替考拉宁的HPLC法测定

目的建立快速测定替考拉宁含量的高效液相色谱法。方法采用Waters Symmetry C18色谱柱(250mm×4.6 mm,5μm),流动相为3.0 g/L无水磷酸二氢钠缓冲液-乙腈,梯度洗脱,流速为1.0 mL/min,柱温为40℃,检测波长为254 nm。结果替考拉宁质量浓度在0.1¹.0 g/L范围内,峰高与质量浓度呈线性关系,相关系数为0.999 9。用标准加入法做回收率试验,回收率结果在98.26%1.0 g/L范围内,峰高与质量浓度呈线性关系,相关系数为0.999 9。用标准加入法做回收率试验,回收率结果在98.26%⁹9.74%。将方法应用于替考拉宁粗粉含量的测定,测定结果的相对标准偏差(n=6)为0.90%。结论该方法快速、准确,可用于替考拉宁生产过程质量控制分析。     

替考拉宁的 HPLC 法测定

目的建立快速测定替考拉宁含量的高效液相色谱法。方法采用WatersSymmetryC18色谱柱（250mm×4．6mm,5μm）,流动相为3．0g／L无水磷酸二氢钠缓冲液-乙腈,梯度洗脱,流速为1．0mL／min,柱温为40℃,检测波长为254nm。结果替考拉宁质量浓度在0．1～1．0g／L范围内,峰高与质量浓度呈线性关系,相关系数为0．9999。用标准加入法做回收率试验,回收率结果在98．26％～99．74％。将方法应用于替考拉宁粗粉含量的测定,测定结果的相对标准偏差（n=6）为0．90％。结论该方法快速、准确,可用于替考拉宁生产过程质量控制分析。     

中药麻鱼石黄汤对金黄色葡萄球菌体外抑菌作用的实验研究

目的讨论中药麻鱼石黄汤及其单体药物对金黄色葡萄球菌的体外抑菌效果。方法分别制备麻鱼石黄汤(包括其单组份)、替考拉宁、哌拉西林的含药培养基,对MRSA、MSSA培养24 h,记录生长的菌落数并进行分析。结果麻鱼石黄汤与替考拉宁对MRSA、MSSA有同样抑菌功效,且优于哌拉西林。麻鱼石黄汤对MRSA与MSSA的抑菌效果无统计学差异。结论应用麻鱼石黄汤治疗临床金黄色葡萄球菌的感染,不论是否为耐药菌株,均可取得良好效果,并可避免替考拉宁引起的不良反应及长期用药引起的毒副作用或耐药性,尤其适用于抗生素过敏者,可为患者节约药品费用,提高临床满意度,使药品得到合理应用。     

替考拉宁对革兰阳性球菌重症肺炎的疗效

目的:分析替考拉宁对革兰阳性球菌重症肺炎的疗效。方法:选取驻马店市中心医院2018年11月至2019年11月收治的78例革兰阳性球菌重症肺炎患者,随机分为对照组和观察组,每组39例,给予观察组患者替考拉宁治疗,给予对照组患者去甲万古霉素治疗,对两组患者细菌清除率与治疗效果进行比较。结果:观察组患者的治疗总有效率高于对照组,差异具有统计学意义(P 0.05);两组患者的痰培养转阴率比较,差异无统计学意义(P 0.05);观察组患者的平均清除时间短于对照组,差异具有统计学意义(P 0.05);观察组患者的不良反应发生率低于对照组,差异具有统计学意义(P 0.05)。结论:给予革兰阳性球菌重症肺炎患者替考拉宁治疗具有显著效果,能够有效清除常见痰菌,治疗安全性和可靠性均较高。     

替考拉宁与万古霉素在中性粒细胞缺乏伴发热的恶性血液病患儿中的有效性和安全性分析

目的 在发生中性粒细胞缺乏伴发热(粒缺伴发热)的恶性血液病儿童患者中比较替考拉宁及万古霉素经验性覆盖革兰阳性菌时的有效性和安全性。方法 使用倾向评分匹配均衡万古霉素组和替考拉宁组患者的基线特征,进而比较两组的临床有效性、谷浓度达标率和达标时间以及肾毒性发生率。结果 最初共纳入126名粒缺伴发热的恶性血液病儿童患者。经匹配后,共纳入74名替考拉宁组患者和37名万古霉素组患者,两组的基线特征均衡可比。用药72 h和用药结束时的临床有效率在两组患者中均无显著性差异(P值分别为0.673和0.477),有效谷浓度的达标率及达标时间也均无显著性差异(P值分别为0.439和0.103)。但替考拉宁治疗组的肾毒性发生率显著低于万古霉素组(P=0.026)。结论 在粒缺伴发热的恶性血液病儿童患者中经验性覆盖革兰阳性菌时,相比万古霉素,更推荐使用肾毒性发生率较低的替考拉宁。     

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。     

利奈唑胺、替考拉宁和万古霉素对耐甲氧西林表皮葡萄球菌体外抗菌活性的影响

目的评价利奈唑胺、替考拉宁和万古霉素3种抗菌药物的体外抗菌活性。方法采用琼脂稀释法对临床收集的320株耐甲氧西林表皮葡萄球菌(MRSE)进行抗菌活性测定,记录其各自的MIC并进行比较。结果利奈唑胺、替考拉宁及万古霉素对革兰阳性球菌均有较大抗菌活性,敏感率分别为100.0%,96.0%,96.1%。对MRSE,利奈唑胺的MIC90是万古霉素的2倍,是替考拉宁的4倍。结论利奈唑胺、替考拉宁以及万古霉素对MRSE均有较大的抗菌作用,利奈唑胺对MRSE的抗菌作用优于替考拉宁和万古霉素,是临床革兰阳性球菌严重感染的有效药物。     

阿奇霉素联合替考拉宁治疗门诊下呼吸道感染的效果

目的：观察阿奇霉素联合替考拉宁治疗门诊下呼吸道感染的效果及安全性。方法：选取郑州市第七人民医院2019年6月至2021年5月期间门诊的112例下呼吸道感染患者,按照随机数字表法分为对照组与观察组,各56例。对照组患者予以阿奇霉素治疗,观察组患者在对照组基础上加用替考拉宁治疗,比较两组患者临床效果、症状消失时间、治疗前后血清肿瘤坏死因子–α（TNF–α）、白细胞介素–6（IL–6）、超敏C反应蛋白（hs–CRP）水平、不良反应发生情况。结果：观察组患者总有效率为98.21%,高于对照组的78.57%,差异具有统计学意义（P <0.05）;观察组患者咳嗽消失时间、发热消失时间、咯痰消失时间均短于对照组,差异具有统计学意义（P <0.05）;观察组患者治疗后血清TNF–α、IL–6、hs–CRP水平均低于对照组,差异具有统计学意义（P <0.05）;两组患者不良反应发生率比较,差异无统计学意义（P> 0.05）。结论：阿奇霉素联合替考拉宁治疗门诊下呼吸道感染患者,可快速缓解患者临床症状,减轻炎症反应,安全性高。     

利奈唑胺治疗MRSA的临床分析

目的探讨利奈唑胺对耐甲氧西林金黄色葡萄球菌(MRSA)的抗菌作用。方法利用琼脂稀释法测定利奈唑胺、万古霉素、替考拉宁3种常用MRSA抗菌药物针对MRSA的药物敏感性和耐药性以及最低抑菌浓度(MIC),探讨比较利奈唑胺与另外2种抗菌药物对MRSA的抗菌作用。结果 3种抗菌药物在试验中表现出的对MR-SA药物敏感性和耐药性有差异,MRSA对利奈唑胺的药物敏感性略高于万古霉素和替考拉宁,耐药性略低于万古霉素和替考拉宁。3种抗菌药物在对MRSA的MIC,半数抑菌范围(MIC50)和90%抑菌范围(MIC90)的比较中存在差异,利奈唑胺在MIC、MIC50、MIC90略低于另外2种药物。结论 3种药物的抗菌作用均非常明显,但利奈唑胺相比于另外2种抗菌药物有一定优势,是今后治疗MRSA感染的首选药物。     

ICU耐甲氧西林金黄色葡萄球菌感染的耐药性分析

目的探讨医院MRSA预防、治疗措施。方法对我院ICU2005年6月至2008年5月期间痰液培养分离的耐甲氧西林金黄色葡萄球菌（MRSA）感染菌株38例进行耐药性分析统计。结果我院ICU3年共发生MRSA38例，均对万古霉素和替考拉宁敏感，对呋喃妥因敏感率71．05％。结论ICU中MRSA的感染率较高，加强MRSA感染的控制应积极进行病原学监测、严格消毒隔离措施、合理使用广谱抗生素，依据药敏试验可选择万古霉素或替考拉宁抗感染治疗。     

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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 population pharmacokinetics of vancomycin (VAN) in Chinese neonates by nonlinear mixes-effects modeling software (NONMEM). METHODS One hundred and fifty-four VAN serum trough data from 91 neonatal patients were retrospectively collected from Suzhou Hospital Affiliated to Nanjing Medical University. A one-compartment model with first order elimination was used to describe structure pharmacokinetic model, and physiological maturity model was employed to screen covariates. The stability and prediction of the final model were evaluated by Bootstrap and normalized prediction distribution error (NPDE). The final model was applied to evaluate the percentage of AUC_{0-24 h}/MIC ?? 400 in neonatal patients by Monte Carlo Simulation, who were stratified according to gestational weeks, age and serum creatinine. RESULTS The weight, postmenstrual age and serum creatinine were identified as the most significant covariate on clearance. Bootstrap and NPDE showed the satisfactory stability and prediction performance of the final model. Moreover, the final model indicated that 96% of neonates with low serum creatinine (15 ??mol??L^-1) were not getting AUC_{0-24 h}/MIC??400, according to the current guidelines. CONCLUSION The population pharmacokinetic model of vancomycin in neonates is established successfully and could provide basis for the individualized therapy in neonatal patients.     

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。     

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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.     

紫杉醇种属间药动学相关性的荟萃分析

 目的 应用基于模型化的荟萃分析的方法,建立紫杉醇种属间相关性的定量评价方法,为新药研发的种属间外推与剂量确定提供参考。 方法 以紫杉醇药动学为关键词,检索Pub-Med、中国知网（CNKI）、万方等数据库建库相关文献。按照纳入排除标准对检索文献进行筛选,并按种属进行分类,摘录每篇文献的血药浓度数据,应用非线性混合效应模型法（NONMEM）分别对人、大鼠、小鼠进行建模。采用正态化预测分布误差（normalized prediction distribution errors,NPDE）法对建立的模型进行验证,并依据相关生长规律法对药物种属间相关系数进行计算。 结果 通过非线性混合效应模型法法模型化,人、大鼠、小鼠的药动学行为均符合二室模型,与文献检索结果一致。正态化预测分布误差对最终模型结果进行可视化检验,模型结果准确可靠。依据相关生长规律法（allometric scaling）对3个种属的清除率CL和总表观分布容积V_total的相关系数进行计算,结果分别为r²=0.997 4和r²=0.937 2,种属间相关系数的线性关系良好。 结论 以紫杉醇为例,成功地建立了基于模型的Meta分析方法,能够定量的评价和预测种属间相关性。     

云南沧源县佤族ABO血型分布及基因频率调查

目的：调查云南沧源县佤族ABO血型分布及基因频率分布情况。方法：对云南沧源县佤族1192例人群红细胞ABO表现型进行了检测;并进行Hardy—Weinberg吻合度测验检测。结果：佤族以A型为多,ABO血型分布为A〉0〉B〉AB;基因频率P基因为0．3383、q基因为0．1882和r基因为0．4735。结论：云南沧源县的ABO血型表现型分布状况及基因频率相对稳定,其分布符合Havdy—Weinberg吻合度平衡。     

Pharmacokinetics of liensinine in rabbits]

A method for the determination of plasma concentration of liensinine with HPLC and pharmacokinetic study of liensinine in rabbits were reported. Assay linearity was shown over the range of 0.125-2.5 micrograms/ml serum with regression coefficient of 0.9997. The mean recoveries of liensinine in plasma (within-day and between-days) were all more than 99% of the dose and the coefficients of variation were less than 5%. After a single intravenous injection of liensinine 6mg/kg to rabbit. The pharmacokinetic characteristics were found to fit a two-compartment open model. Important parameters were: t1/2 alpha = 8.303 min t1/2 beta = 129.960min AUC = 132.67 micrograms.min/ml CL = 0.045 L/min Vc = 2.768 L/kg.     

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。