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目的 :观察载异烟肼(H)、利福平(R)、吡嗪酰胺(Z)复合抗结核药/聚乳酸-羟基乙酸共聚物缓释微球在大鼠体内的缓释特性。方法:选取SD雄性成年大鼠84只,随机分成A、B、C三组,分别设为载药微球组、空白微球组、空白组,于术后1d、3d、1周、2周、4周、6周、8周时分别处死各组4只大鼠,处死时取微球周边1cm肌肉组织和腹腔静脉血5ml,应用高效液相色谱法检测肌肉组织和血清中三种药物浓度;在1周、4周时检测肝、肾功能,留取肝、肾组织观察其组织病理学变化。结果:术后3d时A组中肌肉和血浆中HRZ的药物浓度达到最高,1周后药物的浓度趋于稳定;8周时肌肉组织中HRZ的浓度分别为0.56、0.63、1.51μg/g,均达到了各自的10倍最低有效抑菌浓度,血浆中HRZ浓度分别为0.112、0.046、0.189μg/ml,肌肉中药物浓度和血浆中药物浓度行配对t检验,差异有统计学意义(P<0.05);B、C两组肌肉及血浆中均未检测出HRZ。在1、4周时,对三组大鼠肝、肾功能相关指标进行检测,A与C、A与B、B与C组间两两比较t检验,肝、肾功能各项指标在各检测点均无统计学差异(P>0.05);A、B、C三组大鼠肝、肾组织病理学检查未见明显损伤。结论:HRZ/PLGA微球具有缓慢、平稳释放药物的特性,具有良好的组织生物相容性,可直接植入体内实现局部给药和缓释长程治疗的双重效果。
OBJECTIVE: To observe the sustained-release characteristics of isoniazid (H), rifampicin (R) and pyrazinamide (Z) composite antituberculosis drugs / polylactide-co-glycolide microspheres in rats. Methods: Eighty-four male SD rats were randomly divided into A, B and C groups, which were divided into three groups: drug loading microsphere group, blank microsphere group and blank group. The rats were sacrificed on day 1, 3d, , 4 weeks, 6 weeks and 8 weeks, 4 rats in each group were sacrificed, and 1ml muscular tissue and 5ml peritoneal vein blood in the periphery of the microspheres were sacrificed. High-performance liquid chromatography (HPLC) was used to detect the concentration of three drugs in muscle tissue and serum At 1 week and 4 weeks, liver and renal function were detected, and the histopathological changes of liver and kidney were observed. Results: At 3 days after operation, the concentration of HRZ in muscle and plasma reached the peak in group A, and the concentration of HRZ in muscle and plasma tended to be stable after 1 week. At 8 weeks, HRZ concentrations in muscle tissue were 0.56, 0.63 and 1.51 μg / g, Respectively, reached their respective 10-fold minimum inhibitory concentration, HRZ concentrations in plasma were 0.112,0.046,0.189μg / ml respectively. The paired t test was used to determine the concentration of drug in muscle and plasma concentration of drug (P < 0.05). HRZ was not detected in muscle and plasma of B and C groups. At 1 week and 4 weeks, liver and kidney function-related indexes of three groups of rats were tested. A and C, A and B, B and C groups compared t test, liver and kidney function indicators in each test There was no significant difference between the two groups (P> 0.05). There was no obvious pathological examination in liver, kidney of A, B and C groups. Conclusion: HRZ / PLGA microspheres have the characteristics of slow and steady drug release, good biocompatibility and can be directly implanted into the body to achieve the dual effect of local administration and sustained-release long-range treatment.