扶土抑木法治疗多发性抽动症经验的数据挖掘暨复方中药对TS模型鼠脑内神经递质影响的研究

【作者】 郝宏文；

【导师】 王素梅；

【作者基本信息】 北京中医药大学 ， 中西医结合临床， 2010， 博士

【摘要】 目的：1分析此次研究所收集病历的一般情况；探索导师扶土抑木法治疗多发性抽动症的辨证思维路径；总结导师的处方、用药规律；探索多发性抽动症的证候要素及其靶位的规律及特点。2探索运用数据挖掘方法进行专家临床经验总结整理的可行性。3观察六君子汤合泻青丸加减对TS模型鼠纹状体内单胺类神经递质的影响,探索中药治疗多发性抽动症的可能的作用机理,为临床的进一步应用提供理论依据。方法：1采用传统研究手段与信息技术相结合的方法,遵循“人机结合,以专家为主”的原则,对导师治疗多发性抽动症的临证经验进行整理、结构化处理,再通过数据挖掘、分析、与导师沟通进行确认,分析导师治疗TS的症-证-法-方-药规律,总结导师治疗TS的学术思想。2对多发性抽动症进行证候要素研究,总结证候要素的规律,为多发性抽动症证候的规范化研究做初步探索。3建立IDPN多发性抽动症小鼠模型,分别给予六君子汤合泻青丸与泰必利进行灌胃治疗,观察纹状体内单胺类神经递质的变化。结果：1多发性抽动症的一般情况分析1.1发病年龄、性别比例、遗传性：102例多发性抽动症患儿,男女比例5.38：1,与文献报道一般为3：1～5：1基本相符。发病年龄最小2岁,最大15岁,平均发病年龄为7.05岁,2～6-岁36例(35.29%),6～9-岁40例(39.22%),9～12-岁18例(17.64%),12～15岁8(7.84%)例。对患儿家族史的调查发现,家族里有类似病史的患儿约占11.76%,有一定的家族遗传性。1.2就诊时不自主抽动程度(根据耶鲁综合抽动严重程度量表)就诊时抽动程度为轻度的75例(73.53%),中度有27例(26.47%),重度有0例。其中男性轻度60例,中度26例,女性轻度15例,中度1例；发病年龄在2～6-岁者轻度26例、中度10例；发病年龄在6～9-岁者轻度31例、中度10例；发病年龄在9～12-岁者轻度14例、中度3例；发病年龄在12～15-岁者轻度4例、中度4例。1.3伴有行为障碍情况伴有注意缺陷多动障碍的66例(64.70%),伴有强迫障碍5例(4.90%),伴发攻击行为1例,伴发睡眠障碍4例,伴有自伤行为2例,伴有轻度行为问题(性情方面)的共90例(88.26%),其中性情急躁者44例(43.14%),胆怯者19例(18.63%),性情急躁并胆怯者27例(26.47%)。1.4微量元素情况共有80例进行了末梢血微量元素检查,正常者51例,异常者29例(36.25%)。1.5不自主抽动加重因素20例有比较明确的抽动加重因素,其中12例有感染史(10例上呼吸道感染、1例疱疹性口炎、1例肠炎),占11.76%。1.6首发症状：眼部抽动作为首发症状的73例,占71.57%,吭吭作为首发症状的17例,占16.67%。2治疗多发性抽动症经验2.1中医证型分布规律共757次诊次中,脾虚肝亢334例次,占44.12%,肝郁化火205例次,占27.08%,脾虚痰聚121例次,占15.98%,阴虚风动52例次,占6.87%,其他类型45例,占5.94%。2.2证候要素规律出现频次在5%以上的证候要素为：风550(24.12%),火543(23.82%),痰517(22.68%),阴虚275(12.06%),气虚188(12.06%),共计2073次(90.92%)。证候要素组合形式从单证到5证共有103种组合形式,其中5证形式出现的共42例；4种出现的254例,3种出现的305例,2种出现的74例,单种出现的3例。虚证出现141例,占20.79%。出现频次最多的前5种组合为：痰+火+风(139次)、痰+火+风+阴虚(88次)、痰+火+风+气虚(32次)、火+风(28次)、气虚+火+风(20次)。含痰+火+风组合的共327次,占48.23%。靶位组合规律：5脏均有的4次,与4脏相关的16次,与3脏相关的193次,与2脏相关的376次,与1脏相关的90次,本病与2脏相关的最多,其中尤以肝脾为多,共271次,占39.91%。2.3治法规律涉及的治法共62种,包括了息风469次,化痰427次,健脾346次,平肝311次,清肝264次,清热201次,滋阴152次,疏肝96次,利咽91次,活血59次,养血19次,逐痰15次等。2.4选方规律在常用的复方中,前三位的是：二陈汤／泻青丸用于43例患者中,共用78频次,四君子汤／泻青丸用于30例患者,频次为48次,六君子汤／泻青丸用于9例患儿,共用12频次.2.5用药规律防风550次,占7.5%,木瓜438次,占6.8%,伸筋草435,占6.8%,葛根432次,占6.7%,地龙409次,占6.4%,菊花385次,占6.1%,谷精草359次,乌梢蛇345次,陈皮344次,半夏338次,胆南星336次,柴胡303次,钩藤301次,郁金295次,荆芥286次,白芍269次,知母255次,夏枯草245次等。3复方中药对TS模型鼠纹状体内单胺类神经递质的影响以IDPN诱导的抽动症动物模型为基础,前期实验及同期的行为学检测证明抽动模型造模成功,且复方中药对其治疗有效,测定纹状体内单胺类神经递质及其代谢产物,模型组与空白组相比,DA.NA有明显增高趋势,但其差异无统计学意义,DOPAC、5-HT、5-HIAA亦无统计学差异。与空白组相比,泰必利组NA明显增高(P<0.05),复方组NA明显增高(P<0.01)。与模型组相比,泰必利组、复方组5-HIAA均明显增高(P<0.01)结论：1多发性抽动症于学龄前和学龄儿童发病率最高,男孩的发病率较女孩高；抽动程度在不同性别、各发病年龄、及不同病程的差异无统计学意义；对首发症状的研究显示眼部抽动是运动性抽动中最常见的,吭吭是发声性抽动中最常见的。可伴发多种行为问题其中以注意缺陷多动障碍最多,情绪障碍的轻度异常广泛存在,应及早积极干预,以防加重并影响多发性抽动症的治疗。微量元素异常者以血铅增高最多,在预防和治疗中都应引起关注。2从中医证型、证候要素等多方面总结出导师对多发性抽动症从“风、痰”立论,病在肝脾的临证思路,从治法、方药的规律体现了导师运用扶土抑木法治疗本病的经验。3证候要素及其组合规律显示本病病机复杂,证候要素主要为风、火、痰、气虚、阴虚,证候要素组合以风+火+痰(+X)最多见,证候要素靶位主要在肝、脾,结合证候要素及其靶位进行应证组合,可以得出：本病的病机主要为脾虚痰聚,肝亢风动,使我们从复杂的证候系统中,能够用较少的证候要素来概括疾病的大部分信息,使大家对多发性抽动症的认识更明确,从而达到执简驭繁的辨证效果,同时也从证候要素方面映证了导师的学术思想。4验证了以信息化技术为依托,采用“人机结合,以专家为主”的方法进行中医专家临床经验挖掘总结是可行的。5中药复方治疗多发性抽动症的作用可能是通过下列机制实现的：(1)抑制了多巴胺神经的过度支配或多巴胺受体超敏感,从而减轻抽动；(2)通过5-HIAA水平增高,推测提高了5-HT水平,起到抑制抽动作用；(3)可能影响了多巴胺羟化酶(DβH)的水平或活性,使多巴胺转化为去甲肾上腺素增多,保持多巴胺水平无明显变化。更多还原

【Abstract】 Objective:1 An analysis of the general situation of the Institute to collect medical history; explore tutor’s thinking path of the inhibiting wood and strengthening earth; summary mentor prescription and drug law; explore rules and characteristics of Tourette’s syndrome elements and its target site2 To explore the data-oriented approach to TCM expert clinical experience of finishing the feasibility of mining.3 To observe impact of content of monoamine neurotransmitter in brain of model mice built by IDPN intraperitoneal injection after taking herbal medicine, so as to understand possible mechanism of TCM treatment of TS.Methods:1 Traditional research methods integrated with computer information technology method in accordance with the "man-machine combination of expert-based" principle are used to analyze syndrome-rule-prescription-drug laws, and summary the experience and academical academic treatment of TS of tutor..2 Analysis and summarise the law of element factor of symptom complex of TS, and do a preliminary exploration for the standardization of research to TS symptom complex.3 To observe impact of monoamine neurotransmitter in brain of IDPN-induced model mice by taking liu jun zi tang and xie qing wan, Tiapridal is used as control medicine.Results:1General information102 children are studied,Boys outnumber girls in the ratio of 5.38to 1, and this consistent with previous literature reports. the minimum onset age was 2 years old; the maximum was 15, and average age 7.05.36 cases were 2-6-year-old period (35.29%); 40 cases were 6-9 -year-old (39.22%).attendance tic grade:low grade 75 cases (73.53%), moderate grade 27 cases (26.47%).66 cases are accompanied with ADHD,5 cases accompanied with Obsession,4 cases accompanied with Sleep disorder,1 cases accompanied with attack behaviour. there are 90 children with hot temper or timidity accounting for 88.26%.51 cases Trace Elements are normal,29 cases Trace Elements are abnormal. Patients with a blink of eye as first symptom account for 73, and HangHang for 17 cases. 2 Experience of treatment of Tourette syndromeThe survey shows that splenic asthenia and liver domination was the most frequent TCM syndrome for Tourette syndrome, It followed by stagnated QI transforming into fire, Next syndrome was spleen asthenia and poly-sputum, stirring of wind due to deficiency of YIN was the least.syndrome factor whose occurrence Frequency exceed 5%are wind factor (24.12%), heat factor (23.82%), sputum factor(22.68%), Yin deficiency factor (12.06%), Qi deficiency factor (12.06%).there are many integrated styles, sputum factor+wind factor+heat factor+X is the most popular. The disease location is relative with spleen and liver mostly, summing up to 271 cases (39.91%).62 treatment rules are used by my tutor in curing TS, including trsnquilizing endogenous wind, followed by reducing phlegm, invigorate the spleen, soothing the liver, ect.The Principle of Prescription:during all compound recipes, ER CHEN TANG combined with XIE QING WAN is used for 78 times, SI JUN ZI TANG combined with XIE QING WAN is used for 48 times, LIU JUN ZI TANG combined with XIE QING WAN is used for 12 times.The Principle of using herbs:the most use of frequence are Fangfeng, followed by Mugua, Shenjincao,Gengeng, Dilong, Juhua, Gujingcao, Wushaoshe,etc.Monoamine neurotransmitter in brain of TS model mice:compared with blank controller, NA content in brain of Tiapridal group and compound recipes increase obviously, compared with modeling team,5-HIAA content in brain of Tiapridal group and compound recipes increase obviously (P< 0.01)Conclusion:1 Tourette syndrome has the highest incidence in preschool and school-age, incidence of boys is higher than girls. tic degree of different gender, the age at onset, and different course of the disease was no significant difference. the first symptom of studies have shown that eye blink is a sports tic in the most common, Hang Hang is a vocal tic in the most common. TS is associated with a variety of behavioral problems such as OB, SD, ADHD, etc. mild emotional disturbances and abnormal trace elements in blood lead increased should be focused in the prevention and treatment of TS.2 Article can be concluded from the syndrome, syndrome elements that TS disease is based on "wind, phlegm," target is in liver and spleen, treatment rules is inhibiting wood and strengthening earth3 Laws of syndrome elements and their combinations show a complex pathogenesis of this disease, syndrome factors include wind, heat, phlegm, qi deficiency, yin deficiency mainly. Wind+heat+sputum (+X) is common in syndrome factor combination.syndrome factor target site is mainly in the liver, spleen. combined with elements and their target site, we can conducted:The pathogenesis of this disease is mainly poly sputum Spleen, liver Kang wind-driven. the most information of the disease can be summarized by fewer syndrome elements, so that people is more easy to understand Tourette’s syndrome. it also bears out tutor’s academic thinking. from elements of the syndrome4 Verification of the use of information technology relying on a "man-machine integration, expert-based" approach to Chinese medicine experts’s clinical experience is feasible.5 Effect of Chinese herbal compound curing Tourette’s syndrome may be achieved through the following mechanisms:(1) inhibition of excessive dopamine nerve domination or super-sensitive dopamine receptor; (2)according to 5-HIAA levels increased,5-HT levels may be increased,5-HT plays a role in inhibiting tic; (3) the level or activity of dopamine-hydroxylase (DβH) may be increased to transform dopamine into norepinephrine.更多还原