CN101574357A - 三七皂苷r1对微循环障碍引发的疾病的预防和治疗 - Google Patents
三七皂苷r1对微循环障碍引发的疾病的预防和治疗 Download PDFInfo
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- CN101574357A CN101574357A CNA2008100529946A CN200810052994A CN101574357A CN 101574357 A CN101574357 A CN 101574357A CN A2008100529946 A CNA2008100529946 A CN A2008100529946A CN 200810052994 A CN200810052994 A CN 200810052994A CN 101574357 A CN101574357 A CN 101574357A
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Abstract
本发明涉及中药产品三七皂苷R1的新用途，特别涉及三七皂苷R1对微循环障碍引发的疾病的预防和治疗作用。
Description
技术领域：
本发明涉及中药产品三七皂苷R1的新用途，特别涉及三七皂苷R1对微循环障碍引发的疾病的预防和治疗作用。
背景技术：
缺血再灌注损伤是介入疗法、外科手术、溶栓后出现损伤的主要病理基础。缺血再灌注后白细胞与血管内皮细胞黏附、肥大细胞脱颗粒是血管损伤的主要病理环节。
微循环是包括细动脉、毛细血管、细静脉在内的血管床，占体内血管的90％，是维持新陈代谢的重要部分。高脂血症、高血压、感染、精神刺激、跌打损伤、手术、介入治疗等都可以引起微循环障碍。微循环障碍包括血管径变化、过氧化物产生、血管内皮粘附因子ICAM-1、白细胞粘附因子CD11b/CD18表达、白细胞与血管内皮细胞粘附、血浆白蛋白外漏、血管外肥大细胞脱颗粒释放TNF-α、组织胺、5羟色胺、炎性因子等血管活性物质、以及形成血拴、出血等多环节变化的复杂过程。
中药三七为五加科植物三七(Araliaceae，三七)的干燥根，在中国、韩国、日本及其它亚洲国家广泛用于治疗微循环障碍相关疾病，如心血管疾病、脑血管疾病和肝功能障碍等。三七含有30多种不同类型的皂苷类化合物，其中人参皂苷Rg1(Rg1)，人参皂苷Rb1(Rb1)和三七皂苷R1(R1)较为常见。研究已经证实，三七中的皂苷类化合物(PNS)可以改善缺血-再灌注诱导的肝脏微循环障碍，抑制血小板凝集和血小板粘附分子表达，以及改善血管上皮功能。另有研究报道，三七中的皂苷类化合物可以抑制大鼠白细胞与肠系膜微静脉的粘附，脂多糖(LPS)诱导的嗜中性粒细胞粘附分子CD11b和CD18表达。R1可以抑制抑制蛋白κB(I-κB)降解，从而抑制脂多糖诱导的血管上皮细胞肿瘤坏死因子-α表达。三七皂苷R1是三七主要活性成份，三七皂苷R1的结构如下：
肥大细胞脱颗粒是一型变态反应的主要病理环节，是花粉病，皮肤病，哮喘，腹泻的主要病理基础。
目前，尚不清楚三七皂苷R1对心脑血管疾病的主要病理变化--缺血再灌注引起的微循环障碍是否有预防和治疗作用。本发明经过实验发现三七皂甙R1可以改善缺血再灌注引起的肠系膜微循环障碍，从而达到治疗和/或预防微循环障碍引发的疾病的作用，并提供一种中药药物制剂。
发明内容：
本发明发现中药产品三七皂苷R1的新用途，特别涉及三七皂苷R1对缺血再灌注引起的肠系膜微循环障碍的预防和治疗改善作用。从而将其应用于治疗和/或预防微循环障碍引发的疾病，如：、高脂血症、高血压、感染、精神刺激、跌打损伤、花粉病，皮肤病，哮喘，腹泻、手术或介入治疗等引发的微循环障碍。
本发明发现，三七皂苷R1预给药和后给药可以抑制再灌注后肠系膜细静脉内白细胞的滚动和粘附，抑制肥大细胞脱颗粒。
本发明所述三七皂甙R1，是中药三七中的一种成分，可以从市场上买到，(如：南京青泽医药科技开发有限公司，上海康九化工有限公司有生产)，也可以根据现有技术制备(如中国专利01136697.4从三七生粉提取分离三七皂甙R1、人参皂甙Re、三七素的方法)，符合药用标准即可，优选纯度＞50％，更优选纯度＞90％，最优选纯度＞98％。
本发明所述的药物，是用上述三七皂甙R1作为药物活性成分制备成的药物组合物。
本发明的药物组合物，根据需要可以含有药物可接受的载体，其中三七皂甙R1作为药物活性成分，其在制剂中所占重量百分比可以是0.1-99.9％，其余为药物可接受的载体。本发明的药物组合物，以单位剂量形式存在，所述单位剂量形式是指制剂的单位，如片剂的每片，胶囊的每粒胶囊，口服液的每瓶，颗粒剂每袋，注射剂的每支等。
本发明的药物组合物可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。
本发明的药物组合物，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本发明的药物组合物，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物制剂组合物在使用时根据病人的情况确定用法用量。
本发明所述的治疗用途是通过以下实验证明的：
材料和方法：
三七皂甙R1(简称R1，纯度＞98％)由天津天士力集团(天津，中国)提供。
实验动物
200～250g的Wister雄性大鼠由北京大学医学部动物中心提供，试验前禁食12小时，可以自由饮水，动物合格证号：SCXK(京)2002-0001。动物被置于常规饲养环境，动物的处理按照北京大学医学部规定的动物处理和伦理方针进行。
缺血-再灌注模型的建立及给药。
缺血-再灌注组(I/R)：按30mg/kg体重的用量，取sodium pentobarbital，施腹腔注射进行麻醉。在大鼠的右侧颈静脉插入3号聚乙烯静脉注射管，并留置。沿腹正中线切开20-30mm，轻柔地将近回盲部的回肠取出腹外，展开至有载玻片的观察台上。用37℃的Krebs-Ringer缓冲液连续地在展开的肠系膜上滴加。肠系膜微循环动态用置于37℃恒温箱的倒立生物显微镜(Diaphot TMD-2S，Nikon，东京)，在12V，100W的白光条件下观察。在20倍物镜头下选择观察部位，用有时间显示的录像系统，将观察内容用S-VHS录像带纪录保存。选择的观察部位为直径在25-35um之间的细静脉非分枝部(长度在200μm以上)的微循环血管床。经过10分钟的基础观察之后，用聚乙烯管结扎观察部环流的前肠系膜动静脉10分钟，再解除结扎，将时间调至0处，连续观察同一视野的微循环动态30分钟。
假手术组(Sham)：将大鼠麻醉开腹，不作缺血-再灌注处理。
三七皂苷R1预给药组(R1+I/R)：在缺血20分钟前经颈静脉按5mg/kg/h的给药量连续静滴入R1至观察结束。
三七皂苷R1后给药组(I/R+R1)：在缺血再灌注10分钟后经颈静脉按5mg/kg/h的给药量连续静滴入R1至观察结束。
每组6只大鼠。
微循环动态的观察：
微循环动态用连接于倒立生物显微镜的CCD摄像系统(CC-090，Flovel，东京)和SIT萤光摄影机(C-2400-08、滨松フオトニクス、滨松)连续纪录。
血管径的测定：用video measuring gauge(IV-560，ホウエイ、东京)经时地测血管径。
沿细静脉滚动白细胞数 经时地计数所选细静脉10秒钟内滚动的白细胞数，为滚动白细胞。
粘附于细静脉管壁的白细胞数计数：在纪录的图像上，经时地计数在细静脉管壁的同一部位停留30秒以上的白细胞(粘附白细胞)，计算100μm长细静脉上粘附的白细胞数。
肥大细胞脱颗粒率：在缺血-再灌注30分后，将0.1％toluidine blue滴加在观察部位，用CCD摄像机纪录。用20倍的对物镜计数5个视野的脱颗粒和未脱颗粒的肥大细胞数，计算脱颗粒的肥大细胞占计数的整个肥大细胞数的百分比，为肥大细胞脱颗粒率。
统计处理
各测定值用one-way analysis of variance(ANOVA)处理，各组经时变化用T检验，各组间比较用F检验。各测定值用均值±标准误表示，P＜0.05为有显著意义。
结果
1、三七皂苷R1预给药和后给药对再灌注后大鼠肠系膜细动脉和细静脉血管经的影响。
在本观察时间内，缺血再灌注组大鼠细动脉和细静脉血管径没有发生显著的变化。R1的预给药和后给药都没有引起再灌注后大鼠肠系膜细动脉和细静脉血管径的显著变化。
2、三七皂苷R1预给药和后给药对再灌注后大鼠肠系膜细静脉内滚动白细胞的抑制作用。
如图1所示，Sham组在本观察结束时仅有少量的白细胞沿细静脉滚动。I/R组大鼠在再灌注早期就有白细胞沿细静脉滚动，20分时达到高峰，以后滚动的白细胞数量逐渐减少。R1预给药在再灌注10-20分期间内显著地抑制了白细胞沿细静脉的滚动。在再灌注10分，已经有白细胞沿细静脉滚动时，再投入R1，在给药10分(再灌注20分)后，滚动显著地减少。该结果提示R1可以抑制和改善再灌注引起的白细胞沿细静脉滚动。
3、三七皂苷R1预给药和后给药对再灌注后大鼠肠系膜细静脉粘附白细胞的抑制作用。
如图2所示，Sham组在本观察结束时仅有少量的白细胞粘附于细静脉。I/R组大鼠在再灌注早期就有大量的白细胞粘附于细静脉管壁，随着再灌注的进行，黏附白细胞逐渐增多。R1预给药在再灌注开始时就显著地抑制了白细胞的粘附。在再灌注10分，已经有白细胞黏附于细静脉壁时，再投入R1，在给药10分(再灌注20分)后，黏附白细胞显著地减少。该结果提示R1不但可以抑制再灌注引起的白细胞与血管内皮细胞的黏附，还可以解离已经黏附于血管壁上的白细胞。
4.三七皂苷R1预给药和后给药对再灌注后大鼠肠系膜间质肥大细胞脱颗粒的抑制作用。
图3示R1预给药和后给药对再灌注后肠系膜间质肥大细胞脱颗粒的影响。在再灌注30分后、与假手术组比、I/R组的肥大细胞脱颗粒率显著增加。R1预给药和后给药都可以显著地抑制肥大细胞脱颗粒。该结果提示R1具有抑制肥大细胞脱颗粒的作用。
缺血再灌注后大鼠肠细膜细动静脉血管径没有显著变化，而滚动和粘附在细静脉管壁上的白细胞数、血管外间质组织中的肥大细胞脱颗粒率显著增加。三七皂苷R1的预给药和后给药都可以抑制白细胞的滚动和粘附，抑制肥大细胞脱颗粒。
总之，本发明证明，三七皂苷R1可以预防和治疗缺血再灌注引起的微循环障碍。从而将其应用于治疗和/或预防微循环障碍引发的疾病，如：过敏性疾病、高脂血症、高血压、感染等以及因精神刺激、跌打损伤、花粉病，皮肤病，哮喘，腹泻、手术或介入治疗等引发的微循环障碍。
附图说明：
图1表示Sham组在本观察结束时仅有少量的白细胞沿细静脉滚动。
图2表示Sham组在本观察结束时仅有少量的白细胞粘附于细静脉。
图3表示R1预给药和后给药对再灌注后肠系膜间质肥大细胞脱颗粒的影响。
具体实施方式：
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1
片剂
【处方】三七皂苷R1 105g 微晶纤维素55g 微粉硅胶3g硬脂酸镁1.5g
【制法】取原、辅料分别过100目筛；取三七皂苷R1、硫酸钙、微晶纤维素，混匀，用60％乙醇适量作为粘合剂制软材，过20目筛制颗粒，60℃干燥，取出，过30目筛整粒，加入微粉硅胶及硬脂酸镁，混匀，压片，制成1000片，即得。
实施例2
【处方】三七皂苷R1 85g 硫酸钙118g 微晶纤维素37g微粉硅胶2.4g 硬脂酸镁1.2g
【制法】取原、辅料分别过100目筛；取三七皂苷R1、硫酸钙、微晶纤维素，混匀，用60％乙醇适量作为粘合剂制软材，过20目筛制颗粒，60℃干燥，取出，过30目筛整粒，加入适量微粉硅胶及硬脂酸镁，混匀，压片，制成1000片，即得。
实施例3
【处方】三七皂苷R1 133g 硫酸钙208g 微晶纤维素68g微粉硅胶5g 硬脂酸镁2.5g
【制法】取原、辅料分别过100目筛；取三七皂苷R1、硫酸钙、微晶纤维素，混匀，用60％乙醇适量作为粘合剂制软材，过20目筛制颗粒，60℃干燥，取出，过30目筛整粒，加入适量微粉硅胶及硬脂酸镁，混匀，压片，制成1000片，即得。
实施例4
胶囊
取三七皂甙R1 60g，加入适量淀粉，硬脂酸镁等辅料，制粒，整粒，装入1号胶囊，即得。
实施例5
口服液
取三七皂甙R1 8g，加入适量蔗糖，防腐剂，加水到1000ml，分装成10ml一支，即得口服液。
实施例6
颗粒剂
取三七皂甙R1 80g，加入适量糊精、甜菊素，干式制粒，整粒，分装，即得。
实施例7
注射剂
三七皂甙R1 7g加水溶解，另氯化钠、对羟基苯甲酸乙酯加热水溶解，混匀，调pH值。注射用水稀释至1000ml，用中空纤维膜滤过，灌装，灭菌，即得。
实施例8
注射剂
三七皂甙R1 2g加水溶解，另氯化钠、对羟基苯甲酸乙酯加热水溶解，混匀，调pH值。注射用水稀释至1000ml，用中空纤维膜滤过，灌装，灭菌，即得。
Claims (10)
1、三七皂苷R1或其药物组合物在制备一种治疗和/或预防微循环障碍引发的疾病的药物中的应用。
2、权利要求1的应用，其特征在于，三七皂苷R1预给药和后给药对再灌注后肠系膜细静脉内滚动白细胞有抑制作用。
3、权利要求1的应用，其特征在于，三七皂苷R1预给药和后给药对再灌注后肠系膜细静脉粘附白细胞有抑制作用。
4、权利要求1的应用，其特征在于，三七皂苷R1预给药和后给药对再灌注后肠系膜间质肥大细胞脱颗粒有抑制作用。
5、权利要求1的应用，所述三七皂苷R1是从中药三七中提取获得的，纯度＞50％。
6、权利要求1的应用，所述三七皂苷R1是从中药三七中提取获得的，纯度＞90％。
7、权利要求1的应用，所述应用是对高脂血症、高血压、感染、精神刺激、跌打损伤、花粉病，皮肤病，哮喘，腹泻、手术或介入治疗引发的微循环障碍的应用。
8、权利要求1的应用，其特征在于，所述药物组合物，以三七皂甙R1作为药物活性成分，同时含有药物可接受的载体。
9、权利要求8的应用，其特征在于，所述药物组合物可作为任何可药用的剂型。
10、权利要求9的应用，其特征在于，所述剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂或贴剂。
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| CN103619317A (zh) * | 2011-04-22 | 2014-03-05 | 欧莱雅 | 和细胞外基质结构相关的皮肤色斑分子标签 |
| CN104208085A (zh) * | 2013-06-03 | 2014-12-17 | 天士力制药集团股份有限公司 | 三七皂苷r1对小肠缺血再灌注损伤的保护作用 |
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| CN102048720A (zh) * | 2009-11-05 | 2011-05-11 | 天津天士力制药股份有限公司 | 丹参素、三七皂苷r1,及其配伍对微循环障碍引发的疾病的预防和治疗 |
| WO2011054301A1 (zh) * | 2009-11-05 | 2011-05-12 | 天津天士力制药股份有限公司 | 丹参素、三七皂苷r1或其配伍在制备用于预防和治疗微循环障碍引发的疾病的药物中的应用 |
| US9101640B2 (en) | 2009-11-05 | 2015-08-11 | Tasly Pharmaceutical Group Co., Ltd. | Use of Danshensu, Notoginsenoside R1 or their combination in preparation of medicaments for preventing and treating diseases caused by microcirculation disorder |
| CN103619317A (zh) * | 2011-04-22 | 2014-03-05 | 欧莱雅 | 和细胞外基质结构相关的皮肤色斑分子标签 |
| CN104208085A (zh) * | 2013-06-03 | 2014-12-17 | 天士力制药集团股份有限公司 | 三七皂苷r1对小肠缺血再灌注损伤的保护作用 |
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