CN105561298A - 神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物 - Google Patents
神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物 Download PDFInfo
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Abstract
本发明涉及纽兰格林蛋白在制备用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物中的应用,以及所述用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物的使用方法。特别地,本发明提供了预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的方法,该方法是在患有射血分数保留的心力衰竭或者具有射血分数保留的心力衰竭风险的特殊人群中使用包含纽兰格林蛋白的药物。具体而言,本发明涉及神经调节蛋白在心血管疾病治疗中的新适应症射血分数保留的心力衰竭。
Description
技术领域
本发明涉及纽兰格林蛋白在制备用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物中的应用,以及所述用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物的使用方法。特别地,本发明提供了预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的方法,该方法是在患有射血分数保留的心力衰竭或者具有射血分数保留的心力衰竭风险的特殊人群中使用包含纽兰格林蛋白的药物。具体而言,本发明涉及神经调节蛋白在心血管疾病治疗中的新适应症射血分数保留的心力衰竭。
发明背景
神经调节蛋白(neuregulin,NRG;heregulin,HRG),又叫神经胶质生长因子(glialgrowthfactor,GGF),neu分化因子(newdifferentiationfactor,NDF),为分子量在44KD左右的糖蛋白,它们在细胞间传递信号,是酪氨酸激酶受体ErbB家族的配体。神经调节蛋白家族含4个成员:NRG1,NRG2,NRG3,NRG4(Fallsetal.,ExpCellRes.284:14-30,2003)。NRG1在神经系统、心脏和乳腺中起着重要作用,还有证据显示NRG1信号传递在其他一些器官系统的发育、功能以及人类疾病(包括精神分裂症和乳腺癌)的发病机理中起作用。NRG1有很多异构体。对基因突变小鼠(基因敲除小鼠)的研究说明在N末端区或表皮生长因子(EGF)类似区不同的异构体,其在体功能也不一样。本发明是以神经调节蛋白1β(NRG1β)为基础的。
神经调节蛋白1β为一跨膜蛋白(Holmesetal.,Science256,1205-1210,1992)。膜外部分是N末端,包括免疫球蛋白类似区(Ig-likedomain)和EGF类似区(EGF-likedomain),膜内部分是C末端。在细胞外基质的金属蛋白酶作用下,神经调节蛋白的膜外部分可被酶切下来而呈游离状态,从而有利于和周围细胞表面的ErbB受体结合,激活相应的细胞信号传递。ErbB受体家族也分为四类,ErbB1、ErbB2、ErbB3和ErbB4,它们都是跨膜蛋白,分子量在180-185KD附近。除ErbB2外,它们在膜外的N末端都含配体结合区;除ErbB3外,它们在膜内的C末端都含蛋白酪氨酸激酶活性。其中ErbB1是表皮生长因子的受体,ErbB3和ErbB4都是神经调节蛋白的受体。在神经调节蛋白的受体中,只有ErbB2和ErbB4在心脏表达量较高(Yardenetal.,NatRevMolCellBiol,2:127-137,2001)。
当神经调节蛋白与ErbB3或ErbB4的膜外部分结合时,将引起ErbB3、ErbB4与其他ErbB受体(常常包括ErbB2)形成异源二聚体,或ErbB4自身形成同源二聚体,然后导致受体的膜内部分被磷酸化(Yardenetal.,NatRevMolCellBiol,2:127-137,2001)。磷酸化的膜内部分可进一步与细胞内的多种信号传递蛋白结合,从而激活下游ERK或AKT信号通路,引起一系列细胞反应:包括刺激或抑制细胞增殖、细胞凋亡、细胞迁移、细胞分化或细胞粘连。神经调节蛋白对心脏的发育尤其重要(WO0037095,CN1276381,WO03099300,WO9426298,US6444642,WO9918976,WO0064400,Zhaoetal.,J.Biol.Chem.273,10261-10269,1998)。在胚胎发育早期,神经调节蛋白的表达主要局限于心内膜,随后通过旁分泌途径释放到周围心肌细胞并与细胞膜上的蛋白酪氨酸激酶受体ErbB4膜外部分结合,ErbB4进而与ErbB2形成异源二聚体。ErbB4/ErbB2复合物的形成及激活对早期海绵样心脏形成小梁是必须的。神经调节蛋白、ErbB4和ErbB2三个蛋白基因中的任何一个缺失都会使胚胎没有小梁并在发育早期死于子宫。WO0037095显示一定浓度的神经调节蛋白可持续激活ERK信号通路,促进心肌细胞的生长及分化,引导心肌细胞和细胞粘连处肌节和细胞骨架的重建,改善心肌细胞的结构,增强心肌细胞的收缩。WO0037095及WO003099300还指出神经调节蛋白可用于检测、诊断和治疗各种心血管疾病。
下面列举了与本发明有关的一些现有技术文献:1.Cardiacmusclefunctionandmanipulation:WO0037095;2.生长因子神经调节蛋白及其类似物的新应用:CN1276381;3.Neuregulinbasedmethodsandcompositionfortreatingcardiovasculardiseases:WO03099300;4.ZhaoYY,SawyerDR,BaligaRR,OpelDJ,HanX,MarchionniMAandKellyRA.NeuregulinsPromoteSurvivalandGrowthofCardiacMyocytes.J.Biol.Chem.273,10261-10269(1998);5.Methodsfortreatingmusclediseasesanddisorder:WO9426298;6.Methodsofincreasingmyotubeformationorsurvivalormusclecellmitogenesis,differentiationorsurvivalusinganeuregulin:US6444642.7.Therapeuticmethodscomprisinguseofaneuregulin:WO9918976;8.Methodsfortreatingcongestiveheartfailure:WO0064400;9.HolmesWE,SliwkowskiMX,AkitaRW,HenzelWJ,LeeJ,ParkJW,YansuraD,AbadiN,RaabH,LewisGD,etal.Identificationofheregulin,aspecificactivatorp185erbB2.Science256,1205-1210(1992);10.FallsDL.Neuregulins:functions,formsandsignalingstrategies.ExperimentalCellResearch,284,14-30(2003).11.YardenY,SliwkowskiX.UntanglingtheErbBsignalingNetwork.NatureReviews:MolecularCellBiology,2127-137(2001).
心力衰竭(heartfailure,HF)是各种心脏疾病导致心功能不全的一种综合征,包括收缩性心力衰竭(systolicheartfailure,SHF)和舒张性心力衰竭(diastolicheartfailure,DHF)。2008年,欧洲心脏病学会(ESC)颁布的《急/慢性心衰诊断及治疗指南》又将后者定义为射血分数保留的心力衰竭(HeartFailurewithpreservedejectionfraction,HF-PEF)。收缩性心力衰竭是指心肌收缩力下降使心排血量不能满足机体代谢的需要,器官、组织血流灌注不足,同时出现肺循环和(或)体循环淤血的表现。射血分数保留的心力衰竭(HF-PEF)常常是指舒张性心力衰竭,是由于左心室舒张期主动松弛能力受损和心肌顺应性降低,心肌细胞肥大伴间质纤维化使其僵硬度增加,导致左心室在舒张期的充盈受损,心搏量减少,左室舒张末期压增高而发生的心衰。2006年美国心肺研究院的流行病学资料显示,射血分数保留的心力衰竭或舒张性心衰已占心衰总人数的50%以上。射血分数保留的心力衰竭可单独存在,也可与收缩功能障碍同时出现。射血分数保留的心力衰竭多见于有高血压、糖尿病、左室肥厚的老年女性。
舒张性心力衰竭同收缩性心力衰竭具有类似的症状和体征。患者常有高血压等基础疾病。心衰早期表现为不明原因的疲乏,运动耐力下降,心率每分钟增加15~20次,可能是左心功能降低的早期征兆。继而可出现劳力性呼吸困难、夜间阵发性呼吸困难、高枕睡眠等,患者可能出现腹部或腿部水肿,并以此为首要或惟一症状就诊,而患者的运动耐量损害是逐渐发生的。
心脏的舒张是一个涉及多种因素的较收缩更为复杂的生理过程。因此,射血分数保留的心力衰竭或舒张性心衰的诊断较收缩性心衰更为困难。目前临床上符合下列条件时,可作出诊断:
1.有心衰的典型症状和体征;
2.LVEF正常(或轻度下降≥45%),左心室形态正常;
3.有基础心脏病证据,如高血压患者有左心室肥厚、左心房扩大,超声心动图有左室舒张功能异常的证据;
4.BNP/NT-ProBNP升高;
5.超声心动图未见心瓣膜疾病,并排除心包疾病、肥厚型心肌病、限制性(浸润性)心肌病等。
射血分数保留的心力衰竭或舒张性心衰的发病原因是复杂多样的,而左心室压力/容积机制是一个比较公认的发病机制。高血压病、肥厚型心肌病、主动脉瓣狭窄的患者,心室舒张末压得明显升高,左室容量明显缩小,影响了心室充盈,使压力与容量曲线左移,形成向心性重构,长期存在压力负荷过重而发生舒张性心衰。
心室舒张功能(diastolicfunction)包括心室肌的松弛性(relaxation)(主动耗能过程)和顺应性(compliance)两个阶段。心室松弛性(relaxation)为舒张期单位时间心腔压力的变化(dp/dt),系主动耗能过程。心室顺应性(compliance)为舒张期单位容积的变化引起的压力的变化(dp/dv),系被动充盈过程。松弛是舒张早期心室肌的主动舒张,心肌纤维恢复到收缩期前的长度和压力的能力,是能量依赖Ca2+的转运主动耗能过程。主要包括等容舒张期和舒张早期快速充盈相。反映左室松弛的参数包括:等容舒张期(IVRT)持续时间、压力下降的最大速率(-dp/dt)、二尖瓣E峰减速时间(DT)等。这些由二维超声心动图和血流动力学测试得到的参数能一定程度上评价心脏的舒张功能。
另外,射血分数保留的心力衰竭也缺少特异性的治疗手段,目前的治疗原则包括使用控制血压,降低心室率,利尿减轻体液潴留等针对收缩性心衰改善症状的标准治疗药物,如血管紧张素转换酶抑制剂/血管紧张素II受体抑制剂,β受体阻滞剂,利尿剂等,但却不能改善射血分数保留的心力衰竭的临床症状和预后。最后,射血分数保留的心力衰竭或舒张性心衰的预后不良,患者再次和反复住院率稍高,增加了医疗负担。舒张性心衰发展的结局是收缩性心衰,如何能在舒张性心衰的早期阶段,改善心脏的舒张性能,阻断其进一步恶化途径,是当前舒张性心衰治疗面临的极大挑战。
现有技术文献中没有关于神经调节蛋白对于射血分数保留的心力衰竭或舒张性心力衰竭方面的报道。本发明发现给予哺乳动物神经调节蛋白能显著改善射血分数保留的心力衰竭的症状,可用于制备预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药物。
发明内容
A.发明概述
本发明是基于NRG对心脏发育至关重要,对成年心脏的功能维持也起到非常重要的作用的科学发现;基于NRG可以加强心肌细胞肌小节和细胞骨架以及细胞间连接的形成的科学发现;基于NRG在各种动物模型和临床试验中可以提高心衰动物或病人的心脏功能的科学发现。NRG,NRG多肽,NRG突变体或其它具有NRG样功能的复合物都属于本发明的范畴。神经调节蛋白可与心肌细胞表面的ErbB受体结合,持续激活细胞内的ERK信号通路,改变心肌细胞的结构,从而改善心肌细胞的功能。
本发明的第一个方面,是提供了一种预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的方法。包括对需要或希望预防、治疗或延迟射血分数保留的心力衰竭的哺乳动物特别是人施用有效量的NRG或其功能片段,或编码NRG或其功能片段的核酸,或提高NRG产量和/或功能的物质,从而达到预防、治疗或延迟射血分数保留的心力衰竭的效果。
本发明的第二个方面,是提供了一种预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的药物制剂。该药物制剂包含有效量的NRG或其功能片段,或编码NRG或其功能片段的核酸,或提高NRG产量和/或功能的物质,以及药学上可以接受的载体、赋形剂等。该药物制剂可以和其它可用于预防、治疗或延迟射血分数保留的心力衰竭的药物一起使用。本发明的另一个方面,是提供了一种用于预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的组合物。该组合物包含了本发明所提供的用于预防、治疗或延迟哺乳动物心脏射血分数保留的心力衰竭的药物制剂,以及其它预防、治疗或延迟射血分数保留的心力衰竭的药物。
本发明还提供了一种用于预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的药盒,其中包含了一次或多次使用剂量的上述预防、治疗或延迟射血分数保留的心力衰竭的药物制剂或组合物,以及如何使用该药物制剂或组合物的说明书。
B.定义
除另有定义,这里使用的所有科技术语与本发明所属技术领域的普通技术人员理解含义相同。所有专利文献、专利申请文献、公开的专利文献和其它出版物均作为参考。如本节阐述的定义与上述参考文献所述的定义不一致或相反时,以本节阐述的定义为准。
除非特别指明,在此所用“一个”的意思是“至少一个”或“一个或多于一个”。
此处所用“神经调节蛋白”或“neuregulin”或“NRG”是指能够结合并激活ErbB2、ErbB3、ErbB4或其异源或同源二聚体的蛋白或多肽,包括神经调节蛋白的异构体、神经调节蛋白中的EGF样功能域、包含神经调节蛋白EGF样功能域的多肽、神经调节蛋白的突变体或衍生物以及其它能够激活上述受体的神经调节蛋白样的基因产物。神经调节蛋白还包括NRG-1,NRG-2,NRG-3和NRG-4蛋白、多肽、片段以及具有NRG样功能的复合物。优选的,神经调节蛋白是可以结合并激活ErbB2/ErbB4或ErbB2/ErbB3异源二聚体的蛋白或多肽。作为例子,但并非为了限制的目的,本发明的神经调节蛋白是NRG-1β2异构体的一个片段,即177-237位氨基酸片段,其中包含了EGF样功能域。该片段的氨基酸序列为:SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMASFYKAEELYQ(SEQIDNO:1)。本发明所用神经调节蛋白可以激活上述受体并调节它们的生物学功能,比如刺激骨骼肌细胞合成乙酰胆碱受体;促进心肌细胞的分化、存活以及DNA合成。神经调节蛋白还包括那些具有并不实质性影响生物学功能的保守性突变的神经调节蛋白突变体。本技术领域中普通技术人员熟知,非关键区域的单个氨基酸的突变一般不会引起该蛋白或多肽的生物学功能的改变(参见Watson等人,MolecularBiologyoftheGene,4thEdition,1987,TheBejacmin/CummingsPub.co.,p.224)。本发明所用神经调节蛋白可以从天然的来源分离得到,或者通过重组技术、人工合成或其它手段得到。
此处所用“EGF样功能域”或“EGF-likedomain”是指由neuregulin基因所编码的可以结合并激活ErbB2、ErbB3、ErbB4或其异源或同源二聚体的多肽片段,并且与下述参考文献中描述的EGF受体结合区域具有结构相似性:WO00/64400;Holmes等,Science,256:1205-1210(1992);美国专利5,530,109和5,716,930;Hijazi等,Int.J.Oncol.,13:1061-1067(1998);Chang等,Nature,387:509-512(1997);Carraway等,Nature,387:512-516(1997);Higashiyama等,J.Biochem.,122:675-680(1997);以及WO97/09425。在某些实施方案中,EGF样功能域结合并激活ErbB2/ErbB4或ErbB2/ErbB3异源二聚体。在某些实施方案中,EGF样功能域包含NRG-1的受体结合区氨基酸。在某些实施方案中,EGF样功能域是指NRG-1的第177-226位、177-237位或177-240位氨基酸。在某些实施方案中,EGF样功能域包含NRG-2的受体结合区氨基酸。在某些实施方案中,EGF样功能域包含NRG-3的受体结合区氨基酸。在某些实施方案中,EGF样功能域包含NRG-4的受体结合区氨基酸。在某些实施方案中,EGF样功能域包含美国专利5,834,229中描述的氨基酸序列:AlaGluLysGluLysThrPheCysValAsnGlyGlyGluCysPheMetValLysAspLeuSerAsnPro。
此处所用“射血分数保留的心力衰竭(HF-PEF)”又称之为左心室射血分数(LVEF)正常的心衰(HFNEF),左心室射血分数保持的心衰(HF-PLVEF),收缩功能尚存的心衰(HF-PSF),舒张性心力衰竭(DHF)或舒张性心衰,其是指左心室射血分数(LVEF)正常或轻度下降,主要由于左心室舒张期主动松弛能力受损和心肌顺应性降低,心肌细胞肥大伴间质纤维化使其僵硬度增加,导致左心室在舒张期的充盈受损,心搏量减少,左室舒张末期压增高而发生的心衰。它可单独存在,也可与收缩功能障碍同时出现。
此处所用“等容舒张期(isovolumicrelaxationtime,IVRT)”是指心室处于压力不断下降的等容封闭状态,此时心室开始舒张,主动脉瓣和房室瓣处于关闭状态。当左心室松弛受损时,IVRT延长。当左心室松弛受损改善时,IVRT减少。
此处所用“压力下降速率(-dp/dt)”是指等容舒张期左心室压力下降的速率。其值越大,表明左心室压力下降越快,心脏舒张功能越好,是评价心肌松弛性的可靠性指标之一。
此处所用“二尖瓣E峰”是指心脏二尖瓣口舒张早期峰值(E),反映了左心室快速充盈期通过瓣口的最大血流速度,二尖瓣口血流曲线E峰代表舒张早期左心室主动松弛,反应左心室松弛性。
此处所用“E峰下降时间(DT)”是指二尖瓣E峰下降减速时间,是舒张早期二尖瓣向左房方向运动形成的血流减速时间,反映了在快速充盈期左房室压差变化,其值越小表明压差变化越快。主动松弛性降低一般发生于疾病早期,表现为左心室舒张早期充盈量减少,E峰降低,DT延长>240ms。
此处所用“其它用于治疗射血分数保留的心力衰竭的药物”是指已知的可用于治疗射血分数保留的心力衰竭的药物,包括血管紧张素转换酶抑制剂/血管紧张素II受体抑制剂,β受体阻滞剂,钙离子拮抗剂,环磷酸腺苷,儿茶酚胺类药物,硝酸酯类药物,磷酸酯酶抑制剂,利尿剂,肾素-血管紧张素-醛固酮系统(RAS)拮抗剂,心肌能量优化剂等。
具体实施方式
实施例1:重组人纽兰格林对高血压心衰大鼠的心功能作用研究
研究重组人纽兰格林(rhNRG)对SHR高血压大鼠心衰模型的治疗作用。方法:采用SHR高血压品系大鼠,正常饲养,饲养过程中心超监测其心功能变化,16个月时,射血分数(EF)下降至70%,提示高血压大鼠心衰模型成功建立。高血压心衰大鼠随机分为阴性对照组、NRG治疗组以及卡托普利治疗组,rhNRG连续给药5天,停药2天为一个治疗周期,NRG组共接受了3个治疗周期的治疗。分别于第2和第3个治疗周期结束时,对各组大鼠行心超检查,测定其心功能变化;并于第3个治疗周期结束后,对各组大鼠行血流动力学检测。
1.试验动物
1.1品系、来源:SHR高血压品系大鼠,购自中国科学院动物中心。WKY品系作为SHR的对照,同样购自中国科学院动物中心。
1.2性别、周龄:雄性,6周龄。
1.3饲养:普通啮齿类饲料,自由进食水,12小时光暗循环
2.受试药物
规格:NeucardinTM,61个氨基酸,上海泽生科技开发有限公司生产
3.实验材料
3.1心脏超声诊断仪:PhilipsSonos5500
3.2卡托普利:中美上海施贵宝制药有限公司
4.实验方法
4.1高血压心衰大鼠模型制备
采用SHR高血压品系大鼠,正常饲养,饲养过程中心超监测其心功能变化。饲养16个月后,SHR大鼠射血分数(EF)下降至70%,LVDd、LVDs明显增大,提示高血压大鼠心衰模型成功建立。
4.2分组与给药
模型成功建立后,随机分入阴性对照组、NRG治疗组以及卡托普利治疗组。rhNRG为静脉注射给药,剂量为6.5ug/kg,每日1次,连续给药5天停药2天为一治疗周期,共接受3个治疗周期的治疗。同时,NRG组还灌胃给予饮用水,每日两次;卡托普利的给药方法为灌胃给药,剂量为10mg/kg,每日2次,连续给药。同时尾静脉给予3个治疗周期的NRG赋性剂。阴性对照组分别灌胃给予饮用水及尾静脉注射给予NRG赋性剂。
4.3心超检查
分别于治疗前以及第2和第3个治疗周期结束时,氯胺酮麻醉后对各组大鼠行心超检查,测定其心功能变化。
4.4血流动力学测定
第3个治疗周期结束后,大鼠用3%戊巴比妥腹腔注射麻醉,颈部正中切口,分离左颈总动脉,插管,检测动脉及左心室血流动力学指标。
5.实验结果
与阴性对照组相比,NRG可显著改善高血压大鼠血流动力学,其中-dp/dt显示统计学差异(分别为-7467.6±715.8和-5488.1±1340.3,p=0.016);而卡托普利可显著降低高血压大鼠血压(174.5±33.0vs216.5±23.2和228.0±26.0;p=0.029,p=0.017)。
6.结论
按照6.5ug/kg的剂量给予高血压心衰大鼠rhNRG,连续给药5天,停药2天为一治疗周期,治疗2个周期或3个周期后,可防止左心室舒张末期及收缩末期容积进一步扩大,改善血流动力学,从而全面改善高血压心衰大鼠心功能。从表1的数据来看,卡托普利是通过降血压途径来改善高血压心衰大鼠的心功能,而rhNRG可通过增加等容舒张期左心室压力下降的速率-dp/dt,而非降血压途径来改善高血压心衰大鼠的心功能。
表1给药3个治疗周期后各组血流动力学参数
组别 | MAP | -dp/dt |
阴性对照 | 174.7±16.8 | -5488.1±1340.3 |
NRG | 182.5±18.8 | -7467.6±715.8 |
卡托普利 | 139.9±24.8 | -5441.2±1007.3 |
实施例2:重组人纽兰格林对射血分数保留的心力衰竭患者的心功能作用研究
为了评估重组人纽兰格林对射血分数保留的心力衰竭患者的心功能作用,在上海交通大学附属第六人民医院进行了初步的临床实验,其中安慰剂组2例,试验组2例。
1.主要入选标准:
1.1左心室射血分数(LVEF)≥50%(二维超声心动图诊断);
1.2纽约心功能(NYHA)II或III级;
1.3明确诊断慢性心衰(包括病史,症状,体征),且近1个月临床症状稳定;
1.4接受心衰标准治疗药物已达目标剂量或最大耐受量至少1个月以上,或近1个月内未改变剂量;
1.5理解并签署知情同意书。
2.研究药物:
名称:注射用重组人纽兰格林规格:250μg/支
剂型:注射用冻干粉
给药途径:静脉滴注
安慰剂(零剂量):
名称:重组人纽兰格林冻干剂的赋形剂
剂型:注射用冻干粉
给药途径:静脉滴注
3.给药途径,用量及疗程见表2:
表2给药剂量、途径和疗程
4.数据采集:在筛选期、11-13d和30d,测二维超声心动图的二尖瓣血流频谱。
5.结果及讨论:
表3二尖瓣血流频谱中IVRT和DT的数值变化
从表3中结果可知,给予安慰剂的患者,其IVRT和DT值在逐渐变大;而给予NRG的患者,其IVRT和DT值有明显的下降,显示其舒张功能有一定程度的改善。
上述列举的实施例不会限制本发明的保护范围。在没有背离本发明的宗旨和范围的情况下,本技术领域内的技术人员可以对本发明进行调整和改变。因此,本发明的保护范围应当根据权利要求来定义,而不是通过具体的实施例来限定。
Claims (10)
1.NRG用于制备预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药物的用途。
2.根据权利要求1所述的用途,其中所述NRG是NRG-1。
3.根据权利要求1所述的用途,其中所述NRG包含SEQIDNO:1的氨基酸序列。
4.根据权利要求1所述的用途,其中所述哺乳动物是人。
5.一种用于预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药物制剂,其特征在于其含有有效剂量的NRG。
6.根据权利要求5所述的制剂,其中所述NRG是NRG-1。
7.根据权利要求5所述的制剂,其中所述NRG包含SEQIDNO:1的氨基酸序列。
8.根据权利要求5所述的制剂,其中所述哺乳动物是人。
9.一种用于预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的组合物,其特征在于其含有如权利要求5所述的药物制剂以及其它用于治疗射血分数保留的心力衰竭的药物。
10.一种用于预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药盒,其中含有如权利要求5所述的药物制剂以及如何使用该药物制剂的说明书。
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CN113166218A (zh) * | 2018-04-11 | 2021-07-23 | 信立泰生物医药公司 | 人神经调节蛋白-1(nrg-1)重组融合蛋白组合物和其使用方法 |
CN113677699A (zh) * | 2019-04-01 | 2021-11-19 | 伊莱利利公司 | 神经调节蛋白-4化合物和使用方法 |
CN113677699B (zh) * | 2019-04-01 | 2024-06-11 | 伊莱利利公司 | 神经调节蛋白-4化合物和使用方法 |
WO2021169845A1 (zh) * | 2020-02-24 | 2021-09-02 | 上海泽生科技开发股份有限公司 | 神经调节蛋白用于预防、治疗或延缓心力衰竭的方法和组合物 |
WO2024067817A1 (zh) * | 2022-09-30 | 2024-04-04 | 上海泽生科技开发股份有限公司 | 神经调节蛋白及其应用 |
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CN108064164A (zh) | 2018-05-22 |
RU2017116973A3 (zh) | 2019-05-06 |
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EP3207940A4 (en) | 2018-06-06 |
US20200368317A1 (en) | 2020-11-26 |
JP2020193217A (ja) | 2020-12-03 |
JP2017532343A (ja) | 2017-11-02 |
CA2963322A1 (en) | 2016-04-21 |
KR102603711B1 (ko) | 2023-11-20 |
AU2015333335B2 (en) | 2021-08-05 |
JP2022153417A (ja) | 2022-10-12 |
US20170232068A1 (en) | 2017-08-17 |
EP3207940B1 (en) | 2022-06-01 |
KR20230159650A (ko) | 2023-11-21 |
EP3207940A1 (en) | 2017-08-23 |
AU2015333335A1 (en) | 2017-04-20 |
EP4112068A1 (en) | 2023-01-04 |
CN111407882A (zh) | 2020-07-14 |
AU2021258063A1 (en) | 2021-11-25 |
ES2924395T3 (es) | 2022-10-06 |
US10561709B2 (en) | 2020-02-18 |
RU2017116973A (ru) | 2018-11-19 |
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