CN107073023B - 血管渗漏综合症的预防或治疗组合物 - Google Patents
血管渗漏综合症的预防或治疗组合物 Download PDFInfo
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- CN107073023B CN107073023B CN201680002794.2A CN201680002794A CN107073023B CN 107073023 B CN107073023 B CN 107073023B CN 201680002794 A CN201680002794 A CN 201680002794A CN 107073023 B CN107073023 B CN 107073023B
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- vascular leak
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Abstract
本发明涉及含有人参皂苷F1或Rh1的血管渗漏综合症的预防或治疗用药物组合物；利用所述药物组合物治疗血管渗漏综合症的方法；及含有人参皂苷F1或Rh1的血管渗漏综合症的预防或改善用食品组合物。本发明提供的人参皂苷F1或Rh1不仅能够促进血管新生，还能够抑制血管渗漏，从而能够广泛用于血管渗漏综合症的有效预防或治疗。
Description
技术领域
本发明涉及血管渗漏综合症的预防或治疗用组合物，更具体地，本发明涉及含有人参皂苷F1或Rh1的血管渗漏综合症的预防或治疗用药物组合物；利用所述药物组合物治疗血管渗漏综合症的方法；及含有人参皂苷F1或Rh1的血管渗漏综合症的预防或改善用食品组合物。
背景技术
已知血管壁的截面具有由内皮细胞(endothelium)构成的内层(tunica intima)；由弹性蛋白、胶原纤维等构成的结缔组织(connective tissue)；由平滑肌构成的中膜(tunica media)及由纤维层构成的血管外膜(tunica adventitia)形成的非对称结构，这种血管的非对称结构已知抑制血栓形成，防止血管渗漏，赋予血管流动性。尤其是，由内皮细胞构成的血管内层的表面蓄积糖成分的高分子而形成糖皮质层，所述糖皮质层执行直接调节血管的流动，防止血液和内皮细胞直接接触，抑制血液内成分流入内皮细胞的功能。而且，还参与血管弹性(tone)的调节、血液和组织间流体及溶质交换、白血球移动、止血及血液凝固、炎症反应等多种生理活性。
这种糖皮质层受损时，首先是血管功能损伤，其次是血管相关的生理活性功能受阻碍。因糖皮质层受损而受最大影响的是血管的功能损伤，当糖皮质层由于伤口、手术等机械刺激而受损时，血液内的成分通过内皮细胞脱离到血管外部。这种血液内成分向血管外部脱离的症状叫做血管渗漏(vascular leakage)。所述血管渗漏可以由如上所述的机械刺激诱发之外，还可以由过度的氧自由基而诱发，也可以由消化器官的溃疡、内出血、炎症、血虚、糖尿病等多种疾病而诱发。
这种血管渗漏诱发的疾病的代表例可以举例血管渗漏综合症(vascular leaksyndrome)。已知所述血管渗漏综合症是血浆通过血管壁而向血管外部流出，引发周边组织的浮肿的疾病，大体上是由于使用白细胞介素2进行治疗带来的副作用而发病。但是已知的是不是在所有使用白细胞介素2进行治疗的患者中发病，因为有观点提出可能是因为患者个人的遗传原因而发病，所述血管渗漏综合症又是被认为是一种遗传病。但问题是诱发血管渗漏综合症的患者的样本不容易获得，因此对血管渗漏综合症的血管渗漏症状的研究不容易。因此，作为血管渗漏综合症患者的替代方案，将频繁出现血管渗漏的糖尿病患者作为对象进行多种研究，结果明确了血管渗漏是由于血管内皮细胞生长因子(VEGF；Vascularendothelial growth factor)的过表达而诱发。即，有报道称糖尿病病发时诱发的VEGF过表达分解在内皮细胞的粘黏连结部(adherens junction)中对维持内皮细胞间的结合起重要作用的VE-钙粘着蛋白(cadherin)，诱发内皮细胞间的结合减少及糖皮质层的损伤，由此发生血管渗漏。此外，所述血管渗漏可以由用于治疗心血管类疾病的手术过程而诱发。例如，治疗动脉壁变弱或动脉内测的压力增加时动脉的一部分膨胀的疾病的动脉瘤的方法之一，使用在发生动脉瘤的部位包含的正常血管之间插入支架等假体，从而防止血流进一步流入到膨胀部位的手术方法，所述支架的邻接部位可以诱发血管渗漏。如上所述，在动脉瘤治疗时发生的血管渗漏又称为“血管内漏(endoleak)”，发生所述血管内漏时存在需要重新手术的问题。如上所述，血管渗漏通常导致血液的损失、血压降低等，由此可能诱发贫血或血虚引起的第二次损伤，因此人们积极进行对有效治疗此的方法的研究。
例如，国际公开专利第2010-081172号中公开了能够防止血管渗漏的化合物；韩国授权专利第958578号中公开了动脉瘤治疗时能够防止血管内漏的支架；韩国授权专利第1239495号中公开了一种利用能够表达αA-晶体蛋白(αA-crystallin)基因的重组腺病毒治疗糖尿病视网膜病变的方法；国际公开专利第2014-025127号中公开了抑制VEGF-诱导性VE-钙粘着蛋白分解从而抑制血管渗漏的C-肽。但是上述所开发的技术中支架仅局限地用于动脉瘤的治疗，化合物或C-肽具有副作用发生的可能性，因此需要开发出一种既安全又有效的血管渗漏治疗制剂。
发明内容
技术问题
本发明发明人为了开发安全有效地治疗血管渗漏综合症的制剂而努力研究，结果发现来源于人参的多种人参皂苷化合物显示安全有效的血管渗漏症治疗效果，其中人参皂苷F1或Rh1显示最优异的血管渗漏治疗效果，由此完成了本发明。
技术方案
本发明的一目的在于提供含有人参皂苷F1或Rh1的血管渗漏综合症的预防或治疗用药物组合物。
本发明的另一目的在于提供利用所述药物组合物治疗血管渗漏综合症的方法。
本发明的又一目的在于提供含有人参皂苷F1或Rh1的血管渗漏综合症的预防或改善用食品组合物。
有益效果
本发明提供的人参皂苷F1或Rh1不仅能够促进血管新生，还能抑制血管渗漏，因此可以广泛用于血管渗漏综合症的有效预防或治疗。
附图说明
图1a是示出利用10种人参皂苷处理并培养的HUVEC的照片。
图1b是示出利用上述10种人参皂苷处理并培养的HUVEC中形成的血管数的比较结果的图。
图2a是示出利用10种人参皂苷处理并培养的HRMEC的照片。
图2b是示出利用上述10种人参皂苷处理并培养的HRMEC中形成的血管数的比较结果的图。
图3a是示出利用2种人参皂苷按照不同浓度处理并培养的HUVEC的照片。
图3b是示出利用上述2种人参皂苷按照不同浓度处理并培养的HUVEC中形成的血管数的比较结果的图。
图4a是示出利用2种人参皂苷按照不同浓度处理并培养的HRMEC的照片。
图4b是示出利用上述2种人参皂苷按照不同浓度处理并培养的HRMEC中形成的血管数的比较结果的图。
图5是示出利用3种人参皂苷按照不同浓度(0、3.125、6.25、12.5或25μM)处理并培养的HUVEC的增殖水平的比较结果的图。
图6是示出利用3种人参皂苷按照不同浓度(0、6.25、12.5或25μM)处理并培养的HRMEC的增殖水平的比较结果的图。
图7a是示出以利用3种人参皂苷处理并培养的HUVEC为对象进行细胞移动性分析的结果的照片。
图7b是示出以利用3种人参皂苷处理并培养的HUVEC为对象进行细胞移动性分析而获得的移动细胞比例的比较结果的图。
图8a是示出以利用3种人参皂苷处理并培养的HRMEC为对象进行细胞移动性分析的结果的照片。
图8b是示出以利用3种人参皂苷处理并培养的HRMEC为对象进行细胞移动性分析而获得的移动细胞比例的比较结果的图。
图9是示出人参皂苷F1或Rh1预处理对利用VEGF-A处理HUVEC而诱发的血管渗漏所产生的效果的比较结果的图。
图10a是示出通过依文思蓝染色肉眼确认人参皂苷F1或人参皂苷Rh1对在小鼠的耳中由VEGF-A诱发的血管渗漏症状的效果的结果的照片。
图10b是通过依文思蓝染色水平的定量分析确认人参皂苷F1或人参皂苷Rh1对在小鼠的耳中由VEGF-A诱发的血管渗漏症状的效果的结果的图。
具体实施方式
本发明发明人在为了开发能够更安全有效地预防或治疗血管渗漏综合症的制剂而进行不同研究的过程中注意到人参皂苷。所述人参皂苷化合物是人参或红参中含有的化合物的一种，已知对血管新生或血管损伤伴随的不同疾病显示治疗效果，因此目的是筛选能够最有效地治疗血管渗漏症状的人参皂苷。结果，作为针对作为与血管内皮细胞类似的内皮细胞的人脐静脉血管内皮细胞(Human Umbilical Vascular Endothelial Cells，HUVEC)和人视网膜微血管内皮细胞(Human Retinal Microvascular Endothelial Cells，HRMEC)能够以优异水平促进血管生成的人参皂苷，筛选出人参皂苷Rh1或F1。验证所筛选的Rh1或F1的效果，结果确认其以浓度依赖性方式促进细胞移动，并抑制血管渗漏。
如上所述，迄今为止还没有关于人参皂苷Rh1或F1的血管渗漏抑制效果的报道，由本发明发明人首次明确。
为了达成上述目的，作为本发明的一具体例，提供含有人参皂苷F1或Rh1的血管渗漏综合症的预防或治疗用药物组合物。
本发明的术语“人参皂苷F1”又称为20-O-β-D-吡喃葡萄糖基-20(S)-原人参三醇，化学式为C36H62O9，分子量约为638.87Da，指的是从人参分离的具有下列化学式1所示的结构的化合物。
[化学式1]
根据本发明，所述人参皂苷F1可以用作伴随血管渗漏的疾病的预防或治疗用药物组合物的有效成分。
本发明的术语“人参皂苷Rh1”又称为20(S)-原人参三醇-6-O-β-D-吡喃葡萄糖苷，化学式为C36H62O9，分子量约为638.87Da，指的是从人参分离的具有下列化学式2结构的化合物。
[化学式2]
根据本发明，所述人参皂苷Rh1可以用作伴随血管渗漏的疾病的预防或治疗用药物组合物的有效成分。
本发明的术语“血管渗漏综合症(vascular leak syndrome,vascular leakagesyndrome)”是指血浆通过血管壁向血管外部流出的血管渗漏症状导致的诱发周边组织浮肿的疾病，已知通常是由于使用白细胞介素2治疗的副作用而发病，发病与否是由遗传因素决定。
本发明的术语“血管渗漏(vascular leakage)”是指由形成血管的构成要素中的血管内皮细胞的糖皮质层损伤、血管内皮细胞的结合力缺损等多种原因而导致血管壁透过性增加，血液内成分向血管外部脱离的症状，通常可以通过低血压、末梢浮肿、低白蛋白血症等间接诊断。所述血管渗漏是血管渗漏综合症的主要症状，但除了上述血管渗漏综合症以外还可以是由直接损伤血管构成要素的机械刺激诱发，也可以是由过量的氧自由基而诱发，还可以由消化器官的溃疡、内出血、炎症、血虚、糖尿病等多种疾病而诱发。
根据本发明一实施例，为了筛选具有血管新生促进活性的人参皂苷而从10种人参皂苷化合物(CK、Rh2、Rg3、Rb1、F2、Rd、Re、Rg1、Rh1或F1)中筛选对HUVEC和HRMEC显示优异的血管新生促进活性的人参皂苷，结果确认人参皂苷F1或Rh1显示高水平的促进血管生成的效果(图1及图2)，用他们处理HUVEC时显示浓度依赖性的血管生成促进效果(图3)，促进HUVEC和HRMEC的细胞增殖(图5及图6)，促进HUVEC和HRMEC的细胞移动(图7及图8)，示出抑制用血管内皮生长因子A(VEGF-A)处理HUVEC诱发的血管渗漏的水平的效果(图9)，显示了对在细胞水平(图9)和动物水平(图10a及图10b)用VEGF-A处理而诱发的血管渗漏水平的抑制效果。
从而确认人参皂苷F1或Rh1显示不仅促进血管新生还抑制血管渗漏的效果，这效果不仅在细胞水平中显示还在动物水平中显示,由此可以知道所述人参皂苷F1或Rh1可以用作预防或治疗伴随血管渗漏的疾病的制剂。
尤其，已知VEGF不仅在如癌症和心血管系统疾病的病态下分泌而诱发血管渗漏,而且在形成非正常血管方面起到重大作用。本发明提供的人参皂苷F1或Rh1形成血管同时能够抑制血管渗漏，可以认为所述人参皂苷F1或Rh1显示形成正常新血管的新效果。
因此，本发明提供的人参皂苷F1或Rh1不仅可以用于抑制血管形成的多种血虚疾病，还可以用于治疗由于VEGF分泌而导致正常血管功能消失且形成非正常血管形成的癌症或心血管系统疾病。
此外，本发明组合物可以制造为进一步含有药物组合物制备中通常使用的合适的载体、赋形剂或稀释剂的血管渗漏综合症的预防或治疗用药物组合物的形态，所述载体可以包括非天然载体(non-naturally occuring carrier)。具体地，所述药物组合物分别按照通常的方法剂型化为散剂、颗粒剂、片剂、胶囊剂、混悬液、乳液、糖浆、气雾剂等口服剂型；外用剂；栓剂；灭菌注射溶液等形态而使用。在本发明中，所述药物组合物中可含有的载体、赋形剂及稀释剂可以为乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、金合欢胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等。本发明的药物组合物在制剂化时可以使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋形剂而制备。用于口服给药的固体制剂可以包括片剂、丸剂、粉剂、颗粒剂、胶囊剂等，这些固体制剂可以在所述提取物和其组分中混合1种以上的例如淀粉、碳酸钙(calcium carbonate)、蔗糖(sucrose)、乳糖(lactose)或明胶等赋形剂制造。除了单纯的赋形剂之外，还可以使用硬脂酸镁、滑石等润滑剂。作为用于口服的液体制剂，适用悬浮剂、内服液剂、乳剂、糖浆剂等，除了作为经常使用的单纯稀释剂的水、液体石蜡以外，还可以包括各种赋形剂，例如润湿剂、甜味剂、芳香剂、保存剂等。用于非口服给药的制剂中包括灭菌的水溶液、非水性溶剂、悬浮剂、乳剂、冷冻干燥制剂和栓剂。作为非水性溶剂、悬浮剂，可以使用丙二醇、聚乙二醇、橄榄油等植物性油，油酸乙酯等可注射的酯等。作为栓剂的基剂，可以使用半合成椰油酯/棕榈油酯(witepsol)、聚乙二醇(Macrogol)、吐温61、可可脂、月桂脂、甘油明胶等。
本发明药物组合物中含有的所述人参皂苷F1或Rh1的含量不受特别限制，但作为一例，以最终组合物总重量为基准，可以以0.0001～50重量％的含量含有，作为另一示例，可以以0.01～10重量％的含量含有。
上述本发明的药物组合物可以以药剂学上有效的量给药，本发明中术语“药剂学上有效的量”是指以可适用于医疗治疗或预防的合理的受益/危险比例充分治疗或预防疾病的量，有效用量水平可以由包括根据疾病的轻重程度、药物的活性、患者的年龄、体重、健康状态、性别、患者对药物的敏感度、所使用的本发明组合物的给药时间、给药途径及排出比例、治疗持续时间、与所用的本发明组合物配合或同时使用的药物等要素及其他医学领域公知的要素决定。本发明的药物组合物可以单独给药或与公知的血管渗漏综合症预防或治疗用制剂联用给药。考虑上述所有要素的情况下，以没有副作用的最小量获得最大效果的量给药尤为重要。
本发明的药物组合物给药量根据使用目的、疾病的轻重程度、患者年龄、体重、性别、既往病例或作为有效成分使用的物质的种类等，由本领域技术人员决定。例如，本发明的药物组合物每一成人给药约0.1ng～100mg/kg，优选为1ng～约10mg/kg，本发明的组合物的给药频率可以为1天一次或分割用量分数次给药，但不限于此。所述用量在任何方面来讲都不用于限定本发明范围。
根据本发明另一具体例，提供一种预防或治疗血管渗漏综合症的方法，其包括将上述药学组合物以药剂学上有效的量给药至具有血管渗漏综合症发病可能性或发病的个体的步骤。
本发明的术语“个体”是指具有血管渗漏综合症发病可能性或发病的包括鼠、家畜、人等的哺乳动物、养殖鱼类等，不受特别限制。
针对本发明的血管渗漏综合症预防或治疗用药物组合物的给药途径，只要是所述组合物能够到达靶组织，则可以通过任意通常的给药途径给药。所述组合物可以根据目的通过腹腔内给药、静脉内给药、肌肉内给药、皮下给药、皮内给药、口服给药、鼻内给药、肺内给药、直肠内给药等路径给药，而不受特别现实。但是，口服给药时由于胃酸而使所述人参皂苷F1或Rh1变性，因此口服组合物可以以被涂覆活性药剂或保护其不在胃中分解的方式被剂型化。此外，所述组合物可以通过能够使得活性物质移动到靶细胞的任意装置进行给药。
根据本发明另一具体例，提供一种含有人参皂苷F1或Rh1的血管渗漏综合症预防或改善用食品组合物。
作为所述血管渗漏综合症预防或治疗用药物组合物的有效成分的人参皂苷F1或Rh1，源自作为药用天然物的人参等以往用作中药材而其安全性已得到论证的天然物，从而所述人参皂苷F1或Rh1可以直接食用，也可以制造为有助于血管渗漏综合症的预防或改善的食品形态来吸收。
此时，所述食品中含有的所述人参皂苷F1或Rh1的含量，相对于食品组合物的总重量可以以0.001～50重量％，更优选为0.1～10重量％的含量含有，而没有特别限制。食品为饮料时，以100ml为基准可以以1～10g，优选以2～7g的比例含有。此外，所述组合物还可以含有通常用于食品组合物以提高气味、味道、视觉等的额外成分。例如，可以含有维生素A、维生素C、维生素D、维生素E、维生素B1、维生素B2、维生素B6、维生素B12、烟酸(niacin)、生物素、叶酸(folate)、泛酸(panthotenic acid)等。此外可以含有锌(Zn)、铁(Fe)、钙(Ca)、铬(Cr)、镁(Mg)、锰(Mn)、铜(Cu)等矿物。此外，还可以含有赖氨酸、色氨酸、半胱氨酸、缬氨酸等氨基酸。此外，还可以含有防腐剂(山梨酸钾、苯甲酸钠、水杨酸、脱氢乙酸钠等)、杀菌剂(漂白粉和高度漂白粉、次氯酸钠等)、抗氧化剂(丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)等)、着色剂(焦油色素等)、发色剂(亚硝酸钠、亚硝酸钠等)、漂白剂(亚硫酸钠)、调味剂(MSG谷氨酸钠等)、甜味剂(甘素、环磺酸盐、糖精、钠等)、香料(香草醛、内酯类等)、膨胀剂(明矾、D-酒石酸氢钾等)、强化剂、乳化剂、增粘剂(糊料)、成膜剂、胶基、消泡剂、溶剂、改良剂等食品添加剂(food additives)。上述添加物可以根据食品的种类来选择并以适宜的量使用。
此外，可以利用含有所述人参皂苷F1或Rh1的血管渗漏综合症预防或改善用食品组合物制造血管渗漏综合症预防或改善用功能性保健食品。
作为具体例，利用所述食品组合物可以制造能够预防或改善血管渗漏综合症的加工食品，例如，果子、饮料、酒类、发酵食品、罐头、乳加工食品、肉类加工食品或面条加工食品的形态的功能性保健食品。此时，果子包括饼干、派、蛋糕、面包、糖果、果冻、口香糖、谷物(cereal)(包括谷物片等代餐食品类)等。饮料包括饮用水、碳酸饮料、功能性离子饮料、果汁(例如苹果汁、梨汁、葡萄汁、芦荟汁、柑橘汁、桃汁、胡萝卜汁、番茄汁等)、甜米露等。酒类包括清酒、威士忌、烧酒、啤酒、洋酒、果酒等。发酵食品包括酱油、大酱、辣椒酱等。罐头包括水产物罐头(例如金枪鱼罐头、青花鱼罐头、秋刀鱼罐头、海螺罐头等)、畜产品罐头(牛肉罐头、猪肉罐头、鸡肉罐头、火鸡罐头等)、农产品罐头(玉米罐头、桃罐头、菠萝罐头等)。乳加工食品包括芝士、黄油、酸奶等。肉类加工食品包括炸猪排、炸牛排、炸鸡排、香肠、糖醋肉、炸肉块、宫廷烤牛肉等。面条加工食品包括密封包装生面等面条。此外，所述组合物可以用于甑煮食品(retort food)、汤类等。
本发明的术语“功能性保健食品(functional food)”是与特定保健用食品(foodfor special health use,FoSHU)相同的术语，是指加工成除了营养供给之外，还能够显示生物体调节功能的医学、医疗效果高的食品，所述食品为了获得对血管渗漏综合症的预防或改善有用的效果，可以制备成片剂、胶囊、粉末、颗粒、液状、丸等多种形态。
具体实施例
下面通过实施例更详细说明本发明。但这些实施例仅例示本发明，本发明范围不由这些实施例限定。
实施例1：显示血管新生促进活性的人参皂苷的筛选
利用10种人参皂苷化合物(CK、Rh2、Rg3、Rb1、F2、Rd、Re、Rg1、Rh1或F1)，比较HUVEC(Human Umbilical Vascular Endothelial Cells)和HRMEC(Human RetinalMicrovascular Endothelial Cells)的血管新生促进活性。即，所述HUVEC或HRMEC分别利用2％胎牛血清(FBS)、EGM-2(龙沙公司(Lonza),沃克斯维尔,马里兰州)培养基，在维持5％CO2、37℃的条件下进行培养。在96-孔板中利用基质胶(BD生物科学公司)涂覆1小时，以104个/孔将HUVEC或HRMEC与分别用25μM的人参皂苷化合物(CK、Rh2、Rg3、Rb1、F2、Rd、Re、Rg1、Rh1或F1)处理的0.1％FBS和EBM-2培养基混合后，接种至涂覆有基质胶(matrigel)的96-孔板。培养4小时后，实施管形成分析法(Tube formation assay)，用显微镜观察并照相来比较管数量(图1a、1b、2a及2b)。此时，阴性对照组使用DMSO代替人参皂苷处理并培养的细胞，阳性对照组使用已知促进血管新生的VEGF-A处理并培养。
首先，图1a是示出利用10种人参皂苷处理并培养的HUVEC的照片，图1b是示出利用上述10种人参皂苷处理并培养的HUVEC中形成的血管数的比较结果的图。如图1所示，确认了培养HUVEC时，人参皂苷Ck、Rb2或Rg3显示抑制血管生成效果，人参皂苷Rb1或F2没有显示特别差异，人参皂苷Rd、Re,Rg1,Rh1或F1显示出促进血管生成效果。
然后，图2a是示出利用10种人参皂苷处理并培养的HRMEC的照片，图2b是示出利用上述10种人参皂苷处理并培养的HRMEC中形成的血管数的比较结果的图。如图2所示，确认了培养HRMEC时，人参皂苷Ck、Rb2或Rg3显示抑制血管生成效果，人参皂苷Re、Rb1、Rg1,Rd、F1、F2或Rh1显示出促进管生成效果。
同时，在培养所述HUVEC或HRMEC时共同显示促进血管生成的效果的人参皂苷为Re、Rd、F1或Rh1，其中两种类的细胞培养时显示出比阳性对照组还要高水平的管生成促进效果的为人参皂苷F1或Rh1。
从而，筛选所述人参皂苷F1或Rh1用于以后的实验。
实施例2：依据人参皂苷处理浓度的血管新生促进效果
利用上述实施例1中筛选的人参皂苷F1或Rh1以不同浓度(12.5μM、25μM或50μM)处理并培养按照上述实施例1的方法培养的HUVEC或HRMEC 4小时，实施血管形成分析法以比较所形成的管的数量(图3及图4)。此时，阴性对照组使用利用DMSO代替人参皂苷处理并培养的细胞，阳性对照组使用已知为促进血管新生的VEGF-A处理并培养的细胞。
图3a是示出利用2种人参皂苷按照不同浓度处理并培养的HUVEC的照片，图3b是示出利用上述2种人参皂苷按照不同浓度处理并培养的HUVEC中形成的血管数的比较结果的图。如图3所示，在培养HUVEC时2种人参皂苷都浓度依赖性地促进血管生成，以50μM处理时比阳性对照组显示更高水平的管形成。
图4a是示出利用2种人参皂苷按照不同浓度处理并培养的HRMEC的照片，图4b是示出利用上述2种人参皂苷按照不同浓度处理并培养的HRMEC中形成的血管数的比较结果的图。如图4所示，在培养HRMEC时虽然2种人参皂苷没有显示明显浓度依赖性地促进血管生成的效果，但在各个浓度均显示了比阳性对照组更高水平的管形成。
实施例3：依据人参皂苷处理浓度的细胞增殖促进效果
用上述实施例1中已确认为促进血管形成的三种人参皂苷(F1、Rh1或Rg1)以不同浓度(0μM、3.125μM、6.25μM、12.5μM或25μM)处理并培养根据上述实施例1的方法培养的HUVEC或HRMEC 48小时，以培养细胞为对象实施MTT分析法，比较了细胞增殖水平(图5及图6)。此时，阴性对照组使用利用DMSO代替人参皂苷处理并培养的细胞，阳性对照组使用已知为促进血管新生的VEGF-A处理并培养的细胞。
图5是示出利用3种人参皂苷按照不同浓度(0、3.125、6.25、12.5或25μM)处理并培养的HUVEC的增殖水平的比较结果的图。如图5所示，确认了在培养HUVEC时人参皂苷F1促进约20％的细胞增殖、人参皂苷Rh1促进约100％的细胞增殖以及人参皂苷Rg1促进约60％细胞增殖。
图6是示出利用3种人参皂苷按照不同浓度(0、6.25、12.5或25μM)处理并培养的HRMEC的增殖水平的比较结果的图。如图6所示，确认了在培养HRMEC时3种人参皂苷均促进约20％的细胞增殖。
实施例4：人参皂苷的细胞移动促进效果
以HUVEC或HRMEC为对象，为了确认上述实施例1中确认为促进管形成的3种人参皂苷对细胞移动性的影响，实施了细胞移动性分析。
具体地，在具备培养插件(Culture-insert)的培养容器(Culture-insert ofμ-dish,Ibidi公司)中涂覆0.1％的明胶，添加EGM-2培养基之后，接种了按照上述实施例1的方法培养的HUVEC或HRMEC，培养至饱和度为90％，去除上述插件。然后将培养基替换为含有3种人参皂苷(F1、Rh1或Rg1)25μM和0.1％FBS的EBM-2培养基，接着培养12小时，用显微镜分析了HUVEC或HRMEC细胞的移动水平(图7a、图7b、图8a及图8b)。此时，阴性对照组使用利用DMSO代替人参皂苷处理并培养12小时的细胞，阳性对照组使用已知为促进血管新生的VEGF-A处理并培养12小时的细胞，参考对照组使用了没有培养的细胞。
图7a是示出以利用3种人参皂苷处理并培养的HUVEC为对象进行细胞移动性分析的结果的照片，图7b是示出移动细胞比例的比较结果的图。如图7所示，确认了3种人参皂苷均促进HUVEC的移动性。
图8a是示出以利用3种人参皂苷处理并培养的HRMEC为对象进行细胞移动性分析的结果的照片，图8b是示出移动细胞比例的比较结果的图。如图8所示，确认了3种人参皂苷均促进HRMEC的移动性。
实施例5：人参皂苷的血管渗漏抑制效果
实施例5-1：在细胞水平人参皂苷F1或Rh1对血管渗漏产生的效果分析
利用25μM的上述实施例1中筛选的人参皂苷F1或Rh1对按照上述实施例的方法培养的HUVEC预处理1小时，并利用已知为诱导血管渗漏的VEGF-A进行处理，实施了血管渗透性分析(Vascular permeability assay)(图9)。此时，阴性对照组使用利用DMSO代替人参皂苷处理并培养的细胞，阳性对照组使用已知为促进血管新生的VEGF-A处理并培养的细胞，比较组使用人参皂苷F1或Rh1预处理而没有利用VEGF-A处理的细胞。
图9是示出人参皂苷F1或Rh1预处理对利用VEGF-A处理HUVEC而诱发的血管渗漏所产生的效果的比较结果的图。如图9所示，确认了在利用VEGF-A处理HUVEC时发生了较高水平的血管渗漏，但通过人参皂苷F1或Rh1的预处理得到抑制。同时，还确认了用人参皂苷F1或Rh1预处理后再利用VEGF-A处理HUVEC，相比仅利用人参皂苷F1或Rh1处理HUVEC的情况血管渗漏的水平减少。
实施例5-2：在生物体内人参皂苷F1或Rh1对血管渗漏产生的效果分析
在7周龄ICR雄性小鼠尾部静脉注射200ml的1％依文思蓝(Evans blue)染色药，反应10分钟使得血液变蓝。
接着，在小鼠耳部分别皮内注射
的作为阴性对照组的PBS、作为阳性对照组的
VEGF-A、1.25μM的人参皂苷F1、1.25μM的人参皂苷Rh1、
的VEGF-A/1.25μM的人参皂苷F1或
的VEGF-A/1.25μM的人参皂苷Rh1。
30分钟后，对小鼠进行安乐死，摘取耳部，用肉眼观察血液渗漏的量(图10a)，然后放入甲酰胺中并在37℃下固定24小时，在620nm处测定吸光度，定量评价人参皂苷F1和人参皂苷Rh1的血液渗漏抑制效果(图10b)。
图10a是示出通过依文思蓝染色肉眼确认人参皂苷F1或人参皂苷Rh1对在小鼠的耳中由VEGF-A诱发的血管渗漏症状的效果的结果的照片，图10b是通过依文思蓝染色水平的定量分析确认人参皂苷F1或人参皂苷Rh1对在小鼠的耳中由VEGF-A诱发的血管渗漏症状的效果的结果的图。
如图10a及图10b所示，确认了人参皂苷F1或人参皂苷Rh1在如小鼠的生物体内也能够有效抑制由VEGF-A诱导的血管渗漏症状。
从而，从上述结果可以知道人参皂苷F1或Rh1不仅在细胞水平和动物水平促进血管新生，还显示抑制血管渗漏的效果。
Claims (4)
1.含有人参皂苷F1、人参皂苷Rh1或其组合的药物组合物在制备用于预防或治疗血管渗漏综合症的药品中的用途。
2.根据权利要求1所述的用途，其中，所述人参皂苷F1是具有下列化学式1的结构的化合物，
[化学式1]
3.根据权利要求1所述的用途，其中，所述人参皂苷Rh1是具有下列化学式2的结构的化合物，
[化学式2]
4.根据权利要求1所述的用途，其中，所述药物组合物还含有药学上可接受的载体、赋形剂或稀释剂。
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| KR10-2015-0101239 | 2015-07-16 | ||
| PCT/KR2016/005318 WO2017010673A2 (ko) | 2015-07-16 | 2016-05-19 | 혈관누수 증후군의 예방 또는 치료용 조성물 |
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| EP (1) | EP3181138A4 (zh) |
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| CN102656153A (zh) * | 2009-10-29 | 2012-09-05 | 韩独药品株式会社 | 新型血管渗漏阻断剂 |
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| JP2002322068A (ja) | 2001-02-26 | 2002-11-08 | Japan Science & Technology Corp | 血管再生促進剤 |
| AU2003202159A1 (en) * | 2002-04-08 | 2003-10-27 | Ginseng Science Inc. | Extract of processed panax genus plant, the preparation method thereof, and compositions containing the same |
| JP2004018519A (ja) * | 2002-06-14 | 2004-01-22 | Yuhabu:Kk | 血管壁修復用飲食物 |
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| KR20060000488A (ko) * | 2004-06-29 | 2006-01-06 | 홍림통산(주) | 인삼 또는 홍삼 추출물, 그의 유산균 발효물 및 그의장내세균 발효물로 이루어진 군으로부터 선택된 1종이상의 인삼 추출물 소양증 예방 및 치료제 조성물 |
| KR101182917B1 (ko) | 2005-07-14 | 2012-09-13 | 내셔널 인스티튜트 오브 파마슈티컬 알앤디 컴퍼니 리미티드 | 인삼 2차 배당체를 함유하는 의약 조성물, 그의 제조 방법및 용도 |
| CN102631359A (zh) * | 2007-12-07 | 2012-08-15 | 丽珠集团利民制药厂 | 一种化学结构的人参皂苷在制备用于预防和/或治疗血栓的药物中的用途 |
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| RU2539917C2 (ru) | 2009-01-12 | 2015-01-27 | Аэрпио Терапьютикс Инк. | Способы лечения синдрома сосудистой утечки |
| KR20110007473A (ko) * | 2009-07-16 | 2011-01-24 | 씨제이제일제당 (주) | 진세노사이드 강화 분획물을 포함하는 혈압 강하용 조성물 |
| KR101239495B1 (ko) | 2011-01-21 | 2013-03-05 | 경상대학교산학협력단 | αΑ-크리스탈린 유전자를 발현하는 재조합 아데노바이러스 및 이를 이용한 망막혈관 질환의 유전자 치료 |
| KR101325832B1 (ko) * | 2011-07-14 | 2013-11-05 | 고완석 | 진세노사이드 Ｒｈ2 성분의 함량이 증가된 흑삼 제조방법 및 그 제조방법에 의해 제조된 흑삼제품 |
| KR101646054B1 (ko) | 2012-08-06 | 2016-08-05 | 주식회사 아모그린텍 | C-펩타이드를 포함하는 당뇨성 혈관누출에 의한 질병의 예방 또는 치료용 조성물 |
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| CN1034672A (zh) * | 1988-02-06 | 1989-08-16 | 程孝慈 | 整脉口服液的配方及工艺流程 |
| CN102656153A (zh) * | 2009-10-29 | 2012-09-05 | 韩独药品株式会社 | 新型血管渗漏阻断剂 |
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| Publication number | Publication date |
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| CN107073023A (zh) | 2017-08-18 |
| KR101774932B1 (ko) | 2017-09-06 |
| CA2962201C (en) | 2019-02-26 |
| JP2017528482A (ja) | 2017-09-28 |
| EP3181138A4 (en) | 2018-03-14 |
| JP6386173B2 (ja) | 2018-09-05 |
| EP3181138A2 (en) | 2017-06-21 |
| US20180289727A1 (en) | 2018-10-11 |
| CA2962201A1 (en) | 2017-01-19 |
| WO2017010673A3 (ko) | 2017-03-16 |
| KR20170010296A (ko) | 2017-01-26 |
| US10391110B2 (en) | 2019-08-27 |
| WO2017010673A2 (ko) | 2017-01-19 |
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