CN115884768A - 用于预防和治疗听力损失的方法 - Google Patents
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- CN115884768A CN115884768A CN202180049426.4A CN202180049426A CN115884768A CN 115884768 A CN115884768 A CN 115884768A CN 202180049426 A CN202180049426 A CN 202180049426A CN 115884768 A CN115884768 A CN 115884768A
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- niclosamide
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Abstract
由于化疗或噪声暴露引起的获得性听力损失是一个主要的健康问题，并且顺铂化疗经常会导致癌症患者永久性损失听力。然而，没有FDA批准的用于治疗或预防顺铂或噪声诱发的听力损失的药物。在一个方面，披露了氯硝柳胺、巨大戟醇和伊利司莫作为活性剂治疗听力损害和预防听力损害的用途，以及使用所述组合物来治疗和/或预防听力损害或障碍的方法。本摘要旨在作为扫描工具，用于在特定领域中进行检索的目的，而不旨在限制本发明。
Description
相关申请的交叉引用：本申请根据35USC§119(e)和35U.S.C.§111(a)要求于2020年7月10日提交的美国临时专利申请序列号63/050,568(通过援引特别地特此并入本文)的权益。
关于联邦政府资助的研究或开发的声明：
本发明根据美国国立卫生研究院国家耳聋和其他交流障碍研究所(NationalInstitutes of Health National Institute on Deafness and Other Communication)所授予的授权号1R43 DC018762、R01DC015444、R01DC015010，美国海军研究办公室(Officeof Naval Research)所授予的授权号N00014-18-1-2507，以及国防部(Department ofDefense)所授予的授权号USAMRMC-RH170030在政府支持下完成。政府享有本发明的某些权利。
发明背景：
(1)技术领域。
本发明涉及氯硝柳胺用于治疗、抑制和/或预防听力损失的治疗用途。
(2)背景技术，包括根据37CFR 1.97和37CFR 1.98披露的信息。
由于化疗或噪声暴露引起的获得性听力损失是一个主要的健康问题，并且顺铂化疗经常会导致癌症患者永久性损失听力。然而，没有FDA批准的用于治疗或预防顺铂或噪声诱发的听力损失的药物。基于铂的化疗是各种类型癌症(包括卵巢癌、肺癌、睾丸癌和头颈癌)的护理标准。顺铂是最有效的铂化合物之一，会导致40％-60％接受治疗的癌症患者永久性损失听力。顺铂损伤听觉感觉细胞的已知机制之一是形成DNA加合物，从而导致氧化应激和细胞凋亡。为了减少顺铂对内耳耳蜗细胞的损伤，已在先前的研究中使用各种治疗策略，包括使用抗氧化剂、抗炎剂、钙通道阻滞剂、激酶抑制剂、热休克蛋白和硫醇化合物作为化学去活化剂。例如，硫代硫酸钠(STS)已被证明仅在接受顺铂化疗的局部肝母细胞瘤儿科患者中可有效保护听力；然而，它充当顺铂螯合剂，在其他癌症患者中不能有效避免顺铂诱发的听力损失(CIHL)。
本领域需要对由于噪声、抗生素、化疗期间的顺铂或衰老引起的听力损失的解决方案。所描述的治疗方法是本领域的各种问题(诸如狭窄的治疗窗和安全界限以及干扰顺铂的抗肿瘤活性)的解决方案。
发明内容
本发明提供了一种预防或治疗听力损失的方法，所述方法包括以下步骤：向有需要的动物施用有效量的含有治疗活性剂的药物组合物，其中所述治疗活性剂包括：氯硝柳胺、巨大戟醇(Ingenol)和伊利司莫(Elesclomol)。
本发明主题还包括一种用于通过保护内耳细胞免于死亡来预防或治疗听力损失的组合物，其中所述组合物是有效量的：活性剂，其中所述活性剂选自包括以下项的组：氯硝柳胺、巨大戟醇和伊利司莫或其药学上可接受的盐。
本发明主题还包括一种由以下项制成的药盒：活性剂，其中所述活性剂选自由以下组成的组：氯硝柳胺、巨大戟醇和伊利司莫或其药学上可接受的盐；以及以下项中的一种或多种：(A)至少一种化学治疗剂；至少一种抗生素抑制剂；以及(C)用于预防听力损害的说明书。
附图说明：
包含在本说明书中并构成本说明书的一部分的附图说明了几个方面并且与描述一起用于解释本发明的原理。
图1是示出如何基于来自药物筛选联系图和途径富集分析的数据集的比较来鉴定本发明的化合物从而揭示药物对抗听力损失的作用的示意图。使用L1000CDS2和GDA药物-基因相互作用数据库来分析顺铂抗性癌细胞系及其亲本顺铂敏感性细胞的转录组学谱。然后将每种化合物的差异表达基因与使用原始GEO图谱的KEGG途径富集分析鉴定的那些差异表达基因进行比较，以发现与顺铂抗性有关的重叠基因。在最初的50种药物中，有30种在体外和体内都得到了验证，其中氯硝柳胺作为命中率最高的化合物出现。
图2A-2B示出了顺铂抗性癌细胞系的转录组分析揭示了与鉴定的药物有关的途径和共有的基因靶标。A)使用GSEA分析可从GEO数据库获得的合并的癌细胞系谱，以从KEGG数据库鉴定富集的分子途径。上调的途径以红色显示在左侧，而下调的途径以蓝色显示在右侧。圆圈大小与映射到其各自FDR值的基因数量相关。B)将来源于iLINCS数据库的每种药物的基因表达谱与通过GSEA鉴定的那些差异表达基因进行比较。然后使用相同方向上的重叠基因对药物进行分级。
图3A-F示出了氯硝柳胺对听力损失的保护作用。A)用顺铂(50μM)和实验化合物处理的HEI-OC1细胞中半胱天冬酶-3/7活性的最低水平。将原始半胱天冬酶读数归一化为用顺铂/DMSO处理的细胞和用1％DMSO处理的细胞中的半胱天冬酶活性。氯硝柳胺被示出在4.4μM的剂量下将半胱天冬酶活性降低至与对照细胞相当的水平。数据示出为平均值±标准误差(每个处理n＝3孔)。*P<0.05(单因素ANOVA)。B)通过神经丘计数毛细胞计数定量的用顺铂和实验化合物处理的斑马鱼中的最高保护水平。对SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC的定量揭示了用0.002μM氯硝柳胺预处理的斑马鱼HC中的顺铂损伤显著减少(每组n＝5至8，单因素ANOVA)。C)用媒介物(DMSO)、顺铂以及顺铂+氯硝柳胺(0.002μM至13.3μM)处理的斑马鱼神经丘的荧光染色。D)氯硝柳胺在有顺铂暴露的情况下在HEI-OC1细胞中的剂量反应曲线。E)氯硝柳胺在没有顺铂暴露的情况下在HEI-OC1细胞中的剂量反应曲线。F)通过每个神经丘的毛细胞计数定量的用顺铂和实验化合物处理的斑马鱼中的最高保护水平。对SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC的定量揭示了用0.002μM氯硝柳胺预处理的斑马鱼HC中的顺铂损伤显著减少(每组n＝5至8，单因素ANOVA)。
图4A-4F示出了氯硝柳胺在体内显示出对抗顺铂的耳保护作用。A)与仅用顺铂(Cis)处理的小鼠相比，氯硝柳胺(Nic)在8、12和32kHz下表现出显著降低的ABR阈移(每组n＝8，双因素ANOVA)。B)与仅用顺铂处理的小鼠相比，氯硝柳胺在16和32kHz下表现出显著降低的DPOAE阈移(每组n＝8，双因素ANOVA)。C、D)基线处的波I振幅在所有四个组中均未显示出差异。顺铂暴露后，发现与仅用顺铂处理的小鼠相比，氯硝柳胺增加了8-32kHz的波I振幅(每组n＝8，单因素ANOVA)。E)在32kHz区域用肌球蛋白6(红色)和DAPI(蓝色)染色的耳蜗的免疫荧光图像显示当用顺铂和氯硝柳胺共同处理时毛细胞损失的水平最小。氯硝柳胺被示出可防止顺铂诱发的毛细胞损失。F)从免疫荧光图像定量外毛细胞(OHC)显示，用氯硝柳胺共同处理赋予对顺铂诱发的毛细胞损失的完全保护(每组n＝5，学生t检验)。*P<0.05，数据在所有图中示出为平均值±标准误差。
图5A-5F示出了氯硝柳胺防止噪声诱发的听力损失(NIHL)。A)氯硝柳胺降低斑马鱼神经丘中的NMDA兴奋毒性。从用300μM NMDA和2或18.3nM氯硝柳胺处理的斑马鱼中定量毛细胞计数。在两种测试剂量下，氯硝柳胺均显著显示出比仅用NMDA处理的斑马鱼高的毛细胞计数。(每组n＝5，单因素ANOVA)。B)与盐水+噪声处理的小鼠相比，在有和没有噪声暴露的情况下用氯硝柳胺处理的小鼠在8、12、32、40和63kHz显示出显著降低的ABR阈移(每组n＝8，双因素ANOVA)。C)在10-80dB SPL的所有组中，DPOAE振幅没有差异(每组n＝8，双因素ANOVA)。D)氯硝柳胺处理的小鼠在65-90dB SPL下显示与年龄匹配对照相当的波1振幅，并且在80-和90-dB SPL下显示出比盐水和噪声暴露的小鼠显著更高的波I振幅(每组n＝8，单因素ANOVA)。E)内毛细胞的CtbP2染色显示氯硝柳胺在噪声暴露中防止突触损失(CtbP2为绿色)。F)每个内毛细胞(x轴)的CtbP2斑点(Y轴)的定量，发现用氯硝柳胺处理的小鼠具有比媒介物处理的小鼠显著更高的突触计数(每组n＝4，学生t检验)。*P<0.05，数据在所有图中示出为平均值±标准误差。
图6A-B示出了氯硝柳胺和依泽替米贝(ezetimibe)表现出协同/累加耳保护作用。三维等高线图(A)示出了用不同浓度的氯硝柳胺(TT002)和依泽替米贝处理的斑马鱼中神经丘毛细胞保护的剂量反应，所述图被绘制成协同作用分布。另外，当0.66nM氯硝柳胺(TT002)与1.48μM依泽替米贝(每组n＝5)组合时，针对每个剂量组合计算的Loewe协同作用和拮抗作用得分(B)指示最高的协同活性。显示协同作用的其他剂量组合被示出在深蓝色框中。得分为0和1的剂量组合显示出累加效应。*P<5x 10-2；相对于对照鱼，**P<10-3，***P<10-4，通过Combenefit软件44运行单样本t检验。数据示出为平均值±标准偏差。依泽替米贝是胆固醇吸收抑制剂。
图7示出了氯硝柳胺与顺铂之间在体外的相互作用的HPLC分析。
图8示出了非小细胞肺癌细胞系SHP77和小细胞肺癌细胞系A549在有或没有顺铂和10nM氯硝柳胺的情况下孵育时的存活。单独的氯硝柳胺不影响顺铂-肿瘤杀伤活性。
图9A-9B示出了伊利司莫在有顺铂暴露的情况下的剂量反应曲线。在用顺铂(50μM)处理的HEI-OC1细胞中测量半胱天冬酶3-7活性。将原始半胱天冬酶读数归一化为用顺铂/DMSO处理的细胞和用1％DMSO处理的细胞中的半胱天冬酶活性。伊利司莫被示出在40μM的剂量下将半胱天冬酶活性降低至与对照细胞相当的水平。数据示出为平均值±标准误差(每个处理n＝3孔)。*P<0.05(单因素ANOVA)。B)通过神经丘计数毛细胞计数定量的用顺铂和伊利司莫处理的斑马鱼中的最高保护水平。对SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC的定量揭示了用0.165、1.48和13.3μM伊利司莫预处理的斑马鱼HC中的顺铂损伤显著减少。
图10A-10B示出了巨大戟醇在有顺铂暴露的情况下的剂量反应曲线。在用顺铂(50μM)处理的HEI-OC1细胞中测量半胱天冬酶3-7活性。将原始半胱天冬酶读数归一化为用顺铂/DMSO处理的细胞和用1％DMSO处理的细胞中的半胱天冬酶活性。伊利司莫被示出在40μM的剂量下将半胱天冬酶活性降低至与对照细胞相当的水平。数据示出为平均值±标准误差(每个处理n＝3孔)。*P<0.05(单因素ANOVA)。B)通过神经丘计数毛细胞计数定量的用顺铂和巨大戟醇处理的斑马鱼中的最高保护水平。对SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC的定量揭示了用0.002、0.0183、0.165、1.48μM巨大戟醇预处理的斑马鱼HC中的顺铂损伤显著减少。
具体实施方式
通过参考本发明的以下详细描述和其中包括的实例可以更容易地理解本发明。在披露和描述本发明化合物、组合物、制品、系统、装置和/或方法之前，应当理解，除非另有说明，否则它们不限于具体的合成方法，或者除非另有说明，否则它们不限于特定的试剂，因此它们当然可变化。还应当理解，本文所用的术语仅用于描述特定方面的目的，而不旨在是限制性的。尽管可以在本发明的实践或测试中使用与本文所述的那些相似或等同的任何方法和材料，但现在描述示例性方法和材料。
虽然可以在特定的法定类别(诸如系统法定类别)中描述和要求保护本发明的各方面，但这仅是为了方便，并且本领域技术人员将理解，可以在任何法定类别中描述和要求保护本发明的每个方面。除非另有明确规定，否则决不旨在将本文阐述的任何方法或方面解释为要求以具体顺序执行其步骤。因此，当方法权利要求没有在权利要求或说明书中具体地规定步骤要被限于具体顺序时，决不旨在在任何方面推断顺序。这适用于任何可能的非明确解释基础，包括关于步骤或操作流程安排的逻辑问题、从语法组织或标点符号中得出的简单含义或者说明书中描述的方面的数量或类型。
在一个方面，化合物可以用作用于治疗和/或预防听力损失的疗法。在各个方面，本发明的化合物和组合物可以以药物组合物的形式施用，所述药物组合物根据预期的施用方法配制。本发明的化合物被定义为治疗方案或程序中的治疗活性剂，所述治疗活性剂旨在通过保护内耳细胞免于死亡来预防由于噪声或衰老引起的听力损失，以及预防由于化疗或抗生素诱发的听力损失引起的听力损失。治疗剂意指用于治疗或减轻疾病病症或病痛的化学物质。
现在参考图1和2A-B，基于来自药物筛选联系图和途径富集分析的数据集的比较来鉴定化合物，从而揭示化合物对抗听力损失的作用。开发该方法是为了从多样化的化学空间中获得药物候选物，从而涵盖大范围的生物途径，避免与关注先前报道的途径相关的偏见。所得化合物在用耳毒性损伤物(顺铂、噪声或抗生素暴露(顺铂(图5A/D)、噪声(图5B)和抗生素(图5C)))处理的多种细胞系或小鼠品系中的至少一种与用所述化合物中的一种处理的多种细胞系或小鼠品系中的至少一种之间的基因表达转录组学谱中表现出重叠。这里具体地，所寻求的数据集符合NIHL抗性小鼠品系和NIHL敏感性小鼠品系(129SvJ和CAST)。这里具体地且另外，所寻求的数据集符合顺铂抗性和敏感性癌细胞系、HEI-OC1细胞系以及用和不用顺铂处理的体内小鼠耳蜗单细胞RNA seq。这里同样，另外使用的是暴露于庆大霉素的新生小鼠柯蒂氏器(organ of Corti)的与抗生素处理相关损伤的转录组干扰。与这些数据集的计算结果重叠的化合物包括但不限于：氯硝柳胺、巨大戟醇和伊利司莫。
现在参考图2A-B，顺铂抗性癌细胞系的转录组分析揭示了与鉴定的药物有关的途径和共有的基因靶标。A)使用GSEA分析可从GEO数据库获得的合并的癌细胞系谱，以从KEGG数据库鉴定富集的分子途径。上调的途径以红色显示在左侧，而下调的途径以蓝色显示在右侧。圆圈大小与映射到其各自FDR值的基因数量相关。B)将来源于iLINCS数据库的每种药物的基因表达谱与通过GSEA鉴定的那些差异表达基因进行比较。然后使用相同方向上的重叠基因对药物进行分级。
氯硝柳胺是FDA以前批准的一种药物，自1982年以来广泛用于治疗绦虫感染，在预防性地施用时在斑马鱼和小鼠中对顺铂诱发的听力损失表现出极好的保护作用。氯硝柳胺还在斑马鱼中对红藻氨酸诱发的毛细胞损失以及在小鼠中对噪声诱发的听力损失显示出保护作用。总之，这些数据表明氯硝柳胺可以重新用作对抗顺铂和噪声损伤的耳保护剂。在一个方面，氯硝柳胺可以用作用于治疗和/或预防听力损失的疗法。在各个方面，本发明的化合物和组合物可以以药物组合物的形式施用，所述药物组合物根据预期的施用方法配制。本发明的化合物被定义为治疗方案或程序中的治疗活性剂，所述治疗活性剂旨在通过保护内耳细胞免于死亡来预防由于噪声或衰老引起的听力损失，以及预防由于化疗或抗生素诱发的听力损失引起的听力损失。治疗剂意指用于治疗或减轻疾病病症或病痛的化学物质。
揭示了氯硝柳胺可防止毛细胞凋亡。通过所呈现的模型和数据，氯硝柳胺被鉴定为可在动物中对抗毛细胞损失。模型揭示了耳保护化合物所必需的性质，诸如对抗毛细胞损失的高功效、相对低的毒性、缺乏金属螯合和血脑屏障渗透性。揭示了氯硝柳胺在用于证明针对毛细胞损失的保护作用的小鼠和斑马鱼模型中显示出具有高功效和高亲和力。斑马鱼的侧线神经丘是一种用于测试化合物在体内对抗顺铂毒性的保护性的有价值的模型，因为它们的HC被认为与哺乳动物内耳中的HC同源并且在体内很容易被药物接近。Teitz等人,J.Exp.Med.[实验医学杂志]2；215(4):1187-1203(2018)涉及HEI-OC1的小鼠模型已经显示可有效验证化合物对抗由于顺铂、噪声、抗生素和衰老引起的听力损失的治疗用途。Teitz等人,J.Exp.Med.[实验医学杂志]2；215(4):1187-1203(2018)。
本文所述的化合物和组合物可以使用一种或多种生理学上可接受的载体或赋形剂以常规方式配制。例如，药物组合物可以被配制用于局部或系统施用，例如通过滴入或注入耳中、吹入(诸如耳中)施用、静脉内、局部或口服施用。氯硝柳胺可以通过本领域已知的多种方法合成。Jayaprakash,V.等人,Medicinal Chemistry of Neglected and TropicalDiseases:Advances in the Design and Synthesis of Antimicrobial Agents[被忽视的热带疾病抗的药物化学：微生物剂的设计与合成进展].United States,CRC Press[美国CRC出版社],2019.第348页.RC961.M467。
用于施用的药物组合物的性质取决于施用方式并且可以容易地由本领域普通技术人员确定。在各个方面，药物组合物是无菌的或可灭菌的。本发明中表征的治疗组合物可以含有载体或赋形剂，其中许多是技术人员已知的。可以使用的赋形剂包括缓冲剂(例如，柠檬酸盐缓冲剂、磷酸盐缓冲剂、乙酸盐缓冲剂和碳酸氢盐缓冲剂)、氨基酸、尿素、醇类、抗坏血酸、磷脂、多肽(例如，血清白蛋白)、EDTA、氯化钠、脂质体、甘露醇、山梨糖醇、水和甘油。本发明表征的核酸、多肽、小分子和其他调节化合物可以通过任何标准施用途径施用。例如，施用可以是肠胃外、静脉内、皮下或口服。调节化合物可以根据相应的施用途径以各种方式配制。例如，可以制备液体溶液以用于通过滴入耳中施用、用于注射或用于摄取；可以制备凝胶或粉末以用于摄取或局部施加。用于制备此类配制品的方法是熟知的，并且可以在例如Remington's Pharmaceutical Sciences[雷明顿药物科学],第18版,Gennaro编辑,Mack Publishing Co.,Easton,PA[宾夕法尼亚州伊斯顿的马克出版公司]1990中找到。
在各个方面，所披露的药物组合物包括作为活性成分的所披露的化合物(包括其药学上可接受的盐)、药学上可接受的载体以及任选的其他治疗成分或佐剂。本发明组合物包括适合于口服、直肠、局部和肠胃外(包括皮下、肌内和静脉内)施用的那些，但是在任何给定的情况下最适合的途径将取决于特定的宿主以及活性成分被施用的病症的性质和严重性。药物组合物可以方便地以单位剂型呈现并且通过药学领域熟知的任何方法制备。
在各个方面，本发明的药物组合物可以包括药学上可接受的载体以及本发明的化合物或化合物的药学上可接受的盐。本发明的化合物或其药学上可接受的盐还可以与一种或多种其他治疗活性化合物组合包括在药物组合物中。
在制备用于口服剂型的组合物时，可以使用任何方便的药物介质。本发明的药物组合物包括作为活性成分的本发明的化合物(或其药学上可接受的盐)、药学上可接受的载体以及任选的一种或多种另外的治疗剂或佐剂。本发明组合物包括适合于口服、直肠、局部和肠胃外(包括皮下、肌内和静脉内)施用的组合物，但是在任何给定的情况下最适合的途径将取决于特定的宿主以及活性成分被施用的病症的性质和严重性。药物组合物可以方便地以单位剂型呈现并且通过药学领域熟知的任何方法制备。
适合于肠胃外施用的本发明的药物组合物可以被制备为活性化合物在水中的溶液或悬浮液。可以包括合适的表面活性剂，诸如羟丙基纤维素。也可以在甘油、液体聚乙二醇及其在油中的混合物中制备分散体。此外，可以包括防腐剂以防止微生物的有害生长。
适合于可注射用途的本发明的药物组合物包括无菌水性溶液或分散体。此外，组合物可以是无菌粉末的形式以用于临时制备此类无菌可注射溶液或分散体。在所有情况下，最终的可注射形式必须是无菌的并且必须是易于注射的有效流体。
以下内容旨在举例说明本领域普通技术人员如何制备和评价要求保护的方法、化合物、组合物、制品和/或装置，而不旨在限制本发明的范围。
在各个方面，这些化合物(诸如氯硝柳胺)可以与一种或多种其他药物以药盒的形式组合使用，以在已经已知其他药物会损伤听力时预防、控制、改善听力损害或降低听力损害的风险。
现在参考图3A和图3D-E，化合物保护小鼠内耳细胞系免受顺铂毒性的影响。将豪斯耳研所-柯蒂氏器1(House Ear Institute-Organ of Corti 1)(HEI-OC1)细胞(豪斯研究所(House Research Institute))在33℃和10％CO2下饲养在补充有10％胎牛血清的高葡萄糖杜尔贝科(Dulbecco)改良伊格尔(Eagle)培养基(美国生命技术公司(LifeTechnologies,USA))中，如先前所述(Kalinec等人,2003)。将细胞以8,000个细胞/孔接种在96孔板中并使其贴壁过夜。现在参考图3A，对于药物筛选，在接受顺铂前一小时，将HEI-OC1细胞用浓度在2nM至40μM范围内的30种药物候选物预处理。顺铂剂量(50μM)基于我们先前公布的剂量反应曲线。在Caspase-Glo 3/7测定(威斯康星州麦迪逊的普洛麦格公司(Promega,Madison,WI))之前，将细胞与顺铂和药物候选物一起再共同孵育19小时，如先前所示。另外，将仅有DMSO的细胞和肯帕罗酮(kenpaullone)处理的细胞用作阳性对照以验证我们的结果。将药物制剂中的DMSO浓度调节为0.1％v/v，并且经证实0.5％DMSO对细胞死亡动力学没有影响(Hall等人,2014)。测定的结果一式三份运行，并且归一化为仅含顺铂和仅含培养基的对照。将半胱天冬酶活性百分比用于确定每种化合物的相对保护作用。使用Cytation杂交多模式读数器(美国佛蒙特州威努斯基的伯腾公司(Biotek,Winooski,VT,USA))获得代表每个孔中半胱天冬酶活性的发光检测。使用半胱天冬酶3/7读数和下式计算细胞的保护百分比：
现在参考图3D-E，示出了氯硝柳胺在HEI-OC1细胞中在有和没有顺铂暴露的情况下的剂量反应曲线。使用半胱天冬酶-Glo 3/7测定测量半胱天冬酶活性，然后将结果计算为保护百分比，作为细胞存活/活力的指标。然后绘制每种化合物在测试剂量下的保护百分比以示出剂量反应曲线，并且计算IC50。用氯硝柳胺处理的HEI-OC1细胞在约4.4μM的剂量下达到0％半胱天冬酶活性或完全保护。另外，氯硝柳胺的计算IC50相对低，为280nM。氯硝柳胺的治疗窗较宽，在超过80％的测试剂量范围内显示出一定的保护水平。施用氯硝柳胺的小鼠在IACUC批准的最大IP剂量下没有表现出体重减轻或异常行为。与单独用顺铂处理的小鼠相比，用顺铂(30mg/kg/单次注射)和氯硝柳胺的组合注射的小鼠没有表现出一般毒性。在以下实例中，将氯硝柳胺(5-氯-N-(2-氯-4-硝基苯基)-2-羟基-苯甲酰胺，纯度≥95％)用于所有实验(美国开曼化学公司(Cayman Chemical,USA))。
将上述氯硝柳胺在HEI-OC1细胞中的保护作用与肯帕罗酮(一种已知的CDK2抑制剂，通过减少顺铂诱发的线粒体ROS产生来增强细胞存活)进行比较。肯帕罗酮在HEI-OC1细胞中的作用先前在Teitz等人,J.Exp.Med.[实验医学杂志]215(4):1187-1203(2018)中进行了表征。该比较证明，氯硝柳胺在HEI-OC1细胞中表现出与肯帕罗酮相当的对抗顺铂损伤的保护水平，以及比四种其他基准化合物(硫代硫酸钠、依布硒啉、地塞米松和N-乙酰半胱氨酸)更好的保护作用。
现在参考图3B-C和图3F，通过神经丘计数毛细胞计数定量的用顺铂和实验化合物处理的斑马鱼中的最高保护水平。斑马鱼(Danio rerio)实验幼体是在克雷顿大学(Creighton University)通过机构动物护理和使用委员会(Institutional Animal Careand Use Committee)批准的标准方法饲养的成鱼配对获得的。斑马鱼的侧线神经丘是一种用于测试化合物在体内对抗顺铂毒性的保护性的有价值的系统，因为它们的HC被认为与哺乳动物内耳中的HC同源并且很容易被药物接近。我们使用在HC中表达膜结合GFP的Tg(pou4f3:mGFP)。将实验鱼饲养在28.5℃下的E3培养基(5mM NaCl、0.17mM KCl、0.33mMCaCl2和0.33nM MgSO4，pH 7.2)中。在药物处理后和固定前将动物冷冻麻醉。检查的神经丘SO3和O1-2是颅骨系统的一部分，并且包括耳神经丘、中神经丘和盖神经丘。
对于筛选，将受精后天数(dpf)为5天的Tg(brn3c:GFP)幼体与0.002、0.018、0.165、1.48和13.3μM的41种药物候选物一起预孵育1小时，然后与400μM顺铂一起共同孵育4小时。随后，将动物转移到E3水中5小时，并且在4％多聚甲醛(PFA)中固定过夜(26)。将神经丘HC用抗奥托费林(anti-otoferlin)(HCS-1，DSHB)和抗GFP(NB100-1614，诺伟思生物公司(Novus Biologicals))免疫标记。将这两种标记用于检测和计数神经丘HC，以减少处理后丢失一些HC的机会，因为我们先前注意到与化合物一起孵育会影响GFP表达，使得在荧光显微镜下更难以检测。鉴定耳神经丘、中神经丘和盖神经丘，并且使用具有40倍油物镜的Zeiss AxioSkop 2荧光显微镜手动计数SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC。然后对化合物的效率和效力进行评价，其中评定最高的化合物在较低浓度下显示出较高的保护作用。
对SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC的定量揭示了用0.002μM氯硝柳胺预处理的斑马鱼HC中的顺铂损伤显著减少(每组n＝5至8，单因素ANOVA)。现在参考图3F，在斑马鱼中在多个剂量下对SO3(眶上线神经丘)和O1-2(耳线神经丘)处的HC的定量(每组n＝5至8，单因素ANOVA)。*P<0.05，数据示出为平均值±标准误差(每组n＝5)。*P<0.05，数据在所有图中示出为平均值±标准误差。
现在参考图3B，将数字归一化为仅用300μM顺铂(作为0％保护)或培养基(DMSO；作为100％保护)处理的斑马鱼的数字，以生成每种化合物的保护百分比。基于预防顺铂对神经丘HC的损伤的最有效剂量对药物候选物进行分级(图2B)。在测试的排名前42种化合物中，发现氯硝柳胺是最强效的药物候选物，在测试的最低浓度(0.002μM)下提供最高保护水平(约50％)(图3B)。在0.002μM下实现最大保护作用，表明这是适合于人类使用的浓度。该浓度比人类口服使用2,000mg后的Cmax(18μM)低约9000倍。
现在参考图3C，用氯硝柳胺处理的斑马鱼神经丘的荧光染色。氯硝柳胺被示出在用顺铂处理的斑马鱼中在0.002-13.3μM范围内的浓度下减少毛细胞损失。GFP显示为绿色，并且耳畸蛋白显示为红色(每个药物剂量n＝3，比例尺＝20μm)。
现在参考图4A-F，氯硝柳胺在FVB/NJ小鼠中减弱顺铂诱发的听力损失。小鼠：与小鼠一起使用的程序由克雷顿大学的机构动物护理和使用委员会(IACUC)批准。对于包括顺铂和噪声暴露实验在内的功能评估，使用从杰克逊实验室(Jackson Laboratory)(美国缅因州巴尔港(Bar Harbor,ME,USA))获得的5至7周龄FVB/NJ小鼠，在实验中混合雄性和雌性。对于顺铂和噪声研究，通过腹膜内(IP)注射用10mg/kg氯硝柳胺处理FVB/NJ小鼠。将氯硝柳胺溶解在1％DMSO的生理盐水(0.9％NaCl溶液)中，并且在注射前涡旋多次。在顺铂或噪声暴露前24小时开始处理，每天一次，再持续3天。以分为每天2个剂量的30mg/kg IP注射顺铂。在顺铂处理前和顺铂处理前后7天，一天两次皮下给予动物1mL温热无菌生理盐水，以防止脱水。
现在参考图4A，在顺铂暴露前2-3天和顺铂暴露后5天进行ABR测试。实验组包括：顺铂和1％DMSO、顺铂和氯硝柳胺、仅氯硝柳胺以及接受生理盐水的年龄匹配对照。对于噪声实验，在噪声暴露(下面描述的范例)之前2-3天进行听觉测试，在暴露后第1天进行听觉测试以监测暂时性阈移(TTS)，并且在暴露后第14天进行听觉测试以监测暂时性阈移(PTS)。实验组包括：噪声暴露和生理盐水、噪声暴露和氯硝柳胺、仅氯硝柳胺以及年龄匹配对照。在最终听觉功能测量之后，将小鼠安乐死，并且收集耳蜗用于形态学评估。基于FVB/NJ ABR/DPOAE阈值方差和功效分析的结果，在本研究中每组使用十只FVB/NJ小鼠(每种性别5只)。
为了探究药物在体内对哺乳动物听觉功能的影响，我们首先用四种药物候选物处理5-7周龄FVB/NJ小鼠：用氯硝柳胺(10mg/kg/天)、巨大戟醇(0.3mg/kg/天)、伊利司莫(5mg/kg/天)连续处理4天(IP)，以监测药物的安全性。所有测试剂量均基于先前公布的数据来确定，所述数据显示通过腹膜内(IP)注射的最大无毒剂量。在给定剂量下，没有小鼠表现出体重减轻减少或疼痛和痛苦的迹象。用氯硝柳胺以20mg/kg/天(IP)连续4天处理的小鼠表现出疼痛和痛苦的迹象，包括小鼠弓背和体重减轻20％-30％，因此，10mg/kg/天是本研究中使用的最大剂量。
测定16只小鼠的基线听觉脑干反应(ABR)，所述小鼠被分为接受巨大戟醇、伊利司莫和氯硝柳胺的3个组。小鼠接受上述药物剂量，然后在药物注射的第2天还接受30mg/kg顺铂(IP；每组4只小鼠)。每天监测显示接受巨大戟醇和伊利司莫的小鼠的体重减轻超过20％，并且我们观察到接受这些药物的小鼠在处理后第5天死亡率为40％-60％。单独用顺铂处理的小鼠表现出体重减轻10％-15％。然而，氯硝柳胺处理的小鼠表现出体重减轻小于10％，并且在顺铂注射后第5天的第二次ABR测试中全部存活。
现在参考图4B，顺铂、氯硝柳胺、对照和顺铂-氯硝柳胺处理的小鼠中在8至40kHz范围内的频率下畸变产物耳声发射(DPOAE)阈值的测量。在顺铂注射后第5天，对照组的DPOAE阈值显著低于顺铂处理组。双因素ANOVA和随后的事后Tukey检验的结果显示，在16kHz和32kHz下，顺铂-氯硝柳胺处理的小鼠和单独的顺铂组之间存在统计学显著差异。
现在参考图4C-D，在顺铂注射前和顺铂注射后第5天，在对照和氯硝柳胺处理的小鼠中测量8、16、32和40kHz下的平均波-1振幅。ABR波-1振幅代表耳蜗神经的综合活动。使用双因素ANOVA(组x频率)在基线ABR测量中比较组间85dB SPL刺激的振幅，未检测到组差异(P>0.05)。在顺铂注射后第5天，双因素ANOVA揭示了组x刺激水平存在显著的双因素交互作用，并且事后Tukey检验揭示了顺铂-氯硝柳胺处理的组在85dB SPL的所有测试频率下与仅有顺铂的组相比具有更高的振幅(图4C，D)。
现在参考图4E-2F，小鼠HC在32kHz(通过ABR测量示出的最受保护的频率区域)下的代表性样本(图4E)。HC计数的定量数据显示在图4F中。单因素ANOVA揭示了显著的组效应(P<0.05)。每个频率下的事后检验揭示了在30kHz区域处顺铂-氯硝柳胺组比顺铂组具有更多的HC存活。这些数据证实了氯硝柳胺保护OHC免受顺铂损伤。氯硝柳胺在斑马鱼中保护NMDA诱发的毛细胞损失。将N-甲基-d-天冬氨酸盐(NMDA)施加到斑马鱼神经丘HC也被用于模拟与噪声暴露相关的谷氨酸盐兴奋毒性(Katie S.Kindt和Lavinia Sheets,2018)。将斑马鱼暴露于300μM NMDA后HC计数的结果导致毛细胞损失。然而，与顺铂-DMSO暴露的斑马鱼幼体相比，在顺铂暴露之前用2nM和18nM氯硝柳胺预处理显著增加了HC存活。
现在参考图5，氯硝柳胺在体内在斑马鱼和FVB/NJ小鼠中对NIHL具有保护作用。CIHL和NIHL共享机械共性。现在参考图5A，为了测试氯硝柳胺是否保护HC免受兴奋毒性创伤，使用模拟噪声损伤的斑马鱼模型，将斑马鱼暴露于离子型谷氨酸盐受体激动剂N-甲基-D-天冬氨酸盐(NMDA)(先前显示它在有或没有氯硝柳胺的情况下在斑马鱼侧线器官中引起进行性HC损失(Sheets,2017))。将5-dpf幼体与300μM NMDA一起预孵育50分钟，然后与2nM和18.3nM的氯硝柳胺一起孵育2小时。
现在参考图5B-F，给小鼠注射10mg/kg氯硝柳胺，每次IP注射，每天一次，连续四天：噪声暴露前一天(105dB SPL下8-16kHz)、噪声暴露当天以及噪声暴露后两天。对照动物按相同的时间表接受媒介物注射。
现在参考图5B，通过从保留后阈值中减去暴露前来获得噪声诱发的ABR阈移。每天的双因素ANOVA揭示了在第1天组的主效应显著。Tukey多重比较检验揭示了在第14天氯硝柳胺-噪声暴露组在8kHz至63kHz的所有测试频率内均具有比噪声暴露组低的阈移。
现在参考图5C，在小鼠中在10至80dB SPL范围内的f2频率下测量DPOAE振幅。对于噪声-氯硝柳胺组，在噪声暴露后第15天，DPOAE振幅显著高于噪声-盐水组。使用双因素ANOVA(组x频率)来比较暴露前振幅与第15天振幅。ANOVA揭示了没有显著的双因素组x频率相互作用，表明OHC功能在所有组之间是相似的，并且氯硝柳胺对抗噪声的保护作用可能是由于预防突触病。
现在参考图5D，在噪声暴露后第15天测量10、20、28.3和40kHz下的平均波-I振幅。使用双因素ANOVA(组x刺激水平)在噪声前测试中比较组间10-90dB SPL刺激强度的振幅，未检测到组差异。在第15天，仅使用60-90dB SPL刺激水平，因为许多受试者在60dB SPL以下没有反应。双因素ANOVA揭示了组x刺激水平的显著相互作用(P<0.001)。Tukey事后揭示了与噪声暴露组相比，氯硝柳胺-噪声组在80和90dB SPL下具有较高的振幅(图5D)。波-I振幅的结果显示，噪声-氯硝柳胺组的耳蜗神经活性与年龄匹配对照组相当，并且这些组之间没有统计学显著差异。
现在参考图5E以评估对缎带突触的保护，用CtBP2(突触缎带体中最丰富的蛋白质之一)对耳蜗样本进行免疫染色(Kujawa SG等人2006)。显示了16kHz下小鼠缎带突触的代表性样本。现在参考图5F，缎带突触的外毛细胞计数。16kHz频率下的独立样本t检验揭示了氯硝柳胺-噪声组比盐水-噪声组具有更多的突触缎带存活。在同一耳蜗中，还对OHC进行计数。32kHz下的独立样本t检验揭示了与盐水-噪声处理的动物相比，氯硝柳胺-噪声组中存活的OHC的比例相似。使用16kHz的频率区域进行CtbP2缎带计数，因为已经表明缎带在该频率区域中更丰富。
现在参考图6A-B，将5dpf斑马鱼与媒介物(DMSO)、单独的浓度为300μM的顺铂、顺铂和依泽替米贝(0.002μM至13.3μM)、顺铂和氯硝柳胺(0.02nM至18.3nM)或者顺铂和组合依泽替米贝/氯硝柳胺一起孵育。6小时后，将动物转移到淡水中1小时，然后处死动物并且如上所述处理以用于免疫组织化学和HC计数。为了进一步阐明氯硝柳胺是否与Nrf2活化剂协同作用以保护斑马鱼HC免受顺铂损伤，我们在存在氯硝柳胺和Nrf2活化剂依泽替米贝的情况下测试了HC损伤的程度。
现在参考图6A，氯硝柳胺和依泽替米贝显示出协同/累加耳保护作用。三维等高线图(A)示出了用不同浓度的氯硝柳胺和依泽替米贝处理的斑马鱼中神经丘毛细胞保护的剂量反应，所述图被绘制成协同作用分布。另外，当0.66nM氯硝柳胺与1.48μM依泽替米贝(每组n＝5)组合时，针对每个剂量组合计算的Loewe协同作用和拮抗作用得分(B)指示最高的协同活性。显示协同作用的其他剂量组合被示出在深蓝色框中。得分为0和1的剂量组合显示出累加效应。*P<5x10-2；相对于对照鱼，**P<10-3，***P<10-4，通过Combenefit软件44运行单样本t检验。数据示出为平均值±标准偏差。
单独的依泽替米贝在1.48μM下显示出较高的每个神经丘HC计数，而单独的氯硝柳胺在浓度高于2nM时显示较高的计数。然而，组合两种化合物，氯硝柳胺和依泽替米贝两者在低得多的剂量范围内表现出显著更高的毛细胞计数(每组n＝5，单因素ANOVA)。将斑马鱼用氯硝柳胺(.02-18.3nM范围内)和EZ(.0183-13.3μM范围内)的组合处理。
除了图6A-B，但未示出，将5dpf斑马鱼与媒介物、氯硝柳胺(2nM至1.48μM)和作为阳性对照的nrf2途径活化剂马来酸二甲酯(DEM)一起孵育6小时，以便评价氯硝柳胺对ggcsh(nrf2下游靶标)的作用。Ggcsh先前被验证为斑马鱼中的Nrf2下游靶标(Sheets,2017)。孵育后，从整条鱼中分离出总RNA并且进行处理以测量nrf2下游基因ggcsh的诱导表达。ggcsh的表达在用0.002-1.48μM范围内的氯硝柳胺处理的斑马鱼中显著降低(每组n＝5，单因素ANOVA)。另外，制备Nrf2a吗啉环寡核苷酸，然后将斑马鱼吗啉突变体与顺铂和/或氯硝柳胺一起孵育。给斑马鱼卵注射4.5ng杂乱吗啉环寡核苷酸或nrf2a吗啉环寡核苷酸(5'-CATTTCAATCTCCATCATGTCTCAG SEQ NO:1)。在3dpf，将未注射的吗啉突变体动物暴露于媒介物、顺铂(300μM)、顺铂+氯硝柳胺18.3nM或者单独的氯硝柳胺6小时。恢复1小时后，固定动物并处理以用于免疫组织化学。由于缺乏适当的抗体来检测斑马鱼中的Nrf2蛋白，通过分析谷胱甘肽S-转移酶P1(gstp1)(一种下游靶标)的表达来证实Nrf2a KD。斑马鱼吗啉环寡核苷酸证明nrf2a敲低降低了氯硝柳胺的耳保护作用。未注射的杂乱对照斑马鱼在用顺铂和氯硝柳胺共同处理后显示出显著更高的毛细胞数，而nrf2a敲低斑马鱼显示出与仅用顺铂处理的斑马鱼相似的毛细胞计数(每组n＝5，单因素ANOVA)。这些结果证明氯硝柳胺对抗顺铂耳毒性的保护作用在斑马鱼中需要Nrf2。
现在参考图7，HPLC分析证明氯硝柳胺与顺铂之间没有相互作用：通过化学结合的药物-药物相互作用会对癌症治疗产生负面影响。氯硝柳胺对抗CIHL的保护作用的简单解释是它直接使顺铂失活，类似于临床试验中的几种耳保护剂(STS、依布硒啉等)。为了探究氯硝柳胺与顺铂之间的任何可能的相互作用，我们开发了体外HPLC方法。该方法可使用以下项：HPLC：日本岛津公司(Shimadzu Prominence)-i LC-2030C，柱：安捷伦(Agilent)Eclipse Plus C18，PN-959961-902，5％ACN，95％水：0-2min；ACN连续增加至95％：2-12min；在95％ACN下保持：12-17min；ACN连续降低至5％：17-20min，流速：1mL/min；温度37℃，运行时间：20min。该方法的其他部分可使用1mg/ml的储备溶液(在合适的溶剂中制备并混合以在最终注射溶液中产生1:1和1:10的顺铂和氯硝柳胺的比例)以及纯顺铂和氯硝柳胺。结果表明在几种剂量比的氯硝柳胺和顺铂下氯硝柳胺与顺铂之间没有相互作用(没有第三峰)。我们的体外结果与其在RCC异种移植模型中与顺铂的协同相互作用及其对抗噪声损伤的保护作用一致。
现在参考图8，在有或没有顺铂和10nM氯硝柳胺的情况下孵育的非小细胞肺癌细胞系SHP77和小细胞肺癌细胞系A549的体外模型。借助于Matrigel将细胞饲养在培养物中，如先前在Kelley和Driver,Curr.Protoc.Neurosci.[神经科学实验手册]第(4)章；第(4)单元；34.1-10(2010)中所述。在细胞在培养物中1天后，可添加具有或不具有测试化合物的生长培养基DMEM(12430-054；GIB CO生命科技公司(GIB CO Life Technologies)，含1％FBS[16000-044；GIB CO生命科技公司]和50μg/ml氨苄青霉素)以在37℃下在5％Co2中预孵育1小时，随后可在生长培养基中有或没有测试化合物的情况下在37℃下与50μM顺铂(479306；西格玛奥德里奇公司(Sigma-Aldrich))一起孵育持续24小时。50μM的顺铂浓度可用于外植体测定，因为其一致地显示24小时后小鼠耳蜗中外毛细胞减少约40％。可将耳蜗固定在4％PFA中并且用Alex Fluor 568鬼笔环肽对肌动蛋白进行染色，以确定HC的活力。也可通过DAPI、FM1-43染料摄取和已知HC标记(包括小清蛋白和肌球蛋白7a)的免疫组织化学染色对耳蜗进行染色。可通过共聚焦显微镜对耳蜗进行成像。可以拍摄中圈的两个160μm区域，并且可以计算完整HC的数量。
为了比较氯硝柳胺的外植体测定，可在与上述类似的程序下进行测试已知的基准化合物肯帕罗酮。可在比较测定中使用以下修改：(1)过滤器(Millicell，PICM03050；密理博公司(Millipore))代替6孔培养板中的Matrigel，在过滤器内部和外部均具有1ml培养基溶液；(2)P3 FVB小鼠品系；以及(3)基于顺铂在50、100、150和200μM下的剂量反应，150μM的顺铂剂量在24小时内始终显示出约40％的外毛细胞损失。Teitz等人,J.Exp.Med.[实验医学杂志]215(4):1187-1203(2018)。氯硝柳胺和顺铂共同处理可进一步通过在不同时间段用不同浓度的顺铂处理外植体来表征。例如，可在有或没有测试化合物的情况下使用150μM顺铂，并且可在孵育48小时后进行上述测量。
可使用顺铂洗脱实验来证实CIHL和测试化合物在减轻这种反应中的作用。例如，可在孵育90分钟(IP注射后顺铂在体内留在内耳中的估计时间)后除去各种浓度的顺铂，并且可在不同的孵育时间段后进行上述测量。
现在参考图9A，伊利司莫防止CIHL。使用半胱天冬酶-Glo 3/7测定测量半胱天冬酶活性，然后将结果计算为保护百分比，作为细胞存活/活力的指标。然后绘制每种化合物在测试剂量下的保护百分比以示出剂量反应曲线，并且计算IC50。用伊利司莫处理的HEI-OC1细胞在约40μM的剂量下达到20％半胱天冬酶活性。另外，氯硝柳胺的计算IC50相对低，为0.02μM(图9A)。
现在参考图9B，伊利司莫在斑马鱼中在多个剂量下防止顺铂耳毒性(每组n＝5-8，单因素ANOVA)。*P<0.05，数据示出为平均值±标准误差(每组n＝5)。*P<0.05，数据在所有图中示出为平均值±标准误差。将斑马鱼与0.002、0.018、0.165、1.48和13.3μM的伊利司莫一起孵育1小时，然后与400μM顺铂共同孵育4小时。在0.165、1.48和13.3μM的剂量下，伊利司莫显示出对CIHL的保护作用。
现在参考图10A，巨大戟醇防止CIHL。使用半胱天冬酶-Glo 3/7测定测量半胱天冬酶活性，然后将结果计算为保护百分比，作为细胞存活/活力的指标。然后绘制每种化合物在测试剂量下的保护百分比以示出剂量反应曲线，并且计算IC50。用巨大戟醇处理的HEI-OC1细胞在约40μM的剂量下达到30％半胱天冬酶活性。另外，巨大戟醇的计算IC50相对低，为1.54μM(图10A)。
现在参考图10B，巨大戟醇在斑马鱼中在多个剂量下防止顺铂耳毒性(每组n＝5-8，单因素ANOVA)。*P<0.05，数据示出为平均值±标准误差(每组n＝5)。*P<0.05，数据在所有图中示出为平均值±标准误差。将斑马鱼与0.002、0.018、0.165、1.48和13.3μM的巨大戟醇一起孵育1小时，然后与400μM顺铂共同孵育4小时。在0.002、0.0183、0.165和1.48μM的剂量下，巨大戟醇显示出对CIHL的保护作用。
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虽然已经参照说明的实施例的细节描述了本发明，但是这些细节并不旨在限制如所附权利要求中限定的本发明的范围。其中要求保护专有所有权或特权的本发明的实施例定义如下：
序列表
<110> 听治疗有限责任公司（Ting Therapeutics）
<120> 用于预防和治疗听力损失的方法
<130> 30006.0005A
<150> 63/050,568
<151> 2020-07-10
<160> 1
<170> PatentIn 3.5版
<210> 1
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 合成斑马鱼（Danio rerio）
<400> 1
catttcaatc tccatcatgt ctcag 25
Claims (15)
1.一种用于通过保护内耳细胞免于死亡来预防或治疗听力损失的组合物，其中所述组合物是有效量的：活性剂，其中所述活性剂选自由以下组成的组：氯硝柳胺、巨大戟醇和伊利司莫或其药学上可接受的盐。
2.如权利要求1所述的组合物，所述组合物用于通过保护内耳细胞免于死亡来预防由噪声引起的听力损失。
3.如权利要求1所述的组合物，所述组合物用于预防由化疗诱发的听力损失引起的听力损失。
4.如权利要求1所述的组合物，所述组合物用于预防由抗生素治疗引起的听力损失。
5.如权利要求1所述的组合物，所述组合物包含氯硝柳胺和依泽替米贝的协同组合。
6.如权利要求1所述的组合物，其中所述活性剂是氯硝柳胺。
7.一种药盒，所述药盒包含：活性剂，其中所述活性剂选自由以下组成的组：氯硝柳胺、巨大戟醇和伊利司莫或其药学上可接受的盐；以及以下项中的一种或多种：
(A)至少一种化学治疗剂；(B)至少一种抗生素；(C)用于预防听力损害的说明书。
8.如权利要求7所述的药盒，其中所述活性剂是氯硝柳胺。
9.如权利要求7所述的药盒，其中所述活性剂是巨大戟醇。
10.如权利要求7所述的药盒，其中所述活性剂是伊利司莫。
11.一种预防或治疗听力损失的方法，所述方法包括：
向有需要的动物施用有效量的含有治疗活性剂的药物组合物，其中所述治疗活性剂选自由以下组成的组：氯硝柳胺、巨大戟醇和伊利司莫。
12.如权利要求11所述的方法，所述方法包括保护内耳细胞免受由化学治疗剂引起的死亡。
13.如权利要求11所述的方法，所述方法包括保护内耳细胞免受由噪声引起的死亡，其中所述活性剂是氯硝柳胺。
14.如权利要求12所述的方法，其中所述化学治疗剂是顺铂。
15.如权利要求11所述的方法，所述方法包括保护内耳细胞免受由抗生素治疗引起的死亡。
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