CN103893205B - 一种包含利多卡因和腺苷的心脏停搏液及其制备方法 - Google Patents
一种包含利多卡因和腺苷的心脏停搏液及其制备方法 Download PDFInfo
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- CN103893205B CN103893205B CN201410150766.8A CN201410150766A CN103893205B CN 103893205 B CN103893205 B CN 103893205B CN 201410150766 A CN201410150766 A CN 201410150766A CN 103893205 B CN103893205 B CN 103893205B
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Abstract
本发明涉及心脏停搏液技术领域，具体涉及一种包含利多卡因和腺苷的心脏停搏液及其制备方法。在1000ml器官保存液中，组分分别为：氯化钠5.0-7.0g；氯化钾2.0-3.0g；硫酸镁0.3-0.5g；氯化钙0.05-0.1g；葡萄糖5-8g；利多卡因0.3-0.6g；腺苷100-200mg；黄芪甲苷10-20mg；辅酶Q10？50-80mg；汉防己甲素5-10mg；去甲乌药碱5-10mg；组氨酸5-8g；双蒸水余量。
Description
技术领域
本发明涉及心脏停搏液技术领域，具体涉及一种包含利多卡因和腺苷的心脏停搏液及其制备方法。
背景技术
自20世纪60年代开始心脏手术以来，心脏外科的先驱们一方面尝试几种方式以支持患者的循环，另一方面尝试保护患者的心脏。低温的保护作用不但在心脏局部而且也在全身的应用得到了认可。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更长时间手术的进行，但遗憾的是心肌保护效果始终未达到理想状态，术后仍存在心脏停搏-复灌注损伤。因此，提供一种比仅冷却心肌更好的心肌保护措施是必需的。
心脏停搏液是完成心脏手术的重要保证，其按作用原理可分为以下三大类：去极化停搏液，超极化停搏液和极化停搏液。去极化停搏液是临床使用最多的一类停搏液，常用的去极化停搏液有STH-2液和LA液。但一些研究显示：心血管手术后发生的低心排可能与高钾去极化停搏液的心肌保护不佳有关。其可能的原因有：①去极化停搏液使心肌细胞膜电位降到-50mv以下，但细胞膜电位在-60～-15mv之间，存在内向稳态钠窗口电流，可使心肌细胞发生钠超载；②膜电位在-40～-15mv之间，细胞膜存在内向钙电流，而且去极化状态下肌浆网内钙易于外流，从而加重了细胞内钙超载，钠钙跨膜流动会加重心肌损伤，不利于心肌功能恢复；③去极化停搏液中的高钾可直接损伤冠脉内皮细胞，导致血管内皮细胞和血管的自主调节功能受损。超极化停搏液是1993年由Cohn等首先提出，采用KATP通道开放剂使心肌细胞膜电位发生超极化(大约-110mv)而停搏于舒张期。其中，文献报道常用的钾通道开放剂有腺苷，尼可地尔，吡那地尔等，超极化停搏液已在实验室进行了较长时间的研究，但因其心肌保护效果不确切，至今尚未能应用于临床。同去极化停搏液类似，超极化停搏液也存在跨膜离子和能量失衡的问题。
通过研究发现上述停搏液存在的缺陷，仍需进一步改进，尤其是诱导停搏的时间必须尽可能的缩短，同时使用最低有效容量的停搏液以获得心脏停跳也是适宜的。传统的心肌保护采用化学性心脏停搏加局部低温的方法降低了心肌能量消耗，并加入各种添加剂以期使心脏停搏时缺血缺氧损伤程度降至最低。近年来较多研究的焦点集中在如何降低心脏停搏时的缺血损伤和再灌注后的再灌注损伤。心肌在阻断循环后处于无氧代谢状态，组织缺氧时，由于细胞内葡萄糖在无氧条件下丙酮酸会转化为乳酸，产生大量乳酸，及在体外循环心脏手术中预充乳酸林格液也易使他们发生高乳酸血症，导致严重的乳酸性酸中毒。低温虽降低了细胞的新陈代谢状态，但糖利用和ATP贮存大大降低，心肌细胞在代谢未完全停止的情况下出现能量负平衡。
利多卡因是临床常用药，常用于神经阻滞、治疗心律失常、器官保护等。研究发现，利多卡因浓度≥0.6mmol/L可快速停搏心肌，并且保留其抗炎抗氧化作用，再灌注后可迅速复跳，且复灌后心律失常发生率显著降低。
腺苷是心肌能量代谢的中间产物，在维持心血管系统的内稳态和各种损伤机制中发挥着重要的病理生理作用。腺苷具有调节冠脉循环的作用。腺苷通过持久扩张冠脉，改善心肌氧供，促进葡萄糖内流.补充细胞内高能磷酸键池，增强心脏功能，并拮抗儿茶酚胺作用，使失衡的氧供需与能量代谢重新恢复。此外，腺苷还具有抑制内皮素的释放、防止血小板在微循环中的聚集和升高心肌细胞Mn-SOD的含量等功能。
发明内容
本发明提供了一种包含利多卡因和腺苷的心脏停搏液及其制备方法，克服了上述现有技术之不足，其能有效解决传统的心脏停搏液存在诱导停搏时间过长、需要进行再灌注、复跳后易发生心律失常、易造成心肌损伤、易发生炎性反应和无法携氧的问题。
一种包含利多卡因和腺苷的心脏停搏液，在1000ml器官保存液中，组分分别为：
氯化钠5.0-7.0g；氯化钾2.0-3.0g；硫酸镁0.3-0.5g；
氯化钙0.05-0.1g；葡萄糖5-8g；利多卡因0.3-0.6g；
腺苷100-200mg；黄芪甲苷10-20mg；辅酶Q1050-80mg；
汉防己甲素5-10mg；去甲乌药碱5-10mg；组氨酸5-8g；双蒸水余量。
在本发明的一个实施方案中，在1000ml器官保存液中，所述组分优选为：
氯化钠6.5g；氯化钾2.3g；硫酸镁0.35g；
氯化钙0.07g；葡萄糖6g；利多卡因0.5g；
腺苷130mg；黄芪甲苷15mg；辅酶Q1075mg；
汉防己甲素7mg；去甲乌药碱8mg；组氨酸6g；双蒸水余量。
在本发明的另一个实施方案中，在1000ml器官保存液中，所述组分优选为：
氯化钠6g；氯化钾2.5g；硫酸镁0.4g；
氯化钙0.07g；葡萄糖7g；利多卡因0.4g；
腺苷150mg；黄芪甲苷17mg；辅酶Q1060mg；
汉防己甲素9mg；去甲乌药碱6mg；组氨酸7g；双蒸水余量。
本发明的另一个目的是提供一种制备所述心脏停搏液的方法，具体步骤如下：
(1)将800ml双蒸水加入大于1000ml容器中，再依次加入氯化钠、氯化钾、硫酸镁、氯化钙，搅拌至颜色变清晰；再加入葡萄糖、利多卡因、腺苷、黄芪甲苷、汉防己甲素、组氨酸和去甲乌药碱，搅拌至颜色变清晰；然后加入辅酶Q10，搅拌至颜色变清晰；
(2)将溶液的pH调至7.65，渗透压调至350～385mOsm/L，双蒸水定容至1000ml，放置4℃低温保存备用，即得。
本发明在利多卡因和腺苷的用量上进行了深入的研究，并且结合祖国传统医学的优势，对有关心脏保护的中药提取物及其单体进行了大量复杂的筛选试验，确定最佳中药单体成分及其重量配比，从而获得了一个达到最佳效果的心脏停搏液组方，使用少量的本发明制备的心脏停搏液便能有效使心脏停搏，避免了由于心肌缺血再灌注对心肌的损伤，能够提高一次复跳成功率和降低复跳后心律失常发生率，并且有效减小炎性反应，对心肌细胞起到有效地保护。
具体实施方式
下面将结合附图以及进一步的详细说明来举例说明本发明。需要指出的是，以下说明仅仅是对本发明要求保护的技术方案的举例说明，并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
实施例1
精密称取下述成分：
氯化钠6.5g；氯化钾2.3g；硫酸镁0.35g；
氯化钙0.07g；葡萄糖6g；利多卡因0.5g；
腺苷130mg；黄芪甲苷15mg；辅酶Q1075mg；
汉防己甲素9mg；去甲乌药碱6mg；组氨酸7g。
(1)将800ml双蒸水加入大于1000ml容器中，再依次加入氯化钠、氯化钾、硫酸镁、氯化钙，搅拌至颜色变清晰；再加入葡萄糖、利多卡因、腺苷、黄芪甲苷、汉防己甲素、组氨酸和去甲乌药碱，搅拌至颜色变清晰；然后加入辅酶Q10，搅拌至颜色变清晰；
(2)将溶液的pH调至7.65，渗透压调至370mOsm/L，双蒸水定容至1000ml，放置4℃低温保存备用，即得。
实施例2
精密称取下述成分：
氯化钠6g；氯化钾2.5g；硫酸镁0.4g；
氯化钙0.07g；葡萄糖7g；利多卡因0.4g；
腺苷150mg；黄芪甲苷17mg；辅酶Q1060mg；
汉防己甲素9mg；去甲乌药碱6mg；组氨酸7g；其他制备方法同实施例1。
实施例3
精密称取下述成分：
氯化钠5.0g；氯化钾3.0g；硫酸镁0.5g；
氯化钙0.05g；葡萄糖8g；利多卡因0.6g；
腺苷200mg；黄芪甲苷10mg；辅酶Q1050mg；
汉防己甲素10mg；去甲乌药碱5mg；组氨酸5g；其他制备方法同实施例1。
实施例4
采用离体鼠心非循环式Langendorff灌流功能测试模型，通过与常用的3种供心保存液(Thomas液、Stanford液、UW液)相比较，研究长时间(10小时)4℃保存离体鼠心的保存效果。
SD大鼠，称重，2％戊巴比妥钠0.5-0.7ml经腹腔注射。麻醉后，取仰卧位固定，经左股静脉注入肝素(3mg/Kg)，迅速开胸，于主动脉与右锁骨下动脉交界处离断主动脉，切除心脏。立即把心脏放入含有冷KHB液(4℃)的平皿中，用冷KHB液冲掉残留在主动脉内的血液，插主动脉灌注管并固定(灌注管的末端不应接触主动脉瓣)，将心脏迅速移至Langendorff灌流装置上并开始灌流。灌流压为90cmH2O(8.32Kpa)。从开胸到灌流开始要在50-70秒内迅速完成，超过80秒钟则放弃。心脏复跳后3分钟，用电刺激仪起搏心脏(阳极置于右心耳，阴极固定于右心室。刺激频率为5Hz(300次/分钟)，刺激波形为方波(40mv)。切开右心耳，经右心房、二尖瓣将带有测压导管的球囊送入左心室，测压管的另一端接压力传感器，后者与电生理多导记录仪连接。用于测定心脏功能观察指标一次，包括：
①.左室舒张末压力(LVEDP)
②.左室产生压(LVDP)
③.左室压力微分(+dp/dt)
④.冠脉流量(CF)
冠脉流量的测定：收集经右心房流出的液体，每分钟收集的液体量为冠脉流量(ml/min)。灌流至30分钟时，如果鼠心收缩无力，有心室纤颤左室产生压＜70mmHg，则放弃。
在30分钟时，停止心脏灌流，立即改为灌注心脏停搏液，压力为75cmH2O(7.36Kpa)，停搏液温度4℃，心脏同时表面降温(4℃)，灌注3分种后，置心脏于相应的保存液中。恒温4℃。保存10小时后，心脏恢复灌注(灌注方法同停搏前的方法)，再灌30分钟时，测定心脏功能，切取左心室壁组织，均匀切开2份迅速液氮冷冻保存，以备作能量代谢指标的测定。
具体结果如下：
SD大鼠离体心脏保存10小时后再灌注30分钟时的心功能
| LVEDP(mmHg) | LVDP(mmHg) | +dp/dt | CF | |
| Stanford液 | 53.2±11.6 | 21.3±5.4 | 478±187 | 5.2±0.7 |
| UW液 | 59.5±13.3 | 25.8±4.8 | 534±162 | 5.5±0.8 |
| Thomas液 | 48.2±12.7 | 29.5±5.2 | 567±175 | 5.7±0.8 |
| 实施例1 | 21.4±11.3 | 57.8±6.7 | 1772±365 | 7.4±0.9 |
| 实施例2 | 22.7±10.5 | 59.4±5.8 | 1838±297 | 7.8±0.7 |
| 实施例3 | 24.6±11.5 | 53.4±5.2 | 1674±288 | 7.0±0.4 |
| 对比例1 | 39.2±10.1 | 34.5±4.6 | 978±262 | 6.1±0.4 |
| 对比例2 | 41.6±12.2 | 31.3±4.8 | 931±224 | 6.3±0.5 |
| 对比例3 | 40.9±12.4 | 33.9±4.5 | 953±281 | 6.4±0.6 |
与保存前相比，保存10小时再灌注30分钟心功能的恢复率(％)
| LVDP | +dp/dt | |
| Stanford液 | 41.5％ | 43.7％ |
| UW液 | 44.2％ | 43.8％ |
| Thomas液 | 45.3％ | 46.2％ |
| 实施例1 | 71.1％ | 73.6％ |
| 实施例2 | 75.4％ | 76.5％ |
| 实施例3 | 69.8％ | 70.4％ |
| 对比例1 | 54.7％ | 53.5％ |
| 对比例2 | 51.2％ | 52.8％ |
| 对比例3 | 53.6％ | 54.4％ |
保存10小时再灌注30分钟时心肌高能磷酸盐的含量
| (μmol/g) | ATP | ADP | AMP |
| Stanford液 | 1.42±0.11 | 0.73±0.17 | 0.71±0.15 |
| UW液 | 1.53±0.06 | 0.77±0.15 | 0.65±0.17 |
| Thomas液 | 1.58±0.08 | 0.81±0.18 | 0.81±0.16 |
| 实施例1 | 3.24±0.14 | 1.86±0.22 | 0.93±0.20 |
| 实施例2 | 3.42±0.18 | 1.94±0.24 | 0.98±0.24 |
| 实施例3 | 2.95±0.15 | 1.79±0.21 | 0.89±0.18 |
| 对比例1 | 1.92±0.09 | 0.93±0.12 | 0.63±0.17 |
| 对比例2 | 2.05±0.08 | 1.14±0.15 | 0.75±0.18 |
| 对比例3 | 1.95±0.08 | 1.06±0.14 | 0.74±0.16 |
实施例5
收集病例100例，平均分为6组，在手术中应用本发明制备的心脏停搏液(所有体外循环心脏手术在停搏2h内完成心内操作)，在灌注停搏液之前，对患者心脏用标记物进行标记，灌注停搏液后，在复跳后分别测定各组的心肌损伤生化标记物释放量、心脏排血量、乳酸产生量等指标。
具体结果如下：
cTnI(ng/ml)测定结果
| 基础值 | 心脏复跳2h后 | |
| Stanford液 | 0.03±0.01 | 11.8±3.8 |
| UW液 | 0.04±0.01 | 10.5±2.7 |
| Thomas液 | 0.04±0.01 | 9.9±3.4 |
| 实施例1 | 0.03±0.01 | 5.3±1.9 |
| 实施例2 | 0.04±0.01 | 4.9±1.6 |
| 实施例3 | 0.03±0.01 | 5.4±1.8 |
心排血量的变化(L/min)
| 基础值 | 心脏复跳 | 心脏复跳2h | |
| Stanford液 | 3.4±0.7 | 1.8±0.6 | 2.2±0.5 |
| UW液 | 3.3±0.5 | 1.9±0.5 | 2.3±0.7 |
| Thomas液 | 3.4±0.6 | 1.8±0.5 | 2.3±0.6 |
| 实施例1 | 3.4±0.7 | 2.3±0.4 | 2.8±0.7 |
| 实施例2 | 3.3±0.4 | 2.4±0.5 | 2.9±0.6 |
| 实施例3 | 3.4±0.5 | 2.3±0.4 | 2.8±0.6 |
乳酸产生量(mmol/L)
| 基础值 | 心脏复跳2h | |
| Stanford液 | 0.8±0.3 | 1.9±0.6 |
| UW液 | 0.7±0.2 | 1.7±0.5 |
| Thomas液 | 0.8±0.3 | 1.8±0.7 |
| 实施例1 | 0.8±0.4 | 1.3±0.5 |
| 实施例2 | 0.8±0.2 | 1.2±0.4 |
| 实施例3 | 0.8±0.3 | 1.3±0.5 |
另外，本发明还分别检测统计了心脏诱导停搏时间、一次性复跳成功率、心律失常发生率。
具体结果如下：
| 心脏诱导停搏时间 | 一次性复跳成功率 | 心律失常发生率 | |
| Stanford液 | 67±23s | 83％ | 23％ |
| UW液 | 53±25s | 90％ | 31％ |
| Thomas液 | 58±24s | 87％ | 28％ |
| 实施例1 | 42±18s | 100％ | 12％ |
| 实施例2 | 39±14s | 100％ | 10％ |
| 实施例3 | 43±15s | 100％ | 13％ |
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (2)
1.一种包含利多卡因和腺苷的心脏停搏液，其特征在于，在1000ml器官保存液中，组分分别为：
氯化钠6.5g；氯化钾2.3g；硫酸镁0.35g；
氯化钙0.07g；葡萄糖6g；利多卡因0.5g；
腺苷130mg；黄芪甲苷15mg；辅酶Q1075mg；
汉防己甲素7mg；去甲乌药碱8mg；组氨酸6g；双蒸水余量。
2.一种制备权利要求1所述的心脏停搏液的方法，其特征在于，具体步骤如下：
(1)将800ml双蒸水加入大于1000ml容器中，再依次加入氯化钠、氯化钾、硫酸镁、氯化钙，搅拌至颜色变清晰；再加入葡萄糖、利多卡因、腺苷、黄芪甲苷、汉防己甲素、组氨酸和去甲乌药碱，搅拌至颜色变清晰；然后加入辅酶Q10，搅拌至颜色变清晰；
(2)将溶液的pH调至7.65，渗透压调至350～385mOsm/L，双蒸水定容至1000ml，放置4℃低温保存备用，即得。
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| CN103931605B (zh) | 2004-10-07 | 2015-11-18 | 特兰斯迈迪茨公司 | 用于活体外器官护理的系统和方法 |
| US12010987B2 (en) | 2004-10-07 | 2024-06-18 | Transmedics, Inc. | Systems and methods for ex-vivo organ care and for using lactate as an indication of donor organ status |
| US9078428B2 (en) | 2005-06-28 | 2015-07-14 | Transmedics, Inc. | Systems, methods, compositions and solutions for perfusing an organ |
| US9457179B2 (en) | 2007-03-20 | 2016-10-04 | Transmedics, Inc. | Systems for monitoring and applying electrical currents in an organ perfusion system |
| CA2833266C (en) | 2011-04-14 | 2023-06-27 | Transmedics, Inc. | Organ care solution for ex-vivo machine perfusion of donor lungs |
| US10433539B2 (en) | 2014-04-10 | 2019-10-08 | Tevosol, Inc. | Composition and solution with controlled calcium ion level, and related method and use for reperfusion |
| CA2950759C (en) | 2014-06-02 | 2023-02-21 | Transmedics, Inc. | Ex vivo organ care system |
| CN107105640B (zh) * | 2014-10-24 | 2021-10-12 | 体沃索股份有限公司 | 具有控制的钙离子水平的新型组合物和溶液以及用于再灌注的相关方法和用途 |
| CA2970117A1 (en) | 2014-12-12 | 2016-06-16 | Darren FREED | Apparatus and method for organ perfusion |
| CN104857021A (zh) * | 2015-04-30 | 2015-08-26 | 王涛 | 冷自体血心脏停搏液及其制备方法和应用 |
| EP4533945A1 (en) | 2015-09-09 | 2025-04-09 | TransMedics, Inc. | Aortic cannula for ex vivo organ care system |
| RU2635523C2 (ru) * | 2016-04-29 | 2017-11-13 | Общество С Ограниченной Ответственностью "Кардиосистемфарма" (Ооо "Ксф") | Способ проведения кардиоплегии |
| WO2017205967A1 (en) | 2016-05-30 | 2017-12-07 | Freed Darren | Apparatus and method for ex vivo lung ventilation with a varying exterior pressure |
| CN109769797B (zh) * | 2017-11-13 | 2024-09-10 | 合肥华琪生物工程有限公司 | 一种器官保存液 |
| CN113795247B (zh) * | 2018-12-14 | 2024-04-05 | 陈益祥 | 用于心脏手术的稳定心脏麻痹液 |
| CN117243933B (zh) * | 2023-11-20 | 2024-02-13 | 上海交通大学医学院附属上海儿童医学中心 | 一种含辅酶q10的心脏停搏液组合物及其应用 |
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| US5407793A (en) * | 1991-10-18 | 1995-04-18 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | An aqueous heart preservation and cardioplegia solution |
| CN1344135A (zh) * | 1999-03-23 | 2002-04-10 | 詹姆斯库克大学 | 器官的停止、保护和保存 |
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| US5407793A (en) * | 1991-10-18 | 1995-04-18 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | An aqueous heart preservation and cardioplegia solution |
| CN1344135A (zh) * | 1999-03-23 | 2002-04-10 | 詹姆斯库克大学 | 器官的停止、保护和保存 |
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