ALBERT

Description:    An inexpensive, simple and environmentally friendly method based on dispersive liquid liquid microextraction (DLLME) for rapid determination of benzene derivatives in water samples was proposed. A significant improvement of DLLME procedure was achieved. Trace volume ethyl acetate (60 μL) was exploited as dispersion solvent instead of common ones such as methanol and acetone, the volume of which was more than 0.5 mL, and the organic solvent required in DLLME was reduced to a great extent. Only 83-μL organic solvent was consumed in the whole analytic process and the preconcentration procedure was less than 10 min. The advantageous approach coupled with gas chromatograph-flame ionization detector was proposed for the rapid determination of benzene, toluene, ethylbenzene and xylene isomers in water samples. Results showed that the proposed approach was an efficient method for rapid determination of benzene derivatives in aqueous samples. Content Type Journal Article Category Short Communication Pages 1-5 DOI 10.1007/s10337-012-2215-7 Authors Chun Peng Diao, College of Environmental Science and Engineering, South China University of Technology, Guangzhou Higher Education Mega Center, Guangzhou, 510006 China Chao Hai Wei, College of Environmental Science and Engineering, South China University of Technology, Guangzhou Higher Education Mega Center, Guangzhou, 510006 China Chun Hua Feng, College of Environmental Science and Engineering, South China University of Technology, Guangzhou Higher Education Mega Center, Guangzhou, 510006 China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    Development of a reversed phase high performance liquid chromatographic method for determination of six related impurities in prilocaine substance is reported. The test of related impurities in European Pharmacopoeia (Ph. Eur.) cannot meet the demands with the chromatographic parameters given, therefore different types of chromatographic systems and eight columns have been evaluated in the present study. A new method with a Hypercarb column was developed and validated. This method fulfils the demands in the Ph. Eur., and the validation shows that the method is selective, reproducible, linear, accurate and robust with sufficient limits of detection (0.001–0.004% of 2.5 mg prilocaine mL −1 ) and quantification (0.002–0.009% of 2.5 mg prilocaine mL −1 ). Content Type Journal Article Category Original Pages 1-8 DOI 10.1007/s10337-012-2212-x Authors Janina Sroka-Markovic, Analytical Development, AstraZeneca, 15185 Södertälje, Sweden Linda Johansson, Analytical Development, AstraZeneca, 15185 Södertälje, Sweden Magnus B. O. Andersson, Analytical Development, AstraZeneca, 15185 Södertälje, Sweden Ingrid Granelli, Department of Analytical Chemistry, Stockholm University, 10691 Stockholm, Sweden Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    In the present study, baseline separation of the enantiomers of 16 β-carboline derivatives was successfully achieved using both capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) techniques in short run times (〈15 min) and thus permit the determination of enantiomeric excess. In HPLC methodology, cellulose chiral stationary phase (Chiralcel OD-H) was used with a binary mobile phase constituted of n -hexane/ethanol 85/15 leading to a resolution factor of 12.6 in 15 min. Preparative HPLC allowed to obtain pure enantiomers of two compounds. In CE, chiral selectivity was developed with an in-capillary stacking strategy using anionic (highly sulfated-γ) cyclodextrins 5% (w/v) as chiral selectors and a 60 mM phosphate buffer (pH 2.5) resulting in a resolution of 10.26 in 14 min of analysis. The analytical characteristics of the two developed methods were studied in terms of repeatability, limits of detection and limits of quantification showing their suitability to be extended to all the other molecules. Content Type Journal Article Category Original Pages 1-9 DOI 10.1007/s10337-012-2194-8 Authors Emmanuelle Lipka, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Saïd Yous, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Christophe Furman, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Pascal Carato, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Carole Deghaye, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Jean-Paul Bonte, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Claude Vaccher, Faculté des Sciences Pharmaceutiques et Biologiques, Univ Lille Nord de France, EA 4481, 3 rue du Pr. Laguesse, 59000 Lille, France Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A capillary chromatography system was developed using an open capillary tube and a ternary solvents carrier solution of water-hydrophilic/hydrophobic organic solvent mixture. The chromatography is called a tube radial distribution chromatography (TRDC) system. The TRDC system works without applying high voltages or using specific columns, such as monolithic and packed columns. In this study, the effects of tube materials on separation performance were examined in the TRDC system, by using poly(tetrafluoroethylene) (PTFE; 100–400 μm inner diameter), polyethylene (PE; 200 μm inner diameter), and copolymer of (tetrafluoroethylene–perfluoroalcoxyethylene) (PTFE–PFAE; 100 μm inner diameter) capillary tubes. An analyte solution of 2,6-naphthalenedisulfonic acid and 1-naphthol as a model was subjected to the system with a water–acetonitrile–ethyl acetate carrier solution; 15:3:2 volume ratio (water-rich carrier) and 3:8:4 volume ratio (organic solvent-rich carrier). The flow rates were adjusted to be 0.5 μL min −1 for PTFE and PTFE–PFAE tubes as well as 2.0 μL min −1 for PE tube under laminar flow conditions. These analytes in the solution were separated in this order with the water-rich carrier solution with baseline separation in the three capillary tubes, while they were eluted in the reverse order or not separated with the organic solvent-rich carrier solution. The effects of tube temperature on separation were also examined with the water-rich carrier solution; the best resolutions were observed at 0 °C of the tube temperature. The obtained results were compared with those of fused-silica capillary tube and discussed. Content Type Journal Article Category Short Communication Pages 1-5 DOI 10.1007/s10337-012-2205-9 Authors Yudai Kudo, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Naoya Jinno, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Masahiko Hashimoto, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Kazuhiko Tsukagoshi, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: R.E. Hester and R.M. Harrison (Eds.): Nuclear Power and the Environment Content Type Journal Article Category Book Review Pages 1-2 DOI 10.1007/s10337-012-2208-6 Authors Ken Jones, Knutsford, Cheshire, UK Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    In this study, improved homogeneous liquid–liquid extraction (HLLE), equipped with GC–ECD has been developed for the extraction and determination of organochlorinated pesticides (OCPs) in water. The phase separation phenomenon occurred by temperature in a ternary solvent (water/methanol/chloroform) system. Several factors influencing the extraction efficiency were investigated and optimized with orthogonal array design. Furthermore, in this study, for the first time, before immiscible organic phase formation, different volumes of deionized water were subjected to homogeneous solution to investigate the effect of this factor on the extraction performance of HLLE. Optimal results were as follows: volume of the extracting solvent (chloroform), 50 μL; volume of the consolute solvent (methanol), 1.2 mL; volume of the sample, 2.5 mL; volume of the deionized water, 0.5 mL; time of centrifuge, 7 min. Under the optimum conditions, repeatability was obtained by spiking OCPs at concentration level of 20 μg L −1 , the RSDs varied between 4.8 and 10.7% ( n  = 4). The limits of detection of 0.02–0.12 μg L −1 were obtained for the OCPs. Enrichment factors and the extraction percent of the studied compounds were in the range of 240–300 and 69.2–84.0%, respectively. Finally, the results of the proposed HLLE method were compared with the same HLLE method without addition of deionized water. The results indicated that the proposed method has higher enrichment factors and lower detection limits. Content Type Journal Article Category Original Pages 1-7 DOI 10.1007/s10337-012-2206-8 Authors Farahnaz Rezaei, Department of Analytical Chemistry, Faculty of Chemistry, Iran University of Science and Technology, Narmak, 16846 Tehran, Iran Mohammad-Reza Milani Hosseini, Department of Analytical Chemistry, Faculty of Chemistry, Iran University of Science and Technology, Narmak, 16846 Tehran, Iran Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A sensitive and rapid liquid chromatography–mass spectrometry (LC–MS) assay was established for the quantitation of CYC-116, an antitumor drug, in rat plasma. The chromatographic separation was accomplished on a Kromasil C 18 column (150 mm × 4.6 mm i.d., 5 μm particle size) at an isocratic flow rate of 0.8 mL min −1 using acetonitrile–water–formic acid (23.5:76.5:0.1, v/v/v) as the mobile phase. The plasma extraction was performed by liquid–liquid extraction using ethyl acetate as the solvent, and the extracts were subjected to MS analysis using a quadrupole mass spectrometer. The calibration curve of CYC-116 was linear over the concentration range of 5–2,500 ng mL −1 ( r  = 0.9955). The mean recovery was 85.0 ± 8.0%, and the matrix effect ranged from 90.0 to 110.0%. The intra- and interday precisions were less than 11.8 and 6.6%, respectively, and the accuracy was within ±5.8%. The method was successfully applied to study the pharmacokinetics of CYC-116 in rats after oral administration. Content Type Journal Article Category Original Pages 1-6 DOI 10.1007/s10337-011-2175-3 Authors Jing Su, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Xiaohui Chen, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Qing Li, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Zhiguo Yu, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Xiaoduo Guan, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Lulu Geng, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Kaishun Bi, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016 People’s Republic of China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    Tube radical distribution chromatography (TRDC) uses an untreated open tubular capillary tube and a ternary mixture of solvents (water and hydrophilic/hydrophobic organic solvents) as a carrier solution. A model analyte mixture comprising 1-naphthol, 1-naphthoic acid, 1-naphthalenesulfonic acid, 2,6-naphthalenedisulfonic acid, and 1,3,6-naphthalenetrisulfonic acid was examined by the TRDC and capillary zone electrophoresis (CZE) systems that comprised mainly a capillary tube and a detector. In the TRDC system the elution order of analytes could be changed by altering the component ratios of the solvents, whereas in the CZE system the elution order was changed by altering the electroosmotic flow direction. The experimental data obtained provide clues about the features and utility of TRDC as a new separation method. Content Type Journal Article Category Short Communication Pages 1-6 DOI 10.1007/s10337-012-2203-y Authors Kisuke Tabata, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Naoya Jinno, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Keiichi Noda, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Masahiko Hashimoto, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Kazuhiko Tsukagoshi, Department of Chemical Engineering and Materials Science, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: K. Kamienska-Trela (Ed.): Nuclear Magnetic Resonance. Volume 40. Specialist Periodical Reports of the Royal Society of Chemistry Content Type Journal Article Category Book Review Pages 1-2 DOI 10.1007/s10337-012-2209-5 Authors John C. Lindon, Imperial College London, London, UK Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A simple, selective and highly sensitive method was developed and optimized to determine the most commonly used UV filters with endocrine-disrupting potential in water, namely benzophenone-3 (BP-3), octocrylene (OC), ethylhexyl dimethyl p -aminobenzoate (OD-PABA), ethylhexyl methoxycinnamate, ethylhexyl salicylate (EHS) and homosalate (HMS). Samples were extracted by stir bar sorptive extraction followed by liquid desorption (SBSE-LD). The important factors influencing SBSE-LD were optimized. Under optimal conditions, assays were performed on 50 mL of water sample using stir bars (0.5 mm in film thickness, 10 mm in length) at room temperature. The analytes were determined by liquid chromatography–tandem mass spectrometry with triple quadrupole analyzer using atmospheric pressure chemical ionization. The main parameters in HPLC–APCI–MS/MS were also optimized to provide the best performances for all analytes. Moreover, matrix effect was investigated using two methods the post-column infusion system and the method of spiked matrices after extraction. As a result, no significant matrix effect on the analysis was observed. The method showed good linearity ( R 2 coefficients greater than 0.996 in different water samples after SBSE-LD). Recoveries of the analytes were close to 90%, except for BP-3 (64%) and OC (76%) with relative standard deviation lower than 11%. Detection limits were between 0.6 and 3.3 ng L −1 for all the analytes except for HMS (94 ng L −1 ) and EHS (114 ng L −1 ). This methodology was applied to measure UV filters in seawater, river water and wastewater in different sites of Liguria; BP-3 and OC were found in most of the considered samples at rather low concentration level. Content Type Journal Article Category Original Pages 1-10 DOI 10.1007/s10337-012-2202-z Authors Emanuele Magi, Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 16146 Genoa, Italy Marina Di Carro, Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 16146 Genoa, Italy Carlo Scapolla, Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 16146 Genoa, Italy Kieu T. N. Nguyen, Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 16146 Genoa, Italy Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    Water-soluble sodium poly(aspartate- co -lactide) (PALNa) copolymers with a molar ratio of aspartate-to-lactide units equal to 1:0.6, 1:1.0 and 1:1.5 were studied using NMR spectroscopy to determine the composition as well as SEC-MALS and static light-scattering measurements to determine the molar-mass characteristics of the copolymers. In the copolymer aqueous solutions, high-molar-mass species were detected, most probably due to the incomplete dissolution of the samples. The molar-mass averages determined in water with added simple electrolyte, i.e., NaCl, were much lower than the values determined in pure water. The concentration of the salt, which allows dissolution on a molecular level, and the separation predominantly according to a size-exclusion mechanism depend on the chemical composition of the PALNa copolymers. The optimal mobile phase for the PALNa-1/0.6 and the PALNa-1/1.0 copolymers was 0.1 M NaCl at pH 9, and for the PALNa-1/1.5 copolymer with a higher content of lactide units it was 0.05 M NaCl at pH 9. The molar-mass averages of the PALNa-1/1.0 copolymer, determined by SEC-MALS and static light-scattering measurements, were comparable. Content Type Journal Article Category Original Pages 1-8 DOI 10.1007/s10337-012-2180-1 Authors Maja Gričar, Laboratory for Polymer Chemistry and Technology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Majda Žigon, Laboratory for Polymer Chemistry and Technology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Tina Šmigovec Ljubič, Laboratory for Polymer Chemistry and Technology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Ema Žagar, Laboratory for Polymer Chemistry and Technology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Luigi Mondello (Ed.): Comprehensive Chromatography in Combination with Mass Spectrometry Content Type Journal Article Category Book Review Pages 1-2 DOI 10.1007/s10337-012-2189-5 Authors Edward R. Adlard, Burton, South Wirral, UK Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    Formaldehyde has been highlighted as potential genotoxic impurity (GTI). Trace-level quantification of GTIs in drug substances requires sensitive, precise and accurate analytical methodologies for their estimation in drug substances and control. Analysis and estimation of formaldehyde is very challenging due to its properties namely volatility, high polarity, low molecular weight and over and above the absence of chromophore. This article presents a validated HPLC–UV method which is sensitive to quantification of formaldehyde in active pharmaceutical ingredient. As formaldehyde does not possess chromophore, the developed HPLC method involves derivatization with 2,4-dinitrophenylhydrazine. Using this method, the detection and quantitation limits achieved are 0.5 and 1.5 ppm, respectively. The calibration curve of formaldehyde was linear over the concentration range of 1.5–20 ppm. The method was found to be sensitive, precise and accurate and the proposed method has been successfully applied to estimate formaldehyde content in scale-up batches of bulk drug. Content Type Journal Article Category Original Pages 1-6 DOI 10.1007/s10337-012-2186-8 Authors A. Nageswari, Center of Pharmaceutical Sciences, IST, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, 500072 India K. V. S. R. Krishna Reddy, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Hyderabad, 500078 India K. Mukkanti, Center of Pharmaceutical Sciences, IST, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, 500072 India Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A method combining solid-phase extraction and high-performance liquid chromatography (SPE–HPLC) has been developed for analysis of ten rare ginsenosides including 20( R )-Rh 1 , 20( S )-Rh 1 , 20( R )-Rg 3 , 20( S )-Rg 3 , Rg 5 , Rk 1 , Rg 6 , F 4 , Rk 3 , and Rh 4 in three kinds of injection (Shenfu, Shenmai, and Shengmai). Waters Oasis HLB SPE columns were used to clean and enrich the sample. An Eclipse XDB-C 18 column was used to separate the analytes, with water and acetonitrile as mobile phase components under gradient elution conditions at 30 °C. There were good linear correlations between the signals measured and the concentrations of the ten analytes ( r 2  ≥ 0.9996). Intraday and interday precision were both better than 2.19% and average recovery ranged from 95.25 to 108.83%. The proposed method was successfully applied to determination of the ten analytes in different batches of the injections and the results indicated the method is simple, rapid, and accurate. The proposed method could be used for quality control during manufacture of the injections. Content Type Journal Article Category Original Pages 1-7 DOI 10.1007/s10337-012-2183-y Authors Rui-Jie Yang, College of Chemistry, Jilin University, ChangChun, 130012 Jilin Province, China Xu-Wen Li, College of Chemistry, Jilin University, ChangChun, 130012 Jilin Province, China Hua Yao, College of Chemistry, Jilin University, ChangChun, 130012 Jilin Province, China Mu-Chun Zhang, Department of Urology, China-Japan Union Hospital, Jilin University, ChangChun, 130033 Jilin Province, China Yong-Ri Jin, College of Chemistry, Jilin University, ChangChun, 130012 Jilin Province, China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    In this study, an end-point-based fluorescence assay for soluble epoxide hydrolase (sEH) was transformed into an on-line continuous-flow format. The on-line biochemical detection system (BCD) was coupled on-line to liquid chromatography (LC) to allow mixture analysis. The on-line BCD was based on a flow system wherein sEH activity was detected by competition of analytes with the substrate hydrolysis. The reaction product was measured by fluorescence detection. In parallel to the BCD data, UV and MS data were obtained through post-column splitting of the LC effluent. The buffer system and reagent concentrations were optimized resulting in a stable on-line BCD with a good assay window and good sensitivity (S/N 〉 60). The potency of known sEH inhibitors (sEHis) obtained by LC–BCD correlates well with published values. The LC–BCD system was applied to test how oxidative microsomal metabolism affects the potency of three sEHis. After incubation with pig liver microsomes, several metabolites of sEHis were characterized by MS, while their individual potencies were measured by BCD. For all compounds tested, active metabolites were observed. The developed method allows for the first time the detection of sEHis in mixtures providing new opportunities in the development of drug candidates. Content Type Journal Article Category Original Pages 1-9 DOI 10.1007/s10337-012-2343-0 Authors David Falck, Department of BioMolecular Analysis, VU University Amsterdam, Amsterdam, The Netherlands Nils Helge Schebb, Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA Setyo Prihatiningtyas, Department of BioMolecular Analysis, VU University Amsterdam, Amsterdam, The Netherlands Jiawen Zhang, Department of BioMolecular Analysis, VU University Amsterdam, Amsterdam, The Netherlands Ferry Heus, Department of BioMolecular Analysis, VU University Amsterdam, Amsterdam, The Netherlands Christophe Morisseau, Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA Jeroen Kool, Department of BioMolecular Analysis, VU University Amsterdam, Amsterdam, The Netherlands Bruce D. Hammock, Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA Wilfried M. A. Niessen, Department of BioMolecular Analysis, VU University Amsterdam, Amsterdam, The Netherlands Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A quantitative structure–retention relationship study was performed for 286 flavor compounds with highly structural diversity on different stationary phases of different polarities. Firstly, the structure–retention relationship was statistically explored using constitutional, topological, molecular properties, charge descriptors and quantum chemical descriptors. Some recently developed chemometric methods, such as the ones for robust analysis and variable selection were firstly employed to predict accurately the gas chromatographic retention indices. The stability and validity of models have been tested by internal and external validation, and good robustness and predictive ability were obtained. The resulting QSRR models were well correlated, with the square of correlation coefficient for cross validation, Q 2 , values of 0.9847, 0.9838, 0.9745 and 0.9646 on stationary phase DB5, OV101, OV17 and C20M, respectively. The molecular properties known to be relevant for GC retention index, such as molecular size, branching, electron density distribution and hydrogen bond effect were well covered by generated descriptors. The descriptors used in models on four stationary phases were compared, and some reasonable explanations about gas chromatographic retention mechanism were obtained. The developed model may be useful for the prediction of flavor compounds while experimental data are unavailable. Content Type Journal Article Category Original Pages 1-13 DOI 10.1007/s10337-012-2349-7 Authors Xian Chen, Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha, 410083 People’s Republic of China Hong-Dong Li, Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha, 410083 People’s Republic of China Fang-Qiu Guo, Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha, 410083 People’s Republic of China Jun Yan, Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha, 410083 People’s Republic of China Dong-Sheng Cao, Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha, 410083 People’s Republic of China Yi-Zeng Liang, Research Center of Modernization of Traditional Chinese Medicines, Central South University, Changsha, 410083 People’s Republic of China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    In this paper, the review on application of factorial-based designs in liquid chromatography (LC) is given. The most useful and applicable full factorial design and reduced forms of full factorial design (fractional factorial design and Plackett–Burman design) applied in LC are presented. Literature survey shows that experimental design presents very often used tool in screening, optimization and robustness testing of LC methods. Content Type Journal Article Category Original Pages 1-14 DOI 10.1007/s10337-012-2350-1 Authors Biljana Jančić Stojanović, Department of Drug Analysis, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   To investigate whether general practitioners, hospital physicians and specialized practitioners in psychiatry have similar preferences for initiating treatment with expensive serotonin-specific reuptake inhibitors (SSRIs). Methods   All first-time prescriptions for the SSRIs escitalopram, citalopram and sertraline reported to the Danish National Register of Medicinal Product Statistics from April 1, 2009 until March 31, 2010 were analysed with regard to treatment naivety and type of prescriber. A prescription was considered as first time if the patient had not received a prescription for the same drug within the last 2 years. Patients who had not received a prescription for an antidepressant within 6 months prior to the date of redemption were classified as treatment-naïve. Results   We included 82,702 first-time prescriptions, 65,313 (79 %) of which were for treatment-naïve patients. Of the treatment-naïve patients, 19 % were initially prescribed escitalopram. Hospital physicians prescribed escitalopram to 34 % of their treatment-naïve patients, while practitioners specialized in psychiatry prescribed it to 25 %, and general practitioners prescribed it to 17 %. General practitioners, however, were responsible for initiating 87 % of all treatment-naïve patients. Conclusion   The most expensive SSRI, escitalopram, is prescribed as first choice to one in five patients receiving their first antidepressant of escitalopram, citalopram or sertraline. General practitioners made the bulk of all first-time SSRI prescriptions to treatment-naïve patients. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-5 DOI 10.1007/s00228-012-1447-7 Authors Karen Killerup Poulsen, Faculty of Health and Medicines Sciences, University of Copenhagen, Copenhagen, Denmark Dorte Glintborg, Institute for Rational Pharmacotherapy, Copenhagen, Denmark Søren Ilsøe Moreno, Institute for Rational Pharmacotherapy, Copenhagen, Denmark Steffen Thirstrup, Danish Health and Medicines Authority, Copenhagen, Denmark Lise Aagaard, Institute of Public Health, Clinical Pharmacology, Faculty of Health Sciences, University of Southern Denmark, JB Winsløws Vej 19, 5000 Odense C, Denmark Stig Ejdrup Andersen, Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Bringing pharmacogenetics to the bedside Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1444-x Authors Ankur Gupta, Department of Cardiology, Hartford Hospital, Cardiology, 80 Seymour Street, Hartford, 06106, CT, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   It is recognised that paediatric prescribing errors are prevalent, and that most are made by junior doctors; however, detecting errors in order to demonstrate actual error rates can be difficult. There is evidence to suggest that dosing errors are the most common type of prescribing error in practice, but there has been little research on whether prescribing assessments are an effective reflection of actual practice.This article aims to determine if prescribing error types in a paediatric prescribing competency assessment reflects error types seen in actual practice. Methods   This study was conducted in Royal Manchester Children’s Hospital (RMCH) and the participants were junior doctors working at RMCH in 2010-2011. The intervention was a prescribing competency assessment package at RMCH.The main outcome measurement was the category and rate of prescribing errors. Results were taken from the junior doctors’ prescribing competency assessment. The assessment papers were analysed for errors and the errors were then broken down into pre-defined categories. Results   Rates of prescribing errors in the competency assessment are higher than published results shown in practice (23.1 %). The most common type of prescribing error (incorrect calculation of dose) reflects results seen in actual practice. Conclusion   The types of prescribing errors made in the competency assessment are reflective of errors made in actual practice. Prescribing teaching can be tailored according to the types of errors noted; and the prescribing competency package as a whole can be used to educate junior doctors on good prescribing practice and reduce prescribing errors. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-4 DOI 10.1007/s00228-012-1440-1 Authors Tessa Davis, Medical Leadership Programme, North Western Deanery, Manchester, UK Hong Thoong, Royal Manchester Children’s Hospital, Pharmacy Department, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Anna Kelsey, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Guy Makin, Institute of Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Background/aim   Timed interval cerebrospinal fluid (CSF) sampling by indwelling catheterization can be a valuable corroborative tool for the pharmacokinetic and pharmacodynamic assessment of drugs. CSF sampling in studies on drug candidates for Alzheimer’s disease have been conducted in evaluations of the biomarkers acetylcholine (ACh), tau proteins, amyloid precursor protein and beta-amyloid fragments. The primary aim of this study was to study the feasibility and the burden on the healthy volunteers of serial CSF sampling within the contract research organization environment in order to establish a standardized research tool for future drug development studies. Materials and methods   This study is a validation study in healthy subjects: eight healthy male subjects aged 55–75 years were enrolled. After eligibility had been confirmed, the subjects were admitted to the clinical pharmacology unit 2 days before starting the CSF sampling procedure. Hydration by drip infusion of 2 L saline was performed for 24 h before starting the CSF sampling procedure, and for antithrombotic purposes, Fraxiparine (nadroparine calcium) was given 12 and 36 h after intradural catheterization. CSF catheterization was performed by board-certified anesthesiologists with experience in inserting indwelling intrathecal catheters. Subjects only required to remain in a horizontal position for the first 24 h after removal of the catheter. CSF and blood samples were collected by interval sampling over a 30-h period. Results   The study was completed by seven of the eight subjects. Six subjects who completed the study reported adverse effects (AEs) which were all mild and from which they recovered during their stay in the clinic. A total of 25 AEs were reported of which 13 were considered to be procedure-related. The procedure was well tolerated by all participating subjects, and the VAS scale scores for headache and back pain were low. CSF samples were analyzed for ACh. All values were above the lowest limit of quantification. On average, the ACh concentration started at a low level but rose between 1 and 2 h after insertion of the catheter and then remained high during the whole sampling period up to 30 h. Conclusion   Serial sampling of CSF in seven healthy volunteers up to 30 h occurred without serious complications and was well tolerated. The CSF collected was of good quality and facilitated the assessment of an Alzheimer’s disease-sensitive biomarker. We conclude that this validation study can form the basis for future patient studies aimed at elucidating disease mechanisms and the pharmacodynamics of drugs in the developmental stage. Content Type Journal Article Category Clinical Trial Pages 1-8 DOI 10.1007/s00228-012-1443-y Authors Izaak den Daas, QPS Netherlands BV, Groningen, The Netherlands Johan Wemer, QPS Netherlands BV, Groningen, The Netherlands Khalid Abou Farha, QPS Netherlands BV, Groningen, The Netherlands Wim Tamminga, QPS Netherlands BV, Groningen, The Netherlands Theo de Boer, QPS Netherlands BV, Groningen, The Netherlands Rob Spanjersberg, Department of Anesthesiology, University Groningen, University Medical Center Groningen, Groningen, The Netherlands Michel M. R. F. Struys, Department of Anesthesiology, University Groningen, University Medical Center Groningen, Groningen, The Netherlands Anthony R. Absalom, Department of Anesthesiology, University Groningen, University Medical Center Groningen, Groningen, The Netherlands Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    A heart-cut two-dimensional high-performance liquid chromatography method for enantiomeric determination of salbutamol, salmeterol and atenolol in urine is presented. It involves the use of two separations in a liquid chromatography–liquid chromatography achiral–chiral coupling. Target compounds were previously separated in a primary column (Kinetex™ HILIC, 2.6 μm, 150 × 2.1 mm I.D.) with a mixture of MeOH:ACN:ammonium acetate buffer (5 mM, pH 6) 90:5:5 (v/v/v) as mobile phase at a flow rate of 0.40 mL min −1 . Enantiomeric separation was carried out by transferring peak of each compound through a switching valve to a vancomycin chiral column (Chirobiotic™ V, 2.6 μm, 150 × 2.1 mm I.D.) using MeOH:ammonium acetate buffer (2 mM, pH 4) 97:3 (v/v) as mobile phase at a flow rate of 0.50 mL min −1 . Ultraviolet detection was done at 227 nm. The method was applied to determine target analytes in urine samples after enzymatic hydrolysis with β-glucuronidase from Helix pomatia , followed by a solid-phase extraction procedure using Isolute ® HCX mixed-mode cartridges. Extraction recoveries ranged from 82 to 90 % in urine samples. Detection limits were 0.091–0.095 μg for each enantiomer of atenolol and between 0.058 and 0.076 and 0.18–0.14 μg for enantiomers of salbutamol and salmeterol, respectively (3 mL of urine). Linearity ranges were between 0.5 and 10 μg mL −1 . Intraday and interday reproducibilities of enantiomeric ratio and enantiomeric fraction, expressed as relative standard deviation, were between 1.9 and 9.0 %. The optimized method was successfully applied to the analysis of urine samples obtained from excretion studies in volunteers and in freeze-dried urine samples, containing urinary components with MW 〈 10,000 and components with MW 〉 10,000, spiked with different amounts of studied drugs. Content Type Journal Article Category Original Pages 1-11 DOI 10.1007/s10337-012-2353-y Authors Yung Yang, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avda. Complutense s/n, 28040 Madrid, Spain Noelia Rosales-Conrado, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avda. Complutense s/n, 28040 Madrid, Spain Vanesa Guillén-Casla, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avda. Complutense s/n, 28040 Madrid, Spain María Eugenia León-González, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avda. Complutense s/n, 28040 Madrid, Spain Luis Vicente Pérez-Arribas, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avda. Complutense s/n, 28040 Madrid, Spain Luis María Polo-Díez, Department of Analytical Chemistry, Faculty of Chemistry, Complutense University of Madrid, Avda. Complutense s/n, 28040 Madrid, Spain Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   In this study, direct separation of ketoprofen enantiomers was performed on a Chirobiotic T column. Methods   The effects of the type and amount of the organic modifier, buffer concentration, pH value, temperature and flow rate on retention and selectivity were investigated. Experiments were carried out in the temperature range of 20–40 °C to study the effects of temperature. Thermodynamic parameters were calculated from plots of ln k or ln α versus 1/ T . Molecular dynamics simulation was done to investigate interactions between ketoprofen enantiomers and the chiral selector—teicoplanin. Results   It was observed that pH and flow rate had a large influence on resolution. Baseline separation of ketoprofen enantiomers could be achieved with low amounts of methanol, high temperature and high buffer concentrations. Conclusions   Results from a thermodynamic study and molecular dynamics simulation show that steric hindrance effect, π–π complexation, hydrogen bonding and electrostatic forces are the main driving forces which cause chiral recognition of ketoprofen enantiomers. Content Type Journal Article Category Original Pages 1-9 DOI 10.1007/s10337-012-2352-z Authors Xiaomei He, China Pharmaceutical University, 24 Tongjia Lane, Nanjing, 210009 Jiangsu province, China Rui Lin, Yancheng Health Vocational and Technical College, Yancheng, 224005 China Hua He, China Pharmaceutical University, 24 Tongjia Lane, Nanjing, 210009 Jiangsu province, China Meiling Sun, China Pharmaceutical University, 24 Tongjia Lane, Nanjing, 210009 Jiangsu province, China Deli Xiao, China Pharmaceutical University, 24 Tongjia Lane, Nanjing, 210009 Jiangsu province, China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    In this study, we focused on the studying of taurine complexes with phenol and sodium hypochlorite, and of taurine with sodium hypobromite by spectrometry, reverse phase chromatography and ion-exchange chromatography. The formed complexes were studied under various conditions such as temperature (10, 20, 30, 40, 50 and 60 °C), and/or time of interaction (0, 5, 10, 15, 20, 25 and 30 min). In addition, we optimized high performance liquid chromatography coupled with UV detector for detection of taurine and its complexes with the acids. Taurine–phenol–hypochlorite complex was effectively separated under isocratic elution, mobile phase water:methanol 30:70 %, v : v , flow rate 1 mL min −1 and 55 °C. Taurine-bromamine complex was isolated under the following optimized conditions as isocratic elution, mobile phase water:methanol 85:15 % v : v , flow rate 1 mL min −1 and 55 °C. The limits of detection (3 S/N) were estimated as 1 μM for both types of complexes, i.e. for taurine. Further, we estimated recovery in one sample of urine (male 25 years), commercially achieved energy drink and tea leaves and varied from 79 to 86 %. Further, we aimed our attention at investigating the ability of the above characterized taurine and taurine complexes to scavenge reactive oxygen species. For this purpose, an ion-exchange liquid chromatography with post-column derivatization with ninhydrin and VIS detector was used. It clearly follows from the results obtained that taurine itself reacts with peroxide more intensely than in a bound form, which can be associated with the highest signal decrease. Complexes stabilized structure taurine against peroxide radicals, resulting in slower decreasing of peak heights. The most stable was taurine complexes with phenol and hypobromite. Content Type Journal Article Category Original Pages 1-11 DOI 10.1007/s10337-012-2354-x Authors Lukas Nejdl, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Jiri Sochor, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Ondrej Zitka, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Natalia Cernei, Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, 616 00 Brno, Czech Republic Branislav Ruttkay-Nedecky, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Pavel Kopel, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Petr Babula, Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, 616 00 Brno, Czech Republic Vojtech Adam, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Jaromir Hubalek, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Rene Kizek, Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, 613 00 Brno, Czech Republic Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   To analyse, in older community-dwelling people living in Italy’s Lombardy region, 8-year trends in new users of spironolactone co-prescribed with angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs); blood test monitoring; and independent predictors of appropriate blood test monitoring. Methods   The region’s administrative health database from 2001 to 2008 was used to retrieve yearly frequencies of subjects aged 65+ who started this co-prescription. Multivariate analyses were adjusted for age, sex, local health unit, treatment with beta-blockers, drugs for diabetes, and polypharmacy (i.e., exposure to five or more different drugs). Results   Only new users of spironolactone co-prescribed with ARBs increased from 2001 to 2008 ( P  〈 0.001). In the 6 months before starting the co-prescriptions 96 to 100% of patients measured serum creatinine (mean 99.3%), sodium (97.3%) and potassium (98.6%). Within 3 months of starting the co-prescriptions 96 to 99% of patients measured serum sodium (mean 97.3%) and potassium (98.6%), but on average only 48% of them (range 43 to 53%) measured serum creatinine, with an increase over time (odds ratio [change in regression per year] = 1.03, 95% CI 1.02–1.05, P  〈 0.001). At multivariate analysis polypharmacy was found to be the only independent predictor of such creatinine monitoring ( P  〈 0.001). Conclusions   Our results support the need for greater awareness within the medical community of the potential renal toxicity of the association of spironolactone with ACE-Is and/or ARBs. Adequate short-term monitoring of serum creatinine in all older community-dwelling people who receive such co-prescription is necessary in order to ensure safe usage of these medications. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1401-8 Authors Claudio Bilotta, Geriatric Medicine Outpatient Service, Department of Urban Outpatient Services, Istituti Clinici di Perfezionamento Hospital, viale Doria 52, 20124 Milan, Italy Carlotta Franchi, Laboratory for Quality Assessment of Geriatric Therapies and Services, Mario Negri Institute for Pharmacological Research, via La Masa 19, 20156 Milan, Italy Alessandro Nobili, Laboratory for Quality Assessment of Geriatric Therapies and Services, Mario Negri Institute for Pharmacological Research, via La Masa 19, 20156 Milan, Italy Paola Nicolini, Thoraco-Pulmonary and Cardiocirculatory Department, University of Milan, via F. Sforza 35, 20122 Milan, Italy Codjo Djignefa Djade, Laboratory for Quality Assessment of Geriatric Therapies and Services, Mario Negri Institute for Pharmacological Research, via La Masa 19, 20156 Milan, Italy Mauro Tettamanti, Laboratory for Quality Assessment of Geriatric Therapies and Services, Mario Negri Institute for Pharmacological Research, via La Masa 19, 20156 Milan, Italy Ida Fortino, Regional Health Ministry Lombardy Region, Piazza Città di Lombardia 1, 20124 Milan, Italy Angela Bortolotti, Regional Health Ministry Lombardy Region, Piazza Città di Lombardia 1, 20124 Milan, Italy Luca Merlino, Regional Health Ministry Lombardy Region, Piazza Città di Lombardia 1, 20124 Milan, Italy Carlo Vergani, Department of Medical Sciences, Geriatric Medicine, University of Milan, via Pace 9, 20122 Milan, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Citalopram is a selective serotonin reuptake inhibitor (SSRI) antidepressant that is widely used in clinical practice. Recent data have indicated that high therapeutic citalopram doses may cause electrocardiographic abnormalities, and the regulatory authorities have amended its licenced dosage. The present manuscript reviews the available data concerning citalopram and cardiac toxicity. Methods   Published data concerning the cardiac effects of citalopram were ascertained, and clinical data were considered separately between adverse effects arising from therapeutic use versus toxicity in the setting of intentional overdose. Results   The occurrence of electrocardiographic abnormalities has long been recognised as a complication of acute citalopram overdose; a dose-effect relationship for QT prolongation has been described in a number of large case series, including several cases of torsades de pointes. In contrast, few data indicate the occurrence of QT prolongation and arrhythmia after therapeutic doses, and a dose-effect relationship within the therapeutic range has only recently been established. Citalopram is more likely to cause QT prolongation in patients with metabolic disturbance or pre-existing cardiac disease. Conclusions   A dose-effect relationship for QT prolongation exists across a broad range of citalopram doses, such that caution must be exercised when prescribing high doses or if there are co-existent risk factors for QT effects. The available data illustrate how clinical toxicity data may offer an earlier signal of cardiac effects than ascertained from conventional pharmacovigilance methods. Content Type Journal Article Category Review Article Pages 1-6 DOI 10.1007/s00228-012-1408-1 Authors M. J. Cooke, Pharmacy Department, York Teaching Hospital NHS Foundation Trust, Wigginton Road, York, YO31 8HE UK W. S. Waring, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wigginton Road, York, YO31 8HE UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Objective   Our aim was to characterize Adverse Drug Reactions (ADRs) related to drug–drug interactions (DDIs) related to involvement of cytochrome P450 (CYP450) isoenzymes in a pharmacovigilance database. Methods   ADRs recorded by Midi-Pyrénées PharmacoVigilance center (France) between 1 January and 31 August 2008 were extracted from the French PharmacoVigilance Database (FPVD). Results   Among the 1,205 reported ADRs, 16 (1.3 %), can be explained by involvement of CYP450 isoenzymes (including 4 “serious”). All interactions involved CYP inhibitors, mainly for CYP3A4/5. Conclusion   The percentage of ADRs reported in the pharmacovigilance database and related to CYP450-induced DDIs appears to be relatively low (~ 1–2 %). Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-4 DOI 10.1007/s00228-012-1394-3 Authors Anne Charlotte Danton, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France François Montastruc, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Agnès Sommet, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Geneviève Durrieu, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Haleh Bagheri, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Emmanuelle Bondon-Guitton, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Maryse Lapeyre-Mestre, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Jean-Louis Montastruc, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d’Informations sur le Médicament, Centre Hospitalier Universitaire de Toulouse, Toulouse, France Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   We previously reported that chronic heart failure (CHF) treatments reduce the duration of hospitalisation, even in elderly patients. The present study aimed to determine whether CHF treatment also provides long-term benefits in terms of reduced mortality at 8 years. Methods   A cohort of 281 patients who were admitted to a French teaching hospital with a main diagnosis of CHF were followed through the health insurance databases for 1 year and through the national mortality database for 8 years. Results   Diuretics (236 patients, 84 %) and angiotensin-converting enzyme (ACE) inhibitors (193 patients, 69 %) were the most-frequently prescribed medications. The median duration of survival was 46 months. Mortality rates were significantly lower for patients administered beta-blockers (59 %) and statins (56 %) than for patients not exposed to these drugs (82 %, p  〈 0.001 and 78 %, p  = 0.001 respectively). No significant differences in mortality were observed for spironolactone, diuretics or ACE inhibitors. After adjustment, beta-blocker treatment remained associated with a significantly lower risk of mortality (hazard ratio, HR = 0.54 [0.34–0.84]). After adjustment, the use of two or three CHF drugs was associated with longer survival (HR = 0.53 [0.36–0.77]) than the use of zero or one CHF drug. Statins were also associated with longer survival after adjustment (HR = 0.53 [0.31–0.89]). In patients 75 years of age or older ( n  = 73), only beta-blocker treatment was associated with a significantly lower risk of mortality (HR = 0.31 [0.16–0.63]) in multivariate analysis. Conclusions   The use of beta-blockers was associated with better survival rates. The use of statins was also associated with better survival at 8 years. Randomised controlled trials are required to confirm these observations. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-8 DOI 10.1007/s00228-012-1400-9 Authors Patrick Maison, Service de Pharmacologie Clinique, AP-HP, Hôpital H. Mondor—A. Chenevier, Créteil, 94000 France Gaelle Desamericq, Service de Pharmacologie Clinique, AP-HP, Hôpital H. Mondor—A. Chenevier, Créteil, 94000 France François Hemery, Département d’information médicale, AP-HP, Hôpital H. Mondor—A. Chenevier, Créteil, 94000 France Nicole Elie, National Health Insurance Fund, Créteil, France Aldo Del’Volgo, National Health Insurance Fund, Créteil, France Jean Luc Dubois-Randé, Fédération de Cardiologie, AP-HP, Hôpital H. Mondor—A. Chenevier, Créteil, 94000 France Luc Hittinger, Fédération de Cardiologie, AP-HP, Hôpital H. Mondor—A. Chenevier, Créteil, 94000 France Isabelle Macquin-Mavier, Service de Pharmacologie Clinique, AP-HP, Hôpital H. Mondor—A. Chenevier, Créteil, 94000 France Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    A capillary gas chromatography (GC) procedure has been developed for the determination of four pharmaceutical preparations (famotidine, ranitidine, cimetidine, and metformin) after precolumn derivatization with methylglyoxal (MGo). GC was carried out using an HP-5 column (30 m × 0.32 mm id) at an initial column temperature of 90 °C for 2 min, followed by heating rate of 25 °C min −1 up to 265 °C. Nitrogen flow rate was 2.5 mL min −1 with split ratio 10:1. A linear calibration curve was obtained within 50–1,000 ng mL −1 and the limit of detection (LOD) was within 17–25 ng mL −1 . The derivatization, GC elution, and separation were repeatable in terms of retention time and peak height/peak area with relative standard deviation within ±4.6 %. The procedure was applied to the determination of the drugs in pharmaceutical preparations and the sera of volunteers who were given oral doses of the drugs. The results of the analysis agreed with the labeled values of the pharmaceutical preparations and were 147–4,903 ng mL −1 in serum with an RSD within 1.0–4.2 %, after ingestion of a single dose of 40–500 mg of active ingredient in a tablet. Content Type Journal Article Category Original Pages 1-7 DOI 10.1007/s10337-012-2321-6 Authors Subhan Ali Majidano, Institute of Advanced Research Studies in Chemical Sciences (IARSCS), University of Sindh, Jamshoro, Pakistan Muhammad Yar Khuhawar, Institute of Advanced Research Studies in Chemical Sciences (IARSCS), University of Sindh, Jamshoro, Pakistan Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   The objective of this study was to compare different methods of adjusted indirect comparisons that can be used to investigate the relative bioavailability of different generic products. To achieve this goal, generic artemether/lumefantrine 20/120 mg tablets that have been prequalified by the World Health Organization (WHO) were selected as model products for study. Methods   Data from three bioequivalence studies conducted independently that compared three generics with the same reference product were used to indirectly determine the relative bioavailability between the generics themselves. Results   The different methods of indirect comparison examined in this study provide consistent results. Methods based on the assumption of a large sample size give slightly narrower 90 % confidence intervals. Therefore, the use of methods based on the t test is recommended. Given the precision of the area under the time–concentration curve (AUC) data, it is possible to conclude that the extent of exposure of artemether and lumefantrine is bioequivalent between the different generics studied. However, given the precision of the drug peak concentration (C max ) data, it is not possible to demonstrate equivalence within the conventional acceptance range for all comparisons; it is possible to conclude bioequivalence within the widened acceptance range 75–133 %. Conclusions   From a clinical viewpoint, not only are these prequalified generics bioequivalent and interchangeable with the reference product (Coartem, Novartis), but also the existing indirect evidence makes it possible to conclude that these WHO prequalified products are bioequivalent between themselves with respect to the AUC. The lack of the necessary precision to demonstrate bioequivalence between generics with respect to the C max within the conventional acceptance range does not preclude considering them as interchangeable, if necessary, since C max is considered to be of less clinical relevance for the relevant therapy. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-8 DOI 10.1007/s00228-012-1396-1 Authors Luther Gwaza, Evaluation and Registration Unit, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe John Gordon, Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Canada Jan Welink, Medicines Evaluation Board, Utrecht, The Netherlands Henrike Potthast, Subdepartment of Biostatistics and Pharmacokinetics, Federal Insitute for Drugs and Medical Devices, Bonn, Germany Henrik Hansson, Efficacy and Safety Department 1, Medical Products Agency, Uppsala, Sweden Matthias Stahl, The Prequalification of Medicines Programme Quality Assurance & Safety: Medicines Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland Alfredo García-Arieta, División de Farmacología y Evaluación Clínica, Subdirección de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, C/ Campezo 1. Edificio 8, Planta 2 Oeste, 28022 Madrid, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   To present concept, methods and use of a knowledge database providing assessments of potential fetal risks for all drugs on the Swedish market. Methods   Assessments of fetal risks are made primarily by analyzing prospective epidemiological data from the Swedish Medical Birth Register on drug intake in relation to birth outcome. This is complemented by evaluation of the scientific literature. Following standardized working procedures, a statement is compiled for each substance, which is also classified into one of three categories depending on the estimated risk level. The final documents include drug product names on the market, via linkage to a medicinal products register. The information is free and published on the website www.janusinfo.se . It can also be used as an integrated part of electronic health records. Results   The database covers assessments of fetal risks for close to 1,250 medicinal drug substances on the Swedish market. Each year, 96,000 searches are made, which might be compared to the around 100,000 children born in Sweden yearly. Apart from the Swedish Physicians’ Desk Reference (Fass), the database is the most commonly used resource among specialists within gynaecology and perinatal medicine for information on drugs during pregnancy. Conclusions   A non-commercial knowledge base with assessments of fetal risk of different drugs is valued by health care professionals and is used extensively in Sweden. Based on analyses of national health registers, the database provides unique information on teratogenic drug risks. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-11 DOI 10.1007/s00228-012-1399-y Authors Ulrika Nörby, E-health and Strategic IT, Public Healthcare Administration, Stockholm County Council, P.O. Box 17533, SE-118 91 Stockholm, Sweden Karin Källén, Tornblad Institute, University of Lund, Lund, Sweden Birgit Eiermann, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden Seher Korkmaz, E-health and Strategic IT, Public Healthcare Administration, Stockholm County Council, P.O. Box 17533, SE-118 91 Stockholm, Sweden Birger Winbladh, Department of Clinical Sciences and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden Lars L. Gustafsson, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    A liquid chromatography-mass spectrometry (LC-MS) assay was developed and validated for the quantification of lurasidone, an atypical antipsychotic drug, in rat plasma, bile, and urine. Rat plasma, bile, or urine samples were processed by liquid–liquid extraction and injected onto an LC-MS system for the quantification of lurasidone and ziprasidone (an internal standard). Lurasidone and ziprasidone were separated from endogenous substances using a Gemini C6-Phenyl column with mixture of acetonitrile and 0.1 % formic acid (80:20, v/v ) as the mobile phase. Quantification was performed using the selected ion monitoring mode at m/z 493 for lurasidone and m/z 413 for the IS. The detector response was specific and linear for lurasidone in the concentration range 5–5,000 ng mL −1 The intra- and inter-day accuracy and precision of the method were determined to be within the acceptable criteria for assay validation guidelines. In addition, lurasidone was stable under a variety of processing and handling conditions. Lurasidone concentrations could be readily measured in rat plasma, bile, and urine samples up to 24 h after an intravenous or oral administration, suggesting that the assay can be used in pharmacokinetic studies of lurasidone in rats. Content Type Journal Article Category Original Pages 1117-1128 DOI 10.1007/s10337-012-2294-5 Authors Yoon-Jee Chae, Department of Pharmaceutics, College of Pharmacy, Seoul National University, Gwanak 599, Gwanak-ro, Gwanak-gu, Seoul, 151-742 Republic of Korea Tae-Sung Koo, Graduate School of New Drug Discovery and Development, Chungnam National University, Yuseong, Daejeon, 305-764 Republic of Korea Kyeong-Ryoon Lee, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon, 305-343 Republic of Korea Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893 Journal Volume Volume 75 Journal Issue Volume 75, Numbers 19-20

Description:    Three alkoxyl-functionalized ionic liquids, 1-(3-triethoxysilyl propyl)-3-methyl imidazolium hexafluorophosphate (TESPMIM[PF 6 ]), 1-(3-triethoxysilyl propyl)-3-methyl imidazolium tetrafluoroborate (TESPMIM[BF 4 ]), and 1-(3-triethoxysilyl propyl)-3-methyl imidazolium bis(trifluoromethanesulfonyl)imide (TESPMIM[N(SO 2 CF 3 ) 2 ]), were synthesized and used as selective coating materials to prepare chemically bonded ionic-liquid-based organic–inorganic hybrid solid-phase microextraction (SPME) fibers by sol–gel technology. A possible mechanism of the sol–gel process is proposed, and the successful binding of ionic liquids to the formed silica substrate was confirmed by Fourier-transform infrared spectroscopy (FT-IR). These ionic-liquid-based sol–gel coatings have porous surface structure, high thermal stability, strong solvent resistance, wide pH application range, good coating preparation reproducibility, special selectivity, and extraction efficiency for both polar and nonpolar compounds, such as phenolic environmental estrogens, fatty acids, aromatic amines, alcohols, phthalate esters, and polycyclic aromatic hydrocarbons. The TESPMIM[PF 6 ]- and TESPMIM[BF 4 ]-coated fibers have much lower thermal stability (to 300 and 285 °C, respectively) than TESPMIM[N(SO 2 CF 3 ) 2 ]-coated fiber (to 454 °C). However, the selectivity of these two fibers is higher towards strong polar analytes, while lower towards medium polar or nonpolar analytes compared with TESPMIM[N(SO 2 CF 3 ) 2 ]-based fiber. This could be explained by the fact that different counteranions in ionic liquid structures have different steric hindrance, nucleophilicity, hydrophobicity, and ability to form hydrogen bonds, resulting in significant difference in the characteristics of the ionic-liquid-based SPME fibers, such as the surface morphology, thermal stability, selective extraction ability, etc. This work demonstrates that the performance of the ionic-liquid-based coatings can be simply tuned by changing the counteranions incorporated into the ionic liquid structures. Content Type Journal Article Category Original Pages 1-13 DOI 10.1007/s10337-012-2323-4 Authors Jianjun Shu, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan, 430070 China Chan Li, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan, 430070 China Mingming Liu, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan, 430070 China Hanlan Liu, College of Science, Huazhong Agricultural University, Wuhan, 430070 China Xionghan Feng, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan, 430070 China Wenfeng Tan, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan, 430070 China Fan Liu, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture, College of Resources and Environment, Huazhong Agricultural University, Wuhan, 430070 China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   To explore the impact of UDP-glucuronosyltransferase polymorphisms ( UGT1A9-118(dT) 9/10 , UGT1A9 CI399T , UGT1A9 C-440T and UGT2B7 G211T ) on the pharmacokinetics of mycophenolic acid (MPA) in healthy Chinese volunteers. Methods   We recruited ten healthy volunteers with no polymorphisms (control group), 11 homozygotes of mutants UGT1A9 CI399T and UGT1A9-118(dT) 9/10 , ten heterozygotes of UGT1A9 C440T and seven carriers of UGT2B7 211T from a total of 518 healthy Chinese volunteers. All the volunteers were orally administered a single dose of 1.5 g mycophenolate mofetil (MMF) after an overnight fast. Plasma was then collected 72 h after MMF administration. MPA, MPA-7-O-glucuronide (MPAG) and its acylglucuronide (AcMPAG) were detected by ultra-pressure liquid chromatography with UV detection. Results   Compared with the control group, the UGT1A9 CI399T and UGT1A9-118(dT) 9/10 mutant homozygotes had higher MPAG plasma concentrations. Subjects with UGT1A9-440TC had enhanced MPA exposure while carriers of UGT2B7 211T had higher concentrations of the toxic metabolite, AcMPAG. Conclusions   The current results indicate that UGT1A9 and UGT2B7 genotypes could significantly alter MPA pharmacokinetics in healthy Chinese volunteers after a single oral dose of MMF. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-7 DOI 10.1007/s00228-012-1409-0 Authors Dong Guo, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Liang-Fang Pang, Pharmacy Department, Donghu Hospital, Wuhan, 430079 China Yang Han, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Hong Yang, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Guo Wang, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Zhi-rong Tan, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Wei Zhang, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Hong-Hao Zhou, Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: ACE inhibitors and ribavirin-associated cough: a common undefined predisposing factor? Content Type Journal Article Category Letter to the Editors Pages 1-3 DOI 10.1007/s00228-012-1397-0 Authors Laura Milazzo, Department of Infectious Diseases, Luigi Sacco University Hospital, Via GB Grassi 74, 20157 Milan, Italy Dario Cattaneo, Unit of Clinical Pharmacology, Luigi Sacco University Hospital, Milan, Italy Stefania Cheli, Unit of Clinical Pharmacology, Luigi Sacco University Hospital, Milan, Italy Laurenzia Ferraris, Department of Infectious Diseases, Luigi Sacco University Hospital, Via GB Grassi 74, 20157 Milan, Italy Elisa Colella, Department of Infectious Diseases, Luigi Sacco University Hospital, Via GB Grassi 74, 20157 Milan, Italy Emilio Clementi, Unit of Clinical Pharmacology, Luigi Sacco University Hospital, Milan, Italy Cristina Gervasoni, Department of Infectious Diseases, Luigi Sacco University Hospital, Via GB Grassi 74, 20157 Milan, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Objectives   The main aim of this study was to determine whether CYP2C9 and VKORC1 polymorphisms influence warfarin dose variability during initial dose-finding phase and during maintenance treatment after 360 days. Methods   Two hundred and six consecutive patients who were beginning warfarin therapy were selected. They were assessed for general and clinical characteristics; prescribed warfarin dose; response to therapy on days 7–10, 30, 60, 180, and 360; adverse events; and CYP2C9 *2, *3, *5, *6, *8, *11, and VKORC1 1639G 〉A assays. Results   During the first 30 days of anticoagulation, the relative variability of warfarin dose was significantly associated with CYP2C9*2 and CYP2C9*3 polymorphisms ( p  = 0.02) and with VKORC1 1639G 〉A genotypes ( p  = 0.04). Warfarin variability was also statistically different according to predicted metabolic phenotype and to VKORC1 genotypes after 360 days of treatment, and in the phase between 180 and 360 days (long-term dose variability). Both CYP2C9 and VKORC1 polymorphisms were associated with the international normalized ratio (INR) made between 7 and 10 days/initial dose ratio, adjusted for covariates ( p  〈 0.01 and p  = 0.02, respectively). Patients carrying VKORC1 and CYP2C9 variants presented lower required dose (at the end of follow-up of 360 days) compared to patients carrying wild-type genotypes ( p  = 0.04 and p  = 0.03, respectively). Conclusions   Genetic information on CYP2C9 and VKORC1 is important both for the initial dose-finding phase and during maintenance treatment with warfarin. Content Type Journal Article Category Pharmacogenetics Pages 1-9 DOI 10.1007/s00228-012-1404-5 Authors Paulo Caleb Junior Lima Santos, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP CEP 05403-000, Brazil Carla Luana Dinardo, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP CEP 05403-000, Brazil Isolmar Tadeu Schettert, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP CEP 05403-000, Brazil Renata Alonso Gadi Soares, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP CEP 05403-000, Brazil Liz Kawabata-Yoshihara, University Hospital of the University of Sao Paulo, Internal Medicine Division, Sao Paulo, Brazil Isabela Martins Bensenor, University Hospital of the University of Sao Paulo, Internal Medicine Division, Sao Paulo, Brazil José Eduardo Krieger, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP CEP 05403-000, Brazil Paulo Andrade Lotufo, University Hospital of the University of Sao Paulo, Internal Medicine Division, Sao Paulo, Brazil Alexandre Costa Pereira, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo, SP CEP 05403-000, Brazil Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Numerous studies have documented suboptimal adherence to guideline recommendations in secondary prevention of coronary heart disease (CHD SP ). Clinical practice guidelines (CPGs) are continuously developed to define appropriate patient care, aiming to reduce risk of morbidity and death. The Medication Assessment Tool for CHD SP (MAT-CHD SP ) was developed to assess adherence to CPGs concerning medication therapy and follow-up of patients with CHD SP . The aim of this study was to explore whether the MAT-CHD SP could be applied retrospectively to assess guideline adherence and therapy goal achievement in secondary prevention of CHD. Methods   We collected data from electronic medical records of all patients who underwent percutaneous coronary intervention with stent implantation from January to March 2008 ( n  = 300) and applied the MAT-CHD SP . We measured time for data collection and MAT application and tested reproducibility by calculating Cohen’s kappa (κ) value for inter and intraobserver agreement. Results   A total of 247 MAT applications were analyzed, showing overall applicability of 66 % of the 4,446 MAT-CHD SP criteria and a high reproducibility of MAT-CHD SP application (κ values 0.93 and 0.95 for intra- and interobserver agreement, respectively). Mean time for data collection and MAT-CHD SP application was 11 min. Adherence to criteria concerning prescription was high (〉75 %), but achievement of therapy goals for cholesterol and blood pressure was low (〈50 %). Documentation of lifestyle advice achieved intermediate (50–75 %) or low adherence, as did therapy amendments in patients in whom therapy goals were unachieved at hospital admission. Conclusions   The MAT-CHD SP offers a means to identify both adherence and nonadherence to CPGs concerning CHD SP is applicable in retrospective assessment of CHD SP , and identifies potentials for improved patient care. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-7 DOI 10.1007/s00228-012-1402-7 Authors Beate Hennie Garcia, Hospital Pharmacy of North Norway Trust, Tromsoe, Norway Lars Småbrekke, Department of Pharmacy, University of Tromsoe, Tromsoe, Norway Thor Trovik, Department of Cardiology, University Hospital of Tromsoe, Tromsoe, Norway Trude Giverhaug, Regional Drug Information Centre of North Norway, University Hospital of Tromsoe, Tromsoe, Norway Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates. Methods   Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9. Results   Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4–5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0–1.4], 1.4-fold (90 % CI 1.2–1.6), and 1.3-fold (90 % CI 1.2–1.4) in the maximum plasma concentration (C max ), area under the concentration–time curve from time 0 to infinity (AUC 0-∞ ), and terminal half-life (t 1/2 ), respectively, of midazolam; the time to peak plasma concentration (t max ) was unchanged. Whereas C max and t max were not influenced by almorexant, the AUC 0-∞ of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1–1.4) and the t 1/2 by 1.3-fold (90 % CI 1.0–1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0–3.7) and 3.4-fold (90 % CI 2.6–4.4) in C max and AUC 0-∞ , respectively, for simvastatin; the t 1/2 and t max were unchanged. The C max and AUC 0-∞ of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3–3.5 and 2.2–3.5, respectively; the t max increased by 2 h and the t 1/2 was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant. Conclusions   Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-10 DOI 10.1007/s00228-012-1403-6 Authors Matthias Hoch, Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Petra Hoever, Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Federica Alessi, Biostatistics, Actelion Pharmaceuticals Italia Srl, Imperia, Italy Rudolf Theodor, PHAROS GmbH, Ulm, Germany Jasper Dingemanse, Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Background   Risk factors for stroke are well known in atrial fibrillation (AF) patients, while less is known on the effect of these factors on total mortality. Objective   Our aim was to study the impact of cardiovascular drug classes on mortality in AF patients treated in primary care. Methods   The study population was chosen based on patient data from 75 primary care centres in Sweden compiled in a database. Individuals diagnosed with AF who were older than 45 years were enrolled ( n  = 12,302, of whom 6,660 were men). Cox regression analysis with mortality (years to death) as outcome was conducted in the men and women separately, as well in the age categories 〈80 and ≥80 years, with cardiovascular drugs as independent factors, and age, cardiovascular diagnoses and educational level as covariates. Results   Lower mortality was shown for anticoagulant treatment among men, both younger (〈80 years) [adjusted hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.31–0.61] and older (≥80 years) (adjusted HR 0.47, 95 % CI 0.32–0.69), and among younger women (adjusted HR 0.46, 95 % CI 0.29–0.74), and for antiplatelet treatment in older men (adjusted HR 0.51, 95 % CI 0.35–0.74). Treatment with thiazides was associated with lower mortality among younger men (adjusted HR 0.68, 95 % CI 0.48–0.96), older men (adjusted HR 0.67, 95 % CI 0.46–0.98) and older women (adjusted HR 0.70, 95 % CI 0.52–0.94). Statins were associated with lower mortality among younger patients, in both men (adjusted HR 0.47, 95 % CI 0.32–0.68) and women (adjusted HR 0.54, 95 % CI 0.35–0.82). Conclusions   The differences in age and gender patterns need further exploration. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1395-2 Authors Per Wändell, Centre for Family Medicine, Karolinska Institutet, Alfred Nobels Allé 12, 141 83 Huddinge, Sweden Axel C. Carlsson, Centre for Family Medicine, Karolinska Institutet, Alfred Nobels Allé 12, 141 83 Huddinge, Sweden Kristina Sundquist, Center for Primary Health Care Research, Lund University, Malmö, Sweden Sven-Erik Johansson, Center for Primary Health Care Research, Lund University, Malmö, Sweden Jan Sundquist, Center for Primary Health Care Research, Lund University, Malmö, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Several strategies have been proposed for the prevention of vancomycin-induced nephrotoxicity. Here, we review available evidence supporting the respective strategies. Method   Data were collected by searching the Scopus, PubMed, and Medline databases and the Cochrane database of systematic reviews. The key words used as search terms were “vancomycin,” “nephrotoxicity”, “renal failure,” “renal damage,” “nephroprotective,” “renoprotective”, and “prevention.” Prospective or retrospective observational animal studies that evaluated the effects of a modality for the prevention of vancomycin-induced nephrotoxicity was included. Results and conclusion   Animal studies show beneficial effects of various antioxidants, such as erdosteine, vitamin E, vitamin C, N -acetylcysteine, caffeic acid phenethyl ester, and erythropoietin, in the prevention of vancomycin-induced nephrotoxicity. However, before these agents can be used in clinical practice, their potential benefits must be confirmed in future randomized controlled human studies. Content Type Journal Article Category Review Article Pages 1-8 DOI 10.1007/s00228-012-1406-3 Authors Sepideh Elyasi, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box: 14155/6451, 1417614411 Tehran, Iran Hossein Khalili, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box: 14155/6451, 1417614411 Tehran, Iran Shima Hatamkhani, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box: 14155/6451, 1417614411 Tehran, Iran Simin Dashti-Khavidaki, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box: 14155/6451, 1417614411 Tehran, Iran Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Background and objectives   A large number of clinical studies have well demonstrated that the loss-of-function variant allele CYP2C19 *2 is associated with attenuated response to clopidogrel and increased risk of developing stent thrombosis (ST) in white or black patients with stenting. However, similar association studies on the effect of the CYP2C19 *2 and *3 variants on maximum platelet aggregation (MPA) and the risk of cardiovascular events are currently unavailable for the Chinese patients. This work was aimed at assessing the impact of the CYP2C19 *2 and *3 variants on the antiplatelet effects and adverse cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention (PCI). Methods   The study population consisted of 617 patients undergoing PCI. Genotypes were determined using MALDI/TOF-MS. MPA was measured by light transmittance aggregometry. The clinical end-point was the 1-year incidence of adverse cardiovascular events, including ST. Results   Carriers of CYP2C19 heterozygous (*1/*2, or *1/*3; n  = 278) and mutant homozygous (*2/*2, *2/*3, or *3/*3, n  = 80) genotypes had significantly higher MPA values than noncarriers (*1/*1; n  = 259; P  = 0.036 and 0.007 respectively). Moreover, the presence of the CYP2C19 *2 or *3 mutant allele was significantly associated with an increased risk of developing ST, with the higher risk of ST being seen in patients homozygous for the CYP2C19 *2 or *3 variant allele than in noncarriers (OR, 13.58; 95% CI, 1.49–123.31; P  = 0.012). Furthermore, multivariate analysis revealed an independent association of the presence of CYP2C19 *2 and/or *3 variant alleles with greater MPA values ( P  = 0.001) and increased risk of ST (OR, 11.67; 95% CI, 1.21–78.83; P  = 0.022). However, there was no significant influence of CYP2C19 *2 and *3 on the risk of developing other adverse cardiovascular events. Conclusions   Carriage of the loss-of-function genetic variants CYP2C19 *2 and *3 is significantly associated with attenuated platelet response to clopidogrel and an increased risk of ST in Chinese patients treated with stenting. Content Type Journal Article Category Clinical Trial Pages 1-7 DOI 10.1007/s00228-012-1392-5 Authors Jian-Jun Zou, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009 China Hong-Guang Xie, General Clinical Research Center and Division of Clinical Pharmacology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Shao-Liang Chen, Division of Cardiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Jie Tan, Division of Clinical Pharmacology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Ling Lin, Division of Cardiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Ying-Ying Zhao, Division of Cardiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Hai-Mei Xu, Division of Cardiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Song Lin, Division of Cardiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Juan Zhang, Division of Cardiology, Nanjing Hospital Affiliated to Nanjing Medical University, Nanjing, 210006 China Guang-Ji Wang, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009 China Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    In clinical medicine, urine creatinine concentration is an important marker in the evaluation of renal function and muscular dysfunctions. Herein, we reported a novel method for rapid determination of creatinine in urine by microchip electrophoresis with light-emitting diode induced fluorescence detection. Creatinine was derivatized by fluorescein isothiocyanate, and then quantitatively detected by the developed microchip LED induced fluorescence detection system. The excitation and emission wavelengths were 490 and 523 nm, respectively. The urine samples were analyzed after centrifuge and filtration. A baseline separation was obtained in 〈30 s using 10 mM borate buffer (pH 9.0, containing 45 mM sodium dodecylsulfate), with separation voltage of 1.5 kV. Good linearity was obtained ( r 2  = 0.9978) in the concentration range of 10.0–2.00 × 10 3  μM, and the limit of detection was 2.87 μM ( S/N  = 3). The recovery was 96.0–107 %, and the interday precision was 〈4.5 % ( n  = 6). To validate assay results, we compared the present method with the Jaffe’s colorimetric assay by measuring real urine samples. The method was reliable, sensitive, high-speed, low-cost and suitable for the routine analysis of creatinine in biofluids. Content Type Journal Article Category Original Pages 1-7 DOI 10.1007/s10337-012-2324-3 Authors Shuping Wang, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road of Higher Education Mega Centre, Guangzhou, 510006 People’s Republic of China Xinchun Li, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road of Higher Education Mega Centre, Guangzhou, 510006 People’s Republic of China Jianping Yang, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road of Higher Education Mega Centre, Guangzhou, 510006 People’s Republic of China Xiujuan Yang, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road of Higher Education Mega Centre, Guangzhou, 510006 People’s Republic of China Fenghua Hou, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road of Higher Education Mega Centre, Guangzhou, 510006 People’s Republic of China Zuanguang Chen, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road of Higher Education Mega Centre, Guangzhou, 510006 People’s Republic of China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Mike S. Lee: Mass Spectrometry Handbook Content Type Journal Article Category Book Review Pages 1-2 DOI 10.1007/s10337-012-2325-2 Authors Colin F. Poole, Wayne State University, Detroit, MI, USA Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    CE offers the possibility of fast, cheap and reproducible separations for active compounds of Chinese herbs. Lotusine ( 1 ), liensinine ( 2 ), isoliensinine ( 3 ) and neferine ( 4 ) were the major bioactive alkaloids in lotus plumule, which was used as an important Chinese herb. In this paper, simultaneous separation of 1 – 4 in lotus plumule by nonaqueous CZE has been achieved within 11 min by use of buffer consisting of 80 mM sodium acetate and 40 mM ammonium acetate methanol solution of pH 5.4. Analysis of the four alkaloids in ten plumule samples of Nelumbo nucifera was conducted. Limits of detection (LOD) of 1 – 4 by UV absorbance at 203 nm were achieved in the range of 1.5–2.8 μg mL −1 . Reproducibility (percent RSD) of the analysis by CZE were 2.33, 2.31, 0.78 and 2.58 %, respectively ( n  = 5). Content Type Journal Article Category Original Pages 1-6 DOI 10.1007/s10337-012-2312-7 Authors Guangming Yang, National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, 210046 China Weidong Li, National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, 210046 China Yang Pan, National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, 210046 China Xia Tu, Department of Bio-Pharmacy and Laboratory of Medical Fungi and Phyto-Biotech, Nanjing University of Chinese Medicine, Nanjing, 210029 China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations. Methods   Adducts were quantified in all postdose blood samples using a validated high-performance liquid chromatography electrochemical detection (HPLC-EC) assay. Results   Comparison of pharmacokinetic parameters for adducts did not reveal significant differences between ER and IR formulations, with one exception. Formation rates for adducts were faster for IR than the ER formulation (0.420 ± 0.157 vs. 0.203 ± 0.080 1/h), respectively. Maximum plasma concentrations (C max ) of adducts for IR and ER were 0.108 (±0.020) and 0.100 (±0.028) nmol/ml serum, respectively, and were two orders of magnitude lower than adduct levels previously reported in adults with acute liver failure secondary to APAP. Conclusions   APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-7 DOI 10.1007/s00228-012-1410-7 Authors Laura P. James, Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS) and Arkansas Children’s Hospital Research Institute, Little Rock, AR, USA Angela Chiew, Clinical and Experimental Toxicology Unit, Department of Emergency Medicine, Prince of Wales Hospital, Randwick, NSW, Australia Susan M. Abdel-Rahman, Division of Clinical Pharmacology and Medical Toxicology, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA Lynda Letzig, Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS) and Arkansas Children’s Hospital Research Institute, Little Rock, AR, USA Andis Graudins, Southern Clinical School, Monash University, Clayton, VIC, Australia Peter Day, South Eastern Area Laboratory Services (SEALS Pathology), Prince of Wales Hospital Campus, Randwick, NSW, Australia Dean Roberts, Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS) and Arkansas Children’s Hospital Research Institute, Little Rock, AR, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   We assessed the prevalence of difficulties in swallowing solid oral dosage forms in a general practice population. Reasons, nature, and characteristics of tablets and capsules causing such difficulties were investigated as well as general practitioners’ (GP) awareness of these difficulties. Methods   A questionnaire survey was conducted in 11 general practices and consecutive patients taking at least one solid oral dosage form for ≥4 weeks were invited to respond to a questionnaire at the practices and one at home. Physicians completed a short questionnaire for each included patient. Results   Of all participants ( N  = 1,051), 37.4 % reported having had difficulties in swallowing tablets and capsules. The majority (70.4 %) of these patients was not identified by their GP. The occurrence of swallowing difficulties was related to gender (f〉m), age (young〉old), dysphagia [adjusted odds ratio (adOR): 7.9; p  〈 0.0001] and mental illness (adOR: 1.8; p  〈 0.05). By asking “Do you choke while eating or drinking?”, affected patients could be identified with a sensitivity of 62.6 % and a specificity of 78.1 %. Because of these difficulties, 58.8 % of the affected patients had already modified their drugs in a way that may alter safety and efficacy and 9.4 % indicated to be non-adherent. Conclusions   One in 11 primary care patients had frequent difficulties in swallowing tablets and capsules while GPs grossly underestimated these problems. Therefore, physicians should rule out swallowing difficulties regularly to avoid non-adherence and inappropriate drug modifications. Special attention should be paid to specific patient groups (e.g. women and patients with dysphagia, dysphagia indicators, or mental illness). Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-12 DOI 10.1007/s00228-012-1417-0 Authors Julia T. Schiele, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410,, 69120 Heidelberg, Germany Renate Quinzler, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410,, 69120 Heidelberg, Germany Hans-Dieter Klimm, Department of General Medicine and Health Services Research, University of Heidelberg, Voßstr. 2, 69120, Heidelberg, Germany Markus G. Pruszydlo, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410,, 69120 Heidelberg, Germany Walter E. Haefeli, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410,, 69120 Heidelberg, Germany Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    Phospholipids have been shown to cause matrix effects particularly in liquid chromatography–mass spectrometry (LC–MS) analysis of small molecules. This results in suppression of the analyte signal. This study provides a versatile validated method for the analysis of serotonin in serum along with dopamine and melatonin using LC–MS/MS. It utilises HybridSPE-Precipitation cartridges for the clean-up of serum samples. This technology involves a simple protein precipitation step together with a fast and robust SPE method that is designed to remove phospholipids. Serotonin and dopamine are major neurotransmitters in the brain which affect various functions both in the brain and in the rest of the body. Melatonin plays an important role in the regulation of circadian sleep–wake cycle. Good linear calibrations were obtained for the multiplex assay of analytes in serum samples (0.021–3.268 μmol L −1 ; R 2  = 0.9983–0.9993). Acceptable intra- and inter-day repeatability was achieved for all analytes in serum. Excellent limits of detection (LOD) and limits of quantitation (LOQ) were achieved with LODs of 3.2–23.5 nmol L −1 and the LOQs of 15.4–70.5 nmol L −1 for these analytes in serum. The sample clean-up procedure that was developed provided efficient recovery and reproducibility while also decreasing preparation time and solvent use. A sample storage protocol was established, this was achieved by investigation of sample stability under different storage conditions. Evaluation of matrix effects was also carried out and the influence of ion suppression on analytical results reported. This clean-up protocol was then applied to the analysis of clinical serum samples. Content Type Journal Article Category Original Pages 1-13 DOI 10.1007/s10337-012-2330-5 Authors Merisa Moriarty, Department of Chemistry, PROTEOBIO (Mass Spectrometry Centre for Proteomic and Biotoxin Research), Cork Institute of Technology, Cork, Ireland Aoife Lee, Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork, Ireland Brendan O’Connell, Department of Biological Sciences, Cork Institute of Technology, Bishopstown, Cork, Ireland Mary Lehane, Department of Chemistry, PROTEOBIO (Mass Spectrometry Centre for Proteomic and Biotoxin Research), Cork Institute of Technology, Cork, Ireland Helen Keeley, Child and Adolescent Mental Health Services, Health Service Executive, South, North Cork Area and the National Suicide Research Foundation, Cork, Ireland Ambrose Furey, Team Elucidate and PROTEOBIO (Mass Spectrometry Centre for Proteomic and Biotoxin Research) research groups, Cork Institute of Technology, Cork, Ireland Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Carboxylesterase 1 (CES1) genetic polymorphisms and oseltamivir activation Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1350-2 Authors Hao-Jie Zhu, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, 1600 SW Archer Road, RM PG-06, Gainesville, FL 32610-0486, USA John S. Markowitz, Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Existing drug safety systems with phase II and III studies and post-marketing surveillance by principle do not allow for the recognition of an important class of adverse drug reactions (ADRs). ADRs that are resistant to being detected reliably may a) appear as if they are age-related chronic diseases, which also manifest themselves in a high degree without drug treatment, b) arise in “old” drugs, c) arise during long-term application, and d) arise with the administration to frail and aged populations. Conclusions   “Silent” and multi-factorial health problems evolving from long-term drug treatment must therefore be addressed with a systematic search strategy, as a third track along with the phase II and III studies and spontaneous reporting systems which still exist. Content Type Journal Article Category Special Article Pages 1-3 DOI 10.1007/s00228-012-1371-x Authors Markus Gnädinger, Department of General Practice, University Hospital Zurich, Zurich, Switzerland Hans-Ulrich Mellinghoff, Department of Endocrinology, Diabetology and Osteology, Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   The objective of this study was to identify the most clinically relevant drug–drug interactions (DDIs) at risk of affecting acenocoumarol safety in our tertiary care university hospital, a 2,000 bed institution. Methods   We identified DDIs occurring with acenocoumarol by combining two different sources of information: a 1-year retrospective analysis of acenocoumarol prescriptions and comedications from our Computerized Physician Order Entry (CPOE) system ( n = 2,439 hospitalizations) and a retrospective study of clinical pharmacology consultations involving acenocoumarol over the past 14 years (1994–2007) ( n = 407). We classified these DDIs using an original risk-analysis method. A criticality index was calculated for each associated drug by multiplying three scores based on mechanism of interaction, involvement in a supratherapeutic international normalized ratio (INR) (≥ 6) and involvement in a severe bleeding. Results   One hundred and twenty-six DDIs were identified and weighted. Twenty-eight drugs had a criticality index ≥ 20 and were therefore considered at high risk for interacting with acenocoumarol by increasing its effect: 75% of these drugs involved a pharmacokinetic mechanism and 14 % a pharmacodynamic mechanism. An unknown mechanism of interaction was involved in 11 % of drugs. Conclusion   Twenty-eight specific drugs were identified as being at high risk for interacting with acenocoumarol in our hospital using an original risk-analysis method. Most analyzed drugs interact with acenocoumarol via a pharmacokinetic mechanism. Actions such as the implementation of alerts in our CPOE system should be specifically developed for these drugs. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-11 DOI 10.1007/s00228-012-1358-7 Authors L. Gschwind, Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland V. Rollason, Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland C. Lovis, Division of Medical Information Sciences, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland F. Boehlen, Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland P. Bonnabry, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland P. Dayer, Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland J. A. Desmeules, Division of Clinical Pharmacology and Toxicology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    Graphene, a novel class of carbon nanostructure, possesses an ultra-high specific surface area (theoretical value 2,630 m 2  g −1 ), and both sides of the planar sheets of graphene are available for molecule adsorption. Graphene has already been used for preconcentration, extraction, and electrochemical selective determination. In this study, we used graphene to clean up pigments in cucumber for analysis, and measured eight pyrethroid model analytes using GC with electron capture detection (ECD). The recoveries of the 8 pyrethroids were 75–116 % with RSDs below 10 %, and LOQs ranged from 2.5 to 10 μg kg −1 . Comparative studies showed that graphene was superior to graphitized carbon black for the purification of pigments. We also investigated the ability of graphene to clean up spinach. A promising new adsorbent for pesticide residue analysis was developed. Graphene has significant potential as an effective adsorbent of pigments. Content Type Journal Article Category Original Pages 1-7 DOI 10.1007/s10337-012-2299-0 Authors Xiaoli Wu, College of Science, China Agricultural University, Beijing, 100193 People’s Republic of China Hongyan Zhang, College of Science, China Agricultural University, Beijing, 100193 People’s Republic of China Lixuan Meng, College of Science, China Agricultural University, Beijing, 100193 People’s Republic of China Xiaotong Liu, College of Science, China Agricultural University, Beijing, 100193 People’s Republic of China Yongqiang Ma, College of Science, China Agricultural University, Beijing, 100193 People’s Republic of China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A highly sensitive and rapid method was developed that involves capillary electrophoresis for separation and determination of the stereoisomeric impurity of folinic acid diastereomers. In this method, vancomycin was used as the chiral selector, and a solution of poly(dimethylacrylamide) (PDMA) was prepared for dynamic coating of the capillary wall to minimize the adsorption of vancomycin. This method was optimized for six factors including concentrations of the organic modifier and vancomycin, pH and concentration of the background electrolyte, column temperature, and separation voltage. The following conditions were established: 100 mM Tris-phosphate buffer (pH 6.0) containing 1.0 mM vancomycin and 5 % acetonitrile at 30 °C, and −15 kV applied voltage on the PDMA dynamically coated capillary. Preliminary validation was performed with the determination of limit of quantification and detection, accuracy, precision, and linearity. Under our optimized method, the folinic acid diastereomers were baseline-separated within 7.5 min, and a (6 S ,2′ S )-calcium folinate sample with 0.08 % stereoisomeric impurity was determined. Content Type Journal Article Category Short Communication Pages 1-5 DOI 10.1007/s10337-012-2304-7 Authors Zhaoyan Wang, School of Pharmacy, Lanzhou University, Lanzhou, 730000 China Changjun Mu, School of Life Science, Lanzhou University, Lanzhou, 730000 China Jingwu Kang, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032 China Zhide Hu, School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000 China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A simple and sensitive method for the determination of free aliphatic amines using 10-phenyl-acridone-2-sulfonyl chloride (PASC) as a labeling reagent by high-performance liquid chromatography with fluorescence detection and online mass spectrometry identification (HPLC-FLD-MS) has been developed. Derivatization conditions including reagent concentration, buffer pH, reaction time and temperature were optimized. PASC reacted with aliphatic amines at 50 °C for 4 min in aqueous acetonitrile (ACN) in the presence of sodiumtetraborate–NaOH buffer (0.10 mol L −1 , pH 9.0) to give high yields of PASC-amine derivatives. Derivatives exhibited intense fluorescence with an excitation maximum at λ ex 265 nm and an emission maximum at λ em 418 nm. The separation of derivatives was performed by a reversed-phase Hypersil BDS C8 column in combination with a gradient elution. The identification of derivatives was carried out by online post-column mass spectrometry with atmospheric pressure chemical ionization (APCI) source in positive-ion detection mode. Excellent linear responses were observed with the correlation coefficients of larger than 0.9997, and detection limits (at a signal-to-noise of 3:1) were from 3.0 to 24.3 fmol. Comparing with 10-ethyl-acridine-2-sulfonyl chloride (EASC), PASC exhibited more intense fluorescence and ultraviolet absorbance. The proposed method is sensitive and reproducible for the determination of aliphatic amines from water and soil samples. Content Type Journal Article Category Original Pages 1-10 DOI 10.1007/s10337-012-2298-1 Authors Shujing Ning, Key Laboratory of Life-Organic Analysis of Shandong Province, Qufu Normal University, Qufu, 273156 China Jinmao You, Key Laboratory of Life-Organic Analysis of Shandong Province, Qufu Normal University, Qufu, 273156 China Zhiwei Sun, Key Laboratory of Life-Organic Analysis of Shandong Province, Qufu Normal University, Qufu, 273156 China Shijuan Zhang, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008 China Zhongyin Ji, Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 810008 China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: The influence of VKORC1 3730 G 〉 A polymorphism on warfarin dose: reply Content Type Journal Article Category Letter to the Editors Pages 1-1 DOI 10.1007/s00228-012-1431-2 Authors Michela Cini, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Cristina Legnani, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Benilde Cosmi, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Giuliana Guazzaloca, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Lelia Valdrè, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Mirella Frascaro, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Gualtiero Palareti, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    A simple, rapid and sensitive LC–MS/MS method in positive ion mode was developed and validated to determine CKD-501, lobeglitazone, in human plasma and urine using glipizide as an internal standard (IS). Lobeglitazone is a novel thiazolidinedione (TZDs)-based peroxisome proliferator-activated receptor (PPAR) agonist, used for the management of type-2 diabetes. After mixing the IS, dissolved in acetonitrile, with a plasma or urine sample containing lobeglitazone, 10 μL of supernatant was injected into the LC–MS/MS system. Quantification was performed in the multiple reaction monitoring (MRM) mode using transition of 481.5 → 152.2 ( m / z ) for lobeglitazone and 446.1 → 321.2 ( m / z ) for the IS. The method showed good linearity over concentration ranges of 0.5–1,000 ng mL −1 for plasma and 0.2–250 ng mL −1 for urine ( r 2  ≥ 0.9996). The mean percent extraction recovery of lobeglitazone was 90.8 % for plasma and 87.3 % for urine, while the recoveries of the IS were greater than 86.4 % for both. The intra-day and inter-day precision of plasma ranged from 1.1 to 3.7 and 2.5 to 3.3 % (RSD), respectively, and the intra- and inter-day precision of urine ranged from 1.5 to 2.7 and 3.2 to 3.5 %, respectively. This method is simple, sensitive, and applicable for the pharmacokinetic study of lobeglitazone in human plasma. Most of the urine concentrations of lobeglitazone were below the LLOQ because the lobeglitazone is extensively metabolized. Content Type Journal Article Category Short Communication Pages 1-7 DOI 10.1007/s10337-012-2238-0 Authors Bora Kim, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Hyun-Suk Shin, Analytical Chemistry Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea Jung-Ryul Kim, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Kyung-Soo Lim, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Seo Hyun Yoon, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Sang-Goo Shin, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea In-Jin Jang, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Joo-Youn Cho, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744 Republic of Korea Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    Expanded bed adsorption (EBA) is a practical method for the separation of nanoparticulates. In order to analysis the local hydrodynamic and adsorption behavior of nanoparticle (NP)-based biological feedstock, a modified Nano Biotechnology Group EBA column with a 26-mm inner diameter was used to withdraw liquid from different axial positions of the column. Fabricated egg albumin (EA) NPs with an average size of 70 nm were employed as a model system and viral size/charge mimic to assess the relationship between hydrodynamic and adsorption performance of NPs at the different column regions. The effects of influential factors, including flow velocity and initial concentration of NPs, on NP hydrodynamic behavior and adsorption kinetics along the bed height were investigated. NP hydrodynamic studies confirmed that non-uniform behavior dominated the system and a decreasing trend of liquid mixing/dispersion with increase of bed height was observed in this column. The results demonstrated an increase in the mixing/dispersion at certain bed heights with the increase in both the velocity and feed initial concentration. Breakthrough curves were measured at various column points to determine the adsorption performance [dynamic binding capacity (DBC) and yield] in different bed positions/zones. Yield and DBC of NPs were improved along the bed height, whereas liquid velocity had the opposite effect. Increasing the initial concentration of NPs enhanced only the DBC. Separation of EA NPs under optimal conditions was 87 %, which is an excellent result for a one-pass frontal chromatography method. Content Type Journal Article Category Original Pages 1-12 DOI 10.1007/s10337-012-2235-3 Authors Mohsen Jahanshahi, Nanotechnology Research Institute, Faculty of Chemical Engineering, Babol University of Technology, P.O. Box 484, Babol, Iran Mohammad Taghi Hamed Mosavian, Faculty of Chemical Engineering, Ferdowsi University of Mashhad, Mashhad, Iran Elham Sadat Taheri Otaghsara, Nanotechnology Research Institute, Faculty of Chemical Engineering, Babol University of Technology, P.O. Box 484, Babol, Iran Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description: Purpose   To gain insight into the experiences and handling of adverse drug reactions (ADRs) by the staffs of public primary healthcare (PHC) clinics in Eastern Cape Province, South Africa, as well as their perceptions of related adherence challenges in the treatment and follow-up of human immunodeficiency virus (HIV)-positive patients. Methods   Healthcare providers working at the PHC level in the public sector in the study area were approached and asked to participate in focus group discussions (FGDs). Seven FGDs were conducted with 32 healthcare providers (9 nurses, 23 auxiliary staff). Questions introduced by the moderator of each FGD were freely discussed by the participants. Discussions were audio-recorded and subjected to thematic content analysis. Results   Several challenges in the treatment and follow-up of patients on ART were identified. These include: (1) lack of training of healthcare providers in PHC clinics to confidently identify, manage and treat the ADRs HIV-positive patients receiving ART; (2) patients’ difficulty in communicating information on ADRS; (3) insufficient pharmacovigilance; (4) role of poverty. Conclusion   Both nurses and auxiliary staff expressed lack of knowledge and confidence regarding ADRs in HIV patients and management of this. More emphasis is warranted on training the healthcare providers to identify ADRs and provide adequate advice for continued treatment of patients experiencing potential drug related problems. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-8 DOI 10.1007/s00228-012-1254-1 Authors Karine W. Ruud, Department of Social Pharmacy, School of Pharmacy, University of Oslo, Pb 1068 Blindern, 0316 Oslo, Norway Sunitha C. Srinivas, Faculty of Pharmacy, Pharmacy Administration and Practice, Rhodes University, Grahamstown, 6140 South Africa Else-Lydia Toverud, Department of Social Pharmacy, School of Pharmacy, University of Oslo, Pb 1068 Blindern, 0316 Oslo, Norway Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   The purpose of the study was to characterize the utilization of medication against attention deficit hyperactivity disorder (ADHD) in Denmark between 1995 and 2011 from a national perspective, by using population-based prescription data. Methods   National data on drug use in Denmark between 1 January 1995 and 30 September 2011 were extracted from the Registry of Medicinal Product Statistics (RMPS). Drug utilization was characterized using descriptive statistics. Results   A total of 1,085,090 prescriptions issued to 54,020 persons were identified. The incidence rate was stable in the last 3 years of the study period, and a slightly decreasing incidence rate and a stabilizing prevalence were observed towards the end of this period. The therapeutic intensity was 6.7 defined daily dose/person/day, with large regional differences that ranged from 64 to 145 % of the national average. Methylphenidate accounted for 92.6 % of DDDs used. The general practitioner (GP) rarely initiated treatment, although treatment initiation based on the GP’s advice increased with older age of the patient. Maintenance treatment was found to be distributed roughly equally between prescriber types. For methylphenidate, 1 % of users accounted for 6.1 % of the drug volume and 50 % of users accounted for 84.4 %. The data therefore do not suggest a high proportion of heavy users. Conclusion   The findings of this analysis are mostly reassuring, with the data indicating a seemingly stagnant incidence and prevalence rate and lacking evidence of heavy users. However, the prescriber profile for incident users and the large regional variances raise concerns. It is therefore vital that the use of ADHD drugs is closely monitored. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-8 DOI 10.1007/s00228-012-1265-y Authors Anton Pottegård, Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Winsløwparken 19, 5000 Odense C, Denmark Bine Kjøller Bjerregaard, Medicines Control Division, Statistics and Analysis, Danish Medicines Agency, Axel Heides Gade 1, 2300 København S, Denmark Dorte Glintborg, Institute for Rational Pharmacotherapy, Danish Medicines Agency, Axel Heides Gade 1, 2300 København S, Denmark Jesper Hallas, Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Winsløwparken 19, 5000 Odense C, Denmark Søren Ilsøe Moreno, Institute for Rational Pharmacotherapy, Danish Medicines Agency, Axel Heides Gade 1, 2300 København S, Denmark Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   To determine the influence of itraconazole on the pharmacokinetics, and the CNS and prolactin-elevating effects of domperidone in humans. Methods   Fifteen healthy volunteers received either itraconazole (200 mg daily) or placebo for 5 days with a double blind, randomized, cross-over design. A single oral 20-mg dose of domperidone was administered to subjects on day 5. Plasma domperidone and serum prolactin concentrations were measured. The effects of domperidone on CNS were also assessed using self-rating scales and electroencephalography. Results   Itraconazole significantly increased domperidone AUC 0-∞ (3.2-fold) and C max (2.7-fold) compared with placebo, but had no significant effect on the elimination half-life of domperidone. The CNS effects of domperidone assessed by self-rating of mood and electroencephalography, and the prolactin-elevating effect, were not significantly affected by itraconazole. A counterclockwise hysteresis was evident in the relationship between plasma domperidone and serum prolactin concentrations. Itraconazole shifted the hysteresis to the right. Concentration–effect modeling procedures yielded a significant linear relationship between hypothetical effect site domperidone concentrations and prolactin levels. Itraconazole reduced the slope of the linear relationship. Conclusions   Itraconazole significantly increased plasma domperidone concentrations. The interaction is probably mainly due to a reduced first pass elimination by inhibition of CYP3A and/or MDR1. The clinical significance of the altered relationship between domperidone concentrations and prolactin levels caused by itraconazole is still to be determined. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-8 DOI 10.1007/s00228-012-1258-x Authors Tsuneaki Yoshizato, Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita, 879-5593 Japan Tsutomu Kotegawa, Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita, 879-5593 Japan Hiromitsu Imai, Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita, 879-5593 Japan Kimiko Tsutsumi, Department of Pharmaceutical Medicine and Communication, Faculty of Medicine, Oita University, Oita, Japan Junko Imanaga, Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita, 879-5593 Japan Tetsuji Ohyama, Department of Statistics, Faculty of Medicine, Oita University, Oita, Japan Kyoichi Ohashi, Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita, 879-5593 Japan Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Clinical guidelines concerning treatment of infection are incorporated into prescribing formularies and antimicrobial stewardship policies. The extent to which these influence prescribing is uncertain. In this study, we sought to examine antimicrobial prescribing patterns in patients with cellulitis. Methods   Consecutive adults admitted to hospital due to acute cellulitis between 2008 and 2010 were studied. Data collected were clinical and laboratory markers of sepsis, antimicrobial agent, route of administration, number of i.v. dosages, duration of antimicrobial treatment, and hospital length of stay. Three groups were defined by prescribing that was (i) identical to formulary, (ii) modified appropriately due to microbiological data or prior drug allergy, and (iii) nonformulary prescribing. Comparisons were made between groups using Mann–Whitney tests. Results   There were 306 patients: 167 men (54.6%), median age 66 (range 18–100) years. Prescribing was consistent with formulary recommendations in 253 (82.7%), modified appropriately in 24 (7.8%), and nonformulary in 29 (9.5%). Median [interquartile range (IQR)] duration of hospital stay was 5 (3–8), 7 (5–9, P  = 0.026), and 7 (5 - 14, P  = 0.0006) days, and overall duration of antimicrobial therapy was 12 (9–16), 13 (8–15), and 15 (12–19, P  = 0.0479) days, respectively. No differences were observed in clinical or laboratory markers of sepsis. Conclusions   Prescribing patterns accorded with prevailing guidelines in the majority of patients. Nonetheless, there was nonformulary prescribing in 10% of patients, and this could not be explained by clinical or laboratory measures of disease severity. Further work is needed to explore the factors that contribute to nonformulary prescribing in this group of patients. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-5 DOI 10.1007/s00228-012-1240-7 Authors Matthew S. Davies, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wiggington Road, York, YO31 8HE UK Munro B. Robertson, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wiggington Road, York, YO31 8HE UK Stewart H. A. Brown, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wiggington Road, York, YO31 8HE UK Bethan Saunders, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wiggington Road, York, YO31 8HE UK W. Stephen Waring, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wiggington Road, York, YO31 8HE UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Pharmacokinetic and safety of raltegravir in pregnancy Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1250-5 Authors Leonardo Croci, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Michele Trezzi, Unità Operativa Malattie Infettive, Ospedale Il Ceppo, Viale Matteotti, Pistoia, 51100 Italy Maria Pia Allegri, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Tiziana Carli, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Silvia Chigiotti, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Maria Piera Riccardi, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Barbara Ricciardi, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Mario Toti, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Cesira Nencioni, Unità Operativa Malattie Infettive, Ospedale Misericordia, Via Senese, Grosseto, 58100 Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Comments on article by Kinsella et al. published in the November 2011 issue Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1243-4 Authors Indumathi, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India 605006 Steven A. Dkhar, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India 605006 Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   In modelling studies using pharmacists’ opinions, drug-related morbidity (DRM) and preventable DRM have been more common than in observational studies, and the resulting costs are extensive. Modelling studies’ estimates may vary depending on informants’ profession. The purpose of this modelling study was to estimate the proportion of patients with DRM and preventable DRM and the cost of illness (COI) of DRM in Sweden based on physicians’ expert opinions. Method   A conceptual model of DRM was modified from previous studies. Using a modified Delphi technique, a panel of physicians ( n  = 19) estimated the probabilities of DRM, preventable DRM, and clinical outcomes of DRM separately for outpatients and inpatients. DRM included new medical problems (adverse drug reactions, drug dependence, and intoxications by overdose) and therapeutic failure (insufficient effects of medicines, and morbidity due to untreated indication). A COI analysis included the direct costs of DRM. Results   Physicians estimated that 51 ± 22% [mean ± standard deviation (SD)] of outpatients experience DRM and 12 ± 8% preventable DRM. Of inpatients, 54 ± 17% was estimated to experience DRM and 16 ± 7% preventable DRM. Of outpatients with DRM, 24 ± 11% was estimated to experience preventable DRM, whereas this proportion for inpatients was 31 ± 15%. The estimated COI was 376 euros per outpatient and 838 euros per inpatient. Conclusions   Swedish physicians estimated that every other outpatient and inpatient experiences DRM, which is often preventable and costly. As physicians’ estimates on the proportion of patients with DRM were higher than in observational studies in restricted subpopulations, DRM may be more common in the general population than observational studies suggest. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-11 DOI 10.1007/s00228-012-1244-3 Authors Katja M. Hakkarainen, Nordic School of Public Health NHV, Box 12133, 40242 Gothenburg, Sweden Daniel Alström, Nordic School of Public Health NHV, Box 12133, 40242 Gothenburg, Sweden Staffan Hägg, Nordic School of Public Health NHV, Box 12133, 40242 Gothenburg, Sweden Anders Carlsten, Nordic School of Public Health NHV, Box 12133, 40242 Gothenburg, Sweden Hanna Gyllensten, Nordic School of Public Health NHV, Box 12133, 40242 Gothenburg, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Interpreting randomised trials evaluating newer agents or interferon in multiple sclerosis Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1247-0 Authors Andrea Messori, Laboratorio SIFO di Farmacoeconomia, Area Vasta Centro Toscana, ESTAV, 59100 Prato, Italy Fabiola Del Santo, Laboratorio SIFO di Farmacoeconomia, Area Vasta Centro Toscana, ESTAV, 59100 Prato, Italy Dario Maratea, Laboratorio SIFO di Farmacoeconomia, Area Vasta Centro Toscana, ESTAV, 59100 Prato, Italy Valeria Fadda, Laboratorio SIFO di Farmacoeconomia, Area Vasta Centro Toscana, ESTAV, 59100 Prato, Italy Sabrina Trippoli, Laboratorio SIFO di Farmacoeconomia, Area Vasta Centro Toscana, ESTAV, 59100 Prato, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion. Method   Doses of 2, 4, 8, or 16.0 mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0 mg/h and force-titrated in doubling increments every 3 min to target dose, then maintained for 72 h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8 h after termination of infusion, although oral therapy could be restarted at 4 h. Clevidipine blood levels were obtained during infusion and for 1 hour after termination. Results   Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6 h after termination of the clevidipine infusion. At 8 h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8 h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline. Conclusion   This study supports the use of up to 72 h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated. Content Type Journal Article Category Pharmacodynamics Pages 1-10 DOI 10.1007/s00228-012-1260-3 Authors William B. Smith, Volunteer Research Group, University of Tennessee Medical Center, Knoxville, TN, USA Thomas C. Marbury, Orlando Clinical Research Center, Orlando, FL, USA Steven F. Komjathy, Eli Lilly and Company, Indianapolis, IN, USA Mark S. Sumeray, Aegerion Pharmaceuticals, Cambridge, MA, USA Gregory C. Williams, The Medicines Company, Parsippany, NJ, USA Ming-yi Hu, The Medicines Company, Parsippany, NJ, USA Diane R. Mould, Projections Research, Phoenixville, PA, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Objectives   Pantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated. Methods   Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug. Results   Carriers of CYP2C19*2/*2 ( n  = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type ( CYP2C19*1/*1 , n  = 6) volunteers. In subjects with CYP2C19*17/*17 genotype ( n  = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 ( n  = 6) and CYP2C19*2/*17 ( n  = 6) displayed concentration–time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ z ) by 83.3%, prolongation of terminal half-life (t ½ ) by 572%, a rise in area under the concentration–time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg⋅h/L vs 3.00 ± 1.02 mg⋅h/L, p  〈 0.05) and C max (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p  〈 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p  〈 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2 , * 2/*2 , and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype * 2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h). Conclusion   These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics. Content Type Journal Article Category Pharmacogenetics Pages 1-8 DOI 10.1007/s00228-012-1252-3 Authors Barbara Gawrońska-Szklarz, Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland Urszula Adamiak-Giera, Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland Elżbieta Wyska, Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University, Collegium Medicum, Cracow, Poland Mateusz Kurzawski, Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland Wanda Gornik, Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland Maria Kaldonska, Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland Marek Drozdzik, Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Treatment failures following vancomycin therapy in patients with methicillin-resistant Staphylococcus aureus infections have led to the utilization of higher doses of this antibiotic to achieve the trough concentrations of 10–20 μg/mL recommended by the Infectious Diseases Society of America clinical practice guideline. However, many questions remain on the safety of such high doses of vancomycin, specifically their nephrotoxic effects. In this review, we have collected available evidence on the nephrotoxicity of vancomycin, particularly in terms of its mechanism, incidence, predisposing factors and special target populations. Method   The data were collected by searching Scopus, PubMed, Medline, and Cochrane database systematic reviews. The key words used as search terms were “vancomycin”, “nephrotoxicity”, “renal failure”, “renal damage”, “risk factors”, “infants”, “children”, “adult”, “elderly” and “pregnancy”. We have included all relevant animal and human studies up to the date of publication. Results and conclusion   Vancomycin-induced renal toxicity was reported in 10–20 % and 30–40 % of patients following conventional and high doses of vancomycin therapy, respectively .The most probable mechanism for its nephrotoxicity can be at least partially attributable to an increased production of reactive oxygen species and oxidative stress. There are a number of different risk factors which could accelerate or potentiate the occurrence of vancomycin-induced nephrotoxicity, with the most documented risk factors being high trough vancomycin level (especially 〉20 mg/L) or doses (〉4 g/day), concomitant treatment with nephrotoxic agents, prolonged therapy (even more than 7 days), and admittance to an intensive care unit (especially prolonged stay). It is necessary to carry out more studies, especially those focused on the association between nephrotoxicity and high trough levels of vancomycin. Content Type Journal Article Category Review Article Pages 1-13 DOI 10.1007/s00228-012-1259-9 Authors Sepideh Elyasi, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box 14155/6451, 1417614411 Tehran, Iran Hossein Khalili, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box 14155/6451, 1417614411 Tehran, Iran Simin Dashti-Khavidaki, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O.Box 14155/6451, 1417614411 Tehran, Iran Amirhooshang Mohammadpour, Department of Clinical Pharmacy, Faculty of Pharmacy, Mashhad University of Medical Sciences, Tehran, Iran Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians. Methods   Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg). Results   The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively ( p  = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p  = 0.11). The mean plasma area under the time–concentration curve between time zero and 32 h (AUC 0-32h ) of the N -depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p  〈 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C max ) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete. Conclusions   Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-6 DOI 10.1007/s00228-012-1248-z Authors A. Helldén, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden G. Panagiotidis, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden P. Johansson, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden N. Waters, NeuroSearch Sweden AB, Biotech Center, Gothenburg, Sweden S. Waters, NeuroSearch Sweden AB, Biotech Center, Gothenburg, Sweden J. Tedroff, NeuroSearch Sweden AB, Biotech Center, Gothenburg, Sweden L. Bertilsson, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Objective   Montelukast, a leukotriene receptor antagonist, is used in the treatment of asthma. The objective of the study reported here was to determine whether multiple doses of clarithromycin or fluconazole affect the pharmacokinetics of montelukast. Methods   This was a four-phase cross-over study with a washout period of 2 weeks between phases. In phase 1, 12 volunteers received a single oral dose of 10 mg montelukast. In phase 2, the volunteers received a single, oral dose of 1,000 mg clarithromycin once daily for 2 days, followed by, on day 3, a single oral dose of 10 mg montelukast co-administered with clarithromycin. In phase 3, a single oral dose of 50 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 50 mg fluconazole. In the last phase (phase 4), a single oral dose of 150 mg fluconazole was given once daily for 6 days, followed by, on day 7, a single oral dose of 10 mg montelukast co-administered with 150 mg fluconazole. The plasma concentration of montelukast was measured by high performance liquid chromatography for 24 h. Results   Following clarithromycin co-administration, the area under the concentration–time curve from zero to infinity ( AUC 0-∞ ) of montelukast increased by 144% [90% confidence interval (CI) 2.03–2.86]. The co-administration of a single oral dose of 150 and 50 mg fluconazole decreased the montelukast AUC 0–∞ by 30.7 (90% CI 0.53–0.81) and 38.8% (90% CI 0.57–0.69), respectively. Conclusions   Clarithromycin increased the plasma concentrations of montelukast whereas fluconazole reduced the plasma concentrations of montelukast. The mechanism of the interaction is probably due to interference of the interacting drugs with transporters mediating the uptake of montelukast. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-6 DOI 10.1007/s00228-012-1239-0 Authors Sahar K. Hegazy, Department of Clinical Pharmacy, Tanta University, Tanta, 8310 Egypt Mokhtar M. Mabrouk, Department of Analytical Chemistry, Tanta University, Tanta, 8310 Egypt Alaa E. Elsisi, Department of Pharmacology and Toxicology, Tanta University, Tanta, 8310 Egypt Noha O. Mansour, Bioavailability Unit, Faculty of Pharmacy, Tanta University, Tanta, 8310 Egypt Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Our aim was to describe the adverse drug reactions (ADRs) detected following increased education about pharmacovigilance and drug toxicity in children in Camagüey Province, Cuba. Methods   Over a period of 24 months (January 2009 to December 2010), all reports of suspected ADRs in children to the Provincial Pharmacovigilance Centre in Camagüey Province were analysed. ADRs were classified in relation to causality and severity. Results   There were 533 reports involving suspected ADRs in children in the period. Almost one third of the reports received were classified as moderate (155, 29%) or severe (10, 2%). There was one fatality in association with the use of ceftriaxone. Vaccines and antibiotics were responsible for most of the ADR reports (392, 74%) and for all ten severe ADRs. After an intensive educational package, both within the community and the Children’s Hospital, the number of reports increased from 124 in 2008 to 161 in 2009 and 372 in 2010. This was equivalent to a reporting rate of 879 and 2,031 reports per million children per year for 2009 and 2010, respectively. Conclusions   The incidence of ADRs in children Camagüey Province, Cuba, is greater than previously reported. An educational intervention about pharmacovigilance and drug toxicity in children can improve the reporting of ADRs. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-6 DOI 10.1007/s00228-012-1222-9 Authors Z. Bárzaga Arencibia, Children’s Hospital “Eduardo Agramonte Piña”, Camagüey Province, Cuba A. López Leyva, Provincial Pharmacoepidemiology Department, Camagüey Province, Cuba Y. Mejías Peña, Provincial Pharmacoepidemiology Department, Camagüey Province, Cuba A. R. González Reyes, Provincial Pharmacoepidemiology Department, Camagüey Province, Cuba E. Fernández Manzano, Faculty of Pharmacy, University of Havana, Havana, Cuba I. Choonara, Academic Division of Child Health, University of Nottingham, Derbyshire Children’s Hospital, Derby, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   The aim of this study was to determine the prevalence and pattern of unlicensed and off-label drugs prescribed to hospitalized children at the Department of Paediatrics, University Hospital Rijeka, Croatia. Methods   A prospective cross-sectional study was performed on 1 day each month during a 12 month period and included all hospitalized children and adolescents. Results   A total of 1,643 prescriptions for 198 different drugs were prescribed to 531 out of 691 (77%) hospitalized patients. Forty-six percent of the different drugs were prescribed in an unlicensed or off-label manner. Of all drug prescriptions, 25% were either unlicensed or off-label. Forty-eight percent of the patients received either an unlicensed or off-label drug. The most frequently prescribed off-label drugs were proton pump inhibitors. Conclusion   Unlicensed and off-label drug use is common. It is not illegal and may be clinically appropriate but is associated with a number of clinical, safety, and ethical issues. Regulatory authorities should use existing clinical evidence on the use of off-label and unlicensed drugs in decision making. Marketing authorization holders and national regulatory authorities should monitor for any safety concerns associated with unlicensed and off-label drug use and take appropriate measures as well as identify research priorities and mandate clinical studies to resolve important questions. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-5 DOI 10.1007/s00228-012-1221-x Authors Goran Palčevski, Department of Paediatrics, University Hospital Rijeka, Rijeka, Croatia Nataša Skočibušić, University of Rijeka Medical School, Rijeka, Croatia Vera Vlahović-Palčevski, Unit for Clinical Pharmacology, University Hospital Rijeka, Krešimirova 42, 51000 Rijeka, Croatia Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   To determine whether impaired renal function alters the pharmacokinetics (PK) of vorapaxar or its ability to inhibit thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Methods   This was an open-label study in which 8 patients with end-stage renal disease (ESRD) on hemodialysis and 7 matched (based on age, gender, weight, and height) healthy controls were administered a single 10-mg oral dose of vorapaxar. Blood samples for vorapaxar PK and pharmacodynamic analysis were collected predose and at frequent intervals up to 6 weeks postdose. Results   Mean vorapaxar bioavailability (based on area under the curve of plasma vorapaxar concentration over time) was identical in the two subject groups; the ESRD/healthy geometric mean ratio (GMR, expressed in percent) was 98. Mean maximum observed plasma concentration (77.4–98.2 ng/mL) was numerically lower in patients with ESRD compared with matched controls (GMR = 76; 90% confidence interval = 48 to 118). Median time of maximum observed plasma concentration was 2 h in both subject groups. The observed means for elimination half-life were 186 and 231 h in the ESRD and control groups, respectively. Inhibition of platelet aggregation was similar in the two groups. Four out of 15 (27%) subjects reported adverse events, all of which were characterized by the investigator as mild and unrelated to treatment. Conclusions   ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-8 DOI 10.1007/s00228-012-1217-6 Authors Teddy Kosoglou, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Walter K. Kraft, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA Bharath Kumar, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Paul Statkevich, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Fengjuan Xuan, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Lei Ma, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Lisa K. Jennings, University of Tennessee Health Science Center, Memphis, TN, USA James E. Schiller, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Ronald B. Langdon, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA David L. Cutler, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Leukotriene D 4 (LTD 4 ) is a central mediator in asthma inducing bronchoconstriction and profound disturbances in pulmonary gas exchange in asthmatic subjects. The aim of the study was to compare, for the first time, the influence of the bronchodilators salbutamol (400 μg) and ipratropium (80 μg) on lung function changes induced by inhaled LTD 4 . Methods   Treatments were evaluated in a randomized, three-period, double-blind, placebo-controlled, cross-over study where spirometric and pulmonary gas exchange indices were followed in 12 subjects with mild asthma before and after LTD 4 challenge. Results   Compared with placebo, salbutamol provided significant protection against the fall in FEV 1 (forced expiratory volume in 1 s) after LTD 4 challenge. Salbutamol also abolished the LTD 4 -induced gas exchange disturbances [decreased arterial oxygen tension (PaO 2 ) and increased alveolar–arterial oxygen tension difference (AaPO 2 )]. Ipratropium provided significant but less marked attenuation of the changes in FEV 1 and arterial oxygenation induced by LTD 4 . Conclusion   Despite the equal bronchodilatory effects of salbutamol and ipratropium before the challenge with LTD 4 , salbutamol was superior to ipratropium in preventing spirometric and gas exchange abnormalities. This result indicates a broader action of salbutamol on several of the disturbances that contribute to airway obstruction including, for example, exudation of plasma in the airway mucosa. The clinical implication of this new finding is that in this model of acute asthmatic airway obstruction, salbutamol was more effective than ipratropium. Content Type Journal Article Category Pharmacodynamics Pages 1-9 DOI 10.1007/s00228-012-1256-z Authors Barbro Dahlén, Lung and Allergy Clinic, Department of Medicine at Karolinska University Hospital Huddinge and The Centre for Allergy Research, Karolinska Institutet, 141 86 Stockholm, Sweden Federico P Gómez, Servei de Pneumologia (Thorax Institute), Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain Alejandro Casas, Servei de Pneumologia (Thorax Institute), Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain Peter H Howarth, Southampton General Hospital, University of Southampton, Southampton, UK Sven-Erik Dahlén, Unit for Experimental Asthma & Allergy Research, The National Institute of Environmental Medicine and The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden Robert Rodriguez-Roisin, Servei de Pneumologia (Thorax Institute), Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   To characterize the pharmacokinetics (PK) of oxycodone following intravenous injection and administration of three oral dosage forms (solution, capsule, and controlled-release tablet) in elderly patients (age 76–89 years) undergoing cystoscopy. Methods   This was an open, randomized study with two sequences and two visits in 15 elderly patients. The patients were given intravenous injection (over 10 min) of 5 mg of oxycodone hydrochloride trihydrate. Oxycodone hydrochloride (5 mg in all forms) was orally administered as a solution, a capsule, and a controlled-release tablet. Venous blood samples were collected up to 17 h after oxycodone administration. Population PK parameters were calculated with NONMEM VI 2.0. For intravenous injection we calculated clearance, volume of distribution at steady state, and the half-life of elimination, and for oral dosage forms also the absolute bioavailability. Results   Clearance of the intravenous injections was 28.9 L/h; the volume of distribution at steady state and the half-life of elimination were 186 L and 5.2 h, respectively. The absolute bioavailability of oxycodone was 59 % from oral solutions, 64 % from capsules, and 55 % from controlled-release tablets. Conclusions   Our results indicate that, in the elderly, the bioavailability of the three different oral dosage forms of oxycodone is fairly similar. Content Type Journal Article Category Clinical Trial Pages 1-7 DOI 10.1007/s00228-012-1267-9 Authors Merja Kokki, Department of Anesthesia and Operative Services, Kuopio University Hospital, PO Box 1777, FI-70211 Kuopio, Finland Pyry Välitalo, School of Pharmacy, Department of Health Sciences, University of Eastern Finland, Kuopio, Finland Ilpo Rasanen, Department of Forensic Medicine, Hjelt Institute, University of Helsinki, Helsinki, Finland Sirpa Aaltomaa, Department of Surgery, Kuopio University Hospital, Kuopio, Finland Ilkka Ojanperä, Department of Forensic Medicine, Hjelt Institute, University of Helsinki, Helsinki, Finland Matti Eskelinen, Department of Surgery, Kuopio University Hospital, Kuopio, Finland Hannu Kokki, Department of Anesthesia and Operative Services, Kuopio University Hospital, PO Box 1777, FI-70211 Kuopio, Finland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [mifamurtide (L-MTP-PE)] in healthy adults. Methods   L-MTP-PE 4 mg was administered intravenously over 30 min. Study participants were monitored from 24 h preinfusion until 72 h postinfusion. Blood samples were drawn over 0–72 h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24 h predose through 24 h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90 % confidence intervals were calculated. Results   Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05 ± 0.40 h. PK variability was low, with 〈30 % coefficient of variation in systemic exposure. Serum concentrations of IL-6, TNF-α, and CRP increased following L-MTP-PE infusion. Maximum observed increases in IL-6 and TNF-α occurred at 4 and 2 h, respectively, returning toward baseline by 8 h postdose. L-MTP-PE was generally well tolerated, with no adverse events greater than grade 3. Headache, chills, tachycardia, nausea, and pyrexia were the most frequent adverse events. L-MTP-PE infusion resulted in an increased heart rate without readily apparent QTc prolongation. Conclusions   MTP-PE PK following L-MTP-PE administration were characterized by a short serum half-life and low variability. Increases in IL-6, TNF-α, and CRP and the safety profile were consistent with the immunomodulatory mechanism of action. No clinically significant effect of L-MTP-PE on cardiovascular repolarization was observed based on analysis of ECG QTc intervals. Content Type Journal Article Category Clinical Trial Pages 1-9 DOI 10.1007/s00228-012-1262-1 Authors Karthik Venkatakrishnan, Millennium Pharmaceuticals, Inc., Clinical Pharmacology, 35 Landsdowne Street, Cambridge, MA 02139, USA William G. Kramer, Kramer Consulting LLC, Pharmacokinetics/Pharmacodynamics, North Potomac, MD, USA Timothy W. Synold, Department of Molecular Pharmacology, City of Hope Analytical Pharmacology Core Facility, Duarte, CA, USA Daniel B. Goodman, Cardiocore Inc., Cardiac Safety, Bethesda, MD, USA Evin Sides, AAI Clinic, Infectious Disease Medicine, Morrisville, NC, USA Cristina Oliva, Takeda Global Research and Development Europe, Clinical Research, London, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown. Methods   Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2 g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied. Results   At abscess incision performed 158 ± 112 min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from ≤0.1 (limit of quantification) to 47 (mean 8.4 ± 14.1 ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183 ± 106 mg/L in plasma and 12 ± 16 mg/L in the abscess. A cefpirome concentration of 2 mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics. Conclusions   Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-5 DOI 10.1007/s00228-012-1270-1 Authors Robert Sauermann, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria Thomas Feurstein, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria Rudolf Karch, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria Maria C. Kjellsson, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124 Uppsala, Sweden Walter Jäger, Clinical Pharmacy and Diagnostics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria Michaela Böhmdorfer, Clinical Pharmacy and Diagnostics, University of Vienna, Althanstraße 14, 1090 Vienna, Austria Andreas Püspök, Department of Gastroenterology, Medical University of Vienna, Vienna, Austria Herbert Langenberger, Department of Diagnostic Radiology, Medical University of Vienna, Vienna, Austria Thomas Wild, Academy of Wound Technology, 10 rue de la Loge, 34000 Montpellier, France Stefan Winkler, Department of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria Markus Zeitlinger, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Spontaneous ejaculation with the use of noradrenergic reuptake inhibitors Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1264-z Authors Ingrid Oosterhuis, Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH, s-Hertogenbosch, The Netherlands Léon Heijting, Mental Health Institution, Leiden, The Netherlands Eugène van Puijenbroek, Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH, s-Hertogenbosch, The Netherlands Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   We sought to estimate the prevalence of potentially inappropriate prescribing (PIP) in the Northern Ireland (NI) population aged ≥70 years, to investigate factors associated with PIP and to calculate total gross cost of PIP. Methods   A retrospective cross-sectional population study was carried out in those aged ≥70 years in 2009/2010 who were in primary care in NI. Data were extracted from the Enhanced Prescribing Database, which provides details of prescribed and dispensed medications for each individual registered with a general practitioner. Twenty-eight PIP indicators from the Screening Tool of Older Persons potentially inappropriate Prescriptions (STOPP) criteria were applied to these data. PIP prevalence according to individual STOPP criteria and the overall prevalence of PIP were estimated. The relationship between PIP and polypharmacy, age and gender was examined using logistic regression. Gross cost of PIP was ascertained. Results   The overall prevalence of PIP in the study population ( n  = 166,108) was 34 %. The most common examples of PIP identified were proton pump inhibitors at maximum therapeutic dose for 〉8 weeks (17,931 patients, 11 %), non-steroidal anti-inflammatory drugs 〉3 months (14,545 patients, 9 %) and long-term long-acting benzodiazepines (10,147 patients, 6 %). PIP was strongly associated with polypharmacy, with those receiving seven different medications being fivefold more likely to be exposed to PIP than those on zero to three medications (odds ratio 5.04, 95 % confidence interval 4.84–5.25) The gross cost of PIP was estimated to be €6,098,419 Conclusions   Consistent with other research, the prevalence of PIP was high among the study cohort, increased with polypharmacy and was associated with significant cost. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1249-y Authors Marie C. Bradley, School of Pharmacy, HRB Centre for Primary Care Research, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland Tom Fahey, Division of Population Health Sciences, RCSI Medical School, HRB Centre for Primary Care Research, Royal College of Surgeons In Ireland, Dublin, Ireland Caitriona Cahir, Division of Population Health Sciences, RCSI Medical School, HRB Centre for Primary Care Research, Royal College of Surgeons In Ireland, Dublin, Ireland Kathleen Bennett, Department of Pharmacology and Therapeutics, Trinity Centre for Health Sciences, St James’ Hospital, Dublin, Ireland Dermot O’Reilly, Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland Carole Parsons, School of Pharmacy, HRB Centre for Primary Care Research, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland Carmel M. Hughes, School of Pharmacy, HRB Centre for Primary Care Research, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL Northern Ireland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of escalating single oral doses of ACT-077825, a novel orally active renin inhibitor, in healthy male subjects. Methods   In this single-center, double-blind, placebo- and active-controlled (with enalapril) randomized study, 70 subjects received a single dose of ACT-077825 (1–1,000 mg), placebo, or enalapril 20 mg under fasted conditions. The main pharmacokinetic endpoints were area under the plasma ACT-077825 concentration–time curve from time zero to infinity and the terminal half-life (t 1/2 ). The pharmacodynamic endpoints included immunoactive active renin (iAR) plasma concentrations and plasma renin activity (PRA). Standard laboratory and safety data were collected. Results   Of the few adverse events reported, diarrhea and headache were the most frequent. The pharmacokinetics of ACT-077825 were dose-proportional in the dose range 100 to 1,000 mg. Terminal t 1/2 , best characterized following a dose of 1,000 mg, was 41.6 h and t max 4–5 h post-dose. ACT-077825 dose-dependently increased iAR and decreased PRA, effects that were associated with a decrease in blood pressure at 1,000 mg, similar to following treatment with enalapril. Conclusion   The results provide evidence that ACT-077825, with a pharmacokinetic profile consistent with a once-a-day dosing regimen, may represent an effective antihypertensive agent and pave the way toward a multiple-ascending dose study. Content Type Journal Article Category Clinical Trial Pages 1-10 DOI 10.1007/s00228-012-1253-2 Authors Laurent B. Nicolas, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Marcelo M. Gutierrez, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Christoph Binkert, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Jasper Dingemanse, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   This study was conducted to evaluate relevant new information about ADRs reported in the Spanish paediatric population over a 6-year period. Methods   Adverse drug reactions (ADRs) for individuals aged 0–17 years reported to the Spanish Pharmacovigilance System from 2004 to 2009 were analysed with respect to time, age and sex, category of ADR [System Organ Class (SOC)], seriousness, suspected medicines [level 2 of the Anatomical Therapeutic Chemical (ATC) Classification System] and type of reporter. Results   In total, 4,279 ADR reports corresponding to 8,196 ADRs were analysed, approximately two ADRs per report. The rate of paediatric ADR reports in 2009 was 165 per million, of which nearly half (46 %) were for children (age group 2–11 years). Similar total numbers of ADRs were reported for boys and girls. The most frequent ADRs reported were from the following SOCs: general disorders and administration site conditions (34 %); skin and subcutaneous tissue disorders (15 %); nervous system disorders (14 %). Reports encompassed medicines from various ATC groups: vaccines and anti-infectives for systemic use (67 %); nervous system (9 %); respiratory system (9 %). On average, 37 % of ADRs were classified as serious. There were 33 fatal ADRs, and 35 % of the paediatric population associated with the ADR notifications required hospitalization or extended hospital stay. Conclusions   In Spain, ADR reporting rate in the paediatric population has increased since 2004. The proportion of suspected ADR reports related to vaccines was predominant, which highlights the important role played by nurses. ADR notification of congenital malformations in newborn infants highlights the need for joint action between the Spanish System of Pharmacovigilance of Medicines for Human Use (SEFV-H) and paediatricians, obstetricians and gynaecologists. The publication of safety reports by regulatory agencies is determinant for the increased number of ADR notifications. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-10 DOI 10.1007/s00228-012-1255-0 Authors A. Aldea, Unidad Central de Investigación Clínica y Ensayos Clínicos, Hospital Universitario de Canarias, Ofra, s/n. La Cuesta, 38320 San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain M. García Sánchez-Colomer, Centro de Farmacovigilancia e Información Terapéutica de Canarias, Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain E. Fernández Quintana, Centro de Farmacovigilancia e Información Terapéutica de Canarias, Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain M. García Sáiz, Servicio de Farmacología clínica, Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   To assess the main differences in clinical significance of the prescribing errors intercepted by clinical pharmacists in paediatrics and obstetrics and the reasons for these prescribing errors, as well as the differences in pharmacists’ activity indicators. Methods   The was a cross-sectional epidemiological study analysing the activities of paediatric pharmacists in a maternity and children's hospital with 180 paediatric beds and 138 obstetrics and gynaecology beds between January 2007 and December 2009. The following variables were analysed: clinical significance of prescribing errors intercepted, reason for the error, impact of the intervention by pharmacist, acceptance rate of the recommendation made, medication involved, intervention detection date and observations. Results   A total of 2,449 interventions in medical orders were recorded. Interventions that were not accepted by doctors were excluded, leaving 43 cases (2.1%) of extremely significant interventions and 170 (8.4%) very significant interventions. Interventions in what were deemed to be error-free situations were excluded. Significance testing (based on 2,035 errors detected) showed that 1.7% of the detected errors were potentially lethal (35 cases), while 10.2% (210 cases) were clinically serious. The main reason for the interventions was the detection of a dosage between 1.5- and tenfold higher than the recommended dosage. The overall rate of acceptance of the pharmacist's suggestions was 92.2%. Pharmacists carried out an average of 0.016 interventions/patient-day throughout the study period. Conclusions   Paediatric patients had a fourfold higher risk of serious errors than the maternity population. Pharmacist intervention had a major impact on reducing prescribing errors in the study period, thus improving the quality and efficiency of care provided. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-7 DOI 10.1007/s00228-012-1257-y Authors Cecilia M. Fernandez-Llamazares, Pharmacy Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain Miguel-Ángel Calleja-Hernández, Pharmacy Service, Virgen de las Nieves Hospital, Granada, Spain Silvia Manrique-Rodríguez, Pharmacy Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain Cristina Pérez-Sanz, Pharmacy Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain Esther Durán-García, Pharmacy Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain María Sanjurjo-Sáez, Pharmacy Service, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo 46, 28007 Madrid, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Our aim was to compare pharmacological aspects of two switching strategies from morphine/oxycodone to methadone; the stop and go (SAG) strategy in which methadone is started directly after the initial opioid has been stopped, and the 3-days switch (3DS), in which morphine/oxycodone is gradually changed to methadone by cross-tapering over 3 days. Methods   Forty-two cancer patients with pain and/or opioid side effects were assessed in this randomised trial. Trough serum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days 1, 2, 3, 4, 7, and 14. Primary outcome was number of patients with methadone concentrations in apparent C SS on day 4. Secondary outcomes were exposure to opioids during the first 3 days, interindividual variation of opioid concentrations, and correlation between methadone concentrations and pain intensity (PI) day 3. Results   Thirty-five patients received methadone (16 in the SAG group, 19 in the 3DS group). The median preswitch morphine equivalent doses were 620 (range 350–2000) mg/day in the SAG group and 800 (range 90–3600) mg/day in the 3DS group ( p  = 0.43);42% reached C SS for methadone in the SAG group on day 4 compared with 22% in the 3DS group ( p  = 0.42). The SAG group was significantly less exposed to morphine/M6G/oxycodone and significantly more exposed to methadone in the first 3 days. Methadone showed a low correlation with PI. More patients dropped out after intervention in the SAG group than in the 3DS group (38% vs. 5%; p  = 0.032). One SAG patient suffered from respiratory depression on day 5. Conclusion   The SAG group was initially more exposed to methadone and less to the replaced opioids but without observed clinical benefit and with a higher dropout rate. Patients switched to methadone should be followed closely for the first 5 days, regardless of switching strategy. Content Type Journal Article Category Clinical Trial Pages 1-10 DOI 10.1007/s00228-012-1228-3 Authors Kristin Moksnes, Pain and Palliation Research Group, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Stein Kaasa, Pain and Palliation Research Group, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Ørnulf Paulsen, Pain and Palliation Research Group, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Jan Henrik Rosland, Sunniva Centre for Palliative Care, Haraldsplass Deaconess Hospital, Bergen, Norway Olav Spigset, Department of Clinical Pharmacology, St. Olav’s University Hospital, Trondheim, Norway Ola Dale, Pain and Palliation Research Group, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Background   In the UK, clinicians usually make treatment decisions based on total cholesterol (TC) at the same time supplemented with high-density lipoprotein cholesterol (HDL-C) measurements. We evaluated statin-associated TC concentration change and its impact on cardiovascular (CV) risk reduction in diabetic patients in the setting of usual care. Methods   In a population-based cohort study using a record-linkage database in Tayside, Scotland. we studied 6,697 diabetic patients who had at least two separate TC measurements between 1993 and 2007. Patients were categorized into statin-exposed and statin-unexposed groups according to statin use status during the follow-up. The main outcomes were TC concentration change from baseline, CV events, and all-cause mortality during the follow-up. Multivariate Cox regression models with a time-dependent variable for statins were employed to assess outcome risk. Results   Statin-associated TC concentrations decreased by 1.64 mmol/L (28%) in patients without CV disease (CVD) (5,984) and 1.19 mmol/L (23%) in patients with CVD (713) from 5.90 mmol/L and 5.20 mmol/L at baselines, respectively. Statin use reduced incident and recurrent CV events by 39% and 41%, respectively [adjusted hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.57–0.66; 0.59 95% CI 0.47–0.76) per millimole of TC reduction. For all-cause mortality, the adjusted HRs were 0.39 (95% CI 0.32–0.47) in primary prevention and 0.58 (95% CI 0.42–0.80) in secondary prevention. Conclusion   Statin use was as effective in diabetic patients in the setting of usual care, as in the clinical trials, in both primary and secondary prevention. TC changes can be used as a measure of statin efficacy in the absence of low-density lipoprotein cholesterol (LDL-C) in diabetic patients. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-8 DOI 10.1007/s00228-012-1234-5 Authors Xia Sheng, Medicines Monitoring Unit, Division of Medical Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK Michael J. Murphy, Department of Biochemical Medicine, Division of Clinical & Population Sciences & Education, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK Thomas M. MacDonald, Medicines Monitoring Unit, Division of Medical Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK Li Wei, Medicines Monitoring Unit, Division of Medical Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    Elderly patients are at increased risk of drug-related morbidity and mortality. Avoiding the use of potentially inappropriate medications (PIMs) is one of the strategies that has been widely adopted to reduce the harmful consequences of drug use. There are several PIM screening tools available. In this review, we provide an overview of existing screening tools to detect PIMs in the elderly, emphasizing the advantages and disadvantages of each. Combining previously published and adopted tools (adjusted Beers list, French consensus panel, McLeod’s list, and Lindblad’s list of clinically important drug–disease interactions), we develop a new comprehensive tool that also includes the adjusted Hanlon’s and Malone’s lists of potentially serious drug–drug interactions in the elderly. In addition to listed PIMs and clinically important drug–drug interactions, alternative therapeutic solutions are suggested. The new protocol differentiates: drugs with an unfavorable benefit/risk ratio (to be avoided regardless of the underlying disease/condition), drugs with a questionable efficacy, and drugs to be avoided with certain diseases/conditions, and provides a list of potentially serious drug–drug interactions. A tool consisting of PIMs and potential drug–drug interactions within the same protocol provides more comprehensive quality assessment of drug-prescribing behavior to the elderly, which in turn may lead to better prescribing practices. Content Type Journal Article Category Review Article Pages 1-16 DOI 10.1007/s00228-012-1238-1 Authors Suzana Mimica Matanović, Clinical Pharmacology Unit, University Hospital Center Osijek, Osijek, Croatia Vera Vlahovic-Palcevski, Clinical Pharmacology Unit, University Hospital Center Rijeka, Rijeka, Croatia Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Warfarin dosing is affected by clinical and genetic variants, but the contribution of the genotype associated with warfarin resistance in pharmacogenetic algorithms has not been well assessed yet. We developed a new dosing algorithm including polymorphisms associated both with warfarin sensitivity and resistance in the Italian population, and its performance was compared with those of eight previously published algorithms. Methods   Clinical and genetic data ( CYP2C9*2 , CYP2C9*3 , VKORC1 –1639 G 〉 A, and VKORC1 3730 G 〉 A) were used to elaborate the new algorithm. Derivation and validation groups comprised 55 (58.2% men, mean age 69 years) and 40 (57.5% men, mean age 70 years) patients, respectively, who were on stable anticoagulation therapy for at least 3 months with different oral anticoagulation therapy (OAT) indications. Results   Performance of the new algorithm, evaluated with mean absolute error (MAE) defined as the absolute value of the difference between observed daily maintenance dose and predicted daily dose, correlation with the observed dose and R 2 value, was comparable with or slightly lower than that obtained using the other algorithms. The new algorithm could correctly assign 53.3%, 50.0%, and 57.1% of patients to the low (≤25 mg/week), intermediate (26–44 mg/week) and high (≥ 45 mg/week) dosing range, respectively. Our data showed a significant increase in predictive accuracy among patients requiring high warfarin dose compared with the other algorithms (ranging from 0% to 28.6%). Conclusions   The algorithm including VKORC1 3730 G 〉 A, associated with warfarin resistance, allowed a more accurate identification of resistant patients who require higher warfarin dosage. Content Type Journal Article Category Pharmacogenetics Pages 1-8 DOI 10.1007/s00228-012-1226-5 Authors Michela Cini, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Cristina Legnani, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Benilde Cosmi, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Giuliana Guazzaloca, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Lelia Valdrè, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Mirella Frascaro, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Gualtiero Palareti, Department of Angiology and Blood Coagulation “Marino Golinelli”, University Hospital S. Orsola-Malpighi, Via Albertoni, 15, 40138 Bologna, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Objectives   N-3 fatty acids reduce the risks of cardiovascular morbidity and mortality. Administration of N-3 fatty acids to patients treated with statins may potentiate the treatment effects. We examined the operating mechanisms underlying such a combination. Methods   Thirty-two hypercholesterolemic patients aged 30–70 years with hypercholesterolemia controlled by statins, received sequential treatments with placebo followed by 1.9 g/day of N-3 fatty acids for 23 weeks. Scheduled clinical visits included physical examination, 24-h blood pressure measurement, endothelial function evaluated by pulse wave analysis, analyses for platelet function, inflammation markers [interleukin (IL)-6, plasminogen activator inhibitor-1 (PAI-1)] and oxidative stress parameters (STAT-8-Isoprostane) were undertaken at baseline, after placebo treatment, and after 6 and 20 weeks of N-3 fatty acid intake. Results   Platelets functions were significantly inhibited, whereas endothelial function parameters were unaltered. IL-6 significantly decreased whereas PAI-1and STAT-8-Isoprostane levels remained unaffected. Daytime blood pressure significantly decreased; however, nighttime pressure and heart rate remained unchanged. No evidence of lipid-profile improvement was observed following combined treatment with statins and N-3 fatty acids. Conclusions   In hypercholesterolemic patients, combination of statins and N-3 fatty acid inhibits platelet aggregation, alters inflammatory status, and positively affects daytime blood pressure. Close long-term follow-up might reveal additional beneficial effects of N-3 fatty acids in this patient population. Content Type Journal Article Category Clinical Trial Pages 1-8 DOI 10.1007/s00228-012-1235-4 Authors Keren Doenyas-Barak, Research & Development Unit and Nephrology Division, Assaf Harofeh Medical Center, Tel- Aviv University, Zerifin, 70300 Israel Sylvia Berman, Research & Development Unit and Nephrology Division, Assaf Harofeh Medical Center, Tel- Aviv University, Zerifin, 70300 Israel Ramzia Abu-Hamad, Research & Development Unit, Assaf Harofeh Medical Center, Tel- Aviv University, Zerifin, 70300 Israel Ahuva Golik, Internal Medicine Department A, Assaf Harofeh Medical Center, Tel- Aviv University, Zerifin, 70300 Israel Naomi Rahimi-Levene, Hematology Division, Assaf Harofeh Medical Center, Tel- Aviv University, Zerifin, 70300 Israel Shai Efrati, Research & Development Unit and Nephrology Division, Assaf Harofeh Medical Center, Tel- Aviv University, Zerifin, 70300 Israel Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Adverse drug reactions (ADRs) are a major patient safety issue, and a substantial proportion of ADRs are, in fact, preventable. The aim of this study was to describe the proportion and pattern of preventable ADRs in spontaneously reported suspected ADRs and to study the feasibility of using data from an ADR reporting system for this purpose. Methods   All reports of ADRs, except those in which a vaccine was the suspected drug, submitted to the regional pharmacovigilance center of southeastern Sweden between 2008 and 2009 were analyzed. Causality between the suspected ADR and the medication was assessed using the World Health Organization (WHO) criteria, and preventability was assessed using Hallas criteria. Results   During the study period, 1,290 ADRs were received and 1,255 were classified as having at least a possible causality between a reaction and a drug. Of these, 172 (14%) ADRs were considered preventable, 35 (20%) were classified as definitely preventable, and 137 (80%) as possibly preventable. Of all preventable ADRs, 96 (56%) were related to prescribing, 35 (20%) to administration, and 41 (24%) to clinical and laboratory monitoring of treatment. Warfarin, oxycodone, and ioversol were the most common drugs with preventable ADRs. Conclusions   This study found that a substantial part of reported ADRs are preventable. Most of these are related to drug prescription, suggesting that interventions aiming to reduce preventable ADRs should focus on this process. Moreover, systems for ADR reporting may be useful in the mission of reducing the unsafe use of drugs. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-7 DOI 10.1007/s00228-012-1237-2 Authors Henrik Lövborg, Regional Pharmacovigilance Centre, Department of Clinical Pharmacology, Linköping University Hospital, 581 85 Linköping, Sweden Linda Ring Eriksson, Regional Pharmacovigilance Centre, Department of Clinical Pharmacology, Linköping University Hospital, 581 85 Linköping, Sweden Anna K. Jönsson, Regional Pharmacovigilance Centre, Department of Clinical Pharmacology, Linköping University Hospital, 581 85 Linköping, Sweden Thomas Bradley, Regional Pharmacovigilance Centre, Department of Clinical Pharmacology, Linköping University Hospital, 581 85 Linköping, Sweden Staffan Hägg, Regional Pharmacovigilance Centre, Department of Clinical Pharmacology, Linköping University Hospital, 581 85 Linköping, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   The elderly often use several drugs on a regular basis and are especially at risk for drug-related harm from side effects and interactions. The aim of this study was to explore the overall prevalence of and predictors for potentially inappropriate medication use among Norwegian elderly outpatients. Methods   A pharmaco-epidemiological retrospective cross-sectional survey was undertaken based on data from the Norwegian Prescription Database. Prescriptions from all doctors in Norway, dispensed by pharmacies to home-dwelling elderly ≥70 years in 2008, were included for a total of 11,491,065 prescriptions from 24,540 prescribers to 445,900 individuals (88.3% of the Norwegian population in this age group, 58.9% females). We applied a list of criteria for pharmacological inappropriateness for elderly people (the NORGEP criteria) to determine the prevalence of potentially inappropriate medications (PIMs) and applied a multiple logistic regression model to identify predictors. Results   According to our criteria, 34.8% of the study population (28.5% of the men, 39.3% of the women) was exposed to at least one PIM. Of these, 59.9% represented psychoactive substances. The odds of receiving potentially harmful prescriptions increased with the number of prescribers (OR 3.52, 99% CI 3.44–3.60 for those with ≥5 compared to those with 1 or 2 prescribers). Twenty percent were prescribed more than 10 medications; among these two-thirds had at least one PIM. Adjusted for differences in age distribution and the number of prescribers involved, women were more frequently exposed to PIMs than men, with an odds ratio of 1.60 (99% CI 1.58–1.64). Conclusions   About one-third of the elderly Norwegian population is exposed to potentially inappropriate medications, and elderly females are at particular risk. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-10 DOI 10.1007/s00228-012-1223-8 Authors Gunhild Nyborg, Department of General Practice/Family Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway Jørund Straand, Department of General Practice/Family Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway Mette Brekke, Department of General Practice/Family Medicine, Institute of Health and Society, University of Oslo, Oslo, Norway Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Aim   Our aim was to set up a system to help UK clinical research units to prevent healthy volunteers from participating in more than one non-therapeutic trial simultaneously, or from starting a second trial too soon after the first. Methods   TOPS (The Over-volunteering Prevention System) is internet-based, simple and quick to use, free to users and a charity run by a Board of Trustees. Users enter only two or three pieces of information: (1) ‘National Insurance number’ (NINO) of UK citizens, or ‘passport number’ and country of origin of non-UK citizens, as their identifier, (2) ‘date of last dose’ of trial medicine or (3) ‘never dosed’. Subjects must consent, but TOPS collects only non-personal data, so it does not require Ethics Committee approval and is not covered by the Data Protection Act. Results   A total of 55 research units (29 clinical research organisations, 5 pharmaceutical companies, 13 universities and 8 hospitals) throughout the UK have registered to use TOPS, and have entered 124,906 volunteers since we launched it. All commercial and many non-commercial units now use TOPS. In our unit, no subject has to the best of our knowledge participated in two trials simultaneously. TOPS has reduced to 〈1% the incidence of subjects attempting to volunteer within 3 months of completing another trial elsewhere, and very few have to our knowledge succeeded. Conclusion   TOPS is widely used and effective, and helps research units to comply with UK clinical trial regulations. Content Type Journal Article Category Clinical Trial Pages 1-6 DOI 10.1007/s00228-012-1231-8 Authors M. Boyce, Hammersmith Medicines Research (HMR), Cumberland Avenue, London, NW10 7EW UK M. Walther, Hammersmith Medicines Research (HMR), Cumberland Avenue, London, NW10 7EW UK H. Nentwich, Hammersmith Medicines Research (HMR), Cumberland Avenue, London, NW10 7EW UK J. Kirk, Hammersmith Medicines Research (HMR), Cumberland Avenue, London, NW10 7EW UK S. Smith, Hammersmith Medicines Research (HMR), Cumberland Avenue, London, NW10 7EW UK S. Warrington, Hammersmith Medicines Research (HMR), Cumberland Avenue, London, NW10 7EW UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Comparative adherence to oxybutynin or tolterodine among older patients Content Type Journal Article Category Letter to the Editors Pages 1-1 DOI 10.1007/s00228-012-1224-7 Authors Angus Thompson, School of Pharmacy, University of Tasmania, Hobart, Australia Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   The intake of medications (drugs) without the knowledge of the treating physician (unknown co-medication) and nonadherence strongly influence drug safety. The aim of our study was to objectively assess unknown co-medication and nonadherence in hospitalized patients by screening urine for a large number of drugs using highly sensitive full scan gas chromatograpy/mass spectrometry (GC/MS). Secondary objectives were to determine the relationship of co-medication and nonadherence to the number of drugs prescribed and to compare history-taking by a pharmacist versus a physician. Methods   In 152 patients, the drug histories taken by physicians, patients’ self-reported adherence, and information compiled during as many as three structured interviews conducted by a trained pharmacist on days 1–2, 3–4, and 7–11 of the hospital stay were compared with the GC/MS results from urine samples collected after each interview. Results   In the interviews performed by the pharmacist, 235 additional drugs were identified that were not documented in the chart. Of all the drugs indicated in any interview, 16.9% were identified only by the physician, 24.1% only by the pharmacist, and 59% by both. Overall, in 78% of the patients at least one additional drug was identified by urine screening. The findings suggest overall nonadherence to at least one drug in 13.0% of patients on admission and in 23.3% of patients at any time during hospitalization. Nonadherence was less frequent for critical dose drugs and correlated with the number of prescribed drugs. Conclusions   The drug history among hospitalized patients is often incomplete, and nonadherence and unknown co-medication are alarmingly frequent. This lack of knowledge might impact the overall success of drug therapies in the hospital setting. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1229-2 Authors Florentine Carow, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Karin Rieger, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Ingeborg Walter-Sack, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Markus R. Meyer, Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Building 46, 66421 Homburg, Saar, Germany Frank T. Peters, Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Building 46, 66421 Homburg, Saar, Germany Hans H. Maurer, Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Building 46, 66421 Homburg, Saar, Germany Walter E. Haefeli, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Purpose   Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor, is widely used in association with standard chemotherapy in metastatic cancer. Well tolerated, bevacizumab is sometimes associated with serious adverse drug reactions (ADRs). The objective of this study is to describe the profile of ADRs related to bevacizumab and reported to the French Pharmacovigilance system. Method   All serious cases of ADRs associated with bevacizumab recorded in the French Pharmacovigilance database up to November 31, 2010 were identified and analyzed, focusing on patient information, drug exposure, and characteristics of the ADRs. Categorical variables were compared using the chi-square test when appropriate. Results   A total of 351 serious cases involving 626 ADRs were recorded in the database during the study interval. The most frequent ADRs reported involved the gastrointestinal system (21.9%). The most frequent ADRs included gastrointestinal perforation (4.8%), thromboembolic events (4.0%), pulmonary embolism (3.2%), hypertension (2.7%), gastrointestinal hemorrhage (2.7%), and cerebral hemorrhage or vascular accident (2.6%). The median duration of bevacizumab exposure was four cycles (range 1–30) when ADRs occurred. In 18 cases of death directly caused by ADRs, 50% occurred after only one cycle. In cases of disability, 40% of ADRs were neurologic: neuropathy, paralysis, and paresis. Conclusion   To the best of our knowledge, this is the first analysis of bevacizumab safety profile using data collected in a national pharmacovigilance database. Our study confirms the frequency and seriousness of gastrointestinal, thromboembolic, and hemorrhage events with bevacizumab use and provides a picture of the bevacizumab safety profile in daily medical practice, despite intrinsic limitations. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-5 DOI 10.1007/s00228-012-1232-7 Authors Solène Taugourdeau-Raymond, Hôpital Salvator, Assistance Publique des Hôpitaux de Marseille (AP-HM), Centre Régional de Pharmacovigilance, 249 Boulevard Sainte Marguerite, 13009 Marseille, France F. Rouby, Hôpital Salvator, Assistance Publique des Hôpitaux de Marseille (AP-HM), Centre Régional de Pharmacovigilance, 249 Boulevard Sainte Marguerite, 13009 Marseille, France A. Default, Hôpital Salvator, Assistance Publique des Hôpitaux de Marseille (AP-HM), Centre Régional de Pharmacovigilance, 249 Boulevard Sainte Marguerite, 13009 Marseille, France M.-J. Jean-Pastor, Hôpital Salvator, Assistance Publique des Hôpitaux de Marseille (AP-HM), Centre Régional de Pharmacovigilance, 249 Boulevard Sainte Marguerite, 13009 Marseille, France the French Network of the Pharmacovigilance Centers Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description: Introduction   Bayesian forecasting has been shown to improve the accuracy of pharmacokinetic/pharmacodynamic (PK/PD) models by adding measured values to a population model. It could be done in real time for neuromuscular blockers (NMB) using measured values of effect. This study was designed to assess feasibility and benefit of Bayesian forecasting during a rocuronium target-controlled infusion (TCI). Methods   After internal review board (IRB) approval and informed consent, 21 women scheduled for breast plastic surgery were included. Anesthesia was maintained with propofol, alfentanil, and controlled ventilation through a laryngeal mask. Rocuronium was delivered in TCI with Stanpump software and the Plaud population model. The target effect was 50% blockade until insertion of breast prosthesis; thereafter it was set to 0%. Response to train of four (TOF) at adductor pollicis was recorded using a force transducer. In ten patients, drug delivery was based on the population model. In the others, repeated measures values were entered in the software, and the PK model was adjusted to minimize the error in predicted effect. Model precision was compared between groups using mean prediction error and mean absolute prediction error. Results   At target 50%, model accuracy was not improved with Bayesian adjustments; conversely, post-infusion errors were significantly decreased. The first two measures had the most influence on the model changes. Discussion   Below clinical utility, such adjustments may be used to explore cofactors influencing interindividual and intraindividual variability in NMB dose-response relationship. Similar tools may also be developed for drugs in which a quantitative effect is available, such as electroencephalography (EEG) for hypnotics. Implication   Real-time Bayesian forecasting combining measured values of effect with a population model is suitable to guide NMB-agent delivery using Stanpump software. Content Type Journal Article Category Pharmacodynamics Pages 1-7 DOI 10.1007/s00228-012-1236-3 Authors Cyrus Motamed, Department of Anesthesiology, Gustave Roussy Institute, Villejuif, France Jean-Michel Devys, Department of Anesthesiology, Gustave Roussy Institute, Villejuif, France Bertrand Debaene, Department of Anesthesia and Intensive Care CHU, Inserm Unité 1070, Université de Poitiers France, Poitiers, France Valérie Billard, Department of Anesthesiology, Gustave Roussy Institute, Villejuif, France Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Description:    A liquid chromatographic tandem mass spectrometric (LC–MS–MS) method for the determination of five chemical coccidiostats (decoquinate, diclazuril, halofuginone, nicarbazin, and robenidine) and five ionophore coccidiostats (maduramicin, monensin, narasin, salinomycin, and semduramicin) in yoghurt, kefir, and sour cream is presented. Lasalocid, the sixth ionophore listed in 124/2009/EC was not included because of its extremely dissimilar behavior during sample preparation. Main steps of the method include extraction with acetonitrile, centrifugation, clean-up on Oasis HLB solid phase extraction cartridge, evaporation under nitrogen stream, and LC–MS–MS determination. Selectivity, linearity, sensitivity, accuracy, repeatability, within-laboratory reproducibility, limit of determination, and limit of quantitation were determined during the validation procedure. The method proved to be applicable for both qualitative and quantitative determination of the ten above-mentioned target compounds. In our in-house fermentation experiments, milk fortified with coccidiostats was fermented to get yoghurt, kefir, and sour cream. Our results show that the coccidiostat content did not change significantly during fermentation for any of the target compounds. Content Type Journal Article Category Original Pages 1-9 DOI 10.1007/s10337-012-2236-2 Authors Szilárd Nász, Joint Research and Training Laboratory on Separation Techniques, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, 1117 Hungary Etelka M. Károlyné, Alföldi Tej Kft, Seregélyesi út 127, Székesfehérvár, 8000 Hungary Tamás Rikker, Wessling International Research and Educational Center, Fóti út 56, Budapest, 1047 Hungary Zsuzsanna Eke, Joint Research and Training Laboratory on Separation Techniques, Eötvös Loránd University, Pázmány Péter sétány 1/A, Budapest, 1117 Hungary Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    The use of the large retention index database for identification and filtering of false positive hits in GC–MS analysis of the ylang-ylang essential oil is illustrated. Differences between experimental retention indices and database values of retention indices of candidate compounds provide additional constraints on the list of candidates for a target compound. Over 100 components of ylang-ylang essential oil (total grade) were identified. The main components, with concentrations more than 4 %, are β-caryophyllene, germacrene D, benzyl benzoate, linalool, geranyl acetate, α- (E,E) -farnesene and isobornyl acetate. Content Type Journal Article Category Short Communication Pages 1-8 DOI 10.1007/s10337-012-2231-7 Authors V. I. Babushok, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA N. R. Andriamaharavo, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    The objective of current investigation was to study the degradation behavior of l -DOPA under different conditions by high performance liquid chromatography (HPLC), and to develop and validate a stability-indicating HPLC method. The developed RP-HPLC method was validated with respect to linearity, accuracy, precision and specificity. Oxidation was found to occur in alkaline and to some extent in thermal conditions, while the drug was stable when incubated at acidic conditions and under photolytic stress. The oxidation of l -DOPA was observed to follow first-order kinetics. The degradation rate constants and half-life were calculated. The cytotoxicity and enzymatic degradation of l -DOPA was examined using the human intestinal epithelial Caco-2 cells. The drug was rapidly decarboxylated by aromatic amino acid decarboxylase to dopamine. The conversion of l -DOPA to dopamine was dose- and time-dependent. Content Type Journal Article Category Original Pages 1-10 DOI 10.1007/s10337-012-2229-1 Authors Yong Zhi Zhou, Drug Delivery Research Unit, School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand Raid G. Alany, Drug Delivery Research Unit, School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand Victor Chuang, School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, GPO Box U1987, Perth, WA 6845, Australia Jingyuan Wen, Drug Delivery Research Unit, School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    Aerial parts of Epimedium koreanum Nakai have been used as Herba Epimedii in China. Its anti-osteoporosis effect has attracted much attention in recent years. In this study, a method involving osteoblastic cell (MC3T3-E1 cell line) extraction and high-performance liquid chromatography–electrospray ionisation–mass spectrometry (HPLC–ESI-MS n ) was developed for screening of potential anti-osteoporosis agents in E. koreanum . Four compounds identified as epimedin A, epimedin B, epimedin C and icariin were found to interact with MC3T3-E1 cells and possessed potent osteoblast-stimulating activity as evaluated by cell proliferation [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2 H -tetrazolium bromide (MTT) assay] and differentiation [alkaline phosphatase (ALP) activity and Ca content] in vitro. The results suggest that these four flavonoids are the anti-osteoporosis constituents of Herba Epimedii and that the method combining MC3T3-E1 cell extraction with HPLC–ESI-MS n is rapid and effective in screening anti-osteoporosis agents from traditional Chinese medicines. Content Type Journal Article Category Original Pages 1-9 DOI 10.1007/s10337-012-2232-6 Authors Rui Wang, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009 People’s Republic of China Jian-Guang Luo, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009 People’s Republic of China Ling-Yi Kong, State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009 People’s Republic of China Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893

Description:    A simple method is described for efficient isolation of compounds having an antibacterial effect. Two thyme ( Thymus vulgaris ) essential oils, obtained from the market, were chosen as prospective materials likely to feature several bioactive components when examined by thin layer chromatography coupled with direct bioautography as a screening method. The newly developed infusion overpressured layer chromatographic separation method coupled with direct bioautography assured that only the active components were isolated by means of overrun overpressured layer chromatography (OPLC) with on-line detection and fractionation. Each of the 5 collected fractions represented one of the five antimicrobial essential oil components designated at the screening. The purity and the activity of the fractions were confirmed with chromatography coupled with various detection methods (UV, vanillin–sulphuric acid reagent, direct bioautography). The antibacterial components were identified with GC–MS as thymol, carvacrol, (−)-linalool, diethyl-phthalate, and α-terpineol. The oil component diethyl-phthalate is an artificial compound, used as a plasticizer or detergent base in the industry. Our results support that exploiting its flexibility and the possible hyphenations, OPLC is especially attractive for isolation of antimicrobial components from various matrixes. Content Type Journal Article Category Original Pages 1-9 DOI 10.1007/s10337-012-2233-5 Authors Ágnes M. Móricz, Centre for Agricultural Research, Plant Protection Institute, Hungarian Academy of Sciences, Herman O. Str. 15, Budapest, 1022 Hungary Péter G. Ott, Centre for Agricultural Research, Plant Protection Institute, Hungarian Academy of Sciences, Herman O. Str. 15, Budapest, 1022 Hungary Andrea Böszörményi, Institute of Pharmacognosy, Faculty of Pharmacy, Semmelweis University, Üllői út 26, Budapest, 1085 Hungary Éva Lemberkovics, Institute of Pharmacognosy, Faculty of Pharmacy, Semmelweis University, Üllői út 26, Budapest, 1085 Hungary Emil Mincsovics, OPLC-NIT Engineering Co., Ltd, Budapest Andor Str. 60, Budapest, 1119 Hungary Ernő Tyihák, Centre for Agricultural Research, Plant Protection Institute, Hungarian Academy of Sciences, Herman O. Str. 15, Budapest, 1022 Hungary Journal Chromatographia Online ISSN 1612-1112 Print ISSN 0009-5893