CN103623109B - 一种治疗缺血性脑血管病的中药组合物及其制备方法 - Google Patents
一种治疗缺血性脑血管病的中药组合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种治疗缺血性脑血管病的中药组合物及其制备预防或治疗缺血性脑血管病药物的应用,属于医药技术领域。针对目前缺血性脑血管病的化学治疗药物肝毒性较大,本发明的提供一种治疗或预防缺血性脑血管病的中药组合物,其包括如下组分:黄芩15份、金银花6份、石榴皮10份、文冠果壳10份、薄荷10份、桑枝20份、丹参20份、荷叶10份、川芎5份、秦艽8份、全蝎15份、牛蒡子7份、葛根10份、甘草10份。该中药组合物在治疗缺血性脑血管病方面均具有很好的治疗效果,具有显著的临床推广价值。
Description
技术领域
本发明涉及一种治疗缺血性脑血管病的中药组合物,属于医药技术领域。
背景技术
缺血性脑血管病(ICVD)约占全部脑血管病的80%,具有发病率高、致残率高、治病率高的特点,已经成为严重危害人类健康的疾病之一。缺血性脑血管病是脑血管病中最主要的病种之一,是局部血液循环所提供的氧及其他营养物质与神经元代谢需求之间的骤然供需不平衡,最终导致缺血中央区的神经元受损的一类疾病。短暂性脑缺血发作简称TIA,也称一过性脑缺血发作或小中风,它是由于负责供应脑部血液的动脉血管短时间内供血不足,引起相应动脉负责供血的脑组织发生暂时性功能障碍。此病的主要临床症状常常表现为突然发作的头晕、眼花、眩晕、耳鸣、走路不稳,严重时意识模糊、双目失明或复视、单侧或双侧肢体无力与感觉异常、莫名其妙地摔倒、说话不流利等。能够引发短暂性脑缺血发作的原因颇多,诸如高血压、高脂血症、动脉粥样硬化、糖尿病是最主要和最常见的原因,而过度用脑,情绪激动,寒冷,劳累则可促其发生。
短暂性脑缺血发作每次犯病的时间持续不久,通常是数秒钟、数分钟或数小时不等,最长不超过24小时,因此容易被人忽视。实际上,短暂性脑缺血是脑血管病的先兆或危险信号,如不及时治疗极易恶化发展成为严重脑血管病从而威胁病人生命。据统计,约有25%~40%短暂性脑缺血患者在5年内将产生严重的脑梗塞。因此,对短暂性脑缺血发作应当进行积极治疗,降低血液粘稠度,调整血液的高凝状态,控制和维持血压在正常范围内,终止和减少短暂性脑缺血发作,预防或推迟脑梗塞的发生。
脑梗塞是由于脑动脉粥样硬化,血管内膜损伤使脑动脉管腔狭窄,进而因多种因素使局部血栓形成,使动脉狭窄加重或完全闭塞,导致脑组织缺血、缺氧、坏死,引起神经功能障碍的一种脑血管病。脑缺血和脑梗塞具有十分密切的联系,能够实现对脑缺血的治疗就会进一步延缓或者预防脑梗塞的发生和发展。
脑保护药物是目前神经学界研究的热点,各种药物处于不同研究阶段,但目前还没有一种药物可以对大脑保护取得公认的确切疗效。目前医学上对于脑缺血或脑梗塞的治疗尚没有特效药物,一般临床上建议是控制血压,清淡饮食,并可以服用扩血管药和活血化淤的药或者营养脑细胞的药物改善。但临床实践表明,上述药物的治疗效果并不能令人满意,而这些药物高昂的花费通常让患者苦不堪言。
中医药在治疗缺血性脑血管病方面积累大量的中医理论和临床实践。中医认为,缺血性脑血管病是脑血管意外之一,属于中医的“中风病”,“中风病”为“风、痨、臌、胀”四大难症之首,是仅次于心血管疾病与癌症而位居第三位的威胁人类生命的疾病,老年人易发,并有逐渐年轻化的趋势。缺血型中风病发作前绝大多数病人有先兆,中医称“中风先兆”。病人多有高血脂、高血糖、高粘血症、颈椎病等。主要病理变化是在脑动脉硬化、高脂血症、高粘血症的基础上,血流粘稠而缓慢,或者加上其它因素压迫脑血管,由粘、缓、窄的共同作用,使血管内形成小血栓或血管壁形成了附壁血栓,部分阻塞或者暂短的阻塞了脑血流,造成脑组织的短时缺血、缺氧,病人表现为一过性的头晕目眩、口角流涎、手臂麻木、下肢发软等症状。在“中风先兆”期及时进行防治,可预防中风病发生或者减轻患者的中风病症状,从而降低发病率、致残率及死亡率。传统医药治疗脑梗塞在昔日曾挽救了不少患者的生命,随着西方医学的发展,尽管传统医药倍受冷遇,但一些单方和提纯制剂目前仍广泛应用于临床,如丹参、银杏、川芎、葛根、灯盏花等中药制剂。中华医学会神经病学分会于1998年建议活血化淤的中药可用于急性缺血性脑卒中的治疗,但需要更多高质量的证据应证。目前国外指南中尚无有关中医中药治疗缺血性脑卒中的建议。
发明内容
针对目前医学实践中缺少脑缺血或脑梗塞显效治疗药物,且药物价格高昂的现有技术不足,本发明提供一种能够对脑缺血或脑梗塞具有预防或治疗作用的药物。该药物以中药组合物为主要活性成分,其用于脑缺血或脑梗塞的治疗时,疗效显著,成本低廉,具有良好的医学应用前景。中药组合物为γ-氨基丁酸(GABA)的衍生物,其临床上主要用于癫痫的治疗或预防,因此本发明涉及中药组合物的一种新的医药用途,即中药组合物用于制备预防或治疗脑缺血或脑梗塞药物中的用途。
针对目前缺血性脑血管病临床治疗药物的不足,本发明的第一个目的在于提供一种治疗缺血性脑血管病的中药组合物,该中药组合物在治疗急性缺血性脑血管病、慢性缺血性脑血管病以及过敏性缺血性脑血管病方面具有很好的治疗效果。
本发明一种治疗缺血性脑血管病的中药组合物,由以下重量份的原料制得:黄芩12-16份、金银花5-8份、石榴皮8-12份、文冠果壳8-12份、薄荷8-12份、桑枝18-22份、丹参18-22份、荷叶8-12份、川芎5-8份、秦艽5-8份、全蝎12-16份、牛蒡子5-8份、葛根8-12份、甘草8-12份。
本发明一种治疗缺血性脑血管病的中药组合物,由以下优选重量份的原料制得:黄芩15份、金银花6份、石榴皮10份、文冠果壳10份、薄荷10份、桑枝20份、丹参20份、荷叶10份、川芎5份、秦艽8份、全蝎15份、牛蒡子7份、葛根10份、甘草10份。
黄芩别名山茶根、土金茶根,为唇形科植物,以根入药。有清热燥湿,凉血安胎,解毒功效。主治温热病、上呼吸道感染、肺热咳嗽、湿热黄胆、肺炎、痢疾、咳血、目赤、胎动不安、高血压、痈肿疖疮等症。苍术具有燥湿健脾,祛风散寒,明目的功效,用于湿阻脾胃、脘腹胀满,寒湿白带,湿温病以及湿热下注、脚膝肿痛、痿软无力。治湿阻脾胃,而见脘腹胀满、食欲不振、倦怠乏力、舌苔白腻厚浊等症,常与厚朴、陈皮等配伍应用。
金银花为忍冬科忍冬属植物忍冬及同属植物干燥花蕾或带初开的花。金银花自古被誉为清热解毒的良药。它性甘寒气芳香,甘寒清热而不伤胃,芳香透达又可祛邪。金银花既能宣散风热,还善清解血毒,用于各种热性病,如身热、发疹、发斑、热毒疮痈、咽喉肿痛等证,均效果显著。现代医学表明,金银花含环己六醇、黄酮类、肌醇、皂甙及鞣质等,具有广谱抗菌作用,对金黄色葡萄球菌、痢疾杆菌等多种致病菌均有较强的抑制作用,对钩端螺旋体、流感病毒以及致病霉菌等多种病原微生物亦有抑制作用。此外,金银花还具有明显的抗炎及解热作用,金银花水及酒浸液对试验性肿瘤细胞具有明显的杀伤作用。
石榴皮系维吾尔医常用药材,为石榴科植物石榴(punicagranatum L.)的干燥果皮。石榴皮性酸、味涩,在我国传统医药中主要用于久泻、出血等证。石榴皮中的多酚是一类具有多酚羟基化合物的总称,包括鞣花单宁、没食子单宁、鞣花酸、没食子酸等多种化合物,含量约为其干质量的10%-20%,具有抗菌、抗氧化、抗衰老、抗癌防癌、降血压和预防心脑血管疾病等多种生理和药理活性。
文冠果是我国特有的一种优良木本食用油料树种。文冠果种子含油率为30%-36%,种仁含油率为55%-67%。其中不饱和脂肪酸中的油酸占52.8%-53.3%,亚油酸占37.8%-39.4%,易被人体消化吸收。现有技术显示,文冠果壳中的文冠果壳苷能显著改善多种记忆障碍模型动物的学习记忆能力,特别是可以改善β-淀粉样蛋白所致的学习记忆障碍,抑制海马神经元的变性及脱落,提高大脑对缺氧的耐受能力,增强对神经细胞的保护作用等。这与临床使用的单一作用靶点的胆碱酯酶抑制剂不同,这种通过多个环节发挥脑保护及改善记忆障碍作用的效果,提示文冠果果皮总皂苷及文冠果壳苷有可能成为治疗老年痴呆症的新型药物。药理毒理实验结果表明,文冠果壳苷在μg/kg剂量下即能够显著改善和恢复多种痴呆模型动物的学习记忆能力,也能提高正常动物的学习记忆能力。某些指标较石杉碱甲等治疗老年痴呆症的主流药物效果更好,对阿尔茨海默病(AD)和血管性痴呆(VD)模型均有效,且毒性低。
薄荷,土名叫“银丹草”,为唇形科植物“薄荷”即同属其他干燥全草,多生于山野湿地河旁,根茎横生地下。全株青气芳香。叶对生,花小淡紫色,唇形,花后结暗紫棕色的小粒果。薄荷是中华常用中药之一。它是辛凉性发汗解热药,治流行性感冒、头疼、目赤、身热、咽喉、牙床肿痛等症。外用可治神经痛、皮肤瘙痒、皮疹和湿疹等。光朋温室采摘的薄荷又是春节餐桌上的鲜菜。清爽可口。平常以薄荷代茶,清心明目。
桑枝为桑科植物桑的嫩枝。春末夏初采收,去叶,晒干,或趁鲜切片,晒干。其味苦、微辛,性平。归肝、肺经。清热祛湿通络。用于风湿热痹、四肢关节疼痛。该品能祛风通络利关节,可单独重用该品(以老桑枝为宜)治疗关节红肿热痛等属热痹的关节病变,亦可配合其他药物同用。该品主要作用为祛风通络。主治风湿痹症,而尤宜于上肢痹痛。
丹参具有活血散淤、消肿止血、消炎止痛、调经止痛、扩张冠状动脉、改善心肌缺血状况、降低血压、安神静心、降血糖和抗菌等功效,对***,经闭痛经,症瘕积聚,胸腹刺痛,热痹疼痛,疮疡肿痛,心烦不眠;肝脾肿大,心绞痛等病症有一定的疗效。此外,近代医学实验证明,丹参还具有抗血小板凝聚、降低血液黏度及调节内外凝血***的功能,是一种安全又可靠的治疗心脏血管疾病的天然中药。
荷叶为睡莲科植物莲的叶,全国大部分地区均产。荷叶味苦辛微涩、性凉,归心、肝、脾经、清香升散;具有消暑利湿,健脾升阳,散瘀止血的功效。主治暑热烦渴,头痛眩晕,水肿,食少腹胀,泻痢,白带,脱肛,吐血,衄血,咯血,便血,崩漏,产后恶露不净,损伤瘀血。现代医学证实荷叶对腹泻、水肿、高血脂以及皮肤疾病均有一定的治疗效果。
川芎,原名芎藭。一种中药植物,常用于活血行气,祛风止痛,主要栽培于四川、云南、贵州、广西、湖北等地。川芎辛温香燥,走而不守,既能行散,上行可达巅顶;又入血分,下行可达血海。活血祛瘀作用广泛,适宜瘀血阻滞各种病症;祛风止痛,效用甚佳,可治头风头痛、风湿痹痛等症。昔人谓川芎为血中之气药,殆言其寓辛散、解郁、通达、止痛等功能。本品辛温升散,凡阴虚阳亢及肝阳上亢者不宜应用;月经过多、孕妇亦忌用。
秦艽是龙胆科多年生草本植物,是治风湿关节痛、结核病潮热、黄疸等症的主药之一。在青海尤以黄南产的秦艽质量最佳。是中国重要的传统中药之一,始载于《神农本草经》,列为中品,“秦艽主寒热邪气,寒湿风痹,肢节痛、下水、利小便。”现代药理学研究证实,秦艽碱甲小剂量对小鼠、大鼠的中枢神经***有镇静作用,较大剂量则有中枢兴奋作用,最后导致麻痹而死亡.其能增强戊巴比妥的催眠-麻醉作用.较小剂量注射给药,即能抑制狗肠瘘因灌注氯化亚汞所引起的反射性肠液分泌,即抑制了狗的神经***,这种抑制作用随剂量加大而增强。秦艽碱甲能提高大鼠(光热刺激法)的痛阈,但作用短暂;对小鼠(热板法)亦有镇痛作用,如与元胡索、草乌、天仙子等配伍,能使镇痛作用增强,作用时间延长;但与***合用时,则无互相增强作用。
全蝎食用、药用历史悠久。钳蝎的主要药用成分为蝎毒素(Buthotoxin),据《本草纲目》和《中国药典》载,全蝎具有“熄风镇痉、消炎攻毒、通络止痛”功能;主治“小儿惊风、抽搐痉挛、皮肤病、心脑血管病、炎症、乙肝、肿瘤”等病。全蝎也是一种高档美味佳肴,营养丰富,食之有防病治病、增强免疫力和抗衰老等功能。牛蒡子被称为东洋参,原产中国,《本草纲目》称“牛蒡”(又称大力子)是两年生草本植物,其子、其根均可入药,也可食用,《本草经疏》称其为“散风除热解毒三要药”。现有技术证明其具有显著的抗菌抗病毒效果,并能显著增强机体的免疫能力。全蝎和牛蒡子两种药物连用,可以显著增强机体的免疫能力。
葛根提高肝细胞的再生能力,恢复正常肝脏机能,促进胆汁分泌,防止脂肪在肝脏堆积。并能促进新陈代谢,加强肝脏解毒功能,防止酒精对肝脏的损伤。某些研究表明葛根对学习记忆障碍有明程的治疗作用,葛根醇提取物能显著对抗东度警碱所致的记忆障碍。可用于治疗老年性痴呆,智力障碍,记忆力差等病症。葛根素有明显的降低血糖的作用,葛根所含的黄酮类化合物有降血脂作用,能降低血清胆固醇,降低油三酯,用于治疗高血糖,高血脂病症,有显著疗效。葛根中的微量元素硒、锰、锗等的含量也相当可观。葛根具有发表解肌,透发麻疹,解热生津,升阳止泻之功效。用于外感发热头痛、项强、口渴、麻疹不透,泄泻、高血压颈项强痛等症。现代研究葛根含有20多种异黄酮成分、葛根甙类、三萜类、生物碱及其他活性成分,具有多种药理作用。葛根中的总酮能增加脑及冠状动脉的血流量。葛根对动物和人体的脑循环有明显的促进作用。
甘草味甘甜,性平和,入心、脾、肺、胃四经。生用偏凉,可泻火解毒、缓急止痛;炙用偏温,能散表寒、补中益气。此外,甘草还善于调和药性,解百药之毒,具有抗炎、抗病毒,和保肝解毒及增强免疫功能等作用。由于甘草酸有糖皮质激素样药理作用而无严重不良反应,临床被广泛用于治疗各种急慢性肝炎、支气管炎和艾滋病,还具有抗癌防癌、干扰素诱生剂及细胞免疫调节剂等功能。甘草酸具有降血脂与抗动脉粥样硬化作用,阻止动脉粥样硬化的形成。
制备本发明中药组合物的方法如下:取上述重量组分的各药材,加药材总重量的5-15倍的水,浸泡10-60分钟,煎煮1-4次,每次1-3小时,滤过,合并滤液,滤液减压浓缩至相对密度1.05-1.25的浸膏,该相对密度是在60摄氏度下的检测结果,加入乙醇至含醇量为60-90%(v/v),静置24小时,取上清液,回收乙醇至浓缩,即得。本发明上述中药组合物可以进一步制备成临床上常用的药物制剂,优选为合剂、片剂、胶囊剂。
本发明实施例7中药组合物对脑缺血模型大鼠海马一氧化氮和一氧化氮合酶的影响实验中,中药组合物各治疗组的NO和NOS水平均极显著低于模型组的NO和NOS水平,且明显低于阳性对照药尼莫地平治疗组的NO和NOS水平,提示中药组合物可以显著降低大鼠海马中的过氧化物,对大脑海马神经元具有明显的保护作用。本发明实施例8中中药组合物对脑缺血及其引发的脑梗塞治疗结果显示,中药组合物不仅可以显著降低大鼠脑缺血模型的血清MDA含量,减少自由基对大鼠脑的损伤,而且可以减小脑缺血大鼠的脑梗塞面积,可见中药组合物对缺血性脑损伤疾病特别是脑缺血以及脑缺血引发的脑梗塞具有显著的治疗效果,且这种治疗效果具有剂量依赖性。各给药组大鼠的海马锥体细胞的显微镜下照片显示模型组大鼠海马锥体细胞细胞核皱缩,染色深,细胞碎片多,应用中药组合物治疗后中药组合物组对脑缺血后损伤的神经元具有保护作用,其中中药组合物高剂量组的神经元细胞的细胞形态和数量与模型组具有十分显著的差异。
因此,本发明请求保护中药组合物用于治疗或预防缺血性脑血管病的用途,其中缺血性脑血管病优选为脑缺血或脑梗塞,所述脑梗塞优选为由脑缺血引发的脑梗塞。由于现代动物福利的提高和饮食的复杂性,动物患脑血管疾病机率也明显增加。本发明所述的用途治疗对象可以为人或者动物,所述动物优选为哺乳动物。本发明所述的药物用途中,中药组合物用于预防或治疗脑缺血或脑梗塞时可以根据病情和药物性质选择合适的给药途径,优选为口服给药,用于治疗或预防脑缺血或脑梗塞的给药剂型可以为本发明上述所述的药物制剂,如合剂、片剂、胶囊剂。
本发明所述的药物组合物用于脑缺血或脑梗塞的预防或治疗时具有以下优势:
1)本发明所述用途中中药组合物对脑缺血或脑梗塞治疗和预防效果确切,不仅可以为脑缺血或脑梗塞的治疗提供一种新的用药选择,而且其治疗效果优于阳性药物尼莫地平,适宜推广使用。
2)本发明所述用途中中药组合物对脑缺血和脑梗塞均具有显著的治疗和预防效果,可以延缓脑缺血患者向脑梗塞疾病的转化,降低脑缺血患者的猝死率,提高患者的生存质量和生存时间。
3)本发明所述用途中中药组合物起效剂量低,并可以制备成不同的给药剂型和给药剂量,可以根据患者疾病的严重程度选用合适的给药方案,从而可以大大提高患者的用药依从性,提高药物使用的长期效果。
具体实施方式
以下通过具体实施方式进一步描述本发明,但本发明不仅仅限于以下实施例。在本发明的范围内或者在不脱离本发明的内容、精神和范围内,对本发明所述的中药组合物进行适当改进、替换功效相同的组分,对于本领域技术人员来说是显而易见的,它们都被视为包括在本发明的范围之内。
实施例1本发明的中药组合物合剂
处方:黄芩15份、金银花6份、石榴皮10份、文冠果壳10份、薄荷10份、桑枝20份、丹参20份、荷叶10份、川芎5份、秦艽8份、全蝎15份、牛蒡子7份、葛根10份、甘草10份。
制备方法:取上述重量组分的各药材,加药材总重量的5倍的水,浸泡30分钟,煎煮2次,每次2小时,滤过,合并滤液,滤液减压浓缩至相对密度1.1的浸膏,该相对密度是在60摄氏度下的检测结果,加入乙醇至含醇量为75%(v/v),静置24小时,取上清液,回收乙醇浓缩,加水至1000ml,搅匀,分装,流通蒸汽灭菌35min,即得合剂。
实施例2本发明的中药组合物片剂
处方:黄芩15份、金银花6份、石榴皮10份、文冠果壳10份、薄荷10份、桑枝20份、丹参20份、荷叶10份、川芎5份、秦艽8份、全蝎15份、牛蒡子7份、葛根10份、甘草10份。
制备方法:取上述重量组分的各药材,加药材总重量的10倍的水,浸泡60分钟,煎煮1次,每次1小时,滤过,合并滤液,滤液减压浓缩至相对密度1.25的浸膏,该相对密度是在60摄氏度下的检测结果,加入乙醇至含醇量为80%(v/v),静置24小时,取上清液,回收乙醇至浓缩,真空干燥、制粒,压片即得。
实施例3本发明中药组合物胶囊
处方:黄芩15份、金银花6份、石榴皮10份、文冠果壳10份、薄荷10份、桑枝20份、丹参20份、荷叶10份、川芎5份、秦艽8份、全蝎15份、牛蒡子7份、葛根10份、甘草10份。
制备方法:取上述重量组分的各药材,加药材总重量的8倍的水,浸泡45分钟,煎煮4次,每次1.5小时,滤过,合并滤液,滤液减压浓缩至相对密度1.2的浸膏,该相对密度是在60摄氏度下的检测结果,加入乙醇至含醇量为90%(v/v),静置24小时,取上清液,回收乙醇至浓缩,真空干燥,制粒,装胶囊即得。
本发明中药组合物还可以含有其他药学辅料制成合适的药物制剂,如片剂、胶囊剂等。其中首先将中药组合物制备成中药组合物细粉,所述中药组合物细粉的制备方法为:取上述重量组分的各药材,加药材总重量的5-15倍的水,浸泡10-60分钟,煎煮1-4次,每次1-3小时,滤过,合并滤液,滤液减压浓缩至相对密度1.05-1.25的浸膏,该相对密度是在60摄氏度下的检测结果,加入乙醇至含醇量为60-90%(v/v),静置24小时,取上清液,回收乙醇至浓缩,真空干燥后粉碎即可得到中药组合物细粉。所述的中药组合物细粉可以应用于下述实施例中
实施例4本发明中药组合物片剂制备
处方:中药组合物细粉50g、淀粉25g、糊精35g、低取代羟丙基纤维素5g、60%乙醇适量、硬脂酸镁1g。
制备工艺:称取处方量的、中药组合物细粉、淀粉、糊精和低取代羟丙基纤维素混合均匀。另取适宜量的60%乙醇,加入于混合粉末中,混合均匀后制软材,通过16目筛制粒,60℃以下干燥。干燥后完成后用18目筛进行整粒,筛出干粒中的细粉,与过筛的硬脂酸镁混匀,然后再与干颗粒混和均匀,压片,即得。
实施例5本发明中药组合物片剂制备
处方:中药组合物细粉25g、微晶纤维素180g、羟丙基纤维素15g、8%淀粉浆适量、硬脂酸镁1.5g。
制备工艺:称取处方量的中药组合物细粉、微晶纤维素和羟丙基纤维素混合均匀。另取适宜量的8%淀粉浆溶液,加入混合粉末中,混合均匀后制软材,通过16目筛制粒,60℃以下干燥。干燥后完成后用18目筛进行整粒,筛出干粒中的细粉,与过筛的硬脂酸镁混匀,然后再与干颗粒混和均匀,压片,即得。
实施例6本发明中药组合物胶囊剂制备
处方:中药组合物细粉25g、可压性淀粉40g、乳糖30g、低取代羟丙基纤维素5g、60%乙醇适量。
制备工艺:将处方中的各辅料过100目筛,称取中药组合物细粉与可压性淀粉、乳糖和低取代羟丙基纤维素混合均匀后,加入60%乙醇溶液制软材,18目筛制颗粒,于60℃干燥,16目筛整粒,装填胶囊,即得。
实施例7中药组合物对脑缺血模型大鼠海马一氧化氮和一氧化氮合酶的影响
本试验中发明人采用尼莫地平作为阳性对照药物,它是一种Ca2+通道阻滞剂,通过有效地阻止Ca2+进入细胞内、抑制平滑肌收缩,达到解除血管痉挛之目的。动物实验证明,尼莫地平对脑动脉的作用远较全身其他部位动脉的作用强许多,并且由于它具有很高的脂溶性特点,易透过血脑屏障。此外,可选择性地作用于脑血管平滑肌,扩张脑血管,增加脑血流量,明显减少血管痉挛引起的缺血性脑损伤。
1、材料与方法
1.1动物分组
SPF级健康雄性SD大鼠50只,体重250~300g,由山东大学实验动物中心提供。造模6周后,大鼠随机分为5组,正常对照组、模型组、尼莫地平组、中药组合物高剂量组(高剂量组)和中药组合物低剂量组(低剂量组),每组10只。造模后第7周正常对照组和模型组大鼠分别给予等体积的溶媒灌胃,尼莫地平组大鼠给予30mg/(kg·d),中药组合物高剂量组大鼠给药剂量100mg/(kg·d),中药组合物中剂量组给药剂量50mg/(kg·d)中药组合物低剂量组大鼠给药剂量为10mg/(kg·d),连续给药3周。
1.2试剂和仪器
中药组合物:按实施例2制备工艺制备,中药组合物处方为:黄芩15克、金银花6克、石榴皮10克、文冠果壳10克、薄荷10克、桑枝20克、丹参20克、荷叶10克、川芎5克、秦艽8克、全蝎15g、牛蒡子7g、葛根10g、甘草10克。
尼莫地平:购自山西亚宝药业集团股份有限公司,批号90602;
NO、NOS试剂盒:南京建成生物工程研究所,批号20091210;
一抗nNOS、iNOS、eNOS和t3肌动蛋白抗体:北京博奥森生物技术有限公司,批号s-0156R;羊抗兔Ig-G:北京鼎国生物技术有限公司,批号0090915。
DYCZ-24D型垂直板电泳槽,北京六一仪器厂;
JS-250电泳仪,上海培清科技有限公司;
TS-2000A脱色摇床,江苏其林贝尔仪器制造有限公司;
MDF-U333低温冰箱,SANY0;Precisa XS125电子天平;
UV2550分光光度计,日本岛津。
1.3脑缺血大鼠模型的制备
大鼠术前禁食12h、禁水4h,用10%水合氯醛(0.30ml/100g)腹腔注射麻醉,仰卧固定于木制手术台上。颈前部备皮,酒精、碘酒消毒后,沿腹侧颈正中切开,依次钝性分离皮下脂肪、胸骨舌骨肌和胸锁***肌,再分别分离暴露左、右侧颈总动脉及气管,于近心端和远心端双重结扎后从中间剪断,然后逐层缝合肌肉、皮肤。正常对照组大鼠同法行颈前皮肤切开,分离皮下脂肪。
1.4NO含量和NOS活性的测定
造模后第10周,各组大鼠断头取脑,去除嗅球、小脑,取出大脑海马称重,加入9倍冷生理盐水,电动匀浆机研磨,制成10%匀浆液,3000r/min,离心10min,取上清液,按试剂盒说明书测定NO含量和NOS活性。
各组大鼠新鲜脑组织海马抽提蛋白后取等量的蛋白进行十二烷基硫酸钠聚丙烯酰胺凝胶电泳分离,电转移至硝酸纤维素膜,室温封闭30min,nNOS、iNOS、eNOS和t3肌动蛋白一抗500倍稀释于封闭液中,4℃反应过夜后室温孵育2h。充分漂洗后辣根过氧化物酶标记的二抗羊抗兔IgG1500倍稀释于封闭液中,室温孵育1h。将膜置于DAB显色液中,显影、定影、曝光。利用Quantity one软件分析条带的灰度值。
1.5统计学方法
采用SPSS12.0统计软件,数据以x±s表示,组问比较采用方差分析,方差齐者采用LSD检验,方差不齐者采用Tamhane’S检验,P<0.05为差异有统计学意义。
2结果
2.1各组大鼠海马NO含量和NOS活性的比较
如表1所示,与正常对照组比较,模型组大鼠海马NO含量和NOS活性明显升高(P<0.01);与模型组比较,尼莫地平组和中药组合物各剂量组大鼠海马NO含量和NOS活性明显降低(P<0.05);与阳性对照药尼莫地平相比,中药组合物各剂量组大鼠海马NO含量和NOS活性均显著降低(P<0.05),其中中药组合物高剂量组与尼莫地平治疗组相比具有极显著差异(P<0.01)。
表1各给药组大鼠海马NO含量和NOS活性比较
与正常对照组相比,**P<0.01;与模型组相比,¥P<0.05,¥¥P<0.01;与尼莫地平组相比,#P<0.05,##P<0.01。
2.2各组大鼠海马3种NOS亚型表达的比较
与表2所示,与正常对照组比较,模型组大鼠海马nNOS和iNOS表达明显升高,eNOS表达明显降低(P<0.01);与模型组比较,尼莫地平组和高剂最组大鼠海马nNOS和iNOS表达明显降低,eNOS表达明显升高(P<0.05);与阳性对照药尼莫地平相比,中药组合物各剂量组大鼠海马nNOS和iNOS表达明显降低,eNOS表达明显升高(P<0.05),其中中药组合物高剂量组与尼莫地平治疗组相比具有极显著差异(P<0.01)。
表2各给药组大鼠海马NOS3种亚型表达的比较
与正常对照组相比,**P<0.01;与模型组相比,¥P<0.05,¥¥P<0.01;与尼莫地平组相比,#P<0.05,##P<0.01。
实施例8中药组合物对脑缺血及其引发的脑梗塞的治疗作用
1.实验材料
本实验中所采用的实验动物为雄性SD大鼠,体重为250-300g,室温下12h昼夜节律下饲养,自由饮食。上述实验动物由山东大学实验动物中心提供。本实验中的供试品中药组合物的制备方法及处方同实施例7,对照品为纯水。
本实验使用的相关材料及试剂如下:MDA试剂盒(购自上海史瑞可生物科技有限公司),20%水合氯醛、碘伏、焦油紫、双氧水、酒精、二甲苯、4%多聚甲醛、生理盐水均为实验室常用试剂。本实验主要仪器与设备:大鼠头部固定器、电凝器、721型可见分光光度计、病理组织漂烘处理仪、石蜡切片机、显微镜数码相机均为药理实验室常用仪器。
.实验方法
2.1动物分组:将实验动物随机分为4组:模型组,假手术组,中药组合物高剂量组(100mg/kg),中药组合物中剂量组,中药组合物低剂量组(10mg/kg),每组10只。
2.2大鼠脑缺血模型的建立:实验动物以20%水合氯醛(300-350mg/kg)腹腔注射麻醉后,分离双侧颈总动脉并电凝椎动脉。手术第二天动物于清醒状态下结扎双侧颈总动脉,缺血15分钟后放开动脉夹再灌。缺血时保持其直肠温度在36.5-37.5℃之间。以缺血动物体征表现判断缺血模型的可靠性。大鼠脑缺血模型鉴定标准如下:缺血前大鼠处于完全清醒状态,其生命体征正常。缺血后30-60秒内大鼠即失去知觉和活动能力,翻正反射消失,呈现角弓反张,同时痛觉消失,双侧瞳孔散大,对强光刺激闭睑反射消失,眼球颜色灰白(正常为鲜红色)。假手术组处理同实验组,但不结扎双侧颈总动脉。本实验中采用该方法制备的大鼠脑缺血模型造模成功率达94.5%。
2.3给药途径与时间:中药组合物高剂量组(100mg/kg)和低剂量组(10mg/kg)均在缺血/再灌后第8小时按指定的剂量给药一次,首次给药16小时后以相同剂量再次给药。假手术组和模型组给予相同体积的蒸馏水,给药方案同中药组合物给药组。
、实验观察及指标测定
3.1血清MDA含量测定:中药组合物组和模型组最后1次给药8h后处死大鼠,快速心腔内取血,离心取血清,-20℃冻存;采用硫代巴比妥酸(TBA)比色法测定;操作方法严格按说明书进行。
3.2脑梗死体积测量:经TTC染色的脑片,用数码相机拍照,应用高清晰度彩色病理图文报告分析***测出各区脑梗死面积。根据公式:梗死体积=[左侧半球体积-(右侧半球体积-苍白区体积)]/全脑体积,算出梗死体积百分比。
3.3组织学方法:大鼠经腹腔注射水合氯醛麻醉后,开左胸暴露心脏,将针头自心尖穿过左心室***主动脉,先用38℃左右生理盐水约100ml快速灌洗,然后复灌入冰冷的4%的多聚甲醛250-300ml,30分钟内灌完,灌注后的大鼠断头取脑将其直接用4%的多聚甲醛后固定12小时左右。流水冲洗,冲洗时间同固定时间。然后70%(4h)、80%(4h)、90%(4-12h)、95%(2h×2次)、100%(2h×2次)梯度酒精脱水,二甲苯透明(1.5h)、60℃浸蜡(1h×3次)。取出包埋,4℃保存。石蜡切片机切片,厚5mm。45℃温水中贴片于明胶处理过的载玻片上,40℃烘烤过夜。切片经三次二甲苯脱蜡,100%、90%、70%梯度酒精浸水,0.1%焦油紫(Cresyl violet)染色10-20分钟,按常规方法70%、80%、95%、100%梯度酒精分色,光镜下观察神经元紫色而背景基本无色为止。梯度酒精脱水,二甲苯透明,中性树脂封片后,光镜观察。在高倍镜下观察神经元细胞的存活与凋亡。有清楚的细胞核,胞体着色良好的计为成活神经元细胞;核皱缩,不成形的为凋亡的神经元细胞。
数据处理:
实验结果应用SPSS12.0软件进行分析,各组计量资料以均数±标准差(mean±SD)表示。各组间数据的显著性比较采用t检验;检验结果判定,以p<0.05为差异有显著性。
实验结果
5.1血清MDA含量测定结果:如表3所示,模型组MDA含量显著高于假手术组,表明脑缺血造模前后MDA含量具有显著差异。不论是中药组合物高剂量组还是中药组合物低剂量组,其血清MDA含量均与模型组MDA含量存在显著性差异(P<0.05),其中中药组合物高剂量组与模型组存在极显著性差异(P<0.01)。
5.2脑梗死体积测量结果:如表3所示,假手术组无脑梗死。中药组合物治疗组的脑梗死体积与模型组脑梗死体积相比具有显著性差异(P<0.05),其中中药组合物高剂量组与模型组相比具有极显著性差异(P<0.01)。
表3大鼠各给药组间血清MDA含量和脑梗死体积比较
与模型组比较,*P<0.05;与模型组比较,**P<0.01。
本实验的实验结果显示,中药组合物不仅可以显著降低大鼠脑缺血模型的血清MDA含量,减少自由基对大鼠脑的损伤,而且可以减小脑缺血大鼠的脑梗塞面积,可见中药组合物对缺血性脑损伤疾病特别是脑缺血以及脑缺血引发的脑梗塞具有显著的治疗效果,且这种治疗效果具有剂量依赖性。
Claims (6)
1.一种治疗缺血性脑血管病的中药组合物,其特征在于由以下重量份的原料制得:黄芩15份、金银花6份、石榴皮10份、文冠果壳10份、薄荷10份、桑枝20份、丹参20份、荷叶10份、川芎5份、秦艽8份、全蝎15份、牛蒡子7份、葛根10份、甘草10份。
2.如权利要求1所述的治疗缺血性脑血管病的中药组合物,其特征在于:所述中药组合物为合剂、片剂或胶囊剂。
3.如权利要求1所述的治疗缺血性脑血管病的中药组合物的制备方法,其特征在于包括以下步骤:取各药材,加药材总重量的5-15倍的水,浸泡10-60分钟,煎煮1-4次,每次1-3小时,滤过,合并滤液,滤液减压浓缩至相对密度1.05-1.25的浸膏,该相对密度是在60摄氏度下的检测结果,加入乙醇至含醇量为60-90%v/v,静置24小时,取上清液,回收乙醇至浓缩,即得。
4.权利要求1所述的治疗缺血性脑血管病的中药组合物在制备治疗或预防缺血性脑血管病药物中的用途。
5.如权利要求4所述的治疗缺血性脑血管病的中药组合物,其特征在于:所述的缺血性脑血管病为脑缺血或脑梗塞。
6.如权利要求4所述的治疗缺血性脑血管病的中药组合物,其特征在于:所述的缺血性脑血管病为脑梗塞。
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