Topical gentamicin and ethacrynic acid: effects on cochlear function.
ABSTRACT To determine whether concurrent intravenous administration of the loop diuretic ethacrynic acid potentiates the toxicity of the aminoglycoside antibiotic gentamicin applied topically on the round window.
The authors studied the effects on cochlear sensitivity of co-administered intracardiac ethacrynic acid (40 mg/kg) and high-dose topical gentamicin solution (100%) applied to the round window. Comparisons were made with animals receiving ethacrynic acid plus systemic gentamicin (100 mg/kg); topical gentamicin alone; systemic gentamicin alone; and intravenous ethacrynic acid alone.
Experiments were carried out on pigmented guinea pigs weighing 400 to 500 g. Changes in cochlear function were characterized by monitoring shifts in compound action potential (CAP) thresholds by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid.
After 20 days animals receiving ethacrynic acid in combination with topical gentamicin to the round window failed to demonstrate a significant deterioration in cochlear sensitivity, whereas all animals receiving systemic gentamicin plus ethacrynic acid experienced profound increases in CAP thresholds.
This study supports the contention that ethacrynic acid potentiates aminoglycoside ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph. In addition, this study answers important clinical concerns regarding the safety of the use of topical aminoglycoside agents in combination with loop diuretics.
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ABSTRACT: Uptake and retention of gentamicin by cells in the guinea pig inner ear after a single peritoneal injection or local application on the round window were investigated using immunocytochemistry to localize the drug. The cells that accumulated the drug under the two conditions were the same, but staining for the drug was more intense and was often accompanied by widespread cochlear degeneration following local application. Soon after drug administration by either route, there was diffuse staining for the drug throughout all tissue within the labyrinth, including bone. At later times when distinct cell staining became evident, virtually all cell types were found to be positive, with several cell types staining more darkly for the drug than hair cells, indicating that hair cells were not the most avid in accumulating gentamicin. The infracuticular portion of auditory and vestibular hair cells as well as type III fibrocytes of the spiral ligament were positively stained in almost all cases and these sites were found to be positive for as long as six months post administration. In animals with loss of the organ of Corti, there was unusually intense staining for gentamicin in root cells of the spiral ligament, in marginal cells of the stria vascularis, and in cells of the spiral limbus. Dark staining of surviving cells in cases with overt tissue destruction suggests that variability in the extent of damage caused by the drug was determined more by the degree of its local uptake than by differences in animals' capacities to metabolize the drug systemically. The present results show that gentamicin may damage or destroy all cochlear cells following a single round window application. The findings broaden the scope of our knowledge of cochlear gentamicin uptake and damage and have implications for treatment of patients with vestibular disorders by infusion of aminoglycosides into the middle ear, as well as implications for prospects of rehabilitating patients that have been deafened by aminoglycosides.Journal of the Association for Research in Otolaryngology 07/2003; 4(2):176-95. DOI:10.1007/s10162-002-2036-8 · 2.55 Impact Factor
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ABSTRACT: The treatment of patients with Ménière's disease that do not respond to conventional therapy becomes complicated, particularly when taking into account the issue of hearing damage as well as the control of vertigo. Treatment often involves the intratympanic administration of gentamicin, for which different protocols are used. Hence, it is important that we better understand how this treatment influences hearing, beyond mere audiometric assessments. The aim of this prospective study was to evaluate the effect of intratympanic gentamicin treatment for Ménière's disease on cochlear function, as assessed by otoacoustic emissions. The 41 patients included in the study had been diagnosed with unilateral Ménière's disease as defined by the American Academy of Otolaryngology-Head and Neck Surgery guidelines (1995), and had been refractory to medical treatment for at least 1 year. Intratympanic injections of gentamicin at a concentration of 27 mg/ml were performed at weekly intervals until indications of vestibular hypofunction appeared in the treated ear. Before beginning the treatment and 3 months after ending it, pure tone and speech audiometry tests were performed and the results are expressed in terms of the pure tone average (0.5, 1, 2, and 3 kHz) and the speech discrimination score, respectively. At the same time, a distortion product otoacoustic emission (DPOAE) study was performed and the results are expressed in terms of its presence or absence, and as the amplitude and threshold of the emission. When analyzed 3 months after the treatment had terminated, hearing loss was seen in 13 patients (31.7%). However, no significant change in the threshold and/or amplitude of otoacoustic emissions was observed in any of the patients. Neither were changes in the audiometric stage, number of injections required or the existence of DPOAE before treatment detected. Hence, the treatment method used here for patients with intractable unilateral Ménière's disease can be considered as having a low risk on auditory function, as assessed both audiometrically and with otoacoustic emissions, and can be considered as subablative for hearing function.Audiology and Neurotology 01/2005; 10(2):69-78. DOI:10.1159/000083362 · 1.85 Impact Factor
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ABSTRACT: The application of therapeutic agents to the round window holds great promise in the treatment of inner ear disease. The primary benefit of this route of administration is the ability to achieve high inner ear concentrations of drugs without systemic side effects. Recent research has elucidated the anatomy and physiology of the round window and provided important information on the inner ear pharmacokinetics and the pharmacodynamics of drugs administered intratympanically. Although amino-glycosides and steroids have been most thoroughly studied, many other classes of pharmaceuticals, including otoprotective agents, other antibiotics,and topical anesthetics, have therapeutic potential in the inner ear and will probably be the subject of future studies. The authors believe that direct delivery approaches other than through the round window, perhaps with slow or sustained release formulations, may hold the key to the future treatment of inner ear disorders.Otolaryngologic Clinics of North America 11/2004; 37(5):1035-51. DOI:10.1016/j.otc.2004.04.003 · 1.34 Impact Factor