附子复方治疗类风湿关节炎寒湿阻络证的有效性和安全性的临床研究
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摘要
类风湿关节炎(rheumatoid arthritis, RA)是一种侵害关节和关节周围组织的慢性、全身性、自身免疫性疾病。该病以反复发作的滑膜炎症为特征,最终导致关节畸形及功能障碍。因其病因仍未真正明确,西医尚无根治办法,治疗以控制炎症和关节的损伤,延缓免疫反应引起的组织器官的损伤等为主。类风湿关节炎属中医“痹证”范畴,运用中医传统理论对其进行辨证论治,在临床应用中取得显著临床效果。有毒中药如雷公藤、细辛、乌头类(川乌、草乌与附子)等临床用于治疗痹证,疗效明显。附子因其毒性较川乌、草乌小,具有良好的抗炎、镇痛及免疫抑制作用,通过合理配伍广泛用于RA的治疗,但因其毒副作用限制临床使用。
目的：对临床应用含有不同剂量附子的中药复方治疗类风湿关节炎寒湿阻络证的病例的有效性及安全性进行观察研究,试图总结并探讨临床应用附子的毒性与证候、疗效的相关性,以期能够制定临床上重用附子的临床用药指导原则。
方法：收集160例临床应用运用含附子的中药复方治疗RA(寒湿阻络证)的病例,按附子的不同剂量分为15g、20g、30g组以及50g组,每组各40例,疗程为8周,收集附子用量、用法、配伍、煎煮、疗效及不良反应资料,分别于治疗前、治疗后2、4、6、8周,观察并记录患者临床症状及体征、中医证候总积分,在治疗前及治疗8后对类风湿因子(rheumatoid factor,RF)、血沉(Erythrocyte Sedimentation Rate, ESR)、C反应蛋白(C-reactive protein,CRP)、DAS28(disease activity score in28joints, DAS28)评分等疗效指标,以及血常规、尿常规、大便常规、肝肾功能、心电图等安全性指标,并进行统计学分析,以评价附子复方的临床疗效及安全性。
结果：
1、研究共纳入类风湿关节炎患者160例,其中脱落病例8例(15g组3例,20g组2例,30g组1例,50g组2例),2例因违反治疗方案加用其他影响疗效的药物而被剔除(30g组1例、50g组1例)。完成试验的有效病例共150例,病例脱落率为5%,剔除率为1.25%,脱失率6.75%,小于20%。
2、在临床症状及体征方面,四组患者的晨僵时间、关节压痛数、关节肿胀数、双手平均握力和自身总体评价随观察时点的推移,在治疗2周时上述临床指标即较治疗前出现明显改善,差异有统计学意义(P<0.05)。对相同观察时点的各组组间比较：50g组在治疗治疗2、4、6、8周时上述指标改善效果均优于15g、20g和30g组,差异有统计学意义(P<0.01)；30g组在治疗6、8周时上述指标改善效果优于15g和20g组,差异有统计学意义(P<0.05)；而15g组和20g组在各时点比较,差异无统计学意义(P>0.05)。
3、在实验室指标方面,四组患者治疗后ESR、CRP、RF均较治疗前明显好转,差异具有统计学意义(P<0.01)；对治疗后(第8周)上述实验室指标进行组间比较,50g组明显优于其他三组,差异具有统计学意义(P<0.01),30g组优于15g、20g两组,差异具有统计学意义(P<0.01),15g、20g两组比较差异无统计学意义(P>0.05)。
4、在中医症状、体征方面,四组患者的关节疼痛、关节肿胀、关节压痛、晨僵、关节不利、关节畏寒、全身畏寒等症状在治疗后均有明显改善,差异有统计学意义(P<0.05)。在改善关节疼痛程度、关节肿胀程度、关节压痛程度、关节不利、晨僵、关节畏寒、全身畏寒方面,50g组在治疗2、4、6、8周时疗效均优于其它3组,差异有统计学意义(P<0.05),而15g组、20g组和30g组比较,差异无统计学意义(P>0.05)。同时,在改善患者手足不温、夜间痛甚、神疲乏力方面,尚不能认为四组疗效有差异。
5、在DAS28评分方面,四组患者治疗后DAS28评分均较治疗前明显减低,差异具有统计学意义(P<0.01)；其中50g组较其他3组改善明显,差异具有统计学意义(P<0.01)；30g组较15g组和20g组差异具有统计学意义(P<0.01)；15g组和20g组比较,差异无统计学意义(P>0.05)。对治疗前后DAS28评分减少值比较,50g组的降幅较其它3组明显,差异具有统计学意义(P<0.01)；30g组与15g组、20g组比较,差异具有统计学意义(P<0.01)；15g组和20g组比较,差异无统计学意义(P>0.05)。
6、中医证候疗效判定,15g组的总有效率为91.89%(愈显率0%),20g组的总有效率为92.11%(愈显率2.63%),30g组的总有效率为92.11%(愈显率7.89%),50g组的总有效率为97.3%(愈显率35.14%),经统计分析,四组总有效率比较,差异无统计学意义(P>0.05),但愈显率比较差异具有统计学意义(P<0.01),50g组明显优于其它3组。
7、在安全性评价方面,治疗前后,各组患者血、尿、便常规、心电图及肝、肾功能均在正常范围。附子50g组出现2例不良反应,均因其煎煮方法不当,症状自行缓解。
结论：附子虽是有毒中药,因有良好消炎、止痛及免疫调节作用用于RA的治疗,临床疗效明显,临床应用关键是发挥其疗效而规避或减少其毒性。经临床观察得出初步结论,在辨证准确的前提下,选用适当的剂量,经合理配伍和正确的煎煮方法,附子临床应用是安全并且有效的。
Rheumatoid arthritis(RA) is a chronic, systemic and autoimmune disease, which infringes the joints and tissues around joints. The disease is characterized by recurrent synovitis and lead to joint deformity and dysfunction eventually. It is very difficult to treatment that its etiology is not clear. The main treatment is control the inflammation and joint injury, and delay the pathological lesions caused by immunoreaction. RA is belongs to category of "Arthralgia Syndrom" in traditional Chinese medicine(TCM), which get significant effects under the guide of differential treatment of TCM.In clinical application, toxic herbs have a significant therapeutic effect on the treatment of arthralgia syndrom, such as Tripterygium Wilfordii Hook, Asarum, Aconitum (Radix aconiti kusnezoffii, monkshood roots and aconite). Aconite widely used in the treatment of RA because it's has a good effects of anti-inflammat-ory, analgesic and immunosuppression. In view of the toxicity of the aconite, its clinical application can be limited.
Objective:The clinical study of the efficacy and safety of the aconite compound on the treatment of the RA(cold damp syndrome), that attempt to summarize the correlation of toxicity, syndrome and efficacy, and the guideline of application of high dose of aconite eventualy.
Methods:Collecting160cases of RA (cold damp syndrome) that with the treatment of aconite, and grouping into conventional dose15g,20g,30g and50g group accord to the different dose of aconite, each group of40patients in treatment for eight weeks. Reording the dosage, usage, compatibility, boiling, efficacy and adverse reactions of the application of aconite, All patients were recorded clinical symptoms and signs and syndromes total score at before treatment and2,4,6and8weeks after treatment, while rheumatoid factor (rheumatoid factor, RF), ESR (Erythrocyte Sedimentation Rate, ESR), C-reactive protein (C-reactive protein, CRP), DAS28(disease activity score in28joints, DAS28) score, as well as Blood-routine,Urine-routine,Stool-routine, ECG were measured before and after treatment in order to evaluate the clinical efficacy and safety of compound aconite and safety.
Results:
1. This study included a total of160patients with rheumatoid arthritis(RA), which fall off in8cases(3cases of15g group,2cases of20g group,1cases of30g group and2cases of50g group),2cases were rejected due to breach of treatment and combined with other therapeutic effects of drugs(1case of30g group and lease of50g group). Completed the trial cases of150cases, which expulsion rate was5%, elimination rate was1.25%, the loss rate was6.75%, less than20%.
2. The duration of morning stiffness, tender joint count, swollen joint count, hands mean grip strength and self-evaluation of all patients were improved significantly after treatment2weeks, the difference was statistically significant (P<0.05). The improvement of above indexes was significant in50g group than other groups by the2,4,6,8weeks (P<0.01),30g group was significant different form the other two groups by the6,8weeks (P<0.05), while there were no difference in the15g and20g group at all time points (P>0.05).
3. Between pre and post treatment, there were significant differentces in ESR, CRP, RF of the four groups(P<0.01).50g group was significantly better than other groups (P<0.01),30g group was better Compared with the other two groups (P<0.01),15g and20g group were no difference (P>0.05).
4.The arthralgia, arthroncus, morning stiffness, joint tenderness, joint movement disorder, aversion to cold and other symptoms of TCM were significantly improved in four groups after treatment, the difference was statistically significant (P<0.05). The improvement of50g group in the aspects of arthralgia, arthroncus, morning stiffness, joint tenderness, joint movement disorder and aversion to cold was significant compare with other groups at2,4,6,8weeks (P <0.01), while the difference between the group of15g,20g and30g was not statistically significant (P>0.05). Meanwhile, there was no significant difference between the four groups in the symptom of cold limbs, night pain and lassitude.
5. The DAS28score were improved significantly of all the4groups after treatment of2weeks (P<0.05),50g group was decreased obviously than other groups (P<0.01) and30g group was significant different form the other two groups (P<0.01), while there was no statistical significance between the15g and20g group(P>0.05).50g group was significantly better than other groups in the decrease of DAS28score (P<0.01),30g group was significant different form the other two groups (P<0.01),15g and20g group was no difference (P>0.05).
6.The total effective rates in the group of15g,20g,30g and50g were91.89%,92.11%,92.11%,97.3%and the cured and markedly effective rates were0%,2.63%,7.89%,95.35%,35.14%. The cured and markedly effective rate of50g group was higher than other groups with significant difference (P<0.01),while the total effective rate was no significant difference in the four groups (P>0.05).
7. Between pre and post treatment, the Blood-routine,Urine-routine,Stool-routine, ECG and liver and kidney function were all in normal range. The50g group had Two cases of adverse reaction, due to improper boiling. Half an hour later,all the symptoms disappeared.
Conclusion:The aconite as toxic herbs, it has a great effect on anti-inflammatory, analgesic and immunomodulatory for the treatment of RA, and also has a significant clinical effect. The key of the clinical application is to play its efficacy and to avoid or reduce its toxicity. Through clinical observation,we can draw a preliminary conclusion:By the premise of dialectical exacting, when doctors choose the appropriate dose, the reasonable compatib-ility and correct boiling method, the aconite is safe and effective in clinical application.
目的：对临床应用含有不同剂量附子的中药复方治疗类风湿关节炎寒湿阻络证的病例的有效性及安全性进行观察研究,试图总结并探讨临床应用附子的毒性与证候、疗效的相关性,以期能够制定临床上重用附子的临床用药指导原则。
方法：收集160例临床应用运用含附子的中药复方治疗RA(寒湿阻络证)的病例,按附子的不同剂量分为15g、20g、30g组以及50g组,每组各40例,疗程为8周,收集附子用量、用法、配伍、煎煮、疗效及不良反应资料,分别于治疗前、治疗后2、4、6、8周,观察并记录患者临床症状及体征、中医证候总积分,在治疗前及治疗8后对类风湿因子(rheumatoid factor,RF)、血沉(Erythrocyte Sedimentation Rate, ESR)、C反应蛋白(C-reactive protein,CRP)、DAS28(disease activity score in28joints, DAS28)评分等疗效指标,以及血常规、尿常规、大便常规、肝肾功能、心电图等安全性指标,并进行统计学分析,以评价附子复方的临床疗效及安全性。
结果：
1、研究共纳入类风湿关节炎患者160例,其中脱落病例8例(15g组3例,20g组2例,30g组1例,50g组2例),2例因违反治疗方案加用其他影响疗效的药物而被剔除(30g组1例、50g组1例)。完成试验的有效病例共150例,病例脱落率为5%,剔除率为1.25%,脱失率6.75%,小于20%。
2、在临床症状及体征方面,四组患者的晨僵时间、关节压痛数、关节肿胀数、双手平均握力和自身总体评价随观察时点的推移,在治疗2周时上述临床指标即较治疗前出现明显改善,差异有统计学意义(P<0.05)。对相同观察时点的各组组间比较：50g组在治疗治疗2、4、6、8周时上述指标改善效果均优于15g、20g和30g组,差异有统计学意义(P<0.01)；30g组在治疗6、8周时上述指标改善效果优于15g和20g组,差异有统计学意义(P<0.05)；而15g组和20g组在各时点比较,差异无统计学意义(P>0.05)。
3、在实验室指标方面,四组患者治疗后ESR、CRP、RF均较治疗前明显好转,差异具有统计学意义(P<0.01)；对治疗后(第8周)上述实验室指标进行组间比较,50g组明显优于其他三组,差异具有统计学意义(P<0.01),30g组优于15g、20g两组,差异具有统计学意义(P<0.01),15g、20g两组比较差异无统计学意义(P>0.05)。
4、在中医症状、体征方面,四组患者的关节疼痛、关节肿胀、关节压痛、晨僵、关节不利、关节畏寒、全身畏寒等症状在治疗后均有明显改善,差异有统计学意义(P<0.05)。在改善关节疼痛程度、关节肿胀程度、关节压痛程度、关节不利、晨僵、关节畏寒、全身畏寒方面,50g组在治疗2、4、6、8周时疗效均优于其它3组,差异有统计学意义(P<0.05),而15g组、20g组和30g组比较,差异无统计学意义(P>0.05)。同时,在改善患者手足不温、夜间痛甚、神疲乏力方面,尚不能认为四组疗效有差异。
5、在DAS28评分方面,四组患者治疗后DAS28评分均较治疗前明显减低,差异具有统计学意义(P<0.01)；其中50g组较其他3组改善明显,差异具有统计学意义(P<0.01)；30g组较15g组和20g组差异具有统计学意义(P<0.01)；15g组和20g组比较,差异无统计学意义(P>0.05)。对治疗前后DAS28评分减少值比较,50g组的降幅较其它3组明显,差异具有统计学意义(P<0.01)；30g组与15g组、20g组比较,差异具有统计学意义(P<0.01)；15g组和20g组比较,差异无统计学意义(P>0.05)。
6、中医证候疗效判定,15g组的总有效率为91.89%(愈显率0%),20g组的总有效率为92.11%(愈显率2.63%),30g组的总有效率为92.11%(愈显率7.89%),50g组的总有效率为97.3%(愈显率35.14%),经统计分析,四组总有效率比较,差异无统计学意义(P>0.05),但愈显率比较差异具有统计学意义(P<0.01),50g组明显优于其它3组。
7、在安全性评价方面,治疗前后,各组患者血、尿、便常规、心电图及肝、肾功能均在正常范围。附子50g组出现2例不良反应,均因其煎煮方法不当,症状自行缓解。
结论：附子虽是有毒中药,因有良好消炎、止痛及免疫调节作用用于RA的治疗,临床疗效明显,临床应用关键是发挥其疗效而规避或减少其毒性。经临床观察得出初步结论,在辨证准确的前提下,选用适当的剂量,经合理配伍和正确的煎煮方法,附子临床应用是安全并且有效的。
Rheumatoid arthritis(RA) is a chronic, systemic and autoimmune disease, which infringes the joints and tissues around joints. The disease is characterized by recurrent synovitis and lead to joint deformity and dysfunction eventually. It is very difficult to treatment that its etiology is not clear. The main treatment is control the inflammation and joint injury, and delay the pathological lesions caused by immunoreaction. RA is belongs to category of "Arthralgia Syndrom" in traditional Chinese medicine(TCM), which get significant effects under the guide of differential treatment of TCM.In clinical application, toxic herbs have a significant therapeutic effect on the treatment of arthralgia syndrom, such as Tripterygium Wilfordii Hook, Asarum, Aconitum (Radix aconiti kusnezoffii, monkshood roots and aconite). Aconite widely used in the treatment of RA because it's has a good effects of anti-inflammat-ory, analgesic and immunosuppression. In view of the toxicity of the aconite, its clinical application can be limited.
Objective:The clinical study of the efficacy and safety of the aconite compound on the treatment of the RA(cold damp syndrome), that attempt to summarize the correlation of toxicity, syndrome and efficacy, and the guideline of application of high dose of aconite eventualy.
Methods:Collecting160cases of RA (cold damp syndrome) that with the treatment of aconite, and grouping into conventional dose15g,20g,30g and50g group accord to the different dose of aconite, each group of40patients in treatment for eight weeks. Reording the dosage, usage, compatibility, boiling, efficacy and adverse reactions of the application of aconite, All patients were recorded clinical symptoms and signs and syndromes total score at before treatment and2,4,6and8weeks after treatment, while rheumatoid factor (rheumatoid factor, RF), ESR (Erythrocyte Sedimentation Rate, ESR), C-reactive protein (C-reactive protein, CRP), DAS28(disease activity score in28joints, DAS28) score, as well as Blood-routine,Urine-routine,Stool-routine, ECG were measured before and after treatment in order to evaluate the clinical efficacy and safety of compound aconite and safety.
Results:
1. This study included a total of160patients with rheumatoid arthritis(RA), which fall off in8cases(3cases of15g group,2cases of20g group,1cases of30g group and2cases of50g group),2cases were rejected due to breach of treatment and combined with other therapeutic effects of drugs(1case of30g group and lease of50g group). Completed the trial cases of150cases, which expulsion rate was5%, elimination rate was1.25%, the loss rate was6.75%, less than20%.
2. The duration of morning stiffness, tender joint count, swollen joint count, hands mean grip strength and self-evaluation of all patients were improved significantly after treatment2weeks, the difference was statistically significant (P<0.05). The improvement of above indexes was significant in50g group than other groups by the2,4,6,8weeks (P<0.01),30g group was significant different form the other two groups by the6,8weeks (P<0.05), while there were no difference in the15g and20g group at all time points (P>0.05).
3. Between pre and post treatment, there were significant differentces in ESR, CRP, RF of the four groups(P<0.01).50g group was significantly better than other groups (P<0.01),30g group was better Compared with the other two groups (P<0.01),15g and20g group were no difference (P>0.05).
4.The arthralgia, arthroncus, morning stiffness, joint tenderness, joint movement disorder, aversion to cold and other symptoms of TCM were significantly improved in four groups after treatment, the difference was statistically significant (P<0.05). The improvement of50g group in the aspects of arthralgia, arthroncus, morning stiffness, joint tenderness, joint movement disorder and aversion to cold was significant compare with other groups at2,4,6,8weeks (P <0.01), while the difference between the group of15g,20g and30g was not statistically significant (P>0.05). Meanwhile, there was no significant difference between the four groups in the symptom of cold limbs, night pain and lassitude.
5. The DAS28score were improved significantly of all the4groups after treatment of2weeks (P<0.05),50g group was decreased obviously than other groups (P<0.01) and30g group was significant different form the other two groups (P<0.01), while there was no statistical significance between the15g and20g group(P>0.05).50g group was significantly better than other groups in the decrease of DAS28score (P<0.01),30g group was significant different form the other two groups (P<0.01),15g and20g group was no difference (P>0.05).
6.The total effective rates in the group of15g,20g,30g and50g were91.89%,92.11%,92.11%,97.3%and the cured and markedly effective rates were0%,2.63%,7.89%,95.35%,35.14%. The cured and markedly effective rate of50g group was higher than other groups with significant difference (P<0.01),while the total effective rate was no significant difference in the four groups (P>0.05).
7. Between pre and post treatment, the Blood-routine,Urine-routine,Stool-routine, ECG and liver and kidney function were all in normal range. The50g group had Two cases of adverse reaction, due to improper boiling. Half an hour later,all the symptoms disappeared.
Conclusion:The aconite as toxic herbs, it has a great effect on anti-inflammatory, analgesic and immunomodulatory for the treatment of RA, and also has a significant clinical effect. The key of the clinical application is to play its efficacy and to avoid or reduce its toxicity. Through clinical observation,we can draw a preliminary conclusion:By the premise of dialectical exacting, when doctors choose the appropriate dose, the reasonable compatib-ility and correct boiling method, the aconite is safe and effective in clinical application.
引文
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