Intragastric Acidity Research Articles

Study of antacid effect of the drug Antareit® in healthy volunteers

The aim. Study of pharmacodynamic parameters and confirmation of pharmacodynamic equivalence (bioequivalence) of the drugs Antareit® (INN: magaldrate), chewable tablets, 800 mg (Valenta Pharm JSC, Russia) and Riopan (INN magaldrate), chewable tablets, 800 mg (Takeda GmbH, Germany). Material and methods. An open randomized crossover study was conducted to investigate the pharmacodynamics of the study drug Antareit® and the reference drug Riopan, assessing their bioequivalence after taking 2 chewable tablets of the study or reference drug 3 times a day. The study involved 40 healthy volunteers who were randomized into 2 groups of 20 people depending on the sequence of drug administration in study periods I and II. Intragastric acidity was measured with a pH-probe within 30 minutes before and for one hour after taking the study drugs. Based on the data obtained, 90% confidence intervals (CI) were calculated for the pharmacodynamic parameter AUCABL, reflecting the area above the baseline pH. The safety of the study drugs was assessed by the frequency and severity of adverse events (AEs). Results. Statistical analysis showed that the 90% CI for the ratio of the mean values of the AUC ABL parameter of the study drug to the reference drug did not fall below 80% (90% CI: 80.55–119.49). During the study, 18 adverse events (AEs) were reported in 15.4% (6 of 39) of volunteers in the safety population, and there were no statistically significant differences in the incidence of AEs between groups, nor in the incidence of AEs depending on the drug taken. Conclusion. The studied drugs are pharmacodynamically equivalent and have a similar safety profile when administered repeatedly.

The Impact of Sex on the Response to Proton Pump Inhibitor Treatment.

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment.

Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

BackgroundKeverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. AimsTo evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects. MethodsIn the dose-escalated phase Ia trial, the first 8 subjects received keverprazan 5 mg, the others successively entered 10 mg, 20 mg, 40 mg, 60 mg groups and were randomized to receive keverprazan (n = 8), lansoprazole (LSZ) 30 mg (n = 2) or placebo (n = 2) in each dose group. The phase Ib study randomly enrolled subjects to the fasting-fed (n = 7) or fed-fasting (n = 7) groups for evaluating the food effect of keverprazan. ResultsTwenty (35.71%) adverse events (AEs) occurred in phase Ia, including 13 (32.50%), 3 (37.50%), and 4 (50.00%) AEs in the keverprazan, placebo, and LSZ groups, respectively. Four (28.57%) AEs occurred in Phase Ib. The Tmax of keverprazan was 1.25–1.75 h. Cmax and AUC increased with the dose, and the t1/2, CL/F were 6.00–7.17 h, 88.8–198 L/h, respectively. The intragastric pH >5 holding-time ratio (HTR) increased with the dose but reached a ceiling at 20 mg. In the 30 mg LSZ and 5–60 mg keverprazan groups, the intragastric pH >5 HTRs during 24 h were 57.1%±26.4%, 7.9%±8.1%, 26.2%±22.8%, 80.2%±8.8%, 88.1%±8.6%, and 93.0%±1.7%, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%). ConclusionKeverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.

Treatment of Acid-related Diseases Using Potassium-competitive Acid Blockers

Proton pump inhibitors (PPIs) have several limitations to their efficacy including insufficient acid suppression, slow onset of action, and variable efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers inhibit H+-K+-ATPase in a reversible and K+-competitive manner, are novel acid suppressive drugs with rapid onset of action, meal independence, and prolonged control of intragastric acidity compared to PPIs. Potassium-competitive acid blockers exhibited non-inferior therapeutic efficacies on reflux esophagitis, gastric ulcers, and Helicobacter pylori eradication. The review is focused on the unmet needs across the acid-related diseases and recent updates on clinical studies using vonoprazan and tegoprazan.

Features of duodenogastric refl ux in gastric ulcer

At the moment the approach to the treatment of gastric ulcer (GU) does not depend on the location of the ulcer in one or another part of the stomach. We compared gastric secretion, duodenogastric refl ux characteristics and Helicobacter pylori infection in patients with “high” and “low” gastric ulcers. 96 patients with recurrent GU were examined; 71.9% of men and 28.1% of women. In 58 patients, a “high” localization of the ulcer was detected, and in 38 patients, a “low” (pyloroantral) ulcer was diagnosed. All patients underwent esophagogastroduodenoscopy and daily intragastric pH-metry prior to the appointment of antisecretory therapy. The data were compared with the results of healthy volunteers. The frequency of detection of Helicobacter pylori infection was comparable with diff erent localization of gastric ulcer. We were able to show that with “high” ulcers, intragastric acidity in terms of fundal and antral pH and its circadian dynamics were comparable to healthy people. With “high” ulcers, the frequency of duodenogastric refl ux was close to normal, but their total duration was higher due to an increase in the proportion of prolonged and high refl ux. With “low” gastric ulcers, we noted a very high and monotonous acidity in the body and antrum of the stomach, combined with a decrease in the frequency and duration of duodenogastric refl ux. Consequently, both “high” and “low” stomach ulcers suggest the appointment of antisecretory drugs. At the same time, the detection of “high” stomach ulcers associated with excessive duodenogastric refl ux can be considered as a basis for prescribing bismuth tricalium dicitrate, including as part of the Helicobacter pylori eradication therapy, or ursodeoxycholic acid.

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.

Acid Suppressive Drugs

Histamine H2 receptor antagonists (H2RAs) suppress gastric acid production by blocking H2 receptors in parietal cells. Studies have shown that proton pump inhibitors (PPIs) are superior to H2RAs as a treatment for acid-related disorders, such as peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). PPIs reduce gastric acid production by irreversibly inhibiting the H+/K+ ATPase pump, and they also increase gastric emptying. Although PPIs have differing pharmacokinetic properties, each PPI is effective in managing GERD and PUDs. However, PPIs have some limitations, including short plasma half-lives, breakthrough symptoms (especially at night), meal-associated dosing, and concerns associated with long-term PPI use. Potassium-competitive acid blockers (P-CABs) provide more rapid and profound suppression of intragastric acidity than PPIs. P-CABs are non-inferior to lansoprazole in healing erosive esophagitis and peptic ulcers, and may also be effective in improving symptoms in patients with non-erosive reflux disease. Acid suppressive drugs are the most commonly used drugs in clinical practice, and it is necessary to understand the pharmacological properties and adverse effects of each drug.

Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans

Fexuprazan is a potassium-competitive acid blocker (P-CAB). The compounds in this newly developed drug family suppress intragastric acidity. As there are already other acid-suppressing drugs on the market, such as H2 antagonists and proton pump inhibitors (PPIs), it would be informative to compare the biological effects of fexuprazan against another approved drug with the same indication. The drug concentration predicted by the pharmacokinetic (PK) model could serve as an input function for a pharmacodynamic (PD) model. The apparent pharmacokinetics of fexuprazan could be described by a simpler model. However, a physiologically based pharmacokinetic (PBPK) model was developed in a previous study. A one-compartment model was also proposed in the present study. Both the newly suggested model and the previously validated PBPK model were used as input functions of the PD models. Our simulation revealed that the effects of fexuprazan could be effectively simulated by the proposed PK–PD models. A PK–PD model was also proposed for the oral administration of the PPI reference drug esomeprazole. A model-based analysis was then performed for intragastric pH using several dosing methods. The expected pH could be predicted for both drugs under several dosing regimens using the proposed PK–PD models.

Pharmacodynamics and Pharmacokinetics of the Potassium-Competitive Acid Blocker Vonoprazan and the Proton Pump Inhibitor Lansoprazole in US Subjects.

We assessed pharmacodynamics and pharmacokinetics of a potassium-competitive acid blocker and proton pump inhibitor in US subjects. Healthy adults were randomized to 7-day periods of vonoprazan 20 mg once daily followed by lansoprazole 30 mg once daily or the reverse order, separated by ≥ 7 days of washout. Vonoprazan (N = 40) had higher proportions of 24-hour periods with intragastric pH > 4 than lansoprazole (N = 41,38) on day 1 (62.4% vs 22.6%, P < 0.0001) and day 7 (87.8% vs 42.3%, P < 0.0001). Separation in pH started ∼2.5 hours after the first dose. Vonoprazan provided more rapid and potent inhibition of intragastric acidity than lansoprazole in US subjects.

Review article: potassium-competitive acid blockers for the treatment of acid-related disorders.

Potassium-competitive acid blockers (P-CABs) are a novel group of acid-suppressing medicines for the management of acid-related disorders. To review published clinical pharmacology studies and clinical trials of P-CABs. We conducted a comprehensive literature search including Medline (PubMed), EMBASE, Web of Science and the Cochrane Library from inception until November 2020, for studies of the clinical pharmacology of P-CABs and relevant clinical trials of those that are currently licensed or in development. Most publications concerned vonoprazan, which forms the bulk of this review. It is currently licensed in some Asian and South American countries and is being developed for North America. In clinically relevant doses, P-CABs have produced more rapid and profound suppression of intragastric acidity than proton pump inhibitors (PPIs). Vonoprazan was non-inferior to lansoprazole in healing erosive oesophagitis (2 randomised controlled trials [RCTs] in 1137 subjects) and superior in maintaining remission (1 RCT; 607 subjects). In 2 RCTs (1120 total subjects), both vonoprazan and tegoprazan were non-inferior to lansoprazole for healing peptic ulcers. Three RCTs and numerous non-randomised studies have compared vonoprazan-based and PPI-based regimens for Helicobacter pylori infection; vonoprazan-based triple or dual regimens have been highly effective. P-CABs have some potential advantages over PPIs. To date, most research has been conducted in Asia; results of clinical trials that are underway in the United States and Europe are anticipated in 2021.

PH-Responsive Au(i)-disulfide nanoparticles with tunable aggregation-induced emission for monitoring intragastric acidity.

Aggregation-induced emission (AIE)-featuring Au(i) complexes are superior probes for physiological environment monitoring in living organisms owing to their excellent biocompatibility and efficient luminescent properties. However, the intrinsic obstacle of poor water stability and lack of response to biological stimuli greatly restrict their practical application in biological systems. Herein, water-stable and pH-responsive Au(i)-disulfide nanoparticles (NPs) with AIE characteristics were designed. The NPs were prepared by integrating a pH-responsive moiety, cysteine (Cys), into Au(i)-thiolate (SR) complexes, and the Au(i)-SR-Cys structure was formed through disulfide bonds. Hydrophilic Cys was located on the outer layer of the NPs, endowing the spherical NPs with high stability and remarkable monodispersity in water. In addition, Cys endowed the NPs with pH-responsive characteristics. These unique advantages enable them to hold great promise as luminescent probes to monitor intragastric acidity in an acid suppression therapy. To the best of our knowledge, this work is the first example of luminescent Au(i) materials to monitor physiological changes.

Role of H pylori in GERD- A prospective study

Introduction: The role of Helicobacter pylori in esophageal disease has not been clearly defined. To clarify this issue, we analyzed 120 patients with histologically confirmed esophageal disease. Helicobacter pylori (H. pylori) causes a long-term infection of the human gastric and duodenal mucosa (1). Mucosal colonisation predisposes for peptic ulcer disease, atrophic gastritis and distal (antral) stomach cancer (2), with various effects on gastric acid secretion. Genetic variability of H. pylori is high (3). Several genes have been identified that may play a role in the pathogenicity (4, 5). Most important is the cytotoxin- associated gene A (CagA), which is associated with peptic ulcer disease (6), and intestinal type adenocarcinoma of the stomach (7). Patients with duodenal ulcer often have high basal gastrin levels, high peak acid output and high 24-hour intragastric acidity (8-10). Materials and methods: This investigation was performed at the RL Jalappa Hospital, Tamaka, Kolar in patients who underwent Upper GI Endoscopy. The time of investigation was from January 2016-December 2018. Results: This study included 30 patients with BE out of 120 patients with GERD. The average age of patients in BE group was 52.4 years. (SD } 10.8 yr.) In the GERD group average age was 40.8 years. In all groups included in this study, men were more represented than women. In BE group, H. pylori infection was present in 16.0% of patients. In GERD group, H. pylori infection was present in 42.9%. Conclusion: The prevalence of H. pylori infection in patients with BE was lower in comparison with patients with GERD (p

Pharmacological characteristics and clinical efficacies of a novel potassium-competitive acid blocker, vonoprazan fumarate

Proton pump inhibitors (PPIs) inhibit H+, K+-ATPase, an enzyme which is the final step of gastric acid secretion and is selectively located in the gastric parietal cells. PPIs block the enzyme in a covalent and irreversible binding manner, thus providing better efficacy than previous pharmacological agents such as antacids and histamine H2 receptor antagonists. Although PPIs have been the first-line therapeutic option for acid related diseases (ARDs), there are several limitations to their efficacy, i.e. short half-life in blood, insufficient acid suppression especially at night, necessity of repeated dosages for full action, and large variation in efficacy among patients due to CYP2C19 polymorphism. To overcome these shortcomings, we performed a high-throughput random screening using in-house chemical libraries and further lead optimization to look for the most relevant clinical candidate compounds. As the results of these researches, we discovered vonoprazan fumarate, a novel gastric acid antisecretory agent which inhibits H+, K+-ATPase in a reversible and K+-competitive manner. Vonoprazan exerted a more potent and longer lasting inhibitory effect than lansoprazole on gastric acid secretion in preclinical studies, presumably by its high accumulation profile in the gastric parietal cells. It also exhibited a rapid onset of action and prolonged inhibition of intragastric acidity in humans and showed remarkable effects on multiple ARDs including erosive esophagitis and Helicobacter pylori eradication. Vonoprazan fumarate was approved in 2014 for clinical use in Japan. Vonoprazan is a new therapeutic option which can potentially improve outcomes compared with conventional PPI-based treatments for ARDs.

THE EFFECT OF FOOD ON CLINICAL SYMPTOMS AND INTRAGASTRIC ACIDITY IN DUODENAL ULCER

Objective: to evaluate the effect of food on the clinical symptoms of duodenal ulcer (DU) and postprandial changes in intragastric acidity. Materials and methods. 52 patients with uncomplicated and 56 – with a complicated course of DU in the acute stage were examined. The control group consisted of 50 apparently healthy individuals. All of the subjects completed a questionnaire including questions about food preferences and the effect of food on the clinical symptoms of the disease. Also, all patients conducted 24-hour pH-metry. We calculated basic parameters and postprandial gastric acidity in the stomach. Results . Patients with DU are characterized by night snacks, ignore breakfast, a rare use of the first course, rare use of soup, roughage and fresh fruit, which provoke pain or dyspepsia in patients with DU. The decrease postprandial pH and reducing the time consumtion found in patients with DU, especially pronounced in complicated course of the disease, compared with healthy volunteers. Conclusions. Frequent meals, night snacks, food avoidance “dry rations” and fresh vegetables, fruits typical for patients with DU. Also characteristic of complicated PUD decrease actions alkalizing food, short and low postprandial rise pH.

The gastric acid pocket is attenuated in H. pylori infected subjects

ObjectiveGastric acid secretory capacity in different anatomical regions, including the postprandial acid pocket, was assessed in Helicobacter pylori positive and negative volunteers in a Western population.DesignWe studied 31 H. pylori...

Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases.

Acid-related diseases (ARDs), such as peptic ulcers and gastroesophageal reflux disease, represent a major health-care concern. Some major milestones in our understanding of gastric acid secretion and ARD treatment reached during the last 50years include 1) discovery of histamine H2-receptors and development of H2-receptor antagonists, 2) identification of H+,K+-ATPase as the parietal cell proton pump and development of proton pump inhibitors (PPIs), and 3) identification of Helicobacter pylori (H. pylori) as the major cause of peptic ulcers and development of effective eradication regimens. Although PPI treatments have been effective and successful, there are limitations to their efficacy and usage, i.e. short half-life, insufficient acid suppression, slow onset of action, and large variation in efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers (P-CABs) inhibit H+,K+-ATPase in a reversible and K+-competitive manner, and exhibit almost complete inhibition of gastric acid secretion from the first dose. Many pharmaceutical companies have tried to develop P-CABs, but most of their clinical development has been discontinued due to safety concerns or a similar efficacy to PPIs. Revaprazan was developed in Korea and was the first P-CAB approved for sale. Vonoprazan, approved in 2014 in Japan, has a completely different chemical structure and higher pKa value compared to other P-CABs, and exhibits rapid onset of action and prolonged control of intragastric acidity. Vonoprazan is an effective treatment for ARDs that is especially effective in healing reflux esophagitis and for H. pylori eradication. P-CABs, such as vonoprazan, promise to further improve the management of ARDs.

PWE-071 The Majority of H. Pylori Infected Subjects Have Reduced Intragastric Acidity and Parietal Cell Density which is Most Marked Close to The Gastroesophageal Junction: Abstract PWE-071 Table 1

Introduction A negative association exists between H. pylori infection and both gastroesophageal reflux disease and oesophageal adenocarcinoma. The great majority of the H. pylori infected population are asymptomatic, so we studied healthy volunteers to determine if the infection is associated with changes to the acid secretory capacity of gastric mucosa which may protect individuals from acid reflux. Methods We studied 31 H. pylori positive and 29 H. pylori negative volunteers, matched for age and gender. Jumbo biopsies were taken at eleven pre-determined gastric locations. High resolution pHmetry (12 sensors at 11 mm intervals) and manometry (36 sensors at 7.5 mm intervals) was performed fasted and after a standardised meal. The position of the squamocolumnar junction, marked with two endoscopically placed radio-opaque clips, was visualised radiologically relative to the probes. The biopsy specimens were scored for inflammation and stained with monoclonal antibody to H+/K+ATPase for counting parietal cell (PC) density. Results In the fasting period, at all sensors more than 1.1 cm below the peak LES pressure the median pH was less acidic in H. pylori positives (Table 1). After a meal, intragastric acidity was less in H. pylori positives compared to negatives at sensors 2.2 to 4.4 cm below the peak LES pressure (all p Median PC density (IQR) at mid-greater curve of gastric body was 233 (96) for H. pylori positives and 352 (76) for negatives (p Positive CagA status was associated with reduced intragastric acidity, but had no effect on PC density or mucosal inflammation when compared to CagA negative H. pylori positives. Conclusion The majority of H. pylori infected subjects have reduced intragastric acidity and PC density compared to the uninfected population and the reduction in acidity is most marked close to the GOJ. This may explain the negative association between H. pylori infection and both gastroesophageal reflux disease and oesophageal adenocarcinoma. Disclosure of Interest None Declared

A randomized, crossover pharmacodynamic study of immediate-release omeprazole/sodium bicarbonate and delayed-release lansoprazole in healthy adult volunteers.

Proton pump inhibitors (PPIs) effectively block gastric acid secretion and are the treatment of choice for heartburn. PPIs differ, however, in onset of action and bioavailability. In this single‐center, open‐label, three‐way crossover study, onset of action of immediate‐release omeprazole 20 mg/sodium bicarbonate 1100 mg (IR‐OME) and delayed‐release (DR) lansoprazole 15 mg was evaluated in 63 healthy fasting adults. Subjects were randomized to once daily IR‐OME, or DR‐lansoprazole, or no treatment for 7 days. The primary efficacy endpoint was the earliest time where a statistically significant difference was observed between IR‐OME and DR‐lansoprazole in median intragastric pH scores for three consecutive 5‐min intervals on day 7. Secondary endpoints compared effects of active treatments on days 1 and 7 (e.g., time to sustained inhibition, percentage of time with pH >4). A significant difference in median intragastric pH favoring IR‐OME was observed on day 7 starting at the 10‐ to 15‐min interval postdosing (P = 0.024) and sustaining through the 115‐ to 120‐min interval (P = 0.017). On day 1, IR‐OME achieved sustained inhibition of intragastric acidity significantly faster than DR‐lansoprazole. IR‐OME maintained pH >4 significantly longer than DR‐lansoprazole over a 24‐h period (P = 0.007) on day 7. Overall, results of this study demonstrate IR‐OME is safe and well tolerated and that treatment with IR‐OME results in significantly faster onset of action and better gastric acid suppression at steady state than DR‐lansoprazole.

619 In the Healthy Population, H. pylori Infected Subjects Have Less Intragastric Acidity and This Is Most Marked Close to the Gastroesophageal Junction

619 In the Healthy Population, H. pylori Infected Subjects Have Less Intragastric Acidity and This Is Most Marked Close to the Gastroesophageal Junction

PAI-1 deficiency increases the trophic effects of hypergastrinemia in the gastric corpus mucosa

The gastric hormone gastrin plays a role in organizing the gastric mucosa. Gastrin also regulates the expression of genes that have important actions in extracellular matrix modelling, including plasminogen activator inhibitor (PAI)-1 which is part of the urokinase plasminogen activator (uPA) system. The uPA system (including PAI-1) is associated with cancer progression, fibrosis and thrombosis. Its biological role in the stomach and molecular mechanisms of action are not well understood. The aim of this study was to examine the effect of PAI-1 on the trophic changes observed in gastric corpus mucosa in hypergastrinemia using PAI-1 and/or HK-ATPase beta subunit knockout (KO) mice. HK-ATPase beta subunit KO mice were used as a model of hypergastrinemia. In 12 month old female mice, intragastric acidity and plasma gastrin were measured. The stomachs were examined for macroscopic and histological changes. In mice null for both PAI-1 and HK-ATPase beta (double KO), there was exaggerated hypergastrinemia, increased stomach weight and corpus mucosal thickness, and more pronounced trophic and architectural changes in the corpus compared with HK-ATPase beta KO mice. Genome-wide microarray expression data for the gastric corpus mucosa showed a distinct gene expression profile for the HK-ATPase beta KO mice; moreover, enrichment analysis revealed changes in expression of genes regulating intracellular processes including cytoskeleton remodelling, cell adhesion, signal transduction and epithelial-to-mesenchymal transition (EMT). Genes differentially expressed in the double KO compared with HK-ATPase beta KO mice included the transcription factor Barx2 and the chromatin remodeler gene Tet2, which may be involved in both normal gastric physiology and development of gastric cancer. Based on the present data, we suggest that PAI-1 plays a role in maintaining gastric mucosal organization in hypergastrinemia.