CN107648236B - 一种预防或治疗缺血/再灌注损伤的药物组合物及应用 - Google Patents
一种预防或治疗缺血/再灌注损伤的药物组合物及应用 Download PDFInfo
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Abstract
本发明公开了一种预防或治疗缺血/再灌注损伤的药物组合物，所述药物组合的活性成分由恩利卡生和普纳替尼按重量比1:(0.25—10)组成。本发明的药物组合物能协同性预防和治疗缺血性脑卒中，能显著减轻脑缺血/再灌注损伤。
Description
技术领域
本发明属于生物医药领域，具体涉及一种预防或治疗缺血/再灌注损伤的药物组合物及应用。
背景技术
缺血性脑卒中是严重危害人类健康的常见和多发病，在全球已成为第一致残和第三致死的原因，缺血性脑卒中的发病率约占脑血管病的70-80％。
脑缺血损伤与自由基过度形成、兴奋性氨基酸毒性作用、细胞内钙超载、炎性反应等多种机制有关，无论何种机制，最终的结局都会导致神经细胞死亡、功能破坏、脑梗死灶形成。细胞死亡的方式主要有凋亡和坏死两条途径。在脑缺血损伤中神经细胞凋亡和坏死同时存在。缺血核心区以细胞坏死为主，而周围明暗带以细胞凋亡为主。
细胞凋亡主要包括内源性细胞凋亡通路(线粒体介导的凋亡通路)和外源性细胞凋亡通路(死亡受体介导的凋亡通路)。Caspase家族是一大类凋亡的调控因子,是细胞凋亡的启动者和最后的执行者。脑缺血时，死亡受体介导的凋亡通路激活的caspase-8，进一步激活其下游效应蛋白酶caspase-3及激活线粒体凋亡通路导致细胞凋亡。研究表明，抑制caspase酶活性，够阻止神经凋亡的发展,可减轻脑缺血损伤的程度,缩小梗死范围。半胱天冬酶抑制剂恩利卡生(Emricasan)能特异性抑制caspase-8、caspase-3/7,减轻肝移植缺血/再灌损伤和肺移植缺血/再灌注损伤。
研究表明，坏死也受到各种信号通路严密调控，称为调节性坏死，其中， RIPK1/RIPK3依赖的程序性坏死最受关注。研究表明，RIPK1/RIPK3依赖的程序性坏死存在于多种损伤相关性疾病中，包括缺血性脑卒中、心肌梗死和肾缺血/再灌注损伤。因此，抑制RIPK1/RIPK3依赖的程序性坏死已成为目前减轻缺血性脑卒中神经细胞死亡的有效途径。文献报道，RIPK1抑制剂necrostatin-1(Nec-1)能减少小鼠脑缺血损伤，改善神经功能，该作用与抑制神经细胞的程序性坏死密切相关。然而，Nec-1仅作为工具药用于动物实验，目前临床上尚无针对RIPK1/RIPK3药物用于治疗缺血性脑卒中。新近的研究发现酪氨酸激酶抑制剂普纳替尼(Ponatinib)具有新的功能，能特异性下调RIPK1和RIPK3 的蛋白表达水平,抑制细胞程序性坏死。
脑缺血/再灌注损伤时，如同时抑制caspase酶活性和RIPK1/RIPK3通路，继而抑制神经神经凋亡和神经细胞调节性坏死，极大的减轻缺血/再灌注损伤。而目前尚无这样的治疗方式和治疗药物。目前，现有技术还没有关于恩利卡生和普纳替尼联合应用的报道，尤其没有二者联合应用于预防和治疗缺血/再灌注损伤。
发明内容
本发明旨在解决临床迫切需要解决的问题和疾病的发病机理，根据动物实验结果创造性地提出将恩利卡生和普纳替尼联合，用于预防或治疗脑缺血/再灌注损伤。
为了达到上述目的，本发明提供的技术方案为：
所述预防或治疗缺血和/或再灌注损伤的药物组合物(本文中，以下“/”均表示“和/或”)的活性成分由恩利卡生和普纳替尼按重量比1:(0.25—10)组成，这两种成分均以游离状态或药学上可接受盐的形式存在，以药学可接受盐的形式施用恩利卡生和普纳替尼，这些盐是药学上常用的盐，例如乙酸盐，苯甲酸盐，富马酸盐，马来酸盐，柠檬酸盐，酒石酸盐，2，5一二羟基苯甲酸盐，甲磺酸盐，乙磺酸盐，苯磺酸盐，月佳基磺酸盐，氢醌磺酸盐和对甲苯磺酸盐。优选地，所述药物组合的活性成分由恩利卡生和普纳替尼按重量比1:(0.5—5)组成。更优选地，所述药物组合的活性成分由恩利卡生和普纳替尼按重量比1:1.5组成。该药物组合物可以按照已知技术制备成任意一种药剂学上可以接受的剂型，其中优选剂型为口服制剂，如片剂、胶囊剂、颗粒剂、散剂、口服液或滴丸。
上述药物组合物可用于制备预防或治疗缺血和/或再灌注损伤药物。所述应用的给药方式为皮下注射、静脉注射、肌肉注射或口服给药，优选为口服给药。所述缺血/再灌注损伤是指脑缺血/再灌注损伤、心肌缺血/再灌注损伤、肝缺血/再灌注损伤和肾缺血/再灌注损伤。优选地，所述缺血/再灌注损伤是指脑缺血/再灌注损伤。
与现有技术相比，本发明的有益效果为：
(1)协同性预防或治疗缺血/再灌注损伤，特别是脑缺血/再灌注损伤，提高患者的长期生存率和降低致残率，可适用于脑缺血/再灌注损伤；
(2)降低了药物的不良反应；
(3)与注射给药方式相比，本发明采用口服给药，操作简单，刺激性小，增强病人的依从性。
本发明证实恩利卡生能特异性抑制caspase-8，降低脑缺血/再灌注大鼠神经细胞的凋亡率，缩小脑梗死体积，改善神经学功能，说明恩利卡生有可能用于治疗缺血性脑卒中。而普纳替尼口服目前用于治疗因T315I突变对酪氨酸激酶抑制剂伊马替尼、达沙替尼或尼洛替尼产生耐药的成人慢性粒细胞白血病。新近研究发现普纳替尼具有新的功能，能特异性下调RIPK1和RIPK3的蛋白表达水平,抑制细胞程序性坏死，提示普纳替尼可能具有抑制缺血性脑卒中RIPK1/RIPK3依赖的神经细胞程序性坏死作用，减轻脑缺血/再灌注损伤。该机制有别于其成人慢性粒细胞白血病的机制。普纳替尼用于治疗大鼠脑缺血/ 再灌注损伤，能下调大鼠脑组织中RIPK1和RIPK3的蛋白表达水平，降低大鼠脑梗死体积，改善神经学功能，这一作用优于阳性工具药Nec-1。
总之，本发明的药物组合物能同时抑制caspase酶活性和RIPK1/RIPK3通路，协同性预防和治疗缺血性脑卒中，能显著减轻脑缺血/再灌注损伤。
附图说明
图1：A-大鼠脑组织TTC染色及梗死体积测定，B-大鼠神经学功能评分；
具体实施方式
在下文中，恩利卡生的量和普纳替尼的量以等量的没有成盐的游离形式的恩利卡生和普纳替尼表示。
动物实验：恩利卡生和普纳替尼组合物对缺血性脑卒中的保护作用
实施药品：羧甲基纤维素钠(CMC-Na)购于上海山浦化工有限公司。
将恩利卡生与普纳替尼组合物，用0.5％羧甲基纤维素钠(CMC-Na)作为溶媒制成混悬液。
实验动物：体重250～300g的健康雄性SD大鼠48只。将实验动物在温度25℃、相对湿度60％、自由饮水、定时定量的环境中饲养一周，然后按实验各分组要求口服给药。
建模方法：用脑中动脉阻塞(MCAO)法制备大鼠脑缺血/再灌注损伤模型。步骤如下：(1)分离颈外动脉(CCA),向上分离右颈外动脉(ECA)与颈内动脉(ICA)；(2)用眼科镊暂时夹闭ECA和ICA，并结扎CCA近心端；(3)于CCA远心端放置一打好结的备用丝线，在此线下端剪一小口,将栓线***至颈内动脉，收紧丝线，放开ECA和ICA上的动脉夹，顺ICA将栓线送至颅内；(4)遇阻力而止,从CCA分叉处算起，***深度约为18～ 20mm；(5)缺血120min后，将栓线拔出，缝好皮肤，再灌注24h后处理动物。
模型成功评判标准采用Longa“5分法”对大鼠脑缺血损伤的神经功能缺损进行评分。0分：无神经缺损症状；1分：右前肢不能完全伸直；2分：向右旋转；3分：行走向右侧倾倒；4分：不能自发行走，意识丧失。1～4分为有效模型。
大鼠脑TTC染色和梗死体积测定。大鼠麻醉后，迅速将脑取出，去掉嗅球及后脑，从额极开始切取4张冠状脑片，厚约2.0mm，立刻置于1％TTC溶液中，37℃避光孵育 30min。然后用10％多聚甲醛溶液浸泡固定。梗死区呈现白色，非梗死区呈现红色。将每组脑片排列整齐后进行扫描。再应用ImageJ测出各脑片的梗塞面积，根据公式：梗死体积＝[(各片正面梗死面积之和+各片反面梗死面积之和)/2]×每片厚度,同样方法计算出全脑体积。
实验分组：将实验动物随机分为7组，即：
依次为对照组、假手术组、缺血/再灌注组、恩利卡生+缺血/再灌注组、普纳替尼+缺血/再灌注组、联合用药+缺血/再灌注组组，各组大鼠分别于缺血2h再灌1小时后灌胃1次，按表2的剂量给予相应受试物。
表2实验动物分组及给药
对照组(control组)：不做任何处理。
假手术组(sham组)：将栓线插到脑中动脉分叉处即停。
缺血/再灌注组(I/R)：脑缺血2h，再灌注24h。
恩利卡生(15mg/kg)+脑缺血/再灌注组(Emricasan+I/R)，普纳替尼(20mg/kg)+脑缺血/ 再灌注组(Ponatinib+I/R)，恩利卡生(15mg/kg)+普纳替尼(20mg/kg)+脑缺血/再灌注组 (combination+I/R)，溶媒(0.5％羧甲基纤维素钠做成混悬液)+脑缺血/再灌注组(vehicle+I/R)：缺血2h再灌后1小时灌胃1次(用0.5％羧甲基纤维素钠做成混悬液)。
检测指标：大鼠神经功能评分和梗死体积测定。
实验结果：
对大鼠脑梗死体积及神经功能的影响
图1中的A所示，I/R组有明显的白色梗死灶，而药物组大鼠脑梗死灶显著缩小，明显缓解脑缺血损伤。
图1中B，脑缺血组(I/R)大鼠出现明显的神经运动功能障碍，而恩利卡生、普纳替尼、恩利卡生+普纳替尼联合用药，缺血2小时再灌后1小时给药组均明显改善神经功能缺损症状(p<0.01)。
但本专利不局限于脑缺血/再灌注损伤，因心、肝和肾缺血/再灌注损伤同样存在Caspase 和RIPK1/RIPK3酶活性上调，故该药同样适用于治疗心、肝和肾缺血/再灌注损伤。
Claims (5)
1.一种药物组合物在制备预防或治疗缺血/再灌注损伤药物中的应用，其特征在于，所述药物组合的活性成分由恩利卡生和普纳替尼按重量比1:（0.25—10）组成；所述缺血/再灌注损伤是指脑缺血/再灌注损伤。
2.如权利要求1所述的应用，其特征在于，所述应用中的给药方式为皮下注射、静脉注射、肌肉注射或口服给药。
3.如权利要求2所述的应用，其特征在于，所述应用中的给药方式为口服给药。
4.如权利要求1所述的应用，其特征在于，所述药物组合的活性成分由恩利卡生和普纳替尼按重量比1:（0.5—5）组成。
5.如权利要求1所述的应用，其特征在于，所述药物组合的活性成分由恩利卡生和普纳替尼按重量比1:1.5组成。
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Non-Patent Citations (5)
| Title |
|---|
| A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis;A Fauster et al;《Cell Death and Disease》;20150521;第6卷;1-6 * |
| Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556,in Human Liver Preservation Injury.;E. S. Baskin-Bey et al.;《American Journal of Transplantation》;20071231;第7卷;218–225 * |
| Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia–reperfusion injury;Shizuka Koshinuma et al;《J Anesth 》;20131011;第28卷;235–241 * |
| Necroptosis in Immunity andIschemia-Reperfusion Injury;A. Linkermann et al;《 American Journal of Transplantation 》;20131231;第13卷;2797–2804 * |
| 坏死性凋亡在神经***疾病中作用的研究进展;孟俊杰等;《基础医学与临床》;20160930;第36卷(第9期);1290-1294 * |
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