【作者】 葛鸿庆；

【导师】 刘金文；

【作者基本信息】 广州中医药大学 ， 中医骨伤科学， 2011， 博士

【摘要】 背景膝关节骨性关节炎,是一种常见的多发于中年以后的风湿性疾病。国内初步流行病学调查显示,估计有骨性关节炎的病例约5000万以上,其中膝关节占主要部分,已成为影响中老年人健康以及慢性残疾的重要原因之一。现代医学对膝关节骨性关节炎的病因尚不十分明确,近年来,细胞因子与膝关节骨性关节炎的发病成为新的研究热点,其中分解性细胞因子白细胞介素-1(IL-1)和肿瘤坏死因子(TNF)备受关注。中医认为膝关节骨性关节炎属“痹证”、“骨痹”之范畴,在膝关节骨性关节炎防治方面具有一定的优势。腹针是由薄智云教授创立的一种特殊针法,它继承了传统针灸简、便、廉、验的优点,同时发展了中医“神阙布气”学院。对膝关节骨性关节炎的治疗收到了满意的疗效。随着对腹针的应用实现了辨证条理化、处方标准化、操作规范化,为腹针的科研研究提供了一个很好的平台。目的本研究在系统回顾及研究骨性关节炎现代中西医文献、及古代中医文献的基础上,通过随机对照的临床实验研究,来验证腹针疗法对肾虚血瘀型膝关节骨性关节炎的临床疗效。同时,通过随机对照的动物实验,观察腹针疗法对膝关节骨性关节炎动物模型血清肿瘤坏死因子a (TNF-α)及白细胞介素-1(IL-1)水平的影响,从而在分子生物学水平上,探讨腹针疗法的作用机理及靶点,最终为腹针疗法的进一步推广提供可靠的临床依据及实验基础。方法临床研究部分：对符合纳入条件的150名广东省中医院门诊膝关节骨性关节炎患者,以简单随机的方法将其分为实验组及对照组。对照组予以基础治疗3月(口服盐酸氨基葡萄糖胶囊,0.48/次,3次/日),实验组予以基础治疗+腹针治疗3月。分别在治疗前后及治疗后1月、2月以视觉模拟疼痛评分法(Visual Analogue Scale/Score,简称VAS)及HSS量表进行疼痛及膝关节功能评分,并分析其差异性。同时参照《中药新药临床研究指导原则》中的疾病疗效判定标准及证候疗效判定标准,来评价两组的治疗效果及其差异性。实验研究部分：采用Hulth造模法,建立膝关节骨性关节炎家兔模型共20只,以简单随机的方法将其分为实验组15只,对照组5只。实验组予以腹针治疗,每3天一次,共10次。对照组予以自由喂养,不做任何治疗。分别于造模前后,及治疗后于兔耳缘静脉抽取静脉全血,以EILSA定量法测出血清肿瘤坏死因子α(TNF-α)及白细胞介素-1(IL-1)的含量,并分析其差异性。结果临床研究部分：150名受试者中,中途失访者23名,未能坚持疗程者7名,最终有120名患者完成实验研究,其中实验组68例,对照组52例；两组间性别构成、年龄分布、发病部位、病程、VAS评分、HSS评分及X光Kellgren-Lawrence分级比较无差异性,说明两组间一般情况均衡,具有可比性。实验组与对照组HSS评分均值与X光Kellgren-Lawrence分级呈负相关,即X光分级越高,HSS评分均值越低。实验组与对照组VAS均值与X光Kellgren-Lawrence分级呈正相关,即X光分级越高,VAS均值越高。实验组、对照组各组治疗前后比较,P<0.01,差异非常显著,说明实验组及对照组均有效；治疗后,实验组与治疗组比较,P<0.01,差异非常显著,说明实验组的疗效优于对照组；治疗后1月后,实验组与对照组比较,P<0.05,差异显著,说明实验组疗效较治疗后减弱,但仍优于对照组；治疗后2月,实验组与对照组比较,P>0.05,无统计学意义,说明实验组与对照组疗效无差异性。实验组与对照组疾病疗效评定,两组总有效率比较,P<0.05,差异显著,说明实验组疗效优于对照组。实验组与对照组证候疗效评定,两组总有效率比较,P<0.01,差异非常显著,说明实验组疗效优于对照组。实验研究部分：采用Hulth造模法,在4周后通过电镜观察软骨标本,证实获得满意的膝关节骨性关节炎动物模型。实验组与对照组治疗前,两组动物在体重及血清TNF-α、IL-1含量比较,P>0.05,无统计学意义,说明两组间一般情况均衡,具有可比性。造模后与造模前血清TNF-α及IL-1含量比较,实验组和对照组均升高,P<0.05,差异显著,说明骨性关节炎动物模型血清TNF-α及IL-1含量高于正常；实验组治疗后血清TNF-α及IL-1含量比较,治疗后低于治疗前,P<0.05,差异显著,说明实验组治疗后血清TNF-α及IL-1含量下降；对照组治疗前后血清TNF-α及IL-1含量比较,治疗后高于治疗前,P<0.05,差异显著,说明对照组1月后血清TNF-α及IL-1含量上升。结论通过本项研究,可得出如下结论：1.腹针为一种新的针灸疗法,其治疗膝关节骨性关节炎的处方具有扶正固本、祛风除湿、化瘀通络的作用,经临床研究证实,其治疗效果确切,值得进一步推广。但同时研究发现其作用具有一定的时效性。2.膝关节骨性关节炎的临床辩证以肾虚血瘀型为主,其中肾虚为本,血瘀为标,肾虚血瘀型为本病证型变化之基础。3.腹针治疗后可以降低膝关节骨性关节炎模型动物血清的肿瘤坏死因子α及白细胞介素-1水平,从而保护关节软骨,改善骨性关节炎患者的症状,这可能是腹针治疗膝关节骨性关节炎的作用机理或靶点之一。4.中医治疗膝关节骨性关节炎临床疗效研究中,可根据具体的研究目标,选用HSS评分加《中药新药临床研究指导原则》中的疾病疗效判定标准及证候疗效判定标准,以及VAS和HSS评分表中的一项为宜。同时可设立单独一组科研人员来进行临床疗效的观察,以防止出现偏差。5.细胞因子与膝关节骨性关节炎的发生关系密切,血清肿瘤坏死因子α及白细胞介素-1的水平与软骨的破坏呈正相关。6Hulth造模法,4周后即可获得稳定的动物模型,若要对中、晚期骨性关节炎进行研究,可以适当延长造模时间。7.膝关节骨性关节炎患者的临床症状、体征,与影像学Kellgren-Lawrence分级呈正相关。更多还原

【Abstract】 ObjectivesBased on the systematic review in both the literature of modern integrated Chinese & Western medicine and ancient literature about osteoarthritis, the randomly controlled clinical trials research was conducted to investigate the clinical effect of abdominal acupuncture on knee osteoarthritis defined by Deficiency of Kidney and Blood stasis. The randomized controlled animal experiment was also carried out to examine the effect of abdominal acupuncture on the production of serum tumor necrosis factorα(TNF-α) and Interleukin-1 (IL-1) contents in rabbits with knee osteoarthritis, and to investigate the mechanism and target of abdominal acupuncture at the molecular levels. The study enhanced the reliable clinical evidence and experimental basis and further promote abdominal acupuncture into the practice。Methods150 individuals with knee osteoarthritis who met the inclusive criteria from the Guangdong Hospital of Traditional Chinese Medicine, were randomly divided into treated group and control group. The control group were treated with the primary treatment for 3 months (Glucosamine hydrochloride, P0.0.48, tid), The treated group received both the primary treatment and abdominal acupuncture for 3 months. Respectively, we scored the pain and knee function prior and post to treatment according to Visual Analogue Scale (VAS) and the HSS scale, and analyzed their therapeutic effect and differences according to Guiding Principles of new drug clinical research of Chinese medicine.20 rabbits with knee osteoarthritis were generated according to Hulth procedure,15 into experimental group with treatment of abdominal acupuncture (once every 3 days, a total of 10 times),5 was into control group with regular feeding without treatment. Venous blood was collected via ear vein pricr and post to treatment, TNF-αand IL-1 contents detected with EILSA and compared.ResultsAmong 150 individuals,23 failed to be followed-up,7 were unable to adhere to treatment, the rest of 120 individuals completed the final test,68 of them were in experimental group,52 in control group. Between the two groups, the gender, age, location, course, VAS score, HSS score and X-ray Kellgren-Lawrence grade showed no significant difference, indicating the identification in general condition. The average HSS scores in the two groups were negatively correlated with X-ray Kellgren-Lawrence grade, that is, the higher the X-ray classification, the lower the HSS scores; however, the average VAS scores were positively correlated with X-ray Kellgren-Lawrence grade, the higher the X-ray classification, the higher the VAS scores.Prior and post to treatment, it showed significant differences between groups, P<0.01, indicating that the treatment was valid in the two groups; after the treatment, the experimental group and control group showed significant differences, P<0.01, indicating that the treatment was more effective in experimental group than in control group; one month later after treatment, it showed differences between groups, P<0.05, indicating that the treatment efficacy in experimental group become weaker, though it still better than control group; two months after treatment, it showed no statistically significant differences, P>0.05, indicating there was no difference in the two groups.Evaluation of the therapeutic efficacy between groups showed the significant differences in effective rate, P<0.05, indicating the efficacy in experimental group was better than control group. While the evaluation of syndromes showed stronger significant differences in the rate, P<0.01, indicating the treatment efficacy in experimental group was still better than control group.By Hulth method, animal model of knee osteoarthritis was generated after 4 weeks. Prior and post to treatment, there was no differences in the body weight, serum TNF-α, IL-1 contents between experimental group and control group, P>0.05, indicating identification in general condition. Prior and post to model establishment, the contents of serum TNF-α, IL-1 in both experimental group and control group showed statistics differences, P<0.05, indicating it was higher in animal models than control ones. Before and after treatment, the contents of serum TNF-α, IL-1 in experimental group showed statistics differences, P<0.05, indicating that treatment made it decline. Before and after treatment, the contents of serum TNF-α, IL-1 in control group showed statistics differences, P<0.05, indicating that treatment had the effect.ConclusionsIt was concluded in this study that 1. Abdominal acupuncture needle as a new therapy, proven by clinical studies, is effective in the treatment of knee osteoarthritis, so it is worth promoting, although certain timeliness.2. The clinical dialectical, the syndrome types changes foundation of the knee osteoarthritis is deficiency of Kidney and Blood stasis, between them deficiency of kidney is the root while blood stasis is the branch.3. The study confirms that abdominal acupuncture can reduce the TNF-α, IL-1 contents in animal model of knee osteoarthritis, thus protect the articular cartilage and improve symptoms of osteoarthritis.4. Cytokines is closely related to the incidence of knee osteoarthritis, among them the serum tumor necrosis factor a and interleukin-1 contents is positively correlated with the destruction of cartilage.5. By Hulth method, animal model of knee osteoarthritis was produced after 4 weeks, but to middle and late osteoarthritis, modeling time can be extended.6. Abdominal acupuncture has a positive impact on the regulation of cartilage by cytokine, which may be one of the mechanism or target about abdominal acupuncture for knee osteoarthritis.7. The symptoms and signs in patients with knee osteoarthritis have a positive correlation with the radiological Kellgren-Lawrence grade.更多还原