Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.

AIM: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. METHODS: In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. RESULTS: Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5). CONCLUSIONS: Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.

Effects of 9 Weeks of High- or Moderate-Intensity Training on Cardiorespiratory Fitness, Inhibitory Control, and Plasma Brain-Derived Neurotrophic Factor in Danish Adolescents-A Randomized Controlled Trial.

PURPOSE: The primary aims of this study were to examine the effects of 9 weeks of aerobic training, comprising three 30-min sessions per week, on V̇O2max, inhibitory control, and plasma brain-derived neurotrophic factor (BDNF) levels among adolescents aged 16-19 years. METHODS: One hundred twenty-one untrained or recreationally active adolescents from a Danish high school were enrolled in the study, with 58 females (17.8 ± 0.8 years) and 27 males (18.0 ± 0.9 years) completing it. Participants were randomly divided into three groups performing aerobic training at either moderate-intensity (MIT: 60%-70% heart rate reserve [HRR]) or high-intensity (HIT: 80%-100% HRR) or a passive control group (CON) continuing their habitual lifestyle. Both the training groups exercised for 3×30 min per week for 9 weeks using a combination of cycling and running. Before and after the intervention period maximal oxygen uptake (V̇O2max) and the primary outcomes (inhibitory control measured by a modified flanker task, and resting plasma levels of BDNF) were evaluated. RESULTS: After the intervention period, the HIT group demonstrated a larger increase in V̇O2max compared to both the CON and MIT groups, while no significant effects were observed on inhibitory control or plasma BDNF levels in any training group. However, compared to the CON group, the HIT group exhibited a tendency for greater improvement in the flanker interference score (accuracy), attributable to enhanced accuracy on the incongruent stimuli from pre to post. CONCLUSION: Aerobic training in adolescents increased cardiorespiratory fitness in an intensity-dependent manner, but no clear effects were observed on neither inhibitory control nor resting plasma BDNF levels. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02075944.

Dicloxacillin-warfarin drug-drug interaction-A register-based study and in vitro investigations in 3D spheroid primary human hepatocytes.

AIMS: Dicloxacillin is used to treat staphylococcal infections and we have previously shown that dicloxacillin is an inducer of cytochrome P450 enzymes (CYPs). Here, we employed a translational approach to investigate the effect of a treatment with dicloxacillin on warfarin efficacy in Danish registries. Furthermore, we assessed dicloxacillin as an inducer of CYPs in vitro. METHODS: We conducted a register-based study and analysed international normalized ratio (INR) levels in chronic warfarin users before and after short- and long-term use of dicloxacillin (n = 1023) and flucloxacillin (n = 123). Induction of CYPs were investigated in a novel liver model of 3D spheroid primary human hepatocytes at the level of mRNA, and protein and enzyme activity. RESULTS: Short- and long-term dicloxacillin treatments decreased INR levels by -0.65 (95% confidence interval [CI]: -0.57 to -0.74) and -0.76 (95% CI: -0.50 to -1.02), respectively. More than 90% of individuals experienced subtherapeutic INR levels (below 2) after long-term dicloxacillin treatment. Flucloxacillin decreased INR levels by -0.37 (95% CI: -0.14 to -0.60). In 3D spheroid primary human hepatocytes, the maximal induction of CYP3A4 mRNA, protein and enzyme activity by dicloxacillin were 4.9-, 2.9- and 2.4-fold, respectively. Dicloxacillin also induced CYP2C9 mRNA by 1.7-fold. CONCLUSION: Dicloxacillin induces CYPs and reduces the clinical efficacy of warfarin in patients. This effect is substantially exacerbated during long-term treatment with dicloxacillin. The in vitro results corroborated this drug-drug interaction and correlated to the clinical findings. Caution is warranted for warfarin patients that initiate dicloxacillin or flucloxacillin, especially for a long-term treatment of endocarditis.

Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin-But not through altered drug metabolism in patients with type 2 diabetes.

AIMS: 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. METHODS: 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. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after 3 and 12 weeks of treatment. Drug metabolism, glycaemic control, and inflammation were assessed on each visit. RESULTS: In the Danish and Scottish cohorts (n = 982 and n = 44, respectively), initiating glucose-lowering drugs reduced warfarin efficacy. INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference -0.26; 95% CI -0.35; -0.17) and from 2.33 to 2.13 in the Scottish cohort (-0.21; 95% CI -0.52; 0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n = 10), initiating metformin did not affect drug metabolism after 3 weeks (geometric mean ratio of CYP3A metabolic ratio: 1.12 [95% CI: 0.95; 1.32]) or 12 weeks of metformin treatment. Glycaemic control improved during treatment, while inflammation remained low and unchanged during treatment. CONCLUSIONS: In conclusion, initiation of glucose-lowering drugs among chronic warfarin users seems associated with a reduction in INR, particularly among individuals with a large decrease in HbA1c . This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

Proton Pump Inhibitor Use Is Not Strongly Associated With SARS-CoV-2 Related Outcomes: A Nationwide Study and Meta-analysis.

BACKGROUND & AIMS: Proton pump inhibitor (PPI) use has been associated with increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes. However, meta-analyses show unclear results, leading to uncertainty regarding the safety of PPI use during the ongoing coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a nationwide observational study including all SARS-CoV-2 cases (n = 83,224) in Denmark as of December 1, 2020. The association of current PPI use with risk of infection was examined in a case-control design. We investigated the risk of severe outcomes, including mechanical ventilation, intensive care unit admission, or death, in current PPI users (n = 4473) compared with never users. Propensity score matching was applied to control for confounding. Finally, we performed an updated meta-analysis on risk of SARS-CoV-2 infection and COVID-19 mortality attributable to PPI use. RESULTS: Current PPI use was associated with increased risk of infection; adjusted odds ratio, 1.08 (95% confidence interval [CI], 1.03-1.13). Among SARS-CoV-2 cases, PPI use was associated with increased risk of hospital admission; adjusted relative risk, 1.13 (1.03-1.24), but not with other severe outcomes. The updated meta-analysis showed no association between PPI use and risk of infection or mortality; pooled odds ratio, 1.00 (95% CI, 0.75-1.32) and relative risk, 1.33 (95% CI, 0.71-2.48). CONCLUSIONS: Current PPI use may be associated with an increased risk of SARS-CoV-2 infection and hospital admission, but these results with minimally elevated estimates are most likely subject to residual confounding. No association was found for severe outcomes. The results from the meta-analysis indicated no impact of current PPI use on COVID-19 outcomes.

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries: Interrupted time series regression analysis.

OBJECTIVE: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. METHOD: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. RESULTS: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark -0.08%, 95%CI -0.13, -0.03; England -0.09%, 95%CI -0.13 to -0.06%; the Netherlands -1.84%, 95%CI -2.51 to -1.17%; Scotland -0.34%, 95%CI -0.38 to -0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (-0.12%, 95%CI -0.19 to -0.04), PAD (-0.13%, 95%CI -0.22 to -0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (-0.01%, 95%CI -0.02 to -0.007%), IHD (-0.017, 95%CI -0.02, -0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. CONCLUSION: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings.

Use of tramadol and other analgesics following media attention and risk minimization actions from regulators: a Danish nationwide drug utilization study.

PURPOSE: To describe the use of tramadol and other analgesics in Denmark focusing on the impact of media attention (June and December 2017) and regulatory actions (September 2017 and January 2018) on the use of tramadol. METHODS: Using nationwide registries, we identified all adults who filled a prescription for tramadol and other analgesics from 2014 to 2019. We described incidence rates, prevalence proportions, and total use of tramadol and other analgesics over time. We also described switching between analgesics, treatment duration, skewness in drug use, and doctor-shopping. RESULTS: From early 2017 until the end of 2019, total tramadol use decreased markedly while the use of morphine and oxycodone decreased slightly. The quarterly prevalence of tramadol use decreased from 32/1000 individuals in 2014 to 18/1000 at the end of 2019, dropping mainly at the time of media attention. Concomitantly, the quarterly prevalence increased for oxycodone (from 5.1 to 8.2) and morphine (from 8.5 to 9.8), mainly due to more short-term and sporadic users, and decreased for codeine (14 to 9.6). From 2014 to mid-2017, the incidence of tramadol use was stable (around 2.2/1000 person-months) but dropped in June 2017 to 1.7/1000, coinciding with the media attention. The incidence of tramadol use continued to decrease (to 1.1/1000 at the end of 2019). CONCLUSION: We identified a decline in tramadol use coinciding with the media attention in 2017 and continuing during regulatory actions. There was generally no evidence of unintended effects on the utilization of opioids related to the media attention and regulatory actions.

Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands: An interrupted time series regression analysis.

BACKGROUND: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. METHOD: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression. RESULTS: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (-12.05, 95%CI -18.47 to -5.63) and Scotland (-19.01, 95%CI -26.99 to -11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (-1.72, 95%CI -2.69 to -0.75) and Scotland (-2.38, 95%CI -3.32 to -1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country. CONCLUSION: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands.

PURPOSE: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. METHODS: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. RESULTS: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (-0.42%, 95% CI, -0.66% to -0.18%), England (-0.09%, 95% CI, -0.11% to -0.08%), and Scotland (-0.67%, 95% CI, -0.79% to -0.55%); and falling trends in diclofenac initiation in the Netherlands (-0.03%, 95% CI, -0.06% to -0.01% per quarter) and Scotland (-0.04%, 95% CI, -0.05% to -0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. CONCLUSIONS: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching.

Are Outcomes From an Exercise Therapy and Patient Education Program for Osteoarthritis Associated With Hip and Knee Replacement Within Two Years? A Register-Based Study of 9,339 Patients With Osteoarthritis.

OBJECTIVE: The objective of this study was to determine whether short-term outcomes from exercise therapy and patient education for osteoarthritis (OA) are associated with hip or knee replacement within two years. METHODS: Individual-level data from the Good Life with osteoArthritis in Denmark (GLA:D) Registry were linked to the Danish National Patient Registry and other national registries. Cox proportional hazards models were used to investigate associations between program outcomes (baseline to three-month changes) and time to primary hip or knee replacement. Patients who did not receive joint replacement were censored at two years, time of death, or emigration. RESULTS: A total of 2,304 and 7,035 patients with clinically diagnosed hip and knee OA, respectively, were included. Of these, 30% with hip OA and 10% with knee OA had joint replacement within two years. Postprogram improvements in hip-related quality of life and arthritis self-efficacy (pain subscale) were associated with a reduced hazard of hip replacement (adjusted hazard ratios [HRs] for a 10-unit improvement: 0.74 [95% confidence interval (CI) 0.69-0.80] and 0.90 [95% CI 0.85-0.96], respectively). Improvements in knee pain, knee-related quality of life, and arthritis self-efficacy (pain subscale) were associated with a lower hazard of knee replacement (adjusted HRs for 10-unit improvement: 0.81 [95% CI 0.76-0.86] to 0.90 [95% CI 0.86-0.95], 0.70 [95% CI 0.63-0.78] to 0.79 [95% CI 0.72-0.86], and 0.89 [95% CI 0.83-0.94], respectively). CONCLUSION: The magnitude of improvement in key measures after exercise therapy and education was significantly associated with the likelihood of surgery. Progression to hip replacement was three times higher than progression to knee replacement. This information can guide patient-clinician conversations around anticipated program outcomes.