CN115813933A - Fasudil在制备治疗COVID-19引起的细胞因子风暴的药物组合物中的应用 - Google Patents
Fasudil在制备治疗COVID-19引起的细胞因子风暴的药物组合物中的应用 Download PDFInfo
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Abstract
本发明公开了Fasudil在制备治疗COVID‑19引起的细胞因子风暴的药物组合物中的应用。本发明的Fasudil能够在体内对SARS‑CoV‑2感染具有保护作用及抗炎作用。
Description
技术领域
本发明属于冠状病毒治疗药物技术领域，具体涉及Fasudil在制备治疗COVID-19引起的细胞因子风暴的药物组合物中的应用。
背景技术
人类冠状病毒是一类带有囊膜的正义RNA病毒，可引起人类高致病性疾病，临床症状表现为从轻微的普通感冒到急性呼吸窘迫综合症和死亡。过去二十年爆发的三种高致病性人类冠状病毒：严重急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS)和SARS-CoV-2，展现了人类冠状病毒的大流行潜力。SARS-CoV-2可以引起上、下呼吸道感染，常伴有发热、咳嗽和嗅觉和味觉丧失，而部分患者出现了更严重的症状，包括全身性炎症、组织损伤、急性呼吸窘迫综合征、血栓栓塞并发症、心脏损伤和/或细胞因子风暴，甚至导致死亡。
其中，细胞因子风暴是在SARS-CoV-感染患者中观察到的关键病理特征之一，在严重的人类冠状病毒(CoV)(如SARS和MERS)感染中很常见。COVID-19危重患者中存在高水平的细胞因子。其中TNFα、IL6和IL1β主要由先天免疫细胞释放，可能是 SARS-CoV-2感染晚期患者中细胞因子释放综合征和严重全身炎症反应的主要驱动因素之一。而CCL2/3/5、CXCL8/9/10、IFN-γ、TNFα、IL1β、IL1RA、IL6、IL7、IL8、IL12、 IL33、粒细胞/粒细胞-巨噬细胞集落刺激因子(G-CSF和GM-CSF)、血管内皮生长因子A (VEGFA)和血小板衍生生长因子亚基B(PDGFB)等趋化因子和细胞因子的升高，进一步导致严重的急性呼吸窘迫综合征(ARDS)和组织损伤。细胞因子风暴主要由巨噬细胞、中性粒细胞、树突状细胞、NK细胞、B细胞和T细胞为主的多种免疫细胞的过度激活产生。虽然树突状细胞和巨噬细胞通过抗原递呈激活的SARS-CoV-2特异性T细胞可以在早期介导抗病毒应答，但SARS-CoV-2的免疫逃逸能力可能使T细胞难以产生有效的抗病毒应答，重要的是，T细胞介导的炎症和固有免疫细胞的持续激活可能是导致肺部病理和严重病例中出现的继发性并发症的因素。同时研究发现T细胞或B细胞激活很少的患者病情较轻，而CD4+T细胞和CD8+T细胞过度激活的患者病情更严重，也表明T细胞在介导COVID-19患者炎症反应的作用。这些证据表明COVID-19可能是一个免疫相关疾病，成为首个有强有力证据支持使用免疫疗法的严重急性传染病，因此通过免疫调控的治疗方法将对减轻炎症反应、改善患者的生存、降低死亡率有重要作用。
面对新冠病毒的全球大流行形势，科学家们一直在寻求开发预防、治疗SARS-CoV-2 感染的疫苗和有效药物，但目前还没有具体有效的治疗方法。除了疫苗研发外，主要的治疗药物包括抗病毒药物及免疫调节药物。抗病毒药物针对的是病毒感染进入细胞过程中的介导物，包括受体结合域(RBD)/血管紧张素转换酶2(ACE2)、跨膜蛋白酶丝氨酸2(TMPRSS2)、3C样蛋白酶(Mpro)、RNA依赖的RNA聚合酶(RdRp)等，通常在疾病早期使用。免疫调节药物通常在疾病晚期使用，用于平衡免疫反应，缓解炎症反应、细胞因子风暴及继发的组织损伤和急性呼吸窘迫综合征等症状。旨在减轻疾病严重程度的治疗方法的研发也是全球最重要的优先事项。目前使用的免疫调节药物主要包括三类。第一类是以地塞米松为主的皮质类固醇，多项研究表明地塞米松能够降低患者死亡率，特别是对治疗期间病情加重的患者具有显著有益效果。但值得注意的是，皮质类固醇类药物由于广泛的、非特异的免疫抑制作用，可能在治疗早期对患者产生有害作用。第二类是激酶抑制剂，比如JAK抑制剂巴瑞替尼(baricitinib)。研究表明baracitinib治疗组患者相较于安慰剂组恢复时间更短，并且baracitinib治疗能够降低患者死亡率，在需要高流量氧气或无创通气的亚组中效果更为明显。FDA最近批准baracitinib用于紧急治疗COVID-19。另外，一种胞质多酪氨酸激酶抑制剂伊马替尼(imatinib)也在荷兰一项针对400名COVID-19 住院患者的临床试验中发现具有较好的效果，但是这些发现需要后续试验来验证，并判断哪些患者可能受益于伊马替尼治疗。在研的其他激酶抑制剂包括Bruton’s酪氨酸激酶抑制剂(如ibrutinib、acalabrutinib、zanubrutinib)、磷脂酰肌醇-3激酶(PI3K)/雷帕霉素(mTOR) 抑制剂(如duvelisib、temsirolimus)，以及JAK抑制剂(如ruxolitinib、tofacitinib)。除了部分酪氨酸激酶抑制剂展现出的有益效果外，前期研究已表明酪氨酸激酶的多效性(可以阻断细胞因子信号通路和许多免疫效应因子通路)，以及大部分酪氨酸激酶抑制剂众所周知的临床安全性，说明酪氨酸激酶抑制剂是一个很有潜力的COVID-19治疗方法。第三类是靶向细胞因子的药物，这类药物目前以抗IL1和IL6为主。IL1和IL6均可引起局部效应，如巨噬细胞激活、内皮渗漏和液体外渗，以及全身效应。但是有两项研究发现，IL1 抑制剂anakinra的治疗并未产生显著的效果。而随后的进一步研究发现，anakinra对血浆高可溶性尿激酶纤溶酶原受体(suPAR)的患者有效，因此anakinra的应用需在suPAR含量指导下进行。另外，IL1β阻断剂canakinumab在试验中也没有产生明显效果。相比之下，IL6的阻断疗法似乎更有效。其中托珠单抗(tocilizumab)和salilumab在临床试验中都表现出降低死亡率、改善患者生存的作用。除IL1-IL6轴的促炎细胞因子外，其他促炎细胞因子也参与了COVID-19介导的炎症。临床试验表明抗GM-CSF抗体otilimab对70 岁以上老人有显著效果，但需要注意的是这种年龄依赖性提示其对年轻病人可能产生副反应。另外抗TNF疗法目前也在进行临床试验(NCT04705844)。针对COVID-19的细胞因子靶向治疗策略似乎是一种有吸引力的方法，但考虑到COVID-19介导的炎症反应具有复杂性，而细胞因子特异性靶向治疗效果较为单一，因此可能需要精确检测生物标志物的随机对照试验来帮助进一步确定哪些患者可能受益最多。除了以上三类免疫调节药物外，其他的免疫调控策略还包括抗补体疗法(如抗C5a抗体vilobelimab)、刺激抗病毒防御的干扰素(如IFNβ、IFNγ)等。
COVID-19的抗炎治疗方法虽然已有很大程度的发展，但是目前面临的一个主要困境是，尽管使用了地塞米松和IL6阻断抗体等免疫治疗药物，但一些COVID-19患者的治疗没有改善，仍然存在严重的炎性反应，同时也没有足够的随机对照试验来指导用药。另外宿主-病原体反应和由此产生的免疫环境是异质性的、动态的，这也表明并非每个患者都能从相同的免疫调节治疗策略中受益。因此有必要增加潜在的治疗选择，以应对患者未能产生反应的情况以及进一步缓解严重病例的症状。另外需要注意的是，目前使用的一些抗体疗法或联合疗法面临着价格昂贵的问题，难以保证所有患者获得平等的治疗机会。因此除了增加替代疗法和改善效果外，发现更便宜的替代药物，才能更好的完善COVID-19 的治疗策略。
发明内容
本发明目的在于克服现有技术缺陷，提供Fasudil在制备治疗COVID-19引起的细胞因子风暴的药物组合物中的应用。
本发明的另一目的在于提供Fasudil作为COVID-19诱发产生的炎症因子的广谱抑制剂的应用。
本发明的技术方案如下：
Fasudil在制备治疗COVID-19引起的细胞因子风暴的药物组合物中的应用。
在本发明的一个优选实施方案中，所述细胞因子风暴中的炎症因子至少含有CCL3、 CCI4、CCL5、CKC12、IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、 GM-CSF、IFNβ、IFNγ、TNFα、TNFβ、CXCL12、LTA、IL22和IL21。
进一步优选的，所述细胞因子风暴中的炎症因子由CCL3、CCL4、CCL5、CKC12、 IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNββ、IFNγ、TNFα、 TNFβ、CXCL12、LTA、IL22和IL21组成。
Fasudil作为COVID-19诱发产生的炎症因子的广谱抑制剂的应用。
在本发明的一个优选实施方案中，所述炎症因子至少包括CCL3、CCL4、CCL5、CKC12、IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNβ、 IFNγ、TNFa、TNFβ、CXCL12、LTA、IL22和IL21。
进一步优选的，所述炎症因子由CCL3、CCL4、CCL5、CKC12、IL1β、IL2、IL4、 IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNβ、IFNγ、TNFα、TNFβ、CXCL12、 LTA、IL22和IL21组成。
附图说明
图1为本发明实施例1中S-293T、SARS-CoV-2S CAR-T、THP-1共培养下，分别加入4中筛选药物(#1 Felodipine、#2 Fasudil、#3 Imatinib、#4 Caspofungi)后，所检测的细胞上清中34种细胞因子、趋化因子的分泌量的热图。
图2为本发明实施例2中使用黄金地鼠进行SARS-CoV-2病毒攻毒及药物治疗以评价 Felodipine、Imatinib、Caspofungi、Fasudil体内作用的实验策略图。
图3为本发明实施例2中对照组及Felodipine、Imatinib、Caspofungi、Fasudil治疗组的黄金地鼠的体重变化曲线图及各时间点下的显著性分析表。
图4为本发明实施例2中对照组及Felodipine、Imatinib、Caspofungi、Fasudil治疗组的黄金地鼠的生存曲线图。
图5为本发明实施例2中对照组及Felodipine、Imatinib、Caspofungi、Fasudil治疗组的黄金地鼠在终点(第7天)的肺组织照片。
图6为本发明实施例2中对照组及Felodipine、Imatinib、Caspofungi、Fasudil治疗组的黄金地鼠的肺组织切片的HE染色结果图(以未攻毒黄金地鼠的肺组织作为阴性对照)。
图7为本发明实施例2中对照组及Felodipine、Imatinib、Caspofungi、Fasudil治疗组的黄金地鼠的肺组织切片的HE染色病理评分柱状图(以未攻毒黄金地鼠的肺组织作为阴性对照)。
图8为本发明实施例2中通过RT-qPCR检测的对照组及Felodipine、Imatinib、Caspofungi、Fasudil治疗组的黄金地鼠肺组织中炎症因子基因的表达热图(以未攻毒黄金地鼠的肺组织作为阴性对照，且黄金地鼠中的CXCL15对应IL8)。
图9为本发明实施例2中通过ELISA检测的对照组及Felodipine、Imatinib、Caspofungi、 Fasudil治疗组的黄金地鼠肺组织中代表性炎症因子的表达图(以未攻毒黄金地鼠的肺组织作为阴性对照)。
图10为本发明实施例2中Fasudil和Rho kinase inhibitor Fasudil类似药物同时进行筛选的实验结果图。
具体实施方式
以下通过具体实施方式结合附图对本发明的技术方案进行进一步的说明和描述。
实施例1
本实施例评价了筛选的4种药物(Felodipine、Imatinib、Caspofungi、Fasudil)在细胞因子风暴模型中的抗炎作用。
将新冠毒株S基因克隆到pCAG-eGFP载体中，构建S基因表达载体pCAG-S-eGFP。转染前24h，将293T以1×106每孔铺于六孔板中。转染时将5μL转染试剂LipofectamineTM 3000(Thermo Fisher公司生产)加入125μL基础培养基RMPI 1640中进行稀释；另外将 2.5μgpCAG-S-eGFP质粒及5μL P3000TM试剂(Thermo Fisher公司生产)加入125μL基础培养基RPMI1640中进行稀释，随后将稀释的质粒/P3000TM试剂加入稀释的 LipofectamineTM 3000试剂中混合，室温孵育10-15min后加入293T细胞中。转染24h后，将细胞消化并进行后续实验。
将以上制备的S-293T细胞以2×104接种于96孔板中，37℃、5％CO2培养箱中培养贴壁后，以10∶1的效靶比加入SARS-CoV-2S CAR-T(所用CAR结构为Fc-SARS-CoV-2 CAR，其氨基酸序列如SEQ ID NO.01所示，核苷酸序列如SEQ ID NO.02所示)细胞，并以相对于S-293T细胞10∶1的比例加入THP-1细胞，同时分布加入Felodipine、Imatinib、 Caspofungi、Fasudil使其工作浓度为10μM，共培养72h后；收集细胞上清，使用ProcartaPlex HuCytokine/Chemokine Panel(Invitrogen公司生产)对34种细胞因子、趋化因子的分泌量进行检测。
结果如图1所示，本实施例中筛选的药物Felodipine、Imatinib、Caspofungi和Fasudil 除了抑制IL8和IFNγ的分泌外，对其他细胞因子也产了广谱的抑制作用。
实施例2
本实施例验证了Felodipine、Imatinib、Caspofungi和Fasudil在体内对SARS-CoV-2 感染及引起的炎症反应的作用。
使用8-14周龄的黄金地鼠，用异氟醚麻醉后，鼻注射100μL PBS稀释的1×104pFU剂量的SARS-CoV-2病毒；将黄金地鼠以每组6只分为对照组(untreated)、Felodipine组、Imatinib组、Fasudil组、Caspofungin组5组；分别在第1、2、3、4天分别用15mg/kg 剂量的药物进行治疗，其中Felodipine、Fasudil和Caspofungin使用腹腔给药，Imatinib 通过灌胃给药；观察至对照组黄金地鼠死亡(第7天)，每天通过电子天平测定黄金地鼠的体重(实验策略如图2所示)。第7天处死治疗组黄金地鼠，获得肺组织观察肺部病变情况并拍照，随后通过甲醇固定、脱水、石蜡包埋、切片获得肺组织切片，用于HE染色检测病理情况，根据各肺叶上肺泡间隔增厚及实变、出血、渗出、肺水肿及粘液、炎症细胞的趋化和浸润的情况进行全面病理评分；另外肺组织用Eastep Super Total RNA Extraction Kit(Promega公司生产)提取总RNA，随后通过RT-qPCR检测细胞因子基因。
结果如图3至9所示。图3和图4显示，黄金地鼠在感染后1至6天平均体重持续下降，最终下降超过20％，并且7天内全部死亡；而Felodipine、Imatinib、Fasudil和Caspofungin的治疗下体重下降明显减轻，在第7天，平均体重下降分别为5.2％、2.5％、2.1％和11％，并且4个治疗组的黄金地鼠全部存活。图5显示了第7天各组的肺组织照片，对照组黄金地鼠观察到了严重的肺部病变(包括实变、多灶性和弥漫性充血)，而Felodipine、Imatinib、Fasudil治疗后，没有观察到严重的肺部病变情况，Caspofungin的治疗也对肺部病变有所改善。相对应地，图6和图7显示了肺组织HE染色结果和全面病理评分，也证明Felodipine、Imatinib、Fasudil显著减轻肺部病变，Caspofungin效果稍差。图8的RT-qPCR及图9的ELISA结果显示，Felodipine、Imatinib、Fasudil和Caspofungin治疗组肺组织中检测的炎症因子基因表达相较于对照组显著下调。
本实施例表明Felodipine、Imatinib、Fasudil和Caspofungin在体内对SARS-CoV-2感染具有保护作用及抗炎作用。
进一步的，将Fasudil和Rho kinase inhibitor Fasudil类似药物同时进行筛选，第一轮 IL8 Fasudil和Minoxidil表现较好，但在IFNγ筛选中只有Fasudil具有较强的抑制能力，其它类似药物均被淘汰，结果如图10所示。
本领域普通技术人员可知，法舒地尔(Fasudil)是一种非特异性RhoA/ROCK抑制剂，同时也是一种有效的钙离子通道拮抗剂和血管扩张剂。FDA已批准Fasudil用于雷诺氏病、动脉粥样硬化和肌萎缩性侧索硬化症(ALS)等疾病的临床试验。研究发现，Fasudil具有抑制高胆固醇血症大鼠炎症反应的作用，包括抑制胸主动脉ROCK和NF-kB的激活以及降低血清中IL6、IL8、sICAM-1的水平。Xie等人报道了Fasudil通过调节STAT6和 NF-κB降低过敏性气道炎症和粘液高分泌的作用，该研究中Fasudil不仅可以显著减少炎症细胞数量，还能下调OVA刺激小鼠肺组织中的IL17、IL4和IL13水平。另外一项研究表明Fasudil通过PI3K/Akt和Wnt/β-catenin依赖通路对帕金森病小鼠模型的炎症具有神经保护作用，该研究中Fasudil治疗后IL1β、TNFα、TLR2、p-NF-κB和iNOS的表达降低。Wang等人还报道了，Fasudil能通过恢复肺水通道蛋白5的表达和抑制肺部炎症来减轻脂多糖诱导的肺损伤，该研究同样发现了Fasudil在抑制NF-κB激活、IL6分泌及淋巴细胞浸润的作用。对于Fasudil抗炎作用的研究，只检测个别炎症因子的分泌情况，并不能说明Fasudil的对炎症因子存在广谱抑制作用以支持其在COVID-19中的有效应用。以钙通道拮抗剂Amlodipine为例：在一项研究中发现Amlodipine具有抗关节炎的作用，其对炎症因子的调控表现为降低TNFα、IL6、IL1β的基因表达，但反而使其他细胞因子IL4 和IL10的基因表达增加；另外的研究中Amlodipine可以在自发性高血压大鼠模型中调控 LPS诱导的炎症因子，包括降低TNFα的水平、升高IL6水平，但不影响IL1的水平；说明某一药物对部分细胞因子的抑制作用并不一定能适用于其他细胞因子，并且在不同的疾病下可能存在区别，
SEQ ID NO.01：
MDFQVQIFSFLLISASVIMSRQVQLKESGPGLVAPSQSLSITCTVSGFSLPGYGVNWVRQ PPGKGLEWLGMIWGDGSTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTARYYCAL YGSSYSFAYWGQGTLVTVSAGGGGSGGGGSGGGGSENVLTQSPAIMAASLGQKVTMT CSASSSVSSSYLHWYQQKSGASPKPLIHRTSNLASGVPARFSGSGSGTSYSLTISSVEAED DATYYCQQWSGYPFTFGSGTKLEIKEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKFWVLVVVGGVLACYSLLVTVAFIIFWVRSKRSRLLH SDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSTSLRVKFSRSADAPAYQQGQNQLYNE LNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKG ERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
SEQ ID NO.02：
atggattttcaggtgcagattttcagcttcctgctaatcagtgcctcagtcataatgtctagacaggtgcagctgaaggagtcaggacctggc ctggtggcgccctcacagagcctgtccatcacatgcaccgtctcagggttctcattacccggctatggtgtaaactgggttcgccagcctcc aggaaagggtctggagtggctgggaatgatatggggtgatggaagcacagactataattcagctctcaaatccagactgagcatcagca aggacaactccaagagccaagttttcttaaaaatgaacagtctgcaaactgatgacacagccaggtactactgtgccctctacggtagtag ctactcgtttgcttactggggccaagggactctggtcactgtctctgcaggaggtggcggatctggagggggtggtagcggtggaggcg ggagtgaaaatgtgctcacccagtctccagcaataatggctgcctctctggggcagaaggtcaccatgacctgcagtgccagctcaagtg taagttccagttacttgcactggtaccagcagaagtcaggcgcttcccccaaacccttaattcataggacatccaacctggcttctggagtcc cagctcgcttcagtggcagtgggtctgggacctcttactctctcacaatcagcagcgtggaggctgaagatgatgcaacttattactgccag cagtggagtggttacccattcacgttcggctcggggacaaagttggaaataaaagagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatg ccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatg gcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag aaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatccc agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcac aaccactacacacagaagagcctctccctgtctccgggtaaattttgggtgctggtggtggttggtggagtcctggcttgctatagcttgcta gtaacagtggcctttattattttctgggtgaggagtaagaggagcaggctcctgcacagtgactacatgaacatgactccccgccgccccg ggcccacccgcaagcattaccagccctatgccccaccacgcgacttcgcagcctatcgctccactagtctgagagtgaagttcagcagg agcgcagacgcccccgcgtaccagcagggccagaaccagctctataacgagctcaatctaggacgaagagaggagtacgatgttttggacaagagacgtggccgggaccctgagatggggggaaagccgcagagaaggaagaaccctcaggaaggcctgtacaatgaactgca gaaagataagatggcggaggcctacagtgagattgggatgaaaggcgagcgccggaggggcaaggggcacgatggcctttaccagg gtctcagtacagccaccaaggacacctacgacgcccttcacatgcaggccctgccccctcgctaa
以上所述，仅为本发明的较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。
Claims (6)
1.Fasudil在制备治疗COVID-19引起的细胞因子风暴的药物组合物中的应用。
2.如权利要求1所述的应用，其特征在于：所述细胞因子风暴中的炎症因子至少含有CCL3、CCL4、CCL5、CKC12、IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNβ、IFNγ、TNFα、TNFβ、CXCL12、LTA、IL22和IL21。
3.如权利要求2所述的应用，其特征在于：所述细胞因子风暴中的炎症因子由CCL3、CCL4、CCL5、CKC12、IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNβ、IFNγ、TNFα、TNFβ、CXCL12、LTA、IL22和IL21组成。
4.Fasudil作为COVID-19诱发产生的炎症因子的广谱抑制剂的应用。
5.如权利要求4所述的应用，其特征在于：所述炎症因子至少包括CCL3、CCL4、CCL5、CKC12、IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNβ、IFNγ、TNFα、TNFβ、CXCL12、LTA、IL22和IL21。
6.如权利要求5所述的应用，其特征在于：所述炎症因子由CCL3、CCL4、CCL5、CKC12、IL1β、IL2、IL4、IL5、IL6、IL8、IP10、IL10、IL13、IL18、GM-CSF、IFNβ、IFNγ、TNFα、TNFβ、CXCL12、LTA、IL22和IL21组成。
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Citations (2)
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| US20110190273A1 (en) * | 2008-06-02 | 2011-08-04 | Universiteit Gent | Methods and compositions in the treatment of coronaviruses |
| US20210386821A1 (en) * | 2020-06-10 | 2021-12-16 | Kelsius Laboratories LLC | Therapeutic composition for use in the treatment of covid-19 and other cytokine storm associated disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20110190273A1 (en) * | 2008-06-02 | 2011-08-04 | Universiteit Gent | Methods and compositions in the treatment of coronaviruses |
| US20210386821A1 (en) * | 2020-06-10 | 2021-12-16 | Kelsius Laboratories LLC | Therapeutic composition for use in the treatment of covid-19 and other cytokine storm associated disorders |
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| Title |
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| "法舒地尔对急性柯萨奇B3病毒性心肌炎小鼠的保护作用", 心电与循环, vol. 37, no. 6, pages 375 - 380 * |
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