α-Tocopherol protective effects on gentamicin ototoxicity: an experimental study

Gentamicin, acting as an iron chelator, activates membrane lipid peroxidation (MPL) and induces free radical formation, as observed in vitro and in vivo. Antioxidants, such as α-tocopherol, are able to suppress MLP, thus attenuating tissue damage. The present study was designed to investigate the possible protective effects of α-tocopherol on gentamicin ototoxicity. The study was carried out on albino guinea pigs (250–350 g). The animals were divided into four groups: group A (n = 4), injected with corn oil daily at a dose of 100 mg/kg body weight intramuscularly (IM); group B (n = 10), treated with corn oil at a dose of 100 mg/kg body weight and gentamicin base at a dose of 100 mg/kg body weight (IM); group C (n = 10), treated with gentamicin alone at a dose of 100 mg/kg body weight (IM); and group D (n 10), treated with gentamicin at the same dose plus α-tocopherol acetate at dose of 100 mg/kg body weight (IM). Electrocochleographic recordings were made from an implanted round-window electrode. All animals were treated for 14 days. The compound action potentials (CAPs) were measured at 2–16 kHz at days 0, 10, 14 and 18 after treatment. Changes in cochlear function were characterized as CAP threshold shifts. Morphological changes were analysed by scanning electron microscopy. Gentamicin induced progressive high-frequency hearing loss of 50–60 dB SPL. α-tocopherol co-therapy slowed the progression of hearing loss. The significant loss of outer hair cells (OHCs) in the cochlear basal turn in gentamicin-treated animals was not observed in the cochleas of animals protected with α-tocopherol. This study supports the hypothesis that α-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.     

脑活素拮抗豚鼠庆大霉素耳毒性机理的研究

目的探讨脑活素拮抗豚鼠庆大霉素耳毒性作用机理。方法取听力正常豚鼠60只,随机分为4组,每组15只A组(脑活素组),肌肉注射脑活素360mg·kg-1·d-1;B组(庆大霉素组),肌肉注射庆大霉素120mg·kg-1·d-1;C组(庆大霉素 脑活素组),肌肉注射庆大霉素 脑活素,剂量同上;D组(生理盐水组),肌肉注射等量生理盐水。各组均连续用药10d再饲养一周,第17d处死,取左侧听泡,进行琥珀酸脱氢酶化学组织染色观察其活性;取右侧听泡行石蜡包埋切片,在光镜下进行螺旋神经节细胞计数,免疫组织化学SP法检测脑源性神经生长因子(brain-derivedneurotrophicfactor,BDNF)在耳蜗中的表达。结果庆大霉素 脑活素组螺旋神经节细胞退行性病变数目明显低于庆大霉素组,神经纤维变性明显较少,琥珀酸脱氢酶活性明显增高,BDNF在耳蜗中呈阳性表达。结论脑活素对庆大霉素所致耳毒性有明显保护作用,其机理在于脑活素能拮抗庆大霉素对毛细胞有氧代谢的抑制,与BDNF对螺旋神经元的营养修复作用有关。     

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.     

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.     

Ototoxicity of kanamycin in albino and pigmented guinea pigs. I. A morphologic and electrophysiologic study

Ototoxic drugs of the aminoglycoside type have been shown to accumulate to melanin, suggesting a possible mechanism for their ototoxicity. The present study was undertaken by combining electrophysiologic and morphologic methods to investigate whether the ototoxicity of kanamycin is different in pigmented and albino guinea pigs. In pigmented animals a kanamycin dose of 200 mg per kilogram of body weight per day resulted in hearing loss together with loss of both inner and outer hair cells. The albino animals in the same dose group showed significantly less hearing loss and hair cell degeneration. With daily doses of 20 and 60 mg/kg/day, no difference in ototoxicity was found between the pigmented and albino animals. The results support the hypothesis that affinity of kanamycin to inner ear melanin might be responsible for the difference in ototoxicity between albino and pigmented guinea pigs.     

Comparative ototoxicity of gentamicin in the guinea pig and two strains of rats

Gentamicin ototoxicity and nephrotoxicity were compared in two strains of rats, Sprague-Dawley and Fisher-344, and in the Hartley albino guinea pig. Treatment groups consisting of 8 male rats of each strain and four male guinea pigs were dosed subcutaneously for 14 days with either 80 or 100 mg/kg of gentamicin sulfate in saline. Brainstem auditory evoked response (BAER) thresholds were recorded from each animal in each group on day 11 post-administration. Blood urea-nitrogen and serum creatinine were measured in blood obtained on day 11 post-administration as measures of nephrotoxicity. Kidney weight/body weight ratios were also determined. Loss of sensory hair cells was observed in the basal region of the organ of Corti from all animals treated with 100 mg/kg of gentamicin. The hair cell loss and BAER threshold elevations were greatest in the guinea pigs. Fisher-344 rats showed more extensive hair loss and greater BAER threshold elevations than Sprague-Dawley rats. The Fisher-344 rats exhibited increased blood urea-nitrogen and kidney weight/body weight ratios. Sprague-Dawleys did not suffer any nephrotoxic effects. These data indicate that the Fisher-344 rat is useful animal in which to study aminoglycoside ototoxicity as it exhibits both functional and morphological changes after gentamicin administration.     

Protective effects of alpha-tocopherol against gentamicin-induced Oto-vestibulo toxicity: an experimental study

OBJECTIVE: Free radicals are involved in gentamicin ototoxicity and vestibular dysfunction and it has been demonstrated that free radical scavengers, such as alpha-tocopherol, are able to inactive free radicals, attenuating tissue damage This study was designed to investigate the possible protective effects of alpha-tocopherol against gentamicin-induced oto-vestibulo toxicity. MATERIAL AND METHODS: Adult albino guinea pigs were divided into four groups and were treated for 2 weeks as follows: Group A, controls; Group B, gentamicin plus corn oil; Group C, gentamicin only; and Group D, gentamicin plus alpha-tocopherol. 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 (VORs), respectively. Electrocochleographic recordings were performed using an implanted round window electrode. The compound action potentials (CAPs) at 2, 4, 8 and 16 kHz were measured every 5 days Morphological changes were analysed by means of scanning electron microscopy. RESULTS: Gentamicin induced a consistent reduction in VOR responses and a progressive high-frequency hearing loss of 50-60 dB sound pressure level. Alpha-Tocopherol co-therapy slowed the progression of hearing loss and significantly attenuated the final threshold shifts The impairment of vestibular function was reduced, as evidenced by an increased VOR gain. The massive loss of outer hair cells in the cochlear basal turn and of cristae ampullaris stereocilia in gentamicin-treated animals was not observed in the cochlea of animals protected with alpha-tocopherol. CONCLUSION: This study supports the hypothesis that alpha-tocopherol interferes with gentamicin-induced free radical formation, and suggests that this drug may be useful in preventing aminoglycoside oto-vestibulo toxicity.     

水杨酸盐预防庆大霉素耳毒性的试验研究

目的 探讨大剂量应用庆大霉素时,观察水杨酸钠是否仍有预防耳毒性的作用。方法 选33只健康雄性豚鼠。随机分为A(11只)、B(11只)、C(11只)三组。A组腹腔注射药物庆大霉素+水杨酸钠;B组腹腔注射庆大霉素;C组腹腔注射生理盐水。每组动物用药前、用药后第2、4、6、8、10天分别行双耳ABR的阈值测试。耳蜗铺片光镜下毛细胞记数,分别用SPSS软件进行统计学处理。结果 体重:A组体重平均增加10.2克,B组体重平均减少5.2克,对照组体重平均增加16.5克,A组与B组比较差异有显著性(P<0.01)。ABR检查:第10天A组平均阈值为43.15±6.96,较B组平均83.93±19.33有显著改善(P<0.01),A组与对照组比较无显著性差异(P>0.05)。毛细胞计数:A组比B组损伤毛细胞数减少有显著性差异(P<0.01),B组毛细胞损伤明显增加,与对照组相比有显著性差异,A组与对照组无显著性差异。结论 提示在临床上为了在短期内控制细菌感染采用大剂量的庆大霉素时,仍可用水杨酸来预防其耳毒性。     

Effect of N-acetylcysteine on carboplatin-induced ototoxicity and nitric oxide levels in a rat model

OBJECTIVE: The aim of the present study is to investigate the effect of N-acetylcysteine (NAC) given 30 minutes before carboplatin administration on carboplatin-induced ototoxicity and nitric oxide (NO) levels in a rat model. STUDY DESIGN: Animal study. METHODS: Eighteen Sprague-Dawley rats were divided into three groups that each contained six animals. Intraperitoneal injection of physiologic saline was performed in group 1 twice with an interval of 30 minutes. Group 2 was treated with a single bolus administration of carboplatin at a dose of 256 mg/kg 30 minutes after the intraperitoneal injection of physiologic saline. Group 3 was treated with a single bolus administration of carboplatin at a dose of 256 mg/kg 30 minutes after the intraperitoneal injection of NAC at a dose of 400 mg/kg. Pretreatment and posttreatment distortion product otoacoustic emissions (DPOAE) were performed in rats from all groups. Then, the animals were sacrificed on the fourth day, and cochlear tissue NO and glutathione peroxidase (GSH-Px) levels were measured. RESULTS: The comparison of pre- and posttreatment DPOAE responses did not demonstrate any significant changes for groups 1 and 3. Results of group 2 showed a decrease of the DPOAE amplitude. Cochlear NO levels were significantly higher in rats treated with carboplatin than in controls and in those treated with carboplatin plus NAC (P < .05). Cochlear GSH-Px levels were higher in rats treated with carboplatin plus NAC than in those treated with carboplatin, but the difference did not reach statistical significance (P = .079). CONCLUSIONS: The present study showed that carboplatin at higher doses induced hearing loss and increased NO levels in the cochlea of rats. NAC appears to have a protective effect against carboplatin-induced ototoxicity, which may be related to its inhibitory effect on NO production.     

Ototoxicity resulting from combined administration of metronidazole and gentamicin.

HYPOTHESIS: The hypothesis that metronidazole can augment the ototoxicity of gentamicin was tested. BACKGROUND: Metronidazole and gentamicin are antibiotics that are used in combination to provide broad-spectrum antimicrobial coverage. It has been observed clinically that an increased ototoxic effect occurs when these agents are used in combination. METHODS: Groups of guinea pigs were given various doses of gentamicin alone, various doses of gentamicin in combination with metronidazole, or metronidazole alone. Auditory damage was determined electrophysiologically by measurement of the compound action potential. Hair cell damage was quantified by immunofluorescent microscopy. RESULTS: Electrophysiologic data revealed an augmented ototoxic effect when metronidazole was given with both a moderate and a high dose of gentamicin. Thresholds (dB SPLp) for the compound action potential (N1) for animals receiving a medium dose of gentamicin alone (50 mg/kg) were approximately 20-dB SPLp. This threshold increased to approximately 50-dB SPLp when metronidazole (35 mg/kg) was administered along with the medium-dose gentamicin. Additionally, animals receiving high-dose gentamicin (75 mg/kg) alone demonstrated increased N1 thresholds from 85 to 95 when metronidazole (35 mg/kg) was added to the gentamicin regimen. This effect was evident histopathologically by increased cochlear hair cell damage. Outer hair cell loss for animals receiving medium-dose gentamicin alone did not differ from that of controls. When metronidazole (35 mg/kg) was combined, however, outer hair cell loss increased to approximately 50%. CONCLUSIONS: These data support the clinical observation of augmented ototoxicity in patients receiving combined gentamicin and metronidazole. Caution should be used when administering these two agents together. Clinicians should consider other antibiotic strategies whenever possible.     

灯盏花对庆大霉素内耳毒性的防护作用

目的　探讨灯盏花对庆大霉素耳毒性的防护作用。方法　选用听力正常豚鼠 4 0只 ,随机分为 2组 :非治疗组 (庆大霉素组 ) ;治疗组 (庆大毒素 +灯盏花组 )。两组皆肌肉注射庆大霉素注射液 (12 0mg·kg-1·d-1) ,治疗组同时腹腔注射灯盏细辛注射液 (4 5mg·kg-1·d-1)连续 10天。分别于停药后第 1、7、14、2 1天随机抽取一定数量的豚鼠处死行毛细胞及血管纹的电镜及光镜观察 ,于处死前行畸变产物耳声发射 (DPOAE)、听性脑干反应 (ABR)检测。结果　非治疗组耳蜗功能和结构损害严重 ,外毛细胞的外形及核已固缩 ,血管纹毛细血管数量随用药后时间的延长逐渐稀少、管径狭窄。治疗组耳蜗功能和结构损伤较轻 ,除可见轻度胞质水肿及线粒体固缩外 ,外毛细胞基本正常 ,血管纹毛细血管管径有所增宽 ,DPOAE振幅和ABR波潜伏期、阈值两组比较有显著性差异 (P <0 .0 1)。结论　灯盏花对庆大霉素耳毒性有一定的防护作用     

The Cochlear Ribbon Synaptic Response to Aminogiycoside Ototoxicity in C57BL/6J Mice

Objective To investigate the early change of cochlear ribbon synapses on inner hair cells in response to aminoglycoside ototoxicity. Methods C57BL/6J mice received intraperitoneal injection of gentamicin (100 mg/kg/day), and the apical coil organ of Corti was examined on the 4th, 7th and 10th day (n=10). Litter-mates without gentamicin treatment served as controls (n=10). RIBEYE on the presynaptic membrane and AMPA receptors on the postsynaptic membrane were labeled with CtBP2 or GluR2/3 respectively. Three di-mension reconstruction was conducted using the 3DS MAX 8.0 software. Results There were no disruptions of outer or inner hair cells in all groups. However, the number of ribbon synapses on cochlear inner hair cells increased significantly within 7 days after gentamicin exposure (P<0.01), followed by a significant de-crease after 7 days.Conclusion During the early stage of aminoglycoside ototoxicity, increased population of cochlear ribbon synapses may indicate a significant down-regulation of synaptic function.     

Aspirin ototoxicity in the guinea pig.

Aspirin ototoxicity has been studied on guinea pigs by shiver-audiometry and histological investigation of the cochlear duct. One dose of 350 mg/kg has provoked, after 7 h, a mean hearing loss of 18-24 dB at 0.25-8 kHz, followed by complete recovery in 3 days. The difference between the administration of 50 mg/kg/day and 350 mg/kg/day consists of a wide extension of the frequencies involved, and in about 10 dB a greater hearing loss. In both cases, no appreciable recovery of hearing was observed after 22 days (the histological investigations were negative). The biochemical pathogenesis of aspirin ototoxicity is discussed and periodical audiometric controls before and during salicylate treatment are recommended.     

Effects of alpha-tocopherol on cisplatin-induced ototoxicity in guinea pigs

Cisplatin (CDDP), an antitumor agent widely used in the treatment of head and neck cancers, has dose-limiting side effects such as ototoxicity and nephrotoxicity. Recently, evidence has been accumulated to demonstrate that these side effects are closely related to oxidative stress. In the present study, we attempted to suppress CDDP-induced ototoxicity and nephrotoxicity in guinea pigs by administering alpha-tocopherol, a naturally occurring antioxidant. Hartley albino guinea pigs (250 approximately 300 g) were treated with CDDP (4 mg/kg intraperitoneally (I.P.)) for 3 days in the presence and absence of alpha-tocopherol (50 mg/kg I.P.) injection for 6 days. The combined treatment of animals with alpha-tocopherol distinctly improved the CDDP-induced side effects. These were: loss of Preyer's reflex at high frequencies; distinct elevation of auditory brain stem response threshold at 16 kHz; increased lipid peroxidation in the cochlea determined by the malondialdehyde-thiobarbituric acid method; substantial losses of outer hair cells in the basal and second turns of the cochlea; fragmentation of nuclear DNA detected by the TUNEL method in cochlear hair cells and cells in the stria vascularis; and increases in serum BUN and Cr. These results strongly suggest that alpha-tocopherol suppresses CDDP-induced ototoxicity and nephrotoxicity via the suppression of the increased production of reactive oxygen species.     

Histological effects of co-administration of an ACTH((4-9)) analogue, ORG 2766, on cisplatin ototoxicity in the albino guinea pig

Cisplatin is one of the most potent antineoplastic drugs presently known, but its therapeutic efficacy is seriously limited by several side effects such as ototoxicity. Several compounds that are known for their nephroprotective effects also seem to reduce the incidence and severity of cisplatin-induced ototoxicity. Hamers et al. (1994) and De Groot et al. (1997) investigated the possibly protective effect of concomitant administration of the ACTH((4-9)) analogue ORG 2766 upon cisplatin ototoxicity in guinea pigs. Animals were treated with cisplatin at a daily dose of 2.0 mg/kg for 8 consecutive days and ORG 2766 at a daily dose of 75 mcg/kg for 9 days. Concomitant administration of cisplatin plus ORG 2766 resulted in a bimodal distribution of the electrophysiological data (compound action potential and cochlear microphonics amplitudes) and the histological data (outer hair cell (OHC) counts). It was surmised that this dichotomy might occur at a certain cisplatin dose. We investigated whether this protective effect of ORG 2766 could be enhanced by reducing the daily dose of cisplatin while maintaining the same dose of ORG 2766. Thirty-six animals were treated with daily i.p. injections of cisplatin at a dose of 1.0 mg/kg (n=18) or 1.5 mg/kg (n=18) for 8 consecutive days. When comparing the mean OHC counts of the different experimental groups, treatment with cisplatin at a daily dose of 1.5 mg/kg for 8 consecutive days resulted in a considerable loss of OHCs, which was significantly reduced after co-administration of ORG 2766. Co-treatment with ORG 2766 did not result in a change in the volume of the scala media. The present results are in agreement with the electrophysiological results published earlier (Stengs et al., 1998b).     

Cisplatin ototoxicity and otoprotection with sodium salicylate

Cisplatin is a potent antineoplastic drug widely used for the treatment of cancer in both adults and children. One of its most important side effects is ototoxicity, which leads to irreversible bilateral hearing loss for high frequencies (4–8 kHz). Several studies have tried to identify drugs that, when combined with cisplatin, may act as otoprotectors. The mechanism of ototoxicity of cisplatin is known to be related to changes in the antioxidant mechanisms of hair cells, especially the outer hair cells of the cochlea. Our proposal was to assess the action of sodium salicylate, which has a known antioxidant property, as a possible otoprotector of outer hair cells against the action of cisplatin, using distortion product otoacoustic emissions (DPOAEs) and scanning electron microscopy. The study was conducted on albino guinea pigs divided into two groups: group 1 (n = 9, 18 cochleae) receiving a cisplatin dose of 8.0 mg/kg/day by the intraperitoneal (ip) route for 3 days, group 2 (n = 10, 20 cochleae) receiving 100 mg/kg sodium salicylate by the subcutaneous route followed 90 min later by cisplatin, 8.0 mg/kg/day ip for 3 days, and group 3 (n = 3, six cochleae) treated with 100 mg/kg day sodium salicylate for 3 days. In group 1, there was damage with the absence of cilia in all three rows of outer hair cells in the basal turn, followed by turns 2 and 3. In group 2, hair cells were present in all cochlear turns, but exhibited disarrangement of the ciliary structure, especially in row 1, and the DPOAEs were absent after 3 days of treatment. We conclude that drugs such as sodium salicylate, because of their antioxidant properties, may protect, at least partially, the outer hair cells against cisplatin ototoxicity.     

Protective effects of sodium thiosulfate for cisplatin-mediated ototoxicity in patients with head and neck cancer

Conclusions: Intra-arterial high-dose cisplatin chemoradiation (CRT-IA) with sodium thiosulfate (STS) causes relatively less severe cisplatin ototoxicity than intravenous cisplatin chemoradiation without STS (CRT-IV). The results of this study also suggest that early detection of ototoxicity is possible by testing the hearing loss at ultra-high frequencies. Objectives: To investigate protective effects of STS against cisplatin ototoxicity. Methods: Between 2011 and 2013, 18 patients with head and neck carcinomas were treated with intra-arterial infusions of high-dose cisplatin (range 100–180 mg/body, mean 111 mg/body; range 2–5 courses, mean 3.6 courses) and systemic administration of cisplatin (range 66–185 mg/body, mean 130 mg/body; range 1–3 courses, mean 2.6 courses) and concurrent radiation therapy (range 60–70 Gy, mean 69 Gy). Cisplatin was neutralized by STS in CRT-IA but not in CRT-IV. Results: Intra-arterial infusion in the high-dose cisplatin group caused significant hearing loss at ultra-high frequencies of 10 and 12 kHz (p = 0.028, 0.039, respectively), whereas the group receiving systemic administration of cisplatin had significant hearing loss at high frequencies of 8 and 10 kHz (p = 0.016, 0.027, respectively).     

Topical gentamicin and ethacrynic acid: Effects on cochlear function

Objective: 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. Study Design: 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. Methods: 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. Results: 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. Conclusions: 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.     

Hexachlorobenzene, a dioxin-like compound, disrupts auditory function in rat

Hexachlorobenzene (HCB) is a dioxin-like compound widely distributed in the environment. In this study, we investigated the effects of HCB on the cochlea. Conscious free-moving rats were given HCB per os daily for 4 weeks at doses of 0.16, 4 or 16 mg/kg in olive oil, whereas the control group received olive oil only. The effects of HCB were evaluated at various time intervals, by measuring auditory nerve acoustic thresholds and plasma thyroid hormone concentration by radioimmunoassay. Histological evaluation involved surface preparation and scanning electron microscopy observations of cochlear hair cells. At a dose of 0.16 mg/kg, HCB induced no loss of acoustic sensitivity, whereas at 4 mg/kg, it induced cochlear sensitivity deficits at the mid-frequencies (2-16 kHz) with complete recovery once treatment was stopped. At a dose of 16 mg/kg, permanent threshold shifts were observed at all frequencies tested (from 1 to 32 kHz). Morphological studies showed no cochlear hair cell loss or alteration of stereocilia. HCB treatment reduced circulating thyroxine concentrations. Thyroidectomy had no effect on cochlear sensitivity in control animals. Thus, HCB is a potent oto-toxicant, and its ototoxicity may be independent of its thyroidal effects.     

Aminoglycoside ototoxicity in adult CBA, C57BL and BALB mice and the Sprague-Dawley rat

The availability of genetic information, transgenic and knock-out animals make the mouse a primary model in biomedical research. Aminoglycoside ototoxicity, however, has rarely been studied in mature mice because they are considered highly resistant to the drugs. This study presents models for kanamycin ototoxicity in adult CBA/J, C57BL/6 and BALB/c mouse strains and a comparison to Sprague-Dawley rats. Five-week-old mice were injected subcutaneously twice daily with 400-900 mg kanamycin base/kg body weight for 15 days. Kanamycin induced dose-dependent auditory threshold shifts of up to 70 dB at 24 kHz as measured by auditory brain stem-evoked responses. Vestibular function was also affected in all strains. The functional deficits were accompanied by hair cell loss in both cochlear and vestibular neurosensory epithelia. Concomitant administration of the antioxidant 2,3-dihydroxybenzoate significantly attenuated the kanamycin-induced threshold shifts. In adult male Sprague-Dawley rats, doses of 1 x 500 mg or 2 x 300 mg kanamycin base/kg body weight/day x 14 days induced threshold shifts of approximately 50 dB at 20 kHz. These were accompanied by loss of outer hair cells. The order of susceptibility, BALB>CBA>C57, was not due to differences in the pharmacokinetics of kanamycin. It also did not correlate with the presence of Ahl/Ahl2 genes which predispose C57 and BALB strains, respectively, to accelerated age-related hearing loss. Pigmentation, however, paralleled this rank order suggesting an influence of melanin on cochlear antioxidant status.