CN116531491A - 一种干扰素α1b在制备防治甲型流感病毒感染引发的疾病的药物中的用途 - Google Patents
一种干扰素α1b在制备防治甲型流感病毒感染引发的疾病的药物中的用途 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,本发明提供了一种干扰素α1b在制备防治甲型流感病毒感染引发的疾病的药物中的用途;本发明提供的干扰素α1b单独使用对甲型流感病毒感染引发的疾病的防治效果好,优于奥司他韦,且毒副作用低,可忽略不计。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种干扰素α1b在制备防治甲型流感病毒感染引发的疾病的药物中的用途。
背景技术
流行性感冒病毒(influenza virus),属于正粘病毒科(Orthomyxoviridae),为RNA病毒,包括人流感病毒和动物流感病毒。人流感病毒分为甲(A)、乙(B)、丙(C)三型,分别于1933年、1940年和1949年分离成功,它们是流行性感冒(流感)的病原体。其传染性强,多次引起世界性大流行。其中在1918~1919年甲型流感病毒大流行中,全世界至少有2000万~4000万人死于流感;流感病毒种类多,有100多种亚型。抗原性易发生变异,难予预防或治疗。尽管流感病毒对乙醇、碘伏、碘酊等常用消毒剂敏感,对紫外线和热敏感,56℃条件下30分钟可灭活,并且有流感疫苗,但还是经常发生世界性大流行;目前感染人的主要是甲型流感病毒中的H1N1、H3N2亚型及乙型流感病毒中的Victoria和Yamagata系。潜伏期一般为1~7天,多为2~4天。
干扰素(IFN)是一类具有广谱抗病毒、抗增殖和免疫调节活性的多功能细胞因子家族。IFN能通过与人体细胞表面的受体结合,刺激细胞表达多种抗病毒蛋白,影响细胞代谢过程,包括降解病毒RNA,并抑制病毒RNA和蛋白质的合成;通过诱导未受病毒感染的细胞产生抗病毒蛋白而建立“抗病毒状态”,避免细胞受到病毒的感染。其能提升主要组织相容性复合体(MHC)I抗原的表达水平,增加病毒抗原在感染细胞表面呈现;通过作用抗原提呈细胞(APCS),增强MHCⅡ的表达和抗原提呈功能有利于机体免疫系统对感染病毒细胞的识别;IFN还可以增强适应性免疫细胞的抗病毒功能,包括B淋巴细胞、T淋巴细胞、自然杀伤(NK)细胞和细胞毒T淋巴细胞反应来清除病毒。
根据IFN结合的受体不同,可以分为Ⅰ型、Ⅱ型和Ⅲ型,其中Ⅰ型IFN(主要为α/Βifn)在机体控制病毒感染方面发挥重要作用。在自然情况下,α干扰素(IFNα)是人类应对病毒感染非常重要的免疫保护性细胞因子,其可诱导同种细胞产生抗病毒蛋白,形成抗病毒状态,限制病毒的进一步复制和扩散。但IFN是一个诱生蛋白,只有受到病毒等微生物感染后人体内细胞才会被诱导分泌出IFN。所以,天然IFN的抗病毒作用具有滞后性和暂时性的特点。当人体免疫功能低下时(例如婴幼儿免疫功能发育尚不成熟、成人使用糖皮质激素或者免疫抑制剂)流感病毒更易抑制IFN的产生,导致机体更易发生并发症,成为重症流感患者。因此,尽早给予外源性IFN可抑制病毒复制,并增强免疫细胞清除病毒的能力,达到控制疾病进展的目的。在我国批准上市的IFNα有IFN2a、IFN2b和 IFN1b3种亚型。IFN在临床上应用的给药途径有多种方式,包括皮下和肌肉注射、雾化吸入、局部用药等,用于治疗各种儿童病毒感染性疾病和血液系统疾病。注射IFN后血清药物浓度达峰时间为4~8h,清除半衰期为2.6~5.0h。吸收入血的IFN主要经肾脏分解代谢,少部分IFN通过胆汁分泌和肝脏代谢消除。尽管干扰素是机体抗病毒感染的第一道防线,临床上有用于病毒性肺炎的报告,但干扰素对防治流感病毒感染的效果是未知的。
流感患者和隐性感染者是流感的主要传染源。受感染动物也可成为传染源。从潜伏期末到急性期都有传染性。病人呼吸道分泌物中一般持续排毒3-6天,婴幼儿、免疫功能受损患者排毒时间可超过1周,人感染H5N1/H7N9病例排毒可达1~3周。流感起病急,无并发症者病程呈自限性,多于发病3-4天后体温逐渐消退。但老年人、年幼儿童、孕产妇、肥胖或有慢性基础疾病者,例如慢性呼吸系统疾病、心血管系统疾病(高血压除外)、肾病、肝病、血液系统疾病、神经系统及神经肌肉疾病、代谢及内分泌系统疾病、免疫功能抑制(包括应用免疫抑制剂或HIV感染等致免疫功能低下)等是高危人群,可发展至重症流感。肺炎是流感最常见的并发症,其他并发症有神经系统损伤、心脏损害、肌炎、横纹肌溶解综合征和脓毒性休克等。少数重症病例病情进展快,可以诱发细胞因子风暴,导致全身炎症反应,出现急性呼吸窘迫综合征(ARDS)、休克及多脏器功能衰竭而死亡。流感病毒也是哮喘发作的主要病原体。有哮喘病史的病人常因为流感病毒感染导致哮喘的急性发作或者病情加重。世界上所有国家都高度重视流感病毒的治疗。目前,主要使用神经氨酸酶抑制剂(NAI)对甲型、乙型流感进行治疗,包括奥司他韦、扎那米韦、帕拉米韦,但在抗流感病毒治疗时需要掌握好时机,发病48h内进行抗病毒治疗可减少流感并发症、降低住院患者的病死率、缩短住院时间,发病时间超过48h的重症患者虽然能从抗病毒治疗中获益,然而,治疗效果却是非常有限的。离子通道M2阻滞剂金刚烷胺和金刚乙胺仅对甲型流感病毒有效,因为有耐药,已经不建议使用,且以上药物在应用时均会对人体产生或多或少的毒副作用,如金刚烷胺治疗剂量与产生副作用的剂量很接近,对高龄者及有慢性心肺疾病或肾脏疾病者的剂量和给药计划很难确定;奥司他韦存在导致患者消化道不适的不良反应,包括恶心、呕吐、腹泻、腹痛等,其次是呼吸系统的不良反应,包括支气管炎、咳嗽等,此外还有中枢神经系统的不良反应,如眩晕、头痛、失眠、疲劳等;利巴韦林吸入用药可导致肺功能退化、细菌性肺炎、气胸和心血管反应(血压下降以及心脏停搏)等,罕见贫血和网织红细胞过多的报道,也有结膜炎、皮疹发生,静脉或口服给药后主要的不良反应有溶血性贫血、血红蛋白减低及贫血、乏力等。
流感病毒的中药中医治疗主要是辨证治疗。在轻症,风热犯卫用银翘散合桑菊饮加减,常用金花清感颗粒、连花清瘟胶囊、清开灵颗粒(口服液)、疏风解毒胶囊、银翘解毒类、桑菊感冒类等;儿童用儿童抗感颗粒、小儿豉翘清热颗粒等;热毒袭肺用麻杏石甘汤加减,常用中成药有连花清瘟胶囊、银黄类制剂、莲花清热类制剂等;儿童用小儿肺热咳喘颗粒(口服液)、小儿咳喘灵颗粒(口服液)、羚羊角粉冲服。在重症,毒热壅肺用宣白承气汤加减;毒热内陷,内闭外脱用参附汤加减。中药中医在防治流感病毒感染中有重要作用,但是,还没有发现中药制剂能对流感病毒感染的防治有显著的疗效。
虽然流感病毒感染有上述治疗方法,但是,每年都有流感病毒感染的小流行,对于老年人、年幼儿童、孕产妇、肥胖或有慢性基础疾病者等高危人群,特别是对于发病时间超过48h的患者,仍然有很多的并发症和很高的病死率,需要一种更为有效的预防或治疗流感病毒感染的制剂或治疗方法。
甲型流感每年呈季节性流行,常发生在冬春季。因此,急需开发一种对甲型流感病毒感染引发疾病防治效果好同时副作用低的药物。
发明内容
为了解决上述问题,本发明提供了一种干扰素α1b在制备防治甲型流感病毒感染引发的疾病的药物中的用途。
本发明使用不同剂量干扰素α1b(运德素,北京三元基因药业股份有限公司生产)对甲型流感病毒感染小鼠动物进行干预,通过观察动物发病情况、临床表现、死亡率和肺部组织病变,研究干扰素α1b对甲型流感病毒感染小鼠的影响,证实了干扰素α1b对甲型流感病毒感染引发的疾病有较好的防治作用,且毒副作用低。
进一步地,甲型流感病毒的亚型为H1N1、H3N2、H5N1、H7N2、H7N9中的一种。
进一步地,甲型流感病毒的亚型为H1N1或H7N9。
进一步地,药物包括干扰素α1b和药学上可接受的辅料。
进一步地,药学上可接受的辅料选自缓冲剂、pH调节剂、保护剂中的一种或多种。
进一步地,缓冲剂选自磷酸二氢钠、磷酸氢二钠、醋酸钠或枸橼酸钠中的一种或多种。
进一步地,pH调节剂选自柠檬酸、乳酸、酒石酸、苹果酸、柠檬酸钠、柠檬酸钾中的一种或多种。
进一步地,保护剂选自人白蛋白、人工血浆、促红素、神经生长因子、表皮生长因子、成纤维细胞生长因子、胰岛素样生长因子1、透明质酸酶、白血病抑制因子、白介素、类干扰素活性物质、肿瘤坏死因子中的一种或多种。
进一步地,药学上可接受的辅料至少包括氯化钠和人血白蛋白。
进一步地,药学上可接受的辅料包括氯化钠、枸橼酸、十二水磷酸氢二钠和人血白蛋白。
进一步地,人干扰素α1b与氯化钠、枸橼酸、十二水磷酸氢二钠和人血白蛋白的质量比为1-5: 250-2700:10-60:90-600:500-2000。
进一步地,每1000mL药物中含有:
10mg-50mg人干扰素α1b;
2.5g -27g氯化钠;
0.1g-0.6g枸橼酸;
0.9g-6g十二水磷酸氢二钠;
5g-20g人血白蛋白;
余量为注射用水。
进一步地,药学上可接受的辅料包括磷酸氢二钠、一水合磷酸二氢钠、氯化钠、人血白蛋白和苯扎氯铵。
进一步地,人干扰素α1b与磷酸氢二钠、一水合磷酸二氢钠、氯化钠、人血白蛋白和苯扎氯铵的质量比为1-10:500-2000:100-1000:2500-27000:5000-20000:10-50。
进一步地,每1000ml 药物中含有:
1mg-10mg人干扰素α1b;
0.5 g -2g磷酸氢二钠;
0.1-1g一水合磷酸二氢钠;
2.5g -27g氯化钠;
5g-20g人血白蛋白;
0.01 g -0.05g苯扎氯铵。
进一步地,药物的剂型为雾化吸入剂、注射剂、喷雾剂或口服制剂。
进一步地,药物的剂型为雾化吸入剂,雾化吸入剂的用法用量为2-16μg/kg/次,一天两次。
进一步地,药物的剂型为注射剂,注射剂的用法用量为2-8μg/kg/次,一天两次。
进一步地,药物的剂型为喷雾剂,喷雾剂的用法用量为0.4-1.2μg/鼻孔/次,每天4-6次。
众所周知,干扰素在合理的用量下毒副作用小,可忽略不计,但当用量较大或长期用药时,则会产生发热、肌肉疼痛、关节疼痛、头痛、中性粒细胞减少及抑郁、狂躁、失眠等不良反应,因此现有技术通常将干扰素与利巴韦林、奥司他韦等药物合用,以降低干扰素的用量,达到降低毒副作用的目的;申请人在研发过程中发现,当将干扰素α1b以雾化吸入方式给药时,将用量控制为2-16μg/kg/次,一天两次,或将干扰素以肌注方式给药时,将用量控制为2-8μg/kg/次,一天两次。则单独使用干扰素α1b即可对甲型流感达到很好的防治效果,同时毒副作用低,可忽略不计。
本发明的有益效果在于:干扰素α1b单独使用对甲型流感病毒感染引发的疾病的防治效果好,优于奥司他韦,且毒副作用低,可忽略不计。
附图说明
图1.示出了对照组的小鼠肺部状态图;
图2.示出了实验组的小鼠肺部状态图;
图3.示出了阳性对照组的小鼠肺部HE染色;
图4.示出了正常组的小鼠肺部HE染色;
图5.示出了提前1天使用0.5μg/次/天的干扰素α1b进行雾化给药5天后小鼠肺部HE染色;
图6.示出了提前1天使用8μg/次/天的干扰素α1b进行雾化给药5天后小鼠肺部HE染色;
图7.示出了提前1天使用0.25μg/次/天的干扰素α1b进行肌注给药5天后小鼠肺部HE染色;
图8.示出了提前1天使用4μg/次/天的干扰素α1b进行肌注给药5天后小鼠肺部HE染色;
图9.示出了使用0.5μg/次/天的干扰素α1b进行雾化给药5天后小鼠肺部HE染色;
图10.示出了使用8μg /次/天的干扰素α1b进行雾化给药5天后小鼠肺部HE染色;
图11.示出了使用0.25μg/次/天的干扰素α1b进行肌注给药5天后小鼠肺部HE染色;
图12.示出了使用4μg/次/天的干扰素α1b进行肌注给药5天后小鼠肺部HE染色;
图13.示出了使用奥司他韦灌胃给药5天(0.4mg/d)后小鼠肺部HE染色。
具体实施方式
以下实施例进一步说明本发明的内容,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。
实施例1 、甲流H1N1感染小鼠动物模型的制备
1.1构建流感病毒的小鼠模型
小鼠是常用的动物模型之一,但不是甲型流感的自然宿主,甲型流感病毒不宜直接接种于小鼠,本实施例采用人甲型流感病毒感染小鼠适应传代制备促小鼠肺部适应株,使小鼠发病和死亡,来造成甲型流感的小鼠模型。
方法:将10只雌性balb/c小鼠随机分为实验组和对照组,每组5只,实验组小鼠滴鼻接种50μl甲型流感病毒NYMCX-179A配制的病毒液,对照组小鼠接种等体积的生理盐水。观察小鼠发病及死亡情况,称量体重。染毒5d后,处死小鼠,观察小鼠肺部病变,如图1所示,对照组小鼠肺部状态正常,如图2所示,实验组小鼠肺部肿胀,部分肺叶颜色发红。
取病变较严重较大的鼠肺制成匀浆,取上清200μl接种于10日龄鸡胚尿囊腔,培养48h后,收获尿囊液。血凝试验测定病毒滴度,收集血凝滴度大于1:28的尿囊液。再次将收获的病毒液按照上述方法在小鼠体内传代,直至实验组小鼠出现明显感染体征、体质量减轻、死亡。
造模结果:
1、临床表现:实验组和对照组小鼠体重在第1天、第2天逐日增加,但是从第3天开始,实验组小鼠体重低于对照组,实验组小鼠出现耸毛、发抖、蜷缩弓背等症状。
2、死亡率:如表1所示,实验组小鼠第5天开始出现死亡,到第11天死亡现象停止。死亡多集中于染毒后6、7、8这3天,死亡率80%。所计算的小鼠的LD50,为10-0.5/0.05mL。
综上,甲型流感病毒NYMCX-179A小鼠肺适应株经滴鼻感染小鼠后对鼠感染致病毒力逐代增强,第11天时,发病率达到100.0%,病死率达到100.0%。
实施例2、人干扰素α1b(运德素â)对甲型H1N1流感病毒感染小鼠的预防作用
2.1方法:
将小鼠分为正常组、阳性对照组、干扰素预防1组(给药剂量是0.5μg/次/天)、干扰素预防2组(给药剂量是1μg/次/天,给药方式为雾化)、干扰素预防3组(给药剂量是2μg /次/天,给药方式为雾化)、干扰素预防4组(给药剂量是4μg /次/天,给药方式为雾化)、干扰素预防5组(给药剂量是8μg /次/天,给药方式为雾化)、干扰素预防6组(给药剂量是0.25μg/次/天,给药方式为肌注)、干扰素预防7组(给药剂量是0.5μg/次/天,给药方式为肌注)、干扰素预防8组(给药剂量是1μg/次/天,给药方式为肌注)、干扰素预防9组(给药剂量是2μg/次/天,给药方式为肌注)、干扰素预防10组(给药剂量是4μg/次/天,给药方式为肌注),每组5只,正常组和阳性对照组给与生理盐水,各干扰素组在造模前1天给药,造模成功后继续给药(药物为人干扰素α1b注射液,商品名为运德素,北京三元基因药业股份有限公司生产)5天,观察12d;通过观察小鼠的存活率、存活天数和体重变化,以及检测肺组织病理切片,观察干扰素α1b对甲型H1N1流感病毒感染小鼠的预防作用,实验结果见表2-4和图3-8。
2.2结果
1)如表2所示,干扰素α1b可以降低甲型H1NI流感病毒感染小鼠的死亡率;
2)如表3所示,干扰素α1b可以延长甲型H1N1流感病毒感染小鼠平均生存天数;
3)如表4所示,干扰素α1b可以增加甲型H1N1流感病毒感染小鼠的体重,改善小鼠临床表现。
4)病理学检查
如图4所示,正常组肺脏均未见明显病理改变。如图3所示,阳性对照组动物感染甲型H1N1病毒5天后肺脏呈弥漫性肺炎改变,主要表现为肺血管扩张充血,血管周围水肿、炎性细胞渗出,肺泡间隔弥漫性炎细胞浸润。如图5所示,小鼠经干扰素α1b低剂量(0.5μg/天)雾化预防措施后,血管周围可见较多炎性细胞灶性浸润,肺泡腔内广泛可见较多炎性细胞渗出;如图6所示,小鼠经干扰素α1b高剂量(8μg/天)肌注预防措施后,视野中支气管上皮细胞排列紧密,形态正常,肺泡壁内干净未见明显炎性渗出物。如图7所示,小鼠经干扰素α1b低剂量(0.25μg/天)肌注预防措施后,局部炎性细胞充满肺泡腔,致使组织实质化,两个低剂量预防组的小鼠肺脏病变程度明显,与阳性组相似;如图8所示,小鼠经干扰素α1b高剂量(4μg/天)肌注预防措施后,视野中支气管上皮细胞排列紧密,形态正常,肺泡腔内干净未见明显炎性渗出物。由上可见,随着药物剂量的增加,肺脏病变程度明显数量较阳性组减轻,大剂量预防组的预防效果甚至优于奥司他韦的治疗效果。
实施例3、人干扰素α1b(运德素â)对甲型H1N1流感病毒感染小鼠的治疗作用
3.1方法:
小鼠造模成功后,分为正常组、阳性对照组、干扰素1组(给药剂量是0.5μg/次/天)、干扰素2组(给药剂量是1μg/次/天,给药方式为雾化)、干扰素3组(给药剂量是2μg /次/天,给药方式为雾化)、干扰素4组(给药剂量是4μg /次/天,给药方式为雾化)、干扰素5组(给药剂量是8μg /次/天,给药方式为雾化)、干扰素6组(给药剂量是0.25μg/次/天,给药方式为肌注)、干扰素7组(给药剂量是0.5μg/次/天,给药方式为肌注)、干扰素8组(给药剂量是1μg/次/天,给药方式为肌注)、干扰素9组(给药剂量是2μg/次/天,给药方式为肌注)、干扰素10组(给药剂量是4μg/次/天,给药方式为肌注)和奥司他韦组(给药剂量是0.4mg/次/天,给药方式为灌胃),每组5只,各干扰素组(药物为人干扰素α1b注射液,商品名为运德素,北京三元基因药业股份有限公司生产)和奥司他韦组(药物为奥司他韦,购买厂家为上海罗氏制药有限公司)在造模后持续给药5天,观察12d;通过观察小鼠的存活率、存活天数和体重变化,以及检测肺组织病理切片,观察干扰素α1b对甲型H1N1流感病毒感染小鼠的治疗作用,实验结果见表5-7和图3-4和图9-12。实施例3与实施例2共用相同的正常组和阳性对照组。
3.2结果
1)如表5所示,干扰素α1b可以降低甲型H1NI流感病毒感染小鼠的死亡率;
2)如表6所示,干扰素α1b可以延长甲型H1N1流感病毒感染小鼠平均生存天数;
3)如表7所示,干扰素α1b可以增加甲型H1N1流感病毒感染小鼠的体重,改善小鼠临床表现。
4)病理学检查
如图4所示,正常组肺脏均未见明显病理改变。如图3所示,阳性对照组动物感染甲型H1N1病毒5天后肺脏呈弥漫性肺炎改变,主要表现为肺血管扩张充血,血管周围水肿、炎性细胞渗出,肺泡间隔弥漫性炎细胞浸润。如图13所示,奥司他韦组部肺脏病变范围较模型组小,病变程度较阳性组减少,视野中支气管上皮细胞排列紧密,形态正常;肺泡壁上可见少量炎性细胞浸润。如图9所示,小鼠经干扰素α1b低剂量(0.5μg/天)雾化治疗措施后,肺泡腔变窄,肺泡腔内可见较多炎性细胞渗出;如图10所示,小鼠经干扰素α1b高剂量(8μg/天)肌注治疗措施后,视野中肺泡腔内可见少量炎性细胞渗出。如图11所示,小鼠经干扰素α1b低剂量(0.25μg/天)肌注治疗措施后,局部肺泡腔内可见较多炎性细胞渗出;如图12所示,小鼠经干扰素α1b高剂量(4μg/天)肌注治疗措施后,视野中支气管上皮细胞细胞排列紧密,形态正常,肺泡壁上可见少量炎性细胞浸润,肺泡腔内未见炎性渗出物。由上可见,随着药物剂量的增加,肺脏病变程度明显数量较阳性组减轻,大剂量治疗组的治疗效果优于奥司他韦组的治疗效果。
Claims (10)
1.一种干扰素α1b在制备防治甲型流感病毒感染引发的疾病的药物中的用途。
2.根据权利要求1所述的用途,其特征在于,所述甲型流感病毒的亚型为H1N1、H3N2、H5N1、H7N2、H7N9中的一种。
3.根据权利要求2所述的用途,其特征在于,所述甲型流感病毒的亚型为H1N1或H7N9。
4.根据权利要求1-3任一所述的用途,其特征在于,所述药物包括干扰素α1b和药学上可接受的辅料。
5.根据权利要求4所述的用途,其特征在于,所述药学上可接受的辅料选自缓冲剂、pH调节剂、保护剂中的一种或多种。
6.根据权利要求5所述的用途,其特征在于,所述缓冲剂选自磷酸二氢钠、磷酸氢二钠、醋酸钠或枸橼酸钠中的一种或多种;所述pH调节剂选自柠檬酸、乳酸、酒石酸、苹果酸、柠檬酸钠、柠檬酸钾中的一种或多种。
7.根据权利要求5所述的用途,其特征在于,所述保护剂选自人白蛋白、人工血浆、促红素、神经生长因子、表皮生长因子、成纤维细胞生长因子、胰岛素样生长因子1、透明质酸酶、白血病抑制因子、白介素、类干扰素活性物质、肿瘤坏死因子中的一种或多种。
8.根据权利要求1-3任一项所述的用途,其特征在于,所述药物的剂型为雾化吸入剂、注射剂、喷雾剂或口服制剂。
9.根据权利要求8所述的用途,其特征在于,所述药物的剂型为雾化吸入剂,所述雾化吸入剂的用法用量为2μg/kg/次-16μg/kg/次,一天两次。
10.根据权利要求8所述的用途,其特征在于,所述药物的剂型为注射剂,所述注射剂的用法用量为2μg/kg/次-8μg/kg/次,一天两次。
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