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IScience May 2024Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive...
Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type () mice following whole-brain irradiation. knockout () alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing primary neurons with the conditioned media derived from irradiated or primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.
PubMed: 38655198
DOI: 10.1016/j.isci.2024.109698 -
Frontiers in Pediatrics 2024Gastrointestinal bleeding (GI) is a prevalent condition among pediatric patients, with a reported incidence of 6.4%, often severe enough to require admission to the...
INTRODUCTION
Gastrointestinal bleeding (GI) is a prevalent condition among pediatric patients, with a reported incidence of 6.4%, often severe enough to require admission to the pediatric intensive care unit (PICU). There are multiple therapies utilized in the management of GI bleeding in pediatrics, among which continuous intravenous (IV) infusion of omeprazole is used off-label without standard pediatric dosing recommendations. Reviewing the current literature reveals a lack of studies assessing the efficacy, safety, and appropriate dosing regimen of continuous omeprazole infusion in children with GI bleeding. This study aimed to evaluate the efficacy and safety of continuous IV omeprazole infusion in comparison to other therapeutic modalities in children.
METHODS
This study is a single-center, retrospective chart review of children admitted to the PICU at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. The treatment group included pediatric patients with GI bleeding and receiving omeprazole IV continuous infusion over ≥24 h while the control group included pediatric patients with GI bleeding managed using other therapies. Primary outcomes were the efficacy of omeprazole continuous infusion in stopping GI bleeding, and PICU length of stay (LOS). Secondary outcomes included instances of rebleeding post- therapy discontinuation, transfusion requirements, and the safety of omeprazole continuous infusion.
RESULTS
The study included 81 critically ill pediatric patients, 22 of whom received continuous infusion omeprazole while 59 received other therapies. The results indicated that patients in the control group had a significantly shorter PICU LOS (8 vs. 18.5 days, < 0.001) and bleeding episode (4 vs. 10.5 days, < 0.001) than those in the treatment group. However, no significant differences were observed between the two groups regarding secondary outcomes. The treatment group had a significantly lower all-cause mortality rate during hospitalization compared to the control group (16 patients [72.7%] vs. 56 patients [94.9%], respectively, = 0.005).
CONCLUSION
Empirical use of omeprazole continuous intravenous infusion in children with GI bleeding was not favorable in terms of shortening PICU LOS and duration of GI bleeding. Our study results provide evidence supporting the safety and tolerability of omeprazole continuous infusion. Additional larger studies are necessary to determine the implication of such results.
PubMed: 38650990
DOI: 10.3389/fped.2024.1270911 -
Frontiers in Allergy 2024Eosinophilic esophagitis is a newly recognized entity, in which there is significant evidence available that clearly demonstrates the positive impact of PPIs on reducing...
INTRODUCTION
Eosinophilic esophagitis is a newly recognized entity, in which there is significant evidence available that clearly demonstrates the positive impact of PPIs on reducing esophageal eosinophilia in individuals across different age groups, including children, adolescents, and adults. Multiple mechanisms have been proposed to explain how this treatment effect occurs. In Brazil, there seems to be a lack of studies that have prospectively assessed the clinical and therapeutic response rate in pediatric patients with EoE. The objective of this study was to prospectively evaluate the clinical and therapeutic response of pediatric patients with EoE in a medical center located in southern Brazil, by investigating the effectiveness of PPI treatment.
METHODS
This study is a clinical, prospective, open trial that took place in a pediatric hospital located in southern Brazil. The focus of the study was on patients diagnosed with Eosinophilic Esophagitis (EoE) who were given treatment using omeprazole/esomeprazole at a dosage of 1 mg.kg per dose, twice daily, for a period of 8-12 weeks. Following the treatment period, the patients underwent another endoscopy. Patients who exhibited 15 or less eosinophils in the biopsy conducted after the treatment were considered as responders.
RESULTS
A total of 27 patients was evaluated (74.1% boys). The average age (± standard deviation) was 8 years (±4). Nineteen patients (70.3%) were considered as responders to PPI treatment: 6 patients-22.2%-exhibited a complete response (defined as having 5 or fewer eosinophil per high power field. Additionally, 13 patients-48.1%-demonstrated a partial response, characterized by eosinophil counts exceeding 5 but less than 15 eos/hpf. When comparing the responder and non-responder groups at presentation, a statistical difference was observed in the prevalence of food refusal as a presenting symptom. Food refusal was found to be more prevalent in the non-responder group (87.5% vs. 26.3%, = 0.008). No differences were observed in terms of atopy history and endoscopic scores. Upon comparing the histological findings from the post-treatment endoscopy of the two groups, it was observed that PPI responders exhibited a greater tendency to decrease basal cell hyperplasia ( = 0.06) and intercellular edema ( = 0.08).
CONCLUSION
In this group of pediatric patients with EoE in Southern Brazil most patients showed a high prevalence of histological, endoscopic, and clinical response to PPI treatment. PPIs showed efficacy in Brazilian patients with EoE, most of whom would probably not be able to adequately undergo other treatments.
CLINICAL TRIAL REGISTRATION
https://ensaiosclinicos.gov.br/rg/RBR-2ntbth9, identifier (U1111-1301-1842).
PubMed: 38650863
DOI: 10.3389/falgy.2024.1346843 -
Heliyon Apr 2024The use of proton pump inhibitors in the acute phase of cerebral infarction may lead to adverse long-term outcomes, this study aims to explore the potential of...
BACKGROUND
The use of proton pump inhibitors in the acute phase of cerebral infarction may lead to adverse long-term outcomes, this study aims to explore the potential of electroacupuncture (EA) in replacing omeprazole in exerting post-stroke gastrointestinal protection.
METHODS
A permanent middle cerebral artery infarction model was established using the modified Longa thread occlusion technique. Gastrointestinal motility, gastrointestinal mucosal damage, cerebral infarct volume, and alterations in choline acetyltransferase (ChAT)-positive neurons within the dorsal motor nucleus of the vagus nerve (DMV) were assessed after 7 days of EA at Zusanli (ST36) or omeprazole intervention. To evaluate the role of the vagal nerve in mitigating post-stroke gastrointestinal dysfunction, we employed subdiaphragmatic vagotomy and the ChAT-specific inhibitor α-NETA. Additionally, we utilized methyllycaconitine (MLA), a selective inhibitor of the α7-type nicotinic acetylcholine receptor (α7nAChR), and PNU282987, an agonist, to identify the target of EA.
RESULTS
EA restored ChAT neurons lost in the DMV, activated the vagus nerve and conferred cerebroprotection while ameliorating gastrointestinal mucosal injury and gastrointestinal motility disorders. In addition, following the administration of the α7nAChR antagonist, the attenuation of gastric mucosal injury and inflammatory factors induced by EA was hindered, although gastrointestinal motility still exhibited improvement.
CONCLUSION
EA at ST36 promotes the restoration of cholinergic signaling in the DMV of stroke-afflicted rats, and its excitation of the vagal nerve inhibits gastrointestinal inflammation after stroke via α7nAChR, while improvement in gastrointestinal motility could be mediated by other acetylcholine receptors.
PubMed: 38638995
DOI: 10.1016/j.heliyon.2024.e29426 -
Frontiers in Pharmacology 2024Tacrolimus is metabolized in the liver with the participation of the CYP3A4 and CYP3A5 enzymes. Proton pump inhibitors are used in kidney transplant patients to prevent...
Tacrolimus is metabolized in the liver with the participation of the CYP3A4 and CYP3A5 enzymes. Proton pump inhibitors are used in kidney transplant patients to prevent duodenal and gastric ulcer disease due to glucocorticoids. Omeprazole, unlike famotidine, is a substrate and inhibitor of the enzymes CYP2C19, CYP3A4, CYP3A5. The aim of this study was to compare the impact of omeprazole and famotidine on the pharmacokinetics of tacrolimus. A randomized, non-blinded study involving 22 stabilized adult kidney transplant patients was conducted. Patients received the standard triple immunosuppression regimen and omeprazole 20 mg (n = 10) or famotidine 20 mg (n = 12). The study material consisted of blood samples in which tacrolimus concentrations were determined using the Chemiluminescent Microparticle Immuno Assay method. A single administration of omeprazole increased tacrolimus concentrations at 2 h (day 2) = 11.90 ± 1.59 ng/mL vs. 2 h (day 1 - no omeprazole administration) = 9.40 ± 0.79 ng/mL ( = 0.0443). AUC amounted to 63.07 ± 19.46 ng × h/mL (day 2) vs. 54.23 ± 10.48 ng × h/mL (day 1), ( = 0.0295). AUC amounted to 44.32 ± 11.51 ng × h/mL (day 2) vs. 38.68 ± 7.70 ng × h/mL (day 1), ( = 0.0130). Conversely, no significant changes in values of pharmacokinetic parameters were observed for famotidine. Omeprazole significantly increases blood exposure of tacrolimus. The administration of famotidine instead of omeprazole seems safer for patients following kidney transplantation. clinicaltrials.gov, identifier NCT05061303.
PubMed: 38638867
DOI: 10.3389/fphar.2024.1352323 -
Cureus Mar 2024One of the common inflammatory disorders that substantially affects the stomach and its mucosa is gastritis. It can be induced by non-steroidal anti-inflammatory drugs...
One of the common inflammatory disorders that substantially affects the stomach and its mucosa is gastritis. It can be induced by non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, alcohol, infection, and stress. These factors affect cellular regeneration, mucus production, and bicarbonate secretion, resulting finally in inflammation and ulceration. Ethanol-induced gastritis is one of the commonly used models for studying the pathology of gastritis and investigating the effect of drugs in managing the disease. Several drugs, such as proton pump inhibitors (PPIs), are available to control and correct the pathological signs of gastritis; however, the side effects of such drugs represent an obstacle to their applications in many cases. (QI) Olivier galls are formed as a pathological response to wasp insults to the tree. They are rich in several bioactive molecules, e.g., gallotannins that have been shown to be effective in several inflammatory conditions due to their antioxidant and anti-inflammatory potentials. In this study, we aimed to evaluate the therapeutic potential of QI gall extract (QIGE) in treating ethanol-induced gastritis in rats. To test this, 20 adult male Swiss rats were divided into four groups: healthy control, ethanol-treated (80% in water, 5 ml/kg, per oral gavage), ethanol + omeprazole (20 mg/kg, per oral gavage), and ethanol + QIGE (300 mg/kg, per oral gavage). QIGE was administered for seven days before ethanol administration, which took place three hours after the last QIGE dose. Three hours after ethanol intake, animals were euthanized, gastric content was collected, and stomach tissue was examined for macroscopic changes and then fixed to be further utilized for histological assessment by hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and Masson's trichrome staining. Ethanol treatment significantly decreased gastric pH and increased gastric acidity compared to healthy control. It also induced clear morphological and histological damage and ulceration, depleted mucus on the gastric epithelium, and induced edema and collagen deposition in gastric submucosa. The QIGE treatment ameliorated the changes in gastric pH and total acidity. It also protected stomach tissue from ethanol-induced ulceration, histopathological changes, edema, and collagen deposition. The protective effects of QIGE were comparable to those of omeprazole. In conclusion, QI gall extract possesses a promising gastroprotective effect against ethanol-induced gastritis.
PubMed: 38638752
DOI: 10.7759/cureus.56459 -
BMC Medicine Apr 2024The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug-drug interaction (DDI)...
BACKGROUND
The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug-drug interaction (DDI) phenomenon with a large-scale longitudinal analysis of age and gender differences found in drug administration data from three distinct healthcare systems.
METHODS
This study analyzes drug administrations from population-wide electronic health records in Blumenau (Brazil; 133 K individuals), Catalonia (Spain; 5.5 M individuals), and Indianapolis (USA; 264 K individuals). The stratified prevalences of DDI for multiple severity levels per patient gender and age at the time of administration are computed, and null models are used to estimate the expected impact of polypharmacy on DDI prevalence. Finally, to study actionable strategies to reduce DDI prevalence, alternative polypharmacy regimens using drugs with fewer known interactions are simulated.
RESULTS
A large prevalence of co-administration of drugs known to interact is found in all populations, affecting 12.51%, 12.12%, and 10.06% of individuals in Blumenau, Indianapolis, and Catalonia, respectively. Despite very different healthcare systems and drug availability, the increasing prevalence of DDI as patients age is very similar across all three populations and is not explained solely by higher co-administration rates in the elderly. In general, the prevalence of DDI is significantly higher in women - with the exception of men over 50 years old in Indianapolis. Finally, we show that using proton pump inhibitor alternatives to omeprazole (the drug involved in more co-administrations in Catalonia and Blumenau), the proportion of patients that are administered known DDI can be reduced by up to 21% in both Blumenau and Catalonia and 2% in Indianapolis.
CONCLUSIONS
DDI administration has a high incidence in society, regardless of geographic, population, and healthcare management differences. Although DDI prevalence increases with age, our analysis points to a complex phenomenon that is much more prevalent than expected, suggesting comorbidities as key drivers of the increase. Furthermore, the gender differences observed in most age groups across populations are concerning in regard to gender equity in healthcare. Finally, our study exemplifies how electronic health records' analysis can lead to actionable interventions that significantly reduce the administration of known DDI and its associated human and economic costs.
Topics: Male; Humans; Female; Aged; Middle Aged; Pharmaceutical Preparations; Prevalence; Drug Interactions; Polypharmacy; Comorbidity
PubMed: 38637816
DOI: 10.1186/s12916-024-03384-1 -
International Journal of Molecular... Mar 2024Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50%...
Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 (), , , and genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, = 0.003). rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, = 0.027). EREFS reduction in rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. -75.0% = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, = 0.030). rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants.
Topics: Humans; Eosinophilic Esophagitis; Proton Pump Inhibitors; STAT6 Transcription Factor; Comorbidity; Enteritis; Eosinophilia; Gastritis
PubMed: 38612496
DOI: 10.3390/ijms25073685 -
Journal of Clinical Medicine Mar 2024Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently,... (Review)
Review
Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.
PubMed: 38610738
DOI: 10.3390/jcm13071970 -
Cureus Mar 2024As the global incidence of idiopathic pulmonary fibrosis (IPF) is on the rise, there is a need for better diagnostic criteria, better treatment options, early and... (Review)
Review
As the global incidence of idiopathic pulmonary fibrosis (IPF) is on the rise, there is a need for better diagnostic criteria, better treatment options, early and appropriate diagnosis, adequate care, and a multidisciplinary approach to the management of patients. This systematic review explores the role of proton pump inhibitors (PPIs) in IPF and answers the question, "Does proton pump inhibitor improve only the prognosis of gastroesophageal associated idiopathic pulmonary fibrosis or for other types of idiopathic pulmonary fibrosis too?" We used PubMed (PMC) and Google Scholar for data collection for this systematic review and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting this review. After in-depth literature screening and quality appraisal, 12 articles were selected for this systematic review. On the one hand, the efficacy of PPI therapy is supported by research such as the CAPACITY and ASCEND trials, a pilot randomized control trial (RCT) investigating the role of omeprazole in IPF and a bidirectional two-sample Mendelian randomization (MR) study, respectively. On the other hand, a systematic review and meta-analysis on antacid and antireflux surgery in IPF negate these results and show no statistical significance. Questions regarding the efficacy of PPI therapy must be dealt with in an adequately powered multicenter and double-blinded randomized control trial. The anti-inflammatory properties of antacids can serve as the cornerstone for future trials. In the following systematic review, antacid, antireflux therapy, omeprazole, and proton pump therapy are synonymous with stomach acid suppression therapy.
PubMed: 38606271
DOI: 10.7759/cureus.55980