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目的 :观察复合HRZ/PLGA缓释抗结核药涂层材料在兔脊柱结核病灶的释药特性。方法 :应用兔脊柱结核模型120只,按三联抗痨药异烟肼(INH,H)、利福平(RFP,R)和吡嗪酰胺(PZA,Z)给药剂型及途径不同,随机分为4组(各30只):A组(复合HRZ/PLGA缓释材料局部给药组);B组(局部给药组);C组(灌胃给药组);D组(假手术灌药组)。其中A、B、C三组行L4/5脊柱结核病灶清除及自体髂骨植骨术,D组行假手术。采用高效液相色谱(HPLC)检测术后3d、7d、14d、28d、56d、84d各组病灶骨组织中H、R及Z的浓度,绘制药物浓度-时间曲线;使用DAS 3.2.1统计软件对药动学参数进行分析。结果:A组病灶骨组织中H、R及Z的浓度均在术后3d时达最高,此后随检测时间点的后移三种药物浓度均逐渐下降,至给药后84d时最低(H为6.69±1.42μg/ml;R为6.28±0.77μg/ml;Z为19.88±0.90μg/ml),三种药物浓度在各检测时间点均≥10倍的MIC(即杀菌浓度),对同种药物在不同时间检测的浓度进行两两比较,均有统计学意义(P<0.05);B组病灶骨组织中H、R及Z的浓度在术后3d时均明显增高,此后较快衰减,至给药后14d时三种药物浓度均检测不到,对同种药物在3d与7d检测的浓度进行比较,差异有统计学意义(P<0.05);C组及D组随检测时间点的后移,病灶骨组织中H、R及Z的药物浓度均维持在相对平稳的较低水平,对同组中同种药物在不同时间检测的浓度进行两两比较均无统计学意义(P>0.05),术后84d检测时C组H为3.21±0.32μg/ml、R为3.68±0.42μg/ml、Z为6.68±0.25μg/ml,D组H为3.24±0.33μg/ml、R为3.53±0.44μg/ml、Z为6.39±0.45μg/ml。对A、B、C、D四组同时间点同种药物浓度进行比较:C、D两组间同时间点同种药物浓度比较均无统计学差异(P>0.05);A组病灶骨组织中H、R及Z的浓度均高于C组及D组的浓度,84d检测时A组中的H、R及Z的浓度分别为C组的3.02、1.70及2.97倍,差异有统计学意义(P<0.05);A、C、D三组药物浓度-时间曲线平缓,均未见突释现象;B组存在明显突释现象,药物浓度衰减较快,术后14d后检测不到H、R及Z的浓度。药动学数据分析:A组的曲线下面积、生物半衰期均显著高于B组及C组,差异有统计学意义(P<0.05)。结论:复合HRZ/PLGA缓释抗结核药涂层材料在兔脊柱结核病灶局部可实现三药同时长程、高效、平缓释药。
OBJECTIVE: To observe the drug release characteristics of composite HRZ / PLGA sustained-release anti-TB drug coating in rabbit spinal tuberculosis. Methods: One hundred and twenty rabbits with spinal tuberculosis model were randomly divided into three groups according to different dosage forms and routes of INH, RIF and PZA. (Group A: local administration group); group B (local administration group); group C (intragastric administration group); group D (sham operation irrigation group Medicine group). Among them, A, B, C three groups of L4 / 5 spinal tuberculosis removal and autologous iliac bone graft, D group sham operation. The concentrations of H, R and Z in the bone tissues of the three groups at the 3d, 7d, 14d, 28d, 56d and 84d after operation were determined by HPLC, and the drug concentration-time curve was drawn. Using DAS 3.2.1 statistical software Pharmacokinetic parameters were analyzed. Results: The concentrations of H, R and Z in the bone tissue of group A reached the highest at 3d after operation, and then decreased gradually from the time of detection to the lowest at 84d (H was 6.69 ± 1.42μg / ml; R was 6.28 ± 0.77μg / ml; Z was 19.88 ± 0.90μg / ml). The concentrations of all three drugs were ≥10 times MIC (ie bactericidal concentration) The concentrations of H, R and Z in the bone tissue of group B were significantly increased at 3d postoperatively, and then decayed more rapidly afterwards. The difference was statistically significant (P <0.05) The concentrations of all three drugs were not detected at 14 days after administration. The concentrations of the same drugs detected at 3d and 7d were significantly different (P <0.05) After the shift, the concentration of H, R and Z in the lesion bone tissue was maintained at a relatively low level. There was no significant difference in the concentrations of H, R and Z in different groups (P> 0.05). In the 84th postoperative day, C was 3.21 ± 0.32μg / ml, R was 3.68 ± 0.42μg / ml, Z was 6.68 ± 0.25μg / ml, D was 3.24 ± 0.33μg / ml, R was 3.53 ± 0.44 μg / ml and Z was 6.39 ± 0. 45 μg / ml. A, B, C, D four groups at the same time point with the same drug concentrations were compared: C, D between the two groups at the same time the same drug concentrations were no significant difference (P> 0.05); A group of focal bone tissue The concentrations of H, R and Z in group C were higher than that in group C and group D. The concentrations of H, R and Z in group A were 3.02, 1.70 and 2.97 times of those in group C respectively at 84 days, with significant difference (P <0.05). The drug concentration-time curves in groups A, C and D were gentle, and no burst was observed. In group B there was obvious burst phenomenon, the drug concentration decayed rapidly, and H, R and Z concentrations. Pharmacokinetic data analysis: A area under the curve, biological half-life were significantly higher than the B group and C group, the difference was statistically significant (P <0.05). Conclusion: The composite HRZ / PLGA sustained-release anti-TB drug coating material can achieve long-term, high-efficiency and sustained release of three drugs simultaneously in the local spinal tuberculosis lesions in rabbits.