Suppression of vacuolar-type ATPase and induction of endoplasmic reticulum stress by proton pump inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs), such as esomeprazole, pantoprazole, dexlansoprazole, and rabeprazole, are one of the most commonly prescribed medications. Several studies have linked the long-term use of PPIs to a potentially increased risk of gastric cancer. Therefore, this study aimed to determine the underlying mechanism of PPI-mediated gastric cancer. METHODS: Lysosomes were isolated using immunoprecipitation. The inhibition of vacuolar-type ATPase (V-ATPase) by PPIs was assayed using a PiColorLock Gold Phosphate Detection System. PPI-induced lysosomal stress was analyzed using transcription factor EB (TFEB) nuclear translocation. PPI-induced endoplasmic reticulum (ER) stress was analyzed using the expression of protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Finally, reactive oxygen species (ROS) removal was determined using the activity of superoxide dismutase (SOD). RESULTS: PPIs caused a 70% inhibition of V-ATPase activity at 20 µM, leading to lysosomal stress through TFEB nuclear translocation; ER stress by inducing the expression of PERK, IRE1, and ATF6; and enhanced SOD activity for ROS removal. CONCLUSION: The long-term use of PPIs inhibits lysosomal V-ATPase, leading to ER stress and ROS accumulation, which may result in an increased risk of gastric cancer. Because lysosomes and the ER are common organelles in cells, physicians prescribing PPIs for gastroesophageal reflux and peptic ulcer diseases should pay more attention to the general effects of these agents on the human body.

Efficacy and safety of 7 days versus 10 days triple therapy based on levofloxacin-dexlansoprazole for eradication of Helicobacter pylori: A pilot randomized trial.

BACKGROUND: Levofloxacin-based triple therapies are considered the standard regimen for eradication of Helicobacter pylori (H. pylori) due to decreased sensitivity to clarithromycin and the optimal duration of therapy is still controversial. Besides, there is no complete evidence about dexlansoprazole efficacy in the eradication of H. pylori. AIM: Our study aimed to determine the effectiveness of triple therapy based on levofloxacin-dexlansoprazole as a standard treatment for H. pylori infection and estimate the effect of H. pylori on lipid profile and hemoglobin (Hb). MATERIALS AND METHODS: A pilot prospective randomized trial of a triple therapy based on levofloxacin-dexlansoprazole for H. pylori eradication was conducted at Damanhour Medical National Institute, Egypt; 66 participants with H. pylori infection received levofloxacin (500 mg/day) plus amoxicillin (1 g/12 h) plus dexlansoprazole (60 mg/day). All medications administrated orally for either 7 days or 10 days. Four weeks after treatment, the eradication was assessed by the stool antigen test. RESULTS: The rate of eradication was 63.6% in levofloxacin, amoxicillin, and dexlansoprazole (LAD) 7-day group, and 90.9% in LAD 10-day group. In addition, laboratory test results showed a significant difference in Hb, low-density lipoprotein, high-density lipoprotein, triglyceride, and total cholesterol levels before and after treatment (P < 0.05). CONCLUSION: LAD 10 days is the least duration that provides maximum efficacy for H. pylori in Egyptian participants. In addition, successful treatment of H. pylori infection may reduce the risk of anemia and dyslipidemia. Furthermore, all members of the patient's family should be screened for H. pylori to prevent recurrent infection.

Equivalent efficacies of reverse hybrid and concomitant therapies in first-line treatment of Helicobacter pylori infection.

BACKGROUND AND AIM: Concomitant therapy is a recommended first-line treatment for Helicobacter pylori infection in most national or international consensuses. Reverse hybrid therapy is a modified 14-day concomitant therapy without clarithromycin and metronidazole in the final 7 days. This study aims to test whether 14-day reverse hybrid therapy is non-inferior to 14-day concomitant therapy in the first-line treatment of H. pylori infection. METHODS: Helicobacter pylori-infected adult patients were randomly assigned to receive either reverse hybrid therapy (dexlansoprazole 60 mg o.d. plus amoxicillin 1 g b.d. for 14 days, and clarithromycin 500 mg plus metronidazole 500 mg b.d. for initial 7 days) or concomitant therapy (dexlansoprazole 60 mg once o.d. plus amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg b.d. for 14 days). H. pylori status was assessed 6 weeks after the end of treatment. RESULTS: Helicobacter pylori-infected participants (n = 248) were randomized to receive either 14-day reverse hybrid therapy (n = 124) or 14-day concomitant therapy (n = 124). Intention-to-treat analysis demonstrated that the two therapies had comparable eradication rate (95.2% vs 93.5%; 95% confidence interval, -4.0% to 7.4%; P = 0.582). However, reverse hybrid therapy had a much lower frequency of adverse events than concomitant therapy (20.2% vs 38.7%, P = 0.001). The two therapies exhibited comparable drug adherence (93.5% vs 87.9%, P = 0.125). CONCLUSIONS: Fourteen-day reverse hybrid therapy and 14-day concomitant therapy are equivalent in efficacy for the first-line treatment of H. pylori infection. However, reverse hybrid therapy has fewer adverse events compared with concomitant therapy.

High and Frequent Dose of Dexlansoprazole and Amoxicillin Dual Therapy for Helicobacter pylori Infections: A Single Arm Prospective Study.

BACKGROUND/AIMS: Recently, the eradication rate of Helicobacter pylori (H. pylori) infection has decreased to less than 80% worldwide with the use of clarithromycin-based triple therapy owing to the increased resistance of H. pylori to antibiotics, especially clarithromycin and metronidazole. This prospective study aimed to determine eradication rate of H. pylori following high and frequent doses of extended-release dexlansoprazole and amoxicillin, as a dual therapy in a region with high clarithromycin resistance rate. METHODS: A total of 50 treatment-naïve patients with active H. pylori infections, who were confirmed through via rapid urease test or histology and serology between November 2015 and February 2016 at our hospital, were included for analysis. All enrolled patients were treated with 750 mg amoxicillin and 30 mg dexlansoprazole, four times a day for a total duration of 14 days. Treatment success was determined using urea breath test four weeks after treatment completion. RESULTS: Seven out of the 50 patients (29 men and 21 women; mean age, 57 years) dropped out during the study. The total eradication rate was 52% (26/50), and that for those with a compliance rate of over 90% was 68.4% (26/38). H. pylori infections were not successfully eradicated in patients with a compliance rate of less than 90%. Nine patients (18%) reported side effects, such as mild diarrhea and abdominal fullness. No significant factors, such as smoking and alcohol consumption, affected the infection the eradication rate. CONCLUSIONS: High and frequent doses of proton pump inhibitor-amoxicillin dual therapy were not effective in eradicating H. pylori infection in a province with high clarithromycin resistance rate.

Dexlansoprazole for Heartburn Relief in Adolescents with Symptomatic, Nonerosive Gastro-esophageal Reflux Disease.

BACKGROUND: Proton pump inhibitors are commonly used to treat gastro-esophageal reflux disease (GERD) and nonerosive GERD (NERD) in adolescents and adults. Despite the efficacy of available medications, many patients have persisting symptoms, indicating a need for more effective agents. AIMS: To assess the safety and efficacy of dexlansoprazole dual delayed-release capsules in adolescents for treatment of symptomatic NERD. METHODS: A phase 2, open-label, multicenter study was conducted in adolescents aged 12-17 years. After a 21-day screening period, adolescents with endoscopically confirmed NERD received a daily dose of 30-mg dexlansoprazole for 4 weeks. The primary endpoint was treatment-emergent adverse events (TEAEs) experienced by ≥5% of patients. The secondary endpoint was the percentage of days with neither daytime nor nighttime heartburn. Heartburn symptoms and severity were recorded daily in patient electronic diaries and independently assessed by the investigator, along with patient-reported quality of life, at the beginning and end of the study. RESULTS: Diarrhea and headache were the only TEAEs reported by ≥5% of patients. Dexlansoprazole-treated patients (N = 104) reported a median 47.3% of days with neither daytime nor nighttime heartburn. Symptoms such as epigastric pain, acid regurgitation, and heartburn improved in severity for 73-80% of patients. Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire-Adolescents-Short Form symptom and impact subscale scores (scaled 1-5) each decreased by an average of 0.7 units at week 4. CONCLUSIONS: Use of 30-mg dexlansoprazole in adolescent NERD was generally well tolerated and had beneficial effects on improving heartburn symptoms and quality of life. TRIAL REGISTRATION: This study has the ClinicalTrials.gov identifier NCT01642602.

Safety, tolerability, pharmacokinetics and pharmacodynamics of dexlansoprazole injection in healthy Chinese subjects.

PURPOSE: This study was conducted to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of dexlansoprazole injection in healthy subjects. METHODS: Dexlansoprazole (20-90 mg) or lansoprazole (30 mg) was administrated intravenously to healthy male and female volunteers. All the subjects were sampled for pharmacokinetic (PK) analysis and 64 of them were monitored for 24-h intragastric pH prior to and after administration in the pharmacodynamic (PD) study. RESULTS: Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-τ) for dexlansoprazole injection was dose-proportional over the range of 20-90 mg following a single intravenous administration. Total clearance and half-life (t1/2) was independent of dose, and ranged from 4.69 L/h to 5.85 L/h and from 1.24 h to 2.17 h, respectively. A single dose of dexlansoprazole (30 mg) resulted in higher gastric pH compared to that of lansoprazole, evidenced by a mean 24-h gastric pH of 6.1 ± 1.2 (lansoprazole: 5.4 ± 1.1) and 24-h gastric pH > 6 post drug dose holding time of 64.2 ± 21.0% (lansoprazole: 49.5 ± 21.5%). CONCLUSION: Dexlansoprazole injection was safe and well tolerated for up to 5-day repeated intravenous administration dose of 30 mg. The recommended dosage for dexlansoprazole injection is 30 mg for an adequate gastric acid control.

A Pilot Randomized Controlled Study of Dexlansoprazole MR-Based Triple Therapy for Helicobacter Pylori Infection.

Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a dual delayed release formulation. It is effective for symptom control of patients with gastroesophageal reflux disease. However, its efficacy in the treatment of Helicobacter pylori infection remains unclear. This pilot, randomized, controlled, head-to-head study was conducted to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy was noninferior to double-dose rabeprazole-based triple therapy in the treatment of H pylori infection. Consecutive H pylori-infected subjects were randomly allocated to either 7-day dexlansoprazole MR-based standard triple therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) or rabeprazole-based triple therapy (rabeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily). H pylori status was assessed 6 weeks after the end of treatment. A total of 177 H pylori-infected patients were randomized to receive dexlansoprazole MR-based (n = 90) or rabeprazole-based (n = 87) triple therapy. Intention-to-treat analysis demonstrated no differences between eradication rates of the 2 study groups (83.3% vs 81.6%; P = 0.736). Per-protocol analysis yielded comparable results (85.1% vs 81.2%; P = 0.497). Both groups exhibited similar frequencies of adverse events (7.8% vs 4.6%; P = 0.536) and drug compliance (98.9% vs 97.7%; P = 0.496). Multivariate analysis disclosed that the presence of clarithromycin resistance was the only independent factors predictive of treatment failure with an odds ratio of 6.8 (95% confidence interval: 1.2-37.6). This work demonstrates that single-dose dexlansoprazole MR-based triple therapy yields a similar eradication rate as double-dose rabeprazole-based therapy. Since the pharmaceutical cost of the single-dose dexlansoprazole MR regime is lower than that of the double-dose rabeprazole regimen, dexlansoprazole-based therapy can reasonably be recommended in the first-line treatment of H pylori infection.

The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis.

BACKGROUND: Although many case reports have described patients with proton pump inhibitor (PPI)-induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies. We aimed to evaluate the association between the use of PPI and the risk of developing hypomagnesemia by conducting a systematic review with meta-analysis. METHODS: We conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Library using the primary keywords "proton pump," "dexlansoprazole," "esomeprazole," "ilaprazole," "lansoprazole," "omeprazole," "pantoprazole," "rabeprazole," "hypomagnesemia," "hypomagnesaemia," and "magnesium." Studies were included if they evaluated the association between PPI use and hypomagnesemia and reported relative risks or odds ratios or provided data for their estimation. Pooled odds ratios with 95% confidence intervals were calculated using the random effects model. Statistical heterogeneity was assessed with Cochran's Q test and I2 statistics. RESULTS: Nine studies including 115,455 patients were analyzed. The median Newcastle-Ottawa quality score for the included studies was seven (range, 6-9). Among patients taking PPIs, the median proportion of patients with hypomagnesemia was 27.1% (range, 11.3-55.2%) across all included studies. Among patients not taking PPIs, the median proportion of patients with hypomagnesemia was 18.4% (range, 4.3-52.7%). On meta-analysis, pooled odds ratio for PPI use was found to be 1.775 (95% confidence interval 1.077-2.924). Significant heterogeneity was identified using Cochran's Q test (df = 7, P<0.001, I2 = 98.0%). CONCLUSIONS: PPI use may increase the risk of hypomagnesemia. However, significant heterogeneity among the included studies prevented us from reaching a definitive conclusion.