CN113730422A - 白头翁皂苷b4在制备预防或者治疗非酒精性脂肪肝的药物中的应用 - Google Patents
白头翁皂苷b4在制备预防或者治疗非酒精性脂肪肝的药物中的应用 Download PDFInfo
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- CN113730422A CN113730422A CN202111164740.5A CN202111164740A CN113730422A CN 113730422 A CN113730422 A CN 113730422A CN 202111164740 A CN202111164740 A CN 202111164740A CN 113730422 A CN113730422 A CN 113730422A
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- liver disease
- fatty liver
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- pulsatilla
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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Abstract
本发明公开了白头翁皂苷B4在制备治疗非酒精性脂肪肝的药物中的应用。由于非酒精性脂肪肝病的肝损伤的细胞和分子机制尚不十分清楚,对该病缺少有效的药物治疗方法,故积极探索安全有效的药物治疗是当前的研究热点。现有药物的疗效和安全性有待进一步改善或者验证。本发明公开了新的治疗非酒精性脂肪肝的药物,活性成分为白头翁皂苷B4,实验证实,白头翁皂苷B4可以有效地降低高脂饮食导致的大鼠肝脏的脂质堆积,且疗效与阳性对照药相当,可避免非诺贝特导致肝毒性的副作用,因此可用于预防和治疗非酒精性脂肪性肝病(NAFLD)。
Description
技术领域
本发明属于药物技术,具体涉及白头翁皂苷B4在制备治疗非酒精性脂肪肝的药物中的应用。
背景技术
非酒精性脂肪性肝病(NAFLD)是一种与胰岛素抵抗和遗传易感密切相关的代谢应激性肝损伤,其病理学改变与酒精性肝病(ALD)相似,但患者无过量饮酒史,随着病程的进展依次分为非酒精性单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)、肝硬化和肝细胞癌(HCC)。
目前研究发现代谢综合症(MetS)是NAFLD、NASH发生的最强风险因素,代谢综合症包括腰围增加(如肥胖)、高血糖、高血脂、高血压等。MetS与NAFLD之间的关联可能是双向的,特别是糖尿病和高血压,MetS会增加NAFLD的风险,而NAFLD也可能会加重MetS的几种临床特征和合并症,因此有效治疗NASH也有利于改善MetS症状。此外MetS也是NAFLD患者出现不良心血管疾病(CVD)和总死亡率的重要驱动因素。糖尿病与NAFLD的进展具有最清晰的生物学联系,高达75%的2型糖尿病患者伴有NAFLD。目前胰岛素抵抗也被认为是NAFLD发病机制的组成部分,且随着疾病进展而恶化。50%的高血压患者伴有NAFLD,高血压与纤维化进展密切相关,且NAFLD与动脉硬化、心肌重塑、心力衰竭、肾脏疾病之间已证明存在相关性。
据统计全球约有13亿肝病患者,而中国就有4亿之多,占全球肝病患者的30%以上。调查显示我国乙肝患者9600万、丙肝患者1000万、脂肪肝患者2亿、酒精肝患者6000万,其他肝病患者3700万。近年来,以非酒精性脂肪性肝病(NAFLD)为代表的非感染性肝病的发病率显著上升,其患病率高达15%~40%,已取代病毒性肝病,成为全球第一大肝病,可见NAFLD的临床防治工作任重道远,而临床基础研究更是迫在眉睫。
NAFLD发病机制目前仍处于争论阶段。在传统的“二次打击”学说中,“第一次打击”是肝脏脂肪堆积;“第二次打击”是肝脏脂肪堆积引发的氧化应激和炎性细胞因子的过度释放,导致肝脏炎症和肝纤维化,进而导致肝硬化和肝癌。但根据最新的研究发现,这种观点被认为已经过时。很多分子途径在NASH的发病过程中都起着很重要的作用,甚至不能确定NASH是否总是继发于NAFLD。此外,致病因素在所有患者中并不相同,导致疾病的发病机制和临床表现具有高度的异质性。
NASH被认为是NAFLD的进行性形式,其特征在于肝脏脂肪变性、炎症、肝细胞损伤和不同程度的纤维化。NASH的发生是多因素综合作用的结果,包括肝外因素如饮食因素(碳水化合物、金属离子、饱和脂肪/反式脂肪和胆固醇等)、代谢功能紊乱(胰岛素抵抗和脂肪组织炎症、脂肪因子等)、肝肠轴(肠道炎症和肠道屏障功能障碍、胆汁酸)等;肝内因素如肝细胞压力(氧化应激和内质网应激、脂毒性、线粒体功能障碍)、肝细胞死亡(细胞凋亡、坏死性凋亡、细胞焦亡)、核受体(PPARα、FXR、CAR等)、肝细胞因子等;除此之外还有先天性免疫、宿主遗传学和表观遗传学。
运动与改善不良的生活方式是治疗NAFLD的基础,由于非酒精性脂肪肝病的肝损伤的细胞和分子机制尚不十分清楚,对该病缺少有效的药物治疗方法,故积极探索安全有效的药物治疗是当前的研究热点。
临床上广泛使用的二甲双胍主要是通过激活AMPK而发挥治疗非酒精性脂肪性肝病(特别是NASH)的作用,但这个药物是线粒体复合物I的抑制剂,存在乳酸中毒的风险,并且没有肝脏组织学改善作用。目前临床推荐使用的NASH治疗药物包括胰岛素增敏剂如吡格列酮等,但上述药物的临床疗效有限,且其存在前列腺癌和胰腺癌发生风险增加、体重增加、液体潴留以及女性患者的骨折和心血管事件发生率增加等。
临床在研的抗NASH新药包括法尼酯X受体(FXR)激动剂(如奥贝胆酸)、乙酰辅酶A羧化酶(ACC)抑制剂(如GS-0976)和过氧化物酶体增殖体激活受体(PPARs)激动剂(如pemafibrate)等。然而上述抗NASH新药的疗效和安全性有待进一步验证。综上所述,临床上迫切需要安全、有效的新型治疗非酒精性脂肪性肝病(尤其是NASH)的药物。
发明内容
本发明公开了安全、有效的新型治疗非酒精性脂肪性肝病(尤其是NASH)的药物,具体的,本发明采用如下技术方案:
白头翁皂苷B4在制备预防非酒精性脂肪肝的药物中的应用。
白头翁皂苷B4在制备治疗非酒精性脂肪肝的药物中的应用。
白头翁皂苷B4在制备治疗非酒精性脂肪性肝炎的药物中的应用。
白头翁皂苷B4在制备预防非酒精性脂肪性肝炎的药物中的应用。
白头翁皂苷B4在制备治疗高脂饮食所致的血液中脂肪酸酯和胆固醇异常升高的药物中的应用。
本发明中,非酒精性脂肪肝为高脂饮食所致的非酒精性脂肪肝;非酒精性脂肪性肝炎为高脂饮食所致的非酒精性脂肪性肝炎。
一种预防或者治疗非酒精性脂肪肝的药物,或者预防或者治疗非酒精性脂肪性肝炎的药物,其活性成分为白头翁皂苷B4,还包括常规药物辅料,比如生理盐水。
本发明中,预防或者治疗非酒精性脂肪肝的药物为注射药物或者口服药物。优选的,注射药物的用量为1~20mg/kg,优选2.5~20mg/kg;口服药物的用量为10~100mg/kg,优选12~50mg/kg。都以白头翁皂苷B4计。
由于非酒精性脂肪肝病的肝损伤的细胞和分子机制尚不十分清楚,对该病缺少有效的药物治疗方法,故积极探索安全有效的药物治疗是当前的研究热点。现有药物的疗效和安全性有待进一步改善或者验证。本发明公开了新的治疗非酒精性脂肪肝的药物,活性成分为白头翁皂苷B4,实验证实,白头翁皂苷B4可以有效地降低高脂饮食导致的大鼠肝脏的脂质堆积,且疗效与阳性对照药相当,可避免非诺贝特导致肝毒性的副作用,因此可用于预防和治疗非酒精性脂肪性肝病(NAFLD)。
附图说明
图2为不同给药组大鼠体重的变化曲线;
图3为不同给药组对大鼠摄食量的影响;
图4为给药4周后对NAFLD大鼠肝脏的影响;
图5为给药4周后NAFLD大鼠肝脏HE染色和油红染色切片;
图6为给药4周对NAFLD大鼠血清生化指标的影响。
具体实施方式
本实施例通过白头翁皂苷B4对高脂饮食(HFD)诱导NAFLD大鼠模型的保护作用说明白头翁皂苷B4治疗非酒精性脂肪肝的效果。
动物:雄性SD大鼠75只,SPF级,6周龄,初始体重200±20g;ICR小鼠,6周龄;都购于上海斯莱克实验动物有限责任公司。在苏州大学实验动物中心SPF级动物房饲养,所有动物保持12小时交替的昼夜节律,自由摄食饮水。
仪器:动物体重秤;全自动血生化分析仪;冷冻切片机;倒置显微镜
试剂:白头翁皂苷B4(纯度为99.4%)是根据现有方法从白头翁药材中分离纯化得到(He, et. al., Phytomedicine 56 (2019) 136–146);非诺贝特(fenofibrat)购自上海泰坦科技股份有限公司;高脂饲料购自无锡帆泊生物技术有限公司(D12492,60kcal%);普通饲料购自苏州双狮实验动物饲料科技有限公司。
实施例 大鼠实验
动物分组及造模
一周适应期以后,所有大鼠和按体重随机分为2组进行造模:正常组和高脂饲料模型组。正常组给予普通饲料,正常饮水,高脂饲料模型组给予高脂饲料,正常饮水,造模13周。
13周之后,按体重将正常组随机分为2组,正常对照组(N)、正常+白头翁皂苷B45mg/kg腹腔注射组(N+B4 5mg/kg),将高脂大鼠按体重随机分为6组,即高脂模型组(M)、阳性药非诺贝特20 mg/kg灌胃组、白头翁皂苷B4 5mg/kg高剂量腹腔注射组(B4H i.p)、白头翁皂苷B4 2.5mg/kg低剂量腹腔注射组(B4L i.p)、白头翁皂苷B4 25mg/kg高剂量灌胃组(B4H i.g)和白头翁皂苷B4 12.5mg/kg低剂量灌胃组(B4L i.g)。
给药。连续给药4周(每天注射或者灌胃一次),给药期间正常对照组和正常+白头翁皂苷B4 5mg/kg腹腔注射组给予普通饲料和正常饮水,其余6组给予高脂饲料和正常饮水。实验期间,每周记录各组大鼠体重和摄食量,仔细观察并记录大鼠毛发、粪便及活动情况。
取材。提前12小时禁食不禁水,次日上午腹主动脉取血,处死取肝脏。肝脏右小叶组织用4%多聚甲醛固定,用于HE染色切片和冷冻切片。其余肝组织保存于-80℃冰箱内,以备后续其他指标检测。
生化指标的测定。将全血室温静置2 h,3000 rpm离心15 min,收集血清。使用全自动生化分析仪测定血清中甘油三脂(TG)、总胆固醇(CHO)、低密度脂蛋白胆固醇(LDL)和高密度脂蛋白胆固醇(HDL)的水平。
肝脏组织切片。冷冻切片进行油红染色。将预处理好的组织制作HE染色切片。
实验结果
如图1所示,NAFLD造模6周正常组和高脂饲料模型组的肝组织及HE染色。高脂饲料模型组HE染色切片可观察到肝细胞出现脂肪变性,胞浆中出现许多大小不等的空泡(脂肪滴),边界清晰,将细胞核挤向一侧。肝细胞体积增大、肿胀,细胞核明显,细胞与细胞之间界限不清。
如图2所示,不同给药组对大鼠体重的影响。经过13周的高脂饲料饲养,高脂饲料模型组大鼠的体重明显高于正常组大鼠,呈现出肥胖特征。腹腔注射和灌胃2种给药途径的白头翁皂苷B4和非诺贝特均减缓高脂饲料模型组大鼠的体重增长。
如图3所示,不同给药组对大鼠摄食量的影响。与高脂饲料模型组相比,白头翁皂苷B4 5mg/kg高剂量腹腔注射组(B4H i.p)摄食量显著降低,具有显著性差异(P < 0.05)。
如图4所示,N组大鼠肝脏体积正常,呈红褐色,表面光滑,质软富有弹性,边缘锐利,肝脏切面光滑致密。M组肝脏大鼠肝脏体积明显增大,呈土黄色,质韧,边缘圆钝,肝脏表面包膜紧张,可见散在黄色脂肪斑,切面疏松有油腻感。白头翁皂苷B4治疗组肝脏与正常组接近。
如图5所示,为进一步观察高脂饲料对肝脏的影响,对肝脏进行了病理切片观察。HE染色显示N组肝细胞形态、肝小叶结构正常,胞质丰富,肝索排列整齐呈放射状。M组存在明显的肝细胞脂肪变性,肝小叶界限不清,肝索结抅紊乱,肝组织可见弥漫性、混合性的空泡及气球样改变,细胞肿胀变圆,胞浆疏松,胞内含有大、小脂滴并有融合,部分胞核被挤到胞膜,汇管区和小叶内可见大量中性粒细胞浸润呈灶状积聚,脂变细胞以腺泡区明显。与M组相比,各给药组病变有不同程度减轻,损伤面积明显减小,胞内脂滴及炎性细胞浸润减少,小叶结构不同程度恢复。通过油红O染色能直观地观察到肝脏内的脂肪含量。M组较N组脂肪明显增加,出现大量橘红色脂滴。给予白头翁皂苷B4和非诺贝特治疗后,肝脏内橘红色脂滴减少,疗效相当。
如图6所示,与正常组比较,高脂饲料模型组血清CHO、HDL和LDL水平显著升高;经过腹腔注射和灌胃2种给药途径的白头翁皂苷B4和非诺贝特治疗后,血清CHO、HDL和LDL水平均显著下降。以上结果提示白头翁皂苷B4可通过降低血清CHO、HDL和LDL水平而对肝脏脂质积累发挥一定有益作用。
以上结果表明,白头翁皂苷B4可以有效地降低高脂饮食导致的大鼠肝脏的脂质堆积,且疗效与阳性对照药非诺贝特相当。值得注意的是,临床研究和动物实验发现非诺贝特虽然降低肝脏脂质堆积,但使用此药,应定期检测肝功能,警惕其肝毒性,而白头翁皂苷B4在动物实验中则不具有此类副作用。这提示白头翁皂苷B4在临床应用中有可能避免非诺贝特导致肝毒性的副作用,因此可用于预防和治疗非酒精性脂肪性肝病(NAFLD)。
急性肝损伤与非酒精性脂肪肝发病机制不同,急性肝损伤是指患者在无慢性肝病基础上,由各种因素导致的急性肝脏功能异常。临床上造成急性肝损伤的原因主要有病毒感染、肝毒性药物、食物添加剂、乙醇摄入过量、误服有毒食物、放射线损伤等。肝损伤的发生机制可分为化学性和免疫性。化学机制主要通过细胞色素P450及结合反应产生的中间代谢产物产生损伤,如改变质膜的完整性、线粒体功能失调、细胞内离子浓度变化、降解酶的活性和自由基的作用等;免疫机制则通过细胞因子、一氧化氮、补体及免疫变态反应、病理性细胞凋亡等产生损伤。目前治疗急性肝损伤的药物主要有甘草酸二铵、还原型谷胱甘肽、S-腺苷甲硫氨酸、水飞蓟宾、熊去氧胆酸,此类药物作为NAFLD患者的辅助治疗,尤其对NASH的治疗效果仍需进一步的临床试验证实。而非酒精性脂肪肝是一种慢性肝病,富含饱和脂肪酸和果糖的高热量膳食结构和久坐少动的生活方式也是诱发NAFLD的重要因素。目前治疗NAFLD的药物主要有吡格列酮、二甲双胍、非诺贝特、奥利司他等,主要通过改善胰岛素抵抗,降血脂,减轻体重来发挥治疗NAFLD的效果,但是均没有肝脏组织学改善作用,甚至会诱发罕见但严重的肝损害。综上非酒精性脂肪肝的病症和治疗机理与急性肝损伤并不相同,不能与急性肝损伤等同视之。
本发明首次公开了白头翁皂苷B4在制备预防、治疗非酒精性脂肪肝的药物中的应用。通过白头翁皂苷B4对高脂饮食(HFD)诱导NAFLD大鼠模型的保护作用说明白头翁皂苷B4治疗非酒精性脂肪肝的效果。结果表明,白头翁皂苷B4可以有效地降低高脂饮食导致的大鼠肝脏的脂质堆积,且疗效与阳性对照药非诺贝特相当。尤其是,临床研究和动物实验发现非诺贝特虽然降低肝脏脂质堆积,但使用此药,存在肝毒性的问题,而白头翁皂苷B4在动物实验中则不具有此类副作用。
Claims (10)
1.白头翁皂苷B4在制备预防非酒精性脂肪肝的药物中的应用。
2.白头翁皂苷B4在制备治疗非酒精性脂肪肝的药物中的应用。
3.白头翁皂苷B4在制备治疗非酒精性脂肪性肝炎的药物中的应用。
4.白头翁皂苷B4在制备预防非酒精性脂肪性肝炎的药物中的应用。
5.白头翁皂苷B4在制备治疗高脂饮食所致的血液中脂肪酸酯和胆固醇异常升高的药物中的应用。
6.根据权利要求1至5任意一项所述的应用,其特征在于,药物为注射药物或者口服药物。
7.根据权利要求1至5任意一项所述的应用,其特征在于,药物的活性成分为白头翁皂苷B4。
8.根据权利要求1或者2所述的应用,其特征在于,非酒精性脂肪肝为高脂饮食所致的非酒精性脂肪肝。
9.根据权利要求3或者4所述的应用,其特征在于,非酒精性脂肪性肝炎为高脂饮食所致的非酒精性脂肪性肝炎。
10.一种预防或者治疗非酒精性脂肪肝的药物,或者预防或者治疗非酒精性脂肪性肝炎的药物,其活性成分为白头翁皂苷B4。
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CN114931582A (zh) * | 2022-05-11 | 2022-08-23 | 广西馨海药业科技有限公司 | 白头翁皂苷组合物在制备治疗动脉粥样硬化的药物中的应用 |
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