Potassium-competitive Acid Blocker Research Articles

7-day versus 14-day tegoprazan-based triple therapy to treat Helicobacter pylori infection: Real-world evidence.

Potassium-competitive acid blockers (P-CABs) can be used to eradicate Helicobacter pylori infection. We aimed to evaluate the impact of treatment duration (7 vs 14days) on successful H. pylori eradication with P-CAB-based triple therapy in Korea, where clarithromycin resistance rate is high. We retrospectively reviewed the data of patients who received first-line treatment for H. pylori infection with tegoprazan-based triple therapy (50mg tegoprazan+1000mg amoxicillin+500mg clarithromycin twice daily for 1 or 2weeks). The primary endpoint was the eradication rate in intention-to-treat (ITT) analysis. Of the 948 patients included in the study, 435 and 513 received 7-day and 14-day tegoprazan-based triple therapy, respectively. The eradication rate was higher in the 14-day therapy group than in the 7-day therapy group (ITT, 63.9%; 95% confidence interval [CI], 59.3-68.3%] vs 78.6% [95% CI, 74.9-81.9%], respectively, P<0.001; per-protocol, 70.5% [95% CI, 65.8-74.8%] vs 85.1% [81.7-88.1%], respectively, P<0.001). Overall adverse event rates did not differ between the two groups. Although six patients in the 14-day treatment group discontinued the prescribed medications due to adverse events, four of them (67%) discontinued the medication within 4days. The 14-day tegoprazan-based triple therapy showed a superior eradication rate and acceptable adverse events compared with the 7-day tegoprazan-based triple therapy. A 14-day treatment regimen may be required when H. pylori infection is treated with tegoprazan-based triple therapy in regions with high clarithromycin resistance.

Triple Therapy-Based on Tegoprazan, a New Potassium-Competitive Acid Blocker, for First-Line Treatment of Helicobacter pylori Infection: A Randomized, Double-Blind, Phase III, Clinical Trial

Background/AimsWe examined the efficacy and safety of tegoprazan as a part of first-line triple therapy for Helicobacter pylori eradication.MethodsA randomized, double-blind, controlled, multicenter study was performed to evaluate whether tegoprazan (50 mg)-based triple therapy (TPZ) was noninferior to lansoprazole (30 mg)-based triple therapy (LPZ) (with amoxicillin 1 g and clarithromycin 500 mg; all administered twice daily for 7 days) for treating H. pylori. The primary endpoint was the H. pylori eradication rate. Subgroup analyses were performed according to the cytochrome P450 (CYP) 2C19 genotype, the minimum inhibitory concentration (MIC) of amoxicillin and clarithromycin, and underlying gastric diseases.ResultsIn total, 350 H. pylori-positive patients were randomly allocated to the TPZ or LPZ group. The H. pylori eradication rates in the TPZ and LPZ groups were 62.86% (110/175) and 60.57% (106/175) in an intention-to-treat analysis and 69.33% (104/150) and 67.33% (101/150) in a per-protocol analysis (non-inferiority test, p=0.009 and p=0.013), respectively. Subgroup analyses according to MICs or CYP2C19 did not show remarkable differences in eradication rate. Both first-line triple therapies were well-tolerated with no notable differences.ConclusionsTPZ is as effective as proton pump inhibitor-based triple therapy and is as safe as first-line H. pylori eradication therapy but does not overcome the clarithromycin resistance of H. pylori in Korea (ClinicalTrials.gov identifier NCT03317223).

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.

Vonoprazan-associated nephrotoxicity: extensive real-world evidence from spontaneous adverse drug reaction reports

Vonoprazan-associated nephrotoxicity: extensive real-world evidence from spontaneous adverse drug reaction reports

Hypercontractile esophagus responsive to potassium-competitive acid blockers: a case report

BackgroundHypercontractile esophagus is a rare hypercontractile esophageal motility disorder. The etiology of hypercontractile esophagus is unknown but an association between acid reflux and hypercontractile esophagus has been suggested. We present the first report on the use of potassium-competitive acid blockers in the treatment of hypercontractile esophagus.Case presentationA 43-year-old man presented with dysphagia, chest pain and regurgitation for a period of 1 year. Initial workup showed a twisted lumen with abnormal contractions in the distal esophagus during upper gastrointestinal endoscopy and abnormal acid exposure under 24-h esophageal pH monitoring. The use of standard-dose proton pump inhibitors didn’t relieve his symptoms. Subsequent high-resolution esophageal manometry made a diagnosis of hypercontractile esophagus. Treatment with vonoprazan resulted in symptomatic resolution and abnormal contractions were no longer detected on follow-up high-resolution manometry.ConclusionsPotassium-competitive acid blockers like vonoprazan offer an alternative therapeutic method for patients with hypercontractile esophagus who are refractory to proton pump inhibitor therapy. The use of potassium-competitive acid blockers in hypercontractile esophagus warrants further research and may provide evidence for an acid-related etiology of hypercontractile esophagus.

Trends in proton pump inhibitor use, reflux esophagitis, and various upper gastrointestinal symptoms from 2010 to 2019 in Japan.

The increasing usage of proton pump inhibitors (PPIs) has been reported worldwide, but information on PPI use in East Asia is inadequate. This study aimed to examine the trends in PPI use in Japan, along with the changes in histamine H2 receptor antagonist (H2RA) use, disease rate of reflux esophagitis, and the prevalence of upper gastrointestinal symptoms. We analyzed 217,712 healthy subjects (127,607 men and 90,105 women; 51.4 ± 9.7 years old) participating in the health check program from 2010 to 2019. Various upper gastrointestinal symptoms were evaluated using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) questionnaire. Reflux esophagitis was diagnosed by esophageal erosion using the Los Angeles classification grades A, B, C, and D. From 2010 to 2019, the percentage of PPI users increased markedly from approximately 1.8% to 5.3%, whereas that of H2RA users decreased gradually from approximately 2.5% to 1.9%. The use of all classical types of PPIs (omeprazole, lansoprazole, rabeprazole, and esomerazole) and a new type of PPI, a potassium-competitive acid blocker (vonoprazan), greatly increased during the 10 years. An upward trend in the prevalence of reflux esophagitis was observed from 2010 to 2015, but not from 2016 to 2019, indicating that the monotonic rising prevalence of reflux disease stopped in the middle of the 2010s in Japan. In contrast, various upper gastrointestinal symptoms significantly improved between 2010 and 2019. All 12 FSSG symptoms of PPI users were significantly worse than those of non-PPI users, suggesting that PPIs still cannot completely control upper gastrointestinal symptoms. In conclusion, this study revealed a significant increase in PPI use and a slight decrease in H2RA use from 2010 to 2019. Despite a plateau in the prevalence of reflux esophagitis and considerable improvement in various upper gastrointestinal symptoms, PPI use has continued to increase in Japan.

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.

Ultra-Sensitive Fluorimetric Method for the First Estimation of Vonoprazan in Real Human Plasma and Content Uniformity Test

Vonoprazan (VON) has been approved recently via US-FDA in 2015 as the first in class of potassium competitive acid blocker group. VON is used for management of GIT ulcer, reflux esophagitis and for eradication of Helicobacter pylori. So, the first spectrofluorimetric method was developed for estimation of VON in real human plasma and content uniformity test. The fluorimetric methodology based on reaction of secondary amine group in VON with benzofurazan (0.05% w/v NBD-Cl) reagent as nucleophilic substitution reaction in alkaline medium (0.1 M borate buffer pH 8.2) to produce highly fluorescent product measure at 530 nm after excitation at 465 nm. The linear calibration range was found 15 to 200 ng mL−1 with lower limit of quantitation (LOQ) equal to 8.57 ng mL−1. The method was successfully applied for estimation of VON in pharmacokinetic (PK) and content uniformity studies. The maximum plasma concentration was found to be (Cmax) 71.03 ng mL−1 after maximum time (tmax) equal to 1.5 ± 0.15 h. The presented strategy also applied to ensure concentration of drug in each tablet using content uniformity test with high percent of recovery 100.05 ± 0.66. The proposed method was established for clinical laboratories and therapeutic drug monitoring studies.

Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial

Background & aimsNovel, effective treatments for Helicobacter pylori infection are needed. This study evaluated the efficacy of vonoprazan, a potassium-competitive acid blocker, vs standard treatment on H pylori eradication in the United States and Europe. MethodsIn a randomized, controlled, phase 3 trial, treatment-naïve adults with H pylori infection were randomized 1:1:1 to open-label vonoprazan dual therapy (20 mg vonoprazan twice daily; 1 g amoxicillin 3 times daily), or double-blind triple therapy twice a day (vonoprazan 20 mg or lansoprazole 30 mg; amoxicillin 1 g; clarithromycin 500 mg) for 14 days. The primary outcome was noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains (noninferiority margin = 10%). Secondary outcomes assessed superiority in eradication rates in clarithromycin-resistant infections, and in all patients. ResultsA total of 1046 patients were randomized. Primary outcome eradication rates (nonresistant strains): vonoprazan triple therapy 84.7%, dual therapy 78.5%, vs lansoprazole triple therapy 78.8% (both noninferior; difference 5.9%; 95% confidence interval [CI], −0.8 to 12.6; P < .001; difference –0.3%; 95% CI, −7.4 to 6.8; P = .007, respectively). Eradication rates in clarithromycin-resistant infections: vonoprazan triple therapy 65.8%, dual therapy 69.6%, vs lansoprazole triple therapy 31.9% (both superior; difference 33.9%; 95% CI, 17.7–48.1; P < .001; difference 37.7%; 95% CI, 20.5–52.6; P < .001, respectively). In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5%, difference 12.3%; 95% CI, 5.7–18.8; P < .001; difference 8.7%; 95% CI, 1.9–15.4; P = .013). Overall frequency of treatment-emergent adverse events was similar between vonoprazan and lansoprazole regimens (P > .05). ConclusionBoth vonoprazan-based regimens were superior to proton pump inhibitor–based triple therapy in clarithromycin-resistant strains and in the overall study population. ClinicalTrials.gov; NCT04167670.

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.

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, &lt;i&gt;Helicobacter pylori&lt;/i&gt; 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.