银翘柴桂颗粒治疗流感的临床与实验研究
|
摘要
[背景]流行性感冒(简称流感)是由流感病毒引起的急性呼吸道传染病,是一种常见病和多发病,经常引起地方性流行,有时引起世界性大流行。二十世纪曾发生过五次世界性流感大流行,给人类带来了深重的灾难。流感带来的损失不容忽视,根据美国科学技术委员会的报告,近年来科技发达的美国每年死于流感的人数为2万-4万,流感成为致死率较高的病毒性传染病；每年用于预防流感的费用和流感引起的劳动力损失超过1.2亿美元。可见流感至今仍是严重危害人类生命和健康的一种传染病。
现代医学在研制抗流感病毒的药物和疫苗方面取得了长足的进步。但流感病毒具有不断发生抗原性变异的特点,抗流感病毒的药物和疫苗又具有一定的局限性,并具有不同程度的副作用。因此,目前尚无理想的防治流感的药物,研究并控制流感的工作任重而道远。
流感属于中医的时行感冒范畴,为外感热病的一种。中医在流感的防治方面积累了丰富的经验,具有独特的优势,成为目前防治流感的重要研究方向。在此背景下,本研究综合伤寒论六经辨证理论及温病学卫气营血、三焦辨证理论,进行了寒温并用中药复方银翘柴桂颗粒治疗流感的理论、临床及实验研究。
[目的]通过动物实验探讨银翘柴桂颗粒在调节免疫、保护脏器、抑制病毒等三方面的作用机制,评价其安全性、有效性,并通过临床实验观察该药物的疗效、症状积分改善、体温下降曲线、外周血细胞等相关指标以进一步了解其临床实用性、安全性及有效性,为银翘柴桂颗粒的临床应用提供实验依据。
动物实验研究
[方法]将NIH小鼠随机分为正常对照组、病毒模型组、金刚烷胺组、中药高、中、低剂量组。各组小鼠在乙醚轻度麻醉下,正常对照组用0.9%生理盐水,其余各组用甲型流感病毒FM1稀释液滴鼻以建立流感病毒感染模型。用药组分别以中药高、中、低剂量及金刚烷胺进行干预,然后根据各部分的具体实验安排进行相关指标检测。主要包括实验：1.急性毒性实验；2.银翘柴桂颗粒相关药效学研究(包括肺指数及死亡保护作用研究)；3.银翘柴桂颗粒对流感病毒FM1感染小鼠巨噬细胞吞噬功能的影响。
[结果](1)急性毒性实验：各用药组小鼠无死亡,实验所取各剂量的银翘柴桂颗粒,无明显致毒性,药物安全。(2)对流感病毒FM1感染小鼠肺炎抑制作用实验：病毒感染组的肺指数较正常对照组明显增高,有显著性差异(P<0.05)。与病毒模型组相比,金刚烷胺组、中药高中低各剂量组的肺指数降低,均有显著性差异(P<0.05),中药各组的剂量与肺指数呈负相关、与肺抑制率呈正相关。(3)对流感病毒FM1感染小鼠的死亡保护作用：与病毒模型组相比,中药高、中剂量组生存时间延长,具有显著性差异(P<0.05)；中药高、中、低剂量组对流感病毒感染小鼠的死亡保护率分别是35%、25%、15%；延长生命率是38.06%、32.26%、25.81%；金刚烷胺组对流感病毒感染小鼠的死亡保护率是60%；延长生命率是43.31%；(4)对流感病毒FM1感染小鼠巨噬细胞吞噬功能的影响：病毒模型组OD值最低,与正常对照组比较,P<0.01,差异显著,说明病毒感染小鼠后其巨噬细胞吞噬功能明显降低；各药物治疗组OD值均较病毒模型组为高,P值均<0.01,差异极显著。
[结论]以上结果说明银翘柴桂颗粒能有效抑制流感病毒感染小鼠的肺部炎症改变,并能延长其生存时间,具有明显的死亡保护作用,同时可以提高病毒感染后小鼠巨噬细胞的吞噬功能,起到调节免疫功能的作用。
临床研究
[方法]以西药抗病毒药奥司他韦及金刚烷胺为对照组药物,对银翘柴桂颗粒进行前瞻性、随机、对照研究。对142例流感患者的症状、体征、不同时间点的体温变化、疾病疗效、中医证候疗效、症状积分改善等指标进行临床观察。
[结果](1)银翘柴桂颗粒在不同时间体温变化率均大于西药组,差异有显著统计学意义(P<0.01)；而且中药大剂量组与中药常规剂量组体温变化率比较有显著统计学差异(P<0.01),对三组体温变化曲线进行比较,经球形检验,差异均有统计学意义(P<0.05)。说明银翘柴桂颗粒的退热效果优于西药组,且大剂量银翘柴桂颗粒退热效果更佳；(2)银翘柴桂颗粒的症状积分改善率大于西药组,差异有显著统计学意义(P<0.01),而中药大剂量组与常规剂量组的症状积分改善率无统计学意义(P>0.05)。银翘柴桂颗粒对流感整体症状的改善明显优于西药组,而银翘柴桂颗粒在改善流感整体症状方面的量效关系未显示出统计学意义；(3)银翘柴桂颗粒两组治疗后外周血白细胞总数、中性粒细胞数较疗前降低,差异有统计学意义(P<0.05),但白细胞总数及中性粒细胞数仍在正常参考值范围内变化。银翘柴桂颗粒两组疗后与疗前相比,淋巴细胞绝对值有升高趋势,差异均有显著统计学意义(P<0.01)。(4)银翘柴桂颗粒在疾病疗效、证候疗效、主症疗效均显著优于西药组,差异有统计学意义(P<0.05),银翘柴桂颗粒的整体疗效明显优于西药组。
[结论]银翘柴桂颗粒具有显著的临床疗效,尤其在退热、改善流感症状方面作用显著,并具有调节免疫的功能。
Objective
Influenza is a common frequent acute respiratory tract infectious disease caused by Influenzal Virus (Ⅳ) which rages in some places even around the world. There were five big rages worldwide in the 20th century that destroyed seriously. Losses caused by flu deserve anything but ignoring. According to the report of American National Science and Technology Council, recently about 20,000 to 40,000 people die of flu annually in U. S. Influenza has been a viral infectious disease with high mortality rate. Expenses for preventing flu and labor loss due to flu amount to over 120 million dollars each year. Flu is still an infectious disease, formidably threatening to human health and life.
There is great advance in the anti-virus study in medicine and vaccine in the field of western medicine. However, for the continuous variation of antigen of bird-flu, the limitations and the side effect of the anti-virus medicine and vaccine in some degree, the perfect method to prevent and cure flu has not come out yet. The research for controlling flu has a long way to go.
Flu belongs to "epidemic cold" in traditional Chinese medicine (TCM) theory, one of exogenous febrile diseases. So far the doctors of TCM have accumulated rich experiences in prevention and curing for eternal febrile diseases by different ways with advantages. Then the paper studied the way of treating influenza in basis of unification of "Differentiation of Six Channels" and "Differentiation of Four Systems(wei, qi, ying, and xue)" and "Differentiation of Tri-energizer".Then in order to study the mechanism and pharmacology of cold-warm combinational compound recipe Yinqiaochaigui granules treating influenza, some experiments are did.
Experimental research were done for investigating the mechanism and evaluating the security and effectiveness of Yinqiaochaigui granules on regulation of the immune, protection of the organs and inhibition of the virus. Clinical research were done by observing the effect, the improvement of symptom scores, the curve of temperature drops, blood cells to clear about Yinqiaochaigui granules' practical, security and effectiveness. So it will provide the experimental evidence for the clinical application of Yinqiaochaigui granules.
Experimental Research Methods
To study the mechanism of Yinqiaochaigui granules to cure influenza, we did some experiments. This experiments takes mouse infected by influenza virus dropping nose as the model and uses Yinqiaochaigui granules to carry out experiments. The NIH into the mice is randomly divided into nine groups:normal control group,model control group, Amantadine group, the group on high dose of traditional Chinese medicine, the group on medium dose of traditional Chinese medicine, the group on low dose of traditional Chinese medicine.
There are 10 mice in each group. Under slight anesthesia caused by ether, the mice are infected by dropping influenza virus into the nose. After the day the virus attacks, medicine is given. Then, according to the objective of every expeiment, relevant indexes are measured. The experiments included:1. Acute toxicity of Yinqiaochaigui granules;2.The pharmacodynamics study including the lung exponent and life protection;3. Study of Yinqiaochaigui granules' influence on the phagocytizing function of IV FMi infected mice's macrophages.
Result
(1) Acute toxicity of Yinqiaochaigui granules:There is no mice died. The traditional Chinese medicine low/medium/high dose have no toxicity.
(2)Study of Yinqiaochaigui granules'influence on the inhibition of the IV FM1 infected mice's pneumonia:compared with normal control group,the lung exponent of the model group increase obviously which have significant difference(P<0.05). Compared with the model group,the lung exponent of amantadine group and traditional Chinese medicine low/medium/high dose group all reduced which have significant difference(P<0.05). Besides, the correlation of lung exponent and the medicine dose are negative, inhibition rate of lung and the medicine are positive.
(3) Study of Yinqiaochaigui granules, influence on the protection of theⅣFM1 infected mice, s death:Compared with model group, the average life time of the FM1 infected mice in traditional Chinese medicine of high/medium/low dose groups all improved obviously;The life protection rate of the FM1 infected mice in traditional Chinese medicine of high/medium/low dose groups were 35%,25%,15%. The health extension rate of the FM1 infected mice in traditional Chinese medicine of high/medium/low dose groups were 38.06%, 32.26%,25.18%. The life protection rate and the health extension rate of the FM1 infected mice in amantadine group were 60%,43.31%.
(4) Study of Yinqiaochaigui granules'influence on the phagocytizing function ofⅣFM1 infected mice's macrophages:Compared with normal control group, the OD(optical delnsity) of model group was lower (P<0.05) which indicate the phagocytizing function ofⅣFM1 infected mice's macrophages reduced obviously;Compared with model group, the OD of medication groups were higher(P<0.01).
Conclusion
Summary, Yinqiaochaigui granules can alleviate the pathological changes in the lung of FM1 infected mice and have a protective and life extension effect on FM1 infected mice. Meanwhile, Yinqiaochaigui granules can improve the phagocytizing function ofⅣinfected mice's macrophages so that have the regulative funcation of the immune.
Clinical Research Methods
This research uses the forward-looking clinical stochastic comparison plan. The selected cases collected from the Guangzhou University of Traditional Chinese Medicine First Affiliated Hospital of outpatient and emergency patients, were randomly divided into the traditional Chinese medicine high dose group, the traditional Chinese medicine conventional dose group and the pure western medicine group three groups, integrates the case number is 142 examples. The symptoms, signs, the improvement of symptom scores, the curve of temperature drops of patients were observed in the research.
Result
(1)Compared with the western medicine group,the changing rate of temperature in different time of Yinqiaochaigui granules' groups were higher(P<0.01). And The traditional Chinese medicine conventional dose group and traditional Chinese medicine high dose group were more significant statistic difference (P<0.01). Comparing the curve of temperature drops of the three groups with test of sphericity, the statistic difference were all significant(P<0.05).The result indicate that the effect of defervescence of Yinqiaochaigui granules was superior to western group, high dose Yinqiaoachaigui granules was more effective.
(2) The improvement rate of symptom scores of Yinqiaochaigui granules groups were higher than western group(P<0.01). But the difference between the improvement rate of symptom scores of Yinqiaochaigui granules high dose group and conventional dose group was not significant(P>0.05). Compare with the reduction of integration of flu syndromes, the Yinqiaochaigui groups were superior to the western one. There was not dose-effect relationship between the two groups of Yinqiaochaigui.
(3)The WBC and Neutrophils of Yinqiaochaigui granules goups were reduced after treatment. But the change of WBC and neutrophils was in the normal range. The lymphocytes have increasing tendency after the treatment of Yinqiaochaigui granules groups, the difference was significant (P<0.01).
(4)The therapeutic effect, TCM syndromes effect of Yinqiaochaigui granules groups were superior to the western group, the difference was significant (P<0.05). The integrated effect of Yinqiaochaigui granules was obviously superior to the western medicine.
Conclusion
Yinqiaochaigui granules have the significant clinical effect, especially in the fact of defervescence and alleviating flu symptoms. And the immune regulative funcation of Yinqiaochaigui granules was confirmed.
现代医学在研制抗流感病毒的药物和疫苗方面取得了长足的进步。但流感病毒具有不断发生抗原性变异的特点,抗流感病毒的药物和疫苗又具有一定的局限性,并具有不同程度的副作用。因此,目前尚无理想的防治流感的药物,研究并控制流感的工作任重而道远。
流感属于中医的时行感冒范畴,为外感热病的一种。中医在流感的防治方面积累了丰富的经验,具有独特的优势,成为目前防治流感的重要研究方向。在此背景下,本研究综合伤寒论六经辨证理论及温病学卫气营血、三焦辨证理论,进行了寒温并用中药复方银翘柴桂颗粒治疗流感的理论、临床及实验研究。
[目的]通过动物实验探讨银翘柴桂颗粒在调节免疫、保护脏器、抑制病毒等三方面的作用机制,评价其安全性、有效性,并通过临床实验观察该药物的疗效、症状积分改善、体温下降曲线、外周血细胞等相关指标以进一步了解其临床实用性、安全性及有效性,为银翘柴桂颗粒的临床应用提供实验依据。
动物实验研究
[方法]将NIH小鼠随机分为正常对照组、病毒模型组、金刚烷胺组、中药高、中、低剂量组。各组小鼠在乙醚轻度麻醉下,正常对照组用0.9%生理盐水,其余各组用甲型流感病毒FM1稀释液滴鼻以建立流感病毒感染模型。用药组分别以中药高、中、低剂量及金刚烷胺进行干预,然后根据各部分的具体实验安排进行相关指标检测。主要包括实验：1.急性毒性实验；2.银翘柴桂颗粒相关药效学研究(包括肺指数及死亡保护作用研究)；3.银翘柴桂颗粒对流感病毒FM1感染小鼠巨噬细胞吞噬功能的影响。
[结果](1)急性毒性实验：各用药组小鼠无死亡,实验所取各剂量的银翘柴桂颗粒,无明显致毒性,药物安全。(2)对流感病毒FM1感染小鼠肺炎抑制作用实验：病毒感染组的肺指数较正常对照组明显增高,有显著性差异(P<0.05)。与病毒模型组相比,金刚烷胺组、中药高中低各剂量组的肺指数降低,均有显著性差异(P<0.05),中药各组的剂量与肺指数呈负相关、与肺抑制率呈正相关。(3)对流感病毒FM1感染小鼠的死亡保护作用：与病毒模型组相比,中药高、中剂量组生存时间延长,具有显著性差异(P<0.05)；中药高、中、低剂量组对流感病毒感染小鼠的死亡保护率分别是35%、25%、15%；延长生命率是38.06%、32.26%、25.81%；金刚烷胺组对流感病毒感染小鼠的死亡保护率是60%；延长生命率是43.31%；(4)对流感病毒FM1感染小鼠巨噬细胞吞噬功能的影响：病毒模型组OD值最低,与正常对照组比较,P<0.01,差异显著,说明病毒感染小鼠后其巨噬细胞吞噬功能明显降低；各药物治疗组OD值均较病毒模型组为高,P值均<0.01,差异极显著。
[结论]以上结果说明银翘柴桂颗粒能有效抑制流感病毒感染小鼠的肺部炎症改变,并能延长其生存时间,具有明显的死亡保护作用,同时可以提高病毒感染后小鼠巨噬细胞的吞噬功能,起到调节免疫功能的作用。
临床研究
[方法]以西药抗病毒药奥司他韦及金刚烷胺为对照组药物,对银翘柴桂颗粒进行前瞻性、随机、对照研究。对142例流感患者的症状、体征、不同时间点的体温变化、疾病疗效、中医证候疗效、症状积分改善等指标进行临床观察。
[结果](1)银翘柴桂颗粒在不同时间体温变化率均大于西药组,差异有显著统计学意义(P<0.01)；而且中药大剂量组与中药常规剂量组体温变化率比较有显著统计学差异(P<0.01),对三组体温变化曲线进行比较,经球形检验,差异均有统计学意义(P<0.05)。说明银翘柴桂颗粒的退热效果优于西药组,且大剂量银翘柴桂颗粒退热效果更佳；(2)银翘柴桂颗粒的症状积分改善率大于西药组,差异有显著统计学意义(P<0.01),而中药大剂量组与常规剂量组的症状积分改善率无统计学意义(P>0.05)。银翘柴桂颗粒对流感整体症状的改善明显优于西药组,而银翘柴桂颗粒在改善流感整体症状方面的量效关系未显示出统计学意义；(3)银翘柴桂颗粒两组治疗后外周血白细胞总数、中性粒细胞数较疗前降低,差异有统计学意义(P<0.05),但白细胞总数及中性粒细胞数仍在正常参考值范围内变化。银翘柴桂颗粒两组疗后与疗前相比,淋巴细胞绝对值有升高趋势,差异均有显著统计学意义(P<0.01)。(4)银翘柴桂颗粒在疾病疗效、证候疗效、主症疗效均显著优于西药组,差异有统计学意义(P<0.05),银翘柴桂颗粒的整体疗效明显优于西药组。
[结论]银翘柴桂颗粒具有显著的临床疗效,尤其在退热、改善流感症状方面作用显著,并具有调节免疫的功能。
Objective
Influenza is a common frequent acute respiratory tract infectious disease caused by Influenzal Virus (Ⅳ) which rages in some places even around the world. There were five big rages worldwide in the 20th century that destroyed seriously. Losses caused by flu deserve anything but ignoring. According to the report of American National Science and Technology Council, recently about 20,000 to 40,000 people die of flu annually in U. S. Influenza has been a viral infectious disease with high mortality rate. Expenses for preventing flu and labor loss due to flu amount to over 120 million dollars each year. Flu is still an infectious disease, formidably threatening to human health and life.
There is great advance in the anti-virus study in medicine and vaccine in the field of western medicine. However, for the continuous variation of antigen of bird-flu, the limitations and the side effect of the anti-virus medicine and vaccine in some degree, the perfect method to prevent and cure flu has not come out yet. The research for controlling flu has a long way to go.
Flu belongs to "epidemic cold" in traditional Chinese medicine (TCM) theory, one of exogenous febrile diseases. So far the doctors of TCM have accumulated rich experiences in prevention and curing for eternal febrile diseases by different ways with advantages. Then the paper studied the way of treating influenza in basis of unification of "Differentiation of Six Channels" and "Differentiation of Four Systems(wei, qi, ying, and xue)" and "Differentiation of Tri-energizer".Then in order to study the mechanism and pharmacology of cold-warm combinational compound recipe Yinqiaochaigui granules treating influenza, some experiments are did.
Experimental research were done for investigating the mechanism and evaluating the security and effectiveness of Yinqiaochaigui granules on regulation of the immune, protection of the organs and inhibition of the virus. Clinical research were done by observing the effect, the improvement of symptom scores, the curve of temperature drops, blood cells to clear about Yinqiaochaigui granules' practical, security and effectiveness. So it will provide the experimental evidence for the clinical application of Yinqiaochaigui granules.
Experimental Research Methods
To study the mechanism of Yinqiaochaigui granules to cure influenza, we did some experiments. This experiments takes mouse infected by influenza virus dropping nose as the model and uses Yinqiaochaigui granules to carry out experiments. The NIH into the mice is randomly divided into nine groups:normal control group,model control group, Amantadine group, the group on high dose of traditional Chinese medicine, the group on medium dose of traditional Chinese medicine, the group on low dose of traditional Chinese medicine.
There are 10 mice in each group. Under slight anesthesia caused by ether, the mice are infected by dropping influenza virus into the nose. After the day the virus attacks, medicine is given. Then, according to the objective of every expeiment, relevant indexes are measured. The experiments included:1. Acute toxicity of Yinqiaochaigui granules;2.The pharmacodynamics study including the lung exponent and life protection;3. Study of Yinqiaochaigui granules' influence on the phagocytizing function of IV FMi infected mice's macrophages.
Result
(1) Acute toxicity of Yinqiaochaigui granules:There is no mice died. The traditional Chinese medicine low/medium/high dose have no toxicity.
(2)Study of Yinqiaochaigui granules'influence on the inhibition of the IV FM1 infected mice's pneumonia:compared with normal control group,the lung exponent of the model group increase obviously which have significant difference(P<0.05). Compared with the model group,the lung exponent of amantadine group and traditional Chinese medicine low/medium/high dose group all reduced which have significant difference(P<0.05). Besides, the correlation of lung exponent and the medicine dose are negative, inhibition rate of lung and the medicine are positive.
(3) Study of Yinqiaochaigui granules, influence on the protection of theⅣFM1 infected mice, s death:Compared with model group, the average life time of the FM1 infected mice in traditional Chinese medicine of high/medium/low dose groups all improved obviously;The life protection rate of the FM1 infected mice in traditional Chinese medicine of high/medium/low dose groups were 35%,25%,15%. The health extension rate of the FM1 infected mice in traditional Chinese medicine of high/medium/low dose groups were 38.06%, 32.26%,25.18%. The life protection rate and the health extension rate of the FM1 infected mice in amantadine group were 60%,43.31%.
(4) Study of Yinqiaochaigui granules'influence on the phagocytizing function ofⅣFM1 infected mice's macrophages:Compared with normal control group, the OD(optical delnsity) of model group was lower (P<0.05) which indicate the phagocytizing function ofⅣFM1 infected mice's macrophages reduced obviously;Compared with model group, the OD of medication groups were higher(P<0.01).
Conclusion
Summary, Yinqiaochaigui granules can alleviate the pathological changes in the lung of FM1 infected mice and have a protective and life extension effect on FM1 infected mice. Meanwhile, Yinqiaochaigui granules can improve the phagocytizing function ofⅣinfected mice's macrophages so that have the regulative funcation of the immune.
Clinical Research Methods
This research uses the forward-looking clinical stochastic comparison plan. The selected cases collected from the Guangzhou University of Traditional Chinese Medicine First Affiliated Hospital of outpatient and emergency patients, were randomly divided into the traditional Chinese medicine high dose group, the traditional Chinese medicine conventional dose group and the pure western medicine group three groups, integrates the case number is 142 examples. The symptoms, signs, the improvement of symptom scores, the curve of temperature drops of patients were observed in the research.
Result
(1)Compared with the western medicine group,the changing rate of temperature in different time of Yinqiaochaigui granules' groups were higher(P<0.01). And The traditional Chinese medicine conventional dose group and traditional Chinese medicine high dose group were more significant statistic difference (P<0.01). Comparing the curve of temperature drops of the three groups with test of sphericity, the statistic difference were all significant(P<0.05).The result indicate that the effect of defervescence of Yinqiaochaigui granules was superior to western group, high dose Yinqiaoachaigui granules was more effective.
(2) The improvement rate of symptom scores of Yinqiaochaigui granules groups were higher than western group(P<0.01). But the difference between the improvement rate of symptom scores of Yinqiaochaigui granules high dose group and conventional dose group was not significant(P>0.05). Compare with the reduction of integration of flu syndromes, the Yinqiaochaigui groups were superior to the western one. There was not dose-effect relationship between the two groups of Yinqiaochaigui.
(3)The WBC and Neutrophils of Yinqiaochaigui granules goups were reduced after treatment. But the change of WBC and neutrophils was in the normal range. The lymphocytes have increasing tendency after the treatment of Yinqiaochaigui granules groups, the difference was significant (P<0.01).
(4)The therapeutic effect, TCM syndromes effect of Yinqiaochaigui granules groups were superior to the western group, the difference was significant (P<0.05). The integrated effect of Yinqiaochaigui granules was obviously superior to the western medicine.
Conclusion
Yinqiaochaigui granules have the significant clinical effect, especially in the fact of defervescence and alleviating flu symptoms. And the immune regulative funcation of Yinqiaochaigui granules was confirmed.
引文
[1]CDC 2005. Centers for Disease Control. Prevention and Control of Influenza Recommendations of the Advisory Committee on humunization Practices (ACIP).MWR,2005,54(RR08):1-40.
[2]柯雪帆.伤寒论选读[M].上海：上海科学技术出版社,2006,第二版：90-182.
[3]马文良,陈朝俊.仲景温清并用法的探讨[J].光明中医,2006,21(7)：3-4
[4]冯鑫.《伤寒论》寒温并用法浅析[J].辽宁中医杂志,2005,32(5)：408-409
[5]陈华章.《千金方》制方中寒温并用的探讨[J].中医研究,2001,14(3)：3-4
[6]梁颖瑜.论寒温井用在岭南湿热病治疗中的应用.河北中医,2005,27(5)：351-352
[7]钟红卫.黄淑芬教授寒温并用治疗外感发热的经验.四川中医,2009,27(11)：1-3.
[8]曹田梅,张李兴.夏洪生教授寒温并用经验.深圳中西医结合杂志,2010,20(4)：223-225
[9]何仙童,雷长国.温病用温药小议[J].河北中医,2007,29(2)：136
[10]王正直.从历史发展角度谈寒温统一[J].国医论坛,1993；(1)：22.
[11]裘沛然.伤寒温病论争中的若干问题[J].北京中医学院学报,1983；(4)：5.
[12]郭辉雄.六经是寒温统一的基础[J].北京中医学院学报,1983；(4)：7.
[13]黄松章.伤寒六经为基础的寒温综合论[J].北京中医学院学报,1983；(2)：6.
[14]姜建国.论六经辨证与寒温统一[J].山东中医药大学学报,2000；(1)：10.
[15]邓铁涛.外感病辨证统一小议[J].北京中医学院学报,1983；(3)：6.
[16]万友生.八纲统一寒温证治建立热病学科体系[J].北京中医学院学报,1983；(3)：2.
[17]萧敏材.论伤寒与温病学派之争[J].中医杂志,1962；(11)：1.
[18]沈凤阁.关于六经、卫气营血、三焦辨证如何统一的探讨[J].新医药学杂志,1979；(4)： 7.
[19]肖德馨.六经辨证纲要[J].北京中医学院学报,1981；(3)：1.
[201杨麦青.外感病辨证纲要之我见[J].北京中医学院学报,1983；(4)：9.
[21]金雪明,胡仲诩,等.治疗外感热病的经验[J].江苏中医,1996；(12)：5
[22]吴银根,等.中医外感热病学[M].上海：上海科学技术出版社.1991：38.
[23]符友丰.论外感病辨证中的层次特征[J].医学与哲学,1986；(12)：31.
[24]杨进.外感热病辨证的“三维观”[J].陕西中医,1988；(11)：509.
[25]姜春华.伤寒与温病[J].北京中医学院学报,1984；(1)：2.
[26]邓铁涛.邓铁涛医集[M].北京：人民卫生出版社,1995：92.
[27]时文英,张芳,于春艳.银翘解毒汤治疗流行性感冒32例[J].实用医药杂志,2002,19(3)：177.
[28]张俊庚,张磊,朱爱青.清瘟解毒汤治疗时行感冒[J].山东中医杂志,2002,21(9)：539-540.
[29]张树峰.麻黄汤治疗流行性感冒120例报告[J].中医药信息,1995,(4)：42.
[30]李自强.霍香正气散治疗湿温病28例[J].实用中医药杂志,2007,19(7)：346.
[31]唐惠川.三仁汤加减治疗时行感冒180例观察[J].海南医学,1996,(4)：265-266.
[32]霍光磊.浅谈冬春季时行感冒的治疗体会[J].新疆中医药,2001,19(2)：4-5.
[33]胡兆明.柴胡桂枝汤治疗流行性感冒疗效分析[J].时珍国医医药,1998,9(5)：404.
[34]冯颖娥,何晓凤.柴葛解肌汤和麻杏石甘汤治疗时行感冒102例[J].陕西中医,2003,24(3)：234-235.
[35]孟杰,程红.中医药治疗时行感冒78例[J].河南中医,2002,22(5)：69-70.
[36]单桂敏,李凤玲,王双.针灸治疗流感的疗效观察[J].上海针灸杂志.2003,22(4)： 26.
[37]傅小珉.穴位注射鱼腥草治疗流感性咳嗽[J].现代中西医结合杂志.2001,10(15)：1470.
[38]郭振东.中药抗病毒功效卓越[N].上海中医药报,2000,(2)：2-9.
[39]马丙祥,段晓颖,土志超,等.双花喷雾剂治疗小儿上呼吸道感染临床与实验研究.中国中西医结合杂志,2000,20(9)：655.
[40]胡兴昌,郑伟强.板蓝根粗提液抑制流感病毒的实验研究[J].上海师范大学学报(自然科学版),2003,32(1)：62-65.
[41]冯煦,王鸣,赵友谊,等.北柴胡茎叶总黄酮抗流感病毒的作用[J].植物资源与环境学报,2002,11(4)：15-18.
[42]李丽娅,凌秋,崔洪波等.黄芪多糖抗流感病毒的试验.中国中医药科技,2002,9(6)：354.
[43]Kohavashi M, Davis SM, Utsunomiya T, et al. Antiviral effet of gingyosan, a traditional chinese herbal medicine, on influenza A2 virus infection in mice. Am J Chin Med,1999,27(1):53-62.
[44]卢芳国,田道法,朱应武.麻杏石甘汤及其加味方体外抗流感病毒的实验研究[J].中华中西医临床杂志,2004,4(4)：276-277.
[45]卢芳国,田道法,朱应武,等.麻杏甘石汤加味方对A型流感病毒感染小鼠免疫功能的影响[J].中医药学报,2005,33(2)：36-37.
[46]赵武能,卢芳国,张薇,等.麻杏石甘汤及其加味对A型流感病毒感染小鼠T 细胞亚群的影响[J].实用预防医学,2007,14(2)：278-280.
[47]白木公康,王淑娟,庄严.中药葛根汤治疗流感的作用机制研究[J].日本医学介绍,2003,24(5)：237.
[48]Kurokawa M.葛根汤治疗流感的药效评价[J].和汉医学杂志,1998,15(1)：33-39.
[49]李鹏.蒿芩清胆汤的免疫作用研究[J].中医研究,2004,17(5)：22-23.
[50]莫日根.蒿芩清胆汤抗流感病毒的实验研究[J].中医研究,2005.18(5)：16-18.
[51]Simonson L. Pandemic influenza and mortality past evidence and projections for the future. In Board on Global Health. The threat of pandemic influenza Are we ready? The National Academics Press 2004.
[52]徐杜云.糖链在流感病毒侵袭细胞中的作用.化学通报,2000,(6)：31
[53]Okada A, Miura T, Takeuchi H. Biochemistry,2001,40 (20):6053-6060
[54]Portela A, Zurcher T, Nieto A, et al.Adv Virus Res,1999,54 (1): 319-348
[55]Huang x, Liu T, Muller J, et al. Virology,2001,287 (2):405-416
[56]杜文慧.巨细胞病毒感染的临床研究.中华实验和临床病毒学杂志,1991,(3)：277-280
[57]卓安山.NK细胞的基础和临床研究进展.上海免疫学杂志,1991,11 (3)：180-192
[58]Baggiolini M. Chemokines and leukocyte traffic. Nature,1998,392: 565-568
[59]Zlotnik A, Yoshie 0. Chemokines:a new classification system and their role in immunity. Immunity,2000,12:121-127
[60]Matsukura S, Kokubu G, Noda H,et al. Expression of IL-6, IL-8 and RANTES on human bronchial epithelial cells.NCI-H292.induced by influenza virus A. J Allergy Clin Immunol,1996,98:1080-1087
[61]Adache M, Matsukura S, Tokunaga H, et al. Expression of vytokines on human bronchial epithelial cells induced by influenza virus A. Int Arch Allergy Immulo,1997,113:307-311
[62]Spreger H, Meyer RG, Kanfmann A, et al. Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection. J Exp Med,1996,184:1191-1196
[63]Bussfeld D, Kaufmann A, Meyer RG, et al. Differential mononuclear leukocyte attracting chemokines production after stimulation with active and inactived influenza A virus. Cell immunol,1998,186:1-7
[64]Matsukura S, Pirhonen J, Govenius-Vintola C, et al. Influenza A and Sendai viruses induce differential chemokine gene expression and transcription factor activation in human macrophages. Virology,2000, 276:138-147
[65]Skoner DP, Gentile DA. Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus.J Infect Dis,1999,180:10-14
[66]Fritz RA, Hayden FG, Calfee DP, et al. Nasal cytokine and chenokine responses in experimental influenza A virus infection:results of a placebo-controlled trial of intravenous zanamivir treatment. J Infect Dis,1999,180:586-593
[67]巴德年主编.《当代免疫学技术与应用》.北京医科大学、北京协和医科大学联合出版社,1998,第一版,49-71
[68]毕爱华主编.免疫分子(三)-细胞因子,医学免疫学.人民军医出版社,1995,73
[69]李洪霞.白介素-10对急性肺损伤的保护作用.国外医学呼吸系统分册,2000,20(2)： 94-96
[70]Pajkrt D, Camoglio L, Tiel-van Buul MC, et al. Attenuation of proinflammatory response by recombinnant human IL-10 in human endotoxemia:effect of timing of recombinant human IL-10 administration [J].J Immunol,1997,158:3971
[71]川洪新,郭振辉,毛宝龄.白细胞介素-10和地塞米松对人外周血单个核细胞核因子-KB活化及肿瘤坏死因子产生的影响.解放军医学杂志,1999,24(5)：317-20
[72]Le J, Rilcek J. Tumor necrosis factor and interleukin-1 cytokines with multiple overlapping biological activities. Lab Invest,1987,56: 234-248
[73]杨月亮,赵术胜,裴连平.腮腺炎合并脑膜炎急性期脑脊液中IL-1、IL-6、TNF的变化及意义.临床儿科临床杂志,1998,16：219-220
[74]Hurme M, Lahdenpohja N, Santtila S. Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med,1998,30:469-473
[75]Levi G, Minghetti L, Aloisi F. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie,1998,80:899-904
[76]Kostense S, Sun WH, Coney R, et al. Interleukin 12 administration enhances Thl activity but delays recovery from influenza A virus infection in mice. Antiviral Res,1998,38:117-130
[77]赵武述,陈仁,卞志强.现代临床免疫学.北京：人民军医出版社,1994,140,374
[78]de Waal Malefyt R, Abrams J, BennettB, et al.Interleukin 10 (IL-10) inhibits cytokine synthesis by human macrophage:an autoregulatory role of IL-10 produced by raonocytes.J Exp Med,1991,174:1209-1220
[79]Palese P. Making better influenza virus vaccine? Emer Infect D is 2006,12:61-65.
[80]Gambaryan AS, Robertson JS. Matrisivich MN1 Effects of egg-adaptation on the receptor-binding properties of human influenza A and B viruses [J]. Virology,1999,258(2):232-239.
[81]Lankey KL, Treanor JJ, Betts RF, et al. Recombinant baculovirus in 2fluenza A hemagglutinin vaccines are well tolerated and immunogenic inhealthy adults[J]. J Infect Dis,1996,174(4):838-841.
[82]Treanor JJ, Kotkogg K, Betts RF, et al. Evaluation of trivalent, live,coleadapted(CAIV-T) and inactivated (TIV) in 2 fluenza vaccines in prevention of virus infection and illness following challenge of aeulta with wild-type influenza A (H1N1), A(H3N2),and B viruses [J]. Vaccine,1999,18(9):899-906.
[83]Wareing M D. Tannock GA 1 Live attenuated vaccines against influenza; an historical review[J]. Vaccine,2001,19:3320-3330.
[84]罗勇.苏志芬.新一代流感疫苗[J].国外医学预防诊断治疗用生物制品分册,2004,27(3)：113.
[85]de Jong JC. Beyer W E, Palache AM, et al. Mismatch between the 1997/1998 influenza vaccine=induced antibody response to this strain in the elderly [J]. J Med Virol,2000,61(1):94-99.
[86]Fynan E F, Webster R G, Fuller D H, et al. DNA vaccines protective immunizations by parenteral, mucosal, and gene-gun inoculations[J]. PNAS,1993,90(24):11478-11482.
[87]Chen M W, Cheng T J, Huang Y, et al. A consensus-hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses [J]. PNAS,2008,105 (36):13538-13543.
[88]Kodihalli S, Haynes J R, Robinson H L, et al. Cross protection among lethal H5N2 influenza viruses induced by DNA vaccine to the hemagglutinin[J].J Virol,1997,71(5):3391-3396.
[89]Macklin M D, McCabe D, McGregor M W, et al. Immunization of pigs with a particle mediated DNA vaccine to influenza A virus protects against challenge with homologous virus[J].J Virol,1998,72(2): 1491-1491.
[90]Kodihalli S, Goto H, Kobasa D L, et al. DNA vaccine encoding hemagglutinin provides protective immunity against H5N1 influenza virus infection in mice[J].J Virol,1999,73(3):2094-2098.
[91]Ulmer J B, Donnelly J J, Parker S E, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein[J]. Science, 1993,259(5102):1745-1749.
[92]Tao P, Luo M, Pan Z, et al. Enhanced protective immunity against H5N1 influenza virus DNA expressing a chimeric challenge by hemagglutinin vaccination with in combination with an MHC class I-restricted epitope of nucleoprotein in mice[J]. Antiviral Res,2009,81(3):253-260.
[93]Li G X, Tian Z J, Tong G Z, et al. Fusion of Cad with hemagglutinin enhances protective immunity against swine influenza virus[J]. Res Vet Sci,2009,86(3):406-413.
[94]Luo M, Tao P, Pan Z, et al. Immunization with plasmid DNA encoding influenza A virus nucleoprotein fused to a tissue plasminogen activator signal sequence elicits strong immune responses and protection against HSN1 challenge in mice[J]. J Virol Methods,2008, 154(1-2):121-127
[95]Drape R J, Macklin M D, Dean H J, et al. Epidermal DNA vaccine for influenza is immunogenic in humans[J]. Vaccine,2006,24(21): 4475-4481.
[96]Sharpe M, Lynch D, Loudon P, et al. Protection of mice from H5N1 influenza challenge by prophylactic DNA vaccination using particle mediated epidermal delivery[J]. Vaccine,2007,25(34):6392-6398.
[97]Jones S, Evans K, Loudon P T, et al. DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial[J]. Vaccine,2009,27(18):2506-2512.
[98]Wamg J, KirnS, Kovacs F, et al. Structure of Lhe tramsrnernbrane region of Lhe M2 protein H+ channel [J]. Protein Sci,2001,10(11):2241-2250.
[99]Kelly ML, Cook JA, Brown Augsburger P, et al. Demon strating the intrinsic ion channel activity of virally encoded proteins [J]. FEBS Lett,2003, 552(1):61-67.
[100]Salom D, Hill BR, Lear JD, et al. PH-Dependent tetramerization and amantadine binding of Lhe transmembrane helix M2 from the influenza A virus [J].Biochemistry,2000,39(46):14160-14170.
[101]Jefferson T, Deeks J, Derncheli V, et al. Amantadine and rirnantadine for preventing and treating influenza A in adults [J]. Cochrane Database Syst Rev,2004(3):1169.
[102]Saito R, Sakai T, Sato I, et al. Frequency of amantadine resistant influenza A viruses during two seasons featuring cocirculation of H1N1 and H3N2[J]. J Clin Microbiol,2003,41(5):2164-2165.
[103]Astrahan P, Kass I, Cooper MA, et al. A novel method of resistance for influenza against a channel-blocking antiviral drug[J]. Proteins,2004, 55(2):251-257.
[104]Gubareva V, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors[J]. Lancet,2000,355(9206):827-835.
[105]Gubarea LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants[J]. Antimicrobial Agents Chemother,2001,45(12):3403-3408
[106]stiver G. The treatment of influenza with antiviral drugs[J]. CMAJ, 2003,168(1):49-57.
[107]Gubareva LV Molecular mechanisms of influenza virus resisitance to neuraminidase inhibitors[J]. Virus Tes,2004,103(172):199-203.
[108]Matrosovch M, Klenk HD. Natural and synthetic sialic acid containing inhibitors of influenza virus receptor binding [J]. Rev Med Virol,2003, 13(2):85-97.
[109]Reuter JD, Myc A, Hayes MM, et al. Inhibition of viral adhesion and infection by sialic-acid-conjugated dendritic polymers[J]. Bioconjug Chem,1999,10(2):271-278.
[110]Yoshimoto J. Kakui M. Iwasaki H. et al. Identification of a novel HA conformational change inhibitor of human imfluenzu virus[J]. Arch Virs[J],1999,144(5):865-878.
[111]Abe T. Mizuta T. Hatta T. et al.Antisense therapy of influenza[J]. Eur J Pharm Sci,2001,13(1):61-69.
[112]Ge Q, Eisen HN, Chen J. Use of siRNAs to prevent and treat influenza virus infection[J]. Virus Res,2004,102(1):37-42.
[113]Bertrand JR, Pottier M, Vekris A, et al. Comparison of antisense of oligonucleotides and siRNAs in cell culture and in vivo[J]. Biochem Biophys Res Commun,2002,296(4):1000-1004
[114]郭元吉,程小雯.流行性感冒病毒及其实验技术[M].中国三峡出版社,1997：183
[115]中华人民共和国卫生部药政管理局.中药新药研究指南.1993：118.
[116]徐淑云,主编,药理实验方法学[M].北京：人民卫生出版社,1985,第一版：407
[117]黄祯祥,主编.医学病毒学基础及实验技术[M].北京：科学出版社,1990.
[118]傅继华.病毒学实用实验技术[M].济南：山东科学技术出版社,2001：6
[119]赵武述,陈仁,卞志强.现代临床免疫学.北京：人民军医出版社,1994,第一版：374
[120]富杭育,李晓芹,郭淑英.桂枝汤的药理学研究三、对小鼠非特异性屏障机能的影响.中药药理与临床,1988,4(4)：1-4.
[121]流行性感冒的诊断与治疗指南(修订稿).中华结核与呼吸杂志,2005,28(2)：5-9.
[122]Hurme M, Lahdenpohja N, Santtila S. Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med,1998,30: 469-473
[123]杨占秋,余宏.临床病毒学.北京.中国医药科技出版社,2000,第一版：38
[2]柯雪帆.伤寒论选读[M].上海：上海科学技术出版社,2006,第二版：90-182.
[3]马文良,陈朝俊.仲景温清并用法的探讨[J].光明中医,2006,21(7)：3-4
[4]冯鑫.《伤寒论》寒温并用法浅析[J].辽宁中医杂志,2005,32(5)：408-409
[5]陈华章.《千金方》制方中寒温并用的探讨[J].中医研究,2001,14(3)：3-4
[6]梁颖瑜.论寒温井用在岭南湿热病治疗中的应用.河北中医,2005,27(5)：351-352
[7]钟红卫.黄淑芬教授寒温并用治疗外感发热的经验.四川中医,2009,27(11)：1-3.
[8]曹田梅,张李兴.夏洪生教授寒温并用经验.深圳中西医结合杂志,2010,20(4)：223-225
[9]何仙童,雷长国.温病用温药小议[J].河北中医,2007,29(2)：136
[10]王正直.从历史发展角度谈寒温统一[J].国医论坛,1993；(1)：22.
[11]裘沛然.伤寒温病论争中的若干问题[J].北京中医学院学报,1983；(4)：5.
[12]郭辉雄.六经是寒温统一的基础[J].北京中医学院学报,1983；(4)：7.
[13]黄松章.伤寒六经为基础的寒温综合论[J].北京中医学院学报,1983；(2)：6.
[14]姜建国.论六经辨证与寒温统一[J].山东中医药大学学报,2000；(1)：10.
[15]邓铁涛.外感病辨证统一小议[J].北京中医学院学报,1983；(3)：6.
[16]万友生.八纲统一寒温证治建立热病学科体系[J].北京中医学院学报,1983；(3)：2.
[17]萧敏材.论伤寒与温病学派之争[J].中医杂志,1962；(11)：1.
[18]沈凤阁.关于六经、卫气营血、三焦辨证如何统一的探讨[J].新医药学杂志,1979；(4)： 7.
[19]肖德馨.六经辨证纲要[J].北京中医学院学报,1981；(3)：1.
[201杨麦青.外感病辨证纲要之我见[J].北京中医学院学报,1983；(4)：9.
[21]金雪明,胡仲诩,等.治疗外感热病的经验[J].江苏中医,1996；(12)：5
[22]吴银根,等.中医外感热病学[M].上海：上海科学技术出版社.1991：38.
[23]符友丰.论外感病辨证中的层次特征[J].医学与哲学,1986；(12)：31.
[24]杨进.外感热病辨证的“三维观”[J].陕西中医,1988；(11)：509.
[25]姜春华.伤寒与温病[J].北京中医学院学报,1984；(1)：2.
[26]邓铁涛.邓铁涛医集[M].北京：人民卫生出版社,1995：92.
[27]时文英,张芳,于春艳.银翘解毒汤治疗流行性感冒32例[J].实用医药杂志,2002,19(3)：177.
[28]张俊庚,张磊,朱爱青.清瘟解毒汤治疗时行感冒[J].山东中医杂志,2002,21(9)：539-540.
[29]张树峰.麻黄汤治疗流行性感冒120例报告[J].中医药信息,1995,(4)：42.
[30]李自强.霍香正气散治疗湿温病28例[J].实用中医药杂志,2007,19(7)：346.
[31]唐惠川.三仁汤加减治疗时行感冒180例观察[J].海南医学,1996,(4)：265-266.
[32]霍光磊.浅谈冬春季时行感冒的治疗体会[J].新疆中医药,2001,19(2)：4-5.
[33]胡兆明.柴胡桂枝汤治疗流行性感冒疗效分析[J].时珍国医医药,1998,9(5)：404.
[34]冯颖娥,何晓凤.柴葛解肌汤和麻杏石甘汤治疗时行感冒102例[J].陕西中医,2003,24(3)：234-235.
[35]孟杰,程红.中医药治疗时行感冒78例[J].河南中医,2002,22(5)：69-70.
[36]单桂敏,李凤玲,王双.针灸治疗流感的疗效观察[J].上海针灸杂志.2003,22(4)： 26.
[37]傅小珉.穴位注射鱼腥草治疗流感性咳嗽[J].现代中西医结合杂志.2001,10(15)：1470.
[38]郭振东.中药抗病毒功效卓越[N].上海中医药报,2000,(2)：2-9.
[39]马丙祥,段晓颖,土志超,等.双花喷雾剂治疗小儿上呼吸道感染临床与实验研究.中国中西医结合杂志,2000,20(9)：655.
[40]胡兴昌,郑伟强.板蓝根粗提液抑制流感病毒的实验研究[J].上海师范大学学报(自然科学版),2003,32(1)：62-65.
[41]冯煦,王鸣,赵友谊,等.北柴胡茎叶总黄酮抗流感病毒的作用[J].植物资源与环境学报,2002,11(4)：15-18.
[42]李丽娅,凌秋,崔洪波等.黄芪多糖抗流感病毒的试验.中国中医药科技,2002,9(6)：354.
[43]Kohavashi M, Davis SM, Utsunomiya T, et al. Antiviral effet of gingyosan, a traditional chinese herbal medicine, on influenza A2 virus infection in mice. Am J Chin Med,1999,27(1):53-62.
[44]卢芳国,田道法,朱应武.麻杏石甘汤及其加味方体外抗流感病毒的实验研究[J].中华中西医临床杂志,2004,4(4)：276-277.
[45]卢芳国,田道法,朱应武,等.麻杏甘石汤加味方对A型流感病毒感染小鼠免疫功能的影响[J].中医药学报,2005,33(2)：36-37.
[46]赵武能,卢芳国,张薇,等.麻杏石甘汤及其加味对A型流感病毒感染小鼠T 细胞亚群的影响[J].实用预防医学,2007,14(2)：278-280.
[47]白木公康,王淑娟,庄严.中药葛根汤治疗流感的作用机制研究[J].日本医学介绍,2003,24(5)：237.
[48]Kurokawa M.葛根汤治疗流感的药效评价[J].和汉医学杂志,1998,15(1)：33-39.
[49]李鹏.蒿芩清胆汤的免疫作用研究[J].中医研究,2004,17(5)：22-23.
[50]莫日根.蒿芩清胆汤抗流感病毒的实验研究[J].中医研究,2005.18(5)：16-18.
[51]Simonson L. Pandemic influenza and mortality past evidence and projections for the future. In Board on Global Health. The threat of pandemic influenza Are we ready? The National Academics Press 2004.
[52]徐杜云.糖链在流感病毒侵袭细胞中的作用.化学通报,2000,(6)：31
[53]Okada A, Miura T, Takeuchi H. Biochemistry,2001,40 (20):6053-6060
[54]Portela A, Zurcher T, Nieto A, et al.Adv Virus Res,1999,54 (1): 319-348
[55]Huang x, Liu T, Muller J, et al. Virology,2001,287 (2):405-416
[56]杜文慧.巨细胞病毒感染的临床研究.中华实验和临床病毒学杂志,1991,(3)：277-280
[57]卓安山.NK细胞的基础和临床研究进展.上海免疫学杂志,1991,11 (3)：180-192
[58]Baggiolini M. Chemokines and leukocyte traffic. Nature,1998,392: 565-568
[59]Zlotnik A, Yoshie 0. Chemokines:a new classification system and their role in immunity. Immunity,2000,12:121-127
[60]Matsukura S, Kokubu G, Noda H,et al. Expression of IL-6, IL-8 and RANTES on human bronchial epithelial cells.NCI-H292.induced by influenza virus A. J Allergy Clin Immunol,1996,98:1080-1087
[61]Adache M, Matsukura S, Tokunaga H, et al. Expression of vytokines on human bronchial epithelial cells induced by influenza virus A. Int Arch Allergy Immulo,1997,113:307-311
[62]Spreger H, Meyer RG, Kanfmann A, et al. Selective induction of monocyte and not neutrophil-attracting chemokines after influenza A virus infection. J Exp Med,1996,184:1191-1196
[63]Bussfeld D, Kaufmann A, Meyer RG, et al. Differential mononuclear leukocyte attracting chemokines production after stimulation with active and inactived influenza A virus. Cell immunol,1998,186:1-7
[64]Matsukura S, Pirhonen J, Govenius-Vintola C, et al. Influenza A and Sendai viruses induce differential chemokine gene expression and transcription factor activation in human macrophages. Virology,2000, 276:138-147
[65]Skoner DP, Gentile DA. Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus.J Infect Dis,1999,180:10-14
[66]Fritz RA, Hayden FG, Calfee DP, et al. Nasal cytokine and chenokine responses in experimental influenza A virus infection:results of a placebo-controlled trial of intravenous zanamivir treatment. J Infect Dis,1999,180:586-593
[67]巴德年主编.《当代免疫学技术与应用》.北京医科大学、北京协和医科大学联合出版社,1998,第一版,49-71
[68]毕爱华主编.免疫分子(三)-细胞因子,医学免疫学.人民军医出版社,1995,73
[69]李洪霞.白介素-10对急性肺损伤的保护作用.国外医学呼吸系统分册,2000,20(2)： 94-96
[70]Pajkrt D, Camoglio L, Tiel-van Buul MC, et al. Attenuation of proinflammatory response by recombinnant human IL-10 in human endotoxemia:effect of timing of recombinant human IL-10 administration [J].J Immunol,1997,158:3971
[71]川洪新,郭振辉,毛宝龄.白细胞介素-10和地塞米松对人外周血单个核细胞核因子-KB活化及肿瘤坏死因子产生的影响.解放军医学杂志,1999,24(5)：317-20
[72]Le J, Rilcek J. Tumor necrosis factor and interleukin-1 cytokines with multiple overlapping biological activities. Lab Invest,1987,56: 234-248
[73]杨月亮,赵术胜,裴连平.腮腺炎合并脑膜炎急性期脑脊液中IL-1、IL-6、TNF的变化及意义.临床儿科临床杂志,1998,16：219-220
[74]Hurme M, Lahdenpohja N, Santtila S. Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med,1998,30:469-473
[75]Levi G, Minghetti L, Aloisi F. Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie,1998,80:899-904
[76]Kostense S, Sun WH, Coney R, et al. Interleukin 12 administration enhances Thl activity but delays recovery from influenza A virus infection in mice. Antiviral Res,1998,38:117-130
[77]赵武述,陈仁,卞志强.现代临床免疫学.北京：人民军医出版社,1994,140,374
[78]de Waal Malefyt R, Abrams J, BennettB, et al.Interleukin 10 (IL-10) inhibits cytokine synthesis by human macrophage:an autoregulatory role of IL-10 produced by raonocytes.J Exp Med,1991,174:1209-1220
[79]Palese P. Making better influenza virus vaccine? Emer Infect D is 2006,12:61-65.
[80]Gambaryan AS, Robertson JS. Matrisivich MN1 Effects of egg-adaptation on the receptor-binding properties of human influenza A and B viruses [J]. Virology,1999,258(2):232-239.
[81]Lankey KL, Treanor JJ, Betts RF, et al. Recombinant baculovirus in 2fluenza A hemagglutinin vaccines are well tolerated and immunogenic inhealthy adults[J]. J Infect Dis,1996,174(4):838-841.
[82]Treanor JJ, Kotkogg K, Betts RF, et al. Evaluation of trivalent, live,coleadapted(CAIV-T) and inactivated (TIV) in 2 fluenza vaccines in prevention of virus infection and illness following challenge of aeulta with wild-type influenza A (H1N1), A(H3N2),and B viruses [J]. Vaccine,1999,18(9):899-906.
[83]Wareing M D. Tannock GA 1 Live attenuated vaccines against influenza; an historical review[J]. Vaccine,2001,19:3320-3330.
[84]罗勇.苏志芬.新一代流感疫苗[J].国外医学预防诊断治疗用生物制品分册,2004,27(3)：113.
[85]de Jong JC. Beyer W E, Palache AM, et al. Mismatch between the 1997/1998 influenza vaccine=induced antibody response to this strain in the elderly [J]. J Med Virol,2000,61(1):94-99.
[86]Fynan E F, Webster R G, Fuller D H, et al. DNA vaccines protective immunizations by parenteral, mucosal, and gene-gun inoculations[J]. PNAS,1993,90(24):11478-11482.
[87]Chen M W, Cheng T J, Huang Y, et al. A consensus-hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses [J]. PNAS,2008,105 (36):13538-13543.
[88]Kodihalli S, Haynes J R, Robinson H L, et al. Cross protection among lethal H5N2 influenza viruses induced by DNA vaccine to the hemagglutinin[J].J Virol,1997,71(5):3391-3396.
[89]Macklin M D, McCabe D, McGregor M W, et al. Immunization of pigs with a particle mediated DNA vaccine to influenza A virus protects against challenge with homologous virus[J].J Virol,1998,72(2): 1491-1491.
[90]Kodihalli S, Goto H, Kobasa D L, et al. DNA vaccine encoding hemagglutinin provides protective immunity against H5N1 influenza virus infection in mice[J].J Virol,1999,73(3):2094-2098.
[91]Ulmer J B, Donnelly J J, Parker S E, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein[J]. Science, 1993,259(5102):1745-1749.
[92]Tao P, Luo M, Pan Z, et al. Enhanced protective immunity against H5N1 influenza virus DNA expressing a chimeric challenge by hemagglutinin vaccination with in combination with an MHC class I-restricted epitope of nucleoprotein in mice[J]. Antiviral Res,2009,81(3):253-260.
[93]Li G X, Tian Z J, Tong G Z, et al. Fusion of Cad with hemagglutinin enhances protective immunity against swine influenza virus[J]. Res Vet Sci,2009,86(3):406-413.
[94]Luo M, Tao P, Pan Z, et al. Immunization with plasmid DNA encoding influenza A virus nucleoprotein fused to a tissue plasminogen activator signal sequence elicits strong immune responses and protection against HSN1 challenge in mice[J]. J Virol Methods,2008, 154(1-2):121-127
[95]Drape R J, Macklin M D, Dean H J, et al. Epidermal DNA vaccine for influenza is immunogenic in humans[J]. Vaccine,2006,24(21): 4475-4481.
[96]Sharpe M, Lynch D, Loudon P, et al. Protection of mice from H5N1 influenza challenge by prophylactic DNA vaccination using particle mediated epidermal delivery[J]. Vaccine,2007,25(34):6392-6398.
[97]Jones S, Evans K, Loudon P T, et al. DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial[J]. Vaccine,2009,27(18):2506-2512.
[98]Wamg J, KirnS, Kovacs F, et al. Structure of Lhe tramsrnernbrane region of Lhe M2 protein H+ channel [J]. Protein Sci,2001,10(11):2241-2250.
[99]Kelly ML, Cook JA, Brown Augsburger P, et al. Demon strating the intrinsic ion channel activity of virally encoded proteins [J]. FEBS Lett,2003, 552(1):61-67.
[100]Salom D, Hill BR, Lear JD, et al. PH-Dependent tetramerization and amantadine binding of Lhe transmembrane helix M2 from the influenza A virus [J].Biochemistry,2000,39(46):14160-14170.
[101]Jefferson T, Deeks J, Derncheli V, et al. Amantadine and rirnantadine for preventing and treating influenza A in adults [J]. Cochrane Database Syst Rev,2004(3):1169.
[102]Saito R, Sakai T, Sato I, et al. Frequency of amantadine resistant influenza A viruses during two seasons featuring cocirculation of H1N1 and H3N2[J]. J Clin Microbiol,2003,41(5):2164-2165.
[103]Astrahan P, Kass I, Cooper MA, et al. A novel method of resistance for influenza against a channel-blocking antiviral drug[J]. Proteins,2004, 55(2):251-257.
[104]Gubareva V, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors[J]. Lancet,2000,355(9206):827-835.
[105]Gubarea LV, Webster RG, Hayden FG. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants[J]. Antimicrobial Agents Chemother,2001,45(12):3403-3408
[106]stiver G. The treatment of influenza with antiviral drugs[J]. CMAJ, 2003,168(1):49-57.
[107]Gubareva LV Molecular mechanisms of influenza virus resisitance to neuraminidase inhibitors[J]. Virus Tes,2004,103(172):199-203.
[108]Matrosovch M, Klenk HD. Natural and synthetic sialic acid containing inhibitors of influenza virus receptor binding [J]. Rev Med Virol,2003, 13(2):85-97.
[109]Reuter JD, Myc A, Hayes MM, et al. Inhibition of viral adhesion and infection by sialic-acid-conjugated dendritic polymers[J]. Bioconjug Chem,1999,10(2):271-278.
[110]Yoshimoto J. Kakui M. Iwasaki H. et al. Identification of a novel HA conformational change inhibitor of human imfluenzu virus[J]. Arch Virs[J],1999,144(5):865-878.
[111]Abe T. Mizuta T. Hatta T. et al.Antisense therapy of influenza[J]. Eur J Pharm Sci,2001,13(1):61-69.
[112]Ge Q, Eisen HN, Chen J. Use of siRNAs to prevent and treat influenza virus infection[J]. Virus Res,2004,102(1):37-42.
[113]Bertrand JR, Pottier M, Vekris A, et al. Comparison of antisense of oligonucleotides and siRNAs in cell culture and in vivo[J]. Biochem Biophys Res Commun,2002,296(4):1000-1004
[114]郭元吉,程小雯.流行性感冒病毒及其实验技术[M].中国三峡出版社,1997：183
[115]中华人民共和国卫生部药政管理局.中药新药研究指南.1993：118.
[116]徐淑云,主编,药理实验方法学[M].北京：人民卫生出版社,1985,第一版：407
[117]黄祯祥,主编.医学病毒学基础及实验技术[M].北京：科学出版社,1990.
[118]傅继华.病毒学实用实验技术[M].济南：山东科学技术出版社,2001：6
[119]赵武述,陈仁,卞志强.现代临床免疫学.北京：人民军医出版社,1994,第一版：374
[120]富杭育,李晓芹,郭淑英.桂枝汤的药理学研究三、对小鼠非特异性屏障机能的影响.中药药理与临床,1988,4(4)：1-4.
[121]流行性感冒的诊断与治疗指南(修订稿).中华结核与呼吸杂志,2005,28(2)：5-9.
[122]Hurme M, Lahdenpohja N, Santtila S. Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med,1998,30: 469-473
[123]杨占秋,余宏.临床病毒学.北京.中国医药科技出版社,2000,第一版：38