CN115243774B - 含氨氯地平、氯噻酮和阿米洛利的药物组合物 - Google Patents
含氨氯地平、氯噻酮和阿米洛利的药物组合物 Download PDFInfo
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- CN115243774B CN115243774B CN202080003993.1A CN202080003993A CN115243774B CN 115243774 B CN115243774 B CN 115243774B CN 202080003993 A CN202080003993 A CN 202080003993A CN 115243774 B CN115243774 B CN 115243774B
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Abstract
本发明提供一种治疗难治性高血压的药物组合物,由氨氯地平、氯噻酮和阿米洛利组成。本发明提供的药物组合物针对难治性高血压患者,尤其是低肾素/低醛固酮型的难治性高血压患者提供一种有效的降压药物,同时本发明提供的药物组合物还可加强对难治性高血压患者靶器官的保护作用,降低脑血管事件危险性。
Description
技术领域
本发明提供一种治疗难治性高血压的药物组合物,由氨氯地平、氯噻酮和阿米洛利组成。属于药学领域。
背景技术
难治性高血压(resistant hypertension,RH)约占全部高血压患者的15-20%。在改善生活方式的基础上,联合应用了合理且足量3种降压药物(包括利尿剂)治疗一定时间(≥1个月)后血压仍未达标,或服用≥4种降压药物血压才能有效控制,称为RH【难治性高血压诊断治疗中国专家共识,中华高血压杂志,2013,21(4),321-326】。RH的病因及病理生理学机制是多方面的。有基本病因,也有中枢及局部的神经体液机制等。高盐摄入、肥胖、颈动脉压力反射功能减退是高血压患者血压难以控制的基本原因。在此基础上,循环和组织中的肾素血管紧张素醛固酮系统(rennin-angiotensin-aldosterone system,RAAS)的激活以及中枢或局部组织(特别是肾脏)交感神经活性的过度增高会启动炎症因子、氧化应激过程并促发动脉硬化和动脉粥样硬化的发生和进展,加重了血管结构和功能的异常,从而使增高的血压难以获得控制。RH不仅具有降低血压的“难治性”特点,而且更加容易合并靶器官损害,增加心、脑血管和肾脏疾病患病率。Daugherty等进行了一项大规模的临床试验,经过3.8年的随访,发现1972例(11%)患者发展为慢性肾脏疾病,344例患者死亡,234例发生心脑血管事件(90例发生非致死性心肌梗死、91例发生脑卒中、53例发生充血性心力衰竭)【Daugherty SL,Powers JD,Magid DJ,et al.Incidence and prog-nosis of resistanthypertension in hypertensive patients.Circulation,2012,125(13):1635-1642】。
RH的治疗除矫正不良生活方式(例如减重、限盐、适度酒精摄入、增加运动等)外,通常的三药联合方案推荐肾素血管紧张素系统阻断剂(renin-angiotensin systeminhibitor,RASI)[血管紧张素转换酶抑制剂(angio-tensin converting enzymeinhibitor,ACEI)或血管紧张素受体拮抗剂(angiotensin receptor blocker,ARB)])+钙拮抗剂+噻嗪类利尿剂。血压仍不能达标时可以考虑加用螺内酯(需要评估肾功能和潜在高血钾的风险),或联合β受体阻滞剂、αβ受体阻滞剂或α受体阻滞剂。血压仍不能达标时,可乐定、利血平等中枢神经抑制药物可作为联合方案的第五种降压药物的选择。对于RH的治疗,目前尚无针对性药物。RH的治疗药物目前还在研制阶段,国内已经公开的治疗RH的专利中的药物都含有中药成分,例如中国专利申请201710585463.2把灵芝多糖与常规多联疗法的多种抗高血压药物复配,制成一种能够方便服用的复方制剂;中国专利201110086573.7公开一种治疗难治性高血压的中成药,由沙棘、百里香、长春花、赤芝、黑木耳、余甘子根、红景天、萝芙木、葛根、山楂、决明子组成。众所周知,中药作用机理复杂,通常情况下显效缓慢,治疗周期较长,而RH患者如果血压长期处于高位会产生较大危害,与中药治疗特点不符。
目前国内外尚没有任何一个单一降压药或复方降压药物被批准用于RH的治疗。
氨氯地平属于长效二氢吡啶类钙通道阻滞剂,通过阻滞血管平滑肌细胞外钙离子经细胞膜的钙离子通道进入细胞,直接舒张血管平滑肌,扩张外周血管,降低外周阻力,临床用于治疗高血压和心绞痛。与同类药物比较,氨氯地平作用维持时间长、不良反应少且轻,为临床治疗高血压的一线药物。
氯噻酮通过抑制肾脏远曲小管始端的Na+-Cl-同向转运体,减少Na+、Cl-和水的重吸收,通过排泄体内过多的钠和水,减少细胞外液容量而达到消肿。导致水肿的原因有充血性心力衰竭、急性肺气肿、肝脏病腹水、肾病综合征、急慢性肾炎等,氯噻酮是治疗这些疾病的辅助药物。在降压方面氯噻酮主要用于治疗轻、中度高血压、老年高血压并发心力衰竭等疾病。
阿米洛利是一种作用于远端肾小管和集合管的保钾利尿药,阻碍钠通道,抑制Na+-H+和Na+-K+交换,促使钠、氯排泄而减少K+、H+分泌,其本身促尿钠排泄和抗高血压活性较弱,适用于慢性充血性心力衰竭、肝硬化伴随腹水、原发性醛固酮症所致的低血钾。
现有降压复方药物主要是针对高血压,而非是RH。目前国内外市场上由三种抗高血压药组成的复方产品有氨氯地平缬沙坦氢氯噻嗪、氨氯地平替米沙坦氢氯噻嗪等,其适应症为原发性高血压,不用于高血压的初始治疗。在研阶段的复方或联合用药也较多,例如,中国专利201010116867.5公开了一种用于治疗高血压的含有左旋氨氯地平的复方药物组合物,其包括左旋氨氯地平或其药学上可接受的盐,以及氯噻酮。俞俊柯报道使用苯磺酸氨氯地平联合复方阿米洛利治疗高血压能有效地降低患者的血压(苯磺酸氨氯地平联合复方阿米洛利治疗高血压的效果分析,当代医药论丛,2018年18期,148-149)。Fuchs SandraCosta公开小剂量氯噻酮和阿米洛利合用能有效降低易于被诱发的高血压患者发生风险(Effectiveness of Chlorthalidone Plus Amiloride for the Prevention ofHypertension:The PREVER-Prevention Randomized Clinical Trial.J Am HeartAssoc.2016;5:e004248)。上述无论是单药还是复方都是用来治疗高血压的,无治疗RH的作用。为RH患者提供一种有效且经济的治疗药物已经成为科研工作的研发目标。
发明内容
在精准医学发展趋势下,应对RH患者进行个体化分析,将肾素、醛固酮视为生物标记物,测量它们在RH患者体内的血浆浓度,根据两者的高低不同,可对RH进行病理生理分型,从而使临床用药更具有针对性。根据血浆肾素和醛固酮水平,可将RH患者分为低肾素/高醛固酮、低肾素/低醛固酮和高肾素/高醛固酮等类型。
本发明的目的是针对RH,尤其是低肾素/低醛固酮型RH患者提供一种疗效显著的药物组合物。
为实现上述目的,本发明采用以下技术方案:
一种用于RH的药物组合物,组成成分为
(1)2.5-10mg的氨氯地平;
(2)12.5-100mg的氯噻酮;
(3)2.5-20mg的阿米洛利;
(4)药剂学上可接受的载体。
在本发明提供的药物组合物中,氨氯地平可以以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的氨氯地平作为药物成分,氨氯地平的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请保护的范围内。在本发明中,氨氯地平的药用剂量选自2.5-10mg,优选5-10mg。氨氯地平的盐类、酯类、活性代谢产物或药用前体等存在形式的药用剂量可以进行相应换算。
在本发明提供的药物组合物中,氯噻酮可以以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的氯噻酮作为药物成分,氯噻酮的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请保护的范围内。在本发明中,氯噻酮的药用剂量选自12.5-100mg,优选12.5-50mg。氯噻酮的盐类、酯类、活性代谢产物或药用前体等存在形式的药用剂量可以进行相换算。
在本发明提供的药物组合物中,阿米洛利可以盐类、酯类、活性代谢产物或药用前体等形式存在。本发明提供的阿米洛利作为药物成分,阿米洛利的盐类、酯类、活性代谢产物或药用前体等存在形式也在本申请保护的范围内。在本发明中,阿米洛利的药用剂量选自2.5-20mg,优选5-10mg。阿米洛利的盐类、酯类、活性代谢产物或药用前体等形式存在的药用剂量可以进行相互换算。
在本发明中,组合物有效成分的药用剂量是指该药效成分在该组合物中与其他药效成分组合后使组合物发挥药效的剂量范围。优选剂量是组合物有效成分的药用剂量的优选,优选剂量的药效比药用剂量的药效效果好。通常组合物有效成分的药用剂量包括使组合物产生最大药效的最佳剂量或最佳剂量范围,此最佳剂量或最佳剂量范围将使患者更多获益。
作为一种优选,本发明提供的药物组合物的组成是5mg氨氯地平、12.5mg氯噻酮和5mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是5mg氨氯地平、12.5mg氯噻酮和10mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是5mg氨氯地平、25mg氯噻酮和5mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是5mg氨氯地平、25mg氯噻酮和10mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是5mg氨氯地平、50mg氯噻酮和10mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是10mg氨氯地平、12.5mg氯噻酮和5mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是10mg氨氯地平、12.5mg氯噻酮和10mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是10mg氨氯地平、25mg氯噻酮和5mg阿米洛利。
作为另一种优选,本发明提供的药物组合物的组成是10mg氨氯地平、25mg氯噻酮和10mg阿米洛利。
该药物组合物中还含有药剂学可接受的载体,可制成普通口服制剂,包括普通片剂、普通胶囊、颗粒剂等,制成片剂时所述可药用载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅药,如微晶纤维素、无机盐类、乳糖、氯化钠、柠檬酸和亚硫酸钠等的一种或几种物质的组合物,属于本领域常识。
本发明提供的药物组合物针对RH患者,尤其是低肾素/低醛固酮型RH患者提供一种有效的降压药物。本发明提供的药物组合物的药用有效成分为氨氯地平、氯噻酮和阿米洛利,该组合物治疗RH降压迅速、疗效显著,尤其适用于低肾素/低醛固酮型RH患者。氨氯地平、氯噻酮和阿米洛利均为常用的降压药,如背景技术所述,上述药物单用或药物两两联用或与其他降压药物的联用亦可用于高血压的治疗,但是目前尚无治疗RH的药效。氨氯地平、氯噻酮和阿米洛利组合后治疗RH药效显著,非单药或两两联用所能发挥的。其次,本发明提供的药物组合物降压作用持续时间长,患者服用后全天血压波动小,每天用药一次,即可达到24小时平稳降压。
此外本发明提供的药物组合物还可加强对RH患者靶器官的保护作用,同时降低心脑血管事件危险性。RH引起的靶器官损害,包括左室肥厚、良性小动脉性肾硬化症、恶性小动脉性肾硬化症、肾功能衰竭、视网膜动脉硬化、或高血压眼底病变等。当上述这些损害不能得到有效控制,会导致脑血管事件包括脑梗塞和脑出血的发生,即脑卒中。本发明提供的药物组合物不仅强效降压而且24小时平稳降压,患者服药后全天血压波动小,降低了血压升高和血压急速波动对重要脏器的损害。其次,RH容易诱发血管重塑和内皮功能异常,以及交感神经和肾素-血管紧张素系统过度激活、代谢异常及炎症反应,本发明提供的药物组合物三种药效成分发挥各自作用机制,显著协同改善血压升高导致的这些非血流动力学改变,从而有效保护RH患者靶器官。
应当理解本发明提供的药物含量不是对本发明的限制,而是对本发明的优选,通常情况下,在该含量范围内,该药物能够对患病个体产生有效的治疗效果。患病个体是指患有疾病的独立存在的生命体,在本发明中,生命体尤指人类。应当理解,现有技术中,人类药用含量或药用含量范围可与哺乳动物,例如大鼠、小鼠等,进行换算以得出适合相应动物适用的药用含量或含量范围。
下面结合具体实施方式对本发明做进一步说明,并非对本发明的限定,凡依照本发明内容进行的任何本领域的等同替换,均属于本发明的保护范围。
具体实施方式
实施例1-实施例11制备氨氯地平、氯噻酮和阿米洛利片(1000片)
制备工艺:
将氨氯地平、氯噻酮和阿米洛利混合,加入羧甲淀粉钠、十二烷基硫酸钠混合,再加入微晶纤维素、预胶化淀粉混合均匀,用适量的10%聚维酮乙醇溶液制成软材,制粒、干燥、整粒,将含水量为3%左右的颗粒与适量的硬脂酸镁混合均匀,压片制成1000片即得。
实施例12:制备氨氯地平、氯噻酮和阿米洛利胶囊(1000粒)
配方组成:
制备工艺:
按照处方配比,取乳糖、微晶纤维素、羧甲淀粉钠于100℃左右分别干燥约2小时,羧甲淀粉钠过100目筛,乳糖、微晶纤维素过80目筛;将原料药过100目筛后与上述辅料混合物按混合均匀,制粒,再与适量的山愈酸甘油脂混合均匀,用3号胶囊灌装。制成1000粒即得。
实施例13:制备氨氯地平、氯噻酮和阿米洛利胶囊(1000粒)
配方组成:
制备工艺同实施例12。
实施例14:氨氯地平/氯噻酮/阿米洛利复方制剂对DOCA盐高血压大鼠的降血压及靶器官保护作用
动物模型制备:SD大鼠94只,体重200-220g,雄性,普通日粮饲料喂养,检疫7天后,检测基础血压,随机选择10只大鼠作为假手术组,采用普通饲料继续喂养至实验结束。其余84只大鼠作为模型组,皮下埋植DOCA硅胶管(100mg/只)。模型组大鼠0.8%戊巴比妥钠腹腔注射麻醉,先进行左侧肾脏摘除手术,背位固定,腹部左侧右侧均剪毛,常规消毒,切开左侧腹腔,长约3cm,找到左肾,先对肾动静脉进行结扎,注意不要过于靠近肾门,留出剪切的位置,然后摘除左肾,在腹腔洒入0.2ml青霉素,再逐层缝合,腹腔注射青霉素钠10万单位/只,每日1次,连续2天,右侧腹部剪开表皮,皮下埋植制作好的DOCA硅胶管,再进行缝合(葛顺娜等,DOCA-salt高血压大鼠模型的建立.中国药理学通报,2010;26(6):832-835)。术后进行常规饲养,同时饲1%盐水。假手术组大鼠前期麻醉、切开腹腔、找出左肾操作均同模型组,但不进行结扎与摘除左肾操作,直接洒入青霉素后进行缝合,右侧腹部埋入不含药粉的硅胶管,之后2天也进行青霉素抗感染注射,正常饮水。造模第2周、第4周测定大鼠血压(取测量稳定后,连续3次平均值),验证造模成功与否。
分组及给药:造模4周后进行血压测量,血压稳定在140mmHg以上者为造模成功,将造模成功的大鼠70只,根据血压情况进行分层随机分成模型组和给药组,每组10只,给药体积为1ml/100g体重,每天1次,连续给药13周。对照药物采用氨氯地平缬沙坦氢氯噻嗪片,二联药物采用原料药组合、供试药物采用上述实施例5,11中所制备的复方制剂,按照体表面积换算成大鼠所需剂量。
检测指标:(1)造模结束,检测分组后给药前大鼠血清肾素、醛固酮水平;(2)血压测定给药前和给药4周、给药8周、给药13周血压测定;(3)肾功能指标:尿蛋白、微量白蛋白、肌酐清除率、尿素氮;(4)心功能:左室指数、心脏指数、脑钠肽水平。结果:
(1)模型大鼠血清醛固酮(ALD)和肾素(REN)水平DOCA盐所造成的内分泌型高血压模型,相较与假手术组,模型组大鼠醛固酮水平降低及肾素水平降低(P<0.01)。见表1。
表1各组大鼠给药前ALD和REN水平
与假手术组比较,#P<0.05,##P<0.01
(2)氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠血压的影响各给药周期,与假手术组比较,模型组血压显著升高;与模型组比较,氨氯地平缬沙坦氢氯噻嗪片组、氨氯地平氯噻酮阿米洛利片不同剂量组、氨氯地平+氯噻酮组、氨氯地平+阿米洛利组及氯噻酮+阿米洛利组血压均下降,且与模型组相比具有统计学差异;相较对照药氨氯地平缬沙坦氢氯噻嗪片组,低剂量的氨氯地平氯噻酮阿米洛利片组血压可进一步降低6.8-11.4mmHg,高剂量的复方降压效果显著增强(P<0.05),与两两组合的二联药物相比,三联药物组可以更好地降低血压,进一步的降压幅度10.9-24.2mgHg。
见表2-1.表2-2。
表2-1氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠血压影响
与假手术组比较,#P<0.05,##P<0.01;与模型组比较*P<0.05,**P<0.01;三联复方药物与氨氯地平缬沙坦氢氯噻嗪片组比较,■P<0.05,■■P<0.01,与氨氯地平+氯噻酮组比较△P<0.05,△△P<0.01,与氨氯地平+阿米洛利组比较▲P<0.05,▲▲P<0.01,与氯噻酮+阿米洛利组比较★P<0.05,★★P<0.01
表2-2氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠血压影响
与假手术组比较,#P<0.05,##P<0.01;与模型组比较*P<0.05,**P<0.01;三联复方药物与氨氯地平缬沙坦氢氯噻嗪片组比较,■P<0.05,■■P<0.01,与氨氯地平+氯噻酮组比较△P<0.05,△△P<0.01,与氨氯地平+阿米洛利组比较▲P<0.05,▲▲P<0.01,与氯噻酮+阿米洛利组比较★P<0.05,★★P<0.01
(3)氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠肾功能的影响给药13周后,收集大鼠24h尿液进行尿蛋白及尿微量白蛋白(MALB)检测,模型组大鼠24h尿蛋白及MALB均显著高于假手术组,差异具有显著性,与模型组相比,氨氯地平氯噻酮阿米洛利片组24h尿蛋白及MALB下降(P<0.01)。与氨氯地平缬沙坦氢氯噻嗪片组及各二联药物组合比较,本复方制剂对此模型动物的肾功能改善效果明显增强。
模型肌酐清除率下降、尿素氮水平明显上升,与假手术组具有显著性差异,氨氯地平氯噻酮阿米洛利片给药组肌酐清除率上升、尿素氮下降,且三联药物组合效果优于氨氯地平缬沙坦氢氯噻嗪片组(P<0.05,P<0.01),与二联药物组合相比,三联药物可以进一步改善肾功能,表明复方制剂给药组对肾脏有保护作用明显。
见表3-1,3-2。
表3-1氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠肾功能的影响
与假手术组比较,#P<0.05,##P<0.01;与模型组比较*P<0.05,**P<0.01;三联复方药物,与氨氯地平缬沙坦氢氯噻嗪片组比较,■P<0.05,■■P<0.01,与氨氯地平+氯噻酮组比较△P<0.05,△△P<0.01;与氨氯地平+阿米洛利组比较▲P<0.05,▲▲P<0.01,与氯噻酮+阿米洛利组比较▲P<0.05,★★P<0.01
表3-2氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠肾功能的影响
与假手术组比较,#P<0.05,##P<0.01;与模型组比较*P<0.05,**P<0.01;三联复方药物与氨氯地平缬沙坦氢氯噻嗪片组比较,■P<0.05,■■P<0.01,与氨氯地平+氯噻酮组比较△P<0.05,△△P<0.01,与氨氯地平+阿米洛利组比较▲P<0.05,▲▲P<0.01,与氯噻酮+阿米洛利组比较★P<0.05,★★P<0.01
(4)氨氯地平/氯噻酮/阿米洛利复方制剂对大鼠心脏保护作用脑钠肽(BNP)基因是一种心脏急性期反应基因,在心肌缺血和心室壁应力增加时可刺激脑钠肽的合成和释放。给药13周后,动物处死取血检测血浆脑钠肽水平,取心脏进行称量,并分离左心室称量,计算各组大鼠左心室指数((左心室/心脏重量*1000)/体重)。与假手术组比较,模型组大鼠左心室指数显著升高,表明存在左心室肥大,氨氯地平缬沙坦氢氯噻嗪片有一定改善作用,但效果不如氨氯地平氯噻酮阿米洛利片给药组(P<0.05)。模型组BNP明显升高,提示存在心脏急性期反应,氨氯地平氯噻酮阿米洛利片给药组BNP明显降低(P<0.01),与二联药物组合比较,对心脏保护作用更明显。见表4。
表4氨氯地平/氯噻酮/阿米洛利复方制剂给药对大鼠心脏功能的影响
与假手术组比较,#P<0.05,##P<0.01;与模型组比较*P<0.05,**P<0.01;三联复方药物与氨氯地平缬沙坦氢氯噻嗪片组比较,■P<0.05,■■P<0.01,与氨氯地平+氯噻酮组比较△P<0.05,△△P<0.01,与氨氯地平+阿米洛利组比较▲P<0.05,▲▲P<0.01,与氯噻酮+阿米洛利组比较★P<0.05,★★P<0.01
(5)实验过程中卒中情况
模型组4号动物在给药8周后,出现站立不稳,头部偏向一侧,单独观察一周后死亡,该动物8周测量血压为191mmHg;模型组2号在给药11周时,出现偏瘫、站立不稳,头歪向一侧,旋转步态等表现,并在本周内死亡,该动物8周测定血压为205mmHg。氨氯地平缬沙坦氢氯噻嗪片组5号大鼠在给药8周测压时死亡,前期发现其出现拉稀、站立不稳等症状,其给药4周时所测血压为213mmHg,氯噻酮+阿米洛利组1号大鼠在给药3周时出现偏瘫、站立不稳的情况,根据死亡前动物症状表现,初步认为是卒中死亡。其余各组动物无死亡。
实施例15:氨氯地平/氯噻酮/阿米洛利对DOCA盐高血压大鼠的协同降血压作用
模型制备方法、给药换算同实施例14。动物分组见表5,每组10只,灌胃给药,每天1次,连续给药4周,末次给药后2~4小时测定大鼠收缩压。
金正均Q值法又称概率相加法,根据在量效曲线区内,两种药物联用的药理作用及两种药物单用的药理作用,用如下公式计算Q=EA+B/(EA+EB-EA×EB),式中分子代表“实测合并效应”,分母代表“期望合并效应”,Q为两者之比。Q值<0.85时认为两种药物联用为拮抗作用,0.85<Q值<1.15时认为是相加作用,Q值>1.15时认为是协同作用。为满足药理作用关系的分析,将血压值转化为可以直观体现药理作用强弱的效应,计算公式:Ei=(1-Pi/P模型组)×100%,Pi为各组的血压值,P模型组为模型组的血压值。结果见表5。
与三种二联+单药组合比较,氨氯地平/氯噻酮/阿米洛利联合用药组对DOCA盐高血压大鼠收缩压影响的Q值分别为1.257、1.203、1.295,均>1.15,说明本发明的药物组合物相互之间是协同作用,三种药物配伍合理,可增强药物对DOCA盐高血压大鼠的降压作用。
与三种二联+单药组合比较,氨氯地平/氢氯噻嗪/阿米洛利联合用药组,对DOCA盐型高血压大鼠收缩压的Q值为1.022、0.920、0.986,0.85<Q值<1.15,说明氨氯地平/氢氯噻嗪/阿米洛利药物组合物相互之间是相加作用。氨氯地平/氢氯噻嗪/螺内酯联合用药组对DOCA盐高血压大鼠收缩压影响的Q值分别为0.956、0.890、0.901,0.85<Q值<1.15,说明氨氯地平/氢氯噻嗪/螺内酯组合物相互之间是相加作用。氨氯地平/缬沙坦/氢氯噻嗪联合用药组对DOCA盐高血压大鼠收缩压影响的Q值分别为0.939、1.010、0.975,0.85<Q值<1.15,说明氨氯地平/缬沙坦/氢氯噻嗪组合物相互之间是相加作用。
与两种二联+单药组合比较,氨氯地平/氯噻酮/螺内酯联合用药组对DOCA盐高血压大鼠收缩压影响的Q值分别为0.977、0.972,0.85<Q值<1.15,说明氨氯地平/氯噻酮/螺内酯组合物相互之间是相加作用。氨氯地平/缬沙坦/氯噻酮联合用药组对DOCA盐高血压大鼠收缩压影响的Q值分别为0.998、1.022,0.85<Q值<1.15,说明氨氯地平/缬沙坦/氯噻酮组合物相互之间是相加作用。
表5氨氯地平/氯噻酮/阿米洛利对DOCA盐型高血压大鼠的协同降血压作用
实施例16:氨氯地平+氯噻酮+阿米洛利对RH患者降压疗效和安全性临床试验
入选标准:受试者满足如下所有标准,并无排除标准所规定的任何一项者可被入选。
年龄在40~75岁的患者;坚持使用3种或3种以上降压药物(其中一种是利尿剂)一个月以上,坐位血压(3次测量平均值)符合以下标准:舒张压≥90mmHg或收缩压≥140mmHg,且舒张压<110mmHg或收缩压<180mmHg;自愿参加并签署知情同意书。
排除标准:排除符合以下任何一项者。
(1)妊娠和哺乳期妇女;(2)对药物中成分有过敏史者;(3)有明确过敏体质者;(4)白大衣性高血压;(5)服药依从性差者;(6)已知患严重的内科疾病;(7)存在明显的实验室检查或体征异常者,根据研究者的判断,这种异常显示患者存在严重疾病,或根据研究者的判断,有可能影响对药物疗效或不良事件的观察和评价,不适合参加研究者。(8)在第一次访视前4周内曾经参加任何一种尚未得到国家正式批准上市的试验药物者。
将受试者随机分组,平行对照干预,分别于第4周末和第8周末测定患者血压,以收缩压和收缩压均达标(<140/90mmHg)的患者为血压达标,计算达标率。安全性指标包括:血、尿常规,心电图,肝、肾功能,不良事件。
治疗方案:
A组:继续原来的治疗方案;
B组:停用原来的药物,改用氨氯地平/缬沙坦/氢氯噻嗪片(10/160/25mg);
C组:停用原来的药物,改用氨氯地平5-10mg+氯噻酮12.5-50mg+阿米洛利5-10mg
结果:A组绝大多数患者血压不能达标,B组患者血压达标率有所提高,其中第4周差异有显著性。与A组相比,氨氯地平+氯噻酮+阿米洛利治疗组(C组)患者血压达标率显著提高,第4周、第8周差异均有显著性。与B组比较,氨氯地平+氯噻酮+阿米洛利治疗组(C组)患者血压达标率进一步提高,第8周差异均有显著性。见表6。
常见不良事件(发生率>1%)有:上呼吸道症状、疼痛、肝功能异常、胃肠道症状、脂代谢异常、头晕、皮肤瘙痒、泌尿系统症状、心血管症状,口腔症状,糖代谢异常和面部潮红。不良事件的总发生率在A组为22.0%,B组为19.8%,C组为15.6%,以C组不良事件发生率最低。
表6氨氯地平+氯噻酮+阿米洛利治疗RH患者的血压达标率
与A组比较,*P<0.05,**P<0.01;与B组比较,#P<0.05
实施例17:氨氯地平+氯噻酮+阿米洛利对低肾素/低醛固酮型RH患者降压疗效和安全性临床试验
入选标准:受试者满足如下所有标准,并无排除标准所规定的任何一项者可被入选。
年龄在40~75岁的患者;坚持使用3种或3种以上降压药物(其中一种是利尿剂)一个月以上,坐位血压(3次测量平均值)符合以下标准:舒张压≥90mmHg或收缩压≥140mmHg,且舒张压<110mmHg或收缩压<180mmHg;早晨空腹取血测定为低肾素/低固酮的患者;自愿参加并签署知情同意书。
排除标准:排除符合以下任何一项者。
(1)妊娠和哺乳期妇女;(2)对药物中成分有过敏史者;(3)有明确过敏体质者;(4)白大衣性高血压;(5)服药依从性差者;(6)已知患严重的内科疾病;(7)存在明显的实验室检查或体征异常者,而且根据研究者的判断,这种异常显示患者存在严重疾病,或根据研究者的判断,有可能影响对药物疗效或不良事件的观察和评价,不适合参加研究者;(8)在第一次访视前4周内曾经参加任何一种尚未得到国家正式批准上市的试验药物者;(9)早晨空腹取血测定为高肾素型、或者肾素水平正常的患者;(10)早晨空腹取血测定血浆醛固酮水平正常或者升高的患者。
将分型组受试者随机分组,平行对照干预,分别于第4周末和第8周末测定患者血压,以收缩压和舒张压均达标(<140/90mmHg)的患者为血压达标,计算达标率。安全性指标包括:血、尿常规,心电图,肝、肾功能,不良事件。
治疗方案:
A组:继续原来的治疗方案;
B组:停用原来的药物,改用氨氯地平/缬沙坦/氢氯噻嗪片(10/160/25mg);
C组:停用原来的药物,改用氨氯地平5-10mg+氯噻酮12.5-50mg+阿米洛利5-10mg
A组绝大多数患者血压不能达标,B组患者血压达标率有所提高,第4周、第8周差异均有显著性。与A组相比,氨氯地平+氯噻酮+阿米洛利治疗组(C组)患者血压达标率显著提高,第4周、第8周差异均有显著性。与B组比较,氨氯地平+氯噻酮+阿米洛利治疗组(C组)患者血压达标率进一步提高,第4周、第8周差异均有显著性,见表7。
常见不良事件(发生率>1%)有:上呼吸道症状、肝功能异常、胃肠道症状、脂代谢异常、头晕、皮肤瘙痒、泌尿系统症状、心血管症状,糖代谢异常和面部潮红。不良事件的总发生率在A组为25.6%,B组为28.9%,C组为18.9%,以C组不良事件发生率最低。
表7氨氯地平+氯噻酮+阿米洛利对低肾素/低醛固酮型RH患者的血压达标率
与A组比较,*P<0.05,**P<0.01;与B组比较,##P<0.01
Claims (13)
1.一种用于难治性高血压的药物组合物,组成成分为:
(1)5-10mg的氨氯地平;
(2)12.5-50mg的氯噻酮;
(3)5-10mg的阿米洛利;
(4)药剂学上可接受的载体。
2.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是5mg氨氯地平、12.5mg氯噻酮和5mg阿米洛利。
3.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是5mg氨氯地平、12.5mg氯噻酮和10mg阿米洛利。
4.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是5mg氨氯地平、25mg氯噻酮和5mg阿米洛利。
5.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是5mg氨氯地平、25mg氯噻酮和10mg阿米洛利。
6.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是5mg氨氯地平、50mg氯噻酮和10mg阿米洛利。
7.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是10mg氨氯地平、12.5mg氯噻酮和5mg阿米洛利。
8.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是10mg氨氯地平、12.5mg氯噻酮和10mg阿米洛利。
9.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是10mg氨氯地平、25mg氯噻酮和5mg阿米洛利。
10.根据权利要求1所述的药物组合物,其特征在于药物组合物的组成是10mg氨氯地平、25mg氯噻酮和10mg阿米洛利。
11.根据权利要求1所述的药物组合物,其特征在于所述的药物组合物制成口服制剂。
12.权利要求1所述的药物组合物在制备治疗难治性高血压的药物中的用途。
13.根据权利要求12所述的用途,其特征在于所述的难治性高血压是低肾素/低醛固酮型。
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