CN111658779A - 治疗新型冠状病毒肺炎的联合用药物 - Google Patents
治疗新型冠状病毒肺炎的联合用药物 Download PDFInfo
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Abstract
本发明公开了全新的治疗新型冠状病毒肺炎的联合用药物，属于抗病毒药物领域。本发明的联合用药物是含有同时或分别给药的rSIFN‑co与基线治疗药物的联合用药物；所述基线治疗药物是：1)洛匹那韦利托那韦；或2)阿比多尔。本发明的联合用药物可有效改善中度至重度COVID‑19患者的病情，临床应用前景非常优良。将rSIFN‑co用于制备治疗COVID‑19的药物，具有极其重要的意义。
Description
技术领域
本发明属于抗病毒药物领域。
背景技术
新型冠状病毒肺炎(coronavirus disease 2019，COVID-19)是由严重急性呼吸道综合症冠状病毒(severe acute respiratory syndrome coronavirus 2， SARS-CoV-2)感染引起的肺炎。SARS-CoV-2是一种新型病毒，属于冠状病毒家族，是继SARS-CoV和中东呼吸综合症(MERS)-CoV后，第七种被认识的可感染人类、第三种可引起严重临床综合征的冠状病毒病原体。
研究人员已经尝试了非常多的抗病毒药物，包括某些被开发用于治疗 SARS和MERS的药物，但是效果均不佳，比如，通过评估利巴韦林、喷昔 洛韦、硝唑胺、萘莫司他、氯喹、瑞德西韦、法维吡韦和洛匹那韦对 SARS-CoV-2的体外抑制作用发现，氯喹、瑞德西韦、洛匹那韦、利托那 韦、阿比多尔等在体外对SARS-CoV-2具有很好的控制作用，但是临床实验显示他们的效果并不佳，几乎没有治疗作用，反而容易产生较严重的胃肠 道反应、肾脏功能受损等副作用，不宜长期使用。目前仍未见疗效优良的药 物的相关报道。
干扰素(IFN)是机体感染病毒时，宿主通过抗病毒反应产生的结构类 似、功能相近的低分子糖蛋白。干扰素分为3个主要类型：Ⅰ型干扰素、Ⅱ型干 扰素和III型干扰素。其中I型干扰素(又可以分为α和β两类)可用于临床抗病毒。研究表明，α-干扰素(IFN-α)可联合利巴韦林、奥司他韦、洛匹那韦利 托那韦等抗病毒药物或糖皮质激素治疗SARS、MERS。
新型重组高效复合干扰素(rSIFN-co)是通过改变IFN-α的60个氨基酸遗传密码子的65个碱基而不改变其氨基酸组成产生的一种新型非天然基因工程干扰素，由166个氨基酸组成，分子量为19436.7Da。在本世纪初曾用于抗击 SARS，具有较好的疗效。
发明内容
本发明要解决的问题是：提供治疗新型冠状病毒肺炎的联合用药物。
本发明的技术方案如下：
一种治疗新型冠状病毒肺炎的联合用药物，它是含有同时或分别给药的rSIFN-co与基线治疗药物的联合用药物；
所述基线治疗药物是：
1)洛匹那韦利托那韦；或
2)阿比多尔。
如前述的联合用药物，每单位制剂中rSIFN-co的含量为500万～2400万 IU，每日份制剂中rSIFN-co的含量为1000万～4800万IU。
如前述的联合用药物，每单位制剂中rSIFN-co的含量为1000万～1400 万IU，每日份制剂中rSIFN-co的含量为2000万～2800万IU。
如前述的联合用药物，每单位制剂中rSIFN-co的含量为1200万IU，每日份制剂中rSIFN-co的含量为2400万IU。
进一步的，联合用药物中，rSIFN-co为雾化治疗制剂、肌肉注射制剂或皮下注射制剂。
如前述的联合用药物，单日份制剂中洛匹那韦利托那韦的含量分别为 800mg和200mg。
如前述的联合用药物，单日份制剂中阿比多尔的含量为600mg。
rSIFN-co与基线治疗药物在制备治疗新型冠状病毒肺炎或中东呼吸综合征的联合用药物中的用途，所述基线治疗药物是：
1)洛匹那韦利托那韦；或
2)阿比多尔。
如前述的用途，所述联合用药物中，每单位制剂中rSIFN-co的含量为 500万～2400万IU，每日份制剂中rSIFN-co的含量为1000万～4800万IU；
优选的，每单位制剂中rSIFN-co的含量为1000万～1400万IU，每日份制剂中rSIFN-co的含量为2000万～2800万IU；
进一步优选的，每单位制剂中rSIFN-co的含量为1200万IU，每日份制剂中rSIFN-co的含量为2400万IU。
进一步的，联合用药物中，rSIFN-co为雾化治疗制剂、肌肉注射制剂或皮下注射制剂。
如前述的用途，所述联合用药物中，单日份制剂中洛匹那韦利托那韦的含量分别为800mg和200mg。
如前述的用途，所述联合用药物中，单日份制剂中阿比多尔的含量为 600mg。
本发明的有益效果：
已有研究证明单用洛匹那韦利托那韦或阿比多尔无法有效治疗新型冠状病毒肺炎。本发明将rSIFN-co与洛匹那韦利托那韦联用，或与阿比多尔联用，对新型冠状病毒肺炎有显著的疗效，其效果明显优于IFN-α与洛匹那韦利托那韦联用，或与阿比多尔联用。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例1：rSIFN-co治疗COVID-19的2期临床试验
2020年2月10日-2020年4月5日，发明人进行了一项多中心、随机、对照、单盲、2期临床试验。
试验中使用的rSIFN-co来自四川辉阳生命工程股份有限公司，IFN-α来自天津华立达生物工程有限公司。
编码rSIFN-co的核苷酸序列(SEQ ID NO.1)如下：
rSIFN-co的氨基酸序列(SEQ ID NO.2)如下：
MCDLPQTHSLGNRRALILLAQMRRISPFSCLKDRHDFGFPQEEFDGNQFQKAQAISV LHEMIQQTFNLFSTKDSSAAWDESLLEKFYTELYQQLNDLEACVIQEVGVEETPLMN VDSILAVKKYFQRITLYLTEKKYSPCAWEVVRAEIMRSFSLSTNLQERLRRKE
方法：
招募普通型或重型新冠肺炎患者共102人，并将安全分析集94名受试者随 机分为rSIFN-co组(46人)和IFN-α组(48人)。受试者在接受基线治疗的同 时，接受rSIFN-co(1200万IU)或IFN-α(500万IU)雾化吸入治疗，每天两次。 (既往研究表明，大剂量使用rSIFN-co是安全的，每一剂量可以是＞1000万IU； 但IFN-α容易产生副作用，不能大剂量使用)。主要研究终点是28天疾病缓解， 包括临床缓解时间、影像学炎症吸收时间、病毒核酸转阴时间以及临床缓解 率。
前述基线治疗指：洛匹那韦利托那韦(商品名：克力芝)或阿比多尔治疗。洛匹那韦利托那韦每次2粒口服，每粒含洛匹那韦、利托那韦分别为200mg 和50mg，每日两次，疗程不超过10天；阿比多尔一次200mg口服，一日三次。疗程不超过10天。两组接受基线抗病毒治疗洛匹那韦利托那韦和阿比多尔人数分别为：rSIFN-co组22人和24人，IFN-α组20人和28人，p＝0.548，差异无统计学意义，两组患者接受基线抗病毒药物构成比一致。
所述影像学炎症吸收的标准为：由两位独立的放射科医师根据与基线胸部CT相比，患者肺部磨玻璃影和实变区域的变化进行分级，判断炎症是否吸收。
所述病毒核酸转阴的标准为：连续两次鼻咽拭子、痰或下呼吸道分泌物实时荧光定量PCR检测SARS-CoV-2核酸阴性，两次检测采样间隔时间大于24 小时。
结果：
总体上，rSIFN-co组比IFN-α组的临床缓解时间更短(中位11.5天vs 14.0天,p＝0.019)，炎症吸收更快(中位8.0天vs 10.0天；p＝0.002)，病毒核酸转阴时间更短(中位7.0天vs 10.0天；p＝0.018)。第28天rSIFN-co组临床缓解率显著高于IFN-α组(93.5％vs77.1％)。两组药物不良反应总体较轻， rSIFN-co组无严重不良反应，IFN-α组有1例严重不良反应(呼吸衰竭)。
结论：
与添加IFN-α相比，在基线治疗中添加rSIFN-co明显改善了中度至重度COVID-19患者的病情。已有临床随机对照试验或大样本回顾性分析结果显示，单用洛匹那韦利托那韦或阿比多尔治疗COVID-19无效，因此，本发明的抗病毒作用主要来自干扰素和基线药物的协同作用。
总之，rSIFN-co可与洛匹那韦利托那韦或阿比多尔用于制备治疗新型冠状病毒肺炎的联合用药物，临床效果良好。
SEQUENCE LISTING
<110> 四川大学华西医院
<120> 治疗新型冠状病毒肺炎的联合用药物
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<212> DNA
<213> 人工序列(Artificial sequence)
<400> 1
atgtgtgatt tacctcaaac tcattctctt ggtaaccgtc gcgctctgat tctgctggca 60
cagatgcgtc gtatttcccc gtttagctgc ctgaaagacc gtcacgactt cggctttccg 120
caagaagagt tcgatggcaa ccaattccag aaagctcagg caatctctgt actgcacgaa 180
atgatccaac agaccttcaa cctgttttcc actaaagaca gctctgctgc ttgggacgaa 240
agcttgctgg agaagttcta cactgaactg tatcagcagc tgaacgacct ggaagcatgc 300
gtaatccagg aagttggtgt agaagagact ccgctgatga acgtcgactc tattctggca 360
gttaaaaagt acttccagcg tatcactctg tacctgaccg aaaagaaata ttctccgtgc 420
gcttgggaag tagttcgcgc tgaaattatg cgttctttct ctctgtctac taacctgcag 480
gagcgtctgc gccgtaaaga ataatag 507
<210> 2
<211> 167
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 2
Met Cys Asp Leu Pro Gln Thr His Ser Leu Gly Asn Arg Arg Ala Leu
1 5 10 15
Ile Leu Leu Ala Gln Met Arg Arg Ile Ser Pro Phe Ser Cys Leu Lys
20 25 30
Asp Arg His Asp Phe Gly Phe Pro Gln Glu Glu Phe Asp Gly Asn Gln
35 40 45
Phe Gln Lys Ala Gln Ala Ile Ser Val Leu His Glu Met Ile Gln Gln
50 55 60
Thr Phe Asn Leu Phe Ser Thr Lys Asp Ser Ser Ala Ala Trp Asp Glu
65 70 75 80
Ser Leu Leu Glu Lys Phe Tyr Thr Glu Leu Tyr Gln Gln Leu Asn Asp
85 90 95
Leu Glu Ala Cys Val Ile Gln Glu Val Gly Val Glu Glu Thr Pro Leu
100 105 110
Met Asn Val Asp Ser Ile Leu Ala Val Lys Lys Tyr Phe Gln Arg Ile
115 120 125
Thr Leu Tyr Leu Thr Glu Lys Lys Tyr Ser Pro Cys Ala Trp Glu Val
130 135 140
Val Arg Ala Glu Ile Met Arg Ser Phe Ser Leu Ser Thr Asn Leu Gln
145 150 155 160
Glu Arg Leu Arg Arg Lys Glu
165
Claims (10)
1.一种治疗新型冠状病毒肺炎的联合用药物，其特征在于：它是含有同时或分别给药的rSIFN-co与基线治疗药物的联合用药物；
所述基线治疗药物是：
1)洛匹那韦利托那韦；或
2)阿比多尔。
2.如权利要求1所述的联合用药物，其特征在于：每单位制剂中rSIFN-co的含量为500万～2400万IU，每日份制剂中rSIFN-co的含量为1000万～4800万IU；
优选的，每单位制剂中rSIFN-co的含量为1000万～1400万IU，每日份制剂中rSIFN-co的含量为2000万～2800万IU；
进一步的优选的，每单位制剂中rSIFN-co的含量为1200万IU，每日份制剂中rSIFN-co的含量为2400万IU。
3.如权利要求1所述的联合用药物，其特征在于：联合用药中，rSIFN-co为雾化治疗制剂、肌肉注射制剂或皮下注射制剂。
4.如权利要求1～3任一所述的联合用药物，其特征在于：单日份制剂中洛匹那韦、利托那韦的含量分别为800mg和200mg。
5.如权利要求1～3任一所述的联合用药物，其特征在于：单日份制剂中阿比多尔的含量为600mg。
6.rSIFN-co与基线治疗药物在制备治疗新型冠状病毒肺炎或中东呼吸综合征的联合用药物中的用途，其特征在于：所述基线治疗药物是：
1)洛匹那韦利托那韦；或
2)阿比多尔。
7.如权利要求6所述的用途，其特征在于：所述联合用药物中，每单位制剂中rSIFN-co的含量为500万～2400万IU，每日份制剂中rSIFN-co的含量为1000万～4800万IU；
优选的，每单位制剂中rSIFN-co的含量为1000万～1400万IU，每日份制剂中rSIFN-co的含量为2000万～2800万IU；
进一步优选的，每单位制剂中rSIFN-co的含量为1200万IU，每日份制剂中rSIFN-co的含量为2400万IU。
8.如权利要求6所述的用途，其特征在于：联合用药物中，rSIFN-co为雾化治疗制剂、肌肉注射制剂或皮下注射制剂。
9.如权利要求6～8任一所述的用途，其特征在于：所述联合用药物中，单日份制剂中洛匹那韦利托那韦的含量分别为800mg和200mg。
10.如权利要求6～8任一所述的用途，其特征在于：所述联合用药物中，单日份制剂中阿比多尔的含量为600mg。
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| CN202010577357.1A CN111658779A (zh) | 2020-06-22 | 2020-06-22 | 治疗新型冠状病毒肺炎的联合用药物 |
| PCT/CN2021/101213 WO2021259195A1 (zh) | 2020-06-22 | 2021-06-21 | 治疗新型冠状病毒肺炎的联合用药物 |
| US18/012,025 US20230364193A1 (en) | 2020-06-22 | 2021-06-21 | Combined drug for treating coronarivus disease 2019 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113786478A (zh) * | 2021-10-09 | 2021-12-14 | 成都市公共卫生临床医疗中心 | 一种系统化新型冠状病毒肺炎的抗病毒治疗方法 |
| WO2021259195A1 (zh) * | 2020-06-22 | 2021-12-30 | 四川大学华西医院 | 治疗新型冠状病毒肺炎的联合用药物 |
| CN114191436A (zh) * | 2020-09-16 | 2022-03-18 | 中山大学附属第五医院 | 仿生巨噬细胞膜纳米载药颗粒的合成方法及其在新冠病毒肺炎中的应用 |
| WO2022084381A1 (en) * | 2020-10-20 | 2022-04-28 | Primer Design Limited | Kit and method |
| CN114533706A (zh) * | 2022-02-15 | 2022-05-27 | 深圳市利云德生物技术有限公司 | 一种用于防治呼吸道疾病的雾化吸入制剂及其应用 |
| WO2022166885A1 (en) * | 2021-02-04 | 2022-08-11 | Sichuan Huiyang Life Science & Technology Corp. | Recombinant super-compound interferon (rsifn-co) for treating covid-19 patients with or without symptoms |
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| CN101001644B (zh) * | 2003-08-28 | 2011-09-21 | 辉阳科技美国公司 | 空间构象改变的干扰素及其应用 |
| CN111658779A (zh) * | 2020-06-22 | 2020-09-15 | 四川大学华西医院 | 治疗新型冠状病毒肺炎的联合用药物 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021259195A1 (zh) * | 2020-06-22 | 2021-12-30 | 四川大学华西医院 | 治疗新型冠状病毒肺炎的联合用药物 |
| CN114191436A (zh) * | 2020-09-16 | 2022-03-18 | 中山大学附属第五医院 | 仿生巨噬细胞膜纳米载药颗粒的合成方法及其在新冠病毒肺炎中的应用 |
| WO2022084381A1 (en) * | 2020-10-20 | 2022-04-28 | Primer Design Limited | Kit and method |
| WO2022166885A1 (en) * | 2021-02-04 | 2022-08-11 | Sichuan Huiyang Life Science & Technology Corp. | Recombinant super-compound interferon (rsifn-co) for treating covid-19 patients with or without symptoms |
| CN113786478A (zh) * | 2021-10-09 | 2021-12-14 | 成都市公共卫生临床医疗中心 | 一种系统化新型冠状病毒肺炎的抗病毒治疗方法 |
| CN114533706A (zh) * | 2022-02-15 | 2022-05-27 | 深圳市利云德生物技术有限公司 | 一种用于防治呼吸道疾病的雾化吸入制剂及其应用 |
| CN114533706B (zh) * | 2022-02-15 | 2022-10-14 | 深圳市利云德生物技术有限公司 | 一种用于防治呼吸道疾病的雾化吸入制剂及其应用 |
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| US20230364193A1 (en) | 2023-11-16 |
| WO2021259195A1 (zh) | 2021-12-30 |
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