CN114712453A - 一种中药组合物在抗病毒、保护脏器、提高免疫力药物中的应用 - Google Patents
一种中药组合物在抗病毒、保护脏器、提高免疫力药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种中药组合物在抗病毒、保护脏器、提高免疫力药物中的应用,本发明中药组合物主要由麻黄、石膏、连翘、黄芩、桑白皮、苦杏仁、前胡等药味组成,经试验证实本发明药物能明显抑制冠状病毒HCoV‑229E感染小鼠肺指数增加,缓解肺组织病理性变化,抑制感染小鼠肺脏中冠状病毒HCoV‑229E的复制,调节小鼠免疫T淋巴细胞,改善免疫调节功能,具有减轻病毒感染小鼠肺部炎症损伤以及抑制病毒对肺脏的破坏作用,还具有保护病毒感染小鼠心脏的作用。
Description
技术领域
本发明涉及一种中药组合物在制备抗病毒、提高免疫力、保护心脏、肺脏药物中的应用,属于中草药领域。
背景技术
冠状病毒是成人普通感冒的主要病原之一,在儿童可以引起上呼吸道感染,一般很少波及下呼吸道。冠状病毒感染的潜伏期一般为2至5天,平均为3天。典型的冠状病毒感染呈流涕、不适等感冒症状。已知感染人的冠状病毒共有7种,其中四种在人群中较为常见(HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1),另外三种是MERS病毒(中东呼吸综合征病毒MERS-CoV)、SARS病毒(严重急性呼吸综合征病毒SARS-CoV)和2019新型冠状病毒(2019-nCoV)。
新型冠状病毒肺炎(Corona Virus Disease 2019,COVID-19),简称“新冠肺炎”,患者的以发热、乏力、干咳为主要临床表现,鼻塞、流涕等上呼吸道症状少见,会出现缺氧低氧状态,约半数患者多在一周后出现呼吸困难,严重者快速进展为急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒和出凝血功能障碍,值得注意的是,重症、危重症患者病程中可为中低热,甚至无明显发热,部分患者起病症状轻微,可无发热,多在1周后恢复,多数患者预后良好,少数患者病情危重,甚至死亡。
冠状病毒感染后症状因不同种类而异,常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等,在较严重病例中,感染可导致肺炎、严重急性呼吸综合征、肾衰竭,甚至死亡,对于心脏、肺脏有一定的损伤。
HCoV-229E病毒是冠状病毒的一种,1965年,医学专家用人胚气管培养方法,从普通感冒病人鼻涕中分离出一株病毒,命名为B814病毒。随后,研究人员用人胚肾细胞分离到类似病毒,代表株命名为229E病毒。CoV-229E的感染呈全球性分布,人群普遍易感,多项研究表明,几乎全部儿童在幼年早期菌感染过HCoV-229E,该病毒会导致普通的感冒和上呼吸道感染。
本发明药物经试验证实可以明显抑制冠状病毒HCoV-229E感染小鼠肺指数增加,缓解肺组织病理性变化,抑制感染小鼠肺脏中冠状病毒HCoV-229E的复制,调节小鼠免疫T淋巴细胞,改善免疫调节功能,具有减轻病毒感染小鼠肺部炎症损伤以及抑制病毒对肺脏的破坏作用,还具有保护病毒感染小鼠心脏的作用。
本发明是在申请号为2008100894475的专利基础上进行的改进发明,在此全文引用该专利文件记载的内容,上述专利未公开该中药组合物具有抗HCoV-229E病毒、保护心脏、肺脏、提高免疫力的作用。
发明内容
本发明提供一种中药组合物在制备抗HCoV-229E冠状病毒药物中的应用,该中药组合物由下列重量份的原料药制成:
麻黄52-86;石膏194-324;连翘194-324;黄芩78-130;桑白皮194-324;苦杏仁78-130;前胡78-130;半夏78-130;陈皮78-130;贝母78-130;牛蒡子78-130;金银花78-130;大黄39-65;桔梗46-76;甘草39-65。
本发明中药组合物的原料药的重量份比优选为:
麻黄52;石膏324;连翘194;黄芩78;桑白皮194;苦杏仁130;前胡78;半夏130;陈皮78;贝母78;牛蒡子130;金银花130;大黄39;桔梗76;甘草65。
本发明中药组合物的原料药的重量份比还优选为:
麻黄86;石膏194;连翘324;黄芩130;桑白皮324;苦杏仁78;前胡130;半夏78;陈皮130;贝母130;牛蒡子78;金银花78 ;大黄65;桔梗46;甘草39。
本发明中药组合物的原料药的重量份比还优选为:
麻黄69;石膏259;连翘259;黄芩104;桑白皮259;苦杏仁104;前胡104;半夏104;陈皮104;贝母104;牛蒡子104;金银花104;大黄52;桔梗61;甘草52。
本发明中药组合物的原料药的重量份比还优选为:
麻黄55;石膏254;连翘318;黄芩107;桑白皮203;苦杏仁107;前胡82;半夏105;陈皮84;贝母125;牛蒡子122;金银花113;大黄42;桔梗60;甘草50。
本发明中药组合物中,所述苦杏仁为炒苦杏仁、贝母为浙贝母、金银花为山银花、半夏为清半夏。
本发明中药组合物主要由麻黄、石膏、连翘、黄芩、桑白皮等组成,发挥复方中药的整体调节优势,具有多向性、多层面、多靶点的特点,经实验证实对黏蛋白MUC5AC抑制效果显著。
本发明所述中药可以被有相同或相似功效的中药代替,并且这些药材均可以按照《全国中药炮制规范》或《中药大辞典》炮制。
本发明中药组合物的活性成分由以下步骤制成:
A、按组方比例称取浙贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加40-70%乙醇回流提取2次,每次1-4小时,第一次加8-10倍量,第二次加6-9倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.14-1.16的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次1-4小时,第一次加9-11倍量,第二次加7-9倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.14-1.16的清膏,与步骤B所得的清膏合并,备用;
步骤A所得细粉和步骤C所得合并后的清膏共同构成该药物组合物的活性成分。
本发明药物的剂型为胶囊剂、片剂、散剂、颗粒剂、口服液、软胶囊、丸剂、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂或注射剂。
为使上述剂型能够实现,需在制备这些剂型时加入药学可接受的辅料,例如:填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括:淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等;崩解剂包括:淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素钠等;润滑剂包括:硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等;助悬剂包括:聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等;粘合剂包括,淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等;甜味剂包括:糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等;矫味剂包括:甜味剂及各种香精;防腐剂包括:尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等;基质包括:PEG6000,PEG4000,虫蜡等。
其中片剂由如下步骤制成:
A、按组方比例称取浙贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加40-70%乙醇回流提取2次,每次1-4小时,第一次加8-10倍量,第二次加6-9倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.14-1.16的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次1-4小时,第一次加9-11倍量,第二次加7-9倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.14-1.16的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉与步骤A所得细粉,以乙醇为黏合剂制软材,过筛制粒;按药学常规方法压片即得。
优选的片剂的制备方法为:
A、按组方比例称取浙贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加50%乙醇回流提取2次,每次3小时,第一次加10倍量,第二次加6倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.15的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次2小时,第一次加10倍量,第二次加7倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.15的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉与步骤A所得细粉,以乙醇为黏合剂制软材,过筛制粒干燥后整粒,加入羧甲淀粉钠、微晶纤维素、硬脂酸镁,混匀,压片即得。本发明药物其他剂型的制备方法为:按比例称取原料药,采用常规的制备方法制备,例如,范碧亭《中药药剂学》(上海科学出版社1997年12月第1版)记载的制备工艺,制成药剂学可接受的常规剂型。
本发明还提供该中药组合物在保护心脏损伤药物中的应用,优选为病毒引起的心脏损伤,所述病毒优选为冠状病毒,更优选为HCoV-229E冠状病毒。
本发明还提供该中药组合物在保护肺脏损伤药物中的应用,更优选为病毒引起的肺脏损伤,所述病毒优选为冠状病毒,更优选为HCoV-229E冠状病毒。
本发明还提供了该中药组合物在提高人体免疫力药物中的应用。
附图说明:
图1:动物体重的影响试验
图2:肺组织病理学影响(给药后48h)(×100),其中A为正常对照组;B为模型对照组;C为连花清瘟胶囊组;D为本发明药物低剂量组;E为本发明药物中剂量组;F为本发明药物高剂量组
图3 :对肺组织病理学影响(末次给药后次日)(×100),其中A为正常对照组;B为模型对照组;C为连花清瘟胶囊组;E为本发明药物低剂量组;F为本发明药物中剂量组;G为本发明药物高剂量组。
具体实施方式
下述实施例用于举例说明本发明药物的制备,但其不能对本发明的范围构成任何限制。
实施例1
处方:
麻黄52克;石膏324克;连翘194克;黄芩78克;桑白皮194克;苦杏仁130克;前胡78克;半夏130克;陈皮78克;浙贝母78克;牛蒡子130克;山银花130克;大黄39克;桔梗76克;甘草65克。
制备方法:
A、按组方比例称取浙贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加50%乙醇回流提取2次,每次3小时,第一次加10倍量,第二次加6倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.15的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次2小时,第一次加10倍量,第二次加7倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.15的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉,步骤A所得细粉,以80%乙醇为黏合剂制备软材,过筛制粒,60度干燥后,整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀,按常规制剂方法制成片剂,即得。
实施例2
处方:
麻黄86克;石膏194克;连翘324克;黄芩130克;桑白皮324克;炒苦杏仁78克;前胡130克;半夏78克;陈皮130克;贝母130克;牛蒡子78克;山银花78克;大黄65克;桔梗46克;甘草39克。
制备方法:
A、按组方比例称取贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、炒苦杏仁、半夏、牛蒡子、大黄加40%乙醇回流提取2次,每次4小时,第一次加8倍量,第二次加9倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.14的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次4小时,第一次加9倍量,第二次加7倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.16的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉,步骤A所得细粉,以80%乙醇为黏合剂制备软材,过筛制粒,60度干燥后,整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀,按常规制剂方法制成片剂,即得。
实施例3
处方:
麻黄69克;石膏259克;连翘259克;黄芩104克;桑白皮259克;炒苦杏仁104克;前胡104克;清半夏104克;陈皮104克;浙贝母104克;牛蒡子104克;山银花104克;大黄52克;桔梗61克;甘草52克。
制备方法:
A、按组方比例称取浙贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、炒苦杏仁、清半夏、牛蒡子、大黄加70%乙醇回流提取2次,每次1小时,第一次加10倍量,第二次加6倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.16的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次1小时,第一次加11倍量,第二次加7倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.14的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉,步骤A所得细粉,以80%乙醇为黏合剂制备软材,过筛制粒,60度干燥后,整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀,按常规制剂方法制成片剂,即得。
实施例4:
原料药配方为:
麻黄55克;石膏254克;连翘318克;黄芩107克;桑白皮203克;炒苦杏仁107克;前胡82克;半夏105克;陈皮84克;浙贝母125克;牛蒡子122克;山银花113克;大黄42克;桔梗60克;甘草50克。
制备方法:
A、按组方比例称取浙贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、炒苦杏仁、半夏、牛蒡子、大黄加60%乙醇回流提取2次,每次2小时,第一次加9倍量,第二次加7倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.15的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、山银花、桔梗、甘草,加水煎煮两次,每次2.5小时,第一次加10倍量,第二次加7倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.14的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉,步骤A所得细粉,以80%乙醇为黏合剂制备软材,过筛制粒,60度干燥后,整粒。加入羧甲基淀粉钠、微晶纤维素、硬脂酸镁混匀,按常规制剂方法制成片剂,即得。
实施例5:
麻黄62克石膏220克连翘256克黄芩90克桑白皮300克
苦杏仁90克前胡90克半夏90克陈皮100克贝母100克牛蒡子100克金银花100克大黄50克桔梗66克甘草50克
以上药材,按常规方法制成胶囊剂即得。
实施例6:
麻黄68克石膏215克连翘215克黄芩100克桑白皮220克
苦杏仁90克前胡90克半夏90克陈皮90克贝母90克
牛蒡子90克金银花90克大黄50克桔梗50克甘草50克
以上药材,按常规方法制成颗粒剂即得。
实施例7:
麻黄50克石膏200克连翘300克黄芩100克桑白皮250克
苦杏仁100克前胡100克半夏100克陈皮100克贝母100克
牛蒡子100克金银花100克大黄50克桔梗50克甘草50克
以上药材,按常规方法制成注射剂即得。
实施例8:
麻黄60克石膏200克连翘200克黄芩95克桑白皮230克
苦杏仁95克前胡95克半夏95克陈皮95克贝母95克
牛蒡子95克金银花95克大黄50克桔梗50克甘草50克
以上药材,按常规方法制成丸剂即得。
试验例:
为证实本发明中药组合物具有抗病毒、保护脏器、提高免疫力疗效,用按本发明药物组合物实施例3制备方法,压片前的颗粒作为供试品(以下简称本发明药物)。
2. 试验材料
2.1 供试品
本发明药物,批号:A1401001,规格:1.843g生药/片,有效期至2021年03月,石家庄以岭药业股份有限公司提供。
2.2 阳性对照药
连花清瘟胶囊:批号:B2001013,规格:0.35g/粒,有效期至:2022年06月,由石家庄以岭药业股份有限公司生产。
2.3 实验动物
BALB/c小鼠,SPF级,120只,雌雄各半,体重10.0~14.0g,动物质量合格证号:No.1107272011001651,购于湖南斯莱克景达实验动物有限公司,实验动物生产许可证号:SCXK(湘)2019-0004;饲养于湖南省药物安全评价研究中心屏障环境C区病原微生物安全动物实验室(ABSL-Ⅱ),实验室备案编号:长卫计实备字(2019)第B001号,实验动物使用许可证号:SYXK(湘)2015-0016。
2.4 病毒株:冠状病毒HCoV-229E,编号:ATCC-VR-740,由湖南省疾病预防控制中心赠送,在本中心病原微生物实验室(BSL-Ⅱ,实验室备案编号:长卫计实备字(2019)第B001号)培养和扩增。
2.5 细胞株:人肺成纤维细胞(MRC-5),购于武汉普诺赛生命科技有限公司,在湖南省药物安全评价研究中心细胞室内传代培养。
2.6 主要试剂
DMEM培养基(批号:AD22315267,HyClone公司产品);胎牛血清(批号: M009-6,美国Sciencell公司);白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、肿瘤坏死因子(TNF-α)、脑钠肽(BNP)、白细胞介素-2(IL-2)、白细胞介素-12(IL-12)、T细胞免疫调节因子(TCITRG)、干扰素调节因子(IRF)酶联免疫分析试剂盒,以上试剂盒均由江苏酶免实验公司提供;IL-4流式抗体(批号:2031934)、CD4流式抗体(批号:2115770)、INF-γ流式抗体(批号:2161229)、IL-17A流式抗体(批号:1995433)、CD25流式抗体(批号:2018381)、FoxP3流式抗体(批号:2105941),以上抗体均购自赛默飞世尔科技(中国)有限公司。
2.7 主要仪器
BCR-MI02-72-C11-PPSU型小鼠独立通气笼盒系统(厂家:山东新华医疗器械股份有限公司,本中心编号:578)、BSC1300-Ⅱ-B2型生物安全柜(厂家:山东新华医疗器械股份有限公司,本中心编号:588)、CJ-1F型医用净化工作台(厂家:苏州冯氏实验动物设备有限公司,本中心编号:176)BSCIIB2-1101型生物安全柜(厂家:上海瑞仰净化装备有限公司,本中心编号:019)、3111型CO2培养箱(厂家:美国Thermo Fisher公司,本中心编号:147)、DMIL倒置显微镜(厂家:德国Leica公司,本中心编号:027)、YXQ-50A型立式压力灭菌器(厂家:上海博讯医疗生物仪器股份有限公司,本中心编号:584)、TD4型台式低速离心机(厂家:湖南省凯达实业发展有限公司,本中心编号:101)。
3 实验方法
3.1 病毒的扩增
将MRC-5细胞接种于培养瓶中,当细胞密度达到70~80%时去掉部分的培养基,剩余的刚好覆盖好细胞,分别加入适量的HCoV-229E病毒,待病毒吸附于细胞表面后(约3h左右,每隔30min轻轻晃动培养板,使病毒吸附均匀),更换不含FBS的新鲜培养基,置于37℃、5% CO2加湿的恒温培养箱中培养。96h后(细胞未发生病变则延长培养时间)采取反复冻融法,于3000rpm离心10min以除去细胞残渣,收集上清液,用致细胞病变法(CPE法)测定病毒滴度,以50%组织细胞感染量(TCID50)表示。然后用0.22µm的滤器过滤并分装于冻存管中,进行标注后于-80℃中短期保存或液氮中长期保存,备用。感染动物前,用血球凝集法检测病毒血凝效价,调整至合适滴度。
TCID50=Log(CPE低于50%的病毒稀释度)+距离比例×稀释度间距
其中,距离比例=(高于50%百分数-50)/(高于50%的百分数-低于50%的百分数)
3.2 造模、分组与给药
BALB/c小鼠120只,SPF级,雌雄各半,体重10.0~14.0g,按性别和体重随机分为6组,分别为正常对照组、模型对照组、连花清瘟胶囊组、本发明药物(2.86、5.72、11.44g生药/kg),每组20只动物。乙醚轻微麻醉各组小鼠并经鼻滴入HCoV-229E冠状病毒液(采用血球凝集法检测病毒液血凝效价为6Log2,4℃预冷),60μL/只,连续接种2天,正常对照组经鼻滴入等体积的空白培养基,各组于第2次造模后2h进行首次给药。每天采用纯水将本发明药物配制成浓度为0.143、0.286、0.572g生药/mL药液,连花清瘟胶囊采用纯水配制成浓度为0.156g生药/mL药液,本发明药物低、中、高剂量组、连花清瘟胶囊组小鼠按20mL/kg经口灌胃给予相应浓度的药液,正常对照组和模型对照组给予等体积的纯水,1次/日,连续给药7天。
3.3剂量设计
本发明药物成人临床用量为22g生药/天,计算得成人每日口服剂量为22g生药/天÷60kg≈0.367g生药/kg/天(临床剂量倍数人体重按60kg计算)。根据体表面积法换算成小鼠等效剂量为0.367g生药/kg*bw×60kg×0.0026/0.02kg≈2.86生药/kg。本试验设置选用2.86g生药/kg为小鼠试验的低剂量,另设中、高剂量组,分别相当于等效剂量的2、4倍,即5.72、11.44g生药/kg。具体剂量设计详见表1。
连花清瘟胶囊临床用量为24g生药/天,成人平均体重按60kg计,根据体表面积法换算成小鼠等效剂量约为3.12g生药/kg,本次试验以连花清瘟胶囊小鼠等效剂量作为小鼠试验中连花清瘟胶囊组给药剂量,即3.12g生药/kg。
3.4观察指标
3.4.1 一般生理观察
每天对各组动物进行称重并观察其生理状态,比较动物体重在试验期间的变化。
3.4.2 肺组织中细胞因子含量测定
于给药48h、末次给药后次日,分别从各组中随机选取8只动物,雌雄各半,颈椎脱臼安乐死,解剖取肺脏,然后置匀浆器中,按肺质量(g):0.9%氯化钠注射液(mL)=1:9加入0.9%氯化钠注射液,研磨匀浆,制成鼠肺悬液,4℃环境中3000rpm离心15min,取上清待用。ELISA试剂盒检测小鼠肺脏中IL-2、IL-6、IL-8、IL-12、TNF-α的含量。
3.4.3 外周血中细胞因子检测
于给药48h、末次给药后次日,分别从各组随机选取8只动物,雌雄各半,眼眶取血,4℃环境中3000rpm离心15min,取上清待用。ELISA试剂盒检测小鼠血清中BNP、CK-MB、Tn-I、TCITRG、IRF的含量。
3.4.4 肺组织中免疫细胞检测
于给药48h、末次给药后次日,分别从各组中随机选取8只动物,雌雄各半,颈椎脱臼安乐死,解剖取肺脏,然后置匀浆器中,按肺质量(g):0.9%氯化钠注射液(mL)=1:9加入0.9%氯化钠注射液,研磨匀浆,制成鼠肺悬液。采用流式细胞仪检测小鼠肺脏中T细胞亚群(Th0/Th1/Th2)、调节性/辅助性T细胞(Th17/Treg)。
3.4.5 肺组织病毒滴度检测
于给药48h、末次给药后次日,分别从各组中随机选取10只动物,雌雄各半,颈椎脱臼安乐死,解剖取肺脏,然后置匀浆器中,按肺质量(g):0.9%氯化钠注射液(mL)=1:9加入0.9%氯化钠注射液,研磨匀浆,制成鼠肺悬液。采用血球凝集法检测肺组织中病毒滴度。
3.4.6 肺组织病理学检测
给药48h、末次给药后次日,各组小鼠颈椎脱臼安乐死,解剖取肺脏,经福尔马林灌注固定后,石蜡包埋、切片、HE染色,光镜观察病理改变,并从炎性、血性渗出程度,肺泡上皮破坏程度,肺支架塌陷肺泡上皮增生程度,巨噬细胞浸润小血管周围慢性炎症细胞浸润程度4个方面进行评分。
3.5统计方法
本试验数据有效数字修约按照四舍五入进行,并按照SOP规定进行统计学分析。统计所用软件为SPSS。计量资料以均数±标准差()表示,用Leven’s test方法检验正态性和方差齐性。如果没有统计学意义(P > 0.05),用单因素方差分析(ANOVA)进行统计分析。如果ANOVA有统计学意义(P ≤ 0.05),用LSD test (参数法)进行比较分析。如果方差不齐(P ≤ 0.05),则用Kruskal-Wallis检验。如果Kruskal-Wallis检验有统计学意义(P≤ 0.05),则用Dunnett’s Test (非参数方法)进行比较分析。统计结果以α=0.05为检验界限,其中P ≤ 0.05表示有统计学意义,P ≤ 0.01表示所检验的差别有非常显著性意义。
4 实验结果
4.1 HCoV-229E对MRC-5细胞的半数病毒感染量
如表2所示,将HCoV-229E原液按10倍梯度进行稀释,并与MRC-5细胞共培养,HCoV-229E对MRC-5细胞的半数病毒感染量(TCID50)为10-4.62/0.1mL。
对动物体重的影响
如表3、图1所示,与正常对照组比较,模型对照组D1~D8天体重明显降低(P≤0.01),提示人冠状病毒(HCoV-229E)能够导致小鼠体重下降。与模型对照组比较,给药D4~D7天,本发明药物低剂量组体重明显增加(P≤0.05或P≤0.01);给药D4~D6天,本发明药物中剂量组体重明显增加(P≤0.05或P≤0.01);给药D3~D7,本发明药物高剂量组体重明显增加(P≤0.05或P≤0.01);给药D2~D6天,连花清瘟胶囊组体重明显增加(P≤0.05或P≤0.01)。提示,小鼠感染冠状病毒(HCoV-229E)会造成体重持续下降,经口灌胃给予本发明药物、连花清瘟胶囊能缓解感染小鼠的体重下降。
对肺组织中IL-6、TNF-α、IL-2、IL-8、IL-12含量的影响
如表4所示,给药48h,与正常对照组比较,模型对照组IL-6、TNF-α、IL-2、IL-8、IL-12均明显上升(P ≤ 0.01)。与模型对照组比较,本发明药物中、高剂量组、连花清瘟胶囊组IL-6显著下降(P ≤0.05或P ≤ 0.01),本发明药物低剂量组IL-6呈下降趋势,但无统计学差异;本发明药物低、中、高剂量组、连花清瘟胶囊组TNF-α、IL-8均显著下降(P ≤ 0.05或P ≤ 0.01);本发明药物低、中、高剂量组、连花清瘟胶囊组IL-2均显著下降(P ≤ 0.05或P ≤ 0.01);本发明药物高剂量组、连花清瘟胶囊组IL-12均明显上升(P ≤ 0.05),本发明药物低、中剂量组IL-12呈下降趋势,但无统计学差异。末次给药后次日(D8),与正常对照组比较,模型对照组IL-6、TNF-α、IL-2、IL-8、IL-12均明显上升(P ≤ 0.01)。与模型对照组比较,本发明药物低、中、高剂量组、连花清瘟胶囊组IL-6、TNF-α、IL-2、IL-8均显著下降(P ≤0.05或P ≤ 0.01);本发明药物高剂量组IL-12显著下降(P ≤ 0.05),本发明药物低、中剂量组、连花清瘟胶囊组呈下降趋势,但无统计学差异。提示,小鼠感染冠状病毒(HCoV-229E)会造成肺脏中炎性因子含量上升以及免疫因子的异常变化,经口灌胃给予本发明药物、连花清瘟胶囊能够调节感染小鼠肺脏中炎性因子及免疫因子的含量。
对外周血中BNP、CK-MB、Tn-I的影响
如表5所示,给药48h,与正常对照组比较,模型对照组脑钠肽(BNP)、肌酸磷化脢-同功酶MB(CK-MB)、肌钙蛋白(Tn-I)均明显升高(P ≤ 0.05或P ≤ 0.01)。与模型对照组比较,本发明药物中、高剂量组、连花清瘟胶囊组BNP、Tn-I均明显降低(P ≤ 0.05或P ≤0.01);本发明药物低、中、高剂量组、连花清瘟胶囊CK-MB均明显降低(P ≤ 0.05或P ≤0.01)。末次给药后次日(D8),与正常对照组比较,模型对照组BNP、CK-MB均明显上升(P ≤0.05或P ≤ 0.01),Tn-I呈升高趋势,但无统计学差异。与模型对照组比较,本发明药物高剂量组、连花清瘟胶囊组BNP明显降低(P ≤ 0.05或P ≤ 0.01),本发明药物低、中剂量组BNP呈降低趋势,但无统计学差异;本发明药物低、高剂量组、连花清瘟胶囊组CK-MB均明显下降(P ≤ 0.05或P ≤ 0.01),本发明药物中剂量组CK-MB呈下降趋势,但无统计学差异;本发明药物低、中、高剂量组、连花清瘟胶囊组Tn-I呈降低趋势,但无统计学差异。提示,小鼠感染冠状病毒(HCoV-229E)会造成外周血中心脏相关功能酶的升高,经口灌胃给予本发明药物、连花清瘟胶囊能明显降低外周血中心脏相关功能酶的含量。
对外周血中IRF、TCITRG的影响
如表6所示,给药48h,与正常对照组比较,模型对照组干扰素调节因子(IRF)、细胞免疫调节因子(TCITRG)明显升高(P ≤ 0.05或P ≤ 0.01)。与模型对照组比较,本发明药物低、中、高剂量组、连花清瘟胶囊组TCITRG均明显降低(P ≤ 0.01);本发明药物低、中、高剂量组IRF呈降低趋势,但无统计学差异,连花清瘟胶囊组IRF明显降低(P ≤ 0.05)。末次给药后次日(D8),与正常对照组比较,模型对照组干扰素调节因子(IRF)、细胞免疫调节因子(TCITRG)明显升高(P ≤ 0.05)。与模型对照组比较,本发明药物中、高剂量组IRF明显降低(P ≤ 0.05或P ≤ 0.01),本发明药物低剂量组、连花清瘟胶囊组IRF呈降低趋势,但无统计学差异。与模型对照组比较,本发明药物低、中、高剂量组、连花清瘟胶囊组TCITRG呈降低趋势,但无统计学差异。
对外周血中Th0、Th1/Th2、Treg/Th17的影响
如表7所示,与正常对照组比较,模型对照组Th1/Th2比例明显升高、Treg/Th17比例明显降低(P ≤ 0.05),Th0呈降低趋势,但无统计学差异。与模型对照组比较,本发明药物高剂量组、连花清瘟胶囊组Th1/Th2比例明显降低(P ≤ 0.05)、Treg/Th17比例明显升高(P ≤ 0.05);与模型对照组比较,本发明药物低、中、高剂量组、连花清瘟胶囊组Th0无明显差异。
4.7 对肺脏中冠状病毒HCoV-229E血凝效价的影响
如表8所示,正常对照组比较,给药后48h、末次给药后次日,模型对照组血凝效价明显增加(P ≤ 0.01)。与模型对照组比较,给药后48h,本发明药物中、高剂量组、连花清瘟组血凝效价均明显减小(P ≤ 0.05或P ≤ 0.01);末次给药后次日,本发明药物中、高剂量组、连花清瘟组血凝效价均明显减小(P ≤ 0.01)。提示,本发明药物能降低冠状病毒HCoV-229E在小鼠肺脏中的血凝效价。
对肺指数与肺组织病理学影响
如表9所示,与正常对照组比较,模型对照组给药后48h、末次给药后次日感染小鼠肺脏指数明显升高(P ≤ 0.01)。与模型对照组比较,给药后48h,连花清瘟胶囊组肺脏指数明显降低(P ≤ 0.05);末次给药后次日,本发明药物低、中、高剂量组、连花清瘟胶囊组肺指数明显降低(P ≤ 0.01)。
如表10、图2、3所示,HE染色后镜检结果显示,给药48h,正常对照组肺组织未见明显异常变化,模型对照组动物出现炎性、血性渗出、肺泡上皮破坏、肺支架坍塌、肺泡上皮增生、巨噬细胞浸润以及小血管周围慢性炎症细胞浸润等病理学改变。与模型对照组比较,本发明药物低、中、高剂量组、连花清瘟组病变动物数减少,病变程度减轻。末次给药后次日,模型对照组动物肺脏可见炎性渗出、肺泡结构被破坏以及小血管周围慢性炎症细胞浸润。与模型对照组比较,本发明药物低、中、高剂量组、连花清瘟组病变动物数明显减少,病变程度明显减轻。
5、小结
本研究采取冠状病毒HCoV-229E感染BALB/c小鼠模型,通过观察小鼠生理状态、肺组织炎症情况、病毒滴度、炎性因子的水平,外周血中心脏相关功能酶、免疫调节因子及外周免疫细胞占比情况,评价本发明药物的治疗作用。实验结果显示,与正常对照组比较,模型对照组小鼠感染病毒后体重下降明显,肺指数明显增加,肺组织中病理性变化严重,且肺组织中炎性因子大量增加,提示造模成功。与模型组比较,本发明药物低、中、高剂量(2.86、5.72、11.44g生药/kg)组、连花清瘟胶囊(3.12g生药/kg)组感染小鼠体重均先降低但又快速回升,提示本发明药物、连花清瘟胶囊均能抑制感染小鼠体重下降;给药后48h及末次给后次日,本发明药物中(5.72g生药/kg)、高剂量(11.44g生药/kg)组、连花清瘟胶囊(3.12g生药/kg)组感染小鼠的肺指数明显降低,肺组织病变改善,肺脏中病毒血凝效价明显降低,表明本发明药物、连花清瘟胶囊具有减轻感染小鼠肺部炎症损伤以及抑制病毒对肺脏的破坏作用。
本研究中小鼠外周血淋巴细胞亚群占比显示,与正常对照组比较,模型对照组Th1/Th2细胞比例明显升高、Treg/Th17细胞比例明显降低,表明冠状病毒感染小鼠体内T淋巴细胞比例失衡,出现了严重免疫紊乱。与模型对照组比较,本发明药物高剂量组(11.44g生药/kg)、连花清瘟胶囊组Th1/Th2细胞比例明显降低、Treg/Th17细胞比例明显升高,且本发明药物低、中剂量(2.86、5.72g生药/kg)对Th1/Th2细胞比例有降低趋势,对Treg/Th17细胞比例有升高趋势,提示本发明药物、连花清瘟胶囊有调节小鼠免疫T淋巴细胞的作用。
病原微生物感染机体后引起多种细胞因子(TNF-α,IL-1,IL-6,IL-12,IFN-α,IFN-β,IFN-γ和IL-8等)的大量产生的现象即为细胞因子风暴,能引起急性呼吸窘迫综合征和多脏器衰竭。本研究结果发现,冠状病毒HCoV-229E感染后,模型对照组小鼠肺组织炎性因子IL-6、TNF-α、IL-2、IL-8、IL-12的含量均较正常对照组明显增高;与模型对照组比较,本发明药物和连花清瘟胶囊均能明显降低IL-6、TNF-α、IL-2、IL-8、IL-12的生成,该结果表明二者均能有效减轻细胞因子风暴,这与肺组织病理观察结果一致。
此外,与正常对照组比较,模型对照组感染小鼠外周血中BNP、CK-MB、Tn-I明显升高,提示冠状病毒HCoV-229E感染小鼠心脏亦受到了损伤。与模型对照组比较,本发明药物中、高剂量组、连花清瘟胶囊组小鼠外周血BNP、CK-MB、Tn-I含量成下降趋势,表明本发明药物、连花清瘟胶囊具有保护冠状病毒感染小鼠心脏的作用。
综上所述,本发明药物(2.86、5.72、11.44g生药/kg)、连花清瘟胶囊(3.12g生药/kg)能明显抑制冠状病毒HCoV-229E感染小鼠肺指数增加,缓解肺组织病理性变化,抑制感染小鼠肺脏中冠状病毒HCoV-229E的复制,并能调节感染小鼠外周血淋巴细胞亚群占比,改善免疫功能,降低炎症因子在肺脏中的产生。同时对冠状病毒HCoV-229E感染小鼠心脏具有一定的保护作用。
Claims (15)
1.一种中药组合物在制备抗HCoV-229E冠状病毒药物中的应用,其特征在于所述中药组合物由下列重量份的原料药制成:
麻黄52-86 ;石膏194-324; 连翘194-324 ;黄芩78-130 ;桑白皮194-324;苦杏仁78-130; 前胡78-130; 半夏78-130; 陈皮78-130; 贝母78-130; 牛蒡子78-130; 金银花78-130; 大黄39-65; 桔梗46-76; 甘草39-65。
2.根据权利要求1所述的应用,其特征在于由下列重量份的原料药制成:
麻黄52; 石膏 324; 连翘194; 黄芩78; 桑白皮194; 苦杏仁130; 前胡78; 半夏130;陈皮78; 贝母78; 牛蒡子130; 金银花130; 大黄39; 桔梗76; 甘草65。
3.根据权利要求1所述的应用,其特征在于由下列重量份的原料药制成:
麻黄86;石膏194;连翘324;黄芩130;桑白皮324;苦杏仁78;前胡130;半夏78;陈皮130;贝母130; 牛蒡子78;金银花78 ;大黄65;桔梗46; 甘草39。
4.根据权利要求1所述的应用,其特征在于由下列重量份的原料药制成:
麻黄69;石膏259;连翘259;黄芩104;桑白皮259;苦杏仁104;前胡104;半夏104;陈皮104;贝母104; 牛蒡子104;金银花104;大黄52;桔梗61;甘草52。
5.根据权利要求1所述的应用,其特征在于由下列重量份的原料药制成:
麻黄55;石膏254;连翘318;黄芩107;桑白皮203;苦杏仁107;前胡82;半夏105;陈皮84;贝母125; 牛蒡子122;金银花113;大黄42;桔梗60; 甘草50。
6.根据权利要求1-5任一项所述的应用,其特征在于所述苦杏仁为炒苦杏仁、贝母为浙贝母、金银花为山银花、半夏为清半夏。
7.根据权利要求1-5任一项所述的应用,其特征在于所述药物的活性成分由以下步骤制成:
A、按组方比例称取贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加40-70%乙醇回流提取2次,每次1-4小时,第一次加8-10倍量,第二次加6-9倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.14-1.16的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、金银花、桔梗、甘草,加水煎煮两次,每次1-4小时,第一次加9-11倍量,第二次加7-9倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.14-1.16的清膏,与步骤B所得的清膏合并,备用;
步骤A所得细粉和步骤C所得合并后的清膏共同构成该药物组合物的活性成分。
8.根据权利要求1-5任一项所述的应用,其特征在于所述药物剂型为片剂、胶囊剂、散剂、颗粒剂、口服液、丸剂、酊剂、糖浆剂、栓剂、凝胶剂、喷雾剂或注射剂。
9.根据权利要求8所述的应用,其特征在于所述片剂由以下步骤制成:
A、按组方比例称取贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加40-70%乙醇回流提取2次,每次1-4小时,第一次加8-10倍量,第二次加6-9倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.14-1.16的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、金银花、桔梗、甘草,加水煎煮两次,每次1-4小时,第一次加9-11倍量,第二次加7-9倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.14-1.16的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉与步骤A所得细粉,以乙醇为黏合剂制软材,过筛制粒;按药学常规方法压片即得。
10.根据权利要求9所述的应用,其特征在于所述片剂由以下步骤制成:
A、按组方比例称取贝母,粉碎成细粉,备用;
B、按组方比例称取麻黄、连翘、苦杏仁、半夏、牛蒡子、大黄加50%乙醇回流提取2次,每次3小时,第一次加10倍量,第二次加6倍量,提取液合并,滤过,滤液减压回收乙醇,浓缩至60℃热测相对密度为1.15的清膏,备用;
C、按组方比例称取石膏、桑白皮、前胡、陈皮、金银花、桔梗、甘草,加水煎煮两次,每次2小时,第一次加10倍量,第二次加7倍量,煎液合并,滤过,浓缩至60℃热测相对密度为1.15的清膏,与步骤B所得的清膏合并,备用;
D、将步骤C所得合并的清膏,喷雾干燥,收集喷雾粉备用;
E、步骤D所得喷雾粉与步骤A所得细粉,以乙醇为黏合剂制软材,过筛制粒干燥后整粒,加入羧甲淀粉钠、微晶纤维素、硬脂酸镁,混匀,压片即得。
11.根据权利要求1-5任一项所述所述药物在制备保护心脏损伤药物中的应用。
12.根据权利要求11所述所述的应用,其特征在于所述心脏损伤为病毒引起的心脏损伤。
13.根据权利要求1-5任一项所述药物在制备保护肺脏损伤药物中的应用。
14.根据权利要求13所述的应用,其特征在于所述肺脏损伤为病毒引起的肺脏损伤。
15.根据权利要求1-5任一项所述药物在制备提高人体免疫力药物中的应用。
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