CN1368881A - 肾素-血管紧张素系统抑制剂在预防心血管疾病中的用途 - Google Patents
肾素-血管紧张素系统抑制剂在预防心血管疾病中的用途 Download PDFInfo
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- CN1368881A CN1368881A CN00811394A CN00811394A CN1368881A CN 1368881 A CN1368881 A CN 1368881A CN 00811394 A CN00811394 A CN 00811394A CN 00811394 A CN00811394 A CN 00811394A CN 1368881 A CN1368881 A CN 1368881A
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Abstract
本发明涉及肾素-血管紧张素系统抑制剂或其可药用衍生物,任选地与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合在制备用于预防心血管疾病的药剂中的用途;本发明涉及一种预防心血管疾病的方法,该方法包括下列步骤:对需要这类预防的患者给予有效量的肾素血管紧张素抑制剂或其可药用衍生物,任选地与其它抗高血压药、降胆固醇药、利尿药或阿司匹林的组合;或本发明涉及一种含有肾素-血管紧张素系统抑制剂或其可药用衍生物与降胆固醇药的组合物。
Description
发明领域
本发明涉及肾素-血管紧张素系统抑制剂或其可药用衍生物以及可以任选地与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合在制备用于预防心血管疾病的药剂中的用途;本发明涉及一种预防心血管疾病的方法,该方法包括下列步骤:对需要这种预防的患者给予有效量的肾素血管紧张素系统抑制剂或其可药用衍生物以及可以任选地与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合;或本发明涉及一种含有肾素-血管紧张素系统抑制剂或其可药用衍生物与降胆固醇药的组合产品。
发明背景
可以通过对合成血管紧张素的酶的抑制作用或通过阻断效应位点上的相应受体来推断出是肾素-血管紧张素系统(RAS)。存在许多市售或处于研究阶段的抑制RAS活性的活性剂且它们许多属于两大类:血管紧张素转化酶(ACE)抑制剂,其批准的名称一般以″普利(pril)″结尾或在活性代谢物的情况中以″普利拉(-prilat)″结尾;和血管紧张素受体(更具体地说,目前是AT1受体)拮抗剂(血管紧张肽II拮抗剂),其批准的名称一般以″沙坦(-sartan)″结尾。重要性正逐步显现的其它可能的活性剂可以是一类称作中性内肽酶(NEP)抑制剂的药物,它们也具有ACE-抑制作用或潜在降低RAS活性且由此也称作NEP/ACE-抑制剂。
ACE抑制剂在抑制血管紧张肽转化酶、由此阻断十肽血管紧张肽I向血管紧张肽II转化方面的活性在本领域中是众所周知的。ACE抑制剂的主要药理和临床作用是由对血管紧张肽II合成的抑制作用所产生的。血管紧张肽II是一种有效的升压物质,且由此可以通过对其生物合成的抑制而降低血压、特别是降低与血管紧张肽II相关的动物和人体高压血。ACE抑制剂是各种动物模型中的有效抗高血压药且在临床上用于治疗人体高血压。
ACE抑制剂还用于治疗心脏病,诸如高血压和心力衰竭。已知至少某些ACE抑制剂可以改善(即降低)患有心脏病群体、即具有低射血分数(EF)或心力衰竭(HF)患者中的发病率和死亡率,而其对无心室功能障碍或HF的广泛高危患者群体的作用是未知的。
发明概括
本发明一般涉及肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防心血管疾病的药剂中的用途。
本发明进一步涉及肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防心肌梗死(MI)、绞痛加剧或心脏停博的药剂中的用途。
此外,本发明涉及肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防心血管疾病的药剂中的用途,所述的心血管疾病诸如:例如心肌梗死(MI)、患有心血管风险加剧的患者体内的绞痛加剧或心搏停止,例如其中所述的心血管损害是由于明显的冠心病、短暂局部缺血发作或中风病史或外周血管疾病病史所导致的。
本发明更一般地涉及肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防没有明显左心室功能障碍或心力衰竭的患者体内的心血管疾病的药剂中的用途。
本发明进一步涉及肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防心肌梗死(MI)、中风、心血管死亡或糖尿病患者中的明显肾病的药剂中的用途。
本发明的另一个实施方案是肾素-血管紧张素系统抑制剂或其可药用衍生物与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合在制备用于预防心血管疾病的药剂中的用途,所述的心血管疾病例如有:中风、充血性心力衰竭、心血管死亡、心肌梗死、绞痛加剧、心脏停博或血管再通术。
本发明的另一个实施方案是肾素-血管紧张素系统抑制剂或其可药用衍生物与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合在制备用于预防糖尿病或糖尿病并发症的药剂中的用途。
本发明的另一个实施方案是肾素-血管紧张素系统抑制剂或其可药用衍生物与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合在制备用于预防预先未患充血性心力衰竭的患者的充血性心力衰竭(CHF)的药剂中的用途。
本发明的另一个实施方案是一种用于预防心血管疾病的含有肾素-血管紧张素系统抑制剂或其可药用衍生物和其它抗高血压药、降胆固醇药、利尿药或阿司匹林的组合物。
本发明的另一个实施方案是一种含有肾素-血管紧张素系统抑制剂或其可药用衍生物和降胆固醇药的组合产品。
本发明的另一个实施方案是一种预防例如心肌梗死、绞痛加剧或心脏停博这样的心血管疾病的方法,该方法包括对需要这类预防的患者、且特别是对心血管危险加剧的患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物的步骤。
本发明的另一个实施方案是一种预防心肌梗死、中风、心血管死亡或糖尿病患者体内明显的肾病的方法,该方法包括对所述患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物的步骤。
本发明的另一个实施方案是一种预防例如中风、充血性心力衰竭、心血管死亡、心肌梗死、绞痛加剧、心脏停博或血管再通术这样的心血管疾病或糖尿病或糖尿病并发症的方法,该方法包括对需要这类预防的患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物以及有效量的其它抗高血压药、降胆固醇药、利尿药或阿司匹林的步骤(联合疗法)。
本发明的另一个实施方案是一种预防预先未患充血性心力衰竭的患者的充血性心力衰竭的方法,该方法包括对所述患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物以及有效量的抗高血压药、降胆固醇药、利尿药或阿司匹林的步骤(联合疗法)。发明详述
已经出人意料地发现可以用RAS系统抑制剂在没有明显左心室功能障碍或心力衰竭的广泛高危人群中预防下列疾病或情况:心血管疾病,诸如中风、充血性心力衰竭、心血管死亡、心肌梗死、绞痛加剧、心脏停博;或血管再通术,诸如冠状动脉旁路移植术(CABG)、PTCA、外周血管成形术、切断术、Cariotid动脉内膜切除术;和代谢紊乱,诸如糖尿病或糖尿病并发症,诸如明显的肾病、肾脏透析或激光疗法;或新型微白蛋白尿。
另外的且非常出人意料的是还在例如还用抗高血压药(非RAS系统抑制剂)、利尿药、降胆固醇药或阿司匹林的其它有效疗法治疗的广泛高危患者中观察到了这类对心血管疾病的预防作用。
因此,本发明描述了一种预防心血管疾病的新型方法,该方法包括对需要这类预防的患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物以及可任选的其它抗高血压药、降胆固醇药、利尿药或阿司匹林的步骤。
高危患者是例如那些患有由于明显的冠心病、短暂局部缺血发作或中风病史或外周血管疾病病史所导致的心血管疾病的患者。
另一组高危患者包括患有糖尿病的那些患者。
本文所用的术语″糖尿病″包括I型糖尿病、也称作胰岛素依赖性糖尿病(IDMM)和II型糖尿病、也称作非胰岛素依赖性糖尿病(NIDDM)。
本文所用的术语″糖尿病并发症″包括需要激光疗法或透析的明显的肾病。
本文所用的术语″肾素-血管紧张素系统(RAS)抑制剂或其可药用衍生物″包括通过其自身或在给药时经减少血管紧张肽II合成或阻断其在受体上的作用而阻断血管紧张肽II对血管系统产生负面作用的任意化合物。
RAS抑制剂包括ACE抑制剂、血管紧张肽II拮抗剂和肾素抑制剂及其可药用衍生物,包括前药和代谢物。
术语″血管紧张肽转化酶抑制剂″(″ACE抑制剂″)用来包括活性剂或化合物或两种或多种活性剂或化合物的组合物,它们具有部分或完全阻断以酶促方式将无生理活性的十肽形式的血管紧张肽(″血管紧张肽I″)快速转化成血管收缩性八肽形式的血管紧张肽(″血管紧张肽II″)的能力。术语″ACE抑制剂″还包括所谓的NEP/ACE抑制剂(也称作选择性或双向作用中性内肽酶抑制剂),它具有中性内肽酶(NEP)抑制活性和血管紧张肽转化酶(ACE)抑制活性。
适用于本文的ACE抑制剂的实例包括例如下列化合物:AB-103、血管紧张肽转化酶抑制肽、贝那普利拉、BRL-36378,BW-A575C、CGS-13928C、CL242817、CV-5975、Equaten、EU-4865、EU-4867、EU-5476、foroxymithine、FPL 66564、FR-900456、Hoe-065,15B2、吲哚普利、酮基甲脲类、KRI-1177、KRI-1230、L681176、赖苯普利、MCD、MDL-27088、MDL-27467A、莫维普利、MS-41、nicotianamine,喷托普利、phenacein、匹伏普利、伦唑普利、RG-5975、RG-6134、RG-6207、RGH0399、ROO-911、RS-10085-197、’RS-2039、RS 5139、RS 86127、RU-44403、S-8308、SA-291、螺普利拉、SQ26900、SQ-28084、SQ-28370、SQ-28940,SQ-31440、Synecor、乌替普利、WF-10129、Wy-44221、Wy-44655、Y-23785、Yissum、P-0154、扎普利、Asahi Brewery AB-47、alatriopril、BMS 182657、Asahi Chemical C-111、Asahi ChemicalC-112、Dainippon DU-1777、mixanpril、Prentyl、佐芬普利拉、1(-(1-羧基-6-(4-哌啶基)己基)氨基)-1-氧丙基八氢-1H-吲哚-2-羧酸、Bioproject BP1.137、Chiesi CHF 1514、Fisons FPL-66564、伊屈普利、培哚普利拉和Servier S-5590、阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸肌丙抗增压素、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉和螺普利。
非常关注的一组ACE抑制剂是阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸肌丙抗增压素、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉和螺普利。
许多这些ACE抑制剂是市售可得的,尤其是那些上述组中所列的药物。例如,极为优选的ACE抑制剂雷米普利(已知获自EP 79022)由Aventis销售,例如其商标为Delix或Altace。依那普利或马来酸依那普利和赖诺普利是两种更特别优选的由Merck & Co销售的ACE抑制剂。依那普利的销售商标为Vasotec。赖诺普利的销售商标为Prinivil。
适用于本文的NEP/ACE抑制剂的实例包括下列文献中公开的那些药物:美国专利号5,508,272、5,362,727、5,366,973、5,225,401、4,722,810、5223,516、5,552,397、4,749,688、5,504,080、5,612,359、5,525,723、5,430,145和5,679,671以及欧洲专利申请0481522、0534263、0534396、0534492和0671172。
优选的是作为上述美国专利和欧洲专利申请中优选的那些NEP/ACE抑制剂并将这些文献引入本文作为参考。特别优选的是NEP/ACE抑制剂奥马帕唑普利(omapatrilat)(公开在美国专利号5,508,272中或MDL100240(公开在美国专利号5,430,145中)。
术语″血管紧张肽II拮抗剂″用来包括具有部分或完全阻断血管紧张肽II在血管紧张肽受体、特别是在AT1受体上结合的能力的活性剂或化合物或两种或多种活性剂或化合物的组合物。
适用于本文的血管紧张肽II拮抗剂的实例是例如下列化合物:
醋酸肌丙抗增压素、堪达沙坦西来克斯特(candesartancilexetil)、CGP-63170、EMD-66397、KT3-671、LR-B/081、缬沙坦、A-81282、BIBR-363、BIBS-222、BMS-184698、堪达沙坦(candesartan)、CV11194、EXP-3174、KW-3433、L-161177、L-162154、LR-B/057、LY-235656、PD150304、U-96849、U-97018、UP-275-22、WAY-126227、WK-1492.2K、YM-31472、氯沙坦钾、E-4177、EMD-73495、艾扑沙坦(eprosartan)、HN-65021、爱博沙坦(irbesartan)、L-159282、ME-3221、SL-91.0102、特索沙坦(Tasosartan)、替米沙坦、UP-269-6、YM-358、CGP-49870、GA-0056、L-159689、L-162234、L-162441、L-163007、PD-123177、A-81988、BMS-180560、CGP-38560A、CGP-48369、DA-2079、DE-3489、DuP-167、EXP-063、EXP-6155、EXP-6803、EXP-7711、EXP-9270、FK-739、HR-720、ICI-D6888、ICI-D7155、ICI-D8731、isoteoline、KRI-1177、L-158809、L-158978、L-159874、LR B087、LY-285434、LY-302289、LY-315995、RG-13647、RWJ-38970、RWJ-46458、S-8307、S-8308、saprisartan、沙拉新、Sarmesin、WK-1360、X-6803、ZD-6888、ZD-7155、ZD-8731、BIBS39、CI-996、DMP-811、DuP-532、EXP-929、L163017、LY-301875、XH-148、XR-510、佐拉沙坦和PD-123319。
特别关注的一组血管紧张肽II拮抗剂是醋酸肌丙抗增压素、堪达沙坦西来克斯特、缬沙坦、堪达沙坦、氯沙坦钾、艾扑沙坦、爱博沙坦、特索沙坦或替米沙坦。
适用于本文的肾素抑制剂的实例是例如下列化合物:依那吉仑(enalkrein);RO 42-5892;A 65317;CP 80794;ES 1005;ES 8891;SQ34017;CGP 29287;CGP 38560;SR 43845;U-71038;A 62198;A64662、A-69729、FK 906和FK 744。
可以理解的是RAS抑制剂的可药用衍生物包括RAS抑制剂的生理上可接受的盐,诸如将生理上可接受的盐理解为其有机或无机盐的含义,诸如《Remington氏药物科学》(Remington’s Pharmaceutical Sciences)第17版、1418页(1985)中所述。由于物理和化学稳定性和溶解性的原因,就酸性基团而言,特别优选的是钠、钾、钙和铵盐;就碱性部分而言,特别优选盐酸盐、硫酸盐、磷酸盐或羧酸盐或磺酸盐,诸如例如优选乙酸、柠檬酸、苯甲酸、马来酸、富马酸、酒石酸和对甲苯磺酸。
可以将适用于本文的RAS抑制剂或其可药用衍生物作为与另一种药物的混合物的药物本身或药物制剂的形式用于动物、优选用于哺乳动物且特别是用于人。
本发明还涉及包括至少一种RAS抑制剂和/或其可药用衍生物作为活性组分以及常用的药用无毒赋形剂和助剂的药物制剂并涉及它们在预防心血管疾病和在生产用于心血管疾病的药剂中的用途。该药物制剂通常含有0.1-99重量%、优选0.5-95重量%的RAS抑制剂和/或其可药用衍生物。可以按照本身公知的方式制备该药物制剂。为了达到这一目的,将RAS抑制剂和/或其可药用衍生物与一种或多种固体或液体药物赋形剂和/或助剂混合,且如果需要与其它药物活性化合物混合成合适的给药形式或剂型,然后可以将它们用作人体用药或兽用药的药物。
可以将含有RAS抑制剂和/或其可药用衍生物的药物通过口服、胃肠外、静脉内、直肠或通过吸入给药,优选的给药方式取决于疾病的特定症状。可以将RAS抑制剂和/或其可药用衍生物自身或与药物助剂一起使用,即用于兽用药或人用药。
本领域技术人员以其专业知识为基础可熟练使用适合于所需药物制剂的助剂。除溶剂、胶凝剂、栓剂基质、片剂助剂和其它活性化合物赋形剂外,还能够使用例如抗氧化剂、分散剂、乳化剂、消泡剂、矫味剂、防腐剂、加溶剂或着色剂。
就口服给药剂型而言,将活性化合物与诸如赋形剂、稳定剂或惰性稀释剂这样适合于它们的添加剂混合并通过常规方法混合成合适的给药剂型,诸如片剂、包衣片、硬胶囊、水溶液、醇溶液或油溶液。可以使用的惰性赋形剂有:例如阿拉伯树胶、氧化镁、碳酸镁、磷酸钾、乳糖、葡萄糖或淀粉、特别是玉米淀粉。制剂可以以干颗粒或湿颗粒的形式存在。可能的油赋形剂或溶剂有:例如植物油或动物油,诸如向日葵油或鳕肝油。
就皮下或静脉内给药而言,可以将活性化合物制成溶液、混悬液或乳剂,如果需要,可以将活性化合物与诸如加溶剂、乳化剂或其它助剂这样的常用物质混合。合适的溶剂例如有:水、生理盐水溶液或醇类,例如乙醇、丙醇、甘油;以及其它的糖溶液,诸如葡萄糖或甘露醇溶液;还可以选择上述各种溶剂的混合物。
适合于气溶胶或喷雾剂形式给药的药物制剂例如有通式I的活性化合物溶于可药用溶剂所获得的溶液、混悬液或乳剂,所述的溶剂诸如有、特别是乙醇或水或这类溶剂的混合物。
如果需要,所述制剂还可以含有其它药物助剂,诸如表面活性剂、乳化剂和稳定剂以及推进剂。这类制剂通常含有浓度约为0.1-10%(重量)、特别是约为0.3-3%(重量)的活性化合物。
所给予的活性化合物的剂量和给药频率取决于所用化合物的功效和作用期限、另外还取决于适应证的性质和所治疗哺乳动物的性别、年龄、体重和个体反应性。
体重约为75kg的患者的每日平均剂量至少为0.001mg/kg体重、优选0.01mg/kg到大约20mg/kg体重、优选1mg/kg体重。
还可以将RAS抑制剂和/或其可药用衍生物与其它用于预防上述症状的药理活性化合物一起使用而获得有利的治疗作用。
本发明进一步涉及一种用于预防心血管疾病的组合物,它含有肾素-血管紧张素系统抑制剂或其可药用衍生物以及其它抗高血压药、降胆固醇药、利尿药或阿司匹林。
本发明另外一般涉及RAS抑制剂和/或其可药用衍生物与降胆固醇药的联合用药物。
除以固定组合方式给药外,本发明还涉及RAS抑制剂和/或其可药用衍生物与它抗高血压药、降胆固醇药、利尿药或阿司匹林同时、分别或依次给药的方式。
本发明另外涉及包括RAS抑制剂和/或其可药用衍生物与降胆固醇药的药物制剂(组合物)。
例如,可以通过将各成分紧密混合成粉末或通过将各成分溶解在诸如低级醇这样的合适溶剂中,且之后除去溶剂来制备本发明组合物的药物制剂。
RAS抑制剂和/或其可药用衍生物与降胆固醇药在新型组合物和制剂中的重量比在1∶0.01-1∶100、优选1∶0.1-1∶10的范围。
新型组合物和制剂可以总计含有0.5-99.5%(重量)、特别是4-99%(重量)的这些活性化合物。
当按照本发明用于哺乳动物、优选人体内时,各种活性化合物成分的剂量例如在0.001-100mg/kg/天的范围内改变。
一般来说,这些组合物的各每日剂量可以在将它们单独给药时针对个体的推荐的最低临床剂量的1/5到推荐的最高剂量水平的范围。
通过联合给药,一种组合物成分的作用可以被其它各自的成分所加强,即新型组合物或制剂的作用和/或作用期限较强或持续作用强于各个成分的作用和/或作用期限(协同作用)。与单独给药相比,这种联合给药方式导致各个组合物成分中的剂量降低。新型组合物和制剂因此具有的优点在于所给予的活性化合物的量可显著降低且不需要的副作用可以得到消除或显著减少。
优选的组合物含有例如阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸肌丙抗增压素、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉和螺普利、最优选雷米普利作为RAS抑制剂和洛伐他汀、普伐他汀、辛伐他汀或氟伐他汀作为降胆固醇药。
在定义RAS系统抑制剂与其它抗高血压药、降胆固醇药、利尿药或阿司匹林联合应用的术语″联合疗法″用来包括在一种产生药物联合有益作用的方案中以顺序方式给予各活性剂,且还用来包括以基本上同时的方式、诸如通过口服摄取具有固定比例的这些活性剂的单个胶囊或摄取多个各活性剂的单一胶囊的方式共同给予这些活性剂。
″联合疗法″还包括通过静脉内、肌内或其它胃肠外途径同时或依次给药入体内,包括通过粘膜组织直接吸收,正如在窦通道中发现的。依次给药还包括药物组合,其中可以在不同的时间点和/或通过不同途径给予各个成分,但是这些成分以联合方式起作用以提供有利作用。
术语″有效量″用来限定用于获得预防心血管疾病目的联合疗法、同时避免通常与各活性剂相关的不良副作用的各活性剂的用量。
用于组合物或用于联合疗法的其它抗高血压药类型的实例例如是钙通道阻断剂(或钙拮抗剂)和β-阻断剂。
可用的β-阻断剂包括噻吗洛尔、阿替洛尔、美托洛尔、普萘洛尔(propanolol)、纳多洛尔和吲哚洛尔普萘洛尔(pindololpropanolol)。
可用的钙通道阻断剂包括地尔硫、非洛地平、硝苯地平、氨氯地平、尼莫地平、伊拉地平、尼群地平和维拉帕米。
可用的利尿药包括甲氯噻嗪、氢氯噻嗪、托拉噻咪(torsemide)、美托拉宗、呋塞米、氯噻酮、N-(5-氨磺酰基-1,3,4-噻二唑-2-基)乙酰胺、氨苯蝶啶、氯噻嗪、吲达帕胺、布美他尼、阿米洛利、螺内酯、苄氟噻嗪、苄噻嗪、环噻嗪、喹乙宗、氢氟噻嗪、泊利噻嗪、三氯噻嗪和依他尼酸。
可用的降胆固醇药的实例是抑制素。
将3-羟基-邻甲基戊二酰基-辅酶A(HMGCoA)转化成甲羟戊酸是胆固醇生物合成途径中的早期和限速步骤。该步骤由酶HMOCoA还原酶催化。抑制素因催化该转化步骤而抑制HMGCoA还原酶。抑制素由此是具有共同功效的降胆固醇药。
抑制素包括下面这类化合物:如美国专利4,444,784中公开的辛伐他汀;美国专利4,346,227中公开的普伐他汀;美国专利5,502,199中公开的cerivastatin;美国专利3,983,140中公开的美伐他汀;美国专利4,448,784和美国专利4,450,171中公开的velostatin;美国专利4,739,073中公开的氟伐他汀;美国专利4,804,770中公开的compactin;美国专利4,231,938中公开的洛伐他汀;EP-A 738510中公开的达伐他汀;EP-A 363934中公开的fluindostatin;美国专利4,681,893中公开的atorvastatin;美国专利5,273,995中公开的atorvastatin calcium;和美国专利4,450,171中公开的dihydrocompactin,将上述全部文件引入本文作为参考。
优选的抑制素包括洛伐他汀、普伐他汀、辛伐他汀和氟伐他汀。
阿司匹林通过在活性位点上使血小板环加氧酶乙酰化而以不可逆转的方式使该酶失活。除降低死亡率外,阿司匹林还可缓解中风和心肌梗死。尚不了解阿司匹林的这种有利作用的确切机理。
实施例
本文所列的实施例的含义是以实施本发明的不同方面为典型而不以任何方式来限定本发明。
设计大规模临床试验(HOPE(心脏结果预防评价)研究)以便检验ACE抑制剂雷米普利与安慰剂相比在降低心血管疾病中的作用。使9,297位没有已知低EF或HF的高危患者(≥55岁、患有明显的血管疾病或糖尿病和另一种危险因素)随机接受雷米普利(2.5mg-10mg/天)或对照组接受安慰剂持续5年的平均期限。原发性结果是首先发生心血管(CV)死亡率、心肌梗死或中风的混合结果。本研究因令人信服的有利证据而由独立数据和安全监测委员会(the independent Data and Safety MonitoringBoard)在4.5年时终止。646(13.9%)位属于雷米普利组和816(17.5%)位属于安慰剂组的患者经历了原发性结果(相对危险性RR为0.78,95%置信区间为0.70-0.86;P值=0.000002)。在CV死亡率(6.0%对8.0%,RR为0.75,P值=0.0002)、心肌梗死(9.8%对12.0%,RR为0.68,P值=0.0002)方面分别存在明显和显著降低。在诸如总死亡率(10.3%对12.2%,RR为0.00035)、血管再通术(16.0%对18.4%,RR为0.85,P值=0.0013)、心脏停博(0.8%对1.2%,RR为0.63;P值=0.03)、心衰(7.4%对9.4%,RR为0.78;P值=0.0005)和糖尿病并发症(6.4%对7.7%,RR 0.85;P值=0.017)这样的继发性结果方面也得到了显著降低。其它结果包括绞痛恶化或新出现的绞痛或新出现的心衰(与住院治疗无关)。
雷米普利在没有低EF或心衰的广泛范围的高危患者中显著减少了死亡率、心肌梗死、中风、血管再通术和心衰并预防了糖尿病并发症。
方案和结果如下面列出的实施例中所述。
实施例1研究设计
在双盲、2x2因子的随机化试验中,HOPE评价了雷米普利或维生素E在9541位患者中的作用。对244位患者进行的进一步研究测试了低剂量(2.5mg/天)与全剂量(10mg/天)的雷米普利。将在这244位患者中的原发性结果作为表3的脚注报导。因此,主要结果报导针对的是随机接受10mg雷米普利或等量的安慰剂的9,297位患者。单独报导了维生素E的作用。已经公开了HOPE的设计(《加拿大心脏病学杂志》(Can JCardiology)1996;12(2);127-137),将其简要概括如下:
患者的接纳/排除
男性和女性均有资格,条件是年龄在55岁和55岁以上,目前患有冠状动脉疾病、中风、外周血管疾病或糖尿病加至少一种危险因素(目前或早先患有高血压、总胆固醇升高、低HDL胆固醇、目前吸烟、已知的微白蛋白尿或早先患有血管疾病)。排除下列患者:已知具有低EF的患HF的患者;服用ACE-I或维生素E的患者;患有未加控制的高血压或明显的肾病的患者;或新近的MI(<4周)的患者。在该阶段,使用简单试验以在全部患者(他们中没有一人患心衰或认为需要ACE-I)中测定左心室功能是不切实际的。而对来自进入进一步研究的3个中心的全部患者(n=496)作超声波心动图。发现其中有2.6%的患者具有的EF<0.40。另外,对图的检查鉴定了已经在5285位患者中进行了预随机化和对心室功能的评价。仅对409位患者(7.7%)记录了具有低EF且在随机化前没有一人患有心衰。提供了那些记录具有保持的EF(n=4876)的单独分析结果。在获得书面报告许可后,全部有资格的患者进入试验阶段,其中他们接受2.5mg雷米普利OD、持续7-10天,随后对比接受安慰剂10-14天。将下列情况的患者排除:不服从的患者(服用<80%药丸);经历副作用、肌酸酐或钾水平异常升高的患者或那些退出许可的患者。包括9,541位患者;使9,297位患者随机接受10mg/天的雷米普利或对比接受安慰剂,其中244位患者随机接受低剂量(2.5mg/天)的雷米普利。
在随机化时,指定患者接受2.5mg OD的雷米普利1周,然后再接受3周的5mg OD,随后每日接受一次10mg或对比接受安慰剂。另外,使全部患者随机接受维生素E 400 IU/天或对比接受安慰剂。在1个月、6个月且之后每隔6个月进行随访。在每次随访时,收集有关疾病、接受性和导致改变研究药物的副作用的数据。记录有关其它形式的全部原发和继发情况并使用标准化定义进行集中判定。
研究组织:在18个月期限(1993年12月-1995年6月)内从加拿大(129)、美国(27)、14个西欧国家(76)、阿根廷和巴西(30)以及墨西哥(5)的中心征集患者。每个机构的检察委员会均批准了该方案。组织本研究并由位于预防心脏病学和治疗研究项目,汉密尔顿科学公司研究中心,McMaster大学,汉密尔顿,加拿大Preventive Cardiology andTherapeutics Research Program,Hamilton Health SciencesCorporation Research Centre,McMaster University,Hamilton,Canada的加拿大心血管合作计划部(the Canadian CardiovascularCollaboration Project Office)组织和协调。辅助设计部门位于英国的伦敦、巴西的圣保罗和阿根廷的Rosario。总体研究职责由指导委员会(Steering Committee)承担。
统计分析:本研究开始针对的是平均参与3.5年的参与者。然而,在该期限结束前,指导委员会(the Steering Committee)(对任何结果来说是未知的)推定在治疗具有其完全的作用前可能有一个迟滞期并建议将随访扩展至5年。假定在5年中每年有4%的发病率,那么对9,000位患者中的90%具有检测到相对危险性降低13.5%的能力、使用的2侧α(sided alpha)为0.05,以治疗目的为基础对他们进行分析。使用Kaplan-Meier程序对存活曲线进行评估并使用log-rank检验比较治疗方案。由于使用了因子设计,所以将全部分析分层进行以便对维生素E或对照品随机化。使用用于Cox回归模型中的相互作用的检验来进行亚组分析。也将该模型用于调节关键预后因素中的任何不平衡值所用的治疗作用估计值。经调整和未调整的分析实际上提供了相同的结果,所以仅提供未调整的估计值。
阶段分析、数据监测和早期终止:独立数据和安全监测委员会(DSMB)监测本研究所有方面的进展。计划进行4种正式的阶段分析。用于有利作用的统计监测界限要求将前半部分试验的4个标准偏差与后半部分试验的3个标准偏差进行正交。就不利影响而言,相应的界限分别是3个和2个标准偏差。是决定停止还是继续进行试验将取决于许多其它因素,包括在主要亚组中结果的一致性。在1999年3月22日,独立的DSMB建议终止本试验,这是因为有清楚而持久的证据证明雷米普利的有利作用,即它可以在两次连续观察时连续而明显地通过监测界限。(在原发性结果中相对危险性降低为20%,其中95%Cl为12%-28%,Z为-4.5;p=0.00001)。在4月17日和4月24日举行的两次会议上将该试验结果对研究者公开。在1999年4月15日设定为主要分析用的所有情况的截止点。从4月19日开始停止我们的随访并到1999年6月30日为止完成预定方案。
实施例2
患者的特征:
表1提供了参与本试验的患者的基础特征。其中应注意有2480位女性(26.7%)、5128位大于65岁(55.2%)、8160患有血管疾病(87.8%)、4355位有高血压病史(46.8%)且有3578位患糖尿病(38.5%)。这使得HOPE在中年和糖尿病中和具有相当明显数量的高危高血压女性中进行的ACE-I试验最长。表1:HOPE研究患者的基础特征
雷米普利 | 安慰剂 | |
n(%) | N(%) | |
随机化序数量 | N=4645 | N=4652 |
平均年龄 | 66(7) | 66(7) |
女性数量 | 27.5 | 25.8 |
冠状动脉病史 | 3691(79.5) | 3784(81.3) |
心肌梗塞 | 2410(51.9) | 2482(53.4) |
≤1年 | 452(9.7) | 445(9.6) |
>1年 | 1985(42.7) | 2070(44.5) |
稳定性心绞痛 | 2538(54.6) | 2609(56.1) |
不稳定性心绞痛 | 1179(25.4) | 1188(25.5) |
CABG手术 | 1192(25.7) | 1207(25.9) |
PTCA | 853(18.4) | 806(17.3) |
中风或短暂性缺血发作 | 500(10.8) | 513(11.0) |
外周血管疾病 | 1963(42.3) | 2083(44.8) |
高血压 | 2212(47.6) | 2143(46.1) |
糖尿病 | 1808(38.9) | 1770(38.0) |
已知总胆固醇升高 | 3036(65.4) | 3089(66.4) |
已知低LDL | 842(18.1) | 882(19.0) |
目前吸烟 | 645(13.9) | 674(14.5) |
基线处的药物: | ||
β-阻断剂 | 1820(39.2) | 1853(39.8) |
阿司匹林/其它抗血小板药 | 3497(75.3) | 3577(76.9) |
降脂药 | 1318(28.4) | 1340(28.8) |
利尿药 | 713(15.3) | 706(15.2) |
钙通道阻断剂 | 2152(46.3) | 2228(47.9) |
ECG左心室肥大 | 378(8.1) | 405(8.7) |
患微白蛋白尿的数量 | 955(20.6) | 1008(21.7) |
血压 | 139/79 | 139/79 |
心律 | 69 | 69 |
体质指数 | 28 | 28 |
CABG=冠状动脉旁路移植手术,PTCA=经皮经腔内冠状动脉血管造影术,No.=数量,LDL=低密度脂蛋白。外周血管疾病包括跛行、外周动脉病史或踝-臂BP比<0.90。
实施例3
配合性
在那些被指定到雷米普利组的患者中,接受研究或开放标记ACE-I的比例在1年时为87.4%、在2年时为85.2%、在3年时为82.2%、在4年时为75.5%而在最终的随访时为78.3%。在1年时接受10mg雷米普利的患者为82.9%、在2年时为74.8%、在3年时为71.0%、在4年时为62.8%而在最终随访时仍接受10mg雷米普利的患者为64.6%。在被指定为安慰剂组的那些患者中,接受开放标记ACE-I的比例分别为3.4%、6.0%、8.1%、10.7%和12.7%。在本研究结束时,1.6%的接受雷米普利的患者和1.9%的接受安慰剂的患者开始接受血管紧张肽-2受体拮抗剂。将中断双盲疗法的最常见的原因概括在表2中。在雷米普利组中更多的患者因咳嗽(7.2%对1.7%)或高血压(1.8%对1.4%)而停止了药物治疗。相反,安慰剂组中的患者更多的是因为高血压得不到控制(0.3%对0.6%)或临床情况(1.9%对2.4%)而停止了双盲疗法。因心衰而接受非研究性的ACE-I的患者比例在活性剂组中为3.3%,而在安慰剂组中为4.5%,就蛋白尿而言分别为1.4%对1.6%,而就对高血压的控制率而言分别为4.4%对6.2%。开放标记A-2受体拮抗剂在两组中的应用较少(1.6%对1.9%),而原因反映出了与应用ACE-抑制剂相似的形式(心衰分别为0.6%对0.8%,高血压分别为1.1%对1.3%)。表2:中断双盲治疗的原因
*存活%实施例4
雷米替利 | 安慰剂 | |
随机化数量 | 4645 | 4652 |
任何时间停止的数量* | 1370(33.0) | 1247(30.7) |
永久中断的数量* | 1207(29.1) | 1087(26.7) |
停止的原因 | ||
咳嗽 | 335(7.2%) | 81(1.7%) |
高血压/头晕 | 82(1.8%) | 65(1.4%) |
血管性水肿 | 16(0.3%) | 12(0.3%) |
高血压未得到控制 | 16(0.3%) | 30(0.6%) |
临床情况 | 90(1.9%) | 113(2.4%) |
非研究ACE-I | 124(2.7%) | 187(4.0%) |
使用开放标记ACE-I的原因 | ||
心衰 | 231(5.0%) | 320(6.9%) |
蛋白尿 | 63(1.4) | 73(1.6%) |
高血压 | 205(4.4%) | 289(6.2%) |
血压
BP在进入试验时在两组中均为139/79。在1个月时在活性剂组中下降至133/76而在对照组中下降至137/78、在2年时在活性剂组中下降至135/76而在对照组中下降至138/78,且在本研究结束时在活性剂组中下降至136/76而在对照组中下降至139/77。
实施例5
原发性结果和总死亡率(表3)
在雷米普利组中有646位患者(13.9%)遭遇CV死亡、MI或中风的情况,与之相比,安慰剂组中存在这些情况的有816位患者(17.5%)(RR为0.78;95%Cl为0.70-0.86;p=0.000002)。此外,下列情况均分别得到了极为显著的降低:CV死亡率(278对371;RR为0.75;95%Cl为0.64-0.87;p=0.0002)、MI(453对559;RR为0.80;95%Cl为0.71-0.91;p=0.0005)和中风(155对225;RR为0.68;95%CL为0.56-0.84;p=0.0001)。所有导致死亡率的原因也得到了显著减少(476对567;RR为0.83;95%Cl为0.74-0.94;p=0.0035)。表3:原发性结果及其在HOPE研究中的部分
雷米替利 | 安慰剂 | RRR(95%Cl) | Z | Logrank p | |
随机化数量 | 4645 | 4652 | |||
CV死亡MI,中风* | 646(13.9%) | 816(17.5%) | 0.78(0.70-0.86) | -4.75 | 0.000002 |
CV死亡 | 278(6.0%) | 371(8.0%) | 0.75(0.64-0.87) | -3.72 | 0.0002 |
MI | 453(9.8%) | 559(12.0%) | 0.80(0.71-0.91) | -3.49 | 0.0005 |
中风 | 155(3.3%) | 225(4.8%) | 0.68(0.56-0.84) | -3.70 | 0.0002 |
总死亡率 | 476(10.3%) | 567(12.2%) | 0.83(0.74-0.94) | -2.92 | 0.0035 |
*使用低剂量的雷米普利存在的其它情况34/244。包含的这些情况导致使用雷米普利出现的主要情况占13.9%,而使用安慰剂出现的主要情况占17.5%(RRR为0.78;95%Cl为0.70-0.86)。注意患者可能出现一种以上的情况。
实施例6
继发性和其它结果(表4)
进行血管再通术的患者数量明显减少(742对854;RR为0.85;95%Cl为0.77-0.94;p=0.0013),而HF住院治疗的倾向于较少(150对176;RR为0.84;95% Cl为0.68 to 1.05;p=0.13)。然而,对因不稳定的绞痛而住院治疗没有影响。患有心脏停博(37对58;RR=0.63;p.0.03)、绞痛加剧(1104对1220;RR=0.88;p=0.003)、新出现心衰(343对435;RR=0.78;p=0.0005)、新诊断为糖尿病(108对157;RR=0.69;p=0.003)或那些患有糖尿病并发症(319对378;RR=0.85;p=0.018)的患者数量也明显减少。表4:HOPE研究中的继发性和其它结果
雷米替利 | 安慰剂 | RRR(95%Cl) | Z | Logrank p | |
随机化数量 | 4645 | 4652 | |||
继发结果 | |||||
血管再通术* | 742(16.0%) | 854(18.4%) | 0.85(0.77-0.94) | -3.22 | 0.0013 |
住院治疗的不稳定绞痛* | 564(12.1%) | 573(12.3%) | 0.98(0.87-1.10) | - | 不详 |
糖尿病并发症** | 298(6.4%) | 357(7.7%) | 0.83(0.71-0.97) | -2.39 | 0.017 |
住院治疗的心衰* | 150(3.2%) | 176(3.8%) | 0.84(0.68-1.05) | -1.53 | 0.13 |
其它结果 | |||||
全部心衰** | 343(7.4%) | 435(9.4%) | 0.78(0.67-0.90) | -3.51 | 0.0005 |
心脏停博 | 37(0.8%) | 58(1.2%) | 0.63(0.42-0.96) | -2.19 | 0.03 |
绞痛恶化** | 1104 (23.8%) | 1220(26.2%) | 0.88(0.81-0.96) | -2.98 | 0.0029 |
新诊断的糖尿病 | 108(3.8%) | 157(5.5%) | 0.69(0.54-0.88) | -3.01 | 0.0026 |
具有ECG改变的UA | 179(3.4%) | 185(4.0%) | 0.96(0.78-1.18) | - | 不详 |
集中判定的情况;**包括与住院治疗无关的情况。
+糖尿病并发症包括糖尿病性肾病、肾脏透析和用于糖尿病性肾病的激光疗法。
实施例7
亚组分析(表5)
在下列患者中持续观察到了对原发性结果的有利影响:糖尿病和非糖尿病患者;女性和男性,证实有和没有心血管疾病的那些患者;年龄在65岁和超过65岁的那些患者;处于高血压基线和不处于高血压基线上的患者;和处于微白蛋白尿基线和不处于微蛋白尿基线上的患者。此外,在参与本研究但有或没有证据表明患冠状动脉疾病、患有或未患有MI的两组患者和记录EF≥0.40的那些患者(n=4676)中存在明显的有利作用(317/2339对427/2337;RR为0.73;95%Cl为0.63-0.84;p=0.00002)。表5:不同亚组中雷米普利与安慰剂相比的影响:注意结果的一致性且在大部分情况中95%Cl的上限小于1
患者数量 | 安慰剂比例 | 原发性混合结果RRR(95%Cl) | |
A)预定的亚组 | |||
CVD+ | 8160 | 18.5 | 0.78(0.71-0.87) |
CVD- | 1137 | 10.1 | 0.81(0.56-1.20) |
糖尿病+ | 3578 | 19.6 | 0.76(0.65-0.89) |
糖尿病- | 5719 | 16.3 | 0.79(0.69-0.91) |
B)其它亚组 | |||
年龄<65 | 4169 | 14.0 | 0.82(0.70-0.98) |
年龄65+ | 5128 | 20.5 | 0.75(0.66-0.85) |
男性 | 6817 | 18.5 | 0.79(0.70-0.89) |
女性 | 2480 | 14.7 | 0.76(0.61-0.95) |
高血压+ | 4355 | 19.0 | 0.75(0.65-0.87) |
高血压- | 4942 | 16.3 | 0.81(0.70-0.93) |
CAD+ | 7475 | 18.4 | 0.80(0.71-0.89) |
CAD- | 1822 | 13.9 | 0.71(0.54-0.93) |
已有MI+ | 4892 | 20.7 | 0.79(0.69-0.90) |
已有MI- | 4405 | 14.0 | 0.77(0.65-0.91) |
大脑VD+ | 1013 | 25.5 | 0.73(0.56-0.95) |
大脑VD- | 8284 | 16.6 | 0.79(0.71-0.88) |
PVD+ | 4046 | 21.8 | 0.74(0.64-0.86) |
PVD- | 5251 | 14.1 | 0.84(0.72-0.98) |
MA+ | 1963 | 26.1 | 0.71(0.59-0.86) |
MA- | 7334 | 15.2 | 0.82(0.72-0.92) |
CVD=心血管疾病,CAD=冠状动脉疾病,
MA=微白蛋白尿,PVD=外周血管疾病
实施例8
有利作用的时间过程
在随机化后1年内原发性结果的减少是明显的(167对197;RR为0.85;95%Cl为0.69-1.04),且到2年时具有统计学显著性(323对396;RR为0.81;95%Cl为0.70-0.94)。以存活到当年为基础,相对危险性在第2年为0.78、在第3年为0.74且在第4年为0.73。讨论
HOPE试验最终证明雷米普利,即一种ACE-I对广泛的患者具有有利作用,没有证据显示这些患者患有LV心脏收缩功能障碍或未来高危心血管疾病的HF。死亡率、MI和中风中的每一种均明显减少。冠脉血管再通术、心脏停博和心衰的发展也得到了明显缓解。雷米普利还减少了糖尿病并发症的危险和非糖尿病中糖尿病的发展。ACE-I目前更为广泛的有利作用
这些数据基本上扩充了得益于ACE-I的群体并与在具有低EF或HF和急性MI的患者中进行的预先研究进行相互补充。HOPE研究的主要原理在于ACE抑制作用可预防与局部缺血和粥样硬化以及心衰和左心室功能障碍相关的疾病。为了避免对本研究结果解释中可能出现的混乱,我们有意将我们的试验限制到那些没有HF的患者并排除那些具有已知低EF的患者。然而,本研究确实包括处于与动脉粥样硬化和血栓性血管闭塞相关的结果危险中的大量个体。因此,包括患有冠状动脉疾病(例如不稳定性绞痛、稳定性绞痛或预先进行血管再通术)、以前有大脑血管疾病或外周动脉病史的任何体征的广泛患者。结果,我们已经能够证明ACE-I在患有CV死亡、MI或中风危险增加的动脉粥样硬化临床体征范围的广泛患者中的价值。这种方法既不是主要也不是次要的预防措施,而是相当高危的预防策略,它包括具有未来即将发病的高度可能性的个体,而不包括仅存在特殊危险因素或发生特殊心血管疾病的患者。本结果证实了这种方法在鉴定具有显著比例的CV终点的高危人群中的成功,其中所述的CV终点能够得益于预防动脉粥样硬化或其并发症发展的疗法。这些发现以及两组预试验的那些结果具有主要的临床重要性且表明对HF记录低EF不应是在高危CV情况患者中长期使用ACE-I的标准,这是因为还存在其它临床标准。
有3578位糖尿病患者参与了我们的研究,其中有1100位患者没有CVD的临床体征且其CV结果的危险被降低了约一半。尽管如此,我们仍观察到RRR与本试验中的总体有利作用一致且在这类糖尿病患者中,CV死亡、MI、中风、血管再通术和糖尿病并发症的混合结果均得到了明显减少。与其它预防策略相似的ACE-I的有利作用
在4年的治疗期限内ACE-I有利作用的程度至少与使用其它证明是次要预防措施中所观察到的有利作用的程度一样大,所述的其它次要预防措施诸如使用β阻断剂(Yusuf S等《心血管疾病研究进展》(ProgCardiovasc Dis)1985;27(5):335-371)、阿司匹林(BMJ 1994;308(6921):81-106)和降脂药(Law M.《脂类和心血管疾病》(Lipidsand cardiovascular disease)第13章:Yusuf S,Cairns JA,CammAJ,Fallen EL,Gersh BJ.(编辑),“基于心脏病学的证据”(EvidenceBased Cardiology.)London:BMJ Books,1998.191-205页)。由于在HOPE和ACE-I预试验中使用了广泛的人群、除其它有效疗法和高度可接受性的有利作用外,还极为明确地证明了ACE-I在CV预防和治疗方面具有主要作用。在本试验的第1年中相对危险性的降低约为11%、在第2年中增加到22%(有条件的RRR)、在第3年中为26%且在第4年中为27%。这些数据表明有利作用随至少在第2年中得到维持且可能在未来几年中增加的分散而非常快速的出现。这一结果提示ACE-I的有利作用能够在长期治疗时得到维持且可能得到促进。有利作用是对伴随经证明的药物疗法的补充
在接受诸如阿司匹林、β阻断剂和降脂药这样大量有效治疗的患者中观察到了雷米普利的有利作用,从而表明ACE抑制作用为预防动脉粥样化血栓并发症提供了另外一种手段。仅小部分患者CV死亡率、MI和中风减少可能是由于BP降低,因为作为参与本研究的大部分患者不是高血压患者(经常规定义确定),且BP降低的非常温和(-3收缩压/-2mmHg舒张压)。舒张压BP降低2mm可能最好解释中风患者减少了约一半且心肌梗死患者减少了约四分之一(Collins R.等《柳叶刀》(Lancet)1990;335(8693):827-838)。然而,诸如高血压最佳治疗方法(theHypertension Optimum Treatment)(Hansson L.等《柳叶刀》(Lancet)1998;351(9118):1755-1762)这样的近期试验提示:就高危患者、例如糖尿病而言,降低甚至在″正常″范围内的BP也可以是有利的。此外,对基于20年BP数据的Framingham心脏研究(the Framingham HeartStudy)的近期再分析(Clarke R.等《美国流行病学杂志》(Am JEpidemiology)1999;150(4):(出版中)提示可能低估了从较低BP中预计的有利作用的程度。不管这些情况,ACE-I对心脏或血管系统的其它直接机制可能具有重要性。它包括拮抗血管紧张肽-II对血管收缩、血管平滑肌增生(Lonn EM等《循环》(Ciculation)1994;90(4):2056-2069)和血小板破裂(Schieffer B.等《循环》(Ciculation)(出版中))的直接作用;改善血管内皮功能、减轻LV肥大和促进纤维蛋白溶解(Lonn EM等《循环》(Ciculation)1994;90(4):2056-2069)。
此外,在未证实患有LV心脏收缩功能受损的患者中观察到了因心衰而病情发展或住院的患者数量减少。这些对在具有低EF的患者中进行的SOLVD预防试验且SAVE试验(低EF早期MI后)的补充的数据证明ACE-I可预防心衰的发展;而在记录有低EF和HF的患者中进行的试验表明因心衰而住院治疗的患者在减少。HOPE和这些研究表明ACE-I可能在与左心室收缩功能障碍程度无关的发展中的心衰的高危患者中具有价值。应该考虑到的一点是该结果已经受到包括具有未诊断的低EF的个体的影响的程度。这种可能极低,因为:a)在包括468位连续接受治疗的患者在内的3个中心中进行的大量进一步研究表明仅2.6%的患者具有的EF在.40以下;b)广泛的图检查确定在随机化前仅<5%的患者具有低EF;和c)在记录了保持的心室功能的患者(n=4676)以及在那些预先未患MI(RR为0.79;95%Cl为0.69-0.90;p=0.0004)亚组中观察到了明显的有利作用(RR为0.73;95%Cl为0.63-0.84;p=0.00002)。对糖尿病的有利作用的可能机制
观察到发展中的糖尿病并发症的患者数量和新近诊断为患有糖尿病的患者数量均显著减少。这些作用可能通过改善胰岛素敏感性或胰岛素的肝脏清除率降低来介导。该结果还与近期的卡托普利预防设计试验(captopril prevention project trial)(Hansson L.等《柳叶刀》(Lancet)1999;353(9153):611-616)结果一致,它表明在随机接受卡托普利的患者中新近诊断为糖尿病的数量比接受利尿药或β阻断剂的患者数量减少,且其它试验表明在用ACE-抑制剂治疗的II型糖尿病中糖尿病性肾病的发展得到缓解(Ruggenenti P.等《柳叶刀》(Lancet)1999;354(9176):359-364)。安全性和耐受性
ACE-抑制剂雷米普利在本试验中一般耐受良好。除因咳嗽停用雷米普利的患者数量增加外(超过5%),不存在更为明显频发的其它副作用。因头晕/低血压而停用药物的患者数量有一个不明显的小的增加(0.3%)。大部分患者(约80%)在本试验的4.2年的期限内保持接受ACE-I。结论
HOPE研究清楚地证明雷米普利即一种长效ACE-抑制剂降低了广泛高危患者的死亡率、减少了MI、中风、血管再通术、心脏停博、新出现的心衰和糖尿病并发症。用ACE-抑制剂将1000位患者治疗4年防止了160位患者患上述疾病中的任意一种。
将所有的专利、专利申请、公开的文章、书籍、参考工具书和其中引用的摘要的全部内容引入本文作为参考以便更完整地描述本发明所涉及的本领域的状况。
当可以对上述主题进行各种改变而不会脱离本发明的范围和实质时,将包含在上述说明书中、在附图中所示或在所附权利要求中定义的所有主题解释为描述性的和说明性的且没有限定的含义。能够根据上述教导对本发明进行许多修改和变化。因此,可以理解的是除特别描述的外可以在所附权利要求范围内实施本发明。
Claims (27)
1.肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防心血管疾病的药剂中的用途。
2.权利要求1所述的用途,其中所述的心血管疾病是心肌梗死、绞痛加剧或心脏停博。
3.权利要求1或2所述的用途,用于患有心血管损害加剧的患者。
4.权利要求3所述的用途,其中所述的心血管损害是由于明显的冠心病、短暂局部缺血发作或中风病史或外周血管疾病病史所导致的。
5.肾素-血管紧张素系统抑制剂或其可药用衍生物在制备用于预防心肌梗死、中风、心血管死亡或糖尿病患者中的明显肾病的药剂中的用途。
6.肾素-血管紧张素系统抑制剂或其可药用衍生物与其它抗高血压药、降胆固醇药、利尿药或阿司匹林组合在制备用于预防心血管疾病、糖尿病或糖尿病并发症的药剂中的用途。
7.权利要求6所述的用途,其中所述的心血管疾病是中风、充血性心力衰竭、心血管死亡、心肌梗死、绞痛加剧、心脏停博或血管再通术。
8.权利要求6所述的用途,其中所述的心血管疾病是预先未患充血性心力衰竭的患者的充血性心力衰竭。
9.权利要求1-8中任意一项所述的用途,其中所述的肾素-血管紧张素系统抑制剂是血管紧张肽转化酶抑制剂、血管紧张肽II拮抗剂或它们中任意的可药用衍生物。
10.权利要求9所述的用途,其中所述的血管紧张肽转化酶抑制剂是奥马帕唑普利、MDL100240、阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸肌丙抗增压素、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉和螺普利或其可药用衍生物。
11.权利要求9所述的用途,其中所述的血管紧张肽II拮抗剂是醋酸肌丙抗增压素、堪达沙坦西来克斯特、缬沙坦、堪达沙坦、氯沙坦钾、艾扑沙坦、爱博沙坦、特索沙坦或替米沙坦或其可药用衍生物。
12.权利要求6、7或8所述的用途,其中所述的抗高血压药是钙通道阻断剂或β阻断剂。
13.一种含有肾素-血管紧张素系统抑制剂或其可药用衍生物和降胆固醇药的组合物。
14.一种根据权利要求13的组合物,其中所述的肾素-血管紧张素系统抑制剂是血管紧张肽转化酶抑制剂或其可药用衍生物且所述的降胆固醇药是一种抑制素。
15.一种根据权利要求14的组合物,其中所述的血管紧张肽转化酶抑制剂是omapatrilat、MDL100240、阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸肌丙抗增压素、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉和螺普利或其可药用衍生物;且所述的抑制素是洛伐他汀、普伐他汀、辛伐他汀和氟伐他汀或其可药用衍生物。
16.一种心血管疾病的预防方法。该方法包括对需要这类预防的患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物的步骤。
17.一种权利要求16的方法,其中所述的心血管疾病是心肌梗死、绞痛加剧或心脏停博。
18.一种权利要求16或17的方法,其中所述的患者患有加剧的心血管损害。
19.一种权利要求17的方法,其中所述的心血管损害是由于明显的冠心病、短暂局部缺血发作或中风病史或外周血管疾病病史所导致的。
20.一种预防心肌梗死、中风、心血管死亡或糖尿病患者中的明显肾病的方法,该方法包括对所述患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物的步骤。
21.一种预防心血管疾病、糖尿病或糖尿病并发症的方法,该方法包括对需要这类预防的患者给予有效量的肾素-血管紧张素系统抑制剂或其可药用衍生物以及有效量的其它抗高血压药、或降胆固醇药、或利尿药或阿司匹林的步骤。
22.一种权利要求21的方法,其中所述的心血管疾病是中风、充血性心力衰竭、心血管死亡、心肌梗死、绞痛加剧、心脏停博或血管再通术。
23.一种权利要求21的方法,其中所述的心血管疾病是预先未患充血性心力衰竭的患者体内的充血性心力衰竭。
24.一种权利要求16-23的方法,其中所述的肾素-血管紧张素系统抑制剂是血管紧张肽转化酶抑制剂、血管紧张肽II拮抗剂或它们中任意的可药用衍生物。
25.一种权利要求24的方法,其中所述的血管紧张肽转化酶抑制剂是奥马帕唑普利、MDL100240、阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸肌丙抗增压素、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉和螺普利或其可药用衍生物。
26.一种权利要求24的方法,其中所述的血管紧张肽II拮抗剂是醋酸肌丙抗增压素、堪达沙坦西来克斯特、缬沙坦、堪达沙坦、氯沙坦钾、艾扑沙坦、爱博沙坦、特索沙坦或替米沙坦或其可药用衍生物。
27.一种权利要求21、22或23的方法,其中所述的抗高血压药是钙通道阻断剂或β阻断剂。
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US20050065203A1 (en) * | 2001-10-17 | 2005-03-24 | Salim Yusuf | Method of reducing type 2 diabetes in high risk patients |
PL370270A1 (en) * | 2001-11-23 | 2005-05-16 | Solvay Pharmaceuticals Gmbh | Hypertonia treatment during the acute phase of a cerebrovascular accident |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110833620A (zh) * | 2018-08-15 | 2020-02-25 | 王镕 | 血管紧张素转化酶抑制剂在防治自身免疫性疾病及相应的并发症中的用途 |
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