British Journal of Clinical Pharmacology Impact Factor & Information

Publisher: British Pharmacological Society, Wiley

Journal description

The Journal of The British Pharmacological Society. Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology contains papers and reports on all aspects of drug action in humans: invited review articles, original papers, short communications and correspondence. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. Proceedings of the meetings of the Clinical Section of the British Pharmacological Society are published in abstract form and supplements containing information on new methods, new drugs and new approaches to treatment are supplied free of charge.

Current impact factor: 3.88

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 3.878
2013 Impact Factor 3.688
2012 Impact Factor 3.578
2011 Impact Factor 2.958
2010 Impact Factor 3.063
2009 Impact Factor 3.246
2008 Impact Factor 3.128
2007 Impact Factor 2.681
2006 Impact Factor 2.718
2005 Impact Factor 2.777
2004 Impact Factor 2.546
2003 Impact Factor 2.531
2002 Impact Factor 2.274
2001 Impact Factor 2.213
2000 Impact Factor 2.151
1999 Impact Factor 2.545
1998 Impact Factor 1.846
1997 Impact Factor 1.809
1996 Impact Factor 2.214
1995 Impact Factor 2.048
1994 Impact Factor 1.922
1993 Impact Factor 1.891
1992 Impact Factor 1.733

Impact factor over time

Impact factor

Additional details

5-year impact 3.83
Cited half-life 8.90
Immediacy index 0.89
Eigenfactor 0.02
Article influence 1.15
Website British Journal of Clinical Pharmacology website
Other titles British journal of clinical pharmacology (Online), BJCP
ISSN 1365-2125
OCLC 45425630
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details


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    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification

Publications in this journal

  • Zheng Guan · Linda E Klumpers · Olubukayo-Opeyemi Oyetayo · Jules Heuberger · Joop M A van Gerven · Jasper Stevens ·
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    ABSTRACT: Aim: The severe psychiatric side effects of Cannabinoid receptor type 1 (CB1 ) antagonists hampered its wide development but might be overcome by careful management of drug development with Pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in THC challenge tests in healthy volunteer were constructed. Methods: The pharmacokinetic models of ∆(9) -tetrahydrocannabinol (THC) and four CB1 antagonists were built separately. THC-induced effects on heart rate and visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in pharmacodynamic models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. Results: The final PK model of THC and antagonists was a two-compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. T1/2ke0 ranged from 0.00462 to 63.7 hours for heart rate and from 0.964 to 150 hours for VAS. IC50 ranged from 6.42 to 202 ng/ml for heart rate and from 12.1 to 376 ng/ml for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. Conclusions: PK/PD modelling and simulation approach was suitable for describing and predicting of heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might benefit to guide future studies. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12852
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    ABSTRACT: Despite the revolution in recent decades regarding monoamine involvement in the management of major depressive disorder (MDD), the biological mechanisms underlying this psychiatric disorder are still poorly understood. Currently available treatments require long time courses to establish antidepressant response and a significant percentage of people are refractory to single drug or combination drug treatment. These issues, and recent findings demonstrating the involvement of synaptic plasticity in the pathophysiological mechanisms of MDD, are encouraging researchers to explore the molecular mechanisms underlying psychiatric disease in more depth. The discovery of the rapid antidepressant effect exerted by glutamatergic and cholinergic agents highlight the mammalian target of rapamycin (mTOR) pathwayas a criticalpathway that contributes to the efficacy of these pharmacological agents in clinical and pre-clinical research.The mTOR pathway is a downstream intracellular signal that transmits information after the direct activation of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and neurotrophic factor receptors. Activation of these receptorsis hypothesized to be one of the major axes involved in the synthesis of synaptogenic proteins underlying synaptic plasticity and critical to both the rapid and delayed effects exerted by classicantidepressants. This review focuses on the involvement of mTOR in the pathophysiology of depression and on molecular mechanisms involved in the activity of emerging and classic antidepressant agents. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12845
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    ABSTRACT: In recent years, there have been a number of case reports of severe hypomagnesaemia associated with Proton Pump Inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. To our knowledge, we are the first to perform a prospective study to specifically explore Proton Pump Inhibitor Associated Hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long-term PPI cross-sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12846
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    ABSTRACT: Background: Benzodiazepines and "Z drugs" are often prescribed in residents of nursing homes (NH) despite their well-known deleterious effects. We aimed to investigate if a general intervention on quality of care led to discontinuation of benzodiazepine, and to examine which NH-related factors were associated in change of benzodiazepines use. Methods: IQUARE is a quasi-experimental study, investigating the impact of an intervention based on a geriatric education with NH staff on several quality indicators of care (including appropriate prescriptions). All participating NH received an initial and 18-month audit regarding drug prescriptions and other quality of care variables. The analysis included 3973 residents, 2151 subjects (mean age: 84.6±8.5 years; 74.3% women) in the control group and 1822 (mean age: 85.5±8.1 years; 77.4% women) in the intervention group. Outcomes at 18 months were benzodiazepines use, long-acting benzodiazepines use, new-use of benzodiazepines, and discontinuation. The effect of the intervention was investigated using mixed-effect logistic regression models, including NH variables and residents' health status as confounders. Results: Higher reductions in benzodiazepine use (-2.8% vs. -1.5%) and long-acting benzodiazepine (-3.7% vs. -3.5%) were observed in intervention group, but not statistically significant. None of the structural and organisational NH-related variables predicted either discontinuation or new-use of benzodiazepines; hospitalisations and initial use of meprobamate increased the likelihood of becoming a new-user of benzodiazepines. Multivariate analysis suggested that living in a particular NH could affect benzodiazepines discontinuation. Conclusions: A general intervention designed to improve overall NH quality indicators did not succeed in reducing benzodiazepines use. External factors interfered with the intervention. Further studies are needed to examine which NH-related aspects could impact benzodiazepines discontinuation.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12847
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    ABSTRACT: Aims: 1) Develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time; 2) test possible covariate parameter relationships that could influence clearance and distribution; and 3) assess the impact of fixed-dosing versus a dosing regimen adjusted by body weight. Methods: Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose, and at weeks 4, 8, 16 and 24 (or early termination) in all studies; blood samples were collected at week 32 in two studies. Plasma samples were analysed using a sensitive, specific, validated enzyme-linked immunosorbent assay. Results: A two-compartment model with parallel linear and nonlinear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1), peripheral volume (V2), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 L/day, 2.71 L, 1.98 L, 0.371 L/day, 8.03 µg/day and 27.7 ng/ml, respectively. Inter-individual variability (IIV) was included on CL, V1, V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV. Conclusion: The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk:benefit.This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12850
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    ABSTRACT: Objectives: Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to: Characterise the population-PK of rifampicin in Malawian children and adults with tuberculosis; Simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin; Examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations. Methods: 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included to build a population-PK model using NONMEM (v7.2). Results: A one-compartment model with first-order absorption best described the data. The mean population estimate for CL/F was 23.9 (l/ with inter-individual variability of 46.6%. Exposure was independent from HIV status. Bioavailability on clearance in children was estimated 51% (low compared to adults). Simulations showed significantly lower RIF exposure in children vs. adults. In children average AUC was 13.5 mg∙h/L, which was nearly half that was observed in adults (26.3 mg∙h/L). Using age as a surrogate for weight in dosing bands gave similar results compared to the weight bands. Increasing dose to approximately 15 mg/kg, increased AUC in children to an average of 22 mg∙h/L. bringing expected exposures in children closer to those predicted for adults. Conclusion: The population-PK model developed can be used to optimise rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed-dose combination formulations of TB therapy.This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12848
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    ABSTRACT: Aims: The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design, and reference category. Method: A systematic review of studies published between 1966 and November 2015 was conducted using EMBASE and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations, and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models. Results: Twenty-three studies were included. Compared to non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n=15 studies); major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n=18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n=8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n=4 studies), and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n=4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed. Conclusions: Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12849
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    ABSTRACT: Aim: Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern. Methods: Ten healthy overweight males (aged 20-27 years) were examined in an open-label, cross-over study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations), and a combination of exenatide and the nitric-oxide-synthase inhibitor L-N(G) -monomethyl arginine (L-NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate-pressure-product. Results: Exenatide increased HR by a mean maximum of 6.8 (95%-CI 1.7-11.9) beats/minute (p<0.05), systolic blood pressure (SBP) by 9.8 (3.5-16.1) mmHg (p<0.01) and markers of SNS activity (p<0.05). No changes in total peripheral resistance were observed. Increases in HR, SBP and sympathetic activity were preserved during concomitant L-NMMA-infusion. Conclusions: Our data argue against exenatide-induced reflex tachycardia as response to vasodilation, and rather suggests the involvement of SNS activation in humans. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12843
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    ABSTRACT: Introduction: The haemodynamic effects of intravenous paracetamol have not been systematically investigated. We compared the physiological effects of intravenous mannitol-containing paracetamol, and an equivalent dosage of mannitol, and normal saline 0.9% (NS) in healthy volunteers. Methods: We performed a blinded, triple crossover, randomized trial of 24 adult healthy volunteers. Participants received IV paracetamol (1 g paracetamol + 3.91 g mannitol/100 mL), IV mannitol (3.91 g mannitol/100 mL), and IV NS (100 mL). Composite primary end points were changes in mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) measured pre-infusion, during a 15 minute infusion period, and over a 45 minute observation period. Systemic vascular resistance index (SVRI), cardiac index (CI) were measured at the same time points. Results: Infusion of paracetamol induced a transient yet significant decrease in blood pressures from pre-infusion values (MAP -1.85mmHg (95% CI: -2.6 to -1.1), SBP -0.54mmHg (95% CI: -1.7 to 0.6) and DBP -1.92mmHg (95% CI: -2.6 to -1.2); p<0.0001), associated with a transient reduction in SVRI and an increase in CI. Changes were observed, but to a lesser extent with NS (MAP -0.15mmHg, SBP +1.44mmHg, DBP -0.73mmHg p<0.0001), but not with mannitol (MAP +1.47mmHg, SBP +4.03mmHg, DBP +0.48mmHg; p<0.0001). Conclusions: IV paracetamol caused a transient decrease in blood pressures immediately after infusion. These effects were not seen with mannitol or NS. The physiological mechanism was consistent with vasodilatation. This study provides plausible physiological data in a healthy volunteer setting, supporting transient changes in haemodynamic variables with IV paracetamol and justifies controlled studies in the peri-operative and critical care setting. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12841
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    ABSTRACT: Background: Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS) and concentrations above 1.1 micromol/L have been suggested as a marker of paracetamol-induced hepatotoxicity, but there is little information on the range of concentrations observed during prolonged therapeutic dosing. Aim: To describe the concentration of PPA in serum of subjects taking therapeutic doses of paracetamol for at least 16 days. Methods: Preplanned secondary aim of a prospective controlled randomized (placebo vs 4 g/day paracetamol) trial. Subjects had samples measured every 3 days for a minimum of 16 days. We also measured concentrations on study days 1-3 and on days 16-25 in subsets of patients. PPA were quantified as APAP- CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry. Results: 90% of subjects had detectable PPA after 5 doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 micromol/L on day 7 where they remained. The highest concentration measured was 1.1 micromol/L and two subjects never had detectable PPA. PPA were detected in the serum of 78% of subjects 9 days after their final dose. Conclusions: PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 micromol/L in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12831
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    ABSTRACT: Aim: The purpose is to determine the exposure-response relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients. Methods: 118 patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2:1 to receive everolimus 10 mg (n=79) or placebo (n=39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24, and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48, and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumor growth were determined by enzyme-linked immunosorbent assay (ELISA). Results: Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33 to 0.40], and 0.54 [0.51 to 0.57], respectively; P<0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39 to 1.80]; P<0.001) were seen. Furthermore, baseline VEGF-D and COL-IV levels associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. Conclusions: These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12834
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    ABSTRACT: Aim: To analyze concomitant drug use and its association with outcome in patients (N=17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non-interventional, phase IV XAMOS study. Methods: Concomitant drug use was at the discretion of the treating physician. Prespecified co-medications of interest were cytochrome P450 (CYP) 3A4/P-glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and non-steroidal anti-inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups. Results: CYP3A4/P-glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC regardless of co-medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co-morbidities, had similar higher (>7-fold) incidences of symptomatic arterial but not venous thromboembolic events compared with non-users. NSAID use had no influence on thromboembolic events. However, odds ratios (ORs) for major bleeding events (European Medicines Agency definition) were higher in NSAID users compared with non-users in rivaroxaban (OR=1.50; 95% confidence interval [CI] 1.06, 2.13) and SOC (OR=1.70; CI 1.16, 2.49) groups. In PAI users ORs for major bleeding events were not different compared with non-users in both the rivaroxaban (OR=1.49; CI 0.84, 2.65) and SOC (OR=1.46; CI 0.82, 2.62) groups. Conclusions: Use of NSAIDs in XAMOS was frequent and associated with higher bleeding events in patients receiving rivaroxaban or SOC, although the benefit-risk profile of rivaroxaban compared with SOC was maintained. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12836
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    ABSTRACT: Aim: Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualisation. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyse potential influencing factors. Methods: Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%); (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalised prediction distribution error (NPDE) tests; and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. Results: Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within ± 30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time, and haematocrit), and whether nonlinear kinetics was used. Conclusions: The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of nonlinear pharmacokinetics in modelling might be a promising approach to improving model predictability.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12830
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    ABSTRACT: Aim: To examine mortality risk associated with use of antidepressants and antipsychotics classified with Torsades de Pointes (TdP) risk in elderly. Methods: A matched case-control register study was conducted in people older than 65 years dying outside hospital, 2008-2013 (n= 286 092) and their controls (n = 1 430 460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds ( and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. Results: Use of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53; 95 CI: 1.51-1.56 and 1.63.; 95 CI: 1.61-1.67, respectively) compared to antidepressants classified with conditional TdP risk (OR: 1.25; 95 CI: 1.22-1.28) or without TdP classification (OR: 0.99; 95 CI: 0.94-1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR: 4.57; 95 CI: 4.37-4.78) than antipsychotics with possible risk (OR: 2.58; 95 CI: 2.52-2.64), or without TdP classification (OR: 2.14; 95 CI: 2.03-2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline; and antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. Conclusion: The CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics haloperidol and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12829
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    ABSTRACT: Aim: 4β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A(4) biomarker, which is elevated by use of the CYP3A4 inducer carbamazepine. Our aim was to compare to what extent serum concentration of 4βOHC correlates with dose (presystemic exposure) and steady-state concentration (systemic exposure) of carbamazepine. Methods: The study was based on a therapeutic drug monitoring material, including information about daily doses and steady-state concentrations (Css) of carbamazepine. 4βOHC concentrations were determined in residual serum samples of 55 randomly selected carbamazepine-treated patients and 54 levetiracetam-treated patients (negative controls) by UPLC-APCI-MS/MS after liquid-liquid extraction. Correlations analyses between 4βOHC level and daily dose and Css of carbamazepine, respectively, were performed by Spearman's tests. In addition, 4βOHC levels in females vs. males were compared in induced and non-induced patients. Results: Median 4βOHC concentration was ~10-fold higher in carbamazepine- vs. levetiracetam-treated patients (650 vs. 54 nmol/L, P<0.0001). There was a significant, positive correlation between carbamazepine dose and 4βOHC level (Spearman r=0.53; 95% confidence interval [CI] 0.27-0.72, P<0.001). No significant correlation between carbamazepine Css and 4βOHC level was found (Spearman r=0.14; 95% CI -0.14-0.40, P=0.3). Enzyme-induced females had significantly higher 4βOHC levels than males (P<0.001), while no significant gender difference was found in non-induced patients (P=0.52). Conclusion: Serum concentration of 4βOHC correlates with presystemic, but not systemic exposure of the CYP3A4 inducer carbamazepine. This suggests a stronger inductive effect of carbamazepine on presystemic than systemic CYP3A4 phenotype and might indicate a role of the intestine in 4βOHC formation. Moreover, CYP3A4 inducibility seems to be higher in females than males.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12833
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    ABSTRACT: Aims: In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2 ), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti-platelet drugs. Methods: Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of DEA/NONOate and PGI2 was studied before and following treatment. Results: Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP-6-induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, p < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, p < 0.05) inhibition when DEA/NONOate + PGI2 was present. Conclusions: We demonstrate that PGI2 and NO synergise with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to better predict thrombotic outcomes and adjust therapy to prevent adverse outcomes in individual patients.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12826
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    ABSTRACT: Aim(s): Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity following 5FU or capecitabine (CAP) treatment. Uracil (U) can be used as a probe to determine the systemic DPD activity. This study was performed to assess the sensitivity and specificity of an U loading dose for detecting DPD deficiency. Methods: Cancer patients with Common Toxicity Score (CTC) grade III or IV toxicity after the first or second cycle of 5-FU or capecitabine treatment were asked to participate. Based on DPD activity in PBMCs, patients were divided in 2 groups: DPD activity in PBMCs < 5 nmol/mg*hr (deficient group) and ≥ 5 nmol/mg*hr. U 500 mg m(2) was administered orally and plasma concentrations of U and dihydrouracil (DHU) in plasma were determined. In the deficient group, PCR amplification of all 23 coding exons and flanking intronic regions of DPYD was performed. An U pharmacokinetic model was developed and used to determine Vmax of the DPD enzyme of each patient. Sensitivity and specificity of Vmax, U concentration and the U/DHU concentration ratio were determined. Results: 47 patients were included (19 DPD deficient, 28 DPD normal). Of the pharmacokinetic parameters investigated, a sensitivity and specificity of 80% and 98% respectively was obtained for the U/DHU ratio at t = 120 min. Conclusions: The high sensitivity of the U/DHU ratio at t = 120 min for detecting DPD deficiency as defined by DPD activity in PBMCs, show that the oral U loading dose can effectively identify patients with reduced DPD activity.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12821
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    ABSTRACT: The alcohols, methanol, ethylene glycol and diethylene glycol, have many features in common, the most important of which is the fact that the compounds themselves are relatively nontoxic but are metabolized, initially by alcohol dehydrogenase, to various toxic intermediates. These compounds are readily available worldwide in commercial products as well as in homemade alcoholic beverages, both of which lead to most of the poisoning cases, from either unintentional or intentional ingestion. Although relatively infrequent in overall occurence, poisonings by metabolically-toxic alcohols do unfortunately occur in outbreaks and can result in severe morbidity and mortality. These poisonings have traditionally been treated with ethanol since it competes for the active site of alcohol dehydrogenase and decreases the formation of toxic metabolites. Although ethanol can be effective in these poisonings, there are substantial practical problems with its use and so fomepizole, a potent competitive inhibitor of alcohol dehydrogenase, was developed for a hopefully better treatment for metabolically-toxic alcohol poisonings. Fomepizole has few side effects and is easy to use in practice and it may obviate the need for haemodialysis in some, but not all, patients. Hence, fomepizole has largely replaced ethanol as the toxic alcohol antidote in many countries. Nevertheless, ethanol remains an important alternative because access to fomepizole can be limited, the cost may appear excessive, or the physician may prefer ethanol due to experience.
    British Journal of Clinical Pharmacology 11/2015; DOI:10.1111/bcp.12824