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??OBJECTIVE To study the relativity between patients?? blood concentration of vancomycin and renal function, provide references for rational clinical application.METHODS The blood concentration and renal function of 64 cases of critical patients were monitored after the usage of vancomycin,then retrospectively analyzed combined with clinical date(basic information,bacteriological RESULTS ,clinical curative effect,etc.). RESULTS Pathogenic bacteria was detected from 40 of 64 patients, accounting for 62.5%. The effective rate of vancomycin reached 81.25%. The average value of 79 monitered cases of valley concentration was (17.48??13.22)??g??mL^-1. There was no significant difference of the level of BUN and Scr before and after the treatment of vancomycin,while the level of Ccr had the significant difference. There were significant difference of the level of BUN, Scr, Ccr between the groups of valley concentration <5, 5-10, 10-20 ??g??mL^-1 and the group of >20 ??g??mL^-1. CONCLUSION The application of vancomycin in critical patients is relatively cautions.When using the drug,the drug concentration and renal function can be adjusted according to the RESULTS of blood concentration and renal function.     

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??OBJECTIVE To establish a population pharmacokinetics(PPK) model of vancomycin in adult patients and investigate the factors influencing vancomycin clearance.METHODS The nonlinear mixed-effect model(NONMEM) was used to investigate the population characteristics of vancomycin in adult patients and the serum cystatin C was used as a marker of renal function. The final model was built by forward inclusion approach and backward elimination method. Fitting effect of the model was evaluated by the goodness of fit plots(GOFs). Nonparametric Bootstraps and normalized prediction distribution errors(NPDE) were performed to evaluate the robustness and predictive efficacy of the final model. External model evaluation was conducted using an independent dataset to evaluate the model predictability. RESULTS Vancomycin PPK model was set up via 147 serum trough concentration data from 95 adult patients. The estimated population typical values of clearance rate and apparent volume of distribution were 3.57 L??h^-1 and 63.30 L, respectively. The main factor influencing clearance was renal function. The GOFs showed that the final model was stable and effective, and the fitting degree of the final model was better than that of the base model. The robust rate verified by Bootstrap was 99.45%. All of the relative biases between the median of parameters validated by Bootstrap and the estimated parameters of final model were within ??3%, and the 95% confidence intervals of these validated parameters did not include zero. The NPDE followed the N(0,1) distribution with a global adjust P value of 0.334, which indicated that the model had a high predictive accuracy. External evaluation was performed via an independent dataset of 40 concentration data from 20 patients. The mean prediction error(MPE) and mean absolute prediction error(MAPE) based on population predictions(PRED) was -1.90% and 24.34%, respectively. CONCLUSION Vancomycin PPK model established in the study is of as a good stability and high predictive accuracy, as a reference for developing individualized administration regimens.     

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??OBJECTIVE To investigate the kinetic and thermodynamic characteristics of adsorption of avilamycin on silica gel. METHODS By measuring the adsorption of avilamycin on silica gel at different temperatures, the adsorption kinetics curves and adsorption isotherm were drawn, and the kinetics and thermodynamic parameters were studied. RESULTS The adsorption of avilamycin on silica gel could be described well by Pseudo-second-order model. The adsorption process had feature of shrinking nonreactive core model, and the internal diffusion was the main rate-limiting step. The equilibrium adsorption data of avilamycin on silica gel fit the Langmuir isotherms well. The thermodynamic parameters were as follows:change in entropy (??S) was 108.115 2 J??mol^-1??K^-1, change in enthalpy (??H) was 24.654 6 J??mol^-1, and changes in free energy (??G) were -8.752 9, -8.104 3, and -7.455 6 J??mol^-1 at 309, 303 and 297 K, respectively. CONCLUSION The results of this study provide a theoretical basis for further study on the isolation and purification of high purity avilamycin by silica gel.     

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??OBJECTIVE To explore the antibacterial activity and mechanism of fusidic acid combined with aztreonam on 12 clinical isolates of carbapenem-resistant Pseudomonas aeruginosa (CRPA). METHODS Broth dilution method was used to determine the minimum inhibitory concentration(MIC) of the fusidic acid and aztreonam combination.The MIC of two drugs combination were measured by the checkerboard method and partial inhibitory concentration index (FIC) was calculated to determine the combined effect.The synergistic effect of two drugs was assessed by the disk diffusion susceptibility test and the time-killing curves.Extracellular enzyme activity assay was used to detect the strains extracellular enzyme activity changes of fusidic acid alone and combined with aztreonam. The probable mechanism of the combined use of two drugs was discussed. RESULTS Fusidic acid and aztreonam combination displayed synergistic and additive activity on 61.54% and 38.46% isolates, no antagonism activity was observed.The bacteriostasis circle was obviously increased in two drugs combination, of which 41.67% of the strains were changed from drug resistance to sensitive. The time-killing curves showed that the combined of two drugs had bactericidal effect on the isolate PA 320.Extracellular aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) activity were all increased in a significant difference with the combination of two drugs. CONCLUSION Fusidic acid combined with aztreonam on CRPA is showed synergistic and additive activity in vitro. The mechanism of two drugs in combination may concern with aztreonam help the fusidic acid to overcome the natural hydrophobic antibiotic permeability barriers of gram-negative bacteria.     

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??OBJECTIVE To evaluate the antibacterial effects of colistin combined with fosfomycin against Klebsiella pneumoniae carbapenemase-producing K. pneumonia in vitro. METHODS The minimal inhibitory concentration(MIC) of colistin and fosfomycin against 74 strains of KPC-Kp was determined by agar dilution method and broth microdilution method respectively.The fractional inhibitory concentration index( FICI )was calculated by checkerboard method to determine the combined effect.SixKPC-Kp strains were randomly selected to determine the time-killing curves of colistin and fosfomycin alone or in combination. RESULTS The MIC results: polymyxin sensitivity rate of 100%, fosfomycin sensitivity rate of 35.14%.The FIC results: In 74 strains,12.16% synergism, 39.19% section synergism,6.76% additive effect,41.89% irrelevant,no antagonism found.The results of time-kill assay showed that there was a significant synergistic effect between colistin and fosfomycin in fosfomycin-sensitive strains, while fosfomycin-resistant strains showed no synergistic effect. CONCLUSION In the case of fosfomycin-sensitive strains, the combination of colistin and fosfomycin has synergistic effects on KPC-Kp in vitro, and time-kill assay also shows a good synergistic effect. Resistant strains are poor in synergism.     

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??OBJECTIVE To evaluate the compatibility of 3-layer coextrusion (powder-liquid) infusion bag with lactose azithromycin powder and sodium chloride injection. METHODS The sterile powder of lactose azithromycin was dispensed in different infusion bags and the turbidities were observed after the accelerated test. The dissolve degree of packaging materials and additives, including infusion membrane and inner cap, in different acid, alkali and polar solvent were studied. The extent of migration of packaging material components into the drugs were researched after the lactose azithromycin powder and sodium chloride injection were dispensed in the 3-layer coextrusion (powder-liquid) infusion bag. RESULTS Compared with the four kinds of common membrane, the membrane material we chosed was the best and the turbidities of liquid were meet the specification. In the extraction studies of different test solution, the antioxidant was not checked out, and the content of both Mg and Al was less than 0.05 ??g??mL^-1. In the security evaluation of migration, the maximum migration, the biggest one-day intake value and the accumulated maximum intake of additives in the special infusion bag were far lower than its toxicology statistics. CONCLUSION The quality of 3-layer coextrusion (powder-liquid) infusion bag is good. The migration and adsorption degree of of packaging material are tested to make sure the packaging material could ensure the drug quality and stability. The compatibility of 3-layer coextrusion (powder-liquid) infusion bag with drug is nice.     

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??OBJECTIVE To investigate the adsorption thermodynamics and kinetics of enramycin on XAD-16 macroporous resin. METHODS Series of static adsorption experiments were carried out. The adsorption equilibrium data were fitted to Langmuir and Freundlich isotherm equations, which could describe the adsorption behavior of enramycin on XAD-16 macroporous resin. The thermodynamic properties were described by thermodynamic parameters. Then, pseudo-first-order model and pseudo-second-order model were applied to describe the kinetics of adsorption process. RESULTS The adsorption equilibrium data were agreed with Langmuir isotherm well. Thermodynamic analysis suggested ??H<0, and ??G<0, which indicated the adsortion procedure was a spontaneously exothermic reaction with entropy decrease. The adsorption of enramycin on XAD-16 macroporous resin could be described well by Pseudo-second-order model. CONCLUSION The adsorption thermodynamics and kinetics of enramycin on XAD-16 macroporous resin can supply the theory for the separation and purification of enramycin on XAD-16 macroporous resin.     

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??OBJECTIVE To study the secondary metabolites of marine-derived fungus Aspergillus fumigatus YK-7. METHODS The compounds were isolated by several column chromatographic techniques, including silica gel, ODS, Sephadex LH-20 column chromatography, and HPLC, and their structures were identified on the basis of physicochemical properties and spectroscopic analysis. Trypan blue and MTT methods were applied for determining the effects of the compounds on proliferation of cancer cells in vitro. RESULTS Ten compounds were obtained, and their structures were identified as pseurotin A (1), pseurotin A₁(2), 14-norpseurotin A (3), FD-838 (4), demethoxyfumitremorgin C (5), 9??-hydroxyverruculogen TR-2 (6), 6-methoxyspirotryprostatin B (7), spiro[5H,10H-dipyrrolo[1,2-a:1??,2??-d]pyrazine-2-(3H),2??-[2H]indole]-3??,5,10(1??H)-trione (8), terezine D (9), and 14-hydroxyterezine D (10). CONCLUSION Compounds 3, 6, 7, 9, and 10 are isolated from marine-derived fungus Aspergillus fumigatus for the first time. Compounds 1-4 exhibite moderate antiproliferative activity against selected cancer cell lines in vitro.     

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??OBJECTIVE To review and analyze the clinical characteristics of thrombocytopenia induced by vancomycin. METHODS Databases of PUBMED??EMBASE??CBM??CNKI??VIP and WANFANG data (from built to January 2017) were conducted for case reports published in English or Chinese involving thrombocytopenia induced by vancomycin. Literatures were screened, extracted and statistics analysis by two authors independently. RESULTS A total of 2 428 literatures were searched out and 36 were included involving 37 patients. 70.3% of the patients were male, median age was 55.0 years, most of them had underlying diseases and combined with a variety of drugs, 62.2% of which combined with other antimicrobial agents.The clinical manifestation of ADR was thrombocytopenia or complete blood loss associated with or without bleeding symptoms, 45.9% patients were attacted by severe bleeding.The median time of thrombocytopenia for the first and second time was 7.0 d and 24.0 h, the median cumulative dosage was 8.0 g and 3.5 g, the median platelet counts was 23.0??10⁹L^-1 and 77.0??10⁹L^-1, respectively. The median time to platelet nadir counts for the first and second time was 9.0 d and 24.0 h, the median cumulative dosage was 16.0 g and 3.5 g, the median platelet counts was 10.0??10⁹L^-1 and 58.0??10⁹L^-1, respectively. The median time returned to normal platelet counts for the first and second time was 5.0 d and 4.5 d, respectively.For the third time, a single dose of vancomycin was administered and thrombocytopenia developed within 12 h with a nadir platelet counts of 11.0??10⁹L^-1, the platelet counts restored to normal within 7.0 d. Platelet counts returned to normal in 94.6% of patients after vancomycin was discontinued and/or took other measures, three of them died from various reasons but not the ADR of vancomycin. Vancomycin-dependent antibodies were detected in 59.5% of patients. The correlation evaluation of ADR was definite, probable, and possible in 4, 23, and 10 patients, respectively.CONCLUSION High attention should be put on thrombocytopenia induced by vancomycin, male patients with middle or old age, underlying diseases, renal insufficiency and exposure to drugs were the risk factors of thrombocytopenia .Platelet counts should be closely monitored during the use of vancomycin. Testing for drug-dependent antibodies can be helpful for identifying the cause of thrombocytopenia in patients who were receiving vancomycin. More data is need to confirm the incidence and severity of thrombocytopenia induced by vancomycin.     

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??OBJECTIVE To choose a PPK model of vancomycin most suitable for Chinese pediatric patients, in order to guide the dosage adjustment.METHODS Based on the database of PubMed and CNKI, all studies regarding vancomycin population pharmacokinetics were investigated and their basic information including PPK models was extracted. The data of Chinese pediatric patients who were administered vancomycin and received therapeutic drug monitoring(TDM) were introduced into the reported final PPK models, and the fitting was conducted by model fitting graphics. RESULTS Twelve vancomycin PPK studies during 1986-2014 were included. As judged by the correlation coefficient (R) and R-square(R2) between predicted concentration and measured concentration, the models 4 and 9 presented a relatively better fitting with the data of Chinese pediatric patients we collected. The VPC fitting demonstrated that number 1 model achieved the best fitting. However, because the limited data used in this study was based on irregular sampling time, so the VPC test results were difficult to be distinguished and could only be used as a secondary reference. On the other hand, NPDE has corresponding statistical test, and its evaluation ability for the model is not affected by the factors of the experimental design. NPDE analysis showed that one-compartment model was better than two-compartment model, and model 4 and model 9 achieved better fitting to the collected data than others.CONCLUSION The fitting effects of most reported vancomycin PPK models, except individual models, were poor for the TDM data of Chinese pediatric patients, therefore it is necessary to establish a vancomycin population pharmacokinetic model particularlly for Chinese pediatric patients, in order to guide dosage adjustment more accurately.     

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??OBJECTIVE To characterize the population pharmacokinetics of isoniazid in Chinese tuberculosis patients. METHODS A total of 321 serum samples were obtained from 201 patients receiving oral doses of isoniazid. The effects of 16 covariates including demographics and blood tests to isoniazid??s pharmacokinetics were evaluated. Data analysis was performed using non-linear mixed effects modeling (NONMEM). Prediction-corrected visual prediction check was performed for model evaluation. RESULTS A two-compartment model with first-order absorption and linear elimination can well fit the isoniazid concentration-time data. A ??MIXTURE?? model was used to separate the subpopulation of ??subgroup A?? and ??subgroup B??. Typical clearance of the two subpopulations were 82.7 and 19.3 L??h^-1, respectively. CONCLUSION Model validation shows the final model is reliable, which could be used for individualized treatment.     

替考拉宁在中国成人患者中的群体药动学研究

目的建立中国成年患者的替考拉宁(teicoplanin,TEC)群体药动学(population pharmacokinetics,PPK)模型,考察TEC药动学参数的影响因素。方法前瞻性收集139例革兰阳性球菌感染患者静脉注射TEC后的222份常规监测血药浓度和相关信息,采用一级消除的一室模型进行数据拟合,并应用非线性混合效应模型(nonlinear mixed effect model,NONMEM)程序建立PPK模型。采用Bootstrap、正态预测分布误差法(normalized predictive distribution error,NPDE)进行最终模型评价。利用蒙特卡洛模拟法对给药方案进行优化。结果确定了肌酐清除率(creatinine clearance,CLcr)、白蛋白(albumin,ALB)为影响TEC清除率的主要因素。最终模型为:CL(L·h^-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2。验证表明,模型稳定、有效,且有较好的预测效能。对于不同ALB和CLcr的多数患者起始负荷剂量400 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案可达有效治疗谷浓度。严重感染者需调整负荷剂量至800 mg/q12h,iv,3次,维持剂量400~800 mg·d^-1的给药方案来确保血药浓度达到15 mg·L^-1以上。结论本实验报道了CLcr、ALB对TEC清除率有显著影响,所建模型对TEC在中国成人患者中实现个体化给药具有重要应用价值。     

盐酸氨溴索在中国健康男性志愿者的群体药动学研究

 目的 建立中国健康男性志愿者单剂量口服盐酸氨溴索的群体药物动力学模型,为临床个体化给药提供依据。方法 18名男性健康志愿者随机交叉口服60 mg盐酸氨溴索片或颗粒后,采用GC-ECD测定血药浓度,用非线性混合效应模型（NONMEM）程序建立盐酸氨溴索的群体药物动力学模型,并进行模型验证评价。结果 带有滞后时间的零级协同一级吸收一室模型对数据拟合良好,药物动力学参数CL/F、V/F和K_a的群体典型值及其相对标准误差分别为21.0 L·h^-1 (2.05%)、181.0 L (2.04%)和0.959 h^-1 (16.0%)。采用自举法（Bootstrap）对模型稳定性进行检验,1 000次采样结果显示收敛成功率高于90%。结论 用NONMEM软件拟合建立的盐酸氨溴索群体药动学模型,参数合理,模型稳定可靠。     

用 NONMEM 法建立中国成年患者服用地高辛群体药动学模型

 目的 建立中国成年人中服用地高辛患者的群体药动学（ PPK ）模型,促进个体化给药。 方法 收集 155 名长期规律服用地高辛患者的 262 例次稳态地高辛的测定结果以及相关临床数据。应用 NONMEM 软件求算 PPK 参数值,建立基本模型和最终模型。运用内部验证法,验证模型的可靠性。 结果 地高辛达到稳态时,其 PPK 模型符合口服吸收一室模型。地高辛体内清除和患者血清肌酐浓度、体重、是否有合并用钙离子拮抗剂（ CCB ）、螺内酯 (SPR) 有关。最终模型可表达为： <> CL /<>F=9.33 × 0.512^(SCR/119.1) × [1+0.017 × (Weight - 61.2)] × (1 - 0.21 × CCB) × (1 - 0.19 × SPR) L·kg^-1·h^-1 。 <> K _a =1.54 h ^-1 ; <> V _d /<>F=187 L 。经内部验证法验证,本模型稳定、可靠。新取 5 个地高辛数据应用本模型进行预测,预测结果与临床实际监测结果相符较好。 结论 用 NONMEM 软件成功建立中国成年人服用地高辛的 PPK 模型。     

他克莫司在151例肝移植受者的常规监测的群体药动学研究

 目的考察国人肝移植受者口服他克莫司(Tacrolimus,FK506)常规监测的群体药动学特征,为实施个体化用药提供新途径。方法收集151例肝移植受者FK506的血药浓度数据,应用非线性混合效应法(NONMEM)选择药动学模型和统计学模型,并考察性别(GEN)、年龄(AGE)、体重(BW)、术后时间(POD)、剂量(DOSE)、合并用药、肝肾功能、红细胞压积(HCT)等协变量对药动学参数的影响,建立最终回归模型。并根据Bayesian反馈估算获得个体和群体的药动学参数以及预测血药浓度。结果NONMEM法对151例肝移植受者的总数据集用一级吸收二房室开放模型进行拟合,指数模型表征个体间和个体自身变异。将总数据集随机分为建模组和验证组。用建模组数据获得的群体参数在验证组中有较理想的拟合优度。群体药动学参数为:CL为19 L·h^-1,V2为170 L,Q为71 L·h^-1,V3为324 L,K_a为2.670 h^-1,吸收延迟时间(ALAG)为0.230 h。协变量对药动学参数的影响按照OB J下降的幅度依次为DOSE,BUN,HCT对CL;BUN,DOSE,AGE对V2。经Bayesian反馈得到的预测浓度和实测浓度的相关性为r=0.97。模型的误差分析结果表明,平均绝对权重残差(MAWR)为(11±10)%。结论NONMEM法建立回归模型能较好地估算应用FK506的肝移植受者的个体及群体药动学参数,应用回归模型并利用Bayesian反馈可用于临床个体化给药。     

多民族健康受试者单剂量静滴多沙普仑的群体药动学

 目的 考察多沙普仑在中国汉、蒙、朝、回和维吾尔族健康受试者中的群体药动学特征。方法 根据50例健康受试者单次静脉滴注50 mg盐酸多沙普仑的血药浓度数据,应用NONMEM软件建立群体药动学模型、估算药动学参数值并评估各固定效应对代谢的影响。结果 多沙普仑符合三室模型,药动学参数群体典型值分别为：CL₁ =17.8 L·h^-1,CL₂=10.5 L·h^-1,CL₃ =85.2 L·h^-1,V₁ =17.4 L,V₂ =62.6 L,V₃ =16.8 L。民族因素对于V₂、CL₃、CL₁有显著影响,性别对CL₂有显著影响。结论 NONMEM法建立的多沙普仑群体药动学模型经验证有较好的稳定性,可为临床应用提供参考。     

中药人体群体药代动力学研究关键问题的探讨

针对中药人体群体药代动力学(PPK)研究的关键问题进行总结和探讨.阐述了中药PPK的研究对象、测定指标的选择;认为多成分药代动力学曲线的拟合、有效成分的检测是中药PPK研究的关键问题,并结合中药PPK已有的研究成果,探讨了中药群体药代动力学曲线拟合方法,并分析了其可行性.     

羟基喜树碱注射液在肿瘤患者体内的群体药代动力学

 目的 研究羟基喜树碱在肿瘤患者的群体药动学（ PPK ）特征,为临床调整肿瘤患者的个体用药提供新途径。 方法 60 例肿瘤患者静脉滴注羟基喜树碱后,采集不同时间的静脉血样 260 个点, HPLC 测定羟基喜树碱的血药浓度。以非线性混合效应模型（ NONMEM ）程序法分析羟基喜树碱群体药代动力学参数。 结果 羟基喜树碱二室模型最终的群体药动学参数群体标准值 <> CL ₁ , <> V ₁ , <> CL ₂ , <> V ₂ 分别为（ 18.3 ± 4.71 ） L·h-1 ,（ 12.6 ± 2.15 ） L ,（ 18.3 ± 2.32 ） L·h-1 ,（ 26.8 ± 4.81 ） L 。男性的中央室清除率是女性的 1.512 倍,群体模型有较好的拟合优度。 结论 NONMEM 法对二室模型群体参数估算的血药浓度值与实测值有良好的相关性,性别对中央室清除率参数影响较大。本试验获得的羟基喜树碱群体参数可以为羟基喜树碱在肿瘤病人的临床个体化用药提供支持。