磷霉素减轻顺铂耳毒性的实验研究

本文以听性脑干反应测听、扫描电镜为指标，观察磷霉素对顺铂耳毒性的拮抗作用．用药后顺铂组豚鼠4、8KHzABR阈均明显提高；顺铂 磷霉素组豚鼠仅8KHzABR阈提高。扫描电镜示顺铂组耳蜗第一、二国外毛细胞严重性嵌损；顺铂 磷霉素组耳蜗第一、二回病变轻微。结果表明磷霉素能有效地减轻顺铂引起的耳毒性。     

同时或迟后服用甲状腺激素对抗卡那霉素耳毒性的实验研究

本实验模拟临床，通过四组58耳观察了在肌注卡那霉素同一时刻或迟后一段时间服用甲状腺激素对抗卡那霉素耳毒性的效果，结果提示在肌注卡那霉素早期服用甲状腺激素仍能有效保护听功能，为临床应用甲状腺激素减轻卡那霉素耳毒性提供了初步实验依据．     

黑素和抑制剂对顺铂耳毒性的影响

作回顾了顺铂药效学、耳毒性及黑素和一些抑制剂对其耳毒性的影响；并就黑素、磷霉素和自由基清除剂ＬＡＺＡＲＯＩＤＳ与顺铂耳毒性的相互关系进行了实验研究，认为黑素是影响顺铂耳中毒易感性的一个肯定因素，磷霉素和Ｕ７８５１７Ｆ有希望成为预防顺铂耳中毒的保护剂。     

卡那霉素耳毒性和肾毒性关系的研究

目的探讨氨基甙类抗生素（ＡｍＡｎ）耳每性和肾毒性之间的关系。方法以豚鼠为实验动物,按４００ｍｇ．ｋｇ＾－１．日＾－１肌注卡那霉素１０天后,通过听性脑干反应（ＡＢＲ）测定,耳蜗铺片和透射电镜观察及肾脏功能和形态学改变,观察了豚鼠肌注卡那霉素（ＫＭ）后耳毒性和肾毒性的变化,并进行统计学分析。结果及结论ＫＭ中毒后豚鼠听力下降和肾脏功能的改变二者之间无线性关系,即ＫＭ所产生的耳毒性和肾毒性无相关性。进一步     

银杏叶提取物对豚鼠卡那霉素耳毒性早期干预作用的效果评价

目的建立豚鼠卡那霉素耳毒性聋模型,观察银杏叶提取物对卡那霉素耳毒性聋的早期干预作用。方法将豚鼠随机分成正常对照组(不做任何处理)、卡那霉素组(连续肌肉注射卡那霉素7天)、银杏叶提取物干预组(肌注卡那霉素的同时,于不同时间同时注射银杏叶提取物金钠多)。测定各组动物听性脑干反应(ABR),通过比较各组豚鼠波Ⅲ阈值、100dB SPL声刺激时波Ⅲ潜伏期和峰值差异,评价银杏叶提取物对早期卡那霉素耳毒性的干预作用。结果卡那霉素组ABR波Ⅲ阈值高于正常对照组,差异有统计学意义(P<0.05),说明本实验中卡那霉素成功致聋;卡那霉素组和银杏叶提取物干预各组之间的波Ⅲ阈值差异无统计学意义(P>0.05)。结论卡那霉素耳毒性聋的早期使用银杏叶提取物可能没有任何保护和治疗作用,是否加重耳毒性作用还有待进一步研究。     

抗生素类滴耳剂的耳毒性作用

一些抗生素类滴耳剂是否具有潜在的耳毒性作用一直是一个被热议的问题。近些年来，由于有关一些抗生素类滴耳剂所引起的耳毒性作用的文献报告不断增加，美国、加拿大等国家因抗生素类滴耳剂的耳毒性作用而引发的医疗纠纷也时有发生，再次引起人们对抗生素类滴耳剂的耳毒性作用的关注。因此，本文就抗生素类滴耳剂耳毒性作用的研究状况及其临床使用原则简述如下。     

消炎痛拮抗卡那霉素耳毒作用的实验研究

为研究消炎痛对卡那霉素耳毒性的拮抗作用,本实验用听力正常的健康花斑豚鼠60只,分两组,KF组用卡那霉素450mg/kg ip及速尿60mg/kg iv,观察8天;KFI组用卡那霉素450mg/kgip,速尿60mg/kg iv,半小时后用消炎痛10mg/kg iv,第2-8天继续用消炎痛5mg/kg/d ip。两组动物于用卡那霉素、速尿前及用药后第8天检测ABR,CAP,最后一次检测听功能后,在扫描电镜及光镜下观察耳蜗螺旋器及血管纹。发现KF组ABR(Ⅲ)及CAP(N_1)声反应阈阈值较KFI组明显提高(P<0.05),耳蜗毛细胞出现程度不同的形态学变化,血管纹无水肿。结果提示,消炎痛可减轻卡那霉素的耳毒性。     

顺铂耳毒性机制及耳保护策略研究进展

顺铂作为抗癌一线用药,多用于卵巢癌、前列腺癌、睾丸癌、肺癌、甲状腺癌等癌症的治疗,具有较强的广谱抗癌作用,也常伴有一些副作用,如肾毒性、耳毒性、骨髓抑制等。顺铂的耳毒性可导致双侧永久性听力损失,这会使患者的生活质量受到极大影响,特别是在言语交流和社会发展方面。因此,在应用顺铂治疗癌症的同时,也应注意加强对其耳毒性的防护。目前对顺铂的耳毒性防护,主要集中在应用抗氧化药物、减少细胞摄取和开发新型铂配合物等方面。现将近年来对顺铂耳毒性机制的最新研究进展和新发展的耳保护策略做一综述。     

补肾聪耳胶囊的药效学研究

目的 研究补肾聪耳胶囊对卡那霉素耳毒性和噪声性内耳损伤的保护作用以及其补肾与抗衰老作用.方法 分别采用卡那霉素和噪声损伤制备豚鼠听力损伤模型,老龄大鼠作为老年性聋模型,小鼠作为微循环效应模型,分别给予不同剂量补肾聪耳胶囊,以耳廓反射、脑干诱发电位阈值、耳蜗毛细胞形态变化、甲状腺激素水平及超氧化物歧化酶（SOD）、脂质过氧化物（LPO）为观察指标,比较分析各组的不同变化.结果 口服不同剂量补肾聪耳胶囊后,卡那霉素及噪声组耳廓反射、脑干诱发电位阈值、外毛细胞静纤毛缺失率均有显著改善,老年大鼠T4水平升高 高剂量组红细胞、肾及肾上腺SOD活性显著增高,血清LPO水平明显降低.结论 补肾聪耳胶囊具有补肾和抗衰老效应,对卡那霉素耳毒性和噪声性内耳损伤具有一定保护作用.     

顺氯氨铂的耳毒性

由于抗癌药物顺铂的广泛应用,对其副作用,如耳毒性引起临床普遍关注。本文就顺铂耳毒性特点、中毒因素、病理改变、中毒机制及预防方法等方面作简要综述。认为严密观察、给予适当治疗,可望改善其耳毒性作用。     

Protective effect of fosfomycin against aminoglycoside ototoxicity

The protective effect of fosfomycin against aminoglycoside (dibekacin)-induced ototoxicity was studied in rats. Rats were injected with 100 or 50 mg/kg of dibekacin with or without 500 mg/kg of fosfomycin for 60 or 120 consecutive days. Inner ear damage appeared to be more reduced histopathologically in animals given both dibekacin and fosfomycin than in animals given dibekacin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of dibekacin and fosfomycin. The mechanism of reduced ototoxicity may be as follows: fosfomycin inhibits the accumulation of dibekacin in the kidney, and reduces its concentration in the kidney and serum. Consequently, the amounts of dibekacin reaching the inner ear are decreased, and ototoxicity is reduced.     

Comparative ototoxicity of kanamycin A and kanamycin B in the guinea pig

It has previously been shown that simple compounds with multiple amine groups are ototoxic, the degree of ototoxicity depending on the number of amine groups in the molecule. The relationship between the number of amino groups and ototoxicity in aminoglycoside was studied using kanamycin A and kanamycin B, which contain 4 and 5 amino groups respectively. Forty-five pigmented guinea pigs were injected intratympanically with 0.1 ml of different concentrations of kanamycin A and kanamycin B. The animals were sacrificed 4 days after injection and the organ of Corti was studied by scanning electron microscopy. It was found that on an equimolar basis, kanamycin B (with 5 amino groups) is more cochleotoxic than kanamycin A (with 4 amino groups). The greater cochleotoxic potential of kanamycin B may be explained by the higher cationic nature of the molecule due to protonation of the amino--NH2 groups at physiological pH, resulting in a greater affinity between the drug and the cell membrane.     

Effect of topical fosfomycin on polymyxin B ototoxicity

Fosfomycin is an antibiotic that has been found to reduce the ototoxicity of aminoglycoside antibiotics and cisplatin when systemically coadministered. Polymyxin B, an antibiotic frequently used in ototopical preparations, has been shown to be ototoxic in experimental studies. To investigate the effect of fosfomycin on polymyxin B ototoxicity, topical administration of the two agents into the middle ear cavity was performed. Two groups of chinchillas were used. One group received applications of polymyxin B alone, and the second group received polymyxin B combined with fosfomycin. It was found that application of polymyxin B produces severe damage to the cochlea. However, when polymyxin B was given in combination with fosfomycin, cochlear damage was dramatically reduced. It is likely that in clinical use, a combination of polymyxin B and fosfomycin would demonstrate reduced risk of ototoxicity.     

Amelioration of Cisplatin-Induced ototoxicity by fosfomycin

The continued chemotherapeutic application of cisplatin (cis-diamminedichloroplatinum [II]) necessitates reduction of its doselimiting toxicity without decreasing its tumoricidal effect. This research project evaluated the efficacy of fosfomycin, a phosphonic acid antibiotic, in decreasing or ameliorating the ototoxicity (high frequency sensorineural hearing loss) and nephrotoxicity (renal tubular necrosis and interstitial nephritis) of cisplatin. Experimentally, fosfomycin effectively inhibits aminoglycoside-induced ototoxicity and nephrotoxicity in animals and humans. The efficacy of fosfomycin in blocking platinum-induced toxicity in the guinea pig was evaluated histologically and functionally using cytocochleography and light microscopy of the organ of Corti and the auditory brain stem evoked response (ABR), and light microscopy of renal corticomedullary tissues, small bowel, liver, lung, and peripheral nerve. The results demonstrate that fosfomycin ameliorates the acute renal tubular necrosis and interstitial nephritis and markedly inhibits the elevation of ABR thresholds and simultaneous outer hair cell loss that can result from cisplatinum administration. Fosfomycin should be considered apotential antidote for the dose-limiting ototoxicity and nephrotoxicity of cisplatin chemotherapy.     

Ototoxic interaction of kanamycin and 3-nitropropionic acid

Conclusion. Mitochondrial dysfunction in the cochlea potentiates the ototoxicity of aminoglycosides. Objective. This study examined whether mitochondrial dysfunction in the cochlea affects the ototoxicity of aminoglycosides. Materials and methods. Nineteen guinea pigs were treated with the mitochondrial toxin 3-nitropropionic acid (3-NP), kanamycin, both agents, or normal saline as control. After 14 days, hair cell loss and auditory brainstem response (ABR) were assessed. Results. The administration of 400 mg/kg of kanamycin caused neither hair cell loss nor ABR threshold shift. Administration of 3-NP caused mild ABR threshold shift without significant hair cell loss. Administration of 3-NP and kanamycin caused ABR threshold shift and significant hair cell loss.     

Intratympanic ototoxicity: influence of post-injection survival period

Many studies have been reported on the intratympanic ototoxicity of different drugs in animal models. The recovery periods of the animals following intratympanic drug applications varied among these studies. The present study compares the cochlear damage caused by intratympanic kanamycin following short (4 days) and long (30 days) post-injection survival periods, using the guinea pig as the animal model. The degree of cochlear damage 4 days after kanamycin injection was consistent among the tested animals. The degeneration was mainly confined to the outer hair cells and almost all inner hair were spared. The change 30 days after kanamycin injection was more variable among the animals and both inner and outer hair cells were damaged. This shows that, although the damage to the cochlea after intratympanic aminoglycoside injection is progressive, a short post-injection recovery period is suitable for comparative intratympanic ototoxicity studies.     

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.     

Relationship between ototoxicity of aminoglycoside antibiotics and their transferability into inner ear fluids

The purpose of this study is to clarify the question whether the difference of severity of ototoxicity induced by the aminoglycoside antibiotics depends on the difference of quantity of transferability into inner ear. Aminoglycoside antibiotics (tobramycin, kanamycin, netilmicin and ribostamycin) were injected for 30 consecutive days to rabbits. The relationship between the severity of hair cell damage and concentration of antibiotics in perilymph was investigated. The drug concentration in the perilymph was determined by the bioassay method, and using the surface preparation technique the hair cell damage was observed under a phase contrast microscope. It was concluded that the difference of severity of ototoxicity induced by the aminoglycoside antibiotics is due to the difference of their own toxicity to hair cells but not to the difference of their transferability into the perilymph.     

Interaction of polyanion against kanamycin ototoxicity

We studied whether interference of the electron bindings between kanamycin (KM) and the outer plasma membranes of the hair cells with polyanion such as heparin can reduce ototoxicity. In a short course experiment, KM 200 mg/kg/day was injected intramuscularly 23 times with or without 1 U or 0.5 U of heparin/g/day differently to 22 guinea pigs. The reducing effect of heparin against KM ototoxicity was significant from a comparison of the N1 threshold obtained by the cochleogram. The number of surviving outer hair cells in the heparin groups was significantly greater in the third turn than in the group given KM alone. A long course experiment in which 50 injections of KM with or without 0.5 U of heparin were given intramuscularly to 16 guinea pigs revealed from the pinna reflex, cochlear microphonics and cell counting that heparin could reduce ototoxicity slightly at an early stage or before reaching crucial accumulation.     

卡那霉素对三种小鼠耳毒性比较及对血管纹Na-K-2Cl联合转运子1表达的影响

目的建立小鼠氨基糖甙类抗生素（aminoglycoside antibiotics，AmAn）耳毒性模型，探讨在不同种小鼠中的AmAn耳毒易感性及其对耳蜗血管纹Na—K-2Cl联合转运子-1（Na-K-2Cl cotransporter-1，NKCC1）表达的影响。方法将72只C57BE／6J、CBA／CaJ、NKCC1＋／-小鼠各自随机分为A、B、C、D4组。A组：卡那霉素组；B组：卡那霉素＋2，3-二羟基苯甲酸组；C组：2，3-二羟基苯甲酸组；D组：生理盐水组。各组连续用药14d。各组动物在用药前、用药后第14天及用药后第35天行脑干诱发电位（auditory brainstem response，ABR）检测听功能；耳蜗琥珀酸脱氢酶组织化学染色观察耳蜗形态学变化；免疫组化法观察血管纹NKCC1表达的变化。结果①A组小鼠ABR闽值明显提高（P〈0．01）并伴随外毛细胞的减少；②B组小鼠ABR阈值变化明显小于A组（P〈0．01），外毛细胞的损害也明显减轻；③A组小鼠耳蜗血管纹NKCCl表达减弱，与D组比较有明显差异（P〈0．01），而B组小鼠血管纹NKCC1表达较A组增强（P〈0．01）；④3种小鼠中CBA／CaJ小鼠对AmAn最敏感，C57BE／6J和NKCC1＋／-小鼠对AmAn的易感性无明显差异。结论应用卡那霉素可建立小鼠AmAn耳毒性模型；卡那霉素可抑制血管纹NKCC1的表达；2，3-二羟基苯甲酸拮抗AmAn耳毒性的途径之-可能是通过减轻AmAn对血管纹NKCC1的抑制作用；具有年龄相关性听力损失特性的小鼠对AmAn耳毒作用并不易感。