达氟沙星在家兔对鼠伤寒沙门氏菌的体内药动药效同步模型研究

发布时间：2018-03-16 20:45

本文选题：达氟沙星　切入点：鼠伤寒沙门氏菌　出处：《扬州大学》2017年硕士论文　论文类型：学位论文

【摘要】：达氟沙星属于第三代氟喹诺酮类动物专用抗菌药,具有抗菌谱广、杀菌活性强、药动学特征优良等特点。目前已被众多国家批准用于牛、猪、鸡等动物,治疗由细菌或支原体引起的感染。目前关于达氟沙星的药动学及药效学研究在猪、鸡、鲟等动物有较多报道,但是在小型哺乳动物的报道较少。为此,本文开展了达氟沙星在家兔对鼠伤寒沙门氏菌的体内药动药效(PK/PD)同步模型的研究,以期获得达氟沙星的PK/PD参数,为制定达氟沙星在家兔的合理给药方案,防止耐药性的产生提供试验依据。首先,进行了达氟沙星对鼠伤寒沙门氏菌的体外药效学研究。结果显示,达氟沙星在以LB培养基和兔血清为基质时对鼠伤寒沙门氏菌的MIC均为0.0625μg/mL,MBC 均为 0.125μg/mL(2×MIC),同时测得 MPC 为 0.5μg/mL(8×MIC)。达氟沙星对鼠伤寒沙门氏菌的体外杀菌曲线显示,当药物浓度升高,其杀菌效果也逐渐增强,说明达氟沙星对鼠伤寒沙门氏菌为浓度依赖型杀菌药。其次,通过在健康家兔耳缘静脉注射鼠伤寒沙门氏菌,建立了家兔鼠伤寒沙门氏菌感染模型。感染后的家兔体内各脏器载菌量达106CFU/mL,满足后续试验要求。鼠伤寒沙门氏菌感染兔经口服用不同剂量(1、10、30mg/kgb.w.)的达氟沙星,研究达氟沙星在感染家兔体内的药动学特征。结果表明,低、中、高剂量组 T1/2β 分别为 15.30±6.09h、14.01±9.34h、11.38±3.16h;AUC 分别为2.37±0.64μg·h/mL、14.74±4.94μg·h/mL、36.07±3.65μg·h/mL;Cmax分别为0.18±0.04μg/mL、1.80±0.98μg/mL、3.49±0.91μg/mL;Tmax 分别为:1.60±0.55h,1.80±1.30h和1.40±0.55h。且达氟沙星在1～30 mg/kg剂量范围内,药动学参数AUC24h与给药剂量呈线性关系。通过活菌计数测定家兔按30、20、15、10、7.5、5、2.5、1和Omg/kg给药前后鼠伤寒沙门氏菌的载菌量。利用Sigmoid Emax模型将参数AUC24h/MIC与给药前后载菌量的变化进行拟合。发现AUC24h/MIC与达氟沙星在鼠伤寒沙门氏菌感染兔体内的抗菌活性有着显著的相关性,血液、肝、脾、肺的R2分别为0.8971、0.9186、0.9581、0.8708。最后研究表明当AUC24h/MIC为177.14时,可使鼠伤寒沙门氏菌减少3Logi0CFU/mL,此时达氟沙星对细菌产生杀菌作用。
[Abstract]:Dafloxacin belongs to the third generation fluoroquinolones animal specific antimicrobial agents, with wide antibacterial spectrum, strong bactericidal activity, excellent pharmacokinetic characteristics, and has been approved by many countries for use in cattle, pigs, chickens and other animals. Treatment of infections caused by bacteria or mycoplasma. Pharmacokinetic and pharmacodynamic studies of dafloxacin have been reported in pigs, chickens, Sturgeon and other animals, but less in small mammals. In order to obtain the PK/PD parameters of dafloxacin in rabbits, the pharmacokinetic effect of dflufloxacin against Salmonella typhimurium was studied in this paper. First, the pharmacodynamics of dafloxacin against Salmonella typhimurium in vitro was studied. The MIC of dafloxacin against Salmonella typhimurium in LB medium and rabbit serum was 0.0625 渭 g / mL 路min ~ (-1) 0.125 渭 g 路mL ~ (-1) 路min ~ (2) 路min ~ (-1), and the MPC was 0.5 渭 g / m ~ (L ~ (-1)) 8 脳 m 路min ~ (-1). The bactericidal curve of dafloxacin against Salmonella typhimurium in vitro showed that when the drug concentration was increased, The bactericidal effect of dafloxacin against Salmonella typhimurium was also gradually enhanced, indicating that dafloxacin was a dose-dependent bactericidal agent against Salmonella typhimurium. Secondly, salmonella typhimurium was injected intravenously into the ear of healthy rabbits. The infection model of Salmonella typhimurium in rabbits was established. The amount of bacteria carried in the organs of rabbits after infection was 106 CFU / mL, which met the requirements of subsequent tests. The rabbits infected with Salmonella typhimurium were orally infected with dafloxacin at different doses of 1010mg / kgb.w.@@. The pharmacokinetic characteristics of dafloxacin in infected rabbits were studied. The results showed that T 1 / 2 尾 in low, medium and high dose groups were 15.30 卤6.09hmL 14.01 卤9.34hU 11.38 卤3.16hAUC 2.37 卤0.64 渭 g 路hmL-1 路hmL-1 = 14.74 卤4.94 渭 g 路hmL ~ (-1) 卤3.65 渭 g 路hmL ~ (-1) Cmax = 0.18 卤0.04 渭 g 路mL ~ (-1) 1.80 卤0.98 渭 g / mL ~ (3.49 卤0.91) 渭 g 路mL ~ (-1) T _ (Tmax), respectively, were 1.60 卤0.60 卤0.80 卤1.30 h and 1.40 卤0.55 h, respectively, and the dose of fluoxacin in the range of 130 渭 g 路mL ~ (-1) mg/kg was 1.80 卤0.98 渭 g 路mL ~ (-1) 卤0.98 渭 g 路mL ~ (-1). The pharmacokinetic parameter AUC24h was linearly related to the dosage of the drug. The bacterial load of Salmonella typhimurium was determined by counting live bacteria in rabbits before and after the administration of Omg/kg and the Omg/kg. The Sigmoid Emax model was used to determine the changes of the parameters AUC24h/MIC and the amount of bacteria loaded before and after administration of the drug. It was found that there was a significant correlation between AUC24h/MIC and the antibacterial activity of dafloxacin in rabbits infected with Salmonella typhimurium. The R2 of blood, liver, spleen and lung were 0.8971 1, 0.918 6, 0.958 1 and 0.8708 respectively. The results showed that when AUC24h/MIC was 177.14, Salmonella typhimurium could be reduced by 3 Logi0CFU / mL, and dafloxacin had bactericidal effect on bacteria.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S859.7

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