固本防哮饮治疗儿童哮喘缓解期肺脾气虚证的临床和实验研究
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摘要
支气管哮喘是儿童时期最常见的呼吸道慢性疾病之一,也是一种世界性难治性疾病,随着社会的发展,其发病率有越来越高的趋势。哮喘严重危害个人健康,而且给家庭、社会造成巨大的负担,已成为严重的公共卫生问题,引起世界各国的关注。目前西医对于本病缓解期的治疗尚缺乏理想的方法和药物,而中医药具有独特的优势。哮喘缓解期运用中医药对全身进行调节,扶正固本,提高机体抵抗力,减少减轻哮喘发作,是防治哮喘的有效途径。
固本防哮饮处方是来自我科全国著名儿科专家(全国首批500位名老中医药专家之一)江育仁教授经验方,由炙黄芪、党参、白术、茯苓、煅牡蛎、蝉蜕、陈皮、防风、辛夷、五味子和生甘草组成,具有补肺固表,健脾化痰的功效,在江苏省中医院已经应用30多年,疗效确切,临床应用可减少、减轻哮喘发作,增强患儿体质,提高患儿的生存质量和哮喘缓解率。目前,就此处方申报并获批的科技部“十一五”国家科技支撑计划课题“固本防哮饮治疗儿童哮喘缓解期肺脾气虚证的临床评价”正在试验中。本研究的临床部分属于该课题的一部分,实验部分从免疫及气道病理的角度进一步探讨了该处方及其主要活性成分防治哮喘的作用机制。
临床研究部分
2009年1月至2010年3月,遵循中心随机、平行对照试验的原则,在南京中医药大学附属医院、北京中医药大学附属东方医院、山东中医药大学附属医院、湖南中医药大学第一附属医院,对中医药治疗儿童哮喘缓解期肺脾气虚证的有效性、安全性进行了系统观察,本研究目前仍在进行中,现将至2010年3月为止疗程满6个月病例进行统计分析,共100例,其中中药组51例、西药组49例。
目的
采用中心随机、平行对照、多中心临床研究方法,观察中医和西医两种不同治疗方案的治疗效果,客观评价固本防哮饮用于哮喘缓解期,在减少哮喘发作次数、减轻哮喘发作程度等方面的有效性和安全性。
方法
采用多中心、随机、平行对照的方法,对100例哮喘缓解期患儿进行临床研究,试验组采用固本防哮饮口服配合中药穴位敷贴；对照组用普米克都保吸入,疗程均为6个月。疗程结束后对两组患儿的疾病、证候(主、次症)指标进行疗效评价,两组治疗前后主要指标、症状积分进行比较。采用SPSS 13.0软件对结果进行统计分析,包括卡方检验、t检验、Ridit检验分析。
结果
1.中药组对主要疗效指标包括无喘息症状的天数、哮喘发作次数、哮喘发作严重度、上呼吸道感染次数、下呼吸道感染次数的影响
治疗6个月的观察周期中,两组患儿无喘息症状天数、哮喘发作次数和下呼吸道感染次数,经t检验,无明显差异。中药组6个月的上呼吸道感染次数显著低于西药组,经t检验,有统计学差异,p＜0.05。中药组、西药组在疗程第1、3、6个月,上呼吸道感染次数,3、6个月哮喘发作次数、下呼吸道感染次数均显著低于基线状态,经t检验,有统计学差异,p＜0.01,p＜0.05。两组治疗前后总有效率比较,中药组显著高于西药组,经Ridit检验,有统计学差异,p＜0.05。提示中药组和西药组均能减少哮喘患儿的哮喘发作次数,上、下呼吸道感染次数,但中药组在减少呼吸道感染方面,疗效更加显著。
中、西药组干预后,两组患者均未出现Ⅳ级严重哮喘发作。两组患儿在1、3个月时哮喘发作严重程度比较无明显差异；6个月时经Ridit分析,有显著性差异,p＜0.01,中药组Ⅱ级以上的哮喘发作明显少于西药组。
所以,固本防哮饮是治疗儿童哮喘缓解期有效方剂,在维持哮喘患儿无症状的天数、控制哮喘发作次数方面,与普米克都保疗效相近,但能更好地减轻哮喘发作的严重度,并能更好预防呼吸道感染的发生。
2.中药组对患儿中医证候学的影响
经两组证候疗效比较,除3个月时的出汗症状,6个月时的出汗、食欲食量和舌象外,其余两组证候学各时间点评分无显著差异；3个月中药组出汗评分显著低于西药组,6个月时的出汗、食欲食量和舌象评分显著低于西药组,经t检验,有统计学差异p＜0.05,p＜0.01。提示中药组较西药组能够更好地改善患儿的出汗多,食欲不振、食量少,舌象异常的症状。
中药组1个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、舌象和症状积分均显著低于基线,有统计学差异,(p＜0.05,p＜0.01)；西药组1个月的咳嗽、面色和症状积分均显著低于基线(p＜0.05,p＜0.01)；中药组3个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力和症状积分均显著低于基线(p＜0.05,p＜0.01);西药组3个月的咳嗽、气短和症状积分均显著低于基线(p＜0.05,p＜0.01)；中药组6个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力、食欲食量、大便、舌象和症状积分均显著低于基线(p＜0.01);西药组6个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力和症状积分均显著低于基线(p＜0.05,p＜0.01)。
提示中药组和西药组均能改善患儿哮喘缓解期的临床症状,而中药组在改善患儿出汗、食欲食量、舌象方面更具优势。
3.中药组对患儿合并用药天数的影响
合并用药次数两组相比无显著差异,观察时点1个月、3个月合并用药天数两组相比,无显著差异,6个月时及总合并用药天数中药组显著低于西药组。提示中药组能够缩短患儿合并用药的天数。
4.中药组安全性评价：临床试验期间,未见患者血、尿、便常规、心电图及肝肾功能有异常改变,未见患者有其他不良反应发生,表明固本防哮饮临床应用安全。
结论
四个研究中心100例哮喘缓解期肺脾气虚证患儿,治疗期6个月疗效和安全性评价。
1.治疗前后疗效比较,中药组能显著减少患儿哮喘发作次数,减少上、下呼吸道感染次数,并能使哮喘患儿临床症状：鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力、食欲食量大便、舌象得以改善,使症状总积分显著降低；
2.中药组和西药组疗效比较,固本防哮饮在维持哮喘患儿无症状的天数,控制哮喘发作次数方面,与普米克都保疗效相近,但能更好地减轻哮喘发作的严重度,更好地预防呼吸道感染的发生,缩短患儿合并用药的天数；中药组和西药组均能改善患儿哮喘缓解期的临床症状,而中药组在改善患儿出汗、食欲食量、舌象方面更具优势。
3.安全性评价表明中药组临床应用安全。
本项研究说明,中医治疗方案用于儿童哮喘缓解期肺脾气虚证有效。固本防哮饮是治疗儿童哮喘缓解期肺脾气虚证的有效方剂,临床应用安全。但由于观察周期较短,尚不能确定其停药后的远期疗效,应进一步完成本研究的随访观察期研究,并进行患儿生存质量分析,可以更为客观地显示中医药治疗本病的优势,从而建立儿童哮喘缓解期的规范化中医药治疗方案,形成可推广的儿童哮喘缓解期治疗指南。
实验研究部分
实验一固本防哮饮对哮喘缓解期小鼠的治疗作用
目的初步探讨固本防哮饮对哮喘缓解期小鼠的治疗作用机制。
方法通过腹腔注射和雾化吸入卵蛋白(OVA)致敏,然后多次雾化吸入OVA激发的方法制备哮喘缓解期小鼠模型,在停止激发后给药4周,将模型小鼠分为四组,即模型组、孟鲁司特钠组和固本防哮饮低、高剂量组,末次给药后24h观察药物对小鼠气道反应性、肺泡灌洗液(BALF)细胞计数和细胞分类、BALF中白细胞介素4(IL-4)和γ-干扰素(IFN-γ)水平以及肺脏病理学变化的影响。
结果①模型组小鼠气道反应性显著高于正常对照组,固本防哮饮可以剂量依赖性降低小鼠的气道反应性,降低氯化乙酰胆碱激发后小鼠肺阻力(RL)(p＜0.05,p＜0.01),改善肺功能状态。②模型组小鼠细胞计数显著高于正常对照组,且细胞分类计数中,嗜酸性粒细胞和中性粒细胞也显著高于正常对照组(p＜0.01)。固本防哮饮可以降低BALF中细胞总数和嗜酸性粒细胞、中性粒细胞比例(p＜0.05,p＜0.01),提示给予固本防哮饮后,可以改善模型小鼠的气道嗜酸性粒细胞及中性粒细胞浸润,对于缓解哮喘及预防哮喘发作是有益的。③和模型组相比,固本防哮饮对小鼠BALF中IL-4无明显影响,但是可以显著增加BALF中IFN-γ,上调IFN-γ/IL-4的比值(p<0.05, p<0.01)。IFN-γ和IL-4分别代表体内Thl和Th2的功能水平,提示固本防哮饮可以调节机体Thl和Th2的功能。④正常组小鼠肺脏未见炎细胞浸润,支气管壁完整,黏膜未见充血水肿,管壁和平滑肌厚度正常；而模型组小鼠肺脏可见支气管壁及平滑肌增生、增厚。给予固本防哮饮后,小鼠肺脏病理改变显著改善,支气管壁和平滑肌厚度明显减小,表明固本防哮饮可以改善哮喘小鼠的气道病理进展。
结论固本防哮饮可以降低模型小鼠的气道高反应性、降低BALF中细胞总数,降低BALF中嗜酸性粒细胞和中性粒细胞比例,升高BALF中IFN-γ水平,改善支气管周围炎性细胞浸润,减轻气道重塑。
实验二黄芪甲苷对哮喘缓解期小鼠的气道反应性及气道病理的影响
目的观察黄芪甲苷对哮喘缓解期小鼠的治疗作用及其作用机制,为确定黄芪甲苷是固本防哮饮的主要活性成分奠定基础。
方法通过腹腔注射和雾化吸入OVA致敏,然后多次雾化吸入OVA激发的方法制备哮喘缓解期小鼠模型,末次激发后第二天,将模型小鼠分为四组,即模型组、孟鲁司特钠组和黄芪甲苷低、高剂量组,每日灌胃给药28天,末次给药后24h观察药物对小鼠气道反应性、BALF细胞计数和细胞分类、BALF中IL-4和IFN-γ水平以及肺脏病理学变化的影响。
结果①模型组小鼠气道反应性显著高于正常对照组,黄芪甲苷可以剂量依赖性显著降低氯化乙酰胆碱激发后小鼠肺阻力(RL)(p＜0.05,p＜0.01),改善肺功能状态。②和正常对照组相比,模型组小鼠BALF中炎症细胞显著增加,细胞分类染色显示嗜酸性粒细胞、淋巴细胞和中性粒细胞均显著增加(p＜0.01)。黄芪甲苷可以降低BALF中炎症细胞总数,也可以降低BALF中嗜酸性粒细胞、淋巴细胞和中性粒细胞计数,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。③和正常对照组相比,模型组小鼠BALF中IL-4水平没有明显改变,这和一般的急性哮喘模型不同,但是小鼠BALF中IFN-γ水平显著降低,导致IFN-γ／IL-4比值也降低(p＜0.05,p＜0．01)。黄芪甲苷50 mg/kg.150mg/kg均可以显著升高模型小鼠BALF中IFN-γ水平,升高IFN-γ/IL-4比值,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。④气道病理显示,正常小鼠肺脏几乎没有炎症细胞,气道壁也是完整的,模型组小鼠肺脏有少量的炎症细胞浸润,气道壁明显增厚。黄芪甲苷治疗后小鼠肺脏炎症细胞浸润基本消失,气道壁厚度显著降低,接近正常水平。Masson染色结果显示,正常组小鼠肺脏气道上皮下仅有少量胶原沉积,表现为少量绿色区域。模型组气道上皮下可见大量胶原沉积,经统计后和正常对照组有显著差异(p＜0.01)。黄芪甲苷可以降低模型小鼠气道上皮下胶原沉积,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。PAS染色结果显示,正常组小鼠几乎看不到PAS染色阳性细胞,模型组PAS染色阳性细胞显著增加(p＜0.01),黄芪甲苷50、150mg／kg均可以降低模型小鼠PAS染色阳性细胞,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。结论黄芪甲苷可以显著升高BALF中IFN-γ水平,同时可以减少气道上皮下胶原沉积及气道内黏液分泌。我们的研究表明黄芪甲苷对哮喘缓解期的治疗是有益的,在哮喘缓解期的治疗中,可以作为一个补充治疗方法来弥补现有治疗方法的不足。
Bronchial asthma is the most common chronic respiratory disease in children, as well as a worldwide intractable disease, whose incidence has been increasing with the development of society. Asthma has become a grave public health problem drawing worldwide attention for it not only severely does harm to individual health, but also causes a huge burden to families and society. At present, Western medical treatment of chronic asthma is still lacking of good measures, while Chinese medicine has unique advantages. Traditional Chinese Medicine is an effective therapy on controlling chronic asthma, which can regulate the entire body, support the healthy energy, enhance the power of resistance and reduce the asthma attacks.
The prescription Gubenfangxiao decoction (GBFXD) is an empirical prescription from Professor Jiang Yuren, a countrywide famous pediatrician in our department (one of the Nationally 500 Best Old Chinese Medicine Experts.). This formula consisted of honey-fried Radix Astragali, Radix Codonopsis, Rhizoma Atractylodis Macrocephalae, Poria, calcined Concha Ostreae, Periostracum Cicadae, Pericarpium Citri Reticulatae, Raidix Saposhnikoviae, Flos Magnoliae, Fructus Schisandrae and raw Radix Glycytthizae. It provided the effects of nourishing lung, secured exterior, invigorated spleen and resolved phlegm, have been used in Jiangsu Province Hospital of TCM for more than 30 years, demonstrating the exact efficacy in clinical application of reducing asthma attacks in frequency and degree, enhancing the children's physical fitness, improving the quality of life and asthma remission rate of the sick children. Currently in the national science & technology pillar program during the eleventh five-year plan period, the project based on such prescription, named as "clinical evaluation of GBFXD curing asthenia of pulmonosplenic qi at childish chronic asthma ", has reached the experimental stage after being declared and approved by the Ministry of Science and Technology. Clinical research part of our work belongs to this project, and the experimental part investigates further mechanism of the prescription as well as its active components preventing and curing asthma using views of both immunology and air tube pathology.
Clinical Research Component
From January 2009 to March 2010, following the experimental principle of central randomization and parallel control, we systematically observed the efficacy and safety of TCM curing asthenia of pulmonosplenic qi on childish chronic asthma, at Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Affiliated Oriental Hospital of Beijing University of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, and The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine. Our research does statistical analysis to 100 cases that are treated for more than 6 months, of which 51 cases belong to TCM group,49 cases belong to western drug group.
Object
Using a central randomized, controlled, multicenter clinical trial, we observed the therapeutic efficacies of both Traditional Chinese Medicine treatment and Western Medicine treatment to objectively evaluate the efficacy and safety of TCM on reducing asthma attack in frequency and degree during the remission stage of childhood asthma.
Methods
A multicenter, randomized, controlled method was used to carry out clinical studies on 100 cases of children in asthma remission stage. The trial group administered GBFXD; the control group used Pulmicort Turbuhaler inhaling, both of them were treated for 6 months. Efficacy evaluation of children in both group were carried out after the course of treatment on their primary and secondary clinical disease syndromes. The main indexes as well as symptom scores before and after treatment were compared. SPSS 13.0 software was used for statistical analysis, including chi-square test, t test and Ridit test analysis.
Results
1. Influence of TCM group on the main indexes of therapeutic efficacy including the number of days without asthmatic symptoms, frequency of asthma attacks, asthma severity, frequency of upper respiratory tract infection, and frequency of lower respiratory tract infection.
During the observation period of 6 months treatment, the number of days without asthmatic symptoms, frequency of asthma attacks, and frequency of lower respiratory tract infection of the two groups, had no significant difference by t test. The frequency of upper respiratory tract infection for 6 months TCM group was significantly lower than western medicine group, showing significantly difference by t test, p<0.05. The frequency of upper respiratory tract infection in the 1st,3rd, and 6th month and the frequency of asthma attacks and lower respiratory tract infection in the 3rd, and 6th month of both TCM group and western drug group were significantly lower than baseline, showing significantly difference by t test, p<0.01. Comparing the before and after treatment efficiency of the two groups, TCM group was significantly higher than the western drug group, showing significantly difference by Ridit test, p <0.05. All above-mentioned prompted that TCM group and western drug group both could reduce the frequency of asthma attacks, upper and lower respiratory tract infection, but TCM group showed more significant effect on reducing respiratory infection.
After treatment intervention, patients of neither TCM group nor western drug group showed up gradeⅣserious asthma attacks. The severity of asthma attacks of the two groups in 1,3 months have no significant difference; in 6 months show significant difference by Ridit analysis, p<0.01. And the gradeⅡasthma attacks in TCM group were significantly less than in western drug group.
Therefore, GBFXD is an effective prescription to cure childhood asthma in remission stage. It has similar efficacy to Pulmicort Turbuhaler in maintaining the number of asymptomatic days and controlling frequency of asthma attacks, while can better alleviate the severe degrees of asthma attack and prevent respiratory tract infection.
2. Influence of TCM group on TCM Syndrome of the sick children
Compared by syndromes efficacy, scores of both group at each time point showed no significant difference except 3 months sweating symptoms,6 months sweating, tongue, food intake and appetite.3 months sweating score of TCM group was significantly lower than western drug group, and 6 months sweating, tongue, food intake and appetite scores were significantly lower than western drug group, with statistical difference by t test, p<0.05, p<0.01. This prompted that TCM group could better improve the children's sweating, loss of appetite and food intake, abnormal symptoms of tongue comparing with western drug group.
Nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, tongue, and total symptoms scores of 1 month TCM group were significantly lower than baseline, showing statistical difference (p<0.05, p<0.01); cough, pale, and total symptoms scores of 1 month western drug group were significantly lower than baseline (p<0.05, p<0.01); nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, pale, fatigue, and total symptoms scores of 3 months TCM group were significantly lower than baseline (p<0.05, p<0.01): coughing, shortness of breath, and total symptoms scores of 3 months western drug group were significantly lower than baseline (p<0.05, p<0.01); sneezing, nasal itching, runny nose, cough, shortness of breath, sweating, pale, fatigue, appetite, food intake, stool, tongue, and total symptoms scores of 6 months TCM group were significantly lower than baseline (p<0.01); nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, pale, fatigue, and total symptoms scores of 6 months western drug group were significantly lower than baseline (p<0.05, p<0.01).
The above prompt that both TCM group and western drug group can improve clinical symptoms in remission stage of childhood asthma, while TCM group have advantage to improve children sweating, tongue,appetite and food intake.
3. Influence of TCM group on the number of combination therapy days for the sick children
The number of combination therapy days had no significant difference between the two groups. By observing the number of combination therapy days in 1 month and 3 months, the two groups showed no significant difference; in 6 months and the total period, TCM group was significantly lower than western drug group. This prompted that TCM group can reduce the number of combination therapy days for the sick children.
4. Safety Evaluation of TCM group:
No abnormal blood, urine, stool for routine, ECG, and liver function, as well as other adverse reactions in patients were observed during the clinical trial period, indicating that GBFXD is clinical safety.
Conclusion
Efficacy and safety evaluation after 6-month treated on 100 sick children in four research centers suffering from asthenia of pulmonosplenic qi at asthma remission stage.
1. Comparing the effects before and after treatment, TCM group could significantly reduce the number of asthma attacks, the frequency of upper and lower respiratory tract infection in sick children, improving clinical symptoms in sick children including:nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, pale, appetite, food intake, stool, and significantly reducing tongue, and the total scores.
2.Comparing the effects of TCM group and western drug group, TCM have similar efficacy with Pulmicort Turbuhaler on maintaining the number of asymptomatic days and controlling frequency of asthma attacks, while can better alleviate the severe degrees of asthma attack, prevent respiratory tract infection, and reduce the number of combination therapy days for the sick children. Both TCM group and western drug group can improve clinical symptoms in remission stage of childhood asthma, while TCM group have advantage to improve children sweating, tongue, appetite and food intake.
3. Safety Evaluation showed clinical safety of GBFXD.
Accordingly, GBFXD is an effective prescription to cure childhood asthma in remission stage with clinical safety. However, a short observation period is still not sure of its long-term outcome after withdrawal. The study at follow-up observation period should be further completed and the sick children's quality of lives should be analyzed to display the advantage of TCM treatment on this disease more objectively, so as to establish the standardized TCM treatment plan in remission stage of Childhood asthma, and to form the propagable treatment guidelines for Childhood asthma treatment in remission stage.
Experimental Research Component
1. Therapeutic effects of Gubenfangxiao decoction on chronic asthmatic mice
Aim:To observe the effects of Gubenfangxiao decoction (GBFXD) on chronic asthmatic mice.
Methods:BALB/c mice were sensitized with intraperitoneal OVA injection on day 1 and day 11, and with atomization inhaled OVA on day 11, sensitized mice involved with six 2-days periods of atomization inhaled OVA challenges, then the mice were administered intragastrically with GBFXD or distilled water for 4 weeks. The airway hyperresponsiveness, BALF cell counts and cell classifications, IL-4 and IFN-y levels in BALF and lung histological examinations were observed 24 hours after last administration.
Results:GBFXD decreased the mice airway hyperresponsiveness, BALF inflammation cell counts and eosinophile granulocyte and neutrophil granulocyte ratios in BALF inflammation cells, meanwhile, GBFXD increased IFN-y levels in BALF and decreased eosinophile granulocyte infiltration in airway.
Conclusion:The mechanisms of GBFXD on preventing asthma attack might be ascribed to the decreasing of airway hyperresponsiveness, eosinophile granulocyte infiltration and the increasing of IFN-γlevels.
2. Effects of Astragaloside IV on IFN-gamma level and prolonged airway dysfunction in a murine model of chronic asthma
Background:Astragaloside IV (AST) was the active constituent of Radix Astragali, a Chinese herb traditionally used to treat asthma. The present study was designed to evaluate the efficacies of AST on chronic asthma, and if so, explored the underlying mechanisms involved.
Method:Chronic asthma was induced in mice by sensitization and repeated challenges of ovalbumin (OVA), on which the following outcome measurements were made:(i) in vivo airway responsiveness to intravenous methacholine (MCh, Sigma, St. Louis, Mo.); (ii) total and differential cell counts in bronchoalveolar lavage fluids(BALF); (iii) IL-4 and IFN-gamma levels in BALF supernatants; and (iv) airway morphometry.
Results:In this murine model of chronic asthma, the airway dysfunction and remodeling remained severely, accompanying with suppression of IFN-gamma levels in BALF even four weeks after the final challenge. After oral administration of AST for four weeks, the airway responsiveness to intravenous methacholine was sharply reduced, meanwhile the inflammatory cells were decreased but the IFN-gamma levels increased in BALF. The collagen deposition and mucus production were also reduced by AST.
Conclusion:AST, a natural constituent from Radix Astragali, was beneficial to chronic asthma, thus it should be served as a supplementary therapy in controlling chronic asthma.
固本防哮饮处方是来自我科全国著名儿科专家(全国首批500位名老中医药专家之一)江育仁教授经验方,由炙黄芪、党参、白术、茯苓、煅牡蛎、蝉蜕、陈皮、防风、辛夷、五味子和生甘草组成,具有补肺固表,健脾化痰的功效,在江苏省中医院已经应用30多年,疗效确切,临床应用可减少、减轻哮喘发作,增强患儿体质,提高患儿的生存质量和哮喘缓解率。目前,就此处方申报并获批的科技部“十一五”国家科技支撑计划课题“固本防哮饮治疗儿童哮喘缓解期肺脾气虚证的临床评价”正在试验中。本研究的临床部分属于该课题的一部分,实验部分从免疫及气道病理的角度进一步探讨了该处方及其主要活性成分防治哮喘的作用机制。
临床研究部分
2009年1月至2010年3月,遵循中心随机、平行对照试验的原则,在南京中医药大学附属医院、北京中医药大学附属东方医院、山东中医药大学附属医院、湖南中医药大学第一附属医院,对中医药治疗儿童哮喘缓解期肺脾气虚证的有效性、安全性进行了系统观察,本研究目前仍在进行中,现将至2010年3月为止疗程满6个月病例进行统计分析,共100例,其中中药组51例、西药组49例。
目的
采用中心随机、平行对照、多中心临床研究方法,观察中医和西医两种不同治疗方案的治疗效果,客观评价固本防哮饮用于哮喘缓解期,在减少哮喘发作次数、减轻哮喘发作程度等方面的有效性和安全性。
方法
采用多中心、随机、平行对照的方法,对100例哮喘缓解期患儿进行临床研究,试验组采用固本防哮饮口服配合中药穴位敷贴；对照组用普米克都保吸入,疗程均为6个月。疗程结束后对两组患儿的疾病、证候(主、次症)指标进行疗效评价,两组治疗前后主要指标、症状积分进行比较。采用SPSS 13.0软件对结果进行统计分析,包括卡方检验、t检验、Ridit检验分析。
结果
1.中药组对主要疗效指标包括无喘息症状的天数、哮喘发作次数、哮喘发作严重度、上呼吸道感染次数、下呼吸道感染次数的影响
治疗6个月的观察周期中,两组患儿无喘息症状天数、哮喘发作次数和下呼吸道感染次数,经t检验,无明显差异。中药组6个月的上呼吸道感染次数显著低于西药组,经t检验,有统计学差异,p＜0.05。中药组、西药组在疗程第1、3、6个月,上呼吸道感染次数,3、6个月哮喘发作次数、下呼吸道感染次数均显著低于基线状态,经t检验,有统计学差异,p＜0.01,p＜0.05。两组治疗前后总有效率比较,中药组显著高于西药组,经Ridit检验,有统计学差异,p＜0.05。提示中药组和西药组均能减少哮喘患儿的哮喘发作次数,上、下呼吸道感染次数,但中药组在减少呼吸道感染方面,疗效更加显著。
中、西药组干预后,两组患者均未出现Ⅳ级严重哮喘发作。两组患儿在1、3个月时哮喘发作严重程度比较无明显差异；6个月时经Ridit分析,有显著性差异,p＜0.01,中药组Ⅱ级以上的哮喘发作明显少于西药组。
所以,固本防哮饮是治疗儿童哮喘缓解期有效方剂,在维持哮喘患儿无症状的天数、控制哮喘发作次数方面,与普米克都保疗效相近,但能更好地减轻哮喘发作的严重度,并能更好预防呼吸道感染的发生。
2.中药组对患儿中医证候学的影响
经两组证候疗效比较,除3个月时的出汗症状,6个月时的出汗、食欲食量和舌象外,其余两组证候学各时间点评分无显著差异；3个月中药组出汗评分显著低于西药组,6个月时的出汗、食欲食量和舌象评分显著低于西药组,经t检验,有统计学差异p＜0.05,p＜0.01。提示中药组较西药组能够更好地改善患儿的出汗多,食欲不振、食量少,舌象异常的症状。
中药组1个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、舌象和症状积分均显著低于基线,有统计学差异,(p＜0.05,p＜0.01)；西药组1个月的咳嗽、面色和症状积分均显著低于基线(p＜0.05,p＜0.01)；中药组3个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力和症状积分均显著低于基线(p＜0.05,p＜0.01);西药组3个月的咳嗽、气短和症状积分均显著低于基线(p＜0.05,p＜0.01)；中药组6个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力、食欲食量、大便、舌象和症状积分均显著低于基线(p＜0.01);西药组6个月的鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力和症状积分均显著低于基线(p＜0.05,p＜0.01)。
提示中药组和西药组均能改善患儿哮喘缓解期的临床症状,而中药组在改善患儿出汗、食欲食量、舌象方面更具优势。
3.中药组对患儿合并用药天数的影响
合并用药次数两组相比无显著差异,观察时点1个月、3个月合并用药天数两组相比,无显著差异,6个月时及总合并用药天数中药组显著低于西药组。提示中药组能够缩短患儿合并用药的天数。
4.中药组安全性评价：临床试验期间,未见患者血、尿、便常规、心电图及肝肾功能有异常改变,未见患者有其他不良反应发生,表明固本防哮饮临床应用安全。
结论
四个研究中心100例哮喘缓解期肺脾气虚证患儿,治疗期6个月疗效和安全性评价。
1.治疗前后疗效比较,中药组能显著减少患儿哮喘发作次数,减少上、下呼吸道感染次数,并能使哮喘患儿临床症状：鼻痒喷嚏、流涕、咳嗽、气短、出汗、面色、乏力、食欲食量大便、舌象得以改善,使症状总积分显著降低；
2.中药组和西药组疗效比较,固本防哮饮在维持哮喘患儿无症状的天数,控制哮喘发作次数方面,与普米克都保疗效相近,但能更好地减轻哮喘发作的严重度,更好地预防呼吸道感染的发生,缩短患儿合并用药的天数；中药组和西药组均能改善患儿哮喘缓解期的临床症状,而中药组在改善患儿出汗、食欲食量、舌象方面更具优势。
3.安全性评价表明中药组临床应用安全。
本项研究说明,中医治疗方案用于儿童哮喘缓解期肺脾气虚证有效。固本防哮饮是治疗儿童哮喘缓解期肺脾气虚证的有效方剂,临床应用安全。但由于观察周期较短,尚不能确定其停药后的远期疗效,应进一步完成本研究的随访观察期研究,并进行患儿生存质量分析,可以更为客观地显示中医药治疗本病的优势,从而建立儿童哮喘缓解期的规范化中医药治疗方案,形成可推广的儿童哮喘缓解期治疗指南。
实验研究部分
实验一固本防哮饮对哮喘缓解期小鼠的治疗作用
目的初步探讨固本防哮饮对哮喘缓解期小鼠的治疗作用机制。
方法通过腹腔注射和雾化吸入卵蛋白(OVA)致敏,然后多次雾化吸入OVA激发的方法制备哮喘缓解期小鼠模型,在停止激发后给药4周,将模型小鼠分为四组,即模型组、孟鲁司特钠组和固本防哮饮低、高剂量组,末次给药后24h观察药物对小鼠气道反应性、肺泡灌洗液(BALF)细胞计数和细胞分类、BALF中白细胞介素4(IL-4)和γ-干扰素(IFN-γ)水平以及肺脏病理学变化的影响。
结果①模型组小鼠气道反应性显著高于正常对照组,固本防哮饮可以剂量依赖性降低小鼠的气道反应性,降低氯化乙酰胆碱激发后小鼠肺阻力(RL)(p＜0.05,p＜0.01),改善肺功能状态。②模型组小鼠细胞计数显著高于正常对照组,且细胞分类计数中,嗜酸性粒细胞和中性粒细胞也显著高于正常对照组(p＜0.01)。固本防哮饮可以降低BALF中细胞总数和嗜酸性粒细胞、中性粒细胞比例(p＜0.05,p＜0.01),提示给予固本防哮饮后,可以改善模型小鼠的气道嗜酸性粒细胞及中性粒细胞浸润,对于缓解哮喘及预防哮喘发作是有益的。③和模型组相比,固本防哮饮对小鼠BALF中IL-4无明显影响,但是可以显著增加BALF中IFN-γ,上调IFN-γ/IL-4的比值(p<0.05, p<0.01)。IFN-γ和IL-4分别代表体内Thl和Th2的功能水平,提示固本防哮饮可以调节机体Thl和Th2的功能。④正常组小鼠肺脏未见炎细胞浸润,支气管壁完整,黏膜未见充血水肿,管壁和平滑肌厚度正常；而模型组小鼠肺脏可见支气管壁及平滑肌增生、增厚。给予固本防哮饮后,小鼠肺脏病理改变显著改善,支气管壁和平滑肌厚度明显减小,表明固本防哮饮可以改善哮喘小鼠的气道病理进展。
结论固本防哮饮可以降低模型小鼠的气道高反应性、降低BALF中细胞总数,降低BALF中嗜酸性粒细胞和中性粒细胞比例,升高BALF中IFN-γ水平,改善支气管周围炎性细胞浸润,减轻气道重塑。
实验二黄芪甲苷对哮喘缓解期小鼠的气道反应性及气道病理的影响
目的观察黄芪甲苷对哮喘缓解期小鼠的治疗作用及其作用机制,为确定黄芪甲苷是固本防哮饮的主要活性成分奠定基础。
方法通过腹腔注射和雾化吸入OVA致敏,然后多次雾化吸入OVA激发的方法制备哮喘缓解期小鼠模型,末次激发后第二天,将模型小鼠分为四组,即模型组、孟鲁司特钠组和黄芪甲苷低、高剂量组,每日灌胃给药28天,末次给药后24h观察药物对小鼠气道反应性、BALF细胞计数和细胞分类、BALF中IL-4和IFN-γ水平以及肺脏病理学变化的影响。
结果①模型组小鼠气道反应性显著高于正常对照组,黄芪甲苷可以剂量依赖性显著降低氯化乙酰胆碱激发后小鼠肺阻力(RL)(p＜0.05,p＜0.01),改善肺功能状态。②和正常对照组相比,模型组小鼠BALF中炎症细胞显著增加,细胞分类染色显示嗜酸性粒细胞、淋巴细胞和中性粒细胞均显著增加(p＜0.01)。黄芪甲苷可以降低BALF中炎症细胞总数,也可以降低BALF中嗜酸性粒细胞、淋巴细胞和中性粒细胞计数,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。③和正常对照组相比,模型组小鼠BALF中IL-4水平没有明显改变,这和一般的急性哮喘模型不同,但是小鼠BALF中IFN-γ水平显著降低,导致IFN-γ／IL-4比值也降低(p＜0.05,p＜0．01)。黄芪甲苷50 mg/kg.150mg/kg均可以显著升高模型小鼠BALF中IFN-γ水平,升高IFN-γ/IL-4比值,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。④气道病理显示,正常小鼠肺脏几乎没有炎症细胞,气道壁也是完整的,模型组小鼠肺脏有少量的炎症细胞浸润,气道壁明显增厚。黄芪甲苷治疗后小鼠肺脏炎症细胞浸润基本消失,气道壁厚度显著降低,接近正常水平。Masson染色结果显示,正常组小鼠肺脏气道上皮下仅有少量胶原沉积,表现为少量绿色区域。模型组气道上皮下可见大量胶原沉积,经统计后和正常对照组有显著差异(p＜0.01)。黄芪甲苷可以降低模型小鼠气道上皮下胶原沉积,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。PAS染色结果显示,正常组小鼠几乎看不到PAS染色阳性细胞,模型组PAS染色阳性细胞显著增加(p＜0.01),黄芪甲苷50、150mg／kg均可以降低模型小鼠PAS染色阳性细胞,和模型组相比,有统计学差异(p＜0.05,p＜0.01)。结论黄芪甲苷可以显著升高BALF中IFN-γ水平,同时可以减少气道上皮下胶原沉积及气道内黏液分泌。我们的研究表明黄芪甲苷对哮喘缓解期的治疗是有益的,在哮喘缓解期的治疗中,可以作为一个补充治疗方法来弥补现有治疗方法的不足。
Bronchial asthma is the most common chronic respiratory disease in children, as well as a worldwide intractable disease, whose incidence has been increasing with the development of society. Asthma has become a grave public health problem drawing worldwide attention for it not only severely does harm to individual health, but also causes a huge burden to families and society. At present, Western medical treatment of chronic asthma is still lacking of good measures, while Chinese medicine has unique advantages. Traditional Chinese Medicine is an effective therapy on controlling chronic asthma, which can regulate the entire body, support the healthy energy, enhance the power of resistance and reduce the asthma attacks.
The prescription Gubenfangxiao decoction (GBFXD) is an empirical prescription from Professor Jiang Yuren, a countrywide famous pediatrician in our department (one of the Nationally 500 Best Old Chinese Medicine Experts.). This formula consisted of honey-fried Radix Astragali, Radix Codonopsis, Rhizoma Atractylodis Macrocephalae, Poria, calcined Concha Ostreae, Periostracum Cicadae, Pericarpium Citri Reticulatae, Raidix Saposhnikoviae, Flos Magnoliae, Fructus Schisandrae and raw Radix Glycytthizae. It provided the effects of nourishing lung, secured exterior, invigorated spleen and resolved phlegm, have been used in Jiangsu Province Hospital of TCM for more than 30 years, demonstrating the exact efficacy in clinical application of reducing asthma attacks in frequency and degree, enhancing the children's physical fitness, improving the quality of life and asthma remission rate of the sick children. Currently in the national science & technology pillar program during the eleventh five-year plan period, the project based on such prescription, named as "clinical evaluation of GBFXD curing asthenia of pulmonosplenic qi at childish chronic asthma ", has reached the experimental stage after being declared and approved by the Ministry of Science and Technology. Clinical research part of our work belongs to this project, and the experimental part investigates further mechanism of the prescription as well as its active components preventing and curing asthma using views of both immunology and air tube pathology.
Clinical Research Component
From January 2009 to March 2010, following the experimental principle of central randomization and parallel control, we systematically observed the efficacy and safety of TCM curing asthenia of pulmonosplenic qi on childish chronic asthma, at Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Affiliated Oriental Hospital of Beijing University of Traditional Chinese Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, and The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine. Our research does statistical analysis to 100 cases that are treated for more than 6 months, of which 51 cases belong to TCM group,49 cases belong to western drug group.
Object
Using a central randomized, controlled, multicenter clinical trial, we observed the therapeutic efficacies of both Traditional Chinese Medicine treatment and Western Medicine treatment to objectively evaluate the efficacy and safety of TCM on reducing asthma attack in frequency and degree during the remission stage of childhood asthma.
Methods
A multicenter, randomized, controlled method was used to carry out clinical studies on 100 cases of children in asthma remission stage. The trial group administered GBFXD; the control group used Pulmicort Turbuhaler inhaling, both of them were treated for 6 months. Efficacy evaluation of children in both group were carried out after the course of treatment on their primary and secondary clinical disease syndromes. The main indexes as well as symptom scores before and after treatment were compared. SPSS 13.0 software was used for statistical analysis, including chi-square test, t test and Ridit test analysis.
Results
1. Influence of TCM group on the main indexes of therapeutic efficacy including the number of days without asthmatic symptoms, frequency of asthma attacks, asthma severity, frequency of upper respiratory tract infection, and frequency of lower respiratory tract infection.
During the observation period of 6 months treatment, the number of days without asthmatic symptoms, frequency of asthma attacks, and frequency of lower respiratory tract infection of the two groups, had no significant difference by t test. The frequency of upper respiratory tract infection for 6 months TCM group was significantly lower than western medicine group, showing significantly difference by t test, p<0.05. The frequency of upper respiratory tract infection in the 1st,3rd, and 6th month and the frequency of asthma attacks and lower respiratory tract infection in the 3rd, and 6th month of both TCM group and western drug group were significantly lower than baseline, showing significantly difference by t test, p<0.01. Comparing the before and after treatment efficiency of the two groups, TCM group was significantly higher than the western drug group, showing significantly difference by Ridit test, p <0.05. All above-mentioned prompted that TCM group and western drug group both could reduce the frequency of asthma attacks, upper and lower respiratory tract infection, but TCM group showed more significant effect on reducing respiratory infection.
After treatment intervention, patients of neither TCM group nor western drug group showed up gradeⅣserious asthma attacks. The severity of asthma attacks of the two groups in 1,3 months have no significant difference; in 6 months show significant difference by Ridit analysis, p<0.01. And the gradeⅡasthma attacks in TCM group were significantly less than in western drug group.
Therefore, GBFXD is an effective prescription to cure childhood asthma in remission stage. It has similar efficacy to Pulmicort Turbuhaler in maintaining the number of asymptomatic days and controlling frequency of asthma attacks, while can better alleviate the severe degrees of asthma attack and prevent respiratory tract infection.
2. Influence of TCM group on TCM Syndrome of the sick children
Compared by syndromes efficacy, scores of both group at each time point showed no significant difference except 3 months sweating symptoms,6 months sweating, tongue, food intake and appetite.3 months sweating score of TCM group was significantly lower than western drug group, and 6 months sweating, tongue, food intake and appetite scores were significantly lower than western drug group, with statistical difference by t test, p<0.05, p<0.01. This prompted that TCM group could better improve the children's sweating, loss of appetite and food intake, abnormal symptoms of tongue comparing with western drug group.
Nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, tongue, and total symptoms scores of 1 month TCM group were significantly lower than baseline, showing statistical difference (p<0.05, p<0.01); cough, pale, and total symptoms scores of 1 month western drug group were significantly lower than baseline (p<0.05, p<0.01); nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, pale, fatigue, and total symptoms scores of 3 months TCM group were significantly lower than baseline (p<0.05, p<0.01): coughing, shortness of breath, and total symptoms scores of 3 months western drug group were significantly lower than baseline (p<0.05, p<0.01); sneezing, nasal itching, runny nose, cough, shortness of breath, sweating, pale, fatigue, appetite, food intake, stool, tongue, and total symptoms scores of 6 months TCM group were significantly lower than baseline (p<0.01); nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, pale, fatigue, and total symptoms scores of 6 months western drug group were significantly lower than baseline (p<0.05, p<0.01).
The above prompt that both TCM group and western drug group can improve clinical symptoms in remission stage of childhood asthma, while TCM group have advantage to improve children sweating, tongue,appetite and food intake.
3. Influence of TCM group on the number of combination therapy days for the sick children
The number of combination therapy days had no significant difference between the two groups. By observing the number of combination therapy days in 1 month and 3 months, the two groups showed no significant difference; in 6 months and the total period, TCM group was significantly lower than western drug group. This prompted that TCM group can reduce the number of combination therapy days for the sick children.
4. Safety Evaluation of TCM group:
No abnormal blood, urine, stool for routine, ECG, and liver function, as well as other adverse reactions in patients were observed during the clinical trial period, indicating that GBFXD is clinical safety.
Conclusion
Efficacy and safety evaluation after 6-month treated on 100 sick children in four research centers suffering from asthenia of pulmonosplenic qi at asthma remission stage.
1. Comparing the effects before and after treatment, TCM group could significantly reduce the number of asthma attacks, the frequency of upper and lower respiratory tract infection in sick children, improving clinical symptoms in sick children including:nasal itching and sneezing, runny nose, cough, shortness of breath, sweating, pale, appetite, food intake, stool, and significantly reducing tongue, and the total scores.
2.Comparing the effects of TCM group and western drug group, TCM have similar efficacy with Pulmicort Turbuhaler on maintaining the number of asymptomatic days and controlling frequency of asthma attacks, while can better alleviate the severe degrees of asthma attack, prevent respiratory tract infection, and reduce the number of combination therapy days for the sick children. Both TCM group and western drug group can improve clinical symptoms in remission stage of childhood asthma, while TCM group have advantage to improve children sweating, tongue, appetite and food intake.
3. Safety Evaluation showed clinical safety of GBFXD.
Accordingly, GBFXD is an effective prescription to cure childhood asthma in remission stage with clinical safety. However, a short observation period is still not sure of its long-term outcome after withdrawal. The study at follow-up observation period should be further completed and the sick children's quality of lives should be analyzed to display the advantage of TCM treatment on this disease more objectively, so as to establish the standardized TCM treatment plan in remission stage of Childhood asthma, and to form the propagable treatment guidelines for Childhood asthma treatment in remission stage.
Experimental Research Component
1. Therapeutic effects of Gubenfangxiao decoction on chronic asthmatic mice
Aim:To observe the effects of Gubenfangxiao decoction (GBFXD) on chronic asthmatic mice.
Methods:BALB/c mice were sensitized with intraperitoneal OVA injection on day 1 and day 11, and with atomization inhaled OVA on day 11, sensitized mice involved with six 2-days periods of atomization inhaled OVA challenges, then the mice were administered intragastrically with GBFXD or distilled water for 4 weeks. The airway hyperresponsiveness, BALF cell counts and cell classifications, IL-4 and IFN-y levels in BALF and lung histological examinations were observed 24 hours after last administration.
Results:GBFXD decreased the mice airway hyperresponsiveness, BALF inflammation cell counts and eosinophile granulocyte and neutrophil granulocyte ratios in BALF inflammation cells, meanwhile, GBFXD increased IFN-y levels in BALF and decreased eosinophile granulocyte infiltration in airway.
Conclusion:The mechanisms of GBFXD on preventing asthma attack might be ascribed to the decreasing of airway hyperresponsiveness, eosinophile granulocyte infiltration and the increasing of IFN-γlevels.
2. Effects of Astragaloside IV on IFN-gamma level and prolonged airway dysfunction in a murine model of chronic asthma
Background:Astragaloside IV (AST) was the active constituent of Radix Astragali, a Chinese herb traditionally used to treat asthma. The present study was designed to evaluate the efficacies of AST on chronic asthma, and if so, explored the underlying mechanisms involved.
Method:Chronic asthma was induced in mice by sensitization and repeated challenges of ovalbumin (OVA), on which the following outcome measurements were made:(i) in vivo airway responsiveness to intravenous methacholine (MCh, Sigma, St. Louis, Mo.); (ii) total and differential cell counts in bronchoalveolar lavage fluids(BALF); (iii) IL-4 and IFN-gamma levels in BALF supernatants; and (iv) airway morphometry.
Results:In this murine model of chronic asthma, the airway dysfunction and remodeling remained severely, accompanying with suppression of IFN-gamma levels in BALF even four weeks after the final challenge. After oral administration of AST for four weeks, the airway responsiveness to intravenous methacholine was sharply reduced, meanwhile the inflammatory cells were decreased but the IFN-gamma levels increased in BALF. The collagen deposition and mucus production were also reduced by AST.
Conclusion:AST, a natural constituent from Radix Astragali, was beneficial to chronic asthma, thus it should be served as a supplementary therapy in controlling chronic asthma.
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