用微透析法研究肺炎大鼠灌胃左氧氟沙星的肺部药动学

目的：观察肺炎大鼠模型灌胃左氧氟沙星后在肺组织中的药动学特点.方法：以肺炎链球菌诱导肺炎大鼠模型,之后灌胃左氧氟沙星42 mg/kg.采用微透析技术对大鼠血液和肺组织同步取样,以HPLC法测定血液和肺组织中的药物浓度,计算左氧氟沙星的主要药动学参数和肺组织穿透率.结果：血液和肺组织中的药物浓度变化趋势一致.从第20 min开始,肺组织中的药物浓度始终高于血药浓度.左氧氟沙星的肺组织穿透率为（1.17±0.06）.在血液和肺组织的主要药动学参数分别为：tmax（46.67±20.82）和（43.33±23.09） min,cmax（1.29±0.41）和（1.56±0.70） μg/ml,t12（534.38±381.64）和（591.38±416.08） min,AUCinf（920.33±473.56）和（1196.23±992.35） μg·min·ml-1,在肺组织的分布系数为（1.22±0.56）.结论：肺炎大鼠模型灌胃左氧氟沙星后具有良好的肺组织穿透率和分布系数.     

羟考酮对左旋氧氟沙星在人体内药物动力学的影响

目的研究羟考酮对左旋氧氟沙星(LVFX)在人体内药物动力学的影响。方法8名健康志愿者,单用LVFX或合用羟考酮,用HPLC法测定血药浓度。结果单用LVFX500mg后的药物动力学参数分别为tmax(1.562±1.050)h,cmax(6.6419±0.15860)μg/ml,AUC(47.65±11.29)h*μg/ml,T1/2(β)(7.034±0.941)h;合用羟考酮时,LVFX的药物动力学参数分别为tmax(1.125±0.641)h,cmax(7.652±2.594)μg/ml,AUC(48.74±10.58)h*μg/ml,T1/2(β)(6.275±0.588)h。两者除T1/2ka和cmax外,无显著性差异。结论羟考酮对LVFX在人体内药物动力学参数无影响。     

HPLC法测定血浆中左氧氟沙星及其人体药动学研究

目的 建立人血浆中左氧氟沙星的HPLC-UV测定法,测定健康志愿者口服左氧氟沙星片200 mg后的药代动力学参数,并评价其与参比制剂的生物等效性.方法 血浆样品以20%高氯酸沉淀后,直接取上清液进行PHLC分析,流动相为水：乙腈：三乙胺：冰乙酸（81∶19∶0.5∶1,v/v/v/v）.20名志愿者交叉口服左氧氟沙星片试验和参比制剂200mg,用HPLC法测定血药浓度,计算主要药代动力学参数及相对生物利用度,以判断其生物等效性.结果 在0.05～5μg·mL^-1范围内左氧氟沙星峰面积与浓度呈良好的线性关系,左氧氟沙星片受试制剂和参比制剂的t1/2分别为（6.46±0.77）h和（6.58±1）h,峰浓度分别为（2.74±0.75）μ g·mL^-1和（2.55±0.54）μg·mL^-1,达峰时间分别为（0.9±0.3）h和（1.0±0.5）h.以AUC0-24计算的供试制剂相对生物利用度为（105.55±12.30）%.结论 本文建立的HPLC测定方法灵敏、准确、简便,药动学统计数据表明两种左氧氟沙星片生物等效.     

左旋氧氟沙星血药浓度测定及药物动力学

目的:测定国产左旋氯氟沙星胶囊po后在人体内的药物动力学.方法:10例健康志愿受试者,单次po国产左旋氯氟沙星胶囊,用反相高效液相色谱法测定血浆中药物浓度.结果:左旋氧氟沙星药物动力学参数分别为:C_(?)=(2.12±0.21)μg/ml,t_(?)=(1.16±0 18)h,T_(1/2α)=(1.50±0.65)H,T_(1/2β)=(6.16±1.15)h,CL=(16.27±2.15)L/h,V_d=(70.33±10.94)L,AUC_(0→∞)=(13.72±1.03)(Mg/L)·h.结论:国产左旋氧氟沙星胶囊的主要药物动力学参数与国外文献报道基本一致.     

桔梗总皂苷对左氧氟沙星在小鼠体内的药动学及组织分布的影响

目的 采用高效液相色谱（HPLC）法测定小鼠血浆及组织中左氧氟沙星含量,研究桔梗总皂苷对其药动学规律及组织分布的影响。方法 180只昆明小鼠随机分为两组,组Ⅰ为单独ig左氧氟沙星78 mg/kg,组Ⅱ为同时ig桔梗总皂苷65 mg/kg与左氧氟沙星78 mg/kg,采用HPLC法测定给药5、15、30、45 min及1、1.5、2、4、8 h后的血浆及肝、肺、肾组织样品中的左氧氟沙星浓度。结果 血浆中内源性物质对待测物无干扰;血浆及各组织在检测浓度范围内呈良好线性关系（r²>0.999）;方法日内和日间精密度、稳定性及提取回收率均符合生物样品检测标准;组ⅠAUC_0-t为（143.593±16.56）,组ⅡAUC_0-t为（120.339±15.542）,与组Ⅰ比较,组Ⅱ的AUC明显减小,T_1/2Z显著缩短,T_max明显延长,CLz/F显著增加,C_max及Vz/F无显著性差异;肝、肺、肾组织中左氧氟沙星浓度均迅速提高并快速消除,肺组织中消除速度最快,肺中AUC减少最为明显。结论 合用时,桔梗总皂苷使左氧氟沙星在小鼠体内消除速率明显加快,肺组织中尤为明显,故左氧氟沙星在联合含有桔梗成分的中药治疗肺部疾病时,建议分开服用。     

反相高效液相色谱法测定犬血浆中左氧氟沙星浓度及其犬体内药代动力学

目的 :建立测定犬体内左氧氟沙星血药浓度的反相高效液相色谱法 ,并测定其犬体内药代动力学。方法 :以环丙沙星为内标 ,采用 10 %高氯酸为沉淀剂处理犬血浆样品 ,色谱柱为DIKMADiamon silTM C18,5m ,15 0mm× 4 .6mm ,流动相为甲醇 PBS 三乙胺 异丙醇 (33 6 7 0 .14 0 .4 ,用磷酸调pH为 3.0 ) ,流速 1.2ml·min-1,柱温 2 0℃ ,荧光检测(λex=2 95nm ,λem=4 40nm)。结果 :血药浓度线性范围 0 .2 5～ 5 0mg·L-1(r =0 .9998) ,最低检测限浓度为 0 .0 2mg·L-1(S N >3) ,绝对回收率为 83.0 %～85 .6 % (n =5 ) ,方法回收率为 92 .10 %～ 10 6 .77%(n =5 ) ,日内和日间RSD分别为 1.3%～ 4 .0 %和1.8%～ 8.2 % (n =5 )。结论 :本方法简便、灵敏、精密度高 ,重现性好 ,适用于左氧氟沙星犬体内药代动力学研究及生物等效性研究     

乳酸左旋氧氟沙星胶囊人体生物利用度及其药物动力学

目的 :研究左旋氧氟沙星胶囊的生物利用度及其药物动力学。方法 :HPLC法测定 10名健康受试者口服单剂量乳酸左旋氧氟沙星的药 时数值 ,以PKBP N1程序拟合其药动学参数 ,采用梯形面积法计算其相对生物利用度 ,用方差分析和双单侧t检验法检验其等效性。结果 :乳酸左旋氧氟沙星的片剂和胶囊的药动学参数分别为 :Tmax为 (1.0 8± 0 .31)h和 (0 .78± 0 .14)h ,Cmax为 (2 .0 7± 0 .30 ) μg·ml-1和 (2 .16± 0 .18) μg·ml-1,T1/ 2 为 (7.8± 0 .7)h和 (7.6± 0 .4)h ,AUC0 ∞ 为 (13.4± 2 .1) μg·h·ml-1和 (13.5± 2 .9) μg·h·ml-1。用方差分析和双单侧t检验法检验其Tmax,Cmax,T1/ 2 和AUC ,除Tmax(P <0 .0 5 )外 ,其它药动学参数差异均无显著性。结论 :两种制剂相对生物利用度为 (10 0 .8± 13.1) % ,经方差分析和双单侧t检验法检验 ,结果为等效制剂     

加替沙星与左氧氟沙星治疗呼吸道细菌感染的疗效比较

目的:比较加替沙星与左氧氟沙星治疗敏感性细菌引起的呼吸道感染的疗效与安全性。方法:以左氧氟沙星为对照,在30例受试者中进行了随机双盲、双模拟、平行对照试验。A组15例,每日给予加替沙星4 0 0 m g口服。B组15例,每日给予左氧氟沙星4 0 0 mg口服,治疗7d～14 d。结果:A组患者用药后临床痊愈率10 0 % ,有效率10 0 % ,B组患者用药后临床痊愈率93% ,有效率93%。两组疗效比较,差异无显著性(P>0 .0 5 )。A组与B组的细菌清除率均为10 0 % (P>0 .0 5 ) ,两组不良反应发生率分别为13%与8% (P>0 .0 5 )。结论:加替沙星治疗呼吸道感染疗效及安全性与左氧氟沙星相似。     

左氧氟沙星对多索茶碱在健康人体内药动学的影响

目的研究合用左氧氟沙星对健康受试者多索茶碱血药浓度和药动学的影响。方法对10名男性健康受试者采用自身对照交叉试验设计方法给药,用高效液相色谱(HPLC)法测定多索茶碱血药浓度,采用3P97软件进行数据处理,求出药动学参数。结果合用左氧氟沙星组(试验组)多索茶碱平均血药浓度在停药后0～6 h各时间点(除停药后15 min)与单用多索茶碱组(对照组)相比均无显著差异(P>0.05);对照组和试验组多索茶碱的t_(+β)分别为(1.20±s 0.08)、(1.40±0.25)h;AUC分别为(16±4)、(17±3)mg·h·L~(-1);CL分别为(35±6)、(35±10)L·h~(-1);t_(+α)分别为(0.052±0.013)、(0.33±0.27)h;V_d分别为(6.1±2.1)、(34±30)L。合用左氧氟沙星后多索茶碱的V_D和t_(+α)的增加有显著差异(P<0.05),其余药动学参数在2组间均无显著差异(P>0.05)。结论合用左氧氟沙星对多索茶碱的代谢动力学无影响,但可改变其分布动力学,增大t_(+α)和V_d,2药合用不会引起多索茶碱的体内蓄积,提示2药合用相对安全。     

Clinical efficacy of piperacillin/tazobactam in the treatment of complicated skin and soft tissue infections

Introduction: Complicated skin and soft tissue infections (cSSTIs) are skin and soft tissue infections (SSTIs) that involve deep soft tissue. cSSTIs often require surgical intervention and/or hospitalization. cSSTIs are associated with significant mortality and morbidity, and carry a significant burden on health care systems. Piperacillin/tazobactam has been regarded as a standard treatment for cSSTIs because of its antibiotic spectrum, safety and clinical efficacy. Several antibiotics, as compared to piperacillin/tazobactam, have been evaluated in the treatment of cSSTIs.

Areas covered: This review summarizes randomized controlled trials (RCTs) evaluating the clinical efficacy of piperacillin/tazobactam for the treatment of cSSTIs.

Expert opinion: Piperacillin/tazobactam, which covers most causative organisms in cSSTIs, is the drug of choice for the treatment of cSSTIs. Other options such as ertapenem and moxifloxacin may be reasonable where multiple daily dosing or intravenous administration is inappropriate. But in general, they should be avoided as an empirical treatment because of their highly association with resistant bacteria, which are becoming a global threat. Therefore, piperacilin/tazobactam is appropriate as an empirical therapy for the treatment of SSTIs and should be de-escalated as soon as causative organisms are identified, their drug-sensitivity results are available, and clinical condition becomes stable.     

In vitro pharmacokinetics and pharmacodynamics of levofloxacin against plasmid-mediated quinolone resistant Escherichia coli

AIM： Bacterial resistance to quinolones has traditionally mediated by alteration of the quinolone targets and/or overproduction of efflux pump. Recently, a new mechanism, the plasmid-mediated quinolone resistance named qnr, has been clarified. Qnr and its homologus are widely distributed among gram-negative bacteria. The presence of qnr only slightly elevates the resistance level, however it facilitates the selection of highly resistant strains. In our study, we examined the probable influence of such phenomenon to the clinical regimens of levofloxacin. METHODS： Invitro hollow fiber infection model simulating oral two-compartment pharmacokinetic model was established. In the model, bacteria was incubated in the peripheral compartment without ‘washout effect＇. We designed two therapeutic regimens of levofloxacin, including 500 mg qd （peak 5.12 mg/L; half-time 6.9 h） and 700 mg qd （peak 9.46 mg/L; half-time 6.9 h） for 3 days against E. coli J53 and E. coli 650 _ 3, which canting qnr positive plasmid.[第一段]     

乳酸左氧氟沙星滴眼液在兔眼中的药动学

目的：测定乳酸左氧氟沙星（levofloxacin,LVFX)单次滴眼后不同时间兔眼组织的浓度,计算其药动学参数,研究药动学特点,方法：取32只大白兔分为8组,各组于用药后0．125,0．25,0．50,0．75,1．0,2．0,3．0,4．0h取眼组织,所有检测均采用高效液相色谱法。结果：药物在眼组织Tmax分别为：房水0．940h,虹膜－睫状体0．533h,角膜0．686h,玻璃体0．602h,晶状体0．609h,Cmax分别为：房水0．592μg.ml^-1,虹膜一胰状体1．007μg．g^-1,角膜5．340μg.g^-1,玻璃体0．112μg.ml^-1,晶状体0．124μg.g^-1,T1／2（Kα）：房水0．479h,虹膜一睫状体0．183h,角膜0．192h,玻璃体0．258h,晶状体0．175h,T1/2(Ke)：房水0．919h,虹膜一胰状体0．922h,角膜1．741h,玻璃体0．737h,晶状体1．462h,经用3P97药动学程序拟合符合一室开放模型。结论：单次滴眼在兔眼各组织中LVFX峰浓度均高于大多数致病菌的MIC90,LVEX滴眼液可用于眼内感染的临床治疗和预防。     

左氧氟沙星片的血药浓度测定及相对生物利用度

目的建立左氧氟沙星血药浓度的HPLC-FLU测定法，用于人体生物等效性研究。方法采用单剂量双交叉实验设计，用HPLC-FLU法测定20名健康受试者口服2种左氧氟沙星片剂200mg后的血药浓度。结果受试制剂和参比制剂的扯分别为（7．56±0．44）和（7．72±0．56）h，tmax为（0．8±0．2）和（0．8±0．3）h，ρmax为（2．69±0．56）和（2．71±0．57）mg·L^-1，AUC0→36（18．37±3．43）和（17．66±3．24）mg·h·L^-1，受试制剂的相对生物利用度为（104．6±10．3）％。结论经统计学分析，左氧氟沙星2种国产片剂具有生物等效性。     

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis

OBJECTIVES: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. PATIENTS AND METHODS: The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. RESULTS: The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. CONCLUSION: This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.     

人血清中左氧氟沙星的HPLC测定及其相对生物利用度

目的用HPLC法测定人血清中左氧氟沙星的含量,评价左氧氟沙星胶囊在健康人体内的药动学及生物等效性。方法采用改进的反相HPLC法,测定20名健康受试者单剂量交叉口服100 mg左氧氟沙星供试片或参比片后不同时间点的血药浓度,计算其药动学参数及相对生物利用度,评价两药的生物等效性。结果左氧氟沙星供试片(T)与参比片(R)的药动学参数接近,主要药动学参数为:AUC0~t(R)为6.77±1.74 mg.L-1.h-1、AUC0~t(T)为7.26±1.34 mg.L-1.h-1,AUC0~∞(R)为8.58±1.72 mg.L-1.h-1、AUC0~∞(T)为8.96±1.27 mg.L-1.h-1,Cm ax(R)为0.99±0.16 mg.L-1、Cm ax(T)为0.98±0.18mg.L-1,Tm ax(R)0.93±0.23 h,Tm ax(T)0.96±0.26 h,T1/2α(R)为9.71±3.31 h、T1/2α(T)为11.15±3.55 h。相对生物利用度:分别为110.66±37.14%(T)和113.05±38.89%(R),两均值均在81%~126%内,符合相对生物利用度的要求。生物等效性评价:log(AUC0-t)和log(Cm ax)在制剂间、个体间差异均无显著性。结论两制剂具有生物等效性。     

Tissue pharmacokinetics of clonidine in rats

The antihypertensive drug clonidine exhibits nonlinear pharmacokinetics in man and rats after intravenous injection. In order to define the basis of this nonlinearity, tissue kinetics of clonidine in rats were determined at three dose levels. It was found that tissue concentrations of clonidine were linearly related to dose increases in most organs with the exception of the heart, suggesting that there was a limited binding capacity in this organ. The rate of disappearance of clonidine from most tissues was best described by a monoexponential curve with halflives of 30 to 120 min. An exception was the stomach, and clonidine accumulated in this organ, probably due to a pH partitioning effect of this weak base. Renal clearance of clonidine in rats was also examined and found to decrease by approximately 40% when the dose was increased from 50 g/kg to 250 g/kg. It was concluded that renal clearance and possibly fecal clearance could explain the nonlinear pharmacokinetics of clonidine.This work was supported by a grant from the National Health and Medical Research Council of Australia.     

正常重力和模拟微重力下大鼠左氧氟沙星的药动学比较

目的:比较在正常重力和模拟微重力环境下大鼠左氧氟沙星的药动学特征。方法:大鼠随机分为正常重力组和模拟微重力组,采用Morey's尾吊模型制备模拟微重力大鼠模型,模拟微重力第8天,正常和模型大鼠分别灌胃20mg·kg^-1盐酸左氧氟沙星,给药后设定时间点于眼眶静脉丛采血,采用高效液相色谱-质谱联用方法测定大鼠血浆左氧氟沙星浓度,采用WinNonlin软件计算左氧氟沙星药动学参数C_max,t_max和AUC_0-24h。结果:正常重力和模拟微重力大鼠左氧氟沙星C_max分别为(3.65±0.20),(4.00±0.69)μg·mL^-1;t_1/2β分别为(4.27±1.09),(5.85±1.32)h;AUC_0-24h分别为(18.53±4.06),(14.14±3.78)μg·h·mL^-1。模拟微重力组AUC_0-24h显著降低,t_1/2β显著延长。结论:与正常重力组比较,灌胃盐酸左氧氟沙星模拟微重力组大鼠的药动学性质发生了变化,模拟微重力环境下灌胃左氧氟沙星的疗效可能降低,研究结果提示微重力环境口服盐酸左氧氟沙星的给药剂量可能需要调整。     

运用决策树模型对万古霉素与利奈唑胺治疗皮肤软组织感染进行成本-效果分析

目的:利用决策树模型评价万古霉素和利奈唑胺治疗皮肤软组织感染的成本-效果。方法:选取公开发表的万古霉素与利奈唑胺治疗皮肤软组织感染的临床对照研究,以临床可评估患者随访结束后的临床治愈率为效果指标,以决策树模型进行成本-效果分析。结果:万古霉素和利奈唑胺的治愈率分别为93%和94%,直接成本分别为7 596.96元和10 091.20元,增量成本为249 424.00元。结论:万古霉素治疗皮肤软组织感染的成本-效果优于利奈唑胺。     

Preparation oral levofloxacin colon-specific microspheres delivery: in vitro and in vivo studies

The aim of this study was to prepare levofloxacin-loaded chitosan microspheres and to evaluate their in vitro and in vivo characteristics. Glutaraldehyde-crosslinked microspheres were prepared using a spray-drying method, and characterized in terms of the morphological examination, particle size distribution, entrapment efficiency, drug loading and in vitro release. Pharmacokinetics and colon biodistribution studies were used to evaluate that microspheres have more advantage than the conventional formulations. The surface morphology of the freeze-dried microspheres were smooth, discrete with a regular spherical to near-spherical shape. Size of the microspheres after freeze-drying was 4.96?±?0.76?μm and well-distributed. The zeta potential of microspheres was ?29.3?±?2.1?mV. An average drug loading of 9.3?±?0.4% and encapsulation efficiency of 81.1?±?4.7% of levofloxacin microspheres were obtained with the optimized preparation parameters. The cumulative release rate of levofloxacin microspheres was followed by a sustained release and fitted for classic Higuchi kinetic model. In vivo studies showed that chitosan microspheres are thought to have the potential to maintain levofloxacin concentration within target ranges for a long time, decreasing side effects caused by concentration fluctuation, ensuring the efficiency of treatment and improving patient compliance by reducing dosing frequency. It also does not cause any harmful or toxic effect in colon and rectum as evaluated by histopathologic studies.