Gastric Acid Suppression Research Articles

High-dose proton pump inhibitors are associated with hospitalisation in bronchiectasis exacerbation.

BACKGROUND Bronchiectasis is a common respiratory disease complicated by periodic exacerbations. The association with different degrees of gastric acid suppression has not been well studied.METHODS A retrospective cohort study of 350 patients was conducted to investigate the association of different gastric acid suppressants with bronchiectasis exacerbation that required hospitalisation. Components of FACED (FEV1% predicted, age, chronic colonisation by Pseudomonas aeruginosa, radiological extent of the disease, and dyspnoea) were adjusted in multivariate analysis.RESULTS Among patients with exacerbation of bronchiectasis, 52 (14.9%) required hospitalisation. Prescription of a high-dose of proton pump inhibitors (PPI) was associated with increased risk of bronchiectasis exacerbation requiring hospitalisation (adjusted OR 2.77, 95% CI 1.01-7.59; P = 0.05). There was no significant association with use of a histamine-2 receptor antagonist (H2RA) (OR 1.28, 95% CI 0.32-5.06) or low-dose PPI (OR 1.47, 95% CI 0.42-5.13). Nonetheless, patients prescribed a high dose of PPI required a significantly longer hospital stay for exacerbation (13.1 ± 1.4 days) than patients not prescribed a gastric acid suppressant (8.2 ± 2.6 days) or those on a low dose PPI (8.3 ± 1.3 days) and H2RA (6.50 ± 1.50 days).CONCLUSIONS Risk of bronchiectasis exacerbation requiring hospitalisation was increased among high-dose PPI users, but not those prescribed an H2RA or low-dose PPI.

S1606 A Retrospective Study of Doxycycline-Based Quadruple Therapy versus Tetracycline-Based Quadruple Therapy for the First Line Treatment of Helicobacter pylori

Introduction: The global prevalence of antimicrobial resistance has resulted in challenges with H. pylori eradication. Gastric acid suppression and antibiotic therapy are used to eradicate H. pylori. Cost and shortages inhibit use of tetracycline for first line treatment of H. pylori. Doxycycline represents a possible cost-effective alternative for treating H. pylori. We performed an analysis of first line doxycycline-based quadruple therapy in comparison to tetracycline-based quadruple therapy in the eradication of H. pylori. Methods: A retrospective chart review was conducted using the Advocate Aurora Health database, a multi-hospital community-based system consisting of sixteen hospitals and over 500 sites of care. All patients age 18 and older with documented H. pylori infection treated with either a first line doxycycline-based regimen (DOX) or tetracycline-based regimen (TCN) from January 2012 to April 2022 were included. In total, 3,384 patients were identified. Patients who received prior first-line treatment with other regimens were excluded. All cases were reviewed for confirmation of infection (either by biopsy, breath test or stool antigen testing), the treatment regimen used, and confirmation of H. Pylori eradication (either by biopsy, breath test, or stool antigen). Patients without confirmation of eradication or with pending eradication test results were excluded. Patient demographics were summarized and eradication rates determined. Results: Of the 3,384 reviewed cases, 628 cases met inclusion and exclusion criteria. Of these, 305 patients were treated with DOX and 323 patients were treated with TCN. Based on these numbers, a posteriori non-inferiority calculation with an assumed 85% eradication rate for the TCN and 80% for DOX and 90% power suggested 100 patents were needed per group (HyLown Consulting LLC, Statistical Calculators). The average age for DOX was 57 years and 193/305 (60%) were female. The average age for TCN was 58.5 years and 210/323 (69%) were female. Eradication rates were 87.6% for DOX and 88.2% for TCN (Table). Conclusion: Doxycycline-based quadruple therapy regimen is effective and appears to be non-inferior to tetracycline-based quadruple therapy regimens for first line treatment of H. pylori. Table 1. - The number of patients with tetracycline or doxycycline antibiotic regimens and the eradication rate Doxycycline Regimen # of Patients % of Patients Successful Eradication 283 87.6% Failed Eradication 40 12.4% Total 323 Tetracycline Regimen # of Patients % of Patients Successful Eradication 269 88.2% Failed Eradication 36 11.8% Total 305

S470 Development and Utilization of a Pharmacokinetic/Pharmacodynamic Model for Vonoprazan to Assess the Relationship Between Dose, Exposure, and pH Holding Time Ratio

Introduction: Vonoprazan, a potassium-competitive acid blocker, suppresses gastric acid secretion rapidly and potently over prolonged periods. Gastric acid suppression is key to the healing and maintenance of erosive esophagitis (EE) and the eradication of Helicobacter pylori infection. The daily fraction of time that gastric pH is >4 (the pH >4 holding time ratio [HTR]) is critical for healing of EE; pH >6 HTR is important for eradication of H. pylori infection. Here, we develop and utilize a pharmacokinetic (PK)/pharmacodynamic (PD) model to investigate the relationship between vonoprazan treatment and intragastric pH HTR. Methods: Data from prior Phase 1 single and multiple dose studies with pH measurements were pooled. An existing population PK model was used to estimate individual model parameters and predict PK profiles for study participants on each day with pH measurements. The area under the concentration-time curve between 0 and 24 hours post-dose (AUC0–24h) was merged with pH HTR PD study data. Three direct link PK/PD models characterizing the relationship between AUC0–24h and HTRs for pH >4, >5, and >6 were then derived. The models were used to simulate pH HTRs with between-subject variability; results were summarized as mean and 80% prediction intervals. Results: Data from 245 participants in five different Phase 1 studies were used to derive the PK/PD model. Demographics: 95.1% male; 50.6% Japanese; 49.4% Western. The estimates and 95% confidence intervals for all model parameters are shown in Table. Simulations showed that vonoprazan 20 mg once-daily (QD) and 20 mg twice-daily (BID) are predicted to give pH >4 HTRs of 89.7% and 98.1%, respectively, by Day 7 (Figure). HTRs for pH >6 were 53.1% for vonoprazan 20 mg QD and 75.3% for BID. Conclusion: These results indicate that vonoprazan provides high, dose-dependent pH HTRs and, therefore, consistent, dose-dependent control of 24-hour intragastric acidity. These pH HTRs may explain the high EE healing rates and, when combined with antimicrobials, H. pylori eradication rates seen with vonoprazan in clinical trials.Figure 1.: Predicted Mean and 80% Prediction Interval pH Holding Time Ratio at Days 0 (pre-treatment), 1, 7 and 14. BID, twice daily; QD, once daily. Table 1. - Estimates and 95% CIs for Model Parameters Parameter Role pH >4 Estimate (95% CI) pH >5 Estimate (95% CI) pH >6 Estimate (95% CI) E0 TV (logit) -2.74 (3.77%)(-2.84 to -2.64) -3.18 (1.56%)(-3.27 to -3.09) -3.48 (0.514%)(-3.54 to -3.42) Asian-effect (%) -12.8 (-17.3 to -8.41) -9.23 (-12.7 to -5.74) -5.63 (-8.11 to -3.15) BSV 0.388 (0.310 to 0.465) 0.276 (0.192 to 0.361) 3.16e-05 (-0.286 to 0.286) EC50 TV (ng/mL) 48.2 (43.9 to 52.4) 58.8 (53.1 to 64.5) 99.5 (86.2 to 113) gamma 1.39 (1.20 to 1.58) 1.34 (1.17 to 1.52) 1.62 (1.30 to 1.94) Weight effect (1/kg) 1.50 (0.803 to 2.19) 1.81 (1.19 to 2.44) - BSV 0.319 (0.259 to 0.379) 0.310 (0.252 to 0.368) 0.235 (0.102 to 0.368) Emax TV (logit) 4.80 (102%)(4.53 to 5.07) 4.83 (102%)(4.44 to 5.23) 2.17 (91.9%)(1.65 to 2.70) Weight effect (1/kg) - - -0.0187 (-0.0265 to -0.0108) BSV 1e-04 (6.80e-05 to 0.000132) 1e-04 (5.42e-05 to 0.000146) 0.781 (0.505 to 1.06) ET50 TV (days) 0.432 (0.384 to 0.481) 0.427 (0.369 to 0.485) 0.348 (0.274 to 0.422) delta 1 (fixed) 1 (fixed) 1 (fixed) RUV add.err. (logit) 0.528 (0.475 to 0.580) 0.545 (0.493 to 0.596) 0.498 (0.457 to 0.539) E0 and Emax were estimated on the logit-scale as the pH holding time ratios were logit-transformed; back-transformed estimates on the original percent scale are given for these parameters in round brackets. add.err., additive error; BSV, between subject variability; CI, confidence interval; E0, baseline effect; Emax, theoretical maximum effect achieved at infinite exposure and time; EC50, exposure (AUC) required to achieve 50% of maximum effect (Emax); ET50, time required to achieve 50% of maximum effect; RUV, residual unexplained variability; TV, typical value.

S479 Acute Esophageal Necrosis in Patients With Diabetic Ketoacidosis: A Systematic Review of Diagnostic and Therapeutic Conundrums

Introduction: Acute esophageal necrosis (AEN) associated with diabetic ketoacidosis (DKA) remains an exceedingly rare clinical entity. The likely causal mechanism is related to hypoperfusion and transient hyperglycemic gastric dysmotility, potentially increasing the risk of AEN. To our knowledge, this is the first systematic review of AEN in patients with DKA. Methods: A systematic search of MEDLINE, Embase, Scopus, and Cochrane was conducted for English-only articles published between inception and June 15, 2022. Abstracts from major gastroenterology conferences and bibliography lists were also reviewed. Search terms "esophageal necrosis" and "black esophagus" were combined using the Boolean operators ‘AND’ and ‘OR’ with the terms "diabetic ketoacidosis" and "diabetes mellitus," with all permutations. Two authors independently reviewed each article for eligibility. The search yielded a total of 326 results. However, 28 articles fulfilled the inclusion criteria. Results: A total of 31 case reports only (clinical evidence level: IV) of AEN in the setting of DKA were included, dating from 2014 to 2022. The mean age of patients was 52.81 ± 13.49 years (range: 30–78 years) and 61% of cases were reported in males. Common presenting symptoms were hematemesis (58%), nausea (55%), abdominal pain (53%), vomiting (35%), and altered mental status (19%). Apart from diabetes, major comorbidities were hypertension (29%), alcoholism (23%), GERD (16%), and COPD (10%). On EGD, 58% had pan-esophageal, 26% had mid-to-distal, and 16% of patients had distal segment disease. Esophageal biopsy was documented in 29% of patients. All patients received insulin and fluid replacement therapies. PPIs in 60%, sucralfate in 32%, antifungals in 29%, and antibiotics were administered in 19% of patients. Blood transfusions were performed in 16% of patients. The mortality rate was 6.4%. AEN complications included esophageal stenosis (6%), as well as stricture formation (6%). (Figure) Conclusion: This systematic review reiterates the occurrence of AEN in association with DKA. Overt GI bleeding is a common presentation, but patients may develop nausea, abdominal pain, vomiting, and disorientation as major symptoms. Therefore, endoscopists should keep a low threshold for performing EGD in DKA patients. While the cause-and-effect relation of AEN with hyperglycemia are unclear, fluid replacement and gastric acid suppression are pertinent to the management of AEN.Figure 1.: Upper endoscopy showing necrotic-appearing black esophagus in the lower third of esophagus in a female diabetic patient.

Prognosis of hospital-acquired pneumonia/ventilator-associated pneumonia with Stenotrophomonas maltophilia versus Klebsiella pneumoniae in intensive care unit: A retrospective cohort study.

IntroductionWe collected data on ventilator‐associated pneumonia (VAP) and hospital‐acquired pneumonia (HAP) induced by Stenotrophomonas maltophilia (SM) and Klebsiella pneumoniae (KP) and compared differences between two bacteria in mortality, duration of ventilator use, length of hospital stay, and risk factors for infection.ObjectivesThis study aimed to evaluate the prognosis and to find risk factors of SM‐HAP/VAP versus KP‐HAP/VAP in the intensive care unit (ICU).MethodsThis retrospective cohort study included patients admitted to the ICU between June 2019 and June 2021 and diagnosed with SM‐HAP/VAP or KP‐HAP/VAP. The primary outcome was 28‐day mortality.ResultsNinety‐two HAP/VAP patients (48 with SM‐HAP/VAP and 44 with KP‐HAP/VAP) were included. The 28‐day mortality was 16.7% (8/48 patients) in SM‐HAP/VAP and 15.9% (7/44 patients) in KP‐HAP/VAP (P = 0.922). After adjustment for potential confounders, the hazard ratios for 28‐day mortality in SM‐HAP/VAP were 1.3 (95% CI:0.5–3.7), 1.0 (95% CI:0.4–3.0), 1.4 (95% CI:0.5–4.0), and 1.1 (95% CI:0.4–3.4), respectively.ConclusionSM‐HAP/VAP and KP‐HAP/VAP patients in ICU might have a similar prognosis in mortality, the total duration of the artificial airway and ventilator use, the total length of ICU stay, and hospital stay. The risk factors of SM‐HAP/VAP versus KP‐HAP/VAP might be the artificial airway, ventilator use, gastric tube placement, acid suppressant and antibiotics (especially carbapenem).

The influence of different proton pump inhibitors and potassium-competitive acid blockers on indomethacin-induced small intestinal injury.

The influence of gastric acid inhibitors (GAIs) on nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is controversial. Herein, the influences of different GAIs on NSAID-induced intestinal injury and the underlying mechanisms are clarified. Indomethacin (IND; 10mg/kg/day) was administered to mice to induce small intestinal injury. Disease activity was examined macroscopically and histologically. The permeability of small intestine was evaluated by measuring plasma lipopolysaccharide levels. 16S rDNA sequencing was performed to determine the composition of intestinal flora. Among the four GAIs, ilaprazole (IPZ) significantly attenuated IND-induced small intestinal injury and maintained the integrity of the mucosal barrier. Omeprazole (OPZ) and vonoprazan (VPZ) ameliorated ulceration without significant differences, while rabeprazole (RPZ) failed to protect against the injury. To explore the potential mechanism, we investigated changes in the gut microbiota mediated by GAIs. After 5-day administration, GAIs significantly altered the composition of the gut microbiota. The IND group had a significant decrease in alpha diversity compared with the control group, and this decrease was reversed by OPZ and IPZ treatment, respectively. After IPZ treatment, the community membership was more assembled in the control group than the IND group. Further, we found that Lactobacillus was significantly increased in the groups of OPZ, IPZ, and VPZ, while Bacteroides was significantly increased in the RPZ group. Our results indicated that GAIs have different influences on the mucosal barrier, possibly by altering the composition of intestinal microbiota, and the impacts mediated by various GAIs in the IND-induced intestinal damage model seem different.

Proton Pump Inhibitors in the COVID-19 Pandemic

The safety of proton pump inhibitors (PPIs) use in coronavirus infection (COVID-19) is not well understood. PPIs are potent suppressors of gastric secretion and become one of the ten most widely used drugs in the world. They are expected to influence virus susceptibility, severity, and outcomes in patients diagnosed with COVID-19. This concern is based on their mechanism of action — suppression of gastric acidity, which is considered the first line of defense against infections. Taken together, the results of most studies and meta-analyses support that PPIs use has been associated with increased risk of COVID-19 and severe outcomes. However, taking into account all potential risk factors for disease severity seems impossible in the real world in the context of COVID-19, so conclusions about causal relationships between PPI use and COVID-19 should be treated with great caution. An additional interesting point about the use of PPIs in the pandemic is that it reduced absorption of certain vitamins. On the other hand, several studies have appeared in the literature regarding the protective therapeutic effects of PPIs. There is growing evidence of an immunomodulatory and antifibrotic role of PPIs that could be used in the treatment of COVID-19. In addition, their ability to alkalize the contents of endosomes and lysosomes serves as an obstacle to the penetration of the virus into host cells. This review analyzes the possible effects of PPIs in patients with COVID-19.

Efficacy and safety of high-dose esomeprazole-amoxicillin dual therapy for Helicobacter pylori rescue treatment: a multicenter, prospective, randomized, controlled trial.

Background:High-dose dual therapy (HDDT) with proton pump inhibitors (PPIs) and amoxicillin has attracted widespread attention due to its favorable efficacy in eradicating Helicobacter pylori (H. pylori). This study aimed to compare the efficacy and safety of high-dose PPI–amoxicillin dual therapy and bismuth-containing quadruple therapy for H. pylori rescue treatment.Methods:This was a prospective, randomized, multicenter, non-inferiority trial. Patients recruited from eight centers who had failed previous treatment were randomly (1:1) allocated to two eradication groups: HDDT (esomeprazole 40 mg and amoxicillin 1000 mg three times daily; the HDDT group) and bismuth-containing quadruple therapy (esomeprazole 40 mg, bismuth potassium citrate 220 mg, and furazolidone 100 mg twice daily, combined with tetracycline 500 mg three times daily; the tetracycline, furazolidone, esomeprazole, and bismuth [TFEB] group) for 14 days. The primary endpoint was the H. pylori eradication rate. The secondary endpoints were adverse effects, symptom improvement rates, and patient compliance.Results:A total of 658 patients who met the criteria were enrolled in this study. The HDDT group achieved eradication rates of 75.4% (248/329), 81.0% (248/306), and 81.3% (248/305) asdetermined by the intention-to-treat (ITT), modified intention-to-treat (MITT), and per-protocol (PP) analyses, respectively. The eradication rates were similar to those in the TFEB group: 78.1% (257/329), 84.2% (257/305), and 85.1% (257/302). The lower 95% confidence interval boundary (−9.19% in the ITT analysis, − 9.21% in the MITT analysis, and −9.73% in the PP analysis) was greater than the predefined non-inferiority margin of −10%, establishing a non-inferiority of the HDDT group vs. the TFEB group. The incidence of adverse events in the HDDT group was significantly lower than that in the TFEB group (11.1% vs. 26.8%, P < 0.001). Symptom improvement rates and patients’ compliance were similar between the two groups.Conclusions:Fourteen-day HDDT is non-inferior to bismuth-containing quadruple therapy, with fewer adverse effects and good treatment compliance, suggesting HDDT as an alternative for H. pylori rescue treatment in the local region.Trial registration:Clinicaltrials.gov, NCT04678492.

Quality of life and gastric acid-suppression medication post-laparoscopic fundoplication: a ten years retrospective study

Background: Although medical treatment is the best approach for treating gastroesophageal reflux disease (GERD), surgery has a significant role to play not only in cases of failure of medical treatment but also as in a long-term approach, specifically in young patient. On the other hand, alarming reports have been published concerning the outcomes and usefulness of antireflux surgery (ARS). The aim of this study was to evaluate medium and long-term functional outcomes following ARS performed in our institution over a 10 year period. Methods: This was a retrospective review of patients in our department who underwent primary or redo laparoscopic fundoplication between 2005 and 2015. Evaluation of the outcomes was made using a validated questionnaire specifically dedicated to GERD (the Gastroesophageal Reflux Disease – Health-Related Quality of Life (GERD-HRQL) questionnaire) and by investigation about the continued use of proton-pump inhibitors (PPIs). Exclusion criteria were patients treated for GERD with Roux-en-Y gastric bypass, emergency reduction of hiatal hernia, patients missing from follow-up and patients deceased from unrelated causes. Results: 296 patients out of 309 met the inclusion criteria. Primary procedures included 214 Nissen, 35 Toupet, and 23 Collis gastroplasty; there were additionally 62 redo operations. Neither postoperative mortality nor conversion was observed. The mean follow-up was 8 years post-surgery, and contact was made with 96% of the original group. 85% of the patients had stopped PPI use since their operation (86% after Nissen, 73% after Toupet, 94% after Collis and 82% after redos). 90% of the patients had good to excellent functional results as reported by their GERD-HRQL score, and independent of the type of previous procedure. 31 patients were dissatisfied due to dysphagia in 7 and GERD recurrence in 24. Again 75% were extremely satisfied and 15% satisfied. Our own incidence of redo procedures was 11% but the functional result and satisfaction index were comparable between redo and primary procedures. The addition of Collis gastroplasty in cases of real short oesophagus did not alter the final result. Conclusions: Laparoscopic ARS presents a superior alternative to lifetime medication use and can provide long-term control of GERD symptoms in the majority of patients if it is performed skillfully and in carefully evaluated patients. Based on the present study, we believed that significant improvement in GERD health-related quality of life can be attained following both primary and reoperative ARS.

Basic Aspects and the Overview on Pharmacokinetics and Studies on Drug Distribution- A Panoramic Review

Patients who are in critical condition display a variety of organ dysfunctions and frequently need to be treated with a range of medications, such as sedatives, analgesics, neuromuscular blockers, antibiotics, inotropes, and gastric acid suppressants. A crucial component of treatment for this patient population is comprehending how organ dysfunction might change the pharmacokinetics of medications. Due to gastrointestinal failure, many medications will need to be administered intravenously. When the oral route is an option, hypomotility, changes in gut pH, and enteral feeding may affect bioavailability. The main factors affecting medication clearance, and consequently steady-state drug concentrations, efficacy, and toxicity in a given patient, are hepatic and renal dysfunction. Many medications are cleared from the body primarily through oxidative metabolism, and it is becoming increasingly understood how important it is for critically ill patients to have diminished hepatic cytochrome P450 system activity. Both filtration and secretion clearance pathways are necessary for the elimination of parent medications and their active metabolites, making renal failure equally crucial. Renal failure is frequently a secondary cause of changes in the steady-state volume of distribution, which can lower the body's effective medication concentrations. Failure of the endocrine, endothelium, muscular, or central neurological systems may also have an impact on how a medication is metabolized. For some medications, there is strong evidence that changes in pharmacokinetic characteristics depend on time. To maximize the pharmacodynamic response and result, it is essential to understand the underlying pathophysiology in the critically sick and utilize pharmacokinetic principles in the selection of drug and dosing regimen.

Pharmacokinetic Interactions Between Tegoprazan and Naproxen, Aceclofenac, and Celecoxib in Healthy Korean Male Subjects

PurposeTegoprazan is a potassium-competitive acid blocker used for gastric acid suppression and may be used with NSAIDs to reduce gastrointestinal adverse effects. The aim of this study was to evaluate the pharmacokinetic interaction between tegoprazan and commonly used NSAIDS, namely, naproxen, aceclofenac, and celecoxib. MethodsAn open-label, 3-cohort, randomized, multiple-dose, 3-way crossover study was conducted in healthy male subjects. In cohort 1, tegoprazan (50-mg tablet, once daily) and naproxen (500-mg tablet, twice daily) were administered separately or concurrently for 7 days in each period. In cohort 2, tegoprazan and aceclofenac (100-mg tablet, twice daily) were administered separately or concurrently for 7 days in each period. In cohort 3, tegoprazan and celecoxib (200-mg capsule, twice daily) were administered separately or concurrently for 7 days in each period. Pharmacokinetic blood samples were collected up to 24 hours after the last dose. FindingsSeventeen subjects from cohort 1, sixteen subjects from cohort 2, and thirteen subjects from cohort 3 were included in the pharmacokinetic analysis. In cohort 1, the geometric least squares mean ratios (90% CIs) for AUCτ (AUC profiles over the dosing interval) and Css,max (Cmax at steady state) were 1.01 (0.91–1.12) and 0.99 (0.83–1.17) for tegoprazan, and 1.00 (0.97–1.03) and 1.04 (0.99–1.09) for naproxen, respectively. The values in cohort 2 were 1.03 (0.93–1.13) and 0.94 (0.86–1.04) for tegoprazan, and 1.06 (1.00–1.12) and 1.31 (1.08–1.60) for aceclofenac. The values in cohort 3 were 1.01 (0.86–1.18) and 1.02 (0.87–1.19) for tegoprazan, and 1.08 (0.96–1.22) and 1.18 (0.97–1.43) for celecoxib. ImplicationsChanges in the maximum aceclofenac or celecoxib concentrations were detected after concurrent administration with tegoprazan, which were considered mainly due to the pharmacodynamic effect of tegoprazan. Because systemic drug exposure (shown as AUCτ) was unchanged after concurrent administration of any 3 NSAIDs with tegoprazan, the increase in aceclofenac or celecoxib Css,max when administered with tegoprazan would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT04639804.

Nocturnal acid breakthrough and esophageal acidification during treatment with dexlansoprazole as compared to omeprazole in patients with gastroesophageal reflux disease.

Nocturnal acid breakthrough (NAB) may differ based on duration of proton pump inhibitor (PPI) action and Helicobacter pylori (H. pylori) infection; NAB may influence esophageal acidification (EA) and mucosal damage. Dexlansoprazole, a long-acting PPI, was not compared with omeprazole for NAB, gastric acid suppression, and EA in relation to H. pylori infection. In this prospective open-label comparative observational study, gastroesophageal reflux disease (GERD) patients were evaluated using 24-h dual-channel pH-impedance monitoring while on dexlansoprazole (60 mg, n = 39) and omeprazole (20 mg, n = 41) to study the degree of gastric acid suppression, esophageal acid exposure, and NAB (primary outcome measures). H. pylori was detected by rapid urease test and histology. NAB tended to be frequent with omeprazole than dexlansoprazole (33/41 [80.5%] vs. 23/39 [59%]; p = 0.06). Though nocturnal mean esophageal pH was comparable between the dexlansoprazole and omeprazole groups, its duration was less with the former (181.5 [15.2-334.2] vs. 283 [158-366] min, p = 0.03). NAB was as frequent in the H. pylori-infected than the non-infected group (11/19 [57.9%] vs. 45/61 [73.8%]; p = 0.1). The nocturnal gastric and esophageal pH in the H. pylori-infected group was higher than in the non-infected group (4.6 ± 1.7 vs. 4 ± 1.6, p = 0.157; 6.1 ± 0.6 vs. 5.8 ± 0.6, p = 0.128). Dexlansoprazole tended to increase 24-h and nocturnal mean gastric pH among H. pylori-infected more than omeprazole (5.9 ± 1.1 vs. 4.2 ± 1.7, p = 0.023; 5.7 ± 1.2 vs. 3.8 ± 1.5, p = 0.006). Dexlansoprazole is more effective than omeprazole in suppressing gastric acid secretion, resulting in lesser EA and NAB, particularly in the presence of H. pylori.

Influence of concomitant gastric acid suppressants use on the survival of patients with non-small cell lung cancer treated with programmed death-1/ligand-1 inhibitors: A meta-analysis

IntroductionInfluence of concomitant use of gastric acid suppressants (GAS) on survival of non-small cell lung cancer (NSCLC) patients receiving programmed death-1/ligand-1 (PD-1/PD-L1) inhibitors has rarely been comprehensively evaluated. A meta-analysis was performed to systematically evaluate the effect of concomitant GAS in NSCLC patients receiving PD-1/PD-L1inhibitors. MethodsRelevant observational studies were identified by search of Medline, Embase, and Web of Science databases from inception to May 26, 2022. A random-effect model which incorporates the possible between-study heterogeneity was used to combine the results. ResultsTen retrospective and one prospective cohort studies including 5892 patients were patients were included. Influence of concomitant proton pump inhibitors (PPIs) was evaluated in ten studies, and influence of GAS, including PPIs or histamine type-2 receptor antagonists were evaluated in one study. Pooled results showed that concomitant use of GAS was associated with worse progression-free survival (PFS, adjusted hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.20 to 1.45, P < 0.001; I2 = 0%) and overall survival (OS, adjusted HR: 1.36, 95% CI: 1.26 to 1.48, P < 0.001; I2 = 0%) in NSCLC patients taking PD-1/PD-L1inhibitors. Subgroup analyses indicated that the association between concomitant use of GAS and poor survival in NSCLC patients taking PD-L1inhibitors was consistent in univariate and multivariate studies (P values for subgroup difference both > 0.05 for PFS and OS). ConclusionsThe meta-analysis by summarizing the up-to-date literatures showed that use of GAS, primarily PPIs, may be associated with poor survival outcomes in patients with NSCLC receiving PD-1/PD-L1inhibitors.

Novel Potassium-Competitive Acid Blocker, Tegoprazan, Protects Against Colitis by Improving Gut Barrier Function.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by prolonged inflammation of the gastrointestinal tract. IBD can result from gut barrier dysfunction, altered gut microbiota, and abnormal intestinal immunity induced by environmental factors in genetically susceptible individuals. Proton pump inhibitors (PPIs) such as rabeprazole are frequently employed for gastric acid inhibition. However, long-term PPI administration can alter the intestinal microbiome composition, possibly worsening IBD severity. The present study revealed that tegoprazan, a potassium-competitive acid blocker, significantly improved colitis in mice and enhanced the intestinal epithelial barrier function. Tegoprazan alleviated gut microbiota dysbiosis and enhanced the growth of Bacteroides vulgatus. In turn, B. vulgatus alleviated intestinal inflammation by inhibiting epithelial adhesion of pathogenic bacteria. Unlike rabeprazole, tegoprazan did not induce gut dysbiosis. Our findings provide novel insights into the potential role of tegoprazan as an intestinal protectant for IBD and as a therapeutic agent for gastric acid-related diseases.

Evaluation of a long-acting injectable formulation of omeprazole in healthy dogs.

BackgroundTo evaluate the efficacy of a single intramuscular adminsitration of long‐acting omeprazole (LA‐OMEP) in increasing gastric pH in dogs.HypothesisWe hypothesized that LA‐OMEP would meet in healthy dogs the clinical goals defined for human patients for treatment of gastroduodenal ulceration.AnimalsNine healthy research dogs.MethodsProspective experimental study. Dogs were given a 4 mg/kg intramuscular injection of LA‐OMEP. Intragastric pH was continuously recorded on treatment days 0 to 7. Daily mean pH and mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were determined.ResultsThe mean onset of action for the LA‐OMEP was 98.11 min (SD 46.39). The mean number of days the dogs' pH met established goals for MPT pH ≥3 was 5.5 days (range, 3‐7) and 5.25 days for MPT pH ≥4 (range, 3‐7). Long‐acting omeprazole met the human clinical goals pH ≥3 for 72 hours in 8/8 of the dogs and MPT pH ≥4 for 96 hours in 7/8 of dogs.Conclusions and Clinical ImportanceThe LA‐OMEP formulation produced gastric acid suppression in healthy dogs for an average of 5 days and up to 7 days, after a single intramuscular injection. No major adverse effects were observed.

Harmful Consequences of Proton Pump Inhibitors on Male Fertility: An Evidence from Subchronic Toxicity Study of Esomeprazole and Lansoprazole in Wistar Rats.

Proton pump inhibitors (PPIs) are frequently prescribed as gastric acid-suppressing agents. Nevertheless, there is limited evidence supporting the risk of detrimental effects of PPIs on male fertility. The purpose of the current study was to evaluate the effect of subchronic use of proton pump inhibitors on male fertility. Seventy adult male Wistar rats were assigned into seven groups. The normal control group orally received solvent only. Groups 2, 3, and 4 were orally given esomeprazole while groups 5, 6, and 7 received lansoprazole at 2.5, 5, and 10 mg/kg/day, respectively. After 45 days of treatment, blood samples, epididymis, and testis were collected. Sperm count, motility, and morphology were determined. The level of hormones such as testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and oxidative status of testis tissue, such as superoxide dismutase, catalase, reduced glutathione, malondialdehyde (MDA), and nitric oxide (NO) were estimated. Results demonstrated a significant decline in sperm count, motility, morphology, testosterone, and catalase at 10 mg/kg/day and GSH at 2.5 mg/kg/day. A significant increase in FSH, LH, and MDA at 10 mg/kg/day and NO at 2.5 mg/kg/day was found as compared to the control group. The pathological alterations specifically dilation of Leydig cells, vacuolization, and degeneration of the seminiferous tubules were also evident. It is concluded that PPIs had caused male reproductive toxicity in Wistar rats due to altered levels of hormones such as testosterone, FSH, and LH, elevated levels of NO, and oxidative stress.

Diagnosis and treatment of Helicobacter pylori infection by physicians in China: A nationwide cross-sectional study.

To investigate the current state of knowledge and practice of Helicobacter pylori (H.pylori) infection management in China. This nationwide, multicenter, cross-sectional questionnaire survey was conducted between March and April 2021 with respect to the diagnosis and treatment of H.pylori infection in 31 provinces, encompassing over 1000hospitals in mainland China. General physician information, diagnostic and detection status, eradication treatment, reexamination and follow-up after treatment, and basic knowledge of physicians were collected and compared with the Fifth Chinese National Consensus Report on Management of H.pylori infection and the 2016Maastricht V/Florence guidelines. The subgroup analysis was also performed. Of the 6873 questionnaire respondents, 48.8% were males, and 51.2% were females. Approximately, 26.5% of respondents indicated that their hospitals had dedicated clinics for managing H.pylori infection. Moreover, 88.0% of respondents prescribed a bismuth-containing quadruple regimen as the initial eradication treatment, and 92.7% deemed the gastric acid suppression critical. Furthermore, 91.0% of respondents routinely recommended a reexamination 1-2months after eradication therapy, and 95.1% advised patients to stop PPI treatment at least 2weeks before reexamination. The detail of following (the choice of target population/methods; the choice/availability of drugs/regimens, indications for eradication, factors influencing eradication efficacy/improvement methods and factors influencing adherence, management options/factors influencing relapse; the timing and methods, awareness of reinfection rates/prevention measures, and the approach to continuing education, awareness of guidelines, and acceptance of current core concepts of management) was also described. Subgroup analysis further revealed that significant differences were existed in being gastroenterologist or not, different education level, professional title, years of working, and provincial administrative regions. Chinese physicians' skills and knowledge about the diagnosis and treatment of H.pylori infection could be improved. More works on education are needed in future.

Assessment of the Route of Exposure to Ovalbumin and Cow's Milk Proteins on the Induction of IgE Responses in BALB/c Mice.

Simple SummaryThe mouse model is very valuable to scientists, mainly because many reagents are commercially available for conducting research in this animal model. In the search for a standardized mouse model of food allergy, the route of administration of the proteins of interest is a determinant to successfully sensitizing the mice. Our aim was to evaluate the IgE allergen-specific response to food proteins after their administration by the intragastric or intraperitoneal routes in BALB/c mice. The results show that the intraperitoneal administration of the allergens ovalbumin or cow’s milk protein triggered more robust and consistent immunoglobulin E responses than the intragastric administration of the proteins, whether Sucralfate is used or not (an antacid that can promote sensitization in mice and an allergic response similar to the one triggered in human beings). It is concluded that the intraperitoneal administration of food proteins is better than the intragastric one to sensitize BALB/c mice, even after gastric-acid suppression. We have generated scientific evidence to pave the way in the search for a reproducible mouse model of immunoglobulin E-mediated food allergy to evaluate the safety of crops derived from modern biotechnology, such as genetic engineering, or the safety and effectiveness of new food allergy therapies.BALB/c mice can be orally sensitized to food proteins under acid suppressive medication, mimicking human exposure and triggering a human-like allergic immune response. However, the reproducibility of such an oral food allergy model remains questionable. Our aim was to evaluate the IgE responses triggered against ovalbumin (OVA) and cow’s milk proteins (CMP) after intragastric (IG), either under gastric-acid suppression or not, or intraperitoneal (IP) sensitization in BALB/c mice. OVA (0.2 mg) and different concentrations of CMP were administered with/without the antacid sucralfate by the IG route. For IP sensitization, OVA or CMP (0.5 mg) were administered. ELISA was used to evaluate IgE responses. The IP sensitization protocols triggered more robust and consistent anti-OVA or anti-CMP IgE responses than the intragastric ones (with/without sucralfate) (p < 0.05). 2.7% (1/36), and 5.5% (3/54) of the mice that underwent the sucralfate-assisted IG protocol triggered IgE responses against OVA or CMP, respectively. All the mice were administered OVA or CMP via IP triggered detectable IgE responses. The IP sensitization model is more reliable than the IG one for evaluating the intrinsic sensitizing and/or allergenic potential of food proteins, even if IG immunizations are carried out under gastric-acid suppression.

Food Allergen Nitration Enhances Safety and Efficacy of Oral Immunotherapy in Food Allergy.

(1) Background: Posttranslational protein modifications have been demonstrated to change protein allergenicity. Previously, it was reported that pretreatment with highly nitrated food proteins induced a tolerogenic immune response in an experimental mouse model and in human immune cells. Here, we investigated a possible therapeutic effect of modified proteins and evaluated the safety of oral exposure to highly nitrated proteins in an experimental food allergy model. (2) Methods: BALB/c mice were orally sensitized towards ovalbumin (OVA) under gastric acid suppression. Thereafter, treatment via intragastric gavage with maximally nitrated OVA (nOVAmax) and OVA as a control was performed six times every 2 weeks. On the last day of experiments, all the treated mice were orally challenged with OVA. Systemic anaphylactic reaction was determined by measuring the core body temperature. Moreover, antibody levels, regulatory T cell numbers, cytokine levels and histology of antrum tissues were analyzed. (3) Results: After oral immunotherapy, OVA-specific IgE titers were decreased while IgG1 titers were significantly elevated in the mice receiving OVA. After oral challenge with OVA, nOVAmax-treated allergic animals showed no drop of the core body temperature, which was observed for OVA-allergic and OVA-treated allergic animals. Significantly fewer eosinophils and mast cells were found in the gastric mucosa of the allergic mice after nOVAmax treatment. (4) Conclusions: Oral immunotherapy with nOVAmax reduced allergic reactions upon allergen exposure and the number of allergen effector cells in the gastric mucosa. Thus, maximally nitrated allergens enabled an efficient and safe treatment for food allergy in our experimental model.

Pharmacokinetics and Pharmacodynamics of YYD601, a Dual Delayed-Release Formulation of Esomeprazole, Following Single and Multiple Doses in Healthy Adult Volunteers Under Fasting and Fed Conditions.

BackgroundYYD601 was developed as a novel dual delayed release (DDR) formulation of esomeprazole to prolong the plasma esomeprazole concentration and extend the duration of acid suppression.PurposeThe pharmacokinetic (PK) and pharmacodynamics (PD) characteristics of YYD601 after single and multiple oral administrations were investigated in healthy Korean adults under fasting and fed conditions, and compared with the original esomeprazole capsule.MethodsIn the single-center, randomized, open-label, parallel-design, two-period study, thirty two volunteers were enrolled into four dosing groups, including esomeprazole 40-mg (group A), YYD60130-mg (group B), YYD601 40-mg (group C), and YYD601 60-mg (group D) once daily for 5 days. Blood samples were collected for PK analysis, before and up to 24 h after dosing. For PD characteristics of YYD601, the percentages of time with intragastric pH > 4 over a 24-h period and during night-time following multiple oral administrations were evaluated.ResultsA total of 27 subjects completed the study. YYD601 showed a dual-peak PK profile under fasting condition, with delayed Tmax, compared with conventional formulation. There were no significant differences in the AUC values adjusted for dose between the three YYD601 dosage groups and the conventional esomeprazole 40 mg. The esomeprazole AUC following single and multiple administration decreased with food intake by approximately 33%. YYD601 showed a linear pharmacokinetic profile in the dose range studied. There was no statistically significant difference in increase in mean percentage of time with intragastric pH > 4 for 24-hour and during night-time between the three different doses of YYD601 and the conventional formulation. The treatments were well-tolerated during the study and no serious adverse events were observed.ConclusionYYD601 30 mg has a comparable effect on gastric acid inhibition as conventional esomeprazole 40 mg following once daily oral administration. Single and multiple oral dosing of YYD601 up to 60 mg were safe and well-tolerated throughout the study.Clinical Trial Registryhttp://clinicaltrials.gov, NCT03558477 (date of registration: June 15, 2018; study period: between October 2017 and February 2018).