The effects of the proton pump inhibitor esomeprazole on the bioavailability of regorafenib
Ontology highlight
ABSTRACT:
DISEASE(S): Gist En Mcrc Patienten,Gist And Mcrc Patients
PROVIDER: 2535342 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Primary objectives: 1. To evaluate the area under the plasma concentration-time curve (AUC) of capecitabine alone, compared to capecitabine used with esomeprazole and compared with capacitabine used with esomeprazole and the acid beverage Coca-Cola Classic in patients with CRC or other solid tumours.
Primary endpoints: To evaluate the area under the plasma concentration-time curve (AUC) of capecitabine alone, compared to capecitabine used with esomeprazole and compared with capacitabine used with esomeprazole and the acid beverage Coca-Cola Classic in patients with CRC or other solid tumours.
| 2537538 | ecrin-mdr-crc
Project description:Regorafenib is a novel oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic receptor tyrosine kinases. It is currently registered for GIST and mCRC. When regorafenib is co-administered with an acid suppressive agent, the intra-gastric pH increases, and as a result the equilibrium of ionized/non-ionized regorafenib may shift to the less soluble non-ionized form which reduces regorafenib bioavailability and exposure. Since proton pump inhibitors (PPIs) are often used during regorafenib therapy, this drug-drug interaction (DDI) confronts pharmacists and oncologists with challenges in clinical practice. In this study the investigators will therefore evaluate the impact of PPI-induced intra-gastric pH elevation on regorafenib pharmacokinetics in patients with GIST and mCRC.
| 2217301 | ecrin-mdr-crc
Project description:High-throughput sequencing was used to detect the expression profile of circRNA in PTMC of lymph node metastasis in lateral cervical region, and RT-qPCR was used to detect the expression of circRNA in cancer tissues and normal tissues adjacent to cancer. The receiver operating characteristic (ROC) curve and the area under ROC curve (AUC) were used to evaluate whether CircRNAs could be used as a biomarker for the diagnosis of thyroid cancer. Bioinformatics was used to predict the PTMC-related ceRNA mechanism of lateral cervical lymph node metastasis.
2023-06-08 | GSE205733 | GEO
Project description:BackgroundEsophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery.ObjectiveIn this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities.MethodsWe evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE.ResultsThe EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment.ConclusionThese findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.
| S-EPMC4289084 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) reliably suppress gastric acid secretion and are therefore the first-line treatment for gastric acid-related disorders. Hypomagnesemia (serum magnesium [Mg2+ ] <0.7 mmol/L) is a commonly reported side effect of PPIs. Clinical reports demonstrate that urinary Mg2+ excretion is low in PPI users with hypomagnesemia, suggesting a compensatory mechanism by the kidney for malabsorption of Mg2+ in the intestines. However, the exact mechanism by which PPIs cause impaired Mg2+ absorption is still unknown. In this review, we show that current experimental evidence points toward reduced Mg2+ solubility in the intestinal lumen. Moreover, the absorption pathways in both the small intestine and the colon may be reduced by changes in the expression and activity of key transporter proteins. Additionally, the gut microbiome may contribute to the development of PPI-induced hypomagnesemia, as PPI use affects the composition of the gut microbiome. In this review, we argue that the increase of the luminal pH during PPI treatment may contribute to several of these mechanisms. Considering the fact that bacterial fermentation of dietary fibers results in luminal acidification, we propose that targeting the gut microbiome using dietary intervention might be a promising treatment strategy to restore hypomagnesemia in PPI users.
| S-EPMC9539870 | biostudies-literature
Project description:Proton pump inhibitors (PPIs) are commonly used as a supplement to cancer therapy. Yet, their effect on cancer mortality is largely unknown. Using data from Danish nationwide registries and Cox models regressing of both propensity scores and drug use, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer-specific and noncancer death among PPI users (≥2 prescriptions within six months after diagnosis; n = 36,066) compared with nonusers (<2 prescriptions, n = 311,853) or users of histamine H2 -receptor antagonists (H2 RA; n = 5,152). Adjusted HRs for cancer-specific mortality among postdiagnostic PPI users as compared with nonusers or H2 RA users were 1.29 (95% CI, 1.27-1.32) and 1.15 (95% CI, 1.10-1.20), respectively. HRs for cancer mortality associated with PPI use were highest for ovarian (1.35; 95% CI, 1.20-1.52) and lowest for esophageal cancer (0.91; 95% CI, 0.81-1.04). The associations were stronger among new PPI users after cancer diagnosis, indicating potential confounding. To test the effect of PPIs on tumor growth in a model system free for confounding factors, we investigated the effect of pantoprazole on tumor growth in mice. Pantoprazole (5 mg/kg/day) enhanced tumor growth (p = 0.033) and reduced the antitumor activity of gemcitabine (p = 0.008) in fibrosarcoma-bearing Balb/c mice, but not in immunodeficient Balb/c nude mice. In breast carcinoma-bearing FVB/N mice, pantoprazole had no effect on tumor growth alone but it reduced the life-prolonging effect of doxorubicin significantly (p = 0.007). Taken together, these data raise concerns about the increasing use of PPIs and calls for further studies addressing their safety among cancer patients.
| S-EPMC7611279 | biostudies-literature
Project description:Purpose: Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical obstacle. Development of effective treatment strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Experimental Design: Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and succinate dehydrogenase-deficient GIST) to identify novel kinase targets. In vitro and in vivo studies were performed to evaluate the utility of targeting the identified kinases in GIST. Results: Kinome profiling revealed distinct signatures in three GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in both KIT and PDGFRA-mutant GIST cell lines, as well as notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. Conclusions: These studies provide strong preclinical justification for the use of MK-1775 in GIST.
2021-09-09 | PXD020720 | Pride
Project description:Current guidelines recommend that patients with unexplained chronic cough undergo empirical proton pump inhibitor (PPI) treatment, but scientific evidence for this treatment is lacking. We investigated the effectiveness and appropriate dose of PPI therapy in chronic cough.We included 27 patients with unexplained chronic cough after excluding subjects with positive response to postnasal drip medication. Subjects were randomized to a placebo, standard, and high dose of PPI groups with blinding. The drug or placebo was administered orally for 8 weeks, and the Leicester Cough Questionnaire (LCQ) score and visual analogue scale (VAS) scores were collected.The LCQ score in the PPI group significantly improved from 0 weeks (11.4 ± 1.4) to 4 weeks (14.8 ± 1.4) and to 8 weeks (17.1 ± 1.4), whereas that in the placebo group did not improve from 0 weeks (13.7 ± 1.1) to 8 weeks (11.8 ± 1.4); the difference between the 2 groups was significant (P < 0.001). In subgroup analysis according to reflux, significant improvements in the LCQ score were observed in the PPI group regardless of reflux (P < 0.001 in the reflux group and P < 0.001 in the no reflux group, respectively; P = 0.188 between the 2 groups). In addition, improvements in LCQ and VAS scores between the standard- and high-dose PPI groups were not significantly different; however, adverse reactions were induced by only the high dose (16.7%).The results of this pilot study support the empirical use of the standard dose of PPI for 8 weeks in patients suffering from unexplained chronic cough regardless of whether reflux is present.ClinicalTrial.gov NCT01888549 www.clinicaltrials.gov; cris.nih.go.kr KCT0000543 cris.nih.go.kr/.
| S-EPMC5634560 | biostudies-literature
Project description:A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-? (A?) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by ?- and ?-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on A? production in AD cellular and animal models. We found that lansoprazole enhances A?37, A?40 and A?42 production and lowers A?38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher A?40 levels in brain, indicating that lansoprazole may also exacerbate A? production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.
| S-EPMC3592824 | biostudies-literature
Project description:GoalsThe goal of this study was to elucidate the most important predictors for elevation of gastrin in patients on long-term PPI therapy through analysis of data from 2 published studies in Icelandic patients with erosive GERD.BackgroundGastrin elevation is a known but variable consequence of proton pump inhibitor (PPI) therapy. Concerns have been raised about the clinical importance of chronic PPI induced gastrin elevation.StudyThis cross-sectional analysis included patients with endoscopically verified erosive esophagitis receiving long-term PPI therapy. PPI exposure in dosage over weight (mg/kg) and dosage over body surface area (mg/m) was compared with fasting gastrin levels in two separate multiple linear regression models. Data was collected on age, gender, weight, H. pylori infection, smoking, PPI duration and type.ResultsOverall data from 157 patients (78 females) were analyzed. Median serum gastrin levels were higher in females than males (92 vs. 60?pg/mL; P=0.001). Simple linear regression showed a correlation between serum gastrin levels and gender (P=0.0008) as well as PPI exposure in mg/kg (P=0.0001) and mg/m (P=0.0001). Multiple linear regression analysis showed that PPI exposure, both in mg/kg (?=0.95 [CI=0.4-1.5]; P=0.001) and mg/m (?=0.02 [CI=0.0-0.0]; P=0.0015) along with female gender (?=0.2 [CI=0.0-0.4]; P=0.02) predicted higher gastrin values.ConclusionsDosage and female gender seem to play an important role in the development of gastrin elevation on PPI therapy. A significant correlation was found between fasting serum gastrin and dosage of PPIs over weight and body surface area.
| S-EPMC6800823 | biostudies-literature