复合三联抗结核药涂层材料（HRZ/PLGA）在大鼠体内释药特性观察

Drug-releasing properties of anti-tuberculosis drugs composite in coating material HRZ/PLGA: a study in rats

中文关键词:  脊柱结核  抗结核药  聚乳酸－羟基乙酸  体内  缓释性能  大鼠

英文关键词:Spinal tuberculosis  Anti-TB drug  Poly(lactic-co-glycolic acid)  In vivo  Slow-release  Rat

中文摘要:

  【摘要】 目的：观察复合异烟肼（H）、利福平（R）、吡嗪酰胺（Z）三联抗结核药的聚乳酸－羟基乙酸（PLGA）涂层材料（HRZ/PLGA）在大鼠体内的释药特性。方法：将84只成年SD大鼠随机分为A、B、C三组，每组28只。A组为复合抗结核药HRZ/PLGA涂层材料植入组；B组为抗结核药HRZ植入组；C组为空白未载药PLGA涂层材料植入组，于术后1d、3d、1w、2w、4w、6w、8w时分别麻醉各组大鼠4只，抽取腹腔静脉血液5ml，处死后取体内植入材料或药物周边1cm的肌肉组织，应用高效液相色谱法（HPLC）检测肌肉组织及血清中H、R、Z三种药物的浓度，并于1w、4w时取血检测肝、肾功（AST、ALT、Ur、Cr），2w及6w时取植入局部肌肉组织进行形态学观察。结果：A组在术后3d时HRZ/PLGA涂层材料周边肌肉组织中三药浓度均达最高，2w后药物浓度下降趋势平稳，8w时H、R、Z三药平均浓度分别为0.87、0.92、1.61μg/g，均能达到各自10倍最低抑菌浓度（MIC）；B组在术后3d时植入HRZ周边肌肉组织中三药物浓度均达最高，但药物浓度下降较快，4w时三种药物均不能检测到；C组不能检测到三种药物。A组肌肉检测药物浓度曲线较B组明显平稳、长程。A组静脉血中三种药物浓度明显低于植入HRZ/PLGA涂层材料周边的肌肉组织（P<0.05）。术后1w、4w时各组AST、ALT、Ur、Cr与术前比较差异均无统计学意义（P>0.05）。2w时A组及C组植入局部肌肉组织HE染色观察镜下见炎症细胞及PLGA降解产生空泡存在，6w时炎症细胞及空泡减少，A、B、C三组未见明显细胞坏死。结论：HRZ/PLGA涂层材料在SD大鼠体内释药平稳，持续时间较长，可实现体内局部用药的有效缓释；直接植入体内后组织生物相容性及可塑形性良好，为脊柱结核病灶清除后复合自体骨的局部有效给药提供了新方法。

英文摘要:

  【Abstract】 Objectives: To observe the sustained-release properties of isoniazid(H), rifampicin(R), pyrazinamide(Z) anti-tuberculosis drugs composite/poly(lactic acid-glycolic acid) in coating material(HRZ/PLGA) in rats. Methods: Eighty-four SD adult rats were divided into three groups randomly: HRZ/PLGA group(group A), HRZ group(group B) and the blank copolymer group(group C). Four rats in each group were anesthetized respectively at 1d, 3d, 1w, 2w, 4w, 6w and 8w after surgery, 5ml blood sample was taken through vena cava in each rat. Then rats were killed, and 1cm muscle around the surgery site was obtained. High performance liquid chromatography(HPLC) was applied to detect H, R, Z concentration in the muscle and serum. Liver and kidney functions(AST、ALT、Ur、Cr) were detected at 1w and 4w after surgery, the histopathological changes was observed in muscle tissues of surgery site at 2w and 6w after surgery. Results: In group A, H, R, Z reached the highest drug concentration in muscle and plasma at 3d after surgery, and tended to show a stable descent speed after 2w. The H, R, Z concentrations of group A in muscle were 0.87, 0.92, 1.61μg/g at 8w, which were 10 times as high as their minimum inhibitory concentrations(MIC). The H, R, Z concentrations of group B in muscle reached the highest at 3d after surgery, and dropped sharply, which became undetectable at 4w after surgery. H, R, Z were undetectable in the muscle and plasma of group C. The difference of drug concentration in the muscle and plasma of group A was statistically significant(P<0.05)in the paired t test. In group A, B, C, all the indexes of liver and kidney before surgery, at 1w, and at 4w had no statistical difference(P>0.05). In group A and C, the histopathological of muscle tissues showed some inflammatory cells and empty package, which produced by the degradation of PLGA. The three groups did not have obvious inflammation cell and cell damage. Conclusions: HRZ/PLGA can be sustained and gently released with satisfactory biocompatibility and plasticity in rats. This study provides a new method for local effective administration with combined autologous bone after spinal tuberculosis clearing.