两个厂家的雷公藤多苷片对CIA模型大鼠干预作用比较
|
摘要
目的:观察并比较湖南千金协力(QJ)和浙江得恩德(DED)两个厂家的雷公藤多苷(TG)片口服后对Ⅱ型胶原诱导性关节炎(CIA)大鼠的药效及多脏器的干预作用。方法:72只SD大鼠随机分为正常组,模型组,千金协力TG片临床2倍,6倍等效剂量组(QJ-TG 0. 018,0. 054 g·kg~(-1)),得恩德TG片临床2倍,6倍等效剂量组(DED-TG 0. 018,0. 054 g·kg~(-1))。首次免疫后当天开始灌胃给药,每天1次。二次免疫后观察大鼠关节红肿和畸形症状,评价关节炎临床积分,分别在第21,42天取材,进行炎症关节组织病理学检查;血清酶学方法检测大鼠血清中碱性磷酸酶(ALP),丙氨酸氨基转移酶(ALT),天门冬氨酸氨基转移酶(AST),谷氨酰转移酶(GGT),总胆红素(TBIL),肌酐(CRE)和尿素(UREA)含量;评估大鼠附睾精子畸形率及睾丸与卵巢组织的损伤程度。结果:两个厂家TG片均能改善CIA模型大鼠炎症关节红、肿和畸形症状,降低临床积分,抑制关节滑膜炎症、血管翳、软骨侵蚀和骨破坏的病理改变。其中,QJ-TG 0. 018,0. 054 g·kg~(-1)组和DED-TG 0. 054 g·kg~(-1)组与模型组比较,有统计学差异(P <0. 05,P <0. 01),DED-TG 0. 018 g·kg~(-1)组与模型组比较未见明显变化;两个厂家相同剂量TG比较,DED-TG 0. 054 g·kg~(-1)组在第12和18 d比QJ-TG同剂量组对临床积分的抑制作用明显(P <0. 05)。除DED-TG 0. 054 g·kg~(-1)组能明显升高白细胞数和脾脏指数外,两个厂家TG片对CIA模型大鼠的体质量、其他脏器指数、消化系统、肝肾功能及肝肾病理均无明显影响,却能不同程度增加CIA雄性大鼠精子畸形率,对睾丸曲细精管造成显著损伤,其严重度随剂量和时间增加而增加,而同等剂量下DED-TG的雄性生殖毒性大于QJ-TG。DED-TG 0. 054 g·kg~(-1)组和QJ-TG 0. 054 g·kg~(-1)组除可见卵巢组织中血管分布减少,黄体体积缩小外,未见其他毒性作用。结论:两个厂家TG片2倍和6倍临床等效剂量口服均能延缓大鼠CIA的发病,降低关节炎临床积分,改善关节病理改变,并有一定程度的雄性生殖毒性。高剂量DED-TG比QJ-TG的毒-效作用更明显。
Objective: To compare the effects and multi-organ intervention of tripterygium glycosides( TG) tablet from Hunan Qianjin Xieli( QJ) and Zhejiang Deende( DED) on type Ⅱ collagen-induced arthritis( CIA) in rats. Method: The 72 SD rats were randomly divided into normal group,model group,QJ TG clinical group 2 times,6 times equivalent dose group( QJ-TG 0. 018,0. 054 g·kg-1),derende TG clinical group 2 times,6 times equivalent dose group( DED-TG 0. 018,0. 054 g·kg-1). The intragastric administration was started on the day after the first immunization,once a day. After the second immunization,the symptoms such as redness and swelling of joints were observed,and the clinical score of arthritis were evaluated. The materials were taken for pathological examination of the inflammatory joints on the 21 thand 42 thday. The concentration of alkaline phosphatase( ALP), alanine aminotransferase( ALT), aspartate aminotransferase( AST), gammaglutamyltransferase( GGT),total bilirubin( TBIL),creatinine( CRE) and urea( UREA) in serum were detected by enzymatic assay. The rate of sperm deformity,testicular and ovarian tissue damage in the rat epididymis was assessed. Result: TG from two manufacturers attenuated the inflammation,redness,swelling and deformity of joints in CIA rats,reduced the clinical score and incidence of arthritis in CIA rats. Meanwhile,it also exhibited obvious reduction in all pathological features such as joint synovitis,pannus,cartilage erosion and bone destruction. There were significant differences between the QJ-TG high and low dose groups and the DED-TG high dose group compared with the model group( P < 0. 05,P < 0. 01). There was no significant change in the low dose group of DED-TG compared with the model group. Compared with the same dose of TG in the two manufacturers,the DED-TG 0. 054 g·kg-1 group had a significant inhibitory effect on the clinical scores on the15 th and 18 th days than the QJ-TG same dose group( P < 0. 05). In addition to 0. 054 g·kg-1 dose of DED-TG,the white blood cell count and spleen index were significantly increased. At the same time, two different manufacturers of TG had no effect on body weight,organ index,digestive system,liver and kidney function,liver and kidney pathology of CIA model rats. QJ-TG and DED-TG all significantly increased the rate of male rats sperm malformation and significant damage to testicular seminiferous tubules and the toxicity increased with the increase of dose and time. while the mole reproductive toxicity of DED-TG was higher than that of QJ-TG at the same dose. In the DED-TG 0. 054 g·kg-1 and QJ-TG 0. 054 g·kg-1 group,there were only the reduction of vascular distribution in the ovarian tissue and the reduction of the corpus luteum,and no other toxic effects were observed. Conclusion:Two manufacturers TG2 times( 0. 018 g·kg-1) and 6 times( 0. 054 g·kg-1) clinical equivalent dose can delay the onset of CIA in rats,reduce the clinical score of arthritis,improve the pathological changes of joints,but have a certain degree of male reproductive toxicity. The high-dose DED-TG is more toxic than the QJ-TG.
Objective: To compare the effects and multi-organ intervention of tripterygium glycosides( TG) tablet from Hunan Qianjin Xieli( QJ) and Zhejiang Deende( DED) on type Ⅱ collagen-induced arthritis( CIA) in rats. Method: The 72 SD rats were randomly divided into normal group,model group,QJ TG clinical group 2 times,6 times equivalent dose group( QJ-TG 0. 018,0. 054 g·kg-1),derende TG clinical group 2 times,6 times equivalent dose group( DED-TG 0. 018,0. 054 g·kg-1). The intragastric administration was started on the day after the first immunization,once a day. After the second immunization,the symptoms such as redness and swelling of joints were observed,and the clinical score of arthritis were evaluated. The materials were taken for pathological examination of the inflammatory joints on the 21 thand 42 thday. The concentration of alkaline phosphatase( ALP), alanine aminotransferase( ALT), aspartate aminotransferase( AST), gammaglutamyltransferase( GGT),total bilirubin( TBIL),creatinine( CRE) and urea( UREA) in serum were detected by enzymatic assay. The rate of sperm deformity,testicular and ovarian tissue damage in the rat epididymis was assessed. Result: TG from two manufacturers attenuated the inflammation,redness,swelling and deformity of joints in CIA rats,reduced the clinical score and incidence of arthritis in CIA rats. Meanwhile,it also exhibited obvious reduction in all pathological features such as joint synovitis,pannus,cartilage erosion and bone destruction. There were significant differences between the QJ-TG high and low dose groups and the DED-TG high dose group compared with the model group( P < 0. 05,P < 0. 01). There was no significant change in the low dose group of DED-TG compared with the model group. Compared with the same dose of TG in the two manufacturers,the DED-TG 0. 054 g·kg-1 group had a significant inhibitory effect on the clinical scores on the15 th and 18 th days than the QJ-TG same dose group( P < 0. 05). In addition to 0. 054 g·kg-1 dose of DED-TG,the white blood cell count and spleen index were significantly increased. At the same time, two different manufacturers of TG had no effect on body weight,organ index,digestive system,liver and kidney function,liver and kidney pathology of CIA model rats. QJ-TG and DED-TG all significantly increased the rate of male rats sperm malformation and significant damage to testicular seminiferous tubules and the toxicity increased with the increase of dose and time. while the mole reproductive toxicity of DED-TG was higher than that of QJ-TG at the same dose. In the DED-TG 0. 054 g·kg-1 and QJ-TG 0. 054 g·kg-1 group,there were only the reduction of vascular distribution in the ovarian tissue and the reduction of the corpus luteum,and no other toxic effects were observed. Conclusion:Two manufacturers TG2 times( 0. 018 g·kg-1) and 6 times( 0. 054 g·kg-1) clinical equivalent dose can delay the onset of CIA in rats,reduce the clinical score of arthritis,improve the pathological changes of joints,but have a certain degree of male reproductive toxicity. The high-dose DED-TG is more toxic than the QJ-TG.
引文
[1]姜海平,张艳艳.雷公藤多苷治疗类风湿关节炎的抗炎机制研究[J].亚太传统医药,2017,13(21):57-58.
[2]林兵,杨海跃,刘志宏,等.不同厂家雷公藤多苷片指纹图谱及体内抗炎药效、毒性比较研究[J].中国药师,2019,22(2):206-210,230.
[3] Bevaart L,Vervoordeldonk M J,Tak P P. Evaluation of therapeutic targets in animal models of arthritis:how does it relate to rheumatoid arthritis?[J]. Arthritis Rheum,2010,62(8):2192-2205.
[4] Cuzzocrea S,Mconald M C, Mota-Filipe H,et al.Beneficial effects of tempol, a membrane permeable radical scavenger,in a rodent model of collagen induced arthritis[J]. Arthritis Rheum,2000,43(2):320-328.
[5]马帅,佟继铭,梅爱敏,等.赤雹根总皂苷对CIA模型大鼠的治疗作用及对CD4+、CD8+T细胞表达的影响[J].中药药理与临床,2017,33(4):70-74.
[6] YI J K,Kim H J,YU D H,et al. Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis[J]. Arthritis Rheum,2012,64(7):2191-2200.
[7] ZHANG Y,BAI M,ZHANG B,et al. Uncovering pharmacological mechanisms of wu-tou decoction acting on rheumatoid arthritis through systems approaches:drug-target prediction, network analysis and experimental validation[J]. Sci Rep,2015,doi:10. 1038/srep09463.
[8] Bendele A,Mcabee T,Sennello G,et al. Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis:comparison of efficacy in animal models with human clinical data[J].Arthritis Rheum,1999,42(3):498-506.
[9]郭玉萍,李恩中,张由婧,等.有氧运动对雄性大鼠生精功能的影响及其睾丸i TRAQ定量蛋白组学分析[J].中华男科学杂志,2017,23(9):776-781.
[10]刘丹薇,潘卫,徐国宾,等. 1-磷酸鞘氨醇对雄性小鼠生殖毒性损害的拮抗作用[J].贵阳医学院学报,2016,41(5):515-519.
[11]王桂玲,任春娥,王丽.雷公藤多甙对雌性大鼠不良反应的实验研究[J].河北医药,2009,31(4):416-418.
[12]王启新,陈则华,罗琥捷,等.肉苁蓉不同提取部位改善肾阳虚大鼠性能力的影响[J].中国实验方剂学杂志,2018,24(22):95-101.
[13]李金洋,李军,王君明,等.雷公藤多苷致肝毒及其减毒的研究进展[J].中国老年学杂志,2016,36(17):4359-4361.
[14]杨冬梅,刘俊.雷公藤多苷临床应用及不良反应的研究进展[J].中国医院药学杂志,2018,38(20):2185-2190.
[15]罗岚,江振洲,张陆勇.雷公藤多苷肝毒性发生机制及减毒相关研究进展[J].药物评价研究,2017,40(10):1504-1509.
[16]刘宁,张友文,张丹,等.双环醇对雷公藤多苷诱导小鼠肝损伤的保护作用研究[J].中国药物警戒,2016,13(7):385-388.
[17]赵小梅,刘歆颖,续畅,等.基于LC-MS代谢组学的雷公藤多苷致肝毒性生物标志物的初步筛查[J].中国中药杂志,2015,40(19):3851-3858.
[18]何欣,赵兴华,欧阳五庆.雷公藤多苷纳米乳体外肝肾的细胞毒性[J].中国药理学与毒理学杂志,2010,24(6):476-480.
[19]张茜,金若敏.中药肝肾毒性及肝肾功能检测指标的研究概况[J].中国中医药信息杂志,2011,18(8):105-107.
[20]谷春霞,陶学濂,葛秦生,等.雷公藤多甙片所致闭经原因的探讨[J].中国医学科学院学报,1989,11(2):151-153.
[21]张婷婷,马晓莉.雷公藤多苷致卵巢早衰1例[J].解放军医学院学报,2017,38(12):1167-1168.
[2]林兵,杨海跃,刘志宏,等.不同厂家雷公藤多苷片指纹图谱及体内抗炎药效、毒性比较研究[J].中国药师,2019,22(2):206-210,230.
[3] Bevaart L,Vervoordeldonk M J,Tak P P. Evaluation of therapeutic targets in animal models of arthritis:how does it relate to rheumatoid arthritis?[J]. Arthritis Rheum,2010,62(8):2192-2205.
[4] Cuzzocrea S,Mconald M C, Mota-Filipe H,et al.Beneficial effects of tempol, a membrane permeable radical scavenger,in a rodent model of collagen induced arthritis[J]. Arthritis Rheum,2000,43(2):320-328.
[5]马帅,佟继铭,梅爱敏,等.赤雹根总皂苷对CIA模型大鼠的治疗作用及对CD4+、CD8+T细胞表达的影响[J].中药药理与临床,2017,33(4):70-74.
[6] YI J K,Kim H J,YU D H,et al. Regulation of inflammatory responses and fibroblast-like synoviocyte apoptosis by calcineurin-binding protein 1 in mice with collagen-induced arthritis[J]. Arthritis Rheum,2012,64(7):2191-2200.
[7] ZHANG Y,BAI M,ZHANG B,et al. Uncovering pharmacological mechanisms of wu-tou decoction acting on rheumatoid arthritis through systems approaches:drug-target prediction, network analysis and experimental validation[J]. Sci Rep,2015,doi:10. 1038/srep09463.
[8] Bendele A,Mcabee T,Sennello G,et al. Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis:comparison of efficacy in animal models with human clinical data[J].Arthritis Rheum,1999,42(3):498-506.
[9]郭玉萍,李恩中,张由婧,等.有氧运动对雄性大鼠生精功能的影响及其睾丸i TRAQ定量蛋白组学分析[J].中华男科学杂志,2017,23(9):776-781.
[10]刘丹薇,潘卫,徐国宾,等. 1-磷酸鞘氨醇对雄性小鼠生殖毒性损害的拮抗作用[J].贵阳医学院学报,2016,41(5):515-519.
[11]王桂玲,任春娥,王丽.雷公藤多甙对雌性大鼠不良反应的实验研究[J].河北医药,2009,31(4):416-418.
[12]王启新,陈则华,罗琥捷,等.肉苁蓉不同提取部位改善肾阳虚大鼠性能力的影响[J].中国实验方剂学杂志,2018,24(22):95-101.
[13]李金洋,李军,王君明,等.雷公藤多苷致肝毒及其减毒的研究进展[J].中国老年学杂志,2016,36(17):4359-4361.
[14]杨冬梅,刘俊.雷公藤多苷临床应用及不良反应的研究进展[J].中国医院药学杂志,2018,38(20):2185-2190.
[15]罗岚,江振洲,张陆勇.雷公藤多苷肝毒性发生机制及减毒相关研究进展[J].药物评价研究,2017,40(10):1504-1509.
[16]刘宁,张友文,张丹,等.双环醇对雷公藤多苷诱导小鼠肝损伤的保护作用研究[J].中国药物警戒,2016,13(7):385-388.
[17]赵小梅,刘歆颖,续畅,等.基于LC-MS代谢组学的雷公藤多苷致肝毒性生物标志物的初步筛查[J].中国中药杂志,2015,40(19):3851-3858.
[18]何欣,赵兴华,欧阳五庆.雷公藤多苷纳米乳体外肝肾的细胞毒性[J].中国药理学与毒理学杂志,2010,24(6):476-480.
[19]张茜,金若敏.中药肝肾毒性及肝肾功能检测指标的研究概况[J].中国中医药信息杂志,2011,18(8):105-107.
[20]谷春霞,陶学濂,葛秦生,等.雷公藤多甙片所致闭经原因的探讨[J].中国医学科学院学报,1989,11(2):151-153.
[21]张婷婷,马晓莉.雷公藤多苷致卵巢早衰1例[J].解放军医学院学报,2017,38(12):1167-1168.