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（ｄｅｆｅｒｏｘａｍｉｎｅｍｅｓｙｌａｔｅ,ＤＦＯ）对抗庆大霉素（ｇｅｎｔａｍｉｃｉｎ,ＧＭ）耳毒性作用及其机理。方法豚鼠随机分为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（ａｃｏｕｓｔｉｃｂｒａｉｎｓｔｅｍｒｅｓｐｏｎｓｅ,ＡＢＲ）、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、肌苷以及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４０～６０ｄＢ;ＧＭ＋ＤＦＯ组阈移为１５～２５ｄＢ,差异有显著性（Ｐ＜０．０５）。形态学改变与听力变化一致。ＤＦＯ对ＧＭ血药浓度没有影响。ＧＭ组肾功明显损伤,但肾皮质丙二醛、超氧化物歧化酶和铁离子变化差异无显著性（Ｐ＞０．０５）,ＧＭ＋ＤＦＯ组耳蜗组织丙二醛和铁离子含量较ＧＭ组明显减少（Ｐ＜０．０５）,超氧化物歧化酶含量明显高于ＧＭ组（Ｐ＜０．０５）。结论自由基和铁离子在ＧＭ的耳毒性中起重要作用,ＤＦＯ能有效减轻ＧＭ的耳毒性作用,可能成为有希望的预防药物。     

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     

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     

雏鸡庆大霉素致聋后的听力恢复及表皮生长因子对其恢复的影响

为了探讨庆大霉素（ＧＭ）致聋雏鸡的听力恢复和表皮生长因子（ＥＧＦ）对其听力的影响，将１周龄雏鸡随机分成正常对照组、ＧＭ组和ＥＧＦ组。ＧＭ组雏鸡注射ＧＭ１０ｄ，每天１００ｍｇ／ｋｇ，ＥＧＦ组注射ＧＭ１０ｄ后再注射表皮生长因子（ＥＧＦ）５ｄ，每天１００μｇ／ｋｇ，分别观察ＡＢＲ阈值的变化。结果发现：ＧＭ组停药当天雏鸡ＡＢＲ阈值明显升高（Ｐ＜０．０１），停药后ＡＢＲ阈值逐渐恢复，但２１ｄ仍未恢复正常；ＥＧＦ组停药后与同期ＧＭ组雏鸡比较，ＡＢＲ阈值明显下降。结果提示，ＧＭ致聋雏鸡听力可以恢复，ＥＧＦ可明显促进雏鸡听觉功能恢复。     

畸变产物耳声发射对侧抑制效应的研究

利用ＩＬＯ９２耳动态分析仪，测试２３例（４６耳）正常青年人的畸变产物耳声发射（ＤＰＯＡＥ）和对侧窄带噪声（ＮＢＮ）的影响。结果：（１）对侧ＮＢＮ对ＤＰＯＡＥ的抑制非常明显，随ＮＢＮ强度增加ＤＰＯＡＥ幅值下降增加，二者呈显著负相关（Ｆ２为１～６ｋＨｚ，γ为－０．４９～－０．２４，均Ｐ〈０．０５，斜率０．２６～０．０８ｄＢ／１０ｄＢ）。（２）在Ｆ２为中频（１．２ｋＨｚ）且为中等强度（４５～６５ｄＢＳＰ     

正常清醒豚鼠的畸变产物耳声发射特性

目的 研究正常清醒豚鼠的畸变产物耳声发射（ＤＰＯＡＥ）的特性。方法 采用ＣＥＬＥＳＴＡ ５０３型耳声发射分析仪对２６只正常清醒豚鼠（３５耳）进行ＤＰ图及ＤＰ输入／输出曲线（ＤＰ－Ｉ／Ｏ）的测试，随机选择１１只正常清醒豚鼠（２０耳）进行ＤＰＯＡＥ的重复测试，用ＳＰＳＳ１０．０对数据进行统计分析。结果 在ＤＰ图中，当初始音强度Ｌ１／Ｌ２为 ７０／６５ ｄＢ ＳＰＬ时，正常清醒豚鼠的 ＤＰＯＡＥ幅值随测试频率ｆ０从０．７５－８ｋＨｚ的增加而逐渐升高（２７．９０±１．９６－5０．６５±０．７１）。在 ＤＰ－Ｉ／Ｏ中，当ｆ０分别为４、６、８ ｋＨｚ时，正常清醒豚鼠的ＤＰＯＡＥ幅值随Ｌ１／Ｌ２从７０／６５以５ｄＢ－挡降至１５／１０ ｄＢ ＳＰＬ而呈线性下降（Ｐ＜０．０１），在Ｌ１／Ｌ２为５５／５０或６０／５５ ｄＢ ＳＰＬ处出现饱和或低谷，同一Ｉ／Ｏ曲线上Ｌ１／Ｌ２分别从７０／６５及５５／５０ ｄＢ ＳＰＬ递减至阈值的Ｉ／Ｏ斜率（分别记为ＫＴ及ＫＬ）均接近于１，且ＫＬ大于ＫＴ（Ｐ＜０．０１）。重复测试的ＤＰＯＡＥ幅值差异小（＜ １ｄＢ ＳＰＬ）且无统计学意义（Ｐ＞０．０５）。结论 正常清醒豚鼠ＤＰＯＡＥ测试充分表现了其捡出率高、反应幅值大     

畸变产物耳声发射临床应用价值的探讨

研究了７３例（１３９耳）纯音听阈正常耳及各种感音神经性聋耳的ＤＰＯＡＥ，发现ＤＰＯＡＥ对耳蜗功能异常的改变早于纯音测听，并可精确地反映耳蜗毛细胞在相关频率上的功能状态；ＤＰＯＡＥ幅值及引出率随纯音听阈的提高而下降，当纯音听阈＞５０ｄＢ（ＨＬ）时，ＤＰＯＡＥ幅值明显降低或缺失；蜗后病变耳ＤＰＯＡＥ正常，当蜗后病变累及耳蜗时，ＤＰＯＡＥ幅值可异常，其异常程度与纯音听阈不平行。认为ＤＰＯＡＥ有广泛临床应用价值。     

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     

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.     

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     

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.     

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。     

High-frequency (8 to 16 kHz) reference thresholds and intrasubject threshold variability relative to ototoxicity criteria using a Sennheiser HDA 200 earphone

OBJECTIVE: The first purpose of this study was to determine high-frequency (8 to 16 kHz) thresholds for standardizing reference equivalent threshold sound pressure levels (RETSPLs) for a Sennheiser HDA 200 earphone. The second and perhaps more important purpose of this study was to determine whether repeated high-frequency thresholds using a Sennheiser HDA 200 earphone had a lower intrasubject threshold variability than the ASHA 1994 significant threshold shift criteria for ototoxicity. DESIGN: High-frequency thresholds (8 to 16 kHz) were obtained for 100 (50 male, 50 female) normally hearing (0.25 to 8 kHz) young adults (mean age of 21.2 yr) in four separate test sessions using a Sennheiser HDA 200 earphone. RESULTS: The mean and median high-frequency thresholds were similar for each test session and increased as frequency increased. At each frequency, the high-frequency thresholds were not significantly (p > 0.05) different for gender, test ear, or test session. The median thresholds at each frequency were similar to the 1998 interim ISO RETSPLs; however, large standard deviations and wide threshold distributions indicated very high intersubject threshold variability, especially at 14 and 16 kHz. Threshold repeatability was determined by finding the threshold differences between each possible test session comparison (N = 6). About 98% of all of the threshold differences were within a clinically acceptable range of +/-10 dB from 8 to 14 kHz. The threshold differences between each subject's second, third, and fourth minus their first test session were also found to determine whether intrasubject threshold variability was less than the ASHA 1994 criteria for determining a significant threshold shift due to ototoxicity. The results indicated a false-positive rate of 0% for a threshold shift > or = 20 dB at any frequency and a false-positive rate of 2% for a threshold shift >10 dB at two consecutive frequencies. CONCLUSIONS: This study verified that the output of high-frequency audiometers at 0 dB HL using Sennheiser HDA 200 earphones should equal the 1998 interim ISO RETSPLs from 8 to 16 kHz. Further, because the differences between repeated thresholds were well within +/-10 dB and had an extremely low false-positive rate in reference to the ASHA 1994 criteria for a significant threshold shift due to ototoxicity, a Sennheiser HDA 200 earphone can be used for serial monitoring to determine whether significant high-frequency threshold shifts have occurred for patients receiving potentially ototoxic drug therapy.     

Dynamic changes following combined treatment with gentamicin and ethacrynic acid with and without acoustic stimulation. Cellular uptake and functional correlates

Regional selectivity of gentamicin (GM) ototoxicity was studied in guinea pigs (GPs) using electrophysiological, morphological, autoradiographic and immunohistological observations following combined treatment with GM (150 mg/kg i.m.) and ethacrynic acid (EA) (30 mg/kg i.c. or i.v., 1.5 h after GM injection). The GPs were either continuously stimulated every 5 min with a series of 256 clicks (70 dB peSPL, 10/s) during 3 h for monitoring fast changes in VIII nerve compound action potential (CAP) after the EA injection, and thereafter kept in the animal quarters (background noise of 60 dB SPL) (group I), or similarly monitored for only 10 min after the EA injection and thereafter kept in a soundproof room (around 0 dB SPL) (group II). Whenever GM labelling was observed it was localized only in the sensory hair cells. From 3 h after EA injection, the GPs in group I presented threshold elevations in the high-frequency region, which progressed to 60-80 dB at all frequencies at and after 48 h. Parallel to the threshold pattern, GM uptake in outer hair cells (OHCs) was seen with an increasing concentration from apex toward base from 3 to 24 h, while after 48 h almost all OHCs were destroyed and inner hair cells (IHCs) were marked by GM. In group II no changes in CAP thresholds were observed until more than 24 h, although GM was detected in the hair cells from 6 h on. At this early stage, the distribution of GM lacked a clear pattern, particularly without a clear apex-base gradient, and GM deposits were found only around the basal body. However in both groups, in late stage (greater than 24 h), the base-apex gradient was more pronounced and GM was found throughout the cell body, with a marked concentration below the cuticular plate. These results suggest that GM may penetrate hair cells around the basal body and that activating the cells by sound potentiates both GM uptake and its intracellular toxicity.     

Aminoglycoside Ototoxicity and the Medial Efferent System: I. Comparison of Acute and Chronic Gentamicin Treatments

Recently our laboratory has demonstrated, in the guinea pig (GP), that an intramuscular (i.m.) injection of a high dose of gentamicin (GM) (150 mg/kg), can reversibly block the contralateral efferent suppression of ipsilateral cochlear activity. The aims of the present study were: (1) to investigate this effect with lower doses of GM; and (2) to find out whether this effect could constitute an anticipatory sign of ototoxicity during a chronic GM treatment (60 mg/kg i.m., 10 days). The function of the medial olivocochlear efferent system (MOES) was tested by recording the Vlllth nerve ensemble background activity (EBA) without and with contralateral low level (55 dB SPL) broadband noise stimulation. The results show a dose-dependent effect of GM on contralateral suppression, as the dose of 120 mg/kg induced a smaller blockade of the MOES, compared to 150 mg/kg, and no blockade was observed with lower doses. During the ten-day treatment no significant changes in the EBA without acoustic stimulation, nor in contralateral efferent suppression were detected. GPs monitored over several weeks after the treatment showed progressive reduction of the EBA without contralateral stimulation parallel to reduced suppression coefficients of the EBA, and CAP threshold elevations, denoting impaired cochlear function. Thus, this study demonstrated that a chronic treatment with 60 mg/kg of GM, although ototoxic, does not affect the contralateral efferent suppression, at least before the development of ototoxicity.