CN101327235B - 三七皂甙在制备治疗败血症的药物中的应用 - Google Patents
三七皂甙在制备治疗败血症的药物中的应用 Download PDFInfo
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Abstract
本发明涉及三七皂甙治疗败血症的应用，特别涉及三七总皂苷在治疗和/或预防败血症的应用。
Description
技术领域：
本发明涉及中药产品的新用途，特别涉及三七总皂苷在治疗和/或预防败血症的应用。
背景技术：
三七(Panax notoginseng，PN)是风干后的中国传统中药三七(Burk)F.H.Chen的根。三七皂甙(也称为：三七总皂苷，英文名：Panax Notoginsenosides，PNS)是三七的主要有效成份，由30余种不同的皂甙组成，临床上广泛用于治疗微循环障碍相关性疾病，如心血管疾病和肝功能障碍。
三七皂甙已经列入国家药典，有相应制剂产品上市，如：注射用血塞通。中国专利CN200410058111.4描述了一种三七皂甙的制备方法：三七用水提取，提取液浓缩，乙醇沉淀，上清液除尽乙醇，水溶解后，行大孔树脂HPD400柱色谱，水洗脱除去杂质后，再用90％乙醇洗脱，至有效成分洗脱完全为止，回收醇洗脱液，干燥即得。具体可以采用以下方法获得：取三七药材粉碎成粗粉，加10倍药材重量的70％乙醇，回流提取2次，每次25小时，滤过，合并二次提取液，700C???左右减压回收溶剂，至比重为1.10-1.12的流浸膏。用水稀释，进行大孔树脂HPD400吸附柱吸附，用水洗脱，继以90％乙醇洗脱，90％乙醇洗脱部分700C???左右减压回收溶剂。向上述三七总皂苷溶液中，加入MgO2:AL2O3脱色，过滤，滤液于80℃减压真空干燥，粉碎，即得淡黄色三七总皂苷成品。
败血症是致病菌或条件致病菌侵入血循环中生长繁殖，产生毒素和其他代谢产物所引起的急性全身性感染，临床上以寒战、高热、皮疹、关节痛及肝脾肿大为特征，部分可有感染性休克和迁徙性病灶。引起败血症的原因有：
一、人体因素：
①当皮肤粘膜有破损或发生化脓性炎症时，细菌则容易侵入体内。
②人体的免疫反应可分为非特异性免疫反应及特异性免疫反应两种，后者又可分为细胞免疫与体液免疫两方面。当机体免疫功能下降时，不能充分发挥其吞噬杀灭细菌的作用，即使入侵的细菌量较少，致病力不强也能引起败血症。
③条件致病菌所引起的医源性感染也逐渐增多。
二、细菌因素：
主要与病原菌的毒力和数量有关。毒力强或数量多的致病菌进入机体，引起败血症的可能性较大。
败血症的主要症状是：
1.原发炎症：各种病原菌所引起的原发炎症与其在人体的分布部位有关。原发炎症的特点是局部的红、肿、热、痛和功能障碍。
2.毒血症症状：起病多急骤。常有寒战、高热、发热多为弛张热及或间歇热，亦可呈稽留热、不规则热及双峰热，后者多系革兰阴性杆菌败血症所致。发热同时伴有不同程度的毒血症症状，如头痛、恶心、呕吐、腹胀、腹痛、周身不适、肌肉及关节疼痛等。
3.皮疹：见于部分患者，以瘀点最为多见，多分布于躯干、四肢、眼结膜、口腔粘膜等处，为数不多。
4.关节症状：可出现大关节红、肿、热、痛和活动受限，甚至并发关节腔积液、积脓，多见于革兰阳性球菌、脑膜炎球菌、产碱杆菌等败血症的病程中。
5.感染性休克：约见于1/5～1/3败血症患者，表现为烦燥不安，脉搏细速，四肢厥冷，皮肤花斑，尿量减少及血压下降等，且可发生DIC，系严重毒血症所致。
6.肝脾肿大：一般仅轻度肿大。
根据研究，脂多糖(LPS)是革兰氏阳性细菌细胞壁的组成成分之一，造成了革兰氏阳性细菌导致的人败血症和感染性休克的多种表现。败血症时发生的微循环障是由LPS的过度释放造成的系统性炎症反应，由许多激活的因子所介导，这些因子如粘附分子，活性氧成份(ROS)，以及炎症前体介质如肿瘤坏死因子—α(TNF-α)、白介素—6(IL-6)以及干扰素—γ(INF-γ)。LPS诱导产生的微循环障碍对败血症时发生的器官功能障碍起着关键作用，在这个过程中白细胞沿着内皮旋转并粘附于血管内皮，血管壁产生过氧化氢和肥大细胞脱颗粒都是文献报道的关键步骤。
当前败血症的主要临床治疗方法包括容量复苏，儿茶酚胺的运用和抗生素补偿治疗。这些方法可以增加败血症病人的存活率，但是在临床上会导致血糖升高 以及血压和血钙的下降，并发生出血。临床研究建议采用抗TNF-α治疗对败血症的治疗有所帮助。然而，最近的研究表明这种方法不能治愈败血症且会增加严重败血症病人的死亡率。因而，在LPS导致的败血症中寻找防止出现严重微循环障的方法仍然是个挑战。
本发明人在对三七皂甙进行研究过程中，发现三七皂甙后处理能够抑制白细胞粘附于血管壁、肥大细胞脱颗粒和细胞因子的释放，改善LPS诱导的微循环障碍。对败血症有明显的治疗作用。
发明内容：
本发明提供一种三七皂甙新的治疗用途。所述新的治疗用途，是用三七皂甙治疗因微循环障碍引发的败血症。
为此，本发明提供一种药物新用途，即用三七皂甙制备一种治疗和/或预防败血症的药物。
本发明所述三七皂甙是三七总皂甙，主要成份是人参皂甙Rb、Rg，三七皂甙R1、R2、R3。
本发明所述三七皂甙可以从市场上买到，也可以根据现有技术制备，符合药用标准即可。
如云南瑞宝天然色素有限公司供应的以下标准的三七皂甙：
外观：淡黄色无定型粉末
干燥失重 ≤5％
灼热残渣 ≤0.5％
人参皂甙Rb1 ≥30％
人参皂甙Rg1 ≥20％
总皂甙含量 ≥88％
或按国家标准WS3-B-3590-2001(Z)制备的三七皂甙。
本发明所述制备的药物，是用上述三七皂甙作为药物活性成分制备成的药物制剂组合物。
本发明的药物制剂组合物，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。本发明的药物制剂组合物，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。
本发明的药物制剂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。
本发明的中药制剂，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。
本发明的中药制剂，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。
本发明的制剂在使用时根据病人的情况确定用法用量，可每日服三次，每次1-20剂，如：1-20袋或粒或片，每剂1mg-1000mg。
本发明所述的治疗用途是通过以下实验证明的：
1.实验目的
在LPS诱导的微循环障碍形成之后运用三七皂甙考察其对败血症的作用。
2.材料和方法
2.1LPS和PNS溶液的制备
LPS来源于从Sigma(St Louis，MO)获得的大肠埃希氏菌属O55:B5血浆型，PNS由天津士力集团(中国，天津)提供。两者都溶于盐水溶液。
2.2动物制备
雄性sprague-dawley(SD)大鼠，体重在200～250克之间，由北京大学医学部动物中心提供。SD大鼠试验前禁食不禁水12小时。采用乌拉坦对试验动物进行麻醉(1.25mg/kg，b.w.，i.m.)。试验动物被分为LPS组(n＝6)和LPS+PNS组(n＝6)。对于对照组，在进行10分钟的基础观察之后，施行左颈静脉和左股静脉置管然后注射盐水60分钟。对于LPS组，试验动物接受和对照组一样的处理，只是不经过10分钟的基础观察，通过左股静脉的置管持续注射LPS溶液(2mg/kg/hr)60分钟。对于LPS+PNS组，经过10分钟的基础观察之后，通过左股静脉持续注射LPS溶液(2mg/kg/hr)，在注射LPS溶液之后20分钟开始通过左颈静脉持续注射PNS溶液(5mg/kg/hr)直到观察结束。
2.3肠系膜微循环的活体观察
对于每一个动物，采用正中切口切开试验腹腔(切口长2-3cm)。小心分离肠系膜的回盲部(肠系膜尾部10-15cm的区域)，然后把肠系膜从腹腔内取出并平铺 于透明塑料台之上。通过持续表面灌流37℃生理盐水来保持肠系膜的温度和湿度。采用使用透照器的倒置显微镜(德国，Leica，DM-IRB)观察肠系膜的微循环。在显微镜上安装电视照相机(日本，东芝Jk-TU53H)，图像被传输到一个彩色显示器(韩国，TCL，J2118A)，通过DVD录影带记录仪(中国，Malata DVR-R25)记录传输的影像。开始注射LPS的时间设定为电视定时器的0时点(电视定时器VTG-55B，FOR-A，日本)。
2.4图像分析
选择单支无分枝且无明显弯曲的小静脉进行以下的试验测定，小静脉的直径在30μm到50μm之间，长度200μm左右。
2.4.1小静脉直径的测定
对LPS注射后0分钟，20分钟，30分钟，40分钟，50分钟和60分钟记录的图像，使用Image-Pro Plus5.0(Media Cybernetic，USA)软件分别进行血管直径的测定。在同一位置测定血管直径三次然后取其平均值。
2.4.2红细胞速率的测定
把监视器的CCD转换为高速电视照相系统(FASTCAM-ultima APX，photron，日本)以2000帧/s的速度记录小静脉内红细胞的速率，之后以25帧/s的速度重新播放储存的高速影像。采用Image-Pro Plus5.0软件(Media Cybernetic，USA)测量LPS注射后0分钟，20分钟，30分钟，40分钟，50分钟和60分钟时小静脉内的红细胞的速率(Han et al.，2001)。
2.4.3剪切率测定
小静脉血管壁剪切率(SR)的估算基于公式SR＝2.12×8×[V/D]进行，这里D代表血管平均直径，V为红细胞平均速率，2.12为经验修正因子的中值(Dunne et al.，2002)。
2.4.4粘附白细胞的测定
为了观察粘附于血管壁的白细胞，通过重播记录到的图像来回顾白细胞的动力学行为。在本研究中，把粘附白细胞定义为粘附于同侧血管壁时间超过10s的白细胞。通过随机选择记录图像计数一定的小静脉片断(直径30～50μm，长度为200μm内粘附白细胞的数目，粘附白细胞的数目表示为粘附细胞数目/200μm小静脉[23]。
2.4.5小静脉壁DHR强度的测定
局部添加H2O2敏感的荧光探针二氢诺丹明123(DHR，分子探针)到肠系膜表面来观察小静脉壁的氧化能力。使用贡灯(100W)照射激发产生波长为455mm的荧光到倒置荧光显微镜(DM-IRB，Leica，Germany)观察荧光。然后使用CD记录器在LPS注射后的0分钟，20分钟，30分钟，40分钟，50分钟和60分钟记录荧光影像，采用Image-Pro Plus5.0软件测定小静脉壁和小静脉外间质的荧光强度。将0分钟时的小静脉壁和小静脉间质的荧光强度的差值作为基线值，通过计算各个时间点的小静脉壁和小静脉间质荧光强度的差值与基线值的比值来获得DHR荧光强度比率。
2.4.6从肠系膜小静脉渗漏的白蛋白的测定
在另一个大鼠试验组，通过左颈静脉缓慢注射FITC标记的牛血浆白蛋白(50mg/kg)。经过10分钟的基线观察之后，贡灯(100W)激发产生荧光(波长为455mm)到倒置荧光显微镜(DM-IRB，Leica，Germany)来进行荧光观察，使用CD记录器在LPS注射之后0分钟，20分钟，30分钟，40分钟，50分钟和60分钟记录荧光影像，采用Image-Pro Plus5.0软件测定小静脉壁和小静脉外间质的荧光强度。把0分钟时的小静脉壁和小静脉间质的荧光强度的比值作为基线值，通过每一个时间点的小静脉壁和小静脉间质的荧光强度的比值除以基线值来计算FITC荧光强度比值[24]，计算公式为Rt＝Pt/Po，在这里：
Rt，t时刻的FITC荧光强度比值；
t时刻的小静脉壁和小静脉间质的荧光强度的比值；
P0，0时刻的小静脉壁和小静脉间质的荧光强度的比值，即基线值；
2.4.7肥大细胞脱颗粒的测定
注射LPS之后60分钟，用0.1％的甲苯胺蓝进行组织染色1分钟，然后用盐水漂白。脱颗粒的肥大细胞被鉴定为存在释放细胞内颗粒到周围组织的细胞，计数20×物镜显微镜圆形视野内的细胞数目来确定这类细胞的个数。每个肠系膜窗评估沿微血管系统的5个视野。记录脱颗粒和非脱颗粒的肥大细胞数目，然后计算脱颗粒肥大细胞的比例。
2.4.8CD11b/CD18表达的测定
观察完肠系膜微循环后，从每个试验动物的腹主动脉采集血液后用肝素抗凝(20单位/每ml血液)，然后和1μg FITC标记的抗CD11b及抗CD18抗体(BDBiosciences Pharmingen，美国)在室温下共孵化20分钟。用溶血素(BD BiosciencesImmunocytometer Systems，美国)溶解细胞后PBS洗涤两次。使用流式细胞仪(FACS Calibur，B.D.Co，美国)测定平均的荧光强度。采用FSC-SSC散点图选择中性粒细胞。每份样品需要5千中性粒细胞，然后计算每组的平均的荧光强度。
2.4.9血浆细胞因子的测定
观察完肠系膜微循环之后，经过腹主动脉途径采集试验动物的血液标本进行肝素抗凝(20unit/ml blood)。然后离心分离血浆。在室温下，50μl血浆和标准物质与50μl capture beads共孵化1小时，然后与50μl PE标记的TNF-α和IL-6检测抗体混合，在室温之下共孵化2小时形成三明治复合物。共孵化之后，每管加入1ml洗脱缓冲液(BD Biosciences Pharmingen，美国)，运用流式细胞仪(FACSCalibur，B.D.Co，美国)检测平均荧光强度。采用BD Cytometric Bead Array分析软件进行数据分析(Wong et al.，2004)。
2.5统计分析
所有数值以平均值±S.E(N＝6)表示。采用方差分析和F—检验计算统计显著性。设定P值小于0.05具有显著意义。
3.结果
3.4粘附于小静脉壁白细胞的数目
对照组在整个60分钟的观察期只发现了少量的粘附的白细胞(A，B，C)。经过10分钟的基线观察，在LPS和LPS+PNS组都没有观察到粘附的白细胞(D，G)。在LPS组，注射LPS20分钟(E)和LPS60分钟(F)导致了大量白细胞对血管壁的粘附。在LPS+PNS组，注射LPS之后20分钟导致了粘附于小静脉壁的白细胞数目显著增加(H)，然后开始PNS后处理，导致了粘附白细胞数目的明显降低(I)。
对照组60分钟的观察期只发现了少量粘附的白细胞。相反，LPS组粘附于小静脉壁的白细胞数目进行性增加并和时间呈现线性关系，LPS注射后20分钟为5.0±0.8cells/200μm，而在60分钟时高达12.7±1.4cells/200μm。PNS后处理30分钟显著改善了LPS诱导的白细胞对血管壁的粘附。
3.7肥大细胞脱颗粒
对照组脱颗粒的肥大细胞的百分比为23.91±5.21％，代表本试验中自发发生脱颗粒的肥大细胞。注射LPS60分钟之后脱颗粒的肥大细胞增加到51.20±5.86％。PNS后处理显著地抑制了LPS诱导的肥大细胞脱颗粒，其值达到了23.96±6.12％。
3.8中性粒细胞粘附分子CD11b和CD18的表达
对照组CD11b和CD18的值分别是27.36±2.33和44.31±4.09。LPS刺激之后CD11b和CD18的荧光强度被明显提高，其值分别达到和54.98±4.14和65.83±4.12。PNS后处理抑制了CD11b的荧光强度，但是对于LPS诱导的CD18表达没有影响。
3.9血浆细胞因子浓度
对照组，TNF-α，IL-6and INF-γ的浓度分别是17.68±2.64，22.01±4.60和1.91±0.1ng/L。LPS刺激之后所有测定的细胞因子都迅速升高了，分别达到了252.22±64.10，647.83±182.80和2.63±0.11ng/L。PNS后处理显著的抑制IL-6和INF-γ的产生，在一定程度上改善了TNF-α的释放，但没有达到显著水平。
本试验的结果显示在LPS注射之后20分钟运用PNS后处理对于以上提到的每一个LPS诱导产生改变的效果是，能够显著的减少粘附于小静脉壁白细胞的数目、脱颗粒的肥大细胞的数目以及中性粒细胞CD11b的表达以及LPS诱导的血浆IL-6，INF-γ浓度，这些结果显示运用PNS后处理能够改善PNS诱导的白细胞的粘附，能够改善在本试验条件之下LPS诱导的微循环障碍。这个发现提示，在败血症或感染性休克发生之后使用本发明的药物治疗将会有作用。
总之，我们的试验显示PNS后处理能够通过抑制白细胞粘附于血管壁、肥大细胞脱颗粒和细胞因子的释放来改善LPS诱导的微循环障碍。这些结果为LPS诱导的败血症的临床治疗提供了一个新的可供选择的方法。
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100g 硫酸钙150g 微晶纤维素50g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、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75g 硫酸钙112g 微晶纤维素37g微粉硅胶2.3g 硬脂酸镁1.1g
【制法】取原、辅料分别过100目筛；取三七皂苷、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133g 硫酸钙200g 微晶纤维素66g微粉硅胶4g 硬脂酸镁2g
【制法】取原、辅料分别过100目筛；取三七皂苷、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50g，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5g，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50g，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50g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
应用实例，败血症的治疗
典型病例
患者王××，男性，45岁，公务员，有头痛、恶心、呕吐、腹胀、腹痛、周身不适、肌肉及关节疼痛等，经诊断为败血症
开始注射三七皂甙注射液，规格0.1g/支，每日三次每次3支。半月后自觉症状有明显好转。用药期间无任何不良反应。
Claims (3)
1.三七皂甙在制备一种治疗败血症引发的微循环障碍的药物中的应用，所述败血症是致病菌或条件致病菌侵入血循环中生长繁殖，产生毒素和其他代谢产物所引起的急性全身性感染，所述治疗是通过使用三七皂甙抑制LPS诱导的肥大细胞的脱颗粒，抑制LPS诱导的血浆IL-6和INF-γ浓度的升高，抑制LPS导致的中性粒细胞CD11b表达的提高。
2.权利要求1的应用，其特征在于，所述三七皂甙是三七总皂甙。
3.权利要求2的应用，其特征在于，所述三七总皂甙符合以下标准：
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| 方坤.败血症治疗研究的新进展.《医师进修杂志》.1993,(第6期),33-35. * |
| 武凡,等.三七皂甙Rg1及Rb1对离体大鼠肝细胞损害的保护作用.《中国中西医结合杂志》.2003,第23卷103-106. * |
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