CN110403949A - 红景天苷在制备用于治疗肺纤维化疾病药物中的应用 - Google Patents
红景天苷在制备用于治疗肺纤维化疾病药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种红景天苷在制备用于治疗肺纤维化疾病的药物中的应用，其中，红景天苷的结构式为：本发明所述的红景天苷对肺纤维化有良好的功效，无不良反应，可减缓博莱霉素诱导的小鼠肺纤维化，在治疗、缓解或改善肺纤维化疾病方面具有良好的应用前景。
Description
技术领域
本发明涉及药物化学领域，具体地，涉及一种红景天苷在制备用于治疗肺纤维化疾病药物中的应用。
背景技术
肺纤维化(pulmonaryfibrosis，PF)是许多病因各异的肺间质疾病的终末期临床表现，是以肺泡持续性损伤、成纤维细胞增殖及大量细胞外基质(extracellularmatrix，ECM)沉积为特征，从而导致肺泡和肺间质出现不同程度的炎症和纤维化，进而导致肺结构破坏和呼吸衰竭的一种疾病，所以也称间质性肺疾病(interstitial lung disease，ILD)或弥漫性实质性肺疾病(diffuse parenchymal lung disease，DPLD)。
特发性肺纤维化(idiopathic pulmonary fibrosis，IPF)是最常见的弥漫性肺纤维化疾病，临床上表现为进行性呼吸困难伴刺激性干咳，病情常持续进展，至今病因不明、发病机制不清、缺乏有效的治疗手段，中位生存期仅2-3年。该病好发于50～70岁，特别是有过吸烟史的人群，男性高于女性。随着大气的污染、环境的恶化，流行病学资料报告显示近年来发病率有上升趋势。目前统计IPF的发病率为6.8-16.3/10万，患病率为14-42.7/10万，近年来患病人群呈不断上升趋势。患病人数全球保守估计5000万，预计我国有IPF患者60万左右。每年IPF死亡病例达40000例。
近年来，针对IPF的临床试验药物包括糖皮质激素、秋水仙碱、环孢素A、乙酰半胱胺酸、波生坦、依那西普、抗凝剂、尼达尼布、吡非尼酮及伊马替尼等等，但IPF患者对激素和各种药物的治疗反应普遍较差，目前尚无能确切改善患者最终预后的药物，美国胸科医师学会(ATS)的IPF指南中指出，IPF病人到病情晚期唯一值得推荐且有效的治疗便为肺移植，但由于手术治疗费用昂贵、技术程度复杂、供者肺组织来源紧缺、器官移植伦理学及医疗法律法规不健全等因素的存在，限制了肺移植作为IPF患者治疗方法在我国的开展。
目前针对该病的上市药物只有两个，分别是罗氏的吡非尼酮和勃林格殷格翰的尼达尼布，但都不能有效提高患者生存期，治疗费用高，且临床需求远未得到满足。因此阐明肺纤维化的发生发展机制，探索新的潜在的药物靶点，开发出针对肺纤维化的疗效确认、相对安全、价格合理的药物具有重要的社会意义和医学意义。
红景天为景天科红景天属草本或亚灌木植物,多生长在我国西藏和东北地区的高海拔地段,是一类珍贵的天然植物药材。红景天在国内应用较早且广泛被应用,在中医《本草纲目》与藏医《四部医典》中均有记载,常作为滋补品与药品使用,具有增强人体免疫力、抗衰老、抗辐射、保护心脑血管等功效，还常用来防止高原反应，并是藏族民间医学的止血药。
红景天苷是由红景天干燥根及根茎或干燥全草中提取的一种酚类糖苷化合物,是红景天的主要活性成分，极易溶于水,易溶于甲醇,溶于乙醇,难溶于乙醚。药理研究表明,红景天苷有降血脂、血糖,提高体力、脑力、记忆力、注意力和免疫力的功效,还有抗衰老、缺氧、寒冷、肿瘤、肾损害、骨质疏松、肝纤维化、微波辐射等作用,可用于治疗糖尿病、高血压、肺心病、冠心病、风湿等多种慢性疾病。除上述作用外，研究发现红景天苷有益于改善肺损伤。据报道，红景天苷的预处理可减轻脂多糖或百草枯造成的急性肺损伤，还能减轻慢性缺氧诱发的肺动脉高压。截至目前，关于红景天苷减缓特发性肺纤维化的相关报道较为罕见。
发明内容
针对以上问题，本发明提供了一种红景天苷在制备用于治疗肺纤维化疾病的药物中的应用，其中，所述红景天苷的结构如下式(I)所示：
在以上应用中，所述肺纤维化疾病为特发性肺纤维化疾病。
本发明还提供了一种治疗肺纤维化疾病的药物，包括：：红景天苷在药学上可接受的盐、酯、水合物以及辅料。
在以上药物中，所述肺纤维化疾病为特发性肺纤维化疾病。
在以上药物中，所述鞣花酸在药学上可接受的盐包括有机盐和无机盐。
在以上药物中，所述有机盐包括甲磺酸盐、甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、富马酸盐、柠檬酸盐、苯磺酸盐、对甲基苯磺酸盐、萘磺酸盐、乳酸盐或苯甲酸盐；所述无机盐包括盐酸盐、氢溴酸盐、硫酸盐或磷酸盐。
在以上药物中，所述药物的剂型选自片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂、酒剂、酊剂、露剂、膜剂中一种或几种的组合。
在以上药物中，所述药物的给药方式包括口服、注射、植入、外用、喷雾、吸入中一种或几种的组合。
本发明的研究表明，红景天苷对肺纤维化有良好的功效，无不良反应，可减缓博莱霉素诱导的小鼠肺纤维化，在治疗、缓解或改善肺纤维化疾病方面具有良好的应用前景。
附图说明
图1是各组小鼠支气管肺泡灌洗液(BALF)炎症细胞总数统计结果；
图2是各组小鼠支气管肺泡灌洗液(BALF)中性粒细胞数量统计结果；
图3是各组小鼠支气管肺泡灌洗液(BALF)淋巴细胞数量统计结果；
图4是各组小鼠支气管肺泡灌洗液(BALF)巨噬细胞数量统计结果；
图5是正常组小鼠BALF中总细胞H&E(苏木素伊红)染色结果；
图6是模型组小鼠BALF中总细胞H&E(苏木素伊红)染色结果；
图7是红景天苷治疗组小鼠BALF中总细胞H&E(苏木素伊红)染色结果。
具体实施方式
除有定义外，以下实施例中所用的技术术语具有与本发明所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂，如无特殊说明，均为常规生化试剂；所述实验方法，如无特殊说明，均为常规方法。
下面结合实施例及附图来详细说明本发明。
本发明提供了一种红景天苷在制备用于治疗肺纤维化疾病的药物中的应用，其中，红景天苷的结构如下式(I)所示：
动物实验
红景天苷对博莱霉素诱导的小鼠特发性肺纤维化的影响
肺纤维化动物模型制备：取C57BL/6J，(周龄8-10周)野生型小鼠，将质量分数为10％水合氯醛以0.5mL/100g(体重)给予小鼠腹腔注射麻醉，气管内有创注射2U/Kg博莱霉素。具体实施方式如下：麻醉小鼠后称重记录，将小鼠固定于操作台，颈部用70％酒精消毒，用手术刀在小鼠颈部垂直划开大约1cm长创口，利用显微镊分离组织暴露气管，将注射器经气管软骨环间隙朝向心端刺入气管，然后按2U/kg的计量缓慢注入与其体重相适应体积的博莱霉素生理盐水溶液，立即将动物直立并左右旋转，使药液在肺内均匀分布。
分组情况：正常组(氯化钠组)注射同体积的生理盐水(质量分数为0.9％NaCL)；模型组按照以上方式造模并以相应溶剂水在博莱霉素处理第1至7天时进行滴鼻；红景天苷治疗组在博莱霉素处理第1至7天时，每天通过滴鼻给予小鼠红景天苷溶液，第7天时取材检测各组肺胶原含量及纤维化严重程度。各组每日记录小鼠体重，绘制体重变化曲线。
支气管肺泡灌洗液(BALF)细胞总数和分类细胞计数检测：在博来霉素处理第7天，连接每只小鼠的主支气管，并通过气管插管用1mL PBS缓冲液在肺中进行灌洗，重复上述操作三次。立即离心BALF以获得细胞沉淀，将细胞沉淀重新悬浮在冷PBS中，涂于载玻片上，吹干后置于无水乙醇中固定30min，用H&E染色，以在光学显微镜下区分不同的细胞类型。用血细胞计数器测定总细胞数。
实验结果如下图1和图2所示，由图1可知，与模型组的小鼠相比，红景天苷治疗组小鼠给药后BALF中炎性细胞总数及主要细胞类型中性粒细胞、淋巴细胞、巨噬细胞的数量均明显降低，表明红景天苷能够减轻博来霉素诱导的炎症浸润，并且p<0.05，即统计学上具有极显著性差异；并且由图2可知，H&E染色结果表明红景天苷治疗组小鼠BALF总细胞染色减少，表明红景天苷可有效减缓博来霉素诱导的小鼠肺纤维化早期炎症反应。
综上所述，红景天苷对肺纤维化有良好的功效，无不良反应，可减缓博莱霉素诱导的小鼠肺纤维化早期炎症反应，在治疗、缓解或改善肺纤维化疾病方面具有良好的应用前景。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.一种红景天苷在制备用于治疗肺纤维化疾病的药物中的应用，其特征在于：所述红景天苷的结构如下式(I)所示：
2.根据权利要求1所述的应用，其特征在于：所述肺纤维化疾病为特发性肺纤维化疾病。
3.一种治疗肺纤维化疾病的药物，其特征在于：包括红景天苷在药学上可接受的盐、酯、水合物以及辅料。
4.根据权利要求3所述的药物，其特征在于：所述肺纤维化疾病为特发性肺纤维化疾病。
5.根据权利要求3所述的药物，其特征在于：所述红景天苷在药学上可接受的盐包括有机盐和无机盐。
6.根据权利要求5所述的药物，其特征在于：所述有机盐包括甲磺酸盐、甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、富马酸盐、柠檬酸盐、苯磺酸盐、对甲基苯磺酸盐、萘磺酸盐、乳酸盐或苯甲酸盐；所述无机盐包括盐酸盐、氢溴酸盐、硫酸盐或磷酸盐。
7.根据权利要求3所述的药物，其特征在于：所述药物的剂型选自片剂、胶囊剂、丸剂、栓剂、气雾剂、口服液体制剂、颗粒剂、散剂、注射剂、糖浆剂、酒剂、酊剂、露剂、膜剂中一种或几种的组合。
8.根据权利要求3所述的药物，其特征在于：所述药物的给药方式包括口服、注射、植入、外用、喷雾、吸入中一种或几种的组合。
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