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Summary Background Esomeprazole and rabeprazole are metabolised in the liver by means of the CYP2 C19 enzyme, which has several functional genetic polymorphisms. Among Caucasians, 70% of the population has a fast metaboliser phenotype, 25-30% an intermediate and 2-5% a slow metaboliser phenotype. It is unknown whether different PPIs are affected to the same extent by these phenotypic differences. Aim To compare the acid-inhibitory effects of esomeprazole 40 mg and rabeprazole 20 mg in relation to CYP2 C19 genotype and pharmacokinetics. Methods Eighteen healthy Helicobacter pylori-negative Caucasian subjects with CYP2C19*2-*6 and *17 genotype were included in a randomised investigator-blinded crossover study with esomeprazole 40 mg and rabeprazole 20 mg. Intragastric 24-h pH-monitoring was performed on days 0, 1 and 5 of oral dosing. Results Onset of acid inhibition during the first 4 h after administration did not differ significantly between PPIs. During the upright period, the proportion of time with pH >4 was significantly higher with esomeprazole compared to rabeprazole (52.2 vs. 40.3%, P = 0.003). At day 1 and 5, acid inhibition was significantly greater with esomeprazole than with rabeprazole (median intragastric pH: day 1: 3.7 vs. 3.0, P = 0.008; day 5: 4.7 vs. 3.8, P < 0.001; percentage of time pH >4: day 1: 45 vs. 39%, P = 0.054; day 5: 65 vs. 48%, P < 0.001). Differences in acid inhibition between wt/wt and wt/*2 genotype were significant for both PPIs. Conclusions Once-daily dosing with esomeprazole 40 mg provides a more effective and faster acid-inhibitory effect than rabeprazole 20 mg. The acid-inhibitory effect of esomeprazole and rabeprazole are both influenced by CYP2 C19 polymorphism. [ABSTRACT FROM AUTHOR]

Background Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25–30% of Caucasians) and slow (2–5% of Caucasians) metabolism of PPIs. Aim To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. Methods CYP2C19*2, *3, *4, *5 and *17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2 *2/*17 and 1 *2/*2 were included in a randomized investigator-blinded cross-over study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-h pH-monitoring was performed on days 0, 1 and 5 of oral dosing. Results A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid-inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid-inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at day 1 and 5. Conclusions Esomeprazole provides acid-inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype. [ABSTRACT FROM AUTHOR]

Background The occurrence and the clinical relevance of rebound acid hypersecretion after discontinuation of proton pump inhibitors is unclear. Aim To perform a systematic review of rebound acid hypersecretion after discontinuation of proton pump inhibitors. Methods PubMed, Embase and Central were searched up to October 2005 with indexed terms. Results Eight studies were included, sample size was 6–32. The studies used both basal and stimulated acid output as parameters to study rebound acid hypersecretion and assessed these at different time points and with variable methods. Five studies (including four randomized studies) did not find any evidence for rebound acid hypersecretion after proton pump inhibitor therapy. Of the remaining three studies, the duration of proton pump inhibitor therapy was the longest and two of these studies were the only to assess Helicobacter pylori status of their study subjects. These two studies suggested that rebound acid hypersecretion may occur in H. pylori-negatives after 8 weeks of proton pump inhibitors. Conclusions Studies that have investigated rebound acid hypersecretion after cessation of proton pump inhibitor treatment are heterogenic in design, methods and outcome. There is some evidence from uncontrolled trials for an increased capacity to secrete acid in H. pylori-negative subjects after 8 weeks of treatment. There is no strong evidence for a clinically relevant increased acid production after withdrawal of proton pump inhibitor therapy. [ABSTRACT FROM AUTHOR]

Background: Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU.Methods: A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included.Discussion: No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM?Trial Registration: EudraCT number: 2017-004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018 . Protocol Version 6, Protocol date: 27 November 2019. [ABSTRACT FROM AUTHOR]

A response by the author to a letter to the editor about the article "Systematic review: Rebound Acid Hypersecretion after Therapy with Proton Pump Inhibitors," in the 2007 issue is presented.

Background. Regarding sustainability in the intensive care unit (ICU), there is increasing interest in reducing material waste and avoiding unnecessary procedures. Therapeutic drug monitoring (TDM) of vancomycin, using a dedicated tube, is standard clinical care during treatment with vancomycin. Furthermore, in the ICU, on a daily basis, arterial blood gas (ABG) tests are frequently performed throughout the day. After analysis, a variable volume of blood is discarded. Lithium heparin (LiHep) syringes for ABG tests differ from normally used dipotassium ethylenediaminetetraacetic acid (K2EDTA) tubes. The primary objective was to compare both containers and validate the use of LiHep syringes. Secondary objectives were to evaluate the potential impact on saving materials, nursing time, and costs when implementing vancomycin TDM via LiHep syringes. Methods. Vancomycin analysis from sampling in lithium heparin (LiHep) syringes for ABG tests was validated and compared with the concentrations from conventional sampling in K2EDTA tubes. For method comparison, a Bland–Altman plot and Deming regression analysis were performed. The method was validated for inter- and intra-day precision and accuracy. Vancomycin was analyzed by means of the validated method using a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) autoanalyzer. Furthermore, an analysis was conducted to evaluate the potential impact of implementing vancomycin sampling via ABG tests on savings in materials, nursing time, and costs. Results. From 18 patients, 24 plasma samples in both K2EDTA tubes and LiHep syringes were obtained and compared. The mean relative difference between the two containers was −2.0% (−3.0 to −0.93%). Both the Deming regression analysis and the Bland–Altman plot met the acceptance criteria. Potentially, over 1000 blood draws and accompanying materials and packaging can be saved when vancomycin samples are obtained by means of scavenged LiHep syringes. The vancomycin analysis for LiHep syringes showed a total interday precision of 1.95% and an accuracy of 99.7%. The total intraday precision was 2.22%, and the accuracy was 99.2%. Accuracy and precision values were within the acceptance criteria of recovery 85 to 115% and ≤15%, respectively. Conclusion. No significant differences were found in vancomycin concentration between the two analyses, and the LiHep analysis was validated for further implementation in clinical care. Residual blood from ABG test samples can be used for TDM of vancomycin, resulting in a potential reduction of materials used and the number of blood draws. These results will contribute to a more sustainable TDM process with benefits for the patient. [ABSTRACT FROM AUTHOR]