CN117244033A - 一种治疗卒中后抑郁的中药组合物、制备方法及应用 - Google Patents
一种治疗卒中后抑郁的中药组合物、制备方法及应用 Download PDFInfo
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Abstract
本发明涉及一种治疗卒中后抑郁的中药组合物,所述药物组合物由以下重量的原料药制成:柴胡9份、郁金12份、苍术6份、川芎18份、石菖蒲15份、黄芪15份。将中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封,得到的组合物应用于治疗卒中后抑郁药物中。本发明中药组合物的原料药种类少,易于制备,成本低,且无毒副作用,使用方法简单便捷,易于被患者接受。
Description
技术领域
本发明涉及治疗卒中后抑郁的中药组合物技术领域,具体地说是涉及一种治疗卒中后抑郁的中药组合物、制备方法及应用。
背景技术
卒中后抑郁(poststroke depression,PSD)是指有明显临床症状的卒中(相对于静息性卒中而言)后引发的抑郁症,包括两个要素:(1)必须有脑卒中这个前提:(2)必须符合抑郁症的诊断。PSD还为脑血管疾病后期较为常见的心理障碍,可见患者情绪低落、兴趣减退、悲观、失望、绝望、易激惹、忧愁、淡漠、易哭泣、失眠、多梦、焦虑、精力缺失及躯体化症状等。
现代中医学者认为PSD初病多实,以气、血、湿、痰、火、食郁滞为主,以气郁为基础,病久则由实转虚,引起心脾肝肾气血阴精的亏损,转为虚证,或见虚实夹杂。辨证当分虚实。主要病机是有卒中后风、癖、痰、火交搏郁结致气血逆乱郁滞、痰癖内生、肝气不舒、情志不畅而郁,与心、肝、脾关系密切,实证当以疏肝解郁为主。根据病邪的兼夹,配合清肝泻火、化痰散结、活血化癖、健脾燥湿或芳香化湿、消食和胃等法。虚证宜补,采用养心安神、补益心脾等法。
目前对于PSD的治疗首选药物治疗,在单一药物效果欠佳时可加用心理治疗,联合治疗无效的重度PSD可选用电惊厥治疗。但PS D患者多为高龄且伴有各种躯体疾病,所以用药时要慎重,应选择各种抗抑郁药物的最低有效剂量。由于中医并不能如西医般确切的阐明有效成分、靶部位及作用机制,所以在治疗PSD中还存在极大的发展空间,仍需要进一步的观察和总结,在辨证论治规律下;进一步加强动物模型以及分子生物学等科学规范的实验研究方法,分析药物有效成分,确定作用机理,为临床提供有力的理论依据。
中国专利文献CN113368206A,公开日2021.09.10,公开了一种治疗卒中后抑郁的中药组合物,包括:人参10-20份、茯苓10-20份、远志5-20份、石菖蒲5-20份、川芎5-15份、苍术5-15份、香附2-12份、柴胡2-12份、酸枣仁5-20份、益智仁2-12份、炙甘草5-20份;中国专利文献CN108295168A,公开日2018.07.20,公开一种治疗卒中后抑郁的中药组合物,包括:柴胡15-30份、香附10-20份、当归10-20份、生地10-20份、桃仁10-20份、红花10-15份、枳壳10-20份、陈皮10-20份、赤芍10-20份、白术10-20份、甘草10-15份、桔梗10-20份、牛膝6-20份、川芎10-20份、水蛭4-6份、三七10-15份、茯苓15-20份、石菖蒲15-20份、胆南星12-20份、贯叶金丝桃3-6份、刺五加12-20份、黄连3-6份。上述中药组合物药味数较多,增加了药物制备的程序,较为繁琐,且还存在取材难,价格昂贵和药效不显著等缺点,因此研制能治疗治疗卒中后抑郁且效果明显、药味数适中、便于制备的药物很有必要。
发明内容
本发明的目的之一是提供一种治疗卒中后抑郁的中药组合物,按以下重量份的原料药制成:柴胡9份、郁金12份、苍术6份、川芎18份、石菖蒲15份、黄芪15份。
本发明的另一目的是提供所述的治疗卒中后抑郁的中药组合物的制备方法,包括下述过程:上述6味中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封。
以上任一所述中药组合物在制备治疗卒中后抑郁药物中的应用。
配伍关系:
方中柴胡疏肝解郁,为君药;郁金为臣,辛散性寒,为“血中之气药”,气血同调,既能化血瘀,又能调理气机,能散能行,既能活血,又能行气解郁,有气血同治的功能,以调达血气;苍术性温,
味苦,辛烈,为运脾药,健脾化湿,芳香清窍;川芎行气活血,助柴胡以解肝经之郁滞,增其行气止痛之功;石菖蒲辛开苦燥,芳香走窜,醒脑神,开心窍;黄芪大补脾胃之元气,使气旺血行,瘀去络通。诸药合用,已达到行气解郁、活血化瘀的功效。
本发明优点在于:
1.本发明中药组合物原料药种类少,易于制备,成本低。
2.本发明中药组合物由纯中药制成,无毒副作用,使用方法简单便捷,易于被患者接受。
具体实施方式
下面结合具体实施方式,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1本发明中药组合物一的制备
柴胡9份、郁金12份、苍术6份、川芎18份、石菖蒲15份、黄芪15份,上述6味中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封,每袋150ml药液,每日两次,早晚温服。
对比例1中药组合物一的制备
柴胡9份、郁金10份、苍术8份、川芎14份、石菖蒲19份、黄芪15份,上述6味中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封,每袋150ml药液,每日两次,早晚温服。
实施例2动物实验
材料与方法
药物与试剂
中药组合物一制备:按照实施例1进行制备。
中药组合物二制备:按照对比例1进行制备。
对照组中药组合物一制备:按重量份配比称取柴胡13份、郁金10份、苍术8份、川芎14份、过江龙19份、黄连15份,上述6味中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封。
对照组中药组合物二制备:按重量份配比称取柴胡13份、郁金10份、苍术8份、川芎14份、海螵蛸19份、黄柏15份,上述6味中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封。
西药组:盐酸氟西汀胶囊。
主要试剂:水合氯醛(国药集团化学试剂有限公司);樟脑球(上海绿伞环保科技发展有限公司);生理盐水(上海研生实业有限公司);无水乙醇(上海化学试剂公司);蔗糖(国药集团化学试剂有限公司)。
动物
雄性ICR小鼠,体质量25-28g,105只,雌雄各半,由上海斯莱克实验动物服务有限公司提供。
主要仪器
超纯水机(英国ELGA公司);超低温冰箱(美国Thereto公司);电子天平(瑞士梅特勒托利多公司);精密手术器械(山东新华医疗器械有限公司);离心机(德国艾本德公司);制冰机(北京长流科学仪器有限公司)。
方法与结果
PSD小鼠模型制备
大脑中动脉栓塞法制备局灶性缺血模型(MCAO)
雄性ICR小鼠,适应性喂养3d后,随机取15只作为空白组,剩余90只进行造模。MCAO术:参照文献(Koizumi J,YoshidY,Nakazawa T,et al.Experimental StudiesofIschemicBrain Edema,ANew Experimental Model ofCerebral Embolismin Rats inWhichRecirculation CanBe Introducedinthe Ischemic Area[J].Stroke,1986,8:1)并加以改善,建立永久性MCAO模型。手术前禁食12h但不禁水。造模组小鼠以10%水合氯醛(4ml/kg体质量)腹腔注射麻醉,麻醉后将小鼠固定于手术台上,减去颈前鼠毛,碘伏消毒后在颈部做正中切口,钝性分离皮下组织并暴露出左侧颈总动脉(CCA)、颈外动脉(ECA)、颈内动脉(ICA)、结扎CCA,ECA,在ECA近心端动脉夹夹闭血管并备手术线,在ICA远心端用动脉夹夹闭血管,在ECA距分叉处近心端2mm用眼科剪剪一小口,插入0.26mm硅胶栓线,去除动脉夹,沿着ICA方向慢慢推进,当到达18-20mm长度遇到明显阻力,结扎ICA并用备线固定拴线,扎紧备线,这时栓线进入ICA,通过大脑中动脉(MCA)进入大脑前动脉CACA),阻断了MCA血液来源。术毕逐层缝合,用酒精棉球消毒皮肤缝合处,术毕逐层缝合,用酒精棉球消毒皮肤缝合处,并用青霉素软膏局部擦拭预防皮肤感染。术后环境温度保持在27℃左右,并予以白炽灯对动物头部进行特殊保暖。该模型的成功标志是小鼠麻醉清醒后立即出现病灶对侧Horner征。术后24h根据文献(Longa ZE,WeisteinPR,Carlson S.Reversible middlecerebralarteocclusionwim outcraniectomv in rats.[J].Stroke.1989,20(1):84-89)中的评分标准进行评分。符合标准者(得分1≥分且<4分)入组。
评分标准:
1.完全正常,0分。
2.提起小鼠尾巴离开地面,缺血灶对侧前肢内旋、内收,记1分。
3.将小鼠置于操作台,用手挤压两侧检查其抵抗力,缺血灶对侧抵抗力下降,记2分。
4.观察小鼠行走,向缺血灶对侧转圈者,记3分。
5.损伤严重,己无自主活动,记4分。
慢性不可预知性温和刺激(Chronic unpredictable mild stress,CUMS)
在术后3d相继给予卒中造模成功以及符合标准的小鼠7d慢性不可预知性温和刺激。应激因素包括:电击脚底,寒冷刺激,热刺激,摇晃,夹尾,禁水、禁食,昼夜颠倒。以达到复合制备出脑卒中后抑郁小鼠模型,以上刺激每天随机采取一种。
分组与给药
造模前将小鼠分为以下7组,本发明组一、本发明组二、对照组一、对照组二、模型组、空白组和西药组,将造模成功后的小鼠(造模情况如结果2.5.1)分别按以下分组连续给药4周:
本发明组一:CUMS造模后,每天用本发明中药组合物制备的药液10mL/kg,每日两次,早晚温服。
本发明组二:CUMS造模后,每天用本发明中药组合物制备的药液10mL/kg,每日两次,早晚温服。
对照组一:CUMS造模后,每天用对照组中药组合物一制备的药液10mL/kg,每日两次,早晚温服。
对照组二:CUMS造模后,每天用对照组中药组合物二制备的药液10mL/kg,每日两次,早晚温服。
模型组:CUMS造模后,每天用生理盐水灌胃。
空白组:每天用生理盐水灌胃。
西药组:CUMS造模后,每天用3mg/kg盐酸氟西汀(1mg/mL)灌胃。
评价指标检测
一般状况观察
每天观察各组小鼠的精神状况;进食、饮水情况,记录卒中造模已经复合造模后死亡小鼠;体重反映小鼠生长状况,是抑郁症常用评价指标,在实验开始前对小鼠进行称重,标记为0d,给药前和给药结束分别再测定。
旷野实验(OFT)
旷野试验反应动物模型运动功能及对新鲜事物探索行为,将小鼠置于内空立方体箱内,其内壁四周及底面为黑色,且底面用直线划分为面积相等的25块,根据小鼠活动情况测量出水平及垂直运动得分。穿过水平的正方形(四个爪子进入)的次数作为水平运动得分,以直立次数(小鼠前足抬离底面为垂直活动,前足抬离地面至着地1次为一次评分)为垂直运动得分。
蔗糖偏好实验
所有动物均单笼饲养,测试时每笼放置2个水瓶,一瓶装自来水,一瓶装1%蔗糖溶液,观察小鼠24h饮用自来水量和蔗糖溶液量。实验进行到第12h时调换两个水瓶的位置以消除小鼠可能的饮水习质。计算蔗糖水偏好百分比(=蔗糖水消耗量/总液体消耗量
×100%)。
强迫游泳实验
正式实验前小鼠在实验室首先适应环境至少1h,然后将小鼠放入强迫游泳实验装置(高35cm且直径15cm的透明圆柱形桶,水深35cm,使小鼠在水中前爪攀附于缸壁并且不能以后爪支撑身体为标准,15min后取出动物。正式实验时,将动物置于强迫游泳实验装置,保持水温25±12℃。观察6min,记录后5min内的累计不动时间。
统计学方法
数据处理采用SPSS23.0统计软件,实验结果以平均数±标准误(X±SEM)表示,组内数据比较采用配对t检验,组间数据比较采用两样本独立样本t检验,P<0.05即表示数据间差异有统计学意义。
结果
各组小鼠死亡及造模情况
实验小鼠共105例,参与造模的为90例,在卒中造模后存活68例,Longa排除不符标准8例,卒中造模成功60例,成功率为66.67%;参与PSD造模60例,死亡11例,成功49例,PSD造模成功率为81.66%。见表1。
表1各组小鼠死亡及造模情况
小鼠体重变化
各小鼠在实验前,造模结束后以及给药结束后的体重如表2,各组小鼠实验前的体重量无显著差异,在进行PSD造模后,本发明组、对照组、模型组和西药组的小鼠的体质量都显著低于空白组(P<0.0001);在给药结束后,本发明组、对照组和西药组相较于模型组,小鼠的体质量都有显著的上升(P<0.005,P<0.05);其中本发明组一的小鼠体质量显著高于对照组一和二以及本发明组二(P<0.005,P<0.05);同时本发明组还显著高于西药组(P<0.01)。
表2各组小鼠体重变化(n=64)
组别 | n(例) | 体重量(0d)/g | 体重量(PSD造模结束)/g | 体重量(给药结束)/g |
本发明组一 | 9 | 26.71±0.83 | 21.67±0.951) | 25.90±0.832,4,5,6) |
本发明组二 | 8 | 26.65±0.81 | 21.26±0.851) | 24.40±1.042) |
对照组一 | 9 | 26.71±0.89 | 20.88±1.091) | 23.97±0.902) |
对照组二 | 8 | 26.62±0.75 | 21.26±1.031) | 23.51±1.413) |
模型组 | 7 | 26.34±0.94 | 21.04±0.931) | 22.15±0.751) |
空白组 | 15 | 26.54±0.84 | 27.97±0.84 | 27.12±0.79 |
西药组 | 8 | 26.69±0.97 | 21.21±0.851) | 24.18±0.932) |
注:与空白组比较1)P<0.0001;与模型组比较2)P<0.005,3)P<0.05;与对照组比较4)P<0.005;与本发明组二比较5)P<0.05;与西药组相比6)P<0.01。
各组大鼠旷野实验水平运动得分测定结果
各组小鼠的狂野实验水平运动如表3,各组小鼠在手术前的水平运动基线值无显著差异,给药结束后模型组小鼠的旷野实验水平运动得分显著低于空白组(P<0.0001);而本发明组一、二、对照组一和西药组的小鼠得分都显著高于模型组(P<0.001,P<0.005);且本发明组一小鼠的得分显著高于对照组一和二,本发明组二的得分显著高于对照组二(P<0.005);本发明组一的得分与西药组无显著差异。
表3各组小鼠的旷野实验水平运动得分(格)
组别 | n(例) | 基线值 | 给药结束后 |
本发明组一 | 9 | 60.63±3.58 | 50.38±1.692,4,5) |
本发明组二 | 8 | 59.88±4.52 | 49.63±2.073.5) |
对照组一 | 9 | 60.13±5.62 | 47.75±1.983) |
对照组二 | 8 | 59.50±4.66 | 45.63±1.85 |
模型组 | 7 | 60.71±4.34 | 44.86±2.791) |
空白组 | 15 | 61.29±3.40 | 60.71±3.25 |
西药组 | 8 | 59.38±4.78 | 48.88±1.733) |
注:与空白组比较1)P<0.0001;与模型组比较2)P<0.001;3)P<0.005;与对照组一比较4)P<0.005,与对照组比较5)P<0.005。
蔗糖偏好实验的测定结果
各组小鼠给药后对糖水的偏好率如表4,模型组的小鼠对糖水的偏好率显著低于空白组(P<0.0001);本发明组、对照组和西药组的小鼠对糖水的偏好率都显著高于模型组(P<0.001,P<0.005);其中本发明组的小鼠对糖水的偏好率都显著高于对照组二(P<0.001)。
表4各组小鼠对糖水偏好率的影响(n=64)
注:与空白组比较1)P<0.0001;与模型组比较2)P<0.001,3)P<0.005;与对照组二比较4)P<0.001。
各组小鼠强迫游泳实验的测定结果
各组小鼠给药结束后强迫游泳的实验结果如表5,其中模型组小鼠的游泳不动时间显著低于空白组(P<0.0001);而本发明组、对照组以及西药组的小鼠游泳不动时间都显著高于模型组的小鼠(P<0.0001);其中本发明组一和二的小鼠游泳不动时间都显著高于对照组(P<0.05,P<0.0001,P<0.005)。
表5各组小鼠强迫游泳(n=64,s)
注:与空白组比较1)P<0.0001;与模型组比较2)P<0.0001;与对照组一比较3)P<0.05与对照组二比较5)P<0.0001,6)P<0.005。
综上,本发明组和对照组以及西药组都能在不同程度上具有抗抑郁的作用,可明显改善PSD小鼠快感缺失、行为绝望等抑郁样行为。其中本发明组优于对照组,但整体来看本发明组一的改善效果最为突出。
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 (3)
1.一种治疗卒中后抑郁的中药组合物,其特征在于,所述中药组合物由以下重量份的原料药制成:柴胡9份、郁金12份、苍术6份、川芎18份、石菖蒲15份、黄芪15份。
2.权利要求1所述的治疗卒中后抑郁的中药组合物的制备方法,其特征在于,包括下述过程:
上述6味中药浸泡1小时,加2倍量药材的水,煎煮1.5小时倒出,第2次亦加2倍量药材的水,煎1小时后倒出,合并药液,分袋灌封。
3.权利要求1所述的中药组合物在制备治疗卒中后抑郁药物中的应用。
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