CN116327824B - 一种具有解毒通络功能的中药组合物及其制备方法和应用 - Google Patents
一种具有解毒通络功能的中药组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供一种具有解毒通络功能的中药组合物,是由以下重量份的原料药制成:虎杖14‑22份、连翘14‑22份、垂盆草20‑40份、豨签草14‑22份、鸡血藤9‑21份、黄芪9‑21份、川芎14‑22份。本发明提供了所述中药组合物的用途。其优点在于:本中药组合物以清解热毒、瘀毒,补气活血通络为治疗方法,能够改善患者脑小血管病变相关记忆力下降、认知退化,和/或焦虑抑郁,和/或睡眠障碍等临床症状。细胞实验证明该中药组合物对缺氧复氧所致人脑微血管内皮细胞损伤具有保护作用,能够抑制细胞凋亡。动物实验证明该中药组合物对脑白质慢性缺血损伤具有保护作用。因此,该中药组合物可应用于“热瘀毒聚”病理机制下脑小血管病变相关临床症状的预防和/或治疗。
Description
【技术领域】
本发明涉及一种具有解毒通络功能的中药组合物及其制备方法和应用,具体地说,是以中草药为原料制备的中成药。
【背景技术】
脑血管疾病(Cerebrovascular Disease,CVD)是导致人类死亡的第二大原因,具有高发病率、高死亡率、高致残率、高复发率的特点。近几年研究发现,脑小动脉、微动脉、毛细血管以及小静脉由于各种原因引起病变,可导致患者出现记忆力下降、认知退化、头痛头晕,睡眠、情绪、步态障碍、二便异常等临床症状。大部分患者临床症状较轻,甚至部分患者早期并无明显临床症状,但磁共振成像可见包括新发皮质下小梗死,腔隙灶,脑白质高信号,微出血,或合并扩大的的血管周围间隙等脑实质改变。最终可致25%的中风病因,亦是50%复发性中风的病因,尤其是近年来还发现它与45%的认知功能障碍及独立生活功能下降的发生有关,成为老年人功能丧失、残疾和认知能力下降的主要原因,故在病变早期加以干预防变具有重要意义。
目前,脑大血管病变西医主要以降压、抗血小板、调脂等非特异性治疗为主。有研究表明,与大血管相比,小血管在控制脑血流量中起着更为重要的作用,小阻力动脉结构改变可以预测脑血管事件,但脑小血管病变机制尚不明确,迄今为止缺乏靶向作用强、疗效机制明确的治疗药物。中医认为,脑小血管的生理特点、病理机制、临床特征与“络脉理论”相吻合,络脉是气血津液输布的桥梁和枢纽,络脉分为运行经气的气络和运行血液的血络,络脉理论认为脑小血管、微血管乃脑内之血络。络体细小,气血行缓,具有易滞易瘀、易濡难出、易积成形的病机特点。络失通畅或渗灌失常,导致络气郁滞、络脉瘀阻、络脉绌急、热毒滞络等病机变化。即气机失调、气血津液代谢障碍,产生瘀、痰、水、浊、毒等,各种内邪互为因果,而产生瘀血、痰湿、寒结、热结、寒热互结等合而为病,故临床表现复杂多样。络脉病变多伴随脑髓、脏腑、全身经脉病变,故病变部位广泛。络脉玄府病变进而引起脑髓改变,影响脑及全身神机,导致健忘、注意力和执行力下降、焦虑抑郁、淡漠、易激惹及行为障碍等。由脑病影响全身脏腑同病,则临床症状广泛,表现为偏瘫、构音障碍、步态异常、易跌倒及排尿异常等。
本发明人认为,小血管病变的机制和大血管病变有相似之处,也有不同的特点,总体来说,小血管病变有以下几个重要特点:(1)平滑肌痉挛,导致微循环不畅,这和中医的气滞理论相吻合,高血压在很大程度上也和这种痉挛有关。(2)血管痉挛所致循环障碍,既中医瘀血的形成。(3)小血管痉挛可导致内皮功能障碍、血管壁发生无菌性炎症,即中医之郁久化热现象。(4)痰浊是血管病变中另外一个常见的病理因素,我们将血管病中的痰浊细分为“痰”(粘液和脂肪沉积)和“坚”(纤维和结缔组织增生),而管壁增生是血管病变最重要的关键。综上,脑小血管病变主要是以微循环不畅、内皮功能障碍、炎性反应、小血管管壁硬化等为病理基础。中医认为“无邪不有毒,热从毒化,变从毒起,瘀从毒结也。”小血管微循环不畅,即脑之络脉气机不畅,血行郁滞。络瘀日久化热生毒则形成“热毒”,即内皮功能障碍、血管壁发生无菌性炎症,故中医辨证小血管病变以“热毒”“瘀毒”为主。血运不畅,脑络不能正常输布气血津液,则瘀、痰、浊、热毒等各种内邪互为因果,继而瘀血、痰湿、痰浊、热结等合而为病,久则络脉之形构病变,如绌急、增厚、癥积等。故中医治疗重在解毒通络,应以清解热毒、瘀毒为主,兼以清解痰湿毒、浊毒,补气活血通络为原则。
中医治疗记忆力下降、认知退化、睡眠障碍、焦虑抑郁等均有相应的研究和方药,但缺少对其共病机制的研究和能够实现异病同治的有效方药。关于本发明治疗脑小血管病变的中药组合物目前还未见报道。
【发明内容】
本发明的目的是针对现有技术中的不足,提供一种具有解毒通络功能的中药组合物。
本发明的再一目的是,提供一种上述药物的用途。
为实现上述目的,本发明采取的技术方案是:
一种具有解毒通络功能的中药组合物,是由以下重量份的原料药制成:虎杖14-22份、连翘14-22份、垂盆草20-40份、豨签草14-22份、鸡血藤9-21份、黄芪9-21份、川芎14-22份。
优选地,所述的中药组合物是由以下重量份的原料药制成:虎杖16-20份、连翘16-20份、垂盆草25-35份、豨签草16-20份、鸡血藤12-18份、黄芪12-18份、川芎16-20份。
更优选地,所述的中药组合物是由以下重量份的原料药制成:虎杖18份、连翘18份、垂盆草30份、豨签草18份、鸡血藤15份、黄芪15份、川芎18份。
所述的中药组合物的药剂为片剂、胶囊剂、颗粒、口服液、合剂或糖浆剂。
优选地,所述的中药组合物还包括药学上可接受的辅剂。
如上任一所述的中药组合物的制备方法,具体的步骤为:
(1)按照如上任一所述配比取各原料药:虎杖、连翘、垂盆草、豨签草、鸡血藤、黄芪、川芎,加水浸泡1小时;
(2)第一次加入2倍量药材的水,煎煮0.5小时,煎煮后倒出药液;
(3)第二次加入2倍量药材的水,煎煮0.5小时,煎煮后倒出药液;
(4)合并两次药液,加入药学上可接受的药物辅剂制成临床上可接受的颗粒剂、散剂、胶囊剂、片剂、汤剂或口服液,即可。
为实现上述第二个目的,本发明采取的技术方案是:
如上任一所述的中药组合物在制备预防/治疗脑小血管病变药物中的应用。
优选地,所述的脑小血管病变的病机为热瘀毒聚。
优选地,所述的脑小血管病变的临床表现为记忆力下降、认知退化和/或焦虑抑郁和/或睡眠障碍。
优选地,所述的脑小血管病变的影像学表现为存在腔隙灶和/或新发皮质下小梗死和/或脑白质高信号和/或微出血,或合并扩大的血管周围间隙。
本发明优点在于:
1.本发明人优选各原料药及其之间的配伍,共奏解毒通络之效,充分发挥中药多成分、多途径、多靶点协同作用的治疗特点,能够改善患者脑小血管病变相关的多种临床症状,实现异病同治,具有很好的推广应用价值。
2.方中虎杖为君药,性味苦,寒,在方中起清热解毒、兼活血祛瘀以通经的功效。连翘是著名的清热解毒药,具升浮宣散之力,可流通气血;垂盆草味甘、淡,性凉,有清热解毒功效,利湿则兼以清解湿毒;豨莶草性味辛、苦,寒,祛湿通络,二者具有清热解毒通络之功;鸡血藤温而不烈,活血祛瘀兼有补血功效,可治血瘀兼症;黄芪甘温,具有益气扶正之功。二者合用还能制君药和臣药苦寒,保护脾胃;川芎活血行气,血中之气药,温通血脉,活血袪瘀,并有引药上头的引经功效。诸药合用,共奏清热解毒,活血通络之功,毒祛络通,气血充润,则脑神得养,神机可复。
【附图说明】
图1为中药组合物对HBMECs活力的影响;
图2为中药组合物对H/R-HBMECs细胞增殖的影响;
图3为中药组合物对H/R-HBMECs细胞迁移的影响;
图4为中药组合物对H/R-HBMECs血管生成的影响;
图5为中药组合物对H/R-HBMECs线粒体氧化应激的影响;
图6为中药组合物对细胞凋亡的影响;
图7为中药组合物对H/R-HBMECs内皮细胞炎性因子的影响;
图8为中药组合物颗粒制剂对BCAS小鼠脑白质的保护作用;
图9为LFB染色评估中药组合物颗粒制剂对BCAS小鼠脑白质的保护作用;
图10为免疫荧光染色评估中药组合物颗粒制剂对BCAS小鼠中央胼胝体损伤的保护作用。
【具体实施方式】
下面对本发明提供的具体实施方式作详细说明。
实施例1具有解毒通络功能的中药组合物(一)
虎杖18份、连翘18份、垂盆草30份、豨签草18份、鸡血藤15份、黄芪15份、川芎18份。
实施例2具有解毒通络功能的中药组合物(二)
虎杖18份、连翘16份、垂盆草35份、豨签草14份、鸡血藤21份、黄芪15份、川芎16份。
实施例3具有解毒通络功能的中药组合物(三)
虎杖16份、连翘20份、垂盆草20份、豨签草22份、鸡血藤18份、黄芪12份、川芎20份。
实施例4具有解毒通络功能的中药组合物(四)
虎杖20份、连翘14份、垂盆草40份、豨签草18份、鸡血藤9份、黄芪18份、川芎14份。
实施例5具有解毒通络功能的中药组合物(五)
虎杖14份、连翘22份、垂盆草30份、豨签草16份、鸡血藤21份、黄芪9份、川芎22份。
实施例6具有解毒通络功能的中药组合物(六)
虎杖22份、连翘18份、垂盆草25份、豨签草20份、鸡血藤15份、黄芪21份、川芎18份。
实施例7具有解毒通络功能的中药组合物(七)
虎杖18份、连翘20份、垂盆草20份、豨签草22份、鸡血藤15份、黄芪12份、川芎20份。
实施例8具有解毒通络功能的中药组合物(八)
虎杖16份、连翘14份、垂盆草40份、豨签草18份、鸡血藤21份、黄芪18份、川芎14份。
实施例9具有解毒通络功能的中药组合物(九)
虎杖20份、连翘22份、垂盆草30份、豨签草16份、鸡血藤18份、黄芪9份、川芎22份。
实施例10具有解毒通络功能的中药组合物(十)
虎杖14份、连翘18份、垂盆草25份、豨签草20份、鸡血藤9份、黄芪21份、川芎18份。
实施例11具有解毒通络功能的中药组合物颗粒的制备
取实施例1-10任一所述的中药组合物,加8-10倍量水,煎煮3小时,滤出药汁。再加10倍量水,煎煮2.5小时,滤出药汁,合并二次煎液,静置,滤取上清液,浓缩,放冷,加浓缩液2倍量酒精,搅拌沉淀过夜。取上清液,浓缩至稠浸膏;加适当制药辅料,制粒,干燥,整粒,分装20g/袋。
实施例12具有解毒通络功能的中药组合物片剂/胶囊的制备
取实施例1-10任一所述的中药组合物,加9-11倍量水,煎煮2-3.5小时,滤出药汁。再加9倍量水,煎煮2.5小时,滤出药汁,合并二次煎液,静置,滤取上清液,浓缩,放冷,加浓缩液3倍量酒精,搅拌沉淀过夜。取上清液,浓缩至稠浸膏;加入制药辅料,真空干燥,粉碎制粒,压制成片剂或填充装胶囊。
实施例13具有解毒通络功能的中药组合物合剂/口服液/糖浆剂的制备
取实施例1-10任一所述的中药组合物,加8-11倍量水,煎煮3小时,滤出药汁。再加8倍量水,煎煮3小时,滤出药汁,合并二次煎液,静置,滤取上清液,浓缩,放冷,加浓缩液3.5倍量酒精,搅拌沉淀过夜。取上清液,浓缩至稠浸膏;加适当制药辅料,制成合剂、口服液或糖浆剂。
实施例14细胞实验
1.实验材料与仪器
1.1实验细胞
人脑微血管内皮细胞(HBMECs)购自青旗(上海)生物技术发展有限公司。
1.2试剂
表1主要试剂
1.3仪器
表2主要仪器
2.方法
2.1冻干粉的制备
取虎杖18g,连翘18g,垂盆草30g,豨莶草18g,鸡血藤15g,黄芪15g,川芎18g,将上述中药材以10倍蒸馏水浸渍0.5h,每次回流两次,每次20min。然后使用旋转蒸发器在减压下蒸发合并的提取物,将其置于冷冻干燥机制成冻干粉,-20℃保存备用。取1mg虎杖清脉饮冻干粉溶于1mL DMSO中,配成浓度为1mg/mL的母液,存于-20℃。工作液用DMEM稀释为0.1,0.5,1,2,5,10μg/mL。
2.2细胞复苏
HBMECs细胞培养所用的完全培养基为:高糖型DMEM,并加入10%的胎牛血清以及1%的双抗(青霉素100U/mL,链霉素100μg/mL)。首先将冻存的细胞从-80℃冰箱中取出,迅速置于37℃水浴锅中,期间用手捏住冻存管不停晃动,注意管盖不要碰触液面放止污染。液体融化后,迅速于超净台内将液体吸出,并置于15mL离心管中,并加入1mL的完全培养基,离心:800rpm×3min,吸弃上清,加入2mL DMEM,反复吹打混匀,注意不要有气泡,吸出加入至含有6mL完全培养基的培养皿中。最后置于37℃,CO2含量为5%的培养箱中培养,镜下观察细胞生长至80%左右时消化传代。
2.3细胞传代
镜下观察细胞生长至80%,将旧培养基吸弃,用1mL PBS洗涤一次,加入1mL含0.25%EDTA的胰酶,镜下观察,待细胞形状变圆将胰酶吸弃,加入2mL含10%胎牛血清的DMEM,将细胞从壁上吹落,加入15mL离心管中。离心:800rpm×3min,吸弃上清,加入2mLPBS吹打混匀细胞,离心:800rpm×3min,吸弃上清,加入2mL含10%胎牛血清的DMEM,吹打混匀细胞,取1mL加入含6mL DMEM培养皿中。2-3天换液,取对数期长势良好的细胞进行后续实验。
2.4细胞冻存
将HBMECs旧培养基吸弃,加入1mL PBS洗涤一次,再加入1mL含0.25%EDTA的胰酶,镜下观察,待细胞形状变圆将胰酶吸弃,加入2mL含10%胎牛血清的DMEM,将细胞从壁上吹落,加入15mL离心管中。离心:800rpm×3min,吸弃上清,加入1mL冻存液,置于-80℃冰箱保存。
2.5缺氧复氧(H/R)细胞模型建立
取对数期生长良好的细胞,更换培养基为无血清培养基,并置于缺氧培养箱(94%N2,5%CO2,1%O2)中孵育12h,随后将培养基更换成完全培养基,置于常氧培养箱(5%CO2,95%空气)中孵育8h。
2.6药物处理
接种细胞24h后,将旧培养基吸弃,加入含不同药物的无血清培养基,放入缺氧培养箱中,打开N2和CO2,用封口膜将培养箱封住,待12h后,取出96孔板,吸弃旧培养基,加入含不同药物的有血清培养基,放入常氧培养箱中,待8h后,取出96孔板。
2.7细胞增殖实验
取对数生长的HBMECs,将细胞从皿中消化下来,取10μL滴至计数板中,计数仪计数。以每孔5×103个/100μL细胞数种于96孔板中。加入不同浓度的虎杖清脉饮(0,0.1,0.5,1,2,5,10μg/mL),并按照方法2.5建造缺氧复氧模型。用无血清培养基将CCK8稀释至原浓度的10%。将96孔板中旧培养基吸弃,每孔加入100μL 10%CCK8,37℃孵育30min,酶标仪450nm处检测OD值。细胞存活率(%)=(实验组OD值-空白组OD值)/(对照组OD值-空白组OD值)×100%。
2.8细胞划痕实验
取对数生长的HBMECs,将细胞从皿中消化下来,取10μL滴至计数板中,计数仪计数。以每孔2×105个/mL细胞数种于12孔板中。接种细胞24h后,将旧培养基吸弃,每孔加入1mLPBS,用10μL枪头沿着底板中间划一道垂直线,将PBS吸弃,加入不同浓度的虎杖清脉饮(0,0.5,1,2μg/mL),并按照方法2.5建造缺氧复氧模型。于划痕的0h以及造模结束分别用倒置显微镜拍照观察各孔细胞划痕状态,采用Image J对图像进行分析。
2.9血管生成实验
将96孔板放在冰板上,每孔中加入预先溶解的基质胶(9-12mg/mL)50μL,水平放置,至胶面平滑,忌气泡产生。放入37℃培养箱中孵育15min-1h,至胶凝固。在HBMECs中加入不同浓度的虎杖清脉饮(0,0.5,1,2μg/mL),并按照方法2.5建造缺氧复氧模型。在基质胶孵育期间,将按照不同组别处理好的细胞进行消化、计数,以每孔1×104个细胞铺于已经凝好的基质胶上,8h后进行拍照,采用Image J对血管生成分支的长度进行计算分析。
2.10线粒体氧化应激检测
取对数生长的HBMECs细胞,从壁上吹落,1mL细胞悬液每孔(含5×104个细胞)加入到12孔板中培养过夜,按照方法2.5造模加药(0,0.5,1,2μg/mL)。吸除培养液,每孔加入500μL JC-1染色工作液[按照JC-1:超纯水=1:160的比例向超纯水中加入200×JC-1,充分混匀,再向其中加入JC-1(5×)染色缓冲液,混匀,得到JC-1染色工作液]。培养箱孵育20min,孵育期间,用蒸馏水配制适量的(1×)JC-1染色缓冲液[按照JC-1(5×)染色缓冲液:蒸馏水=1:4的比例向蒸馏水中加入JC-1(5×)染色缓冲液,得到(1×)JC-1染色缓冲液],存放于4℃冰箱。细胞经药物和造模处理结束后,吸除上清,用(1×)JC-1缓冲液清洗两次,每孔300μL。最后加入300μLPBS,高内涵细胞成像仪拍照观察。
2.11流式细胞仪检测细胞凋亡
将对数生长的HBMECs细胞按照5×105个/mL铺于6孔板中,按照方法2.5造模加药(0,0.5,1,2μg/mL)。细胞培养结束,用不含EDTA的胰酶消化,加入至15mL离心管中,2000rpm,4℃离心10min,弃上清。加入1mL PBS重悬,加入至1.5mL EP管中(洗涤细胞),2000rpm,4℃离心10min,弃上清。加入100μL 1×FITC结合液(母液为10×,用蒸馏水稀释为1×),吹打混匀。加入FITC染料5μL,室温避光孵育10min,再加入PI染料5μL,避光孵育5min。上机前再加入100μL 1×FITC结合液,贝克曼流式细胞仪上机检测。
2.12内皮细胞炎性因子检测
收集经虎杖清脉饮和缺氧复氧处理的HBMECs上清液。采用ELISA法检测ICAM-1、VCAM-1、IL-1β和VEGF的表达。
3.结果
3.1虎杖清脉饮对HBMECs活力无影响
为了检测虎杖清脉饮对H/R-HBMECs增殖的影响,本申请人首先对虎杖清脉饮的安全剂量进行了测定。CCK8结果显示,虎杖清脉饮在0.1-2μg/mL时,对细胞活力无影响,如图1所示。
3.2虎杖清脉饮促进H/R-HBMECs增殖
在安全浓度基础上,HBMECs进行了缺氧12h复氧8h的处理,结果显示,虎杖清脉饮在0.5-2μg/mL时可以促进细胞增殖,如图2所示。
3.3虎杖清脉饮促进H/R-HBMECs细胞迁移
为了检测虎杖清脉饮对H/R-HBMECs细胞迁移的能力的影响,本申请人采用划痕实验来验证。结果表明,H/R处理会减缓HBMECs的细胞迁移能力,加入虎杖清脉饮(1,2μg/mL)会促进H/R-HBMECs的愈合能力,表明虎杖清脉饮可以促进H/R-HBMECs细胞迁移,如图3所示。
3.4虎杖清脉饮促进H/R-HBMECs血管生成
血管生成是内皮细胞的特性,本申请人采用小管生成模拟体外血管生成,最终用Image J对血管生成分支的长度进行比较。结果表明,单纯H/R处理血管生成受阻,加入虎杖清脉饮(0.5,1,2μg/mL)会促进小管生成分支的长度,表明虎杖清脉饮可以促进H/R-HBMECs血管生成,如图4所示。
3.5虎杖清脉饮能够抑制线粒体氧化应激
HBMECs经JC-1染色后,采用高内涵细胞成像仪拍照观察。正常组的线粒体膜电位高,细胞胞浆呈红色荧光(颜色部分:因说明书附图中呈现灰色,以此说明)。当细胞受到损伤时,线粒体膜电位会发生降低,细胞胞浆红色荧光显著减少,绿色荧光增多,最终采用R/G代表线粒体膜电位的改变。实验结果表明,H/R损伤致使HBMECs绿色荧光增多,表明线粒体膜电位降低,而虎杖清脉饮处理过后红色荧光强度增多,绿色荧光强度减少,说明虎杖清脉饮能够逆转H/R致使的线粒体膜电位损伤,如图5所示。
3.6虎杖清脉饮能够抑制细胞凋亡
流式细胞仪可以定量分析经Annexin V和PI双染后各组处于不同凋亡时期的细胞比例。结果显示,与正常组比较,H/R处理可显著增加HBMECs的细胞凋亡比例,而加入虎杖清脉饮(1,2μg/mL)可以呈现剂量依赖性地减少凋亡细胞数量,如图6所示。
3.7虎杖清脉饮能够抑制内皮细胞炎症反应
如图7所示,H/R损伤后ICAM-1、VCAM-1和IL-1β显著升高,而虎杖清脉饮治疗可逆转上述变化,虎杖清脉饮可能通过抑制炎症反应发挥保护作用。其次,H/R处理导致VEGF表达下降,而虎杖清脉饮可以增加VEGF的表达。
4.结论
该中药组合物可以保护H/R-HBMECs,具体表现为:促进细胞增殖、迁移及血管生成,同时可以抑制炎性反应、氧化应激和细胞凋亡。
实施例15动物实验
1.实验材料
1.1实验动物
60只雄性C57/BLJ系小鼠,8-10周龄,体重为20-22g。小鼠购买于上海市计划生育科学研究所(上海,中国),许可证号:SCXK(沪)2018-0006。在标准SPF级饲养环境下,小鼠被安置通风良好的笼子中,在12小时光照/12小时黑暗周期下,自由获得食物和水。
1.2药品与试剂
虎杖清脉颗粒(HZQMG)由江阴天江公司(江苏,中国)生产,批号为2108342,每克颗粒相当于3.84g生药饮片;LFB染色试剂盒购自北京索莱宝科技有限公司(G3245);牛血清白蛋白购自Sigma公司(A1933-5G);MBP抗体购自novusbio公司(NB600-717);MAG抗体购自absin公司(abs137146);GFAP和Iba1购自CST公司(#80788,#17198)。
1.3实验主要仪器
微弹簧圈购自无锡萨密你弹簧有限公司;磁共振扫描使用bruker 11.7T磁共振系统(BioSpec 117/16,德国);共聚焦显微镜(FV1200 Olympus,日本)。
2.实验方法
2.1模型制备
本研究使用双侧颈总动脉缩窄(BCAS)小鼠模型。小鼠用5%的异氟烷诱导深度麻醉,然后用2%异氟烷维持。在小鼠颈部正中纵向切开约1cm,用镊子分离两侧颈动脉鞘,使颈总动脉暴露。假手术组小鼠完成上述操作后缝合切口,BCAS组小鼠使用2个微弹簧圈分别缠绕在小鼠两侧的颈总动脉。手术过程中保持小鼠体温在36.5-37℃,术后观察和照顾小鼠,直到意识清醒并恢复。
2.2分组与给药
小鼠被随机分为三组:假手术组,BCAS组和虎杖清脉颗粒治疗组,每组20只。术后第一天开始灌胃给药,假手术组小鼠予以假灌胃刺激,BCAS模型组小鼠予以生理盐水,治疗组小鼠予以虎杖清脉颗粒(5g/kg)治疗。
2.3高场强11.7T核磁共振检测小鼠白质区域损伤
磁共振扫描使用bruker 11.7T磁共振系统。小鼠在2.5%异氟醚,氧气浓度2.5L/min条件下麻醉,用齿杆和耳杆将小鼠约束在支架上进行数据采集,扫描过程中连续监测呼吸和心率。MRI扫描采用TurboRARE-T2脉冲序列:重复时间(TR)=8000ms,回声时间(TEs)=18.0ms,回声空间:9ms,slice orientation:axial。切片厚度=0.6mm,视场(FOV)=16.0×16.0mm2。采用回波平面成像(EPI)弥散张量序列(TR=18.14ms,TEs=2500ms,层厚=0.5mm,FOV=2.0×2.0cm2,image size=180×180mm,diffusion direction=30)矩阵获取弥散张量图像(DTI)。由一名对实验干预分组不知情的人对白质感兴趣区域,胼胝体(CC)、内囊(IC)、前联合(AC)及视束(Opt)的各向异性分数(FA)、径向弥散系数(RD)及平均扩散系数(AD)值进行分析。
2.4快蓝(LFB)染色检测小鼠白质区域损伤
将小鼠用1%戊巴比妥钠麻醉(10ml/kg,i.p.),使用PBS进行心脏灌注,然后使用冰冷4%PFA进行灌注固定。将大脑完整取出,通过固定、脱水、透明后制成石蜡组织块。使用莱卡切片机切片,石蜡切片厚度为4微米。LFB染色按照手册进行。切片经过脱蜡复水后放入95%乙醇清洗,然后放入Fastblue染色液,室温过夜。经95%乙醇和去离子水清洗后用luxol分化液和70%乙醇分色,使白质和灰质清晰。然后用焦油紫复染。经去离子水清洗后,进行梯度脱水,透明化,最后封片。使用光学显微镜观察脑白质区域,包括胼胝体、内囊、视束和前联合区白质损伤,白质破坏的严重程度据此分级:0级=无破坏;1级=神经纤维紊乱;2级=形成明显空泡;3级=有髓纤维消失。
2.5免疫荧光染色检测小鼠胼胝体区域髓鞘轴突损伤及胶质细胞激活
将石蜡切片脱蜡、复水,用Tris-EDTA进行抗原修复。用0.1M PBS洗涤三次,然后用0.25%Triton-X100在PBS中渗透。室温避光孵育用10%牛血清白蛋白(Sigma–Aldrich)封闭1小时后,将载玻片与一级抗体MBP(1:400,NB600-717,novusbio),MAG(1:200,abs137146,absin),GFAP(1:200,#80788,CST)和Iba1(1:800,#17198,CST),在4℃下孵育过夜,然后用3%过氧化氢溶液灭火内源性过氧化氢酶活性。在室温下无光条件下,与相应二级孵育抗体1小时。切片用共聚焦显微镜成像,使用image J软件分析,在每次免疫荧光染色实验中,共聚焦设置保持不变。所有评估均由一名盲研究者进行。
3.实验结果
3.1虎杖清脉颗粒对BCAS小鼠脑白质损伤的保护作用
本申请人首先使用MRI评估了小鼠胼胝体(CC)、内囊(IC)、前连合(AC)及视束(Opt)部位的损伤(图8A)。如图8D所示,大脑的T2加权MRI图像未检测到三组之间明显的结构变化。弥散张量图像(DTI)序列是一种神经成像技术,允许对白质进行无创评估,检测的内容包括FA、RD和AD。FA值可以反应白质结构完整性,RD值可以反应反映了白质束的髓鞘化,AD可以反映轴突完整性。如图8D FA图像所示,与假手术组和虎杖清脉颗粒治疗组相比,双侧颈总动脉缩窄(BCAS)组小鼠胼胝体部位显示出更低的信号。进一步分析显示,除Opt区域外,BCAS小鼠CC、IC、AC部位的FA值显著下降,而虎杖清脉颗粒给药组小鼠的上述部位FA值较BCAS组小鼠增高(图8B),这表明虎杖清脉颗粒可以改善BCAS小鼠的白质结构完整性。如图8C所示,BCAS小鼠的RD值CC和IC部位的RD值显著上升,虎杖清脉颗粒治疗后CC和IC部位的RD值显著降低,提示BCAS造模4周会导致白质髓鞘化降低,而虎杖清脉颗粒可以减轻白质髓鞘化损伤。如图8E所示,BCAS组小鼠胼胝体部位AD值较假手术组显著下降,而虎杖清脉颗粒治疗可以逆转此改变。磁共振检测结果表明,虎杖清脉颗粒可以减轻BCAS引起的白质完整性降低、髓鞘化减弱及轴突损伤。本申请人进一步通过LFB染色评估了上述白质部位的损伤。结果发现,造模4周后,BCAS组小鼠中央胼胝体、旁胼胝体、内囊、前连合及视束部位的出现白质破坏。如图9(a、b)所示,除Opt区域外,BCAS小鼠CC、IC、AC区域出现明显空泡及髓鞘丢失,其中胼胝体部位的白质破坏最为严重,这与磁共振扫描结果一致。虎杖清脉颗粒给药后,上述区域的白质破坏明显逆转。
3.2虎杖清脉颗粒对BCAS小鼠中央胼胝体损伤的保护作用
本申请人通过免疫荧光染色评估了中央胼胝体部位的损伤,图10(a、b)所示。髓鞘碱性蛋白(MBP)可以表征髓鞘脱失,髓鞘相关糖蛋白(MAG)是髓鞘-轴突完整性的标志物。我们发现,BCAS组小鼠胼胝体部位MBP和MAG表达较假手术组显著降低,而虎杖清脉颗粒给药可以增加MBP和MAG的表达,表明其可以减轻胼胝体部位髓鞘-轴突损伤。同时,还观察到了BCAS组小鼠胼胝体部位星形胶质细胞和小胶质细胞的显著激活,表现为GFAP和Iba1表达增加,而虎杖清脉颗粒组小鼠上述现象减弱,表明虎杖清脉颗粒可以减弱BCAS后胼胝体部位的神经胶质增生。
4.结论
本发明中药组合物可以显著减轻脑慢性缺血小鼠模型脑胼胝体、内囊、前连合及视束部位的髓鞘及轴突损伤,减轻缺血后胶质细胞激活,表明本发明中药组合物对脑慢性低灌注模型小鼠脑白质损伤具有明显的保护作用。
实施例16临床实验
1.资料
1.1研究对象
65例患者来源于上海中医药大学附属岳阳中西医结合医院神经内科病房或门诊。
1.2诊断标准
西医影像学诊断参考2013年神经影像学血管性改变标准报告小组标准,影像学表现为存在腔隙灶、和/或新发皮质下小梗死、和/或脑白质高信号、和/或微出血,或合并扩大的血管周围间隙;
中医证型诊断参考《中医诊断学》及朱文锋《证素辨证学》诊断为热瘀毒聚。
1.3纳入标准
(1)符合西医影像学诊断标准:头颅磁共振有下列表现之一:近期皮质下小梗死、脑白质高信号(WMH)、腔隙灶、微出血(CMB),或合并扩大的血管周围间隙(EPVS);
(2)符合“热瘀毒聚”证中医诊断标准;
(3)年龄≥30周岁且≤70周岁,性别不限;
(4)理解、同意参加本研究并签署知情书。
1.4排除标准
(1)颅内大血管狭窄≥50%;
(2)存在视、听觉障碍,不能配合检查及认知量表评估;
(3)存在大面积心源性栓塞和脑梗塞;
(4)由其他疾病(如多发性硬化症,代谢性脑病,中毒性脑病或颅内多发性血管炎)引起的高白质信号;
(5)严重的骨关节炎以及严重的关节和肌肉疼痛可能会限制患者的运动;或合并严重心、肝、肾、血液系统等疾病,或其他严重原发性疾病、精神病者;
(6)已知对治疗方案中的药物过敏;
(7)妊娠期或哺乳期妇女。
1.5治疗方案
对照组(常规西药治疗+虎杖清脉颗粒安慰剂)和实验组(常规西药治疗+虎杖清脉颗粒)。虎杖清脉颗粒组成:虎杖18g、连翘18g、垂盆草30g、豨签草18g、鸡血藤15g、黄芪15g、川芎18g。虎杖清脉颗粒由江阴天江公司(江苏,中国)生产,批号为2108342,患者每日2次,每次2包,用200ml温开水冲服,两组疗程均为12周。
1.6观察指标
(1)中医证候积分:参考《中医诊断学》及朱文锋《证素辨证学》自拟中医证候积分量表,将患者的症状、体征等资料,分别进行加权求和。症重,按权值×1.5计量;症中等,按权值×1计量;症轻,按权值×0.7计量,加权后的总分值>20分,可诊断为该证候;
(2)神经心理学量表:MoCA、MMSE、听觉词语学习测验(AVLT)、连线测验(TMT)、数字广度测验(DST)、数字符号测验(SDMT)、斯特鲁色词测验(Stroop)、复杂图形(CFT)、言语流畅性(CVFT)、波士顿命名测验(BNT)、HAMD、HAMA、匹兹堡睡眠质量指数(PSQI);
(3)实验室检查:血常规、肝肾功能、血脂血糖等。
1.7临床疗效判定
(1)临床痊愈:中医临床症状、体征消失或基本消失,积分减少≥95%;
(2)显效:症状、体征明显改善,积分减少≥70%;
(3)有效:症状、体征有所好转,积分减少≥30%;
(4)无效:症状、体征未见改善,甚或加重,积分减少不足30%。
参照2002版《中药新药临床研究指导原则》,采用尼莫地平法,疗效指数=[(治疗前积分-治疗后积分)/治疗前积分]×100%。
2.结果
2.1两组患者一般资料比较
两组患者的基线资料各个指标均无显著的统计学差异,p>0.05,见表3。
表3两组患者一般资料比较
2.2观察指标比较
如表4所示,两组患者的常规实验室指标治疗前后均无显著的统计学差异,p>0.05。
表4治疗前后两组患者常规实验室指标比较
如表5所示,对两组患者治疗前后MoCA、MMSE、听觉词语学习测验(AVLT)、连线测验(TMT)、数字广度测验(DST)、斯特鲁色词测验(Stroop)、复杂图形(CFT)、言语流畅性(CVFT)、波士顿命名测验(BNT)、HAMD、HAMA、匹兹堡睡眠质量指数(PSQI)、中医症候积分进行统计学分析。结果显示,对照组治疗前后各项指标均不具有显著的统计学差异(p>0.05),而实验组TMT、HAMD、HAMA、PSQI、中医证候积分治疗后相对于治疗前均出现显著的降低,AVLT治疗后相对于治疗前出现显著的增高,差异均具有显著的统计学意义(p<0.001)。而组间比较显示,治疗前两组各项指标均无显著的统计学差异(p>0.05),治疗后实验组TMT(p<0.05)、HAMD(p<0.05)、HAMA(p<0.01)、PSQI(p<0.05)、中医证候积分(p<0.01)较对照组均显著降低,差异具有统计学意义,而治疗后实验组AVLT较对照组显著增高,差异具有统计学意义(p<0.05)。
表5治疗前后两组患者量表评分比较
注:与治疗前相比,***p<0.001;与对照组相比,#p<0.05,##p<0.01。
2.3中医证候疗效比较
如表6所示,实验组患者总有效率为78.1%,组间中医证候总疗效比较差异具有统计学意义(p<0.001)。
表6治疗后两组患者中医证候积分总疗效比较
注:与对照组相比,***p<0.001。
3.结论
本发明中药组合物能够改善患者脑小血管病变相关的记忆力下降、认知退化和/或焦虑抑郁,和/或睡眠障碍等临床症状。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明方法的前提下,还可以做出若干改进和补充,这些改进和补充也应视为本发明的保护范围。
Claims (10)
1.一种预防和/或治疗脑小血管病变的中药组合物,其特征在于,是由以下重量份的原料药制成:虎杖14-22份、连翘14-22份、垂盆草20-40份、豨签草14-22份、鸡血藤9-21份、黄芪9-21份、川芎14-22份。
2.根据权利要求1所述的中药组合物,其特征在于,是由以下重量份的原料药制成:虎杖16-20份、连翘16-20份、垂盆草25-35份、豨签草16-20份、鸡血藤12-18份、黄芪12-18份、川芎16-20份。
3.根据权利要求2所述的中药组合物,其特征在于,是由以下重量份的原料药制成:虎杖18份、连翘18份、垂盆草30份、豨签草18份、鸡血藤15份、黄芪15份、川芎18份。
4.根据权利要求1-3任一项所述的中药组合物,其特征在于,所述的中药组合物的药剂为颗粒剂、片剂、胶囊剂、口服液或糖浆剂。
5.根据权利要求4所述的中药组合物,其特征在于,所述的中药组合物还包括药学上可接受的辅剂。
6.根据权利要求1-3任一项所述的中药组合物的制备方法,其特征在于,具体的步骤为:
(1)按照如上所述配比取各原料药:虎杖、连翘、垂盆草、豨签草、鸡血藤、黄芪、川芎,加水浸泡1小时;
(2)第一次加入2倍量药材的水,煎煮0.5小时,煎煮后倒出药液;
(3)第二次加入2倍量药材的水,煎煮0.5小时,煎煮后倒出药液;
(4)合并两次药液,加入药学上可接受的药物辅剂制成临床上可接受的颗粒剂、散剂、胶囊剂、片剂、汤剂或口服液,即可。
7.根据权利要求1-3任一项所述的中药组合物在制备预防和/或治疗脑小血管病变药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述的脑小血管病变的病机为热瘀毒聚。
9.根据权利要求7所述的应用,其特征在于,所述的脑小血管病变的临床表现为记忆力下降、认知退化、焦虑抑郁、睡眠障碍中的一种或多种。
10.根据权利要求7所述的应用,其特征在于,所述的脑小血管病变的影像学表现为存在腔隙灶、新发皮质下小梗死、脑白质高信号、微出血、扩大的血管周围间隙中的一种或多种。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1943771A (zh) * | 2005-10-08 | 2007-04-11 | 河北以岭医药研究院有限公司 | 通过作用于nei网络治疗血管病变的药物 |
CN102048852A (zh) * | 2010-12-17 | 2011-05-11 | 马耀茹 | 治疗脑梗塞和缓解肢体痉挛的口服药物 |
CN105030919A (zh) * | 2015-07-02 | 2015-11-11 | 王厚中 | 一种治疗脑出血的药物组合物 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1943771A (zh) * | 2005-10-08 | 2007-04-11 | 河北以岭医药研究院有限公司 | 通过作用于nei网络治疗血管病变的药物 |
CN102048852A (zh) * | 2010-12-17 | 2011-05-11 | 马耀茹 | 治疗脑梗塞和缓解肢体痉挛的口服药物 |
CN105030919A (zh) * | 2015-07-02 | 2015-11-11 | 王厚中 | 一种治疗脑出血的药物组合物 |
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