CN111888358A - 安罗替尼在制备用于治疗肝纤维化疾病的药物中的应用 - Google Patents
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Abstract
本发明提供了一种安罗替尼(Anlotinib)在制备用于治疗肝纤维化疾病的药物中的应用，其中，安罗替尼的结构如下式(I)所示：
研究表明，安罗替尼对肝纤维化有良好的功效，无不良反应，可减缓四氯化碳诱导的小鼠肝纤维化，在治疗、缓解或改善肝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，涉及一种安罗替尼在制备用于治疗肝纤维化疾病药物中的应用。
背景技术
肝纤维化是肝脏组织不断损伤修复导致的，其主要诱因有病毒感染、免疫紊乱、酒精性脂肪肝和非酒精性脂肪肝等。肝纤维化发生的确切机制尚未阐明，细胞外基质沉积是肝纤维化的一个突出特征。当肝脏受到损伤后，受损的肝细胞释放促纤维化因子，使肝星状细胞活化并不断增殖，转化为肌成纤维细胞表型，分泌合成大量胶原和蛋白多糖等ECM大量蓄积在肝脏细胞间液中形成瘢痕，最终形成肝纤维化。
肝纤维化是一个可逆的愈合过程，并作为肝硬化的前期阶段，如未能及时有效的治疗，将最终发展为肝癌。因此，肝纤维化的治疗受到广泛关注。然而并没有针对肝纤维化的上市药物，现在主要是针对病因治疗、减少ECM形成和促进ECM降解、抗炎护肝、肝移植等，但效果欠佳。因此需要对肝纤维化的分子机制深入分析，研发出疗效确切安全性高的抗肝纤维化药物具有重要的社会意义。
安罗替尼是一种新型小分子多靶点酪氨酸激酶抑制剂，能有效抑制 VEGFR、PDGFR、FGFR、c-Kit等激酶，具有抗肿瘤血管生成和抑制肿瘤生长的作用。2018年，安罗替尼获得国家药品监督管理局(NMPA)批准上市，用于既往至少接受过两种化疗后出现进展或复发的局部晚期或转移性非小细胞肺癌患者的治疗。
发明内容
针对以上问题，本发明提供了一种安罗替尼在制备用于治疗肝纤维化
疾病的药物中的应用，其中，所述安罗替尼的结构如下式(I)所示：
(I)。
在以上应用中，所述安罗替尼的剂量为1mg/kg～300mg/kg。
本发明还提供了一种治疗肝纤维化疾病的药物，包括：安罗替尼以及安罗替尼在药学上可接受的盐、酯、水合物以及辅料。
在以上药物中，所述安罗替尼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、乳酸盐和苯甲酸盐；所述无机盐包括盐酸盐、氢溴酸盐、硫酸盐和磷酸盐。
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、膜剂或它们的组合。
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、吸入或它们的组合。
本发明的研究表明，安罗替尼对肝纤维化有良好的功效，无不良反应，可减缓四氯化碳诱导的小鼠肝纤维化，在治疗、缓解或改善肝纤维化疾病方面具有良好的应用前景。
附图说明
图1是各组小鼠体重变化曲线。
图2是各组小鼠中叶肝的胶原含量图。(*，p<0.05，即统计学上具有显著性差异)
图3是各组小鼠HE和Sirius red染色。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应该理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
本发明提供了一种安罗替尼在制备用于治疗肝纤维化疾病的药物中的应用，其中，安罗替尼的结构如下式(I)所示：
实施例1
安罗替尼对四氯化碳诱导的小鼠肝纤维化的影响
肝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，麻醉小鼠后称重记录并腹腔注射20％的1ml/kg的四氯化碳(橄榄油作为溶剂)，3次/周，持续8周。
分组情况：对照组腹腔注射同体积的橄榄油；模型组按照以上方式造模并以相应溶剂橄榄油在四氯化碳处理后第1天开始腹腔注射直至试验结束；安罗替尼治疗组在四氯化碳处理第29天至第56天试验结束，每天通过灌胃给予小鼠5mg/kg安罗替尼，以相应溶剂生理盐水作为对照。每周记录一次小鼠体重，第56天时检测各组肝胶原含量及纤维化严重程度。
小鼠体重变化记录：每周记录小鼠体重，持续8周。对小鼠体重进行统计。观察小鼠8周体重变化。
肝胶原含量检测(即羟脯氨酸含量测定)：在四氯化碳腹腔注射第56 天处死小鼠，分离小鼠中叶肝，放入5mL安培瓶，120℃烘箱烘干，加入 3ml浓度为12mol/L的盐酸，120℃下水解6小时，水解后用浓度为10 mol/L的NaOH调整pH至6.5-8.0，使用孔径为5μm的过滤器过滤残渣，得滤液，滤液中加入PBS(磷酸盐缓冲溶液)调整总体积为10mL，得到样品A；取50μL样品A，加入350μL去离子水，加入200mL质量浓度为1.41％的氯胺T(Chloramine T)溶液，室温孵育20分钟，加入200μL 质量浓度为18.9％的高氯酸溶液(perchloric acid，室温孵育5分钟，加入 200μL质量浓度为20％的对二甲氨基苯甲醛(P-DMAB)溶液，65℃孵育 20分钟，得到样品B；取200μL样品B至96孔板中测定样品B在570nm 波长处的吸光值，利用L-羟脯氨酸标准品(Sigma)的浓度与吸光度为横纵坐标，绘制标准曲线，依据标准曲线对应的回归方程，计算所测样品羟脯氨酸的浓度。此外，在如下表2中示出了相应的数据，即对照组组、模型组组、安罗替尼治疗组小鼠的中叶肝羟脯氨酸含量。
表2安罗替尼抑制四氯化碳诱导的羟脯氨含量(微克/中叶肝)
对肝组织切片进行病理染色：将小鼠肝经过多聚甲醛固定、常规脱水、石蜡包埋、切片、HE/Sirius red(天狼星红)染色、中性树胶封片处理后，应用正置显微镜采集HE/Sirius red染色图像数据。
实验结果如下图1至图3所示，由图1可知，从第四周到第八周安罗替尼治疗后小鼠体重增长速度高于模型组，表明安罗替尼治疗后可以改善小鼠的健康状况。由图2可知，与模型组的小鼠相比，安罗替尼治疗组小鼠的肝组织中羟脯氨酸含量明显降低，表明安罗替尼能够减轻四氯化碳所诱导的胶原含量，抑制四氯化碳诱导的肝组织中胶原的合成，并且p<0.05，即统计学上具有显著性差异；由图3可知，HE染色观察和统计分析表明，与模型组相比，安罗替尼治疗组，炎性细胞浸润明显减少，肝脏结构更完整。Sirius red染色观察表明安罗替尼治疗组的小鼠肝纤维化程度明显低于模型组小鼠，表明安罗替尼可有效减缓四氯化碳诱导的小鼠肝纤维化。
综上，安罗替尼对肝纤维化有良好的功效，无不良反应，可改善四氯化碳诱导的小鼠肝纤维化，在治疗、缓解或改善肝纤维化疾病方面具有良好的应用前景。
以上仅为本发明的具体实施方式，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 (7)
1.安罗替尼在制备用于治疗肝纤维化疾病的药物中的应用，其中，所述安罗替尼的结构如下式(I)所示：
2.根据权利要求1所述的应用，其特征在于：所述安罗替尼的剂量为1mg/kg～300mg/kg。
3.一种治疗肝纤维化疾病的药物，其特征在于：包括安罗替尼，以及安罗替尼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：所述安罗替尼在药学上可接受的盐包括有机盐和无机盐。
5.根据权利要求4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、乳酸盐和苯甲酸盐；所述无机盐包括盐酸盐、氢溴酸盐、硫酸盐和磷酸盐。
6.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、膜剂或它们的组合。
7.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、吸入或它们的组合。
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