Long-term proton pump inhibitors therapy and prevalence of hyperprolactinaemia: A cross-sectional study in outpatient gastroenterology clinics.

Objectives: To evaluate serum prolactin and macroprolactin levels in patients on long-term proton pump inhibitors therapy. METHODS: The cross-sectional study was conducted from January 2018 to November 2019 after approval from the ethics review committee of the Commission on Science and Technology for Sustainable Development in the South University, Abbottabad, Pakistan. The study included patients from two gastroenterology outpatient clinics in the Khyber Pakhtunkhwa province using proton pump inhibitors for ≥3 months either alone or in combination with either histamine receptor antagonists or prokinetics. Blood samples were collected from each patient for hormonal screening. Data was analysed using SPSS 25. RESULTS: Of the 166 patients, 101(60.8%) were females and 65(39.2%) were males. The overall mean age was 42.5±14.2 years, and the median serum prolactin level was 23.2ng/ml (interquartile range: 14.0-38.0ng/ml). There were 96(58%) patients with normoprolactinaemia and 70(42%) with hypreprolactinaemia. There were 19(11.4%) patients using combination therapy, while the rest were on proton pump inhibitors monotherapy. There was a significant increase in serum prolactin level with combination therapy compared to monotherapy (p=0.001). Patients having treatment duration 11-20 months (p=0.006) and >40 months (p=0.001) were at high risk of developing hyperprolactinaemia. CONCLUSIONS: Long-term use of proton pump inhibitors could increase serum prolactin levels, and appropriate evaluation is essential for clinical management.

Should the use of omeprazole be allowed during equestrian competition?

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. OBJECTIVES: 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?' STUDY DESIGN: 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. MAIN LIMITATIONS: 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.

CONTEXTO: Priorizar o bem­estar 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 bem­estar. Essa discrepância é motivo de preocupação para o público. OBJETIVOS: 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 ético­legal baseado em pesquisa documental. METODOLOGIA: 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. RESULTADOS: O público de esporte equino têm uma variedade de interesses (frequentemente conflitantes), enquanto todos compartilham o interesse em otimizar o bem­estar 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 bem­estar 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 bem­estar. 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.

Omeprazole-Loaded Copper Nanoparticles for Mitochondrial Damage Mediated Synergistic Anticancer Activity against Melanoma Cells.

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.

Retrospective evaluation of the effect of acid suppressant drugs on leukocyte ratios in dogs with mast cell tumors.

BACKGROUND: Acid suppressant drugs (ASDs) are commonly used to decrease gastric acid production, but some evidence exists that ASDs exert immunomodulatory effects. Such an effect has not been investigated in dogs for which ASDs are routinely prescribed. HYPOTHESIS: Compared to naïve subjects, dogs treated with ASDs will exhibit differences in leukocyte ratios after treatment. ANIMALS: Fifty-one dogs with mast cell tumors (MCTs). MATERIALS AND METHODS: Dogs with MCT that were either AS naïve or treated with ASDs (i.e., histamine-2-receptor antagonists [H2RA] or proton pump inhibitors [PPI]) were included in this retrospective study. Subjects were categorized into 3 treatment groups (AS naïve, H2RA treated, and PPI treated), and leukocyte ratios (neutrophil:eosinophil, lymphocyte:monocyte, and neutrophil:lymphocyte [NLR]) were calculated before and after treatment. A mixed effects analysis of variance on ranks was used to assess differences in ratios between treatments, between pre- and post-treatment time points, and between pre- and post-time points for each treatment. Concurrent administration of antihistamines, corticosteroids, and chemotherapeutic drugs was assessed as a confounding factor. RESULTS: Famotidine (n = 14/14) and omeprazole (n = 12/12) were the only H2RA and PPI used, respectively. Dogs receiving famotidine had a significant increase in median NLR from pre- to post-treatment (3.429; range, 1.417-15 to 5.631; range, 2.654-92; P < 0.01) compared to PPI treated or AS naïve dogs. No differences existed in chemotherapeutic drug or corticosteroid use between groups. CONCLUSIONS: A significant difference in NLR was identified in famotidine treated dogs compared with omeprazole treated or AS naïve dogs.

Uncommon triggers of insulin autoimmune syndrome: a case report.

BACKGROUND: Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial, hypoglycemic episodes. We report a case of a previously healthy 67-year-old man presenting with recurrent fasting hypoglycemia culminating in a diagnosis of insulin autoimmune syndrome linked to omeprazole and probably spices, namely, coriander, and ginger. CASE PRESENTATION: A previously healthy 67-year-old Sinhalese man presented with recurrent syncopal attacks for 3 months, which were found to be hypoglycemic episodes. He experienced mainly fasting hypoglycemic attacks, at a frequency gradually increasing to daily attacks. His cardiovascular, respiratory, abdominal, and neurologic examinations were normal. He was found to have insulin levels > 6000 mU/L and a post-polyethylene glycol insulin recovery of less than 9.5%. Contrast-enhanced computed tomography of the pancreas was normal. The diagnosis of insulin autoantibody syndrome was confirmed by testing for the insulin autoantibody level, yielding a level of > 300 U/mL. With regard to a possible trigger, he had a history of omeprazole intake for 2 weeks, 4 weeks prior to the onset of symptoms. He also consumed an herbal supplement containing coriander and ginger extracts daily for a period of 1 year, approximately 2 years prior to the onset of hypoglycemic attacks. He was commenced on prednisolone 30 mg daily, and hypoglycemic episodes responded dramatically, and thus he was tapered off corticosteroids. CONCLUSION: Omeprazole-induced insulin autoantibody syndrome is likely in this patient; however, the known hypoglycemic effects of coriander and ginger make it worthwhile to consider a possible association with insulin autoantibody syndrome. In addition, this case report highlights the need to consider insulin autoantibody syndrome even in patients presenting with fasting hypoglycemic attacks.

Protective effect of astaxanthin on indomethacin-induced gastric ulcerations in mice.

Gastric ulcer disease remains one of the common medical burdens affecting millions worldwide due to its prevalent risk factors with the chronic usage of non-steroidal anti-inflammatory drugs at the top, reportedly through the stimulation of oxidative stress and triggering of inflammatory and apoptotic cascades in the gastric mucosa. Astaxanthin, a dietary keto-carotenoid derived from marine organisms is gaining a wide interest as a nutraceutical for its pronounced antioxidant properties. Here, we aim to examine the potential modulatory role of astaxanthin on indomethacin-induced gastric ulceration in experimental mice. Twenty-four Swiss albino mice were randomly distributed into four groups: a control group, an indomethacin group, and two groups pre-treated with either omeprazole or astaxanthin. The gastric tissues were assessed using gross morphology, ulcer scoring, gastric juice acidity, as well as reduced glutathione (GSH) and malondialdehyde (MDA) levels. Histopathological examination and immunostaining for nuclear factor-kappa B (NF-κB) and caspase-3 levels were also employed. Indomethacin group tended to show a higher number of mucosal ulcerations relative to control and pre-treated groups. The indomethacin group also showed significantly lower GSH levels and higher MDA levels relative to control. Immunostaining of gastric tissue sections showed a higher reactivity to NF-κB and caspase-3 in indomethacin group. Astaxanthin pre-treatment significantly elevated gastric juice pH, normalized GSH levels, and lowered the indomethacin-induced elevations in MDA, NF-κB, and caspase-3 levels. These results indicate that astaxanthin exhibits a comparable protective effect to omeprazole, against indomethacin-induced gastric ulceration. This anti-ulcerogenic effect could be mediated through its antioxidant, anti-inflammatory, and anti-apoptotic modulatory activities.

Analytical quality by design-based development of a capillary electrophoresis method for Omeprazole impurity profiling.

Omeprazole (OME) is a proton pump inhibitor used to treat gastroesophageal reflux disease associated conditions. The current study presents an Analytical Quality by Design-based approach for the development of a CE method for OME impurity profiling. The scouting experiments suggested the selection of solvent modified Micellar ElectroKinetic Chromatography operative mode using a pseudostationary phase composed of sodium dodecyl sulfate (SDS) micelles and n-butanol as organic modifier in borate buffer. A symmetric three-level screening matrix 37//16 was used to evaluate the effect of Critical Method Parameters, including Background Electrolyte composition and instrumental settings, on Critical Method Attributes (critical resolution values, OME peak width and analysis time). The analytical procedure was optimized using Response Surface Methodology through a Central Composite Orthogonal Design. Risk of failure maps made it possible to define the Method Operable Design Region, within which the following optimized conditions were selected: 72 mM borate buffer pH 10.0, 96 mM SDS, 1.45 %v/v n-butanol, capillary temperature 21 °C, applied voltage 25 kV. The method was validated according to ICH guidelines and robustness was evaluated using a Plackett-Burman design. The developed procedure enables the simultaneous determination of OME and seven related impurities, and has been successfully applied to the analysis of pharmaceutical formulations.

Omeprazole and risk of osteoarthritis: insights from a mendelian randomization study in the UK Biobank.

BACKGROUND: A former cohort study has raised concern regarding the unanticipated hazard of omeprazole in expediting osteoarthritis (OA) advancement. The precise nature of their causal evidence, however, remains undetermined. The present research endeavors to investigate the underlying causal link between omeprazole and OA through the application of mendelian randomization (MR) analysis. METHODS: The study incorporated the ukb-a-106 and ukb-b-14,486 datasets. The investigation of causal effects employed methodologies such as MR-Egger, Weighted median, Inverse variance weighted (IVW) with multiplicative random effects, and IVW (fixed effects). The IVW approach was predominantly considered for result interpretation. Sensitivity analysis was conducted, encompassing assessments for heterogeneity, horizontal pleiotropy, and the Leave-one-out techniques. RESULTS: The outcomes of the MR analysis indicated a causal relationship between omeprazole and OA, with omeprazole identified as a contributing risk factor for OA development (IVW model: OR = 1.2473, P < 0.01 in ukb-a-106; OR = 1.1288, P < 0.05 in ukb-b-14,486). The sensitivity analysis underscored the robustness and dependability of the above-mentioned analytical findings. CONCLUSION: This study, employing MR, reveals that omeprazole, as an exposure factor, elevates the risk of OA. Considering the drug's efficacy and associated adverse events, clinical practitioners should exercise caution regarding prolonged omeprazole use, particularly in populations with heightened OA risks. Further robust and high-quality research is warranted to validate our findings and guide clinical practice.

Omeprazole taken once every other day can effectively prevent aspirin-induced gastrointestinal mucosal damage in rats.

BACKGROUND: Proton-pump inhibitors (PPIs) prevent aspirin-associated gastric and duodenal mucosal damage. However, long-term use of PPIs can lead to various adverse reactions, such as gastric polyps and enterochromaffin-like cell hyperplasia. Current research indicates that the abovementioned adverse reactions are mainly related to hypergastrinemia. We investigated whether low-frequency administration of omeprazole could effectively repair aspirin-induced mucosal damage and reduce the increase in gastrin levels associated with long-term use of PPIs. METHODS: Sprague‒Dawley rats were divided into four treatment groups: daily aspirin, daily aspirin and omeprazole once every day (qd), daily aspirin and omeprazole once every other day (qod), and daily aspirin and omeprazole once every three days (1/d3). After 15 days of feeding, blood samples were collected, and the stomachs of sacrificed rats were subjected to macroscopic, histological, and immunohistochemical studies. Moreover, in clinical practice, patients with peptic ulcers caused by aspirin took a standard dose of omeprazole (20 mg) every other day. Two months later, gastroscopy was performed to examine the healing of the ulcers. RESULTS: Both the omeprazole qd and omeprazole qod administrations effectively prevented aspirin-induced gastric peptic ulcers, with no significant difference between the two groups in the inhibition of parietal cell secretion of gastric acid and cell apoptosis. However, omeprazole 1/d3 failed to completely prevent aspirin-induced gastric mucosal injury. Notably, the gastrin levels, cell proliferation ability and cholecystokinin B receptor expression of the omeprazole qd group were significantly higher than those of the omeprazole qod group. In clinical work, patients with peptic ulcers caused by aspirin were given a standard dose of omeprazole every other day, and their ulcers healed after 2 months, as observed by gastroscopy. CONCLUSIONS: Omeprazole administration once every other day can effectively prevent aspirin-induced peptic ulcers and reduce hypergastrinemia, which may reduce the long-term adverse effects of PPI treatment.

Nuevas herramientas para la revisión de la medicación: PRM en pacientes en tratamiento con inhibidores de la bomba de protones / New tools for medication review: DRP in patients treatment with proton pump inhibitors

Objetivo Analizar mediante el programa de revisión de la medicación, Revisem®, la prevalencia de problemas relacionados con la medicación (PRM) en pacientes de la provincia de Valencia que estaban en tratamiento activo con inhibidores de la bomba de protones (IBP) en 2022. Diseño Estudio observacional descriptivo y retrospectivo. Material y métodos Se analizó el historial farmacoterapéutico (HFT) de 295 pacientes siguiendo los criterios propuestos por la Pharmaceutical Care Network Europe, utilizando la plataforma digital Revisem® del Muy Ilustre Colegio Oficial de Farmacéuticos de Valencia (MICOF). Resultados La edad media de los pacientes fue 81,8 ± 11,1 años y 66,4% fueron mujeres. Se detectó al menos un PRM en 97,3% de los pacientes. De los PRM analizados, 46,9% fueron interacciones, de las cuales 29,7% implicaban un IBP, siendo el omeprazol el de mayor frecuencia. Los PRM con IBP se relacionan de forma significativa con determinadas condiciones del paciente y grupos farmacológicos, como son el sexo femenino, la edad superior a 54 años y la polifarmacia. Conclusiones La plataforma digital Revisem®, permite la detección de una alta prevalencia de PRM a nivel provincial. La aplicación de nuevas herramientas tecnológicas para detectar la prevalencia de PRM es fundamental para optimizar los tratamientos de los pacientes. (AU)

Objective To analyze, using the medication review program, Revisem®, the prevalence of drug-related problems (DRP) in patients in the province of Valencia who were on active treatment with proton pump inhibitors (PPI) in 2022. Design Descriptive and retrospective observational study. Material and methods The pharmacotherapeutic history of 295 patients was analyzed following the criteria proposed by the Pharmaceutical Care Network Europe, using the Revisem® digital platform of the Muy Ilustre Colegio Oficial de Farmacéuticos (MICOF). Results The mean age of the patients was 81.8 ± 11.1 years and 66.4% were women. At least one DRP was detected in 97.3% of patients. 46.9% of the DRP analyzed were interactions, of which 29.7% involved a PPI, with omeprazole being the most frequent. DRPs with PPI are significantly related to certain patient conditions and pharmacological groups, such as female sex, age over 54 years and polypharmacy. Conclusions The application of the Revisem® digital platform allows the detection of a high prevalence of DRP at the provincial level. The application of new technological tools to detect the prevalence of DRP is essential to optimize patient treatments. (AU)

Assessment of omeprazole and famotidine effects on the pharmacokinetics of tacrolimus in patients following kidney transplant-randomized controlled trial.

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 (p = 0.0443). AUC0-6 amounted to 63.07 ± 19.46 ng × h/mL (day 2) vs. 54.23 ± 10.48 ng × h/mL (day 1), (p = 0.0295). AUC2-6 amounted to 44.32 ± 11.51 ng × h/mL (day 2) vs. 38.68 ± 7.70 ng × h/mL (day 1), (p = 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. Clinical Trial Registration: clinicaltrials.gov, identifier NCT05061303.

The Role of Proton Pump Inhibitors in the Realm of Idiopathic Pulmonary Fibrosis and its Associated Comorbidities: A Systematic 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.

Efficacy and safety of empiric treatment with omeprazole continuous infusion in critically ill children with gastrointestinal bleeding.

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, p < 0.001) and bleeding episode (4 vs. 10.5 days, p < 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, p = 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.

Prospective Randomized Controlled Clinical Trial of the Long-Term Effects of Omeprazole on Healthy Dogs.

The use of omeprazole as a preventive treatment for gastrointestinal ulcers in veterinary medicine has been questioned during previous years. The aim of the present study is to assess the long-term effect of omeprazole on cobalamin and serum gastrin levels in healthy dogs. Eighteen healthy dogs were included: 10 in the control group and 8 in the omeprazole group. Three samples were collected: before starting the treatment (T0), 30 days after the start of treatment (T1), and at 60 days (T2). The mean cobalamin value (ng/L) in the control group was 481.4 (±293.70) at T0, 481.4 (±170.21) at T1, and 513.2 (±174.50) at T2. In the omeprazole group, the values were 424.62 (±161.57) at T0, 454.5 (±160.96) at T1, and 414.87 (±127.90) at T2. No statistically significant changes were detected in cobalamin levels between the three-time period in both study groups. These results agree with previous findings in felines but contrast with human medicine studies. The median gastrin values (pg/mL) in the control group were 62.45 [30.17-218.75] at T0, 76.06 [30.67-199.87] at T1, and 63.02 [35.81-176.06] at T2. The median gastrin value in the omeprazole group was 67.59 [55.96-101.60] at T0, 191.77 [75.31-1901.77] at T1, and 128.16 [43.62-1066.46] at T2. Statistically significant differences were detected (p = 0.008), indicating an increase in gastrin levels after initiating treatment with omeprazole. In conclusion, the increased levels of gastrin observed in this population underscore the importance of conducting a comprehensive clinical assessment to identify potential gastrointestinal disorders, particularly in consideration of the usage of omeprazole as a preventive treatment.

The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum.

The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. Trichophyton rubrum is the most commonly isolated fungus in dermatophytosis. In T. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast Saccharomyces cerevisiae polyamine transport kinase 2 (Ptk2), and found that T. rubrum Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both T. rubrum and S. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in S. cerevisiae. Overexpression of T. rubrum Pma1 (TrPma1) in T. rubrum Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes.

Long-term administration of omeprazole in mice: a study of behavior, inflammatory, and oxidative stress alterations with focus on central nervous system.

Chronic use of omeprazole has been linked to central effects alongside with the global concern of increasing appearance of neuropsychiatric disorders. This study aimed to identifying behavioral, inflammatory, and oxidative stress alterations after long-term administration of omeprazole. C57BL/6 mice were divided in groups: OME and Sham, each received either solutions of omeprazole or vehicle, administered for 28 days by gavage. Results observed in the omeprazole-treated mice: Decrease in the crossing parameter in the open field, no change in the motor performance assessed by rotarod, an immobility time reduction in the forced swimming test, improved percentage of correct alternances in the Ymaze and an exploration time of the novel object reduction in the novel object recognition. Furthermore, a reduced weight gain and hippocampal weight were observed. There was an increase in the cytokine IL1-ß levels in both prefrontal cortex (PFC) and serum, whereas TNF-α increased only in the PFC. Nitrite levels increased in the hippocampus (HP) and PFC, while malondialdehyde (MDA) and glutathione (GSH) levels decreased. These findings suggest that omeprazole improves depressive-like behavior and working memory, likely through the increase in nitrite and reduction in MDA levels in PFC and HP, whereas, the impairment of the recognition memory is more likely to be related to the reduced hippocampal weight. The diminished weight gain might be associated with the IL-1ß increased levels in the peripheral blood. Altogether, omeprazole showed to have the potential to impact at central level and inflammatory and oxidative parameters might exert a role between it.

Cardiotoxic Effects Produced by Omeprazole and Methylene Blue in an Animal Model of Cardiac Ischemia and Reperfusion and Potential Implications for the Pharmacological Strategy for Vasoplegic Syndrome.

Defined as systemic hypotension caused by intense vasodilation due to the loss of systemic vascular resistance, vasoplegic syndrome (VS) is associated with elevated morbidity and mortality in humans. Although vasopressors such as norepinephrine and vasopressin are the first-choice drugs for VS treatment, several other drugs such as methylene blue (MB) can be used as adjuvant therapy including rescue therapy. To develop new pharmacological strategies to reduce the risk of VS, we investigated the effects of treatments with MB (2 mg/kg/IV), omeprazole (OME, 10 mg/kg/IV), and their combination in an animal model of cardiac ischemia-reperfusion (CIR). The ventricular arrhythmia (VA), atrioventricular block (AVB), and lethality (LET) incidence rates caused by CIR (evaluated via ECG) and serum levels of the cardiac lesion biomarkers creatine kinase-MB (CK-MB) and troponin I (TnI) in adult rats pretreated with saline solution 0.9% and submitted to CIR (SS + CIR group) were compared to those pretreated with MB (MB + CIR group), OME (OME + CIR group), or the MB + OME combination (MB + OME + CIR group). The AVB and LET incidence rates in the MB + CIR (100%), OME + CIR (100%), and MB + OME + CIR (100%) groups were significantly higher compared to the SS + CIR group (60%). The serum level of CK-MB in these groups were also significantly higher compared to the SS + CIR group, demonstrating that the treatments before CIR with MB, OME, and MB + OME produced similar effects in relation to cardiac function and the occurrence of lesions. These results demonstrate that the treatment of animals subjected to the CIR protocol with OME produced the same effects promoted by the treatment with MB, which may suggest the possibility of using OME alone or in combination with MB in medical clinics in treatment of VS.

Development of a New Bioequivalent Omeprazole Product.

Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.

Catalytic enhancements in cytochrome P450 2C19 by cytochrome b5.

Human cytochrome P450 2C19 catalyzes P450 enzyme reactions of various substrates, including steroids and clinical drugs. Recombinant P450 2C19 enzyme with histidine tag was successfully expressed in Escherichia coli and purified using affinity column chromatography. Ultra-performance liquid chromatography-tandem mass (UPLC-MS/MS) spectrometry showed that the purified P450 2C19 enzyme catalyzed 5-hydroxylation reaction of omeprazole. The purified enzyme displayed typical type I binding spectra to progesterone with a Kd value of 4.5 ± 0.2 µM, indicating a tight substrate binding. P450 2C19 catalyzed the hydroxylation of progesterone to produce 21-hydroxy (OH) as a major and 17-OH product as a minor product. Steady-state kinetic analysis of progesterone 21-hydroxylation indicated that the addition of cytochrome b5 stimulated a five-times catalytic turnover number of P450 2C19 with a kcat value of 1.07 ± 0.08 min-1. The molecular docking model of progesterone in the active site of P450 2C19 displayed that the 21-carbon of progesterone was located close to the heme with a distance of 4.7 Å, suggesting 21-hydroxylation of progesterone is the optimal reaction of P450 2C19 enzyme for a productive orientation of the substrate. Our findings will help investigate the extent to which cytochrome b5 affects the metabolism of P450 2C19 to drugs and steroids. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00219-8.

Structure-Guided Evolution of Cyclohexanone Monooxygenase Toward Bulky Omeprazole Sulfide: Substrate Migration and Stereoselectivity Inversion.

Structure-guided engineering of a CHMO from Amycolatopsis methanolica (AmCHMO) was performed for asymmetric sulfoxidation activity and stereoselectivity toward omeprazole sulfide. Initially, combinatorial active-site saturation test (CASTing) and iteratively saturation mutagenesis (ISM) were performed on 5 residues at the "bottleneck" of substrate tunnel, and MT3 was successfully obtained with a specific activity of 46.19 U/g and R-stereoselectivity of 99 % toward OPS. Then, 4 key mutations affecting the stereoselectivity were identified through multiple rounds of ISM on residues at the substrate binding pocket region, resulting MT8 with an inversed stereoselectivity from 99 % (R) to 97 % (S). MT8 has a greatly compromised specific activity of 0.08 U/g. By introducing additional beneficial mutations, MT11 was constructed with significantly increased specific activity of 2.29 U/g and stereoselectivity of 97 % (S). Enlarged substrate tunnel is critical to the expanded substrate spectrum of AmCHMO, while reshaping of substrate binding pocket is important for stereoselective inversion. Based on MD simulation, pre-reaction states of MT3-OPSproR, MT8-OPSproS, and MT11-OPSproS were calculated to be 45.56 %, 17.94 %, and 28.65 % respectively, which further confirm the experimental data on activity and stereoselectivity. Our results pave the way for engineering distinct activity and stereoselectivity of BVMOs toward bulky prazole thioethers.