CN1049115C - 防御心肺脑低氧损害的复方制剂 - Google Patents

防御心肺脑低氧损害的复方制剂 Download PDF

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CN1049115C
CN1049115C CN93112302A CN93112302A CN1049115C CN 1049115 C CN1049115 C CN 1049115C CN 93112302 A CN93112302 A CN 93112302A CN 93112302 A CN93112302 A CN 93112302A CN 1049115 C CN1049115 C CN 1049115C
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CN1079399A (zh
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方琰
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Abstract

本发明针对心肺脑低氧损害的关键环节，采用以抗氧化酶类氧自由基拮抗剂为先导，以β－受体激动剂和P2受体激动剂相互作用形成三元复合物，与苯烷基胺类钙拮抗剂配伍，促使复方中各组份药效相加，毒副反应拮抗，总药效胜于复方中各单体。复方不仅可(1)降低低氧引起的肺动脉压升高，增加心输出量，(2)保持体循环压、心率稳定，增强心肌收缩力，(3)降低低氧/复氧后脑耗氧量(CMCO2)，而且能促使大脑皮层电兴奋恢复，具有防卸低氧/复氧脑损害的新潜力，为心肺脑复苏用药提供了新配方。

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防御心肺脑低氧损害的复方制剂
本发明涉及一种防御心肺脑低氧损害复方制剂的制备方法。
低氧是引发心肺脑功能衰竭的重要因素之一，心肺脑低氧损害的防御是当今临床研究的热点。现代医学研究表明，低氧时心肺脑血管β受体、P2受体活性下降，氧自由基生成引发内膜损害及细胞内钙内流增加，是导致心肺脑损害的关键。针对上述关键环节，国内外曾有研究采用单一药物如：异搏啶，或异丙肾上腺素，或超氧化物歧化酶治疗心肺脑低氧损害，均药效不佳，其毒性反应大于药效。经查新检索，未见有关防御心肺脑低氧损害的复方制剂文献。
本发明的目的是提供一种无毒副作用且药效高的防御心肺脑低氧损害的复方制剂。
本发明采用生物系统分析法，计算机辅助和正交优选法以及电子自旋共振技术(ESR)，经低氧动物模型实验，获得防御心肺脑低氧损害的复方。本复方以抗氧化酶类氧自由基拮抗剂为先导，与β一受体激动剂和P2受体激动剂相互作用形成三元复合物，与苯烷剂胺类钙拮抗剂配伍，促使复方中各组份药效相加，毒副反应拮抗。本发明复方的组份由异丙肾上腺素(Isoprenaline)，三磷酸腺苷(Adennosine triphosphate)，异搏啶(Verapamil)，超氧化物歧化酶(Superoxide dismutase)配比配制。复方浓度的配比按适应证不同，分别配制不同的规格，四种组份按抗低氧脑损害；抗低氧复氧脑损害及心肺血液动力学紊乱；清除氧自由基和保护红细胞膜流变性的作用，分别按1∶1∶1∶1；1∶2∶2∶2；1∶3∶3∶3配制。
本发明复方采用下列各组份药物浓度时，可显著降低低氧引起的特异性肺动脉压升高，改善低氧引起的心输出量减少，保护低氧时皮层神经传导兴奋性，清除低氧引起的氧自由基生成，并且使红细胞的变形能力升高，同时对体循环压、心肌收缩力、心律及呼吸功能无显著抑制。
本发明复方各组份最佳药物浓度范围如下：(每百毫升含毫克数)
异搏啶(Verapamil)                       8×10-5％至4.0％
异丙肾上腺素(Isoprenaline)              6×10-6％至3×10-2％
超氧化物歧化酶(Superoxide dismutase)    2.0×10-4％至6.0×10-1％
三磷酸腺苷(Adenosine triphophate)       10×10-3％至5×10-1％实施例：
按中华人民共和国卫生部颁发的药典规范配制如下药液：
1.制备盐酸异搏啶溶液2.5毫克/5毫升
2.制备含2毫克/100毫升盐酸异丙肾上腺素溶液
3.制备含2毫克/2毫升超氧化物歧化酶的磷酸钠缓冲液
4.制备含20毫克/3.3毫升三磷酸腺苷的磷酸钠缓冲液
5.分别取最佳浓度范围内的各组份溶质数，常温下均匀混合后，加0.5M(容积克分子浓度)磷酸钠溶液缓冲至100毫升，置-20℃保存备用。
取26只新西兰纯种兔雌雄各半，体重2.5±0.2公斤，麻醉诱导后，标准低氧气体(90％N2+5％CO2+5％O2)经呼吸机的混合气体吸入端吸入5分钟，使呼气末二氧化碳浓度(ET CO2％)维持在3.5％至5.0％之间。按正交设计评价各组份对兔脑皮层体感诱发电位(SEP)的影响，随机安排常氧、低氧、复氧对照/用药，静注上述保存备用复方，了解用药最佳时机、最佳配方、各组分相互作用。结果表明，复方中各组份互为影响；低氧前预注上述复方，总药效优于复方中各单体，无毒副作用，并且使低氧/复氧后脑皮层体感诱发电位(SEP)提前恢复，P2潜伏期、N2P1峰值显著大于对照值。上述复方不仅可降低低氧/复氧后脑耗氧量(CMRO2)，而且能促进大脑皮层电兴奋恢复，具有防御性低氧/复氧脑损害的治疗新潜力。附图说明：
图1.是复方清除氧自由基的电子自旋共振图谱
1：g⊥：氧自由基特征信号＝2.0068
2：g‖：氧自由基特征信号＝2.0923
表1.低氧时复方对心肺血流动力学的影响
表2.低氧时复方和复方各组份对心肺血流动力学的影响
表3.复方和复方各组份清除氧自由基的效应
表4.复方对低氧红细胞变形能力的影响表5.复方和复方各组份对低氧脑损害的保护作用
△：变化量  ↓：降低  ↑：升高A：异搏啶B：异丙肾上腺素C：超氧化物歧化酶D：三磷酸腺苷ABCD：复方MPAP：平均肺动脉压HR：心率MAP：平均动脉压AUC：心力环面积PaLv：肺泡压Compl：肺顺应性EtCO2：呼出二氧化碳浓度PCWP：肺毛细血管嵌压CI：心指数E：自由基清除率ID：红细胞变形能力指数表1.
           100％O2      10％O2      10％O2+MixturePalv.          11.4±3.61    10.8±3.74    10.8±2.96(cm H2O)Compl.         16.8±3.42    17.3±3.67    17.7±3.63(ml/cm H2O)Etco2(％)     3.67±0.56    3.49±0.72    3.71±0.64HR(bpm)        239±64.3     234±28.74    236±29.99MPAP(kPa)      1.74±0.5     3.2±0.7**   2.0±0.5**PCWP(kPa)      0.4±0.5      0.7±0.5      0.7±0.7CI             4.39±1.94    3.61±1.18** 5.06±1.48**(L/min/M2)AUC            49071         49426.7       50400MAP(kPa)       10.6±2.0     11.4±2.8     10.2±2.8**P＜0.01表2.
    A     B     C     D     ABCD
MPAP(kPa) △↓0.798 △↓1.197 △↓0.798 △↓1.333 △↓2.261
HR(bpm) △↓53 △↑34 △↓49 △↓39 △↓3
MAP(kPa) △↓9.443 △↓6.384 △↑1.862 △↓14.76 △↓0.665
AUC △↓800 △↓14000 △↓2600 △↑18400 △↑9600
表3.
     A        B       C       D       ABCDE     3.1*10-4  0.50    0.20    0.20    1.09* *P＜0.05表4.
  A       B        C        D        ABCDID    1.52    2.636    2.636    2.626    9.166** **P＜0.01表5.MS：       A       B      C       D      ABCDP2(ms)   231.00  7.22   141.12  53.05  450.00**N1P1(v) 0.00    0.32   0.13    0.25   1.45**N1P2(v) 0.25    0.72   0.50    0.06   1.45** **P＜0.01

Claims (1)

1、一种防御心肺脑低氧损害的复方制剂，其特征在于其由下面组份组成，且各组份浓度范围为每百毫升含毫克数：
异搏啶              8×10-5至4.0
异丙肾上腺素        6×10-6至3×10-2
超氧化物歧化酶      2.0×10-4至6.0×10-1
三磷酸腺苷          10×10-3至5×10-1。
CN93112302A 1993-01-01 1993-01-01 防御心肺脑低氧损害的复方制剂 Expired - Lifetime CN1049115C (zh)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2006097029A1 (fr) * 2005-03-15 2006-09-21 Zhongshan Hospital, Fudan University Jonction conductrice quantique autodirectrice et auto-assemblee de nanomedecine et procede de realisation
WO2007009326A1 (en) * 2005-07-15 2007-01-25 Zhongshan Hospital, Fudan University A self-assembled and bistable quantum wire array of nano-medicine and its preparation process
CN100438912C (zh) * 2004-12-31 2008-12-03 复旦大学附属中山医院 自组装发光导电纳米药物晶体和超薄膜及其制备方法
US8304758B2 (en) 2006-12-20 2012-11-06 Zhongshan Hospital, Fudan University Process of constructing oxidation-reduction nanomedicine quantum dots room temperature quantum bit networks

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CN102172323B (zh) * 2005-07-15 2013-10-09 复旦大学附属中山医院 纳米药物自组装双稳态量子线阵列及其制备方法

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US4918072A (en) * 1985-10-09 1990-04-17 Basf Aktiengesellschaft Platelet aggregation inhibiting composition

Non-Patent Citations (1)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100438912C (zh) * 2004-12-31 2008-12-03 复旦大学附属中山医院 自组装发光导电纳米药物晶体和超薄膜及其制备方法
WO2006097029A1 (fr) * 2005-03-15 2006-09-21 Zhongshan Hospital, Fudan University Jonction conductrice quantique autodirectrice et auto-assemblee de nanomedecine et procede de realisation
CN1834001B (zh) * 2005-03-15 2011-05-04 复旦大学附属中山医院 纳米药物自导向自组装量子化电导结及其制备方法
WO2007009326A1 (en) * 2005-07-15 2007-01-25 Zhongshan Hospital, Fudan University A self-assembled and bistable quantum wire array of nano-medicine and its preparation process
US8574570B2 (en) 2005-07-15 2013-11-05 Zhongshan Hospital, Fudan University Bi-stable quantum wire array of self-assembled nanomedicine and the preparation method therefor
US8304758B2 (en) 2006-12-20 2012-11-06 Zhongshan Hospital, Fudan University Process of constructing oxidation-reduction nanomedicine quantum dots room temperature quantum bit networks

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