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Ototoxicity: Drug-Induced hearing loss
... 10,11 Following the 1940s, subsequent decades have been associated with new clinical reports of chemically-induced auditory dysfunction and deafness, particularly loop diuretics in the 1960s, antineoplastic drugs (cisplatin and derivatives) and solvents during the 1970s, and metal-chelating agents in the 1980s. 1 Auditory, vestibular, and toxicology research laboratories around the world are investigating the mechanisms by which these classes of ototoxins induce their cytotoxic effects, as each of these compounds have little or no pharmaceutical or chemical overlap. These are briefly reviewed below. ...
... 10 The following year saw the first of many reports of aminoglycoside ototoxicity in tuberculosis patients, 12 initiating a search for other bactericidal aminoglycosides that were less ototoxic. 1 Today, the most frequently used aminoglycosides include amikacin, gentamicin, and tobramycin. Despite their ototoxic potential, aminoglycosides remain an essential part of the clinicians' prescriptive arsenal against bacterial infections, particularly in premature babies as prophylaxis against bacterial infection in the United States. ...
... Today, salicylate, in the form of aspirin, is the most frequently consumed drug, with no confirmed reports of permanent ototoxicity. 1 Significantly, aspirin has been shown to have prophylactic effects against heart attacks, stroke, and blood clot formation (thrombosis). 104 In addition, aspirin has a protective affect against gentamicin-and cisplatin-induced ototoxicity, presumptively through an antioxidant mechanism. ...
The modern era of evidence-based ototoxicity emerged in the 1940s following the discovery of aminoglycosides and their ototoxic side effects. New classes of ototoxins have been identified in subsequent decades, notably loop diuretics, antineoplastic drugs, and metal chela-tors. Ototoxic drugs are frequently nephrotoxic, as both organs regulate fluid and ion composition. The mechanisms of ototoxicity are as diverse as the pharmacological properties of each ototoxin, though the generation of toxic levels of reactive oxygen species appears to be a common denominator. As mechanisms of cytotoxicity for each ototoxin continue to be elucidated, a new frontier in ototoxicity is emerging: How do ototoxins cross the blood-labyrinth barrier that tightly regulates the composition of the inner ear fluids? Increased knowledge of the mechanisms by which systemic ototoxins are trafficked across the blood-labyrinth barrier into the inner ear is critical to developing new pharmacotherapeutic agents that target the blood-labyrinth barrier to prevent trafficking of ototoxic drugs and their cytotoxic sequelae. Learning Outcomes: As a result of this activity, the participant will be able to (1) describe how ototoxic drugs enter the cochlea and hair cells to induce their cytotoxic effect, and (2) describe the importance of the blood-labyrinth barrier in cochlea function and otoprotection.
... En ningún caso se sugiere la realización de estudios clínicos interdisciplinares con otras profesiones involucradas en la evaluación e intervención de la audición para realizar un seguimiento profundo de la AR. Respecto a la medicación, los reportes sugieren controlar la sulfasalazina, suspender los corticosteroides e incluir antioxidante N-acetil cisteína, vitamina E y el salicilato de sodio (64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79). ...
... Con el SS se puede inferir que las lesiones o alteraciones en la audición son en la cóclea, la cual produce HNS. Respecto a la ototóxicidad, se registró que la única HNS reversible es la que se trata con los salicilatos (67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81). ...
Introducción. En la actualidad no hay cifras sobre las personas que padecen artritis reumatoide (AR), lupus eritematoso sistémico (LES) o síndrome de Sjögren (SS) ni información sobre las alteraciones auditivas que puede causar el tratamiento farmacológico utilizado para controlar dichas enfermedades.Objetivo. Evidenciar las posibles afectaciones y alteraciones audiológicas y vestibulares producidas por AR, LES y SS o su tratamiento farmacológico.Materiales y métodos. Se analizaron los hallazgos clínicos de herramientas diagnósticas y procedimientos de prevención e intervención de alteraciones auditivas en artículos de investigación publicados en español, inglés, francés y portugués en bases de datos científicas entre los años 2000 y 2016.Resultados. Se extrajeron 62 artículos de investigación (31 de AR, 5 de LES, 12 de SS, 5 de Hipoacusia inmunomediada, 9 de medicamentos ototóxicos), 1 tesis doctoral sobre AR, 1 tesis doctoral sobre AR y LES y 1 guía de práctica clínica para la detección temprana, diagnóstico y tratamiento de AR. Se evidenció que las pérdidas auditivas con mayor reporte son hipoacusia neurosensorial, lesiones en cadena osicular y vestíbulo-coclear.Conclusiones. Se confirmó la relación entre las lesiones audiológicas y AR, LES y SS, pero aun no es claro el desarrollo de los ototóxicos.
... 25,26 They are often given without monitoring yet they are known to be a major cause of preventable deafness worldwide. 27 In the developing countries, the choice of treatment depends mainly on the affordability rather than the safety. In this particular study, we did not record any case of ototoxicity from this group of aminoglycosides possibly because these patients are managed at a special centre that is outside the general hospital environment. ...
... This report is in consonance with the findings of Torun et al [4] via a retrospective study conducted in Turkey where Ototoxicity from MDR-TB therapy yielded 41.8%. Other reports include de Jagger et al [5], in a 14 day case controlled study carried out among patients on prolonged therapy of aminoglycosides for TB therapy in the Netherlands 18%; Schacht [6], 10-20% in acute infection therapy and more in tuberculosis. ...
ABSTRACTS:
To investigate the Cochleo-vestibular clinical and audiometric findings in Multi and Extreme Drug Resistance(MDR and XDR) tuberculosis(TB) patients on treatment and make recommendations.
A cross-sectional study of adult MDR and XDR-TB patients was conducted in a general hospital in Cape-Town-South-Africa. Ethical approval was secured and all consenting patients administered with pretested and validated questionnaire under the guidance of International Classification of Functioning, Disability and Health(ICF) Checklist-version-2.1a. Audiometric evaluation included: Otoscopy, Diagnostic Audiometry and Tympanometry. The data analyses were done with SPSS version 16, Chi-square and StatCalc-7.
Fifty-three adults, ages 18-60 (mean-33 years) comprising 26 males and 27 females participated in the study. Hospital stay duration varied from 1-18 months (mean-6 months) and all were on anti-Koch's second line drugs (regimen 2). MDR TB group were 45(85%) and XDR 8(15%). Vertigo was the most common vestibular symptoms, 24(45%) whereas, tinnitus 23(42%) and hearing loss 13(25%) were most frequent auditory complaints. Bilateral sensorineural hearing losses of varying degrees were confirmed in 23(47%).There was no association between gender and age with hearing loss [χ2 (P = 0.16, ά = 0.05) and (p = 0.13, ά = 0.05)]. Furthermore, MDR and XTR TB groups [20/42 Vs 3/8; Z = 0.46 and P = 0.64], showed no difference in pattern of the hearing losses.
A multi-disciplinary close surveillance of MDR and XDR TB patients on therapy is imperative. Finally, researches into therapeutic trials on antidotes and potent safer substitutes for aminoglycosides in the management are recommended.
Background:
The previous 30 years have provided information on the mechanisms of cell death in the inner ear after noise exposure, ototoxic drug injury, and during aging, and clinical trials have emerged for all of these acquired forms of hearing loss. Sudden hearing loss is less well understood, but restoration of hearing after sudden hearing loss is also a long-standing drug target, typically using steroids as an intervention but with other agents of interest as well.
Purpose:
The purpose of this review was to describe the state of the science regarding clinical testing of investigational medicinal products for the inner ear with respect to treatment or prevention of acquired hearing loss.
Data collection and analysis:
Comprehensive search and summary of clinical trials listed in the National Library of Medicine (www.
Clinicaltrials:
gov) database identified 61 clinical trials.
Results:
Study phase, status, intervention, and primary, secondary, and other outcomes are summarized for studies assessing prevention of noise-induced hearing loss, prevention of drug-induced hearing loss, treatment of stable sensorineural hearing loss, and treatment of sudden sensorineural hearing loss.
Conclusion:
This review provides a comprehensive summary of the state of the science with respect to investigational medicinal products for the inner ear evaluated in human clinical trials, and the current challenges for the field.
Noise is a major cause of hearing loss in the air base. There are lots of risk factors of hearing loss including noise, and hearing loss can be accelerated by combined effects of these risk factors. Here in, we reviewed risk factors of hearing loss, and analysed key risk factors inducing hearing loss in the air base. Risk factors exacerbating hearing loss with noise were mainly investigated in this research because noise could not be an avoidable risk factor in the air base. Analysed data will contribute to make green environment minimizing hearing loss of pilots and supporting personnels in the air base.
The ototoxicity of a number of marketed drugs is well documented, and there is an absence of convenient techniques to identify and eliminate this unwanted effect at a pre-clinical stage. We have assessed the validity of the larval zebrafish, or more specifically its lateral line neuromast hair cells, as a microplate-scale in vivo surrogate model of mammalian inner ear hair cell responses to ototoxin exposure. Here we describe an investigation of the pathological and functional consequences of hair cell loss in lateral line neuromasts of larval zebrafish after exposure to a range of well known human and non-human mammalian ototoxins. Using a previously described histological assay, we show that hair cell damage occurs in a concentration-dependent fashion following exposure to representatives from a range of drug classes, including the aminoglycoside antibiotics, salicylates and platinum-based chemotherapeutics, as well as a heavy metal. Furthermore, we detail the optimisation of a semi-automated method to analyse the stereotypical startle response in larval zebrafish, and use this to assess the impact of hair cell damage on hearing function in these animals. Functional assessment revealed robust and significant attenuation of the innate startle, rheotactic and avoidance responses of 5 day old zebrafish larvae after treatment with a number of compounds previously shown to induce hair cell damage and loss. Interestingly, a startle reflex (albeit reduced) was still present even after the apparent complete loss of lateral line hair cell fluorescence, suggesting some involvement of the inner ear as well as the lateral line neuromast hair cells in this reflex response. Collectively, these data provide evidence to support the use of the zebrafish as a pre-clinical indicator of drug-induced histological and functional ototoxicity.
Research in mammalian hair cell regeneration is hampered by a lack of in vivo model of adult mouse inner ear injury. In the present study we investigated the effects of a combination of a single dose of aminoglycoside followed by a loop diuretic in adult mice. The auditory brainstem response threshold shift, extent and defining characteristics of the cochlear lesion were assessed and verified at different time points post-treatment. Our data indicated that this drug combination caused the rapid and extensive death of outer hair cells (OHCs). OHC death presented throughout the cochlea that commenced in the basal turn by 24 h and progressed apically. In contrast, inner hair cell (IHC) loss was delayed and mild. Terminal deoxynucleotidyl transferase dUTP nick end labelling-positive nuclei demonstrated that the majority of OHCs died via an apoptotic pathway. Auditory threshold shifts of up to 90 dB SPL indicated a profound hearing loss. In addition, the endocochlear potential (EP) in the drug-treated animals displayed a significant decline at 12 h post-treatment followed by recovery by 48 h post-treatment. Despite this recovery, there was a significant and progressive decrease in strial vascularis thickness, which was predominantly due to atrophy of marginal cells. The present study reproduced an adult mouse model of aminoglycoside-induced hearing loss. The mechanism underlying the recovered EP in the model with extensive hair cell death is discussed.
It is well-known that the modern history of salicylates began in 1899 when the compound acetylsalicylic acid was registered and introduced commercially as "aspirin" by the Bayer Company of Germany. As a matter of fact, however, remedies made from willow bark had been used to treat fever and rheumatic complaints at least since 1763, when Edward Stone described their efficacy against malarian fever. A number of Italian scientists made significant contributions during the long period of research leading up to the synthesis of acetylsalicylic acid and its widespread use in rheumatic diseases. In this paper we will review the contributions of some of these researchers, beginning with Bartolomeo Rigatelli, who in 1824 used a willow bark extract as a therapeutic agent, denominating it "salino amarissimo antifebbrile" (very bitter antipyretic salt). In the same year, Francesco Fontana described this natural compound, giving it the name "salicina" (salicin). Two other Italian chemists added considerably to current knowledge of the salicylates: Raffaele Piria in 1838, while working as a research fellow in Paris, extracted the chemical compound salicylic acid, and Cesare Bertagnini in 1855 published a detailed description of the classic adverse event associated with salicylate overdoses--tinnitus--which he studied by deliberately ingesting excessive doses himself. Bertagnini and above all Piria also played conspicuous roles in the history of Italy during the period of the Italian Risorgimento, participating as volunteers in the crucial battle of Curtatone and Montanara during the first Italian War of Independence.
cis-Dichlorodiammine platinum (II) (NSC-119 875), an agent with potent antineoplastic activity which also induces renal, intestinal, and bone marrow toxicity, was tested for ototoxic effects in guinea pigs. Ototoxicity was evaluated by the disappearance of Preyer's reflex in response to pure tones of 5, 7, and 10 kHz and by histopathological evaluation of the inner ear with surface preparations or midmodiolar sections. Groups of five guinea pigs treated with 8–40 ip injections of cis-dichlorodiammine platinum (II) 1 mg/kg (5 doses/wk) or with 10–15 doses of 1.5 mg/kg developed permanent deafness and histopathological lesions with pronounced loss of outer hair cells in the lower turns of the organ of Corti. Frequently, entire rows of outer hair cells disappeared and only a few isolated hair cells remained intact. Moderate numbers of outer pillar cells were missing and occasional inner hair cells and pillar cells were also damaged. Hair cell lesions included degeneration, complete cytolysis, and replacement by phalangeal scars. Single doses of 6, 9, 12, or 18 mg/kg of cis-dichlorodiammine platinum (II) produced permanent hearing loss as early as Day 3 and a scattered pattern of outer hair cell loss on Day 4 with cytological changes similar to but less severe than those observed for multiple doses. Neomycin sulfate-treated guinea pigs used as positive controls (eight consecutive daily doses of 150–250 mg/kg) showed a similar pattern of hair cell loss as produced by cis-dichlorodiammine platinum (II). Positive controls treated with a single dose of 6-aminonicotinamide from 2.5 to 20 mg/kg, developed severe damage to both inner and outer hair cells, pillar cells, and spiral ganglia. Occasional strial atrophy was also observed.
Thirty-one patients with metastatic cancer were treated with cis-diamminedichloroplatinum (II), CACP, in dosages ranging from 7.5 to 200 mg/m2 BSA per course. Twenty-two patients received more than one course. Toxicity to the initial course of CACP, up to 90 mg/m2 BSA, was minimal and transient in most patients. At higher dosage levels or following repeat courses, the drug-related toxicity was more severe. Drug-related toxicity was more severe in patients with abnormal excretory tracts. The most common and earliest side effects were nausea and vomiting. Hyperuricemia commonly occurred shortly after administration of CACP. A dosage-dependent, generally transient, nephrotoxicity was noted within the first 10 days after a course of CACP. Moderate leukopenia and thrombocytopenia, as well as a progressive normocytic anemia with marrow erythroid hypoplasia, were observed as late as 3 to 4 weeks after injection of this agent. Audiologic impairment above the frequency range of normal speech was detected by audiometry. Objective tumor regression was seen in five patients, four of whom experienced moderate-to-severe toxicity.
From a historical standpoint, the problems of ototoxicity came in two major stages. The first, in the nineteenth century, indirectly resulted from the chemical extraction, purification and, sometimes later, synthesis of the active components of traditional drugs, which led to their use in larger doses. The second stage, in the twentieth century, derived from the drive to find more and more effective antibacterial agents, which often had damaging side effects on the inner ear. These effects were highlighted by the development of more sophisticated techniques to detect and measure the ototoxic actions of drugs. The present brief account traces some early reports of ototoxicity from the time of Richard Morton (1692) onwards.