Efficacy of esomeprazole in patients with acid-peptic disorders.

Esomeprazole (Nexium) is a new proton pump inhibitor that provides more effective acid control compared with other proton pump inhibitors. In patients with gastroesophageal reflux disease, standard doses of esomeprazole maintain intragastric pH above 4 for significantly longer periods compared with standard doses of other proton pump inhibitors after 5 days of treatment. Esomeprazole is approved for the treatment of symptomatic gastroesophageal reflux disease, the healing of erosive esophagitis, and maintenance of healing. In clinical trials, esomeprazole 40 mg once daily for up to 8 weeks provided higher rates of healing of erosive esophagitis and a greater proportion of patients with sustained resolution of heartburn, than either omeprazole 20 mg or lansoprazole 30 mg once daily. For the maintenance of healing, esomeprazole 20 mg once daily provided significantly higher rates of maintained healing of erosive esophagitis after 6 months of treatment compared with lansoprazole 15 mg once daily. Esomeprazole is also approved for use as part of a triple-drug therapy regimen in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in patients with duodenal ulcer disease. The side effect profile of esomeprazole is similar to that of omeprazole. Many patients with acid-related disorders may benefit from the more rapid symptom relief, higher rates of healing of erosive esophagitis, and improved maintenance of healing that can be achieved with esomeprazole.     

Healing and relapse rates in gastroesophageal reflux disease treated with the newer proton-pump inhibitors lansoprazole, rabeprazole, and pantoprazole compared with omeprazole, ranitidine, and placebo: evidence from randomized clinical trials

BACKGROUND: The older proton pump inhibitor (PPI) omeprazole and the newer PPIs lansoprazole, rabeprazole, and pantoprazole are approved for the acute and maintenance treatment of gastroesophageal reflux disease (GERD). OBJECTIVE: On the basis of the results of randomized clinical trials, this study sought to estimate healing and relapse rates in acute and maintenance treatment of GERD with the newer PPIs compared with omeprazole, the histamine2-receptor antagonist ranitidine (the most frequent non-PPI comparator in studies of PPIs), and placebo. METHODS: A search of MEDLINE was conducted to identify randomized, controlled clinical trials that included a PPI in > or =1 treatment arm and assessed the healing of erosive esophagitis endoscopically. The primary outcome for studies of acute therapy was healing rate, and the primary outcome for studies of maintenance therapy was relapse rate. RESULTS: Fifty-three studies were identified, of which 38 involved acute therapy (12 excluded) and 15 maintenance therapy. None of the studies of pantoprazole met the inclusion criteria for maintenance therapy. The 8-week overall healing rate ratios in the comparison of newer PPIs with omeprazole 20 mg/d were as follows: lansoprazole 30 mg/d, 1.02 (95% CI, 0.98-1.06): rabeprazole 20 mg/d, 0.93 (95% CI, 0.87-1.00); and pantoprazole 40 mg/d, 0.98 (95% CI, 0.90-1.07). In the comparison of any PPI with ranitidine 300 mg/d, the ratios were as follows: lansoprazole, 1.62 (95% CI, 1.46-1.76); rabeprazole, 1.36 (95% CI, 1.20-1.54); pantoprazole, 1.60 (95% CI, 1.33-1.96); and omeprazole, 1.58 (95% CI, 1.41-1.78). Relapse rates over 1 year of treatment were similar between lansoprazole and rabeprazole. Compared with ranitidine, there were statistically significant differences in the rates of resolution of heartburn symptoms (P < 0.002), ulcer healing (P < 0.05), and relapse (P < 0.01). Similar results were seen in the comparison of PPIs with placebo in terms of rates of resolution of heartburn symptoms (P < 0.01), ulcer healing (P < 0.001), and relapse (P < 0.006). CONCLUSIONS: In this study, the newer PPIs were of similar efficacy to omeprazole in terms of heartburn control, healing rates, and relapse rates. All the PPIs were superior to ranitidine and placebo in healing erosive esophagitis and decreasing relapse rates.     

The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.     

Esomeprazole for acid peptic disorders

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of esomeprazole, a new proton-pump inhibitor (PPI). DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted for relevant literature using the terms esomeprazole, Nexium, and H199/18. Abstracts from the XXXII Nordic Meeting of Gastroenterology and journal articles provided by AstraZeneca were reviewed. STUDY SELECTION AND DATA EXTRACTION: All available studies on the pharmacology, pharmacokinetics, clinical efficacy, and safety of esomeprazole were reviewed. DATA SYNTHESIS: Esomeprazole is a new PPI and is the S-isomer of racemic omeprazole. Esomeprazole has demonstrated acid control comparable to that of the other PPIs currently available. Esomeprazole undergoes less hepatic metabolism compared with omeprazole, and thus may result in less interpatient variability among slow and fast metabolizers of CYP2C19. The oral bioavailability of esomeprazole is approximately 89% with a dose of 40 mg, and the half-life is approximately 1.5 hours. Esomeprazole is effective in the healing of erosive esophagitis, with a rate of healing at week 8 of 93.7% (p < 0.001). In maintenance therapy of healed erosive esophagitis, esomeprazole maintained healing rates >90% (6-mo trial). Esomeprazole is comparable with omeprazole (both in combination with appropriate antibiotics) in the eradication of Helicobacter pylori, with eradication rates of 89.7% and 87.8%, respectively. The drug is well tolerated. The few adverse effects associated with esomeprazole are diarrhea, headache, nausea, abdominal pain, respiratory infection, and sinusitis. CONCLUSIONS: Esomeprazole is a safe and effective PPI. It is effective in the treatment of peptic ulcer disease and gastroesophageal reflux disease.     

Long-term maintenance treatment of reflux esophagitis resistant to H2-RA with PPI (lansoprazole)

97 patients in 49 hospitals with erosive esophagitis unhealed after at least 8 weeks treatment with H2-RA were given primary treatment with 30 mg lansoprazol once daily. After 8 weeks of treatment with lansoprazol, 75(77%) patients were endoscopically healed. Healed patients were then given maintenance treatment with either 30 mg lansoprazol once daily, 15 mg lansoprazol once daily or 20 mg famotidine twice daily for 24 weeks. 86% of patients randomized to 30 mg lansoprazol, 70% of patients randomized to 15 mg lansoprazol were maintained in endoscopic healing throughout 24 weeks as compared with only 12% of patients randomized to famotidine in endoscopic healing. After 24 weeks of lansoprazol treatment basal gastrin levels were moderately increased. However no significant histopathologic lesion was found in the oxyntic gland mucosa. PPI(lansoprazol) was far superior to H2-RA(famotidine) in preventing recurrence of healed erosive esophagitis. A goal achieved without adverse events and significant abnormalities in the oxyntic mucosal exocrine or endocrine cell but a moderate increase in basal gastrine levels.     

Clinical effect of proton pump inhibitors on reflux esophagitis]

The clinical efficacy of proton pump inhibitors (PPI, omeprazole 20 mg or lansoprazole 30 mg), once daily, after breakfast, was studied in patients with erosive/ulcerative reflux esophagitis. The following results were obtained. 1) Twenty-four hour esophageal pH monitoring was performed before treatment and on 7th day of PPI medications. Omeprazole reduced the percent time pH less than 4 from 29.1 to 1.2 and lansoprazole from 68.0 to 2.4. 2) The cumulative disappearance rate of overall symptom was 52% after 1 week and 62% after 2 weeks with omeprazole these were 66% and 91%, and with lansoprazole respectively 3) The endoscopic healing rate was 63% was after 2 weeks and 76% after 4 weeks with omeprazole medication, and 76% and 97% respectively with lansoprazole. These results indicate that PPI medication inhibits the acid reflux almost completely and is a more useful therapeutic agent for GERD than H2-antagonists.     

Dexlansoprazole MR – A review

Abstract

Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a novel system, the dual delayed release formulation. The drug has been shown to be efficacious in healing erosive esophagitis as compared with lansoprazole. When compared to placebo, dexlansoprazole provided significantly higher maintenance rates for healed esophageal mucosa in patients with erosive esophagitis and symptom control in patients with non-erosive reflux disease. Dexlansoprazole could be taken without regard to food. Overall, dexlansoprazole is well tolerated and has a comparable side-effect profile to lansoprazole.     

Dexlansoprazole MR: a review

Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a novel system, the dual delayed release formulation. The drug has been shown to be efficacious in healing erosive esophagitis as compared with lansoprazole. When compared to placebo, dexlansoprazole provided significantly higher maintenance rates for healed esophageal mucosa in patients with erosive esophagitis and symptom control in patients with non-erosive reflux disease. Dexlansoprazole could be taken without regard to food. Overall, dexlansoprazole is well tolerated and has a comparable side-effect profile to lansoprazole.     

An overview of the success and failure of surgical therapy: standards against which the outcome of endoscopic therapy is measured

Medical therapy for reflux disease has evolved from frequent antacid use to once daily proton pump inhibitor therapy. Despite the efficacy of these agents in healing erosive esophagitis, there are several short-comings with medical therapy including incomplete symptom relief, the need for continuous maintenance therapy, and cost. Endoscopic and laparoscopic treatments for reflux disease are appealing because they could reduce or eliminate the need for chronic maintenance therapy with medications. While there is evidence of high quality on the efficacy of medical therapy from randomized controlled trials, data on endoscopic procedures and surgery is more limited. This article summarizes the needed studies and the standards against which these procedures should be measured.     

Effect of high-dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.

BACKGROUNDS AND AIM: Lansoprazole is mainly metabolized by cytochrome P4502C19 (CYP2C19) in the liver. The effect of lansoprazole is assumed to be insufficient in subjects who are homozygous extensive metabolizers of CYP2C19. This study aimed to examine whether the CYP2C19 genotype status affected the acid-inhibitory effects of lansoprazole and to develop a strategy to overcome this pharmacogenetic problem. METHODS: Eighteen Helicobacter pylori-negative healthy volunteers, whose CYP2C19 genotypic status had been assessed, participated in the study. They consisted of 7 subjects who were homozygous extensive metabolizers, 7 subjects who were heterozygous extensive metabolizers, and 4 subjects who were poor metabolizers of CYP2C19, who took a placebo or lansoprazole 30 mg once daily in the morning for 8 days. On day 8 of dosing, 24-hour intragastric pH values were recorded. Five of the homozygous extensive metabolizer subjects underwent the 24-hour intragastric pH monitoring on day 8 of dosing of lansoprazole 30 mg 4 times daily. RESULTS: When lansoprazole 30 mg was given once daily, the mean 24-hour intragastric pH values in the subjects who were homozygous extensive metabolizers, heterozygous extensive metabolizers, and poor metabolizers were 4.5, 4.9, and 5.5, respectively (P <.005). On day 8 of dosing of lansoprazole 30 mg 4 times daily in subjects who were homozygous extensive metabolizers, the mean 24-hour intragastric pH value was 7.4. CONCLUSION: The effect of lansoprazole on intragastric pH depended significantly on CYP2C19 genotype status. Complete acid inhibition could be achieved by the frequent administration of lansoprazole (eg, 30 mg 4 times daily) in subjects who were homozygous extensive metabolizers. A genotyping test of CYP2C19 status appears useful for prescribing an optimal dosing scheme of lansoprazole.     

Influence of antisecretory treatment with proton pump inhibitors on serum pepsinogen I levels

It has been reported in literature that serum pepsinogen levels rise during omeprazole and lansoprazole administration. However, the influence of pantoprazole and esomeprazole on serum pepsinogens levels is still to be assessed. The aim of this study was to evaluate the influence of proton pump inhibitor (PPI) therapy on pepsinogen I (PGI) levels. PGI and gastrin (G17) levels (EIA; Biohit, Helsinki, Finland) in 126 consecutive patients (M 57; F 69, mean age 53, range 15-91), with upper gastrointestinal symptoms at baseline condition and after 2 months of PPI treatment, were evaluated. Patients underwent a therapy schedule based on: omeprazole 20 mg b.i.d. (20 patients), pantoprazole 40 mg b.i.d. (27 patients), esomeprazole 40 mg b.i.d. (29 patients), lansoprazole 30 mg b.i.d. (21 patients) and rabeprazole 20 mg b.i.d. (26 patients) for 2 months. A significant increase in serum PGI (sPGI) levels was found after a 2-month treatment for all five different PPIs: omeprazole, pantoprazole, esomeprazole, lansoprazole and rabeprazole (P < 0.05). The effect of rabeprazole on sPGI was less pronounced as compared with other PPIs, whereas esomeprazole achieved superior sPGI levels, with no overall statistically significant difference among the five groups (P > 0.05). However, a comparison within a single group of PPIs showed a statistical significance when the esomeprazole group was compared with the rabeprazole group (P = 0.007). sPGI levels are significantly influenced by antisecretory therapy, rising under PPI treatment. Moreover, a statistically significant difference in sPGI levels between the rabeprazole and esomeprazole groups has been demonstrated.     

Gastroesophageal reflux disease: current treatment approaches.

Gastroesophageal reflux disease is a common, usually lifelong, disorder resulting from chronic abnormal exposure of the lower esophagus to gastric contents. Motor dysfunction of the lower esophageal sphincter is the primary cause of this disease. At this writing, no medical therapies can completely resolve abnormal lower esophageal sphincter function; therefore, the treatment of gastroesophageal reflux disease centers on suppression of intragastric acid secretion. Available acid-suppressant medications include proton pump inhibitors, H2-receptor antagonists, and antacids. Of these, the proton pump inhibitors are recognized generally as the mainstays of both short-term and long-term therapy for gastroesophageal reflux disease. All have a low incidence of side effects and are well tolerated by most patients. Five proton pump inhibitors are available currently for patients with gastroesophageal reflux disease. Of these, esomeprazole has shown greater efficacy in controlling intragastric acidity than the others. For patients with erosive esophagitis, esomeprazole has demonstrated higher healing rates and more rapid sustained resolution of heartburn than omeprazole or lansoprazole after up to 8 weeks of once-daily treatment. Because new therapies for gastroesophageal reflux disease are highly effective, patients can be reassured that their disease will be well controlled and their symptoms resolved with a safe and appropriate treatment.     

The efficacy of extended-interval dosing of omeprazole in keeping gastroesophageal reflux disease patients symptom free.

The potential economic advantage of alternate-day therapy for GERD maintenance must be weighed against the potential cost of failure before it can be widely instituted. The studies presented have helped develop a clinical picture of the patients who may benefit from alternate-day therapy without risk of complications or potential increases in management costs. Bank et al., reporting on a group of patients, found that patients with Grade II-IV disease had a 61% success rate at two to eight years. Bank defined success as both maintenance of endoscopic healing and symptom control. Ladas et al. found a 66.7% success rate defined as clinical and endoscopic remission in Grades II-III disease. Kurucar et al. monitored symptom control and esophageal complications in his patients and found the regimen to have a 26% success rate in Grades III-IV disease. Lind et al. found that 83% of patients could remain symptom free with on-demand therapy if they were endoscopy-negative at baseline. The results of the Mantides et al. study are important because they imply that alternate-day omeprazole therapy may be more effective than alternatives for step-down treatment, such as ranitidine or cisapride. Furthermore, patients can be educated to increase their frequency of use if symptoms should arise. Not only does this give the patient a sense of self-empowerment over his or her disease state, but it avoids the cost of switching to a PPI due to failure with an H2RA or a motility agent. Alternate-day use of omeprazole should be attempted only during the maintenance phase of GERD therapy. Patients requiring >20 mg/d to achieve healing appeared to be poor candidates for alternate-day omeprazole maintenance therapy. Based on available studies, it would seem that patients with Grades 0-II GERD would benefit most from alternate-day therapy. A role for alternate-day therapy in Grades III-IV is apparent from the results presented but requires greater caution in view of the differing success rates (26-61%) in various studies. With Grades II-III esophagitis, a mean 24-hour gastric pH >6 and a gastric pH <4 less than 10% of the time during the initial healing phase with omeprazole 20 mg/d appeared to be associated with success on alternate-day therapy. Evidence that all marketed PPIs have similar success is not available and should not be extrapolated from the data presented. Evidence that downward dosage adjustments of PPIs versus extending dosage intervals are effective in the maintenance of GERD should be recognized. Lansoprazole has been approved for treating erosive esophagitis at 30 mg/d, with the maintenance dose established at 15 mg/d. Studies showing that lansoprazole 15 mg/d is more effective than alternate-day therapy with lansoprazole 30 mg exist, although similar studies with omeprazole have not been performed. The abstracts describing the use of alternate-day omeprazole accounted for all enrollees and included endoscopic grading or pH monitoring to document disease severity at baseline. Most also included these same objective measures as end points in combination with symptom control. This strengthens the data since the positive predictive value of typical symptoms is variable. However, there are also several significant limitations. Abstracts provide only limited information on methods. All studies other than Lind et al. lacked randomization. This study was also the only one that blinded patients to their treatment. Sample sizes for the majority of the trials were quite small. Statistical analyses were not performed on any of the trial results with the exception of the trial by Lind et al. In light of the lack of evidence of statistical significance as well as study design flaws, conclusions should be drawn cautiously. Larger well-designed trials looking at both the efficacy and cost-effectiveness of alternate day omeprazole are required before a definitive recommendation can be made.     

Combination drug therapy for gastroesophageal reflux disease

OBJECTIVE: To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD). DATA SOURCES: Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug. DATA SYNTHESIS: Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.     

Lessons from two cases of anaphylaxis to proton pump inhibitors

What is known and Objective: Proton pump inhibitors (PPIs), which are widely used for the treatment of peptic ulcers and gastroesophageal diseases, reduce both basal and stimulated gastric acid secretion by inhibiting the parietal cell enzyme H(+)‐K(+)‐adenosine triphosphatase. There have been several reports of hypersensitivity reactions to PPIs but anaphylaxis is very rare. We report on two cases of anaphylaxis to PPIs. Case summary: Our two interesting and instructive cases of anaphylaxis to PPIs relate to the orally disintegrating form of lansoprazole and omeprazole. The first patient had taken esomeprazole 20 mg/day for 1 month without any side effects before experiencing anaphylaxis to lansoprazole. To our knowledge, this is the first report of anaphylaxis to the orally disintegrating form of lansoprazole. In the second case, the patient was misdiagnosed with penicillin allergy which she suffered from earlier. What is new and Conclusion: Physicians need to be more aware of the possibility of hypersensitivity to PPIs.     

Esomeprazole in acute and maintenance treatment of reflux oesophagitis: a multicentre prospective study

INTRODUCTION: The aim of this study was to assess the efficacy and safety of esomeprazole 40 mg once daily (q.d.) in healing reflux oesophagitis at 4 and 8 weeks, and the efficacy of esomeprazole 20 mg q.d. for 12 weeks in the maintenance of remission. METHODS: A total of 235 patients with endoscopically proven reflux oesophagitis were enrolled in this study, which consisted of two phases (healing and maintenance therapy). Patients who showed complete endoscopic and symptomatic healing at the end of 4 or 8 weeks were switched to maintenance treatment with esomeprazole 20 mg q.d. for 12 weeks. The primary efficacy endpoint was healing of reflux oesophagitis at week 8. Secondary assessments included the proportion of patients with symptomatic relapse in the maintenance phase. RESULTS: At the end of week 8, 88% (95% life-table confidence intervals [CI]: 84%, 92%) of patients were healed endoscopically and 90.6% of the patients were asymptomatic. Patient age, gender and Helicobacter pylori status had no effect on the efficacy of treatment. During the 12-week maintenance treatment phase, symptomatic relapse ratios were 0.5%, 2.2%, and 0%, for the first, second, and third 4-week periods, respectively. The proportions of patients satisfied with treatment were 95% and 99.4% at the end of acute and maintenance treatment, respectively. The most common adverse effects were headache, upper respiratory tract infection and abdominal pain. CONCLUSIONS: Esomeprazole is effective in the healing of reflux oesophagitis, the resolution of heartburn, and in maintaining symptomatic remission. The effectiveness of esomeprazole in patients with gastroesophageal reflux disease is not affected by the presence of H. pylori.     

Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data

BACKGROUND: The clinical outcome of acid-related disorders treated by proton pump inhibitors (PPIs) might be dependent on the polymorphically expressed cytochrome P450 (CYP) 2C19, which is involved in PPI metabolism. We tested whether esomeprazole-induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype. METHODS: Two hundred five patients with GERD (Los Angeles classification grade A or B) were included in a case-control study according to endoscopic outcome (healed versus unhealed group, matched for confounders) after treatment with 40 mg esomeprazole daily for 4 weeks. The frequency of CYP2C19 genotypes was determined as the primary outcome measure for both groups. In a second trial plasma levels of esomeprazole and corresponding CYP2C19 and CYP3A4 metabolites (5-hydroxyomeprazole and omeprazole sulfone) were monitored in 10 CYP2C19 wild-type patients with GERD after the first and last doses (day 7) of 40 mg esomeprazole daily to calculate metabolic ratios. RESULTS: CYP2C19 wild-type (n = 148) and heterozygous (n = 51) or homozygous variant (n = 6) patients did not differ with respect to baseline characteristics. The frequency distribution of CYP2C19 genotypes was not different between patients with complete (75/100) and incomplete (73/105) healing (P = .65). When a single esomeprazole dose and multiple dosing were compared, the low contribution of CYP2C19 to the elimination of esomeprazole decreased further by 50%. In contrast, the CYP3A4-dependent formation of omeprazole sulfone increased by 40%, and consequently, the metabolic ratio of omeprazole sulfone to 5-hydroxyomeprazole was elevated from 7.9 to 19.3 (P = .0004). CONCLUSION: In contrast to other PPIs, esomeprazole-induced healing of GERD is unrelated to the CYP2C19 genotype, which can be explained by the metabolic shift toward the CYP3A4-mediated pathway.     

Vonoprazan vs lansoprazole for the treatment of artificial gastric ulcer after endoscopic submucosal dissection: a prospective randomized comparative study

Vonoprazan is a potent inhibitor of gastric acid secretion and may have better response than proton pump inhibitors (PPIs) in the treatment of endoscopic submucosal dissection induced artificial ulcers. However, reported outcomes remain controversial. In this study, we conducted a prospective, randomized comparative trial to evaluate healing effects of vonoprazan and lansoprazole on endoscopic submucosal dissection (ESD)-induced ulcers. We enrolled 216 patients who underwent endoscopic submucosal dissection for early gastric neoplasms. They were randomly divided into vonoprazan (20 mg/day) and lansoprazole (30 mg/day) groups. The primary endpoint was the reduction rate of ulcer and complete healing (scar) ratio of ESD-induced ulcers at 4 and 8 weeks. Finally, 101 patients of the vonoprazan group and 95 patients of the lansoprazole group were included in the analysis. There were no significant differences in the reduction rate between the vonoprazan and lansoprazole groups at either timepoint (4 weeks, 94.0 vs 93.4%; 8 weeks, 99.8 vs 99.9%, respectively). The complete healing ratio at 4 and 8 weeks did not differ significantly between the vonoprazan and lansoprazole groups (4 weeks, 11.9 vs 12.6%; 8 weeks, 87.1 vs 86.3%, respectively). In the anti-H. pylori-antibody negative or positive patients, there were no significant differences in the reduction rate and complete healing ratio between the vonoprazan and lansoprazole groups. Regardless of treatment choice, the overall complete healing ratio at 8 weeks was significantly higher in the anti-H. pylori-antibody negative patients than the positive patients (p = 0.006). The healing effects of vonoprazan on ESD-induced ulcers were comparative to those of lansoprazole.     

Phase I, multicenter, randomized, open-label study evaluating the pharmacokinetics and safety profile of repeated once-daily doses of intravenous esomeprazole in children 0 to 17 years of age

BackgroundSeveral oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children.ObjectiveThe aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children.MethodsIn this multicenter, open-label study, hospitalized patients (0–17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0–1 month of age), 1.0 mg/kg (1–11 months of age), 10 mg (1–5 years of age), 10 or 20 mg (6–11 years of age), or 20 or 40 mg (12–17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed.ResultsFifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC_τ ranged from 6.9 μmol · h/L (10 mg, 6–11 years) to 17.6 μmol · h/L (40 mg, 12–17 years). The mean C_ss,max ranged from 3.7 μmol/L (0.5 mg/kg, 0–1 month) to 10.5 μmol/L (40 mg, 12–17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs.ConclusionsIntravenous esomeprazole at doses resulting in targeted AUC_τ and C_ss,max similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.