| Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Ototoxicity I will start off with our case presentation, describe the anatomy and physiology, then go into the multiple drugs that can cause systemic toxicity in addition to the multiple medications that can cause topical toxicity, and we will talk about some of the interventions involved with ototoxicity. RP is a 71-year-old white male with past medical history of coronary artery disease, hypertension, and chronic renal failure requiring hemodialysis. He presented with a rapidly progressive bilateral hearing loss and non-pulsatile tinnitus. It began after he underwent coronary artery bypass at an outside hospital inthespring of 2003, which was complicated by postoperative liver failure and elevated ammonia levels. Subsequently, he developed a hyperammonemic encephalopathy, which required a 3-4 month course of oralneomycin. He denied any otorrhea, otalgia, vertigo, or previous ear surgery. On exam, he is a well appearing elderly male in no acute distress. His external auditory canals were clear. His TMs were clear. Otherwise, his otolaryngologic exam was within normal limits. His audiogram demonstrated a severe-to-profound bilateral sensorineural hearing loss with absent DPOEs. CT of the temporal bones was obtained demonstrating no abnormalities. He underwent a right cochlear implantation with the nucleus device in May 2004 after obtaining medical clearance. His postoperative course was uneventful, and he has demonstrated good audiologic results after implantation. In 2001, he had some high frequency sensorineural hearing loss most likely attributing to present acusis. His speech discrimination score was 92% on the right and 96% on the left. This is at the end of 2004. After the neomycin administration, we can see a profound loss and no discrimination whatsoever. This is him after the cochlear implantation. We only implanted the right side. This is just the difference between the body aid and the behind-the-ear aid. Ototoxic substances can enter the cochlea and the vestibulevia the vascular system or the CSF via the internal auditory canal or the cochlearaqueduct. It can also enter through roundwindowvia the middle ear. Tight junctions between endothelial cells at the capillary levels with surrounding pericytes and the thick basal lamina compose the bloodperilymph and the blood stria barriers. The cochlea is an organ that is tuned tonotopically along its length based on the stiffness of the basilar membrane, so that accounts for its passive mechanics. We are all aware of the traveling fluid wave that comes through the cochlea and causes basilarmembrane motion and subsequent stereocilia deflection. It has been shown that this basilar membrane motion is greater in the living cochlea than in the dead one, and this is due to the cochlear amplifier. The cochlear amplifier is essentially positive feedback loop within the cochlea that amplifies the traveling waves. An outer hair cell electro-motility functions as the cochlear amplifier; therefore, accounting for the cochlea’s active mechanics and allowing for improved sensitivity and frequency selectivity. Outer hair cells are one of the most commonly damaged cells due to ototoxicityin the organ of Corti, and the degree of change after ototoxicity in outer hair cells varies from altered stereocilia anatomy to complete loss of the cell. Here you can see the outer cell surrounding, which is the supporting cell around outer hair cell, subsurface cisternae, the mitochondria and Golgi apparatus of the stereocilia. Stria vascularis is another portion of the cochlea that is frequently susceptible to ototoxicity. The lateral wall, composed of spiral ligament and stria vascularis, is responsible for any cochlear potential in obtaining the potassium concentration. The stria vascularis is composed of three layers of cells, the marginal cells, intermediate cells, and the basilar cells, which have tight end gap junctions between them, which isolate the intercellular fluid from its surroundings. The vestibular system is composed of the semicircular canals with the crista ampullaris and the cupula and the utricle and saccule with a macule, and the otolith organs are type I, which are stimulatory cells and type II, which are inhibitory cells. The vestibuloocular reflex is the most important pathway with regard to monitoring ototoxicity; basically, a reflex to maintain a stable retinal image with active head movements. When an active head movement is not accompanied by an equal and opposite conjugate eye movement, retinal slip occurs. Aminoglycoside toxicity in which a patient's complaints of blurred vision with head movements are better known as oscillopsia. There is a supportive note in this chart that bilateral peripheral loss will lead to no nystagmus and no vertigo. However, these patients will exhibit oscillopsia and gait ataxia. With a unilateral loss nystagmus and ototoxicity, the fast component will be away from the affected ear and obey Alexander's law. Salicylates were first described to have ototoxic effects in 1877 by Muller. They occur in 11 of every 1000 patients and occur when the plasma levels reach greater than 0.35 mg/mL or 10-12 325 mg tablets per day. First manifestation is tinnitus, which is usually total at 79 KHz, and then the hearing loss as a mild-to-moderate bilateral reversible high-frequency sensorineural hearing loss. After stopping the medication, recovery is usually approximately 24-72 hours. There is a strong correlation between hearing loss and unbalanced hearing levels; and the salicylates primary affect the first row of outer hair cells in the basal turn and cause vacuolization of the ER, bending of the stereocilia, dilation of the subsurface cisternae, and decreased outer hair cell turgor, increased stiffness, and inability to contract. Other theories include decreased cochlear blood flow and biochemical alteration and impairment such as decreased prostaglandins and increased leukotrienes. Quinine is another medication that was used in the treatment of malaria and is frequently used now in the treatment of nocturnal leg cramps. Its clinical presentation is the same salicylates and is termed cinchonine after the bark of the tree from which it is derived. Outer hair cells are affected similarly to salicylates. There is also decreased blood flow, and 20% of patients will be symptomatic after 200-300 mg per day injection. Mercury and lead are both heavy metals that can be ototoxic, mainly through neurodegeneration. Auditory toxicity was first reported due to new diuretics in 1965 when 6% of patients receiving furosemide or Lasix developed temporary hearing loss. This is a medication that is frequently used in neonatal ICU for patients with bronchopulmonary dysplasia. It demonstrates prolonged half-life with renal impairment and synergistic ototoxicity with aminoglycosides. Its main effect is on the stria vascularis, inhibition of the sodium – potassium pump and degenerative changes in the stria vascularis with edema and cystic formation causes a transient to permanent sensorineural hearing loss. Its ototoxic effects are based on the administrative route, infusion rate, bolus dose, and the duration of treatment. Furosemide is the most common, which is Lasix. A nthranilic acid is not used as frequently. Interestingly, bumetanide is actually a 40 times more potent diuretic than furosemide with less ototoxic effects; however, it is significantly more costly. Cisplatin is frequently used in testicular, ovarian, cervical, head and neck, bladder, and lung cancer and recurrent lymphoma. Its toxicity is due to the development of platinum DNA inner strain crosslinks and it causes a permanent high-frequency sensorineural hearing loss and tinnitus. Its incidence is approximately 50-60% in patients taking a total cumulative dose greater than 200 mg. It affects both the outer hair cells and the stria vascularis mainly through free radical generation. Carboplatin, interestingly, causes less ototoxicity and its first effects are actually on the inner hair cells, not the outer hair cells. Nedaplatin is another type of alkylating agent causing ototoxicity. Predisposing factors include the dose, duration, and bolus treatment, elderly patients, young patients, irradiation, previous history of hearing loss, renal disease, concomitant use of other ototoxic agents such as aminoglycosides. Deferoxamine is an iron chelator that is frequently used in iron overdose and in patients with multiple transfusions such as for chronic anemia or thalassemia. It exhibits a high-frequency sensorineural hearing loss, which may or may not be reversible, and most likely causes damage to the organ of Corti. The risk factors for auditory toxicity in Deferoxamine are young age, dose, increased ferritin, and monthly administration. Paradoxically Deferoxamine in lower doses has been used more recently in animal studies for its iron chelating and antioxidant effects to prevent ototoxicity. Vinca alkaloids have been implicated to be ototoxic in higher doses. However, as they are used frequently in combination with other potentially ototoxic chemotherapeutic agents, determining whether a vinca alkaloid in itself is responsible is not possible. Systemic aminoglycosides are one of the most well-known medications for the ototoxic effects. They cause a vestibular toxicity and a cochlear toxicity with streptomycin, gentamicin, and turbomycin causing vestibular ototoxicity, and kanamycin and neomycin and casein being cochlear toxic. Streptomycin was the first medication to be identified as ototoxic in 1944 for its treatment for tuberculosis. Incidence of cochlear toxicity is approximately 5%, and vestibular toxicity is 3%. Although it does cause an irreversible high-frequency sensorineural hearing loss, at first it is temporary due to reversible blockade of the calcium channels, which is evidenced by decreased cochlear microphonics. Although the concentrations reach the peak in the period at two to five hours after the injection, the hearing loss will not manifest until much later as the drug may be present in the inner ear for months after treatment leading to delayed hearing loss. Risk factors include duration of therapy, recurrent bacteremia, renal dysfunction, elevated temperature, liver dysfunction, advanced age, concomitant ototoxic drugs, high serum concentrations, and preexisting hearing disorders. Note, our patient had three of these: renal dysfunction, liver dysfunction, and preexisting presbycusis. Systemic aminoglycosides work in following mechanism: the cationic aminoglycoside binds with the inionic outer hair cell membrane. It is internalized via endocytosis and then it forms free radicals. On this chart, the molecular oxygen is transformed to superoxide radical by aminoglycoside and iron. This superoxide radical is basically then broken down to superoxide dismutase to hydrogen peroxide, and then that is broken down by the Fenton reaction with iron to the hydroxyl radical. Aminoglycoside can also form the nitric oxide radical, which combines with a superoxide radical to form a deadly peroxynitrite radical. These reactive oxygen species cause a decrease in the antioxidant effects of the cell, glutathione depletion and activate signaling pathways through kinases, capsases, leading to apoptosis again. Again, the first row of outer hair cells is first affected in the basal turn and then the second row, third row, followed by inner hair cells. In vestibule type I, vestibular hair cells are most commonly affected as noted by Dr. Igarashi and Dr. Alfred. Here you can see a type I cell that is degenerated with preservation of the type II cells. Semicircular canals are most frequently affected. Another theory is based on the over activation of glutamic receptorson cochlear synapsis, which can cause cytotoxicity. Genetic factors must be mentioned in systemic aminoglycoside toxicity. Approximately 17-33% of patients who exhibit aminoglycoside ototoxicity will have a genetic defectand the most common is a 1555G mitochondrial 12S ribosomal RNA mutation and then there are these two others, 961 and 1494. Phenotypically these genes are more likely to be expressed in Asia, specifically in China, and these mutations are thought to cause aminoglycosides combined with increased affinity and decreased ATP generation in the mitochondria. Much of the evidence of ototoxicity due to macrolide is anecdotal and subjected to case reports. However, it is thought to cause a reversible high-frequency sensorineural hearing loss with risk factors including dose, duration, and renal impairment. Currently the mechanism is still not fully understood, although it is believed to damage the organ of Corti and the central and auditory pathways. Most of our knowledge on topical ototoxicity is based on animal studies. It is difficult to extrapolate those findings in animal studies to humans for the following reasons. One, the round window is hidden under this deep niche, as we know, in humans. In about 20% of humans, we may have a small mucous membrane. These are protective mechanisms from topical drops in the middle ear. In addition, this is the round window membrane in the rodent, 12 microns; here it is in the baboon, 30 microns; and here it is in the human, 70 microns, much thicker and, with middle ear inflammation, this may even become thicker. Ototoxicity in humans may also be under appreciated as the fist ototoxic effects have been shown to occur at the high frequencies, very high frequencies which usually are not tested. The middle ear edema and inflammation may reduce drug contact with the round window. Schuknecht described the first topical cochlear toxicity in late 1950s using streptomycin in cats, and later used it for his Ménière's patients. Kohonen and Tarkkanen described neomycin cochlear toxicity in 1969 in guinea pigs, and Cortisporin otic was used by Meyerhoff and Wright both in the chinchilla and in the baboon. You can see they demonstrate a normal outer hair cell in comparison to the outer hair cell loss after Cortisporin otic application. Here it is in the baboon, three rows of outer hair cells and then subsequent loss. Here you can see these gaps at the arrows where the inner hair cells were lost. Olivier described the first topical gentamycin induced vestibular toxicity, and there have been 54 cases reported human vestibular toxicity in the literature. Now it may take time for this topical drop to traverse through the round window and reach vestibular organs; therefore, maximum vestibular may occur one week after treatment. Although the concentrations employed in the treatment of Ménière's are much higher than the commercially available drops, the duration of treatment is much shorter. In 1992, Lundy and Graham performed a survey of US otolaryngologists, and 84.1% of them stated that they would use topical aminoglycosides in patients with TM perforations, and 94% in patients with PE tubes. Similar reports were reported by the British in 1999, and they feel the risks of toxicity are low compared to the risks of ear disease. However, suspicion is that this percentage may have dropped with the popularity of the fluoroquinolone drops. Propylene glycol is a solvent and penetrant enhancer, which is frequently used in Cortisporin Otic. It is not severely toxic to the inner ear in concentrations of the present topical drops. However, it does cause significant middle ear inflammation. This is the normal TM in a chinchilla, and this is five days after propylene glycol application with a TM perforation. You can see there is hyperplasia of the epithelium in the mucosal layer and disruption of the fibrotic layer. Here you can see migration of the epithelial layer into the fibrotic layer, and this actually has been shown to from cholesteatomas in these patients. As you can see here, there is invasion in to the bone. Here you can see the TM in the chinchilla and with epithelial migration and formation of the cholesteatoma leading on to the promontory. Polymyxin B has mainly been studied in animal studies and has shown via topical route hair cell loss and stria vascularis changes; and there have only actually been ten reported human cases of ototoxicity due to neomycin or polymyxin drops with TM perforations. Ototoxicity has been shown in guinea pigs after chloramphenicol drops; however, there is no hard evidence for this in humans, and only case reports In many of these reports, the agent was combined propylene glycol or ethanol. Most of our studies from antifungals come from animal studies as well as guinea pigs, demonstrating auditory brain stem threshold shifts. The most common agents that can cause ototoxicity with TM perforation are alcohol, acetic acid, and gentian violet, which can also be significantly vestibular toxic in guinea pigs. Clotrimazole is actually appearing to be one of the safest and most effective ototopical antifungal with an open middle ear. Surgical disinfectants and antiseptics. Chlorhexidine and ethanol have been shown to demonstrate cochlear and vestibular toxicity in guinea pigs with PE tubes, and the detergent in povidone-iodine solution causes cochlear toxicity in animals as well as it allowing for increased penetrance through the round window. Ordinary ammonium compounds have also demonstrated ototoxicity, and the recommendation is that if you are going to fill the canal with a TM perforation, the obvious iodine solution is best used and will cause the least ototoxicity. In 2004, American Otolaryngology Head and Neck Surgery came out with a consensus panel for recommendations on ototopical antibiotics. This was Dr. Roland, Dr. Stewart, and Dr. M. Hannley, and they recommended that one possible topical antibiotic free of potential ototoxicity should be used and preferred. Use potential ototoxic topicals only in infected ears, and stop shortly after infection has resolved or if the patient is symptomatic. The patient should be warned of the potential for ototoxicity and call if they develop dizziness, vertigo, hearing loss, or tinnitus. If the TM is intact and middle ear or mastoid is closed, then there is no risk in using potentially ototoxic topical medication. In the same supplement, Dr. Manolidis published a study that demonstrated that quinoline drops actually are as effective as aminoglycoside topicals in acute otitis externa, acute otitis media with tympanostomy tubes, prophylaxis for tube otorrhea and chronic suppurative otitis media. In terms of audiologic monitoring, the basic audiogram is essential. High-frequency audiometry is useful to assess for an early loss; however, it may be difficult to obtain and is not readily performed. Otoacoustic emissions are very useful and are nonresponsive for a comatose patient. It is important to obtain baseline audiometry, although it may be difficult in some patients. For chemotherapy, specifically with cisplatin, it is important to test just prior to each round and every six months for one to two years after administration. For aminoglycosides, it is important to test weekly to bi-weekly and four to six weeks after application. Speech and Hearing Association criteria for cochlear toxicity are greater than 20-decibel loss at one frequency, 10 decibel loss or greater at two adjacent frequencies, or complete loss of response at all three adjacent frequencies. Head-shake test actually shows 80% possible predicted value and unilateral vestibular dysfunction. The dynamic illegible "E" test is when the head is shaking and visual loss of more than three lines on a Snellen chart is positive for oscillopsia. Other vestibular battery tests include rotation chair, e.g., nystagmography. So, the first step is prevention of ototoxicity, and we can do this by avoiding previously mentioned ototoxic medications. Now, there is no notifying for aminoglycoside threshold serum level that is a precipitating factor as to ototoxicity; however, it is believed that this may be due to worsening nephrotoxicity causing accumulation of these ototoxic agents. Aminoglycoside ototoxicity is related to the total amount of drug given, not the peak concentration level; therefore, peak and trough are controversial as to whether or not it is good to monitor ototoxicity. The best monitoring is through the serum creatinine, and monitoring nephrotoxicity every two to three days, ensuring the patient is well-hydrated and obtaining family history to rule out genetic factors; and single dosage aminoglycosides have been shown to improve nephrotoxicity, but not ototoxicity versus multiple daily dosage. Oto-protective therapies that have recently come out are the antioxidants such as the superoxide dismutasecompounds, sodium disulphate, deferoxamine, and even salicylate. Many of these are still experimental and only used on animals. For aminoglycosides similarly, there are mainly antioxidant compounds that have been used to trap the free radicals, which can be used topically prior to aminoglycoside topical application; growth factors, the antioxidants, glutethimide, deferoxamine, salicylates Interestingly, this past year, Yeosh Raphael, from Michigan published a study using gene therapy after inducing aminoglycoside toxicity in guinea pigs. Using a gene called Mat1, he was able to generate hair cells from progenitor cells using this gene therapy and was actually able to restore hearing in some of these guinea pigs. In summary, aminoglycosides and cisplatin comprise the majority of systemic medications causing ototoxicity. Topical otic drops with potential ototoxicity should be used cautiously in patients with tympanostomy tubes or TM perforations. Support and monitor duration closely and use this only in infected ears. Prevention is primary, but future interventions include antioxidants, and gene therapy. I would like to briefly discuss some of the research that was done by John S. Oghalai’s lab, a laboratory for cochlear mechanics using gene therapy. Now we talked about cochlear mechanics and outer hair cell electromotility. Prestin is believed to be what causes this outer hair cell electromotility. It is actually found in the lateral wall of the outer hair cell, as you can see here. In response to changes in the membrane potential of the outer hair cell in stereocilia deflection, prestin actually alters its confirmation and consequently the length and contraction of the sound and demonstrates that prestin norm mice actually have profound sensorineural hearings. We hypothesize in our project that the introduction of the prestin genes in the prestin norm mouse may restore the cochlear amplifier. Our goals were to demonstrate histologic proof of prestin transduction of the mouse cochlea using an adenoviral vector containing prestin and GFP. Our second goal is to assess the physiologic effects of the prestin transduction on the cochlea using ABR in these mice. We measured ABR in wild type in prestin norm mice prior to cochleostomy; we performed a cochleostomy and injected one microliter of antiviral vector into the scala media. We retested ABR after four days and then sacrificed some mice after cardiac perfusion, harvested the cochlea and prepared them for cross-section. Here is a view of our surgical procedure. You can see the periauricular nerve of the SCM. Here is the tympanicbulla equivalent to our mastoid. Here is the tympanic bulla that is open. You can see the stria here, and the stapedial artery that is persistent in the mouse and here is the cochleostomy. Here is the insertion of the micropipette into the cochleostomy with injection of the adenoviral vector. We performed all this on the left ear, and the right ear was our control. Here is the SCM retracted, and we are exposing the tympanic bulla, here and there you can see the digastric muscle of the tympanic bullae there. We are opening up tympanic bulla here to access the cochlea, we drill open more of the tympanic bulla to see the stria and the stapedial artery, then we drill over the stria vascularis to try and enter the scala media and make a small cochleostomy there. You can see the cochleostomy is actually made right there, and we suck up the adenoviral vector with micropipette and insert the micro pipette for injection. We then harvest the cochlea and section the roof of the cochlea to reveal the modiolus and the turns of the cochlea, and then we sectioned one turn of the cochlea with the modiolus here and we can see the outer coating around it, and here is a single turn modiolus here, outer hair cells and stria and the spiral ligament. We were able to demonstrate transduction of our supporting cells as you can see by the GFP stain here. This is a phalloidin stain for actin filaments, which are common supporting cells. Here we can see both the GFP and the phalloidin stain on our supporting cells. Here we can see our three rows of outer hair cells, which are stained not only with phalloidin but also with GFP, demonstrating transduction, and that can he seen here as well with the three rows of outer hair cells. In terms of our physiologic effects, we can see that this is the hearing prior to cochleostomy. There is some hearing loss from opening up of the bulla, but four days afterwards we can see that our controlled mice actually were deaf after cochleostomy and viral injection. Here our prestin norm mice do have some residual hearing in the mid frequencies, but after cochleostomy again, these were profoundly deaf. Therefore in this study we demonstrated that prestin transduction of the organ of Corti cells is possible in the mouse model. However, preserving hearing and using adenoviral injection in the mouse cochlea is quite difficult due to the small anatomy of the mouse and the mechanical trauma induced by injection. We are now using the laser Doppler to monitor dorsal membrane motion after prestin transduction and hopefully, with refinement of our technique, we will be able to preserve and eventually restore hearing. Case Presentation: On physical examination, he was a well-appearing elderly male in no acute distress. Bilateral external auditory canals and tympanic membranes were clear. The rest of his otorhinolaryngologic exam was within normal limits. His audiogram demonstrated severe to profound bilateral sensorineural hearing loss with absent DPOAE's. A CT of the temporal bones was obtained and demonstrated no abnormalities. After obtaining medical clearance, he was taken to the operating room for right cochlear implantation on May 27. 2004. His postoperative course was uneventful and he has demonstrated good audiologic results after implantation. Bibliography: Aursnes J. Ototoxic effect of iodine disinfectants. Acta Otolaryngol 1982;93:219-226. Bacino C, Prezant TR, Bu X, Fournier P, Fischel-Ghodsian N. Susceptibility mutations in the mitochondria) small ribosomal RNA gene in aminoglycoside induced deafness. Pharmacogenetics 1995;5:165-172. Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of xtendedinterval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:786795. Bath AP, Walsh RM, Bance ML, Rutka JA. Ototoxicity of topical gentamicin preparations. Laryngoscope 1999;109:1088-1093. Blakley BW, Gupta AK, Myers SF, Schwan S. Risk factors for ototoxicity due to cisplatin. Arch Otolaryngol Head Neck Surg 1994;120:541-546. Brien JA. Ototoxicity associated with salicylates. A brief review. Drug Saf 1993;9:143-148. Cazals Y, Homer KC, Huang ZW. Alterations in average spectrum of cochleoneural activity by long-term salicylate treatment in the guinea pig: A plausible index of tinnitus. J Neuropysiol 1998;80:2113-21120. Douek EE, Dodson HC, Bannister LH. The effects of sodium salicylate on the cochlea of guinea pigs. J Laryngol Otol 1983;97:793-799. Dumas G, Bessard G, Gavend M, Charachon R. Risk of deafness following ototopical administration of aminoglycoside antibiotic. Therapie 1980;35:357-363. Fischel-Ghodsian N, Prezant TR, Bu X, Oztas S. Mitochondrial ribosomal RNA gene mutation in a patient with sporadic aminoglycoside ototoxicity, AmJ Otolaryngol 1993;14:399-403. Forge A, Schacht J. Aminoglycoside antibiotics. Audiol Neurotol 2000;5:3-22. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: A meta-analysis. Ann Intern Med 1996;124:717-725. Igarashi M, Lundquist PG, Afford BR, Miyata H. Experimental ototoxicity of gentamicin in squirrel monkeys. J Infect Dis 1971;124:114. Ishii T, Bernstein JM, Balogh K Jr. Distribution of tritium-labeled salicylate in the cochlea. An autoradiographical study. Ann Otol Rhino Laryngol 1967;76:368-376. Jung TT, Rhee CK, Lee CS, Park YS, Choi DC. Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs and quinine. Otolaryngol Clin North Am 1993;26:791-810. Kan -no H, Yamanobe S, Rybak LP. The ototoxicity of deferoxamine mesylate. Am J Otolaryngol 1995;16:148-152. Karlsson KK, Flock B, Flock A. Ultrastructural changes in the outer hair cells of the guinea pig cochlea after exposure to quinine. Acta Otolaryngol 1991;111:500-505. Kohonen A, Tarkkanen JV. Dihydrostreptomycin and kanamycin ototoxicity. An experimental study by surface preparation technique. Laryngoscope 1966;76:1671-1680. Leliever WC. Topical gentamicin-induced positional vertigo. Otolaryngol Head Neck Surg 1985;93:553-555. Linder TE, Zwicky S, Brandle P. Ototoxicity of ear drops: A clinical perspective. Am J Otol 1995;16:653-657. Lue AJ, Brownell WE. Salicylate, induced changes in outer hair cell lateral wall stiffness. Hear Res 1999;135:163-168. Lundy LB, Graham MD. Am J Otol 1993;14:141-146. Maher A, Bassiouny A, Moawad MK, Hendawy DS. Otomycosis: An experimental evaluation of six antimycotic agents. J Laryngol Otol 1982;96:205-213. Maher JF, Schreiner GE. Studies on ethacrynic acid in patients with refractory edema. Ann Intern Med 1965;62:15-29. Manolidis S, Friedman R, Harmley M, Roland PS, Matz G, Rybak L, Stewart MG, Weber P, Owens F. Comparative efficacy of aminoglycoside versus fluoroquinolone topical antibiotic drops. Otolaryngol Head Neck Surg 2004;130:583-588. Marsh RR, Tom LW. Ototoxicity of antimycotics. Otolaryngol Head Neck Surg 1989;100:134136. Masaki M, Wright CG, Lee DH, Meyerhoff WL, Effects of otic drops on chinchilla tympanic membrane. Arch Otolaryngol Head Neck Surg 1988;114:1007-1011. Masaki M, Wright CG, Lee DH, Meyerhoff WL. Experimental cholesteatoma. Epidermal ingrowth through tympanic membrane following middle ear application of propylene glycol. Acta Otolaryngol 1989;108:113-121. Matz G, Rybak L, Roland PS, Harmley M, Friedman R, Manolidis S, Stewart MG, Weber P, Owens F. Ototoxicity of ototopical antibiotic drops in humans. Otolaryngol Head Neck Surg 2001;130:S79-S82. Mintz U. Amir J, Pinkhas J, de Vries A. Transient perceptive deafness due to erythromycin lactobionate. JAMA 1973;225:1122-1123. Morizono T. Toxicity of ototopical drugs: Animal modeling. Ann Otol Rhinol Laryngol Suppl 1990;148:42-45. Moroso MJ, Blair RL. A review of cis-platinum ototoxicity. J Otolaryngol 1983;12:365-369. Oghalai JS. Cochlear hearing loss. In: Jackler RK, Brackmann DE (editors). Neurotology, 2 ndedition. Philadelphia: Elsevier-Mosby; 2005. pp. 589-606. Parker FL, James GW. The effect of various topical antibiotic and antibacterial agents on the middle and firmer ear of the guinea-pig. J Pharm Pharmacol 1978;30:236-239. Prazma J, Thomas WG, Fischer ND, Preslar MJ. Ototoxicity of the ethacrynic acid. Arch Ololaryngol 1972;95:448-456. Prezant TR., Agapian JV, Bohlman MC, Bu X, Oztas S, Qui WQ, Amos KS, Cortopassi GA, Jaber L. Rotter JI, et al. Mitochondrial ribosomal RNA mutation associated with both antibioticinduced and non-syndromic deafness. Nat Genet 1993;4:289-294. Rhee CK, Park YS, Jung TT, Park Q. Effects of leukotrienes and prostaglandins on cochlear blood flow in the chinchilla. Eur Arch Otorhinolaryngol 1999;256:479-483. Roland PS, Rutka JA. Ototoxicity. New York : Thieme; 2004. Roland PS, Rybak L, Hannley M, Matz G, Stewart MG, Manolidis S, Friedman R, Weber P, Owens F. Animal ototoxicity of topical antibiotics and the relevance to clinical treatment of human subjects. Otolaryngol Head Neck Surg 2004;130:557-578. Rudnick MD. Ginsberg IA, Huber PS. Aminoglycoside ototoxicity following middle ear injection. Ann Otol Rhinol Laryngol Suppl 1980;89:1-28. Schuknecht HF. Ablation therapy in the management of Meniere’s disease. Acta Otolaryngol 1957;47:1-42. Schwartz GH, David DS, Riggio RR, Stenzel KH, Rubin AL. Ototoxicity induced by furosemide. N EngI J Med 1970;282:14l3-1414. Shehata WE, Brownell WE, Dieter R. Effects of salicylate on shape, electromotility and membrane characteristics of isolated outer hair cells from guinea pig cochlea. Acta Otolaryngol 1991;111:707-718. Silverstein H, Yules RB. The effect of diuretics on cochlear potentials and inner ear fluids. Laryngoscope 1971;81:873-888. Tang HY, Hutcheson E, Neil S, Drummond-Borg M, Speer M, Afford RL. Genetic susceptibility to aminoglycoside ototoxicity: How many are at risk? Genet Med 2002;4:336-345. Wright CG, Meyerhoff WL, Halama AR. Ototoxicity of neomycin and polymyxin B following middle ear application in the chinchilla and baboon. Am J Otol 1987;8:495-499. Wu WJ, Sha SH, Schacht J. Recent advances in understanding aminoglycoside ototoxicity and its prevention. Audiol Neurotol 2002;7:171-174. Zhoa H, Li R, Wang Q, Yan Q Deng JH, Han Q Bai Y, Young WY, Guan MX. Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C 1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet 2004;74:139-152. BCM Public | BCM Intranet | Privacy Notices | Contact BCM | BCM Site Map | ©2001-2005
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