CN108210927A - 一种用于治疗动脉粥样硬化的药物组合物 - Google Patents
一种用于治疗动脉粥样硬化的药物组合物 Download PDFInfo
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- CN108210927A CN108210927A CN201810184441.XA CN201810184441A CN108210927A CN 108210927 A CN108210927 A CN 108210927A CN 201810184441 A CN201810184441 A CN 201810184441A CN 108210927 A CN108210927 A CN 108210927A
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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Abstract
本发明涉及一种用于治疗动脉粥样硬化的药物组合物及其用途，其包括左旋精氨酸(L‑精氨酸)和血小板聚集抑制剂及其药学上可接受的盐或酯，以及一种或多种药学上可接受的载体。其中血小板聚集抑制剂包括阿司匹林，氯吡格雷和沙格雷酯及其药学上可接受的盐或酯。上述组合物用于预防和/或治疗动脉粥样硬化，减少动脉粥样硬化的发病率和死亡率。
Description
技术领域
本发明属于药物领域，涉及一种用于治疗动脉粥样硬化的药物组合物及其在预防和/或治疗动脉粥样硬化的用途。
背景技术
心血管疾病是目前危害人类健康的主要疾病之一，其较高的发病率、致残率和死亡率给社会与居民带来沉重的负担。其最基本的病理过程是动脉粥样硬化。
动脉粥样硬化发生发展的原因包括血脂的聚集、内皮细胞损伤和炎症反应。内皮功能受损是动脉粥样硬化发生的始动环节，能反映动脉粥样硬化发展的严重程度。高脂血症、高血压、糖尿病、吸烟、高尿酸血症等动脉粥样硬化危险因素首先导致内皮功能受损，而内皮功能受损是以内皮依赖的血管舒张功能障碍为代表的，其中内皮细胞合成与释放的一氧化氮(nitric oxide，NO)减少是其主要原因。NO是由一氧化氮合酶(nitric oxidesynthase，NOS)催化L-精氨酸生成髙渗透性小分子。NO不仅使血管舒张，也可以阻止血小板粘附和聚集、白细胞粘附和向动脉壁的迁移，抑制血管平滑肌细胞的増生，而这些都是动脉粥样硬化发生发展的关键环节。NO还具有维持内环境稳态和阻止细胞调亡的作用，NO可阻止内皮细胞的调亡，避免内皮细胞损伤，起到抗动脉粥样硬化的作用。NOS有3种形式:神经型nNOS (neuronal nitric oxide synthase，nNOS)、诱导型iNOS ( infucible nitricoxide synthase，iNOS)和内皮型eNOS (endothelial nitric oxide synthase，eNOS)，内皮型的结构和功能正常是冠状动脉保持正常舒缩状态、避免冠状动脉受损、调节内皮细胞功能的重要条件，许多急性、慢性疾病如动脉粥样硬化、高脂血症、缺血性心肌病、糖尿病、高血压都能发现iNOS活性升高、eNOS活性降低为特征的现象。
精氨酸（L-Arg）最初是Schlus在巧1886年从植物羽扇豆苗中分离提取的，1895年Hedin从动物蛋白质中也分离出来了精氨酸，在体内起生理作用的主要是L-精氨酸，L-精氨酸是NOS的底物，在NOS的作用下，生成NO和L-瓜氨酸。多项研究表明在很多内皮功能受损的相关疾病中，如急性冠脉综合症、充血性也衰、心肌缺血再灌注、高血压、高脂血症、阿尔茨海默病,补充外源性精氨酸，可以通过NO途径使内皮功能得以修复，改善心脏功能、减轻缺血再灌注损伤和减少心律失常的发生。
大量临床试验证明抗血小板药物在动脉粥样硬化相关疾病中能够降低缺血性事件的发生率和死亡率。传统的观点认为这主要得益于抗血小板药物抑制动脉粥样硬化斑块破裂所导致的血小板聚集，从而减少急性闭塞性缺血事件的发生，目前己明确认为:动脉粥样硬化是一种涉及循环血小板、白细胞与血管壁上各种细胞相互作用的炎症性疾病。斑块的不断进展和破裂与炎症反应的程度密切相关，血小板作为一种炎症细胞，蕴含各种炎症介质，其活化后释放和表达各种炎症介质参与炎症反应。有研究显示激活的血小板能够促进动脉粥样硬化病变的形成和发展。
阿司匹林( Asp) 是一种传统的非甾体类抗炎药，低剂量阿司匹林可预防动脉血栓的形成。阿司匹林是一种不可逆的血小板环氧化酶( COX) 抑制剂，通过抑制COX -1阻止花生四烯酸转化为前列腺素G，从而起到阻止TXA2的产生和抗血小板活化聚集的作用，最终发挥减少血栓形成的效果，是目前临床应用最为广泛的抗血小板药物。阿司匹林的常见不良反应为消化道症状，主要有恶心、呕吐、上腹疼痛、上腹胀、反酸、烧心、呕血、黑便等症状，并容易诱发消化道溃疡。
氯吡格雷(Clo)为第二代P2Y12受体拮抗剂，是噻氯匹定的衍生物。氯吡格雷也是前体药物，经口服吸收后，在肝药酶代谢作用下转化为活性代谢产物，与血小板表面的ADP受体结合，抑制血小板聚集。与其他同类药物相比，氯吡格雷在预防急性血管事件发生方面优于阿司匹林。对于高危患者( 指曾发生脑卒中、外周动脉疾病、症状性冠状动脉疾病或糖尿病的患者) ，其预防效果可能更加明显。其抗血栓作用比噻氯匹定和阿司匹林强，在安全性方面也有明显的提高。氯吡格雷已成为继阿司匹林之后临床最主要的抗血小板药物。
5-HT 是一种神经递质和血管活性物质，人体内超过90% 的5-HT 储存在血小板内。血小板的5-HT 受体有两类: 5-HT1受体和5-HT2受体。血液中的5-HT2可以激活血小板及血管平滑肌的5-HT2受体，促进血栓的形成。因此研究血管5-HT2受体来开发抗血小板药物，对于治疗心血管疾病有重大意义。沙格雷酯（Sar）可以特异性地与5-HT2受体结合，从而抑制血小板的聚集，临床上可用于慢性缺血性血管闭塞症等多种血栓性疾病。
专利CN101032562 公开了一种具有调节血压和保护心脑血管系统的保健品，主要通过精氨酸和山楂提取物的组合，达到降低血压和保护心脑血管系统的效果。
专利CN104667283 公开了一种治疗血脂异常和动脉粥样硬化的复方药物组合物，其中刚开了使用沙格雷酯和5-羟色胺合成抑制剂联合使用来防治动脉粥样硬化。
专利CN102755336 公开了一种包含格雷类药物和阿司匹林的药物组合物，用于预防或治疗急性冠脉综合征、心绞痛和心脑血管病。
然而，现有技术中并没有公开联合使用精氨酸和血小板聚集抑制剂用于治疗和/或预防动脉粥样硬化的报道。
发明内容
为解决现有技术中对于治疗和/或预防动脉粥样硬化药物不足的技术问题，本发明人偶然发现，将精氨酸和血小板聚集抑制剂作为药物组合物联合使用来治疗动脉粥样硬化，获得了协同改善动脉粥样硬化的作用，可用于动脉粥样硬化相关疾病的预防和治疗，获得了意想不到的效果。
为了解决上述问题，本发明进行了提供了一种用于治疗动脉粥样硬化的药物组合物，其中包括左旋精氨酸(L-Arg)和血小板聚集抑制剂及其药学上可接受的盐或酯，以及一种或多种药学上可接受的载体。
其中所述血小板聚集抑制剂包括阿司匹林(Asp)，氯吡格雷(Clo)和沙格雷酯(Sar)及其药学上可接受的盐或酯，优选盐酸氯吡格雷，盐酸沙格雷酯。
其中所述左旋精氨酸和血小板聚集抑制剂的质量比为1:10-10:1。
其中所述药物组合物被制备成为固体制剂。
所述固体制剂选自片剂、胶囊、颗粒剂、滴丸等。
左旋精氨酸(L-Arg)和血小板聚集抑制剂及其药学上可接受的盐或酯在制备治疗动脉粥样硬化的药物组合物中的用途。
其中所述血小板聚集抑制剂包括阿司匹林(Asp)，氯吡格雷(Clo)和沙格雷酯(Sar)及其药学上可接受的盐或酯，优选盐酸氯吡格雷，盐酸沙格雷酯。
其中所述左旋精氨酸和血小板聚集抑制剂的质量比为1:10-10:1。
其中所述药物组合物被制备成为固体制剂。
其中所述固体制剂选自片剂、胶囊、颗粒剂、滴丸等。
在通过药物对高脂饲料喂养致大鼠血脂异常模型的治疗作用的研究中发现：经过高脂饲料喂养的大鼠，其血清中TC、TG、LDL-C浓度均有明显升高，HDL-C浓度明显降低， TC/HDL-C比值明显增大。单独给予精氨酸治疗后，血清中TC、TG、LDL-C、HDL-C的浓度变化以及TC/HDL-C比值相对于高血脂组变化均不明显；而单独给予阿司匹林、氯吡格雷或沙格雷酯治疗后，血清中TC、TG、LDL-C浓度均有所降低，HDL-C浓度升高， TC/HDL-C比值变小；经过精氨酸+血小板聚集抑制剂组联合治疗后，血清中TC、TG、LDL-C浓度均有显著降低，HDL-C浓度显著升高，TC/HDL-C比值大大缩小，提示精氨酸和血小板聚集抑制剂联合使用对治疗高脂饲料喂养引起的血脂异常有明显的协同抑制作用，对动脉粥样硬化具有协同治疗作用。
具体实施方式
下面对本发明的较佳实施进行详细阐述，以使本发明的优点和特征能更易于被本领域技术人员理解。
药物对高脂饲料喂养致大鼠血脂异常模型的治疗作用
1.1 实验动物
将180只Wistar大鼠随机分成按体重随机分为18组，每组10只，分别为对照组、高血脂组，精氨酸治疗组，阿司匹林治疗组，氯吡格雷治疗组，沙格雷酯治疗组，精氨酸+阿司匹林治疗组（4个配比组）；精氨酸+氯吡格雷治疗组（4个配比组），精氨酸+沙格雷酯治疗组（4个配比组）。对照组:以普通饲料、普通饮水饲养90天；除对照组以外，其他各组均以高脂饲料、普通饮水饲养90天。高脂饲料在正常饲料基础上加入2%胆固醇、0. 5%胆酸钠、0. 2%丙硫氧嘧啶和3%猪油。
1.2 给药方案
对照组和高血脂组注射等量生理盐水，其余各给药组在喂养高胆固醇饲料的同时，给予20.0mg/kg/次的治疗药物，每天2次，共90天。
其中含有精氨酸的组给予L-精氨酸，含有阿司匹林的组给予阿司匹林，含有氯吡格雷的组给予盐酸氯吡格雷，含有沙格雷酯的组给予盐酸沙格雷酯。
其中精氨酸(L-Arg)+阿司匹林(Asp)按不同配比的四种配方为：
L-Arg+Asp-1，L-Arg：Asp=4:1；L-Arg+Asp-2，L-Arg：Asp=1:1；
L-Arg+Asp-3，L-Arg：Asp=1:2；L-Arg+Asp-4，L-Arg：Asp=1:5。
其中精氨酸(L-Arg)+氯吡格雷(Clo)按不同配比的四种配方为：
L-Arg+Clo -1，L-Arg：Clo =4:1；L-Arg+Clo -2，L-Arg：Clo =1:1；
L-Arg+Clo -3，L-Arg：Clo =1:2；L-Arg+Clo -4，L-Arg：Clo =1:5。
其中精氨酸(L-Arg)+沙格雷酯(Sar)按不同配比的四种配方为：
L-Arg+ Sar -1，L-Arg：Sar =4:1；L-Arg+ Sar -2，L-Arg：Sar =1:1；
L-Arg+ Sar -3，L-Arg：Sar =1:2；L-Arg+ Sar -4，L-Arg：Sar =1:5。
1.3 检测方法
血脂水平测定：90天后，从大鼠腹主动脉采集动脉血，不抗凝， 3 000 r /m in离心15m in，分离出血清，取1m l用全自动生化分析仪检测血清总胆固醇(TC)、甘油三酯(TG )、高密度脂蛋白(HDL-C)及低密度脂蛋白(LDL-C)。
1.4 统计分析
实验数据经统计软件处理, 行方差分析, 各处理组均数间行两两比较用Student-Newman-Keuls法, 以(x±s)表示, P <0.05 具有统计学差异，P <0.01 具有非常明显的统计学差异。
1.5 结果分析
1.5.1 精氨酸、阿司匹林以及精氨酸+阿司匹林各组对高脂饲料喂养致大鼠血脂异常模型的影响。
从表1中可以看出，经过高脂饲料喂养的大鼠，在高血脂组中，其血清中TC、TG、LDL-C浓度均有明显升高，HDL-C浓度明显降低， TC/HDL-C比值明显增大。表现出动物模型出现了明显的血脂异常以及发生动脉粥样硬化的症状。单独给予精氨酸后，血清中TC、TG、LDL-C、HDL-C的浓度变化以及TC/HDL-C比值相对于高血脂组变化均不明显，提示精氨酸对血脂水平没有显著改善。单独给予阿司匹林后，相对于高血脂组血清中TC、TG、LDL-C浓度均有所降低，HDL-C浓度升高， TC/HDL-C比值变小，P <0.05 具有统计学差异。而Arg+Asp2-4组相对于高血脂组血清中TC、TG、LDL-C浓度均有显著降低，HDL-C浓度显著升高，TC/HDL-C比值大大缩小, 相对于高血脂组P <0.01，具有显著地统计学差异；并且复方Arg+Asp2-4组的效果显著好于单独给予阿司匹林组（P <0.05），结果显示，Arg与Asp按照1:1～1:5的比例进行组合，对治疗高脂饲料喂养引起的血脂异常有明显的协同作用。
表1 精氨酸+阿司匹林对大鼠血脂异常模型的影响(x±s, mmo l /L)
| 组别 | TC | TG | HDL-C | LDL-C | TC/HDL-C |
| 对照组 | 3.14±1.21 | 0.96±0.33 | 1.31±0.49 | 1.66±0.56 | 2.85 |
| 高血脂组 | 15.71±4.81 | 2.87±0.93 | 0.88±0.25 | 12.14±5.32 | 17.85 |
| Arg | 14.19±5.03 | 2.64±0.77 | 0.91±0.38 | 11.47±4.11 | 15.59 |
| Asp | 9.49±3.73* | 1.75±0.76* | 1.04±0.38* | 7.61±2.44* | 9.52* |
| Arg+Asp-1 | 6.95±2.44* | 1.37±0.41* | 1.08±0.29* | 5.21±1.86* | 6.44* |
| Arg+Asp-2 | 5.43±1.77**/# | 1.33±0.42**/# | 1.12±0.35**/# | 3.88±1.28**/# | 4.85**/# |
| Arg+Asp-3 | 4.98±1.35**/# | 1.21±0.44**/# | 1.15±0.33**/# | 3.64±1.11**/# | 4.33**/# |
| Arg+Asp-4 | 4.87±1.27**/# | 1.18±0.29**/# | 1.15±0.19**/# | 3.51±0.53**/# | 4.23**/# |
与高血脂组相比，*表示p＜0.05，**表示p＜0.01；
与阿司匹林组相比，#表示P＜0.05。
1.5.2 精氨酸、氯吡格雷以及精氨酸+氯吡格雷各组对高脂饲料喂养致大鼠血脂异常模型的影响。
从表2中可以看出，单独给予氯吡格雷后，相对于高血脂组血清中TC、TG、LDL-C浓度均有所降低，HDL-C浓度升高， TC/HDL-C比值变小，P <0.05 具有统计学差异。而Arg+Clo各组相对于高血脂组血清中TC、TG、LDL-C浓度均有显著降低，HDL-C浓度显著升高，TC/HDL-C比值大大缩小, Arg+Clo-1、Arg+Clo-3、Arg+Clo-4相对于高血脂组P <0.05，Arg+Clo-2相对于高血脂组P <0.01，具有显著地统计学差异；并且复方组Arg+Clo-2的效果显著好于单独给予氯吡格雷组（P <0.05），结果显示，Arg与Clo按照1:1的比例进行组合，对治疗高脂饲料喂养引起的血脂异常有明显的协同作用。
表2 精氨酸+氯吡格雷对大鼠血脂异常模型的影响(x±s, mmol /L)
| 组别 | TC | TG | HDL-C | LDL-C | TC/HDL-C |
| 对照组 | 3.14±1.21 | 0.96±0.33 | 1.31±0.49 | 1.66±0.56 | 2.85 |
| 高血脂组 | 15.71±4.81 | 2.87±0.93 | 0.88±0.25 | 12.14±5.32 | 17.85 |
| Arg | 14.19±5.03 | 2.64±0.77 | 0.91±0.38 | 11.47±4.11 | 15.59 |
| Clo | 9.95±4.04* | 1.86±0.88* | 0.97±0.32* | 8.15±2.75* | 10.25* |
| Arg+Clo-1 | 6.61±3.29* | 1.37±0.45* | 0.99±0.30* | 5.21±1.77* | 6.68* |
| Arg+ Clo-2 | 6.32±2.11**/# | 1.30±0.48**/# | 1.12±0.21**/# | 4.62±1.53**/# | 5.64**/# |
| Arg+ Clo-3 | 6.73±2.77* | 1.34±0.56* | 0.97±0.19* | 5.19±0.95* | 6.93* |
| Arg+ Clo-4 | 7.12±2.38* | 1.39±0.16* | 0.98±0.32* | 5.43±0.19* | 7.26* |
与高血脂组相比，*表示p＜0.05，**表示p＜0.01；
与氯吡格雷组相比，#表示P＜0.05。
1.5.3 精氨酸、沙格雷酯以及精氨酸+沙格雷酯各组对高脂饲料喂养致大鼠血脂异常模型的影响。
从表3中可以看出，单独给予沙格雷酯后，相对于高血脂组血清中TC、TG、LDL-C浓度均有所降低，HDL-C浓度升高， TC/HDL-C比值变小，P <0.05 具有统计学差异。而Arg+Sar各组相对于高血脂组血清中TC、TG、LDL-C浓度均有显著降低，HDL-C浓度显著升高，TC/HDL-C比值大大缩小, 相对于高血脂组P <0.01，具有显著地统计学差异；并且复方组的效果显著好于单独给予沙格雷酯组（P <0.05），提示产生了协同效应。而且Arg+Sar-3治疗使TC/HDL-C比值缩小到接近对照组水平，这对于血脂异常导致的动脉粥样硬化的预防及治疗可能有特别意义；结果提示，Arg与Sar按照一定比例进行组合，对治疗高脂饲料喂养引起的血脂异常有明显的协同作用，按重量配比，Arg与Sar的比例范围为：4:1～1:5，以Arg：Asp＝1:2复方(Arg+Sar-3)的疗效最好。
表3 精氨酸+沙格雷酯对大鼠血脂异常模型的影响(x±s, mmo l /L)
| 组别 | TC | TG | HDL-C | LDL-C | TC/HDL-C |
| 对照组 | 3.14±1.21 | 0.96±0.33 | 1.31±0.49 | 1.66±0.56 | 2.85 |
| 高血脂组 | 15.71±4.81 | 2.87±0.93 | 0.88±0.25 | 12.14±5.32 | 17.85 |
| Arg | 14.19±5.03 | 2.64±0.77 | 0.91±0.38 | 11.47±4.11 | 15.59 |
| Sar | 10.23±3.36* | 2.37±0.72* | 0.95±0.25* | 8.81±3.07* | 10.76* |
| Arg+Sar-1 | 6.21±2.99**/# | 1.41±0.35**/# | 1.06±0.25**/# | 5.04±1.04**/# | 5.85**/# |
| Arg+ Sar-2 | 5.76±1.53**/# | 1.35±0.22**/# | 1.14±0.31**/# | 4.39±1.21**/# | 5.05**/# |
| Arg+ Sar-3 | 3.64±1.02**/# | 1.18±0.13**/# | 1.25±0.27**/# | 1.96±0.52**/# | 2.91**/# |
| Arg+Sar-4 | 5.31±2.22**/# | 1.33±0.30**/# | 1.17±0.28**/# | 3.98±1.46**/# | 4.54**/# |
与高血脂组相比，*表示p＜0.05，**表示p＜0.01；
与沙格雷酯组相比，#表示P＜0.05。
Claims (10)
1.一种用于治疗动脉粥样硬化的药物组合物，其中包括左旋精氨酸(L-Arg)和血小板聚集抑制剂及其药学上可接受的盐或酯，以及一种或多种药学上可接受的载体。
2.根据权利要求1所述的药物组合物，其中所述血小板聚集抑制剂包括阿司匹林(Asp)，氯吡格雷(Clo)和沙格雷酯(Sar)及其药学上可接受的盐或酯，优选盐酸氯吡格雷，盐酸沙格雷酯。
3.根据权利要求1所述的药物组合物，其中所述左旋精氨酸和血小板聚集抑制剂的质量比为1:10-10:1。
4.根据权利要求1所述的药物组合物，其中所述药物组合物被制备成为固体制剂。
5.根据权利要求4所述的药物组合物，其中所述固体制剂选自片剂、胶囊、颗粒剂、滴丸等。
6.左旋精氨酸(L-Arg)和血小板聚集抑制剂及其药学上可接受的盐或酯在制备治疗动脉粥样硬化的药物组合物中的用途。
7.根据权利要求6所述的用途，其中所述血小板聚集抑制剂包括阿司匹林(Asp)，氯吡格雷(Clo)和沙格雷酯(Sar)及其药学上可接受的盐或酯，优选盐酸氯吡格雷，盐酸沙格雷酯。
8.根据权利要求6所述的用途，其中所述左旋精氨酸和血小板聚集抑制剂的质量比为1:10-10:1。
9.根据权利要求6所述的用途，其中所述药物组合物被制备成为固体制剂。
10.根据权利要求9所述的用途，其中所述固体制剂选自片剂、胶囊、颗粒剂、滴丸等。
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| CN105188667A (zh) * | 2013-03-27 | 2015-12-23 | 佛多斯大学医学研究中心(C·H·U·V) | 用于治疗和/或预防再狭窄的药物制剂 |
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