培土清心方治疗特应性皮炎的临床观察及作用机理初探
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摘要
研究背景
特应性皮炎(atopic dermatitis，AD)主要累及儿童和青少年，长期反复发作的瘙痒、皮损是其主要的临床表现，严重影响患者身心健康。随着社会经济发展和外界环境变化，国内外的流行病学调查均显示其发病率呈明显的上升趋势。本病的病因病机尚未完全阐明，多认为与遗传、环境、免疫、微生物感染、精神因素等多种因素的综合作用有关。目前关于AD治疗的国际性指南定义的治疗目标为：减轻症状和体征、预防或减少复发、长期治疗以防止疾病加重、减缓病程。可以看出目前的西医治疗主要是缓解症状。而特应性皮炎是中医治疗具有优势的病种之一，因此本病的中医治疗已成为研究的热点。目前研究多为专方验方治疗特应性皮炎的疗效观察，对于治则治法的研究虽已逐渐有人提出，但涉及的治则治法还甚少，对于机理的研究更需进一步阐明。因此，本研究以导师在长期临床实践中所总结的培土清心法来治疗特应性皮炎患者，在既往的临床研究已初步证实该法有效的基础上进一步观察其疗效；并对其可能的作用机理进行探讨：首先从目前中医药治疗AD的实验研究中涉及比较多的血清总IgE、ECP的水平进行研究；其次从AD为心身疾病的特点及神经内分泌免疫网络在心身疾病中可能的作用为出发点，结合目前特应性皮炎研究中的神经源性机制，选择了在神经源性机制中研究较多的神经生长因子(NGF)和P物质(SP)指标进行了相关研究。
目的
1．通过检测AD患者血清中总IgE、ECP，以探讨二者在特应性皮炎发病机制中的作用；
2．通过检测AD患者血清中NGF、SP的水平，以探讨NGF、SP在AD发病机制中的作用；
3．观察治疗前后AD患者SCORAD积分的变化，以评价导师的经验方培土清心方对特应性皮炎的疗效。
4．研究培土清心方对AD患者血清总IgE、ECP、NGF、SP的影响，探求培土清心法治疗特应性皮炎可能的机制，以指导临床实践，并为新药开发奠定一定的基础。
方法
本研究选择55例AD患者为研究对象，于治疗前及治疗后1个月、3个月分别记录SCORAD积分。并在55名患者中随机选取38名于治疗前及治疗后3个月时进行血清学指标的检测，另以15名健康志愿者为对照。具体检测方法：以Pharmacia公司CAP变应原检测系统检测血清中的总IgE、ECP，ELISA法检测血清中NGF、SP的水平。并对各项血清学指标间以及血清学指标与患者SCORAD积分间进行相关分析。
统计学方法：采用SPSS13.0统计软件包建立数据库并进行统计分析。计量资料采用均数±标准差进行统计描述，计量资料两组比较采用独立样本t检验，前后比较用配对t检验或重复测量数据方差分析，计数资料采用x~2检验，方差不齐时治疗前后数据采用配对符号秩和检验，等级资料采用Mann—whitney秩和检验进行比较，检验水平α=0.05。
结果
1．特应性皮炎发病相关因素调查分析：对入选的55例患者进行发病相关因素的问卷调查，结果发现：由饮食因素引起和加重的有27例(49.09％)，其中又以海鲜类食物为主；其发病和加重与季节明显相关的有50例(90.90％)，具体以何季节为主，无明显倾向性；受情志因素影响的有9例(16.36％)。55例AD患者中，调查结果显示有30例合并有过敏性鼻炎或哮喘或二者合并存在，占54.54％，其中同时合并此二种疾病者9例，占16.36％。家族史方面：调查结果显示55例AD患者中，其家族中有过敏性疾病者为34例，占61.82％，其中以过敏性鼻炎者最为多见。情绪因素方面：调查结果显示55例AD中受情绪因素影响的有32例，占58.18％，其中以紧张情绪影响最为明显。
2．临床疗效观察：本临床观察共纳入55例符合标准的AD患者，用中药培土清心方内服，辅以润肤剂外用治疗，以涵盖AD 6个主要他觉症状和瘙痒、睡眠两个最主要主观症状的SCORAD积分进行评价，结果显示治疗前的SCORAD评分为55.458±15.051，治疗1月后为49.410±12.331，较疗前明显降低，差异有显著性统计学意义(P＜0.01)；治疗3月后为34.684±8.824，较疗前及疗后1月明显降低，差异有显著性统计学意义(P＜0.01)；治疗后较治疗前患者皮损严重度及瘙痒、睡眠都得以明显改善，差异有统计学意义。用尼莫地平法评价总体疗效：55例患者中2例显效，占3.66％；好转49例，占89.09％；4例无效，占7.25％；总有效率为92.75％。治疗过程中没有观察到明显的不良反应。说明培土清心法对临床治疗AD有一定指导价值。
3．血清中总IgE的测定：AD患者治疗前血清总IgE为2175.162±1982.798KU／L，明显高于正常对照组(45.287±35.753 KU／L)，差异有显著性统计学意义(P＜0.01)；治疗后AD组血清总IgE较治疗前降低，差异有显著性统计学意义(P＜0.01)，治疗后与对照组比较，仍明显高于正常对照组，差异有显著性统计学意义(P＜0.01)。相关分析结果显示总IgE与SCORAD积分间存在正相关关系(r=0.586，P=0.001)。
4．血清中ECP的测定：AD患者治疗前血清ECP为29.953±42.752 ug／L，明显高于正常对照组(7.867±6.629ug／L)，差异有显著性统计学意义(P＜0.01)；治疗后血清ECP水平较治疗前明显下降，差异有统计学意义(P＜0.05)，但与对照组比较差异无统计学意义(P＞0.05)。相关分析结果显示ECP与SCORAD积分间存在相关关系(R~2=0.052，P=0.049)，但相关性不显著。
5．总IgE与ECP相关关系：相关分析结果显示血清总IgE与ECP治疗前存在正相关关系，治疗后相关关系不明显(治疗前r=0.329，P=0.044；治疗3个月后r=0.124，P=0.457)。
6．血清中NGF水平：AD患者治疗前血清NGF水平为251.914±216.054 pg／ml，明显高于正常对照组(105.859±21.471pg／ml)，差异有显著性统计学意义(P＜0.01)；治疗前AD患者按Rajka评分分为中、重度两组，其血清NGF的水平分别为120.962±69.167 pg／ml、413.675±227.282 pg／ml，两组间差异有显著性统计学意义(P＜0.01)；治疗前NGF积分与SCORAD间存在正相关关系。治疗前后配对统计学分析表明，治疗后患者NGF血清水平为107.273±109.187pg／ml，较疗前(251.914±216.054 pg／ml)明显下降，差异有显著性统计学意义(P＜0.01)，且疗后与正常对照组血清NGF水平(105.859±21.471pg／ml)比较差异无统计学意义(P＞0.05)。
7．血清中SP水平：AD患者治疗前SP血清水平为67.332±42.919 pg／ml，明显高于正常对照组(30.987±7.909 pg／ml)，差异有显著性统计学意义(P＜0.01)；AD患者治疗前按Rajka评分分为中、重度两组，血清SP的水平分别为43.487±13.949pg／ml、96.787±48.459 pg／ml，中度与重度明显不同，差异有显著性统计学意义(P＜0.01)；治疗前AD患者SP与SCORAD相关分析结果：SP与SCORAD积分间存在正相关关系；患者治疗前后配对分析表明，治疗后患者SP血清水平为46.581±26.480 pg／ml，较治疗前显著下降，差异有统计学意义(P＜0.05)；治疗后与正常对照组(30.987±7.909pg／ml)相比，差异有显著性统计学意义(P＜0.01)。
8．NGF与SP的相关关系：治疗前存在正相关关系，治疗后相关关系不明显(治疗前r=0.556，P＜0.001；治疗3个月后r=0.283，P=0.085)。
结论
1．用中药培土清心方内服治疗AD患者，治疗后皮损严重度及瘙痒、睡眠都得以明显改善，差异有统计学意义。说明培土清心法治疗AD疗效确切。并且在治疗期间没有观察到明显的副反应，初步证实本法治疗AD的安全性，是值得推广的治疗方法。
2．本研究也证实了大多数AD患者血清总IgE、ECP水平明显升高，且血清总IgE与病情成相关性，而ECP水平与病情无明显相关性。说明此二者均参与了AD的发病，而且血清总IgE水平可作为反映AD患者病情严重程度的血清学指标之一。
3．AD患者血清中NGF、SP水平均较对照组明显升高，差异有统计学意义，证实NGF及SP参与了AD的发病，支持AD发病机制中的神经源性机制。
4．AD患者治疗前血清NGF及SP水平与Rajka评分和SCORAD积分均存在正相关关系，提示NGF及SP与AD病情严重程度有关。
5．中药培土清心法治疗AD，可明显降低血清中总IgE、ECP、NGF、SP水平，说明其作用是多靶点的，其治疗机制可能与免疫学、神经源性机制相关。
6．神经肽拮抗剂及释放调节剂的研制将有可能为AD的治疗展示新的前景。
Background
Atopic dermatitis is characterized by chronic and relapsing pruritus andskin lesions resulting in great impacts on the physical and psychologicalstatus of the patients, usually occurring in children and adolescent. Theprevalence of the disease has been increasing according to domestic andinternational epidemiological datas, with development of social economy andenvironmental changes. Despite equivocal theory of etiology and pathogenesisfor the disease, it seems that atopic dermatitis results from syntheticalaction involved in genetic, environmental, immunological, microbial,psychological factors and so on. Present guideline for atopic dermatitisproposes that the core of treatment of AD is to ameliorate symptoms and signs,control the recurrence, and prevent from deterioration and progression.Therefore, controls of episodes of symptoms represent new trends and viewpointsconsidered management of atopic dermatitis. The chineses medicine fortreatment of atopic dermatitis becomes the warm spots due to its uniquesuperiority. However, most researches in this field revolve around clinicalobservation of therapeutic effects of several empirical formulas whilethere're less therapeutic principles and mechanism discussions. For thisreason, the unique formula of hilling and clearing away heart-fire, stemedfrom advisor's long-term clinical practice, is further discussed in thisstudy, including its therapeutic effects and potential therapeutic mechanisms.Since most studies demonstrate that atopic dermatitis is associated withimmunological factors, it's warranted in this study for the choices of itemsof immunoglobulin E and eosinophil cationic protein. On the other hand, moreand more attentions were paid upon the theory of neuroendocrine-immune network,the new explanation for mechanism of the psychosomatic disease; nerve growth factor and substance P are regarded as another research focus in this studyfor their important role in the pathology and pathophysiology of atopicdermatitis.
Objective
1. Serum immunoglobulin E and eosinophil cationic protein are examined toexplore their role in the pathogenesis of atopis dermatitis.
2. Therapeutic effects of advisor's empirical formula of hilling andclearing away heart-fire are evaluated through observation of changes ofSCORAD index before and after treatment.
3. Influence on the serum LgE, ECP, NGF, and SP is studied to discusspotential therapeutic mechanisms of advisor's empirical formula for atopicdermatitis. The research methods and results may provide new direction forclinical practice and become basis of development of new medicine.
Methods
55 patients diagnosed atopic dermatitis are admitted to this clinical trial.Scores of SCORAD index are collected before treatment, 1 month and 3 monthsafter treatment respectively. At the meantime, 38 cases are randomly chosenout of those 55 patients, controlled by 15 cases of normal volunteers. CAPallergen test system (Pharmacia Ltd) is then used for examination of serumIgE and ECP and ELISA assay for determination of serum NGF and SP. Correlationanalysis is conducted to explore the association between the serum items andscores of SCORAD index.
Results
1. Risk factors of atopic dermatitis. Questionnaire research is made toscreen potential risk factors of atopic dermatitis in 55 admitted patients.The final outcomes indicate that the disease is associated with diet, climateand season changes, sentiment and emotion abnormality, and past allergichistory and family history. Among those, onset and episodes of the diseaseare correlated with diet factor in 27 cases (especial the sea food), thechanges of season in 50 cases without dominant season trend, sentiment factorin 9 cases and emotion factor in 32 cases (especial the strain mood). In 55cases, 30 cases have history of allergic rhinitis, ashma, or both of them,in which 9 casese suffered from the two diseases. Further study also findsthat their relatives of 34 cases have the history of allergic diseases,especial the allergic rhinitis.
2. Clinical observation of therapeutic effects. Management regimen isconsisited of oral medicine of empirical formula of the hilling and clearingaway heart-fire and external application of emollients. Therapeutic effectsare evaluated through SCORAD index. The mean values of SCORAD are55.458±15.051 before the treatmen, 49.410±12.331 1 month after treatment,and 34.684±8.824 3 month after treatment, respectively. Compared to thescores of SCORAD before treatment, the scores of SCORAD after treatment areboth statistically significant (P＜0.01). The symptoms of pruritus and skinlesions are obvious improved and the quality of sleep is accordingly enhanced.The total effective rate, evaluated by Nimodipine method, is 92.75%,including excellence in 2 cases, improving in 49 cases, inefficacy in 4 cases.No adverse event was observed in the study. These preliminary outcomes of theclinical trial firtly demonstrated that the advisor's empirical formula isclinically practical in some degree.
3. Examination of total serum IgE. The mean value of serum IgE is2175.162±1982.798KU/L before the treatment, higher than that of normalcontrol group (45.287±35.753 KU/L). The difference between them isstatistically significant (P＜0.01). The mean value of serum IgE decreasesstatistically significant compared with that of before treatment (P＜0. 01).The final results seems that although undergoing management, the serum IgEafter treatment is still higher than that of normal control group withstatistical significance (P＜0.01). Correlation analysis indicates that thescore of SCORAD is positively associated with values of total serum IgE.
4. Tests of serum ECP. The mean value of serum ECP is 29.953±42.752 ug/L,higher than that of normal control group (7.867±6.629ug/L). The differenceis statistically significant (P＜0.05). The decrease of serum ECP aftertreatment is also statistically significant (P＜0.01) compared to that ofbefore treatment and no statistical significance are found between serum IgEafter treatment and that of normal control group (P＞0.05). Mild correlationis found between the score of SCORAD and value of serum ECP. However, suchassociation seems little important.
5. Correlation of total serum IgE and ECP. Correlation analysis indicatesthat there's positive association between total serum IgE and ECP, whereasit becomes slightly significant after treatment. The correlation coefficientis 0.329 (P=0.044) before treatment and 0.124 (P=0.457) 3 months after treatment, respectively.
6. The changes of serum NGF. The mean value of serum NGF is 251.914±216.054pg/ml, higher than that of normal control group (105.859±21.471 pg/ml) withstatistical significance (P＜0.01). The patients are further assigned to 2groups including moderate (120.962±69.167) pg/ml and serious group(413.675±227.282)pg/ml according to Rajka scales system. Variaration betweengroups is statistically significant (P＜0.01). Correlation analysisdemonstrates that the score of SCORAD is positively associated with the valueof serum NGF with statistical significance before treatment. Paired t-testanalysis is uses to demonstrate that the mean value of serum NGF after treatment(107.273±109.187 pg/ml) is statistically significantly lower than that ofbefore treatment (251.914±216.054 pg/ml) (P＜0.01). On the contrary, nostatistical significance is found when it's compared to that of normal controlgroup (105.859±21.471 pg/ml) (P＞0.05).
7. Analysis of values of serum SP. The mean value of serum SP is 67.332±42.919 pg/ml, higher than that of normal control group (30. 987±7.909 pg/ml)with statistical significance (P＜0.01). The patients are further assigned to2 groups including moderate (43.487±13.949 pg/ml) and serious group(96.787±48.459 pg/ml) according to Rajka scales system. Variaration betweengroups is statistically significant (P＜0.01). Correlation analysisdemonstrates that the score of SCORAD is positively associated with the valueof serum SP with statistical significance before treatment. Paired t-testanalysis is uses to demonstrate that the mean value of serum SP after treatment(46.581±26.480 pg/ml) is statistically significantly lower than that ofbefore treatment (P＜0.05). What's more, statistical significance is alsofound when it's compared to that of normal control group (30.987±7.909pg/ml) (P＜0.01).
8. Association of serum NCF and SP. The positive correlation is demonstratedbetween serum NGF and SP before treatment while such correlation becomes littlesignificant. The coeeficient correlation is 0.556 (P=0.000) before treatmentand 0.283 (0.085) respectively.
Conclusions
1. The empirical formula of hilling and clearing away heart-fire hasundoutable therapeutic effects for atopic dermatitis, illuminated by the factsthat the symptoms of pruritus, disturbance of sleep, and skin lesions are significantly enhanced after treatment. No case reports adverse events duringperiods of therapy and the regimen discussed in this study thus may bealternative management for atopic dermatitis in the future.
2. The elevated serum IgE and ECP exsisted in patients of atopic dermatitisare demonstrated in this study again. No correlation is found between valuesof serum ECP and degree of severity of the disease but serum IgE. Therefore,it's reasonable to postulate that values of total serum IgE can be regardedas serum index for reflection of status of atopic dermatitis.
3. Laboratory darns combined with clinical observation support thatneurogenic mechanism plays a key role in pathogenesis of atopic dermatitis.Compared to that of normal control group, the elevation of serum NGF and SPindicates that these factors is involved in the onset and flare of atopicdermatitis.
4. The values of NGF and SP are associated with status of AD, based oncorrelation between serum NGF and SP, Rajka Index, and SCORAD scores.
5. The empirical formula of hilling and clearing away heart-fire maygenerate its therapeutic effects through downregulating levels of serum totalIgE、ECP、NGF、SP. According to theses outcomes, it's proposed that therapeuticmechanism of the formula may be multi-target and associated with regulationof immunological and neurogenic factors.
6. Development of neuropeptide antagonists and releasing regulators mayprovide new promise for treatment of atopic dermatitis in the future.
特应性皮炎(atopic dermatitis，AD)主要累及儿童和青少年，长期反复发作的瘙痒、皮损是其主要的临床表现，严重影响患者身心健康。随着社会经济发展和外界环境变化，国内外的流行病学调查均显示其发病率呈明显的上升趋势。本病的病因病机尚未完全阐明，多认为与遗传、环境、免疫、微生物感染、精神因素等多种因素的综合作用有关。目前关于AD治疗的国际性指南定义的治疗目标为：减轻症状和体征、预防或减少复发、长期治疗以防止疾病加重、减缓病程。可以看出目前的西医治疗主要是缓解症状。而特应性皮炎是中医治疗具有优势的病种之一，因此本病的中医治疗已成为研究的热点。目前研究多为专方验方治疗特应性皮炎的疗效观察，对于治则治法的研究虽已逐渐有人提出，但涉及的治则治法还甚少，对于机理的研究更需进一步阐明。因此，本研究以导师在长期临床实践中所总结的培土清心法来治疗特应性皮炎患者，在既往的临床研究已初步证实该法有效的基础上进一步观察其疗效；并对其可能的作用机理进行探讨：首先从目前中医药治疗AD的实验研究中涉及比较多的血清总IgE、ECP的水平进行研究；其次从AD为心身疾病的特点及神经内分泌免疫网络在心身疾病中可能的作用为出发点，结合目前特应性皮炎研究中的神经源性机制，选择了在神经源性机制中研究较多的神经生长因子(NGF)和P物质(SP)指标进行了相关研究。
目的
1．通过检测AD患者血清中总IgE、ECP，以探讨二者在特应性皮炎发病机制中的作用；
2．通过检测AD患者血清中NGF、SP的水平，以探讨NGF、SP在AD发病机制中的作用；
3．观察治疗前后AD患者SCORAD积分的变化，以评价导师的经验方培土清心方对特应性皮炎的疗效。
4．研究培土清心方对AD患者血清总IgE、ECP、NGF、SP的影响，探求培土清心法治疗特应性皮炎可能的机制，以指导临床实践，并为新药开发奠定一定的基础。
方法
本研究选择55例AD患者为研究对象，于治疗前及治疗后1个月、3个月分别记录SCORAD积分。并在55名患者中随机选取38名于治疗前及治疗后3个月时进行血清学指标的检测，另以15名健康志愿者为对照。具体检测方法：以Pharmacia公司CAP变应原检测系统检测血清中的总IgE、ECP，ELISA法检测血清中NGF、SP的水平。并对各项血清学指标间以及血清学指标与患者SCORAD积分间进行相关分析。
统计学方法：采用SPSS13.0统计软件包建立数据库并进行统计分析。计量资料采用均数±标准差进行统计描述，计量资料两组比较采用独立样本t检验，前后比较用配对t检验或重复测量数据方差分析，计数资料采用x~2检验，方差不齐时治疗前后数据采用配对符号秩和检验，等级资料采用Mann—whitney秩和检验进行比较，检验水平α=0.05。
结果
1．特应性皮炎发病相关因素调查分析：对入选的55例患者进行发病相关因素的问卷调查，结果发现：由饮食因素引起和加重的有27例(49.09％)，其中又以海鲜类食物为主；其发病和加重与季节明显相关的有50例(90.90％)，具体以何季节为主，无明显倾向性；受情志因素影响的有9例(16.36％)。55例AD患者中，调查结果显示有30例合并有过敏性鼻炎或哮喘或二者合并存在，占54.54％，其中同时合并此二种疾病者9例，占16.36％。家族史方面：调查结果显示55例AD患者中，其家族中有过敏性疾病者为34例，占61.82％，其中以过敏性鼻炎者最为多见。情绪因素方面：调查结果显示55例AD中受情绪因素影响的有32例，占58.18％，其中以紧张情绪影响最为明显。
2．临床疗效观察：本临床观察共纳入55例符合标准的AD患者，用中药培土清心方内服，辅以润肤剂外用治疗，以涵盖AD 6个主要他觉症状和瘙痒、睡眠两个最主要主观症状的SCORAD积分进行评价，结果显示治疗前的SCORAD评分为55.458±15.051，治疗1月后为49.410±12.331，较疗前明显降低，差异有显著性统计学意义(P＜0.01)；治疗3月后为34.684±8.824，较疗前及疗后1月明显降低，差异有显著性统计学意义(P＜0.01)；治疗后较治疗前患者皮损严重度及瘙痒、睡眠都得以明显改善，差异有统计学意义。用尼莫地平法评价总体疗效：55例患者中2例显效，占3.66％；好转49例，占89.09％；4例无效，占7.25％；总有效率为92.75％。治疗过程中没有观察到明显的不良反应。说明培土清心法对临床治疗AD有一定指导价值。
3．血清中总IgE的测定：AD患者治疗前血清总IgE为2175.162±1982.798KU／L，明显高于正常对照组(45.287±35.753 KU／L)，差异有显著性统计学意义(P＜0.01)；治疗后AD组血清总IgE较治疗前降低，差异有显著性统计学意义(P＜0.01)，治疗后与对照组比较，仍明显高于正常对照组，差异有显著性统计学意义(P＜0.01)。相关分析结果显示总IgE与SCORAD积分间存在正相关关系(r=0.586，P=0.001)。
4．血清中ECP的测定：AD患者治疗前血清ECP为29.953±42.752 ug／L，明显高于正常对照组(7.867±6.629ug／L)，差异有显著性统计学意义(P＜0.01)；治疗后血清ECP水平较治疗前明显下降，差异有统计学意义(P＜0.05)，但与对照组比较差异无统计学意义(P＞0.05)。相关分析结果显示ECP与SCORAD积分间存在相关关系(R~2=0.052，P=0.049)，但相关性不显著。
5．总IgE与ECP相关关系：相关分析结果显示血清总IgE与ECP治疗前存在正相关关系，治疗后相关关系不明显(治疗前r=0.329，P=0.044；治疗3个月后r=0.124，P=0.457)。
6．血清中NGF水平：AD患者治疗前血清NGF水平为251.914±216.054 pg／ml，明显高于正常对照组(105.859±21.471pg／ml)，差异有显著性统计学意义(P＜0.01)；治疗前AD患者按Rajka评分分为中、重度两组，其血清NGF的水平分别为120.962±69.167 pg／ml、413.675±227.282 pg／ml，两组间差异有显著性统计学意义(P＜0.01)；治疗前NGF积分与SCORAD间存在正相关关系。治疗前后配对统计学分析表明，治疗后患者NGF血清水平为107.273±109.187pg／ml，较疗前(251.914±216.054 pg／ml)明显下降，差异有显著性统计学意义(P＜0.01)，且疗后与正常对照组血清NGF水平(105.859±21.471pg／ml)比较差异无统计学意义(P＞0.05)。
7．血清中SP水平：AD患者治疗前SP血清水平为67.332±42.919 pg／ml，明显高于正常对照组(30.987±7.909 pg／ml)，差异有显著性统计学意义(P＜0.01)；AD患者治疗前按Rajka评分分为中、重度两组，血清SP的水平分别为43.487±13.949pg／ml、96.787±48.459 pg／ml，中度与重度明显不同，差异有显著性统计学意义(P＜0.01)；治疗前AD患者SP与SCORAD相关分析结果：SP与SCORAD积分间存在正相关关系；患者治疗前后配对分析表明，治疗后患者SP血清水平为46.581±26.480 pg／ml，较治疗前显著下降，差异有统计学意义(P＜0.05)；治疗后与正常对照组(30.987±7.909pg／ml)相比，差异有显著性统计学意义(P＜0.01)。
8．NGF与SP的相关关系：治疗前存在正相关关系，治疗后相关关系不明显(治疗前r=0.556，P＜0.001；治疗3个月后r=0.283，P=0.085)。
结论
1．用中药培土清心方内服治疗AD患者，治疗后皮损严重度及瘙痒、睡眠都得以明显改善，差异有统计学意义。说明培土清心法治疗AD疗效确切。并且在治疗期间没有观察到明显的副反应，初步证实本法治疗AD的安全性，是值得推广的治疗方法。
2．本研究也证实了大多数AD患者血清总IgE、ECP水平明显升高，且血清总IgE与病情成相关性，而ECP水平与病情无明显相关性。说明此二者均参与了AD的发病，而且血清总IgE水平可作为反映AD患者病情严重程度的血清学指标之一。
3．AD患者血清中NGF、SP水平均较对照组明显升高，差异有统计学意义，证实NGF及SP参与了AD的发病，支持AD发病机制中的神经源性机制。
4．AD患者治疗前血清NGF及SP水平与Rajka评分和SCORAD积分均存在正相关关系，提示NGF及SP与AD病情严重程度有关。
5．中药培土清心法治疗AD，可明显降低血清中总IgE、ECP、NGF、SP水平，说明其作用是多靶点的，其治疗机制可能与免疫学、神经源性机制相关。
6．神经肽拮抗剂及释放调节剂的研制将有可能为AD的治疗展示新的前景。
Background
Atopic dermatitis is characterized by chronic and relapsing pruritus andskin lesions resulting in great impacts on the physical and psychologicalstatus of the patients, usually occurring in children and adolescent. Theprevalence of the disease has been increasing according to domestic andinternational epidemiological datas, with development of social economy andenvironmental changes. Despite equivocal theory of etiology and pathogenesisfor the disease, it seems that atopic dermatitis results from syntheticalaction involved in genetic, environmental, immunological, microbial,psychological factors and so on. Present guideline for atopic dermatitisproposes that the core of treatment of AD is to ameliorate symptoms and signs,control the recurrence, and prevent from deterioration and progression.Therefore, controls of episodes of symptoms represent new trends and viewpointsconsidered management of atopic dermatitis. The chineses medicine fortreatment of atopic dermatitis becomes the warm spots due to its uniquesuperiority. However, most researches in this field revolve around clinicalobservation of therapeutic effects of several empirical formulas whilethere're less therapeutic principles and mechanism discussions. For thisreason, the unique formula of hilling and clearing away heart-fire, stemedfrom advisor's long-term clinical practice, is further discussed in thisstudy, including its therapeutic effects and potential therapeutic mechanisms.Since most studies demonstrate that atopic dermatitis is associated withimmunological factors, it's warranted in this study for the choices of itemsof immunoglobulin E and eosinophil cationic protein. On the other hand, moreand more attentions were paid upon the theory of neuroendocrine-immune network,the new explanation for mechanism of the psychosomatic disease; nerve growth factor and substance P are regarded as another research focus in this studyfor their important role in the pathology and pathophysiology of atopicdermatitis.
Objective
1. Serum immunoglobulin E and eosinophil cationic protein are examined toexplore their role in the pathogenesis of atopis dermatitis.
2. Therapeutic effects of advisor's empirical formula of hilling andclearing away heart-fire are evaluated through observation of changes ofSCORAD index before and after treatment.
3. Influence on the serum LgE, ECP, NGF, and SP is studied to discusspotential therapeutic mechanisms of advisor's empirical formula for atopicdermatitis. The research methods and results may provide new direction forclinical practice and become basis of development of new medicine.
Methods
55 patients diagnosed atopic dermatitis are admitted to this clinical trial.Scores of SCORAD index are collected before treatment, 1 month and 3 monthsafter treatment respectively. At the meantime, 38 cases are randomly chosenout of those 55 patients, controlled by 15 cases of normal volunteers. CAPallergen test system (Pharmacia Ltd) is then used for examination of serumIgE and ECP and ELISA assay for determination of serum NGF and SP. Correlationanalysis is conducted to explore the association between the serum items andscores of SCORAD index.
Results
1. Risk factors of atopic dermatitis. Questionnaire research is made toscreen potential risk factors of atopic dermatitis in 55 admitted patients.The final outcomes indicate that the disease is associated with diet, climateand season changes, sentiment and emotion abnormality, and past allergichistory and family history. Among those, onset and episodes of the diseaseare correlated with diet factor in 27 cases (especial the sea food), thechanges of season in 50 cases without dominant season trend, sentiment factorin 9 cases and emotion factor in 32 cases (especial the strain mood). In 55cases, 30 cases have history of allergic rhinitis, ashma, or both of them,in which 9 casese suffered from the two diseases. Further study also findsthat their relatives of 34 cases have the history of allergic diseases,especial the allergic rhinitis.
2. Clinical observation of therapeutic effects. Management regimen isconsisited of oral medicine of empirical formula of the hilling and clearingaway heart-fire and external application of emollients. Therapeutic effectsare evaluated through SCORAD index. The mean values of SCORAD are55.458±15.051 before the treatmen, 49.410±12.331 1 month after treatment,and 34.684±8.824 3 month after treatment, respectively. Compared to thescores of SCORAD before treatment, the scores of SCORAD after treatment areboth statistically significant (P＜0.01). The symptoms of pruritus and skinlesions are obvious improved and the quality of sleep is accordingly enhanced.The total effective rate, evaluated by Nimodipine method, is 92.75%,including excellence in 2 cases, improving in 49 cases, inefficacy in 4 cases.No adverse event was observed in the study. These preliminary outcomes of theclinical trial firtly demonstrated that the advisor's empirical formula isclinically practical in some degree.
3. Examination of total serum IgE. The mean value of serum IgE is2175.162±1982.798KU/L before the treatment, higher than that of normalcontrol group (45.287±35.753 KU/L). The difference between them isstatistically significant (P＜0.01). The mean value of serum IgE decreasesstatistically significant compared with that of before treatment (P＜0. 01).The final results seems that although undergoing management, the serum IgEafter treatment is still higher than that of normal control group withstatistical significance (P＜0.01). Correlation analysis indicates that thescore of SCORAD is positively associated with values of total serum IgE.
4. Tests of serum ECP. The mean value of serum ECP is 29.953±42.752 ug/L,higher than that of normal control group (7.867±6.629ug/L). The differenceis statistically significant (P＜0.05). The decrease of serum ECP aftertreatment is also statistically significant (P＜0.01) compared to that ofbefore treatment and no statistical significance are found between serum IgEafter treatment and that of normal control group (P＞0.05). Mild correlationis found between the score of SCORAD and value of serum ECP. However, suchassociation seems little important.
5. Correlation of total serum IgE and ECP. Correlation analysis indicatesthat there's positive association between total serum IgE and ECP, whereasit becomes slightly significant after treatment. The correlation coefficientis 0.329 (P=0.044) before treatment and 0.124 (P=0.457) 3 months after treatment, respectively.
6. The changes of serum NGF. The mean value of serum NGF is 251.914±216.054pg/ml, higher than that of normal control group (105.859±21.471 pg/ml) withstatistical significance (P＜0.01). The patients are further assigned to 2groups including moderate (120.962±69.167) pg/ml and serious group(413.675±227.282)pg/ml according to Rajka scales system. Variaration betweengroups is statistically significant (P＜0.01). Correlation analysisdemonstrates that the score of SCORAD is positively associated with the valueof serum NGF with statistical significance before treatment. Paired t-testanalysis is uses to demonstrate that the mean value of serum NGF after treatment(107.273±109.187 pg/ml) is statistically significantly lower than that ofbefore treatment (251.914±216.054 pg/ml) (P＜0.01). On the contrary, nostatistical significance is found when it's compared to that of normal controlgroup (105.859±21.471 pg/ml) (P＞0.05).
7. Analysis of values of serum SP. The mean value of serum SP is 67.332±42.919 pg/ml, higher than that of normal control group (30. 987±7.909 pg/ml)with statistical significance (P＜0.01). The patients are further assigned to2 groups including moderate (43.487±13.949 pg/ml) and serious group(96.787±48.459 pg/ml) according to Rajka scales system. Variaration betweengroups is statistically significant (P＜0.01). Correlation analysisdemonstrates that the score of SCORAD is positively associated with the valueof serum SP with statistical significance before treatment. Paired t-testanalysis is uses to demonstrate that the mean value of serum SP after treatment(46.581±26.480 pg/ml) is statistically significantly lower than that ofbefore treatment (P＜0.05). What's more, statistical significance is alsofound when it's compared to that of normal control group (30.987±7.909pg/ml) (P＜0.01).
8. Association of serum NCF and SP. The positive correlation is demonstratedbetween serum NGF and SP before treatment while such correlation becomes littlesignificant. The coeeficient correlation is 0.556 (P=0.000) before treatmentand 0.283 (0.085) respectively.
Conclusions
1. The empirical formula of hilling and clearing away heart-fire hasundoutable therapeutic effects for atopic dermatitis, illuminated by the factsthat the symptoms of pruritus, disturbance of sleep, and skin lesions are significantly enhanced after treatment. No case reports adverse events duringperiods of therapy and the regimen discussed in this study thus may bealternative management for atopic dermatitis in the future.
2. The elevated serum IgE and ECP exsisted in patients of atopic dermatitisare demonstrated in this study again. No correlation is found between valuesof serum ECP and degree of severity of the disease but serum IgE. Therefore,it's reasonable to postulate that values of total serum IgE can be regardedas serum index for reflection of status of atopic dermatitis.
3. Laboratory darns combined with clinical observation support thatneurogenic mechanism plays a key role in pathogenesis of atopic dermatitis.Compared to that of normal control group, the elevation of serum NGF and SPindicates that these factors is involved in the onset and flare of atopicdermatitis.
4. The values of NGF and SP are associated with status of AD, based oncorrelation between serum NGF and SP, Rajka Index, and SCORAD scores.
5. The empirical formula of hilling and clearing away heart-fire maygenerate its therapeutic effects through downregulating levels of serum totalIgE、ECP、NGF、SP. According to theses outcomes, it's proposed that therapeuticmechanism of the formula may be multi-target and associated with regulationof immunological and neurogenic factors.
6. Development of neuropeptide antagonists and releasing regulators mayprovide new promise for treatment of atopic dermatitis in the future.
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48．李彦希．曲尼司特治疗异位性皮炎临庆观察及试验研究．2005[D]．四川大学．
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