Introduction. Sporotrichosis is a subcutaneous infection caused by dimorphic Sporothrix species embedded in the clinical clade. Fungi have virulence factors, such as biofilm and melanin production, which contribute to their survival and are related to the increase in the number of cases of therapeutic failure, making it necessary to search for new options.Gap statement. Proton pump inhibitors (PPIs) have already been shown to inhibit the growth and melanogenesis of other fungi.Aim. Therefore, this study aimed to evaluate the effect of the PPIs omeprazole (OMP), rabeprazole (RBP), esomeprazole, pantoprazole and lansoprazole on the susceptibility and melanogenesis of Sporothrix species, and their interactions with itraconazole, terbinafine and amphotericin B.Methodology. The antifungal activity of PPIs was evaluated using the microdilution method, and the combination of PPIs with itraconazole, terbinafine and amphotericin B was assessed using the checkerboard method. The assessment of melanogenesis inhibition was assessed using grey scale.Results. The OMP and RBP showed significant MIC results ranging from 32 to 256 µg ml-1 and 32 to 128 µg ml-1, respectively. Biofilms were sensitive, with a significant reduction (P<0.05) in metabolic activity of 52% for OMP and 50% for RBP at a concentration of 512 µg ml-1 and of biomass by 53% for OMP and 51% for RBP at concentrations of 512 µg ml-1. As for the inhibition of melanogenesis, only OMP showed inhibition, with a 54% reduction.Conclusion. It concludes that the PPIs OMP and RBP have antifungal activity in vitro against planktonic cells and biofilms of Sporothrix species and that, in addition, OMP can inhibit the melanization process in Sporothrix species.

Our understanding of the use of acid-suppressant drugs (ASDs) in companion animals is largely centered around the treatment of acid-related disorders including gastroesophageal reflux and gastrointestinal ulceration. The companion article by Grady et al, JAVMA, October 2024, summarizes our current knowledge of the efficacy of and indications for ASDs for the treatment of acid-related disorders. Far less is understood about both the benefits of and potential for adverse effects of ASDs outside of the parietal cell including those directed toward inflammation and immunomodulation, tumorigenesis, fibrosis, and oxidative stress. In this Currents in One Health article, we summarize the pH-independent properties of ASDs as demonstrated in studies conducted largely in humans and rodents. The objective of this review is to highlight and increase awareness of the pH-independent effects of ASDs to elucidate the need for further veterinary research in this area.

Keloid disease (KD) is a common connective tissue disorder of unknown aetiopathogenesis with ill-defined treatment. Keloid scars present as exophytic fibroproliferative reticular lesions post-cutaneous injury, remain benign yet behave locally aggressive and expansive. To date, there is limited understanding, and validation of biomarkers identified through combined proteomic and genomic evaluation of KD. Therefore, the aim here was to identify putative-causative candidates in KD, by performing a comprehensive proteomics analysis of subcellular fractions as well as the whole cell, coupled with transcriptomics data analysis of normal compared with KD fibroblasts. We then applied novel integrative bioinformatics analyses to demonstrate that NF-kappa-Beta-p65 (RELA) from the cytosolic fraction and Calpain-2 (CAPN2) from the whole cell lysate were significantly up-regulated in KD and associated with alterations in relevant key signalling pathways including apoptosis. Our findings were further confirmed by showing upregulation of both RELA and CAPN2 in KD using flow cytometry and immunohistochemistry. Moreover, functional evaluation using real-time cell analysis and flow cytometry, demonstrated that both omeprazole and dexamethasone inhibited the growth of KD fibroblasts by enhancing the rate of apoptosis. In conclusion, to our knowledge previously unreported, subcellular fractionation and metaproteogenomic analyses have identified two novel biomarkers of relevance to keloid diagnostics and therapeutics.

BACKGROUND: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications. Recently, PPI use has been linked to the development of chronic kidney disease (CKD) and cardiovascular events. Our study aimed to investigate the relationship between PPI use and the incidence of chronic kidney disease using a systematic review and meta-analysis.
METHODS: We performed a comprehensive literature search in PubMed, Embase, and Cochrane databases from their inception until March 2024 for relevant studies. We compared outcomes between patients using PPIs, those not using PPIs, and those using histamine-2 receptor antagonists (H2RAs). Endpoints were pooled using the DerSimonian-and-Laird random-effects model as the hazard ratio (HR) with 95% confidence intervals (CIs).
RESULTS: Our analysis included twelve studies with a total of 700,125 participants (286,488 on PPIs, 373,848 not on PPIs, and 39,789 on H2RAs), with follow-up periods ranging from three months to 14 years. The current meta-analysis revealed that PPI use is associated with a statistically significant increased risk of incident CKD (HR: 1.26, 95% CI: 1.16-1.38, p < 0.001) compared with non-users. Moreover, the risk of incident CKD is significantly higher in patients with PPI use compared to H2RA use (HR: 1.34, 95% CI: 1.13-1.59, p < 0.001). The results remained unchanged in terms of magnitude and direction after a leave-one-out analysis for both outcomes.
CONCLUSIONS: Our multifaceted analysis showed that PPI use was associated with a higher incidence of CKD when compared to non-PPI use and H2RA use, respectively. These findings advocate for heightened vigilance and judicious use of long-term PPIs. Further large prospective longitudinal studies are warranted to validate these observations.

Currently, Biopharmaceutics Classification System (BCS) classes I and III are the only biological exemptions of immediate-release solid oral dosage forms eligible for regulatory approval. However, through virtual bioequivalence (VBE) studies, BCS class II drugs may qualify for biological exemptions if reliable and validated modeling is used. Here, we sought to establish physiologically based pharmacokinetic (PBPK) models, in vitro-in vivo relationship (IVIVR), and VBE models for enteric-coated omeprazole capsules, to establish a clinically-relevant dissolution specification (CRDS) for screening BE and non-BE batches, and to ultimately develop evaluation criteria for generic omeprazole enteric-coated capsules. To establish omeprazole\'s IVIVR based on the PBPK model, we explored its in vitro dissolution conditions and then combined in vitro dissolution profile studies with in vivo clinical trials. The predicted omeprazole pharmacokinetics (PK) profiles and parameters closely matched the observed PK data. Based on the VBE results, the bioequivalence study of omeprazole enteric-coated capsules required at least 48 healthy Chinese subjects. Based on the CRDS, the capsules\' in vitro dissolution should not be < 28%-54%, < 52%, or < 80% after two, three, and six hours, respectively. Failure to meet these dissolution criteria may result in non-bioequivalence. Here, PBPK modeling and IVIVR methods were used to bridge the in vitro dissolution of the drug with in vivo PK to establish the BE safety space of omeprazole enteric-coated capsules. The strategy used in this study can be applied in BE studies of other BCS II generics to obtain biological exemptions and accelerate drug development.

BACKGROUND: Prioritising equine welfare, making evidenced-based policy, and consistent decision-making across sports are crucial to maintaining the social licence for equestrian sport. Regulations on the use of omeprazole during competition differ; all regulators argue that their rules prioritise welfare. This discrepancy is a matter of concern to the public and equestrian stakeholders.
OBJECTIVE: To apply Campbell\'s Ethical Framework for the use of Horses in Sport to the question: \'Should the use of omeprazole be allowed during equestrian competition?\'
METHODS: A desk-based ethico-legal study.
METHODS: Campbell\'s Ethical Framework for the Use of Horses in Sport was applied in a stepwise fashion: definition of the ethical question; analysis of the evidence base; consideration of stakeholders\' interests; harm:benefit analysis; application of the three central tenets of the framework, and formulation of conclusions and recommendations.
RESULTS: Stakeholders in equine sports have a variety of (frequently conflicting) interests; all of them share an interest in optimising equine welfare. The incidence of EGUS in competition horses is high. Omeprazole is a cornerstone treatment. There are currently discrepancies in regulation about the use of omeprazole during competitions. Recent evidence suggests that withholding omeprazole treatment for two clear days before competition allows the recurrence of squamous EGUS, whereas withholding treatment on the day of competition only does not have that effect.
CONCLUSIONS: The current state of scientific knowledge about the use of omeprazole in horses. The analysis did not consider possible health and thus welfare effects of the out-of-competition treatment with omeprazole.
CONCLUSIONS: Based on recent scientific evidence, if horses are being treated with omeprazole outside of competition then treatment on the day of competition should be permitted on welfare grounds. Revision of regulations around the use of omeprazole during competition by governing bodies is necessary to safeguard the ethical use of horses in sport.
UNASSIGNED: Priorizar o bem‐estar equino, elaborar políticas baseadas em evidências e tomar decisões consistentes em todos os esportes são cruciais para manter a licença social para o esporte equestre. As regulamentações sobre o uso de omeprazol durante a competição diferem; todos os reguladores argumentam que suas regras priorizam o bem‐estar. Essa discrepância é motivo de preocupação para o público.
OBJECTIVE: Aplicar o Modelo Ético de Campbell para o Uso de Cavalos em Esportes1 à pergunta: ‘Deve o uso de omeprazol ser permitido durante a competição equestre?’ DESENHO DO ESTUDO: Um estudo ético‐legal baseado em pesquisa documental.
METHODS: O Modelo Ético de Campbell para o Uso de Cavalos em Esportes1 foi aplicado de forma gradual: definição da questão ética; análise da base de evidências; consideração dos interesses do público alvo; uma análise de dano:benefício; aplicação dos três princípios centrais do modelo; e formulação de conclusões e recomendações.
RESULTS: O público de esporte equino têm uma variedade de interesses (frequentemente conflitantes), enquanto todos compartilham o interesse em otimizar o bem‐estar equino. A incidência de EGUS (Síndrome da Úlcera Gástrica Equina) em cavalos de competição é alta, a qual o omeprazol é um tratamento fundamental. Atualmente, há discrepâncias na regulamentação sobre o uso de omeprazol durante competições. Evidências recentes sugerem que a suspensão do tratamento com omeprazol por 2 dias antes da competição permite a recorrência da EGUS da porção escamosa, enquanto a suspensão do tratamento apenas no dia da competição não tem esse efeito. PRINCIPAIS LIMITAÇÕES: O estado atual do conhecimento científico sobre o uso de omeprazol em cavalos. A análise não considerou possíveis efeitos sobre a saúde e, portanto, sobre o bem‐estar do tratamento com omeprazol fora da competição. CONCLUSÕES: Com base em evidências científicas recentes, se os cavalos estão sendo tratados com omeprazol fora da competição, o tratamento no dia da competição deve ser permitido por razões de bem‐estar. A revisão das regulamentações sobre o uso de omeprazol durante a competição pelos órgãos reguladores é necessária para salvaguardar o uso ético dos cavalos no esporte.

UNASSIGNED: Proton pump inhibitors (PPIs) are a widely prescribed class of drugs, potentially interacting with a large number of medicines, especially among older patients with multimorbidity and polypharmacy. Beyond summary of product characteristics (SPCs), interaction checkers (ICs) are routinely used tools to help clinicians in medication review interventions.
UNASSIGNED: To assess the consistency of information on drugs potentially interacting with PPIs as reported in their SPCs and different ICs.
UNASSIGNED: This cross-sectional study was conducted using data from SPCs for 5 PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) and 5 ICs (ie, INTERCheck WEB, Micromedex, Lexicomp, Epocrates, and drugs.com). Information from the SPCs and the ICs were extracted between July 15 and 30, 2023.
UNASSIGNED: The main outcome was the level of agreement among SPCs and the 5 ICs in identifying drugs potentially interacting with PPIs and attributing drug-drug interaction (DDI) severity categories. The level of agreement was computed using Gwet AC1 statistic on the 5 ICs and by comparing 4-sets and 2-sets of ICs. As a sensitivity analysis, the level of agreement in listing PPI-related DDIs was evaluated using Cohen κ and Fleiss κ coefficients.
UNASSIGNED: Considering SPCs and the 5 ICs, a total of 518 potentially interacting drugs with omeprazole were reported, 455 for esomeprazole, 433 for lansoprazole, 421 for pantoprazole, and 405 for rabeprazole. As compared with the ICs, the SPCs reported a much smaller number of drugs potentially interacting with PPIs, with proportions ranging from 2.7% (11 potentially interacting drugs) for rabeprazole to 7.6% (33 potentially interacting drugs) for lansoprazole of the total identified drugs at risk of interaction with a PPI. The overall level of agreement among the 5 ICs for identifying potential interactions was poor (from 0.23 [95% CI, 0.21-0.25] for omeprazole to 0.27 [95% CI, 0.24-0.29] for pantoprazole and 0.27 [95% CI, 0.25-0.29] for rabeprazole). Similarly, the level of agreement was low in 4-set and 2-set analyses as well as when restricting the analysis to the potential DDIs identified as severe (range, 0.30-0.32).
UNASSIGNED: This cross-sectional study found significant disagreement among different ICs and SPCs, highlighting the need to focus on standardizing DDI databases. Therefore, to ensure evaluation and prevention of clinically relevant DDIs, it is recommended to revise multiple ICs and consult with specialists, such as clinical pharmacologists, particularly for patients with complex medical conditions.

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 μg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

Equine gastric ulcer syndrome (EGUS) is a prevalent condition in horses, affecting up to 93% of racehorses. Comprising the equine squamous gastric disease (ESGD) and the equine glandular gastric disease (EGGD), EGUS poses significant health challenges. Saliva, a non-invasive and easily obtainable sample, is increasingly recognized for its potential as a source of biomarkers in horses. This study investigates changes in saliva analytes using automated assays before and after EGUS treatment, aiming to identify biomarkers indicative of treatment success or failure. A total of 28 horses diagnosed with EGUS were treatment with omeprazole for six weeks and further divided into successful (n = 15) or unsuccessful (n = 13) treatment group. Saliva samples were collected before and after treatment, and analytes related to enzymes, metabolites, proteins, redox biomarkers, and minerals were measured using an automated chemistry analyzer. Results revealed that horses with successful treatment, indicated by reduced EGGD and ESGD scores, showed significant increases in bicarbonate and urea, and decreases in adenosine deaminase (ADA), and creatine kinase (CK). Conversely, horses with non-successful treatment showed no significant changes in salivary analytes. These analytes have the advantages of an easy and fast measurement and the possibility of being applied in routine. Further studies with larger populations should be performed to establish the possible practical application of these analytes as biomarkers of treatment.

Metallic nanoparticles are promising candidates for anticancer therapies. Among the different metallic systems studied, copper is an affordable and biologically available metal with a high redox potential. Copper-based nanoparticles are widely used in anticancer studies owing to their ability to react with intracellular glutathione (GSH) to induce a Fenton-like reaction. However, considering the high metastatic potential and versatility of the tumor microenvironment, modalities with a single therapeutic agent may not be effective. Hence, to enhance the efficiency of chemotherapeutic drugs, repurposing them or conjugating them with other modalities is essential. Omeprazole is an FDA-approved proton pump inhibitor used in clinics for the treatment of ulcers. Omeprazole has also been studied for its ability to sensitize cancer cells to chemotherapy and induce apoptosis. Herein, we report a nanosystem comprising of copper nanoparticles encapsulating omeprazole (CuOzL) against B16 melanoma cells. The developed nanoformulation exerted significant synergistic anticancer activity when compared with either copper nanoparticles or omeprazole alone by inducing cell death through excessive ROS generation and subsequent mitochondrial damage.