脊柱结核病灶中抗痨药物浓度的测定

Measurement of the concentration of three anti-tuberculosis drugs in the focus of spinal tuberculosis and its clinical significance

目的研究脊柱结核病椎各部位抗结核药物的分布特点,为脊柱结核化疗方案与手术治疗方法的改进提供理论依据.方法24例应用2SHRZ/2.5H2R2Z2(4.5个月)方案化疗结合手术治疗的脊柱结核患者,按有无病椎骨硬化分为硬化组和非硬化组.化疗第4周手术,依据手术取材时间分为术晨服药后120～130、180～190 min两个时相点,取硬化组的病椎硬化壁、硬化壁外'亚正常骨'、硬化壁内结核病变组织和非硬化组的病椎结核病变组织、病变组织外'亚正常骨'以及两组患者的血浆、髂骨,采用高效液相色谱法测定上述样本的药物浓度.结果(1)吡嗪酰胺(PZA)和异烟肼(INH)各时相血药浓度与文献报道健康人单次服药的药时数据相近,利福平(RFP)则低25%,各药血药浓度高于髂骨及病椎组织中的药物浓度.(2)两组中'亚正常骨'与髂骨内的INH和RFP均达到了各自的杀菌浓度水平,PZA超过其细胞内酸性条件下MIC的5倍.三种药物各自在'亚正常骨'与自身对照的髂骨之间浓度相近.(3)硬化组中硬化壁的药物浓度仅为各药的最小抑菌浓度水平(MICs),远低于壁外围'亚正常骨',壁内的结核病变组织中未检出上述三种药.(4)非硬化组结核坏死、干酪组织中RFP及PZA的浓度相当于各自的MICs,远低于其他组分,而INH却达到细胞内杀菌浓度.结论INH、RFP和PZA在脊柱结核患者正常骨与病椎'亚正常骨'中可达到有效治疗浓度,而在硬化壁极低,远低于治疗浓度水平;硬化壁内的病变组织无药物分布.硬化骨的存在成为抗结核化疗药物难于在椎体病灶内渗透的主要屏障.

Objective To study the distribution of rifampin(RFP), isoniazid(INH) and pyrazi-namide(PZA) in the focus of spinal tuberculosis in order to provide the regimen of chemotherapy and surgi-cal treatment of spinal tuberculosis. Methods Twenty-four patients with spinal tuberculosis were divided into sclerotic group or non-sclerotic group according to the radiographic features of lesion. All patients re-ceived chemotherapy with 2SHRZ/2.5 H2R2Z2 for a duration of 4.5 months. 4 weeks after chemotherapy, all patients underwent surgery and specimen of serum, ilium and vertebral tissues including sclerotic wall, sub-normal osseous tissue, focus inside sclerotic wall (sclerotic group) and destructive focus, peripheral subnor-mal osseous tissue (non-sclerotic group) were obtained during operation at 120-130 and 180-190 minutes after oral intake in the morning respectively. The levels of 3 drugs in the specimen were measured using HPLC method. Results 1) The concentration levels of INH and PZA in serum were similar to the data in the literature, but the level of RFP was only 75% of that in the literature. The levels of 3 drugs in osseous tissue were significantly less than those of blood. 2) Concentrations of isoniazid and rifampicin in self-control ilium and sub-normal bone tissue were within or exceeded the bactericidal concentration values,and pyrazi-namide was five fold of it's minimal inhibitory concentration (MIC) in acid cellular condition. There were no significant differences between sub-normal bone and self-control ilium of 3 drugs concentration. 3) Concen-tration of 3 drugs in sclerotic bone wall were approximate to MIC respectively in sclerotic group and much lower than sub-normal bone. There was no drug distribution of focus inside sclerotic bone wall. 4) RFP and PZA in focus of non-sclerotic group corresponded to the levels of MIC respectively, though much lower than in other parts of vertebral tissues, but the INH in focus was of bactericidal level. Conclusion The sclerotic bone of affected vertebra plays an important role to block the drug's penetration into tuberculosis focus.