Search Results (182)

Objectives: This study aims to identify the reactive metabolite of acetaminophen (AAP) and the cyanopyrrolidine metabolite of saxagliptin in human induced pluripotent stem cell-derived hepatic organoids (HHOs) and to compare them with human liver microsomes (HLMs) and plateable cryopreserved human hepatocytes (CHHs) to evaluate the feasibility of HHOs for reactive metabolite screening and metabolite profiling. Methods: AAP (50 μM) or sax-agliptin (50 μM) was incubated for 1 h at 37 °C in HLMs with or without NADPH-generating solution and 0.5 mM reduced glutathione (GSH). AAP (50 μM) was incubated for 24 h in HHOs and CHHs at 37 °C in a CO₂ incubator. AAP and saxagliptin metabolites in the reaction mixtures were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Results: N-acetyl-p-benzoquinone imine (NAPQI) was identified in the incubation mixture of HLMs with AAP, and its levels were reduced in the presence of GSH, accompanied by increased formation of AAP–GSH adduct. Incubation of AAP with HHOs for 24 h resulted in the formation of NAPQI, AAP–GSH, AAP–glucuronide, and AAP–sulfate. Moreover, CYP1A2 induction using omeprazole treatment increased the formation of AAP and AAP–GSH conjugate from phenacetin, reflecting enhanced CYP1A2 activity in both CHHs and HHOs. The findings indicate that HHOs are a suitable platform for reactive metabolites, such as NAPQI and AAP–GSH adducts, under chronic exposure and metabolic modulator intervention. Additionally, CHHs and HHOs exhibited similar saxagliptin metabolite profiles after incubation with saxagliptin and generated cysteine conjugates of saxagliptin and its hydroxylated metabolite. Conclusions: HHOs system can be used as an in vitro model for screening reactive metabolites, comparable to those obtained with CHHs. Full article

Introduction: High-output stoma (HOS) is a frequent and morbid complication following ileostomy formation. Proton pump inhibitors (PPIs) may reduce intestinal secretions, but no randomized trial has yet tested whether intensified intravenous omeprazole treatment prevents or mitigates early postoperative HOS. We aim to determine whether intensified PPI dosing reduces early postoperative ileostomy output compared with standard dosing. Methods and Analysis: STOP-HOS-1 is a randomized, parallel-group, open-label, superiority trial conducted at two academic centers in Poland. The target sample size is 100 adults undergoing the formation of a loop or end ileostomy. Participants will be randomized 1:1 to receive either: intensified omeprazole group—80 mg IV loading dose, followed by 40 mg IV twice daily through postoperative day (POD) 10, or standard omeprazole group—40 mg IV once daily through POD 10. The primary outcome is mean ileostomy output (mL/24 h) across POD 1–3. A ≥250 mL/day reduction is prespecified as clinically meaningful. Key secondary outcomes include: incidence of HOS (≥1000 mL/day for ≥3 consecutive days or ≥1400 mL on any single day), time to output stabilization (<1400 mL/day for 3 consecutive days), dehydration-related complications (hyponatremia, hypokalemia, acute kidney injury), length of hospital stay and 30-day readmission rate. The primary analysis will follow the intention-to-treat principle. One interim safety analysis is planned after enrollment of the first 20 patients. Discussion: Although PPIs are commonly used to reduce ileostomy output, high-quality evidence in the early postoperative setting is lacking. STOP-HOS-1 targets the critical period when output is most variable, and complications are most frequent, using a pragmatic randomized design and an objective, clinically meaningful primary endpoint. Conclusions: STOP-HOS-1 will provide the first randomized evidence on whether intensified postoperative PPI therapy reduces early ileostomy output and HOS-related morbidity, informing future standards of care. Full article

This study describes the clinicopathological features of seven canine cases showing a diffuse cobblestone-like gastric mucosal pattern on endoscopy. Cases were retrospectively retrieved from endoscopic databases (2017–2025). Clinical data, treatment history, endoscopic findings, and histology were reviewed. Endoscopically, all dogs exhibited thickened, irregular, and poorly distensible gastric folds. Histopathologic examination showed mild-to-moderate foveolar hyperplasia, variable cystic dilation of the fundic glands, mild chronic lymphoplasmacytic inflammation, and interstitial fibrosis. Parietal-cell population was variably increased and predominant (hyperplasia). Because these features can overlap widely among reactive and hyperplastic gastropathies, interpretation required correlation with clinical and endoscopic findings in addition to histopathology. All dogs had a history of prolonged omeprazole administration, and most showed clinical improvement after dose reduction or treatment withdrawal. Follow-up endoscopy in two dogs documented divergent outcomes, with marked improvement in one dog and only minimal changes in the other. These findings suggest that this cobblestone-like pattern represents a benign, reactive, and potentially regressive gastropathy, possibly associated with chronic acid suppression. Recognition of this appearance may assist clinicians in differentiating reactive gastropathy from proliferative or neoplastic conditions and supports prudent use of long-term proton pump inhibitors in dogs with chronic gastrointestinal disease. Full article

The overprescription of gastroprotectants, in particular acid suppressants in dogs, is of increasing concern in veterinary medicine. There have been specific guidelines published to document the appropriate use of this class of drugs; however, the injudicious use of gastroprotectants continues to be a concern and is often not evidence-based. The primary objective of the present study was to evaluate the veterinary prescription of gastroprotectants for dogs in Spain. A survey employing a snowball recruitment effect was distributed among small animal medicine veterinarians practicing in Spain. A total of 265 veterinarians participated in the survey. Proton pump inhibitors (PPIs) were found to be the most commonly prescribed gastroprotectant utilised by 50.6% of the participants. Veterinarians with fewer years of clinical experience and those focusing on the fields of internal medicine, emergency, and anaesthesia were more likely to adhere to evidence-based guidelines in their prescribing practices. Those who prescribed gastroprotectants less frequently tended to rely on PPIs and on international consensus guidelines. Although the main indications in which Spanish veterinarians used gastroprotectants was supported by scientific evidence, the injudicious administration of this class of drugs for disorders lacking robust scientific evidence or recommendations was well documented. Full article

Background: The gut microbiome might be affected by proton-pump inhibitors (PPIs), increasing the risk of Clostridioides difficile infection (CDI); however, the association between PPIs and Clostridioides difficile infection (CDI) remains controversial. Aim: The aim of this study is to reevaluate the association between PPIs and CDI based on pharmacovigilance data, taking competition bias into account. Methods: PPI-related CDI adverse event reports, based on the Food and Drug Administration adverse event reporting system database from 2004 to 2023, were analyzed. Included PPI cases were stratified into CDI and non-CDI groups. Disproportionality analysis was performed using the reporting odds ratio (ROR) and information component (IC). The effect of competition bias on signal detection was quantitatively investigated. Age-stratified analyses were conducted to assess residual confounding. Results: A total of 238,470 PPI reports were included, with 1268 cases in the CDI group and 237,202 cases in the non-CDI group. Initial analysis revealed a significant PPI-CDI association (ROR = 2.36, 95% confidence interval (95%CI) 2.19 to 2.53; IC = 1.21, 95%CI 0.97 to 1.45), with CDI signals detected for five PPI agents, including pantoprazole, omeprazole, lansoprazole, rabeprazole, and dexlansoprazole. After excluding competition from antibacterial drugs, CDI signal strength decreased substantially (ROR = 1.47, 95%CI 1.34 to 1.62; IC = 0.55, 95%CI 0.23 to 0.87), retaining a significant CDI signal only for rabeprazole and pantoprazole. Upon further exclusion of antibacterial or immunosuppressive drug users and renal injury event cases, CDI signal strength decreased (ROR = 1.48, 95%CI 1.32 to 1.66; IC = 0.56, 95%CI 0.18 to 0.94), with pantoprazole as the sole CDI signal drug. Age-stratified analyses demonstrated complete signal loss after antibacterial drug adjustment across all age groups. Conclusions: The current large-scale pharmacovigilance study indicated that the observed PPI-CDI association may be mediated predominantly by antibacterial drug co-exposure rather than PPI direct causation. Full article

Background: Recent studies have associated the presence of the CYP2C:TG haplotype with increased metabolism of CYP2C19 substrates such as escitalopram and sertraline, suggesting a potential regulatory interaction between CYP2C18 and CYP2C19. However, this association has not been demonstrated for other CYP2C19 substrates. Objective: This study aims to elucidate the role of the CYP2C:TG haplotype in modulating CYP2C19 activity using the omeprazole metabolic ratio (MR) within a cocktail drug approach, to characterize its distribution and prevalence among Native Mexican populations, and to evaluate its potential impact on CYP2C19 metabolic phenotypes. Materials and Methods: A total of 256 volunteers from various ethnic native groups from Mexico were genotyped for CYP2C19 (*2, *3, *4, *5, *17) and the CYP2C haplotype (rs2860840 and rs11188059). The MR of omeprazole to 5-hydroxyomeprazole was analyzed to determine individual CYP2C19 metabolic phenotypes and assess metabolic capacity. Results: The CYP2C:TG haplotype was the most prevalent (42.77%), followed by CYP2C:CG (35.74%) and CYP2C:TA (21.48%). The CYP2C:TG haplotype was consistently associated with the CYP2C19*1 allele. Significant differences in logMR values were observed between individuals with and without the TG haplotype (p = 0.02). A trend toward increased metabolic activity associated with CYP2C:TG was observed across most CYP2C19 metabolizer groups, except for rapid metabolizers. No significant association was found between molecular ancestry and the presence or functionality of the haplotype. Conclusions: The CYP2C:TG haplotype appears to be associated with increased CYP2C19 activity, warranting further functional validation before clinical implementation. Full article

Background/Objectives: Cirrhosis significantly alters physiological function and drug metabolism, particularly for medications primarily metabolized by CYP2C19 and CYP3A4. This study aims to establish a physiologically based pharmacokinetic (PBPK) modelling framework capable of predicting pharmacokinetic changes across different stages of cirrhosis, and to determine optimal dosing regimens that achieve drug exposure levels comparable to those in healthy individuals. Methods: We constructed a physiologically based pharmacokinetic (PBPK) model that incorporates six drugs, including omeprazole, lansoprazole, midazolam, ondansetron, verapamil, and alfentanil, which are metabolized primarily by CYP2C19 or CYP3A4. The pharmacokinetics of these drugs following oral or injectable administration were simulated in 1000 virtual healthy subjects, and the PBPK model was validated using clinical data. The model was further adapted to account for physiological changes in cirrhotic patients, extending its application to a population of 1000 virtual patients with liver cirrhosis. Results: Most observed data fell within the 5th and 95th percentiles of the virtual patient simulation results. Additionally, for most simulations, the area under the concentration-time curve (AUC) and peak concentration (C_max) were within 0.5- to 2-fold of the observed values. Sensitivity analysis indicated that the reduced expression of metabolizing enzymes increased plasma concentrations of drugs, which was a major factor contributing to the elevated drug exposure in patients with cirrhosis. The clinical dosing regimens of the CYP2C19 substrate omeprazole and the CYP3A4 substrate ondansetron were optimized for use in cirrhotic patients. Conclusions: The developed PBPK model successfully predicted the pharmacokinetics of CYP2C19 and CYP3A4 substrates in both healthy individuals and cirrhotic patients and can be effectively used for dose optimization in cirrhotic populations. Full article

This study aimed to synthesize zinc oxide nanoparticles (ZnO-NPs) via a green sustainable approach using Raphanus sativus (L.) root extract and evaluate their gastroprotective effect against ethanol-induced gastric injury in rats. ZnO-NPs were characterized through UV–Vis spectroscopy, FT-IR, TEM, zeta potential analysis, and XRD. LC- MS-coupled metabolic profiling was employed to identify different phytochemical compounds in the plant. Oxidative stress biomarkers (GSSG, GPX, and CAT), gastric secretions (gastrin and histamine), inflammatory cytokines (TNF-α and NF-κB), and molecular markers (MMP-10 and pERK1/2) were evaluated. Treatment with ZnO-NPs and plant extract restored antioxidant enzyme activity in a dose-dependent manner and decreased oxidative and inflammatory markers. Histopathological and histochemical analyses confirmed the protection of the gastric mucosa. The ZnO-NPs at (200 mg/kg), showed superior efficacy over the extract and, in some cases, displayed equivalent or enhanced effects relative to the reference drug omeprazole. In silico findings support the gastroprotective potential of the plant by demonstrating strong binding associations for major phytochemicals. This paper highlights that green-synthesized ZnO-NPs exhibit a significant gastroprotective effect through the modulation of oxidative stress and inflammatory pathways, indicating their promise as a safe and effective alternative treatment for gastric ulcers. Full article

Inorganic nitrite contributes to the nitrosation of biomolecules and exerts antioxidant effects. The proton pump inhibitor omeprazole has pro-oxidant effects, inhibits the formation of nitroso species in the stomach, and abrogates the blood pressure-lowering effects of orally administered nitrite. Here, we examine whether a two-week treatment with nitrite leads to tissue nitrosation that scales with local thiol concentrations and whether oral nitrite treatment can prevent the pro-oxidant effects of omeprazole. Male Sprague–Dawley rats received daily doses of omeprazole 10 mg/kg i.p. (or vehicle) and sodium nitrite 15 mg/kg by gavage (or water) for 14 days. Animals were euthanized 6 h after the last nitrite dose, and blood and tissues (brain, heart, and liver) were collected for biochemical analyses. We found that nitrite treatment increased liver nitrite and total nitroso species (RxNO) concentrations approximately eight-fold (with minor increases in other organs), and omeprazole treatment attenuated these effects. Nitrite treatment selectively elevated non-protein thiol concentrations in the liver, but not in animals also receiving omeprazole. Tissue thiol elevation was associated with increased nitrosation of hepatic proteins, which was prevented by omeprazole. Nitrite upregulated mRNA expression of microsomal glutathione S-transferase-1 (Mgst1) and decreased superoxide and hydrogen peroxide production, especially in rats co-treated with omeprazole. While omeprazole increased liver xanthine oxidoreductase (XOR), nitrite treatment attenuated this effect. These results demonstrate that oral nitrite treatment robustly elevates nitrite and RxNO concentrations in the liver, and these effects are associated with increased hepatic glutathione production and an upregulation of Mgst1 expression, counteracting the pro-oxidant effects induced by omeprazole. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with a severe stromal reaction mediated by pancreatic stellate cells (PSCs), leading to increased resistance to chemotherapy and radiotherapy. Following a repurposing concept, this preclinical study investigates the potential of approved drugs, known to be modulators of cellular copper transport, in combination with cisplatin for therapeutic approaches in PDAC. Two major strategies were pursued: (i) inhibiting copper transporters ATP7A and B with tranilast (TR) and omeprazole (OM) to block the cellular copper and, potentially, also cisplatin efflux, and (ii) using the chelator elesclomol (ES) to elevate intracellular copper and cisplatin levels. Human cell lines PanC-1 (PDAC), HPaSteC (PSC), and their co-culture, as well as the hepatocellular carcinoma cell line HepG2 as a reference model, were used. In addition to an analysis of the expression of copper transport proteins, the dynamics of cellular copper uptake and transport were monitored using a [⁶⁴Cu]CuCl₂ radiotracer approach. In vitro, all drugs enhanced cellular copper uptake and/or reduced copper efflux. Moreover, all drugs contributed to the enhanced cellular anticancer activity of cisplatin, with ES being the most effective compound. The results suggest that the targeted modulation of copper transport mechanisms may offer novel adjuvant approaches for the treatment of PDAC. Full article

Identifying reliable negative control compounds is essential for determining the sensitivity and specificity of screening assays. However, well-characterized negative controls for developmental neurotoxicity behavioral assays in larval zebrafish (Danio rerio) are lacking. This study evaluated nine chemicals with no reported evidence of mammalian developmental neurotoxicity, and a positive control (fluoxetine) for developmental and neurodevelopmental (i.e., behavioral) toxicity in zebrafish. Embryos were exposed to each chemical (≤100 µM) during development, 0–5 days post-fertilization (dpf), then assessed as larvae (6 dpf) using a locomotor behavior light–dark transition test. Behavior was analyzed using two methods: (1) the traditional method, comparing the average total distance moved, and (2) a 13-endpoint approach analyzing 13 aspects of the locomotor profile. Results showed that ibuprofen, omeprazole, and fluoxetine induced developmental toxicity (teratogenesis), with fluoxetine also causing behavioral neurotoxicity. Behavioral effects of developmental exposure to selegiline hydrochloride depended on the analysis method. Exposure to the other six chemicals (D-mannitol, glycerol, L-ascorbic acid, metformin hydrochloride, saccharin, and sodium benzoate), as well as ibuprofen or omeprazole, did not produce behavioral effects using either analysis method. Identifying negative control chemicals is essential for evaluating behavioral alterations precipitated by unknown substances and will assist with screening new chemicals for neurodevelopmental toxicity. Full article

Gastric ulcer (GU) is a common gastrointestinal disorder that impacts quality of life. Currently, several drugs are available for GU treatment, including proton pump inhibitors like omeprazole (OMP); however, their use is limited by numerous potential adverse effects. Glycyrrhizic acid (GLY), a natural anti-inflammatory agent, exhibits promising gastroprotective properties; however, its use is likewise limited by numerous potential adverse effects. This study aimed to synthesize GLY nanoparticles (GLY-NPs) to enhance their therapeutic potential and to comparatively evaluate their efficacy against OMP in an ethanol-induced GU in male Wistar rats. GLY-NPs were synthesized via a hydrothermal method and characterized using TEM, XRD, FTIR, and zeta potential analyses. In vivo, GLY-NPs significantly attenuated gastric mucosal damage compared to OMP, as evidenced by macroscopic and histopathological analyses. Biochemical assays revealed that GLY-NPs markedly improved antioxidant defenses by elevating SOD, catalase, and glutathione peroxidase activities while reducing MDA levels, surpassing the effects of OMP. Furthermore, GLY-NPs modulated inflammatory responses by downregulating p38 MAPK, NF-κB, and TNF-α expression, concomitant with upregulation of the anti-inflammatory cytokine IL-10. Mechanistic insights indicated that GLY-NPs favorably regulated key signaling pathways implicated in gastric mucosal protection, including suppression of the JAK2/STAT3 and TGF-β1/Smad3 pathways, alongside activation of the SIRT1/FOXO1/PGC-1α axis. In conclusion, these findings indicate that GLY-NPs offer higher gastroprotective effects relative to traditional OMP therapy through comprehensive modulation of oxidative stress, inflammation, and molecular signaling pathways. This study highlights GLY-NPs as a potent nanotherapeutic candidate for the effective management of GU. Full article

Impactions of the jejunum are rarely described in the literature. The current case series describes six cases of adult horses with jejunal impactions with feed material diagnosed by exploratory celiotomy. Horses underwent exploratory celiotomy based off of their degree of pain despite medical management and concerns for a primary strangulating small intestinal lesion. All jejunal impactions were relieved via manual decompression of the impaction into the cecum. None of the cases underwent a resection or anastomosis at the site of impaction. All horses were treated with gastroprotectants (omeprazole or sucralfate) post-operatively; 3/6 horses underwent a gastroscopy and were diagnosed with squamous gastric ulceration prior to treatment. Despite post-operative complications, 5/6 horses survived to hospital discharge. Full article

Background/Objectives: Oxidative stress is a pathophysiological factor that causes challenging issues in the treatment of several diseases, including gastric ulcer, inflammatory diseases, and adenocarcinomas. V. paradoxa and P. biglobosa are African plants whose parts are used for treating diseases, including gastrointestinal pathologies. This study aimed to characterize the gastroprotective, antioxidant, and anti-inflammatory activities of V. paradoxa and P. biglobosa stem bark extracts based on various solvents. Methods: The phytochemical screening and antioxidant evaluation were performed using radical scavenging (ABTS and DPPH) and reduction (FRAP and APM) methods. The anti-inflammatory activity was performed through an egg albumin denaturation model. The toxicological evaluation was performed on Artemia salina and female Wistar rat models, and the gastroprotective activity was carried out on an ethanolic-induced gastric ulcer rat model. Results: The results reported that V. paradoxa stem bark extracts contain catechin, epicatechin, ferulic acid, apigenin-7-gluc, and hesperidin, while P. biglobosa bark contains chlorogenic acid, catechin, caffeine, epicatechin, and cichoric acid. In the DPPH assay, the lowest scavenging capacities were 1.8 ± 0.21 mmol AAE/mg of dry extract (V. paradoxa, 97% ethanol) and 11.43 ± 0.208 mmol AAE/mg of dry extract (P. biglobosa, 50% ethanol). Similarly, for ABTS, the lowest scavenging capacities were 0.9726 ± 0.03952 mmol AAE/mg of dry extract (V. paradoxa, methanol with 1% HCl) and 1.3 mmol AAE/mg of dry extract (P. biglobosa, 97% ethanol), indicating strong antioxidant capacity. In the FRAP assay, both species reached a maximum reducing power of 2.39 mMol AAE/mg of dry extract (methanolic extract for V. paradoxa; methanol + 1% HCl for P. biglobosa). For APM, the 97% ethanolic extracts again showed the highest total antioxidant capacities: 31.78 ± 1.481 mMol AAE/mg (V. paradoxa) and 31.21 ± 0.852 mMol AAE/mg (P. biglobosa). The stem bark extracts of both V. paradoxa and P. biglobosa were revealed to be harmless in the Artemia salina as well as the rat model. The extracts of V. paradoxa as well as P. biglobosa exerted a stronger gastroprotective effect than omeprazole, a commonly used reference molecule. Conclusions: These extracts, rich in compounds exhibiting strong antioxidant, anti-inflammatory, and gastroprotective activities, surpassed omeprazole in ulcer protection in rat models. Their safety was confirmed in both Artemia salina and rodent assays. Future studies will explore their immunomodulatory, antiproliferative activities in vitro and in vivo and, specifically, the efficacy of isolated compounds in gastric adenocarcinoma models to assess these plants’ anticancer potential and elucidate their underlying mechanisms. Full article

Candida spp. are ubiquitous yeasts that are part of most mammals’ microbiota and can become opportunistic pathogens under predisposing conditions. Interestingly, recent studies in human medicine report an increased abundance of Candida spp. in association with inflammatory bowel disease (IBD). Gastrointestinal candidiasis has been primarily reported in neonatal foals, but not in adult horses. The aim of this study is to describe the morphological, histopathological, and microbiological features of gastric lesions associated with Candida infiltration in five horses referred to two tertiary hospitals for different reasons. Clinical features, findings from gastroscopy, gastric, and duodenal biopsies, as well as fungal and bacterial cultures obtained from gastric lesions will be reported. Macroscopically, gastric lesions showed a characteristic yellow/white pseudo-membranous appearance, similar to lesions reported in foals. The presence of Candida spp. was confirmed by positive culture and/or histopathological evidence of fungal infiltration on the gastric epithelium. Three out of five horses showed histopathological changes in duodenal biopsies, potentially suggesting IBD. These results demonstrate that gastric candidiasis can occur in adult horses. Further research is needed to elucidate the pathogenesis, predisposing factors, and clinical relevance of Candida spp. infections in the equine stomach, as well as their potential impact on gastrointestinal health and overall performance. Full article