Ototoxic Agents Research Articles

Effects of age on the distortion product otoacoustic emission growth functions

Age-related hearing loss (presbycusis) is thought to result from age-related degeneration (aging) of the cochlea plus the cumulative effects of extrinsic damage (noise and other ototoxic agents) and intrinsic disorders (e.g. systemic diseases). Previous studies have implicated dysfunction of the hair cells (sensory presbycusis) as the principal mechanism of age-related hearing loss. However, recent evidence from quiet-reared gerbils suggests that cochlear aging results primarily from atrophy of the stria vascularis, which is associated with diminished endocochlear potential (EP), spiral ganglion atrophy, and a relatively flat audiometric loss, termed metabolic presbycusis. Because it is not currently possible to measure EP directly in the clinical setting, we wondered if cochlear metabolic dysfunction might be evidenced indirectly from existing clinical tests, specifically, the input–output (IO) growth function of the distortion product (DP) otoacoustic emissions in relation to behavioral hearing threshold levels (HTL). We anticipated finding discordance between the IO functions and HTL with either a greater decline with age in HTL than in IO functions if an age-related metabolic dysfunction of the cochlea was operant, or a greater loss of IO function than HTL if outer hair cell dysfunction was the dominant pathology. To address this supposition we analyzed existing auditory data from a large cohort of adults to determine the change with age in three aspects of the DP IO function: area under the curve, threshold, and slope. The analyses demonstrated a greater effect of age on HTL than on the DP IO measures. This effect supports the hypothesis that strial dysfunction is a substantive factor in cochlear aging. The etiology and mechanisms for this dysfunction are conjectural at present.

Mitochondrial cytochrome oxidase immunolabeling in aged human temporal bones

Presbycusis, an age-related hearing loss, is accompanied by histopathological cochlear changes including variable amounts of degeneration of the auditory receptors, neurons and the stria vascularis. The causes of degeneration are unknown, although acoustic trauma and exposure to ototoxic agents are certainly contributors to the cellular degeneration. Acquired mitochondrial DNA defects are postulated as important determinants of aging in neuromuscular tissues. The cochlear neurons are highly metabolic and are, therefore, likely to be affected by mitochondrial DNA defects. Sequence analysis has demonstrated a significant number of acquired mutations in the cytochrome oxidase gene in the neurons from aged human cochleas. The current study used immunohistochemical labeling of cytochrome oxidase in the neuronal cell bodies in archival celloidin sections to evaluate relationships among label density, hearing loss, number of neurons and mitochondrial DNA changes within individual cochleas. Label density was less in many aged temporal bones, but not all. There was no relationship among any other variables. It is concluded that while there may be a decrease in the amount of cytochrome oxidase expression in aged spiral ganglion cell bodies, there are many other factors that contribute to hearing loss and cellular degeneration.

Recommendations for cancer prevention trials using potentially ototoxic test agents.

Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents. These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.

Intratympanic gentamicin therapy for vertigo in nonserviceable ears

Purpose: Intratympanic ototoxic agents have become a widely accepted means of managing vertigo in patients with Meniere's disease while preserving residual hearing. We investigated expanding the indications for intratympanic gentamicin to include control of vertigo in patients without serviceable hearing in the involved ear caused by a variety of end-organ pathologies. Materials and Methods: We present a retrospective series of 6 patients suffering from vertigo caused by end-organ disease, in an ear without serviceable hearing. Two patients suffered from delayed endolymphatic hydrops, 3 from Meniere's disease, and 1 from poststapedectomy vertigo. These patients chose unilateral vestibular ablation with serial intratympanic gentamicin injection rather than labyrinthectomy for a variety of reasons. Conventional electronystagmography (ENG) testing and audiometry were completed on all patients. The ENG testing included bithermal calorics and rotational testing. All patients had a magnetic resonance image with gadolinium to exclude retrocochlear or central pathology. Rotational testing was repeated before each injection and at the conclusion of therapy to assess changes in the peripheral vestibular response. The patients' subjective response to therapy was followed. Results: Follow-up has been 10 to 69 months with successful control of vertigo in all patients. Conclusions: Intratympanic gentamicin therapy offers a minimally invasive, ambulatory, low morbidity, cost-effective means of managing vertigo in patients with nonserviceable hearing. (Am J Otolaryngol 2001;22:111-115. Copyright © 2001 by W.B. Saunders Company)

Antimycotic therapy in otomycosis with tympanic membrane perforation

Especially after prolonged antibiotic ototopic therapy otomycosis is not rare. An inoculation of fungi into the tympanic cavity however may have serious sequelae. Therefore an eradication of fungi from the external auditory canal is imperative before surgery. In addition to thorough cleaning of the outer ear canal antimycotic preparations are recommended in treating otomycosis. However, all of the commercially available ear drops contain ototoxic agents. In the case of defects of the tympanic membrane a damage of the inner ear may result. Alternatively, we suggest an aqueous solution of Miconazol 0,5%.

Toxicity of single daily dose gentamicin in stem cell transplantation.

To determine the safety of single daily dose (SDD) gentamicin in recipients of stem cell transplantation (SCT), we evaluated all adult patients at MD Anderson Cancer Center who received SDD gentamicin for treatment of febrile neutropenia. Thirty-three patients received gentamicin 5 mg/kg i.v. every 24 h. Mean duration of therapy was 7 days (range 3-32 days). All patients received vancomycin and 17 received cisplatinum. All patients had normal renal function prior to therapy. Serum gentamicin levels were monitored only when renal function deteriorated. The incidence of nephrotoxicity and clinically significant ototoxicity was 3% and 12%, respectively. All four patients who developed ototoxicity had normal renal function before and during therapy. The mean duration of gentamicin therapy was significantly longer in patients who developed ototoxicity, 20 days vs 9 days (P = 0.001). Patients treated with SDD gentamicin for >10 days were more likely to develop ototoxicity (P = 0.045). Single daily dosing of gentamicin was associated with clinically significant ototoxicity in 12% of our patients. A larger randomized EORTC trial evaluating SDD vs MDD amikacin failed to detect a difference in ototoxicity. However, the median duration of therapy was only 8 days. The increased incidence of ototoxicity in our study may be due to prolonged therapy, type of aminoglycoside used, concomitant ototoxic agents, small sample size, or a combination of the above.

Noise in the Pediatric Intensive Care Unit

The pediatric intensive care unit is an environment filled with dedicated caregivers, state-of-the-art monitors, and machines that collectively work to provide the best care possible for critically ill children. A previously unappreciated result of having these resources mingled together is the elevated level of environmental noise. Although the levels of noise do not reach OSHA levels (>85 dB for 8 continuous hours) that cause noise-induced hearing loss, the patients are exposed to continuous moderate noise levels that may cause hearing impairment if mixed with other ototoxic agents. In addition, these noise exposures may result in abnormalities in the stress response as well as in sleep patterns. This article reviews the physiology of hearing, the consequences of noise pollution as it relates to pediatric patients, and preventive measures used to reduce noise pollution in a pediatric intensive care setting. Considerations for further research efforts are also discussed.

Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice.

Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.

Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma.

Children with neuroblastoma receiving high-dose carboplatin as part of their conditioning regimen for autologous marrow transplantation have a high incidence of speech frequency hearing loss. We evaluated hearing loss in 11 children with advanced stage neuroblastoma who underwent autologous marrow transplantation, following a conditioning regimen containing high-dose carboplatin (2g/m2, total dose). Audiometric evaluations were obtained at diagnosis, prior to and following transplant. Exposure to other known ototoxins also was assessed. All patients sustained worsening of hearing following high-dose carboplatin. Nine of the 11 children (82%) had evidence of speech frequency hearing loss post transplant for which hearing aids were recommended (grades 3-4). Three of the nine children had speech frequency loss prior to transplant which progressed following transplant. The entire group was heavily pre-treated with platinum-containing chemotherapy pre-BMT and had extensive exposure to other ototoxins, including aminoglycoside antibiotics, diuretics, and noise exposure - all of which could have exacerbated the effects of carboplatin. High-dose carboplatin is ototoxic, particularly in patients who have been primed with previous platinum therapy or other ototoxic agents. We conclude that further efforts are needed to monitor and minimize this complication. In cases where hearing loss is inevitable due to cumulative ototoxic exposures, families need to be adequately prepared for the tradeoffs of potentially curable therapy.

Direct detection of ototoxicant-induced reactive oxygen species generation in cochlear explants

The proposal that free-radical generation contributes to the ototoxicities of several chemical agents was studied utilizing electron paramagnetic resonance (EPR) spectrometry to detect directly ototoxicant- induced reactive oxygen species formation in cochlear tissue. Guinea pig cochlear explants in chelexed artificial perilymph (AP; 200 μl) were exposed to an ototoxicant or AP for 10 min. Ototoxic agents included gentamicin sulfate (4.0 mM), kanamycin monosulfate (4.0 mM), ethacrynic acid (0.5 mM), furosemide (0.3 mM), cisplatin (0.1 mM), trimethyltin chloride (0.1 mM), and quinine HCl (3.0 mM). Following incubation, 20 μl of AP/ototoxicant mixture was replaced by the filtered spin trap, 5,5-dimethylpyrroline- N-oxide (DMPO). After 10 min, the EPR spectrum of the mixture was obtained. Four line EPR spectra of relative intensities 1:2:2:1, associated with hydroxyl radical (OH )/DMPO adduct formation, were evidenced by reaction mixtures containing cochlear explants exposed to each ototoxicant. Cisplatin, quinine and the loop diuretics produced weak OH-associated EPR signals in the absence of a cochlear explant, which were amplified in its presence. Deferoxamine quenched all OH spectral peaks. Peroxide levels, assayed in parallel experiments, were diminished by each ototoxicant relative to those seen following AP exposure, suggesting possible H 2O 2 conversion to OH. These data support the proposal that various ototoxic agents are capable of reactive oxygen species generation or promotion in cochlear tissues.

Localization of ornithine decarboxylase (ODC) in the cochlea of the immature rat

Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, is important in cochlear development. Whereas tissue specific differences in cochlear ODC activity have been demonstrated, cellular localization of ODC protein in the inner ear of the immature rat has not. ODC was localized in inner ear structures using an ODC polyclonal antibody and the effects of cycloheximide on ODC immunoreactivity and enzymatic activity were determined. Tissues demonstrating elevated enzymatic activity contained cells with the strong immunoreactivity. ODC activity was highest in the organ of Corti and lateral wall followed by the cochlear nerve. Immunoreactivity was demonstrated throughout the cochlea with intense staining of the hair cells, pillar cells, Deiter's cells, inner sulcus cells, basilar membrane, stria vascularis, spiral ganglion cell bodies and cochlear nerve fibers. Cycloheximide rapidly diminished cochlear ODC activity and expression of ODC protein. The half-life of cochlear ODC was 30 min. Localization of cellular sites of ODC is important in understanding the role of the ODC-polyamine pathway in cochlear development and will be a valuable marker for tissue damage from ototoxic agents.

Ototoxicity of topical otomicrobial agents.

Topical antimicrobial solutions are used commonly for prevention or treatment of purulent otorrhea even though most solutions contain ototoxic agents. This study compares the cochlear and middle ear toxicity of cortisporin otic solution (COS), 0.3% gentamicin ophthalmic solution (GOS), benzalkonium chloride (0.026% and 0.05%), and 1.0% Ofloxacin, a new quinolone antibiotic. Saline 0.9% was used as a control. The agent was instilled daily for 7 days into the bulla of juvenile guinea pigs. The animals were sacrificed on the 14th day. The organ of Corti was examined using surface preparation light microscopy and scanning electron microscopy. The tympanic membrane (TM) and adjacent middle ear mucosa were examined with light microscopy. The average cochlear hair cell damage was 66% for COS, 6.5% for GOS, and 1% for Ofloxacin, benzalkonium and saline. COS and benzalkonium 0.05% produced moderate mucosal thickening and inflammation. However, this was not statistically different from the mild mucosal thickening produced by saline, GOS, Ofloxacin and 0.026% benzalkonium. There was statistically significant mild to moderate thickening of the TM for all agents compared to the saline control.

Reliability of auditory brainstem responses from sequenced high-frequency (> or = 8 kHz) tonebursts.

An auditory brainstem response method is described for evoking responses to 4 high-frequency (8, 10, 12 and 14 kHz) tonebursts in the same amount of time normally required to obtain responses to single tonebursts. Reliability of responses to high-frequency toneburst stimuli presented in the conventional manner (one at a time) has been previously documented. In the present study, high-frequency tonebursts were presented to 20 normal-hearing subjects singly and in a 4-stimulus sequence. The reliability of resulting responses did not differ significantly between single- and multiple-stimulus test conditions. It is concluded that this sequenced-stimulus concept could be developed for use in serial monitoring of individuals receiving ototoxic agents as well as being broadly applicable to clinical situations in which patients cannot or will not respond voluntarily.

Second messengers in the cochlea.

Second messengers are vital to the regulation of nearly every aspect of cellular physiology. Evidence is reviewed for the role of second messengers in cochlear fluid homeostasis, hair cell adaptation, motility and synaptic activity. We suggest that the elucidation of the role of second messengers in the regulation of cochlear physiology will be important for the therapeutic management of otopathologies and the side effects of ototoxic agents.

Carboplatin ototoxicity in the chinchilla: lesions of the vestibular sensory epithelium.

Carboplatin (cis-Diammine-1,1-cyclobutane dicarboxylate platinum II; CBDCA) is a second generation platinum analog with less nephrotoxicity and cochlear ototoxicity than cisplatin, the first generation platinum chemotherapeutic agent. Studies in many animal species have indicated that carboplatin ototoxicity is expressed as damage to cochlear outer hair cells. The lesion is similar, though less severe, than that resulting from cisplatin intoxication. Recent investigations by our laboratory have demonstrated a species-specific ototoxicity of carboplatin in the chinchilla cochlea. Contrary to other animal models, the inner hair cells are the focus of damage; the outer hair cells often sustain little or no damage. Clinical evidence points to vestibular dysfunction in some patients treated with platinum-containing anti-tumoural agents. However, no morphological studies have shown degeneration of the sensory cells in the vestibular labyrinth resulting from carboplatin treatment. The objective of the present study was to determine whether, in view of its unique toxicity in the chinchilla, carboplatin has any toxic effect on the vestibular end organs. Preliminary investigations of the vestibule by light and scanning electron microscopy indicate that sensory cell cilia became exfoliated or deformed in the crista, utricle and in one instance in the saccule. In general the pattern of damage is similar to that caused by other known ototoxic agents including aminoglycosides and cisplatin.

Ototoxicity

This article describes the pathophysiology of ototoxic agents and contains a list of potential ototoxic agents including a list of animal species in which the toxicity has been documented or research studies performed.

Otoacoustic emissions: an approach for monitoring aminoglycoside-induced ototoxicity.

Ototoxic drugs, such as aminoglycosides, affect outer hair cell integrity in the inner ear. Transiently evoked otoacoustic emission (TEOAE) characteristics are related to outer hair cell function and can be expected to reflect the influence of ototoxic agents. Transiently evoked otoacoustic emissions were measured during amikacin sulfate therapy in nine patients. The duration of treatment for individual patients ranged from 9 to 33 days. A reversible decrease of overall TEOAE level, occurring after a treatment period longer than 16 days, was found in the majority of patients. The monitoring of TEOAEs is proposed as a method for early identification and, as a result, prevention of aminoglycoside-induced ototoxicity.

Cochlear function after selective inner hair cell degeneration induced by carboplatin

The ototoxicity of carboplatin, a second generation anti-cancer agent, was examined using the chinchilla as an animal model. In animals treated with a clinical therapeutic dose (400 mg/m 2), the dominant degenerative change is to inner hair cells (IHCs). This is in sharp contrast to most other ototoxic agents, which damage primarily the outer hair cells (OHCs). Functional changes to the cochlea have been evaluated in carboplatin treated subjects by recording cochlear action potentials (CAP) and cochlear microphonics (CM); cochlear lesions were evaluated using scanning electron microscopy. In carboplatin treated animals, CAP thresholds to tone-pip stimuli were elevated in proportion to IHC damage in corresponding cochlear regions. In contrast, CM amplitudes and ‘thresholds’ remained close to normal in most cases, reflecting the preservation of OHCs in the basal turn. These results indicate a high degree of independence between the inner and outer hair cell systems in the cochlear transduction mechanism. We suggest that this species-specific preparation with selective IHC loss will provide a valuable tool for studying, separately, the role of OHCs in both afferent and efferent cochlear function.

Kanamycin depletes cochlear polyamines in the developing rat

Developing mammals are more sensitive to aminoglycoside antibiotics and other ototoxic agents than adults, with maximum sensitivity occurring during the period of anatomic and functional maturation of the cochlea. For the aminoglycoside antibiotics, the hypersensitive period in rats occurs during the second and third postnatal weeks. Toxicity is initially expressed as outer hair cell (OHC) damage in the high-frequency, basal region of the cochlea. Distortion-product otoacoustic emissions (DPOAEs), physiologic measures of OHC function, are particularly sensitive to aminoglycoside exposure during the period of rapid cochlear physiologic development. Toxicity is characterized by increased DPOAE thresholds and decreased amplitudes. The mechanism of developmental sensitivity to aminoglycosides is unknown. A potential biochemical target of aminoglycosides is the ornithine decarboxylase (ODC)-polyamine pathway. ODC activity is elevated in the developing rat cochlea, aminoglycosides inhibit cochlear ODC in developing rats, and alpha-difluoromethylornithine (a specific ODC inhibitor) impairs development of cochlear function. In the present study we demonstrate an incomplete polyamine response to aminoglycoside damage, characterized by inhibition of the polyamines spermidine and spermine and accumulation of putrescine in the organ of Corti. Aminoglycoside inhibition of polyamine synthesis may mediate developmental ototoxic hypersensitivity by interfering with developmental and repair processes.

Does topical antibiotic prophylaxis reduce post-tympanostomy tube otorrhea?

Purulent otorrhea is the most common complication of tympanostomy tube (TT) insertion. It may occur in the postoperative period or at any time during the sojourn of the tube. The efficacy of topical antimicrobial prophylaxis against purulent postoperative otorrhea (PPO) has been examined in 5 prospective, randomized studies; all demonstrated a reduction in PPO from topical antimicrobial prophylaxis, but in only 1 study was the difference statistically significant. Because the 5 studies used 2 different experimental designs--by-patient, and by-ear--a single meta-analysis could not be done. However, the by-patient studies met the criteria for meta-analysis, which demonstrated a combined odds ratio of 0.12 (95% confidence interval 0.04 to 0.37, p = .0002). This represents an 85% reduction in otorrhea, which is judged to be clinically as well as statistically significant. We conclude from the available evidence that prophylactic use of topical antimicrobial agents following TT insertion consistently reduces the rate of PPO. However, the low incidence of PPO and the heterogeneity of the published studies prevent making a final judgment for or against the continued use of these agents. Therefore, given that these potentially ototoxic agents are frequently administered to prevent postoperative otorrhea, further study of this subject is warranted. In the meantime, we recommend judicious use of these agents following TT insertion in those cases at higher risk for PPO, namely those with mucoid or purulent effusion.