CN103908460A - 三七皂苷Fc的医药用途 - Google Patents
三七皂苷Fc的医药用途 Download PDFInfo
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- CN103908460A CN103908460A CN201310601145.2A CN201310601145A CN103908460A CN 103908460 A CN103908460 A CN 103908460A CN 201310601145 A CN201310601145 A CN 201310601145A CN 103908460 A CN103908460 A CN 103908460A
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Abstract
本发明涉及医药学领域，特别是涉及一种三七皂苷Fc的医药用途。本发明的三七皂苷Fc可用于防治各种血栓性疾病。
Description
技术领域
本发明涉及医药领域，特别是涉及一种三七皂苷Fc的医药用途。
背景技术
血栓形成（thrombosis）是指在一定条件下血液中的有形成分在血管（多数为小血管）形成栓子，导致血管部分或全部堵塞、相应组织器官血供障碍的病理过程。依其组成成分，血栓可分为：血小板血栓、红细胞血栓、纤维蛋白血栓、混合血栓等四种。按形成血栓的血管种类，血栓又可分为动脉性血栓、静脉性血栓以及毛细血管性血栓。
血栓栓塞（thromboembolism）是指血栓从其形成部位脱落，在随血液流动的过程中部分或全部堵塞某些血管，进而导致相应组织器官缺血、缺氧、坏死（动脉血栓）和/或瘀血水肿（静脉血栓）的病理过程。
以上两种病理过程所引发的疾病，临床上通称为血栓性疾病。本病的病因及发病机制十分复杂，迄今尚未完全明确，但近年的研究表明，血栓性疾病的发生、发展主要与下列两种因素有关：
一、血小板数量增加，活性增强。各种导致血小板数量增加、活性增强的因素，均有诱发、促进血栓性疾病发生的可能性，如血小板增多症、机械、化学、生物及免疫反应等导致的血小板破坏加速等。目前认为，血小板因素在动脉血栓形成（如心肌梗死）的发病中具有更为重要的地位。
二、血液凝固性增高。在多种生理及病理状态下，人体的凝血活性可显著增强，表现为某些凝血因子水平升高或活性增加，如妊娠、高龄及创伤感染等所致的应激反应以及高脂血症、恶性肿瘤等。而血液的高凝状态正是血栓性疾病的发病基础。
三七皂苷Fc（Notoginsenoside Fc）是一种天然的皂苷类化合物，主要存在于三七中。研究发现，三七皂苷具有降血脂、抗肿瘤、抗氧化等作用。
发明内容
本发明的目的旨在提供一种三七皂苷Fc的新的医药用途。
具体地说，本发明提供了一种三七皂苷Fc在制备血小板聚集抑制剂中的应用。
本发明的第二方面是提供了一种三七皂苷Fc在制备凝血抑制剂中的应用。
本发明的第三方面是提供了一种具有血栓性疾病防治作用的药物组合物或食品，它包含治疗有效量的三七皂苷Fc。
在一优选例中，所述血栓性疾病为血小板聚集功能亢进或高凝血症。
本发明的第四方面是提供了一种三七皂苷Fc在制备血小板聚集抑制剂中的应用，所述三七皂苷Fc的浓度为0.01-400μM。
本发明的第五方面是提供了一种三七皂苷Fc在制备凝血抑制剂中的应用，所述三七皂苷Fc的浓度为0.01-240mg/ml。
本发明的第六方面是提供了一种三七皂苷Fc在制备治疗或预防血栓性疾病的药物组合物的应用，所述三七皂苷Fc的浓度为0.01-240mg/kg。
本发明的第七方面是提供了一种三七皂苷Fc在制备治疗或预防血栓性疾病的药物组合物的应用，所述血栓性疾病是：动脉性血栓、静脉性血栓和毛细血管性血栓，所述三七皂苷Fc的浓度为0.01-240mg/kg。
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体现了Fc对血小板聚集率的影响；
图2体现了Fc对血小板聚集率的量效关系；
图3体现了Fc对整体动物血小板聚集率的影响；
图4体现了Fc对大鼠断尾凝血时间影响；
图5体现Fc对大鼠活化部分凝血活酶时间；
图6体现了Fc对大鼠与人类凝血四项指标的影响；
图7体现了Fc对人类PT时间的影响。
具体实施方式
本发明的问世部分是基于这样一个意外发现：三七皂苷Fc可以明显抑制大鼠的血小板聚集，延长活化部分凝血活酶时间。因此，三七皂苷Fc有望开发成为一种抑制血小板聚集的物质即血小板聚集抑制剂和/或一种抑制凝血的物质即凝血抑制剂，所述“血小板聚集抑制剂”和“凝血抑制剂”可以是各种形式的物质，包括但不限于：药物、保健品、食品、日用品等等。用三七皂苷Fc制备的这些“血小板聚集抑制剂”和“凝血抑制剂”可用于防治各种血栓性疾病如动脉性血栓、静脉性血栓以及毛细血管性血栓等。
进而，本发明提供了三七皂苷Fc在制备血小板聚集抑制剂中的应用。
本发明还提供了三七皂苷Fc在制备凝血抑制剂中的应用。
本发明还提供了一种具有血栓性疾病防治作用的的药物组合物或食品，它包含治疗有效量的三七皂苷Fc。
较优选的，所述血栓性疾病为血小板聚集功能亢进或高凝血症。
本发明还提供了一种三七皂苷Fc在制备血小板聚集抑制剂中的应用，所述三七皂苷Fc的浓度为0.01-400μM。
本发明还提供了一种三七皂苷Fc在制备凝血抑制剂中的应用，所述三七皂苷Fc的浓度为0.01-240mg/ml。
本发明还提供了一种三七皂苷Fc在制备治疗或预防血栓性疾病的药物组合物的应用，所述三七皂苷Fc的浓度为0.01-240mg/kg。
本发明还提供了一种三七皂苷Fc在制备治疗或预防血栓性疾病的药物组合物的应用，所述血栓性疾病为：动脉性血栓、静脉性血栓和毛细血管性血栓，所述三七皂苷Fc的浓度为0.01-240mg/kg。
本发明的三七皂苷Fc（Notoginsenoside Fc）的分子式为：C58H98O26，分子量为：1210.63，其结构式如下：
本发明的三七皂苷Fc可通过商业途径从Sigma化学公司、成都曼斯特生物科技有限公司等处购买获得，或者用本领域的常规方法从三七皂苷中分离获得。其纯度均符合药用标准。
以将本发明的三七皂苷Fc制成药物为例。本发明的三七皂苷Fc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三七皂苷Ft1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三七皂苷Fc。“可药用载体”不会破坏本发明的三七皂苷Fc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。
本发明的三七皂苷Fc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。
本发明的三七皂苷Fc以及其药物组合物的给药途径可以为口服、舌下、经皮、经肌肉或皮下、皮肤粘膜、静脉、尿道、阴道等。
除了制成药物之外，亦可在本发明的三七皂苷Fc中加入抗氧化剂、色素、酶制剂等各种食品添加剂，按本领域的常规方法制成保健食品。
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：
本实施例中所用的三七皂苷Fc来源为上海中医药大学中药研究所分离、制备，（氯吡格雷购自中国生物制品检定所）。所用样品的纯度均符合药用标准。
1、实验材料
1.1药材
三七皂苷Fc（分子量1211.38，HPLC纯度≥99%，中药研究所）；氯吡格雷（分子量419.90，HPLC纯度≥98%，购自中国生物制品鉴定所）；人类标准血浆、凝血四项测试试剂（均购自德国SIEMENS公司）；二磷酸腺苷（ADP）（购自Sigma公司）
1.2实验动物
体重230±20g的SD大鼠，由上海中医药大学实验动物中心提供，动物合格证号：SYXK（沪）2008-0016。置于常规饲养环境，自由进食和饮水。
2、实验方法
2.1Fc对血小板聚集的影响
2.1.1体外血小板聚集实验：抽取的血液加入枸橼酸钠抗凝。100g离心5min，取上清，即得富血小板（PRP）；将所得PRP加入前列腺环素（2μg/ml），离心5min（700g）；再加入0.9％的生理盐水清洗两次；清洗后将血小板悬浮于Tyrodebuffered中，并使其浓度为4*108，备用；按比浊法进行血小板聚集测定：将血小板血浆置于比色管杯中，加入诱聚剂（ADP：5-腺苷二磷酸二钠盐：1×10-4mol/L）。后，用小磁粒进行搅拌，血小板逐渐聚集，血浆浊度降低，透光度增加。记录此变化，形成血小板聚集的动态曲线。以PRP的聚集率和透光度为0，以悬浮液所测得的聚集率和透光度为100%，用血小板聚集仪进行自动测定、记录、描绘血小板聚集曲线。对抑制或促进聚集的判断，主要观察是否与诱导剂发生协同作用或拮抗作用。发生协同作用即为促进血小板聚集，发生拮抗作用的即为抑制血小板聚集。
2.1.2整体动物血小板聚集实验：动脉血流中的血小板当接触丝线的粗糙表面是粘附与线上，在其表面形成血小板血栓。血小板的粘附聚集功能受到抑制时，血栓重量较轻。因此，从血栓重量可测知血小板粘附聚集功能的情况。
2.1.2整体动物凝血功能评价
2.1.2.1大鼠断尾凝血时间测定：以利剪将大鼠尾尖0.5cm处横断，待血液自行溢出后开始记时，每隔30s用滤纸吸去血滴1次，直至血流自然停止（滤纸吸时无血）为止，即为出血时间。
2.1.2.2凝血四项指标测定：1）凝血四项指标：凝血酶原时间（prothrombintime，PT）：主要反映内源性凝血系统状况，常用于监测肝素用量。增高见于血浆因子Ⅷ、因子Ⅸ和因子XI水平减低：如血友病A、血友病B及因子XI缺乏症；降低见于高凝状态：如促凝物质进入血液及凝血因子的活性增高等情况；活化部分凝血活酶时间（activated partial thromboplatin time,APTT）：主要反映内源性凝血系统状况，常用于监测肝素用量。增高见于血浆因子Ⅷ、因子Ⅸ和因子XI水平减低：如血友病A、血友病B及因子XI缺乏症；降低见于高凝状态：如促凝物质进入血液及凝血因子的活性增高等情况；凝血酶时间测定（thrombintime，TT）：主要反映纤维蛋白原转为纤维蛋白的时间。增高见于DIC纤溶亢进期，低（无）纤维蛋白原血症，异常血红蛋白血症，血中纤维蛋白（原）降解产物（FDPs）增高；降低无临床意义；纤维蛋白原（Fibrinogen，FIB）：主要反映纤维蛋白原的含量。增高见于急性心肌梗死减低见于DIC消耗性低凝溶解期、原发性纤溶症、重症肝炎、肝硬化；
2.2分组及给药方法
空白对照：0.9％生理盐水（NS）。
诱导剂组：二磷酸腺苷（ADP）（10mM）
阳性对照药：氯吡格雷（5mM）。
用药组：每组六只，Fc用双蒸水溶解（配置各个不同浓度的溶液）。
2.4统计分析
所有实验数据均重复3次，结果以平均值±标准差表示，采用SPSS13.0统计软件对实验数据采用单向方差分析（One-way ANOVA）及LSD检验，P<0.05为统计学上差异有显著性。
3、结果
3.1三七皂苷Fc对血小板聚集的抑制作用。
3.1.1Fc对血小板聚集率的影响
图1和表1体现了三七皂苷Fc对血小板聚集率的影响，由图1可见：诱导剂（ADP）单用组聚集率为52.9%，联合引用Fc（给药剂量均为200μM）后聚集率为25.8%，Fc组的聚集率小于诱导剂单用组（*P<0.05），并小于阳性药组（*P<0.05）。这说明Fc拮抗诱导剂诱导的血小板聚集。
另外，由图1可见：总提取物组聚集率为40.1%，明显高于Fc给药组（25.8%）（**P<0.01），这说明Fc单体在抑制血小板聚集的药效上优于总提取物给药组。
表1三七皂苷Fc对血小板聚集的量效关系
3.1.1Fc对血小板聚集率的量效关系
图2体现了三七皂苷Fc对血小板聚集率的量效关系，由图2可见：Fc（0.1μM、10μM、20μM、30μM、40μM）对血小板聚集抑制作用的量效关系，从0.1μM---40μM的剂量范围内，血小板聚集率逐渐下降。随着剂量的增加，聚集率依次下降。聚集率从最初的47.9%，降至28.1%，降幅达19.8%。其IC50值为13.5μM。
3.1.3Fc对整体动物血小板聚集率的影响
图3体现了Fc对整体动物血小板聚集率的影响，由图3可见：三七皂苷Fc的在体血小板聚集功能的影响。通过对湿重血栓的称重我们发现：Fc在体情况下仍有很强的活性。我们采用静脉注射的方法，给予大鼠Fc：8.1mg/kg。给药五分钟后开始体外侧枝循环，循环十五分钟后即终止循环，取出血栓沉重。空白对照组与Fc给药组差异性显著（**P<0.01）。
3.2三七皂苷Fc对血液凝血功能的影响
3.2.1Fc对大鼠断尾凝血时间测定
图4体现了Fc对大鼠断尾凝血时间影响，由图4可见：Fc对于大鼠断尾出血时间，有着明显的影响。Fc的血栓重量为28.2mg，；明显小于空白组：37.2mg（**P<0.01）。
3.3Fc对大鼠与人类凝血四项指标的影响
图5和表2体现Fc对大鼠活化部分凝血活酶时间（activated partialthromboplatin time,APTT）的影响，由图5可见：Fc在5μg/ml、10μg/ml、20μg/ml、80μg/ml、160μg/ml五个剂量组对APTT的量效关系。不同剂量表现出效应的逐渐增强，Ft1的剂量5μg/ml APTT时间为：19秒，240μg/ml为32秒。变化幅度为13秒。
表2三七皂苷Fc对大鼠APTT时间的量效关系
图6体现Fc对人类凝血四项指标的影响，由图6可见：Fc明显延长APTT时间，在80μg/ml剂量水平，APTT时间达到126秒，明显高于空白组（91秒）（**P<0.01）。PT时间也长于空白组（*P<0.05）；Ft1在240μg/ml的剂量水平，APTT时间仅为82秒，明显低于空白组（91秒）（**P<0.01）。PT时间为17秒，明显低于空白组（20秒）（*P<0.05）。
图7体现Fc对人类PT时间的影响：PT也长于空白组（*P<0.05）；。PT时间为17秒，明显低于空白组（20秒）（*P<0.05）。
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 (8)
1.三七皂苷Fc在制备血小板聚集抑制剂中的应用。
2.三七皂苷Fc在制备凝血抑制剂中的应用。
3.一种具有血栓性疾病防治作用的药物组合物或食品，其特征在于，它包含治疗有效量的三七皂苷Fc。
4.根据权利要求3所述的药物组合物或食品，其特征在于，所述血栓性疾病为血小板聚集功能亢进或高凝血症。
5.三七皂苷Fc在制备血小板聚集抑制剂中的应用，所述三七皂苷Fc的浓度为0.01-400μM。
6.三七皂苷Fc在制备凝血抑制剂中的应用，所述三七皂苷Fc的浓度为0.01-240mg/ml。
7.三七皂苷Fc在制备治疗或预防血栓性疾病的药物组合物中的应用，所述三七皂苷Fc的浓度为0.01-240mg/kg。
8.三七皂苷Fc在制备治疗或预防血栓性疾病的药物组合物中的应用，所述血栓性疾病是：动脉性血栓、静脉性血栓和毛细血管性血栓，所述三七皂苷Fc的浓度为0.01-240mg/kg。
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| CN104784193B (zh) * | 2014-01-16 | 2019-12-13 | 上海中医药大学 | 一种原人参二醇型三七皂苷的制药用途 |
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| CN107582560B (zh) * | 2017-10-13 | 2020-02-28 | 杨中林 | 木通皂苷d的溶血栓作用及其应用 |
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| CN103536610B (zh) | 2015-03-11 |
| CN103908460B (zh) | 2018-01-05 |
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