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奥司他韦与替代疗法抗H1N1感染效果的Meta分析

2014-12-15张瑞新柳伟伟

中国医药导报 2014年31期
关键词:感染

张瑞新++柳伟伟

[摘要] 目的 研究奥司他韦与非化学合成药物替代疗法抗H1N1感染的效果及安全性。 方法 检索在Medline、Embase、CBMdisk、CNKI全文数据库以及万方中文期刊全文数据库2014年1月1日之前公开发表的有关流感治疗的文献。采用Cochrane协作网提供的Review Manager 4.2软件做Meta分析。采用加权平均数作为系统评价的指标并计算其95%可信区间。 结果 7篇随机对照临床研究最终纳入本次分析,其中5篇为连花清瘟胶囊与奥司他韦的比较,2篇为银翘散加减方与奥司他韦的比较。系统评价的结果显示,在病毒核酸阴转方面,银翘散组方加减与奥司他韦[WMD = -6.21,95%CI(-84.19,71.76),P = 0.88]以及连花清瘟胶囊与奥司他韦[WMD = -0.24,95%CI(-4.79,4.31),P = 0.92]的效果相似;在退热时间方面,银翘散组方加减与奥司他韦[WMD = 5.66,95%CI(-32.02,43.35),P = 0.77]效果相似,而连花清瘟胶囊要优于奥司他韦[WMD = -4.65,95%CI(-8.91,-0.38),P = 0.03];在咳嗽缓解方面,连花清瘟胶囊的效果优于奥司他韦且两者差异有高度统计学意义[WMD = -9.79,95%CI(-14.61,-4.97),P < 0.01]。 结论 中药替代疗法在抗流感病毒感染方面有积极作用。

[关键词] H1N1;感染;替代或补充医学

[中图分类号] R511.7 [文献标识码] A [文章编号] 1673-7210(2014)11(a)-0052-05

Meta-analysis of efficacy of Oseltamivir and substitution therapy for anti- H1N1 infection

ZHANG Ruixin1 LIU Weiwei2

1.Pharmacy Division, 302 Hospital of PLA, Beijing 100039, China; 2.Statistics Teaching and Research Section, Graduate School, Academy of Military Medical Sciences, Beijing 100850, China

[Abstract] Objective To study the efficacy and security of Oseltamivir and substitution therapy for anti- H1N1 infection. Methods Medline, Embase, CBMdisk, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Database were searched for the literature about the treatment of influenza before January 1, 2014. Meta-analysis was performed using the software of Review Manager 4.2. Weighted mean difference and its 95% confidence interval were calculated.

Results A total of 7 randomized controlled trials were identified, including the comparison of Oseltamivir with Lianhuaqingwen Capsule (5 randomized controlled trials) or Yinqiao Powder (2 randomized controlled trials). Based on the systematic evaluation, compared to Oseltamivir, the Yinqiao Powder [WMD = -6.21, 95%CI (-84.19, 71.76), P = 0.88] and Lianhuaqingwen Capsule [WMD = -0.24, 95%CI (-4.79, 4.31), P = 0.92] had similar effect in turning viral nucleic acid negative. Compared to Oseltamivir, the Yinqiao Powder had similar effect in defervescence [WMD = 5.66, 95%CI (-32.02, 43.35), P = 0.77], thus the Lianhuaqingwen Capsule were more effective in defervescence [WMD = -4.65, 95%CI (-8.91, -0.38), P = 0.03], and cough alleviation [WMD = -9.79, 95%CI (-14.61, -4.97), P < 0.01]. Conclusion Alternative medicine exhibited potential positive effect in the treatment of influenza.

[Key words] H1N1; Infection; Alternative or complementary medicine

当前,流感仍旧是威胁人类健康的全球性主要公共卫生问题[1]。作为重要的抗流感病毒治疗药物,奥司他韦被广泛用于人类感染流感病毒后的抗感染治疗。文献报道,奥司他韦可以阻止流感病毒颗粒从被感染的宿主细胞中释放,缩短流感症状的持续时间以及降低严重并发症的出现[2]。然而,病毒的耐药出现是奥司他韦最主要的缺点[3]。所以,寻求安全有效的奥司他韦替代疗法势在必行。

在我国,中医治疗传染性疾病有悠久的历史。有研究显示,中医药用于流感病毒感染的治疗是有效的[4],但相关循证医学的证据并不多见。本文采用循证医学方法,对目前报道的中医药治疗流感的随机对照临床研究(randomized controlled trial,RCT)结果进行荟萃分析,以期为临床合理用药提供有价值的参考。

1 资料与方法

1.1 文献检索

检索2014年1月1日之前在Medline、Embase、CBMdisk、CNKI 全文数据库以及万方中文期刊全文数据库公开发表的文献,并追查所有纳入文献的参考文献。外文数据库检索语种为英语。检索词包括“alternative therapy”、“complementary therapy”、“oseltamivir”、“influenza”、“替代治疗”、“补充治疗”、“奥司他韦”、“流感”等。

1.2 纳入与排除标准

纳入同时符合下列条件的研究:①患者年龄≥3岁且有明确的临床和实验室证据;②研究设计为随机对照临床研究;③对照组的治疗采用奥司他韦,治疗组的干预措施为相对固定的替代治疗方法。排除综述、短篇报道以及不能提供全文的文献。

1.3 质量控制

由2名检索人员独立检索并纳入文献,进行文献质量评价和资料提取,然后交叉核对,意见不一致时通过讨论或征求第三方研究者意见解决。质量评价主要从是否采用随机分组、分配方案是否实施盲法、是否报道了退出和失访3个方面进行。

1.4 疗效判定

以发热持续时间、咳嗽持续时间以及病毒脱落(病毒RNA阴转)时间为疗效判定指标。

1.5 统计学方法

采用Cochrane协作网提供的Review Manager 4.2软件(Cochrane Collaboration,Oxford,United Kingdom)行Meta分析。采用加权平均数(weighted mean difference,WMD)作为系统评价的指标,并计算其95%可信区间(confidence interval,CI)。异质性判定依据χ2和I2计算结果:若P > 0.05表明各研究结果之间无统计学异质性,采用固定效应模型进行分析;反之则采用随机效应模型进行分析。

2 结果

2.1 纳入文献一般情况

共检索到2139篇相关文献,经题目和摘要浏览后共有50篇全文文献入选,再经详细阅读和评价后最终纳入7篇RCT研究文献。具体纳入文献及其样本量、干预措施和研究设计见表1。

表1 纳入文献的特征

注:RCT:随机对照试验

2.2 文献分析

2.2.1 银翘散与奥司他韦治疗效果比较 2个试验比较了银翘散与奥司他韦治疗流感的效果。两种药物无论在退热方面[WMD=5.66,95%CI(-32.02,43.35),P = 0.77]还是病毒RNA阴转方面的疗效差异均无统计学意义[WMD=-6.21,95%CI(-84.19,71.76),P = 0.88]。见图1、2。

3 讨论

流感具有较强的传染性,且可引起严重并发症。流感病毒能直接作用于呼吸道上皮,引起上皮细胞脱落坏死、气管炎性细胞浸润及水肿、支气管扩张。病理研究显示,流感病毒感染的支气管表层黏膜上有少量出血,肺泡壁毛细血管扩张充血,有少量单核细胞和淋巴细胞浸润,肺泡腔内有大量水肿液、红细胞和纤维素渗出等病理变化[1]。由于流感病毒的抗原性不断漂移与变异,用流感疫苗预防该病的流行受到一定的限制,导致到目前为止仍没有有效防治流感的方法,因此近年来中草药抗病毒研究已成为当今医药开发关注的热点。

作为替代疗法(alternative therapy),中医通过综合调整人体的功能来诊疗疾病,在全球受到越来越高的重视和欢迎[12]。银翘散是传统中医组方,由连翘、银花、苦桔梗、薄荷、竹叶、生甘草、荆芥穗、淡豆豉、牛蒡子等中药组成。连花清瘟胶囊是中成药,由连翘、金银花、炙麻黄、炒苦杏仁、石膏、板蓝根、绵马贯众、鱼腥草、广藿香、大黄、红景天、薄荷脑、甘草等十几味中药构成;其中,连翘清热解毒,消肿散结;金银花清热透表,解毒利咽,凉血止痢,二者为君药。石膏生用清热泻火,除烦止渴;板蓝根清热,凉血,利咽;大黄泻下攻积,泻火解毒,凉血祛瘀,清热利湿;均为臣药。麻黄发汗解表,宣肺平喘,利水消肿,温经通腠;炒苦杏仁宣肺止咳,降气平喘,润肠通便,杀虫解毒;鱼腥草清热解毒,消痈排脓,利尿通淋;广藿香祛暑解表,化湿醒脾,理气和胃;红景天清肺止咳,健脾养心,止血散瘀;薄荷脑疏散风热,清头目,利咽喉,透疹,结郁;均为佐药。甘草清热、利湿、解毒,调和诸药为使药。诸药合用具有清瘟解毒、宣肺泄热之功效。

奥司他韦是一种抗病毒化学合成药物,其活性代谢产物是强效的选择性的流感病毒神经氨酸酶抑制剂。奥司他韦通过抑制病毒从被感染的细胞中释放,从而减少流感病毒的传播。奥司他韦口服后经胃肠道吸收,在肝脏酯酶的作用下转化为活性代谢产物奥司他韦羧酸而起作用。奥司他韦及其活性代谢产物可分布至肺、气管、鼻黏膜和中耳等病毒感染部位[13-16]。相对于奥司他韦明确的药代学和药效学分布,对银翘散和连花清瘟胶囊等中药抗流感病毒的具体机制还不明确。原因在于中药治疗疾病的机制较复杂,组方药中具体哪一味还是哪几味的相互作用产物起到了实际治疗作用很难被判断。虽然有研究提示连花清瘟胶囊具有综合抑制和多环节抗H1N1流感病毒作用和对病毒吸附的预防作用,还可以抑制病毒吸附后的复制增殖以及直接杀伤病毒[17],但确定银翘散或连花清瘟胶囊如何发挥退热和抗病毒作用仍是一个长远课题。

基于本Meta分析的结果,银翘散加减在退热和流感病毒RNA阴转方面的效果与奥司他韦相似;连花清瘟胶囊虽然在流感病毒RNA阴转方面未表现出优于奥司他韦的效果,但它在缩短热程方面确实存在优势。而且,虽然具体机制不明,但两种中医药在安全性方面没有严重不良反应报道。最值得一提的是,与奥司他韦日益显著的耐药性相比,中医药在病毒耐药方面存在一定优势。

鉴于目前中医药治疗流感病毒感染的RCT研究不多见[18-20],本文纳入文献的数量相对不多,这是本文的局限性所在。但本文在文献检索、纳入标准以及统计分析方面均严格遵循标准的荟萃分析流程,采用国际通用的Review Manager软件绘制森林图,所以,本文结果可以为临床提供有价值的用药参考。

[参考文献]

[1] Gupta D,Varghese,Gupta S,et al. Increasing oral absorption of polar neuraminidase inhibitors:a prodrug transporter approach applied to oseltamivir analogue [J]. Mol Pharm,2013,10(2):512-522.

[2] Yang MS,Law FC,Wong RN,et al. Interaction between oseltamivir and herbal medicines used for treating avian influenza [J]. Hong Kong Med J,2012,18(6):34-36.

[3] Wang YG,Jiang M,Wang RB,et al. Duration of viral shedding of influenza A(H1N1)virus infection treated with oseltamivir and/or traditional Chinese medicine in China:a retrospective analysis [J]. J Tradit Chin Med,2012,32(2):1448-1455.

[4] Liu Z,Wang J,Zhang J,et al. An extract from the earthworm Eisenia fetida non-specifically inhibits the activity of influenza and adenoviruses [J]. J Tradit Chin Med,2012, 32(4):657-663.

[5] Duan ZP,Jia ZH,Zhang J,et al. Natural herbal medicine Lianhuaqingwen capsule anti-influenza A(H1N1)trial:a randomized,double blind,positive controlled clinical trial [J]. Chin Med J(Engl),2011,124(18):2925-2933.

[6] 马羽萍,郭雅玲,康立,等.中药治疗甲型H1N1流感疗效分析[J].陕西中医,2010,30(10):1351-1353.

[7] 刘更新,张艳霞,杨继清.连花清瘟胶囊治疗甲型H1N1流感随机对照临床研究[J].疑难病杂志,2010,9(1):323-325.

[8] 李宝法,张长青,付敏,等.连花清瘟胶囊治疗甲型H1N1流感临床研究[J].医药论坛杂志,2009,30(23):91-92.

[9] 耿丽梅,于向艳.连花清瘟胶囊联合放血拔罐治疗甲型H1N1流感38例[J].河北中医,2011,33(5):753-754.

[10] 张文胜,何成诗,王玥莲.四川省中医药管理局协定处方治疗甲型H1N1流感的临床研究[J].甘肃中医,2011, 24(1):20-22.

[11] 郑海鹏,杨湛,张复春,等.甲型H1N1流感中医治疗疗效分析[J].中华中医药杂志,2010,25(5):780-782.

[12] Wong LY,Leung PC,Pang SY,et al. A herbal formula for prevention of influenza-like syndrome:a double-blind randomized clinical trial [J]. Chin J Integr Med,2013,19(4):253-259.

[13] Greene SK,Li L,Shay DK,et al. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project,2007-2010 [J]. Pharmacoepidemiol Drug Saf,2013,22(4):335-344.

[14] Smith JR,Rayner CR,Donner B,et al. Oseltamivir in seasonal, pandemic, and avian influenza:a comprehensive review of 10-years clinical experience [J]. Adv Ther,2011, 28(11):927-959.

[15] Schirmer P,Holodniy M. Oseltamivir for treatment and prophylaxis of influenza infection [J]. Expert Opin Drug Saf,2009,8(3):357-371.

[16] Groves T. What does oseltamivir do, and how will we know? [J]. BMJ,2013,347:f4687.

[17] 莫红缨,柯昌文,郑劲平,等.连花清瘟胶囊体外抗甲型流感病毒的实验研究[J].中药新药与临床药理,2007, 18(1):5-9.

[18] Hsu CH,Hwang KC,Chao CL,et al. The lesson of supplementary treatment with Chinese medicine on severe laboratory-confirmed SARS patients [J]. Am J Chin Med,2006,34(6):927-935.

[19] Richard M,de Graaf M,Herfst S. Avian influenza A viruses:from zoonosis to pandemic[J]. Future Virol,2014,9(5):513-524.

[20] Zhang SJ,Chen Z,Li GW,et al. Effect of the Haoqinqingdan decoction on damp-heat syndrome in rats with influenza viral pneumonia [J]. Asian Pac J Trop Med,2013, 6(8):653-657.

(收稿日期:2014-06-18 本文编辑:程 铭)

鉴于目前中医药治疗流感病毒感染的RCT研究不多见[18-20],本文纳入文献的数量相对不多,这是本文的局限性所在。但本文在文献检索、纳入标准以及统计分析方面均严格遵循标准的荟萃分析流程,采用国际通用的Review Manager软件绘制森林图,所以,本文结果可以为临床提供有价值的用药参考。

[参考文献]

[1] Gupta D,Varghese,Gupta S,et al. Increasing oral absorption of polar neuraminidase inhibitors:a prodrug transporter approach applied to oseltamivir analogue [J]. Mol Pharm,2013,10(2):512-522.

[2] Yang MS,Law FC,Wong RN,et al. Interaction between oseltamivir and herbal medicines used for treating avian influenza [J]. Hong Kong Med J,2012,18(6):34-36.

[3] Wang YG,Jiang M,Wang RB,et al. Duration of viral shedding of influenza A(H1N1)virus infection treated with oseltamivir and/or traditional Chinese medicine in China:a retrospective analysis [J]. J Tradit Chin Med,2012,32(2):1448-1455.

[4] Liu Z,Wang J,Zhang J,et al. An extract from the earthworm Eisenia fetida non-specifically inhibits the activity of influenza and adenoviruses [J]. J Tradit Chin Med,2012, 32(4):657-663.

[5] Duan ZP,Jia ZH,Zhang J,et al. Natural herbal medicine Lianhuaqingwen capsule anti-influenza A(H1N1)trial:a randomized,double blind,positive controlled clinical trial [J]. Chin Med J(Engl),2011,124(18):2925-2933.

[6] 马羽萍,郭雅玲,康立,等.中药治疗甲型H1N1流感疗效分析[J].陕西中医,2010,30(10):1351-1353.

[7] 刘更新,张艳霞,杨继清.连花清瘟胶囊治疗甲型H1N1流感随机对照临床研究[J].疑难病杂志,2010,9(1):323-325.

[8] 李宝法,张长青,付敏,等.连花清瘟胶囊治疗甲型H1N1流感临床研究[J].医药论坛杂志,2009,30(23):91-92.

[9] 耿丽梅,于向艳.连花清瘟胶囊联合放血拔罐治疗甲型H1N1流感38例[J].河北中医,2011,33(5):753-754.

[10] 张文胜,何成诗,王玥莲.四川省中医药管理局协定处方治疗甲型H1N1流感的临床研究[J].甘肃中医,2011, 24(1):20-22.

[11] 郑海鹏,杨湛,张复春,等.甲型H1N1流感中医治疗疗效分析[J].中华中医药杂志,2010,25(5):780-782.

[12] Wong LY,Leung PC,Pang SY,et al. A herbal formula for prevention of influenza-like syndrome:a double-blind randomized clinical trial [J]. Chin J Integr Med,2013,19(4):253-259.

[13] Greene SK,Li L,Shay DK,et al. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project,2007-2010 [J]. Pharmacoepidemiol Drug Saf,2013,22(4):335-344.

[14] Smith JR,Rayner CR,Donner B,et al. Oseltamivir in seasonal, pandemic, and avian influenza:a comprehensive review of 10-years clinical experience [J]. Adv Ther,2011, 28(11):927-959.

[15] Schirmer P,Holodniy M. Oseltamivir for treatment and prophylaxis of influenza infection [J]. Expert Opin Drug Saf,2009,8(3):357-371.

[16] Groves T. What does oseltamivir do, and how will we know? [J]. BMJ,2013,347:f4687.

[17] 莫红缨,柯昌文,郑劲平,等.连花清瘟胶囊体外抗甲型流感病毒的实验研究[J].中药新药与临床药理,2007, 18(1):5-9.

[18] Hsu CH,Hwang KC,Chao CL,et al. The lesson of supplementary treatment with Chinese medicine on severe laboratory-confirmed SARS patients [J]. Am J Chin Med,2006,34(6):927-935.

[19] Richard M,de Graaf M,Herfst S. Avian influenza A viruses:from zoonosis to pandemic[J]. Future Virol,2014,9(5):513-524.

[20] Zhang SJ,Chen Z,Li GW,et al. Effect of the Haoqinqingdan decoction on damp-heat syndrome in rats with influenza viral pneumonia [J]. Asian Pac J Trop Med,2013, 6(8):653-657.

(收稿日期:2014-06-18 本文编辑:程 铭)

鉴于目前中医药治疗流感病毒感染的RCT研究不多见[18-20],本文纳入文献的数量相对不多,这是本文的局限性所在。但本文在文献检索、纳入标准以及统计分析方面均严格遵循标准的荟萃分析流程,采用国际通用的Review Manager软件绘制森林图,所以,本文结果可以为临床提供有价值的用药参考。

[参考文献]

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[7] 刘更新,张艳霞,杨继清.连花清瘟胶囊治疗甲型H1N1流感随机对照临床研究[J].疑难病杂志,2010,9(1):323-325.

[8] 李宝法,张长青,付敏,等.连花清瘟胶囊治疗甲型H1N1流感临床研究[J].医药论坛杂志,2009,30(23):91-92.

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[13] Greene SK,Li L,Shay DK,et al. Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project,2007-2010 [J]. Pharmacoepidemiol Drug Saf,2013,22(4):335-344.

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[17] 莫红缨,柯昌文,郑劲平,等.连花清瘟胶囊体外抗甲型流感病毒的实验研究[J].中药新药与临床药理,2007, 18(1):5-9.

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[19] Richard M,de Graaf M,Herfst S. Avian influenza A viruses:from zoonosis to pandemic[J]. Future Virol,2014,9(5):513-524.

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(收稿日期:2014-06-18 本文编辑:程 铭)

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