Round window pH manipulation alters the ototoxicity of systemic cisplatin

doi:10.1016/S0378-5955(03)00330-7

Hearing Research

Volume 187, Issues 1–2, January 2004, Pages 44-50

https://doi.org/10.1016/S0378-5955(03)00330-7 Get rights and content

Abstract

The effect of manipulation of pH on the ototoxicity of systemic cisplatin was studied in Wistar rats. After control auditory brainstem responses (ABR) were performed, the auditory bullae were opened and acidic (pH 6.0), neutral (pH 7.4) or basic (pH 9.0) phosphate-buffered saline (PBS) was applied to fill the round window niche (RWN). After 30 min, 13 mg/kg cisplatin solution or saline was administered intraperitoneally. After 3 days, follow-up ABRs were performed and cochleae were processed for morphological analysis. Animals that received basic PBS on the RWN and cisplatin intraperitoneally had significantly smaller ABR threshold shifts compared to rats pretreated with neutral pH buffer (P<0.05). Animals that received acidic PBS on the RWN and systemic cisplatin showed significantly greater ABR threshold shifts compared to those pretreated with neutral pH buffer (P<0.05). No significant threshold changes were observed in animals that received buffer of any pH on the RWN, followed by saline intraperitoneally. Semiquantitative analysis of hair cell survival confirmed a protective effect by basic PBS against cisplatin and a synergistic effect by acidic PBS on cisplatin ototoxicity (P<0.05). It appears that changes in cochlear pH can modulate the ototoxic effects of systemically applied cisplatin.

Introduction

Cisplatin (cis-diamminedichloroplatinum) is an antineoplastic agent that is widely used against a variety of neoplasms. High dose cisplatin produces severe dose-limiting side effects, such as nephrotoxicity, gastrointestinal toxicity, peripheral neuropathy, myelosuppression and ototoxicity (Piel et al., 1974, Rybak, 1981, Fausti et al., 1999).

The antineoplastic efficacy of cisplatin is known to be affected by pH. Groos et al. (1986) reported increased cytotoxicity of cisplatin under acidic conditions, and decreased cytotoxicity under alkaline conditions in transitional carcinoma cells in vitro. Atema et al. (1993) reported the potentiation of cisplatin cytotoxicity in mouse leukemia cells in acidic conditions. Laurencot et al. (1995) also reported that acidic conditions potentiate the cytotoxicity of cisplatin in mouse mammary tumor cells. We previously reported that the ototoxicity of locally applied cisplatin is inhibited by the local application of basic phosphate-buffered saline (PBS) and potentiated by acidic PBS in the chinchilla (Tanaka et al., 2003). In the present study, we investigated the effects of locally applied PBS of variable pH on the ototoxicity of systemically applied cisplatin using the rat.

Section snippets

Animals

Twenty healthy male rats (207–342 g), free of external or middle ear pathology, were used in this study. At the time of application of solutions to the round window niche (RWN), no scar tissue or other pathology was noted. All animals had free access to commercial food and water and were maintained in an environment with controlled temperature and 12 h light–dark cycles. All procedures of this study were approved by the Southern Illinois University School of Medicine Laboratory Animal Care and

ABRs

In group 1, the animals received basic PBS on one RWN and neutral PBS on the opposite RWN and cisplatin intraperitoneally. The ABR threshold changes for the neutral PBS ears were 18.3±3.1, 20.0±5.8, 16.7±4.9, 18.3±6.5, 31.7±6.0 and 36.7±8.4 dB (mean±S.E.M.) for click, 2, 4, 8, 16 and 32 kHz, respectively. The threshold shifts for basic PBS ears were 5.0±5.0, 6.7±4.9, 3.3±2.1, 5.0±3.4, 13.3±5.6 and 15.0±6.7 dB for click, 2, 4, 8, 16 and 32 kHz, respectively (Fig. 1). There were significant

Discussion

We previously reported that locally applied basic PBS could protect against the ototoxicity of locally applied cisplatin and locally applied acidic PBS could potentiate the ototoxicity of cisplatin applied to the round window (Tanaka et al., 2003). Because cisplatin is a low molecular weight (MW) compound (300), we expected it to readily cross the round window membrane. Low MW compounds can freely cross the round window (Juhn et al., 1989, Okuno and Nomura, 1984), while the passage of higher MW

Acknowledgements

This research was supported by National Institutes of Health NIH (NIDCD) Grant RO1 DC02396.

References (30)

A. Andersson et al.
Determination of the acid dissociation constant for cis-diammineaquachloroplatinum(II) ion. A hydrolysis product of cisplatin
J. Pharm. Sci.
(1994)
A. Ekborn et al.
Cisplatin-induced hearing loss: Influence of the mode of drug administration in the guinea pig
Hear. Res.
(2000)
K. Ikeda et al.
The preparation of acetic acid for use in otic drops and its effect on endocochlear potential and pH in inner ear fluid
Am. J. Otolaryngol.
(1989)
T. Kamimura et al.
Effect of 4-methylthiobenzoic acid on cisplatin-induced ototoxicity in the rat
Hear. Res.
(1999)
K.D. Korver et al.
Round window application of D-methionine provides complete cisplatin otoprotection
Otolaryngol. Head Neck Surg.
(2002)
C.T. Tan et al.
Effects of gentamicin and pH on [Ca²⁺]_i in apical and basal outer hair cells from guinea pigs
Hear. Res.
(2001)
F. Tanaka et al.
Influence of pH on the ototoxicity of cisplatin: a round window application study
Hear. Res.
(2003)
J.R. Yachnin et al.
The kinetics and cytotoxicity of cisplatin and its monohydrated complex
Cancer Lett.
(1998)
A. Atema et al.
Potentiation of DNA-adduct formation and cytotoxicity of platinum-containing drugs by low pH
Int. J. Cancer
(1993)
J.K. Barton et al.
A crystalline platinum blue: Its molecular structure, chemical reactivity and possible relevance to the mode of action of antitumor platinum drugs
Ann. NY Acad. Sci.
(1978)

F. Bertolero et al.

Changes in renal handling of platinum in cisplatinum-treated rats following induction of met abolic acidosis or alkalosis

Res. Commun. Chem. Pathol. Pharmacol.

(1982)

Q. Chau et al.

Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant

Cancer Chemother. Pharmacol.

(1999)

A. Ekborn et al.

Ototoxicity, nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig

Cancer Chemother. Pharmacol.

(2003)

S.A. Fausti et al.

An individualized, sensitive frequency range for early detection of ototoxicity

Ear Hear.

(1999)

M.V. Goycoolea

Clinical aspects of round window membrane permeability under normal and pathological conditions

Acta Otolaryngol.

(2001)

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N-acetylcysteine is a thiol-containing antioxidant, which has shown otoprotective effects in in vitro as well as in vivo models of cisplatin-induced hearing loss. Systemic administration of antioxidants, however, is associated with the major potential drawback of interference with the tumoricidal effect of cisplatin. This therapeutic limitation can be overcome by local intratympanic injection of the antioxidant N-acetylcysteine, which results in very restricted systemic uptake of the drug, whilst intracochlear drug levels are substantially higher. Furthermore, osmolality and pH properties of formulations for intratympanic injection need to be controlled, as they impact the fraction of drug crossing the barriers of the inner ear and could potentially damage middle and inner ear structures. This study focused on (i) the evaluation of concentration–time profiles of N-acetylcysteine in perilymph, cerebrospinal fluid and plasma after intratympanic administration, (ii) the influence of the dosage form, i.e. a thermoreversible poloxamer 407 hydrogel versus a solution, on N-acetylcysteine pharmacokinetics, and (iii) the development of a pH- and osmolality-adjusted formulation for intratympanic N-acetylcysteine delivery.
49 female albino guinea pigs were randomized into two treatment groups, receiving either a single intratympanic injection of a 4% N-acetylcysteine poloxamer 407 hydrogel or a 4% N-acetylcysteine solution. 8 animals served as untreated controls. N-acetylcysteine levels in perilymph, cerebrospinal fluid and plasma were monitored over a period of 24 h. Samples were taken at 1, 3, 6, 12 and 24 h (poloxamer 407 hydrogel group) and 1, 6 and 24 h (solution group) post injection, and analysed by high performance liquid chromatography-tandem mass spectrometry. Intratympanic application of the 4% N-acetylcysteine poloxamer 407 hydrogel resulted in a 4-fold larger perilymph area under the concentration–time curve (0–24 h) than topical administration of the equally concentrated N-acetylcysteine solution but in similar plasma N-acetylcysteine levels. N-acetylcysteine concentrations in the cerebrospinal fluid were below the level of detection (5 ng/ml) in both treatment groups. N-acetylcysteine-containing formulations applied to the middle ear were isohydric and osmolality was reduced by up to 200 mosmol/kg compared to equally concentrated formulations used in previous studies.
In summary, we were able to demonstrate that the intratympanic injection of thermoreversible poloxamer 407 hydrogels increases and sustains N-acetylcysteine delivery to the inner ear. Given the low plasma N-acetylcysteine levels after topical application and the physiological pH and osmolality of the hydrogel, the risk of compromising the antineoplastic effects of cisplatin therapy and of local side effects is minimal.
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Citation Excerpt :
Acute acidification of endolymph by experimental techniques reduces the EP of the endolymph [9,21]. In a study of the effects of administration of acidic or basic saline on the round window of cochlea in animals receiving cisplatin, ototoxicity is increased under acidic conditions and decreased under alkaline conditions [25]. Consistently, metabolic acidosis and impairment of cochlea pH regulation are associated with hearing loss.
The cochlear stria vascularis produces endolymph and thereby plays an active role in inner ear homeostasis. We recently reported that the H⁺/myo-inositol cotransporter (HMIT) gene is expressed in the stria vascularis. Here, we examined the protein localization of HMIT and Na⁺/myo-inositol cotransporter 1 (SMIT1) in the stria vascularis by immunohistochemistry. HMIT and SMIT1 were detected in the lateral wall of the cochlear duct. HMIT was widely detected throughout the stria vascularis, while SMIT1 was enriched in the strial basal cells. To examine the localization of HMIT in the stria vascularis in more detail, dissociated strial cells were immunostained, which resulted in the detection of HMIT immunoreactivity in marginal cells. These results indicate that HMIT is expressed in marginal cells and basal cells of the stria vascularis, while SMIT1 expression is enriched in basal cells. We speculate that HMIT and SMIT1 may play important roles in the homeostasis of cochlear fluids, for example by participating in pH regulation and osmoregulation.
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The environment of the inner ear is highly regulated in a manner that some solutes are permitted to enter while others are excluded or transported out. Drug therapies targeting the sensory and supporting cells of the auditory and vestibular systems require the agent to gain entry to the fluid spaces of the inner ear, perilymph or endolymph, which surround the sensory organs. Access to the inner ear fluids from the vasculature is limited by the blood-labyrinth barriers, which include the blood-perilymph and blood-strial barriers. Intratympanic applications provide an alternative approach in which drugs are applied locally. Drug from the applied solution enters perilymph through the round window membrane, through the stapes, and under some circumstances, through thin bone in the otic capsule. The amount of drug applied to the middle ear is always substantially more than the amount entering perilymph. As a result, significant amounts of the applied drug can pass to the digestive system, to the vasculature, and to the brain. Drugs in perilymph pass to the vasculature and to cerebrospinal fluid via the cochlear aqueduct. Conversely, drugs applied to cerebrospinal fluid, including those given intrathecally, can enter perilymph through the cochlear aqueduct. Other possible routes in or out of the ear include passage by neuronal pathways, passage via endolymph and the endolymphatic sac, and possibly via lymphatic pathways. A better understanding of the pathways for drug movements in and out of the ear will enable better intervention strategies.
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In addition, the acidification of cochlear endolymph may contribute to the loss of the endocochlear potential by enhancing oxidative stress through acid-activation of the K+ channel KCNQ1 (Unsold et al., 2000) and an increase in the rate of transepithelial K+ secretion across stria marginal cells, which would be associated with an increase in metabolism (Singh and Wangemann, 2008). Indeed, the endocochlear potential is reduced by experimental maneuvers that lead to an acute acidification of cochlear fluids (Ikeda et al., 1987a; Sterkers and Saumon, 1984) and acidification of cochlear fluids has been shown to increase free radical stress, whereas alkalinization has a protective effect on hearing (Tanaka et al., 2004). The luminal acidification and the loss of the endocochlear potential may jointly contribute to the approximately 100-fold elevation in the endolymphatic Ca2+ concentration (Ikeda et al., 1987b; Wangemann et al., 2007).
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Distortion-product otoacoustic emissions and auditory brainstem responses sensitivity assessment in cisplatin-induced ototoxicity in rats
2009, Brazilian Journal of Otorhinolaryngology
Citation Excerpt :
Anther variable parameter is the type of stimuli used. Most of the authors prefer the tone burst, with or without clicks22,28,29,33,37,42, 44–50, 52, 53. The tone burst has the advantage of assessing hearing in a frequency-specific way.
Cisplatin (cis-diamminedicloroplatinum) is an antineoplastic drug used in the treatment of a variety of cancers, especially head-and-neck cancer. Its ototoxicity, however, has been noted as a common side-effect which limits its use and causes significant morbidity.
to assess distortion-product otoacoustic emissions (DPOAE) and brainstem evoked response audiometry (BERA) sensitivity to detect secondary ototoxicity caused by different doses and means of administration of cisplatin in rats.
Experimental.
Male Wistar rats were intraperitoneally (i.p.) injected with 24 mg/kg cisplatin, divided into three equal doses (8mg/kg) or a single i.p. injection of 16 mg/kg. The animals were evaluated by distortion product otoacoustic emission (DPOAE) or brainstem evoked response audiometry (BERA) on the 3rd and 4th days after the cisplatin injection.
Treatment with cisplatin 24 mg/kg resulted in significant DPOAE decrease and it raised the BERA electrophysiological threshold. The 16mg/kg dose could not significantly reduce the DPOAE amplitude, but it raised the animals' hearing thresholds – detected by the BERA.
In rats, BERA was more sensitivity than DPOAE at detecting cisplatin-induced ototoxicity in rats considering different doses and means of administration.

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Round window pH manipulation alters the ototoxicity of systemic cisplatin

Abstract

Introduction

Section snippets

Animals

ABRs

Discussion

Acknowledgements

J. Pharm. Sci.

Hear. Res.

Am. J. Otolaryngol.

Hear. Res.

Otolaryngol. Head Neck Surg.

Hear. Res.

Hear. Res.

Cancer Lett.

Potentiation of DNA-adduct formation and cytotoxicity of platinum-containing drugs by low pH

Int. J. Cancer

A crystalline platinum blue: Its molecular structure, chemical reactivity and possible relevance to the mode of action of antitumor platinum drugs

Ann. NY Acad. Sci.

Changes in renal handling of platinum in cisplatinum-treated rats following induction of met abolic acidosis or alkalosis

Res. Commun. Chem. Pathol. Pharmacol.

Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant

Cancer Chemother. Pharmacol.

Ototoxicity, nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig

Cancer Chemother. Pharmacol.

An individualized, sensitive frequency range for early detection of ototoxicity

Ear Hear.

Clinical aspects of round window membrane permeability under normal and pathological conditions

Acta Otolaryngol.