载三联抗痨药硫酸钙/聚氨基酸缓释材料在兔脊柱结核模型体内的缓释性能

摘要

BACKGROUND: Calcium sulfate/poly amino acid compound materials carrying triple anti-tuberculosis drugs have been proved to have excellent slow release performance based on our preliminary studies on the physical and chemical properties and the release properties of the compound materials.OBJECTIVE: To observe the slow release performance of the calcium sulfate/poly(amino acid) compound material carrying triple anti-tuberculosis drugs in a rabbit model of spinal tuberculosis.METHODS: Twenty-four New Zealand white rabbits were used to make L4-5 spinal tuberculosis models and divided into two groups in a random way following removal of tuberculosis lesions. Calcium sulfate/poly amino acid compound material carrying isoniazide, rifampicin, pyrazinamide or calcium sulfate/poly(amino acid)compound material with no drugs was implanted into the defect in the experimental or control group,respectively. At 2, 4, 6 and 8 weeks after implantation, the concentrations of isoniazid, rifampicin and pyrazinamide in the defect region, including the bone tissue, adjacent psoas major and inferior vena cava,were measured.RESULTS AND CONCLUSION: In the experimental group, the isoniazid levels in the damaged bone tissue and psoas major were kept in minimum bactericidal concentration (MBC) at 8 weeks after implantation and in the minimum inhibitory concentration (MIC) at the end of 12 weeks after implantation, while its level in the vein was kept in MBC at 2 weeks and in MIC at 8 weeks. The rifampicin levels in the bone tissue and psoas major were kept in MBC at 4 weeks after implantation and in the MIC at 8 weeks after implantation, while its level in the vein was kept MIC at 4 weeks.The pyrazinamide levels in the damaged bone tissue and psoas major were kept in MBC at 8 weeks after implantation and in the MIC until 8 weeks after implantation, while its level in the vein was kept MIC at 8 weeks. In the control group,there were no levels of isoniazid, rifampicin and pyrazinamide in the damaged bone tissue, adjacent psoas major and inferior vena cava in comparison with the baseline. These results show that isoniazid, rifampicin and pyrazinamide in the defect region can achieve sustained slow release in the rabbit model of spinal tuberculosis after implantation of the calcium sulfate/poly(amino acid) compound material carrying triple anti-tuberculosis drugs. In addition, the local drug concentration and duration in the defect region are better than those in the blood.%背景:前期研究已对载三联抗痨药硫酸钙/聚氨基酸人工缓释材料进行了理化性能、体内体外缓释释药性能等方面的深入研究,证实其具有良好的局部缓释性能.目的:探究在兔脊柱结核模型病灶中,载三联抗痨药硫酸钙/聚氨基酸人工缓释材料的药物缓释性能.方法:取24只新西兰大白兔,制作L4-5椎体脊柱结核模型,清除结核病灶后,随机分2组干预,实验组于骨缺损处植入载异烟肼、利福平、吡嗪酰胺三联抗痨药的硫酸钙/聚氨基酸人工骨材料,对照组植入硫酸钙/聚氨基酸人工骨材料.植入后2,4,6,8周,检测植骨处骨质及邻近腰大肌组织、下腔静脉血中异烟肼、利福平、吡嗪酰胺的浓度.结果与结论:实验组中,①异烟肼植入后8周在病椎骨和腰大肌中仍可维持最低杀菌浓度,植入后12周时尚处于最低抑菌浓度;在静脉血中最低杀菌浓度仅可持续2周,最低抑菌浓度仅可维持到植入后第8周;②利福平植入后4周在腰大肌和病椎骨组织中可为最低杀菌浓度,最低抑菌浓度能持续到植入后8周;静脉血中最低抑菌浓度度仅可持续到植入后4周;③吡嗪酰胺在腰大肌和病椎骨组织中最低杀菌浓度可持续到植入后8周,最低抑菌浓度度可持续到植入后12周;而静脉血中药物浓度到植入后8周仍可达到最低抑菌浓度.对照组植骨处骨质、下腔静脉血及邻近腰大肌标本中均未检测到相关药物浓度,其结果可用于基线校对.结果表明,在兔脊柱结核模型病椎缺损处植入载三联抗痨药硫酸钙/聚氨基酸人工缓释材料后,3种抗痨药物均可持续、缓慢释放,局部药物浓度及持续时间均高于全身血液中的浓度和持续时间.