抗结核药物及方案对结核性脑炎治疗作用及药物的药代动力学／药效学研究

Study on Therapeutic Effect of Anti-TB Drugs and Regimens for Tuberculosis Meningitis and PK/PD of These Drugs

目的测定三种抗结核药在健康和结核性脑膜炎小鼠脑组织中的浓度，评价几种单药和联合方案抗肺结核和结核性脑膜炎的活性；评价其药代动力学／药效学（PK／PD）参数。方法通过小鼠静脉感染H37Rv建立结核性脑膜炎模型，健康和结核性脑膜炎小鼠分别连续给予利福平（RFP）、左氧氟沙星（Lfx）、英西沙星（Mfx）5d后，于不同的时间点取血和脑组织样本，HPLC法测定药物浓度，计算PK及PK／PD参数：结核性脑膜炎小鼠以常用于结核性脑膜炎治疗的几种抗结核药单药和Lfx、Mfx以及几种联合方案进行治疗，于给药56d后进行肺、脑活菌计数，应用单因素方差分析，比较各药及化疗方案抗肺结核和结核性脑膜炎活性；并结合PK／PD参数进行评价。结果结核性脑膜炎小鼠的脑组织中RFP、Lfx、Mfx的AUC0.24分别增加56．0％、148.5％、80.4％：AUC0.24／MIC分别为445．0、16．5、7．4；各组治疗8周后，对肺结核的治疗除吡嗪酰胺（PZA）、Lfx以外，均有显著疗效；对结核性脑膜炎的治疗，除Lfx组以外，均有显著疗效，且异烟肼（INH）、PZA、丙硫异烟胺（Pro）、RFP＋INH＋Pto（RHPto）、RFP＋INH＋Lfx（RHLfx）、RFP＋INH＋Mfx（RHMfx）各组有非常显著的疗效，与空白对照组相比分别下降1．87、1．26、0．97、1．42、1．31、1．33、1．32log10CFU。结论结核性脑膜炎小鼠的脑组织药量相比健康小鼠有显著增加；依据结核性脑膜炎患者的不同情况，可以选用这几种联合化疗方案进行治疗。

objective To determinte the concentrations of three anti-TB drugs are increased in the brain tissue of health and TB meningitis（ MTB） model mice, study the pharmacokinetics/pharmacodynamics （PK/PD） parameters of them in plasma and brain tissue using healthy and MTB model mice, evaluate the activities of these drugs respectively and combinations of them, provide information for the treatment of MTB based on their activities and parameters. Methods MTB mice model was developed through injecting H37Rv into the tail vein of mice. After administrated RFP, Lfx, Mfx for 5 days, the plasma and brain tissue of healthy and MTB mice were gotten at different time points and the concentrations of these drugs were determined by HPLC, and then obtain the PK and PK/PD parameters. The mice were given Lfx, Mfx and other drugs usually used to therapy TB al^ne ~r combination, CFU in lungs and brain tissues were obtained after treatment for 8 weeks and these data together with the PK and PK/PD parameters were analyzed to evaluate the efficiency of treating pulmonary TB and MTB. Results The AUC0.24 of RFP, Lfx, Mfx were increased by 56. 0%, 148.5%, 80. 4%, AUC0.24/MIC were 445.0, 16. 5, 7. 4 respectively after treatment for 8 weeks, except PZA, Lfx that the CFU were decreased more. For MTB, every groups except Lfx were effective and INH, RHPto, RHLfx, RHMfx were more effective. Conclusions The amounts of drugs entering into the brain tissue increase while the brain was infected by H37Rv when compared with that of healthy mice; RHPto, RHLfx, RHMfx are effective combinations to therapy MTB, so all of them can be choosed as therapeutic remedy for different patients.