British Journal of Clinical Pharmacology

AIM: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. This study aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug-drug-contraindications (DDCI) in section "contraindications" and references to sections "special warnings and precautions for use" (here as "warnings") and"interaction with other medicinal products and other forms of interaction" (here as "interactions") METHODS: SmPCs of 693 commonly prescribed drugs were analyzed regarding absolute DDCI in "contraindications" sections...

AIM: To study the prevalence of prescribing medicines for off-label (OL) use and unlicensed (UL) medicines for children during hospitalisation in 2021 and to assess changes compared to 2011. METHODS: The study included all patients aged under 18 years old who were treated in the neonatal intensive care unit (NICU) or general paediatric ward of Kuopio University Hospital (KUH), Finland, during 4 weeks in April and May 2021. Their background data and daily information on medicine prescriptions were collected from patient records...

AIMS: Comprehensively investigate prescribing in usual care of hospitalised older people with respect to polypharmacy; potentially inappropriate medications (PIMS) according to Beers Criteria; and cumulative anticholinergic and sedative medication exposure calculated with Drug Burden Index (DBI). Specifically, to quantify exposure to these measures on admission, changes between admission and discharge, associations with adverse outcomes and medication costs. METHODS: Established new retrospective inpatient cohort of 2000 adults aged ≥75 years, consecutively admitted to six hospitals in Sydney, Australia, with detailed information on medications, clinical characteristics, and outcomes...

AIM: Thyroidectomy is frequently associated with substantial postoperative pain. Esketamine, an N-methyl-D-aspartate receptor antagonist, has been demonstrated to be effective in multiple analgesia scenarios. We hypothesized that intraoperative administration of esketamine may reduce perioperative opioid consumption and postoperative pain in patients undergoing thyroidectomy. METHODS: Sixty patients undergoing thyroidectomy were randomly assigned to two groups. Patients in the esketamine group received a pre-incisional intravenous bolus of esketamine (0...

Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism. First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (International Normalized Ratio (INR)) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients...

AIMS: Detection and characterization of idiosyncratic drug-induced liver injury (DILI) currently relies on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study we aimed to evaluate the potential of osteopontin, cytokeratin-18 (caspase-cleaved: ccK18 and total: K18), α-glutathione-S-transferase and microRNA-122 as new DILI biomarkers. METHODS: Serial blood samples were collected from 32 DILI and 34 non-DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using ELISA assays or single-molecule arrays...

AIM: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes...

BACKGROUND AND PURPOSE: In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated. EXPERIMENTAL APPROACH: Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4 h: AUC2-4 and estimated partial metabolic clearance: eClmet ) before, at steady-state, and after discontinuation of 3 x 1000 mg metamizole/d orally for 8 d...

AIMS: Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PD) modeling to further examine the underlying mechanisms of anxiety treatment and addiction. METHODS: Data and parameter values for this study were obtained from PubMed and DrugBank literature searches. The PBPK models for alprazolam were developed using PK-Sim software and PD models were implemented with the MonolixSuite 2021R platform...

BACKGROUND: Comparative data between the HAS-BLED, GARFIELD-AF and ORBIT score are limited in anticoagulated Asian patients with AF. We compared the performance of the three scores in a nationwide registry. METHODS: AF patients treated with OACs in the COOL-AF registry were studied. We fitted the variables of the HAS-BLED, GARFIELD-AF and ORBIT score to major bleeding in Cox model. We explored a modified HAS-BLED by addition of sex and body weight. Discrimination, calibration, net reclassification index (NRI) and decision curve analysis were used to compare the performance of the three models...

AIMS: Nusinersen is administered intrathecally for treating spinal muscular atrophy (SMA). Procedural sedation is common with intrathecal treatment in children. The purpose of this study is to emphasize that intrathecal treatment of pediatric patients with SMA I, II, and III can be tolerated with procedural sedation instead of general anesthesia. METHODS: Data were collected the from the anesthesia charts and electronic medical records of 14 pediatric patients with SMA types I, II, and III who underwent procedural sedation for repeated intrathecal treatments for SMA...

AIM: Dihydropyrimidine dehydrogenase (DPD) deficiency can be detected by phenotyping (measurement of plasma uracil (U), with U≥16μg/L defining a partial deficiency) and/or by genotyping (screening for the four most frequent DPYD variants). We aimed to determine the proportion of discrepancies between phenotypic and genotypic approaches and to identify possible explanatory factors. METHODS: Data from patients who underwent both phenotyping and genotyping were retrospectively collected...

INTRODUCTION: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self-controlled case series study was used to compare the risk before and after treatment initiation. METHODS: Literature search was conducted using PubMed, Embase, and the Cochrane Library to identify observational studies on methylphenidate and fractures...

The climate crisis has implications for the physical and mental health of people worldwide, while, paradoxically, healthcare itself contributes significant greenhouse gas emissions. Healthcare professionals need to be prepared to both mitigate the impacts of climate change and also manage the health effects of the climate crisis. Widespread adoption of sustainable healthcare models is required, with sustainability-driven improvements in clinical pharmacology intrinsically linked to this. Recognizing that education and training are essential steps to equip medical professionals with the knowledge to face the unprecedented challenges that the climate crisis presents, here, with reference to pharmacology and therapeutics, we discuss how the theme of Education for Sustainable Healthcare (ESH) can be integrated into undergraduate and postgraduate teaching programmes and how barriers to successful implementation can be tackled...

AIM: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants. METHODS: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4 mg, 8 mg or 16 mg once daily for 8 days...

AIM: Recent case reports have suggested that sodium-glucose co-transporter 2 inhibitors (SGLT2i) may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2i and statins. METHODS: We queried the Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2i, statins, or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2i and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0), and an extension of the proportional reporting ratio (PRR) (two-criteria set; safety signal if both criteria are met), using the full FAERS dataset as reference set...

Coadministration of hepatitis C virus (HCV) direct-acting antivirals (DAA) with anti-epileptics or mood stabilizers with cytochrome P450 (CYP) and/or drug transport inducing properties is contraindicated due to concerns of subtherapeutic DAA levels that can lead to treatment failure and viral resistance. The recommended strategy is to change the interacting medication to a different agent that does not have inducing properties but this is not always possible depending on the clinical scenario. We report on three patients who received DAAs for their HCV infection while remaining on the contraindicated anti-epileptic or mood stabilizer by utilizing CYP and drug transport inhibitors as pharmacokinetic enhancers to attempt to overcome the induction effects and maximize chances of achieving sustained virologic response (SVR)...

BACKGROUND: There is no consensus on the hemorrhagic risk associated with potential interactions between commonly used CYP3A4 inhibitors and direct oral anticoagulants (DOACs). METHODS: Macrolide antibiotics and azole antimycotics were investigated in this study. Data from Food and Drug Administration Adverse Event Reporting System was retrieved from July 2010 to September 2021. Hemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals (CIs) based on the "interaction/non-interaction" methodology as (a/c) / (b/d), and considered significant when the lower limit of 95% CI was >1 and the case number of "interaction" group was ≥3...

AIM: Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains the standard of care. CYP2C19 genetic polymorphisms cause variable Clopidogrel bioactivation. Increased function (CYP2C19*17) allele carriers (rapid metabolizers (RM) or ultrarapid metabolizers (UM)), are Clopidogrel hyper-responders, hence more susceptible to Clopidogrel related bleeding. Since current guidelines recommend against routine genotyping following PCI, data on the clinical utility of CYP2C19*17 genotype guided strategy are sparce...

AIMS: Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users. METHODS: In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2...