Effect Of Proton Pump Inhibitors Research Articles

The Role of Acid Suppressants in the Prevention of Anticoagulant-Related Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

Background/AimsAlthough acid suppressants are widely used for the prevention or treatment of drug-induced upper gastrointestinal bleeding (GIB), evidence regarding the prevention of anticoagulant-related GIB is scarce. The aim of this study was to evaluate the protective effect of acid suppressants against anticoagulant-related GIB.MethodsA systematic review was conducted of studies that evaluated the protective effect of acid suppressants against anticoagulant-related GIB found in PubMed, the Cochrane library, Embase, and KoreaMed from the date of database inception to April 2018. Random effect model meta-analyses with sensitivity analyses were conducted. The methodological quality of each included publication was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies. Publication bias was assessed.ResultsIn total, six nested case-control or cohort studies were identified and analyzed. Proton-pump inhibitors (PPI) had a protective effect against upper GIB in patients on dicumarinics (risk ratio [RR], 0.56; 95% confidence interval [CI], 0.38 to 0.83; I2, 0%); however, the histamine-2 receptor antagonist did not have the same effect (RR, 0.97; 95% CI, 0.52 to 1.81; I2, 0%). Acid suppressants did not have a protective effect against GIB in patients on dabigatran (hazard ratio, 0.78; 95% CI, 0.44 to 1.37; I2, 81.8%).ConclusionsThe protective effect of PPIs against dicumarinics-related upper GIB was clear, while there was no evidence supporting the protective effect of acid suppressants against dabigatran-related GIB. However, in the absence of randomized trials demonstrating a lack of bias, solid conclusions cannot be drawn.

Effect of Gastric Acid Suppressants on Response to a Physical Activity Intervention and Major Mobility Disability in Older Adults: Results from the Lifestyle Interventions for Elders (LIFE) Study.

Proton pump inhibitors (PPIs) and histamine2 receptor antagonists (H2 RAs) are associated with pharmacologic effects that may be detrimental to mobility and response to physical activity. Mobility disability and injurious fall outcomes in PPI and H2 RA users were compared with nonusers in this secondary analysis of data from the Lifestyle Interventions for Elders (LIFE) study. Participants ages 70-89years were randomized to a physical activity (PA) or successful aging intervention and evaluated by medication use. Confounders included baseline demographic characteristics, physical function, cognitive function, sleep quality, and acid reflux symptoms that were adjusted via propensity score weighting. Outcomes were incident and persistent major mobility disability (MMD and pMMD) and injurious falls. Weighted proportional hazard models evaluated independent and interaction effects of PPIs and H2 RAs. No interaction was found between PPIs and H2 RAs and the PA intervention. Drug use associations were significant for H2 RAs (hazard ratio [HR] 1.74 [95% confidence interval [CI] 1.12-2.68]) and PPIs (HR 1.32 [95% CI 1.02-1.70]) compared with nonusers for pMMD. PPIs were associated with increased injurious falls compared with nonusers (HR 1.44 [95% CI 1.06-1.96]). Pooling of data from the H2 RA and PPI exposure groups showed a 26% increase in MMD (HR 1.26 [95% CI 1.07-1.48]), a 44% increase in pMMD (HR 1.44 [95% CI 1.16-1.77]), and a 48% increase in injurious falls (HR 1.48 [95% CI 1.15-1.91]) compared with nonusers. All direct comparisons between PPIs and H2 RAs were nonsignificant. Compared with nonusers, participants using either PPIs or H2 RAs had an increased risk of MMD, pMMD, and injurious falls. It is not known if these effects are related to the individual pharmacology of each medication, reduced acid secretion, or the underlying disease state. Further study is required to determine causality.

Proton pump inhibitors co-prescribed with warfarin reduce warfarin control as measured by time in therapeutic range.

Warfarin is an oral anticoagulant that requires ongoing monitoring with time in therapeutic range (TTR), a common measure of the quality of warfarin control and likelihood of adverse events including bleeds. Numerous factors can influence these warfarin outcomes including drug interactions. Proton pump inhibitors (PPIs) have been reported to interact with warfarin but there remain conflicting reports with regard to the impact on bleeds and limited data on TTR. Therefore, the aim of this study was to determine the effect of PPIs on warfarin control using TTR and bleeds as endpoints. Retrospective data were collected for patients managed by a warfarin management clinic in Queensland. Data collected included current medications, reported bleeds and INR results to calculate TTR. Patients were grouped as taking PPIs or not taking PPIs. Analysis of TTR and bleeds occurred for these groups both before and after exclusions of other medication reported to interact with warfarin. Of the 4494 included patients, almost half (44.5%) were taking PPIs with esomeprazole most commonly (34.8%) prescribed. Patients taking PPIs had significantly reduced TTR compared with patients not taking PPIs both before (78.5±9.7% vs 81.7±10.2%, P<0.0001) and after (84.4±5.1% vs 89.4±8.0%, P<0.0001) excluding all other interacting medications with warfarin. Patients taking PPIs also had significantly higher incidence of minor bleeds compared with patients not taking PPIs (32.4% vs 26.1%, P=0.0487). Patients taking PPIs with warfarin had significantly lower TTRs and higher incidence of minor bleeds. This combination warrants additional caution and monitoring with warfarin control as measured by TTR potentially affected.

Proton pump inhibitors and adverse effects in kidney transplant recipients: A meta-analysis.

BACKGROUNDThe adverse renal effects of proton pump inhibitors (PPIs) are increasingly recognized in both the general population and patients with chronic kidney disease. Several pharmacokinetic studies have also raised concerns regarding the interaction between PPIs and immunosuppressive drugs in transplant patients. Whether the adverse effects of PPIs have a clinical significance in kidney transplant recipients remains unclear. We performed this meta-analysis to assess the risk of adverse effects in kidney transplant recipients on PPI compared with those without PPI exposure.AIMTo investigate the risk of acute rejection, graft loss, hypomagnesemia, renal dysfunction, and overall mortality in kidney transplant recipients on PPI compared with those without PPI exposure.METHODSA systematic review was conducted in MEDLINE, EMBASE, and Cochrane databases from inception through October 2018 to identify studies that evaluated the adverse effects of PPIs in kidney transplant recipients, including biopsy-proven acute rejection, graft loss, hypomagnesemia, renal function, and overall mortality. Effect estimates from the individual studies were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird. The protocol for this meta-analysis is registered with PROSPERO, No. CRD42018115676.RESULTSFourteen observational studies with 6786 kidney transplant recipients were enrolled. No significant association was found between PPI exposure and the risk of biopsy-proven acute rejection at ≥ 1 year [pooled odds ratio (OR), 1.25; 95% confidence interval (CI), 0.82-1.91, I2 = 55%], graft loss at 1 year (pooled OR = 1.30, 95%CI: 0.75-2.24, I2 = 0%) or 1-year mortality (pooled OR = 1.53, 95%CI: 0.90-2.58, I2 = 34%). However, PPI exposure was significantly associated with hypomagnesemia (pooled OR = 1.56, 95%CI: 1.19-2.05, I2 = 27%). Funnel plots and Egger regression asymmetry test were performed and showed no publication bias.CONCLUSIONPPI use was not associated with significant risks of higher acute rejection, graft loss, or 1-year mortality. However, the risk of hypomagnesemia was significantly increased with PPI use. Thus, future studies are needed to assess the impact of PPIs on long-term outcomes.

A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors

Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene, which cause uncontrolled IL-1β secretion. Proton pump inhibitors (PPIs), which are commonly used as inhibitors of gastric acid production, also have anti-inflammatory properties, protect mice from sepsis, and prevent IL-1β secretion by monocytes from patients with CAPS. We sought to develop a novel Nlrp3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches. We generated KI mice by engineering the N475K mutation, which is associated with the CAPS phenotype, into the mouse Nlrp3 gene. KI and wild-type mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. Mutant Nlrp3 KI mice displayed features that recapitulate the immunologic and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum proinflammatory cytokines, inflammatory infiltrates in various organs, and amyloid deposits in the spleen, liver, and kidneys. Toll-like receptor stimulated macrophages from KI mice secreted high levels of IL-1β, IL-18, and IL-1α but low amounts of IL-1 receptor antagonist. Treatment of KI mice with PPIs had a clear clinical effect, showing a reduction in inflammatory manifestations, regression of amyloid deposits, and normalization of proinflammatory and anti-inflammatory cytokine production by macrophages. Nlrp3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in patients with CAPS and other IL-1-driven diseases.

Proton pump inhibitor: The dual role in gastric cancer.

Proton pump inhibitors (PPIs) are one of the most frequently used medications for upper gastrointestinal diseases. However, a number of physicians have raised concern about the serious side effects of long-term use of PPIs, including the development of gastric cancer. Recent epidemiological studies have reported a significant association between long-term PPI intake and the risk of gastric cancer, even after successful Helicobacter pylori eradication. However, the effects of PPIs on the development of pre-malignant conditions such as atrophic gastritis or intestinal metaplasia are not fully known, suggesting the need for comprehensive and confirmative studies are needed in the future. Meanwhile, several experimental studies have demonstrated the effects of PPIs in reducing chemoresistance in gastric cancer cells by modulating the acidic microenvironment, cancer stemness and signal transducer and activator of transcription 3 (STAT3) signaling pathway. The inhibitory effects of PPIs on STAT3 activity may overcome drug resistance and enhance the efficacy of conventional or targeted chemotherapeutic agents. Taken together, PPIs may “play dual role” in gastric carcinogenesis and treatment of gastric cancer.

Effect of proton pump inhibitors on mortality of cirrhotic patients with pneumonia.

ObjectivePneumonia is life-threatening in patients with liver cirrhosis. Proton pump inhibitors (PPIs) may increase the risk of these patients developing pneumonia. However, whether PPIs increase mortality in patients with cirrhosis and pneumonia remain unknown.MethodsWe used the Taiwan National Health Insurance Database to enroll 1,201 cirrhotic patients with pneumonia without active gastrointestinal bleeding who were receiving PPIs and were hospitalized between January 1, 2010 and December 31, 2013. A one-to-three propensity score match was performed to select a comparison group based on age, gender, and comorbid disorders.ResultsThe overall 30-day and 90-day all-cause mortality rates were 13.7% and 26.9% in the PPI group, and 14.3% and 25.1% in the non-PPI group, respectively. After Cox regression model adjusting for age, gender, and comorbid disorders, the hazard ratios of the effect of PPIs on 30-day and 30 to 90-day mortality were 0.94 (95% Confidence Interval [CI], 0.79–1.12, P = 0.468) and 1.26 (95% CI, 1.05–1.52; P = 0.013), respectively.ConclusionsPPIs were not associated with 30-day mortality among cirrhotic patients with pneumonia but not active gastrointestinal bleeding. However, prolonged PPI therapy may be associated with higher mortality.

Lansoprazole inhibits the cysteine protease legumain by binding to the active site.

Proton pump inhibitors (PPIs) are prodrugs used in the treatment of peptic ulcer diseases. Once activated by acidic pH, the PPIs subsequently inhibit the secretion of gastric acid by covalently forming disulphide bonds with the SH groups of the parietal proton pump, that is the H+ /K+ -ATPase. Long-term use of PPIs has been associated with numerous adverse effects, including bone fractures. Considering the mechanism of activation, PPIs could also be active in acidic micro-environments such as in lysosomes, tumours and bone resorption sites. We suggested that the SH group in the active site of cysteine proteases could be susceptible for inhibition by PPIs. In this study, the inhibition by lansoprazole was shown on the cysteine proteases legumain and cathepsin B by incubating purified proteases or cell lysates with lansoprazole at different concentrations and pH conditions. The mechanism of legumain inhibition was shown to be a direct interaction of lansoprazole with the SH group in the active site, and thus blocking binding of the legumain-selective activity-based probe MP-L01. Lansoprazole was also shown to inhibit both legumain and cathepsin B in various cell models like HEK293, monoclonal legumain over-expressing HEK293 cells (M38L) and RAW264.7 macrophages, but not in human bone marrow-derived skeletal (mesenchymal) stem cells (hBMSC-TERT). During hBMSC-TERT differentiation to osteoblasts, lansoprazole inhibited legumain secretion, alkaline phosphatase activity, but had no effects on in vitro mineralization capacity. In conclusion, lansoprazole acts as a direct covalent inhibitor of cysteine proteases via disulphide bonds with the SH group in the protease active site. Such inhibition of cysteine proteases could explain some of the off-target effects of PPIs.

Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil.

Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites. We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20mg/day) at least 1week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000mg/m2) was administered 1h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116). Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites. Rabeprazole does not affect capecitabine pharmacokinetics.

Proton pump inhibitors versus Cryptococcus species: effects on in vitro susceptibility and melanin production.

Aim: This study aimed to evaluate the effects of proton pump inhibitors (PPIs) on growth and melanin production by Cryptococcus spp. Materials & methods: Minimum inhibitory concentrations (MICs) of omeprazole, esomeprazole, rabeprazole, pantoprazole and lansoprazole against Cryptococcus spp. were determined and the effect of PPIs on melanin production was evaluated, in the presence or absence of copper sulfate or glutathione. Results: PPIs showed MICs ranging from 125-1000μg/ml and decreased melanization by Cryptococcus cells. Addition of copper sulfate or gluthatione restored melanogenesis of cells grown in the presence of PPIs. The presence of PPIs and glyphosate decreased copper sulfate toxicity (1mM). Conclusion: PPIs inhibited melanogenesis of Cryptococcus spp., possibly by chelating copper or inhibiting copper ATPase transport.

Lansoprazole-Induced Thrombocytopenia in a Critically Ill Patient: A Case Report

Introduction: Proton pump inhibitors (PPIs) may rarely cause thrombocytopenia. To our knowledge, only one case of lansoprazole-induced thrombocytopenia has been reported previously. Case: We report a case of a 50-year-old South Asian male who was admitted to the intensive care unit (ICU) after cardiac arrest during general anesthesia for ureteroscopy. During ICU stay, his platelet count dropped from 315×103/µL to 57×103/µL after 5 days of initiation of lansoprazole for stress-ulcer prophylaxis. After excluding other causes of thrombocytopenia; lansoprazole was stopped and his platelets recovered over the next few days. Later exposure to lansoprazole resulted in another drop in his platelet count with subsequent recovery after discontinuation of lansoprazole. A review of his home medications showed that he had been taking pantoprazole prior to hospitalization. Discussion: Thrombocytopenia has been previously reported with different PPIs. In the previously reported lansoprazole-induced thrombocytopenia, the level of certainty was not high due to lack of re-exposure. In the present case, another exposure to lansoprazole, without intention of rechallenge, reproduced the same adverse drug reaction (ADR). Although platelet-reactive antibodies testing was not available to confirm causation in this case, the Naranjo score was 8 which indicated probable causation by lansoprazole. Despite probable lansoprazole-induced thrombocytopenia, our patient had been tolerating pantoprazole. This finding highlights the different effects of individual PPIs on platelet counts in the same patient. Conclusion: Lansoprazole may cause thrombocytopenia. However, patients who develop lansoprazole-induced thrombocytopenia may tolerate other PPIs.

Quel est le VRAI risque au long cours des inhibiteurs de la pompe à protons ?

Proton pump inhibitors (PPIs) are among the most prescribed drugs in the world. While their efficacy in acute management is indisputable, it has long been suggested that PPI therapy is safe in the long term. In recent years, there has been growing and justified concern about the long-term risks of PPIs. The majority of reported side effects are based on observational studies with a low level of evidence. Concerning digestive risks, PPIs seem to increase the risk of Salmonella and Campylobacter infections. However, the link between PPIs and Clostridium difficile infection is not established. Long-term PPIs may be responsible for an increased risk of gastric cancer according to several recent studies. With regard to extra-digestive risks, PPIs are associated with a moderate increase in the risk of chronic renal failure via an interstitial nephritis mechanism. PPIs also provide martial deficiency and may be associated with vitamin B12 and magnesium deficiency in some patients. Other adverse reactions have been suggested without any causal relationship being established (i.e., dementia or bone fractures, cardiovascular risk). In this review we will discuss the different long-term adverse effects of PPIs and their level of evidence.

Fracture risk of young adults receiving proton-pump inhibitors and H2-receptor antagonists.

Proton-pump inhibitors (PPI) and histamine (type 2) receptor antagonists (H2RA) have the potential to interfere with calcium metabolism. Several authors have evaluated the effect of these medications on fracture incidence in older adults. A recent large epidemiologic study demonstrated a higher risk of fractures in young adults receiving PPI. To evaluate the effect of PPI and H2RA use on fracture incidence in a large retrospective cohort of military recruits representative of general population of young adults. A retrospective cohort of 254265 male and 234670 female non-combat military conscripts ages 18-25. Subjects were divided into three groups by PPI use (no PPI use, 1-100 tablets and more than 100 tablets) and two groups by H2RA use (no H2RA use, any H2RA use). Multivariate logistic regression was used to adjust fracture risk for age, BMI, education level, socio-economic level, ethnic origin, occupation and duration of follow-up in months. At least one fracture during the study period. Use of PPI and H2RA was not associated with an increased risk of fractures. In men, the predictors of an increased fracture risk were higher BMI (OR=1.007, P<0.001), origin from a developing country (OR=1.15, P<0.001) and service as a driver (OR=1.11, P<0.001). Higher education, higher socioeconomic status and service as an officer or as an administrative worker had a protective effect on fracture incidence. In women, fractures were associated with higher BMI (OR=1.035, P<0.001). Origin from a developed country, as well as service as an officer or an administrative worker was associated with lower fracture risk. There was no association between the use of PPI or H2-antagonists and fracture incidence in this retrospective cohort of healthy young military recruits.

Effectiveness and Safety of Clopidogrel Co-administered With Statins and Proton Pump Inhibitors: A Korean National Health Insurance Database Study.

Simultaneous competition for cytochrome P450 (CYP) 2C19 and CYP3A4 might diminish clopidogrel's antiplatelet effect by impacting its metabolic activation. This pharmacoepidemiologic study investigated whether proton pump inhibitors (PPIs) and CYP3A4-metabolized statins individually and jointly increase thrombotic events by attenuating clopidogrel's effectiveness. From Korean nationwide claims data (2007-2015), we selected 59,233 patients who initiated clopidogrel and statins after coronary stenting and compared thrombotic risks by PPI or CYP3A4-metabolized statin use or both. PPIs were associated with increased thrombotic risks (hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45), unlike CYP3A4-metabolized statins (HR 1.03, 95% CI 0.98-1.07). PPIs with high CYP2C19-inhibitory potential were more relevant than those with low potential (HR 1.28, 95% CI 1.02-1.61). Joint effects of PPIs and CYP3A4-metabolized statins were nonsignificant (relative excess risk due to interaction -0.14, 95% CI -0.34 to 0.07). Concurrent PPIs were associated with increased thrombotic risks in patients receiving clopidogrel and statins; CYP3A4-metabolized statins did not exacerbate PPI-associated risks.

Meta-Analysis of Efficacy and Safety of Proton Pump Inhibitors with Dual Antiplatelet Therapy for Coronary Artery Disease.

There is inconsistency in the literature regarding the clinical effects of proton pump inhibitors (PPI) when added to dual antiplatelet therapy (DAPT) in subjects with coronary artery disease (CAD). We performed meta-analysis stratified by study design to explore these differences. 39 studies [4 randomized controlled trials (RCTs) and 35 observational studies) were selected using MEDLINE, EMBASE and CENTRAL (Inception-January 2018). In 221,204 patients (PPI = 77,731 patients, no PPI =143,473 patients), RCTs restricted analysis showed that PPI did not increase the risk of all-cause mortality (Risk Ratio (RR): 1.35, 95% Confidence Interval (CI), 0.56-3.23, P = 0.50, I2 = 0), cardiovascular mortality (RR: 0.94, 95% CI, 0.25-3.54, P = 0.92, I2 = 56), myocardial infarction (MI) (RR: 0.97, 95% CI, 0.62-1.51, P = 0.88, I2 = 0) or stroke (RR: 1.11, 95% CI, 0.25-5.04, P = 0.89, I2 = 26). However, PPI significantly reduced the risk of gastrointestinal (GI) bleeding (RR: 0.32, 95% CI, 0.20-0.52, P < 0.001, I2 = 0). Conversely, analysis of observational studies showed that PPI significantly increased the risk of all-cause mortality (RR: 1.25, 95% CI, 1.11-1.41, P < 0.001, I2 = 82), cardiovascular mortality (RR: 1.25, 95% CI, 1.03-1.52, P = 0.02, I2 = 71), MI (RR: 1.30, 95% CI, 1.16-1.47, P < 0.001, I2 = 82) and stroke (RR: 1.60, 95% CI, 1.43-1.78, P < 0.001, I2 = 0), without reducing GI bleeding (RR: 0.74, 95% CI, 0.45-1.22, P = 0.24, I2 = 79). Meta-analysis of RCTs endorsed the use of PPI with DAPT for reducing GI bleeding without worsening cardiovascular outcomes. These findings oppose the negative observational data regarding effects of PPI with DAPT.

Vonoprazan versus proton pump inhibitors in treating post-endoscopic submucosal dissection ulcers and preventing bleeding: Protocol for meta-analysis of randomized controlled trials and observational studies.

Vonoprazan is a potassium-competitive acid blocker (P-CAB). It is often used in Japan for Helicobacter pylori (H pylori) eradication, gastroesophageal reflux disease, and endoscopic submucosal dissection (ESD) ulcers and bleeding. This meta-analysis aims to evaluate whether vonoprazan has better therapeutic effect on ESD-induced ulcers and bleeding than proton pump inhibitors (PPIs) at different length of treatment periods (2, 4, and 8 weeks). This meta-analysis will include both randomized controlled trials (RCTs) and observational studies discussing the effectiveness of vonoprazan and PPIs on ESD-induced ulcers and bleeding. Information of studies will be collected from PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar. Studies will be selected according to the eligibility criteria and data will be extracted by 2 people and compared with each other to keep in consistency. Cochrane risk of bias tool will be used to assess RCTs and the Newcastle-Ottawa Quality Assessment Scale will be used to assess the observational studies. Meta-analysis based on the random-effects model will be conducted to compare the differences of ulcers' shrinkage ratios (%) and the odds ratios (OR) of scars' stages and delayed bleeding. Publication bias will be evaluated using funnel plots and Egger's regression test. Heterogeneity will be assessed with the I statistics. Sensitivity analysis will be conducted on follow-up periods. The evidential quality of the findings will be assessed with the Grading of Recommendations Assessment Development and Evaluation (GRADE) profiler. The findings of the present systematic review will be critical for physicians, patients, and policymakers regarding the use of vonoprazan in ESD-induced ulcers. PROSPERO registration number: CRD42018116855.

Analysis of symptomatic marginal ulcers in patients who underwent Whipple’s operation for peri-ampullary tumors

Introduction: We investigated the incidence and risk factors associated with the development of marginal ulcers (MUs) after Whipple’s operation and analyzed their relationship with the use of prophylactic proton pump inhibitors (PPIs). Finally, our goal was to provide evidence of the effectiveness of prophylactic PPIs for preventing MUs after Whipple’s operation. Method: The study included 1338 consecutive patients. Clinico-postoperative outcomes of 72 MUs and 1266 non-MUs were compared and analyzed. We performed a sub-analysis of 72 patients with MU diagnosed within (n=18) and after 4 months (n=54). The risk factors associated with MU incidence were analyzed. Result: Of the 1338 patients, 72 (5.4%) were diagnosed as having MU. Over time, the incidence of MU decreased. Eighteen patients (25.0%) were diagnosed during the first 4 months; and 48 (66.7%), within 16 months. Cumulative MU incidence significantly differed according to the duration of prophylactic PPI use (≥4 months : 7.1% vs <4 months: 10.1%, p<0.001). The duration of prophylactic PPI use was identified as a risk factor in the multivariable analysis (hazard ratio, 2.294; 95% confidence interval, 1.436–3.664; p=0.001). Conclusion: MU was more frequent within 4 months after Whipple’s operation, but occurred even after 40 months. Two-thirds or more of the patients were diagnosed as having MU within 16 months after surgery. The duration of the prophylactic PPI use was an independent risk factor in the multivariable analysis. We therefore recommend the use of prophylactic PPIs for >16 months after Whipple’s operation for periampullary tumors.

Investigation the relaxant effects of proton pump ınhibitors and their relaxation mechanism on sheep sphincter of Oddi.

Using a relaxant agent before an endoscopic retrograde cholangiopancreatography (ERCP) might reduce complications. We aimed to investigate the relaxant effects of proton pump inhibitors (PPIs) on sheep sphincter of Oddi (SO) and the mechanisms that might take part in this relaxant effect. The sheep SO was mounted in an organ bath filled with Krebs-Ringer bicarbonate solution under 1.5 g tension and the relaxant effects of PPIs were evaluated in the tissues precontracted by carbachol (10-6 mol/l). The relaxant responses to the PPIs were tested in the presence of various blockers to enlighten the underlying mechanism by the PPIs. The PPIs exerted relaxant responses in a concentration-dependent manner in the sheep SO (P < 0.05). Esomeprazole produced the strongest relaxation. The administration of atropine, indomethacin, L-NAME, methylene blue, clotrimazole, glibenclamide, and 4-aminopyridine into the organ baths did not change the relaxations induced by PPIs in vitro (P> 0.05). On the other hand, Ca+2-activated potassium channel blocker tetraethylammonium (TEA) reduced the relaxation responses created by PPIs (P < 0.05). The present study suggests that PPIs create relaxation on SO partially via Ca+2-activated potassium channels. PPIs, especially esomeprazole, may be beneficial during the ERCP procedure. Further clinical studies are needed to confirm our results.

Proton Pump Inhibitor Ameliorates Taste Disturbance among Patients with Laryngopharyngeal Reflux: A Randomized Controlled Study.

Patients with laryngopharyngeal reflux (LPR) were reported to suffer from hypogeusia that affects quality of life. Proton pump inhibitor (PPI) is a useful drug in the treatment of LPR, but its effect on hypogeusia is not known. We therefore assessed the effects of PPI or a histamine H2 receptor antagonist (H2 blocker) on hypogeusia among patients with LPR. Both PPI and H2 blocker could inhibit acid reflux. LPR was diagnosed with reflux finding score and reflux symptom index. The visual analogue scale (VAS) of taste disturbance symptoms and the gustatory tests were assessed before and 8 weeks after treatment with esomeprazole, a PPI (20 patients, aged 50.0 ± 1.7 years) or famotidine, a H2 blocker (20 patients, aged 47.1 ± 1.8 years). There were no significant differences in VAS scores and recognition thresholds for four basic tastes between the two groups before treatment. Only PPI therapy significantly decreased the VAS scores, suggesting the improvement of taste perception. Moreover, PPI therapy significantly decreased recognition thresholds for bitter taste in the anterior tongue (chorda tympani nerve area) and the thresholds in the posterior tongue (glossopharyngeal nerve area) for salty, sour, and bitter tastes. By contrast, H2-blocker therapy caused no significant changes of thresholds in the anterior tongue, but improved the threshold only for bitter in the posterior tongue, the value of which was however significantly higher than that in PPI group. In conclusion, PPI could ameliorate hypogeusia by improving bitter, salty, and sour tastes among patients with LPR.

Modification of gastric cancer risk associated with proton pump inhibitors by aspirin after Helicobacter pylori eradication.

AimAlthough proton pump inhibitors (PPIs) can prevent aspirin-induced upper gastrointestinal bleeding, a clinical dilemma exists as long-term use of PPI may also increase the risk of gastric cancer even after Helicobacter pylori (HP) eradication. We aimed to investigate the potential interaction between aspirin and PPIs on GC risk in patients who have HP eradicated.ResultsOf the 63,397 HP eradicated subjects (median follow-up 7.6 years), 153 (0.24%) developed GC. PPIs were associated with a higher GC risk among non-aspirin users (aHR: 3.73, 95% CI:2.11–6.60) but not among aspirin users (aHR: 0.35, 95% CI:0.04–2.74).Materials and MethodsThis is a post-hoc analysis based on a previously published territory-wide retrospective cohort study on the potential risk of PPIs on GC. Adults who had received an outpatient prescription of clarithromycin-based triple therapy for HP between 2003 and 2013 were identified. The adjusted hazard ratio (aHR) of GC with PPIs, stratified according to aspirin use, was calculated by Cox model with propensity score adjustment of other covariates.ConclusionsThe potential harmful effects of PPIs on GC development appear to be limited to non-aspirin users. Co-prescription of PPIs is therefore recommended for HP-eradicated patients who are at risk of aspirin-induced UGIB.