Proton Pump Inhibitors in IPF: A Call for Clinical Trials.
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ABSTRACT:
SUBMITTER: Ghebre YT
PROVIDER: S-EPMC5966555 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Proton Pump Inhibitors in IPF: A Call for Clinical Trials.
Frontiers in pharmacology 20180517
The recent FDA approval of two drugs, pirfenidone and nintedanib, for the treatment of idiopathic pulmonary fibrosis (IPF) has fueled interest in the development of additional drugs to treat the disease or its major clinical complications including cough and acute exacerbations. Since 2015, there are at least a dozen active interventional studies that are testing the efficacy of novel pharmacotherapies, exercise or stem cells in modifying the disease process in IPF. Additionally, there are combi ...[more]
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Project description:RATIONALE:Proton pump inhibitors (PPIs) are popular drugs for gastroesophageal reflux, which are now available for long-term use without medical supervision. Recent reports suggest that PPI use is associated with cardiovascular, renal, and neurological morbidity. OBJECTIVE:To study the long-term effect of PPIs on endothelial dysfunction and senescence and investigate the mechanism involved in PPI-induced vascular dysfunction. METHODS AND RESULTS:Chronic exposure to PPIs impaired endothelial function and accelerated human endothelial senescence by reducing telomere length. CONCLUSIONS:Our data may provide a unifying mechanism for the association of PPI use with increased risk of cardiovascular, renal, and neurological morbidity and mortality.
| S-EPMC4902745 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) increase osteoporotic fracture risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption (FCA). Existing studies provide conflicting information regarding the direct effects of PPIs on FCA. We evaluated the effect of PPI therapy on FCA. We recruited women at least 5 years past menopause who were not taking acid suppressants. Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method. Two FCA studies were performed 1 month apart to establish baseline calcium absorption. The third study occurred after taking omeprazole (40?mg/day) for 30 days. Each participant consumed the same foods during all FCA studies; study meals replicated subjects' dietary habits based on 7-day diet diaries. Twenty-one postmenopausal women ages 58?±?7 years (mean?±?SD) completed all study visits. Seventeen women were white, and 2 each were black and Hispanic. FCA (mean?±?SD) was 20%?±?10% at visit 1, 18%?±?10% at visit 2, and 23%?±?10% following 30?±?3 days of daily omeprazole (p?=?.07, ANOVA). Multiple linear regression revealed that age, gastric pH, serum omeprazole levels, adherence to omeprazole, and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3. The 1,25-dihydroxyvitamin D(3) level at visit 2 was the only variable (p?=?.049) associated with the change in FCA between visits 2 and 3. PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use. Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture.
| S-EPMC3179281 | biostudies-literature
Project description:BACKGROUND AND AIMS:Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. METHODS:The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. RESULTS:211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. CONCLUSIONS:The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.
| S-EPMC4853569 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and increased serum gastrin concentration. PPI and pH8 treatment (alkalization) of CMT93 mouse colon cancer cells inhibited cell growth and invasion, increased oxidative stress and apoptosis, and decreased mitochondrial volume and protein levels of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2. In contrast, gastrin treatment enhanced growth and invasion, decreased oxidative stress and apoptosis, and increased mitochondrial volume and cyclin D1 and pERK1/2 levels. Concurrent treatment with a PPI, pH8, and gastrin increased aldehyde dehydrogenase activity and also enhanced liver metastasis in the BALB/c strain of mice. PPI administration was associated with Clostridiumperfringens enterotoxin (CPE) in CRC lesions. CPE treatment activated yes-associated protein (YAP) signals to enhance proliferation and stemness. The orthotopic colon cancer model of CMT93 cells with long-term PPI administration showed enhanced tumor growth and liver metastasis due to gastrin and YAP activation, as indicated by gastrin receptor knockdown and treatment with a YAP inhibitor. These findings suggest that PPI promotes CRC growth and metastasis by increasing gastrin concentration and YAP activation, resulting in gut flora alteration and fecal alkalization. These findings suggest that PPI use in colorectal cancer patients might create a risk of cancer promotion.
| S-EPMC7312442 | biostudies-literature
Project description:To evaluate the characteristics of the prescription of the proton pump inhibitor drugs (PPI) and the adherence to the indications of the guidelines regulating the reimbursement limitations set forth by the Italian Drug Agency.Thirty general practitioners (GP) participated in the study, providing data on more than 40000 patients in total. The population was divided into non occasional users of PPI drugs (PPI users) and non-users (PPI non-users) based on evidence of a prescription of at least 3 packs of PPIs in the last 90 d before analysis. The data provided allowed an assessment of compliance with the requirements of eligibility for PPI reimbursement according to the Italian Drug Agency rules, in order to obtain subpopulations which complied or not with the rules.Six thousand three hundred and twenty-two patients were found to be PPI users, accounting for 14.9% of the patient population. PPI users were more frequently female, older and more frequently diagnosed with gastroesophageal reflux disease, gastric or duodenal ulcers, arthropathy, heart disease and cancer than the rest of the population. PPI users had more frequently received prescriptions for non-steroidal ant-inflammatory drugs (NSAIDS), acetylsalicylic acid (ASA), oral anticoagulant therapy (OAT) and systemic steroids. PPI reimbursement resulted applicable to 69.3% of the PPI users, but a potential for reimbursement of PPI prescriptions was identified in the non PPI users for the treatment of peptic or reflux disease (8.5%) and for the protection of gastric damage caused by NSAIDS (6.1%). Patients who are potentially eligible for reimbursement are older, diagnosed with arthropathy and heart disease more frequently and most commonly receive NSAID and ASA prescriptions compared with PPI users who do not satisfy eligibility requirements. Patients in whom it was not possible to identify conditions related to prescription suitability were more frequently associated with use of OAT.A substantial number of patients who apparently do not meet prescription suitability conditions can be identified, but among non PPI users on the contrary, it is possible to identify an equal number of patients for whom prescription would be suitable. Poor suitability can be identified in the population receiving OAT. Thus, there is scope for decreasing inappropriate use of PPI drugs by adhering to certain criteria and by involving all interested parties.
| S-EPMC5547376 | biostudies-other
Project description:Background and aimsPotassium-Competitive Acid Blockers (P-CABs) have been used in Helicobacter pylori (H. pylori) eradication therapies in recent years. However, the efficacy and safety of P-CABs compared to Proton-Pump Inhibitors (PPIs) in this setting remain controversial.MethodsThe efficacy and safety of P-CABs and PPIs for H. pylori eradication were compared in a meta-analysis based on a systematic literature search of major electronic databases for relevant Randomized Controlled Trials (RCTs).ResultsSeven studies and 1,168 patients were included. The pooled eradication rate determined by Intention-To-Treat (ITT) analysis was 90.2% for P-CAB-based and 75.5% for PPI-based triple therapy (pooled RR [95% CI] = 1.17 [1.08-1.28], p < 0.001). The Per-Protocol (PP) analysis also demonstrated significant superiority of P-CABs (pooled eradication rate = 92.4% vs. 77.8%; pooled RR [95% CI] = 1.14 [1.03-1.26], p < 0.01). In a subgroup evaluation, P-CABs were significantly better than PPIs as a first-line eradication therapy, in both the ITT analysis (pooled eradication rate = 91.8% vs. 76.4%; pooled RR [95% CI] = 1.18 [1.10-1.28], p < 0.0001) and the PP analysis (pooled eradication rate = 93.0% vs. 78.6%; pooled RR [95% CI] = 1.13 [1.02-1.26], p < 0.05). However, P-CABs were not superior to PPIs when administered as salvage therapy, as determined in the ITT (75.0% vs. 66.0%, pooled RR [95% CI] = 1.11 [0.69-1.78], p = 0.66) and PP (85.7% vs. 70.0%, pooled RR [95% CI] = 1.20 [0.82-1.75], p = 0.34) analyses. In a subgroup analysis limited to Japanese patients, both the ITT analysis (pooled eradication rate = 89.6% vs. 73.9%; RR [95% CI] = 1.21 [1.14-1.29], p < 0.01) and the PP analysis (pooled eradication rate = 92.0% vs. 75.7%; RR [95% CI] = 1.18 [1.06-1.32], p < 0.01) showed that P-CABs were significantly superior compared to PPIs as triple eradication therapy. However, in the subgroup analysis of patients from other countries, there was no significant difference in either the ITT analysis (pooled eradication rate = 93.8% vs. 85.2%; RR [95% CI] = 1.10 [0.99-1.22], p = 0.07) or PP analysis (pooled eradication rate = 95.0% vs. 90.8%; RR [95% CI] = 1.05 [0.98-1.14], p = 0.17). The incidence of adverse events associated with the two regimens did not significantly differ (P-CABs vs. PPIs: 33.6% vs. 40.0%; RR [95% CI] = 0.84 [0.71‒1.00], p = 0.05). The incidence of serious adverse events and dropout rate due to adverse events also did not differ (p = 0.44 and p = 0.67, respectively).ConclusionsThe efficacy of P-CAB-based triple therapy is superior to that of PPI-based triple therapy as a first-line approach to H. pylori eradication, particularly in Japanese patients. As salvage therapy, the efficacy of the two treatments did not significantly differ. The tolerability of P-CAB-based and PPI-based triple therapy was comparable, as was the incidence of adverse events.
| S-EPMC9278030 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) were clinically introduced more than 25 years ago and have since proven to be invaluable, safe, and effective agents for the management of a variety of acid-related disorders. Although all members in this class act in a similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflux disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Longer-acting PPIs and technology to prolong conventional PPI activity have been developed to specifically address these limitations and may improve clinical outcomes.
| S-EPMC5221858 | biostudies-literature
Project description:Proton-pump inhibitors (PPIs) are commonly used after kidney transplantation and there is rarely an incentive to discontinue treatment. In the general population, PPI use has been associated with hypomagnesaemia. We aimed to investigate whether PPI use is associated with plasma magnesium, 24-h urinary magnesium excretion and hypomagnesaemia, in kidney transplant recipients (KTR). Plasma magnesium and 24-h urinary magnesium excretion were measured in 686 stable outpatient KTR with a functioning allograft for ≥1 year from the TransplantLines Food and Nutrition Biobank and Cohort-Study (NCT02811835). PPIs were used by 389 KTR (56.6%). In multivariable linear regression analyses, PPI use was associated with lower plasma magnesium (β: -0.02, P = 0.02) and lower 24-h urinary magnesium excretion (β: -0.82, P < 0.001). Moreover, PPI users had a higher risk of hypomagnesaemia (plasma magnesium <0.70 mmol/L), compared with non-users (Odds Ratio (OR): 2.12; 95% confidence interval (CI) 1.43-3.15, P < 0.001). This risk tended to be highest among KTR taking high PPI dosages (>20 mg omeprazole Eq/day) and was independent of adjustment for potential confounders (OR: 2.46; 95% CI 1.32-4.57, P < 0.005). No interaction was observed between PPI use and the use of loop diuretics, thiazide diuretics, tacrolimus, or diabetes (Pinteraction > 0.05). These results demonstrate that PPI use is independently associated with lower magnesium status and hypomagnesaemia in KTR. The concomitant decrease in urinary magnesium excretion indicates that this likely is the consequence of reduced intestinal magnesium absorption. Based on these results, it might be of benefit to monitor magnesium status periodically in KTR on chronic PPI therapy.
| S-EPMC6947083 | biostudies-literature
Project description:Two proton pump inhibitors, tenatoprazole and esomeprazole, were previously shown to inhibit HIV-1 egress by blocking the interaction between Tsg101, a member of the ESCRT-I complex, and ubiquitin. Here, we deepen our understanding of prazole budding inhibition by studying a range of viruses in the presence of tenatoprazole. Furthermore, we investigate the relationship between the chemistry of prodrug activation and HIV-1 inhibition for diverse prazoles currently on the market. We report that tenatoprazole is capable of inhibiting the replication of members of the enveloped filo, alpha, and herpes virus families but not the flavivirus group and not the non-enveloped poliovirus. Another key finding is that prazole prodrugs must be activated inside the cell, while their rate of activation in vitro correlated to their efficacy in cells. Our study lays the groundwork for future efforts to repurpose prazole-based compounds as antivirals that are both broad-spectrum and selective in nature.
| S-EPMC7055211 | biostudies-literature
Project description:IntroductionProton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.
| S-EPMC5942154 | biostudies-literature