Proton Pump Inhibitor Treatment Research Articles

Proton-Pump Inhibitors in Eosinophilic Esophagitis: A Review Focused on the Role of Pharmacogenetics

Proton-pump inhibitors (PPIs) are the most administered first-line treatment for eosinophilic esophagitis (EoE). However, only around half of EoE patients respond histologically to a double dosage of PPI. In addition, 70% of responders maintain EoE in remission after tapering the PPI dose. In order to avoid endoscopy with biopsies—the only accurate method of assessing PPI response—efforts have been made to identify PPI responder patients. The clinical or endoscopic features and biomarkers evaluated so far, however, have not proven to be sufficient in predicting PPI response. Although new approaches based on omics technologies have uncovered promising biomarkers, the specialized and complex procedures required are difficult to implement in clinical settings. Alternatively, PPI pharmacogenetics based on identifying variations in CYP2C19 and STAT6 genes have shown promising results in EoE, and could easily be performed in most laboratories. Other genetic variations have also been associated with PPI response and may explain those cases not related to CYP2C19 or STAT6. Here, we provide an overview of PPI treatment in EoE and evidence of how genetic variations in CYP2C19 and other genes could affect PPI effectiveness, and also discuss studies evaluating the role of pharmacogenetics in predicting PPI response in patients with EoE.

Current Status of Anti-Reflux Surgery as a Treatment for GERD.

Anti-reflux surgery (ARS) is an efficient treatment option for gastroesophageal reflux disease (GERD). Despite growing evidence of the efficacy and safety of ARS, medications including proton pump inhibitors (PPIs) remain the most commonly administered treatments for GERD. Meanwhile, ARS can be an effective treatment option for patients who need medications continuously or for those who are refractory to PPI treatment, if proper candidates are selected. However, in practice, ARS is often regarded as a last resort for patients who are unresponsive to PPIs. Accumulating ARS-related studies indicate that surgery is equivalent to or better than medical treatment for controlling typical and atypical GERD symptoms. Furthermore, because of overall reduced medication expenses, ARS may be more cost-effective than PPI. Patients are selected for ARS based on endoscopic findings, esophageal acid exposure time, and PPI responsiveness. Although there is limited evidence, ARS may be expanded to include patients with normal acid exposure, such as those with reflux hypersensitivity. Additionally, other factors such as age, body mass index, and comorbidities are known to affect ARS outcomes; and such factors should be considered. Nissen fundoplication or partial fundoplication including Dor fundoplication and Toupet fundoplication can be chosen, depending on whether the patient prioritizes symptom improvement or minimizing postoperative symptoms such as dysphagia. Furthermore, efforts to reduce and manage postoperative complications and create awareness of the long-term efficacy and safety of the ARS are recommended, as well as adequate training programs for new surgeons.

A Meta-analysis of PPIs Plus Alginate Versus PPIs Alone for the Treatment of GERD

To systematically evaluate the clinical efficacy and safety of proton-pump inhibitors (PPIs) combined with alginate versus PPIs alone in the treatment of gastroesophageal reflux disease (GERD). Randomised Controlled Trials (RCTs) of PPIs combined with alginate and PPIs alone for the treatment of GERD in PubMed, Embase, and The Cochrane Library were searched and screened, and the risk assessment of bias and statistical analysis were performed using Rev Man 5.4 software. A total of four RCTs (608 patients) were included. Before and after treatment, the change of heartburn score in the experimental group increased compared with the control group, but the difference was not statistically significant [Standard Mean Difference (SMD)=-0.29, 95%CI (-0.78, 0.19), P>0.05]; The change of HRDQ heartburn score increased, but the difference was not statistically significant [SMD=-0.40, 95%CI (-1.04, 0.24), P>0.05]; The number of days without heartburn during the 28-day treatment period increased, but the difference was not statistically significant [OR=1.16, 95%CI (0.37, 3.61), P>0.05]; The amount of reflux score increased, but the difference was not statistically significant [SMD=-0.30, 95%CI (-0.71, 0.11), P>0.05]; The amount of change in HRDQ regurgitation score increased, but the difference was not statistically significant [SMD=-0.05，95%CI （-1.57，0.17），P>0.05]； There was no statistically significant difference in adverse events with treatment [OR=0.93, 95%CI (0.58, 1.47), P>0.05]. In the treatment of GERD, the efficacy of PPIs combined with alginate is improved compared with PPIs alone, but there is no significant difference, and alginate does not increase the occurrence of adverse events in PPIs treatment. In the future, more subdivisions of GERD subtypes and more high-quality studies are needed to further improve the treatment strategy of GERD-related diseases.

Analysis of Helicobacter pylori resistance in patients with different gastric diseases

Helicobacter pylori (H. pylori) resistance is the most important risk factor for eradication failure. However, in most regions, antibiotic resistance rates of H. pylori in patients with different types of gastric mucosal lesions are still unclear. An 8-year clinical retrospective cohort study involving 2847 patients was performed. In this study, we first summarized and compared the resistance status of H. pylori in different years, ages, sexes, and gastric diseases. The resistance profiles of amoxicillin (AMX), clarithromycin (CLR), levofloxacin (LVX) and furazolidone (FR) and their changing trends in the clinic were described. Then, multiple antibiotic resistance in different gastric diseases and years were described and compared. The relationship between proton pump inhibitor (PPI) medication history and antibiotic resistance in H. pylori was also explored. Finally, an antibiotic resistance risk model was constructed for clinical resistance risk prediction. The overall resistance rates of AMX, CLR, LVX and FR in gastric diseases were 8.18%, 38.11%, 43.98%, and 13.73%, respectively. The mono resistance, double resistance, triple resistance, and quadruple resistance rates were 30.17%, 25.96%, 6.46%, and 0.63%, respectively. Compared with the period from 2014 to 2016, the rates of mono-resistance and multiple resistance all showed relatively downward trends in the past 5 years. Factors including age, sex, type of gastric lesions and recent PPI treatment history are associated with the antibiotic resistance rate of H. pylori. Atrophic gastritis is an important clinical feature of high-risk antibiotic resistance in H. pylori-infected patients. Patients with atrophic gastritis have higher risk of resistant strains infection. In this study, our data provide the association between antibiotic resistance of H. pylori and gastritis pattern, which indicate the higher risk of resistant strain infection if the patients with atrophic gastritis, PPI history and older age.

Expert Opinion on the Prescription Practice of Rabeprazole and Other Common Proton Pump Inhibitors for Patients with Gastroesophageal Reflux Disease

Objective: The current survey-based study aims to provide further insights on expert opinion regarding the commonly prescribed PPIs in clinical practice, with a specific focus on the use of oral rabeprazole 20 mg as a treatment for gastroesophageal reflux disease (GERD) maintenance therapy in Indian settings.
 Methodology: The questionnaire-based survey involving 25 questions collected perspectives of experts across various regions of India regarding the prescription practice of rabeprazole 20 mg and other proton-pump inhibitors (PPIs) for treating GERD symptoms.
 Results: Out of 512 study participants, 44% reported obesity as the common comorbid condition observed in GERD patients, while 28% noted co-morbid diabetes mellitus. According to 68% of the respondents, rabeprazole demonstrated superiority over other PPIs in terms of quicker onset of action, maintaining intragastric pH >4 over 24 hours’ post-dose, and reduced nighttime heartburn. For GERD patients with functional dyspepsia and gastroparesis, 52% of responders favored the addition of domperidone as a prokinetic drug to the PPI treatment. Moreover, the majority of participants (61.91%) observed that rabeprazole 20 mg did not cause a delay in stomach emptying, nor did it raise somatostatin levels or alter baseline motilin levels in GERD patients. These findings underscore the effectiveness of rabeprazole 20 mg in comparison to omeprazole and lansoprazole.
 Conclusion: Experts recommended rabeprazole 20 mg as the preferred treatment option over omeprazole and lansoprazole for GERD patients with coexisting obesity and diabetes mellitus conditions. Additionally, over half of the respondents reported using a combination of domperidone and other PPIs for GERD patients with functional dyspepsia and gastroparesis.

Timely Cessation of Proton Pump Inhibitors in Critically Ill Patients Impacts Morbidity and Mortality: A Propensity Score-Matched Cohort Study.

Proton pump inhibitors (PPIs) are among the drugs most commonly used in critically ill patients. Although mainly applied temporarily for stress ulcer prophylaxis, their application is frequently not terminated. Potential adverse effects of PPI treatment could impact the outcome in case of unnecessary and, therefore, avoidable long-term continuation. We tested the hypotheses that nonindicated PPI therapy continued beyond hospital discharge is associated with increased morbidity, rehospitalization rate, and mortality. Nationwide retrospective cohort study considering critically ill patients treated on German ICUs between January, 2017, and December, 2018 with a 2-year follow-up. A total of 591,207 patient datasets of a German healthcare insurer were screened. We identified 11,576 ICU patients who received PPI therapy for the first time during their index ICU stay without having an indication for its continuation. The cohort was stratified into two groups: 1) patients without further PPI therapy and 2) patients with continuation of PPI therapy beyond 8 weeks after hospital discharge. Frequency of predescribed adverse events associated with PPI therapy, 1-year rehospitalization rate, and 2-year mortality were determined. The proportion of patients with continued PPI therapy without an objectifiable indication was 41.7% (4,825 of 11,576 patients). These patients had a 27% greater risk of pneumonia (odds ratio [OR] 1.27; 95% CI, 1.15-1.39; p < 0.001) and a 17% greater risk of cardiovascular events (OR 1.17; 95% CI, 1.08-1.26; p < 0.001). Continued PPI therapy was associated with a 34% greater risk of rehospitalization (OR 1.34; 95% CI, 1.23-1.47) and a nearly 20% greater 2-year mortality risk (hazard ratio 1.17; 95% CI, 1.08-1.27; p = 0.006). These data demonstrate that an unnecessary continuation of PPI therapy after hospital discharge may significantly impact morbidity and mortality. To avoid potentially harmful overuse of a PPIs, intensivists should ensure timely cessation of a temporarily indicated PPI therapy.

Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor

Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D2 receptor (D2R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D2R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.

Budget Impact of RefluxStop™ as a Treatment for Patients with Refractory Gastro-oesophageal Reflux Disease in the United Kingdom.

Background: Gastro-oesophageal reflux disease (GORD) is a common condition associated with heartburn and regurgitation. Standard of care for GORD patients in the UK involves initial treatment with proton pump inhibitors (PPIs) and laparoscopic antireflux surgery in patients unwilling to continue or intolerant of long-term PPI treatment. Recently, RefluxStop™, a novel, implantable medical device, has proven to be an efficacious and cost-effective treatment for patients with GORD. The current analysis aimed to describe the budget impact of introducing RefluxStop™ within National Health Service (NHS) England and Wales. Objectives: To estimate the more immediate, short-term clinical and economic effects of introducing RefluxStop™ as a therapeutic option for patients with GORD treated within NHS England and Wales. Methods: A model adherent to international best practice guidelines was developed to estimate the budget impact of introducing RefluxStop™ over a 5-year time horizon, from an NHS perspective. Two hypothetical scenarios were considered, one without RefluxStop™ (comprising PPI treatment, laparoscopic Nissen fundoplication, and magnetic sphincter augmentation using the LINX® system) and one with RefluxStop™ (adding RefluxStop™ to the aforementioned treatment options). Clinical benefits and costs associated with each intervention were included in the analysis. Results: Over 5 years, introducing RefluxStop™ allowed the avoidance of 347 surgical failures, 39 reoperations, and 239 endoscopic esophageal dilations. The financial impact of introducing RefluxStop™ was £3 029 702 in year 5, corresponding to a 1.68% increase in annual NHS spending on GORD treatment in England and Wales. Discussion: While the time horizon was too short to capture some of the adverse events of PPIs and complications of GORD, such as the development of Barrett's esophagus or esophageal cancer, the use of RefluxStop™ was associated with a substantial reduction in surgical complications, including surgical failures, reoperations, and endoscopic esophageal dilations. This favorable clinical profile resulted in cost offsets for the NHS and contributed to the marginal budget impact of RefluxStop™ estimated in the current analysis. Conclusions: Introducing RefluxStop™ as a treatment option for patients with GORD in England and Wales may be associated with clinical benefits at the expense of a marginal budget impact on the NHS.

Budget Impact of RefluxStopTM as a Treatment for Patients with Refractory Gastro-oesophageal Reflux Disease in the United Kingdom

Background: Gastro-oesophageal reflux disease (GORD) is a common condition associated with heartburn and regurgitation. Standard of care for GORD patients in the UK involves initial treatment with proton pump inhibitors (PPIs) and laparoscopic antireflux surgery in patients unwilling to continue or intolerant of long-term PPI treatment. Recently, RefluxStop™, a novel, implantable medical device, has proven to be an efficacious and cost-effective treatment for patients with GORD. The current analysis aimed to describe the budget impact of introducing RefluxStop™ within National Health Service (NHS) England and Wales. Objectives: To estimate the more immediate, short-term clinical and economic effects of introducing RefluxStop™ as a therapeutic option for patients with GORD treated within NHS England and Wales. Methods: A model adherent to international best practice guidelines was developed to estimate the budget impact of introducing RefluxStop™ over a 5-year time horizon, from an NHS perspective. Two hypothetical scenarios were considered, one without RefluxStop™ (comprising PPI treatment, laparoscopic Nissen fundoplication, and magnetic sphincter augmentation using the LINX® system) and one with RefluxStop™ (adding RefluxStop™ to the aforementioned treatment options). Clinical benefits and costs associated with each intervention were included in the analysis. Results: Over 5 years, introducing RefluxStop™ allowed the avoidance of 347 surgical failures, 39 reoperations, and 239 endoscopic esophageal dilations. The financial impact of introducing RefluxStop™ was £3 029 702 in year 5, corresponding to a 1.68% increase in annual NHS spending on GORD treatment in England and Wales. Discussion: While the time horizon was too short to capture some of the adverse events of PPIs and complications of GORD, such as the development of Barrett’s esophagus or esophageal cancer, the use of RefluxStop™ was associated with a substantial reduction in surgical complications, including surgical failures, reoperations, and endoscopic esophageal dilations. This favorable clinical profile resulted in cost offsets for the NHS and contributed to the marginal budget impact of RefluxStop™ estimated in the current analysis. Conclusions: Introducing RefluxStop™ as a treatment option for patients with GORD in England and Wales may be associated with clinical benefits at the expense of a marginal budget impact on the NHS.

Salivary pepsin as an independent predictor of treatment response for laryngopharyngeal reflux: prospective cohort study with multivariate analysis

To analyze the predictive value of salivary pepsin for treatment outcomes in laryngopharyngeal reflux (LPR) using multivariate analysis that includes various associated factors. This prospective cohort study was conducted between August 2020 and August 2022. Patients with LPR who had symptoms lasting more than 1 month and a reflux symptom index (RSI) of 14 or higher were enrolled. The participants received a 2-month regimen of proton pump inhibitors (PPIs) treatment and lifestyle modification. Salivary pepsin was checked using fasting saliva before treatment. Salivary pepsin was detected more frequently in the good treatment response group (61.1%), compared to 14.3% in the poor response group. Similarly, patients with higher compliance to lifestyle modifications (> 90%) had a higher chance of a good response (91.7%) compared to those with lower compliance, who had a 53.8% chance of a good response. Other clinical factors have no significant association with treatment response. In multivariate analysis, both pretreatment salivary pepsin and higher compliance with lifestyle modification were found to be independent factors for treatment response (OR 14.457, CI 1.075 ~ 194.37 for both). This study found that positive salivary pepsin and strict lifestyle modification are independent predictors of treatment outcomes in LPR.

The Impact of Sex on the Response to Proton Pump Inhibitor Treatment.

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment.

IBC-Oxford University2023_BJSOral_15Conversion of Sleeve Gastrectomy to Roux-en-Y Gastric Bypass: Indications, Management and Results

Abstract Introduction Sleeve gastrectomy (SG) represents more than 60% of bariatric procedures worldwide. Conversion of SG to Roux-en-Y gastric bypass (RYGB) for weight loss failure (WLF) or gastro-oesophageal reflux disease (GERD) is increasing. Intrathoracic migration of the sleeve often seems associated. Aim The aim of our study was to analyse the relevance of the indications, the prevalence of an associated de novo hiatal hernia, and the outcomes of the conversion of SG to RYGB. Methods This is a retrospective study of prospectively collected data including all the patients who underwent a conversion of SG to RYGB from August 2013 to December 2022. 2 groups were compared: patients operated on because of weight loss failure (WLF group) and those operated on for GERD (GERD group). Results We analysed in both groups demographic data, the incidence of an associated hiatal hernia, morbidity, weight loss outcomes and resolution of symptoms. 59 patients were included with an average follow-up of 30.5 months: 46 patients in the GERD group (78%) were compared to 13 patients (22%) in the WLF group. Groups were comparable regarding age (47) and gender (women: 74%); BMI at conversion and prevalence of comorbidities were significantly higher in the WLF group (41.8 kg/m² vs 33.3, p=0.0001). In the GERD group: on preoperative gastroscopy, 30% (14/46) had a grade B esophagitis, 48% (22/46) had a significant hiatal hernia which required a posterior crural closure versus 23% (3/13) in the WLF group, not requiring a surgical treatment (p = 0.02). Conversion was very effective on GERD symptoms (93% of improvement), 52% of the patients stopped proton pump inhibitor treatment. In the WLF group, mean percentage total weight loss (% TWL) was 15.3%, significantly greater than in the GERD group (% TWL=4.6%, p = 0.01). The complication rate was 10% at 30 days and 3.4% after 30 days, not significantly different between groups (p = 1 and 1 respectively). Conclusions The main indication of conversion of SG to RYGB was because of GERD: in these indications, the incidence of intrathoracic migration of the sleeve is high requiring a surgical treatment with a very good efficacy on resolution of symptoms. Weight loss results were disappointing.

IBC-Oxford University2023_BJSOral_12Conversion of Sleeve Gastrectomy to Roux-en-Y Gastric Bypass: Indications, Management and Results

Abstract Introduction Sleeve gastrectomy (SG) represents more than 60% of bariatric procedures worldwide. Conversion of SG to Roux-en-Y gastric bypass (RYGB) for weight loss failure (WLF) or gastro-oesophageal reflux disease (GERD) is increasing. Intrathoracic migration of the sleeve often seems associated. Aim The aim of our study was to analyse the relevance of the indications, the prevalence of an associated de novo hiatal hernia, and the outcomes of the conversion of SG to RYGB. Methods This is a retrospective study of prospectively collected data including all the patients who underwent a conversion of SG to RYGB from August 2013 to December 2022. 2 groups were compared: patients operated on because of weight loss failure (WLF group) and those operated on for GERD (GERD group). Results We analysed in both groups demographic data, the incidence of an associated hiatal hernia, morbidity, weight loss outcomes and resolution of symptoms. 59 patients were included with an average follow-up of 30.5 months: 46 patients in the GERD group (78%) were compared to 13 patients (22%) in the WLF group. Groups were comparable regarding age (47) and gender (women: 74%); BMI at conversion and prevalence of comorbidities were significantly higher in the WLF group (41.8 kg/m² vs 33.3, p=0.0001). In the GERD group: on preoperative gastroscopy, 30% (14/46) had a grade B esophagitis, 48% (22/46) had a significant hiatal hernia which required a posterior crural closure versus 23% (3/13) in the WLF group, not requiring a surgical treatment (p = 0.02). Conversion was very effective on GERD symptoms (93% of improvement), 52% of the patients stopped proton pump inhibitor treatment. In the WLF group, mean percentage total weight loss (% TWL) was 15.3%, significantly greater than in the GERD group (% TWL=4.6%, p = 0.01). The complication rate was 10% at 30 days and 3.4% after 30 days, not significantly different between groups (p = 1 and 1 respectively). Conclusions The main indication of conversion of SG to RYGB was because of GERD: in these indications, the incidence of intrathoracic migration of the sleeve is high requiring a surgical treatment with a very good efficacy on resolution of symptoms. Weight loss results were disappointing.

Modern aspects of managing patients with non-erosive reflux disease

A review of current  data  on the management of patients with non-erosive reflux disease  (NERD) was made. Diagnosis of gastroesophageal reflux disease  (GERD) is based  on symptom analysis, endoscopic  evaluation of the esophageal mucosa, objective  evidence of gastric contents reflux into the esophagus during pH-impedancemetry, and response to therapeutic intervention. Treatment for GERD should include weight loss if overweight, lifestyle modification, and dietary modification. Current consensus recommends starting NERD treatment with once-daily proton pump inhibitors (PPIs), but only 50% of patients with this pathology respond to such therapy. Incomplete response to PPIs is a reason  to increase  the dose of PPI and add Gaviscon to treatment to neutralize the post-prandial “acid pocket”. Gaviscon is especially effective in patients with postprandial or nocturnal symptoms and in those with hiatal hernia. The mechanism  of action of Gaviscon is based  on the formation  of an alginate “raft” on the surface of the gastric contents, which neutralizes the acid and blocks its pathological effect to esophageal mucosa. A modern meta-analysis on the NERD treatment, which included  23 studies  and 10,735  patients, showed  the  efficacy of Gaviscon monotherapy comparable to PPIs in treatment for 4 weeks. The combination of a PPI with Gaviscon offers the opportunity to optimize response to treatment in NERD patients with an incomplete response to PPIs monotherapy. The Russian Gastroenterological Association thinks that alginates can be used both as monotherapy for mild clinical variants of NERD and in complex treatment regimens  for various GERD variants.

On-demand Versus Continuous Maintenance Treatment With a Proton Pump Inhibitor for Mild Gastroesophageal Reflux Disease: A Prospective Randomized Multicenter Study.

It remains unclear which maintenance treatment modality is most appropriate for mild gastroesophageal reflux disease (GERD). We aimed to compare on-demand treatment with continuous treatment using a proton pump inhibitor (PPI) in the maintenance treatment for patients with non-erosive GERD or mild erosive esophagitis. Patients whose GERD symptoms improved after 4 weeks of standard dose PPI treatment were prospectively enrolled at 25 hospitals. Subsequently, the enrolled patients were randomly assigned to either an on-demand or a continuous maintenance treatment group, and followed in an 8-week interval for up to 24 weeks. A total of 304 patients were randomized to maintenance treatment (continuous, n = 151 vs on-demand, n = 153). The primary outcome, the overall proportion of unwillingness to continue the assigned maintenance treatment modality, failed to confirm the non-inferiority of on-demand treatment (45.9%) compared to continuous treatment (36.1%). Compared with the on-demand group, the GERD symptom and health-related quality of life scores significantly more improved and the overall satisfaction score was significantly higher in the continuous treatment group, particularly at week 8 and week 16 of maintenance treatment. Work impairment scores were not different in the 2 groups, but the prescription cost was less in the on-demand group. Serum gastrin levels significantly elevated in the continuous treatment group, but not in the on-demand group. Continuous treatment seems to be more appropriate for the initial maintenance treatment of non-erosive GERD or mild erosive esophagitis than on-demand treatment. Stepping down to on-demand treatment needs to be considered after a sufficient period of continuous treatment.

Oral Bioavailability and Pharmacokinetics of Sildenafil Orally Disintegrating Tablets under Various Gastric pH Levels Following Administration of Omeprazole in Rats.

Sildenafil citrate, an oral drug used to treat erectile dysfunction, has low water solubility and oral bioavailability. The solubility is greatly influenced by the pH, changing from 37.25 mg/mL to 0.22 mg/mL with a change in pH from 1.2 to 8.0. This indicates that the absorption may decrease in patients who use drugs, such as proton pump inhibitors (PPIs), for gastroesophageal reflux disease. To improve the absorption of sildenafil citrate at various gastric pH levels, a sildenafil citrate orally disintegrating tablet (ODT), which has a rapid disintegration feature, was produced by a 3D printing technique. Our study investigated the pharmacokinetic parameters of the sildenafil citrate ODT in rats after oral administration and compared the absorption of the sildenafil citrate ODT and sildenafil citrate commercial tablet (RLD), with and without PPI treatment. The LC/MS/MS analysis of the plasma sildenafil concentration revealed that the area under curve from time 0 to infinity (AUC0-∞) of sildenafil in the sildenafil citrate ODT group was significantly higher than in the sildenafil citrate RLD group whether it was in combination with the PPI or not (274.8% and 144%, respectively; p < 0.05). The relative systemic bioavailability of sildenafil citrate RLD significantly decreased with the PPI, but that of sildenafil citrate ODT was not affected by the PPI. These results indicate that the relative systemic bioavailability of sildenafil citrate ODT was increased when it was prepared using the 3D printing technique and the absorption of this formulation was not affected by the PPI.

Composite score of physiomechanical esophageal function using functional lumen imaging probe panometry in eosinophilic esophagitis

Background and AimsThe evaluation provided by functional lumen imaging probe (FLIP) Panometry includes esophageal distensibility/compliance (mechanics) of the esophageal body and esophagogastric junction (EGJ) and esophageal motility (secondary peristalsis). We aimed to develop a composite score using these parameters to characterize physiomechanical function in patients with eosinophilic esophagitis (EoE). Methods215 adult patients with EoE that completed FLIP Panometry during sedated endoscopy with esophageal biopsies were included. FLIP metrics of esophageal body Compliance, Contractile response, Distensibility plateau, and maximum EGJ Diameter (C2D2) were scored as 0 for normal, vs 1 or 2 for increasing degree of abnormality. Scores were summed to calculate the composite “C2D2” score. ResultsThe C2D2 score had a significant positive correlation with mucosal eosinophil count (rho=0.241) and total endoscopic (EREFS) score (rho=0.467). Among patients off treatment at baseline evaluation (n=46), future proton pump inhibitor (PPI)-responders (i.e. achieved mucosal eosinophil count <15 per hpf after PPI treatment) had lower C2D2 scores than PPI-non-responders (median (IQR) 2 (1-3) vs 4 (2-6); P=0.003). A regression model (that controlled for age, sex, and baseline eosinophil count) showed a C2D2 score ≤3 had an odds ratio (95% confidence interval) of 14.5 (2.6-85) to predict future PPI-response. However, total EREFS scores (P=0.142) and baseline eosinophil count (P=0.480) did not differ between PPI-responders and PPI-non-responders. ConclusionsThis composite score of FLIP Panometry metrics, the C2D2 score, may facilitate characterizing physiomechanical function in EoE and serve as an objective outcome measure.

Digestive Tract Cancer-Related Adverse Events Correlated with Proton Pump Inhibitors Use: A Pharmacovigilance Study of the FDA Adverse Event Reporting System

Background. Proton pump inhibitors (PPIs) are widely used to treat digestive system diseases. Previous studies have suggested conflicting results between PPI treatment and the risk for digestive tract cancers (DTCs). This study aimed to assess the effect of PPI use on DTCs by data mining of the FDA Adverse Event Reporting System (FAERS) database. Method. This study examined the correlations between six PPI agents and DTCs by mining the FAERS database from January 2004 to September 2021 by using OpenVigil 2.1. The reporting odds ratio (ROR) defined as the ratio between the odds of reporting a specific adverse event for one drug divided by the corresponding odds for all other drugs, with 95% confidence intervals (CIs), was used to detect statistically significant correlations between PPIs and DTCs. High-level terms (HLTs) and preferred terms (PTs) were defined by the Medical Dictionary for Regulatory Activities 24.0 (MedDRA24.0). Result. A total of 2553 DTC adverse event reports were screened, with positive signals obtained from gastric neoplasms malignant (GNM) (ROR: 1.09, 95% CI: 1.01–1.18) and bile duct neoplasms malignant (BDNM) (ROR: 1.80, 95% CI: 1.44–2.25). Esomeprazole showed the strongest signal (ROR: 1.85, 95% CI: 1.66–2.06) for GNM, while rabeprazole for BDNM (ROR: 2.94, 95% CI: 1.32–6.56), and female PPI users had a higher risk of BDNM (ROR: 2.44, 95% CI: 1.77–3.35). Among subordinate PTs, adenocarcinoma gastric and the combination of “bile duct cancer” and “cholangiocarcinoma” were highly correlated with PPI use. Conclusion. By mining the FAERS database, we provided important clues for the correlation between PPI use and DTC risk.

Pantoprazole promotes sustained intestinal carriage of multidrug-resistant Escherichia coli in amoxicillin-treated mice.

The main objective of this study was to compare extended-spectrum β-lactamase (ESBL) Escherichia coli fecal titers during 12 days between two groups: mice who received proton pump inhibitors (PPIs) and those that did not. We tested three different in vivo models: model 1, high inoculum (106 CFU ml-1); model 2, low inoculum (102 CFU ml-1); and model 3, low inoculum and 2-day amoxicillin wash-out. There was no significant difference between the two groups in fecal ESBL E. coli titers in models 1 and 2. The fecal titers of ESBL E. coli were probably too high to show differences in colonization related to PPI treatment. By introducing a 2-day wash-out period after stopping amoxicillin (model 3), the fecal ESBL E. coli titers were higher in the PPI-treated mice during 12 days (3 log versus 11 log day CFU g-1; P<0.05). This result highlighted that PPIs promote stable ESBL E. coli digestive carriage in mice. Fecal quantitative PCR showed that mice with low ESBL E. coli fecal titers had a much higher concentration of equol-producing bacteria, Muribaculum sp., and Adlercreutzia caecimuris. Pantoprazole treatment promotes sustained digestive carriage of ESBL E. coli in amoxicillin-treated mice.

Proton pump inhibitors in eosinophilic esophagitis (EoE) related to oral immunotherapy: is it as effective as in other EoE?

PPI treatment is as effective in EoE with OIT as it is in EoE due to other etiologies. • Proton pump inhibitor (PPI) treatment is effective for achieving clinical response and histologic remission in some patients with eosinophilic esophagitis (EoE). • EoE has also been reported to be triggered by oral immunotherapy (OIT). • PPI treatment in EoE with OIT is as effective as treatment for EoE due to other etiologies.