Potassium-competitive Acid Blocker Research Articles

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.

Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump.

As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K+-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases.

Mucoprotectants

The gastric mucosa is constantly exposed to gastric acid and pepsin. Moreover, various factors, such as nonsteroidal anti-inflammatory drugs, <i>Helicobacter pylori</i> infection, ethanol, stress, and aging, can damage the gastrointestinal mucosa. Nevertheless, even under these harsh conditions, the gastric mucosa is structurally maintained by various processes, referred to as “defense mechanisms.” Mucosal defense mechanisms are complicated; however, the most important elements are known to be the gastric epithelium and mucus layer, which are stimulated by prostaglandins and nitric oxide. Peptic ulcers result from an imbalance between these aggressive and defensive factors. Methods to prevent or treat peptic ulcers can be classified into two classes: 1) inhibition of gastric acid secretion and 2) promotion of mucosal defense factors. Drugs that reduce gastric acid secretion include proton pump inhibitors, histamine H2 antagonists, and potassium-competitive acid blockers. Mucoprotectants prevent peptic ulcers by promoting peptic ulcer healing. Mucoprotectants can work by two main mechanisms of action; one is independent of prostaglandins, and the other is related to prostaglandin activity. Bismuth, sucralfate, and misoprostol have been traditionally used to protect the gastric mucosa from gastric acid and pepsin. Currently, several mucoprotectants, such as rebamipide, ecabet sodium, polaprezinc, teprenone, and DA-9601, are prescribed in clinical practice. This review aims to provide information to clinicians by examining the characteristics of each drug, including their mechanism of action, research results, effective dose, and side effects.

The efficacy and safety of keverprazan, a novel potassium-competitive acid blocker, in treating erosive oesophagitis: a phase III, randomised, double-blind multicentre study.

Keverprazan is a novel potassium-competitive acid blocker (P-CAB) with a strong acid-suppressive capacity that may provide clinical benefit in acid-related diseases. This study aimed to explore the non-inferior efficacy and safety of keverprazan to lansoprazole in treating erosive oesophagitis (EO). This was a phase III, randomised, double-blind multicentre study. Patients were randomised to receive keverprazan 20 mg once daily or lansoprazole 30 mg once daily for 4-8 weeks. EO healing rates and adverse events (AEs) were compared between the keverprazan group and the lansoprazole group. A total of 238 patients comprised the full analysis set (FAS) while 221 patients comprised the per-protocol set (PPS). For FAS analysis, the EO healing rates at week 8 were 95.8% (114/119) and 89.9% (107/119) for keverprazan and lansoprazole respectively. For PPS analysis, the EO healing rates at week 8 were 99.1% (110/111) and 92.7% (102/110) for keverprazan and lansoprazole respectively. Non-inferiority of keverprazan compared with lansoprazole according to EO healing rates at 8 weeks was demonstrated in both FAS (difference: 5.8% [95% CI: -0.6% to 12.3%]; p= 0.081) and PPS (difference: 6.1% [95% CI: 1.1%-11.2%]; p= 0.018) analysis. Drug-related AEs were reported in 34.5% (41/119) patients of the keverprazan group and 25.2% (30/119) patients of the lansoprazole group with no significant difference (p= 0.156). No severe AE happened in the keverprazan group. This study demonstrated the non-inferior efficacy of keverprazan to lansoprazole in treating EO. The incidences of drug-related AEs were comparable between keverprazan and lansoprazole.

MP03-12 ASSOCIATION OF USE OF POTASSIUM COMPETITIVE ACID BLOCKERS AND EFFECTIVENESS OF PEMBROLIZUMAB IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA

You have accessJournal of UrologyCME1 May 2022MP03-12 ASSOCIATION OF USE OF POTASSIUM COMPETITIVE ACID BLOCKERS AND EFFECTIVENESS OF PEMBROLIZUMAB IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA Wataru Fukuokaya, Takahiro Kimura, Kazumasa Komura, Taizo Uchimoto, Kazuki Nishimura, Yu Oyama, Hirokazu Abe, Haruhito Azuma, Jun Miki, and Shin Egawa Wataru FukuokayaWataru Fukuokaya More articles by this author , Takahiro KimuraTakahiro Kimura More articles by this author , Kazumasa KomuraKazumasa Komura More articles by this author , Taizo UchimotoTaizo Uchimoto More articles by this author , Kazuki NishimuraKazuki Nishimura More articles by this author , Yu OyamaYu Oyama More articles by this author , Hirokazu AbeHirokazu Abe More articles by this author , Haruhito AzumaHaruhito Azuma More articles by this author , Jun MikiJun Miki More articles by this author , and Shin EgawaShin Egawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002515.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Evidence showed that proton pump inhibitor use was associated with worse survival of patients with metastatic urothelial carcinoma (UC) treated with pembrolizumab. Potassium competitive acid blocker (P-CAB) is a new class of acid blockers which has distinct advantages compared to other conventional proton pump inhibitors (PPI) in terms of the effectiveness for acid suppression. However, the impact of its use on the effectiveness of pembrolizumab in these patients is still unclear. We investigated the impact of P-CAB use on the effectiveness of pembrolizumab in patients with metastatic UC. METHODS: We retrospectively analyzed the records of 227 patients with metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) per immune response evaluation criteria in solid tumors were also compared. Multivariable Cox regression models were performed to evaluate the association between P-CAB use and these outcomes. RESULTS: Overall, 30 (13.2%) and 56 (24.7%) patients used P-CABs and PPIs, respectively. Median follow-up period of was 12.8 months (95% CI: 10.6 to 19.3). There were significant differences in baseline platelet count (median; P-CAB users vs. PPI users vs. non-users: 292.5 vs. 271 vs. 249 *1000/uL; P=0.047) and the use of concomitant analgesics (P-CAB users vs. PPI users vs. non-users: 22 [73.3%] vs. 28 [50.0%] vs. 38 [27.0%]; P <0.001). Multivariable Cox regression models showed that both P-CAB and PPI use were associated with worse OS (P-CAB, hazard ratio [HR]: 2.51, 95% confidence interval [CI]: 1.44 to 4.38, P=0.001; PPI, HR: 1.58, 95% CI: 0.96 to 2.61, P=0.072) and iPFS (P-CAB, HR: 1.79, 95% CI: 1.12 to 2.86, P=0.015; PPI, HR: 1.56, 95% CI: 1.07 to 2.28, P=0.021). CONCLUSIONS: Similar to PPI, P-CAB use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e24 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wataru Fukuokaya More articles by this author Takahiro Kimura More articles by this author Kazumasa Komura More articles by this author Taizo Uchimoto More articles by this author Kazuki Nishimura More articles by this author Yu Oyama More articles by this author Hirokazu Abe More articles by this author Haruhito Azuma More articles by this author Jun Miki More articles by this author Shin Egawa More articles by this author Expand All Advertisement PDF DownloadLoading ...

Application of Heterocycles as an Alternative for the Discovery of New Anti-ulcer Compounds: A Mini-Review.

A peptic ulcer is a lesion located in the esophagus, stomach, and upper intestine, caused by an imbalance between acid secretion and the release of protective mucus. This pathology is prevalent in approximately 14% of the world population and is commonly treated with proton pump inhibitors and type 2 histaminergic receptor antagonists, however, these drugs present concerning side effects that may lead to gastric cancer. In this sense, this research aimed to present the main heterocyclics studied in recent years. The screening method for the choice of articles was based on the selection of publications between 2000 and 2021 present in the Science Direct, Web of Science, Capes, and Scielo databases, by using the descriptors ''new derivatives'', "heterocyclics" "antiulcerogenic", "gastroprotective" and "antisecretor". This research showed that the most used rings in the development of anti-ulcer drugs were benzimidazole, quinazoline, thiazole, and thiadiazole. The results also portray several types of modern in silico, in vitro and in vivo assays, as well as the investigation of different mechanisms of action, with emphasis on proton pump inhibition, type 2 histaminergic receptor blockers, potassium competitive acid blockers, type E prostaglandin agonism, anti-secretory activity and anti-oxidant action. Additionally, the review evidenced the presence of the nitrogen atom in the heterocyclic ring as a determinant of the potential of the compound. This research suggests new alternatives for the treatment of gastric lesions, which may be more potent and cause fewer side effects than the currently used, and tend to evolve into more advanced studies in the coming years.

Network Meta-analysis Comparing Vonoprazan and Proton Pump Inhibitors for Heartburn Symptoms in Erosive Esophagitis.

This systematic review and network meta-analysis aimed to assess the relative efficacy of vonoprazan and proton pump inhibitors (PPIs) on early heartburn symptom resolution in patients with erosive esophagitis. Limited available data directly compare the efficacy of vonoprazan, a first-in-class potassium-competitive acid blocker, with PPIs in erosive esophagitis. We conducted a systematic literature review (in MEDLINE and CENTRAL) and subsequent network meta-analysis according to Cochrane and PRISMA guidelines. Double-blind, randomized controlled trials in adults with erosive esophagitis treated with vonoprazan or a PPI were included in the analysis. Primary outcomes were heartburn symptom resolution rate on Day 1 and Day 7. The study was performed with all available data, using a random effects model within a Bayesian framework. Overall, 10 randomized controlled trials were included in the network meta-analysis. For heartburn resolution rate on Day 1 (9 of 10 trials), vonoprazan 20 mg once daily (QD) was superior to placebo (median odds ratio=16.75, 95% credible interval: 2.16-207.80). Point estimates numerically favored vonoprazan 20 mg QD over other comparators. For heartburn resolution rate on Day 7 (10 of 10 trials), vonoprazan 20 mg QD was superior to placebo and other comparators except rabeprazole 20 mg QD. Point estimates numerically favored vonoprazan 20 mg QD over rabeprazole 20 mg QD. In this study, vonoprazan 20 mg QD was equally effective in heartburn resolution on Day 1, and equally or more effective on Day 7 versus PPIs in adults with erosive esophagitis.

Design, synthesis and biological evaluation of novel 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives as potent potassium-competitive acid blockers

With the aim to discover a novel potent potassium-competitive acid blocker (P-CAB) agent, a series of 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4–c]pyrazole derivatives were synthesized, and their H+/K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 3′-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4–c]pyrazol-2(4H)-yl)methyl)-[1,1′-biphenyl]-3-carboxamide not only exhibited potent H+/K+-ATPase inhibitory activity but olso showed potent inhibitory action in vivo on histamine-stimulated gastric acid secretion. In addition, the lead compound displayed favourable oral pharmacokinetic properties in rats, which was worthy of further study as a novel P-CAB agent.

Cost-effectiveness analysis of vonoprazan versus proton pump inhibitors in the treatment of reflux esophagitis in China.

BackgroundProton pump inhibitors (PPIs) have been recommended as standard of care for reflux esophagitis (RE). Vonoprazan (VPZ), a novel potassium-competitive acid blocker (P-CAB), has been approved in China after demonstrating clinical benefit in RE. However, there are not any published literature reported the cost-effectiveness of VPZ compared with PPI in Chinese healthcare setting. Thus, this study aimed to estimate the cost-effectiveness of VPZ compared with PPIs for the treatment of RE patients in China and take advantage of this result to inform healthcare decision-making.MethodsA Markov model was developed to predict the effectiveness and costs of VPZ for 4 weeks and PPI group for 8 weeks in RE treatment over a 5-year time horizon from a healthcare system perspective. Four health states within healing and maintenance phases were defined in the model: mucosa healed, mucosa unhealed, relapse, and death. Transition probabilities including healing rate and relapse rate were derived from a single-arm meta-analysis and mortality were obtained from Chinese life table. Drug costs and other medical expenses were retrieved from China tendering prices and local clinical expert estimation. Utility parameters were derived from published literature. Both health outcomes and costs were discounted at a rate of 5% annually. Quality-adjusted life years (QALYs), direct medical costs and incremental cost-effectiveness ratios were evaluated. Uncertainty was assessed by one-way and probabilistic sensitivity analysis (PSA).ResultsThe healing rate for VPZ and PPI were 90% (95% CI: 82–97%) and 74% (95% CI: 71–76%) at week 4 respectively and were 94% (95% CI: 88–99%) and 87% (95% CI: 85–88%) at week 8 respectively. Treatment with VPZ resulted in 4.35 QALYs at a total cost of USD 1,354 over 5 years. Compared with the PPI group, treating RE with VPZ was associated with 0.02 QALYs gained and a cost saving of USD 943. Thus, VPZ should be considered as the dominant treatment option. The model results were deemed robust in sensitivity analyses.ConclusionsVPZ generates incremental QALYs at a lower cost compared with PPI, thus could be considered as an optional choice in the treatment of patients with RE.

Health Care Cost Analysis of PPI or P-CAB-First Treatment in Patients With Gastroesophageal Reflux Disease.

The aim was to examine actual health care cost in patients with gastroesophageal reflux disease (GERD) who were initiated on proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) as first-line therapy in Japanese real-world clinical settings. To date, cost-utility evaluation of acid-suppressants treatment in Japan has only been conducted by model analysis. A cost utilization analysis was performed using a Japanese nationwide hospital-based claim database by extracting patients with GERD initiated on either PPI or P-CAB (242,102 pairs) and esomeprazole (EPZ) or P-CAB (241,825 pairs). Health care costs were compared in each comparison cohort with propensity-score matched pairs. The switching rates of initial acid-suppressants were also examined. Baseline characteristics were well-balanced after matching. The 3-year mean cumulative GERD-related and hospitalization costs per patient were ¥142,620 and ¥122,444 in PPI-first and P-CAB-first treatment groups, and ¥105,263 and ¥121,958 in EPZ-first and P-CAB-first treatment groups, respectively. Most hospitalization costs were non-GERD related in all the groups. The switching rates of PPI to P-CAB and P-CAB to PPI in 12 months were 7.5% and 20.2%, respectively. In this propensity-score matched analysis, health care cost was higher in patients with GERD initiated on PPI than in those initiated on P-CAB mainly owing to non-GERD-related hospitalization cost, whereas it was lower in those initiated on EPZ than in those initiated on P-CAB. When considering health care costs except hospitalization costs, PPI-first treatment was less expensive than P-CAB-first treatment. Low switching rate from PPI to P-CAB in the real-world practice may partially explain the discrepancy.

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.

Fertility and early embryonic development toxicity and toxicokinetic study of KFP-H008 in Sprague-Dawley rats.

The novel potassium competitive acid blocker, KFP-H008, developed to overcome the shortcomings of proton pump inhibitors. In this study, KFP-H008 was administered by oral gavage at doses of 0 (control), 15, 45, and 150 mg/kg to Sprague-Dawley rats (24 animals per sex per group). Body weight, food consumption, mortality, sexual cycle, mating behavior, pregnancy, sperm motility, and relative organ weights were evaluated. In a concomitant toxicokinetic (TK) study (10 animals per sex per group), plasma TK parameters and tissue distribution of KFP-H008 were tested. There were obvious effects at the dosage of 150 mg/kg to male rats with decreases of prostate weight and lower weight gain; to female rats with lower weight gain, hair off, and lower corpus luteum count. There were no effects on litter parameters. Time to reach maximum plasma concentrations for KFP-H008 was between 0.5 and 1.0hr for the 15 and 45 mg/kg groups, while for the 150 mg/kg group it had a delay to 2hr. Overall, the NOAEL of KFP-H008 was considered to be 45 mg/kg in both genders and the TK study shows that exposure (area under the curve) of male rats was about 1,091.0 ± 530.8μg/Lhr and to female rats was 1,030.5 ± 512.5μg/Lhr. Administration of KFP-H008although reaches the reproductive organs, it demonstrated no significant effects on reproductive organs, it did not affect mating, fertility, pregnancy, growth, or morphologic development.

Night-time gastric acid suppression by tegoprazan compared to vonoprazan or esomeprazole.

AimsNocturnal acid breakthrough has been considered an unmet need of proton‐pump inhibitors. Tegoprazan, a novel potassium‐competitive acid blocker, is expected to show improved properties for this unmet need. This study was aimed to compare night‐time acid suppression by tegoprazan with that by vonoprazan or esomeprazole, and to explore the effect of CYP2C19 phenotypes on acid‐suppressive effects.MethodsA randomized, open‐label, 3‐period, 6‐sequence crossover study was conducted. A single oral dose of tegoprazan 50 mg, vonoprazan 20 mg or esomeprazole 40 mg was administered at night in each period. Continuous intragastric pH was monitored at baseline and after each dosing.ResultsSixteen healthy subjects (6 CYP2C19 extensive metabolizers, 5 intermediate metabolizers, 5 poor metabolizers) completed the study. After a single dose of tegoprazan, intragastric pH increased more rapidly to over 4 at approximately 1 hour compared to the other treatments, and elevated intragastric pH was maintained stably at night. Tegoprazan exhibited night‐time acid suppression for slightly but not significantly longer than vonoprazan, and greater than esomeprazole; % time at pH ≥ 4 at night was 66.0%, 60.5% and 36.1% for tegoprazan, vonoprazan and esomeprazole, respectively. Night‐time acid suppression by tegoprazan and vonoprazan was not dependent on CYP2C19 phenotypes, while that by esomeprazole tended to be influenced by CYP2C19 phenotypes.ConclusionTegoprazan produced more rapid, potent and well sustained night‐time acid suppression vs. vonoprazan or esomeprazole when administered at night. Furthermore, tegoprazan showed no CYP2C19 phenotype dependency in acid suppression. It suggests the potential of tegoprazan, especially in preventing nocturnal acid breakthrough.

Novel Cocrystals of Vonoprazan: Machine Learning-Assisted Discovery.

Vonoprazan (VPZ) is the first-in-class potassium-competitive acid blocker (P-CAB), and has many advantages over proton pump inhibitors (PPIs). It is administered as a fumarate salt for the treatment of acid-related diseases, including reflux esophagitis, gastric ulcer, and duodenal ulcer, and for eradication of Helicobacter pylori. To discover novel cocrystals of VPZ, we adopted an artificial neural network (ANN)-based machine learning model as a virtual screening tool that can guide selection of the most promising coformers for VPZ cocrystals. Experimental screening by liquid-assisted grinding (LAG) confirmed that 8 of 19 coformers selected by the ANN model were likely to create new solid forms with VPZ. Structurally similar benzenediols and benzenetriols, i.e., catechol (CAT), resorcinol (RES), hydroquinone (HYQ), and pyrogallol (GAL), were used as coformers to obtain phase pure cocrystals with VPZ by reaction crystallization. We successfully prepared and characterized three novel cocrystals: VPZ–RES, VPZ–CAT, and VPZ–GAL. VPZ–RES had the highest solubility among the novel cocrystals studied here, and was even more soluble than the commercially available fumarate salt of VPZ in solution at pH 6.8. In addition, novel VPZ cocrystals had superior stability in aqueous media than VPZ fumarates, demonstrating their potential for improved pharmaceutical performance.

A Population Pharmacokinetic Model of Vonoprazan: Evaluating the Effects of Race, Disease Status, and Other Covariates on Exposure.

Vonoprazan, a potassium‐competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed‐effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non‐Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non‐Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non‐Asian populations.

A study for every second day administration of vonoprazan for maintenance treatment of erosive GERD (ESD von GERD): a multicenter randomized cross-over study.

Vonoprazan is a potassium competitive acid blocker used to treat erosive gastroesophageal reflux disease (GERD) with stronger, more stable acid-suppressing effects than proton pump inhibitors (PPIs). This study clarified the usefulness and superiority of vonoprazan administered every second day over PPIs in the maintenance therapy of erosive GERD. This is a prospective, multicenter, open-label, two-period randomized cross-over study. Patients were randomized to either the vonoprazan-lansoprazole (VP-LZ) group, who were given vonoprazan 10mg for the first 4weeks and then lansoprazole 15mg for the next 4weeks both administered once every second day, or the lansoprazole-vonoprazan (LZ-VP) group, who were treated in reverse. GERD symptoms were compared using symptom diaries, the frequency scale for symptoms of GERD (FSSG), and the gastrointestinal symptom rating scale (GSRS). We enrolled 122 patients between December 2017 and May 2019. Symptoms were well controlled in vonoprazan administration and lansoprazole administration were 93.6% and 82.1%, respectively, with a significant difference on McNemar's test (P = 0.003). During the second 4weeks, 94.4% and 76.7% of patients in the VP-LZ and LZ-VP groups, respectively, were well controlled following for ≥ 6 consecutive days a week (P = 0.009). During the first 4weeks, 96.7% and 80.0% of patients were well controlled with < 1 weekly in the VP-LZ and LZ-VP groups, respectively, during the first 4weeks (P = 0.007). GERD symptoms, assessed via FSSG and GSRS, significantly decreased with vonoprazan administration once every second day. Vonoprazan administered once every second day could be an effective alternative to PPIs in the maintenance treatment of erosive GERD (UMIN000030393).

Serum Gastrin and Pepsinogen Levels after Administration of Acid Secretion Inhibitors for Ulcers due to Endoscopic Submucosal Dissection in Patients with Early Gastric Cancer.

Acid secretion inhibitors, such as proton pump inhibitors (PPIs) and potassium competitive acid blockers (PCABs), are used to treat ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer. These drugs can influence serum gastrin and pepsinogen (PG) levels; however, their definite effects remain unclear. This open-label, randomized study investigated the effect of acid secretion inhibitors on the serum gastrin and pepsinogen levels. In total, 76 patients were enrolled in the study. They underwent gastric ESD and received a PPI (n = 21) or PCAB (n = 55). Changes in the serum gastrin and PG levels before and 4 weeks after administration were examined. Patient factors associated with the alteration of serum PG or gastrin levels were identified. The median serum levels of gastrin, PGI, and PGII before the administration of the acid secretion inhibitors were 110.5 pg/mL, 36.4 ng/mL, and 8.9 ng/mL, respectively; after administration, the levels increased to 300 pg/mL, 64.7 ng/mL, and 15.8 ng/mL, respectively (P < 0.01). Univariate analysis revealed that PCABs led to a more significant increase in the serum gastrin and PG levels as compared to PPIs. Furthermore, the PG levels were significantly increased in patients with previous Helicobacter pylori infections than in those with current infections. In conclusion, the serum gastrin and PG levels increased after the use of acid secretion inhibitors. This elevation was affected by the type of drug used, whereas the elevation in PGs was affected by the patient's background as well.

Potassium-competitive acid blockers, a new therapeutic class, and their role in acid-related diseases: a narrative review.

A new therapeutic class, potassium-competitive acid blockers (P-CABs), has emerged in Brazil to promote a superior antisecretory effect addressing the unmet needs related to acid-related disease management. Vonoprazan fumarate showed a good safety profile and was approved by the Brazilian regulatory agency - ANVISA. This narrative review was conducted to review the general concepts regarding P-CABs, focussing on vonoprazan fumarate. A literature search was conducted through April-May 2021 using official databases with a combination of MeSH controlled vocabulary and text words. The authors selected articles that described pivotal and novel insights about P-CABs and vonoprazan fumarate. Vonoprazan is a drug of the P-CABs class newly approved for the management of acid-related diseases in Brazil. P-CABs achieve rapid, potent, and prolonged acid suppression (including night-time) and promise to address some unmet clinical needs in GERD. Furthermore, considering the difficulties encountered in attaining effective symptomatic control - particularly at night - using currently available PPIs, this new drug class is promising. This review brings important information about vonoprazan, a new therapeutic option in Brazil, which may be considered as a valuable tool for managing acid-related diseases.

Potassium-Competitive Acid Blocker and Proton Pump Inhibitor-Based Regimens for First-Line Helicobacter pylori Eradication: A Network Meta-Analysis.

Effective acid suppression is a crucial component of Helicobacter pylori (H.pylori) eradication regimens. Approved treatments include dual, triple, and quadruple therapies composed of certain antibiotics in combination with proton pump inhibitors (PPIs). Vonoprazan, a potassium-competitive acid blocker, provides more potent and durable acid suppression than PPIs. We compared the efficacy of vonoprazan-based therapies vs approved standard regimens using new evidence from the phase 3 pHalconHP trial in North America and Europe. Studies reporting first-line H.pylori eradication rates from empiric treatment with Food and Drug Administration-approved therapies and vonoprazan-containing therapies were identified via bibliographic searches of systematic literature reviews and a subsequent MEDLINE/Embase search using index terms for H.pylori and eradication. Randomized controlled trials comparing 2 or more relevant comparators were included in Bayesian network meta-analyses for grouped and distinct therapies. Twenty-three distinct regimens from 42 trials including 12,773 patients were identified. Vonoprazan-based triple therapy showed the highest relative efficacy (odds ratio: 2.73, 95% credible interval 2.11, 3.54) and 72.1% probability of being the best. North American, Western, and global scenarios were largely consistent. Vonoprazan-based therapies demonstrated higher odds of H.pylori eradication than each PPI-based triple therapy. Furthermore, vonoprazan-based triple therapy was superior to bismuth subcitrate quadruple therapy (odds ratio: 1.60, 95% credible interval: 1.07, 2.38). Vonoprazan-based eradication regimens represent novel treatments for H.pylori infection on a global scale, offering efficacy that, in this analysis, is superior to PPI-based triple therapy and comparable or better than bismuth quadruple therapy.

Vonoprazan vs. Lansoprazole for the treatment of endoscopic submucosal dissection induced gastric ulcer: a systematic review and meta-analysis.

Vonoprazan is a potassium competitive acid blocker (P-CAB) approved in Japan in 2014 to treat endoscopic submucosal dissection (ESD)-induced ulcers and bleeding or perforation. Therefore, this meta-analysis aimed to determine whether Vonoprazan is more effective than Lansoprazole in the treatment of ESD-induced ulcers which include ulcer healing and shrinking rate, among others. Randomized controlled trials (RCT) and retrospective studies were collected from the PubMed (Medline), Embase, Web of science and Cochrane Library databases. Meanwhile, studies were selected according to predetermined qualification criteria and data were extracted by two researchers. The quality of the methods for published papers was evaluated using the modified Jadad scale. Five studies were included in this meta-analysis, the ulcer healing rate effect was not significantly higher in the intervention groups than in the control groups at 4 weeks, [OR：1.07 (0.51, 2.22), 95% CI, I2=2%, Z=0.18, P=0.86]. There was no significant difference in the ulcer shrinkage rate at 4 weeks [MD：0.20 (-1.51, 1.92), 95% CI, I2=0%, P=0.82] and 8 weeks [MD: -0.09 (-0.30, 0.12), 95% CI, I2=0%, P=0.39]. There was no significant difference between Vonoprazan and Lansoprazole in the ulcers induced by treatment after 4 weeks and 8 weeks of treatment with ESD.