CN104510752A - 紫檀烷苷的医药用途 - Google Patents
紫檀烷苷的医药用途 Download PDFInfo
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- CN104510752A CN104510752A CN201410838023.XA CN201410838023A CN104510752A CN 104510752 A CN104510752 A CN 104510752A CN 201410838023 A CN201410838023 A CN 201410838023A CN 104510752 A CN104510752 A CN 104510752A
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- lignum pterocarpi
- pterocarpi indici
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- indici alkane
- alkane glycosides
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及医药学领域，特别是涉及一种紫檀烷苷的医药用途及其药物组合物。本发明的紫檀烷苷可用于制备防治帕金森氏病的药物或保健品。
Description
技术领域
本发明涉及医药保健品领域，特别是涉及一种紫檀烷苷的医药用途及其药物组合物。
背景技术
帕金森病(Parkinson's disease,PD)，又名震颤麻痹，常见于中老年人，是一类常见的神经系统变性疾病。其病理特点是中枢神经系统锥体外系功能障碍的慢性进行性病变，以中脑黑质致密部多巴胺能神经元进行性变性缺失、纹状体多巴胺能水平下降为主要特征。其发病隐匿，病程进展缓慢，临床主要表现为静止性震颤、运动迟缓、肌强直和姿势步态障碍等运动症状，部分患者可伴有嗅觉减退、自主神经功能失调、睡眠障碍、认知损害等非运动性症状，生活质量严重受损，最终导致失去生活自理能力。至今，其病因及发病机制尚未明确，亦无令人满意的有效治疗方法。
目前国内外治疗PD主要以药物去补充多巴胺或治疗因脑内多巴胺不足导致其信号转导障碍，包括左旋多巴胺(通常结合了多巴脱羧酶抑制剂或COMT抑制剂)、多巴胺激动剂。另外胆碱能拮抗剂或金刚烷胺在震颤等运动并发症上有较好疗效。但在长期服药后，脑内神经元对药物敏感性降低，可能导致“异动症”或“药效波动”的出现。例如“剂末恶化”或称“开关现象”，即药效维持时间变短，在下次服药前就提早恢复到无药效的PD病态，需要调整服药频率、换用左旋多巴控释剂、增加长半衰期的DR激动剂或增加MAO-B抑制剂等来减少中后期病患对疗效不稳定的困扰。而除了药物治疗之外，针对使用药物效果不佳的患者亦可考虑手术治疗，如深脑刺激术(Deep BrainStimulation)、苍白核烧灼术(Pallidotomy)、十二指肠多巴胺灌输术(DuoDopa)等加以治疗。职能治疗、物理治疗和语言治疗等可以为患者恢复动作功能和语言、吞咽功能提供帮助。合理选用药物和理疗可以控制或减轻运动并发症，预防继发性的功能障碍，但是现有的医疗技术暂时不能根治帕金森。
紫檀烷类化合物主要分布在豆科药材中，紫檀烷苷(Astrapterocarpan)是从中药黄芪中分离提取得到的活性单体成分，研究表明紫檀烷苷具有抗肿瘤、抗菌、抗氧化等作用。
发明内容
本发明的目的旨在提供一种紫檀烷苷的新的医药用途及其药物组合物。
具体地说，本发明的第一方面是提供了紫檀烷苷或其药学上可接受的盐、水合物或前药在制备防治帕金森氏病的药物或保健品中的应用。
在一优选例中，所述的紫檀烷苷是作为唯一的活性成分应用于防治帕金森氏病的药物或保健品的制备中。
本发明的第二方面是提供了一种可防治帕金森氏病的药物组合物，它包含治疗有效量的紫檀烷苷或其药学上可接受的盐、水合物或前药。
本发明的第三方面是提供了一种可防治帕金森氏病的保健品，它包含有效量的紫檀烷苷或其药学上可接受的盐、水合物或前药。
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紫檀烷苷对MPP+处理的SH-SY5Y细胞活力的影响(**，p<0.01；***，p<0.001；阳性药：黄芩素)。
图2紫檀烷苷显著调节MPP+处理的SH-SY5Y细胞的蛋白表达。
图3紫檀烷苷对MPTP诱导帕金森小鼠黑质区基因表达的影响(*，p<0.05；**，p<0.01；***，p<0.001)。
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：紫檀烷苷对MPTP诱导的帕金森小鼠模型中脑多巴胺能神经元损伤具有一定保护作用；能够减轻MPP+诱导的细胞凋亡和细胞形态改变，并能进一步调控神经元凋亡通路的关键分子，即下调Bax基因和Caspase 3基因的表达、上调Bcl2基因的表达，故而其有望开发为防治帕金森病的药物或保健品。
进而，本发明的第一方面是提供了紫檀烷苷或其药学上可接受的盐、水合物或前药在制备防治帕金森氏病的药物或保健品中的应用。
较优选地，所述的紫檀烷苷是作为唯一的活性成分应用于防治帕金森氏病的药物或保健品的制备中。
本发明的第二方面是提供了一种可防治帕金森氏病的药物组合物，它包含治疗有效量的紫檀烷苷或其药学上可接受的盐、水合物或前药。
本发明的第三方面是提供了一种可防治帕金森氏病的保健品，它包含有效量的紫檀烷苷或其药学上可接受的盐、水合物或前药。
如本领域的技术人员所知，本发明的紫檀烷苷(9，10-二甲氧基紫檀烷-3-O-β-D-葡萄糖苷)具有如下结构通式：
分子式：C23H28O10分子量：464.47
本发明还包括上述化合物的相应的所有药学上可以接受的盐、水合物或前药。这些盐可以由化合物中带正电荷的部分(例如，胺基)与具有相反电性的带负电荷(例如，三氟醋酸)形成；或者由化合物中带负电荷的部分(例如，羧基)与正电荷(例如，钠、钾、钙、镁)形成。化合物可以含有一个非芳香性的双键，具有一个或多个不对称中心。所以，这些化合物可以作为外消旋的混合物、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。所有这些异构体都是可预期的。所述的“紫檀烷苷的前药”通常指一种物质，当用适当的方法施用后，可在受试者体内进行代谢或化学反应而转变成紫檀烷苷或其盐。
本发明的紫檀烷苷可从蒙古黄芪中分离制备获得；或者通过商业途径购买获得，其纯度均符合药用标准；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 Organic Transformations,VCHPublishers(1989)；T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for OrganicSynthesis,John Wiley and Sons(1994)；and L.Paquette,ed.,Encyclopedia of Reagents for OrganicSynthesis,John Wiley and Sons(1995)中都有公开。
以将本发明的紫檀烷苷制成药物为例。本发明的紫檀烷苷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紫檀烷苷及可药用载体。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紫檀烷苷。“可药用载体”不会破坏本发明的紫檀烷苷的药学活性，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。
本发明的紫檀烷苷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。
本发明的紫檀烷苷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紫檀烷苷治疗帕金森氏病活性研究
1.SH-SY5Y细胞培养
SH-SY5Y细胞培养于含10％胎牛血清的DMEM培养基(100U·mL-1青霉素和100μg·mL-1链霉素)，37℃、5％CO2培养箱中培养并继代。
2.MTT法检测细胞活性
取对数生长期SH-SY5Y细胞以1×105个/mL浓度接种于96孔板中培养过夜。实验中紫檀烷苷(10、25、50、75、100μM)预处理4h后，加入1mM的MPP+作用24h。而后每孔加入10μL含5g/L的MTT溶液继续培养4h，每孔加入150μL DMSO充分振荡，待蓝色颗粒完全溶解后用全自动酶标仪测定570nm处的吸光度值，定量反映细胞存活率。
3.Western blot法检测蛋白表达
取对数生长期SH-SY5Y细胞，按1×106个/ml的浓度接种于6孔细胞培养板中培养过夜。紫檀烷苷50μM预处理4h后，加入1mM的MPP+作用24h。处理结束后，弃培养基，4℃PBS清洗1遍，每孔加100μL裂解液(含1％的磷酸酶抑制剂1和2)，冰上裂解10min后，15000rpm，4℃离心15min。取上清，BCA法测定蛋白浓度。分别取30μg样品，进行SDS-PAGE电泳。电泳结束后，湿法转膜1h，5％脱脂牛奶封闭1h，分别在4℃及相应的一抗(抗体稀释度参照说明书进行)孵育过夜，然后与HRP标记的山羊抗小鼠或山羊抗兔的二抗常温孵育1h，最后以ECL-prime试剂盒显色，暗房曝光、显影及定影。
4.动物模型的建立及分组给药
48只C57BL/6雄性小鼠，12周龄，随机分为4组，每组12只，分别为对照组、模型组、紫檀烷苷给药组(100mg·kg-1)及阳性药美多芭组(50mg·kg-1)。连续灌胃15天，于第11天开始灌胃前1h腹腔注射MPTP 30mg·kg-1(对照组给予等体积生理盐水)，连续5天，末次给药后一天处死、取材。
5.实时定量PCR检测基因表达
用Trizol法从小鼠黑质区提取总RNA，Nanodrop蛋白核酸分析仪测定RNA浓度。取2μg总RNA，反转录试剂盒(Thermo)逆转成cDNA。将上述转录产物cDNA，用ddH2O按1:5比例稀释后作为模板，进行实时定量PCR反应，检测黑质区中Caspase 3和Bcl-2基因表达，内参基因选用GAPDH，引物序列如表1所示。PCR反应条件如下：95℃预变性30sec后，进行95℃5sec变性，60℃30sec退火，共40个循环。
表1小鼠PCR引物序列
结果：
1.紫檀烷苷对MPP+诱导的SH-SY5Y细胞活力的影响
如图1A所示，MPP+作用24h后导致SH-SY5Y细胞存活率下降为61％，而紫檀烷苷预处理4h后(50、75、100μM)明显抑制MPP+所造成的细胞损伤，并呈一定剂量依赖；细胞形态学研究发现MPP+作用下的细胞形态有明显皱缩并凋亡，而紫檀烷苷和阳性药黄芩素则能明显抑制MPP+造成的凋亡(图1B)。
2.紫檀烷苷对MPP+处理SH-SY5Y细胞蛋白表达的影响
如图2所示，1-4分别为空白对照组、MPP+处理组、紫檀烷苷(50μM)组、阳性药黄芩素(50μM)组。和对照组相比较，MPP+处理SH-SY5Y细胞后诱发Bax增高和Bcl-2的降低；而经紫檀烷苷处理之后，MPP+处理后引起的Bax增高和Bcl-2的降低均得到显著抑制。
3.紫檀烷苷对MPTP诱导帕金森小鼠黑质区基因表达的影响
如图3所示，与空白组相比，MPTP处理能显著上调小鼠黑质区Caspase 3(p<0.001)的基因表达、显著下调Bcl-2(p<0.001)的基因表达；经过100mg·kg-1紫檀烷苷处理之后，小鼠黑质区Caspase 3的基因表达显著下调(p<0.05)、Bcl-2的基因表达显著上调(p<0.05)。
结论：
本研究通过实验证实：紫檀烷苷对MPTP诱导帕金森小鼠模型中脑多巴胺能神经元损伤具有一定保护作用；能够减轻MPP+诱导的细胞凋亡和细胞形态改变；并能进一步调控神经元凋亡通路的关键分子，即下调Bax和Caspase 3基因的表达、上调Bcl2基因的表达，提示其在帕金森病中的应用价值，有望开发为临床上防治帕金森病的药物。
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 (4)
1.紫檀烷苷或其药学上可接受的盐、水合物或前药在制备防治帕金森氏病的药物或保健品中的应用。
2.如权利要求1所述的应用，其特征在于，所述的紫檀烷苷是作为唯一的活性成分应用于防治帕金森氏病的药物或保健品的制备中。
3.一种可防治帕金森氏病的药物组合物，其特征在于，它包含治疗有效量的紫檀烷苷或其药学上可接受的盐、水合物或前药。
4.一种可防治帕金森氏病的保健品，其特征在于，它包含有效量的紫檀烷苷或其药学上可接受的盐、水合物或前药。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1876012A (zh) * | 2006-04-29 | 2006-12-13 | 丽珠医药集团股份有限公司 | 党参黄芪组合物在治疗神经系统疾病中的应用 |
| CN1990483A (zh) * | 2005-12-28 | 2007-07-04 | 中国科学院大连化学物理研究所 | 一种黄芪中多种异黄酮成分的分离制备方法 |
| CN101912114A (zh) * | 2010-08-06 | 2010-12-15 | 合肥工业大学 | 一种改善记忆的组合物 |
| CN104107183A (zh) * | 2013-04-17 | 2014-10-22 | 北京大学 | 黄芪紫檀烷苷在制备免疫抑制剂方面的用途 |
-
2014
- 2014-12-25 CN CN201410838023.XA patent/CN104510752B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990483A (zh) * | 2005-12-28 | 2007-07-04 | 中国科学院大连化学物理研究所 | 一种黄芪中多种异黄酮成分的分离制备方法 |
| CN1876012A (zh) * | 2006-04-29 | 2006-12-13 | 丽珠医药集团股份有限公司 | 党参黄芪组合物在治疗神经系统疾病中的应用 |
| CN101912114A (zh) * | 2010-08-06 | 2010-12-15 | 合肥工业大学 | 一种改善记忆的组合物 |
| CN104107183A (zh) * | 2013-04-17 | 2014-10-22 | 北京大学 | 黄芪紫檀烷苷在制备免疫抑制剂方面的用途 |
Non-Patent Citations (1)
| Title |
|---|
| 何得宾等: "帕金森病的药物研究现状及进展", 《牡丹江医学院学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107021988A (zh) * | 2017-04-25 | 2017-08-08 | 山东省中医药研究院 | 一种从怀槐中提取的紫檀烷苷类化合物及其提取方法和在制备抗肿瘤药物中的应用 |
| CN111346103A (zh) * | 2020-04-14 | 2020-06-30 | 遵义医科大学珠海校区 | 一种药物组合物及其应用 |
| CN111346103B (zh) * | 2020-04-14 | 2021-02-02 | 遵义医科大学珠海校区 | 一种药物组合物及其应用 |
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