salicylates and Hearing-Loss--Sensorineural

This review has the purpose to summarize concentration-effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine-induced increase in hearing threshold and its recovery can be analysed according to 'the psychophysical power function'. The power function is a special case of the Hill equation when the stimulus (e.g. a drug concentration) is exceedingly small compared with the concentration that would elicit a half-maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence the presence, magnitude, and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self-attained most comfortable speech level and the acoustic stapedius reflex are not affected, that is the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but performed with different molecular mechanisms.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antimalarials; Aspirin; Dose-Response Relationship, Drug; Hair Cells, Auditory, Outer; Hearing Loss, Sensorineural; Humans; Mechanotransduction, Cellular; Molecular Structure; Quinine; Salicylates; Severity of Illness Index; Tinnitus

Early after the development of aspirin, almost 150 years ago, its auditory toxicity has been associated with high doses employed in the treatment of chronic inflammatory diseases. Tinnitus, loss of absolute acoustic sensitivity and alterations of perceived sounds are the three auditory alterations described by human subjects after ingestion of large doses of salicylate. They develop over the initials days of treatment but may then level off, fluctuate or decrease, and are reversible within a few days of cessation of treatment. They may also occur within hours of ingestion of an extremely large dose. Individual subjects vary notably as to their susceptibility to salicylate-induced auditory toxicity. Tinnitus may be the first subjective symptom, and is often described as a continuous high pitch sound of mild loudness. The hearing loss is slight to moderate, bilaterally symmetrical and affects all frequencies with often a predominance at the high frequencies. Alterations of perceived sounds include broadening of frequency filtering, alterations in temporal detection, deterioration of speech understanding and hypersensitivity to noise. Behavioral conditioning of animals provides evidence for mild and reversible hearing loss and tinnitus, similar to those observed in humans. Anatomical examinations revealed significant alterations only at outer hair cell lateral membrane. Electrophysiological investigations showed no change in endocochlear resting potential, and small changes in the compound sensory potentials, cochlear microphonic and summating potential, at low acoustic levels. Measures of cochlear mechanical responses to sounds indicated a clear loss of absolute sensitivity and an associated broadening of frequency filtering, both of a magnitude similar to audiometric alterations in humans, but at extremely high salicylate levels. Otoacoustic emissions demonstrated changes in the mechano-sensory functioning of the cochlea in the form of decrease of spontaneous emissions and reduced nonlinearities. In vitro measures of isolated outer hair cells showed reduction of their fast motile responses which are thought to be at the origin of cochlear absolute sensitivity and associated fine filtering. Acoustically evoked neural responses from the eighth nerve to the auditory cortex showed reversible and mild losses of absolute sensitivity and associated broadening of frequency filtering. There is no evidence of a direct alteration of cochlear efferent innervation. Evi

Topics: Adolescent; Adult; Aged; Animals; Auditory Threshold; Chinchilla; Cochlea; Female; Hearing Loss, High-Frequency; Hearing Loss, Sensorineural; Hearing Tests; Humans; Male; Mice; Middle Aged; Pitch Perception; Rats; Salicylates; Speech Perception; Tinnitus

Topics: Animals; Animals, Newborn; Female; Gentamicins; Guinea Pigs; Hair Cells, Auditory; Hearing Loss, Noise-Induced; Hearing Loss, Sensorineural; Magnesium; Magnesium Deficiency; Pregnancy; Rats; Salicylates; Salicylic Acid

The hair cells of the cochlea (neuroepithelium) represent the primary target in most drug-induced ototoxic adverse effects on hearing (e.g. aminoglycoside antibiotics). To what extent an exogenically-induced morphologic damage to hair cells is reversible is not known. In aging structurally altered hair cells can persist for years likewisely not any longer participating in sensory transduction as the hair cells degenerate, secondary changes occur in the spiral ganglion cells and the neuronal pathways. Following heavy metal poisoning an adverse effect is observed on both central and peripheral innervation of the cochlea and only minor primary changes occur in the receptor cells. The link between function and morphology in the cochlea is very obvious regarding the high and middle frequencies with a distinct tonotopic localisation whereas for low frequencies (below 1 khz) such a specific morphologic correlation is lacking. Ototoxic effects primarily affecting the source for the production of endolymph, i.e. the stria vascularis, become manifest at all frequencies and at a rather early stage. Independent of type of substance penetrating into the inner ear, the substance has a considerably slower elimination rate as compared with all other compartments in the body. The toxicity of the drugs seems to be more related to its tissue binding capacity and saturation of receptor sites than related to the concentration of the drug in endo-or perilymph.

Topics: Age Factors; Aminoglycosides; Animals; Anti-Bacterial Agents; Antimalarials; Antineoplastic Agents; Cochlear Implants; Diuretics; Drug Evaluation; Drug Evaluation, Preclinical; Embryo, Mammalian; Endolymph; Fever; Hair Cells, Auditory; Hearing Loss, Sensorineural; Humans; Kidney Diseases; Kinetics; Labyrinth Diseases; Metals; Rats; Salicylates; Stria Vascularis

Tinnitus or subjective hearing loss, or both, were reported by 61 of 134 (45%) patients with rheumatoid arthritis (RA) taking regular salicylates and by 73 of 182 (40%) untreated healthy subjects. In the patients with RA mean salicylate levels were not higher in those with tinnitus than in those without tinnitus, but levels were significantly higher in those with subjective hearing loss than in those with no symptoms. Twenty five per cent of the patients with RA had tinnitus or subjective hearing loss with salicylate levels less than 1.42 mmol/l. Audiometric responses in 31 patients correlated poorly with symptoms. Tinnitus and subjective hearing loss may be too non-specific to be reliable as tools for adjusting the salicylate level into the therapeutic range.

Topics: Adult; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Aspirin; Audiometry; Clinical Trials as Topic; Hearing Loss, Sensorineural; Humans; Middle Aged; Salicylates; Tinnitus

Pendrin is a transmembrane protein encoded by the SLC26A4 gene that functions in maintaining ion concentrations in the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Variants in the SLC26A4 gene are responsible for sensorineural hearing loss. Although pendrin localizes to the plasma membrane, we previously identified that 8 missense allele products of SLC26A4 were retained in the intracellular region and lost their anion exchange function. We also found that 10 mM salicylate induced the translocation of 4 out of 8 allele products from the intracellular region to the plasma membrane and restored their anion exchanger activity. However, since 10 mM salicylate exhibits cytotoxicity, the use of chemical compounds with less cell toxicity is needed. In the present study, therefore, salicylate derivatives were used as the chemical compounds and their effects on the p.H723R allele products of SLC26A4 were investigated.. HEK293 cells were transfected with the cDNA of p.H723R. Cell proliferation, viability and toxicity assays were performed to investigate the response and health of cells in culture after treatment with four types of salicylate derivatives, i.e., 2-hydroxybenzyl alcohol, 2,3-dihydroxybenzoic acid, 2'-hydroxyacetophenone and methyl salicylate. The effects of these salicylate derivatives on the localization of the p.H723R were investigated by immunofluorescence microscopy.. The application of 10 mM salicylate showed an increase in cell toxicity and decrease in cell viability, leading to a significant decrease in cell proliferation. In contrast, the application of 1 mM salicylate derivatives did not show any significant increase in cell toxicity and decrease in cell viability, corresponding to a logarithmic increase in cell concentration with an increase in culture time. Immunofluorescence experiments showed that the p.H723R retained in the endoplasmic reticulum (ER). Among the salicylate derivatives applied, 2-hydroxybenzyl alcohol induced the translocation of p.H723R from the ER to the plasma membrane 3 h after its application.. The results obtained showed that 2-hydroxybenzyl alcohol restored the localization of the p.H723R allele products of SLC26A4 from the ER to the plasma membrane at a concentration of 1 mM by 3 h after its administration with less cytotoxicity than 10 mM salicylate.

Topics: Alleles; Hearing Loss, Sensorineural; HEK293 Cells; Humans; Membrane Transport Proteins; Mutation; Salicylates; Sulfate Transporters

Ototoxic side effects such as sensorineural hearing loss and tinnitus can be caused by acute salicylate intoxication. Bilateral symmetric sensori- neural hearing loss involving all tested frequencies is a typical pattern of hearing loss in acute salicylate intoxication, which usually resolves within 2 or 3 days without any specific treatment for ototoxicity. Herein, we report a case of suicidal aspirin intoxication resulting in sudden bilateral hearing loss and vertigo. The patient exhibited spontaneous downbeat nystagmus, and the mechanism underlying this characteristic nystagmus is discussed.

Topics: Aspirin; Hearing Loss, Bilateral; Hearing Loss, Sensorineural; Hearing Loss, Sudden; Humans; Nystagmus, Pathologic; Salicylates; Suicidal Ideation

Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight™. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW™ and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1mM, respectively, and a sustained effect was observed 12h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10mM concentration and a sustained effect was not observed even at 6h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients.

Topics: Amino Acid Substitution; Benzyl Alcohols; Cell Membrane; Goiter, Nodular; Hearing Loss, Sensorineural; HEK293 Cells; Humans; Membrane Transport Proteins; Microscopy, Fluorescence; Salicylates; Sulfate Transporters

Sensory hearing loss is predominantly caused by the destruction of cochlear outer hair cells (OHCs), inner hair cells (IHCs), or spiral ganglion cells (SGCs). There have been a number of attempts to differentiate between these etiologies of hearing loss, using various psychoacoustic and physiologic paradigms.. Here we investigate the potential of the auditory brainstem response (ABR) input/output function for such differential diagnosis. On the basis of the saturation of the OHC-based cochlear amplifier, it was hypothesized that selective impairment of OHCs would reduce ABR amplitudes at low to moderate but not at high sound levels. Selective impairment of IHCs or SGCs would reduce ABR amplitudes more or less uniformly across sound level. Finally, a mix of OHC and IHC or SGC impairment would reduce ABR amplitudes at all sound levels but less so at high levels depending on the relative contribution of OHC impairment to the hearing loss.. To test these hypotheses, normal-hearing adult guinea pigs were intravenously injected with either salicylate, furosemide, or quinine, under ketamine anesthesia. ABRs, as well as distortion-product otoacoustic emissions (DPOAEs), were measured as a function of the sound stimulus level before and after drug injection.. Following salicylate injection, ABR amplitudes were reduced only at low-moderate stimulus levels. Following furosemide or quinine injection, ABR amplitudes were reduced at all levels but less so at high ones. This is in accord with the expectation that acute salicylate administration selectively affects the OHCs, while furosemide and quinine affect both OHCs and IHCs/SGCs. Such differential diagnosis was not possible solely on the basis of DPOAE amplitudes, which were unchanged at high stimulus levels after the injection of each of the three drugs. Comparison of ABR and DPOAE threshold shifts could also differentiate the effects of salicylate from those of furosemide and quinine but could not, for example, unequivocally point to salicylate's selective impairment of OHCs.. ABR amplitudes appear suitable for differentiating between damage to OHCs and IHCs/SGCs, at least in a controlled experimental setting where pre- and postmanipulation data are available. This could be useful for noninvasively testing the effects of drugs or acoustic overstimulation on the cochlea, at least in the laboratory. Clinical applicability would seem to be limited by the high variability in ABR amplitudes among normal-hearing humans but might be feasible in the future if regular ABR testing entered into routine clinical practice.

Topics: Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Diuretics; Evoked Potentials, Auditory, Brain Stem; Female; Furosemide; Guinea Pigs; Hair Cells, Auditory, Inner; Hair Cells, Auditory, Outer; Hearing Loss, Sensorineural; Male; Otoacoustic Emissions, Spontaneous; Quinine; Salicylates; Spiral Ganglion

The SLC26A4 gene encodes the transmembrane protein pendrin, which is involved in the homeostasis of the ion concentration of the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene cause sensorineuronal hearing loss. However, the mechanisms responsible for such loss have remained unknown. Therefore, in this study, we focused on the function of ten missense pendrin mutations (p.P123S (Pendred syndrome), p.M147V (NSEVA), p.K369E (NSEVA), p.A372V (Pendred syndrome/NSEVA), p.N392Y (Pendred syndrome), p.C565Y (NSEVA), p.S657N (NSEVA), p.S666F (NSEVA), p.T721M (NSEVA) and p.H723R (Pendred syndrome/NSEVA)) reported in Japanese patients, and analyzed their cellular localization and anion exchanger activity using HEK293 cells transfected with each mutant gene. Immunofluorescent staining of the cellular localization of the pendrin mutants revealed that p.K369E and p.C565Y, as well as wild-type pendrin, were transported to the plasma membrane, while 8 other mutants were retained in the cytoplasm. Furthermore, we analyzed whether salicylate, as a pharmacological chaperone, restores normal plasma membrane localization of 8 pendrin mutants retained in the cytoplasm to the plasma membrane. Incubation with 10 mM of salicylate of the cells transfected with the mutants induced the transport of 4 pendrin mutants (p.P123S, p.M147V, p.S657Y and p.H723R) from the cytoplasm to the plasma membrane and restored the anion exchanger activity. These findings suggest that salicylate might contribute to development of a new method of medical treatment for sensorineuronal hearing loss caused by the mutation of the deafness-related proteins, including pendrin.

Topics: Asian People; Biological Transport; Cell Line; Cell Membrane; Cell Survival; Cytoplasm; Hearing Loss, Sensorineural; Humans; Japan; Membrane Transport Proteins; Microscopy, Fluorescence; Mutation, Missense; Protein Transport; Salicylates; Sulfate Transporters; Transfection

Salicylate has recently been demonstrated to protect against the auditory and vestibular side effects of aminoglycoside antibiotics. Similarities in the toxic mechanisms suggest salicylate as a treatment strategy to prevent the ototoxic side effects of cisplatin (CDDP). We first tested protection of the inner ear in Wistar rats receiving a single infusion of 16 mg CDDP/kg body weight with or without treatment with 100 mg/kg salicylate (bid) for 5 days beginning one day before the CDDP infusion. Cisplatin induced a threshold shift of more than 30 dB (at 14 kHz; measured by auditory evoked brain stem response) that was significantly reduced by salicylate. We then examined the protective potential of salicylate on the cochlea, peripheral nerves, and kidney in a rat model of breast cancer--Fisher344 rats implanted with highly metastatic MTLn3 breast cancer cells. Animals received 3 x 5 mg CDDP/kg (given every third day), and salicylate was administered at 100 mg/kg (bid) from 2 days before to 3 days after CDDP treatment. Salicylate significantly attenuated the CDDP-induced threshold shift from approximately 20 dB (at 16 and 24 kHz) to approximately 5 dB, and drastically reduced the loss of cochlear outer hair cells. Likewise, salicylate protected kidney function (measured as plasma blood urea nitrogen and creatinine levels) from CDDP toxicity. Protection of nerve conduction velocities of both sensory and motor nerves was minimal. The chemotherapeutic efficacy of CDDP on suppression of tumor mass and cancer cell metastasis remained unaffected by salicylate. The results suggest that administration of salicylate may become the basis of an effective therapeutic intervention against the ototoxic and nephrotoxic side effects associated with CDDP chemotherapy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Auditory Threshold; Blood Urea Nitrogen; Breast Neoplasms; Cisplatin; Drug Antagonism; Evoked Potentials, Auditory, Brain Stem; Female; Hair Cells, Auditory, Outer; Hearing Loss, Sensorineural; Kidney Diseases; Kidney Function Tests; Male; Neoplasms, Experimental; Neural Conduction; Rats; Rats, Inbred F344; Rats, Wistar; Salicylates

Whereas cochlear impairment after intravenous ingestions of salicylates is well known, reports of cochlear symptoms after topical application are quite rare. The extent of the ototoxic salicylate impact is increased by diabetes, renal insufficiency, and alcoholism.. This study presents a case report of a female patient who suffered a repeated, symmetric, pancochlear, reversible inner ear impairment after two treatments with salicylate containing ointment for psoriasis. The correlation of the salicylate therapy with the observed inner ear lesions is obvious due to the close interval between these incidences and to the audiologic criteria typical for salicylate intoxication.. Audiologic controls should be carried out during extended local application of salicylate containing ointment.

Topics: Adult; Audiometry, Pure-Tone; Auditory Threshold; Female; Hearing Loss, Sensorineural; Humans; Keratolytic Agents; Nystagmus, Physiologic; Ointments; Otoacoustic Emissions, Spontaneous; Psoriasis; Salicylates; Salicylic Acid; Tinnitus

A 36-year-old woman, hospitalized because of an exacerbation of psoriasis, developed fever, sudden deafness and severe metabolic acidosis after treatment with a 10% salicylic acid containing ointment for four days. The use of salicylic acid on large areas of inflamed skin enhances the risk of transcutaneous resorption and intoxication. High serum concentrations (> 300 mg/l) of salicylic acid deregulate the blood glucose metabolism and cause damage to the inner ear. After timely intervention such symptoms are largely reversible.

Topics: Acute Disease; Adult; Female; Hearing Loss, Sensorineural; Humans; Keratolytic Agents; Ointments; Psoriasis; Salicylates

Ototoxic drugs such as salicylates, the aminoglycoside antibiotics, loop diuretics, cisplatin, erythromycin, and vancomycin are widely used in clinical practice. The most commonly used are aspirin and the aminoglycoside antibiotics. This chapter briefly discusses the pharmacology of the commonly prescribed ototoxic drugs and the doses that may result in ototoxicity. An outline for the monitoring of ototoxic drugs is presented. The role of topical ear drops as a possible cause of ototoxicity is reviewed.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cisplatin; Diuretics; Erythromycin; Hearing Loss, Sensorineural; Humans; Salicylates; Vancomycin

The interaction of noise with a variety of other agents and with some physical characteristics of the individual to produce noise-induced hearing loss is reviewed critically. The review is restricted, for the most part, to publications since 1970. Other agents interacting with steady-state noise that are reviewed here include: (1) ototoxic drugs (kanamycin, neomycin, ethacrynic acid, furosemide, and salicylates), (2) impulse noise, and (3) whole-body vibration. Physical characteristics of the individual that are reviewed are: (1) age, (2) presence of previous hearing loss from prior noise exposure, (3) eye color, and (4) race. Suggestions for future research in this general area are also made. Some of these suggestions are as follows: (1) to extend studies of the interaction of steady-state noise with impulse noise, salicylates, and whole-body vibration to encompass a broader range of exposure conditions, including exposure conditions typically encountered by the worker, (2) to develop an animal model of presbycusis to explore the interactions of noise-induced hearing loss and presbycusis, and (3) to explore the potential interactions resulting from concurrent exposure to multiple agents, such as impulse noise and ototoxic drugs, in younger, more susceptible animals.

Topics: Acoustic Stimulation; Age Factors; Animals; Ethacrynic Acid; Eye Color; Furosemide; Hearing Loss, Noise-Induced; Hearing Loss, Sensorineural; Humans; Kanamycin; Melanins; Neomycin; Presbycusis; Risk; Salicylates; Vibration