CN102349923A - L-肉碱和葡萄糖治疗心血管疾病的应用 - Google Patents
L-肉碱和葡萄糖治疗心血管疾病的应用 Download PDFInfo
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 70
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- 239000008103 glucose Substances 0.000 title claims abstract description 31
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 title claims description 12
- 230000002526 effect on cardiovascular system Effects 0.000 title 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
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- XADVIIFXTSUEOO-UHFFFAOYSA-N 2-aminoethanesulfonic acid;magnesium Chemical compound [Mg].NCCS(O)(=O)=O XADVIIFXTSUEOO-UHFFFAOYSA-N 0.000 claims description 2
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- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- JMTCDHVHZSGGJA-UHFFFAOYSA-M potassium hydrogenoxalate Chemical compound [K+].OC(=O)C([O-])=O JMTCDHVHZSGGJA-UHFFFAOYSA-M 0.000 claims description 2
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- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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Abstract
本发明描述了L-肉碱或它的药学上可接受的盐之一与葡萄糖组合在制备药物中的应用，所述药物用于减少由急性心肌梗塞造成的死亡数，减少梗塞患者处于医院的重症监护下的天数，和减少梗塞后心力衰竭的发作次数，其中在发作急性心肌梗塞症状仅仅几小时内，以9克/天的初始剂量，静脉内地施用L-肉碱；并联合1000-1500mL 5％葡萄糖溶液，持续5天，此后以4克/天的剂量经口施用，继续L-肉碱治疗。
Description
本申请是专利申请号为200580023475.1的发明专利申请的分案申请。
本发明涉及L-肉碱和葡萄糖作为药物的联合应用，所述药物可以用于减少由急性心肌梗塞造成的死亡数，减少梗塞患者处于医院的重症监护下的天数，和减少梗塞后心力衰竭的发作次数。
必须将要施用的L-肉碱的日剂量溶解在2个或3个500ml瓶的5％葡萄糖溶液中，并静脉内地施用。重要的是，根据本发明的联合治疗，应当在发生急性心肌梗塞症状仅几小时内开始，以9克的初始剂量持续5天，此后应当继续治疗，每天用4克剂量的单独的L-肉碱，经口施用。
梗塞后心力衰竭是由于心脏不能泵出足以满足各组织的代谢需要的量的血液。
急性心肌梗塞(AMI)会造成形态功能改变，后者经常诱发进行性左心室扩张(“心室重塑”现象)。
可以将AMI后的心室扩张视作总体代偿机制，其目的在于，在存在射血分数减少的情况下，维持充足的心输出量。
心室扩张的程度，是AMI患者的最重要的预后指标。
具有相对更大的心室容积的患者，处于更大的未来心脏事件的危险(Circulation 1987；76：44-51)。
因此，从临床-预后的观点看，梗塞后的心室重塑现象的限制是很重要的(Circulation 1994；89：68-75)。该现象的限制，可以通过两种机理来实现：(a)通过早期心肌再灌注，限制梗塞区域的范围(它是将来的扩张的主要决定因素)(Circulation 1989；79：441-444)，和/或(b)通过施用ACE抑制剂，减少壁应力和由此减轻未参与梗塞过程的心肌区域的进行性扩张。
当血栓性梗阻向全面的、永久的血管闭塞的方向迅速演变时，所致的灌注的缺乏，会在仅仅几小时的时间内，导致心肌细胞坏死，并从而导致梗塞。即时的和长期的预后取决于一系列因素，其中最重要的是坏死区域的大小和由此引起的早期和晚期并发症。因此，显然地，现代急性梗塞治疗的首要目的是，减小梗塞区域的大小。该目的经常通过再灌注操作来实现，无论是药理学的(血栓溶解剂)、机械的(PTCA)例如血管成形术，还是手术的(搭桥)。一般而言，再灌注越早且越有效，坏死区域越将小。后者也受其它因素的影响，尽管程度较小，其中的第一个因素是心肌氧耗量，其取决于心率、心肌收缩力和壁张力。那么，根本重要的是所有能减少心脏工作负荷、而同时维持足够的循环输出的那些措施，无论是药理学的还是其它的。
在由急性心肌梗塞导致死亡的所有患者中，超过一半是在最初几小时内死亡。
已经知道用于治疗心力衰竭和急性心肌梗塞的药物。
β-受体阻断剂是具有抗心律失常性质的药物，如果在梗塞发作的早期使用，明显地更具活性。
硝基衍生物(Nitroderivative)是通常通过静脉输注施用的药物，用于通过对心外膜血管的血管扩张，改善心肌灌注。
硝普钠是对小动脉和静脉区发挥双重作用的药物。该化合物会产生冠脉和肾脏的血管扩张，从而增强心肌灌注和利尿。
L-肉碱是一种已知的化合物，其制备方法描述于US 4,254,053。
已经知道L-肉碱和葡萄糖的联合应用。
US 4,320,145描述了含有L-肉碱的葡萄糖溶液，其可以用于促进葡萄糖的肌肉吸收，从而预防过量的胰岛素分泌。
还知道L-肉碱在治疗心脏病中的应用。
在Drugs Exp.Clin.Res 1992；18(8)：355-65中，描述了L-肉碱在梗塞患者中的应用，其中在患者已经出院后，开始L-肉碱的口服治疗。
在Eur Heart J.1989 Jun；10(6)：502-8中，描述了L-肉碱在梗塞患者中的应用，其中评价了L-肉碱的抗心律失常和代谢作用。在该研究中，据报道在L-肉碱治疗组和安慰剂治疗组中各有2例死亡。
在J.Am.Coll.Cardiol 1995 Aug；26(2)：380-7中，描述了L-肉碱在梗塞患者中的延长应用，和它在开始治疗后3、6和12个月时对左心室容积的影响。在该研究中，在梗塞24小时内施用L-肉碱，死亡率评价表明，在整个住院治疗阶段，治疗组中有11名患者死亡，而对照组有14名。在测试的两组中观察到的死亡数的差异的非显著性是明显的。
在Am.Heart J.2000 Feb；139(2 Pt 3)：S115-9(它是心脏病学领域关于L-肉碱的代谢作用的综述)中报道了L-肉碱是有效的，因为它对脂类和碳水化合物代谢具有代谢作用。
在Lancet 1982 Jun.19；1(8286)：1419-20中，报道了死于梗塞的患者的心脏组织样品的分析，与死于梗塞以外的原因的人的心脏组织样品平行进行，显示了在(心脏病患者的)不受梗塞影响的心脏区域中，游离肉碱的水平等于对照组的水平，而在梗塞的心脏组织区域中的游离肉碱的水平低于对照组的水平。
在Postgrad Med.J.1996 Jan；72(843)：45-50中，描述了L-肉碱在开始治疗前24小时阶段内呈现出梗塞症状的患者中的应用。在该研究中，以2g/天的剂量施用L-肉碱，在开始治疗后28天，对照组的死亡数是6，治疗组是4。在测试的两组中观察到的死亡数的差异的非显著性是明显的。
在Am.J.Cardiovasc Pathol 1990；3(2)：131-42中，描述了L-肉碱在实验动物(狗)的实验性心脏缺血模型中的应用，其中在这些动物中证实了L-肉碱增强心脏脂类代谢的活性。
在Drugs Exptl.Clin.Res.X(4)219-223(1984)中，描述了以40mg/kg/天(2.8g/天)的剂量使用L-肉碱。对照组的死亡数是1，而治疗组没有死亡。而且，在该研究中，将治疗组分成2个小组，其中之一在发作梗塞征象4小时内用L-肉碱治疗，另一组在发作梗塞征象后4小时治疗。在他们对结果的讨论中，作者声称，他们在发作梗塞症状4小时内治疗的患者和发作这样的症状后4小时治疗的患者之间没有发现统计学显著的差异。
在″Pergamon Press 1986″出版的标题为“Clinical aspects ofhuman carnitine deficiency”的另一篇出版物中，描述了“盲法”临床试验，其中招募了351位急性心肌梗塞患者，其梗塞症状在开始L-肉碱治疗8小时内已经开始发生。在该临床试验中，患者每8小时静脉内地接受3克L-肉碱(9克/天)。L-肉碱治疗持续48小时(对照组接受盐水溶液)。在开始治疗后7天时分析死亡率，没有显示对照组和L-肉碱治疗组之间的显著差异。
在这些L-肉碱研究(或本申请中未提及的其它研究)中，都没有公开或暗示L-肉碱和葡萄糖可以联合用于治疗梗塞后心力衰竭，减少梗塞患者处于医院的重症监护下的天数，和减少由急性心肌梗塞造成的死亡数。
一定数目的急性心肌梗塞患者，在重症监护科住院治疗的第一周中仍然继续死亡，并且之后也继续死亡，甚至当用可得到的所有适当的药理学的和技术的手段治疗时亦如此。而且，单独的L-肉碱，无论是使用迄今为止被采用的和在上述出版物中描述的治疗方案，还是与所述的适当的且可得到的药理学的和技术的手段相联合，与使用普通药物治疗的患者相比，尽管会改善所治疗的患者的一般状况，却不能降低死亡率。
因此，仍然存在可强烈感知的对新药物或新组合的需要，其可以用于减少由急性心肌梗塞造成的死亡数，减少梗塞患者处于医院的重症监护下的天数，和减少梗塞后心力衰竭的发作次数。
现在，已经令人惊讶地且意外地发现，L-肉碱或它的药学上可接受的盐之一与葡萄糖的联合应用，可以用于减少由急性心肌梗塞造成的死亡数，减少梗塞患者处于医院的重症监护下的天数，和减少梗塞后心力衰竭的发作次数。
L-肉碱和葡萄糖的联合应用是指，同时施用其中溶解了9克L-肉碱的5％葡萄糖溶液(1000/1500mL/天，静脉内地)，或施用5％葡萄糖溶液(1000/1500mL/天，静脉内地)，且平行地静脉内地施用9克/天的L-肉碱，以单剂量或分剂量(例如3g×3次施用/天i.v.)。
L-肉碱的药学上可接受的盐是指，L-肉碱和酸的任何盐，其不会产生毒副作用。
这些酸是药理学家和药学专家众所周知的；这样的盐的非限制性实例是：氯化物，溴化物，乳清酸盐，天冬氨酸盐，酸性天冬氨酸盐，酸性柠檬酸盐，柠檬酸镁，磷酸盐，酸性磷酸盐，延胡索酸盐和酸性延胡索酸盐，延胡索酸镁，乳酸盐，马来酸盐和酸性马来酸盐，草酸盐，酸性草酸盐，巴莫酸盐，酸性巴莫酸盐，硫酸盐，酸性硫酸盐，磷酸葡萄糖，酒石酸盐和酸性酒石酸盐，磷酸甘油，粘酸盐，酒石酸镁，2-氨基乙磺酸盐，2-氨基乙磺酸镁，甲磺酸盐，酒石酸胆碱，三氯醋酸盐和三氟醋酸盐。
L-肉碱的药学上可接受的盐也指FDA批准的和在本文中引作参考的出版物Int.J.of Pharm.33(1986)，201-217中列出的盐。
于是，本发明的目的是，L-肉碱或它的药学上可接受的盐之一与葡萄糖组合在制备药物中的联合应用，所述药物用于减少由急性心肌梗塞造成的死亡数，减少梗塞患者处于医院的重症监护下的天数，和减少梗塞后心力衰竭的发作次数，其中在发作急性心肌梗塞症状仅仅几小时内，优选地在发作急性心肌梗塞症状6小时内，更优选地在4小时内，开始L-肉碱和葡萄糖的静脉内治疗；以9克/天溶解在1000-1500mL 5％葡萄糖溶液中的初始L-肉碱剂量，连续施用治疗5天，此后以4克/天的剂量，经口服继续L-肉碱治疗。
下面的实施例解释了本发明。
实施例1
进行临床试验，其目的在于，评价L-肉碱的施用对急性心肌梗塞患者的短期、中期和长期发病率和死亡率的影响。试验设计是多中心随机的、双盲的、安慰剂-对照的、平行组试验。
招募了共计2,296名年龄低于80岁的男性和女性患者，并再分组。在前5天，以9g/天的剂量，静脉内地施用研究化合物L-肉碱；从第6天至第180天，经口施用4g/天。
更具体地，在一组患者中，静脉内地施用溶解在无菌盐水溶液中的L-肉碱，而在另一组患者中，将其溶解在医院科室中使用的普通5％葡萄糖溶液中施用。
对照组接受用于治疗梗塞的标准治疗，没有L-肉碱。
根据当地临床实践中采用的程序，施用伴随治疗。
评价的功效参数是，死亡率的降低，重症监护天数的减少，和梗塞后心力衰竭的发作次数的减少。
入选标准
●典型的胸痛持续＞30分钟，经口或静脉内施用硝酸盐不缓解；
●在D，和导联aVL和/或至少2个邻近的胸前导联中，ST-段抬高≥0.2mV的ECG；
●症状发作和研究随机化之间经过的时间间隔＜12小时；
●年龄＜80岁；
●书面的知情同意书。
淘汰标准
●妊娠或哺乳；
●血液动力学有意义的心瓣膜病；
●肥厚性或扩张性心肌病；
●先天性心脏病；
●临床上严重的肝病和肾病；
●酒精滥用；
●与较差的寿命预期有关的其它疾病；
●可能造成对治疗和/或定期检查依从性差的状况；
●入选另一试验。
用9g/天溶解在1000/1500mL葡萄糖溶液中的L-肉碱治疗的患者，表现出比对照组低的死亡率，且所述的死亡率与在用溶解于盐水中的L-肉碱治疗的组中记录的死亡率相当。为此，下面的表1/A给出了安慰剂组与L-肉碱治疗的患者相比的死亡率数据，无论L-肉碱是溶解在盐水中还是溶解在葡萄糖溶液中(在该试验中包括的患者的总数)。
表1/A
RR＝相对危险性
下面的表1/B给出了与安慰剂治疗的对照组相比，用溶解在葡萄糖溶液中的L-肉碱治疗的患者组的死亡率数据。
表1/B
RR＝相对危险性
与用溶解在盐水中的L-肉碱治疗的患者组相比，用溶解在葡萄糖溶液中的L-肉碱治疗的梗塞患者组表现出重症监护天数的统计学显著的减少。
表2报道所得到的结果。
表2
与用溶解在盐水中的L-肉碱治疗的患者组相比，用L-肉碱和葡萄糖溶液治疗的患者组表现出梗塞后心力衰竭的发作次数的统计学显著的减少。
表3报道所得到的结果。
表3
由初级护理医师基于他或她的经验和患者的总体状况所建议，也由于根据本发明的化合物没有毒性，根据本发明使用的L-肉碱剂量和治疗方案可以经受改变。
根据本发明的静脉内施用制剂，包括在合适的介质中的溶液或悬浮液，所述介质例如盐水溶液，蒸馏水，葡萄糖溶液或其它。
根据本发明的经口施用制剂，包括片剂，胶囊，粉末，颗粒，糖浆剂，酏剂，溶液或悬浮液。
Claims (6)
1.L-肉碱或它的药学上可接受的盐之一与葡萄糖在制备药物中的联合应用，所述药物用于与用L-肉碱治疗的对照组相比减少患者急性心肌梗塞引起的死亡发生数，
其中在发生急性心肌梗塞症状6小时内，以9克/天的初始剂量，静脉内地施用L-肉碱，并联合1000-1500mL 5％葡萄糖溶液，持续5天，此后以4克/天的剂量经口继续施用L-肉碱或其药学上可接受的盐之一，因此与对照组相比由心肌梗塞引起的死亡发生数降低。
2.根据权利要求1的应用，其中在发生急性心肌梗塞症状4小时内，施用所述的L-肉碱和葡萄糖溶液。
3.根据权利要求1的应用，其中所述的L-肉碱的药学上可接受的盐选自氯化物，溴化物，乳清酸盐，天冬氨酸盐，酸性天冬氨酸盐，酸性柠檬酸盐，柠檬酸镁，磷酸盐，酸性磷酸盐，延胡索酸盐和酸性延胡索酸盐，延胡索酸镁，乳酸盐，马来酸盐和酸性马来酸盐，草酸盐，酸性草酸盐，巴莫酸盐，酸性巴莫酸盐，硫酸盐，酸性硫酸盐，磷酸葡萄糖，酒石酸盐和酸性酒石酸盐，磷酸甘油，粘酸盐，酒石酸镁，2-氨基乙磺酸盐，2-氨基乙磺酸镁，甲磺酸盐，酒石酸胆碱，三氯醋酸盐和三氟醋酸盐。
4.根据权利要求1的应用，其中所述的L-肉碱溶解在1000-1500mL 5％葡萄糖溶液中施用。
5.根据权利要求1的应用，其中L-肉碱与葡萄糖溶液平行地施用，以单剂量或分剂量，溶解在合适的介质例如蒸馏水、盐水溶液、或葡萄糖溶液中。
6.根据权利要求1的应用，其中经口施用的L-肉碱是片剂，胶囊，粉末，颗粒，糖浆剂，酏剂，悬浮液或溶液的形式。
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| EP0627161A1 (en) * | 1993-06-02 | 1994-12-07 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Use of L-carnitine and alkanoyl L-carnitines in the storage of blood for transfusions and stabilizing solutions containing them |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4320145A (en) * | 1979-10-05 | 1982-03-16 | Claudio Cavazza | Pharmaceutical composition for parenteral nutrition comprising L-carnitine or acyl L-carnitines |
| EP0627161A1 (en) * | 1993-06-02 | 1994-12-07 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Use of L-carnitine and alkanoyl L-carnitines in the storage of blood for transfusions and stabilizing solutions containing them |
Non-Patent Citations (2)
| Title |
|---|
| 催俊友等: "急性心肌梗塞早期应用L-肉碱临床疗效观察", 《江苏临床医学杂志》 * |
| 马宏星等: "肉碱与心血管疾病", 《心血管病学进展》 * |
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