Administration Of Proton Pump Inhibitors Research Articles

Characterization of intestine-specific TRPM6 knockout C57BL/6J mice: effects of short-term omeprazole treatment.

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg2+ balance. Disturbance in Mg2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4days) omeprazole treatment on intestinal Mg2+ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6-/-) mice. To do this, forty-eight adult male C57BL/6J mice (50% TRPM6fl/fl and 50% Vill1-TRPM6-/-) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20mg/kg bodyweight omeprazole or placebo for 4days. Vill1-TRPM6-/- mice had a significantly lower 25Mg2+ absorption compared to control TRPM6fl/fl mice, accompanied by lower Mg2+ serum levels, and urinary Mg2+ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn2+ transporter Slc30a10. However, no changes in Mn2+ serum, urine, and feces levels were observed. Moreover, 4days omeprazole treatment did not affect Mg2+ homeostasis as no changes in serum 25Mg2+ and total Mg2+ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6-/- mice have a lower Mg2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg2+ absorption in both Vill1-TRPM6-/- and TRPM6fl/fl mice. This suggests that TRPM6-mediated Mg2+ absorption in the intestines is not affected by short-term PPI administration.

The Use of Proton Pump Inhibitors in Patients with Liver Cirrhosis: Real Life Experience.

(1) Background: Proton pump inhibitors (PPIs) are commonly prescribed for gastric disorders. In patients with liver cirrhosis, PPI use is associated with an increased risk of spontaneous bacterial peritonitis and increased mortality rates; therefore, they should be used with caution. This study aims to evaluate the appropriateness of PPI prescriptions in hospitalized cirrhotic patients against current clinical guidelines to identify patterns of misuse and guide better prescribing practices. (2) Methods: A retrospective study was conducted on liver cirrhosis inpatients in an internal medicine department from January 2022 to May 2023. The primary measure was the proportion of PPI prescriptions aligned with clinical guidelines. Medical files were entirely reviewed by researchers to assess the appropriateness of PPI prescriptions using the current guidelines. Outcomes included the identification of common reasons for PPI prescription and the rate of inappropriate PPI use among the study population. (3) Results: The study included 189 cirrhotic patients, with PPIs prescribed to 95 (50.2%) patients during hospitalization and 75 (39.7%) patients at discharge. Among those, 47.4% of the inpatients and 34.7% at discharge had no valid indication for PPI administration. The most common reason for PPI prescription during hospital stays was gastritis, followed by antiplatelet use in high-risk patients, ulcers, and upper gastrointestinal bleeding. The most common inappropriate indication was portal hypertensive gastropathy (PHG), followed by treatment with corticosteroids and anticoagulants alone. We did not find an association between PPI administration during hospital stays and infections. Only in 4% of cases patients should have received PPIs and did not. (4) Conclusions: There is a concerning overprescription of PPIs in cirrhotic patients, often deviating from established guidelines. It subjects patients to unnecessary risks. There is an urgent need for increased awareness and adherence to clinical guidelines regarding PPI prescriptions in cirrhotic patients.

Proton Pump Inhibitor Prescription in Nursing Home Residents: Prevalence, Appropriateness, and Associated Factors-A Secondary Data Analysis from Three German Regions and the Impact of Guideline Recommendations.

Despite reliable evidence of adverse drug effects, the substantially increased prescription rates of proton pump inhibitors (PPIs) remain at a high level. This study analyzed the appropriateness of PPI prescriptions among residents of nursing homes in three regions of Germany. Baseline data of a cluster-randomized controlled trial were used to determine the prevalence of PPI prescriptions, the validity of indications, and the adequacy of the prescribed dosages according to 1. their drug approvals and 2. valid recommendation guidelines. Regression analyses were conducted to assess associated factors. A total of 437 residents in 37 nursing homes were included (mean age 83 ± 9.2 years, 72% women). The PPI prescription prevalence was 44% (n = 193). In 52/193 (27%) there was no adequate indication, and in 54 (39%) of 138 indicated PPI prescriptions it was overdosed. Yet, in only less than one-third (28%) of "adequate" prescriptions, the indication was according to the PPI approvals, whereas the majority (72%) were off-label indications in line with valid guideline recommendations. Non-indicated PPI prescription was associated with the total number of prescribed drugs (OR 1.32; 95% CI 1.18-1.62; p = 0.013). There were no associations with age, level of care dependency, cognitive impairment, prescription of psychotropic drugs, number of chronic diseases, number of physicians' consultations, or study region. To conclude, in 55%, the high prescription prevalence among residents was either not indicated or overdosed. In total, only 20% (39/193) of cases of PPI use complied with the approved indications. There is a need for quality control of 1. PPI administration in German nursing homes, and 2. of guideline recommendations expanding the off-label PPI use by 72% within the indication scale, predominantly from wide prescription for low-dose ASA.

The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.

Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of cytochrome P450 (CYP)3A4 and P-glycoprotein involvement. The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4(rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg). Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30μM. Additionally, both omeprazole and rabeprazole (10µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasmaconcentration) Cmaxand area under the plasmaconcentration-time curve(AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h. The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.

SUBA-itraconazole in the treatment of systemic fungal infections.

Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent protonpump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now USFDA approved in the treatment of blastomycosis, histoplasmosisand aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edemaand drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.

Impact of proton pump inhibitors on the efficacy of androgen receptor signaling inhibitors in metastatic castration-resistant prostate cancer patients.

Proton pump inhibitors (PPIs) are widely used due to their affordability and minimal severe side effects. However, their influence on the efficacy of cancer treatments, particularly androgen receptor signaling inhibitors (ARSIs), remains unclear. This study investigates the impact of PPI usage on the treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 117 mCRPC patients were retrospectively analyzed and divided into two groups based on the concomitant use of PPI at the initiation of ARSI treatment: PPI+ (n = 38) and PPI- (n = 79). Patient characteristics, including age at ARSI treatment administered, prostate-specific antigen (PSA) value at ARSI treatment administered, International Society of Urological Pathology grade group at prostate biopsy, metastatic site at ARSI treatment administered, prior docetaxel (DTX) treatment, and type of ARSI (abiraterone acetate or enzalutamide) were recorded. Progression-free survival (PFS), overall survival (OS), and PSA response rates were compared between the two groups. Patients were further stratified by clinical background to compare PFS and OS between the two groups. The PPI- group exhibited significantly extended PFS and a trend toward improved OS. For PSA response (reduction of 50% or more from baseline), the rates were 62.3% and 45.9% in the PPI- group and the PPI+ group, respectively. For deep PSA response (reductions of 90% or more from baseline), the rates were 36.4% and 24.3% in the PPI- group and the PPI+ group, respectively. The effects were consistent across subgroups divided by prior DTX treatment and type of ARSI administered. The administration of PPIs appears to diminish the therapeutic efficacy of ARSIs in mCRPC patients. Further prospective studies are needed to confirm these findings and explore the biological mechanisms involved.

Prognostic Impact of the Administration of Antibiotics and Proton Pump Inhibitors in Immune Checkpoint Inhibitor Combination Therapy for Advanced Renal Cell Carcinoma.

The prognostic impact of the administration of antibiotics and proton pump inhibitors (PPIs) in immune checkpoint inhibitor (ICI) therapy for advanced cancer has recently been documented. However, how these drugs affect the outcomes of first-line ICI combination therapy for advanced renal cell carcinoma (RCC) remains unclear. We retrospectively evaluated the data of 128 patients with RCC who received first-line ICI combination therapy. The patients were grouped according to their history of antibiotics and PPIs use one month before the initiation of ICI combination therapy. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) after ICI combination therapy were compared between patients treated with and without antibiotics or PPIs. Of the 128 patients, 30 (23%) and 44 (34%) received antibiotics and PPIs, respectively. Patients treated with antibiotics exhibited shorter PFS and OS compared to those who did not receive antibiotics (median PFS: 4.9 vs. 16.1 months, p<0.0001; OS: 20.8 vs. 49.0 months, p=0.0034). Multivariate analyses showed that antibiotic administration was an independent predictor of shorter PFS (hazard ratio: 2.54: p=0.0002) and OS (hazard ratio: 2.56: p=0.0067) after adjusting for other covariates. In contrast, there were no significant differences in either PFS or OS between patients who received PPIs and those who did not. (PFS: p=0.828; OS: p=0.105). Antibiotics administration before ICI combination therapy was negatively associated with outcomes of first-line ICI combination therapy for advanced RCC. Therefore, careful monitoring is required for potentially high-risk patients undergoing ICI combination therapy.

Overutilization of Proton Pump Inhibitors (PPIs) in a Community-Based Hospital: A QI Initiative

Introduction: Proton pump inhibitors (PPIs) are indicated for GERD, erosive esophagitis, and prophylactic use in patients at high risk for stress ulcerations. Long-term PPI therapy is associated with increased incidence of C. diff infections and community- and hospital-acquired pneumonia. Discontinuation of stress ulcer prophylaxis upon discharge and reevaluation of continued therapy will help reduce chronic, inappropriate treatment, which predisposes patients to adverse side effects. Aim: We sought to reform the process of inpatient PPI prescriptions based on clinical indications of therapy in order to reduce use and associated costs of PPIs by 30% over 6 months. Model for Improvement: We obtained an IRB exemption for a retrospective chart review study and collected pre-intervention data from 200 patients who had received PPI therapy between July-Aug 2022. Of these, 186 met inclusion criteria. We identified PPT overuse among all inpatient admissions, including those admitted under teaching services. Evaluating the timing of PPI initiation after admission, we found that a majority (83.8%) were started upon admission; 28.5% required PPIs throughout; and 25.2% of orders were placed within 1 day of discharge. The average duration of therapy was 3.9  2.59 days. On average, 50.5% of patients had a prior diagnosis of GERD, gastritis, or erosive esophagitis, justifying initiation of PPI therapy. However, almost a third (32.8%) met the criteria for stress ulcer prophylaxis. 17% of the cohort developed an adverse side effect, and almost 53% of patients were discharged with a new prescription for PPI. Measures: Root cause analysis revealed a lack of knowledge regarding adverse PPI effects leading to longer hospital stays. During the first PDSA, we conducted a session on “Use of PPI Inhibitors: Indications for Inpatient Prescriptions and Stress Ulcer Prophylaxis” in April 2023, educating Internal Medicine and Family Medicine resident teaching services about PPI therapy indications, contraindications, and adverse effects. Results: After our educational intervention, we collected and analyzed data from May 2023 to August 2023 and found 301 patients who met inclusion criteria. Their average age was 73.29 years. 169 patients (56%) had pre-existing diagnoses (GERD or erosive esophagitis), justifying initiation of Protonix. Of the remaining 132 without pre-existing conditions, 44 (35%) met criteria for starting stress ulcer prophylaxis. This was a 3% increase in appropriate utilization when compared to our pre-intervention data. 181 patients were discharged with a prescription for pantoprazole, of which 46 were PPI-naïve prior to admission. Conclusion: We found a decrease in inappropriate inpatient PPI administration by 3% after education. Although the post-intervention sample size was larger, the education resulted in a positive response in 1 month. The next PDSA cycle will alter the EMR order to provide only 3 orders for pantoprazole – one oral, one IV, and one for infusion, and orders will also require the selection of indication.

Concomitant Administration of VEGFR Tyrosine Kinase and Proton Pump Inhibitors May Impair Clinical Outcome of Patients With Metastatic Renal Cancer

IntroductionThe administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC). Patients and MethodsTotal 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as “no concomitant PPIs (PPI−)” if no PPIs were administered during TKIs, and as “concomitant PPIs (PPI+)” if the administration of PPIs was at least 75% of the time during which TKIs were given. ResultsEighty patients administered pazopanib were PPI− and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI− (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI− (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI− (6 months vs. not reached, P = .04). No correlation with adverse events was found. ConclusionsThis study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use.

Viral Infection in Upper Gastrointestinal Tract

Viral infections of the upper gastrointestinal (GI) tract are not uncommon in clinical practice; however, these are frequently observed in immunocompromised patients and rarely in immunocompetent hosts. Compared with esophagitis, which may be associated with clinically significant outcomes, the stomach is a relatively rare site for opportunistic infections in immunocompetent patients. The most common clinically relevant upper GI tract viral infections include cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus infections. CMV esophagitis and gastritis, which primarily occur in immunocompromised patients, necessitate antiviral treatment, whereas immunocompetent patients typically respond to proton pump inhibitor administration. Most EBV-induced gastric infections are asymptomatic. However, EBV infection is a known etiological contributor to stomach cancer. EBV-associated gastric cancer shows distinctive clinical, pathological, genetic, and post-genetic mutation features and is therefore a clinically significant entity. Herpetic esophagitis usually affects immunocompromised patients and is uncommon in immunocompetent individuals. In this review, we discuss the general aspects and recent studies that have reported esophageal and gastric infections in immunocompromised patients.

Proton pump inhibitors and gastrointestinal symptoms among patients with COVID-19 infection

Introduction The administration of proton pump inhibitors (PPIs) is anticipated to elevate an individual’s susceptibility to enteric infections as a result of altering the gut flora. The influence of PPIs on the clinical manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still uncertain. This study aims to investigate the impact of PPI usage on the clinical manifestation of COVID-19, namely its gastrointestinal symptoms. Methods This is a cross-sectional cohort study involving COVID-19 patients. Patients were interviewed using a predesigned questionnaire that asked about their demographics, clinical manifestations of COVID-19 infection, and the extent and type of PPIs in use. PPI usage was confirmed by reviewing patients’ electronic medical records. The primary outcome was to establish any association between the use of PPI and the symptoms and clinical presentation of COVID-19. Results Out of a total of 254 participants, 69 (27.2%) were considered PPI users. Patients who were on PPI medications reported a significantly lower rate of myalgia (27.5% vs 51.9%; p = 0.0006) and heartburn (5.7% vs 15.6%; p = 0.03) but had a significantly higher rate of abdominal pain (27.5% vs 13.5%; p = 0.001) and diarrhoea (28.9% vs 14.5%, p = 0.02) when compared to those who were not using PPIs. Patients on PPIs were also shown to have significantly higher odds of developing diarrhoea (OR 2.0, 95% CI: 1.08 to 3.93, p = 0.02) and abdominal pain (OR 2.0, 95% CI: 1.22 to 3.93, p = 0.03), but a lower risk of developing myalgia (OR 0.5, 95% CI: 0.3 to 0.9, p = 0.02) when compared to non-PPI users. Conclusion This study shows that the use of PPIs could impact COVID-19 clinical presentation toward more gastrointestinal manifestations. Further studies investigating the link between other acid suppression medications and COVID-19 manifestations and severity should be carried out.

Overlapping approach Proton Pump Inhibitors/Nux vomica-Heel as new intervention for gastro-esophageal reflux management: Delphi consensus study.

Gastro-esophageal reflux disease (GERD) may affect the upper digestive tract; up to 20% of population in Western nations are affected by GERD. Antacids, histamine H2-receptor antagonists, and Proton Pump Inhibitors (PPIs) are considered the referring medications for GERD. Nevertheless, PPIs must be managed carefully because their use, especially chronic, could be linked with some adverse effects. An effective and safe alternative pharmacological tool for GERD is needed. After the identification of potentially new medications to flank PPIs, it is mandatory to revise and improve good clinical practices even through a consensus process. To optimize diagnosis and treatment guidelines for GERD through a consensus based on Delphi method. The availability of clinical studies describing the action of the multicomponent/multitarget medication Nux vomica-Heel, subject of the consensus, is the basic prerequisite for the consensus itself. A modified Delphi process was used to reach a consensus among a panel of Italian GERD specialists on the overlapping approach PPIs/Nux vomica-Heel as a new intervention model for the management of GERD. The Voting Consensus group was composed of 49 Italian Medical Doctors with different specializations: Gastroenterology, otolaryngology, geriatrics, and general medicine. A scientific committee analyzed the literature, determined areas that required investigation (in agreement with the multiple-choice questionnaire results), and identified two topics of interest: (1) GERD disease; and (2) GERD treatment. Statements for each of these topics were then formulated and validated. The Delphi process involved two rounds of questioning submitted to the panel experts using an online platform. According to their routinary GERD practice and current clinical evidence, the panel members provided feedback to each questionnaire statement. The experts evaluated 15 statements and reached consensus on all 15. The statements regarding the GERD disease showed high levels of agreement, with consensus ranging from 70% to 92%. The statements regarding the GERD treatment also showed very high levels of agreement, with consensus ranging from 90% to 100%. This Delphi process was able to reach consensus among physicians in relevant aspects of GERD management, such as the adoption of a new approach to treat patients with GERD based on the overlapping between PPIs and Nux vomica-Heel. The consensus was unanimous among the physicians with different specializations, underlying the uniqueness of the agreement reached to identify in the overlapping approach between PPIs and Nux vomica-Heel a new intervention model for GERD management. The results support that an effective approach to deprescribe PPIs through a progressive decalage timetable (reducing PPIs administration to as-needed use), should be considered. Nux vomica-Heel appears to be a valid opportunity for GERD treatment to favor the deprescription of PPIs and to maintain low disease activity together with the symptomatology remission.

Prevalence and appropriateness of omeprazole prescription in dogs at a veterinary teaching hospital before and after the publication of the ACVIM consensus statement on the rational administration of gastrointestinal protectants.

Overprescribing of acid suppressants is a common phenomenon in human and small animal patients, leading to potential deleterious gastrointestinal (GI) and non-GI consequences. The impact of consensus statements on veterinary prescribing habits in clinical practice have not been fully evaluated. This study aimed to compare the prescribing habits of the proton pump inhibitor (PPI), omeprazole, in dogs in an academic veterinary teaching hospital before and after the publication of the American College of Veterinary Internal Medicine (ACVIM) consensus statement on rational use of gastrointestinal protectants. Evaluation of the prescribing habits of omeprazole in dogs during the years 2017 and 2021 was retrospectively compared. These years were selected to reflect a 12-month period prior to and following the publication of the consensus statement. One hundred dogs from each year were randomly selected. Dose, frequency of administration, duration of treatment, concurrent prescription of more than one gastroprotectant and indications for prescribing omeprazole were analyzed. A significant increase in the cases that received omeprazole q12h (p < 0.0001) or that underwent a tapering dose after ≥4 week-therapy (p > 0.0001) was detected after the publication of the 2018 ACVIM consensus statement. Considering the indications, there was also a significant increase in the appropriate prescription of omeprazole in the second compared to the first period of study (p < 0.0001). Fifteen of 16 clinicians (94%) involved in the prescription of omeprazole indicated that their reading of the consensus statement had changed their clinical practice regarding PPI administration in dogs. These results support the beneficial impact of the ACVIM consensus statement on the judicious prescribing of omeprazole in an academic veterinary hospital. These results should not be extrapolated to first-opinion veterinary practices, and further efforts should be made to ensure that PPIs are prescribed prudently with a clear indication and regular review of the appropriateness of continued administration to minimize possible risks and adverse drug interactions.

Mathematical Modeling of Magnesium Homeostasis in Male Rats

Magnesium (Mg2+) is an important cofactor for numerous biological processes, including protein synthesis, nucleic acid stability, and neuromuscular excitability. Extracellular magnesium is tightly regulated, with plasma [Mg2+] maintained relatively constant between 1.6 and 2.3 mg/dL under normal physiological conditions. Almost all of the body’s Mg2+ (approximately 99%) is either stored in bone or within cells (DOI: 10.1053/j.ackd.2018.01.003). A normal daily Mg2+ intake averages around 300 mg, about half of which is absorbed by the intestine. The kidneys reabsorb 95-98% of the filtered Mg2+ and excrete only 2-5% through urine. To understand the interplay between intestine, kidneys, and bones to maintain Mg2+ homeostasis, we developed a computational model of Mg2+ homeostasis for male rats and incorporated it with a male rat calcium (Ca2+) homeostasis model. Our model consists of five compartments: plasma, intestine, kidneys, bones, and parathyroid gland. The model also includes parathyroid hormone and vitamin D3 since they significantly regulate Mg2+ and Ca2+ homeostasis. We used this model to simulate three conditions: change in dietary Mg2+, change in dietary vitamin D3, and administration of proton-pump inhibitors. In the case of variation in dietary Mg2+, our model predicted that the body compensates mainly through decreasing (in case of low dietary Mg2+) and increasing (in case of high dietary Mg2+) urinary Mg2+ excretion and the Mg2+ content in the rapidly exchangeable bone pool. Change in dietary Mg2+ does not have any significant effect on Ca2+ homeostasis. On the other hand, change in dietary vitamin D3 has significant effect on both Mg2+ and Ca2+ homeostasis, with the effect being more pronounced for Ca2+ compared to Mg2+. Our model predicted significant changes in intestinal Mg2+ and Ca2+ absorption, PTH secretion, urinary Mg2+ and Ca2+ excretion, and Mg2+ and Ca2+ content in the rapidly exchangeable bone pool following change in dietary vitamin D3. Administration of proton pump inhibitors (PPIs) such as omeprazole, which are a class of medicine commonly used to reduce stomach acid production, affect Mg2+ and Ca2+ transport in the intestine. PPIs reduce intestinal Mg2+ and Ca2+ absorption by 3.5-fold and 40%, respectively. The body compensates for this huge drop in intestinal Mg2+ absorption by tapping into the Mg2+ stored in the rapidly exchangeable bone pool in addition to decreasing urinary Mg2+ excretion. By contrast, the body can compensate for the drop in intestinal Ca2+ absorption by only decreasing urinary Ca2+ excretion. Thus, this model can be used to understand the compensatory mechanisms adopted by the body to maintain Mg2+ and Ca2+ homeostasis under various pathophysiological conditions and drug administrations. This work was supported by the Canada 150 Research Chair program, National Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, and Canada Institutes of Health Research (CIHR) Project Grant to Anita Layton. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3β.

Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3β, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3β knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3β phosphorylation and facilitate primary tumor progression and metastasis.

Dual acid-pump blocking as novel therapeutic approach to treatment of acid-related diseases

Proton-pump inhibitors are highly efficient in the treatment of acid-related disease; however, their efficacy in treating reflux symptoms, healing esophageal erosions and peptic ulcers and eradicating Helicobacter pylori is sometimes suboptimal. Potassium-competitive acid blockers have a different mechanism of action, resulting in higher and longer-lasting increases in intragastric pH, which is neither non-inferior or superior to those of proton-pump inhibitors. The pharmacology, metabolism and mechanism of action of these drugs are different, therefore, it is hypothesised, that their combined use might be of clinical benefit through increased intragastric pH. This hypothesis is supported by pharmacological, physiological and microbiological data. The combined administration of proton-pump inhibitors and potassium-competitive acid blockers should be investigated in short-term therapy (4–8 weeks); if their complementary or additive effect is proven, dual acid pump blocking can be of further benefit in managing gastroesophageal reflux disease, peptic ulcers and eradicating Helicobacter pylori infection, in cases refractory to current therapies. For safety reasons, long-term administration of this combination as maintenance treatment should be avoided.

Clinical Impact of Proton Pump Inhibitor and Potassium-Competitive Acid Blocker for Predicting the Curability of Endoscopic Resection in Ulcerative Early Gastric Cancer

Introduction: Endoscopic diagnosis is essential for predicting the curability of early gastric cancer (EGC; R0 resection) before treatment, but the relationship between ulcerative lesions and clinical outcomes remains unclear. We aimed to investigate the effect of proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) on the morphological changes of ulcerative EGCs and its relevance to the clinical outcomes. Methods: Altogether, 143 patients with differentiated ulcerative EGC that were resected by endoscopic submucosal dissection were retrospectively identified and divided into the following two cohorts depending on their PPI/P-CAB administration status: PPI/P-CAB (n = 76) and non-PPI/P-CAB (n = 67) cohorts. Furthermore, in each cohort, the patients were further divided into the improved and unimproved subgroups based on the ulcerative changes. Results: In the PPI/P-CAB cohort, the deep submucosal invasion and lymphovascular invasion rates were significantly higher in the unimproved subgroup than in the improved subgroup, resulting in a significantly lower R0 resection rate. Contrarily, no significant differences were found between the two subgroups in the non-PPI/P-CAB cohort. The significance of PPI/P-CAB administration was observed only in the ulcerative EGCs with open-type atrophy (R0 resection rate; improved vs. unimproved, 90.9% vs. 48.0%, p = 0.001). When the finding of improved ulcer with PPI/P-CAB administration was used as the indication of endoscopic resection in ulcerative EGCs with open-type atrophy, high sensitivity (78.9%) and accuracy (76.3%) rates for the curability were observed, which were higher than those of conventional endoscopic diagnosis alone (p = 0.021). Conclusion: PPI or P-CAB administration might contribute to the potential selection of ulcerative EGCs, enabling endoscopic curative resection.

Medical therapy has similar hemostatic efficacy with endoscopic treatment for PUB patients with adherent clot (FIIb ulcers).

Currently, there is no clear consensus on whether medical treatment or endoscopic treatment should be used for peptic ulcer bleeding patients with adherent clot. The aim of this study is to investigate the hemostatic effects of medical treatment, single endoscopic treatment, and combination endoscopic treatment for peptic ulcer bleeding (PUB) patients with adherent clot. We retrospectively analyzed PUB patients with adherent clot who underwent endoscopic examination or treatment in our center from March 2014 to January 2023 and received intravenous administration of proton pump inhibitors. Patients were divided into medical treatment (MT) group, single endoscopic treatment (ST) group, and combined endoscopic treatment (CT) group. Subsequently, inverse probability of treatment weighting (IPTW) was performed to calculate the rebleeding rate. A total of 605 eligible patients were included in this study. After IPTW, the rebleeding rate in the MT group on days 3, 7, 14, and 30 were 13.3 (7.3), 14.2 (7.8), 14.5 (7.9), and 14.5 (7.9), respectively; the rebleeding rates in the ST group were 17.4 (5.1), 20.8 (6.1), 20.8 (6.1), and 20.8 (6.1), respectively; the rebleeding rates in the CT group were 0.4 (0.9), 1.7 (3.3), 2.3 (4.5), and 2.3 (4.5), respectively. Although the rebleeding rate in the medical treatment group was higher, there was no significant difference among the three groups on days 3, 7, 14, and 30 (P = 0.132, 0.442, 0.552, and 0.552). Medical therapy has similar hemostatic efficacy with endoscopic treatment for PUB patients with adherent clot (FIIb ulcers). However, for patients with more risk factors and access to well-equipped endoscopy centers, endoscopic treatment may be considered. The choice of treatment approach should be based on the individual conditions of the patient, as well as other factors such as medical resources available.

Renal failure following the administration of proton pump inhibitors; a mini-review article on recent findings

Renal failure following the administration of proton pump inhibitors; a mini-review article on recent findings

Endoscopic and clinical features of gastric emphysema

Gastric emphysema is characterized by the presence of intramural gas in the stomach without bacterial infection. Due to its rarity, most reports on gastric emphysema have been limited to single-case studies, and this condition’s clinical and endoscopic features have not been thoroughly investigated. In this study, we analyzed 45 patients with gastric emphysema from 10 institutions and examined their characteristics, endoscopic features, and outcomes. The mean age at diagnosis of gastric emphysema in our study population (35 males and 10 females) was 68.6 years (range, 14–95 years). The top five underlying conditions associated with gastric emphysema were the placement of a nasogastric tube (26.7%), diabetes mellitus (20.0%), post-percutaneous endoscopic gastrostomy (17.8%), malignant neoplasms (17.8%), and renal failure (15.6%). Among the 45 patients, 42 were managed conservatively with fasting and administration of proton pump inhibitors. Unfortunately, seven patients died within 30 days of diagnosis, and 35 patients experienced favorable recoveries. The resolution of gastric emphysema was confirmed in 30 patients through computed tomography (CT) scans, with a mean duration of 17.1 ± 34.9 days (mean ± standard deviation [SD], range: 1–180 days) from the time of diagnosis to the disappearance of the gastric intramural gas. There were no instances of recurrence. Endoscopic evaluation was possible in 18 patients and revealed that gastric emphysema presented with features such as redness, erosion, coarse mucosa, and ulcers, with fewer mucosal injuries on the anterior wall (72.2%), a clear demarcation between areas of mucosal injury and intact mucosa (61.1%), and predominantly longitudinal mucosal injuries on the stomach folds (50.0%). This study is the first English-language report to analyze endoscopic findings in patients with gastric emphysema.