CN110522904A - 一种抑制血压升高的聚合血红蛋白 - Google Patents
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Abstract
本发明公开了一种抑制血压升高的聚合血红蛋白，该聚合血红蛋白包括纯聚合血红蛋白和辅助剂，该辅助剂选自N‑乙酰基‑L‑半胱氨酸、硝酸甘油或谷胱甘肽中的一种，所述纯聚合血红蛋白和辅助剂质量比为5‑50:1。优选辅助剂为N‑乙酰基‑L‑半胱氨酸，优选纯聚合血红蛋白和辅助剂质量比为10‑30:1。本发明的聚合血红蛋白可显著降低由注射血红蛋白而引起血压升高问题，并且能够有效延长血红蛋白的保存时间。
Description
技术领域
本发明属于生物制药领域，特别涉及一种抑制血压升高的聚合血红蛋白。
背景技术
据估计，全世界每年献血量超过7亿5千万单位，而在世界卫生组织191个成员国中仅有43％对献血者进行了丙肝病毒(HCV)、艾滋病病毒(HIV)和乙肝病毒(HBV)的检测；每年至少有1亿3千万单位的捐献血液未对上述可以经血液传播的病毒进行检测；不安全的输血或注射每年导致8-16万人感染HBV，2.3-4.7万人感染HCV，8-16万人感染HIV。由于输血安全性问题的屡次出现、输血量增多而献血量减少的矛盾、误输血导致溶血甚至死亡、人类红细胞储存时间短以及自然灾难和战争等等原因，致使人们努力去寻找一种具有与血液相同功能的代用品-人工血液代用品。
目前人工血液代用品有两大类：来源于血红蛋白的血红蛋白类氧载体(hemoglobin-based oxygen carriers,HBOCs)和氟碳乳剂(perfluorocarbons,PFCs)。其中，血红蛋白类氧载体是近几十年来国内外红细胞代用品研究的热点。特别是随着对天然氧载体(即血红蛋白)结构与性能的清晰认识，已使它成为血液代替品的最佳候选。
但是，输注HBOCs经常会引起体循环血压和肺动脉压升高的副反应，正常生理状态下血容量充足，血管收缩引起血压升高，而在休克血容量降低时如果毛细血管前微动脉收缩，则毛细血管塌陷，导致组织供氧和营养物质减少、二氧化碳浓度升高，从而给机体带来不利影响。目前认为引起血管收缩的观点也不一致，其中一种为NO清除理论。认为其可能的机制是游离的无基质血红蛋白在血液循环中可以通过血管内皮细胞间隙渗出到血管间质与NO结合并清除NO，而NO是内皮细胞形成的一种血管舒张因子，具有强大的松弛血管平滑肌作用。已有试验为这种理论提供了证据，血红蛋白与NO有很高的亲和力，在细菌或是酵母菌中表达的突变的血红蛋白与NO的亲和力降低，这种突变的血红蛋白只引起较少的试验动物产生了高血压；另外有试验在重组人血红蛋白中加入一个色氨酸，并用谷氨酰胺代替远端组氨酸，造成NO受体结合部位受阻碍，NO难以结合但是不影响氧的释放特性，该动物试验中也未表现出明显的升压效应；另外，Stamler等认为高血压的程度高低与血红蛋白清除NO的比例有关。NO与氧合血红蛋白结合，使得血红蛋白的二价铁变成三价铁，NO与去氧血红蛋白结合时生成Hb[Fe2+]NO，导致血管收缩。这也是血红蛋白类溶液是否能应用于临床的重要因素。因此急需研制一种聚合血红蛋白，以在输注血红蛋白时能够有效抑制血压升高。
发明内容
本发明要解决的技术问题是提供一种抑制血压升高的聚合血红蛋白，可显著降低由注射血红蛋白而引起血压升高问题，并且能够有效延长血红蛋白的保存时间。
为解决上述技术问题，本发明提供了一种抑制血压升高的聚合血红蛋白，该聚合血红蛋白包括纯聚合血红蛋白和辅助剂，该辅助剂选自N-乙酰基-L-半胱氨酸、硝酸甘油或谷胱甘肽中的一种，所述纯聚合血红蛋白和辅助剂质量比为5-50:1。本发明中采用的纯聚合血红蛋白可以采用市售的任何聚合血红蛋白，没有特别限制。
上述抑制血压升高的聚合血红蛋白，其中，所述辅助剂为N-乙酰基-L-半胱氨酸。
上述抑制血压升高的聚合血红蛋白，其中，所述纯聚合血红蛋白和辅助剂质量比为5-40:1，进一步优选为10-30:1。
上述抑制血压升高的聚合血红蛋白，其中，所述纯聚合血红蛋白由下述方法制成：经抗凝血采集、洗涤去除血清和血小板、0.65um中空纤维进一步洗涤红细胞、低渗法溶解红细胞释放血红蛋白、100kd与30kd超滤粗纯血红蛋白、离子层析法进一步纯化血红蛋白、戊二醛聚合、硼氢化钠终止、超滤换液而得到的终产品纯聚合血红蛋白。
上述抑制血压升高的聚合血红蛋白，其中，所述制得的纯聚合血红蛋白溶液浓度为4-7g/dl。
本发明抑制血压升高的聚合血红蛋白具有如下有益效果：
1、本发明的抑制血压升高的聚合血红蛋白，在纯聚合血红蛋白中加入辅助剂，能够促进NO合成及提高利用效率，对血红蛋白结合并清除NO的特性起到了有效抵消，可明显降低输注血红蛋白引起血压升高的副作用。加入的辅助剂能作为NO分子载体并增加体内NO的生物利用度，发挥NO生理效应，促进收缩的微循环血管扩张，有效增加血液对组织氧输送和释放，纠正组织缺氧，防止细胞进一步坏死；
2、本发明抑制血压升高的聚合血红蛋白中加入的辅助剂可以将氧合的血红蛋白还原成活性血红蛋白，可有效延长血红蛋白的保存时间。
具体实施方式
下面结合实施例详细描述本发明。
实施例1
取纯聚合血红蛋白和辅助剂N-乙酰基-L-半胱氨酸(NAC)混合，其中纯聚合血红蛋白和N-乙酰基-L-半胱氨酸的质量比为10:1，纯聚合血红蛋白溶液浓度为4g/dl，制得抑制血压升高的聚合血红蛋白。
选择健康犬禁食12小时，自由进水。手术前，静脉注射芬太尼0.025mg/kg/h，咪达唑仑0.4mg/kg/h，异丙酚3mg/kg静脉注射或气管插管和机械通气。在室内空气(20％氧气)中使用1-2％异氟醚维持麻醉。用碘伏棉球和酒精棉球将手术部位消毒后开始进行手术。顿性分离颈静脉、外周动脉，并颈静脉植入导管，用于注射，接入多道生理记录仪用以记录血压变化。按每千克体重输注0.4克本实施例制得的抑制血压升高的聚合血红蛋白，输注速度最快为10ml/kg/hr，记录动脉血压值，结果见表1。
实施例2-6
与实施例1的制备方法相同，不同之处在于纯聚合血红蛋白和N-乙酰基-L-半胱氨酸(NAC)的质量比不同。
对比例1
对比例1为向健康犬直接输注不含有NAC的聚合血红蛋白，输注方法同实施例1，动脉血压值见表1。
表1
注：对照例为不输注聚合血红蛋白时，健康犬的血压值。
通过表1可以看出，在聚合血红蛋白注射量为0.4g/kg的情况下，选择纯聚合血红蛋白:NAC质量比为5-50:1的范围均能够抑制血压升高，但纯聚合血红蛋白:NAC质量比在50:1时，由于加入的NAC量较少，抑制血压升高的效果不明显，在聚合血红蛋白:NAC质量比为5:1-30:1时，抑制效果明显，与未输注聚合血红蛋白时健康犬的血压接近，聚合血红蛋白:NAC质量比为10:1和5:1时，健康犬的动脉压差别很小，此时，继续增加NAC的含量对抑制血压的效果也不会明显增强，因此本发明优选纯聚合血红蛋白:NAC质量比为10:1-30:1。
实施例7
与实施例1的制备方法相同，不同之处在于辅助剂为硝酸甘油。对健康犬进行输注的方法与实施例1相同，输注后动脉血压值见表2。
实施例8
与实施例1的制备方法相同，不同之处在于辅助剂为谷胱甘肽。对健康犬进行输注的方法与实施例1相同，输注后动脉血压值见表2。
表2
注：对照例为不输注聚合血红蛋白时，健康犬的血压值。
通过表2可以看出，在聚合血红蛋白注射量为0.4g/kg的情况下，在纯聚合血红蛋白中加入辅助剂硝酸甘油或谷胱甘肽或NAC都具有抑制血压升高的作用，其中，NAC抑制血压升高的效果最好，本发明中优选NAC。
实施例9和实施例10
采用实施例1制得抑制血压升高的聚合血红蛋白，对健康犬进行输注，输注方法与实施例1相同，不同之处在于输注量不同，结果见表3。
表3
注：对照例为不输注聚合血红蛋白时，健康犬的血压值。
通过表3可知，本发明的抑制血压升高的聚合血红蛋白在输注量为0.2-0.6/kg体重的范围内，均可以有效抑制输注带来的血压升高问题，效果明显，方案可行。
Claims (6)
1.一种抑制血压升高的聚合血红蛋白，该聚合血红蛋白包括纯聚合血红蛋白和辅助剂，该辅助剂选自N-乙酰基-L-半胱氨酸、硝酸甘油或谷胱甘肽中的一种，所述纯聚合血红蛋白和辅助剂质量比为5-50:1。
2.如权利要求1所述的抑制血压升高的聚合血红蛋白，其中，所述辅助剂为N-乙酰基-L-半胱氨酸。
3.如权利要求1或2所述的抑制血压升高的聚合血红蛋白，其中，所述纯聚合血红蛋白和辅助剂质量比为5-40:1。
4.如权利要求3所述的抑制血压升高的聚合血红蛋白，其中，所述纯聚合血红蛋白和辅助剂质量比为10-30:1。
5.如权利要求1所述的抑制血压升高的聚合血红蛋白，其中，所述纯聚合血红蛋白由下述方法制成：经抗凝血采集、洗涤去除血清和血小板、0.65um中空纤维进一步洗涤红细胞、低渗法溶解红细胞释放血红蛋白、100kd与30kd超滤粗纯血红蛋白、离子层析法进一步纯化血红蛋白、戊二醛聚合、硼氢化钠终止、超滤换液而得到的终产品纯聚合血红蛋白。
6.如权利要求5所述的抑制血压升高的聚合血红蛋白，其中，所述制得的纯聚合血红蛋白溶液浓度为4-7g/dl。
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