赖氨酸阿司匹林对庆大霉素耳毒性的保护作用

目的探讨庆大霉素与赖氨酸阿司匹林混合用药对庆大霉素耳毒性的保护作用。方法健康♂豚鼠30只,随机分为3组:庆大霉素(GM)组、庆大霉素联合赖氨酸阿司匹林(GM LAP)组和对照组。GM组:12mg·kg-1,sc,qd;GM LAP组:GM 12 mg·kg-1 LAP 135 mg·kg-1,sc,qd。对照组:不给予任何药物。采用听性脑干反应(ABR)和耳蜗铺片观察用药前后听阈及耳蜗毛细胞形态学改变。结果GM组1、8 kHz ABR4 wk平均阈移与GM LAP组间差异有统计学意义(P<0．05)。耳蜗铺片结果显示,GM组底圈毛细胞有损伤,与正常组比较排列不整齐,毛细胞损伤向上逐渐减轻,与听阈升高的程度相平行;而GM LAP组的毛细胞排列整齐,无损伤。结论赖氨酸阿司匹林对庆大霉素耳毒性有保护作用。     

中毒性耳聋内耳超微结构的观察

本文以耳蜗听毛细胞的透射电镜变化观察卡那霉素的耳毒性作用。结果表明：注射卡那霉素后，听毛细胞内线粒体的数目减少，病变轻者线粒体固缩，部分线粒体嵴结构不清，多泡体大量出现，部分多泡体破裂，胞浆基质溶解液化。说明卡那霉素对耳蜗听毛细胞具有耳毒性。     

鼓室内注射庆大霉素对耳蜗的毒性及刺五加的保护作用

目的探讨豚鼠局部应用用庆大霉素的耳蜗毒性作用,以及刺五加有无减轻庆大霉素耳蜗毒性的作用。方法选择健康豚鼠44只,随机分为三组:I为庆大霉素组,II为庆大霉素 刺五加组,III为生理盐水组;采用鼓膜穿刺法向豚鼠鼓室内注射药物,II组同时腹腔注射刺五加注射液;给药2周后检测三组动物的脑干诱发电位(ABR)的阈值变化,并取三组动物耳蜗底周标本行耳蜗铺片及切片,扫描及透射电镜检查。结果给药后I组ABR阈值与II组差异有显著性(P<0.01),耳蜗形态学观察示II组毛细胞受损程度较I组为轻。结论豚鼠鼓室内注射庆大霉素具有明显的耳蜗毒性,联合应用中药刺五加具有对抗庆大霉素耳毒性的作用。     

氨基苷类药物耳毒性的治疗策略

临床应用的氨基苷类抗生素能损伤内耳毛细胞.引起患者听力损伤.其损伤机制是在耳蜗中产生自由氧,从而激活毛细胞死亡通路,继发细胞凋亡.目前,保护内耳免受耳毒性药物损伤的策略一.     

防治药物性耳聋5要点

耳毒性药物能破坏感知声音最重要又最脆弱的部位——耳蜗毛细胞。毛细胞是听觉神经的末梢感受器。正常情况下毛细胞把声能转化成生物电冲动传给大脑听觉中枢。人才能听到各种声音。耳毒性药物专门伤害耳蜗毛细胞，让人不能感受外界声音。这种聋属于“感音神经性聋”。现代医学难以治愈。     

血管内皮生长因子对顺铂所致豚鼠耳蜗损伤的拮抗作用

目的应用微渗透压泵将血管内皮生长因子(VEGF)导入豚鼠耳蜗,观察VEGF对顺铂所致耳蜗毒性的拮抗作用。方法豚鼠ip顺铂造成耳蜗损伤。将VEGF以微渗透压泵导入实验组豚鼠右耳蜗,对照组导入等量磷酸缓冲液。用扫描电镜观察两组豚鼠右耳蜗毛细胞的损伤,同时检测并比较两组豚鼠右耳在实验前、后听觉脑干诱发电位(ABR)听阈的改变。结果对照组豚鼠右耳毛细胞的损伤明显重于实验组,且其ABR听阈显著高于实验组。结论微渗透压泵耳蜗灌注VEGF对顺铂所致的活体耳蜗损伤有明显的拮抗作用。     

地塞米松对双氯芬酸钠肝损伤的保护作用

目的探讨地塞米松(dexamethasone,Dex)对双氯芬酸钠诱导的大鼠药物性肝损伤的保护作用及部分机制。方法大鼠随机分为正常对照组、模型对照组、Dex(10 mg.kg-1)给药组。Dex(10 mg.kg-1)腹腔注射,1 h后腹腔注射双氯芬酸钠100 mg.kg-1,24 h后检测ALT和AST活性、测定肝匀浆中MDA、GSH含量和GSH-Px、SOD活性,观察肝组织病理学变化,并测肝线粒体膜电位、线粒体肿胀度、NADH水平、SDH及ATPase活性。结果模型对照组血清ALT、AST升高,光镜下可见肝小叶内肝细胞片状坏死,肝匀浆MDA含量升高,GSH、GSH-Px和SOD含量降低,肝线粒体NADH含量、SDH及ATPase活性降低。Dex可明显降低ALT、AST活性(P<0.05),减轻肝脏炎症,降低肝匀浆中MDA含量(P<0.01),升高GSH含量、GSH-Px和SOD活性以及线粒体中NADH含量、SDH及ATPase活性(P<0.01)。结论 Dex对双氯芬酸钠诱导的大鼠药物性肝损伤有保护作用,作用机制可能与减轻线粒体损伤有关。     

氨基糖苷类药物耳毒性的斑马鱼模型的研究

氨基糖苷类抗生素因其抗菌谱广、抗菌能力强,半个多世纪以来一直是临床上常用的抗菌素之一。但氨基糖苷类抗生素具有很强的耳毒和肾毒作用,在药物致聋因素中排在首位。本研究以庆大霉素(gentamycin)、新霉素(neomycin)、链霉素(streptomycin)等3种氨基糖苷类抗生素为代表性药物,研究其对斑马鱼胚胎发育的毒性作用和对幼体毛细胞的损伤作用,并探索了该损伤与听觉相关基因之间的联系。结果显示:①3种药物的致死作用都具有明显的浓度依赖性,其致死作用的强弱顺序为链霉素>新霉素>庆大霉素;②3种药物处理的5 dpf(day past fertilization)幼体出现身体失衡及体位异常,以及耳囊结构的异常变化;③毛细胞染色实验可观察到,3种药物作用的毛细胞和神经丘均出现明显的损伤和数量减少;④与听觉器官发育相关的基因eya1、val、otx2、dlx6a均随3种抗生素药物浓度的升高,出现差异性的表达水平下调。本研究首次探索了这3种耳毒性氨基糖苷类抗生素处理与斑马鱼听囊结构和听觉基因表达的相关性;并证明利用斑马鱼建立简便、准确、直观、快速地检测药物耳毒性的模型和检测方法的可行性。     

α-硫辛酸对顺铂致小鼠耳蜗毛细胞损伤的保护作用的体外研究

目的:研究α-硫辛酸(LA)对顺铂致离体小鼠耳蜗毛细胞损伤的保护作用。方法:分离3～5d的新生昆明种小鼠耳蜗基底膜,在含有1%牛血清白蛋白培养基中培养24h,分为对照组、模型组(顺铂16μg.mL-1)、药物对照(LA0.5mmol.L-1)组和低、高浓度LA(顺铂16μg.mL-1+LA0.2、0.5mmol.L-1)组(n=10),分别加入含相应药物的新鲜培养基2mL,培养24h,观察各组耳蜗毛细胞组织形态变化,计算内、外毛细胞缺失百分率,检测Bax、Bcl-2的表达情况。结果:与对照组比较,模型组小鼠耳蜗毛细胞出现纤毛倒伏、排列紊乱,内、外毛细胞缺失百分率、Bax表达水平明显增加(P<0.01),Bcl-2表达明显减弱(P<0.01);与模型组比较,低、高浓度LA组小鼠耳蜗毛细胞的形态改变明显减轻,内、外毛细胞缺失百分率、Bax表达明显减弱(P<0.05或P<0.01),Bcl-2表达明显增强(P<0.05),且高浓度组改善效果明显优于低浓度组(P<0.05);对照组与药物对照组比较无明显差异(P>0.05)。结论:LA对离体培养的顺铂致小鼠耳蜗毛细胞损伤具有保护作用。     

丹参注射液拮抗链霉素耳中毒的实验研究

目的探讨链霉素(streptomyc in,SM)耳中毒过程中豚鼠耳蜗毛细胞凋亡及碱性成纤维细胞生长因子(basic fibro-b last growth factor,bFGF)表达,以及丹参注射液(salvia m ilti-orrh iza in jection,DS)的拮抗作用。方法40只豚鼠随机分为4组,利用TUNEL标记技术、SABC免疫组化方法及图像分析技术,结合听性脑干反应(aud itory brainstem response,ABR)测试,观察耳毒性损伤过程中凋亡情况及bFGF的表达。结果用药10 d后,SM组ABR阈值明显升高,DS+SM组ABR阈值明显低于SM组,差异有显著性(P<0.01)。SM组耳蜗毛细胞凋亡染色呈强阳性表达,DS+SM组呈弱阳性表达。免疫组化结果表明,SM组bFGF的表达明显低于DS+SM组。结论SM耳中毒时ABR阈值升高,凋亡表达增强,bFGF表达稍有增强。DS能有效的降低SM所致的ABR阈值升高,并抑制凋亡的发生,同时增强bFGF的表达,从而减轻SM的耳毒性损伤,提示DS对SM耳毒性损伤有拮抗作用,这一拮抗作用可能与bFGF表达增强有关。     

WM88拮抗庆大霉素耳毒性实验观察

目的:初步了解WM88拮抗庆大霉素耳毒性的性能及其影响力.方法:设置庆大霉素组与庆大霉素加不同剂量WM88(10mg、20mg)的两组进行比较,观察听性脑干反应(ABR)阈值,眼震电图(ENG)的频率,了解其听功能及前庭功能的变化.仅结合耳蜗铺片琥珀酸脱氢酶(SDH)染色方法和扫描电镜观察耳蜗形态学变化.结果:听生理检查数据统计显示各组间无显著性差异;形态结果显示各组间无显著性差异.结论:本实验没有发现WM88对庆大霉素引起的耳蜗和前庭毒性有拮抗作用.     

庆大霉素耳中毒后血管纹HSP70 mRNA的表达及川芎嗪的保护作用

目的研究川芎嗪(TMP)对庆大霉素(GM)中毒豚鼠耳蜗血管纹热休克蛋白HSP70 mRNA表达的影响。方法应用原位杂交、图像分析技术并结合听脑干反应(ABR)的测试,观察TMP对GM耳中毒豚鼠耳蜗血管纹HSP70 mRNA表达的影响。结果GM组耳蜗血管纹ABR阈值为(36.55±6.13)dB,TMP+GM组对应值为(21.09±4.50)dB,二组之间差异有显著意义(P<0.01);GM组耳蜗血管纹HSP70 mRNA表达的平均灰度值为(89.31±1.47)dB,TMP+GM组对应值为(94.16±2.15)dB,二组之间差异有显著意义(P<0.01)。各组HSP70 mRNA表达与ABR阈值高度相关(r=-0.8734~-0.9841,P<0.001)。结论HSP70在耳蜗血管纹细胞的转录和翻译是不同的,TMP减少耳蜗血管纹HSP70 mRNA表达,改善听功能。     

黄芩苷对庆大霉素致耳蜗螺旋神经节细胞损伤作用的影响

目的：探讨黄芩苷(baicalin，BA)对庆大霉素(gentamicin，GM)致小鼠耳蜗螺旋神经节(spiral ganglion，SG)细胞毒性的拮抗作用。方法：用MTT法检测庆大霉素对SG细胞的毒性作用以及黄芩苷对此作用的影响，用紫外分光光度法分别测定各实验组SG细胞总超氧化物歧化酶(T-SOD)活性，谷胱甘肽过氧化物酶(GSH-PX)活性以及丙二醛(MDA)含量。结果：黄芩苷可显著抑制GM所导致的SG细胞中T-SOD和GSH-PX活性降低及MDA含量升高。结论：黄芩苷通过清除耳蜗螺旋神经节细胞内氧自由基和抑制脂质过氧化反应，拮抗庆大霉素耳毒性作用。     

Ethanol extract of Piper longum L. attenuates gentamicin-induced hair cell loss in neonatal cochlea cultures

Piper longum L. (PL), also as known as long pepper, a well-known spice and traditional medicine in Asia and Pacific islands, has been reported to exhibit wide spectrum activity including antioxidant activity. However, little information is available on its protective effect on gentamicin (GM) induced ototoxicity which is commonly regarded as being mediated by reactive oxygen species and reactive nitrogen species. This study was undertaken to investigate the protective effect of PL ethanol extract on gentamicin-induced hair cell loss in neonatal cochlea cultures. Cochlea cultures from postnatal day 2-3 mice were used for analysis of the protective effects of PL against gentamicin-induced hair cell loss by phalloidin staining. E. coil cultures were used to determine whether PL interferes with the antibiotic activity of GM. Nitric oxide (NO)-scavenging activity of PL was also measured in vitro. GM induced significant dose-dependent hair cell loss in cochlea cultures. However, without interfering with the antibiotic activity of GM, PL showed a significant and concentration-dependent protective effect against GM-induced hair cell loss, and hair cells retained their stereocilia well. In addition, PL expressed direct scavenging activity toward NO radical liberated within solution of sodium nitroprusside. These findings demonstrate the protective effect of PL on GM-induced hair cell loss in neonatal cochlea cultures, and suggest that it might be of therapeutic benefit for treatment of GM-induced ototoxicity.     

较低血浓度下庆大霉素耳毒性的研究

耳毒性药物仍是我国目前致小儿耳聋的主要原因。既往国内外有关耳毒药物的报道大多在大剂量或长疗程等特定条件下进行。但近年来亦有临床个案对治疗剂量下庆大霉素发生耳中毒作了报告。本文以豚鼠为实验     

Effects of Chronic Lithium on Ototoxicity Induced by Gentamicin and Amikacin in Guinea-Pigs

Abstract: The effects of chronic lithium co-therapy on the expression of gentamicin and amikacin ototoxicity were tested in guinea-pigs. Intramuscular injection of different doses of gentamicin (5, 10 mg/kg/day) and amikacin (150, 300 mg/kg/ day) for three weeks, induced hearing loss consistent with the established pattern of aminoglycoside ototoxicity. Lithium salts remains one of the most widely used treatment for depressive illness. Administration of lithium chloride (600 mg/1, 35 days) in drinking water changed auditory brainstem response in a time-dependent manner. Pretreatment of animals with lithium chloride after seven days induced significant alterations in wave latency and interval. The present study assesses the protective effects of chronic lithium on gentamicin-induced ototoxicity in guinea pig. The results suggest that duration of lithium administration may be involved in auditory brainstem response changes and the observations could be accounted for, at least partially, by lithium- and aminoglycosides-induced perturbations of the phosphoinositide cascade within the inner ear.     

Red ginseng protects against gentamicin-induced balance dysfunction and hearing loss in rats through antiapoptotic functions of ginsenoside Rb1

The authors evaluated the protective effects of Korean red ginseng (KRG) against gentamicin (GM)-induced unilateral vestibular and hearing dysfunction and investigated its effective mechanism using in vitro cell cultures. Vestibular function was comprehensively evaluated by a scoring system that ranged from 0 (normal) to 3 (worst) points, using head tilt, tail hanging, and swimming tests. The GM group showed significantly more deteriorated vestibular function (0 point – 5 rats, 1 point – 1 rat, 2 points – 3 rats, and 3 points – 3 rats) than the KRG + GM group (0 point – 9 rats and 1 point – 1 rat) (p < 0.01). The hearing thresholds were better in the KRG + GM group than in the GM group (p < 0.05). Quantitative analysis of hair cell damage in the scanning electron microscopy was closely related with vestibular and hearing functional results. In vitro study showed that ginsenoside Rb1 (gRb1) attenuated reactive oxygen species production, suppressed JNK activation, up-regulated Bcl-xL and down-regulated Bax, cytochrome c, caspase 3, and cleaved poly (ADP-ribose) polymerase in GM-treated VOT-E36 cells. These findings suggest that KRG including gRb1 component protects against vestibular/hearing dysfunction by inhibiting apoptotic pathways when ototoxicity is induced by unilateral intratympanic injection with GM in rats.     

Ototoxicity of micronomicin sulfate--audiometric assessment

Micronomicin sulfate (MCR) is a new aminoglycoside antibiotic, and its antibacterial spectrum is similar to that of gentamicin (GM). According to the animal test, MCR has less ototoxicity than other aminoglycoside antibiotics such as GM. To check its clinical ototoxicity, MCR was given intramuscularly to 20 patients at dose of 120--240 mg/day, respectively for 2--8 days, and audiometry was carried out before and after administration of MCR. No evident change was detected between the preadministration hearing levels and the postadministration hearing levels. These data suggest that MCR is sufficiently safe in ototoxicity within dose of 120 mg/day for 4 days.     

Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin

One of the side effects of cisplatin therapy in malignant neoplasms is ototoxicity. This effect shows a wide inter-individual range which is more variable than the pharmacokinetic parameters. Oxidative stress has been implicated in cisplatin ototoxicity. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1 and GSTT1), encode low-activity variants (GSTP1) or are associated with variable inducibility (GSTM3). The aim of our study was to investigate genetic risk factors involved in the ototoxicity of cisplatin and to determine whether the polymorphisms in five GST genes affect the individual risk of ototoxicity by cisplatin. Two groups of patients were analyzed in this study: group H, 20 patients early and highly sensitive to the ototoxicity of cisplatin; and group N, 19 patients with no hearing impairment under comparable doses of the drug. We found a protective effect for the GSTM3*B allele with a frequency of 0.18 in the group with normal hearing after therapy versus 0.025 in the group with hearing impairment. (chi2=5.37; p=0.02).     

Mechanism of Cisplatin Ototoxicity: Antioxidant System

Abstract: The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post-treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats were sacrified and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45±0.012 nmol/mg] after cisplatin administration compared to 0.95±012 nmol/mg in control cochleae (P<0.05). Superoxide dismutase, catalase activities and malondialehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration. Alterations in the activity of antioxidant enzymes, an increase in malondialdehyde levels, and depletion of cochlear GSH suggest a role for reactive oxygen species mediated damage of the cochlea in cisplatin toxicity. These biochemical changes were accompanied by the elevation of ABR threshold that appears to correlate well with alterations in antioxidant systems which could be the cause of cisplatin ototoxicity.