[Efficacy of rabeprazole for the treatment of gastroesophageal reflux disease in a 7-day non-interventional trial].

AIM: To evaluate the efficacy of seven-day treatment with rabeprazole (Razo®) 20 mg once daily in patients with NERD and esophagitis based on monitoring the results of pH-impedancemetry of the stomach and esophagus and assessment of clinical symptoms. MATERIALS AND METHODS: Thirty patients with typical GERD manifestations were examined. The study included patients who underwent pH-impedancemetry, endoscopic examination, and were prescribed treatment with rabeprazole at a dose of 20 mg once a day. Clinical monitoring was performed during three visits: before treatment, after 3 days, and after 7 days of treatment. Control pH-impedancemetry was performed after 7 days of therapy. The third visit was the endpoint of the study. RESULTS: After 7 days of treatment, the response rate for heartburn was 86.7% in the overall group of patients with GERD, 94.4% in those with NERD, and 75.0% in patients with esophagitis stage A and B. After 7 days of therapy with rabeprazole, we registered a significant decrease in the total number of refluxes (from 88 to 54; p<0.001), the number of acid refluxes (from 53 to 22; p<0.001), the DeMeester index (from 23.81 to 7.62; p<0.001), and AET (from 7.54 to 2.01; p<0.001) in the esophagus and an increase in the median daily pH (from 1.8 to 5.4; p<0.001) and the time with pH>4 in the stomach (from 2.57 hours and 10.7% up to 12.3 hours and 51.3%; p<0.001). 7-day therapy with rabeprazole was accompanied by a significant improvement in GERD patients in all parameters of quality of life. 100% of patients with GERD rated their satisfaction with therapy as "good" and "very good". CONCLUSION: As a result of 7-day therapy of patients with NERD and esophagitis with Razo® at a dose of 20 mg per day, an excellent clinical response was obtained, confirmed by a marked optimization of pH-impedancemetry parameters.

The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug-Drug Interactions.

BACKGROUND AND OBJECTIVES: Numerous clinical concerns have been expressed regarding the potential worsening of cyclin-dependent kinase 4/6 inhibitor effects in breast cancer patients because of co-administration of proton pump inhibitors. Hence, this study evaluated the effects of proton pump inhibitors on the pharmacokinetics of palbociclib and ribociclib in terms of  cytochrome P450 (CYP) 3A4 and P-glycoprotein involvement. METHODS: The effects of omeprazole and rabeprazole on drug metabolism and efflux of these drugs were investigated using molecular docking, metabolic stability assay in rat liver microsomes, human recombinant CYP3A4 (rCYP3A4) enzymes, and Caco-2 cell monolayers, and in vivo pharmacokinetics with omeprazole and rabeprazole in (5 and 10 mg/kg) 30 min and 7 days before orally dosing palbociclib and ribociclib (10 mg/kg). RESULTS: Omeprazole and rabeprazole inhibited CYP3A4 enzyme activity in rCYP3A4 baculosomes with a 50-60% inhibition at 30 µM. Additionally, both omeprazole and rabeprazole (10 µm) significantly reduced the P-glycoprotein-mediated drug efflux of palbociclib and ribociclib. The 7-day pretreatment of omeprazole at a dose of 10 mg/kg resulted in 24% and 26% reductions in palbociclib's mean maximum plasma concentration) Cmax and area under the plasma concentration-time curve (AUC0-24 h), respectively. Palbociclib's pharmacokinetics were not significantly altered by the pretreatment with rabeprazole; however, ribociclib pharmacokinetics exhibited an 83.94% increase in AUC0-24 h. CONCLUSION: The findings indicate that long-term treatment with therapeutic doses of both omeprazole and rabeprazole can alter the pharmacokinetics of palbociclib and ribociclib. The co-administration of rabeprazole may alter the pharmacokinetics of palbociclib and ribociclib via CYP enzyme and P-glycoprotein inhibition.

Agreement of Different Drug-Drug Interaction Checkers for Proton Pump Inhibitors.

Importance: 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. Objective: To assess the consistency of information on drugs potentially interacting with PPIs as reported in their SPCs and different ICs. Design, Setting, and Participants: 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. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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.

A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells.

FOXM1, a proto-oncogenic transcription factor, plays a critical role in cancer development and treatment resistance in cancers, particularly in breast cancer. Thus, this study aimed to identify potential FOXM1 inhibitors through computational screening of drug databases, followed by in vitro validation of their inhibitory activity against breast cancer cells. In silico studies involved pharmacophore modeling using the FOXM1 inhibitor, FDI-6, followed by virtual screening of DrugBank and Selleckchem databases. The selected drugs were prepared for molecular docking, and the crystal structure of FOXM1 was pre-processed for docking simulations. In vitro studies included MTT assays to assess cytotoxicity, and Western blot analysis to evaluate protein expression levels. Our study identified Pantoprazole and Rabeprazole as potential FOXM1 inhibitors through in silico screening and molecular docking. Molecular dynamics simulations confirmed stable interactions of these drugs with FOXM1. In vitro experiments showed both Pantoprazole and Rabeprazole exhibited strong FOXM1 inhibition at effective concentrations and that showed inhibition of cell proliferation. Rabeprazole showed the inhibitor activity at 10 µM in BT-20 and MCF-7 cell lines. Pantoprazole exhibited FOXM1 inhibition at 30 µM and in BT-20 cells and at 70 µM in MCF-7 cells, respectively. Our current study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1 and inhibit its activity and downstream signaling, including eEF2K and pEF2, in breast cancer cells. These findings indicate that rabeprazole and pantoprazole inhibit FOXM1 and breast cancer cell proliferation, and they can be used for FOXM1-targeted therapy in breast or other cancers driven by FOXM1.

Rabeprazole mitigates obesity-induced chronic inflammation and insulin resistance associated with increased M2-type macrophage polarization.

Macrophage polarization is closely associated with obesity-induced chronic inflammation and insulin resistance. Proton pump inhibitor Rabeprazole has long been used to treat gastritis and gastric ulcers. However, whether Rabeprazole plays a role in macrophage polarization during obesity is unknown. Here, we show that Rabeprazole suppresses M1-type macrophage-mediated inflammation, leads to increased M2-type macrophages and alters the polarization status from M1 to M2 in vitro. Mechanistically, Rabe-regulated macrophage polarization is associated with inhibition of NF-κB and activation of STAT6 signaling pathways. Furthermore, Rabeprazole induces M2-type adipose tissue macrophages and alleviates chronic inflammation, improving glucose tolerance and insulin sensitivity in high-fat diet-fed mice. In addition, Rabeprazole increases CD206+ M2-type liver macrophages and relieves liver inflammation, alleviating liver injury and lipid accumulation. Thus, our findings show that Rabeprazole effectively regulates macrophage polarization and controls obesity-associated chronic inflammation and insulin resistance, thus providing a potential therapeutic strategy against obesity-associated metabolic diseases.

[Comparison of the effectiveness of rabeprazole original and generic products in the monotherapy of gastroesophageal reflux disease].

AIM: To compare the effectiveness of rabeprazole original and generic products in the treatment of gastroesophageal reflux disease (GERD) using impedance-pH monitoring. MATERIALS AND METHODS: Patients (n=35) diagnosed with GERD were divided into two groups. Group 1 patients (n=17, 45.2±1.7 years) received the rabeprazole original product (Pariet) 20 mg/day; Group 2 patients (n=18, 48.1±1.9 years) received 20 mg/day of a generic product. On Day 10 of therapy, all patients underwent 24-hour esophagus impedance-pH monitoring (Ohmega, Medical Measurement Systems, the Netherlands). The percentage of time with pH<4 in the esophagus, the total number and number of acidic, slightly acidic and slightly alkaline gastroesophageal refluxes (GERs), the latency period, and the duration of rabeprazole action were analyzed. The clinical efficacy of the drug was assessed using the GerdQ questionnaire. Statistical data were processed using Microsoft Office 2010 (Excel) and Biostat 2000 software packages. RESULTS: No significant differences were noted between the two groups of patients by gender, age, body mass index, smoking frequency, and GERD type (p>0.05). The average duration of action of the rabeprazole original product was significantly higher than that of the generics (13.2±0.6 and 8.8±0.7 h, respectively, p<0.05). In the rabeprazole original product group, compared to the generics group, the following values were lower: total GERs - 47.0 [43.3; 60.0] and 71.8 [54.3; 95.0], respectively, p<0.05; percentage of time with intraesophageal pH<4 - 1.8 [0.5; 2.3] and 2.1 [0.3; 6.8], respectively, p<0.05; the number of acidic GERs - 4.7 [2.2; 12.0] and 23.3 [12.6; 32.0], respectively, p<0.05. The total GerdQ questionnaire score in Group 1 was significantly lower than in Group 2 (5.4±0.1 vs 6.9±0.4, respectively; p>0.05). CONCLUSION: In treating GERD with the rabeprazole original product compared to generics, a significantly longer duration of acid production suppression, a more pronounced decrease in esophageal acidification, and a more statistically significant clinical improvement were observed.

Repurposing rabeprazole sodium as an anti-Clostridium perfringens drug by inhibiting perfringolysin O.

AIMS: Clostridium perfringens infections affect food safety, human health, and the development of the poultry feed industry. Anti-virulence is an alternative strategy to develop new drug. Perfringolysin O (PFO) is an exotoxin of C. perfringens that has been demonstrated to play critical roles in the pathogenesis of this organism, promising it an attractive target to explore drugs to combat C. perfringens infection. METHODS AND RESULTS: Based on an activity-based screening, we identified six PFO inhibitors from the Food and Drug Administration (FDA)-approved drug library, among which rabeprazole sodium (RS) showed an optimal inhibitory effect with an IC50 of 1.82 ± 0.746 µg ml-1. The GLY57, ASP58, SER190, SER193-194, ASN199, GLU204, ASN377, THR379, and ALA200 in PFO interacted with RS during binding based on an energy analysis and H-bond analysis. This interaction blocked the oligomer formation of PFO, thereby inhibiting its cytotoxicity. RS treatment significantly increased the survival rate and alleviated pathological damage in C. perfringens or PFO-treated Galleria mellonella. CONCLUSIONS: RS could potentially be used as a candidate drug for treating C. perfringens infection.

Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase.

Trypanosoma cruzi is the causative agent of American trypanosomiasis, which mainly affects populations in Latin America. Benznidazole is used to control the disease, with severe effects in patients receiving this chemotherapy. Previous studies have demonstrated the inhibition of triosephosphate isomerase from T. cruzi, but cellular enzyme inhibition has yet to be established. This study demonstrates that rabeprazole inhibits both cell viability and triosephosphate isomerase activity in T. cruzi epimastigotes. Our results show that rabeprazole has an IC50 of 0.4 µM, which is 14.5 times more effective than benznidazole. Additionally, we observed increased levels of methyl-glyoxal and advanced glycation end products after the inhibition of cellular triosephosphate isomerase by rabeprazole. Finally, we demonstrate that the inactivation mechanisms of rabeprazole on triosephosphate isomerase of T. cruzi can be achieved through the derivatization of three of its four cysteine residues. These results indicate that rabeprazole is a promising candidate against American trypanosomiasis.

Augmented nephroprotective effect of liraglutide and rabeprazole via inhibition of OCT2 transporter in cisplatin-induced nephrotoxicity in rats.

AIMS: Cisplatin, a widely used anticancer treatment, has a marked nephrotoxic effect. This nephrotoxic effect is linked to the triggering of oxidative stress, inflammation, activation of mitogen-activated protein kinase (MAPK) pathway as well as apoptosis. The purpose of the present research was to examine the possible ameliorative effect of liraglutide and/or rabeprazole on cisplatin-induced nephrotoxicity in rats and to underline the potential molecular pathways involved. MAIN METHODS: Rats were divided into five groups: Control, cisplatin, liraglutide (200 µg/kg/day, i.p), rabeprazole (10 mg/kg/day, orally) and liraglutide + rabeprazole combination groups. All treatments were given for 7 days. Cisplatin was given as a single dose (7 mg/kg, i.p) at day 4 to induce nephrotoxicity in all groups except the control group. KEY FINDINGS: Treatment with liraglutide and/or rabeprazole prior to cisplatin maintained the function and morphology of kidney via decreasing cisplatin renal uptake by significant inhibition of OCT2. Besides, they showed a significant increase in GLP-1 receptor expression. Liraglutide and/or rabeprazole significantly attenuated the levels of TNF-α. ICAM, NF-κB, and downregulated MAPK pathway proteins such as JNK, and ERK1/2. Moreover, they maintained oxidant antioxidant balance by decreasing MDA level and increasing GSH level and CAT activity. Additionally, liraglutide and/or rabeprazole exhibited antiapoptotic effect evidenced by the decreased caspase-3 level and Bax expression and the increased Bcl-2 expression. SIGNIFICANCE: The current study showed that both liraglutide and rabeprazole exerted a nephroprotective effect against cisplatin-induced renal toxicity in rats. Interestingly, co-treatment with both drugs showed an augmented effect.

Metagenomic Changes of Gut Microbiota following Treatment of Helicobacter pylori Infection with a Simplified Low-Dose Quadruple Therapy with Bismuth or Lactobacillus reuteri.

BACKGROUND: Probiotic supplementation to antibiotic regimens against Helicobacter pylori infection has been proposed to improve eradication rate and to decrease detrimental effects on gut microbiota. AIMS: To evaluate microbiota modifications due to a low-dose quadruple therapy with bismuth or Lactobacillus reuteri. METHODS: Forty-six patients infected with H. pylori were prospectively enrolled in a single-centre, randomized controlled trial to receive b.i.d. with meals for 10 days low-dose quadruple therapy consisting of rabeprazole 20 mg and bismuth (two capsules of Pylera® plus 250 mg each of tetracycline and metronidazole), or the same dose of rabeprazole and antibiotics plus Gastrus® (L. reuteri), one tablet twice-a-day for 27 days. Stool samples were collected at the enrolment, at the end and 30-40 days after the treatment. Gut microbiota composition was investigated with 16S rRNA gene sequencing. RESULTS: Eradication rate was by ITT 78% in both groups, and by PP analysis 85.7% and 95.5% for Gastrus® and bismuth group, respectively. Alpha and beta diversity decreased at the end of treatment and was associated with a reduction of bacterial genera beneficial for gut homeostasis, which was rescued 30-40 days later in both groups, suggesting a similar impact of the two regimens in challenging bacterial community complexity. CONCLUSIONS: Low-dose bismuth quadruple therapy proved to be effective with lower costs and amount of antibiotics and bismuth. Gastrus® might be an option for patients with contraindications to bismuth. L. reuteri was unable to significantly counteract dysbiosis induced by antibiotics. How to administer probiotics to prevent gut microbiota alterations remains an open question.

Identification of novel and potential PPARγ stimulators as repurposed drugs for MCAO associated brain degeneration.

Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.

Rabeprazole Promotes Vascular Repair and Resolution of Sepsis-Induced Inflammatory Lung Injury through HIF-1α.

There are currently no effective treatments for sepsis and acute respiratory distress syndrome (ARDS). The repositioning of existing drugs is one possible effective strategy for the treatment of sepsis and ARDS. We previously showed that vascular repair and the resolution of sepsis-induced inflammatory lung injury is dependent upon endothelial HIF-1α/FoxM1 signaling. The aim of this study was to identify a candidate inducer of HIF-1α/FoxM1 signaling for the treatment of sepsis and ARDS. Employing high throughput screening of a library of 1200 FDA-approved drugs by using hypoxia response element (HRE)-driven luciferase reporter assays, we identified Rabeprazole (also known as Aciphex) as a top HIF-α activator. In cultured human lung microvascular endothelial cells, Rabeprazole induced HIF1A mRNA expression in a dose-dependent manner. A dose-response study of Rabeprazole in a mouse model of endotoxemia-induced inflammatory lung injury identified a dose that was well tolerated and enhanced vascular repair and the resolution of inflammatory lung injury. Rabeprazole treatment resulted in reductions in lung vascular leakage, edema, and neutrophil sequestration and proinflammatory cytokine expression during the repair phrase. We next used Hif1a/Tie2Cre knockout mice and Foxm1/Tie2Cre knockout mice to show that Rabeprazole promoted vascular repair through HIF-1α/FoxM1 signaling. In conclusion, Rabeprazole is a potent inducer of HIF-1α that promotes vascular repair and the resolution of sepsis-induced inflammatory lung injury via endothelial HIF-1α/FoxM1 signaling. This drug therefore represents a promising candidate for repurposing to effectively treat severe sepsis and ARDS.

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors.

Belumosudil is a selective Rho-associated protein kinase 2 inhibitor. Inhibition of Rho-associated protein kinase 2 has emerged as a promising treatment for chronic graft-versus-host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent. As such, this 2-part clinical drug-drug interaction study was conducted to assess the effect of itraconazole (a strong CYP3A4 inhibitor), rifampicin (a strong CYP3A4 inducer), rabeprazole, and omeprazole (both proton pump inhibitors) on the pharmacokinetics of belumosudil. No clinically relevant change in belumosudil exposure was observed following a 200-mg single oral dose of belumosudil with itraconazole; however, exposure of main metabolite, KD025m2, was decreased. Consistent with the proposed metabolic pathway of belumosudil, the strong CYP3A4 inducer rifampicin significantly decreased exposure of belumosudil and KD025m2 and increased KD025m1 exposure. When a 200-mg single oral dose of belumosudil was coadministered with both rabeprazole and omeprazole, parent and metabolite exposures were largely reduced, suggesting that belumosudil dosage should be increased when given with PPIs. Administration of belumosudil with and without perpetrator drugs was safe, and no notable adverse events were reported.

An analysis of the biopharmaceutical behaviour of proton pump inhibitors with different physicochemical properties.

At present, little information on the biopharmaceutical behaviour of proton pump inhibitors (PPIs) describing their absorption and biodistribution in vivo has been reported because the extreme instability of PPIs in the gastrointestinal environment makes it difficult to analyze such behaviour. In this work, a modified rat in situ intestinal perfusion model was employed to investigate absorption in the gastrointestinal tract and subsequent biodistribution of several PPIs (ilaprazole, esomeprazole and rabeprazole), which have different physicochemical properties. Our data indicated that PPIs exhibited significantly enhanced absorption rates in the whole intestine, including the duodenum, jejunum, ileum and colon, corresponding to the increase in the oil-water partition coefficient (LogP). PPIs and corresponding salt types showed no obvious differences in absorption, implying that solubility changes in the PPI have little effect on its absorption in the gastrointestinal tract. Among these PPIs, ilaprazole presented a more stable intestinal absorption behaviour, as well as more distribution and longer residence time in the stomach by HPLC-MS/MS analysis and radioactivity counts after 14C radiolabelling. These results may be useful information for PPI optimization and oral formulation design.

Rabeprazole inhibits inflammatory reaction by inhibition of cell pyroptosis in gastric epithelial cells.

BACKGROUND: Helicobacter pylori (H. pylori) is a common pathogen in development of peptic ulcers with pyroptosis. Rabeprazole, a critical component of standard triple therapy, has been widely used as the first-line regimen for H. pylori infectious treatment. The aim of this study to explore the function of Rabeprazole on cell pyroptosis in vitro. METHODS: The clinical sample from patients diagnosed with or without H. pylori-infection were collected to analyze by Immunohistochemistry (IHC). Real-time quantitative PCR (qPCR), western blot (WB) and enzyme linked immunosorbent assay (Elisa) were performed to analyze the effect of Rabeprazole on cell pyroptosis, including LDH, IL-1ß and IL-18. RESULTS: In this study, we showed that Rabeprazole regulated a phenomenon of cell pyroptosis as confirmed by lactate dehydrogenase (LDH) assay. Further results showed that Rabeprazole inhibited cell pyroptosis in gastric epithelial cells by alleviating GSDMD-executed pyroptosis, leading to decrease IL-1ß and IL-18 mature and secretion, which is attributed to NLRP3 inflammasome activation inhibition. Further analysis showed that ASC, NLRP3 and Caspase-1, was significantly repressed in response to Rabeprazole stimulation, resulting in decreasing cleaved-caspase-1 expression. Most important, NLRP3 and GSDMD is significantly increased in gastric tissue of patients with H. pylori infection. CONCLUSION: These findings revealed a critical role of Rabeprazole in cell pyroptosis in patients with H. pylori infection, suggesting that targeting cell pyroptosis is an alternative strategy in improving H. pylori treatment.

Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants.

Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.

Measurement of low-grade inflammation of the esophageal mucosa with electrical conductivity shows promise in assessing PPI responsiveness in patients with GERD.

A device that can easily measure electrical impedance might be a helpful tool for investigating the pathophysiology of gastroesophageal reflux disease. The first aim of this study was to validate our newly developed bioelectrical admittance measurement (BAM) through in vitro experimentation. The second aim was to investigate whether evaluation of BAM by this measurement differed between patients with heartburn according to their response to proton pump inhibitor (PPI) therapy. Caco-2 cell monolayers and three-dimensional tissues were examined by BAM using a frequency response analyzer. BAM was also used to measure the impedance through cell layers. Subsequently, BAM was performed during endoscopy in 41 patients experiencing heartburn without esophageal mucosal breaks. After 2-wk administration of 20-mg rabeprazole twice daily, patient responses to PPI were classified as "good" or "poor" according to their clinical course. In each patient, histological alterations and gene expression levels of inflammation mediators and tight junction proteins were evaluated. Impedance profiles indicated that monolayer Caco-2 cells on top of eight-layered normal human dermal fibroblasts had the highest magnitude of impedance over the range of frequencies. In vivo results revealed that patients with good responses to PPI displayed significantly higher admittance. Severity of low-grade inflammation was significantly associated with esophageal wall admittance. Moreover, esophageal wall admittance may be more closely related to basal zone hyperplasia than dilatation of intercellular spaces. Thus, BAM may be able to detect abnormalities in the subepithelial layer of the esophagus.NEW & NOTEWORTHY Bioelectrical admittance measurement is a new method to evaluate esophageal mucosal permeability vertically during upper gastrointestinal endoscopy. Measurement of low-grade inflammation of the esophageal mucosa with electrical conductivity shows promise in assessing proton pump inhibitor responsiveness in patients with gastroesophageal reflux disease. As various gastrointestinal diseases are associated with changes in mucosal permeability, bioelectrical admittance measurement is expected to be clinically applied to therapeutic decision-making for these diseases in the future.

Prazoles Targeting Tsg101 Inhibit Release of Epstein-Barr Virus following Reactivation from Latency.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus responsible for several diseases, including cancers of lymphoid and epithelial cells. EBV cancers typically exhibit viral latency; however, the production and release of EBV through its lytic phase are essential for cancer development. Antiviral agents that specifically target EBV production do not currently exist. Previously, we reported that the proton pump inhibitor tenatoprazole, which blocks the interaction of ubiquitin with the ESCRT-1 factor Tsg101, inhibits production of several enveloped viruses, including EBV. Here, we show that three structurally distinct prazoles impair mature particle formation postreactivation and identify the impact on stages of replication. The prazoles did not impair expression of lytic genes representative of the different kinetic classes but interfered with capsid maturation in the nucleus as well as virion transport from the nucleus. Replacement of endogenous Tsg101 with a mutant Tsg101 refractory to prazole-mediated inhibition rescued EBV release. These findings directly implicate Tsg101 in EBV nuclear egress and identify prazoles as potential therapeutic candidates for conditions that rely on EBV replication, such as chronic active EBV infection and posttransplant lymphoproliferative disorders. IMPORTANCE Production of virions is necessary for the ubiquitous Epstein-Barr virus (EBV) to persist in humans and can set the stage for development of EBV cancers in at-risk individuals. In our attempts to identify inhibitors of the EBV lytic phase, we previously found that a prazole proton pump inhibitor, known to block the interaction of ubiquitin with the ESCRT-1 factor Tsg101, blocks production of EBV. We now find that three structurally distinct prazoles impair maturation of EBV capsids and virion transport from the nucleus and, by interfering with Tsg101, prevent EBV release from lytically active cells. Our findings not only implicate Tsg101 in EBV production but also identify widely used prazoles as candidates to prevent development of posttransplant EBV lymphomas.

Rabeprazole: A comprehensive profile.

Rabeprazole belongs to the class of anti-secretory drugs, with benzimidazoles substitution. These drugs induce gastric acid secretion through precise inhibition of the enzyme H+/K+-ATPase (acid or proton pump). This effect helps to treat and prevent conditions in which gastric acid directly aggravates symptoms such as duodenal and gastric ulcers. This chapter includes a comprehensive review of rabeprazole in terms of nomenclature, its physical-chemical properties, methods of preparation and ADME profiles. In addition, the chapter also includes a review of several methods for analysis of rebeprazole in its dosage forms and biological fluids.

Efficacy of Sucralfate-Combined Quadruple Therapy on Gastric Mucosal Injury Induced by Helicobacter pylori and Its Effect on Gastrointestinal Flora.

BACKGROUND: This study explored the therapeutic efficacy of standard triple therapy combined with sucralfate suspension gel as well as the mechanisms of action in mouse models of H. pylori infection. MATERIALS AND METHODS: C57BL/6J mice were randomly divided into 5 groups: NC (natural control), HP (H. pylori infection), RAC (rabeprazole, amoxicillin, and clarithromycin), RACS (RAC and sucralfate suspension gel), and RACB (RAC and bismuth potassium citrate). HE staining and electron microscopy were performed to estimate histological and ultrastructural damages. The IL-8, IL-10, and TNF-α of gastric antrum tissues were measured by immunohistochemistry and qRT-PCR. ZO-1 and Occludin were also detected with immunohistochemistry. The genomes of gastric and fecal microbiota were sequenced. RESULTS: The eradication rate of H. pylori in the RACS group was higher than the RAC group. RACS therapy had protective effects on H. pylori-induced histological and ultrastructural damages, which were superior to the RAC group. RACS therapy reduced the protein and mRNA levels of IL-8 compared with the RAC group. The expression of Occludin in the RACS group was significantly higher than that of the RAC group. The composition of gastric and fecal microbiota for RACS was similar to the RACB group according to PCA. CONCLUSIONS: The RACS regimen eradicated H. pylori infection effectively and showed RACS had protective effects against H. pylori-induced histological and ultrastructural damage. The mechanisms of RACS effects included decreasing IL-8, enhancing Occludin, and transforming gastric microbiota. Moreover, RACS and RACB have a similar effect on gastrointestinal flora.