Intratympanic gentamicin in monolateral Meniere’s disease: our experience

The aim of this study was to verify the efficacy of a modified Odkvist titration protocol of intratympanic gentamicin application in the control of vertigo attacks and the effects on the auditory and vestibular function in a group of 71 patients affected by monolateral MD resistant to medical therapy. All the patients underwent an intratympanic administration of a 1-ml solution containing 26.6 mg of gentamicin sulfate. The treatment protocol provided one to three injections for a total amount of gentamicin varying from 26.6 to 80 mg. Five days after the first gentamicin administration, cochlear and vestibular function tests were performed. The worsening of the PTA greater than 15 dB, the appearance of clinical signs of vestibulotoxicity such as imbalance or persistent spontaneous nystagmus beating away from the injected ear or of a curative vertigo were the criteria taken into consideration to stop the treatment. In the absence of any sign, a second and third injection were performed. The presence of an unchanged frequency of the attacks at least 3 months after the previous cycle was the parameter considered to perform a second or third cycle. Seventeen (24%) patients were submitted to a second cycle of therapy and two (3%) to a third cycle. After a mean follow-up period of 20.3 months (range: 3 to 48) all 71 patients experienced good control of the vertigo attacks: grade A in 46 cases and grade B in 25 cases according to the AAO-HNS CoHE criteria. The pure tone average (PTA) hearing threshold (500–3,000 Hz) worsened in 19 patients, improved in 5 and was unchanged in 47. On the basis of the experience acquired during the treatment, we progressively decreased the number of injections from 3/cycle to a 1–2/cycle of therapy. Moreover, in the later phase of the study re-injections were administered 1 or 2 weeks after the previous application and avoided in the presence of signs of depression of the vestibular and/or cochlear function. A residual caloric excitability was found in 30% of the cases. Vertigo control doesnt seem to be linked to the achievement of vestibular inexcitability. The marker of successful gentamicin treatment at short-term is the appearance of signs of curative vertigo and/or vestibular imbalance, and at long-term the disappearance of vertigo attacks.     

Concentration gradient along the scala tympani after local application of gentamicin to the round window membrane

OBJECTIVES: The distribution of gentamicin along the fluid spaces of the cochlea after local applications has never previously been demonstrated. Computer simulations have predicted that significant basal-apical concentration gradients might be expected, and histologic studies indicate that hair cell damage is greater at the base than at the apex after local gentamicin application. In the present study, gradients of gentamicin along the cochlea were measured. METHODS: A recently developed method of sampling perilymph from the cochlear apex of guinea pigs was used in which the samples represent fluid originating from different regions along the scala tympani. Gentamicin concentration was determined in sequential apical samples that were taken after up to 3 hours of local application to the round window niche. RESULTS: Substantial gradients of gentamicin along the length of the scala tympani were demonstrated and quantified, averaging more than 4,000 times greater concentration at the base compared with the apex at the time of sampling. Peak concentrations and gradients for gentamicin varied considerably between animals, likely resulting from variations in round window membrane permeability and rates of perilymph flow. CONCLUSIONS: The large gradients for gentamicin demonstrated here in guinea pigs account for how it is possible to suppress vestibular function in some patients with a local application of gentamicin without damaging auditory function. Variations in round window membrane permeability and in perilymph flow could account for why hearing losses are observed in some patients.     

Methylcobalamin as antagonist to transient ototoxic action of gentamicin.

The objective of this study was to determine whether methylcobalamin inhibits the ototoxic action of gentamicin. Fourteen pigmented guinea pigs were randomly divided into experimental and control groups. Each animal in the experimental group was given a large single dose of gentamicin (125 mg/kg i.m.), followed by immediate administration of methylcobalamin (1 mg kg i.m.). In the control group, the animals received gentamicin only, at the same dose as the experimental group. The compound action potentials (CAPs) in the right ears of animals were measured using a signal processor before and 15, 30, 45, 60 and 75 min after injection of the drugs. The sound stimulus was presented by means of clicks and tone pips at 2, 4 and 8 kHz. Following the electro-physiological tests, the animal was sacrificed and prepared for scanning electron microscopic observation. There was prolongation of latency and diminution of amplitude of CAPs N1 and N2 15 min after injection of gentamicin. Although the N1-N2 intervals increased as the time after injection of gentamicin increased, the variations were still within normal ranges. In contrast, there was no prolongation of N1 latencies or N1-N2 intervals 30 min after injection in the experimental group. There were no marked changes in N1 or N2 amplitudes, compared with the results before injection, in the experimental group. The firing mechanism of the inner ear may be affected by a single dose of gentamicin. This suggests that the transient ototoxic action of gentamicin hardly affected the conductive function of the nerve fibres, even though the firing function of the inner ear was influenced. Methylcobalamin may inhibit the ototoxic side effects of gentamicin.     

Methylcobalamin as Antagonist to Transient Ototoxic Action of Gentamicin

The objective of this study was to determine whether methylcobalamin inhibits the ototoxic action of gentamicin. Fourteen pigmented guinea pigs were randomly divided into experimental and control groups. Each animal in the experimental group was given a large single dose of gentamicin (125 mg/kg i.m.), followed by immediate administration of methylcobalamin (1 mg kg i.m.). In the control group, the animals received gentamicin only, at the same dose as the experimental group. The compound action potentials (CAPs) in the right ears of animals were measured using a signal processor before and 15, 30, 45, 60 and 75 min after injection of the drugs. The sound stimulus was presented by means of clicks and tone pips at 2, 4 and 8 kHz. Following the electro-physiological tests, the animal was sacrificed and prepared for scanning electron microscopic observation. There was prolongation of latency and diminution of amplitude of CAPs N₁ and N₂ 15 min after injection of gentamicin. Although the N₁-N₂ intervals increased as the time after injection of gentamicin increased, the variations were still within normal ranges. In contrast, there was no prolongation of N₁ latencies or N₁-N₂ intervals 30 min after injection in the experimental group. There were no marked changes in N₁ or N₂ amplitudes, compared with the results before injection, in the experimental group. The firing mechanism of the inner ear may be affected by a single dose of gentamicin. This suggests that the transient ototoxic action of gentamicin hardly affected the conductive function of the nerve fibres, even though the firing function of the inner ear was influenced. Methylcobalamin may inhibit the ototoxic side effects of gentamicin.     

Prevention of gentamicin induced ototoxicity by trimetazidine in animal model

OBJECTIVE: To show the efficacy of intra-peritoneally administered trimetazidine to prevent gentamicin ototoxicity, which is still an important cause of profound deafness among children in different parts of the world. METHODS: Two groups of Swiss albino mice received daily intra-muscular injections of gentamicin for 30 days. One of the groups received trimetazidine intra peritoneally in addition to the gentamicin. Auditory thresholds of the animals were measured by evoked brain stem response at the beginning and the end of the study. Results were compared to the results of the control group, which received intra peritoneal saline injections. RESULTS: Both groups receiving gentamicin injections had significant auditory threshold shifts, but in the group receiving additional trimetazidine, the threshold shift was not statistically significant when compared to control group. Threshold shift in gentamicin group significantly differed from that of the control group (p=0.0001) and gentamicin+trimetazidine group (p=0.0001), on the other hand there was no statistically significant difference between control group and trimetazidine+gentamicin group (p=0.102). CONCLUSION: Gentamicin ototoxicity can be prevented by intra peritoneal trimetazidine injections in animal model. This treatment modality may be a mode of protection from gentamicin ototoxicity in children.     

Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial

In the treatment of serious infection by aminoglycoside antibiotics multiple daily treatment with netilmicin is considered to be the least toxic. Studies comparing netilmicin with gentamicin using the less toxic once-daily schedule are lacking. A randomized prospective study was designed to evaluate the efficacy and toxicity of once-daily netilmicin with gentamicin treatment in patients with serious infections. Consecutive patients with serious infections were randomized between gentamicin 4 mg/kg q24h iv or netilmicin 5.5 mg/kg q24h iv. Exclusion criteria were neutropenia or severe renal failure. A good clinical response was observed in 50 of the 54 evaluable patients (92.6%) treated with gentamicin and in 48/52 (92.3%) netilmicin treated patients. Nephrotoxicity developed in 5/72 (6.9%) gentamicin patients and in 10/69 (14.5%) treated with netilmicin. Audiometry was performed with high-frequency audiometry when possible; no significant differences were found between the two aminoglycosides. We conclude that with once-daily treatment no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated.     

The early kinetics of gentamicin uptake into the inner ear

Transtympanic gentamicin administration has become a popular modality in the treatment of Ménière's disease. This modality and other inner-ear medical therapy are gaining increased clinical and scientific attention. We previously described the kinetics and effects of gentamicin uptake into the inner ear after delivery of the medicine into the middle ear using a variety of different techniques and sustained-release modalities [1]. In our previous work, we reported an early peak perilymph concentration and the presence of intracellular gentamicin at the 4-hour time point. We also demonstrated the activation of inner-ear damage pathways at this early time point. In this report, we examine the kinetics of gentamicin at very early time points, 1 and 2 hours after administration. Healthy adult chinchillas underwent implantation of middle-ear sustained-release devices (one to each ear) containing gentamicin. The animals then were maintained in a neutral position and underwent perilymph gentamicin sampling at the two predetermined time points. This technique allowed us to assess accurately very early time point inner-ear gentamicin kinetics and to compare the activity. The samples then were run for concentration using mass spectrometry. The information gained from this study may increase our scientific understanding about the effects of gentamicin on the inner ear and may allow clinicians to treat patients more effectively for inner-ear disorders.     

The role of deferoxamine in the prevention of gentamicin ototoxicity: a histological and audiological study in guinea pigs

CONCLUSION: The addition of deferoxamine to gentamicin seems to confer partial functional and histological protection to the cochlea. OBJECTIVE: Aminoglycosides are known ototoxic agents. The toxicity occurs via an activation process involving the formation of an iron-gentamicin complex with free radical production. Iron chelation will supposedly limit this toxic effect. This study aimed to determine the possible cochleoprotective role of deferoxamine on the ototoxic effect of gentamicin. MATERIALS AND METHODS: Sixty healthy active guinea pigs, weighing 400-600 g, with an average age of 6 months were used. They were divided into three groups. Group 1 received intramuscular gentamicin 8 mg/kg/day, group 2 received gentamicin 8 mg/kg/day and deferoxamine 150 mg/kg twice daily for 19 days and group 3 served as a control. All animals had a baseline measurement of distortion product oto-acoustic emissions. At the end of 33 days they were submitted to another measurement and then the animals were sacrificed and their cochleas were examined histologically by light and transmission electron microscopy. RESULTS: In group 1 the mean amplitude post-injection ranged from 5.83 dB at 1001 Hz to 22.33 dB at 6348 Hz. In the deferoxamine + gentamicin group the mean amplitude post-injection ranged from 5.10 dB at 1001 Hz, to 24.45 dB at 6348 Hz. This was statistically significant. At 4004, 5042 and 6348 Hz group 2 showed less histological damage than group 1.     

Comparison of noninvasive evaluation of endolymphatic hydrops in Meniere's disease and endolymphatic space in healthy volunteers using magnetic resonance imaging

Conclusion. The addition of deferoxamine to gentamicin seems to confer partial functional and histological protection to the cochlea. Objective. Aminoglycosides are known ototoxic agents. The toxicity occurs via an activation process involving the formation of an iron–gentamicin complex with free radical production. Iron chelation will supposedly limit this toxic effect. This study aimed to determine the possible cochleoprotective role of deferoxamine on the ototoxic effect of gentamicin. Materials and methods. Sixty healthy active guinea pigs, weighing 400–600 g, with an average age of 6 months were used. They were divided into three groups. Group 1 received intramuscular gentamicin 8 mg/kg/day, group 2 received gentamicin 8 mg/kg/day and deferoxamine 150 mg/kg twice daily for 19 days and group 3 served as a control. All animals had a baseline measurement of distortion product autoacoustic emissions. At the end of 33 days they were submitted to another measurement and then the animals were sacrificed and their cochleas were examined histologically by light and transmission electron microscopy.Results. In group 1 the mean amplitude post-injection ranged from 5.83 dB at 1001 Hz to 22.33 dB at 6348 Hz. In the deferoxamine + gentamicin group the mean amplitude post-injection ranged from 5.10 dB at 1001 Hz, to 24.45 dB at 6348 Hz. This was statistically significant. At 4004, 5042 and 6348 Hz group 2 showed less histological damage than group 1.     

The role of antioxidants in protection from ototoxic drugs

A number of studies have shown that cisplatin and gentamicin ototoxic effects may result from free radical-mediated damage due to the reduction of antioxidant substances and an increased lipid peroxidation. The authors summarize the results obtained evaluating the auditory and vestibular functions and the inner ear hair cell morphology and survival after administration of antioxidant agents against cisplatin and gentamicin. In the first experiment, albino guinea pigs were treated with gentamicin (100 mg/kg per day, i.m.) alone or gentamicin (100 mg/kg per day, i.m.) plus alpha-tocopherol (100 mg/kg per day, i.m.) for 2 weeks. In a second experiment, albino guinea pigs were injected with cisplatin (2.5 mg/kg per day) or cisplatin (2.5 mg/kg per day) plus tiopronin (300 mg/kg) for 6 days. Electrocochleographic recordings were made from an implanted round window electrode. In all experiments compound action potentials (CAPs) were measured at 2-16 kHz. Changes in cochlear function were characterized as CAP threshold shifts. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VOR). Frequency stimulation parameters ranged from 0.02 to 0.4 Hz and peak-to-peak amplitude was 20 degrees. Morphological changes were analysed by light microscopy and scanning electron microscopy. Both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol. However, tiopronin co-therapy slowed the progression of hearing loss in cisplatin-treated animals and significantly attenuated the final threshold shifts. Cisplatin had little effect on the hair cells of cristae ampullares and maculae. Vestibular function was completely preserved in tiopronin co-treated animals. In conclusion, antioxidants such as alpha-tocopherol or tiopronin interfere with gentamicin and cisplatin damage and this suggests that they may be useful in preventing oto-vestibulotoxicity. Therefore, it is important to develop protective strategies that permit the avoidance of the toxic side effects of these drugs without interfering with their therapeutic effects.     

Delayed onset of ototoxic effects of gentamicin in treatment of Menière's disease. Rationale for extremely low dose therapy

Five patients with Menière's disease and disabling vertigo were treated with two intratympanic instillations of gentamicin given at an interval of about 12 h. Although no further gentamicin treatment was given despite the absence of any discernible effects on the vestibular endorgan at that time, all patients developed vertigo and nystagmus beating toward the untreated ear within 3 to 5 days after the last instillation. Neither at the 3 month follow-up nor 1 year later did the treated ear show any reaction to bithermal caloric stimulation despite the fact that the hearing levels were almost the same as before treatment. All 5 patients obtained complete relief from attacks of vertigo, but had persisting tinnitus. As gentamicin has been shown to be slowly eliminated from the inner ear, and may thus exert persistent ototoxic effect, it is suggested that gentamicin treatment should not be continued until symptoms of ototoxic effects on the inner ear can be discerned. Extremely low-dose treatment may produce sufficient loss of vestibular function to provide relief from vertigo, and with less risk of affecting the hearing level.     

Systemic absorption of gentamicin nasal irrigations

OBJECTIVE: To determine if gentamicin nasal irrigation is systemically absorbed, and to identify any ototoxic side effects related to its use. DESIGN: Retrospective review of 12 patients treated with gentamicin nasal irrigations (30 cc of 80 mg/L solution used bilaterally twice daily). METHODS: Serum gentamicin levels were assayed after the course treatment. Pure tone audiometry (250-8000 Hz) and distortion product otoacoustic emissions (DP-OAEs) at 7280, 5133, 3640 and 2560 Hz were obtained before and after therapy. RESULTS: Twelve patients (age 4 to 74, mean 43) with chronic rhinosinusitis were treated for 3-15 weeks (mean 7 weeks). All patients had undergone previous endoscopic sinus surgery. Ten patients had pretreatment cultures that grew organisms sensitive to gentamicin (Pseudomonas, Proteus, or methacillin resistant Staphylococcus aureus), and three patients had cystic fibrosis. Ten of 12 patients (83%) had detectable posttreatment levels of gentamicin, with a mean serum level of 0.42 mcg/mL (range 0.3 to 0.7 mcg/mL). Four of 12 patients (33%) had serum gentamicin levels within the normal range for gentamicin trough (0.5 to 2 mcg/mL). Comparison of pre- and posttreatment audiologic data revealed no significant change in PTA or DP-OAE, except for the right ear at 8000 Hz on PTA (p = 0.035) where a mean of 7 dB loss was observed. No patient reported hearing loss or vertigo during treatment. CONCLUSION: Gentamicin nasal irrigation may be systemically absorbed. Although the otologic consequences of this finding are questionable, patients receiving gentamicin nasal irrigations should be counseled regarding this hypothetical possibility.     

庆大霉素慢性耳中毒对听觉和传出神经功能的影响

目的：探讨庆大霉素慢性耳中毒对听觉和传出神经功能的影响。方法：在庆大霉素应用前后通过观察对侧噪声（ＣＬＮ）对听神经复合动作电位（ＣＡＰ）的影响确定内侧橄榄耳蜗（ＭＯＣ）系统功能,通过测试在４,６,８,１０和１２ｋＨｚ的ＣＡＰ反应阈确定听功能。结果：注射庆大霉素后３周和１１周。ＣＬＮ对ＣＡＰ的抑制效应呈进行性、不可逆性消除,且以１１周最明显,ＣＡＰ反应阈分别上升１０和２５ｄＢ,与耳蜗传出神经和毛细胞     

慢性庆大霉素损伤后豚鼠前庭上皮细胞的凋亡和再生观察

目的：观察慢性庆大霉素中毒后豚鼠前庭上皮的损伤和修复过程，探讨前庭毛细胞凋亡和再生的关系。方法：采用末脱氧核苷酸转移酶介导的dUTP缺口末端标记（terninal deoxyuncleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling，TUNEL）法，观察前庭感觉上皮细胞的凋亡，采用5′-溴-2-脱氧尿苷（bromodeoxyuridine，Brdu）免疫细胞化学法观察前庭上皮的再生过程。结果：对照组没有观察到TUNEL和Brdu阳性细胞。停止庆大霉素注射1天至3周均可观察到TUNEL阳性细胞，但1天组阳性细胞数量最多，3周仍有阳性细胞存在，阳性细胞主要位于毛细胞层。停止庆大霉素注射后1天组支持细胞层和毛细胞层均有Brdu标记阳性细胞，3d组支持细胞层阳性细胞显著增多，1周组毛细胞层也出现较多阳性细胞，2周组Brdu标记阳性细胞主要位于毛细胞层，3周仍可观察到Brdu标记阳性细胞。结论：慢性庆大霉素耳中毒后豚鼠前庭上皮细胞凋亡增加，凋亡与增殖伴随存在，前庭毛细胞的损伤可能是其增殖的触发因素。增殖过程表现为支持细胞增生向毛细胞增生移行的趋势，支持细胞增殖并转化成毛细胞可能是前庭上皮细胞损伤修复机理之一。     

The ototoxic effects of different doses of gentamicin on the cochlea of pigmented guinea pigs

The aims of this study were twofold: to obtain baseline data on gentamicin ototoxicity in the pigmented guinea pig, and to compare this data with an earlier study in the albino guinea pig. Animals were given ten consecutive daily doses, subcutaneously, of gentamicin at either 50, 75 or 100 mg/kg. Control animals received equivalent volumes of saline. After 3 weeks the animals were killed and their cochleae examined by light microscopy for hair cell damage. Hair cell damage was mapped onto cochleograms and subsequently quantified. Three sets of comparisons of hair cell damage were made: gentamicin group versus control group for each dose; comparisons between doses; pigmented animals versus albino animals. It was found that cochlear hair cell damage increased with increasing dose of gentamicin: 50 mg/kg was minimally ototoxic, 75 mg/kg was more ototoxic and 100 mg/kg was highly ototoxic, affecting a large extent of the spiral organ. There was a large (statistically significant) difference between the lower doses and the damage caused by 100 mg/kg. The pigmented-albino animal comparison showed albino guinea pigs to be more susceptible to gentamicin.     

Round window gentamicin absorption: an in vivo human model

OBJECTIVE/HYPOTHESIS: Using a novel human labyrinthine sampling model, in vivo gentamicin absorption through the round window can be measured. STUDY DESIGN: A prospective study. METHODS: Gentamicin was delivered either transtympanically (preoperative) or through a facial recess approach (intraoperative). The lateral semicircular canal and vestibule were opened, and by means of a microsyringe, labyrinthine fluid was aspirated. A sample of serum was also drawn. In all patients cerebrospinal fluid was also drawn. The samples were analyzed using a standard chemistry analyzer. RESULTS: Intratympanic gentamicin diffused through the round window membrane and achieved concentrations in the labyrinthine fluid ranging from 0 to 16 mg/L. Intratympanic gentamicin was absorbed into the systemic circulation in 4 of 11 patients with serum levels ranging from 0.3 to 0.4 mg/L. No gentamicin was detected in the cerebrospinal fluid. CONCLUSIONS: Intratympanic gentamicin diffuses rapidly through the round window membrane and achieves significant levels in the inner ear. Thus, this new model can be used to assess round window permeability to clinically relevant medications such as steroids and ototopical antibiotics.     

Uptake of gentamicin by vestibular efferent neurons and superior olivary complex after transtympanic administration in guinea pigs

Transtympanic administration of gentamicin is a widely accepted and effective approach for treating patients with intractable vertigo. Previous studies have demonstrated the uptake, distribution and effects of gentamicin in peripheral vestibular and cochlear structures after transtympanic injection. However, little is known about whether transtympanically administered gentamicin is trafficked into more central auditory and vestibular structures and its effect on these structures. In this study, we used immunofluorescence to determine the distribution of gentamicin within the auditory and vestibular brainstem. We observed gentamicin immunolabeling bilaterally in the vestibular efferent neurons, and in the superior olivary complex, and ipsilaterally in the cochlear nucleus 24h after transtympanic administration of gentamicin, and that the drug could still be detected in these locations 30 days after injection. In contrast, no gentamicin labeling was detected in the vestibular nuclear complex. In the vestibular efferent neurons and superior olivary complex, gentamicin labeling was detected in the cytoplasm and cell processes, while in the cochlear nucleus gentamicin is mainly localized outside and adjacent to the cell bodies of neurons. Nerve fibers in cochlear nucleus, root of eighth nerve, as well as descending pathways from the superior olivary complex, are also immunolabeled with gentamicin continuously. Based on these data, we hypothesize that retrograde axonal transport of gentamicin is responsible for the distribution of gentamicin in these efferent nuclei including vestibular efferent neurons and superior olivary complex and anterograde axonal transport into the ipsilateral cochlear nucleus.     

Time course of apoptotic cell death in guinea pig cochlea following intratympanic gentamicin application

CONCLUSIONS: The present study showed that the molecular signal that promotes the death of cochlear hair cells (HCs) induced by intratympanic gentamicin application is significant before the manifestation of morphological and functional changes. OBJECTIVES: The effect of agents that protect the HCs from aminoglycoside ototoxicity is influenced by the timing of their administration. However, morphological, functional and molecular changes in the cochlea in the early stage following aminoglycoside application have rarely been studied. Therefore, we examined the chronological changes in the cochlea following intratympanic gentamicin application. MATERIALS AND METHODS: Small pieces of gelatin sponge soaked with gentamicin (40 mg/ml) were placed on the round window membrane of mature guinea pigs, and the tympanic bulla was filled with gentamicin solution. They were euthanized at 6, 12, 18, 24, and 48 h following gentamicin application. Auditory brainstem responses (ABRs) were measured before gentamicin application and immediately before euthanasia, and the extent of missing and TUNEL-positive HCs was evaluated. RESULTS: ABR thresholds significantly increased 18 h or later following gentamicin application, and the loss of HCs was seen at 24 and 48 h. While functional and morphological changes were not evident until 18 h after gentamicin application, substantial amounts of TUNEL-positive HCs appeared at 12 h.     

Long-term effects of chemotherapy for acute lymphoblastic leukemia on the medial olivocochlear bundle: effects of different cumulative doses of gentamicin

OBJECTIVE: The treatment of acute lymphoblastic leukemia (ALL) often combines a neurotoxic chemotherapeutic protocol such as Berlin-Frankfurt-Munster-95 (BFM-95) with gentamicin, an antibiotic known to have an early and quickly reversed impact on olivocochlear reflex in animal studies. This study investigates whether this combination has any long-term side effects on the medial olivocochlear bundle (MOCB). METHODS: In all 47 children of the study suppression of distortion product otoacoustic emissions (DPOAEs) by contralateral application of white noise (WN) was used to assess the function of the MOCB. The population was divided into three groups depending on the time interval between the end of therapy and examination. The group examined shortly after chemotherapy included 12 children who had received low gentamicin doses (less than 13 days). The group evaluated 2 years after therapy involved another 12 children who had required medium gentamicin doses (more than 13, less than 23 days). The group examined 3 years after therapy included a subgroup of 12 children to whom low gentamicin doses were infused and another 11 children with high gentamicin doses (more than 23 days). RESULTS: Three years after therapy the olivocochlear reflex was efficiently produced in both subgroups of low and high gentamicin doses. Two years after therapy, contralateral WN induced increase of DPOAEs at 4 of the 12 examined frequencies. Shortly after therapy, WN increased, instead of suppressing, DPOAEs at five frequencies. CONCLUSION: This abnormal result of contralateral noise application perceived as impaired cochlear efferent innervation may indicate that ALL-BFM-95 exerts a toxic effect on the MOCB, which is slowly reversed within the first 3 years after chemotherapy and does not seem to be affected in the long term by different cumulative doses of gentamicin.     

Perilymphatic calcium and VIII nerve action potentials during gentamicin bolus i.v. injections. A preliminary study

Life-threatening human sepsis is often treated using bolus intravenous aminoglycoside injections with transient deafness as a reported side effect. Young adult cats were given various high dosages of gentamicin in bolus injections (1 ml in 30 s). Scala vestibuli calcium and gentamicin, blood gentamicin and compound action potentials of the VIII nerve were measured shortly after the injections and 45 min later. An obvious relationship could be demonstrated between levels of gentamicin, decreased calcium content and acoustic thresholds elevation. Even after a high dose of 175 mg/kg that abolished action potentials at t = 2 min, recovery invariably occurred. It is believed that the reported transient hearing loss in humans may be partly attributable to a temporary blockage of calcium by gentamicin.