Lage ciclosporinespiegel na kort rifampicinegebruik : immuunsuppressie kan langdurig tekortschieten

Cyclosporin is an immunosuppressive agent with a wide range of therapeutic uses. In transplant patients, it is used for the prevention of rejection and graft-versus-host reactions. The metabolism and bioavailability of cyclosporin can be significantly and persistently influenced through induction of CYP3A4 caused by the concomitant use of rifampicin. However, awareness of the need for the timely and frequent monitoring of cyclosporin levels during and especially after treatment with rifampicin has not fully been addressed. Here, we describe 3 patient cases concerning significant episodes of sub-therapeutic cyclosporin levels after short-term rifampicin therapy. Rifampicin was administered for three to five days and decreased cyclosporin levels were observed ± 7 days after the initiation of rifampicin, and continued during the following weeks even after the cessation of rifampicin therapy. Cyclosporin dosage-adjustments were made based on the cyclosporin blood levels and all 3 patients showed good therapeutic and clinical responses.Zelfs kortdurend gebruik van het antibioticum rifampicine kan de ciclosporineconcentratie in het bloed verlagen. Daarom moet de bloedspiegel van dit immunosuppressivum goed gemonitord worden bij patiënten die ook rifampicine krijgen, ook als de patiënt al gestopt is met het middel. Om afstoting van transplantaten of graft-versus-hostreacties te voorkómen, is het vaak nodig de ciclosporinedosering aan te passen

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Recognition of Impaired Atomoxetine Metabolism Because of Low CYP2D6 Activity

Ten out of 100 children treated for attention deficit hyperactivity disorder with standard doses of atomoxetine were selected by a neurologist for cytochrome P450 2D6 and cytochrome P450 209 genotyping, based on late response (>9 weeks) and adverse effects (gastrointestinal problems, sleeping disorders, malaise, inactivity, and mood instabilities). After genotyping, eight children were confirmed to have compromised cytochrome P450 2D6 activity because of at least one nonfunctional or less functional allele. Cytochrome P450 C19 is a minor pathway in atomoxetine metabolism and therefore of less importance. Tailored therapeutic advice was given to the neurologist. Four children with compromised cytochrome P450 2D6 activity responded better after decreasing their atomoxetine dose. The other four ceased treatment because of initial adverse effects. These cases indicate that compromised atomoxetine metabolism can be recognized, based on adverse effects and late response to atomoxetine. Physicians should be aware of the typical pattern of adverse effects and late response in atomoxetine treatment, possibly indicating compromised cytochrome P450 2D6 activity. Cytochrome P450 2D6 genotyping before atomoxetine treatment may be beneficial in preventing overdosing or early cessation. Further research is needed to establish the cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping in atomoxetine treatment. (C) 2010 by Elsevier Inc. All rights reserved

Recognition of Impaired Atomoxetine Metabolism Because of Low CYP2D6 Activity

Ten out of 100 children treated for attention deficit hyperactivity disorder with standard doses of atomoxetine were selected by a neurologist for cytochrome P450 2D6 and cytochrome P450 209 genotyping, based on late response (>9 weeks) and adverse effects (gastrointestinal problems, sleeping disorders, malaise, inactivity, and mood instabilities). After genotyping, eight children were confirmed to have compromised cytochrome P450 2D6 activity because of at least one nonfunctional or less functional allele. Cytochrome P450 C19 is a minor pathway in atomoxetine metabolism and therefore of less importance. Tailored therapeutic advice was given to the neurologist. Four children with compromised cytochrome P450 2D6 activity responded better after decreasing their atomoxetine dose. The other four ceased treatment because of initial adverse effects. These cases indicate that compromised atomoxetine metabolism can be recognized, based on adverse effects and late response to atomoxetine. Physicians should be aware of the typical pattern of adverse effects and late response in atomoxetine treatment, possibly indicating compromised cytochrome P450 2D6 activity. Cytochrome P450 2D6 genotyping before atomoxetine treatment may be beneficial in preventing overdosing or early cessation. Further research is needed to establish the cost versus benefit ratio of prospective cytochrome P450 2D6 genotyping in atomoxetine treatment. (C) 2010 by Elsevier Inc. All rights reserved.Afdeling Klinische Chemie en Laboratoriumgeneeskunde (AKCL

Influence of macrolide maintenance therapy and bacterial colonisation on exacerbation frequency and progression of COPD (COLUMBUS):Study protocol for a randomised controlled trial

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive development of airflow limitation that is poorly reversible. Because of a poor understanding of COPD pathogenesis, treatment is mostly symptomatic and new therapeutic strategies are limited. There is a direct relationship between the severity of the disease and the intensity of the inflammatory response. Besides smoking, one of the hypotheses for the persistent airway inflammation is the presence of recurrent infections. Macrolide antibiotics have bacteriostatic as well as anti-inflammatory properties in patients with cystic fibrosis and other inflammatory pulmonary diseases. There is consistent evidence that macrolide therapy reduces infectious exacerbations, decreases the requirement for additional antibiotics and improves nutritional measures. Because of these positive effects we hypothesised that maintenance macrolide therapy may also have beneficial effects in patients with COPD who have recurrent exacerbations. The effects on development of bacterial resistance to macrolides due to this long-term treatment are unknown. Until now, studies investigating macrolide therapy in COPD are limited. The objective of this study is to assess whether maintenance treatment with macrolide antibiotics in COPD patients with three or more exacerbations in the previous year decreases the exacerbation rate in the year of treatment and to establish microbial resistance due to the long-term treatment. METHODS/DESIGN: The study is set up as a prospective randomised double-blind placebo-controlled single-centre trial. A total of 92 patients with COPD who have had at least three exacerbations of COPD in the previous year will be included. Subjects will be randomised to receive either azithromycin 500 mg three times a week or placebo. Our primary endpoint is the reduction in the number of exacerbations of COPD in the year of treatment. DISCUSSION: We investigate whether long-term therapy with macrolide antibiotics can prevent exacerbations in patients with COPD. Additionally, our study aims to assess the effect of long-term use of macrolide on the development of antimicrobial resistance and on inflammatory parameters related to COPD. We believe this study will provide more data on the effects of macrolide treatment in patients in COPD and will add more knowledge on its working mechanisms. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT0098524

Pharmacokinetics of nifedipine slow-release during sustained tocolysis

Item does not contain fulltextOBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slowrelease half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm(c) software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 +/- 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature

Chloroquine for treatment of COVID-19 results in subtherapeutic exposure and prolonged QTc intervals

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Prevention of severe infectious complications after colorectal surgery using oral non-absorbable antimicrobial prophylaxis: results of a multicenter randomized placebo-controlled clinical trial

BACKGROUND: Surgical site infections (SSIs) are common complications after colorectal surgery. Oral non-absorbable antibiotic prophylaxis (OAP) can be administered preoperatively to reduce the risk of SSIs. Its efficacy without simultaneous mechanical cleaning is unknown. METHODS: The Precaution trial was a double-blind, placebo-controlled randomized clinical trial conducted in six Dutch hospitals. Adult patients who underwent elective colorectal surgery were randomized to receive either a three-day course of preoperative OAP with tobramycin and colistin or placebo. The primary composite endpoint was the incidence of deep SSI or mortality within 30 days after surgery. Secondary endpoints included both infectious and non-infectious complications at 30 days and six months after surgery. RESULTS: The study was prematurely ended due to the loss of clinical equipoise. At that time, 39 patients had been randomized to active OAP and 39 to placebo, which reflected 8.1% of the initially pursued sample size. Nine (11.5%) patients developed the primary outcome, of whom four had been randomized to OAP (4/39; 10.3%) and five to placebo (5/39; 12.8%). This corresponds to a risk ratio in the intention-to-treat analysis of 0.80 (95% confidence interval (CI) 0.23-2.78). In the per-protocol analysis, the relative risk was 0.64 (95% CI 0.12-3.46). CONCLUSIONS: Observational data emerging during the study provided new evidence for the effectiveness of OAP that changed both the clinical and medical ethical landscape for infection prevention in colorectal surgery. We therefore consider it unethical to continue randomizing patients to placebo. We recommend the implementation of OAP in clinical practice and continuing monitoring of infection rates and antibiotic susceptibilities. TRIAL REGISTRATION: The PreCaution trial is registered in the Netherlands Trial Register under NL5932 (previously: NTR6113) as well as in the EudraCT register under 2015-005736-17