CN103055059B - 金泽组合药物在制备治疗肺心病及并发症药物中的应用 - Google Patents
金泽组合药物在制备治疗肺心病及并发症药物中的应用 Download PDFInfo
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Abstract
本发明在传统金泽方的基础上,提供了该方在制备治疗肺心病及并发症肺动脉高压药物中的应用;本发明提供的金泽组合药物治疗肺心病具有良好的活性,并且对于肺心病的并发症肺动脉高压,包括药物和毒物所致肺动脉高压、肺部疾病或低氧血症所致肺动脉高压具有疗效。
Description
技术领域
本发明涉及一种中药配方的新适应症,更具体的说涉及金泽组合药物在制备治疗肺心病及并发症肺动脉高压药物中的应用。
技术背景
慢性肺源性心脏病(肺心病)是呼吸系统的一种常见病,是由肺组织、肺血管或胸廓的慢性病变引起肺组织结构和(或)功能异常,产生肺血管阻力增加,肺动脉压力增高,使右心室扩张或(和)肥厚,伴或不伴右心功能衰竭的心脏病。肺动脉高压是慢性肺心病发生、发展的病理生理学基础,并对其病情和预后具有重要的意义。2001年提出的《慢性阻塞性肺疾病(COPD)全球倡议》指出,肺动脉高压(pulmonary artery hypertension,PAH)是COPD发展至肺心病的关键病理环节,并指出中度COPD患者往往合并肺动脉高压(PAH),重度患者一定合并有PAH。因此降低PAH,逆转肺血管的病理变化是目前肺心病治疗研究的重点之一。
我国肺心病的患病率约为0.4%,占≧15岁人群约0.7%。一旦患病,严重影响人体的健康,可造成劳动力丧失。2001年提出的《慢性阻塞性肺疾病(COPD)全球倡议》指出,PAH是COPD发展至肺心病的关键病理环节,并指出中度COPD患者往往合并PAH,重度患者一定合并有PAH。
现代医学认为PAH的治疗包括:(1)基本治疗,主要是针对基础疾病和相关危险因素进行治疗。(2)PAH的传统治疗,主要包括华法令抗凝、吸氧、利尿剂和地高辛、多巴胺等,主要是针对右心功能不全和肺动脉原位血栓形成。(3)肺动脉血管扩张剂,目前临床上应用的血管扩张剂有:钙离子拮抗剂,前列环素类似物,内皮素(Er)受体拮抗剂及5型磷酸二酯酶抑制剂等。理想的肺血管扩张剂应具备如下条件:(1)使肺血管阻力降低20%以上;(2)使心搏出量增加或无变化;(3)使肺动脉压下降或无变化;(4)使体循环压无改变或下降,但不引起低血压症状。国内临床上传统的血管扩张剂有硝酸甘油、硝普钠、酚妥拉明等,这些药物对于左心疾病相关PAH的治疗效果较好,但这些药物具有非选择性降压的特点,往往造成低血压,从而使心、脑、肾供血不足,加重其缺血状态,而且多数药物在降低肺动脉压的同时也降低了PaO2,并使心搏出量(CO)下降,加重心力衰竭,反而对PAH的持续治疗不利。近年来国内外开发了一些降低肺动脉压的新药物,如前列环素类似物伊洛前列素,非选择性ET受体拮抗剂波生坦(bosentan),选择性ETA受体拮抗剂(sitaxsentan、Ambrisentan,ET)益米乐等,但是由于以上药物价格昂贵,限制了在基层医院的使用,且临床应用时间较短,远期疗效尚需进一步观察。
发明内容
传统医学认为:肺心病属于中医学“肺胀”范畴,一般认为本病多属本虚标实,本虚以气阴两虚为主,标实主要以血瘀水停、痰浊阻肺为主。在不同的病理过程中只有虚实的偏重,并无纯虚纯实证,本病的急性期亦然,患者常常存在气阴两虚、痰瘀阻肺并存的特点,所以临床上常用益气养阴、活血化瘀的治法。临床研究发现,泽泻联合雪胆治疗肺心病心力衰竭具有一定疗效。有学者对其作用机制进行了初步研究。通过动物研究发现,含泽泻低温氧合血肺动脉灌注可通过降低促炎细胞因子的水平,提高抗炎细胞因子的水平,减轻体外循环相关的全身炎症反应。
以活体小鼠为实验模型,用肾上腺素加重心脏负担,增加心肌耗氧量使其低压缺氧,结果显示:肾上腺素组(1mg/kg,皮下注射)平均生存时间与对照组相比减少了47.5%(P﹤0.01);雪胆的95%乙醇浸出物(0.3g/kg,腹腔注射)加肾上腺素组平均生存时间比肾上腺素组延长64.8%(P﹤0.05),但与对照组相比无明显差异(P﹥0.05);说明雪胆醇浸出物能适度改善由于肾上腺素增加心肌耗氧量而致低压缺氧状况,对心肌缺氧有保护作用。离体兔心灌注实验表明,泽泻醇提物的水溶性部分能显著增加冠脉流量,对心率无明显影响,对心肌收缩力呈轻度的抑制作用。体外实验发现泽泻对正常有肝硬变大鼠具有明显的血管扩张作用。这可能是通过血管内皮细胞增加前列环素(PGI2)和一氧化氮的释放而发挥扩展血管作用,该作用具有血管内皮依赖性。
本发明在传统金泽方的基础上,提供了该方在制备治疗肺心病及并发症肺动脉高压药物中的应用。
金泽组合药物在制备治疗肺心病及并发症药物中的应用。
金泽组合药物在制备治疗所述肺心病的并发症肺动脉高压药物中的应用。
所述治疗肺动脉高压是指动脉性肺动脉高压、肺部疾病或低氧血症所致肺动脉高压中的任意一种或几种病症。
所述动脉性肺动脉高压包括药物和毒物所致肺动脉高压、相关性肺动脉高压、特发性肺动脉高压。
所述肺部疾病或低氧血症所致肺动脉高压包括慢性高原病、肺泡通气不足、其他伴有限制性、阻塞性或混合性通气障碍的肺部疾病。
所述金泽组合药物为雪胆和泽泻的原药材粉碎混合物或/和雪胆和泽泻的原提取物的混合物。
所述金泽组合药物中雪胆:泽泻的重量比为1:1-20。
所述金泽组合药物的剂型包括胶囊剂、片剂以及丸剂。
本发明的有益技术效果是:本发明提供的金泽组合药物治疗肺心病具有良好的活性,并 且对于肺心病的并发症肺动脉高压,包括药物和毒物所致肺动脉高压、肺部疾病或低氧血症所致肺动脉高压具有疗效。
具体实施方式
实施例1 金泽组合药物的制备
称量雪胆原药材1kg、泽泻原药材1kg,分别粉碎成粗粉,照流浸膏剂与浸膏剂项下的渗鹿法,分别用95%乙醇浸渍24小时后进行渗漉,至渗漉液色淡为止,漉液减压回收乙醇,浓缩成稠膏。泽泻稠膏用热蒸馏水洗涤二次,与雪胆稠膏合并,即得金泽组合药物I;
称量雪胆胆原药材1kg、泽泻原药材10kg,按上述方法即得金泽组合药物II;
称量雪胆胆原药材1kg、泽泻原药材20kg,按上述方法即得金泽组合药物III。
在药物生产中可将金泽组合药物I、II、III加辅料适量,混匀,制成颗粒,干燥,装入胶囊,得到金泽胶囊;也可以将金泽组合药物I、II、III加辅料适量,混匀,制成颗粒,干燥,压制成片;或者将金泽组合药物I、II、III加辅料适量,制成丸剂。
实施例2 金泽组合药物对大鼠肺心病的活性作用考察
60只SD大鼠随机分为6组:正常对照组,模型组,实施例1提供的金泽组合药物I、II、III组和硝苯地平组,每组各10只。用乙醇和生理盐水(2:8)混合液配制1%MGT溶液(60mg/kg)一次性腹腔注射造模,正常对照组则给予同等剂量乙醇和生理盐水(2:8)混合液。造模后第2天开始灌胃,空白组、模型组每天生理盐水灌胃1ml/kg,金泽组合药物I、II、III组每天给药量以原药材重量计算分别为3g/kg、3g/kg、3g/kg,硝苯地平组每天剂量10mg/kg,每只大鼠每天均灌胃两次,连续给药28天,在末次给药后1小时采集标本。
心脏置于10%中性甲醛溶液中固定1周,称取右心室(RV)和左心室加室间隔(LV+S)的重量,并以RV/(LV+s)比值作为右心肥厚指数。
采用放免法测定测定血浆ET-1、TXB2、6-keto-PGF1α水平,严格按照说明书操作。
酸还原酶法测定,血清NO2-,NO3-浓度反映NO含量,严格按照说明书操作。
每组随机选取8个标本,RT-PCR检测ET-1mRNA的表达。每一样本以目的条带与β-actin条带灰度的比值作为样本的表达。
取右下肺置于10%中性甲醛溶液中固定1周,常规石蜡制片,HE染色。光学显微镜下利用HPIAS-1000病理图文分析系统采集图像,测量肺小动脉管壁厚度、血管直径、管腔面积、血管总面积,然后计算管壁厚度与血管半径百分比[WT(%)]、管壁面积与血管总面积百分比[WA(%)],管腔面积与血管总面积百分比[LA(%)];每张切片均选取3~5个小动脉进行定量分析,并取其平均值进行统计学分析。
统计方法所得数据以均数±标准差表示,采用SPSS13.0统计软件包进行处理。多样 本均数比较采用单因素方差分析,以P<0.05作为差异具有统计学意义。
各组大鼠右心肥厚指数、血TXB2、6-keto-PGE1α、ET-1水平、NO含量及肺组织ET-1mRNA表达的比较见表1。
表1 各组大鼠右心肥厚指数、血TXB2、6-keto-PGE1α、ET-1、NO及ET-1mRNA表达的比较
注:与正常组比较△P﹤0.05,与模型组比较*P﹤0.05,#P﹤0.01。
各组大鼠肺小动脉病理形态学的变化正常组:大鼠肺小动脉管壁菲薄,内皮细胞扁平连续,厚薄较一致。模型组:在细支气管周围或其它部位的小动脉管腔变小、不规则,部分呈裂隙状,平滑肌细胞增生肥厚明显,内皮细胞变性肿胀,突向血管腔内,甚至坏死脱落。各治疗组:大鼠肺小动脉血管壁稍增厚、管腔略有变窄。各组大鼠WT%、WA%、LA%结果比较见表2。
表2 各组大鼠肺小动脉WT%、WA%、LA%测定结果的比较
注:与正常组比较△P﹤0.05,与模型组比较*P﹤0.05,#P﹤0.01。
目前认为肺血管收缩、原位血栓形成和肺血管重构是肺动脉高压发生,发展的重要病理生理基础。NO和ET-1是一对重要的血管舒缩调节因子,NO通过抑制血管平滑肌细胞(VSMC)的增生、收缩、白细胞黏附、血小板聚集和黏着等维持血管通畅;ET-1是迄今为止所发现的最强的缩血管因子之一,可引起肺动脉、肺毛细血管、肺静脉强烈收缩,肺循环阻力增加;生理状态下两者处于平衡状态,若分泌异常则可致肺血管反应异常,促使肺血管重构及肺动脉高压形成。本实验结果证实模型组大鼠NO含量下降,ET-1水平及ET-1mRNA表达明显升高,而金泽组合药物则能逆转两者平衡的失调,从而改善肺血管的舒缩功能。
血栓素(TXA2)是具有强烈促进血小板聚集、血管及支气管平滑肌收缩的生物活性物质;前列环素(PGI2)可抗血小板聚集及扩张血管。由于TXA2和PGI2生物半衰期短,可迅速降解为TXB2和6-keto-PGF1α,故测定后二者浓度可分别反映TXA2及PGI2的水平。正常生理状态下二者保持动态平衡,共同维持血管张力和血小板正常生理功能,若其平衡失调则可造成血小板聚集,是血栓形成的原因之一。本实验表明模型组大鼠6-keto-PGF1α含量下降,TXB2水平则明显升高, 而金泽组合药物则能逆转两者平衡的失调,进而改善血液的高凝状态,防止肺血管内原位血栓的形成。
肺血管重构是肺动脉高压不可逆发展的基本因素,也是对血管扩张降压药物产生抵抗的主要原因,因此如何阻止及逆转肺血管重构是有效防治肺动脉高压的关键环节,本实验结果显示模型组大鼠出现肺血管重构,给予金泽组合药物干预后肺血管重构明显减轻,其中高剂量组尤为明显,其肺血管形态与正常对照组无差异(P﹤0.05)。
综上所述,金泽组合药物具有降低右心肥厚指数,减轻肺血管重构,抑制血中TXB2、ET-1及肺组织ET-1mRNA生成与表达,上调血中6-keto-PGF1α。和NO水平等作用。提示金泽组合药物可能通过调节TXB2、6-keto-PGF1α、NO、ET-1的代谢失衡以及减轻肺血管重构,从而降低肺动脉压,在一定程度上防治肺心病。
实施例3 金泽组合药物对肺动脉高压活性作用考察1
健康Wister大鼠6O只,雌雄各半,6月龄,体重(230±20)g。按体重随机分为6组。即正常空白对照组、模型组、卡托普利组和实施例1所述的金泽组合药物组。
实验前先将动物常规饲养1周,然后对各组进行造模,将野百合碱配成2%的水溶液,每只大鼠按60mg/kg一次性腹腔注射。空白组以同剂量注射用水腹腔注射;2周后开始给药。金泽组合药物组按含生药3.0g/kg,采用灌胃给药方法,每天上午1次,连续给药l5天。卡托普利给药剂量为6.75mg/kg。NO、ET-1的检测方法与实施例2相同。
用SPSS 11.0统计软件包作统计处理,实验数据用表示。先进行组间方差齐性检验,在方差齐性检验的基础上作方差分析,组间两两比较的q检验。实验结果见表3所示。
表3 金泽组合药物对血液中指标NO和ET的影响
注:与正常组比较△P﹤0.05,与模型组比较*P﹤0.05,#P﹤0.01。
NO与ET的作用相互协调,相互制约。NO通过cGMP介导抑制ET的合成和抑制DNA的有丝分裂,从而拮抗ET的缩血管和促血管平滑肌细胞增生的效应。如果NO合成分泌减少、相对不足或ET增加,致NO/ET-1失调,将使肺血管收缩,平滑肌细胞增生及肺内血小板聚集,血栓形成,导致肺动脉高压加重。
实验结果表明:模型组ET明显高于正常空白对照组,而NO明显低于正常空白对照组,表明ET-1、NO的失衡参与肺心病肺动脉高压的形成。用金泽组合药物治疗后,ET-1明显下降, NO明显升高,说明金泽组合药物通过降低血中ET,提高NO浓度,扩张肺血管,减轻肺循环阻力,来改善肺心病肺动脉高压。
实施例4 金泽组合药物对肺动脉高压活性作用考察2
将Wistar大鼠5O只(体重250-350g)随机分为5组,即川芎嗪预防组、金泽组合药物I、II、III预防组,生理盐水对照组、川芎嗪治疗组及金泽组合药物I、II、III治疗组。用2O%乌拉坦(O.5ml/100g体重)腹腔注射麻醉后行气管插管,右心室插管和颈动脉插管术。用光电RM-6000型多导生理记录仪依次记录右心室收缩压(RVSP,因RVSP与PASP基本相等,故本文用RVSP表示PAP的变化)、颈动脉平均压(CAMP)HR及心阻抗血流图;股静脉插管备给药用。
川芎嗪预防组采用静脉注射给药,金泽组合药物预防组采用灌胃给药,大鼠给药后,吸入1O%O2、9O%N2的混合气体进行缺氧试验,重复记录各项指标以观察效果;各治疗组大鼠吸入1O%O2、9O%N2的混合气体2min后,按各预防组给药方式给药,在此低氧条件下观察效果。药物剂量为:注射川芎嗪80mg/kg、注射生理盐水3.2ml/kg,金泽组合药物给药方式参考实施例3。
计算公式PVR(kPa·s/L)=RVSP/CO中以RVSP代替肺血管灌注压,计算所得PVR稍大于实际水平。
药物预防缺氧对大鼠体/肺循环血液动力学的影响见表4。给药后大鼠的RVSP,PVR在低氧条件下未见升高,反而略有降低,但差异异无显著性;cAMP明显降低;川芎嗪预防组CO无显著性改变;金泽组合药物预防组C0增加;生理盐水对照组RVSP与PVR明显升高,CO与cAMP降低。表明川芎嗪与金泽组合药物均有明显抑制低氧所致的升高PAP与PVR及减少CO的作用,与生理盐水对照组相比有非常显著性差异。但川芎嗪组与金泽组合药物组间的作用差异除CO外均无显著性。
表4 药物对大鼠缺氧实验影响的比较
注:缺氧前后比较*P﹤0.05,#P﹤0.01,◇P﹤0.001;与生理盐水比较□P﹤0.05, △P﹤0.001;与川芎嗪预防组比较☆P﹤0.05
药物对低氧性肺动脉高压大鼠的影响见表5。两组RVSP、PVR,cAMP及HR于给药后均显著下降,SVR亦下降,但差异无显著性;CO增加;且金泽组合药物组降低RVSP及PVR的作用优于川芎嗪组。
表4 药物对低氧性肺动脉高压大鼠的影响
注:缺氧前后比较*P﹤0.05,#P﹤0.01,◇P﹤0.001;与川芎嗪预防组比较☆P﹤0.05
研究结果,金泽组合药物与川芎嗪能完全阻抑缺氧条件下PAP的升高与PVR的增加,且金泽组合药物降低PAP与PVR的作用优于川芎嗪,这可能是由于金泽组合药物中的雪胆和泽泻药物具有协同作用。
实验结果显示,川芎嗪静脉注射后即5min内PVSP有不同程度的降低,1O-15min内显示最大降压作用,20-30min内作用消失。金泽组合药物口服60min内RVSP显示不同程度的降低,3-4h显示最大降压效果,10h时效果仍明显,提示金泽组合药物中有效成分的半衰期较川芎嗪长。川芎嗪与金泽组合药物降低PAH及PVR的作用机理可能与如下机制有关:(1)拮抗Ca2+内流,选择性松弛血管平滑肌;(2)通过兴奋肺血管上的受体而达到扩张肺血管,缓解低氧性PAH的作用;(3)抑制血小板聚集,减少内源性花生四烯酸的释放,提高细胞内cAMP水平,调节TXA2/PGI2的平衡,使肺血管舒张;(4)通过降低心肌耗氧量,改善心功能,增强耐缺氧能力及心脏代偿功能而起作用。(5)降低血粘度,改善肺血运状态,使PVR减少,PAP降低。
本研究采用了不同剂型,结果初步表明金泽组合药物与川芎嗪在降低PAP与PVR、增加CO、改善心功能等方面的作用是一致的,且降低PAP与PVR的疗效优于川芎嗪。本研究结果提示,金泽组合药物对治疗慢性肺心病、肺动脉高压有良好的应用前景。
Claims (2)
1.金泽组合药物在制备治疗肺心病及并发症肺动脉高压药物中的应用;
其中,所述金泽组合药物为重量比为1:1-20的雪胆和泽泻提取物的混合物;
所述金泽组合药物的制备方法为:分别将雪胆和泽泻粉碎成粗粉,照流浸膏剂与浸膏剂项下的渗漉法,分别用95%乙醇浸渍24小时后进行渗漉,至渗漉液色淡为止,漉液减压回收乙醇,浓缩成稠膏;
泽泻稠膏用热蒸馏水洗涤二次,与雪胆稠膏合并,得到金泽组合药物。
2.根据权利要求1所述的应用,其特征在于:所述治疗肺动脉高压是指动脉性肺动脉高压、肺部疾病或低氧血症所致肺动脉高压中的任意一种或几种病症。
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肺心病的诊断及并发症;杨玺;《中国社区医师》;20100531;第12卷(第10期);第6页 * |
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