CN115605199A - 包含大脑氨肽酶抑制剂、利尿剂和全身性肾素-血管紧张素系统阻断剂的药物组合 - Google Patents
包含大脑氨肽酶抑制剂、利尿剂和全身性肾素-血管紧张素系统阻断剂的药物组合 Download PDFInfo
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- CN115605199A CN115605199A CN202180031280.0A CN202180031280A CN115605199A CN 115605199 A CN115605199 A CN 115605199A CN 202180031280 A CN202180031280 A CN 202180031280A CN 115605199 A CN115605199 A CN 115605199A
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- diuretic
- enalapril
- angiotensin
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Abstract
本发明涉及一种药物组合,其包括:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由血管紧张素I转化酶抑制剂(ACEI)与1型血管紧张素II受体(AT1R)拮抗剂组成的组的全身性肾素‑血管紧张素系统阻断剂。所述组合特别适用于治疗高血压和相关疾病与病状。
Description
技术领域
本发明涉及一种药物组合,其包括:(i)(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)或其药学上可接受的盐或溶剂化物;(ii)利尿剂;以及(iii)选自由血管紧张素I转化酶抑制剂(ACEI)与1型血管紧张素II受体(AT1R)拮抗剂组成的组的全身性肾素-血管紧张素系统阻断剂,以及用于治疗高血压和相关疾病与病状的方法。
背景技术
动脉高血压(Arterial hypertension,HTN)是一个全球性的公共卫生问题。根据世界卫生组织的统计数据(世界卫生组织2013,全球高血压简报:无声杀手,全球公共卫生危机,世界卫生日(World Health Organization 2013.A global brief onhypertension:Silent killer,global public health crisis.World Health Day)),全世界三分之一的成年人患有高血压(blood pressure,BP),且HTN的患病率正在急剧上升。从现在至2025年,高血压成年人的数量可能会增加至60%,达到15.6亿。
HTN是冠状动脉心脏疾病、心脏衰竭、中风以及肾功能不全的主要危险因素之一。其被认为是大约一半的中风和心脏病的原因。有效的BP管理已被证明是降低心血管风险和减少中风、心脏病发作和心脏衰竭发生率的最佳决定因素。对于大多数收缩BP≥140mmHg或舒张BP≥90mmHg的成人,推荐使用抗高血压药物。但是,尽管高BP与心血管发病率和死亡率之间的流行病学关联是众所周知的,尽管有足够的证据证明抗高血压治疗是合理的,且有超过75种抗高血压剂分布在多达9个不同的类别中,但BP往往没有得到充分控制。事实上,大约三分之二被诊断患有HTN的患者BP没有得到控制(<140/90mmHg)(Benjamin EJ等人,心脏病和中风统计-2018年更新:美国心脏协会的报告(Heart Disease and StrokeStatistics-2018update:a report from the American Heart Association).Circulation.2018;137:e67–e492),在低收入和中等收入的国家,超过70%接受治疗的HTN患者BP不受控制。
不受控制的HTN在肥胖患者、非洲血统患者以及其他少数民族患者,以及患有糖尿病或肾功能不全的患者中更为常见,在这些患者中,高BP与低肾素水平相关。全世界大约20%的高血压人群符合明显难治性HTN的标准(尽管同时使用了包括利尿剂在内的3种不同类别足够剂量的抗高血压药物,但BP仍高于目标水平,或者在同时服用包括利尿剂在内的至少4不同的类别的抗高血压药物时BP低于目标水平)(Carey RM等人,难治性高血压:检测、评估和管理:美国心脏协会的科学声明(Resistant hypertension:detection,evaluation,and management:A Scientific Statement from the American HeartAssociation).Hypertension.2018;72:e53–e90)。因此,仍然存在尚未满足的医学需求,即通过替代途径开发新的、有效且安全的抗高血压药物类别,并探索新的药物关联以进一步改善患者的BP控制并降低相关的心血管风险。
HTN是一种动脉病症,其原因通常仍然未知。其是一种多因素和多基因病症,其中各种机制或多或少地导致血压升高。可能参与的外在因素包括肥胖、久坐不动的生活方式、过量的酒精或盐摄入以及压力。提出发挥作用的内在因素包括液体潴留、交感神经系统活动和血管收缩。通过不同的作用机制作用于这些内在因素的几类抗高血压剂被广泛用于治疗HTN和相关疾病与病状,那些类别包括噻嗪类利尿剂(thiazide diuretic agent)、β-肾上腺素能阻断剂(“β-阻断剂”)、α/β肾上腺素能阻断剂、非特异性肾上腺素能阻断剂、血管紧张素I转化酶(EC3.4.15.1)抑制剂(ACEI)、1型血管紧张素II受体(AT1R)拮抗剂(或阻断剂[ARB])、钙通道拮抗剂或阻断剂(CCB)、肾素抑制剂以及直接血管扩张剂。每种治疗类别包括非常多的药物,其中下面列出的药物是其类别的代表但并非唯一的成员。
噻嗪类利尿剂包括氯噻嗪(chlorothiazide)、氢氯噻嗪(hydrochlorothiazide)(或HCTZ)、氯噻酮(chlorthalidone)、吲达帕胺(indapamide)、聚噻嗪(polythiazide)以及氢氟噻嗪(hydroflumethiazide)。此类药物通过多种机制降低BP。通过促进钠的流失以降低血量。同时血管壁的压力、周边血管阻力降低。噻嗪类利尿剂常作为减轻轻度HTN的首选药物,常与其他抗高血压药物组合使用。具体而言,氢氯噻嗪和少量氯噻酮与特定ACEI、ARB、β-阻断剂以及其他利尿剂的组合,是目前可用的抗高血压组合药物。
CCB包括氨氯地平(amlodipine)、地尔硫卓(diltiazem)、非洛地平(felodipine)、伊拉地平(isradipine)、尼卡地平(nicardipine)、硝苯地平(nifedipine)、尼索地平(nisoldipine)、维拉帕米(verapamil)。CCB通过阻止钙进入心脏和动脉细胞来降低BP。钙会使心脏和动脉收缩更加剧烈。通过阻断钙,钙通道阻断剂可使血管放松和打开。CCB具有短效和长效两种形式。短效药物起效快速,但其作用仅能持续几个小时。长效药物缓慢释放以提供更持久的效果。CCB也常与其他抗高血压药物或降胆固醇药物(如他汀类药物)组合使用。具体而言,氨氯地平与特定的ACEI和ARB的组合,是目前可用于治疗HTN的组合药物。
ACEI通过抑制血管紧张素II(AngII)的产生而起效,血管紧张素II(AngII)是一种肽物质,通过作用于AT1受体,诱导血管收缩和钠潴留,从而导致水潴留和血量增加。目前市场上有许多ACEI,包括卡托普利(captopril)、雷米普利(ramipril)、喹那普利(quinapril)、依那普利(enalapril)、培哚普利(perindopril)、赖诺普利(lisinopril)、福辛普利(fosinopril)以及贝那普利(benazepril)。这些药物之间的主要区别在于其起效和作用持续时间。
ARB,如洛沙坦(losartan)、坎地沙坦(candesartan)、艾比沙坦(irbesartan)、替米沙坦(telmisartan)、缬沙坦(valsartan)、奥美沙坦(olmesartan)、依普罗沙坦(eprosartan)以及阿齐沙坦(azilsartan),其阻断AngII对AT1受体的作用,而非阻断其产生(如ACEI)。
因此,ACEI和ARB靶向全身性肾素-血管紧张素系统(systemic renin-angiotensin system,RAS),更具体地说是AngII,通过抑制ACE或防止血管紧张素II与AT1受体结合来阻止其形成。在此两种情况下,抑制都会导致血管舒张与BP降低。
最近的证据支持控制心血管功能和体液稳态的功能性RAS也存在于大脑中(Llorens-Cortes C.和Mendelsohn FA,大脑血管紧张素系统的组织和功能作用(Organisation and functional role of the brain angiotensin system).J ReninAngiotensin Aldosterone Syst 2002年9月;3增刊1:S39-S48)。大脑RAS的高活性,特别是氨肽酶A(aminopeptidase A,APA,一种膜结合锌金属蛋白酶,在体内参与大脑AngII和血管紧张素III(AngIII)的转化)的高活性在调节各种HTN动物模型中的BP水平中起到了关键作用(Marc Y.和Llorens-Cortes C,大脑肾素-血管紧张素系统在高血压中的作用:对新治疗的启示(The role of the brain renin-angiotensin system in hypertension:Implications for new treatment).Prog Neurobiol.2011年7月7日;95(2):89-103)。几项研究指出在大脑中,AngIII而非AngII(已知在周边的)构成控制BP和精氨酸升压素(arginine vasopressin,AVP)释放的大脑RAS的主要效应肽之一(Zini S.等人,使用特定氨肽酶抑制剂鉴定脑血管紧张素II和III的代谢途径:血管紧张素III在控制升压素释放中的主要作用(Identification of metabolic pathways of brain angiotensin II andIII using specific aminopeptidase inhibitors:Predominant role of angiotensinIII in the control of vasopressin release).Proc.Natl.Acad.Sci.USA 1996年10月15日;93(21):11968-73)。此外,大脑AngIII对高血压动物的BP控制具有强直刺激作用(Reaux A.等人,氨肽酶A抑制剂作为潜在的中枢抗高血压剂(Aminopeptidase Ainhibitors as potential central antihypertensive agents).Proc Natl Acad Sci US A.1999年11月9日;96(23):13415-20)。因此,大脑APA,即大脑RAS中生成AngIII的酶,构成了治疗动脉高血压的相关治疗目标,而具有中枢活性的APA抑制剂代表了一类新的抗高血压剂(Gao J.等人,一种通过氨肽酶A抑制剂阻断大脑肾素-血管紧张素系统活性来治疗高血压的新策略(A new strategy for treating hypertension by blocking theactivity of the brain renin-angiotensin system with aminopeptidase Ainhibitors).Clin Sci(Lond).2014年8月;127(3):135-48)。
在这些新型抗高血压剂中,可以特别提到非瑞巴司他(firibastat,也称为RB150或QGC001),其为选择性氨肽酶A(APA)抑制剂3-氨基-4-巯基丁烷磺酸(也称为EC33)的前药。非瑞巴司他在化学上定义为(3S)-3-氨基-4[[(2S)-2-氨基-4-磺丁基]二硫烷基)]丁烷-1-磺酸,或(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)。非瑞巴司他可为PCT/EP2011/067524中公开的三水合物形式。
在自发性高血压大鼠(spontaneously hypertensive rat,SHR,一种基本HTN实验模型)(Marc Y.等人,口服活性氨肽酶A抑制剂对自发性高血压大鼠的中枢抗高血压作用(Central antihypertensive effects of orally active aminopeptidase Ainhibitors in spontaneously hypertensive rats).Hypertension.2012年8月;60(2):411-8)中,以及在清醒的高血压醋酸脱氧皮质酮(deoxycorticosterone acetate,DOCA)盐大鼠(一种与盐敏感性和低血浆肾素水平相关的HTN实验模型,已知对全身性RAS阻断剂反应不佳)(Bodineau L.等人,口服活性氨肽酶A抑制剂降低血压:一种治疗高血压的新策略(Orally active aminopeptidase A inhibitors reduce blood pressure:a newstrategy for treating hypertension).Hypertension.2008年5月;51(5):1318-25)中,非瑞巴司他(15至150mg/kg)的口服施用诱导BP呈现剂量依赖性降低。有趣的是,在DOCA盐大鼠和SHR中,发现非瑞巴司他会降低BP,首先是通过减少升压素释放、增加水性利尿以及尿钠排泄,从而降低血量和BP以控制其数值,其次是通过降低交感神经张力,从而降低血管阻力且因此降低BP。此外,在轻度至中度高血压患者(Azizi M.等人中枢活性氨肽酶A抑制剂非瑞巴司他治疗高血压的双盲随机安慰剂对照交叉药效学试验研究(A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of thecentrally active aminopeptidase A inhibitor,firibastat,in hypertension).JHypertens.2019年8月;37(8):1722-1728)中,以及在已知由于高盐敏感性、低血浆肾素活性或交感神经系统高活性而对例如ACEi和ARB的全身RAS阻断剂的BP反应不佳的各种高风险高血压人群(Ferdinand KC.等人,创新药大脑氨肽酶A抑制剂非瑞巴司他在多种族高血压超重患者中的疗效和安全性(Efficacy and Safety of Firibastat,A First-in-ClassBrain Aminopeptidase A Inhibitor,in Hypertensive Overweight Patients ofMultiple Ethnic Origins).Circulation.2019年7月9日;140(2):138-146)中,均发现使用非瑞巴司他的单药治疗会降低BP。
HTN初始药物治疗的经典方法着重于单药治疗,根据临床参数和患者特征(年龄、种族、是否存在合并症)按优先级排列抗高血压药物。然而,在临床实践中应用此一策略并没有那么成功,心血管疾病仍然导致大量的死亡和残疾。HTN的病理生理复杂性通常限制了使用单一抗高血压药物实现重要的BP降低。单药治疗经常刺激代偿性反射,抵消药理学诱导的BP降低。此种代偿往往会阻碍成功的BP降低。当高血压患者不能充分控制其BP时,尝试与实现所需治疗目标的选择是增加单药治疗的剂量(这会增加副作用的风险)或在可能的情况下使用作用于不同机制的抗高血压药物的组合,这往往会对BP产生更强烈的影响。在某些情况下,已将具有不同作用机制的抗高血压药物组合使用,以更好地靶向导致HTN的多种潜在生理途径。然而,简单地使用具有不同作用模式的药物的任何组合并不一定产生具有优势的组合。不应合并没有累加抗高血压作用的药物类别。例如,CCB不应与利尿剂组合作为双重治疗,因为此两种药物类别均是利尿钠,会引起RAS的反射活化。此外,若组合使用的理由是为了改善BP控制,则ACEI(或ARB)不应与β-阻断剂组合使用。最后,组合直接作用于RAS的药物,包括ACEI、ARB或肾素抑制剂是不合理的。虽然一些抗高血压组合可能具有协同降BP作用,但其他组合可能没有益处或甚至有负面影响。例如,两种通过不同药理机制抑制交感神经活动的抗高血压剂,即中枢作用的α-肾上腺素能激动剂可乐定(clonidine)与周边α-肾上腺素能拮抗剂哌唑嗪(prazosin)的组合在抗高血压治疗中是不合适的。因此,若患者接受此两种药物中的一种治疗,添加另一种药物不会导致BP进一步下降,反而使BP升高(Kapocsi J.等人,哌唑嗪在原发性高血压患者中部分阻断可乐定引起的低血压(Prazosin partly blocks clonidine-induced hypotension in patients withessential hypertension).Eur J Clin Pharmacol.1987;32(4):331-4)。
抗高血压单药治疗使不超过30-40%的患者BP恢复正常,即使是轻度至中度HTN(1期或2期)患者,但对3期HTN患者与以BP快速正常化为重要目标的高/非常高风险患者并不完全有效。因此,在其最新的动脉HTN管理指南中,欧洲高血压学会和欧洲心脏病学会ESH/ESC建议,在所有高血压患者中,以及显然当患者初始BP高或因存在器官损伤、糖尿病或心肾疾病而被归类为高/非常高的心血管风险时,应以两种抗高血压药物的组合开始药物治疗,优选以一粒药丸的形式开始药物治疗(Williams B.等人,2018ESC/ESH,动脉高血压管理指南(Guidelines for the management of arterial hypertension).Eur HeartJ.2018年9月1日;39(33):3021-3104)。同样地,2017年美国心脏病学会以及美国心脏协会指南也指出,对于2期HTN且平均BP高于其BP目标超过20/10mmHg的成人,建议使用2种不同类别的一线药物作为单独的药剂或单一药丸组合开始进行抗高血压药物治疗(WheltonPK.等人2017ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA,成人高血压预防、检测、评估和管理指南:执行摘要:美国心脏病学会/美国心脏协会临床实践指南工作组的报告(Guideline for the Prevention,Detection,Evaluation,and Management of HighBlood Pressure in Adults:Executive Summary:A Report of the American Collegeof Cardiology/American Heart Association Task Force on Clinical PracticeGuidelines).J Am Coll Cardiol.2018年5月15日;71(19):2199-2269)。
除了使用可用的药物储备改善已治疗的高血压患者的BP控制外,流行病学研究支持开发新的替代抗高血压药物组合的必要性,这些组合可能会干扰涉及难以治疗和/或难治性高血压患者BP升高的发生和维持的机制,以降低心血管疾病的相关风险如心肌梗塞、心跳停止、中风或肾功能不全。
在此种情况下,本发明人确定了一种非常有前途的药物组合,允许产生显著的降血压功效,其可以改善难以治疗或难治性高HTN患者的BP控制。出乎意料地,本发明人确定了三种药物的组合:(i)非瑞巴司他,一种大脑APA抑制剂;(ii)利尿剂;以及(iii)全身性RAS阻断剂,通过不同且互补的作用机制发挥其抗高血压功效,并具有显著的降血压效果。更具体地,在构成盐敏感性HTN实验模型的清醒的高血压DOCA盐大鼠中发现,非瑞巴司他、氢氯噻嗪以及依那普利的组合比单独施用这些药物中的每一种并且甚至比施用每种双药组合(即,非瑞巴司他与依那普利组合,非瑞巴司他与氢氯噻嗪组合,以及氢氯噻嗪与依那普利组合)获得更大的治疗效果。
附图说明
图1.(A)在清醒DOCA盐大鼠中,单独或组合口服给予依那普利、HCTZ或非瑞巴司对平均动脉血压(MABP)的影响。
在清醒DOCA盐大鼠中,在基线时或在单次口服施用盐水、依那普利(10mg/kg)、HCTZ(10mg/kg)、非瑞巴司他(30mg/kg)、非瑞巴司他(30mg/kg)+依那普利(10mg/kg)、非瑞巴司他(30mg/kg)+HCTZ(10mg/kg)、依那普利(5mg/kg)+HCTZ(5mg/kg)、非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)5小时后的MABP值(mmHg,平均值±SEM)。(每种治疗n=6)。采用单因子ANOVA,其后在与相应的基线MABP值相比时进行Sidak多重比较检验,ns:不显著;*P<0.05;**P<0.01;***P<0.0001。
图1.(B)在清醒DOCA盐大鼠中,在单次口服施用单独或组合给予的依那普利、HCTZ或非瑞巴司他之后,给药后5小时平均动脉血压(MABP)相对于基线的变化。
在清醒DOCA盐大鼠(每组n=6)中,在单次口服施用盐水、依那普利(10mg/kg)、HCTZ(10mg/kg)、非瑞巴司他(30mg/kg)、非瑞巴司他(30mg/kg)+依那普利(10mg/kg)、非瑞巴司他(30mg/kg)+HCTZ(10mg/kg)、依那普利(5mg/kg)+HCTZ(5mg/kg)、非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)5小时后,MABP(mmHg)相对于基线之变化平均值±SEM。采用单因子ANOVA,其后在与接受盐水的DOCA盐大鼠中获得的MABP值的变化相比时进行Sidak多重比较,*P<0.01;**P<0.001;***P<0.0001;或在与接受非瑞巴司他+依那普利+HCTZ的DOCA盐大鼠中获得的MABP值的变化相比时进行Tukey多重比较检验,#P<0.05;##P<0.01;###P<0.0001。
图2.在清醒DOCA盐大鼠中,单独或组合口服给予的依那普利、HCTZ或非瑞巴司他对心率(HR)的影响。
在清醒DOCA盐大鼠中,在基线时或在单次口服施用盐水、依那普利(10mg/kg)、HCTZ(10mg/kg)、非瑞巴司他(30mg/kg)、非瑞巴司他(30mg/kg)+依那普利(10mg/kg)、非瑞巴司他(30mg/kg)+HCTZ(10mg/kg)、依那普利(5mg/kg)+HCTZ(5mg/kg)、非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)5小时后的HR值(bpm,平均值±SEM)。(每种治疗n=6)。采用单因子ANOVA,其后在与相应的基线HR值相比时进行Sidak多重比较检验,ns:不显著。
图3.(A)在清醒DOCA盐大鼠中,长期口服施用以组合形式经口给予的依那普利、HCTZ或非瑞巴司他之后,平均动脉血压(MABP)的时间进程。
在清醒DOCA盐大鼠中,在第8天,在基线时、在连续8天每天长期口服施用盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)5、9或24小时后的MABP值(mmHg,平均值±SEM)。(每种治疗n=12)。采用单因子ANOVA,其后在与在接受盐水的DOCA盐大鼠中获得的相应研究时间的MABP值相比时进行Holm-Sidak多重比较检验,*P<0.05;**P<0.01;***P<0.0001。
图3.(B)在清醒DOCA盐大鼠中,在8天期间每天长期口服施用组合给予的依那普利、HCTZ或非瑞巴司他之后,平均动脉血压(MABP)相对于基线变化的时间进程。
在清醒DOCA盐大鼠中,自基线至第8天在连续8天期间每天长期口服施用盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)之后5、9或24小时的MABP(mmHg)变化的平均值±SEM。(每种治疗n=12)。采用单因子ANOVA,其后在与接受盐水的DOCA盐大鼠中获得的MABP值的变化相比时进行Holm-Sidak多重比较检验,*P<0.05;**P<0.01;***P<0.0001;或在与接受非瑞巴司他加+依那普利+HCTZ的DOCA盐大鼠中获得的MABP值的变化相比时进行Sidak多重比较检验,#P<0.05。
图4.在清醒DOCA盐大鼠中,长期口服施用以组合形式给予的依那普利、HCTZ或非瑞巴司他之后,心率(HR)的时间进程。
在清醒DOCA盐大鼠中,在8天期间每天长期口服施用盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)5、9或24小时后的HR值(bpm,平均值±SEM)。(每种治疗n=12)。采用单因子ANOVA,其后在与接受盐水或依那普利+HCTZ的DOCA盐大鼠相比时进行Tukey多重比较检验,ns:不显著。
图5.在清醒高血压DOCA盐大鼠中,长期口服RB150治疗对血浆精氨酸升压素(AVP)释放的作用。
在清醒DOCA盐大鼠中,在10天的每天长期口服施用盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)之后,通过放射免疫分析来评估血浆AVP水平。其结果表示为每毫升血浆中AVP的皮克数。值表示为针对每种条件单独分析的10只动物的平均值±SEM。采用单因子ANOVA,其后在与接受盐水或依那普利+HCTZ的DOCA盐大鼠中获得的相应血浆AVP值相比时进行Tukey多重比较检验,ns:不显著;*P<0.05;**P<0.001。
发明内容
在一种实施方式中,本发明涉及一种药物组合,其包含:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由ACEI和ARB组成的组的第三活性成分。
所述组合特别适用于治疗动脉HTN或间接或直接相关的疾病。
根据本发明的另一种实施方式,公开了一种用于治疗HTN和间接或直接相关的疾病的方法。本发明的方法和用途包括向需要此种治疗的受试者施用有效量的药物组合物,所述药物组合物包括:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由ACEI和ARB组成的组的第三活性成分;或者,在适当的情况下,对于每种活性成分(i)-(iii)其药学上可接受的盐或溶剂化物。
在又一种实施方式中,本发明涉及一种包含如上述定义的药物组合的套装药剂盒,用于同时或依次施用,优选地用于同时施用。
具体实施方式
本发明涉及一种药物组合,其包含:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由ACEI和ARB组成的组的第三活性成分;更具体而言,用于治疗动脉HTN或间接或直接相关的疾病。
本发明同样涉及(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由ACEI和ARB组成的组的第三活性成分,在制备用于治疗动脉HTN或间接或直接相关的疾病的药物中的用途。
本发明同样涉及一种用于治疗动脉HTN或间接或直接相关的疾病的方法,包括向包含人类和非人类受试者在内的患者施用治疗有效量的(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由ACEI和ARB组成的组的第三活性成分。
本发明还涉及一种套装药剂盒,其包括(i)非瑞巴司他或其药学上可接受的盐或溶剂化物;(ii)利尿剂或其药学上可接受的盐或溶剂化物;以及(iii)选自由ACEI和ARB或其药学上可接受的盐或溶剂化物组成的组的第三活性成分,其用于同时或依次施用所述三种活性成分(i)-(iii);更优选地,所述药剂盒呈活性成分(i)至(iii)的一种或多种单独剂量单位或包含活性成分(i)至(iii)的药物组合物的形式。
根据本发明,术语“包含”(以及其他类似的术语,例如“含有”和“包括”)是“开放式的”,且通常可以解释为包括所有特别提到的特征以及任何任择的、附加的以及未指定的特征。根据具体实施方式,其也可以被解释为短语“基本上由…组成”,其中包含不会对所主张的本发明的基本和新颖特征产生实质性影响的指定的特征和任何任择的、附加的以及未指定的特征;或短语“由…组成”,其中仅包含特定特征,除非另有说明。
根据本发明,利尿剂更具体地包括氯噻嗪、氢氯噻嗪、氯噻酮、吲达帕胺、呋塞米(furosemide)、托拉塞米(torsemide)、阿米洛利(amiloride)、氨苯蝶啶(triamterene)、螺内酯(spironolactone)和依普利酮(eplerenone)。根据一种优选的实施方式,利尿剂选自由氢氯噻嗪、氯噻酮、吲达帕胺和阿米洛利组成的组。更具体而言,利尿剂为氢氯噻嗪。
根据本发明,ACEI更具体地包括赖诺普利、依那普利、喹那普利、雷米普利、贝那普利、卡托普利、西拉普利(cilazapril)、福辛普利、咪达普利(imidapril)、莫昔普利(moexipril)、群多普利(trandolapril)或培哚普利。根据一种优选的实施方式,ACEI选自由依那普利、培哚普利、雷米普利、赖诺普利和贝那普利组成的组。更具体而言,ACEI为依那普利。
根据本发明,ARB更具体地包括洛沙坦、坎地沙坦、艾比沙坦、替米沙坦、缬沙坦、奥美沙坦、依普罗沙坦和阿齐沙坦。根据一种优选的实施方式,ARB选自由洛沙坦、坎地沙坦、缬沙坦、奥美沙坦和阿齐沙坦组成的组。更具体而言,ARB为缬沙坦。
在适当的情况下,本文所定义的每种活性成分也包括其药学上可接受的盐或溶剂化物。
非瑞巴司他在化学上定义为(3S)-3-氨基-4[[(2S)-2-氨基-4-磺丁基]二硫烷基)]丁烷-1-磺酸,或也称为(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)。因此,所有那些术语在本文中可以互换使用,并且包括其两性离子形式、药学上可接受的盐或溶剂化物,包括水合物形式。非瑞巴司他可为PCT/EP2011/067524中公开的三水合物形式。术语“非利巴司他”在本文中是指(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)、其两性离子形式、药学上可接受的盐或溶剂化物,包括水合物形式。
非瑞巴司他可称为选择性氨肽酶A(APA)抑制剂3-氨基-4-巯基丁烷磺酸(也称为EC33)的同型二聚体(homodimer),通过在两个3-氨基-4-巯基丁烷磺酸分子的硫醇基团之间建立二硫键而产生。二聚化使分子更适合作为前药穿过肠胃道和血脑屏障。进入大脑后,非瑞巴司他被大脑还原酶裂解以产生两个活性分子EC33,其抑制大脑APA活性、阻断大脑AngIII形成并降低BP。
(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)及其作为抗高血压剂的用途已在专利申请WO2004/007441中公开。已证实了非瑞巴司他治疗(500mg,每日2次)对轻度至中度高血压患者以及各种高风险高血压人群的抗高血压功效(Azizi M.等人,中枢活性氨肽酶A抑制剂非瑞巴司他治疗高血压的双盲随机安慰剂对照交叉药效学试验研究(A pilotdouble-blind randomized placebo-controlled crossover pharmacodynamic study ofthe centrally active aminopeptidase A inhibitor,firibastat,in hypertension).JHypertens.2019年8月;37(8):1722-1728;Ferdinand KC.等人,创新药大脑氨肽酶A抑制剂非瑞巴司他在多种族高血压超重患者中的疗效和安全性(Efficacy and Safety ofFiribastat,A First-in-Class Brain Aminopeptidase A Inhibitor,in HypertensiveOverweight Patients of Multiple Ethnic Origins).Circulation.2019年7月9日;140(2):138-146)。
如上所述,下文所提及的(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)或非瑞巴司他包括两性离子形式及其药学上可接受的盐和溶剂化物。
本领域技术人员会理解,非瑞巴司他可含有至少一个正电荷和一个负电荷,因此非瑞巴司他包括其两性离子形式。在化学中,两性离子(也称为内盐,inner salt)是具有两个或更多个官能团的分子,在这些官能团中,至少一个带正电荷以及一个带负电荷,而不同官能团上的电荷互相平衡,且整个分子为电中性的。
有机化学领域的专家会理解,许多有机化合物可与溶剂形成复合物,其中有机化合物在溶剂中反应或自溶剂中沉淀或结晶。这些复合物被称作“溶剂化物”。例如,与水的复合物被称为“水化物”。这些组分(或活性成分)(i)-(iii)的溶剂化物在本发明的范围内。(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)的溶剂化物在本发明的范围内。有机化合物可以超过一种的结晶形式存在。例如,结晶形式可能因溶剂化物而异。因此,(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)或其药学上可接受的溶剂化物的所有晶型均在本发明的范围内。
本领域技术人员也会理解,(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)也可以其药学上可接受的盐的形式使用。(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)的药学上可接受的盐包括由药学上可接受的无机或有机酸或碱以及季铵盐与氨基酸形成的常规盐。合适的酸盐的更具体实例包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、过氯酸盐、富马酸盐、乙酸盐、丙酸盐、琥珀酸盐、乙醇酸盐、甲酸盐、乳酸盐、马来酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、丙二酸盐、羟基马来酸盐、苯乙酸盐、谷氨酸盐、苯甲酸盐、水杨酸盐、富马酸盐、甲苯磺酸盐、甲磺酸盐、萘-2-磺酸盐、苯磺酸盐、羟基萘甲酸盐、氢碘酸盐、苹果酸盐、固醇酸盐、单宁酸盐等。其他酸盐如草酸盐,虽本身非药学上可接受的,但可用于制备用作获得本发明化合物及其药学上可接受的盐的中间体的盐。合适的碱性盐的更具体实例包括钠盐、锂盐、钾盐、镁盐、铝盐、钙盐、锌盐、N,N'-二苄基乙二胺盐、氯普鲁卡因(chloroprocaine)盐、胆碱盐、二乙醇胺盐、乙二胺盐、N-甲基葡糖胺盐以及普鲁卡因(procaine)盐。合适的氨基酸盐的更具体实例包括L-以及D-形式的色氨酸、丝氨酸、胱氨酸、缬氨酸、精氨酸、甘氨酸、精氨酸或赖氨酸。PCT/EP2013/072028中公开了(3S,3S')4,4'-二硫烷二基双(3-氨基丁烷-1-磺酸)与L-赖氨酸的结晶形式以及制备其结晶形式的方法。
在优选实施方式中,与HTN间接或直接相关的疾病选自由以下组成的组:心脏、周边与脑血管系统、大脑、眼以及肾的疾病。具体而言,疾病包括原发性和继发性动脉HTN、暴病发作、心肌缺血、心脏衰竭、肾衰竭、心肌梗塞、周边血管疾病、糖尿病性蛋白尿、X症候群或青光眼。更具体而言,也可包括高血压糖尿病患者的肾病、视网膜病或神经病。根据一种特定实施方式,间接或直接相关的疾病为心脏衰竭。
在本发明的上下文中,术语治疗表示治愈性、对症性和预防性治疗。本发明的组合或组合物可用于患有HTN的受试者。本发明的组合或组合物不一定治愈患有HTN的患者,但会以令人满意的方式控制BP,从而延迟或减缓HTN的进展或由此预防HTN的进一步并发症,例如上述间接或直接相关的疾病。这会因此改善患者的病情。本发明的组合或组合物也可施用于那些尚未患有间接或直接相关疾病但通常会患上这些疾病或患有所述疾病的风险增加的人,以使他们不会患上所述疾病。因此,治疗也包括延迟个体的间接或直接相关疾病的发展,该个体最终会发展所述疾病或将由于年龄、家族史、遗传或染色体异常而处于患病风险中。通过延迟间接或直接相关疾病的发作,本发明的组合物在个体通常会患上所述疾病的时期内防止了个体患上所述疾病,或降低了若非施用本发明的组合物直至个体最终患上所述疾病之时所述疾病的发展速度或其一些影响。
术语“患者”、“受试者”、“个体”等术语在本文中可互换使用,指任何人类或非人类哺乳动物受试者,包括人类、实验室、家养、野生或农场动物。在某些非限制性实施方式中,患者、受试者或个体是人。在其他实施方式中,患者、受试者或个体是家养动物,例如猫科动物或犬科动物受试者,农场动物例如但不限于牛、马、山羊、绵羊和猪受试者、野生动物(无论是野生或在动物园中);研究动物,例如小鼠、大鼠、兔子、山羊、绵羊、猪、狗、猫等动物;鸟类物种,例如鸡、火鸡、鸣禽等动物,即,用于兽医医疗用途。优选地,受试者是无论其性别(男性或女性)或年龄的人类患者,通常为成年人。
出乎意料地,发明人确定了至少三种药物的组合:(i)非瑞巴司他,一种大脑APA抑制剂;(ii)利尿剂;以及(iii)全身性RAS阻断剂,通过不同且互补的作用机制发挥其抗高血压功效,并允许显著的降血压效果。此种组合出人意料的优点通过增强的降BP效果以及相对于每种药物的双重组合观察到的改善的益处来说明。包含(i)非瑞巴司他;(ii)利尿剂;以及(iii)全身性RAS阻断剂的组合代表了一种非常有前景的疗法,用于在HTN患者中,且尤其在患有难以治疗HTN的患者中,且更具体地在无法通过双重治疗(例如利尿剂和全身性RAS阻断剂)充分控制的高血压患者中,改善BP控制。更具体地,包含(i)非瑞巴司他;(ii)利尿剂;以及(iii)全身性RAS阻断剂的组合构成了高血压患者,且更具体地为高风险高血压患者,包括那些对盐敏感、血浆肾素活性低或交感神经系统高活性的高血压患者的替代或辅助疗法。已知此类患者与对使用单独作为单一药物治疗或组合为双重治疗的利尿剂和/或全身性RAS阻断剂的抗高血压治疗反应不佳相关。
在一种实施方式中,本发明涉及一种药物组合,其包含:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由ACEI和ARB组成的全身性RAS阻断剂的组的第三活性成分。
在一种优选实施方式中,利尿剂选自由氢氯噻嗪、吲达帕胺、呋塞米和氯噻酮组成的组。在一种更优选实施方式中,利尿剂为氢氯噻嗪。
在另一种优选实施方式中,全身性RAS阻断剂选自由依那普利、培哚普利、雷米普利和贝那普利组成的ACEI的组,或选自由洛沙坦、缬沙坦、坎地沙坦和阿齐沙坦组成的ARB的组。在一种更优选实施方式中,全身性RAS阻断剂是依那普利或缬沙坦。
在一种实施方式中,本发明涉及一种药物组合,其包含:(i)非瑞巴司他;(ii)氢氯噻嗪;以及(iii)依那普利。
根据本发明的一种实施方式,(i)非瑞巴司他、(ii)利尿剂以及(iii)全身性RAS阻断剂以分开的药物组合物的形式同时或依次施用,每种药物组合物包含在药学上可接受的媒剂中的活性成分(i)-(iii)中的一种。在另一种实施方式中,(i)非瑞巴司他、(ii)利尿剂以及(iii)全身性RAS阻断剂以两种单独的药物组合物的形式同时或依次施用;一种药物组合物包含选自组分(i)-(iii)的所述活性成分中的一种,且另一种药物组合物包含选自组分(i)-(iii)的所述活性成分中的另外两种,每种药物组合物还包含药学上可接受的媒剂。在另一种实施方式中,(i)非瑞巴司他、(ii)利尿剂以及(iii)全身性RAS阻断剂以单一药物组合物的形式同时施用,该药物组合物进一步包含药学上可接受的媒剂。在本发明的上下文中,术语“药物组合”是指这些方面中的一种或另一种。
根据其中(i)非瑞巴司他、(ii)利尿剂以及(iii)全身性RAS阻断剂以两种单独的药物组合物的形式同时或依次施用的实施方式,包含所述活性成分之一的药物组合物优选为包含非瑞巴司他的药物组合物,并且包含选自组分(i)-(iii)的所述活性成分中的另外两种的第二药物组合物是包含活性成分(ii)以及(iii)的药物组合物,所述药物组合物中的每一种还包含药学上可接受的媒剂。
根据本发明的药物组合或组合物可用于治疗HTN或间接或直接相关的疾病。在治疗动脉HTN中,根据本发明的药物组合的活性成分的优选剂量是治疗有效剂量,尤其是那些可商购的剂量。
如上所述的本发明的药物组合物有利地包含一种或多种药学上可接受的支撑体或媒剂。术语“药学上可接受的支撑体”是指自药理学/毒理学观点来看对于受试者可接受以及自物理/化学观点来看在组成、配制、稳定性、受试者接受度以及生物利用度方面对于制造药物化学家可接受的载剂、佐剂或赋形剂。
更优选地,组合物旨在用于口服施用,因此药学上可接受的支撑体或媒剂适合于口服施用。作为实例,可以提及与药物用途兼容且本领域技术人员已知的盐水、生理、等渗、缓冲溶液等。
如上所述的药物组合物可以通过将三种活性成分的全部或每一种或两种独立地与生理学上可接受的支撑体、赋形剂、粘合剂、稀释剂等混合来制备。本发明的药物组合物更具体地用于三种活性成分(i)-(iii)同时依次施用,优选地用于同时施用。
接着将药物组合物口服或非口服施用,例如通过非经肠、静脉内、皮肤、鼻、直肠途径或通过气雾剂递送至肺。若活性成分独立配制,则相应的制剂可使用稀释剂临时混合在一起,接着施用或可彼此独立地连续或依次施用。
优选地,本发明的组合物为口服施用。
本发明的药物组合物包括制剂,例如颗粒剂、粉剂、片剂、凝胶胶囊剂、糖浆剂、乳剂和混悬剂,以及用于非口服施用的形式,例如注射剂、喷雾剂或栓剂。
药物形式可以通过已知的常规技术制备。
口服施用的固体药物剂型的制备将通过以下方法进行:将赋形剂(例如乳糖、蔗糖、淀粉、甘露醇等)、崩解剂(例如碳酸钙、羧甲基纤维素钙等)、粘合剂(例如淀粉、阿拉伯树胶、羧甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素等)以及润滑剂(例如滑石、硬脂酸镁等)例如添加至活性成分中,其后将所得混合物压片。若需要,可以通过已知技术对片剂进行包衣,以掩盖味道(例如用可可粉、薄荷等)或允许活性成分的肠溶或持续释放。可以添加药学上可接受的着色剂。药物形式,例如片剂、粉剂、小袋剂以及凝胶胶囊剂可用于口服施用。
用于口服施用的液体药物形式包括溶液剂、混悬剂和乳剂。水溶液可以通过将活性成分溶解在水中,接着在必要时加入调味剂、着色剂、稳定剂以及增稠剂来获得。为了提高溶解度,可加入乙醇、丙二醇或其他药学上可接受的非水溶剂。口服使用的水性混悬剂可通过将细碎的活性成分与黏性产品,例如天然或合成树胶、树脂、甲基纤维素或羧甲基纤维素钠一起分散在水中而获得。
注射用药物剂型例如可通过以下方法获得。将活性成分溶解、悬浮或乳化于具有分散剂、防腐剂、等渗剂以及其他添加剂(例如,若需要,增溶剂或稳定剂)的水性介质(例如蒸馏水、生理盐水、林格氏溶液等)或油性介质(例如植物油,如橄榄油、芝麻油、棉籽油、玉米油等,或丙二醇)中。
外用药物形式可以自含有活性成分的固体、半固体或液体组合物获得。举例而言,为了获得固体形式,将活性成分单独或作为混合物用赋形剂和增稠剂处理以将其转化为粉末。液体药物组合物以与注射剂形式基本相同的方式制备,如前所述。半固体药物形式优选呈水性或油性凝胶形式或呈油膏形式。这些组合物可任选地含有pH调节剂以及其他添加剂。
本发明的组合物或活性成分的治疗有效量(即,有效剂量)由本领域技术人员决定。更具体地,有效量是允许降低以及维持BP以控制BP的量,具体而言,建议<140/90mmHg的BP目标。
应当理解,用于治疗所需的本发明活性成分的量将随着所治疗病状的性质以及受试者的年龄和病情而变化,且最终由主治医师或兽医决定。然而,一般而言,用于成人治疗的剂量通常为每天或每隔一天在50mg至1500mg范围内的非瑞巴司他。对于第二活性成分利尿剂以及选自由ACEI和ARB组成的全身性RAS阻断剂的组的第三活性成分,用于治疗的剂量会考虑其建议剂量。
根据一种特定实施方式,在一种、两种或三种单独的药物组合物中,本发明的药物组合包含100mg和400mg之间(例如250mg)的量的非瑞巴司他;5mg和15mg之间(例如6.25mg或12.5mg)的量的氢氯噻嗪;以及2.5mg和15mg之间(例如5mg或10mg)的量的依那普利。
根据另一种优选实施方式,在一种、两种或三种单独的药物组合物中,本发明的药物组合包含300mg和600mg之间(例如500mg)的量的非瑞巴司他;5mg和15mg之间(例如6.25mg或12.5mg)的量的氢氯噻嗪;以及2.5mg和15mg之间(例如5mg或10mg)的量的依那普利。
根据另一具体实施方式,在一种、两种或三种单独的药物组合物中,本发明的药物组合包含700mg和1200mg之间(例如1000mg)的量的非瑞巴司他;10mg和30mg之间(例如12.5mg或25mg)的量的氢氯噻嗪;以及10mg和50mg之间(例如20mg或40mg)的量的依那普利。
所需剂量可方便地以单种剂量单位或以适当间隔施用的几种分开的剂量单位形式存在,例如每天或每隔一天以两个、三个、四个或更多个亚剂量施用。根据本发明的组合物可包含按重量计0.1-99%的每种活性成分,方便地,对于片剂和胶囊剂,按重量计为30-95%,对于液体制剂,按重量计为3-50%,%相对于所述组合物的总量表示。本发明的活性成分的施用频率为每天或每隔一天施用一至两次。
药物组合的活性成分的相对比例可依据受试者病情以及所选择的利尿剂以及全身性RAS阻断剂而改变。举例而言,非瑞巴司他相对于氢氯噻嗪或依那普利的重量比可为10/1至300/1,优选地为25/1至200/1。
药物组合可连同施用说明一起包括在容器、包装或分配器中,也称为药剂盒。在药品说明书中给出了关于相应的活性成分(i)-(iii)或包含所述活性成分的药物组合物的组合施用的相应说明。
本发明因此涉及一种适用于通过上述方法或用途进行治疗的药剂盒。这些药剂盒包含如上定义的药物组合,包含(i)非瑞巴司他、(ii)利尿剂以及(iii)选自由ACEI和ARB组成的全身性RAS阻断剂的组的第三活性成分,用于同时或依次施用,优选用于同时施用。更具体而言,该药剂盒包含如上所定义之活性成分(i)至(iii)或包含活性成分(i)至(iii)的药物组合物的一种或多种(例如两种或三种)单独的(单一或分开的)剂量单位。
根据一种特定实施方式,套装药剂盒包含药物组合,其中(ii)利尿剂选自由氢氯噻嗪、吲达帕胺、阿米洛利和氯噻酮组成的组,并且(iii)全身性肾素-血管紧张素系统阻断剂选自由血管紧张素I转化酶抑制剂组成的组,所述血管紧张素I转化酶抑制剂由依那普利、培哚普利、雷米普利和贝那普利组成,或选自由1型血管紧张素II受体拮抗剂组成的组,所述1型血管紧张素II受体拮抗剂由洛沙坦、缬沙坦、坎地沙坦、艾比沙坦和阿齐沙坦组成。
根据一种更特定实施方式,本发明的药剂盒包括药物组合,其中(ii)利尿剂为氢氯噻嗪,并且(iii)全身性肾素-血管紧张素系统阻断剂为依那普利。
根据另一种特定实施方式,本发明的药剂盒包括药物组合,其中(ii)利尿剂为氢氯噻嗪,并且(iii)全身性肾素-血管紧张素系统阻断剂为缬沙坦。
根据另一种特定实施方式,套装药剂盒包括药物组合,其中(ii)利尿剂为吲达帕胺,并且(iii)全身性肾素-血管紧张素系统阻断剂为培哚普利。
根据又一种特定实施方式,套装药剂盒包括药物组合,其中(ii)利尿剂为氯噻酮,并且(iii)全身性肾素-血管紧张素系统阻断剂为阿齐沙坦。
药剂盒的单独剂量单位优选为一起制成一包,且在施用前混合或依次施用。
对于作为固定组合物(即所述三种活性成分之间确定的量和具体重量比)同时施用,也可制备包括所有三种活性成分(i)-(iii)的单一药物制剂。
本发明也涉及(i)非瑞巴司他、(ii)利尿剂以及(iii)选自由如上定义的ACEI和ARB组成的组的第三种活性成分的用途,其用于制备药物或一种、两种或三种如上定义的药物组合物,旨在治疗动脉HTN或间接或直接相关的疾病。
术语向同一受试者或患者“同时或依次施用”活性成分可能在长达2小时或甚至长达6小时内的时间内进行。举例而言,该术语包括(1)三种活性成分的同时施用(即所有三种活性成分的施用在少于10分钟的时间内进行,例如从30秒至5分钟),(2)在3小时内分别施用三种活性成分,以及(3)每小时分别施用三种活性成分中的每一种。根据一优选实施方式,根据(1)同时共同施用活性成分。
以下,根据本发明组合物的实施例作为非限制性说明给出。
实施例
除非另有说明,否则量以重量为基础表示。
材料与方法
药物
非瑞巴司他由PCAS(Limay,法国)所合成。血管紧张素转化抑制剂(ACEI)依那普利购自Sequoia Research(Pangbourne,英国)。利尿剂氢氯噻嗪(HCTZ)购自Sigma-Aldrich(Saint-Louis,美国)。
将药物溶解在无菌盐水中,用于体内通过胃管灌食施用口服。
动物
雄性醋酸脱氧皮质酮(DOCA)盐大鼠购自Charles River Laboratories(L'Arbresle,法国),体重250至350g。动物以分派隐匿(allocation concealment)方式随机分配至每一组别,并以遮盲程序(blinding procedure)与编码系统(coding system)进行动物护理,且外科手术是依据指令2010/63/EU进行。该项目已提交给相应的伦理委员会并获得授权:CEEA编号59,参考号01962.01。动物保持在人造光下(12小时光照/12小时黑暗循环),随意获取标准饮食和盐水(0.9%NaCl,0.2%KCl)。
手术方法以及平均动脉BP记录
雄性DOCA盐大鼠用3%异氟醚(Piramal,UK)麻醉以进行诱导,并用1.5-2%异氟醚进行维持。将导管(.011"X.024"X.0065")插入右股动脉以监测平均动脉血压(MABP)和心率(HR)。该导管通过皮下隧道从颈部离开。在记录MABP之前,允许动物从手术中恢复至少48小时。在施用前30分钟至1小时记录MABP基线。血压记录开始后1小时,单独或者以不同剂量组合经口服途径向清醒的自由活动大鼠施用非瑞巴司他(30mg/kg)、依那普利(5或10mg/kg)以及HCTZ(5或10mg/kg)。在化合物施用后,监测BP 6小时。MABP使用MatLab系统(Phymep,Paris,法国)计算,该系统由一个MatLab硬件单元以及CHART软件组成,在Macintosh计算机上运作。MABP和HR的测量值由BP信号计算。
对于长期治疗,使用三组DOCA盐大鼠。每天通过胃管灌食口服施用盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)。在第8天,以上述方式将导管插入右股动脉以监测平均动脉血压(MABP)。让动物恢复至少24小时。在第9天,在药物施用前30分钟至1小时记录MABP基线。通过胃管灌食口服施用盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)。接着在药物施用后的不同时间点(5、9和24小时)记录MABP。每次纪录时间持续1小时。
用于AVP水平以及电解质测量的血浆采集
在第10天治疗(盐水、依那普利(5mg/kg)+HCTZ(5mg/kg)或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg))后5小时通过断头处死大鼠。将躯干血(6-7mL)收集到冰上每毫升血液含有0.05mL的0.3M EDTA(pH 7.4)或者每毫升血液50单位的肝素锂的冷却管中,并在4℃下以5000rpm离心15分钟。
AVP放射免疫分析
通过添加0.2倍体积的3M HCl酸化血浆,并在-80℃下储存直至进行AVP测定。样品在冰上解冻,其后在4℃下以20,000×g离心20分钟。通过将0.5mL上清液与0.5mL的1%三氟乙酸(TFA)混合并加载至预先用2mL的100%乙腈洗涤并用5mL的1%TFA平衡的Sep-Pak C18短柱(Waters,Massachusetts,USA)上,从血浆中提取AVP。接着用3mL的1%TFA洗涤管柱,并用1.5mL的100%乙腈洗脱AVP。将样品冻干并溶解在0.35mL的RIA缓冲液(19mM NaH2PO4·H2O、81mM Na2HPO4·2H20、50mM NaCl、0.1%TritonX-100、0.01%NaN3、0.1%BSA)中。血浆AVP水平是通过放射免疫分析(RIA)用0.1mL血浆测定,使用在2:3的稀释度下显示与催产素(oxytocin)无交叉反应的0.1mL对AVP-[Arg8]具有特异性的多克隆兔抗血清(PeninsulaLaboratories International,San Carlo,CA,USA),和0.1mL[125I]-(Tyr2Arg8)-AVP2000Ci/mmol(PerkinElmer,Waltham,Massachusetts,USA)在15,000dpm作为追踪剂,在4℃下培育隔夜。添加了0.1mL山羊抗兔IgG血清以及0.1mL来自PeninsulaLaboratoriesInternational(San Carlo,CA,USA)的正常兔血清,并将所得混合物在室温下培育2小时。其后加入0.5mL RIA缓冲液,并在4℃下以2,600×g离心20分钟。除去上清液,并测定沉淀物的放射性。AVP RIA的检测限制为每管0.2pg。
血浆电解质测量
用Caretium Medical Instruments Co.(Shenzhen,China)的电解质分析仪测定血浆中钠和钾的浓度。
统计分析
定量数据显示为平均值±SEM。使用d'Agostino-Pearson检验评估正态性。在验证残差呈正态分布后执行ANOVA。若正态性已确认,则多组之间的比较通过单因子ANOVA进行,其后是Tukey、Holm-Sidak或Sidak的多重比较检验。若P值<0.05,则认为差异是显著的。使用Prism软件(GraphPad Software)进行统计分析。
结果
单独或组合急性口服施用非瑞巴司他、依那普利以及HCTZ对自由活动的DOCA盐大
鼠的BP和HR的影响
在DOCA盐大鼠中,非瑞巴司他(30mg/kg)单独施用诱导BP显著下降(-35.4±5.2mmHg),而依那普利(10mg/kg)或HCTZ(10mg/kg)单独给予则没有诱导任何BP显著下降变化(图1)。依那普利(5mg/kg)+HCTZ(5mg/kg)、非瑞巴司他(30mg/kg)+依那普利(10mg/kg)或非瑞巴司他(30mg/kg)+HCTZ(10mg/kg)的双重组合使动脉BP分别显著降低36.9±4.4mmHg、11.6±3.7mmHg以及30.1±9.9mmHg(图1)。
在清醒DOCA盐大鼠中,同时口服施用非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg),显著并大大降低MABP(图1),而不会显著改变HR(图2)。施用后5小时观察到MABP的最大降低(-63.3±9.1mmHg)。由非瑞巴司他+依那普利+HCTZ的三重组合诱导的BP降低,与单独施用每种化合物诱导的BP降低显著不同。此外,由非瑞巴司他+依那普利+HCTZ的组合诱导的BP降低,与所有其他的双重组合(非瑞巴司他+依那普利、非瑞巴司他+HCTZ以及依那普利+HCTZ)诱导的降低显著不同。
综上所述,非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)的组合增强了非瑞巴司他(30mg/kg)所诱导的BP降低,甚至比依那普利(5mg/kg)+HCTZ(5mg/kg)的双重组合更强。这些出乎意料地结果表明,在DOCA盐模型中,非瑞巴司他、依那普利以及HCTZ之间存在协同作用,分别阻断大脑和全身性RAS活性,并增加利尿作用,导致BP显著降低。
9天长期口服施用非瑞巴司他、依那普利以及HCTZ对自由活动的DOCA盐大鼠的BP
和HR的影响。
在警觉的DOCA盐大鼠中研究依那普利(5mg/kg)+HCTZ(5mg/kg)的双重组合或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)的三种组合的9天长期的每天口服施用对BP和HR的影响。在第9天,研究在警觉的DOCA盐大鼠中在24小时期间口服施用这些组合对BP影响的时间进程。
在清醒DOCA盐大鼠中,在5小时和9小时之后,同时口服施用依那普利(5mg/kg)+HCTZ(5mg/kg),或非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)显著并大大降低MABP(图3),而没有显著改变HR(图4)。由非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)的三重组合诱导的MABP降低在施用后5小时达到最大,且在9小时后持续存在,其MABP分别为61.9±6.2mmHg以及49.3±7.4mmHg(P<0.0001)的显著降低(图3)。在24小时后,未观察到BP下降。
施用5小时后,非瑞巴司他(30mg/kg)+依那普利(5mg/kg)+HCTZ(5mg/kg)的三重组合诱导的BP降低,与依那普利(5mg/kg)+HCTZ(5mg/kg)的双重组合诱导的BP降低显著不同(分别为61.9±6.2mmHg以及31.3±8.2mmHg(P<0.05))。
如在急性治疗中,使用非瑞巴司他(30mg/kg/天)+依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的三重组合进行9天长期治疗,增强了非瑞巴司他(30mg/kg/天)诱导的BP降低。当将其效果与依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的双重组合进行比较时,其协同作用更加显著。这些结果也表明,在重复施用后,对非瑞巴司他(30mg/kg/天)+依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的三重组合的抗高血压效果不存在耐受性。
整体而言,这些数据表明,即使在重复施用后,非瑞巴司他、依那普利以及HCTZ之间仍存在协同作用,以调节高血压DOCA盐大鼠的BP。
使用非瑞巴司他、依那普利以及HCTZ的三重组合,可同时阻断大脑RAS高活性、全身性RAS活性以及增加利尿,其代表了一种新颖和原创的HTN治疗方法,使得能够进一步降低高血压患者,更具体地说难以治疗和难治性高血压患者的血压。
10天长期口服施用非瑞巴司他、依那普利以及HCTZ对清醒高血压DOCA盐大鼠的血
浆精氨酸升压素(AVP)水平的影响。
在第10天,接受长期口服盐水治疗的DOCA盐大鼠的血浆AVP(也称为抗利尿激素)水平为28.2±3.3pg/mL。与接受长期盐水的DOCA盐大鼠相比,每天重复口服施用依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的双重组合、或非瑞巴司他(30mg/kg/天)+依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的三重组合的DOCA盐大鼠的血浆AVP水平,在施用5小时后增加107%和40%(分别为58.3±4.0pg/mL和39.6±5.3pg/mL相对于28.2±3.3pg/mL)(图5)。
接受依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的双重组合长期治疗的DOCA盐大鼠,与接受非瑞巴司他(30mg/kg/天)+依那普利(5mg/kg/天)+HCTZ(5mg/kg/天)的三重组合长期治疗的DOCA盐大鼠之间血浆AVP水平的差异为18.8pg/mL。在依那普利和HCTZ的双重组合中加入非瑞巴司他,使在接受此种双重组合的DOCA盐大鼠中观察到的血浆AVP水平的增加,减少了62%(采用单因子ANOVA,其后为Tukey检验,P<0.05)。
Claims (21)
1.一种药物组合,其包括:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由血管紧张素I转化酶抑制剂以及1型血管紧张素II受体拮抗剂组成的组的全身性肾素-血管紧张素系统阻断剂,用于治疗动脉高血压或间接或直接相关的疾病,特别是心脏衰竭。
2.根据权利要求1所述的药物组合,其中所述利尿剂选自由氯噻嗪、氢氯噻嗪、氯噻酮、吲达帕胺、呋塞米、托拉塞米、阿米洛利、氨苯蝶啶、螺内酯和依普利酮组成的组;更优选地,所述利尿剂选自由氢氯噻嗪、氯噻酮、吲达帕胺和阿米洛利组成的组。
3.根据权利要求1或2所述的药物组合,其中所述利尿剂为氢氯噻嗪。
4.根据前述权利要求中任一项所述的药物组合,其中所述全身性肾素-血管紧张素系统阻断剂选自由赖诺普利、依那普利、喹那普利、雷米普利、贝那普利、卡托普利、西拉普利、福辛普利、咪达普利、莫昔普利、群多普利或培哚普利组成的血管紧张素转化酶抑制剂的组;更优选地,所述血管紧张素转化酶抑制剂选自由依那普利、培哚普利、雷米普利、赖诺普利和贝那普利组成的组。
5.根据前述权利要求中任一项所述的药物组合,其中所述全身性肾素-血管紧张素系统阻断剂为依那普利。
6.根据权利要求1至3中任一项所述的药物组合,其中所述全身性肾素-血管紧张素系统阻断剂选自由1型血管紧张素II受体拮抗剂组成的组,所述1型血管紧张素II受体拮抗剂由洛沙坦、坎地沙坦、艾比沙坦、替米沙坦、缬沙坦、奥美沙坦、依普罗沙坦和阿齐沙坦组成,更优选地,选自由洛沙坦、缬沙坦、坎地沙坦、艾比沙坦和阿齐沙坦组成的组。
7.根据权利要求1至3或权利要求6中任一项所述的药物组合,其中所述全身性肾素-血管紧张素系统阻断剂为缬沙坦。
8.根据权利要求1所述的药物组合,其中所述利尿剂为氢氯噻嗪,并且所述全身性肾素-血管紧张素系统阻断剂为依那普利。
9.根据权利要求1所述的药物组合,其中所述利尿剂为氢氯噻嗪,并且所述全身性肾素-血管紧张素系统阻断剂为缬沙坦。
10.根据权利要求1所述的药物组合,其中所述利尿剂为吲达帕胺,并且所述全身性肾素-血管紧张素系统阻断剂为培哚普利。
11.根据权利要求1所述的药物组合,其中所述利尿剂为氯噻酮,并且所述全身性肾素-血管紧张素系统阻断剂为阿齐沙坦。
12.根据权利要求8所述的药物组合,其包含量在100mg至1500mg范围内的非瑞巴司他、量在5mg至30mg范围内的氢氯噻嗪,以及量在2.5mg至50mg范围内的依那普利。
13.根据权利要求8所述的药物组合,其包含量在300mg至600mg范围内的非瑞巴司他、量在5mg至15mg范围内的氢氯噻嗪,以及量在2.5mg至15mg范围内的依那普利。
14.根据权利要求1至13中任一项所述的药物组合,其中三种活性成分同时或依次施用;优选地同时施用。
15.一种套装药剂盒,其包括药物组合,所述药物组合包含:(i)非瑞巴司他;(ii)利尿剂;以及(iii)选自由血管紧张素I转化酶抑制剂以及1型血管紧张素II受体拮抗剂组成的组的全身性肾素-血管紧张素系统阻断剂,呈组分(i)至(iii)的一种、两种或三种单独单位的形式,用于同时或依次施用;优选地用于同时施用。
16.根据权利要求15所述的药剂盒,其中(ii)所述利尿剂选自由氢氯噻嗪、吲达帕胺、阿米洛利和氯噻酮组成的组;并且(iii)所述全身性肾素-血管紧张素系统阻断剂选自由血管紧张素I转化酶抑制剂组成的组,所述血管紧张素I转化酶抑制剂由依那普利、培哚普利、雷米普利和贝那普利组成,或选自由1型血管紧张素II受体拮抗剂组成的组,所述1型血管紧张素II受体拮抗剂由洛沙坦、缬沙坦、坎地沙坦、艾比沙坦和阿齐沙坦组成。
17.根据权利要求15所述的药剂盒,其中(ii)所述利尿剂为氢氯噻嗪,并且(iii)所述全身性肾素-血管紧张素系统阻断剂为依那普利。
18.根据权利要求15所述的药剂盒,其中(ii)所述利尿剂为氢氯噻嗪,并且(iii)所述全身性肾素-血管紧张素系统阻断剂为缬沙坦。
19.根据权利要求15所述的药剂盒,其中(ii)所述利尿剂为吲达帕胺,并且(iii)所述全身性肾素-血管紧张素系统阻断剂为培哚普利。
20.根据权利要求15所述的药剂盒,其中(ii)所述利尿剂为氯噻酮,并且(iii)所述全身性肾素-血管紧张素系统阻断剂为阿齐沙坦。
21.根据权利要求15至20中任一项所述的药剂盒,其适用于治疗高血压和相关疾病和病状。
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TW202029962A (zh) * | 2018-10-26 | 2020-08-16 | 法商量子基因科技有限公司 | 胺肽酶a抑制劑及包含其的醫藥組合物 |
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CA3176024A1 (en) | 2021-11-11 |
TW202207917A (zh) | 2022-03-01 |
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