CN116911513A - 硝唑尼特及其体内代谢物替唑尼特在制备抗心衰药物中的应用 - Google Patents
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Abstract
本发明公开了硝唑尼特及其体内代谢物替唑尼特在制备抗心衰药物中的应用，本发明通过研究发现硝唑尼特(式I)具有抑制高脂饲料联合L‑NAME诱导小鼠心衰的作用，硝唑尼特可抑制心脏肥大、心脏纤维化，显著降低模型小鼠血压，改善小鼠运动耐力，改善小鼠心脏舒张功能。硝唑尼特属于前药，吸收后迅速代谢为代谢产物替唑尼特(式II)发挥体内作用。因此，硝唑尼特及其体内代谢物替唑尼特可以应用在制备抗心衰(包括射血分数下降型心衰和射血分数保留型心衰)药物中。本发明为心衰治疗提供了新的有效的技术手段，具有广阔的应用前景。
Description
技术领域
本发明涉及药物的应用，特别涉及硝唑尼特及其体内代谢物替唑尼特在制备抗心衰药物中的应用。
背景技术
心力衰竭(心衰)是心脏结构、功能异常而导致心脏泵血功能失代偿的一种临床综合征，心衰总体分为射血分数下降型心衰(HFrEF，heart failure with reduced ejectionfraction)和射血分数保留型心衰(HFpEF，heart failure with preserved ejectionfraction)。心衰患者5年死亡风险高达50％，危害严重，是当前心血管领域的世界难题，亟待发现新的治疗药物。
硝唑尼特是一种抗寄生虫药，临床用于隐孢子虫和肠贾第鞭毛虫引起的腹泻，其抗寄生虫作用与抑制寄生虫敏感的厌氧能量代谢有关，因此对哺乳动物安全性高。硝唑尼特口服吸收好，不良反应少，体内吸收后完全代谢为替唑尼特发挥作用，原型药硝唑尼特在体内无法检出。
发明内容
发明目的：针对现有技术存在的问题，本发明提供硝唑尼特(Nitazoxanide，邻[N-(5-硝基噻唑-2-基)氨基甲酰]苯酚乙酸酯)或者替唑尼特(Tizoxanide)在制备抗心衰药物中的应用，用于开发新型抗心衰药物，解决现有治疗药物缺乏的问题。
本发明还提供一种预防和/或治疗心衰的药物(包括射血分数下降型心衰和射血分数保留型心衰)组合物。
技术方案：为了实现以上技术目的，本发明提供硝唑尼特及其药学上可接受的盐在制备抗心衰药物中的应用；其中硝唑尼特的化学结构式如式I所示：
本发明所述的硝唑尼特的体内代谢物替唑尼特及其药学上可接受的盐在制备抗心衰中的应用；其中替唑尼特的化学结构式如式II所示：
其中，所述心衰包括射血分数下降型心衰和射血分数保留型心衰。
其中，所述化合物硝唑尼特或替唑尼特可作为药用盐使用或者溶剂化物组成的药物组合物。
其中，所述药用盐为化合物与金属离子或药学上可接受的胺或铵离子形成的盐。
其中，所述金属离子包括钠、钾或钙离子，所述胺包括乙二胺或氨丁三醇。
本发明所述的预防和/或治疗心衰的药物组合物，其含有所述的硝唑尼特或替唑尼特或其药学上可接受的盐或溶剂化物作为活性成分和药学上可接受的载体。
其中，所述化合物与载体的组合物为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
本发明通过建立高脂饲料(high fat diet,HFD)联合L-NAME(eNOS抑制剂)诱导小鼠心衰模型(Schiattarella GG,et al.Nitrosative stress drives heart failurewith preserved ejection fraction.Nature.2019；568(7752):351-6.)，口服途径给予硝唑尼特，发现硝唑尼特显著抑制模型小鼠的心脏肥大和心脏纤维化，改善模型小鼠的心脏舒张功能，提高模型小鼠运动耐力，降低模型小鼠血压。硝唑尼特口服在体内完全代谢为代谢产物替唑尼特(Tizoxanide)，因此，硝唑尼特的改善心衰作用是来自替唑尼特的作用。因此本发明进一步提出硝唑尼特和替唑尼特及其药学上可接受的盐或以其为基础进行改造后的化合物在制备抗心衰药物中的应用。
有益效果：与现有技术相比，本发明具有如下优点：
本发明首次提出了硝唑尼特及其体内代谢物替唑尼特在制备抗心衰药物(包括射血分数下降型心衰和射血分数保留型心衰)中的应用，发现新型抗心衰药物。本发明中使用高脂饲料(high fat diet,HFD)联合L-NAME(eNOS抑制剂)诱导小鼠心衰模型(Schiattarella GG,et al.Nitrosative stress drives heart failure withpreserved ejection fraction.Nature.2019；568(7752):351-6.)，证明硝唑尼特体内用药对心衰的改善作用。硝唑尼特本身就是临床用药，口服吸收好，不良反应少，本发明的提出为心衰治疗提供了新的有效的技术手段，具有广阔的应用前景。
附图说明：
图1.硝唑尼特改善HFD联合L-NAME诱导的小鼠心脏肥大、心脏纤维化和舒张功能障碍。(A)实验设计示意图；(B)心脏的代表照片；(C)心脏重量和心脏重量指数统计结果；n＝15；(D)心脏WGA染色代表照片及心肌细胞横断面积比较，每组7个心脏；(E)心脏Masson染色的代表照片及纤维化面积统计结果，每组7个心脏；(F)超声心动数据E/A、射血分数(EF％)和短轴缩短率(FS％)统计结果，数据以mean±SEM表示，n＝15，**P<0.01vs.ND.#P<0.05vs.HFD+L-NAME。ND(normal diet),正常饲料；HFD(high fat diet),高脂饲料；Nit(nitazoxanide)，硝唑尼特。
图2.硝唑尼特抑制HFD联合L-NAME诱导的小鼠血压升高。(A)硝唑尼特给药10周小鼠尾动脉血压统计结果；(B)硝唑尼特给药26周小鼠尾动脉血压统计结果；数据以mean±SEM表示，每组n＝15，**P<0.01vs.ND.##P<0.01vs.HFD+L-NAME.SBP：systolic bloodpressure，收缩压；DBP：diastolic blood pressure，舒张压；MBP：mean blood pressure，平均压；ND(normal diet)，正常饲料；HFD(high fat diet)，高脂饲料；Nit(nitazoxanide)，硝唑尼特。
图3.硝唑尼特改善HFD联合L-NAME诱导的小鼠运动耐力下降。(A)硝唑尼特给药16周小鼠跑步距离统计结果；(B)硝唑尼特给药27周小鼠跑步距离统计结果；数据以mean±SEM表示，每组n＝15，**P<0.01vs.ND；##P<0.01vs.HFD+L-NAME；ND(normal diet)，正常饲料；HFD(high fat diet)，高脂饲料；Nit(nitazoxanide)，硝唑尼特。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例1
硝唑尼特对高脂饲料(high fat diet,HFD)联合L-NAME(eNOS抑制剂)诱导的小鼠心衰的作用。
1材料和方法
1.1实验动物：
雄性C57BL/6N小鼠，7周龄，体重：18-22g；购自江苏集萃药康生物科技股份有限公司。
1.2饲料：
正常标准饲料(Normal Diet，M10110C2)购自上海博派生物科技有限公司。
高脂饲料(High Fat Diet，M22022204)购自上海博派生物科技有限公司。
1.3试剂：
硝唑尼特(Nitazoxanide)：上海阿达玛斯试剂，CAS号：55981-09-4。
羧甲基纤维素钠(CMC-Na)：沪试，CAS号：9004-32-41.4
实验方法:
采用7周龄雄性C57BL/6N小鼠按照标准饲养环境，饲养室内相对湿度55％～60％，温度维持在24±1℃，12小时昼夜交替，自由采食。适应性喂养7天后，按体重分为3组。ND(normal diet)组，普通饲料喂养，普通饲料脂肪含量为10％。HFD+L-NAME组，高脂饲(highfat diet,HFD)料喂养，高脂饲料脂肪含量为60％，每千克饲料中添加750毫克L-NAME，每日灌胃给予对照溶剂。HFD+L-NAME+Nit组，高脂饲料喂养，高脂饲料脂肪含量为60％，每千克饲料中添加750毫克L-NAME，每日灌胃给予硝唑尼特(150mg/kg)。记录各组小鼠体重和采食量，喂养周期32周。取材前进行心脏超声检测、血压测量和运动耐力测试等。动物处死后，收集心脏样本进行检测。
2、结果
高脂饲料(high fat diet,HFD)联合L-NAME(eNOS抑制剂)诱导的小鼠心衰模型(Schiattarella GG,et al.Nitrosative stress drives heart failure withpreserved ejection fraction.Nature.2019；568(7752):351-6.)，可以模拟临床心衰病理特征。
本实施例的实验中硝唑尼特体内吸收后完全代谢为替唑尼特发挥作用，原型药硝唑尼特在体内无法检出，因此动物给药不需进行替唑尼特实验。
32周取材结果显示HFD+L-NAME组小鼠表现明显心脏肥大和心脏间质纤维化，HFD+L-NAME+Nit组中，硝唑尼特(150mg/kg)给药具有抑制心脏肥大和心脏纤维化的作用(附图-1A-1E)；超声心动图结果显示HFD+L-NAME组小鼠E/A值升高，而HFD+L-NAME+Nit组中，硝唑尼特(150mg/kg)给药抑制了小鼠E/A值的升高(附图1F)，说明硝唑尼特可改善HFD+L-NAME诱导的心脏僵硬；分别在第10周、26周测定了小鼠收缩压、舒张压和平均动脉压，结果显示硝唑尼特(150mg/kg)给药可显著降低HFD+L-NAME诱导的小鼠收缩压、舒张压和平均动脉压升高(附图2)；分别在第16周、27周测定了小鼠跑步耐力，结果显示硝唑尼特(150mg/kg)给药可显著改善HFD+L-NAME诱导的小鼠运动耐力下降(附图3)。
以上结果说明硝唑尼特口服途径给药(150mg/kg)，具有抑制高脂饲养(high fatdiet,HFD)联合L-NAME(eNOS抑制剂)诱导的小鼠心衰的作用，硝唑尼特可抑制模型小鼠心脏肥大、心脏纤维化，显著降低心衰小鼠血压，改善小鼠运动耐力，改善小鼠心脏舒张功能。
Claims (8)
1.硝唑尼特及其药学上可接受的盐在制备抗心衰药物中的应用，其中硝唑尼特的化学结构式如式I所示：
2.替唑尼特及其药学上可接受的盐在制备抗心衰药物中的应用，其中替唑尼特的化学结构式如式II所示：
3.根据权利要求1或2所述的应用，其特征在于，所述心衰包括射血分数下降型心衰和射血分数保留型心衰。
4.根据权利要求1或2所述的应用，其特征在于，所述化合物硝唑尼特或替唑尼特可作为药用盐使用或者溶剂化物组成的药物组合物。
5.根据权利要求4所述的应用，其特征在于，所述药用盐为化合物与金属离子或药学上可接受的胺或铵离子形成的盐。
6.根据权利要求5所述的应用，其特征在于，所述金属离子包括钠、钾或钙离子，所述胺包括乙二胺或氨丁三醇。
7.一种预防和/或治疗心衰的药物组合物，其含有权利要求1所述的硝唑尼特或权利要求2所述的替唑尼特或其药学上可接受的盐或溶剂化物作为活性成分和药学上可接受的载体。
8.根据权利要求7所述的药物组合物，所述化合物与载体的组合物为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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