CN107174593B - 银杏叶提取物与支链氨基酸在制备预防/治疗脂肪肝和/或脂肪变性的药物中的应用 - Google Patents
银杏叶提取物与支链氨基酸在制备预防/治疗脂肪肝和/或脂肪变性的药物中的应用 Download PDFInfo
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Abstract
本发明涉及银杏叶提取物(GBE)与支链氨基酸(BCAA)在制备预防/治疗脂肪肝和/或脂肪变性的药物中的应用,证实了GBE与支链氨基酸在预防/治疗过程中的协同作用。本发明将GBE和BCAA组合用于制备治疗脂肪肝和脂肪变性。经试验证明,其对脂肪肝和脂肪变性均可以获得较好的效果,同时在肝损伤及防止脂肪肝的形成上具有保护作用。另外通过体内试验研究了GBE与BCAA的组合方式,为两者治疗和防止脂肪肝提供依据。BCAA的加入提高了GBE在治疗脂肪肝和脂肪变性的作用,在治疗脂肪肝时更为安全。
Description
技术领域
本发明涉及药物制剂领域,具体涉及银杏叶提取物(GBE)与支链氨基酸(BCAA)的组合在制备治疗脂肪肝和/或脂肪变性的药物中的应用。
背景技术
银杏是一种古代植物,又称作为公孙树或者白果树,该植物的树叶和果实均有重要的药物作用价值,可广泛应用于各种临床疾病的治疗。60年代中期德国科学家发现银杏叶提取物对心脑血管病和外周循环障碍疾病,有较好的治疗。近10年来,有关银杏叶提取物的化学成分,药理作用和药动学研究取得较大进展。
银杏叶提取物有效药物作用成分为内酯类物质,其在靶细胞膜受体发挥一定的药理作用,明显减轻和缓解正常细胞内的毒性反应,并明显恢复脑组织的正常生理学功能作用。近些年相关药物实验研究结果证实,银杏内酯能明显预防和抑制血小板的异常聚集现象,缓解血栓素增加的现象。此外银杏叶提取物还能够显著性降低冠心病患者血清胆固醇和甘油的表达水平,进而起到降低血液的凝滞程度,阻碍动脉粥样硬化发展过程和降低冠心病发病率等多重药理作用。
脂肪肝系中性脂肪在肝内蓄积过多所致,主要为甘油三酯。脂类在肝内蓄积超过肝重的5%,或在组织学上50%以上的肝实质脂肪化时,均可成为脂肪肝。脂肪肝是肝毒性的早起表现,如能早起诊断、早期治疗,可以阻止脂肪肝的进一步发展,甚至可以使其逆转。治疗措施包括:(1)去除病因;(2)调整饮食;(3)应用降脂药物。许多中药对脂肪肝有效,主要有丹参、决明子、何首乌等。中药的最大优点就是副作用小,具有广泛的开发前景。但是关于中药的有效成分和作用机理尚不明确。
在组成机体蛋白的20种氨基酸中,只有三种带有支链的氨基酸,分别是亮氨酸、异亮氨酸和缬氨酸,合称为支链氨基酸(BCAA)。动物体不能自身合成的三种必需氨基酸,必须从外界摄取获得。BCAA在蛋白质合成及降解、能量平衡及营养信号等方面具有调节作用。临床上BCAA可通过调整代谢来治疗和预防重症肝炎,且可恢复衰竭肝脏的代谢功能,即表明BCAA的补充疗法对肝损伤的治疗作用。另外研究发现,2型糖尿病患者体内下调BCAA的分解代谢,且BCAA在脂类代谢方面具有一定的作用。
脂肪肝发病机制复杂,需要多靶点干预,中医药由于其多靶点作用在脂肪肝的预防上占有重要位置。有研究表明,银杏叶提取物在调节高脂饮食大鼠的肝脏和血液的胆固醇水平有一定的作用,且对高脂饮食大鼠的脂肪沉积具有抑制作用。同时,已有报道表明,银杏叶提取物对脂肪肝的具有减轻作用。中国申请CN200510127742.1,CN200510038908.2,CN201410612953.3均以不同形式揭示银杏叶提取物在制备治疗脂肪肝和/或脂肪变性的药物中的应用。
目前为止,现有技术中没有关于银杏叶提取物与支链氨基酸的组合在制备治疗脂肪肝和脂肪变性的报道。针对银杏叶提取物在治疗脂肪肝的同时,支链氨基酸的保护肝损伤作用及脂类代谢的调节是否能够提高银杏叶提取物的治疗效果,已有技术也没有类似的暗示或尝试。
发明内容
本发明的第一目的在于提供银杏提取物和支链氨基酸在制备预防/治疗脂肪肝和/或脂肪变性的药物中的应用。
本发明所述的银杏提取物是指以银杏为原料,经提取后得到的混合物,所述混合物中主要成分包括银杏黄酮类、银杏萜内酯类化合物。本发明所述的银杏提取物尤其优选以醇提-酯萃法提取得到。
本发明所述的支链氨基酸为亮氨酸、缬氨酸和异亮氨酸的混合物,可市售购得。
优选地,本发明所述支链氨基酸具体成分为44.0%亮氨酸,25.5%异亮氨酸,30.5%缬氨酸,可购自于美国Sigma公司。
本发明发现银杏叶提取物在调节高脂饮食大鼠的肝脏和血液的胆固醇水平有一定的作用,且对高脂饮食大鼠的脂肪沉积具有抑制作用,且对脂肪肝的重要因素甘油三酯的水平有控制作用。而进一步结合支链氨基酸的组合有利于银杏叶提取物提高对脂肪肝的治疗效果,加强对肝脏的保护及预防脂肪肝的形成。
另外,本发明进一步发现,当银杏叶提取物与支链氨基酸的质量比为1:1~4时,二者的协同效应最为显著,尤其是银杏叶提取物和支链氨基酸的质量比为1:1、1:2和1:4时,对脂肪肝和脂肪变性的预防/治疗效果最好。
本发明所述的脂肪肝是指由于各种原因引起的肝细胞内脂肪堆积过多的病变,如营养过剩、肥胖、糖尿病、高脂血症和营养不良中的任一种或多种因素造成的脂肪肝;具体的临床表现包括疲劳、恶心、食欲不振、腹胀、肝区疼痛等,病理表现包括肝脏较大程度重大、表面光滑、质地中等应变、大泡性肝脂肪变性、肝纤维化和肝硬化等。其中,银杏叶提取物与支链氨基酸联用对于脂肪肝的预防和治疗都具有突出的活性,其中,尤其对于原发性脂肪肝和非酒精性脂肪肝的疗效更为显著。
本发明所述的脂肪变性是指除脂肪细胞外的实质细胞内出现脂滴或脂滴明显增多的现象,多发生于肝细胞。肝脏的脂肪变性与肝脏的脂肪代谢有关。当肝脏脂肪代谢过程中的任何一个环节发生障碍,均可造成肝细胞的脂肪变性:①脂蛋白的合成发生障碍;②中性脂肪合成过多;③脂肪酸氧化障碍。肝脏脂肪变性的病理变化表现为肝增大,色变黄,触之质如泥块并有油腻感。微血管局部坏死,肝细胞气球样变。光镜下早期肝脂肪变性,可表现为在肝细胞核周围出现小的脂肪空泡。之后随着脂肪变性的加重,空泡逐渐变大,分布于整个胞浆中。严重者融合成一个大泡,将细胞核挤向一边,形态与脂肪细胞类似。肝淤血时,小叶中央区缺血较重,因此脂肪变性首先在中央区发生。其中,银杏叶提取物与支链氨基酸联用对于脂肪变性的预防和治疗都具有突出的活性,其中,尤其对于肝脏表面脂肪空泡较多的肝脏脂肪变性的疗效更为显著。
本发明同时提供了一种用于预防/治疗脂肪肝和/或脂肪变性的组合物,所述组合物的活性成分包括银杏叶提取物与支链氨基酸。
优选地,所述组合物中,银杏叶提取物与支链氨基酸的质量比为1:1~4。
更优选地,所述银杏叶提取物与支链氨基酸的质量比为1:1、1:2或1:4。
本发明所述的组合物,除活性成分外,还可以进一步加入药学上可接受的载体以进一步制备成制剂。
有关药学上可接受的载体的汇编可以在《药物赋形剂手册》等工具书中找到。尤其是,所述的载体包括赋形剂,如淀粉、水等;润滑剂,如硬脂酸镁等;崩解剂,如微晶纤维素等;填充剂,如乳糖等;粘结剂,如预胶化淀粉、糊精等;甜味剂;抗氧化剂;防腐剂、矫味剂、香料等。
其中,所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、乳剂、注射剂、喷雾剂、气雾剂、凝胶剂、霜剂或贴膏剂形式存在。在制剂过程中,关于具体的辅料选择、处方设计及制备工艺等均为本领域技术人员所掌握,本发明对此不作特别限定。
本发明对银杏叶提取物+支链氨基酸的药理机制的阐明将有助于其进一步开发,为脂肪肝和脂肪变性提供新的药物靶点及先导化合物。
本发明主要针对GBE与BCAA的组合对去卵巢雌性大鼠体内脂肪肝和脂肪变性的作用及其药理机制,通过肝脏组织学分析和脂类代谢相关蛋白的表达分析,证实了GBE与BCAA对脂肪肝的预防/治疗效果。经试验证明,其对脂肪肝和脂肪变性均可以获得较好的效果,同时在肝损伤及防止脂肪肝的形成上具有保护作用。另外通过体内试验研究了GBE与BCAA的组合方式,为两者治疗和防止脂肪肝提供依据。BCAA的加入提高了GBE在治疗脂肪肝和脂肪变性的作用,在治疗脂肪肝时更为安全。
附图说明
图1为肝脏组织学分析示意图,左列为苏木精和伊红染色的石蜡切片,右列为油红O染色的冰冻切片,比例=50μm;
图2为GBE与BCAA对大鼠肝脏甘油三酯含量影响的示意图,数据表示方法为均值±标准误,n=10;a-c:同行均值具有不同肩标,差异显著(P<0.05);
图3为GBE与BCAA对大鼠肝脏CPT-1A蛋白表达影响示意图,数据表示方法为均值±标准误,n=10;a-c:同行均值具有不同肩标,差异显著(P<0.05);
图4为GBE与BCAA对大鼠肝脏CPT-1A酶活性影响的示意图,数据表示方法为均值±标准误,n=10;a-c:同行均值具有不同肩标,差异显著(P<0.05);
图5为不同比例GBE与BCAA对大鼠BRL3A肝细胞CPT-1A蛋白表达影响示意图,数据表示方法为均值±标准误;a-c:同行均值具有不同肩标,差异显著(P<0.05)。
具体实施方式
本发明通过高脂饲料及高脂饲料组添加100mg GBE/kg、100mg BCAA/kg、100mgGBE/kg+100mg BCAA/kg体重,饲养210克双侧卵巢切除的雌性大鼠12周。试验结束后,处死大鼠,采集肝脏组织。通过肝组织学分析、肝脏甘油三酯含量、CPT-1A活性的测定以及Western blot测定CPT-1A蛋白的表达,来阐述银杏叶提取物对脂肪肝和肝脏脂肪变性的影响及作用机制。通过油酸(OA)和棕榈酸(PA)诱导大鼠BRL3A肝细胞脂肪肝,通过添加GBE与BCAA的不同比例探究二者之间最佳的治疗脂肪肝的组合。
实验例1:
动物来源:SD大鼠,雌性,体重210g,购自北京实验动物中心;
饲料配方:基础饲料参照美国营养学会(AIN)-93啮齿动物的日粮,含大豆粉及无苜蓿粉。高脂饲料(HFD)为AIN-93改良配方,含有35%的脂肪(60%脂肪能量)。
分组和处理:40只210克双侧卵巢切除(OVX)的雌性大鼠,经适应性饲养一周后,随机分成4组(n=10),即:
高脂饲料组(对照组,灌胃玉米油);
高脂饲料添加GBE组(灌胃,玉米油中添加100mg GBE/kg体重);
高脂饲料添加BCAA组(灌胃,玉米油中添加100mg BCAA/kg体重);
高脂饲料添加GBE+BCAA组(灌胃,玉米油中添加100mg GBE/kg和100mg BCAA/kg体重);
试验方法:每周5天灌胃。饲养12周后,处死大鼠,采集肝脏组织。以上动物实验的所有操作都是符合动物实验指南,并经中国农业大学动物实验道德委员会批准。
试验结果:
(1)福尔马林固定和石蜡包埋的肝组织经过常规的苏木精和伊红染色。用油红O染色冰冻切片测定脂肪沉积。肝脏组织学根据脂肪变性、炎症细胞、肝细胞气球样变、炎症活动度和纤维化程度进行检查和评分。
根据肝脏组织学观察发现,高脂饲料饲喂12周后,大鼠出现了严重的脂肪变性,表现为肝脏微血管局部坏死和炎症(图1)。另一方面,添加GBE可以很好的缓解肝脏脂肪变性。通过组织切片发现在GBE添加组中,门静脉周围和静脉周围区域含有较少和较小的坏死点。高脂饲料组添加GBE、BCAA、GBE+BCAA均显著降低脂肪变性(表1)。此外,通过检测大鼠肝脏中炎症细胞的渗透物,相比于对照组,添加GBE、BCAA、GBE+BCAA组的炎症细胞的数量均下降。另外,通过观察大鼠肝脏炎症活动度和纤维化程度,发现GBE和BCAA单独添加均能降低这两项的评分,且GBE与BCAA的组合添加效果更佳显著,能够更好的缓解脂肪的变性情况。因此GBE与BCAA的组合能够通过降低肝脏炎症活动度和纤维化程度来更好的缓解肝脏的脂肪变性。
表1 高脂诱导OVX大鼠肝脏组织病理学病变情况
§肝细胞气球样变的评分为负数(不存在)或正数(存在);
ξ炎症活动度计分分为汇管区(P)、小叶内(L)、碎屑坏死(PN)及桥接坏死(BN)四项,每项依病变轻、中、重程度分别计以1、3、4分,计分公式为P+L+2(PN+BN)。因为BN、PN的严重度与预后直接相关,故其计分2倍于其它病变,在实际应用中,对二者依其轻、中、重程度直接计以2、6、8分,总分为四项计分之和;
ζ纤维化计分分中央静脉周和窦周(L)、汇管区(P)及纤维隔(S)三项,“中央静脉周及窦周”纤维化仅限于小叶内尚未构成纤维间隔者,程度相对较轻,依轻、重程度分别计1、2分;“汇管区”依纤维化范围是单纯扩大、有隔相连或已发生肝硬化给予1、2、3分;“纤维隔”的计分依间隔的数量(N)与宽度(W)及间隔内胶原沉积密度综合评分,如仅见一个极细间隔,则宽度计以0.5分,纤维化占肝穿标本2/3,计4分。总分为P+L+2(N×W)。
*表示P<0.05,**表示P<0.001,与HFD相比。
(2)大鼠肝脏甘油三酯的含量
酶法试剂盒测定甘油三酯。大鼠肝脏甘油三酯含量如图2所示,高脂饲料组的肝脏甘油三酯含量均高于其余三个处理组,GBE和BCAA单独添加均显著降低肝脏甘油三酯的含量,且两者之间的作用没有显著性差异。另外,GBE与BCAA的组合添加到高脂饲料的大鼠中,发现显著降低了肝脏甘油三酯的含量,且组合效果显著强于GBE与BCAA的单独作用,二者具有一定的叠加效应(协同增效作用)。因此,二者的联用对于脂肪肝的治疗起到显著的效果。
(3)大鼠肝脏CPT-1A表达和CPT-1A的活性
按照商业CPT-1A活性检测试剂盒测定大鼠肝脏CPT-1A的活性,Western blot测定CPT-1A蛋白表达。蛋白电泳转移到聚偏二氟乙烯膜(PVDF),封闭后孵育一抗(0.2mg/mL)(Santa Cruz Biotechnology),再孵育结合有辣根过氧化物酶二抗(HRP)。使用增强型化学发光(ECL)HRP底物(Pierce,Rockford,IL)进行免疫复合物的测定。用NIH Image J程序进行定量。
CPT-1A作为线粒体脂肪酸运输的关键酶,可调节线粒体内部脂质代谢,减少脂肪沉积。Western blot结果发现GBE组显著提高肝脏CPT-1A的蛋白表达(图3),而BCAA组对肝脏CPT-1A的蛋白表达无显著性作用,但是GBE与BCAA的组合显著的提高肝脏CPT-1A的表达,且二者的协同效果显著强于单独添加GBE组的效果,能够更有效的防止肝脏的脂肪沉积。同时,CPT-1A活性检测试剂盒测定也发现GBE与BCAA的组合添加能够更有效的提高肝脏CPT-1A的活性,促进脂肪酸的氧化。因此,GBE与BCAA的组合叠加效应能够更好的促进脂肪酸的氧化,防止肝脏脂肪的沉积,对脂肪肝的治疗更有效。
实验例2:GBE与BCAA不同比例对大鼠BRL3A肝细胞CPT-1A表达的影响
大鼠肝细胞BRL3A细胞系购自中国科学院典型培养物保藏委员会细胞库,培养在含10%胎牛血清的DMEM/F-12培养基中。培养基中含有100U/ml的青霉素,50μg/ml的链霉素,细胞培养在37℃,5%CO2的培养箱中。培养基两天更换一次。细胞用1mM的油酸(OA)和棕榈酸(PA)(OA:PA=2:1)处理24小时,诱发脂肪变性,模拟体内脂肪肝。同时用200μg/mlGBE、200μg/mlBCAA、200μg/mlGBE+BCAA(25、50、100、200、400、800、1600μg/ml)等处理细胞24小时,然后收集细胞用于后续的Western blot分析检测肝细胞CPT-1A蛋白表达,具体步骤参照实验例1。
Western blot结果发现200μg/mlGBE不能显著提高大鼠肝细胞CPT-1A蛋白的表达,而同浓度的BCAA却可以显著的提高OA/PA诱导的大鼠BRL3A肝细胞CPT-1A的蛋白表达,缓解脂肪酸导致的脂肪肝。当GBE与BCAA组合添加到脂肪酸诱导的大鼠BRL3A肝细胞中发现,当GBE与BCAA的添加比例为8:1和4:1时,其对CPT-1A的表达与对照组无显著差异,而当其二者比例为2:1时,对CPT-1A的蛋白表达有显著的提高,与对照组相比,能够显著提高细胞脂肪酸的氧化。当BCAA的添加量增多,即GBE与BCAA的添加比例1:1、1:2、1:4时,三组极显著的提高细胞CPT-1A的蛋白表达,且作用效果显著强于其他处理组。另外当添加比例为1:8时,细胞中CPT-1A的蛋白表达下降,恢复到与对照组没有显著差异的水平,这可能与高浓度BCAA之间存在的拮抗作用有关(图5)。由此可见GBE与BCAA的组合在体内试验中也可以显著的缓解大鼠肝细胞的脂肪肝,且GBE与BCAA的添加比例为1:1~1:4,尤其1:1、1:2、1:4时,其作用效果最佳。
实施例1
本实施例提供了一种药物组合物,该药物组合物中,银杏叶提取物与支链氨基酸的质量比为1:1。
实施例2
本实施例提供了一种药物组合物,该药物组合物中,银杏叶提取物与支链氨基酸的质量比为1:2。
实施例3
本实施例提供了一种药物组合物,该药物组合物中,银杏叶提取物与支链氨基酸的质量比为1:4。
虽然,上面以最佳实施例详细说明了本发明,但本领域技术人员应当知晓,在不偏离本发明思想和精神的前提下,对本发明做出的任何改进和修饰,仍属于本发明要求保护的范围内。
Claims (4)
1.银杏叶提取物与支链氨基酸在制备预防/治疗脂肪肝的药物中的应用;所述银杏叶提取物与支链氨基酸的质量比为1:1、1:2或1:4,所述的支链氨基酸成分为44.0%亮氨酸,25.5%异亮氨酸,30.5%缬氨酸;所述脂肪肝为原发性脂肪肝或非酒精性脂肪肝。
2.根据权利要求1所述的应用,其特征在于:所述的银杏提取物为EGB761®标准化提取物。
3.一种用于预防/治疗脂肪肝的组合物,其特征在于:所述组合物的活性成分包括银杏叶提取物与支链氨基酸;所述组合物中,银杏叶提取物与支链氨基酸的质量比为1:1、1:2或1:4;所述的支链氨基酸成分为44.0%亮氨酸, 25.5%异亮氨酸,30.5%缬氨酸;所述脂肪肝为原发性脂肪肝或非酒精性脂肪肝。
4.根据权利要求3所述的组合物,其特征在于:所述的组合物为片剂、胶囊剂、丸剂、散剂、颗粒剂或糖浆剂。
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CN101919884A (zh) * | 2009-06-09 | 2010-12-22 | 上海生物芯片有限公司 | 银杏叶提取物在制备治疗脂肪肝药物中的应用及组合物 |
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CN101919884A (zh) * | 2009-06-09 | 2010-12-22 | 上海生物芯片有限公司 | 银杏叶提取物在制备治疗脂肪肝药物中的应用及组合物 |
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