The slow release performance of calcium sulfate/poly(amino acid) compound materials carrying triple anti-tuberculosis drugs in a rabbit model of spinal tuberculosis

doi:10.3969/j.issn.2095-4344.2017.10.008

Abstract

Abstract:

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.

Key words: Calcium Sulfate, Isoniazid, Rifampin, Tissue Engineering

CLC Number:

R318

Wang Qian1, Geng Guang-qi2, Cong Xiao-ming3, Liu Hai-tao2, Shi Jian-dang2, Wang Zi-li2, Ma Wen-xin2, Sun Yu-hang4 . The slow release performance of calcium sulfate/poly(amino acid) compound materials carrying triple anti-tuberculosis drugs in a rabbit model of spinal tuberculosis[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(10): 1520-1526.

Figures/Tables 6

由实验组HPLC色谱图可知，吡嗪酰胺的出峰时间约为2.7 min，异烟肼的出峰时间约为3.4 min，利福平的出峰时间约为8.9 min (图1-3)。对照组未检测到抗痨药物浓度，测得色谱图用于基线校对。文献表明，异烟肼对结核杆菌的最低抑菌浓度为 0.02-0.05 mg/L，最低杀菌浓度为10倍的最低抑菌浓度[18-19]；利福平对结核分枝杆菌和其他分枝杆菌的最低抑菌浓度为0.39-1.56 mg/L、最低杀菌浓度为0.78-3.125 mg/L；吡嗪酰胺的最低抑菌浓度还存在争议，当在pH=5.5的环境中的最低抑菌浓度为12.5 mg/L，在50 mg/L时即有杀灭结核分枝杆菌的功效。异烟肼植入后2周时，在静脉血、病灶骨组织及腰大肌中均达到最低杀菌浓度；植入后4，8周时，在病灶骨组织及腰大肌中达到最低杀菌浓度，在静脉血中仅达到最低抑菌浓度；植入后12周时，病灶骨组织及腰大肌中达到最低抑菌浓度，而静脉血中未测到。植入后2，4周时，利福平在病灶骨组织及腰大肌中均可达到最低杀菌浓度，但在静脉血中仅仅达到最低抑菌浓度的水平；植入后8周时，在病灶骨组织及腰大肌中仍然可达到最低抑菌浓度，而此时静脉血中未达到最低抑菌浓度；植入后12周时，在病灶骨组织中可检测到存在，但未达到最低抑菌浓度水平，而腰大肌及静脉血中未测到利福平。植入后2，4，8周时，吡嗪酰胺在病灶骨组织及腰大肌中均达到最低杀菌浓度水平，同时在静脉血中也均达到最低抑菌浓度水平；植入后12周时，在病灶骨组织及腰大肌中仍然能够达到最低抑菌浓度水平，此时在静脉血中吡嗪酰胺未达到最低抑菌浓度水平。使用Kruskal-Wallis H 检验，当P < 0.01时，按照a=0.05的水准，则认为同一时间两个样本药物浓度存在统计学意义。然后用Nemenyi法进行两两样本之间的比较，采用a=0.05的水准，认为同一时间腰大肌与病灶骨组织中药物浓度没有差别，而同一时间病灶骨组织中的药物浓度高于同期静脉血中的药物浓度，同时同一时间腰大肌中药物浓度则要高于同期静脉血中的药物浓度。 "

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