类风湿性关节炎病证结合治疗优化方案研究及基本方痹愈汤实验研究
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摘要
类风湿性关节炎(RA)是一种以对称性、多关节炎为主要表现的慢性、全身性自身免疫性疾病。我国经过初步流行病学调查发现,RA的发病率为0.3～0.5%,男女发病比例约为1∶3。目前无论对于中医还是西医,RA都是一种难治性疾病,主要是由于对其病因及发病机制缺乏全面深入地了解。
目前西医对RA的治疗多采用非甾体类消炎药(NSAIDs)和改善病情的药物(DMARDs)。NSAIDs虽能迅速控制早期RA患者的症状,但不能控制其病理过程,长期使用可引起关节软骨损伤。因此,近10年来西医治疗RA强调联合用药:一线药物(NSAIDs)加二线药物(慢作用抗风湿药、免疫抑制剂),其中二线药物本身也应联合用药,如甲氨喋呤、柳氮磺胺吡啶、羟氯喹、来氟米特等联合应用,但这类药物的联合应用给病人造成很大的经济及精神负担,往往因为毒副作用或对其毒副作用的恐惧而使病人终止用药,难以达到预期效果。
中医治疗RA有其独特的优势,既能够抗炎镇痛,又具有免疫调节效应,表现出整体调节、多层次、多靶点的作用,而且还能缓解和对抗西药毒副作用。大量的实验研究表明,补益肝肾、活血化瘀、祛风除湿的中药有促进软骨与骨质的修复,增加骨密度,抑制血管增生,增强纤维蛋白溶解,抗炎镇痛,免疫调节等作用,中医药治疗RA已显示出其独特的疗效。
本课题在导师胡荫奇主任医师的悉心指导下,着眼于发挥中医辨证论治的优势,选择湿热痹阻证、寒湿痹阻证、肝肾亏虚证及痰瘀痹阻证为研究RA的切入点,探讨临床治疗RA的优化方案。
主要进行了以下三方面的研究工作:
1理论研究
1.1 RA的中医药研究进展
在查阅大量RA文献的基础上,对RA的中医证候学研究及中医药治疗进展进行了回顾。通过复习文献发现,中药治疗RA有疗效好、副作用少的优点,同时也分析了以往针对RA中医证候及治疗研究中所存在的问题,提出了今后研究工作的思路与方法。
1.2 RA的药物治疗进展
系统总结了现代医学治疗RA的药物治疗进展,因目前尚没有一种疗效确切的特效药物,使得目前现代医学治疗RA仍处于一种摸索的阶段,并且很多药物的毒副作用要大于其疗效,因此我们应该发挥中医学的优势,并不断寻求中医与现代医学治疗RA的切入点。
1.3类风湿性关节炎与OPG/RANK/RANKL系统
RA的病理特征是滑膜慢性炎症,软骨吸收、骨质破坏和骨纤维化。实验证明这一过程需要破骨细胞的参与,破骨细胞的激活需要RANKL与RANK的结合,OPG作为肿瘤坏死因子家族成员之一,可竞争性抑制RANKL与RANK的结合,抑制破骨细胞的活化,促进其凋亡,从而抑制骨破坏的发生。
1.4甲氨喋呤治疗类风湿性关节炎作用机制及不良反应
甲氨喋呤(methotrexate,MTX)作为一种DMARDs,因其疗效确定、服用方便、安全性高等原因,现在国内外已被广泛用于RA的治疗,并取得了一定的疗效。本文综述了其作用机制及不良反应。
1.5研究基础及可行性论证
阐述了本项目的研究基础及其可行性。
2类风湿性关节炎病证结合治疗优化方案的临床研究
目的:本研究是在辨证论治及现代药理研究成果的基础上,结合导师多年的临床经验,选择湿热痹阻证、寒湿痹阻证、肝肾亏虚证及痰瘀痹阻证为研究RA的切入点,探讨临床治疗RA的优化方案。
方法:全部65例患者按就诊顺序随机分为治疗组、对照组。治疗组予中药痹愈汤加辨证论治方(日2次)口服,;对照组予中药痹愈汤加辨证论治方(日2次)及甲氨喋呤(10mg/w)口服。采用有关标准对各组病例的一般情况、临床症状、体征及实验室检查等项目进行较为系统地观察记录,全部数据运用SPSS12.0软件进行统计学处理。
结果:临床研究结果显示,治疗组与对照组均可有效改善患者的临床症状、体证及实验室检查(P＜0.05),两组间无明显差别(P＞0.05),治疗组的不良反应情况要好于对照组(P＞0.05)。病证结合方法治疗RA的方案与在其基础上加用甲氨喋呤的临床近期疗效相当,且不良反应低,无严重不良事件,可以作为RA的有效治疗方法。
创新点:本研究的优化方案是在辨证论治的基础上结合现代药理研究成果,经过多年临床实践进行优化组合而成。该方案的特点是根据病人具体证候和临床检验指标的不同,通过辨证应用既针对中医证候又针对免疫功能紊乱、炎性指标等具有特异性治疗作用的敏感中药组方配伍,使辨证论治与现代药理成果搭配更和谐更合理,治疗更有针对性,具有较大的临床推广价值。
3基本方痹愈汤实验研究
目的:采用CIA大鼠模型,经中药痹愈汤高、中剂量组及西药甲氨喋呤组进行对比治疗,HE染色观察其对CIA大鼠踝关节病理结构改变的影响,并检测血清中OPG、OPGL的表达情况,旨在探讨中药痹愈汤治疗RA骨侵蚀的作用机制。
方法:选取50只SD雄性大鼠,随机分为正常组、模型组、甲氨喋呤组、痹愈汤中剂量组、痹愈汤高剂量组,每组10只。除正常组外,每组大鼠双足跖部注射含Ⅱ胶原的弗氏完全佐剂制作胶原诱导的关节炎模型。在造模后1周,除模型组外,各用药组分别连续给药5周,在造模及用药前后观察大鼠的一般情况,并记录体重,用游标卡尺测量右足跖部厚度,观察药物对CIA大鼠一般情况的影响。用药结束后,摘取右侧踝关节进行固定、脱钙、石蜡包埋、HE染色,光镜下观察关节病理变化。采用ELISA法检测大鼠血清中OPG、OPGL水平。应用SPSS12.0统计软件进行统计分析。
结果:痹愈汤高、中剂量组均能有效改善CIA大鼠的全身情况,可显著抑制CIA大鼠踝关节肿胀,病理切片显示可减轻滑膜组织增生、炎性细胞浸润、抑制血管翳的形成,软骨破坏程度减弱。痹愈汤可提高胶原诱导型关节炎大鼠OPG的表达,使OPG/OPGL表达升高,抑制破骨细胞的增殖活化,从而阻止或延缓骨侵蚀、骨破坏的发生。
创新点:OPG、OPGL为近几年研究比较热点的有关骨破坏、骨侵蚀的指标,大多数研究中以原位杂交的方法检测其表达,对于血清学检测的报道并不多见。本实验研究通过检测试验大鼠血清中的OPG、OPGL水平及OPG/OPGL的变化,探讨痹愈汤对类风湿性关节炎骨侵蚀和骨破坏的作用机制。
Rheumatoid arthritis(RA) is a chronic autoimmunity disease of which the main symptom is symmetry multiple arthritis.It is reported that the incidence rate of RA is 0.3～0.5%according to the rudiment epidemiological investigation in our country.The ratio of male to female is 1:3.RA regardless of for traditional Chinese medicine or Western medicine,is still a kind of difficult treat disease. Major is the cause of this disease with pathologyical mechanism lack all-sidely thorough understanding.Though it is reported that traditional Chinese medicine works well on it,but its research is restricted due to various classification standard of different signs of RA,and no unified standard and reproducibility of clinical effect.This research stresses on taking good advantage of seeking disease causes and determining treatment from patterns identified of TCM under the direction of Pro.Hu Yinqi,we choose the Demp-heat Obstruction Syndrome、the Cold-demp Obstruction Syndrome、the Difficiencecy of Silver and Kidney Syndrome、the Phlegm-blood Stasis Syndrome as an enter point to study the optimization project of RA treatment by TCM rules.The following is our research in three aspects:
1 Literature study
1.1 Advances in TCM of RA
The general situation of study on the TCM syndromes of RA and advances in TCM treatment of RA were reviewed on the basis of looking up a great amount of literature of RA.It was found that treatment of RA with TCM has the following advantages:good therapeutic effect and less side-effect etc.It was analysed the questions in the study on TCM syndromes and treatment of RA.The thoughts and methods of research in future were advanced.
1.2 Advances in Western Medicine treatment of RA
In this part,we summarized the advances of treatment of Western Medicine,there wasn't an effective medicine be found with the exact effection till now,it make the treatment of RA in Western Medicine in a research situation.Most medicines had more side-effect than they worked,so we must search a point which can combine the treatments of RA in TCM and Western Medicine.
1.3 RA and OPG/RANK/RANKL system
Rheumatoid Arthritis is a course of bone erosion.The evidence coming from experiment shows that Osteoclast is necessary for this course.Osteoclast activation need the action of RANKL and it' s receptor RANK.As one of the nember of tumor necrosis factor(TNF),OPG can joint the RANKL by competitive combination,and stop the joint to RANK.It can inhibit the activation of Osteoclast and increase the apoptosis of Osteoclast to inhibit the absole of bone.
1.4 Effect mechanism and side-effects of MTX in treating RA
MTX,a kind of DMARDs,is widely accepted in treating RA for it' s confirmable effection、、high security.The text summarized the effect mechanism and side-effects of MTX in treating RA.
1.5 The foundation of the research and the argumentation of feasibility
To expatiate the foundation of the research and the argumentation of feasibility.
2 Clinical study of optimization project in treating RA by TCM rules
Objective:This research stresses on taking good advantage of seeking disease causes and determining treatment from patterns identified of TCM and on the basis of the modern pharmacody study,combining the teacher' s clinical experience,we choose the Demp-heat Obstruction Syndrome、the Cold-demp Obstruction Syndrome、the Difficiencecy of Silver and Kidney Syndrome、the Phlegm-blood Stasis Syndrome as an enter point to study the optimization project of RA treatment by TCM rules.
Method:All the patients were divided into four groups in random:the treatment group and the control group.The patients in the treatment group took BiYuTang(twice a day)and the patients of the other group took BiYuTang(twice a day) and MTX(10mg/w).Relevant criteria were then used to compare those groups in terms of general condition of the patients,clinical symptoms and signs and results from laboratory tests.All the data collected have been statistically analyzed with SPSS12.0 software.
Results:Clinical research result shows,all the patients' clinical symptoms and signs and results from laboratory tests are effectively improved in the two groups(P＜0.05),the result has no obvious difference(P＞0.05),the side-effect of the treatment group is better than the control group(P＞0.05).The project of combination disease and syndrome to treat RA is effective.
3 Trial research
Objective:In our studies we plan to further elucidate the mechanism of BiYuTang in curing bone erosion in RA by using the animal model of CIA rats,the CIA rats were feed with BiYuTang high dose、common dose and MTX for five weeks,HE staining sbserve pathological change under high microscope,detect the level of OPG and OPGL in serum.The aim of this study is to investigate the therapeutic mechanism of BiYuTang in curing bone erosion in RA through these methods.
Method:50 health SD male mice was divided into 5 groups(normal group,model group,common dose group,high dose group and MTX group in random,each group contains 10 mice).In the first part,the CIA rats was successful established by injection the mixture of TypeⅡcollagen with Fraud' s adjuvants in ankle joint skin of both feet.After 1 week of immunization,the CIA rats were feed with BiYuTang high dose、common dose and MTX for five weeks except modle group.Common group and modle group were feed equal volume Sodium Chloride.During this period,the changes of the general status,swelling of the rats have been recorded at different time.After five weeks of treatment,the rats put to death and the serum was collected.HE staining observe the pathological change of ankle joint by microscope,ELISA to detect OPG、OPGL level in serum,the data was statistics by SPSS software.
Results:BiYuTang high dose、common dose could markedly reduce the degree of rat pedal swelling,improve general status.The pathologicals results showed that synovialis hyperplasia and inflammation,inflammatory cell infiltration,formation of pannus and the erosion of cartilage and bones.Group of BiYuTang and MTX could lessen synovialis hyperplasia,restrain inflammatory cell infiltrate,inhibit pannus formation and relieve bone destruction.BiYuTang can increase the expression of OPG snd OPG/OPGL,decrease the osteoclast multiplication and activation,restrain or prolong the damage of bone.
目前西医对RA的治疗多采用非甾体类消炎药(NSAIDs)和改善病情的药物(DMARDs)。NSAIDs虽能迅速控制早期RA患者的症状,但不能控制其病理过程,长期使用可引起关节软骨损伤。因此,近10年来西医治疗RA强调联合用药:一线药物(NSAIDs)加二线药物(慢作用抗风湿药、免疫抑制剂),其中二线药物本身也应联合用药,如甲氨喋呤、柳氮磺胺吡啶、羟氯喹、来氟米特等联合应用,但这类药物的联合应用给病人造成很大的经济及精神负担,往往因为毒副作用或对其毒副作用的恐惧而使病人终止用药,难以达到预期效果。
中医治疗RA有其独特的优势,既能够抗炎镇痛,又具有免疫调节效应,表现出整体调节、多层次、多靶点的作用,而且还能缓解和对抗西药毒副作用。大量的实验研究表明,补益肝肾、活血化瘀、祛风除湿的中药有促进软骨与骨质的修复,增加骨密度,抑制血管增生,增强纤维蛋白溶解,抗炎镇痛,免疫调节等作用,中医药治疗RA已显示出其独特的疗效。
本课题在导师胡荫奇主任医师的悉心指导下,着眼于发挥中医辨证论治的优势,选择湿热痹阻证、寒湿痹阻证、肝肾亏虚证及痰瘀痹阻证为研究RA的切入点,探讨临床治疗RA的优化方案。
主要进行了以下三方面的研究工作:
1理论研究
1.1 RA的中医药研究进展
在查阅大量RA文献的基础上,对RA的中医证候学研究及中医药治疗进展进行了回顾。通过复习文献发现,中药治疗RA有疗效好、副作用少的优点,同时也分析了以往针对RA中医证候及治疗研究中所存在的问题,提出了今后研究工作的思路与方法。
1.2 RA的药物治疗进展
系统总结了现代医学治疗RA的药物治疗进展,因目前尚没有一种疗效确切的特效药物,使得目前现代医学治疗RA仍处于一种摸索的阶段,并且很多药物的毒副作用要大于其疗效,因此我们应该发挥中医学的优势,并不断寻求中医与现代医学治疗RA的切入点。
1.3类风湿性关节炎与OPG/RANK/RANKL系统
RA的病理特征是滑膜慢性炎症,软骨吸收、骨质破坏和骨纤维化。实验证明这一过程需要破骨细胞的参与,破骨细胞的激活需要RANKL与RANK的结合,OPG作为肿瘤坏死因子家族成员之一,可竞争性抑制RANKL与RANK的结合,抑制破骨细胞的活化,促进其凋亡,从而抑制骨破坏的发生。
1.4甲氨喋呤治疗类风湿性关节炎作用机制及不良反应
甲氨喋呤(methotrexate,MTX)作为一种DMARDs,因其疗效确定、服用方便、安全性高等原因,现在国内外已被广泛用于RA的治疗,并取得了一定的疗效。本文综述了其作用机制及不良反应。
1.5研究基础及可行性论证
阐述了本项目的研究基础及其可行性。
2类风湿性关节炎病证结合治疗优化方案的临床研究
目的:本研究是在辨证论治及现代药理研究成果的基础上,结合导师多年的临床经验,选择湿热痹阻证、寒湿痹阻证、肝肾亏虚证及痰瘀痹阻证为研究RA的切入点,探讨临床治疗RA的优化方案。
方法:全部65例患者按就诊顺序随机分为治疗组、对照组。治疗组予中药痹愈汤加辨证论治方(日2次)口服,;对照组予中药痹愈汤加辨证论治方(日2次)及甲氨喋呤(10mg/w)口服。采用有关标准对各组病例的一般情况、临床症状、体征及实验室检查等项目进行较为系统地观察记录,全部数据运用SPSS12.0软件进行统计学处理。
结果:临床研究结果显示,治疗组与对照组均可有效改善患者的临床症状、体证及实验室检查(P＜0.05),两组间无明显差别(P＞0.05),治疗组的不良反应情况要好于对照组(P＞0.05)。病证结合方法治疗RA的方案与在其基础上加用甲氨喋呤的临床近期疗效相当,且不良反应低,无严重不良事件,可以作为RA的有效治疗方法。
创新点:本研究的优化方案是在辨证论治的基础上结合现代药理研究成果,经过多年临床实践进行优化组合而成。该方案的特点是根据病人具体证候和临床检验指标的不同,通过辨证应用既针对中医证候又针对免疫功能紊乱、炎性指标等具有特异性治疗作用的敏感中药组方配伍,使辨证论治与现代药理成果搭配更和谐更合理,治疗更有针对性,具有较大的临床推广价值。
3基本方痹愈汤实验研究
目的:采用CIA大鼠模型,经中药痹愈汤高、中剂量组及西药甲氨喋呤组进行对比治疗,HE染色观察其对CIA大鼠踝关节病理结构改变的影响,并检测血清中OPG、OPGL的表达情况,旨在探讨中药痹愈汤治疗RA骨侵蚀的作用机制。
方法:选取50只SD雄性大鼠,随机分为正常组、模型组、甲氨喋呤组、痹愈汤中剂量组、痹愈汤高剂量组,每组10只。除正常组外,每组大鼠双足跖部注射含Ⅱ胶原的弗氏完全佐剂制作胶原诱导的关节炎模型。在造模后1周,除模型组外,各用药组分别连续给药5周,在造模及用药前后观察大鼠的一般情况,并记录体重,用游标卡尺测量右足跖部厚度,观察药物对CIA大鼠一般情况的影响。用药结束后,摘取右侧踝关节进行固定、脱钙、石蜡包埋、HE染色,光镜下观察关节病理变化。采用ELISA法检测大鼠血清中OPG、OPGL水平。应用SPSS12.0统计软件进行统计分析。
结果:痹愈汤高、中剂量组均能有效改善CIA大鼠的全身情况,可显著抑制CIA大鼠踝关节肿胀,病理切片显示可减轻滑膜组织增生、炎性细胞浸润、抑制血管翳的形成,软骨破坏程度减弱。痹愈汤可提高胶原诱导型关节炎大鼠OPG的表达,使OPG/OPGL表达升高,抑制破骨细胞的增殖活化,从而阻止或延缓骨侵蚀、骨破坏的发生。
创新点:OPG、OPGL为近几年研究比较热点的有关骨破坏、骨侵蚀的指标,大多数研究中以原位杂交的方法检测其表达,对于血清学检测的报道并不多见。本实验研究通过检测试验大鼠血清中的OPG、OPGL水平及OPG/OPGL的变化,探讨痹愈汤对类风湿性关节炎骨侵蚀和骨破坏的作用机制。
Rheumatoid arthritis(RA) is a chronic autoimmunity disease of which the main symptom is symmetry multiple arthritis.It is reported that the incidence rate of RA is 0.3～0.5%according to the rudiment epidemiological investigation in our country.The ratio of male to female is 1:3.RA regardless of for traditional Chinese medicine or Western medicine,is still a kind of difficult treat disease. Major is the cause of this disease with pathologyical mechanism lack all-sidely thorough understanding.Though it is reported that traditional Chinese medicine works well on it,but its research is restricted due to various classification standard of different signs of RA,and no unified standard and reproducibility of clinical effect.This research stresses on taking good advantage of seeking disease causes and determining treatment from patterns identified of TCM under the direction of Pro.Hu Yinqi,we choose the Demp-heat Obstruction Syndrome、the Cold-demp Obstruction Syndrome、the Difficiencecy of Silver and Kidney Syndrome、the Phlegm-blood Stasis Syndrome as an enter point to study the optimization project of RA treatment by TCM rules.The following is our research in three aspects:
1 Literature study
1.1 Advances in TCM of RA
The general situation of study on the TCM syndromes of RA and advances in TCM treatment of RA were reviewed on the basis of looking up a great amount of literature of RA.It was found that treatment of RA with TCM has the following advantages:good therapeutic effect and less side-effect etc.It was analysed the questions in the study on TCM syndromes and treatment of RA.The thoughts and methods of research in future were advanced.
1.2 Advances in Western Medicine treatment of RA
In this part,we summarized the advances of treatment of Western Medicine,there wasn't an effective medicine be found with the exact effection till now,it make the treatment of RA in Western Medicine in a research situation.Most medicines had more side-effect than they worked,so we must search a point which can combine the treatments of RA in TCM and Western Medicine.
1.3 RA and OPG/RANK/RANKL system
Rheumatoid Arthritis is a course of bone erosion.The evidence coming from experiment shows that Osteoclast is necessary for this course.Osteoclast activation need the action of RANKL and it' s receptor RANK.As one of the nember of tumor necrosis factor(TNF),OPG can joint the RANKL by competitive combination,and stop the joint to RANK.It can inhibit the activation of Osteoclast and increase the apoptosis of Osteoclast to inhibit the absole of bone.
1.4 Effect mechanism and side-effects of MTX in treating RA
MTX,a kind of DMARDs,is widely accepted in treating RA for it' s confirmable effection、、high security.The text summarized the effect mechanism and side-effects of MTX in treating RA.
1.5 The foundation of the research and the argumentation of feasibility
To expatiate the foundation of the research and the argumentation of feasibility.
2 Clinical study of optimization project in treating RA by TCM rules
Objective:This research stresses on taking good advantage of seeking disease causes and determining treatment from patterns identified of TCM and on the basis of the modern pharmacody study,combining the teacher' s clinical experience,we choose the Demp-heat Obstruction Syndrome、the Cold-demp Obstruction Syndrome、the Difficiencecy of Silver and Kidney Syndrome、the Phlegm-blood Stasis Syndrome as an enter point to study the optimization project of RA treatment by TCM rules.
Method:All the patients were divided into four groups in random:the treatment group and the control group.The patients in the treatment group took BiYuTang(twice a day)and the patients of the other group took BiYuTang(twice a day) and MTX(10mg/w).Relevant criteria were then used to compare those groups in terms of general condition of the patients,clinical symptoms and signs and results from laboratory tests.All the data collected have been statistically analyzed with SPSS12.0 software.
Results:Clinical research result shows,all the patients' clinical symptoms and signs and results from laboratory tests are effectively improved in the two groups(P＜0.05),the result has no obvious difference(P＞0.05),the side-effect of the treatment group is better than the control group(P＞0.05).The project of combination disease and syndrome to treat RA is effective.
3 Trial research
Objective:In our studies we plan to further elucidate the mechanism of BiYuTang in curing bone erosion in RA by using the animal model of CIA rats,the CIA rats were feed with BiYuTang high dose、common dose and MTX for five weeks,HE staining sbserve pathological change under high microscope,detect the level of OPG and OPGL in serum.The aim of this study is to investigate the therapeutic mechanism of BiYuTang in curing bone erosion in RA through these methods.
Method:50 health SD male mice was divided into 5 groups(normal group,model group,common dose group,high dose group and MTX group in random,each group contains 10 mice).In the first part,the CIA rats was successful established by injection the mixture of TypeⅡcollagen with Fraud' s adjuvants in ankle joint skin of both feet.After 1 week of immunization,the CIA rats were feed with BiYuTang high dose、common dose and MTX for five weeks except modle group.Common group and modle group were feed equal volume Sodium Chloride.During this period,the changes of the general status,swelling of the rats have been recorded at different time.After five weeks of treatment,the rats put to death and the serum was collected.HE staining observe the pathological change of ankle joint by microscope,ELISA to detect OPG、OPGL level in serum,the data was statistics by SPSS software.
Results:BiYuTang high dose、common dose could markedly reduce the degree of rat pedal swelling,improve general status.The pathologicals results showed that synovialis hyperplasia and inflammation,inflammatory cell infiltration,formation of pannus and the erosion of cartilage and bones.Group of BiYuTang and MTX could lessen synovialis hyperplasia,restrain inflammatory cell infiltrate,inhibit pannus formation and relieve bone destruction.BiYuTang can increase the expression of OPG snd OPG/OPGL,decrease the osteoclast multiplication and activation,restrain or prolong the damage of bone.
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