应用畸变产物耳声发射和扩展高频测听对顺铂耳毒性的临床研究

目的：应用0．5—16kHz畸变产物耳声发射(distortion product otoacoustic emissions,DPOAE)和扩展高频测听对顺铂耳毒性进行临床研究。方法:对24例应用顺铂进行初次化疗的妇科肿瘤病人于化疗前后分别进行0．5—16kHz DPOAE、常频纯音测听及扩展高频测听检查，比较DPOAE和常频纯音测听、扩展高频测听的结果。结果：顺铂化疗后扩展高频区纯音听阈升高，DPOAE在3kHz、4kHz处及扩展高频区下降明显。结论：常频DPOAE较常频纯音测听更敏感，和扩展高频测听检查一样均可用于顺铂耳毒性的监测。扩展高频DPOAE可能比常频DPOAE更敏感。DPOAE与纯音听闻可能并非一一对应关系。病人对顺铂的易感性可能随着年龄的增加逐渐减低。     

顺铂及其耳毒性

顺铂是一种用于化疗的铂制剂，在临床上广泛应用于抗肿瘤治疗。然而由于顺铂所具有的肾毒性和耳毒性以及神经毒性等毒副作用，致使其临床应用受到一定的限制。顺铂损害耳蜗的三个主要靶目标分别是血管纹和毛细胞以及螺旋神经节，这三个靶目标在顺铂的作用下都以细胞凋亡的方式实现其程序化自我毁灭，因此顺铂耳中毒模型是一个典型的内耳细胞凋亡模型。顺铂造成的细胞内氧自由基活动增加和抗氧化酶类的活性丧失是产生细胞损害的重要因素之一，因而抗氧化治疗可有效降低顺铂对耳蜗中上述三个靶目标的破坏程度。顺铂在Caspase（半胱氨酸天冬氨酸蛋白酶）径路上激发的毛细胞凋亡是首先启动Caspase－8的活动，说明毛细胞膜表面的细胞死亡因子受体是顺铂诱导毛细胞凋亡的一根导火索；螺旋神经节细胞的凋亡却是被顺铂同时启动了Caspase－8和Caspase－9，因此螺旋神经节细胞的凋亡不但是因为细胞膜表面的死亡因子受体因受顺铂刺激而发出凋亡的信号，而且还会被从线粒体释放出的细胞色素C启动其凋亡自毁程序。肿瘤抑制基因p53是出现在顺铂耳中毒早期的一个促使细胞凋亡的重要“杀手”，应用Superarray技术发现顺铂激发的耳蜗毛细胞和螺旋神经节凋亡基因主要涉及p53，肿瘤坏死因子家族，Death domain family（死亡结构域家族），Bcl－2family，Card family（Caspase相关的招募域家族），和GTP signal transdution（三磷酸鸟苷信号转导）等多条凋亡通路，其中p53信号通路是顺铂诱导毛细胞和螺旋神经节凋亡的主线，因此应用p53抑制剂－Pifithrin仅可以通过有效阻止p53的活动而减轻顺铂诱导的毛细胞凋亡。分裂素激活的蛋白激酶在顺铂诱导的内耳细胞凋亡过程中也扮演了重要的角色．应用PD98059可以通过暂时抑制分裂素激活的蛋白激酶活性和p53磷酸化以及Caspase的活动延迟耳蜗毛细胞凋亡的起始阶段，但不能完全阻止病变的扩展，因而PD98059对顺铂引起的耳蜗毛细胞凋亡仅具有短期保护效应。     

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。     

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...     

顺铂耳毒性的研究进展

顺铂被广泛用于治疗各种癌症,但具有一定的耳毒性作用。近年来的研究发现,顺铂可通过多种途径诱导听力减退,主要包括耳蜗组织损害、氧化应激损伤和细胞凋亡等。某些基因的突变或者缺失会加重或改善顺铂造成的耳毒性。另外,铁死亡也参与顺铂引起的耳毒性作用。对顺铂耳毒性相关机制的不断研究,将促进听力保护药物的研发及临床应用。     

鼓室注射地塞米松拮抗顺铂耳毒性的研究

目的：探讨鼓室注射地塞米松对顺铂致听觉损伤的保护作用。方法将55只豚鼠分为4组：正常对照组（I组）10只,腹腔注射生理盐水16 ml／kg;地塞米松组（II组）15只,经鼓室注射地塞米松10 mg／ml;顺铂组（III组）15只,单次腹腔注射顺铂16 mg／kg;顺铂＋地塞米松组（IV组）15只,经鼓室注射地塞米松10 mg／ml ,1小时后腹腔注射顺铂16 mg／kg。给药前及给药后第7天测试各组豚鼠听性脑干反应（auditory brainstem response, ABR）,并检测耳蜗组织丙二醛（malondiadehyde,MDA）含量和超氧化物歧化酶（superoxide dismutase,SOD）活性。结果 I～IV组给药前ABR反应阈分别为28．50±4．74、28．67±5．82、26．67±4．88和27．33±5．30 dB nHL,差异无统计学意义（P＞0．05）;给药后I组和II组ABR反应阈分别为29．00±3．94和31．33±5．81 dB nHL,给药前后差异无统计学意义（P＞0．05）;给药后III组和IV组ABR反应阈为55．33±4．81、40．67±3．72 dB nHL,均显著高于给药前（P＜0．05）,但IV组ABR反应阈低于III组（P＜0．05）。给药后I组 MDA含量和SOD活性分别为2．01±0．07 mmol／L和234．10±13．09 U／ml,II组分别为2．06±0．09 mmol／L和233．20±13．24 U／ml,两组比较差异无统计学意义（P＞0．05）,III、IV组 MDA含量分别为5．74±0．17、3．51±0．18 mmol／L,显著高于I、II 组（均为P＜0．05）,但IV组 MDA含量显著低于 III 组（P＜0．001）;III、IV 组 SOD 活性分别为107．90±14．21、162．70±11．25 U／ml,明显低于I、II组（均为P＜0．05）,但IV组的SOD活性显著高于III组（P＜0．001）。结论鼓室注射地塞米松对顺铂耳毒性具有一定的拮抗作用。     

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。     

畸变产物耳声发射在豚鼠庆大霉素中毒性耳聋早期监测中的作用

目的 研究畸变产物耳声发射（DPOAE）在豚鼠庆大霉素（gentamycin,GM）中毒性耳聋早期监测中的作用.方法经畸变产物耳声发射检测及耳廓反射正常的豚鼠16只（31耳）随机分成两组.GM组8只（16耳）每天肌肉注射GM100 mg/kg,连续10天;对照组8只（15耳）肌肉注射等量0.9%生理盐水10天.每组在肌肉注射前、注射第3、7天测试DPOAE,对1、2,4、6 kHz的DPOAE幅值进行比较分析.结果①对照组豚鼠在肌肉注射0.9%生理盐水的第3、7、10天与注射前比较,DPOAE引出率为100%,1、2,4、6 kHz的幅值差异无统计学意义（P＞0.05）.②GM组在肌肉注射庆大霉素第3天DPOAE的幅值与注射前及对照组比较,4、6 kHz处幅值差异有统计学意义（P＜0.05）;肌肉注射庆大霉素第7天,2,4、6 kHz处幅值差异有统计学意义（P＜0.05）.结论肌肉注射庆大霉素第3天即可发现豚鼠DPOAE 4 kHz以上的高频听力损害,第7天发现4 kHz以下的低频听力损害.     

DPOAE对系统性低血压患者的耳蜗功能监测及其临床意义

目的用畸变产物耳声发射(distortion-product otoacoustic emission,DPOAE)来观察系统性低血压和慢性进行性听力损伤的关系。方法实验组为34例体检中发现的系统性低血压患者(诊断标准:舒张压<60mmHg,收缩压<90mmHg),对照组由年龄、性别相匹配的30例正常人组成,两组在同一实验室中进行了生化、心血管、耳鼻咽喉专科和纯音测听、声阻抗、DPOAE等听力学检查。将两组的各项结果进行比较。结果实验组DPOAE听力图结果显示16例患者有一个以上频率轻到中度的听力损伤,主要在低频范围。与对照组相比,实验组的DPOAE幅值在一个以上的频率低下甚至缺失。结论系统性低血压有可能是导致耳蜗功能损伤的因子之一,而DPOAE可作为早期监测此类患者耳蜗功能损伤情况的有效工具。     

The Effect of Dexpanthenol on Ototoxicity Induced by Cisplatin

ObjectivesThis study was aimed to investigate the protective effects of dexpanthenol (Dxp) on against cisplatin-induced ototoxicity. MethodsTo examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status (including malondialdehyde, superoxide dismutase, catalase, glutathione, glutathione peroxidase, total oxidant status, total antioxidant status, and oxidative stress index) were evaluated. Thirty-two adult female Wistar albino rats were randomly divided into 4 equal groups; control (K), cisplatin (C), cisplatin plus Dxp (CD), and Dxp (D). In all groups DPOAEs measurements, between 996 and 10,078 Hz as DPOAEs and input/output functions, were performed on days 0, 1th, 5th, and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. ResultsIn the C group, statistically significant differences were detected at all frequencies between 0 and 5 days and 0 and 12 days measurements (P<0.05). Serum level of oxidant and antioxidant status were detected statistically significantly changed in this group versus K group (P<0.05). Contrary to the C group, in the CD group hearing ability was seen largely preserved at many frequencies and serum levels of all biochemical parameters were shifted toward normal values, similar to the K group. No significant differences were detected in the either D or K group’s measurements. ConclusionAccording to these results, Dxp may prevent cisplatin-induced ototoxicity.     

An Evaluation of the Protective Effects of Thymoquinone on Amikacin-Induced Ototoxicity in Rats

Objectives

In this study we investigated the probable protective effects of thymoquinone on amikacin-induced ototoxicity in rats.

Methods

Thirty-two healthy rats were divided into four groups (amikacin, amikacin+thymoquinone, thymoquinone, and no treatment). Thymoquinone was fed to the rats via oral gavage in a dose of 40 mg/kg/day throughout the study period of 14 days. Amikacin was given by the intramuscular route in a dose of 600 mg/kg/day. Audiological assessment was conducted by the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests, administered to all rats at the beginning of the study, and also on days 7 and 15. Biochemical parameters were calculated at the termination of the study to evaluate the oxidative status.

Results

There were significant decreases in DPOAE values and significant increases in ABR thresholds of the amikacin group on days 7 and 15, as compared to the amikacin+thymoquinone group. While ABR thresholds of the amikacin group increased significantly on days 7 and 15 as compared to their initial values, there were no significant differences between the initial and the 7th and 15th day values of ABR thresholds in the amikacin+thymoquinone group. Total oxidant status and oxidative stress index values of the amikacin+thymoquinone group were significantly lower than those of the amikacin group. Total antioxidant status values of the amikacin+thymoquinone group were significantly higher than those of the amikacin group.

Conclusion

Our study has demonstrated that the ototoxic effect brought forth by amikacin could be overcome with the concurrent use of thymoquinone.     

顺铂致豚鼠螺旋神经节细胞凋亡及Caspase-3活化的研究

目的：探讨顺铂的耳毒性作用与螺旋神经节细胞（sprial glanglion cell,SGC)凋亡的关系，及SGC的凋亡是否与凋亡蛋白酶Caspase-3信号转导有关。方法：取40只听力正常的豚鼠，随机分为顺铂1、2、4天组和对照组，每天检测听性脑干反应（ABR）和40Hz相关电位以观察豚鼠高，低频的听阈变化，并用TNEL法检测凋亡细胞数量变化，免疫组化检测SGC中Caspase-3p20活性片段的表达。结果：随着注射顺铂时间的延长，豚鼠听力逐渐下降，同时SGC的TUNEL染色明显增强，Caspase-3p20活性片段的表达增高，与对照组比较均有显著性差异（P＜0．01），结论：顺铂的耳毒性损害机制与SGC的凋亡有关；顺铂所致的SGC凋亡过程中有Caspase-3p20的激活。     

谷胱苷肽治疗早期庆大霉素耳中毒实验观察

目的了解庆大霉素(GM)早期耳中毒后,应用谷胱苷肽(GSH)治疗能否改善听力。方法选听力正常豚鼠30只,随机分3组,观察组12只(肌注GM100mg.kg-1*d-1,一旦ABR阈移10dB以上立即停药观察),治疗组12只(按观察组用药,停药,停药后再用GSH5天),对照组6只(仅肌注等量盐水)。所有动物在用药前后均检测ABR之波Ⅲ反应阈。停药二周后处死作耳蜗铺片。结果观察组停用GM二周后复查ABR阈移继续增大(P＜0.01)。治疗组停用GM二周后无明显阈移(P＞0.05)。对照组则前后无变化。耳蜗毛细胞形态变化与功能变化基本一致。结论早期GM耳中毒一旦出现ABR阈移即使立即停药听力损害仍将继续加重;GSH能阻止在耳蜗内蓄积的GM对听力进一步损害。     

5-磷酸二酯酶抑制剂对庆大霉素所致豚鼠耳毒性影响的研究

目的 探讨5-磷酸二酯酶(PDE5)抑制剂对庆大霉素所致豚鼠耳毒性的听功能及耳蜗形态学的影响.方法 采用随机数字表法将36只豚鼠分为空白对照组、庆大霉素组和PDE5抑制剂组,每组各12只;其中空白对照组未给予特殊处理,庆大霉素组和PDE5抑制剂组给予连续腹腔注射庆大霉素120 mg·kg-1·d-13周后,庆大霉素组继...     

Evaluation of the Protective Effect of Beta Glucan on Amikacin Ototoxicity Using Distortion Product Otoacoustic Emission Measurements in Rats

Objectives

This experimental study investigated the possible protective effect of beta glucans on amikacin ototoxicity.

Methods

Thirty-eight rats with normal distortion product otoacoustic emissions (DPOAEs) were divided into four groups. Group K was the control group. Group A was injected intramuscularly (i.m.) with amikacin 600 mg/kg/day between days 1-15. Group AB was given beta glucan gavage 1 mg/kg/day on days 0-15 and given amikacin 600 mg/kg/day i.m. on days 1-15. Group B was administered only beta glucan gavage, 1 mg/kg/day, on days 0-15. The DPOAEs were elicited in different frequency regions between 2,003 and 9,515 Hz, as distortion product diagrams (DPgrams), before and after the medication was administered, in all groups, on days 1, 5, 10, and 15.

Results

No significant changes in the DPgrams were observed in group K. In group A, significant deterioration was observed at the 8,003 and 9,515 Hz frequencies on day 10, and at the 3,991, 4,557, 5,660, 6,726, 8,003, and 9,515 Hz frequencies on day 15. For group AB, statistically significant deterioration was observed at the 2,824, 8,003, and 9,515 Hz frequencies on day 15. The results for group B showed a significant improvement of hearing at the 2,378, 2,824, 3,363, and 3,991 Hz frequencies on day 1, at the 3,363, 3,991, and 8,003 Hz frequencies on day 10, and at the 8,003 Hz frequency on day 15.

Conclusion

This study suggests that amikacin-induced hearing loss in rats may be limited to some extent by concomitant use of beta glucan.     

Evidence for multiple DPOAE components based upon group delay of the 2f(1)-f(2) distortion in the gerbil

The cochlear delay of the 2f₁−f₂ distortion product otoacoustic emission (DPOAE) was measured using the phase gradient method. With a constant f₂ and swept f₁, the resulting phase change of 2f₁−f₂ was used to calculate the group delay for f₂ frequencies from 1 to 60 kHz. For f₂ frequencies between 2 and 60 kHz, the group delays were between 2.2 and 0.11 ms and continuously decreased for increasing f₂ and for increasing primary stimulus levels. For f₂ frequencies below 2 kHz, the group delay decreased to around 1 ms and was largely independent of stimulus level. The ratio curves resulting from the f₁ sweeps for high frequencies (f₂>16 kHz) displayed the typical mammalian shape with a peak in the level of 2f₁−f₂ for a larger primary frequency separation (f₂/f₁>1.15) and decreasing 2f₁−f₂ level for smaller primary separation. In addition to this typical level maximum, for f₂ frequencies from about 1.8 to 16 kHz, the ratio curves displayed a second component in the form of an increase in the level of 2f₁−f₂ for small primary separation at higher primary levels (level of f₂>30 dB SPL). For f₂ frequencies below 1.8 kHz, only the second component and no typical ratio peak as for higher f₂ could be observed and the associated group delay was always close to 0.8 ms. Several possible causes for this behavior are discussed, including different modes of DPOAE generation and modulation as well as changes in the nature of mechanical processing from base to apex in the gerbil cochlea. To evaluate the relative sensitivity of non-linear cochlear mechanics, an iso-distortion threshold curve was constructed from acoustical growth functions of the 2f₁−f₂ DPOAE at optimum primary separation, by plotting the level of f₂ sufficient to evoke a distortion of −10 dB SPL as a function of f₂. This distortion audiogram resembled the neuronal and behavioral audiogram for frequencies >2.5 kHz but failed to reflect the sensitivity for lower frequencies. This may be a consequence of more linear frequency processing in the apex.