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BackgroundCough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough.MethodsSingle-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency.ResultsForty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole.ConclusionsA large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

Gastric cancer is a leading cause of cancer-related deaths in China. Affecting more than 40% of the world’s population, Helicobacter pylori is a major risk factor for gastric cancer. While previous clinical trials indicated that eradication of H. pylori could reduce gastric cancer risk, this remains to be shown using a population-based approach. We conducted a community-based, cluster-randomized, controlled, superiority intervention trial in Linqu County, China, with individuals who tested positive for H. pylori using a 13 C-urea breath test randomly assigned to receiving either (1) a 10-day, quadruple anti- H. pylori treatment (comprising 20 mg of omeprazole, 750 mg of tetracycline, 400 mg of metronidazole and 300 mg of bismuth citrate) or (2) symptom alleviation treatment with a single daily dosage of omeprazole and bismuth citrate. H. pylori -negative individuals did not receive any treatment. We examined the incidence of gastric cancer as the primary outcome. A total of 180,284 eligible participants from 980 villages were enrolled over 11.8 years of follow-up, and a total of 1,035 cases of incident gastric cancer were documented. Individuals receiving anti- H. pylori therapy showed a modest reduction in gastric cancer incidence in intention-to-treat analyses (hazard ratio 0.86, 95% confidence interval 0.74–0.99), with a stronger effect observed for those having successful H. pylori eradication (hazard ratio 0.81, 95% confidence interval 0.69–0.96) than for those who failed treatment. Moderate adverse effects were reported in 1,345 participants during the 10-day treatment. We observed no severe intolerable adverse events during either treatment or follow-up. The findings suggest the potential for H. pylori mass screening and eradication as a public health policy for gastric cancer prevention. Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000979 . A cluster-randomized trial carried out across 980 villages in a high-risk region in China found that systematic treatment of antibiotics, omeprazole and bismuth modestly reduced gastric cancer incidence in Helicobacter pylori -positive populations.

Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Boehringer Ingelheim and Canadian Institutes of Health Research.

Tacrolimus is metabolized in the liver with the participation of cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). Omeprazole, unlike famotidine, is a substrate and inhibitor of CYP2C19, CYP3A4, CYP3A5 enzymes. The aim of the study is to compare the effect of omeprazole and famotidine on the tacrolimus concentration and the kidney transplant function. A randomized study was conducted in 24 adult patients with stable kidney transplant function who received a standard triple immunosuppression regimen. Patients were assigned to the group I (n = 12) additionally receiving omeprazole (20 mg) or the group II (n = 12) receiving famotidine (20 mg). At the time of qualification and during follow-up visits, tacrolimus blood concentration and selected laboratory tests were performed. Statistical analysis was performed using the MedCalc system. The value of tacrolimus concentration in the blood increased after a year in the group I (7.27 ± 2.33 vs 9.20 ± 2.46 ng/mL, p = 0.0478). A reduction in tacrolimus dosage was observed after three years in the group I (3.56 ± 1.75 vs 2.78 ± 1.00 mg, p = 0.0440) and in the group II (2.72 ± 0.84 vs 2.10 ± 0.48 mg, p = 0.0051). There was significant difference in the percentage changes of glomerular filtration rate between the groups after 3 years of the study (− 5.56% vs 9.13%, p = 0.0343). Omeprazole significantly change the concentration of tacrolimus in the blood when administered together with tacrolimus after one year of observation. There was no effect of famotidine or omeprazole on the function of the kidney transplant. ClinicalTrials.gov identifier: NCT05061303.

In patients receiving dual antiplatelet therapy, omeprazole reduced the risk of upper-GI toxic effects but did not increase the risk of cardiovascular events; statistical power to assess cardiovascular events was low, however, so the findings are not definitive. On the basis of data from several studies, clopidogrel has become the second most commonly used prescription drug worldwide. 1 – 9 Gastrointestinal hemorrhage is the most common serious bleeding complication from the use of long-term antiplatelet therapy. 10 , 11 Data from randomized studies support the concept that therapies reducing acidity decrease gastrointestinal complications of antiplatelet therapy involving aspirin, though the data are largely based on endoscopic end points; observational data also support this effect. 12 – 16 Randomized, controlled trials have shown that proton-pump inhibitors (PPIs) reduce the rate of recurrent gastrointestinal bleeding in high-risk patients receiving aspirin. 17 Observational studies, however, have suggested that . . .

Background and Objective Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug–drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H 2 -receptor antagonist; both NCT01539655). Methods Four open-label, phase I studies were conducted in healthy volunteers: n  = 14 (metformin), n  = 14 (digoxin), n  = 17 (midazolam), n  = 16 (omeprazole), n  = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1–4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Results Vandetanib + metformin increased metformin area under the plasma concentration–time curve from zero to infinity (AUC 0–∞ ) and maximum observed plasma concentration (C max ) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CL R ) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC 0–last ) and C max by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CL R . Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Conclusion Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug–drug interactions.

Helicobacter pylori is associated with benign and malignant diseases of the upper gastrointestinal tract, and increasing antibiotic resistance has made alternative treatments necessary. Our aim was to assess the efficacy and safety of a new, single-capsule treatment versus the gold standard for H pylori eradication. We did a randomised, open-label, non-inferiority, phase 3 trial in 39 sites in Europe, comparing the efficacy and safety of 10 days of quadruple therapy with omeprazole plus a single three-in-one capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline (quadruple therapy) versus 7 days of omeprazole, amoxicillin, and clarithromycin (standard therapy) in adults with recorded H pylori infection. Patients were randomly assigned treatment according to a predetermined list independently generated by Quintiles Canada (Ville St-Laurent, QC, Canada). Our study was designed as a non-inferiority trial but was powered to detect superiority. Our primary outcome was H pylori eradication, established by two negative 13C urea breath tests at a minimum of 28 and 56 days after the end of treatment. Our assessment for non-inferiority was in the per-protocol population, with subsequent assessment for superiority in the intention-to-treat population (ie, all participants randomly assigned treatment). This study is registered with ClinicalTrials.gov, number NCT00669955. 12 participants were lost to follow-up and 101 were excluded from the per-protocol analysis. In the per-protocol population (n=339), the lower bound of the CI for treatment with quadruple therapy was greater than the pre-established non-inferiority margin of −10% (95% CI 15·1–32·3; p<0·0001). In the intention-to-treat population (n=440), eradication rates were 80% (174 of 218 participants) in the quadruple therapy group versus 55% (123 of 222) in the standard therapy group (p<0·0001). Safety profiles for both treatments were similar; main adverse events were gastrointestinal and CNS disorders. Quadruple therapy should be considered for first-line treatment in view of the rising prevalence of clarithromycin-resistant H pylori, especially since quadruple therapy provides superior eradication with similar safety and tolerability to standard therapy. Axcan Pharma Inc.

Background: Eradication of H. pylori is a challenging issue in many parts of the world including Egypt. Aim: To evaluate the safety and efficacy of adding nitazoxanide as an adjuvant drug to the standard clarithromycin-based regimen, a single-center phase 4 prospective superiority parallel open-label randomized controlled trial was conducted. Methodology: Two hundred naïve H. pylori-positive patients were randomly distributed into 4 groups in ratio 1:1:1:1; Group 1: 50 patients were treated by clarithromycin 500mg bid, amoxicillin1gm bid, omeprazole 20 mg, Group 2: 50 patients were treated by clarithromycin 500mg bid, metronidazole 500mg bid, omeprazole 20 mg bid, group 3: 50 patients were treated by clarithromycin 500mg bid, nitazoxanide 500mg bid, omeprazole 20 mg bid, and group 4: 50 patients were treated by clarithromycin 500mg bid, amoxicillin1gm bid, nitazoxanide 500mg bid, omeprazole 20 mg bid. All patients were treated for 14 days and assessed 4 weeks after treatment. Results: Adding nitazoxanide to standard clarithromycin based triple therapy achieved a high eradication rate of 84% in intention to treat analysis (ITT), and 89.36% in per protocol (PP) analysis with high significant p (0.01). Conclusions: adding nitazoxanide as an adjuvant drug to the standard clarithromycin-based regimen is effective and could be used as a first line regimen in the eradication of H. pylori.

Proton pump inhibitors are essential for treating moderate-to-severe gastroesophageal reflux, peptic ulcers, esophagitis, and related conditions by increasing gastric pH and inhibiting hydrogen ion discharge into the stomach. However, prolonged use may lead to adverse effects along with reduced efficacy. Our research investigates the strategic modification of omeprazole (OMP) derivatives to improve their binding affinity to targeted proteins, thereby enhancing their chemical reactivity, stability, and toxicity profiles. A total of 22 novel OMP analogues were designed through structural alterations, focusing on the benzimidazole and pyridine rings. The geometrical attributes of the analogues were further confirmed through spectral and quantum computational analysis based on density functional theory (DFT) and a B3LYP/6-31G+ G (d, p) basis set. The molecular docking with PTAAC1 presented that most of the analogues had similar or higher binding affinities and nonbonding interactions, including OMP3, OMP19, and OMP21, with binding energies of -7.3, -8.3, and -8.1 kcal/mol compared to the OMP at -7.1 kcal/mol. Pharmacokinetic, biological, and toxicological profiles via ADMET and PASS predictions also demonstrated increased safety and therapeutic potential. MD simulation also showed good stability of OMP3, OMP19, and OMP21 in binding to PTAAC1, and the RMSD, RMSF, ligand RMSD, rGyr, SASA, MolSA, PolSA, and hydrogen bond analysis also suggested superior drug potential compared to OMP. Additionally, the post-simulation MM/GBSA analysis revealed that OMP3 (-36.91 kcal/mol) outperformed OMP19 (-26.45) and OMP21 (-12.61). The protein binding site’s high stability and elevated negative binding free energy value further indicate a robust compound-protein interaction with OMP3. However, principal component analysis (PCA) showed the highest variance for OMP21, accounting for 50.66%, 21.58%, and 6.51%, respectively, for PC1, PC2, and PC3. These findings could lead to the development of OMP3 and OMP21 as potential next-generation PPIs with enhanced pharmacological activity and improved side-effect profiles, necessitating more in vitro and in vivo testing.

•Low-fat food intake increased AUC(0-96h), AUC(0-∞), and Cmax of imlunestrant.•Concomitant administration of omeprazole did not alter imlunestrant PK parameters.•400 mg imlunestrant were well tolerated when dosed in the fasted or fed state.•400 mg imlunestrant were well tolerated when dosed alone or with omeprazole. To assess the effect of low-fat food intake and the effect of a gastric acid reducing agent (omeprazole) on imlunestrant pharmacokinetics (PK), safety, and tolerability. A phase 1, open-label cohort study (NCT04840888) in healthy adult females of non-childbearing potential Food effect was evaluated in cohort 1 in which, participants were randomized (1:1) to fasted/fed or fed/fasted crossover treatment sequences and received one dose of 400 mg imlunestrant once-daily in each fed (a low-fat meal; 500 calories, 13% fat) or fasted state with 4 days washout period between doses. Omeprazole’s effect was evaluated in cohort 2, in which participants received imlunestrant in fixed treatment sequence with a washout period between doses: (1) a single dose of 400 mg imlunestrant alone on Day 1, (2) no treatment between Day 2–Day 5, (3) 40 mg omeprazole alone once-daily between Day 5–8, and (4) 400 mg imlunestrant + 40 mg omeprazole on Day 9. Blood samples for PK assessments were collected for the evaluation of the areas under the concentration curve AUC(0-96h), AUC(0-∞), maximum observed drug concentration (Cmax), time of maximum observed drug concentration (Τmax); their geometric least squares (GLS) mean ratios were calculated. Safety assessments involved monitoring of adverse events (AEs), clinical chemistry, hematology, vital signs, 12-lead electrocardiogram, and physical examination. Eight females were enrolled in cohort 1 and 10 in cohort 2. In cohort 1, PK parameters were statistically significantly increased with GLS mean ratios (90% CI): 1.99 (1.67, 2.36) in AUC(0-96h), 2.04 (1.41, 2.94) in AUC(0-∞), and 3.55 (2.83, 4.45) in Cmax, following dosing with imlunestrant in the fed state compared to the fasted state. The change in Τmax was not statistically significant. In cohort 2, the change in PK parameters of imlunestrant when dosed alone and in the presence of the PPI omeprazole were not statistically significant and were comparable. Imlunestrant was well tolerated, and no clinically meaningful findings were recorded in either cohort. Low-fat food intake resulted in increases of ∼2-fold in AUC and ∼3.6-fold in Cmax. Therefore, patients will be instructed to abstain from food consumption two hours before and one hour after taking imlunestrant. Concomitant use of imlunestrant and omeprazole displayed a low risk of drug-drug interaction, therefore imlunestrant may be taken with a proton pump inhibitor such as omeprazole. A single oral dose of 400 mg imlunestrant was generally well tolerated in healthy females regardless of food or omeprazole intake.