中西医结合治疗初治继发性肺结核方案的临床与实验研究
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摘要
目的客观评价中西医结合治疗初治继发性肺结核方案的疗效及安全性,部分阐明中西医结合疗法治疗初治继发性肺结核的基础药效,初步探索其相关作用机制,为中医药在肺结核防治领域的临床应用提供科学依据。
方法临床试验研究.研究设计：采用多中心、大样本、随机对照研究方案。研究对象：采用计算机中央随机系统将310例初治继发性肺结核患者随机分配到对照组和试验组,并根据痰涂片结果(涂阴/涂阳=1:1)施行分层随机。干预措施：对照组采用2HRZE/4HR化疗方案治疗；试验组采用2HRZE/4HR化疗方案联合辨证中药治疗。观测指标：中医症状积分、痰菌涂片、胸部X片、SF-36生活质量评分、药物不良反应症状、血常规、肝肾功、空腹葡萄糖、血尿酸。基础实验研究采用流式细胞技术检测初治继发性肺结核患者治疗前后T细胞亚群(CD3、CD4、CD8)及Th1/Th2相关细胞因子(IL-2、IFN-γ、IL-4、IL-6、IL-10、TNF-a)的含量变化；采用病理形态学方法观察中药双百口服液与HR联合应用对BCG所致小鼠肺损伤的病理形态学影响；采用小鼠负重游泳试验评价中药双百口服液的抗疲劳作用；采用异烟肼联合利福平致大鼠肝损伤模型观察中药双百口服液对大鼠血清中ALT、AST以及肝组织中CYP2E1、MDA、SOD、GSH-Px含量的影响。
结果临床试验研究患者中医证候疗效判定结果显示,对照组总有效率为90.5%,治愈率为13.8%；试验组总有效率为99.3%,治愈率为51.1%。对照组1月痰菌转阴率为59.3%,试验组1月痰菌转阴率为87.8%,两组患者2月累计痰菌转阴率差异无统计学意义。治疗1月后,对照组胸部X片病灶出现吸收的患者比例为52.6%,试验组为85.6%；治疗6月后,对照组胸部X片病灶明显吸收的患者比例为60.3%,试验组为82.0%。SF-36生活质量评分结果显示,试验组在改善患者生理功能、生理职能、一般健康状况、精力、情感职能、精神健康方面优于对照组。治疗期间,对照组患者持续胃肠道反应发生率为48.3%,试验组为7.9%。抗结核化疗药物对血常规的影响主要表现为PLT和WBC的降低,对照组PLT低于正常值的患者比例为12.38±3.85%,试验组为6.35±4.16%；对照组WBC低于正常值的患者比例为12.93±2.44%,试验组为4.45±1.78%。对照组ALT大于正常值的患者比例最高为29.3%,试验组为16.5%；对照组AST大于正常值的患者比例最高为17.2%,试验组为11.5%。两种治疗方案对患者肾功能指标的影响并不显著,对空腹血糖值的影响也较小。两组患者在接受治疗后,血尿酸均明显升高,此后随着强化期的结束,患者血尿酸含量逐渐降至正常范围。
基础实验研究初治继发性肺结核患者治疗前后T淋巴细胞亚群的整体变化较小,治疗前CD4+、CD8+T淋巴细胞数量小于正常值的患者比例相对较高,治疗6月后CD4+、CD8+T淋巴细胞数量小于正常值的患者比例相对减少,试验组与对照组相比较,差异无统计学意义。治疗前,患者Thl细胞功能是降低的,表现为IL-2及IFN-γ的血清含量较治疗后低；经治疗后,两组患者血清IL-2水平出现先升高后降低的变化,试验组患者升高程度明显大于对照组；试验组患者血清IFN-γ水平也同样出现先升高后降低的变化,而对照组血清IFN-γ水平无明显变化；两组患者血清TNF-a水平在治疗过程中逐渐下降,试验组下降幅度大于对照组。治疗前,Th2细胞功能处于增高状态,其表现为血清IL-4、IL-6、IL-10水平较治疗结束时高；经治疗后,两组患者血清IL-4、IL-6、IL-10含量明显降低,两组比较,差异无统计学意义。中药双百口服液与异烟肼、利福平联合应用可减轻BCG肺损伤模型小鼠的肺部炎症损伤,减少上皮样细胞肉芽肿形成,促进肺组织损伤修复。中药双百口服液可明显延长小鼠负重游泳时间,具有抗疲劳作用。中药双百口服液与异姻肼、利福平联合应用可对抗异烟肼和利福平导致的大鼠血清ALT、AST升高,可降低大鼠肝组织中CYP2E1、MDA的含量,稳定SOD的含量,提高GSH-Px的含量。
结论中西医结合治疗初治继发性肺结核方案疗效确切,安全性较高,其作用优势表现为辨证中药治疗与抗结核化疗药物的联合应用可有效减轻抗结核化疗药物的毒副作用,增强化疗药物的抗痨效果。中西医结合治疗方案的减毒增效作用可能与其增强人体免疫功能,激活与抗结核杆菌相关的细胞免疫,减轻肺组织炎症,减少上皮样细胞肉芽肿的形成,促进肺组织损伤修复,提高机体运动耐力及抗疲劳能力,抑制细胞色素酶CYP2E1及增强肝组织抗氧化能力有关。
Objective
To objectively evaluate the therapeutic effect and safety of regimen of integrated traditional Chinese and western medicine in treating untreated secondary pulmonary tuberculosis; partially expound the basic efficacy of integration of traditional Chinese and western medicine in treating untreated secondary pulmonary tuberculosis, and initially explore its correlated mechanism of action, and provide scientific evidences for clinical application of TCM in preventing and treating pulmonary tuberculosis.
Methods
Clinical trial
Study design:applied research design of multicenter, large sample, and randomized controlled. Object of study:randomly assigned310cases of untreated secondary pulmonary tuberculosis to control group and experimental group by applying computer central stochastic system, and carried out stratified random based on results of sputum smear (smear-negative/smear-positive=1:1). Interventions:the control group was treated by chemotherapy with2HRZE/4HR; while the experimental group was treated by integrated chemotherapy with2HRZE/4HR and herbal treatment on the basis of syndrome differentiation.Observation index:TCM symptoms integral, sputum smears, chest X-rays, SF-36scales in measuring QOL, and symptoms of adverse drug reactions, Routine blood indexes, liver and kidney function indexes, fasting plasma glucose (FPG), and blood uric acid (BUA).
Experimental study
Changes of T-cell subsets (CD3, CD4. CD8) and Th1/Th2(IL-2,IFN-γ, IL-4, IL-6, IL-10, TNF-α) of untreated secondary tuberculosis pulmonary patients before and after the treatment were tested by flow cytometry. The effect of combined application of Shuang Bai Kou Fu Ye (Shuangbai Oral Liquid,双百口服液) and HR on BCG induced lung injury mice was observed by pathological morphology method. The anti-fatigue effect of Shuang Bai Kou Fu Ye was evaluated by mice weight loading swimming test. The effect of Shuang Bai Kou Fu Ye on ALT, AST in serum, and content of CYP2E1, MDA, SOD, and GSH-Px in hepatic tissue was observed by rat liver injury model induced by combination of Isoniazid and Rifampicin.
Results
Clinical trial
The determination results of global clinical efficacy assessment of TCM syndromes shown that total effective rate of control group is90.5%, cure rate is13.8%; and those of experimental group is99.3%and51.1%respectively.1month later, the negative-inverted rate of sputum bacteria of control group was59.3%, and that of experimental group was87.8%; while for that of2month later, the deffrence was not statistical significant between two groups.1month treatment later, the patients' proportion of control group with lesion obsorption shown by chest-X rays was52.6%, and that of experimental group was85.6%. While6months later, that of control group and experimental group was52.6%and85.6%respectively. The results of SF-36 scales shown that physical functioning, role-physical, general health, vitality, role-emotional, mental health of patients in experimental group were better than control group. During the treatment, the incidence of continuous gastrointestinal reaction of patients in control patients was48.3%, and that of experimental group was7.9%. The main influence of antituberculous chemotherapy drugs on blood routine test was PLT and WBC reduction. The portion of patients in control group with PLT lower than normal value was12.38±3.85%, and that of experimental group was6.35±4.16%; while for WBC, the rate of two groups were12.93±2.44%and4.45±1.78%respectively. The highest portion of patients in control group with ALT higher than normal value was29.3%, and that of experimental group was16.5%; while that of AST was17.2%and11.5%respectively. Both regimens had no significant effect on kidney function index, and minor effect on FPG. Afer the treatment, the BUA of both groups increased significantly, however, as ending of the intensive treatment, the BUA gradually reduced to normal range.
Experimental study
There were minor changes of T-cell subsets of untreated secondary pulmonary tuberculosis before and after the treatment. Before the treatment, the portion of patients with less counts than normal value of CD4+, CD8+T-lymphocyte was relatively higher, while6months after the treatment, the portion was relatively reduced. Compared the experimental group with control group, the defference was not statistical significant. Before the treatment, the function of Thl was reduced, manifested by lower content of IL-2and IFN-y in blood serum than post-treatment. After the treatment, IL-2of both groups increased first and decreased then, and the increasing range of experimental group was larger than control group. IFN-y of experimental group also increased first and decreased then, but no significant change for control group. The content of TNF-a in both groups were reducing gradually during the treatment, and the range of experimental group was larger than control group. Before the treatment, the function of Th2cells was hyperactive, manifested by higher level of IL-4, IL-6, and IL-10in blood serum than post-treatment. After the treatment, the content of IL-4, IL-6, IL-10in blood serum reduced significantly, but compared two groups, the difference was not statistical significant. Combined application of Shuang Bai Kou Fu Ye, Isoniazid, and Rifampicin could relieve lung inflammatory injury of BCG induced lung injury model mice, reduce the generation of epithelioid cell granuloma, and promote the repair of lung tissue injury. Shuang Bai Kou Fu Ye could significantly prolong the swimming time of wight loading mice, and had effect of anti-fatigue. Combined application of Shuang Bai Kou Fu Ye, Isoniazid, and Rifampicin could resist rising of ALT and AST caused by Isoniazid, and Rifampicin, reduce content of CYP2E1and MDA in hepatic tissue, stabilize content of SOD, and increase content of GSH-Px.
Conclusion
The regimen of integrated traditional Chinese and western medicine treatment for untreated secondary pulmonary tuberculosis is effective and safe. The advantages manifest in effectively reducing toxicity and side effects, and reinforcing anti-tuberculosis effect of chemotherapy drugs with combined application of herbal treatment on basis of syndrome differentiation and anti-tuberculosis chemotherapy drugs. The action of toxicity-reducing and effect-reiforcing of regimen of integrated traditional Chinese and western medicine treatment may be related with reinforcing immune function, activating cytoimmunity related to anti-tubercle bacillus, relieving the inflammation of lung tissue, reducing the generation of epithelioid cell granuloma, promoting the repair of lung tissue injury, improving exercise tolerance and effect of anti-fatigue, inhibiting cytochrome CYP2E1, and enhancing antioxidant capacity of hepatic tissue.
方法临床试验研究.研究设计：采用多中心、大样本、随机对照研究方案。研究对象：采用计算机中央随机系统将310例初治继发性肺结核患者随机分配到对照组和试验组,并根据痰涂片结果(涂阴/涂阳=1:1)施行分层随机。干预措施：对照组采用2HRZE/4HR化疗方案治疗；试验组采用2HRZE/4HR化疗方案联合辨证中药治疗。观测指标：中医症状积分、痰菌涂片、胸部X片、SF-36生活质量评分、药物不良反应症状、血常规、肝肾功、空腹葡萄糖、血尿酸。基础实验研究采用流式细胞技术检测初治继发性肺结核患者治疗前后T细胞亚群(CD3、CD4、CD8)及Th1/Th2相关细胞因子(IL-2、IFN-γ、IL-4、IL-6、IL-10、TNF-a)的含量变化；采用病理形态学方法观察中药双百口服液与HR联合应用对BCG所致小鼠肺损伤的病理形态学影响；采用小鼠负重游泳试验评价中药双百口服液的抗疲劳作用；采用异烟肼联合利福平致大鼠肝损伤模型观察中药双百口服液对大鼠血清中ALT、AST以及肝组织中CYP2E1、MDA、SOD、GSH-Px含量的影响。
结果临床试验研究患者中医证候疗效判定结果显示,对照组总有效率为90.5%,治愈率为13.8%；试验组总有效率为99.3%,治愈率为51.1%。对照组1月痰菌转阴率为59.3%,试验组1月痰菌转阴率为87.8%,两组患者2月累计痰菌转阴率差异无统计学意义。治疗1月后,对照组胸部X片病灶出现吸收的患者比例为52.6%,试验组为85.6%；治疗6月后,对照组胸部X片病灶明显吸收的患者比例为60.3%,试验组为82.0%。SF-36生活质量评分结果显示,试验组在改善患者生理功能、生理职能、一般健康状况、精力、情感职能、精神健康方面优于对照组。治疗期间,对照组患者持续胃肠道反应发生率为48.3%,试验组为7.9%。抗结核化疗药物对血常规的影响主要表现为PLT和WBC的降低,对照组PLT低于正常值的患者比例为12.38±3.85%,试验组为6.35±4.16%；对照组WBC低于正常值的患者比例为12.93±2.44%,试验组为4.45±1.78%。对照组ALT大于正常值的患者比例最高为29.3%,试验组为16.5%；对照组AST大于正常值的患者比例最高为17.2%,试验组为11.5%。两种治疗方案对患者肾功能指标的影响并不显著,对空腹血糖值的影响也较小。两组患者在接受治疗后,血尿酸均明显升高,此后随着强化期的结束,患者血尿酸含量逐渐降至正常范围。
基础实验研究初治继发性肺结核患者治疗前后T淋巴细胞亚群的整体变化较小,治疗前CD4+、CD8+T淋巴细胞数量小于正常值的患者比例相对较高,治疗6月后CD4+、CD8+T淋巴细胞数量小于正常值的患者比例相对减少,试验组与对照组相比较,差异无统计学意义。治疗前,患者Thl细胞功能是降低的,表现为IL-2及IFN-γ的血清含量较治疗后低；经治疗后,两组患者血清IL-2水平出现先升高后降低的变化,试验组患者升高程度明显大于对照组；试验组患者血清IFN-γ水平也同样出现先升高后降低的变化,而对照组血清IFN-γ水平无明显变化；两组患者血清TNF-a水平在治疗过程中逐渐下降,试验组下降幅度大于对照组。治疗前,Th2细胞功能处于增高状态,其表现为血清IL-4、IL-6、IL-10水平较治疗结束时高；经治疗后,两组患者血清IL-4、IL-6、IL-10含量明显降低,两组比较,差异无统计学意义。中药双百口服液与异烟肼、利福平联合应用可减轻BCG肺损伤模型小鼠的肺部炎症损伤,减少上皮样细胞肉芽肿形成,促进肺组织损伤修复。中药双百口服液可明显延长小鼠负重游泳时间,具有抗疲劳作用。中药双百口服液与异姻肼、利福平联合应用可对抗异烟肼和利福平导致的大鼠血清ALT、AST升高,可降低大鼠肝组织中CYP2E1、MDA的含量,稳定SOD的含量,提高GSH-Px的含量。
结论中西医结合治疗初治继发性肺结核方案疗效确切,安全性较高,其作用优势表现为辨证中药治疗与抗结核化疗药物的联合应用可有效减轻抗结核化疗药物的毒副作用,增强化疗药物的抗痨效果。中西医结合治疗方案的减毒增效作用可能与其增强人体免疫功能,激活与抗结核杆菌相关的细胞免疫,减轻肺组织炎症,减少上皮样细胞肉芽肿的形成,促进肺组织损伤修复,提高机体运动耐力及抗疲劳能力,抑制细胞色素酶CYP2E1及增强肝组织抗氧化能力有关。
Objective
To objectively evaluate the therapeutic effect and safety of regimen of integrated traditional Chinese and western medicine in treating untreated secondary pulmonary tuberculosis; partially expound the basic efficacy of integration of traditional Chinese and western medicine in treating untreated secondary pulmonary tuberculosis, and initially explore its correlated mechanism of action, and provide scientific evidences for clinical application of TCM in preventing and treating pulmonary tuberculosis.
Methods
Clinical trial
Study design:applied research design of multicenter, large sample, and randomized controlled. Object of study:randomly assigned310cases of untreated secondary pulmonary tuberculosis to control group and experimental group by applying computer central stochastic system, and carried out stratified random based on results of sputum smear (smear-negative/smear-positive=1:1). Interventions:the control group was treated by chemotherapy with2HRZE/4HR; while the experimental group was treated by integrated chemotherapy with2HRZE/4HR and herbal treatment on the basis of syndrome differentiation.Observation index:TCM symptoms integral, sputum smears, chest X-rays, SF-36scales in measuring QOL, and symptoms of adverse drug reactions, Routine blood indexes, liver and kidney function indexes, fasting plasma glucose (FPG), and blood uric acid (BUA).
Experimental study
Changes of T-cell subsets (CD3, CD4. CD8) and Th1/Th2(IL-2,IFN-γ, IL-4, IL-6, IL-10, TNF-α) of untreated secondary tuberculosis pulmonary patients before and after the treatment were tested by flow cytometry. The effect of combined application of Shuang Bai Kou Fu Ye (Shuangbai Oral Liquid,双百口服液) and HR on BCG induced lung injury mice was observed by pathological morphology method. The anti-fatigue effect of Shuang Bai Kou Fu Ye was evaluated by mice weight loading swimming test. The effect of Shuang Bai Kou Fu Ye on ALT, AST in serum, and content of CYP2E1, MDA, SOD, and GSH-Px in hepatic tissue was observed by rat liver injury model induced by combination of Isoniazid and Rifampicin.
Results
Clinical trial
The determination results of global clinical efficacy assessment of TCM syndromes shown that total effective rate of control group is90.5%, cure rate is13.8%; and those of experimental group is99.3%and51.1%respectively.1month later, the negative-inverted rate of sputum bacteria of control group was59.3%, and that of experimental group was87.8%; while for that of2month later, the deffrence was not statistical significant between two groups.1month treatment later, the patients' proportion of control group with lesion obsorption shown by chest-X rays was52.6%, and that of experimental group was85.6%. While6months later, that of control group and experimental group was52.6%and85.6%respectively. The results of SF-36 scales shown that physical functioning, role-physical, general health, vitality, role-emotional, mental health of patients in experimental group were better than control group. During the treatment, the incidence of continuous gastrointestinal reaction of patients in control patients was48.3%, and that of experimental group was7.9%. The main influence of antituberculous chemotherapy drugs on blood routine test was PLT and WBC reduction. The portion of patients in control group with PLT lower than normal value was12.38±3.85%, and that of experimental group was6.35±4.16%; while for WBC, the rate of two groups were12.93±2.44%and4.45±1.78%respectively. The highest portion of patients in control group with ALT higher than normal value was29.3%, and that of experimental group was16.5%; while that of AST was17.2%and11.5%respectively. Both regimens had no significant effect on kidney function index, and minor effect on FPG. Afer the treatment, the BUA of both groups increased significantly, however, as ending of the intensive treatment, the BUA gradually reduced to normal range.
Experimental study
There were minor changes of T-cell subsets of untreated secondary pulmonary tuberculosis before and after the treatment. Before the treatment, the portion of patients with less counts than normal value of CD4+, CD8+T-lymphocyte was relatively higher, while6months after the treatment, the portion was relatively reduced. Compared the experimental group with control group, the defference was not statistical significant. Before the treatment, the function of Thl was reduced, manifested by lower content of IL-2and IFN-y in blood serum than post-treatment. After the treatment, IL-2of both groups increased first and decreased then, and the increasing range of experimental group was larger than control group. IFN-y of experimental group also increased first and decreased then, but no significant change for control group. The content of TNF-a in both groups were reducing gradually during the treatment, and the range of experimental group was larger than control group. Before the treatment, the function of Th2cells was hyperactive, manifested by higher level of IL-4, IL-6, and IL-10in blood serum than post-treatment. After the treatment, the content of IL-4, IL-6, IL-10in blood serum reduced significantly, but compared two groups, the difference was not statistical significant. Combined application of Shuang Bai Kou Fu Ye, Isoniazid, and Rifampicin could relieve lung inflammatory injury of BCG induced lung injury model mice, reduce the generation of epithelioid cell granuloma, and promote the repair of lung tissue injury. Shuang Bai Kou Fu Ye could significantly prolong the swimming time of wight loading mice, and had effect of anti-fatigue. Combined application of Shuang Bai Kou Fu Ye, Isoniazid, and Rifampicin could resist rising of ALT and AST caused by Isoniazid, and Rifampicin, reduce content of CYP2E1and MDA in hepatic tissue, stabilize content of SOD, and increase content of GSH-Px.
Conclusion
The regimen of integrated traditional Chinese and western medicine treatment for untreated secondary pulmonary tuberculosis is effective and safe. The advantages manifest in effectively reducing toxicity and side effects, and reinforcing anti-tuberculosis effect of chemotherapy drugs with combined application of herbal treatment on basis of syndrome differentiation and anti-tuberculosis chemotherapy drugs. The action of toxicity-reducing and effect-reiforcing of regimen of integrated traditional Chinese and western medicine treatment may be related with reinforcing immune function, activating cytoimmunity related to anti-tubercle bacillus, relieving the inflammation of lung tissue, reducing the generation of epithelioid cell granuloma, promoting the repair of lung tissue injury, improving exercise tolerance and effect of anti-fatigue, inhibiting cytochrome CYP2E1, and enhancing antioxidant capacity of hepatic tissue.
引文
[1]卫生部疾病预防控制局,卫生部医政司,中国疾病预防控制中心.中国结核病防治规划实施工作指南(2008版)[M].北京：中国协和医科大学出版社,2009；27-28
[2]中华中医药学会.中医内科常见病诊疗指南中医病证部分[M].北京：中国中医药出版社,2008；14-15
[3]WS288-2008.中华人民共和国卫生行业标准肺结核诊断标准[S].北京：人民卫生出版社
[4]Ware JE, Kosinski M, Keller S. SF-36 Physical and Mental Health Summary Scales:A User's Manual [M]. Boston, MA:The Health Institute, New England Medical Center; 1994
[5]郑筱萸.中药新药临床研究指导原则[M].北京：中国医药科技出版社,2004；58
[6]Chen L, Wang J, Zganiacz A, et al. Single Intranasal Mucosal Mycobacterium bovis BCG Vaccination Confers Improved Protection Compared to Subcutaneous Vaccination against Pulmonary Tuberculosis[J]. Infection and Immunity,2004; 72(1): 238-246
[7]魏伟,吴希美,李元建.药理实验方法学第4版[M].北京：人民卫生出版社.2010；71
[8]肖志勇.抗结核药物的毒副作用及其防治[J].现代中西医结合杂志,2001；10(23)：2323
[9]董芳,王胜圣,周杰,等.中医药防治肺结核的优势及发展趋势[J].中医临床研究,,2011；3(12)：113-114
[10]Raja A. Immunology of tuberculosis[J]. Indian J Med Res,2004; 120(4):213-232
[11]吴守芝,宋俊峰.结核分枝杆菌致病机制与免疫[J].中华结核和呼吸杂志,2003；26(2)：101-103
[12]Grotzke JE, Lewinsohn DM. Role of CD8+ T lymphocytes in control of mycobacterium tuberculosis infection [J]. Microbes Infect,2005; 7(4):776-788.
[13]Lazarevic V, Nolt D, Flynn J. Long-term control of Mycobacterium tuberculosis infecion is mediated by dynamic immune responses [J]. J Immunol,2005; 175(2):1107-1117
[14]雷建平.正确认识CD8细胞在结核病免疫治疗效果评价中的意义[J].中华结核和呼吸杂志,2003；26(2)：112-113
[15]Pichugin AV, Petrovskaya SN, Apt AS. H2 complex controls CD4/CD8 ratio, recurrent responsiveness to repeated stimulations, and resistance to activation-induced apoptosis during T cell response to mycobacterial antigens [J]. J Leukoc Biol,2006; 79(4):739-746
[16]于春宝,左云,王俊玲,等.肺结核病人细胞免疫功能的研究[J].临床肺科杂志,2008；13(2)：138-139
[17]Lin Y, Zhang M, Hofman FM, et al. Absence of a prominent Th2 cytokine response in human tuberculosis. Infect Immun,1996; 64:1351-1356
[18]Brown DB, Miles BA, Zwilling HS. Growth of bacterium tuberculosis in BCG-resistant and susceptible mice:establishment of latency and reactivation [J]. Infect Immun,1993; 63:2243-2245
[19]Mosmann TR, Moore KW. The role of IL-10 in cross-regulation of Thl and Th2 responses [J]. Immunol Today,1991; 12:A49-A53
[20]Gajewski TF, Fitch FW. Anti-proliferative effect of IFN-γ in immune regulation. Ⅰ. IFN-γ inhibits the proliferation of Th2 but not Thl murine helper T lymphocyte clones [J]. J Immunol,1988; 140:4245-4252
[21]Flesch IE, Kaufmann SH. Mechanisms involved in mycobacteria growth inhibition by gamma interferon-activated bone marrow macrophages:role of reactive nitrogen intermediates. Infect Immun,1991; 59:3213-3218.
[22]巴德年.当代免疫学技术与应用.北京：北京医科大学中国协和医科大学联合出版社,1998；66
[23]Ivan Roitt, Jonathan Brostoff, David Male. Immunology, Sixth edition [M]. Harcourt Publishers Limited,2001; 379
[24]Ivan Roitt, Jonathan Brostoff, David Male. Immunology, Sixth edition [M]. Harcourt Publishers Limited,2001; 126
[25]Appelberg R, Orme IM, Pinto De Sousa MI, et al. In vitro effects of IL-4 on IFN γ-induced macrophage activation [M]. Immunology,1992; 76:583.
[26]张学群,刘红梅,王洪霞.抗结核药物副作用的对策[J].临床肺科杂志,2004；9(4)：405
[27]Sun F,Chen Y,Xiang Y, et al. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury:a meta-analysis[J]. Int J Tuberc Lung Dis,2008; 12(9):994-1002
[28]刘晨辉,乐江.细胞色素P4.50 CYP2E1酶构型特征及其表达调控机制研究进展[J].中国药理学与毒理学杂志,20l0；24(2)：155
[29]Saukkonen J J, Cohn D L, Jasmer R M, et a.l An official ATS statement: hepatotoxicity of antituberculosis therapy [J]. Am J Respir Crit CareMed,2006; 174(8): 935-952.
[30]陈慧敏,高南南.中药抗氧化作用治疗酒精性肝损伤的研究进展[J].中华中医药杂志,2009；24(7)：912
[31]肖霞,王公法,王群.过度训练对大鼠心肌线粒体MDA,SOD,GSH-Px,PLA2及Ca2+浓度的影响[J].海南大学学报,2009；27(1)：34-36
[32]李萍,赵莹,余霆.肌酐在肾小球滤过功能损伤诊断中的价值的系统评价[J].中国循证医学杂志,2004；4(11)：752
[33]冯治宇,马志明,邝浩斌.肺结核合并糖尿病的疗效分析[J].现代医院,2010；10(7)：50-51.
[34]杨焕群,蔡志敏,王渚钦.肺结核病合并糖尿病134例临床特点分析[J].广东医学,2010；31(14)：1854-1855
[35]施华芳,姜冬九,李乐之,等.病人依从性的研究进展[J].中华护理杂志,2003；38(2)：]34
[36]Ormerod L P, Prescott R J. Interrelations between relapses, drug regimens and compliance with treatment in tuberculosis [J]. Respir Med.1991; 85(3):239
[37]米志奎,陈小平.肺结核板式组合药化疗的依从性因素分析[J].安徽医药,2011；15(10)：1247
[38]林勇明,严非,陈求扬,等.肺结核病患者治疗依从性影响因素分析[J].中国公共卫生,2006；22(12)：1468
[39]康华,蒋晓莲.肺结核病人服药依从性的研究进展[J].护理学杂志,2004；19(15)：76-77
[40]沈建恩,雷涛,王祖恩,等.肺结核病人化疗依从性相关因素研究[J].中国防痨杂志,2007；29(2)：133
[41]周明霞.影响肺结核患者化疗依从性相关因素及预防对策临[J].临床和实验医学杂志,2012；11(2)：138
[1]何家荣主编.实用结核病学[M].北京：科学技术文献出版社,2000；6
[2]闻玉梅.现代医学微生物学[M].上海：上海医科大学出版社,1999；504
[3]徐瑞兰.猫爪草胶囊治疗颈部淋巴结结核204例临床分析[J].中国防痨杂志,2002；24(1)：54.
[4]张玉明.猫爪草胶囊加基本化疗方案治疗初发肺结核[J].临床肺科杂志,2002；7(4)：85.
[5]詹莉,戴华成,杨治平等.小毛莨内酯影响耐药结核患者外周血淋巴细胞SHSP和GLS表达的研究[J].中国中药杂志,2002；27(9)：677.
[6]刘金伟,王金河,仲斌,等.大蒜素结核杆菌体外抑菌效果观察[J].人民军医,2001；44(4)：236.
[7]汪仲元.大蒜素、黄连素对结合杆菌抑制能力的测定[J].山东医刊,1961；11：36.
[8]匡铁吉,董梅,宋萍：等.黄连素对结合分枝杆菌的体外抑菌作用[J].中国中药杂志,2001；26(12)：867.
[9]胡树德.中药优福宁的毒性及体外抗结核活性的实验研究[J].中国中药科技,1998；5(1)：12.
[10]李华安,李洪栋,曲迅,等.水车前抗结核的初步研究[J].中国中药杂志,1995；20(2)：115.
[11]李洪敏,冯端浩：曹晶,等.中药苦参碱对结核杆菌的抑制作用[J].解放军药学学报,2002；18(6)：383.384.
[12]路西明,王建刚,侯香波,等.白头翁对利福平异烟肼肝毒性研究[J].中国中医药信息杂志,1998；5(8)：17-21.
[13]路西明,王建刚.王建军,等.中药白头翁治疗淋巴结核52例[J].北京中医药大学学报,1995,18(3)：封底.
[14]尹海波,王颖,郑太坤,等.中国莅草属植物的研究进展[J].辽宁中医学院学报,2001；3(1)：60-61.
[15]贺新怀,席孝贤.中医药免疫学[M].北京：人民军医出版社,2002；296.
[16]国家医药管理局中草药情报中心站.植物药有效成分手册,第1版[M].北京：人民卫生出版社,1986；576-679.
[17]焦安国,滑东方.中药回生灵抗结核作用实验研究概述[J].中国中医药科技,1995；2(5)：46-47.
[18]王玲,张才军,谢蒲伶,等.杨氏欣痨宁胶囊对结核杆菌感染豚鼠模型的保护效应[J].山东中医杂志,2003；22(1)：D7-D8.
[19]郭威,刘佳文,马伟路,等.扶正益气合剂抗结核杆菌活性的初步研究[J].临床肺科杂志,2001；6(1)：24.
[20]李建国,樊蔚虹,张莉,等.抗痨颗粒药理作用的实验研究[J].中国中医药信息杂 志,2000；7(7)：21.
[21]王璞,罗永艾,黄习臣,等.肺泰胶囊辅助治疗初治肺结核的临床研究[J].重庆医科大学学报,2005；30(6)：881-883.
[22]陈星浩,宁小艳,吕红.复方益肝灵胶囊预防抗结核药对肝损害疗效观察[J].现代医药卫生,2006；12：1771-1772.
[23]吴英梅,黄永雄,袁桂秀.五酯胶囊预防抗结核药对肝功能损害疗效观察[J].广东药学,2005;3：40-42,
[24]罗凯.益肺止咳胶囊辅助治疗复治涂阳肺结核临床观察[J].医药论坛,2009；13：70-72.
[25]中药抗结核病新药“芪贝胶囊”问世[J].中国中医药信息杂志,2001；5：24.
[2]中华中医药学会.中医内科常见病诊疗指南中医病证部分[M].北京：中国中医药出版社,2008；14-15
[3]WS288-2008.中华人民共和国卫生行业标准肺结核诊断标准[S].北京：人民卫生出版社
[4]Ware JE, Kosinski M, Keller S. SF-36 Physical and Mental Health Summary Scales:A User's Manual [M]. Boston, MA:The Health Institute, New England Medical Center; 1994
[5]郑筱萸.中药新药临床研究指导原则[M].北京：中国医药科技出版社,2004；58
[6]Chen L, Wang J, Zganiacz A, et al. Single Intranasal Mucosal Mycobacterium bovis BCG Vaccination Confers Improved Protection Compared to Subcutaneous Vaccination against Pulmonary Tuberculosis[J]. Infection and Immunity,2004; 72(1): 238-246
[7]魏伟,吴希美,李元建.药理实验方法学第4版[M].北京：人民卫生出版社.2010；71
[8]肖志勇.抗结核药物的毒副作用及其防治[J].现代中西医结合杂志,2001；10(23)：2323
[9]董芳,王胜圣,周杰,等.中医药防治肺结核的优势及发展趋势[J].中医临床研究,,2011；3(12)：113-114
[10]Raja A. Immunology of tuberculosis[J]. Indian J Med Res,2004; 120(4):213-232
[11]吴守芝,宋俊峰.结核分枝杆菌致病机制与免疫[J].中华结核和呼吸杂志,2003；26(2)：101-103
[12]Grotzke JE, Lewinsohn DM. Role of CD8+ T lymphocytes in control of mycobacterium tuberculosis infection [J]. Microbes Infect,2005; 7(4):776-788.
[13]Lazarevic V, Nolt D, Flynn J. Long-term control of Mycobacterium tuberculosis infecion is mediated by dynamic immune responses [J]. J Immunol,2005; 175(2):1107-1117
[14]雷建平.正确认识CD8细胞在结核病免疫治疗效果评价中的意义[J].中华结核和呼吸杂志,2003；26(2)：112-113
[15]Pichugin AV, Petrovskaya SN, Apt AS. H2 complex controls CD4/CD8 ratio, recurrent responsiveness to repeated stimulations, and resistance to activation-induced apoptosis during T cell response to mycobacterial antigens [J]. J Leukoc Biol,2006; 79(4):739-746
[16]于春宝,左云,王俊玲,等.肺结核病人细胞免疫功能的研究[J].临床肺科杂志,2008；13(2)：138-139
[17]Lin Y, Zhang M, Hofman FM, et al. Absence of a prominent Th2 cytokine response in human tuberculosis. Infect Immun,1996; 64:1351-1356
[18]Brown DB, Miles BA, Zwilling HS. Growth of bacterium tuberculosis in BCG-resistant and susceptible mice:establishment of latency and reactivation [J]. Infect Immun,1993; 63:2243-2245
[19]Mosmann TR, Moore KW. The role of IL-10 in cross-regulation of Thl and Th2 responses [J]. Immunol Today,1991; 12:A49-A53
[20]Gajewski TF, Fitch FW. Anti-proliferative effect of IFN-γ in immune regulation. Ⅰ. IFN-γ inhibits the proliferation of Th2 but not Thl murine helper T lymphocyte clones [J]. J Immunol,1988; 140:4245-4252
[21]Flesch IE, Kaufmann SH. Mechanisms involved in mycobacteria growth inhibition by gamma interferon-activated bone marrow macrophages:role of reactive nitrogen intermediates. Infect Immun,1991; 59:3213-3218.
[22]巴德年.当代免疫学技术与应用.北京：北京医科大学中国协和医科大学联合出版社,1998；66
[23]Ivan Roitt, Jonathan Brostoff, David Male. Immunology, Sixth edition [M]. Harcourt Publishers Limited,2001; 379
[24]Ivan Roitt, Jonathan Brostoff, David Male. Immunology, Sixth edition [M]. Harcourt Publishers Limited,2001; 126
[25]Appelberg R, Orme IM, Pinto De Sousa MI, et al. In vitro effects of IL-4 on IFN γ-induced macrophage activation [M]. Immunology,1992; 76:583.
[26]张学群,刘红梅,王洪霞.抗结核药物副作用的对策[J].临床肺科杂志,2004；9(4)：405
[27]Sun F,Chen Y,Xiang Y, et al. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury:a meta-analysis[J]. Int J Tuberc Lung Dis,2008; 12(9):994-1002
[28]刘晨辉,乐江.细胞色素P4.50 CYP2E1酶构型特征及其表达调控机制研究进展[J].中国药理学与毒理学杂志,20l0；24(2)：155
[29]Saukkonen J J, Cohn D L, Jasmer R M, et a.l An official ATS statement: hepatotoxicity of antituberculosis therapy [J]. Am J Respir Crit CareMed,2006; 174(8): 935-952.
[30]陈慧敏,高南南.中药抗氧化作用治疗酒精性肝损伤的研究进展[J].中华中医药杂志,2009；24(7)：912
[31]肖霞,王公法,王群.过度训练对大鼠心肌线粒体MDA,SOD,GSH-Px,PLA2及Ca2+浓度的影响[J].海南大学学报,2009；27(1)：34-36
[32]李萍,赵莹,余霆.肌酐在肾小球滤过功能损伤诊断中的价值的系统评价[J].中国循证医学杂志,2004；4(11)：752
[33]冯治宇,马志明,邝浩斌.肺结核合并糖尿病的疗效分析[J].现代医院,2010；10(7)：50-51.
[34]杨焕群,蔡志敏,王渚钦.肺结核病合并糖尿病134例临床特点分析[J].广东医学,2010；31(14)：1854-1855
[35]施华芳,姜冬九,李乐之,等.病人依从性的研究进展[J].中华护理杂志,2003；38(2)：]34
[36]Ormerod L P, Prescott R J. Interrelations between relapses, drug regimens and compliance with treatment in tuberculosis [J]. Respir Med.1991; 85(3):239
[37]米志奎,陈小平.肺结核板式组合药化疗的依从性因素分析[J].安徽医药,2011；15(10)：1247
[38]林勇明,严非,陈求扬,等.肺结核病患者治疗依从性影响因素分析[J].中国公共卫生,2006；22(12)：1468
[39]康华,蒋晓莲.肺结核病人服药依从性的研究进展[J].护理学杂志,2004；19(15)：76-77
[40]沈建恩,雷涛,王祖恩,等.肺结核病人化疗依从性相关因素研究[J].中国防痨杂志,2007；29(2)：133
[41]周明霞.影响肺结核患者化疗依从性相关因素及预防对策临[J].临床和实验医学杂志,2012；11(2)：138
[1]何家荣主编.实用结核病学[M].北京：科学技术文献出版社,2000；6
[2]闻玉梅.现代医学微生物学[M].上海：上海医科大学出版社,1999；504
[3]徐瑞兰.猫爪草胶囊治疗颈部淋巴结结核204例临床分析[J].中国防痨杂志,2002；24(1)：54.
[4]张玉明.猫爪草胶囊加基本化疗方案治疗初发肺结核[J].临床肺科杂志,2002；7(4)：85.
[5]詹莉,戴华成,杨治平等.小毛莨内酯影响耐药结核患者外周血淋巴细胞SHSP和GLS表达的研究[J].中国中药杂志,2002；27(9)：677.
[6]刘金伟,王金河,仲斌,等.大蒜素结核杆菌体外抑菌效果观察[J].人民军医,2001；44(4)：236.
[7]汪仲元.大蒜素、黄连素对结合杆菌抑制能力的测定[J].山东医刊,1961；11：36.
[8]匡铁吉,董梅,宋萍：等.黄连素对结合分枝杆菌的体外抑菌作用[J].中国中药杂志,2001；26(12)：867.
[9]胡树德.中药优福宁的毒性及体外抗结核活性的实验研究[J].中国中药科技,1998；5(1)：12.
[10]李华安,李洪栋,曲迅,等.水车前抗结核的初步研究[J].中国中药杂志,1995；20(2)：115.
[11]李洪敏,冯端浩：曹晶,等.中药苦参碱对结核杆菌的抑制作用[J].解放军药学学报,2002；18(6)：383.384.
[12]路西明,王建刚,侯香波,等.白头翁对利福平异烟肼肝毒性研究[J].中国中医药信息杂志,1998；5(8)：17-21.
[13]路西明,王建刚.王建军,等.中药白头翁治疗淋巴结核52例[J].北京中医药大学学报,1995,18(3)：封底.
[14]尹海波,王颖,郑太坤,等.中国莅草属植物的研究进展[J].辽宁中医学院学报,2001；3(1)：60-61.
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