ALBERT

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung:    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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: 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

Beschreibung: Purpose   We compared the quality and pattern of use of antibiotics to treat urinary tract infection (UTI) between institutionalized and home-dwelling elderly. Methods   We analyzed the quality of use of UTI antibiotics in Swedish people aged ≥65 years at 30 September 2008 (1,260,843 home-dwelling and 86,721 institutionalized elderly). Data regarding drug use, age and sex were retrieved from the Swedish Prescribed Drug Register and information about type of housing from the Social Services Register. In women, we assessed: (1) the proportion who use quinolones (should be as low as possible); (2) the proportion treated with the recommended drugs (pivmecillinam, nitrofurantoin, or trimethoprim) (proportions should be about 40 %, 40 % and 15–20 %, respectively); In men, we assessed: (1) the proportion who used quinolones or trimethoprim (should be as high as possible). Results   The 1-day point prevalence for antibiotic use for UTI was 1.6 % among institutionalized and 0.9 % among home-dwelling elderly. Of these, about 15 % of institutionalized and 19 % of home-dwelling women used quinolones. The proportion of women treated with the recommended drugs pivmecillinam, nitrofurantoin or trimethoprim was 29 %, 27 % and 45 % in institutions and 40 %, 28 % and 34 % for home-dwellers. In men treated with antibiotics for UTI, quinolones or trimethoprim were used by about 76 % in institutions and 85 % in home-dwellers. Conclusions   Our results indicate that recommendations for UTI treatment with antibiotics are not adequately followed. The high use of trimethoprim amongst institutionalized women and the low use of quinolones or trimethoprim among institutionalized men need further investigation. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-7 DOI 10.1007/s00228-012-1374-7 Authors Ylva Haasum, Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Gävlegatan 16, 113 30 Stockholm, Sweden Johan Fastbom, Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Gävlegatan 16, 113 30 Stockholm, Sweden Kristina Johnell, Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Gävlegatan 16, 113 30 Stockholm, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies. Methods   Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers ( n  = 24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers ( n  = 24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (≥7 days). Results   Ticagrelor increased mean atorvastatin maximum plasma concentration (C max ) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin C max and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased C max and AUC of analysed atorvastatin metabolites by 13–55 % and 32–67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co-administration of ticagrelor with each statin was well tolerated. Conclusions   Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor C max in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses 〉40 mg with ticagrelor should be avoided. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-11 DOI 10.1007/s00228-012-1369-4 Authors Renli Teng, Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA Patrick D. Mitchell, Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA Kathleen A. Butler, Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Our aim was to evaluate whether dronedarone authorization impacts antiarrhythmic drug prescribing in Sweden and Emilia Romagna (Italy). Methods   Prescriptions of classes I and III antiarrhythmics, expressed as defined daily doses per thousand inhabitants per day (DDD/TID) were monthly using information collected from pharmacy-reimbursed databases. Interrupted time series analysis was applied to compare prescription data over the 2009–2011 period. Results   In Emilia Romagna, the overall consumption of antiarrhythmics was six times as high as in Sweden (7.6 vs. 1.2 DDD/TID). In the first year on the market, dronedarone represented 1.0 % in Italy and 10.7 % in Sweden of the overall antiarrhythmic prescriptions. In Sweden, dronedarone authorization generated an increase in the prescription trend of antiarrhythmics (trend change +0.02; p  〈 0.001) without variation in amiodarone use In Emilia Romagna, dronedarone marketing did not influence the prescription pattern of either overall antiarrhythmics or amiodarone. Conclusions   Emilia Romagna and Sweden substantially differ in terms of overall antiarrhythmic use. Although clinical guidelines place dronedarone among first-choice treatments for atrial fibrillation, amiodarone prescribing was not affected in either country by the entry of dronedarone, probably due to a cautious approach by clinicians in line with regulatory recommendations and safety warnings. Content Type Journal Article Category Short Communication Pages 1-6 DOI 10.1007/s00228-012-1377-4 Authors Carlo Piccinni, Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 48, I-40126 Bologna, BO, Italy Emanuel Raschi, Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 48, I-40126 Bologna, BO, Italy Elisabetta Poluzzi, Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 48, I-40126 Bologna, BO, Italy Aurora Puccini, Drug Policy Service, Emilia Romagna Region Health Authority, Bologna, Italy Thomas Cars, Public Healthcare Services Committee Administration, Stockholm County Council, Stockholm, Sweden Björn Wettermark, Public Healthcare Services Committee Administration, Stockholm County Council, Stockholm, Sweden Igor Diemberger, Institute of Cardiology, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy Giuseppe Boriani, Institute of Cardiology, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy Fabrizio De Ponti, Department of Medical and Surgical Sciences, University of Bologna, Via Irnerio, 48, I-40126 Bologna, BO, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   There is increasing reported use of synthetic cannabinoid receptor agonists (SCRA) across Europe. To date, there is limited information on the acute toxicity (harm) related to the use of these products. We describe here a case in which an individual developed convulsions related to the use of the SCRA AM-2201. Case report   A 20 year old male smoked a "Spice" (SCRA-containing) product called “Black Mamba,” and rapidly after smoking, he had a generalised self-terminating tonic-clonic convulsion. After a 2 h observation period in the Emergency Department (ED), he self-discharged against medical advice. Subsequent analysis of urine collected at the time of presentation to the ED detected metabolites of AM-2201; no other drugs were detected on extensive analytic screening. Discussion   This is the first case of convulsions related to the use of SCRA described in Europe, and the first case of convulsions related to the use the SCRA AM-2201 confirmed by analysis of biological samples. It is important for emergency physicians, clinical toxicologists and clinical pharmacologists managing those presenting with acute toxicity related to the use of SCRA to analytically confirm the exact compound(s) involved, to enable accurate description of the acute toxicity associated with individual SCRA. Content Type Journal Article Category Pharmacodynamics Pages 1-4 DOI 10.1007/s00228-012-1379-2 Authors David McQuade, Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK Simon Hudson, HFL Sport Science, Fordham, Cambridgeshire, UK Paul I. Dargan, Guy’s and St Thomas’ NHS Foundation Trust and King’s Health Partners, London, UK David M. Wood, Guy’s and St Thomas’ NHS Foundation Trust and King’s Health Partners, London, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30–80 ng/mL during the first year post-transplantation. Methods   Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. Results   The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k f ), 0.11 day −1 ; clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V C /F), 237 L; basal concentration (C 0 ),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. Conclusions   We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-8 DOI 10.1007/s00228-012-1378-3 Authors Sihem Benaboud, EA3620, Université Paris Descartes, Sorbonne Paris Cité, Paris, France Saïk Urien, EA3620, Université Paris Descartes, Sorbonne Paris Cité, Paris, France Eric Thervet, Service de Néphrologie, Hôpital Européen Georges Pompidou, AP-HP, Université Paris Descartes, Paris, France Dominique Prié, Service d’Explorations Fonctionnelles, Hôpital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France Christophe Legendre, Service de Transplantation Rénale, Hôpital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France Jean-Claude Souberbielle, Service d’Explorations Fonctionnelles, Hôpital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France Déborah Hirt, EA3620, Université Paris Descartes, Sorbonne Paris Cité, Paris, France Gérard Friedlander, Service d’Explorations Fonctionnelles, Hôpital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France Jean Marc Treluyer, EA3620, Université Paris Descartes, Sorbonne Paris Cité, Paris, France Marie Courbebaisse, Service d’Explorations Fonctionnelles, Hôpital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Anaphylaxis is a potentially fatal systemic adverse drug reaction (ADR). It is an unpredictable and mostly dose-independent event that occurs suddenly following exposure to the causative drug. Our objective was to characterize a case series of anaphylactic reactions reported to the Portuguese Pharmacovigilance authority during the past decade. Patients’ demographic data and implicated drugs were analyzed as well as the severity of the ADR and time trends. Methods   This study was a retrospective analysis of episodes of anaphylaxis, defined according to the Second Symposium on the Definition and Management of Anaphylaxis Criteria, reported to the Portuguese Pharmacovigilance System between 1 January 2000 and 1 November 2010 Results   Amongst the 16,157 ADR reported to the Portuguese Pharmacovigilance System during the 10-year study period, we found 918 (6 %) cases of anaphylaxis that met the proposed criteria. The age of the patients varied from 7 days to 91 years, with 87 cases (9 %) of anaphylaxis involving patients under 18 years of age. There was an overall female predominance (67 %), but the majority of pediatric patients were male (56 %). There was a trend toward increased reporting as the decade progressed, and 31 % (284) of all anaphylaxis cases were reported during the last 2 years of the study period. Of the anaphylaxis episodes reported, 19 % led to hospitalization and 24 (3 %) had a fatal outcome. Antibiotics were responsible for most cases (17 %) followed by nonsteroidal anti-inflammatory drugs/acetaminophen (13 %), antineoplastic/cytotoxic drugs and immune-modulators. Vaccines and radiographic contrast media were also important contributors to an anaphylactic event. Conclusions   In this series of drug-related anaphylaxis, we found that most of the reported episodes were associated with widely used drugs, such as antibiotics and analgesics. Anaphylaxis can occur at any age. The female gender was more highly represented, with the exception of pediatric patients. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1376-5 Authors Inês Ribeiro-Vaz, Northern Pharmacovigilance Centre, Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal Joana Marques, Northern Pharmacovigilance Centre, Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal Pascal Demoly, Allergy Unit, Département de Pneumologie, Hôpital Arnaud de Villeneuve, Montpellier, France Jorge Polónia, Northern Pharmacovigilance Centre, Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal Eva Rebelo Gomes, ImmunoAlergology Department, Porto Hospitalar Centre, Porto, Portugal Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range. Methods   We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL. Results   We used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg. Conclusions   The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-9 DOI 10.1007/s00228-012-1373-8 Authors Jun Tanaka, Clinical Study Management Division, Bell Medical Solutions Inc., Tokyu Bldg. East NO. 3, 2-16-8, Minami-Ikebukuro, Toshimaku, Tokyo, 171-0022 Japan Hidefumi Kasai, Clinical Study Management Division, Bell Medical Solutions Inc., Tokyu Bldg. East NO. 3, 2-16-8, Minami-Ikebukuro, Toshimaku, Tokyo, 171-0022 Japan Kenji Shimizu, Division of Research and Development, Nobelpharma Co. Ltd., Tokyo, Japan Shigeki Shimasaki, Division of Research and Development, Nobelpharma Co. Ltd., Tokyo, Japan Yuji Kumagai, Clinical Trial Center, Kitasato University East Hospital, Kanagawa, Japan Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Background/Aim   Statin treatment improves endothelial function. It is matter of debate, however, if this effect of statins is due to their action on low-density lipoprotein cholesterol (LDL-C) or to other non-lipidic (pleiotropic) effects. The aim of this study was to evaluate whether the effect of pravastatin on endothelial function is mediated by pleiotropic effects. We therefore compared the effect of pravastatin and ezetimibe, a cholesterol absorption inhibitor, at doses yielding similar reductions in LDL-C and examined the effect of the two treatments on flow-mediated dilation (FMD) in hypercholesterolemic subjects. Methods   A total of 33 moderately hypercholesterolemic patients were randomized into three treatment groups to receive ezetimibe 10 mg/day ( n  = 10), pravastatin 10 mg/day ( n  = 13) or no treatment (control, n  = 10) for 6 weeks. To assess endothelial function, we determined FMD of the brachial artery non-invasively by high-resolution ultrasound before and after treatment. Results   Ezetimibe and pravastatin treatment reduced LDL-C (mean ± standard error) to a similar extent (−20.6 ± 4.1 vs. −24.1 ± 4.0 %, respectively; P  = 0.4771), while no decrease was observed in the control group. FMD increased significantly after treatment with ezetimibe (from 11.4 ± 5.7 to 16.8 ± 3.6 %; P  = 0.022) and with pravastatin (from 13.7 ± 4.9 to 17.5 ± 4.4 %; P  = 0.0466), but not in the control group. There were no differences in the endothelial function changes between the two treatment groups. Conclusions   In this study, two treatments that lower cholesterol via different mechanisms improved endothelial function to a similar extent, suggesting that the observed effect can be explained by the reduction of cholesterol levels. Content Type Journal Article Category Clinical Trial Pages 1-6 DOI 10.1007/s00228-012-1345-z Authors Liliana Grigore, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Sara Raselli, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Katia Garlaschelli, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Laura Redaelli, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Giuseppe D. Norata, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Angela Pirillo, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Alberico L. Catapano, Center for the Study of Atherosclerosis–SISA Lombardia, Bassini Hospital, Via Gorki 50, 20092 Cinisello Balsamo, Milan, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate. Methods   This was an open-label trial in healthy male subjects. In part 1 (pilot, n  = 8) and part 3 ( n  = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran. Results   Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC τ,ss were 135% (90% CI 107–169%) and 132% (90% CI 112–156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC τ,ss ratio test/reference: 91.9%, 90% CI 78.7–107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC 0−24 was 103%; 90% CI 80.3–131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation. Conclusions   When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent. Content Type Journal Article Category Clinical Trial Pages 1-13 DOI 10.1007/s00228-012-1304-8 Authors Sebastian Härtter, Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine, Biberach an der Riss, Germany Regina Sennewald, Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine, Biberach an der Riss, Germany Cornelia Schepers, Boehringer Ingelheim Pharma GmbH & Co. KG, Medical Data Services, Ingelheim am Rhein, Germany Sybille Baumann, CRS, Clinical Research Services Mannheim GmbH, Mannheim, Germany Holger Fritsch, Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine, Biberach an der Riss, Germany Jeffrey Friedman, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   The antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEi) is attributed partially to increased nitric oxide bioavailability. It is possible that functional polymorphisms in endothelial nitric oxide synthase ( eNOS ) and bradykinin receptor B2 ( BDKRB2 ) genes may affect the antihypertensive response to enalapril. Methods   We evaluated 106 hypertensive patients treated only with enalapril for 60 days. The difference between the mean arterial pressure (MAP) before and after the antihypertensive treatment was defined as ΔMAP. If ΔMAP were below or above the median value, the patients were classified as poor responders (PR) or good responders (GR), respectively. eNOS genotypes for the T -786 C, G894T and 4b/4a polymorphisms were determined and haplotype frequencies were estimated by PHASE and Haplo.stats programs. The C -58 T and BE1 +9/-9 polymorphisms of BDKRB2 genes and their haplotypes were determined by DNA sequencing. Robust multifactor dimensionality reduction analysis was used to characterize gene–gene interactions. Results   The TC/CC genotypes and the C allele for the eNOS T -786 C polymorphism were more frequent in GR than in PR. Furthermore, the TT genotype for the BDKRB2 C -58 T polymorphism was more frequent in PR than GR. No other significant differences in genotypes or haplotypes were found. However, we found significant gene–gene interactions: the CC genotype for the BDKRB2 C -58 T polymorphism was associated with response to enalapril depending on eNOS T -786 C genotypes. Conclusions   These findings suggest that eNOS T -786 C and BDKRB2 C -58 T polymorphisms may synergically affect the antihypertensive response to enalapril. Content Type Journal Article Category Pharmacogenetics Pages 1-11 DOI 10.1007/s00228-012-1326-2 Authors P. S. Silva, Department of Pharmacology, State University of Campinas, Campinas, SP, Brazil V. Fontana, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil M. R. Luizon, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil R. Lacchini, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil W. A. Silva Jr., Department of Genetics, Faculty of Medicine of Ribeirao Preto, Ribeirao Preto, SP, Brazil C. Biagi, Santa Casa of Araçatuba, Araçatuba, SP, Brazil J. E. Tanus-Santos, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent. Methods   After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator. Results   Patients with an LVEF of 〈40 % (16 patients) or those with an LVEF of ≥ 40 %  and 〈60 % (40 % ≤ LVEF 〈 60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of ≥60 % (53 patients) (2.29 ± 0.95 or 2.79 ± 0.99 vs. 3.50 ± 1.04 L/h; p  〈 0.001 or p  〈 0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of 〈40 % ( r  = 0.828) and 40 % ≤ LVEF 〈 60 % ( r  = 0.773), but also with an LVEF in patients with a CLcr of 〈60 mL/min ( r  = 0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance ( r 2  = 0.649). Conclusions   Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-9 DOI 10.1007/s00228-012-1340-4 Authors Yuko Shimamoto, Department of Pharmacy, National Hospital Organization–Osaka National Hospital, Osaka, Japan Tsuyoshi Fukuda, Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Shinjiro Tominari, Department of Infectious Diseases, National Hospital Organization–Osaka National Hospital, Osaka, Japan Kyoko Fukumoto, Department of Clinical Pharmacokinetics, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan Kazuyuki Ueno, Department of Clinical Pharmacokinetics, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan Min Dong, Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Kazuhiko Tanaka, Department of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Osaka, Japan Takuma Shirasaka, Department of Infectious Diseases, National Hospital Organization–Osaka National Hospital, Osaka, Japan Katsuya Komori, Department of Pharmacy, National Hospital Organization–Osaka National Hospital, Osaka, Japan Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Background   Population-based drug utilization databases that comprehensively capture an entire population’s drug dispensing are scarce resources for epidemiological studies. This study aimed to examine the prescription-dispensing rates in children in British Columbia (BC) and describe the differences in the dispensing of medications in BC versus children in the United States (US) and Europe. Methods   The study population was children aged 0–17 years in BC ( n  = 855,541). Children with at least one prescription dispensed in 2007 were identified using the provincial outpatient prescription dispensing database. All prescriptions were grouped on the basis of the Anatomical Therapeutic Chemical (ATC) classification system. Prevalence of drug dispensing was calculated in each age group, gender, and therapeutic class. Results   Fifty-five percent of BC children were dispensed at least one prescription in 2007. Antibacterials for systemic use, dermatological corticosteroids, and drugs for obstructive airway diseases were commonly dispensed in each age group. The percentage of children who received psychoanaleptics was two to five times higher than rates reported in European countries, but 30% lower than rates reported in the US. Conclusions   Half of the BC population 〈18 years received at least one prescription in 2007. Significant variations in drug dispensing were highlighted between BC, the US, and Europe. Future studies are needed to examine the outcomes of the prescribing in terms of benefit and harm. A variety of factors (e.g., disease prevalence rates, drug prescribing preferences) are likely to contribute to disparate dispensing of specific drug classes and should be principal factors in the investigation. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-8 DOI 10.1007/s00228-012-1343-1 Authors Tingting Zhang, Faculty of Pharmaceutical Sciences, University of British Columbia (UBC), Vancouver, BC, Canada M. Anne Smith, Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, Canada Pat G. Camp, James Hogg Research Centre, UBC, Vancouver, BC, Canada Salomah Shajari, Pharmaceutical Outcomes Programme, BC Children’s Hospital, Vancouver, Canada Stuart M. MacLeod, Provincial Health Services Authority, Vancouver, BC, Canada Bruce C. Carleton, Faculty of Pharmaceutical Sciences, University of British Columbia (UBC), Vancouver, BC, Canada Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Interaction between ciclopirox and acenocoumarol Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1347-x Authors José A. Morales-Molina, Pharmacy Department, Hospital de Poniente, 04700 El Ejido, Almería, Spain Rosario Pérez-Moyano, Hematology Department, Hospital de Poniente, 04700 El Ejido, Almería, Spain Anna Fayet-Pérez, Pharmacy Department, Hospital de Poniente, 04700 El Ejido, Almería, Spain Olivia Urquízar-Rodríguez, Pharmacy Department, Hospital de Poniente, 04700 El Ejido, Almería, Spain M. José Gíménez-López, Hematology Department, Hospital de Poniente, 04700 El Ejido, Almería, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   The use of antidepressants during pregnancy is common. Some studies suggest an association between in utero exposure to antidepressants and the occurrence of pulmonary diseases like asthma later in life. Serotonin reuptake inhibitors (SSRIs) as well tricyclic antidepressants (TCAs) are thought to be involved in the development of the respiratory rhythm generator (RRG) and the maturation of the formation of surfactant. In this study the use of drugs for pulmonary diseases in children who were exposed to antidepressants in utero were compared with non-exposed children. Methods   The pharmacy prescription database IADB.nl was used for a cohort study in which the use of drugs for pulmonary disease in children after in utero exposure to antidepressants (TCAs, SSRIs) was compared with children with no antidepressant exposure in utero. Drugs for pulmonary diseases were applied as a proxy for disturbed development of the respiratory tract. Results   A small though significant increase in the incidence risk ratio (IRR) of the use of drugs for pulmonary disease was found after any-time in utero exposure to SSRIs, adjusted for maternal use of antibiotics, of 1.17 (95 % CI 1.16–1.18). An increase was also seen when we looked specifically for the use of SSRIs in at least the first trimester (IRR = 1.18, 95 % CI 1.17–1.20). An increased IRR in the use of drugs for pulmonary disease was also seen when children were exposed to TCAs, but this was not statistically significant. However, in both groups our sample size was rather small. The effect size is modest and may also be confounded by maternal smoking. Conclusions   In utero exposure to SSRIs leads to a statistically significant increase in the use of drugs for pulmonary diseases, especially when exposure occurred during the first trimester of pregnancy. The increase in the use of drugs for pulmonary disease may also be related to other factors. Therefore, further study is recommended. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-7 DOI 10.1007/s00228-012-1314-6 Authors P. G. J. ter Horst, Department of Clinical Pharmacy, Isala Klinieken, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands H. J. Bos, Unit of PharmacoEpidemiology & PharmacoEconomics, Department of Pharmacy, University of Groningen, Groningen, The Netherlands L. T. W. de Jong-van de Berg, Unit of PharmacoEpidemiology & PharmacoEconomics, Department of Pharmacy, University of Groningen, Groningen, The Netherlands B. Wilffert, Unit of Pharmacotherapy & Pharmaceutical Care, Department of Pharmacy, University of Groningen, Groningen, The Netherlands Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Aims   To determine the extent and time-course of hepatic and intestinal cytochrome P450 3A (CYP3A) inactivation due to the mechanism-based inhibitor clarithromycin. Methods   Intestinal and hepatic CYP3A inhibition was examined in 12 healthy volunteers following the administration of single and multiple doses of oral clarithromycin (500 mg). Intestinal biopsies were obtained under intravenous midazolam sedation at baseline and after the first dose, on days 2–4, and on days 6–8 of the clarithromycin treatment. The formation of 1′-hydroxymidazolam in biopsy tissue and the serum 1′-hydroxymidazolam:midazolam ratio were indicators of intestinal and hepatic CYP3A activity, respectively. Results   Intestinal CYP3A activity decreased by 64 % ( p  = 0.0029) following the first dose of clarithromycin, but hepatic CYP3A activity did not significantly decrease. Repeated dosing of clarithromycin caused a significant decrease in hepatic CYP3A activity ( p  = 0.005), while intestinal activity showed little further decline. The CYP3A5 or CYP3A4*1B genotype were unable to account for inter-individual variability in CYP3A activity. Conclusions   Following the administration of clarithromycin, the onset of hepatic CYP3A inactivation is delayed compared to that of intestinal CYP3A. The time-course of drug–drug interactions due to clarithromycin will vary with the relative contribution of intestinal and hepatic CYP3A to the clearance and bioavailability of a victim substrate. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-10 DOI 10.1007/s00228-012-1339-x Authors Sara K. Quinney, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Srikar R. Malireddy, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Raj Vuppalanchi, Gastroenterology/Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Mitchell A. Hamman, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Naga Chalasani, Gastroenterology/Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA J. Christopher Gorski, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Stephen D. Hall, Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   This study was performed to determine the oral pharmacokinetics (PK) of EV-077 and its effects on pharmacodynamic (PD) markers. EV-077 blocks prostanoid-induced and isoprostane-induced cellular activation, and is in development for the treatment of vascular inflammation and associated complications of type-2 diabetes.. Methods   This single-ascending-dose mono-centre study was randomised, placebo-controlled, and double-blinded within each dose group. Seven EV-077 doses were administered sequentially as an oral solution: 0.0125, 0.125, 0.375, 0.75, 1.25, 1.875 and 2.5 mg/kg body weight. PK, platelet aggregation, bleeding time and safety parameters were measured. Seven to eight healthy male subjects were dosed per group: five to six subjects received EV-077 and two subjects received placebo. Results   Tmax was reached rapidly between 0.5 h and 1.0 h. Both Cmax and AUC increased linearly with the dose. The apparent terminal half-life (t½z) increased with the dose, most likely reflecting the increasing last quantifiable concentration with increasing dose; at 2.5 mg/kg, it was 2.7-6.9 h. Measurement of platelet aggregation showed no effect at 0.0125 mg/kg, and a full and reversible inhibition at doses of 0.125-2.5 mg/kg. The average bleeding time was dose-dependently prolonged, but was always below 9 min. The PK/PD profile showed that at plasma concentrations above 20 ng/ml, EV-077 platelet aggregation was completely inhibited (〉90 %). All tested doses were well tolerated. Conclusions   Orally administered EV-077 was well tolerated, readily absorbed, reached Cmax within 1 h, with a linear PK based on Cmax and AUC. The inhibition of platelet aggregation was complete and reversible at doses of 0.125 mg/kg and higher, and average bleeding time was below 9 min. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-7 DOI 10.1007/s00228-012-1348-9 Authors A. Richardson, AR Pharma Projects, Marlow, SL7 3PG, UK K. S. Sakariassen, KellSa s.a.s., I-13900 Biella, BI, Italy J.-P. Meyer, Evolva, CH-4153 Reinach, Switzerland P. Alberts, Evolva, CH-4153 Reinach, Switzerland A. S. Sorensen, Evolva, CH-4153 Reinach, Switzerland Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Zotepine-related myopathy in a patient with schizophrenia Content Type Journal Article Category Letter to the Editors Pages 1-2 DOI 10.1007/s00228-012-1346-y Authors I-Ming Chen, Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan Ming H. Hsieh, Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan Tzung-Jeng Hwang, Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan Chen-Chung Liu, Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Aim   Our aim was to characterize utilization patterns for drugs used to treat attention deficit/hyperactivity disorder (ADHD) on the level of the individual patient among Danish users, focusing on treatment duration, doses used, and concurrent use of ADHD and non-ADHD drugs. Methods   Using the Danish Registry of Medicinal Product Statistics, we extracted data on 1,085,099 prescriptions for ADHD drugs issued to a total of 54,024 persons in the study period 1 January 1995 to 30 September 2011. For users in the final year of the study period, we further extracted 315,365 prescriptions for non-ADHD drugs. Drug utilization was characterized using descriptive statistics. Results   The mean duration of ADHD treatment was highest (3.6–4.2 years) for patients initiating therapy at a young age (age〈13). Dropout rate after receiving only one prescription was highest among off-label users (age〈6 and age 〉17). All age categories showed an increase in the average daily dosage of methylphenidate used from 2003 to 2010. Concomitant treatment with methylphenidate and atomoxetine was rare, as only 2 % of methylphenidate treatment overlapped with atomoxetine treatment. Nineteen percent of methylphenidate instant-release treatment overlapped with methylphenidate controlled-release treatment. Users of ADHD drugs across all age categories had an increased use of drugs related to the nervous system, especially antipsychotics [standardized morbidity rate (SMR), 6.4–19.5] and antiepileptics (SMR, 4.0–5.5). Conclusion   We found certain traits that warrant further investigation: the apparent increase in average daily doses, the low adherence to treatment among off-label users, and the increased use of other psychotropic medication. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-10 DOI 10.1007/s00228-012-1344-0 Authors Anton Pottegård, Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Winsløwparken 19, 2, 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 Health and Medicines Authority, Axel Heides Gade 1, 2300 København S, Denmark Lisbeth Sandal Kortegaard, Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Harald Selmers Vej 66, 8240 Risskov, Denmark Jesper Hallas, Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Winsløwparken 19, 2, 5000 Odense C, Denmark Søren Ilsøe Moreno, Institute for Rational Pharmacotherapy, Danish Health and Medicines Authority, Axel Heides Gade 1, 2300 København S, Denmark Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Introduction   Bisphosphonates are used worldwide to treat osteoporosis and, thus, to prevent fractures. Though they have been proven in clinical trials to avoid some fractures, their effectiveness in reducing hip fractures is unclear. The aim of the present study was to explore the relationship between bisphosphonate use and hip fracture trends in Spain. Methods   For this purpose, an ecologic study spanning 2002 to 2008 was conducted in Spain. Consumption data were obtained from the Spanish Ministry of Health and Social Policy. The number of hip fractures was obtained from hospital discharges; annual hip fracture rates were determined and standardized using the Spanish 2002 population census. A linear regression was performed between fracture rate and use of bisphosphonates; R 2 and Pearson correlation coefficient were calculated. Results   From 2002 to 2008, dispensed prescriptions of bisphosphonates in Spain increased from 3.28 to 17.66 DDD/1,000 inhabitants per day. In the same period, the crude hip fracture rate increased from 2.85 to 3.02 cases per 1,000 inhabitants older than 50 years; however, when age standardized rates were estimated, the rate declined from 2.85 to 2.79. Analyzed by sex, the standardized rate for men slightly increased from 1.45 to 1.48, while for women the rate significantly dropped from 4.00 to 3.91. Conclusion   A small effect of bisphosphonates on hip fracture rates can not be ruled out; however, other factors might partially explain this decline. Assuming this medication was the only cause for hip fracture rate reduction, the elevated medication cost to avoid a single hip fracture makes it necessary to explore less expensive interventions. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-6 DOI 10.1007/s00228-012-1337-z Authors L. H. Martín Arias, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain C. Treceño, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain P. García-Ortega, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain J. Rodríguez-Paredes, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain A. Escudero, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain M. Sáinz, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain I. Salado, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain V. Velasco, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain A. Carvajal, Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To examine the impact of a new model of care, in which a clinical pharmacist conducts structured medication reviews and a multi-professional team collates systematic medication care plans, on the number of unidentified DRPs in a hospital setting. Methods   In a prospective two-period study, patients admitted to an internal medicine ward at the University Hospital of Lund, Sweden, were included if they were ≥ 65 years old, used ≥ 3 medications on a regular basis and had stayed on the ward for ≥ 5 weekdays. Intervention patients were given the new model of care and control patients received conventional care. DRPs were then retrospectively identified after study completion from blinded patient records for both intervention and control patients. Two pairs of evaluators independently evaluated and classified these DRPs as having been identified/unidentified during the hospital stay and according to type and clinical significance. The primary endpoint was the number of unidentified DRPs, and the secondary endpoints were the numbers of unidentified DRPs within each type and clinical significance category. Results   The study included a total of 141 (70 intervention and 71 control) patients. The intervention group benefited from a reduction in the total number of unidentified DRPs per patient during the hospital stay: intervention group median 1 (1st–3rd quartile 0–2), control group 9 (6–13.5) (p 〈 0.001), and also in the number of medications associated with unidentified DRPs per patient: intervention group 1 (0–2), control group 8 (5–10) (p 〈 0.001). All sub-categories of DRPs that were frequent in the control group were significantly reduced in the intervention group. Similarly, the DRPs were less clinically significant in the intervention group. Conclusions   A multi-professional team, including a clinical pharmacist, conducting structured medication reviews and collating systematic medication care plans proved very effective in reducing the number of unidentified DRPs for elderly in-patients. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1368-5 Authors Åsa Bondesson, The Department of Medicines Management and Informatics, Region Skåne, Kristianstad, Sweden Tommy Eriksson, Department of Clinical Sciences, Lund University, Lund, Sweden Annika Kragh, Department of Health Sciences, Division of Geriatric Medicine, Lund University, Malmö, Sweden Lydia Holmdahl, Department of Medicine, Skåne University Hospital, Malmö, Sweden Patrik Midlöv, Department of Clinical Sciences in Malmö, General Practice/Family Medicine, Lund University, Lund, Sweden Peter Höglund, Department of Clinical Pharmacology, Lund University, Lund, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   The aim of this clinical study was to investigate a previously proposed mechanism of ketoconazole-mediated inhibition of cytochrome P450 3A (CYP3A) induction. Methods   A two-phase, randomized, cross-over, open, mono-centre trial was carried out. Participants received ketoconazole and St John’s wort for 8 days to study the proposed suppression of St John’s wort-mediated induction of CYP3A at the transcriptional level. In the second phase, we studied the inhibitory effect of a single dose of ketoconazole directly at the enzyme level during CYP3A induction by St John’s wort. Midazolam served as a marker substance of CYP3A activity using an established limited sampling strategy. Results   After 8 days of simultaneous ketoconazole and St John’s wort administration, CYP3A-mediated midazolam metabolism was strongly inhibited (81 % decrease in clearance). Following the induction of CYP3A with St John’s wort (6.6-fold increase in clearance on day 8), a single dose of ketoconazole strongly inhibited midazolam metabolism to the same degree (82 % decrease in clearance in relation to baseline). An induction of midazolam metabolism was observed after discontinuation of both drugs in both study phases. These results apparently contradict the in vitro results where ketoconazole showed an inhibitory effect on the transcription of CYP3A genes. Conclusions   Ketoconazole is a strong inhibitor of CYP3A, also when used concomitantly with St John’s wort. In therapeutic doses it does not inhibit pregnane X receptor-mediated induction of CYP3A in vivo. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-7 DOI 10.1007/s00228-012-1388-1 Authors Ines Fuchs, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Verena Hafner-Blumenstiel, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Christoph Markert, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Jürgen Burhenne, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Johanna Weiss, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Walter Emil Haefeli, Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany Gerd Mikus, 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

Beschreibung: TOPS: an internet-based system to prevent healthy subjects from over-volunteering for clinical trials Content Type Journal Article Category Letter to the Editors Pages 1-1 DOI 10.1007/s00228-012-1351-1 Authors Malcolm Boyce, Corporate Services, Hammersmith Medicines Research, London, UK Mavi Walther, Corporate Services, Hammersmith Medicines Research, London, UK Hilke Nentwich, Corporate Services, Hammersmith Medicines Research, London, UK John Kirk, Corporate Services, Hammersmith Medicines Research, London, UK Stephen Smith, Corporate Services, Hammersmith Medicines Research, London, UK Steve Warrington, Corporate Services, Hammersmith Medicines Research, London, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Aim   To test the ability a new Spanish primary care research database (BIFAP) to capture the association between upper gastrointestinal bleeding (UGIB) and NSAIDs and other drugs and compare the results with previous studies. Methods   We performed a nested case–control study in persons aged 40–90 years old included in the period 2001–2005. Potential cases were selected through a computer search followed by an individual blinded review. Controls matched for age, sex and calendar year were randomly selected. The exposure window was defined as 0–30 days before the index date. Adjusted odds ratios were obtained through unconditional logistic regression models. Results   In a study cohort of 669,115 subjects (1,576,442 person-years) we retrieved 1,193 valid incident cases. Increased risks were found with current use of NSAIDs (RR = 1.72; 95 %CI: 1.41–2.09), metamizole (1.52; 1.09–2.13), low-dose aspirin (1.74; 1.37–2.21), other antiplatelet drugs (1.73; 1.27–2.36), and oral anticoagulants (2.00; 1.44–2.77). We did not find an increased risk with current use of oral corticosteroids (1.11; 0.66–1.86), SSRIs (1.05; 0.77–1.42), or paracetamol (1.00; 0.82–1.23). Acid-suppressing drugs reduced the risk among users of NSAIDs (0.58; 0.39–0.85), particularly in users with antecedents of peptic ulcer (0.16; 0.05–0.58). We detected a decreasing time-trend in the relative risk and the population attributable proportion associated with NSAIDs over the study period. Conclusions   The increased risk of UGIB associated with NSAIDs was lower than previously reported, which could partly be explained by methodological differences, but a decreasing burden over time of this drug safety problem is suggested. BIFAP has shown to be a valuable tool for pharmacoepidemiological research. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-11 DOI 10.1007/s00228-012-1386-3 Authors Francisco J. de Abajo, BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices, Madrid, Spain Miguel J. Gil, BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices, Madrid, Spain Verónica Bryant, BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices, Madrid, Spain Julia Timoner, BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices, Madrid, Spain Belén Oliva, BIFAP Research Unit, Division of Pharmacoepidemiology and Pharmacovigilance, Spanish Agency for Medicines and Medical Devices, Madrid, Spain Luis A. García-Rodríguez, Spanish Centre for Pharmacoepidemiological Research (CEIFE), Madrid, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Objective   To assess the potential damage to patients from the inappropriate use of placebo. Methods   Pivotal clinical trials of new drugs were evaluated for the treatment of multiple sclerosis following effective treatment with beta interferons and glatiramer acetate. The differences in the relapse rate between the experimental arms of the trials with interferons and glatiramer and the placebo groups were calculated. Results   In ten pivotal trials, 2,752 patients were given placebo instead of the best proven treatments. The annualized relapse rate was reported for 2,405 of these patients. Patients receiving placebo suffered 630 more relapses than those treated with interferons or glatiramer. Conclusions   The inappropriate use of placebo in clinical trials unduly harms patients. The use of standard active comparators would preserve patients’ rights and better define the respective clinical value of new medicines Content Type Journal Article Category Point of View Pages 1-4 DOI 10.1007/s00228-012-1383-6 Authors Silvio Garattini, Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156 Milan, Italy Vittorio Bertelé, Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156 Milan, Italy Rita Banzi, Istituto di Ricerche Farmacologiche Mario Negri, Via Giuseppe La Masa 19, 20156 Milan, Italy Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Background   Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line pharmacological treatment. Purpose   The aim of our study was to compare all-cause discontinuation rate of methylphenidate and its pharmaceutical presentations with placebo in adults with ADHD. Methods   This was a systematic review and meta-analysis of randomized controlled trials comparing methylphenidate with placebo in adults with ADHD. All-cause treatment discontinuation was the primary endpoint. The efficacy in reducing ADHD symptoms and safety were the secondary endpoints. Results   Twelve studies (2,496 patients) met the inclusion criteria. Four racemic methylphenidate and one dexmethylphenidate presentations were investigated. The rate of all-cause treatment discontinuation was greater with methylphenidate than with placebo, but this difference was not statistically significant [odds ratio (OR) 1.19, 95 % confidence interval (95 % CI) 0.82–1.74, P  = 0.37, I 2  = 64 %] This finding reached the conventional threshold of statistical significance after one outlier study was excluded (OR 1.44, 95 % CI 1.14–1.82, P  = 0.002, I 2  = 0). Methylphenidate was more efficacious than placebo for reducing ADHD symptoms and it was associated with a higher proportion of patients dropping out due to adverse effects. Conclusions   Despite reducing ADHD symptoms, methylphenidate showed no advantage over placebo in terms of treatment discontinuation. More attention should be given in the future to the endpoint “all-cause treatment discontinuation” when making regulatory decisions and developing clinical guidelines involving the treatment of ADHD in adulthood. Content Type Journal Article Category CLINICAL TRIAL Pages 1-10 DOI 10.1007/s00228-012-1390-7 Authors Xavier Castells, Department of Medical Sciences, TransLab research group, Universitat de Girona, Girona, Spain Ruth Cunill, Parc Sanitari Sant Joan de Déu, Unitat d’Hospitalització Psiquiàtrica Penitenciària, Barcelona, Spain Dolors Capellà, Department of Medical Sciences, TransLab research group, Universitat de Girona, Girona, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Background   The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 ( CYP2C19 ) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population. Materials and methods   Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity. Results   Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0–13 vs. 2.0; 0–11, respectively; p  = 0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles ( CYP2C19*2,*3 ) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele ( CYP2C19*17 ) than among non-carriers, although this difference was not significant. Conclusion   Patients with CYP2C19 ( *2 or *3 ) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy. Content Type Journal Article Category Pharmacogenetics Pages 1-8 DOI 10.1007/s00228-012-1381-8 Authors K. Subraja, Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India S. A. Dkhar, Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India R. Priyadharsini, Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India B. K. Ravindra, Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India D. G. Shewade, Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India S. Satheesh, Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India M. G. Sridhar, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India S. K. Narayan, Department of Neurology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India C. Adithan, Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To investigate the association of ethnicity with objectively, electronically measured adherence to inhaled corticosteroids (ICS) in a multicultural population of children with asthma in the city of Amsterdam. Methods   The study was designed as a prospective, observational multicenter study in which adherence to ICS and potential risk factors for adherence to ICS were measured in a cohort of Moroccan and native Dutch children with asthma. Electronic adherence measurements were performed for 3 months per patient using a Real Time Medication Monitoring (RTMM) system. Ethnicity and other potential risk factors, such as socio-economic status, asthma control and parental medication beliefs, were extracted from medical records or parent interviews. The association between adherence and ethnicity was analysed using multivariate linear regression analysis. Results   A total of 90 children (aged 1–11 years) were included in the study and data of 87 children were used for analysis. Average adherence to ICS was 49.3 %. Native Dutch children showed higher adherence to ICS than Moroccan children (55.9 vs. 42.5 %, respectively; p  = 0.044, univariate analysis). After correction for confounders (〉3 annual visits to the paediatric outpatient clinic, regular use of a spacer during inhalation), the final regression model showed that ethnicity was independently associated with adherence ( p  = 0.028). Conclusions   In our Western European population of inner city children with asthma, poor adherence to ICS was a serious problem, and even somewhat more so in ethnic minorities. Paediatricians involved in asthma treatment should be aware of these cultural differences in medication-taking behaviour, but further studies are needed to elucidate the causal mechanism. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-8 DOI 10.1007/s00228-012-1380-9 Authors Erwin Vasbinder, Department of Hospital Pharmacy, Erasmus Medical Center, Room L-030, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Nordin Dahhan, St. Lucas Andreas Hospital, Amsterdam, The Netherlands Bart Wolf, St. Lucas Andreas Hospital, Amsterdam, The Netherlands Jan Zoer, St. Lucas Andreas Hospital, Amsterdam, The Netherlands Ellen Blankman, BovenIJ Hospital, Amsterdam, The Netherlands Diederik Bosman, BovenIJ Hospital, Amsterdam, The Netherlands Liset van Dijk, Nivel, Utrecht, The Netherlands Patricia van den Bemt, Department of Hospital Pharmacy, Erasmus Medical Center, Room L-030, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Aim   Inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), are partially attributable to an increased secretion of proinflamatory cytokines, such as tumour necrosis factor (TNF) and interleukin-1β (IL1β), which play essential roles in the disease pathogenesis and are target molecules for specific therapy. Given the inter-individual variability in the response to the anti-TNF monoclonal antibody infliximab, the aim of our study was to explore the predictive value of TNF and/or IL1β as surrogate markers of infliximab response. Methods   Serial serum concentrations of TNF and IL1β and TNF promoter region and IL1B polymorphisms were determined in 47 patients (29 CD and 18 UC) receiving infliximab and correlated with treatment response. Results   Baseline serum concentrations of TNF and IL1β were higher in UC patients than in CD patients ( p  = 0.0097 and 0.0024, respectively). CD patients showing 〈0.64 pg/ml IL1β at baseline were more frequently responders than non-responders ( p  = 0.036), and the C allele of the IL1B polymorphism was associated with higher IL1β serum concentrations ( p  = 0.026) and with poorer clinical remission after 14 weeks of infliximab treatment. No significant association was found between serum TNF concentration or TNF polymorphism and patient response to infliximab. Conclusion   This is the first study evaluating the pharmacogenetic role of the rs1143634 polymorphism of IL1B and TNF polymorphisms in infliximab-treated IBD patients. We found an association between the rs1143634 C allele and higher serum IL1β concentrations and a lower response to infliximab treatment in CD patients that warrants the interest of future studies in larger and independent series. Content Type Journal Article Category Pharmacogenetics Pages 1-8 DOI 10.1007/s00228-012-1389-0 Authors Diana Lacruz-Guzmán, Pharmacy Department, Santa Lucía General University Hospital (HGUSL), Cartagena, Spain Daniel Torres-Moreno, Molecular Pathology and Pharmacogenetics Group FFIS011, Pathology Department, HGUSL, Calle Mezquita s/n, 30202 Cartagena, Spain Francisco Pedrero, Day Hospital, HGUSL, Cartagena, Spain Patricia Romero-Cara, Gastroenterology Department, HUGSL, Cartagena, Spain Iván García-Tercero, Gastroenterology Department, HUGSL, Cartagena, Spain Javier Trujillo-Santos, Internal Medicine, HUGSL, Cartagena, Spain Pablo Conesa-Zamora, Molecular Pathology and Pharmacogenetics Group FFIS011, Pathology Department, HGUSL, Calle Mezquita s/n, 30202 Cartagena, Spain Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. Methods   Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. Results   Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration–time curve from time 0 to infinity (AUC 0-∞ ) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC 0-∞ explained by UGT2B15 was 66.7 % ( P  〈 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant ( UGT2B15*2/*2 ) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). Conclusions   These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group. Content Type Journal Article Category Pharmacogenetics Pages 1-8 DOI 10.1007/s00228-012-1382-7 Authors Frances Stringer, Takeda Pharmaceutical Company, 1-1, Doshomachi 4-Chome, Chuo-Ku, Osaka, 540-8645 Japan Graham Scott, Takeda Global Research & Development, London, UK Marian Valbuena, Takeda Global Research & Development, London, UK Judith Kinley, Takeda Global Research & Development, London, UK Mitsuhiro Nishihara, Takeda Global Research & Development, 26-1, Muraoka-Higashi 2-chome, Fujisawa, 251-8555 Japan Richard Urquhart, Takeda Global Research & Development, 26-1, Muraoka-Higashi 2-chome, Fujisawa, 251-8555 Japan Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of talinolol, a probe drug for P-glycoprotein (P-gp) activity in humans. Methods   Fourteen healthy adult male subjects were enrolled in a two-phase randomized crossover-design study. In each phase the volunteers received placebo or compound glycyrrhizin tablets (75 mg glycyrrhizin three times daily) for 6 days. On the seventh day, a single oral dose of 100 mg talinolol was administered, and blood samples were obtained to determine plasma talinolol concentrations, measured in plasma by high-performance liquid chromatography with an ultraviolet detector. Non-compartmental analysis was used to characterize talinolol plasma concentration–time profiles. All pharmacokinetics parameters were calculated using DAS ver. 2.1 software, and statistical analyses were performed with SPSS ver. 13.0 software. Analysis of variance was used to check the difference of the means of the pharmacokinetic parameters between the two treatments at a significance level of 0.05. Results   All treatments were well tolerated during the study period. The geometric mean ± standard deviation of the AUC 0–∞ for talinolol treated by glycyrrhizin and talinolol treated by placebo was 2,218.3 ± 724.3 and 1,988.2 ± 649.2 ng·h/mL, respectively. The 90 % confidence intervals for the ratio of adjusted geometric means (glycyrrhizin:placebo) for AUC 0–∞ and C max fell wholly within the interval [80, 125]. Six days of glycyrrhizin treatment resulted in no significant alterations in the pharmacokinetic parameters (AUC 0–∞ , AUC 0–24 , C max , t max , t ½ ) for talinolol. Conclusions   Continuous glycyrrhizin administration had no induction effect on the expression of P-gp in our trial. Further research is needed to study the direct inhibition effect of glycyrrhizin on the function of P-gp with the simultaneous administration of both glycyrrhizin and P-gp substrate. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-7 DOI 10.1007/s00228-012-1391-6 Authors Miao Yan, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Ping-Fei Fang, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Huan-De Li, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Ping Xu, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Yi-Ping Liu, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Feng Wang, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Hua-Lin Cai, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Qin-You Tan, Clinical Pharmacy & Pharmacology Research Institute, The Second Xiangya Hospital, Central South University, Renmin Middle Road 139, Changsha, Hunan 410011, China Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   While some people remain fit and active as they grow older, others experience complex problems: disease, dependency and disability. Frailty is a term used to describe this latter group, capturing differences in health status among older people. Many frail older people have multiple chronic co-morbidities and functional impairments and, according to guidelines for the management of individual conditions, should be prescribed long lists of medications. However, older people (particularly those who are frail) are often excluded from drug trials, and treatment decisions are therefore based on evidence extrapolated from more robust patient groups with fewer physiological deficits. The risk of adverse drug reactions (ADRs) increases with increasing patient frailty, and polypharmacy has negative consequences above and beyond the risks of individual drugs. Increasing numbers of medications are associated with a higher likelihood of non-adherence and a significantly greater risk of ADRs. Older people taking five or more medications are at higher risk of delirium and falls, independent of medication indications. Methods   This is a short review of the different approaches to defining and measuring frailty. We summarise the factors contributing to ADRs in frail older people and describe the pharmacokinetic and pharmacodynamics changes associated with ageing and frailty. By considering goals of care for frail older people, we explore how the appropriateness of medication prescribing for older people could be improved. Conclusion   Since all physicians are likely to provide care for this group of vulnerable patients, understanding the concept of frailty may help to optimise medication prescribing for older people. The incorporation of frailty measures into future clinical studies of drug effects and pharmacokinetics is important if we are to improve medication use and guide drug doses for fit and frail older people. Content Type Journal Article Category Review Article Pages 1-8 DOI 10.1007/s00228-012-1387-2 Authors Ruth E. Hubbard, Centre for Research in Geriatric Medicine, School of Medicine, Princess Alexandra Hospital/The University of Queensland, Woolloongabba, Brisbane, Queensland 4102, Australia M. Sinead O’Mahony, Department of Geriatric Medicine, School of Medicine, Llandough Hospital/Cardiff University, 3rd Floor, Academic Centre, Penlan Road, Penarth, South Wales CF64 2XX, UK Kenneth W. Woodhouse, Department of Geriatric Medicine, School of Medicine, Llandough Hospital/Cardiff University, 3rd Floor, Academic Centre, Penlan Road, Penarth, South Wales CF64 2XX, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) has not previously been measured with a selective technique. The primary aims were to examine the pharmacokinetics of active cisplatin and its monohydrated complex (MHC) during HIPEC using a specific measuring technique, to compare cisplatin’s systemic absorption with oxaliplatin, and to compare active cisplatin levels to that of total platinum. Methods   Ten patients treated with cytoreductive surgery and HIPEC (cisplatin 50 mg/m 2 ,doxorubicin 15 mg/m 2 ) were recruited. Blood and perfusate samples were drawn during and after HIPEC. Cisplatin analysis was conducted using liquid chromatography (LC) with post-column derivatization with diethyldithiocarbamate and compared with inductively coupled plasma-mass spectrometry (ICP-MS). Results   The mean half-life (t1/2) of perfusate cisplatin was 18.4 min, with area under the time-concentration curve (AUC) 0–90 min of 2.87 mM·min and estimated 0–60 min of 2.45 mM·min. The absorption t1/2 was 9.0 min for cisplatin and 18.2 min for oxaliplatin. The ratio of total platinum to active cisplatin increased in a linear manner by time of perfusion. Conclusions   Cisplatin is absorbed quicker than oxaliplatin. Lowering the perfusion time to 60 min does not significantly change the pharmacokinetics of cisplatin, and is therefore to be considered. As the HIPEC perfusion progresses, the ICP-MS technique does not adequately reflect active cisplatin levels in the perfusate. Content Type Journal Article Category Pharmacokinetics and Disposition Pages 1-8 DOI 10.1007/s00228-012-1405-4 Authors P. H. Cashin, Department of Surgical Sciences, Uppsala University Hospital, 751 85 Uppsala, Sweden H. Ehrsson, Research Department, Karolinska Pharmacy, Karolinska Institute, Stockholm, Sweden I. Wallin, Research Department, Karolinska Pharmacy, Karolinska Institute, Stockholm, Sweden P. Nygren, Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, Uppsala University, Uppsala, Sweden H. Mahteme, Department of Surgical Sciences, Uppsala University Hospital, 751 85 Uppsala, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To test if two of the adverse event triggers proposed by the Institute of Healthcare Improvement can detect adverse drug events (ADEs) in a UK secondary care setting, using an electronic prescribing and health record system. Methods   In order to identify triggers for over-anticoagulation and potential opioid overdose and we undertook a retrospective review of electronic medical and prescription records from 54,244 hospital admissions over a 1-year period, alongside a review of medical incident reports. Once prescription data were linked to triggers and duplicates were removed, case note review eliminated the false positive ADEs. Additionally, we tested the use of an electronic algorithm for the International Normalized Ratio (INR) ≥6 trigger. Results   The INR ≥6 electronic trigger identified 46 potential ADEs and the naloxone electronic trigger identified 82 ADEs. Based on the available case note review, the INR ≥6 trigger had a positive predictive value (PPV) of 38 % (14/37) and the naloxone trigger had a PPV of 91 % (61/67). The electronic algorithm for the INR ≥6 trigger identified 12 ADEs, thus reducing the need of case note review. This was in comparison with one and two critical incidents reported in the trust medical incident reports system, which respectively related to over-coagulation with warfarin and over-sedation with opioid medication. Conclusions   We have integrated automated and manual methods of detecting ADEs using previously defined triggers. Incorporating electronic triggers in already established electronic health records with prescription and laboratory test data can improve the detection of ADEs, and potentially lead to methods to avert them. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-5 DOI 10.1007/s00228-012-1327-1 Authors Ugochi Nwulu, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK Krishnarajah Nirantharakumar, School of Health and Population Sciences, University of Birmingham, Birmingham, B15 2TT UK Rachel Odesanya, School of Health and Population Sciences, University of Birmingham, Birmingham, B15 2TT UK Sarah E. McDowell, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK Jamie J. Coleman, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To describe and assess the outcomes of Periodic Safety Update Report (PSUR) evaluations of biopharmaceuticals. Methods   A cross-sectional analysis was performed of follow-up requirements of PSURs submitted for centrally approved biopharmaceuticals in the European Union between 1 July 2008 and 30 June 2010. A follow-up analysis on a subset of products that submitted multiple PSURs within the study period was also performed. Results   The cross-sectional analysis included 70 PSURs. Potential safety concerns occurred in 57 (83 %) of all PSURs, and 26 (37 %) concluded a need to change the Summary of Product Characteristics (SPC). In comparison to newer products, products authorized for more than 10 years contained significantly fewer potential safety concerns (60 vs. 92 %; p  〈 0.01) and required fewer SPC changes (15 vs. 46 %; p  = 0.03). For 45 products, multiple PSURs were submitted that could be included in a follow-up analysis. For this subset of products, of the 106 newly identified safety potential safety issues, 7 (7%) resulted in requirements for label changes in the following PSUR. Conclusions   PSURs facilitate communication between regulators and marketing authorization holders. Potential safety concerns occur for the majority of biopharmaceuticals and throughout their lifecycle, but for established products PSUR evaluations rarely lead to regulatory actions. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-10 DOI 10.1007/s00228-012-1317-3 Authors Hans C. Ebbers, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, P.O. Box 80 082, 3508 TB Utrecht, The Netherlands Aukje K. Mantel-Teeuwisse, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, P.O. Box 80 082, 3508 TB Utrecht, The Netherlands Fakhredin A. Sayed-Tabatabaei, Medicines Evaluation Board, Utrecht, The Netherlands Ellen H. M. Moors, Innovation Studies, Copernicus Institute of Sustainable Development, Utrecht University, Utrecht, The Netherlands Huub Schellekens, Innovation Studies, Copernicus Institute of Sustainable Development, Utrecht University, Utrecht, The Netherlands Hubert G. M. Leufkens, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, P.O. Box 80 082, 3508 TB Utrecht, The Netherlands Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Transdermal buprenorphine patches provide comparable pain relief to that of low-potency opioids in elderly individuals. However, specific data on their use in elderly individuals is limited. This study investigated and compared the PK of buprenorphine transdermal patches in elderly (≥75 years) versus younger (50–60 years) individuals. Methods   This was a multiple-dose, open-label, parallel-group study in healthy volunteers split into two age groups (younger, 50–60 years; elderly, ≥75 years) with 37 individuals in each. Study participants received two consecutive 7-day buprenorphine 5 μg/h transdermal patch applications, and blood samples were collected on the week of the second patch application [day 7 (predose), days 8, 9, 10, 12, and 14] to determine PK at steady state. Pharmacokinetic parameters were determined for buprenorphine and norbuprenorphine. Safety was assessed by analyzing adverse events, hematology, clinical chemistry, urine analysis, vital signs, electrocardiogram (ECG), and physical examinations. Results   The area under the plasma concentration-time curve at steady state (AUC tau ), measured over one dosing interval, was similar for elderly [mean ± standard deviation (SD) 9,940 pg/h/ml (4,827 pg/h/ml] and younger [mean ± SD 11,309 (3,670 pg/h/ml] individuals. Bioequivalence was not demonstrated between groups, which may be attributable to the relatively high level of variability in individual plasma profiles. More adverse events were reported by younger (216) than elderly (164) study participants. Conclusions   No dosage alterations are necessary for PK reasons when treating elderly people with buprenorphine transdermal patches. Content Type Journal Article Category Clinical Trial Pages 1-7 DOI 10.1007/s00228-012-1320-8 Authors Nabil Al-Tawil, Karolinska Trial Alliance Phase 1 Unit, M62, Karolinska University Hospital, Stockholm, Sweden Ingegerd Odar-Cederlöf, Karolinska University Hospital, Huddinge, Sweden Anna-Carin Berggren, Mundipharma AB, Göteborg, 41263 Sweden Helen E. Johnson, Mundipharma Research Limited, Cambridge, UK Jan Persson, Karolinska University Hospital, Huddinge, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   To investigate the impact of the integration of the drug-drug interaction database SFINX into primary health care records on the prevalence of potentially serious drug-drug interactions. Methods   The study was a controlled before-and-after study on the prevalence of potential drug-drug interactions before and after the implementation of SFINX at 15 primary healthcare centres compared with 5 centres not receiving the intervention. Data on dispensed prescriptions from health care centres were retrieved from the Swedish prescribed drug register and analysed for September–December 2006 (pre-intervention) and September–December 2007 (post-intervention). All drugs dispensed during each 4 month period were regarded as potentially interacting. Results   Use of SFINX was associated with a 17% decrease, to 1.81 × 10 −3 from 2.15 × 10 −3 interactions per prescribed drug-drug pair, in the prevalence of potentially serious drug-drug interactions ( p  = 0.042), whereas no significant effect was observed in the control group. The change in prevalence of potentially serious drug-drug interactions did not differ significantly between the two study groups. The majority of drug-drug interactions identified were related to chelate formation. Conclusion   Prescriptions resulting in potentially serious drug-drug interactions were significantly reduced after integration of the drug-drug interaction database SFINX into electronic health records in primary care. Further studies are needed to demonstrate the effectiveness of drug-drug interaction warning systems. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-7 DOI 10.1007/s00228-012-1338-y Authors M. L. Andersson, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden Y. Böttiger, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden J. D. Lindh, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden B. Wettermark, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden B. Eiermann, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   High-dimensional propensity score (hd-PS) adjustment has been proposed as a tool to improve control for confounding in pharmacoepidemiological studies using longitudinal claims databases. We investigated whether hd-PS matching improved confounding by indication in a study of Cox-2 inhibitors (coxibs) and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and their association with the risk of upper gastrointestinal complications (UGIC). Methods   In a cohort study of new users of coxibs and tNSAIDs we compared the effectiveness of these drugs to reduce UGIC using hd-PS matching and conventional propensity score (PS) matching in the German Pharmacoepidemiological Research Database. Results   The unadjusted rate ratio (RR) of UGIC for coxib users versus tNSAID users was 1.21 [95 % confidence interval (CI) 0.91–1.61]. The conventional PS matched cohort based on 79 investigator-identified covariates resulted in a RR of 0.84 (0.56–1.26). The use of the hd-PS algorithm based on 900 empirical covariates further decreased the RR to 0.62 (0.43–0.91). Conclusions   A comparison of hd-PS matching versus conventional PS matching resulted in improved point estimates for studying an intended treatment effect of coxibs versus tNSAIDs when benchmarked against results from randomized controlled trials. Content Type Journal Article Category Pharmacoepidemiology and Prescription Pages 1-9 DOI 10.1007/s00228-012-1334-2 Authors E. Garbe, Department of Clinical Epidemiology, BIPS–Institute for Epidemiology and Prevention Research, Achterstr. 30, 28359 Bremen, Germany S. Kloss, Department of Clinical Epidemiology, BIPS–Institute for Epidemiology and Prevention Research, Achterstr. 30, 28359 Bremen, Germany M. Suling, Department of Clinical Epidemiology, BIPS–Institute for Epidemiology and Prevention Research, Achterstr. 30, 28359 Bremen, Germany I. Pigeot, Department of Clinical Epidemiology, BIPS–Institute for Epidemiology and Prevention Research, Achterstr. 30, 28359 Bremen, Germany S. Schneeweiss, Division of Pharmacoepidemiology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970

Beschreibung: Purpose   Gamma-glutamyl hydrolase ( GGH ), cyclin D1 ( CCND1 ) and thymidylate synthase ( TS ) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). Methods   The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH ( -354 G 〉 T and 452 C 〉 T ), CCND1 ( 870 A 〉 G) and TYMS ( variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. Results   According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype ( p  = 0.003). No other significant association were observed. Conclusion   The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T 〉 G polymorphism may have high predictive value for myelosuppression in RA patients. Content Type Journal Article Category Pharmacogenetics Pages 1-7 DOI 10.1007/s00228-012-1341-3 Authors Biljana Jekic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Ljiljana Lukovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Vera Bunjevacki, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Vera Milic, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Ivana Novakovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Tatjana Damnjanovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Jelena Milasin, Institute of Biology and Human Genetics, Faculty of Dentistry, University of Belgrade, 1 Dr Subotica Str, 11000 Belgrade, Serbia Branka Popovic, Institute of Biology and Human Genetics, Faculty of Dentistry, University of Belgrade, 1 Dr Subotica Str, 11000 Belgrade, Serbia Nela Maksimovic, Institute of Human Genetics, Faculty of Medicine, University of Belgrade, 26 Visegradska Str, 11000 Belgrade, Serbia Nemanja Damjanov, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Goran Radunovic, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Ljiljana Kovacevic, Institute of Rheumatology, Faculty of Medicine, University of Belgrade, 69 Resavska Str, 11000 Belgrade, Serbia Maja Krajinovic, Centre de Recherche, CHU Sainte-Justine, Departments of Pediatrics and Pharmacology, University of Montréal, 3175 Chemin de la Côte-Ste-Catherine, Montreal, QC H3T 1C5, Canada Journal European Journal of Clinical Pharmacology Online ISSN 1432-1041 Print ISSN 0031-6970