益气活血解毒法抗溃疡性结肠炎复发的临床疗效评价及理论机制研究

【作者】 刘果；

【导师】 王新月；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2009， 博士

【摘要】 1研究目的本课题以溃疡性结肠炎(UC)慢性复发型和慢性持续型患者作为研究对象,依据随机、对照原则,以益气活血解毒为法的溃结复发方进行干预治疗,对其进行临床疗效及抗复发情况评价,同时结合实验研究从调节机体免疫紊乱状态,抑制炎症,调节细胞信号转导角度探讨其抗复发作用机制,寻找中医药作用的靶点,进一步明确其抗UC复发的作用机制,确立以伏邪论治抗UC复发的思路和方法,为中医药抗UC复发确立理论根据,扩展伏邪理论的应用范围。2研究方法2.1临床疗效及抗复发疗效评价研究本课题依据相关标准,进行严格的临床研究设计,结合具体临床实际,采用随机、阳性对照的方法,以东直门医院、东方医院、中日友好医院的门诊和住院患者为研究对象,选择溃疡性结肠炎慢性复发型和慢性持续型病例60例,治疗组给予以益气活血解毒为法的抗溃结复发方(生黄芪30g炒白术15g茯苓15g赤白芍各10g三七粉(冲)3g生蒲黄10g炒五灵脂10g黄连10g煨木香10g焦槟榔20g连翘10g)加减治疗,对照组给予柳氮磺胺吡啶(SASP)(4～6g/d)治疗。疗程均为3个月,对有效病例随访6个月,主要观察临床综合疗效、复发率、中医证候疗效、临床活动指数与血小板计数及内镜指数的变化。2.2抗复发作用机制研究2.2.1抗复发作用机制临床研究本课题依据相关标准,进行严格的临床研究设计,结合具体临床实际,采用随机、阳性对照的方法,以东直门医院、东方医院、中日友好医院的门诊和住院患者为研究对象,选择溃疡性结肠炎慢性复发型活动期和慢性持续型病例60例,治疗组给予以益气活血解毒为法的抗溃结复发方加减治疗,对照组给予柳氮磺胺吡啶(SASP)(4～6g/d)治疗。疗程均为3个月,对有效病例随访6个月,主要观察两组治疗前后及随访时的指标变化。主要指标:①血清抗中性粒细胞胞浆抗体(ANCA)含量变化;②结肠黏膜组织Smad7表达水平变化③结肠黏膜组织转录调节因子IκBα表达水平变化。3结果3.1疗效及抗复发作用评价①治疗3个月后,治疗组临床综合疗效优于对照组(P<0.05),两组完全缓解率(85.71%vs44.44%)及总有效率(100.0%vs74.07%)亦经统计学检验,存在显著差异(P<0.05)。②疗程结束后对两组经治疗后完全缓解及有效的患者(治疗组28例,对照组20例)随访6个月,调查其复发情况。治疗组6个月复发率明显低于对照组(17.86%vs70.00%),经统计学检验,存在极显著差异(P<0.01)。③治疗组对中医证候积分的近期及远期改善均优于对照组(P<0.01)。④治疗组在临床活动指数改善、血小板计数方面,近期疗效及远期疗效均优于对照组(P<0.05vsP<0.01)。⑤治疗组在内镜指数改善方面,远期疗效优于对照组(P<0.01)。⑥治疗组在3个月的疗程中不良反应率为0,明显低于对照组(25.93%)。统计学检验有显著差异(P<0.05)。3.2抗复发作用机制研究3.2.1临床研究①血清抗中性粒细胞胞浆抗体(ANCA)中药组ANCA阴转率明显高于西药组,且在治疗UC复发时疗效也高于西药组,显示出其在改善病人整体免疫紊乱状态方面的优势。ANCA对UC的鉴别诊断是有意义的;P-ANCA与UC活动性有一定关系,特别是P-ANCA阳性的UC患者可作为监测UC活动的指标;目前还不能肯定“ANCA→肠粘膜血管炎→UC发生”这样的因果关系;②结肠黏膜组织Smad7UC患者结肠黏膜组织Smad7表达高于正常组(P<0.01),而复发组患者结肠黏膜组织Smad7表达高于未复发组(P<0.01),治疗后及随访时治疗组结肠黏膜组织Smad7表达皆低于对照组(P<0.05)。③结肠黏膜组织转录调节因子IκBαUC患者结肠黏膜组织IκBα表达低于正常组(P<0.01),而复发组结肠黏膜组织IκBα表达低于未复发组(P<0.01),治疗后及随访时,治疗组结肠黏膜组织IκBα表达皆高于对照组(P<0.05)。4结论以透发伏邪为目的,以益气活血解毒立法组成的抗溃结复发方治疗慢性复发型活动期和慢性持续型UC患者取得了满意的临床综合疗效。与柳氮磺胺吡啶对照组比较,本方有效地阻抑了溃疡性结肠炎的缓解后复发。其中本方在提高完全缓解率及总有效率、改善中医证候积分、临床活动指数、内镜指数方面作用皆优于后者,且未出现明显的毒副作用。其抗复发作用机制可能是:①降低UC患者的肠粘膜Smad7表达,有可能减少了TGF-β1信号通路的干扰,发挥了TGF-β1对粘膜炎症的负调控机制,有效地抑制了结肠黏膜局部炎症的持续存在,促进粘膜上皮的愈合;②提高IκBα的表达,有可能抑制了NF-κB慢性激活,减少促炎性细胞因子的释放,从而避免了结肠黏膜局部炎症的持续存在;③降低患者血清ANCA含量,改善病人整体免疫紊乱状态,其可能机制为减少了对中性粒细胞、单核细胞的活化、降低了黏附分子的表达及炎性细胞的趋化。更多还原

【Abstract】 ObjectiveUlcerative colitis(chronic nonspecific ulcerative colitis) is a disease of digestive tract characterised by chronic inflammation and ulceration of colonic mucous membrane.Clinical manifestation:mucus,pus and blood stool;diarrhea; abdominal pain;tenesmus and so on.It has anfractousive pathogenesy,which they affect each other and even emerge vicious cycle.It causes UC easily to relapse and last a very long period.At present,aminosalicylic acid,cortex steroid hormone and immunomodulator is the effective western medicine.In active stage of ulcerative colitis,these medicine can quickly control the symptoms.The clinical remission rate is high.But the disease is easily recur after drug withdrawal.And side reaction is multi with long-term medication,which causes very low compliance.Professor Wang Xinyue,my tutor who studies UC based on the theory of Traditional Chinese Medicine and Modern Medicine,expound it accurately. Kuijiefufafang is my tutor’s proved recipe based on treating with p norishing Qi, promoting blood circulation,removing toxic materials.The topic evaluate its therapeutic and resisting relapse effect.It meanwhile investigates the mechanism of resisting relapse effect from the view of restraining the reaction of inflammatory injury,promoting the repair of colonic mucous membrane combining.We deeply analyze the mechanism of repressing recur after henosis in order to offer the objective evidence of reasonably selecting the treating method and medicine.MethodsThe CR study was strictly designed under correlated standard.In combination with actual clinical situation,adopting random positive control method,on the basis of diagnosis criterion established on Inflammatory Bowel Disease Seminar at Jinnan in 2007,60 cases of chronic recurrent type in UC active phase and chronic type was selected from out-patient clinic(OPD) and ward of Dongzhimen Hospital, Dongfang Hospital,China-Japan friendship Hospital,treated group received tutor’s proved recipe(parching excrementum pteropi 10g,raw pollen typhae 10g, angelicae 10g,red and white peony root 10g apiece,charred semen arecae 10g, roasted radix aucklandiae 10g,coptidis rhizoma 10g,amoorcorn tree bark 10g, raw astragali 30g,forsythia suspensa 20g,parching atractylodes macrocephala 10g),control group received sulfasalazine(SASP),(4-6g/d).Both treatment course was 3 months,and attended by 6 months partly,mainly observed index:1. Therapeutic effect,including clinical general effect,change of TCM syndrome,the change of clinical activity index(CAI),endoscopic index(EI) and relapse rate.2. serum Antineutrophil cytoplasmic antibody(ANCA) 3.colon mucous membrane Smad7 and IκBα.ResultsEvaluation of therapeutic effect and resisting relapse effect①Clinical general therapeutic effect of treated group is better than control group;Including the total remission percentage of two groups,total effective percentage of two group,the statistic significant is difference,treated group is obviously better than control group.②After treatment,the relapse rate in six months of treated group is obviously lower than that of control group.③Syndrome scores of treated group was dropped apparently,the forward improvement of treated group is better than control group.④CAI and EI of treated group significantly dropped after treatment,the forward improvement of control group was better than control group(P<0.01).⑤There was no obvious ill-effect on treated group,which is obviously lower than control group.Researching on mechanism of resisting relapseClinical index:①Serum ANCA concentration of patients in UC active phase were remarkably higher than normal value.ANCA is significant in differential diagnosis of UC;P-ANCA has something to do with the reactiveness of UC,especially patients with positive P-ANCA which can be an index monitoring the active UC;The casual relation among ANCA→vasculitis of intestinal mucosa→UC was not sure;The rate of ANCA becoming negative of.the herbal group is obviously higher than the western medicine group,so was when treating the recurrent UC which showed the preponderance in improving the patients’immunologic derangement.②Colon mucous Smad7 concentration of patients in UC active phase were remarkably higher than normal value.Colon mucous Smad7 concentration in relapse phase of UC patients were significantly higher than that of not relapse patients.After treatment and after six months of attending,colon mucous Smad7 concentration of treated group were significantly lower than that of control group.③Colon mucous IκBαconcentration of patients in UC active phase were remarkably lower than normal value.Colon mucous IκBαconcentration in relapse phase of UC patients were significantly lower than that of not relapse patients.After treatment and after six months of attending,colon mucous IκBαconcentration of treated group were significantly higher than that of control group.ConclusionWe have got satisfied therapeutic effect in treating UC by using the methods of norishing Qi,promoting blood circulation,removing toxic materials guided by determination of treatment based on differentiation of syndromes.And the therapeutic effect was obviously better than SASP.Especially in the TCM syndrome,CAI,EI,and resisting relapse,showed its superiority.Compared with western medicine,it had no obvious ill-effect.The following is the contra-relapse mechanism of Chinese medicine:1.Restraining the multi expression of Smad7, preventing the aggregation of inflamed cell;2.Raising the expression of ANCA, down regulating the condition of local immunity;3.Raising the expression of Colon mucous IκBαsince nonage so as to enhance mucosa epithelial cell proliferation,lessen apoptosis,promoting the repair of injuried mucous membrane in later stage.更多还原