CN106822903A - 用于治疗心衰的药物组合物及其应用 - Google Patents
用于治疗心衰的药物组合物及其应用 Download PDFInfo
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- CN106822903A CN106822903A CN201710077124.3A CN201710077124A CN106822903A CN 106822903 A CN106822903 A CN 106822903A CN 201710077124 A CN201710077124 A CN 201710077124A CN 106822903 A CN106822903 A CN 106822903A
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- vilazodone
- heart failure
- statins
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Abstract
本发明属于药物领域,具体涉及一种用于治疗心衰的药物组合物及其应用。所述药物组合物由维拉佐酮和他汀类药物组成。所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.01‑0.2∶1。
Description
技术领域
本发明属于药物领域,具体涉及一种用于治疗心衰的药物组合物及其应用。
背景技术
心力衰竭是各种心血管疾病的终末阶段,各种内外因素若导致心脏前后负荷长期过重,心肌病损及收缩力减弱,均可导致心力衰竭的发生。随着医学发展,心衰治疗亦在不断进展。随着心衰研究和认识的不断深入。近几年,心力衰竭的病理生理概念出现了根本的改变,人们发现,慢性心力衰竭症状和血流动力学恶化的背后,存在着严重的神经内分泌激素紊乱,即交感神经肾上腺素系统和肾素-醛固酮系统(RAAS)的过度激活,而它们的激活程度与长期预后变化成正相关;心衰时免疫活动异常,多种免疫机制参与心衰的病理生理过程。
目前心衰的治疗药物主要包括血管紧张素转化酶抑制剂(ACEI)、利尿药物、p受体阻断药、血管紧张素II受体阻断药、醛固酮抑制剂、洋地黄类强心剂、血管扩张药、正性肌力药以及抗血栓药物等。这些药物对心衰能起到不错的治疗效果,但由于它们有各自的毒副作用,限制了许多心衰患者的使用。
他汀类药物是通过抑制肝脏胆固醇合成限速酶-HMG-CoA,进而减少总胆固醇和低密度脂蛋白胆固醇的合成;并能上调肝脏低密度脂蛋白受体基因表达,使LDL受体合成增加,增加血液中LDL-C的清除,是目前临床较为常用的降血脂一线药物。近年来研究表明,他汀类药物对心衰患者的心功能、生活质量指数以及生存率方面均有明显的改善作用,具体机制仍然不是十分明确,可能与他汀类药物可以抑制炎症反应、抗心肌重构以及对神经体液调节等作用相关。但是长期应用他汀类药物具有不可避免地副作用,例如,胃肠道刺激、肝功能影响、高血糖以及肌病等。
维拉佐酮(商品名Vlibryd)是首个吲哚烷基胺类新型抗抑郁药,其中文化学名称为5-[4-[4-(5-氰基-1H-吲哚-3-基)丁基]-1-哌嗪基]-2-苯并呋喃草酰胺盐酸盐。目前其作用机制尚不明确,有研究认为其属于5-羟色胺IA(5-HT1A)部分激动剂而发挥抗抑郁作用,但也有研究表明其在CNS中通过选择性抑制5-HT再摄取位点,通过优化突触前和突出后位点5-HT的调节来加强5-HT的传递从而发挥抗抑郁作用。目前没有关于维拉佐酮在心血管疾病中应用的相关报道。
发明内容
本发明的第一方面在于提供一种治疗心衰的药物组合物,其由维拉佐酮和他汀类药物组成。
在一个实施方案中,所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.01-0.2∶1。
在另一个实施方案中,所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.05-0.1∶1。
在进一步地实施方案中,所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.06∶1。
在又一个实施方案中,所述他汀类药物选自:阿托伐他汀、瑞舒伐他汀、辛伐他汀、匹伐他汀、氟伐他汀、普伐他汀、罗苏伐他汀、洛伐他汀、柏伐他汀、克伐他汀、达伐他汀、格仑伐他汀、美伐他汀、替伐他汀、或其药学上可接受的盐;具体地说,更佳地选自:阿托伐他汀、辛伐他汀、洛伐他汀、或其药学上可接受的盐。
在更进一步地实施方案中,所述药物组合物由维拉佐酮、他汀类药物和依诺昔酮组成。具体地说,维拉佐酮、他汀类药物和依诺昔酮的重量比为0.01-0.2∶1∶0.005-0.1;优选为0.06∶1∶0.01。
本发明的第二方面在于提供一种包含所述药物组合物的制剂,其由所述药物组合物和药学上可接受的辅料制备而成。
在一个实施方案中,所述药物制剂为口服制剂,所述辅料选自淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖、硬脂酸镁、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙母、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮、碳酸氢钠、枸橼酸、酒石酸、低取代羟丙基纤维素、金合欢胶、琼脂和藻酸中的一种或多种。
本发明的第三方面是提供所述药物组合物在制备治疗心衰药物中的应用。
上述所述的医药用途中,根据动物病情以及用药部位可以将上述药物组合物制备成合适的药物制剂以方便用药,对于所述药物组合物的给药时间和给药次数需要根据病情的具体诊断结果而定,这在本领域技术人员掌握的技术范围之内。例如,将对大鼠心衰模型的治疗方案应用于人身上,所有药物对人的有效剂量可以通过该药物对大鼠的有效剂量进行换算,这对于本领域的普通技术人员来说是显而易见的。
本发明在体内和体外试验中发现,维拉佐酮和他汀类药物在心衰治疗方面表现出明显的协同作用;在提高疗效的同时还可以有效降低他汀类药物的剂量,从而减少其副作用对患者的伤害。
具体实施方式
下面将结合举例详细说明本发明。需要指出的是,以下说明仅仅是对本发明要求保护的技术方案的举例说明,并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
实施例1药物组合物对H9C2心肌细胞的保护作用
将H9C2心肌细胞用DMEM培养基(含10%的FBS)置于孵箱(37℃,5%CO2)中进行培养,待细胞融合至80%左右进行传代,收获的心肌细胞按5000个/孔铺于24孔板中,用DMEM培养基(含10%的FBS)培养2天后,换无血清DMEM培养基后进行以下试验:
(1)药物组合物对阿霉素诱导的心肌细胞凋亡的影响
将各孔细胞随机分组,具体分为对照组、模型组以及各给药组(每组5孔),模型组和各给药组细胞添加终浓度为10-7mol/L的阿霉素;对照组添加等量无血清培养基。孵育6h后,各给药组添加不同剂量的药物,对照组和模型组添加等量无血清培养基,再孵育18h后,分别收集各孔细胞,采用Annexin V/PT试剂盒进行标记,上流式细胞仪进行检测各组细胞的凋亡率(Annexin V阳性并且PT阴性)。
具体结果如下:
**表示与模型组以及单味药组相比,P<0.01(one-way ANOVA)
(2)药物组合物对LPS(脂多糖)诱导的心肌细胞炎症损伤的影响
分组及给药方案及检测方法同(1),区别在于将阿霉素替换为LPS,LPS剂量为100ng/ml,具体结果如下:
**表示与模型组以及单味药组相比,P<0.01(one-way ANOVA)
实施例2药物组合物对LAD结扎心衰大鼠模型的影响
模型制备:雄性SD大鼠,体重250±50g,每组10只。1%戊巴比妥钠(50mg/kg)腹腔注射麻醉,将大鼠仰位固定于自制鼠板上。行气管插管,小动物呼吸机室内空气通气,频率70次/min,潮气量7-8ml。持续监测心电图变化。胸部剪毛、备皮,将心电图电极针埋在左下肢及右上肢皮下,沿左侧第4肋间剪开皮肤,皮下组织、胸前肌肉及筋膜,于左侧剪断第四肋,用血管钳沿第四肋钝性分离肋间肌3cm长,打开胸腔,撑开肋骨,用左手拇指及四指将心脏挤出胸腔。在左心耳与肺动脉圆锥之间找到与左冠状动脉伴行的心大静脉,在左心耳下方2mm处用眼科针6-0丝线穿线,进针深度约1-1.5mm,宽约2-3mm,结扎冠状动脉左前降支(假手术组只穿线不结扎)。结扎后把心脏迅速放回胸腔。心电图显示ST段显著抬高或异常Q波时;即表明急性心肌缺血造模成功。迅速缝合胸壁,停止人工呼吸,清除呼吸道分泌物,缝合关闭气;结扎10min心电图ST段没有变化者淘汰。
术后常规喂养大鼠2周后开始给药,各药物组合物组灌胃给药,假手术组和模型组给予等量生理盐水(含i%CMC-Na),给药6周后采用彩色超声多普勒心动图测定各组大鼠的左室收缩末期容积(ESV)、左室舒张末期容积(EDV)、左室射血分数(LVEF)和左室每搏输出量(SV);然后处死大鼠取血及心肌组织进行相关测定。
各给药组给药方案如下:
维拉佐酮 | 辛伐他汀 | 依诺昔酮 | |
给药组1 | 15mg/kg | - | - |
给药组2 | - | 15mg/kg | - |
给药组3 | - | - | 15mg/kg |
给药组4 | 0.85mg/kg | 14.15mg/kg | - |
给药组5 | 0.86mg/kg | 14mg/kg | 0.14mg/kg |
具体结果如下:
1)对心衰大鼠心功能的影响
*或**为药物组与模型组相比,P<0.05或0.01,##与假手术组相比,P<0.01,one-way ANOVA
2)对大鼠心肌组织中MMP-2和MMP-9蛋白含量的影响,取各组大鼠左室心肌组织,固定、包埋和切片,免疫组化法进行测定,采用多功能彩色图像分析系统进行图像分析,每只大鼠观察六片,测定平均灰度值,结果如下:
平均灰度值 | MMP-2 | MMP-9 |
假手术组 | 197.4±8.2 | 184.3±8.6 |
模型组 | ||
给药组1 | 109.3±9.1 | 121.4±8.1 |
给药组2 | ||
给药组3 | 99.4±8.3 | 101.9±9.1 |
给药组4 | ||
给药组5 |
实施例3药物组合物对慢性心衰大鼠模型的影响
模型制备:取雄性SD大鼠,体重250±50g,每组10只。1%戊巴比妥麻醉,大鼠腹部切口,在右肾动脉及左肾动脉上方放置动脉夹,使大鼠腹主动脉截面积缩窄为原来的50-60%,存活大鼠置动物笼中饲养,假手术组只手术而不放置动脉夹。
术后常规喂养大鼠12周后开始给药,各药物组合物组灌胃给药,假手术组和模型组给予等量生理盐水(含1%CMC-Na),给药4周后对大鼠进行相关检测。
各给药组给药方案如下:
(1)各组大鼠的血流动力学指标检测
给药结束后,将大鼠麻醉,分离右侧颈总动脉,以肝素生理盐水充盈插管,连接生物医学信号采集处理系统,将插管逆行送入左心室记录其左心室收缩压(LVSP,mmHg)、左室舒张末期压(LVEDP,mmHg)、左室内压最大上升速率(+dp/dt,mmHg/s)和左室内压最大下降速率(-dp/dt,mmHg/s),具体结果如下:
LVSP | LVEDP | +dp/dt | -dp/dt | |
假手术组 | 137.2±12.4 | 1.0±0.8 | 4532±517 | 4213±494 |
模型组 | ||||
给药组1 | 95.6±11.7 | 12.9±3.9 | 2257±458 | 2394±482 |
给药组2 | 101.4±12.1 | 11.2±3.4 | ||
给药组3 | 90.7±11.3 | 14.6±3.6 | 2012±387 | 2204±433 |
给药组4 | ||||
给药组5 |
(2)形态学指标
测定血液动力学指标后,处死大鼠,称大鼠体重,并取大鼠心脏称重,计算心体比(即心脏重量与体重比),具体结果如下:
需要指出的是,在实施例1-3的试验中,本发明对5-HT相关药物进行了相同试验,结果发现5-HT再摄取抑制剂氯西汀或5-HT受体激动剂苄非哌胺在和辛伐他汀联用的效果(氯西汀或苄非哌胺与辛伐他汀的重量比为0.06∶1)没表现出明显的协同效果,联用药物组活性与等剂量辛伐他汀的活性相当。同样,在5-HT再摄取抑制剂氯西汀或5-HT受体激动剂苄非哌胺和辛伐他汀以及依诺昔酮的联合应用的试验中,没有发现三者之间的协同作用效果,活性与等剂量辛伐他汀组相当或者降低。
本发明内容仅仅举例说明了要求保护的一些具体实施方案,其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合,这些经组合而得到的技术方案也在本申请保护范围内,就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (9)
1.一种治疗心衰的药物组合物,其由维拉佐酮和他汀类药物组成。
2.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.01-0.2∶1。
3.根据权利要求2所述的药物组合物,其特征在于,所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.05-0.1∶1。
4.根据权利要求2所述的药物组合物,其特征在于,所述药物组合物中,维拉佐酮和他汀类药物的重量比为0.06∶1。
5.根据权利要求1所述的药物组合物,其特征在于,所述他汀类药物选自:阿托伐他汀、瑞舒伐他汀、辛伐他汀、匹伐他汀、氟伐他汀、普伐他汀、罗苏伐他汀、洛伐他汀、柏伐他汀、克伐他汀、达伐他汀、格仑伐他汀、美伐他汀、替伐他汀、或其药学上可接受的盐;具体地说,更佳地选自:阿托伐他汀、辛伐他汀、洛伐他汀、或其药学上可接受的盐。
6.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物由维拉佐酮、他汀类药物和依诺昔酮组成。具体地说,维拉佐酮、他汀类药物和依诺昔酮的重量比为0.01-0.2∶1∶0.005-0.1;优选为0.06∶1∶0.01。
7.一种包含权利要求1-6任一项所述药物组合物的制剂,其由所述药物组合物和药学上可接受的辅料制备而成。
8.根据权利要求7所述的药物制剂,其特征在于,所述药物制剂为口服制剂,所述辅料选自淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖、硬脂酸镁、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙母、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮、碳酸氢钠、枸橼酸、酒石酸、低取代羟丙基纤维素、金合欢胶、琼脂和藻酸中的一种或多种。
9.权利要求1-6任一项所述的药物组合物在制备治疗心衰药物中的应用。
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