Proton Pump Inhibitors Directly Block hERG-potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans

2021 ◽  
Author(s):  
Pietro Enea Lazzerini ◽  
Alessandra Cartocci ◽  
Yongxia Sarah Qu ◽  
Simona Saponara ◽  
Simone Furini ◽  
...  
Keyword(s):  
Risk Factors ◽  
Potassium Channel ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Free Energy Calculations ◽  
Hek293 Cells ◽  
Qtc Prolongation ◽  
Herg Current ◽  
Us Veterans ◽  
The Impact

Background - Worldwide, there are millions of chronic proton pump inhibitors (PPIs) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part due to a higher risk of QTc-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the underlying mechanism, and therefore serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data. Methods - First, the effect of different PPIs on the ether-a-go-go -related-gene potassium channel (hERG) current was evaluated in HEK293-cells expressing hERG. Then, free energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of QTc prolongation was assessed in a retrospective observational cohort of 3867 US Veterans, including 1289 PPI-treated subjects. Results - Clinically-relevant concentrations of different PPIs induced a significant inhibition of the hERG-current in-vitro , pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class-effect is likely due to direct PPIs binding to hERG-channel pore cavity. Accordingly, in a US Veterans cohort, PPI treatment was independently associated with a ~20-40% increased risk of QTc prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated. Conclusions - Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote QTc prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.

Risk of Clostridium difficile-Associated Disease Among Patients Receiving Proton-Pump Inhibitors in a Quebec Medical Intensive Care Unit

2007 ◽  
Vol 28 (11) ◽  
pp. 1305-1307 ◽  
Author(s):  
Mathieu Beaulieu ◽  
David Williamson ◽  
Gilbert Pichette ◽  
Jean Lachaine
Keyword(s):  
Risk Factors ◽  
Intensive Care Unit ◽  
Intensive Care ◽  
Clostridium Difficile ◽  
Gastric Acid ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Medical Intensive Care Unit ◽  
Antibiotic Use ◽  
Medical Intensive Care

Our study was conducted to determine whether use of gastric acid-suppressive agents increased the risk of Clostridium difficile-associated disease (CDAD) in a medical intensive care unit of one of the first hospitals to be threatened by the current CDAD epidemic in Quebec, Canada. Our findings suggest that efforts to determine risk factors for CDAD should focus on other areas, such as older age and antibiotic use.

scholarly journals Risk of QTc Interval Prolongation Associated With Circulating Anti‐Ro/SSA Antibodies Among US Veterans: An Observational Cohort Study

2021 ◽  
Vol 10 (4) ◽  
Author(s):  
Pietro Enea Lazzerini ◽  
Gabriele Cevenini ◽  
Yongxia Sarah Qu ◽  
Frank Fabris ◽  
Nabil El‐Sherif ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Small Sample ◽  
Observational Cohort Study ◽  
Current Evidence ◽  
Qtc Interval ◽  
Qtc Prolongation ◽  
Increased Risk ◽  
Observational Cohort ◽  
Us Veterans

Background Anti‐Sjögren's syndrome‐related antigen A‐antibodies (anti‐Ro/SSA‐antibodies) are responsible for a novel form of acquired long‐QT syndrome, owing to autoimmune‐mediated inhibition of cardiac human ether‐a‐go‐go‐related gene‐potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample‐size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti‐Ro/SSA‐antibodies in a large population of unselected subjects. Methods and Results This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti‐Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate‐corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti‐Ro/SSA‐positive (8.3%). Subjects who were anti‐Ro/SSA‐positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26–2.21] for QTc >470/480 ms; 2.32 [1.54–3.49] for QTc >490 ms; 2.77 [1.66–4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT‐prolonging drugs were added to the model. Nevertheless, stepwise‐fully adjusted OR for the higher cutoffs remained significantly increased in anti‐Ro/SSA‐positive subjects, particularly for QTc >500 ms (2.27 [1.34–3.87]). Conclusions Anti‐Ro/SSA‐antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti‐Ro/SSA‐positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.

scholarly journals Impact of NPS MedicineWise General Practitioner education programs and Choosing Wisely Australia recommendations on prescribing of Proton Pump Inhibitors in Australia

2019 ◽  
Author(s):  
Jianyun Wu ◽  
Scott Dickinson ◽  
Zain Elgebaly ◽  
Suzanne Gaye Blogg ◽  
Aine Heaney ◽  
...  
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
High Strength ◽  
Choosing Wisely ◽  
Education Programs ◽  
Time Series Analyses ◽  
Low Strength ◽  
Practitioner Education ◽  
The Impact ◽  
Pharmaceutical Benefits Scheme

Abstract Background This study evaluated the impact of multifaceted NPS MedicineWise programs conducted in 2009 and 2015 that targeted general practitioners (GPs) to reduce unnecessary prescribing of proton pump inhibitors (PPIs). Methods Time series analyses of the dispensing rates of concessional PPI scripts between January 2006 and June 2016 using the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule (MBS) databases in Australia. Participants were GPs with dispensed PPI prescriptions to concessional patients between January 2006 and June 2016. The interventions were National NPS MedicineWise PPI educational programs in 2009 and 2015 delivered to all practising GPs in Australia. The 2015 intervention coincided with the release of Choosing Wisely Australia recommendations from the RACGP. Outcome measures included monthly dispensing rates of standard and low strength PPIs prescribed by GPs among concessional patients in Australia. Results Following the 2009 NPS MedicineWise program we observed a 6.7% reduction in the expected dispensing rate of standard strength PPIs among concessional patients between January 2006 and March 2015, and a total 8.6% reduction by June 2016 following the launch of the 2015 program. We observed a significant increase of 5.6% in the expected dispensing rate of low strength PPIs among concessional patients between April 2009 and March 2015, and no significant change in trend following the 2015 program. Conclusions The NPS MedicineWise programs were associated with reductions in the dispensing rate of standard strength PPIs, and with an increase in the dispensing rate of low-strength PPIs by June 2016. Although the rate of high-strength PPI prescribing is declining, these formulations still constitute the majority of PPI use in Australia. Regular interventions to sustain and improve PPI management by GPs may be warranted.

Mo1083 Risk Factors for Relapse of Gastroesophageal Reflux Disease (GERD) in Primary Care Patients Previously Succeeded With Proton Pump Inhibitors Treatment

2012 ◽  
Vol 142 (5) ◽  
pp. S-590-S-591
Author(s):  
Magda Sofia Pacio-Quiterio ◽  
Jose Emilio G Rodriguez-Aguilar ◽  
Alvaro Montiel-Jarquin ◽  
Juan C. Lopez-Alvarenga ◽  
Sergio R. Sobrino-Cossio ◽  
...  
Keyword(s):  
Risk Factors ◽  
Primary Care ◽  
Gastroesophageal Reflux Disease ◽  
Gastroesophageal Reflux ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Reflux Disease ◽  
Primary Care Patients

scholarly journals Proton Pump Inhibitors are Risk Factors for Viral Infections: Even for COVID-19?

2020 ◽  
Vol 40 (10) ◽  
pp. 897-899 ◽  
Author(s):  
Bruno Charpiat ◽  
Nathalie Bleyzac ◽  
Michel Tod
Keyword(s):  
Risk Factors ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Viral Infections

scholarly journals The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo

2018 ◽  
Vol 108 ◽  
pp. 60-64 ◽  
Author(s):  
Miao Yan ◽  
Zhu-feng Wu ◽  
Dan Tang ◽  
Feng Wang ◽  
Yi-wen Xiao ◽  
...  
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
The Impact

Proton Pump Inhibitors and Dabigatran Therapy: Impact on Gastric Bleeding and Dabigatran Plasma Levels

2019 ◽  
Vol 45 (08) ◽  
pp. 846-850 ◽  
Author(s):  
Tomáš Bolek ◽  
Matej Samoš ◽  
Ingrid Škorňová ◽  
Peter Galajda ◽  
Ján Staško ◽  
...  
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Plasma Levels ◽  
Thrombin Inhibitor ◽  
Gi Bleeding ◽  
Gastric Bleeding ◽  
Increased Risk ◽  
The Impact ◽  
Dabigatran Therapy

AbstractDabigatran etexilate, a direct thrombin inhibitor, is now frequently used for long-term pharmacological prevention of stroke or systemic embolism in patients with atrial fibrillation. However, such long-term dabigatran therapy (DT) significantly increases the risk of upper gastrointestinal (GI) bleeding. This increased risk of gastric bleeds might be reduced with gastroprotective agents, such as proton pump inhibitors (PPIs). PPIs coadministrated with dabigatran reduce the risk of upper GI bleeding in patients on long-term oral DT. Nevertheless, there is heated discussion regarding interactions between PPI and dabigatran that lead to decreases in dabigatran plasma levels. This article reviews up to date data about the risk of gastric bleeding on dabigatran, the impact of PPI on the reduction of gastric bleeding, and the interaction between PPI and dabigatran leading to decreased dabigatran plasma levels.

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