【作者】 张秀英；

【导师】 佟恒敏；

【作者基本信息】 东北农业大学 ， 基础兽医学， 2001， 博士

【摘要】 本文以HPLC法为药物浓度定量手段，应用MCPKP房室分析程序处理药物浓度时间数据，采用试管二倍稀释法研究了单诺杀星对鸡败血支原体与大肠杆菌的体外抗菌活性；在240只健康和支原体--大肠杆菌合并感染鸡体内的血药动力学特征、生物利用度及组织动力学特征；对210只人工合并感染支原体与大肠杆菌鸡的药效试验。并采用回归分析法研究了血药浓度与组织药物浓度间的相关性。 体外抑菌试验的结果表明：支原体和大肠杆菌对单诺沙星高度敏感。单诺沙星对MGs₆和大肠杆菌O₇₈的体外MIC值均为0.063μg/ml。其抗菌活性分别是对照药恩诺沙星的2倍和4倍，是泰乐菌素的8倍和16倍。60只健康鸡和60只支原体-大肠杆菌合并感染鸡按5mg/kg剂量静注单诺沙星，其药时数据符合无吸收开放式二室模型。主要动力学参数是：t_1/2α为0.3400和0.5034h，t_{1 2β}为7.3184和6.8485h，AUC为3.2872和4.0633mg/l.h，Vd为16.0631和12.1604L/kg，Cl_B为1.5211和1.23051/kg/h。60只健康鸡和60只合并感染鸡口服相同剂量单诺沙星后，血浆的药时数据符合一级吸收二室模型。肝脏、肾脏、心脏、肺脏的药时数据符合一级吸收三项指数方程；心脏的药时数据符合一级吸收二项指数方程。健康鸡血浆、肝脏、肾脏、心脏、肺脏及肌肉的主要动力学参数是：t_{1 2ka}分别为0.2428、0.3524、0.3541、0.2643、0.3377和0.2536（h）。t_1/2α分别为0.8917、1.1212、0.7189、1.6142和0.4437（h）。t_{1 2β}分别为8.7936、3.6025、4.4570、10.2940、4.3283和5.9578（h）。Tp分别为0.9377、1.0665、0.9362、0.9993、0.9962和1.4381（h）。C_max分别为0.5487、2.8419、2.4295、0.2668、1.7042和0.2726（μg/ml）。AUC分别为3.0523、13.586、10.4180、2.1521、9.6888、2.7157（mg/l.h）。T_cp分别为12.613、18.0730、18.8790、8.0557、19.693、13.8600（h）。 合并感染鸡血浆、肝脏、肾脏、心脏、肺脏及肌肉的主要动力学参数是：t_{1 2ka}分别为0.3182、0.1743、0.2579、0.2507、0.3335、0.1841（h）。t_1/2α分别为1.5502、1.1916、1.2122、0.8186、1.7968（h）。t_{1 2β}分别为12.6200、3.9086、4.6030、11.5326、4.5960、5.9457（h）。Tp分别为1.1107、0.8125、0.9286、0.9705、1.2661、1.2211（h）。Cmax分别为0.5106、2.7711、2.3652、0.207、1.6616、0.2367（μg/ml）。AUC分别为3.6602、13.82、10.0830、1.8005、11.1520、2.2956（mg/l.h）。Tcp分别为13.046、9.6900、17.5330、6.5973、20.826、12.408（h）。 单诺沙星在健康鸡体内的药动学特征是：内服吸收迅速且完全，体内分布广泛，博土学位论文 单诺沙星在健康和支原体－大肠杆菌感染鸡的药动学与药效学研究 东北农业大学一消除缓慢，生物利用度高。组织动力学的研究结果表明，组织中的药物浓度以肝脏、肾脏浓度最高，其次是肺脏，均显著高于血浆中的药物浓度，心脏、肌肉中浓度最低。除心脏外，其余组织的有效浓度维持时间均显著长于血浆。根据药物消除规律推算出血浆及组织中药物浓度降至 0．01 m／ml所需的时间，健康鸡血液、肝脏、肾脏、心脏、肺脏及肌肉分别为：34．代、28．IO、28．55、肘．95、30．咒、34．扰(m：病鸡所需的时间分别为 47，8、31．68、29．65、38．36、34．29、34．42（h）。药物在血浆和心脏中残留的时间最长。鸡败血支原体与大肠杆菌合并感染使肝脏、肾脏、肺脏的分布半衰期、血浆和组织消除半衰期、有效浓度维持时间及药物在组织中的残留时间延长。肺脏的曲线下面积增加。肝脏、肾脏、肺脏有效浓度维持时间分别比血浆长 6．644、4 487。7．78（h） 210只30 日龄的雏鸡人工感染支原体－大肠秆菌后，应用单诺沙星、恩诺沙星和泰乐菌素饮水治疗的试验结果表明：25、50、100mg／L的单诺沙星连续饮水五天，对合并感染有显著的疗效。在治愈率、有效率、增重、减少死亡率、抗体反应阳性率、气囊损伤率和病原分离数量方面相当或忧于50mg／L恩诺沙星，优于500mg／L的泰乐菌素。 对血药浓度与组织药物浓度进行回归分析的结果表明，血药浓度与组织药物浓度间存在着显著的相关性。曲线回归的效果优于直线回归。根据药动学方程和回归方程可以间接预测组织含药量。 根据药动学与药效学的研究结果制订出单诺沙星的临床用药方案为；按 sing／kg b．w．剂量每隔12h内服一次，连用3天：也可将药物以25－50mg几饮水或50－100my屿混饲。更多还原

【Abstract】 In this paper, the vitro activity of danofloxacin against MGs~ and E. Coil. 078 were determined by tube-test serial two fold dilution; plasma pharmacokinetic test bioavailability tissue kinetics of danofloxacin in 240 healthy and M6-E. Coil infected chickens were investigated by using the HPLC method: and therapeutic efficacy of danofioxacin on 210 chickens infected with MG-E.Coil. were studies following oral administration through drinking water, The concentrations versus time data were analyzed using MCPKP pharmacokintic programs0 The dynamic interrelated analysis of danofloxacin levels between plasma and tissues were performed with pharmacokintic method and regression analysis method0 The indirectly predictive equations about the drug concentration in tissue were established,, The results of in vitro activity of danofloxacin indicated that MGs6 and E. Coil.078 were high sensitive to danofloxacin and the MICs were 0.063 3.?g/ml, The vitro activity of danofloxacin were 2 times and 4 times stronger than that of enofloxacin, 8 times and 16 times stronger than that of tylosin, respectively. Following administration danofloxacin intravenously, the concentrations versus time data in healthy and infected chickens (60 each of group) were fitted with a two- compartment model with .?- The main phamacokintic parameters were as following: ta.,. were 0.3400 and 0.5034h; t1128were 7.3 184 and 6.8485h; AUC were 3.2827 and 4.0633mg/1.h: Vd were 16.0631 and 12.1604L/kg; Cl5 were 1.5211 and I .2305L/kg/h.The pharmacokinetics of danofloxacin in plasma and tissues following oral administration5mg/kg were investigated in another two same number groups The concentration-time course in the plasma could be described by two-compartment open model with first 梠rder absorption rate. The concentrations-time course of the liver, kidney and lung were conformed to following triexponential equation; and the muscle performed to bioexponential equation. The main kinetic parameters for the plasma, liver, kidney. heart, 3 lung and muscle in the healthy chickens were as following , respectively: 0. 2428, 0. 3524,0. 3541, 0. 2643, 0. 3377and 0. 2536 (hX t100: 0.8917 ,1.1212,0.7189,l.6142 and 0.4437 (h)0 t1 2~: 8. 7936, 3. 6025, 4. 4570, 10. 2940, 4. 3283 and 5. 9578 (h)0 Tp:0. 9377, 1. 0665, 0. 9362, 0. 9993, 0. 9962 and 1. 4381 (h)0 Cniax :0. 5487 , 2. 8419, 2. 4295, 0. 2668, 1. 7042 and 0. 2726 (~ g/ml) AUC:3.0523, 13.586,10.4180,2.1521,9.6888 and 2.7157(mg/1.h)0 Tcp:12. 613, 18. 0730, 18. 8790, 8. 0557, 19. 693 and 13. 8600~ The main kinetic parameters of the infected chickens for the plasma. liver, kidney. heart. lung and muscle were as following , respectively: 0. 3182, 0. 1743, 0. 2579, 0. 2507, 0. 3335 and 0. 1841 (h)0 t1!20: 1. 5502, 1. 1916, 1.2122,0.8186 and 1. 7968 (h)0 t ~ 12.6200,3.9086,4. 6030, 11. 5326,4. 5960 and 5.9457 (h)~ Tp: 1. 1107,0.8125,0.9286,0.9705. 1.2661 and 1.2211 (h)0 Ctnax: 0. 5106, 2. 7711, 2. 3652,0. 207, 1. 6616 and 0.2367 ( ~g/m1) AUC: 3. 6602, 13. 82, 10. 0830, 1. 8005, 11. 1520 and 2. 2956 (mg/I. h). Tcp: 13. 046, 9. 6900, 17. 5330, 6. 5973, 20. 826 and 12. 408 (hX The pharmacokintic characteristics of danofloxacin in the healthy chickens were as following: it was absorbed rapidly and completely; distributed widely; eliminated slowly; and had excellent bioavailiability following oral administration. The results of tissues kin更多还原