中医药抗溃疡性结肠炎复发的临床研究

【作者】 林芳冰；

【导师】 王新月；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2007， 硕士

【摘要】 1研究目的溃疡性结肠炎(Ulcerative Colitis,UC)又称非特异性溃疡性结肠炎,是一种原因不明的慢性直肠和结肠炎性疾病。因其治愈难度大、病程长,且与结肠癌的发病有关,被世界卫生组织列为现代难治病之一。西医目前无特效治疗药物,且停药后易复发,长期应用副反应多,对顽固性病例疗效不理想。中医药治疗本病有明显的优势,主要表现在降低复发率、改善生活质量及安全性等方面,总体疗效优于西药治疗。本课题从调节细胞免疫功能、抑制炎症损伤反应、改善微循环状态等方面,深入探讨UC复发的病理机制,并以健脾益气活血、清热化湿解毒的中药复方进行干预,对其预防本病复发的疗效进行客观评价,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,确立中药抗UC复发治疗的新思路和方法,为中药抗UC复发寻找理论根据。2研究方法本课题以《中药新药临床指导原则》(2002年,试行)中药新药治疗慢性非特异性溃疡性结肠炎的临床研究指导原则为具体参照标准,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、301医院、306医院的门诊和住院患者为研究对象,依据2000年成都全国炎症性肠病学术研讨会制定的溃疡性结肠炎的诊断标准,选择溃疡性结肠炎慢性复发型活动期的病例87例,治疗组予健脾益气活血、清热化湿解毒的中药汤剂(生炙黄芪各15g炒白术15g茯苓15g赤白芍各10g当归10g三七粉(冲)3g生蒲黄(包)10g炒五灵脂10g黄连10g黄柏10g煨木香10g焦槟榔10g连翘10g公英10g)加减治疗,对照组予柳氮磺胺吡啶(SASP)(4～6g/d)治疗。疗程均为3个月,对部分病例随访6个月,主要观察:(1)疗效观察,包括临床综合疗效,复发率,中医证候疗效,内镜黏膜疗效,临床活动指数、内镜指数的变化,以及生活质量评价的变化。(2)两组治疗前后及随访时的指标变化:外周血CD4+/CD8+/CD3+细胞,血清肿瘤坏死因子-α(TNF-α)、血浆血栓烷素B2(TXB2)、6-酮前列腺素1α(6-Keto-PGF1α)、及TXB2/6-Keto-PGF1α比值。其中TNF-α、TXB2、6-Keto-PGF1α同时检测正常人20例作为正常对照。3结果3.1疗效观察结果(1)治疗组临床综合疗效优于对照组(P<0.001);两组完全缓解率(68.18% vs41.86%)和总有效率(95.45% vs 74.42%)比较有统计学意义,治疗组明显优于对照组。(2)两组半年内复发率(治疗组6.67%,对照组50.00%),经统计学检验,有统计学意义(P<0.001),表明中药抗复发作用明显优于柳氮磺胺吡啶。(3)治疗组的中医证候积分远期改善明显优于对照组(P<0.001)。(4)治疗组临床活动指数和内镜指数治疗后较对照组明显下降(均P<0.05),治疗组远期改善亦优于对照组(P<0.001)。(5)治疗组未出现显著的不良反应,而对照组则出现了3例不良反应,1例因不良反应停药。(6)治疗后6个月,治疗组的病理分级与内镜分级均明显低于对照组(P<0.001)。(7)治疗后6个月,治疗组的生活质量改善情况明显优于对照组(P<0.001)。3. 2免疫学指标变化(1)活动期UC患者外周血CD3+细胞计数、CD8+细胞计数、CD8+细胞百分比均明显高于正常参考值,CD4+/CD8+比值、CD4+百分比明显低于正常参考值。未发现UC患者外周血CD4+细胞绝对计数与正常参考值的差别。UC复发患者CD3+细胞绝对计数、CD8+细胞绝对计数与百分比均显著高于未复发患者,CD4+/CD8+比值、CD4+细胞百分比显著低于未复发患者。治疗后、随访时及二者差值:治疗组外周血CD3+细胞绝对计数、CD8+细胞绝对计数及百分比均显著低于对照组,CD4+/CD8+比值、CD4+细胞百分比显著高于对照组。治疗组随访值与治疗后检测值比较,CD3+细胞绝对计数、CD8+细胞绝对计数及百分比、CD4+/CD8+比值、CD4+细胞百分比无统计学意义(P>0.05);对照组随访值与治疗后检测值比较,CD3+细胞绝对计数、CD4+细胞绝对计数与CD8+细胞绝对计数及百分比有显著差异(P<0.05)。(2)治疗前,UC患者血清TNF-α水平均高于正常值(P<0.001);复发UC患者的血清TNF-α含量明显高于未复发患者。治疗后治疗组血清TNF-α水平均明显低于对照组(P<0.001)。随访时治疗组血清TNF-α水平均明显低于对照组(P<0.001),与治疗后检测值比较治疗组无统计学意义,而对照组差异显著(P<0.001)。(3)治疗前,UC患者血浆TXB2、6-Keto-PGF1α含量,TXB2/6-Keto-PGF1α比值均高于正常值(P<0.001);复发UC患者的血浆TXB2、6-Keto-PGF1α含量,TXB2/6-Keto-PGF1α比值明显高于未复发患者。治疗后治疗组血浆TXB2、6-Keto-PGF1α含量,TXB2/6-Keto-PGF1α比值均明显低于对照组(P<0.001)。随访时治疗组血浆TXB2、6-Keto-PGF1α含量,TXB2/6-Keto-PGF1α比值均明显低于对照组(P<0.001),与治疗后检测值比较治疗组无统计学意义,而对照组差异显著(P<0.001)。4结论中医辨证论治治疗溃疡性结肠炎取得了满意的疗效,抗复发效果明显优于柳氮磺胺吡啶。尤其在中医证候学、内镜指数、病理状态方面,显示出中医药在改善溃疡性结肠炎患者生活质量方面具有巨大优势,而且与西药相比无明显毒副作用。可能的作用机制是:①抑制T淋巴细胞亚群的过度增殖,调节亢进的细胞免疫功能;调节T淋巴细胞亚群比例的失衡,改善全身细胞免疫状态;②抑制炎性介质TNF-α的大量表达,阻止炎性细胞的聚集;③改善微循环高凝状态,促进溃疡愈合。④改善患者生活质量,从整体调整患者身心状态,达到治愈UC和减少复发的目的。综上所述,中医药主要通过以上方面,阻断免疫损伤过程,抑制黏膜损伤,促进黏膜愈合,并阻抑愈合后复发。更多还原

【Abstract】 Background and ObjictiveUlcerative colitis (chronic nonspecific ulcerative colitis) is adisease of digestive tract characterised by chronic inflammation andulceration of colonic mucous membrane. Etiopathogenisis andpathogenesis of the disease is not very clear. Because of its difficultyto cure ,long course of disease and easily to be cancer of colon,it hasbeen known as difficuly disease in the world.At present,there are noeffective western medicine in treating UC. Even these medicines canquickly control the symptoms,the clinical remission rate is high. Andthe disease is easily recurring after drug withdrawal. And side reactionis multi with long-term medication. These medicines are not ideal tointractable cases. Chinese medicine has remarkable preponderance intreating this disease and is obviously superior to western medicine intotal curative effect.The topic is beginning with the mechanism of immunologic injury,controling the reaction of inflammatory and improving the microcosmiccirculation . We deeply investigate the mechanism of chinese Medicinemethods in treating from the aspects of regulating cellular immunefunction, restraining the reaction of inflammatory injury, promoting therepair of colonic mucous membrane. We deeply analyze the mechanism ofrepressing recur after henosis in order to offer the objective evidenceof reasonably selecting the treating method and medicine. Thus, we canpropose the multiple rings treating theory of UC and the way ofmicrocosmic syndrome differentiation.MethodsThe study was strictly designed under the guidance of GUIDELINE FORNEW DRUGS CLINICAL TRIALS (1997 Edition 3) Guidelines for Treament ofChronic Unspecific Ulcerative Colitis with Chinese Materia Medica. Incombination with actual clinical situation, adopting random positivecontrol method, on the basis of diagnosis criterion established onInflammatory Bowel Disease Seminar at chengdu in 2000, 87 case of chronicrecurrent type in UC active phase was selected from out-patient clinic(OPD) and ward of Dongzhimen Hospital, 301 Hospital, 306 Hospital,treated group received tutor’s proved recipe (trogopterus xanthipesmilne-edwards excrement 10g , typha angustifolia pollen10g, root and redpaeonia root of herbaceous peony 10g apiece,Chinese angelica 6g,driedbetel palm10g, the rhizome of Chinese goldthread 10g, the bark of a corktree 10g , saussurea lappa Clarke root 10g ,forsythia10g, bge root 20g),control group received sulfasalazine (SASP), (4-6g/d). Both treatment course was 3 months, and attend 6 months, main observed index: 1.Therapeutic effect, including clinical general effect, change of TCMsyndrome, therapeutic effect of mucous membrane under endoscope,therapeutic effect of mucous membrane under microscope, the change ofclinical activity index, CAI, endoscopic index. 2. Immue index of bothgroups before and after treatment, CD4+/CD8+/CD3+of peripheral blood,serum Tumornecrosis factor-alpha (TNF-α), plasma TetramethylpyrazineB2(TXB2), 6-keto-prostaglandin F1α(6-Keto-PGF1α). TNF-α,TXB2, 6-Keto-PGF1αwere also detected in 20 normal persons as normal control.ResultsObservation of therapeutic effect1. Clinical general therapeutic effect of treated group is betterthan control group (P<0.001); the total remission percentage of two group(68.18% vs 41.86%), total effective percentage of two group(95.45% vs74.42%), the statistic significant is difference, treated group isobviously better than control group.2.After treatment, the relapse rate in six months of treated groupis obviously lower than that of control group(P<0.001).3. Syndrome scores of treated group was dropped apparently, theforward improvement of treated group is better than control group(P<0.001).4. Clinical activity index (CAI) and endoscopic index of treatedgroup significantly dropped after treatment (P<0.05), the forwardimprovement of control group was better than control group (P<0.001).5. There was no obvious ill-effect on treated group, but three casesof control group had ill-effect, one case stopped receiving treatmentbecause of it.6. After six months of treatment, the pathologic grade and endoscopegrade of the treated group significantly lower than control group(P<0.001).7. After six months of treatment, the qualities of the treated groupwere significiantly better than control group (P<0.001).The change of immune index1. CD3+ cellular counting, CD8+ cellular counting and percentage ofperipheral blood in active phase of UC patients were significantly higherthan that of normal reference criterion, ratio of CD4+/CD8+, and CD4+ cellular percentage were significantly lowerer than that normalreference criterion, and have relationship with degree of disease andlesion range. There was no difference of CD4+ cellular counting ofperipheral blood between UC patients and healthy people.CD3+ cellular counting ,CD8+ cellular counting and percentage ofperipheral blood in relapse phase of UC patients were significantlyhigher than that of not relapse patients, ratio of CD4+/CD8+, and CD4 +cellular percentage were significantly lowerer than that not relapsepatients.CD3+ cellular counting ,CD8+ cellular counting and percentage ofperipheral blood in treated group were significantly lower than that ofcontrol group, ratio of CD4+/CD8+, and CD4+cellular percentage weresignificantly higher than that of control group after treatment and aftersix months of treatment, CD3+ cellular counting,CD8+ cellular countingand percentage, ratio of CD4 + /CD8 + , CD4 + cellular percentage ofperipheral blood in treated group after six months of treatment weresimilar compared with them after treatment. And CD3+ cellular counting,CD4+cellular counting ,CD8+ cellular counting and percentage in controlgroup after six months of treatment were significantly differentcompared with them after treatment(P<0.05).2. Serum TNF-αconcentration of patients in UC active phase wereremarkblely higher normal value (P<0.001).Serum TNF-αconcentration in relapse phase of UC patients weresignificantly higher than that of not relapse patients.After treatment, serum TNF-αconcentration of treated group weresignificantly lower than that of control group (P<0.001). After sixmonths of treatment, serum TNF-αconcentration of treated group weresignificantly lower than that of control group (P<0.001);The value oftreated group were similar compared with them after treatment; The valueof control group had significantly diffrence compared with them aftertreatment(P<0.001).3.Plasma TXB2、6-Keto-PGF1αconcentration and ratio ofTXB2/6-Keto-PGF1αof patients in UC active phase were remarkblely highernormal value (P<0.001).Plasma TXB2、6-Keto-PGF1αconcentration and ratio ofTXB2/6-Keto-PGF1αin relapse phase of UC patients were significantlyhigher than that of not relapse patients.After treatment, Plasma TXB2、6-Keto-PGF1αconcentration and ratio ofTXB2/6-Keto-PGF1αof treated group were significantly lower than that ofcontrol group (P<0.001). After six months of treatment, Plasma TXB2、6-Keto-PGF1αconcentration and ratio of TXB2/6-Keto-PGF1αof treatedgroup were significantly lower than that of control group (P<0.001);Thevalues of treated group were similar compared with them after treatment;The value of control group had significantly diffrence compared with themafter treatment (P<0.001).ConclusionsWe have got satisfied therapeutic effect in treating UC by using themethods of determination of treatment based on differentiation ofsyndromes. And the therapeutic effect was obviously better than SASP.Especially in the TCM syndrome, endoscopic index, pathologic index and contra- relapse, showed its superiority in the betterment of livingquality. Compared with western medicine, it had no obvious ill-effect.The following is the contra- relapse mechanism of Chinese medicine: 1.Restraining the excessive generation of T type of lymphocyte subgroup,regulating the accentuated cellular immune function; regulating thedisequilibrium of T type of lymphocyte subgroup, improving cellularimmunity all over the body;2. Restraining the multi expression of TNF-α, preventing the aggregation of inflamed cell;3. Promoting thecirculation of blood so as to promote the repair of injuried mucousmembrane. 4. Improving the qualities of the patients. Therefore, weconsider that chinese medicine has the role of prevent immunologic injury,restraining mucosa injury, promoting repair, so can repress recur afterhenosis .更多还原