重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的随机对照试验
|
摘要
1．目的
通过现场随机对照试验(randomized controlled trials，RCT)，对远策一号重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的有效性、安全性进行评价，并对其药物经济学价值进行初步分析。
2．方法
(1)采用随机、对照、双盲的平行设计，以某军兵种驻三个地区(广东广州、广东佛山、广西柳州)的2005年度入伍新兵1500人(全部为男性)为研究对象，将符合入选条件的1449名新兵随机分成实验组和对照组，分别使用药物(干扰素1.8×10~6IU／天)和安慰剂，连续使用5天，并在用药前和用药后15天分别采血，ELISA法检测5种常见呼吸道病毒血清IgM抗体水平，比较实验组和对照组的感染率，评价远策一号重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的有效性和保护效果。
(2)记录用药5天及用药后5天期间所有的“可疑不良反应”，对1449名新兵用药期间的体温异常、咳嗽、咽干等多项“可疑不良反应”进行统计描述和分析，并进一步判断反应是否与所试药物有关。
(3)根据随机对照试验的结果资料，对远策一号重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的成本-效果分析(cost-effectiveness analysis，CEA)和成本-效益分析(cost-benefit analysis，CBA)进行初步的分析。
3．结果
(1)随机对照试验中随机化分组进入实验组721例，对照组728人，实验组脱落7例，完成714例，对照组脱落12例，完成716例。两组人群的年龄、文化程度、籍贯等基线情况具有良好的可比性。试验前两组呼吸道病毒IgM抗体的阳性率差异没有统计学意义。
对试验前抗体阴性者用药后血清呼吸道病毒抗体阳性率分析表明，用药组腺病毒(adenovirus，ADV)、呼吸道合胞病毒(respiratory syncytialvirus，RSV)、A型流感病毒(influenza A，IFV-A)、B型流感病毒(influenza B，IFV-B)、副流感病毒(parainfluenza viruses，PIV)五种病毒抗体的阳性率均低于对照组，其中ADV、IFV-A、IFV-B、PIV四种病毒抗体阳性率的差异具有统计学意义(P＜0.05)。遵循研究方案(per protocol，PP)分析和意向性(intention to treat，ITT)分析结果一致。常见的呼吸道病毒ADV、IFV-A、IFV-B、PIV的保护率分别达到了57.6％、71.7％、72.8％、74.2％，每预防一例感染需要治疗的人数(number needed to treat，NNT)分别为24、6、9、8人(PP分析)，达到了较为理想的预防呼吸道病毒感染的保护效果。以对PIV，IFV-B两种病毒的预防效果最佳。
(2)全试验过程中未发生严重不良事件。所有观察到不良反应均为轻微流感样症状，共终止试验7人(实验组1例，对照组6例，均为害怕出现的药物副作用，主动要求终止试验)，所有出现的症状均为轻度可逆反应，持续时间短，无须特殊处理，停药后消失。两组用药5天期间各种症状的平均发生率比较，咽干和鼻涕带血症状发生率的差异有统计学意义。实验组发生咽干和鼻涕带血的概率分别是对照组的1.699和1.783倍。对两组人群每天的各种不良反应发生率分别进行比较，咽干、流鼻涕、鼻涕带血和咽痛的发生率存在统计学差异，药物引起1例咽干、流鼻涕、鼻涕带血或者咽痛不良事件所需要的人数(numberneeded to harm，NNH)分别为9、29、50、94人。
(3)成本效果分析显示每预防1例ADV、IFV-A、IFV-B或PIV病毒分别需要花费人民币72.0元、18.0元、24.0元、24.0元。增量成本效果分析人群的ADV、IFV-A、IFV-B、PIV四种病毒的感染率每下降一个百分点需要的成本分别是527.56元、133.52元、180.25元、183.31元。
成本效益分析只考虑直接治疗药费开支，投入1元用药成本可以获得1.53元的收益，考虑直接治疗药费和间接开支，投入1元用药成本可以获得3.12元的收益。
4．结论
(1)远策一号重组人干扰素α-2b喷雾剂能有效的预防新兵呼吸道常见病毒的感染，对呼吸道病毒感染高发的新兵人群具有良好的保护效果。
(2)远策一号重组人干扰素α-2b喷雾剂使用过程中没有发现严重不良事件。不良反应主要为咽干、流鼻涕等轻度流感样症状。本药物在新兵人群中使用安全可靠。
(3)远策一号重组人干扰素α-2b喷雾剂具有比较理想的经济学价值，具有广泛推广使用的可行性。
Objective:
This randomized controlled trial try to evaluate the effectiveness and safety ofrecombinant human interferonα-2b nasal spray for the prevention of respiratory viralinfections in recruits, and to analyse potential economic value bypharmacoeconomics methods.
Methods:
(1) The parallel double blind randomized controlled design was adopted, and1500 recruits from three districts (Guangzhou and Foshan in Guangdong, Liuzhouin Guangxi) included 721 qualified recruits were assigned randomly to theexperimental group, which take recombinant human interferonα-2b nasal spray lastedfor 5days. The other 728 qualified recruits were in the control group which takeplacebo instead lasted for 5 days as well. Blood was collected before the trial and 15days after taking recombinant human interferonα-2b nasal spray or placebo. Theantibody level against five common respiratory viruses was detected by ELISA. Fromthe comparison of infection positive rate between experimental group and controlgroup, we come to the conclusion of effectiveness and safety of recombinant humaninterferonα-2b nasal spray for preventing infection.
(2) All adverse reactions were recorded five days during and after trial,including abnormal body temperature, cough, dry throat and so on, which werestatistically described and analyzed. The relevance between adverse reactions andrecombinant human interferonα-2b nasal spray was concluded by observation andanalysis during the trial, and the effectiveness of adverse reactions was classified tofive degrees to judge the relevance.
(3) According to the result of randomized controlled trial, Cost-effectivenessanalysis and Cost-benefit analysis of recombinant human interferonα-2b wereevaluated.
Results
(1) After randomization, 721 recruits entered into experimental group, and 728recruits enter into control group. During the trial, 7 cases in experimental group and12 cases in control group were excluded. There were no differences in age, nativeplace,education between two groups. Moreover, the levels of respiratory virus IgMantibodies before trial are also comparable well.
Comparison of respiratory virus IgM positive rate in two groups of recruits whoare respiratory virus IgM negative before the trial showed that the positive rate of allfive respiratory viruses IgM of experimental group were lower than those in thecontrol group, including adenovirus (ADV), respiratory syncytialvirus (RSV),influenza A(IFV-A), influenza B (IFV-B), parainfluenza viruses (PIV). Among five viruses, the positive rate of four of them has statistical significance(P＜0.05). Theanalytic results of per protocol (PP) and intention to treat (ITT) are coherent. Theprotective rates of four common respiratory viruses ADV、IFV-A, IFV-B, PIV are57.6%、71.7%、72.8%、74.2%, which means that 24, 6, 9, and 8 persons should betreated in order to prevent one infection case. The prevention to two viruses of PIV,IFV-B was most efficient.
(2) During the trial, no severe adverse reactions was observed. All adversereactions were insignificant influenza-like syndrome. One case in the experimentalgroup and 6 cases in the control group required out of trial for fear of secondary effect.All adverse reactions were reversible, only lasted for a few days, and recovered afterstopping trial without treatment. The comparison of average occurrence of eachsymptom between two groups during five days treatment showed that there wasstatistic significance in throat dry and bloody nasal mucus, the experimental groupwere 1.699 and 1.783 times than control group respectively. The adverse reactionsoccurrences each day during trial had statistical significance in throat dry, runningnose, bloody nasal mucus, and pharyngodynia, and 9, 29, 50, and 94 persons shouldbe treated if one case of respective adverse reactions happened.
(3) Cost-benefit analysis show that to prevent one case of ADV、IFV-A、IFV-Band PIV need to spend 72, 18, 24, and 24 Yuan respectively. From Cost-benefitanalysis, one percent decrease of four common respiratory viruses infectionprevalence needs to cost 527.26, 133.52, 180.25, and 183.31 Yuan. When the cost ofdirect treatment considered only, one yuan cost can have 1.53 yuan return incost-benefit analysis, and when direct treatment and indirect cost considered, oneyuan can have 3.12 yuan return.
Conclusions
(1) Recombinant human interferonα-2b nasal spray is effective to preventcommon respiratory viruses infection in recruits and have protective efficiency.
(2) No severe adverse reactions was observed during the treatment ofrecombinant human interferonα-2b nasal spray, only some insignificantinfluenza-like syndrome, such as throat dry, nasal mucus. Recombinant humaninterferonα-2b nasal spray is safe when using in the recruits.
(3) Recombinant human interferonα-2b nasal spray have optimistic economicpotential, and is feasible to popularize.
通过现场随机对照试验(randomized controlled trials，RCT)，对远策一号重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的有效性、安全性进行评价，并对其药物经济学价值进行初步分析。
2．方法
(1)采用随机、对照、双盲的平行设计，以某军兵种驻三个地区(广东广州、广东佛山、广西柳州)的2005年度入伍新兵1500人(全部为男性)为研究对象，将符合入选条件的1449名新兵随机分成实验组和对照组，分别使用药物(干扰素1.8×10~6IU／天)和安慰剂，连续使用5天，并在用药前和用药后15天分别采血，ELISA法检测5种常见呼吸道病毒血清IgM抗体水平，比较实验组和对照组的感染率，评价远策一号重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的有效性和保护效果。
(2)记录用药5天及用药后5天期间所有的“可疑不良反应”，对1449名新兵用药期间的体温异常、咳嗽、咽干等多项“可疑不良反应”进行统计描述和分析，并进一步判断反应是否与所试药物有关。
(3)根据随机对照试验的结果资料，对远策一号重组人干扰素α-2b喷雾剂预防新兵呼吸道病毒感染的成本-效果分析(cost-effectiveness analysis，CEA)和成本-效益分析(cost-benefit analysis，CBA)进行初步的分析。
3．结果
(1)随机对照试验中随机化分组进入实验组721例，对照组728人，实验组脱落7例，完成714例，对照组脱落12例，完成716例。两组人群的年龄、文化程度、籍贯等基线情况具有良好的可比性。试验前两组呼吸道病毒IgM抗体的阳性率差异没有统计学意义。
对试验前抗体阴性者用药后血清呼吸道病毒抗体阳性率分析表明，用药组腺病毒(adenovirus，ADV)、呼吸道合胞病毒(respiratory syncytialvirus，RSV)、A型流感病毒(influenza A，IFV-A)、B型流感病毒(influenza B，IFV-B)、副流感病毒(parainfluenza viruses，PIV)五种病毒抗体的阳性率均低于对照组，其中ADV、IFV-A、IFV-B、PIV四种病毒抗体阳性率的差异具有统计学意义(P＜0.05)。遵循研究方案(per protocol，PP)分析和意向性(intention to treat，ITT)分析结果一致。常见的呼吸道病毒ADV、IFV-A、IFV-B、PIV的保护率分别达到了57.6％、71.7％、72.8％、74.2％，每预防一例感染需要治疗的人数(number needed to treat，NNT)分别为24、6、9、8人(PP分析)，达到了较为理想的预防呼吸道病毒感染的保护效果。以对PIV，IFV-B两种病毒的预防效果最佳。
(2)全试验过程中未发生严重不良事件。所有观察到不良反应均为轻微流感样症状，共终止试验7人(实验组1例，对照组6例，均为害怕出现的药物副作用，主动要求终止试验)，所有出现的症状均为轻度可逆反应，持续时间短，无须特殊处理，停药后消失。两组用药5天期间各种症状的平均发生率比较，咽干和鼻涕带血症状发生率的差异有统计学意义。实验组发生咽干和鼻涕带血的概率分别是对照组的1.699和1.783倍。对两组人群每天的各种不良反应发生率分别进行比较，咽干、流鼻涕、鼻涕带血和咽痛的发生率存在统计学差异，药物引起1例咽干、流鼻涕、鼻涕带血或者咽痛不良事件所需要的人数(numberneeded to harm，NNH)分别为9、29、50、94人。
(3)成本效果分析显示每预防1例ADV、IFV-A、IFV-B或PIV病毒分别需要花费人民币72.0元、18.0元、24.0元、24.0元。增量成本效果分析人群的ADV、IFV-A、IFV-B、PIV四种病毒的感染率每下降一个百分点需要的成本分别是527.56元、133.52元、180.25元、183.31元。
成本效益分析只考虑直接治疗药费开支，投入1元用药成本可以获得1.53元的收益，考虑直接治疗药费和间接开支，投入1元用药成本可以获得3.12元的收益。
4．结论
(1)远策一号重组人干扰素α-2b喷雾剂能有效的预防新兵呼吸道常见病毒的感染，对呼吸道病毒感染高发的新兵人群具有良好的保护效果。
(2)远策一号重组人干扰素α-2b喷雾剂使用过程中没有发现严重不良事件。不良反应主要为咽干、流鼻涕等轻度流感样症状。本药物在新兵人群中使用安全可靠。
(3)远策一号重组人干扰素α-2b喷雾剂具有比较理想的经济学价值，具有广泛推广使用的可行性。
Objective:
This randomized controlled trial try to evaluate the effectiveness and safety ofrecombinant human interferonα-2b nasal spray for the prevention of respiratory viralinfections in recruits, and to analyse potential economic value bypharmacoeconomics methods.
Methods:
(1) The parallel double blind randomized controlled design was adopted, and1500 recruits from three districts (Guangzhou and Foshan in Guangdong, Liuzhouin Guangxi) included 721 qualified recruits were assigned randomly to theexperimental group, which take recombinant human interferonα-2b nasal spray lastedfor 5days. The other 728 qualified recruits were in the control group which takeplacebo instead lasted for 5 days as well. Blood was collected before the trial and 15days after taking recombinant human interferonα-2b nasal spray or placebo. Theantibody level against five common respiratory viruses was detected by ELISA. Fromthe comparison of infection positive rate between experimental group and controlgroup, we come to the conclusion of effectiveness and safety of recombinant humaninterferonα-2b nasal spray for preventing infection.
(2) All adverse reactions were recorded five days during and after trial,including abnormal body temperature, cough, dry throat and so on, which werestatistically described and analyzed. The relevance between adverse reactions andrecombinant human interferonα-2b nasal spray was concluded by observation andanalysis during the trial, and the effectiveness of adverse reactions was classified tofive degrees to judge the relevance.
(3) According to the result of randomized controlled trial, Cost-effectivenessanalysis and Cost-benefit analysis of recombinant human interferonα-2b wereevaluated.
Results
(1) After randomization, 721 recruits entered into experimental group, and 728recruits enter into control group. During the trial, 7 cases in experimental group and12 cases in control group were excluded. There were no differences in age, nativeplace,education between two groups. Moreover, the levels of respiratory virus IgMantibodies before trial are also comparable well.
Comparison of respiratory virus IgM positive rate in two groups of recruits whoare respiratory virus IgM negative before the trial showed that the positive rate of allfive respiratory viruses IgM of experimental group were lower than those in thecontrol group, including adenovirus (ADV), respiratory syncytialvirus (RSV),influenza A(IFV-A), influenza B (IFV-B), parainfluenza viruses (PIV). Among five viruses, the positive rate of four of them has statistical significance(P＜0.05). Theanalytic results of per protocol (PP) and intention to treat (ITT) are coherent. Theprotective rates of four common respiratory viruses ADV、IFV-A, IFV-B, PIV are57.6%、71.7%、72.8%、74.2%, which means that 24, 6, 9, and 8 persons should betreated in order to prevent one infection case. The prevention to two viruses of PIV,IFV-B was most efficient.
(2) During the trial, no severe adverse reactions was observed. All adversereactions were insignificant influenza-like syndrome. One case in the experimentalgroup and 6 cases in the control group required out of trial for fear of secondary effect.All adverse reactions were reversible, only lasted for a few days, and recovered afterstopping trial without treatment. The comparison of average occurrence of eachsymptom between two groups during five days treatment showed that there wasstatistic significance in throat dry and bloody nasal mucus, the experimental groupwere 1.699 and 1.783 times than control group respectively. The adverse reactionsoccurrences each day during trial had statistical significance in throat dry, runningnose, bloody nasal mucus, and pharyngodynia, and 9, 29, 50, and 94 persons shouldbe treated if one case of respective adverse reactions happened.
(3) Cost-benefit analysis show that to prevent one case of ADV、IFV-A、IFV-Band PIV need to spend 72, 18, 24, and 24 Yuan respectively. From Cost-benefitanalysis, one percent decrease of four common respiratory viruses infectionprevalence needs to cost 527.26, 133.52, 180.25, and 183.31 Yuan. When the cost ofdirect treatment considered only, one yuan cost can have 1.53 yuan return incost-benefit analysis, and when direct treatment and indirect cost considered, oneyuan can have 3.12 yuan return.
Conclusions
(1) Recombinant human interferonα-2b nasal spray is effective to preventcommon respiratory viruses infection in recruits and have protective efficiency.
(2) No severe adverse reactions was observed during the treatment ofrecombinant human interferonα-2b nasal spray, only some insignificantinfluenza-like syndrome, such as throat dry, nasal mucus. Recombinant humaninterferonα-2b nasal spray is safe when using in the recruits.
(3) Recombinant human interferonα-2b nasal spray have optimistic economicpotential, and is feasible to popularize.
引文
[1] 侯云德主编．急性呼吸道病毒感染的病原学与防治[M]．北京：中国协和医科大学出版社，2005：1-9．
[2] 陈清．关于流行性感冒大流行的几个问题[J]．医学与哲学．2005：26(12)：20-22．
[3] 候云德主编．干扰素及其临床应用[M]．南京：江苏人民科技出版社，1981．
[4] Sung RY, YinJ, Oppenheimer SJ, et al. Treatment of respiratory syncytial virus infection with recombinant interferon alfa-2a. Arch Dis Child, 1993:69 (4) :440-2.
[5] Higgins PG, Phillpotts RJ, Scott GM, et al. Intranasal interferon as protection against experimental respiratory coronavirus infection in volunteers.Antimicrob AgentsChemother. 1983 Nov; 24(5): 713-5.
[6] Monto AS, Albrecht JK, Schwartz SA, et al. Demonstration of dose-response relationship in seasonal prophylaxis of respiratory infections with alpha-2b interferon. Antimicrob Agents Chemother. 1988 Jan; 32(1): 47-50.
[7] Higgins PG, Barrow GI, Tyrrell DA, et al. The efficacy of intranasal interferon alpha-2a in respiratory syncytial virus infection in volunteers. Antiviral Res. 1990 Jul; 14(1): 3-10.
[8] Phillpotts RJ, Higgins PG, Willman JS. Intranasal lymphoblastoid interferon ("Wellferon") prophylaxis against rhinovirus and influenza virus in volunteers. J Interferon Res. 1984 Fall: 4(4): 535-41.
[9] Farr BM, Gwaltney, JM Jr, Adams KF , et al. Intranasal interferon-alpha 2 for prevention of natural rhinovirus colds. Antimicrob Agents Chemother. 1984 Jul: 26(1): 31-4.
[10] Hayden FG, Albrecht JK, Kaiser DL et al . Prevention of natural colds by contact prophylaxis with intranasal alpha 2-interferon. N Engl J Med. 1986 Jan 9; 314(2): 71-5.
[11] Douglas RM, Moore BW, Miles HB, et al. Prophylactic efficacy of intranasal alpha 2-interferon against rhinovirus infections in the family setting.N Engl J Med. 1986 Jan 9; 314(2): 65-70.
[12] Isomura S, Ichikawa T, Miyazu M, et al. The preventive effect of human interferon-alpha on influenza infection modification of clinical manifestations of influenza in children in a dosed community. Biken J. 1982 Sep; 25(3): 131-7.
[13] Iuldashev AK, Slepushkin AN, Khodzhaeva MA, et al. Prophylactic efficacy of reaferon in viral hepatitis A and acute respiratory infections in children Zh Mikrobiol Epidemiol Immunobiol. 1988May; (5): 65-9.
[14] Jefferson TO, Tyrrell D. Antivirals for the common cold. Coehrane Database Syst Rev. 2001; (3): CD002743. Review.
[15] 朱既明．呼吸道传染病．流行病学[M]．北京：人民出版社，1997：312～343．
[16] 段佩若，张容德，林京．8个地区部队官兵流感样疾病发病、缺勤及用药情况调查[J]．解放军预防医学杂志，2001；19(3)：194-195．
[17] 于德宪，刘翼，楚心唯．重组人干扰素α-2b喷雾剂预防军人呼吸道病毒感染的现场试验[J]．疾病控制杂志，2005；9(1)：39-41．
[18] 秦颖，詹思延．NNT：综合评价药物疗效及不良反应新指标[J]．药物不良反应杂志，2001：01：62-65．
[19] Laupaeis A, Sackett DL, Roberts RS. An assessment of C linlcaliy usefuL measures of the consequences of treatment.N Engl J Med. 1988; 318(26): 1728.
[20] 张丽兰，侯云德，吴淑华，等．黄芪对基因工程人α-2b型干扰素抗鼻病毒14型的协同作用[J]．中华实验和临床病毒学杂志，1996；1：77-80．
[21] 段招军，张丽兰，谢志萍，等．不同型别重组人干扰素在细胞培养上抗SARS病毒的研究[J]．中国实验和病毒学杂志，2003；17：205-208．
[22] Turner RB, Felton A, Kosak K, et al. Prevention of experimental coronavirus colds with intranasal alpha-2b interferon. Infect Dis. 1986 Sep; 154(3):443-7.
[23] 胡亚美，江载芳，主编．诸福棠实用儿科学[M]．第7版．北京：人民卫生出版社，2002：1197-1203．
[24] 骆毅，于际生，杜庆生，等．干扰素及其临床应用[M]．北京：中国科学技术出版社，1991：55-64．
[25] Hayden FG, GwaltenyJM. Intranasal interferon alpha-2 for prevention of rhinovirus infection and illnessJ . J Infectdis, 1983 ; 148: 543.
[26] Samo TC, Greenberg SB, Palmer JM, etal. Intranasally applied recombinant leukocyte A interferon in normal volunteers.Ⅱ. Determination of minimal effective and tolerable dose. J Infect Dis. 1984Aug; 150(2): 181-8.
[27] Hayden FG, Mills SE, Johns ME. Human tolerance and histopathologic effects of long-term administration of intranasal interferon-alpha 2. J Infect Dis. 1983 Nov; 148(5):914-21.
[28] Samo TC, Greenberg SB, Couch RB, et al. Efficacy and tolerance of intranasally applied recombinant leukocyte A interferon in normal volunteers. J Infect Dis. 1983 Sep; 148(3): 535-42.
[29] Scott GM, Onwubalili JK, Robinson JA, et al . Tolerance of one-month intranasal interferon. J Med Virol. 1985 Oct; 17(2): 99-106.
[30] MontoAS, Schwartzsa , AlbrechtJK. Ineffectivenessof postexposure pro phylaxisof rhinovirus infection with low-dosein tranasal alpha-2b in terferon infamiliesJ. Antimicrob Agents Chemother. 1989; 33: 387.
[31] 何兰杰，刘萍，白启君．重组人干扰素ω鼻喷剂不良反应临床观察[J]．宁夏医学杂志：2005；27(3)：197-198．
[32] 孙忠实，朱珠．干扰素喷鼻剂初议[J]．中国药学杂志，2003；38(7)：550—551．
[33] 陈平雁．定量数据重复测量的方差分析[J]．中华创伤骨科杂志，2003：5(1)： 67-70．
[34] 张福奎．α-干扰素的不良反应[J]．临床肝胆病杂志，2001；17(2)：80-82．
[35] 陈清，张丽兰，于德宪．重组人干扰素α-2b喷雾剂人群试验的安全性评价[J]．中华实验和临床病毒学杂志．2005：19(3)：211-215．
[36] Jefferson TO, Tyrreli D. Vaccines for the common cold (protocol for a Cochrane review). Cochrane Library. Issue 3. Chichester: John Wiley, 2004.
[37] 陈文．药物经济学概论[J]．中国医学导刊，2002：(3)：45-47．
[38] 胡善联，杨莉，陈慧云主编．药物经济学评价指南研究[M]．上海：复旦大学出版社．2004：23．
[39] http://health.sohu.com/20050913/n240378809.shtml．第一个进入中国的流感疫苗一“凡尔灵”．
[40] Dominique Castagliola PHD , Antoine Flahaull MD , DavidGalinec BSC, et al . A Poutine Tool for Detection and As2 sessmen of Epidemics of Influenza-like Syndromes inFrance. Am J Public Health . 1991; 81 (11) :97.
[41] Szekely L, Bikk A, Galffy G. Prevention of acute respiratory infections in healthy young adults by using oral immunomodulators.Orv Hetil. 1997 Oct 26; 138(43): 2743-6.
[42] 张钧．药物经济学概论[J]．药学实践杂志，1995；13(1)：3～6．
[43] Bootman, R Townsend , W McGhan. Principles of Pharmacoeconomics, Harvey Whitney Books: Cincinnati, 1999.
[44] 孙利华编著．药物经济学与新药研究开发[M]．北京：化学工业出版社，2003．
[45] 中华人民共和国编中国统计年鉴——2006 http://www.stats.gov.cn/tjsj/ndsj/2006/indexch.htm.
[46] 总后卫生部，中国人民解放军旅团卫生队长教材[M]．北京：解放军出版社，1999：238．
[47] Ridderhoff. K, Remund. D. The Department of Defense pharmacy benefit management program. Mil-Med, 2005; 170(4): 302-305.
[48] 中华人民共和国卫生部．《2005年卫生统计公报》．
[49] 储文功．药物经济学在军队药事管理中的应用[J]．中国处方药，2006；4(49)：23-25．
[2] 陈清．关于流行性感冒大流行的几个问题[J]．医学与哲学．2005：26(12)：20-22．
[3] 候云德主编．干扰素及其临床应用[M]．南京：江苏人民科技出版社，1981．
[4] Sung RY, YinJ, Oppenheimer SJ, et al. Treatment of respiratory syncytial virus infection with recombinant interferon alfa-2a. Arch Dis Child, 1993:69 (4) :440-2.
[5] Higgins PG, Phillpotts RJ, Scott GM, et al. Intranasal interferon as protection against experimental respiratory coronavirus infection in volunteers.Antimicrob AgentsChemother. 1983 Nov; 24(5): 713-5.
[6] Monto AS, Albrecht JK, Schwartz SA, et al. Demonstration of dose-response relationship in seasonal prophylaxis of respiratory infections with alpha-2b interferon. Antimicrob Agents Chemother. 1988 Jan; 32(1): 47-50.
[7] Higgins PG, Barrow GI, Tyrrell DA, et al. The efficacy of intranasal interferon alpha-2a in respiratory syncytial virus infection in volunteers. Antiviral Res. 1990 Jul; 14(1): 3-10.
[8] Phillpotts RJ, Higgins PG, Willman JS. Intranasal lymphoblastoid interferon ("Wellferon") prophylaxis against rhinovirus and influenza virus in volunteers. J Interferon Res. 1984 Fall: 4(4): 535-41.
[9] Farr BM, Gwaltney, JM Jr, Adams KF , et al. Intranasal interferon-alpha 2 for prevention of natural rhinovirus colds. Antimicrob Agents Chemother. 1984 Jul: 26(1): 31-4.
[10] Hayden FG, Albrecht JK, Kaiser DL et al . Prevention of natural colds by contact prophylaxis with intranasal alpha 2-interferon. N Engl J Med. 1986 Jan 9; 314(2): 71-5.
[11] Douglas RM, Moore BW, Miles HB, et al. Prophylactic efficacy of intranasal alpha 2-interferon against rhinovirus infections in the family setting.N Engl J Med. 1986 Jan 9; 314(2): 65-70.
[12] Isomura S, Ichikawa T, Miyazu M, et al. The preventive effect of human interferon-alpha on influenza infection modification of clinical manifestations of influenza in children in a dosed community. Biken J. 1982 Sep; 25(3): 131-7.
[13] Iuldashev AK, Slepushkin AN, Khodzhaeva MA, et al. Prophylactic efficacy of reaferon in viral hepatitis A and acute respiratory infections in children Zh Mikrobiol Epidemiol Immunobiol. 1988May; (5): 65-9.
[14] Jefferson TO, Tyrrell D. Antivirals for the common cold. Coehrane Database Syst Rev. 2001; (3): CD002743. Review.
[15] 朱既明．呼吸道传染病．流行病学[M]．北京：人民出版社，1997：312～343．
[16] 段佩若，张容德，林京．8个地区部队官兵流感样疾病发病、缺勤及用药情况调查[J]．解放军预防医学杂志，2001；19(3)：194-195．
[17] 于德宪，刘翼，楚心唯．重组人干扰素α-2b喷雾剂预防军人呼吸道病毒感染的现场试验[J]．疾病控制杂志，2005；9(1)：39-41．
[18] 秦颖，詹思延．NNT：综合评价药物疗效及不良反应新指标[J]．药物不良反应杂志，2001：01：62-65．
[19] Laupaeis A, Sackett DL, Roberts RS. An assessment of C linlcaliy usefuL measures of the consequences of treatment.N Engl J Med. 1988; 318(26): 1728.
[20] 张丽兰，侯云德，吴淑华，等．黄芪对基因工程人α-2b型干扰素抗鼻病毒14型的协同作用[J]．中华实验和临床病毒学杂志，1996；1：77-80．
[21] 段招军，张丽兰，谢志萍，等．不同型别重组人干扰素在细胞培养上抗SARS病毒的研究[J]．中国实验和病毒学杂志，2003；17：205-208．
[22] Turner RB, Felton A, Kosak K, et al. Prevention of experimental coronavirus colds with intranasal alpha-2b interferon. Infect Dis. 1986 Sep; 154(3):443-7.
[23] 胡亚美，江载芳，主编．诸福棠实用儿科学[M]．第7版．北京：人民卫生出版社，2002：1197-1203．
[24] 骆毅，于际生，杜庆生，等．干扰素及其临床应用[M]．北京：中国科学技术出版社，1991：55-64．
[25] Hayden FG, GwaltenyJM. Intranasal interferon alpha-2 for prevention of rhinovirus infection and illnessJ . J Infectdis, 1983 ; 148: 543.
[26] Samo TC, Greenberg SB, Palmer JM, etal. Intranasally applied recombinant leukocyte A interferon in normal volunteers.Ⅱ. Determination of minimal effective and tolerable dose. J Infect Dis. 1984Aug; 150(2): 181-8.
[27] Hayden FG, Mills SE, Johns ME. Human tolerance and histopathologic effects of long-term administration of intranasal interferon-alpha 2. J Infect Dis. 1983 Nov; 148(5):914-21.
[28] Samo TC, Greenberg SB, Couch RB, et al. Efficacy and tolerance of intranasally applied recombinant leukocyte A interferon in normal volunteers. J Infect Dis. 1983 Sep; 148(3): 535-42.
[29] Scott GM, Onwubalili JK, Robinson JA, et al . Tolerance of one-month intranasal interferon. J Med Virol. 1985 Oct; 17(2): 99-106.
[30] MontoAS, Schwartzsa , AlbrechtJK. Ineffectivenessof postexposure pro phylaxisof rhinovirus infection with low-dosein tranasal alpha-2b in terferon infamiliesJ. Antimicrob Agents Chemother. 1989; 33: 387.
[31] 何兰杰，刘萍，白启君．重组人干扰素ω鼻喷剂不良反应临床观察[J]．宁夏医学杂志：2005；27(3)：197-198．
[32] 孙忠实，朱珠．干扰素喷鼻剂初议[J]．中国药学杂志，2003；38(7)：550—551．
[33] 陈平雁．定量数据重复测量的方差分析[J]．中华创伤骨科杂志，2003：5(1)： 67-70．
[34] 张福奎．α-干扰素的不良反应[J]．临床肝胆病杂志，2001；17(2)：80-82．
[35] 陈清，张丽兰，于德宪．重组人干扰素α-2b喷雾剂人群试验的安全性评价[J]．中华实验和临床病毒学杂志．2005：19(3)：211-215．
[36] Jefferson TO, Tyrreli D. Vaccines for the common cold (protocol for a Cochrane review). Cochrane Library. Issue 3. Chichester: John Wiley, 2004.
[37] 陈文．药物经济学概论[J]．中国医学导刊，2002：(3)：45-47．
[38] 胡善联，杨莉，陈慧云主编．药物经济学评价指南研究[M]．上海：复旦大学出版社．2004：23．
[39] http://health.sohu.com/20050913/n240378809.shtml．第一个进入中国的流感疫苗一“凡尔灵”．
[40] Dominique Castagliola PHD , Antoine Flahaull MD , DavidGalinec BSC, et al . A Poutine Tool for Detection and As2 sessmen of Epidemics of Influenza-like Syndromes inFrance. Am J Public Health . 1991; 81 (11) :97.
[41] Szekely L, Bikk A, Galffy G. Prevention of acute respiratory infections in healthy young adults by using oral immunomodulators.Orv Hetil. 1997 Oct 26; 138(43): 2743-6.
[42] 张钧．药物经济学概论[J]．药学实践杂志，1995；13(1)：3～6．
[43] Bootman, R Townsend , W McGhan. Principles of Pharmacoeconomics, Harvey Whitney Books: Cincinnati, 1999.
[44] 孙利华编著．药物经济学与新药研究开发[M]．北京：化学工业出版社，2003．
[45] 中华人民共和国编中国统计年鉴——2006 http://www.stats.gov.cn/tjsj/ndsj/2006/indexch.htm.
[46] 总后卫生部，中国人民解放军旅团卫生队长教材[M]．北京：解放军出版社，1999：238．
[47] Ridderhoff. K, Remund. D. The Department of Defense pharmacy benefit management program. Mil-Med, 2005; 170(4): 302-305.
[48] 中华人民共和国卫生部．《2005年卫生统计公报》．
[49] 储文功．药物经济学在军队药事管理中的应用[J]．中国处方药，2006；4(49)：23-25．