CN101400345A - 心脏停搏液 - Google Patents

心脏停搏液 Download PDF

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Publication number
CN101400345A
CN101400345A CNA200780009035XA CN200780009035A CN101400345A CN 101400345 A CN101400345 A CN 101400345A CN A200780009035X A CNA200780009035X A CN A200780009035XA CN 200780009035 A CN200780009035 A CN 200780009035A CN 101400345 A CN101400345 A CN 101400345A
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solution
cardioplegic solution
heart
cardioplegic
xylitol
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埃里克·盖加斯
蒂埃里·卡雷尔
亨德里克·特瓦埃尔莱
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Universitaet Bern
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Universitaet Bern
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

本发明涉及在手术过程中停止心肌和保护心肌的新的心脏停搏液。与现有标准的溶液相比，根据本发明的心脏停搏液提供了几个优点，及包含硫酸镁七水合物，氯化钾，盐酸普鲁卡因和木糖醇。

Description

心脏停搏液
技术领域
本发明涉及心脏手术。更准确地涉及在心脏手术过程中可以使用的心脏停搏液。
背景技术
在20世纪60年代开始心脏手术时，外科医生先驱们一方面尝试几种策略以支持患者的循环，和另一方面尝试保护患者的心脏。冷冻的保护作用不但在心脏上而且也在整个身体上得到了认可。心脏外科手术随后的发展主要利用了体外循环部件的渐进改进，可允许越来越复杂和越长时间的手术。因此，一种比只冷却心肌更好的保护是必需的。
理解心细胞新陈代谢有助于研发保护心脏组织的策略。从外科的观点看，心脏停搏是通过向心血管灌注溶液以获得诱导的心跳停止，所述溶液以顺行的方式通过冠状动脉，或者逆行通过冠状静脉。从生理学的观点看，所述溶液代表了可逆地停止心脏的可能性。最后，从新陈代谢的观点看，所述溶液保护心细胞免受由暂时缺氧诱导的可能伤害。几种类型的溶液已经被测试并在世界范围内常规地用于心脏手术。这些溶液是：
晶体心停搏液(
Figure A200780009035D0003141511QIETU
 cardioplegia)
血心停搏液(Blood cardioplegia)
冷心停搏液(Cold cardioplegia)
温心停搏液(Warm cardioplegia)
以下现有技术公开内容涉及心脏停搏液：
WO 03/057206；WO 02/11741；RU 2145843；WO 99/32172；WO96/18293；US 5407793；US 5290766；US 5139789；US 4988515；EP 0054635。
然而有改进现有的心脏停搏液的需要。尤其是，心跳停止必须尽可能的短。最小化使用的溶液的使用量以获得心跳停止也是适宜的。
发明内容
发明人惊奇地发现，如果心脏停搏液含有以下成分，就能获得改进的心脏停搏液。
-硫酸镁七水合物
-氯化钾
-盐酸普鲁卡因
-木糖醇
有利地，每1000ml使用以下的量：
-硫酸镁七水合物       3-5g
-氯化钾               0-100mM
-盐酸普鲁卡因         1000-5000mg
-木糖醇               0-80g
在这个情况下，溶液优选地缓冲到pH6.5。
在优选的实施方式中，每1000ml使用以下精确的量：
-硫酸镁七水合物        4g等于162mM(MW＝246.48)
-氯化钾                50mM等于373mg(MW＝74.55)
-盐酸普鲁卡因          3000mg等于11mM(MW＝272.78)
-木糖醇                45g等于296mM(MW＝152.15)
在这个情况下，溶液用0.1M氯化钠被有利地缓冲到pH6.5。
与所有其它的现有技术的心脏停搏液比较，根据本发明的所述溶液尤其提供了以下优点：
1.立即心跳停止(10-20秒)。所有现有技术溶液需要几分钟(常规5分钟)的灌注，以允许安全地心跳停止和保护。根据本发明的溶液不但显著地减少手术时间，而且更重要的是显著地减少所谓的“缺血时间”，即心肌没有灌注新鲜血液的时间。实际上，缺血时间和术后损伤具有明显的相关性。因此，根据本发明的溶液有助于改善整个结果，尤其是这种类型的手术的早期结果。
2.根据本发明的溶液的总体积可以是只有100ml。所有目前可获得的溶液由至少1升的晶体溶液组成。这意味着发生了显著的血液稀释，结果是手术期间和手术后的血细胞比容值通常少于0.25并需要异体输血。减少的血细胞比容。根据本发明的溶液减少了血液稀释，结果减少了术后水肿。
3.根据本发明的溶液允许一次注射后至少有60分钟的持续效果。所有其它可获得的心脏停搏液需要重复或持续的灌注。类似于刚才的前述，该优点允许减少手术时间和缺血时间，具有随后已述的益处。
4.简化技术，由外科医生自己一个人进行直接注射。实际上目前可获得的心脏停搏液，必须组织或多或少复杂的灌注系统并基本上由第三人操作。减少其他人进行的操作明显地有助于减少可能的所谓心技术事件或意外事故如气栓。
5.最后和最重要地，同其它目前可获得的溶液相比，根据本发明的溶液提供了更高的心肌保护。实际上，发明人已经发现与其它的心脏停搏溶液相比，术后心肌酶的水平，换句话说心细胞损伤的标记已经减少了。最后，在手术结束时，心脏更频密地自主返回到窦性心律。
制备(多个实施例)
溶液优选地在室温下制备，基本上在18和24℃之间。当保存在4℃下最长30天的时间，制剂被认为可安全使用。
在优选的实施方式中，将包括在溶液中的物质在没有标记的50ml随时可用的注射器中混合在一起。
已经发现，如果加入柠檬酸钠，可以获得在放置至少6到12个月的时间后稳定的溶液。
例如，在上述优选的实施方式中，可以使用160mmol/l的钠和53.2mmol/l的柠檬酸根。在120℃下进行20分钟的灭菌。
外科手术(实施例)
基本上在正中胸骨切开术和心脏及其大血管套管插入术后，开始CPB并以100％的流速进行。经证实正确地解除心腔的套管后，阻断升主动脉并将心脏停搏液注入主动脉根部。心脏立即停止并随后立即开始心脏手术。例外地，需要将在第三个50ml的注射器内的成分注入具有更高BMI的患者中。不排除局部冷却。在手术结束时，在开放主动脉前不需要热射。
临床体验
根据本发明的心脏停搏液在几个患者上进行了试验。发明人没有记录到与该溶液有关的任何个别不良作用。与现有技术的心脏停搏液相比，根据本发明的溶液在总的心跳停止时间(立即)和保护方面看来很有效。术后恢复加快。根据本发明的心脏停搏液可以有利地与MECC(微ECC)用于进行冠状动脉搭桥术，所述MECC是循环装置，被设计为通过减小例如预充容量(在与患者连接前填充系统需要的体积)以及减小由血液与异物(充氧器、换热器、管材、滤器等)接触诱导的炎症反应，以最小化标准心肺转流术产生的副作用。在其它的手术中，例如，如在瓣膜手术中，其中心脏必须充分打开，通过起始施用100ml的根据本发明的心脏停搏液，接着进行常规5分钟的灌注传统的血液心脏停搏混合物，引发心脏停跳。通常，类似于MECC辅助的手术，单个100ml的心脏停搏液注射是足够的。

Claims (4)

1.心脏停搏液，包括：
-硫酸镁七水合物
-氯化钾
-盐酸普鲁卡因
-木糖醇
2.根据权利要求1的心脏停搏液，其中每1000ml使用以下的量：
-硫酸镁七水合物           3-5g
-氯化钾                   0-100mM
-盐酸普鲁卡因             1000-5000mg
-木糖醇                   0-80g
3.根据权利要求2的心脏停搏液，其中每1000ml使用以下精确的量：
-硫酸镁七水合物             4g
-氯化钾                     50mM
-盐酸普鲁卡因               3000mg
-木糖醇                     45g
4.制备心脏停搏液的方法，其包括将以下成分混合的步骤：
-硫酸镁七水合物
-氯化钾
-盐酸普鲁卡因
-木糖醇
CNA200780009035XA 2006-03-15 2007-03-14 心脏停搏液 Pending CN101400345A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103933540A (zh) * 2014-03-26 2014-07-23 王寿世 一种心脏停搏液

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PT2328593E (pt) * 2008-08-22 2015-04-13 Universität Bern Preparação cardioplégica
WO2016007041A1 (ru) * 2014-07-11 2016-01-14 Общество С Ограниченной Ответственностью "Кардиосистемфарма" (Ооо "Ксф") Универсальный кардиоплегический раствор (варианты)
RU2635523C2 (ru) * 2016-04-29 2017-11-13 Общество С Ограниченной Ответственностью "Кардиосистемфарма" (Ооо "Ксф") Способ проведения кардиоплегии

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103933540A (zh) * 2014-03-26 2014-07-23 王寿世 一种心脏停搏液

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Application publication date: 20090401