., K. Jones, and K. Hughes. 2001. “Efficacy, Safety, and Use of
Ginkgo Biloba in Clinical and Preclinical Applications.” Alternative
Therapies in Health And Medicine 7 (5): 70–86, 88–90.
Meyer, F. 2016. Efficacy of trans-tympanic injections of a sodium thiosulfate
gel to prevent cisplatin-induced ototoxicity (STS001). https://clinicaltrials.
gov (Identification No. NCT02281006).
Miman, M.C., O. Ozturan, M. Iraz, T., Erdem, and E. Olmez. 2002.
“Amikacin Ototoxicity Enhanced by Ginkgo Biloba Extract (EGb 761).”
Hearing Research 169 (1–2): 121–129. doi:10.1016/S0378-5955(02)00385-4.
Muldoon, L.L., M.A. Pagel, R.A. Kroll, R.E. Brummett, N.D. Doolittle, E.G.
Zuhowski, M.J. Egorin and E.A. Neuwelt. 2000. “Delayed Administration
of Sodium Thiosulfate in Animal Models Reduces Platinum Ototoxicity
Without Reduction of Antitumor Activity.” Clinical Cancer Research 6 (1):
309–315.
Neuwelt, E.A., R.E. Brummett, L.G. Remsen, R.A. Kroll, M.A. Pagel, C.I.
McCormick, S. Guitjens, and L.L. Muldoon. 1996. “In vitro and Animal
Studies of Sodium Thiosulfate as A Potential Chemoprotectant Against
Carboplatin-Induced Ototoxicity.” Cancer Research 56 (4): 706–709.
Oishi, N., A. Kendall, and J. Schacht. 2014. “Metformin Protects Against
Gentamicin-Induced Hair Cell Death in Vitro but not Ototoxicity in
Vivo.” Neuroscience Letters 583: 65–59. doi:10.1016/j.neulet.2014.09.028.
Omenn, G.S. 1998. “Chemoprevention of Lung Cancer: The Rise and Demise
of Beta-Carotene.” Annual Review of Public Health 19: 73–99. doi:10.1146/
annurev.publhealth.19.1.73.
Omenn, G.S. 2007. “Chemoprevention of Lung Cancers: Lessons from
CARET, the Beta-Carotene and Retinol Efficacy Trial, and Prospects for
the Future.” European Journal of Cancer Prevention 16 (3): 184–191.
doi:10.1097/01.cej.0000215612.98132.18.
Otto, W.C., R.D. Brown, L. Gage-White, S. Kupetz, M. Anniko, J.E. Penny,
and C.M. Henley. 1988. “Effects of Cisplatin and Thiosulfate Upon
Auditory Brainstem Responses of Guinea Pigs.” Hearing Research 35 (1):
79–85. doi:10.1016/0378-5955(88)90042-1.
€
Ozel, €
H.E., F. Ozdo gan, S.G. G€ urgen, E. Esen, S. Genç, and A. Selçuk. 2016.
“Comparison of the Protective Effects of Intratympanic Dexamethasone
and Methylprednisolone Against Cisplatin-Induced Ototoxicity.” Journal of
Laryngology & Otology 130 (3): 225–234. doi:10.1017/S0022215115003473.
Petremann, M., C.T. Van Ba, A. Broussy, C. Romanet, and J. Dyhrfjeld-
Johnsen. 2017. Oral Administration of Clinical Stage Drug Candidate
INTERNATIONAL JOURNAL OF AUDIOLOGY 95
SENS-401 Effectively Reduces Cisplatin-induced Hearing Loss in
Rats. Otology and Neurotology 38 (9): 1355–1361. doi:10.1097/
MAO.0000000000001546.
Pouyatos, B., C. Gearhart, A. Nelson-Miller, S. Fulton, and L. Fechter. 2007.
“Oxidative Stress Pathways in the Potentiation of Noise-Induced Hearing
Loss by Acrylonitrile.” Hearing Research 224 (1–2): 61–74. doi:10.1016/
j.heares.2006.11.009.
Rabau, S. 2015. The Effect of Coenzyme Q10 on Hearing and Tinnitus
Characteristics of Chronic Tinnitus Patients. https://clinicaltrials.gov
(Identification No. NCT02353650).
Riga, M.G., L. Chelis, S. Kakolyris, S. Papadopoulos, S. Stathakidou, E.
Chamalidou, N. Xenidis, et al. 2013. “Transtympanic Injections of N-
Acetylcysteine for the Prevention of Cisplatin-Induced Ototoxicity: A
Feasible Method with Promising Efficacy.” American Journal of Clinical
Oncology 36 (1): 1–6. doi:10.1097/COC.0b013e31822e006d.
Rybak, L.P., K. Husain, C. Morris, C. Whitworth, and S. Somani. 2000.
“Effect of Protective Agents Against Cisplatin Ototoxicity.” American
Journal of Otolaryngology 21 (4): 513–520.
Rybak, L.P., K. Husain, C. Whitworth, and S.M. Somani. 1999. “Dose
Dependent Protection by Lipoic Acid Against Cisplatin-Induced
Ototoxicity in Rats: Antioxidant Defense System. Toxicological Sciences 47
(2): 195–202. doi:10.1093/toxsci/47.2.195.
Rybak, L.P., C.A. Whitworth, D. Mukherjea, and V. Ramkumar. 2007.
“Mechanisms of Cisplatin-Induced Ototoxicity and Prevention.” Hearing
Research 226 (1–2): 157–167. doi:10.1016/j.heares.2006.09.015.
Rybak, L.P., C. Whitworth, S. Somani. 1999. “Application of Antioxidants
and Other Agents to Prevent Cisplatin Ototoxicity.” Laryngoscope 109
(11): 1740–1744. doi:10.1097/00005537-199911000-00003.
Sha, S.H., J.H. Qiu, and J. Schacht. 2006. “Aspirin to Prevent Gentamicin-
Induced Hearing Loss.” New England Journal of Medicine 354 (17):
1856–1857. doi:10.1056/NEJMc053428.
Sha, S.H., and J. Schacht. 1999. Salicylate Attenuates Gentamicin-induced
Ototoxicity. Laboratory Investigation 79: 807–813.
Sha, S. H., and J. Schacht. 2000. “Antioxidants Attenuate Gentamicin-Induced
Free Radical Formation in Vitro and Ototoxicity in Vivo: D-Methionine is
a Potential Protectant.” Hearing Research 142 (1–2): 34–40. doi:10.1016/
S0378-5955(00)00003-4.
Stewart, L. 1999. “Chemotherapy for Advanced Ovarian Cancer.” Cochrane
Library. 1: CD001418. doi:10.1002/14651858.CD001418.
Stypulkowski, P.H. 1990. “Mechanisms of Salicylate Ototoxicity.” Hearing
Research 46 (1–2): 113–145. doi:10.1016/0378-5955(90)90144-E.
Sun, C., X. Wang, D. Chen, X. Lin, D. Yu, and H. Wu. 2016.
“Dexamethasone Loaded Nanoparticles Exert Protective Effects Against
Cisplatin-Induced Hearing Loss by Systemic Administration.” Neuroscience
Letters 619: 142–148. doi:10.1016/j.neulet.2016.03.012.
Takumida, M., R. Popa, and M. Anniko. 1999. “Free Radicals in the Guinea
Pig Inner Ear Following Gentamicin Exposure.” Journal for Oto-Rhino-
Laryngology and Its Related Specialties 61 (2): 63–70. doi:10.1159/
000027643.
Tokgoz, B., C. Ucar, I. Kocyigit, M. Somdas, A. Unal, A. Vural, M.
Sipahioglu, et al. 2011. “Protective Effect of N-Acetylcysteine from Drug-
Induced Ototoxicity in Uraemic Patients with CAPD Peritonitis.”
Nephrology Dialysis Transplantation 26 (12): 4073–4078. doi:10.1093/ndt/
gfr211.
Villani, V., C. Zucchella, G. Cristalli, E. Galie, F. Bianco, D. Giannarelli, S.
Carpano, G. Spriano, and A. Pace. 2016. “Vitamin E Neuroprotection
Against Cisplatin Ototoxicity: Preliminary Results from a Randomized,
Placebo-Controlled Ttrial.” Head & Neck 38 (S1): E2118. doi:10.1002/
hed.24396.
Waissbluth, S., P. Salehi, X. He, S.J. Daniel. 2013. “Systemic Dexamethasone
for the Prevention of Cisplatin-Induced Ototoxicity.” European
Archives of Oto-Rhino-Laryngology 270 (5): 1597–1605. doi:10.1007/
s00405-012-2150-0.
Wang, J., J.-L. Puel. 2008. “From Cochlear Cell Death Pathways to New
Pharmacological Therapies.” Mini-Reviews in Medicinal Chemistry 8 (10):
1006–1019. doi:10.2174/138955708785740599.
Yamashita, D., H.Y. Jiang, C.G. Le Prell, J. Schacht, and J.M. Miller. 2005.
“Post-exposure Treatment Attenuates Noise-Induced Hearing Loss.”
Neuroscience 134 (2): 633–642. doi:10.1016/j.neuroscience.2005.04.015.
Yamasoba, T., A.L. Nuttall, C. Harris, Y. Raphael, and J.M. Miller. 1998.
“Role of Glutathione in Protection Against Noise-Induced Hearing Loss.”
Brain Research 784 (1–2): 82–90. doi:10.1016/S0006-8993(97)01156-6.
Yoo, J., S.J. Hamilton, D. Angel, K. Fung, J. Franklin, L.S. Parnes, D. Lewis,
et al. 2014. “Cisplatin Otoprotection Using Transtympanic L-N-
Acetylcysteine: A Pilot Randomized Study in Head and Neck Cancer
Patients. Laryngoscope 124 (3): E87–E94. doi:10.1002/lary.24360.