CN116637113A - 棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用 - Google Patents
棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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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
本发明公开了棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,发明首次发现棕榈碱能够缓解铂类或氨基糖苷类药物引起的耳毒性。棕榈碱对耳蜗毛细胞丢失具有改善作用,可有效用于解决铂类或氨基糖苷类药物引起的耳毒性,具有能开发成治疗或预防药物耳毒性引发的听力障碍的药物的前景,为临床上治疗或预防铂类、氨基糖苷类药物耳毒性听力障碍提供新的治疗选择。
Description
技术领域
本发明涉及药物性耳病领域,具体涉及棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用。
背景技术
听力障碍是全世界流行最广的一种疾病。随着人口老龄化、耳毒性药物滥用、噪声以及环境污染,耳聋及听力减退人群有逐年上升的趋势,耳聋已成为影响社会政治和经济的全球性健康问题。目前,临床上常用的助听器和人工耳蜗移植虽然在一定程度上改善了患者的听力,但其效果依赖于患者本身具有的毛细胞的数量和质量,因此找到能够有效缓解毛细胞损伤的方法及作用机制对防治感音神经性聋至关重要。
铂类和氨基糖苷类药物引起的毛细胞损伤是最常见的药物性耳聋的因素,在铂类及氨基糖苷类药物广泛应用的时代背景下,寻找一种药物,可以用来挽救、缓解或者抑制耳毒性药物引起的听力损失,对感音神经性耳聋治疗或预防具有重要意义。
发明内容
本发明的目的是提供棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,为临床上治疗或预防铂类、氨基糖苷类药物耳毒性听力障碍提供新的治疗选择。
为实现上述目的,本发明提供的技术方案是:
棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用。
棕榈碱的结构式为:
具体地,本发明的耳毒性为听力损伤或听力缺失。
具体地,本发明的耳毒性为感音神经性耳聋。
具体地,本发明的耳毒性为铂类或氨基糖苷类药物引起的耳蜗毛细胞丢失,棕榈碱对其引起的耳蜗毛细胞丢失有改善作用。
可将棕榈碱制备成口服制剂、注射剂或外用制剂:
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,注射方式包括静脉注射、肌内注射和皮下注射;所述的外用制剂选自滴剂、喷雾剂或凝胶剂。
特别地,可将棕榈碱制备成耳内施用制剂。
本发明中棕榈碱的剂量为25-100mg/kg体重。
本发明还包括药学上可接受的载体。
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。
本发明所述填充剂包括淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等;所述润滑剂包括硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆等;所述粘合剂包括水、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;所述崩解剂包括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;所述助悬剂包括多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等;所述溶剂包括水、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。
与现有技术相比,本发明的有益效果是:
本发明采用现代药物研究方法对能够治疗或预防耳毒性的药物进行深入开发、研究,通过大量筛选工作,首次发现棕榈碱(PA)能够缓解铂类或氨基糖苷类药物引起的耳毒性。棕榈碱对耳蜗毛细胞丢失具有改善作用,可有效用于解决铂类或氨基糖苷类药物引起的耳毒性,具有能开发成治疗或预防药物耳毒性引发的听力障碍的药物的前景,为该领域的临床预防或治疗提供更多的选择。
附图说明
图1:棕榈碱保护顺铂诱导的小鼠听力缺失(x±SD,n=4),****P<0.0001;***P<0.0001;**P<0.01,*P<0.05;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;cis指顺铂cisplatin。
图2:棕榈碱保护顺铂诱导的毛细胞丢失(x±SD,n=3)。****P<0.0001;***P<0.0001;**P<0.01,*P<0.05;图2中A表示小鼠耳蜗毛细胞计数的统计图,图2中A的三个横坐标标注分别代表基底膜的顶部、中部、底部;图2中B表示耳蜗毛细胞免疫荧光图,放大倍数100x,Myosin 7a标记毛细胞,DAPI标记细胞核。
图3:棕榈碱保护新霉素诱导的小鼠听力缺失(x±SD,n=4),****P<0.0001;***P<0.0001;**P<0.01,*P<0.05;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;neo指新霉素neomysin。
图4:棕榈碱保护新霉素诱导的毛细胞丢失(x±SD,n=3)。****P<0.0001;***P<0.0001;**P<0.01,*P<0.05;图4中A表示小鼠耳蜗毛细胞计数的统计图,图4中A的三个横坐标标注分别代表基底膜的顶部、中部、底部;图4中B表示耳蜗毛细胞免疫荧光图,放大倍数100x,Myosin 7a标记毛细胞,DAPI标记细胞核。
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。
本发明提供了棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用。
棕榈碱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匡草等植物中提取分离得到,也可以购自市售产品。
现代药理学试验已经充分证实,棕榈碱能参与生命细胞的各种活动,具有一定的降血压,抗炎症,抗氧化等功效。
在本文所述的医药用途中,对于棕榈碱的给药时间、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,在下文具体实施方式部分用药效学实验及其结果来进一步说明棕榈碱在制药领域中的用于预防或治疗铂类或氨基糖苷类药物耳毒性所致的听力障碍的新用途。
下述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氨基糖苷类药物诱导的小鼠耳毒性模型及用棕榈碱处理实验:
一、在类毛细胞系HEI-OC1中加入适量氨基糖苷类药物,观察氨基糖苷类药物处理后的类毛细胞损伤情况;用不同浓度棕榈碱处理24h,通过记录其中类毛细胞存活情况,以选择合适浓度进行后续实验;
二、取出生后三天内小鼠,解剖耳蜗,并取出基底膜进行培养,加入适量氨基糖苷类药物,观察氨基糖苷类药物处理后的毛细胞损伤情况;用不同浓度棕榈碱处理24h,通过记录其中毛细胞存活情况,以选择合适浓度进行后续实验;
三、选用C57BL/6小鼠,测听后注射适量棕榈碱以及氨基糖苷类药物,对照组注射相同浓度的生理盐水,然后进行ABR听力脑干反应检测。
通过体外实验以及通过小鼠听力脑干反应和毛细胞染色的方法判断棕榈碱对氨基糖苷类药物造成的听力损伤的保护作用。
实施例2顺铂诱导的小鼠耳毒性模型及用棕榈碱处理实验:
一、在类毛细胞系HEI-OC1中加入适量顺铂,观察顺铂处理后的类毛细胞损伤情况;用不同浓度棕榈碱处理24h,通过记录其中类毛细胞存活情况,以选择合适浓度进行后续实验;
二、取出生后三天内小鼠,解剖耳蜗,并取出基底膜进行培养,加入适量顺铂,观察顺铂处理后的毛细胞损伤情况;用不同浓度棕榈碱处理24h,通过记录其中毛细胞存活情况,以选择合适浓度进行后续实验;
三、选用C57BL/6小鼠,测听后注射适量棕榈碱以及顺铂,对照组注射生理盐水,然后进行ABR听力脑干反应检测。
通过体外实验以及通过小鼠听力脑干反应和毛细胞染色的方法判断棕榈碱对顺铂造成的听力损伤的保护作用。
下面以新霉素作为氨基糖苷类的代表药物进行实验。
实施例3棕榈碱对顺铂/新霉素诱导的小鼠耳毒性的作用研究:
一、动物分组及实验:
选取4周龄C57BL/6J小鼠(购自南京青龙山动物繁殖场)用于顺铂实验,随机分为4组:空白对照组(生理盐水0.2ml/只)、损伤组(顺铂4mg/kg)、棕榈碱组(棕榈碱50mg/kg)、和棕榈碱+损伤组(棕榈碱50mg/kg+顺铂4mg/kg),连续腹腔注射对应药物4天,建立顺铂损伤模型;7天后对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。
选取1周龄C57BL/6J小鼠(购自南京青龙山动物繁殖场)用于新霉素实验,随机分为3组:空白对照组(生理盐水0.2ml只)、损伤组(新霉素50mg/kg)、棕榈碱+损伤组(棕榈碱50mg/kg+新霉素50mg/kg)分别连续颈部皮下注射对应药物7天,建立新霉素损伤模型;14天后对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。
二、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;将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。
三、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。
四、实验结果:
(1)棕榈碱对顺铂诱导小鼠听力损失的保护作用:
如图1中A所示,为4周龄小鼠给予生理盐水/顺铂/棕榈碱/顺铂和棕榈碱腹腔注射给药4天,4-7天后ABR检测小鼠听力水平并通过免疫荧光进行毛细胞计数。
如图1中B所示,顺铂损伤后小鼠24kHz、32kHz的ABR阈值显著升高,棕榈碱单独注射与空白对照没有明显差异,而同时应用顺铂和棕榈碱能够显著改善顺铂诱导的听力损伤。
(2)棕榈碱对顺铂诱导耳蜗毛细胞丢失的改善作用:
如图2中A和图2中B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底圈毛细胞数目与空白对照组相比显著减少,而棕榈碱对耳蜗毛细胞缺失(基底膜)具有保护作用。
(3)棕榈碱对新霉素诱导小鼠听力损失的保护作用:
如图3中A所示,为1周龄小鼠给予生理盐水/新霉素/新霉素和棕榈碱颈部皮下注射给药7天,14天后ABR检测小鼠听力水平并通过免疫荧光进行毛细胞计数。
如图3中B所示,新霉素损伤后小鼠4kHz、8kHz、12kHz、16kHz、24kHz、32kHz的ABR阈值显著升高,而同时应用新霉素和棕榈碱能够显著改善新霉素诱导的听力损伤。
(4)棕榈碱对新霉素诱导耳蜗毛细胞丢失的改善作用:
如图4中A和图4中B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,而棕榈碱对耳蜗毛细胞缺失(基底膜)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.棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用。
2.根据权利要求1所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:所述的耳毒性为听力损伤或听力缺失。
3.根据权利要求1所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:所述的耳毒性为感音神经性耳聋。
4.根据权利要求1所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:所述的耳毒性为铂类或氨基糖苷类药物引起的耳蜗毛细胞丢失,棕榈碱对其引起的耳蜗毛细胞丢失有改善作用。
5.根据权利要求1所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:将棕榈碱制备成口服制剂、注射剂或外用制剂。
6.根据权利要求5所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于: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,注射方式包括静脉注射、肌内注射和皮下注射;所述的外用制剂选自滴剂、喷雾剂或凝胶剂。
7.根据权利要求1所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:将棕榈碱制备成耳内施用制剂。
8.根据权利要求1所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:棕榈碱的剂量为25-100mg/kg体重。
9.根据权利要求1-8任一项所述的棕榈碱在制备治疗或预防铂类或氨基糖苷类药物引起的耳毒性的药物中的应用,其特征在于:还包括药学上可接受的载体。
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CN106551930A (zh) * | 2015-09-29 | 2017-04-05 | 浙江大学 | 延胡索乙素在制备抗顺铂毒性药物中的应用 |
WO2020262971A1 (ko) * | 2019-06-25 | 2020-12-30 | 동아대학교 산학협력단 | 미토콘드리아 기능이상으로 인한 질환의 예방 또는 치료용 조성물 |
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CN106551930A (zh) * | 2015-09-29 | 2017-04-05 | 浙江大学 | 延胡索乙素在制备抗顺铂毒性药物中的应用 |
WO2020262971A1 (ko) * | 2019-06-25 | 2020-12-30 | 동아대학교 산학협력단 | 미토콘드리아 기능이상으로 인한 질환의 예방 또는 치료용 조성물 |
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