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Cell Death & Disease Oct 2019MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET...
MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed in EGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance.
Topics: A549 Cells; Animals; Carcinoma, Non-Small-Cell Lung; Celecoxib; Cell Proliferation; Cyclooxygenase 2; Drug Resistance, Neoplasm; Female; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mitogen-Activated Protein Kinase Kinases; Pantoprazole; Progression-Free Survival; Proto-Oncogene Proteins c-met; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 31611604
DOI: 10.1038/s41419-019-2020-4 -
Wiadomosci Lekarskie (Warsaw, Poland :... 2021The aim: Of the work was to determine the content of pro- and anti-inflammatory cytokines in the blood serum of the control group rats and after 28 days of inhibiting...
OBJECTIVE
The aim: Of the work was to determine the content of pro- and anti-inflammatory cytokines in the blood serum of the control group rats and after 28 days of inhibiting HCl secretion in the stomach by proton pump blockers "Omeprazole" and "Pantoprazole".
PATIENTS AND METHODS
Materials and methods: The studies were performed on 30 white non-linear male rats weighing 160-180 g, divided into three groups with 10 animals in each. The control (group 1) were injected intraperitoneally with water for injections within 28 days once a day. Group 2 was administered omeprazole. Group 3 was administered pantoprazole. The concentration of cytokines in the blood serum of rats was determined by the enzyme immunoassay method. For statistic data processing, Student's t-criterion for independent samples was applied.
RESULTS
Results: After prolonged administration of omeprazole and pantoprazole, the blood serum concentrations of IFNγ, TNFα, IL-1 in rats increased by 58.5% and 3.41%, 73.3% and 48.4%, 80.2% and 40.8%, respectively, and IL-12B 40p decreased by 36.6% when using omeprazole and was almost indistinguishable from the control values when pantoprazole was administered. With administration of omeprazole, IL-4 concentration decreased by 39.8% and that of pantoprazole increased by 3.86% compared to the control. Administration of omeprazole and pantoprazole did not affect IL-6 concentration.
CONCLUSION
Conclusion: Inhibition of hydrochloric acid secretion in the stomach of rats for 28 days using omeprazole and pantoprazole led to an imbalance between pro- and anti-inflammatory cytokines. The adverse effect of pantoprazole was less pronounced than that of omeprazole.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Benzimidazoles; Cytokines; Male; Proton Pump Inhibitors; Serum; Sulfoxides
PubMed: 34459754
DOI: No ID Found -
International Journal of Molecular... Nov 2022Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal...
Proton pump inhibitors (PPIs) are one of the most prescribed drugs around the world. PPIs induce microbiota modulation such as obesity both in humans and in animal models. However, since PPIs can induce microbiota modulation despite the absence of a high-fat diet or weight gain, it is an interesting model to correlate microbiota modulation with the establishment of non-alcoholic fatty liver disease (NAFLD). We investigated the effect of pantoprazole treatment on TLR4 signaling and liver histology in C57BL/6J mice for 60 days, trying to correlate microbiota modulation with some aspects of liver injury. We performed glucose (GTT) and insulin (ITT) tolerance tests, serum lipopolysaccharide (LPS) dosage, liver histology, liver and intestine extraction for Western blot and qPCR. Fecal microbiota were investigated via metagenomics. Chronic treatment with pantoprazole induced microbiota modulation and impaired ileum barrier integrity, without an association with insulin resistance. Furthermore, increased circulating LPS and increased Toll-like receptor 4 (TLR4) and TGFβ downstream signaling may have an important role in the development of the observed liver microvesicular steatosis and fibrosis. Finally, this model of PPI-induced changes in microbiota might be useful to investigate liver microvesicular steatosis and fibrosis.
Topics: Mice; Humans; Animals; Toll-Like Receptor 4; Gastrointestinal Microbiome; Pantoprazole; Proton Pump Inhibitors; Lipopolysaccharides; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Fibrosis
PubMed: 36430244
DOI: 10.3390/ijms232213766 -
Frontiers in Psychiatry 2023QT prolongation carries the risk of ventricular tachyarrhythmia (Torsades de Pointes) and sudden cardiac death. Psychotropic drugs can affect ventricular repolarization...
INTRODUCTION
QT prolongation carries the risk of ventricular tachyarrhythmia (Torsades de Pointes) and sudden cardiac death. Psychotropic drugs can affect ventricular repolarization and thus prolong the QT interval. The present study sought to investigate the risk factors (pharmacological and non-pharmacological) of severe QT prolongation in gerontopsychiatric patients.
METHODS
Electrocardiograms of patients on a gerontopsychiatric ward were screened for QT prolongation. Medication lists were examined utilizing the AzCERT classification. Potential drug interactions were identified with the electronic drug interaction program mediQ.
RESULTS
The overall prevalence of QT prolongation was 13.6%, with 1.9% displaying severe QT prolongation (≥ 500 ms). No statistically significant differences between patients with moderate and severe QT prolongation were identified; however, patients with severe QT prolongation tended to take more drugs ( = 0.063). 92.7% of patients with QT prolongation took at least one AzCERT-listed drug, most frequently risperidone and pantoprazole. Risperidone and pantoprazole, along with pipamperone, were also most frequently involved in potential drug interactions. All patients displayed additional risk factors for QT prolongation, particularly cardiac diseases.
CONCLUSION
In addition to the use of potentially QT-prolonging drugs, other risk factors, especially cardiac diseases, appear to be relevant for the development of QT prolongation in gerontopsychiatric patients. Pantoprazole was frequently involved in potential drug interactions and should generally not be used for more than 8 weeks in geriatric populations. As clinical consequences of QT prolongation were rare, potentially QT-prolonging drugs should not be used overcautiously; their therapeutic benefit should be considered as well. It is paramount to perform diligent benefit-risk analyses prior to the initiation of potentially QT-prolonging drugs and to closely monitor their clinical (side) effects.
PubMed: 37032947
DOI: 10.3389/fpsyt.2023.1157996 -
International Journal of Environmental... May 2019The number of patients with gastroesophageal problems taking proton pump inhibitors (PPIs) is increasing. Several studies suggested a possible association between PPIs... (Review)
Review
The number of patients with gastroesophageal problems taking proton pump inhibitors (PPIs) is increasing. Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. This review aimed to investigate the longitudinal studies published in the last five years on the relationship between PPIs and fracture risk. The mechanism underlying this relationship was also explored. Overall, PPIs were positively associated with elevated fracture risk in multiple studies ( = 14), although some studies reported no significant relationship ( = 4). Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, mineral absorption, and muscle strength, contributing to increased fracture risk among PPI users. As a conclusion, there is a potential relationship between PPIs and fracture risks. Therefore, patients on long-term PPI treatment should pay attention to bone health status and consider prophylaxis to decrease fracture risk.
Topics: Hip Fractures; Humans; Incidence; Proton Pump Inhibitors
PubMed: 31060319
DOI: 10.3390/ijerph16091571 -
Andrology Nov 2020The effects of PPIs on human sperm fertilizing capacity were poorly investigated although these drugs are widely over-used. Two publications retrospectively studied...
BACKGROUND
The effects of PPIs on human sperm fertilizing capacity were poorly investigated although these drugs are widely over-used. Two publications retrospectively studied relationships between any PPI intake and sperm parameters from patients consulting at infertility clinics, but the conclusions of these reports were contradictory. Only two reports investigated the effects of lansoprazole and omeprazole on sperm motility and found lansoprazole to be deleterious and omeprazole to be neutral for sperm motility. The inconsistency of the PPI effect in the previous reports emphasizes the need for more basic research on human spermatozoa, taking into account the hypothesis that the different PPI drugs may have different effects on sperm physiology.
OBJECTIVES
Do PPIs, which are among the most widely sold drug in the word, impact negatively human sperm capacitation and sperm motility?
MATERIALS AND METHODS
The effects of PPIs on human sperm maturation and motility were analyzed by CASA, flow cytometry, and Western blot.
RESULTS
We tested the impact of 6 different PPIs on human sperm motility and capacitation. We showed that pantoprazole, but not the other PPIs, decreased sperm progressive motility and capacitation-induced sperm hyperactivation. We therefore investigated further the effects of pantoprazole on sperm capacitation, and we observed that it had a significant deleterious effect on the capacitation-induced hyperpolarization of the membrane potential and capacitation-associated protein phosphorylation.
DISCUSSION AND CONCLUSION
Our results indicate that exposure to pantoprazole has an adverse effect on the physiological competence of human spermatozoa. As the capacitation process takes place within the female tract, our results suggest that PPIs intake by the female partner may impair in vivo sperm maturation and possibly fertilization. Moreover, the absence of adverse effect by PPIs on mouse sperm emphasizes the need to develop reprotox assays using human material to better assess the effects of medication intake on sperm physiology.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Fertilization; Humans; Lansoprazole; Male; Membrane Potentials; Middle Aged; Omeprazole; Pantoprazole; Phosphorylation; Proton Pump Inhibitors; Rabeprazole; Retrospective Studies; Semen Analysis; Sperm Capacitation; Sperm Maturation; Sperm Motility; Spermatozoa; Young Adult
PubMed: 32609951
DOI: 10.1111/andr.12855 -
Experimental and Therapeutic Medicine Jun 2023The present network meta-analysis aimed to enhance the corresponding evidence with respect to the efficacy and safety of pharmaceuticals treatments. Frequentist network...
The present network meta-analysis aimed to enhance the corresponding evidence with respect to the efficacy and safety of pharmaceuticals treatments. Frequentist network meta-analysis was used. Medical literature up to November 2022 was searched for randomized clinical trials assessing the efficacy and safety of these pharmaceuticals, either compared with each other or compared with placebo. With the exception of ranitidine (300 mg four times daily) and vonoprazan (20 mg once daily) having lower safety than placebo, the efficacy and safety of the remaining treatments were superior to placebo. Cimetidine (400 mg four times daily) and pantoprazole (40 mg once daily) were ranked first in terms of efficacy. The frequentist network meta-analysis shows that for cimetidine (except 400 mg once daily), famotidine, rabeprazole, ilaprazole, lansoprazole (except 7.5 mg once daily) and omeprazole (except 10 mg once daily or 30 mg once daily), the efficacy comparison between the different doses of each of the aforementioned pharmaceuticals did not indicate statistically significant differences. In conclusion, pantoprazole (40 mg once daily) was the best choice for the initial non-eradication treatment of patients with duodenal ulcer, and cimetidine (400 mg twice daily), omeprazole (20 mg once daily), lansoprazole (15 mg once daily), ilaprazole (5 mg once daily) and rabeprazole (10 mg once daily) could be used as the first choice. If the aforementioned pharmaceuticals cannot be prescribed, famotidine (40 mg twice daily) is recommended.
PubMed: 37206569
DOI: 10.3892/etm.2023.11971 -
Journal of the American Medical... Dec 2022Thoughtful integration of interruptive clinical decision support (CDS) alerts within the electronic health record is essential to guide clinicians on the application of...
Thoughtful integration of interruptive clinical decision support (CDS) alerts within the electronic health record is essential to guide clinicians on the application of pharmacogenomic results at point of care. St. Jude Children's Research Hospital implemented a preemptive pharmacogenomic testing program in 2011 in a multidisciplinary effort involving extensive education to clinicians about pharmacogenomic implications. We conducted a retrospective analysis of clinicians' adherence to 4783 pharmacogenomically guided CDS alerts that triggered for 12 genes and 60 drugs. Clinicians adhered to the therapeutic recommendations provided in 4392 alerts (92%). In our population of pediatric patients with catastrophic illnesses, the most frequently presented gene/drug CDS alerts were TPMT/NUDT15 and thiopurines (n = 3850), CYP2D6 and ondansetron (n = 667), CYP2D6 and oxycodone (n = 99), G6PD and G6PD high-risk medications (n = 51), and CYP2C19 and proton pump inhibitors (omeprazole and pantoprazole; n = 50). The high adherence rate was facilitated by our team approach to prescribing and our collaborative CDS design and delivery.
Topics: Humans; Child; Decision Support Systems, Clinical; Pharmacogenetics; Cytochrome P-450 CYP2D6; Retrospective Studies; Electronic Health Records
PubMed: 36228116
DOI: 10.1093/jamia/ocac187 -
Clinical and Experimental Dental... Oct 2022Proton pump inhibitors, such as omeprazole and pantoprazole, are frequently prescribed for the treatment of acid reflux. However, those medications have been shown to... (Review)
Review
OBJECTIVES
Proton pump inhibitors, such as omeprazole and pantoprazole, are frequently prescribed for the treatment of acid reflux. However, those medications have been shown to affect a variety of physiologic processes, including bone homeostasis and the gastrointestinal microbiome. The objective of this study was to assess the relationship between proton pump inhibitors and attachment levels around teeth and dental implants. A scoping review was performed to assess the extent and quality of the relevant literature.
MATERIALS AND METHODS
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) and searched four relevant biomedical literature databases in addition to the grey literature. Keywords in the title and abstract fields, and subject headings for proton pump inhibitors, teeth, and dental implants were included as search terms.
RESULTS
Overall search results identified 791 publications which, after applying the inclusion and exclusion criteria, yielded 27 publications that were further analyzed for relevance and quality of scientific evidence. The majority of eligible publications were retrospective cohort studies. Following critical analysis, 13 publications, including six abstracts, were used to assess the effect of proton pump inhibitors on tissue attachment around teeth and dental implants.
CONCLUSIONS
There are few high-quality studies describing the effect of proton pump inhibitors on tissue attachment around teeth and dental implants. Nevertheless, among the included papers with the fewest confounding factors, there was a positive relationship between proton pump inhibitors and soft tissue attachment levels around teeth, and a predominantly negative but variable effect of proton pump inhibitors on the bone level around dental implants. Additional well-controlled prospective studies are required to fully elucidate those relationships.
Topics: Dental Implants; Humans; Omeprazole; Pantoprazole; Proton Pump Inhibitors; Retrospective Studies
PubMed: 35799099
DOI: 10.1002/cre2.616 -
Revista Espanola de Enfermedades... Mar 2023A 53-year-old lady with dysfunctional renal transplant and post-surgical hypoparathyroidism with phosphocalcic metabolism impairment was admitted to hospital because of...
A 53-year-old lady with dysfunctional renal transplant and post-surgical hypoparathyroidism with phosphocalcic metabolism impairment was admitted to hospital because of long-lasting epigastric pain and nausea. An esophagogastroduodenoscopy was performed, visualising a nodular lesion of 1 cm diameter with a depressed and ulcerated base. Microscopically the lesion was in relation with a metastatic calcinosis ulcer. Pantoprazole was initiated and serum phosphocalcic levels adjusted, achieving symptom remission. In the follow-up esophagogastroduodenoscopy, the lesion was healing with a fibrinous base and the histopathological report diagnosed superficial gastritis.
PubMed: 36896929
DOI: 10.17235/reed.2023.9495/2023