通痹合剂2号治疗RA近期疗效观察及对雄性大鼠抗生育作用的研究
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摘要
类风湿关节炎(rheumatoid arthritis,RA)是一种以累及周围关节为主的系统性炎症性自身免疫病,致残率高。多年来,尽管学术界对RA的治疗策略进行了广泛深入的研究,但治疗效果难尽人意,大多数患者出现程度不等的功能障碍和关节畸形。RA是造成我国人群丧失劳动力和致残的主要疾病之一。
中医药治疗RA疗效确定,副作用少,耐受性好,治疗费用低,具有独特的优势。陈纪藩教授在有效抗RA复方通痹灵合剂基础上创制的通痹合剂2号,方以南蛇藤配伍川续断,十余年的临床应用表明该复方有很好的抗炎抗风湿疗效,但迄今未经系统的临床疗效观察。同时由于该复方中的南蛇藤具有生殖毒性,长期服用会影响女性月经及导致男性不育,限制了其临床的推广应用。
本课题临床研究部分对通痹合剂2号治疗活动性RA的疗效进行系统的观察、分析,实验部分以雄性大鼠为研究对象,探讨通痹合剂2号雄性抗生育作用的靶器官、作用特点、量效关系及可逆性,旨在为临床安全用药提供一定的临床依据和科学实验依据。
1通痹合剂2号治疗RA的近期疗效观察
选择30例服用通痹合剂2号治疗的活动性RA患者,治疗时间为3个月,对患者治疗前后的肿胀关节数、压痛关节数、患者对疼痛的VAS评分、患者对病情的VAS评分、医生对病情的VAS评分、患者功能评估(HAQ)及血沉(ESR)、C反应蛋白(CRP)、类风湿因子(RF)进行观察、分析,采用ACR50标准评估患者的病情改善。同时对患者服药前后的血白细胞(WBC)、血红蛋白(HGB)、血小板(PLT)、谷草转氨酶(AST)、谷丙转氨酶(ALT)、血白蛋白(Alb)、尿素(BUN)、血肌酐(CR)的值进行监测和对比,对服药后可能出现的胃肠道不适、皮疹或皮损作记录,并观察女性患者月经变化情况。
结果显示,治疗3个月后,患者肿胀关节数、压痛关节数减少,晨僵时间缩短,患者对疼痛的VAS评分、患者和医生对病情的VAS评分及患者的HAQ,较治疗前明显好转(P＜0.05);ESR、CRP、RF滴度明显降低(P＜0.05),18例患者病情改善达到ACR50标准。服药期间患者的肝肾功、血象无异常,2例出现轻微胃肠道不适反应,加用护胃药可缓解。女性患者月经受到明显的影响,出现月经后期、经量减少、行经天数减少等月经功能失调的症状,部分女性患者出现面部色素沉着、可愈性颜面皮肤轻微破损。
2通痹合剂2号对雄性大鼠抗生育作用的研究
90只雄性大鼠随机分为5组,每组18只:正常对照组(ZC组),喂服过滤自来水10ml·kg~(-1)·d~(-1);通痹合剂2号剂量1组(HJ1组),喂服通痹合剂2号水煎液30g·kg~(-1)·d~(-1);通痹合剂2号剂量2组(HJ2组),喂服通痹合剂2号水煎液10g·kg~(-1)·d~(-1);南蛇藤剂量1组(NST1组),喂服南蛇藤水煎液22.5g·kg~(-1)·d~(-1);南蛇藤剂量2组(NST2组),喂服南蛇藤水煎液7.5g·kg~(-1)·d~(-1)。实验开始后,所有大鼠开始灌胃,每日一次,根据体重调整药量。给药60日后,第一次半数取材,测定相应指标,包括:睾丸重量、体积,精液常规分析,睾丸及附睾组织病理切片,以及血WBC、HB、PLT、ALT、AST、Alb、BUN、Cr的值;对余下的半数大鼠乙醚麻醉后眼眶取血,测定血清睾酮(T)、促卵泡生成激素(FSH)、促黄体生成素(LH)、雌二醇(E2)的含量,而后停药恢复饲养。停药72日后,第二次取材,重复测定上述指标。
研究结果显示,给药60日后,HJ2组大鼠睾丸形态、重量、体积、精子计数和精子密度与正常组比较无差异,生精上皮精子发生良好,支持细胞、基底膜和睾丸间质均无异常,附睾管中充满精子和分泌物,抗生育效应仅表现为附睾精子活动力下降为零,停药72日后,精子活动力完全恢复正常。HJ1组给药60日后,睾丸形态萎软,睾丸体积、重量、精子计数和密度较HJ2组明显下降(P＜0.01),生精上皮发生严重生精功能障碍,停药72日后无恢复迹象。给药60日及停药72日后,NST2组睾丸重量、体积、精子计数和密度较HJ2组均明显下降(P＜0.01),睾丸生精小管呈轻、中度生精功能障碍;与HJ1组比较,NST1组睾丸重量、体积、精子计数和密度无差异(P＞0.05),两组睾丸组织损害程度相同。
血清性激素的测定结果显示,给药60日和停药72日,包括HJ1组、HJ2组在内的所有给药组大鼠血清FSH、LH、E2四项性激素含量与正常组比较均无明显差异,血清T显示出统计学差异,但无实际意义,提示本课题研究条件下通痹合剂2号中THH的抗生育作用并非通过干扰大鼠血清性激素水平这一途径而产生效果。
血分析和肝肾功的测定结果显示,给药60日和停药72日,HJ1组和HJ2组血WBC、HGB、PLTBUN、CR值,与正常组比较无统计学差异(P＞0.05)。给药60日后,HJ1组和HJ2组Alb值较ZC组有所下降,但在大鼠的正常生理参考值范围内。HJ2组AST和ALT值较ZC组偏低(P＜0.05)。
3结论
通痹合剂2号在临床常用剂量(1g/kg/d)下治疗活动性RA具有很好的近期疗效,对患者的肝肾功、血象及胃肠道无明显副作用,是一种安全而有效的抗RA中药复方。同时该复方对女性月经有明显的影响,因此对年轻或有生育要求的女性患者而言,又当慎用。
通痹合剂2号对雄性大鼠具有明显的抗生育作用,靶器官为睾丸和附睾,作用强度呈剂量—效应关系,在10g/Kg/d剂量(相当于成人临床常用抗RA剂量的1.6倍)下,其抗生育作用完全具有可逆性。
一定剂量条件下,川续断能够拮抗南蛇藤的抗生育作用,减轻南蛇藤的生殖毒性。
通痹合剂2号的雄性抗生育作用并非通过干扰大鼠血清性激素水平这一途径而产生效果。
Rheumatoid arthritis(RA)is a systemic inflammatory autoimmune disease, with high rate of disability.Although the therapy strategy of RA has been studied extensively for many years,but the therapeutic outcome is not satisfied.Joint destruction occur in more than half patients.It is one of major diseases which cause loss of labor force and disability in China.
Chinese medicine therapy on RA has distinct predominance,with definite curative effect,few by-effect,good tolerance and low expense.Prof.Ji-Fan CHEN make out one new composition named Tong Bi 2 Composition(TB2C)according to Tong Bi Ling Composition,which has wonderful curative effect for RA.It is made up of Tripterygium Hypoglaucum Hutch(THH)and Dipsacus Asperoides. Although clinical application of more than one decade indicate that this composition works well for RA,no systematic clinical research has ever been done about it.THH possess reproduction toxicity,when taken for a long time, it can result in menstrual disorder and male sterility.That's why its clinical application is confined.
The clinical research was done to evaluate the curative effect for RA.And also,the experiment was done to approach antifertility effects of TB2C in male rats,and to investigate the sites,dose-effect relationship,reciprocity and possible mechanisms of the antifertility action.The researches help to provide clinical and experimental evidences for the treatment on RA by TB2C.
1 Study on the Recent Curative Effect in Active RA by Tong Bi 2 Composition
Thirty patients with active RA were treated with TB2C for 3 months. Clinical assessment using the American College of Rheumatology(ACR)criteria for improvement was performed at baseline and at the end of 3 months. Simultaneously the possible adverse reactions of TB2C were recorded,the clinical index including not only WBC,HGB,PLT,AST,ALT,Alb,BUN and CR in blood,but alsogastrointestinal tract indisposition,skin rash,skin damage,and women' s menstrual disorder,et al.
The clinical result showed that after 3 months' treatment,the patients' swollen joint count and tender joint count decreased,morning stiffness time shortened,compared with that before treatment,showing statistical difference (P＜0.05),as well as the laboratory index such as ESR,CRP and RF tite(P＜0.05). In addition,there was remarkable improvement in disease activity following the TB2C treatment.At the end of 3 months,the percent age of ACR50 was 60 %(18/30).During the treatment period,no adverse reaction happened to liver function,kidney function,hemogram or gastrointestinal tract.Almost all the women patients got menstrual disorder after 3 months,such as delayed menorrhea,spanomenorrhea,and so on.In addition,hyperpigmentation,skiin rash and skin damage happened to some women patients.
2 Resach on the Antifertility Action on Male Rats by Tong Bi 2 Composition
90 male rats,weight 180～220g,were randomly divided into 5 groups, 18 in each group.The control group were given by gastric gavage filtering tap water at a dose of lOml·kg~(-1)·d~(-1).In the same way the TB2C 1 group were given TB2C at a dose of 30g·kg~(-1)·d~(-1),as well the TB2C 2 group at a dose of 10g·kg~(-1)·d~(-1).The NST 1 group were given THH water elixation at a dose of 22.5g·kg~(-1)·d~(-1),while the NST 2 group were given THH water elixation at a dose of 7.5g·kg~(-1)·d~(-1).All rats were given by gastric gavage water or drug from the 1st day,once a day,last 60 days.Body weight was assessed every 5 days and the dose was adjusted accordingly.When administration 60d,one half the rats were sacrificed,and the corresponding index were measured,including testicle weight,testicle volume,the motility and counted number and density of sperm, pathological section of testicle and epididymis,the level of serum T,FSH, LH and E2,as well the level of WBC,HB,PLT,ALT,AST,Alb,BUN and Cr.When discontinuation 72d,the remnant half rats were sacrificed,and the above index were also measured in the same way.
The findings showed,after administration 60d,no difference was seen in the TB2C 2 group compared with the control group,except that the motility of sperm from caudal epididymides dropped to zero.But after discontinuation 72d,the motility of sperm of the TB2C 2 group completed recovery.After administration 60d,a significant decrease in testicle weight,testicle volume, the counted number and density of sperm,were seen in the TB2C 1 group compared with the TB2C 2 group(P＜0.01).30g·kg~(-1)·d~(-1)of TB2C caused the damaged structures of testicle and epididymis,and after discontinuation 72d,the damaged structures didn't recover.And a significant decrease in testicle weight,testicle volume,the counted number and density of sperm,were seen in the NST 2 group compared with the TB2C 2 group(P＜0.01),while no difference was seen in the NST 1 group compared with the TB2C 1 group(P＞0.05).
The findings also showed that no evident difference was seen on the level of FSH,LH and E2 between the 4 drug-given groups and the control group. Although a slight but statistically significant difference on the level of blood serum T was seen in the drug-given groups compared with the control group, which had no practical significance.Also no evident difference was seen on the level of FSH,LH and E2 between the 4 drug-given groups and the control group(P＞0.05).
3 Conclusion
Tong Bi 2 Composition at the level of clinical frequently used dose (1g/kg/d)is effective and safe in patients with active RA.It can obviously affects women' menstruation,so it should be used carefully on young women. Tong Bi 2 Composition has a male antifertity effect in rats,testicle and epididymis are the target organ of the action.The antifertility action displays a dose-effect relationship.And the serum sexual hormone level did not show apparent changes,indicating that it may not play a significant role in TB2C-induced infertility.TB2C-induced infertility at dosage 10g/Kg/d foe 60 days in male rats possesses reciprocity.At a limited dosage level,Dipsacus Asperoides can rivalry the toxic action caused by THH in reproductive organ of male rats.Tong Bi 2 Composition at 10g/Kg/d and 30g/Kg/d dosages has no harmful effects on hemogram,liver and kidney function in male rats.
中医药治疗RA疗效确定,副作用少,耐受性好,治疗费用低,具有独特的优势。陈纪藩教授在有效抗RA复方通痹灵合剂基础上创制的通痹合剂2号,方以南蛇藤配伍川续断,十余年的临床应用表明该复方有很好的抗炎抗风湿疗效,但迄今未经系统的临床疗效观察。同时由于该复方中的南蛇藤具有生殖毒性,长期服用会影响女性月经及导致男性不育,限制了其临床的推广应用。
本课题临床研究部分对通痹合剂2号治疗活动性RA的疗效进行系统的观察、分析,实验部分以雄性大鼠为研究对象,探讨通痹合剂2号雄性抗生育作用的靶器官、作用特点、量效关系及可逆性,旨在为临床安全用药提供一定的临床依据和科学实验依据。
1通痹合剂2号治疗RA的近期疗效观察
选择30例服用通痹合剂2号治疗的活动性RA患者,治疗时间为3个月,对患者治疗前后的肿胀关节数、压痛关节数、患者对疼痛的VAS评分、患者对病情的VAS评分、医生对病情的VAS评分、患者功能评估(HAQ)及血沉(ESR)、C反应蛋白(CRP)、类风湿因子(RF)进行观察、分析,采用ACR50标准评估患者的病情改善。同时对患者服药前后的血白细胞(WBC)、血红蛋白(HGB)、血小板(PLT)、谷草转氨酶(AST)、谷丙转氨酶(ALT)、血白蛋白(Alb)、尿素(BUN)、血肌酐(CR)的值进行监测和对比,对服药后可能出现的胃肠道不适、皮疹或皮损作记录,并观察女性患者月经变化情况。
结果显示,治疗3个月后,患者肿胀关节数、压痛关节数减少,晨僵时间缩短,患者对疼痛的VAS评分、患者和医生对病情的VAS评分及患者的HAQ,较治疗前明显好转(P＜0.05);ESR、CRP、RF滴度明显降低(P＜0.05),18例患者病情改善达到ACR50标准。服药期间患者的肝肾功、血象无异常,2例出现轻微胃肠道不适反应,加用护胃药可缓解。女性患者月经受到明显的影响,出现月经后期、经量减少、行经天数减少等月经功能失调的症状,部分女性患者出现面部色素沉着、可愈性颜面皮肤轻微破损。
2通痹合剂2号对雄性大鼠抗生育作用的研究
90只雄性大鼠随机分为5组,每组18只:正常对照组(ZC组),喂服过滤自来水10ml·kg~(-1)·d~(-1);通痹合剂2号剂量1组(HJ1组),喂服通痹合剂2号水煎液30g·kg~(-1)·d~(-1);通痹合剂2号剂量2组(HJ2组),喂服通痹合剂2号水煎液10g·kg~(-1)·d~(-1);南蛇藤剂量1组(NST1组),喂服南蛇藤水煎液22.5g·kg~(-1)·d~(-1);南蛇藤剂量2组(NST2组),喂服南蛇藤水煎液7.5g·kg~(-1)·d~(-1)。实验开始后,所有大鼠开始灌胃,每日一次,根据体重调整药量。给药60日后,第一次半数取材,测定相应指标,包括:睾丸重量、体积,精液常规分析,睾丸及附睾组织病理切片,以及血WBC、HB、PLT、ALT、AST、Alb、BUN、Cr的值;对余下的半数大鼠乙醚麻醉后眼眶取血,测定血清睾酮(T)、促卵泡生成激素(FSH)、促黄体生成素(LH)、雌二醇(E2)的含量,而后停药恢复饲养。停药72日后,第二次取材,重复测定上述指标。
研究结果显示,给药60日后,HJ2组大鼠睾丸形态、重量、体积、精子计数和精子密度与正常组比较无差异,生精上皮精子发生良好,支持细胞、基底膜和睾丸间质均无异常,附睾管中充满精子和分泌物,抗生育效应仅表现为附睾精子活动力下降为零,停药72日后,精子活动力完全恢复正常。HJ1组给药60日后,睾丸形态萎软,睾丸体积、重量、精子计数和密度较HJ2组明显下降(P＜0.01),生精上皮发生严重生精功能障碍,停药72日后无恢复迹象。给药60日及停药72日后,NST2组睾丸重量、体积、精子计数和密度较HJ2组均明显下降(P＜0.01),睾丸生精小管呈轻、中度生精功能障碍;与HJ1组比较,NST1组睾丸重量、体积、精子计数和密度无差异(P＞0.05),两组睾丸组织损害程度相同。
血清性激素的测定结果显示,给药60日和停药72日,包括HJ1组、HJ2组在内的所有给药组大鼠血清FSH、LH、E2四项性激素含量与正常组比较均无明显差异,血清T显示出统计学差异,但无实际意义,提示本课题研究条件下通痹合剂2号中THH的抗生育作用并非通过干扰大鼠血清性激素水平这一途径而产生效果。
血分析和肝肾功的测定结果显示,给药60日和停药72日,HJ1组和HJ2组血WBC、HGB、PLTBUN、CR值,与正常组比较无统计学差异(P＞0.05)。给药60日后,HJ1组和HJ2组Alb值较ZC组有所下降,但在大鼠的正常生理参考值范围内。HJ2组AST和ALT值较ZC组偏低(P＜0.05)。
3结论
通痹合剂2号在临床常用剂量(1g/kg/d)下治疗活动性RA具有很好的近期疗效,对患者的肝肾功、血象及胃肠道无明显副作用,是一种安全而有效的抗RA中药复方。同时该复方对女性月经有明显的影响,因此对年轻或有生育要求的女性患者而言,又当慎用。
通痹合剂2号对雄性大鼠具有明显的抗生育作用,靶器官为睾丸和附睾,作用强度呈剂量—效应关系,在10g/Kg/d剂量(相当于成人临床常用抗RA剂量的1.6倍)下,其抗生育作用完全具有可逆性。
一定剂量条件下,川续断能够拮抗南蛇藤的抗生育作用,减轻南蛇藤的生殖毒性。
通痹合剂2号的雄性抗生育作用并非通过干扰大鼠血清性激素水平这一途径而产生效果。
Rheumatoid arthritis(RA)is a systemic inflammatory autoimmune disease, with high rate of disability.Although the therapy strategy of RA has been studied extensively for many years,but the therapeutic outcome is not satisfied.Joint destruction occur in more than half patients.It is one of major diseases which cause loss of labor force and disability in China.
Chinese medicine therapy on RA has distinct predominance,with definite curative effect,few by-effect,good tolerance and low expense.Prof.Ji-Fan CHEN make out one new composition named Tong Bi 2 Composition(TB2C)according to Tong Bi Ling Composition,which has wonderful curative effect for RA.It is made up of Tripterygium Hypoglaucum Hutch(THH)and Dipsacus Asperoides. Although clinical application of more than one decade indicate that this composition works well for RA,no systematic clinical research has ever been done about it.THH possess reproduction toxicity,when taken for a long time, it can result in menstrual disorder and male sterility.That's why its clinical application is confined.
The clinical research was done to evaluate the curative effect for RA.And also,the experiment was done to approach antifertility effects of TB2C in male rats,and to investigate the sites,dose-effect relationship,reciprocity and possible mechanisms of the antifertility action.The researches help to provide clinical and experimental evidences for the treatment on RA by TB2C.
1 Study on the Recent Curative Effect in Active RA by Tong Bi 2 Composition
Thirty patients with active RA were treated with TB2C for 3 months. Clinical assessment using the American College of Rheumatology(ACR)criteria for improvement was performed at baseline and at the end of 3 months. Simultaneously the possible adverse reactions of TB2C were recorded,the clinical index including not only WBC,HGB,PLT,AST,ALT,Alb,BUN and CR in blood,but alsogastrointestinal tract indisposition,skin rash,skin damage,and women' s menstrual disorder,et al.
The clinical result showed that after 3 months' treatment,the patients' swollen joint count and tender joint count decreased,morning stiffness time shortened,compared with that before treatment,showing statistical difference (P＜0.05),as well as the laboratory index such as ESR,CRP and RF tite(P＜0.05). In addition,there was remarkable improvement in disease activity following the TB2C treatment.At the end of 3 months,the percent age of ACR50 was 60 %(18/30).During the treatment period,no adverse reaction happened to liver function,kidney function,hemogram or gastrointestinal tract.Almost all the women patients got menstrual disorder after 3 months,such as delayed menorrhea,spanomenorrhea,and so on.In addition,hyperpigmentation,skiin rash and skin damage happened to some women patients.
2 Resach on the Antifertility Action on Male Rats by Tong Bi 2 Composition
90 male rats,weight 180～220g,were randomly divided into 5 groups, 18 in each group.The control group were given by gastric gavage filtering tap water at a dose of lOml·kg~(-1)·d~(-1).In the same way the TB2C 1 group were given TB2C at a dose of 30g·kg~(-1)·d~(-1),as well the TB2C 2 group at a dose of 10g·kg~(-1)·d~(-1).The NST 1 group were given THH water elixation at a dose of 22.5g·kg~(-1)·d~(-1),while the NST 2 group were given THH water elixation at a dose of 7.5g·kg~(-1)·d~(-1).All rats were given by gastric gavage water or drug from the 1st day,once a day,last 60 days.Body weight was assessed every 5 days and the dose was adjusted accordingly.When administration 60d,one half the rats were sacrificed,and the corresponding index were measured,including testicle weight,testicle volume,the motility and counted number and density of sperm, pathological section of testicle and epididymis,the level of serum T,FSH, LH and E2,as well the level of WBC,HB,PLT,ALT,AST,Alb,BUN and Cr.When discontinuation 72d,the remnant half rats were sacrificed,and the above index were also measured in the same way.
The findings showed,after administration 60d,no difference was seen in the TB2C 2 group compared with the control group,except that the motility of sperm from caudal epididymides dropped to zero.But after discontinuation 72d,the motility of sperm of the TB2C 2 group completed recovery.After administration 60d,a significant decrease in testicle weight,testicle volume, the counted number and density of sperm,were seen in the TB2C 1 group compared with the TB2C 2 group(P＜0.01).30g·kg~(-1)·d~(-1)of TB2C caused the damaged structures of testicle and epididymis,and after discontinuation 72d,the damaged structures didn't recover.And a significant decrease in testicle weight,testicle volume,the counted number and density of sperm,were seen in the NST 2 group compared with the TB2C 2 group(P＜0.01),while no difference was seen in the NST 1 group compared with the TB2C 1 group(P＞0.05).
The findings also showed that no evident difference was seen on the level of FSH,LH and E2 between the 4 drug-given groups and the control group. Although a slight but statistically significant difference on the level of blood serum T was seen in the drug-given groups compared with the control group, which had no practical significance.Also no evident difference was seen on the level of FSH,LH and E2 between the 4 drug-given groups and the control group(P＞0.05).
3 Conclusion
Tong Bi 2 Composition at the level of clinical frequently used dose (1g/kg/d)is effective and safe in patients with active RA.It can obviously affects women' menstruation,so it should be used carefully on young women. Tong Bi 2 Composition has a male antifertity effect in rats,testicle and epididymis are the target organ of the action.The antifertility action displays a dose-effect relationship.And the serum sexual hormone level did not show apparent changes,indicating that it may not play a significant role in TB2C-induced infertility.TB2C-induced infertility at dosage 10g/Kg/d foe 60 days in male rats possesses reciprocity.At a limited dosage level,Dipsacus Asperoides can rivalry the toxic action caused by THH in reproductive organ of male rats.Tong Bi 2 Composition at 10g/Kg/d and 30g/Kg/d dosages has no harmful effects on hemogram,liver and kidney function in male rats.
引文
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