摘要
1.目的
溃疡性结肠炎(ulcerative colitis,UC)是一种慢性非特异性结肠炎性疾病,在我国的发病率日益升高,并以慢性复发型最为多见。该病病因仍然不清,目前的研究认为精神因素、环境因素、遗传易感性、免疫反应及肠道局部微环境协同参与了本病的发病。最新的治疗策略是诱导、维持临床症状和黏膜炎症的缓解,重建肠黏膜屏障平衡,减少复发和并发症,改善患者的生活质量。由于病因的尚不明确,治疗方法仍以支持疗法和控制炎症改善症状为主,疗效并不满意。但是我们拥有中医中药这一宝贵资源,近年来中医药治疗溃疡性结肠炎的研究取得了显著进展。相对于西医,中药具有高安全性和作用的多向性的特点,在控制患者不良反应,减少复发,改善患者生存质量方面有明显优势。但目前,中医药治疗本病的研究尚存在许多问题,如可重复性差,缺乏循证医学证据等。
导师张燕生教授在长年的临证中发现溃疡性结肠炎慢性复发型患者活动期多表现为肝郁脾虚,瘀毒内蕴。针对此病机,以培土泄木,理气活血为法,治疗上我们运用自拟方慢溃宁Ι号(现由我院制剂室生产,名为舒肝健脾颗粒),通过多年来的观察临床上取得了良好效果。为此,本课题选择溃疡性结肠炎慢性复发型活动期辨证为肝郁脾虚、瘀毒内蕴者作为研究对象,观察舒肝健脾颗粒的治疗效果并探讨其作用的内在机理。
2.方法
实验研究
实验研究部分采用较为成熟的的2,4,6-三硝基苯磺酸(TNBS)叠加束缚应激刺激法制作溃疡性结肠炎肝郁脾虚大鼠模型,分别设空白组、模型组、西药组、中药大、中、小剂量组共六组,西药组选用柳氮磺呲啶(SASP),中药选用本院自制药舒肝健脾颗粒(SGJP),分为大、中、小三个剂量。实验研究由三个实验组成。
实验一采用2,4,6-三硝基苯磺酸(TNBS)/乙醇溶液灌肠加束缚法制作溃疡性结肠炎肝郁脾虚大鼠模型,观察造模大鼠一般情况,疾病活动指数(DAI)和组织学损伤(结肠组织CMDI评分)。
实验二观察SGJP对溃疡性结肠炎肝郁脾虚模型大鼠结肠组织的VIP含量的影响。
实验三观察SGJP对溃疡性结肠炎肝郁脾虚模型大鼠结肠组织IL-1β和IL-10的影响。
临床研究
临床研究部分以《中药新药临床指导原则》(2002年)中的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的临床研究设计,采用随机、阳性药平行对照临床研究试验设计方法,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,以东方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属于肝郁脾虚、瘀毒内蕴的完整病例46例,随机分为两组。治疗组口服SGJP每日三次,每次12克;对照组口服柳氮磺吡啶(SASP)每次1克,每日3次。疗程均为4周,主要观察:临床综合疗效,中医证候疗效,临床主要症状(腹泻、便血、腹痛)变化、部分实验室指标、精神障碍、内镜指数的变化等。
3.结果
实验结果
DAI与CMDI评分:舒肝健脾颗粒各组和SASP组在治疗后第一周开始出现DAI下降趋势,实验终点时均有好转,舒肝健脾颗粒各剂量组DAI均低于SASP(1.67±0.71)和模型(2.56±0.88)组,其中舒肝健脾颗粒中剂量组降低至0.78±0.67,与SASP相比差异具有统计学意义(P<0.05),这提示舒肝健脾颗粒可减轻临床症状,且疗效优于传统药物SASP。舒肝健脾颗粒中剂量组CMDI指数(1.44±0.53)低于模型组(3.3±0.6),差异具有统计学意义(P<0.01),亦低于SASP组(2.47±0.96),差异具有统计学意义(P<0.05)。以上可以说明舒肝健脾颗粒对溃疡性结肠炎肝郁脾虚造模大鼠有良好保护作用,可以减轻大鼠的UC症状,并可以减轻其结肠组织损伤。
结肠组织VIP含量影响:本次研究发现溃疡性结肠炎肝郁脾虚模型大鼠结肠组织VIP是升高的,并且SGJP各剂量可以明显改善溃疡性结肠炎肝郁脾虚型模型大鼠结肠组织中的VIP含量异常升高,疗效明显优于SASP组,其中中剂量组VIP降低最为显著。
结肠组织IL-1β与IL-10含量影响:造模后各组IL-10均降低,IL-1β均升高,两治疗组均能升高IL-10和降低IL-1β水平,其中SGJP组的疗效显著高于SASP组,但SGJP中剂量组疗效最好,因此可以认为SGJP对可以有效地控制溃疡性结肠炎肝郁脾虚模型大鼠的局部炎症反应从而达到控制病情的治疗作用。
临床疗效
临床综合疗效:舒肝健脾颗粒组优于对照组(P<0.05);两组总有效率(95.65% vs 69.57%)比较有统计学意义;两组完全缓解率比较无统计学意义。中医证候疗效:舒肝健脾颗粒组疗效优于对照组(P<0.05),而两组总有效率(95.65% vs 73.91%)比较亦有统计学意义。
内镜黏膜疗效:舒肝健脾颗粒组也取得了较为满意的疗效,舒肝健脾颗粒组也取得了较为满意的疗效,与对照组相比内镜黏膜疗效的总有效率分别为91.3%和78.26%,有显著统计学意义(P<0.05)。
舒肝健脾颗粒组主要症状腹泻、便血、腹痛的总有效率分别为95.65%、82.61%、95.65%,其中腹泻、便血的疗效优于对照组( P<0.05),而两组腹痛疗效比较无差别(P>0.05),但从数值上看,有高于SASP组的趋势。对患者血小板计数(PLT)的影响:治疗后,两组PLT值均降低,两组治疗后PLT值比较无显著性差异(P>0.05)。两组PLT下降值比较亦无显著差异(P>0.05)。
对主要精神症状的影响:两组治疗后HAMA评分比较无显著差异(P>0.05)。两组HAMA积分下降值比较仍无统计学差异(P>0.05)。治疗后,两组HAMD积分下降值比较,P<0.05,有统计学差异,舒肝健脾颗粒组对HAMD评分的改善疗效明显好于对照组。
4.结论
舒肝健脾颗粒对于溃疡性结肠炎慢性复发型活动期肝郁脾虚型患者的治疗效果优于柳氮磺吡啶,尤其在改善患者抑郁情绪及中医证候方面,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的明显优势。本次实验研究证实疏肝健脾颗粒对溃疡性结肠炎肝郁脾虚模型大鼠有着良好的保护作用,可以调节神经免疫内分泌系统,下调应激反应,控制局部炎症,从而显示出优于柳氮磺吡啶的疗效。
1. Objective
Ulcerative colitis (UC) is a nonspecific inflammatory disease of rectum and colon, chronic recurrent type is most commonplace. Pathogenesis of the disease is not very clear. Environment, microorganism, heredity and immune factors may have relationship with it, among all of above, immune factors have been seriously concerned. Modern therapy strategy has been changed into inductive and maintenance care based on evidencebased medicine, but the side effects of western medicine restrict its clinical using, there are no positive appraisal for some brand-new treatment and medicine. Traditional Chinese Medicine shows its superiority in improving quality of life, lowering recurrence rate, but there are still many problems need to be resolved, lacking in the evidencebased medicine.
My tutor Professor Zhang Yansheng considers UC active phase of chronic recurrent type has specific characteristic syndrome type of TCM, that is: deficiency of spleen yang, retention of damp-heat and blood are common. Thus, I selected UC active phase of chronic recurrent type as the research objective, observing its treatment effects and inquiring its pathology mechanism.
2. Methods
The UC of liver stagnation and spleen deficiency rats model was induced by TNBS and ties, and divided 6 groups: normal group; model group; SASP treatment group; 3 variant SGJP treatment group included large dose group, medium and little dose group. The study was strictly designed under the guidance of“Guide line for New Drugs Clinical Trials”Guidelines for Treatment of Chronic Unspecific Ulcerative Colitis with Chinese Materia Medica. In combination with actual clinical situation, adopting random positive control method, on the basis of diagnosis criterion established on Inflammatory Bowel Disease Seminar at Chengdu in 2000, 46 cases of chronic recurrent type in UC active phase was selected from out-patient clinic (OPD) and wards of Dongfang Hospital. Therapeutic effect includes clinical general effect, change of TCM syndrome, change of emotional handicap ,change of main clinical symptom (diarrhea, hematochezia, abdominal pain).
3. Results
DAI of SGJP is lower than that of SASP. There is statistic significant difference, implying that SGJP can reduce clinical symptom and that its effect is better than SASP. CMDI of SGJP is lower than that of SASP. There is statistic significant difference.
IL-10 of each group is reduced and IL-1βof each group is increased. The effect of SGJP is better than that of SASP. Therefore, SGJP can efficiently control UC of liver stagnation and spleen deficiency rats.
VIP of UC of liver stagnation and spleen deficiency rats is increased. SGJP can obviously improve the VIP of UC of liver stagnation and spleen deficiency rats. Clinical general therapeutic effect of treated group is better than control group ( P<0.05); total effective percentage of two group (95.65% vs 69.57% ), there is no statistic significant difference.
Therapeutic effect of TCM syndrome treated group is superior to control group ( P<0.01), full recovery or significant effect percentage of TCM syndrome was obviously better than control group.
The change of main clinical symptom (diarrhea, hematochezia) had significant difference between the tow group, and the therapeutic effect of SGJP group is better.The change of abdominal pain of both group had no significant difference, but considering the numeric figure, the control group was potentially higher than treated group. Before treatment, PLT of each group has no obvious difference (P>0.05). After treatment, PLT of each group has lowered, there is still no statistical diference in PLT between SASP group and SGJP group ( P>0.05 ).
Before treatment, HAMA and HAMD of each group have no obvious difference (P>0.05). After treatment, HAMA and HAMD have lowered. The descending value of HAMD has statistical diference between SASP group and SGJP group (P<0.05).
4. Conclusion
The SGJP made from Chinese herbs which have the effects of dispersing stagnated liver qi for strengthening spleen and activating blood, can increase the IL-10 and reduce the IL-1β, VIP level of local colon tissue. Compared with western medicine, the therapeutic effect is better, espcially in the Depressive disorder and TCM syndrome, and it had no obvious ill-effect.
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