CN101282741B - 治疗或预防缺血性再灌注损伤或多器官衰竭的方法 - Google Patents

治疗或预防缺血性再灌注损伤或多器官衰竭的方法 Download PDF

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CN101282741B
CN101282741B CN2006800372597A CN200680037259A CN101282741B CN 101282741 B CN101282741 B CN 101282741B CN 2006800372597 A CN2006800372597 A CN 2006800372597A CN 200680037259 A CN200680037259 A CN 200680037259A CN 101282741 B CN101282741 B CN 101282741B
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S·贾尔卡南
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Kangzhe Pharmaceutical Co., Ltd, Shenzhen City
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
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Abstract

本发明涉及治疗活性剂在制备用于预防或治疗个体缺血性再灌注损伤或多器官衰竭的方法中的药物制剂的用途。根据本发明，所述治疗剂为普通(plain)的干扰素β，且所述治疗剂意图不与影响个体腺苷水平的一种或多种治疗剂同时给药。

Description

治疗或预防缺血性再灌注损伤或多器官衰竭的方法
本发明涉及通过给所述个体施用有效量的干扰素β来预防或治疗个体的缺血性再灌注损伤或多器官衰竭的方法。
发明背景
用于描述发明背景的本文中使用的出版物和其它材料，尤其是提供有关实施额外细节的例子，引入本文作为参考。
若干病症，包括腹部损伤、肠梗阻、心血管手术和休克，可导致肠缺血性再灌注损伤(IRI)。重要的是，除引起局部损伤之外，IRI还触发远距离器官的系统炎性应答，导致所谓的多器官衰竭的综合症。在这种综合症中肺尤其易受损伤。这种损伤最显著的病征是血管通透性增加(血管渗露)和中性粒细胞聚集。继肠IRI之后的肺损伤主要是由于肠促炎性细胞因子释放的结果。肠IRI增加了肠通透性和细菌内毒素的随后释放，其促进多器官衰竭中的系统炎症。从激活的嗜中性白细胞中释放的其它介质也发挥重要的作用。
CD73(外-5′-核苷酸酶，5′-NT)为在淋巴细胞以及内皮和上皮细胞表面表达的一种糖蛋白。CD73通过其酶促作用调节白细胞粘附。它催化AMP水解成腺苷。CD73产生的腺苷降低含氧量低的组织中的血管通透性和中性粒细胞汇集。然而，在IRI中CD73在远器官损伤中的作用未知。由于在IRI中血管渗漏的中心作用，经腺苷或通过其它机理调节通透性变化的分子可能是抗多器官衰竭的潜在靶标。由于已知干扰素β既诱发CD73表达(和腺苷产生)又具有其它的免疫调节作用，我们研究了其在多器官衰竭的远器官损伤中的应用。
公布的国际专利申请WO 2004/084933公开了细胞因子用于诱发内皮CD73表达和随后增加个体腺苷水平的用途。描述了干扰素β与一磷酸腺苷(AMP)组合在治疗大鼠多器官衰竭中的用途。
公布的美国专利申请US 2004/0105843涉及干扰素β在缺氧/缺血相关性血流阻抗中的用途。该方法旨在预防血流阻抗如阻塞。然而，该文献没有提及任何关于缺血性再灌注损伤的治疗或预防。再灌注损伤指一段时间缺血之后血流返回到组织引起的组织损伤。血液中氧和营养素的缺乏已经引起了病症，其中血液循环的恢复可导致由氧引起的炎症和氧化性损伤而不是正常功能的恢复。
现在发明人已经出人意料地发现多器官衰竭或缺血性再灌注损伤可通过只应用普通的干扰素β来成功地预防或治疗，即不同时施用AMP、腺苷二磷酸(ADP)或腺苷三磷酸(ATP)或任何其它影响个体腺苷水平的治疗剂。
发明概述
因此，本发明涉及一种通过给所述个体施用有效量的干扰素β来预防或治疗个体疾病的方法，所述疾病选自缺血性再灌注损伤和多器官衰竭。
发明详述
定义和优选的实施方案：
术语“治疗”应理解为包括疾病的完全治愈和所述疾病的改善或缓解。
术语“干扰素β”应理解为包括任何干扰素β。因此，它应包括任何亚型，如干扰素β1a、干扰素β1b等、及其混合物。
术语“预防”应理解为包括完全阻止、预防、以及降低个体患所述疾病的风险。该术语还应理解为包括在很早期(例如在手术前、在中风和梗塞患者完全诊断之前)通过施用本发明方法的干扰素β对组织的预失调节以预防组织损伤。
术语“个体”指人或动物主体。
表述“有效量”指包括足以产生期望的治疗结果的本发明治疗剂的任何数量，尤其是在施用于动物或人主体时。
尽管可能干扰素β的治疗效果是由腺苷水平的升高介导的，任选地是由于施用干扰素β之后CD73表达的增强，但还是要强调可能涉及其它机理，尤其在多器官衰竭中。因此，干扰素β的作用应理解为不限于任何特定的作用机理。
根据一个优选的实施方案，创伤患者或梗塞或中风患者一旦进入护理，任选地即使最终诊断结论没有完全弄清楚，就开始施用干扰素β。在外科手术情况下在手术之前例如在手术开始12h之前已经开始施用干扰素β可能是有用的。
治疗有效量、给药途径和剂型：
给予需要本发明干扰素β治疗的治疗有效量可能取决于许多因素，例如包括患者的年龄和体重、需要治疗的明确的病症及其严重程度、以及给药途径。精确的量将最终由主治医师判断。因此，本发明的实施可能涉及任何剂量、与其它治疗有效的药物组合、用于口服、局部、吸入或肠胃外给药的药物制剂或递送系统。
本发明治疗剂的的给药量和给药方案可由治疗炎症相关性病症、如再灌注损伤、中风、器官移植、创伤、或多器官衰竭综合症领域的普通技术人员容易确定。
根据本发明可以假定一种例如皮下、肌内、静脉内或经皮给予干扰素β的作用形式是要增强抗炎的腺苷的局部浓度。这克服了与腺苷的使用相关的问题，其具有很短的半衰期因此对于治疗应用不是最理想的。
本发明的干扰素β优选可通过输注或注射施用。血管内输注通常采用装在输液袋或瓶内的肠胃外溶液进行，可与控制肠胃外溶液给药速率的各种系统相连。干扰素β可以另外根据本发明以气雾剂的形式施用。
输液或注射的优选制剂可包括载体(如人血清白蛋白)、药学上可接受的盐、缓冲液(如磷酸盐)和/或其它药学上可接受的赋形剂。活性成分干扰素β可以例如1-50×106IU/ml的量提供。该制剂可优选以冻干粉剂形式在剂型中提供，在给药前通过加入水或其它适于注射的溶液来制备。
干扰素β可给予遭受炎症或处于炎症风险之中的患者。那些炎症性病症的类型例如为中风和心肌梗塞过程中的缺血性再灌注损伤。器官移植和创伤也通常与主要炎症成分相关。
本发明将通过下列非限制的实施例阐述。
实施例1
在多器官衰竭中用普通干扰素β治疗小鼠
体重、性别和年龄匹配的C57Black小鼠用于该研究。
手术前的治疗和手术步骤
在诱发多器官衰竭之前通过皮下注射干扰素β(6000IU/剂量)或PBS进行连续三天的治疗。为了手术，用盐酸氯胺酮(100mg/kg体重，IP)和甲苯噻嗪(10mg/kg)体重，IP)将小鼠麻醉。通过剖腹剖开肠系膜上动脉并用微血管夹钳夹30分钟。在该步骤期间将总共2ml的灭菌盐水皮下注入小鼠以补偿蒸发引起的体液丧失。在该缺血时间段之后松开微血管夹钳。在4小时的再灌注之后处死动物并收集组织样本。
肺内血管渗漏分析
在处死前5分钟让小鼠静脉内接受荧光素缀合的右旋糖酐(分子量70kDa，25mg/kg体重，在0,2ml的无菌盐水中)。这种荧光染料不会从完好的容器中泄漏。从肺组织样本上剪下7微米冷冻部分并在荧光显微镜中检测。超过预定阈值的组织荧光强度和渗漏面积由×200放大倍数的数码照相机收集的图像利用Image J计算机软件来计算。
结果：
在对照治疗的小鼠中检测容器外面的FITC-右旋糖酐，作为血管损伤和内皮细胞屏障渗漏性的指标。相反，用干扰素-β治疗的小鼠没有观察到血管系统外的渗漏。表1总结了以渗漏面积计算的结果，表2总结了超出预定阈值的荧光强度。因此，干扰素β治疗能防止动物不受肺内多器官衰竭的不利影响。这些数据表明干扰素β治疗作为在易感染多器官衰竭病症(手术、损伤)中的预防措施是有用的，它可以用于已有的疾病中多器官衰竭的治疗。
表1.渗漏面积
Figure S2006800372597D00041
a)占总面积的百分比
表2.荧光强度
Figure S2006800372597D00042
a)平均荧光强度
应当理解本发明的方法可并入各种实施方案的形式中，其中只有一些在本文中公开。对于本领域专家将是显而易见的是：存在其它实施方案并且它们不背离本发明的精神。因此，所描述的实施方案是示例性的，而不应当解释为是限制性的。

Claims (1)

1.单独普通的干扰素β在制备用于预防或治疗个体的多器官衰竭的方法中的药物制剂的用途，其中所述药物制剂意图不与影响个体腺苷水平的一种或多种治疗剂同时给药。
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