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Sample records for gastric proton pump

  1. Beyond gastric acid reduction: Proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells

    SciTech Connect

    Becker, Jan C. . E-mail: beckeja@uni-muenster.de; Grosser, Nina; Waltke, Christian; Schulz, Stephanie; Erdmann, Kati; Domschke, Wolfram; Schroeder, Henning; Pohle, Thorsten

    2006-07-07

    Proton pump inhibitors (PPIs) have been demonstrated to prevent gastric mucosal injury by mechanisms independent of acid inhibition. Here we demonstrate that both omeprazole and lansoprazole protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the heme oxygenase-1 (HO-1) inhibitor ZnBG. Exposure to either PPI resulted in a strong induction of HO-1 expression on mRNA and protein level, and led to an increased activity of this enzyme. Expression of cyclooxygenase isoforms 1 and 2 remained unaffected, and COX-inhibitors did not antagonize HO-1 induction by PPIs. Our results suggest that the antioxidant defense protein HO-1 is a target of PPIs in both endothelial and gastric epithelial cells. HO-1 induction might account for the gastroprotective effects of PPIs independently of acid inhibition, especially in NSAID gastropathy. Moreover, our findings provide additional perspectives for a possible but yet unexplored use of PPIs in vasoprotection.

  2. Effects of proton pump inhibitors on gastric emptying: a systematic review.

    PubMed

    Sanaka, Masaki; Yamamoto, Takatsugu; Kuyama, Yasushi

    2010-09-01

    The proton pump inhibitor (PPI) is widely used for the treatment of gastroesophageal reflux disease, peptic ulcer diseases, and functional dyspepsia. The pathogenesis of these acid-related and/or functional upper gastrointestinal disorders is potentially associated with abnormal gastric emptying. To date, variable effects of PPIs on gastric emptying have been reported. Therefore, it is relevant to gather and analyze published information on this topic. A systematic literature search has been performed, showing that the delaying effect of PPIs on gastric emptying of solid meals is consistent, whereas the effect of PPIs on the emptying of liquids is inconsistent. The underlying mechanisms whereby PPIs may affect gastric emptying have been discussed, most of which still remain hypothetic. Gastric emptying of solids involves a process of peptic hydrolysis. PPIs impair the hydrolytic digestion by inhibiting acid-dependent peptic activity, thereby delaying the solid emptying. Gastric emptying of liquids largely depends on volume and energy density of intragastric contents. PPIs variably modify the volume and the energy density by reducing gastric fluid secretion, thereby modifying the liquid emptying in an unpredictable manner. Hypergastrinemia has been considered to delay gastric emptying, but it seems of minor importance in the regulation of gastric emptying during PPI use. The delayed emptying of solids due to PPI therapy may have clinical implications in the management of gastroesophageal reflux disease, functional dyspepsia, as well as diabetes. PMID:20012198

  3. 16S community profiling identifies proton pump inhibitor related differences in gastric, lung and oropharyngeal microflora

    PubMed Central

    Rosen, Rachel; Hu, Lan; Amirault, Janine; Khatwa, Umakanth; Ward, Doyle V.; Onderdonk, Andrew

    2015-01-01

    Objectives To test the hypothesis that PPI use results in changes in gastric microflora which, through full column reflux, results in lung and oropharyngeal microflora changes. Study design We performed a prospective, cross sectional cohort study of 116 children (57 off and 59 on PPIs) undergoing simultaneous bronchoscopy and upper endoscopy for the evaluation of chronic cough. We performed 16S sequencing on gastric, bronchoalveolar lavage and oropharyngeal fluid. Fifty patients also underwent multichannel intraluminal impedance (pH-MII) testing. Results Streptococcus was more abundant in the gastric fluid of patients taking proton pump inhibitors (PPIs) and there was a significant correlation with PPI dose (mg/kg/day) and abundance of gastric Streptococcus (p=0.01). There was also a significant difference in the abundance of oropharyngeal Streptococcus in PPI treated patients. Eight unique bacterial genera were found in the gastric and lung fluid but not in the oropharyngeal suggesting exchange between the two sites and two of the seven (Lactococcus, Acinetobacter) were more abundant in patients with more full column reflux, suggesting direct aspiration. Principal component analysis revealed greater overlap between gastric and lung than oropharyngeal microflora. Conclusions PPI use was associated with differences in gastric, lung and oropharyngeal microflora. Although microflora exchange can occur between all three sites, gastric and lung microflora are more closely related and the mechanism of exchange between sites may be aspiration of full column reflux. PMID:25661411

  4. Proton Pump Inhibitors Inhibit Pancreatic Secretion: Role of Gastric and Non-Gastric H+/K+-ATPases

    PubMed Central

    Tozzi, Marco; Giannuzzo, Andrea; Sørensen, Christiane E.; Novak, Ivana

    2015-01-01

    The mechanism by which pancreas secretes high HCO3- has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3- from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H+/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition it may provide a protective pH buffer zone and K+ recirculation. Furthermore, it seems relevant to re-evaluate whether PPIs should be used in treatment therapies where pancreatic functions are already compromised. PMID:25993003

  5. Verbascoside isolated from Tectona grandis mediates gastric protection in rats via inhibiting proton pump activity.

    PubMed

    Singh, Neetu; Shukla, Nivedita; Singh, Pratibha; Sharma, Rolee; Rajendran, S M; Maurya, Rakesh; Palit, Gautam

    2010-10-01

    Evidences have suggested that Tectona grandis (TG) attenuates gastric mucosal injury; however its mechanism has not yet been established. The aim of present study was to evaluate the gastroprotective mechanism of ethanolic extract of TG (E-EtOH), butanolic fraction (Fr-Bu) and to identify its active constituents. Anti-ulcer activities were evaluated against cold restraint (CRU) and pyloric ligation (PL) induced gastric ulcer models and further confirmed through H(+) K(+)-ATPase inhibitory activity. Cytoprotective activity was evaluated in alcohol (AL) induced gastric ulcer model and further through PGE(2) level. E-EtOH and Fr-Bu attenuated ulcer formation in CRU. Moreover E-EtOH and Fr-Bu displayed potent anti-secretory activity as evident through reduced free acidity and pepsin activity in PL, confirmed further by in vitro inhibition of H(+) K(+)-ATPase activity. In addition cytoprotective potential of E-EtOH and Fr-Bu were apparent with protection in AL model, increased PGE(2) content and enhanced mucin level in PL. Phytochemical investigations of Fr-Bu yielded terpenoides and a phenolic glycoside, verbascoside. The anti-secretory mechanism of verbascoside mediated apparently through inhibition of H(+) K(+)-ATPase with corresponding decrease in plasma gastrin level, is novel to our finding. Gastroprotection elicited by TG might be through proton pump inhibition and consequent augmentation of the defensive mechanism. PMID:20388534

  6. Teaching the Fundamentals of Biological Research with Primary Literature: Learning from the Discovery of the Gastric Proton Pump

    ERIC Educational Resources Information Center

    Zhu, Lixin

    2011-01-01

    For the purpose of teaching collegians the fundamentals of biological research, literature explaining the discovery of the gastric proton pump was presented in a 50-min lecture. The presentation included detailed information pertaining to the discovery process. This study was chosen because it demonstrates the importance of having a broad range of…

  7. Can proton pump inhibitors reduce rebleeding following Histoacryl sclerotherapy for gastric variceal hemorrhage?

    PubMed Central

    Kim, Ka Rham; Jun, Chung Hwan; Cho, Kyu Man; Wi, Jin Woo; Park, Seon Young; Cho, Sung Bum; Lee, Wan Sik; Park, Chang Hwan; Joo, Young Eun; Kim, Hyun Soo; Choi, Sung Kyu; Rew, Jong Sun

    2015-01-01

    Background/Aims: To evaluate the efficacy of proton pump inhibitors (PPIs) in reducing rebleeding and bleeding-related death rates after endoscopic gastric variceal obliteration (GVO) using N-butyl-2-cyanoacrylate (NBC). Methods: This study enrolled 341 patients who were consecutively diagnosed with and treated for bleeding gastric varices. The patients were divided into PPI and non-PPI groups, and their endoscopic findings, initial hemostasis outcomes, rebleeding and bleeding-related death rates, and treatment-related complications were analyzed. Results: The rate of initial hemostasis was 97.1%. rebleeding occurred in 2.2% of patients within 2 weeks, 3.9% of patients within 4 weeks, 18.9% of patients within 6 months, and 27.6% of patients within 12 months of the GVO procedure. A previous history of variceal bleeding (relative risk [RR], 1.955; 95% confidence interval [CI], 1.263 to 3.028; p = 0.003) and use of PPIs (RR, 0.554; 95% CI, 0.352 to 0.873; p = 0.011) were associated with rebleeding. Child-Pugh class C (RR, 10.914; 95% CI, 4.032 to 29.541; p < 0.001), failure of initial hemostasis (RR, 13.329; 95% CI, 2.795 to 63.556; p = 0.001), and the presence of red-colored concomitant esophageal varices (RR, 4.096; 95% CI, 1.320 to 12.713; p = 0.015) were associated with bleeding-related death. Conclusions: The prophylactic use of PPIs reduces rebleeding after GVO using NBC in patients with gastric variceal hemorrhage. However, prophylactic use of PPIs does not reduce bleeding-related death. PMID:26354053

  8. Proton pump inhibitor administration delays rebleeding after endoscopic gastric variceal obturation

    PubMed Central

    Jang, Won Seok; Shin, Hyun Phil; Lee, Joung Il; Joo, Kwang Ro; Cha, Jae Myung; Jeon, Jung Won; Lim, Jun Uk

    2014-01-01

    AIM: To clarify the efficacy of proton pump inhibitors (PPIs) after endoscopic variceal obturation (EVO) with N-butyl-2-cyanoacrylate. METHODS: A retrospective study was performed on 16 liver cirrhosis patients with gastric variceal bleeding that received EVO with injections of N-butyl-2-cyanoacrylate at a single center (Kyung Hee University Hospital at Gangdong) from January 2008 to December 2012. Medical records including patient characteristics and endoscopic findings were reviewed. Treatment results, liver function, serum biochemistry and cirrhosis etiology were compared between patients receiving PPIs and those that did not. Furthermore, the rebleeding interval was compared between patients that received PPI treatment after EVO and those who did not. RESULTS: The patient group included nine males and seven females with a mean age of 61.8 ± 11.7 years. Following the EVO procedure, eight of the 12 patients that received PPIs and three of the four non-PPI patients experienced rebleeding. There were no differences between the groups in serum biochemistry or patient characteristics. The rebleeding rate was not significantly different between the groups, however, patients receiving PPIs had a significantly longer rebleeding interval compared to non-PPI patients (22.2 ± 11.2 mo vs 8.5 ± 5.5 mo; P = 0.008). The duration of PPI use was not related to the rebleeding interval. A total of six patients, who had ulcers at the injection site, exhibited a shorter rebleeding interval (16.8 ± 5.9 mo) than patients without ulcers (19.9 ± 3.2 mo), though this difference was not statistically significant. CONCLUSION: PPI therapy can extend the rebleeding interval, and should therefore be considered after EVO treatment for gastric varices. PMID:25493026

  9. Influence of proton pump inhibitors on gastritis diagnosis and pathologic gastric changes

    PubMed Central

    Nasser, Soumana C; Slim, Mahmoud; Nassif, Jeanette G; Nasser, Selim M

    2015-01-01

    AIM: To investigate the influence of proton pump inhibitors (PPIs) exposure on the diagnosis of Helicobacter pylori (H. pylori) gastritis and intestinal metaplasia. METHODS: Chronic PPI use is associated with masking of H. pylori infection. Patients with H. pylori infection are predisposed to gastric and duodenal ulcers, and long-term infection with this organism has been associated with gastric mucosal atrophy and serious long-term complications, such as gastric lymphoma and adenocarcinoma. Three hundred patients diagnosed with gastritis between January 2008 and April 2010 were included in our study. The computerized medical database of these patients was reviewed retrospectively in order to assess whether the type of gastritis diagnosed (H. pylori vs non-H. pylori gastritis) is influenced by PPI exposure. H. pylori density was graded as low, if corresponding to mild density following the Updated Sydney System, or high, if corresponding to moderate or severe densities in the Updated Sydney System. RESULTS: Patients were equally distributed between males and females with a median age at the time of diagnosis of 50 years old (range: 20-87). The histological types of gastritis were classified as H. pylori gastritis (n = 156, 52%) and non-H. pylori gastritis (n = 144, 48%). All patients with non-H. pylori gastritis had inactive chronic gastritis. Patients with no previous PPI exposure were more likely to be diagnosed with H. pylori gastritis than those with previous PPI exposure (71% vs 34.2%, P < 0.001). Intestinal metaplasia was more likely to be detected in the latter patients (1.4% vs 6.5%, P = 0.023). Multivariate analysis has also demonstrated that in the presence of previous PPI exposure (OR = 0.217, 95%CI: 0.123-0.385), GERD (OR = 0.317, 95%CI: 0.132-0.763, P = 0.01), alcohol intake (OR = 0.396, 95%CI: 0.195-0.804, P = 0.01), the detection of H. pylori was less likely. Chronic use of PPIs may mask H. pylori infections promoting the diagnosis of non-H. pylori

  10. Non-Specific Gastric Inflammation in Children is Associated with Proton Pump Inhibitor Treatment for More than 6 Weeks

    PubMed Central

    Rosas-Blum, Eduardo; Tatevian, Nina; Hashmi, Syed Shahrukh; Rhoads, Jon Marc; Navarro, Fernando

    2014-01-01

    Background and Aims: Non-specific gastric inflammation (NSGI) is a commonly reported pathological finding. We investigated if it is associated with the use of proton pump inhibitors (PPIs) in children at a single tertiary center. Methods: We performed an IRB-approved chart review of all endoscopy and biopsy reports of patients who underwent esophagogastroduodenoscopy between July 2009 and July 2010 (n = 310). Demographic data, dose, duration of exposure to PPI, and biopsy results were collected and analyzed. All esophageal, gastric, and duodenal biopsies were independently reviewed by a pathologist. Patients with acute gastritis, moderate/severe chronic gastric inflammation, or Helicobacter pylori infection were excluded. The presence of NSGI was compared between patients exposed and not exposed to PPI as well as between patients with different doses and durations of PPI exposure to assess for potential associations. Results: A total of 193 patients were included: 88 (46%) had a history of PPI use and 48 (25%) were found to have NSGI. Compared to patients not exposed to PPI, the odds ratio of NSGI in patients exposed to PPIs was 2.81 (95% CI: 1.36–5.93). The odds ratio of NSGI in patients exposed to PPI for >3 months was 4.53 (95% CI: 1.69–11.97). Gender, ethnicity, and age were not associated with NSGI. No histological differences were found in the esophagus and duodenum between patients exposed and not exposed to PPI. Conclusion: This study found that PPI exposure is associated with NSGI with a higher risk for those exposed for >3 months. As the clinical implications of NSGI are not known, judicious use of PPIs is needed. Prospective studies are required to confirm and to determine the etiologic factors (i.e., alteration of the gastric pH, serum gastrin) that may be related with the presence of NGSI. PMID:24479108

  11. Proton pump inhibitors

    MedlinePlus

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by glands in ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  12. Acidic Digestion in a Teleost: Postprandial and Circadian Pattern of Gastric pH, Pepsin Activity, and Pepsinogen and Proton Pump mRNAs Expression

    PubMed Central

    Yúfera, Manuel; Moyano, Francisco J.; Astola, Antonio; Pousão-Ferreira, Pedro; Martínez-Rodríguez, Gonzalo

    2012-01-01

    Two different modes for regulation of stomach acid secretion have been described in vertebrates. Some species exhibit a continuous acid secretion maintaining a low gastric pH during fasting. Others, as some teleosts, maintain a neutral gastric pH during fasting while the hydrochloric acid is released only after the ingestion of a meal. Those different patterns seem to be closely related to specific feeding habits. However, our recent observations suggest that this acidification pattern could be modified by changes in daily feeding frequency and time schedule. The aim of this study was to advance in understanding the regulation mechanisms of stomach digestion and pattern of acid secretion in teleost fish. We have examined the postprandial pattern of gastric pH, pepsin activity, and mRNA expression for pepsinogen and proton pump in white seabream juveniles maintained under a light/dark 12/12 hours cycle and receiving only one morning meal. The pepsin activity was analyzed according to the standard protocol buffering at pH 2 and using the actual pH measured in the stomach. The results show how the enzyme precursor is permanently available while the hydrochloric acid, which activates the zymogen fraction, is secreted just after the ingestion of food. Results also reveal that analytical protocol at pH 2 notably overestimates true pepsin activity in fish stomach. The expression of the mRNA encoding pepsinogen and proton pump exhibited almost parallel patterns, with notable increases during the darkness period and sharp decreases just before the morning meal. These results indicate that white seabream uses the resting hours for recovering the mRNA stock that will be quickly used during the feeding process. Our data clearly shows that both daily illumination pattern and feeding time are involved at different level in the regulation of the secretion of digestive juices. PMID:22448266

  13. Plant proton pumps.

    PubMed

    Gaxiola, Roberto A; Palmgren, Michael G; Schumacher, Karin

    2007-05-25

    Chemiosmotic circuits of plant cells are driven by proton (H(+)) gradients that mediate secondary active transport of compounds across plasma and endosomal membranes. Furthermore, regulation of endosomal acidification is critical for endocytic and secretory pathways. For plants to react to their constantly changing environments and at the same time maintain optimal metabolic conditions, the expression, activity and interplay of the pumps generating these H(+) gradients have to be tightly regulated. In this review, we will highlight results on the regulation, localization and physiological roles of these H(+)- pumps, namely the plasma membrane H(+)-ATPase, the vacuolar H(+)-ATPase and the vacuolar H(+)-PPase. PMID:17412324

  14. Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells.

    PubMed Central

    Nagata, K; Satoh, H; Iwahi, T; Shimoyama, T; Tamura, T

    1993-01-01

    The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacter pylori cells; the 50% inhibitory concentrations were between 3.6 and 9.5 microM, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents N-ethylmaleimide and idoacetamide were also examined for their inhibition of the urease activity; their 50% inhibitory concentrations were 100- to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth. PMID:8494373

  15. Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells.

    PubMed

    Nagata, K; Satoh, H; Iwahi, T; Shimoyama, T; Tamura, T

    1993-04-01

    The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacter pylori cells; the 50% inhibitory concentrations were between 3.6 and 9.5 microM, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents N-ethylmaleimide and idoacetamide were also examined for their inhibition of the urease activity; their 50% inhibitory concentrations were 100- to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth. PMID:8494373

  16. A possible involvement of Nrf2-mediated heme oxygenase-1 up-regulation in protective effect of the proton pump inhibitor pantoprazole against indomethacin-induced gastric damage in rats

    PubMed Central

    2012-01-01

    Background Proton pump is an integral membrane protein that is ubiquitous ATP binding cassette (ABC) involved in many transport processes in all living organisms, among which a specialized form of pump, so called p-type proton pump, exists in the parietal cells of stomach. Though proton pump inhibitors (PPIs) are frequently prescribed to prevent nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastric damage, the acid suppressive actions do not suffice to explain. Methods In order to document the effects of pantoprazole, one of PPIs, on the NSAIDs-induced gastric damage, in vitro and in vivo studies were performed. Immunocytochemistry, Western blot analysis, electrophoretic mobility shift assay and RT-PCR were conducted to evaluate the induction of heme oxygenase-1 (HO-1) through Nrf2 activation in normal gastric mucosal RGM-1 cells or in vivo stomach tissues from rats treated with indomethacin and/or pantoprazole. Results Pantoprazole activated Nrf2 through inactivation of Keap1, after which the expression of HO-1 was significantly increased in a dose-dependent manner in RGM-1 cells. Increased ARE-DNA binding activity was observed maximally at 1 h with 300 μM of pantoprazole. The expression of HO-1 induced by pantoprazole was significantly associated with the increased in vitro tube formation (P < 0.05) and angiogenic factors including VEGF, bFGF, and HIF-1α. Indomethacin markedly increased the expressions of TNF-α, IL-1ß, IL-8, NOX-1, ICAM-1 and VCAM, whereas pantoprazole significantly decreased the expressions of indomethacin-induced these inflammatory mediators in accord with pantoprazole-induced HO-1 (P < 0.05) as documented with HO-1 inhibitor. In vivo model of indomethacin-induced gastric damage could validate in vitro-drawn results that pantoprazole remarkably protected against indomethacin-induced gastric damage, in which zinc protoporphyrin (5 mg/kg, ip) significantly abolished the protective efficacy of pantoprazole. Conclusion These results

  17. 1-Arylsulfonyl-2-(pyridylmethylsulfinyl) benzimidazoles as new proton pump inhibitor prodrugs.

    PubMed

    Shin, Jai Moo; Sachs, George; Cho, Young-moon; Garst, Michael

    2009-01-01

    New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition. PMID:20032890

  18. 1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New Proton Pump Inhibitor Prodrugs

    PubMed Central

    Shin, Jai Moo; Sachs, George; Cho, Young-moon; Garst, Michael

    2010-01-01

    New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition. PMID:20032890

  19. Histamine 2 Receptor Antagonists and Proton Pump Inhibitors.

    PubMed

    Brinkworth, Megan D; Aouthmany, Mouhammad; Sheehan, Michael

    2016-01-01

    Within the last 50 years, the pharmacologic market for gastric disease has grown exponentially. Currently, medical management with histamine 2 receptor antagonist and proton pump inhibitors are the mainstay of therapy over surgical intervention. These are generally regarded as safe medications, but there are growing numbers of cases documenting adverse effects, especially those manifesting in the skin. Here we review the pharmacology, common clinical applications, and adverse reactions of both histamine 2 receptor antagonists and proton pump inhibitors with a particular focus on the potential for allergic reactions including allergic contact dermatitis. PMID:27172303

  20. Can proton pump inhibitors accentuate skin aging?

    PubMed

    Namazi, Mohammad Reza; Jowkar, Farideh

    2010-02-01

    Skin aging has long been important to human beings and in recent years this field has received tremendous attention by both researchers and the general population. Cutaneous aging includes two distinct phenomena, intrinsic aging and photoaging, and is characterized mainly by the loss of collagen fibers from dermis. Proton pump inhibitors (PPIs) are widely prescribed gastric acid-reducing agents that are usually consumed for long periods in some conditions such as gastroesophageal reflux disease. We suggest that PPIs can accentuate skin aging by two mechanisms. First, through increasing intralysosomal PH, PPIs can suppress transforming growth factor-beta (TGFbeta) processing and consequently decrease its secretion. Second, through inhibiting MNK, a P-type ATPase with steady-state localization at the trans-Golgi network, PPIs can hamper copper transport and consequently curb lysyl oxidase activity. PMID:20470945

  1. Long Term Proton Pump Inhibitor Use and Gastrointestinal Cancer

    PubMed Central

    Graham, David Y.; Genta, Robert M.

    2010-01-01

    Proton pump inhibitors profoundly affect the stomach and have been associated with carcinoid tumors in female rats. There is now sufficient experience with this class of drugs to allow reasonable estimation of their safety in terms of cancer development. Long term proton pump inhibitor use is associated with an increase in gastric inflammation and development of atrophy among those with active Helicobacter pylori infections. The actual risk is unknown but is clearly low. However, it can be markedly reduced or eliminated by H. pylori eradication leading to the recommendation that patients considered for long term proton pump inhibitor therapy be tested for H. pylori infection and if present, it should be eradicated. Oxyntic cell hyperplasia, glandular dilatations, and fundic gland polyps may develop in H. pylori-uninfected patients, but these changes are believed to be reversible and without significant cancer risk. PMID:19006608

  2. Pancreatic Bicarbonate Secretion Involves Two Proton Pumps*

    PubMed Central

    Novak, Ivana; Wang, Jing; Henriksen, Katrine L.; Haanes, Kristian A.; Krabbe, Simon; Nitschke, Roland; Hede, Susanne E.

    2011-01-01

    Pancreas secretes fluid rich in digestive enzymes and bicarbonate. The alkaline secretion is important in buffering of acid chyme entering duodenum and for activation of enzymes. This secretion is formed in pancreatic ducts, and studies to date show that plasma membranes of duct epithelium express H+/HCO3− transporters, which depend on gradients created by the Na+/K+-ATPase. However, the model cannot fully account for high-bicarbonate concentrations, and other active transporters, i.e. pumps, have not been explored. Here we show that pancreatic ducts express functional gastric and non-gastric H+-K+-ATPases. We measured intracellular pH and secretion in small ducts isolated from rat pancreas and showed their sensitivity to H+-K+ pump inhibitors and ion substitutions. Gastric and non-gastric H+-K+ pumps were demonstrated on RNA and protein levels, and pumps were localized to the plasma membranes of pancreatic ducts. Quantitative analysis of H+/HCO3− and fluid transport shows that the H+-K+ pumps can contribute to pancreatic secretion in several species. Our results call for revision of the bicarbonate transport physiology in pancreas, and most likely other epithelia. Furthermore, because pancreatic ducts play a central role in several pancreatic diseases, it is of high relevance to understand the role of H+-K+ pumps in pathophysiology. PMID:20978133

  3. Proton pump inhibitors decrease melanogenesis in melanocytes

    PubMed Central

    BAEK, SEUNG-HWA; LEE, SANG-HAN

    2015-01-01

    Proton pump inhibitors (PPIs) are widely used as inhibitors of gastric juice secretion for treatment of gastroesophageal reflux disease. However, there are no previous studies of the effects on melanogenesis resulting from PPI treatments. Therefore, the aim of the present study was to investigate the effects of PPIs on melanogenesis in melan-a cells derived from immortalized mouse melanocytes. Tyrosinase activity and copper-chelating activity were measured spectrophotometrically. In addition, the melanin content and viability of melan-a cells treated with PPIs were assessed and the mRNA levels of melanogenesis-associated genes were measured by reverse transcription-polymerase chain reaction. Treatment with rabeprazole, but not the other PPIs tested, resulted in strong, dose-dependent inhibition of mushroom tyrosinase (TYR). By contrast, each of the PPIs tested exhibited copper-chelating activity. Treatment of melan-a cells with 100 µM concentrations of the PPIs resulted in significantly reduced melanin synthesis and reduced expression of several melanogenesis-associated genes, including TYR, TYR-related protein-1 (TRP-1) and TRP-2, and microphthalmia-associated transcription factor, but did not result in cytotoxic effects. These results suggest that PPIs inhibit melanin biosynthesis in melan-a cells via the downregulation of melanogenesis-associated genes. Furthermore, the findings indicate that PPIs in general could be utilized as skin-whitening agents and/or as biomaterial for treating hyperpigmentation disorders. PMID:26405553

  4. Proton pump inhibitors and pain.

    PubMed

    Smith, Howard S; Dhingra, Reena; Ryckewaert, Lori; Bonner, Dave

    2009-01-01

    There may be a relationship between proton pump inhibitors (PPIs) and iron absorption. PPIs may decrease the amount of iron absorbed gastrointestinally specifically due to alteration of the pH in the duodenum. Restless legs syndrome (RLS) is a sensorimotor disorder that includes an urge to move legs, accompanied or caused by uncomfortable and unpleasant sensations in the legs; the urge to move begins or worsens during periods of rest or inactivity, the urge to move is partially or totally relieved by movement, and the urge is worse or only occurs at night. In the majority of the restless leg syndrome population, the sensation is deep seated, often described as being in the shin bones, and most commonly felt between the knee and ankle. It may be described as a creepy, shock-like, tense, electric, buzzing, itchy, or even numb sensation. A subpopulation of this restless leg syndrome patient population experiences restless leg syndrome associated pain (RLSAP) that has been described as a deep "achy pain." This pain has not been found to be relieved by many of the typical over the counter analgesics. Often, constant movement of the legs appears to be the only remedy, as these sensations usually appear during periods of rest. Furthermore, there appears to be an association between iron deficiency and those suffering from Restless Leg Syndrome (RLS). The authors theorize that there may be a possible correlation between PPIs and the symptoms (e.g. pain) associated with RLS. The authors propose that PPIs, such as omeprazole, may interfere with iron absorption in certain patients and that a subpopulation of patients who develop significant iron deficiency characterized by low serum ferritin levels while on PPIs may also develop RLS-like symptoms (including RLSAP). While there is no robust direct evidence to support any associations of PPIs and iron deficiency or PPIs associated with RLS-like symptoms (including RLSAP), it is hoped that this manuscript may spark research

  5. Proton Pumps: Mechanism of Action and Applications

    NASA Technical Reports Server (NTRS)

    Lanyi, Janos K.; Pohorille, Andrew; DeVincenzi, Donald L. (Technical Monitor)

    2001-01-01

    Recent progress in understanding molecular structures and mechanisms of action of proton pumps has paved the way to their novel applications in biotechnology. Proton pumps, in particular bacteriorhodopsin and ATP synthases, are capable of continuous, renewable conversion of light to chemical, mechanical or electrical energy, which can be used in macro- or nano-scale devices. The capability of protein systems incorporated into liposomes to generate ATP, which can be further used to drive chemical reactions, and to act as molecular motors has been already demonstrated. Other possible applications of such biochemical devices include targeted drug delivery and biocatalytic re actors. All these devices might prove superior to their inorganic alternatives.

  6. Bacteriorhodopsin: a paradigm for proton pumps?

    PubMed

    Lanyi, J K

    1995-01-01

    Recent studies of the photochemistry of wild type and mutant bacteriorhodopsins, their proton release and uptake kinetics, and their X-ray diffraction structure have suggested a hypothesis for the way energy is coupled in this light-driven proton pump. The first and critical step in converting light energy to a vectorial proton potential is the transfer of the Schiff base proton to D85 which causes dissociation of the Schiff base-counterion complex. Removal of this primarily coulombic interaction destabilizes the protein structure, and results in transition to an alternative conformation in which the two proton conduction pathways between the active site and the membrane surfaces are reorganized. Recovery of the initial charge state of the Schiff base and D85 must therefore occur through a series of unidirectional proton transfers that create a transmembrane electrochemical proton gradient. Passage of the transported proton through the two peripheral protein domains appears to utilize hydrogen bonded networks containing aspartate, arginine and bound water. This kind of mutual interaction between the active site and the protein conformation that determines the conductive pathways to the two membrane surfaces may have relevance to ion pumps in general. PMID:17023319

  7. [Myoclonic encephalopathy associated with proton pump inhibitors].

    PubMed

    Boulliat, J; Polard, E; Colin, F; Bentué-Ferrer, D; Allain, H

    2004-03-01

    Two men (66 and 73 Years) with a cardiovascular history were hospitalized for rapid onset encephalopathy associated with myoclonia and an extrapyramidal syndrome. On the basis of the French Pharmacovigilance system, this symptomatology has been attributed to the coadministration of a proton pump inhibitor, lansoprazole (15mg/day) with levodopa. Lansoprazole withdrawal led to a normalisation of the situation. PMID:15037850

  8. Obscure bleeding colonic duplication responds to proton pump inhibitor therapy.

    PubMed

    Jacques, Jérémie; Projetti, Fabrice; Legros, Romain; Valgueblasse, Virginie; Sarabi, Matthieu; Carrier, Paul; Fredon, Fabien; Bouvier, Stéphane; Loustaud-Ratti, Véronique; Sautereau, Denis

    2013-09-21

    We report the case of a 17-year-old male admitted to our academic hospital with massive rectal bleeding. Since childhood he had reported recurrent gastrointestinal bleeding and had two exploratory laparotomies 5 and 2 years previously. An emergency abdominal computed tomography scan, gastroscopy and colonoscopy, performed after hemodynamic stabilization, were considered normal. High-dose intravenous proton pump inhibitor (PPI) therapy was initiated and bleeding stopped spontaneously. Two other massive rectal bleeds occurred 8 h after each cessation of PPI which led to a hemostatic laparotomy after negative gastroscopy and small bowel capsule endoscopy. This showed long tubular duplication of the right colon, with fresh blood in the duplicated colon. Obscure lower gastrointestinal bleeding is a difficult medical situation and potentially life-threatening. The presence of ulcerated ectopic gastric mucosa in the colonic duplication explains the partial efficacy of PPI therapy. Obscure gastrointestinal bleeding responding to empiric anti-acid therapy should probably evoke the diagnosis of bleeding ectopic gastric mucosa such as Meckel's diverticulum or gastrointestinal duplication, and gastroenterologists should be aware of this potential medical situation. PMID:24124344

  9. Proton pump inhibitory therapy: then and now.

    PubMed Central

    Schepp, W.

    1996-01-01

    Proton pump inhibitors (PPIs) have been established as the new "gold standard" for traditional acid-inhibitory treatment of the so called "peptic" diseases. Due to the high antisecretory and ulcer-healing potency of omeprazole, no major improvements of the efficacy in ulcer healing and pain relief can be expected. Pantoprazole, as a further development in PPIs, is characterized by improved pharmacokinetic behavior as well as by higher tissue selectivity and binding specificity and by a very low potential to interact with the cytochrome P450 enzyme system. These characteristics may provide the basis for a low potential for side effects and for a more favorable interaction profile, although the clinical relevance of these potential advantages remains to be proven. Reflux esophagitis will also remain a domain for the traditional use of PPIs in the future. However, in the treatment of gastroduodenal ulcers, the acid inhibitory potential of PPIs will be used mainly to facilitate the eradication of H. pylori. PMID:9112749

  10. Prophylactic proton pump inhibitors in femoral neck fracture patients - A life - and cost-saving intervention.

    PubMed

    Singh, R; Trickett, R; Meyer, Cer; Lewthwaite, S; Ford, D

    2016-07-01

    Introduction Acute gastrointestinal stress ulceration is a common and serious complication of trauma. Prophylactic proton pump inhibitors (PPIs) or histamine receptor antagonists have been used in poly-trauma, burns and head and spinal injuries, as well as on intensive care units, for the prevention of acute gastric stress ulcers. Methods We prospectively studied the use of prophylactic PPIs in with femoral neck fracture patients, gathering data on all acute gastric ulcer complications, including coffee-ground vomiting, malena and haematemesis. We then implemented a treatment protocol in which all patients were given prophylactic PPIs, again prospectively collecting all data. Results Five hundred and fifteen patients were included. Prior to prophylactic PPI, 15% of patients developed gastric stress ulcer complications, with 3% requiring acute intervention with oesophagogastroduodenoscopy (OGD), 5% requiring transfusions and 4% experiencing surgical delays. All patients had delayed discharges. Following PPI implementation, no patients developed gastric stress ulcer complications. Conclusions Femoral neck fracture patients create a substantial workload for orthopaedic units. The increasingly elderly population often have comorbidities, and concomitantly use medications with gastrointestinal side effects. This, combined with the stress of a fracture and preoperative starvation periods increases the risk of gastric ulcers. Here, the use of prophylactic PPIs statistically reduced the incidence of gastric stress ulcers in patients with femoral neck fractures, resulting in fewer surgical delays, reduced length of hospital stay and reduced stress ulcer-related mortality. PMID:27055405

  11. Influence of proton pump inhibitor use in gastrointestinal polyps.

    PubMed

    Hsu, Wen-Hung; Wu, I-Chen; Kuo, Chao-Hung; Su, Yu-Chung; Lu, Chien-Yu; Kuo, Fu-Chen; Jan, Chang-Ming; Wang, Wen-Ming; Wu, Deng-Chyang; Yu, Fang-Jung

    2010-02-01

    Proton pump inhibitors (PPIs) are the most potent anti-acid agents and are extensively used worldwide. PPI-induced hypergastrinemia is one of the very few side effects associated with these drugs. However, because hypergastrinemia is related to the occurrence of colonic adenomatous polyps, the purpose of this study was to analyze the relationship between the occurrence of gastrointestinal polyps and hypergastrinemia induced by PPIs. This study included 259 patients who underwent colonoscopy and esophagogastroduodenoscopy between January and August 2007. Chart records, including medication history and fasting plasma gastrin level, were reviewed and analyzed. Any subtle polypoid lesions in the stomach and colon were sampled by biopsy for histological examination. Helicobacter pylori infection status was examined by a rapid urea test during esophagogastroduodenoscopy. All patients underwent endoscopy examinations. A total of 122 patients were receiving PPI treatment for either peptic ulcer disease or reflux esophagitis and were included as the study group. The remaining 137 patients were not treated with PPIs and served as the non-PPI group. The mean fasting gastrin level in PPI users versus non-PPI users was 121.8 ng/L versus 56.8 ng/L, respectively (p < 0.001). Although the prevalence of gastric gland polyps was higher in the PPI group (65.6% vs. 37.2%, p < 0.001), there was no difference in the prevalence of colonic adenomatous polyps observed (22.13% vs. 22.62%, p = 0.928). In conclusion, the prevalence of gastric polyps, particularly fundic gland polyps, was higher among PPI users. However, the prevalence of colonic polyps was not affected by PPI use, regardless of past history of colonic adenomatous polyps. PMID:20123595

  12. Antiplatelet agents and proton pump inhibitors – personalizing treatment

    PubMed Central

    Lin, Eugene; Padmanabhan, Rajiv; Moonis, Majaz

    2010-01-01

    Introduction: Antiplatelet therapy remains one of the cornerstones in the management of non-cardioembolic ischemic stroke. However, a significant percentage of patients have concomitant gastroesophageal reflux or peptic ulcer disease that requires acid-reducing medications, the most powerful and effective being the proton pump inhibitors (PPIs). Antiplatelet efficacy, at least in vivo, and particularly for clopidogrel, has been shown to be reduced with concomitant proton pump inhibitor use. Whether this is clinically relevant is not clear from the limited studies available. Methods: We conducted an extensive review of studies available on Medline related to pharmacodynamic interactions between the antiplatelet medications and proton pump inhibitors as well as clinical studies that addressed this potential interaction. Results: Based on the present pharmacodynamic and clinical studies we did not find a significant interaction that would reduce the efficacy of antiplatelet agents with concomitant user of proton pump inhibitors. Conclusions: Patients on antiplatelet agents after a transient ischemic attack or ischemic stroke can safely use aspirin, and extended release dipyridamole/aspirin with proton pump inhibitors. Patients on clopidogrel may use other acid-reducing drugs besides proton pump inhibitors. In rare cases where proton pump inhibitors and clopidogrel have to be used concurrently, careful close monitoring for recurrent vascular events is required. PMID:23226046

  13. Proton pump inhibitors alter the composition of the gut microbiota

    PubMed Central

    Goodrich, Julia K; Maxan, Maria-Emanuela; Freedberg, Daniel E; Abrams, Julian A; Poole, Angela C; Sutter, Jessica L; Welter, Daphne; Ley, Ruth E; Bell, Jordana T; Spector, Tim D; Steves, Claire J

    2016-01-01

    Objective Proton pump inhibitors (PPIs) are drugs used to suppress gastric acid production and treat GI disorders such as peptic ulcers and gastro-oesophageal reflux. They have been considered low risk, have been widely adopted, and are often over-prescribed. Recent studies have identified an increased risk of enteric and other infections with their use. Small studies have identified possible associations between PPI use and GI microbiota, but this has yet to be carried out on a large population-based cohort. Design We investigated the association between PPI usage and the gut microbiome using 16S ribosomal RNA amplification from faecal samples of 1827 healthy twins, replicating results within unpublished data from an interventional study. Results We identified a significantly lower abundance in gut commensals and lower microbial diversity in PPI users, with an associated significant increase in the abundance of oral and upper GI tract commensals. In particular, significant increases were observed in Streptococcaceae. These associations were replicated in an independent interventional study and in a paired analysis between 70 monozygotic twin pairs who were discordant for PPI use. We propose that the observed changes result from the removal of the low pH barrier between upper GI tract bacteria and the lower gut. Conclusions Our findings describe a significant impact of PPIs on the gut microbiome and should caution over-use of PPIs, and warrant further investigation into the mechanisms and their clinical consequences. PMID:26719299

  14. Helicobacter pylori urease inhibition by rabeprazole, a proton pump inhibitor.

    PubMed

    Tsuchiya, M; Imamura, L; Park, J B; Kobashi, K

    1995-08-01

    We investigated the inhibitory effects of four gastric proton pump inhibitors (PPIs): rabeprazole, a novel benzimidazole PPI, omeprazole, lansoprazole and AG-2000, on the urease activity of Helicobacter pylori (H. pylori). Their 50% inhibitory concentrations (I50s) were found to be 0.29, 5.4, 9.3 and 0.3 microM respectively. Rabeprazole and omeprazole were also potent inhibitors of Jack bean and Proteus mirabilis cellular ureases. The thioether derivative of rabeprazole, one of its metabolites, had no inhibitory effect on H. pylori urease, despite being reported as a more potent inhibitor of H. pylori growth than rabeprazole. The inhibitory effect of rabeprazole was prevented completely and reversed considerably by the addition of sulfhydryl compounds, such as beta-mercaptoethanol, glutathione and dithiothreitol. Moreover, the addition of beta-mercaptoethanol recovered the urease activity inhibited by rabeprazole. From these results, we expected that rabeprazole inhibited H. pylori urease activity by forming disulfide bonds between it and the active site of the enzyme. PMID:8535394

  15. Proton Pump Inhibitors and the Prescribing Cascade.

    PubMed

    Rababa, Mohammad; Al-Ghassani, Amal Ali; Kovach, Christine R; Dyer, Elaine M

    2016-04-01

    HOW TO OBTAIN CONTACT HOURS BY READING THIS ARTICLE Instructions 1.3 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded once you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. To obtain contact hours you must: 1. Read the article, "Proton Pump Inhibitors and the Prescribing Cascade" found on pages 23-31, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website listed above to register for contact hour credit. You will be asked to provide your name; contact information; and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until March 31, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. ACTIVITY OBJECTIVES 1. Describe the prescribing cascade of proton pump inhibitors (PPI) in nursing home residents. 2. Identify the statistically

  16. Computer-aided design of a proton pump

    NASA Technical Reports Server (NTRS)

    New, Michael H.; Pohorille, Andrew; Chang, Sherwood (Technical Monitor)

    1997-01-01

    The use of transmembrane proton gradients in energy transduction is an almost universal feature of life on earth. These proton gradients are established and maintained by specialized assemblies of proteins which actively pump protons across membranes. One broad class of proton pumps uses captured light energy to drive the proton pumping. Our goal is to elucidate the minimum structural requirements of a light-driven proton-pump. There are two basic components to a simple light-driven proton pump: a source of photo-generated protons and a "gate-keeper" which prevents these protons from reattaching themselves to their source. A wide variety of molecules in the membrane, even as simple as polycyclic aromatic hydrocarbons, are capable of releasing protons when illuminated. Our work is therefore focused on the design of the "gate-keeper." Our initial model involves a pair of proton acceptors, coupled to each other by a transient water bridge, and supported in the membrane by a small bundle of peptide helices. Upon illumination, the proton source transfers its proton to the:- first acceptor of the gate-keeper. While the reverse reaction is highly probable, all that is needed to ensure irreversibility is a nonvanishing probability that the proton will be transferred to the second acceptor across a transient water bridge. Back transfer of the proton to the first acceptor, and thence to the proton source, is impeded by the free energy required to move the proton uphill towards the. proton source and by the disruption of the transient water bridge. As a prototypical water-bridged proton transfer system, we are studying the transfer of a proton across a water bridge from a formic acid to a formate anion. With a pK(sub alpha), of 3.7. formic acid is a good model for the acidic amino acids glutamate and aspartate which are good candidates for gate-keeper proton acceptors. Simulations of proton transfer reactions in a membrane are complicated by the quantum mechanical nature of

  17. Proton pump inhibitors and risk of dementia

    PubMed Central

    Thongprayoon, Charat; Panjawatanan, Panadeekarn; Ungprasert, Patompong

    2016-01-01

    Background Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications. Recent studies have raised a concern over increased risk of dementia among PPIs users but the results of those studies were inconsistent. We conducted this systematic review and meta-analysis to summarize all available data. Methods A literature search was performed in MEDLINE and EMBASE database from inception to April 2016. Observational studies that reported risk of dementia among PPIs users compared with non-users were included. Point estimates were extracted from individual studies and pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random-effect, generic inverse variance method. Results Four studies were included in the analysis. Pooled RR of dementia among PPIs users compared with non-users was 1.08 (95% CI, 0.82–1.43). Sensitivity analysis including only cohort studies demonstrated a higher risk with pooled RR of 1.44 (95% CI, 1.36–1.52). Conclusions Our study demonstrated an increased risk of dementia among PPIs users. Whether this association is causal requires further investigations. PMID:27429966

  18. Antiplatelet drug interactions with proton pump inhibitors

    PubMed Central

    Scott, Stuart A; Obeng, Aniwaa Owusu; Hulot, Jean-Sébastien

    2014-01-01

    Introduction Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent. Areas covered This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated. Expert opinion Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers. PMID:24205916

  19. Are proton pump inhibitors really so dangerous?

    PubMed

    Savarino, Vincenzo; Dulbecco, Pietro; Savarino, Edoardo

    2016-08-01

    For decades, millions of patients with acid-related disorders have had their acid inhibited effectively and safely first with H2-receptor antagonists (H2RAs) and then with proton pump inhibitors (PPI). As with any pharmacological agent, PPIs have been reported to be associated with some adverse events, but several recent large-scale observational studies have evidenced new and serious abnormalities generally linked to their chronic use. However, these studies have often important limitations for their frequent retrospective design and other methodological drawbacks, such as selection biases of the analyzed populations and the presence of various confounding factors. Overall, although the conclusions of these pharmacovigilant investigations must be taken into account and can generate important hypotheses for future research, they do not have to create panic among patients and alarmism among physicians. On considering the weakness of these studies, we suggest physicians should not refrain from continuing to use PPIs, if these drugs are given for medical indications clearly established in the literature and, more importantly, they should not be induced to shift to H2RAs, a class of antisecretory agents that are much less effective than PPIs. A return to the past is potentially dangerous for the patients, taking into account the well-known success of PPIs in the wide spectrum of all acid-related conditions. PMID:27321544

  20. Antisecretory and antiulcer effect of T-330, a novel reversible proton pump inhibitor, in rats.

    PubMed

    Kinoshita, M; Saito, N; Tamaki, H

    1997-03-01

    The antisecretory and antiulcer effects of T-330 (2-[(2-dimethylaminobenzyl)sulfinyl]-1-(3-methylpyridine-2-yl)imidazole) , a novel reversible proton pump inhibitor, were studied in rats. T-330 suppressed dibutyryl cyclic AMP-stimulated acid formation in isolated rat gastric mucosal cells with the IC50 value of 0.57 microM. In chronic fistula rats, intravenous, intraduodenal and oral administration of T-330 inhibited pentagastrin-stimulated gastric acid secretion; the ED50 values calculated from the peak inhibition were 0.36, 0.43 and 0.73 mg/kg, respectively. T-330 also reduced dimaprit-stimulated gastric acid secretion following its intraduodenal injection (ED50 0.85 mg/kg). The antisecretory activities of T-330 following its intraduodenal and oral administration were 3-6- and 4-10-times more potent than those of omeprazole and ranitidine, respectively, while the duration of action of T-330 was apparently shorter than that of omeprazole and was almost equal to that of ranitidine. Oral or duodenal administration of T-330 inhibited the development of acid-related damage (water-immersion- and aspirin-induced gastric lesions, cysteamine-induced duodenal ulcers and reflux esophagitis) with equal or higher potency than omeprazole or ranitidine. Furthermore, T-330 prevented ethanol-induced gastric lesions. These findings indicate that T-330 exerts its antiulcer effect mainly via its potent antisecretory action and partly via its gastroprotective action. PMID:9085044

  1. Multimorbidities and Overprescription of Proton Pump Inhibitors in Older Patients

    PubMed Central

    Delcher, Anne; Hily, Sylvie; Boureau, Anne Sophie; Chapelet, Guillaume; Berrut, Gilles; de Decker, Laure

    2015-01-01

    Objectives To determine whether there is an association between overprescription of proton pump inhibitors (PPIs) and multimorbidities in older patients. Design Multicenter prospective study. Setting Acute geriatric medicine at the University Hospital of Nantes and the Hospital of Saint-Nazaire. Participants Older patients aged 75 and over hospitalized in acute geriatric medicine. Measurements Older patients in acute geriatric medicine who received proton pump inhibitors. Variables studied were individual multimorbidities, the burden of multimorbidity evaluated by the Cumulative Illness Rating Scale, age, sex, type of residence (living in nursing home or not), functional abilities (Lawton and Katz scales), nutritional status (Body Mass Index), and the type of concomitant medications (antiaggregant, corticosteroids’, or anticoagulants). Results Overprescription of proton pump inhibitors was found in 73.9% older patients. In the full model, cardiac diseases (odds ratio [OR] = 4.17, p = 0.010), metabolic diseases (OR = 2.14, p = 0.042) and corticosteroids (OR = 5.39, p = 0.028) were significantly associated with overprescription of proton pump inhibitors. Esogastric diseases (OR = 0.49, p = 0.033) were negatively associated with overprescription of proton pump inhibitors. Conclusion Cardiac diseases and metabolic diseases were significantly associated with overprescription of proton pump inhibitors. PMID:26535585

  2. Proton pump inhibitors affect the gut microbiome

    PubMed Central

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Tigchelaar, Ettje F; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    2016-01-01

    Background and aims Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. Methods The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. Results 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10−38). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. Conclusions The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs. PMID:26657899

  3. Crystal structure of the plasma membrane proton pump.

    PubMed

    Pedersen, Bjørn P; Buch-Pedersen, Morten J; Morth, J Preben; Palmgren, Michael G; Nissen, Poul

    2007-12-13

    A prerequisite for life is the ability to maintain electrochemical imbalances across biomembranes. In all eukaryotes the plasma membrane potential and secondary transport systems are energized by the activity of P-type ATPase membrane proteins: H+-ATPase (the proton pump) in plants and fungi, and Na+,K+-ATPase (the sodium-potassium pump) in animals. The name P-type derives from the fact that these proteins exploit a phosphorylated reaction cycle intermediate of ATP hydrolysis. The plasma membrane proton pumps belong to the type III P-type ATPase subfamily, whereas Na+,K+-ATPase and Ca2+-ATPase are type II. Electron microscopy has revealed the overall shape of proton pumps, however, an atomic structure has been lacking. Here we present the first structure of a P-type proton pump determined by X-ray crystallography. Ten transmembrane helices and three cytoplasmic domains define the functional unit of ATP-coupled proton transport across the plasma membrane, and the structure is locked in a functional state not previously observed in P-type ATPases. The transmembrane domain reveals a large cavity, which is likely to be filled with water, located near the middle of the membrane plane where it is lined by conserved hydrophilic and charged residues. Proton transport against a high membrane potential is readily explained by this structural arrangement. PMID:18075595

  4. Biological proton pumping in an oscillating electric field.

    PubMed

    Kim, Young C; Furchtgott, Leon A; Hummer, Gerhard

    2009-12-31

    Time-dependent external perturbations provide powerful probes of the function of molecular machines. Here we study biological proton pumping in an oscillating electric field. The protein cytochrome c oxidase is the main energy transducer in aerobic life, converting chemical energy into an electric potential by pumping protons across a membrane. With the help of master-equation descriptions that recover the key thermodynamic and kinetic properties of this biological "fuel cell," we show that the proton pumping efficiency and the electronic currents in steady state depend significantly on the frequency and amplitude of the applied field, allowing us to distinguish between different microscopic mechanisms of the machine. A spectral analysis reveals dominant reaction steps consistent with an electron-gated pumping mechanism. PMID:20366348

  5. Gloeobacter Rhodopsin, Limitation of Proton Pumping at High Electrochemical Load

    PubMed Central

    Vogt, Arend; Wietek, Jonas; Hegemann, Peter

    2013-01-01

    We studied the photocurrents of a cyanobacterial rhodopsin Gloeobacter violaceus (GR) in Xenopus laevis oocytes and HEK-293 cells. This protein is a light-driven proton pump with striking similarities to marine proteorhodopsins, including the D121-H87 cluster of the retinal Schiff base counterion and a glutamate at position 132 that acts as a proton donor for chromophore reprotonation during the photocycle. Interestingly, at low extracellular pHo and negative voltage, the proton flux inverted and directed inward. Using electrophysiological measurements of wild-type and mutant GR, we demonstrate that the electrochemical gradient limits outward-directed proton pumping and converts it into a purely passive proton influx. This conclusion contradicts the contemporary paradigm that at low pH, proteorhodopsins actively transport H+ into cells. We identified E132 and S77 as key residues that allow inward directed diffusion. Substitution of E132 with aspartate or S77 with either alanine or cysteine abolished the inward-directed current almost completely. The proton influx is likely caused by the pKa of E132 in GR, which is lower than that of other microbial ion pumping rhodopsins. The advantage of such a low pKa is an acceleration of the photocycle and high pump turnover at high light intensities. PMID:24209850

  6. The impact of proton pump inhibitors on the human gastrointestinal microbiome

    PubMed Central

    Freedberg, Daniel E.; Lebwohl, Benjamin; Abrams, Julian A.

    2014-01-01

    Potent gastric acid suppression using proton pump inhibitors (PPIs) is common in clinical practice yet may have important effects on human health that are mediated through changes in the gastrointestinal microbiome. Acting through pH-dependent or pH-independent mechanisms, PPIs have the potential to alter the normal microbiota throughout the human gastrointestinal lumen. In the esophagus, PPIs change the normal bacterial milieu to decrease distal esophageal exposure to inflammatory Gram-negative bacteria which may lower the risk of Barrett's esophagus. In the stomach, PPIs alter the abundance and location of gastric Helicobacter pylori and other bacteria, which has implications for peptic ulcer disease and gastric malignancy. In the small bowel, PPIs cause polymicrobial small bowel bacterial overgrowth and have been associated with the diagnosis of celiac disease. In the colon, PPIs associate with incident but not recurrent Clostridium difficile infection, putatively through alterations in commensal colonic anaerobes. Our understanding of the effect of gastric acid suppression on the human gastrointestinal microbiome is incomplete but is rapidly advancing. PMID:25439276

  7. Structure of a Prokaryotic Virtual Proton Pump at 3.2 Astroms Resolution

    SciTech Connect

    Fang, Y.; Jayaram, H; Shane, T; Partensky, L; Wu, F; williams, C; Xiong, Y; Miller, C

    2009-01-01

    To reach the mammalian gut, enteric bacteria must pass through the stomach. Many such organisms survive exposure to the harsh gastric environment (pH 1.5-4) by mounting extreme acid-resistance responses, one of which, the arginine-dependent system of Escherichia coli, has been studied at levels of cellular physiology, molecular genetics and protein biochemistry. This multiprotein system keeps the cytoplasm above pH 5 during acid challenge by continually pumping protons out of the cell using the free energy of arginine decarboxylation. At the heart of the process is a 'virtual proton pump' in the inner membrane, called AdiC, that imports L-arginine from the gastric juice and exports its decarboxylation product agmatine. AdiC belongs to the APC superfamily of membrane proteins, which transports amino acids, polyamines and organic cations in a multitude of biological roles, including delivery of arginine for nitric oxide synthesis, facilitation of insulin release from pancreatic beta-cells, and, when inappropriately overexpressed, provisioning of certain fast-growing neoplastic cells with amino acids. High-resolution structures and detailed transport mechanisms of APC transporters are currently unknown. Here we describe a crystal structure of AdiC at 3.2 A resolution. The protein is captured in an outward-open, substrate-free conformation with transmembrane architecture remarkably similar to that seen in four other families of apparently unrelated transport proteins.

  8. Structure of a prokaryotic virtual proton pump at 3.2 Å resolution

    SciTech Connect

    Fang, Yiling; Jayaram, Hariharan; Shane, Tania; Kolmakova-Partensky, Ludmila; Wu, Fang; Williams, Carole; Xiong, Yong; Miller, Christopher

    2009-09-15

    To reach the mammalian gut, enteric bacteria must pass through the stomach. Many such organisms survive exposure to the harsh gastric environment (pH 1.5-4) by mounting extreme acid-resistance responses, one of which, the arginine-dependent system of Escherichia coli, has been studied at levels of cellular physiology, molecular genetics and protein biochemistry. This multiprotein system keeps the cytoplasm above pH 5 during acid challenge by continually pumping protons out of the cell using the free energy of arginine decarboxylation. At the heart of the process is a 'virtual proton pump' in the inner membrane, called AdiC, that imports L-arginine from the gastric juice and exports its decarboxylation product agmatine. AdiC belongs to the APC superfamily of membrane proteins, which transports amino acids, polyamines and organic cations in a multitude of biological roles, including delivery of arginine for nitric oxide synthesis, facilitation of insulin release from pancreatic {beta}-cells, and, when inappropriately overexpressed, provisioning of certain fast-growing neoplastic cells with amino acids. High-resolution structures and detailed transport mechanisms of APC transporters are currently unknown. Here we describe a crystal structure of AdiC at 3.2 {angstrom} resolution. The protein is captured in an outward-open, substrate-free conformation with transmembrane architecture remarkably similar to that seen in four other families of apparently unrelated transport proteins.

  9. Dexlansoprazole – a new-generation proton pump inhibitor

    PubMed Central

    Radwan, Piotr

    2015-01-01

    Dexlansoprazole modified release (MR) is an R-enantiomer of lansoprazole and a new-generation proton pump inhibitor exhibiting high efficacy in the treatment of symptoms and lesions associated with erosive oesophagitis caused by gastroesophageal reflux disease (GERD). The dual release of the active ingredient – in the duodenum and the small intestine – makes it possible to achieve two peak concentrations at various times, within two and five hours of administration. Dexlansoprazole MR ensures the longest maintenance of drug concentration in the plasma of all known proton pump inhibitors, and the longest proton pump inhibitory effect. The basic indications for the drug include all forms of gastroesophageal reflux disease, especially with night-time heartburn and sleep disorders resulting from GERD. Dexlansoprazole can be taken regardless of meal times. It has a good safety profile and carries a low risk of adverse interactions with other drugs. PMID:26759624

  10. M2 Proton Channel: Toward a Model of a Primitive Proton Pump

    NASA Astrophysics Data System (ADS)

    Wei, Chenyu; Pohorille, Andrew

    2015-06-01

    Transmembrane proton transfer was essential to early cellular systems in order to transduce energy for metabolic functions. The reliable, efficient and controlled generation of proton gradients became possible only with the emergence of active proton pumps. On the basis of features shared by most modern proton pumps we identify the essential mechanistic steps in active proton transport. Further, we discuss the mechanism of action of a small, transmembrane M2 proton channel from influenza A virus as a model for proton transport in protocells. The M2 channel is a 94-residue long, α-helical tetramer that is activated at low pH and exhibits high selectivity and directionality. A shorter construct, built of transmembrane fragments that are only 24 amino acids in length, exhibits very similar proton transport properties. Molecular dynamics simulations on the microsecond time-scale carried out for the M2 channel provided atomic level details on the activation of the channel in response to protonation of the histidine residue, His37. The pathway of proton conduction is mediated by His37, which accepts and donates protons at different interconverting conformation states when pH is lower than 6.5. The Val27 and Trp41 gates and the salt bridge between Asp44 and Arg45 further enhance the directionality of proton transport. It is argued that the architecture and the mechanism of action similar to that found in the M2 channel might have been the perfect starting point for evolution towards the earliest proton pumps, indicating that active proton transport could have readily emerged from simple, passive proton channels.

  11. M2 proton channel: toward a model of a primitive proton pump.

    PubMed

    Wei, Chenyu; Pohorille, Andrew

    2015-06-01

    Transmembrane proton transfer was essential to early cellular systems in order to transduce energy for metabolic functions. The reliable, efficient and controlled generation of proton gradients became possible only with the emergence of active proton pumps. On the basis of features shared by most modern proton pumps we identify the essential mechanistic steps in active proton transport. Further, we discuss the mechanism of action of a small, transmembrane M2 proton channel from influenza A virus as a model for proton transport in protocells. The M2 channel is a 94-residue long, α-helical tetramer that is activated at low pH and exhibits high selectivity and directionality. A shorter construct, built of transmembrane fragments that are only 24 amino acids in length, exhibits very similar proton transport properties. Molecular dynamics simulations on the microsecond time-scale carried out for the M2 channel provided atomic level details on the activation of the channel in response to protonation of the histidine residue, His37. The pathway of proton conduction is mediated by His37, which accepts and donates protons at different interconverting conformation states when pH is lower than 6.5. The Val27 and Trp41 gates and the salt bridge between Asp44 and Arg45 further enhance the directionality of proton transport. It is argued that the architecture and the mechanism of action similar to that found in the M2 channel might have been the perfect starting point for evolution towards the earliest proton pumps, indicating that active proton transport could have readily emerged from simple, passive proton channels. PMID:25777465

  12. Channelrhodopsin-2 is a leaky proton pump

    PubMed Central

    Feldbauer, Katrin; Zimmermann, Dirk; Pintschovius, Verena; Spitz, Julia; Bamann, Christian; Bamberg, Ernst

    2009-01-01

    Since its discovery, the light-gated cation channel Channelrhodopsin-2 (ChR2) has proven to be a long-sought tool for the noninvasive, light-activated control of neural cells in culture and in living animals. Although ChR2 is widely used in neurobiological applications, little is known about its molecular mechanism. In this work, the unitary conductance of ChR2 was determined for different cations, for example 40 fS at 200 mM NaCl and −60 mV, using noise analysis. The kinetics of the ion channel obtained by noise analysis is in excellent agreement with the photocurrent kinetics obtained by voltage-clamp and time-resolved spectroscopy. The inward rectification of the channel could be explained by the single channel parameters. ChR2 represents an ion channel with a 7 transmembrane helix motif, even though the sequence homology of its essential amino acids to those of the light-driven H+ pump bacteriorhodopsin (bR) is high. Here, we also show that when ChR2 is expressed in electrofused giant HEK293 cells or reconstituted on planar lipid membranes, it can indeed act as an outwardly driven H+ pump, demonstrating that ChR2 is bifunctional, and in-line with other microbial rhodopsins, a H+ pump but with a leak that shows ion channel properties. PMID:19590013

  13. Proton/sodium pumping pyrophosphatases: the last of the primary ion pumps.

    PubMed

    Tsai, Jia-Yin; Kellosalo, Juho; Sun, Yuh-Ju; Goldman, Adrian

    2014-08-01

    Membrane-bound pyrophosphatases (M-PPases) are homodimeric enzymes that couple the generation and utilization of membrane potentials to pyrophosphate (PPi) hydrolysis and synthesis. Since the discovery of the link between PPi use and proton transport in purple, non-sulphur bacteria in the 1960s, M-PPases have been found in all three domains of life and have been shown to have a crucial role in stress tolerance and in plant maturation. The discovery of sodium-pumping and sodium/proton-pumping M-PPases showed that the pumping specificity of these enzymes is not limited to protons, further suggesting that M-PPases are evolutionarily very ancient. The recent structures of two M-PPases, the Vigna radiata H(+)-pumping M-PPase and Thermotoga maritima Na(+)-pumping M-PPase, provide the basis for understanding the functional data. They show that M-PPases have a novel fold and pumping mechanism, different to the other primary pumps. This review discusses the current structural understanding of M-PPases and of ion selection among various M-PPases. PMID:24768824

  14. Sodium and Proton Effects on Inward Proton Transport through Na/K Pumps

    PubMed Central

    Mitchell, Travis J.; Zugarramurdi, Camila; Olivera, J. Fernando; Gatto, Craig; Artigas, Pablo

    2014-01-01

    The Na/K pump hydrolyzes ATP to export three intracellular Na (Nai) as it imports two extracellular K (Ko) across animal plasma membranes. Within the protein, two ion-binding sites (sites I and II) can reciprocally bind Na or K, but a third site (site III) exclusively binds Na in a voltage-dependent fashion. In the absence of Nao and Ko, the pump passively imports protons, generating an inward current (IH). To elucidate the mechanisms of IH, we used voltage-clamp techniques to investigate the [H]o, [Na]o, and voltage dependence of IH in Na/K pumps from ventricular myocytes and in ouabain-resistant pumps expressed in Xenopus oocytes. Lowering pHo revealed that Ho both activates IH (in a voltage-dependent manner) and inhibits it (in a voltage-independent manner) by binding to different sites. Nao effects depend on pHo; at pHo where no Ho inhibition is observed, Nao inhibits IH at all concentrations, but when applied at pHo that inhibits pump-mediated current, low [Na]o activates IH and high [Na]o inhibits it. Our results demonstrate that IH is a property inherent to Na/K pumps, not linked to the oocyte expression environment, explains differences in the characteristics of IH previously reported in the literature, and supports a model in which 1), protons leak through site III; 2), binding of two Na or two protons to sites I and II inhibits proton transport; and 3), pumps with mixed Na/proton occupancy of sites I and II remain permeable to protons. PMID:24940773

  15. Sodium and proton effects on inward proton transport through Na/K pumps.

    PubMed

    Mitchell, Travis J; Zugarramurdi, Camila; Olivera, J Fernando; Gatto, Craig; Artigas, Pablo

    2014-06-17

    The Na/K pump hydrolyzes ATP to export three intracellular Na (Nai) as it imports two extracellular K (Ko) across animal plasma membranes. Within the protein, two ion-binding sites (sites I and II) can reciprocally bind Na or K, but a third site (site III) exclusively binds Na in a voltage-dependent fashion. In the absence of Nao and Ko, the pump passively imports protons, generating an inward current (IH). To elucidate the mechanisms of IH, we used voltage-clamp techniques to investigate the [H]o, [Na]o, and voltage dependence of IH in Na/K pumps from ventricular myocytes and in ouabain-resistant pumps expressed in Xenopus oocytes. Lowering pHo revealed that Ho both activates IH (in a voltage-dependent manner) and inhibits it (in a voltage-independent manner) by binding to different sites. Nao effects depend on pHo; at pHo where no Ho inhibition is observed, Nao inhibits IH at all concentrations, but when applied at pHo that inhibits pump-mediated current, low [Na]o activates IH and high [Na]o inhibits it. Our results demonstrate that IH is a property inherent to Na/K pumps, not linked to the oocyte expression environment, explains differences in the characteristics of IH previously reported in the literature, and supports a model in which 1), protons leak through site III; 2), binding of two Na or two protons to sites I and II inhibits proton transport; and 3), pumps with mixed Na/proton occupancy of sites I and II remain permeable to protons. PMID:24940773

  16. Spectrophotometric Determination of Certain Benzimidazole Proton Pump Inhibitors

    PubMed Central

    Syed, A. A.; Syeda, Ayesha

    2008-01-01

    Spectrophotometric method for the determination of certain proton pump inhibitors belonging to the benzimidazole class of compounds has been developed. The method is based on the reaction of omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole with iron (III) and subsequent reaction with ferricyanide under neutral condition which yields Prussian blue product with maximum absorption at 720–730 nm. The commonly encountered excipients and additives that often accompany pharmaceutical preparations did not interfere with the determination. The method was applied for the determination of omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole in pharmaceutical preparations and no difference was found statistically. Thus, the spectrophotometric method can be applied as inexpensive, rapid, easy, accurate and precise method for the routine analysis of the five proton pump inhibitors in pharmaceutical preparations. PMID:20046782

  17. [Mechanisms of proton pumping in bacteriorhodopsin]. Progress report

    SciTech Connect

    Ebrey, T.G.

    1995-12-31

    This report consists of two parts namely a brief statement of the progress made during the past four years of the project and more extensive discussion of the current state of understanding of molecular mechanisms controlling the proton pump (bacteriorhodopsin). Detailed descriptions are provided of how the protein undergoes conformational changes on absorbing a photon. Studies are described where the protein structure has been manipulated and the biochemical properties are assessed.

  18. Eosinophilic esophagitis that develops during therapy with proton pump inhibitors : case series and possible mechanisms.

    PubMed

    Orel, R; Murch, S; Amil Dias, J; Vandenplas, Y; Homan, M

    2016-01-01

    Therapy with proton-pump inhibitors (PPIs) results in remission in at least one third of patients with esophageal eosinophilia, presumably because of both their acid-related and anti-inflammatory mechanisms of action. However, eosinophilic esophagitis (EoE) may also develop during therapy with PPIs. We present a case series of four children who were initially diagnosed with infectious esophagitis, gastroesophageal reflux disease or gastric ulcer, who had no eosinophilic infiltration of the esophagus, but subsequently developed symptoms, endoscopic features and histological picture of typical EoE. We discuss mechanisms of action of PPIs of likely relevance to an increased risk of development of EoE in some patients, such as their influence on mucosal barrier function, interference with pH-related protein digestion by pepsin, and antigen processing by immune cells. PMID:27382946

  19. Resolution of Fundic Gland Polyposis following Laparoscopic Magnetic Sphincter Augmentation and Subsequent Cessation of Proton Pump Inhibitors

    PubMed Central

    Brockmeyer, Joel R.; Connolly, Erin E.; Wittchow, Richard J.; Kothari, Shanu N.

    2015-01-01

    Gastric polyps occur from a variety of sources and are found commonly on upper endoscopy. We present the case of a 49-year-old female who presented for evaluation for antireflux surgery with a history of fundic gland polyposis who required twice-daily proton pump inhibitors (PPIs) for control of her gastric reflux. After verifying that she met criteria for surgery, she underwent an uncomplicated laparoscopic magnetic sphincter augmentation placement. With the cessation of PPIs following surgery, the fundic gland polyposis resolved. Fundic gland polyps may occur sporadically or within certain syndromes, such as familial adenomatous polyposis. Multiple possible inciting factors exist, including the use of PPIs. This is the first reported case of the resolution of numerous fundic gland polyps following the completion of laparoscopic magnetic sphincter augmentation. PMID:26600954

  20. Effect of the proton pump inhibitor omeprazole on the gastrointestinal bacterial microbiota of healthy dogs.

    PubMed

    Garcia-Mazcorro, Jose F; Suchodolski, Jan S; Jones, Katherine R; Clark-Price, Stuart C; Dowd, Scot E; Minamoto, Yasushi; Markel, Melissa; Steiner, Jörg M; Dossin, Olivier

    2012-06-01

    The effect of a proton pump inhibitor on gastrointestinal (GI) microbiota was evaluated. Eight healthy 9-month-old dogs (four males and four females) received omeprazole (1.1 mg kg(-1) ) orally twice a day for 15 days. Fecal samples and endoscopic biopsies from the stomach and duodenum were obtained on days 30 and 15 before omeprazole administration, on day 15 (last day of administration), and 15 days after administration. The microbiota was evaluated using 16S rRNA gene 454-pyrosequencing, fluorescence in situ hybridization, and qPCR. In the stomach, pyrosequencing revealed a decrease in Helicobacter spp. during omeprazole (median 92% of sequences during administration compared to > 98% before and after administration; P = 0.0336), which was accompanied by higher proportions of Firmicutes and Fusobacteria. FISH confirmed this decrease in gastric Helicobacter (P < 0.0001) and showed an increase in total bacteria in the duodenum (P = 0.0033) during omeprazole. However, Unifrac analysis showed that omeprazole administration did not significantly alter the overall phylogenetic composition of the gastric and duodenal microbiota. In feces, qPCR showed an increase in Lactobacillus spp. during omeprazole (P < 0.0001), which was accompanied by a lower abundance of Faecalibacterium spp. and Bacteroides-Prevotella-Porphyromonas in the male dogs. This study suggests that omeprazole administration leads to quantitative changes in GI microbiota of healthy dogs. PMID:22324305

  1. Clinical relevance of clopidogrel-proton pump inhibitors interaction

    PubMed Central

    Bouziana, Stella D; Tziomalos, Konstantinos

    2015-01-01

    Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal anti-inflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk. PMID:25949846

  2. Exchangers man the pumps: Functional interplay between proton pumps and proton-coupled Ca(2+) exchangers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tonoplast-localised proton-coupled Ca(2+) transporters encoded by cation/H(+) exchanger (CAX) genes play a critical role in sequestering Ca(2+) into the vacuole. These transporters may function in coordination with Ca(2+) release channels, to shape stimulus-induced cytosolic Ca(2+) elevations. Recen...

  3. The Proton Pump Inhibitor Non-Responder: A Clinical Conundrum

    PubMed Central

    Hussain, Zilla H; Henderson, Emily E; Maradey-Romerao, Carla; George, Nina; Fass, Ronnie; Lacy, Brian E

    2015-01-01

    Gastroesophageal reflux disease (GERD) is a highly prevalent chronic condition where in stomach contents reflux into the esophagus causing symptoms, esophageal injury, and subsequent complications. Proton pump inhibitors (PPI) remain the mainstay of therapy for acid suppression. Despite their efficacy, significant proportions of GERD patients are either partial or non-responders to PPI therapy. Patients should be assessed for mechanisms that can lead to PPI failure and may require further evaluation to investigate for alternative causes. This monograph will outline a diagnostic approach to the PPI non-responder, review mechanisms associated with PPI failure, and discuss therapeutic options for those who fail to respond to PPI therapy. PMID:26270485

  4. Effect of a proton pump inhibitor on the pharmacokinetics of imatinib

    PubMed Central

    Egorin, Merrill J; Shah, Dhvani D; Christner, Susan M; Yerk, Mara A; Komazec, Kristin A; Appleman, Leonard R; Redner, Robert L; Miller, Brian M; Beumer, Jan H

    2009-01-01

    AIMS Imatinib mesylate (Gleevec®/Glivec®), which has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumours (GIST), has been reported to cause gastric upset. Consequently, proton pump inhibitors (PPI) are frequently co-administered with imatinib. Because PPI can elevate gastric pH and delay gastric emptying or antagonize ATP-binding-cassette transporters, they could influence imatinib absorption and pharmacokinetics. We aimed to evaluate whether use of omeprazole has a significant effect on imatinib pharmacokinetics. METHODS Twelve healthy subjects were enrolled in a two-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg imatinib orally. In the other period, 40 mg omeprazole (Prilosec®) was administered orally for 5 days, and on day 5 it was administered 15 min before 400 mg imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS, and data were analyzed non-compartmentally. RESULTS PPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 µg ml−1 h alone vs 33.1 µg ml−1 h with omeprazole, P= 0.64; 80% power), maximum plasma concentration (Cmax) (2.04 µg ml−1 alone vs 2.02 µg ml−1 with omeprazole, P= 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P= 0.13). CONCLUSIONS Our results indicate that the use of omeprazole does not significantly affect the pharmacokinetics of imatinib, as opposed to, for example, dasatinib where PPI decreased AUC and Cmax two-fold. PMID:19740393

  5. Effect of proton pump inhibitors on glycemic control in patients with diabetes

    PubMed Central

    Takebayashi, Kohzo; Inukai, Toshihiko

    2015-01-01

    Gastrin is a linear peptide hormone which is secreted mostly in the stomach pyloric antrum G cells. Although the main role of this hormone is the promotion of the secretion of gastric acid from the stomach parietal cells, gastrin can also behave as a growth factor and stimulate gastric cell proliferation. It is also reported that gastrin promotes β cell neogenesis in the pancreatic ductal complex, modest pancreatic β cell replication, and improvement of glucose tolerance in animal models, in which the remodeling of pancreatic tissues is promoted. These findings suggest the possibility that gastrin has the potential to promote an increase of β cell mass in pancreas, and therefore that gastrin may improve glucose tolerance. Proton pump inhibitors (PPIs) are wildly used clinically for the therapy of gastro-esophageal reflex disease, gastritis due to excess stomach acid, and gastric ulcers. PPIs indirectly elevate serum gastrin levels via a negative feedback effect. Recent evidence has revealed the beneficial effect of PPIs on glycemic control especially in patients with type 2 diabetes mellitus (T2DM), probably via the elevation of the levels of serum gastrin, although the detailed mechanism remains unclear. In addition, the beneficial effects of a combination therapy of gastrin or a PPI with a glucagon-like peptide-1 receptor agonist on glycemic control in animal models have been demonstrated. Although PPIs may be possible candidates for a new approach in the therapy of diabetes, a prospective, long-term, randomized, double-blind, placebo-controlled study is needed to establish the effect of PPIs on glycemic control in a large number of patients with T2DM. PMID:26322158

  6. Halorhodopsin pumps Cl– and bacteriorhodopsin pumps protons by a common mechanism that uses conserved electrostatic interactions

    PubMed Central

    Gunner, M. R.

    2014-01-01

    Key mutations differentiate the functions of homologous proteins. One example compares the inward ion pump halorhodopsin (HR) and the outward proton pump bacteriorhodopsin (BR). Of the nine essential buried ionizable residues in BR, six are conserved in HR. However, HR changes three BR acids, D85 in a central cluster of ionizable residues, D96, nearer the intracellular, and E204, nearer the extracellular side of the membrane to the small, neutral amino acids T111, V122, and T230, respectively. In BR, acidic amino acids are stationary anions whose proton affinity is modulated by conformational changes, establishing a sequence of directed binding and release of protons. Multiconformation continuum electrostatics calculations of chloride affinity and residue protonation show that, in reaction intermediates where an acid is ionized in BR, a Cl– is bound to HR in a position near the deleted acid. In the HR ground state, Cl– binds tightly to the central cluster T111 site and weakly to the extracellular T230 site, recovering the charges on ionized BR-D85 and neutral E204 in BR. Imposing key conformational changes from the BR M intermediate into the HR structure results in the loss of Cl– from the central T111 site and the tight binding of Cl– to the extracellular T230 site, mirroring the changes that protonate BR-D85 and ionize E204 in BR. The use of a mobile chloride in place of D85 and E204 makes HR more susceptible to the environmental pH and salt concentrations than BR. These studies shed light on how ion transfer mechanisms are controlled through the interplay of protein and ion electrostatics. PMID:25362051

  7. Halorhodopsin pumps Cl- and bacteriorhodopsin pumps protons by a common mechanism that uses conserved electrostatic interactions.

    PubMed

    Song, Yifan; Gunner, M R

    2014-11-18

    Key mutations differentiate the functions of homologous proteins. One example compares the inward ion pump halorhodopsin (HR) and the outward proton pump bacteriorhodopsin (BR). Of the nine essential buried ionizable residues in BR, six are conserved in HR. However, HR changes three BR acids, D85 in a central cluster of ionizable residues, D96, nearer the intracellular, and E204, nearer the extracellular side of the membrane to the small, neutral amino acids T111, V122, and T230, respectively. In BR, acidic amino acids are stationary anions whose proton affinity is modulated by conformational changes, establishing a sequence of directed binding and release of protons. Multiconformation continuum electrostatics calculations of chloride affinity and residue protonation show that, in reaction intermediates where an acid is ionized in BR, a Cl(-) is bound to HR in a position near the deleted acid. In the HR ground state, Cl(-) binds tightly to the central cluster T111 site and weakly to the extracellular T230 site, recovering the charges on ionized BR-D85 and neutral E204 in BR. Imposing key conformational changes from the BR M intermediate into the HR structure results in the loss of Cl(-) from the central T111 site and the tight binding of Cl(-) to the extracellular T230 site, mirroring the changes that protonate BR-D85 and ionize E204 in BR. The use of a mobile chloride in place of D85 and E204 makes HR more susceptible to the environmental pH and salt concentrations than BR. These studies shed light on how ion transfer mechanisms are controlled through the interplay of protein and ion electrostatics. PMID:25362051

  8. A new group of eubacterial light-driven retinal-binding proton pumps with an unusual cytoplasmic proton donor.

    PubMed

    Harris, Andrew; Ljumovic, Milena; Bondar, Ana-Nicoleta; Shibata, Yohei; Ito, Shota; Inoue, Keiichi; Kandori, Hideki; Brown, Leonid S

    2015-12-01

    One of the main functions of microbial rhodopsins is outward-directed light-driven proton transport across the plasma membrane, which can provide sources of energy alternative to respiration and chlorophyll photosynthesis. Proton-pumping rhodopsins are found in Archaea (Halobacteria), multiple groups of Bacteria, numerous fungi, and some microscopic algae. An overwhelming majority of these proton pumps share the common transport mechanism, in which a proton from the retinal Schiff base is first transferred to the primary proton acceptor (normally an Asp) on the extracellular side of retinal. Next, reprotonation of the Schiff base from the cytoplasmic side is mediated by a carboxylic proton donor (Asp or Glu), which is located on helix C and is usually hydrogen-bonded to Thr or Ser on helix B. The only notable exception from this trend was recently found in Exiguobacterium, where the carboxylic proton donor is replaced by Lys. Here we describe a new group of efficient proteobacterial retinal-binding light-driven proton pumps which lack the carboxylic proton donor on helix C (most often replaced by Gly) but possess a unique His residue on helix B. We characterize the group spectroscopically and propose that this histidine forms a proton-donating complex compensating for the loss of the carboxylic proton donor. PMID:26260121

  9. Proton pump inhibitor-induced Sweet’s syndrome: report of acute febrile neutrophilic dermatosis in a woman with recurrent breast cancer

    PubMed Central

    Cohen, Philip R.

    2015-01-01

    Background: Sweet’s syndrome, also referred to as acute febrile neutrophilic dermatosis, can either occur as an idiopathic disorder or associated with another condition, including cancer, or induced by exposure to a drug. Proton pump inhibitors selectively inhibit gastric parietal cell H+-K+-adenosine triphosphatase and are most commonly used for the treatment of gastroesophageal reflux disease. Purpose: Proton pump inhibitor-associated Sweet’s syndrome is described in a woman with recurrent breast cancer. Methods: PubMed was used to search the following terms, separately and in combination: acute febrile neutrophilic dermatosis, breast cancer, malignancy, paraneoplastic, proton pump inhibitor, and Sweet’s syndrome. All papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. Results: Proton pump inhibitors have previously been associated with cutaneous adverse reactions including maculopapular rash, subacute cutaneous lupus erythematosus and toxic epidermal necrolysis. However, drug-induced Sweet’s syndrome has not been observed in patients receiving proton pump inhibitors. The reported woman developed Sweet’s syndrome after initial exposure and subsequent repeat challenge to proton pump inhibitors; subsequent studies also observed recurrence of her breast cancer presenting as metastases to her stomach and bone. Conclusions: Drug-induced Sweet’s syndrome has most commonly been associated with granulocyte colony stimulating factor in oncology patients. Malignancy-associated Sweet’s syndrome has been observed in patients with solid tumors, including breast cancer. Confirmation of proton pump inhibitor-induced Sweet’s syndrome, by repeat challenge with another medication in the same class of drug, was observed in a woman with breast cancer; although the subsequent discovery of recurrent breast cancer presenting as gastric mucosa and vertebral metastases also raises the possibility of concurrent

  10. Proton pump inhibitor prescription abuse and sepsis in cirrhosis

    PubMed Central

    Picardi, Antonio; Vespasiani-Gentilucci, Umberto

    2016-01-01

    Proton pump inhibitors (PPIs) represent one of the most extensively prescribed classes of drugs in general and in patients with liver cirrhosis. Many prescriptions are made without a clear adherence to standard indications. As a class of ordinarily well tolerated drug, PPIs are not free of side-effects and concerns have been raised about a possible role for PPIs in predisposing patients to an increased risk of bacterial infections and sepsis. As evidences of different power are accumulating on this topic, prospective studies are needed to reach a more universal agreement, but definitely more attention is needed by prescribers in being more adherent to the few recognized indications for the use of PPIs, particularly in patients with liver cirrhosis. Otherwise, doctors could run the risk of being accused of “abused” prescription. PMID:26855807

  11. [Proton pump inhibitors: not as safe as they seem].

    PubMed

    van Herwaarden, N; Bos, J M; Veldman, B; Kramers, C

    2016-01-01

    - Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. However, some patients use them without a good indication.- Although PPIs are generally safe, there is an increasing number of signals of potentially serious side effects.- This article gives an overview of the incidence and prevalence of the following side effects: gastroenteritis, respiratory tract infections, hypomagnesaemia, renal function disorders, vitamin B12 and iron deficiency, dementia, osteoporosis and fractures.- It is important to prescribe a PPI only when there is a good indication for use. Patients with chronic PPI use should be checked periodically to see whether there is still an indication.- If any of the listed side effects should occur, it is advisable to consider PPI as a possible cause. PMID:27438396

  12. Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors

    PubMed Central

    Janett, Simone; Camozzi, Pietro; Peeters, Gabriëlla G. A. M.; Lava, Sebastiano A. G.; Simonetti, Giacomo D.; Goeggel Simonetti, Barbara; Bianchetti, Mario G.; Milani, Gregorio P.

    2015-01-01

    In 2006, hypomagnesemia was first described as a complication of proton-pump inhibitors. To address this issue, we systematically reviewed the literature. Hypomagnesemia, mostly associated with hypocalcemic hypoparathyroidism and hypokalemia, was reported in 64 individuals on long-term proton-pump inhibitors. Hypomagnesemia recurred following replacement of one proton-pump inhibitor with another but not with a histamine type-2 receptor antagonist. The association between proton-pump inhibitors and magnesium metabolism was addressed in 14 case-control, cross-sectional studies. An association was found in 11 of them: 6 reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia, 2 found that this tendency is more pronounced in patients concurrently treated with diuretics, carboplatin, or cisplatin, and 2 found a relevant tendency to hypomagnesemia in patients with poor renal function. Finally, findings likely reflecting decreased intestinal magnesium uptake were observed on treatment with proton-pump inhibitors. Three studies did not disclose any relationship between magnesium metabolism and treatment with histamine type-2 receptor antagonists. In conclusion, proton-pump inhibitors may cause hypomagnesemia. In these cases, switching to a histamine type-2 receptor antagonist is advised. PMID:26064102

  13. Gastroesophageal reflux symptoms not responding to proton pump inhibitor: GERD, NERD, NARD, esophageal hypersensitivity or dyspepsia?

    PubMed Central

    Bashashati, Mohammad; Hejazi, Reza A; Andrews, Christopher N; Storr, Martin A

    2014-01-01

    Gastroesophageal reflux (GER) is a common gastrointestinal process that can generate symptoms of heartburn and chest pain. Proton pump inhibitors (PPIs) are the gold standard for the treatment of GER; however, a substantial group of GER patients fail to respond to PPIs. In the past, it was believed that acid reflux into the esophagus causes all, or at least the majority, of symptoms attributed to GER, with both erosive esophagitis and nonerosive outcomes. However, with modern testing techniques it has been shown that, in addition to acid reflux, the reflux of nonacid gastric and duodenal contents into the esophagus may also induce GER symptoms. It remains unknown how weakly acidic or alkaline refluxate with a pH similar to a normal diet induces GER symptoms. Esophageal hypersensitivity or functional dyspepsia with superimposed heartburn may be other mechanisms of symptom generation, often completely unrelated to GER. Detailed studies investigating the pathophysiology of esophageal hypersensitivity are not conclusive, and definitions of the various disease states may overlap and are often confusing. The authors aim to clarify the pathophysiology, definition, diagnostic techniques and medical treatment of patients with heartburn symptoms who fail PPI therapy. PMID:24719900

  14. [Proton pump inhibitors and clopidogrel: a hazardous association?].

    PubMed

    Szymezak, J; Gaussem, P

    2013-02-01

    Proton pump inhibitors (PPI) and antiplatelet agents, especially aspirin and clopidogrel, are among the most prescribed medications worldwide. Their co-administration is justified by the increased risk of gastrointestinal bleeding related to the antiplatelet therapy. The issue of the interaction between PPI and clopidogrel has been raised with the emergence of the concept of "high on-clopidogrel platelet reactivity" (or "clopidogrel resistance") together with the discovery of the role of CYP2C19 isoform in the pharmacokinetics of those two medications. Indeed, CYP2C19 is involved in the conversion of the clopidogrel pro-drug into its active metabolite and is involved in the metabolisation of PPI into inactive metabolites, acting as substrates/inhibitors of CYP2C19. Despite their heterogeneity, most pharmacodynamic studies have shown a decreased clopidogrel antiplatelet effect when associated to PPI, especially those with the highest CYP2C19 inhibiting activity (omeprazole, lansoprazole, rabeprazole). On the other hand, clinical studies are inconclusive. Retrospective studies have shown an increased risk of major cardiovascular events or mortality when clopidogrel and PPI are associated in comparison with clopidogrel alone, particularly in the patients with the higher cardiovascular risk. However, the two prospective randomized studies published so far did not find any interaction and confirmed the benefit of PPI on the gastrointestinal bleeding. As a conclusion, as the clinical studies are not conclusive, the French health authorities have recently removed the alert about this interaction. PPI and clopidogrel can thus be co-prescribed. PMID:23200799

  15. Clinical evidence of interaction between clopidogrel and proton pump inhibitors

    PubMed Central

    Lin, Shoa-Lin; Chang, Hui-Min; Liu, Chun-Peng; Chou, Li-Ping; Chan, Jaw-Wen

    2011-01-01

    Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular (CV) and cerebrovascular disease. Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention, compared with aspirin alone. Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy, current guidelines recommend combined use of a proton pump inhibitor (PPI) to decrease the risk of bleeding. Data from previous pharmacological studies have shown that PPIs, which are extensively metabolized by the cytochrome system, may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients receiving both clopidogrel and PPIs than in those without PPIs. However, other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users. These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs, existing clinical data regarding the interaction between clopidogrel and PPIs, and tries to provide recommendations for health care professionals. PMID:21666816

  16. F"orster-type mechanism of the redox-driven proton pump

    NASA Astrophysics Data System (ADS)

    Mourokh, Lev; Smirnov, Anatoly; Nori, Franco

    2007-03-01

    We propose a model to describe an electronically-driven proton pump in the cytochrome c oxidase (CcO). We examine the situation when the electron transport between the two sites embedded into the inner membrane of the mitochondrion occurs in parallel with the proton transfer from the protonable site that is close to the negative (inner) side of the membrane to the other protonable site located nearby the positive (outer) surface of the membrane. In addition to the conventional electron and proton tunnelings between the sites, the Coulomb interaction between electrons and protons localized on the corresponding sites leads to so-called F"orster transfer, i.e. to the process when the simultaneous electron and proton tunnelings are accompanied by the resonant energy transfer between the electrons and protons. Our calculations based on reasonable parameters have demonstrated that the F"orster process facilitates the proton pump at physiological temperatures. We have examined the effects of an electron voltage build-up, external temperature, and molecular electrostatics driving the electron and proton energies to the resonant conditions, and have shown that these parameters can control the proton pump operation.

  17. Case report of proton pump inhibitor responsive esophageal eosinophilia: why 2 months of proton pump inhibitors is required.

    PubMed

    Lipka, S; Muhammad, A; Champeaux, A; Richter, J E

    2016-08-01

    Eosinophilic esophagitis (EoE) is a chronic inflammatory disease defined by the 2nd EoE consensus panel as: 'symptoms related to esophageal dysfunction, ≥15 eosinophils per high-power field, eosinophilia that persists after a trial of proton pump inhibitor (PPI) therapy, and exclusion of other secondary causes of esophageal eosinophilia'. After Ngo et al. first reported a case series of 3 patients initially diagnosed with eosinophilic esophagitis responding endoscopically and histologically to PPI therapy, the term PPI-responsive esophageal eosinophilia has evolved. Several studies have since confirmed the existence of this entity. Although recent ACG guidelines call for a 2-month course of PPI followed by endoscopy biopsies this recommendation is classified as a strong recommendation with 'low evidence', and has not been proven in the literature. We present a case of PPI-REE treated with rabeprazole 20 mg BID for 2 months, and describe simultaneous symptom resolution with histological and endoscopic remission of disease. This unique case with serial endoscopy and histology at baseline and monthly suggests the current recommendation of at least two months therapy with PPIs dosed twice daily is appropriate. Future studies will need to address duration of high dose therapy, whether patients can be stepped down to once a day PPI, and therapeutic strategy for transient responders. PMID:24842729

  18. Multiscale simulations reveal key features of the proton-pumping mechanism in cytochrome c oxidase.

    PubMed

    Liang, Ruibin; Swanson, Jessica M J; Peng, Yuxing; Wikström, Mårten; Voth, Gregory A

    2016-07-01

    Cytochrome c oxidase (CcO) reduces oxygen to water and uses the released free energy to pump protons across the membrane. We have used multiscale reactive molecular dynamics simulations to explicitly characterize (with free-energy profiles and calculated rates) the internal proton transport events that enable proton pumping during first steps of oxidation of the fully reduced enzyme. Our results show that proton transport from amino acid residue E286 to both the pump loading site (PLS) and to the binuclear center (BNC) are thermodynamically driven by electron transfer from heme a to the BNC, but that the former (i.e., pumping) is kinetically favored whereas the latter (i.e., transfer of the chemical proton) is rate-limiting. The calculated rates agree with experimental measurements. The backflow of the pumped proton from the PLS to E286 and from E286 to the inside of the membrane is prevented by large free-energy barriers for the backflow reactions. Proton transport from E286 to the PLS through the hydrophobic cavity and from D132 to E286 through the D-channel are found to be strongly coupled to dynamical hydration changes in the corresponding pathways and, importantly, vice versa. PMID:27339133

  19. Pathways of proton transfer in the light-driven pump bacteriorhodopsin

    NASA Technical Reports Server (NTRS)

    Lanyi, J. K.

    1993-01-01

    The mechanism of proton transport in the light-driven pump bacteriorhodopsin is beginning to be understood. Light causes the all-trans to 13-cis isomerization of the retinal chromophore. This sets off a sequential and directed series of transient decreases in the pKa's of a) the retinal Schiff base, b) an extracellular proton release complex which includes asp-85, and c) a cytoplasmic proton uptake complex which includes asp-96. The timing of these pKa changes during the photoreaction cycle causes sequential proton transfers which result in the net movement of a proton across the protein, from the cytoplasmic to the extracellular surface.

  20. Understanding the cytochrome c oxidase proton pump: thermodynamics of redox linkage.

    PubMed Central

    Musser, S M; Chan, S I

    1995-01-01

    The cytochrome c oxidase complex (CcO) catalyzes the four-electron reduction of dioxygen to water by using electrons from ferrocytochrome c. Redox free energy released in this highly exergonic process is utilized to drive the translocation of protons across a transmembrane electrochemical gradient. Although numerous chemical models of proton pumping have been developed, few attempts have been made to explain the stepwise transfer of energy in the context of proposed protein conformational changes. A model is described that seeks to clarify the thermodynamics of the proton pumping function of CcO and that illustrates the importance of electron and proton gating to prevent the occurrence of the more exergonic electron leak and proton slip reactions. The redox energy of the CcO-membrane system is formulated in terms of a multidimensional energy surface projected into two dimensions, a nuclear coordinate associated with electron transfer and a nuclear coordinate associated with elements of the proton pump. This model provides an understanding of how a transmembrane electrochemical gradient affects the efficiency of the proton pumping process. Specifically, electron leak and proton slip reactions become kinetically viable as a result of the greater energy barriers that develop for the desired reactions in the presence of a transmembrane potential. PMID:7647257

  1. Salicylate effects on proton gradient dissipation by isolated gastric mucosal surface cells.

    PubMed

    Olender, E J; Woods, D; Kozol, R; Fromm, D

    1986-11-01

    The effects of salicylate were examined on Na+/H+ exchange by isolated gastric mucosal surface cells loaded with H+ and resuspended in a buffered medium. Choline salicylate (pH 7.4) increases the dissipation of an intracellular proton gradient which was measured using acridine orange. The exchange of extracellular Na+ with intracellular H+ by surface cells not only remains intact but also is enhanced upon exposure to salicylate. This was confirmed by cellular uptake of 22Na and titration of cellular H+ efflux. Salicylate increases Na+/H+ exchange via a pathway predominantly sensitive to amiloride. However, the data also suggest that salicylate dissipates an intracellular proton gradient by an additional mechanism. The latter is independent of extracellular Na+ and not due to a generalized increase in cellular permeability. PMID:3020564

  2. Proton pump inhibitor alone vs proton pump inhibitor plus mucosal protective agents for endoscopic submucosal dissection-induced ulcer: a systematic review and meta-analysis

    PubMed Central

    Nishizawa, Toshihiro; Suzuki, Hidekazu; Kanai, Takanori; Yahagi, Naohisa

    2015-01-01

    Mucosal protective agents may improve healing of patients with endoscopic submucosal dissection-induced ulcers. The present study systematically evaluated published clinical trials to determine whether combined therapeutic use of mucosal protective agents and proton pump inhibitors can improve the outcome of patients with endoscopic submucosal dissection-induced ulcers compared to treatment with proton pump inhibitors alone. PubMed, the Cochrane Library, and the Igaku-Chuo-Zasshi database were searched to identify eligible randomized trials for systematic review. We identified 11 randomized trials for inclusion in our study (1,160 patients). Pooled endoscopic submucosal dissection-induced ulcer healing rates were 45.8% and 34.4% for patients with or without mucosal protective agents, respectively. The odds ratio was 2.28 (95% confidence interval, 1.57–3.31) with no significant study heterogeneity. In conclusion, the systematic review and meta-analysis showed that the combined therapeutic use of proton pump inhibitors and mucosal protective agents improved healing rates of endoscopic submucosal dissection-induced ulcers compared to treatment with proton pump inhibitor monotherapy. PMID:25759512

  3. Electrogenic active proton pump in Rana esculenta skin and its role in sodium ion transport.

    PubMed Central

    Ehrenfeld, J; Garcia-Romeu, F; Harvey, B J

    1985-01-01

    Kinetic and electrophysiological studies were carried out in the in vitro Rana esculenta skin, bathed in dilute sodium solution, to characterize the proton pump and coupling between sodium absorption (JNa+n) and proton excretion (JH+n). JNa+n and JH+n were both dependent on transepithelial potential (psi ms); hyperpolarizing the skin decreased JNa+n and increased JH+n; depolarization produced the opposite effects. Amiloride (5 X 10(-5) M) at a clamped psi ms of +50 mV inhibited JNa+n without affecting JH+n. Variations of psi ms or pH had identical effects on JH+n. Ethoxzolamide inhibited JH+n and simultaneously increased psi ms by 15-30 mV. These changes were accompanied by depolarization of the apical membrane potential psi mc from -47 to -25 mV and an increase in apical membrane resistance of 30%; no significant effects on basolateral membrane potential (psi cs) and resistance (Rb) nor on shunt resistance (Rj) were observed. The proton pump appears to be localized at the apical membrane. The proton pump was also inhibited by deoxygenation, oligomycin, dicyclohexylcarbodiimide and vanadate (100, 78, 83 and 100% inhibition respectively). The variations of JH+n and of the measured electrical currents were significantly correlated. These findings are supportive evidence of a primary active proton pump, electrogenic and strictly linked to aerobic metabolism. The current-voltage (I-V) relation of the proton pump was obtained as the difference in the I-V curves of the apical membrane extracted before and after proton-pump inhibition by ethoxzolamide during amiloride block of sodium transport. The proton-pump current (IP) was best described by a saturable exponential function of psi mc. Maximal pump current (ImaxP) was calculated to be 200 nequiv h-1 cm-2 at a psi mc of +50 mV and the pump reversal potential ERP was -130 mV. The effect of ethoxzolamide to depolarize psi mc was dependent on the relation between psi mc and ERP. Maximal induced depolarization occurred at a

  4. Effect of gastric acid suppressants on human gastric motility

    PubMed Central

    Parkman, H; Urbain, J; Knight, L; Brown, K; Trate, D; Miller, M; Maurer, A; Fisher, R

    1998-01-01

    Background—The effect of histamine H2 receptor antagonists on gastric emptying is controversial. 
Aims—To determine the effects of ranitidine, famotidine, and omeprazole on gastric motility and emptying. 
Patients and methods—Fifteen normal subjects underwent simultaneous antroduodenal manometry, electrogastrography (EGG), and gastric emptying with dynamic antral scintigraphy (DAS). After 30 minutes of fasting manometry and EGG recording, subjects received either intravenous saline, ranitidine, or famotidine, followed by another 30 minutes recording and then three hours of postprandial recording after ingestion of a radiolabelled meal. Images were obtained every 10-15 minutes for three hours to measure gastric emptying and assess antral contractility. Similar testing was performed after omeprazole 20 mg daily for one week. 
Results—Fasting antral phase III migrating motor complexes (MMCs) were more common after ranitidine (9/15 subjects, 60%), famotidine (12/15, 80%), and omeprazole (8/12, 67%) compared with placebo (4/14, 29%; p<0.05). Postprandially, ranitidine, famotidine, and omeprazole slowed gastric emptying, increased the amplitude of DAS contractions, increased the EGG power, and increased the antral manometric motility index. 
Conclusions—Suppression of gastric acid secretion with therapeutic doses of gastric acid suppressants is associated with delayed gastric emptying but increased antral motility. 

 Keywords: gastric motility; gastric emptying; histamine H2 receptor antagonists; proton pump inhibitors; gastric acid secretion; scintigraphy PMID:9536950

  5. Proton pump inhibitors and vascular function: A prospective cross-over pilot study

    PubMed Central

    Ghebremariam, Yohannes T.; Cooke, John P.; Khan, Fouzia; Thakker, Rahul N.; Chang, Peter; Shah, Nigam H.; Nead, Kevin T.; Leeper, Nicholas J.

    2015-01-01

    Background Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. Methods We conducted a controlled open-label cross-over pilot study among 21 adults aged 18 and older who are healthy (n = 11) or have established clinical cardiovascular disease (n = 10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2 week washout period, participants were crossed-over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. Results We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = −0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow mediated vasodilation during the course of this study. Conclusions In this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies. PMID:25835348

  6. Molecular mechanisms controlling proton pumping by bacteriorhodopsin. Final report

    SciTech Connect

    Crouch, Rosalie K.; Ebrey, Thomas G.

    2000-02-10

    Bacteriorhodopsin (bR) is the simplest biological system for the transduction of light energy. Light energy is directly converted to transmembrane proton gradient by a single, small membrane protein. The extraordinary stability of bR makes it an outstanding subject for bioenergetic studies. This project has focused on the role of interactions between key residues of the pigment involved in light-induced proton transfer. Methods to estimate the strength of these interactions and their correlation with the rate and efficiency of proton transfer have been developed. The concept of the coupling of the protonation states of key groups has been applied to individual steps of the proton transfer with the ultimate goal of understanding on the molecular level the driving forces for proton transport and the pathway of the transported proton in bT. The mechanism of light-induced proton release, uptake and the mechanism of recovery of initial state of bT has been examined. The experiments were performed with genetically engineered, site-specific mutants of bR. This has enabled us to characterize the role of individual amino acid residues in bR. Time resolved and low temperature absorption spectroscopy and light-induced photocurrent measurements were used in order to study the photochemical cycle and proton transfer in mutant pigments. Chemical modification and crosslinking of both the specific amino acids to the chromophore or to other amino acids were used to elucidate the role of light-induced conformational changes in the photocycle and the structure of the protein in the ground state. The results of this project provided new knowledge on the architecture of the proton transfer pathways inside the protein, on the mechanism of proton release in bR, and on the role of specific amino acid residues in the structure and function of bR.

  7. Proton Pump Inhibitor Therapy Is Associated With Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation

    PubMed Central

    Kang, Seong Hee; Yim, Hyung Joon; Kim, Seung Young; Suh, Sang Jun; Hyun, Jong Jin; Jung, Sung Woo; Jung, Young Kul; Koo, Ja Seol; Lee, Sang Woo

    2016-01-01

    Abstract Endoscopic variceal band ligation (EVL) is an effective procedure to control and prevent variceal bleeding in patients with liver cirrhosis, but it can be complicated by bleeding from post-EVL ulcers. Several studies have reported that proton pump inhibitors (PPIs) decrease the size of post-EVL ulcers. However, evidence are limited as to whether PPIs actually reduce the risk of bleeding after EVL. This study aimed to analyze the factors associated with bleeding after prophylactic EVL and to assess the effect of PPI therapy. Five hundred and five cirrhotic patients with high risk esophageal varices who received primary prophylactic EVL were included for this retrospective cohort study. Post-EVL bleeding was defined as bleeding after prophylactic EVL within 8 weeks evidenced by the occurrence of melena or hematemesis, or by a decrease of hemoglobin by >2.0 g/dL. If evidence of bleeding from ulceration of the EVL sites was confirmed by endoscopy, we defined it as post-EVL ulcer bleeding. Fourteen patients developed bleeding after prophylactic EVL. Factors associated with post-EVL bleeding included alcohol as etiology, low albumin, high total bilirubin, high Child-Pugh score, high MELD score, coexistence of gastric varices, and not administrating PPI medication by univariate analysis. In multivariate logistic analysis, Co-existing gastric varix (odds ratio [OR] 5.680, P = 0.005] and not administrating PPIs (OR 8.217, P = 0.002) were associated with bleeding after prophylactic EVL. In the subgroup analysis excluding patients whose gastric varices were treated, not administering PPI medication (OR 8.827, P = 0.008) was the sole factor associated with post-EVL bleeding. We suggest that PPI therapy needs to be considered in patients receiving prophylactic EVL to reduce the risk of bleeding after prophylactic EVL. PMID:26937932

  8. Characterization of a Cyanobacterial Chloride-pumping Rhodopsin and Its Conversion into a Proton Pump.

    PubMed

    Hasemi, Takatoshi; Kikukawa, Takashi; Kamo, Naoki; Demura, Makoto

    2016-01-01

    Light-driven ion-pumping rhodopsins are widely distributed in microorganisms and are now classified into the categories of outward H(+) and Na(+) pumps and an inward Cl(-) pump. These different types share a common protein architecture and utilize the photoisomerization of the same chromophore, retinal, to evoke photoreactions. Despite these similarities, successful pump-to-pump conversion had been confined to only the H(+) pump bacteriorhodopsin, which was converted to a Cl(-) pump in 1995 by a single amino acid replacement. In this study we report the first success of the reverse conversion from a Cl(-) pump to a H(+) pump. A novel microbial rhodopsin (MrHR) from the cyanobacterium Mastigocladopsis repens functions as a Cl(-) pump and belongs to a cluster that is far distant from the known Cl(-) pumps. With a single amino acid replacement, MrHR is converted to a H(+) pump in which dissociable residues function almost completely in the H(+) relay reactions. MrHR most likely evolved from a H(+) pump, but it has not yet been highly optimized into a mature Cl(-) pump. PMID:26578511

  9. Conversion of a light-driven proton pump into a light-gated ion channel

    PubMed Central

    Vogt, A.; Guo, Y.; Tsunoda, S. P.; Kateriya, S.; Elstner, M.; Hegemann, P.

    2015-01-01

    Interest in microbial rhodopsins with ion pumping activity has been revitalized in the context of optogenetics, where light-driven ion pumps are used for cell hyperpolarization and voltage sensing. We identified an opsin-encoding gene (CsR) in the genome of the arctic alga Coccomyxa subellipsoidea C-169 that can produce large photocurrents in Xenopus oocytes. We used this property to analyze the function of individual residues in proton pumping. Modification of the highly conserved proton shuttling residue R83 or its interaction partner Y57 strongly reduced pumping power. Moreover, this mutation converted CsR at moderate electrochemical load into an operational proton channel with inward or outward rectification depending on the amino acid substitution. Together with molecular dynamics simulations, these data demonstrate that CsR-R83 and its interacting partner Y57 in conjunction with water molecules forms a proton shuttle that blocks passive proton flux during the dark-state but promotes proton movement uphill upon illumination. PMID:26597707

  10. Crystallographic structure of xanthorhodopsin, the light-driven proton pump with a dual chromophore

    PubMed Central

    Luecke, Hartmut; Schobert, Brigitte; Stagno, Jason; Imasheva, Eleonora S.; Wang, Jennifer M.; Balashov, Sergei P.; Lanyi, Janos K.

    2008-01-01

    Homologous to bacteriorhodopsin and even more to proteorhodopsin, xanthorhodopsin is a light-driven proton pump that, in addition to retinal, contains a noncovalently bound carotenoid with a function of a light-harvesting antenna. We determined the structure of this eubacterial membrane protein–carotenoid complex by X-ray diffraction, to 1.9-Å resolution. Although it contains 7 transmembrane helices like bacteriorhodopsin and archaerhodopsin, the structure of xanthorhodopsin is considerably different from the 2 archaeal proteins. The crystallographic model for this rhodopsin introduces structural motifs for proton transfer during the reaction cycle, particularly for proton release, that are dramatically different from those in other retinal-based transmembrane pumps. Further, it contains a histidine–aspartate complex for regulating the pKa of the primary proton acceptor not present in archaeal pumps but apparently conserved in eubacterial pumps. In addition to aiding elucidation of a more general proton transfer mechanism for light-driven energy transducers, the structure defines also the geometry of the carotenoid and the retinal. The close approach of the 2 polyenes at their ring ends explains why the efficiency of the excited-state energy transfer is as high as ≈45%, and the 46° angle between them suggests that the chromophore location is a compromise between optimal capture of light of all polarization angles and excited-state energy transfer. PMID:18922772

  11. Direct observation of proton pumping by a eukaryotic P-type ATPase.

    PubMed

    Veshaguri, Salome; Christensen, Sune M; Kemmer, Gerdi C; Ghale, Garima; Møller, Mads P; Lohr, Christina; Christensen, Andreas L; Justesen, Bo H; Jørgensen, Ida L; Schiller, Jürgen; Hatzakis, Nikos S; Grabe, Michael; Pomorski, Thomas Günther; Stamou, Dimitrios

    2016-03-25

    In eukaryotes, P-type adenosine triphosphatases (ATPases) generate the plasma membrane potential and drive secondary transport systems; however, despite their importance, their regulation remains poorly understood. We monitored at the single-molecule level the activity of the prototypic proton-pumping P-type ATPase Arabidopsis thaliana isoform 2 (AHA2). Our measurements, combined with a physical nonequilibrium model of vesicle acidification, revealed that pumping is stochastically interrupted by long-lived (~100 seconds) inactive or leaky states. Allosteric regulation by pH gradients modulated the switch between these states but not the pumping or leakage rates. The autoinhibitory regulatory domain of AHA2 reduced the intrinsic pumping rates but increased the dwell time in the active pumping state. We anticipate that similar functional dynamics underlie the operation and regulation of many other active transporters. PMID:27013734

  12. Use of Proton Pump Inhibitors and Subsequent Risk of Celiac Disease

    PubMed Central

    Lebwohl, Benjamin; Spechler, Stuart J.; Wang, Timothy C.; Green, Peter H.R.; Ludvigsson, Jonas F.

    2013-01-01

    Background The prevalence of celiac disease and the use of medications that inhibit acid secretion have both increased in recent decades. Aims To explore the association between antisecretory medication exposure and subsequent development of celiac disease. Methods In this population-based case control study, we identified patients with celiac disease diagnosed at all pathology departments in Sweden from July 2005 through February 2008. Patients were matched by age and gender with up to 5 controls. We identified prior prescriptions for proton pump inhibitors and histamine-2 receptor antagonists in all subjects. We used conditional logistic regression to measure the association between these prescriptions and the subsequent diagnosis of celiac disease. Results Prior proton pump inhibitor prescription was strongly associated with celiac disease (OR 4.79; 95% CI 4.17-5.51). Patients prescribed both proton pump inhibitors and histamine-2 receptor antagonists had a higher risk of celiac disease (OR 5.96; 95% CI 3.58-9.91) than those prescribed proton pump inhibitors alone (OR 4.91; 95% CI 4.26-5.66) or histamine-2 receptor antagonists alone (OR 4.16; 95% CI 2.89-5.99). Conclusions Exposure to antisecretory medications is associated with a subsequent diagnosis of celiac disease. The persistence of this association after excluding prescriptions in the year preceding the celiac disease diagnosis suggests a causal relationship. PMID:24035759

  13. The mechanism for proton pumping in cytochrome c oxidase from an electrostatic and quantum chemical perspective.

    PubMed

    Blomberg, Margareta R A; Siegbahn, Per E M

    2012-04-01

    The mechanism for proton pumping in cytochrome c oxidase in the respiratory chain, has for decades been one of the main unsolved problems in biochemistry. However, even though several different suggested mechanisms exist, many of the steps in these mechanisms are quite similar and constitute a general consensus framework for discussing proton pumping. When these steps are analyzed, at least three critical gating situations are found, and these points are where the suggested mechanisms in general differ. The requirements for gating are reviewed and analyzed in detail, and a mechanism is suggested, where solutions for all the gating situations are formulated. This mechanism is based on an electrostatic analysis of a kinetic experiment fior the O to E transition. The key component of the mechanism is a positively charged transition state. An electron on heme a opens the gate for proton transfer from the N-side to a pump loading site (PLS). When the negative charge of the electron is compensated by a chemical proton, the positive transition state prevents backflow from the PLS to the N-side at the most critical stage of the pumping process. The mechanism has now been tested by large model DFT calculations, and these calculations give strong support for the suggested mechanism. PMID:21978537

  14. Structural insights into the proton pumping by unusual proteorhodopsin from nonmarine bacteria.

    PubMed

    Gushchin, Ivan; Chervakov, Pavel; Kuzmichev, Pavel; Popov, Alexander N; Round, Ekaterina; Borshchevskiy, Valentin; Ishchenko, Andrii; Petrovskaya, Lada; Chupin, Vladimir; Dolgikh, Dmitry A; Arseniev, Alexander S; Arseniev, Alexander A; Kirpichnikov, Mikhail; Gordeliy, Valentin

    2013-07-30

    Light-driven proton pumps are present in many organisms. Here, we present a high-resolution structure of a proteorhodopsin from a permafrost bacterium, Exiguobacterium sibiricum rhodopsin (ESR). Contrary to the proton pumps of known structure, ESR possesses three unique features. First, ESR's proton donor is a lysine side chain that is situated very close to the bulk solvent. Second, the α-helical structure in the middle of the helix F is replaced by 3(10)- and π-helix-like elements that are stabilized by the Trp-154 and Asn-224 side chains. This feature is characteristic for the proteorhodopsin family of proteins. Third, the proton release region is connected to the bulk solvent by a chain of water molecules already in the ground state. Despite these peculiarities, the positions of water molecule and amino acid side chains in the immediate Schiff base vicinity are very well conserved. These features make ESR a very unusual proton pump. The presented structure sheds light on the large family of proteorhodopsins, for which structural information was not available previously. PMID:23872846

  15. Proton pumping kinetics and origin of nitrate inhibition of tonoplast-type H+-ATPase

    SciTech Connect

    Tu, S.I.; Nagahashi, G.; Brouillette, J.N.

    1987-08-01

    A tonoplast-type vesicle preparation, substantially free from other subcellular membranes, was obtained from corn roots by equilibrium sucrose density gradient centrifugation. At pH 6.5 and in the presence of chloride ions, the tonoplast-type ATPase activity as measured by Pi release, was inhibited by nitrate ions. The ATPase activity was insensitive to molybdate and vanadate, indicating a minimum nonspecific phosphatase and plasma membrane contamination. The vesicles exhibited an ATP hydrolysis-supported proton uptake which was measured by the absorption change of acridine orange. The ATP hydrolysis supported uptake and the subsequent perturbant-induced release of protons (decay) was described by a kinetic model which was previously developed to evaluate the coupling between proton pumping and the primary energy yielding process for other biomembranes. The proton pumping activity was more sensitive to nitrate ions then was ATP hydrolysis. The differential effect and the kinetic analysis of nitrate inhibition led us to suggest that (i) the coupling between Pi release and proton pumping was indirect in nature and (ii) the primary inhibitory effect of nitrate ion was originated from an interaction with a protogenic protein domain which is functionally linked to the ATPase in the tonoplast-type membrane.

  16. Proton Pump Inhibitors Decrease Eotaxin-3 Expression in the Proximal Esophagus of Children with Esophageal Eosinophilia

    PubMed Central

    Park, Jason Y.; Zhang, Xi; Nguyen, Nathalie; Souza, Rhonda F.; Spechler, Stuart J.; Cheng, Edaire

    2014-01-01

    Objective Besides reducing gastric acid secretion, proton pump inhibitors (PPIs) suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal epithelial cells through acid-independent, anti-inflammatory mechanisms. To explore acid-inhibitory and acid-independent, anti-inflammatory PPI effects in reducing esophageal eosinophilia, we studied eotaxin-3 expression by the proximal and distal esophagus of children with esophageal eosinophilia before and after PPI therapy. In vitro, we studied acid and bile salt effects on IL-13-stimulated eotaxin-3 expression by esophageal epithelial cells. Design Among 264 children with esophageal eosinophilia seen at a tertiary pediatric hospital from 2008 through 2012, we identified 10 with esophageal biopsies before and after PPI treatment alone. We correlated epithelial cell eotaxin-3 immunostaining with eosinophil numbers in those biopsies. In vitro, we measured eotaxin-3 protein secretion by esophageal squamous cells stimulated with IL-13 and exposed to acid and/or bile salt media, with or without omeprazole. Results There was strong correlation between peak eosinophil numbers and peak eotaxin-3-positive epithelial cell numbers in esophageal biopsies. Eotaxin-3 expression decreased significantly with PPIs only in the proximal esophagus. In esophageal cells, exposure to acid-bile salt medium significantly suppressed IL-13-induced eotaxin-3 secretion; omeprazole added to the acid-bile salt medium further suppressed that eotaxin-3 secretion, but not as profoundly as at pH-neutral conditions. Conclusion In children with esophageal eosinophilia, PPIs significantly decrease eotaxin-3 expression in the proximal but not the distal esophagus. In esophageal squamous cells, acid and bile salts decrease Th2 cytokine-stimulated eotaxin-3 secretion profoundly, possibly explaining the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid reflux is greatest, a PPI

  17. Development of a tritium monitor combined with an electrochemical tritium pump using a proton conducting oxide

    SciTech Connect

    Tanaka, M.; Sugiyama, T.

    2015-03-15

    The detection of low level tritium is one of the key issues for tritium management in tritium handling facilities. Such a detection can be performed by tritium monitors based on proton conducting oxide technique. We tested a tritium monitoring system composed of a commercial proportional counter combined with an electrochemical hydrogen pump equipped with CaZr{sub 0.9}In{sub 0.1}O{sub 3-α} as proton conducting oxide. The hydrogen pump operated at 973 K under electrolysis conditions using tritiated water vapor (HTO). The proton conducting oxide extracts tritium molecules (HT) from HTO and tritium concentration is measured by the proportional counter. The advantage of the proposed tritium monitoring system is that it is able to convert HTO into molecular hydrogen.

  18. Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance

    PubMed Central

    Balza, E; Piccioli, P; Carta, S; Lavieri, R; Gattorno, M; Semino, C; Castellani, P; Rubartelli, A

    2016-01-01

    Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1β that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1β systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1β to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions. PMID:27441656

  19. Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance.

    PubMed

    Balza, E; Piccioli, P; Carta, S; Lavieri, R; Gattorno, M; Semino, C; Castellani, P; Rubartelli, A

    2016-01-01

    Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1β that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1β systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1β to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions. PMID:27441656

  20. High-Performance Genetically Targetable Optical Neural Silencing via Light-Driven Proton Pumps

    PubMed Central

    Chow, Brian Y.; Han, Xue; Dobry, Allison S.; Qian, Xiaofeng; Chuong, Amy S.; Li, Mingjie; Henninger, Michael A.; Belfort, Gabriel M.; Lin, Yingxi; Monahan, Patrick E.; Boyden, Edward S.

    2009-01-01

    The ability to silence the activity of genetically specified neurons in a temporally precise fashion would open up the ability to investigate the causal role of specific cell classes in neural computations, behaviors, and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate very powerful, safe, multiple-color silencing of neural activity. The gene archaerhodopsin-31 (Arch) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in mouse cortex and illuminated with yellow light. Arch mediates currents of several hundred picoamps at low light powers, and supports neural silencing currents approaching 900 pA at light powers easily achievable in vivo. In addition, Arch spontaneously recovers from light-dependent inactivation, unlike light-driven chloride pumps that enter long-lasting inactive states in response to light. These properties of Arch are appropriate to mediate the optical silencing of significant brain volumes over behaviourally-relevant timescales. Arch function in neurons is well tolerated because pH excursions created by Arch illumination are minimized by self-limiting mechanisms to levels comparable to those mediated by channelrhodopsins2,3 or natural spike firing. To highlight how proton pump ecological and genomic diversity may support new innovation, we show that the blue-green light-drivable proton pump from the fungus Leptosphaeria maculans4 (Mac) can, when expressed in neurons, enable neural silencing by blue light, thus enabling alongside other developed reagents the potential for independent silencing of two neural populations by blue vs. red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of “optogenetic” voltage and ion modulator, which will broadly empower new neuroscientific, biological, neurological, and psychiatric investigations. PMID:20054397

  1. Antagonism of Fluconazole and a Proton Pump Inhibitor against Candida albicans

    PubMed Central

    Liu, Ning-Ning

    2015-01-01

    Hospitalized ill patients, at risk for invasive candidiasis, often receive multiple medications, including proton pump inhibitors (PPIs). The antifungal fluconazole perturbs the vacuolar proton ATPase. The PPI omeprazole antagonized Candida albicans growth inhibition by fluconazole. A C. albicans codon-adapted pHluorin, Ca.pHluorin, was generated to measure cytosolic pH. The fungal cytosol was acidified by omeprazole and realkalinized by coexposure to fluconazole. Vacuolar pH was alkalinized by fluconazole. Off-target effects of any medication on fungal pathogens may occur. PMID:26596946

  2. Proton pump inhibitor-induced exfoliative dermatitis: A case report

    PubMed Central

    QIU, ZHIHONG; LIU, HONGTAO; HE, LIEN; MA, YINLING; SONG, HAOJING; BAI, WANJUN; YU, MEILING

    2016-01-01

    A 74-year-old female patient was admitted to hospital following a road accident with pains in the chest, abdomen, waist, back, nose, left wrist and lower limbs. After 1 week, the patient presented with gastrointestinal bleeding, and thus was treated with protein pump inhibitors (PPIs), including lansoprazole, esomeprazole and omeprazole enteric-coated tablets, in order to inhibit acid secretion and attenuate bleeding. However, the patient developed skin rashes on the chest and right lower limb and foot 28 days following treatment initiation. The skin rashes spread and ulcerated after 3 days, and were associated with tracheal mucosal injury and hemoptysis. Subsequently, treatment of the patient with PPIs was terminated, after which the tracheal hemoptysis and skin rashes markedly improved. In addition, no new skin rashes appeared following termination of the PPI treatment. In the present case, long-term treatment of an elderly patient with PPIs may have induced exfoliative dermatitis, due to hepatic ischemia, hypoxia and acute renal failure, which may have decreased the metabolism of PPIs, resulting in the accumulation of PPI metabolites. PMID:26893644

  3. Acido-basic properties of proton pump inhibitors in aqueous solutions.

    PubMed

    Kristl, Albin

    2009-01-01

    The pharmacological characteristics of proton pump inhibitors are related to their protolytic behavior estimated by their pK(a) values. Lansoprazole is a potent anti-acid drug from this group. Because of its poor stability a rapid spectrophotometric method was developed for the determination of its pK(a) values. Three pK(a) values were obtained: an acidic pK(a1) = 8.84 and two basic, pK(a2) = 4.15 and pK(a3) = 1.33. These pK(a) values were discussed from the point of lansoprazole structure and instability with the aim of locating basic and acidic moieties in the molecule of proton pump inhibitors. They were also compared with experimentally determined pK(a) values from the literature and with some pK(a) values calculated by different programs. PMID:18720145

  4. Mutation of a single residue in the ba3 oxidase specifically impairs protonation of the pump site

    PubMed Central

    von Ballmoos, Christoph; Gonska, Nathalie; Lachmann, Peter; Gennis, Robert B.; Ädelroth, Pia; Brzezinski, Peter

    2015-01-01

    The ba3-type cytochrome c oxidase from Thermus thermophilus is a membrane-bound protein complex that couples electron transfer to O2 to proton translocation across the membrane. To elucidate the mechanism of the redox-driven proton pumping, we investigated the kinetics of electron and proton transfer in a structural variant of the ba3 oxidase where a putative “pump site” was modified by replacement of Asp372 by Ile. In this structural variant, proton pumping was uncoupled from internal electron transfer and O2 reduction. The results from our studies show that proton uptake to the pump site (time constant ∼65 μs in the wild-type cytochrome c oxidase) was impaired in the Asp372Ile variant. Furthermore, a reaction step that in the wild-type cytochrome c oxidase is linked to simultaneous proton uptake and release with a time constant of ∼1.2 ms was slowed to ∼8.4 ms, and in Asp372Ile was only associated with proton uptake to the catalytic site. These data identify reaction steps that are associated with protonation and deprotonation of the pump site, and point to the area around Asp372 as the location of this site in the ba3 cytochrome c oxidase. PMID:25733886

  5. A thermo-physical analysis of the proton pump vacuolar-ATPase: the constructal approach

    PubMed Central

    Lucia, Umberto; Ponzetto, Antonio; Deisboeck, Thomas S.

    2014-01-01

    Pumping protons across a membrane was a critical step at the origin of life on earth, and it is still performed in all living organisms, including in human cells. Proton pumping is paramount to keep normal cells alive, e.g. for lysosomal digestion and for preparing peptides for immune recognition, but it goes awry in cancer cells. They acidify their microenvironment hence membrane voltage is lowered, which in turn induces cell proliferation, a hallmark of cancer. Proton pumping is achieved by means of rotary motors, namely vacuolar ATPases (V-ATPase), which are present at many of the multiple cellular interfaces. Therefore, we undertook an examination of the thermodynamic properties of V-ATPases. The principal result is that the V-ATPase-mediated control of the cell membrane potential and the related and consequent environmental pH can potentially represent a valuable support strategy for anticancer therapies. A constructal theory approach is used as a new viewpoint to study how V-ATPase can be modulated for therapeutic purposes. In particular, V-ATPase can be regulated by using external fields, such as electromagnetic fields, and a theoretical approach has been introduced to quantify the appropriate field strength and frequency for this new adjuvant therapeutic strategy. PMID:25342534

  6. Proton pump inhibition prevents gastrointestinal bleeding in ultramarathon runners: a randomised, double blinded, placebo controlled study

    PubMed Central

    Thalmann, M; Sodeck, G H; Kavouras, S; Matalas, A; Skenderi, K; Yannikouris, N; Domanovits, H

    2006-01-01

    Background Ultra‐endurance running is emerging as a popular sport in Western industrialised countries. Gastrointestinal bleeding has been reported to be an adverse effect in these runners. Objective To see if the oral administration of a proton pump inhibitor would reduce the incidence of gastrointestinal bleeding in an ultramarathon. Methods In a randomised, double blinded, placebo controlled study, a prophylactic regimen of three days of an oral proton pump inhibitor (pantoprazole 20 mg) was tested in healthy athletes participating in the Spartathlon ultramarathon. The incidence of gastrointestinal bleeding was assessed by a stool guaiac test. Results Results were obtained for 70 healthy volunteers. The data for 20 of 35 runners in the intervention group and 17 of 35 runners in the placebo group were entered into the final analysis. At the end of the ultramarathon, two subjects in the intervention group and 12 in the placebo group had positive stool guaiac tests (risk difference 0.86; 95% confidence interval 0.45 to 0.96; p  =  0.001). Conclusion A short prophylactic regimen of oral proton pump inhibition can successfully decrease the incidence of gastrointestinal bleeding in participants in an ultramarathon. PMID:16556794

  7. Empiric treatment of children with gastroesophageal reflux-like symptoms: Effect of proton pump inhibitors.

    PubMed

    Gündüz, Mehmet; Yamaç, Pınar; Baysoy, Gökhan

    2015-01-01

    Gastroesophageal reflux disease is an important cause of morbidity in childhood. Although various diagnostic methods are available, short course of empiric treatment with a proton pump inhibitor is widely used in adults as a diagnostic test. Data about empiric treatment is scarce in children. The aim of this study is to evaluate the effectiveness of empiric treatment of reflux-like symptoms in children. Pediatric gastroenterology outpatient files were searched and patients with a diagnosis of gastroesophageal reflux were found. Patient complaints, history and the treatments provided were recorded. Treatment naive patients older than 2 years of age with symptoms suggestive of gastroesophageal reflux were selected and included if they were given empiric treatment with a proton pump inhibitor. Empiric treatment was found to be effective in 78% of patients. Treatment response tended to be better in children older than 5 years of age. Of the 22 non-responders 9 underwent endoscopy and pathological findings were discovered in 7 of them. Treatment of children with gastroesophageal reflux symptoms with a proton pump inhibitor might significantly decrease the need for extensive evaluations. However it is important to investigate non-responders to empiric therapy, as it seems there might be high probability of pathological findings. PMID:27411415

  8. A thermo-physical analysis of the proton pump vacuolar-ATPase: the constructal approach.

    PubMed

    Lucia, Umberto; Ponzetto, Antonio; Deisboeck, Thomas S

    2014-01-01

    Pumping protons across a membrane was a critical step at the origin of life on earth, and it is still performed in all living organisms, including in human cells. Proton pumping is paramount to keep normal cells alive, e.g. for lysosomal digestion and for preparing peptides for immune recognition, but it goes awry in cancer cells. They acidify their microenvironment hence membrane voltage is lowered, which in turn induces cell proliferation, a hallmark of cancer. Proton pumping is achieved by means of rotary motors, namely vacuolar ATPases (V-ATPase), which are present at many of the multiple cellular interfaces. Therefore, we undertook an examination of the thermodynamic properties of V-ATPases. The principal result is that the V-ATPase-mediated control of the cell membrane potential and the related and consequent environmental pH can potentially represent a valuable support strategy for anticancer therapies. A constructal theory approach is used as a new viewpoint to study how V-ATPase can be modulated for therapeutic purposes. In particular, V-ATPase can be regulated by using external fields, such as electromagnetic fields, and a theoretical approach has been introduced to quantify the appropriate field strength and frequency for this new adjuvant therapeutic strategy. PMID:25342534

  9. Implications of over-the-counter proton pump inhibitors for patient counseling by pharmacists.

    PubMed

    Simonson, William

    2013-01-01

    The article reviews the literature on the role of the pharmacist in patient counseling and discusses how that role may apply to patients with frequent heartburn who are seeking an over-the-counter (OTC) treatment. Searches of the National Library of Medicine PubMed database were conducted using the terms "heartburn," "nonprescription," "therapy," "pharmacist," and "counseling," supplemented by additional searches on counseling for prescription products, and by the author's knowledge of pharmacy practice and the scientific literature. Accurate recognition of the signs of heartburn are an important first step in counseling a patient on the appropriate OTC medication; immediate referral to a health care provider is mandatory if cardiac pain or certain gastrointestinal symptoms are present. When counseling a patient about treatments for heartburn, the pharmacist should practice effective listening in an environment that is conducive to communication by the patient. Proton pump inhibitors are effective for the treatment of heartburn; the histamine2 receptor antagonists and antacids should also be considered for appropriate patients. Adverse events have been noted with proton pump inhibitors; however, overall the benefits significantly outweigh the risks and problems are unlikely to arise during the 2-week duration of OTC treatment of heartburn. Pharmacists can provide valuable services to patients with frequent heartburn, particularly with regard to counseling about the condition and appropriate OTC therapy. The availability of numerous OTC products, including antacids, histamine2 receptor antagonists, and proton pump inhibitors, enables pharmacists to fulfill an important clinical role and improve patient satisfaction. PMID:21642828

  10. Infrared spectroscopic demonstration of a conformational change in bacteriorhodopsin involved in proton pumping.

    PubMed Central

    Ormos, P

    1991-01-01

    Infrared spectral changes in bacteriorhodopsin (bR) were followed during the slow decay of the M intermediate in the temperature region 240-260 K. The decay of the M form is characterized by the disappearance of the ethylenic bands and the bands indicating the reprotonation of the Schiff base. The route of Schiff-base reprotonation completely changes between 240 K and 260 K. At 240 K reprotonation occurs from Asp-85, the group to which the proton was released during M formation, and there is no pumping. At 260 K Schiff-base reprotonation takes place through Asp-96 from the cytoplasmic side, in the normal sequence assumed for proton pumping. The dramatic change in the route of Schiff-base reprotonation is coupled to a protein conformational change characterized by the change of the ratio of the two amide I bands at 1658 cm-1 and 1669 cm-1. This conformational change is interpreted as the conformational switch crucial for proton pumping: a protein relaxation following M formation results in a local rearrangement of the group, in the vicinity of the Schiff base. The rearrangement changes the accessibility of the Schiff base and provides that its deprotonation and reprotonation occur on different sides. The conformational change has characteristics typical for relaxations in proteins. In addition, it is shown that at 260 K an equilibrium exists between the M and N forms. Images PMID:1846442

  11. Redox-induced activation of the proton pump in the respiratory complex I

    PubMed Central

    Sharma, Vivek; Belevich, Galina; Gamiz-Hernandez, Ana P.; Róg, Tomasz; Vattulainen, Ilpo; Verkhovskaya, Marina L.; Wikström, Mårten; Hummer, Gerhard; Kaila, Ville R. I.

    2015-01-01

    Complex I functions as a redox-linked proton pump in the respiratory chains of mitochondria and bacteria, driven by the reduction of quinone (Q) by NADH. Remarkably, the distance between the Q reduction site and the most distant proton channels extends nearly 200 Å. To elucidate the molecular origin of this long-range coupling, we apply a combination of large-scale molecular simulations and a site-directed mutagenesis experiment of a key residue. In hybrid quantum mechanics/molecular mechanics simulations, we observe that reduction of Q is coupled to its local protonation by the His-38/Asp-139 ion pair and Tyr-87 of subunit Nqo4. Atomistic classical molecular dynamics simulations further suggest that formation of quinol (QH2) triggers rapid dissociation of the anionic Asp-139 toward the membrane domain that couples to conformational changes in a network of conserved charged residues. Site-directed mutagenesis data confirm the importance of Asp-139; upon mutation to asparagine the Q reductase activity is inhibited by 75%. The current results, together with earlier biochemical data, suggest that the proton pumping in complex I is activated by a unique combination of electrostatic and conformational transitions. PMID:26330610

  12. Voltage Dependence of Proton Pumping by Bacteriorhodopsin Mutants with Altered Lifetime of the M Intermediate

    PubMed Central

    Geibel, Sven; Lörinczi, Èva; Bamberg, Ernst; Friedrich, Thomas

    2013-01-01

    The light-driven proton pump bacteriorhodopsin (BR) from Halobacterium salinarum is tightly regulated by the [H+] gradient and transmembrane potential. BR exhibits optoelectric properties, since spectral changes during the photocycle are kinetically controlled by voltage, which predestines BR for optical storage or processing devices. BR mutants with prolonged lifetime of the blue-shifted M intermediate would be advantageous, but the optoelectric properties of such mutants are still elusive. Using expression in Xenopus oocytes and two-electrode voltage-clamping, we analyzed photocurrents of BR mutants with kinetically destabilized (F171C, F219L) or stabilized (D96N, D96G) M intermediate in response to green light (to probe H+ pumping) and blue laser flashes (to probe accumulation/decay of M). These mutants have divergent M lifetimes. As for BR-WT, this strictly correlates with the voltage dependence of H+ pumping. BR-F171C and BR-F219L showed photocurrents similar to BR-WT. Yet, BR-F171C showed a weaker voltage dependence of proton pumping. For both mutants, blue laser flashes applied during and after green-light illumination showed reduced M accumulation and shorter M lifetime. In contrast, BR-D96G and BR-D96N exhibited small photocurrents, with nonlinear current-voltage curves, which increased strongly in the presence of azide. Blue laser flashes showed heavy M accumulation and prolonged M lifetime, which accounts for the strongly reduced H+ pumping rate. Hyperpolarizing potentials augmented these effects. The combination of M-stabilizing and -destabilizing mutations in BR-D96G/F171C/F219L (BR-tri) shows that disruption of the primary proton donor Asp-96 is fatal for BR as a proton pump. Mechanistically, M destabilizing mutations cannot compensate for the disruption of Asp-96. Accordingly, BR-tri and BR-D96G photocurrents were similar. However, BR-tri showed negative blue laser flash-induced currents even without actinic green light, indicating that Schiff base

  13. Gastric explosion induced by argon plasma coagulation and prevention strategies.

    PubMed

    Freiman, John Saul; Hampe, Toni

    2014-12-01

    We describe the occurrence of an iatrogenic explosion induced by argon plasma coagulation in a 70-year-old man undergoing gastroscopy. Combustible gases in the stomach may have been released by bacterial overgrowth as a result of partial gastric outlet obstruction (caused by a gastric tumor) and reduced acidity (from proton pump inhibitor therapy). We propose a stepwise process during upper endoscopy to prevent this devastating complication, comprising aspiration, preinsufflation with CO2, and then coagulation. PMID:25041867

  14. Potential regulatory phosphorylation sites in a Medicago truncatula plasma membrane proton pump implicated during early symbiotic signaling in roots.

    PubMed

    Nguyen, Thao T; Volkening, Jeremy D; Rose, Christopher M; Venkateshwaran, Muthusubramanian; Westphall, Michael S; Coon, Joshua J; Ané, Jean-Michel; Sussman, Michael R

    2015-08-01

    In plants and fungi the plasma membrane proton pump generates a large proton-motive force that performs essential functions in many processes, including solute transport and the control of cell elongation. Previous studies in yeast and higher plants have indicated that phosphorylation of an auto-inhibitory domain is involved in regulating pump activity. In this report we examine the Medicago truncatula plasma membrane proton pump gene family, and in particular MtAHA5. Yeast complementation assays with phosphomimetic mutations at six candidate sites support a phosphoregulatory role for two residues, suggesting a molecular model to explain early Nod factor-induced changes in the plasma membrane proton-motive force of legume root cells. PMID:26188545

  15. Time esophageal pH < 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors

    PubMed Central

    Gerson, Lauren B; Triadafilopoulos, George; Sahbaie, Peyman; Young, Winston; Sloan, Sheldon; Robinson, Malcolm; Miner, Philip B; Gardner, Jerry D

    2008-01-01

    Background A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure. Aim We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4. Methods We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion. Results The prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux. Conclusion In GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period. PMID:18498663

  16. Prescribing patterns and economic costs of proton pump inhibitors in Colombia

    PubMed Central

    Fernández, Alejandra; Castrillón, Juan Daniel; Campo, Carlos Felipe; Echeverri, Luis Felipe; Gaviria, Andrés; Londoño, Manuel José; Ochoa, Sergio Andrés; Ruíz, Joaquín Octavio

    2013-01-01

    Objective: To determine the prescribing patterns for proton pump inhibitors and to estimate the economic cost of their use in a group of patients affiliated with the Colombian Health System. Methods: This is a descriptive observational study. Data for analysis consisted of prescriptions dispensed between October 1st, 2010 and October 31st, 2010 and were collected from a systematic database of 4.2 million members. Socio-demographic variables were considered along with the defined daily dose,comedication, convenience of the indication for proton pump inhibitor use and costs. Results: In this study, 113,560 prescriptions were dispensed in 89 cities, mostly to women (57.6%) with a mean age of 54.4 ± 18.7 years; the drugs were omeprazole (n= 111.294; 97.81%),esomeprazole (n= 1.378; 1.2%), lansoprazole (n= 524; 0.4%), pantoprazole and rabeprazole. The indication for 87.349 of the formulas (76.9%) was justified and statistically associated with the use of NSAIDs, antithrombotics, corticosteroids, anti-ulcer, antibiotics and prokinetics. No justification was found for 26.211 (23.1%) of the prescriptions, which were associated with antidiabetics, antihypertensives, hypolipidemics and others (p <0.001).The annual justified cost was estimated to be US$ 1,654,701 and the unjustified cost was estimated to be U.S. $2,202,590, as calculated using the minimum reference prices. Discussion: Each month, the Colombian health system is overloaded by unjustified costs that include payments for non-approved indications of proton pump inhibitors and for drugs outside the list of essential medications. This issue is contributing to rising costs of healthcare in Colombia. PMID:24892316

  17. [Chronic use of proton pump inhibitors: is the risk of osteoporosis and fractures real?].

    PubMed

    Martí-Cabrera, Miguel; Martí-Masanet, Miguel; Esplugues, Juan V

    2011-04-01

    Proton pump inhibitors (PPI) are one of the most widely used groups of drugs and their potential toxicity is periodically reviewed, emphasizing aspects originally considered secondary. The present review analyzes the physiological and pharmacological bases and the scarce clinical evidence for a potential association between the continued administration of PPI and the development of osteoporosis and bone fractures. Both disorders are clearly related to calcium homeostasis and are highly important in elderly patients due to their poor general prognosis and disabling consequences. PMID:21419526

  18. Hypomagnesaemia associated with long-term use of proton pump inhibitors

    PubMed Central

    Toh, James Wei Tatt; Ong, Evonne; Wilson, Robert

    2015-01-01

    Hypomagnesaemia and associated hypocalcaemia and hypoparathyroidism have been increasingly recognised as rare long-term side-effects of proton pump inhibitors (PPIs). The PPIs may inhibit active magnesium (Mg) absorption by interfering with transcellular transient receptor potential melastatin-6 and -7 (TRPM 6 and 7) channels. More recent cell culture studies have suggested concomitant inhibition of passive Mg absorption by omeprazole. After being treated with a range of PPIs, the four patients in our case series developed hypomagnesaemia, which responded to withdrawal of therapy and initiation of Mg replacement. Their clinical course and management demonstrate key aspects of hypomagnesaemia associated with long-term use of PPIs. PMID:25138239

  19. Evidence-based assessment of proton-pump inhibitors in Helicobacter pylori eradication: A systematic review

    PubMed Central

    Nagaraja, Vinayak; Eslick, Guy D

    2014-01-01

    Peptic ulcer disease continues to be issue especially due to its high prevalence in the developing world. Helicobacter pylori (H. pylori) infection associated duodenal ulcers should undergo eradication therapy. There are many regimens offered for H. pylori eradication which include triple, quadruple, or sequential therapy regimens. The central aim of this systematic review is to evaluate the evidence for H. pylori therapy from a meta-analytical outlook. The consequence of the dose, type of proton-pump inhibitor, and the length of the treatment will be debated. The most important risk factor for eradication failure is resistance to clarithromycin and metronidazole. PMID:25356018

  20. Conformational changes in the archaerhodopsin-3 proton pump: detection of conserved strongly hydrogen bonded water networks.

    PubMed

    Clair, Erica C Saint; Ogren, John I; Mamaev, Sergey; Kralj, Joel M; Rothschild, Kenneth J

    2012-01-01

    Archaerhodopsin-3 (AR3) is a light-driven proton pump from Halorubrum sodomense, but little is known about its photocycle. Recent interest has focused on AR3 because of its ability to serve both as a high-performance, genetically-targetable optical silencer of neuronal activity and as a membrane voltage sensor. We examined light-activated structural changes of the protein, retinal chromophore, and internal water molecules during the photocycle of AR3. Low-temperature and rapid-scan time-resolved FTIR-difference spectroscopy revealed that conformational changes during formation of the K, M, and N photocycle intermediates are similar, although not identical, to bacteriorhodopsin (BR). Positive/negative bands in the region above 3,600 cm( - 1), which have previously been assigned to structural changes of weakly hydrogen bonded internal water molecules, were substantially different between AR3 and BR. This included the absence of positive bands recently associated with a chain of proton transporting water molecules in the cytoplasmic channel and a weakly hydrogen bonded water (W401), which is part of a hydrogen-bonded pentagonal cluster located near the retinal Schiff base. However, many of the broad IR continuum absorption changes below 3,000 cm( - 1) assigned to networks of water molecules involved in proton transport through cytoplasmic and extracellular portions in BR were very similar in AR3. This work and subsequent studies comparing BR and AR3 structural changes will help identify conserved elements in BR-like proton pumps as well as bioengineer AR3 to optimize neural silencing and voltage sensing. PMID:23277676

  1. Proton Pump Inhibitor Therapy Is Associated With Reduction of Early Bleeding Risk After Prophylactic Endoscopic Variceal Band Ligation: A Retrospective Cohort Study.

    PubMed

    Kang, Seong Hee; Yim, Hyung Joon; Kim, Seung Young; Suh, Sang Jun; Hyun, Jong Jin; Jung, Sung Woo; Jung, Young Kul; Koo, Ja Seol; Lee, Sang Woo

    2016-02-01

    Endoscopic variceal band ligation (EVL) is an effective procedure to control and prevent variceal bleeding in patients with liver cirrhosis, but it can be complicated by bleeding from post-EVL ulcers. Several studies have reported that proton pump inhibitors (PPIs) decrease the size of post-EVL ulcers. However, evidence are limited as to whether PPIs actually reduce the risk of bleeding after EVL. This study aimed to analyze the factors associated with bleeding after prophylactic EVL and to assess the effect of PPI therapy.Five hundred and five cirrhotic patients with high risk esophageal varices who received primary prophylactic EVL were included for this retrospective cohort study. Post-EVL bleeding was defined as bleeding after prophylactic EVL within 8 weeks evidenced by the occurrence of melena or hematemesis, or by a decrease of hemoglobin by >2.0 g/dL. If evidence of bleeding from ulceration of the EVL sites was confirmed by endoscopy, we defined it as post-EVL ulcer bleeding.Fourteen patients developed bleeding after prophylactic EVL. Factors associated with post-EVL bleeding included alcohol as etiology, low albumin, high total bilirubin, high Child-Pugh score, high MELD score, coexistence of gastric varices, and not administrating PPI medication by univariate analysis. In multivariate logistic analysis, Co-existing gastric varix (odds ratio [OR] 5.680, P = 0.005] and not administrating PPIs (OR 8.217, P = 0.002) were associated with bleeding after prophylactic EVL. In the subgroup analysis excluding patients whose gastric varices were treated, not administering PPI medication (OR 8.827, P = 0.008) was the sole factor associated with post-EVL bleeding.We suggest that PPI therapy needs to be considered in patients receiving prophylactic EVL to reduce the risk of bleeding after prophylactic EVL. PMID:26937932

  2. Towards theoretical analysis of long-range proton transfer kinetics in biomolecular pumps

    PubMed Central

    König, P. H.; Ghosh, N.; Hoffmann, M.; Elstner, M.; Tajkhorshid, E.; Frauenheim, Th.; Cui, Q.

    2008-01-01

    Motivated by the long-term goal of theoretically analyzing long-range proton transfer (PT) kinetics in biomolecular pumps, a number of technical developments were made in the framework of QM/MM simulations. A set of collective reaction co-ordinates is proposed for characterizing the progress of long-range proton transfers; unlike previous suggestions, the new coordinates can describe PT along highly non-linear three-dimensional pathways. Calculations using a realistic model of carbonic anhydrase demonstrated that adiabatic mapping using these collective coordinates gives reliable energetics and critical geometrical parameters as compared to minimum energy path calculations, which suggests that the new coordinates can be effectively used as reaction coordinate in potential of mean force calculations for long-range PT in complex systems. In addition, the generalized solvent boundary potential was implemented in the QM/MM framework for rectangular geometries, which is useful for studying reactions in membrane systems. The resulting protocol was found to produce water structure in the interior of aquaporin consistent with previous studies including much larger number of explicit solvent and lipid molecules. The effect of electrostatics for PT through membrane protein was also illustrated with a simple model channel embedded in different dielectric continuum environments. The encouraging results observed so far suggest that robust theoretical analysis of long-range PT kinetics in biomolecular pumps can soon be realized in a QM/MM framework. PMID:16405327

  3. Proton-pump inhibitors in patients requiring antiplatelet therapy: new FDA labeling.

    PubMed

    Johnson, David A; Chilton, Robert; Liker, Harley R

    2014-05-01

    Proton-pump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper gastrointestinal bleeding. Proton-pump inhibitors should also be considered for patients receiving antiplatelet therapy who have other risk factors for gastrointestinal bleeding, including use of aspirin. Thus, evidence of pharmacokinetic and pharmacodynamic interactions between PPIs and consequent impaired effectiveness of the antiplatelet agent clopidogrel has caused concern. Here, we discuss comparative studies suggesting that the extent to which a PPI reduces exposure to the active metabolite of clopidogrel and attenuates its antithrombotic effect differs among PPIs. Although a clinically meaningful effect of the interaction between PPIs and clopidogrel on cardiovascular outcomes has not been established, these studies provided the basis for recent changes in US Food and Drug Administration (FDA) labeling for several PPIs and clopidogrel. New labeling suggests that PPI use among patients taking clopidogrel be limited to pantoprazole, rabeprazole, lansoprazole, or dexlansoprazole. Because comparative studies indicate that omeprazole and esomeprazole have a greater effect on the CYP2C19-mediated conversion of clopidogrel to its active metabolite and, consequently, clopidogrel's effect on platelet reactivity, FDA labeling recommends avoiding omeprazole and esomeprazole in patients taking clopidogrel. Even a 12-hour separation of dosing does not appear to prevent drug interactions between omeprazole and clopidogrel. PMID:24918808

  4. Expression and functioning of retinal-based proton pumps in a saltern crystallizer brine.

    PubMed

    Oren, Aharon; Abu-Ghosh, Said; Argov, Tal; Kara-Ivanov, Eliahu; Shitrit, Dror; Volpert, Adi; Horwitz, Rael

    2016-01-01

    We examined the presence of bacteriorhodopsin and other retinal protein pigments in the microbial community of the saltern crystallizer ponds in Eilat, Israel, and assessed the effect of the retinal-based proton pumps on the metabolic activity. The biota of the hypersaline (~309 g salts l(-1)) brine consisted of ~2200 β-carotene-rich Dunaliella cells and ~3.5 × 10(7) prokaryotes ml(-1), most of which were flat, square or rectangular Haloquadratum-like archaea. No indications were obtained for massive presence of Salinibacter. We estimated a concentration of bacteriorhodopsin and bacteriorhodopsin-like pigments of 3.6 nmol l(-1). When illuminated, the community respiration activity of the brine samples in which oxygenic photosynthesis was inhibited by 3-(3-4-dichlorophenyl)-1,1-dimethylurea, decreased by 40-43 %. This effect was interpreted to be the result of competition between two energy yielding systems: the bacteriorhodopsin proton pump and the respiratory chain. The results presented have important implications for the interpretation of many published data on photosynthetic and respiratory activities in hypersaline environments. PMID:26507954

  5. Engineering a Chemical Switch into the Light-driven Proton Pump Proteorhodopsin by Cysteine Mutagenesis and Thiol Modification.

    PubMed

    Harder, Daniel; Hirschi, Stephan; Ucurum, Zöhre; Goers, Roland; Meier, Wolfgang; Müller, Daniel J; Fotiadis, Dimitrios

    2016-07-25

    For applications in synthetic biology, for example, the bottom-up assembly of biomolecular nanofactories, modules of specific and controllable functionalities are essential. Of fundamental importance in such systems are energizing modules, which are able to establish an electrochemical gradient across a vesicular membrane as an energy source for powering other modules. Light-driven proton pumps like proteorhodopsin (PR) are excellent candidates for efficient energy conversion. We have extended the versatility of PR by implementing an on/off switch based on reversible chemical modification of a site-specifically introduced cysteine residue. The position of this cysteine residue in PR was identified by structure-based cysteine mutagenesis combined with a proton-pumping assay using E. coli cells overexpressing PR and PR proteoliposomes. The identified PR mutant represents the first light-driven proton pump that can be chemically switched on/off depending on the requirements of the molecular system. PMID:27294681

  6. Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice

    PubMed Central

    Hess, Mark W.; de Baaij, Jeroen H. F.; Gommers, Lisanne M. M.; Hoenderop, Joost G. J.; Bindels, René J. M.

    2015-01-01

    Background Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. Methods Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. Results Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. Conclusions This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies. PMID:26397986

  7. Functional and Photochemical Characterization of a Light-Driven Proton Pump from the Gammaproteobacterium Pantoea vagans.

    PubMed

    Sudo, Yuki; Yoshizawa, Susumu

    2016-05-01

    Photoactive retinal proteins are widely distributed throughout the domains of the microbial world (i.e., bacteria, archaea, and eukarya). Here we describe three retinal proteins belonging to a phylogenetic clade with a unique DTG motif. Light-induced decrease in the environmental pH and its inhibition by carbonyl cyanide m-chlorophenylhydrazone revealed that these retinal proteins function as light-driven outward electrogenic proton pumps. We further characterized one of these proteins, Pantoea vagans rhodopsin (PvR), spectroscopically. Visible spectroscopy and high-performance liquid chromatography revealed that PvR has an absorption maximum at 538 nm with the retinal chromophore predominantly in the all-trans form (>90%) under both dark and light conditions. We estimated the pKa values of the protonated Schiff base of the retinal chromophore and its counterion as approximately 13.5 and 2.1, respectively, by using pH titration experiments, and the photochemical reaction cycle of PvR was measured by time-resolved flash-photolysis in the millisecond timeframe. We observed a blue-shifted and a red-shifted intermediate, which we assigned as M-like and O-like intermediates, respectively. Decay of the M-like intermediate was highly sensitive to environmental pH, suggesting that proton uptake is coupled to decay of the M-like intermediate. From these results, we propose a putative model for the photoreaction of PvR. PMID:26970049

  8. Mechanism of proton pumping by plant plasma membrane H+-ATPase: role of residues in transmembrane segments 5 and 6.

    PubMed

    Palmgren, M G; Buch-Pedersen, M J; Møller, A L

    2003-04-01

    The mechanism of proton pumping by P-type plasma membrane H(+)-ATPases is not well clarified. Site-directed mutagenesis studies suggest that Asp684, situated in transmembrane segment M6, is involved in coordination of proton(s) in plant plasma membrane H(+)-ATPase. This hypothesis is supported by atomic models of H(+)-ATPases built on the basis of the crystal structure of the related SERCA1a Ca(2+)-ATPase. However, more biochemical, genetic, and structural studies are required before we will be able to understand the nature of the proton binding site(s) in P-type H(+)-ATPases and the mechanism of action of these pumps. PMID:12763795

  9. Pretreatment Gastric Lavage Reduces Postoperative Bleeding after Endoscopic Submucosal Dissection for Gastric Neoplasms

    PubMed Central

    Takahashi, Yuka; Itakura, Jun; Ueda, Ken; Suzuki, Shoko; Yasui, Yutaka; Tamaki, Nobuharu; Nakakuki, Natsuko; Takada, Hitomi; Ueda, Masako; Hayashi, Tsuguru; Kuwabara, Konomi; Takaura, Kenta; Higuchi, Mayu; Komiyama, Yasuyuki; Yoshida, Tsubasa; Izumi, Namiki

    2016-01-01

    Aim For patients receiving endoscopic submucosal dissection (ESD), there is urgent need pertaining to the prevention of postoperative bleeding. We conducted a retrospective propensity score-matched study that evaluated whether pre-ESD gastric lavage prevents postoperative bleeding after ESD for gastric neoplasms. Methods From September 2002 to October 2015, the 760 consecutive patients receiving ESD for gastric neoplasm were enrolled and data regarding them were retrospectively analyzed. All patients received conventional preventive treatment against delayed bleeding after ESD, including the administration of proton pump inhibitor and preventive coagulation of visible vessels, at the end of the ESD procedure. Results Pre-ESD risk factors for postoperative bleeding included tumor size and no gastric lavage. Using multivariate analysis tumor size >2.0 cm (HR 2.90, 95% CI 1.65–5.10, p = 0.0002) and no gastric lavage (HR 3.20, 95% CI 1.13–9.11, p = 0.029) were found to be independent risk factors. Next, we evaluated the effect of gastric lavage on the prevention of post-ESD bleeding using a propensity score-matching method. A total of 284 subjects (142 per group) were selected. Adjusted odds ratio of gastric lavage for post-ESD bleeding was 0.25 (95% CI 0.071–0.886, p = 0.032). Conclusion Pretreatment gastric lavage reduced postoperative bleeding in patients receiving ESD for gastric neoplasm. PMID:26871449

  10. The Effect of Helicobacter pylori Infection, Aging, and Consumption of Proton Pump Inhibitor on Fungal Colonization in the Stomach of Dyspeptic Patients

    PubMed Central

    Massarrat, Sadegh; Saniee, Parastoo; Siavoshi, Farideh; Mokhtari, Reyhane; Mansour-Ghanaei, Fariborz; Khalili-Samani, Saman

    2016-01-01

    Background: The importance of coinfection of Helicobacter pylori (H.pylori) and Candida albicans (C. albicans) in the development of gastric diseases is not known. In this study, the frequency of concurrent infection of H. pylori and C. albicans in dyspeptic patients was assessed while considering age, gender, and PPI consumption of patients. Methods: Gastric biopsies were taken from 74 yeast-positive dyspeptic patients and gastric disease, age, gender, and proton pump inhibitor (PPI) consumption of subjects were recorded. One antral biopsy was used for rapid urease test (RUT) and one for H. pylori and yeast cultivation and smear preparation. Bacterial isolates were identified according to spiral morphology and the biochemical characteristics. Yeast isolates were identified on Chromagar and by the Nested-PCR amplification of C. albicans-specific topoisomerase II gene. Twenty-seven biopsy smears were Gram-stained and examined by the light microscope for observing H. pylori and yeast cells. Results: Fifty-four (73%) of patients were >40 year. Of 68 patients with PPI consumption record, 46 (67.6%) consumed PPI (p = 0). Comparison of patients in peptic ulcer group (12, 16.2%) with (6, 8.1%) or without (6, 8.1%) H. pylori or in gastritis group (62, 83.8%) with (25, 33.8%) or without (37, 50%) H. pylori showed no significant difference (p > 0.05). Of the 46 patients who consumed PPI, 13 (17.5%) were H. pylori-positive and 33 (44.6%) H. pylori-negative (p = 0). Ten out of twenty-seven smears showed the occurrence of H. pylori cells, including three with yeast cells. Of the 17 H. pylori-negative smears, three showed the occurrence of yeast cells only. Yeasts stained Gram-positive or Gram-negative and appeared as single or budding cells. Conclusion: The older age and PPI consumption could favor fungal colonization in the human stomach. The occurrence of a considerable number of H. pylori-positive or H. pylori-negative patients with gastritis or peptic ulcer shows that co

  11. Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms

    PubMed Central

    William, Jeffrey H; Danziger, John

    2016-01-01

    Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia (PPIH) has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective, controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the field of PPIH and the proposed mechanisms of this effect. PMID:26981439

  12. The role of proton pump inhibitor therapy in the management of eosinophilic esophagitis.

    PubMed

    Molina-Infante, Javier; Prados-Manzano, Raul; Gonzalez-Cordero, Pedro Luis

    2016-09-01

    Eosinophilic esophagitis (EoE) is a chronic esophageal disease characterized by a Th2 inflammatory response triggered by food/environmental allergens. Solid data confirm that up to half of patients with suspected EoE achieve complete remission on proton pump inhibitors (PPI) therapy. This disease phenotype is currently labelled as PPI-responsive esophageal eosinophilia (PPI-REE). Albeit initially believed to represent gastro-esophageal reflux disease (GERD), evolving evidence has underscored that PPI-REE and EoE show a significant overlap regarding clinic, endoscopic, histologic, Th2 immune-mediated inflammation and gene expression features. Moreover, PPI therapy can effectively reverse Th2 inflammation and the EoE transcriptome expression in PPI-REE patients. Therefore, EoE and PPI-REE likely represent a common allergic disorder, where PPI therapy should be considered a short- and long-term therapeutic asset, along with diet and topical steroids. PMID:27097787

  13. [Proton Pump Inhibitor and High-dose Methotrexate: Two Cases Reports].

    PubMed

    Evrard, Julien; Farnier, Elodie; Carcel, Corine; Lachenal, Florence; Vial, Thierry; Pont, Emmanuelle

    2015-01-01

    Methotrexate (MTX) is a cytotoxic agent prescribed at high dose in treatment of malignancy. Association of MTX to proton pump inhibitor (PPI) is not recommended if doses are more than 20 mg per weeks and only to take into account for smaller doses. Review relate some cases of delayed elimination of methotrexate in patients taking PPI, which increase risk of toxic event. However, currently there is no status quo on interaction between PPI and MTX according to available data. We report two clinical cases illustrating one more time a toxic event to MTX in presence of PPI. In absence of risk/benefit ratio set correctly, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk. PMID:26242498

  14. Magnesium Deficiency and Proton-Pump Inhibitor Use: A Clinical Review.

    PubMed

    William, Jeffrey H; Danziger, John

    2016-06-01

    The association of proton-pump inhibitor (PPI) use and hypomagnesemia has garnered much attention over the last 5 years. A large body of observational data has linked chronic PPI use with hypomagnesemia, presumably due to decreased intestinal absorption and consequent magnesium deficiency. However, despite the increasing prevalence of this highly popular class of medicine, and despite potential significant risks associated with magnesium depletion, including cardiac arrhythmias and seizures, there are no well-designed studies to delineate the nature of this observed association. Consequently, providers must use best judgment to inform clinical decision making. This review summarizes the current body of evidence linking PPI use with hypomagnesemia, acknowledges the possibility of significant residual confounding in the observational data, explains potential physiologic mechanisms, and offers clinical recommendations. PMID:26582556

  15. Delirium in the geriatric unit: proton-pump inhibitors and other risk factors

    PubMed Central

    Otremba, Iwona; Wilczyński, Krzysztof; Szewieczek, Jan

    2016-01-01

    Background Delirium remains a major nosocomial complication of hospitalized elderly. Predictive models for delirium may be useful for identification of high-risk patients for implementation of preventive strategies. Objective Evaluate specific factors for development of delirium in a geriatric ward setting. Methods Prospective cross-sectional study comprised 675 consecutive patients aged 79.2±7.7 years (66% women and 34% men), admitted to the subacute geriatric ward of a multiprofile university hospital after exclusion of 113 patients treated with antipsychotic medication because of behavioral disorders before admission. Comprehensive geriatric assessments including a structured interview, physical examination, geriatric functional assessment, blood sampling, ECG, abdominal ultrasound, chest X-ray, Confusion Assessment Method for diagnosis of delirium, Delirium-O-Meter to assess delirium severity, Richmond Agitation-Sedation Scale to assess sedation or agitation, visual analog scale and Doloplus-2 scale to assess pain level were performed. Results Multivariate logistic regression analysis revealed five independent factors associated with development of delirium in geriatric inpatients: transfer between hospital wards (odds ratio [OR] =2.78; confidence interval [CI] =1.54–5.01; P=0.001), preexisting dementia (OR =2.29; CI =1.44–3.65; P<0.001), previous delirium incidents (OR =2.23; CI =1.47–3.38; P<0.001), previous fall incidents (OR =1.76; CI =1.17–2.64; P=0.006), and use of proton-pump inhibitors (OR =1.67; CI =1.11–2.53; P=0.014). Conclusion Transfer between hospital wards, preexisting dementia, previous delirium incidents, previous fall incidents, and use of proton-pump inhibitors are predictive of development of delirium in the geriatric inpatient setting. PMID:27103793

  16. Deprescribing in a family health team: a study of chronic proton pump inhibitor use.

    PubMed

    Walsh, Kate; Kwan, Debbie; Marr, Patricia; Papoushek, Christine; Lyon, W Kirk

    2016-06-01

    BACKGROUND Proton pump inhibitors (PPIs) are often used inappropriately, without an indication, or for longer durations than recommended. Few tools exist to guide reassessment of their continued use and deprescribing if required. We aimed to reduce inappropriate drug use by developing and implementing a PPI deprescribing tool and process in a family medicine unit. ASSESSMENT OF PROBLEM Primary care providers of adults taking a PPI for 8 weeks with an upcoming periodic health examination were reminded to reassess therapy via electronic medical record (EMR) messaging. A PPI Deprescribing Tool was uploaded into the EMR as a second reminder and to guide reassessment and deprescribing where indicated. Ten weeks after the examination a chart review assessed changes to PPI use. A follow up survey of providers assessed the utility and barriers to implementing the Deprescribing Tool. RESULTS Forty-three of 46 patients on PPIs (93%) had their PPI reassessed, resulting in 11 patients (26%) having their PPI deprescribed. Strategies for Improvement Routine reassessment of long-term medications is often overlooked because of extensive demands on primary care providers' time. Deprescribing likely improved because potentially eligible patients were identified to the provider and a tool was provided at the time of the encounter to guide the deprescribing process. LESSONS Reassessment and deprescribing of PPIs can be supported by implementing a standardised process and use of guidance tools for clinicians. Providers found the timely and selective reminder message to deprescribe the most useful component of the intervention. KEYWORDS proton pump inhibitor; deprescribing; reassessment; primary care; medication therapy management; gastroesophageal reflux disease. PMID:27477559

  17. Clopidogrel and proton pump inhibitors - where do we stand in 2012?

    PubMed Central

    Drepper, Michael D; Spahr, Laurent; Frossard, Jean Louis

    2012-01-01

    Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended. PMID:22611308

  18. Evidence-based support for the use of proton pump inhibitors in cancer therapy.

    PubMed

    Fais, Stefano

    2015-01-01

    'We can only cure what we can understand first', said Otto H. Warburg, the 1931 Nobel laureate for his discovery on tumor metabolism. Unfortunately, we still don't know too much the mechanisms underlying of cancer development and progression. One of the unsolved mystery includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg's discovery, that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. One of the most mechanism to survive to the acidic tumor microenvironment are proton exchangers not allowing intracellular acidification through a continuous elimination of H(+) either outside the cells or within the internal vacuoles. This article wants to comment a translational process through which from the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed chemosensitizers as well, we have got to the clinical proof of concept that PPI may well be included in new anti-cancer strategies, and with a solid background and rationale. PMID:26597250

  19. Thermal and Spectroscopic Characterization of a Proton Pumping Rhodopsin from an Extreme Thermophile*

    PubMed Central

    Tsukamoto, Takashi; Inoue, Keiichi; Kandori, Hideki; Sudo, Yuki

    2013-01-01

    So far retinylidene proteins (∼rhodopsin) have not been discovered in thermophilic organisms. In this study we investigated and characterized a microbial rhodopsin derived from the extreme thermophilic bacterium Thermus thermophilus, which lives in a hot spring at around 75 °C. The gene for the retinylidene protein, named thermophilic rhodopsin (TR), was chemically synthesized with codon optimization. The codon optimized TR protein was functionally expressed in the cell membranes of Escherichia coli cells and showed active proton transport upon photoillumination. Spectroscopic measurements revealed that the purified TR bound only all-trans-retinal as a chromophore and showed an absorption maximum at 530 nm. In addition, TR exhibited both photocycle kinetics and pH-dependent absorption changes, which are characteristic of rhodopsins. Of note, time-dependent thermal denaturation experiments revealed that TR maintained its absorption even at 75 °C, and the denaturation rate constant of TR was much lower than those of other proton pumping rhodopsins such as archaerhodopsin-3 (200 ×), Haloquadratum walsbyi bacteriorhodopsin (by 10-times), and Gloeobacter rhodopsin (100 ×). Thus, these results suggest that microbial rhodopsins are also distributed among thermophilic organisms and have high stability. TR should allow the investigation of the molecular mechanisms of ion transport and protein folding. PMID:23740255

  20. Water exit pathways and proton pumping mechanism in B-type cytochrome c oxidase from molecular dynamics simulations.

    PubMed

    Yang, Longhua; Skjevik, Åge A; Han Du, Wen-Ge; Noodleman, Louis; Walker, Ross C; Götz, Andreas W

    2016-09-01

    Cytochrome c oxidase (CcO) is a vital enzyme that catalyzes the reduction of molecular oxygen to water and pumps protons across mitochondrial and bacterial membranes. While proton uptake channels as well as water exit channels have been identified for A-type CcOs, the means by which water and protons exit B-type CcOs remain unclear. In this work, we investigate potential mechanisms for proton transport above the dinuclear center (DNC) in ba3-type CcO of Thermus thermophilus. Using long-time scale, all-atom molecular dynamics (MD) simulations for several relevant protonation states, we identify a potential mechanism for proton transport that involves propionate A of the active site heme a3 and residues Asp372, His376 and Glu126(II), with residue His376 acting as the proton-loading site. The proposed proton transport process involves a rotation of residue His376 and is in line with experimental findings. We also demonstrate how the strength of the salt bridge between residues Arg225 and Asp287 depends on the protonation state and that this salt bridge is unlikely to act as a simple electrostatic gate that prevents proton backflow. We identify two water exit pathways that connect the water pool above the DNC to the outer P-side of the membrane, which can potentially also act as proton exit transport pathways. Importantly, these water exit pathways can be blocked by narrowing the entrance channel between residues Gln151(II) and Arg449/Arg450 or by obstructing the entrance through a conformational change of residue Tyr136, respectively, both of which seem to be affected by protonation of residue His376. PMID:27317965

  1. Slow release delivery of rioprostil by an osmotic pump inhibits the formation of acute aspirin-induced gastric lesions in dogs and accelerates the healing of chronic lesions without incidence of side effects.

    PubMed

    Katz, L B; Shriver, D A

    1989-10-01

    Rioprostil, a primary alcohol prostaglandin E1 analog, inhibits gastric acid secretion and prevents gastric lesions induced by a variety of irritants in experimental animals. Because rioprostil is relatively short-acting, it would be of significant benefit clinically if its duration of action could be extended to allow once daily dosing. This investigation demonstrates that when administered via an osmotically driven pump (Osmet, Alza Corp.), rioprostil prevents the acute effects of aspirin on the gastric mucosa of dogs, accelerates the healing of aspirin-induced gastric lesions, and heals preexisting aspirin-induced gastric lesions during chronic administration of aspiring. The potency of rioprostil against acute gastric lesion formation was greatest when delivered from a 24-hr release pump (ED50 = 0.77 micrograms/kg/24 hr) and was 37 times greater than when administered as a single oral bolus. In addition, this activity occurred at doses which had little or no gastric antisecretory activity in betazole-stimulated Heidenhain pouch dogs. When delivered from a 24-hr pump, rioprostil (100 micrograms/kg/24 hr) healed preexisting aspirin-induced gastric lesions within 8 days after removal of aspirin, or after 15 days during continued daily aspirin administration. Additional studies determined that administration of rioprostil at doses of 720, 1440, or 2160 micrograms/kg/24 hr (935-2805 times the gastroprotective ED50 in 24 hr pumps) was well tolerated, with only slight, transient increases in body temperature, softening of the stools, and mild sedation at the highest dose. Administration of rioprostil daily for 5 days at 960 micrograms/kg/24 hr from 24-hr release pumps was also well tolerated by all dogs with no evidence of any accumulation of effect of rioprostil. In summary, administration of rioprostil via an osmotic pump increases its potency and duration of action against the gastric lesion-inducing effect of aspirin, and maintains a wide ratio of safety. PMID

  2. Cyanobacterial Light-Driven Proton Pump, Gloeobacter Rhodopsin: Complementarity between Rhodopsin-Based Energy Production and Photosynthesis

    PubMed Central

    Choi, Ah Reum; Shi, Lichi; Brown, Leonid S.; Jung, Kwang-Hwan

    2014-01-01

    A homologue of type I rhodopsin was found in the unicellular Gloeobacter violaceus PCC7421, which is believed to be primitive because of the lack of thylakoids and peculiar morphology of phycobilisomes. The Gloeobacter rhodopsin (GR) gene encodes a polypeptide of 298 amino acids. This gene is localized alone in the genome unlike cyanobacterium Anabaena opsin, which is clustered together with 14 kDa transducer gene. Amino acid sequence comparison of GR with other type I rhodopsin shows several conserved residues important for retinal binding and H+ pumping. In this study, the gene was expressed in Escherichia coli and bound all-trans retinal to form a pigment (λmax  = 544 nm at pH 7). The pKa of proton acceptor (Asp121) for the Schiff base, is approximately 5.9, so GR can translocate H+ under physiological conditions (pH 7.4). In order to prove the functional activity in the cell, pumping activity was measured in the sphaeroplast membranes of E. coli and one of Gloeobacter whole cell. The efficient proton pumping and rapid photocycle of GR strongly suggests that Gloeobacter rhodopsin functions as a proton pumping in its natural environment, probably compensating the shortage of energy generated by chlorophyll-based photosynthesis without thylakoids. PMID:25347537

  3. Photoactive mitochondria: in vivo transfer of a light-driven proton pump into the inner mitochondrial membrane of Schizosaccharomyces pombe.

    PubMed

    Hoffmann, A; Hildebrandt, V; Heberle, J; Büldt, G

    1994-09-27

    The light-driven proton pump bacteriorhodopsin (bR) from Halobacterium salinarium has been genetically transferred into the inner mitochondrial membrane (IM) of the eukaryotic cell Schizosaccharomyces pombe, where the archaebacterial proton pump replaces or increases the proton gradient usually formed by the respiratory chain. For targeting and integration, as well as for the correct orientation of bR in the IM, the bacterioopsin gene (bop) was fused to signal sequences of IM proteins. Northern and Western blot analysis proved that all hybrid gene constructs containing the bop gene and a mitochondrial signal sequence were expressed and processed to mature bR. Fast transient absorption spectroscopy showed photocycle activity of bR integrated in the IM by formation of the M intermediate. Experiments with the pH-sensitive fluorescence dye 2',7'-bis(2-carboxyethyl)-5 (and -6)-carboxyfluorescein revealed bR-mediated proton pumping from the mitochondrial matrix into the intermembrane space. Glucose uptake measurements under anaerobic conditions showed that yeast cells containing photoactive mitochondria need less sugar under illumination. In summary, our experiments demonstrate the functional genetic transfer of a light energy converter to a naturally nonphotoactive eukaryotic organism. PMID:7937771

  4. Novel expression and characterization of a light driven proton pump archaerhodopsin 4 in a Halobacterium salinarum strain.

    PubMed

    Cao, Zhen; Ding, Xiaoyan; Peng, Bo; Zhao, Yingchun; Ding, Jiandong; Watts, Anthony; Zhao, Xin

    2015-01-01

    Archaerhodopsin 4 (AR4), a new member of the microbial rhodopsin family, is isolated from Halobacterium species xz515 in a Tibetan salt lake. AR4 functions as a proton pump similar to bacteriorhodopsin (BR) but with an opposite temporal order of proton uptake and release at neutral pH. However, further studies to elucidate the mechanism of the proton pump and photocycle of AR4 have been inhibited due to the difficulty of establishing a suitable system in which to express recombinant AR4 mutants. In this paper, we report a reliable method for expressing recombinant AR4 in Halobacterium salinarum L33 with a high yield of up to 20mg/l. Experimental results show that the recombinant AR4 retains the light-driven proton pump characteristics and photo-cycling kinetics, similar to that in the native membrane. The functional role of bacterioruberin in AR4 and the trimeric packing of AR4 in its native and recombinant forms are investigated through light-induced kinetic measurements, two-dimensional solid-state NMR experiments, dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR). Such approaches provide new insights into structure-function relationships of AR4, and form a basis for other archaeal rhodopsins. PMID:25559161

  5. Efficacy of levofloxacin, amoxicillin and a proton pump inhibitor in the eradication of Helicobacter pylori in Brazilian patients with peptic ulcers

    PubMed Central

    Silva, Fernando Marcuz; de Queiroz, Elaine Cristina Silveira; Navarro-Rodriguez, Tomás; Barbuti, Ricardo Correa; Mattar, Rejane; Iriya, Kiyoshi; Lee, Jin Hwa; Eisig, Jaime Natan

    2015-01-01

    OBJECTIVES: The eradication of Helicobacter (H.) pylori allows peptic ulcers in patients infected with the bacteria to be cured. Treatment with the classic triple regimen (proton pump inhibitor, amoxicillin and clarithromycin) has shown decreased efficacy due to increased bacterial resistance to clarithromycin. In our country, the eradication rate by intention to treat with this regimen is 83%. In Brazil, a commercially available regimen for bacterial eradication that uses levofloxacin and amoxicillin with lansoprazole is available; however, its efficacy is not known. Considering that such a treatment may be an alternative to the classic regimen, we aimed to verify its efficacy in H. pylori eradication. METHODS: Patients with peptic ulcer disease infected with H. pylori who had not received prior treatment were treated with the following regimen: 30 mg lansoprazole bid, 1,000 mg amoxicillin bid and 500 mg levofloxacin, once a day for 7 days. RESULTS: A total of 66 patients were evaluated. The patients’ mean age was 52 years, and women comprised 55% of the sample. Duodenal ulcers were present in 50% of cases, and gastric ulcers were present in 30%. The eradication rate was 74% per protocol and 73% by intention to treat. Adverse effects were reported by 49 patients (74%) and were mild to moderate, with a prevalence of diarrhea complaints. CONCLUSIONS: Triple therapy comprising lansoprazole, amoxicillin and levofloxacin for 7 days for the eradication of H. pylori in Brazilian peptic ulcer patients showed a lower efficacy than that of the classic triple regimen. PMID:26039946

  6. What are the effects of proton pump inhibitors on the small intestine?

    PubMed Central

    Fujimori, Shunji

    2015-01-01

    Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked. PMID:26078557

  7. What are the effects of proton pump inhibitors on the small intestine?

    PubMed

    Fujimori, Shunji

    2015-06-14

    Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked. PMID:26078557

  8. "Frozen" block copolymer nanomembranes with light-driven proton pumping performance.

    PubMed

    Kuang, Liangju; Fernandes, Donald A; O'Halloran, Matthew; Zheng, Wan; Jiang, Yunjiang; Ladizhansky, Vladimir; Brown, Leonid S; Liang, Hongjun

    2014-01-28

    Cellular membranes are natural nanoengineering devices, where matter transport, information processing, and energy conversion across the nanoscale boundaries are mediated by membrane proteins (MPs). Despite the great potential of MPs for nanotechnologies, their broad utility in engineered systems is limited by the fluidic and often labile nature of MP-supporting membranes. Little is known on how to direct spontaneous reconstitution of MPs into robust synthetic nanomembranes or how to tune MP functions through rational design of these membranes. Here we report that proteorhodopsin (PR), a light-driven proton pump, can be spontaneously reconstituted into "frozen" (i.e., glassy state) amphiphilic block copolymer membranes via a charge-interaction-directed reconstitution mechanism. We show that PR is not enslaved by a fluidic or lipid-based membrane environment. Rather, well-defined block copolymer nanomembranes, with their tunable membrane moduli, act as allosteric regulators to support the structural integrity and function of PR. Versatile membrane designs exist to modulate the conformational energetics of reconstituted MPs, therefore optimizing proteomembrane stability and performance in synthetic systems. PMID:24358932

  9. Effect of food or proton pump inhibitor treatment on the bioavailability of dacomitinib in healthy volunteers.

    PubMed

    Ruiz-Garcia, Ana; Masters, Joanna C; Mendes da Costa, Laure; LaBadie, Robert R; Liang, Yali; Ni, Grace; Ellery, Craig A; Boutros, Tanya; Goldberg, Zelanna; Bello, Carlo L

    2016-02-01

    This phase 1, open-label crossover study evaluated the relative bioavailability of dacomitinib in healthy volunteers under fed and fasted conditions and following coadministration with rabeprazole, a potent acid-reducing proton pump inhibitor (PPI). Twenty-four male subjects received a single dacomitinib 45-mg dose under 3 different conditions separated by washout periods of ≥ 16 days: coadministered with rabeprazole 40 mg under fasting conditions; alone under fasting conditions; and alone after a high-fat, high-calorie meal. Increased peak exposure of 23.7% (90% confidence interval [CI], 5.3%-45.2%) was detected with dacomitinib taken after food versus fasting. The adjusted geometric mean ratio (fed/fasted) for area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 114.2% (90%CI, 104.7%-124.5%) and not considered clinically meaningful. In the fasted state, a decrease in dacomitinib AUCinf was observed following rabeprazole versus dacomitinib alone (PPI+fasted/fasted alone): 71.1% (90%CI, 61.7%-81.8%). Dacomitinib was generally well tolerated. Dacomitinib may be taken with or without food. Use of long-acting acid-reducing agents, such as PPIs with dacomitinib should be avoided if possible. Shorter-acting agents such as antacids and H2-receptor antagonists may have lesser impact on dacomitinib exposure and may be preferable to PPIs if acid reduction is clinically required. PMID:26179237

  10. Are proton pump inhibitors a new antidiabetic drug? A cross sectional study

    PubMed Central

    Boj-Carceller, Diana; Bocos-Terraz, Pilar; Moreno-Vernis, Miguel; Sanz-Paris, Alejandro; Trincado-Aznar, Pablo; Albero-Gamboa, Ramón

    2011-01-01

    AIM: To investigate the effect of proton pump inhibitors (PPIs) on glycemic control (HbA1c) in type 2 diabetic patients. METHODS: A cross-sectional study of consecutive in-patients admitted to hospital in any department during the first semester of the year 2010 who had a recent HbA1c measurement. The study excluded those with a diagnosis of hyperglycemic decompensation, diabetic onset or pregnancy. It compared HbA1c levels of those taking PPIs and those not. RESULTS: A total of 97 patients were recruited. The average HbA1C level was 7.0% ± 1.2%. Overall PPI consumption was 55.7%. HbA1c was significantly lower in individuals who took PPIs: -0.6%, 95% CI: -0.12 to -0.83. People who used PPIs with some type of insulin therapy had a HbA1c reduction by -0.8%, 95% CI: -0.12 to -1.48. For the rest of subgroup analysis based on the antidiabetic drug used, PPI consumption always exhibited lower HbA1c levels. CONCLUSION: PPIs seems to be consistently associated with better glycemic control in type 2 diabetes. HbA1c reduction observed is similar to incretin-based therapies. PMID:22174957

  11. Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

    PubMed

    Canitano, Andrea; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Federici, Cristina; Fais, Stefano

    2016-07-01

    Multiple Myeloma (MM) is the second most common hematological malignancy and is responsive to a limited number of drugs. Unfortunately, to date, despite the introduction of novel drugs, no relevant increase in survival rates has been obtained. Proton pump inhibitors (PPIs) have been shown to have significant antitumor action as single agents as well as in combination with chemotherapy. This study investigates the potential anti-tumor effectiveness of two PPIs, Lansoprazole and Omeprazole, against human MM cells. We found that Lansoprazole exerts straightforward efficacy against myeloma cells, even at suboptimal concentrations (50 µM), while Omeprazole has limited cytotoxic action. The Lansoprazole anti-MM effect was mostly mediated by a caspase-independent apoptotic-like cytotoxicity, with only a secondary anti-proliferative action. This study provides clear evidence supporting the use of Lansoprazole in the strive against MM with an efficacy proven much higher than current therapeutical approaches and without reported side effects. It is however conceivable that, consistent with the results obtained in other human tumors, Lansoprazole may well be combined with existing anti-myeloma therapies with the aim to improve the low level of efficacy of the current strategies. PMID:27084522

  12. Proton Pump Inhibitor Use and Magnesium Concentrations in Hemodialysis Patients: A Cross-Sectional Study

    PubMed Central

    Nakashima, Akio; Ohkido, Ichiro; Yokoyama, Keitaro; Mafune, Aki; Urashima, Mitsuyoshi; Yokoo, Takashi

    2015-01-01

    Magnesium concentration is a proven predictor of mortality in hemodialysis patients. Recent reports have indicated that proton pump inhibitor (PPI) use affects serum magnesium levels, however few studies have investigated the relationship between PPI use and magnesium levels in hemodialysis patients. This study aimed to clarify the association between PPI use and serum magnesium levels in hemodialysis patients. We designed this cross sectional study and included 1189 hemodialysis patients in stable condition. Associations between PPI and magnesium-related factors, as well as other possible confounders, were evaluated using a multiple regression model. We defined hypomagnesemia as a value < 2.0 mg/dL, and created comparable logistic regression models to assess the association between PPI use and hypomagnesemia. PPI use is associated with a significantly lower mean serum magnesium level than histamine 2 (H2) receptor antagonists or no acid-suppressive medications (mean [SD] PPI: 2.52 [0.45] mg/dL; H2 receptor antagonist: 2.68 [0.41] mg/dL; no acid suppressive medications: 2.68 [0.46] mg/dL; P = 0.001). Hypomagnesemia remained significantly associated with PPI (adjusted OR, OR: 2.05; 95% CI: 1.14–3.69; P = 0.017). PPI use is associated with an increased risk of hypomagnesemia in hemodialysis patients. Future prospective studies are needed to explore magnesium replacement in PPI users on hemodialysis. PMID:26618538

  13. Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases

    PubMed Central

    Gurbel, Paul A; Tantry, Udaya S; Kereiakes, Dean J

    2010-01-01

    Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in ‘high risk’ and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided. PMID:21701635

  14. Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

    PubMed Central

    Zhou, Quan; Yan, Xiao-Feng; Pan, Wen-Sheng; Zeng, Su

    2008-01-01

    Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole. PMID:18442220

  15. Proton pump inhibitor Lansoprazole is a nuclear Liver X Receptor agonist

    PubMed Central

    Cronican, Andrea A.; Fitz, Nicholas F.; Pham, Tam; Fogg, Allison; Kifer, Brionna; Koldamova, Radosveta; Lefterov, Iliya

    2010-01-01

    The liver X receptors (LXRα and LXRβ) are transcription factors that control the expression of genes primarily involved in cholesterol metabolism. In brain, in addition to normal neuronal function, cholesterol metabolism is important for APP proteolytic cleavage, secretase activities, Aβ aggregation and clearance. Particularly significant in this respect is the LXR mediated transcriptional control of APOE, which is the only proven risk factor for late onset Alzheimer’s disease. Using a transactivation reporter assay for screening pharmacologically active compounds and off patent drugs we identified the Proton Pump Inhibitor Lansoprazole as an LXR agonist. In secondary screens and counter-screening assays, it was confirmed that Lansoprazole directly activates LXR, increases the expression of LXR target genes in brain-derived human cell lines, and increases Abca1 and Apo-E protein levels in primary astrocytes derived from wild type but not LXRα/β double knockout mice. Other PPIs activate LXR as well, but the efficiency of activation depends on their structural similarities to Lansoprazole. The identification of widely used, drug with LXR agonist-like activity opens the possibility for systematic preclinical testing in at least two diseases – Alzheimer’s disease and atherosclerosis. PMID:20060385

  16. Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial.

    PubMed

    Freedberg, Daniel E; Toussaint, Nora C; Chen, Sway P; Ratner, Adam J; Whittier, Susan; Wang, Timothy C; Wang, Harris H; Abrams, Julian A

    2015-10-01

    We conducted an open-label crossover trial to test whether proton pump inhibitors (PPIs) affect the gastrointestinal microbiome to facilitate Clostridium difficile infection (CDI). Twelve healthy volunteers each donated 2 baseline fecal samples, 4 weeks apart (at weeks 0 and 4). They then took PPIs for 4 weeks (40 mg omeprazole, twice daily) and fecal samples were collected at week 8. Six individuals took the PPIs for an additional 4 weeks (from week 8 to 12) and fecal samples were collected from all subjects at week 12. Samples were analyzed by 16S ribosomal RNA gene sequencing. We found no significant within-individual difference in microbiome diversity when we compared changes during baseline vs changes on PPIs. There were, however, significant changes during PPI use in taxa associated with CDI (increased Enterococcaceae and Streptococcaceae, decreased Clostridiales) and taxa associated with gastrointestinal bacterial overgrowth (increased Micrococcaceae and Staphylococcaceae). In a functional analysis, there were no changes in bile acids on PPIs, but there was an increase in genes involved in bacterial invasion. These alterations could provide a mechanism by which PPIs predispose to CDI. ClinicalTrials.gov ID NCT01901276. PMID:26164495

  17. Meta-analysis of the efficacy of proton pump inhibitors for the symptoms of laryngopharyngeal reflux.

    PubMed

    Liu, C; Wang, H; Liu, K

    2016-07-01

    The objective of this study was to perform a systematic review and meta-analysis to assess the effectiveness of proton pump inhibitors (PPI) for reflux disease in adult patients with laryngopharyngeal symptoms. A comprehensive search of Cochrane Library, EMBASE, Ovid EBM Reviews, and PubMed was performed for English-language literature about laryngopharyngeal reflux (LPR), in September 2014. The papers were filtered using pre-defined inclusion and exclusion criteria. Eight papers were identified and included in this meta-analysis. The sample comprised a pooled total of 370 patients, of which 210 and 160 patients took PPIs and placebo, respectively. The difference between PPIs and placebo groups in overall improvement of symptoms in adult patients with LPR was not statistically significant (RR=1.22; 95%CI=0.93-1.58; P=0.149). The difference in cough improvement was also not significant between PPIs and placebo groups (RR=0.65; 95%CI=0.30-1.41; P=0.279). PMID:27383119

  18. Meta-analysis of the efficacy of proton pump inhibitors for the symptoms of laryngopharyngeal reflux

    PubMed Central

    Liu, C.; Wang, H.; Liu, K.

    2016-01-01

    The objective of this study was to perform a systematic review and meta-analysis to assess the effectiveness of proton pump inhibitors (PPI) for reflux disease in adult patients with laryngopharyngeal symptoms. A comprehensive search of Cochrane Library, EMBASE, Ovid EBM Reviews, and PubMed was performed for English-language literature about laryngopharyngeal reflux (LPR), in September 2014. The papers were filtered using pre-defined inclusion and exclusion criteria. Eight papers were identified and included in this meta-analysis. The sample comprised a pooled total of 370 patients, of which 210 and 160 patients took PPIs and placebo, respectively. The difference between PPIs and placebo groups in overall improvement of symptoms in adult patients with LPR was not statistically significant (RR=1.22; 95%CI=0.93-1.58; P=0.149). The difference in cough improvement was also not significant between PPIs and placebo groups (RR=0.65; 95%CI=0.30-1.41; P=0.279). PMID:27383119

  19. Proton Pump Inhibitor Use Is not Associated with Cardiac Arrhythmia in Critically Ill Patients

    PubMed Central

    Chen, Kenneth P.; Lee, Joon; Mark, Roger G.; Feng, Mornin; Celi, Leo A.; Danziger, John

    2016-01-01

    Hypomagnesemia can lead to cardiac arrhythmias. Recently, observational data has linked chronic proton pump inhibitor (PPI) exposure to hypomagnesemia. Whether PPI exposure increases the risk for arrhythmias has not been well studied. Using a large, single center inception cohort of critically ill patients, we examined whether PPI exposure was associated with admission electrocardiogram (ECG) readings of a cardiac arrhythmia in over 8000 patients. There were 24.5% PPI users while 6% were taking a histamine 2 antagonist. 14.3% had a cardiac arrhythmia. PPI use was associated with a 1.18 (95% CI=1.02–1.36, p=0.02) unadjusted and 0.96 (95% CI=0.83–1.12, p=0.62) adjusted risk of arrhythmia. Amongst diuretic users (n=2468), PPI use was similarly not associated with an increased risk of cardiac arrhythmia. In summary, in a large cohort of critically ill patients, PPI exposure is not associated with an increased risk of cardiac arrhythmia. PMID:25655574

  20. Attitude and Knowledge of Indian Emergency Care Residents towards Use of Proton Pump Inhibitors

    PubMed Central

    Padhy, Biswa Mohan; Bhadauria, Hemant Singh; Gupta, Yogendra Kumar

    2014-01-01

    Objective. Several studies carried out in developed countries have reported disproportionately high usage of acid suppressive drugs, especially proton pump inhibitors (PPIs). However, systematic assessment of attitude and practices of health care providers towards the use of these drugs in developing countries is lacking. In this study, we assessed the knowledge, attitude, and preferences of resident doctors posted in the emergency department of a tertiary care hospital in North India, towards the use of PPIs. Methods. A questionnaire based survey was carried out. Results. Fifty resident doctors responded to the questionnaire. Thirty-six percent reported prescribing acid suppressive drugs for majority of their patients, while 12% prescribed them to almost all patients they attended. Acute gastritis was the most common indication for prescribing PPI/H2 blockers (50%). The majority of respondents (92%) regarded PPIs as their first choice in acid suppressive agents and 58% administered it through intravenous route. Knowledge about PPI related adverse effects was low. Conclusions. Emergency care residents in India also tend to overuse PPIs in a manner similar to their counterparts in developed countries. Specific measures may be helpful in preventing such practices.

  1. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.

    PubMed

    Yitshak-Sade, Maayan; Gorodischer, Rafael; Aviram, Micha; Novack, Lena

    2016-01-01

    Fetal exposure to H2 blockers (H2 Bs) or proton pump inhibitors (PPIs) has been reported to be associated with asthma in children. We evaluated the risk of asthma in offspring following prenatal H2 Bs. We enrolled 91 428 children and their mothers who resided in southern Israel during 1998-2011. The computerized medications database was linked with records from the district hospital. Of the eligible children, 11 227 developed asthma, and overall 5.5% had been exposed to H2 Bs or PPIs prenatally. The risk of developing asthma was slightly higher in the group exposed to H2 Bs or PPIs (RR, 1.09; P = .023). At greater risk were children whose mothers purchased these medications more than 3 times (RR, 1.22; P = .038) or exposed to >20 defined daily doses or prenatally exposed to lansoprazole. The statistical association was significant and depended on magnitude of exposure and specific medication, but the absolute risk was low. The association between maternal consumption of H2 Bs or PPIs and asthma and childhood remained statistically significant 2 years after delivery, raising the possibility of confounding by the indication phenomenon. In view of the findings, a causal relationship could not be ascertained, and an unidentified etiological factor could be operative. PMID:26096778

  2. Use of proton-pump inhibitors among adults: a Danish nationwide drug utilization study

    PubMed Central

    Pottegård, Anton; Broe, Anne; Hallas, Jesper; de Muckadell, Ove B. Schaffalitzky; Lassen, Annmarie T.; Lødrup, Anders B.

    2016-01-01

    Background: The use of proton-pump inhibitors (PPIs) has increased over the last decade. The objective of this study was to provide detailed utilization data on PPI use over time, with special emphasis on duration of PPI use and concomitant use of ulcerogenic drugs. Methods: Using the nationwide Danish Prescription Registry, we identified all Danish adults filling a PPI between 2002 and 2014. Using descriptive statistics, we reported (i) the distribution of use between single PPI entities, (ii) the development in incidence and prevalence of use over time, (iii) measures of duration and intensity of treatment, and (iv) the prevalence of use of ulcerogenic drugs among users of PPIs. Results: We identified 1,617,614 adults using PPIs during the study period. The prevalence of PPI use increased fourfold during the study period to 7.4% of all Danish adults in 2014. PPI use showed strong age dependency, reaching more than 20% among those aged at least 80 years. The proportion of users maintaining treatment over time increased with increasing age, with less than10% of those aged 18–39 years using PPIs 2 years after their first prescription, compared with about 40% among those aged at least 80 years. The overall use of ulcerogenic drugs among PPI users increased moderately, from 35% of users of PPI in 2002 to 45% in 2014. Conclusions: The use of PPIs is extensive and increasing rapidly, especially among the elderly. PMID:27582879

  3. A new hypothesis on the simultaneous direct and indirect proton pump mechanisms in NADH-quinone oxidoreductase (complex I)

    PubMed Central

    Ohnishi, Tomoko; Nakamaru-Ogiso, Eiko; Ohnishi, S. Tsuyoshi

    2010-01-01

    Recently, Sazanov’s group reported the X-ray structure of whole complex I [Nature, 465, 441 (2010)], which presented a strong clue for a “piston-like” structure as a key element in an “indirect” proton pump. We have studied the NuoL subunit which has a high sequence similarity to Na+/H+ antiporters, as do the NuoM and N subunits. We constructed 27 site-directed NuoL mutants. Our data suggest that the H+/e− stoichiometry seems to have decreased from (4H+/2e−) in the wild-type to approximately (3H+/2e−) in NuoL mutants. We propose a revised hypothesis that each of the “direct” and the “indirect” proton pumps transports 2H+ per 2e−. PMID:20816962

  4. The effects of diet ingredients on gastric ulceration and stereotypies in gestating sows

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Stereotypies in swine can be altered with various feedstuffs, but it is unknown how this will affect the development of gastric ulcers. The objective of this experiment was to determine the effects of a proton pump inhibitor and sodium bicarbonate on ulcerations of the pars esophagea (UPE) region of...

  5. His-75 in Proteorhodopsin, a Novel Component in Light-driven Proton Translocation by Primary Pumps*S⃞

    PubMed Central

    Bergo, Vladislav B.; Sineshchekov, Oleg A.; Kralj, Joel M.; Partha, Ranga; Spudich, Elena N.; Rothschild, Kenneth J.; Spudich, John L.

    2009-01-01

    Proteorhodopsins (PRs), photoactive retinylidene membrane proteins ubiquitous in marine eubacteria, exhibit light-driven proton transport activity similar to that of the well studied bacteriorhodopsin from halophilic archaea. However, unlike bacteriorhodopsin, PRs have a single highly conserved histidine located near the photoactive site of the protein. Time-resolved Fourier transform IR difference spectroscopy combined with visible absorption spectroscopy, isotope labeling, and electrical measurements of light-induced charge movements reveal participation of His-75 in the proton translocation mechanism of PR. Substitution of His-75 with Ala or Glu perturbed the structure of the photoactive site and resulted in significantly shifted visible absorption spectra. In contrast, His-75 substitution with a positively charged Arg did not shift the visible absorption spectrum of PR. The mutation to Arg also blocks the light-induced proton transfer from the Schiff base to its counterion Asp-97 during the photocycle and the acid-induced protonation of Asp-97 in the dark state of the protein. Isotope labeling of histidine revealed that His-75 undergoes deprotonation during the photocycle in the proton-pumping (high pH) form of PR, a reaction further supported by results from H75E. Finally, all His-75 mutations greatly affect charge movements within the PR and shift its pH dependence to acidic values. A model of the proteorhodopsin proton transport process is proposed as follows: (i) in the dark state His-75 is positively charged (protonated) over a wide pH range and interacts directly with the Schiff base counterion Asp-97; and (ii) photoisomerization-induced transfer of the Schiff base proton to the Asp-97 counterion disrupts its interaction with His-75 and triggers a histidine deprotonation. PMID:19015272

  6. Proton pump inhibitor step-down therapy for GERD: A multi-center study in Japan

    PubMed Central

    Tsuzuki, Takao; Okada, Hiroyuki; Kawahara, Yoshiro; Takenaka, Ryuta; Nasu, Junichiro; Ishioka, Hidehiko; Fujiwara, Akiko; Yoshinaga, Fumiya; Yamamoto, Kazuhide

    2011-01-01

    AIM: To investigate the predictors of success in step-down of proton pump inhibitor and to assess the quality of life (QOL). METHODS: Patients who had heartburn twice a week or more were treated with 20 mg omeprazole (OPZ) once daily for 8 wk as an initial therapy (study 1). Patients whose heartburn decreased to once a week or less at the end of the initial therapy were enrolled in study 2 and treated with 10 mg OPZ as maintenance therapy for an additional 6 mo (study 2). QOL was investigated using the gastrointestinal symptom rating scale (GSRS) before initial therapy, after both 4 and 8 wk of initial therapy, and at 1, 2, 3, and 6 mo after starting maintenance therapy. RESULTS: In study 1, 108 patients were analyzed. Their characteristics were as follows; median age: 63 (range: 20-88) years, sex: 46 women and 62 men. The success rate of the initial therapy was 76%. In the patients with successful initial therapy, abdominal pain, indigestion and reflux GSRS scores were improved. In study 2, 83 patients were analyzed. Seventy of 83 patients completed the study 2 protocol. In the per-protocol analysis, 80% of 70 patients were successful for step-down. On multivariate analysis of baseline demographic data and clinical information, no previous treatment for gastroesophageal reflux disease (GERD) [odds ratio (OR) 0.255, 95% CI: 0.06-0.98] and a lower indigestion score in GSRS at the beginning of step-down therapy (OR 0.214, 95% CI: 0.06-0.73) were found to be the predictors of successful step-down therapy. The improved GSRS scores by initial therapy were maintained through the step-down therapy. CONCLUSION: OPZ was effective for most GERD patients. However, those who have had previous treatment for GERD and experience dyspepsia before step-down require particular monitoring for relapse. PMID:21472108

  7. Proton pump inhibitors and risk of periampullary cancers--A nested case-control study.

    PubMed

    Chien, Li-Nien; Huang, Yan-Jiun; Shao, Yu-Hsuan Joni; Chang, Chen-Jung; Chuang, Ming-Tsang; Chiou, Hung-Yi; Yen, Yun

    2016-03-15

    Considerable attention has been focused on long-term use of proton pump inhibitor (PPI) medications in relation to increased risk of cancer via stimulation of DNA-damaged cells. The aim of this study is to examine the dose-dependent effect of PPI on periampullary cancers in a national population-based cohort. A nested case-control analysis was constructed based on Taiwan's National Health Insurance Research Database and the Taiwan Cancer Registry between the years 2000 and 2010. Cases involving patients diagnosed with periampullary cancers were selected and controls were matched to cases according to age, sex and observational period. A "PPI user" was defined as any patient receiving more than 28 cumulative defined daily doses as measured by prescription drug claims. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to the level of PPI exposure. A total of 7,681 cases and 76,762 matched controls were included with a mean follow-up period of 6.6 years (SD: 2.0). The odds of PPI exposure in patients with periampullary cancers were higher than that of control patients with an adjusted OR of 1.35 (95% CIs: 1.16-1.57). Our results also showed that PPI exposure was slightly linked to periampullary cancers in dose-dependent manner. A similar association was observed in patients who solely took PPI but no eradication therapy for Helicobacter pylori infection. Long-term PPI use was associated with an increased risk of periampullary cancers in the current population-based study. Physicians must weigh potential risks of long-term maintenance against therapeutic benefit. PMID:26488896

  8. Cost-Effectiveness of Chemoprevention with Proton Pump Inhibitors in Barrett’s Esophagus

    PubMed Central

    Freedberg, Daniel E.; Abrams, Julian A.; Wang, Y. Claire

    2015-01-01

    Background Proton pump inhibitors (PPIs) may reduce the risk of esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus. PPIs are prescribed for virtually all patients with Barrett’s esophagus, irrespective of the presence of reflux symptoms, and represent a de facto chemopreventive agent in this population. However, long-term PPI use has been associated with several adverse effects, and the cost-effectiveness of chemoprevention with PPIs has not been evaluated. Aim The purpose of this study was to assess the cost-effectiveness of PPIs for the prevention of EAC in Barrett’s esophagus without reflux. Methods We designed a state-transition Markov micro-simulation model of a hypothetical cohort of 50-year-old white men with Barrett’s esophagus. We modeled chemoprevention with PPIs or no chemoprevention, with endoscopic surveillance for all treatment arms. Outcome measures were life-years, quality-adjusted life years (QALYs), incident EAC cases and deaths, costs, and incremental cost-effectiveness ratios. Results Assuming 50 % reduction in EAC, chemoprevention with PPIs was a cost-effective strategy compared to no chemoprevention. In our model, administration of PPIs cost $23,000 per patient and resulted in a gain of 0.32 QALYs for an incremental cost-effectiveness ratio of $12,000/QALY. In sensitivity analyses, PPIs would be cost-effective at $50,000/QALY if they reduce EAC risk by at least 19 %. Conclusions Chemoprevention with PPIs in patients with Barrett’s esophagus without reflux is cost-effective if PPIs reduce EAC by a minimum of 19 %. The identification of subgroups of Barrett’s esophagus patients at increased risk for progression would lead to more cost-effective strategies for the prevention of esophageal adenocarcinoma. PMID:24795040

  9. In Vitro Study of the Variable Effects of Proton Pump Inhibitors on Voriconazole

    PubMed Central

    Niece, Krista L.; Boyd, Natalie K.

    2015-01-01

    Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 μg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections. PMID:26124167

  10. The interaction between clopidogrel and proton pump inhibitors (PPI): is there any clinical relevance?

    PubMed Central

    Sharma, Rakesh K; Reddy, Hanumanth K; Sharma, Rohit K; Moazazi, Mathilde; Elango, Lovett; Singh, Vibhuti N; Williams, D Keith; Voelker, Donald J

    2010-01-01

    The potential interaction between clopidogrel and proton pump inhibitors (PPI) in patients with acute coronary syndrome (ACS) raises serious concerns for cardiologists. However, in patients on this combination of drugs, there is no conclusive evidence of an increase in adverse cardiovascular events. From pharmacologic and pharmacodynamic perspectives, there is a real interaction between clopidogrel and PPIs because of the competitive inhibition of CYP2C19 isoenzyme which is required for biotransformation of clopidogrel to its active metabolite. The consequent decrease in the availability of this active metabolite leads to attenuation of antiplatelet efficacy of clopidogrel. In several observational trials, it was shown that decreased antiplatelet effect of clopidogrel due to PPIs may translate into poor cardiovascular outcomes. However, an incomplete RCT (COGENT) and a post hoc analysis of two large trials (PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trial) showed no significant adverse cardiovascular events with this combination. Caution is however needed in patients who are hypometabolizers of clopidogrel putting them at a higher risk of adverse coronary events. Since 3% of patients are likely to be hypometabolizers of clopidogrel, routine combination of clopidogrel and PPIs should be avoided. There is a heightened awareness of this interaction following multiple advisory warnings. At the same time, one should not withhold PPIs in patients who are at a high risk of developing gastrointestinal (GI) bleeding. In these patients, selected choices of PPI such as pantoprazole may be helpful and for low risk patients, serious consideration should be given to H2 receptor antagonists or antacids. Therefore, while not compromising the cardioprotective effect of antiplatelet agents, the gastroprotective benefit of PPI should be strongly considered in patients who need both. Health care providers should remain alert to more outcome data. Future researchers will need to demonstrate

  11. Trends in the coprescription of proton pump inhibitors with clopidogrel: an ecological analysis

    PubMed Central

    Juurlink, David N.; Gomes, Tara; Paterson, J. Michael; Hellings, Chelsea; Mamdani, Muhammad M.

    2015-01-01

    Background: In early 2009, 2 observational studies and a US Food and Drug Administration (FDA) advisory addressed the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. One study suggested that pantoprazole could be used safely in this setting, whereas the other study and the FDA advisory did not distinguish among PPIs. We examined trends in PPI prescribing among clopidogrel recipients in the period following these events. Methods: We conducted a population-based time series analysis of Ontario residents aged 66 years or older for whom clopidogrel was prescribed between Apr. 1, 1999, and Sept. 30, 2013. We determined the proportion of clopidogrel recipients dispensed a PPI during each quarter and the proportions who received pantoprazole or other PPIs. The outcome of interest was change in the use of pantoprazole. Results: In the final quarter of 2008, pantoprazole represented 23.7% of all PPI prescriptions dispensed to patients receiving clopidogrel. Following the publications and FDA advisory in early 2009, pantoprazole use increased substantially. By the end of 2009, this medication accounted for 52.5% of all PPI prescriptions issued to patients receiving clopidogrel; by the end of the study period, it accounted for 71.0% of all PPI prescriptions dispensed to such patients (p < 0. 001). We also observed a modest drop in overall PPI use among clopidogrel recipients beginning in early 2009. Interpretation: In 2009, the prescribing of PPIs with clopidogrel changed substantially in Ontario, with pantoprazole rapidly becoming the most commonly prescribed agent in its class. However, a modest decline in overall PPI use also occurred that may reflect suboptimal translation of emerging drug safety information to clinical practice. PMID:26770965

  12. [Clopidogrel--proton pump inhibitors drug interaction: implications to clinical practice].

    PubMed

    Fontes-Carvalho, Ricardo; Albuquerque, Aníbal

    2010-10-01

    Recent studies have raised the concern that proton pump inhibitors (PPIs) could potentially interfere with clopidogrel antiplatelet effect. This association is frequent in clinical practice and is recommended by recent consensus guidelines in patients taking dual antiplatelet therapy to prevent gastrointestinal (GI) bleeding. Clopidogrel is a pro-drug which needs to be metabolized into its active metabolite, by cytochrome P450, especially by CYP2C19 isoenzyme. Various PPIs can inhibit CYP2C19, which could possibly decrease clopidogrel bioactivation process and, therefore, its antiplatelet effect. Various platelet function studies have shown that omeprazol can significantly decrease clopidogrel inhibitory effect on platelet P2Y12 receptor, leading to an increase in the number of patients who are "nonresponders" to clopidogrel. These pharmacokinetic studies also shown that this is not probably a class effect of PPIs, because they are metabolized to varying degrees by CYP2C19. The clinical impact of these observations remains uncertain, because various observational studies have shown conflicting results, and remains to demonstrate if PPIs can really increase the risk of cardiovascular events in patients taking clopidogrel. In this review we will discuss the pharmacokinetic basis underlying this drug interaction, the effect of different PPIs on platelet function tests and we will analyze in detail the potential clinical implications of using this association, both on cardiovascular and gastrointestinal events. Until further data is available, some clinical strategies can be recommended: (1) individual gastrointestinal risk assessment, with PPIs administration only to patients on dual anti-platelet therapy with additional GI risk factors; (2) preferential use of PPIs that have shown less interference with clopidogrel efficacy; (3) wide separation of PPI and clopidogrel dosing to minimize the risk of interaction (PPI may be given before breakfast and clopidogrel at

  13. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries

    PubMed Central

    Mo, Chen; Sun, Gang; Lu, Ming-Liang; Zhang, Li; Wang, Yan-Zhi; Sun, Xi; Yang, Yun-Sheng

    2015-01-01

    AIM: To determine the preventive effect and safety of proton pump inhibitors (PPIs) in low-dose aspirin (LDA)-associated gastrointestinal (GI) ulcers and bleeding. METHODS: We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register from inception to December 2013, and checked conference abstracts of randomized controlled trials (RCTs) on the effect of PPIs in reducing adverse GI events (hemorrhage, ulcer, perforation, or obstruction) in patients taking LDA. The preventive effects of PPIs were compared with the control group [taking placebo, a cytoprotective agent, or an H2 receptor antagonist (H2RA)] in LDA-associated upper GI injuries. The meta-analysis was performed using RevMan 5.1 software. RESULTS: We evaluated 8780 participants in 10 RCTs. The meta-analysis showed that PPIs decreased the risk of LDA-associated upper GI ulcers (OR = 0.16; 95%CI: 0.12-0.23) and bleeding (OR = 0.27; 95%CI: 0.16-0.43) compared with control. For patients treated with dual anti-platelet therapy of LDA and clopidogrel, PPIs were able to prevent the LDA-associated GI bleeding (OR = 0.36; 95%CI: 0.15-0.87) without increasing the risk of major adverse cardiovascular events (MACE) (OR = 1.00; 95%CI: 0.76-1.31). PPIs were superior to H2RA in prevention of LDA-associated GI ulcers (OR = 0.12; 95%CI: 0.02-0.65) and bleeding (OR = 0.32; 95%CI: 0.13-0.79). CONCLUSION: PPIs are effective in preventing LDA-associated upper GI ulcers and bleeding. Concomitant use of PPI, LDA and clopidogrel did not increase the risk of MACE. PMID:25954113

  14. Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis.

    PubMed

    Molina-Infante, Javier; Bredenoord, Albert J; Cheng, Edaire; Dellon, Evan S; Furuta, Glenn T; Gupta, Sandeep K; Hirano, Ikuo; Katzka, David A; Moawad, Fouad J; Rothenberg, Marc E; Schoepfer, Alain; Spechler, Stuart J; Wen, Ting; Straumann, Alex; Lucendo, Alfredo J

    2016-03-01

    Consensus diagnostic recommendations to distinguish GORD from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPIs) unexpectedly uncovered an entity called 'PPI-responsive oesophageal eosinophilia' (PPI-REE). PPI-REE refers to patients with clinical and histological features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that patients with PPI-REE and patients with EoE at baseline are clinically, endoscopically and histologically indistinguishable and have a significant overlap in terms of features of Th2 immune-mediated inflammation and gene expression. Furthermore, PPI therapy restores oesophageal mucosal integrity, reduces Th2 inflammation and reverses the abnormal gene expression signature in patients with PPI-REE, similar to the effects of topical steroids in patients with EoE. Additionally, recent series have reported that patients with EoE responsive to diet/topical steroids may also achieve remission on PPI therapy. This mounting evidence supports the concept that PPI-REE represents a continuum of the same immunological mechanisms that underlie EoE. Accordingly, it seems counterintuitive to differentiate PPI-REE from EoE based on a differential response to PPI therapy when their phenotypic, molecular, mechanistic and therapeutic features cannot be reliably distinguished. For patients with symptoms and histological features of EoE, it is reasonable to consider PPI therapy not as a diagnostic test, but as a therapeutic agent. Due to its safety profile, ease of administration and high response rates (up to 50%), PPI can be considered a first-line treatment before diet and topical steroids. The reasons why some patients with EoE respond to PPI, while others do not, remain to be elucidated. PMID:26685124

  15. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors

    PubMed Central

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-01-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors. PMID:26212113

  16. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population

    PubMed Central

    Bauer-Mehren, Anna; Ghebremariam, Yohannes T.; Iyer, Srinivasan V.; Marcus, Jake; Nead, Kevin T.; Cooke, John P.; Leeper, Nicholas J.

    2015-01-01

    Background and Aims Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches. Methods Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population. Results In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000. Conclusions Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation. PMID:26061035

  17. In vitro study of the variable effects of proton pump inhibitors on voriconazole.

    PubMed

    Niece, Krista L; Boyd, Natalie K; Akers, Kevin S

    2015-09-01

    Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 μg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections. PMID:26124167

  18. Clinical usefulness of limited sampling strategies for estimating AUC of proton pump inhibitors.

    PubMed

    Niioka, Takenori

    2011-03-01

    Cytochrome P450 (CYP) 2C19 (CYP2C19) genotype is regarded as a useful tool to predict area under the blood concentration-time curve (AUC) of proton pump inhibitors (PPIs). In our results, however, CYP2C19 genotypes had no influence on AUC of all PPIs during fluvoxamine treatment. These findings suggest that CYP2C19 genotyping is not always a good indicator for estimating AUC of PPIs. Limited sampling strategies (LSS) were developed to estimate AUC simply and accurately. It is important to minimize the number of blood samples because of patient's acceptance. This article reviewed the usefulness of LSS for estimating AUC of three PPIs (omeprazole: OPZ, lansoprazole: LPZ and rabeprazole: RPZ). The best prediction formulas in each PPI were AUC(OPZ)=9.24 x C(6h)+2638.03, AUC(LPZ)=12.32 x C(6h)+3276.09 and AUC(RPZ)=1.39 x C(3h)+7.17 x C(6h)+344.14, respectively. In order to optimize the sampling strategy of LPZ, we tried to establish LSS for LPZ using a time point within 3 hours through the property of pharmacokinetics of its enantiomers. The best prediction formula using the fewest sampling points (one point) was AUC(racemic LPZ)=6.5 x C(3h) of (R)-LPZ+13.7 x C(3h) of (S)-LPZ-9917.3 x G1-14387.2×G2+7103.6 (G1: homozygous extensive metabolizer is 1 and the other genotypes are 0; G2: heterozygous extensive metabolizer is 1 and the other genotypes are 0). Those strategies, plasma concentration monitoring at one or two time-points, might be more suitable for AUC estimation than reference to CYP2C19 genotypes, particularly in the case of coadministration of CYP mediators. PMID:21372537

  19. Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors.

    PubMed

    Sarafoff, Nikolaus; Sibbing, Dirk; Sonntag, Ulrich; Ellert, Julia; Schulz, Stefanie; Byrne, Robert A; Mehilli, Julinda; Schömig, Albert; Kastrati, Adnan

    2010-09-01

    Clopidogrel is a prodrug that is converted via the hepatic cytochrome P450 system into its active thiol metabolite. Evidence is accumulating that proton pump inhibitors (PPIs) inhibit this enzymatic pathway and may therefore attenuate the antiplatelet effect of clopidogrel. The objective of this study was to investigate whether patients on clopidogrel therapy after drug-eluting stent (DES) placement who also receive a PPI are at higher risk of stent thrombosis (ST). This is a retrospective analysis of patients who received dual antiplatelet treatment including clopidogrel after DES placement. Outcomes were compared according to PPI therapy. The primary endpoint was the incidence of definite ST at 30 days. Secondary endpoints were death, combined death or ST and myocardial infarction (MI). The study population included 3,338 patients and 698 patients (20.9%) received PPIs. Patients receiving a PPI had a higher risk profile at baseline. Multivariate analysis showed that PPI treatment was not independently associated with the occurrence of ST [adjusted HR 1.8 (95% CI: 0.7-4.7), p=0.23] or MI [adjusted HR 1.3 (0.8-2.3), p=0.11]. PPI treatment was significantly associated with death [adjusted HR 2.2 (1.1-4.3), p=0.02] and death or ST [adjusted HR 3.3(1.7-6.7), p=0.02]. Concomitant treatment with a PPI in patients receiving dual antiplatelet treatment after coronary stenting is not an independent predictor of ST. The higher mortality is probably due to confounding as patients on PPIs had a higher risk profile at baseline. PMID:20664905

  20. Proton pump inhibitors and risk of periampullary cancers—A nested case–control study

    PubMed Central

    Chien, Li‐Nien; Huang, Yan‐Jiun; Shao, Yu‐Hsuan Joni; Chang, Chen‐Jung; Chuang, Ming‐Tsang; Chiou, Hung‐Yi

    2015-01-01

    Considerable attention has been focused on long‐term use of proton pump inhibitor (PPI) medications in relation to increased risk of cancer via stimulation of DNA‐damaged cells. The aim of this study is to examine the dose‐dependent effect of PPI on periampullary cancers in a national population‐based cohort. A nested case–control analysis was constructed based on Taiwan's National Health Insurance Research Database and the Taiwan Cancer Registry between the years 2000 and 2010. Cases involving patients diagnosed with periampullary cancers were selected and controls were matched to cases according to age, sex and observational period. A “PPI user” was defined as any patient receiving more than 28 cumulative defined daily doses as measured by prescription drug claims. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to the level of PPI exposure. A total of 7,681 cases and 76,762 matched controls were included with a mean follow‐up period of 6.6 years (SD: 2.0). The odds of PPI exposure in patients with periampullary cancers were higher than that of control patients with an adjusted OR of 1.35 (95% CIs: 1.16–1.57). Our results also showed that PPI exposure was slightly linked to periampullary cancers in dose‐dependent manner. A similar association was observed in patients who solely took PPI but no eradication therapy for Helicobacter pylori infection. Long‐term PPI use was associated with an increased risk of periampullary cancers in the current population‐based study. Physicians must weigh potential risks of long‐term maintenance against therapeutic benefit. PMID:26488896

  1. Idiopathic Pulmonary Fibrosis: Novel Concepts of Proton Pump Inhibitors as Antifibrotic Drugs.

    PubMed

    Ghebre, Yohannes T; Raghu, Ganesh

    2016-06-15

    The prevalence of abnormal acid gastroesophageal reflux (GER) is higher in patients with idiopathic pulmonary fibrosis (IPF) than in matched control subjects. Several studies demonstrated that more than one-third of patients with IPF have abnormal esophageal acid exposures. In addition, many of these studies indicate that the majority of patients with IPF have silent reflux with no symptoms of GER. Findings of abnormal reflux persist in a large proportion of patients with IPF placed on antacid therapy such as proton pump inhibitors (PPIs). This seemingly paradoxical observation suggests that either patients with IPF are somehow resistant to PPI-based intervention or PPIs are inherently unable to suppress acid GER. By contrast, patients with IPF who undergo Nissen fundoplication surgery are effectively relieved from the complications of GER, and retrospective studies suggest improved lung function. Retrospective, anecdotal data suggest a beneficial role of PPIs in IPF including stabilization of lung function, reduction in episodes of acute exacerbation, and enhanced longevity. The recent evidence-based guidelines for treatment of IPF approved conditional recommendation of PPIs for all patients with IPF regardless of their GER status. Recently, we have reported that PPIs possess antiinflammatory and antifibrotic activities by directly suppressing proinflammatory cytokines, profibrotic proteins, and proliferation of lung fibroblasts. Our study provides an alternative explanation for the beneficial effect of PPIs in IPF. In this Perspective, we reviewed emerging progress on antifibrotic effect of PPIs using IPF as a disease model. In addition, we summarized surgical and pharmacological interventions for GER and their downstream effect on lung physiology. PMID:27110898

  2. Expression of HSP72 in the gastric mucosa is regulated by gastric acid in rats-Correlation of HSP72 expression with mucosal protection

    SciTech Connect

    Wada, Isao; Otaka, Michiro . E-mail: otaka@med.akita-u.ac.jp; Jin, Mario; Odashima, Masaru; Komatsu, Koga; Konishi, Noriaki; Matsuhashi, Tamotsu; Horikawa, Youhei; Ohba, Reina; Itoh, Hideaki; Watanabe, Sumio

    2006-10-20

    Background and aim: The real mechanism of adaptive cytoprotection in the gastric mucosa is not well established. In the present study, we investigated the effect of acid suppressing agents on a 72-kDa heat shock protein (HSP72) expression, which is known as endogenous cytoprotective factor, in the gastric mucosa. Also, the association of gastric mucosal protective function against HCl-challenge was compared between HSP72-induced and -reduced group. Materials and methods: Expression of HSP72 was measured by Western blotting in the gastric mucosa before and after administration of famotidine or omeprazole. The gastric mucosal protective function against 0.6 N HCl was compared between control group and HSP72-reduced group. Also, the effect of increased expression of gastric HSP72 by additional administration of zinc sulfate or zinc L-carnosine, which is known as HSP72-inducer, on mucosal protective function was studied. Results: HSP72 expression in the gastric mucosa was reduced by acid suppressing agents. The lowest expression level of HSP72 was observed 12 h (famotidine, H2-receptor antagonist) or 48 h (omeprazole, proton pump inhibitor) after administration. The gastric mucosal protective ability against 0.6 N HCl was also reduced when HSP72 expression was decreased by famotidine or omeprazole. This phenomenon was reversed by HSP72 induction by additional administration of zinc derivatives. Conclusion: Our results might indicate that the expression of HSP72 in the gastric mucosa is physiologically regulated by gastric acid, and that HSP72 induction could be important in view of mucosal protection especially when HSP72 expression is reduced by administration of acid suppressing agents such as proton pump inhibitor or H2 receptor antagonist.

  3. [CMV-associated gastric ulcer in an immunocompetent male patient].

    PubMed

    Kastenbauer, U; Ließ, H; Kremer, M

    2016-07-01

    This article reports the case of a 45-year-old male immunocompetent patient who presented with acute epigastric pain and vomiting. Diagnostic tests confirmed a recent cytomegalovirus (CMV) infection as a contributory cause of a florid gastric ulcer. Primary CMV infections affecting the upper gastrointestinal tract are rare in immunocompetent adults. In this case treatment with a proton pump inhibitor and eradication of concomitant Helicobacter pylori colonization led to a full recovery. Anti-CMV treatment was not necessary. PMID:27080250

  4. ATP4a is required for development and function of the Xenopus mucociliary epidermis - a potential model to study proton pump inhibitor-associated pneumonia.

    PubMed

    Walentek, Peter; Beyer, Tina; Hagenlocher, Cathrin; Müller, Christina; Feistel, Kerstin; Schweickert, Axel; Harland, Richard M; Blum, Martin

    2015-12-15

    Proton pump inhibitors (PPIs), which target gastric H(+)/K(+)ATPase (ATP4), are among the most commonly prescribed drugs. PPIs are used to treat ulcers and as a preventative measure against gastroesophageal reflux disease in hospitalized patients. PPI treatment correlates with an increased risk for airway infections, i.e. community- and hospital-acquired pneumonia. The cause for this correlation, however, remains elusive. The Xenopus embryonic epidermis is increasingly being used as a model to study airway-like mucociliary epithelia. Here we use this model to address how ATP4 inhibition may affect epithelial function in human airways. We demonstrate that atp4a knockdown interfered with the generation of cilia-driven extracellular fluid flow. ATP4a and canonical Wnt signaling were required in the epidermis for expression of foxj1, a transcriptional regulator of motile ciliogenesis. The ATP4/Wnt module activated foxj1 downstream of ciliated cell fate specification. In multiciliated cells (MCCs) of the epidermis, ATP4a was also necessary for normal myb expression, apical actin formation, basal body docking and alignment of basal bodies. Furthermore, ATP4-dependent Wnt/β-catenin signaling in the epidermis was a prerequisite for foxa1-mediated specification of small secretory cells (SSCs). SSCs release serotonin and other substances into the medium, and thereby regulate ciliary beating in MCCs and protect the epithelium against infection. Pharmacological inhibition of ATP4 in the mature mucociliary epithelium also caused a loss of MCCs and led to impaired mucociliary clearance. These data strongly suggest that PPI-associated pneumonia in human patients might, at least in part, be linked to dysfunction of mucociliary epithelia of the airways. PMID:25848696

  5. Correlation between virulence gene expression and proton pump inhibitors and ambient pH in Clostridium difficile: results of an in vitro study.

    PubMed

    Stewart, David B; Hegarty, John P

    2013-10-01

    Proton pump inhibitors (PPIs) are associated with the development of Clostridium difficile infection in humans. Though it is assumed that PPIs mediate this effect through gastric acid suppression, there has been little investigation into whether PPIs, or ambient pH, might directly affect the expression of C. difficile toxin genes. In the present study, C. difficile ribotypes 001, 027 and 078 obtained from human subjects were grown under anaerobic conditions prepared at pHs of 5, 7.3 and 9. Matched trios were exposed to 100 µM and 200 µM of omeprazole along with PPI untreated controls. Custom designed reverse transcription quantitative PCR hydrolysis probes were used to assess C. difficile gene expression for toxins A (tcdA), B (tcdB) and binary toxin (cdtB), as well as their positive regulators (tcdR and cdtR), using rrsA, which encodes 16S rRNA, as a constitutively expressed reference gene. tcdC and codY, negative regulators of toxin expression, were also assessed. Basic pH resulted in greater expression of tcdA, and with PPI exposure a 120-fold higher expression was noted with ribotype 001. tcdB and cdtB expressions were much less responsive to pH or PPIs, though a clear response to acidic pH and PPI exposure was observed in ribotype 027. tcdC and codY expressions were largely unaffected, except with ribotype 027; low pH and PPIs resulted in their greater expression, though to a lesser degree than with toxin genes and their positive regulators. Non-neutral pH and PPI exposure appear to have an effect on C. difficile, one that has a net effect towards toxin gene expression. PMID:23800596

  6. Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility

    PubMed Central

    2014-01-01

    Background The role of the gut microbiome in arresting pathogen colonization and growth is important for protection against Clostridium difficile infection (CDI). Observational studies associate proton pump inhibitor (PPI) use and CDI incidence. We hypothesized that PPI use affected the distal gut microbiome over time, an effect that would be best explored by time-longitudinal study of healthy subjects on PPI in comparison to treatment-naïve CDI subjects. This study enrolled nine healthy human subjects and five subjects with treatment-naïve CDI. After random assignment to a low (20 mg/day) or high (2× 20 mg/day) dose group, fecal samples were collected from the nine healthy subjects before, during, and after 28 days of PPI use. This was done in conjunction with pre-treatment fecal collection from CDI subjects. High-throughput sequencing (16S rRNA) was performed on time-longitudinal samples to assess changes to the healthy gut microbiome associated with prolonged PPI usage. The healthy samples were then compared to the CDI subjects to explore changes over time to the gut microbiome associated with PPI use and potentially related to CDI. Results We report that PPI usage at low and high dosages, administered for 28 days, resulted in decreases to observed operational taxonomic unit (OTU) counts after both 1 week and 1 month. This decrease resulted in observed OTU levels that were similar to those found in treatment-naïve CDI patients, which was partly reversible after a 1 month recovery period. We did not detect a dose-dependent difference in OTU levels nor did we detect significant changes in taxa previously reported to be affected by PPI treatment. Conclusion While our observation of diminishing observed OTU counts during PPI therapy is a preliminary finding in a small cohort, our hypothesis that PPIs disrupt the healthy human gut microbiome is supported in this group. We conclude that decreases in observed species counts were reversible after cessation of

  7. Proton Pump Inhibitors and Hospitalization with Hypomagnesemia: A Population-Based Case-Control Study

    PubMed Central

    Zipursky, Jonathan; Macdonald, Erin M.; Hollands, Simon; Gomes, Tara; Mamdani, Muhammad M.; Paterson, J. Michael; Lathia, Nina; Juurlink, David N.

    2014-01-01

    Background Some evidence suggests that proton pump inhibitors (PPIs) are an under-appreciated risk factor for hypomagnesemia. Whether hospitalization with hypomagnesemia is associated with use of PPIs is unknown. Methods and Findings We conducted a population-based case-control study of multiple health care databases in Ontario, Canada, from April 2002 to March 2012. Patients who were enrolled as cases were Ontarians aged 66 years or older hospitalized with hypomagnesemia. For each individual enrolled as a case, we identified up to four individuals as controls matched on age, sex, kidney disease, and use of various diuretic classes. Exposure to PPIs was categorized according to the most proximate prescription prior to the index date as current (within 90 days), recent (within 91 to 180 days), or remote (within 181 to 365 days). We used conditional logistic regression to estimate the odds ratio for the association of outpatient PPI use and hospitalization with hypomagnesemia. To test the specificity of our findings we examined use of histamine H2 receptor antagonists, drugs with no causal link to hypomagnesemia. We studied 366 patients hospitalized with hypomagnesemia and 1,464 matched controls. Current PPI use was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio, 1.43; 95% CI 1.06–1.93). In a stratified analysis, the risk was particularly increased among patients receiving diuretics, (adjusted odds ratio, 1.73; 95% CI 1.11–2.70) and not significant among patients not receiving diuretics (adjusted odds ratio, 1.25; 95% CI 0.81–1.91). We estimate that one excess hospitalization with hypomagnesemia will occur among 76,591 outpatients treated with a PPI for 90 days. Hospitalization with hypomagnesemia was not associated with the use of histamine H2 receptor antagonists (adjusted odds ratio 1.06; 95% CI 0.54–2.06). Limitations of this study include a lack of access to serum magnesium levels, uncertainty regarding diagnostic coding of

  8. Current Diagnosis and Management of Suspected Reflux Symptoms Refractory to Proton Pump Inhibitor Therapy

    PubMed Central

    2014-01-01

    Suspected reflux symptoms that are refractory to proton pump inhibitors (PPIs) are rapidly becoming the most common presentation of gastroesophageal reflux disease (GERD) in patients seen in gastroenterology clinics. These patients are a heterogeneous group, differing in symptom frequency and severity, PPI dosing regimens, and responses to therapy (from partial to absent). Before testing, the physician needs to question the patient carefully about PPI compliance and the timing of drug intake in relation to meals. Switching PPIs or doubling the dose is the next step, but only 20% to 25% of the group refractory to PPIs will respond. The first diagnostic test should be upper gastrointestinal endoscopy. In more than 90% of cases, the results will be normal, but persistent esophagitis may suggest pill esophagitis, eosinophilic esophagitis, or rarer diseases, such as lichen planus, Zollinger-Ellison syndrome, or genotype variants of PPI metabolism. If the endoscopy results are normal, esophageal manometry and especially reflux testing should follow. Whether patients should be tested on or off PPI therapy is controversial. Most physicians prefer to test patients off PPIs to identify whether abnormal acid reflux is even present; if it is not, PPIs can be stopped and other diagnoses sought. Testing patients on PPI therapy allows nonacid reflux to be identified, but more than 50% of patients have a normal test result, leaving the clinician with a conundrum—whether to stop PPIs or continue them because the GERD is being treated adequately. Alternative diagnoses in patients with refractory GERD and normal reflux testing include achalasia, eosinophilic esophagitis, gastroparesis, rumination, and aerophagia. However, more than 50% will be given the diagnosis of functional heartburn, a visceral hypersensitivity syndrome. Treating patients with PPI-refractory GERD–like symptoms can be difficult and frustrating. Any of the following may help: a histamine-2 receptor antagonist

  9. Proton pump inhibitor for non-erosive reflux disease: A meta-analysis

    PubMed Central

    Zhang, Ji-Xiang; Ji, Meng-Yao; Song, Jia; Lei, Hong-Bo; Qiu, Shi; Wang, Jing; Ai, Ming-Hua; Wang, Jun; Lv, Xiao-Guang; Yang, Zi-Rong; Dong, Wei-Guo

    2013-01-01

    AIM: To evaluate the efficacy, safety and influential factors of proton pump inhibitor (PPI) treatment for non-erosive reflux disease (NERD). METHODS: PubMed, MEDLINE, EMBASE and the Cochrane Library were searched up to April 2013 to identify eligible randomized controlled trials (RCTs) that probed into the efficacy, safety and influential factors of PPI treatment for NERD. The rates of symptomatic relief and adverse events were measured as the outcomes. After RCT selection, assessment and data collection, the pooled RRs and 95%CI were calculated. This meta-analysis was performed using the Stata 12.0 software (Stata Corporation, College Station, Texas, United States). The level of evidence was estimated by the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Seventeen RCTs including 6072 patients met the inclusion criteria. The results of the meta-analysis showed that PPI treatment was significantly superior to H2 receptor antagonists (H2RA) treatment (RR = 1.629, 95%CI: 1.422-1.867, P = 0.000) and placebo (RR = 1.903, 95%CI: 1.573-2.302, P = 0.000) for the symptomatic relief of NERD. However, there were no obvious differences between PPI and H2RA (RR = 0.928, 95%CI: 0.776-1.110, P = 0.414) or PPI and the placebo (RR = 1.000, 95%CI: 0.896-1.116, P = 0.997) regarding the rate of adverse events. The overall rate of symptomatic relief of PPI against NERD was 51.4% (95%CI: 0.433-0.595, P = 0.000), and relief was influenced by hiatal hernia (P = 0.030). The adverse rate of PPI against NERD was 21.0% (95%CI: 0.152-0.208, P = 0.000), and was affected by hiatal hernia (P = 0.081) and drinking (P = 0.053). CONCLUSION: PPI overmatched H2RA on symptomatic relief rate but not on adverse rate for NERD. Its relief rate and adverse rate were influenced by hiatal hernia and drinking. PMID:24363534

  10. PUMPS

    DOEpatents

    Thornton, J.D.

    1959-03-24

    A pump is described for conveving liquids, particure it is not advisable he apparatus. The to be submerged in the liquid to be pumped, a conduit extending from the high-velocity nozzle of the injector,and means for applying a pulsating prcesure to the surface of the liquid in the conduit, whereby the surface oscillates between positions in the conduit. During the positive half- cycle of an applied pulse liquid is forced through the high velocity nozzle or jet of the injector and operates in the manner of the well known water injector and pumps liquid from the main intake to the outlet of the injector. During the negative half-cycle of the pulse liquid flows in reverse through the jet but no reverse pumping action takes place.

  11. Three-dimensional structure prediction of the NAD binding site of proton-pumping transhydrogenase from Escherichia coli.

    PubMed

    Fjellström, O; Olausson, T; Hu, X; Källebring, B; Ahmad, S; Bragg, P D; Rydström, J

    1995-02-01

    A three-dimensional structure of the NAD site of Escherichia coli transhydrogenase has been predicted. The model is based on analysis of conserved residues among the transhydrogenases from five different sources, homologies with enzymes using NAD as cofactors or substrates, hydrophilicity profiles, and secondary structure predictions. The present model supports the hypothesis that there is one binding site, located relatively close to the N-terminus of the alpha-subunit. The proposed structure spans residues alpha 145 to alpha 287, and it includes five beta-strands and five alpha-helices oriented in a typical open twisted alpha/beta conformation. The amino acid sequence following the GXGXXG dinucleotide binding consensus sequence (residues alpha 172 to alpha 177) correlates exactly to a typical fingerprint region for ADP binding beta alpha beta folds in dinucleotide binding enzymes. In the model, aspartic acid alpha 195 forms hydrogen bonds to one or both hydroxyl groups on the adenosine ribose sugar moiety. Threonine alpha 196 and alanine alpha 256, located at the end of beta B and beta D, respectively, create a hydrophobic sandwich with the adenine part of NAD buried inside. The nicotinamide part is located in a hydrophobic cleft between alpha A and beta E. Mutagenesis work has been carried out in order to test the predicted model and to determine whether residues within this domain are important for proton pumping directly. All data support the predicted structure, and no residue crucial for proton pumping was detected. Since no three-dimensional structure of transhydrogenase has been solved, a well based tertiary structure prediction is of great value for further experimental design in trying to elucidate the mechanism of the energy-linked proton pump. PMID:7777492

  12. Regulatory assembly of the vacuolar proton pump VoV1-ATPase in yeast cells by FLIM-FRET

    NASA Astrophysics Data System (ADS)

    Ernst, Stefan; Batisse, Claire; Zarrabi, Nawid; Böttcher, Bettina; Börsch, Michael

    2010-02-01

    We investigate the reversible disassembly of VOV1-ATPase in life yeast cells by time resolved confocal FRET imaging. VOV1-ATPase in the vacuolar membrane pumps protons from the cytosol into the vacuole. VOV1-ATPase is a rotary biological nanomotor driven by ATP hydrolysis. The emerging proton gradient is used for secondary transport processes as well as for pH and Ca2+ homoeostasis in the cell. The activity of the VOV1-ATPase is regulated through assembly / disassembly processes. During starvation the two parts of VOV1-ATPase start to disassemble. This process is reversed after addition of glucose. The exact mechanisms are unknown. To follow the disassembly / reassembly in vivo we tagged two subunits C and E with different fluorescent proteins. Cellular distributions of C and E were monitored using a duty cycle-optimized alternating laser excitation scheme (DCO-ALEX) for time resolved confocal FRET-FLIM measurements.

  13. Effects of trimebutine maleate on gastric motility in patients with gastric ulcer.

    PubMed

    Kamiya, T; Nagao, T; Andou, T; Misu, N; Kobayashi, Y; Hirako, M; Hara, M; Fujinami, T

    1998-12-01

    The effects of trimebutine maleate (TM), a prokinetic drug, on gastrointestinal motility in patients with gastric ulcer were investigated. Twenty patients with active gastric ulcers were allocated to two groups; 10 patients received a proton pump inhibitor alone (PPI group), given orally, and 10 patients received oral TM in combination with a PPI (PPI + TM group), each for a period of 8 weeks. Electrogastrography (EGG) and gastric emptying were measured before and after the treatment period. During the active ulcer stage, tachygastria (more than 0.06 Hz) or bradygastria (less than 0.04 Hz) in the EGG frequency were observed in 9 patients either before or after meals. During the healed ulcer stage, tachygastria or bradygastria was observed in 4 of 10 patients in the PPI group, while in the PPI + TM group, 1 patient had tachygastria and none had bradygastria. Postprandial dip (PD) was observed in 3 of the 20 patients during the active stage, while after treatment, PD was observed in 3 patients in the PPI group and in 6 patients in the PPI + TM group, respectively. Gastric emptying in the PPI group did not show any change between before and after treatment, while that in the PPI + TM group improved significantly after treatment. These results suggest that TM may have an ameliorative effect on abnormal gastric motility in patients with gastric ulcer. PMID:9853554

  14. Tritium Sequestration in Gen IV NGNP Gas Stream via Proton Conducting Ceramic Pumps

    SciTech Connect

    Chen, Fanglin Frank; Adams, Thad M.; Brinkman, Kyle; Reifsnider, Kenneth

    2011-09-30

    Several types of high-temperature proton conductors based on SrCeO3 and BaCeO3 have been systematically investigated in this project for tritium separation in NGNP applications. One obstacle for the field application is the chemical stability issues in the presence of steam and CO2 for these proton conductors. Several strategies to overcome such issues have been evaluated, including A site doping and B site co-doping method for perovskite-structured proton conductors. Novel zirconium-free proton conductors have also been developed with improved electrical conductivity and enhanced chemical stability. Novel catalytic materials for the proton-conducting separation membranes have been investigated. A tubular geometry proton-conducting membrane has been developed for the proton separation membranes. Total dose rate estimated from tritium decay (beta emission) under realistic membrane operating conditions, combined with electron irradiation experiments, indicates that proton ceramic materials possess the appropriate radiation stability for this application.

  15. Thin-Layer Chemical Modulations by a Combined Selective Proton Pump and pH Probe for Direct Alkalinity Detection.

    PubMed

    Afshar, Majid Ghahraman; Crespo, Gastón A; Bakker, Eric

    2015-07-01

    We report a general concept based on a selective electrochemical ion pump used for creating concentration perturbations in thin layer samples (∼40 μL). As a first example, hydrogen ions are released from a selective polymeric membrane (proton pump) and the resulting pH is assessed potentiometrically with a second membrane placed directly opposite. By applying a constant potential modulation for 30 s, an induced proton concentration of up to 350 mM may be realized. This concept may become an attractive tool for in situ titrations without the need for sampling, because the thin layer eventually re-equilibrates with the contacting bulk sample. Acid-base titrations of NaOH and Na2 CO3 are demonstrated. The determination of total alkalinity in a river water sample is carried out, giving levels (23.1 mM) comparable to that obtained by standard methods (23.6 mM). The concept may be easily extended to other ions (cations, anions, polyions) and may become attractive for environmental and clinical applications. PMID:26014101

  16. A case of hypereosinophilic syndrome presenting with intractable gastric ulcers

    PubMed Central

    Park, Tae Young; Choi, Chang Hwan; Yang, Suh Yoon; Oh, In Soo; Song, In-Do; Lee, Hyun Woong; Kim, Hyung Joon; Do, Jae Hyuk; Chang, Sae Kyung; Cho, Ah Ra; Cha, Young Joo

    2009-01-01

    We report a rare case of hypereosinophilic syndrome (HES) presenting with intractable gastric ulcers. A 71-year-old man was admitted with epigastric pain. Initial endoscopic findings revealed multiple, active gastric ulcers in the gastric antrum. He underwent Helicobacter pylori (H pylori) eradication therapy followed by proton pump inhibitor (PPI) therapy. However, follow-up endoscopy at 4, 6, 10 and 14 mo revealed persistent multiple gastric ulcers without significant improvement. The proportion of his eosinophil count increased to 43% (total count: 7903/mm3). Abdominal-pelvic and chest computed tomography scans showed multiple small nodules in the liver and both lungs. The endoscopic biopsy specimen taken from the gastric antrum revealed prominent eosinophilic infiltration, and the liver biopsy specimen also showed eosinophilic infiltration in the portal tract and sinusoid. A bone marrow biopsy disclosed eosinophilic hyperplasia as well as increased cellularity of 70%. The patient was finally diagnosed with HES involving the stomach, liver, lung, and bone marrow. When gastric ulcers do not improve despite H pylori eradication and prolonged PPI therapy, infiltrative gastric disorders such as HES should be considered. PMID:20027690

  17. Toward a chemical mechanism of proton pumping by the B-type cytochrome c oxidases: Application of Density Functional Theory to cytochrome ba3 of Thermus thermophilus

    PubMed Central

    Fee, James A.; Case, David A.; Noodleman, Louis

    2009-01-01

    A mechanism for proton pumping by the B-type cytochrome c oxidases is presented in which one proton is pumped in conjunction with the weakly-exergonic, two-electron reduction of Fe-bound O2 to the Fe-Cu bridging peroxodianion, and three protons are pumped in conjunction with the highly-exergonic, two-electron reduction of Fe(III)-−O-O−-Cu(II) to form water and the active oxidized enzyme, Fe(III)-−OH, Cu(II). The scheme is based on the active site structure of cytochrome ba3 from Thermus thermophilus, which is considered to be both necessary and sufficient for coupled O2 reduction and proton pumping when appropriate gates are in place (not included in the model). Fourteen detailed structures obtained from DFT geometry optimization are presented that are reasonably thought to occur during the four-electron reduction of O2. Each proton pumping step takes place when a proton resides on the imidazole ring of I-His376 and the large active site cluster has a net charge of +1 due to an uncompensated, positive charge formally associated with CuB. Density functional theory (DFT) of four types was applied to determine the energy of each intermediate, and standard thermochemical approaches were used to obtain the reaction free energies for each step in the catalytic cycle. This application of DFT generally conforms with previously suggested criteria for a valid model [P. E. M. Siegbahn & M. A. R. Blomberg (2000) 100 421 - 437] and, shows how the chemistry of O2-reduction in the heme a3-CuB dinuclear center can be harnessed to generate an electrochemical proton gradient across the lipid bilayer. PMID:18928258

  18. In vivo inhibition of gastric acid secretion by the aqueous extract of Scoparia dulcis L. in rodents.

    PubMed

    Mesía-Vela, Sonia; Bielavsky, Monica; Torres, Luce Maria Brandão; Freire, Sonia Maria; Lima-Landman, Maria Teresa R; Souccar, Caden; Lapa, Antonio José

    2007-05-01

    The freeze-dried aqueous extract (AE) from the aerial parts of Scoparia dulcis was tested for its effects on experimental gastric hypersecretion and ulcer in rodents. Administration of AE to animals with 4h pylorus ligature potently reduced the gastric secretion with ED(50)s of 195 mg/kg (rats) and 306 mg/kg (mice). The AE also inhibited the histamine- or bethanechol-stimulated gastric secretion in pylorus-ligated mice with similar potency suggesting inhibition of the proton pump. Bio-guided purification of the AE yielded a flavonoid-rich fraction (BuF), with a specific activity 4-8 times higher than the AE in the pylorus ligature model. BuF also inhibited the hydrolysis of ATP by H(+),K(+)-ATPase with an IC(50) of 500 microg/ml, indicating that the inhibition of gastric acid secretion of Scoparia dulcis is related to the inhibition of the proton pump. Furthermore, the AE inhibited the establishment of acute gastric lesions induced in rats by indomethacin (ED(50)=313 mg/kg, p.o.) and ethanol (ED(50)=490 mg/kg, p.o.). No influence of the AE on gastrointestinal transit allowed discarding a possible CNS or a cholinergic interaction in the inhibition of gastric secretion by the AE. Collectively, the present data pharmacologically validates the popular use of Scoparia dulcis in gastric disturbances. PMID:17300892

  19. Positive Darwinian selection in the piston that powers proton pumps in complex I of the mitochondria of Pacific salmon.

    PubMed

    Garvin, Michael R; Bielawski, Joseph P; Gharrett, Anthony J

    2011-01-01

    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm. PMID:21969854

  20. Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon

    PubMed Central

    Garvin, Michael R.; Bielawski, Joseph P.; Gharrett, Anthony J.

    2011-01-01

    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm. PMID:21969854

  1. Nitric oxide contributes to minerals absorption, proton pumps and hormone equilibrium under cadmium excess in Trifolium repens L. plants.

    PubMed

    Liu, Shiliang; Yang, Rongjie; Pan, Yuanzhi; Ma, Mingdong; Pan, Jiang; Zhao, Yan; Cheng, Qingsu; Wu, Mengxi; Wang, Maohua; Zhang, Lin

    2015-09-01

    Nitric oxide (NO) is a stress-signaling molecule in plants that mediates a wide range of physiological processes and responses to metal toxicity. In this work, various NO modulators (NO donor: SNP; NO scavenger: cPTIO; NO synthase inhibitor: l-NAME; and SNP analogs: sodium nitrite/nitrate and sodium ferrocyanide) were investigated to determine the role of NO in Trifolium repens L. plants exposed to Cd. Cd (100μM) markedly reduced biomass, NO production and chlorophyll (Chl a, Chl b and total Chl) concentration but stimulated reactive oxygen species (ROS) and Cd accumulation in plants. SNP (50μM) substantially attenuated growth inhibition, reduced hydrogen peroxide (H2O2) and malonyldialdehyde (MDA) levels, stimulated ROS-scavenging enzymes/agents, and mitigated the H(+)-ATPase inhibition in proton pumps. Interestingly, SNP considerably up-regulated the levels of jasmonic acid (JA) and proline in plant tissues but down-regulated the levels of ethylene (ET) in both shoots and roots and the level of salicylic acid (SA) in roots only, which might be related to the elevated NO synthesis. Additionally, SNP (25-200μM) regulated mineral absorption and, particularly at 50μM, significantly enhanced the uptake of shoot magnesium (Mg) and copper (Cu) and of root calcium (Ca), Mg and iron (Fe). Nevertheless, the effects of SNP on plant growth were reversed by cPTIO and l-NAME, suggesting that the protective effect of SNP might be associated with NO synthesis in vivo. Moreover, SNP analogs did not display roles similar to that of SNP. These results indicated that NO depleted Cd toxicity by eliminating oxidative damage, enhancing minerals absorption, regulating proton pumps, and maintaining hormone equilibrium. PMID:25966334

  2. Microbial light-activatable proton pumps as neuronal inhibitors to functionally dissect neuronal networks in C. elegans.

    PubMed

    Husson, Steven J; Liewald, Jana F; Schultheis, Christian; Stirman, Jeffrey N; Lu, Hang; Gottschalk, Alexander

    2012-01-01

    Essentially any behavior in simple and complex animals depends on neuronal network function. Currently, the best-defined system to study neuronal circuits is the nematode Caenorhabditis elegans, as the connectivity of its 302 neurons is exactly known. Individual neurons can be activated by photostimulation of Channelrhodopsin-2 (ChR2) using blue light, allowing to directly probe the importance of a particular neuron for the respective behavioral output of the network under study. In analogy, other excitable cells can be inhibited by expressing Halorhodopsin from Natronomonas pharaonis (NpHR) and subsequent illumination with yellow light. However, inhibiting C. elegans neurons using NpHR is difficult. Recently, proton pumps from various sources were established as valuable alternative hyperpolarizers. Here we show that archaerhodopsin-3 (Arch) from Halorubrum sodomense and a proton pump from the fungus Leptosphaeria maculans (Mac) can be utilized to effectively inhibit excitable cells in C. elegans. Arch is the most powerful hyperpolarizer when illuminated with yellow or green light while the action spectrum of Mac is more blue-shifted, as analyzed by light-evoked behaviors and electrophysiology. This allows these tools to be combined in various ways with ChR2 to analyze different subsets of neurons within a circuit. We exemplify this by means of the polymodal aversive sensory ASH neurons, and the downstream command interneurons to which ASH neurons signal to trigger a reversal followed by a directional turn. Photostimulating ASH and subsequently inhibiting command interneurons using two-color illumination of different body segments, allows investigating temporal aspects of signaling downstream of ASH. PMID:22815873

  3. The CarO rhodopsin of the fungus Fusarium fujikuroi is a light-driven proton pump that retards spore germination

    PubMed Central

    García-Martínez, Jorge; Brunk, Michael; Avalos, Javier; Terpitz, Ulrich

    2015-01-01

    Rhodopsins are membrane-embedded photoreceptors found in all major taxonomic kingdoms using retinal as their chromophore. They play well-known functions in different biological systems, but their roles in fungi remain unknown. The filamentous fungus Fusarium fujikuroi contains two putative rhodopsins, CarO and OpsA. The gene carO is light-regulated, and the predicted polypeptide contains all conserved residues required for proton pumping. We aimed to elucidate the expression and cellular location of the fungal rhodopsin CarO, its presumed proton-pumping activity and the possible effect of such function on F. fujikuroi growth. In electrophysiology experiments we confirmed that CarO is a green-light driven proton pump. Visualization of fluorescent CarO-YFP expressed in F. fujikuroi under control of its native promoter revealed higher accumulation in spores (conidia) produced by light-exposed mycelia. Germination analyses of conidia from carO− mutant and carO+ control strains showed a faster development of light-exposed carO− germlings. In conclusion, CarO is an active proton pump, abundant in light-formed conidia, whose activity slows down early hyphal development under light. Interestingly, CarO-related rhodopsins are typically found in plant-associated fungi, where green light dominates the phyllosphere. Our data provide the first reliable clue on a possible biological role of a fungal rhodopsin. PMID:25589426

  4. Structural and Functional Studies of a Newly Grouped Haloquadratum walsbyi Bacteriorhodopsin Reveal the Acid-resistant Light-driven Proton Pumping Activity*

    PubMed Central

    Hsu, Min-Feng; Fu, Hsu-Yuan; Cai, Chun-Jie; Yi, Hsiu-Pin; Yang, Chii-Shen; Wang, Andrew H.-J.

    2015-01-01

    Retinal bound light-driven proton pumps are widespread in eukaryotic and prokaryotic organisms. Among these pumps, bacteriorhodopsin (BR) proteins cooperate with ATP synthase to convert captured solar energy into a biologically consumable form, ATP. In an acidic environment or when pumped-out protons accumulate in the extracellular region, the maximum absorbance of BR proteins shifts markedly to the longer wavelengths. These conditions affect the light-driven proton pumping functional exertion as well. In this study, wild-type crystal structure of a BR with optical stability under wide pH range from a square halophilic archaeon, Haloquadratum walsbyi (HwBR), was solved in two crystal forms. One crystal form, refined to 1.85 Å resolution, contains a trimer in the asymmetric unit, whereas another contains an antiparallel dimer was refined at 2.58 Å. HwBR could not be classified into any existing subgroup of archaeal BR proteins based on the protein sequence phylogenetic tree, and it showed unique absorption spectral stability when exposed to low pH values. All structures showed a unique hydrogen-bonding network between Arg82 and Thr201, linking the BC and FG loops to shield the retinal-binding pocket in the interior from the extracellular environment. This result was supported by R82E mutation that attenuated the optical stability. The negatively charged cytoplasmic side and the Arg82–Thr201 hydrogen bond may play an important role in the proton translocation trend in HwBR under acidic conditions. Our findings have unveiled a strategy adopted by BR proteins to solidify their defenses against unfavorable environments and maintain their optical properties associated with proton pumping. PMID:26483542

  5. Structural and Functional Studies of a Newly Grouped Haloquadratum walsbyi Bacteriorhodopsin Reveal the Acid-resistant Light-driven Proton Pumping Activity.

    PubMed

    Hsu, Min-Feng; Fu, Hsu-Yuan; Cai, Chun-Jie; Yi, Hsiu-Pin; Yang, Chii-Shen; Wang, Andrew H-J

    2015-12-01

    Retinal bound light-driven proton pumps are widespread in eukaryotic and prokaryotic organisms. Among these pumps, bacteriorhodopsin (BR) proteins cooperate with ATP synthase to convert captured solar energy into a biologically consumable form, ATP. In an acidic environment or when pumped-out protons accumulate in the extracellular region, the maximum absorbance of BR proteins shifts markedly to the longer wavelengths. These conditions affect the light-driven proton pumping functional exertion as well. In this study, wild-type crystal structure of a BR with optical stability under wide pH range from a square halophilic archaeon, Haloquadratum walsbyi (HwBR), was solved in two crystal forms. One crystal form, refined to 1.85 Å resolution, contains a trimer in the asymmetric unit, whereas another contains an antiparallel dimer was refined at 2.58 Å. HwBR could not be classified into any existing subgroup of archaeal BR proteins based on the protein sequence phylogenetic tree, and it showed unique absorption spectral stability when exposed to low pH values. All structures showed a unique hydrogen-bonding network between Arg(82) and Thr(201), linking the BC and FG loops to shield the retinal-binding pocket in the interior from the extracellular environment. This result was supported by R82E mutation that attenuated the optical stability. The negatively charged cytoplasmic side and the Arg(82)-Thr(201) hydrogen bond may play an important role in the proton translocation trend in HwBR under acidic conditions. Our findings have unveiled a strategy adopted by BR proteins to solidify their defenses against unfavorable environments and maintain their optical properties associated with proton pumping. PMID:26483542

  6. Role of proton pump of mitochondria-rich cells for active transport of chloride ions in toad skin epithelium.

    PubMed Central

    Larsen, E H; Willumsen, N J; Christoffersen, B C

    1992-01-01

    1. Active Cl- currents were studied in short-circuited toad skin epithelium in which the passive voltage-activated Cl- current is zero. Under visual control double-barrelled microelectrodes were used for impaling principal cells from the serosal side, or for measuring the pH profile in the solution bathing the apical border. 2. The net inward (active) 36Cl- flux of 27 +/- 8 pmol s-1 cm-2 (16) (mean +/- S.E.M (number of observation)) was abolished by 2 mM-CN- (6.3 +/- 3.5 pmol s-1 cm-2 (8)). The active flux was maintained in the absence of active Na+ transport when the latter was eliminated by either 100 microM-mucosal amiloride, replacement of mucosal Na+ with K+, or by 3 mM-serosal ouabain. 3. In Ringer solution buffered by 24 mM-HCO3- -5% CO2 mucosal amiloride reversed the short circuit current (ISC). The outward ISC was maintained when gluconate replaced mucosal Cl-, and it was reversibly reduced in CO2-free 5 mM-Tris-buffered Ringer solution (pH = 7.40) or by the proton pump inhibitor oligomycin. These observations indicate that the source of the outward ISC is an apical proton pump. 4. Amiloride caused principal cells to hyperpolarize from a basolateral membrane potential, Vb, of -73 +/- 3 (22) to -93 +/- 1 mV (26), and superfusion with CO2-free Tris-buffered Ringer solution induced a further hyperpolarization (Vb = -101 +/- 1 mV (26)) which could be blocked by Ba2+. The CO2-sensitive current changes were null at Vb = EK (potassium reversal potential, -106 +/- 2 mV (55)) implying that they are carried by K+ channels in the basolateral membrane. Such a response cannot account for the inhibition of the outward ISC which by default seems to be located to mitochondria-rich (MR) cells. 5. In the absence of mucosal Cl- a pH gradient was built up above MR cells with pH = 7.02 +/- 0.04 (42) and pH increasing to 7.37 +/- 0.02 (10) above principal cells (pH = 7.40 in bulk solution buffered by 0.1 mM-Tris). This observation localizes a proton pump to the apical membrane

  7. [Gastric Acid].

    PubMed

    Ruíz Chávez, R

    1996-01-01

    Gastric acid, a product of parietal cells secretion, full fills multiple biological roles which are absolutely necessary to keep corporal homeostasis. The production of the acid depends upon an effector cellular process represented in the first step by histamine, acetilcholine and gastrin, first messengers of the process. These interact with specific receptors than in sequence activate second messengers -cAMP and the calcium-calmodulin system- which afterwards activate a kinase. An specific protein is then phosphorilated by this enzyme, being the crucial factor that starts the production of acid. Finally, a proton bomb, extrudes the acid towards the gastric lumen. The secretion process mentioned above, is progressive lyactivated in three steps, two of which are stimulators -cephalic and gastric phases- and the other one inhibitor or intestinal phase. These stages are started by mental and neurological phenomena -thought, sight, smell or memory-; by food, drugs or other ingested substances; and by products of digestion. Changes in regulation of acid secretion, in the structure of gastro-duodenal mucosal barrier by a wide spectrum of factors and agents including food, drugs and H. pylori, are the basis of acid-peptic disease, entity in which gastric acid plays a fundamental role. From the therapeutic point of view, so at the theoretical as at the practical levels, t is possible to interfere with the secretion of acid by neutralization of some of the steps of the effector cellular process. An adequate knowledge of the basics related to gastric acid, allows to create strategies for the clinical handling of associated pathology, specifically in relation to peptic acid disease in all of the known clinical forms. PMID:12165790

  8. Proton pump inhibitors suppress iNOS-dependent DNA damage in Barrett's esophagus by increasing Mn-SOD expression

    SciTech Connect

    Thanan, Raynoo; Ma, Ning; Iijima, Katsunori; Abe, Yasuhiko; Koike, Tomoyuki; Shimosegawa, Tooru; Pinlaor, Somchai; Hiraku, Yusuke; Oikawa, Shinji; Murata, Mariko; Kawanishi, Shosuke

    2012-05-04

    Highlights: Black-Right-Pointing-Pointer Inflammation by Barrett's esophagus (BE) is a risk factor of its adenocarcinoma (BEA). Black-Right-Pointing-Pointer 8-Nitroguanine and 8-oxodG are inflammation-related DNA lesions. Black-Right-Pointing-Pointer DNA lesions and iNOS expression were higher in the order, BEA > BE > normal tissues. Black-Right-Pointing-Pointer Proton pump inhibitors suppress DNA damage by increasing Mn-SOD via Nrf2 activation. Black-Right-Pointing-Pointer DNA lesions can be useful biomarkers to predict risk of BEA in BE patients. -- Abstract: Barrett's esophagus (BE), an inflammatory disease, is a risk factor for Barrett's esophageal adenocarcinoma (BEA). Treatment of BE patients with proton pump inhibitors (PPIs) is expected to reduce the risk of BEA. We performed an immunohistochemical study to examine the formation of nitrative and oxidative DNA lesions, 8-nitroguanine and 8-oxo-7,8-dihydro-2 Prime -deoxygaunosine (8-oxodG), in normal esophageal, BE with pre- and post-treatment by PPIs and BEA tissues. We also observed the expression of an oxidant-generating enzyme (iNOS) and its transcription factor NF-{kappa}B, an antioxidant enzyme (Mn-SOD), its transcription factor (Nrf2) and an Nrf2 inhibitor (Keap1). The immunoreactivity of DNA lesions was significantly higher in the order of BEA > BE > normal tissues. iNOS expression was significantly higher in the order of BEA > BE > normal tissues, while Mn-SOD expression was significantly lower in the order of BEA < BE < normal tissues. Interestingly, Mn-SOD expression and the nuclear localization of Nrf2 were significantly increased, and the formation of DNA lesions was significantly decreased in BE tissues after PPIs treatment for 3-6 months. Keap1 and iNOS expression was not significantly changed by the PPIs treatment in BE tissues. These results indicate that 8-nitroguanine and 8-oxodG play a role in BE-derived BEA. Additionally, PPIs treatment may trigger the activation and nuclear translocation

  9. V-ATPase Proton Pumping Activity Is Required for Adult Zebrafish Appendage Regeneration

    PubMed Central

    Monteiro, Joana; Aires, Rita; Becker, Jörg D.; Jacinto, António; Certal, Ana C.; Rodríguez-León, Joaquín

    2014-01-01

    The activity of ion channels and transporters generates ion-specific fluxes that encode electrical and/or chemical signals with biological significance. Even though it is long known that some of those signals are crucial for regeneration, only in recent years the corresponding molecular sources started to be identified using mainly invertebrate or larval vertebrate models. We used adult zebrafish caudal fin as a model to investigate which and how ion transporters affect regeneration in an adult vertebrate model. Through the combined use of biophysical and molecular approaches, we show that V-ATPase activity contributes to a regeneration-specific H+ ef`flux. The onset and intensity of both V-ATPase expression and H+ efflux correlate with the different regeneration rate along the proximal-distal axis. Moreover, we show that V-ATPase inhibition impairs regeneration in adult vertebrate. Notably, the activity of this H+ pump is necessary for aldh1a2 and mkp3 expression, blastema cell proliferation and fin innervation. To the best of our knowledge, this is the first report on the role of V-ATPase during adult vertebrate regeneration. PMID:24671205

  10. Renal intercalated cells are rather energized by a proton than a sodium pump

    PubMed Central

    Chambrey, Régine; Kurth, Ingo; Peti-Peterdi, Janos; Houillier, Pascal; Purkerson, Jeffrey M.; Leviel, Françoise; Hentschke, Moritz; Zdebik, Anselm A.; Schwartz, George J.; Hübner, Christian A.; Eladari, Dominique

    2013-01-01

    The Na+ concentration of the intracellular milieu is very low compared with the extracellular medium. Transport of Na+ along this gradient is used to fuel secondary transport of many solutes, and thus plays a major role for most cell functions including the control of cell volume and resting membrane potential. Because of a continuous leak, Na+ has to be permanently removed from the intracellular milieu, a process that is thought to be exclusively mediated by the Na+/K+-ATPase in animal cells. Here, we show that intercalated cells of the mouse kidney are an exception to this general rule. By an approach combining two-photon imaging of isolated renal tubules, physiological studies, and genetically engineered animals, we demonstrate that inhibition of the H+ vacuolar-type ATPase (V-ATPase) caused drastic cell swelling and depolarization, and also inhibited the NaCl absorption pathway that we recently discovered in intercalated cells. In contrast, pharmacological blockade of the Na+/K+-ATPase had no effects. Basolateral NaCl exit from β-intercalated cells was independent of the Na+/K+-ATPase but critically relied on the presence of the basolateral ion transporter anion exchanger 4. We conclude that not all animal cells critically rely on the sodium pump as the unique bioenergizer, but can be replaced by the H+ V-ATPase in renal intercalated cells. This concept is likely to apply to other animal cell types characterized by plasma membrane expression of the H+ V-ATPase. PMID:23610411

  11. Role of vacuolar membrane proton pumps in the acidification of protein storage vacuoles following germination.

    PubMed

    Wilson, Karl A; Chavda, Burzin J; Pierre-Louis, Gandhy; Quinn, Adam; Tan-Wilson, Anna

    2016-07-01

    During soybean (Glycine max (L.) Merrill) seed development, protease C1, the proteolytic enzyme that initiates breakdown of the storage globulins β-conglycinin and glycinin at acidic pH, is present in the protein storage vacuoles (PSVs), the same subcellular compartments in seed cotyledons where its protein substrates accumulate. Actual proteolysis begins to be evident 24 h after seed imbibition, when the PSVs become acidic, as indicated by acridine orange accumulation visualized by confocal microscopy. Imidodiphosphate (IDP), a non-hydrolyzable substrate analog of proton-translocating pyrophosphatases, strongly inhibited acidification of the PSVs in the cotyledons. Consistent with this finding, IDP treatment inhibited mobilization of β-conglycinin and glycinin, the inhibition being greater at 3 days compared to 6 days after seed imbibition. The embryonic axis does not appear to play a role in the initial PSV acidification in the cotyledon, as axis detachment did not prevent acridine orange accumulation three days after imbibition. SDS-PAGE and immunoblot analyses of cotyledon protein extracts were consistent with limited digestion of the 7S and 11S globulins by protease C1 starting at the same time and proceeding at the same rate in detached cotyledons compared to cotyledons of intact seedlings. Embryonic axis removal did slow down further breakdown of the storage globulins by reactions known to be catalyzed by protease C2, a cysteine protease that normally appears later in seedling growth to continue the storage protein breakdown initiated by protease C1. PMID:27043965

  12. A long road towards the structure of respiratory complex I, a giant molecular proton pump.

    PubMed

    Sazanov, Leonid A; Baradaran, Rozbeh; Efremov, Rouslan G; Berrisford, John M; Minhas, Gurdeep

    2013-10-01

    Complex I (NADH:ubiquinone oxidoreductase) is central to cellular energy production, being the first and largest enzyme of the respiratory chain in mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the inner mitochondrial membrane and is involved in a wide range of human neurodegenerative disorders. Mammalian complex I is composed of 44 different subunits, whereas the 'minimal' bacterial version contains 14 highly conserved 'core' subunits. The L-shaped assembly consists of hydrophilic and membrane domains. We have determined all known atomic structures of complex I, starting from the hydrophilic domain of Thermus thermophilus enzyme (eight subunits, nine Fe-S clusters), followed by the membrane domains of the Escherichia coli (six subunits, 55 transmembrane helices) and T. thermophilus (seven subunits, 64 transmembrane helices) enzymes, and finally culminating in a recent crystal structure of the entire intact complex I from T. thermophilus (536 kDa, 16 subunits, nine Fe-S clusters, 64 transmembrane helices). The structure suggests an unusual and unique coupling mechanism via long-range conformational changes. Determination of the structure of the entire complex was possible only through this step-by-step approach, building on from smaller subcomplexes towards the entire assembly. Large membrane proteins are notoriously difficult to crystallize, and so various non-standard and sometimes counterintuitive approaches were employed in order to achieve crystal diffraction to high resolution and solve the structures. These steps, as well as the implications from the final structure, are discussed in the present review. PMID:24059518

  13. Asymmetric Dimethylarginine versus Proton Pump Inhibitors Usage in Patients with Stable Coronary Artery Disease: A Cross-Sectional Study

    PubMed Central

    Kruszelnicka, Olga; Świerszcz, Jolanta; Bednarek, Jacek; Chyrchel, Bernadeta; Surdacki, Andrzej; Nessler, Jadwiga

    2016-01-01

    A recent experimental study suggested that proton pump inhibitors (PPI), widely used to prevent gastroduodenal complications of dual antiplatelet therapy, may increase the accumulation of the endogenous nitric oxide synthesis antagonist asymmetric dimethylarginine (ADMA), an adverse outcome predictor. Our aim was to assess the effect of PPI usage on circulating ADMA in coronary artery disease (CAD). Plasma ADMA levels were compared according to PPI use for ≥1 month prior to admission in 128 previously described non-diabetic men with stable CAD who were free of heart failure or other coexistent diseases. Patients on PPI tended to be older and with insignificantly lower estimated glomerular filtration rate (GFR). PPI use was not associated with any effect on plasma ADMA (0.51 ± 0.11 (SD) vs. 0.50 ± 0.10 µmol/L for those with PPI (n = 53) and without PPI (n = 75), respectively; p = 0.7). Additionally, plasma ADMA did not differ between PPI users and non-users stratified by a history of current smoking, CAD severity or extent. The adjustment for patients’ age and GFR did not substantially change the results. Thus, PPI usage does not appear to affect circulating ADMA in non-diabetic men with stable CAD. Whether novel mechanisms of adverse PPI effects on the vasculature can be translated into clinical conditions, requires further studies. PMID:27092494

  14. Asymmetric Dimethylarginine versus Proton Pump Inhibitors Usage in Patients with Stable Coronary Artery Disease: A Cross-Sectional Study.

    PubMed

    Kruszelnicka, Olga; Świerszcz, Jolanta; Bednarek, Jacek; Chyrchel, Bernadeta; Surdacki, Andrzej; Nessler, Jadwiga

    2016-01-01

    A recent experimental study suggested that proton pump inhibitors (PPI), widely used to prevent gastroduodenal complications of dual antiplatelet therapy, may increase the accumulation of the endogenous nitric oxide synthesis antagonist asymmetric dimethylarginine (ADMA), an adverse outcome predictor. Our aim was to assess the effect of PPI usage on circulating ADMA in coronary artery disease (CAD). Plasma ADMA levels were compared according to PPI use for ≥1 month prior to admission in 128 previously described non-diabetic men with stable CAD who were free of heart failure or other coexistent diseases. Patients on PPI tended to be older and with insignificantly lower estimated glomerular filtration rate (GFR). PPI use was not associated with any effect on plasma ADMA (0.51 ± 0.11 (SD) vs. 0.50 ± 0.10 µmol/L for those with PPI (n = 53) and without PPI (n = 75), respectively; p = 0.7). Additionally, plasma ADMA did not differ between PPI users and non-users stratified by a history of current smoking, CAD severity or extent. The adjustment for patients' age and GFR did not substantially change the results. Thus, PPI usage does not appear to affect circulating ADMA in non-diabetic men with stable CAD. Whether novel mechanisms of adverse PPI effects on the vasculature can be translated into clinical conditions, requires further studies. PMID:27092494

  15. Analysis, occurrence, fate and risks of proton pump inhibitors, their metabolites and transformation products in aquatic environment: A review.

    PubMed

    Kosma, Christina I; Lambropoulou, Dimitra A; Albanis, Triantafyllos A

    2016-11-01

    Proton pump inhibitors (PPIs) which include omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole, are extensively used for the relief of gastro-intestinal disorders. Despite their high worldwide consumption, PPIs are extensively metabolized in human bodies and therefore are not regularly detected in monitoring studies. Very recently, however, it has been shown that some omeprazole metabolites may enter and are likely to persist in aquatic environment. Hence, to fully assess the environmental exposures and risks associated with PPIs, it is important to better understand and evaluate the fate and behavior not only of the parent compound but also of their metabolites and their transformation products arising from biotic and abiotic processes (hydrolysis, photodegradation, biodegradation etc.) in the environment. In this light, the purpose of this review is to summarize the present state of knowledge on the introduction and behavior of these chemicals in natural and engineering systems and highlight research needs and gaps. It draws attention to their transformation, the increase contamination by their metabolites/TPs in different environmental matrices and their potential adverse effects in the environment. Furthermore, existing research on analytical developments with respect to sample treatment, separation and detection of PPIs and their metabolites/TPs is provided. PMID:27380396

  16. Clopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution?

    PubMed Central

    2010-01-01

    Background Dual therapy with aspirin and clopidogrel increases the risk of gastrointestinal bleeding. Therefore, co-therapy with a proton pump inhibitor (PPI) is recommended by most guidelines. However, there are warnings against combining PPIs with clopidogrel because of their interactions with cytochrome P450 isoenzyme 2C19 (CYP2C19). Methods The effects of the combined or separate intake of 20 mg of omeprazole and 75 mg of clopidogrel on the clopidogrel-induced inhibition of platelet aggregation were measured in four healthy subjects whose CYP2C19 exon sequences were determined. The effects of co-therapy with 10 mg of rabeprazole were also examined. Results Two subjects showed the wild-type CYP2C19 sequence. The concurrent intake of omeprazole had no effect on clopidogrel-induced platelet inhibition in these subjects. Two subjects were heterozygous for the *2 allele, with predicted reduced CYP2C19 activity. One of them was a clopidogrel non-responder. In the second heterozygous subject, omeprazole co-therapy reduced the clopidogrel anti-platelet effect when taken simultaneously or separately. However, the simultaneous intake of rabeprazole did not reduce the clopidogrel effect. Conclusion The clopidogrel-PPI interaction does not seem to be a PPI class effect. Rabeprazole did not affect the clopidogrel effect in a subject with a clear omeprazole-clopidogrel interaction. The separate intake of PPI and clopidogrel may not be sufficient to prevent their interaction. PMID:20562062

  17. CYP2C19 Phenoconversion by Routinely Prescribed Proton Pump Inhibitors Omeprazole and Esomeprazole: Clinical Implications for Personalized Medicine.

    PubMed

    Klieber, Martin; Oberacher, Herbert; Hofstaetter, Silvia; Beer, Beate; Neururer, Martin; Amann, Anton; Alber, Hannes; Modak, Anil

    2015-09-01

    The phenotype pantoprazole-(13)C breath test (Ptz-BT) was used to evaluate the extent of phenoconversion of CYP2C19 enzyme activity caused by commonly prescribed proton pump inhibitors (PPI) omeprazole and esomprazole. The Ptz-BT was administered to 26 healthy volunteers and 8 stable cardiovascular patients twice at baseline and after 28 days of PPI therapy to evaluate reproducibility of the Ptz-BT and changes in CYP2C19 enzyme activity (phenoconversion) after PPI therapy. The average intrapatient interday variability in CYP2C19 phenotype (n = 31) determined by Ptz-BT was considerably low (coefficient of variation, 17%). Phenotype conversion resulted in 25 of 26 (96%) nonpoor metabolizer (non-PM) volunteers/patients as measured by the Ptz-BT at baseline and after PPI therapy. The incidence of PM status by phenotype following administration of omeprazole/esomeprazole (known inhibitors of CYP2C19) was 10-fold higher than those who are genetically PMs in the general population, which could have critical clinical implications for personalizing medications primarily metabolized by CYP2C19, such as clopidogrel, PPI, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, phenytoin, etc. The Ptz-BT can rapidly (30 minutes) evaluate CYP2C19 phenotype and, more importantly, can identify patients with phenoconversion in CYP2C19 enzyme activity caused by nongenetic factors such as concomitant drugs. PMID:26159874

  18. Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and safety of dexlansoprazole

    PubMed Central

    Mermelstein, Joseph; Mermelstein, Alanna Chait; Chait, Maxwell M

    2016-01-01

    Gastroesophageal reflux disease is the most common upper gastroenterology disorder in the US. It is associated with a variety of complications and significantly impacts quality of life. Proton pump inhibitors are the most effective treatment. Dexlansoprazole modified release (MR) is a proton pump inhibitor that employs a novel release formulation that prolongs its absorption and allows for more flexibility in dosing. Dexlansoprazole MR can be dosed without regard to food intake or time of day, and once-daily dosing may replace twice-daily dosing of other agents. Dexlansoprazole MR is effective for healing and maintenance of erosive esophagitis, and for the treatment of nonerosive disease, including nocturnal gastroesophageal reflux disease. Dexlansoprazole MR is safe and well tolerated, and can improve quality of life. PMID:27471402

  19. Regulation of the plasma membrane proton pump (H(+)-ATPase) by phosphorylation.

    PubMed

    Haruta, Miyoshi; Gray, William M; Sussman, Michael R

    2015-12-01

    In plants and fungi, energetics at the plasma membrane is provided by a large protonmotive force (PMF) generated by the family of P-type ATPases specialized for proton transport (commonly called PM H(+)-ATPases or, in Arabidopsis, AHAs for Arabidopsis H(+)-ATPases). Studies have demonstrated that this 100-kDa protein is essential for plant growth and development. Posttranslational modifications of the H(+)-ATPase play crucial roles in its regulation. Phosphorylation of several Thr and Ser residues within the carboxy terminal regulatory domain composed of ∼100 amino acids change in response to environmental stimuli, endogenous hormones, and nutrient conditions. Recently developed mass spectrometric technologies provide a means to carefully quantify these changes in H(+)-ATPase phosphorylation at the different sites. These chemical modifications can then be genetically tested in planta by complementing the loss-of-function aha mutants with phosphomimetic mutations. Interestingly, recent data suggest that phosphatase-mediated changes in PM H(+)-ATPase phosphorylation are important in mediating auxin-regulated growth. Thus, as with another hormone (abscisic acid), dephosphorylation by phosphatases, rather than kinase mediated phosphorylation, may be an important focal point for regulation during plant signal transduction. Although interactions with other proteins have also been implicated in ATPase regulation, the very hydrophobic nature and high concentration of this polytopic protein presents special challenges in evaluating the biological significance of these interactions. Only by combining biochemical and genetic experiments can we attempt to meet these challenges to understand the essential molecular details by which this protein functions in planta. PMID:26476298

  20. In Vitro Activities of Rabeprazole, a Novel Proton Pump Inhibitor, and Its Thioether Derivative Alone and in Combination with Other Antimicrobials against Recent Clinical Isolates of Helicobacter pylori

    PubMed Central

    Kawakami, Yoshiyuki; Akahane, Takayuki; Yamaguchi, Masaru; Oana, Kozue; Takahashi, Yuko; Okimura, Yukie; Okabe, Tadashi; Gotoh, Akira; Katsuyama, Tsutomu

    2000-01-01

    The MICs of rabeprazole sodium (RPZ), a newly developed benzimidazole proton pump inhibitor (PPI), against 133 clinical Helicobacter pylori strains revealed a higher degree of activity than the another two PPIs, lansoprazole and omeprazole. Time-kill curve assays of RPZ, when combined with amoxicillin, clarithromycin, or metronidazole, disclosed that synergistic effects were demonstrated in combination with each antibiotic examined. Moreover, no apparent antagonistic effect appeared among all of the strains tested. PMID:10639386

  1. Inhibitory effects of a β-dunnione compound MB12662 on gastric secretion and ulcers.

    PubMed

    Jo, In-Geun; Park, Dongsun; Kyung, Jangbeen; Kim, Dajeong; Cai, Jingmei; Kim, Jihyun; Kwak, Tae Hwan; Yoo, Sang-Ku; Jeong, Heon-Sang; Kim, Yun-Bae

    2013-09-01

    The effects of a β-dunnione compound MB12662 on the gastric secretion and ulcers were investigated in rats. In order to assess the effects of MB12662 on the gastric secretion and acidity, rats were subjected to pylorus ligation operation, and 6 hours later, gastric fluid was collected. Treatment with MB12662 reduced the gastric fluid volume to 47.3% of control level and increased pH. In an alcohol-induced ulcer model, rats were orally administered 3 mL/kg of ethanol, and 1 hour later, the ulcer lesions ware measured under a stereomicroscope. MB12662 reduced ulcer index in a dose-dependent manner which was much stronger than a proton-pump inhibitor pantoprazole. In a stress-induced ulcer model, rats were subjected to water-immersion restraint stress, and 5 hours later, the ulcer lesions ware examined. MB12662 also attenuated the stress-induced gastric lesions, although the efficacy of MB12662 was lower than that of pantoprazole. Therefore, it is suggested that MB12662 could be a candidate compound for the prevention or treatment of gastric ulcers induced by gastric over-secretion and alcoholic hangover. PMID:24106514

  2. Helicobacter pylori modulation of gastric acid.

    PubMed Central

    Calam, J.

    1999-01-01

    Helicobacter pylori plays major causative roles in peptic ulcer disease and gastric cancer. Elevated acid secretion in patients with duodenal ulcers (DUs) contributes to duodenal injury, and diminished acid secretion in patients with gastric cancer allows carcinogen-producing bacteria to colonize the stomach. Eradication of H. pylori normalizes acid secretion both in hyper-secreting DU patients and hypo-secreting relatives of gastric cancer patients. Therefore, we and others have asked how H. pylori causes these disparate changes in acid secretion. H. pylori gastritis more or less restricted to the gastric antrum in DU patients is associated with increased acid secretion. This is probably because gastritis increases release of the antral acid-stimulating hormone gastrin and diminished mucosal expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines including TNFalpha may cause these changes in endocrine function. Gastritis involving the gastric corpus tends to diminish acid secretion, probably because bacterial products and cytokines including IL-1 inhibit parietal cells. Pharmacological inhibition of acid secretion increases corpus gastritis in H. pylori-infected subjects, so it is envisaged that gastric hypo-secretion of any cause might become self-perpetuating. H. pylori-associated mucosal atrophy will also contribute to acid hypo-secretion and is more likely in when the diet is high in salt or lacking in antioxidant vitamins. Data on gastric acid secretion in patients with esophagitis are limited but suggest that acid secretion is normal or slightly diminished. Nevertheless, H. pylori infection may be relevant to the management of esophagitis because: (i) H. pylori infection increases the pH-elevating effect of acid inhibiting drugs; (ii) proton pump inhibitors may increase the tendency of H. pylori to cause atrophic gastritis; and (iii) successful eradication of H. pylori is reported to increase the likelihood of

  3. Gastric mucosa in Mongolian and Japanese patients with gastric cancer and Helicobacter pylori infection

    PubMed Central

    Matsuhisa, Takeshi; Yamaoka, Yoshio; Uchida, Tomohisa; Duger, Davaadorj; Adiyasuren, Battulga; Khasag, Oyuntsetseg; Tegshee, Tserentogtokh; Tsogt-Ochir, Byambajav

    2015-01-01

    AIM: To investigate the characteristics of gastric cancer and gastric mucosa in a Mongolian population by comparison with a Japanese population. METHODS: A total of 484 Mongolian patients with gastric cancer were enrolled to study gastric cancer characteristics in Mongolians. In addition, a total of 208 Mongolian and 3205 Japanese consecutive outpatients who underwent endoscopy, had abdominal complaints, no history of gastric operation or Helicobacter pylori eradication treatment, and no use of gastric secretion inhibitors such as histamine H2-receptor antagonists or proton pump inhibitors were enrolled. This study was conducted with the approval of the ethics committees of all hospitals. The triple-site biopsy method was used for the histologic diagnosis of gastritis and H. pylori infection in all Mongolian and Japanese cases. The infection rate of H. pylori and the status of gastric mucosa in H. pylori-infected patients were compared between Mongolian and Japanese subjects. Age (± 5 years), sex, and endoscopic diagnosis were matched between the two countries. RESULTS: Approximately 70% of Mongolian patients with gastric cancer were 50-79 years of age, and approximately half of the cancers were located in the upper part of the stomach. Histologically, 65.7% of early cancers exhibited differentiated adenocarcinoma, whereas 73.9% of advanced cancers displayed undifferentiated adenocarcinoma. The infection rate of H. pylori was higher in Mongolian than Japanese patients (75.9% vs 48.3%, P < 0.0001). When stratified by age, the prevalence was highest among young patients, and tended to decrease in patients aged 50 years or older. The anti-East-Asian CagA-specific antibody was negative in 99.4% of H. pylori-positive Mongolian patients. Chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia scores were significantly lower in Mongolian compared to Japanese H. pylori-positive patients (P < 0.0001), with the exception of the intestinal

  4. Docosahexaenoic acid, an omega-3 polyunsaturated acid protects against indomethacin-induced gastric injury.

    PubMed

    Pineda-Peña, Elizabeth Arlen; Jiménez-Andrade, Juan Miguel; Castañeda-Hernández, Gilberto; Chávez-Piña, Aracely Evangelina

    2012-12-15

    Previous studies have shown gastroprotective effect of fish oil in several experimental models. However, the mechanisms and active compounds underlying this effect are not fully understood. Fish oil has several components; among them, one of the most studied is docosahexaenoic acid (DHA), which is an omega-3 long-chain polyunsaturated fatty acid. The aim of this study was to examine the gastroprotective effect of DHA as a pure compound in a rat model of indomethacin-induced gastric injury as well as elucidate some of the mechanism(s) behind DHA's gastroprotective effect. Indomethacin was orally administered to induce an acute gastric injury (3, 10 and 30mg/kg). Omeprazol (a proton pump inhibitor, 30mg/kg, p.o.) and DHA (3, 10, 30mg/kg, p.o.) were gavaged 30 and 120min, respectively, before indomethacin insult (30mg/kg p.o.). Three hours after indomethacin administration, rats were sacrificed, gastric injury was evaluated by determining the total damaged area. A sample of gastric tissue was harvested and processed to quantify prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) levels by enzyme-linked immunosorbent assay. Indomethacin produced gastric injury in dose-dependent manner. DHA protected against indomethacin-induced gastric damage, and this effect was comparable with omeprazol's gastroprotective effect. DHA did not reverse the indomethacin-induced reduction of PGE(2) gastric levels. In contrast, DHA partially prevented the indomethacin-induced increase in LTB(4) gastric levels. This is the first report demonstrating DHA's gastroprotective effect as a pure compound. Furthermore, the results reveal that the gastroprotective effect is mediated by a decrease in gastric LTB(4) levels in indomethacin-induced gastric damage. PMID:23063544

  5. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    PubMed

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. PMID:25721922

  6. Transoral Incisionless Fundoplication Effective in Eliminating GERD Symptoms in Partial Responders to Proton Pump Inhibitor Therapy at 6 Months

    PubMed Central

    Barnes, William E.; Simoni, Gilbert; Shughoury, Ahmad B.; Mavrelis, Peter G.; Raza, Mamoon; Heise, Jeffrey A.; Turgeon, Daniel G.; Fox, Mark A.

    2015-01-01

    Background. Incomplete control of troublesome regurgitation and extraesophageal manifestations of chronic gastroesophageal reflux disease (GERD) is a known limitation of proton pump inhibitor (PPI) therapy. This multicenter randomized study compared the efficacy of transoral incisionless fundoplication (TIF) against PPIs in controlling these symptoms in patients with small hiatal hernias. Methods. Between June and August 2012, 63 patients were randomized at 7 US community hospitals. Patients in the PPI group were placed on maximum standard dose (MSD). Patients in the TIF group underwent esophagogastric fundoplication using the EsophyX2 device. Primary outcome was elimination of daily troublesome regurgitation or extraesophageal symptoms. Secondary outcomes were normalization of esophageal acid exposure (EAE), PPI usage and healing of esophagitis. Results. Of 63 randomized patients (40 TIF and 23 PPI), 3 were lost to follow-up leaving 39 TIF and 21 PPI patients for analysis. At 6-month follow-up, troublesome regurgitation was eliminated in 97% of TIF patients versus 50% of PPI patients, relative risk (RR) = 1.9, 95% confidence interval (CI) = 1.2-3.11 (P = .006). Globally, 62% of TIF patients experienced elimination of regurgitation and extraesophageal symptoms versus 5% of PPI patients, RR = 12.9, 95% CI = 1.9-88.9 (P = .009). EAE was normalized in 54% of TIF patients (off PPIs) versus 52% of PPI patients (on MSD), RR = 1.0, 95% CI = 0.6-1.7 (P = .914). Ninety percent of TIF patients were off PPIs. Conclusion. At 6-month follow-up, TIF was more effective than MSD PPI therapy in eliminating troublesome regurgitation and extraesophageal symptoms of GERD. PMID:24756976

  7. Bone Mineral Density Changes Among Women Initiating Proton Pump Inhibitors or H2 Receptor Antagonists: A SWAN Cohort Study

    PubMed Central

    Solomon, Daniel H; Diem, Susan J; Ruppert, Kristine; Juan Lian, Yin; Liu, Chih-Chin; Wohlfart, Alyssa; Greendale, Gail A; Finkelstein, Joel S

    2015-01-01

    Proton pump inhibitors (PPIs) have been associated with diminished bone mineral density (BMD) and an increased risk of fracture; however, prior studies have not yielded consistent results, and many have suboptimal ascertainment of both PPI use and BMD. We used data from the Study of Women’s Health Across the Nation (SWAN), a multicenter, multi-ethnic, community-based longitudinal cohort study of women across the menopause transition to examine the association between annualized BMD changes and new use of PPIs. We compared changes in BMD in new PPI users with changes in BMD in new users of histamine 2 receptor antagonists (H2RAs) and with changes in BMD in subjects who did not use either class of medications. Mixed linear regression models included recognized risk factors for osteoporosis, including demographics, menopausal transition stage, body mass index (BMI), lifestyle factors, as well as comorbidities and concomitant medications. To provide further evidence for the validity of our analytic approach, we also examined the effects of hormone-replacement therapy (HT), a class of medications that should reduce bone loss, on changes in BMD as an internal positive control group. We identified 207 new users of PPIs, 185 new users of H2RAs, and 1,676 non-users. Study subjects had a mean age of 50 years and were followed for a median of 9.9 years. Adjusted models found no difference in the annualized BMD change at the lumbar spine, femoral neck, or total hip in PPI users compared with H2RA users or non-users. These results were robust to sensitivity analyses. BMD increased as expected in HT users, supporting the validity of our study design. These longitudinal analyses plus similar prior studies argue against an association between PPI use and BMD loss. PMID:25156141

  8. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome

    PubMed Central

    Rassen, Jeremy A.; Choudhry, Niteesh K.; Avorn, Jerry; Schneeweiss, Sebastian

    2010-01-01

    Background Recent studies have raised concerns about reduced efficacy of clopidogrel when used concurrently with proton pump inhibitors (PPIs), but those studies may have overestimated the risk. Methods and Results We studied the potential for increased risk of adverse cardiovascular events among users of clopidogrel with concurrent use of PPIs versus without, in three large cohorts of patients ≥ 65 years treated between 2001-2005. All patients had undergone percutaneous coronary intervention or been hospitalized for acute coronary syndrome in Pennsylvania, New Jersey, or British Columbia, and had subsequently initiated treatment with clopidogrel. We recorded myocardial infarction (MI) hospitalization, death, and revascularization among PPI users and non-users. We assessed our primary endpoint of MI or death using cohort-specific and pooled regression analyses. 18,565 clopidogrel users entered our analysis. On a pooled basis, 2.6% of those who also initiated a PPI versus 2.1% of PPI non-users had an MI hospitalization; 1.5% versus 0.9% died, and 3.4% versus 3.1% underwent revascularization. The propensity score-adjusted rate ratio for the primary endpoint of MI or death was 1.22 (95% confidence interval 0.99 to 1.51); for death 1.20 (0.84, 1.70); and for revascularization, 0.97 (0.79 to 1.21). Matched analyses generally yielded similar results. Conclusions Though point estimates indicated a slightly increased risk of MI or death in older patients initiating both clopidogrel and a PPI, we did not observe conclusive evidence of a clopidogrel/PPI interaction of major clinical relevance. Our data suggest that should this effect exist, is unlikely to exceed a 20% risk increase. PMID:19933932

  9. Characteristics of symptomatic reflux episodes in Japanese proton pump inhibitor-refractory non-erosive reflux disease patients

    PubMed Central

    Nakagawa, Kenichiro; Koike, Tomoyuki; Iijima, Katsunori; Saito, Masahiro; Kikuchi, Hiroki; Hatta, Waku; Ara, Nobuyuki; Uno, Kaname; Asano, Naoki; Shimosegawa, Tooru

    2015-01-01

    AIM: To clarify the pathogenesis of gastroesophageal reflux disease symptoms in non-erosive reflux disease (NERD) patients. METHODS: Thirty-five NERD patients with persistent symptoms, despite taking rabeprazole 10 mg twice daily for at least 8 wk, were included in this study. All patients underwent 24 h combined impedance - pH on rabeprazole. The symptom index (SI) was considered to be positive if ≥ 50%, and proximal reflux episodes were determined when reflux reached 15 cm above the proximal margin of the lower esophageal sphincter. RESULTS: In 14 (40%) SI-positive patients, with liquid weakly acid reflux, the occurrence rate of reflux symptoms was significantly more frequent in proximal reflux episodes (46.7%) than in distal ones (5.7%) (P < 0.001). With liquid acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (38.5%) and distal ones (20.5%) (NS). With mixed liquid-gas weakly acid reflux, the occurrence rate of reflux symptoms in proximal reflux episodes was significantly more frequent (31.0%) than in distal reflux ones (3.3%) (P < 0.001). With mixed liquid-gas acid reflux, there were no significant differences in the occurrence rate of reflux symptoms between proximal reflux episodes (29.4%) and distal ones (14.3%) (NS). CONCLUSION: The proximal extent of weakly acidic liquid and mixed liquid-gas reflux is a major factor associated with reflux perception in SI-positive patients on proton pump inhibitor therapy. PMID:26715820

  10. In vitro dissolution of proton-pump inhibitor products intended for paediatric and geriatric use in physiological bicarbonate buffer.

    PubMed

    Liu, Fang; Shokrollahi, Honaz

    2015-05-15

    Proton-pump inhibitor (PPI) products based on enteric coated multiparticulates are design to meet the needs of patients who cannot swallow tablets such as children and older adults. Enteric coated PPI preparations exhibit delays in in vivo absorption and onset of antisecretory effects, which is not reflected by the rapid in vitro dissolution in compendial pH 6.8 phosphate buffer commonly used for assessment of these products. A more representative and physiological medium, pH 6.8 mHanks bicarbonate buffer, was used in this study to evaluate the in vitro dissolution of enteric coated multiparticulate-based PPI products. Commercially available omeprazole, lansoprazole and esomeprazole products were subject to dissolution tests using USP-II apparatus in pH 4.5 phosphate buffer saline for 45 min (acid stage) followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, all nine tested products displayed rapid and comparable dissolution profiles meeting the pharmacopeia requirements for delayed release preparations. In pH 6.8 mHanks buffer, drug release was delayed and failed the pharmacopeia requirements from most enteric coated preparations. Despite that the same enteric polymer, methacrylic acid-ethyl acrylate copolymer (1:1), was applied to all commercial multiparticulate-based products, marked differences were observed between dissolution profiles of these preparations. The use of pH 6.8 physiological bicarbonate (mHanks) buffer can serve as a useful tool to provide realistic and discriminative in vitro release assessment of enteric coated PPI preparations and to assist rational formulation development of these products. PMID:25746736

  11. The use of proton pump inhibitors decreases the risk of diabetes mellitus in patients with upper gastrointestinal disease

    PubMed Central

    Lin, Hsiu-Chen; Hsiao, Yu-Ting; Lin, Hsiu-Li; Uang, Yow-Shieng; Cheng, Hui-Wen; Wang, Ying; Wang, Li-Hsuan

    2016-01-01

    Abstract Objectives: The aim of this study was to investigate the effects of proton pump inhibitors (PPIs) on the risk of diabetes mellitus (DM) among patients with upper gastrointestinal disease (UGID). Methods: This was a retrospective cohort study with a follow-up period of 5 years. We identified 388,098 patients who were diagnosed with UGID between 2000 and 2006 from the Longitudinal Health Insurance Database of the Taiwan National Health Insurance program. We used Cox proportional hazard ratio (HR) to compare the risk of DM between UGID patients received PPIs and those did not receive PPIs. HRs were adjusted for possible confounders, including age, sex, hypertension, gout and/or hyperuricemia, coronary artery disease, stroke, pancreatitis, hyperlipidemia, obesity, H2-blocker use, and clozapine or olanzapine use. The dose-related effects of PPIs on the risk of DM were evaluated according to the defined daily dose (DDD). Results: The adjusted HR was 0.80 (95% CI, 0.73–0.88) for the study group (UGID patients with PPIs) compared with comparison group I (UGID patients without PPIs). Among patients who used PPIs, those older than 60 years of age had a lower risk of DM (HR, 0.73; 95% CI, 0.63–0.83) than those younger than 40 years. Additionally, the effect of PPIs was significantly dose-dependent (P for trend <0.001). Patients with UGID who received >540 DDDs of PPIs exhibited the greatest reduction in the risk of DM. Conclusions: Our results demonstrated a decreased risk of DM in UGID patients who used PPIs; the risk appeared to be significantly dose-dependent. PMID:27428221

  12. Changes in Practice Patterns of Clopidogrel in Combination with Proton Pump Inhibitors after an FDA Safety Communication

    PubMed Central

    Guérin, Annie; Mody, Reema; Carter, Valerie; Ayas, Charles; Patel, Haridarshan; Lasch, Karen; Wu, Eric

    2016-01-01

    Objectives In 2009, the FDA issued a warning that omeprazole–a proton pump inhibitor (PPI)–reduces the antithrombotic effect of clopidogrel by almost half when taken concomitantly. This study aims to analyze the impact of the FDA Safety Communications on prescribing clopidogrel together with PPIs. Methods This retrospective study identified clopidogrel users from the Truven Health Analytics MarketScan Databases (01/2006–12/2012). Rates of clopidogrel-PPI combination therapy were estimated in 6-month intervals for patients with ≥1 clopidogrel prescription fill, then were analyzed pre- and post-safety communication (11/17/2009). Analyses were also conducted by grouping PPIs into CYP2C19 inhibitors (omeprazole and esomeprazole) and CYP2C19 non-inhibitors (pantoprazole, lansoprazole, dexlansoprazole, and rabeprazole). Results Overall, 483,074 patients met the selection criteria; of these, 157,248 used a clopidogrel-PPI combination. On average, 30.5% of patients in the pre- and 19.9% in the post-communication period used a clopidogrel-PPI combination therapy. Among clopidogrel users, the probability of using clopidogrel-PPI combinations fell by over 40% in the post-communication period (OR = 0.57; p<0.001); the proportion of patients using esomeprazole fell from 12.9% to 5.3%, and the proportion using omeprazole fell from 10.1% to 6.3%. Among combination therapy users, the probability of patients using a combination with a CYP2C19 inhibitor decreased by 53% (OR = 0.47; p<0.001); however, 31.5% of patients were still prescribed a clopidogrel-PPI combination therapy. Trends were similar for all and newly treated patients, regardless of clopidogrel indication and physician specialty. Conclusions The FDA Safety Communication resulted in a reduction in the number of patients undergoing combination therapy; however approximately one-third of patients still used combination therapy post-communication. PMID:26727382

  13. Acute Coronary Syndromes, Gastrointestinal Protection, and Recommendations Regarding Concomitant Administration of Proton-Pump Inhibitors (Omeprazol/Esomeprazole) and Clopidogrel.

    PubMed

    Lozano, Iñigo; Sanchez-Insa, Esther; de Leiras, Sergio Rodríguez; Carrillo, Pilar; Ruiz-Quevedo, Valeriano; Pinar, Eduardo; Gopar-Gopar, Silvia; Bayon, Jeremías; Mañas, Pilar; Lasa, Garikoitz; CruzGonzalez, Ignacio; Hernandez, Felipe; Fernandez-Portales, Javier; Fernandez-Fernandez, Javier; Pérez-Serradilla, Ana; de la Torre Hernandez, José M; Gomez-Jaume, Alfredo

    2016-02-01

    The Food and Drug Administration and the European Medicines Agency sent a warning in 2010 discouraging the concomitant use of clopidogrel with omeprazole or esomeprazole. The purpose is to know the gastroprotective approach in patients with acute coronary syndrome (ACS) and the level of follow-up of the alert. In 17 hospitals with catheterization laboratory in Spain, 1 per region, we studied 25 consecutive patients per hospital whose diagnosis of discharge since October 1, 2013, had been any type of ACS. We analyzed their baseline clinical profile, the gatroprotective agents at admission and discharge and the antiplatelet therapy at discharge. The number of patients included was 425: age 67.2 ± 12.5 years, women 29.8%, diabetes 36.5%. The patients presented unstable angina in 21.6%, non-ST-elevation myocardial infarction in 35.3% and ST-elevation myocardial infarction in 43.1%. Conservative approach was chosen in 17.9%, bare-metal stents 32.2%, ≥ 1 drug-eluting stent 48.5%, and surgery 1.4%. Aspirin was indicated in 1.9%, aspirin + clopidogrel 73.6%, aspirin + prasugrel 17.6%, and aspririn + ticagrelor 6.8%. Gastroprotective agents were present in 40.2% patients at admission and this percentage increased to 93.7% at discharge. Of the 313 (73.6%) on clopidogrel in 96 (30.6%) was combined with omeprazole and 3 (0.95%) with esomeprazole, whereas the most commonly used was pantoprazole with 190 patients (44.7%). In conclusion, almost the totality of the patients with an ACS receive gastroprotective agents at the moment of discharge, most of them with proton-pump inhibitors. In one every 3 cases of the patients who are on clopidogrel, the recommendation of the Food and Drug Administration and the European Medicines Agency is not followed. PMID:26708640

  14. Association Between Recent Use of Proton Pump Inhibitors and Nontyphoid Salmonellosis: A Nested Case-Control Study

    PubMed Central

    Wu, Hau-Hsin; Chen, Yung-Tai; Shih, Chia-Jen; Lee, Yi-Tzu; Kuo, Shu-Chen; Chen, Te-Li

    2014-01-01

    Background. The association between proton pump inhibitors (PPIs) and nontyphoid salmonellosis (NTS) continues to be debated. The current study was designed to determine the association between use of oral PPIs and the diagnosis of NTS. Methods. The Taiwan National Health Insurance Research Database from 2000 to 2010 was searched for cases of NTS, defined by the International Classification of Disease, Ninth revision, Clinical Modification. A nested case-control study in hospitalized population was conducted using 4 controls for each case patient (14 736 case patients and 58 944 controls), matched for age, month and year of entry, Charlson comorbidity index score, and well-known predisposing factors for NTS, including autoimmune diseases, acquired immunodeficiency syndrome, diabetes, cirrhosis, transplantation, gastrointestinal operations or diseases, and malignancies. Results. Persons with NTS had a higher rate of using oral PPIs within the prior year (adjusted odds ratio [OR], 2.09; 95% confidence interval [CI], 1.95–2.24; P < .001). The association was greatest for current PPI use (adjusted OR, 5.39; 95% CI, 4.79–6.06; P < .001). Although use of H2-receptor antagonists (adjusted OR, 1.84; 95% CI, 1.71–1.98), antibiotics (5.21; 4.81–5.64), steroids (3.18; 2.99–3.39), and nonsteroidal anti-inflammatory drugs (2.37; 2.26–2.48) within the 30 days were also associated with NTS, the linkage between PPI use and NTS remained significant in the subgroup without these medications. Conclusions. The use of oral PPIs was associated with the occurrence of NTS. The risk waned with time after discontinuation. PMID:25091310

  15. Analysis of the Interaction between Clopidogrel, Aspirin, and Proton Pump Inhibitors Using the FDA Adverse Event Reporting System Database.

    PubMed

    Suzuki, Yukiya; Suzuki, Honami; Umetsu, Ryogo; Uranishi, Hiroaki; Abe, Junko; Nishibata, Yuri; Sekiya, Yasuaki; Miyamura, Nobuteru; Hara, Hideaki; Tsuchiya, Teruo; Kinosada, Yasutomi; Nakamura, Mitsuhiro

    2015-01-01

    Clopidogrel is an antiplatelet agent widely used in combination with aspirin to limit the occurrence of cardiovascular (embolic/thrombotic) events. Consensus guidelines recommend proton pump inhibitors (PPIs) as a gastrointestinal (GI) prophylactic measure for all patients receiving dual antiplatelet therapy with clopidogrel and aspirin. The objective of this study was to analyze the effect of the simultaneous use of clopidogrel, aspirin, and PPIs on hemorrhagic and embolic/thrombotic events using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Reports of hemorrhagic and embolic/thrombotic events between 2004 and 2013 were analyzed with a reporting odds ratio (ROR) algorithm and logistic regression methods. The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify such events. Regarding hemorrhagic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 4.40 (95% confidence interval [CI], 4.02-4.81) and 3.40 (95% CI, 2.84-4.06), respectively. For embolic/thrombotic events, the adjusted RORs of the concomitant use of aspirin and clopidogrel and those of PPIs prescribed with aspirin and clopidogrel were 2.37 (95% CI, 2.16-2.59) and 2.38 (95% CI, 2.00-2.84), respectively. Among patients included in the FAERS database, the concurrent use of aspirin and clopidogrel with PPIs reduced the adjusted ROR of GI hemorrhagic events. PPIs had little influence on the adjusted ROR of embolic/thrombotic events. These results support the use of PPIs as a preventive measure against GI hemorrhagic events for patients receiving clopidogrel and aspirin. PMID:25947914

  16. Tonoplast lipid composition and proton pump of pineapple fruit during low-temperature storage and blackheart development.

    PubMed

    Zhou, Yuchan; Pan, Xiaoping; Qu, Hongxia; Underhill, Steven J R

    2014-05-01

    Vacuole represents a major storage organelle playing vital roles in pH homoeostasis and cellular detoxification. The chemical and functional properties of tonoplast in response to chilling temperature and their roles in chilling injury are largely unknown. In the current study, lipid composition of tonoplast and the activities of two vacuolar proton pumps, H?-ATPase (V-ATPase) and H?-pyrophosphatase (V-PPase), were investigated in accordance with the development of blackheart, a form of chilling injury in pineapple fruit (Ananas comosus). Chilling temperature at 10 °C for 1 week induced irreversible blackheart injury in concurrence with a substantial decrease in V-ATPase activity. By contrast, the activity was increased after 1 week at 25 °C. The activity of V-PPase was not changed under both temperatures. Level of total phospholipids of tonoplast decreased at 10 °C, but increased at 25 °C. There was no change at the level of total glycolipids under both temperatures. Thus, low temperature increased the ratio of total glycolipids vs. total phospholipids of tonoplast. Phosphatidylcholine and phosphatidylethanolamine were the predominant phospholipids of tonoplast. Low temperature increased the relative level of phosphatidic acid but decreased the percentage of both phosphatidylcholine and phosphatidylethanolamine. Unsaturated fatty acids accounted for over 60 % of the total tonoplast fatty acids, with C18:1 and C18:2 being predominant. Low temperature significantly decreased the percentage of C18:3. Modification of membrane lipid composition and its effect on the functional property of tonoplast at low temperature were discussed in correlation with their roles in the development of chilling injury in pineapple fruit. PMID:24658889

  17. Cloning and expression of vacuolar proton-pumping ATPase subunits in the follicular epithelium of the bullfrog endolymphatic sac.

    PubMed

    Yajima, Shinya; Kubota, Makoto; Nakakura, Takashi; Hasegawa, Takahiro; Katagiri, Nobuto; Tomura, Hideaki; Sasayama, Yuichi; Suzuki, Masakazu; Tanaka, Shigeyasu

    2007-02-01

    In an investigation aimed at clarifying the mechanism of crystal dissolution of the calcium carbonate lattice in otoconia (the mineral particles embedded in the otolithic membrane) of the endolymphatic sac (ELS) of the bullfrog, cDNAs encoding the A- and E-subunits of bullfrog vacuolar proton-pumping ATPase (V-ATPase) were cloned and sequenced. The cDNA of the A-subunit consisted of an 11-bp 5'-untranslated region (UTR), a 1,854-bp open reading frame (ORF) encoding a protein comprising 617 amino acids with a calculated molecular mass of 68,168 Da, and a 248-bp 3'-UTR followed by a poly(A) tail. The cDNA of the E-subunit consisted of a 72-bp 5'-UTR, a 681-bp ORF encoding a protein of 226 amino acids with a calculated molecular mass of 26,020 Da, and a 799-bp 3'-UTR followed by a poly(A) tail. Western blot and immunofluorescence analyses using specific anti-peptide antisera against the V-ATPase A- and E-subunits revealed that these subunits were present in the ELS, urinary bladder, skin, testes, and kidneys. In the ELS, positive cells were scattered in the follicular epithelium which, as revealed by electron microscopy, corresponds to the location of mitochondria-rich cells. These findings suggest that V-ATPase, including the A- and E-subunits, exists in mitochondria-rich cells of the ELS, which might be involved in dissolution of the calcium carbonate crystals in the lumen of the ELS. PMID:17409728

  18. Protective Effect of Proton Pump Inhibitor for Survival in Patients with Gastroesophageal Reflux Disease and Idiopathic Pulmonary Fibrosis

    PubMed Central

    Lee, Chang Min; Lee, Dong Ho; Ahn, Byung Kyu; Hwang, Jae Jin; Yoon, Hyuk; Shin, Cheol Min; Park, Young Soo; Kim, Nayoung

    2016-01-01

    Background/Aims The prevalence of gastroesophageal reflux disease (GERD) is high in patients with idiopathic pulmonary fibrosis (IPF). GERD may cause chronic microaspiration that leads to repeated subclinical lung injury, which leads to pulmonary fibrosis. Although some studies have suggested that proton pump inhibitors (PPI) were associated with a good prognosis in IPF, their effects remain unclear. Methods We retrospectively reviewed 786 consecutive adult patients with IPF at Seoul National University Bundang Hospital between April 2003 and March 2015. Results Mean duration of follow-up was 2.6 ± 2.8 years. Of the 786 patients with IPF, 107 (13.6%) were given diagnoses of GERD, and 103 (13.1%) died due to IPF-related pneumonia or respiratory failure. The prevalence of GERD and the cumulative incidence of de novo GERD increased depending on the period of follow-up in patients with IPF. Patients administered PPI for more than four months had a lower IPF-related mortality rate than patients on PPI less than 4 months (Log-rank P-value = 0.024 in Kaplan-Meier curve). In a univariate and multivariate Cox regression hazard model, younger age (hazard ratio [HR], 1.06; 95% CI, 1.03–1.10; P = 0.001), higher initial forced vital capacity (HR, 0.98; 95% CI, 0.96–0.99; P = 0.004), and longer duration of PPI use (HR, 0.97; 95% CI, 0.95–1.00; P = 0.022), but not a diagnosis of GERD, were significantly associated with lower IPF-related mortality. Conclusions In Korean patients with IPF, the prevalence of GERD was lower than in other countries. PPI use for at least 4 months may have a protective effect against IPF-related mortality. PMID:26932897

  19. Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation.

    PubMed

    Tentzeris, Ioannis; Jarai, Rudolf; Farhan, Serdar; Brozovic, Ivan; Smetana, Peter; Geppert, Alexander; Wojta, Johann; Siller-Matula, Jolanta; Huber, Kurt

    2010-12-01

    The aim of the study was to evaluate the effect of the concomitant treatment with proton-pump inhibitors (PPIs) and clopidogrel on the incidence of stent thrombosis, acute coronary syndrome (ACS) and death in patients who underwent percutaneous coronary intervention (PCI) and stent implantation. In total, 1,210 patients under dual antiplatelet therapy, who underwent PCI and stent implantation, were included in a prospective registry from January 2003 until December 2006. The patients were divided retrospectively into those with or without long-term PPI treatment (for the duration of dual antiplatelet therapy). All-cause mortality, cardiovascular death, re-hospitalisation for re-ACS, stent thrombosis, as well as the combined endpoint all-cause death, re-ACS or stent thrombosis were evaluated over a mean follow-up period of 7.8 (± 3.63) months (range 1-12 months). Propensity score analysis was performed to reduce potential selection bias and exhibited no significant difference between the two study groups with respect to all-cause mortality, cardiovascular death, re-ACS, stent thrombosis and the combined endpoint. In pre-specified subgroup analyses performed in patients presenting with ACS and referred for acute PCI or for stable patients referred for elective PCI, receiving drug-eluting stents or bare metal stents, in diabetics or non-diabetics, in males or females, and in patients older than 75 years or ≤75 years of age use of PPIs had no significant impact on clinical outcome. Our data suggest that a combined use of clopidogrel as part of dual antiplatelet therapy (DAPT) after coronary stenting and PPIs does not significantly influence the clinical outcome. PMID:20941464

  20. The parietal cell gastric H, K-ATPase also functions as the Na, K-ATPase and Ca-ATPase in altered states.

    PubMed

    Ray, Tushar

    2013-01-01

    This article offers an explanation for the apparent lack of Na, K-ATPase activity in parietal cells although ouabain has been known to inhibit gastric acid secretion since 1962. The gastric H, K-ATPase (proton-pump) seems to be acting in altered states, thus behaving like a Na, K-ATPase (Na-pump) and/or Ca-ATPase (Ca-pump) depending on cellular needs.  This conclusion is based on the following findings. First, parietal cell fractions do not exhibit Na, K-ATPase activity at pH 7.0 but do at pH 8.5. Second, the apical plasma membrane (APM) fraction exhibits a (Ca or Mg)-ATPase activity with negligible H, K-ATPase activity. However, when assayed with Mg alone in presence of the 80 k Da cytosolic proton-pump activator (HAF), the APM fraction reveals remarkably high H, K-ATPase activity, suggesting the observed low affinity of Ca (or Mg)-ATPase is an altered state of the latter. Third, calcium (between 1 and 4 µM) shows both stimulation and inhibition of the HAF-stimulated H, K-ATPase depending on its concentration, revealing a close interaction between the  proton-pump activator and local Ca concentration in gastric H, K-ATPase function. Such interactions suggest that Ca is acting as a terminal member of the intracellular signaling system for the HAF-regulated proton-pump. It appears that during resting state, the HAF-associated H, K-ATPase remains inhibited by Ca (>1 µM) and, prior to resumption of acid secretion the gastric H, K-ATPase acts temporarily as a Ca-pump for removing excess Ca from its immediate environment. This conclusion is consistent with the recent reports of immunochemical co-localization of the gastric H, K-ATPase and Ca-ATPase by superimposition in parietal cells, and a transitory efflux of Ca immediately preceding the onset of acid secretion. These new perspectives on proton-pump function would open new avenues for a fuller understanding of the intracellular regulation of the ubiquitous Na-pump. PMID:24555080

  1. The parietal cell gastric H, K-ATPase also functions as the Na, K-ATPase and Ca-ATPase in altered states

    PubMed Central

    Ray, Tushar

    2013-01-01

    This article offers an explanation for the apparent lack of Na, K-ATPase activity in parietal cells although ouabain has been known to inhibit gastric acid secretion since 1962. The gastric H, K-ATPase (proton-pump) seems to be acting in altered states, thus behaving like a Na, K-ATPase (Na-pump) and/or Ca-ATPase (Ca-pump) depending on cellular needs.  This conclusion is based on the following findings. First, parietal cell fractions do not exhibit Na, K-ATPase activity at pH 7.0 but do at pH 8.5. Second, the apical plasma membrane (APM) fraction exhibits a (Ca or Mg)-ATPase activity with negligible H, K-ATPase activity. However, when assayed with Mg alone in presence of the 80 k Da cytosolic proton-pump activator (HAF), the APM fraction reveals remarkably high H, K-ATPase activity, suggesting the observed low affinity of Ca (or Mg)-ATPase is an altered state of the latter. Third, calcium (between 1 and 4 µM) shows both stimulation and inhibition of the HAF-stimulated H, K-ATPase depending on its concentration, revealing a close interaction between the  proton-pump activator and local Ca concentration in gastric H, K-ATPase function. Such interactions suggest that Ca is acting as a terminal member of the intracellular signaling system for the HAF-regulated proton-pump. It appears that during resting state, the HAF-associated H, K-ATPase remains inhibited by Ca (>1 µM) and, prior to resumption of acid secretion the gastric H, K-ATPase acts temporarily as a Ca-pump for removing excess Ca from its immediate environment. This conclusion is consistent with the recent reports of immunochemical co-localization of the gastric H, K-ATPase and Ca-ATPase by superimposition in parietal cells, and a transitory efflux of Ca immediately preceding the onset of acid secretion. These new perspectives on proton-pump function would open new avenues for a fuller understanding of the intracellular regulation of the ubiquitous Na-pump. PMID:24555080

  2. Acid, protons and Helicobacter pylori.

    PubMed Central

    Sachs, G.; Meyer-Rosberg, K.; Scott, D. R.; Melchers, K.

    1996-01-01

    The anti-ulcer drugs that act as covalent inhibitors of the gastric acid pump are targeted to the gastric H+/K+ ATPase by virtue of accumulation in acid and conversion to the active sulfenamide. This results in extremely effective inhibition of acid secretion. Appropriate dosage is able to optimize acid control therapy for reflux and peptic ulcer disease as compared to H2 receptor antagonists. However, clinical data on recurrence show that Helicobacter pylori eradication should accompany treatment of the lesion. These drugs have been found to synergize with many antibiotics for eradication. The survival of aerobes depends on their ability to maintain a driving force for protons across their inner membrane, the sum of a pH and potential difference gradient, the protonmotive force (pmf). The transmembrane flux of protons across the F1F0 ATPase, driven by the pmf, is coupled to the synthesis of ATP. The internal pH of H. pylori was measured using the fluorescent dye probe, BCECF, and the membrane potential defined by the uptake of the carbocyanine dye, DiSC3 [5] at different pHs to mimic the gastric environment. The protonmotive force at pH 7.0 was composed of a delta pH of 1.4 (-84mV) and a delta potential difference of -131mV, to give a pmf of -215 mV. The effect of variations in external pH on survival of the bacteria in the absence of urea correlated with the effect of external pH on the ability of the bacteria to maintain a pmf. The effect of the addition of 5 mM urea on the pmf was measured at different medium pH values. Urea restored the pmf at pH 3.0 or 3.5, but abolished the pmf at pH 7.0 or higher, due the production of the alkalinizing cation, NH3. Hence H. pylori is an acid-tolerant neutrophile due to urease activity, but urease activity also limits its survival to an acidic environment. These data help explain the occupation of the stomach by the organism and its distribution between fundus and antrum. This distribution and its alteration by proton pump

  3. Inhibition of gastric H+, K(+)-ATPase activity by compounds from medicinal plants.

    PubMed

    Freitas, Cristina Setim; Baggio, Cristiane Hatsuko; Mayer, Bárbara; dos Santos, Ana Cristina; Twardowschy, André; Santos, Cid Aimbiré de Moraes; Marques, Maria Consuelo Andrade

    2011-09-01

    H+, K(+)-ATPase enzyme is a therapeutic target for the treatment of gastric disturbances. Several medicinal plants and isolated compounds inhibit the acid gastric secretion through interaction with the proton pump. In order to add new properties to some natural constituents, five compounds, a benzylated derivative of vincoside, a diterpene (abietic acid) and three alkaloids (cephaeline, vinblastine and vindoline), were tested for their activities on gastric H+, K(+)-ATPase isolated from rabbit stomach. All the compounds inhibited H+, K(+)-ATPase activity with varied potency. The IC50 value for benzylvincoside was 121 (50-293) microM, and for abietic acid 177 (148-211) microM. The alkaloids cephaeline, vinblastine and vindoline inhibited the H+, K(+)-ATPase activity with IC50 values of 194, 761 and 846 microM, respectively. The results suggest that benzylvincoside, abietic acid and cephaeline can be important sources for the development of anti-secretor agents. PMID:21941891

  4. Proton pump inhibitors

    MedlinePlus

    ... used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a condition in which food or ... MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol . 2013;108:308-28. ...

  5. Efficacy of alfacalcidol and alendronate on lumbar bone mineral density in osteoporotic patients using proton pump inhibitors

    PubMed Central

    Asaoka, Daisuke; Nagahara, Akihito; Hojo, Mariko; Matsumoto, Kenshi; Ueyama, Hiroya; Matsumoto, Kohei; Izumi, Kentaro; Takeda, Tsutomu; Komori, Hiroyuki; Akazawa, Yoichi; Shimada, Yuji; Osada, Taro; Watanabe, Sumio

    2016-01-01

    It has been indicated that proton pump inhibitor (PPI) use is associated with a loss of the anti-fracture efficacy of alendronate (AD). However, there are few prospective studies that have investigated the efficacy of AD on lumbar bone mineral density (BMD) in osteoporotic patients who are using PPIs. Thus, the aim of the present study was to investigate the efficacy of alfacalcidol (AC) and AD on lumbar BMD in osteoporotic patients using PPIs. A prospective, randomized, active control study enrolled such osteoporotic patients (age, ≥50 years). The patients were randomly assigned to receive AC (1 µg/day) or AD (35 mg/week) and were followed up for one year. Patient profiles were maintained, and lumbar BMD, bone-specific alkaline-phosphatase (BAP) and collagen type-I cross-linked N-telopeptide (NTX), upper gastrointestinal endoscopy results, and the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) were evaluated. Percentage changes in lumbar BMD, NTX, BAP, and change in FSSG score from baseline to the end of one year of treatment were investigated. Sixteen patients were eligible for analysis (eight assigned to receive AC, eight assigned to receive AD). The percentage change in lumbar BMD from baseline to the end of treatment was −0.4±4.0% for the AC group vs. 6.8±6.3% for the AD group (P=0.015). No significant percentage change of BAP and NTX between the two groups was observed. Subsequent to one year of treatment, the FSSG score did not change from the baseline values for either study group, and no new bone fractures or esophagitis were observed in either group of patients. The findings demonstrated that in osteoporotic patients using concomitant PPIs, there was a greater increase in lumbar BMD after one year of treatment with AD compared with AC. However, the number of study subjects was small; thus, further, large prospective studies are required to determine the effect of AD in osteoporotic patients using concomitant PPIs. PMID

  6. Changes in serum magnesium concentration after use of a proton pump inhibitor in patients undergoing percutaneous coronary intervention

    PubMed Central

    Park, Sang-Ho; Lee, Sun-hyo; Lee, Ji-Sung; Shin, Won-Yong; Gil, Hyo-Wook; Yang, Jong-Oh; Lee, Eun-Young; Hong, Sae-Yong

    2015-01-01

    Background Although cross-sectional studies have suggested a relationship between proton pump inhibitor (PPI) use and hypomagnesemia, no large-scale cohort study has been conducted to date. Here, we examined the changes in serum magnesium levels in response to PPI use. We hypothesized that PPI use might change the serum magnesium concentration. Methods Of the 2,892 patients hospitalized for percutaneous coronary intervention between January 2007 and May 2012, 1,076 patients with normal baseline (1.6–2.5 mg/dL) and follow-up serum magnesium concentrations were enrolled. These patients were divided into two groups: the PPI group and the control group. Results The mean follow-up period was 9.51 ± 2.94 months. The incidence of hypomagnesemia (< 1.6 mg/dL) was 0.4% (3/834) in the PPI group and 0.4% (1/242) in the control group (P = 0.904). The change in magnesium levels did not differ between the two groups, and this result was maintained in the analysis of covariance after adjusting for confounding factors (P = 0.381). Moreover, magnesium levels did not significantly differ between the long-term (duration of use ≥ 12 months, n = 71) and short-term PPI groups (duration of use < 12 months, n = 763), and the control group (n = 242; P = 0.620). The effect of PPI use on change in serum magnesium concentration was affected by the use of multiple diuretics (−0.01 ± 0.25 mg/dL; P = 0.025), although a single diuretic use with PPI did not alter the change in magnesium level (0.12 ± 0.27 mg/dL). Conclusion Changes in magnesium levels might be subtle after PPI use in patients with normal baseline magnesium values. PMID:26484029

  7. Mealtime-related dosing directions for proton-pump inhibitors in gastroesophageal reflux disease: physician knowledge, patient adherence.

    PubMed

    Solem, Caitlyn; Mody, Reema; Stephens, Jennifer; Macahilig, Cynthia; Gao, Xin

    2014-01-01

    OBJECTIVE To describe physicians' knowledge, patients' adherence, and perceptions of both regarding mealtime-related dosing directions for proton-pump inhibitors (PPIs). DESIGN Chart review and survey of patients and physicians. SETTING United States, with data collected between January and July 2011. PARTICIPANTS Patients being treated for gastroesophageal reflux disease (GERD) with PPIs and their prescribing physicians. MAIN OUTCOME MEASURES Patient- and physician-reported perception of PPI mealtime-related directions as important/inconvenient (seven-point Likert scale; 7 = very important/very inconvenient); physician-reported knowledge of PPI mealtime-related dosing directions based on whether the agent is labeled to be taken 30-60 minutes before eating (DIR-esomeprazole magnesium [Nexium-AstraZeneca], lansoprazole, and omeprazole) or labeled to be taken regardless of meals (NoDIR-dexlansoprazole [Dexilant-Takeda], rabeprazole, and pantoprazole); and patient-reported PPI mealtime-related directions received and adherence to directions. RESULTS Physicians (n = 262) recruited 501 patients who had been prescribed PPIs (262 DIR/239 NoDIR; mean age 51 years, 37% men, 56% nonerosive GERD [29% undocumented]). Across PPIs, physicians frequently reported incorrect directions or "did not know directions" (29% for esomeprazole to 69% for pantoprazole). While 98% of patients reported receiving directions from their physicians and 55% from their pharmacists, only 65% of DIR patients and 18% of NoDIR received directions consistent with product labeling. Physicians perceived greater inconvenience than patients (4.4 vs. 1.6, P < 0.001) and greater importance (5.2 vs. 4.5, P < 0.001) of mealtime-related directions. Overall, 81% of patients reported taking their PPI as directed. CONCLUSION While this patient cohort was adherent to directions given, physicians' directions were often inconsistent with product labeling. Understanding physician and patient knowledge gaps may be

  8. Risk of Community-Acquired Pneumonia with Outpatient Proton-Pump Inhibitor Therapy: A Systematic Review and Meta-Analysis

    PubMed Central

    Lambert, Allison A.; Lam, Jennifer O.; Paik, Julie J.; Ugarte-Gil, Cesar; Drummond, M. Bradley; Crowell, Trevor A.

    2015-01-01

    Background Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults. Methods We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients ≥18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy. Results Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31). Discussion Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain. PMID:26042842

  9. Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study

    PubMed Central

    Pouwels, S.; Lalmohamed, A.; Souverein, P.; Cooper, C.; Veldt, B. J.; Leufkens, H. G.; de Boer, A.; van Staa, T.

    2010-01-01

    Summary Previous studies evaluated the association between proton pump inhibitor (PPI) use and subsequent fracture risk, but they showed ambiguous results. Therefore, the objective was to evaluate this association in a different study population. Our findings show that there is probably no causal relationship between PPI use and hip fracture risk. Introduction Previous studies evaluated the association between PPI use and subsequent fracture risk, but they showed ambiguous results. To further test these conflicting results, the objective of this study was to evaluate the association between the use of PPIs and the risk of hip/femur fracture in a different study population. Methods A case-control study was conducted using data from the Dutch PHARMO record linkage system. The study population included 6,763 cases aged 18 years and older with a first hip/femur fracture during enrolment and 26,341 age-, gender- and region-matched controls. Results Current users of PPIs had an increased risk of hip/femur fracture yielding an adjusted odds ratio (AOR) of 1.20 (95% CI 1.04–1.40). Fracture risk attenuated with increasing durations of use, resulting in AORs of 1.26 (95% CI 0.94–1.68) in the first 3 months, 1.31 (95% CI 0.97–1.75) between 3 and 12 months, 1.18 (95% CI 0.92–1.52) between 13 and 36 months and 1.09 (95% CI 0.81–1.47) for use longer than 36 months. Conclusion Our findings show that there is probably no causal relationship between PPI use and hip fracture risk. The observed association may be the result of unmeasured distortions: although current use of PPIs was associated with a 1.2-fold increased risk of hip/femur fracture, the positive association was attenuated with longer durations of continuous use. Our findings do not support that discontinuation of PPIs decreases risk of hip fracture in elderly patients. PMID:20585937

  10. A peroxide bridge between Fe and Cu ions in the O2 reduction site of fully oxidized cytochrome c oxidase could suppress the proton pump

    PubMed Central

    Aoyama, Hiroshi; Muramoto, Kazumasa; Shinzawa-Itoh, Kyoko; Hirata, Kunio; Yamashita, Eiki; Tsukihara, Tomitake; Ogura, Takashi; Yoshikawa, Shinya

    2009-01-01

    The fully oxidized form of cytochrome c oxidase, immediately after complete oxidation of the fully reduced form, pumps protons upon each of the initial 2 single-electron reduction steps, whereas protons are not pumped during single-electron reduction of the fully oxidized “as-isolated” form (the fully oxidized form without any reduction/oxidation treatment) [Bloch D, et al. (2004) The catalytic cycle of cytochrome c oxidase is not the sum of its two halves. Proc Natl Acad Sci USA 101:529–533]. For identification of structural differences causing the remarkable functional difference between these 2 distinct fully oxidized forms, the X-ray structure of the fully oxidized as-isolated bovine heart cytochrome c oxidase was determined at 1.95-Å resolution by limiting the X-ray dose for each shot and by using many (≈400) single crystals. This minimizes the effects of hydrated electrons induced by the X-ray irradiation. The X-ray structure showed a peroxide group bridging the 2 metal sites in the O2 reduction site (Fe3+-O−-O−-Cu2+), in contrast to a ferric hydroxide (Fe3+-OH−) in the fully oxidized form immediately after complete oxidation from the fully reduced form, as has been revealed by resonance Raman analyses. The peroxide-bridged structure is consistent with the reductive titration results showing that 6 electron equivalents are required for complete reduction of the fully oxidized as-isolated form. The structural difference between the 2 fully oxidized forms suggests that the bound peroxide in the O2 reduction site suppresses the proton pumping function. PMID:19164527