CN1437484A - 含有β-受体阻滞剂和任选的降胆固醇剂的新型制剂 - Google Patents
含有β-受体阻滞剂和任选的降胆固醇剂的新型制剂 Download PDFInfo
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- CN1437484A CN1437484A CN01811540A CN01811540A CN1437484A CN 1437484 A CN1437484 A CN 1437484A CN 01811540 A CN01811540 A CN 01811540A CN 01811540 A CN01811540 A CN 01811540A CN 1437484 A CN1437484 A CN 1437484A
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Abstract
本发明涉及一种含β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺和物中以低于50mg的维持剂量存在,具体地说是在25-47mg的范围内,并任选含有降胆固醇剂。本发明还涉及一种治疗方法以及该制剂在治疗动脉粥样硬化症和相关疾病中的应用。
Description
发明领域
本发明涉及一种含β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺和物中以低于50mg的维持剂量存在。本发明还涉及一种治疗方法以及该制剂在治疗动脉粥样硬化和相关症状中的应用。
发明背景
由于动脉粥样硬化症已经成为工业时代最普遍的健康问题,所以对于能够进一步降低其风险的新药物的需求一直都很迫切。
许多药剂,例如我们所知的β-受体阻滞剂类对于许多心血管疾病都有积极的作用,但是对于动脉粥样硬化症的作用却鲜为人知。已经证明,β-受体阻滞剂在继发的(The Norwegian Multicenter Studygroup,N Engl J Med,304:801-807,1981;Olsson等人,J Am CollCardiol,5:1428-1437,1985;MERIT-HF Study Group,Lancet,353:2001-2007,1999)以及原发预防性研究中(Wikstrand等人,JAMA,259:1976-1982,1988)可以减少心血管疾病的发生和死亡。在动物试验中,β-受体阻滞剂可以减轻由饮食(stlund-Lindqvist等人,Arteriosclerosis,8:40-45,1988)和紧张(Kaplan等人,Eur Heart J,8:928-944;Pettersson等人,Curr Op in Cardiol3:S9-S14,1988)引起的动脉粥样硬化的程度,但没有直接的证据表明β-受体阻滞剂具有抗动脉粥样硬化的作用,该作用与他汀类药物(statin)对于人体所显示的颈动脉内膜中层增厚(IMT)的效用类似。
将β1选择性阻滞剂与降脂类药物向健康志愿者组合给药来观察其对运动中脂肪代谢、氨含量和努力知觉的影响已在Br.J.ClinPharmacol 1997 43卷,第3期291-300页上公开。被研究的组合是1)美托洛尔(控释剂型)和氟伐他汀,2)美托洛尔(控释剂)和苯扎贝特,3)阿替洛尔(普通剂型)和氟伐他汀,以及4)阿替洛尔(普通剂型)和苯扎贝特。这篇文章得出结论认为这四种组合每一种都可以导致脂肪代谢明显降低,增加血浆中氨的浓度和提升运动知觉。组合1)有最小的副作用,但制剂的不同被认为是造成它与组合3)作用有差别的重要因素。
氟伐他汀与阿替洛尔组合对于高血压和高胆固醇血症患者的作用已在Scand.J.Print Health Care 1999,17卷122-127作出报道。其结论认为阿替洛尔的作用并没有受到同时给药的氟伐他汀的影响,反过来亦如此。但是生活方式的影响也是这个研究的特点,所以从此研究得出的结论还不是很清楚。
在Hypertension,1992,19卷,3242报道了有关对接受过洛伐他汀和抗高血压药物包括β1肾上腺素受体阻滞剂治疗的患者进行结果分析。该文章的结论是,受限于种种局限性,但没有证据表明稀释的洛伐他汀与常用的抗高血压药剂同时给药会引起脂质和脂蛋白的变化或是改变洛伐他汀的安全分布。
Presse Med Volume 1996,25卷,第40期,2013-2016中结论是在与氟伐他汀联合使用时,β1肾上腺素受体阻滞剂阿替洛尔的作用并没有受到抑制。但是氟伐他汀对于脂质代谢的作用在与血管紧张肽转化酶抑制剂卡托普利联合使用时要强于与阿替洛尔联合使用时的作用。
低剂量的美托洛尔用于治疗高血压和心脏病已经有报道,但是这些报道表明使用低剂量美托洛尔会产生不同程度的功效。Westergren等人在Current Therapeutic Research,1994 55卷,第2期,142中描述了采用控释片剂量为50mg的美托洛尔(为通常用于立即释放型美托洛尔每日剂量的一半)治疗中轻度高血压。报道认为这个剂量美托洛尔的耐受性好。但是Sanderson等人在British Heart Journal,1995,74卷,502中宣称,6.25mg低剂量的美托洛尔每天两次给药对有严重心脏衰竭的患者是非常危险的。
Garnett发表在Americal Journal of Health-SystemPharmacology,1995,52卷,1639的综述中描述了HMG-CoA还原酶抑制剂的药代动力学图谱,探索并证明了特定药物间的交互作用。
WO 98/02357公开了一种用于装载药物活性成分或其组合的纸盒。所提及的这类组合之一是β-受体阻滞剂如美托洛尔或一硝酸异山梨醇酯与降脂物质如氟伐他汀的组合。此申请没有公开任何关于这些组合疗效的数据。
WO 99/11260公开了一种阿托伐他汀和一种抗高血压剂的组合,但在该申请中没有公开数据。
WO 97/38694公开了一种HMG-CoA还原酶(3-羟基-3-甲基戊二酸单酰辅酶A还原酶)抑制剂与叶酸以及选自包括β-受体阻滞剂的其他种类药物的组合。
WO 00/38725公开了一种小肠胆汁运输抑制剂与包括抗高血压药物如β-受体阻滞剂在内的其他种类药物的组合,但没有提供数据。
发明概述
本发明涉及一种含β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺和物中以低于50mg的维持剂量,特别是在10-47mg,尤其是25-47mg的量存在。本发明还涉及一种治疗方法以及该制剂在治疗动脉粥样硬化,包括食物导致的和紧张导致的动脉粥样硬化、冠状动脉粥样硬化、颈动脉斑块、高血压、糖尿病、中风、心血管死亡、心绞痛、间歇性跛行和心肌梗塞中的应用。发明详述
已经惊奇地发现,低剂量的β-受体阻滞剂,尤其是美托洛尔可以降低由颈动脉斑块引起的临床健康无症状的颈动脉内膜中层增厚的增长速度,同时对于抑止动脉粥样硬化的发展也有良好的作用。
在一方面,本发明涉及含β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺和物中以25-47mg的维持剂量存在,β-受体阻滞剂的剂量优选低于30mg,最优选为25mg。
在本申请中,术语“β-受体阻滞剂”指其药理作用可阻断β1受体的任何药剂。此外,在本申请中,术语“β-受体阻滞剂”还包括β-受体阻滞剂的化学改进剂,例如酯类、立体异构物、药物前体和代谢物,可以是活性或非活性的,以及其可接受的药用盐类或溶剂化物,或这些盐类的溶剂化物。
在本申请中所提到的短语“低于50mg的维持剂量”是指能阻断β1受体的任何β受体阻滞剂的最高剂量,其效果与47mg的美托洛尔琥珀酸盐的效果相似。
β1受体的阻滞程度被定义为在24小时内减少由于运动引起的心率的增加。
本申请所指β受体阻滞剂包括但不仅限于选自下列的组合:醋丁洛尔、阿普洛尔、氨磺洛尔、阿罗洛尔、阿替洛尔、苯呋洛尔、倍他洛尔、贝凡洛尔、比索洛尔、波吲洛尔、布库洛尔、布非洛尔、丁呋洛尔,布尼洛尔、布拉洛尔、丁非洛尔、卡拉洛尔、卡替洛尔、卡维地洛、塞利洛尔、塞他洛尔、氯拉洛尔、地来洛尔、依泮洛尔、茚诺洛尔、拉贝洛尔、左布诺洛尔、甲吲哚洛尔、美替洛尔、美托洛尔、莫普洛尔、纳多洛尔、萘肟洛尔、奈必洛尔、尼普地洛、氧烯洛尔、喷布洛尔、吲哚洛尔、普拉骆尔、丙萘洛尔、普萘洛尔、索他洛尔、硫氧洛尔、他林洛尔、特他洛尔、替利洛尔、噻吗洛尔、托利落尔、希苯洛尔以及他们的立体异构物和可接受的药用盐类或溶剂化物,或是这些盐类的溶剂化物。
在本发明中,β-受体阻滞剂是指适宜的美托洛尔或阿替洛尔,以及它们的立体异构物和它们的可接受的药用盐类或溶剂化物,或这些盐类的溶剂化物。具体地说β-受体阻滞剂是美托洛尔琥珀酸盐(在US5,001,161中公开)、美托洛尔酒石酸盐或美托洛尔延胡索酸盐。
因此,在本发明的另一个实施方案中,β-受体阻滞剂是美托洛尔或其可接受的药用盐类,或这些盐类的溶剂化物。美托洛尔可以美托洛尔琥珀酸盐、美托洛尔延胡索酸盐或美托洛尔酒石酸盐的形式存在。
为了临床应用,β-受体阻滞剂被制成用于口服、静脉注射、皮下、经气管、经支气管、经鼻内、经肺、经皮、经口腔的、经直肠、经肠胃外的或其他给药形式的药用制剂。该药用制剂包含β-受体阻滞剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体掺和物中存在。
制剂中活性成分适宜总量为约0.1%-约95%(w/w),更为适宜的是0.5%-50%(w/w),尤其是1%-25%(w/w)。
本发明的另一方面提供了一种药用制剂,其含有维持剂量的低于50mg的β受体阻滞剂和一种降胆固醇剂如HMG-CoA还原酶抑制剂。HMG-CoA还原酶抑制剂可选自下列他汀:阿托伐他汀、西立伐他汀、氟伐他汀、itavastatin、洛伐他汀、美伐他汀、尼可他汀、尼伐他汀、普伐他汀、辛伐他汀或者它们可接受的药用盐类,尤其是钠盐或钙盐,或者它们的溶剂化物,或是这些盐类的溶剂化物。这种他汀的一个例子是一种化学名称为(E)-7[4-(4-氟化苯)-6-异丙基-2-[甲基(甲磺酰)-氨基]-嘧啶-5-基](3R,5S)-3,5-二羟基庚-6-烯醇酸的组合,以及它的钙盐和钠盐(在欧洲专利申请,公开号EP-A-0521471和Bioorganic and Medicinal Chemistry,(1997),5(2),437-444中公开)。优选的β受体阻滞剂和它们优选的剂量如以上所述。
在本专利申请中,术语“降胆固醇剂”包括HMG-CoA还原酶抑制剂的化学改进剂如酯类、立体异构物、药物前体和代谢物,无论是活性或非活性的。对于降胆固醇剂来说,在临床实践中使用的任何剂量都可以用于本发明的制剂中。
β受体阻滞剂与降胆固醇剂的摩尔比值的范围可以为约1000∶1-1∶1000。β受体阻滞剂与降胆固醇剂的摩尔比值适宜的范围是300∶1-1∶300,尤其是50∶1-1∶50。
在制备本发明的药用制剂时,该活性成分可以和固体、粉末成分,例如乳糖、蔗糖、山梨糖醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶或其他合适的成分,以及分解剂和润滑剂例如硬脂酸镁、硬脂酸钙、硬脂酰延胡索酸钠盐和聚乙二醇蜡相混合。然后可将该混合物制成药丸或压成药片。
活性成分在混合入制剂之前可事先分别与其它非活性成分混合。活性成分也可在与非活性成分混合制成制剂前先互相混合。
软明胶胶囊可以由包含发明的活性成分、植物油、脂肪或其它软化明胶胶囊的适宜赋形剂的胶囊制备。硬明胶胶囊可以含有与固体粉末例如乳糖、蔗糖、山梨糖醇、甘露醇、土豆淀粉、玉米淀粉、支链淀粉、纤维素衍生物或明胶相混合的活性成分。
直肠给药的单位剂量可以制备成(i)含有与中性脂肪基混合的活性成分的栓剂;(ii)含有与植物油、石蜡油或其它合适的明胶直肠胶囊赋形剂相混合的活性成分的明胶直肠胶囊;(iii)即用型灌肠剂;(iv)在给药前溶入适当的溶剂即可使用的干粒灌肠制剂。
液体制剂可以制成糖浆或悬浮液,例如含有活性成分和由例如糖或糖醇和乙醇、水、甘油、1,2-丙二醇和聚乙二醇的混合物组成其余物质的溶液和悬浮液。如果需要,这类液体制剂可以含有着色剂、调味剂、防腐剂、糖精和羧甲基纤维素或其它增稠剂。液体制剂也可以制成干燥粉末,在使用前加入适当的溶剂使用。
经胃肠外给药的溶液可以制成溶于可接受的药用溶剂中的本发明制剂的溶液。这些溶液可以含有稳定成分、防腐剂和/或缓冲剂。经胃肠外给药的溶液也可以制成干燥制剂型,在使用前与合适的溶剂混合使用。
给药组合的剂量取决于相关的指标,患者的年龄、体重和性别,也可以由医生决定。剂量的范围尤其为0.01mg/kg-10mg/kg,但是每天的总剂量不能超过50mg。医疗和制药用途
本发明还提供了一种含有β-受体阻滞剂的药物制剂在医疗中的应用,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺和物中以低于50mg的维持剂量,特别是低于30mg和优选为25-47mg,特别是25mg的量存在,特别是用于预防和治疗动脉粥样硬化中的应用;本发明还提供了这类制剂在制造用于预防或治疗动脉粥样硬化药物和中的应用,以及一种医疗或预防方法,其包括给患有或易患动脉粥样硬化患者服用有效剂量的β-受体阻滞剂。
术语“医疗”在这里包括对于人或其它哺乳动物,在活体内或在活体外进行的预防、诊断和治疗方案。
本发明中的制剂预计将会用于预防和治疗动脉粥样硬化症,特别是用于那些患有或易患冠状动脉粥样硬化和颈动脉斑块的患者。
本发明中制剂预计将进一步用于预防和治疗一般性的心血管并发症,包括但不只限于食物和紧张导致的动脉粥样硬化症、心血管死亡、高血压、糖尿病、心绞痛、间歇性跛行、心肌梗塞,包括急性心肌梗塞,和中风。
更特别地,本发明制剂预计将用于预防与动脉粥样硬化进展有关的和/或与动脉粥样硬化症和斑块有关的急性血管故障,包括但不限于中风、心肌梗死(MI)、认知力下降、外周血管疾病和肾功能衰竭等临床症状。
另一方面,本发明提供一种含有β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以25-47mg的维持剂量存在,该制剂可用于制造预防或治疗易感患者充血性心脏衰竭(CHF)和心血管死亡的药物。β-受体阻滞剂的剂量优选低于30mg,最优选为25mg。该制剂可以任选含有以上描述的降胆固醇剂。
本发明另一方面是分部分的药剂盒,其包括:
(i)装有低于50mg的维持剂量,优选范围为25-47mg的β-受体阻滞剂的容器和
(ii)装有HMG-CoA还原酶抑制剂的容器,该抑制剂为(E)-7[4-(4-氟化苯)-6-异丙基-2-[甲基(甲磺酰)-氨基]-嘧啶-5-基](3R,5S)-3,5-二羟基庚-6-烯醇酸或可接受的药用盐类,特别是钠盐或钙盐,或其溶剂化物,或这些盐的溶剂化物
以及用于将β-受体阻滞剂和HMG-CoA还原酶抑制剂连续、分别或同时向患者给药的设备,这种给药对于患者来说是必要或有益的。
本发明的另一方面是分部件的药剂盒,其包括:
(i)一种含有β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以低于50mg的维持剂量,优选为25-47mg的量存在;和
(ii)含有降胆固醇剂的药用制剂,该降胆固醇剂在与可接受的药用佐剂、稀释剂或载体的掺合物中存在;
其中β-受体阻滞剂和降胆固醇剂的提供形式都适于两者联合给药。
“联合给药”是指分别含有β-受体阻滞剂和降胆固醇剂的制剂在相关症状的治疗过程中,同时、分别或相继给药,这些症状可以是急性或慢性的。这个术语特别指两种制剂给药(任选重复)时间相隔很短,这样在相关症状的治疗过程中,与两种制剂分别给药(任选重复),即缺少另外一种制剂的给药方法相比使患者得到更大的疗效。但是必须强调的是β-受体阻滞剂在此之前从未用于抗动脉粥样硬化症,例如用于血胆固醇过多或血脂蛋白过多的患者。联合给药在特定症状的治疗过程中是否会起到更大的作用,取决于所要治疗或预防的症状,但是也可由本领域的技术人员按常规来确定。
因此,术语“联合给药”包括两种制剂中任何一种在给药(任选重复)时可以先给、后给或是与其它成分同时给药。在本文中所用的“同时给药”和“在同一时间给药”包括单独剂量的β-受体阻滞剂和降胆固醇剂都在48小时之内给药,例如24小时。
以下的实施例是要说明本发明,而不是以任何方式限制本发明的范围。实施例
设计一项大型临床试验用于研究低剂量β-受体阻滞剂美托洛尔与安慰剂相比对于颈动脉内膜中层增厚发展的作用以及测量在36个月内对于颈动脉斑块无症状者进行双盲治疗的临床结果。这项研究是随机、双盲、平行组、安慰剂对照、单中心研究的。
研究人群包括男性和女性的无症状者,年龄从47岁到70岁,在右颈动脉有一个斑块。进入研究的人群随机选中50%被邀请参加颈动脉疾病的流行病研究。1548名参加试验者接受了选入测试(随访一人)包括医疗史、身体检查、实验室检查和对右颈动脉进行的2向B型超音波检查。参加试验者在右颈动脉有定量的病变,那些对于研究草案没有禁忌症候的被邀请参加。在所有人中,有793人随机挑选合格。所有参加者提供书面同意书。主要的排除指标为在之前三个月内有心肌梗死、心绞痛或中风史,对于右颈动脉有手术史,常规使用β-受体阻滞剂或他汀类,血压收缩压高于160mmHg或舒张压高于95mmHg,血胆固醇过多(>8.0mmol/L),高血糖需要或被怀疑需要胰岛素治疗,以及研究者认为不适宜参加试验的人。
随机过程是由计算机产生随机数字表完成。参加者根据因子设计随机分到四个药物组合组中:安慰剂/安慰剂,美托洛尔(25mg o.d)/安慰剂,氟伐他汀(40mg o.d.)/安慰剂或美托洛尔(25mg o.d.)/氟伐他汀(40mg o.d.)。安慰剂分别与美托洛尔CR/XL片剂(AstraZenecaAB,Mlndal,Sweden)和氟伐他汀(Novartis Ltd,Basel,Switzerland)胶囊完全相同。
主要的结果指标为普通颈动脉(10mm长部分)的内膜中层平均厚度(IMTmean)的变化和颈动脉球部最大内膜中层厚度(IMTmax)的变化。在治疗中对于氟伐他汀和美托洛尔的安全性和耐药性的模式通过与安慰剂比较不利事件和实验室结果来估计。死亡以及心血管疾病终点事件的发生率被检测。
每位参加者在第一年被访视4次(在1月、3月、6月和12月),在此之后每6个月一次。体重每6个月称一次,每年检查一次禁食血脂图谱(总胆固醇、低密度脂蛋白、高密度脂蛋白和甘油三酯)。肝转氨酶(AST、ALT)和肌酸激酶(CK)在第一年和其后每年每次访视时获得。AST或ALT值≥3倍和CK值≥10倍高于正常值上限即被认为在研究过程中有升高。颈动脉超声波检查在基线和治疗后18个月以及36个月后进行。对于血浆胆固醇和甘油三酯过高的受试者建议采用低脂饮食,如果这样的受试者在不知道其随机分组的情况下胆固醇值持续偏高则交予独立的脂质紊乱专家。在研究中出现其它症状例如高血压、充血性心脏衰竭或异常的实验室检测值根据现存的指导处理。在对参加者的每次访视中将问及在上次访视后有关其住院治疗、急性心肌梗塞和中风的情况。在研究结束时将获得所有受试者的生命状况。
在研究中使用了一个Acuson 128 CT系统(Acuson,MountainView,California)和一个7MHz的转换器。检查过程和图象分析,正如在其它文章(Wendelhag等人,Clin Physiol,11:565-577,1991;Wendelhag等人,Stroke,28:2195-2200,1997)中描述的一样,是由经过专门培训,通过完成一定的教育课程(Berglund,等人,J InternMed,236:581-586,1994)而获得资格的超声检查员进行的。简而言之,右颈动脉叉在事先定义的视窗范围内被扫描,该视窗包括普通颈动脉远端3厘米、分叉处和颈动脉内外各1厘米,对于斑块定义为在病灶处内膜中层厚度大于1.2mm。在远端壁上对内膜中层复合体厚度的测量是根据主要边缘原则,使用特殊设计的计算机辅助图象分析系统,它是以自动探测回声结构为基础,但也可以由操作者选择手动修正。每个影像是在不知道受试者随机分组的情况下进行分析的。
根据以前的经验(Furberg等人,Circulation,90:1679-1687,1994)可以预期在安慰剂组中每年颈动脉内膜中层平均厚度增长率约为15μm每年,标准差为30μm。分别根据退出率为20%,显著性水平为5%(双测),把握度为0.90和治疗效果≥75%(氟伐他汀)和30%(美托洛尔)来决定从每组抽出200人即总共800人作为样本量。主要疗效变量,普通颈动脉内膜中层平均厚度变化和球部最大内膜中层厚度变化用线性模型进行分析,以内膜中层厚度变化作为因变量,治疗作为一个因素。内膜中层厚度基线和测量之间的时间作为共变量包括在模型中。
随机产生具有良好对照的治疗组(见表1)。低密度脂蛋白胆固醇平均基线为4.1mmol/L。在基线和研究过程中其它心血管组合(例如利尿剂、钙离子通道阻滞剂、血管紧张肽转化酶抑制剂、阿司匹林和对妇女进行的绝经后激素替代疗法)在各个治疗组中使用相同(没有显示数据)。平均随访时间为35.9(范围为8-40)个月。治疗的代谢和生理作用
与安慰剂组相比,美托洛尔使血清中的甘油三酯增加了0.14mmol/L,但是对于其它代谢指标没有观察到作用。与安慰剂组相比,美托洛尔组的平均心率下降了2.5次/分钟,而血压和内腔直径并没有显著变化。对颈动脉内膜中层厚度的治疗效果
在表1和表2中给出了基线超声波检查的数据。在安慰剂组观察到的每年普通颈动脉内膜中层平均厚度进展速度为13±53μm。在安慰剂组中每年分叉部内膜中层最大厚度的进展速度为89±154μm。氟伐他汀,而非美托洛尔,在治疗36个月后与安慰剂组相比降低了普通颈动脉内膜中层平均厚度进展速度(组间年变化平均差异:-9,95%可信区间[CI]:-15至-3μm,p=0.002),见表2-3。
美托洛尔与安慰剂组相比在治疗36个月后减慢颈动脉球部内膜中层最大厚度的进展速度(组间年变化平均差异:-23,95%可信区间CI:-44至-3μm,p=0.014),见表2-3。这个效果在治疗18个月后已经得到证实(组间年变化平均差异:-58,95%可信区间CI:-94至-23μm,p=0.004)。在治疗36个月后,美托洛尔CR/XL还可以降低基线血清胆固醇≥6.5mmol/L的亚组的颈动脉球部内膜中层最大厚度的进展速度(组间年变化平均差异:-53,95%可信区间CI:-87至-19μm,p=0.001)。在随访中心血管故障的发生
18位参加者发生了心血管故障(CVD)故障(1名受试者发生了致命的和7名受试者发生了非致命的心肌梗塞,2名由于心肌缺血性疾病立即死亡,以及8名发生了非致命的中风)。美托洛尔组中的心血管故障发生率要低于安慰剂组(5:13例,p=0.055),图2。相应数字在氟伐他汀和安慰剂组中分别为7和11,p=0.350。耐药性
从随机治疗中永久的退出在美托洛尔组中为15%,在氟伐他汀组中为21%,在安慰剂组中为23%。在两种药物联合使用的组中退出率为25%。在氟伐他汀组中的女性与在安慰剂组中的相比会经常出现短暂的肝脏酶的升高(10.2%对1.8%)。在治疗组之间,数种不利事件或癌症的发病率没有差别。
表1特征
治疗组
安慰剂/ 美托洛尔/ 美托洛尔/
安慰剂 安慰剂 氟伐他汀性别男,n(%) 92(46.2) 89(44.7) 86(43.7)女,n(%) 107(53.8) 110(55.3) 111(56.3)年龄(年岁) 61.9±5.4 61.1±5.6 62.2±5.2目前吸烟者(%) 57(28.6) 63(31.7) 66(33.5)体质指数(kg/m2) 25.6±3.7 25.6±3.8 25.4±3.4收缩压(mm Hg) 139.1±14.6 137.9±15.0 139.1±13.7舒张压(mm Hg) 84.5±8.0 84.5±6.9 84.8±6.6心率(beats/min) 69.5±9.0 68.9±8.4 70.2±9.0高血压史,n(%) 22(11.1) 21(10.6) 24(12.2)血清胆固醇(mmol/L) 6.05±0.98 6.14±1.03 6.14±0.93≥6.5mmol/L,n(%) 66(33.2) 70(35.4) 68(34.7)LDL(mmol/L) 4.1±0.9 4.2±1.0 4.2±0.9HDL(mmol/L) 1.40±0.41 1.35±0.37 1.39±0.35甘油三酯(mmol/L) 1.21(0.48-3.57) 1.18(0.46-4.57) 1.12(0.41-4.61)高脂血症史,n(%) 31(15.6) 42(21.1) 37(18.8)禁食后血糖(mmol/L) 5.1±0.9 5.2±0.7 5.1±0.6NIDDM史,n(%) 10(5.0) 7(3.5) 5(2.5)CVD史,n(%) 7(3.5) 8(4.0) 8(4.1)颈动脉超声波普通颈动脉IMT平均(μm) 898±171 920±197 903±205分叉部颈动脉IMT最大球部 1875±505 1936±651 1970±652(μm)
各治疗组中随机分配的BCAPS参加者被选择的基线特征。缩写:LDL:低密度脂蛋白;HDL:高密度脂蛋白;NIDDM:非依赖型胰岛素糖尿病;CVD:心血管疾病;IMT:内膜中层厚度。
表2特征 治疗组
安慰剂 美托洛尔 安慰剂 氟伐他汀普通颈动脉IMT平均(μm)受试者人数 390 393 394 389基线(±SD) 893±170 912±202 910±186 895±18818个月(±SD) 896±176 908±205 913±186 890±19636个月(±SD) 917±203 934±220 945±216 905±205Δ18个月到基线(±SD) 3±10 -5±12 3±11 -5±11Δ36个月到基线(±SD) 24±13 22±13 36±15 11±11Δ36个月组间(95%CI) -2(-20至17) -25(-44至-
7)分叉部颈动脉IMT平均(μm)受试者人数 369 364 375 358基线(±SD) 1875±541 1936±634 1886±570 1926±60918个月(±SD) 1982±572 1937±572 1954±589 1965±55436个月(±SD) 2133±630 2003±624 2097±670 2095±652Δ18个月到基线(±SD) 112±376 23±325 72±373 63±334Δ36个月到基线(±SD) 227±421 154±411 211±455 170±374Δ36个月组间(95%CI) -73(-133至- -41(-102至
13) 19)
在基线、18个月和36个月时普通及分叉部颈动脉内膜中层厚度的平均值和变化的平均值是对相应的治疗组随访而得。IMT,内膜中层厚度;SD,标准偏差;CI,可信区间。
表3结果测量 治疗 β-系数 标准误差 p-值IMT平均CCA
氟伐他汀
18个月 -0.0135 0.008 0.077
36个月 -0.0275 0.009 0.002
美托洛尔
18个月 0.0049 0.008 0.524
36个月 0.0012 0.009 0.897IMT平均分叉部
氟伐他汀
18个月 0.0009 0.029 0.940
36个月 -0.0132 0.013 0.329
美托洛尔
18个月 -0.0367 0.013 0.004
36个月 -0.0333 0.013 0.014
在36个月中分别对普通颈动脉内膜中层平均厚度和颈动脉分叉部内膜中层最大厚度进展的治疗效果(μm)。目的到治疗的分析。分别为了颈动脉内膜中层平均厚度和颈动脉内膜中层最大厚度的基线,以及测量的时间间隔而作出调整。
Claims (19)
1.一种含有β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以25-47mg的维持剂量存在。
2.权利要求1的药用制剂,其中β-受体阻滞剂的剂量是25mg。
3.权利要求1或2的药用制剂,其中β-受体阻滞剂是美托洛尔或其立体异构物,或其可接受的药用盐,或是该盐的溶剂化物。
4.权利要求3的药用制剂,其中β-受体阻滞剂是美托洛尔琥珀酸盐、美托洛尔酒石酸盐或美托洛尔延胡索酸盐。
5.一种含有β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以低于50mg的维持剂量存在,其中还进一步含有降胆固醇剂。
6.权利要求1-4中任一项的药用制剂,其中还进一步含有降胆固醇剂。
7.权利要求6的药用制剂,其中的降胆固醇剂是一种HMG-CoA还原酶抑制剂。
8.权利要求7的药用制剂,其中的HMG-CoA还原酶抑制剂选自阿托伐他汀、西立伐他汀、洛伐他汀、尼伐他汀、普伐他汀和辛伐他汀。
9.权利要求8中的药用制剂,其中HMG-CoA还原酶抑制剂是氟伐他汀。
10.权利要求9的药用制剂,其中HMG-CoA还原酶抑制剂是(E)-7[4-(4-氟化苯)-6-异丙基-2-[甲基(甲磺酰)-氨基]-嘧啶-5-基](3R,5S)-3,5-二羟基庚-6-烯醇酸或其可接受的药用盐或溶剂化物,或是该盐的溶剂化物。
11.权利要求6-10中任一项的药用制剂,其β-受体阻滞剂和降胆固醇剂的摩尔比值范围约为1000∶1-1∶1000,尤其是300∶1-1∶300。
12.权利要求1-11中任一项的制剂用于医疗中的应用。
13.一种预防或治疗患有或易患动脉粥样硬化症的患者的方法,该方法包括用如权利要求1-11中任一项所定义的制剂向患者给药。
14.一种含有β-受体阻滞剂的药用制剂在制造预防或治疗动脉粥样硬化症的药物中的应用,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体掺合物中以低于50mg的维持剂量存在。
15.一种含有β-受体阻滞剂的药用制剂在制造预防或治疗食物引起和紧张引起的动脉粥样硬化症、高血压、糖尿病、心绞痛、间歇性跛行、心肌梗塞,包括急性心肌梗塞,和中风的药物中的应用,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以低于50mg的维持剂量存在。
16.一种含有β-受体阻滞剂的药用制剂在制造预防或治疗中风、心肌梗塞(MI)、认知力下降、外周血管疾病和肾功能衰竭的药物中的应用,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以低于50mg的维持剂量存在。
17.一种含有β-受体阻滞剂的药用制剂在制造针对易感者治疗或预防充血性心脏衰竭(CHF)或心血管死亡的药物中的应用,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以25-47mg的维持剂量存在。
18.一种分部分的药剂盒,包括:
(i)装有低于50mg维持剂量的β-受体阻滞剂的容器和
(ii)装有为(E)-7[4-(4-氟化苯)-6-异丙基-2-[甲基(甲磺酰)-氨基]-嘧啶-5-基](3R,5S)-3,5-二羟基庚-6-烯醇酸或可接受的药用盐,特别是钠盐或钙盐,或其溶剂化物,或这些盐的溶剂化物的HMG-CoA还原酶抑制剂的容器,
以及用于将β-受体阻滞剂和HMG-CoA还原酶抑制剂连续、分别或同时向患者给药的设备,而这种给药对于患者来说是必要或有益的。
19.一种分部分的药剂盒,包括:
(i)一种含有β-受体阻滞剂的药用制剂,该β-受体阻滞剂在与可接受的药用佐剂、稀释剂或载体的掺合物中以低于50mg的维持剂量存在;和
(ii)含有降胆固醇剂的药用制剂,该降胆固醇剂在与可接受的药用佐剂、稀释剂或载体的掺合物中存在;
其中β-受体阻滞剂和降胆固醇剂的提供形式都适于两者联合给药。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE00023549 | 2000-06-22 | ||
SE0002354A SE0002354D0 (sv) | 2000-06-22 | 2000-06-22 | New formulation |
Publications (1)
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CN1437484A true CN1437484A (zh) | 2003-08-20 |
Family
ID=20280209
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN01811540A Pending CN1437484A (zh) | 2000-06-22 | 2001-06-15 | 含有β-受体阻滞剂和任选的降胆固醇剂的新型制剂 |
Country Status (28)
Country | Link |
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US (2) | US20030191177A1 (zh) |
EP (1) | EP1296716B1 (zh) |
JP (1) | JP2003535875A (zh) |
KR (1) | KR20030010750A (zh) |
CN (1) | CN1437484A (zh) |
AR (1) | AR028699A1 (zh) |
AT (1) | ATE344675T1 (zh) |
AU (1) | AU2001274766A1 (zh) |
BG (1) | BG107373A (zh) |
BR (1) | BR0111790A (zh) |
CA (1) | CA2411100A1 (zh) |
CZ (1) | CZ20024181A3 (zh) |
DE (1) | DE60124400T2 (zh) |
EE (1) | EE200200703A (zh) |
ES (1) | ES2274892T3 (zh) |
HK (1) | HK1054508A1 (zh) |
HU (1) | HUP0302371A3 (zh) |
IL (1) | IL153245A0 (zh) |
IS (1) | IS6653A (zh) |
MX (1) | MXPA02012957A (zh) |
NO (1) | NO20026177L (zh) |
NZ (1) | NZ523188A (zh) |
PL (1) | PL360484A1 (zh) |
RU (1) | RU2271802C2 (zh) |
SE (1) | SE0002354D0 (zh) |
SK (1) | SK18072002A3 (zh) |
WO (1) | WO2001097751A2 (zh) |
ZA (1) | ZA200209908B (zh) |
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US8415364B2 (en) | 2003-11-26 | 2013-04-09 | Duke University | Method of preventing or treating glaucoma |
KR100582347B1 (ko) * | 2004-12-30 | 2006-05-22 | 한미약품 주식회사 | 3-하이드록시-3-메틸글루타릴 조효소 a 환원효소 억제제및 고혈압 치료제의 복합제제 및 그의 제조방법 |
KR100836321B1 (ko) | 2006-10-31 | 2008-06-09 | 현대자동차주식회사 | 차량용 모니터 장치 |
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US5175187A (en) * | 1989-03-06 | 1992-12-29 | Soorianarain Baligadoo | Synergistic compositions for the treatment of coronary insufficiency and methods of use thereof |
US5455269A (en) * | 1989-03-06 | 1995-10-03 | Baligadoo; Soorianarain | Synergistic compositions of amiodarone and beta blockers |
ATE141049T1 (de) * | 1991-03-18 | 1996-08-15 | Sepracor Inc | Zubereitung und verfahren enthaltend optisch reines s-metoprolol |
JP2648897B2 (ja) * | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
NO177455C (no) * | 1993-06-04 | 1995-09-20 | Gerrit Elmenhorst | Anordning ved apparat for fremstilling av brannslukkende skum |
JP2000508659A (ja) * | 1996-04-17 | 2000-07-11 | メルク エンド カンパニー インコーポレーテッド | 心血管疾患関連の危険性を低減する組み合わせ療法 |
SE9602762D0 (sv) * | 1996-07-12 | 1996-07-12 | Astra Ab | Carton and blank for forming the same |
US5998458A (en) * | 1997-06-25 | 1999-12-07 | University Technology Corporation | Method of treating heart failure |
GT199800126A (es) * | 1997-08-29 | 2000-01-29 | Terapia de combinacion. | |
JP2002533411A (ja) * | 1998-12-23 | 2002-10-08 | ジー.ディー.サール エルエルシー | 心臓血管に適用するための組み合わせ |
-
2000
- 2000-06-22 SE SE0002354A patent/SE0002354D0/xx unknown
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2001
- 2001-06-11 AR ARP010102759A patent/AR028699A1/es not_active Application Discontinuation
- 2001-06-15 BR BR0111790-4A patent/BR0111790A/pt not_active IP Right Cessation
- 2001-06-15 DE DE60124400T patent/DE60124400T2/de not_active Expired - Fee Related
- 2001-06-15 RU RU2002133205/15A patent/RU2271802C2/ru not_active IP Right Cessation
- 2001-06-15 WO PCT/SE2001/001380 patent/WO2001097751A2/en not_active Application Discontinuation
- 2001-06-15 MX MXPA02012957A patent/MXPA02012957A/es unknown
- 2001-06-15 PL PL36048401A patent/PL360484A1/xx not_active Application Discontinuation
- 2001-06-15 IL IL15324501A patent/IL153245A0/xx unknown
- 2001-06-15 KR KR1020027017474A patent/KR20030010750A/ko not_active Application Discontinuation
- 2001-06-15 CA CA002411100A patent/CA2411100A1/en not_active Abandoned
- 2001-06-15 JP JP2002503228A patent/JP2003535875A/ja active Pending
- 2001-06-15 NZ NZ523188A patent/NZ523188A/en unknown
- 2001-06-15 EE EEP200200703A patent/EE200200703A/xx unknown
- 2001-06-15 CN CN01811540A patent/CN1437484A/zh active Pending
- 2001-06-15 AT AT01941409T patent/ATE344675T1/de not_active IP Right Cessation
- 2001-06-15 EP EP01941409A patent/EP1296716B1/en not_active Expired - Lifetime
- 2001-06-15 CZ CZ20024181A patent/CZ20024181A3/cs unknown
- 2001-06-15 SK SK1807-2002A patent/SK18072002A3/sk unknown
- 2001-06-15 ES ES01941409T patent/ES2274892T3/es not_active Expired - Lifetime
- 2001-06-15 AU AU2001274766A patent/AU2001274766A1/en not_active Abandoned
- 2001-06-15 US US10/311,201 patent/US20030191177A1/en not_active Abandoned
- 2001-06-15 HU HU0302371A patent/HUP0302371A3/hu unknown
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2002
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- 2002-12-11 BG BG107373A patent/BG107373A/bg unknown
- 2002-12-11 IS IS6653A patent/IS6653A/is unknown
- 2002-12-20 NO NO20026177A patent/NO20026177L/no not_active Application Discontinuation
-
2003
- 2003-09-22 HK HK03106811.1A patent/HK1054508A1/zh unknown
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Also Published As
Publication number | Publication date |
---|---|
IS6653A (is) | 2002-12-11 |
HK1054508A1 (zh) | 2003-12-05 |
JP2003535875A (ja) | 2003-12-02 |
KR20030010750A (ko) | 2003-02-05 |
MXPA02012957A (es) | 2003-05-15 |
US20060252814A1 (en) | 2006-11-09 |
DE60124400T2 (de) | 2007-10-31 |
WO2001097751A2 (en) | 2001-12-27 |
SK18072002A3 (sk) | 2003-08-05 |
EP1296716B1 (en) | 2006-11-08 |
NZ523188A (en) | 2006-06-30 |
RU2271802C2 (ru) | 2006-03-20 |
WO2001097751A3 (en) | 2002-03-28 |
HUP0302371A2 (hu) | 2003-11-28 |
ATE344675T1 (de) | 2006-11-15 |
SE0002354D0 (sv) | 2000-06-22 |
AR028699A1 (es) | 2003-05-21 |
IL153245A0 (en) | 2003-07-06 |
ES2274892T3 (es) | 2007-06-01 |
NO20026177D0 (no) | 2002-12-20 |
PL360484A1 (en) | 2004-09-06 |
BR0111790A (pt) | 2003-05-20 |
BG107373A (bg) | 2003-09-30 |
HUP0302371A3 (en) | 2007-03-28 |
EP1296716A2 (en) | 2003-04-02 |
CZ20024181A3 (cs) | 2003-04-16 |
DE60124400D1 (de) | 2006-12-21 |
US20030191177A1 (en) | 2003-10-09 |
ZA200209908B (en) | 2004-03-05 |
NO20026177L (no) | 2002-12-20 |
CA2411100A1 (en) | 2001-12-27 |
AU2001274766A1 (en) | 2002-01-02 |
EE200200703A (et) | 2004-08-16 |
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