Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment.

Aims: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions.

Methods: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics.

Performance of thin Vivacit-E hip liners: no relevant wear during ex vivo testing at high acetabular inclination angle.

Background And Purpose: There is concern among clinicians regarding the performance of thin, highly cross-linked polyethylene acetabular liners at high inclination angles that cause edge contact and high contact stresses. We studied ex vivo wear performance of thin, vitamin-E grafted, highly cross-linked polyethylene (Vivacit-E) liners in relation to high acetabular inclination angle.

Materials And Methods: Wear of Vivacit-E acetabular liners (thickness 4.

Prediction model for an early revision for dislocation after primary total hip arthroplasty.

Dislocation is one of the most common complications after primary total hip arthroplasty (THA). Several patient-related risk factors for dislocation have been reported in the previous literature, but only few prediction models for dislocation have been made. Our aim was to build a prediction model for an early (within the first 2 years) revision for dislocation after primary THA using two different statistical methods.

The COVID-19 policymaking under the auspices of parliamentary constitutional review: The case of Finland and its implications.

This article explores the dynamic interaction of emergency policies and parliamentary constitutional review in the early policy response to the COVID-19 outbreak in Finland. A thorough analysis of the official records of Parliament's Constitutional Law Committee shows how the Government's use of delegated emergency powers raised particular concerns about inter-institutional transparency during the state of emergency. These findings prompt an enquiry into whether delegated emergency powers and the related quest for centralized transparency-led accountability produced a rupture in the theory of complex multicentric policymaking.

Periprosthetic Femoral Fracture Is a Leading Cause of Early Revision With Taper-Slip Stems in Primary Total Hip Arthroplasty: An Analysis of 2765 Total Hip Arthroplasties From a High-Volume Hospital.

Background: In 2016, the CPT stem replaced the Exeter stem as the main cemented stem at our institution. We assessed the prevalence of revision for periprosthetic femoral fracture (PFF) in patients operated on with either CPT or Exeter stem and compared the risk for revision between these stems.

Methods: Primary total hip arthroplasties either performed in 2012-2015 with Exeter stem (n = 1443) or in 2017-2018 with CPT stem (n = 1322) were included.

Implant survival of 662 dual-mobility cups and 727 constrained liners in primary THA: small femoral head size increases the cumulative incidence of revision.

Background and purpose - In total hip arthroplasty (THA), the risk for dislocation can be reduced using either dual-mobility cups (DMCs) or constrained liners (CLs). There are few studies comparing these concepts in primary THA. Therefore, we compared the cumulative incidence of revision in primary THA patients treated with DMC or CL with varying head sizes with conventional THA patients as reference group.

Lifetime antimicrobial use is associated with weight status in early adolescence-A register-based cohort study.

Background: Antimicrobial agents (AMs) are the most prescribed drugs to children. Early and repeated exposure to AMs in infancy is associated with increased risk of childhood overweight and obesity.

Aims: We extended the investigation of AMs use, from birth to early adolescence, and evaluated their association with weight status.

Antimicrobial drug use in the first decade of life influences saliva microbiota diversity and composition.

Background: The human microbiota contributes to health and well-being. Antimicrobials (AM) have an immediate effect on microbial diversity and composition in the gut, but next to nothing is known about their long-term contribution to saliva microbiota. Our objectives were to investigate the long-term impact of AM use on saliva microbiota diversity and composition in preadolescents.

Increased risk for dislocation after introduction of the Continuum cup system: lessons learnt from a cohort of 1,381 THRs after 1-year follow-up.

Background and purpose - The introduction of new total hip replacements (THRs) is known to be associated with an increased risk for complications. On completion of a competitive procurement process, a new uncemented cup system was introduced into general use at our institution in 2016. We launched this study after the introduction to assess (1) the incidence of early dislocations of the old (Pinnacle) and the new (Continuum) cup systems, and (2) whether the cup design would affect the risk for dislocation.

A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.

Background: Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates.

Objective: This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail.

Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction.

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics.

Varying but reduced use of postoperative mobilization restrictions after primary total hip arthroplasty in Nordic countries: a questionnaire-based study.

Background and purpose - Mobilization has traditionally been restricted following total hip arthroplasty (THA) in an attempt to reduce the risk of dislocation and muscle detachment. However, recent studies have questioned the effect and rationale underlying such restrictions. We investigated the use of postoperative restrictions and possible differences in mobilization protocols following primary THA in Denmark (DK), Finland (FIN), Norway (NO), and Sweden (SWE).

Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans.

A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically.

Withdrawal from long-term use of zopiclone, zolpidem and temazepam may improve perceived sleep and quality of life in older adults with primary insomnia.

Long-term use of benzodiazepines or benzodiazepine receptor agonists is widespread, although guidelines recommend short-term use. Only few controlled studies have characterized the effect of discontinuation of their chronic use on sleep and quality of life. We studied perceived sleep and quality of life in 92 older (age 55-91 years) outpatients with primary insomnia before and after withdrawal from long-term use of zopiclone, zolpidem or temazepam (BZDA).

Voriconazole greatly increases the exposure to oral buprenorphine.

Purpose: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.

Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers.

Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo.

CYP3A4*22 Impairs the Elimination of Ticagrelor, But Has No Significant Effect on the Bioactivation of Clopidogrel or Prasugrel.

CYP3A enzymes participate in the elimination of ticagrelor and the bioactivation of clopidogrel and prasugrel. We studied the effects of functional CYP3A genetic variants (CYP3A4*22; rs35599367 and CYP3A5*3; rs776746) on the pharmacokinetics and pharmacodynamics of ticagrelor, clopidogrel, and prasugrel. Six healthy volunteers with the CYP3A4*1/*22 and CYP3A5*3/*3 genotype (CYP3A4*22 carriers), eight with the CYP3A4*1/*1 and CYP3A5*1/*3 genotype (CYP3A5 expressors), and 11-13 with the CYP3A4*1/*1 and CYP3A5*3/*3 genotypes (controls) ingested single doses of ticagrelor, clopidogrel, and prasugrel on separate occasions.

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients.

Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia.

Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel.

Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel.

Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.

The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y inhibitors on montelukast pharmacokinetics. Clopidogrel (300 mg on day 1 and 75 mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.

Clopidogrel Carboxylic Acid Glucuronidation is Mediated Mainly by UGT2B7, UGT2B4, and UGT2B17: Implications for Pharmacogenetics and Drug-Drug Interactions.

The antiplatelet drug clopidogrel is metabolized to an acyl--d-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl--d-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLMs and HIMs, respectively) and selected human recombinant UGTs based on preliminary screening.