CN113398145B - 含nad与氨氯地平的药物组合物及其用途 - Google Patents
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Abstract
本发明涉及医药组合物领域，提供了一种治疗或预防心力衰竭的药物组合物，所述药物组合物包括烟酰胺腺嘌呤二核苷酸(NAD)与氨氯地平或其溶剂合物或其异构体或药学上可接受的盐。所述含NAD与氨氯地平的药物组合物具有协同预防或治疗心力衰竭，特别是射血分数保留的心力衰竭的作用。
Description
技术领域
本发明属于生物医药技术领域。更具体地，涉及一种治疗或预防心力衰竭的联用组合药物及其应用。
背景技术
心力衰竭又称“心肌衰竭”，是指心脏当时不能搏出同静脉回流及身体组织代谢所需相称的血液供应。往往由各种疾病引起心肌收缩能力减弱，从而使心脏的血液输出量减少，不足以满足机体的需要，并由此产生一系列症状和体征。心瓣膜疾病、冠状动脉硬化、高血压、内分泌疾患、细菌毒素、急性肺梗塞、肺气肿或其他慢性肺脏疾患等均可引起心脏病而产生心力衰竭的表现。妊娠、劳累、静脉内迅速大量补液等均可加重有病心脏的负担，而诱发心力衰竭。目前临床上对心力衰竭的治疗主要通过合理使用血管扩张剂增加心脏收缩力，改善心功能。
烟酰胺腺嘌呤二核苷酸(NAD)也称为辅酶Ⅰ，是人体最重要的氧化还原酶的辅酶，参与多种生化反应，在细胞能量代谢中起关键作用。有文献(林敏聪,张胜军.NAD+在心肌保护方面的研究与应用[J].临床医学研究与实践,2020,005(016):197-198)报道：NAD+的抗心肌重塑机制也可能在干预心衰的发展过程中发挥作用。
氨氯地平(amlodipine)，化学名为6-甲基-2-(2-氨基乙氧基)甲基-4-(2-氯苯基)-1,4-二氢-3,5-吡啶二甲酸甲乙酯，为一种治疗高血压及冠状动脉疾病的药物。
目前心力衰竭治疗药物中，尚无烟酰胺腺嘌呤二核苷酸与氨氯地平或其溶剂合物或其异构体或药学上可接受的盐联合或制备成药物组合物用于心力衰竭治疗的报道。
发明内容
本发明的目的是提供一种治疗心力衰竭的药物组合物。本发明欲解决的技术问题是现有技术中抗心力衰竭药物在治疗心力衰竭时疗效不足且副作用较大的技术问题。
本发明的目的是这样实现的：
在一个实施例中，提供了一种药物组合物，所述药物组合物包含烟酰胺腺嘌呤二核苷酸(NAD)与氨氯地平或其溶剂合物或其异构体或药学上可接受的盐。
所述烟酰胺腺嘌呤二核苷酸与氨氯地平或其溶剂合物或其异构体或药学上可接受的盐的质量比为1-100:1-100或1-50:1-50。优选地，烟酰胺腺嘌呤二核苷酸与氨氯地平或其溶剂合物或其异构体或药学上可接受的盐的质量比为1-25:1-25或1-10:1-10或1-5:1-5或1-3:1-3。
所述氨氯地平药学上可接受的盐为甲磺酸盐、苯磺酸盐、醋酸盐、酒石酸盐、天冬酸盐、马来酸盐、硫酸盐、盐酸盐或氢溴酸盐；所述氨氯地平异构体为左旋氨氯地平或右旋氨氯地平或消旋氨氯地平。
在一个实施例中，所述药物组合物还包括其它抗心衰药物。
在一个实施例中，所述药物组合物还包括药学上可接受的辅料；所述药学上可接受的辅料选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、增溶剂、助溶剂、乳化剂、着色剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂中的一种或多种。
在一个实施例中，提供了一种药物制剂，所述药物制剂包括权利上述任一项所述的药物组合物。优选地，所述药物制剂选自片剂、胶囊、散剂、合剂、丸剂、粒剂、溶液剂、浆剂、膏剂、栓剂、雾剂、注射剂、搽剂、冻干口腔崩解片或酊剂。
在另一个实施例中，提供了上述任一项所述的药物组合物或上述任一项所述的药物制剂在制备治疗或预防心力衰竭药物的用途。优选地，所述心力衰竭选自射血分数保留的、射血分数中间值的或射血分数降低的心力衰竭。
本发明将烟酰胺腺嘌呤二核苷酸与氨氯地平或其溶剂合物或其异构体或药学上可接受的盐制备成药物组合物用于心力衰竭治疗，扩大了心力衰竭的用药选择范围，同时二者联用取得了协同增效的效果。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些图获得其他的附图。
图1烟酰胺腺嘌呤二核苷酸和苯磺酸氨氯地平联合应用对左心室重量系数的影响
图2烟酰胺腺嘌呤二核苷酸与苯磺酸氨氯地平联合应用对左心室射血分数的影响
图3烟酰胺腺嘌呤二核苷酸和苯磺酸氨氯地平联合应用对心肌线粒体膜电位和ATP水平的影响
图4心肌纤维化水平观察
图5心肌组织透射电镜观察
具体实施方式
下面通过具体实施例，对本发明的技术方案进行详细说明。
建立心力衰竭模型：SHR大鼠出生后1～2个月出现心肌细胞变性，灶状坏死；出生后2～3个月出现心肌纤维化；4～5个月出现心肌肥大，心室扩张等病理变化；15个月以上出现明显的心力衰竭和左心室泵血障碍。参考文献，本实验选择14周龄雄性SHR大鼠，采用高脂/高盐饲料喂养，可以加速心脏功能恶化，建立心力衰竭模型。
实施例1烟酰胺腺嘌呤二核苷酸与苯磺酸氨氯地平联合应用对左心室重量系数的影响
烟酰胺腺嘌呤二核苷酸与苯磺酸氨氯地平联合应用，将大鼠按照表1进行分组并给药，观察对左心室重量系数的影响。
表1大鼠的分组及给药方案
给药12周后，测定各组左心室重量系数(见图1)。与WKY组相比，SHR大鼠左心室重量系数显著增加(P<0.01)，受试药物组可不同程度降低模型大鼠左心室重量系数，NAD+AL组有明显降低作用(P<0.01)，其中AL和NAD联用可见协同效果(**P<0.01，与WKY组相比；#P<0.05，##P<0.01，联用组与单用组相比)。
实施例2烟酰胺腺嘌呤二核苷酸与苯磺酸氨氯地平联合应用对左心室射血分数的影响
烟酰胺腺嘌呤二核苷酸与苯磺酸氨氯地平联合应用，将大鼠按照表2进行分组并给药，观察对左心室射血分数的影响。
表2大鼠的分组及给药方案
给药12周后测定各组射血分数，结果见图2。与WKY大鼠相比，模型组SHR大鼠射血分数有明显下降。与模型组相比，给药12周后，其他所有给药组射血分数均有明显升高。给药组之间对比，NAD+AL组相较于NAD组或AL组，具有显著性差异(P<0.01)，表明NAD+AL组联用具有明显的协同效果(**P<0.01，与WKY组相比；#P<0.05，##P<0.01，联用组与单用组相比)。
实施例3NAD与苯磺酸氨氯地平联合应用对心肌线粒体膜电位和ATP水平的影响
NAD与苯磺酸氨氯地平药物联合应用，将大鼠按照表3进行分组并给药，观察对心肌线粒体膜电位和ATP水平的影响。
表3大鼠的分组及给药方案
给药12周后测定各组心肌线粒体膜电位和ATP水平(见图3)。与WKY组相比，SHR大鼠心肌线粒体膜电位显著降低(P<0.01)，同时ATP水平也有所下降。NAD+AL组可以明显恢复SHR大鼠心肌线粒体膜电位，同时升高ATP水平，其中AL和NAD联用相较于AL组或NAD单用，可见协同效果(**P<0.01，与WKY组相比；#P<0.05，##P<0.01，联用组与单用组相比)。
实施例4心肌纤维化水平观察(Masson三色染色法观察)
按照实施例1进行分组，并给药。给药12周后进行透射电镜观察(见图4)。WKY组心肌肌束间有极少量胶原纤维，相邻细胞的胶原纤维网完好，着色淡。SHR组心肌间质可见明显纤维化改变及胶原沉积，各受试药物组均可明显减轻心肌胶原沉积，其中AL、NAD组均有改善，AL+NAD组改善作用更为明显。
实施例5透射电镜观察
按照实施例1进行分组，并给药。给药12周后进行透射电镜观察(见图5)。WKY大鼠心肌纤维结构完整，排列紧密，质膜清晰深染；线粒体区域聚集肌原纤维束间，大多均匀分布，嵴膜清晰，形态结构完整。SHR模型组心肌纤维排列松散，走形紊乱，可见肌节断裂，长短不一，肌丝灶性溶解、消失等异常状态；心肌线粒体分布紊乱，数量减少，形态不规则，出现肿胀、变形、固缩等多种异常形状，且线粒体内部可见嵴膜浅染或缺失，甚至空泡样变性。NAD组心肌纤维走向较好，排列欠紧密，与模型组相比有较好改善；心肌线粒体数量、分布和形态基本正常，改善作用较明显。AL组心肌纤维排列松散，可见部分肌纤维损害；心肌线粒体数量有所减少，形态偏圆，嵴可见但嵴膜染色变浅。NAD+AL组心肌纤维和线粒体形态优于NAD组。
以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围，其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (11)
1.一种治疗或预防心力衰竭的药物组合物，包含烟酰胺腺嘌呤二核苷酸与氨氯地平或其药学上可接受的盐；所述烟酰胺腺嘌呤二核苷酸与氨氯地平或其药学上可接受的盐的质量比为1-10:1-10。
2.如权利要求1所述的组合物，其特征在于：所述烟酰胺腺嘌呤二核苷酸与氨氯地平或其药学上可接受的盐的质量比为1-5:1-5。
3.如权利要求1所述的组合物，其特征在于：所述烟酰胺腺嘌呤二核苷酸与氨氯地平或其药学上可接受的盐的质量比为1-3:1-3。
4.如权利要求1所述的组合物，其特征在于：所述氨氯地平药学上可接受的盐为甲磺酸盐、苯磺酸盐、醋酸盐、酒石酸盐、天冬酸盐、马来酸盐、硫酸盐、盐酸盐或氢溴酸盐。
5.如权利要求1所述的组合物，其特征在于：所述药物组合物还包括其它抗心衰药物。
6.如权利要求1-5中任一项所述的组合物，其特征在于：还包括药学上可接受的辅料。
7.如权利要求6所述的组合物，其特征在于：所述药学上可接受的辅料选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、增溶剂、助溶剂、乳化剂、着色剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂中的一种或多种。
8.一种治疗或预防心力衰竭的药物制剂，其特征在于：所述药物制剂包括权利要求1-7中任一项所述的组合物。
9.如权利要求8所述的药物制剂，其特征在于：所述药物制剂选自片剂、胶囊、散剂、合剂、丸剂、粒剂、溶液剂、浆剂、膏剂、栓剂、雾剂、注射剂、搽剂、冻干口腔崩解片或酊剂。
10.权利要求1-7中任一项所述的组合物或权利要求8-9中任一项所述的药物制剂在制备治疗或预防心力衰竭药物中的用途。
11.如权利要求10所述的用途，其特征在于，所述心力衰竭选自射血分数保留的、射血分数中间值的或射血分数降低的心力衰竭。
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