CN116617237A - 黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用 - Google Patents
黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明涉及黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,本发明首次发现了黄柏酮在预防或治疗顺铂或氨基糖苷类药物导致的药物性听力损失和噪声性听力损失方面的用途。实验结果表明,黄柏酮对顺铂、氨基糖苷类药物或噪声诱导的小鼠听力损失具有保护作用,对顺铂、氨基糖苷类药物或噪声诱导的耳蜗毛细胞丢失具有改善作用。黄柏酮可有效用于顺铂、氨基糖苷类药物导致的药物性听力损失和噪声性听力损失的预防和治疗,具有开发成相应药物的应用前景。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用。
背景技术
药物性听力损失(Drug induced-hearing loss)是暴露于耳毒性药物所引起的一种进行性的感音神经性聋。耳毒性药物可造成听觉系统损伤,其对听觉器官的损害是多方面的,主要损害部位是耳蜗,引起内耳缺血、缺氧及自由基的过量累积等。有研究发现,在耳毒性药物暴露时,耳蜗毛细胞处于应激状态,细胞中的钙稳态遭到破坏,线粒体膜电位降低,通过呼吸链产生活性氧自由基(reactive oxygen species,ROS)被释放到细胞质中,细胞内氧化和抗氧化的平衡被打破,引起毛细胞死亡,形成永久性听力损失。面对严重的药物性耳聋现状,发掘有效保护药物是近年来听觉领域研究的重点之一。目前,临床上尚无能够有效预防或治疗药物性耳聋的治疗手段和药物。
噪声性听力损失(Noise induced-hearing loss)又称为噪声性耳聋,是暴露于损害性噪声环境中所引起的一种进行性的感音神经性聋。噪声暴露可造成听觉系统损伤。对于短时间暴露于噪声环境引起的听力下降,离开噪声环境后几周内可自然恢复的现象称为短暂性听力损失,离开噪声环境后不可以自然恢复的现象称为永久性听力损失。噪声对听觉器官的损害是多方面的,主要损害部位是耳蜗,引起内耳缺血、缺氧及自由基的过量累积等。有研究发现,在噪声暴露时,耳蜗毛细胞处于应激状态,细胞中钙稳态遭到破坏,线粒体膜电位降低,通过呼吸链产生活性氧自由基(reactive oxygen species,ROS)被释放到细胞质中,细胞内氧化和抗氧化的平衡被打破,引起毛细胞死亡,形成永久性听力损失。面对严重的噪声性耳聋现状,发掘有效保护药物是近年来听觉领域研究的重点之一。目前,临床上尚无能够有效预防或治疗噪声性耳聋的治疗手段和药物。
黄柏是为芸香科植物黄皮树Phellodendron chinense Schneid.或黄檗Phellodendron amurense Rupr.的干燥树皮,具有清热燥湿,泻火除蒸,解毒疗疮的功效,可用于湿热泻痢,疮疡肿毒,耳鸣眩晕等。黄柏酮是从黄柏中提取得到的一种天然小分子柠檬苦素类三萜化合物,不溶于水。研究发现黄柏酮具有免疫调节、抗氧化、抗肿瘤等药理作用。另有研究表明,黄柏酮能够保护肺上皮细胞和神经元细胞,减轻缺血-再灌注损伤。
目前,尚未见黄柏酮预防或治疗顺铂及新霉素导致的药物性听力损失和噪声性听力损失方面的报道。
发明内容
本发明的目的是提供黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用。
为实现上述目的,本发明提供的技术方案是:
黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用。
进一步地,所述的听力损失包括耳鸣、听力减退或听力丧失。
进一步地,所述的噪声引起的听力损失为爆震性耳聋。
进一步地,所述的噪声是指频率为4-60kHz、强度为90-150dB的噪声。
进一步地,黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力阈值上移的药物中的应用。
进一步地,黄柏酮在制备治疗或预防铂类或氨基糖苷类药物耳毒性或噪声导致的耳蜗毛细胞存活率下降的药物中的应用。
作为优选的方案,黄柏酮的应用剂量为3-5mg/kg体重。
作为优选的方案,制备成口服制剂、注射剂或外用制剂。
作为优选的方案,还包括药学上可接受的载体。
所述的口服制剂选自口服液、片剂、粉剂、胶囊剂或颗粒剂;所述的注射剂选自水针剂或注射用无菌粉末;所述的外用制剂选自滴剂、喷雾剂或凝胶剂。
作为可选的方式,在上述用途中,所述药物适于以下各种施用方式,可以是口服施用或胃肠外施用或耳内施用。
优选地,所述胃肠外施用包括静脉注射、肌内注射和皮下注射。
与现有技术相比,本发明的有益效果是:
黄柏酮为传统中药材提取产物,本发明首次发现了黄柏酮在预防或治疗顺铂或氨基糖苷类药物导致的药物性听力损失和噪声性听力损失方面的用途。实验结果表明,黄柏酮对顺铂、氨基糖苷类药物或噪声诱导的小鼠听力损失具有保护作用,对顺铂、氨基糖苷类药物或噪声诱导的耳蜗毛细胞丢失具有改善作用。由此可见,黄柏酮可有效用于顺铂、氨基糖苷类药物导致的药物性听力损失和噪声性听力损失的预防和治疗,具有开发成相应药物的应用前景。
附图说明
图1:黄柏酮保护顺铂诱导的小鼠听力损失实验图。图1中A表示体内动物实验流程图,图1中B表示ABR检测不同组别小鼠听力(x±SD,n=5),图1中C表示小鼠耳蜗毛细胞免疫荧光图,放大倍数100X,Myosin7a标记毛细胞,DAPI标记细胞核,图1中D表示耳蜗毛细胞计数的统计图(x±SD,n=3);*P<0.05,**P<0.01,***P<0.001。
图2:黄柏酮保护新霉素诱导的小鼠听力损失实验图。图2中A表示体内动物实验流程图,图2中B表示ABR检测不同组别小鼠听力(x±SD,n=4),图2中C表示小鼠耳蜗毛细胞免疫荧光图,放大倍数100X,Myosin7a标记毛细胞,DAPI标记细胞核,图2中D表示耳蜗毛细胞计数的统计图(x±SD,n=3);*P<0.05,**P<0.01,***P<0.001。
图3:黄柏酮保护噪声诱导的小鼠听力损失实验图。图3中A表示体内动物实验流程图,图3中B表示ABR检测不同组别小鼠听力(x±SD,n=6),图3中C表示小鼠耳蜗毛细胞免疫荧光图,放大倍数100X,Myosin7a标记毛细胞,DAPI标记细胞核,图3中D表示耳蜗毛细胞计数的统计图(x±SD,n=3);*P<0.05,**P<0.01,***P<0.001。
具体实施方式
以下通过实施例的形式对本发明的上述内容再作进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容所实现的技术均属于本发明的范围。
黄柏酮作为黄皮树或黄檗树皮中最有效的活性成分,是黄柏的精华所在。现代药理学试验已经充分证实,黄柏酮能够显著提高机体的免疫功能,参与生物体的免疫调节,参与生命细胞的各种活动,具有一定的降血压,降血脂,降血糖,抗炎症,抗氧化,抗衰老,抗肿瘤等功效。而黄柏酮的高生物活性使得它比目前临床上常用的口服小分子三萜化合物的免疫活性强几百倍。也有实验进一步证明,黄柏酮具有抗氧化,抗衰老免疫调节,抑制肿瘤细胞复制等多种药理活性。
本发明使用的黄柏酮可以采用本领域常规的天然产物提取方法从含有该活性成分的黄皮树或黄檗等植物中提取分离得到,也可以购自市售产品。
本发明药学上可接受的载体是指药物制剂领域常规的药物载体,选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、矫味剂、溶剂、表面活性剂中的一种或几种。
其中,所述填充剂选自淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等;所述润滑剂选自硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆等;所述粘合剂选自水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等;所述崩解剂选自淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等;所述助悬剂选自多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等;所述溶剂选自水、平衡的盐溶液等。
上述各种剂型可以根据药物制剂领域的常规工艺制备而成。
在本文所述的医药用途中,对于黄柏酮的给药时间、给药次数和给药频率等等,需要根据病情的具体诊断结果而定,这在本领域技术人员掌握的技术范围之内。
将对动物的治疗方案应用于人体上,所有药物对人的有效剂量可以通过该药物对动物的有效剂量进行换算,这对于本领域的普通技术人员而言也是容易实现的。
为了更好地理解本发明的实质,在以下具体实施方式部分用药效学实验及其结果来进一步说明黄柏酮在制药领域中的用于预防或治疗铂类及氨基糖苷类导致的药物性听力损失和噪声性听力损失的用途。
本发明中,Neo指新霉素Neomysin;Cis指顺铂Cisplatin;Ob指黄柏酮。
实施例中所使用的实验方法,如无特殊说明均为常规方法,所用的试剂、方法和设备,如无特殊说明均为本技术领域常规试剂、方法和设备。
实施例1黄柏酮对铂类药物引起的听力损失的保护作用研究
1.动物分组及实验:
选取6周龄C57BL/6J小鼠(购自南京青龙山动物繁殖场),随机分为4组:空白对照组、顺铂给药组(4mg/kg)、黄柏酮给药组(4mg/kg)、顺铂/黄柏酮联合给药组。4组小鼠在第0天进行听性脑干反应(ABR)测听。从第1天开始黄柏酮给药组和顺铂/黄柏酮联合给药组小鼠进行黄柏酮腹腔注射给药,每天1次,连续3天;之后顺铂给药组、黄柏酮给药组和顺铂/黄柏酮联合给药组小鼠分别继续进行腹腔注射给药,每天1次,连续4天;空白对照组给生理盐水,第1天到第7天,每天一次;于第11天对4组小鼠进行听性脑干反应(ABR)测听及耳蜗毛细胞免疫荧光计数分析。
2.听性脑干反应(ABR):
根据体重对小鼠进行戊巴比妥钠腹腔注射麻醉,将麻醉状态小鼠置于屏蔽室中37℃恒温垫,将检测电极插入小鼠头顶中央皮下位置,参考电极插入小鼠左耳廓下方皮下,接地电极插入小鼠大腿外侧皮,声波装置置于小鼠左耳处,然后分别采用4kHz、8kHz、12kHz、16kHz、24kHz、32kHz纯音进行刺激,声波强度从90dB逐渐降低到10dB,直到记录不到可重复波形,最后记录到可重复波形的刺激强度为小鼠听力阈值。
3.小鼠耳蜗毛细胞免疫荧光计数:
小鼠处死后快速断头,打开听泡,将获得的耳蜗组织于4%多聚甲醛(PFA)固定24h后进行EDTA脱钙,脱钙完全后将耳蜗放到磷酸盐缓冲液PBS中,在解剖镜下剥离出基底膜;用毛细胞标记物(Myosin 7a)进行免疫荧光染色;在ZEISS900激光共聚焦显微镜下观察,从而对小鼠耳蜗毛细胞进行计数统计分析。
统计分析方法:采用Graphpad prism 9.0软件通过单因素方差分析(ANOVA)和Dunnett检验计算统计显着性差异,P值<0.05认为具有显著性差异。
4.实验结果:
4.1黄柏酮对铂类引起小鼠听力损失的保护作用和耳蜗毛细胞丢失的改善作用:
如图1中A所示,6周龄小鼠根据分组给予不同处理。
如图1中B所示,顺铂损伤后小鼠12kHz、16kHz、24kHz、32kHz的ABR阈值显著升高;单独使用黄柏酮腹腔注射对小鼠听力无明显影响;联合使用后能够显著改善噪声诱导的听力功能障碍。
如图1中C和图3中D所示,小鼠解剖耳蜗基底膜铺片后通过免疫荧光实验发现,顺铂损伤后小鼠耳蜗中圈、底圈毛细胞数目与空白对照组相比显著减少;单独使用黄柏酮对小鼠内耳毛细胞数量无显著影响;黄柏酮对顺铂诱导耳蜗毛细胞缺失(中圈和底圈)具有保护作用。
实施例2黄柏酮对氨基糖苷类药物引起的小鼠听力损失的保护作用研究
1.动物分组及实验:
选取新生C57BL/6J小鼠(购自南京青龙山动物繁殖场),随机分为3组:空白对照组、新霉素给药组(4mg/kg)、新霉素/黄柏酮联合给药组。3组小鼠在第0天进行听性脑干反应(ABR)测听;从第7天开始,新霉素给药组和新霉素/黄柏酮联合给药组小鼠分别进行腹腔注射给药,每天1次,连续7天,同时空白对照组给生理盐水,每天一次;于第30天对3组小鼠进行ABR测听及耳蜗毛细胞免疫荧光计数分析。
2.听性脑干反应(ABR):
同实施例1
3.小鼠耳蜗毛细胞免疫荧光计数:
同实施例1
统计分析方法:采用Graphpad prism 9.0软件通过单因素方差分析(ANOVA)和Dunnett检验计算统计显着性差异,P值<0.05认为具有显著性差异。
4.实验结果:
4.1黄柏酮对氨基糖苷类引起小鼠听力损失的保护作用和耳蜗毛细胞丢失的改善作用:
如图2中A所示,新生小鼠根据分组给予不同处理。
如图2中B所示,新霉素损伤后小鼠24kHz和32kHz的ABR阈值显著升高;联合使用后能够显著改善新霉素诱导的听力功能障碍。
如图2中C和图3中D所示,小鼠解剖耳蜗基底膜铺片后通过免疫荧光实验发现,新霉素损伤后小鼠耳蜗底圈毛细胞数目与空白对照组相比显著减少;黄柏酮对新霉素诱导耳蜗毛细胞缺失(中圈和底圈)具有保护作用。
实施例3黄柏酮对噪声引起的小鼠听力损失的保护作用研究
1.动物分组及实验:
选取6周龄C57BL/6J小鼠(购自南京青龙山动物繁殖场),随机分为3组:空白对照组、模型组(噪声损伤组)、黄柏酮给药组(4mg/kg)。黄柏酮给药组小鼠通过腹腔注射给药,每天一次,连续3天,同时空白对照组给生理盐水,每天一次。第4天对模型组和黄柏酮给药组小鼠采用120dB单次白噪声暴露2小时的方式建立永久性噪声损伤听力模型,第6天对三组小鼠进行听ABR测听及耳蜗毛细胞免疫荧光计数分析。
2.听性脑干反应(ABR):
同实施例1
3.小鼠耳蜗毛细胞免疫荧光计数:
同实施例1
统计分析方法:采用Graphpad prism 9.0软件通过单因素方差分析(ANOVA)和Dunnett检验计算统计显着性差异,P值<0.05认为具有显著性差异。
4.实验结果:
4.1黄柏酮对噪声引起小鼠听力损失的保护作用和耳蜗毛细胞丢失的改善作用:
如图1中A所示,6周龄小鼠给予不同处理。
如图3中B所示,噪声损伤后小鼠8kHz、12kHz、16kHz、32kHz的ABR阈值显著升高,单独黄柏酮腹腔注射后能够显著改善噪声诱导的听力功能障碍。
如图3中C和图3中D所示,小鼠解剖耳蜗基底膜铺片后通过免疫荧光实验发现,噪声损伤后小鼠耳蜗中圈、底圈毛细胞数目与空白对照组相比显著减少,而黄柏酮对噪声诱导耳蜗毛细胞缺失(中圈和底圈)具有保护作用。
以上所述,仅是本发明的较佳实施例,并非对本发明作任何形式上的限制,任何熟悉本专业的技术人员,在不脱离本发明技术方案范围内,依据本发明的技术实质,对以上实施例所作的任何简单的修改、等同替换与改进等,均仍属于本发明技术方案的保护范围之内。
Claims (9)
1.黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用。
2.根据权利要求1所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:所述的听力损失包括耳鸣、听力减退或听力丧失。
3.根据权利要求1所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:所述的噪声引起的听力损失为爆震性耳聋。
4.根据权利要求3所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:所述的噪声是指频率为4-60kHz、强度为90-150dB的噪声。
5.根据权利要求1所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力阈值上移的药物中的应用。
6.根据权利要求1所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:黄柏酮在制备治疗或预防铂类或氨基糖苷类药物耳毒性或噪声导致的耳蜗毛细胞存活率下降的药物中的应用。
7.根据权利要求1所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:黄柏酮的应用剂量为3-5mg/kg体重。
8.根据权利要求1所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:制备成口服制剂、注射剂或外用制剂。
9.根据权利要求8所述的黄柏酮在制备治疗或预防铂类或氨基糖苷类药物或噪声引起的听力损失的药物中的应用,其特征在于:还包括药学上可接受的载体。
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DAFEI LI 等: "The Role of Nrf2 in Hearing Loss", 《FRONTIERS IN PHARMACOLOGY》, vol. 12, pages 1 - 11 * |
SHENGMEI XU 等: "Obacunone activates the Nrf2-dependent antioxidant responses", 《PROTEIN & CELL》, vol. 7, no. 9, pages 684 - 688, XP036044474, DOI: 10.1007/s13238-016-0297-y * |
明瑞杰 等: "细胞自噬与感音神经性听力损失", 《中华耳鼻咽喉头颈外科杂志》, vol. 56, no. 7, pages 777 - 783 * |
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