CN110787272A - 一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用 - Google Patents
一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用。本发明通过实验证明了根据中药复方制备而得的药物可以有效减少肝脏脂肪堆积，有效减缓非酒精性脂肪性肝炎引起的炎症病灶，肝脏纤维化有所缓解，进一步拓展了中药复方的应用。
Description
技术领域
本发明属于非酒精性脂肪性肝炎领域，特别涉及一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用。
背景技术
非酒精性脂肪性肝炎(NASH)是非酒精性脂肪性肝病(NAFLD)的活动加重状态，以肝实质细胞脂肪样变性，同时伴有炎症反应、组织学改变和持续的肝损伤为主要特征。研究发现，NASH是隐源性肝硬化的重要原因之一，故预后不佳，约30％-40％的NASH合并进展性肝纤维化，10％-15％并发肝硬化，3％进展至最终的肝衰竭，严重危害人类健康。因此，对NASH的防治是阻止非酒精性脂肪性肝病持续发展的关键。目前，中医界对NASH病因病机的认识已渐趋一致，但具体的治疗原则依学者经验、学识等的不同，呈现出多样化的特点。中医在改善肝功能，调节脂质代谢上具有比较明显的疗效和优势，尤其是在“整体观念”和“辨证论治”的指导下，在改善患者的生存质量上具有较为明显的优势。中药复方治疗NASH不是单纯降脂药物的简单堆积，而是各药物之间交互作用的结果。目前针对中药复方的实验研究主要以药效为主，而且多集中在对中药复方调控肝功能ALT、AST、TC、TG等的评估。
西方NAFLD的患病率为20％～40％，亚洲为12％～30％。10％～20％的NAFLD被诊断为NASH，全球NASH的患病率为3％～5％。若能对NASH及其相关肝纤维化早发现、诊断和治疗，延缓其向肝硬化和肝癌进展，则具有重要临床意义。
发明内容
本发明所要解决的技术问题是提供一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用，通过实验证明了根据中药复方制备而得的药物可以有效减少肝脏脂肪堆积，有效减缓非酒精性脂肪性肝炎引起的炎症病灶，肝脏纤维化有所缓解，进一步拓展了中药复方的应用。
本发明提供了一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用，所述中药复方包括白术、枳壳、姜黄、五味子、丹参、葛根、泽泻和白芍。
所述中药复方的制备方法具体步骤如下：
取丹参、葛根、泽泻、白芍分别加水10倍量、8倍量，煎煮，煎液过滤，滤液合并，滤液浓缩至相对密度1.08-1.12，冷却后在搅拌下加乙醇使含醇量至70％，静置沉淀，取上清液，过滤，滤液浓缩至相对密度为1.1～1.2，得到浓缩物，备用；另取白术、枳壳、姜黄、五味子分别加70％乙醇10倍量、8倍量，加热回流，合并回流液，过滤，滤液浓缩至相对密度为1.1～1.2，与备用的浓缩物合并，干燥，即得。
所述中药复方配以辅料，最后制粒和/或压片成制剂。
有益效果
本发明通过实验证明了根据中药复方制备而得的药物可以有效减少肝脏脂肪堆积，有效减缓非酒精性脂肪性肝炎引起的炎症病灶，肝脏纤维化有所缓解，进一步拓展了中药复方的应用。
附图说明
图1为给药8周大鼠肝脏中TG(A)、TC(B)的变化。
图2A为给药8周后各组大鼠肝脏组织的HE染色显示的组织形态变化(200×)。
图2B为给药8周后各族大鼠肝脏组织的HE染色显示的组织形态变化(400×)。
图3A为给药8周后各组大鼠肝脏组织的油红染色显示的脂肪滴(200×)。
图3B为给药8周后各组大鼠肝脏组织的油红染色显示的脂肪滴(400×)。
图4为给药8周后各组大鼠肝脏组织的天狼猩红染色显示的纤维化(200×)。
图5为给药8周后大鼠肝脏切片的NAS打分(包括脂肪堆积，炎症，气球样变性)。
图6为给药8周后大鼠肝脏的TNF-α用RT-PCR法检测(A)以及用ELISA法检测(B)。
图7为给药8周后大鼠肝脏促纤维化基因mRNA水平的检测(A为胶原酶含量、B为胶原蛋白含量)。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，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。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
1.动物造模
选用Wistar大鼠，雄性，6-8周，200-220g，购自澳门大学动物中心。实验分为正常对照组，MCS对照组，MCD模型组，阳性药对照组及受试药给药组若干。所有实验大鼠均饲养在动物房中提前适应环境至少7天。MCS对照组、MCD模型组、阳性药对照组及受试药给药组的大鼠先进行一周的过度饮食，即在一周的时间内，MCS对照组由正常饲料逐渐过渡为MCS饮食；MCD模型组、阳性药对照组及受试药给药组由正常饲料逐渐过渡为MCD饮食。饮食过渡期结束后，按照实验分组，给予大鼠正常饲料，MCS饲料，或MCD饲料，并按计划给予阳性药或受试药物。总体饮食及给药方案见表1，详细的给药方法、给药剂量见各部分实验。
表1总体饮食及给药方案
2.受试方剂配制方法如表2所示：
表2
注：A、B为其他中药样品。
3.中药复方工艺流程：
处方如表3所示：
表3
| 名称 | 白术 | 枳壳 | 姜黄 | 五味子 | 丹参 | 葛根 | 泽泻 | 白芍 | 共计 |
| 处方(g) | 3 | 2 | 2 | 2 | 3 | 3 | 3 | 2 | 20 |
制法：
取丹参、葛根泽泻、白芍分别加水10倍量、8倍量，煎煮2次，第一次2小时，第二次1.5小时，煎液过滤，滤液合并，浓缩至相对密度1.08-1.12(80±2℃)，放冷，在搅拌下加乙醇使含醇量至70％，静置沉淀，取上清液，过滤，滤液浓缩至相对密度为1.1～1.2(50℃～55℃)，备用；另取白术、枳壳、姜黄、五味子分别加70％乙醇10倍量、8倍量，加热回流2次，第一次1.5小时，第二次1小时，合并回流液，过滤，滤液浓缩至相对密度为1.1～1.2(50℃～55℃)，与上述备用的浓缩物合并，干燥，中药复方干膏粉，加入辅料适量，混匀，制粒，压制成片。
受试方剂待测剂量及给药方式如表4所示：
表4
4.实验结果
①给药期间大鼠的体重变化及肝脏与体重比值(LBW ratio)的变化
通过各组大鼠体重的变化可以看出(见表5)：与正常对照组相比，MCS饮食不会导致大鼠体重明显的变化，而MCD饮食会导致大鼠体重逐渐下降；与MCD组相比，阳性药Elafibranor及各给药组的干预都未影响大鼠MCD饮食导致的体重下降。
通过各组大鼠肝脏与体重比值的变化可以看出(见表6)：与正常对照组相比，MCS饮食略微降低了大鼠的肝脏体重比值，而MCD饮食会导致这一指标显著的上升；与MCD组相比，阳性药Elafibranor没有降低肝脏体重比值，中药复方低、中、高剂量组、A方中剂量组以及B方中剂量对大鼠的肝脏体重比值都无显著性影响。
表5给药期间大鼠体重(g)的变化
0周表示过渡饮食期间，1～8周为给药期间。结果以mean±SD表示；MCD组与MCS组相比，显著性差异表示为###p<0.001,阳性药及各给药组组与MCD组相比，显著性差异表示为*p<0.05,**p<0.01。
表6给药结束后大鼠肝脏重量的变化及肝脏/体重比值的变化
| Liver mass(grams) | Liver mass to body mass ratio(％) | |
| Control | 10.32±0.3536 | 2.600±0.05657 |
| MCS | 7.313±0.5409 | 2.040±0.08756 |
| MCD | 7.393±0.6490 | 3.780±0.2650<sup>###</sup> |
| Elafibranor | 8.657±1.178 | 4.256±0.3556<sup>＊</sup> |
| JPHX(0.60g/kg) | 7.397±0.8010 | 4.087±0.3631 |
| JPHX(1.21g/kg) | 6.626±1.738 | 3.661±0.4950 |
| JPHX(2.42g/kg) | 6.810±0.8942 | 3.575±0.3935 |
| B(0.60g/kg) | 7.789±0.7547 | 4.036±0.3420 |
| A(0.40g/kg) | 7.238±0.5803 | 3.711±0.2969 |
②给药8周大鼠肝脏中的TG、TC的变化
通过图1A、B可以看出：第8周时，MCD饮食组大鼠肝脏中的TG、TC显著升高，中药复方低剂量和中剂量减少了肝脏脂肪堆积。
③给药期间大鼠血清中的TG、TC、ALT及AST的变化
通过第2、4、6、8周大鼠TG及TC的变化可以看出(表7、表8)：MCD饮食在第2～6周可以显著性的降低血清TG，而各给药组对MCD饮食引起的血清TG降低无显著性影响；MCD饮食在第4周和第8周时表现出对血清TC的显著性的降低，中药复方高中低三个剂量组及B方中剂量组对此降低有显著的回升作用，其他给药组也有一定的回升作用。
通过第2、4、6、8周大鼠ALT及AST的变化可以看出(表9、表10、表11)：MCD饮食在4周起就引起了ALT及AST的显著性升高。与MCD组相比，阳性药Elafibranor及中药复方高中低三个剂量组，B方中剂量组，在4～8周的观测期内都可显著性地降低ALT，而A方中剂量组对MCD引起的ALT升高没有显著的影响；与MCD组相比，阳性药Elafibranor，中药复方低中高三个剂量组，B方中剂量组以及A方中剂量组，在4～8周的观测期内都可显著性地降低MCD导致的AST升高。
表7给药期间大鼠血清中TG(mmol/L)的变化
| Week2 | Week4 | Week6 | Week8 | |
| Control | 0.4715±0.03778 | 0.6310±0.1548 | 0.6984±0.1354 | 0.3424±0.05135 |
| MCS | 1.010±0.2422 | 0.9469±0.1526 | 0.9557±0.1435 | 0.5131±0.1805 |
| MCD | 0.5120±0.05780<sup>###</sup> | 0.5781±0.09350<sup>###</sup> | 0.5014±0.09747<sup>###</sup> | 0.3734±0.03963 |
| Elafibranor | 0.4635±0.09559 | 0.5709±0.06965 | 0.4275±0.06424 | 0.3785±0.06613 |
| JPHX(0.60g/kg) | 0.7249±0.2238<sup>*</sup> | 0.5813±0.07707 | 0.4431±0.1570 | 0.3629±0.1132 |
| JPHX(1.21g/kg) | 0.4367±0.1144 | 0.6902±0.1319 | 0.3509±0.06851 | 0.3532±0.07040 |
| JPHX(2.42g/kg) | 0.3842±0.04158 | 0.5785±0.1580 | 0.3741±0.1110 | 0.3299±0.09665 |
| B(0.60g/kg) | 0.4181±0.1507 | 0.5716±0.06469 | 0.4675±0.09474 | 0.2676±0.04869 |
| A(0.40g/kg) | 0.5830±0.2413 | 0.6995±0.1690 | 0.4691±0.1129 | 0.3155±0.05760 |
表8给药期间大鼠血清中TC(mmol/L)的变化
| Week2 | Week4 | Week6 | Week8 | |
| Control | 1.917±0.3382 | 2.222±0.3207 | 2.907±0.3052 | 2.600±0.5025 |
| MCS | 1.708±0.3255 | 2.251±0.4265 | 2.165±0.3409 | 2.203±0.2962 |
| MCD | 2.231±0.6163 | 1.141±0.1778<sup>###</sup> | 1.682±0.4065 | 1.287±0.2194<sup>#</sup> |
| Elafibranor | 2.131±0.3174 | 1.642±0.2149 | 2.276±0.5108 | 2.343±0.4808<sup>***</sup> |
| JPHX(0.60g/kg) | 2.247±0.4734 | 2.091±0.6110<sup>***</sup> | 2.408±0.3916<sup>*</sup> | 2.222±0.7076<sup>**</sup> |
| JPHX(1.21g/kg) | 2.465±0.3393 | 1.897±0.5129<sup>**</sup> | 2.326±0.7657 | 2.147±0.4404<sup>**</sup> |
| JPHX(2.42g/kg) | 2.838±0.1228 | 2.047±0.3075<sup>***</sup> | 2.104±0.2477 | 2.215±0.4301<sup>**</sup> |
| B(0.60g/kg) | 2.985±0.4297<sup>**</sup> | 2.234±0.5405<sup>***</sup> | 2.177±0.2794 | 2.175±0.3281<sup>**</sup> |
| A(0.40g/kg) | 2.540±0.7409 | 1.925±0.4472<sup>**</sup> | 1.933±0.5118 | 1.734±0.4515 |
表9给药期间大鼠血清中ALT(U/L)的变化
表10给药期间大鼠血清中AST(U/L)的变化
| Week2 | Week4 | Week6 | Week8 | |
| Control | 44.12±2.382 | 27.48±11.89 | 37.59±5.272 | 21.01±3.081 |
| MCS | 41.88±10.66 | 19.10±5.737 | 30.08±2.950 | 35.75±15.25 |
| MCD | 19.32±5.555<sup>###</sup> | 38.53±16.61<sup>##</sup> | 35.48±5.507 | 34.38±2.509 |
| Elafibranor | 17.99±2.717 | 17.08±3.281<sup>***</sup> | 24.97±3.914<sup>*</sup> | 15.19±5.119<sup>***</sup> |
| JPHX(0.60g/kg) | 16.98±4.174 | 23.12±4.510<sup>**</sup> | 22.14±4.902<sup>**</sup> | 19.23±6.640<sup>***</sup> |
| JPHX(1.21g/kg) | 20.03±4.690 | 17.19±4.346<sup>***</sup> | 24.91±2.782<sup>*</sup> | 17.22±4.277<sup>***</sup> |
| JPHX(2.42g/kg) | 13.58±1.563 | 18.18±4.177<sup>***</sup> | 23.88±8.994<sup>*</sup> | 14.36±3.184<sup>***</sup> |
| B(0.60g/kg) | 17.62±5.277 | 20.22±4.612<sup>***</sup> | 27.82±7.722 | 17.66±4.582<sup>***</sup> |
| A(0.40g/kg) | 18.27±4.280 | 25.52±7.032<sup>**</sup> | 26.15±8.552<sup>*</sup> | 20.15±5.562<sup>***</sup> |
表11给药期间大鼠血清中AST/ALT比值的变化
| Week2 | Week4 | Week6 | Week8 | |
| Control | 8.964±7.009 | 3.419±2.439 | 4.888±1.124 | 2.124±0.3558 |
| MCS | 10.70±2.611 | 1.885±0.6614 | 4.125±0.6701 | 3.282±1.100 |
| MCD | 1.094±0.6219<sup>###</sup> | 0.6971±0.2927<sup>##</sup> | 1.270±0.2295 | 1.477±0.8793<sup>###</sup> |
| Elafibranor | 2.788±1.020 | 1.711±0.3229<sup>**</sup> | 3.139±0.8978 | 1.925±0.7393 |
| JPHX(0.60g/kg) | 2.560±1.838 | 1.519±0.5495<sup>*</sup> | 1.289±0.3836 | 1.126±0.4739 |
| JPHX(1.21g/kg) | 1.666±0.6193 | 0.8836±0.3103 | 1.293±0.4825 | 1.461±0.5425 |
| JPHX(2.42g/kg) | 2.892±0.8354 | 1.098±0.5568 | 1.125±0.5817 | 1.540±0.5089 |
| B(0.60g/kg) | 1.871±0.8277 | 0.8380±0.3810 | 1.304±0.4418 | 1.078±0.3993 |
| A(0.40g/kg) | 1.129±0.9081 | 0.5885±0.2526 | 1.007±0.3275 | 0.9582±0.2192 |
结果以mean±SD表示，MCD组与MCS组相比，显著性差异表示为#p＜0.05，##p＜0.01，###p＜0.001，阳性药及各给药组与MCD组相比，显著性差异表示为*p＜0.05，**p＜0.01，***p＜0.001。
④大鼠肝脏HE染色结果
由图2A和2B可知，通过HE染色可以看出，MCD饮食组的大鼠肝脏组织中有明显的脂肪滴、气球化细胞死亡、炎症病灶现象；而阳性药Elafibranor可以显著的改善以上四项指标；中药复方高中两个剂量组中及A方中剂量组的大鼠中，脂肪滴明显变小，具有脂肪滴的组织比例变小，而A方中剂量组中，脂肪滴的大小有显著的减小，但肝组织中依然广泛分布着脂肪滴；中药复方高中低三个剂量组，B方中剂量组及A方中剂量组的大鼠中，炎症病灶的现象亦有减少。
⑤大鼠肝脏油红O染色结果
由图3A和3B可知，MCD饮食组的大鼠肝脏组织中有明显的脂肪滴(红色)，而阳性药Elafibranor给药组中基本观察不到成形的脂肪滴；中药复方中低两个剂量组中，脂肪滴的数量和大小有所减少，中药复方高剂量组中，脂肪滴的数量和大小都有显著的改善，已经观察不到聚集成大滴的脂肪滴；B方中剂量组的大鼠中，脂肪滴有所变小，具有脂肪滴的组织比例明显变小。
⑥大鼠肝脏天狼猩红染色结果(200X)
由图4可知，MCD饮食组的大鼠肝脏组织中有轻微的纤维化情况(红色)，而阳性药Elafibranor给药组和中药复方中低高三个剂量组，以及另外两个方中药复方和A方显示无明显的纤维化情况。该结果也和纤维化相关基因的RT-PCR结果相一致。
⑦NAS评价肝脏病理学
由图5可知，中药复方可以缓解由蛋氨酸胆碱造成的肝脏病变，可以减少肝脏脂肪堆积以及炎症情况。经过给予蛋氨酸胆碱缺乏饲料后，模型组显现出脂肪堆积严重，有Kuffer细胞浸润，在经不同剂量的中药中药复方治疗后，脂肪堆积减少，炎症水平下降。B方也降低了由蛋氨酸胆碱造成的脂肪堆积，A对脂肪堆积缓解作用效果。
⑧TNF-α的检测
由图6A和6B可知，蛋氨酸胆碱缺乏导致肝脏炎症水平的上升，在给药中药复方8周后，炎症水平有所下降。结果也和HE染色结果一致。
⑨纤维化相关基因mRNA水平的检测
由图7A和7B可知，蛋氨酸胆碱缺乏导致肝脏纤维化水平的上升，在给药中药复方8周后，纤维化有所下降，结果和天狼猩红结果一致。
根据以上实验结果可知，根据中药复方制备而得的药物可以有效减少肝脏脂肪堆积，有效减缓非酒精性脂肪性肝炎引起的炎症病灶，肝脏纤维化有所缓解，进一步拓展了中药复方的应用。
Claims (3)
1.一种中药复方在制备治疗非酒精性脂肪性肝炎的药物中的应用，其特征在于：所述中药复方包括白术、枳壳、姜黄、五味子、丹参、葛根、泽泻和白芍。
2.根据权利要求1所述的应用，其特征在于：所述中药复方的制备方法具体步骤如下：
取丹参、葛根、泽泻、白芍分别加水10倍量、8倍量，煎煮，煎液过滤，滤液合并，滤液浓缩至相对密度1.08-1.12，冷却后在搅拌下加乙醇使含醇量至70％，静置沉淀，取上清液，过滤，滤液浓缩至相对密度为1.1～1.2，得到浓缩物，备用；另取白术、枳壳、姜黄、五味子分别加70％乙醇10倍量、8倍量，加热回流，合并回流液，过滤，滤液浓缩至相对密度为1.1～1.2，与备用的浓缩物合并，干燥，即得。
3.根据权利要求1所述的应用，其特征在于：所述中药复方配以辅料，最后制粒和/或压片成制剂。
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