CN113244241A - 一种防治出血性脑卒中的药物组合物及其应用 - Google Patents
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Abstract
本发明公开了一种防治出血性脑卒中的药物组合物及其应用,涉及生物医药技术领域。本发明的药物组合物在制备治疗出血性脑卒中药物中的应用,其中药物组合物包括:VX‑740、N‑乙酰基半胱氨酸(NAC)、去铁酮,其中药物的质量比可为:VX‑740(1‑2)、NAC(3‑5)、去铁酮(5‑7)。采用Ⅶ型胶原酶构建出血性脑卒中模型,评价该药物组合物在出血性卒中的作用,发现本发明涉及的药物组合物可改善出血性脑卒中模型小鼠的出血量、神经损伤。将本发明涉及的药物混合后制成药物组合物,可减低出血性脑卒中模型小鼠的死亡率,改善出血性脑卒中。
Description
技术领域
本发明涉及防治出血性脑卒中的药物组合物,属于医药技术领域。
背景技术
出血性脑卒中是指由于各种原因导致的脑血管破裂而引起的一种疾病,其常见病因有高血压长期控制不良,大动脉炎和脑动脉瘤破裂等。目前,针对出血性脑卒中无特效药物,因此开发改善出血性脑卒中的新型药物,减低脑卒中的死亡率十分必要与迫切。
发明内容
本发明的目的在于提供防治出血性脑卒中的药物组合物。
本发明提供了防治出血性脑卒中的药物组合物,其含有VX-740或其盐、NAC或其盐、去铁酮或其盐。
进一步地,VX-740:NAC:去铁酮重量配比为1-4:2-6:4-8。
优选地,VX-740:NAC:去铁酮重量配比为1-2:3-5:5-6。
进一步地,所述的药物组合物是以VX-740或其盐、NAC或其盐、去铁酮或其盐为活性成分,加入药学上可接受的辅料或者辅助性成分,制备而成的制剂。
本发明的另一方面提供了上述任一项药物组合物在制备防治出血性脑卒中药物中的用途。
进一步地,所述的用途满足以下至少一项:所述的药物降低出血性脑卒中死亡率;所述的药物减出血性脑卒中出血量;所述的药物降低出血性脑卒中神经损伤;所述的药物减低出血性脑卒中炎性因子水平。
本发明研究发现Caspase-1抑制剂VX-740、NAC、去铁酮联合使用可显著减低胶原酶诱导的出血性脑卒中小鼠模型出血量、神经损伤和死亡率。更为重要的是,本发明提供了这三种药物组合的最优配比,发现在此配比下,其能更好的改善出血性脑卒中。VX-740:NAC:去铁酮重量配比为1-4:2-6:4-8;优选地,VX-740:NAC:去铁酮重量配比为1-2:3-5:5-6。
本发明的应用能够为出血性脑卒中的治疗提供新的药物来源,具有潜在的重大经济效应和社会效益。以VX-740、NAC、去铁酮为活性成分制备而成的制剂,具有作为出血性脑卒中防治药物的应用前景,按照国家创新药物审批办法开发研制,有望成为高效低毒防治出血性脑卒中的创新药物,产业化前景广阔。
具体实施方式
实施例药物对脑梗模型的影响
随机将SD大鼠分成3组,分别是假手术组、模型组、药物干预组,每组10只。药物组进行药物组合灌胃干预(VX-740:12mg/kg;NAC:24mg/kg;去铁酮:36mg/kg)重量配比为3~4:1~2:5~6),每天早晚各一次,干预十四天。
造模:末次给药1h后,腹腔注射3.5%戊巴比妥钠麻醉C57BL/6小鼠,并于俯卧位固定于立体定位仪上,使用碘酒局部消毒、切开小鼠皮肤、暴露颅骨钻孔,利用微量进样器缓慢注射含0.3μl的VII型胶原酶(0.35U),滞留针5min后缓慢拔出针头,骨胶覆盖颅骨钻孔,缝合皮肤。假手术组小鼠,以同样的方法入针但不注射。神经行为学评分:神经功能测定于脑出血模型制作24小时进行。1)采用Zea-Longa评分标准对其神经功能进行评分。出血性脑卒中愈严重,其神经功能损伤症状愈明显,神经功能评分愈高。1分:小鼠未损伤侧前肢不能完全伸展;2分:小鼠身体向未损伤侧转圈,并成追尾状;3分:小鼠行走时身体向未损伤侧倾倒;4分:小鼠出现意识障碍,不能自主行走。2)脑出血量的测定:造模24h后戊巴比妥钠腹腔麻醉,PBS心脏灌注后,马上取脑,剪刀切下小鼠出血侧大脑,生理盐水冲洗除去表面的血液,而后匀浆,取上清液用血红蛋白检测试剂盒检测脑内血红蛋白含量,利用IL-1β试剂盒检测脑组织炎性因子水平。3)24小时内检测各组小鼠死亡率。试验结果如表1~表4所示。
表1
表1示出了药物组合物对出血性脑卒中模型死亡率的影响。从表1可知,药物组合物可以减少出血性脑卒中死亡率。数值以均值±SED表示。n=10,p#<0.05vs Model。
表2
分组 | 脑组织血红蛋白含量(μg/mL) |
假手术组 | 420±45 |
模型组 | 876±67 |
药物组合组 | 620±76<sup>#</sup> |
表2示出了药物组合对出血性脑卒中模型血红蛋白含量的影响。从表2可知,药物组合可以减少出血性脑卒中模型脑组织血红蛋白含量。数值以均值±SED表示。n=10,p#<0.05vs Model。
表3
分组 | 神经学评分(Zea-Longa评分) |
假手术组 | 0 |
模型组 | 2.4±0.3 |
药物组合组 | 1.1±0.3<sup>#</sup> |
表3示出了药物组合对出血性脑卒中模型神经学评分的影响。从表3可知,药物组合可以减少出血性脑卒中模型神经损伤。数值以均值±SED表示。n=10,p#<0.05vs Model。
表4
分组 | 脑组织IL-1β水平(ng/mL) |
假手术组 | 0.12±0.06 |
模型组 | 1.89±0.21 |
药物组合组 | 1.22±0.14<sup>#</sup> |
表4示出了药物组合对脑组织IL-1β水平的影响。从表4可知,药物组合可以减少出血性脑卒中模型脑组织炎性因子水平。数值以均值±SED表示。n=10,p#<0.05vs Model。
从以上数据,我们发现组合药物VX-740、N-乙酰基半胱氨酸、去铁酮可显著出血性脑卒中模型的出血量、炎性因子、死亡率和神经学损伤,具有优良的防治出血性脑卒中效果。
Claims (6)
1.防治出血性脑卒中的药物组合物,其特征是:含有如下所示的化合物或其盐:
VX-740、N-乙酰基半胱氨酸(NAC)、去铁酮。
2.如权利要求1所述的药物组合物,其特征是:VX-740:NAC:去铁酮重量配比为1~4:2~6:4~8。
3.如权利要求2所述的药物组合物,其特征是:VX-740:NAC:去铁酮重量配比为1~2:3~5:5~6。
4.如权利要求1~3任一项所述的药物组合物,其特征是:它是以VX-740或其盐、NAC或其盐、去铁酮或其盐为活性成分,加入药学上可接受的辅料或者辅助性成分,制备而成的制剂。
5.权利要求1~4任意一项所述药物组合物在制备防治出血性脑卒中药物中的用途。
6.如权利要求5所述的用途,其特征是:满足以下至少一项:
所述的药物降低出血性脑卒中死亡率;
所述的药物减出血性脑卒中出血量;
所述的药物降低出血性脑卒中神经损伤;
所述的药物减低出血性脑卒中炎性因子水平。
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WO2022213230A1 (zh) * | 2021-04-05 | 2022-10-13 | 四川大学华西医院 | 一种药物组合及其在制备防治缺血性脑卒中药物中的应用 |
CN116392486A (zh) * | 2023-05-29 | 2023-07-07 | 四川大学华西医院 | 一种防治缺血性脑卒中的药物组合物及其应用 |
CN116407557A (zh) * | 2023-05-29 | 2023-07-11 | 四川大学华西医院 | 一种防治出血性脑卒中的药物组合物及其应用 |
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WO2022213230A1 (zh) * | 2021-04-05 | 2022-10-13 | 四川大学华西医院 | 一种药物组合及其在制备防治缺血性脑卒中药物中的应用 |
CN116392486A (zh) * | 2023-05-29 | 2023-07-07 | 四川大学华西医院 | 一种防治缺血性脑卒中的药物组合物及其应用 |
CN116407557A (zh) * | 2023-05-29 | 2023-07-11 | 四川大学华西医院 | 一种防治出血性脑卒中的药物组合物及其应用 |
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