甲磺酸去铁胺抗庆大霉素耳毒性作用及机理研究

目的 探讨铁螯合剂甲磺酸去铁胺对抗庆大霉素耳毒性作用及其机理。方法 豚发为ＧＭ组（１７只）、ＤＦＯ组（８只）、ＧＭ＋ＤＦＯ组（１７只）及对照组（８只）,采用听性脑干反应,耳蜗铺片及透射电镜技术,观察用药前后听反应阈及形态学变化,检测血清尿素氮、革以及ＧＭ浓度,同时测定耳蜗和肾皮质组织中丙二醛、超氧化物歧化酶和铁离子含量。结果 ＧＭ组８ｋＨｚＡＢＲ阈移为４－６０ｄＢ;ＧＭ＋ＤＦＯ组阈移为１５－２５ｄ     

甲磺酸去铁胺对抗庆大霉素耳毒性的实验研究

目的观察铁螯合剂———甲磺酸去铁胺（ｄｅｆｅｒｏｘａｍｉｎｅｍｅｓｙｌａｔｅ,ＤＦＯ）对抗庆大霉素（ｇｅｎｔａｍｉｃｉｎ,ＧＭ）耳毒性的作用。方法将豚鼠随机分为ＧＭ组、ＤＦＯ组、ＧＭ＋ＤＦＯ组及对照组,采用听性脑干反应（ＡＢＲ）、耳蜗铺片及透射电镜技术,观察用药前后听阈及形态学改变,并检测ＤＦＯ对庆大霉素血药浓度的影响。结果ＧＭ组８ｋＨｚＡＢＲ阈值逐渐升高４０～６０ｄＢ;ＧＭ＋ＤＦＯ组阈移为１５～２５ｄＢ,差异显著（Ｐ＜０．０５）。高频听阈损伤明显比低频更重（Ｐ＜０．０１）。形态学变化与听力变化平行。ＤＦＯ对庆大霉素血药浓度没有影响。结论证实ＤＦＯ能有效减轻ＧＭ的耳毒性作用,ＤＦＯ可能成为预防庆大霉素耳毒性的有效药物。     

聚DL-天冬氨酸对庆大霉素耳毒性拮抗作用的实验研究

目的　研究聚ＤＬ天冬氨酸（ｐｏｌｙ ＤＬａｓｐａｒｔｉｃ ａｃｉｄ,ＰＡＡ） 对Ｆ３４４ 大鼠庆大霉素（ｇｅｎｔａｍｉｃｉｎ,ＧＭ） 耳毒性的拮抗作用。方法　选用健康Ｆ３４４ 大鼠５０ 只,随机分４ 组：Ⅰ为ＧＭ、Ⅱ为ＰＡＡ＋ ＧＭ、Ⅲ为ＰＡＡ、Ⅳ为生理盐水对照组;通过观测４ 组大鼠不同时期、不同频率听性脑干反应（ａｕｄｉｔｏｒｙ ｂｒａｉｎｓｔｅｍ ｒｅｓｐｏｎｓ,ＡＢＲ）阈值的改变;计数耳蜗毛细胞死亡率,以观察ＰＡＡ对Ｆ３４４ 大鼠ＧＭ 耳蜗毒性的拮抗作用;用双向扩散血清培养基检测法观察ＰＡＡ 对ＧＭ 抗菌活性的影响。结果　Ⅰ组短纯音１０ ｋＨｚ、８ ｋＨｚ ＡＢＲ阈值与其他３ 组差异有显著性（ Ｐ＜ ０．０１） ,给药１８ ｄ 耳蜗毛细胞死亡率与其他３ 组间差异也有显著性（ Ｐ＜０ ．０１）。结论　ＰＡＡ对庆大霉素的耳毒性具有拮抗作用,且不减低其抗菌活性。     

自由基清除剂二甲基亚砜对庆大霉素耳蜗毒性的影响

观察豚鼠同时注射二甲基亚砜（ＤＭＳＯ）与庆大霉素（ＧＭ）及单独注射ＧＭ等几组动物后，耳蜗听功能、扫描电镜所见及耳蜗和血清中脂质过氧化物（ＬＰＯ）丙二醛（ＭＤＡ）含量的变化。结果表明ＧＭ＋ＤＭＳＯ组动物ＡＰ阈值较ＧＭ组明显降低，ＡＰ（Ｎ＿１）潜伏期ＧＭ组较ＧＭ＋ＤＭＳＯ组显著延长，耳蜗扫描电镜显示ＧＭ＋ＤＭＳＯ组毛细胞受损程度较ＧＭ组明显为轻。耳蜗中ＭＤＡ检测表明，ＧＭ组耳蜗中ＭＤＡ含量较ＧＭ＋ＤＭＳＯ组明显增高（Ｐ＜０．０１）。提示自由基引起耳蜗ＬＰＯ可能是ＧＭ耳毒性机制之一；ＤＭＳＯ可减轻ＧＭ的耳毒性。     

聚DL—天冬氨酸对庆大霉素耳毒性拮抗作用的实验研究

目的 研究聚ＤＬ－天冬氨酸（ＰＡＡ）对Ｆ－３４４大鼠庆大霉素（ＧＭ）耳毒性的拮抗作用。方法 选用健康Ｆ－３４４大鼠５０只,随机分４组：Ｉ为ＧＭ、Ⅱ为ＰＡＡ＋ＧＭ、Ⅲ为ＰＡＡ、Ⅳ为生理盐水对照组;通过观测４组大鼠不同时期、不同频率听性脑干反应（ＡＢＲ）阈值的改变;计数耳蜗毛细胞死亡率,以观察ＰＡＡ对Ｆ－３４４大鼠ＧＭ耳蜗毒性的拮抗作用;用双向扩散血清培养基检测法观察ＰＡＡ对ＧＭ抗菌活性的影响。结果     

畸变产物耳声发射与响度重振现象关系的探讨

目的探讨响度重振与耳蜗主动机制异常之间的关系，为耳声发射用于诊断耳蜗性病变提供更多指标。方法通过对２０例（４０耳）健康人、５０例（６３耳）常规重振检测频率阳性者和１１例（１５耳）蜗后性聋耳进行畸变产物耳声发射（ｄｉｓｔｏｒｔｉｏｎｐｒｏｄｕｃｔｏｔｏａｃｏｕｓｔｉｃｅｍｉｓｉｏｎ，ＤＰＯＡＥ）的输入－输出（Ｉ／Ｏ）曲线的测试和分析。结果重振检测阳性的患耳不同频率ＤＰＯＡＥ的Ｉ／Ｏ曲线斜率的均值与健康人对应频率Ｉ／Ｏ曲线斜率的均值相比明显增大（Ｐ＜０．０１），其ＤＰＯＡＥ的检测阈也明显提高。结论响度重振与耳蜗主动机制异常有特定联系，ＤＰＯＡＥ的Ｉ／Ｏ曲线对耳蜗主动机制的评价更直观、准确，可能成为一种有价值的诊断耳蜗性病变的指标。     

畸变产物耳声发射幅值与超高频纯音听阈的关系

目的 探讨畸变产物耳声发射（ｄｉｓｔｏｒｔｉｏｎ ｐｒｏｄｕｃｌｓ ｏｔｏａｃｏｕｓｔｉｃ ｅｍｍｉｓｓｉｏｎ,ＤＰＯＡＥ）与超高频纯音听阈用于早期耳蜗性听力损害的听力监测的可能性。方法 ＤＰＯＡＥ以配对初始音诱发,两音强度均为７０ｄＢ ＳＰＬ,频率比为１：１．２,频率范围０．５￣８ｋＨｚ。测定常规频率（１２５Ｈｚ￣８ｋＨｚ）及超高频率（９￣２０ｋＨｚ）的纯音听阈。比较正常听阈组与不正常听阈值的Ｄ     

短时纯音暴露对正常人畸变产物耳声发射幅值及频谱时间序列的影响

探讨在耳蜗功能早期轻微损害时畸变产物耳声发射（ＤＰＯＡＥ）幅值及频谱时间序列的特征,促进ＤＰＯＡＥ的临床应用。方法：用 １３０ｄＢ ＳＰＬ的 ４ ｋＨｚ纯音对 １５例听力正常人（３０耳）进行 ３ ｍｉｎ的短时暴露,造成听力暂时性阈移后,用ＩＬＯ－９０耳声发射仪记录、分析暂时性阈移（ＴＴＳ）时ＤＰＯＡＥ的幅值、时间序列的特征,并与纯音暴露前进行对比。结果：正常人经过短时纯音暴露后,０．５,１,２ ｋＨｚ纯音和宽带噪声的声反射阈升高,纯音暴露前后０．５、１、２ ｋＨｚ与ＢＢＮ之间的平均反射阈差值分别为（９．７８±６．９８）,（８．０４±５．５８）,（１３．０±５．５８） ｄＢ ＨＬ和（８．８２±６．２３）,（５．７５±４．４２）,（９．０５±２．２７）ｄＢ ＨＬ,声反射阈差值缩小。纯音暴露前后６ ｋＨｚＤＰＯＡＥ幅值分别为（６．００±３．４５）和（１．７２±１. ２３） ｄＢ ＳＰＬ,降低４．２８ ｄＢ ＳＰＬ,时间序列变异系数为（５．１８±１．６３）％,时间序列曲线稳定性降低,ＤＰＯＡＥ幅值与时间序列结合发现８０％的人ＤＰＯＡＥ处于异常范围。结论：ＤＰＯＡＥ的幅值与时间序列结合分析有诊断耳蜗功能早期轻微受损的临床价值。     

成纤维细胞生长因子耳蜗内灌注防治爆震性聋的实验研究

选用豚鼠１９只，震前于圆窗龛放银球电极测复合动作电位（ＣＡＰ）反应阈，爆震后测ＣＡＰ，于耳蜗底回打孔，分别灌注酸性成纤维细胞生长因子（ａＦＧＦ）和碱性成纤维细胞生长因子（ｂＦＧＦ），４８小时后再测ＣＡＰ，处死动物做耳蜗琥珀酸脱氢酶（ＳＤＨ）组化染色铺片。结果爆震后灌注ｂＦＧＦ、ａＦＧＦ两组动物４８小时ＣＡＰ平均阈值分别为８８．７ｄＢ和９３．２ｄＢ，而单纯打孔组和灌注外淋巴组ＣＡＰ平均阈值分别为１１９．４ｄＢ和１０７．５ｄＢ，差异有显著性（Ｐ＜０．０５和０．０１）。铺片结果示灌流生长因子两组动物耳蜗毛细胞损伤程度比其他两组要轻。结果提示ｂＦＧＦ、ａＦＧＦ耳蜗内灌注对爆震性聋ＣＡＰ反应阈恢复有促进作用，在耳蜗声损伤过程中有保护和修复功用。     

豚鼠噪声暴露后畸变产物耳声发射与外毛细胞的改变

为观察豚鼠噪声暴露后畸变产物耳声发射（ＤＰＯＡＥ）与内耳毛细胞的改变，将１６只健康豚鼠分为３组，正常对照组３只，噪声后即刻组３只，７ｄ组１０只。暴露于１１５ｄＢ ＳＰＬ模拟潜艇机舱噪声中４ｈ，暴露后即刻及７ｄ检测ＤＯＰＡＥ听力图及Ｉ／Ｏ函数曲线，光镜及扫描电镜观察耳蜗毛细胞的改变。暴露即刻组ＤＰＯＡＥ振幅消失（Ｐ〈０．０１），７ｄ后又恢复至暴震前的基线水平（Ｐ〉０．０５）。光镜及扫描电镜显示耳蜗２     

庆大霉素对豚鼠耳肾毒性的相关性实验研究

目的 探讨豚鼠庆大霉素耳性与肾毒性的关系。方法 通过ＡＢＲ测试,耳蜗铺片毛细胞片数,血液庆大霉素药代动力学分析,血ＢＵＮ、Ｃｒ值测定,肾标光镜下观察等方法,观察肌注庆大霉互后豚鼠的耳蜗功能及肾功能变化。结果 肌注庆大霉素二周组ＡＢＲ的ＩＶ波反应阈阈移明显高于肌注庆大霉素一周组及其生理盐水对照组。光镜下耳蜗铺片毛细胞计数二周组毛细胞缺失数明显多于一周组对于对照组。肌注纱二周组的血清庆大霉素清除率明显     

白藜芦醇拮抗庆大霉素耳毒性的实验研究

目的观察白黎芦醇（resveratrol,Res）对抗庆大霉素耳毒性的作用.方法将豚鼠随机分为庆大霉素（gentamicin, GM）组、白藜芦醇剂量I＋GM组 （ResI ）、白黎芦醇剂量II＋GM组（ResII）、白黎芦醇剂量III＋GM组（ResIII）及对照组.采用听性脑干反应（ABR）、耳蜗铺片及透射电镜技术,观察用药前后各组动物听阈及耳蜗毛细胞形态学改变,并检测血清丙二醛、超氧化物岐化酶含量、肾功能以及庆大霉素血药浓度.结果 ResIII组血液中丙二醛较GM组明显减少（P〈0.05）,GM＋Res各组超氧化物歧化酶活性均明显高于GM组（P〈0.05）,同时GM组1、8 kHz ABR 4 周平均阈移与ResIII剂量组间差异显著（P〈0.05）.形态学改变与听力变化一致.Res对庆大霉素血药浓度没有影响.结论大剂量Res能有效减轻GM的耳毒性作用,且不影响庆大霉素的抗菌作用.     

Attenuation of Neomycin Ototoxicity by Iron Chelation

Increasing evidence suggests that aminoglycoside ototoxicity is mediated by the formation of an aminoglycoside-iron complex and that the creation of this complex is a preliminary step in generation of free radical species and subsequent hair cell death. In this study we have assessed the ability of the iron chelator deferoxamine to attenuate the hearing loss induced by an ototoxic dose of the aminoglycoside neomycin (100 mg/kg per day for 14 days). Experiments were carried out on pigmented guinea pigs weighing 250 to 300 g. Changes in auditory sensitivity were characterized by monitoring shifts in compound action potential(CAP) thresholds, recorded through indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results show that animals receiving neomycin alone suffered a mean threshold shift exceeding 35 dB at all test frequencies (2.0, 4.0, and 8.0 kHz) 30 days after initiation of treatment. In comparison, all animals receiving cotherapy of neomycin and deferoxamine (150 mg/kg twice daily for 14 days) maintained their CAP threshold, suggesting significant protection from neomycin ototoxicity. A statistical comparison of treatment groups showed that in the animals receiving cotherapy with neomycin and deferoxamine, deferoxamine produced a significant protective effect against neomycin-induced ototoxicity (P < 0.001). These results provide further evidence of the intrinsic role of iron in aminoglycoside ototoxicity and suggest that deferoxamine may have a therapeutic role in attenuating the cytotoxic action of aminoglycoside antibiotics.     

alpha-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 alpha-tocopherol, are able to suppress MLP, thus attenuating tissue damage. The present study was designed to investigate the possible protective effects of alpha-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 alpha-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. alpha-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 alpha-tocopherol. This study supports the hypothesis that alpha-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.     

Experimental study on polyaspartic acid inhibition of gentamicin-induced generation of reactive oxygen species in guinea pig cochlea]

OBJECTIVE: To observe the polyaspartic acid(PAA) inhibition of gentamicin-induced reactive oxygen species generation in cochlea of guinea pig and to investigate the protective mechanism of polyaspartic acid on gentamicin ototoxicity. METHODS: Eighty-eight guinea pigs were divided randomly into four groups (GM, PAA + GM, PAA, and Saline). Gentamicin-induced reactive oxygen species (ROS) formation in cochlear tissue was detected directly with electron paramagnetic resonance (EPR) spectrometry at 1st, 5th and 10th day after administration of the drugs. At the same time, ABRs of guinea pigs were recorded and ultrastructural changes of lysosomes in the cochlear hair cells were observed with transmission electron microscopy. RESULTS: 1. At 1st day after administration of PAA and GM, there was some increase in EPR spectrometry in group GM and PAA + GM, There was no significant difference of ABR thresholds and ultrastructural changes of lysosomes in the cochlear hair cells among four groups(P > 0.05). 2. At 5th day, there was significant increase in of EPR spectrometry in group I (37.74 +/- 4.10, P < 0.01). At 10th day after administration of PAA and GM, there was no significant difference in EPR spectrometry among four groups (P > 0.05). In GM group, ultrastructural changes of lysosomes beneath cuticular plate of cochlear hair cells were more significant at 10th day than those at 5th day, including the increased number and volume of lysosome. In group GM, the longer the gentamicin administrated, the more significant increase in ABR thresholds had been noted. CONCLUSION: PAA significantly inhibits gentamicin-induced reactive oxygen species generation in cochlea of guinea pig, which showed that PAA has protective effect on gentamicin-ototoxicity and -phospholipidosis in guinea pigs.     

应用畸变产物耳声发射观察褪黑素对庆大霉素耳毒性拮抗作用

目的 研究褪黑素（melatonin,MLT)对庆大霉素（gentamicin,GM)耳毒性的拮抗作用。方法 实验分为GM组，MTL＋GM组及生理盐水对照组，采用豚鼠畸变产物耳声发射（distortion product otoacoustic emission,DPOAE)，观察用药后DPOAE幅值及I／O曲线斜率的变化。结果 GM组用药3后，4，6，8kHz DPOAE幅值同对照组相比有显著性差异（P＜0．01）；I／O曲线斜率变小，在4，6，8kHz与对照组相比有显著性差异（P＜0．01）。GM＋MLT组用药后各频率段DPOAE幅值，与对照组相比地显著性差异；I／O曲线斜率无明显改变，同对照组相比无显著性差异（P＞0．05）。结论 MLT能有效拮抗庆大霉素的耳毒性作用。     

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.     

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