CN111053781A - 连翘酯苷a的新用途 - Google Patents
连翘酯苷a的新用途 Download PDFInfo
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- CN111053781A CN111053781A CN202010059605.3A CN202010059605A CN111053781A CN 111053781 A CN111053781 A CN 111053781A CN 202010059605 A CN202010059605 A CN 202010059605A CN 111053781 A CN111053781 A CN 111053781A
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- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
本发明涉及医药学领域,特别是涉及一种皂苷化合物的新的医药用途。本发明的连翘酯苷A可用于制备防治非酒精性脂肪性肝病的药物。
Description
技术领域
本发明涉及医药领域,特别是涉及一种皂苷类化合物的新用途。
背景技术
非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是指排除过量饮酒和其他明确的损肝因素,以弥漫性肝细胞大泡性脂肪变为主要病理特征的临床综合征。NAFLD包括单纯性脂肪肝(nonalcoholic fatty liver,NAFLD)、非酒精性脂肪性肝炎(non-alcoholic ateatohepatitis,NASH)以及相关由此进一步演变发展的肝硬化和肝癌。非酒精性脂肪性肝病(NAFLD)影响全球25%的成年人,是全球最常见的慢性肝病。随着肥胖和糖尿病患者的增多,NAFLD已成为西方发达国家慢性肝病和肝功能试验异常的首要病因,并呈现全球化和低龄化趋势。在中国,目前患有脂肪肝的人口占全国的20~30%,NAFLD的普通成人患病率高达15%以上,其中非酒精性脂肪肝(NAFL)10~20年肝硬化率为0.6%~3%,非酒精性脂肪肝炎(NASH)10~15年肝硬化率可达15%~25%。目前尚无治疗NAFLD的特效药物。对于非酒精性脂肪性肝病的预防、治疗是全世界科研人员、临床医生所面临的巨大挑战。
连翘酯苷A(Forsythiaside A,FTA)是清热解毒中药连翘(Forsythiae Fructus)中的主要活性成分。连翘(拉丁学名:Forsythia suspense),又名黄花条、连壳、青翘等;果实入药;性味苦凉微寒;具有清热,解毒,散结,消肿的功效。
发明内容
本发明的目的旨在提供一种连翘酯苷A的新的医药用途。
具体地说,本发明的第一方面是提供了连翘酯苷A在制备防治非酒精性脂肪性肝病的药物中的应用。
较优选地,所述的连翘酯苷A是作为唯一的原料药应用于防治非酒精性脂肪性肝病的药物的制备中。
本发明各个方面的细节将在随后的章节中得以详尽描述。通过下文以及权利要求的描述,本发明的特点、目的和优势将更为明显。
附图说明
图1是FTA降低MCD诱导小鼠NAFLD进程中升高的血清中ALT、AST酶活力(A.ALT;B.AST)。MCS:MCS饲料喂养的对照组,MCD:MCD饲料诱导的模型组,MCD+FTA(20mg/kg)组;MCD+FTA(80mg/kg)组。数据均用平均数±标准误(Mean±SEM)表示;与空白组相比,*P<0.05,**P<0.01,***P<0.001;与模型组相比,#P<0.05,##P<0.01,###P<0.001。
图2是肝组织病理H&E染色图。MCS:MSC饲料喂养的对照组;MCD:MCD饲料诱导的模型组;MCD+FTA(20mg/kg)组;MCD+FTA(80mg/kg)组。
图3是FTA降低MCD诱导升高的肝组织中甘油三酯(TG)和游离脂肪酸(NEFA)的含量(A.TG;B.NEFA)。MCS:MCS饲料喂养的对照组;MCD:MCD饲料诱导的模型组;MCD+FTA(20mg/kg)组;MCD+FTA(80mg/kg)组。数据均用平均数±标准误(Mean±SEM)表示,与空白组相比,*P<0.05,**P<0.01,***P<0.001;与模型组相比,#P<0.05,##P<0.01,###P<0.001。
图4是肝组织病理Masson染色和天狼星红染色图(A.Masson染色;B.天狼星红染色)。MCS:MSC饲料喂养的对照组;MCD:MCD饲料诱导的模型组;MCD+FTA(20mg/kg)组;MCD+FTA(80mg/kg)组。
图5是FTA降低MCD诱导升高的肝脏羟脯胺酸含量。MCS:MCS饲料喂养的对照组;MCD:MCD饲料诱导的模型组;MCD+FTA(20mg/kg)组;MCD+FTA(80mg/kg)组。数据均用平均数±标准误(Mean±SEM)表示,与空白组相比,*P<0.05,**P<0.01,***P<0.001;与模型组相比,#P<0.05,##P<0.01,###P<0.001。
具体实施方式
本发明人通过体内和体外实验研究,意外地发现连翘酯苷A能够显著性地减轻诱非酒精性脂肪性肝病动物的肝损伤。故而,该化合物可用于制备防治非酒精性脂肪性肝病的药物。
如本领域的技术人员所知,本发明的连翘酯苷A具有如下结构通式:
分子式:C29H36O15 分子量:624.59
本发明的连翘酯苷A可通过本领域的常规方法从本犀科植物连翘Forsythiasuspense(Thunb.)Vahl的干燥果实中提取获得,或者利用市售原料,通过现有技术中传统的化合物合成方法合成获得。本领域的普通技术人员根据现有公知技术可以合成本发明的化合物。合成的化合物可以进一步通过柱色谱法、高效液相色谱法或结晶等方式进一步纯化。
合成化学改造、保护官能团方法学(保护或去保护)对合成应用化合物是很有帮助的,并且是现有技术中公知的技术,如R.Larock,Comprehensive OrganicTransformations,VCH Publishers(1989);T.W.Greene and P.G.M.Wuts,ProtectiveGroups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999);L.Fieser andM.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley andSons(1994);and L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,John Wiley and Sons(1995)中都有公开。
本发明的连翘酯苷A可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成分的本发明的连翘酯苷A及可药用载体。较佳地,本发明的药物组合物含有0.1~99.9%重量百分比的作为活性成分的本发明的连翘酯苷A。“可药用载体”不会破坏本发明的连翘酯苷A的药学活性,同时其有效用量,即能发挥药物载体作用时的用量对人体无毒。
所述可药用载体包括但不限于:软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂(如微晶纤维素)、填充剂(如淀粉、葡萄糖、无水乳糖和乳糖珠粒)、崩解剂(如交联PVP、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素)、润滑剂(如硬脂酸镁)以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
本发明的连翘酯苷A以及其药物组合物可按本领域常规方法制备并可以通过肠道或非肠道或局部途径给药。口服制剂包括胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等;非肠道给药制剂包括注射液等;局部给药制剂包括霜剂、贴剂、软膏剂、喷雾剂等。优选为口服制剂。
本发明的连翘酯苷A以及其药物组合物的给药途径可以为口服、舌下、经肌肉或皮下、静脉、尿道、阴道等。
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。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比率、比例、或份数按重量计。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征,或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用,说明书中所揭示的各个特征,可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明,所揭示的特征仅为均等或相似特征的一般性例子。
实施例1
以蛋氨酸-胆碱缺乏饲料(MCD)诱导小鼠非酒精性脂肪性肝炎评价连翘酯苷A(FTA)对非酒精性脂肪性肝病的治疗作用,具体方法如下:
1.实验材料
1.1实验动物
C57BL/6雄性小鼠,体重18~22g,购自上海斯莱克实验动物有限责任公司。小鼠饲养温度(22±1)℃,相对湿度(65±10)%,照明时间每天12h。
1.2受试药品及其制备
MCS对照饲料(饲料代码TP3005G)及MCD模型饲料(饲料代码TP3005GS),南通特洛菲饲料科技有限公司。
连翘酯苷A购自上海源叶生物技术有限公司,纯度98%以上。称取连翘酯苷A,溶于生理盐水,制备成2mg/mL及4mg/mL的均一溶液。
2.实验方法
2.1.动物实验方案
将实验动物随机分为4组,每组7只,分别为:MSC饲料喂养的空白对照组;MCD饲料喂养诱导的模型组;MCD+FTA(20mg/kg)组;MCD+FTA(80mg/kg)组。实验共需时长7周,第一周为过渡期,除正常组采用MCS饲料喂养一周之外,其他组小鼠第1天~第2天均采用MCD饲料与MCS饲料以1:2混合后喂养;第3天~第4天均采用MCD饲料与MCS饲料以1:1混合后喂养;第5天~第6天均采用MCD饲料与MCS饲料以2:1混合后喂养;第七天开始采用MCD饲料喂养。从第2周开始至实验结束,共计6周为正式实验,正常组用MCS饲料喂养,第6周开始每日灌胃生理盐水10mL/kg,共计2周;模型组用MCD饲料喂养,第6周开始每日灌胃生理盐水10mL/kg,共计2周;FTA(20mg/kg)组用MCD饲料喂养,第6周开始每日灌胃FTA(20mg/kg),共计2周。FTA(40mg/kg)组用MCD饲料喂养,第6周开始每日FTA(40mg/kg),共计2周。持续给药2周后,各组禁食4小时,进行处理取材,摘取眼球取血,供测定血清生化指标,解剖取肝组织,液氮速冻,放于-80℃保存备用。
2.2血清中ALT、AST酶活性检测
将取自小鼠眼球的血浆在4℃冰箱静置2h以上后,常温、860g离心15min,取上清即血清,采用ALT、AST试剂盒(南京建成生物试剂有限公司)检测血清中ALT/AST水平。
2.3肝组织H&E病理染色
取相同部位(肝大叶)肝组织进行病理学检查,用10%甲醛溶液固定,石蜡包埋,切片,一部分石蜡切片留取待用,一部分石蜡切片用苏木精-伊红染色,光学显微镜下观察,评估各组形态变化。
2.4肝组织中甘油三酯(TG)含量检测
称取小鼠肝脏组织25mg,按照重量(g):体积(mL)=1:9的比例,加入9倍体积的匀浆介质无水乙醇,冰水浴条件下机械匀浆,2500转/分,离心10分钟,取上清液待测。在96孔板中选择一个空白孔,一个标准孔,其它为样本空,分别在空白孔,标准孔及样本孔中加入2.5μL蒸馏水、标准品和样本,每孔加入250μL工作液,混匀后,37℃孵育10分钟,波长510nm,酶标仪测定各孔吸光度值。数据计算处理后结果如图4所示。组织样本计算公式:
甘油三酯含量=(样本OD值-空白OD值)÷(校准OD值-空白OD值)×校准品浓度(mmol/L)÷待测样本蛋白浓度(gprot/L)
2.5肝组织中游离脂肪酸(NEFA)含量检测
准确称取组织重量20mg,按重量(g):体积(mL)=1:9的比例,加入9倍体积的生理盐水,冰水浴条件下机械匀浆,制成10%的匀浆,2500转/分,离心10分钟,取上清测定。在96孔板中选定一个空白孔加入4μL双蒸水,选定一个校准孔加入1.00mmol/L的校准品4μL,其余为样本孔加入样本4μL,分别在各孔中加入试剂一200μL,混匀,37℃孵育5min,在波长546nm处读取吸光度值A1,各孔加入试剂二50μL,混匀,37℃孵育5min,读取吸光度值A2,计算ΔA=A2-A1。
组织样本NEFA浓度=(ΔA样本-ΔA空白)÷(ΔA标准品-ΔA空白)×校准品浓度(mmol/L)÷待测样本蛋白浓度(gprot/L)
2.6 Masson染色
石蜡切片脱蜡至水,依次自来水和蒸馏水洗,然后用Regaud苏木精染液或Weigert苏木精液染核5-10min,充分水洗。用Masson丽春红酸性复红液5-10min,以2%冰醋酸水溶液浸洗片刻。用1%磷钼酸水溶液分化3-5min,不经水洗,直接用苯胺蓝或光绿液染5min,以0.2%冰醋酸水溶液浸洗片刻。最后用95%酒精、无水酒精、二甲苯透明、中性树胶封固。
2.7天狼星红染色
石蜡切片常规脱蜡至水,用人大青石蓝液染5-10min,蒸馏水洗3次。然后用天狼星红饱和苦昧酸浓染15-30min,用无水乙醇直接分化与脱水。最后用二甲苯透明,中性树胶封固。
2.8羟脯氨酸(HYP)含量测定
2.8.1配液
按照南京建成HYP试剂盒要求配置好试剂一、试剂二、试剂三、试剂四。
2.8.2样本前处理
精确称取样本50mg,准确加水解液0.5ml,混匀。加盖后95℃水解20min。各管加入0.5ml调PH甲液,混匀后用调PH乙液调PH至6.0~6.8。然后加双蒸水至5ml,混匀。取0.5ml稀释的水解液加活性炭混匀,3500转/分离心10min,取上清液0.25ml。按照试剂盒要求分别加入试剂一、试剂二、试剂三,混匀,60℃水浴15min,冷却后,3500转/分离心10min,取上清于波长550nm,测定各管吸光度值。
2.8.3计算公式
羟脯氨酸含量=(测定OD值-空白OD值)÷(标准OD值-空白OD值)×标准品浓度×(水解液总体积÷组织湿重)
2.9数据统计
实验数据以平均值±标准误(Mean±SEM)表示,采用SPSS 16.0软件进行统计,组之间用One-Way ANOVA统计方法进行方差分析。数据均用平均数±标准误(Mean±SEM)表示,与空白组相比,*P<0.05,**P<0.01,***P<0.001;与模型组相比,#P<0.05,##P<0.01,###P<0.001。
3.实验结果
3.1连翘酯苷A(FTA)减少MCD饲料诱导的小鼠肝功能损伤
MCD饲料喂养小鼠组,血清中ALT、AST酶活性明显升高;FTA(20mg/kg)组及FTA(80mg/kg)组小鼠血清的ALT、AST水平明显低于MCD模型组,各组间差异具有统计学意义。实验结果显示,FTA能够降低MCD诱导NAFLD进程中升高的小鼠ALT、AST酶活性,减轻肝功能损害(图1)。
肝组织H&E染色结果显示,MCD模型组中有明显的肝细胞坏死及气球样变,FTA给药可明显改善这些现象(图2)。
3.2连翘酯苷A(FTA)改善MCD诱导NAFLD进程中小鼠的肝脏炎症
肝组织H&E染色结果显示,MCD模型组肝组织中伴有明显的炎性细胞浸润,而FTA给药后肝组织的炎性浸润得到明显的改善。
3.3连翘酯苷A(FTA)减少MCD诱导NAFLD进程中小鼠肝脏的脂质堆积
MCD饲料喂养小鼠导致肝组织中TG和NEFA的含量明显上升,而FTA(20mg/kg)、FTA(40mg/kg)组小鼠肝组织中TG和NEFA的含量明显低于MCD模型组,各组间差异具有统计学意义。实验结果显示,FTA能够减少MCD诱导NAFLD进程中小鼠肝组织中TG和NEFA含量的升高,减轻小鼠肝组织中脂质的堆积(图3)。
3.4连翘酯苷A(FTA)减少MCD诱导NAFLD进程中小鼠肝纤维化
肝组织Masson染色和天狼星红染色结果显示,MCD模型组肝组织中伴有明显的胶原沉积,而FTA给药后胶原沉积得到明显改善(图4)。
MCD饲料喂养小鼠导致肝组织中羟脯胺酸含量明显上升,而FTA(20mg/kg)、FTA(40mg/kg)组小鼠肝组织中羟脯胺酸含量明显低于MCD模型组,各组间差异具有统计学意义。实验结果显示,FTA能够减少MCD诱导NAFLD进程中小鼠肝组织中羟脯胺酸含量的升高,减轻小鼠肝组织中胶原沉积(图5)。
实施例2(片剂的制备)
取连翘酯苷A 500g,喷入适量75%乙醇,加入17.5%微晶纤维素,其中内加7.5%微晶纤维素和20%淀粉,制成颗粒,干燥,外加10%微晶纤维素和1%的硬脂酸镁,混匀压片。
实施例3(滴丸剂的制备)
取连翘酯苷A 500g,以PGE4000为基质,与药物的比例为1:1.5,二甲基硅油为冷凝剂,滴制。
实施例4(胶囊剂的制备)
取连翘酯苷A 500g,加入5%硬脂酸镁,混匀装入硬胶囊。
本发明所涉及的多个方面已做如上阐述。然而,应理解的是,在不偏离本发明精神之前提下,本领域专业人员可对其进行等同改变和修饰,所述改变和修饰同样落入本申请所附权利要求的覆盖范围。
Claims (2)
1.连翘酯苷A在制备防治非酒精性脂肪性肝病的药物中的应用。
2.如权利要求1所述的用途,其特征在于,所述的连翘酯苷A是作为唯一的原料药应用于防治非酒精性脂肪性肝病的药物的制备中。
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CN101134040A (zh) * | 2006-08-30 | 2008-03-05 | 山东绿叶天然药物研究开发有限公司 | 连翘酯苷在制备治疗或预防急慢性肝损伤及肝纤维化的药物中的应用 |
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张立伟等: "连翘酯甙分离提取及抑制弹性蛋白酶活性研究", 《化学研究与应用》 * |
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