An update on drug-drug interactions associated with proton pump inhibitors.

INTRODUCTION: Proton pump inhibitors (PPIs) block the gastric H/K-ATPase, therefore inhibiting acid gastric secretion, leading to an increased pH (>4). They account for an extremely high number of prescriptions worldwide. Numerous drug-drug interactions have been described with PPIs, but all the described interactions do not have clinical significance. AREAS COVERED: This review will discuss the latest updates on drug-drug interactions with PPIs, focusing on the last 10-year publications in the following areas: anti-infective agents, anticancer drugs, antiplatelet agents and anticoagulants, and antidiabetics. EXPERT OPINION: Although pharmacokinetic interactions of PPIs have been described with many drugs, their clinical relevance remains controversial. However, given the extremely high number of people being treated with PPIs, clinicians should remain vigilant for interactions that may be clinically significant and require dose adjustment or therapeutic monitoring. Interestingly, not all PPIs have the same pharmacokinetic and pharmacodynamic profile, with some having a strong potential to inhibit CYP2C19, such as omeprazole, esomeprazole, and lansoprazole, while others, pantoprazole, rabeprazole, and dexlansoprazole, are weak CYP2C19 inhibitors. These may be preferred depending on co-prescribed treatments.In addition, new formulations have been developed to prevent some of the gastric pH-dependent drug interactions and should be evaluated in further large-scale prospective comparative studies.

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.

Identification of the New In Vivo Metabolites of Ilaprazole in Rat Plasma after Oral Administration by LC-MS: In Silico Prediction of the H+/K+-ATPase Inhibitor.

Ilaprazole is a proton pump inhibitor used to treat digestive diseases. In this study, blood samples were collected after oral administration of ilaprazole and prepared by liquid-liquid extraction. The metabolites of ilaprazole were detected by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and LC-MSn. A total of twelve in vivo metabolites were detected in rat plasma and six new metabolites of ilaprazole, including one reductive metabolite with sulfide (M3), two hydroxylated metabolites with sulfoxide (M7 and M8), and three oxidative metabolites with sulfone (M9, M11, and M12), were identified. The possible metabolic pathways of ilaprazole and the fragmentation behaviors of its metabolites were elucidated. The result of the in silico prediction indicates that all the new metabolites showed the potential ability to inhibit H+/K+-ATPase activity.

Curcumin as an In Vivo Selective Intestinal Breast Cancer Resistance Protein Inhibitor in Cynomolgus Monkeys.

To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selective BCRP inhibition, in addition to several well known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole. Oral area under the plasma concentration-time curve (AUC) and bioavailability of well known BCRP (sulfasalazine and rosuvastatin), P-glycoprotein (fexofenadine, aliskiren, and talinolol), and CYP3A (midazolam) substrates were investigated in the presence and absence of inhibitors. Oral exposures of sulfasalazine and rosuvastatin were markedly elevated by curcumin with minimal changes in systemic clearance, whereas pharmacokinetic alterations after fexofenadine, aliskiren, and talinolol oral exposure were limited. Curcumin increased oral midazolam exposure without affecting systemic clearance, presumably owing to partial inhibition of intestinal CYP3A. Lapatinib increased the oral AUC for sulfasalazine to a greater extent than curcumin did, whereas pantoprazole had a smaller effect. However, lapatinib also exerted significant effects on fexofenadine, failed to selectively discriminate between BCRP and P-glycoprotein inhibition, and had an effect on oral midazolam exposure comparable with that of curcumin. Thus, pharmacokinetic evaluation in monkeys demonstrated that pretreatment with curcumin as an in vivo selective BCRP inhibitor was more appropriate than pretreatment with lapatinib and pantoprazole for the assessment of the impact of BCRP on gastrointestinal absorption in nonrodent models.

The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats.

PURPOSE: Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals. METHODS: Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography. RESULTS: After surgery, body weight development was equal among groups (P g = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35). CONCLUSIONS: Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.

Tsg101 chaperone function revealed by HIV-1 assembly inhibitors.

HIV-1 replication requires Tsg101, a component of cellular endosomal sorting complex required for transport (ESCRT) machinery. Tsg101 possesses an ubiquitin (Ub) E2 variant (UEV) domain with a pocket that can bind PT/SAP motifs and another pocket that can bind Ub. The PTAP motif in the viral structural precursor polyprotein, Gag, allows the recruitment of Tsg101 and other ESCRTs to virus assembly sites where they mediate budding. It is not known how or even whether the UEV Ub binding function contributes to virus production. Here, we report that disruption of UEV Ub binding by commonly used drugs arrests assembly at an early step distinct from the late stage involving PTAP binding disruption. NMR reveals that the drugs form a covalent adduct near the Ub-binding pocket leading to the disruption of Ub, but not PTAP binding. We conclude that the Ub-binding pocket has a chaperone function involved in bud initiation.

Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier.

Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma. CHEMICAL COMPOUNDS INCLUDED IN THIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).

Pantoprazole blocks the JAK2/STAT3 pathway to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response.

OBJECTIVE: Cancer cachexia is often present in patients with advanced malignant tumors, and the subsequent body weight reduction results in poor quality of life. However, there has been no progress in developing effective clinical therapeutic strategies for skeletal muscle wasting in cancer cachexia. Herein, we explored the functions of pantoprazole on cancer cachexia skeletal muscle wasting. METHODS: The mouse colon adenocarcinoma cell line C26 was inoculated in the right forelimb of male BALB/C mice to establish a cancer cachexia model. The animals were treated with or without different concentrations of pantoprazole orally, and the body weight, tumor growth, spontaneous activity, and muscle functions were determined at various time points. Two weeks later, the levels of serum IL-6 and TNF-α, the mRNA levels of gastrocnemius JAK2 and STAT3, and the expression levels of p-JAK2, p-STAT3, Fbx32, and MuRF1 were examined with ELISA assay, qRT-PCR assay, and Western blotting, respectively. Further studies were performed to assess the levels of Fbx32 and MuRF1 expression and morphological changes. RESULTS: Pantoprazole can alleviate cancer cachexia-induced body weight reduction and inhibit skeletal muscle wasting in a dose-dependent manner. Our results indicated that pantoprazole treatment can decrease the levels of serum IL-6 and TNF-α (56.3% and 67.6%, respectively), and inhibit the activation of the JAK2/STAT3 signaling pathway. Moreover, the expression levels of MuRF1 and Fbx32 were also suppressed after pantoprazole treatment. CONCLUSION: Our findings suggested that pantoprazole can alleviate cancer cachexia skeletal muscle wasting by inhibiting the inflammatory response and blocking the JAK2/STAT3 or ubiquitin proteasome pathway.

Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity.

BACKGROUND: Autophagy is a survival mechanism that allows recycling of cellular breakdown products, particularly in stressed cells. Here we evaluate the hypotheses that up-regulation of autophagy is a common mechanism of resistance to chemotherapy, and that drug resistance can be reversed by inhibiting autophagy with a proton pump inhibitor. METHODS: We exposed human PC3, LNCaP and MCF7 cells to seven clinically-used chemotherapy drugs ± pantoprazole, examined the up-regulation of autophagy and the effect on cellular proliferation by Western Blots, MTS assay and colony-forming assay. The distribution of drug effects and of autophagy was quantified in LNCaP tumor sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3 and p62. RESULTS: All anticancer drugs led to up-regulation of autophagy in cultured tumor cells. Pantoprazole inhibited the induction of autophagy in a time- and dose-dependent manner, and sensitized cancer cells to the seven anti-cancer drugs. Treatment of LNCaP xenografts with paclitaxel induced both DNA damage and autophagy; autophagy was inhibited and markers of toxicity were increased by pantoprazole. CONCLUSIONS: Induction of autophagy is a general mechanism associated with resistance to anticancer drugs and that its inhibition is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes.

Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea.

BACKGROUND/AIMS: Concerns that proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel could hamper the appropriate prescription of PPIs. We evaluated the influence of pantoprazole on the antiplatelet effect of clopidogrel compared with ranitidine, which is regarded as safe, after stratification of the population according to the presence of a cytochrome (CYP) 2C19 polymorphism in Korea. METHODS: Forty patients who underwent dual antiplatelet therapy were randomized to receive pantoprazole (n=20) or ranitidine (n=20). Platelet aggregation was evaluated by impedance aggregometry at baseline (D0) and 8 days after acid-lowering treatments (D9). CYP2C19 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: After co-treatment, the percentage of clopidogrel low-response was 11.1% (2/18) in the pantoprazole group and 10.5% (2/19) in the ranitidine group (p=0.954). The impedance values with adenosine diphosphate stimulus after acid-lowering treatments did not significantly differ between the two groups. In a multiple regression analysis, only ST-elevation myocardial infarction was marginally associated with a reduced antiplatelet effect (odds ratio, 12.07; 95% confidence interval, 0.84 to 173.78). However, pantoprazole use did not affect the antiplatelet effect after correction for the CYP2C19 polymorphism. CONCLUSIONS: This study showed that pantoprazole does not increase platelet aggregation in patients receiving dual antiplatelet therapy (ClinicalTrials.gov number: NCT02733640).

Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase.

T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo.

Nose-to-brain transport of imatinib mesylate: A pharmacokinetic evaluation.

The delivery of drugs to the brain is a constant challenge due to limitations imposed by the blood-brain barrier (BBB). Various methods of bypassing the BBB are under investigation. One approach is intranasal administration, where the olfactory region of the nasal cavity extends up to the cranial cavity and provides direct access to the brain. The pharmacokinetics of this transport and factors that determine transport rates and capacity is of vital importance for evaluating the clinical value of this route. Here, the pharmacokinetics of intranasally administered imatinib has been explored. Imatinib is distributed into the brain following intravenous administration, and then rapidly removed. Following intravenous administration, the brain/plasma ratio for imatinib was calculated to be 2% and remained at this ratio for 30min. The brain/plasma ratio following intranasal administration, however, was found to be 5.3% and remained at this ratio for up to 90min. Imatinib was found to be rapidly transported into the brain via the olfactory region, by shutting down the nose-to-blood-to-brain transport with epinephrine. The increased brain concentration of imatinib (0.33µg/g tissue) achieved by intranasal administration, compared with an IV injection, is likely to provide a model for developing a wide range of CNS active molecules that were previously removed from consideration as drug candidates due to their lack of CNS access. Furthermore, brain imatinib levels were increased by co-administration of the p-gp substrates, elacridar and pantoprazole, showing that both compounds were able to inhibit the elimination of imatinib from the brain.

Does Pantoprazole Affect the On-Treatment Platelet Reactivity in Patients With Acute STEMI Treated With ADP Receptor Blockers?-A Pilot Prospective Study.

BACKGROUND: Proton pump inhibition (PPI) administrated together with adenosine diphosphate (ADP) receptor blockers (ADPRB) significantly reduces the risk of gastrointestinal bleeding. Nevertheless, there is a heated discussion about an interaction between PPI and ADPRB that leads to high on-treatment platelet reactivity (HTPR). STUDY QUESTION: Is there a relationship between pantoprazole PPI and HTPR on ADPRB therapy in patients with acute ST-elevation myocardial infarction (STEMI). METHODS: Single center pilot study in patients with acute STEMI was performed. This study enrolled totally 87 patients (34 clopidogrel-treated and 53 new ADPRB-treated patients). Pantoprazole was administrated in 33 patients. HTPR was detected with ADP-induced light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation analysis. Samples were taken before coronary angiography (sample 1) and on the next day after the procedure (sample 2). RESULTS: No significant differences were found in pantoprazole-treated patients and patients without PPI neither in sample 1 (59.2 ± 29.5% vs. 54.9 ± 22.7%, P = 0.49) nor in sample 2 (43.8 ± 27.2% vs. 37.0 ± 22.9%, P = 0.30). Similarly, there were no significant differences in the platelet reactivity index of vasodilator-stimulated phosphoprotein phosphorylation in both samples (sample 1: 53.3 ± 29.8% vs. 65.0 ± 20.5%, P = 0.11; sample 2: 30.8 ± 27.1% vs. 40.6 ± 27.5%, P = 0.19). A comparison of clopidogrel and new ADP receptor blockers in patients on pantoprazole PPI did not reveal significant differences in on-treatment platelet reactivity. CONCLUSIONS: This study did not reveal interaction between pantoprazole and ADPRB in patients with acute STEMI.

Galloylquinic acid derivatives from Copaifera langsdorffii leaves display gastroprotective activity.

Nine new methylated galloylquinic acids were isolated from an aqueous fraction of Copaifera langsdorffii (Fabaceae-Caesalpinioideae) leaf hydroalcoholic extract (3-8, 11, 12, and 14), along with three known methylated galloylquinic acids (1, 2, and 15) and four galloylquinic acids (9, 10, 13, and 16). These compounds were characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. They were further tested in a gastroprotection assay (Ethanol-HCl induced ulcer model in mice), in which all of them significantly reduced the total lesion area, and increased the cure ratio in comparison with pantoprazole. Also, the tested compounds displayed cytotoxicity against gastric adenocarcinoma cells.

Proton pump inhibitor pantoprazole inhibits the proliferation, self­renewal and chemoresistance of gastric cancer stem cells via the EMT/ß­catenin pathways.

The cancer stem cell (CSC) model suggests that a small subset of cancer cells possess stem cell properties and plays a crucial role in tumor initiation, metastasis and resistance to anticancer therapy. Exploration of the specific therapies targeting at CSCs has been a crucial issue in antitumor research. Gastric cancer (GC) cells often exist in an ischemic microenvironment with acidic conditions in vivo, thus maintenance of cellular pH homeostasis is important for the survival and function of GC cells. Proton pump inhibitors (PPIs) may prevent intracellular proton extrusions which consequently reduce cancer cell survival under acidic conditions. The effects of PPIs on the suppression of the viability and invasiveness of GC cells have been reported, but the functional role of pantoprazole (PPZ) in GC cells remains unknown. In this study, we found that when cells were treated with PPZ, the 5­fluorouracil (5­FU) chemosensitivity was upregulated, meanwhile the sphere formation ability and the relative expression levels of stem cell markers CD44, CD24, ABCG2, EpCAM and Lgr5 were significantly decreased. It was hypothesized that PPZ inhibits the GC CSCs. Successively a sphere formation culture was performed to establish CSC models and the effect of PPZ on GC CSCs from SGC-7901 and HGC­27 cells was explored. The addition of PPZ reduced the relative expression of CSC markers and anti­drug markers accompanied by a decrease in proliferation, 5­FU chemoresistance and self­renewal capacity via epithelial­mesenchymal transition (EMT)/ß­catenin pathways. The study suggests that PPZ could be a promising novel specific therapeutic strategy for targeting GC CSCs.

No effects of pantoprazole on the pharmacokinetics of rosuvastatin in healthy subjects.

PURPOSE: Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin. METHODS: The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers (n = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N-desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N-desmethylrosuvastatin excretion were measured in urine. RESULTS: Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91-1.16]), AUC0-∞ (1.03 [0.89-1.19]) and renal clearance (0.96 [0.85-1.09]) were all within the pre-specified range of 0.8-1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin. CONCLUSIONS: Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.

Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase.

T-cell-originated protein kinase (TOPK) is highly expressed in several cancer cells and promotes tumorigenesis and progression, and therefore, it is an important target for drug treatment of tumor. Pantoprazole (PPZ) was identified to be a TOPK inhibitor from FDA-approved drug database by structure based virtual ligand screening. Herein, the data indicated that pantoprazole inhibited TOPK activities by directly binding with TOPK in vitro and in vivo. Ex vivo studies showed that pantoprazole inhibited TOPK activities in JB6 Cl41 cells and HCT 116 colorectal cancer cells. Moreover, knockdown of TOPK in HCT 116 cells decreased their sensitivities to pantoprazole. Results of an in vivo study demonstrated that i.p. injection of pantoprazole in HCT 116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after pantoprazole treatment. In short, pantoprazole can suppress growth of colorectal cancer cells as a TOPK inhibitor both in vitro and in vivo.

Negative Effect of Proton-pump Inhibitors (PPIs) on Helicobacter pylori Growth, Morphology, and Urease Test and Recovery after PPI Removal--An In vitro Study.

BACKGROUND: Proton-pump inhibitor (PPI) consumption does lead to false-negative results of Helicobacter pylori diagnostic tests such as biopsy culture and rapid urease test (RUT). MATERIALS AND METHODS: Helicobacter pylori isolates from 112 dyspeptic patients with (56.5%) or without (43.5%) PPI consumption were recruited for examining the negative effects of omeprazole (OMP), lansoprazole (LPZ), and pantoprazole (PAN) on H. pylori viability, morphology, and urease, in vitro. The effect of a sublethal concentration of OMP on bacterial features and their recovery after removal of OMP was also assessed. RESULTS: Of 112 culture-positive gastric biopsies, 87.5% were RUT positive and 12.5% RUT negative. There was a significant correlation between negative RUT results and PPI consumption (p < .05). OMP (minimum inhibitory concentration, MIC 32 µg/mL) and LPZ (MIC 8 µg/mL) inhibited the growth of 78.6% of H. pylori isolates. OMP and LPZ inhibited urease of 90.3% of isolates between 0 and 40 minutes and 54.4% between 20 and 40 minutes, respectively. PAN did not inhibit H. pylori growth and urease. Three 3-day (9 days) consecutive subcultures of H. pylori on brucella blood agar (BBA) supplemented with OMP resulted in reduced bacterial viability (1+), compared with control (4+), change of spiral morphology to coccoid, and reduction in pink color intensity in urea agar. Bacterial growth (1+), morphology, and urease test did not improve after the first 3-day and second 3-day (6 days) subcultures on BBA. However, relative recovery occurred after the third 3-day (9 days) subculture and complete recovery was observed after the fourth 3-day (12 days) subculture, as confluent growth (4+), 100% spiral cells, and strong urease test. CONCLUSION: Proton-pump Inhibitors exert transient negative effects on H. pylori viability, morphology, and urease test. Accordingly, cessation of PPI consumption at least 12 days before endoscopy could help avoiding false-negative results of H. pylori diagnostic tests.

Gastric acid induces mucosal H2S release in rats by upregulating mRNA and protein expression of cystathionine gamma lyase.

It is well known that hydrogen sulfide (H2S) protects the gastric mucosa against gastric acid and other noxious stimulants by several mechanisms but until now the effect of gastric acid on H2S production has not been evaluated. This study was performed to determine the effect of basal and stimulated gastric acid secretion on mRNA and protein expression of cystathionine gamma lyase (CSE) and cystathionine beta synthase (CBS), and on mucosal release of H2S in rats. Seventy-two male rats were randomly assigned into 9 groups (8 in each)-control, distention, and pentagastrin-induced gastric acid secretion groups. The effects of 15% alcohol solution, propargylglycine (PAG), L-NAME, and pantoprazole were also investigated. Under anesthesia, animals underwent tracheostomy and midline laparotomy. A catheter was inserted into the stomach through the duodenum for gastric washout. At the end of the experiments, the animals were killed and the gastric mucosa was collected to measure H2S concentration and to quantify mRNA expression of CSE and CBS by quantitative real-time PCR, and expression of their proteins by western blot. Basal and stimulated gastric acid secretion increased mucosal levels of H2S, and mRNA and protein expression of CSE. Pantoprazole and L-NAME reversed H2S release and restored protein expression of CSE to the control level. Pantoprazole, but not propargylglycine, pretreatment inhibited the elevated level of protein expression of eNOS in response to distention-induced gastric acid secretion. Our findings indicated that NO mediated the stimulatory effect of gastric acid on H2S release and protein expression of CSE.

In Silico Profiling of the Potentiality of Curcumin and Conventional Drugs for CagA Oncoprotein Inactivation.

The oncoprotein cytotoxic associated gene A (CagA) of Helicobacter pylori plays a pivotal role in the development of gastric cancer, so it has been an important target for anti-H. pylori drugs. Conventional drugs are currently being implemented against H. pylori. The inhibitory role of plant metabolites like curcumin against H. pylori is still a major scientific challenge. Curcumin may represent a novel promising drug against H. pylori infection without producing side effects. In the present study, a comparative analysis between curcumin and conventional drugs (clarithromycin, amoxicillin, pantoprazole, and metronidazole) was carried out using databases to investigate the potential of curcumin against H. pylori targeting the CagA oncoprotein. Curcumin was filtered using Lipinski's rule of five and the druglikeness property for evaluation of pharmacological properties. Subsequently, molecular docking was employed to determine the binding affinities of curcumin and conventional drugs to the CagA oncoprotein. According to the results obtained from FireDock, the binding energy of curcumin was higher than those of amoxicillin, pantoprazole, and metronidazole, except for clarithromycin, which had the highest binding energy. Accordingly, curcumin may become a promising lead compound against CagA+ H. pylori infection.