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Introduction: The concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) potentially increases the risk of acute kidney injury (AKI). However, the risk of AKI has not been comprehensively assessed for the concomitant use of NSAIDs with gastroprotective agents such as misoprostol and PPIs. The objective of this study was to evaluate whether the use of various gastroprotective agents affects the risk of AKI in patients receiving NSAIDs., Methods: The data analyzed were obtained from the JMDC hospital-based administrative claims database between April 2014 and August 2022. Histamine-2 receptor antagonists (H2RAs) were compared with PPIs or misoprostol in patients receiving NSAIDs. The primary outcome was the incidence of AKI. The covariates considered were age and sex, admission to intensive care unit, presence of comorbidities based on the modified Charlson Comorbidity Index, and use of renin-angiotensin system inhibitors, loop diuretics, other diuretics, and lithium. AKI was identified by changes in serum creatinine. The distribution of AKI was analyzed using the log-rank test, and estimates of the incidence of AKI were compared among the groups using a Cox proportional hazards model with time-varying variables. Models were adjusted using a doubly robust method that accounts for the inverse probability of treatment weighting at baseline while adjusting for covariates., Results: After screening, 11,688 patients were eligible for inclusion (1729 for H2RAs, 368 for misoprostol, and 9591 for PPIs). AKI occurred in 0.5% of H2RA recipients and 1.1% of PPI recipients; no AKI was observed in the misoprostol group. Compared with H2RAs, the risk of AKI tended to be higher with PPIs (adjusted hazard ratio 1.83, 95% confidence interval 0.92-3.63, p = 0.08)., Conclusion: Compared with H2RAs, PPIs may increase the risk of AKI in patients receiving NSAIDs, although no statistically significant difference was observed. Further research is required to assess the risk trade-off with consideration of both peptic ulcer prevention and the increased risk of AKI in patients concurrently treated with NSAIDs and H2RAs, misoprostol, or PPIs., (© 2024 The Author(s). Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Objectives: To determine whether concomitant use of ceftriaxone and oral or intravenous lansoprazole increases the risk of ventricular arrhythmia and cardiac arrest in the real-world setting in Japan., Methods: The data analyzed were obtained from the JMDC hospital-based administrative claims database for the period April 2014 to August 2022. Patients who received a proton pump inhibitor (PPI) while receiving ceftriaxone or sulbactam/ampicillin were identified. The frequency of ventricular arrhythmia and cardiac arrest was analyzed according to whether oral or intravenous PPI was concomitant with ceftriaxone or sulbactam/ampicillin. Estimates of the incidence of ventricular arrhythmia and cardiac arrest were then compared among the groups, using the Fine-Gray competing risk regression model., Results: The results showed that the risk of ventricular arrhythmia and cardiac arrest was significantly higher with concomitant ceftriaxone and oral lansoprazole (hazard ratio 2.92, 95% confidence interval 1.99-4.29, P < 0.01) or intravenous lansoprazole (hazard ratio 4.57, 95% confidence interval 1.24-16.80, P = 0.02) than with concomitant sulbactam/ampicillin and oral or intravenous lansoprazole., Conclusions: Oral and intravenous lansoprazole may increase the risk of ventricular arrhythmia and cardiac arrest in patients who are receiving ceftriaxone., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Proton pump inhibitor (PPI) use may be associated with renal dysfunction. Renal dysfunction in PPI users requires evaluation of development and progression risks simultaneously, using estimated glomerular filtration rate (eGFR) slope, which indicates changes in eGFR per year. To the best of our knowledge, no studies have evaluated eGFR slope in PPI users. This study investigated the association between PPI use and renal dysfunction using eGFR slope. A single-center cohort study was conducted using the health records data at Hamamatsu University Hospital in Japan. Participants were defined as first users of acid-suppressing drugs (PPIs or Histamine H 2 receptor antagonists (H 2 RAs)) from 2010 to 2021 and continuously prescribed for  ≥ 90 days. The H 2 RA group was used for the propensity-score matching (PSM) to the PPI group to minimize the effects of confounders. The eGFR slope was estimated using a linear mixed effects model. Participants were stratified by baseline eGFR and age, respectively, as subgroup analyses. A total of 4,649 acid-suppressing drug users met the inclusion criteria, including 950 taking H 2 RAs and 3,699 PPIs. After PSM, 911 patients were assigned to each group. The eGFR slopes of the PPI and H 2 RA users were -4.75 (95% CI: -6.29, -3.20) and -3.40 (-4.38, -2.42), respectively. The difference between the groups was not significant. Significant declines in eGFR were observed with PPIs with baseline eGFR ≥ 90 and age  < 65. PPI use for  ≥ 90 days may hasten eGFR decline compared to H 2 RA use, especially in patients with eGFR  ≥ 90 or age  < 65., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Aims: Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk., Methods: Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study., Results: Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users., Conclusions: The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

A recent study suggested that proton pump inhibitor (PPI) use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) was associated with poor clinical outcomes. However, the clinical impact of PPI use on the outcome of patients receiving ICIs for postoperative recurrent NSCLC is unknown. The outcomes of 95 patients with postoperative recurrence of NSCLC receiving ICIs at 3 medical centers in Japan were analyzed. We conducted adjusted Kaplan-Meier survival analyses with the log-rank test, a Cox proportional hazards regression analysis, and a logistic regression analysis using inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves revealed that the progression-free survival (PFS), but not the overall survival (OS), was significantly longer in patients who did not receive PPIs than in those who did receive them. The IPTW-adjusted Cox regression analysis revealed that PPI use was an independent poor prognostic factor for the PFS and OS. Furthermore, in the IPTW-adjusted logistic regression analysis, PPI non-use was an independent predictor of disease control. In this multicenter and retrospective study, PPI use was associated with poor clinical outcomes in patients with postoperative recurrence of NSCLC who were receiving ICIs. PPIs should not be prescribed indiscriminately to patients with postoperative recurrence of NSCLC who intend to receive ICIs. These findings should be validated in a future prospective study., Competing Interests: The authors have declared that no competing interests exist.

Background: There is no established view of how gastric acid suppression affects the time for gastric emptying. Vonoprazan fumarate shows potent and durable gastric acid inhibitory effects, but its effects on gastric emptying have not been studied widely. We investigated the effects of vonoprazan fumarate on gastric emptying and measured serum gastrin and plasma ghrelin levels in healthy adults., Methods: Ten participants were administered 10 mg vonoprazan fumarate daily for 14 days, then 20 mg vonoprazan fumarate daily for 14 days. The gastric emptying breath test was performed and serum gastrin levels were measured at baseline and after each medication administration period. The protocol was then repeated, with the gastric emptying breath test and serum gastrin and plasma desacyl-ghrelin levels measured at baseline and the end of the medication trial., Results: Mean serum gastrin levels increased in a dose-dependent manner [baseline: 104.7 ± 50.4, after 10 mg protocol: 328 ± 123.8, after 20 mg protocol: 555 ± 378.8 (pg/mL, mean ± standard deviation), p = 0.0008]. There was a significant difference between the gastric emptying breath test Tmax at baseline and just after the 20 mg protocol (baseline: 45.5 ± 15.3, after 20 mg protocol: 60.5 ± 19.6 min, p = 0.0418). Plasma desacyl-ghrelin levels increased significantly just after the 20 mg protocol compared to those at baseline [baseline: 222.3 ± 106.4, after 20 mg protocol: 366.2 ± 178.6 (fmol/mL), p = 0.0008]., Conclusions: In healthy adults, 14 days of vonoprazan fumarate administration at 20 mg/day delayed gastric emptying., Trial Registration: This clinical trial was registered in the University hospital Medical Information Network Clinical Trial Registry (Trial No. UMIN000039199 and UMIN000042969)., (© 2021. Japanese Society of Gastroenterology.)

Background: Behavioral disorders, such as supragastric belching (SGB) and rumination syndrome (RS), which may be treated by cognitive behavioral therapy, are common in patients with reflux symptoms refractory to proton pump inhibitors (PPI). Vonoprazan (VPZ) has been used as a new type of acid inhibitor in Japan since 2015. We herein investigated the prevalence of behavioral disorders in patients with VPZ-refractory reflux symptoms and attempted to identify predictive factors., Methods: We retrospectively analyzed esophagogastroduodenograms, high-resolution manometry, and 24-h multiluminal impedance pH-metry (MIIpH) in patients with VPZ-refractory reflux symptoms (heartburn or regurgitation) receiving 20 mg VPZ who underwent these tests at our hospital between January 2015 and April 2020. Patients were divided as follows: non-erosive reflux disease with pathological esophageal acid exposure (NERD), functional heartburn (FH), reflux hypersensitivity (RH), excessive (> 13 per day) SGB, and possible RS based on MIIpH parameters., Results: Among 49 patients, 6 (12.2%) had SGB, 4 (8.2%) possible RS, 29 (59.2%) FH, 9 (18.4%) RH, and 1 (2%) NERD. Possible RS patients had more postprandial non-acid reflux events than FH patients (p < 0.05). The multivariate logistic regression analysis did not identify any predictive factors with statistical significance., Conclusion: More than 20% patients with VPZ-refractory reflux symptoms had behavioral disorders. The use of HRM and MIIpH may be clinically relevant for a better diagnosis and more specific treatment.

The real-world status of proton pump inhibitor (PPI) use in patients with atrial fibrillation (AF) receiving antithrombotic treatment is largely unknown. The All Nippon AF In the Elderly (ANAFIE) Registry, a prospective, multicenter, observational study, aimed to determine treatment patterns, risk factors, and outcomes among elderly (aged ≥75 years) Japanese non-valvular AF (NVAF) patients in the real-world clinical setting. The present subanalysis of the ANAFIE Registry determined the PPI prescription status of 32,490 elderly Japanese NVAF patients. Patients were stratified by PPI use (PPI+) or no PPI use (PPI-). Risk scores for stroke (CHADS2, CHA2DS2-VASc) and bleeding (HAS-BLED), anticoagulant use, time in therapeutic range (TTR) for warfarin, and anticoagulant/antiplatelet combination use were evaluated. PPIs were used in 11,981 (36.9%) patients. Compared with the PPI- group, the PPI+ group included a greater proportion of female patients (45.2% vs 41.3%; P <0.0001) and had significantly higher CHADS2, CHA2DS2-VASc, and HAS-BLED scores (P <0.0001 for each) as well as higher prevalences of several comorbidities. In the PPI+ group, 54.6% of patients did not have gastrointestinal (GI) disorders and were likely prescribed a PPI to prevent GI bleeding events. Most of the patients with a GI disorder in the PPI+ group had reflux esophagitis. Compared with patients not receiving anticoagulants, a significantly higher proportion of patients receiving anticoagulants received PPIs. For patients receiving anticoagulants, antiplatelet drugs, and both drugs, rates of PPI use were 34.1%, 44.1%, and 53.5%, respectively (P <0.01). Although the rate of PPI use was the highest for NVAF patients receiving both antiplatelet and anticoagulants, no clear differences were observed in the anticoagulants used. These data suggest that PPIs were actively prescribed in high-risk cases and may have been used to prevent GI bleeding among elderly NVAF patients receiving antithrombotic drugs. Trial registration: UMIN000024006., Competing Interests: The authors have read the journal’s policy and have the following potential competing interests: Tetsuya Kimura, Jumpei Kaburagi, and Atsushi Takita are paid employees of Daiichi Sankyo Co., Ltd., Tokyo, Japan. Yuji Mizokami received research funding from Daiichi Sankyo, and remuneration from Daiichi Sankyo. Takatsugu Yamamoto received remuneration from Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Takeda Pharmaceutical, Otsuka Pharmaceutical, and AstraZeneca. Hirotsugu Atarashi received remuneration from Daiichi Sankyo. Takeshi Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol-Myers Squibb. Masaharu Akao received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Takanori Ikeda received research funding from Daiichi Sankyo and Bayer, and remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Bristol-Myers Squibb. Yukihiro Koretsune received remuneration from Daiichi Sankyo, Bayer, and Nippon Boehringer Ingelheim. Ken Okumura received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. Wataru Shimizu received research funding from Bristol-Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim, and patent royalties/licensing fees from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. Hiroyuki Tsutsui received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, and Pfizer Japan, scholarship funding from Daiichi Sankyo, and consultancy fees from Pfizer Japan, Bayer, and Nippon Boehringer Ingelheim. Kazunori Toyoda received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. Atsushi Hirayama participated in a course endowed by Boston Scientific Japan, and has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. Masahiro Yasaka received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Pfizer Japan. Takenori Yamaguchi acted as an Advisory Board member of Daiichi Sankyo and received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. Satoshi Teramukai received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo. Tetsuya Kimura, Jumpei Kaburagi, and Atsushi Takita are employees of Daiichi Sankyo. Hiroshi Inoue received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, and Nippon Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors would like to declare the following patents/patent applications associated with this research: Daiichi Sankyo has launched Nexium® (esomeprazole magnesium hydrate) which is one of the proton pump inhibitors.

Background: Supragastric belching (SGB) may play a role in the pathophysiology of proton pump inhibitors (PPIs)-refractoriness in gastroesophageal reflux disease (GERD). SGB may be present in up to 40% of reflux symptoms in PPI-refractory GERD. Most reports on SGB have come from Western countries, and little is known about the prevalence and relevance of SGB in Asian refractory GERD patients. This study aimed at comparing the role of SGB in GERD patients in Japan and the UK., Methods: We re-analyzed impedance-pH monitoring tracings from patients who were referred to tertiary centers in Japan and the UK due to PPI-refractory reflux symptoms. The prevalence of excessive SGB and the impact of SGB on reflux symptoms were compared between the two countries., Results: Impedance-pH tracings from124 Japanese and 83 British patients were re-analyzed. Japanese patients were significantly younger and had smaller body mass index than the British (P < 0.001). Japanese patients had significantly lower prevalence of excessive SGB (18.5%) than the UK (36.1%) irrespective of reflux phenotype (P = 0.006). Logistic regression analysis showed that the geographical/cultural difference was the only factor associated with the different prevalence of SGB (odds ratio; 2.91, 95% CI 1.09-7.73, P = 0.032). SGB were related to typical reflux symptoms very rarely in Japan [0% (0-4.9)] compared to the UK [35% (0-54.1)] (P = 0.071)., Conclusions: The prevalence of SGB and their impact on reflux symptoms is significantly lower in Japan compared to the UK. The difference is not related to reflux parameters but might come from ethnic/cultural factors to be further characterized.

Background: A small proportion of Helicobacter pylori-infected individuals in Japan suffer failure of eradication therapy with third-line regimens containing the potent acid suppressor, vonoprazan, and a quinolone., Objectives: This prospective study evaluated the efficacy and safety of rifabutin-based triple therapy with vonoprazan for refractory H pylori infection., Methods: Patients who failed H pylori eradication by clarithromycin-based first-line, metronidazole-based second-line, and sitafloxacin-based third-line therapies were recruited. After obtaining informed consent, patients received eradication therapy with vonoprazan (20 mg), amoxicillin (750 mg), and rifabutin (150 mg) twice daily for 10 days. Eradication was confirmed by a negative H pylori stool antigen or urea breath test at least 8 weeks after the end of therapy., Results: Nineteen patients were included in the study. All of the patients completed the course of medication. Eradication of H pylori was confirmed in all of the patients (19/19; 100%, 95% confidence interval; 83-100%). The most common adverse event was soft stool/diarrhea (4/19, 21%). No severe adverse event was observed., Conclusions: Ten-day rifabutin with amoxicillin and vonoprazan triple therapy appears to be effective and safe for refractory H pylori infections. However, considering the recent publications showing high eradication rates with vonoprazan amoxicillin dual therapy, confirmation will require future studies comparing our new therapy with vonoprazan-amoxicillin dual with similar doses and duration and with vonoprazan-rifabutin dual therapy., (© 2020 John Wiley & Sons Ltd.)

What Is Known and Objective: Esomeprazole, the S-isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM ® . Esomeprazole was developed to provide further improvement on efficacy for acid-related diseases with higher systemic bioavailability due to the less first-pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%-10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included., Methods: In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model., Results and Discussion: CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10-mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased., What Is New and Conclusion: The established population PK model well described the esomeprazole PK and model-predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK., (© 2020 John Wiley & Sons Ltd.)

Proton pump inhibitors (PPIs) are used to treat acid-related disorders such as peptic ulcer and gastroesophageal reflux disease. Recently, vonoprazan, a novel potassium-competitive acid blocker (P-CAB), has been introduced as more effective treatment option. The purpose of this study was to clarify the adverse events associated with vonoprazan compared to PPIs using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. The database comprised 11,433 reports associated with PPIs, and 636 reports with vonoprazan. Hepatic and skin disorders were commonly detected in both PPIs and vonoprazan. There was a significant association of interstitial lung disease with PPIs as a class (ROR: 1.61, 95%CI: 1.47-1.77), but not with vonoprazan. Vonoprazan was strongly associated with haemorrhagic enterocolitis (ROR, 86.5; 95%CI, 59.7125). Among the PPIs, the signal score of microscopic colitis was noteworthy in the case of lansoprazole (ROR, 405; 95%CI, 348-472). It is suggested that there is a diversity in the strength of the association between PPIs and vonoprazan with adverse events. Our results may provide useful information for the treatment of acid-related disorders, but further research with more data is needed to finally clarify this.

Background: Although 7-day triple therapy, consisting of vonoprazan, amoxicillin (AMO), and clarithromycin (CLA), is recommended for Helicobacter pylori (H. pylori) eradication in adults. However, the importance of reducing antibiotic use in pediatric patients is well recognized. Therefore, our aim was to compare the effectiveness and safety of vonoprazan and AMO (VA) dual therapy to vonoprazan-based (VAC) triple therapy for H. pylori eradication in a cohort of treatment-naïve junior high school students in Japan., Methods: This was a prospective observational study of second-year junior high-school students in Yurihonjo and Nikaho Cities, Japan. Between 2015 and 2017, 161 students were treated with VAC-triple therapy (20 mg vonoprazan, 750 mg AMO, and 200 mg CLA, twice a day for 7 days), while 60 students were treated with VA-dual therapy (20 mg vonoprazan and 750 mg AMO, twice a day for 7 days) since 2018. The success rate of H. pylori eradication and drug-related adverse events were compared between the two therapy groups. Intention-to-treat (ITT) and per-protocol (PP) analyses were performed., Results: Groups were comparable at baseline. The ITT and PP eradication rates were 85.0% (95% confidence interval [CI] 75.8-94.2%) and 86.4% (95% CI 77.4-95.5%), respectively, with VA-dual therapy and 82.0% (95% CI 76.0%-87.9%) and 84.1% (95% CI 78.3-89.8%), respectively, with VAC-triple therapy. VA-dual therapy was non-inferior to VAC-triple therapy (ITT, p = 0.018; PP, p = 0.020). The adverse event rate was 10.0% with VA-dual therapy and 19.8% with VAC-triple therapy (p = 0.108)., Conclusions: The effectiveness of VA-dual therapy was comparable to that of VAC-triple therapy in H. pylori treatment-naïve junior high school students, while reducing the use of antibiotics.

Background: Vonoprazan (V), a potassium-competitive acid blocker, has a more durable acid-inhibitory effect as compared with standard-dose proton pump inhibitors (PPIs) but has not been compared with 2-4 times higher daily PPI doses administered in two divided doses., Aims: To evaluate the acid-inhibitory effect of V 10/20 mg once-daily (OD; V10/V20) vs rabeprazole (R) 10/20 mg twice-daily (BID; R20/R40) in healthy Japanese volunteers., Methods: This multicentre, randomised, open-label, two-period, crossover study compared V10 or V20 vs R20, or V20 vs R40 using three cohorts of 10 healthy Japanese adults. Within each cohort, subjects were randomised to receive V or R for 7 days and, following a washout period ≥7 days, the other treatment for 7 days. On day 6 of each period, 24-hours multichannel gastric impedance-pH monitoring was performed. Percent times pH ≥ 3, ≥4 and ≥5 (pH 3, 4 and 5 holding time ratios [HTRs]) in 24 hours were evaluated as primary pharmacodynamic endpoints., Results: Acid-inhibitory effect (24-hours pH 3 HTR) of V20 was greater than those of R20 (91.0% vs 65.3%; P = .0049) and R40 (98.5% vs 85.9%; P = .0073). Similar results were obtained for 24-hours pH 4 and 5 HTRs. V20 also achieved greater nocturnal pH 4 (91.5% vs 73.2%; P = .0319) and 5 HTRs (78.8% vs 62.2%; P = .0325) as compared with R40. One subject (20%) developed diarrhoea while receiving R40 which was considered treatment-related., Conclusions: Compared with 2-4 times the standard daily dose of R, V20 exerts a more potent and durable acid-inhibitory effect. Trial identifier: UMIN000022198 (www.umin.ac.jp/ctr/index.htm)., (© 2020 John Wiley & Sons Ltd.)

Helicobacter pylori can infect the gastric mucosa and cause chronic inflammation, resulting in various diseases, including gastric cancer. Eradication of H. pylori in all infected subjects is recommended; however, the number of H. pylori strains with antibiotic resistance has increased, and the eradication rate has decreased. Vonoprazan, a potassium-competitive acid blocker, produces a stronger acid-inhibitory effect than proton pump inhibitors (PPIs). The H. pylori eradication rate with vonoprazan was found to be higher than that with PPIs. The H. pylori eradication rate with vonoprazan-based triple therapy (vonoprazan, amoxicillin, and clarithromycin) was approximately 90% and had an incidence of adverse events similar to that of PPIs. We review the current situation of H. pylori eradication in Japan, the first country in which vonoprazan was made available.

Background: Gastroesophageal reflux disease (GERD) can be treated using a vonoprazan-first strategy (first-line treatment with vonoprazan), or esomeprazole-first/rabeprazole-first strategies (first-line treatment with proton-pump inhibitors [PPIs], esomeprazole/rabeprazole, followed by a switch to vonoprazan). This cost-utility analysis used long-term simulation modeling to evaluate the cost-effectiveness of a vonoprazan-first strategy compared with the esomeprazole-first and rabeprazole-first strategies., Methods: A Markov simulation model was developed to evaluate the cost-effectiveness of vonoprazan-first, esomeprazole-first, and rabeprazole-first strategies, comprising healing and maintenance therapies, over 5 years (4-week cycles). Healing therapy began with the administration of a normal dose of drug per real-world practice. If patients were not healed endoscopically, either a longer duration of healing therapy was provided (vonoprazan), the dose was increased (rabeprazole), or patients were switched to vonoprazan (immediately for esomeprazole, and after dose-escalation for rabeprazole, respectively). Healed patients received maintenance (lower/same dose as healing therapy). Recurrence resulted in re-challenge with healing therapy. Transition probabilities were derived from the results of indirect comparisons (network meta-analysis) and costs calculated from the Japanese payer perspective. Outcomes were defined as quality-adjusted life years (QALYs), with utilities based on published values., Results: Expected costs of the vonoprazan-, esomeprazole-, and rabeprazole-first strategies were ¥36,194, ¥76,719, and ¥41,105, respectively, over 5 years. QALY gains for vonoprazan-first strategy versus the esomeprazole- and rabeprazole-first strategies were 0.014 and 0.003, respectively. Both estimated incremental cost-effectiveness ratios were dominant and robust to two sensitivity analyses., Conclusions: Vonoprazan-first strategy increased QALYs and appeared to be cost-effective for GERD patients compared with the esomeprazole- or rabeprazole-first strategies.

Background: The incidence of peptic ulcers unrelated to H. pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs), termed idiopathic peptic ulcers (IPUs), has increased worldwide. We recently reported that IPUs were refractory to proton pump inhibitor (PPI) treatment. Vonoprazan, which was recently developed in Japan, has shown a more potent acid-inhibitory effect than ordinary PPIs. In the present study, we compared the healing rates among peptic ulcers of different etiologies following treatment with vonoprazan., Method: A multicenter observational study was performed at six participating hospitals in Akita Prefecture, Japan. Consecutive patients who had endoscopically confirmed gastro-duodenal ulcers were enrolled between August 2016 and March 2018. For each patient, the Helicobacter pylori infection status and NSAID use, including aspirin, were checked, and 20 mg vonoprazan was administered for 6 weeks for duodenal ulcers and 8 weeks for gastric ulcers. The healing status was checked by endoscopy at the end of vonoprazan treatment. Patients were divided into four subgroups according to the H. pylori status and NSAID usage., Results: The proportion of IPUs was 18.2%. A total of 162 patients completed the study protocol. The healing rate of IPUs was marginally lower than that of simple H. pylori-associated ulcers (81.2% vs. 93.5%, P = 0.05). Similarly, the healing rate of NSAID-related ulcers, irrespective of concomitant H. pylori infection, was significantly lower than that of simple H. pylori-associated ulcers., Conclusions: Six- or 8-week vonoprazan treatment still seems to be insufficient for healing IPUs. Longer-term vonoprazan or another treatment option may be required to heal potentially refractory peptic ulcers.

Background: Proton pump inhibitors (PPI) are widely used for the treatment of gastric acid-related disease, but they are not approved for use in children in Japan. To assess the safety, pharmacokinetics, pharmacodynamics, and efficacy (gastrointestinal symptom improvement) of PPI in Japanese pediatric patients with gastric acid-related disease, we conducted an 8 week, open-label, parallel-group, multicenter, phase I/III study of once-daily oral esomeprazole use., Methods: Japanese children, aged 1-14 years with gastric acid-related disease, were stratified by weight and age into five groups (10 patients/group) to receive esomeprazole as granules for suspension (10 mg) or capsules (10 mg or 20 mg) once daily., Results: Esomeprazole was absorbed and eliminated rapidly in all groups, with a median time to reach maximum plasma concentration of 1.47-1.75 h, an arithmetic mean terminal elimination half-life of 0.80-1.37 h, and a weight-correlated apparent total body clearance of 0.216-0.343 L/h/kg. Area under the plasma concentration-time curve during a dosage interval and maximum plasma drug concentration were generally higher in groups given a higher dose (20 mg) or with a lower age/weight, but also in patients identified as poor metabolizers on cytochrome P450 2C19 genotype. Most patients who had any upper gastrointestinal symptoms at baseline were asymptomatic at the end of the study. Thirty-three patients (66%) reported ≥1 adverse events, including three patients who reported serious adverse events not judged to be causally related to esomeprazole., Conclusions: Oral esomeprazole, at 10 mg or 20 mg once daily, had a similar safety, efficacy, and pharmacokinetic profile in Japanese pediatric patients to that previously seen in adults and Caucasian children., (© 2018 The Authors. Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.)

Background: Erlotinib is used for treating non-small cell lung cancer (NSCLC). Intestinal absorption of erlotinib is impaired under gastric pH elevation; therefore, coadministration of gastric acid suppressants may provide lower blood concentration of erlotinib. We investigated the effects of erlotinib coadministration with proton pump inhibitors (PPIs) and histamine H2 receptor blockers (H2RBs) on the plasma concentration of erlotinib and erlotinib-induced adverse reaction in patients with NSCLC., Methods: Forty-two patients receiving erlotinib therapy for NSCLC were recruited for this study. Association of adverse reactions (rash and diarrhea) with plasma concentration of erlotinib was examined. Plasma concentration-to-dose (C/D) ratios and oral clearance (CL/F), which was estimated by population pharmacokinetic analysis of plasma concentrations of erlotinib, were compared among 3 patient groups: without coadministration of gastric acid suppressants (control group), with coadministration of PPI (PPI group), and coadministration of H2RB (H2RB group)., Results: Patients with grade ≥2 rash had higher plasma concentrations of erlotinib compared with those with grade ≤1 [1.02 (0.43-2.60) versus 0.67 (0.10-1.85) mcg/mL, P < 0.01]. The C/D ratios of erlotinib in the PPI and H2RB groups were lower than that in the control group [0.39 (0.08-0.76) and 0.48 (0.33-0.81) versus 0.51 (0.28-1.28) mcg·mL·mg·kg], where statistical significance was observed between PPI and control groups (P < 0.05). The population pharmacokinetic estimated oral CL/F in the PPI and H2RB groups were higher than that in the control group [5.55 (3.36-14.52) and 4.82 (2.08-6.32) versus 3.95 (2.01-10.44) L/h], where statistical significance was observed between PPI and control groups (P < 0.05)., Conclusions: Plasma concentrations of erlotinib in patients under coadministration of gastric acid suppressants were lower than those without gastric acid suppressants through drug interaction, suppressing the intestinal absorption of erlotinib. The magnitude of this drug interaction was more pronounced in the coadministration of PPI compared with H2RB.

L-Asparaginase has significantly improved outcome for children with acute lymphoblastic leukemia and has become an essential component of multiagent chemotherapy. However, there are many adverse events due to L-asparaginase, including acute pancreatitis. The pathology of L-asparaginase-associated pancreatitis (AAP) remains unclear. We compared patients who developed AAP (n=29) and random matched controls (n=36) who had been enrolled in the Japan Association of Childhood Leukemia Study of the ALL-02 protocol. AAP and control patients were matched for age, sex, treatment, and protocol risk. We examined correlations between AAP development and clinical symptoms, laboratory data, and concomitant medication. Abdominal pain and nausea were common presenting symptoms for AAP. There was an increased risk of AAP in patients using gastric acid-suppressing agents and antithrombin (AT) supplementation. Mean fibrinogen and AT levels before the onset of AAP were lower in AAP patients than in controls. Decreased AT and fibrinogen levels resulting from the strong suppression of protein synthesis by L-asparaginase were predictive signs for AAP. Our epidemiological approach should prove clinically useful for the diagnosis the AAP as early as possible.

Background: Rabeprazole at 10 or 20 mg twice daily (b.i.d.) has been reported to be highly effective in the treatment of proton pump inhibitor (PPI)-resistant reflux esophagitis (RE) that is refractory to the standard once-daily PPI regimen. We evaluated the efficacy and safety of rabeprazole maintenance therapy at 10 mg once daily (q.d.) or b.i.d. for longer than 8 weeks., Methods: Patients with RE refractory to standard PPI regimens for at least 8 weeks were enrolled. They were treated with rabeprazole at 10 or 20 mg b.i.d. for 8 weeks during the open-label treatment period. After endoscopic examination, those with confirmed healing entered the subsequent double-blind maintenance therapy. During this period, the subjects were randomized to receive rabeprazole 10 mg q.d. (control) or 10 mg b.i.d. The primary endpoint was the endoscopic no-recurrence rate at Week 52., Results: In total, 517 subjects entered the treatment, and 359 subjects continued on maintenance therapy. The full analysis set for central assessment included 343 subjects. The no-recurrence rate at Week 52 was significantly higher in the b.i.d. group (73.9%; p < 0.001, χ 2 test) than in the q.d. group (44.8%). In particular, the b.i.d. regimen was more effective in all subgroups with Los Angeles Classification Grade B to D at treatment entry., Conclusions: In the maintenance treatment of PPI-resistant RE, rabeprazole at 10 mg b.i.d. exerted a stronger recurrence-preventing effect than 10 mg q.d. over 52 weeks. No particular safety issues were noted during long-term administration. ClinicalTrials.gov number: NCT02135107.

Helicobacter pylori (H. pylori) infection remains to be the major cause of important upper gastrointestinal diseases such as chronic gastritis, peptic ulcer, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. H. pylori management in ASEAN: the Bangkok consensus report gathered key opinion leaders for the region to review and evaluate clinical aspects of H. pylori infection and to develop consensus statements, rationales, and grades of recommendation for the management of H. pylori infection in clinical practice in ASEAN countries. This ASEAN Consensus consisted of 34 international experts from 10 ASEAN countries, Japan, Taiwan, and the United States. The meeting mainly focused on four issues: (i) epidemiology and disease association; (ii) diagnostic tests; (iii) management; and (iv) follow-up after eradication. The final results of each workshop were presented for consensus voting by all participants. Statements, rationale, and recommendations were developed from the available current evidence to help clinicians in the diagnosis and treatment of H. pylori and its clinical diseases., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment., Materials and Methods: Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature., Results: The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6-96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0-101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies., Conclusions: Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature.

Background: The bacterial resistance of Helicobacter pylori to antimicrobial agents such as clarithromycin and metronidazole has been increasing worldwide, leading to the failure of eradication treatment. Here, we present an eradication regimen consisting of four-times-daily dosing (q.i.d.) of rabeprazole with potent acid inhibition., Aim: To investigate the efficacy of eradication therapy with rabeprazole q.i.d. and amoxicillin or sitafloxacin in Japanese infected with a metronidazole-resistant strain., Methods: We retrospectively investigated the efficacy of eradication regimens with rabeprazole q.i.d. for 7 days in 111 Japanese pooled patients infected with a metronidazole-resistant strain of H. pylori at Hamamatsu University School of Medicine Hospital or the Shiga University of Medical Science Hospital: 1, with sitafloxacin 100 mg twice daily (b.i.d.) (n = 82); 2, with amoxicillin 500 mg q.i.d. (n = 15); and 3, with amoxicillin q.i.d. and sitafloxacin b.i.d.-combined regimen (n = 14). Eradication status was assessed at 8 weeks via a 13 C-urea breath test., Results: Eradication rate on intention-to-treat analysis was 93.7% (95% confidence interval: 87.4-97.4%, 104/111), irrespective of the high prevalence of strains resistant to clarithromycin (81.1%, 90/111) and levofloxacin (42.3%, 47/111). No significant differences in eradication rates were observed among the different treatment regimens (p = .408), eradication history (p = .096) and different CYP2C19 genotypes (p = .789). On multivariate analysis, no significant risk factor for eradication failure by therapy with potent acid inhibition was seen., Conclusion: In Japanese patients infected with metronidazole-resistant strains of H. pylori, eradication rates exceeding 90% can be achieved using appropriate dosing of antibiotic agents with strain susceptibility (amoxicillin q.i.d. and/or sitafloxacin b.i.d.) together with acid inhibition for a full 24 h and rabeprazole 10 mg q.i.d. These findings may be further evidence for dual therapy with rabeprazole q.i.d. and an antibiotic agent (amoxicillin q.i.d. or sitafloxacin b.i.d.) in Japanese patients with metronidazole-resistant strains., (© 2016 John Wiley & Sons Ltd.)

Background and Aims: In Japan, 7-day triple therapy for Helicobacter pylori including clarithromycin (CAM) was approved in 2000. However, antibiotic resistance subsequently reduced this rate to an unacceptable level (70%). Vonoprazan, an orally bioavailable potassium-competitive acid blocker (P-CAB), was approved in Japan in 2014. This could improve eradication rates by increasing the intragastric pH, thus increasing bacterial antibiotic susceptibility. This study compared the efficacy of 7-day triple therapies that included CAM and vonoprazan or proton pump inhibitor (PPI)., Methods: We prospectively analyzed H. pylori eradication rates in 146 patients receiving 7-day triple therapy containing P-CAB (April 2015 to September 2015), and in a retrospective cohort of 1,305 patients who received 7-day triple therapy containing a PPI (April 2011 to September 2015)., Results: H. pylori was eradicated in a significantly higher number of P-CAB-treated patients (89.7% [131/146]) than PPI-treated patients (73.9% [965/1305]; p < 0.05). The eradication rates in P-CAB-treated CAM-sensitive and CAM-resistant bacteria were 100% (44/44) and 87.5% (28/32), respectively, which were significantly higher than the corresponding rates in PPI-treated patients (88.0% [22/25] and 53.8% [7/13], p < 0.05)., Conclusion: P-CAB improved the efficacy of CAM-containing 7-day triple therapy and would be a valuable first-line treatment for H. pylori infection.

Aim: To clarify the pathogenesis of gastroesophageal reflux disease symptoms in non-erosive reflux disease (NERD) patients., Methods: Thirty-five NERD patients with persistent symptoms, despite taking rabeprazole 10 mg twice daily for at least 8 wk, were included in this study. All patients underwent 24 h combined impedance - pH on rabeprazole. The symptom index (SI) was considered to be positive if ≥ 50%, and proximal reflux episodes were determined when reflux reached 15 cm above the proximal margin of the lower esophageal sphincter., Results: In 14 (40%) SI-positive patients, with liquid weakly acid reflux, the occurrence rate of reflux symptoms was significantly more frequent in proximal reflux episodes (46.7%) than in distal ones (5.7%) (P < 0.001). With liquid acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (38.5%) and distal ones (20.5%) (NS). With mixed liquid-gas weakly acid reflux, the occurrence rate of reflux symptoms in proximal reflux episodes was significantly more frequent (31.0%) than in distal reflux ones (3.3%) (P < 0.001). With mixed liquid-gas acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (29.4%) and distal ones (14.3%) (NS)., Conclusion: The proximal extent of weakly acidic liquid and mixed liquid-gas reflux is a major factor associated with reflux perception in SI-positive patients on proton pump inhibitor therapy.

Background: Low-dose aspirin (ASA) is effective for secondary prevention of ischemic stroke but can increase the risks of hemorrhagic stroke, upper gastrointestinal bleeding (UGIB), and dyspepsia. Prophylactic administration of proton pump inhibitors (PPIs) reduces the risks of these digestive symptoms. We investigated the cost effectiveness of adding a PPI to ASA therapy for ischemic stroke patients in Japan., Methods: A Markov state-transition model was developed to compare the cost effectiveness of ASA monotherapy with ASA plus PPI co-therapy in patients with histories of upper gastrointestinal ulcers and ischemic stroke. The model takes into account ASA adherence rate and adverse effects due to ASA, including hemorrhagic stroke and UGIB. The analysis was performed from the perspective of healthcare payers in 2013., Results: In the base case, total life-years by PPI co-therapy and monotherapy were 16.005 and 15.932, respectively. The difference in duration of no therapy (no ASA or PPI) between the therapies was 558.5 days, which would prevent 30.3 recurrences of ischemic stroke per 1000 person-years. The incremental cost-effectiveness ratio of PPI co-therapy relative to monotherapy was ¥1,191,665 (US$11,458) per life-year gained. In a one-way sensitivity analysis, PPI co-therapy was consistently cost effective at a willingness to pay of ¥5,000,000 (US$48,077) per life-year gained. In a probabilistic sensitivity analysis, the probability that PPI co-therapy was cost effective was 89.74% at the willingness to pay., Conclusions: Co-therapy with ASA plus PPI appears to be cost-effective compared with ASA monotherapy. The addition of PPI also appeared to prolong the duration of ASA therapy, thereby reducing the risk of ischemic stroke.

Aim: To investigate the optimum period of treatment for post endoscopic submucosal dissection (ESD) ulcers., Methods: Patients who underwent ESD for gastric cancer were randomized to two groups and treated with esomeprazole 20 mg per day for 4 wk (4W group) or 2 wk (2W group). At 4 wk after ESD, we measured the size of the artificial ulcers by endoscopy and determined the ulcer healing rate, compared with the size of the ESD specimens. This randomized controlled trial study was approved by our ethics committee and registered in the UMIN Clinical Trial Registry., Results: A total of 60 consecutive patients were included in the study. All patients received rebamipide 300 mg per day for 4 wk. One patient in 2W group who showed bleeding within two weeks and received endoscopic treatment was excluded from further analysis. The numbers of patients with ulcers in the healing/scar stage in the 2W and 4W groups at 4 wk after ESD were 20/6 and 28/5, respectively, with no significant difference. The ulcer healing rate in the 2W and 4W groups were 96.1% [95% confidence interval (CI): 94.6%-97.55] vs 94.8% (95%CI: 92.6%-97.1%), respectively, with no statistical difference (UMIN000006951)., Conclusion: Two-wk treatment with a proton pump inhibitor is as effective as four-week treatment for healing post ESD ulcers.

Since National Health Insurance covered eradication therapy for H. pylori infected gastritis, all patients with H. pylori infection could be received eradication under insurance. Cure of H. pylori infection improves histological gastritis, also atrophic change, and intestinal metaplasia. Prevention of H. pylori associated diseases such as gastric cancer is expected. According to Insurance instruction, it is carried out in order of endoscopic diagnosis of chronic gastritis, diagnosis of H. pylori infection, and eradication treatment. Endoscopic examination prior to H. pylori diagnosis is necessary for screening of gastric cancer. Endoscopic finding of RAC (regular arrangement of collecting venules) in the angle of stomach suggests lack of infection with H. pylori, disappearance of RAC suspects H. pylori infection.

Background: Patients with gastroesophageal reflux disease (GERD) frequently have symptoms of dyspepsia in addition to reflux symptoms. Treatment options for dyspepsia are not standardized. The aim of this study was to clarify the therapeutic effect of lansoprazole on dyspepsia in Japanese patients with GERD., Methods: GERD patients with dyspepsia were enrolled and treated with lansoprazole 15 or 30 mg once daily for 4 weeks. Reflux and dyspeptic symptoms were assessed by questionnaires before treatment, and 2 and 4 weeks after the start of lansoprazole treatment., Results: In the effectiveness analysis set (n = 12,653), heartburn was reported by 91.6 % of patients at study enrollment. Postprandial fullness was the most frequently reported dyspepsia symptom at the start of the study, reported by 79.0 % of enrolled patients. After 4 weeks of lansoprazole treatment, heartburn symptoms were improved in 75.7 % of patients and symptoms of postprandial fullness were improved in 68.7 % of patients. The therapeutic effect of low and high doses of lansoprazole on dyspepsia, as well as on reflux symptoms, was approximately 10 % higher in patients with endoscopy-confirmed erosive esophagitis (60.1-82.2 %), than in patients with non-erosive reflux diseases (53.0-73.3 %). Lansoprazole was well tolerated., Conclusion: In this large-scale clinical study, lansoprazole effectively relieved dyspepsia in addition to reflux symptoms in patients with GERD.

Eradication of H. pylori in patients allergic to penicillin should be performed using regimens without penicillin derivatives. We treated a total of 28 patients allergic to penicillin with a proton pump inhibitor (PPI), metronidazole (250 mg bid) and sitafloxacin (100 mg bid) for one to two weeks. At four to eight weeks after the treatment, the patients underwent the [(13)C]-urea breath test. The overall eradication rate was 100.0%. Mild adverse events were observed. Triple therapy with a PPI, metronidazole and sitafloxacin is well tolerated and effective for the eradication of H. pylori in patients allergic to penicillin.

Objective: To provide further insights on the risks of gastrointestinal (GI) complications in individuals using low-dose aspirin (LDA), we investigated the concomitant use of LDA and antisecretory drugs. Additionally, we examined the frequency distributions of prescribing sequences for LDA and antisecretory drugs., Methods: Data from a computerized prescription order entry system was analyzed at the National Cerebral and Cardiovascular Center of Japan. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pomp inhibitors (PPIs) was examined over the period from January 2001 to December 2010. Prescription sequence symmetry analyses were used to identify LDA-induced H2RAs or PPIs users., Results: In December 2010, PPIs accounted for 9.9% of the prescriptions for buffered LDA users and 16.1% of those for enteric-coated LDA users. Incident use of PPIs occurred more frequently among enteric-coated LDA users than buffered LDA users (17.6% vs. 11.0%, respectively). Prescription sequence symmetry analyses of PPI use revealed significant associations with enteric-coated LDA use, resulting in adjusted sequence ratios of 1.82 (95%CI, 1.11 - 3.03) and 1.87 (95% CI, 1.26 - 2.83) at intervals of 182 and 365 days, respectively. Enteric-coated LDA users tended to initiate PPI therapy on the same date more frequently than buffered LDA users (35.1% vs. 10.8%, respectively)., Conclusions: Our findings do not support the notion that entericcoated LDA products confer a lower risk for GI complications than buffered formulations, but may conversely imply that the risk of GI complications associated with buffered LDA is lower than that of enteric-coated LDA.

Gastric endoscopic submucosal dissection (ESD) causes artificial gastric ulcers and there is no consensus regarding the optimal perioperative management in terms of prevention of intra- or postoperative bleeding and promotion of healing. Traditionally, 8-week administration of proton pump inhibitors (PPI) and mucosal protective agents were used in the same way as for peptic ulcer management. However, recent studies have revealed that prior use of PPI might reduce intraoperative bleeding or early-phase postoperative bleeding, and combination of histamine-2 receptor antagonist (H2RA), and second-look endoscopy might have a similar effect on postoperative bleeding to PPI. Additionally, the advantage of PPI over H2RA is not proven and the optimal duration of PPI may be shortened until 2 weeks when the deteriorating factors for ESD ulcer are excluded. Furthermore, mucosal protective agents may facilitate ulcer healing. Further studies are needed to determine the optimal treatment protocol before and after ESD for both prevention of bleeding complication and promotion of ulcer healing, by using available antisecretory agents and mucosal protective agents., (© 2013 The Authors. Digestive Endoscopy © 2013 Japan Gastroenterological Endoscopy Society.)

Objectives: Approximately 10% of patients with reflux esophagitis (RE) are not cured with the standard 8-week q.d. regimen with a proton pump inhibitor (PPI). Thus, b.i.d. dosing is often used in refractory RE (rRE) patients, although there has been no report of endoscopically confirmed healing with b.i.d. dosing of PPIs. This study aimed to assess the efficacy and safety of 8-week therapy with rabeprazole (RPZ) sodium at 20 mg b.i.d. or 10 mg b.i.d. as compared with RPZ at 20 mg q.d. in patients with RE refractory to the standard PPI regimen in Japan., Methods: Endoscopically confirmed rRE patients (Los Angeles grade A-D) who had received a standard PPI regimen for at least 8 weeks were randomized in a double-blind manner into groups receiving RPZ at 20 and 10 mg b.i.d. or 20 mg q.d. (control) daily for up to 8 weeks. The primary efficacy endpoint was the rate of endoscopically confirmed healing after week 8., Results: A total of 337 rRE patients treated at 71 sites were randomized. The rate of endoscopically confirmed healing after 8 weeks was significantly higher in those who received RPZ at 20 mg b.i.d. (77.0%, P = 0.003) and 10 mg b.i.d. (78.4%, P = 0.001) as compared with 20 mg q.d. (58.8%), and the rates of resolution of heartburn after week 8 were 80.0%, 74.0%, and 56.4%, respectively. All treatment regimens were well tolerated., Conclusions: Regimens of RPZ at 20 and 10 mg b.i.d. for 8 weeks were more effective than 20 mg q.d. with regard to endoscopically confirmed healing and symptom resolution of RE refractory to a standard PPI regimen.

Background: To seek a promising therapeutic regimen for proton pump inhibitor (PPI)-refractory patients with gastroesophageal reflux disease (GERD) after the standard PPI treatment, we compared the efficacies of rikkunshito (a Japanese traditional medication) combined with rabeprazole (RPZ) and a double dose of RPZ in a prospective randomized multicenter trial in Japanese PPI-refractory GERD patients., Methods: One hundred and four patients with GERD symptoms remaining after 4-week treatment with RPZ (10 mg/day) were randomly assigned to 4 weeks of either combination therapy [rikkunshito (7.5 g/day) with a standard dose of RPZ (10 mg/day)] or a double dose of RPZ (20 mg/day). The primary endpoint was the improvement rate, calculated based on the frequency scale for the symptoms of GERD (FSSG) before and after treatment. Subgroup analysis was also performed with respect to each subject's background factors such as reflux esophagitis (RE)/non-erosive GERD (NERD), age, gender, and body mass index (BMI)., Results: Four-week treatment with rikkunshito combined with RPZ significantly decreased the FSSG score from 17.6 ± 6.5 to 12.0 ± 6.9, similar to the decrease seen on treatment with a double dose of RPZ. Regarding the therapeutic improvement rate, there were also significant effects in both groups. However, in the subgroup analysis based on RE/NERD, the improvement rate of male NERD patients in the rikkunshito group was significantly greater than that of such patients in the other group (P < 0.05). In the rikkunshito group, the treatment was more effective in NERD patients with a low BMI than in those with a high BMI (P < 0.05)., Conclusion: Rikkunshito combined with standard-dose RPZ therapy may be a useful new strategy for PPI-refractory GERD patients.

Background and Aims: Proton pump inhibitors (PPI) have been rarely used for prevention of upper gastrointestinal bleeding (UGIB) induced by non-steroidal anti-inflammatory drugs (NSAIDs) and/or aspirin in Japan. The increased incidence of UGIB in the aged society is becoming a serious problem. The aim of this study was to retrospectively evaluate whether PPI can prevent UGIB., Methods: We examined records of 2367 patients (aged 67.9 ± 15.1 years, male 1271) attending the only hospital serving the rural area, with little population movement. We investigated the correlation between the frequency of usage of medicine (PPI, histamine 2 receptor antagonists [H2RA], NSAIDs, aspirin) and incidence of UGIB over 12 years. UGIB was defined as cases with hematemesis and/or melena and definite bleeding at upper gastrointestinal endoscopy. The annual incidence of UGIB of inhabitants (16,065 ± 375.3 persons/year) was evaluated. The frequency of usage of medicine was compared with the total number of patients prescribed any medication (1080 ± 33.2 persons/year)., Results: The frequency of PPI usage has increased significantly 4.6%→30.8% (P < 0.05). NSAIDs and aspirin usage increased significantly in the latter half of the survey period (P < 0.05). The annual incidence of UGIB significantly decreased 160.8 →23.6/100,000 inhabitants per annum (P ≤ 0.05) due to widespread use of PPI. No patients died due to UGIB after 2006. The incidence of UGIB and the prevalence of PPI usage were found to have a negative correlation (r = -0.804, P = 0.0016)., Conclusions: By widespread use of PPI, UGIB and related death has declined significantly. This survey showed that continuous PPI treatment decreases UGIB and related death in community medicine., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background/aims: The management of peptic ulcers has dramatically changed and the incidence of elective surgery for gastroduodenal peptic ulcers has markedly decreased; hence, the incidence of emergency surgery for perforated peptic ulcers has slightly increased. In select cases, conservative therapy can be used as an alternative for treating perforated gastroduodenal ulcers. In this study, we evaluated the efficacy of percutaneous abdominal drainage for the conservative treatment of perforated gastroduodenal ulcers., Methodology: We retrospectively studied 51 patients who had undergone conservative therapy for perforated gastroduodenal ulcers. These patients were divided into 2 groups on the basis of the initial treatment with conservative therapy with or without percutaneous drainage: group PD included patients who had undergone percutaneous drainage and group NPD, patients who had undergone non-percutaneous drainage., Results: In the PD group, 14.3% (n=3) of the patients did not respond to conservative therapy, while this value was 43.3% (n=13) in the NPD group. The 2 groups differed significantly with respect to conversion from conservative therapy to surgery (p<0.0352)., Conclusions: Conservative therapy for perforated gastroduodenal ulcers should be performed only in the case of patients meeting the required criteria; its combination with percutaneous intraperitoneal drainage is effective as initial conservative therapy.

Objective: Triple therapy with rabeprazole (RPZ), amoxicillin (AMPC) and metronidazole (MNZ) (RPZ+AMPC+MNZ therapy: RAM therapy) has been approved by the Japanese Ministry of Health, Labour and Welfare as a second-line therapy for Helicobacter pylori-positive gastric and duodenal ulcers in Japan. The present multicenter prospective observational study aimed to investigate the safety and efficacy of RAM therapy in clinical practice., Methods: Patients with H. pylori-positive gastric or duodenal ulcers (including ulcer scars) in whom first-line therapy was unsuccessful were administered 10 mg of RPZ, 750 mg of AMPC and 250 mg of MNZ twice daily for seven days (total: 14 doses) based on an approved dose and regimen. Patient background factors, including complications, previous medical history, concomitant drugs, eradication results and adverse events were recorded by the investigator., Results: The incidence of adverse drug reactions was 2.21% and the H. pylori eradication rate was 92.8%. Subgroup analyses performed to investigate the patient background factors affecting safety and efficacy revealed no factors that significantly affected the incidence of adverse drug reactions or the H. pylori eradication rate., Conclusion: Amid reports of decreased eradication rates with clarithromycin-based first-line therapy, the >90%H. pylori eradication rate achieved in the present study demonstrates the clinical efficacy of RAM therapy in subjects in whom first-line therapy is unsuccessful.

Background: Data on acid and non-acid reflux patterns and esophageal function in Japanese patients with non-erosive reflux disease (NERD) are limited. The aim of this study was to use combined multichannel intraluminal impedance pH monitoring (MII-pH) and high-resolution manometry (HRM) to investigate the characteristics of Japanese patients who were treated with a "double-dose" (20 mg) of rabeprazol (a proton-pump inhibitor; PPI) for persistent symptoms of NERD., Methods: Twenty-five patients who complained of typical gastroesophageal reflux disease symptoms, which had occurred more than twice a week despite treatment with rabeprazol, were enrolled in the study. All patients underwent upper endoscopy, esophageal HRM, and 24-h MII-pH monitoring while double-dose PPI therapy was continued., Results: Twelve (48.0%) of the patients had a positive symptom index (SI) with 234 recorded symptoms, 127 (54.3%) of which were related to reflux episodes. Of those with reflux episodes, 29 (22.8%) were related to acid reflux, while 98 (77.2%) were the result of a weaker acidic reflux. In acid reflux and in mixed (liquid-gas) reflux, the proximal esophageal region was involved to a significantly greater degree (P<0.002 and P=0.005, respectively) than the distal region. In liquid reflux, there was no difference between the distal and proximal regions. HRM showed that proximal motility parameters were significantly more defective than in those of healthy volunteers., Conclusions: MII-pH monitoring indicated that weakly acidic reflux and mixed refluxate in the proximal esophagus is the major cause of persistent symptoms in patients with NERD who are being treated with PPI. HRM showed that proximal esophageal dysfunction might be a key condition that facilitates reflux.

Objective: Although aspirin has been widely prescribed for the prevention of cardiovascular events, its risk of gastrointestinal complications is of great concern. Despite expectations for such, few data are available on the prevalence or incidence of gastrointestinal complications in aspirin users in Japan. The Management of Aspirin-induced GastroIntestinal Complications (MAGIC) is the first attempt at collaboration among cardiologists, neurologists, and gastroenterologists to obtain such findings. We aim to share all about the MAGIC study., Methods: The MAGIC is a prospective cohort study involving patients taking low-dose aspirin (81 mg to 325 mg per day) for longer than 1 month. Participants are recruited from multiple disease categories, including those with coronary artery disease, cerebrovascular disease, atrial fibrillation, and other cardiovascular conditions requiring antithrombotic therapy. Its duration of follow-up is 1 year. At baseline and 1 year follow-up, all participants will undergo endoscopic examination. The primary outcome is upper gastrointestinal complications, classified as erosions, ulcers, and bleeding. Secondary outcomes include LANZA score, non-fatal cardiovascular events, any bleeding, cancer, and death., Results: 1,533 participants were entered in the MAGIC cohort. By underlying disease, about 45% of them had coronary artery diseases, followed by cerebrovascular diseases (35%), atrial fibrillation (10%) and other cardiovascular diseases (10%)., Conclusions: The MAGIC study will yield important findings with regard to the prevalence and incidence of gastrointestinal complications and related risk factors for low-dose aspirin users. It may also report that use of anti-secretory agents such as proton pump inhibitors reduces the risk of such complications.

Backgrounds: Some non-erosive reflux disease (NERD) and reflux esophagitis (RE) patients are unresponsive to a proton pump inhibitor (PPI) at standard dose. We investigated the predictive marker of the efficacy of PPI for GERD patients including NERD and RE treated with standard and increased doses of a PPI., Methods: Patients with symptomatic gastroesophageal reflux disease (GERD) (NERD and RE) were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. The RPZ dosage was increased to 10 mg twice daily for an additional 2 weeks and again to 20 mg twice daily for another 2 weeks if heartburn was not relieved. Baseline characteristics and efficacy of RPZ were assessed on the basis of a heartburn diary and frequency scale for symptoms of GERD (FSSG)., Results: Complete heartburn relief rates after 4 weeks were 42.5% (31/73) and 67.9% (19/28) in NERD and RE groups, respectively, which rose to 68.9 and 91.7% after dose escalation. Multivariate analysis revealed that parameters associated with resistance to RPZ 10 mg once daily were female, non-smoking, frequent heartburn, low score for question 4 (Q4) of the FSSG (subconsciously rubbing the chest), and high scores for Q3 (heavy stomach after meal) and Q7 (unusual sensation in the throat). Frequent heartburn and a high score for Q7 were associated with resistance to RPZ 20 mg twice daily. FSSG scores of patients resistant to RPZ were significantly higher in comparison with responders before and during treatment., Conclusions: FSSG could predict response to a PPI for symptomatic GERD. Increase of RPZ dose is useful for treatment of GERD refractory to the standard dose of RPZ.

Aim: To investigate the predictors of success in step-down of proton pump inhibitor and to assess the quality of life (QOL)., Methods: Patients who had heartburn twice a week or more were treated with 20 mg omeprazole (OPZ) once daily for 8 wk as an initial therapy (study 1). Patients whose heartburn decreased to once a week or less at the end of the initial therapy were enrolled in study 2 and treated with 10 mg OPZ as maintenance therapy for an additional 6 mo (study 2). QOL was investigated using the gastrointestinal symptom rating scale (GSRS) before initial therapy, after both 4 and 8 wk of initial therapy, and at 1, 2, 3, and 6 mo after starting maintenance therapy., Results: In study 1, 108 patients were analyzed. Their characteristics were as follows; median age: 63 (range: 20-88) years, sex: 46 women and 62 men. The success rate of the initial therapy was 76%. In the patients with successful initial therapy, abdominal pain, indigestion and reflux GSRS scores were improved. In study 2, 83 patients were analyzed. Seventy of 83 patients completed the study 2 protocol. In the per-protocol analysis, 80% of 70 patients were successful for step-down. On multivariate analysis of baseline demographic data and clinical information, no previous treatment for gastroesophageal reflux disease (GERD) [odds ratio (OR) 0.255, 95% CI: 0.06-0.98] and a lower indigestion score in GSRS at the beginning of step-down therapy (OR 0.214, 95% CI: 0.06-0.73) were found to be the predictors of successful step-down therapy. The improved GSRS scores by initial therapy were maintained through the step-down therapy., Conclusion: OPZ was effective for most GERD patients. However, those who have had previous treatment for GERD and experience dyspepsia before step-down require particular monitoring for relapse.

Lansoprazole (LPZ), amoxicillin (AMPC) and clarithromycin (CAM) are commonly used drugs (LAC regimen) for Helicobacter pylori (H. pylori) eradication, but the eradication rate with this regimen was reported to be 70% to 90%. A few studies have reported that a successful eradication was associated with the CYP2C19 genotype, which influences the metabolism of proton pump inhibitors (PPI) including LPZ. This study examined the changes in the H. pylori eradication rates between the periods before and after the commencement of a routine genetic test for CYP2C19 at the Daiko Medical Center in Nagoya, Japan, in November, 2005. Subjects were patients who visited the Center during the period from June, 2004 to August, 2010. The patients were classified into three groups according to their CYP2C19 genotype: rapid metabolizers (RM) with a *1*1 genotype, intermediate metabolizers (IM) with a *1*2 or *1*3 genotype, and poor metabolizers (PM) with a *2*2, *2*3, or *3*3 genotype. Non-rapid metabolizers (IM and PM) were basically treated with a LAC regimen, while RMs were treated with a RAM reg imen(rabeprazole, AMPC, and metronidazole). The eradication rate was 80.0% (n=90) for the period without the genetic testing and 88.7% (n=124) for the period with the genetic testing (chi2=3.11, p=0.078). The age-sex adjusted odds ratio of eradication success was 2.29 (95% confidence interval, 0.99-5.28, p=0.051) for the latter period relative to the former period among those less than 70 years of age. Those results suggested that the routine genetic test which allows a choice of the RAM regimen for R M improved the eradication rate.

Objective: The aim of this prospective clinical study was to evaluate the efficacy and safety of long-term proton pump inhibitor (PPI) treatment for two years in Japanese patients with reflux esophagitis (RE)., Methods: The efficacy and safety of two-year (104-week) treatment with rabeprazole (RPZ) 10 mg were studied in patients confirmed to have been cured of RE by PPI and who required long-term maintenance therapy with PPI. We performed serial endoscopy, checked gastroesophageal reflux disease (GERD) symptoms, adverse events, laboratory values and serum gastrin. We also monitored gastric mucosal histology, atrophy and polyps., Results: The endoscopic non-relapse rate for RE was 87.3% for the 104-week period. GERD symptoms improved based on the fact that the mean change from baseline in GERD symptom score after treatment was a negative value. Treatment was safe; and atrophy was found to have developed in virtually no cases. A few new benign fundic gland or hyperplastic polyps developed throughout the study, but no ECL carcinoids were found to have developed. Serum gastrin levels tended to increase up to 24 weeks, but there were no subsequent changes thereafter up to 104 weeks., Conclusion: The results confirmed oral RPZ 10 mg to be effective for maintenance therapy in Japanese patients with RE. Although effects on the gastric mucosa were not ruled out, long-term use of RPZ was confirmed to be safe overall.

This two-way crossover study investigated possible differences between the proton pump inhibitors, omeprazole and rabeprazole, in their effect on gastric acid secretion in Japanese subjects with differing cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) genotypes. A total of 23 Helicobacter pylori-negative healthy volunteers received omeprazole 20 mg/day and rabeprazole 10 mg/day. Each drug treatment was given for a continuous 7-day period allocated in random order, with an interval of at least 1 week between drug treatment periods to allow for wash-out. Intragastric pH was measured on days 1 and 7. Overall median intragastric pH levels at 7 and 8 h after the first administration were significantly higher with omeprazole. There was no significant difference in intragastric pH in homozygous extensive metabolizers, whereas intragastric pH was significantly higher with omeprazole in combined data from heterozygous extensive metabolizers and poor metabolizers at 6, 7 and 8 h after the first drug administration. There were no significant differences in intragastric pH between omeprazole and rabeprazole irrespective of genotype on day 7 of administration. In conclusion, on day 1 the time to onset of the antisecretory action of 20 mg/day omeprazole was more rapid than that of 10 mg/day rabeprazole in Japanese individuals who have a higher incidence of the CYP2C19 poor metabolizer genotype, however by day 7 no difference in antisecretory effect was found, regardless of genotype.

The recent trend of gastroduodenal ulcer bleeding in Japan has not been elucidated in detail and the data for a new categorized type, artificial ulcer bleeding, is completely lacking. The purpose of this paper is to elucidate current managements and outcomes of peptic and artificial ulcer bleeding in Japan. A retrospective multicenter study of consecutive case series was carried out during one year at nine departments of high-volume hospitals in Japan. The study included 325 consecutive patients (239 with peptic ulcers and 86 with artificial ulcers) with bleeding nonmalignant gastroduodenal ulcers that were revealed by emergency endoscopy between January 2008 and December 2008. Hemostasis was carried out mainly using endoscopic treatments. Rates of successful initial hemostasis, rebleeding, transfer to surgery, and death were recorded according to peptic and artificial ulcer bleeding. Additionally, preferred endoscopic methods, concomitant use of antisecretory drugs, and timing of second-look endoscopy were also measured. A total of 227 (99.1%) of 229 peptic ulcer patients with endoscopic treatment and all (100%) 84 artificial ulcer patients underwent successful tentative hemostasis. Rebleeding occurred in 23 peptic ulcer patients (10.1%) and 10 artificial ulcer patients (11.9%). One peptic ulcer patient and two artificial ulcer patients had final surgical rescue due to rebleeding. No death was observed. Monotherapy was predominant (around 65% of cases) in both types of ulcers. The coagulation forceps method was more frequently applied in artificial ulcers (P < 0.05). A per oral proton pump inhibitor was more frequently used in artificial ulcers (P < 0.05), although an intravenous proton pump inhibitor was used in the majority of patients in both types of ulcers. The frequency of second-look endoscopy in peptic ulcers (88%) was significantly higher than that in artificial ulcers (71%) (P < 0.05). There seemed to be no rule as to the timing of second-look endoscopy, although it was most frequently performed on the day after hemostasis. The recent outcomes of endoscopic treatment for nonmalignant gastroduodenal bleeding in Japan were excellent in both peptic and artificial ulcers with similar efficacies. Although they were minor findings, some differences in applied endoscopic methods, concomitant use of antisecretory drugs, and presence of second-look endoscopy were observed.

The guidelines on the management of Helicobacter pylori were updated at the European Helicobacter study group third Maastricht consensus conference in March 2005. Especially, this conference emphasis on the management of non ulcer dyspepsia, GERD, and the patients who use non steroidal anti-inflammatory drug. Eradication of H. pylori is recommended in patients with peptic ulcer, low grade MALT lymphoma, atrophic gastritis, unexplained iron deficiency anemia, chronic idiopathic thrombocytopenic purpura and first degree relatives of patients with gastric cancer. H. pylori eradication is less effective than proton pomp inhibitor(PPI) treatment in preventing ulcer recurrence in long term NSAIDs users. This meeting also emphasized on the relationship between H. pylori and gastric cancer. The guideline concluded that H. pylori eradication has the potential to reduce the risk of gastric cancer development. Japanese guideline in 2003 does not mention the effect of eradication for prevention of gastric cancer. The H. pylori eradication and new strategy should be desirable for global strategy of gastric cancer prevention.

Drug selection for the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer was analyzed pharmacoeconomically. Two patterns consisting of continuation of an NSAID plus administration of the prostaglandin (PG) preparation misoprostol (PG model) for 8 weeks and continuation of an NSAID plus administration of the proton-pump inhibitors omeprazole and lansoprazole (PPI model) for 8 weeks were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drugs and gastric ulcer, and cost-comparative analyses were conducted based on the number of persons who had ulcer healing as health outcomes. Costs were estimated with respect to health expenditures from the third-party payer (public) perspective. In the case of continuation of an NSAID plus administration of the proton-pump inhibitor omeprazole for 8 weeks, the health outcomes improved and costs were reduced in comparison with continuation of an NSAID plus administration of misoprostol, thus making the administration of omeprazole the dominant choice. With continuation of an NSAID plus administration of lansoprazole for 8 weeks, the cost-savings of lansoprazole were inferior to those of misoprostol. The generic omeprazole product was the most cost-saving among the four drugs (misoprostol, original omeprazole product, generic omeprazole product, and lansoprazole) examined.