CN103906521A - S-腺苷甲硫氨酸、维生素e和维生素c在预防和治疗心血管功能障碍中的应用 - Google Patents
S-腺苷甲硫氨酸、维生素e和维生素c在预防和治疗心血管功能障碍中的应用 Download PDFInfo
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Abstract
本发明提供一种用于治疗或预防心血管功能障碍的方法。该方法为服用治疗有效量的(a)(i)S-腺苷甲硫氨酸或其衍生物或药学上可接受的盐,和(ii)N-乙酰半胱胺酸或其衍生物或药学上可接受的盐中的一种或多种物质;(b)维生素E或其衍生物或其药学上可接受的盐;以及(c)维生素C或其衍生物或其药学上可接受的盐和药学上可接受的载体。
Description
相关申请的交叉引用
本申请请求保护2011年4月15日提交的、申请号61/476,014、题为USE OFS-ADENOSYLMETHIONINE,VITAMIN E,AND VITAMIN C FOR THE PREVENTION ANDTREATMENT OF CARDIOVASCULAR DYSFUNCTION的美国专利申请的权益和优先权。在此详细描述中以引用的方式并入该申请的全部内容。
技术领域
本发明涉及药物组合物,具体涉及用于预防和治疗心血管功能障碍的药物组合物。
背景技术
心血管功能障碍是涉及会影响肺部,脑部,肾脏和其他身体部位,包括心脏和血管的循环系统的功能紊乱。心血管功能障碍可以通过压力-容积指数或血流动力学参数的变化来衡量。例如前负荷补充搏出功(PRSW),心室收缩末期压力-容积关系(ESPVR),dP/dtmax-舒张末期容积关系(dP/dtmax–EDV),最大倒电容(Emax),左室收缩峰压(Pes),左心室舒张末压(Ped);最大左心室压力上升和下降率(分别为dP/dtmax和dP/dtmin),左心室压力衰减时间常数(tau);射血分数(EF),按体重标准化的心输出量(心排血指数,CI);按体重标准化的搏出功(SWI);和总外周阻力指数(TPRI)。
传统的对心血管功能障碍的预防和治疗涉及生活饮食习惯的改变和手术。用于预防心血管功能障碍的药物包括阿司匹林,洋地黄,血管紧张素转换酶(ACE)抑制剂,β-受体阻滞药,硝酸盐,钙通道阻滞剂,利尿剂,降血胆固醇剂,和溶血栓剂。
一种药物组合物,包含:(a)S-腺苷甲硫氨酸,其衍生物或其药学上可接受的盐,(b)维生素E,其衍生物或其药学上可接受的盐,和(c)维生素C,其衍生物或其药学上可接受的盐,和(d)药学上可接受的载体(合起来为SAMEC),已知可协同作用于治疗氧化性肝损伤,依赖肝胰岛素敏化物质的胰岛素耐受性(HDIR)(美国专利申请号S.N.814886),和用于预防HDIR随衰老而加重,和与衰老和蔗糖添加剂相关的消化系统紊乱(Lautt et al,2008;Ming Z,etal.Can.J.Physiol.Pharmacol.87:873-882(2009))。SAMEC原被发明者调配用以通过保护细胞的水溶和脂质成分和线粒体与谷胱甘肽水平,为由硫代乙酰胺引起的重急性自由基肝毒提供抗氧化保护(Lautt et al.,2008,Ming et al.,2006,Ming et al.,2009)。SAMEC的其他作用还未知。
发明内容
本发明提供了药学上有效量的S-腺苷甲硫氨酸或N-乙酰半胱氨酸,维生素E,和维生素C的组合对于预防和治疗心血管功能障碍的令人惊讶的用途。
在第一个方面,本发明提供一种用于治疗或预防心血管功能障碍的药物组合物,该药物组合物包含S-腺苷甲硫氨酸,或N-乙酰半胱氨酸,维生素E,维生素C和药学上可接受的载体心血管功能障碍。
本发明的另外的方面和特征会在本专业领域人员阅读下文中申请的描述和具体实施并结合附图后,显得更加明显。
附图说明
在图1至12中,“年轻”表示9周大的大鼠,“52C”表示食用对照食物的52周大的大鼠;“52A”表示服用增添SAMEC食物的,52周大的大鼠;“52S”表示服用高蔗糖食物的52周大的大鼠。“52T”表示服用高蔗糖,并添加SAMEC的食物的52周大的大鼠。
图1为SAMEC对衰老大鼠的压力-容积指数,心室收缩末期压力-容积关系(ESPVR)的作用的柱状图。
图2为SAMEC对衰老大鼠的压力-容积指数,Emax的作用的柱状图。
图3为SAMEC对衰老大鼠的压力-容积指数,dP/dt-EDV的作用的柱状图。
图4为SAMEC对衰老大鼠的压力-容积指数,前负荷补充搏出功(PRSW)的作用的柱状图。
图5为SAMEC对衰老大鼠的基线血流动力学参数(baseline hemodynamic parameter),心排血指数(CI)的作用的柱状图。
图6为SAMEC对衰老大鼠的基线血流动力学参数,搏出功指数(SWI)的作用的柱状图。
图7为SAMEC对衰老大鼠的基线血流动力学参数,dP/dtmax的作用的柱状图。
图8为SAMEC对衰老大鼠的基线血流动力学参数,-dP/dtmin的作用的柱状图。
图9为SAMEC对衰老大鼠的基线血流动力学参数,射血分数(EF%)的作用的柱状图。
图10为SAMEC对衰老大鼠的基线血流动力学参数,左心室压力衰减时间常数(tau)的作用的柱状图。
图11为SAMEC对衰老大鼠的基线血流动力学参数,左心室舒张末压(Ped)的作用的柱状图。
图12为SAMEC对衰老大鼠的基线血流动力学参数,总外周阻力指数(TPRI)的作用的柱状图。
图13展示了由SAMEC提供的、在射血分数,前负荷补充搏出功,舒张压降低的最大速率,收缩压升高的最大速率,dP/dtmax-EDV,总外周阻力,左心室压力衰减的时间常数,心室收缩末期压力-容积关系,搏出功指数和心排血指数方面对与年龄相关的心血管损伤的保护率的柱状图。
图14为由SAMEC提供的、在前负荷补充搏出功,舒张压降低的最大速率,收缩压升高的最大速率,心室收缩末期压力-容积关系,dP/dtmax-EDV,射血分数,左心室压力衰减的时间常数,总外周阻力,搏出功指数和心排血指数方面对与年龄和蔗糖摄入量相关的心血管功能障碍的保护率的柱状图。
具体实施方式
本发明确定S-腺苷甲硫氨酸,维生素E,和维生素C(SAMEC)的组合治疗能够治疗与衰老有关的心血管功能障碍,而且对于普通病人和食用高糖食物的患者都有疗效。N-乙酰半胱氨酸可用于替代S-腺苷甲硫氨酸。
衰老会增强氧化应激。本发明人调配一种独特的可协同作用的抗氧化药物混合物(cocktail),缩写为SAMEC,由S-腺苷甲硫氨酸,维生素E,和维生素C(SAMEC)组成。该混合物能同时保护细胞的水溶和脂质成分和线粒体功能与谷胱甘肽水平。该混合物被开发为治疗由硫代乙酰胺引起的重急性自由基肝毒的工具。该混合物只有当三种组分同时使用的时候才能起作用,呈戏剧性的协同作用。本发明人已证明SAMEC可保护与衰老和糖摄入相关的心血管功能损害。
在此使用的术语“S-腺苷甲硫氨酸”包括其衍生物,偶联物,代谢产物和药学上可接受的盐(参考例子:美国专利号3,893,999和4,057,686)。S-腺苷甲硫氨酸及其盐可通过自然形成,半合成,生物工程,合成或提取,或结合任意以上方法制成。
在此使用的术语“N-乙酰半胱氨酸”包括其衍生物,偶联物,代谢产物和药学上可接受的盐。N-乙酰半胱氨酸及其盐可通过自然形成,半合成,生物工程,合成或提取,或结合任意以上方法制成。
在此使用的术语“维生素E”包括α,β,γ,和δ-生育酚,和他们的衍生物,偶联物,代谢产物和盐。该维生素E也可以是是α,β,γ,和δ生育酚的混合物。α形式为天然形成的右旋体,称为d-α生育酚(d-2,5,7,8-四甲基-2-(4',8',12'-三甲基十三烷基)-6-色满醇)。其他可用的维生素E的形式包括:d-α生育酚乙酸酯,d-α生育酚琥珀酸盐,d-α生育酚烟酸酯,和d-α生育酚亚油酸酯。相对应的dl形式也可以使用,包括dl-α生育酚,dl-α生育酚乙酸酯,dl-α生育酚琥珀酸盐,dl-α生育酚烟酸酯,dl-α生育酚亚油酸酯和它们的衍生物,偶联物,代谢产物和盐。
在此使用的术语“包括维生素C”包括抗坏血酸和它的衍生物,偶联物,代谢产物和盐。这些衍生物包括,例如:氧化产物例如脱氢抗坏血酸,抗坏血酸的可食用的盐,解释性地举例来说,钙,钠,镁,钾,和锌抗坏血酸盐。术语维生素C包括这些衍生物和其他业内人士可识别出来的维生素C衍生物(例如:美国专利号5,137,723和5,078,989)包括维生素C脂和盐。这些都可用于此发明。
S-腺苷甲硫氨酸,维生素E,维生素C可以为合适的药学上可接受的盐。S-腺苷甲硫氨酸,维生素E,维生素C的功能性衍生物,偶联物,和代谢产物也可用于制备本专利所述的药物组合物。
S-腺苷甲硫氨酸被选择作为组分之一是因为它可保护肝线粒体。该保护最有可能是通过增加谷胱甘肽的产生来进行。N-乙酰半胱氨酸可以有同样的效果,因此N-乙酰半胱氨酸+维生素E+维生素C也将同样有效。
本发明的药物组合物可以通过传统的方法,利用一种或多种生理上可接受的载体来制备,该生理上可接受的载体包括便于将活性化合物加入可药学上使用的制剂的赋形剂和助剂。剂型可根据不同的给药方式进行选择。
对于口服给药,可通过将活性化学物质与本领域公知的药学可接受的载体结合而简单地制成该化合物。这些载体可将发明的化学物制成片剂,丸剂,糖衣丸剂,胶囊,口服液,胶剂,糖浆,浆剂,悬浮液或其他,用以给接受治疗的病人口服。口服药物制剂可通过固体赋形剂,可选择地打磨成混合物,加工混合物颗粒,并在需要的时候,加入合适的助剂,以制成片剂或糖衣药丸的核。具体的,合适的赋形剂为,填充剂如糖,包括乳糖,蔗糖,甘露醇,或山梨醇;纤维素制剂,例如玉米淀粉,小麦淀粉,大米淀粉,马铃薯淀粉,明胶,黄蓍胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠,和/或者聚乙烯吡咯烷酮(PVP)。需要的时候,可以加入崩解剂,例如交联聚乙烯吡咯烷酮,琼脂,或藻酸或其盐如藻酸钠。
糖衣丸需外包合适的包衣。为此,可以用浓缩的糖溶液,该溶液可选择性地含有阿拉伯树胶,滑石粉,聚乙烯吡咯烷酮,卡波普凝胶,聚乙二醇,和/或者二氧化钛,漆液,与合适的有机溶剂或溶剂混合物。染料或色素可被加入至片剂或糖衣中,以识别或区分不同的活性化合物的剂量的组合。
可口服使用的口服制剂包括由明胶制成的硬胶囊和由明胶及塑化剂,例如甘油或山梨醇制成的密封的软胶囊。硬胶囊中的活性化合物可与填充剂,如乳糖;粘合剂如淀粉;和/或者润滑油,如滑石粉或硬脂酸镁;及可选择的稳定剂混合。在软胶囊中,该活性化合物可溶解或悬浮于合适的液体中,例如脂肪油,液体石蜡,或液体聚乙二醇。此外,也可以添加稳定剂。所有口服剂型的剂量应适应于该给药方式。
对于口腔含化给药,该组合物应以常规的方式制成片剂或锭剂的形式。
此外,该化合物可通过缓释系统释放,例如包含治疗剂的固体疏水性聚合物形成的半渗透基体。本领域技术人员已经建立并已知很多缓释材料。缓释胶囊可根据他们的化学性质的不同,持续释放该化合物几个星期至一百天以上。根据该治疗剂的化学性质和生物稳定性,可使用附加的,稳定蛋白质的方法。
该药物组合物也可包含合适的固体或凝胶相载体或赋形剂。
该载体或赋形剂的例子包括但不局限于碳酸钙,磷酸钙,各类糖,淀粉,纤维素衍生物,明胶和聚合物例如聚乙二醇。
本发明中的多种化合物可以是带有药学相容性的反离子的盐。药学上相容性盐可以由许多种酸形成,包括但不限于盐酸,硫酸,醋酸,乳酸,酒石酸,苹果酸,琥珀酸等。在水溶液中或其他质子化溶剂中,盐比相应的游离碱更容易溶解。
合适的给药途径,例如,包括口服给药。优选的,以预防为目的的给药方式为长期每日口服。
根据本发明治疗心血管功能障碍的方法包括给有需要的病人服用治疗有效量的S-腺苷甲硫氨酸,维生素E,维生素C。
药理活性剂的“有效量”或“治疗有效量”是指无毒,但是药物或制剂的量足以提供理想效果。在本发明中的组合疗法中,组合物中一种成分的“有效量”是指当与该组合物中的其他成分结合使用时,该成分的量可提供理想效果。对不同的治疗对象来说,根据对象的不同,“有效”量将不相同,这取决于个体的年龄和一般身体状况,具体的活性剂或药剂等等。本领域技术人员可通过常规的实验确定任意一个个体的合适的“有效”量。
SAMEC的给药方案可根据病人的体重和临床上心血管功能障碍的程度来选择,更好地针对病人的个体情况进行治疗。
本发明所涵盖的任何活性剂的治疗有效量是根据本领域技术人员所知的和在此公布的一些因素所决定的。具体地,这些因素包括:服用的化合物,剂型,给药方式,病人的性别,年龄,体重和被治疗的病情的严重程度,是否有影响胃肠道,肝胆系统,肾脏系统的并发症。判断剂量和毒性的方法是本领域技术人员所熟知的,一般通过先进行动物实验,若无明显动物毒性,继而做人类实验。应该监测病人的药物副作用的病症,和毒性,特别是肝功能方面。
对于哺乳动物给药,特别是人的给药,如要口服,希望每日剂量水平为:维生素E,100到900毫克;维生素C,200到2000毫克;S-腺苷甲硫氨酸,200到1600毫克,或N-乙酰半胱氨酸400到800毫克。无论如何,医生将决定最适合某个个体的实际剂量,该剂量将根据年龄,体重和病人对药的反应而不同。以上剂量是一般情况下的例子。个别情况需要更大或更小的用量也在本专利的保护范围之内。
在本发明的优选实施例中,治疗有效量为:S-腺苷甲硫氨酸400毫克,维生素C500毫克,维生素E300毫克。S-腺苷甲硫氨酸可用N-乙酰半胱氨酸替代,优选的剂量为500毫克。
治疗有效量的药物可以通过不同的组合方式给药,在各种组合方式中成分可以是单剂量单位或多于一个剂量单位。例如,本发明的组合可以以每天单剂量单位给药,其中所有成分都存在于例如单个胶囊或片剂中。也可以通过结合多于一个剂量单位给药,每个剂量单位包括至少一种成分或者两种或多种成分混合于单个剂量单位中。例如,S-腺苷甲硫氨酸,维生素E,维生素C的组合可以以S-腺苷甲硫氨酸的丸剂,胶囊,或者片剂,加上维生素E和维生素C的单独的丸剂,胶囊,或者片剂来给药。
S-腺苷甲硫氨酸,维生素E,维生素C的组合可包括在单独药剂单位中的每种成分,或在一个药剂单位中的两种成分,例如在同一个胶囊中结合,而其他的成分在单独的剂量单位中。或者,如上面所解释的那样,所有的三种成分都在相同的(也就是同一个)剂量单位中。这些组合可以以试剂盒或吸塑包装的形式提供,其中各种成分的多个计量单位被置于同一个包装或容器中,用于联合给药至人或者动物。例如,S-腺苷甲硫氨酸,维生素E,维生素C中的每一个的单剂量单位(例如,药片,胶囊)与用于联合给药的说明书一同被置于同一个吸塑包装内。这些组合可以被放于试剂盒,吸塑包装,药包,或用收缩膜包裹后瓶装,其中各种成分的多个剂量单位设置在同一个分配单位中,用于联合给药至人或者动物。
虽然此发明描述时提及了解释性的实施,可以理解的是,本发明并不局限于这些实施例。本领域技术人员可以对其做多种改变和调整。所有这些改变和调整都包含在附加的权利要求中。
实施例1:S-腺苷甲硫氨酸,维生素E,维生素C在治疗和预防心血管功能障碍中的应
用
动物和动物组:雄性斯普拉-道来氏大鼠(Charles River,St.Constant,魁北克,加拿大),7周大(体重200-225克),每两只一笼,置于受控的条件下(22±1℃,12h光照/12h黑暗循环)。喂以标准鼠粮(66%玉米淀粉中的碳水化合物,20%蛋白质和5%脂质),无限水供应,在此状态下饲养两周以适应室内环境。随后动物被分为四组:第一组(老年对照组)以正常食物喂养;第二组(SAMEC治疗组),以添加了SAMEC(S-腺苷甲硫氨酸(SAMe)(0.5g.kg食物),维生素C(12.5g.kg食物),和维生素E(1.5g.kg食物))的正常食物喂养;第三组(蔗糖组)以正常食物,与含有5%蔗糖的水喂养(50ml/只/日,同时供应正常的自来水);和第四组(蔗糖+SAMEC治疗组)喂以添加了SAMEC的正常食物,与含5%蔗糖的饮用水。由于日均食物消耗为20g,维生素C的日均摄入约为250mg.kg体重,维生素E为30mg.kg体重,S-腺苷甲硫氨酸19mg.kg体重。
这四组中的大鼠在6个月和12个月时测试(N=13只/组)。年轻成年大鼠(N=14只)在第9周时,以标准鼠粮饲养,作为6个月和12个月的老年大鼠的对照组。每两个星期进行一次体重检测。在整个过程中,按照预定的时间表,每一个星期监测一次食物和水的摄入。以植入微型芯片的方法确认动物身份。
每两个星期进行一次体重检测。在整个过程中,按照预定的时间表,每一个星期监测一次食物和水的摄入。以植入微型芯片的方法确认动物身份。
手术准备:为了建立一个稳定的餐后状态,所有大鼠将禁食8小时,然后在手术准备前两小时,开始重新喂食。通过腹腔注射戊巴比妥钠(54.7mg/kg;CEVA Sante Animal S.A.,利布尔讷,法国)麻醉大鼠。麻醉状态通过用套管持续在颈静脉输入戊巴比妥钠(0.5mg/ml-1生理盐水50μl.min-1)维持,需要时,快速浓注0.54mg(0.01ml)。大鼠被置于控温手术台(HarvardApparatus,Kent,英国),直肠温度被监控且控制在37.0-37.5℃。自主呼吸通过气管引导管进行。
为了监测平均动脉压(MAP),导出动脉血样,以及进行静脉给药,按照之前所述方式(Lautt,2003)实行动静脉分流。扼要地说,两根导管(聚乙烯管PE60)用硅胶管相连,其中一根导管插入右股动脉,另一根插入右股静脉。
血液循环中的支流与记录分流压力的压力传感器相连,在通向该血液循环的静脉一侧的硅胶管被加紧的时候,测量全身的动脉压。血样从分流中动脉一侧抽取,用于血糖的测量。分流中的血流确保了动脉血葡萄糖浓度的实时监测,这对上述的动态正葡萄糖钳夹技术是非常重要的。一根输液线被插入分流中的静脉侧,用于静脉药物的输送。另一根输液线与颈静脉相连,用于输入葡萄糖。动物被肝素化(100IU.kg-1)以防止血管分流器处凝血。
血液动力学和左心室压力-容积的测量:为了评估血液动力学与左心室(LV)压力-容积的关系,一个带有微尖电导压力-容积(P-V)的导管(size1.9F,Scisense Inc.,London,ON,加拿大)被置入右颈动脉,并推进左心室。导管的位置经细心调整直至得到稳定的P-V循环。导管与EMKA信息处理器相连,所有数据用IOX数据获取/分析系统(EMKA Technologies,FallsChurch,弗吉尼亚,美国)以抽样率1000Hz的速度数码获取并分析。大鼠腹腔被打开,并且肝脏和隔膜之间的下腔静脉被作为实验前准备对象,用以准备短暂性静脉闭塞以减少心脏前负荷。
下述参数被记录和分析:心率(HR),平均动脉压(MAP),左室收缩峰压(Pes),左心室舒张末压(Ped);最大左心室压力上升和下降率(分别为dP/dtmax和dP/dtmin),左心室压力衰减时间常数(tau),射血分数(EF),搏出量(SV),心输出量(CO),搏出功(SW)。心输出量按体重标准化(心排血指数,CI)。搏出功按体重标准化(SWI)。总外周阻力指数(TPRI)根据公式TPRI=MAP/CI计算。
此外,左心室压力-容积关系通过压力-容积循环进行评估。该压力-容积循环是在压缩外部血管导致下腔静脉短暂性静脉闭塞的时候记录的。利用IOX软件计算前负荷补充搏出功(PRSW),心室收缩末期压力-容积关系(ESPVR),心室舒张末期压力-容积关系(EDPVR),dP/dtmax-舒张末期容积关系(dP/dtmax–EDV)和最大倒电容(Emax)。
电导管的校正:按照IOX的建议,通过电导管的容积信号被校正,以获取平行电导和心输出量。不像传统的指标如射血分数和dP/dtmax,这些额外的、由压力-容积分数得来的参数,是更具体,更直接的心室功能的指标,不依赖于心脏负荷情况和心率(14,28)。扼要地说,静脉注射20μl已预热的10%的生理盐水后,通过P-V关系的改变,IOX软件会计算平行电导量,用以修正心脏质量容积(cardiac mass volume)。在实验的最后,为了校正心导管所测量的心输出量,一个V型的超声血管周流量探针(大小:3mm)被置于胸主动脉弓部用于测量心输出量(T206,Transonic Systems Inc.,纽约州,美国)。心脏被移出体外。左右心室被分开并称重。
化学品:人胰岛素从诺和诺德(Bagsvaerd,丹麦),购买。阿托品,维生素C(L-抗坏血酸),和维生素E((±)-α-生育酚)从Sigma购买。S-腺苷甲硫氨酸从Now Foods(Bloomingdale,伊利诺斯州,美国)购买。胰岛素和阿托品溶解于生理盐水中。抗氧化剂由Research Diets Inc.(NewBrunswick,新泽西州,美国)混合入正常大鼠食物中。血浆胰岛素浓度通过ELISA(ALPCO,Windham,新罕布什尔,美国)测定。
统计分析:数值以平均值±标准误差的形式示出。当适用的时候,数据通过单侧或双侧t检验。但需要比较不同组的多个平均值时,进行单因素方差分析然后进行图基检验。统计显著性设置为当p<0.05时。使用线性回归的方法。
结果
衰老对心血管功能和SAMEC疗效的影响。SAMEC治疗提高了52周大鼠的心血管功能。如图1至9所示,与没有接受SAMEC治疗的大鼠(图中柱52C)相比,接受SAMEC治疗的大鼠(图中柱52A)呈现出心血管功能提高的有益效果(图1-4所示的压力-容积指数,图5-12所示的基线血液动力学参数)。对比没有接受SAMEC治疗的同龄大鼠来说,这些有益效果包括更高的:ESPVR(图1),Emax(图2),dP/dtmax–EDV(图3),PRSW(图4),CI(图5),SWI(图6),dP/dtmax(图7),dP/dtmin(图8)和EF%(图9)。有益效果也包括减少的:Tau(图10),Ped(图11)和TPRI(图12)。
图13示出了由SAMEC所提供的对只与年龄相关的受损心血管功能的保护率。保护率由以下公式计算:百分保护率=[1-(Y-A)/(Y-C)],其中Y代表对年轻的9周大鼠的作用,C表示对食用对照食物的,52周大鼠的作用,A表示对食用添加SAMEC的食物的52周大鼠的作用。SAMEC提高了与衰老相关的,EF%,PRSW,dP/dtmax,dP/dtmin,dP/dtmax–EDV,总外周阻力指数,左心室压力衰减时间常数,心室收缩末期压力-容积关系,SWI,和CI的保护率。
蔗糖饮食对老龄大鼠心脏功能和SAMEC疗效的影响。如图1-9所示,与服用正常食物的对照组(图中柱52C)相比,喂以蔗糖的52周大鼠(图中柱52S)有心脏机能衰弱的趋势。SAMEC治疗提高了同时食用SAMEC和蔗糖的大鼠(柱52T)的心脏功能,与仅食用蔗糖的大鼠(柱52S)相比,在52周时,呈现出提高心脏功能的有益效果。与仅仅使用蔗糖的相同年龄的大鼠相比,这些有益效果包括较高的:ESPVR(图1),Emax(图2),dP/dtmax–EDV(图3),PRSW(图4),CI(图5),SWI(图6),dP/dtmax(图7),dP/dtmin(图8)和EF%(图9)。有益效果也包括减少的:Tau(图10),Ped(图11)和TPRI(图12)。同时食用SAMEC与蔗糖的大鼠心脏功能被提高到与只服用SAMEC同龄实验组相似的程度,参照参数:ESPVR(图1),Emax(图2),PRSW(图4),SWI(图6),dP/dtmin(图8),Tau(图10),和TRPI(图12)。
在图14中示出了SAMEC的对与衰老和高蔗糖食物相关的受损心脏功能的保护率。保护率由以下公式计算:百分保护率=[1-(Y-A)/(Y-C)],其中Y地表对年轻的9周大鼠的作用,C代表对食用对照饮食的52周大鼠的作用,A代表对食用添加SAMEC的饮食的52周大鼠的作用。SAMEC提高了与衰老和高蔗糖食物相关指数的保护率。这些指数包括PRSW,dP/dtmin,dP/dtmax,心室收缩末期压力-容积关系,dP/dtmax–EDV,EF,左心室压力衰减时间常数,总外周阻力指数,SWI,和CI。
鼠类老化心脏的病理生理学特征与人类老龄人的类似(Dai DF,Rabinovitch PS.Cardiacaging in mice and humans:the role of mitochondrial oxidative stress.Trends Cardiovasc Med19(7):213-20,2009)。此纵向研究比较了9,26和52周大的大鼠的心脏功能。和之前的研究结果一致,我们的数据显示心脏的收缩和舒张功能都逐渐随着年龄增大而衰弱,并且在52周大时变得在统计上显著。分析与负载相关的指标,EF%,dP/dtmax,dP/dtinin,和HR分别下降了14,22,19,和16%。Tau增加了27%。此外,反映固有收缩功能的负载相关指数,包括ESPVR,Emax,dP/dt-EDV和PRSW,也分别减少了36,45,47和22%。然而,发明人观查到,虽然指示舒张末期心肌硬度的舒张末期压力显著升高,但与年轻对照组相比,52周大鼠的EDPVR并没有明显的变化。
上述描述意在解释本发明的配置和使用方法,并未暗示任何限制条件。在不脱离本发明的精神或范围的前提下,本领域技术人员可以对本发明的方法和产品做出修改和变换。本文引用的参考文献在此通过引用将其并入。
Claims (17)
1.一种用于预防或治疗心血管功能障碍的方法,包括施用治疗有效量的:
1)以下各种物质中的一种或多种:
(a)S-腺苷甲硫氨酸,其衍生物或药学上可接受的盐,和(b)N-乙酰半胱胺酸,其衍生物或药学上可接受的盐;
2)维生素E或其衍生物或其药学上可接受的盐;和
3)维生素C或其衍生物或其药学上可接受的盐。
2.根据权利要求1所述的方法,其特征在于,所述心血管功能障碍是慢性的。
3.根据权利要求1所述的方法,其特征在于,所述心血管功能障碍是急性的。
4.根据权利要求1所述的方法,其特征在于,所述心血管功能障碍是与衰老相关的。
5.根据权利要求1所述的方法,其特征在于,所述心血管功能障碍是与高糖食物相关的。
6.根据权利要求1所述的方法,其特征在于,病人食用高糖饮食。
7.根据权利要求1所述的方法,其特征在于,心血管功能障碍的指标选自:前负荷补充搏出功(PRSW)减少;心室收缩末期压力-容积关系(ESPVR)的减少;dP/dtmax-舒张末期容积关系(dP/dtmax–EDV)的减少;最大倒电容(Emax);左室收缩峰压(Pes);左心室舒张末压(Ped);最大左心室压力上升和下降率(分别为dP/dtmax和dP/dtmin);左心室压力衰减时间常数(tau);射血分数(EF),按体重标准化的心输出量(心排血指数,CI);按体重标准化的搏出功(SWI);和总外周阻力指数(TPRI)。
8.根据权利要求1所述的方法,其特征在于,S-腺苷甲硫氨酸,其衍生物或药学上可接受的盐,或N-乙酰半胱胺酸,其衍生物或药学上可接受的盐的治疗有效量为每日口服200至1600毫克。
9.根据权利要求1所述的方法,其特征在于,S-腺苷甲硫氨酸或其衍生物或其药学上可接受的盐、与N-乙酰半胱胺酸或其衍生物或其药学上可接受的盐中的一种或多种物质的治疗有效量为每日口服400毫克。
10.根据权利要求1所述的方法,其特征在于,维生素E、其衍生物或其药学上可接受的盐的治疗有效量为每日口服100至900毫克。
11.根据权利要求1所述的方法,其特征在于,维生素E、其衍生物或其药学上可接受的盐的治疗有效量为每日口服300毫克。
12.根据权利要求1所述的方法,其特征在于,维生素C、其衍生物或其药学上可接受的盐的治疗有效量为每日口服200至2000毫克。
13.根据权利要求1所述的方法,其特征在于,维生素C、其衍生物或其药学上可接受的盐的治疗有效量为每日口服500毫克。
14.根据权利要求1所述的方法,其特征在于,(a)S-腺苷甲硫氨酸、其衍生物或其药学上可接受的盐,和(b)N-乙酰半胱胺酸、其衍生物或药学上可接受的盐中的一种或多种物质的治疗有效量为每日口服400毫克,维生素E、其衍生物或其药学上可接受的盐的治疗有效量为每日口服300毫克,维生素C、其衍生物或其药学上可接受的盐的治疗有效量为每日口服500毫克。
15.根据权利要求1所述的方法,其特征在于,(1),(2),(3)同时给药。
16.根据权利要求1所述的方法,其特征在于(1),(2),(3)在同一天给药。
17.治疗有效量的、(a)S-腺苷甲硫氨酸、其衍生物或其药学上可接受的盐,和(b)N-乙酰半胱胺酸、其衍生物或药学上可接受的盐中的一种或多种物质;维生素E或其衍生物或其药学上可接受的盐;和维生素C或其衍生物或其药学上可接受的盐;在制备用于治疗或预防心血管功能障碍的药物中的应用。
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