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In recent times, proton pump inhibitors (PPI) are frequently prescribed to manage acid reflux and to aid in completion of course of medication, which cause gastric irritation. Although this practice may minimize compliance to drug therapies and probably prevent development of drug resistance, the adverse effects of chronic PPI use have to be assessed. Inadvertent chronic use of PPIs has been found to inhibit normal gastrointestinal microbiome and even bone metabolism. The current study aimed to review available evidence based literature to understand the beneficial effects of PPIs weighed against their adversities with respect to periodontal and peri-implant health. The search strategy was followed according to the PRISMA guidelines for systematic reviews. Proton pump inhibitors, periodontal disease, dental implant (DI) and bone osseointegration were used as key MESH terms to search and select the required articles for review. While primary inclusion criteria were original researches, published in English, between 2014 to till-date, case reports, reviews and editorial communications were excluded. The overall search strategy resulted in 445 articles. Applying the inclusion and exclusion criteria 37 articles were selected. Scrutinizing the abstracts for relevance, 17 publications were finally selected for review. This included three in vivo animal studies evaluating DI osseointegration and 14 retrospective clinical studies (nine in patients with dental implants, four in patients with periodontitis and one evaluating bone quality using panoramic radiographs). Findings from this systematic review revealed a plausible relationship between chronic PPI use and poor peri-implant bone health leading to early DI failure, and mandibular osteoporotic changes. On the contrary, use of PPI among patients with periodontitis, resulted in an improvement in periodontal health and reduction in periodontal disease severity. [ABSTRACT FROM AUTHOR]

Knowledge about voice prosthesis microbial colonization is vital in laryngectomized patients' quality of life (QoL). Herein, we aimed to explore the relationship between oral microbial patterns, demographic variables and voice prosthesis performance. Thirty laryngectomy patients were assessed for microbial colonization in their voice prostheses and oral cavities. Factors like age, proton pump inhibitor (PPI) usage, and alcohol consumption were considered. Participants' average age was 74.20 ± 7.31 years, with a majority on PPIs. Staphylococcus aureus was the most common bacterium in prostheses (53 %), followed by Pseudomonas aeruginosa (27 %). Candida albicans was the primary fungal colonizer (67 %). A statistically significant moderate correlation was found between fungal species before and after oral rinsing (p = 0.035, Phi=0.588, Cramer's V = 0.416). Voice prosthesis and oral cavity microbiota profiles showed significant concordance (kappa=0.315, p < 0.004). Among subgroup analyses, bacterial patterns of colonization did not significantly influence VHI (p = 0.9555), VrQoL (p = 0.6610), or SF-36 (p = 0.509) scores. Conversely, fungal patterns of VP colonization significantly impacted subjective voice scores, with Candida krusei demonstrating better VHI (35.25 ± 3.63 vs. 44.54 ± 6.33; p = 0.008), VrQoL (7.13 ± 1.69 vs. 10.73 ± 2.00; p = 0.001), and SF-36 (69.36 ± 7.09 vs. 76.50 ± 7.73; p = 0.051) scores compared to C. albicans. There was a significant correlation between the oral microbiota and voice prosthesis colonization. These insights can inform improved care strategies for voice prostheses, enhancing patient outcomes. [ABSTRACT FROM AUTHOR]

Safety and efficacy are the most critical factors for the development of modern medications. For oral drugs, evaluating drug exposure under various conditions is one of the most important outcomes for clinical trials. These data will help to better understand the safety and efficacy of new drugs. Studies involving potential drug-drug interactions, proton pump inhibitors, and intake of food are often conducted to assess the above. Among the above, the influence of food on exposure to the drug is one of the key data sets for regulatory submission. Since food may have either a positive or negative effect on drug exposure, it is important to obtain an early assessment of the food effect. To better forecast and plan for clinical studies, substantial efforts have been made in the industry to develop modeling and in-vitro and in–vivo assays. Despite the efforts, predicting the effect of food on exposure without integrating the dynamic of the gastrointestinal tract in the assessment remains challenging. In this study, we evaluated the utilization of the dynamic Gastro-Intestinal Model (Tiny-TIM) for the food effect of over 20 drugs/formulations in development or on the market that covers all BCS classes. In general, the Tiny-TIM predicted food effects were in good agreement with the reported data in humans. This suggests that Tiny-TIM can successfully capture the impact of physicochemical properties on absorption under the influence of food. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the treatment outcomes of proton-pump inhibitors (PPIs) in patients with contact granuloma (CG) and to investigate the parameters of 24 h combined dual channel pH/impedance (24 h pH/MII) monitoring, which are reliable for predicting the response to PPI of CG patients. : We reviewed the medical records of patients with CG who had been treated with PPIs and had completed more than 6 months of follow-up. We classified the patients into two groups (cured vs. persistent), according to their PPI treatment outcomes. Reflux events were categorized into three groups based on pharyngeal pH during reflux: 1) acid reflux (pH < 4), 2) weak acid reflux (4 < pH < 7), and 3) weak alkaline reflux (pH >7), as detected by a proximal probe. We compared the results of 24h-pH/MII between the two groups and used receiver operating characteristic curve (ROC) analysis to determine the cutoff values of significant parameters for predicting responses to PPIs. : Among 22 patients who completed at least 6 months of PPI treatment and follow-up, weak acid reflux events were more frequently observed in persistent group than in the cured group (p = 0.046), and the proportion of weak acid reflux was also higher in the persistent group (p = 0.031) than in the cured group. Reliable parameters predictive of a poor response to PPIs were a number of weak acid reflux events ≥ 11 (area under the curve [AUC], 0.775; p = 0.03) and a proportion of weak acid reflux events ≥ 56.7 % (AUC, 0.763; p = 0.038) in ROC analyses. : Weak acid reflux was identified as a significant factor associated with the treatment outcomes of PPIs in patients with CG. A number of weak acid reflux events ≥ 11 is considered to be the most reliable predictor of a poor response to PPIs in patients with CG. [ABSTRACT FROM AUTHOR]

Deprescribing opportunities may differ across health care systems, nursing home settings, and prescribing cultures. The objective of this study was to compare the prevalence of STOPPFrail medications according to frailty status among residents of nursing homes in Australia, China, Japan, and Spain. Secondary cross-sectional analyses of data from 4 cohort studies. A total of 1142 residents in 31 nursing homes. Medication data were extracted from resident records. Frailty was assessed using the FRAIL-NH scale (non-frail 0–2; frail 3–6; most-frail 7–14). Chi-square tests and prevalence ratios (PRs) were used to compare STOPPFrail medication use across cohorts. In total, 84.7% of non-frail, 95.6% of frail, and 90.6% of most-frail residents received ≥1 STOPPFrail medication. Overall, the most prevalent STOPPFrail medications were antihypertensives (53.0% in China to 73.3% in Australia, P <.001), vitamin D (nil in China to 52.7% in Australia, P <.001), lipid-lowering therapies (11.1% in Japan to 38.9% in Australia, P <.001), aspirin (13.5% in Japan to 26.2% in China, P <.001), proton pump inhibitors (2.1% in Japan to 32.0% in Australia, P <.001), and antidiabetic medications (12.3% in Japan to 23.5% in China, P =.010). Overall use of antihypertensives (PR, 1.15; 95% CI, 1.06–1.25), lipid-lowering therapies (PR, 1.78; 95% CI, 1.45–2.18), aspirin (PR, 1.31; 95% CI, 1.04–1.64), and antidiabetic medications (PR, 1.31; 95% CI, 1.00–1.72) were more prevalent among non-frail and frail residents compared with most-frail residents. Antihypertensive use was more prevalent with increasing frailty in China and Japan, but less prevalent with increasing frailty in Australia. Antidiabetic medication use was less prevalent with increasing frailty in China and Spain but was consistent across frailty groups in Australia and Japan. There were overall and frailty-specific variations in prevalence of different STOPPFrail medications across cohorts. This may reflect differences in prescribing cultures, application of clinical practice guidelines in the nursing home setting, and clinician or resident attitudes toward deprescribing. [ABSTRACT FROM AUTHOR]

Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism. Repurposing the anti-ulcer drug lansoprazole stimulates adipose thermogenesis and energy expenditure by inhibiting PHOSPHO1, offering a novel therapeutic approach for managing obesity and associated metabolic disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Abnormal DeMeester score on pH monitoring is a well-established predictor of favorable outcome after antireflux surgery (ARS). Esophageal pH monitoring also facilitates analysis of the temporal association between symptoms and reflux episodes. This association can be expressed with several symptom–reflux association indices with symptom association probability (SAP) being the most reliable. SAP is often used as an adjunct to DeMeester score during preoperative assessment of patients seeking ARS. However, data on the utility of SAP in predicting ARS outcome is limited. The aim of this study was to determine the utility of SAP as an adjunct to DeMeester score in predicting outcomes after fundoplication. Methods: Records of patients who underwent primary fundoplication from 2015 to 2021 were reviewed. Patients with a preoperative DeMeester score >14.7 on Bravo pH monitoring were included. A SAP >95% was considered SAP-positive. Favorable outcome was defined as freedom from proton pump inhibitors (PPIs) and patient satisfaction at 1 year postoperatively. Outcomes were compared based on the presence and number of SAP-positive symptoms, individual typical and atypical SAP-positive symptoms, and within demographic, clinical, and reflux severity subgroups. Results: The final study population consisted of 597 patients (71.4% female) with a median (IQR) age of 59.0 (49–67). At a mean (SD) follow-up of 10.5 (8) months, 82.0% patients achieved favorable outcome (satisfaction and freedom from PPI), freedom from PPI was 91.7%, and satisfaction was 87.4%. SAP was positive in 430 (72.0%) patients, of which 221 (37.0%) had one SAP-positive symptom, 164 (27.5%) had two SAP-positive symptoms, and 45 (7.5%) had all three SAP-positive symptoms. There was no association between having at least one SAP-positive symptom and favorable outcome (p=0.767). There was no difference in favorable outcome between patients with one, two, or all SAP-positive symptoms (0.785). Outcomes were comparable for SAP-positive typical (p=0.873) and atypical symptoms (p=1.000) and all individual symptoms (p>0.05). Outcomes were also comparable within all subgroups (p>0.05). Conclusion: Symptom association probability with an abnormal DeMeester score did not enhance the prediction of antireflux surgery outcome. These findings suggest that SAP should not be used in surgical decision-making in patients with objective evidence of reflux. [ABSTRACT FROM AUTHOR]

To investigate awareness of proton pump inhibitor (PPI) side effects and the resulting changes in reflux mana management among members of the American Broncho-Esophagological Association (ABEA) caring for adult patients in light of increasing concern for PPIs long-term adverse effects. Cross-sectional survey study Online surveys were electronically distributed to ABEA members assessing awareness of PPI side effects and current practice in reflux management. 374 ABEA members were contacted, of whom, 43 (11.5%) completed the survey. The majority of respondents (94.1%) selected laryngology as their principal focus. The entire cohort warned their patients about PPI side effects, with highest concern for osteoporotic risk. Most respondents (88.2%) had changed their PPI prescription frequency in light of recent studies on PPI side effects, with 55.9% avoiding PPI prescription and 94.1% limiting the duration of PPI courses. Instead of PPIs, 73.5% of responders prescribe H2-receptor blockers. The primary reasons for starting patients on PPIs were typical gastroesophageal reflux symptoms (47.1%), followed by laryngopharyngeal reflux symptoms (41.2%), and endoscopic findings suspicious for reflux (11.8%). Finally, the majority of respondents (82.4%) had referred at least one patient for surgical management of gastroesophageal reflux in the past year. The majority of surveyed ABEA members were concerned about reports of PPI adverse effects and had modified their prescription patterns as a result. Avoidance of PPI recommendation was common, along with the preference for H2 blockers in the management of GERD and LPR. PPI side effects of greatest concern to broncho-esophagologists treating adult patients were osteoporosis, renal dysfunction and dementia. 5 [ABSTRACT FROM AUTHOR]

Gastric disorders have significant relevance to the fields of both anaesthesia and intensive care medicine. Pneumonitis and development of pneumonia in the perioperative period are significant complications following aspiration of gastric acid and stomach contents. Anaesthetists play a key role in minimizing this risk through careful patient selection, pre-assessment and pharmacological management of gastric acid. Proton pump inhibitors are the most used drug class to reduce the risk of stress-related mucosal damage in intensive care and perioperatively. Histamine-2 receptor antagonists and sucralfate are also effective but not routinely used in clinical practice. Sodium citrate is still commonly used in obstetric anaesthesia. Ventilated patients in intensive care may also suffer from intestinal failure either subsequent to postoperative ileus, pharmacological treatments or as part of multi-organ dysfunction. Many strategies have been proposed for the management of intestinal failure in critical care however evidence is lacking in this area. Prokinetics including metoclopramide and erythromycin remain key drugs in the management of intestinal failure in current practice. [ABSTRACT FROM AUTHOR]

The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost–value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. [ABSTRACT FROM AUTHOR]

Cytochrome P450 CYP102A1 is a prototypic biocatalyst that has great potential in chemical synthesis, drug discovery, and biotechnology. CYP102A1 variants engineered by directed evolution and/or rational design are capable of catalyzing the oxidation of a wide range of organic compounds. However, it is difficult to foresee the outcome of engineering CYP102A1 for a compound of interest. Here, we introduce UniDesign as a computational framework for enzyme design and engineering. We tested UniDesign by redesigning CYP102A1 for stereoselective metabolism of omeprazole (OMP), a proton pump inhibitor, starting from an active but nonstereoselective triple mutant (TM: A82F/F87V/L188Q). To shift stereoselectivity toward (R)-OMP, we computationally scanned three active site positions (75, 264, and 328) for mutations that would stabilize the binding of the transition state of (R)-OMP while destabilizing that of (S)-OMP and picked three variants, namely UD1 (TM/L75I), UD2 (TM/A264G), and UD3 (TM/A328V), for experimentation, based on computed energy scores and models. UD1, UD2, and UD3 exhibit high turnover rates of 55 ± 4.7, 84 ± 4.8, and 79 ± 5.7 min−1, respectively, for (R)-OMP hydroxylation, whereas the corresponding rates for (S)-OMP are only 2.2 ± 0.19, 6.0 ± 0.68, and 14 ± 2.8 min−1, yielding an enantiomeric excess value of 92, 87, and 70%, respectively. These results suggest the critical roles of L75I, A264G, and A328V in steering OMP in the optimal orientation for stereoselective oxidation and demonstrate the utility of UniDesign for engineering CYP102A1 to produce drug metabolites of interest. The results are discussed in the context of protein structures. [ABSTRACT FROM AUTHOR]

Health care deciders are aware of the inappropriate use of proton pump inhibitors (PPIs). To reduce inappropriate prescriptions, the Conseil du Médicament (CdM) issued a practice guideline and the Régie de l'Assurance Maladie du Quebec (RAMQ) asked prescribers to justify its use by writing a specific indication code for their patients to obtain drug coverage. This study aimed to evaluate the effectiveness of the intervention by the RAMQ to reduce inappropriate PPI prescription. A cross-sectional quasi-experimental prospective study was performed in an emergency department. Patients aged 18 years or older were included in 2016 to 2017 and 2019 to 2021 in the pre- and postintervention group, respectively. The proportion of patients on PPI without an appropriate indication were identified from patient interviews and chart review. A total of 871 and 1475 patients were recruited in the pre- and postintervention groups. According to the CdM guideline, the proportion of inappropriate PPI prescription was 30.7% (n = 267) in the preintervention group and 49.1% (n = 724) in the postintervention group (P < 0.001). According to the RAMQ criteria, the proportion of inappropriate PPI prescription was of 76.1% (n = 663) and 81.4% (n = 1200) in the pre- and postintervention group, respectively (P < 0.001). This study highlights the ineffectiveness of the codes for PPI prescriptions in reducing inappropriate prescriptions. It seems that the obligation to write a code does not lead to a reassessment of PPI indication. [ABSTRACT FROM AUTHOR]

Introduction: Marginal ulcer (MU) is a common complication following Roux-en-Y gastric bypass (RYGB) with an incidence rate of up to 25%. Several studies have evaluated different risk factors associated with MU with inconsistent findings. In this meta-analysis, we aimed to identify the predictors of MU after RYGB. Methods: A comprehensive literature search of PubMed, Embase, and Web of Science databases was conducted through April 2022. All studies that used a multivariate model to assess risk factors for MU after RYGB were included. Pooled odds ratios (OR) with 95% confidence intervals (CI) for risk factors reported in ≥ 3 studies were obtained within a random-effects model. Results: Fourteen studies with 344,829 patients who underwent RYGB were included. Eleven different risk factors were analyzed. Meta-analysis demonstrated that Helicobacter pylori (HP) infection (OR 4.97 [2.24–10.99]), smoking (OR 2.50 [1.76–3.54]), and diabetes mellitus (OR 1.80 [1.15–2.80]), were significant predictors of MU. Increased age, body mass index, female gender, obstructive sleep apnea, hypertension, and alcohol use were not predictors of MU. There was a trend of an increased risk of MU associated with nonsteroidal anti-inflammatory drugs (OR 2.43 [0.72–8.21]) and a lower risk of MU with proton pump inhibitors use (OR 0.44 [0.11–2.11]). Conclusions: Smoking cessation, optimizing glycemic control, and eradication of HP infection reduce the risk of MU following RYGB. Recognition of predictors of MU after RYGB will allow physicians to identify high-risk patients, improve surgical outcomes, and reduce the risk of MU. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) are effective in reducing marginal ulcers after pancreatoduodenectomy. However, their impact on perioperative complications has not been defined. We retrospectively analyzed the effect of postoperative PPIs on 90-day perioperative outcomes in all patients who underwent pancreatoduodenectomy at our institution from April 2017 to December 2020. 284 patients were included; 206 (72.5%) received perioperative PPIs, 78 (27.5%) did not. The two cohorts were similar in demographics and operative variables. Postoperatively, the PPI cohort had significantly higher rates of overall complications (74.3% vs. 53.8%) and delayed gastric emptying (28.6% vs. 11.5%), p < 0.05. However, no differences in infectious complications, postoperative pancreatic fistula, or anastomotic leaks were seen. On multivariate analysis, PPI was independently associated with a higher risk of overall complications (OR 2.46, CI 1.33–4.54) and delayed gastric emptying (OR 2.73, CI 1.26–5.91), p = 0.011. Four patients developed marginal ulcers within 90-days postoperatively; all were in the group who received PPIs. Postoperative proton pump inhibitor use was associated with a significantly higher rate of overall complications and delayed gastric emptying after pancreatoduodenectomy. [ABSTRACT FROM AUTHOR]

During the analysis of benziamidazole-class irreversible proton pump inhibitors, an unusual mass spectral response with the mass-to-charge ratio at [M+10]+ intrigued us, as it couldn't be assigned to any literature known relevant structure, intermediate or adduct ion. Moreover, this mysterious mass pattern of [M+10]+ has been gradually observed by series of marketed proton pump inhibitors, viz. omeprazole, pantoprazole, lansoprazole and rabeprazole. All the previous attempts to isolate the corresponding component were unsuccessful. The investigation of present work addresses this kind of signal to a pyridinium thiocyanate mass spectral intermediate (10) , which is the common fragment ion of series of labile aggregates. The origin of such aggregates can be traced to the reactive intermediates formed by acid-promoted degradation. These reactive intermediates tend to react with each other and give raise series of complicated aggregates systematically in a water/acetonitrile solution by electrospray ionization. The structure of the corresponding pyridinium thiocyanate species of omeprazole (10a) has been eventually characterized with the help of synthetic specimen (10a′). Our structural proposal as well as its origin was supported by in situ nuclear magnetic resonance, chemical derivatization and colorimetric experiments. [Display omitted] • A common MS-intermediate among benziamidazole-class PPIs has been identified. • Structure of the corresponding pyridinium thiocyanate intermediate has been characterized. • Origin of such pseudo related substance has been investigated by a variety of methods. [ABSTRACT FROM AUTHOR]

Several reports have shown that the use of proton pump inhibitors (PPIs) and antibiotics (Abx) can reduce the efficacy of immune checkpoint inhibitors in various cancers. To date, however, the association of immune checkpoint inhibitors with PPI and/or Abx in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M SCCHN) has not been reported. We retrospectively reviewed patients with platinum-refractory R/M SCCHN treated with nivolumab from May 2017 and March 2020 in our institute. Primary sites included the oral cavity, oropharynx, hypopharynx and larynx. The relationship between prognostic parameters, such as overall survival (OS), progression-free survival (PFS), PFS2 and PFS3, and clinical factors, including PPI or Abx use, was examined, and the creation of prognostic classification was also attempted. Of 110 patients identified, 56 patients received PPI and 24 patients received Abx within 30 days before or after the initiation of nivolumab. With a median follow-up of 17.2 months (range: 13.8–25.0), median PFS, PFS2, PFS3 and OS were 3.2, 8.1, 14.0 and 17.2 months, respectively. In univariate analysis, the use of PPI and of Abx was significantly associated with poor prognosis in all parameters (PFS, PFS2, PFS3 and OS). Median OS (hazard ratio; 95%confidence interval, p -value) by these covariates were 13.6 versus 23.8 months (1.70; 1.01–2.87, p = 0.046) for PPI and 10.0 versus 20.1 months (1.85; 1.00–3.41, p = 0.048) for Abx, respectively. Furthermore, these factors showed mutually independent adverse associations on multivariate analysis. The use of PPI and Abx attenuated the efficacy of nivolumab in R/M SCCHN. Further prospective evaluation is warranted. • The potential association with proton pump inhibitor and Abx use and immune checkpoint inhibitor efficacy has been reported. • We retrospectively reviewed 110 recurrent or metastatic head and neck squamous cell carcinoma patients who received nivolumab. • The use of proton pump inhibitor and antibiotics independently worsened the efficacy of nivolumab. • Avoiding unnecessary use of these agents may improve prognosis in this population. [ABSTRACT FROM AUTHOR]

Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis, the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO 2 nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn2+ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H+-ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular β-D-glucose for H 2 O 2 self-supply and generation of additional cytoplasm H+. The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization, suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON)-GOx@MnO 2 nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn2+ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H 2 O 2 self-supply and addition of cytoplasm H+ to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H+-ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization. [Display omitted] [ABSTRACT FROM AUTHOR]

Assessment of vancomycin-resistant Enterococcus faecium (VREfm) prevalence upon hospital admission and analysis of risk factors for colonization. From 2014 to 2018, patients were recruited within 72 hours of admission to seven participating German university hospitals, screened for VREfm and questioned for potential risk factors (prior multidrug-resistant organism detection, current/prior antibiotic consumption, prior hospital, rehabilitation or long-term care facility stay, international travel, animal contact and proton pump inhibitor [PPI]/antacid therapy). Genotype analysis was done using cgMLST typing. Multivariable analysis was performed. In 5 years, 265 of 17,349 included patients were colonized with VREfm (a prevalence of 1.5%). Risk factors for VREfm colonization were age (adjusted OR [aOR], 1.02; 95% CI, 1.01–1.03), previous (aOR, 2.71; 95% CI, 1.87–3.92) or current (aOR, 2.91; 95% CI, 2.60–3.24) antibiotic treatment, prior multidrug-resistant organism detection (aOR, 2.83; 95% CI, 2.21–3.63), prior stay in a long-term care facility (aOR, 2.19; 95% CI, 1.62–2.97), prior stay in a hospital (aOR, 2.91; 95% CI, 2.05–4.13) and prior consumption of PPI/antacids (aOR, 1.29; 95% CI, 1.18–1.41). Overall, the VREfm admission prevalence increased by 33% each year and 2% each year of life. 250 of 265 isolates were genotyped and 141 (53.2%) of the VREfm were the emerging ST117. Multivariable analysis showed that ST117 and non-ST117 VREfm colonized patients differed with respect to admission year and prior multidrug-resistant organism detection. Age, healthcare contacts and antibiotic and PPI/antacid consumption increase the individual risk of VREfm colonization. The VREfm admission prevalence increase in Germany is mainly driven by the emergence of ST117. [ABSTRACT FROM AUTHOR]

There is an increasing interest in inappropriate proton pump inhibitors prescription (InPPIp), as defined by the National Institute for Clinical Excellence (NICE) guidelines. To evaluate the rate, trend over time and factors associated with InPPIp upon discharge from internal medicine departments. We evaluated patients discharged from internal medicine departments with a PPI prescription in 2014 and 2017 at an academic referral center according to a developed algorithm. A total of 3,982 patients were included (50.8% women, 74% ≥ 65 years). The rate of InPPIp was 44.3% (95% CI 42.8–45.9) for the entire cohort; 68.1% for subjects aged < 65 years and 36.0% for those aged ≥ 65 years (p <0.001); 43.2% in 2014 and 45.6% in 2017 (p = 0.130). In a decision-tree analysis, after the exclusion of 448 patients with gastrointestinal indications, 89.4% (1,580/1,766) of all InPPIp cases were of patients without dual antiplatelet treatment (DAPT) and 8.6% (151/1,766) were of patients younger than 65 years, who were taking aspirin. The rate of InPPIp is high, especially among patients not receiving DAPT and young patients taking aspirin. Time trend analysis showed no improvement over time. Our algorithm may serve as an automated quality measuring tool to reduce InPPIp. [ABSTRACT FROM AUTHOR]

Evidence on the effectiveness of proton pump inhibitors (PPI) as adjuvant therapy to improve maldigestion in people with cystic fibrosis (pwCF) is limited and there is increasing concern on possible side effects. We conducted a matched cohort study based on paediatric and adult pwCF who received PPI for ≥3 months. Treated patients were matched to a group of patients who never received PPI using a nearest neighbour propensity score matching based on sex, year of birth, CFTR genotype and pancreatic insufficiency. The study included 160 pwCF: 80 treated and 80 untreated patients. Over a median follow-up of 2 years, no significant differences in changes in BMI z-score were detected between groups (adjusted mean difference: 0.06, 95% CI: -0.17–0.30). At baseline 25% (n = 20) of the treated patients and 22.5% (n = 18) of the untreated patients had a positive culture for P. aeruginosa (Pa). At follow-up percentages of Pa positive cultures increased to 47.5% (n = 38) in the treated group and to 26.3% (n = 21) in the untreated group (adjusted mean difference: 23.1%, 95% CI: 10.8–35.3). Prolonged PPI therapy should be used cautiously in pwCF since it may increase the risk of respiratory infection by Pa. In addition, such treatment does not seem to improve nutritional status. [ABSTRACT FROM AUTHOR]

Histamine-2 receptor antagonists (H2RAs) may induce a higher risk of developing delirium than proton pump inhibitors (PPIs), but current evidence is insufficient. Therefore, this study aimed to investigate whether anti-ulcer drugs increase delirium risk. Data were obtained from the medical records of patients admitted to a hospital due to trauma. We compared the incidence of delirium in patients who received H2RAs and PPIs with that in patients who received no anti-ulcer drugs. A total of 150, 158, and 238 patients received H2RAs, PPIs, and no anti-ulcer drugs, respectively. Delirium incidence was significantly higher in patients who received H2RAs (34.0%) and PPIs (44.9%) than in those who did not receive anti-ulcer drugs (22.3%). Even after adjustment for possible confounding factors, the association between H2RAs and delirium remained (adjusted OR 1.78; 95% CI 1.04–3.05), but that between PPIs and delirium was attenuated (adjusted OR 1.25; 95% CI 0.71–2.23). Our results show that H2RAs are associated with delirium risk. We replicated findings of a previous data-driven study. Clinicians need to consider the effect of delirium in anti-ulcer drug selection. • This study compares delirium risk of anti-ulcer drugs in trauma patients. • Histamine-2 receptor antagonists (H2RAs) are associated with delirium risk. • Association of PPIs and delirium was attenuated after adjustment for fentanyl and benzodiazepine use. [ABSTRACT FROM AUTHOR]

For decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited. Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks. Patients with healing were rerandomized to once-daily vonoprazan, 10 mg, vonoprazan, 20 mg, or lansoprazole, 15 mg, for 24 weeks. Primary end points, percentage with healing by week 8 endoscopy, and maintenance of healing at week 24 endoscopy, were assessed in noninferiority comparisons (noninferiority margins, 10%), with superiority analyses prespecified if noninferiority was demonstrated. Analyses of primary and secondary end points were performed using fixed-sequence testing procedures. Among 1024 patients in the healing phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the exploratory analysis of healing (92.9 vs 84.6%; difference, 8.3%; 95% confidence interval [CI], 4.5%–12.2%). Secondary analyses showed vonoprazan was noninferior in heartburn-free days (difference, 2.7%; 95% CI, −1.6% to 7.0%), and superior in healing Los Angeles Classification Grade C/D esophagitis at week 2 (difference, 17.6%; 95% CI, 7.4%–27.4%). Among 878 patients in the maintenance phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the secondary analysis of maintenance of healing (20 mg vs lansoprazole: difference, 8.7%; 95% CI, 1.8%–15.5%; 10 mg vs lansoprazole: difference, 7.2%; 95% CI, 0.2%–14.1%) and secondary analysis of maintenance of healing Grade C/D esophagitis (20 mg vs lansoprazole: difference, 15.7%; 95% CI, 2.5%–28.4%; 10 mg vs lansoprazole: difference, 13.3%; 95% CI, 0.02%–26.1%). Vonoprazan was noninferior and superior to the PPI lansoprazole in healing and maintenance of healing of erosive esophagitis. This benefit was seen predominantly in more severe erosive esophagitis. (ClinicalTrials.gov: NCT04124926). [Display omitted] [ABSTRACT FROM AUTHOR]

• Recent large studies substantially changed the observational evidence about the cardiovascular effect of proton pump inhibitors (PPIs). • PPI intake does not increase the risk of first cardiovascular events. • Previous reports of increased cardiovascular mortality can largely be explained by publication bias and observational study design biases. Observational research has indicated that proton pump inhibitors (PPIs) might increase the long-term risk of cardiovascular events. This study evaluated the evidence from observational studies for an effect of PPI monotherapy on the risk of incident cardiovascular events and cardiovascular mortality. The databases MEDLINE, EMBASE, and Scopus were systematically searched up to September 2021. The primary outcome was first cardiovascular event, i.e. first myocardial infarction or first ischaemic stroke. The secondary outcome was cardiovascular mortality. Studies were included following a detailed risk of bias assessment with the ROBINS-I tool. Sensitivity and bias analyses adjusted for potential publication bias, immortal time bias, and unmeasured confounding. We included ten studies with 75,371 first cardiovascular events, as well as seven studies on cardiovascular mortality with 50,329 cardiovascular deaths in total. The pooled hazard ratios (HRs) for PPI use and cardiovascular events were 1.05 with a 95% confidence interval of (0.96; 1.15) before and 0.99 (0.93; 1.04) after adjusting for observational study design bias. The pooled HRs for PPI use and cardiovascular mortality were 1.27 (1.11; 1.44) before and 1.06 (0.96; 1.16) after adjusting for publication bias and observational study design bias. It is questionable, whether PPI monotherapy constitutes a cardiovascular risk factor. [ABSTRACT FROM AUTHOR]

Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib. Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as "no concomitant PPIs" or "concomitant PPIs"; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice. A total of 128 patients were consecutively enrolled in the study; 78 belonged to the "no concomitant PPIs" group and 50 to the "concomitant PPIs" group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities. The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting. • Changes of gastric pH by PPIs may significantly affect the bioavailability of tyrosine kinase inhibitors. • Our findings support the hypothesis that long-term treatment with PPI does not compromise the efficacy of ribociclib. • Consistent with our results, data from the literature show no effect of gastric pH changes on ribociclib pharmacokinetics. [ABSTRACT FROM AUTHOR]

• Efficacy and safety of vonoprazan and high-dose amoxicillin (VHA) dual therapy in eradicating Helicobacter pylori was evaluated. • VHA dual therapy is significantly more effective than bismuth quadruple therapy based on proton pump inhibitors (P-BQT). • H. pylori eradication rates of over 90% were seen with 10-day VHA and 14-day VHA. • VHA dual therapy had fewer adverse events and similar compliance compared with that of the control. Vonoprazan is a new acid-suppressing drug that provides an additional choice for eradicating Helicobacter pylori. The effectiveness and safety of vonoprazan and high-dose amoxicillin (VHA) dual therapy requires study in a systematic analysis. A comprehensive search of the literature from the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to 16 May 2024. Trials comparing H. pylori eradication rates, adverse events, and compliance of VHA dual therapy with that of other therapies were included. RevMan 5.4 was used for statistical analysis. Eleven randomised controlled trials (RCTs) and two retrospective clinical studies with 4570 samples were included. VHA dual therapy had superior H. pylori eradication rates (intention-to-treat [ITT]: 86.0% vs. 80.7%; odds ratio [OR]=1.36; 95% confidence interval [CI] 1.07–1.73; P =0.01; per-protocol [PP]: 90.6% vs. 85.7%; OR=1.42; 95% CI 1.07–1.88; P =0.02), fewer adverse events (15.4% vs. 27.7%; OR=0.49; 95% CI 0.35–0.68, P <0.0001), and similar compliance (94.6% vs. 93.2%; OR=1.27; 95% CI 0.98–1.64; P =0.07) compared with other guideline therapies. According to subgroup analysis with PP data, VHA dual therapy is more effective than bismuth quadruple therapy based on proton-pump inhibitors (P-BQT) (93.5% vs. 89.3%; OR=1.76; 95% CI 1.03–3.00; P =0.04). In addition, the eradication rates for 7-day, 10-day and 14-day VHA dual therapy were 65% (95% CI 0.55–0.75), 92% (95% CI 0.91–0.94) and 93% (95% CI 0.90–0.97), respectively. VHA dual therapy for 10 or 14 days showed superior efficacy and safety compared with therapies recommended by the guidelines and should be prioritised for adoption. [Display omitted] [ABSTRACT FROM AUTHOR]

• This was a randomised, positive drug-controlled study with a non-inferior design. • This study evaluated the efficacy of keverprazan-based quadruple therapy for Helicobacter pylori infection. • A regimen of keverprazan 20 mg twice daily proved to be effective against H. pylori. • The eradication rate with keverprazan therapy was superior to that with proton pump inhibitor (PPI) in the per protocol set. Keverprazan is a novel potassium-competitive acid blocker. The advantages of keverprazan as a potent acid suppressor in Helicobacter pylori eradication have not yet been demonstrated. The aim of this study was to evaluate the efficacy of keverprazan as a component of bismuth quadruple therapy in H. pylori treatment. Adult patients with H. pylori infection were enrolled and randomised to take keverprazan (KEV group)- or esomeprazole (ESO group)-quadruple therapy. The regimens contained keverprazan 20 mg or esomeprazole 20 mg, clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 240 mg and were administered twice daily for 14 days. The primary endpoint was the H. pylori eradication rate at 4 weeks after treatment. The full analysis set showed that the H. pylori eradication rates were 87.8% (252/287) and 82.52% (236/286) for the KEV and ESO groups, respectively (difference: 5.29%; 95% confidence interval [CI]: -0.55–11.18). Keverprazan was superior to esomeprazole in terms of eradication rate in the per protocol set (P =0.0382). The eradication rates for patients resistant or non-resistant to clarithromycin were both numerically higher in the KEV group than the ESO group (83.45% vs. 76.98% for clarithromycin-resistance; 92.31% vs. 88.16% for clarithromycin-non-resistance). The incidence of adverse events was similar in the KEV and ESO groups (76.31% vs. 77.62%), with most adverse events (>90%) being mild in severity. No TEAEs led to death in either group. Keverprazan 20 mg twice daily, used as a component of bismuth quadruple therapy, provided effective H. pylori eradication and was non-inferior to an esomeprazole-based regimen. [Display omitted] [ABSTRACT FROM AUTHOR]

We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15–0.28) versus without concomitant statins (aHR: 0.31 [0.24–0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS. • Exposure to metformin or statins did not alter the efficacy of apalutamide. • Patients who received concomitant metformin or ACEI had improved MFS. • Patients who jointly received metformin, statins, and ACEI had improved MFS. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs), which inhibit gastric acid secretion, are frequently prescribed to patients with Parkinson's disease (PD). Levodopa, the gold-standard treatment for PD, demonstrates enhanced solubility in acidic environments. Although PPIs increase gastric pH and may affect levodopa absorption, the effect of concomitant PPI use on levodopa pharmacokinetics in patients with PD remains unknown. This study aimed to investigate the effect of the concomitant use of esomeprazole, a PPI, on the pharmacokinetics of levodopa and carbidopa and clinical symptoms in patients with PD. We prospectively enrolled 40 patients with PD and compared the pharmacokinetics of levodopa and carbidopa and clinical symptoms before and two weeks after the concomitant use of esomeprazole. The plasma concentrations of levodopa 30 min after concomitant oral administration of levodopa and esomeprazole were significantly lower (4.92 ± 4.10 μmol/L) than those without concomitant esomeprazole use (6.26 ± 3.75 μmol/L; p = 0.027). The plasma concentrations of carbidopa showed no significant differences with respect to concomitant esomeprazole use. Significant elevation was recorded in all subscores of the Movement Disorder Society-sponsored revision of the Unified Parkinson's disease Rating Scale scores after concomitant use of esomeprazole. No significant differences were observed between Helicobacter pylori -negative and Helicobacter pylori -positive patients. Non-elderly patients (age ≤ 70 years) tended to be more susceptible to the effect of esomeprazole on levodopa pharmacokinetics and clinical symptoms. The unnecessary use of PPIs should be avoided in patients with PD, especially in non-elderly patients, to improve absorption of levodopa. • This study prospectively enrolled 40 patients with Parkinson's disease. • Concomitant use of esomeprazole reduced the plasma concentrations of levodopa. • Plasma concentrations of carbidopa were not significantly altered. • Presence or absence Helicobacter pylori infection did not affect the results. • Non-elderly patients tended to be more susceptible to the effect of esomeprazole. [ABSTRACT FROM AUTHOR]

• The extensive use of PPIs can interfere with the efficacy of oral therapies. • PPIs affect the survival of mRCC patients treated with pazopanib and cabozantinib. • The concomitant use of PPIs and TKIs requires an evaluation of benefits and risks. The 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). Total 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. Eighty 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. This study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use. The extensive use of proton pump inhibitors (PPIs) poses the problem of their interference on the absorption of oral therapies and on the efficacy of the therapy. This study demonstrates an association between administration of PPIs and impaired PFS in mRCC patients treated with pazopanib and cabozantinib. It is recommended caution when prescribing PPIs and TKIs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Green and feasible HPLC-DAD method for the estimation of the second-line drugs for H. pylori. • Application of the known metric tools for greenness and practicability evaluation. • Application of the method to a pharmacokinetic study in rats. • Comparison between the new method and the reported ones in terms of greenness and feasibility. Improving the environmental friendliness of laboratory procedures has become very strongly recommended. In this research, several metric tools evaluating the analytical methods, including eco-scale, analytical greenness calculator (AGREE), green analytical procedure index (GAPI), red–green–blue software (RGB) and blue applicability grade index (BAGI) have been used to assess the greenness, performance and practicality of a new useful HPLC-DAD method. The main cause of peptic ulcers and the problems that follow is Helicobacter pylori. Due to the bacteria's high resistance, different medications are co-administered to overcome the resistance and manage the symptoms. Two antibiotics are mostly used to decrease bacterial resistance in addition to proton pump inhibitors. Pantoprazole, Levofloxacin, and Amoxicillin are co-administered in a triple therapy regimen for suppressing Helicobacter pylori. In this work, the first-time simultaneous estimation of the three medications in rat plasma has been designed and utilized to investigate pharmacokinetics using a new HPLC method with outstanding greenness and practicability. The method involved using a C18 analytical column with an eluent of acetonitrile: 0.03 M Na 2 HPO 4 buffer (20:80, v/v) of 1.5 mL min−1 flow rate. Oxytetracycline was used as an internal standard and the drugs were determined at 230 nm. The validation protocol was adopted according to FDA instructions, and the results proved the ability of the new method to estimate the three medications in rat plasma. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) are widely used for acid-related gastrointestinal disorders; however, concerns have arisen about their prolonged and inappropriate use. Although generally considered safe, recent evidence has linked PPI use with an increased risk of kidney disease, stomach cancer, pneumonia, dementia, cardiovascular events and potential bone health problems. This systematic review examines the effects of PPIs on bone health, including osteoporosis and changes in phosphocalcic and magnesium metabolism, through a comprehensive analysis of the recent literature. The relationship between PPIs, bone mineral density and fracture risk, especially in populations with comorbidities, is complex and we propose a focus based on recent data. Studies of the effect of PPI use on bone mineral density have shown mixed results and require further investigation. Observational studies have indicated an increased risk of fractures, particularly vertebral fractures, associated with PPI use. Recent meta-analyses have confirmed an association between PPI use and hip fractures with a dose-dependent effect. More recently, PPIs have been associated with serious disturbances in phosphocalcic and magnesium metabolism that require careful management and discontinuation. Proton pump inhibitor-induced hypomagnesemia (PPIH) is a well-established phenomenon. In addition, hypocalcemia secondary to severe hypomagnesemia has been described. Despite growing evidence of PPI-related risks, further research is essential to better understand the complex mechanisms, as most data are from observational studies and do not establish a causal relationship. This review emphasizes the need for judicious prescription practices, particularly in long-term use scenarios and rheumatological contexts. [ABSTRACT FROM AUTHOR]

This study evaluates the antibacterial effectiveness of Origanum vulgare hydroethanolic extract, both independently and in combination with antibiotics, against Escherichia coli strains associated with avian colibacillosis—a significant concern for the poultry industry due to the rise of antibiotic-resistant E. coli. The urgent demand for new treatments is addressed by analyzing the extract's phytochemical makeup via High-Performance Liquid Chromatography (HPLC), which identified sixteen phenolic compounds. Antibacterial activity was determined through agar diffusion and the measurement of minimum inhibitory and bactericidal concentrations (MIC and MBC), showing moderate efficacy (MIC: 3.9 to 7.8 mg/mL, MBC: 31.2 to 62.4 mg/mL). Combining the extract with antibiotics like ampicillin and tetracycline amplified antibacterial activity, indicating a synergistic effect and highlighting the importance of combinatory treatments against resistant strains. Further analysis revealed the extract's mechanisms of action include disrupting bacterial cell membrane integrity and inhibiting ATPase/H+ proton pumps, essential for bacterial survival. Moreover, the extract effectively inhibited and eradicated biofilms, crucial for preventing bacterial colonization. Regarding cytotoxicity, the extract showed no hemolytic effect at 1 to 9 mg/mL concentrations. These results suggest Origanum vulgare extract, particularly when used with antibiotics, offers a promising strategy for managing avian colibacillosis, providing both direct antibacterial benefits and moderating antibiotic resistance, thus potentially reducing the economic impact of the disease on the poultry industry. [Display omitted] [ABSTRACT FROM AUTHOR]

Esomeprazole is the most popular proton pump inhibitor for treating gastroesophageal reflux disease. Previously, a phenylacetone monooxygenase mutant LnPAMOmu15 (LM15) was obtained by protein engineering for asymmetric synthesis of esomeprazole using pyrmetazole as substrate. To scale up the whole cell asymmetric synthesis of esomeprazole and reduce the cost, in this work, an Escherichia coli whole-cell catalyst harboring LM15 and formate dehydrogenase from Burkholderia stabilis 15516 (Bst FDH) were constructed through optimized gene assembly patterns. CRISPR/Cas9 mediated insertion of P trc promoter in genome was done to enhance the expression of key genes to increase the cellular NADP supply in the whole cell catalyst, by which the amount of externally added NADP+ for the asymmetric synthesis of esomeprazole decreased to 0.05 mM from 0.3 mM for reducing the cost. After the optimization of reaction conditions in the reactor, the scalable synthesis of esomeprazole was performed using the efficient LM15- Bst FDH whole-cell as catalyst, which showed the highest reported space-time yield of 3.28 g/L/h with 50 mM of pyrmetazole loading. Isolation procedure was conducted to obtain esomeprazole sodium of 99.55 % purity and > 99.9 % ee with 90.1 % isolation yield. This work provides the basis for production of enantio-pure esomeprazole via cost-effective whole cell biocatalysis. [Display omitted] • The gene assembly pattern was optimized for co-expressing monooxygenase mutant LM15 and Bst FDH. • Strong promoter P trc was inserted by genome editing for enhancing coenzyme biosynthesis. • The whole cell catalyst converted 60 mM substrate to enantiopure esomeprazole. • Isolation procedure was constructed to obtain esomeprazole sodium with high purity and yield. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cancer patients are polymedicated and are at risk of drug interactions. • Proton pump inhibitors decrease absorption of many TKIs and CDK 4/6 inhibitors. • They decrease the diversity in microbiome, decreasing efficacy of immunotherapies. • The Precautionary Principle is of interest until we have new contradictory data. • PPIs may be replaced in most cases by antacids or H2 blockers. Proton pump inhibitors (PPIs) are widely used in cancer patients despite accumulating data showing that they can impact the efficacy of major anticancer drugs. This is particularly important with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (CPIs). Most TKIs require gastric acidity for their absorption and some retrospective series demonstrated that coprescription decreases the survival benefit of some TKI use (erlotinib, gefitinib and pazopanib). Relations between microbiota, the immune system, and the efficacy of immunotherapy are now obvious, just as modifications to gut flora after PPIs use are well-known. Many retrospective articles, including articles based on individual-participant data from randomized studies, demonstrated that patients treated with CPIs have a poorer outcome (overall survival, progression-free survival and response rate) when they received PPIs concomitantly, while there was no impact of such coprescription among patients in control arms, not treated with immunotherapies. Similar data were also observed in patients treated with palbociclib. For these interactions, it is very important to use the precautionary principle and warn patients and physicians about this. In patients who require acid suppression because of severe symptoms, using antacids or H2 blockers could be recommended. [ABSTRACT FROM AUTHOR]

Antibiotics are modifiable risk factors for Clostridioides difficile infection (CDI), driving pathogenesis via gut microbiome disruption. The management of patients with CDI prescribed concomitant non-CDI antibiotics is problematic and influences CDI outcome and recurrence risk. Though an assessment of the ongoing requirement for concomitant antibiotics is essential, discontinuation is often not possible. Antibiotics for other reasons might also need to be commenced during CDI therapy. Attempts to minimise the number and duration of antibiotics with a change to a low-risk class are recommended. Fidaxomicin might be preferable to vancomycin due to it having less effect on the gut microbiome; however, vancomycin is also acceptable. Metronidazole should be avoided and proton pump inhibitors discontinued. Access to fidaxomicin might be limited; hence, it should be prioritised for patients at high risk of recurrence. There is insufficient evidence to support extending anti-CDI therapy duration and concerns regarding microbiome effect remain. The addition of bezlotoxumab might be considered if multiple additional risk factors for recurrent CDI exist, though the amount of evidence is low. Investigational approaches to reduce the effect of concomitant antibiotics on the gut microbiome could further optimise CDI treatment in the presence of concomitant antibiotic use in the future. [ABSTRACT FROM AUTHOR]

• Some patients may achieve suboptimal drug levels on the delayed release tablet of posaconazole. • Levels need to be obtained for all patients on posaconazole. • Diarrhea and the concomitant use of proton pump inhibitors are associated with subtherapeutic levels. • Obesity is not a factor associated with subtherapeutic levels in our settings. • Administration using a nasogastric tube can be a reasonable alternative in patients. Posaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. We retrospectively analyzed the factors associated with posaconazole levels <1.25 μg/ml in 164 patients receiving the DR tablet for therapeutic purposes. Of the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P -value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P -value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. This is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option. [ABSTRACT FROM AUTHOR]

As proton pump inhibitors (PPI) were shown to impact the effectiveness of immune checkpoint inhibitors (ICI) in lung and bladder cancers, we sought to evaluate the effect of PPIs on the outcomes patients with metastatic renal cell carcinoma (mRCC) treated with ICI. Introduction: Proton pump inhibitors (PPI) may influence the gut microbiome and thus impact the effectiveness of immune checkpoint inhibitors (ICI). The effect of PPIs on the outcomes of ICI has not been fully explored and investigated in metastatic renal cell carcinoma (mRCC). Methods: This retrospective analysis used prospectively collected data from the GETUG-AFU 26 NIVOREN (NCT03013335) phase II study which enrolled 729 mRCC patients of whom 720 were treated with nivolumab. The main objective of this analysis was to evaluate the impact of PPI on the efficacy and safety outcomes of mRCC patients. PPI use was defined as PPI administration on the day of ICI initiation. Results: Of the 707 patients with mRCC analyzed in this study, 196 (27.7%) were PPI users. The majority of PPI users were males (80.6%), had an ECOG performance status of 0-1 (78.9%) and a nephrectomy (82.1%). Almost two-thirds of the patients had a favorable and intermediate IMDC risk category and 52% received nivolumab in the third line and beyond. PPI use did not correlate with PFS or OS (HR = 0.89, 95% CI 0.74-1.08 and HR = 1.24; 95% CI, 0.98-1.58, respectively). Grade 3-5 nivolumab-related adverse events were more common among PPI users (25.5% vs. 15.3%). Conclusions: This real-world study suggests that PPI use in patients with mRCC does not impact the efficacy outcomes but may influence the safety of nivolumab which warrants further investigations. [ABSTRACT FROM AUTHOR]

Concerns regarding adverse events associated with the use of acid suppressants have increased. However, the impact of proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs) on the risk of atherosclerotic cardiovascular disease (ASCVD) remains unknown. This study aimed to estimate the risk of ASCVD in association with the use of PPIs and H2RAs. This prospective cohort study included participants without cardiovascular diseases or anti-hypertensive treatment at baseline (2006–2010) in the UK Biobank. The outcomes were ASCVD and each subtype (coronary artery disease, myocardial infarction, peripheral artery disease, and ischemic stroke). The association was estimated by Cox proportional-hazards models. Among 316,730 individuals (aged 50–88 years), during a median of 12.5 years of follow-up, we documented 13,503 (4.3%) incident ASCVD. Regular PPIs use was associated with a higher risk of ASCVD (HR: 1.16, 95% CI: 1.09–1.23) and every subtype of ASCVD. Among each type of PPIs, omeprazole (HR: 1.19, 95% CI: 1.11–1.28), lansoprazole (HR: 1.11, 95% CI: 1.02–1.22), and pantoprazole (HR: 1.40, 95% CI: 1.00–1.97) were associated with a higher risk of ASCVD. Stratification analysis showed that PPIs use was associated with a higher risk of ASCVD among individuals without indications of medications for PPIs. In addition, use of H2RAs was not related to the risk of ASCVD (HR: 0.97, 95% CI: 0.85–1.11). PPIs were associated with increased risk of ASCVD, particularly amongst participants without indications for medication. Our findings are of important practical significance and suggest that clinicians should be cautious in prophylactic use of PPIs. [Display omitted] • Evidence of association between proton pump inhibitors (PPIs) and atherosclerotic cardiovascular disease (ASCVD) is lacking. • PPI use was related to a higher risk of ASCVD. • Histamine‐2 receptor antagonists (H2RAs) use was not related to the risk of ASCVD. • Effect of different types of PPIs on the risk of ASCVD was various. • Higher ASCVD risks were observed among PPI users without indications for medication. [ABSTRACT FROM AUTHOR]

Drugs, in general, exhibit their pharmacological activity in binding with intracellular targets. Numerous anticancer and antibacterial drugs target DNA as one of their primary intracellular targets. Dexlansoprazole (DLP) is a heterocyclic compound containing benzimidazole moiety and a proton pump inhibitor used to treat gastroesophageal reflux disease. The interaction of dexlansoprazole with calf thymus DNA (ct-DNA) has been studied using biophysical methods. The UV–Visible studies revealed a binding constant of 2.15 ± 0.3 × 104 M−1 which is close to the value of 2.44 ± 0.3 × 104 M−1 obtained from the fluorescence studies. Competitive displacement studies using the fluorescence spectroscopic method with ethidium bromide and Hoechst as DNA markers suggested the groove binding mode of DLP in ct-DNA. The groove binding mode of DLP in ct-DNA was complemented by the results of viscosity and DNA melting studies. Further studies on the effect of ionic strength and potassium iodide on DLP binding with ct-DNA supported the observed binding mode. Circular dichroism studies reflected no significant conformational variation in ct-DNA after the interaction. The binding mode obtained from the experimental studies was corroborated by the molecular docking studies that showed the position of DLP in the minor groove of ct-DNA along with the receptor interface restudies involved in the interaction. [ABSTRACT FROM AUTHOR]

We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications. We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival. Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53–0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52–0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54–0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54–0.69). Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted. • Concomitant medications affect clinical outcomes from immune checkpoint inhibitors. • We previously validated a prognostic drug score in European patients with NSCLC. • We explored the prognostic ability of the drug score in Japanese patients with NSCLC. • The use of probiotics might mitigate the deleterious effect of antibiotics. • Racial differences should be considered when investigating this topic. [ABSTRACT FROM AUTHOR]

1. Understand the potential and impact of patient-centered interventions to facilitate deprescribing. 2. Apply the evidence from our implementation research hybrid-type I multisite randomized controlled trial to increase the uptake of deprescribing in their clinical and research settings. Inappropriate medication use and polypharmacy is a common issue among palliative care populations and older adults. Deprescribing (proactively stopping or de-escalating a medication) can offer a multitude of benefits. Here, we describe the significant impact of a patient-directed intervention for deprescribing proton pump inhibitors (PPIs), sulfonylureas/insulin, and high-dose gabapentin. Deprescribing (proactively stopping or de-escalating a medication) offers a multitude of benefits for older adults and palliative care populations.(1,2) Patient-focused deprescribing interventions have potential to facilitate deprescribing.(3) We conducted a multisite randomized controlled trial to examine the impact of a patient-centered deprescribing intervention. We hypothesized greater deprescribing for participants receiving an informational deprescribing brochure compared to control subjects. We targeted proton pump inhibitors (PPIs), sulfonylureas/insulin, and high-dose gabapentin. These medications are named in the OncPal deprescribing guideline and may offer limited benefits to older adults and palliative care populations.(4,5) We identified Veterans meeting eligibility criteria for one of the three medication-based groups at three VA Medical Centers with scheduled primary care appointments from 4/2021-10/2022 and mailed them the applicable brochure. Our control cohort consisted of Veterans who would have been eligible in each medication group and seen by study providers from 10/2019-4/2020. The primary outcome – deprescribing – was assessed 6 months post intervention. We calculated basic descriptive statistics to characterize study cohorts. We identified associations between our primary outcome of deprescribing and patient and provider characteristics using hierarchical generalized linear modeling to account for the nesting of patients within providers and providers within medical centers. The total sample comprised the intervention cohort (n=2539) and the control cohort (n=2532). Intervention subjects were significantly more likely to have deprescribing (OR 1.17; 95% CI 1.03-1.33; p=0.017) compared to controls. In hierarchical multivariable models, the intervention cohort was 1.21 times more likely to have deprescribing compared to controls (95%CI 1.05-1.38; p=0.008). Compared to the other groups gabapentin (OR 1.8, 95% CI 1.31-2.48) had greater odds of deprescribing. Patient-directed educational materials are an effective, low-tech intervention to promote deprescribing. Inappropriate medication use is a common and relevant issue among palliative care populations and older adults. Incorporating patient-engagement strategies can increase the clinical uptake of deprescribing. Pain and symptom control/Palliative care in chronic, non-malignant illness [ABSTRACT FROM AUTHOR]

Background: Anti-reflux mucosectomy (ARMS) is a choice for proton pump inhibitor (PPI)-dependent patients with gastroesophageal reflux disease (GERD). We present an extended anti-reflux mucosectomy, named ligation-assisted anti-reflux mucosectomy (L-ARMS). The aim of this study was to assess the feasibility of the procedure and short-term outcomes on PPI use and symptom resolution. Methods: Institutional review board approval was obtained for retrospective review of a prospectively collected database including patients who underwent L-ARMS. L-ARMS includes mucosa ligation and endoscopic mucosectomy without submucosal injection around the squamocolumnar junction. The GERD symptoms, endoscopy, 24-h pH monitoring results, and manometry were collected by chart review. Voluntary validated surveys assessed symptomatic improvement over time. Results: There were 69 patients available for review. The procedure was technically completed in all cases with no severe complications, and the average operation time was 33 min. At 6 months after L-ARMS, treatment with PPIs had been halted in 55.1% of the patients, 30.4% of the enrolled patients used PPIs occasionally, and the lower esophageal sphincter (LES) pressure, DeMeester scores, and GERD-health-related quality of life questionnaire (GERD-HRQL) scores showed a significant improvement compared with the baseline measurements (P < 0.001). Forty-five patients complained of mild dysphagia and were relieved in 4 weeks with no specific treatment. Compared to patients without dysphagia, patients complained of dysphagia after surgery had better clinical benefits indicated by GERD-HRQL and DeMeester score. Conclusions: As a modified ARMS, L-ARMS is an effective procedure for controlling GERD symptoms, esophageal acid exposure, and LES pressure, which can be safely performed endoscopically in a time-saving and simple manner. [ABSTRACT FROM AUTHOR]

Background/purpose: Clarithromycin-based standard triple therapy is still commonly adopted by 81.4% of physicians in real-world practice but yields low eradication rates. Therefore, we conducted this study to compare the efficacy of gastric juice-guided therapy for first-line eradication with the standard triple therapy, in order to provide an alternative to real-world practice.Methods: A total of 182 treatment-naïve Hp-infected patients were included and randomly allocated to either susceptibility-guided therapy (SGT) with gastric juice PCR or Clarithromycin-based standard triple therapy (STT) for 7 days.Results: The intention-to-treat eradication rates were 89% (81/91) in SGT and 75.8% in STT (p < 0.031). The per-protocol eradication rates were 91.0% (81/89) in SGT and 79.3% (69/87) in STT (p < 0.034). Among the subgroups of different antibiotic resistance, patients with SGT demonstrated superior eradication rates (91.7% vs 45.5%, p < 0.027) in the subgroup of both clarithromycin resistance and levofloxacin resistance.Conclusion: This prospective randomized controlled trial demonstrated the reliable efficacy of susceptibility-guided therapy via gastric juice PCR for the first-line Hp eradication. In Asia-Pacific area, where standard triple therapy is still adopted by the majority of the physicians, it is a recommended alternative to overcome the increasing antibiotic resistance. [ABSTRACT FROM AUTHOR]

Long-term, high-dose, daily proton pump inhibitors (PPI) may impact outcomes associated with distal radius fractures (DRF). The hypothesis was that differences existed in patient demographics, but there existed no differences in injury patterns, interventions, post-operative complications, and patient-reported outcomes between patients not on a PPI and patients on a PPI with a DRF. An IRB-approved, post-hoc analysis of patients with DRF from 2012 through 2018 was performed. Patients included were age ≥18 years, sustained a DRF, had completed medical and medication records, Quick Disabilities of the Arm, Shoulder and Hand (DASH) scores, Global Assessment of Functioning (GAF) scores, visual analogue scale (VAS) pain scores, and a minimum of 1-year follow-up. Patients were stratified into two cohorts. Cohort one patients had no prescription or over-the-counter PPI use (no PPI cohort). Cohort two patients had adherence to a long-term, high-dose, daily PPI (PPI cohort). Two hundred and eighty-one DRF patients were included. Of these 281 patients, 240 were in the no PPI cohort and 41 were in the PPI cohort. Patients in the PPI cohort had more median nerve injuries (12% versus 3%, p = 0.025) and radial shaft fractures (5% versus 0%, p = 0.020), less contralateral upper extremity injuries (0% versus 4%, p = 0.001), and more post-operative nonunions (7% versus 1%, p = 0.029) compared to patients in the no PPI cohort. Long-term, high-dose, daily PPI's may be associated with more median nerve injuries and radial shaft fractures, less contralateral upper extremity injuries, and more post-operative nonunions compared to DRF patients not on a PPI. [ABSTRACT FROM AUTHOR]