本文選題：達(dá)氟沙星　切入點(diǎn)：鼠傷寒沙門(mén)氏菌　出處：《揚(yáng)州大學(xué)》2017年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：達(dá)氟沙星屬于第三代氟喹諾酮類(lèi)動(dòng)物專(zhuān)用抗菌藥,具有抗菌譜廣、殺菌活性強(qiáng)、藥動(dòng)學(xué)特征優(yōu)良等特點(diǎn)。目前已被眾多國(guó)家批準(zhǔn)用于牛、豬、雞等動(dòng)物,治療由細(xì)菌或支原體引起的感染。目前關(guān)于達(dá)氟沙星的藥動(dòng)學(xué)及藥效學(xué)研究在豬、雞、鱘等動(dòng)物有較多報(bào)道,但是在小型哺乳動(dòng)物的報(bào)道較少。為此,本文開(kāi)展了達(dá)氟沙星在家兔對(duì)鼠傷寒沙門(mén)氏菌的體內(nèi)藥動(dòng)藥效(PK/PD)同步模型的研究,以期獲得達(dá)氟沙星的PK/PD參數(shù),為制定達(dá)氟沙星在家兔的合理給藥方案,防止耐藥性的產(chǎn)生提供試驗(yàn)依據(jù)。首先,進(jìn)行了達(dá)氟沙星對(duì)鼠傷寒沙門(mén)氏菌的體外藥效學(xué)研究。結(jié)果顯示,達(dá)氟沙星在以LB培養(yǎng)基和兔血清為基質(zhì)時(shí)對(duì)鼠傷寒沙門(mén)氏菌的MIC均為0.0625μg/mL,MBC 均為 0.125μg/mL(2×MIC),同時(shí)測(cè)得 MPC 為 0.5μg/mL(8×MIC)。達(dá)氟沙星對(duì)鼠傷寒沙門(mén)氏菌的體外殺菌曲線顯示,當(dāng)藥物濃度升高,其殺菌效果也逐漸增強(qiáng),說(shuō)明達(dá)氟沙星對(duì)鼠傷寒沙門(mén)氏菌為濃度依賴(lài)型殺菌藥。其次,通過(guò)在健康家兔耳緣靜脈注射鼠傷寒沙門(mén)氏菌,建立了家兔鼠傷寒沙門(mén)氏菌感染模型。感染后的家兔體內(nèi)各臟器載菌量達(dá)106CFU/mL,滿(mǎn)足后續(xù)試驗(yàn)要求。鼠傷寒沙門(mén)氏菌感染兔經(jīng)口服用不同劑量(1、10、30mg/kgb.w.)的達(dá)氟沙星,研究達(dá)氟沙星在感染家兔體內(nèi)的藥動(dòng)學(xué)特征。結(jié)果表明,低、中、高劑量組 T1/2β 分別為 15.30±6.09h、14.01±9.34h、11.38±3.16h;AUC 分別為2.37±0.64μg·h/mL、14.74±4.94μg·h/mL、36.07±3.65μg·h/mL;Cmax分別為0.18±0.04μg/mL、1.80±0.98μg/mL、3.49±0.91μg/mL;Tmax 分別為:1.60±0.55h,1.80±1.30h和1.40±0.55h。且達(dá)氟沙星在1～30 mg/kg劑量范圍內(nèi),藥動(dòng)學(xué)參數(shù)AUC24h與給藥劑量呈線性關(guān)系。通過(guò)活菌計(jì)數(shù)測(cè)定家兔按30、20、15、10、7.5、5、2.5、1和Omg/kg給藥前后鼠傷寒沙門(mén)氏菌的載菌量。利用Sigmoid Emax模型將參數(shù)AUC24h/MIC與給藥前后載菌量的變化進(jìn)行擬合。發(fā)現(xiàn)AUC24h/MIC與達(dá)氟沙星在鼠傷寒沙門(mén)氏菌感染兔體內(nèi)的抗菌活性有著顯著的相關(guān)性,血液、肝、脾、肺的R2分別為0.8971、0.9186、0.9581、0.8708。最后研究表明當(dāng)AUC24h/MIC為177.14時(shí),可使鼠傷寒沙門(mén)氏菌減少3Logi0CFU/mL,此時(shí)達(dá)氟沙星對(duì)細(xì)菌產(chǎn)生殺菌作用。
[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 鹵6.09hmL 14.01 鹵9.34hU 11.38 鹵3.16hAUC 2.37 鹵0.64 渭 g 路hmL-1 路hmL-1 = 14.74 鹵4.94 渭 g 路hmL ~ (-1) 鹵3.65 渭 g 路hmL ~ (-1) Cmax = 0.18 鹵0.04 渭 g 路mL ~ (-1) 1.80 鹵0.98 渭 g / mL ~ (3.49 鹵0.91) 渭 g 路mL ~ (-1) T _ (Tmax), respectively, were 1.60 鹵0.60 鹵0.80 鹵1.30 h and 1.40 鹵0.55 h, respectively, and the dose of fluoxacin in the range of 130 渭 g 路mL ~ (-1) mg/kg was 1.80 鹵0.98 渭 g 路mL ~ (-1) 鹵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.
【學(xué)位授予單位】：揚(yáng)州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：S859.7

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