WO2023087421A1 - 一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用 - Google Patents

一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用 Download PDF

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WO2023087421A1
WO2023087421A1 PCT/CN2021/135671 CN2021135671W WO2023087421A1 WO 2023087421 A1 WO2023087421 A1 WO 2023087421A1 CN 2021135671 W CN2021135671 W CN 2021135671W WO 2023087421 A1 WO2023087421 A1 WO 2023087421A1
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drug
polymerized hemoglobin
injection
hemoglobin
sodium
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游可为
李剑波
张彦鹏
石松
王文刚
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润方（北京）生物医药研究院有限公司
润方(北京)生物科技有限公司
游可为
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Definitions

  • Acute ischemic stroke refers to a clinical category of ischemia and hypoxic necrosis in local brain tissue caused by various causes of cerebral blood supply disorder, followed by corresponding neurological deficits. syndrome. It has the characteristics of "three highs" of high morbidity, high disability and high mortality. Research by Devin et al showed that more than 70% of AIS is permanent ischemic stroke (pMCAO).
  • Stroke is the third cause of death in most western countries, but in recent years stroke has become the first cause of death in my country, and the clinical incidence of AIS accounts for 80% of stroke.
  • GBD Global Burden of Disease
  • stroke is the number one cause of years of life lost (YLL) in my country.
  • AIS is the most common type of stroke, because 80% to 90% of AIS is caused by thrombus blocking cerebral arteries. After a blockage or severe narrowing of a cerebral artery cuts off blood flow to the brain, the central part of the brain loses its blood supply within minutes, and blood oxygen levels drop rapidly. Progressive pathophysiological reactions lead to severe ischemia and hypoxic injury in the core infarction area, and the peripheral part of the brain tissue may receive a certain amount of blood flow through vascular collateral circulation to maintain it above the pump level and require energy for electrical activity Below is the ischemic penumbra. This is partly because stroke prognosis depends on the size of the infarct and the number of cells in the ischemic penumbra rescued after reperfusion.
  • rt-PA tissue plasminogen activator
  • the present invention provides an application of polymerized hemoglobin in the preparation of a drug for treating ischemic stroke.
  • the drug of the present invention is a hemoglobin oxygen carrier with colloidal solution properties.
  • the dose can relieve the "blood shortage" caused by arterial blockage, and can perform oxygen loading-unloading from the lungs to tissues and organs, relieve tissue damage and cell death caused by ischemia and hypoxia, and save the ischemic penumbra Cell number, while increasing the blood oxygen level, reducing the metabolic rate of ischemic tissue and reducing the oxidative stress injury of reperfusion.
  • the first object of the present invention is to provide an application of polymerized hemoglobin in the preparation of a drug for treating ischemic stroke.
  • the medicine is prepared by adding medically acceptable auxiliary materials to polymerized hemoglobin.
  • the medicament contains 30.0-130.0 g of polymerized hemoglobin per 1 L of the medicament.
  • neuroprotective agents can also be added to the drug.
  • the adjuvant is prepared by dissolving in 1L of water for injection by weight, and the specific proportions are as follows: 0.87-6.6 g of sodium chloride, 0.3-0.67 g of potassium chloride, and 0-0.6 g of monopotassium alpha-ketoglutarate 0.18g, magnesium chloride hexahydrate 0 ⁇ 0.81g, histidine monohydrochloride 0 ⁇ 3.77g, histidine 0 ⁇ 27.92g, tryptophan 0 ⁇ 0.4g, mannitol 0 ⁇ 0.4g, dihydrate chlorination Calcium 0.002-0.2g, acetylcysteine 2.0-2.28g, sodium hydroxide 0-0.48g, sodium lactate 0-3.1g.
  • the drug is the following substances dissolved in 1L of water for injection, and the specific proportions are as follows: 130.0g of polymerized hemoglobin, 3.2g of sodium chloride, 0.48g of potassium chloride, 0.15g of calcium chloride dihydrate, and 0.15g of sodium hydroxide 0.23g, sodium lactate 1.75g, acetylcysteine 2.14g.
  • the drug is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: 65.0 g of polymerized hemoglobin, 6.6 g of sodium chloride, 0.3 g of potassium chloride, 0.2 g of calcium chloride dihydrate, and 0.2 g of sodium hydroxide 0.48g, sodium lactate 3.0g, acetylcysteine 2.0g, edaravone 13.70mg.
  • the drug is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: 65.0 g of polymerized hemoglobin, 6.6 g of sodium chloride, 0.3 g of potassium chloride, 0.2 g of calcium chloride dihydrate, and 0.2 g of sodium hydroxide 0.48g, sodium lactate 3.0g, acetylcysteine 2.0g.
  • the drug is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: 65.0 g of polyhemoglobin, 0.87 g of sodium chloride, 0.3 g of potassium chloride, and 0.18 g of monopotassium alpha-ketoglutarate , Magnesium chloride hexahydrate 0.81g, histidine monohydrochloride 3.77g, histidine 27.92g, tryptophan 0.4g, mannitol 0.4g, calcium chloride dihydrate 0.002g, acetylcysteine 2.28g.
  • the drug is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: 30.0 g of polyhemoglobin, 1.45 g of sodium chloride, 0.6 g of potassium chloride, and 0.12 g of monopotassium alpha-ketoglutarate , magnesium chloride hexahydrate 0.6g, histidine monohydrochloride 2.2g, histidine 14.0g, tryptophan 0.27g, mannitol 0.13g, calcium chloride dihydrate 0.002g, citicoline 37.14mg.
  • the polymerized hemoglobin in the present invention is derived from human or animal hemoglobin after modification to form a stable molecular polymer, thereby prolonging the half-life of natural hemoglobin in blood and avoiding its depolymerization into dimers in vivo.
  • Drugs prepared from polymerized hemoglobin are non-toxic, non-immunogenic, and have good rheological properties, longer circulation residence time and normal physiological metabolic pathways.
  • the drug administration routes described in the present invention include, but are not limited to, intravenous injection and arterial injection.
  • the polymerized hemoglobin drug of the present invention is a hemoglobin oxygen carrier and a colloidal solution.
  • Small dose perfusion will not bring tissue damage and cell death caused by reperfusion to the brain, but can relieve arterial blockage "Blood shortage" caused by hemoglobin from the lungs to tissues and organs to carry out oxygen-loading-deoxygenation, relieve the damage caused by ischemia and hypoxia, further save the number of cells in the ischemic penumbra, and then make rt-PA veins
  • the stroke "therapeutic window" of thrombolysis for 6 hours is extended, so that more patients who cannot be treated within the limited "therapeutic window” can be effectively treated within a wide period of time;
  • the medicine of the present invention is a erythrocyte substitute, a colloidal solution, the particle size of polymerized hemoglobin is only one-thousandth of that of erythrocytes, and can pass through narrow capillaries to reach capillary beds that erythrocytes cannot reach, and then After perfusion, the blood flow in the cortical penumbra and the reduction of partial oxygen partial pressure in the tissue are improved, and the number of nerve cells that are dysfunctional but not yet dead due to ischemic injury around the infarct can be saved as much as possible, so that they can return to normal and promote neurogenesis. The function gradually recovered. Histopathological analysis of the cortical penumbra showed that compared with autologous red blood cells, hemoglobin perfused the microvessels better, and the stenotic changes were alleviated. Can act as a neuroprotective agent;
  • the polymerized hemoglobin prepared by the method of the present invention has higher oxygen-carrying-oxygen release characteristics, and can specifically block the pathophysiological process of cerebral ischemia and hypoxia, alleviate the death of nerve cells, and reduce the damage of nerve cells , play a role in neuroprotection, thereby prolonging the treatment window of ischemic stroke, improving the outcome, improving survival efficiency and improving the quality of life.
  • the animal experiment carried out by the polymerized hemoglobin drug according to the present invention adopts the animal model of permanent ischemic stroke (pMCAO) in the test, which is different from the application in the prior art in transient ischemic stroke (tMCAO) animal model, pMCAO is more practically consistent with the symptoms of more than 70% of AIS clinical patients.
  • pMCAO permanent ischemic stroke
  • Neuroprotective agents are added to the medicine of the present invention, which can further protect nervous tissue, reduce cerebral edema, and improve brain circulation through mechanisms such as scavenging oxygen free radicals, and can improve the function of mitochondria and inhibit oxygen free radicals , and inhibit cell apoptosis.
  • Figure 1 is a TTC staining diagram of the brain of 1 pMCAO rats in the sham operation group
  • Figure 2 is a TTC staining diagram of the brain of 2 pMCAO rats in the sham operation group
  • Figure 3 is a TTC staining diagram of the brain of 3 pMCAO rats in the sham operation group
  • Figure 4 is a TTC staining diagram of the brain of 1pMCAO rats in the drug group
  • Fig. 5 is the brain TTC staining picture of drug group 2 pMCAO rats
  • Figure 6 is a TTC staining diagram of the brains of 3 pMCAO rats in the drug group
  • Figure 7 is a TTC staining diagram of the brain of model 1 pMCAO rats.
  • Figure 8 is a TTC staining diagram of the brain of model 2 pMCAO rats.
  • Figure 9 is a TTC staining diagram of the brain of model 3 pMCAO rats.
  • Figure 10 is a band diagram of the target protein
  • Figure 11 is a diagram of Caspase-3 content.
  • Polyhemoglobin in the following examples is prepared according to the method of Example 1 in CN110563836A.
  • This embodiment comprises the medicine of polymerized hemoglobin, and described medicine is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: polymerized hemoglobin 130.0g, sodium chloride 3.2g, potassium chloride 0.48g, calcium chloride dihydrate 0.15g, 0.23g sodium hydroxide, 1.75g sodium lactate, 2.14g acetylcysteine.
  • This embodiment contains a compound drug of polymerized hemoglobin and a neuroprotective agent.
  • the drug is the following substances dissolved in 1L of water for injection, and the specific ratios are as follows: 65.0 g of polymerized hemoglobin, 6.6 g of sodium chloride, 0.3 g of potassium chloride, Calcium chloride dihydrate 0.2g, sodium hydroxide 0.48g, sodium lactate 3.0g, acetylcysteine 2.0g, edaravone 13.70mg.
  • This embodiment comprises the medicine of polymerized hemoglobin, and described medicine is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: polymerized hemoglobin 65.0g, sodium chloride 6.6g, potassium chloride 0.3g, calcium chloride dihydrate 0.2g, 0.48g of sodium hydroxide, 3.0g of sodium lactate, 2.0g of acetylcysteine.
  • This embodiment includes the medicine of polymerized hemoglobin, and the described medicine is that the following substances are dissolved in 1L of water for injection, and the specific proportions are as follows: polymerized hemoglobin 65.0g, sodium chloride 0.87g, potassium chloride 0.3g, alpha-ketopentadiene Monopotassium acid salt 0.18g, magnesium chloride hexahydrate 0.81g, histidine monohydrochloride 3.77g, histidine 27.92g, tryptophan 0.4g, mannitol 0.4g, calcium chloride dihydrate 0.002g, acetyl semi Cystine 2.28g.
  • This embodiment contains a compound drug of polymerized hemoglobin and a neuroprotective agent.
  • the drug is dissolved in 1L of water for injection as follows: 30.0 g of polymerized hemoglobin, 1.45 g of sodium chloride, 0.6 g of potassium chloride, Alpha-ketoglutaric acid monopotassium salt 0.12g, magnesium chloride hexahydrate 0.6g, histidine monohydrochloride 2.2g, histidine 14.0g, tryptophan 0.27g, mannitol 0.13g, calcium chloride dihydrate 0.002g, citicoline 37.14mg.
  • the grouping and dosage of SD rats are shown in Table 1, and the rats were injected into the tail vein 3 hours after the model was established.
  • Blood samples were collected through the femoral artery at the onset of pMCAO and 24 hours after administration, and blood gas analysis was performed immediately.
  • the TTC staining diagram of the brain TTC of 1-3pMCAO rats in the sham operation group is shown in Figure 1-3
  • the TTC staining diagram of the brain TTC of the 1-3pMCAO rats in the drug group is shown in Figure 4-6
  • the TTC staining diagram of the brain TTC of the 1-3pMCAO rats in the model group The staining diagram is shown in Figure 7-9.
  • Test Example 2 Drugs containing polymerized hemoglobin and compound drugs containing polymerized hemoglobin and edaravone on the effects of intravenous injection on inflammatory factors in rats with permanent ischemic stroke (pMCAO)
  • Test drug the compound drug comprising polymerized hemoglobin and edaravone prepared in Example 2, wherein the hemoglobin content is 65.0g/L, and the edaravone is 13.70mg/L;
  • Positive drug 1 the drug containing polymerized hemoglobin prepared in Example 3, wherein the hemoglobin content is 65.0 g/L;
  • Test animals same as Test Example 1.

Abstract

提供一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用，所述药物为一种血红蛋白载氧剂，也是一种胶体溶液，聚合血红蛋白粒径尺寸仅为红细胞的千分之一。小剂量灌注不会给脑部带来再灌注导致的组织损伤和细胞死亡，反而能够缓解动脉阻塞造成的"血荒"，同时血红蛋白执行肺部到组织和器官的载氧-卸氧，对大脑因缺血缺氧导致的病理生理过程进行针对性阻断，挽救缺血半暗带的神经细胞，减少神经细胞的死亡数，起到神经保护的作用。所述药物中也可加入神经保护剂制备成复方药物，对缺血半暗带神经细胞的保护效果更加明显，更能延长rt-PA静脉溶栓6h的卒中"治疗窗"。

Description

一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用 技术领域
本发明属于医药技术领域，具体涉及一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用。
背景技术
正常成人脑组织耗氧量占全身耗氧量的20％～30％，脑组织的能量来源主要为糖的有氧代谢，几乎无能量储备，因此对缺血、缺氧损害十分敏感。急性缺血性脑卒中(acute ischem ic stroke，A IS)是指各种原因所致脑部血液供应障碍导致局部脑组织发生缺血、缺氧性坏死，继而出现相应神经功能缺损的一类临床综合征。其具有高发病率、高致残率和高病死率这“三高”特点。Devin等人研究表明AIS的70％以上为永久性缺血脑卒中(pMCAO)。
脑卒中在西方大多数国家是居民的第三死因，而近年来在我国脑卒中已跃居居民死因首位，其中AIS在临床上的发病率占卒中的80％。根据《Lancet Neurology》杂志发布的2016年全球疾病负担(GBD)数据显示，脑卒中是造成我国寿命年损失(YLL)的第一位病因。
脑卒中以AIS最多见，由于80％～90％AIS均是血栓堵塞脑动脉所致。脑动脉阻塞或严重狭窄导致脑部血液流动阻断后，中心部分脑组织在数分钟内丧失了血液供应，血氧水平快速降低。进展的病理生理反应导致核心梗死区域发生严重的缺血、缺氧损伤，周边部分的脑组织可能通过血管侧支循环得到一定量的血流，使之维持在泵水平之上、电活动需要能量之下，即缺血半暗带。这部分是脑卒中预后所依赖于梗死灶的大小及再灌注后挽救的缺血半暗带细胞数。增加血氧水平、降低缺血组织的代谢率以及减轻再灌注的氧化应激损伤是拯救缺血半暗带的紧急措施。在代谢重建、结构重建、功能重建三个神经细胞 恢复阶段中代谢重建尤为重要。由于脑代谢主要依靠葡萄糖氧化的有氧代谢，所以充分的氧和能量供给十分重要，因而所有治疗均应围绕如何提高供能供氧，使神经细胞进行有效代谢开展。AIS临床上治疗的关键是尽早开通闭塞的脑血管，在缺血脑组织出现坏死之前，及时恢复血供，从而挽救缺血半暗带，最终降低缺血性脑卒中的病死率及致残率。虽然尚无成熟的治疗方案来防治脑卒中的发生及其神经功能的丧失，但许多实验药物在动物模型上可明显减少脑梗死的体积，并已在临床进行双盲试验，以验证其疗效，这为人类战胜此类疾病带来了希望。
目前，AIS最有效的药物治疗仍是超早期内(≤6h)给予重组组织型纤溶酶原激活剂(rt—PA)静脉溶栓，可显著改善预后，是唯一被国内外脑血管病指南一致推荐。面对脑卒中防控的严峻形势，早期启动急性脑卒中的治疗是必要的。公认有效的治疗方式是溶栓。由于溶栓6h“治疗窗”较窄，溶栓率尚不足5％，所以越来越多的学者倾向于神经保护治疗。神经保护治疗是通过影响缺血瀑布的生化过程来阻断神经细胞出现的能量缺乏、兴奋性氨基酸毒性作用、细胞去极化和坏死等病理现象。目前临床常用的神经保护剂依达拉奉、神经节苷脂、丁苯酞，长春西汀、胞磷胆碱在进行网状meta分析后，认为在短期内有些可以改善神经缺损功能，但总体疗效并不显著，需要高质量头对头的研究对结果进一步的验证。
鉴于以上原因，特提出本发明。
发明内容
为了解决现有技术存在的以上问题，本发明提供了一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用，本发明所述的药物是一种具有胶体溶液性质的血红蛋白载氧剂，小剂量能够缓解动脉堵塞造成的“血荒”，并能从肺部到组织和器官中执行载氧-卸氧，缓解缺血缺氧带来的组织损伤和细胞死亡，挽救的缺血半暗带细胞数，同时增加血氧水平、降低缺血组织的代谢率以及减轻再灌注的氧化应激损伤。
本发明的第一目的，提供了一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用。
进一步的，所述的药物为聚合血红蛋白加入医学上可接受的辅料制成。
进一步的，所述的药物中每1L药物中含聚合血红蛋白为30.0～130.0g。
进一步的，所述的药物中还可加入临床常用的神经保护剂。
进一步的，所述的辅料以重量计溶解在1L注射用水中制成，具体比例如下：氯化钠0.87～6.6g、氯化钾0.3～0.67g、alpha-酮戊二酸单钾盐0～0.18g、六水氯化镁0～0.81g、一水一盐酸组氨酸0～3.77g、组氨酸0～27.92g、色氨酸0～0.4g、甘露醇0～0.4g、二水氯化钙0.002～0.2g、乙酰半胱氨酸2.0～2.28g、氢氧化钠0～0.48g、乳酸钠0～3.1g。
进一步的，所述的临床常用的神经保护剂包括以下中的一种或几种，具体为所述的神经保护剂以重量计溶解在1L注射用水中，具体比例为依达拉奉3.0～60.0mg、神经节苷脂14.0～55.0mg、丁苯酞65.0～315.0mg，长春西汀15.0～125.0mg、胞磷胆碱65.0～520.0mg。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白130.0g、氯化钠3.2g、氯化钾0.48g、二水氯化钙0.15g、氢氧化钠0.23g、乳酸钠1.75g、乙酰半胱氨酸2.14g。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.48g、乳酸钠3.0g、乙酰半胱氨酸2.0g、依达拉奉13.70mg。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.48g、乳酸钠3.0g、乙酰半胱氨酸2.0g。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠0.87g、氯化钾0.3g、alpha-酮戊二酸单钾盐 0.18g、六水氯化镁0.81g、一水一盐酸组氨酸3.77g、组氨酸27.92g、色氨酸0.4g、甘露醇0.4g、二水氯化钙0.002g、乙酰半胱氨酸2.28g。
进一步的，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白30.0g、氯化钠1.45g、氯化钾0.6g、alpha-酮戊二酸单钾盐0.12g、六水氯化镁0.6g、一水一盐酸组氨酸2.2g、组氨酸14.0g、色氨酸0.27g、甘露醇0.13g、二水氯化钙0.002g、胞磷胆碱37.14mg。
进一步的，所述药物剂型为注射剂。
本发明的中的聚合血红蛋白来源于人源或动物源的血红蛋白经修饰后形成一种稳定的分子聚合物，从而延长天然血红蛋白在血液中的半衰期，并避免其在体内解聚成二聚体。以聚合血红蛋白制备的药物具有无毒性，无免疫原性，并且具有良好的流变学性质，较长的循环停留时间和正常的生理代谢途径等特点。
本发明的聚合血红蛋白按照公开号CN110563836A中交联血红蛋白的制备方法制成而成。
本发明中所述的药物给药途径包括但不限于静脉注射、动脉注射途径。
与现有技术相比，本发明的有益效果为：
(1)本发明所述的聚合血红蛋白药物为一种血红蛋白载氧剂、也是一种胶体溶液，小剂量灌注不会给脑部带来再灌注导致的组织损伤和细胞死亡，反而能够缓解动脉阻塞造成的“血荒”，同时血红蛋白从肺部到组织和器官中执行载氧-卸氧，缓解缺血缺氧带来的损伤，进一步挽救缺血半暗带细胞数，进而使rt-PA静脉溶栓6h的卒中“治疗窗”延长，这样可使更多不能在限定“治疗窗”内治疗的患者能在宽泛的时间段内得到有效的治疗；
(2)本发明所述的药物是红细胞代用品，是一种胶体溶液，聚合血红蛋白粒径尺寸仅为红细胞的千分之一，可通过狭窄的毛细管，能够到达红细胞到达不了的毛细管床，再灌注后，皮质半暗区的血流和组织部分氧分压的降低得到改善，尽可能挽救梗死灶周围因缺血性损伤导致功能异常但尚未死亡的神经细 胞数，使其恢复正常并促进神经功能逐渐恢复，皮质半暗带的组织病理学分析显示与自体红细胞相比，血红蛋白对微血管的灌注较好，狭窄变化减轻，血红蛋白可显著抑制缺氧/复氧处理细胞中活性氧的产生，也可作为一种神经保护剂；
(3)采用本发明的方法制备的聚合血红蛋白具有较高的携氧-释氧特点，对大脑缺血缺氧的病理生理过程进行针对性阻断，缓解神经细胞的死亡，减轻神经细胞的损伤，起到神经保护的作用，从而延长缺血性脑卒中的治疗窗，改善结局，提高生存效率和改善生存质量。
(4)本发明所述的聚合血红蛋药物进行的动物实验，试验中采用永久性缺血性脑卒中(pMCAO)的动物模型，不同于现有技术中的应用在瞬时性缺血性脑卒中(tMCAO)的动物模型，pMCAO更实际符合AIS70％以上临床患者的症状。
(5)本发明所述的药物中加入神经保护剂，可进一步通过清除氧自由基等机制，保护神经组织，减轻脑水肿，进而改善脑内循环，并且可以提升线粒体的功能，抑制氧自由基，并抑制细胞凋亡等作用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1是假手术组1 pMCAO大鼠大脑TTC染色图；
图2是假手术组2 pMCAO大鼠大脑TTC染色图；
图3是假手术组3 pMCAO大鼠大脑TTC染色图；
图4是药物组1pMCAO大鼠大脑TTC染色图；
图5是药物组2 pMCAO大鼠大脑TTC染色图；
图6是药物组3 pMCAO大鼠大脑TTC染色图；
图7是模型1 pMCAO大鼠大脑TTC染色图；
图8是模型2 pMCAO大鼠大脑TTC染色图；
图9是模型3 pMCAO大鼠大脑TTC染色图；
图10是目的蛋白条带图；
图11是Caspase-3含量图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案进行详细的描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所得到的所有其它实施方式，都属于本发明所保护的范围。
以下实施例中的聚合血红蛋白按照CN110563836A中实施例1的方法制备而成。
实施例1
本实施例包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白130.0g、氯化钠3.2g、氯化钾0.48g、二水氯化钙0.15g、氢氧化钠0.23g、乳酸钠1.75g、乙酰半胱氨酸2.14g。
实施例2
本实施例包含聚合血红蛋白和神经保护剂的复方药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.48g、乳酸钠3.0g、乙酰半胱氨酸2.0g、依达拉奉13.70mg。
实施例3
本实施例包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.48g、乳酸钠3.0g、乙酰半胱氨酸2.0g。
实施例4
本实施例包含聚合血红蛋白的药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠0.87g、氯化钾0.3g、alpha-酮戊二酸单钾盐0.18g、六水氯化镁0.81g、一水一盐酸组氨酸3.77g、组氨酸27.92g、色氨酸0.4g、甘露醇0.4g、二水氯化钙0.002g、乙酰半胱氨酸2.28g。
实施例5
本实施例包含聚合血红蛋白和神经保护剂的复方药物，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白30.0g、氯化钠1.45g、氯化钾0.6g、alpha-酮戊二酸单钾盐0.12g、六水氯化镁0.6g、一水一盐酸组氨酸2.2g、组氨酸14.0g、色氨酸0.27g、甘露醇0.13g、二水氯化钙0.002g、胞磷胆碱37.14mg。
试验例1包含聚合血红蛋白的药物对永久性缺血性脑卒中(pMCAO)大鼠静脉注射有效性研究
受试药物：实施例3制备的包含聚合血红蛋白药物，其中血红蛋白含量65.0g/L；
阳性药物：乳酸林格氏液；规格：20.0ml/支；
试验动物：SD大鼠，体重250～300g，雄性，购自北京维通利华实验动物技术有限公司，受试动物饲养于无菌的独立送风的笼中，垫料为60Co辐射消毒的玉米芯垫料，粒径4～6mm。饲以专门为小鼠配制的消毒饲料，自由饮用纯净水。动物实验室内温度保持在25℃左右，相对湿度保持在40～70％，每日光照12h。
1.实验方法：
1.1建模
SD大鼠均打耳标
pMCAO大鼠模型制备：改进的Longa线栓法制备SD大鼠MCAO模型。10％水合氯醛腹腔注射麻醉大鼠，剃毛器除去大鼠颈部和腹部位的毛发，75％乙醇消毒，腹面朝上仰卧位固定于操作台的垫板上，用手术刀在颈正中行纵切口大约2cm，拨开颈部浅层颈膜，拨离由二腹肌、胸锁乳突肌和肩胛舌骨肌间 的间隙粘膜，暴露颈总动脉(CCA)、颈外动脉(ECA)和颈内动脉(ICA)，在CCA远心端和近心端及ECA处挂丝线备用。微动脉夹暂时夹闭ICA后，近心端结扎CCA、ECA，在距颈总动脉分叉部4mm处剪一小口，并在小口下系一松结。用眼科镊将线栓经该口顺ECA插入，ECA游离端拉向外上方，使之与ICA走向平行，拉直与ICA的夹角。将线栓顺ICA走行，轻柔缓慢推进，插入深度约18mm左右(即线栓到达ICA与CCA分叉处)，感到推进有轻度阻力为止，系紧预先打好的松结。系紧栓结后剪短留下体内的线栓，逐层缝合切口并消毒。术后将大鼠保持侧卧位，并注意伤口是否有出血，呼吸道是否畅通等情况。
手术假手术组大鼠制备：SD大鼠，用10％水合氯醛腹腔注射麻醉，剃毛器除去大鼠颈部和腹部位的毛发，75％乙醇消毒，腹面朝上仰卧位固定于操作台的垫板上，用手术刀在颈正中行纵切口大约2cm，拨开颈部浅层颈膜，拨离由二腹肌、胸锁乳突肌和肩胛舌骨肌间的间隙粘膜，暴露颈总动脉(CCA)、颈外动脉(ECA)和颈内动脉(ICA)，拨动血管后逐层缝合切口并消毒。术后将大鼠保持侧卧位，并注意伤口是否有出血，呼吸道是否畅通等情况。
1.2分组及给药剂量
SD大鼠分组及给药剂量见表1，距大鼠造模后3h尾静脉注射给药。
表1分组及给药剂量
组别 受试药物 剂量
模型组 乳酸林格氏液 12.31ml/kg
药物组 聚合血红蛋白药物 800mg/kg
假手术组 生理盐水 12.31ml/kg
2.评估指标
2.1神经功能评分
在pMCAO发作、给药后24h，分别由2名分组不知情的观察者采用Bederson评分法(见表2)进行神经功能评估并记录。
表2 Bederson评分法
评分等级 神经症状
0 无神经损伤症状
1 提尾时损伤对侧前肢不能伸直
2 损伤对侧前肢屈曲，无转圈行为
3 损伤对侧前肢屈曲，伴自发转圈行为
4 不能自发行走，意识不清
5 死亡
2.2血气分析
分别在pMCAO发作、给药后24h时经股动脉采集血样，立刻进行血气分析。
2.3脑梗死体积的测定和脑水肿评估
待24h神经功能评估后，各组(n＝4)大鼠分别安乐死，按TTC法进行染色。完整取出大鼠全脑组织(去除小脑)，0.9％生理盐水漂洗，将动物脑组织放入特制的脑切片模具槽中，用薄双面刀片将脑组织切成6片，每片厚度约2mm。按照前后顺序将脑切片放入TTC(2，3，5-氯化三苯基四氮唑)染色液中，37℃避光染色30min。30min后将脑切片从TTC染液中取出，置于10％中性福尔马林溶液中，4℃冰箱固定24h。脑切片固定后，按顺序排列，照相(前侧面和尾侧面均拍照)。将照片导入图像分析软件，测量梗死区域(白色区域)和正常区域(红色区域)面积，按公式：V＝Σ[(A1+A2)×d/2]计算各区域体积和整脑体积，其中A1、A2分别为脑切片前侧面和尾侧面相应区域面积，d为切片厚度。
脑梗死(％)＝(对侧半球体积-同侧非梗死体积)/对侧半球体积；
脑水肿(％)＝(同侧半球体积-对侧半球体积)/对侧半球体积。
其中，假手术组1-3pMCAO大鼠大脑TTC染色图如图1-3所示，药物组1-3pMCAO大鼠大脑TTC染色图如图4-6所示，模型组1-3pMCAO大鼠大脑TTC染色图如图7-9所示。
3.实验结果
3.1神经功能评分
在pMCAO发作、给药后24h，分别经2名分组不知情的观察者采用Bederson评分法(见表2)对实验大鼠进行神经功能评估，结果假手术组大鼠评分均为0分，模型组和药物组大鼠评分均≥3分。
3.2血气分析
通过血气分析数据结果分析可知，给药24h相比造模后，氧分压(PaO 2)：假手术组和药物组升高较快，而模型组有一定的缓慢升高；血红蛋白浓度(ctHb)：假手术组和药物组升高较快，而模型组有缓慢升高或抑制；结合氧(FO 2Hb)：假手术组和药物组有一定升高，而模型组有缓慢升高或抑制。结果如表3所示。
表3血气分析检测结果
Figure PCTCN2021135671-appb-000001
3.3脑梗死体积的测定
通过脑梗死体积测定的结果分析可知，假手术组脑部几乎无脑梗死，药物组相比模型组脑部梗死体积有明显改善，结果如表4所示。
表4脑梗死体积测定结果
Figure PCTCN2021135671-appb-000002
3.3脑水肿评估
通过脑水肿测定的结果分析可知，假手术组脑部几乎无水肿，药物组相比模型组脑部水肿有明显改善，结果如表5所示。
表5脑水肿体积测定结果
Figure PCTCN2021135671-appb-000003
试验例2包含聚合血红蛋白的药物与包含聚合血红蛋白和依达拉奉的复方药物对永久性缺血性脑卒中(pMCAO)大鼠静脉注射对炎症因子研究
受试药物：实施例2制备的包含聚合血红蛋白和依达拉奉的复方药物，其中血红蛋白含量65.0g/L，依达拉奉为13.70mg/L；
阳性药物1：实施例3制备的包含聚合血红蛋白药物，其中血红蛋白含量65.0g/L；
阳性药物2：依达拉奉注射液(规格：20ml:30mg；国药集团国瑞药业有限公司)
试验动物：同试验例1。
1.实验方法：
1.1建模
同试验例1。
2.2分组及给药剂量
SD大鼠分组及给药剂量见表6，距大鼠造模后3h尾静脉注射给药。
表6分组及给药剂量
Figure PCTCN2021135671-appb-000004
2.评估指标
2.1神经功能评分
同试验例1。
2.2免疫印迹实验
样品经SDS-PAGE分胶检测Caspase-3、HIF-1、IL-6和GAPDH蛋白条带。
2.3 Caspase-3检测
取动物部分脑组织，称重后冰浴环境下用PBS制成10％匀浆，离心后取上清，测定蛋白浓度后按试剂盒说明书检测Caspase-3含量。
3.结果
3.1神经功能评分
在pMCAO发作、给药后24h，分别经2名分组不知情的观察者采用Bederson评分法对实验大鼠进行神经功能评估，结果假手术组大鼠评分均为0分，模型组、阳性药物1组、阳性药物2组和受试药物组大鼠评分均≥3分。
3.2免疫印迹实验
目的蛋白条带如图10，根据目的蛋白条带图中结果表明，在缺血性脑卒中实验中，相比模型组，聚合血红蛋白组和依达拉奉组都具有一定的神经保护作用，而受试药物组对神经的保护效果更好，接近于假手术组。
3.3 Caspase-3含量
Caspase-3含量如图11，Caspase-3在细胞凋亡中起到不可替代的作用，其含量的趋势结果也证明了目的蛋白条带的上述结果，受试药物组更优于单药成分的聚合血红蛋白药物组和依达拉奉药物组。
本发明人对其他实施例也做了上述试验，结果基本一致，由于篇幅有限，不再一一列举。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以所述权利要求的保护范围为准。

Claims (10)

  1. 一种聚合血红蛋白在制备治疗缺血性脑卒中药物的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述的药物为聚合血红蛋白加入医学上可接受的辅料制成。
  3. 根据权利要求1或2所述的应用，其特征在于：所述的药物还可加入临床常用的神经保护剂。
  4. 根据权利要求1或2所述的应用，其特征在于，所述的药物中每1L药物中含聚合血红蛋白为30.0～130.0g。
  5. 根据权利要求2所述的应用，其特征在于，所述的辅料以重量计溶解在1L注射用水中制成，具体比例如下：氯化钠0.87～6.6g、氯化钾0.3～0.67g、alpha-酮戊二酸单钾盐0～0.18g、六水氯化镁0～0.81g、一水一盐酸组氨酸0～3.77g、组氨酸0～27.92g、色氨酸0～0.4g、甘露醇0～0.4g、二水氯化钙0.002～0.2g、乙酰半胱氨酸2.0～2.28g、氢氧化钠0～0.48g、乳酸钠0～3.1g。
  6. 根据权利要求3所述的应用，其特征在于：所述的临床常用的神经保护剂包括以下中的一种或几种，具体为所述的神经保护剂以重量计溶解在1L注射用水中，具体比例为依达拉奉3.0～60.0mg、神经节苷脂14.0～55.0mg、丁苯酞65.0～315.0mg，长春西汀15.0～125.0mg、胞磷胆碱65.0～520.0mg。
  7. 根据权利要求1～6任意一项所述的应用，其特征在于，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.48g、乳酸钠3.0g、乙酰半胱氨酸2.0g、依达拉奉13.70mg。
  8. 根据权利要求1～6任意一项所述的应用，其特征在于，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠6.6g、氯化钾0.3g、二水氯化钙0.2g、氢氧化钠0.48g、乳酸钠3.0g、乙酰半胱氨酸2.0g。
  9. 根据权利要求1～6任意一项所述的应用，其特征在于，所述的药物为以下各物质溶解在1L注射用水中，具体比例如下：聚合血红蛋白65.0g、氯化钠0.87g、氯化钾0.3g、alpha-酮戊二酸单钾盐0.18g、六水氯化镁0.81g、一水一盐酸组氨酸3.77g、组氨酸27.92g、色氨酸0.4g、甘露醇0.4g、二水氯化钙0.002g、乙酰半胱氨酸2.28g。
  10. 根据权利要求1～9任意一项所述的应用，其特征在于，所述药物剂型为注射剂。
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