抗结核新药吡法齐明组合用药的体外及小鼠体内抗结核活性研究  

Study on the pharmacodynamic activity of combinations with the new anti-tuberculosis drug pyrifazimine in vitro and in vivo in mouse

作　　者：刘海婷 付雷[1] 王彬[1] 王宁 李东硕 丁杨明 姚蓉 祁雪婷 陆宇[1] Liu Haiting;Fu Lei;Wang Bin;Wang Ning;Li Dongshuo;Ding Yangming;Yao Rong;Qi Xueting;Lu Yu(Beijing Chest Hospital,Capital Medical University,Beijing Key Laboratory of Drug Resistance Tuberculosis Research,Department of Pharmacology,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing 101149,China)

机构地区：[1]首都医科大学附属北京胸科医院耐药结核病研究北京市重点实验室北京市结核病胸部肿瘤研究所药物学研究室,北京101149

出　　处：《中华结核和呼吸杂志》2022年第6期560-566,共7页Chinese Journal of Tuberculosis and Respiratory Diseases

基　　金：国家自然科学基金(82173862);北京市自然科学基金(7212150)。

摘　　要：目的评价吡法齐明(pyrifazimine,TBI-166)与抗耐药结核病A组药物贝达喹啉(bedaquiline,BDQ)、莫西沙星(moxifloxacin,MFX)及新型抗结核药物德拉马尼(delamanid,DLM)、SQ109、Q203、PBTZ169两药组合在体外及小鼠体内的抗结核活性,为TBI-166联合用药提供依据。方法本研究自2020年9月至2021年7月。应用棋盘法测定TBI-166与BDQ、MFX、DLM、SQ109、PBTZ169两药组合的相互作用,时间杀菌曲线法评估具有部分协同作用的两药组合的抗结核活性;BALB/c小鼠急性结核病模型评价两药联用组(TBI-166+BDQ、TBI-166+SQ109、TBI-166+PBTZ169、TBI-166+Q203)与单药组(TBI-166、BDQ、SQ109、PBTZ169、Q203)治疗4和8周的抗结核活性,采用独立样本t检验进行数据分析。结果 TBI-166与抗结核药物联用后,最低药物浓度(MIC)降至应用单药的6.25%~25.00%,TBI-166分别与BDQ、SQ109、PBTZ169两药联用后,部分抑制浓度指数(FICI)值分别为0.56、0.75、0.75;时间杀菌实验显示TBI-166分别与BDQ、SQ109、PBTZ169两药组合作用于结核分枝杆菌14 d后与单药应用时相比活菌量减少了至少3 log10 CFU/ml;在小鼠实验中发现BDQ、SQ109和PBTZ169分别与TBI-166组合后与单药组相比肺组织活菌量较少,其中TBI-166+BDQ组小鼠在治疗4周后肺组织培养阴性,小鼠肺内活菌数比BDQ单药组低1.49 log10CFU(P<0.01)。结论体外及小鼠体内实验揭示TBI-166分别与BDQ、SQ109、PBTZ169联用后均具有协同抗结核活性。Objective To evaluate two-drug combination interaction between pyrifazimine(TBI-166)and anti-drug-resistant tuberculosis group A drugs Bedaquiline(BDQ),Moxifloxacin(MFX)and the new anti-tuberculosis drug Delamanid(DLM),SQ109,Q203,and PBTZ169 in vitro and in vivo in mouse,so as to provide basis for TBI-166 combination therapy.Methods This study was performed from September 2020 to July 2021.The chessboard method was used to evaluate the interaction between TBI-166 and BDQ,MFX,DLM,SQ109,and PBTZ169.The time-killing kinetics method was used to evaluate the anti-tuberculosis activity of the two-drug combination with partial synergy.The BALB/c mouse acute infection model was used to evaluate the anti-tuberculosis activity at 4 and 8 weeks in the two-drug combination group(TBI-166+BDQ,TBI-166+SQ109,TBI-166+PBTZ169,TBI-166+Q203)and monotherapy groups(TBI-166,BDQ,SQ109,PBTZ169,Q203).Data analysis was performed using an independent sample t-test.Results After TBI-166 combined with anti-tuberculosis drugs,MIC was reduced to 6.25%to 25.00%of TBI-166 monotherapy.After TBI-166 combined with BDQ,SQ109 and PBTZ169,the partial inhibitory concentration index(FICI)values were 0.53,0.75 and 0.75,respectively;the time sterilization experiment showed that the viable population of Mycobacterium tuberculosis treated with two-drug combination of TBI-166 and BDQ,SQ109,PBTZ169 for 14 days decreased at least 3 log10 CFU/ml.In the mouse experiments,it was found that,the amount of viable bacteria in lung tissue of BDQ,SQ109 and PBTZ169 combined with TBI-166 groups was lower than that of the monotherapy group,respectively.The lung tissue culture of mice in the TBI-166+BDQ group was negative after 4 weeks of treatment,and the number of live bacteria in the lungs of the TBI-166+BDQ group was 1.49 log10CFU lower than that of the BDQ monotherapy group(P<0.01).Conclusion In vitro and in vivo experiments in mice revealed that TBI-166 had synergistic anti-tuberculosis activity after being combined with BDQ,SQ109 and PBTZ169,respectively.

关 键 词：结核 抗结核药 药物疗法 联合 TBI-166 

分 类 号：R965[医药卫生—药理学]