CN113398120A - 阿比多尔在制备预防或治疗SARS-CoV-2病毒所致疾病的药物中的用途 - Google Patents
阿比多尔在制备预防或治疗SARS-CoV-2病毒所致疾病的药物中的用途 Download PDFInfo
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Abstract
本发明提供阿比多尔或其药学上可接受的盐在制备预防或治疗SARS‑CoV‑2病毒的药物中的用途,本发明首次发现并证实了盐酸阿比多尔在体外对新型冠状病毒SARS‑CoV‑2感染Vero E6细胞致细胞病变具有抑制作用,并能显著抑制SARS‑CoV‑2诱导炎症因子TNF‑a、IL‑6、MCP‑1和IP‑10的mRNA过度表达,可快速使其应用于抵抗SARS‑CoV‑2病毒感染,缓解疫情。
Description
技术领域
本发明涉及阿比多尔的新药物用途,具体涉及阿比多尔在制备预防或治疗SARS-CoV-2病毒所致疾病的药物中的应用。
背景技术
冠状病毒属于套式病毒目、冠状病毒科、冠状病毒属,是一类具有囊膜、基因组为线性单股正链的RNA病毒,是自然界广泛存在的一大类病毒。病毒基因组5′端具有甲基化的帽状结构,3′端具有poly(A)尾,基因组全长约27-32kb,是目前已知RNA病毒中基因组最大的病毒。冠状病毒仅感染脊椎动物,与人和动物的多种疾病有关,可引起人和动物呼吸道、消化道和神经系统疾病。
2019新型冠状病毒(SARS-CoV-2,也有命名为2019-nCoV)是目前已知的第7种可以感染人的冠状病毒,其余6种分别是HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV(引发重症急性呼吸综合征)和MERS-CoV(引发中东呼吸综合征),它是一种新的从未在人类或动物中发现过的冠状病毒。新型冠状病毒传播迅速,感染后引起呼吸困难、发热、咳嗽、气促等症状,且导致肺炎、严重急性呼吸综合征、肾衰竭,甚至死亡等严重后果。新型冠状病毒引起的严重后果与炎症风暴直接相关。炎症风暴,也称细胞因子风暴,是由感染、药物或某些疾病引起的免疫系统过度激活,一旦发生将对人体细胞进行无差别攻击,可迅速引起单器官或多器官功能衰竭,最终威胁生命。武汉中南医院的医生发现新型冠状病毒肺炎重症患者相比轻症患者,血浆多种促炎因子(IL2、IL7、IL10、GSCF、IP10、MCP1、MIP1A、TNFα)表达水平明显更高,而这些炎性指标提示重症患者发生了细胞因子风暴(参见Huang C,Wang Y,Li X,Ren L,Zhao J,Hu Y,Zhang L,Fan G,Xu J,Gu X,et al:Clinical featuresof patients infected with 2019novel coronavirus in Wuhan,China.The Lancet2020)。目前对于新型冠状病毒所致疾病没有特异治疗方法。
阿比多尔(Arbidol,也称阿比朵尔)是非核苷类抗病毒类药物,化学名为6-溴-4-(二甲氨基甲基)-5-羟基-1-甲基-2-(苯硫甲基)-1H-吲哚-3-羧酸乙酯,是一种抗病毒药物和免疫刺激剂,用于防治流行性感冒和其它急性呼吸道病毒感染,它对甲、乙型流感病毒的抗病毒活性最为显著,具有毒性低、耐受性良好的特点。该药能抑制甲、乙型流感病毒复制的早期阶段,能抑制病毒与细胞浆膜的融合以及病毒与内吞囊泡之间的膜融合。同时阿比多尔在体内还可诱导产生干扰素,对巨噬细胞的吞噬功能有显著的活化作用,具有免疫调节功能。
已经发现阿比多尔在某些冠状病毒导致的疾病中可能有治疗效果。专利文献CN100344284C中公开了通过体外病毒筛选实验,证明了阿比多尔对SARS病毒感染引起的呼吸道疾病有治疗效果。专利文献CN106074506A中公开了通过运用体外三种抗病毒药效评价模型,发现盐酸阿比多尔对中东呼吸道病毒有抗病毒作用,可阻断中东呼吸系统综合征冠状病毒感染宿主细胞,可用于治疗中东呼吸系统综合征冠状病毒感染引起的疾病。虽然阿比多尔对某些冠状病毒感染具有抑制作用,但SARS-CoV-2是一种新发现的冠状病毒,其生物学特性尚不明确,引起疾病的临床症状与已知冠状病毒性疾病存在差异。目前没有文献公开并证实阿比多尔在预防或治疗SARS-CoV-2病毒感染方面的效果,更无人报道阿比多尔是否对SARS-CoV-2病毒感染引起的炎症风暴有抑制作用。在疫情期间,证实阿比多尔在抗SARS-CoV-2病毒感染和抑制病毒引起炎症风暴方面的效果对于指导临床治疗至关重要。
发明内容
为了解决上述技术问题,本发明的目的在于提供一种阿比多尔或其药学上可接受的盐在制备预防或治疗SARS-CoV-2病毒所致疾病的药物中的用途。优选的,预防或治疗SARS-CoV-2病毒所致疾病包括抑制SARS-CoV-2病毒感染细胞,和/或,预防或治疗SARS-CoV-2病毒感染引起的炎症风暴,和/或,预防或治疗重症新型冠状病毒肺炎;进一步优选的,预防或治疗SARS-CoV-2病毒诱导的炎症因子TNF-a、IL-6、MCP-1和IP-10过度表达。
本发明所述阿比多尔药学上可接受的盐选自马来酸盐、水杨酸盐、戊二酸盐、龙胆酸盐、富马酸盐、琥珀酸盐、苯甲酸盐、甲磺酸盐、盐酸盐、乙酸盐、丙酸盐、乳酸盐、三氟乙酸盐、柠檬酸盐、酒石酸盐、苹果酸盐、焦谷氨酸盐、醋酸盐、磷酸盐。进一步的,本发明所述阿比多尔药学上可接受的盐优选为盐酸盐。
本发明所述的用途中,所述的药物是以阿比多尔或其药学上可接受的盐作为有效成分的药物组合物。
本发明所述的用途中,所述的药物还可含有其它的抗病毒成分。
本发明还涉及以阿比多尔或其药学上可接受的盐作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。所述药物或药物组合物包含阿比多尔或其药学上可接受的盐与一种或多种药学上可接受的载体。所述的药物组合物还可含有其它的抗病毒成分。
本发明所述药物或药物组合物可制成适于人或动物使用的任何剂型,例如可以是液体剂型、固体剂型或半固体剂型。液体剂型包括但不限于溶液剂、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型包括但不限于片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸等;半固体剂型包括但不限于软膏剂、凝胶剂、糊剂等。
阿比多尔或其药学上可接受的盐在所述药物或药物组合物中的质量百分比通常为0.1-95重量%。
阿比多尔或其药学上可接受的盐在所述药物或药物组合物中的含量通常为1mg-500mg。优选为25mg、50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg。
本发明的另一个目的还包括提供一种预防或治疗SARS-CoV-2病毒所致疾病的方法,所述方法包括给予受试者或患者治疗有效量的阿比多尔或其药学上可接受的盐。所述SARS-CoV-2病毒所致疾病包括SARS-CoV-2病毒感染细胞,和/或SARS-CoV-2病毒感染引起的炎症风暴等疾病,和/或重症新型冠状病毒肺炎。优选的,所述疾病包括SARS-CoV-2病毒诱导的炎症因子TNF-a、IL-6、MCP-1和IP-10过度表达的疾病。
阿比多尔已在临床使用,其安全性、药物代谢特性、毒副作用已经明确。而本发明通过运用三种体外抗病毒药效评价模型,首次发现并证实了盐酸阿比多尔在体外对新型冠状病毒SARS-CoV-2感染Vero E6细胞致细胞病变具有抑制作用,具有低毒高效的优势;并能显著抑制SARS-CoV-2诱导炎症因子TNF-a、IL-6、MCP-1和IP-10的mRNA过度表达,说明阿比多尔不仅可以阻止SARS-CoV-2感染细胞引起细胞病变,对于SARS-CoV-2感染引起的炎症风暴也有抑制作用,可用于新型冠状病毒,尤其是重症新型冠状病毒肺炎的治疗。本发明发现并验证阿比多尔抗SARS-CoV-2的新用途将可快速使其应用于抗新型冠状病毒感染,对于治疗新型冠状病毒肺炎、缓解疫情有重要意义。
附图说明
图1盐酸阿比多尔细胞毒性检测结果图
图2盐酸阿比多尔抑制SARS-CoV-2感染Vero E6细胞致细胞病变的药效检测结果图
图3盐酸阿比多尔抑制SARS-CoV-2诱导炎症因子TNF-a、IL-6、MCP-1和IP-10过表达的检测结果图
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
一、实验材料:
1.受试药物:盐酸阿比多尔。
2.细胞:VeroE6和Huh-7细胞,由广州呼吸健康研究院呼吸疾病国家重点实验室病毒室保存提供。
3.病毒:SARS-CoV-2,滴度为TCID50=10-6/100μL,由广州海关技术中心BSL-3实验室(呼吸疾病国家重点实验室高致病病原微生物研究室)-80℃保存提供。使用病毒滴度为100TCID50。
二、抗病毒药效结果判定标准:
三、效果试验
(一)细胞毒性试验(MTT法)
(1)受试药物及分组:
表1:药物名称、实验浓度和分组
(2)无菌96孔培养板,每孔加入100μL浓度为2×105cells/mL VeroE6细胞,37℃、5%CO2培养24小时;
(3)96孔板单层细胞用PBS洗涤1次,每孔加入100μL 2倍梯度稀释的药物。空白对照组和正常细胞对照组每孔加入等体积培养液,37℃培养4日;
(4)每孔加入浓度为5mg/mL的MTT溶液20μL,继续孵育4小时。弃上清,每孔加入100μL DMSO,低速振荡5分钟,使结晶物充分融解;
(5)选择490nm波长,在酶联免疫仪上测定吸光值,计算抑制率。抑制率=(正常细胞对照组平均OD值—药物组平均OD值)/(正常细胞对照组平均OD值-空白对照组平均OD值)×100%。Reed-Meunch法计算药物半数毒性浓度(CC50)。
(6)以上实验操作均在BSL-2实验室内完成。
试验结果:如图1所示,MTT试验结果表明,在VeroE6细胞中,盐酸阿比多尔半数无毒浓度(CC50)为44.025μM。
(二)抗病毒试验
(1)受试药物及分组:
设立细胞对照、空白对照(溶剂对照)、病毒对照(阴性对照)、阳性药物对照(氯喹或瑞德西韦)、实验组;
表2:药物名称、实验浓度
(2)无菌96孔培养板,每孔加入100μL浓度为2×105cells/mL VeroE6细胞,37℃5%CO2培养24小时;
(3)培养板实验组和病毒对照组加入100TCID50病毒液100μL/孔,37℃5%CO2培养箱吸附2h;
(4)2h后,弃去96孔培养板中细胞培养液;受试药物稀释成表2中的各个浓度,每个浓度3个复孔,100μl/孔加入上述药液;
(5)细胞37℃,5%CO2孵箱孵育3-4天;
(6)光学显微镜下观察细胞病变(CPE),细胞出现病变程度按以下6级标准记录:“-”无病变出现;“±”为细胞病变少于10%;“+”为细胞病变约25%;“++”为细胞病变约50%;“+++”为约75%的细胞出现病变:“++++”为75%以上病变。采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC50)。
(7)以上实验操作均在BSL-3实验室内完成。
试验结果:如图2所示,盐酸阿比多尔在此次实验的治疗模式中IC50为11.63μM。
(三)RT-qPCR检测炎症因子mRNA试验
(1)Huh-7细胞接种至6孔板中,分为正常组(Ctrl组)、病毒组(V组)、药效组(ARB-15μM+V、ARB-7.5μM+V和ARB-3.25μM+V)和药物对照组。细胞长至单层后,弃去培养液,用PBS洗一次,病毒组和药效组接种1000个TCID50的SARS-CoV-2冠状病毒,正常组和药物对照组加入无血清培养基,37℃吸附1小时。
(2)弃去病毒液,药效组加入不同浓度药物溶液1mL。药物对照组加入最高浓度的药物1mL,正常组和病毒组加入等体积无血清培养基。37℃作用48小时后,弃上清,PBS洗细胞一次,加入TRIzol试剂裂解细胞提取RNA。RT-qPCR检测细胞因子mRNA。
(3)以上实验操作均在BSL-3实验室内完成。
试验结果:通过RT-qPCR检测细胞因子mRNA的表达,采用GraphPad Prism5.0分析计算结果,如图3所示,盐酸阿比多尔显著抑制SARS-CoV-2诱导炎症因子TNF-a、IL-6、MCP-1和IP-10的mRNA过度表达。
四、结论
上述结果表明盐酸阿比多尔在体外对新型冠状病毒SARS-CoV-2感染Vero E6细胞致细胞病变具有抑制作用(选择指数SI为3.79),毒性低的同时效果高;并能显著抑制SARS-CoV-2诱导炎症因子TNF-a、IL-6、MCP-1和IP-10的mRNA过度表达。说明阿比多尔不仅可以阻止SARS-CoV-2感染细胞引起细胞病变,对于SARS-CoV-2感染引起的炎症风暴也有抑制作用。提示,阿比多尔可用于抗新型冠状病毒感染,对于治疗新型冠状病毒肺炎(尤其是重症新型冠状病毒肺炎)、缓解疫情有重要意义。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.阿比多尔或其药学上可接受的盐在制备预防或治疗SARS-CoV-2病毒所致疾病的药物中的用途,优选的,预防或治疗SARS-CoV-2病毒所致疾病包括抑制SARS-CoV-2病毒感染细胞,和/或预防或治疗SARS-CoV-2病毒感染引起的炎症风暴,和/或重症新型冠状病毒肺炎。
2.根据权利要求1所述的用途,其特征在于,所述疾病为SARS-CoV-2病毒感染引起的炎症风暴和/或重症新型冠状病毒肺炎。
3.根据权利要求1所述的用途,所述疾病为SARS-CoV-2病毒诱导的炎症因子TNF-a、IL-6、MCP-1和IP-10的过度表达的疾病。
4.根据权利要求1-3任一项所述的用途,其特征在于,所述阿比多尔药学上可接受的盐选自马来酸盐、水杨酸盐、戊二酸盐、龙胆酸盐、富马酸盐、琥珀酸盐、苯甲酸盐、甲磺酸盐、盐酸盐、乙酸盐、丙酸盐、乳酸盐、三氟乙酸盐、柠檬酸盐、酒石酸盐、苹果酸盐、焦谷氨酸盐、醋酸盐、磷酸盐。
5.根据权利要求1-4任一项所述的用途,其特征在于,所述阿比多尔药学上可接受的盐为盐酸盐。
6.根据权利要求1-5任一项所述的用途,其特征在于,所述的药物是以阿比多尔或其药学上可接受的盐作为有效成分的药物组合物。
7.根据权利要求1-6任一项所述的用途,其特征在于,所述的药物或药物组合物还含有其它的抗病毒成分。
8.根据权利要求1-7任一项所述的用途,其特征在于,所述药物或药物组合物包括阿比多尔或其药学上可接受的盐与一种或多种药学上可接受的载体。
9.根据权利要求1-8任一项所述的用途,其特征在于,所述药物或药物组合物中阿比多尔或其药学上可接受的盐的质量百分比为0.1-95重量%。
10.根据权利要求1-9任一项所述的用途,其特征在于,所述药物或药物组合物为临床可接受的剂型,包括液体剂型、固体剂型或半固体剂型;液体剂型包括但不限于溶液剂、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型包括但不限于片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸等;半固体剂型包括但不限于软膏剂、凝胶剂、糊剂等。
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CN1552321A (zh) * | 2003-06-05 | 2004-12-08 | 中奇制药技术(石家庄)有限公司 | 阿比朵尔在制备预防和治疗sars病毒药物中的用途 |
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邱胤达等: "新型冠状病毒SARS-CoV-2 及抗COVID-19 药物研究进展" * |
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