Evaluation of Bayesian estimation in comparison to NONMEM for population pharmacokinetic data analysis: Application to pefloxacin in intensive care unit patients

The pharmacokinetics of pefloxacin (PF) were investigated in a population of 74 intensive care unit patients receiving 400 mg bid as 1-hr infusion using (i) Bayesian estimation (BE) of individual patient parameters followed by multiple linear regression (MLR) analysis and (ii) NONMEM analysis. The data consisted of 3 to 9 PF plasma levels per patient measured over 1 to 3 dosage intervals (total 113) according to four different limited (suboptimal) sampling 3-point protocols. Twenty-nine covariates (including 15 comedications) were considered to explain the interpatient variability. Predicted PFCLfor a patient with median covariates values was similar in both BE/ MLR and NONMEM analysis (4.02 and 3.92 L/hr, respectively). Bilirubin level and age were identified as the major determinants of PFCLby both approaches with similar predicted magnitude of effects (about 40 and 30% decrease of median CL,respectively). Confounding effects were observed between creatinine clearance (26% decrease of PF CLin the BE/MLR model), simplified acute physiology score (a global score based on 14 biological and clinical variables) (18% decrease of median CLin the NONMEM model) and age (entered in both models) which were highly correlated in our data base. However, both models predicted similar PF CLfor actual subpopulations by using actual covariate values. Finally, the NONMEM analysis allowed identification of an effect of weight on CL(decrease of CL for weight <65 kg) whereas the BE/MLR analysis predicted an increase of CLin patients treated with phenobarbital. In conclusion, both approaches allowed identification of the major risk factors of PF pharmacokinetics in ICU patients. Their potential use at different stages of drug development is discussed.     

Evaluation of Bayesian estimation in comparison to NONMEM for population pharmacokinetic data analysis: application to pefloxacin in intensive care unit patients.

The pharmacokinetics of pefloxacin (PF) were investigated in a population of 74 intensive care unit patients receiving 400 mg bid as 1-hr infusion using (i) Bayesian estimation (BE) of individual patient parameters followed by multiple linear regression (MLR) analysis and (ii) NONMEM analysis. The data consisted of 3 to 9 PF plasma levels per patient measured over 1 to 3 dosage intervals (total 113) according to four different limited (suboptimal) sampling 3-point protocols. Twenty-nine covariates (including 15 comedications) were considered to explain the interpatient variability. Predicted PF CL for a patient with median covariates values was similar in both BE/MLR and NONMEM analysis (4.02 and 3.92 L/hr, respectively). Bilirubin level and age were identified as the major determinants of PF CL by both approaches with similar predicted magnitude of effects (about 40 and 30% decrease of median CL, respectively). Confounding effects were observed between creatinine clearance (26% decrease of PF CL in the BE/MLR model), simplified acute physiology score (a global score based on 14 biological and clinical variables) (18% decrease of median CL in the NONMEM model) and age (entered in both models) which were highly correlated in our data base. However, both models predicted similar PF CL for actual subpopulations by using actual covariate values. Finally, the NONMEM analysis allowed identification of an effect of weight on CL (decrease of CL for weight < 65 kg) whereas the BE/MLR analysis predicted an increase of CL in patients treated with phenobarbital. In conclusion, both approaches allowed identification of the major risk factors of PF pharmacokinetics in ICU patients. Their potential use at different stages of drug development is discussed.     

Selection correction in panel data models: An application to the estimation of females' wage equations

Summary In recent years a number of panel estimators have been suggested for sample selection models, where both the selection equation and the equation of interest contain individual effects which are correlated with the explanatory variables. Not many studies exist that use these methods in practise. We present and compare alternative estimators, and apply them to a typical problem in applied econometrics: the estimation of the wage returns to experience for females. We discuss the assumptions each estimator imposes on the data, and the problems that occur in our applications. This should be particularly useful to practitioners who consider using such estimators in their own application. All estimators rely on the assumption of strict exogeneity of regressors in the equation of interest, conditional on individual specific effects and the selection mechanism. This assumption is likely to be violated in many applications. Also, life history variables are often measured with error in survey data sets, because they contain a retrospective component. We show how this particular measurement error, and not strict exogeneity can be taken into account within the estimation methods discussed.     

便隐血试验免疫学方法的临床应用效果评价

目的:探讨和评价便隐血试验免疫学方法的临床应用效果。方法:对800例便隐血试验采用免疫学方法进行检测并进行结果分析。结果:便隐血试验结果与临床有较好的一致性,假阴性率为3.4%。结论:便隐血试验免疫学方法有良好的临床应用效果,但单独应用存在一定的缺陷,假阴性是需要解决的主要问题。     

Patent Evaluation: A simple method for the characterization of nucleic acids

Summary

Novelty: A rapid and simple method for nucleic acid hybridization is claimed.

Biology: The method involves the deposition of a nucleic acid sample onto the surface of the microporous layer of a reaction capsule which consists of an absorbent filter commercialized under the trade name Porex. Further solutions, including the wash and prehybridization solution, blocking agents, antibody reagents and chromogenic substrates, are all applied to the membrane via normal micropipettes. After a hybridization period of one hour, up to 10 pg of pBR358 DNA has been detected.     

Measurement and correlation of solubility data for albendazole in ten pure solvents and two binary solvent systems from 278.15 K to 323.15 K

The equilibrium solubility of albendazole (ABZ) in ten single solvents and two binary solvent mixtures of different ratio was measured by a typical static method combined with ultraviolet (UV) spectrophotometry within the temperature range from 278.15 K to 323.15 K. Meanwhile, the modified Apelblat model, Van't Hoff equation and λh equation were used to correlate the solubility data of ABZ in pure solvent, the modified Apelblat model, λh equation, Sun model, GSM equation and NRTL model were used to correlate the solubility data of ABZ in binary mixed solvent, the 100RD, 100ARD, 103RMSD and 103ORMSD values of the above models were calculated respectively. The results show that the experimental data of six models have a good correlation with the calculated data. Especially, the Van't Hoff equation in pure solvent has the best fitting effect, and the GSM equation in binary mixed solvent has the best fitting effect. Additionally, the Van't Hoff equation was used to calculate and evaluate the thermodynamic properties of the ABZ dissolution process, including enthalpy (ΔdisH), entropy (ΔdisS) and Gibbs free energy (ΔdisG).     

A rapid, simple, specific liquid chromatographic-electrospray mass spectrometry method for the determination of finasteride in human plasma and its application to pharmacokinetic study

A fast, accurate, sensitive, selective and reliable method using reversed-phase high-performance liquid chromatography-mass spectrometry coupling with an electrospray ionization interface was developed and validated for the determination of finasteride in human plasma. After deprotienation with acetonitrile, centrifugation, evaporation to dryness and dissolving in mobile phase, satisfactory separation was achieved on a Hypersil-Keystone C(18) reversed-phase column using a mobile phase consisting of acetonitrile-water (46:54, v/v), 0.1% acetic acid and 0.1% trifluoracetic acid. Carbamazepine (IS) was used as internal standard. This method involved the use of the [M+H](+) ions of finasteride and IS at m/z 373 and 237 with the selective ion monitoring (SIM) mode. The calibration curve was linear in the range of 0.2-120 ng ml(-1). The limit of quantification for finasteride in plasma was 0.2 ng ml(-1) with good accuracy and precision. The intra-assay precision and accuracy were in the range of 2.1-11.2% and -1.3% to 8.5%, respectively. The inter-assay precision and accuracy were in the order of 3.4-12.1% and -1.5% to 11.5%, respectively. The mean sample extract recoveries of the method were higher than 85% and 74% for finasteride and internal standard (IS), respectively. The assay has been successfully used to estimate the pharmacokinetics of finasteride after oral administration of a 5mg tablet of finasteride to 24 healthy volunteers.     

治未病理论在IBS患者健康宣教中的应用及效果评价

目的 探讨中医治未病理论在肠易激综合征（IBS）患者健康宣教中的效果。方法选取2010年1月至2011年1月在我院接受治疗的肠易激综合征患者36例,随机平均分为观察组和对照组,对照组给予常规护理和教育,观察组在对照组的基础上运用中医治未病理论进行健康教育。结果观察组患者平均每年住院（2．3±1．2）次,每年住院（14．5±2．6）天;对照组患者平均每年住院（5．3±2．7）次,每年住院（28．6±4．8）天。结论运用中医治未病理论对IBS患者进行健康宣教,可明显改善患者病情。     

Effect of using an incorrect elimination rate constant in application of the Wagner–Nelson method to theophylline data in cases of zero order absorption

Some authors have used an elimination rate constant derived from one theophylline treatment (e.g. the elixir) to apply the Wagner–Nelson method to concentration–time data from another treatment (e.g. a sustained-release form). Since there is considerable intrasubject variation in the elimination rate constant of theophylline such a practice usually involves use of an incorrect rate constant. By means of theoretical treatment and simulations the effects of such a practice are shown and illustrated.     

改良DCAP法在大学药剂学实践教学中的应用

药剂学实践体系内容繁多,系统性和实践性较强,不易融会贯通。抓住制药企业《药品生产质量管理规范》（GMP）为主线,合理安排药剂学实践课程体系,结合改良DCAP法,由浅入深、循序渐进式地实施实践课堂模块学习,帮助学生系统掌握知识。在教学过程中,采用多种教学方法,激发学生的学习主动性,提高学习效果。     

欧洲医药保健网分类系统在中枢神经系统药物相关问题中的干预效果评价

目的 运用欧洲医药保健网（PCNE）分类系统对中枢神经系统药物相关问题（DRPs）进行分析与评估,为临床药师进行合理用药提供依据。方法 选择2020年7月至2021年7月入住新疆医科大学附属中医医院神经内科并且服用中枢神经系统药物的病人,临床药师从药学服务中对发现的DRPs进行干预,并借助PCNE(V9.0)分类系统进行分类汇总。结果 纳入654例服用中枢神经系统药物的病人,106例（16.21%）病人共发生112个DRPs。其中DRPs的问题类别集中在治疗安全性（74.11%）和治疗有效性（16.07%）。DRPs发生频率较高的药物为抗精神病药、苯二氮?类药、抗焦虑抑郁药、解热镇痛抗炎药及抗痴呆药和改善脑代谢药。DRPs的原因主要是药物选择（79.65%）,其次是剂量选择（9.73%）。临床药师共进行了257次介入,其中207次介入被接受,成功率为80.54%。干预接受程度最高的是药物不良反应上报（100%）,其次是与病人层面（96.97%）、药物层面（77.98%）及医师层面（76.42%）。发生9例（1.37%）药物不良反应,临床药师参与评价及干预,9例病人均转归良好。结论 PC...     

Use of darbepoetin alfa in European clinical practice for the management of chemotherapy-induced anaemia in four tumour types: final data from the CHOICE study

Abstract

Objectives:

The CHOICE study was a prospective, multicentre, observational study designed to assess levels of adherence in current clinical practice to the European product label and EORTC guidelines for the treatment of chemotherapy-induced anaemia (CIA) with darbepoetin alfa (DA). Here we present data split by tumour types: breast, colorectal, ovarian and lung.     

Powder flow analysis: A simple method to indicate the ideal amount of lactose fines in dry powder inhaler formulations

Many efforts have been made in the past to understand the function of lactose fines which are given as a ternary component to carrier-based dry powder inhaler formulations. It is undisputed that fines can significantly improve the performance of such formulations, but choosing the right amount of fines is a crucial point, because too high concentrations can have negative effects on the dispersion performance. The aim of this study was to indicate the optimal concentration of fines with a simple test method. For this purpose, mixtures with salbutamol sulfate and two different lactose carriers were prepared with a high shear mixer, measured with a FT4 powder rheometer and tested for fine particle delivery with two different inhaler devices. A correlation between the fluidization energy, measured with the aeration test set up, and the fine particle fractions (FPF) could be proven. This also applied for the aeration ratio, as well as the permeability of the powder samples. In addition, drug-free mixtures hardly differed in their rheological properties from mixtures containing the active pharmaceutical ingredient (API), which indicates that the method could be suitable for cost-saving screening trials. Furthermore, important aspects that explain the function of fines, such as the saturation of active sites, the formation of agglomerates and an increase in fluidization energy, could be shown in this study.     

Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: An in silico comparison with mutagenic and nonmutagenic carcinogens across tissues

In vitro studies on hexavalent chromium [Cr(VI)] indicate that reduced forms of this metal can interact with DNA and cause mutations. Recently, Cr(VI) was shown to induce intestinal tumors in mice; however, Cr(VI) elicited redox changes, cytotoxicity and hyperplasia – suggesting involvement of tissue injury rather than direct mutagenesis. Moreover, toxicogenomic analyses indicated limited evidence for DNA damage responses. Herein, we extend these toxicogenomic analyses by comparing the gene expression patterns elicited by Cr(VI) with those of four mutagenic and four nonmutagenic carcinogens. To date, toxicogenomic profiles for mutagenic and nonmutagenic duodenal carcinogens do not exist, thus duodenal gene changes in mice were compared to those elicited by hepatocarcinogens. Specifically, duodenal gene changes in mice following exposure to Cr(VI) in drinking water were compared to hepatic gene changes previously identified as potentially discriminating mutagenic and nonmutagenic hepatocarcinogens. Using multivariate statistical analyses (including logistic regression classification), the Cr(VI) gene responses clustered apart from mutagenic carcinogens and closely with nonmutagenic carcinogens. These findings are consistent with other intestinal data supporting a nonmutagenic mode of action (MOA). These findings may be useful as part of a full weight of evidence MOA evaluation for Cr(VI)-induced intestinal carcinogenesis. Limitations to this analysis will also be discussed.     

Determination of pinostrobin in rat plasma by LC-MS/MS: application to pharmacokinetics

A rapid and sensitive method for the determination of pinostrobin in rat plasma was developed using liquid chromatography tandem mass spectrometry (LC-MS/MS) for the first time. Isoliquiritigenin was used as an internal standard in rat plasma. Chromatographic separation was performed on an HiQ Sil C₁₈ column with isocratic elution at a flow rate of 1 mL/min. The mobile phase consisted of water and methanol (9:91, v/v) containing 0.1% formic acid. The quantification limit was 10 ng/mL within a linear range of 10-1000 ng/mL (R = 0.9984). The intra- and inter-day assay precision ranged from 3.8-5.3% to 3.2-5.2%, respectively, and the intra- and inter-day assay accuracy was between 93.2-95.1% and 95.5-104.3%, respectively. Our results indicated that the LC-MS/MS method is effective for pharmacokinetic study of pinostrobin in rat plasma.     

Rapid and simultaneous measurement of midazolam, 1'-hydroxymidazolam and digoxin by liquid chromatography/tandem mass spectrometry: application to an in vivo study to simultaneously measure P-glycoprotein and cytochrome P450 3A activity

In order to simultaneously determine in vivo P-glycoprotein (P-gp) and Cytochrome P450 3A (CYP3A) activity, a new, rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has been developed and fully validated to simultaneously determine midazolam (MDZ, as CYP3A substrate), 1'-hydroxymidazolam (1'-OHMDZ) and digoxin (DG, as P-gp substrate) in rat plasma using digitoxin as the internal standard (IS). After a single step liquid-liquid extraction with tert-butyl methyl ether/dichloromethane (75:25, v/v), analytes were subjected to LC-MS/MS analysis using positive electro-spray ionization (ESI(+)) under selected reaction monitoring mode (SRM). Chromatographic separation was performed on an XTerra MS C18 column (50mm×2.1mm, i.d. 3.5μm). The MS/MS detection was conducted by monitoring the fragmentation of 326.05 → 244.00 (m/z) for MDZ, 342.02 →168.01 (m/z) for 1'-OHMDZ, 798.33 → 651.36(m/z) for DG and 782.67 → 635.24 (m/z) for IS. The method had a chromatographic running time of 3min and linear calibration curves over the concentrations of 2-400ng/mL for MDZ and 1'-OHMDZ and 0.5-100ng/mL for DG. The recoveries of the method were 86.8-96.3% for MDZ, 84.6-86.4% for 1'-OH MDZ, and 81.7-85.1% for DG. The lower limit of quantification (LLOQ) of the method was 2ng/mL for MDZ and 1'-OHMDZ and 0.5ng/mL for DG. The intra- and inter-batch precision were less than 15% for all quality control samples at concentrations of 5, 50 and 320ng/mL for MDZ and 1'-OHMDZ and 1, 10 and 80ng/mL for DG. The validated LC-MS/MS method has been successfully used to analyze the concentrations of MDZ, 1'-OH MDZ and DG in rat plasma for simultaneous measurement of in vivo P-gp and CYP 3A activity.