CN116036097A - 川贝母在制备抗呼吸道病毒的药物中的用途 - Google Patents
川贝母在制备抗呼吸道病毒的药物中的用途 Download PDFInfo
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Abstract
本发明提供了贝母素甲、贝母素乙、贝母辛或其盐、西贝母碱、西贝母碱苷中的任意一种或多种在制备抗呼吸道病毒的药物中的用途。本发明还公开了以上述川贝母生物碱为活性成分的药物,可以有效抑制和/或治疗冠状病毒、人偏肺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、风疹病毒、腺病毒、巨细胞病毒、柯萨奇病毒、埃可病毒、单纯疱疹病毒、水痘‑带状疱疹病毒或鼻病毒等呼吸道病毒感染,为临床提供了一种新的选择。
Description
技术领域
本发明属于生物医药领域,具体涉及川贝母在制备抗呼吸道病毒的药物中的用途。
背景技术
呼吸道病毒是以呼吸道为入侵门户,在呼吸道粘膜上皮细胞增殖,引起呼吸道局部感染或呼吸道以外组织器官病变的病毒,其侵入上呼吸道会导致咽喉炎、鼻窦炎等疾病,侵入下呼吸道则引起肺部感染性疾病,例如造成呼吸道病毒肺炎。常见的呼吸道病毒包括流行性感冒病毒、副流感病毒、巨细胞病毒、腺病毒、鼻病毒、冠状病毒,和某些肠道病毒,如柯萨奇、埃可病毒等,以及单纯疱疹、水痘-带状疱疹、风疹、麻疹等病毒等,婴幼儿还常由呼吸道合胞病毒感染产生肺炎。此外,部分肠道病毒如柯萨奇病毒、埃可病毒也可通过呼吸道感染导致出现肺炎的症状。
多种呼吸道病毒感染引发的肺炎严重威胁着人们的健康,因此寻找发现新的抗呼吸道病毒的药物非常有必要。
川贝母为我国传统名贵中药材之一,是百合科植物川贝母Fritillaria cirrhosaD.Don、暗紫贝母F.unibracteata Hsiao et K.C.Hsia、甘肃贝母F.przewalskii Maxim.、梭砂贝母F.delavayi Franch.、太白贝母F.taipaiensis P.Y.Li或瓦布贝母F.unibracteata Hsiao et K.C.Hsia var.wabuensis(S.Y.Tang et S.C.Yue)Z.D.Liu,S.Wang et S.C.Chen的干燥鳞茎,具有很高的药用价值和市场地位。川贝母是我国传统的珍稀药用植物,主要生长于四川,具有镇咳祛痰、清热润肺、散结消痈等功效。生物碱类成分是川贝母中的主要活性成分,具有抗氧化、抗炎、镇痛、抗肿瘤等作用,主要的几种生物碱类包括贝母素甲(Peimine)、贝母素乙(Peiminine)、贝母辛(盐酸盐)(Peimisinehydrochloride)、西贝母碱(Sipeimine)、西贝母碱苷(Sipeimine-3-β-D-glucoside),结构如下所示。然而,川贝母或其活性成分对呼吸道病毒的作用和机理目前尚未见报道。
发明内容
本发明提供了贝母素甲、贝母素乙、贝母辛或其盐、西贝母碱、西贝母碱苷中的任意一种或多种在制备抗呼吸道病毒的药物中的用途。
进一步地,上述药物是治疗和/或预防呼吸道病毒引起的呼吸道感染的药物,所述呼吸道感染是上呼吸道感染和/或下呼吸道感染。
更进一步地,上述治疗和/或预防上呼吸道感染的药物包括治疗和/或预防鼻炎、咽炎、鼻窦炎、中耳炎、喉炎和/或会厌炎的药物;
所述治疗和/或预防下呼吸道感染的药物包括治疗和/或预防气管炎、支气管炎和/或肺炎的药物。
进一步地,上述药物是降低呼吸道病毒活性的药物。
进一步地,上述呼吸道病毒是冠状病毒、人偏肺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、风疹病毒、腺病毒、巨细胞病毒、肠道病毒、单纯疱疹病毒、水痘-带状疱疹病毒或鼻病毒;所述肠道病毒包括柯萨奇病毒、埃可病毒,优选为人偏肺病毒。
本发明提供了一种抗呼吸道病毒的药物,它是以贝母素甲、贝母素乙、贝母辛或其盐、西贝母碱、西贝母碱苷中的任意一种或多种为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
进一步地,上述呼吸道病毒是冠状病毒、人偏肺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、风疹病毒、腺病毒、巨细胞病毒、肠道病毒、单纯疱疹病毒、水痘-带状疱疹病毒或鼻病毒;所述肠道病毒包括柯萨奇病毒、埃可病毒。
进一步地,上述制剂中活性成分含量为1~1000μM,优选为6.25~200μM,更优选为50~200μM。
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。
附图说明
图1为川贝母生物碱(贝母素甲(Peimine)、贝母素乙(Peiminine)、贝母辛盐酸盐(Peimisine hydrochloride)、西贝母碱(Sipeimine)、西贝母碱苷(Sipeimine-3-β-D-glucoside))对16HBE作用的细胞活性测试结果。
图2为川贝母生物碱(贝母素甲(Peimine)、贝母素乙(Peiminine)、贝母辛盐酸盐(Peimisine hydrochloride)、西贝母碱(Sipeimine)、西贝母碱苷(Sipeimine-3-β-D-glucoside))对细胞中HMPV病毒滴度测试结果。
图3为川贝母生物碱(贝母素甲(Peimine)、贝母素乙(Peiminine)、贝母辛盐酸盐(Peimisine hydrochloride)、西贝母碱(Sipeimine)、西贝母碱苷(Sipeimine-3-β-D-glucoside))、利巴韦林灌胃对小鼠体重变化的影响情况。
图4为川贝母生物碱(贝母素甲(Peimine)、贝母素乙(Peiminine)、贝母辛盐酸盐(Peimisine hydrochloride)、西贝母碱(Sipeimine)、西贝母碱苷(Sipeimine-3-β-D-glucoside))、利巴韦林灌胃鼠肺脏病毒滴度的影响测定结果。
图5为川贝母生物碱(贝母素甲(Peimine)、贝母素乙(Peiminine)、贝母辛盐酸盐(Peimisine hydrochloride)、西贝母碱(Sipeimine)、西贝母碱苷(Sipeimine-3-β-D-glucoside))、利巴韦林灌胃对小鼠肺脏影响的HE染色结果。
具体实施方式
除另有说明外,本发明所用原料均为已知产品,通过购买市售产品所得。
本发明利用Vero-E6细胞培养HMPV活病毒,分离得到病毒液(MOI=10),用于后续实验。
实施例1、本发明含贝母素甲的药物的制备
贝母素甲加细胞培养基配制成浓度为6.25μM、12.5μM、25μM、50μM、100μM、200μM的溶液。
实施例2、本发明含贝母素乙的药物的制备
贝母素乙加细胞培养基配制成浓度为6.25μM、12.5μM、25μM、50μM、100μM、200μM的溶液。
实施例3、本发明含贝母辛盐酸盐的药物的制备
贝母辛盐酸盐加细胞培养基配制成浓度为6.25μM、12.5μM、25μM、50μM、100μM、200μM的溶液。
实施例4、本发明含西贝母碱的药物的制备
西贝母碱加细胞培养基配制成浓度为6.25μM、12.5μM、25μM、50μM、100μM、200μM的溶液。
实施例5、本发明含西贝母碱苷的药物的制备
西贝母碱苷加细胞培养基配制成浓度为6.25μM、12.5μM、25μM、50μM、100μM、200μM的溶液。
实验例1、细胞毒性实验
细胞复苏:从液氮罐中取出冻存的16HBE细胞,迅速放至37℃水浴锅中摇晃溶解,将溶解后的细胞加入到已经吸取3ml培养液的15ml BD管中,800rpm离心4min,弃去上清加入1ml的培养液重悬,重悬后的细胞加入到T25培养瓶中,放入培养箱中培养。
细胞铺板:将16HBE细胞培养至接近80%时,消化,重悬细胞并计数,稀释细胞浓度为1*105/mL;每孔100μL加入到96孔板;细胞加药不同浓度(6.25μM、12.5μM、25μM、50μM、100μM、200μM)的川贝母生物碱溶液;设置对照孔和空白孔;放入孵箱过夜培养24h。吸出含药培养液,用PBS清洗三次,加入新的培养液,并加入10μL的CCK-8试剂;作用1-4h后,使用酶标仪测定450nm吸光度值,按照以下公式,计算细胞存活率。
A=AC-A0/Ab-A0
Ac为加药孔;
Ab为含有细胞的未加药孔;
A0为不含细胞的未加药孔;
得到的结果如图1所示,结果表明,在各浓度的川贝母生物碱作用下,16HBE细胞的细胞活性均高于80%,说明川贝母生物碱(贝母素甲、贝母素乙、西贝母碱、西贝母碱苷、贝母辛)无明显细胞毒性。
实验例2、抑制病毒活性实验
1、实验前一天将对数生长期的细胞消化重悬后,将2*105/孔16HBE细胞接种于24孔板,生长过夜。第二天,细胞汇合度达到70-80%,加入HMPV病毒液200μL(MOI=10),孵箱中感染2h;吸取病毒并用PBS清洗三遍,配制含药溶液(0μM、6.25μM、12.5μM、25μM、50μM、100μM、200μM的川贝母生物碱溶液),实验组分别每孔加入相应的含药溶液。作用24h后,弃去上清,使用总提取RNA试剂盒提取RNA,按说明书操作提取RNA。使用逆转录试剂盒(AG11706-S),将提取到的RNA进行逆转录;使用TaqMan荧光探针法,荧光定量PCR(Q-PCR),根据Q-PCR实验中不同组别的Cq值,考察加入不同浓度川贝母生物碱后细胞内病毒载量。
结果如图2所示,实验结果表明,加入贝母素乙的含药溶液能有效降低细胞内病毒滴度,说明贝母素乙可以有效抑制细胞中病毒活性,其他的生物碱成分作用不明显。
实验例3、小鼠病毒感染治疗实验
购买5-6weeks的BALB/c小鼠,17-20g;雌性;适应一周。
实验分组:(共3组,每组3只):
1、病毒感染组(人偏肺病毒HMPV);2、药物组(实施例1~5),给药剂量为100mg/kg;3、利巴韦林组,给药剂量为50mg/kg;
实验步骤:
1、实验前准备,小鼠随机分组,标记;
a.病毒准备:实验前将病毒从-80℃冰箱取出,置于冰上;
b.麻醉:小鼠称重后腹腔注射1%的戊巴比妥(剂量为50mg/kg体重),置于饲养笼内,等待约5~10min;
2、病毒滴注
将麻醉后的小鼠固定,纯化的HMPV病毒对小鼠进行滴鼻处理(病毒滴度为107),充分打开气道,两只鼻孔交替滴入病毒液10μL,共滴注60μL;观察小鼠情况,直至小鼠苏醒,可采取适当保暖措施。
3.病毒组每日给予灌胃0.4ml的生理盐水,药物组每日口服灌胃0.4ml川贝母生物碱溶液;利巴韦林组每日灌胃利巴韦林溶液100μL;
4.连续给药4天,并称量小鼠体重;观察小鼠的状态;5天后,摘眼球取血;取小鼠肺组织分别置于EP管冻于-80℃冰箱中考察肺脏病毒滴度。另取一部分固定于多聚甲醛溶液中,考察小鼠肺组织免疫组化及病理变化:HE染色:肺组织右上叶置于准备好的福尔马林(4%多聚甲醛),浸泡液大于肺组织3倍,至少浸泡24h后放入包埋盒内水洗过夜,脱水,经石蜡包埋,石蜡切片,烘烤后脱蜡后开始HE染色。
A.眼球取血:
小鼠摘眼球取血,1500rpm,4℃;离心10min,小心吸取上清。用于病毒滴度检测(Q-PCR)、炎性因子水平(ELISA)、免疫细胞种类考察(淋巴细胞;T细胞;巨噬细胞)。
B.病毒滴度测定
称量相同重量的小鼠肺组织5mg,加入试剂盒裂解液,Qiagen组织裂解仪器裂解组织5min,提取组织内总RNA。其余步骤同细胞RNA提取过程。
结果如图3~4所示,可以看出,小鼠感染HMPV病毒后,小鼠体重会下降,而利巴韦林及川贝母生物碱给药组可以改善小鼠体重降低。生物碱给药组及利巴韦林组小鼠肺脏的病毒滴度低于HMPV组,且具有统计学差异,说明给药组能显著降低小鼠体内的病毒滴度,对HMPV感染具有治疗作用。利巴韦林组相较于生物碱给药组病毒滴度更低,但无统计学差异。
如图5所示,HE染色结果表明,病毒感染小鼠后,肺组织内会出现肺泡腔的破裂、炎症浸润血管壁增厚等,加入川贝母生物碱(贝母素甲、贝母素乙、西贝母碱、西贝母碱苷、贝母辛)等可以减轻部分症状,说明川贝母生物碱可用于偏肺病毒感染的肺脏保护。
综上,本发明提供了贝母素甲、贝母素乙、贝母辛或其盐、西贝母碱、西贝母碱苷中的任意一种或多种在制备治疗和/或预防呼吸道病毒肺炎的药物中的用途。可以有效抑制和/或治疗冠状病毒、人偏肺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、风疹病毒、腺病毒、巨细胞病毒、柯萨奇病毒、埃可病毒、单纯疱疹病毒、水痘-带状疱疹病毒或鼻病毒等呼吸道病毒感染,有很好的临床应用前景。
Claims (10)
1.贝母素甲、贝母素乙、贝母辛或其盐、西贝母碱、西贝母碱苷中的任意一种或多种在制备抗呼吸道病毒的药物中的用途。
2.如权利要求1所述的用途,其特征在于,所述药物是治疗和/或预防呼吸道病毒引起的呼吸道感染的药物,所述呼吸道感染是上呼吸道感染和/或下呼吸道感染。
3.如权利要求2所述的用途,其特征在于,所述治疗和/或预防上呼吸道感染的药物包括治疗和/或预防鼻炎、咽炎、鼻窦炎、中耳炎、喉炎和/或会厌炎的药物;
所述治疗和/或预防下呼吸道感染的药物包括治疗和/或预防气管炎、支气管炎和/或肺炎的药物。
4.如权利要求1~3任一项所述的用途,其特征在于,所述药物是降低呼吸道病毒活性的药物。
5.如权利要求1~3任一项所述的用途,其特征在于,所述呼吸道病毒是冠状病毒、人偏肺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、风疹病毒、腺病毒、巨细胞病毒、肠道病毒、单纯疱疹病毒、水痘-带状疱疹病毒或鼻病毒;所述肠道病毒包括柯萨奇病毒、埃可病毒。
6.如权利要求5所述的用途,其特征在于,所述病毒是人偏肺病毒。
7.一种抗呼吸道病毒的药物,其特征在于,它是以贝母素甲、贝母素乙、贝母辛或其盐、西贝母碱、西贝母碱苷中的任意一种或多种为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
8.如权利要求7所述的药物,其特征在于,所述呼吸道病毒是冠状病毒、人偏肺病毒、流感病毒、副流感病毒、呼吸道合胞病毒、麻疹病毒、腮腺炎病毒、风疹病毒、腺病毒、巨细胞病毒、肠道病毒、单纯疱疹病毒、水痘-带状疱疹病毒或鼻病毒;所述肠道病毒包括柯萨奇病毒、埃可病毒。
9.如权利要求7或8所述的药物,其特征在于,所述制剂中活性成分含量为1~1000μM。
10.如权利要求9所述的药物,其特征在于,所述制剂中活性成分含量为6.25~200μM;优选为50~200μM。
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陶晓倩等: "基于网络药理学和分子对接技术的金振口服液干预新型冠状病毒肺炎(COVID-19)的作用机制研究", 中草药, vol. 51, no. 9, 31 May 2020 (2020-05-31), pages 2 * |
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