Efficacy and Safety of Vonoprazan in Patients With Nonerosive Gastroesophageal Reflux Disease: A Randomized, Placebo-Controlled, Phase 3 Study.

OBJECTIVES: To assess the efficacy and safety of vonoprazan on heartburn symptoms in patients with nonerosive reflux disease (NERD) (ClinicalTrials.gov: NCT02954848). METHODS: This phase 3, double-blind, placebo-controlled study included Japanese patients aged 20 years and older with grade N/M NERD and recurrent heartburn. Patients received placebo (n = 245) or vonoprazan 10 mg (n = 238) for 4 weeks. The primary efficacy outcome was frequency of heartburn experienced by patients during the treatment period (proportion of days without heartburn). Other outcomes included cumulative improvement rates of heartburn, proportion of patients with complete heartburn resolution in the fourth week of treatment, and safety. RESULTS: Compared with placebo, the proportion of days without heartburn was not significantly higher in the vonoprazan group in the full analysis (primary end point, 72.55% vs 61.50%, vonoprazan vs placebo, P = 0.0643) but was significantly higher in the per-protocol-set sensitivity analysis (P = 0.0341). Early onset of response and significantly greater cumulative improvement rates of heartburn were observed in the vonoprazan group (P = 0.0003). In a post hoc analysis, a greater proportion of patients with complete heartburn resolution in the fourth week of treatment were reported in the vonoprazan group (P = 0.0023). Incidence of treatment-emergent adverse events was similar between treatment groups (23.5% vs 23.3%); most treatment-emergent adverse events were mild in severity. DISCUSSION: Although vonoprazan 10 mg was not superior to placebo with respect to proportion of days without heartburn in Japanese patients with NERD, vonoprazan had a significantly higher cumulative rate of heartburn resolution and was well tolerated.

The safety and effectiveness of vonoprazan-based Helicobacter pylori eradication therapy; a prospective post-marketing surveillance.

Background: The safety and effectiveness of vonoprazan-based Helicobacter pylori (H. pylori) eradication therapy in routine clinical practice, and patient characteristics that influence safety and effectiveness, have not been well investigated.Methods: H. pylori-positive patients with gastric ulcer, duodenal ulcer, idiopathic thrombocytopenic purpura, history of endoscopic treatment of early gastric cancer, and gastritis were enrolled. Patients received vonoprazan 20 mg, amoxicillin (AMPC) 750 mg, and clarithromycin (CAM) 200-400 mg twice daily for 7 days for the first-line eradication. For the second-line eradication, vonoprazan, AMPC, and metronidazole (MTZ) 250 mg were administered. The incidence of adverse drug reactions (ADRs) and eradication rates were evaluated.Results: The incidences of ADRs with vonoprazan/AMPC/CAM and vonoprazan/AMPC/MTZ were 3.22% (16/497) and 1.89% (1/53), respectively. Commonly reported ADRs were diarrhea, nausea, dysgeusia, feces soft, and rash. The eradication rates of the first-line therapy and the second-line therapy were 91.24% (427/468) and 95.45% (42/44), respectively. No notable differences in ADRs and eradication rates were observed when stratified by patient demographic characteristics.Conclusion: No new safety concerns were observed, and the effectiveness of vonoprazan-based triple therapy was confirmed in routine clinical practice.Trial registration: This study is registered at the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-153003).

Maintenance for healed erosive esophagitis: Phase III comparison of vonoprazan with lansoprazole.

AIM: To compare vonoprazan 10 and 20 mg vs lansoprazole 15 mg as maintenance therapy in healed erosive esophagitis (EE). METHODS: A total of 607 patients aged ≥ 20 years, with endoscopically-confirmed healed EE following 8 wk of treatment with vonoprazan 20 mg once daily, were randomized 1:1:1 to receive lansoprazole 15 mg (n = 201), vonoprazan 10 mg (n = 202), or vonoprazan 20 mg (n = 204), once daily. The primary endpoint of the study was the rate of endoscopically-confirmed EE recurrence during a 24-wk maintenance period. The secondary endpoint was the EE recurrence rate at Week 12 during maintenance treatment. Additional efficacy endpoints included the incidence of heartburn and acid reflux, and the EE healing rate 4 wk after the initiation of maintenance treatment. Safety endpoints comprised adverse events (AEs), vital signs, electrocardiogram findings, clinical laboratory results, serum gastrin and pepsinogen I/II levels, and gastric mucosa histopathology results. RESULTS: Rates of EE recurrence during the 24-wk maintenance period were 16.8%, 5.1%, and 2.0% with lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg, respectively. Vonoprazan was shown to be non-inferior to lansoprazole 15 mg (P < 0.0001 for both doses). In a post-hoc analysis, EE recurrence at Week 24 was significantly reduced with vonoprazan at both the 10 mg and the 20 mg dose vs lansoprazole 15 mg (5.1% vs 16.8%, P = 0.0002, and 2.0% vs 16.8%, P < 0.0001, respectively); by contrast, the EE recurrence rate did not differ significantly between the two doses of vonoprazan (P = 0.1090). The safety profiles of vonoprazan 10 and 20 mg were similar to that of lansoprazole 15 mg in patients with healed EE. Treatment-related AEs were reported in 11.4%, 10.4%, and 10.3% of patients in the lansoprazole 15 mg, vonoprazan 10 mg, and vonoprazan 20 mg arms, respectively. CONCLUSION: Our findings confirm the non-inferiority of vonoprazan 10 and 20 mg to lansoprazole 15 mg as maintenance therapy for patients with healed EE.

Vonoprazan, a Novel Potassium-Competitive Acid Blocker, Should Be Used for the Helicobacter pylori Eradication Therapy as First Choice: A Large Sample Study of Vonoprazan in Real World Compared with Our Randomized Control Trial Using Second-Generation Proton Pump Inhibitors for Helicobacter pylori Eradication Therapy.

BACKGROUND/AIMS: Phase III study demonstrated that vonoprazan-based Helicobacter pylori eradication therapy achieved higher eradication rate compared with lansoprazole. However, there is no study that evaluated the efficacy of vonoprazan in a large sample in real world. We investigated the eradication rate and safety of vonoprazan-based eradication therapy compared with our randomized control trial using second-generation proton pump inhibitor (PPIs). METHODS: (First study) A total of 147 patients who have H. pylori infection were randomly assigned to receive either, esomeprazole (EPZ) group and rabeprazole (RPZ) group. (Second study) 1,688 patients who have H. pylori infection underwent primary eradication with triple therapy involving vonoprazan. In both studies, triple therapy with amoxicillin, clarithromycin, and PPI or vonoprazan was performed, and eradication effect was assessed by an urea breath test. RESULTS: (First study) Eradication rate was 77.5% in the EPZ group and 68.4% in the RPZ group; no significant difference was observed between the 2 groups. (Second study) The successful primary eradication rate was 90.8%. There was no severe adverse effect. CONCLUSIONS: The eradication rate of vonoprazan-based triple therapy was remarkably higher compared with second-generation PPIs-based triple therapy in real world. Vonoprazan is very likely to become the first option for future eradication therapy.

Vonoprazan prevents low-dose aspirin-associated ulcer recurrence: randomised phase 3 study.

OBJECTIVE: Compare efficacy and safety of vonoprazan and lansoprazole for secondary prevention of low-dose aspirin (LDA)-associated peptic ulcers in a 24-week study and long-term extension therapy in separate study. DESIGN: Double-blind, randomised, non-inferiority study; single-blind extension study at 104 Japanese sites, including 621 patients (439 in extension) with a history of peptic ulcers who required long-term LDA therapy. Randomised (1:1:1, computer generated) patients received lansoprazole 15 mg (n=217), vonoprazan 10 mg (n=202) or vonoprazan 20 mg (n=202) once daily for 24 weeks (double blind) and ≤2 years (extension). The following measurements were made: 24-week (primary outcome; double blind) and 12-week peptic ulcer recurrence rate, 24-week GI bleeding rate, cumulative incidences of peptic ulcer recurrence and GI bleeding, treatment-emergent adverse events, laboratory results, serum gastrin and pepsinogen I/II concentrations. RESULTS: The 24-week peptic ulcer recurrence rate was 2.8%, 0.5% and 1.5% in the lansoprazole 15 mg, vonoprazan 10 mg and vonoprazan 20 mg groups, respectively. Vonoprazan was non-inferior (Farrington and Manning test: margin 8.7%, significance level 2.5%) to lansoprazole. In the post hoc analyses of the extension study, peptic ulcer recurrence rates were significantly lower with vonoprazan 10 mg (log-rank test, P=0.039), but not vonoprazan 20 mg (P=0.260), compared with lansoprazole 15 mg. GI bleeding rates were higher with lansoprazole compared with two doses of vonoprazan in both 24-week study and extension study. CONCLUSION: Vonoprazan (10 and 20 mg) was as effective as lansoprazole (15 mg) in preventing peptic ulcer recurrence during LDA therapy, had a similar long-term safety profile and was well tolerated. TRIAL REGISTRATION NUMBERS: NCT01452763; NCT01456247.

Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study.

OBJECTIVE: To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use. DESIGN: A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study. RESULTS: The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference -2.2%,95% CI -6.2% to 1.8%, p<0.001; -2.1%,95% CI -6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified. CONCLUSION: The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg). TRIAL REGISTRATION NUMBERS: NCT01452750, NCT01456260; Results.

A randomized, double-blind study to evaluate the acid-inhibitory effect of vonoprazan (20 mg and 40 mg) in patients with proton-pump inhibitor-resistant erosive esophagitis.

BACKGROUND: Standard treatment for patients with erosive esophagitis (EE) is proton-pump inhibitors (PPIs), but some patients are resistant to PPIs. We aimed to evaluate the acid-inhibitory effects and efficacy of a novel potassium-competitive acid blocker (vonoprazan) in patients with PPI-resistant EE. METHODS: This randomized, double-blind, multicenter study of vonoprazan evaluated gastric and esophageal pH over a 24-hour period as the primary endpoint and EE healing rate as the secondary endpoint. Following a 7 to 14-day run-in period (lansoprazole 30 mg treatment), patients with endoscopically confirmed PPI-resistant EE received vonoprazan 20 mg or 40 mg for 8 weeks. RESULTS: Patients were randomized to receive vonoprazan 20 mg (n = 9) or 40 mg (n = 10). Over a 24-hour period; both groups showed a significant increase from baseline in the percentage of time gastric pH ≥ 4, referred to as pH 4 holding time ratio (HTR): an increase from 73.21% to 96.46% in the 20 mg group, and from 69.97% to 100.00% in the 40 mg group. Increases from baseline in esophageal pH 4 HTRs were not significant. The 40 mg group showed greater increases in gastric and esophageal pH 4 HTRs compared with the 20 mg group, but differences between groups were not significant. After 8 weeks' treatment, the healing rate in subjects with baseline EE grades A-D was 60.0% (3/5 patients) in the 20 mg group and 71.4% (5/7 patients) in the 40 mg group. Vonoprazan was generally well tolerated. One patient (40 mg group) experienced four treatment-emergent adverse events (TEAEs) (unrelated to study drug), leading to study discontinuation. CONCLUSIONS: Vonoprazan 20 mg and 40 mg effectively inhibited gastric acid secretion over a 24-hour period with significantly increased gastric pH 4 HTR, and resulted in an EE healing rate > 60.0% in this study. Vonoprazan treatment may be valuable for patients with PPI-resistant EE.

Exploratory Research on Latent Esophageal Motility Disorders in Dysphagia Patients.

BACKGROUND/AIMS: High-resolution manometry (HRM) has been applied to assess esophageal motility disorders. However, the frequency and types of motility disorders in patients with dysphagia, which are frequently seen in clinical practice, are not clear. We evaluated latent esophageal motility disorders associated with dysphagia. METHODS: The study included patients without erosive esophageal mucosal damage and with dysphagia symptoms refractory to at least 8 weeks of standard-dose proton pump inhibitors. After enrolment, HRM was used to evaluate for esophageal motility disorder based on the Chicago classification. RESULTS: Esophageal motility disorder was found in 58 of 100 patients and was classified based on the causes: achalasia (13%), esophagogastric junction outflow obstruction (16%), distal esophageal spasms (3%), weak peristalsis (14%), frequently failed peristalsis (5%), and hypertensive peristalsis (7%). CONCLUSION: Primary esophageal motility disorder was found in approximately 50% of cases in dysphagia patients. Therefore, esophageal motility disorder is not an uncommon condition and should be sought for in order to elucidate precisely the cause of dysphagia.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015.

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

Albumin and apolipoprotein H mRNAs in human plasma as potential clinical biomarkers of liver injury: analyses of plasma liver-specific mRNAs in patients with liver injury.

CONTEXT: Plasma liver-specific mRNAs are useful biomarkers of hepatotoxicity in rats. OBJECTIVE: To investigate the potential application of liver-specific mRNAs as biomarkers for liver injury in humans. METHODS: We determined the plasma levels of liver-specific mRNAs by real-time qRT-PCR in healthy donors and patients with liver injury. RESULTS: Plasma levels of albumin (ALB) and apolipoprotein H (APOH) mRNAs increased in patients with elevated serum alanine aminotransferase. These mRNAs also increased in plasma after transcatheter arterial chemoembolization, which induces specific injury to liver. CONCLUSIONS: We demonstrated the potential application of plasma ALB and APOH mRNAs as clinical biomarkers for liver injury.

Evaluation of the Efficacy and Safety of Vonoprazan in Patients with Nonerosive Gastroesophageal Reflux Disease: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study.

BACKGROUND: For many patients, current treatments do not adequately resolve heartburn in nonerosive reflux disease (NERD). OBJECTIVE: To compare vonoprazan and placebo with respect to the frequency and severity of heartburn in patients with NERD. METHODS: This Phase III, double-blind, placebo-controlled, parallel-group, multicenter study included patients in Japan aged ≥20 years with Grade N or M NERD and recurrent acid reflux symptoms. Patients were blinded and randomized 1:1:1 to receive placebo or vonoprazan 10 mg or 20 mg. The primary efficacy outcome was the proportion of days without heartburn measured by patient scores during the 4-week treatment period. RESULTS: Eight hundred twenty-seven patients were randomized (placebo: n = 278, vonoprazan 10 mg: n = 278, and vonoprazan 20 mg: n = 271). Median proportion of days without heartburn was 7.4% (placebo), 10.3% (vonoprazan 10 mg), and 12.0% (vonoprazan 20 mg). Proportion of days without heartburn was not statistically significant between the vonoprazan and placebo groups (P = 0.2310 [10 mg] and P = 0.0504 [20 mg]). Mean severity of heartburn was significantly higher with placebo (median score = 1.070) than with vonoprazan 10 mg (median score = 0.990; P = 0.0440) and 20 mg (median score = 0.960; P = 0.0139). Patients whose symptoms improved at Week 2 experienced significantly increased proportion of days without heartburn and reduced mean severity of heartburn at Week 4 with vonoprazan compared with placebo (proportion of days without heartburn: P = 0.0004 [10 mg] and P = 0.0001 [20 mg] and mean severity: P < 0.0001 [10 mg] and P < 0.0001 [20 mg]). A significant difference in median proportion of days without heartburn was observed for vonoprazan 20 mg compared with placebo in patients with Grade M NERD. Incidence of treatment-emergent adverse events was 32.7% (placebo), 27.7% (vonoprazan 10 mg), and 28.0% (vonoprazan 20 mg). CONCLUSIONS: Vonoprazan at doses of 10 mg and 20 mg are not superior to placebo with respect to proportion of days without heartburn, whereas the mean severity of heartburn is lower with vonoprazan compared with placebo in patients with NERD. ClinicalTrials.gov identifier: NCT01474369.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Rising TAK-438 (Vonoprazan) Doses in Healthy Male Japanese/non-Japanese Subjects.

OBJECTIVES: To evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 (vonoprazan, a potassium-competitive acid blocker) in healthy male subjects. METHODS: In two phase I, randomized, double-blind, placebo-controlled, single rising-dose studies, healthy male subjects (Japan N=84; UK N=63) received a single TAK-438 dose (1-120 mg in Japan and 1-40 mg in the UK). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (intragastric pH). RESULTS: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax up to 2 h). Estimated mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional. No clear difference in TAK-438 pharmacokinetics was observed between Japanese and non-Japanese subjects. Acid suppression was dose dependent and similar in both studies. The 24-h intragastric pH ≥4 holding time ratio with 40 mg TAK-438 was 92% in Japan and 87% in the UK. TAK-438 was well tolerated, with no adverse events reported in Japanese subjects; 10 of 63 UK subjects experienced 12 treatment-emergent adverse events (non-serious). Increases in serum gastrin and pepsinogen I and II concentrations were observed at doses ≥10 mg, but there were no changes in alanine aminotransferase concentrations. CONCLUSIONS: Single oral doses of TAK-438 20-120 mg caused rapid, profound, and 24-h suppression of gastric acid secretion in healthy male subjects, regardless of geographical region, and TAK-438 was well tolerated at all doses studied, making it a potential alternative to proton pump inhibitors for the treatment of acid-related disorders.

Therapeutic effect of intensive granulocyte and monocyte adsorption apheresis combined with thiopurines for steroid- and biologics-naïve Japanese patients with early-diagnosed Crohn's disease.

BACKGROUND: Early induction with biologics can reduce complications in patients with Crohn's disease (CD) and improve their quality of life. The safety of biologics, however, is uncertain. Granulocyte and monocyte adsorptive apheresis (GMAA) is a natural biologic therapy that selectively removes granulocytes and monocytes/macrophages and has few severe adverse effects. The effects of GMAA on patients with early-diagnosed CD are unclear. We investigated the effects of GMAA combined with thiopurines on patients with early-diagnosed CD. METHODS: Twenty-two corticosteroid- and biologic-naïve patients with active early-diagnosed CD were treated with intensive GMAA (twice per week) combined with thiopurines administration. Active early-diagnosed CD was defined as follows: (i) within 2years after diagnosis of CD, (ii) with no history of both surgical treatment and endoscopic dilation therapy, and (iii) Crohn's Disease Activity Index (CDAI) was higher than 200. We investigated the ratios of clinical remission defined as CDAI was less than or equal to 150 at 2, 4, 6 and 52weeks and mucosal healing defined as a Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) as 0 at 6 and 52weeks. Adverse events were recorded at each visit. RESULTS: The ratios of clinical remission at 2, 4, and 6 weeks were 6 of 22 (27.2%), 12 of 22 (54.5%), and 17 of 22 (77.2%), respectively. At 52 weeks, 18 of 21 patients (81.8%) were in clinical remission. The ratios of mucosal healing at 6 and 52 weeks were 5 of 22 (22.7%) and 11 of 22 (50%), respectively. The difference in the mucosal healing ratio was significant between 6 and 52 weeks (p = 0.044). No serious adverse effects were observed during this study. CONCLUSIONS: Combination therapy with intensive GMAA and thiopurines administration rapidly induced high remission in patients with active early-diagnosed CD without serious adverse effect. Mucosal healing was observed in 50.0% of enrolled patients. This combination therapy might be a rational option for patients with early-diagnosed CD.

Sleep disturbances and refractory gastroesophageal reflux disease symptoms in patients receiving once-daily proton pump inhibitors and efficacy of twice-daily rabeprazole treatment.

BACKGROUND: Nighttime acid reflux that influences refractory symptoms is strongly associated with sleep disturbances. The aim of this study was to examine the associations between sleep disturbances and refractory gastroesophageal reflux disease (GERD) symptoms in patients receiving once daily proton pump inhibitors (PPI) and the efficacy of twice-daily rabeprazole treatment. METHOD: In a multicenter survey, 433 GERD patients receiving once-daily PPI treatment completed a self-report questionnaire that included the Frequency Scale for the Symptoms of GERD (FSSG) and questions about sleep disturbances. Study cases were defined as patients with an FSSG score ≥8. Of the 222 study cases, 106 individuals received rabeprazole 10 mg twice daily for 4-8 weeks. RESULTS: Of the 433 subjects, 222 patients revealed FSSG scores of ≥8. Use of a half dose of PPI was associated with such cases. PPI-refractory symptoms were found in 46% of patients with standard-dose PPI treatment. Nighttime symptoms (OR = 2.56), daytime sleepiness (OR = 1.64), and poorer sleep quality (OR = 1.67) were significantly associated with refractory GERD symptoms. Twice-daily rabeprazole treatment significantly improved FSSG scores and sleep disturbances. CONCLUSION: About half of the GERD patients receiving once-daily standard-dose PPI treatment had refractory GERD symptoms. Sleep disturbances were significantly associated with refractory GERD symptoms. Twice-daily rabeprazole treatment was effective in such cases.

Endoscopic evaluation of low-dose aspirin-induced gastric and duodenal ulcers during prophylaxis with lansoprazole.

BACKGROUND/AIMS: To compare the endoscopic features of LDA-induced ulcers developing during secondary prophylaxis with lansoprazole (LPZ) and gefarnate (GFN). METHODOLOGY: All ulcers that had developed during prophylaxis with LPZ (15mg once daily) and GFN (50mg twice daily) in a prospective, randomized, double-blind trial, were reviewed and compared by a panel of expert endoscopists, based on endoscopic images available from the trial, to provide evidence for efficacy of LPZ versus GFN in secondary prophylaxis in patients with endoscopically confirmed ulcer scars. RESULTS: A total of 6 and 53 patients had developed gastric or duodenal ulcers during prophylaxis with LPZ and GFN, respectively. Six gastric ulcers seen in those given LPZ were "small" and "shallow", while, of the 38 gastric ulcers seen those given GFN, 44.7% and 55.3% were "medium" or "large" and "small", respectively. Ulcers associated with blood coagula were seen only in those given GFN. Duodenal ulcers developed in 15 and 0 patients given GFN and LPZ, respectively. CONCLUSIONS: The ulcers developing during prophylaxis with GFN and LPZ varied in their features. The study findings may be useful when devising a strategy for prophylaxis of ulcers in high-risk patients receiving LDA therapy in a routine clinical setting.

Predictive factors associated with the success of pneumatic dilatation in Japanese patients with primary achalasia: a study using high-resolution manometry.

BACKGROUND/AIMS: A new classification of achalasia using high-resolution manometry (HRM) has recently been suggested. Pneumatic dilatation (PD) is a common treatment for primary achalasia. The usefulness of the new classification and HRM for the treatment and follow-up of patients after PD is unknown. The aim of this study was to evaluate the PD effectiveness and the predictive factors of success in Japanese patients with achalasia using HRM and the new classification of achalasia. METHODS: Twenty-five patients were diagnosed with primary achalasia using HRM and treated by PD in our hospital. We evaluated symptom scores and esophageal manometry 6 and 12 months after the first PD. RESULTS: After the first PD treatment, remission occurred in 24 out of 25 (96.0%) patients at 6 months and in 19 out of 25 (76.0%) patients at 12 months. With the new classification of achalasia, the success rates were 83.3, 80.0 and 50% for types I, II and III, respectively, 12 months after PD. The median age of the successful group was significantly greater than that of the failure group (47.1 vs. 37.0 years, p < 0.05). The median residual lower esophageal sphincter (LES) pressure 6 months after PD in the successful group was significantly lower than that of the failure group (9.0 vs. 15.5 mm Hg, p < 0.05). CONCLUSION: Good predictors of PD success were old age (>40 years) and residual LES pressures less than 15 mm Hg 6 months after PD.

Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis positive for cytomegalovirus.

BACKGROUND AND AIM: Cytomegalovirus (CMV) exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies. The conditions under which CMV reactivation occurs in patients with UC, however, is unclear. In addition, the diagnostic and treatment strategies for UC positive for CMV have not been established. Granulocyte and monocyte adsorptive apheresis (GMAA) is natural biological therapy for UC in which the granulocytes/macrophages producing inflammatory cytokines are removed. We investigated the rate of colonic CMV reactivation and the efficacy of GMAA in active UC patients positive for CMV without concomitant corticosteroid (CS) therapy. METHODS: Fifty-one active UC patients without concomitant CS therapy were enrolled. Colonic CMV reactivation was examined by real-time polymerase chain reaction (PCR) using biopsy specimen and/or histological examination. All patients were treated with intensive GMAA (twice per week). Rates of clinical remission and mucosal healing were compared between UC patients positive and negative for CMV. RESULTS: Of 51 patients, 15 (29.4%) were diagnosed as CMV positive. The clinical remission rates following intensive GMAA did not differ between UC patients positive and negative for CMV (73.3% vs 69.4%, p=0.781). Proportion of patients achieving mucosal healing was also similar between these two groups. CMV-DNA became negative in all UC patients positive for CMV who achieved clinical remission 1 week after completion of intensive GMAA. CONCLUSIONS: Intestinal inflammation might trigger CMV reactivation in a subpopulation of active UC patients without CS treatment. GMAA could be a promising option for active UC positive for CMV.

Comparison of PPIs and H2-receptor antagonists plus prokinetics for dysmotility-like dyspepsia.

AIM: To compare efficacy of proton pump inhibitors (PPIs) with H(2)-receptor antagonists (H(2)RAs) plus prokinetics (Proks) for dysmotility-like symptoms in functional dyspepsia (FD). METHODS: Subjects were randomized to receive open-label treatment with either rabeprazole 10 mg od (n = 57) or famotidine 10 mg bid plus mosapride 5 mg tid (n = 57) for 4 wk. The primary efficacy endpoint was change (%) from baseline in total dysmotility-like dyspepsia symptom score. The secondary efficacy endpoint was patient satisfaction with treatment. RESULTS: The improvement in dysmotility-like dyspepsia symptom score on day 28 was significantly greater in the rabeprazole group (22.5% ± 29.2% of baseline) than the famotidine + mosapride group (53.2% ± 58.6% of baseline, P < 0.0001). The superior benefit of rabeprazole treatment after 28 d was consistent regardless of Helicobacter pylori status. Significantly more subjects in the rabeprazole group were satisfied or very satisfied with treatment on day 28 than in the famotidine + mosapride group (87.7% vs 59.6%, P = 0.0012). Rabeprazole therapy was the only significant predictor of treatment response (P < 0.0001), defined as a total symptom score improvement ≥ 50%. CONCLUSION: PPI monotherapy improves dysmotility-like symptoms significantly better than H(2)RAs plus Proks, and should be the treatment of first choice for Japanese FD.

Lansoprazole for secondary prevention of gastric or duodenal ulcers associated with long-term non-steroidal anti-inflammatory drug (NSAID) therapy: results of a prospective, multicenter, double-blind, randomized, double-dummy, active-controlled trial.

BACKGROUND: Low-dose lansoprazole has not been intensively evaluated for its efficacy in the prevention of recurrent gastric or duodenal ulcers in patients receiving long-term non-steroidal anti-inflammatory drug (NSAID) therapy for pain relief in such diseases as rheumatoid arthritis, osteoarthritis, and low back pain. METHODS: This multi-center, prospective, double-blind, randomized, active-controlled study involving 99 sites in Japan was designed to compare the efficacy of lansoprazole (15 mg daily) with gefarnate (50 mg twice daily). Patients with a history of gastric or duodenal ulcers who required long-term NSAID therapy were randomized to receive lansoprazole 15 mg daily (n = 185) or gefarnate 50 mg twice daily (n = 181) and followed up for 12 months or longer prospectively. RESULTS: The cumulative incidence of gastric or duodenal ulcer at days 91, 181, and 361 from the start of the study was calculated by the Kaplan-Meier method as 3.3, 5.9, and 12.7%, respectively, in the lansoprazole group versus 18.7, 28.5, and 36.9%, respectively, in the gefarnate group. The risk for ulcer development was significantly (log-rank test, P < 0.0001) lower in the lansoprazole group than in the gefarnate group, with the hazard ratio being 0.2510 (95% CI 0.1400-0.4499). A long-term follow-up study showed an acceptable safety profile for low-dose lansoprazole therapy, with diarrhea as the most frequent adverse event. CONCLUSION: Lansoprazole was superior to gefarnate in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term NSAID therapy.

Combined pH-impedance monitoring and high-resolution manometry of Japanese patients treated with proton-pump inhibitors for persistent symptoms of non-erosive reflux disease.

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.