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Sample records for bacteriorhodopsin-like proton pump

  1. Xanthorhodopsin: a bacteriorhodopsin-like proton pump with a carotenoid antenna.

    PubMed

    Lanyi, Janos K; Balashov, Sergei P

    2008-01-01

    Xanthorhodopsin is a light-driven proton pump like bacteriorhodopsin, but made more effective for collecting light by its second chromophore, salinixanthin, a carotenoid. Action spectra for transport and fluorescence of the retinal upon excitation of the carotenoid indicate that the carotenoid functions as an antenna to the retinal. The calculated center-to-center distance and angle of the transition moments of the two chromophores are 11 A and 56 degrees , respectively. As expected from their proximity, the carotenoid and the retinal closely interact: tight binding of the carotenoid, as indicated by its sharpened vibration bands and intense induced circular dichroism in the visible, is removed by hydrolysis of the retinal Schiff base, and restored upon reconstitution with retinal. This antenna system, simpler than photosynthetic complexes, is well-suited to study features of excited-state energy migration.

  2. Strongly hydrogen-bonded water molecule present near the retinal chromophore of Leptosphaeria rhodopsin, the bacteriorhodopsin-like proton pump from a eukaryote.

    PubMed

    Sumii, Masayo; Furutani, Yuji; Waschuk, Stephen A; Brown, Leonid S; Kandori, Hideki

    2005-11-22

    Leptosphaeria rhodopsin (LR) is an archaeal-type rhodopsin found in fungi, and is the first light-driven proton-pumping retinal protein from eukaryotes. LR pumps protons in a manner similar to that of bacteriorhodopsin (BR), a light-driven proton pump of haloarchaea. The amino acid sequence of LR is more homologous to that of Neurospora rhodopsin (NR) than BR, whereas NR has no proton-pumping activity. These facts raise the question of how the proton-pumping function is achieved. In this paper, we studied structural changes of LR following the retinal photoisomerization by means of low-temperature Fourier transform infrared (FTIR) spectroscopy, and compared the obtained spectra with those for BR and NR. While the light-induced photoisomerization from the all-trans to 13-cis form was commonly observed among LR, BR, and NR, we found that the structural changes of LR are closer to those of BR than to those of NR in terms of detailed vibrational bands of retinal and protein. The most prominent difference was seen for the water O-D stretching vibrations (measured in D2O). LR exhibits an O-D stretch of water at 2257 cm(-1), indicating the presence of a strongly hydrogen-bonded water molecule. Such strongly hydrogen-bonded water molecules (O-D stretch at <2400 cm(-1)) were observed for BR, but not for NR. Comprehensive studies of BR mutants and archaeal rhodopsins have revealed that strongly hydrogen-bonded water molecules are found only in the proteins exhibiting proton-pumping activity, suggesting that strongly hydrogen-bonded water molecules and transient weakening of their binding are essential for the proton-pumping function of rhodopsins. This observation for LR provided additional experimental evidence of the correlation between strongly hydrogen-bonded water molecules and proton-pumping activity of archaeal rhodopsins.

  3. Proton pump inhibitors

    MedlinePlus

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

  4. Proton pump inhibitor-induced hypomagnesemic hypoparathyroidism.

    PubMed

    Swaminathan, Krishnan

    2015-01-01

    Proton pump inhibitors are the one of the most widely used drugs in the world. Hypomagnesemic hypoparathyroidism has been reported with different proton pump inhibitors with prolonged oral use. We report the first reported case of possible such effect with intravenous preparation of proton pump inhibitor. This case report raises awareness among physicians worldwide of this often unknown association, as life-threatening cardiac and neuromuscular complications can arise with unrecognized hypocalcemia and hypomagnesemia with proton pump inhibitors.

  5. Proton pump inhibitor-induced hypomagnesemic hypoparathyroidism

    PubMed Central

    Swaminathan, Krishnan

    2015-01-01

    Proton pump inhibitors are the one of the most widely used drugs in the world. Hypomagnesemic hypoparathyroidism has been reported with different proton pump inhibitors with prolonged oral use. We report the first reported case of possible such effect with intravenous preparation of proton pump inhibitor. This case report raises awareness among physicians worldwide of this often unknown association, as life-threatening cardiac and neuromuscular complications can arise with unrecognized hypocalcemia and hypomagnesemia with proton pump inhibitors. PMID:26069375

  6. Protons and how they are transported by proton pumps.

    PubMed

    Buch-Pedersen, M J; Pedersen, B P; Veierskov, B; Nissen, P; Palmgren, M G

    2009-01-01

    The very high mobility of protons in aqueous solutions demands special features of membrane proton transporters to sustain efficient yet regulated proton transport across biological membranes. By the use of the chemical energy of ATP, plasma-membrane-embedded ATPases extrude protons from cells of plants and fungi to generate electrochemical proton gradients. The recently published crystal structure of a plasma membrane H(+)-ATPase contributes to our knowledge about the mechanism of these essential enzymes. Taking the biochemical and structural data together, we are now able to describe the basic molecular components that allow the plasma membrane proton H(+)-ATPase to carry out proton transport against large membrane potentials. When divergent proton pumps such as the plasma membrane H(+)-ATPase, bacteriorhodopsin, and F(O)F(1) ATP synthase are compared, unifying mechanistic premises for biological proton pumps emerge. Most notably, the minimal pumping apparatus of all pumps consists of a central proton acceptor/donor, a positively charged residue to control pK(a) changes of the proton acceptor/donor, and bound water molecules to facilitate rapid proton transport along proton wires.

  7. Mechanisms of proton pumping in bacteriorhodopsin

    SciTech Connect

    Ebrey, T.G.

    1991-01-01

    The purple membrane of Halobacterium halobium probably represents the simplest biological solar energy conversion system. Light absorbed by bacteriorhodopsin directly leads to the transport of protons across the cell membrane. The resulting chemosmotic potential can be used to make ATP. An additional feature of the purple membrane is its ability to pump protons over a wide variety of salt concentration including in extreme saline environments. This project investigates the relationship between the transport of protons across the membrane and structure and conformation of bacteriorhodospin. We have proposed experiments to study the pH dependence of proton pumping. Secondly, we are examining the role of divalent cations and the effect of the large surface potential of the purple membrane on the proton pumping function of this membrane using the photocurrents associated with the pumping process. Finally we are studying the role of proteinatable amino acids in proton transport. 16 refs.

  8. Pharmacology of Proton Pump Inhibitors

    PubMed Central

    Shin, Jai Moo; Sachs, George

    2010-01-01

    The gastric H,K-ATPase is the primary target for the treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pKa of about 4.0, which allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa of about 1.0. PPIs are acid-activated prodrugs that convert to sulfenic acids or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. Because of covalent binding, their inhibitory effects last much longer than their plasma half-life. However, the short half-life of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. PPIs with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori. PMID:19006606

  9. [Safety of proton pump inhibitors].

    PubMed

    Esplugues, Juan V; Martí-Cabrera, Miguel; Ponce, Julio

    2006-11-25

    The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid-related diseases. The considerable prevalence of these diseases and the need for maintaining the administration of the drug during considerably long periods results in this therapeutic group being one of the most widely used. However, in spite of their extensive use, there continue to emerge concerns about their potential toxicity; concerns surrounding the specificity of their mechanism of action and a consequential suspicion that something so potent must involve harmful effects. PPIs act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+-ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. In the present article, the adverse effects of PPIs are reviewed, with special emphasis on those related to their continued administration and on the special circumstances of patients, as in the case of the elderly, those with liver failure, pregnant and breastfeeding mothers and children. All the PPIs on the market share a common chemical basis and there are no great differences in their potential adverse effects, the possibility of them promoting opportunist infections or their capacity to generate pharmacokinetic interactions with other drugs, which, if occur, are generally insignificant. After two decades of use, PPIs have proved to be very effective and safe drugs.

  10. Dynamics of the Plasma Membrane Proton Pump.

    PubMed

    Guerra, Federico; Bondar, Ana-Nicoleta

    2015-06-01

    Proton transfer over distances longer than that of a hydrogen bond often requires water molecules and protein motions. Following transfer of the proton from the donor to the acceptor, the change in the charge distribution may alter the dynamics of protein and water. To begin to understand how protonation dynamics couple to protein and water dynamics, here we explore how changes in the protonation state affect water and protein dynamics in the AHA2 proton pump. We find that the protonation state of the proton donor and acceptor groups largely affects the dynamics of internal waters and of specific hydrogen bonds, and the orientation of transmembrane helical segments that couple remote regions of the protein. The primary proton donor/acceptor group D684, can interact with water molecules from the cytoplasmic bulk and/or other protein groups.

  11. Proton pumping accompanies calcification in foraminifera

    NASA Astrophysics Data System (ADS)

    Toyofuku, Takashi; Matsuo, Miki Y.; de Nooijer, Lennart Jan; Nagai, Yukiko; Kawada, Sachiko; Fujita, Kazuhiko; Reichart, Gert-Jan; Nomaki, Hidetaka; Tsuchiya, Masashi; Sakaguchi, Hide; Kitazato, Hiroshi

    2017-01-01

    Ongoing ocean acidification is widely reported to reduce the ability of calcifying marine organisms to produce their shells and skeletons. Whereas increased dissolution due to acidification is a largely inorganic process, strong organismal control over biomineralization influences calcification and hence complicates predicting the response of marine calcifyers. Here we show that calcification is driven by rapid transformation of bicarbonate into carbonate inside the cytoplasm, achieved by active outward proton pumping. Moreover, this proton flux is maintained over a wide range of pCO2 levels. We furthermore show that a V-type H+ ATPase is responsible for the proton flux and thereby calcification. External transformation of bicarbonate into CO2 due to the proton pumping implies that biomineralization does not rely on availability of carbonate ions, but total dissolved CO2 may not reduce calcification, thereby potentially maintaining the current global marine carbonate production.

  12. Proton pumping accompanies calcification in foraminifera

    PubMed Central

    Toyofuku, Takashi; Matsuo, Miki Y.; de Nooijer, Lennart Jan; Nagai, Yukiko; Kawada, Sachiko; Fujita, Kazuhiko; Reichart, Gert-Jan; Nomaki, Hidetaka; Tsuchiya, Masashi; Sakaguchi, Hide; Kitazato, Hiroshi

    2017-01-01

    Ongoing ocean acidification is widely reported to reduce the ability of calcifying marine organisms to produce their shells and skeletons. Whereas increased dissolution due to acidification is a largely inorganic process, strong organismal control over biomineralization influences calcification and hence complicates predicting the response of marine calcifyers. Here we show that calcification is driven by rapid transformation of bicarbonate into carbonate inside the cytoplasm, achieved by active outward proton pumping. Moreover, this proton flux is maintained over a wide range of pCO2 levels. We furthermore show that a V-type H+ ATPase is responsible for the proton flux and thereby calcification. External transformation of bicarbonate into CO2 due to the proton pumping implies that biomineralization does not rely on availability of carbonate ions, but total dissolved CO2 may not reduce calcification, thereby potentially maintaining the current global marine carbonate production. PMID:28128216

  13. 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.

  14. Vacuolar proton pumps in malaria parasite cells.

    PubMed

    Moriyama, Yoshinori; Hayashi, Mitsuko; Yatsushiro, Shouki; Yamamoto, Akitsugu

    2003-08-01

    The malaria parasite is a unicellular protozoan parasite of the genus Plasmodium that causes one of the most serious infectious diseases for human beings. Like other protozoa, the malaria parasite possesses acidic organelles, which may play an essential role(s) in energy acquisition, resistance to antimalarial agents, and vesicular trafficking. Recent evidence has indicated that two types of vacuolar proton pumps, vacuolar H+-ATPase and vacuolar H+-pyrophosphatase, are responsible for their acidification. In this mini-review, we discuss the recent progress on vacuolar proton pumps in the malaria parasite.

  15. (Mechanism of proton pumping by bacteriorhodopsin)

    SciTech Connect

    Ebrey, T.G.

    1987-01-01

    Two methods were used to test the hypothesis that proteolysis of the C-terminal tail of bacteriorhodopsin affects the quantum efficiency of proton pumping. An apparent good correlation was found between the amount of the slowly decaying forms of the M intermediate and the number of protons pumped. This also suggests that the photocycle may contain M (fast) and M (slow) in different branches. Using artificial analogues of bacteriorhodopsin, the ring portion of the retinal was shown not to be an important factor in determining the photochemical and proton pumping properties of the artificial pigments, but that modification of the chain is. At least four double bonds along the chain are necessary for efficient proton pumping. The purple membrane normally contains several different cations tightly bound and it was shown that removal of these cations changes the color of the membrane from purple to blue. We proposed that cations acted by modulation of the surface potential and hence the local proton concentration near the membrane. A new intermediate was found in the bacteriorhodopsin photocycle, R. This new intermediate can explain several quite perplexing observations that have been made about the photocycle. The conformation of the retinal of the third rhodopsin-like pigment in Halobacteria, sensory rhodopsin, is all-trans and that light isomerizes the chromophore to the 13-cis conformation. 26 refs.

  16. [Safety of the proton pump inhibitors].

    PubMed

    Oscanoa Espinoza, Teodoro Julio

    2011-01-01

    Proton Pump Inhibitors (PPI) are consumed by millions of people around the world, either by prescription or self-medication, some medications of this group are Over-the-counter (OTC) medicines. PPIs have been associated with hypergastrinemia, rebound acid hypersecretion, malabsorption, osteoporosis and infections. This is an updated review of clinical pharmacology aspects of IPBS, with emphasis on safety aspects.

  17. [Prescription for proton pump inhibitors in geriatrics].

    PubMed

    Schonheit, Claire; Le Petitcorps, Hélène; Pautas, Éric

    2015-01-01

    Proton pump inhibitors are widely prescribed, notably for the over 65s, despite there being significant side effects in the geriatric population. It is therefore important that doctors, caregivers and patients are fully aware of the recognised indications of PPIs and on the less well-known problems inherent to their prescription. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  18. Proton pump of clathrin-coated vesicles

    SciTech Connect

    Xie, X.

    1985-01-01

    Clathrin-coated vesicles were prepared from bovine brain catalyze ATP-driven proton translocation and a /sup 32/Pi-ATP exchange reaction. N-ethylmaleimide (NEM) at 1 mM and dicyclohexylcarbodiimide (DCCD) at 0.5 mM inhibit the pump completely, whereas neither vanadate, efrapeptin, NaN/sub 3/, nor mitochondrial ATPase inhibitor has an effect. The coated vesicle proton pump is characterized by ATP specificity. dATP, but no other nucleotide, can replace ATP as a substrate. The pump is electrogenic and the electrogenicity is neutralized by chloride or bromide serving as co-ions. ATP-driven proton translocation can be observed in the absence of chloride, provided that the membrane potential is collapsed by K/sup +/ moving out in the presence of valinomycin. Chloride transport can be observed independent of proton movements in the absence of ATP, provided that an inside positive membrane potential is generated by K/sup +/ influx in the presence of valinomycin. The proton-translocating ATPase of coated vesicles was solubilized with a nonionic detergent polyoxyethylene 9 lauryl ether, and purified about 700 fold to near homogeneity. During purification the enzymatic activity was lost. A purified brain phospholipid fraction restored the activity and was subsequently identified as phosphatidylserine.

  19. Water Pathways in the Bacteriorhodopsin Proton Pump

    SciTech Connect

    Bondar, A.N.; Fischer, S.; Smith, Jeremy C

    2010-01-01

    Internal water molecules play key roles in the functioning of the light-driven bacteriorhodopsin proton pump. Of particular importance is whether during the proton-pumping cycle the critical water molecule w402 can relocate from the extracellular to the cytoplasmic side of the retinal Schiff base. Here, classical mechanical and combined quantum mechanical/molecular mechanical reaction path computations are performed to investigate pathways and energetic factors influencing w402 relocation. Hydrogen bonding between w402 and the negatively charged Asp85 and Asp212 largely opposes repositioning of the water molecule. In contrast, favorable contributions from hydrogen bonding of w402 with the Schiff base and Thr89 and from the untwisting of the retinal polyene chain lower the energetic cost for water relocation. The delicate balance between the competing contributions underlies the need for highly accurate calculations and structural information.

  20. Water pathways in the bacteriorhodopsin proton pump.

    PubMed

    Bondar, Ana-Nicoleta; Fischer, Stefan; Smith, Jeremy C

    2011-01-01

    Internal water molecules play key roles in the functioning of the light-driven bacteriorhodopsin proton pump. Of particular importance is whether during the proton-pumping cycle the critical water molecule w402 can relocate from the extracellular to the cytoplasmic side of the retinal Schiff base. Here, classical mechanical and combined quantum mechanical/molecular mechanical reaction path computations are performed to investigate pathways and energetic factors influencing w402 relocation. Hydrogen bonding between w402 and the negatively charged Asp85 and Asp212 largely opposes repositioning of the water molecule. In contrast, favorable contributions from hydrogen bonding of w402 with the Schiff base and Thr89 and from the untwisting of the retinal polyene chain lower the energetic cost for water relocation. The delicate balance between the competing contributions underlies the need for highly accurate calculations and structural information.

  1. Proton pump inhibitors: predisposers to Alzheimer disease?

    PubMed

    Fallahzadeh, M K; Borhani Haghighi, A; Namazi, M R

    2010-04-01

    The abnormal processing of amyloid-beta peptide (A beta) and resultant formation of fibrillar A beta (fA beta) are major events in the pathogenesis of Alzheimer disease (AD). Microglia as the phagocytic cells of the brain can engulf and digest fA beta within their acidic lysosomes. The lysosomes of AD patients are less acidic and therefore less capable of clearance of fA beta. Vacuolar proton pumps (V-ATPases) which are found abundantly in microglia and macrophages, acidify lysosomes by pumping protons into these structures. Proton pump inhibitors (PPIs) can inhibit V-ATPases of the lysosomes. These drugs are shown to penetrate the blood-brain barrier in animals. PPIs are consumed for long periods in conditions such as gastroesophageal reflux disease, with the resultant exposure of the human brain to the substantial amounts of PPIs. We hypothesize that by blocking the V-ATPases on microglial lysosomes, PPIs may basify lysosomes and hamper degradation of fA beta. Chronic consumption of PPIs may thus be a risk factor for AD.

  2. The Value of Branded Proton Pump Inhibitors

    PubMed Central

    Peura, David A.; Berardi, Rosemary R.; Gonzalez, Javier; Brunetti, Louis

    2011-01-01

    The prevalence of gastroesophageal reflux disease (GERD) continues to rise, placing an increasing burden on our health care system. Proton pump inhibitors (PPIs) are the most effective and widely used therapy for GERD. Many PPIs are now available in generic and over-the-counter forms, and managed care formularies often choose these as their preferred drug for GERD treatment. However, newer-generation branded PPIs, as a result of differences in their pharmacokinetic and pharmacodynamic profiles, may offer clinical advantages over generic PPIs. This article discusses these differences and the advantages they offer and suggests possible ways to incorporate the newer PPIs into formularies. PMID:21931475

  3. Hypomagnesemia associated with a proton pump inhibitor.

    PubMed

    Matsuyama, Jun; Tsuji, Kunihiro; Doyama, Hisashi; Kim, Fae; Takeda, Yasuhito; Kito, Yosuke; Ito, Renma; Nakanishi, Hiroyoshi; Hayashi, Tomoyuki; Waseda, Yohei; Tsuji, Shigetsugu; Takemura, Kenichi; Yamada, Shinya; Okada, Toshihide; Kanaya, Honin

    2012-01-01

    Severe hypomagnesemia is a serious clinical condition. Proton pump inhibitor (PPI) induced hypomagnesemia has been recognized since 2006. In March 2011 the U.S. Food and Drug Administration advised that long-term use of PPI can induce hypomagnesemia. We report the first Japanese case of hypomagnesemia associated with chronic use of PPIs in a 64-year-old man hospitalized for nausea, bilateral ankle arthritis, and tremor of the extremities who had convulsions 3 days after admission. Blood analysis showed severe hypomagnesemia. He had been taking rabeprazole (10 mg/day) for 5 years. After stopping rabeprazole and correcting the electrolytes imbalances, his symptoms improved without recurrence.

  4. Mechanism of a proton pump analyzed with computer simulations

    SciTech Connect

    Bondar, A.N.; Smith, Jeremy C; Elstner, Marcus

    2009-04-01

    Understanding the mechanism of proton pumping requires a detailed description of the energetics and sequence of events associated with the proton transfers, and of how proton transfer couples to conformational rearrangements of the protein. Here, we discuss our recent advances in using computer simulations to understand how bacteriorhodopsin pumps protons. We emphasize the importance of accurately describing the retinal geometry and the location of water molecules

  5. Proton transport by halorhodopsin

    SciTech Connect

    Varo, G.; Brown, L.S.; Needleman, R.

    1996-05-28

    In halorhodopsin from Natronobacterium pharaonis, a light-driven chloride pump, the chloride binding site also binds azide. When azide is bound at this location the retinal Schiff base transiently deprotonates after photoexcitation with light >530 nm, like in the light-driven proton pump bacteriorhodopsin. As in the photocycle of bacteriorhodopsin, pyranine detects the release of protons to the bulk. The subsequent reprotonation of the Schiff base is also dependent on azide, but with different kinetics that suggest a shuttling of protons from the surface as described earlier for halorhodopsin from Halobacterium salinarium. The azide-dependent, bacteriorhodopsin-like photocycle results in active electrogenic proton transport in the cytoplasmic to extracellular direction, detected in cell envelope vesicle suspensions both with a potential-sensitive electrode and by measuring light-dependent pH change. We conclude that in halorhodopsin an azide bound to the extracellular side of the Schiff base, and another azide shuttling between the Schiff base and the cytoplasmic surface, fulfill the functions of Asp-85 and Asp-96, respectively, in bacteriorhodopsin. Thus, although halorhodopsin is normally a chloride ion pump, it evidently contains all structural requirements, except an internal proton acceptor and a donor, of a proton pump. This observation complements our earlier finding that when a chloride binding site was created in bacteriorhodopsin through replacement of Asp-85 with a threonine, that protein became a chloride ion pump. 52 refs., 9 figs.

  6. Adverse Risks Associated With Proton Pump Inhibitors

    PubMed Central

    2009-01-01

    Proton pump inhibitors (PPIs) are among the most commonly utilized agents for treatment of symptomatic disorders of the upper gastrointestinal tract, accounting for a significant proportion of sales of both over-the-counter and prescription formulations. A systematic review of the literature was conducted via MEDLINE to evaluate the most rigorous studies linking the potential risk of PPI therapy with adverse events. Emerging data illustrate the potential risks associated with both short-and long-term PPI therapy, including Clostridium difficile–associated diarrhea, community-acquired pneumonia, osteoporotic fracture, vitamin B12 deficiency, and inhibition of antiplatelet therapy. Due to these associations, it is recommended that clinicians assess the continuing need for PPI therapy and use the lowest possible dose to achieve the desired therapeutic goals.

  7. Active membrane fluctuations with proton pumps

    NASA Astrophysics Data System (ADS)

    Szmelter, Adam; Chen, Kejia; Granick, Steve

    2014-03-01

    We investigate nonequilibrium membrane fluctuations in giant unilamellar vesicles (GUVs) by reconstituting the light-activated proton pump, bacteriorhodopsin (BR). Once activated, BR is known to form oligomers in model membranes, with an unknown effect on fluctuation amplitude. By using the UV-crosslinkable lipid, 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine, we localize BR and prevent light-induced oligomerization. This system allows us to selectively switch on and off active fluctuations and to turn off diffusion (oligomerization) using green and UV light, respectively. We compare active membrane fluctuations with trapped and freely diffusing BR using an interferometric technique with sub nanometer and microsecond resolution. Remarkable dependence is found on whether BR is localized or freely diffusing.

  8. 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

  9. Proton Pump Inhibitors and Risk of Rhabdomyolysis.

    PubMed

    Duncan, Scott J; Howden, Colin W

    2017-01-01

    Proton pump inhibitors (PPIs) have been associated with a variety of adverse events, although the level of evidence for many of these is weak at best. Recently, one national regulatory authority has mandated a change to the labeling of one PPI based on reports of possible associated rhabdomyolysis. Thus, in this review we summarize the available evidence linking PPI use with rhabdomyolysis. The level of evidence is insufficient to establish a causal relationship and is largely based on sporadic case reports. In general, patients with suspected PPI-associated rhabdomyolysis have not been re-challenged with a PPI after recovery. The mechanism whereby PPIs might have been associated with rhabdomyolysis is unclear but possibly related to interaction with concomitantly administered drugs such as HMG-CoA reductase inhibitors (statins). For patients with rhabdomyolysis, a careful search must be made for possible etiological factors. In patients who recover from an episode of possible PPI-related rhabdomyolysis but do not have a genuine requirement for PPI treatment, the PPI should not be re-introduced. For those with a definite indication for ongoing PPI treatment, the PPI can be re-introduced but should preferably not be administered with a statin.

  10. Recent safety concerns with proton pump inhibitors.

    PubMed

    Chen, Joan; Yuan, Yuhong Cathy; Leontiadis, Grigorios I; Howden, Colin W

    2012-02-01

    There have been recent concerns about the safety of proton pump inhibitors (PPIs). We focus here on 3 specific concerns-the possible interaction between PPIs and clopidogrel, the postulated link between PPI use and fractures, and the possibility that long-term PPI use might lead to hypomagnesemia. There is evidence for an in vitro interaction between clopidogrel and at least some PPIs. The Food and Drug Administration (FDA) has warned against the use of certain PPIs by patients on clopidogrel. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole. PPI use may be a weak risk factor for certain fractures, but the quality of evidence is relatively poor and there is a strong possibility of confounding. The mechanism whereby PPI use might increase fracture risk is unknown. Currently, no additional measures concerning calcium supplementation or bone mineral density monitoring are recommended for patients on a PPI. The FDA has suggested monitoring serum magnesium levels in patients on PPI therapy. The mechanism and frequency of PPI-induced hypomagnesemia are unclear. PPI treatment should not be withheld from patients who genuinely require it, but the PPI should be taken in the lowest effective dose and only for as long as clinically indicated. The same is, of course, true for all medicines. The benefits of PPI therapy greatly outweigh the risks.

  11. 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

  12. 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

  13. Water Molecules in Short- and Long-Distance Proton Transfer Steps of Bacteriorhodopsin Proton Pumping

    SciTech Connect

    SMITH, JEREMY C.

    2009-07-01

    The proton pumping cycle of bacteriorhodopsin consists of five consecutive proton transfer steps in which water molecules are likely to play critical roles. The role of water molecules in bacteriorhodopsin function is reviewed, with emphasis on computations of the retinal Schiff base deprotonation reaction and the open questions regarding the participation of water molecules in the longer-distance proton transfer reactions.

  14. Proton pump inhibitors for functional dyspepsia.

    PubMed

    Pinto-Sanchez, Maria Ines; Yuan, Yuhong; Bercik, Premysl; Moayyedi, Paul

    2017-03-08

    Functional dyspepsia (FD or non-ulcer dyspepsia) is defined as continuous or frequently recurring epigastric pain or discomfort for which no organic cause can be found. Acid suppressive therapy, including proton pump inhibitors (PPIs), has been proposed as a therapeutic option in FD, but its efficacy remains controversial. While PPIs are generally considered safe and well tolerated, they have been associated with adverse events, especially in the long term. For this reason, decisions on whether to initiate or continue PPI therapy should be made based on an appropriate clinical indication. Therefore, we conducted a systematic review to evaluate whether PPI therapy provides symptomatic relief in FD. To determine the efficacy of proton pump inhibitors in the improvement of global symptoms of dyspepsia and quality of life compared to placebo, H2 receptor antagonists or prokinetics, in people with functional dyspepsia. We searched in the following electronic databases: the Cochrane Library (to January 2016), MEDLINE (OvidSP; to February 2016), Embase (OvidSP; to February 2016), and SIGLE grey literature (up to February 2016) and clinical trial registries; we handsearched abstracts from conferences up to February 2016. We screened non-systematic reviews, systematic reviews and guidelines to identify any additional trials. We contacted trialists to obtain missing information. All randomized controlled trials (RCTs) comparing any PPI with placebo, H2 receptor antagonists (H2RAs) or prokinetics for the treatment of FD. Participants were adults (aged 16 years or greater) with an adequate diagnosis of FD (any validated criteria such as Rome I, II, III or Lancet Working Group). Two review authors independently assessed eligibility, trial quality and extracted data. We collected data on dyspeptic symptoms, quality of life and number of overall adverse events. Specific adverse events were beyond the scope of this review. We identified 23 RCTs from 22 papers (with 8759

  15. Do proton pump inhibitors decrease calcium absorption?

    PubMed

    Hansen, Karen E; Jones, Andrea N; Lindstrom, Mary J; Davis, Lisa A; Ziegler, Toni E; Penniston, Kristina L; Alvig, Amy L; Shafer, Martin M

    2010-12-01

    Proton pump inhibitors (PPIs) increase osteoporotic fracture risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption (FCA). Existing studies provide conflicting information regarding the direct effects of PPIs on FCA. We evaluated the effect of PPI therapy on FCA. We recruited women at least 5 years past menopause who were not taking acid suppressants. Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method. Two FCA studies were performed 1 month apart to establish baseline calcium absorption. The third study occurred after taking omeprazole (40 mg/day) for 30 days. Each participant consumed the same foods during all FCA studies; study meals replicated subjects' dietary habits based on 7-day diet diaries. Twenty-one postmenopausal women ages 58 ± 7 years (mean ± SD) completed all study visits. Seventeen women were white, and 2 each were black and Hispanic. FCA (mean ± SD) was 20% ± 10% at visit 1, 18% ± 10% at visit 2, and 23% ± 10% following 30 ± 3 days of daily omeprazole (p = .07, ANOVA). Multiple linear regression revealed that age, gastric pH, serum omeprazole levels, adherence to omeprazole, and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3. The 1,25-dihydroxyvitamin D(3) level at visit 2 was the only variable (p = .049) associated with the change in FCA between visits 2 and 3. PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use. Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture.

  16. Proton pump inhibitors: impact on glucose metabolism.

    PubMed

    Boj-Carceller, Diana

    2013-02-01

    Diabetes mellitus is a complex chronic disease associated with an absolute insulin deficiency in type 1 diabetes (T1D) and a progressive deterioration of β-cell function in type 2 diabetes (T2D). T2D pathophysiology has numerous defects including incretin deficiency/resistance. Gastrin has demonstrated to be an islet growth factor (like glucagon-like peptide-1, epidermal growth factor, transforming growth factor-α,…) and be able to restore a functional β-cell mass in diabetic animals. This hormone is likely to stimulate insulin secretion during an ordinary protein-rich meal, this is, to have an incretin-like effect. Proton pump inhibitors (PPIs) can raise serum gastrin concentration significantly and therefore, affect to glucose metabolism through promoting β-cell regeneration/expansion and also enhancing insulin secretion. The present paper aims to review studies concerning the effect of PPIs on glucose metabolism. Several research groups have recently explored the potential role of this class of drugs on glycemic control, mainly in T2D. The results show antidiabetic properties for the PPIs with a global glucose-lowering power around 0.6-0.7 % points of HbA1c, but the level of evidence for the available literature is still not high. If these data start to become demonstrated in the ongoing clinical trials, PPIs could become a new antidiabetic agent with a good and safe profile for T2D and even useful for T1D, particularly in the area of islet transplantation to preserve β-cell mass.

  17. 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

  18. Biological Proton Pumping in an Oscillating Electric Field

    NASA Astrophysics Data System (ADS)

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

    2009-12-01

    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.

  19. Blockage of intracellular proton extrusion with proton extrusions with proton pump inhibitor induces apoptosis in gastric cancer.

    PubMed

    Yeo, Marie; Kim, Dong-Kyu; Park, Hee Jin; Cho, Sung Won; Cheong, Jae Youn; Lee, Kwang Jae

    2008-01-01

    Proton pump inhibitors have been used for treatment of acid-related gastroesophageal diseases and they act as potent inhibitors of gastric acid pump, H(+)/K(+)-ATPase. Since cancer cells in vivo often exist in an ischemic microenvironment with a lower pH, maintenance of cellular pH is important for cell survival. In this study, we evaluated whether blocking of proton extrusion with proton pump inhibitors could inhibit the viability of gastric cancer cells. Treatment of human gastric cancer cells with proton pump inhibitors significantly attenuated cell viability in a time- and dose-dependent manner. The pro-apoptotic activity of proton pump inhibitors was mediated by release of cytochrome c and caspases activation. Gastric cancer cells showed the resistance to acidity of culture medium, which was related with a remarkable increase of extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the acidic condition. This ERK1/2 phosphorylation was completely inhibited by pretreatment with proton pump inhibitors, suggesting that its inhibitory action on phosphorylation of ERK1/2 might contribute to the induction of apoptosis in gastric cancer cells. In conclusion, our results suggest novel therapeutic approaches for gastric cancer with proton pump inhibitors.

  20. Exploring the proton pump and exit pathway for pumped protons in cytochrome ba3 from Thermus thermophilus.

    PubMed

    Chang, Hsin-Yang; Choi, Sylvia K; Vakkasoglu, Ahmet Selim; Chen, Ying; Hemp, James; Fee, James A; Gennis, Robert B

    2012-04-03

    The heme-copper oxygen reductases are redox-driven proton pumps. In the current work, the effects of mutations in a proposed exit pathway for pumped protons are examined in the ba(3)-type oxygen reductase from Thermus thermophilus, leading from the propionates of heme a(3) to the interface between subunits I and II. Recent studies have proposed important roles for His376 and Asp372, both of which are hydrogen-bonded to propionate-A of heme a(3), and for Glu126(II) (subunit II), which is hydrogen-bonded to His376. Based on the current results, His376, Glu126(II), and Asp372 are not essential for either oxidase activity or proton pumping. In addition, Tyr133, which is hydrogen-bonded to propionate-D of heme a(3), was also shown not to be essential for function. However, two mutations of the residues hydrogen-bonded to propionate-A, Asp372Ile and His376Asn, retain high electron transfer activity and normal spectral features but, in different preparations, either do not pump protons or exhibit substantially diminished proton pumping. It is concluded that either propionate-A of heme a(3) or possibly the cluster of groups centered about the conserved water molecule that hydrogen-bonds to both propionates-A and -D of heme a(3) is a good candidate to be the proton loading site.

  1. Exploring the proton pump and exit pathway for pumped protons in cytochrome ba3 from Thermus thermophilus

    PubMed Central

    Chang, Hsin-Yang; Choi, Sylvia K.; Vakkasoglu, Ahmet Selim; Chen, Ying; Hemp, James; Fee, James A.; Gennis, Robert B.

    2012-01-01

    The heme-copper oxygen reductases are redox-driven proton pumps. In the current work, the effects of mutations in a proposed exit pathway for pumped protons are examined in the ba3-type oxygen reductase from Thermus thermophilus, leading from the propionates of heme a3 to the interface between subunits I and II. Recent studies have proposed important roles for His376 and Asp372, both of which are hydrogen-bonded to propionate-A of heme a3, and for Glu126II (subunit II), which is hydrogen-bonded to His376. Based on the current results, His376, Glu126II, and Asp372 are not essential for either oxidase activity or proton pumping. In addition, Tyr133, which is hydrogen-bonded to propionate-D of heme a3, was also shown not to be essential for function. However, two mutations of the residues hydrogen-bonded to propionate-A, Asp372Ile and His376Asn, retain high electron transfer activity and normal spectral features but, in different preparations, either do not pump protons or exhibit substantially diminished proton pumping. It is concluded that either propionate-A of heme a3 or possibly the cluster of groups centered about the conserved water molecule that hydrogen-bonds to both propionates-A and -D of heme a3 is a good candidate to be the proton loading site. PMID:22431640

  2. 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.

  3. 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.

  4. Proton pump inhibitor responsive esophageal eosinophilia, a distinct disease entity?

    PubMed

    Munday, William; Zhang, Xuchen

    2014-08-14

    Recent studies have suggested the existence of a patient population with esophageal eosinophilia that responds to proton pump inhibitor therapy. These patients are being referred to as having proton pump inhibitor responsive esophageal eosinophilia (PPI-REE), which is currently classified as a distinct and separate disease entity from both gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). The therapeutic effect of proton pump inhibitor (PPI) on PPI-REE is thought to act directly at the level of the esophageal mucosa with an anti-inflammatory capacity, and completely independent of gastric acid suppression. The purpose of this manuscript is to review the mechanistic data of the proposed immune modulation/anti-inflammatory role of the PPI at the esophageal mucosa, and the existence of PPI-REE as a distinct disease entity from GERD and EoE.

  5. A natural light-driven inward proton pump

    PubMed Central

    Inoue, Keiichi; Ito, Shota; Kato, Yoshitaka; Nomura, Yurika; Shibata, Mikihiro; Uchihashi, Takayuki; Tsunoda, Satoshi P.; Kandori, Hideki

    2016-01-01

    Light-driven outward H+ pumps are widely distributed in nature, converting sunlight energy into proton motive force. Here we report the characterization of an oppositely directed H+ pump with a similar architecture to outward pumps. A deep-ocean marine bacterium, Parvularcula oceani, contains three rhodopsins, one of which functions as a light-driven inward H+ pump when expressed in Escherichia coli and mouse neural cells. Detailed mechanistic analyses of the purified proteins reveal that small differences in the interactions established at the active centre determine the direction of primary H+ transfer. Outward H+ pumps establish strong electrostatic interactions between the primary H+ donor and the extracellular acceptor. In the inward H+ pump these electrostatic interactions are weaker, inducing a more relaxed chromophore structure that leads to the long-distance transfer of H+ to the cytoplasmic side. These results demonstrate an elaborate molecular design to control the direction of H+ transfers in proteins. PMID:27853152

  6. Stereoselective disposition of proton pump inhibitors.

    PubMed

    Andersson, Tommy; Weidolf, Lars

    2008-01-01

    It is estimated that about half of all therapeutic agents are chiral, but most of these drugs are administered in the form of the racemic mixture, i.e. a 50/50 mixture of its enantiomers. However, chirality is one of the main features of biology, and many of the processes essential for life are stereoselective, implying that two enantiomers may work differently from each other in a physiological environment. Thus, receptors or metabolizing enzymes would recognize one of the ligand enantiomers in favour of the other. With one exception, all presently marketed proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole and rabeprazole--used for the treatment of gastric acid-related diseases are racemic mixtures. The exception is esomeprazole, the S-enantiomer of omeprazole, which is the only PPI developed as a single enantiomer drug. The development of esomeprazole (an alkaline salt thereof, e.g. magnesium or sodium) was based on unique metabolic properties that clearly differentiated esomeprazole from omeprazole, the racemate. At comparable doses, these properties led to several clinical advantages, for example higher bioavailability in the majority of patients, i.e. the extensive metabolizers (EMs; 97% in Caucasian and 80-85% in Asian populations), lower exposure in poor metabolizers (PMs; 3% in Caucasian and 15-20% in Asian populations) and lower interindividual variation. For the other, i.e. racemic, PPIs there are some data available on the characteristics of the individual enantiomers, and we have therefore undertaken to analyse the current literature with the purpose of evaluating the potential benefits of developing single enantiomer drugs from lansoprazole, pantoprazole and rabeprazole. For lansoprazole, the plasma concentrations of the S-enantiomer are lower than those of the R-enantiomer in both EMs and PMs, and, consequently, the variability in the population or between EMs and PMs is not likely to decrease with either of the lansoprazole

  7. 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

  8. [Pharmacogenic osteoporosis beyond cortisone. Proton pump inhibitors, glitazones and diuretics].

    PubMed

    Kann, P H; Hadji, P; Bergmann, R S

    2014-05-01

    [corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

  9. Proton pump (H+/K+-ATPase) expression in human larynx.

    PubMed

    Stevanović, Siniša; Radić, Radivoje; Kačarević, Željka Perić; Bedeković, Vladimir; Aras, Ivana; Baudoin, Tomislav; Šoš, Dario; Vrselja, Zvonimir; Ivkić, Mirko

    2015-12-01

    The goal of our study was to investigate and to identify the existence of proton pump in different parts of larynx. The presence of acidic content in this area is known to be connected to several laryngeal diseases. It is mostly developed by upward recurrence of acidic gastric content, but there are some signs that the acid can be produced in the larynx as well, because of the proton pump activity in laryngeal mucosa. The study was performed on two types of specimens: (1) 50 cadaver larynges and (2) 11 surgical larynges obtained after laryngectomy. Samples were taken from supraglottis, glottis and subglottic areas and immunohistochemistry for the beta subunit of the proton pump was done. The presence of proton pump was proved in seromucous glands in laryngeal supraglottic area, but it was also, for the first time, found in human chondrocytes in the thyroid and epiglottic cartilage. These new findings could encourage further research that would illuminate better the etiopathogenesis not only of laryngopharyngeal reflux, but also the pathophysiology of cartilaginous disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Potential of light-harvesting proton pumps for bioenergy applications.

    PubMed

    Walter, Jessica M; Greenfield, Derek; Liphardt, Jan

    2010-06-01

    Concerns about the security and longevity of traditional energy sources have increased interest in alternative methods of energy production, particularly those which utilize abundantly available solar energy. Solar energy can be harvested either indirectly through the conversion of plant or algal byproducts into biofuels or directly using engineered microorganisms. Here we summarize the main features of light-harvesting proton pumps, which may provide a relatively simple way to boost the efficiency of energy-limited biological processes in fuel production. This family of proton pumps, which includes bacteriorhodopsin and proteorhodopsin, directly uses light energy to create a proton motive force (pmf) which can be used by other enzymes to facilitate active transport, regulate transmembrane proteins, or to generate ATP and NADH.

  11. 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.

  12. (Mechanism of proton pumping by bacteriorhodopsin). Progress report

    SciTech Connect

    Not Available

    1984-01-01

    Several discoveries that we believe will impact on the study of light energy transduction by bacteriorhodopsin are described. First we reported that removal of the C-terminal tail of bacteriorhodopsin caused a large decrease in the number of protons released by light. Second, we showed that proteolysis of bacteriorhodopsin cell envelope vesicles led to a similar affect on the protons pumped by light. Third, we have begun studies and reported preliminary results on using fluorescent dyes coupled to carboxyl groups on the C-terminal tail to study the conformation of the tail as a function of environmental conditions. Fourth, we have also made a correlation between a particular photocycle intermediate, the slowly decaying form of M, and proton pumping by light absorbed by M/sup slow/, a similar pH dependence, and a similar temperature dependence. Fifth, we have shown that bacteriorhosopsin binds calcium and magnesium very tightly. Removal of these divalent cations had a very large effect on the color, photochemistry, and proton pumping by bacteriorhodopsin. Finally, we have made monoclonal determinants of bacteriorhodopsin and are using these antibodies in several different ways to study bacteriorhodopsin. 8 refs.

  13. Proton pumping in cytochrome c oxidase: energetic requirements and the role of two proton channels.

    PubMed

    Blomberg, Margareta R A; Siegbahn, Per E M

    2014-07-01

    Cytochrome c oxidase is a superfamily of membrane bound enzymes catalyzing the exergonic reduction of molecular oxygen to water, producing an electrochemical gradient across the membrane. The gradient is formed both by the electrogenic chemistry, taking electrons and protons from opposite sides of the membrane, and by proton pumping across the entire membrane. In the most efficient subfamily, the A-family of oxidases, one proton is pumped in each reduction step, which is surprising considering the fact that two of the reduction steps most likely are only weakly exergonic. Based on a combination of quantum chemical calculations and experimental information, it is here shown that from both a thermodynamic and a kinetic point of view, it should be possible to pump one proton per electron also with such an uneven distribution of the free energy release over the reduction steps, at least up to half the maximum gradient. A previously suggested pumping mechanism is developed further to suggest a reason for the use of two proton transfer channels in the A-family. Since the rate of proton transfer to the binuclear center through the D-channel is redox dependent, it might become too slow for the steps with low exergonicity. Therefore, a second channel, the K-channel, where the rate is redox-independent is needed. A redox-dependent leakage possibility is also suggested, which might be important for efficient energy conservation at a high gradient. A mechanism for the variation in proton pumping stoichiometry over the different subfamilies of cytochrome oxidase is also suggested. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

  14. Proton pump inhibitors: the good, the bad, and the unwanted.

    PubMed

    Chubineh, Saman; Birk, John

    2012-11-01

    Proton pump inhibitors (PPIs) are one of the most commonly prescribed classes of medications in the United States. By inhibiting gastric H/K adenosine triphosphatase via covalent binding to the cysteine residues of the proton pump, they provide the most potent acid suppression available. Long-term PPI use accounts for the majority of total PPI use. Absolute indications include peptic ulcer disease, chronic nonsteroidal anti-inflammatory drugs use, treatment of Helicobacter pylori, and erosive esophagitis. Although PPIs are generally considered safe, numerous adverse effects, particularly associated with long-term use have been reported. Many patients receiving chronic PPI therapy do not have clear indications for their use, prompting consideration for reduction or discontinuation of their use. This article reviews the indications for PPI use, the adverse effects/risks involved with their use, and conditions in which their use is controversial.

  15. Hypersensitivity to proton pump inhibitors: lansoprazole-induced Kounis syndrome.

    PubMed

    Vlahos, Nicholas P; Vavilis, George K; Giannelou, Ageliki G; Georgopoulou, Christina N; Kommata, Varvara J; Kougias, Constantinos T; Tsartsalis, Dimitrios N; Kounis, George N; Mazarakis, Andreas; Batsolaki, Maria; Gouvelou-Deligianni, Geogia V; Hahalis, George; Kounis, Nicholas G

    2009-05-29

    Proton pump inhibitors are commonly used in clinical practice for the treatment of peptic ulcer and gastroesophageal reflux and are well tolerated by the patients. Their use is rarely associated with hypersensitivity and anaphylactic reactions. According to the reports in the Uppsala Monitoring Center database the frequency of hypersensitivity reactions out of all reported adverse reactions for proton pump inhibitors and H2-histamine receptor antagonists was between 0.2% and 0.7%. A few cases of hypersensitivity to lansoprazole have been reported. We report a patient who developed Kounis syndrome after taking 30 mg of lansoprazole. This is the first report of Kounis syndrome associated with lansoprazole administration in the world literature.

  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. The mechanochemistry of V-ATPase proton pumps.

    PubMed Central

    Grabe, M; Wang, H; Oster, G

    2000-01-01

    The vacuolar H(+)-ATPases (V-ATPases) are a universal class of proton pumps that are structurally similar to the F-ATPases. Both protein families are characterized by a membrane-bound segment (V(o), F(o)) responsible for the translocation of protons, and a soluble portion, (V(1), F(1)), which supplies the energy for translocation by hydrolyzing ATP. Here we present a mechanochemical model for the functioning of the V(o) ion pump that is consistent with the known structural features and biochemistry. The model reproduces a variety of experimental measurements of performance and provides a unified view of the many mechanisms of intracellular pH regulation. PMID:10827963

  18. [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.

  19. How May Proton Pump Inhibitors Impair Cardiovascular Health?

    PubMed

    Sukhovershin, Roman A; Cooke, John P

    2016-06-01

    Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.

  20. Retinal-Based Proton Pumping in the Near Infrared

    PubMed Central

    2017-01-01

    Proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) are retinal-based light-driven proton pumps that absorb visible light (maxima at 520–540 nm). Shifting the action spectra of these proton pumps beyond 700 nm would generate new prospects in optogenetics, membrane sensor technology, and complementation of oxygenic phototrophy. We therefore investigated the effect of red-shifting analogues of retinal, combined with red-shifting mutations, on the spectral properties and pump activity of the resulting pigments. We investigated a variety of analogues, including many novel ones. One of the novel analogues we tested, 3-methylamino-16-nor-1,2,3,4-didehydroretinal (MMAR), produced exciting results. This analogue red-shifted all of the rhodopsin variants tested, accompanied by a strong broadening of the absorbance band, tailing out to 850–950 nm. In particular, MMAR showed a strong synergistic effect with the PR-D212N,F234S double mutant, inducing an astonishing 200 nm red shift in the absorbance maximum. To our knowledge, this is by far the largest red shift reported for any retinal protein. Very importantly, all MMAR-containing holoproteins are the first rhodopsins retaining significant pump activity under near-infrared illumination (730 nm light-emitting diode). Such MMAR-based rhodopsin variants present very promising opportunities for further synthetic biology modification and for a variety of biotechnological and biophysical applications. PMID:28094925

  1. Retinal-Based Proton Pumping in the Near Infrared.

    PubMed

    Ganapathy, Srividya; Venselaar, Hanka; Chen, Que; de Groot, Huub J M; Hellingwerf, Klaas J; de Grip, Willem J

    2017-02-15

    Proteorhodopsin (PR) and Gloeobacter rhodopsin (GR) are retinal-based light-driven proton pumps that absorb visible light (maxima at 520-540 nm). Shifting the action spectra of these proton pumps beyond 700 nm would generate new prospects in optogenetics, membrane sensor technology, and complementation of oxygenic phototrophy. We therefore investigated the effect of red-shifting analogues of retinal, combined with red-shifting mutations, on the spectral properties and pump activity of the resulting pigments. We investigated a variety of analogues, including many novel ones. One of the novel analogues we tested, 3-methylamino-16-nor-1,2,3,4-didehydroretinal (MMAR), produced exciting results. This analogue red-shifted all of the rhodopsin variants tested, accompanied by a strong broadening of the absorbance band, tailing out to 850-950 nm. In particular, MMAR showed a strong synergistic effect with the PR-D212N,F234S double mutant, inducing an astonishing 200 nm red shift in the absorbance maximum. To our knowledge, this is by far the largest red shift reported for any retinal protein. Very importantly, all MMAR-containing holoproteins are the first rhodopsins retaining significant pump activity under near-infrared illumination (730 nm light-emitting diode). Such MMAR-based rhodopsin variants present very promising opportunities for further synthetic biology modification and for a variety of biotechnological and biophysical applications.

  2. The proton pump of heme-copper oxidases.

    PubMed

    Papa, S; Capitanio, N; Glaser, P; Villani, G

    1994-05-01

    Proton pumping heme-copper oxidases represent the terminal, energy-transfer enzymes of respiratory chains in prokaryotes and eukaryotes. The CuB-heme a3 (or heme o) binuclear center, associated with the largest subunit I of cytochrome c and quinol oxidases, is directly involved in the coupling between dioxygen reduction and proton pumping. The role of the other subunits is less clear. The following aspects will be covered in this paper: i) the efficiency of coupling in the mitochondrial aa3 cytochrome c oxidase. In particular, the effect of respiratory rate and protonmotive force on the H+/e- stoichiometry and the role of subunit IV; ii) mutational analysis of the aa3 quinol oxidase of Bacillus subtilis addressed to the role of subunit III, subunit IV and specific residues in subunit I; iii) possible models of the protonmotive catalytic cycle at the binuclear center. The observations available suggest that H+/e- coupling is based on the combination of protonmotive redox catalysis at the binuclear center and co-operative proton transfer in the protein.

  3. A nanomechanical device based on light-driven proton pumps.

    PubMed

    Ren, Quan; Zhao, Ya-Pu; Han, Li; Zhao, Hui-Bin

    2006-03-28

    In this paper, a hybrid device based on a microcantilever interfaced with bacteriorhodopsin (bR) is constructed. The microcantilever, on which the highly oriented bR film is self-assembled, undergoes controllable and reversible bending when the light-driven proton pump protein, bR, on the microcantilever surface is activated by visible light. Several control experiments are carried out to preclude the influence of heat and photothermal effects. It is shown that the nanomechanical motion is induced by the resulting gradient of protons, which are transported from the KCl solution on the cytoplasmic side of the bR film towards the extracellular side of the bR film. Along with a simple physical interpretation, the microfabricated cantilever interfaced with the organized molecular film of bR can simulate the natural machinery in converting solar energy to mechanical energy.

  4. The value of branded proton pump inhibitors: formulary considerations.

    PubMed

    Peura, David A; Berardi, Rosemary R; Gonzalez, Javier; Brunetti, Louis

    2011-07-01

    The prevalence of gastroesophageal reflux disease (GERD) continues to rise, placing an increasing burden on our health care system. Proton pump inhibitors (PPIs) are the most effective and widely used therapy for GERD. Many PPIs are now available in generic and over-the-counter forms, and managed care formularies often choose these as their preferred drug for GERD treatment. However, newer-generation branded PPIs, as a result of differences in their pharmacokinetic and pharmacodynamic profiles, may offer clinical advantages over generic PPIs. This article discusses these differences and the advantages they offer and suggests possible ways to incorporate the newer PPIs into formularies.

  5. 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

  6. Proton pump inhibitor-induced hypomagnesemia: A new challenge

    PubMed Central

    Florentin, Matilda; Elisaf, Moses S

    2012-01-01

    Proton pump inhibitors (PPIs) are commonly used in clinical practice for the prevention and treatment of peptic ulcer, gastritis, esophagitis and gastroesophageal reflux. Hypomagnesemia has recently been recognized as a side effect of PPIs. Low magnesium levels may cause symptoms from several systems, some of which being potentially serious, such as tetany, seizures and arrhythmias. It seems that PPIs affect the gastrointestinal absorption of magnesium. Clinicians should be vigilant in order to timely consider and prevent or reverse hypomagnesemia in patients who take PPIs, especially if they are prone to this electrolyte disorder. PMID:24175253

  7. Carboxyl groups and the proton pump of bacteriorhodopsin

    SciTech Connect

    Herz, J.M.; Packer, L.

    1983-08-01

    Chemical modification and spin-labeled studies of purple membranes isolated from Halobacterium halobium have provided the first evidence for buried carboxyl residues within the hydrophobic, membrane-protein domains. Spin label data showed that modification of buried carboxyl residues resulted in loss of protein activity. A pH-sensitive, chromophoric reporter group demostrated that a carboxyl residue in a hydrophobic membrane environment interacts with the retinal chromophore of bacteriorhodopsin. These results appear consistent with the idea that carboxyl residues in hydrophobic environments may be a general feature required for activity of membrane proton pumps.

  8. Proton Pumping of the Yeast Plasma Membrane H+-ATPase

    DTIC Science & Technology

    1993-08-16

    function of the yeast plasma membrane H+- ATPase. This ATPase is a P-type cation transporter composed of a single protein of 100,000 Da molecular...August 16, 1993 ] Final 25 Sep 89 - 14 May 94 / 4. TITLE AND SUBTITLE S UDN UBR Proton Pumping of the Yeast Plasma Membrane HW-AT~ase G. AUTOR(S)DAALO3...Maximum 200 words) This proposal was to study the structure and function of the yeast plasma membrane H+-ATPase. We I proposed to study I )the

  9. Proton Pump Inhibitor-Induced Remission of Lymphocytic Esophagitis

    PubMed Central

    Sandhu, Naemat; Miick, Ronald; Govil, Yogesh

    2016-01-01

    Lymphocytic esophagitis is a chronic condition that has been described in the literature; however, there is little information describing its characteristics and treatment. We present a case of lymphocytic esophagitis that was identified following food impaction. Repeat esophagogastroduodenoscopy (EGD) with biopsy showed a marked decrease in lymphocytic infiltration after a 6-week course of twice-daily high-dose proton pump inhibitor (PPI). After initiation of the high-dose PPI regimen, the patient had no further episodes of dysphagia or food impaction. We propose that treating lymphocytic esophagitis with twice-daily PPI can improve symptoms and show histologic evidence of improvement. PMID:28119946

  10. Occupational Airborne Contact Dermatitis From Proton Pump Inhibitors.

    PubMed

    DeKoven, Joel G; Yu, Ashley M

    2015-01-01

    Few published reports have described occupational contact dermatitis from proton pump inhibitor (PPI) exposure in the literature. We present an additional case of a 58-year-old male pharmaceutical worker with an occupational airborne allergic contact dermatitis to PPIs confirmed by patch testing. This is a novel report of workplace exposure to dexlansoprazole and esomeprazole PPIs with resultant clinical contact allergy and relevant positive patch test results to these 2 agents. A literature review of all previously reported cases of occupational contact dermatitis to PPI is summarized. The case also emphasizes the importance of even minute exposures when considering workplace accommodation.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  12. Effects of proton pump inhibitors on pediatric inflammatory esophagogastric polyps.

    PubMed

    Choi, Kyong Eun; Kim, Mi Jin; Lee, Ji Hyuk; Lee, Jong Seung; Lee, Jee Hyun; Choe, Yon Ho

    2012-01-01

    The aim of this study was to investigate the effects of proton pump inhibitors on symptomatic inflammatory esophagogastric polyps (IEPs) in a pediatric cohort and to determine the optimal duration of treatment. The 11 patients with IEPs were managed with lansoprazole. Follow-up endoscopies were performed at 2 and 6 months after the start of medication. Medication was discontinued when the clinical symptoms completely resolved and the polyp size was reduced by more than 50% compared to the initial size. The initial polyp size was 13.7 ± 3.3 mm. After 2 months of medication, the polyp size was reduced to 8.0 ± 5.8 mm. At 6 months, the polyp size was 4.7 ± 2.2 mm. The mean duration of medication was 4.8 ± 2.1 months. The duration of medication and the change in the polyp size appeared to have a linear correlation (p < 0.001). According to the formula used to calculate polyp size, the optimal duration of treatment was more than 7 months for complete resolution of the polyps. Proton pump inhibitor was effective for the treatment of IEPs. About 5 months of lansoprazole was adequate to treat IEPs in children. The optimal duration for complete resolution of the polyp might be more than 7 months. Copyright © 2012 S. Karger AG, Basel.

  13. Proton pump inhibitor associated hypomagnasaemia ‐ a cause for concern?

    PubMed Central

    Begley, Joe; Smith, Trevor; Barnett, Kirsty; Strike, Paul; Azim, Adnan; Spake, Claire

    2016-01-01

    Aims In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. Methods To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross‐sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. Results For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross‐sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. Conclusion We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually. PMID:26613375

  14. Proton pump inhibitor associated hypomagnasaemia - a cause for concern?

    PubMed

    Begley, Joe; Smith, Trevor; Barnett, Kirsty; Strike, Paul; Azim, Adnan; Spake, Claire; Richardson, Tristan

    2016-04-01

    In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross-sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually. © 2015 The British Pharmacological Society.

  15. Proton Pump Inhibitors Display Antitumor Effects in Barrett's Adenocarcinoma Cells.

    PubMed

    Chueca, Eduardo; Apostolova, Nadezda; Esplugues, Juan V; García-González, María A; Lanas, Ángel; Piazuelo, Elena

    2016-01-01

    Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H(+)-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H(+)-VATPase was assessed through the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H(+)-VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H(+)-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated.

  16. Proton Pump Inhibitors Display Antitumor Effects in Barrett's Adenocarcinoma Cells

    PubMed Central

    Chueca, Eduardo; Apostolova, Nadezda; Esplugues, Juan V.; García-González, María A.; Lanas, Ángel; Piazuelo, Elena

    2016-01-01

    Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H+-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H+-VATPase was assessed through the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H+-VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H+-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated. PMID:27932981

  17. 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.

  18. 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

  19. 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.

  20. Mammalian complex I pumps 4 protons per 2 electrons at high and physiological proton motive force in living cells.

    PubMed

    Ripple, Maureen O; Kim, Namjoon; Springett, Roger

    2013-02-22

    Mitochondrial complex I couples electron transfer between matrix NADH and inner-membrane ubiquinone to the pumping of protons against a proton motive force. The accepted proton pumping stoichiometry was 4 protons per 2 electrons transferred (4H(+)/2e(-)) but it has been suggested that stoichiometry may be 3H(+)/2e(-) based on the identification of only 3 proton pumping units in the crystal structure and a revision of the previous experimental data. Measurement of proton pumping stoichiometry is challenging because, even in isolated mitochondria, it is difficult to measure the proton motive force while simultaneously measuring the redox potentials of the NADH/NAD(+) and ubiquinol/ubiquinone pools. Here we employ a new method to quantify the proton motive force in living cells from the redox poise of the bc(1) complex measured using multiwavelength cell spectroscopy and show that the correct stoichiometry for complex I is 4H(+)/2e(-) in mouse and human cells at high and physiological proton motive force.

  1. Mammalian Complex I Pumps 4 Protons per 2 Electrons at High and Physiological Proton Motive Force in Living Cells*

    PubMed Central

    Ripple, Maureen O.; Kim, Namjoon; Springett, Roger

    2013-01-01

    Mitochondrial complex I couples electron transfer between matrix NADH and inner-membrane ubiquinone to the pumping of protons against a proton motive force. The accepted proton pumping stoichiometry was 4 protons per 2 electrons transferred (4H+/2e−) but it has been suggested that stoichiometry may be 3H+/2e− based on the identification of only 3 proton pumping units in the crystal structure and a revision of the previous experimental data. Measurement of proton pumping stoichiometry is challenging because, even in isolated mitochondria, it is difficult to measure the proton motive force while simultaneously measuring the redox potentials of the NADH/NAD+ and ubiquinol/ubiquinone pools. Here we employ a new method to quantify the proton motive force in living cells from the redox poise of the bc1 complex measured using multiwavelength cell spectroscopy and show that the correct stoichiometry for complex I is 4H+/2e− in mouse and human cells at high and physiological proton motive force. PMID:23306206

  2. 25 Years of Proton Pump Inhibitors: A Comprehensive Review.

    PubMed

    Strand, Daniel S; Kim, Daejin; Peura, David A

    2017-01-15

    Proton pump inhibitors (PPIs) were clinically introduced more than 25 years ago and have since proven to be invaluable, safe, and effective agents for the management of a variety of acid-related disorders. Although all members in this class act in a similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflux disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Longer-acting PPIs and technology to prolong conventional PPI activity have been developed to specifically address these limitations and may improve clinical outcomes.

  3. [All proton pump inhibitors are equally efficacious in standard dosages].

    PubMed

    Hellström, Per M; Vitols, Sigurd

    2003-06-19

    Proton pump inhibitors (PPIs) are today used at different recommended doses for treatment of acid-related gastro-esophageal, gastric and gastro-duodenal diseases. We reviewed the literature regarding inhibition of acid secretion and healing rates for the different PPIs. Acid secretion in vitro and in vivo as well as healing and relapse rates were similar on a milligram basis for omeprazole, lansoprazole, rabeprazole, and pantoprazole. Rabeprazole had a somewhat faster onset of inhibition of acid secretion; the clinical value of this however seems limited. Esomeprazole had a somewhat stronger inhibitory effect on acid secretion in vivo compared with other PPIs. Studies demonstrating an important clinical advantage of esomeprazole compared to other PPIs are however lacking.

  4. 25 Years of Proton Pump Inhibitors: A Comprehensive Review

    PubMed Central

    Strand, Daniel S.; Kim, Daejin; Peura, David A.

    2017-01-01

    Proton pump inhibitors (PPIs) were clinically introduced more than 25 years ago and have since proven to be invaluable, safe, and effective agents for the management of a variety of acid-related disorders. Although all members in this class act in a similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflux disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Longer-acting PPIs and technology to prolong conventional PPI activity have been developed to specifically address these limitations and may improve clinical outcomes. PMID:27840364

  5. Do proton pump inhibitors protect against cancer progression in GERD?

    PubMed

    Miyashita, Tomoharu; Shah, Furhawn A; Harmon, John W; Marti, Guy P; Matsui, Daisuke; Okamoto, Koichi; Makino, Isamu; Hayashi, Hironori; Oyama, Katsunobu; Nakagawara, Hisatoshi; Tajima, Hidehiro; Fujita, Hideto; Takamura, Hiroyuki; Murakami, Manabu; Ninomiya, Itasu; Kitagawa, Hirohisa; Fushida, Sachio; Fujimura, Takashi; Ohta, Tetsuo

    2013-08-01

    Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents.

  6. Long-term safety concerns with proton pump inhibitors.

    PubMed

    Ali, Tauseef; Roberts, David Neil; Tierney, William M

    2009-10-01

    Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Their use has resulted in dramatic improvements in treatment of peptic ulcer disease and gastroesophageal reflux disease. Despite an acceptable safety profile, mounting data demonstrate concerns about the long-term use of PPIs. To provide a comprehensive review regarding the concerns of long-term PPI use, a literature search was performed to identify pertinent original and review articles. Despite study shortcomings, the collective body of information overwhelmingly suggests an increased risk of infectious complications and nutritional deficiencies. Data regarding any increased risk in gastric or colon malignancy are less convincing. PPIs have revolutionized the management and complications of acid-related disorders with a high margin of safety; however, with the data available, efforts to reduce the dosing of or discontinue the use of PPIs must be reassessed frequently.

  7. A bacterial proteorhodopsin proton pump in marine eukaryotes.

    PubMed

    Slamovits, Claudio H; Okamoto, Noriko; Burri, Lena; James, Erick R; Keeling, Patrick J

    2011-02-08

    Proteorhodopsins are light-driven proton pumps involved in widespread phototrophy. Discovered in marine proteobacteria just 10 years ago, proteorhodopsins are now known to have been spread by lateral gene transfer across diverse prokaryotes, but are curiously absent from eukaryotes. In this study, we show that proteorhodopsins have been acquired by horizontal gene transfer from bacteria at least twice independently in dinoflagellate protists. We find that in the marine predator Oxyrrhis marina, proteorhodopsin is indeed the most abundantly expressed nuclear gene and its product localizes to discrete cytoplasmic structures suggestive of the endomembrane system. To date, photosystems I and II have been the only known mechanism for transducing solar energy in eukaryotes; however, it now appears that some abundant zooplankton use this alternative pathway to harness light to power biological functions.

  8. Controversy of proton pump inhibitor and clopidogrel interaction: a review.

    PubMed

    Tan, H J

    2010-12-01

    A proton pump inhibitor (PPI) is often co-prescribed with clopidogrel to reduce the gastrointestinal risk of bleeding ulcers in patients following acute coronary syndrome or a stent implant. However, the safety issue of such practice has been scrutinized after some studies reporting an increased incidence of cardiovascular events and mortality, although there have also been contrary research reports. This has lead to a warning statement from the US Food and Drug Administration cautioning the concomitant use of PPI and clopidogrel. This review examines the evidence of PPI as gastroprotective agent, histamine H(2) antagonists as an alternative therapy, the influence of PPI on the antiplatelet effect of clopidogrel, and the controversies of various studies. © 2010 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

  9. Proton pump inhibitor-induced hypomagnesaemia and hypocalcaemia: case review

    PubMed Central

    Sivakumar, Jonathan

    2016-01-01

    Proton pump inhibitor (PPI)-induced hypomagnesaemia is a rare but serious adverse effect of a widely prescribed medication. It has become an increasingly recognised complication since 2006, with the U.S. Food and Drug Administration issuing a warning for this risk with regards to long-term PPI use. We present the case of PPI-associated hypomagnesaemia and hypocalcaemia. A 91 year old male presented with tetany from severe hypomagnesaemia and hypocalcaemia. This condition occurred in the context of 18 months of PPI use, and resolved following cessation of PPI therapy and the replenishment of magnesium and calcium stores. Monitoring of magnesium, calcium and potassium levels is crucial in patients prescribed PPIs long-term; especially the elderly patient. PMID:28078056

  10. Proton pump inhibition--the ultimate control of acid secretion

    SciTech Connect

    Zdon, M.J.; Ballantyne, G.H.; Schafer, D.E.; Tyshkov, M.; Cambria, R.P.; Modlin, I.M.

    1986-04-01

    The cellular mechanisms of acid secretion by the parietal cell (PC) include stimulation of membrane receptors, increases in cytosolic cyclic AMP levels, and activation of protein kinase systems. These events culminate in stimulation of a membrane-based proton pump. This consists of a non-electrogenic H+-K+-ATPase which transports H+ ions into the secretory canaliculus of the PC in exchange for the cation K+. It has been proposed that blockade of this proton pump would result in inhibition of acid secretion by all classes of acid secretagogues. Thus, the effects of membrane receptor agonists as well as any agents which augment cellular cAMP levels should be inhibited. Substituted benzimidazoles are weak bases which prevent acid secretion by blocking the H+-K+-ATPase system. In order to test the above hypothesis, we investigated the effects of the substituted benzimidazole H168/68 and cimetidine (C) on histamine (H) and 8B-stimulated acid secretion. The rabbit isolated gastric gland (IGG) model was used and acid secretion assessed by the accumulation of /sup 14/C-labeled weak base aminopyrine (AP) within the IGG in response to secretagogue stimulation. H168/68 and C both inhibited H (5 X 10(-5) M)-stimulated (/sup 14/C)AP accumulation in a concentration-dependent manner (P less than 0.05). H168/68 inhibited both H- and 8B-stimulated (/sup 14/C)AP accumulation (P less than 0.05), while C inhibited only H-stimulated (/sup 14/C)AP accumulation (P less than 0.05). H168/68 suppressed (/sup 14/C)AP below even unstimulated levels of (/sup 14/C)AP accumulation. These results support the hypothesis that H168/68 inhibits the PC distal to cAMP stimulation.

  11. Converting a light-driven proton pump into a light-gated proton channel.

    PubMed

    Inoue, Keiichi; Tsukamoto, Takashi; Shimono, Kazumi; Suzuki, Yuto; Miyauchi, Seiji; Hayashi, Shigehiko; Kandori, Hideki; Sudo, Yuki

    2015-03-11

    There are two types of membrane-embedded ion transport machineries in nature. The ion pumps generate electrochemical potential by energy-coupled active ion transportation, while the ion channels produce action potential by stimulus-dependent passive ion transportation. About 80% of the amino acid residues of the light-driven proton pump archaerhodopsin-3 (AR3) and the light-gated cation channel channelrhodopsin (ChR) differ although they share the close similarity in architecture. Therefore, the question arises: How can these proteins function differently? The absorption maxima of ion pumps are red-shifted about 30-100 nm compared with ChRs, implying a structural difference in the retinal binding cavity. To modify the cavity, a blue-shifted AR3 named AR3-T was produced by replacing three residues located around the retinal (i.e., M128A, G132V, and A225T). AR3-T showed an inward H(+) flux across the membrane, raising the possibility that it works as an inward H(+) pump or an H(+) channel. Electrophysiological experiments showed that the reverse membrane potential was nearly zero, indicating light-gated ion channeling activity of AR3-T. Spectroscopic characterization of AR3-T revealed similar photochemical properties to some of ChRs, including an all-trans retinal configuration, a strong hydrogen bond between the protonated retinal Schiff base and its counterion, and a slow photocycle. From these results, we concluded that the functional determinant in the H(+) transporters is localized at the center of the membrane-spanning domain, but not in the cytoplasmic and extracellular domains.

  12. Vacuolar-type proton pumps in insect epithelia

    PubMed Central

    Wieczorek, Helmut; Beyenbach, Klaus W.; Huss, Markus; Vitavska, Olga

    2009-01-01

    Summary Active transepithelial cation transport in insects was initially discovered in Malpighian tubules, and was subsequently also found in other epithelia such as salivary glands, labial glands, midgut and sensory sensilla. Today it appears to be established that the cation pump is a two-component system of a H+-transporting V-ATPase and a cation/nH+ antiporter. After tracing the discovery of the V-ATPase as the energizer of K+/nH+ antiport in the larval midgut of the tobacco hornworm Manduca sexta we show that research on the tobacco hornworm V-ATPase delivered important findings that emerged to be of general significance for our knowledge of V-ATPases, which are ubiquitous and highly conserved proton pumps. We then discuss the V-ATPase in Malpighian tubules of the fruitfly Drosophila melanogaster where the potential of post-genomic biology has been impressively illustrated. Finally we review an integrated physiological approach in Malpighian tubules of the yellow fever mosquito Aedes aegypti which shows that the V-ATPase delivers the energy for both transcellular and paracellular ion transport. PMID:19448071

  13. Proton pump-driven cutaneous chloride uptake in anuran amphibia.

    PubMed

    Jensen, Lars Jørn; Willumsen, Niels Johannes; Amstrup, Jan; Larsen, Erik Hviid

    2003-12-30

    Krogh introduced the concept of active ion uptake across surface epithelia of freshwater animals, and proved independent transports of Na(+) and Cl(-) in anuran skin and fish gill. He suggested that the fluxes of Na(+) and Cl(-) involve exchanges with ions of similar charge. In the so-called Krogh model, Cl(-)/HCO(3)(-) and Na(+)/H(+) antiporters are located in the apical membrane of the osmoregulatory epithelium. More recent studies have shown that H(+) excretion in anuran skin is due to a V-ATPase in mitochondria-rich (MR) cells. The pump has been localized by immunostaining and H(+) fluxes estimated by pH-stat titration and mathematical modelling of pH-profiles in the unstirred layer on the external side of the epithelium. H(+) secretion is voltage-dependent, sensitive to carbonic-anhydrase inhibitors, and rheogenic with a charge/ion-flux ratio of unity. Cl(-) uptake from freshwater is saturating, voltage independent, and sensitive to DIDS and carbonic-anhydrase inhibitors. Depending on anuran species and probably on acid/base balance of the animal, apical exit of protons is coupled to an exchange of Cl(-) with base (HCO(3)(-)) either in the apical membrane (gamma-type of MR cell) or in the basolateral membrane (alpha-type MR cell). The gamma-cell model accounts for the rheogenic active uptake of Cl(-) observed in several anuran species. There is indirect evidence also for non-rheogenic active uptake accomplished by a beta-type MR cell with apical base secretion and basolateral proton pumping. Several studies have indicated that the transport modes of MR cells are regulated via ion- and acid/base balance of the animal, but the signalling mechanisms have not been investigated. Estimates of energy consumption by the H(+)-ATPase and the Na(+)/K(+)-ATPase indicate that the gamma-cell accomplishes uptake of NaCl in normal and diluted freshwater. Under common freshwater conditions with serosa-positive or zero V(t), the K(+) conductance of the basolateral membrane

  14. [Influence of proton pump inhibitors on intestinal fermentative profile: a case-control study].

    PubMed

    Senderovky, Melisa; Lasa, Juan; Dima, Guillermo; Peralta, Daniel; Argüello, Mariano; Soifer, Luis

    2014-01-01

    Proton pump inhibitors could have an impact on the results of breath tests performed in patients with irritable bowel syndrome. This impact could be due to the development of small intestine bacterial overgrowth. To compare the prevalence of fermentative profile alterations of irritable bowel syndrome patients exposed and not-exposed to proton pump inhibitor therapy. Subjects with irritable bowel syndrome were enrolled. A validated questionnaire assessing symptom severity as well as proton pump inhibitor treatment was delivered. A lactulose breath test was undertaken by each enrolled subject. Fermentative profile (area under the curve of hydrogen excretion/time) was compared between proton pump inhibitors consumers and non-consumers. Furthermore, small intestine bacterial overgrowth prevalence was compared. Two hundred and twenty five patients were enrolled. No significant differences were found on the fermentative profile between groups [AUC mediana 3,776 (rango 2,124-5,571) vs 4,347 (rango 2,038-5,481), P = 0.3]. Small intestine bacterial overgrowth prevalence was similar as well [33% vs 27.5%]. These differences remained non-significant after adjusting for proton pump inhibitor dose and treatment time. Surprisingly, symptom score was significantly higher in those patients under proton pump inhibitor therapy [28.5 (23-26) vs 23 (15-29), P = 0.01]. Proton pump inhibitors have no significant influence on lactulose breath tests, regardless of the dosage and time of administration.

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

    PubMed

    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.

  16. 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

  17. V-type ATPase proton pump expression during enamel formation.

    PubMed

    Sarkar, Juni; Wen, Xin; Simanian, Emil J; Paine, Michael L

    2016-01-01

    Several diseases such as proximal and distal renal tubular acidosis and osteoporosis are related to intracellular pH dysregulation resulting from mutations in genes coding for ion channels, including proteins comprising the proton-pumping V-type ATPase. V-type ATPase is a multi-subunit protein complex expressed in enamel forming cells. V-type ATPase plays a key role in enamel development, specifically lysosomal acidification, yet our understanding of the relationship between the endocytotic activities and dental health and disease is limited. The objective of this study is to better understand the ameloblast-associated pH regulatory networks essential for amelogenesis. Quantitative RT-PCR was performed on tissues from secretory-stage and maturation-stage enamel organs to determine which of the V-type ATPase subunits are most highly upregulated during maturation-stage amelogenesis: a time when ameloblast endocytotic activity is highest. Western blot analyses, using specific antibodies to four of the V-type ATPase subunits (Atp6v0d2, Atp6v1b2, Atp6v1c1 and Atp6v1e1), were then applied to validate much of the qPCR data. Immunohistochemistry using these same four antibodies was also performed to identify the spatiotemporal expression profiles of individual V-type ATPase subunits. Our data show that cytoplasmic V-type ATPase is significantly upregulated in enamel organ cells during maturation-stage when compared to secretory-stage. These data likely relate to the higher endocytotic activities, and the greater need for lysosomal acidification, during maturation-stage amelogenesis. It is also apparent from our immunolocalization data, using antibodies against two of the V-type ATPase subunits (Atp6v1c1 and Atp6v1e1), that significant expression is seen at the apical membrane of maturation-stage ameloblasts. Others have also identified this V-type ATPase expression profile at the apical membrane of maturation ameloblasts. Collectively, these data better define the

  18. Extracellular Protons Regulate the Extracellular Cation Selectivity of the Sodium Pump

    PubMed Central

    Milanick, Mark A.; Arnett, Krista L.

    2002-01-01

    The effects of 0.3–10 nM extracellular protons (pH 9.5–8.0) on ouabain-sensitive rubidium influx were determined in 4,4′-diisocyanostilbene-2, 2′-disulfonate (DIDS)-treated human and rat erythrocytes. This treatment clamps the intracellular H. We found that rubidium binds much better to the protonated pump than the unprotonated pump; 13-fold better in rat and 34-fold better in human erythrocytes. This clearly shows that protons are not competing with rubidium in this proton concentration range. Bretylium and tetrapropylammonium also bind much better to the protonated pump than the unprotonated pump in human erythrocytes and in this sense they are potassium-like ions. In contrast, guanidinium and sodium bind about equally well to protonated and unprotonated pump in human red cells. In rat red cells, protons actually make sodium bind less well (about sevenfold). Thus, protons have substantially different effects on the binding of rubidium and sodium. The effect of protons on ouabain binding in rat red cells was intermediate between the effects of protons on rubidium binding and on sodium binding. Remarkably, all four cationic inhibitors (bretylium, guanidinium, sodium, and tetrapropylammonium) had similar apparent inhibitory constants for the unprotonated pump (∼5–10 mM). The Kd for proton binding to the human pump, with the empty transport site facing extracellularly is 13 nM, whereas the extracellular transport site loaded with sodium is 9.5 nM, and with rubidium is 0.38 nM. In rat red cells there is also a substantial difference in the Kd for proton binding to the sodium-loaded pump (14.5 nM) and the rubidium-loaded pump (0.158 nM). These data suggest that important rearrangements occur at the extracellular pump surface as the pump moves between conformations in which the outward facing transport site has sodium bound, is empty, or has rubidium bound and that guanidinium is sodium-like and bretylium and tetrapropylammonium are rubidium-like. PMID

  19. A case series of proton pump inhibitor-induced hypomagnesemia.

    PubMed

    Hoorn, Ewout J; van der Hoek, Joost; de Man, Rob A; Kuipers, Ernst J; Bolwerk, Clemens; Zietse, Robert

    2010-07-01

    Proton pump inhibitor (PPI)-induced hypomagnesemia has been recognized since 2006. Our aim was to further characterize the clinical consequences and possible mechanisms of this electrolyte disorder using 4 cases. Two men (aged 63 and 81 years) and 2 women (aged 73 and 62 years) had been using a PPI (esomeprazole, pantoprazole, omeprazole, and rabeprazole, 20-40 mg) for 1-13 years. They developed severe hypomagnesemia (magnesium, 0.30 +/- 0.28 mEq/L; reference, 1.40-2.10 mEq/L) with hypocalcemia (calcium, 6.4 +/- 1.8 mg/dL), relative hypoparathyroidism (parathyroid hormone, 43 +/- 6 pg/mL), and extremely low urinary calcium and magnesium excretion. One patient was admitted with postanoxic encephalopathy after a collapse likely caused by arrhythmia. The others had electrocardiogram abnormalities (prolonged QT interval, ST depression, and U waves). Concomitant hypokalemia (potassium, 2.8 +/- 0.1 mEq/L) was considered the trigger for these arrhythmias. Hypomagnesemia-induced kaliuresis (potassium excretion, 65 +/- 24 mEq/L) was identified as the cause of hypokalemia. This series of PPI-induced hypomagnesemia shows that this is a generic effect. It also indicates that hypomagnesemia may occur within 1 year of PPI therapy initiation and can have serious clinical consequences, likely triggered by the associated hypokalemia. A high index of suspicion is required in PPI users for unexplained hypomagnesemia, hypocalcemia, hypokalemia, or associated symptoms.

  20. Metformin plus proton pump inhibitors therapy: the cobalamin deficiency challenge.

    PubMed

    Purchiaroni, F; Galli, G; Annibale, B

    2015-07-01

    It is known in literature that metformin and proton pump inhibitors (PPIs) are associated to cobalamin levels reduction independently but still very little is known about the combination of the two drugs in cobalamin levels decrease. Currently there are no published data concerning the management of patients with cobalamin deficiency related to the concomitant use of the aforementioned drugs. We present the case of a 65 year-old white man with an history of renal cell carcinoma, melanoma and hepatic nodular sclerosis Hodgkin's lymphoma, who was under treatment with metformin because of diabetes and with pantoprazole because of Barrett's esophagus. He came to our attention because of a progressive reduction of cobalamin levels without related anemia. We decided to continue metformin and pantoprazole therapy and we treated the patient with intramuscular injection of cobalamin to avoid the vitamin deficiency consequences. Up to now no published data are available concerning the management of patients with cobalamin deficiency related to the concomitant use of metformin and PPIs. Our case report faces this clinical problem in terms of therapeutic management.

  1. Hypomagnesemia Among Outpatient Long-Term Proton Pump Inhibitor Users.

    PubMed

    Biyik, Murat; Solak, Yalcin; Ucar, Ramazan; Cifci, Sami; Tekis, Dilek; Polat, İlker; Göktepe, Mevlüt Hakan; Sakiz, Davut; Ataseven, Huseyin; Demir, Ali

    Proton pump inhibitors (PPIs) are extensively prescribed drugs usually used for a long period. Recent reports linked PPI use with development of hypomagnesemia. However, there is still uncertainty regarding risk of hypomagnesemia in outpatients who were on long-term PPI use. Thus, we aimed to evaluate frequency of hypomagnesemia among a well-defined outpatient patient cohort with no other possible risk factors affecting serum magnesium levels. This was a case-control study carried out at the outpatient gastroenterology clinic of a University hospital. Patients who were on PPI therapy for at least 6 months without diuretic use and chronic kidney disease were included. Patients who were subjected to the same inclusion and exclusion criteria and not using PPI were included as control subjects. One hundred fifty-four patients and 84 control subjects were included. The mean duration of PPI use was 27.5 ± 2.5 months. Mean serum magnesium levels of PPI users and nonusers were 2.17 ± 0.20 mg/dL and 2.19 ± 0.15 mg/dL, respectively. None of the patient had a serum magnesium level below laboratory lower range of 1.7 mg/dL. Our results showed that for typical gastroenterology outpatient clinic patients with no other risk factors affecting serum magnesium levels, long-term PPI use did not affect serum magnesium levels.

  2. 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.

  3. Allosteric interactions and proton conducting pathways in proton pumping aa(3) oxidases: heme a as a key coupling element.

    PubMed

    Capitanio, Nazzareno; Palese, Luigi Leonardo; Capitanio, Giuseppe; Martino, Pietro Luca; Richter, Oliver-Matthias H; Ludwig, Bernd; Papa, Sergio

    2012-04-01

    In this paper allosteric interactions in protonmotive heme aa(3) terminal oxidases of the respiratory chain are dealt with. The different lines of evidence supporting the key role of H(+)/e(-) coupling (redox Bohr effect) at the low spin heme a in the proton pump of the bovine oxidase are summarized. Results are presented showing that the I-R54M mutation in P. denitrificans aa(3) oxidase, which decreases by more than 200mV the E(m) of heme a, inhibits proton pumping. Mutational amino acid replacement in proton channels, at the negative (N) side of membrane-inserted prokaryotic aa(3) oxidases, as well as Zn(2+) binding at this site in the bovine oxidase, uncouples proton pumping. This effect appears to result from alteration of the structural/functional device, closer to the positive, opposite (P) surface, which separates pumped protons from those consumed in the reduction of O(2) to 2 H(2)O. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. 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

    2016-07-05

    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.

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

    PubMed Central

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

    2016-01-01

    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

  6. 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.

  7. Stochastic resonance in a proton pumping Complex I of mitochondria membranes.

    PubMed

    Kaur, D; Filonenko, I; Mourokh, L; Fendler, C; Blick, R H

    2017-09-29

    We make use of the physical mechanism of proton pumping in the so-called Complex I within mitochondria membranes. Our model is based on sequential charge transfer assisted by conformational changes which facilitate the indirect electron-proton coupling. The equations of motion for the proton operators are derived and solved numerically in combination with the phenomenological Langevin equation describing the periodic conformational changes. We show that with an appropriate set of parameters, protons can be transferred against an applied voltage. In addition, we demonstrate that only the joint action of the periodic energy modulation and thermal noise leads to efficient uphill proton transfer, being a manifestation of stochastic resonance.

  8. 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.

  9. Does Barrett's esophagus regress after surgery (or proton pump inhibitors)?

    PubMed

    Spechler, Stuart Jon

    2014-01-01

    Barrett's esophagus, the condition in which metaplastic columnar epithelium that predisposes to cancer development replaces the squamous epithelium that normally lines the distal esophagus, is a complication of gastroesophageal reflux disease (GERD). Metaplasia is a potentially reversible condition, and partial regression of Barrett's metaplasia has been documented with effective medical or surgical therapy for GERD. The important issue for patient management is not whether antireflux treatment causes Barrett's esophagus to regress, but rather whether antireflux therapy prevents cancer in Barrett's esophagus. Proton pump inhibitors (PPIs) would be expected to prevent this cancer because they heal reflux esophagitis, reduce exposure to a potential carcinogen (acid), and might prevent acid-induced proliferation and cancer-promoting cytokine secretion by esophageal epithelial cells. Furthermore, observational studies have shown that PPI use is associated with a decreased incidence of neoplasia in Barrett's esophagus. In theory, successful antireflux surgery, which eliminates the reflux of both acid and bile, should be better for cancer prevention than medical therapy, which only decreases the reflux of acid. However, high-quality studies show no significant difference in cancer incidence between medically and surgically treated patients with GERD and Barrett's esophagus. Furthermore, for individual patients with nondysplastic Barrett's metaplasia, the cancer risk is so small and the number needed to treat for cancer prevention with surgery so large, that it does not matter whether or not surgery provides a tiny margin of extra protection against cancer beyond that provided by medical therapy. The cost and risks of the operation overwhelm any small, additional cancer protective benefit. Antireflux surgery is very effective at controlling the endoscopic signs and symptoms of GERD, but the operation should not be recommended to patients solely with the rationale that it

  10. Inappropriate use of proton pump inhibitors in a local setting

    PubMed Central

    Chia, Christopher Tze Wei; Lim, Wan Peng; Vu, Charles Kien Fong

    2014-01-01

    INTRODUCTION There are growing concerns that the use of proton pump inhibitors (PPIs) may be inappropriate in instances that do not conform to evidence-based indications. This point-prevalence study aimed to investigate the frequency, indications and appropriateness of use of PPIs in hospitalised patients on a randomly chosen day. METHODS On a randomly chosen day, all inpatients were documented, and those on any form of PPIs on that day were determined. Indications for maintaining these patients on PPIs were obtained from the electronic medical records, which were then recorded and cross-referenced against a list of accepted indications adapted from the US Food and Drug Administration (FDA)-approved list. RESULTS In all, 1,025 inpatients were documented. Of the 477 (46.5%) inpatients using PPIs, only 219 (45.9%) fulfilled the FDA-approved indications, while the majority (n = 258, 54.1%) did not. Overall, PPIs were not strictly indicated for use in 206 (43.2%) inpatients, according to FDA criteria. Of the 477 inpatients on PPIs, 52 (10.9%) had borderline indications based on expert consensus/guidelines other than FDA criteria. CONCLUSION Although the use of PPIs is prevalent in hospitals, less than half of the hospitalised patients using PPIs in our study had evidence-based indications that supported such use. The overuse of PPIs has a negative impact on healthcare costs and may lead to adverse effects. Steps to curb the inappropriate use of PPIs should address factors such as indications for the initiation of PPIs, and reassessment of the need for ongoing PPI use in inpatients upon discharge and during outpatient reviews. PMID:25091884

  11. Uses of proton pump inhibitors and serum potassium levels.

    PubMed

    Gau, Jen-Tzer; Heh, Victor; Acharya, Utkarsh; Yang, Yu-Xiao; Kao, Tzu-Cheg

    2009-09-01

    Proton pump inhibitor (PPI) may suppress adrenal cortical steroid synthesis and release, thereby leading to electrolyte disturbances. Both hyponatremia and hyperkalemia in the setting of PPI therapy have been documented in case reports. The objective of this study was to examine the association between serum potassium (K(+)) level and PPI use. A retrospective data analysis of hospitalized adults aged > or = 65 years during 2006, including PPI users (N = 257) and PPI non-users (N = 388), was conducted. Multiple linear and logistic regression analyses were used to assess the association between PPI use and serum K(+) level. PPI users [mean age (SD):79.7 (8.0) years; 70% female] had significantly higher serum K(+) levels than PPI non-users [80.2 (8.8) years; 64% female] on admission [4.13 (0.62) vs. 3.97 (0.57) mmol/L; p < 0.001]. The linear regression model revealed that > or = 2 defined daily dose (DDD) units of PPI use were a significantly positive contributor to serum K(+) levels (p = 0.021) after adjusting for age, serum creatinine levels, sex, history of diabetes, and uses of the following drugs: angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker, beta blocker, diuretics, spironolactone, K(+) supplement, non-steroidal anti-inflammatory drugs, atypical antipsychotics, and narcotics. However, multiple logistic regression model revealed that high dose PPI therapy was not associated with an increased risk for hyperkalemia occurrence (p = 0.762). Higher serum K(+) levels were observed among PPI users when compared to PPI non-users. High daily dose PPI therapy may be an independent positive predictor of serum potassium levels.

  12. Proton pump inhibitors prescribing following the introduction of generic drugs.

    PubMed

    Cammarota, Simona; Bruzzese, Dario; Sarnelli, Giovanni; Citarella, Anna; Menditto, Enrica; Riegler, Salvatore; Savino, Ivana G; Vozzella, Letizia; Piccinocchi, Gaetano; Napoli, Luigi; Arpino, Giovanni; Cuomo, Rosario

    2012-10-01

    In many countries, the introduction of generic proton pump inhibitors (PPIs) onto the pharmaceutical market increased the phenomenon of therapeutic substitution in acid-related disorders (ARDs). To investigate the treatment of ARDs in an Italian primary care setting from 2005 to 2008 by verifying: (i) dynamics of PPI prescribing; (ii) predictors of PPI switching; and (iii) healthcare resource consumption costs. This was a retrospective cohort study of 102 general practitioners (GPs) who managed an average of 150000 inhabitants in Naples. Multilevel logistic regression was used to assess the potential predictors of both PPI switching and termination. Primary care costs were expressed as the cost of ARD management per PPI user year. The percentage of PPI users with ARD increased from 5·5% (2005) to 7·0% (2008) (P<0·0001), especially for dyspepsia (from 9·5% to 13·7%; P<0·0001) and chronic treatments (from 23·4% to 29·4%; P<0·0001). PPI switching rose from 13·0% to 16·7% during the period observed (P<0·0001). Calendar years, long-term treatments and gastroesophageal reflux disease were positive predictors of PPI switching. Primary care costs relating to PPI switchers increased by 61·14€ compared with nonswitchers (P<0·0001). The introduction of generic PPIs onto the Italian market was associated with an increasing amount of PPI prescribing related to chronic treatments, unlicensed indications (e.g. dyspespsia) and therapeutic substitutions. Growing overall costs linked to the phenomenon of PPI switching was also found. Our data support the need to assess the effects of the introduction of generic drugs on both clinical outcomes and the cost management of ARDs. © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.

  13. Bone density in proton pump inhibitors users: a prospective study.

    PubMed

    Ozdil, Kamil; Kahraman, Resul; Sahin, Abdurrahman; Calhan, Turan; Gozden, Erdem H; Akyuz, Umit; Erer, Burak; Sokmen, Mehmet H

    2013-09-01

    Patients with gastroesophageal reflux disease (GERD) receive long-term therapy with proton pump inhibitor (PPI) agents. Several studies have recently been published suggesting that treatment with PPI may cause bone fractures, although the number of prospective studies in this regard is limited. The aim of this study is to prospectively investigate the effect of PPIs on bone density. Between March 2009 and January 2011, 114 GERD patients (18-56 years) and 110 healthy controls were included in the present study. Bone mineral densitometry (BMD) by using dual-energy X-ray absorptiometry was assessed at lumbar spine and femur neck. BMD measurements were performed on all subjects at the beginning of the study. The patients were divided according to three drugs by their treatment with esomeprazole, lansoprazole, or pantoprazole. The study group was followed for at least 6 months on PPI therapy, and then BMD measurements were repeated. The mean duration of treatment with PPIs was 8.5 ± 2.3 months. In patients receiving PPIs, the mean reduction in total vertebra T score following treatment compared to pre-treatment values was 00.23 ± 0.42 units (95 % CI 0.15-0.30) (p < 0.01), while the mean reduction in the femur T score was 0.10 ± 0.40 units (95 % CI 0.03-0.18) (p = 0.03). Reduction following treatment in L4 and total vertebra T scores of lansoprazole group was significantly higher than of pantoprazole group (p = 0.04). Reduction in femur T score of esomeprazole group was higher than of lansoprazole group and pantroprazole group, but it is not statistically significant. Treatment with a PPI results in a significant reduction in bone density. Close monitoring is beneficial for patients who are to receive long-term treatment with PPI.

  14. Gastric neuroendocrine neoplasms and proton pump inhibitors: fact or coincidence?

    PubMed

    Cavalcoli, Federica; Zilli, Alessandra; Conte, Dario; Ciafardini, Clorinda; Massironi, Sara

    2015-01-01

    Reporting on three cases of gastric neuroendocrine tumors (g-NETs) in patients taking long-term proton pump inhibitors (PPIs). These tumors are not classifiable considering current criteria. g-NETs are currently grouped as: types 1 and 2, related to hypergastrinemia due to chronic atrophic gastritis and Zollinger-Ellison syndrome respectively, and type 3, normogastrinemic and more aggressive. Although the g-NETs onset in patients taking PPIs is biologically plausible, only a few cases have been reported so far. From January 2005 to July 2014, 31 g-NETs were referred to our Unit: 24 (77%), one (3%) and three (10%) resulted types 1, 2 and 3, respectively. Three cases (10%) did not meet the current classification criteria. The three patients were administered long-term PPIs for gastro-esophageal reflux disease. Patient 1: a 78-year-old man, with a 4-mm well-differentiated g-NET (Ki-67<1%) and marked hypergastrinemia. Patient 2: a 58-year-old man affected by a 6-mm well-differentiated (Ki-67 = 4%) g-NET, with normal gastrin levels. Patients 3: a 67-year-old woman with an 18-mm well-differentiated g-NET (Ki-67 <2%), with mild hypergastrinemia. In the three patients, histology and pertinent blood tests excluded chronic atrophic gastritis, Helicobacter pylori infection or Zollinger-Ellison syndrome. The first two patients underwent endoscopic polypectomy; in the third case total gastrectomy was performed. Further clinical, endoscopic and imaging follow-up did not show any g-NET recurrence. The present data point to the existence and epidemiological relevance of g-NETs associated with PPIs intake. These neoplasms are not included in the current classification, thus their treatment and follow-up have not been established.

  15. Clinical predictors associated with proton pump inhibitor-induced hypomagnesemia.

    PubMed

    Kim, Sunyong; Lee, Hyuk; Park, Chan Hyuk; Shim, Choong Nam; Lee, Hyun Jik; Park, Jun Chul; Shin, Sung Kwan; Lee, Sang Kil; Lee, Yong Chan; Kim, Ha Yan; Kang, Dae Ryong

    2015-01-01

    There is increasing evidence and case reports regarding proton pump inhibitor (PPI)-induced hypomagnesemia. Our study aimed to clarify the relationship between PPI use and serum magnesium levels and to specify high-risk patients. We retrospectively studied 112 consecutive patients aged 20 years or older who were treated with PPI for ≥30 days and whose serum magnesium levels were available for the PPI treatment period. We compared the mean level of serum magnesium of the enrolled patients with PPI treatment with matched controls. There were no significant differences between the matched PPI users (n = 105) and nonusers (n = 210) in the magnesium levels (0.85 ± 0.09 vs. 0.86 ± 0.16 mM, P = 0.297). In a subgroup analysis of a PPI user group, hypomagnesemia could be observed in 32 patients but not in 80 patients. In multivariate analyses, PPI use for >1 year, age less than 45 years, and concurrent cisplatin or carboplatin use were significantly associated with PPI-induced hypomagnesemia {P = 0.042, odds ratio [OR; 95% confidence interval (CI)]: 5.388 [1.056-27.493]; P = 0.007, OR [95% CI]: 4.710 [1.523-14.571]; P = 0.007, OR [95% CI]: 13.404 [2.066-86.952], respectively} after adjusting for confounders. This study shows that long-term PPI use is associated with hypomagnesemia in hospitalized adult patients. Therefore, serum magnesium levels should be checked before the initiation of PPI treatment and during the treatment period in patients, particularly those concurrently using platinum-based chemotherapy or who are expected to use PPI for long periods.

  16. Effect of proton pump inhibitor on esophageal eosinophilia.

    PubMed

    Schroeder, Shauna; Capocelli, Kelley E; Masterson, Joanne C; Harris, Rachel; Protheroe, Cheryl; Lee, James J; Furuta, Glenn T

    2013-02-01

    Differentiation between the common etiologies of dense esophageal eosinophilia such as gastroesophageal reflux disease (GERD) and eosinophilic esophagitis can be difficult. We hypothesized that histologic features may provide diagnostic clues concerning the etiology of esophageal eosinophilia. : We performed a retrospective chart review of 204 children with the diagnosis of esophagitis characterized by ≥ 15 eosinophils (eos) per high-power field (HPF) in at least 1 biopsy. We then restricted our analysis to subjects who had received at least 8 weeks of only proton pump inhibitors (PPIs) followed by endoscopy and who had a clinicopathologic response to this treatment. Symptoms, endoscopic findings, and pathologic descriptions were reviewed and an eosinophil peroxidase (EPX) index was determined to assess for degranulation/eosinophil activation. Of the 204 identified charts, 7 subjects identified met the inclusion criteria. Five of these 7 patients showed a clinicopathologic response to PPIs after their follow-up endoscopy, (mean peak eosinophil count: 92 vs 5 eos/HPF, and EPX index: 39.2 vs 14.6, pre- and posttreatment, respectively). Two patients experienced initial resolution of symptoms and esophageal eosinophilia with PPI therapy; however, within 17-23 months they redeveloped symptoms and esophageal eosinophilia while receiving PPI therapy at the time of a third endoscopy (mean peak eosinophil count: 40 vs 11 vs 36 eos/HPF, and EPX index: 44 vs 21 vs 36.5, pre-, post- and posttreatment, respectively). No clinicopathologic features or degranulation patterns differentiated subjects with GERD/PPI responsive esophageal eosinophilia from those who had transient response to PPI treatment. No clinicopathologic features differentiated subjects who responded to PPI treatment. PPI treatment can be helpful to exclude GERD and PPI responsive esophageal eosinophilia but long-term follow-up is critical in the management of esophagitis.

  17. Proton-pumping mechanism of cytochrome c oxidase: a kinetic master-equation approach.

    PubMed

    Kim, Young C; Hummer, Gerhard

    2012-04-01

    Cytochrome c oxidase is an efficient energy transducer that reduces oxygen to water and converts the released chemical energy into an electrochemical membrane potential. As a true proton pump, cytochrome c oxidase translocates protons across the membrane against this potential. Based on a wealth of experiments and calculations, an increasingly detailed picture of the reaction intermediates in the redox cycle has emerged. However, the fundamental mechanism of proton pumping coupled to redox chemistry remains largely unresolved. Here we examine and extend a kinetic master-equation approach to gain insight into redox-coupled proton pumping in cytochrome c oxidase. Basic principles of the cytochrome c oxidase proton pump emerge from an analysis of the simplest kinetic models that retain essential elements of the experimentally determined structure, energetics, and kinetics, and that satisfy fundamental physical principles. The master-equation models allow us to address the question of how pumping can be achieved in a system in which all reaction steps are reversible. Whereas proton pumping does not require the direct modulation of microscopic reaction barriers, such kinetic gating greatly increases the pumping efficiency. Further efficiency gains can be achieved by partially decoupling the proton uptake pathway from the active-site region. Such a mechanism is consistent with the proposed Glu valve, in which the side chain of a key glutamic acid shuttles between the D channel and the active-site region. We also show that the models predict only small proton leaks even in the absence of turnover. The design principles identified here for cytochrome c oxidase provide a blueprint for novel biology-inspired fuel cells, and the master-equation formulation should prove useful also for other molecular machines. .

  18. Proton-pumping mechanism of cytochrome c oxidase: A kinetic master-equation approach

    PubMed Central

    Kim, Young C.; Hummer, Gerhard

    2011-01-01

    Cytochrome c oxidase (CcO) is an efficient energy transducer that reduces oxygen to water and converts the released chemical energy into an electrochemical membrane potential. As a true proton pump, CcO translocates protons across the membrane against this potential. Based on a wealth of experiments and calculations, an increasingly detailed picture of the reaction intermediates in the redox cycle has emerged. However, the fundamental mechanism of proton pumping coupled to redox chemistry remains largely unresolved. Here we examine and extend a kinetic master-equation approach to gain insight into redox-coupled proton pumping in CcO. Basic principles of the CcO proton pump emerge from an analysis of the simplest kinetic models that retain essential elements of the experimentally determined structure, energetics, and kinetics, and that satisfy fundamental physical principles. The master-equation models allow us to address the question of how pumping can be achieved in a system in which all reaction steps are reversible. Whereas proton pumping does not require the direct modulation of microscopic reaction barriers, such kinetic gating greatly increases the pumping efficiency. Further efficiency gains can be achieved by partially decoupling the proton uptake pathway from the ative-site region. Such a mechanism is consistent with the proposed Glu valve, in which the side chain of a key glutamic acid shuttles between the D channel and the active-site region. We also show that the models predict only small proton leaks even in the absence of turnover. The design principles identified here for CcO provide a blueprint for novel biology-inspired fuel cells, and the master-equation formulation should prove useful also for other molecular machines. PMID:21946020

  19. Aspartic acid substitutions affect proton translocation by bacteriorhodopsin.

    PubMed Central

    Mogi, T; Stern, L J; Marti, T; Chao, B H; Khorana, H G

    1988-01-01

    We have substituted each of the aspartic acid residues in bacteriorhodopsin to determine their possible role in proton translocation by this protein. The aspartic acid residues were replaced by asparagines; in addition, Asp-85, -96, -115, and -112 were changed to glutamic acid and Asp-212 was also replaced by alanine. The mutant bacteriorhodopsin genes were expressed in Escherichia coli and the proteins were purified. The mutant proteins all regenerated bacteriorhodopsin-like chromophores when treated with a detergent-phospholipid mixture and retinal. However, the rates of regeneration of the chromophores and their lambda max varied widely. No support was obtained for the external point charge model for the opsin shift. The Asp-85----Asn mutant showed not detectable proton pumping, the Asp-96----Asn and Asp-212----Glu mutants showed less than 10% and the Asp-115----Glu mutant showed approximately equal to 30% of the normal proton pumping. The implications of these findings for possible mechanisms of proton translocation by bacteriorhodopsin are discussed. PMID:3288985

  20. A conserved asparagine in a P-type proton pump is required for efficient gating of protons.

    PubMed

    Ekberg, Kira; Wielandt, Alex G; Buch-Pedersen, Morten J; Palmgren, Michael G

    2013-04-05

    The minimal proton pumping machinery of the Arabidopsis thaliana P-type plasma membrane H(+)-ATPase isoform 2 (AHA2) consists of an aspartate residue serving as key proton donor/acceptor (Asp-684) and an arginine residue controlling the pKa of the aspartate. However, other important aspects of the proton transport mechanism such as gating, and the ability to occlude protons, are still unclear. An asparagine residue (Asn-106) in transmembrane segment 2 of AHA2 is conserved in all P-type plasma membrane H(+)-ATPases. In the crystal structure of the plant plasma membrane H(+)-ATPase, this residue is located in the putative ligand entrance pathway, in close proximity to the central proton donor/acceptor Asp-684. Substitution of Asn-106 resulted in mutant enzymes with significantly reduced ability to transport protons against a membrane potential. Sensitivity toward orthovanadate was increased when Asn-106 was substituted with an aspartate residue, but decreased in mutants with alanine, lysine, glutamine, or threonine replacement of Asn-106. The apparent proton affinity was decreased for all mutants, most likely due to a perturbation of the local environment of Asp-684. Altogether, our results demonstrate that Asn-106 is important for closure of the proton entrance pathway prior to proton translocation across the membrane.

  1. A Conserved Asparagine in a P-type Proton Pump Is Required for Efficient Gating of Protons*

    PubMed Central

    Ekberg, Kira; Wielandt, Alex G.; Buch-Pedersen, Morten J.; Palmgren, Michael G.

    2013-01-01

    The minimal proton pumping machinery of the Arabidopsis thaliana P-type plasma membrane H+-ATPase isoform 2 (AHA2) consists of an aspartate residue serving as key proton donor/acceptor (Asp-684) and an arginine residue controlling the pKa of the aspartate. However, other important aspects of the proton transport mechanism such as gating, and the ability to occlude protons, are still unclear. An asparagine residue (Asn-106) in transmembrane segment 2 of AHA2 is conserved in all P-type plasma membrane H+-ATPases. In the crystal structure of the plant plasma membrane H+-ATPase, this residue is located in the putative ligand entrance pathway, in close proximity to the central proton donor/acceptor Asp-684. Substitution of Asn-106 resulted in mutant enzymes with significantly reduced ability to transport protons against a membrane potential. Sensitivity toward orthovanadate was increased when Asn-106 was substituted with an aspartate residue, but decreased in mutants with alanine, lysine, glutamine, or threonine replacement of Asn-106. The apparent proton affinity was decreased for all mutants, most likely due to a perturbation of the local environment of Asp-684. Altogether, our results demonstrate that Asn-106 is important for closure of the proton entrance pathway prior to proton translocation across the membrane. PMID:23420846

  2. Review article: immediate-release proton-pump inhibitor therapy--potential advantages.

    PubMed

    Howden, C W

    2005-12-01

    The absorption of most oral proton-pump inhibitors is delayed by the enteric coating required to protect the acid-labile proton-pump inhibitor from degradation in the stomach and, as a result, antisecretory effect is also delayed. This article provides an overview of the pharmacokinetics and pharmacodynamics of a new immediate-release omeprazole [(IR-OME) Zegerid power for oral suspension; Santarus Inc., San Diego, CA, USA] and its potential advantages over delayed-release proton-pump inhibitors. Immediate-release omeprazole has a higher mean peak plasma omeprazole concentration (C(max)) and a significantly shorter mean time to reach C(max) (t(max)) than delayed-release omeprazole. Immediate-release omeprazole 40 mg has a prolonged antisecretory effect with median intragastric pH above 4.0 for 18.6 h/day at steady-state, after 7 days of once daily dosing. The sodium bicarbonate in immediate-release omeprazole protects the uncoated omeprazole from degradation by gastric acid. The accelerated antisecretory action of immediate-release omeprazole compared with delayed-release omeprazole may be due to the activation of proton pumps by the rapid neutralization of intragastric acid by the sodium bicarbonate. The faster onset of action seen with immediate-release omeprazole is not achieved by using an antacid with a delayed-release proton-pump inhibitor, because administering antacids with conventional delayed-release proton-pump inhibitors does not significantly enhance absorption of the proton-pump inhibitor. In conclusion, immediate-release omeprazole is associated with rapid absorption of omeprazole and rapid onset of antisecretory effect, without compromising the duration of acid suppression.

  3. Expanding the View of Proton Pumping in Cytochrome c Oxidase through Computer Simulation

    PubMed Central

    Peng, Yuxing; Voth, Gregory A.

    2011-01-01

    In cytochrome c oxidase (CcO), a redox-driven proton pump, protons are transported by the Grotthuss shuttling via hydrogen-bonded water molecules and protonatable residues. Proton transport through the D-pathway is a complicated process that is highly sensitive to alterations in the amino acids or the solvation structure in the channel, both of which can inhibit proton pumping and enzymatic activity. Simulations of proton transport in the hydrophobic cavity showed a clear redox state dependence. To study the mechanism of proton pumping in CcO, multi-state empirical valence bond (MS-EVB) simulations have been conducted, focusing on the proton transport through the D-pathway and the hydrophobic cavity next to the binuclear center. The hydration structures, transport pathways, effects of residues, and free energy surfaces of proton transport were revealed in these MS-EVB simulations. The mechanistic insight gained from them is herein reviewed and placed in context for future studies. PMID:22178790

  4. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update.

    PubMed

    Wedemeyer, Ralph-Steven; Blume, Henning

    2014-04-01

    Proton pump inhibitors (PPIs) are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. These drug-drug interactions have been previously reviewed. However, the current knowledge is likely to have advanced, so a thorough review of the literature published since 2006 was conducted. This identified new studies of drug interactions that are modulated by gastric pH. These studies showed the effect of a PPI-induced increase in intragastric pH on mycophenolate mofetil pharmacokinetics, which were characterised by a decrease in the maximum exposure and availability of mycophenolic acid, at least at early time points. Post-2006 data were also available outlining the altered pharmacokinetics of protease inhibitors with concomitant PPI exposure. New data for the more recently marketed dexlansoprazole suggest it has no impact on the pharmacokinetics of diazepam, phenytoin, theophylline and warfarin. The CYP2C19-mediated interaction that seems to exist between clopidogrel and omeprazole or esomeprazole has been shown to be clinically important in research published since the 2006 review; this effect is not seen as a class effect of PPIs. Finally, data suggest that coadministration of PPIs with methotrexate may affect methotrexate pharmacokinetics, although the mechanism of interaction is not well understood. As was shown in the previous review, individual PPIs differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole sodium (pantoprazole-Na) have been studied most extensively. Several studies have shown that omeprazole carries a considerable potential for drug interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4. In contrast, pantoprazole-Na appears to have

  5. Proton pump inhibitors: perspectives of patients and their GPs.

    PubMed

    Grime, J; Pollock, K; Blenkinsopp, A

    2001-09-01

    There is growing concern with the rapid increase in prescribing proton pump inhibitor drugs (PPIs) for a variety of gastrointestinal disorders, and the escalating costs associated with this trend. Explanations have included that general practitioners (GPs) prescribe PPIs inappropriately and that patients demand PPIs and use them as a way of avoiding having to make lifestyle changes. To compare the perspectives of GPs and their patients on the need for PPIs, to examine the pressure to prescribe, and to examine the effect of PPIs on lifestyle. Qualitative comparative study based on semi-structured interviews. Twenty-six GPs in seven practices in the West Midlands and 82 of their patients on repeat prescriptions for PPIs. Interviews were conducted covering a wide range of topics, including: experience, cause, course, and outcome of stomach problems; effectiveness of PPIs; and role of lifestyle in controlling symptoms. The transcripts were studied repeatedly to look for the occurrence and distribution of material relating to these issues, as well as other responder-driven issues. Codebooks were devised to enable a simple categorisation and systematic comparison of cases. GPs and patients agreed about the severity and unpleasantness of stomach symptoms for which PPIs were prescribed. While GPs and patients regarded PPIs as a very effective treatment, GPs rated their efficacy more highly than patients. Half of the GP interviews reproduced the stereotype of the demanding patient and of patients using PPIs to support unhealthy lifestyles. There was little evidence from patient interviews to support either stereotype. Doctors underestimated patient concerns about side-effects, safety, and long-term use of PPIs, and the willingness of patients to achieve the minimum effective dose by experimenting with their treatment. GPs felt that the pressure to prescribe PPIs was outweighed by the pressure not to prescribe, and most GPs had responded to the call to cut the prescribing of

  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. Review article: similarities and differences among delayed-release proton-pump inhibitor formulations.

    PubMed

    Horn, J R; Howden, C W

    2005-12-01

    Proton-pump inhibitors are acid-labile, and require an enteric coating to protect them from degradation in the stomach when given orally. However, this leads to delayed absorption and onset of action of the proton-pump inhibitor. This article aims to review the similarities and differences between the various formulations of delayed release proton-pump inhibitors. Delayed-release omeprazole and delayed-release lansoprazole have been suspended in sodium bicarbonate for tube administration; however, for omeprazole, absorption is further impaired and antisecretory effects are disappointing. Although such formulations may be more convenient for clinical use in certain patient groups, absorption of the proton-pump inhibitor is still influenced by residual enteric coating. There are few differences among the currently available delayed-release proton-pump inhibitors with respect to their pharmacodynamic effects during chronic administration. There are minor formulation-based pharmacokinetic differences among these agents, primarily reflected in their bioavailability following the first few doses. Differences in bioavailability may explain slight differences in the rate of onset of maximal antisecretory effect. However, minor pharmacodynamic and pharmacokinetic differences are not associated with meaningful differences in clinical outcomes.

  8. 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

  9. 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.

  10. Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation.

    PubMed

    Wen, Ting; Dellon, Evan S; Moawad, Fouad J; Furuta, Glenn T; Aceves, Seema S; Rothenberg, Marc E

    2015-01-01

    Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery. In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities. We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE. The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment. These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated

  11. Modeling light-driven proton pumps in artificial photosynthetic reaction centers.

    PubMed

    Ghosh, Pulak Kumar; Smirnov, Anatoly Yu; Nori, Franco

    2009-07-21

    We study a model of a light-induced proton pump in artificial reaction centers. The model contains a molecular triad with four electron states (i.e., one donor state, two photosensitive group states, and one acceptor state) as well as a molecular shuttle having one electron and one proton-binding sites. The shuttle diffuses between the sides of the membrane and translocates protons energetically uphill: from the negative side to the positive side of the membrane, harnessing for this purpose the energy of the electron-charge separation produced by light. Using the methods of quantum transport theory we calculate the range of light intensity and transmembrane potentials that maximize both the light-induced proton current and the energy transduction efficiency. We also study the effect of temperature on proton pumping. The light-induced proton pump in our model gives a quantum yield of proton translocation of about 55%. Thus, our results explain previous experiments on these artificial photosynthetic reaction centers.

  12. Hypomagnesaemia due to use of proton pump inhibitors--a review.

    PubMed

    Kuipers, M T; Thang, H D; Arntzenius, A B

    2009-05-01

    Magnesium homeostasis is essential for many intracellular processes and depends on the balance of intestinal absorption and renal excretion. Hypomagnesaemia may arise from various disorders. We review the literature on hypomagnesaemia due to the use of proton pump inhibitors, as illustrated by a case of a 76-year-old woman with muscle cramps and lethargy caused by hypomagnesaemia and hypocalcaemia with a low parathyroid hormone level while using esomeprazole, a proton pump inhibitor (PPI). After oral magnesium repletion both abnormalities resolved. Fractional magnesium excretion was low, excluding excessive renal loss. A causal relation with PPI use was supported by the recurrence of hypomagnesaemia after rechallenge. In the past decade our understanding of transcellular magnesium transport was enhanced by the discovery of several gene mutations i.e. transient receptor potential melastin (TR PM) 6 and 7. In this light we discuss the possible aetiology of proton pump inhibitor related hypomagnesaemia.

  13. Proton pumping by cytochrome oxidase as studied by time-resolved stopped-flow spectrophotometry.

    PubMed Central

    Antonini, G; Malatesta, F; Sarti, P; Brunori, M

    1993-01-01

    The H+/e- stoichiometry for the proton pump of cytochrome c oxidase reportedly varies between 0 and 1, depending on experimental conditions. In this paper, we report the results obtained by a combination of transient optical spectroscopy with a time resolution of 10 ms and a singular value decomposition analysis to follow the kinetics, separate the observed spectral components, and quantitate the stoichiometry of the pump. By using cytochrome oxidase reconstituted into small unilamellar vesicles, we show that the time courses of ferrocytochrome c oxidation and phenol red acidification or alkalinization fit a simple kinetic scheme. The fitting procedure leads to unbiased and objective determination of the H+/e- ratio under various experimental conditions. The proton-pumping stoichiometry was found to be 1.01 +/- 0.10, independent of the number of turnovers, proton back-leak rate, or type of experiment (oxidant or reductant pulse). PMID:8392182

  14. Glycocardiolipin modulates the surface interaction of the proton pumped by bacteriorhodopsin in purple membrane preparations.

    PubMed

    Corcelli, Angela; Lobasso, Simona; Saponetti, Matilde Sublimi; Leopold, Andreas; Dencher, Norbert A

    2007-09-01

    Glycocardiolipin is an archaeal analogue of mitochondrial cardiolipin, having an extraordinary affinity for bacteriorhodopsin, the photoactivated proton pump in the purple membrane of Halobacterium salinarum. Here purple membranes have been isolated by osmotic shock from either cells or envelopes of Hbt. salinarum. We show that purple membranes isolated from envelopes have a lower content of glycocardiolipin than standard purple membranes isolated from cells. The properties of bacteriorhodopsin in the two different purple membrane preparations are compared; although some differences in the absorption spectrum and the kinetic of the dark adaptation process are present, the reduction of native membrane glycocardiolipin content does not significantly affect the photocycle (M-intermediate rise and decay) as well as proton pumping of bacteriorhodopsin. However, interaction of the pumped proton with the membrane surface and its equilibration with the aqueous bulk phase are altered.

  15. Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region.

    PubMed

    Reyes, Carlen; Formiga, Francesc; Coderch, Marta; Hoyo, Jordi; Ferriz, Gemma; Casanovas, Jordi; Monteserín, Rosa; Brotons, Carlos; Rojas, Marta; Moral, Irene

    2013-02-01

    To determine whether there is an increased risk of hip fracture associated with the use of proton pump inhibitors in a Mediterranean area after adjusting for other potential risk factors. Retrospective multicenter case-control study carried out in 6 primary health care centers in Catalonia, Spain. Cases were patients aged 50years and over with a fragility hip fracture registered between January 2007 and December 2010, matched with 2 controls by sex and age. use of proton pump inhibitors (type, dosage) in the 5years previous to the hip fracture, socio-demographic data, body mass index, alcohol and tobacco consumption as well as health conditions and drugs associated with an increase risk of fragility hip fracture. 358 cases were matched with 698 controls. The mean age was 82years old in both groups. Women represented 77.1% in the case group and 76.9% in the control group. Crude association between proton pump inhibitors and hip fracture was 1.44 (95% CI, 1.09-1.89) and adjusted OR was 1.24 (95% CI, 0.93-1.65). No association was found with the continuous or discontinuous use of proton pump inhibitors, OR 1.17 (95% CI, 0.77-1.79), and OR of 1.16 (95% CI, 0.85-1.60) respectively. No association was found when restricting the analysis by sex, OR of 1.19 (95% CI, 0.27-5.14) or by age, younger or older than 80years, OR of 0.72 (95% CI, 0.24-2.15). The use of proton pump inhibitors was not associated with an increased risk of hip fracture after adjusting for other risk factors in a Mediterranean area. This result suggests the existence of protective environmental factors linked to this southern area of Europe that eventually could compensate for the potential harm produced by proton pump inhibitors. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Functional Dissection of the Proton Pumping Modules of Mitochondrial Complex I

    PubMed Central

    Sokolova, Lucie; Zwicker, Klaus; Barth, Hans-Dieter; Morgner, Nina; Heide, Heinrich; Steger, Mirco; Nübel, Esther; Zickermann, Volker; Kerscher, Stefan; Brutschy, Bernhard; Radermacher, Michael; Brandt, Ulrich

    2011-01-01

    Mitochondrial complex I, the largest and most complicated proton pump of the respiratory chain, links the electron transfer from NADH to ubiquinone to the pumping of four protons from the matrix into the intermembrane space. In humans, defects in complex I are involved in a wide range of degenerative disorders. Recent progress in the X-ray structural analysis of prokaryotic and eukaryotic complex I confirmed that the redox reactions are confined entirely to the hydrophilic peripheral arm of the L-shaped molecule and take place at a remarkable distance from the membrane domain. While this clearly implies that the proton pumping within the membrane arm of complex I is driven indirectly via long-range conformational coupling, the molecular mechanism and the number, identity, and localization of the pump-sites remains unclear. Here, we report that upon deletion of the gene for a small accessory subunit of the Yarrowia complex I, a stable subcomplex (nb8mΔ) is formed that lacks the distal part of the membrane domain as revealed by single particle analysis. The analysis of the subunit composition of holo and subcomplex by three complementary proteomic approaches revealed that two (ND4 and ND5) of the three subunits with homology to bacterial Mrp-type Na+/H+ antiporters that have been discussed as prime candidates for harbouring the proton pumps were missing in nb8mΔ. Nevertheless, nb8mΔ still pumps protons at half the stoichiometry of the complete enzyme. Our results provide evidence that the membrane arm of complex I harbours two functionally distinct pump modules that are connected in series by the long helical transmission element recently identified by X-ray structural analysis. PMID:21886480

  17. Conjecture Regarding Posttranslational Modifications to the Arabidopsis Type I Proton-Pumping Pyrophosphatase (AVP1)

    PubMed Central

    Pizzio, Gaston A.; Hirschi, Kendal D.; Gaxiola, Roberto A.

    2017-01-01

    Agbiotechnology uses genetic engineering to improve the output and value of crops. Altering the expression of the plant Type I Proton-pumping Pyrophosphatase (H+-PPase) has already proven to be a useful tool to enhance crop productivity. Despite the effective use of this gene in translational research, information regarding the intracellular localization and functional plasticity of the pump remain largely enigmatic. Using computer modeling several putative phosphorylation, ubiquitination and sumoylation target sites were identified that may regulate Arabidopsis H+-PPase (AVP1- Arabidopsis Vacuolar Proton-pump 1) subcellular trafficking and activity. These putative regulatory sites will direct future research that specifically addresses the partitioning and transport characteristics of this pump. We posit that fine-tuning H+-PPases activity and cellular distribution will facilitate rationale strategies for further genetic improvements in crop productivity. PMID:28955362

  18. Are higher doses of proton pump inhibitors better in acute peptic bleeding?

    PubMed

    Villalón, Alejandro; Olmos, Roberto; Rada, Gabriel

    2016-06-24

    Although there is broad consensus about the benefits of proton pump inhibitors in acute upper peptic bleeding, there is still controversy over their optimal dosing. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 27 randomized trials addressing this question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded high-dose proton pump inhibitors probably result in little or no difference in re-bleeding rate or mortality. The risk/benefit and cost/benefit balance probably favor use of low-doses.

  19. Electrostatic study of the proton pumping mechanism in bovine heart cytochrome C oxidase.

    PubMed

    Popović, Dragan M; Stuchebrukhov, Alexei A

    2004-02-18

    Cytochrome c oxidase (CcO) is the terminal enzyme of the cell respiratory chain in mitochondria and aerobic bacteria. It catalyzes the reduction of oxygen to water and utilizes the free energy of the reduction reaction for proton pumping across the inner-mitochondrial membrane, a process that results in a membrane electrochemical proton gradient. Although the structure of the enzyme has been solved for several organisms, the molecular mechanism of proton pumping remains unknown. In the present paper, continuum electrostatic calculations were employed to evaluate the electrostatic potential, energies, and protonation state of bovine heart cytochrome c oxidase for different redox states of the enzyme along its catalytic cycle. Three different computational models of the enzyme were employed to test the stability of the results. The energetics and pH dependence of the P-->F, F-->O, and O-->E steps of the cycle have been investigated. On the basis of electrostatic calculations, two possible schemes of redox-linked proton pumping are discussed. The first scheme involves His291 as a pump element, whereas the second scheme involves a group linked to propionate D of heme a(3). In both schemes, loading of the pump site is coupled to ET between the two hemes of the enzyme, while transfer of a chemical proton is accompanied by ejection of the pumped H(+). The two models, as well as the energetics results are compared with recent experimental kinetic data. The proton pumping across the membrane is an endergonic process, which requires a sufficient amount of energy to be provided by the chemical reaction in the active site. In our calculations, the conversion of OH(-) to H(2)O provides 520 meV of energy to displace pump protons from a loading site and overall about 635 meV for each electron passing through the system. Assuming that the two charges are translocated per electron against the membrane potential of 200 meV, the model predicts an overall efficiency of 63%.

  20. A study on the relation between proton pump inhibitor and gastric giardiasis.

    PubMed

    Kader, S A; Mansour, A M; Mohran, Z; el-Taoil, A; Abdalla, K F

    1998-04-01

    Thirty patients treated with proton pump inhibitor and still having symptoms related to gastritis or peptic ulcers were subjected to upper gastrointestinal endoscopy and gastric biopsy for detection of giardiasis in these cases. Results showed presence of 3 (10%) cases of gastric giardiasis, intestinal metaplasia and presence of H. pylori in these cases. It is concluded that there may be a relation between the presence of gastric giardiasis and the intake of proton pump inhibitor. The endoscopists have to search for gastric giardiasis especially in the presence of H. pylori and/or intestinal metaplasia.

  1. Optimal use of proton pump inhibitors for treating acid peptic diseases in primary care.

    PubMed

    Tack, J; Louis, E; Persy, V; Urbain, D

    2013-12-01

    Heartburn, reflux and epigastric pain are frequently encountered symptoms in primary care medicine. Acid peptic diseases such as peptic ulcer and gastrointestinal reflux disease have a high prevalence, can have important impact on patient quality of life and represent a considerable health care cost. Proton pump inhibitors (PPIs) are the most potent pharmacological inhibitors of gastric acid secretion currently available and are the mainstay medical therapy for acid peptic diseases. This review summarizes current evidence on treatment of acid-peptic diseases with proton pump inhibitors and provides primary care clinicians with best practice guidelines for optimal use of these drugs.

  2. A case of gastric polyposis in antral area of stomach following prolonged proton-pump therapy

    PubMed Central

    Alqutub, Adel Nazmi; Masoodi, Ibrahim

    2010-01-01

    We describe the clinical scenario of a young male with history of non ulcer dyspepsia who had endoscopic evidence of gastric polyposis in antral area. The polyps disappeared four months after proton pump inhibitors were stopped. Proton pump inhibitors have been linked to gastric fundal polyposis and not antral gland polyposis. This is the first report originating from an Asian country describing antral gland polyposis (AGPs) in a patient on long-term PPI therapy with no evidence of Helicobacter pylori. A case report with brief review is presented. PMID:20930929

  3. [Proton pump inhibitors in gastro-oesophageal reflux disease: what is the further step?].

    PubMed

    Simon, Mireille; Zerbib, Frank

    2013-01-01

    Optimisation of proton pump inhibitors use may improve reflux symptoms in 20-25% of the patients. Pathological gastro-oesophageal reflux should be documented in a patient with refractory reflux symptoms using upper endoscopy and/or pH testing. While on proton pump inhibitors twice daily, persistent symptoms are not related to gastro-oesophageal refluxdisease(GERD) in 50% of the patients. The new anti-reflux compounds have yet a limited efficacy and side effects that currently limit their development.

  4. Piston-assisted proton pumping in Complex I of mitochondria membranes

    NASA Astrophysics Data System (ADS)

    Mourokh, Lev; Filonenko, Ilan

    2014-03-01

    Proton-pumping mechanism of Complex I remains mysterious because its electron and proton paths are well separated and the direct Coulomb interaction seems to be negligible. The structure of this enzyme was resolved very recently and its functionality was connected the shift of the helix HL. We model the helix as a piston oscillating between the protons and electrons. We assume that positive charges are accumulated near the edges of the helix. In the oxidized state, the piston is attracted to electrons, so its distance to the proton sites increases, the energy of these sites decreases and the sites can be populated. When electrons proceed to the drain, elastic forces return the piston to the original position and the energies of populated proton sites increase, so the protons can be transferred to the positive site of the membrane. In this work, we explore a simplified model when the interaction of the piston with electrons is replaced by a periodic force. We derive quantum Heisenberg equations for the proton operators and solve them jointly with the Langevin equation for the piston position. We show that the proton pumping is possible in such structure with parameters closely resembling the real system. We also address the feasibility of using such mechanism in nanoelectronics.

  5. Crystallographic Structure of Xanthorhodopsin, the Light-Driven Proton Pump With a Dual Chromophore

    SciTech Connect

    Luecke, H.; Schobert, B.; Stagno, J.; Imasheva, E.S.; Wang, J.M.; Balashov, S.P.; Lanyi, J.K.

    2009-05-19

    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-{angstrom} 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 pK{sub a} 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 {approx}45%, and the 46{sup o} 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.

  6. The cytochrome ba3 oxygen reductase from Thermus thermophilus uses a single input channel for proton delivery to the active site and for proton pumping

    PubMed Central

    Chang, Hsin-Yang; Hemp, James; Chen, Ying; Fee, James A.; Gennis, Robert B.

    2009-01-01

    The heme-copper oxygen reductases are redox-driven proton pumps that generate a proton motive force in both prokaryotes and mitochondria. These enzymes have been divided into 3 evolutionarily related groups: the A-, B- and C-families. Most experimental work on proton-pumping mechanisms has been performed with members of the A-family. These enzymes require 2 proton input pathways (D- and K-channels) to transfer protons used for oxygen reduction chemistry and for proton pumping, with the D-channel transporting all pumped protons. In this work we use site-directed mutagenesis to demonstrate that the ba3 oxygen reductase from Thermus thermophilus, a representative of the B-family, does not contain a D-channel. Rather, it utilizes only 1 proton input channel, analogous to that of the A-family K-channel, and it delivers protons to the active site for both O2 chemistry and proton pumping. Comparison of available subunit I sequences reveals that the only structural elements conserved within the oxygen reductase families that could perform these functions are active-site components, namely the covalently linked histidine-tyrosine, the CuB and its ligands, and the active-site heme and its ligands. Therefore, our data suggest that all oxygen reductases perform the same chemical reactions for oxygen reduction and comprise the essential elements of the proton-pumping mechanism (e.g., the proton-loading and kinetic-gating sites). These sites, however, cannot be located within the D-channel. These results along with structural considerations point to the A-propionate region of the active-site heme and surrounding water molecules as the proton-loading site. PMID:19805275

  7. The cytochrome ba3 oxygen reductase from Thermus thermophilus uses a single input channel for proton delivery to the active site and for proton pumping.

    PubMed

    Chang, Hsin-Yang; Hemp, James; Chen, Ying; Fee, James A; Gennis, Robert B

    2009-09-22

    The heme-copper oxygen reductases are redox-driven proton pumps that generate a proton motive force in both prokaryotes and mitochondria. These enzymes have been divided into 3 evolutionarily related groups: the A-, B- and C-families. Most experimental work on proton-pumping mechanisms has been performed with members of the A-family. These enzymes require 2 proton input pathways (D- and K-channels) to transfer protons used for oxygen reduction chemistry and for proton pumping, with the D-channel transporting all pumped protons. In this work we use site-directed mutagenesis to demonstrate that the ba(3) oxygen reductase from Thermus thermophilus, a representative of the B-family, does not contain a D-channel. Rather, it utilizes only 1 proton input channel, analogous to that of the A-family K-channel, and it delivers protons to the active site for both O2 chemistry and proton pumping. Comparison of available subunit I sequences reveals that the only structural elements conserved within the oxygen reductase families that could perform these functions are active-site components, namely the covalently linked histidine-tyrosine, the Cu(B) and its ligands, and the active-site heme and its ligands. Therefore, our data suggest that all oxygen reductases perform the same chemical reactions for oxygen reduction and comprise the essential elements of the proton-pumping mechanism (e.g., the proton-loading and kinetic-gating sites). These sites, however, cannot be located within the D-channel. These results along with structural considerations point to the A-propionate region of the active-site heme and surrounding water molecules as the proton-loading site.

  8. Characteristics of redox-linked proton ejection in cytochrome c oxidase reconstituted in phospholipid vesicles. New observations support mechanisms different from proton pumping.

    PubMed

    Papa, S; Lorusso, M; Capitanio, N; De Nitto, E

    1983-06-27

    Experimental observations reveal a number of characteristics of the redox-linked proton ejection from cytochrome c oxidase vesicles, which apparently cannot be explained by a proton pumping activity of the oxidase. These observations seem, on the other hand, to provide useful elements for alternative explanation(s) of the proton ejection. It is proposed here that the process is scalar and not vectorial and can derive from redox-linked rupture of protonated salt-bridges in the oxidase-lipid complex.

  9. What are the precautions with proton pump inhibitor use for reflux disease?

    PubMed

    Mospan, Cortney M

    2015-12-01

    Gastroesophageal reflux disease (GERD) affects 10% to 20% of the western world's population. Current treatment guidelines recommend proton pump inhibitors (PPIs) as first-line therapy. Although PPIs cause mild adverse reactions, they pose risks, particularly for older adults with comorbidities.

  10. Time-resolved Fourier transform infrared spectroscopy of the polarizable proton continua and the proton pump mechanism of bacteriorhodopsin.

    PubMed Central

    Wang, J; El-Sayed, M A

    2001-01-01

    Nanosecond-to-microsecond time-resolved Fourier transform infrared (FTIR) spectroscopy in the 3000-1000-cm(-1) region has been used to examine the polarizable proton continua observed in bacteriorhodopsin (bR) during its photocycle. The difference in the transient FTIR spectra in the time domain between 20 ns and 1 ms shows a broad absorption continuum band in the 2100-1800-cm(-1) region, a bleach continuum band in the 2500-2150-cm(-1) region, and a bleach continuum band above 2700 cm(-1). According to Zundel (G., J. Mol. Struct. 322:33-42), these continua appear in systems capable of forming polarizable hydrogen bonds. The formation of a bleach continuum suggests the presence of a polarizable proton in the ground state that changes during the photocycle. The appearance of a transient absorption continuum suggests a change in the polarizable proton or the appearance of new ones. It is found that each continuum has a rise time of less than 80 ns and a decay time component of approximately 300 micros. In addition, it is found that the absorption continuum in the 2100-1800-cm(-1) region has a slow rise component of 190 ns and a fast decay component of approximately 60 micros. Using these results and those of the recent x-ray structural studies of bR(570) and M(412) (H. Luecke, B. Schobert, H.T. Richter, J.-P. Cartailler, and J. K., Science 286:255-260), together with the already known spectroscopic properties of the different intermediates in the photocycle, the possible origins of the polarizable protons giving rise to these continua during the bR photocycle are proposed. Models of the proton pump are discussed in terms of the changes in these polarizable protons and the hydrogen-bonded chains and in terms of previously known results such as the simultaneous deprotonation of the protonated Schiff base (PSB) and Tyr185 and the disappearance of water molecules in the proton release channel during the proton pump process. PMID:11159463

  11. Optical silencing of C. elegans cells with light-driven proton pumps.

    PubMed

    Okazaki, Ayako; Takahashi, Megumi; Toyoda, Naoya; Takagi, Shin

    2014-08-01

    Recent development of optogenetic techniques, which utilize light-driven ion channels or ion pumps for controlling the activity of excitable cells, has greatly facilitated the investigation of nervous systems in vivo. A new generation of optical silencers includes outward-directed proton pumps, such as Arch, which have several advantages over currently widely used halorhodopsin (NpHR). These advantages include the resistance to inactivation during prolonged illumination and the ability to generate a larger optical current from low intensity light. C. elegans, with its small transparent body and well-characterized neural circuits, is especially suitable for optogenetic analyses. In this article, we will outline the practical aspects of using of Arch and other proton pumps as optogenetic tools in C. elegans.

  12. 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.

  13. Redox-Coupled Proton Pumping in Cytochrome c Oxidase: Further insights from Computer Simulation

    PubMed Central

    Xu, Jiancong; Voth, Gregory A.

    2008-01-01

    The membrane-bound enzyme cytochrome c oxidase, the terminal member in the respiratory chain, converts oxygen into water and generates an electrochemical gradient by coupling the electron transfer to proton-pumping across the membrane. Here we have investigated the dynamics of an excess proton and the surrounding protein environment near the active sites. The multi-state empirical valence bond (MS-EVB) molecular dynamics method was used to simulate the explicit dynamics of proton transfer through the critically important hydrophobic channel between Glu242 (bovine notation) and the D-propionate of heme a3 (PRDa3) for the first time. The results from these molecular dynamics simulations indicate that the PRDa3 can indeed re-orientate and dissociate from Arg438, despite the high stability of such an ion pair, and has the ability to accept protons via bound water molecules. Any large conformational change of the adjacent heme a D-propionate group is, however, sterically blocked directly by the protein. Free energy calculations of the PRDa3 side chain isomerization and the proton translocation between Glu242 and the PRDa3 site have also been performed. The results exhibit a redox state-dependent dynamical behavior and indicate that reduction of the low-spin heme a may initiate internal transfer of the pumped proton from Glu242 to the PRDa3 site. PMID:18155154

  14. Evidence for an ATP-Dependent Proton Pump on the Golgi of Corn Coleoptiles 1

    PubMed Central

    Chanson, Alain; Taiz, Lincoln

    1985-01-01

    Corn (Zea mays L. cv Trojan T929) coleoptile membranes were fractionated on sucrose density gradients, and ATP-dependent proton pumping activity was localized by the techniques of [14C]methylamine uptake and quinacrine fluorescence quenching. Two peaks of proton pumping activity were detected: a light peak (1.07 grams/cubic centimeter) corresponding to the previously characterized tonoplast-type H+-ATPase, and a second peak (1.13 grams/cubic centimeter) which coincided with the Golgi markers, latent UDPase, and glucan synthase I. The second peak was lighter than that of the plasma membrane marker, uridine diphosphoglucose-sterol glucosyltransferase (1.16 grams/cubic centimeter) and was not inhibited by vanadate, an inhibitor of the plasma membrane ATPase. The activity was also better correlated with the Golgi cisternae marker, glucan synthase I, than with latent UDPase, a secretory vesicle marker, but a secretory vesicle location cannot be ruled out. The tonoplast-type and Golgi proton pumps were similar in several respects, including a pH optimum at 7.2, stimulation by chloride, inhibition by diethylstilbestrol and N,N′-dicyclohexylcarbodiimide (DCCD), insensitivity to oligomycin and azide, and nucleotide specificity for Mg2+-ATP. However, the Golgi H+ pump was much less sensitive to nitrate and iodide, and more sensitive to the anion channel blockers, 4-acetamido-4′-isothiocyano-2,2′-stilbene sulfonic acid (SITS) and 4,4′-diisothiocyano-2,2′-stilbene disulfonic acid (DIDS) than the tonoplast-type H+-pump. The Golgi pump, but not the tonoplast-type pump, was stimulated by valinomycin in the presence of KCl. It is concluded that the Golgi of corn coleoptiles contains a KCl-stimulated H+-ATPase which can acidify the interior of Golgi cisternae and associated vesicles. PMID:16664222

  15. High-performance genetically targetable optical neural silencing by light-driven proton pumps.

    PubMed

    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

    2010-01-07

    The ability to silence the activity of genetically specified neurons in a temporally precise fashion would provide the opportunity to investigate the causal role of specific cell classes in neural computations, behaviours and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate powerful, safe, multiple-colour silencing of neural activity. The gene archaerhodopsin-3 (Arch) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in the 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. Furthermore, 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 channelrhodopsins 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 maculans (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 versus red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of 'optogenetic' voltage and ion modulator, which will broadly enable new neuroscientific, biological, neurological and psychiatric investigations.

  16. Endosomal pathways for water channel and proton pump recycling in kidney epithelial cells.

    PubMed

    Brown, D; Sabolić, I

    1993-01-01

    The plasma membrane composition of virtually all eukaryotic cells is maintained and continually modified by the recycling of specific protein and lipid components. In the kidney collecting duct, urinary acidification and urinary concentration are physiologically regulated at the cellular level by the shuttling of proton pumps and water channels between intracellular vesicles and the plasma membrane of highly specialized cell types. In the intercalated cell, hydrogen ion secretion into the urine is modulated by the recycling of vesicles carrying a proton pumping ATPase to and from the plasma membrane. In the principal cell, the antidiuretic hormone, vasopressin, induces the insertion of vesicles that contain proteinaceous water channels into the apical cell membrane, thus increasing the permeability to water of the epithelial layer. In both cell types, 'coated' carrier vesicles are involved in this process, but whereas clathrin-coated vesicles are involved in the endocytotic phase of water channel recycling, the transporting vesicles in intercalated cells are coated with the cytoplasmic domains of the proton pumping ATPase. By a combination of morphological and functional techniques using FITC-dextran as an endosomal marker, we have shown that recycling endosomes from intercalated cells are acidifying vesicles but that they do not contain water channels. In contrast, principal cell vesicles that recycle water channels do not acidify their lumens in response to ATP. These non-acidic vesicles lack functionally important subunits of the vacuolar proton ATPase, including the 16 kDa proteolipid that forms the transmembrane proton pore. Because these endosomes are directly derived via clathrin-mediated endocytosis, our results indicate that endocytotic clathrin-coated vesicles are non-acidic compartments in principal cells. In contrast, recycling vesicles in intercalated cells contain large numbers of proton pumps, arranged in hexagonally packed arrays on the vesicle

  17. Photocurrent generation based on a light-driven proton pump in an artificial liquid membrane.

    PubMed

    Xie, Xiaojiang; Crespo, Gastón A; Mistlberger, Günter; Bakker, Eric

    2014-03-01

    Biological light-driven proton pumps use light to move protons across a cell membrane, creating a proton gradient. Although photochromic compounds such as spiropyrans can reversibly convert between two structures with differing pKa values, spiropyrans have not been used to generate either a light-driven proton pump or an electrical current. Here, we report an artificial light-harvesting system based on a supported liquid membrane doped with a spiropyran. Irradiating the membrane with ultraviolet light induces a ring-opening reaction, converting spiropyran to merocyanine, whereas irradiation with visible light induces the reverse reaction. When the membrane is irradiated with ultraviolet and visible light on opposite sides, H(+) is taken up by merocyanine, carried through the polymeric membrane and released on the other side. We show that this system produces a light-induced proton flux, an electrical current with an efficiency of ∼0.12%, an open-circuit voltage of ∼210 mV and a membrane gradient of ∼3.6 ΔpH units. Alternating the sides illuminated with ultraviolet and visible light generates an alternating current.

  18. Effect of xenon binding to a hydrophobic cavity on the proton pumping cycle in bacteriorhodopsin.

    PubMed

    Hayakawa, Naoki; Kasahara, Takashi; Hasegawa, Daisuke; Yoshimura, Keiko; Murakami, Midori; Kouyama, Tsutomu

    2008-12-26

    To understand the functional role of apolar cavities in bacteriorhodopsin, a light-driven proton pump found in Halobacterium salinarum, we investigated the crystal structure in pressurized xenon or krypton. Diffraction data from the P622 crystal showed that one Xe or Kr atom binds to a preexisting hydrophobic cavity buried between helices C and D, located at the same depth from the membrane surface as Asp96, a key residue in the proton uptake pathway. The occupation fraction of Xe or Kr was calculated as approximately 0.32 at a pressure of 1 MPa. In the unphotolyzed state, the binding of Xe or Kr caused no large deformation of the cavity. However, the proton pumping cycle was greatly perturbed when an aqueous suspension of purple membrane was pressurized with xenon gas; that is, the decay of the M state was accelerated significantly (~5 times at full occupancy), while the decay of an equilibrium state of N and O was slightly decelerated. A similar but much smaller perturbation in the reaction kinetics was observed upon pressurization with krypton gas. In a glycerol/water mixture, xenon-induced acceleration of M decay became less significant in proportion to the water activity. Together with the structure of the xenon-bound protein, these observations suggest that xenon binding helps water molecules permeate into apolar cavities in the proton uptake pathway, thereby accelerating the water-mediated proton transfer from Asp96 to the Schiff base.

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

    PubMed

    Liu, Ning-Ning; Köhler, Julia R

    2016-02-01

    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.

  20. Proton pump inhibitor-amoxicillin-clarithromycin versus proton pump inhibitor-amoxicillin-metronidazole as first-line Helicobacter pylori eradication therapy.

    PubMed

    Nishizawa, Toshihiro; Suzuki, Hidekazu; Suzuki, Masayuki; Takahashi, Masahiko; Hibi, Toshifumi

    2012-09-01

    The aim of this study was to compare the efficacy and tolerability of the first-line Helicobacter pylori (H. pylori) eradication regimen composed of proton pump inhibitor, clarithromycin, and amoxicillin, with those of a regimen composed of proton pump inhibitor, metronidazole, and amoxicillin. Data of patients, who were administered the first-line H. pylori eradication regimen at Tokyo Medical Center between 2008 and 2011, were reviewed. All patients had H. pylori gastritis without peptic ulcer disease. The 7-day triple regimen composed of lansoprazole, clarithromycin, and amoxicillin was administered to 55 patients, and that composed of omeprazole, metronidazole, and amoxicillin was administered to 55 patients. Intention-to-treat and per-protocol eradication rates were 74.5 and 80.4%, respectively, for the regimen of lansoprazole, clarithromycin, and amoxicillin, whereas the corresponding rates were 96.4 and 100%, respectively, for the regimen of omeprazole, metronidazole, and amoxicillin. In conclusion, first-line H. pylori eradication therapy composed of omeprazole, metronidazole, and amoxicillin was significantly more effective than that composed of lansoprazole, clarithromycin, and amoxicillin, without differences in tolerability.

  1. Cooperative coupling and role of heme a in the proton pump of heme-copper oxidases.

    PubMed

    Papa, S; Capitanio, N; Villani, G; Capitanio, G; Bizzoca, A; Palese, L L; Carlino, V; De Nitto, E

    1998-10-01

    In the last few years, evidence has accumulated supporting the applicability of the cooperative model of proton pumps in cytochrome systems, vectorial Bohr mechanisms, to heme-copper oxidases. The vectorial Bohr mechanism is based on short- and long-range protonmotive cooperative effects linked to redox transitions of the metal centers. The crystal structure of oxidized and reduced bovine-heart cytochrome c oxidase reveals, upon reduction, the occurrence of long-range conformational changes in subunit I of the oxidase. Analysis of the crystal structure of cytochrome c oxidase shows the existence of hydrogen-bonded networks of amino acid residues which could undergo redox-linked pK shifts resulting in transmembrane proton translocation. Our group has identified four proteolytic groups undergoing reversible redox-linked pK shifts. Two groups result in being linked to redox transitions of heme a3. One group is apparently linked to CuB. The fourth group is linked to oxido-reduction of heme a. We have shown that the proton transfer resulting from the redox Bohr effects linked to heme a and CuB in the bovine oxidase displays membrane vectorial asymmetry, i.e., protons are taken up from the inner aqueous space (N), upon reduction, and released in the external space (P), upon oxidation of the metals. This direction of proton uptake and release is just what is expected from the vectorial Bohr mechanism. The group linked to heme a, which can transfer up to 0.9 H+/e- at pHs around neutrality, can provide the major contribution to the proton pump. It is proposed that translocation of pumped protons, linked to electron flow through heme a, utilizes a channel (channel D) which extends from a conserved aspartate at the N entrance to a conserved glutamate located between heme a and the binuclear center. The carboxylic group of this glutamic acid, after having delivered, upon electron flow through heme a, pumped protons towards the P phase, once reprotonated from the N phase, moves

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

    PubMed

    Qiu, Zhihong; Liu, Hongtao; He, Lien; Ma, Yinling; Song, Haojing; Bai, Wanjun; Yu, Meiling

    2016-02-01

    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.

  3. Therapeutic substitution post-patent expiry: the cases of ACE inhibitors and proton pump inhibitors.

    PubMed

    Vandoros, Sotiris

    2014-05-01

    This paper examines whether there is a switch in total (originator and generic) consumption after generic entry from molecules that face generic competition towards other molecules of the same class, which are still in-patent. Data from six European countries for the time period 1991 to 2006 are used to study the cases of angiotensin-converting enzyme inhibitors and proton pump inhibitors. Empirical evidence shows that patent expiry of captopril and enalapril led to a switch in total (off-patent originator and generic) consumption towards other in-patent angiotensin-converting enzyme inhibitors, whereas patent expiry of omeprazole led to a switch in consumption towards other proton pump inhibitors. This phenomenon makes generic policies ineffective and results in an increase in pharmaceutical expenditure due to the absence of generic alternatives in the market of in-patent molecules. Copyright © 2013 John Wiley & Sons, Ltd.

  4. Gastroesophageal reflux in children: pathogenesis, prevalence, diagnosis, and role of proton pump inhibitors in treatment.

    PubMed

    Gold, Benjamin D; Freston, James W

    2002-01-01

    A substantial percentage of infants, children and adolescents experience gastroesophageal reflux disease (GERD) and its accompanying symptoms, as well as disease complications. The diagnosis of GERD in children is made based upon the child's history, and data derived primarily from pH monitoring tests and endoscopy. In those children with confirmed reflux disease, the options for management parallel those recommended in adult patients, with the first step consisting of lifestyle changes. Surgical procedures may also be performed; however, these are rarely recommended prior to an adequate course of pharmacologic therapy, and appropriate case selection is important. Among the current pharmacotherapeutic options available in the US, the prokinetic agents and the acid-inhibitory agents (histamine-2 receptor antagonists, proton pump inhibitors) are the most widely used. The clinical utility of the prokinetic agents has been limited by the recent withdrawal of cisapride from the US marketplace and the potential for irreversible central nervous system complications with metoclopramide. Numerous clinical studies performed in adults, and several studies involving children, have demonstrated that the proton pump inhibitors are more effective than the histamine-2 receptor antagonists in the relief of GERD symptoms and healing of erosive esophagitis. In children, omeprazole and lansoprazole may be administered as the intact oral capsule, or in those who are unable or unwilling to swallow, the granule contents of the capsule may be mixed with soft foods (e.g. apple sauce) or fruit drinks/liquid dietary supplements prior to oral administration with no detrimental effects on pharmacokinetics, bioavailability, or pharmacodynamics. Studies performed with omeprazole and lansoprazole in children have shown pharmacokinetic parameters that closely resemble those observed in adults. In over a decade of use in adults, the proton pump inhibitor class of agents has been found to have a

  5. The relationship between long-term proton pump inhibitor therapy and skeletal frailty.

    PubMed

    Lau, Arthur N; Tomizza, Michael; Wong-Pack, Matthew; Papaioannou, Alexandra; Adachi, Jonathan D

    2015-08-01

    Proton pump inhibitors (PPIs) are a commonly prescribed class of medications. Their use has been associated with an increased rate of fractures, most notably hip fractures. However, there does not seem to be a clear association between PPI use and bone mineral density measurements, assessed by dual X-ray absorptiometry. The mechanism by which PPI use increases the risk of fractures remains unclear. This review will summarize the current evidence on this topic.

  6. Atomistic Characterization of the First Step of Calcium Pump Activation Associated with Proton Countertransport.

    PubMed

    Ramírez-Salinas, G Lizbeth; Espinoza-Fonseca, L Michel

    2015-08-25

    The calcium pump [sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA)] transports Ca(2+) from the cytosol to the SR lumen at the expense of ATP hydrolysis and proton countertransport, thus playing a central role in Ca(2+) homeostasis and muscle contractility. Proton countertransport via deprotonation of transport site residue Glu309 is a critical first step in SERCA activation because it accelerates the E2-E1 structural transition. Previous studies have suggested that flipping of Glu309 toward the cytosol constitutes the primary mechanism for Glu309 deprotonation, but no conclusive data to support this hypothesis have been published. Therefore, we performed three independent 1 μs molecular dynamics simulations of the E2 state protonated at transport site residues Glu309, Glu771, and Glu908. Structural analysis and pKa calculations showed that Glu309 deprotonation occurs by an inward-to-outward side-chain transition. We also found that Glu309 deprotonation and proton countertransport occur through transient (~113 ps) water wires connecting Glu309 with the cytosol. Although both mechanisms are operational, we found that transient water wire formation, and not Glu309 flipping, is the primary mechanism for Glu309 deprotonation and translocation of protons to the cytosol. The outward-to-inward transition of protonated Glu309 and the presence of water wires suggest that protons from the cytosol might be passively transported to the lumen via Glu309. However, structural analysis indicates that passive SR proton leakage into the lumen unlikely occurs through Glu309 in the E2 state. These findings provide a time-resolved visualization of the first step in the molecular mechanism of SERCA activation and proton transport across the SR.

  7. A proton pumping pyrophosphatase in acidocalcisomes of Herpetomonas sp.

    PubMed

    Soares Medeiros, Lia Carolina A; Moreira, Bernardo Luis Moraes; Miranda, Kildare; de Souza, Wanderley; Plattner, Helmut; Hentschel, Joachim; Barrabin, Hector

    2005-04-01

    Acidocalcisomes are acidic calcium storage organelles found in several microorganisms. They are characterized by their acidic nature, high electron density, high content of polyphosphates and several cations. Electron microscopy contrast tuned images of Herpetomonas sp. showed the presence of several electron dense organelles ranging from 100 to 300 nm in size. In addition, X-ray element mapping associated with energy-filtering transmission electron microscopy showed that most of the cations, namely Na, Mg, P, K, Fe and Zn, are located in their matrix. Using acridine orange as an indicator dye, a pyrophosphate-driven H+ uptake was measured in cells permeabilized by digitonin. This uptake has an optimal pH of 6.5-6.7 and was inhibited by sodium fluoride (NaF) and imidodiphosphate (IDP), two H+-pyrophosphatase inhibitors. H+ uptake was not promoted by ATP. Addition of 50 microM Ca2+ induced the release of H+, suggesting the presence of a Ca2+/H+ countertransport system in the membranes of the acidic compartments. Na+ was unable to release protons from the organelles. The pyrophosphate-dependent H+ uptake was dependent of ion K+ and inhibited by Na+ Herpetomonas sp. immunolabeled with monoclonal antibodies raised against a Trypanosoma cruzi V-H+-pyrophosphatase shows intense fluorescence in cytoplasmatic organelles of size and distribution similar to the electron-dense vacuoles. Together, these results suggest that the electron dense organelles found in Herpetomonas sp. are homologous to the acidocalcisomes described in other trypanosomatids. They possess a vacuolar H+-pyrophosphatase and a Ca2+/H+ antiport. However, in contrast to the other trypanosomatids so far studied, we were not able to measure any ATP promoted H+ transport in the acidocalcisomes of this parasite.

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

    PubMed

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

    2014-10-24

    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.

  9. Proton pump inhibitors as anti vacuolar-ATPases drugs: a novel anticancer strategy.

    PubMed

    Spugnini, Enrico P; Citro, Gennaro; Fais, Stefano

    2010-05-08

    The vacuolar ATPases are ATP-dependent proton pumps whose functions include the acidification of intracellular compartments and the extrusion of protons through the cell cytoplasmic membrane. These pumps play a pivotal role in the regulation of cell pH in normal cells and, to a much greater extent, in tumor cells. In fact, the glucose metabolism in hypoxic conditions by the neoplasms leads to an intercellular pH drift towards acidity. The acid microenvironment is modulated through the over-expression of H+ transporters that are also involved in tumor progression, invasiveness, distant spread and chemoresistance. Several strategies to block/downmodulate the efficiency of these transporters are currently being investigated. Among them, proton pump inhibitors have shown to successfully block the H+ transporters in vitro and in vivo, leading to apoptotic death. Furthermore, their action seems to synergize with conventional chemotherapy protocols, leading to chemosensitization and reversal of chemoresistance. Aim of this article is to critically revise the current knowledge of this cellular machinery and to summarize the therapeutic strategies developed to counter this mechanism.

  10. 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.

  11. Comparative Study of Proton Pump Inhibitors on Dexamethasone Plus Pylorus Ligation Induced Ulcer Model in Rats

    PubMed Central

    Thippeswamy, A. H. M.; Sajjan, M.; Palkar, M. B.; Koti, B. C.; Viswanathaswamy, A. H. M.

    2010-01-01

    The present study was designed to compare ulcer protective effect of proton pump inhibitors viz. omeprazole, rabeprazole and lansoprazole against dexamethasone plus pylorus ligation induced ulcer model. Dexamethasone (5 mg/kg) was used as an ulcerogen. Dexamethasone suspended in 1% CMC in water was given orally to all the rats 15 min after the pylorus ligation. Omeprazole (20 mg/kg), rabeprazole (20 mg/kg), and lansoprazole (20 mg/kg) were administered by oral route 30 min prior to ligation was used for ulcer protective studies, gastric secretion and mucosal studies. Effects of proton pump inhibitors were determined by the evaluation of various biochemical parameters such as ulcer index, free and total acidity, gastric pH, mucin, pepsin and total proteins. Oral administration of proton pump inhibitors showed significant reduction in gastric acid secretion and ulcer protective activity against dexamethasone plus pylorus ligation induced ulcer model. The % protection of omeprazole, rabeprazole and lansoprazole was 84.04, 89.36 and 79.78, respectively. Rabeprazole significantly inhibited the acid-pepsin secretion and increased the gastric mucin secretion. The observations made in the present study suggest that rabeprazole is the most effective gastric antisecretory and ulcer healing agent as compared to omeprazole and lansoprazole. PMID:21188049

  12. Proton Pump Inhibition Increases Rapid Eye Movement Sleep in the Rat

    PubMed Central

    Jha, Sushil K.

    2014-01-01

    Increased bodily CO2 concentration alters cellular pH as well as sleep. The proton pump, which plays an important role in the homeostatic regulation of cellular pH, therefore, may modulate sleep. We investigated the effects of the proton pump inhibitor “lansoprazole” on sleep-wakefulness. Male Wistar rats were surgically prepared for chronic polysomnographic recordings. Two different doses of lansoprazole (low: 1 mg/kg; high: 10 mg/kg) were injected intraperitoneally in the same animal (n = 7) and sleep-wakefulness was recorded for 6 hrs. The changes in sleep-wakefulness were compared statistically. Percent REM sleep amount in the vehicle and lansoprazole low dose groups was 9.26 ± 1.03 and 9.09 ± 0.54, respectively, which increased significantly in the lansoprazole high dose group by 31.75% (from vehicle) and 34.21% (from low dose). Also, REM sleep episode numbers significantly increased in lansoprazole high dose group. Further, the sodium-hydrogen exchanger blocker “amiloride” (10 mg/kg; i.p.) (n = 5) did not alter sleep-wake architecture. Our results suggest that the proton pump plays an important role in REM sleep modulation and supports our view that REM sleep might act as a sentinel to help maintain normal CO2 level for unperturbed sleep. PMID:24701564

  13. Architecture of complex I and its implications for electron transfer and proton pumping.

    PubMed

    Zickermann, Volker; Kerscher, Stefan; Zwicker, Klaus; Tocilescu, Maja A; Radermacher, Michael; Brandt, Ulrich

    2009-06-01

    Proton pumping NADH:ubiquinone oxidoreductase (complex I) is the largest and remains by far the least understood enzyme complex of the respiratory chain. It consists of a peripheral arm harbouring all known redox active prosthetic groups and a membrane arm with a yet unknown number of proton translocation sites. The ubiquinone reduction site close to iron-sulfur cluster N2 at the interface of the 49-kDa and PSST subunits has been mapped by extensive site directed mutagenesis. Independent lines of evidence identified electron transfer events during reduction of ubiquinone to be associated with the potential drop that generates the full driving force for proton translocation with a 4H(+)/2e(-) stoichiometry. Electron microscopic analysis of immuno-labelled native enzyme and of a subcomplex lacking the electron input module indicated a distance of 35-60 A of cluster N2 to the membrane surface. Resolution of the membrane arm into subcomplexes showed that even the distal part harbours subunits that are prime candidates to participate in proton translocation because they are homologous to sodium/proton antiporters and contain conserved charged residues in predicted transmembrane helices. The mechanism of redox linked proton translocation by complex I is largely unknown but has to include steps where energy is transmitted over extremely long distances. In this review we compile the available structural information on complex I and discuss implications for complex I function.

  14. Architecture of complex I and its implications for electron transfer and proton pumping

    PubMed Central

    Zickermann, Volker; Kerscher, Stefan; Zwicker, Klaus; Tocilescu, Maja A.; Radermacher, Michael; Brandt, Ulrich

    2009-01-01

    Proton pumping NADH:ubiquinone oxidoreductase (complex I) is the largest and remains by far the least understood enzyme complex of the respiratory chain. It consists of a peripheral arm harbouring all known redox active prosthetic groups and a membrane arm with a yet unknown number of proton translocation sites. The ubiquinone reduction site close to iron-sulfur cluster N2 at the interface of the 49-kDa and PSST subunits has been mapped by extensive site directed mutagenesis. Independent lines of evidence identified electron transfer events during reduction of ubiquinone to be associated with the potential drop that generates the full driving force for proton translocation with a 4 H+/2e− stoichiometry. Electron microscopic analysis of immuno-labelled native enzyme and of a subcomplex lacking the electron input module indicated a distance of 35–60 Å of cluster N2 to the membrane surface. Resolution of the membrane arm into subcomplexes showed that even the distal part harbours subunits that are prime candidates to participate in proton translocation because they are homologous to sodium/proton antiporters and contain conserved charged residues in predicted transmembrane helices. The mechanism of redox linked proton translocation by complex I is largely unknown but has to include steps where energy is transmitted over extremely long distances. In this review we compile the available structural information on complex I and discuss implications for complex I function. PMID:19366614

  15. [Alteration of transport activity of proton pumps in coleoptile cells during early development stages of maize seedlings].

    PubMed

    Shishova, M F; Tankeliun, O V; Rudashevskaia, E L; Emel'ianov, V V; Shakhova, N V; Kirpichnikova, A A

    2012-01-01

    Comparative analysis of the transport activity of proton pumps (plasmalemma H+-ATPase, vacuolar H+-ATPase, and vacuolar H+-pyrophosphatase) in the membrane preparations obtained from coleoptile cells ofetiolated maize seedlings (Zea mays L.) was carried out. The highest level ofvacuolar pyrophosphatase activity was observed during the early development of coleoptile cells under growth intensification through the elongation. The role of ATPase pumps of tonoplast and plasmalemma in the transport of hydrogen ions increases during further development. The plasmalemma activity in this process is higher. When the growth stops, the activity of proton pumps becomes significantly lower. Nevertheless, their substrate specificity and sensitivity to proton pump inhibitors do not change, which can be an evidence of physiological significance of pumps in the maintenance of cell homeostasis.

  16. Route, mechanism, and implications of proton import during Na+/K+ exchange by native Na+/K+-ATPase pumps.

    PubMed

    Vedovato, Natascia; Gadsby, David C

    2014-04-01

    A single Na(+)/K(+)-ATPase pumps three Na(+) outwards and two K(+) inwards by alternately exposing ion-binding sites to opposite sides of the membrane in a conformational sequence coupled to pump autophosphorylation from ATP and auto-dephosphorylation. The larger flow of Na(+) than K(+) generates outward current across the cell membrane. Less well understood is the ability of Na(+)/K(+) pumps to generate an inward current of protons. Originally noted in pumps deprived of external K(+) and Na(+) ions, as inward current at negative membrane potentials that becomes amplified when external pH is lowered, this proton current is generally viewed as an artifact of those unnatural conditions. We demonstrate here that this inward current also flows at physiological K(+) and Na(+) concentrations. We show that protons exploit ready reversibility of conformational changes associated with extracellular Na(+) release from phosphorylated Na(+)/K(+) pumps. Reversal of a subset of these transitions allows an extracellular proton to bind an acidic side chain and to be subsequently released to the cytoplasm. This back-step of phosphorylated Na(+)/K(+) pumps that enables proton import is not required for completion of the 3 Na(+)/2 K(+) transport cycle. However, the back-step occurs readily during Na(+)/K(+) transport when external K(+) ion binding and occlusion are delayed, and it occurs more frequently when lowered extracellular pH raises the probability of protonation of the externally accessible carboxylate side chain. The proton route passes through the Na(+)-selective binding site III and is distinct from the principal pathway traversed by the majority of transported Na(+) and K(+) ions that passes through binding site II. The inferred occurrence of Na(+)/K(+) exchange and H(+) import during the same conformational cycle of a single molecule identifies the Na(+)/K(+) pump as a hybrid transporter. Whether Na(+)/K(+) pump-mediated proton inflow may have any physiological or

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

    PubMed

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

    2015-09-15

    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.

  18. 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

  19. Effects of rikkunshito on quality of life in patients with gastroesophageal reflux disease refractory to proton pump inhibitor therapy

    PubMed Central

    Kawai, Takashi; Hirayama, Yoji; Oguchi, Aiko; Ishii, Fumi; Matushita, Masanao; Kitayama, Naoya; Morishita, Shinji; Hiratsuka, Noboru; Ohata, Ken; Konishi, Hiroyuki; Kishino, Maiko; Nakamura, Shinichi

    2017-01-01

    We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6–8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.

  20. Effect of proton pump inhibitors on markers of risk for high-grade dysplasia and oesophageal cancer in Barrett's oesophagus.

    PubMed

    Hillman, L C; Chiragakis, L; Shadbolt, B; Kaye, G L; Clarke, A C

    2008-02-15

    It has been shown that the presence on diagnosis of endoscopic macroscopic markers indicates a high-risk group for Barrett's oesophagus. To determine whether proton pump inhibitor therapy prior to diagnosis of Barrett's oesophagus influences markers for risk development of subsequent high-grade dysplasia/adenocarcinoma. A review of all patients with Barrett's oesophagus entering a surveillance programme was undertaken. Five hundred and two patients diagnosed with Barrett's oesophagus were assessed on diagnosis for endoscopic macroscopic markers or low-grade dysplasia. Subsequent development of high-grade dysplasia/adenocarcinoma was documented. The relationship between the initiation of proton pump inhibitor therapy prior to the diagnosis of BE and the presence of macroscopic markers or low-grade dysplasia at entry was determined. Fourteen patients developed high-grade dysplasia/adenocarcinoma during surveillance. Patients who entered without prior proton pump inhibitor therapy were 3.4 times (95% CI: 1.98-5.85) more likely to have a macroscopic marker or low-grade dysplasia than those patients already on a proton pump inhibitor. Use of proton pump inhibitor therapy prior to diagnosis of Barrett's oesophagus significantly reduced the presence of markers used to stratify patient risk. Widespread use of proton pump inhibitors will confound surveillance strategies for patients with Barrett's oesophagus based on entry characteristics but is justified because of the lower risk of neoplastic progression.

  1. Voltage dependence of proton pumping by bacteriorhodopsin mutants with altered lifetime of the M intermediate.

    PubMed

    Geibel, Sven; Lörinczi, Éva; 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

  2. 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

  3. Apical endosomes isolated from kidney collecting duct principal cells lack subunits of the proton pumping ATPase.

    PubMed

    Sabolić, I; Wuarin, F; Shi, L B; Verkman, A S; Ausiello, D A; Gluck, S; Brown, D

    1992-10-01

    Endocytic vesicles that are involved in the vasopressin-stimulated recycling of water channels to and from the apical membrane of kidney collecting duct principal cells were isolated from rat renal papilla by differential and Percoll density gradient centrifugation. Fluorescence quenching measurements showed that the isolated vesicles maintained a high, HgCl2-sensitive water permeability, consistent with the presence of vasopressin-sensitive water channels. They did not, however, exhibit ATP-dependent luminal acidification, nor any N-ethylmaleimide-sensitive ATPase activity, properties that are characteristic of most acidic endosomal compartments. Western blotting with specific antibodies showed that the 31- and 70-kD cytoplasmically oriented subunits of the vacuolar proton pump were not detectable in these apical endosomes from the papilla, whereas they were present in endosomes prepared in parallel from the cortex. In contrast, the 56-kD subunit of the proton pump was abundant in papillary endosomes, and was localized at the apical pole of principal cells by immunocytochemistry. Finally, an antibody that recognizes the 16-kD transmembrane subunit of oat tonoplast ATPase cross-reacted with a distinct 16-kD band in cortical endosomes, but no 16-kD band was detectable in endosomes from the papilla. This antibody also recognized a 16-kD band in affinity-purified H+ ATPase preparations from bovine kidney medulla. Therefore, early endosomes derived from the apical plasma membrane of collecting duct principal cells fail to acidify because they lack functionally important subunits of a vacuolar-type proton pumping ATPase, including the 16-kD transmembrane domain that serves as the proton-conducting channel, and the 70-kD cytoplasmic subunit that contains the ATPase catalytic site. This specialized, non-acidic early endosomal compartment appears to be involved primarily in the hormonally induced recycling of water channels to and from the apical plasma membrane of

  4. How cytochrome c oxidase can pump four protons per oxygen molecule at high electrochemical gradient.

    PubMed

    Blomberg, Margareta R A; Siegbahn, Per E M

    2015-03-01

    Experiments have shown that the A-family cytochrome c oxidases pump four protons per oxygen molecule, also at a high electrochemical gradient. This has been considered a puzzle, since two of the reduction potentials involved, Cu(II) and Fe(III), were estimated from experiments to be too low to afford proton pumping at a high gradient. The present quantum mechanical study (using hybrid density functional theory) suggests a solution to this puzzle. First, the calculations show that the charge compensated Cu(II) potential for CuB is actually much higher than estimated from experiment, of the same order as the reduction potentials for the tyrosyl radical and the ferryl group, which are also involved in the catalytic cycle. The reason for the discrepancy between theory and experiment is the very large uncertainty in the experimental observations used to estimate the equilibrium potentials, mainly caused by the lack of methods for direct determination of reduced CuB. Second, the calculations show that a high energy metastable state, labeled EH, is involved during catalytic turnover. The EH state mixes the low reduction potential of Fe(III) in heme a3 with another, higher potential, here suggested to be that of the tyrosyl radical, resulting in enough exergonicity to allow proton pumping at a high gradient. In contrast, the corresponding metastable oxidized state, OH, is not significantly higher in energy than the resting state, O. Finally, to secure the involvement of the high energy EH state it is suggested that only one proton is taken up via the K-channel during catalytic turnover.

  5. Apical endosomes isolated from kidney collecting duct principal cells lack subunits of the proton pumping ATPase

    PubMed Central

    1992-01-01

    Endocytic vesicles that are involved in the vasopressin-stimulated recycling of water channels to and from the apical membrane of kidney collecting duct principal cells were isolated from rat renal papilla by differential and Percoll density gradient centrifugation. Fluorescence quenching measurements showed that the isolated vesicles maintained a high, HgCl2-sensitive water permeability, consistent with the presence of vasopressin-sensitive water channels. They did not, however, exhibit ATP-dependent luminal acidification, nor any N-ethylmaleimide-sensitive ATPase activity, properties that are characteristic of most acidic endosomal compartments. Western blotting with specific antibodies showed that the 31- and 70-kD cytoplasmically oriented subunits of the vacuolar proton pump were not detectable in these apical endosomes from the papilla, whereas they were present in endosomes prepared in parallel from the cortex. In contrast, the 56-kD subunit of the proton pump was abundant in papillary endosomes, and was localized at the apical pole of principal cells by immunocytochemistry. Finally, an antibody that recognizes the 16-kD transmembrane subunit of oat tonoplast ATPase cross-reacted with a distinct 16-kD band in cortical endosomes, but no 16-kD band was detectable in endosomes from the papilla. This antibody also recognized a 16-kD band in affinity- purified H+ ATPase preparations from bovine kidney medulla. Therefore, early endosomes derived from the apical plasma membrane of collecting duct principal cells fail to acidify because they lack functionally important subunits of a vacuolar-type proton pumping ATPase, including the 16-kD transmembrane domain that serves as the proton-conducting channel, and the 70-kD cytoplasmic subunit that contains the ATPase catalytic site. This specialized, non-acidic early endosomal compartment appears to be involved primarily in the hormonally induced recycling of water channels to and from the apical plasma membrane of

  6. The Mg2+-containing Water Cluster of Mammalian Cytochrome c Oxidase Collects Four Pumping Proton Equivalents in Each Catalytic Cycle.

    PubMed

    Yano, Naomine; Muramoto, Kazumasa; Shimada, Atsuhiro; Takemura, Shuhei; Baba, Junpei; Fujisawa, Hidenori; Mochizuki, Masao; Shinzawa-Itoh, Kyoko; Yamashita, Eiki; Tsukihara, Tomitake; Yoshikawa, Shinya

    2016-11-11

    Bovine heart cytochrome c oxidase (CcO) pumps four proton equivalents per catalytic cycle through the H-pathway, a proton-conducting pathway, which includes a hydrogen bond network and a water channel operating in tandem. Protons are transferred by H3O(+) through the water channel from the N-side into the hydrogen bond network, where they are pumped to the P-side by electrostatic repulsion between protons and net positive charges created at heme a as a result of electron donation to O2 bound to heme a3 To block backward proton movement, the water channel remains closed after O2 binding until the sequential four-proton pumping process is complete. Thus, the hydrogen bond network must collect four proton equivalents before O2 binding. However, a region with the capacity to accept four proton equivalents was not discernable in the x-ray structures of the hydrogen bond network. The present x-ray structures of oxidized/reduced bovine CcO are improved from 1.8/1.9 to 1.5/1.6 Å resolution, increasing the structural information by 1.7/1.6 times and revealing that a large water cluster, which includes a Mg(2+) ion, is linked to the H-pathway. The cluster contains enough proton acceptor groups to retain four proton equivalents. The redox-coupled x-ray structural changes in Glu(198), which bridges the Mg(2+) and CuA (the initial electron acceptor from cytochrome c) sites, suggest that the CuA-Glu(198)-Mg(2+) system drives redox-coupled transfer of protons pooled in the water cluster to the H-pathway. Thus, these x-ray structures indicate that the Mg(2+)-containing water cluster is the crucial structural element providing the effective proton pumping in bovine CcO.

  7. A blue-shifted light-driven proton pump for neural silencing.

    PubMed

    Sudo, Yuki; Okazaki, Ayako; Ono, Hikaru; Yagasaki, Jin; Sugo, Seiya; Kamiya, Motoshi; Reissig, Louisa; Inoue, Keiichi; Ihara, Kunio; Kandori, Hideki; Takagi, Shin; Hayashi, Shigehiko

    2013-07-12

    Ion-transporting rhodopsins are widely utilized as optogenetic tools both for light-induced neural activation and silencing. The most studied representative is Bacteriorhodopsin (BR), which absorbs green/red light (∼570 nm) and functions as a proton pump. Upon photoexcitation, BR induces a hyperpolarization across the membrane, which, if incorporated into a nerve cell, results in its neural silencing. In this study, we show that several residues around the retinal chromophore, which are completely conserved among BR homologs from the archaea, are involved in the spectral tuning in a BR homolog (HwBR) and that the combination mutation causes a large spectral blue shift (λmax = 498 nm) while preserving the robust pumping activity. Quantum mechanics/molecular mechanics calculations revealed that, compared with the wild type, the β-ionone ring of the chromophore in the mutant is rotated ∼130° because of the lack of steric hindrance between the methyl groups of the retinal and the mutated residues, resulting in the breakage of the π conjugation system on the polyene chain of the retinal. By the same mutations, similar spectral blue shifts are also observed in another BR homolog, archearhodopsin-3 (also called Arch). The color variant of archearhodopsin-3 could be successfully expressed in the neural cells of Caenorhabditis elegans, and illumination with blue light (500 nm) led to the effective locomotory paralysis of the worms. Thus, we successfully produced a blue-shifted proton pump for neural silencing.

  8. Design of Photoactive Ruthenium Complexes to Study Electron Transfer and Proton Pumping in Cytochrome Oxidase

    PubMed Central

    Durham, Bill; Millett, Francis

    2011-01-01

    This review describes the development and application of photoactive ruthenium complexes to study electron transfer and proton pumping reactions in cytochrome c oxidase (CcO). CcO uses four electrons from Cc to reduce O2 to two waters, and pumps four protons across the membrane. The electron transfer reactions in cytochrome oxidase are very rapid, and cannot be resolved by stopped-flow mixing techniques. Methods have been developed to covalently attach a photoactive tris(bipyridine)ruthenium group [Ru(II)] to Cc to form Ru-39-Cc. Photoexcitation of Ru(II) to the excited state Ru(II*), a strong reductant, leads to rapid electron transfer to the ferric heme group in Cc, followed by electron transfer to CuA in CcO with a rate constant of 60,000 s−1. Ruthenium kinetics and mutagenesis studies have been used to define the domain for the interaction between Cc and CcO. New ruthenium dimers have also been developed to rapidly inject electrons into CuA of CcO with yields as high as 60%, allowing measurement of the kinetics of electron transfer and proton release at each step in the oxygen reduction mechanism. PMID:21939635

  9. A combined picture from theory and experiments on water oxidation, oxygen reduction and proton pumping.

    PubMed

    Siegbahn, Per E M; Blomberg, Margareta R A

    2009-08-14

    In order to illustrate how theory and experiments can be combined, examples are taken from two projects that have been going on for a decade. The goal is to obtain the full mechanistic picture of water oxidation in photosystem II and proton pumping in cytochrome c oxidase. It is argued that for obtaining a complete description of these processes, both experiments and theoretical calculations are needed. It is obvious that there are aspects, which are out of reach for computations, but there are also key aspects that can not be obtained by experiments. This concerns very short-lived species but also, in the case of photosynthesis in particular, structural information that is presently out of reach. The main contributions from theory in the present cases, is for photosynthesis a mechanism for O-O bond formation including new and improved structures for all S-states, and for proton pumping a plausible and simple mechanism for proton gating. The examples also illustrate that sometimes rather qualitative experimental information can be of highest importance.

  10. Design of photoactive ruthenium complexes to study electron transfer and proton pumping in cytochrome oxidase.

    PubMed

    Durham, Bill; Millett, Francis

    2012-04-01

    This review describes the development and application of photoactive ruthenium complexes to study electron transfer and proton pumping reactions in cytochrome c oxidase (CcO). CcO uses four electrons from Cc to reduce O(2) to two waters, and pumps four protons across the membrane. The electron transfer reactions in cytochrome oxidase are very rapid, and cannot be resolved by stopped-flow mixing techniques. Methods have been developed to covalently attach a photoactive tris(bipyridine)ruthenium group [Ru(II)] to Cc to form Ru-39-Cc. Photoexcitation of Ru(II) to the excited state Ru(II*), a strong reductant, leads to rapid electron transfer to the ferric heme group in Cc, followed by electron transfer to Cu(A) in CcO with a rate constant of 60,000s(-1). Ruthenium kinetics and mutagenesis studies have been used to define the domain for the interaction between Cc and CcO. New ruthenium dimers have also been developed to rapidly inject electrons into Cu(A) of CcO with yields as high as 60%, allowing measurement of the kinetics of electron transfer and proton release at each step in the oxygen reduction mechanism.

  11. Enhancement of survival and electricity production in an engineered bacterium by light-driven proton pumping.

    PubMed

    Johnson, Ethan T; Baron, Daniel B; Naranjo, Belén; Bond, Daniel R; Schmidt-Dannert, Claudia; Gralnick, Jeffrey A

    2010-07-01

    Microorganisms can use complex photosystems or light-dependent proton pumps to generate membrane potential and/or reduce electron carriers to support growth. The discovery that proteorhodopsin is a light-dependent proton pump that can be expressed readily in recombinant bacteria enables development of new strategies to probe microbial physiology and to engineer microbes with new light-driven properties. Here, we describe functional expression of proteorhodopsin and light-induced changes in membrane potential in the bacterium Shewanella oneidensis strain MR-1. We report that there were significant increases in electrical current generation during illumination of electrochemical chambers containing S. oneidensis expressing proteorhodopsin. We present evidence that an engineered strain is able to consume lactate at an increased rate when it is illuminated, which is consistent with the hypothesis that proteorhodopsin activity enhances lactate uptake by increasing the proton motive force. Our results demonstrate that there is coupling of a light-driven process to electricity generation in a nonphotosynthetic engineered bacterium. Expression of proteorhodopsin also preserved the viability of the bacterium under nutrient-limited conditions, providing evidence that fulfillment of basic energy needs of organisms may explain the widespread distribution of proteorhodopsin in marine environments.

  12. 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

    2015-08-04

    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.

  13. Respiratory Complex I in Bos taurus and Paracoccus denitrificans Pumps Four Protons across the Membrane for Every NADH Oxidized.

    PubMed

    Jones, Andrew J Y; Blaza, James N; Varghese, Febin; Hirst, Judy

    2017-03-24

    Respiratory complex I couples electron transfer between NADH and ubiquinone to proton translocation across an energy-transducing membrane to support the proton-motive force that drives ATP synthesis. The proton-pumping stoichiometry of complex I (i.e. the number of protons pumped for each two electrons transferred) underpins all mechanistic proposals. However, it remains controversial and has not been determined for any of the bacterial enzymes that are exploited as model systems for the mammalian enzyme. Here, we describe a simple method for determining the proton-pumping stoichiometry of complex I in inverted membrane vesicles under steady-state ADP-phosphorylating conditions. Our method exploits the rate of ATP synthesis, driven by oxidation of NADH or succinate with different sections of the respiratory chain engaged in catalysis as a proxy for the rate of proton translocation and determines the stoichiometry of complex I by reference to the known stoichiometries of complexes III and IV. Using vesicles prepared from mammalian mitochondria (from Bos taurus) and from the bacterium Paracoccus denitrificans, we show that four protons are pumped for every two electrons transferred in both cases. By confirming the four-proton stoichiometry for mammalian complex I and, for the first time, demonstrating the same value for a bacterial complex, we establish the utility of P. denitrificans complex I as a model system for the mammalian enzyme. P. denitrificans is the first system described in which mutagenesis in any complex I core subunit may be combined with quantitative proton-pumping measurements for mechanistic studies.

  14. Respiratory Complex I in Bos taurus and Paracoccus denitrificans Pumps Four Protons across the Membrane for Every NADH Oxidized*

    PubMed Central

    Jones, Andrew J. Y.; Blaza, James N.; Varghese, Febin; Hirst, Judy

    2017-01-01

    Respiratory complex I couples electron transfer between NADH and ubiquinone to proton translocation across an energy-transducing membrane to support the proton-motive force that drives ATP synthesis. The proton-pumping stoichiometry of complex I (i.e. the number of protons pumped for each two electrons transferred) underpins all mechanistic proposals. However, it remains controversial and has not been determined for any of the bacterial enzymes that are exploited as model systems for the mammalian enzyme. Here, we describe a simple method for determining the proton-pumping stoichiometry of complex I in inverted membrane vesicles under steady-state ADP-phosphorylating conditions. Our method exploits the rate of ATP synthesis, driven by oxidation of NADH or succinate with different sections of the respiratory chain engaged in catalysis as a proxy for the rate of proton translocation and determines the stoichiometry of complex I by reference to the known stoichiometries of complexes III and IV. Using vesicles prepared from mammalian mitochondria (from Bos taurus) and from the bacterium Paracoccus denitrificans, we show that four protons are pumped for every two electrons transferred in both cases. By confirming the four-proton stoichiometry for mammalian complex I and, for the first time, demonstrating the same value for a bacterial complex, we establish the utility of P. denitrificans complex I as a model system for the mammalian enzyme. P. denitrificans is the first system described in which mutagenesis in any complex I core subunit may be combined with quantitative proton-pumping measurements for mechanistic studies. PMID:28174301

  15. TOPPITS: Trial Of Proton Pump Inhibitors in Throat Symptoms. Study protocol for a randomised controlled trial.

    PubMed

    Watson, Gillian; O'Hara, James; Carding, Paul; Lecouturier, Jan; Stocken, Deborah; Fouweather, Tony; Wilson, Janet

    2016-04-01

    Persistent throat symptoms and Extra Oesophageal Reflux (EOR) are among the commonest reasons for attendance at a secondary care throat or voice clinic. There is a growing trend to treat throat symptom patients with proton pump inhibitors (PPIs) to suppress stomach acid, but most controlled studies fail to demonstrate a significant benefit of PPI over placebo. In addition, patient views on PPI use vary widely. A UK multi-centre, randomised, controlled trial for adults with persistent throat symptoms to compare the effectiveness of treatment with the proton pump inhibitor (PPI) lansoprazole versus placebo. The trial includes a six-month internal pilot, during which three sites will recruit 30 participants in total, to assess the practicality of the trial and assess the study procedures and willingness of the patient population to participate. If the pilot is successful, three additional sites will be opened to recruitment, and a further 302 participants recruited across the six main trial sites. Further trial sites may be opened, as necessary. The main trial will continue for a further 18 months. Participants will be followed up for 12 months from randomisation, throughout which both primary and secondary outcome data will be collected. The primary outcome is change in Reflux Symptom Index (RSI) score, the 'area standard' for this type of assessment, after 16 weeks (four months) of treatment. Secondary outcomes are RSI changes at 12 months after randomisation, Quality of Life assessment at four and 12 months, laryngeal mucosal changes, assessments of compliance and side effects, and patient-reported satisfaction. TOPPITS is designed to evaluate the relative effectiveness of treatment with a proton pump inhibitor versus placebo in patients with persistent throat symptoms. This will provide valuable information to clinicians and GPs regarding the treatment and management of care for these patients, on changes in symptoms, and in Quality of Life, over time. ISRCTN

  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. FTIR spectroscopic study on individual amino acid residues in the proton pumping process of bacteriorhodopsin

    NASA Astrophysics Data System (ADS)

    Liu, Xiaomei

    1998-05-01

    My thesis project has concentrated on clarifying the role of individual amino acids such as tyrosine, arginine and threonine in the active proton transferring process of Bacteriorhodopsin(bR). BR is a protein found in the purple membrane of Halobacteria salinarium. The main function of bR is to transfer a proton from the interior side of the cell to the external medium upon illumination by visible light. BR belongs to a family of retinal- containing membrane proteins which includes rhodopsin, a visual receptor found in the eye, and sensory rhodopsin I, a light receptor for phototaxis found in H. salinarium. Complete understanding of the proton transferring mechanism of bR can help explain the energy transduction and active ion transport in biological systems. This information also provides insight into other members of the retinal-containing protein family. To study the behavior of a single amino acid in a protein which consists of 248 amino acids, I employed the Fourier transform infrared (FTIR) difference spectroscopy technique. This was combined with the recently developed genetic engineering method of site directed isotope labeling (SDIL). As complementary work, I also characterized the vibrational properties of individual amino acids in various environments. Because of the high resolution and sensitivity of FTIR difference spectroscopy, along with the ability of SDIL to detect structural changes at the single amino acid level, we are able to determine changes in the structure of specific amino acids at different steps in bR photocycle. My research results provide strong evidence for a proton pump model. This model predicts the participation of tyrosine 185 and one or more threonines in a hydrogen bonded chain which can transfer proton across the membrane. My data also suggest a more accurate model for the proton release step which involves arginine 82.

  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. Proton Pump Inhibitor use in Hospitalized Patients: Is Overutilization Becoming a Problem?

    PubMed Central

    Durand, Cheryl; Willett, Kristine C.; Desilets, Alicia R.

    2012-01-01

    Proton pump inhibitors (PPIs) are among the most common classes of medications prescribed. Though they were previously thought of as safe, recent literature has shown risks associated with their use including increased risk for Clostridium difficile infection, pneumonia, and fractures. Due to these risks, it is important to determine if PPIs are being used appropriately. This review evaluates seven studies in hospitalized patients. Additionally, this review evaluates literature pertaining to recently discovered adverse reactions; all studies found PPIs are being overutilized. Findings highlight the importance of evaluating appropriate therapy with these agents and recommending discontinuation if a proper indication does not exist. PMID:24833936

  20. [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. Copyright © 2010 Elsevier España, S.L. All rights reserved.

  1. [Adverse events associated with long-term use of proton pump inhibitors].

    PubMed

    Reimer, Christina; Bytzer, Peter

    2012-09-24

    Proton pump inhibitors (PPI) remain the leading therapy for acid-related disorders. Long-term PPI use increases the risk of pneumonia and enteric bacterial infections and of nosocomial Clostridium difficile-associated diarrhoea. PPIs do not lead to vitamin B12 or iron deficiencies and do not induce malignancies or increase the risk of major birth defects. Prolonged PPI use may be a weak risk factor for certain fractures and results in hypergastrinaemia and parietal cell hyperplasia leading to rebound acid hypersecretion, which may induce symptoms on withdrawal of therapy.

  2. Proton Pump Inhibitor Prophylaxis After Gastric Bypass Does Not Cause Hypomagnesemia.

    PubMed

    Boerlage, Thomas C C; van Hees, Charlotte L E; Huitema, Alwin D R; Lauw, Fanny N

    2016-03-01

    Proton pump inhibitor (PPI)-induced hypomagnesemia is currently a major topic. Patients undergoing Roux-en-Y gastric bypass are generally prescribed PPI prophylaxis after surgery. We investigated the prevalence of hypomagnesemia in our bariatric population. We reviewed the files of 1000 postoperative patients for serum magnesium level during PPI use. We found only five cases of hypomagnesemia, none of which was evidently related to PPI use. We conclude that the risk of hypomagnesemia during 1 year of prophylactic PPI use after Roux-en-Y gastric bypass (RYGB) is minimal and laboratory screening is probably not necessary.

  3. 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

  4. 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.

  5. The role of the pharmacist in the selection and use of over-the-counter proton-pump inhibitors.

    PubMed

    Boardman, Helen F; Heeley, Gordon

    2015-10-01

    Heartburn and other symptoms of gastro-oesophageal reflux occur in ~30% of survey respondents in multiple countries worldwide. Heartburn and acid regurgitation are common complaints in the pharmacy, where patients frequently seek relief through medication and advice. The growing number of proton-pump inhibitors available in the over-the-counter setting provides an efficacious choice to patients experiencing frequent heartburn. Pharmacists can assist patients in their treatment decisions whilst inquiring about alarm symptoms that should prompt a physician referral. Aim of the review Provide pharmacists with a review of current clinical research and expert guidelines on use of over-the-counter proton-pump inhibitors. This narrative review was conducted to identify publications relevant to the following themes: overview of available treatments for frequent episodes of heartburn/acid regurgitation; treatment algorithms providing guidance on when to use over-the-counter proton-pump inhibitors; and the role of the pharmacist in the use of over-the-counter proton-pump inhibitors. Frequent symptoms of acid reflux, such as heartburn and acid regurgitation, can interfere substantially with daily life activities. Proton-pump inhibitors are the most efficacious treatment for frequent reflux symptoms and are recommended as an appropriate initial treatment in uncomplicated cases. Proton-pump inhibitors have varying pharmacokinetics and pharmacodynamics across the class; 20 mg esomeprazole has higher bioavailability and exposure than over-the-counter omeprazole, for example. However, differences in clinical efficacy for symptom relief have not been demonstrated. The safety and tolerability of proton-pump inhibitors have been well established in clinical trial and post-marketing settings, and use of a short regimen is associated with a very low likelihood of missing a more serious condition. Pharmacists can assist patients with accurate self-diagnosis by asking short, simple

  6. Western blot confirmation of the H+/K+-ATPase proton pump in the human larynx and submandibular gland.

    PubMed

    Altman, Kenneth W; Kinoshita, Yayoi; Tan, Melin; Burstein, David; Radosevich, James A

    2011-11-01

    The authors have previously demonstrated the H(+)/K(+)-ATPase (proton pump) in human larynx and lung glands via immunohistochemistry (IHC). The present hypothesis is that the proton pump is expressed in other seromucinous glands of the digestive tract that can be confirmed by IHC and Western blot analysis. Prospective controlled tissue analysis study. Academic medical institution. Ten anonymous fresh-frozen donor specimens were obtained, comprising 3 submandibular glands, 4 larynges, and 3 normal stomach specimens for control. Submandibular gland sections were immunostained with 2 monoclonal antibodies selectively reactive with α or β subunits of the H(+)/K(+)-ATPase. Western blot analysis was performed on all specimens. Consistent IHC staining was observed in the submandibular gland specimens for both α and β subunits. Western blot analysis revealed very strong expression for the stomach at 100 kDa, corresponding to the α protein, and weak but notable banding for all larynx and submandibular gland specimens. Similar findings were noted for the 60- to 80-kDa glycosylated β subunit protein, as well as the 52-kDa β subunit precursor for all specimens. The H(+)/K(+)-ATPase (proton) pump is present in the human larynx and submandibular gland although in much lower concentrations than in the stomach. Proton pump involvement in human aerodigestive seromucinous glands may have a role in protecting mucosa from acid environments (local or systemic), explain heightened laryngeal sensitivity in those patients with laryngopharyngeal reflux, and be a site of action for proton pump inhibitor pharmacotherapy.

  7. Effects of membrane curvature and pH on proton pumping activity of single cytochrome bo3 enzymes.

    PubMed

    Li, Mengqiu; Khan, Sanobar; Rong, Honglin; Tuma, Roman; Hatzakis, Nikos S; Jeuken, Lars J C

    2017-09-01

    The molecular mechanism of proton pumping by heme-copper oxidases (HCO) has intrigued the scientific community since it was first proposed. We have recently reported a novel technology that enables the continuous characterisation of proton transport activity of a HCO and ubiquinol oxidase from Escherichia coli, cytochrome bo3, for hundreds of seconds on the single enzyme level (Li et al. J Am Chem Soc 137 (2015) 16055-16063). Here, we have extended these studies by additional experiments and analyses of the proton transfer rate as a function of proteoliposome size and pH at the N- and P-side of single HCOs. Proton transport activity of cytochrome bo3 was found to decrease with increased curvature of the membrane. Furthermore, proton uptake at the N-side (proton entrance) was insensitive to pH between pH6.4-8.4, while proton release at the P-side had an optimum pH of ~7.4, suggesting that the pH optimum is related to proton release from the proton exit site. Our previous single-enzyme experiments identified rare, long-lived conformation states of cytochrome bo3 where protons leak back under turn-over conditions. Here, we analyzed and found that ~23% of cytochrome bo3 proteoliposomes show ΔpH half-lives below 50s after stopping turnover, while only ~5% of the proteoliposomes containing a non-pumping mutant, E286C cytochrome bo3 exhibit such fast decays. These single-enzyme results confirm our model in which HCO exhibit heterogeneous pumping rates and can adopt rare leak states in which protons are able to rapidly flow back. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. The photosynthetic water oxidase: its proton pumping activity is short-circuited within the protein by DCCD

    PubMed Central

    Jahns, Peter; Polle, Andrea; Junge, Wolfgang

    1988-01-01

    The photosynthetic water oxidase is composed of ˜15 polypeptides which are grouped around two functional parts: photosystem II and the catalytic manganese centre. Photochemically driven vectorial electron transfer between the manganese centre and bound plastoquinone causes deprotonation–protonation reactions at opposite sides of the thylakoid membrane. Thereby the water oxidase acts as a proton pump. Incubation of stacked thylakoids with N,N'-dicyclohexylcarbodiimide (DCCD) short-circuited its proton pumping activity. Under flashing light, the extent of both proton release into the lumen by water oxidation and of proton uptake from the medium by reduced quinone was diminished. Instead there was a rapid electrogenic backreaction with a strong H/D-isotope effect. Apparently protons which were produced by water oxidation were channelled across the transmembrane protein to the bound quinone. A more rapid protonation of the reduced quinone was evident from a shortening of the time lag for the reduction of photosystem I. These effects were paralleled by the preferential labelling with [14C]DCCD in stacked thylakoids of two polypeptides with 20 and 24 kd apparent molecular mass. These may be capping the oxidizing and the reducing terminus of the water oxidase to control proton extrusion and proton uptake respectively. Images PMID:16453830

  9. Characteristics of the proton pump in rat renal cortical endocytotic vesicles.

    PubMed

    Sabolić, I; Burckhardt, G

    1986-05-01

    The characteristics of the H+ pump in isolated rat renal endocytotic vesicles were studied by the delta pH-sensitive dye acridine orange, the voltage-sensitive dye 3,3'-dipropylthiadicarbocyanine iodide, and by a coupled optical ATPase assay. Intravesicular acidification depended on ATP and Mg2+ concentrations with half-maximal activations at 73 and 77 microM, respectively. CTP, GTP, UTP, and ITP partially supported acidification, but ADP and AMP did not. Ouabain, ethoxzolamide, levamisole, and vanadate did not inhibit H+ uptake into endocytotic vesicles. Oligomycin inhibited partially. Depending on concentration and preincubation time, Dio-9, filipin, N-ethylmaleimide (NEM), and dicyclohexylcarbodiimide (DCCD) inhibited H+ uptake completely. Filipin and, partially, DCCD acted nonspecifically by dissipating pH gradients. A specific cation was not required for the H+ pump; Zn2+ inhibited. Compared with mannitol, ATP-driven H+ uptake was stimulated by SCN- greater than Cl- greater than Br- greater than I- much greater than HPO4(2-) = gluconate = HCO3- = F-, but not by SO4(2-), NO3-, CH3COO-, S2O3(2-), and S4O6(2-). Chloride stimulated H+ uptake from the outside of the vesicles with an apparent Km of 27 mM. In the absence of Cl-, ATP-driven proton uptake was increased by intravesicular K+ and valinomycin, suggesting that the pump is electrogenic. The electrogenicity, however, could not be demonstrated with voltage-sensitive dyes. The vesicle membrane contains no significant K+ and Cl- conductances; only a conductance for H+ was found. The vesicles exhibited an ouabain-, oligomycin-, and vanadate-insensitive ATPase activity that was inhibited by DCCD and NEM. Our data indicate the presence of an electrogenic H+ pump in endocytotic vesicles from rat renal proximal tubules with similar characteristics as H+ pumps present in various intracellular (nonmitochondrial) membranes.

  10. Toward theoretical analysis of long-range proton transfer kinetics in biomolecular pumps.

    PubMed

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

    2006-01-19

    Motivated by the long-term goal of theoretically analyzing long-range proton transfer (PT) kinetics in biomolecular pumps, researchers made a number of technical developments in the framework of quantum mechanics-molecular mechanics (QM/MM) simulations. A set of collective reaction coordinates is proposed for characterizing the progress of long-range proton transfers; unlike previous suggestions, the new coordinates can describe PT along highly nonlinear 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 a much larger number of explicit solvent and lipid molecules. The effect of electrostatics for PT through a 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.

  11. 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.

  12. 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.

  13. Review article: prevention of stress-related mucosal bleeding with proton-pump inhibitors.

    PubMed

    Maton, P N

    2005-12-01

    Stress-related gastric mucosal bleeding occurs in a substantial number of critically ill patients, with clinically important gastrointestinal bleeding prolonging intensive care stay and increasing mortality. This paper reviews the role of proton-pump inhibitors in the prevention of stress-related mucosal bleeding. Bleeding prophylaxis appears to be warranted in patients in intensive care units on mechanical ventilation or those who have coagulopathy. Intravenous histamine H2 receptor antagonists, particularly cimetidine, have demonstrated efficacy for the prevention of bleeding in critically ill patients. Standard delayed-release proton-pump inhibitors have not been extensively studied in this patient group, but there are some data to support their efficacy in increasing intragastric pH, and in the case of intravenous pantoprazole in preventing gastrointestinal bleeding. In a large, randomized controlled trial, immediate-release omeprazole [(IR-OME) Zegerid powder for oral suspension; Santarus Inc., San Diego, CA, USA] administered via gastric tube, was as effective as intravenous cimetidine in the prevention of clinically significant bleeding, and more effective in increasing gastric pH. Effective antisecretory therapy does not appear to increase the risk of nosocomial pneumonia. In conclusion, immediate-release omeprazole provides a safe and effective alternative to intravenous cimetidine for the prevention of stress-related mucosal bleeding in critically ill patients.

  14. 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

  15. The vacuolar H+-ATPase: a universal proton pump of eukaryotes.

    PubMed Central

    Finbow, M E; Harrison, M A

    1997-01-01

    The vacuolar H+-ATPase (V-ATPase) is a universal component of eukaryotic organisms. It is present in the membranes of many organelles, where its proton-pumping action creates the low intra-vacuolar pH found, for example, in lysosomes. In addition, there are a number of differentiated cell types that have V-ATPases on their surface that contribute to the physiological functions of these cells. The V-ATPase is a multi-subunit enzyme composed of a membrane sector and a cytosolic catalytic sector. It is related to the familiar FoF1 ATP synthase (F-ATPase), having the same basic architectural construction, and many of the subunits from the two display identity with one another. All the core subunits of the V-ATPase have now been identified and much is known about the assembly, regulation and pharmacology of the enzyme. Recent genetic analysis has shown the V-ATPase to be a vital component of higher eukaryotes. At least one of the subunits, i.e. subunit c (ductin), may have multifunctional roles in membrane transport, providing a possible pathway of communication between cells. The structure of the membrane sector is known in some detail, and it is possible to begin to suggest how proton pumping is coupled to ATP hydrolysis. PMID:9210392

  16. 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.

  17. A quantum chemical study of the mechanism for proton-coupled electron transfer leading to proton pumping in cytochrome c oxidase

    NASA Astrophysics Data System (ADS)

    Blomberg, Margareta R. A.; Siegbahn, Per E. M.

    2010-10-01

    The proton pumping mechanism in cytochrome c oxidase, the terminal enzyme in the respiratory chain, has been investigated using hybrid DFT with large chemical models. In previous studies, a gating mechanism was suggested based on electrostatic interpretations of kinetic experiments. The predictions from that analysis are tested here. The main result is that the suggestion of a positively charged transition state for proton transfer is confirmed, while some other suggestions for the gating are not supported. It is shown that a few critical relative energy values from the earlier studies are reproduced with quite high accuracy using the present model calculations. Examples are the forward barrier for proton transfer from the N-side of the membrane to the pump-loading site when the heme a cofactor is reduced, and the corresponding back leakage barrier when heme a is oxidised. An interesting new finding is an unexpected double-well potential for proton transfer from the N-side to the pump-loading site. In the intermediate between the two transition states found, the proton is bound to PropD on heme a. A possible purpose of this type of potential surface is suggested here. The accuracy of the present values are discussed in terms of their sensitivity to the choice of dielectric constant. Only one energy value, which is not critical for the present mechanism, varies significantly with this choice and is therefore less certain.

  18. The voltage-dependent proton pumping in bacteriorhodopsin is characterized by optoelectric behavior.

    PubMed

    Geibel, S; Friedrich, T; Ormos, P; Wood, P G; Nagel, G; Bamberg, E

    2001-10-01

    The light-driven proton pump bacteriorhodopsin (bR) was functionally expressed in Xenopus laevis oocytes and in HEK-293 cells. The latter expression system allowed high time resolution of light-induced current signals. A detailed voltage clamp and patch clamp study was performed to investigate the DeltapH versus Deltapsi dependence of the pump current. The following results were obtained. The current voltage behavior of bR is linear in the measurable range between -160 mV and +60 mV. The pH dependence is less than expected from thermodynamic principles, i.e., one DeltapH unit produces a shift of the apparent reversal potential of 34 mV (and not 58 mV). The M(2)-BR decay shows a significant voltage dependence with time constants changing from 20 ms at +60 mV to 80 ms at -160 mV. The linear I-V curve can be reconstructed by this behavior. However, the slope of the decay rate shows a weaker voltage dependence than the stationary photocurrent, indicating that an additional process must be involved in the voltage dependence of the pump. A slowly decaying M intermediate (decay time > 100 ms) could already be detected at zero voltage by electrical and spectroscopic means. In effect, bR shows optoelectric behavior. The long-lived M can be transferred into the active photocycle by depolarizing voltage pulses. This is experimentally demonstrated by a distinct charge displacement. From the results we conclude that the transport cycle of bR branches via a long-lived M(1)* in a voltage-dependent manner into a nontransporting cycle, where the proton release and uptake occur on the extracellular side.

  19. Light-Induced Proton Pumping with a Semiconductor: Vision for Photoproton Lateral Separation and Robust Manipulation.

    PubMed

    Maltanava, Hanna M; Poznyak, Sergey K; Andreeva, Daria V; Quevedo, Marcela C; Bastos, Alexandre C; Tedim, João; Ferreira, Mário G S; Skorb, Ekaterina V

    2017-07-19

    Energy-transfer reactions are the key for living open systems, biological chemical networking, and the development of life-inspired nanoscale machineries. It is a challenge to find simple reliable synthetic chemical networks providing a localization of the time-dependent flux of matter. In this paper, we look to photocatalytic reaction on TiO2 from different angles, focusing on proton generation and introducing a reliable, minimal-reagent-consuming, stable inorganic light-promoted proton pump. Localized illumination was applied to a TiO2 surface in solution for reversible spatially controlled "inorganic photoproton" isometric cycling, the lateral separation of water-splitting reactions. The proton flux is pumped during the irradiation of the surface of TiO2 and dynamically maintained at the irradiated surface area in the absence of any membrane or predetermined material structure. Moreover, we spatially predetermine a transient acidic pH value on the TiO2 surface in the irradiated area with the feedback-driven generation of a base as deactivator. Importantly we describe how to effectively monitor the spatial localization of the process by the in situ scanning ion-selective electrode technique (SIET) measurements for pH and the scanning vibrating electrode technique (SVET) for local photoelectrochemical studies without additional pH-sensitive dye markers. This work shows the great potential for time- and space-resolved water-splitting reactions for following the investigation of pH-stimulated processes in open systems with their flexible localization on a surface.

  20. 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

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

    PubMed

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

    2015-01-01

    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. 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. 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. 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.

  2. 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.

  3. Characterization of In Vitro Proton Pumping by Microsomal Vesicles Isolated from Corn Coleoptiles 1

    PubMed Central

    Mettler, Irvin J.; Mandala, Suzanne; Taiz, Lincoln

    1982-01-01

    Corn (Zea mays L. cv Golden Cross Bantam) coleoptile microsomal vesicles have been isolated which are capable of ATP-driven H+-transport as measured by [14C]methylamine accumulation and quinacrine fluorescence quenching. Formation of the pH gradient in vitro shows a high specificity for ATP·Mg, is temperature-sensitive, exhibits a pH optimum at 7.5, and is inhibited by carbonyl cyanide-m-chlorophenylhydrazone. Of the divalent cations tested, Mn2+ is almost as effective as Mg2+, while Ca2+ is ineffective. Excess divalent cations, particularly Ca2+, reduces the pH gradient. H+ transport is strongly promoted by anions, especially chloride, while potassium does not affect pump activity. Studies with 36Cl− indicate that ATP-driven H+ transport into the vesicles is associated with chloride uptake. Both carbonyl cyanide-m-chlorophenylhydrazone and the anion transport inhibitor, 4,4′-diisothiocyano-2,2′-disulfonic acid stilbene, inhibit methylamine accumulation and 36Cl− uptake. Proton pumping is also blocked by diethyl stilbestrol and N,N′-dicyclohexylcarbodiimide, but is insensitive to oligomycin and vanadate. These properties of the pump are inconsistent with either a mitochondrial or plasma membrane origin. PMID:16662754

  4. Redox Bohr effects and the role of heme a in the proton pump of bovine heart cytochrome c oxidase.

    PubMed

    Capitanio, Giuseppe; Martino, Pietro Luca; Capitanio, Nazzareno; Papa, Sergio

    2011-10-01

    Structural and functional observations are reviewed which provide evidence for a central role of redox Bohr effect linked to the low-spin heme a in the proton pump of bovine heart cytochrome c oxidase. Data on the membrane sidedness of Bohr protons linked to anaerobic oxido-reduction of the individual metal centers in the liposome reconstituted oxidase are analysed. Redox Bohr protons coupled to anaerobic oxido-reduction of heme a (and Cu(A)) and Cu(B) exhibit membrane vectoriality, i.e. protons are taken up from the inner space upon reduction of these centers and released in the outer space upon their oxidation. Redox Bohr protons coupled to anaerobic oxido-reduction of heme a(3) do not, on the contrary, exhibit vectorial nature: protons are exchanged only with the outer space. A model of the proton pump of the oxidase, in which redox Bohr protons linked to the low-spin heme a play a central role, is described. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Protein-bound water as the determinant of asymmetric functional conversion between light-driven proton and chloride pumps.

    PubMed

    Muroda, Kosuke; Nakashima, Keisuke; Shibata, Mikihiro; Demura, Makoto; Kandori, Hideki

    2012-06-12

    Bacteriorhodopsin (BR) and halorhodopsin (HR) are light-driven outward proton and inward chloride pumps, respectively. They have similar protein architecture, being composed of seven-transmembrane helices that bind an all-trans-retinal. BR can be converted into a chloride pump by a single amino acid replacement at position 85, suggesting that BR and HR share a common transport mechanism, and the ionic specificity is determined by the amino acid at that position. However, HR cannot be converted into a proton pump by the corresponding reverse mutation. Here we mutated 6 and 10 amino acids of HR into BR-like, whereas such multiple HR mutants never pump protons. Light-induced Fourier transform infrared spectroscopy revealed that hydrogen bonds of the retinal Schiff base and water are both strong for BR and both weak for HR. Multiple HR mutants exhibit strong hydrogen bonds of the Schiff base, but the hydrogen bond of water is still weak. We concluded that the cause of nonfunctional conversion of HR is the lack of strongly hydrogen-bonded water, the functional determinant of the proton pump.

  6. [In vitro susceptibility of Trichomonas vaginalis to metronidazole, ornidazole and proton pump inhibitors pantoprazole and esomeprazole].

    PubMed

    Aksoy Gökmen, Ayşegül; Girginkardeşler, Nogay; Kilimcioğlu, Ali Ahmet; Şirin, Mümtaz Cem; Özbilgin, Ahmet

    2016-01-01

    The current treatment of trichomoniasis is based on the use of 5-nitroimidazole derivatives. Although metronidazole is reliable, inexpensive and highly effective against anaerobic microorganisms and protozoa, the development of metronidazole-resistant T.vaginalis strains pose to an increasing problem. Nitroimidazoles are compounds having azomycin (2-nitroimidazole) chemical structure and are obtained from Streptomyces strains. Benzimidazole, which is found in the structure of proton pump inhibitors, is also present in the other components that have antiprotozoal activity. In this study, the in vitro susceptibility of T.vaginalis against metronidazole, ornidazole, and the proton pump inhibitors which are tested recently as antiprotozoal agents; pantoprazole and esomeprazole was investigated. For this purpose a clinical T.vaginalis strain which was formerly isolated and stored after cryopreservation process in our laboratory was used. Minimum inhibitory concentration (MIC) and minimum lethal concentration (MLC) values of those agents against to this strain were determined in vitro by dilution method in 24-well cell culture plates. Trypticase yeast extract maltose medium, horse serum and antibiotic (penicillin + streptomycin) were distributed to each well of cell culture plates and after metronidazole, ornidazole, pantoprazole and esomeprazole solutions were added to two wells for each as 800, 400, 200, 100, 50 and 25 µg/ml, followed by the addition of 1 ml 5x10(3) T.vaginalis trophozoites into each well. Plates were incubated at 37°C, and viability and motility of the trophozoites were evaluated under light microscope at 24, 48 and 72 hours after incubation. MIC and MLC values of metronidazole/ornidazole in the 72(th) hour were found as 50 µg/ml and 100 µg/ml, respectively. MIC and MLC values for pantoprazole in the 72th hour were 200 µg/ml and 400 µg/ml, while the values for esomeprazole were 400 µg/ml ve 800 µg/ml, respectively. As a result, T

  7. The physiological background behind and course of development of the first proton pump inhibitor.

    PubMed

    Lundell, Lars

    2015-06-01

    Gastric acid secretion and its related diseases and their treatments have generated important contributions to gastroenterology and its development as an autonomous medical specialty. The discovery of histamine receptors and the subsequent H2-receptor antagonists (1972) changed the practice of gastroenterology forever. Gastric acid was effectively inhibited and ulcers could be healed to an extent which had not previously been seen. An additional milestone along the same avenue was offered by the identification of hydrogen potassium adenosine triphosphatase (H(+)K(+)-ATPase) as the proton pump of the parietal cell. Nowadays, proton pump inhibitors (PPIs) are widely used. However, we need to reconsider the physiology and pathophysiology of acid secretion and its long-term inhibition to avoid potential negative effects on general health. PPIs are generally considered among the safest class of drugs. In the late 1960s, a research project was initiated to develop an antisecretory drug which could be used in acid hypersecretory disease states such as peptic ulcer disease based on the option to synthesize a local anesthetic drug that could be orally administered and therefore have its main action on the gastrin cells. This concept was soon found to be a blind track and further development of the basic compounds CMN131 by the synthesis of H77/67 were found to be active in the gastric acid secretion, and the benzimidazol analog of H77/67 was then synthesized a year later and was tested and found to exert powerful acid inhibitory effects. Binding studies with the substituted benzimidazoles clarified specific binding to H+/K+/ATPase in the secretory vesicles of the parietal cells. Since weak bases like aminopyrine accumulate in the acid compartment of the parietal cells, the chemists changed the substituents of the heterocyclic ring and obtained a compound with a weak base property with an optimal PkA value, thereby maximizing the accumulation of the compound at the site of

  8. FTIR spectroscopy of a light-driven compatible sodium ion-proton pumping rhodopsin at 77 K.

    PubMed

    Ono, Hikaru; Inoue, Keiichi; Abe-Yoshizumi, Rei; Kandori, Hideki

    2014-05-08

    Krokinobacter eikastus rhodopsin 2 (KR2) is a light-driven sodium ion pump that was discovered in marine bacteria. Although KR2 is able to pump lithium ions similarly, it is converted into a proton pump in potassium chloride or salts of larger cations. In this paper, we applied light-induced difference Fourier-transform infrared (FTIR) spectroscopy to KR2, a compatible sodium ion-proton pump, at 77 K. The first structural study of the functional cycle showed that the structure and structural changes in the primary processes of KR2 are common to all microbial rhodopsins. The red shifted K formation (KR2K) was accompanied by retinal photoisomerization from an all-trans to a 13-cis form, resulting in a distorted retinal chromophore. The observed hydrogen out-of-plane vibrations were H/D exchangeable, indicating that the chromophore distortion by retinal isomerization is located near the Schiff base region in KR2. This tendency was also the case for bacteriorhodopsin and halorhodopsin but not the case for sensory rhodopsin I and II. Therefore, ion pumps such as proton, chloride, and sodium pumps exhibit local structural perturbations of retinal at the Schiff base moiety, while photosensors show more extended structural perturbations of retinal. The retinal Schiff base of KR2 forms a hydrogen bond that is stronger than in BR. KR2 possesses more protein-bound water molecules than other microbial rhodopsins and contains strongly hydrogen-bonded water (O-D stretch at 2333 cm(-1) in D2O). The light-induced difference FTIR spectra at 77 K were identical between the two states functioning as light-driven sodium ion and proton pumps, indicating that the structural changes in the primary processes are identical between different ion pump functions in KR2. In other words, it is unknown which ions are transported by molecules when they absorb photons and photoisomerize. It is likely that the relaxation processes from the K state lead to an alternative function, namely a sodium

  9. Complete Resolution of Pseudomalignant Erosion in a Reflux Gastroesophageal Polyp with Proton Pump Inhibitor

    PubMed Central

    Nakajima, Takahiko; Yagi, Haruo; Baba, Hayato; Minamisaka, Takashi; Miwa, Shigeharu; Hayashi, Shinichi; Nishida, Takeshi; Hatta, Hideki; Tsuneyama, Koichi; Imura, Johji

    2015-01-01

    Pseudomalignant erosion is a diagnostic pitfall for pathologists in the differential diagnosis of malignant neoplasms. Here, we present a challenging case of a biopsy specimen from the eroded head of a polyp at the esophagogastric junction. A malignant neoplasm could not be ruled out due to the presence of bizarre stromal cells. A second biopsy performed after the administration of a proton pump inhibitor (PPI) for 4 weeks revealed endoscopic resolution of the polyp along with the complete histological resolution of the bizarre stromal cells and led to the diagnosis of pseudomalignant erosion in a reflux gastroesophageal polyp. In conclusion, histological and endoscopic response to PPI therapy is an important clue for the correct diagnosis of reflux gastroesophageal polyps with pseudomalignant erosion. PMID:26688768

  10. Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy

    PubMed Central

    Ang, Daphne; How, Choon How; Ang, Tiing Leong

    2016-01-01

    About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux-related events that is proven on functional oesophageal tests. PMID:27779277

  11. Clostridium difficile Infection and Proton Pump Inhibitor Use in Hospitalized Pediatric Cystic Fibrosis Patients.

    PubMed

    Pohl, John F; Patel, Raza; Zobell, Jeffery T; Lin, Ellen; Korgenski, E Kent; Crowell, Kody; Mackay, Mark W; Richman, Aleesha; Larsen, Christian; Chatfield, Barbara A

    2011-01-01

    Children with cystic fibrosis (CF) often take proton pump inhibitors (PPIs), which helps improve efficacy of fat absorption with pancreatic enzyme replacement therapy. However, PPI use is known to be associated with Clostridium difficile-(C. diff-) associated diarrhea (CDAD). We retrospectively evaluated the incidence of C. diff infection from all pediatric hospital admissions over a 5-year period at a single tertiary children's hospital. We found significantly more C. diff-positive stool tests in hospitalized patients with CF compared to patients with no diagnosis of CF. However, use of a PPI was not associated with an increased risk of CDAD in hospitalized CF patients. In summary, C. diff infection is more common in hospitalized pediatric CF patients although PPI use may not be a risk factor for CDAD development in this patient population.

  12. 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

  13. Proton pump inhibitors for the treatment of cancer in companion animals.

    PubMed

    Walsh, Megan; Fais, Stefano; Spugnini, Enrico Pierluigi; Harguindey, Salvador; Abu Izneid, Tareq; Scacco, Licia; Williams, Paula; Allegrucci, Cinzia; Rauch, Cyril; Omran, Ziad

    2015-09-04

    The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.

  14. [Chronic use of proton-pump inhibitors associated with giardiasis: A rare cause of hypomagnesemic hypoparathyroidism?].

    PubMed

    François, M; Lévy-Bohbot, N; Caron, J; Durlach, V

    2008-11-01

    Hypomagnesemia is a rare cause of hypoparathyroidism that can have a very serious clinical presentation. We report the case of a 62-year-old woman hospitalized for exploration of acute tetraparesis with vomiting and swallowing disorders associated with a severe hypocalcemia. Biological explorations revealed hypoparathyroidism (PTH=16ng/L) related to low plasma and erythrocyte magnesium (0.32 and 1.32mmol/L, respectively) as well as hypocalciuria and hypomagnesuria linked to gastrointestinal malabsorption. Etiologic investigations led to the discovery of Giardiasis lamblia on duodenal biopsies and a long-term treatment with proton pump inhibitors (PPI) (omeprazole followed by esomeprazole), both being recently described as causal factors of hypomagnesemic hypoparathyroidism. After treatment of the parasite (by metronidazole) and discontinuation of the PPI, both calcium and magnesium levels returned to normal. Selective malabsorption has been previously reported in patients with giardiasis. The specific mechanism of PPI participation in the genesis of hypomagnesemia remains a subject of debate.

  15. Trans/13-cis isomerization is essential for both the photocycle and proton pumping of bacteriorhodopsin

    SciTech Connect

    Chang, C.H.; Govindjee, R.; Ebrey, T.; Bagley, K.A.; Dollinger, G.; Eisenstein, L.; Marque, J.; Roder, H.; Vittitow, J.; Fang, J.M.

    1985-04-01

    An analogue of bacteriorhodopsin whose chromophore is based on all-trans retinal was studied. A five-membered ring was built around the 13-14 double bond so as to prohibit trans to 13-cis isomerization. No light-induced photochemical changes were seen, other than those due to a small amount (approximately 5%) of unbleached bacteriorhodopsin remaining in the apomembrane used for regeneration. The techniques used included flash photolysis at room and liquid nitrogen temperatures and Fourier-transform infrared difference spectroscopy. When the trans-fixed pigment was incorporated into phospholipid vesicles, no evidence of light-initiated proton pumping could be found. The results indicate that trans to 13-cis isomerization is essential for the photochemical transformation and function of bacteriorhodopsin.

  16. 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.

  17. Review of pharmacokinetic and pharmacodynamic modeling and safety of proton pump inhibitors and aspirin.

    PubMed

    Gesheff, Martin G; Franzese, Christopher J; Bliden, Kevin P; Contino, Chase J; Rafeedheen, Rahil; Tantry, Udaya S; Gurbel, Paul A

    2014-09-01

    The efficacy of aspirin in primary and secondary prevention of cardiovascular diseases has been convincingly demonstrated. Gastrointestinal (GI) adverse effects with aspirin may lead to poor adherence and/or discontinuation of treatment. Proton pump inhibitors (PPIs) have been used for more than 20 years as the first choice for treating peptic ulcers and their bleeding complications, gastroesophageal reflux disease, non-steroidal anti-inflammatory drug-induced GI lesions and dyspepsia. Adherence becomes a major concern when aspirin is co-prescribed with PPIs to prevent GI adverse effects. Combining aspirin and PPIs into one tablet is an effective approach to address aspirin-related GI adverse effects and increase adherence to aspirin therapy for the prevention of cardiovascular diseases.

  18. Which is the best choice for gastroesophageal disorders: Melatonin or proton pump inhibitors?

    PubMed Central

    de Oliveira Torres, Joanna Dulce Favacho; de Souza Pereira, Ricardo

    2010-01-01

    Melatonin is used in many countries to improve sleep disorders. Melatonin is a hormone produced by the pineal gland and enterochromaffin cells which control sleep and gastrointestinal motility. Low levels of melatonin lead to gastroesophageal reflux disease (GERD). Most of patients with GERD have a sleep disorder. So, low melatonin levels is the main cause of insomnia. Beyond this, it has an inhibitory action on gastric acid secretion and seems to control the lower esophageal sphincter. Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. Omeprazole (one of the PPIs) and melatonin have similarities in their chemical structures. Therefore, we could consider omeprazole as a rough copy of melatonin. In this paper, we compare the advantages and disadvantages of the clinical use of melatonin and PPIs. PMID:21577303

  19. Proton-pump inhibition and gastric giardiasis: a causal or casual association?

    PubMed

    Reynaert, H; Fernandes, E; Bourgain, C; Smekens, L; Devis, G

    1995-12-01

    Two patients who developed gastric giardiasis after 2 weeks of treatment with omeprazole 20 mg b.i.d. followed by omeprazole 20 mg per day for 2-6 weeks are described. In one patient, gastric giardiasis occurred in the presence of only mild intestinal metaplasia. In the other patient, Giardia lamblia infection had resolved 4 weeks after the cessation of omeprazole treatment, which, to our knowledge, is the first case reported in the literature. It is tempting to speculate that gastric giardiasis can develop in the absence of mucosal abnormalities during hypochlorhydria induced by treatment with a high dose of a proton-pump inhibitor. Specific treatment may not be required if the drug can be stopped and no other gastric disease causing hypochlorhydria is present.

  20. 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. © 2015, The American College of Clinical Pharmacology.

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

    PubMed

    William, Jeffrey H; Danziger, John

    2016-03-06

    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.

  2. Negative chronotropic effect of proton pump inhibitors on frog-heart preparation.

    PubMed

    Gautam, Chander Shekhar; Utreja, Amita; Goel, Divya; Sandhu, Gurpreet; Gogia, Nidhi

    2009-01-01

    Proton pump inhibitors (PPIs) have been known to cause bradycardia. We evaluated the effect of three PPIs, i.e. omeprazole, rabeprazole and pantoprazole on the heart rate of frog. The in situ frog heart preparation was set up. Heart rate and amplitude of contraction were studied following administration of different doses of the three PPIs. Statistical analysis was done by using Graphpad statistical software system. After 1 mg of omeprazole and rabeprazole, and 2 mg pantoprazole, the heart rate was similar as compared to baseline (p >0.05). After 2 mg of omeprazole and rabeprazole, and 4 mg pantoprazole, the reduction in heart rate was significant (p <0.05). In addition, pantoprazole caused negative ionotropic effect. The three PPIs showed a dose-dependent negative chronotropic effect in the frog heart prepration.

  3. Immediate and Delayed Hypersensitivity Reactions to Proton Pump Inhibitors: Evaluation and Management.

    PubMed

    Otani, Iris M; Banerji, Aleena

    2016-03-01

    PPIs are among the most commonly administered medications in the USA and are generally well tolerated. Immediate and delayed immune-mediated hypersensitivity reactions are rare but increasingly recognized adverse effects of proton pump inhibitors (PPIs). Immediate hypersensitivity reactions can occur due to IgE-mediated hypersensitivity to PPIs and can be evaluated by immediate hypersensitivity skin testing and oral provocation challenge testing. A desensitization protocol can be used when PPI use cannot be avoided in an allergic patient. Delayed hypersensitivity reactions to PPIs have also been reported. Occupational exposures causing cutaneous reactions to PPIs are the most commonly reported delayed hypersensitivity reaction, followed by drug-induced subacute cutaneous lupus erythematosus. This review presents a summary of the clinical presentation, diagnostic evaluation, and management of immune-mediated hypersensitivity reactions to PPIs.

  4. Management of proton pump inhibitor responsive-esophageal eosinophilia and eosinophilic esophagitis: Controversies in treatment approaches

    PubMed Central

    Kochar, Bharati; Dellon, Evan S.

    2015-01-01

    Eosinophilic esophagitis (EoE) is a chronic immune mediated clinicopathologic disease. The prevalence of EoE is approximately 1/2000 persons, EoE is now the most common cause of food impactions, and health care expenditures approach $1 billion annually. This paper will discuss challenges related to proton pump inhibitor responsive esophageal eosinophilia (PPI-REE), including distinguishing this condition from EoE and understanding mechanisms of the PPI response. For EoE, we will review multiple ongoing debates about treatment and monitoring strategies, including selecting treatment outcomes, optimizing medication formulations, approaching the steroid-refractory patient, conducting dietary elimination, prescribing long-term maintenance therapy, and performing esophageal dilation. PMID:26365201

  5. Management of proton pump inhibitor responsive-esophageal eosinophilia and eosinophilic esophagitis: controversies in treatment approaches.

    PubMed

    Kochar, Bharati; Dellon, Evan S

    2015-01-01

    Eosinophilic esophagitis (EoE) is a chronic immune-mediated clinicopathologic disease. The prevalence of EoE is approximately 1/2000 persons, EoE is now the most common cause of food impactions, with healthcare expenditures approaching US$ 1 billion annually. This article will discuss challenges related to proton pump inhibitor responsive esophageal eosinophilia, including distinguishing this condition from EoE and understanding the mechanisms behind the PPI response. For EoE, we will review multiple ongoing debates about treatment and monitoring strategies, including selecting treatment outcomes, optimizing medication formulations, approaching the steroid-refractory patient, conducting dietary elimination, prescribing long-term maintenance therapy and performing esophageal dilation.

  6. pH dependence of light-driven proton pumping by an archaerhodopsin from Tibet: comparison with bacteriorhodopsin.

    PubMed

    Ming, Ming; Lu, Miao; Balashov, Sergei P; Ebrey, Thomas G; Li, Qingguo; Ding, Jiandong

    2006-05-01

    The pH-dependence of photocycle of archaerhodopsin 4 (AR4) was examined, and the underlying proton pumping mechanism investigated. AR4 is a retinal-containing membrane protein isolated from a strain of halobacteria from a Tibetan salt lake. It acts as a light-driven proton pump like bacteriorhodopsin (BR). However, AR4 exhibits an "abnormal" feature--the time sequence of proton release and uptake is reversed at neutral pH. We show here that the temporal sequence of AR4 reversed to "normal"--proton release preceding proton uptake--when the pH is increased above 8.6. We estimated the pK(a) of the proton release complex (PRC) in the M-intermediate to be approximately 8.4, much higher than 5.7 of wide-type BR. The pH-dependence of the rate constant of M-formation shows that the pK(a) of PRC in the initial state of AR4 is approximately 10.4, whereas it is 9.7 in BR. Thus in AR4, the chromophore photoisomerization and subsequent proton transport from the Schiff base to Asp-85 is coupled to a decrease in the pK(a) of PRC from 10.4 to 8.4, which is 2 pK units less than in BR (4 units). This weakened coupling accounts for the lack of early proton release at neutral pH and the reversed time sequence of proton release and uptake in AR4. Nevertheless the PRC in AR4 effectively facilitates deprotonation of primary proton acceptor and recovery of initial state at neutral pH. We found also that all pK(a)s of the key amino acid residues in AR4 were elevated compared to those of BR.

  7. Diagnostic ELISA for parietal cell autoantibody using tomato lectin-purified gastric H+/K(+)-ATPase (proton pump).

    PubMed

    Chuang, J S; Callaghan, J M; Gleeson, P A; Toh, B H

    1992-01-01

    Circulating parietal cell autoantibodies, a useful diagnostic marker for autoimmune gastritis and pernicious anaemia, are currently routinely tested by serum immunofluorescence reactivity with frozen sections of rodent stomach. The major molecular targets of these parietal cell autoantibodies have recently been demonstrated to be the alpha- and the beta-subunits of the gastric H+/K(+)-ATPase (proton pump). We have demonstrated that tomato lectin binds specifically to the beta-subunit of the proton pump and concomittantly co-purifies the alpha-subunit. In the present study, we have exploited the latter observation for the development of a diagnostic ELISA for the detection of parietal cell autoantibodies and compared the performance of this assay with an ELISA using crude gastric membranes. The ELISAs were tested on 72 parietal cell autoantibody-positive sera, 72 parietal cell autoantibody-negative sera and 72 disease-control sera. The ELISA using lectin-purified canine proton pump was superior to that using crude canine gastric membranes in that it was about two-fold more sensitive (82% vs. 43%). With an assay sensitivity of 82% and a specificity of 90%, we propose that the ELISA using the lectin-purified proton pump is a rapid, simple, sensitive and specific diagnostic immunoassay for parietal cell autoantibodies.

  8. 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…

  9. [Impact of pharmacotherapeutic warnings on the prescription of clopidogrel and proton pump inhibitors in hospitalised patients].

    PubMed

    Sánchez Ruiz-Gordoa, M; Tenías Burillo, J M; Ruiz Martín de la Torre, R; Valenzuela Gámez, J C

    2012-01-01

    To estimate the frequency of clopidogrel prescriptions in association with proton pump inhibitors (PPIs) in patients hospitalised with circulatory pathologies, after the publication of several warnings about this association. To identify and quantify the magnitude of the factors related to the prescription of both drugs. Observational, analytical, longitudinal, and retrospective study assessing changes in prescription of clopidogrel-PPIs association after and before the first official warning (about these drugs' interactions) was published. We selected all patients with a code indicating a circulatory system disease in the Minimum Basic Data Set, who had been prescribed clopidogrel during hospital admission. We also evaluated proton pump inhibitor use in these patients (omeprazole and pantoprazole). 5678 patients diagnosed with circulatory diseases were admitted during 2009, and clopidogrel was prescribed in 13.6% of them. In the pre-warning period, clopidogrel-PPIs prescriptions were significantly higher than in the post-warning period (80, 8% vs 48, 6%), especially in omeprazole. The combined prescription was lower if the circulatory diagnosis was the main cause for hospitalisation, if the patient had heart disease, if the patient was admitted in Internal Medicine/Cardiology or Intensive care units, and if the period of time was further from warning. Combined prescription has decreased since the first warning, above all in patients with a primary circulatory heart disease. Omeprazole is a potent CYP2C19 inhibitor, so it was used in lower rates than pantoprazole in association with clopidogrel. Medical departments related to cardiovascular disease followed the warning more than others. Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.

  10. Blood Pressure-Lowering Effect of Orally Ingested Nitrite Is Abolished by a Proton Pump Inhibitor.

    PubMed

    Montenegro, Marcelo F; Sundqvist, Michaela L; Larsen, Filip J; Zhuge, Zhengbing; Carlström, Mattias; Weitzberg, Eddie; Lundberg, Jon O

    2017-01-01

    Inorganic nitrate and nitrite from dietary and endogenous sources are metabolized to NO and other bioactive nitrogen oxides that affect blood pressure. The mechanisms for nitrite bioactivation are unclear, but recent studies in rodents suggest that gastric acidity may influence the systemic effects of this anion. In a randomized, double-blind, placebo-controlled crossover study, we tested the effects of a proton pump inhibitor on the acute cardiovascular effects of nitrite. Fifteen healthy nonsmoking, normotensive subjects, aged 19 to 39 years, were pretreated with placebo or esomeprazole (3×40 mg) before ingesting sodium nitrite (0.3 mg kg(-1)), followed by blood pressure monitoring. Nitrite reduced systolic blood pressure by a maximum of 6±1.3 mm Hg when taken after placebo, whereas pretreatment with esomeprazole blunted this effect. Peak plasma nitrite, nitrate, and nitroso species levels after nitrite ingestion were similar in both interventions. In 8 healthy volunteers, we then infused increasing doses of sodium nitrite (1, 10, and 30 nmol kg(-1) min(-1)) intravenously. Interestingly, although plasma nitrite peaked at similar levels as with orally ingested nitrite (≈1.8 µmol/L), no changes in blood pressure were observed. In rodents, esomeprazole did not affect the blood pressure response to the NO donor, DEA NONOate, or vascular relaxation to nitroprusside and acetylcholine, demonstrating an intact downstream NO-signaling pathway. We conclude that the acute blood pressure-lowering effect of nitrite requires an acidic gastric environment. Future studies will reveal if the cardiovascular complications associated with the use of proton pump inhibitors are linked to interference with the nitrate-nitrite-NO pathway. © 2016 American Heart Association, Inc.

  11. 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

  12. Intravenous proton pump inhibitors for peptic ulcer bleeding: Clinical benefits and limits.

    PubMed

    Cheng, Hsiu-Chi; Sheu, Bor-Shyang

    2011-03-16

    Peptic ulcer bleeding is a common disease and recurrent bleeding is an independent risk factor of mortality. Infusion with proton pump inhibitors (PPIs) prevents recurrent bleeding after successful endoscopic therapy. A gastric acidic environment of less than pH 5.4 alters coagulation function and activates pepsin to disaggregate platelet plugs. Gastric acid is secreted by H(+), K(+)-ATPase, naming the proton pump. This update review focuses on the mechanism and the role of PPIs in the clinical management of patients with peptic ulcer bleeding. An intravenous omeprazole bolus followed by high-dose continuous infusion for 72 h after successful endoscopic therapy can prevent the recurrent bleeding. In the Asian, however, the infusion dosage can possibly be diminished whilst preserving favorable control of the intragastric pH and thereby still decreasing rates of recurrent bleeding. Irrespective of the infusion dosage of PPIs, rates of recurrent bleeding remain high in patients with co-morbidities. Because recurrent peptic ulcer bleeding may be prolonged in those with co-morbidities, a low-dose infusion of IV PPIs for up to 7-day may result in better control of recurrent bleeding of peptic ulcers. Due to the inter-patient variability in CYP2C19 genotypes, the infusion form of new generation PPIs, such as esomeprazole, should be promising for the prevention of recurrent bleeding. This article offers a comprehensive review of clinical practice, highlighting the indication, the optimal dosage, the duration, and the potential limitation of PPIs infusion for peptic ulcer bleeding.

  13. Effectiveness and safety of proton pump inhibitors in infantile gastroesophageal reflux disease.

    PubMed

    Higginbotham, Tanner W

    2010-03-01

    To evaluate the efficacy and safety of proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux disease (GERD) in infants <1 year of age. A literature search was conducted through PubMed (up to December 2009), International Pharmaceutical Abstracts (1970-December 2009), and The Cochrane Library (up to December 2009) using combinations of the following key search terms: proton pump inhibitor, GERD, infant, children, pediatric, omeprazole, rabeprazole, lansoprazole, esomeprazole, and pantoprazole. Reference citations from identified articles were also reviewed. All double-blind, placebo-controlled trials published in English that evaluated the safety and efficacy of PPIs in infants with GERD were included in this review. Trials involving children older than 12 months were not included. GERD is a source of pain and discomfort in adults; yet, in infants, symptoms that are thought to be indicative of painful stimuli have no clear cause-and-effect relationship with infant GERD. PPIs are beneficial in relieving symptoms of GERD in the adult population, but their usefulness in decreasing GERD-associated behaviors in infants is still questionable, despite a large increase in PPI prescribing for children <1 year of age. In all studies reviewed, infants treated with PPIs did not experience a significant decrease in behaviors perceived to be caused by GERD. The largest placebo-controlled trial to date found that rates of adverse events were increased in the PPI group compared with the placebo group, whereas the other trials reviewed reported no difference in adverse effects with the use of PPIs. Clinical trials reveal that PPI therapy is not an effective treatment for common infant GERD-associated symptoms. Evidence supporting safety of PPI use in infants is conflicting, and more large-scale, randomized, placebo-controlled trials are necessary to better establish the role of PPIs in infant GERD.

  14. Roles of subunit NuoL in the proton pumping coupling mechanism of NADH:ubiquinone oxidoreductase (complex I) from Escherichia coli.

    PubMed

    Narayanan, Madhavan; Sakyiama, Joseph A; Elguindy, Mahmoud M; Nakamaru-Ogiso, Eiko

    2016-10-01

    Respiratory complex I has an L-shaped structure formed by the hydrophilic arm responsible for electron transfer and the membrane arm that contains protons pumping machinery. Here, to gain mechanistic insights into the role of subunit NuoL, we investigated the effects of Mg(2+), Zn(2+) and the Na(+)/H(+) antiporter inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) on proton pumping activities of various isolated NuoL mutant complex I after reconstitution into Escherichia coli double knockout (DKO) membrane vesicles lacking complex I and the NADH dehydrogenase type 2. We found that Mg(2+) was critical for proton pumping activity of complex I. At 2 µM Zn(2+), proton pumping of the wild-type was selectively inhibited without affecting electron transfer; no inhibition in proton pumping of D178N and D400A was observed, suggesting the involvement of these residues in Zn(2+) binding. Fifteen micromolar of EIPA caused up to ∼40% decrease in the proton pumping activity of the wild-type, D303A and D400A/E, whereas no significant change was detected in D178N, indicating its possible involvement in the EIPA binding. Furthermore, when menaquinone-rich DKO membranes were used, the proton pumping efficiency in the wild-type was decreased significantly (∼50%) compared with NuoL mutants strongly suggesting that NuoL is involved in the high efficiency pumping mechanism in complex I.

  15. Structural identification of cation binding pockets in the plasma membrane proton pump

    PubMed Central

    Ekberg, Kira; Pedersen, Bjørn P.; Sørensen, Danny M.; Nielsen, Ann K.; Veierskov, Bjarke; Nissen, Poul; Palmgren, Michael G.; Buch-Pedersen, Morten J.

    2010-01-01

    The activity of P-type plasma membrane H+-ATPases is modulated by H+ and cations, with K+ and Ca2+ being of physiological relevance. Using X-ray crystallography, we have located the binding site for Rb+ as a K+ congener, and for Tb3+ and Ho3+ as Ca2+ congeners. Rb+ is found coordinated by a conserved aspartate residue in the phosphorylation domain. A single Tb3+ ion is identified positioned in the nucleotide-binding domain in close vicinity to the bound nucleotide. Ho3+ ions are coordinated at two distinct sites within the H+-ATPase: One site is at the interface of the nucleotide-binding and phosphorylation domains, and the other is in the transmembrane domain toward the extracellular side. The identified binding sites are suggested to represent binding pockets for regulatory cations and a H+ binding site for protons leaving the pump molecule. This implicates Ho3+ as a novel chemical tool for identification of proton binding sites. PMID:21098259

  16. Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis

    PubMed Central

    Mori, Shiori; Kadochi, Yui; Luo, Yi; Fujiwara-Tani, Rina; Nishiguchi, Yukiko; Kishi, Shingo; Fujii, Kiyomu; Ohmori, Hitoshi; Kuniyasu, Hiroki

    2017-01-01

    AIM To elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined. METHODS Collagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry. RESULTS CT26 cells expressed a Na+-H+ exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor β and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease. CONCLUSION From these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis. PMID:28321159

  17. 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.

  18. The proton to electron stoichiometry of steady-state photosynthesis in living plants: A proton-pumping Q cycle is continuously engaged

    PubMed Central

    Sacksteder, Colette A.; Kanazawa, Atsuko; Jacoby, Michael E.; Kramer, David M.

    2000-01-01

    A noninvasive technique is introduced with which relative proton to electron stoichiometries (H+/e− ratios) for photosynthetic electron transfer can be obtained from leaves of living plants under steady-state illumination. Both electron and proton transfer fluxes were estimated by a modification of our previously reported dark-interval relaxation kinetics (DIRK) analysis, in which processes that occur upon rapid shuttering of the actinic light are analyzed. Rates of turnover of linear electron transfer through the cytochrome (cyt) b6f complex were estimated by measuring the DIRK signals associated with reduction of cyt f and P700. The rates of proton pumping through the electron transfer chain and the CFO-CF1 ATP synthase (ATPase) were estimated by measuring the DIRK signals associated with the electrochromic shifting of pigments in the light-harvesting complexes. Electron transfer fluxes were also estimated by analysis of saturation pulse-induced changes in chlorophyll a fluorescence yield. It was shown that the H+/e− ratio, with respect to both cyt b6f complex and photosystem (PS) II turnover, was constant under low to saturating illumination in intact tobacco leaves. Because a H+/e− ratio of 3 at a low light is generally accepted, we infer that this ratio is maintained under conditions of normal (unstressed) photosynthesis, implying a continuously engaged, proton-pumping Q cycle at the cyt b6f complex. PMID:11121034

  19. 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

  20. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Specific proton pump inhibitors E3810 and lansoprazole affect the recovery process of gastric secretion in rats differently.

    PubMed

    Tomiyama, Y; Morii, M; Takeguchi, N

    1994-11-29

    After a single subcutaneous administration (30 mg/kg) of proton pump inhibitor 2-[(4-(3-methoxypropoxy)-3-methylpyridin-2-yl)-methylsulfiny l]- 1H-benzimidazole sodium salt (E3810), or lansoprazole in rats, time courses of inhibitory and recovery processes of acid secretion in vivo and pump enzyme activity in isolated microsomes were measured. The acid secretion rate which reflects H+,K(+)-ATPase activity in the secretory canalicular (apical) membrane was compared with that in the microsomal fraction which consists mostly of resting, intracellularly-pooled tubulovesicles. We found that the canalicular pump was first inhibited, followed by slow inhibition of the microsomal pump enzyme activity, with the rate of the latter process depending on the inhibitors. It took 2.5 hr for the half-maximal inhibition of the microsomal pump in E3810-treated rats, and 6 hr in lansoprazole-treated rats. The acid secretion and the microsomal enzyme activity completely recovered within 48 hr after the administration of E3810, but recovered by only 20% even 96 hr after the administration of lansoprazole. Incubation with dithiothreitol of isolated microsomes obtained from E3810-treated rats reactivated the enzyme activity, but not from rats treated with lansoprazole. These results suggest that dissociation of inhibitor from the pump and/or intracellular transport of the pump is affected differently by these inhibitors. Furthermore, it is possible that the half life of the proton pump protein is much longer (greater than 96 hr) than the previously proposed value of 30-48 hr.

  2. Phytoremediation potential of Arabidopsis thaliana, expressing ectopically a vacuolar proton pump, for the industrial waste phosphogypsum.

    PubMed

    Khoudi, Habib; Maatar, Yafa; Brini, Faïçal; Fourati, Amine; Ammar, Najoua; Masmoudi, Khaled

    2013-01-01

    Phosphogypsum (PG) is a by-product of the phosphorus-fertiliser industry and represents an environmental concern since it contains pollutants such as cadmium (Cd). We have recently shown that the overexpression of a proton pump gene (TaVP1) in transgenic tobacco (Nicotiana tabacum) led to an enhanced Cd tolerance and accumulation. The aim of this study was to evaluate the potential of transgenic Arabidopsis thaliana plants harbouring the TaVP1 gene to phytoremediate phosphogypsum. A pot experiment was carried out under greenhouse conditions. Transgenic A. thaliana plants harbouring the TaVP1 gene were grown on various substrates containing phosphogypsum (0, 25, 50 and 100 %) for 40 days. At the end of the growth period, we examined the growth (germination, root length, fresh weight) and physiological parameters (chlorophyll and protein contents, catalase activity and proteolysis) as well as the cadmium, Mg, Ca, and P contents of the A. thaliana plants. In order to evaluate Cd tolerance of the A. thaliana lines harbouring the TaVP1 gene, an in vitro experiment was also carried out. One week-old seedlings were transferred to Murashige and Skoog agar plates containing various concentrations of cadmium; the germination, total leaf area and root length were determined. The growth and physiological parameters of all A. thaliana plants were significantly altered by PG. The germination capacity, root growth and biomass production of wild-type (WT) plants were more severely inhibited by PG compared with the TaVP1 transgenic A. thaliana lines. In addition, TaVP1 transgenic A. thaliana plants maintained a higher antioxidant capacity than the WT. Interestingly, elemental analysis of leaf material derived from plants grown on PG revealed that the transgenic A. thaliana line accumulated up to ten times more Cd than WT. Despite its higher Cd content, the transgenic A. thaliana line performed better than the WT counterpart. In vitro evaluation of Cd tolerance showed that TaVP1

  3. Proton pump inhibitors in GORD An overview of their pharmacology, efficacy and safety.

    PubMed

    Savarino, Vincenzo; Di Mario, Francesco; Scarpignato, Carmelo

    2009-03-01

    Gastric acid secretion is a complex phenomenon under nervous and hormonal influence. The stimulation of proton pump (H(+), K(+)-ATPase) in the parietal cell represents the final step of acid secretion and this knowledge has led to the development of a class of drugs, the proton pump inhibitors (PPIs), which are targeted at blocking this enzyme. Chemically, all the available PPIs consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution. As a class, they are the most potent inhibitors of gastric acid secretion available. Although there are differences among PPIs concerning their pharmacokinetics, pharmacodynamics, influence by food and antacids as well as potential for drug interactions, it is not always evident whether these often subtle differences are clinically relevant. A careful evaluation of the available studies reveals that rabeprazole and esomeprazole achieve more rapid acid inhibition than other PPIs. Also, the effect of rabeprazole is less dependent upon genetic make-up than all other PPIs, giving rise to less inter-subject variability and leading to a more predictable effect. Esomeprazole, by inhibiting its own catabolism, makes all patients slow metabolizers, but could expose them to potential drug interactions. PPIs are the mainstay of medical treatment of gastro-oesophageal reflux disease (GORD), in that they are able to provide 80-85% healing rate of oesophageal lesions, including ulcers, and to reduce the incidence of complications like strictures as well as dysplasia and adenocarcinoma in Barrett's oesophagus (BO). Also relief of symptoms can be achieved in about 80% of cases, even though this benefit is reduced by a factor of approximately 20% in patients with non-erosive reflux disease (NERD). Their effect on Barrett's oesophagus and the extra-oesophageal manifestations of GORD is much less consistent. In general, the tolerability profile of PPIs is good in both short- and long-term clinical trials

  4. A vacuolar-type proton pump in a vesicle fraction enriched with potassium transporting plasma membranes from tobacco hornworm midgut

    SciTech Connect

    Wieczorek, H.; Weerth, S.; Schindlbeck, M.; Klein, U.

    1989-07-05

    Mg-ATP dependent electrogenic proton transport, monitored with fluorescent acridine orange, 9-aminoacridine, and oxonol V, was investigated in a fraction enriched with potassium transporting goblet cell apical membranes of Manduca sexta larval midgut. Proton transport and the ATPase activity from the goblet cell apical membrane exhibited similar substrate specificity and inhibitor sensitivity. ATP and GTP were far better substrates than UTP, CTP, ADP, and AMP. Azide and vanadate did not inhibit proton transport, whereas 100 microM N,N'-dicyclohexylcarbodiimide and 30 microM N-ethylmaleimide were inhibitors. The pH gradient generated by ATP and limiting its hydrolysis was 2-3 pH units. Unlike the ATPase activity, proton transport was not stimulated by KCl. In the presence of 20 mM KCl, a proton gradient could not be developed or was dissipated. Monovalent cations counteracted the proton gradient in an order of efficacy like that for stimulation of the membrane-bound ATPase activity: K+ = Rb+ much greater than Li+ greater than Na+ greater than choline (chloride salts). Like proton transport, the generation of an ATP dependent and azide- and vanadate-insensitive membrane potential (vesicle interior positive) was prevented largely by 100 microM N,N'-dicyclohexylcarbodiimide and 30 microM N-ethylmaleimide. Unlike proton transport, the membrane potential was not affected by 20 mM KCl. In the presence of 150 mM choline chloride, the generation of a membrane potential was suppressed, whereas the pH gradient increased 40%, indicating an anion conductance in the vesicle membrane. Altogether, the results led to the following new hypothesis of electrogenic potassium transport in the lepidopteran midgut. A vacuolar-type electrogenic ATPase pumps protons across the apical membrane of the goblet cell, thus energizing electroneutral proton/potassium antiport. The result is a net active and electrogenic potassium flux.

  5. Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed

    PubMed Central

    2013-01-01

    Background Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H + −rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. Method MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. Results Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. Conclusion This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy. PMID

  6. Aspartate-histidine interaction in the retinal schiff base counterion of the light-driven proton pump of Exiguobacterium sibiricum.

    PubMed

    Balashov, S P; Petrovskaya, L E; Lukashev, E P; Imasheva, E S; Dioumaev, A K; Wang, J M; Sychev, S V; Dolgikh, D A; Rubin, A B; Kirpichnikov, M P; Lanyi, J K

    2012-07-24

    One of the distinctive features of eubacterial retinal-based proton pumps, proteorhodopsins, xanthorhodopsin, and others, is hydrogen bonding of the key aspartate residue, the counterion to the retinal Schiff base, to a histidine. We describe properties of the recently found eubacterium proton pump from Exiguobacterium sibiricum (named ESR) expressed in Escherichia coli, especially features that depend on Asp-His interaction, the protonation state of the key aspartate, Asp85, and its ability to accept a proton from the Schiff base during the photocycle. Proton pumping by liposomes and E. coli cells containing ESR occurs in a broad pH range above pH 4.5. Large light-induced pH changes indicate that ESR is a potent proton pump. Replacement of His57 with methionine or asparagine strongly affects the pH-dependent properties of ESR. In the H57M mutant, a dramatic decrease in the quantum yield of chromophore fluorescence emission and a 45 nm blue shift of the absorption maximum with an increase in the pH from 5 to 8 indicate deprotonation of the counterion with a pK(a) of 6.3, which is also the pK(a) at which the M intermediate is observed in the photocycle of the protein solubilized in detergent [dodecyl maltoside (DDM)]. This is in contrast with the case for the wild-type protein, for which the same experiments show that the major fraction of Asp85 is deprotonated at pH >3 and that it protonates only at low pH, with a pK(a) of 2.3. The M intermediate in the wild-type photocycle accumulates only at high pH, with an apparent pK(a) of 9, via deprotonation of a residue interacting with Asp85, presumably His57. In liposomes reconstituted with ESR, the pK(a) values for M formation and spectral shifts are 2-3 pH units lower than in DDM. The distinctively different pH dependencies of the protonation of Asp85 and the accumulation of the M intermediate in the wild-type protein versus the H57M mutant indicate that there is strong Asp-His interaction, which substantially lowers

  7. Synthesis of a DOTA(Gd3+)-conjugate of proton-pump inhibitor pantoprazole for gastric wall imaging studies

    PubMed Central

    Maharvi, Ghulam M.; Bharucha, Adil E.; Fauq, Abdul H.

    2014-01-01

    Magnetic resonance imaging (MRI) is used to evaluate gastrointestinal (GI) structure and functions in humans. Despite filling the viscus lumen with a contrast agent, visualization of the viscus wall is limited. To overcome this limitation, we de novo synthesized a conjugate that covalently combines a Gd-based MRI contrast agent, encaged with a chelating agent (DOTA), with pantoprazole, which is a widely used proton pump inhibitor that binds to proton pumps in the stomach and colon. The DOTA linkage was installed at a mechanism-based strategic location in the pantoprazole molecule to minimize a possible negative effect of the structural modification on the drug. It is anticipated that by defining the wall of the stomach and colon, this compound will facilitate functional MRI of the GI tract in humans. PMID:23511016

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

    PubMed

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

    2010-10-08

    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(-).

  9. 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

  10. Introduction of proton pump inhibitors--consequences for surgical treatment of peptic ulcer.

    PubMed

    Tonus, C; Weisenfeld, E; Appel, P; Nier, H

    2000-01-01

    This retrospective study analyzes the influence of different factors on morbidity and mortality after surgical treatment of peptic ulcer. At the Municipal Hospital of Offenbach, Germany, from 1985-1996, 485 patients underwent surgery. Of the 485 patients, 70.7% (343) were diagnosed to have duodenal ulcer and 29.2% (142) had suffered from gastric ulcer. During this period, 79.2% (384) of the operations were performed under emergency conditions because of acute complications (56% of these with perforation, 20% with penetration, 24% with ulcer bleeding), whereas the rest was done electively. Two hundred and ninety-one (60%) patients were male, the average age was 59 years and 71.7% (348) of the patients had certain concomitant diseases. We observed complications in 48% of the cases with a total postoperative mortality of 21%. Between 1985 and 1996 the total number of ulcer surgeries performed at the Municipal Hospital Offenbach per year has stayed almost constant. However, a definite increase of acute operations in addition to a decrease of elective interventions was noticed. The dissatisfying results of surgical treatment of peptic ulcer after the introduction of proton pump inhibitors seems to be the consequence of the negative selection of patients mentioned above. A connection could be proved between the age and condition of the patient, the type of the surgical intervention (acute or elective) and the morbidity and mortality after the surgery.

  11. An Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor ADMA

    PubMed Central

    Ghebremariam, Yohannes T.; LePendu, Paea; Lee, Jerry C.; Erlanson, Daniel A.; Slaviero, Anna; Shah, Nigam H.; Leiper, James; Cooke, John P.

    2013-01-01

    Background Proton pump inhibitors (PPIs) are gastric acid suppressing agents widely prescribed for the treatment of gastro-esophageal reflux disease (GERD). Recently, several studies in patients with acute coronary syndrome (ACS) have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events (MACE). The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed. Methods and Results Plasma ADMA is an endogenous inhibitor of nitric oxide synthase (NOS). Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely due to its attenuation of the vasoprotective effects of endothelial NOS. We find that PPIs elevate plasma asymmetric dimethylarginine (ADMA) level and reduce nitric oxide (NO) levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to, and inhibit dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Conclusions We present a plausible biological mechanism to explain the association of PPIs with increased MACE in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with use of the PPIs in the general population. PMID:23825361

  12. Drug-Induced Subacute Cutaneous Lupus Erythematosus Associated with Proton Pump Inhibitors.

    PubMed

    Aggarwal, Nitish

    2016-06-01

    Subacute cutaneous lupus erythematosus (SCLE) is an autoimmune disease that may be induced by proton pump inhibitors (PPIs) in at-risk populations. The US FDA does not recognize SCLE as an adverse event associated with PPIs. We queried the FDA Adverse Event Reporting System database, which contains adverse event case reports submitted by the public as well as by industry, and analyzed the data to quantify passive pharmacovigilance signals for SCLE associated with PPIs. A disproportionality analysis of the signals yielded a significant association between SCLE and PPIs. Discontinuation of PPI resulted in remission, with PPI re-challenge causing SCLE to reoccur. A follow-up analysis also yielded a significant association between SCLE and H2 receptor antagonists. We conducted a brief literature survey of published case reports and studies to discern the validity of PPI-induced SCLE signals. Healthcare prescribers and patients should be made aware that SCLE can be induced by PPIs. In such cases, PPIs should be discontinued and alternative clinical treatment sought. Regulatory bodies such as the FDA should incorporate the adverse reaction in PPI prescription labels.

  13. Increased health costs from mandated Therapeutic Substitution of proton pump inhibitors in British Columbia.

    PubMed

    Skinner, B J; Gray, J R; Attara, G P

    2009-04-15

    In 2003, British Columbia's PharmaCare programme implemented a drug reimbursement policy called Therapeutic Substitution, which required patients with acid-related diseases, primarily gastro-oesophageal reflux disease (GERD), to make a medically unnecessary switch from their prescribed proton pump inhibitor (PPI) to the cheapest available brand name PPI (Pariet, rabeprazole sodium), comprising a different (nongeneric) chemical. To evaluate the independent effects of PPI Therapeutic Substitution on individual healthcare utilization among those complying with the policy. We used the BC Ministry of Health Services' individual-level linked data, allowing isolation of healthcare utilization for the entire population of PPI consumers from 2002 to 2005. After controlling for individual case variation in age, gender and a proxy for pre-existing health status, regression analysis revealed statistically significant greater overall use of PPIs, physician services and hospital services independently associated with patients who complied with Therapeutic Substitution. Over the 3-year period 2003-2005, this represented net healthcare expenditures totalling approximately C$43.51 million (C$9.11 million in total PPI drug expenditures, C$24.65 million for physician services and C$9.75 million for hospital services). Medically unnecessary drug switching caused by compliance with Therapeutic Substitution policy appears to be independently associated with higher overall healthcare utilization.

  14. Accumulating Evidence for a Drug–Drug Interaction Between Methotrexate and Proton Pump Inhibitors

    PubMed Central

    Mackey, Ann Corken; Kluetz, Paul; Jappar, Dilara; Korvick, Joyce

    2012-01-01

    Background. A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug–drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs). Methods. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs. Results. A search of the AERS database and existing literature found several individual case reports of drug–drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction. Conclusion. There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug–drug interaction between high-dose methotrexate and PPIs. Physicians should be alerted to this potential drug–drug interaction in patients receiving concomitant high-dose methotrexate and PPIs. PMID:22477728

  15. Comparative study and optimisation of the administration mode of three proton pump inhibitors by nasogastric tube.

    PubMed

    Messaouik, D; Sautou-Miranda, V; Bagel-Boithias, S; Chopineau, J

    2005-08-11

    Patients in intensive care often develop stress-induced ulcers. As a preventive measure, proton pump inhibitors (PPIs) are administered by nasogastric tube. However, some PPIs can block the tube. The aim of this study was to compare the behaviour of three PPIs (omeprazole, lanzoprazole and esomeprazole) during the transit of the granules through the tube and to optimise their modes of administration. For each IPP, the experiment was designed to study the influence of four variables: the tube material (silicone or polyurethane), the solvent used to dilute the granules (water or apple juice), the mode of administration (in two or three doses) and the rinse volume (10 or 20 ml). We counted the granules before transit and at the tube outlet, and assayed the active drug ingredient by UV spectrometry. The assay showed complete transit of esomeprazole through the tube, but average losses of omeprazole and lanzoprazole of 39 and 33%, respectively, were observed. No significant improvement was obtained by the variables 'diluent' and 'mode of administration'. The variable 'rinse' had a significant influence. For lanzoprazole, a polyurethane tube allowed recovery of on average 86% of the active ingredient. Esomeprazole is thus the choice PPI for the treatment of patients by nasogastric tube. Using a polyurethane tube and a rinse volume of 20 ml, the administration of lanzoprazole by tube can be considered. Use of omeprazole is not recommended because none of the modes of administration tested ensured that a sufficient concentration of active ingredient reached the stomach.

  16. Perils and pitfalls of long-term effects of proton pump inhibitors.

    PubMed

    Wilhelm, Sheila M; Rjater, Ryan G; Kale-Pradhan, Pramodini B

    2013-07-01

    This review summarizes the literature regarding long-term adverse effects of proton pump inhibitors (PPIs). A PubMed search (1966 to February 2013) for English language studies was conducted using key terms PPI: omeprazole, esomeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, pneumonia, Clostridium difficile, osteoporosis, risk of fractures, thrombocytopenia, rhabdomyolysis, anemia, iron deficiency, hypomagnesemia, vitamin B₁₂ and nephritis. The risk of pneumonia was increased 27-39% in short-term use of PPIs in three meta-analyses. C. difficile infections were also associated with the use of PPIs (odds ratio: 2.15; 95% CI: 1.81-2.55; p < 0.00001). This effect appears to be dose related. The US FDA has recently issued a warning regarding fractures and the impaired magnesium absorption associated with the use of PPI. Thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis and acute interstitial nephritis have also been reported with the use of PPIs. There is mounting evidence that PPIs are associated with serious adverse effects. Practitioners should be vigilant and counsel patients accordingly.

  17. 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

  18. 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.

  19. 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

  20. Adverse effects of proton-pump inhibitor use in older adults: a review of the evidence

    PubMed Central

    Maes, Marina L.; Fixen, Danielle R.; Linnebur, Sunny Anne

    2017-01-01

    Proton-pump inhibitors (PPIs) are a widely prescribed class of medications used to treat acid-related disorders and use has significantly increased over the last few decades. PPIs are often inappropriately prescribed and since they have been on the market, a number of post-marketing studies have been published demonstrating associations between longer duration of PPI therapy and a number of adverse effects that are a concern in older adults. The objective of this review is to discuss the existing literature of potential adverse effects with long-term PPI use in older adults and to summarize the implications in clinical practice. A PubMed search was conducted to identify studies evaluating the potential long-term adverse effects of PPI therapy in older adults, and publications were selected based on relevant criteria. PPIs have been associated with an increased risk of a number of adverse effects including osteoporotic-related fractures, Clostridium difficile infection, community-acquired pneumonia, vitamin B12 deficiency, kidney disease, and dementia, demonstrated by a number of case-control, cohort studies, and meta-analyses. Older adults should be periodically evaluated for the need for continued use of PPI therapy given the number of potential adverse effects associated with long-term use. PMID:28861211

  1. Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor.

    PubMed

    Jianu, Constantin S; Lange, Ove J; Viset, Trond; Qvigstad, Gunnar; Martinsen, Tom C; Fougner, Reidun; Kleveland, Per M; Fossmark, Reidar; Hauso, Øyvind; Waldum, Helge L

    2012-01-01

    We present a case of a gastric neuroendocrine carcinoma in a patient with a history of long-term proton pump inhibitor (PPI) use. A 49-year-old man using PPI for the last 15 years due to gastroesophageal reflux disease developed progressive dysphagia, dyspepsia and weight loss. Upper gastrointestinal endoscopy, endoscopic ultrasonography and abdominal CT diagnosed a malignant tumor localized to a hiatal hernia. Fasting serum chromogranin A and gastrin concentrations were elevated (32 nmol/l and 159 pmol/l, respectively). Helicobacter pylori PCR analysis of antral biopsies was negative. Biopsies from endoscopically normal oxyntic mucosa showed enterochromaffin-like (ECL) cell hyperplasia. Tumor biopsies revealed a poorly differentiated neuroendocrine carcinoma. Sevier-Munger staining, immunohistochemistry and electron microscopy indicated ECL cell as origin of the tumor cells. Concerns have previously been raised about the safety of long-term PPI use due to a possible increased risk of cancer. This case illustrates a patient with a poorly differentiated neuroendocrine carcinoma with ECL cell characteristics probably induced by hypergastrinemia secondary to long-term PPI use.

  2. Comparative safety and efficacy of proton pump inhibitors in paediatric gastroesophageal reflux disease.

    PubMed

    Kierkus, Jaroslaw; Oracz, Grzegorz; Korczowski, Bartosz; Szymanska, Edyta; Wiernicka, Anna; Woynarowski, Marek

    2014-05-01

    Gastroesophageal reflux is one of the most common reasons for referrals to paediatricians or paediatric gastroenterologists. Gastric acid-buffering agents, mucosal surface barriers and gastric anti-secretory agents are the main groups of medications currently used for treating gastroesophageal reflux disease (GERD) in children. Recently, the use of proton pump inhibitors (PPIs) for the treatment of GERD in children has increased considerably. Their effectiveness in healing erosive oesophagitis in paediatric subjects and in improving GERD symptoms has been established in many studies. However, the effectiveness in other clinical conditions and the long-term safety of PPIs for paediatric GERD have not been fully established yet and thus are still under debate. Therefore, the aim of this article is to provide a comparative review of the efficacy, safety and tolerability of PPIs in paediatric GERD. The available data suggest that short-term use of PPIs is well tolerated. Adverse events tend to be of a mild-to-moderate nature, with headache being the most frequently reported treatment-related adverse event. However, further well-designed trials and observational studies are still needed to clarify the efficacy and safety of PPIs in the paediatric population, especially in infants under the age of 12 months.

  3. [Safety and interactions of proton pump inhibitors: lessons learned in millions of patients].

    PubMed

    Esplugues, Juan V; Martí-Cabrera, Miguel

    2010-05-01

    After many years of widespread use, proton pump inhibitors (PPI) have been demonstrated to be relatively safe. The most frequently associated adverse reactions are mild with scarce clinical effects. These agents produce hypergastrinemia but this adverse effect has not been related to the development of malignancies. PPI seem to facilitate certain bacterial infections in the gastrointestinal and respiratory tracts. However, these infections are easily treated and therefore do not limit the prescription of PPI. From the pharmacokinetic point of view, the possibility of interactions with other drugs metabolized by the cytochrome P450 system has been described but these interactions generally seem to have little clinical or therapeutic importance. However, regulatory agencies are currently stressing the hypothetical interaction between PPI (especially omeprazole) and clopidogrel, which reduces the latter's antiplatelet effect. Although this recommendation should be followed, this interaction should be specifically evaluated to determine its clinical effect and the possible alternatives in patients at risk of gastrointestinal bleeding. Lastly, the present article reviews PPI administration in special, currently debated situations, such as in pregnant or breastfeeding women.

  4. Efficacy and safety of proton pump inhibitors in the management of pediatric gastroesophageal reflux disease.

    PubMed

    Tjon, James A; Pe, Michael; Soscia, Joanna; Mahant, Sanjay

    2013-09-01

    Proton pump inhibitors (PPIs) are commonly prescribed to infants and children for managing gastroesophageal reflux disease (GERD). Recently published literature illustrates conflicting evidence on the efficacy of PPIs in infants and children. Randomized controlled trials and systematic reviews have demonstrated a lack of efficacy of PPIs, specifically in young infants. Furthermore, emerging evidence also suggests that PPIs are not as benign as once thought, with newer data implicating a potential association of PPIs with an increased risk of respiratory tract infections, gastrointestinal infections, bone fractures, hypomagnesemia, and the occurrence of rebound hyperacidity after discontinuation of PPI therapy. To summarize the emerging data in children, we reviewed the literature to assess the efficacy and safety of PPIs in managing pediatric GERD. Despite conflicting evidence on the efficacy of PPIs, most studies in children demonstrated some benefit when compared with placebo. With respect to the safety of PPIs in children, only a few small studies and case reports indicated a potential association of PPIs with an increased risk of respiratory tract or gastrointestinal infections, bone fractures, and hypomagnesemia; however, many of those studies had their own limitations. From the review, it is clear that further well-designed trials and observational studies are needed to shed more light on the efficacy and safety of PPIs in the pediatric population.

  5. Gastric juice for the diagnosis of H pylori infection in patients on proton pump inhibitors

    PubMed Central

    Yakoob, Javed; Rasool, Shahid; Abbas, Zaigham; Jafri, Wasim; Abid, Shahab; Islam, Muhammad; Ahmad, Zubair

    2008-01-01

    AIM: To determine the efficacy of gastric juice polymerase chain reaction (PCR) for the detection of H pylori infection in comparison with histology and gastric antral biopsy PCR in patients on a proton pump inhibitor (PPI). METHODS: Eighty-five consecutive patients with dyspeptic symptoms were enrolled. Gastric biopsies for histology, PCR and gastric juice were collected at endoscopy for PCR of the H pylori urease C gene (ure C). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, positive and negative likelihood ratio for PCR of gastric juice for the H pylori ure C gene was compared to histology and gastric antral biopsy H pylori ure C PCR in patients with and without PPI. RESULTS: Gastric juice PCR was positive in 66 (78%) patients. Histology showed H pylori associated gastritis in 57 (67%). Gastric biopsy PCR was positive in 72 (85%). In patients not taking PPI, the sensitivity, specificity, PPV, NPV, accuracy and positive and negative likelihood ratio for gastric juice PCR were 89%, 72%, 91%, 67%, 90%, 85%, 3.1 and 0.1 respectively. In patients on PPI these values were 86%, 100%%, 100%, 29%, 86%, 9.5 and 1.4, respectively. CONCLUSION: Gastric juice PCR for the diagnosis of H pylori infection has increased sensitivity compared to histology with PPI. The use of gastric juice PCR is recommended to confirm H pylori status in patients taking PPIs. PMID:18330944

  6. 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.

  7. Long-term pretreatment with proton pump inhibitor and Helicobacter pylori eradication rates

    PubMed Central

    Yoon, Seung Bae; Park, Jae Myung; Lee, Jong-Yul; Baeg, Myong Ki; Lim, Chul-Hyun; Kim, Jin Soo; Cho, Yu Kyung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gyu

    2014-01-01

    AIM: To investigate whether proton pump inhibitor (PPI) pretreatment influences Helicobacter pylori eradication rate. METHODS: We retrospectively reviewed H. pylori-infected patients who were treated with a standard triple regimen (PPI, amoxicillin 1 g, and clarithromycin 500 mg, all twice daily for 7 d). The diagnosis of H. pylori infection and its eradication was assessed with the rapid urease test, histological examination by silver staining, or the 13C-urea breath test. We divided the patients into two groups: one received the standard eradication regimen without PPI pretreatment (Group A), and the other received PPI pretreatment (Group B). The patients in Group B were reclassified into three groups based on the duration of PPI pretreatment: Group B-I (3-14 d), Group B-II (15-55 d), and Group B-III (≥ 56 d). RESULTS: A total of 1090 patients were analyzed and the overall eradication rate was 80.9%. The cure rate in Group B (81.2%, 420/517) was not significantly different from that in Group A (79.2%, 454/573). The eradication rates in Group B-I, B-II and B-III were 80.1% (117/146), 81.8% (224/274) and 81.4% (79/97), respectively. CONCLUSION: PPI pretreatment did not affect H. pylori eradication rate, regardless of the medication period. PMID:24574779

  8. Comparative risk of ischemic stroke among users of clopidogrel together with individual proton pump inhibitors

    PubMed Central

    Bilker, Warren B.; Brensinger, Colleen M.; Flockhart, David A.; Freeman, Cristin P.; Kasner, Scott E.; Kimmel, Stephen E.; Hennessy, Sean

    2015-01-01

    Background and Purpose There is controversy and little information concerning whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We therefore aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. Methods We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999–2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole and pantoprazole—with pantoprazole serving as the referent. The endpoint was hospitalization for acute ischemic stroke, defined by International Classification of Diseases 9th Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Results Among 325,559 concomitant users of clopidogrel and a PPI, we identified 1,667 ischemic strokes for an annual incidence of 2.4% (95% confidence interval: 2.3–2.5). Adjusted hazard ratios for ischemic stroke vs. pantoprazole were: 0.98 (0.82–1.17) for esomeprazole; 1.06 (0.92–1.21) for lansoprazole; 0.98 (0.85–1.15) for omeprazole; and 0.85 (0.63–1.13) for rabeprazole. Conclusions PPIs of interest did not increase the rate of ischemic stroke among clopidogrel users when compared to pantoprazole, a PPI thought to be devoid of the potential to interact with clopidogrel. PMID:25657176

  9. 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

  10. 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.

  11. Adverse Event Reporting for Proton Pump Inhibitor Therapy: An Overview of Systematic Reviews.

    PubMed

    Abramowitz, Jason; Thakkar, Punam; Isa, Arton; Truong, Alan; Park, Connie; Rosenfeld, Richard M

    2016-10-01

    To assist clinicians in counseling patients regarding the risk of adverse events from proton pump inhibitors (PPIs), by synthesizing evidence from published systematic reviews of antireflux therapy. Cochrane Library, CINAHL, PubMed, Web of Knowledge. Overview based on PRISMA reporting standards (preferred reporting items for systematic reviews and meta-analyses) of English-language meta-analyses and systematic reviews of PPI therapy for reflux disease through December 2014. Two independent investigators assessed study eligibility, rated the review quality with AMSTAR criteria (assessing the methodological quality of systematic reviews), and abstracted data for adverse events. Thirty-three systematic reviews met inclusion criteria. The most commonly reported adverse events were community-acquired pneumonia (odds ratios, 1.04-1.92), with a greater association noted with shorter duration of therapy and higher doses. Hip fractures were also associated with PPI use (odds ratios, 1.16-1.50), especially with long-term therapy. Last, enteric infection with Clostridium difficile was more common with PPI therapy (odds ratios, 1.69-1.33). Other less commonly reported adverse events included electrolyte and vitamin deficiency. Risk factors for adverse events are reported in the text. Our overview shows that PPI therapy is associated with significant and potentially serious adverse events that should be discussed with patients. The effect sizes and risk factors provided should facilitate this discussion and promote shared decision making. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

  12. Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation.

    PubMed

    Hernández-Ochoa, B; Navarrete-Vázquez, G; Nava-Zuazo, C; Castillo-Villanueva, A; Méndez, S T; Torres-Arroyo, A; Gómez-Manzo, S; Marcial-Quino, J; Ponce-Macotela, M; Rufino-González, Y; Martínez-Gordillo, M; Palencia-Hernández, G; Esturau-Escofet, N; Calderon-Jaimes, E; Oria-Hernández, J; Reyes-Vivas, H

    2017-08-10

    Giardiasis is a worldwide parasitic disease that affects mainly children and immunosuppressed people. Side effects and the emergence of resistance over current used drugs make imperative looking for new antiparasitics through discovering of new biological targets and designing of novel drugs. Recently, it has determined that gastric proton-pump inhibitors (PPI) have anti-giardiasic activity. The glycolytic enzyme, triosephosphate isomerase (GlTIM), is one of its potential targets. Therefore, we employed the scaffold of PPI to design new compounds aimed to increase their antigiardial capacity by inactivating GlTIM. Here we demonstrated that two novel PPI-derivatives (BHO2 and BHO3), have better anti-giardiasic activity than omeprazole in concentrations around 120-130 µM, without cytotoxic effect on mammal cell cultures. The derivatives inactivated GlTIM through the chemical modification of Cys222 promoting local structural changes in the enzyme. Furthermore, derivatives forms adducts linked to Cys residues through a C-S bond. We demonstrated that PPI can be used as scaffolds to design better antiparasitic molecules; we also are proposing a molecular mechanism of reaction for these novel derivatives.

  13. Proton Pump Inhibitors and the Risk of Osseointegrated Dental Implant Failure: A Cohort Study.

    PubMed

    Wu, Xixi; Al-Abedalla, Khadijeh; Abi-Nader, Samer; Daniel, Nach G; Nicolau, Belinda; Tamimi, Faleh

    2017-04-01

    Proton pump inhibitors (PPIs) have a negative impact on bone accrual. Because osseointegration is influenced by bone metabolism, this study investigates the association between PPIs and the risk of osseointegrated implant failure. This retrospective cohort study included a total of 1,773 osseointegrated dental implants in 799 patients (133 implants in 58 PPIs users and 1,640 in 741 non-users) who were treated at the East Coast Oral Surgery Clinic in Moncton, Canada, from January 2007 to September 2015. Kaplan-Meier estimator was used to describe the hazard function of dental implant failure by PPIs usage. Multilevel mixed effects parametric survival analyses were used to test the association between PPIs exposure and risk of implant failure adjusting for potential confounders. The failure rates were 6.8% for people using PPIs compared to 3.2% for non-users. Subjects using PPIs had a higher risk of dental implant failure (HR = 2.73; 95% CI = 1.10-6.78) compared to those who did not use the drugs. The findings suggest that treatment with PPIs may be associated with an increased risk of osseointegrated dental implant failure.

  14. Helicobacter pylori therapy in children: a focus on proton pump inhibitors.

    PubMed

    Chiesa, Claudio; Anania, Caterina; Pacifico, Lucia; Olivero, Giuseppe; Osborn, John F

    2011-01-01

    Over the last two decades, there have been many studies on children who have sought an effective and safe treatment to eradicate Helicobacter pylori infection, but as yet, no therapy regimen has been found which is always effective and safe. Differences in drug response among pediatric patients are common. Such individual variability in drug response is multifactorial, including environmental, genetic, development and disease determinants that affect the disposition of a given drug. In pediatric efficacy studies for the management of H. pylori eradication in children, the most commonly tested regimen has contained a combination of proton pump inhibitor (PPI), clarithromycin and amoxicillin, followed by triple therapies containing PPI, clarithromycin and nitroimidazoles. Thus, PPIs are an integral part of triple therapy for H. pylori eradication in children with gastroduodenal disease. In this article, we comprehensively review, from a pediatric point of view, the literature on the clinical, pharmacologic and microbiologic properties of PPIs. We also discuss genetic, developmental and other host-related factors that may affect the efficacy of these drugs. Finally, we provide some guidance regarding their potential role and limitations for H. pylori eradication in children. Copyright © 2011 S. Karger AG, Basel.

  15. Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits

    PubMed Central

    Lué, Alberto; Lanas, Angel

    2016-01-01

    Proton pump inhibitors (PPIs) represent a milestone in the treatment of acid-related diseases, and are the mainstay in preventing upper gastrointestinal bleeding in high-risk patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding (LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated gastrointestinal bleeding should be directed toward preventing both upper and lower gastrointestinal damage. Future research should be directed toward identifying patients at low-risk for gastrointestinal events associated with the use of NSAIDs or aspirin to avoid inappropriate PPI prescribing. Alternatively, the efficacy of new pharmacologic strategies should be evaluated in high-risk groups, with the aim of reducing the risk of both upper and lower gastrointestinal bleeding in these patients. PMID:28082800

  16. The therapeutic effectiveness of the coadministration of weekly risedronate and proton pump inhibitor in osteoporosis treatment.

    PubMed

    Tanaka, Mizue; Itoh, Soichiro; Yoshioka, Taro; Yamashita, Kimihiro

    2014-01-01

    This trial was conducted to investigate the long-term effects of proton pump inhibitor (PPI) coadministration on the efficacy of weekly risedronate treatment for osteoporosis. Ninety-six women over 50 years old with low bone mineral density (BMD) participated in this trial. Subjects were randomly divided into 2 groups: a 17.5 mg dose of sodium risedronate was administered weekly, with or without a daily 10 mg dose of sodium rabeprazole (n = 49 and 47 in the BP + PPI and BP groups, resp.). The following biomarkers were measured at the baseline and every 3 months: bone-specific alkaline phosphatase, N-terminal telopeptide of type I collagen corrected for creatinine, parathyroid hormone, BMD of the lumbar spine, and physical parameters evaluated according to the SF-36v2 Health Survey. Statistical comparisons of these parameters were performed after 6, 12, 18, and 24 months. The Δ values of improvement in physical functioning after 12 months and bodily pain after 6 and 12 months in the BP + PPI group were significantly larger than those in the BP group. These results suggest that PPI does not adversely affect bone metabolism. Alternatively, approved bone formation by concomitant PPI treatment may have had favorable effects on the improvement of bodily pain and physical functions.

  17. Liquid chromatographic resolution of proton pump inhibitors including omeprazole on a ligand exchange chiral stationary phase.

    PubMed

    Ha, Jin Joo; Choi, Hee Jung; Jin, Jong Sung; Jeong, Euh Duck; Hyun, Myung Ho

    2010-10-08

    A ligand exchange chiral stationary phase (CSP) developed previously in this laboratory by bonding (R)-phenylglycinol derivative, sodium N-[(R)-2-hydroxy-1-phenylethyl]-N-undecylaminoacetate, to silica gel was successfully applied to the resolution of proton pump inhibitors (PPIs) including omeprazole, pantoprazole, lansoprazole and rabeprazole. For example, the separation factors (α) for the resolution of omeprazole, pantoprazole, lansoprazole and rabeprazole were 4.27, 5.28, 2.77 and 4.06, respectively, and the resolutions (R(S)) were 2.53, 2.55, 1.93, and 2.01, respectively, when 65% acetonitrile aqueous solution containing 0.5mM CuSO(4) and 0.05mM triethylamine was used as a mobile phase. Based on the chromatographic behaviors for the resolution of PPI analogues on CSP 1, a chiral recognition mechanism utilizing the sulfoxide oxygen and the benzimidazole ring nitrogen of PPIs as bidentate coordination donors to form an enantioselective ternary complex with the central Cu(II) ion and the chiral stationary bidentate ligand was proposed. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. CYP2C19 genotype and pharmacokinetics of three proton pump inhibitors in healthy subjects.

    PubMed

    Sakai, T; Aoyama, N; Kita, T; Sakaeda, T; Nishiguchi, K; Nishitora, Y; Hohda, T; Sirasaka, D; Tamura, T; Tanigawara, Y; Kasuga, M; Okumura, K

    2001-06-01

    To predict the CYP2C19 genotype-dependence in anti-Helicobacter pylori (H. pylori) therapy when lansoprazole or rabeprazole was used instead of omeprazole as a proton pump inhibitor (PPI). A comparative pharmacokinetic study with each PPI was designed as an open, randomized, and crossover study of 18 Japanese healthy volunteers who were classified into the homozygous, heterozygous extensive metabolizer and the poor metabolizer based on the CYP2C19 genotype determined by PCR-RFLP method. Each subject received a single oral dose of 20 mg omeprazole, 30 mg lansoprazole, or 20 mg sodium rabeprazole, with at least 1 week washout period between treatments. Plasma concentrations of PPIs and their metabolites were monitored until 12 h after medication. Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference. The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype. CYP2C19 genotype dependence will be found in the anti-H. pylori therapy even when lansoprazole is used as the PPI.

  19. Gastric microbiota is altered in oesophagitis and Barrett's oesophagus and further modified by proton pump inhibitors.

    PubMed

    Amir, Itay; Konikoff, Fred M; Oppenheim, Michal; Gophna, Uri; Half, Elizabeth E

    2014-09-01

    Gastro-oesophageal reflux can cause inflammation, metaplasia, dysplasia and cancer of the oesophagus. Despite the increased use of proton pump inhibitors (PPIs) to treat reflux, the incidence of oesophageal adenocarcinoma has increased rapidly in Europe and in the United States in the last 25 years. The reasons for this increase remain unclear. In this study, we aimed to determine whether the microbiota of the gastric refluxate and oesophageal biopsies differs between patients with heartburn and normal-appearing oesophageal mucosa versus patients with abnormal oesophageal mucosa [oesophagitis or Barrett's oesophagus (BE)] and to elucidate the effect of PPIs on the bacterial communities using 16S rRNA gene pyrosequencing. Significant differences in the composition of gastric fluid bacteria were found between patients with heartburn and normal oesophageal tissue versus patients with oesophagitis or BE, but in the oesophagus-associated microbiota differences were relatively modest. Notably, increased levels of Enterobacteriaceae were observed in the gastric fluid of oesophagitis and BE patients. In addition, treatment with PPIs had dramatic effects on microbial communities both in the gastric fluids and the oesophageal tissue. In conclusion, gastric fluid microbiota is modified in patients with oesophagitis and BE compared with heartburn patients with normal biopsies. Furthermore, PPI treatment markedly alters gastric and oesophageal microbial populations. Determining whether the changes in bacterial composition caused by PPIs are beneficial or harmful will require further investigation. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

  20. Additional Benefits of Routine Drugs on Gastrointestinal Cancer: Statins, Metformin, and Proton Pump Inhibitors.

    PubMed

    Joo, Moon Kyung; Park, Jong-Jae; Chun, Hoon Jai

    2017-09-08

    Commonly used medications including statins, metformin, and proton pump inhibitors (PPIs) effectively reduce the risk of esophageal, gastric, and colorectal cancer (CRC). A number of observational studies and meta-analyses have shown that long-term statin use significantly reduces the incidence of gastrointestinal (GI) cancer. Moreover, statin use after GI cancer diagnosis has been significantly associated with better prognosis in large-scale cohort studies. Metformin was rigorously evaluated in a population-based study and meta-analysis, and was found to have an unexpected benefit in the prevention and prolonged survival of CRC patients with type 2 diabetes mellitus. In contrast, few studies have demonstrated the chemopreventive effect of metformin for esophageal and gastric cancer. Recent observational studies have demonstrated that PPIs effectively reduce the progression of nondysplastic Barrett's esophagus into esophageal adenocarcinoma in a dose-dependent manner. However, the association between chronic PPI use and CRC or gastric cancer risk is still controversial. It was expected that these 3 routinely used medicines would show a synergistic effect with conventional systemic chemotherapy in advanced GI cancers. However, recent phase III studies failed to show significantly better outcomes. Key Messages: Further studies are needed to identify "additional" anticancer effects of these commonly used medicines. © 2017 S. Karger AG, Basel.

  1. Evidence for activation of an active electrogenic proton pump in Ehrlich ascites tumor cells during glycolysis

    SciTech Connect

    Heinz, A.; Sachs, G.; Schafer, J.A.

    1981-01-01

    The addition of glucose to a suspension of Ehrlich ascites tumor cells results in rapid acidification of the extracellular medium due to lactic acid production. The nature of the H+ efflux mechanism has been studied by measuring the time course of the acidification, the rate of proton efflux, the direction and relative magnitude of the H+ concentration gradient, and the voltage across the membrane. Using the pH-sensitive dye acridine orange, we have established that after addition of 10 mM glucose an outward-directed H+ concentration gradient develops. As the rate of glycolysis slows, the continued extrusion of H+ reverses the direction of the H+ concentration gradient. Changes in absorbance of the voltage-sensitive dye diethyloxadicarbocyanine iodide (DOCC), and changes in the distribution of the lipid permeant cation tetraphenyl phosphonium, showed a dramatic and persistent hyperpolarization of the membrane voltage after glucose addition. The hyperpolarization was prevented by the protonophore tetrachlorosalicylanalide (TCS) and by valinomycin, but not by the neutral-exchange ionophore nigericin. Inhibitors of lactate efflux were found to reduce the rate of acidification after glucose addition but they had no effect on the magnitude of the resulting hyperpolarization. On the basis of these and other data we suggest that an active electrogenic pump mechanism for H+ efflux may be activated by glucose and that this mechanism operates independently of the lactate carrier system.

  2. Bacterial Overgrowth and Irritable Bowel Syndrome: Unifying Hypothesis or a Spurious Consequence of Proton Pump Inhibitors?

    PubMed Central

    Spiegel, Brennan M.R.; Chey, William D.; Chang, Lin

    2010-01-01

    Some studies indicate that small intestinal bacterial overgrowth (SIBO), as measured by hydrogen breath tests (HBT), is more prevalent in patients with irritable bowel syndrome (IBS) vs. matched controls without IBS. Although the data are conflicting, this observation has led to the hypothesis that SIBO may be a primary cause of IBS. Yet, it remains unclear whether SIBO is truly fundamental to the pathophysiology of IBS, or is instead a mere epiphenomenon or bystander of something else altogether. We hypothesize that SIBO might be a byproduct of the disproportionate use of proton pump inhibitors (PPIs) in IBS, as follows: (1) IBS patients are more likely than controls to receive PPI therapy; (2) PPI therapy may promote varying forms of SIBO by eliminating gastric acid; and (3) existing studies linking SIBO to IBS have not adjusted for or excluded the use of PPI therapy. When linked together, these premises form the basis for a simple and testable hypothesis: the relationship between SIBO and IBS may be confounded by PPIs. Our article explores these premises, lays out the argument supporting this “PPI hypothesis,” discusses potential implications, and outlines next steps to further investigate this possibility. PMID:19086951

  3. [Proton pump inhibitors: impact of professional practice evaluation on prescriptions pertinence].

    PubMed

    Fuzier, R; Maguès, J-P; Dupuis, E; Pomiès, S; Segui, S; Sénard, J-M

    2011-11-01

    To improve the quality of proton pump inhibitors (PPI) prescription in an orthopaedic department. Prospective professional practice evaluation study. A specific protocol concerning the best practice for using PPI in the perioperative period was established by anaesthesiologists and validated by all prescribers, according to recent recommendations published by French Afssaps. PPI prescription pertinence, mainly using the oral route, was based upon the presence of clearly identified risk factors. PPI mensual consumption and severe gastric complications were analyzed and compared with those obtained from the previous year. Ten months after the beginning of the protocol, the pertinence of PPI prescription was analyzed in 20 randomly selected medical records. Data are expressed in defined daily dose (DDD). After one year, a 35.5% decrease in oral PPI consumption was noted (901 ± 211 before vs 581 ± 235 DDD, after, P<0.05). A similar trend to a decrease in intravenous PPI consumption was observed (40 ± 23 vs 22 ± 26, P=0.06). During the same period, the overall incidence of severe gastric complication remained stable. The PPI prescription was pertinent in 85% of selected medical records. This study confirmed the interest of professional practice evaluation protocols to improve PPI prescription. A strong implication of all medical staff members is mandatory to maintain such benefits over time. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  4. Addition of cranberry to proton pump inhibitor-based triple therapy for Helicobacter pylori eradication

    PubMed Central

    Seyyedmajidi, Mohammadreza; Ahmadi, Anahita; Hajiebrahimi, Shahin; Seyedmajidi, Seyedali; Rajabikashani, Majid; Firoozabadi, Mona; Vafaeimanesh, Jamshid

    2016-01-01

    Objective: Proton pump inhibitor-based triple therapy with two antibiotics for Helicobacter pylori eradication is widely accepted, but this combination fails in a considerable number of cases. Some studies have shown that cranberry inhibits the adhesion of a wide range of microbial pathogens, including H. pylori. The aim of this study was to assess the effect of cranberry on H. pylori eradication with a standard therapy including lansoprazole, clarithromycin, and amoxicillin (LCA) in patients with peptic ulcer disease (PUD). Methods: In this study, H. pylori-positive patients with PUD were randomized into two groups: Group A: A 14-day LCA triple therapy with 30 mg lansoprazole bid, 1000 mg amoxicillin bid, and 500 mg clarithromycin bid; Group B: A 14-day 500 mg cranberry capsules bid plus LCA triple therapy. A 13C-urea breath test was performed for eradication assessment 6 weeks after the completion of the treatment. Findings: Two hundred patients (53.5% males, between 23 and 77 years, mean age ± standard deviation: 50.29 ± 17.79 years) continued treatment protocols and underwent 13C-urea breath testing. H. pylori eradication was achieved in 74% in Group A (LCA without cranberry) and 89% in Group B (LCA with cranberry) (P = 0.042). Conclusion: The addition of cranberry to LCA triple therapy for H. pylori has a higher rate of eradication than the standard regimen alone (up to 89% and significant). PMID:27843960

  5. One year treatment of Barrett's oesophagus with proton pump inhibitors (a multi-center study).

    PubMed

    Babic, Z; Bogdanovic, Z; Dorosulic, Z; Petrovic, Z; Kujundzic, M; Banic, M; Marusic, M; Heinzl, R; Bilić, B; Andabak, M

    2015-12-01

    Aim of the study was to investigate the effects of 1-year therapy by different proton pump inhibitors (PPIs) on epithelial tissue and surrounding inflammatory changes in Barrett's oesophagus, in patients who have abandoned invasive therapy. A group of 120 patients (sampled in 60-month period, from 61201 upper gastrointestinal endoscopies) who were diagnosed both, endoscopically and pathohistologically with Barrett's oesophagus, and who have abandoned invasive therapeutic approach were enrolled in study. Treatment with different PPIs was initiated and continued for a year. At the end of treatment, patients were reassessed by endoscopy with tissue biopsy and pathohistological analysis. No difference in regenerating squamous epithelium or degree of dysplasia was seen between different treatment groups. Interestingly, most patients receiving pantoprazole (94%) ended up with thinner squamous epithel (P<0.0001). The squamous epithel was consider thinner only if its total thickness, measured on histological specimen, was smaller for more than 50% of the thickness before therapy. Significantly less of difference (P<0.0014) was seen with patients receiving lansoprazole (65%) and (P<0.003) omeprazole (50%). Regeneration of the squamous epithel was the same for all PPIs but not good enough to stop the progression of the disease.

  6. The power of pharmacological sciences: the example of proton pump inhibitors.

    PubMed

    Spector, Reynold; Vesell, Elliot S

    2006-01-01

    Critics have questioned the foundational principles of pharmacological sciences and modern drug therapy; they also claim that drug therapy is often too expensive or of uncertain value. Contemporaneously, alternative medicine has bloomed. Yet the US government began to pay for drug therapy under Medicare in 2006, an explicit recognition of the value of modern drug therapy. To clarify this confusion, we review the philosophical and scientific foundations of pharmacology, drug discovery and development, the attendant strategies and successful results. We also review and answer the major attacks on the philosophical and scientific foundations of modern pharmacology and drug therapy. Finally, we define the characteristics of an ideal drug. As an example of the principles and strategies of modern pharmacological sciences and their successful application, we focus on the discovery and development of proton pump inhibitors (PPIs) of stomach acid production. This class of drugs approaches the ideal and exemplifies successful application of modern pharmacological principles to drug discovery and development. Moreover, the use of PPIs as a pharmacological tool allowed the resolution of important scientific questions, e.g., the role of stomach acid in peptic diseases of the stomach, duodenum and esophagus.

  7. Double-dose, new-generation proton pump inhibitors do not improve Helicobacter pylori eradication rate.

    PubMed

    Choi, Hyo Sun; Park, Dong Il; Hwang, Sang Jun; Park, Jung Sik; Kim, Hong Joo; Cho, Yong Kyun; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik

    2007-12-01

    Up to present, omeprazole plus two antibiotics are used for Helicobacter pylori eradication therapy . Few studies have compared double-dose new-generation, proton pump inhibitors (PPI) with omeprazole. Therefore, we conducted a randomized, prospective study to evaluate differences in H. pylori eradication rates by PPI type. Between January 2006 and December 2006, 576 consecutive patients with proven H. pylori infection were enrolled prospectively. Four different PPIs [omeprazole 20 mg b.i.d. (old generation), or pantoprazole 40 mg b.i.d., rabeprazole 20 mg b.i.d., or esomeprazole 40 mg b.i.d. (new generation)] were added to clarithromycin (500 mg b.i.d.) and amoxicillin (1 g b.i.d.) for 1 week. By intention-to-treat analysis, no difference was found between the eradication rates of these four PPIs: 64.9% (omeprazole, n = 148), 69.3% (pantoprazole, n = 140), 69.3% (rabeprazole, n = 140), and 72.9% (esomoprazole, n = 148). When eradication rates were analyzed according to whether patients had an ulcer or not on a per-protocol basis, no difference was found between the eradication rates of the four PPIs. However, side-effects were more common in the esomeprazole-based triple therapy group than in the other groups (p < .05). No convincing evidence was obtained that double-dose new-generation PPIs have better H. pylori eradication rates and tolerability than omeprazole.

  8. 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.

  9. Prescribing patterns of proton pump inhibitors in older hospitalized patients in a Scottish health board.

    PubMed

    Jarchow-Macdonald, Anna Amrit; Mangoni, Arduino A

    2013-10-01

    Proton-pump inhibitors (PPI) are extensively prescribed worldwide. However, little information is available on PPI prescribing patterns, associated clinical and demographic factors, and potential drug-drug interactions in frail older patients. Data on clinical and demographic characteristics, and full medication exposure were collected in a consecutive series of 361 older patients (age 84 ± 7 years) admitted to two acute geriatric admission units (Aberdeen, National Health Service Grampian) between 1 February 2010 and 30 June 2010. A set of predetermined criteria was used to assess appropriateness of PPI prescribing. PPI were prescribed in 148 patients (41.0%). Inappropriate overprescribing was observed in 127 patients (35.2% of the study population, 85.8% of patients prescribed PPI). PPI were inappropriately not prescribed in 20 patients (48.8% of patients with an indication for PPI treatment). Regression analysis showed that the total number of non-PPI prescribed drugs (OR 1.08; 95%CI 1.01-1.15) and a higher Charlson Comorbidity Index (OR 1.08; 95%CI 1.001-1.16) were independently associated with inappropriate PPI overprescribing. Potential drug-drug interactions were found in 75 patients (22.8% of the study population), mainly in patients with PPI overprescribing. Inappropriate PPI prescribing is common in frail older hospitalized patients, and might increase the risk of drug-drug interactions. Polypharmacy and comorbidity were independently associated with inappropriate PPI prescribing in this group. © 2013 Japan Geriatrics Society.

  10. Proton pump induced thrombocytopenia: A case report and review of literature.

    PubMed

    Kallam, Avyakta; Singla, Abhishek; Silberstein, Peter

    2015-01-01

    Proton pump inhibitors (PPIs) are not widely recognized as a cause of drug-induced thrombocytopenia. Literature is mainly confined to case reports and has been insufficient to explore the possibility that this adverse event may be attributed to a class effect of PPI therapy. We present a case where platelet counts dropped from 177 (×10(3) per mm(3)) to 47 (×10(3) per mm(3)) within 6 days after the patient was switched from omeprazole to pantoprazole. There have been case reports of thrombocytopenia caused by PPIs; however, this is noted to be extremely rare. In our case, the patient developed thrombocytopenia on two separate occasions of exposure to pantoprazole, which resolved after stopping the medicine, thus providing definite proof of pantoprazole causing thrombocytopenia. Moreover, the patient did not have thrombocytopenia with omeprazole, thus suggesting that thrombocytopenia with PPIs might be an individual drug effect rather than a class effect. This occurrence has been reported in three other case reports as well. From the nine case reports that we have reviewed, direct causal relationship was found in a few reports only. It has been hypothesized that this adverse effect may be immune mediated, but further investigations are still needed to identify the exact pathogenesis.

  11. Systematic review: symptoms of rebound acid hypersecretion following proton pump inhibitor treatment.

    PubMed

    Lødrup, Anders Bergh; Reimer, Christina; Bytzer, Peter

    2013-05-01

    While the physiological existence of rebound acid hypersecretion (RAHS) after withdrawal of proton pump inhibitors (PPI) therapy is established, the clinical implications are less certain. It has been speculated that a clinical relevant rebound phenomenon may be responsible for difficulties in getting off acid-suppressive medication and partly explain the increase in long-term use of PPI. A number of studies addressing this issue have been published recently. The authors aimed to systematically review the existing evidence of clinically relevant symptoms caused by acid rebound following PPI treatment. PubMed was searched using the terms "rebound acid hypersecretion" and generic names of PPIs. Five studies were included. Two studies on asymptomatic volunteers found that 44% experienced acid-related symptoms up to 4 weeks after treatment was withdrawn. Symptoms were generally mild to moderate and mainly heartburn and regurgitation. Three studies, using patients with reflux disease, found no signs of symptoms caused by acid rebound. Gastric acid rebound hypersecretion following PPI therapy induces reflux-like symptoms post-treatment in asymptomatic volunteers, but the significance of this in patient populations is not clear. The studies in patients with reflux disease found no evidence of symptomatic RAHS, but these studies were hampered by severe methodological weaknesses.

  12. Inulin significantly improves serum magnesium levels in proton pump inhibitor-induced hypomagnesaemia.

    PubMed

    Hess, M W; de Baaij, J H F; Broekman, M; Bisseling, T M; Haarhuis, B; Tan, A; Te Morsche, R; Hoenderop, J G J; Bindels, R J M; Drenth, J P H

    2016-06-01

    Proton pump inhibitors (PPI) are among the most widely prescribed drugs to treat gastric acid-related disorders. PPI-induced hypomagnesaemia, a defect in intestinal absorption of Mg(2+) , can be a severe side effect of chronic PPI use. To restore serum Mg(2+) concentrations in PPI-induced hypomagnesaemia patients by dietary supplementation with inulin fibres. Eleven patients with PPI-induced hypomagnesaemia and 10 controls were treated with inulin (20 g/day). Each trial consisted of two cycles of 14-day inulin treatment followed by a washout period of 14 days. Patients continued to use their PPI. Serum Mg(2+) levels served as the primary endpoint. Inulin significantly enhanced serum Mg(2+) levels from 0.60 to 0.68 mmol/L in PPI-induced hypomagnesaemia patients, and from 0.84 to 0.93 mmol/L in controls. As a consequence 24 h urinary Mg(2+) excretion was significantly increased in patients with PPI-induced hypomagnesaemia (0.3-2.2 mmol/day). Symptoms related to hypomagnesaemia, including muscle cramps and paraesthesia, were reduced during intervention with inulin. Inulin increases serum Mg(2+) concentrations under PPI maintenance in patients with PPI-induced hypomagnesaemia. © 2016 John Wiley & Sons Ltd.

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

    PubMed

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

    2014-06-01

    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.

  15. Proton pump inhibitor prescribing and costs in a large outpatient clinic.

    PubMed

    Hood, William; McJunkin, Brittain; Warnock, Alicia; Girme, Aditi; Smith, Nelson; Robinson, Brandon

    2014-01-01

    Concerns have been raised regarding potential adverse effects and high costs of proton pump inhibitors (PPIs). Our objective was to assess issues of PPI utilization and expense in a large outpatient clinic population. Two hundred-fifty-nine outpatient records were reviewed regarding PPI prescribing and indications during 2009. A cost analysis was performed to project cost differences if histamine-2 receptor antagonists (H2RAs) were used as an alternative to PPIs in appropriate clinical situations. Eighty-three (32.0%) were taking PPIs. Problem-listed gastroesophageal reflux disease (GERD) was the primary diagnosis in 69 (83.1%) of patients on PPIs. GERD was not apparent by documented history and/or endoscopy in 46.3% of problem-listed GERD patients. Symptom severity had been documented in only 36.2%. Cost analysis projected substantial savings if H2RAs had been used initially for mild to moderate symptoms. Outpatient PPI prescribing indications are not well documented and PPI use is probably excessive. H2RA therapy is likely underutilized.

  16. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease.

    PubMed

    Cicala, Michele; Emerenziani, Sara; Guarino, Michele Pier Luca; Ribolsi, Mentore

    2013-10-21

    Gastro-esophageal reflux disease (GERD) is one of the most prevalent chronic diseases. Although proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive esophagitis and for symptom relief, several studies have shown that up to 40% of GERD patients reported either partial or complete lack of response of their symptoms to a standard PPI dose once daily. Several mechanisms have been proposed as involved in PPIs resistance, including ineffective control of gastric acid secretion, esophageal hypersensitivity, ultrastructural and functional changes in the esophageal epithelium. The diagnostic evaluation of a refractory GERD patients should include an accurate clinical evaluation, upper endoscopy, esophageal manometry and ambulatory pH-impedance monitoring, which allows to discriminate non-erosive reflux disease patients from those presenting esophageal hypersensitivity or functional heartburn. Treatment has been primarily based on doubling the PPI dose or switching to another PPI. Patients with proven disease, not responding to PPI twice daily, are eligible for anti-reflux surgery.

  17. Proton Pump Inhibitor Use Is Associated With a Reduced Risk of Infection with Intestinal Protozoa.

    PubMed

    Sheele, Johnathan M

    2017-09-11

    Proton pump inhibitors (PPIs) can kill some human protozoan parasites in cell culture better than the drug metronidazole. Clinical data showing an antiprotozoal effect for PPIs are lacking. The objective of the study is to determine if PPI use is associated with a reduced risk of having intestinal parasites. We obtained electronic medical record data for all persons who received a stool ova and parasite (O & P) examination at our tertiary care academic medical center in Cleveland, Ohio, between January 2000 and September 2014. We obtained the person's age, whether they were taking a PPI at the time of the O & P examination, and whether the pathology report indicated the presence of any parasites. χ(2) with Yates correction was used to determine if PPI use was associated with stool protozoa. Three intestinal protozoa were identified in 1199 patients taking a PPI (0.3%), and 551 intestinal parasites were identified in the 14,287 patients not taking a PPI (3.9%). There was a statistically significant lower likelihood of finding protozoa in the stool of a person taking a PPI compared with those not taking a PPI (P < .0001). Patients taking a PPI were statistically less likely to have an intestinal protozoa reported on stool O & P examination compared with those not taking a PPI. Copyright © 2017 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  18. The influence of proton pump inhibitors and other commonly used medication on the gut microbiota.

    PubMed

    Imhann, Floris; Vich Vila, Arnau; Bonder, Marc Jan; Lopez Manosalva, Ailine G; Koonen, Debby P Y; Fu, Jingyuan; Wijmenga, Cisca; Zhernakova, Alexandra; Weersma, Rinse K

    2017-07-04

    Proton pump inhibitors (PPIs), used to treat gastro-esophageal reflux and prevent gastric ulcers, are among the most widely used drugs in the world. The use of PPIs is associated with an increased risk of enteric infections. Since the gut microbiota can, depending on composition, increase or decrease the risk of enteric infections, we investigated the effect of PPI-use on the gut microbiota. We discovered profound differences in the gut microbiota of PPI users: 20% of their bacterial taxa were statistically significantly altered compared with those of non-users. Moreover, we found that it is not only PPIs, but also antibiotics, antidepressants, statins and other commonly used medication were associated with distinct gut microbiota signatures. As a consequence, commonly used medications could affect how the gut microbiota resist enteric infections, promote or ameliorate gut inflammation, or change the host's metabolism. More studies are clearly needed to understand the role of commonly used medication in altering the gut microbiota as well as the subsequent health consequences.

  19. Protons pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits.

    PubMed

    Lué, Alberto; Lanas, Angel

    2016-12-28

    Proton pump inhibitors (PPIs) represent a milestone in the treatment of acid-related diseases, and are the mainstay in preventing upper gastrointestinal bleeding in high-risk patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin. However, this beneficial effect does not extend to the lower gastrointestinal tract. PPIs do not prevent NSAID or aspirin-associated lower gastrointestinal bleeding (LGB). PPIs may increase both small bowel injury related to NSAIDs and low-dose aspirin treatment and the risk of LGB. Recent studies suggested that altering intestinal microbiota by PPIs may be involved in the pathogenesis of NSAID-enteropathy. An increase in LGB hospitalization rates may occur more frequently in older patients with more comorbidities and are associated with high hospital resource utilization, longer hospitalization, and increased mortality. Preventive strategies for NSAID and aspirin-associated gastrointestinal bleeding should be directed toward preventing both upper and lower gastrointestinal damage. Future research should be directed toward identifying patients at low-risk for gastrointestinal events associated with the use of NSAIDs or aspirin to avoid inappropriate PPI prescribing. Alternatively, the efficacy of new pharmacologic strategies should be evaluated in high-risk groups, with the aim of reducing the risk of both upper and lower gastrointestinal bleeding in these patients.

  20. New methods for determining proton pumping ability and electron transfer activity of the cytochrome bc1 complex.

    PubMed

    Qu, Yuangang; Dong, Fang

    2015-02-01

    It is important to determine the electron transfer activity and proton pumping ability of the cytochrome bc1 complex for better understanding its structure and function. In this study, several methods for determining the electron transfer and proton pumping of the bc1 complex, including the traditional and the new methods, are presented and evaluated. For determining the proton pumping ability of the bc1 complex, the new stopped-flow method has a higher accuracy than the traditional pH meter method, and the new spectrophotometer method is more convenient than the traditional pH meter method. In measuring the electron transfer activity of the bc1 complex, the new stopped-flow method is more accurate and has a higher separating capacity than the traditional spectrophotometer method. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

  1. Pump

    SciTech Connect

    Johnson, J.W.; Abdul.Hye, A.B.M.

    1983-10-25

    A pump for injecting chemicals into a well employs a pivot arm for synchronous movement with a well pump. The pivot arm causes reciprocation of a plunger within the body of the chemical pump. The plunger, during its upward stroke causes the entry of chemicals from an outside source into the pump body and, during its downward stroke, causes the exiting of the chemicals into the well. (2 claims.

  2. Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: A meta-analysis

    PubMed Central

    Wang, Wei-Hong; Huang, Jia-Qing; Zheng, Ge-Fan; Xia, Harry Hua-Xiang; Wong, Wai-Man; Lam, Shiu-Kum; Wong, Benjamin Chun-Yu

    2005-01-01

    AIM: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE). METHODS: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model. RESULTS: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs, 1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vs standard dose H2RAs, 1.59 (95%CI, 1.44-1.75); standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis. CONCLUSION: H2RAs are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis. PMID:15996033

  3. The selectivity of the Na(+)/K(+)-pump is controlled by binding site protonation and self-correcting occlusion.

    PubMed

    Rui, Huan; Artigas, Pablo; Roux, Benoît

    2016-08-04

    The Na(+)/K(+)-pump maintains the physiological K(+) and Na(+) electrochemical gradients across the cell membrane. It operates via an 'alternating-access' mechanism, making iterative transitions between inward-facing (E1) and outward-facing (E2) conformations. Although the general features of the transport cycle are known, the detailed physicochemical factors governing the binding site selectivity remain mysterious. Free energy molecular dynamics simulations show that the ion binding sites switch their binding specificity in E1 and E2. This is accompanied by small structural arrangements and changes in protonation states of the coordinating residues. Additional computations on structural models of the intermediate states along the conformational transition pathway reveal that the free energy barrier toward the occlusion step is considerably increased when the wrong type of ion is loaded into the binding pocket, prohibiting the pump cycle from proceeding forward. This self-correcting mechanism strengthens the overall transport selectivity and protects the stoichiometry of the pump cycle.

  4. The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors.

    PubMed

    Sychev, D A; Denisenko, N P; Sizova, Z M; Grachev, A V; Velikolug, K A

    2015-01-01

    Proton pump inhibitors, which are widely used as acid-inhibitory agents for the treatment of peptic ulcers, are mainly metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). CYP2C19 has genetic polymorphisms, associated with extensive, poor, intermediate or ultra-rapid metabolism of proton pump inhibitors. Genetic polymorphisms of CYP2C19 could be of clinical concern in the treatment of peptic ulcers with proton pump inhibitors. To investigate the frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles and genotypes in Russian patients with peptic ulcers. We retrospectively reviewed the cases of 971 patients of Caucasian origin with Russian nationality from Moscow region with endoscopically and histologically proven ulcers, 428 males (44%) and 543 females (56%). The mean age was 44.6±11.9 years (range: 15-88 years). DNA was extracted from ethylenediaminetetraacetic acid whole blood samples (10 mL). The polymorphisms CYP2C19 681G.A (CYP2C19*2, rs4244285), CYP2C19 636 G.A (CYP2C19*3, rs4986893) and CYP2C19 -806 C.T (CYP2C19*17, rs12248560) were evaluated using real-time polymerase chain reaction. Regarding CYP2C19 genotype, 317 patients (32.65%) out of 971 were CYP2C19*1/*1 carriers classified as extensive metabolizers. Three hundred and eighty-six (39.75%) with CYP2C19*1/*17 or CYP2C19*17/*17 genotype were ultra-rapid metabolizers. Two hundred and fifty-one people (25.85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. The allele frequencies were the following: CYP2C19*2 - 0.140, CYP2C19*3 - 0.006, CYP2C19*17 - 0.274. There is a high frequency of CYP2C19 genotypes associated with modified response to proton pump inhibitors in Russian patients with peptic ulcers. Genotyping for CYP2C19 polymorphisms is suggested to be a useful tool for personalized dosing of proton pump inhibitors.

  5. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know.

    PubMed

    Robinson, Malcolm; Horn, John

    2003-01-01

    Proton pump inhibitors (PPIs) [omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole] are widely utilised for the treatment of gastro-oesophageal reflux disease, as well as other acid-related disorders. All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H(+)/K(+)-adenosine triphosphatase (ATPase), but the physicochemical properties of these drugs result in variations in the degree of acid suppression, as well as the speed of onset of acid inhibition. Such differences may impact on the clinical performance of PPIs, and this manuscript discusses data that may help clinicians choose between the available PPIs for specific clinical situations and indications. The characteristics of PPIs that have been developed subsequent to omeprazole offer several advantages over this prototype PPI, particularly with respect to the onset of acid suppression and reduced potential for inter-individual pharmacokinetic variation and drug interactions. Newer agents inhibit H(+)/K(+)-ATPase more rapidly than omeprazole and emerging clinical data support potential clinical benefits resulting from this pharmacological property. Although key pharmacokinetic parameters (time to maximum plasma concentration and elimination half-life) do not differ significantly among PPIs, differences in the hepatic metabolism of these drugs can produce inter-patient variability in acid suppression, in the potential for pharmacokinetic drug interactions and, quite possibly, in clinical efficacy. All PPIs undergo significant hepatic metabolism. Because there is no direct toxicity from PPIs, there is minimal risk from the administration of any of them - even to patients with significant renal or hepatic impairment. However, there are significant genetic polymorphisms for one of the cytochrome P450 (CYP) isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole

  6. 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

  7. Evaluation of a Proton Pump Inhibitor for Sleep Bruxism: A Randomized Clinical Trial.

    PubMed

    Ohmure, H; Kanematsu-Hashimoto, K; Nagayama, K; Taguchi, H; Ido, A; Tominaga, K; Arakawa, T; Miyawaki, S

    2016-12-01

    Bruxism is a repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or bracing or thrusting of the mandible. Recent advances have clarified the relationship between gastroesophageal reflux and sleep bruxism (SB). However, the influence of pharmacological elimination of gastric acid secretion on SB has not been confirmed. The authors aimed to assess the efficacy of a proton pump inhibitor (PPI) on SB and to examine the gastrointestinal (GI) symptoms and endoscopic findings of the upper GI tract in SB patients. The authors performed a randomized double-blind placebo-controlled crossover study at Kagoshima University Hospital. Twelve patients with polysomnography (PSG)-diagnosed SB underwent an assessment of GI symptoms using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) and esophagogastroduodenoscopy. At baseline (i.e., before interventions), the mean frequencies of electromyography (EMG) bursts and rhythmic masticatory muscle activity (RMMA) episodes were 65.4 ± 49.0 bursts/h and 7.0 ± 4.8 episodes/h, respectively, and at least 1 RMMA episode with grinding noise was confirmed in all participants. The mean FSSG score was 8.4 ± 5.6, and 41.7% of patients were diagnosed with gastroesophageal reflux disease. Mild reflux esophagitis was confirmed in 6 patients. PSG, including EMG of the left masseter muscle and audio-video recording, was performed on days 4 and 5 of administration of 10 mg of the PPI (rabeprazole) or placebo. PPI administration yielded a significant reduction in the frequency of EMG bursts, RMMA episodes, and grinding noise. No significant differences were observed regarding the swallowing events and sleep variables. Since the clinical application of PPI for SB treatment should remain on hold at present, the results of this trial highlight the potential application of pharmacological gastroesophageal reflux disease treatment for SB patients. Larger scale studies are warranted to

  8. 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

  9. Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease.

    PubMed

    Klatte, Derk C F; Gasparini, Alessandro; Xu, Hong; de Deco, Pietro; Trevisan, Marco; Johansson, Anna L V; Wettermark, Björn; Ärnlöv, Johan; Janmaat, Cynthia J; Lindholm, Bengt; Dekker, Friedo W; Coresh, Josef; Grams, Morgan E; Carrero, Juan J

    2017-09-01

    Proton pump inhibitors (PPI) have been associated with acute kidney injury and recent studies suggest that they may be associated with the risk of chronic kidney disease (CKD). We performed a retrospective analysis using the Stockholm creatinine measurements database, which contains information on diagnoses, dispensation claims, and laboratory test results for all citizens in the Stockholm region from 2007 through 2010. We identified new users of PPIs (n = 105,305) and new users of H2 blockers (H2B; n = 9578); data on renal outcomes were collected for a median 2.7 years. The primary outcome was progression CKD, defined as doubling of creatinine or decrease in estimated glomerular filtration rate of 30% or more. Secondary outcomes were end-stage renal disease and acute kidney injury. Complete collection of repeated PPI and H2B dispensations at pharmacies in Sweden allowed modeling the time-dependent risk associated with cumulative PPI exposure. Users of PPIs, compared with users of H2Bs, had an increased risk for doubled levels of creatinine (1985 events; adjusted hazard ratio [HR], 1.26; 95% CI, 1.05-1.51) and decrease in estimated glomerular filtration rate of 30% or more (11,045 events; 1.26; 95% CI, 1.16-1.36). PPI use also associated with development of end-stage renal disease (HR, 2.40; 95% CI, 0.76-7.58) and acute kidney injury (HR, 1.30; 95% CI, 1.00-1.69). There was a graded association between cumulative exposure to PPIs and risk of CKD progression. This was not the case for cumulative H2B use. Initiation of PPI therapy and cumulative PPI exposure is associate with increased risk of CKD progression in a large, North European healthcare system. Although consistent, the association was modest in magnitude, and cannot exclude residual confounding. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Bone fracture and the interaction between bisphosphonates and proton pump inhibitors: a meta-analysis

    PubMed Central

    Yang, Si-Dong; Chen, Qian; Wei, Hai-Kun; Zhang, Feng; Yang, Da-Long; Shen, Yong; Ding, Wen-Yuan

    2015-01-01

    Objective: Recent studies suggested an increased risk of fractures with interaction between bisphosphonates (BPs) and proton pump inhibitors (PPIs). We performed a meta-analysis of fractures between patients taking BPs/PPIs and those taking BPs only. Methods: We conducted a PubMed database and Ovid database search, as well as Cochrane Library search (up to July 2014) for studies assessing the association between fractures and BPs or/and PPIs. We performed random effects meta-analysis of odds ratios (OR) according to fracture type and conducted subgroup analyses by race and BP subtypes. Heterogeneity was assessed using Q statistics and I2 statistic. Results: After study selection, 4 unique studies (5 comparisons) including 57259 patients were available for this meta-analysis. Pooled analysis of overall fracture risk of BP+PPI group versus BP group showed a significant increase in risk of fractures (OR = 1.52, P = 0.025), with substantial heterogeneity. However, heterogeneity was drastically reduced in subgroup of Asian (I2 = 24% and P = 0.251), and fracture risk showed a significant increase (OR = 1.75, P = 0.026). In contrast, heterogeneity was little eliminated in subgroup of European, and fracture risk was no statistical difference (OR = 1.42, P = 0.068). Three studies including 4 comparisons reported on spine fracture were included in the pooled analysis demonstrating an increased spine fracture risk associated with BP/PPI interaction (OR = 1.60, 95% CI 1.13-2.26, P = 0.008, I2 = 58.6%). Conclusions: This meta-analysis suggests that there is an interaction associated with increased fracture risk (particularly for spine and Asian race) between BP and PPI use. Clinicians should carefully evaluate such risk factors for osteoporosis in patients taking BPs, before routinely prescribing PPIs, and make a careful judgment as to whether PPIs may be safe for patients at high risk of fractures. PMID:26131063

  11. Validation of the Reflux Symptom Questionnaire Electronic Diary in Partial Responders to Proton Pump Inhibitor Therapy

    PubMed Central

    Vakil, Nimish; Björck, Karin; Denison, Hans; Halling, Katarina; Karlsson, Maria; Paty, Jean; Silberg, Debra G; Rydén, Anna

    2012-01-01

    OBJECTIVES: We aimed to develop and validate the Reflux Symptom Questionnaire electronic Diary (RESQ-eD) for use in clinical trials in patients with a partial response to proton pump inhibitor (PPI) therapy, using methods that meet US Food & Drug Administration (FDA) regulatory standards. METHODS: Patient interviews were performed to elicit new items and evaluate existing items from the Reflux Disease Questionnaire. The instrument's measurement properties were evaluated, based on data from two clinical trials of patients with gastroesophageal reflux disease (GERD) with a partial response to PPIs who received lesogaberan or placebo as an add-on to PPI therapy. RESULTS: The content validity phase resulted in 13 RESQ-eD items. Principal component analysis supported a four-domain structure. All domains had a high inter-item correlation (Cronbach's alpha lower 95% confidence limit: 0.87–0.95). Test-retest reliability was good to excellent (intraclass correlation coefficient: 0.65–0.85). Convergent and discriminant validity was confirmed by correlation assessments referencing the Gastrointestinal Symptom Rating Scale. The RESQ-eD demonstrated a good ability to capture change in mean intensity and proportion of symptom-free days. Confirmatory psychometric evaluation verified internal consistency reliability, test-retest reliability, and ability to capture change. CONCLUSIONS: The RESQ-eD demonstrated good content validity and psychometric properties in the clinical trial setting in patients with GERD who have a partial response to PPI therapy. To our knowledge, the RESQ-eD is the first electronic symptom diary for use in partial responders to PPI that has been developed in line with the FDA guidance on patient-reported outcomes. PMID:23238029

  12. Proton Pump Inhibitors Inhibit Metformin Uptake by Organic Cation Transporters (OCTs)

    PubMed Central

    Nies, Anne T.; Hofmann, Ute; Resch, Claudia; Schaeffeler, Elke; Rius, Maria; Schwab, Matthias

    2011-01-01

    Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT) 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3), which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs) with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole) are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC50) were in the low micromolar range (3–36 µM) and thereby in the range of IC50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy. PMID:21779389

  13. Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors.

    PubMed

    Kumar, Kirthi R; Iqbal, Ramiz; Coss, Elizabeth; Park, Christina; Cryer, Byron; Genta, Robert M

    2013-12-01

    A causal relationship between oxyntic glands dilatation with protruding parietal cells, referred to as proton pump inhibitor (PPI) effects, and PPI use has been suspected but not established. We designed this study to evaluate the association between these changes and the use of PPIs and histamine2-receptor blockers (H2-blockers). We obtained five Sydney System-compliant biopsy specimens from patients recruited into a therapeutic trial for H. pylori. Medication history with details on PPI and H2-blockers use was collected. Two blinded pathologists graded gastritis and the intensity of putative PPI effects using a 0 to 3 scale. PPI and H2-blocker use was then disclosed and the accuracy of pathologists' assessment was analyzed. There were 138 H. pylori-negative and 104 positive patients. In H. pylori-negative patients the histologic assessment for PPI use had 77.5% sensitivity and 51.8% specificity, with a positive predictive value of 86.9% and a negative predictive value of 35.9%. In H. pylori-positive patients, sensitivity was 74.1% and specificity 26.1%. Positive and negative predictive values were 55.8% and 44.4%, respectively. Neither glandular dilatations nor parietal cell protrusions related to H2-blocker use. We conclude that these changes are associated with PPI use only in H. pylori-negative subjects. In H. pylori gastritis, so-called PPI-effects were equally prevalent in PPI-users and non-users, indicating that other factors are involved in the induction of oxyntic cell hyperplasia. We suggest that comments regarding the supposed evidence of PPI use are too often wrong to be useful and should be avoided in the diagnosis of gastric biopsy specimens.

  14. Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma

    PubMed Central

    Hong, Ji Eun; Cho, Young Jae; Ryu, Ji Yoon; Choi, Jung-Joo; Lee, Sang Hoon; Yoon, Gun; Kim, Woo Young; Do, In-Gu; Kim, Min Kyu; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

    2015-01-01

    This study was designed to investigate whether proton pump inhibitors (PPI, V-ATPase blocker) could increase the effect of cytotoxic agents in chemoresistant epithelial ovarian cancer (EOC). Expression of V-ATPase protein was evaluated in patients with EOC using immunohistochemistry, and patient survival was compared based on expression of V-ATPase mRNA from a TCGA data set. In vitro, EOC cell lines were treated with chemotherapeutic agents with or without V-ATPase siRNA or PPI (omeprazole) pretreatment. Cell survival and apoptosis was assessed using MTT assay and ELISA, respectively. In vivo experiments were performed to confirm the synergistic effect with omeprazole and paclitaxel on tumor growth in orthotopic and patient-derived xenograft (PDX) mouse models. Expression of V-ATPase protein in ovarian cancer tissues was observed in 44 patients (44/59, 74.6%). Higher expression of V-ATPase mRNA was associated with poorer overall survival in TCGA data. Inhibition of V-ATPase by siRNA or omeprazole significantly increased cytotoxicity or apoptosis to paclitaxel in chemoresistant (HeyA8-MDR, SKOV3-TR) and clear cell carcinoma cells (ES-2, RMG-1), but not in chemosensitive cells (HeyA8, SKOV3ip1). Moreover, the combination of omeprazole and paclitaxel significantly decreased the total tumor weight compared with paclitaxel alone in a chemoresistant EOC animal model and a PDX model of clear cell carcinoma. However, this finding was not observed in chemosensitive EOC animal models. These results show that omeprazole pretreatment can increase the effect of chemotherapeutic agents in chemoresistant EOC and clear cell carcinoma via reduction of the acidic tumor microenvironment. PMID:26418900

  15. Proton pump inhibitors use in hemodialysis patients and serum magnesium levels

    PubMed Central

    Erdem, Emre

    2015-01-01

    Hypomagnesemia is reported in patients who use proton pump inhibitors (PPIs). We investigated the effect of PPIs use on serum magnesium levels in hemodialysis patients. Our study was conducted in a hemodialysis center including 75 end stage renal disease patients. PPI use and duration were investigated. All patients were dialyzed using a dialysate magnesium level of 0.5-0.75 mmol/L. After at least one month of hemodialysis with the mentioned dialysate, laboratory tests were performed. Fifty-four patients (72%) used PPIs while 21 (28%) did not. The mean duration of PPI use was 42.5 ± 35 months. There was no significant difference between serum magnesium levels of patients who used and did not use PPIs (2.73 ± 0.3 vs. 2.88 ± 0.3 mg/dL, P = ns). There were 15 patients (20%) with a dialysate magnesium level of 0.5 mmol/l and 60 patients (80%) with a dialysate magnesium level of 0.75 mmol/L. The mean serum magnesium levels of patients with a dialysate magnesium level of 0.5 mmol/L was 2.45 ± 0.3 mg/dL while that of patients with a dialysate magnesium level of 0.75 mmol/L was 2.85 ± 0.3 mg/dL (P<0.0001). In hemodialysis patients, PPI use did not affect serum magnesium levels. The most important factor affecting the serum magnesium levels in hemodialysis patients is the dialysate magnesium concentration. PMID:26885127

  16. Proton pump inhibitors reduce the size and acidity of the acid pocket in the stomach.

    PubMed

    Rohof, Wout O; Bennink, Roelof J; Boeckxstaens, Guy E

    2014-07-01

    The gastric acid pocket is believed to be the reservoir from which acid reflux events originate. Little is known about how changes in position, size, and acidity of the acid pocket contribute to the therapeutic effect of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD). Thirty-six patients with GERD (18 not taking PPIs, 18 taking PPIs; 19 men; age, 55 ± 2.1 y) were analyzed by concurrent high-resolution manometry and pH-impedance monitoring after a standardized meal. The acid pocket was visualized using scintigraphy after intravenous administration of (99m)technetium-pertechnetate. The size of the acid pocket was measured and its position was determined, relative to the diaphragm, using radionuclide markers on a high-resolution manometry catheter. At the end of the study, the acid pocket was aspirated, and its pH level was measured. The number of reflux episodes was comparable between patients on and off PPIs, but the number of acid reflux episodes was reduced significantly in patients on PPIs. In patients on PPIs, the acid pocket was smaller and more frequently located below the diaphragm. The mean pH of the acid pocket was significantly lower in patients not taking PPIs (n = 6) than in those who were (n = 16) (0.9; range, 0.7-1.2 vs 4.0; range, 1.6-5.9; P < .001). The pH of acid pockets correlated significantly with the lowest pH values measured for refluxate (r = 0.72; P < .01). Based on analyses of acid pockets in patients with GERD, the acid pocket appears to be a reservoir from which reflux occurs when patients are receiving PPIs. PPIs might affect the size, acidity, or position of the acid pocket, which contributes to the efficacy in patients with GERD. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  17. Guidelines for proton pump inhibitor prescriptions in paediatric intensive care unit.

    PubMed

    Joret-Descout, P; Dauger, S; Bellaiche, M; Bourdon, O; Prot-Labarthe, S

    2017-02-01

    Background Stress ulcer prophylaxis (SUP) is recommended in some situations to prevent upper gastrointestinal bleeding and is a component of standard care for patients admitted to the intensive care unit (ICU). Proton pump inhibitors (PPIs), already among the most widely prescribed drug classes, are being increasingly used. Objective To describe PPI prescribing patterns and their changes after the dissemination of guidelines. Setting Paediatric ICU (PICU), Robert-Debré Teaching Hospital, Paris, France, which admits about 800 patients annually, from full-term neonates to 18-year-olds. Method Prospective observational study with two 6-week observation periods (July-August and September-October, 2013), before and after dissemination in the PICU of PPI prescribing guidelines. Main outcome measure Changes in PPI prescribing patterns (prevalence, dosage, and indication) after the guidelines. Results The number of patients admitted to the PICU was 77 (mean age 4.6 years [range 1 day-18 years]) before and 70 (mean age 3.8 years [range 1 day-17 years]) after the guidelines. During both periods, SUP was the most common reason for PPI prescribing. The proportion of patients prescribed PPIs dropped significantly, from 51% before the guidelines to 30% after the guidelines (p < 0.001). Mean daily dosage also decreased significantly, from 1.5 mg/kg/(range 0.5-4.4) to 1.1 mg/kg (range 0.7-1.8) (p < 0.002). None of the patients experienced upper gastrointestinal bleeding during either period. Conclusion Off-label PPI prescribing for SUP was common in our PICU. The introduction of guidelines was associated with a significant decrease in PPI use and dosage. This study confirms that guidelines can change PPI prescribings patterns in paediatric practice.

  18. Delayed release film coating applications on oral solid dosage forms of proton pump inhibitors: case studies.

    PubMed

    Missaghi, Shahrzad; Young, Cara; Fegely, Kurt; Rajabi-Siahboomi, Ali R

    2010-02-01

    Formulation of proton pump inhibitors (PPIs) into oral solid dosage forms is challenging because the drug molecules are acid-labile. The aim of this study is to evaluate different formulation strategies (monolithic and multiparticulates) for three PPI drugs, that is, rabeprazole sodium, lansoprazole, and esomeprazole magnesium, using delayed release film coating applications. The core tablets of rabeprazole sodium were prepared using organic wet granulation method. Multiparticulates of lansoprazole and esomeprazole magnesium were prepared through drug layering of sugar spheres, using powder layering and suspension layering methods, respectively. Tablets and drug-layered multiparticulates were seal-coated, followed by delayed release film coating application, using Acryl-EZE(R), aqueous acrylic enteric system. Multiparticulates were then filled into capsules. The final dosage forms were evaluated for physical properties, as well as in vitro dissolution testing in both compendial acid phase, 0.1N HCl (pH 1.2), and intermediate pH, acetate buffer (pH 4.5), followed by phosphate buffer, pH 6.8. The stability of the delayed release dosage forms was evaluated upon storage in accelerated conditions [40 degrees C/75% relative humidity] for 3 months. All dosage forms demonstrated excellent enteric protection in the acid phase, followed by rapid release in their respective buffer media. Moreover, the delayed release dosage forms remained stable under accelerated stability conditions for 3 months. Results showed that Acryl-EZE enteric coating systems provide excellent performance in both media (0.1N HCl and acetate buffer pH 4.5) for monolithic and multiparticulate dosage forms.

  19. 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

  20. Single enantiomer versus racemate: chiral distinction in the proton pump inhibitors omeprazole and esomeprazole.

    PubMed

    Marom, Hili; Pogodin, Sergey; Agranat, Israel

    2014-04-01

    Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral-switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6-311G(d,p), the 6-methoxy∙∙∙6-methoxy and 5-methoxy∙∙∙5-methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG(298,(RS-SS))) between the cyclic C2-(S,S)- and Ci-(R,S)-dimers with two intermolecular hydrogen bonds are 3.8, 1.9 (with BSSE counterpoise correction), and -6.9 (with D3 dispersion and BSSE counterpoise corrections) kJ/mol. Adding water as an implicit solvent (polarized continuum model [PCM] model) resulted in a chiral distinction energy of -3.3 kJ/mol, indicating a reversal of the order of the relative stabilities of C2-(S,S)- and Ci-(R,S)-dimers. The chiral distinction free energies between the corresponding (less stable) C1-dimers with one intermolecular hydrogen bond are -9.3, -5.8 (with BSSE CC), 17.6 (D3 + BSSE CC), and -3.2 (H2O) kJ/mol. The results highlight the contention that omeprazole is not just a superposition of its enantiomer constituents. They are consistent with the pharmacological evidence of enantiomer-enantiomer interactions in omeprazole versus esomeprazole and the differences between the drugs omeprazole and esomeprazole magnesium and support the lodged application for regulatory supplementary protection certificate (SPC) exclusivity for the esomeprazole-related combination drug Vimovo. Copyright © 2014 Wiley Periodicals, Inc.

  1. Usefulness of baseline impedance in patients with proton pump inhibitor-refractory nonerosive reflux disease.

    PubMed

    Kohata, Yukie; Fujiwara, Yasuhiro; Yamagami, Hirokazu; Tanigawa, Tetsuya; Shiba, Masatsugu; Watanabe, Kenji; Watanabe, Toshio; Tominaga, Kazunari; Arakawa, Tetsuo

    2015-03-01

    Approximately more than half of patients with non-erosive reflux disease (NERD) do not respond to proton pump inhibitor (PPI) therapy. Although NERD is a heterogeneous entity, previous study showed that multichannel intraluminal impedance (MII)-pH monitoring could distinguish reflux-related disease from PPI-refractory NERD. The aim of this study was to examine the usefulness of baseline impedance in PPI-refractory NERD patients. We used MII-pH monitoring to analyze reflux parameters, symptom index (SI), and baseline impedance in 37 PPI-refractory NERD patients on PPI. Reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified as having reflux-related disease based on abnormal reflux parameters or positive SI (≥ 50%), or non-reflux-related disease, including functional heartburn, based on negative SI with normal reflux parameters. A total of 26 of the 37 subjects were diagnosed with reflux-related disease, including eight with acid-reflux type and 18 with non-acid-reflux type, and nine with functional heartburn and two with pseudohypersalivation. There were no significant differences in the clinical characteristics of the acid-reflux type, non-acid-reflux type, and functional heartburn groups. The baseline impedance value in the acid-reflux type (1245 ± 392 Ω) was significantly lower than that in the non-acid-reflux type (2824 ± 1160 Ω) and functional heartburn (3546 ± 1353 Ω) groups. Baseline impedance values inversely correlated with reflux percent time, acid-reflux time, and acid exposure time. Among patients with PPI-refractory NERD, acid-reflux type was associated with lower baseline impedance compared with non-acid-reflux type and functional heartburn. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  2. Survey of findings in patients having persistent heartburn on proton pump inhibitor therapy.

    PubMed

    Mandaliya, R; DiMarino, A J; Cohen, S

    2016-01-01

    In patients with refractory heartburn while on proton pump inhibitor (PPI) therapy, changing drugs or increasing treatment to a twice a day (b.i.d.) dose has become a common practice. This study aims to study patients with persistent heartburn while on PPI therapy and to determine if persistent symptom indicates the need for more aggressive or different therapy. A retrospective review of impedance-pH tracings on PPI therapy (q.d. or b.i.d.) for patients with persistent heartburn was performed. DeMeester score, impedance, and symptom sensitive index (SSI) were used as indices. Statistical analyses were performed using chi-squared test with Yates correction and paired t-test. One hundred consecutive patients, (female 50%, male 50%, mean age 54 [range 16-83] years) were studied on q.d. (n = 45) or b.i.d. PPI (n = 55). Only 20% of the patients had abnormal DeMeester score; 41% had an abnormal impedance score and 56% had abnormal SSI; 29% had all indices normal. There was no difference between patients taking q.d. versus b.i.d. PPI for abnormal DeMeester score (22 vs. 18%), impedance (38 vs. 44%) and SSI (53 vs. 58%); P = 0.80, 0.69, and 0.77, respectively. In 56 patients with positive SSI, symptoms were due to acid reflux in 8 (14%) patients, nonacid reflux in 31 (55%) patients, and combined acid and nonacid reflux in 17 (30%) patients. Patients with persistent heartburn on PPI therapy show a variety of disorders: (i) acid reflux (20%); (ii) nonacid reflux (26%); (iii) positive SSI (56%); (iv) all normal indices (29%). These studies indicate that persistent heartburn on PPI therapy is a complex problem that may not respond to simply increasing acid inhibition. © 2014 International Society for Diseases of the Esophagus.

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

    PubMed

    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

    2015-09-01

    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). 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. 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. 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.

  4. A retrospective analysis of the role of proton pump inhibitors in colorectal cancer disease survival

    PubMed Central

    Graham, C.; Orr, C.; Bricks, C.S.; Hopman, W.M.; Hammad, N.; Ramjeesingh, R.

    2016-01-01

    Background Proton pump inhibitors (ppis) are a commonly used medication. A limited number of studies have identified a weak-to-moderate association between ppi use and colorectal cancer (crc) risk, but none to date have identified an effect of ppi use on crc survival. We therefore postulated that an association between ppi use and crc survival might potentially exist. Methods We performed a retrospective chart review of 1304 crc patients diagnosed from January 2005 to December 2011 and treated at the Cancer Centre of Southeastern Ontario. Kaplan–Meier analysis and Cox proportional hazards regression models were used to evaluate overall survival (os). Results We identified 117 patients (9.0%) who were taking ppis at the time of oncology consult. Those taking a ppi were also more often taking asa or statins (or both) and had a statistically significantly increased rate of cardiac disease. No identifiable difference in tumour characteristics was evident in the two groups, including tumour location, differentiation, lymph node status, and stage. Univariate analysis identified a statistically nonsignificant difference in survival, with those taking a ppi experiencing lesser 1-year (82.1% vs. 86.7%, p = 0.161), 2-year (70.1% vs. 76.8%, p = 0.111), and 5-year os (55.2% vs. 62.9%, p = 0.165). When controlling for patient demographics and tumour characteristics, multivariate Cox regression analysis identified a statistically significant effect of ppi in our patient population (hazard ratio: 1.343; 95% confidence interval: 1.011 to 1.785; p = 0.042). Conclusions Our results suggest a potential adverse effect of ppi use on os in crc patients. These results need further evaluation in prospective analyses. PMID:28050148

  5. Influence of proton pump inhibitor treatment on Helicobacter pylori stool antigen test

    PubMed Central

    Kodama, Masaaki; Murakami, Kazunari; Okimoto, Tadayoshi; Fukuda, Yoshihiro; Shimoyama, Tadashi; Okuda, Masumi; Kato, Chieko; Kobayashi, Intetsu; Fujioka, Toshio

    2012-01-01

    AIM: To investigate the effects of proton pump inhibitor (PPI) treatment on stool antigen test using the TestMate pylori enzyme immunoassay. METHODS: This study assessed 28 patients [16 men and 12 women; mean age (63.1 ± 5.9) years; range, 25-84 years] who underwent stool antigen test and urea breath test (UBT) before and after PPI administration. RESULTS: Using the UBT as the standard, the sensitivity, specificity and agreement of the stool antigen test in all 28 patients were 95.2%, 71.4%, and 89.3%, respectively, before PPI administration, and 88.9%, 90.9%, and 89.3%, respectively, after PPI treatment. Mean UBT values were 23.98% ± 5.33% before and 16.19% ± 4.75% after PPI treatment and, in 15 patients treated for ≥ 4 wk, were significantly lower after than before 4 wk of PPI treatment (12.58% ± 4.49% vs 24.53% ± 8.53%, P = 0.048). The mean optical density (A450/630) ratios on the stool antigen test were 1.16 ± 0.20 before and 1.17 ± 0.24 after PPI treatment (P = 0.989), and were 1.02 ± 0.26 and 0.69 ± 0.28, respectively, in the group treated for > 4 wk (P = 0.099). CONCLUSION: The stool antigen test was equally sensitive to the UBT, making it a useful and reliable diagnostic method, even during PPI administration. PMID:22228969

  6. 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

  7. Proton-pump inhibitor therapy and vitamin B12 status in an inpatient hospital setting.

    PubMed

    Hartman, Brenda; Donnelly-VanderLoo, Mary; Watson, Tiffany; O'Connor, Colleen; Madill, Janet

    2016-06-23

    The risk for impaired vitamin B12 status increases with age, as does the use of proton pump inhibitors (PPI). Long-term use of PPIs is associated with several nutritional deficiencies including B12. Currently, there are no recommendations for B12 screening among patients taking PPIs. Data were abstracted on B12 concentrations, B12-containing supplement use, medications, and select hematological values from a retrospective chart review of 658 adults, 391 with serum B12 concentrations, admitted to 6 different medical units at 2 regional hospitals in Southwestern Ontario between 2010 and 2012. We found no difference between PPI users and nonusers and serum B12 concentrations (404 ± 224 vs 369 ± 213 pmol/L; P = 0.0690). This may be due to use of B12 containing multivitamins in 41% of PPI users. Regression modelling found that aging increases the odds of having an impaired B12 status (<220 pmol/L) by 1.4 times and those using B12 supplements are almost 4 times more likely to have an impaired status. Mean corpuscular volume was not related to B12 status. In this population, older PPI users are more likely to be using multivitamins, which may delay nutritional deficiencies. However, the lower B12 concentrations of PPI users taking only B12 supplements is a concern and requires further research. Finally, physicians need to be aware that mean corpuscular volume is no longer recommended as an effective biomarker for B12 screening and updated screening protocols need to be used to reduce the possibility of adverse neurological effects from impaired B12 status.

  8. 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

  9. Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus.

    PubMed

    Peura, David A; Wilcox, C Mel

    2014-01-01

    Aspirin, used at low doses (75-325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well-documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co-therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed-dose combinations of low-dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett's esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed-dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition.

  10. Proton pump inhibitor administration via nasogastric tube in pediatric practice: comparative analysis with protocol optimization.

    PubMed

    Ponrouch, M P; Sautou-Miranda, V; Boyer, A; Bourdeaux, D; Montagner, A; Chopineau, J

    2010-05-10

    Proton pump inhibitors (PPIs) are largely prescribed to children because their efficacy and tolerance are now well-established. One disadvantage resides in the absence of liquid form which causes problems for their administration in nasogastric tubes. Indeed, the absence of use recommendations involves many misuses responsible for inefficiency and/or tube obstruction. We tried to evaluate if PPIs can be administered through pediatric nasogastric tubes. We administered four PPIs (Omeprazole, esomeprazole, lansoprazole and lansoprazole orally disintegrating tablet) through nasogastric tubes. For each PPI a study plan was drawn up to assess the influence of different variables: the volume of water to dissolve or put in suspension the PPIs (2ml or 5ml), the volume of tube flush-through water post-PPI administration (2ml, 5ml or 10ml), the length (50cm or 125cm) and the diameter (6 or 8 French) of the polyurethane tubes. For each assay an analysis of each active ingredient at the tube outlet by UV spectrometry was carried out. All 6 F tubes were obstructed by PPIs. Through 8 F tubes, we observed a mean recovery of active ingredient of 86.2% for lansoprazole orally disintegrating tablet, 36.9% for esomeprazole but only 7.1% for lansoprazole and 3.9% for omeprazole. It is disadvised using omeprazole and lansoprazole through 8 F nasogastric tubes because no condition ensures the transit of an efficient concentration of active ingredient. For esomeprazole, the best conditions of administration were a water volume of 5ml and a rinse volume of 5ml but only a half of the microgranules administered were recovered. The most satisfactory results were obtained with lansoprazole orally disintegrating tablet. A 5ml volume of water diluent for suspension and a 10ml volume of flush-through water made it possible to deliver the full lansoprazole dose administered.

  11. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  12. Race affects healing of erosive oesophagitis in patients treated with proton pump inhibitors.

    PubMed

    Sharma, P; Johnson, D A; Monyak, J T; Illueca, M

    2011-08-01

    Erosive oesophagitis appears to be more common in white vs. nonwhite patients with gastro-oesophageal reflux disease (GERD). To evaluate the association between race and erosive oesophagitis healing in patients with GERD treated with once-daily proton pump inhibitors (PPIs). Data from five double-blind trials of once-daily treatment with esomeprazole 40mg vs. omeprazole 20mg or lansoprazole 30mg for erosive oesophagitis healing (evaluated at weeks 4 and 8 by endoscopy) were pooled and stratified by baseline race and Los Angeles (LA) severity grade. Multiple logistic regression models were fit with erosive oesophagitis healing (dependent variable) and race (independent variable), with adjustments for treatment, study, baseline LA grade, age, gender, BMI, Helicobacter pylori status, hiatal hernia and interactions of these factors with race. Of 11,027 patients, 91% were white. Nonwhite (n=978) and black (n=613) patients were less likely to have severe baseline erosive oesophagitis (LA grade C or D) than white patients [adjusted OR: 0.69 (95% CI, 0.61-0.79) and 0.67 (0.57-0.78), respectively; P<0.0001]. At week 8, nonwhite and black patients had lower healing rates than white patients [OR: 0.75 (0.63-0.89) and 0.67 (0.54-0.83), respectively; P≤0.001]. Greater odds of healing were associated with less severe baseline LA grade, increasing age, hiatal hernia, esomeprazole treatment (vs. lansoprazole or omeprazole) and lansoprazole treatment (vs. omeprazole) (all P≤0.0009); no factor interacted significantly with race. Nonwhite patients with GERD had less severe baseline erosive oesophagitis, but were less likely than white patients to have erosive oesophagitis healing after 8-week PPI therapy. © 2011 Blackwell Publishing Ltd.

  13. Proton Pump Inhibitor-Responsive Oesophageal Eosinophilia: An Entity Challenging Current Diagnostic Criteria for Eosinophilic Oesophagitis

    PubMed Central

    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; Wen, Ting; Straumann, Alex; Lucendo, Alfredo J.

    2016-01-01

    Consensus diagnostic recommendations to distinguish gastro-oesophageal reflux disease (GORD) from eosinophilic oesophagitis (EoE) by response to a trial of proton pump inhibitors (PPI) unexpectedly uncovered an entity called “PPI-responsive oesophageal eosinophilia” (PPI-REE). PPI-REE refers to patients with clinical and histologic features of EoE that remit with PPI treatment. Recent and evolving evidence, mostly from adults, shows that PPI-REE and EoE patients at baseline are clinically, endoscopically and histologically indistinguishable, and have 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 PPI-REE patients, similar to the effects of topical steroids in EoE patients. Additionally, recent series have reported that EoE patients 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 immunologic 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 histologic 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 EoE patients respond to PPI, while others do not, remain to be elucidated. PMID:26685124

  14. Comparative study: Vonoprazan and proton pump inhibitors in Helicobacter pylori eradication therapy

    PubMed Central

    Sakurai, Kouichi; Suda, Hiroko; Ido, Yumi; Takeichi, Takayuki; Okuda, Ayako; Hasuda, Kiwamu; Hattori, Masahiro

    2017-01-01

    AIM To compare the effectiveness and safety of vonoprazan-based therapy with proton pump inhibitor (PPI)-based therapies to treat Helicobacter pylori (H. pylori). METHODS We retrospectively analysed data from first-line (vonoprazan or PPI with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 d) (n = 1353) and second-line (vonoprazan or PPI with 250 mg metronidazole and 750 mg amoxicillin twice daily for 7 d) (n = 261) eradication treatments for H. pylori -positive patients with associated gastrointestinal diseases from April 2014 to December 2015 at Hattori Clinic, Japan. The primary endpoint was the eradication rate, which was assessed with a full analysis set. The secondary endpoints were adverse events and related factors. RESULTS After the first-line treatments, the eradication rates for vonoprazan, esomeprazol, rabeprazole, and lansoprazole were 87.9% (95%CI: 84.9%-90.5%), 71.6% (95%CI: 67.5%-75.5%), 62.9% (95%CI: 52.0%-72.9%), and 57.3% (95%CI: 50.4%-64.1%), respectively. The vonoprazan eradication rate was significantly higher than that of the PPIs (P < 0.01). Interestingly, smoking did not affect the H. pylori eradication rate in the vonoprazan group (P = 0.34), whereas it decreased the rates in the PPI groups (P = 0.013). The incidence of adverse events in the vonoprazan group was not different from the PPI group (P = 0.054), although the vonoprazan group exhibited a wider range of adverse events. Vonoprazan-based triple therapy was highly effective as a second-line treatment, with an eradication rate similar to that of PPI-based therapy. CONCLUSION Vonoprazan might be superior to PPIs in first-line H. pylori therapy, particularly for smokers. However, caution is required due to possible adverse events. PMID:28216974

  15. Acidification of endocytic vesicles by an ATP-dependent proton pump

    PubMed Central

    1983-01-01

    One of the early events in the pathway of receptor-mediated endocytosis is the acidification of the newly formed endocytic vesicle. To examine the mechanism of acidification, we used fluorescein-labeled alpha 2- macroglobulin (F-alpha 2M) as a probe for endocytic vesicle pH. Changes in pH were determined from the change in fluorescein fluorescence at 490-nm excitation as measured with a microscope spectrofluorometer. After endocytosis of F-alpha 2M, mouse fibroblast cells were permeabilized by brief exposure to the detergent digitonin. Treatment with the ionophore monensin or the protonophore carbonyl cyanide p- trifluoromethoxyphenylhydrazone (FCCP) caused a rapid increase in the pH of the endocytic vesicle. Upon removal of the ionophore, the endocytic vesicle rapidly acidified only when MgATP or MgGTP was added. Neither ADP nor the nonhydrolyzable analog, adenosine 5'-(beta, gamma- imido)triphosphate (AMP-PNP) could support acidification. The ATP- dependent acidification did not require a specific cation or anion in the external media. Acidification was insensitive to vanadate and amiloride but was inhibited by Zn2+ and the anion transport inhibitor diisothiocyanostilbene disulfonic acid (DIDS). We also examined the acidification of lysosomes with the permeabilized cell system, using fluorescein isothiocyanate dextran as probe. DIDS inhibited the ATP- dependent reacidification of lysosomes, although at a lower concentration than that for inhibition of endocytic vesicle reacidification. These results demonstrate that endocytic vesicles contain an ATP-dependent acidification mechanism that shares similar characteristics with the previously described lysosomal proton pump. PMID:6224803

  16. Safety of the long-term use of proton pump inhibitors

    PubMed Central

    Thomson, Alan BR; Sauve, Michel D; Kassam, Narmin; Kamitakahara, Holly

    2010-01-01

    The proton pump inhibitors (PPIs) as a class are remarkably safe and effective for persons with peptic ulcer disorders. Serious adverse events are extremely rare for PPIs, with case reports of interstitial nephritis with omeprazole, hepatitis with omeprazole and lansoprazole, and disputed visual disturbances with pantoprazole and omeprazole. PPI use is associated with the development of fundic gland polyps (FGP); stopping PPIs is associated with regression of FGP. In the absence of Helicobacter pylori infection, the long-term use of PPIs has not been convincingly proven to cause or be associated with the progression of pre-existing chronic gastritis or gastric atrophy or intestinal metaplasia. Mild/modest hypergastrinemia is a physiological response to the reduction in gastric acid secretion due to any cause. The long-term use of PPIs has not been convincingly proven to cause enterochromaffin-like cell hyperplasia or carcinoid tumors. PPIs increase the risk of community acquired pneumonia, but not of hospital acquired (nosocomial) pneumonia. There is no data to support particular care in prescribing PPI therapy due to concerns about risk of hip fracture with the long-term use of PPIs. Long-term use of PPIs does not lead to vitamin B12 deficiencies, except possibly in the elderly, or in persons with Zollinger-Ellison Syndrome who are on high doses of PPI for prolonged periods of time. There is no convincingly proven data that PPIs increase the risk of Clostridium difficile-associated diarrhea in persons in the community. The discontinuation of PPIs may result in rebound symptoms requiring further and even continuous PPI use for suppression of symptoms. As with all medications, the key is to use PPIs only when clearly indicated, and to reassess continued use so that long-term therapy is used judiciously. Thus, in summary, the PPIs are a safe class of medications to use long-term in persons in whom there is a clear need for the maintenance of extensive acid inhibition

  17. 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

  18. 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

  19. [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

  20. Proton pump inhibitors for reflux therapy in infants: effectiveness determined by impedance pH monitoring.

    PubMed

    Castellani, Christoph; Huber-Zeyringer, Andrea; Bachmaier, Gerhard; Saxena, Amulya K; Höllwarth, Michael E

    2014-04-01

    To evaluate the influence of proton pump inhibitors (PPI) in predominantly milk-fed infants with symptoms of GERD by 24-h pH-multichannel intraluminal impedance (24-h pH-MII). Ten infants (8 males and 2 females) with a mean gestational age of 39 weeks (28-40) were included. 24-h pH-MII was performed before prescription and during intake of PPI. Total acid exposure time, bolus exposure time (acidic/non-acidic/total) and the number of refluxes (acidic/non-acidic/total) were determined. Clinical symptoms were recorded and used to calculate the Reflux Symptom Index (RSI) and the Symptom Severity Index (SSI). There was a significant decrease in the number of acidic refluxes, total acid exposure and acidic bolus exposure time. However, this went along with a significant increase in non-acidic bolus exposure time. The total number of refluxes and the total bolus exposure time remained unchanged. Under PPI, a decrease of SSI and RSI for pain-related symptoms could be observed. For respiratory symptoms and vomiting however no significant changes could be demonstrated. Under PPI, an improvement of pain-related symptoms could be shown. The decrease of acid exposure went along with an increase of non-acidic refluxes resulting in almost constant total reflux numbers. This finding is interpreted as main reason for some persisting symptoms despite adequate PPI dosage. Concluding from our data PPI therapy should only be indicated in case of pain, but has no effect in case of vomiting or recurrent respiratory symptoms.

  1. Effect of Long-Term Proton Pump Inhibitor Therapy on Nutritional Status in Elderly Hospitalized Patients.

    PubMed

    Nakamichi, Mariko; Wakabayashi, Hidetaka

    2016-01-01

    The purpose was to investigate the association between proton pump inhibitor (PPI) therapy and nutritional status in elderly hospitalized patients. Participants were 190 elderly patients admitted to the long-term care wards, convalescence rehabilitation wards, and community integrated care wards in January 2015. Nutritional status was assessed using the mini nutritional assessment short-form (MNA-SF). The PPI use group was compared with the PPI non-use group regarding nutrition status. Logistic regression analysis was used to examine whether the period of PPI therapy was associated independently with malnutrition following adjustment for covariates including gender, age, and serum albumin level. Forty-one patients were male (22%) and 149 patients were female (78%), with a mean age of 85.4±8.4. Fifty-three patients (28%) took PPIs (with a median prescription period of 91 d, ranging from 51 to 227). With a MNA-SF score of 7 points or lower designated as malnutrition, there was no significant difference in nutritional status between the PPI and non-PPI groups (p=0.172). The median MNA-SF scores in the PPI and non-PPI groups were 9 vs 7 points, respectively. Logistic regression analysis showed that long-term PPI therapy (odds ratio, 0.994; 95% confidence interval 0.990-0.999) was significantly associated with improved nutritional status. The presence or absence of PPI therapy is not associated with malnutrition in elderly hospitalized patients. Longer-term PPI therapy may improve nutritional status.

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

    PubMed

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

    2015-10-01

    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.

  3. COST-UTILITY OF ASPIRIN AND PROTON PUMP INHIBITORS FOR PRIMARY PREVENTION

    PubMed Central

    Earnshaw, Stephanie R.; Scheiman, James; Fendrick, A. Mark; McDade, Cheryl; Pignone, Michael

    2011-01-01

    Background Aspirin reduces myocardial infarction but increases gastrointestinal bleeding. Proton pump inhibitors (PPIs) may reduce upper gastrointestinal bleed. We estimate the cost-utility of aspirin treatment with or without PPI for coronary heart disease (CHD) prevention among men at different risks for CHD and gastrointestinal bleed. Methods We updated a Markov model to compare costs and outcomes of low-dose aspirin+PPI (omeprazole 20-mg daily), low-dose aspirin alone, or no treatment for CHD prevention. We performed lifetime analyses in men with different risks for cardiovascular events and gastrointestinal bleed. Aspirin reduced nonfatal myocardial infarction by 30%, increased total stroke by 6%, and increased gastrointestinal bleed risk 2-fold. Adding PPI reduced upper gastrointestinal bleed by 80%. Annual aspirin cost was $13.99; generic PPI was $200. Results In 45-year-old men with 10-year CHD risk of 10% and 0.8/1,000 annual gastrointestinal bleed risk, aspirin ($17,571 and 18.67 quality-adjusted life years [QALYs]) was more effective and less costly than no treatment ($18,483 and 18.44 QALYs). Compared with aspirin alone, aspirin+PPI ($21,037 and 18.68 QALYs) had an incremental cost/QALY of $447,077. Results were similar in 55- and 65-year-old men. The incremental cost/QALY of adding PPI was less than $50,000/QALY at annual gastrointestinal bleed probabilities greater than 4–6/1,000. Conclusion Aspirin for CHD prevention is less costly and more effective than no treatment in men over 45 with greater than 10-year, 10% CHD risks. Adding PPI is not cost-effective for men with average gastrointestinal bleed risk but may be cost-effective for selected men at increased risk for gastrointestinal bleed. PMID:21325111

  4. Black Spot, a Novel Gastric Finding Potentially Induced by Proton Pump Inhibitors

    PubMed Central

    Hatano, Yu; Haruma, Ken; Ayaki, Maki; Kamada, Tomoari; Ohtani, Hiroshi; Murao, Takahisa; Manabe, Noriaki; Mori, Hirohito; Masaki, Tsutomu; Shiotani, Akiko

    2016-01-01

    Objective We have recently discovered new gastric lesions with black spots. There have been no reports about black spots and their clinicopathological features. We therefore report the clinicopathological features of black spots and assess their causes and mechanisms. Methods Sixty-four patients with black spots among 26,620 Japanese patients that underwent endoscopy between May 2012 and October 2014 were enrolled. Endoscopic findings of black spots were defined as black pigmentations in the gastric mucosa by conventional endoscopy. We investigated the clinicopathological characteristics, including gender, age, underlying diseases and medications, endoscopic and pathologic findings of patients with black spots. Results The prevalence of patients with black spots was 0.24%. Of sixty-four cases, 44 (68.8%) were taking proton pump inhibitors (PPIs). Eight (12.5%) were taking corticosteroids. There were 10 cases (15.6%) with decreased renal function. All black spots were identified only in the fundic gland region. Forty-one (64.1%) patients had multiple (more than ten) black spots. There were two different types: black spots on the flat mucosa and black spots on fundic gland polyps. Pathologically, parietal cell protrusions, fundic gland cysts and brownish pigmentation in fundic gland cysts were seen in 26 (76.5%), 23 (67.6%) and 6 (17.6%) patients, respectively. Conclusion We herein describe gastric black spots as a new gastric mucosal finding that arises only in the fundic gland region. The black spots are pathologically brownish pigmentations in fundic gland cysts. Adverse events of PPIs and parietal cell protrusion caused by PPI use are strongly considered to be one of the etiologies of black spots. PMID:27803398

  5. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD.

    PubMed

    Xie, Yan; Bowe, Benjamin; Li, Tingting; Xian, Hong; Balasubramanian, Sumitra; Al-Aly, Ziyad

    2016-10-01

    The association between proton pump inhibitors (PPI) use and risk of acute interstitial nephritis has been described. However, whether exposure to PPI associates with incident CKD, CKD progression, or ESRD is not known. We used Department of Veterans Affairs national databases to build a primary cohort of new users of PPI (n=173,321) and new users of histamine H2-receptor antagonists (H2 blockers; n=20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR<60 ml/min per 1.73 m(2) and of incident CKD (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients treated with PPI also had a significantly elevated risk of doubling of serum creatinine level (HR, 1.53; 95% CI, 1.42 to 1.65), of eGFR decline >30% (HR, 1.32; 95% CI, 1.28 to 1.37), and of ESRD (HR, 1.96; 95% CI, 1.21 to 3.18). Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days. Examination of risk of renal outcomes in 1:1 propensity score-matched cohorts of patients taking H2 blockers versus patients taking PPI and patients taking PPI versus controls yielded consistent results. Our results suggest that PPI exposure associates with increased risk of incident CKD, CKD progression, and ESRD.

  6. Proton pump inhibitors increase the incidence of bone fractures in hepatitis C patients.

    PubMed

    Mello, Michael; Weideman, Rick A; Little, Bertis B; Weideman, Mark W; Cryer, Byron; Brown, Geri R

    2012-09-01

    While proton pump inhibitors (PPI) may increase the risk of bone fractures, the incidence of new bone fractures in a chronic hepatitis C virus (HCV) infected cohort, with or without PPI exposure, has not been explored. A retrospective cohort study of the incidence of bone fractures over 10 years in 9,437 HCV antibody positive patients in the Dallas VA Hepatitis C Registry was performed. The study endpoint was the incidence of verified new bone fractures per patient-years (pt-yrs) in PPI users compared to non-PPI users. PPI use was defined as those taking a PPI for ≥360 days. Pt-yrs of exposure for PPI users began on the first PPI prescription date, and pt-yrs of exposure for non-PPI users began with first date of any non-PPI prescription. For both HCV groups, the final date of patients' study duration was defined by end of PPI exposure, bone fracture occurrence, death or end of study evaluation period. Exclusion criteria included use of bone health modifying medications ≥30 days. Statistical differences in fracture incidence between groups were determined by multivariate regression analysis. Among the total study population analyzed (n = 2,573), 109 bone fractures occurred. Unadjusted bone fracture incidences were 13.99/1,000 pt-yrs vs. 5.86/1,000 pt-yrs in PPI and non-PPI users, respectively. The adjusted hazard ratio for new bone fractures was 3.87 (95 % CI 2.46-6.08) (p < 0.001) in PPI users. In patients with chronic HCV, use of PPI for >1 year increased the risk of new bone fractures by more than threefold.

  7. The appropriate use of proton pump inhibitors (PPIs): Need for a reappraisal.

    PubMed

    Savarino, Vincenzo; Dulbecco, Pietro; de Bortoli, Nicola; Ottonello, Andrea; Savarino, Edoardo

    2017-01-01

    The advent of powerful acid-suppressive drugs, such as proton pump inhibitors (PPIs), has revolutionized the management of acid-related diseases and has minimized the role of surgery. The major and universally recognized indications for their use are represented by treatment of gastro-esophageal reflux disease, eradication of Helicobacter pylori infection in combination with antibiotics, therapy of H. pylori-negative peptic ulcers, healing and prophylaxis of non-steroidal anti-inflammatory drug-associated gastric ulcers and control of several acid hypersecretory conditions. However, in the last decade, we have witnessed an almost continuous growth of their use and this phenomenon cannot be only explained by the simple substitution of the previous H2-receptor antagonists, but also by an inappropriate prescription of these drugs. This endless increase of PPI utilization has created an important problem for many regulatory authorities in terms of increased costs and greater potential risk of adverse events. The main reasons for this overuse of PPIs are the prevention of gastro-duodenal ulcers in low-risk patients or the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anticoagulant treatment without risk factors for gastro-duodenal injury, the overtreatment of functional dyspepsia and a wrong diagnosis of acid-related disorder. The cost for this inappropriate use of PPIs has become alarming and requires to be controlled. We believe that gastroenterologists together with the scientific societies and the regulatory authorities should plan educational initiatives to guide both primary care physicians and specialists to the correct use of PPIs in their daily clinical practice, according to the worldwide published guidelines. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  8. Proton Pump Inhibitor Use and Risk of Hip Fracture in Kidney Transplant Recipients.

    PubMed

    Lenihan, Colin R; Sukumaran Nair, Sumi; Vangala, Chandan; Ramanathan, Venkat; Montez-Rath, Maria E; Winkelmayer, Wolfgang C

    2017-05-01

    Posttransplantation bone disease is a significant problem, with few well-evidenced therapeutic options. Proton pump inhibitors (PPIs) are associated with hip fracture in the general population and are widely prescribed for kidney transplant recipients. A case-control study. From the US Renal Data System, we identified from diagnoses and procedures 231 kidney transplant recipients with a first hip fracture. Cases were matched at the hip fracture index date with 15,575 controls on age, sex, race, and transplantation year. PPI use. First hip fracture. In the year prior to the index date, a PPI was prescribed to 65.4% of cases and 57.4% of controls. Additionally, in 34.6% of cases and 28.9% of controls, a PPI was prescribed for >80% of the year preceding the index date (higher PPI users). Unadjusted ORs of hip fracture associated with any and higher PPI use were 1.55 (95% CI, 1.18-2.05) and 1.65 (95% CI, 1.2-2.27), respectively. When adjusted for baseline demographic, clinical, and pharmacologic covariables, any and higher PPI use remained associated with hip fracture, with ORs of 1.39 (95% CI, 1.04-1.84) and 1.41 (95% CI, 1.02-1.95), respectively. Potential residual confounding through either incorrectly ascertained or unavailable confounders; cohort limited to Medicare beneficiaries receiving low-income subsidy. In summary, PPI use was associated with hip fracture risk in the US kidney transplant population. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  9. Is there a relationship between hypomagnesemia and proton-pump inhibitors in patients on chronic hemodialysis?

    PubMed

    Mikolasevic, I; Milic, S; Stimac, D; Zaputovic, L; Lukenda Zanko, V; Gulin, T; Jakopcic, I; Klaric, D; Gulin, M; Orlic, L

    2016-05-01

    We investigated the association among long-term proton-pump inhibitors (PPIs) use with serum magnesium (Mg) levels in chronic hemodialysis (HD) patients, as well as possible association among PPI use and increased risk of cardiovascular (CVD) morbidity in HD patients. Of 418 HD patients that were screened for inclusion, 136 were excluded due to incomplete medical data, duration of renal replacement therapy (RRT) for less than 12months, use of Mg-based-phosphate binders or other Mg-based medications or either to presence of chronic increased GI losses. Among 282 patients included in the study, 170 patients were on PPIs. Serum Mg levels were significantly lower among PPI users vs. non-users (0.94±0.2 vs. 1.03±0.2mmol/L; p<0.0001). The median duration of PPI use was 27±9.6months (range from 12 to 108) and it was not significantly associated with Mg levels (r=0.116; p=0.167). Additionally, residual renal function didn't show a significant correlation with Mg concentration (r=-0.102; p=NS) in both groups of patients. The use of PPIs was an independent and strong predictor of low Mg concentrations even in multivariate analysis (OR 3.05; 95% CI 1.2498-7.4594, p=0.01). On the other hand, the daily dose of PPIs was not associated with low Mg levels. PPI users had a higher rate of adverse CVD events during the 1 year of follow-up in comparison to non-PPI users but that difference wasn't statistically significant (17.6% vs. 10.7%; p=0.110). We have found a significant association between PPI use and lower serum Mg levels in chronic HD patients. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  10. Proton Pump Inhibitors Are Not Associated With Acute Kidney Injury in Critical Illness.

    PubMed

    Lee, Joon; Mark, Roger G; Celi, Leo Anthony; Danziger, John

    2016-12-01

    Recent epidemiologic data linking proton pump inhibitor (PPI) use to acute and chronic kidney dysfunction is yet to be validated in other populations, and mechanisms have not been explored. Using a large, well phenotyped inception cohort of 15 063 critically ill patients, we examined the risk of acute kidney injury (AKI), as defined by the Kidney Disease Improving Global Outcomes criteria guidelines, according to prior use of a PPI, histamine-2 receptor antagonist (H2 RA), or neither. A total of 3725 (24.7%) patients reported PPI use prior to admission, while 905 (6.0%) patients reported H2 RA use. AKI occurred in 747 (20.0%) and 163 (18.0%) of PPI and H2 RA users respectively, compared to 1712 (16.2%) of those not taking acid suppressive medications. In unadjusted analysis, PPI and H2 RA users had a 28% (95%CI 1.17-1.41, P < .001) and 10% (95%CI 0.91-1.30, P = .31) higher risk of AKI compared to those taking neither class of medication. However, in sequential models that included adjustment for demographics, cardiovascular comorbidities, indications for PPI use, and severity of illness, the effect of PPI on the risk of AKI was attenuated, and in the adjusted analysis, PPI was not associated with AKI (OR 1.02; 95%CI 0.91-1.13, P = .73). The presence of sterile pyuria and hypomagnesemia did not modify the association between PPI use and AKI. In summary, after adjustment for demographics, illness severity, and the indication for PPI use, PPI use prior to admission is not associated with critical illness AKI. © 2016, The American College of Clinical Pharmacology.

  11. [Proton Pump Inhibitor-responsive Esophageal Eosinophilia: An Overview of Cases from One University Hospital Center].

    PubMed

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

    2016-04-25

    Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease, with eosinophilic infiltration limited to the esophagus. A minority of EoE patients respond well to proton pump inhibitor (PPI) therapy alone, and that condition is labelled PPI-responsive esophageal eosinophilia (PPI-REE). The prevalence of PPI-REE among EoE cases is unknown. We aimed to identify clinical manifestations of PPI-REE, and the proportion of PPI-REE among all EoE cases. We reviewed pathology of the 4,075 patients who underwent esophageal biopsy at an institution from March 2003 to July 2015. EoE was diagnosed based on esophageal symptoms and eosinophilic infiltration limited to the esophagus, with ≥15 eosinophils per high-power field. We collected endoscopic and pathologic findings, and clinical features for these patients. Thirteen (0.3%) patients were diagnosed with EoE. Clinical manifestations were dysphagia (30.8%), foreign body sensation (23.1%), regurgitation (23.1%), cough (15.4%), heartburn (15.4%), nausea (7.7%), dyspepsia (7.7%). The endoscopic findings noted were polypoid lesion (23.1%), whitish plaque or exudate (23.1%), linear furrow (7.7%), concentric ring (7.7%), nodularity (7.7%), erosion (7.7%), and normal (30.8%). Of these patients, five had a favorable course with PPI as monotherapy. The proportion of EoE among all patients undergoing endoscopic biopsy was 0.3%. Of those, PPI-REE comprised 38%. Most of the endoscopic findings were atypical or normal when compared to the typical findings in EoE. In conclusion, patients who present with symptoms related to esophageal dysfunction need esophageal biopsy, regardless of the endoscopic findings. Moreover, patients diagnosed with EoE need to be treated first with PPI alone.

  12. Predictive Factors of Response to Proton Pump Inhibitors in Korean Patients With Gastroesophageal Reflux Disease

    PubMed Central

    Kim, Sung Eun; Kim, Nayoung; Oh, Sooyeon; Kim, Hee Man; Park, Moo In; Lee, Dong Ho; Jung, Hyun Chae

    2015-01-01

    Background/Aims Proton pump inhibitors (PPIs) are widely used in the treatment of gastroesophageal reflux disease (GERD). However, some patients fail to respond to PPI therapy. We investigated the efficacy of response to PPI therapy in patients with GERD symptoms. Methods A total of 179 subjects with GERD symptoms were prospectively enrolled and diagnosed with non-erosive reflux disease (NERD, n = 100) and erosive reflux disease (n = 79) by gastroscopy and Bernstein test and/or 24-hour esophageal pH testing. Subjects then received a standard dose of daily PPI therapy for at least 4 weeks. PPI therapy response was evaluated using questionnaires including questions about demographics, GERD symptoms, GERD impact scale, Epworth sleepiness scale, Pittsburgh sleep quality index (PSQI), hospital anxiety and depression scale, and abbreviated version of the World Health Organization quality of life scale. Results The rates of complete (≥ 80%), satisfactory (≥ 50%), partial (< 50%), and refractory response in the 179 participants were 41.3%, 30.2%, 18.4%, and 10.1%, respectively. Thus, overall response rate (complete and satisfactory responses) was 71.5%. Multivariate analysis showed body mass index < 23 kg/m2 (OR, 2.20; 95% CI, 1.12–4.34), higher total PSQI score (OR, 1.20; 95% CI, 1.05–1.35), history of psychotherapy or neuropsychiatric medication (OR, 2.44; 95% CI, 1.23–4.85), and NERD (OR, 3.30; 95% CI, 1.54–7.11) were associated with poor response to PPI therapy. Conclusions Psychological factors, sleep dysfunction, body mass index < 23 kg/m2, and NERD seem to be the major factors that lead to a poor response to PPI treatment in patients with GERD symptoms. PMID:25537676

  13. The association of proton pump inhibitors and hypomagnesemia in the community setting.

    PubMed

    Markovits, Noa; Loebstein, Ronen; Halkin, Hillel; Bialik, Martin; Landes-Westerman, Janet; Lomnicky, Joseph; Kurnik, Daniel

    2014-08-01

    Evidence for the association between hypomagnesemia and proton pump inhibitors (PPIs), highlighted by the 2011 FDA Drug Safety Communication, rests mainly on studies in hospitalized patients. Our objectives were to determine the prevalence of hypomagnesemia and its association with PPIs in the community setting. We performed a retrospective cross-sectional analysis of a large health maintenance organization administrative database, including ambulatory patients with ≥1 serum magnesium concentrations between 2008 and 2011, the lowest referred to as "index magnesium." In cases with any (index magnesium ≤0.7 mmol/L) or severe (≤0.55 mmol/L) hypomagnesemia, we analyzed (vs. controls, >0.7 mmol/L) the association with PPI or H2 -blocker use during the 4-12 months preceding the index magnesium by logistic regression analysis, adjusting for confounders. Among 95,205 subjects, 5,696 (6.0%) had any hypomagnesemia, which was severe in 454 (0.5%), with twofold higher prevalences in those with established risk factors. PPI use during the 4 months preceding the index magnesium was more common in cases of any hypomagnesemia (adjusted OR = 1.66; 95% CI, 1.55-1.78) and severe hypomagnesemia (adjusted OR = 3.79; 2.99-4.82) than in controls without acid suppression. Hypomagnesemia remained significantly associated with PPI use when using H2 -blocker-users as reference (adjusted OR = 1.25 [P = 0.003] and 2.65 [P < 0.001] for any and severe hypomagnesemia, respectively). We conclude that hypomagnesemia is associated with PPI use in ambulatory patients.

  14. The Proton Pump Inhibitor Lansoprazole Improves the Skeletal Phenotype in Dystrophin Deficient mdx Mice

    PubMed Central

    Sali, Arpana; Many, Gina M.; Gordish-Dressman, Heather; van der Meulen, Jack H.; Phadke, Aditi; Spurney, Christopher F.; Cnaan, Avital; Hoffman, Eric P.; Nagaraju, Kanneboyina

    2013-01-01

    Background In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology. Methodology/Principal Findings We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions. Conclusions/Significance Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant

  15. Role of Acid and Weakly Acidic Reflux in Gastroesophageal Reflux Disease Off Proton Pump Inhibitor Therapy

    PubMed Central

    Sung, Hea Jung; Moon, Sung Jin; Kim, Jin Su; Lim, Chul Hyun; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gye

    2012-01-01

    Background/Aims Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. Methods We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. The characteristics of acid and weakly acidic reflux were evaluated. Symptomatic and asymptomatic reflux were compared according to GERD subtypes and individual symptoms. Results Forty-two patients (22 males, mean age 46 years) were diagnosed as GERD (17 erosive reflux disease, 9 pH(+) non-erosive reflux disease [NERD], 9 hypersensitive esophagus and 7 symptomatic NERD). A total of 1,725 reflux episodes were detected (855 acid [50%], 857 weakly acidic [50%] and 13 weakly alkaline reflux [< 1%]). Acid reflux was more frequently symptomatic and bolus clearance was longer compared with weakly acidic reflux. In terms of globus, weakly acidic reflux was more symptomatic. Symptomatic reflux was more frequently acid and mixed reflux; these associations were more pronounced in erosive reflux disease and symptomatic NERD. The perception of regurgitation was related to acid reflux, while that of globus was more related to weakly acidic reflux. Conclusions In patients not taking PPI, acid reflux was more frequently symptomatic and had longer bolus clearance. Symptomatic reflux was more frequently acid and mixed type; however, weakly acidic reflux was associated more with globus. These data suggest a role for impedance-pH data in the evaluation of globus. PMID:22837877

  16. Factors associated with residual gastroesophageal reflux disease symptoms in patients receiving proton pump inhibitor maintenance therapy

    PubMed Central

    Kawara, Fumiaki; Fujita, Tsuyoshi; Morita, Yoshinori; Uda, Atsushi; Masuda, Atsuhiro; Saito, Masaya; Ooi, Makoto; Ishida, Tsukasa; Kondo, Yasuyuki; Yoshida, Shiei; Okuno, Tatsuya; Yano, Yoshihiko; Yoshida, Masaru; Kutsumi, Hiromu; Hayakumo, Takanobu; Yamashita, Kazuhiko; Hirano, Takeshi; Hirai, Midori; Azuma, Takeshi

    2017-01-01

    AIM To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice. METHODS The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed. RESULTS The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients’ GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P < 0.005). In erosive esophagitis patients, the FSSG scores of the CYP2C19 rapid metabolizers (RMs) were significantly higher than the scores of the poor metabolizers and intermediate metabolizers (total scores: 16.7 ± 8.6 vs 7.8 ± 5.4, P < 0.05; acid reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P < 0.005). In contrast, the FSSG scores of the CYP2C19 RMs in the non-erosive reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01). CONCLUSION Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms. PMID:28373773

  17. Influence of Proton-Pump Inhibitors on the Luminal Microbiota in the Gastrointestinal Tract

    PubMed Central

    Tsuda, Ayumi; Suda, Wataru; Morita, Hidetoshi; Takanashi, Kageyasu; Takagi, Atsushi; Koga, Yasuhiro; Hattori, Masahira

    2015-01-01

    Objectives: The objective of this study was to investigate comparatively the influence of proton-pump inhibitors (PPI) administration on three bacterial communities in the oral cavity, stomach, and colon along the alimentary tract. Methods: Forty-five subjects including 18 patients taking PPI were enrolled. Stimulated saliva, gastric fluid (GF), and feces were obtained from each subject for the microbiota analysis through bacterial 16S rRNA gene profiling using the pyrosequencing method. Results: The species richness (alpha diversity) was similar among these three microbiota, whereas the interindividual diversity (beta diversity) was much higher in the fecal microbiota compared with that in the others. The UniFrac analysis indicated that the salivary and GF microbiota were similar to one another; however, both differed greatly from the fecal microbiota in the overall bacterial community structure. In the comparison between PPI-users and PPI-nonusers, a bacterial cell number increase of ~1,000 times was found in the GF of PPI-users using culturing methods, whereas the bacterial number and composition were nearly identical between the two groups using quantitative PCR and a similarity search based on 16S profiling. The beta diversity significantly increased in both the salivary and GF microbiota of PPI-users compared with PPI-nonusers. Conclusions: These results suggest that the GF microbiota has recently moved from the saliva. Bacterial overgrowth in the GF by PPI administration may be due to a lack of killing rather than proliferation of the bacteria in the acid-suppressed stomach. The biological significance of the increase in beta diversity by PPI administration remains unclear. PMID:26065717

  18. Pantoprazole, a proton pump inhibitor, increases orthodontic tooth movement in rats

    PubMed Central

    Shirazi, Mohsen; Alimoradi, Houman; Kheirandish, Yasaman; Etemad-Moghadam, Shahroo; Alaeddini, Mojgan; Meysamie, Alipasha; Fatahi Meybodi, Seyed Amir Reza; Dehpour, Ahmad Reza

    2014-01-01

    Objective(s): Pantoprazole, is a proton pump inhibitor (PPI) prescribed for the treatment of upper gastrointestinal disorders, which in high doses has been suggested to decrease calcium absorption leading to hypocalcaemia and therefore osteoporosis. The aim of this study was to assess whether pantoprazol, could alter the rate of orthodontic tooth movement (OTM) in rats. Materials and Methods: A time course study was established using 72 rats which were divided into six groups of 12 samples each (four: vehicle; eight: pantoprazole + vehicle). Pantoprazole at a dose of 200 mg/kg suspended in carboxymethyl cellulose (0.25 percent) was administered by a gastric tube. The upper incisors and first molars were ligated by a 5 mm nickel-titanium closed-coil spring to deliver an initial force of 60 g. Animals were euthanized two weeks after orthodontic treatment followed by assessment of tooth movement and histomorphometric evaluation of the detached maxillae. Lateral skull radiographs were obtained once a week, starting from the first day to the 6th week of the study. OTM and bone density data were analyzed using independent sample t-test and repeated measures ANOVA. Results: No significant changes in OTM measurements and optical density were observed in vehicle-receiving animals during the study (P=0.994). OTM was significantly increased after six weeks pantoprazole therapy which continued until the 7th week of the experiment (P=0.007). Optical density significantly increased in the pantoprazole-treated rats after six weeks. Conclusion: Long term PPI therapy at high doses could lead to osteoporosis and enhanced OTM. PMID:25140207

  19. Comparison of infusion or low-dose proton pump inhibitor treatments in upper gastrointestinal system bleeding.

    PubMed

    Songür, Yildiran; Balkarli, Ayşe; Acartürk, Gürsel; Senol, Altug

    2011-04-01

    The most effective schedule of proton pump inhibitor (PPI) administration following endoscopic hemostasis of bleeding ulcers remains uncertain. To compare the treatment effects of continuous infusion and low-dose esomeprazole therapies in patients with non-variceal upper gastrointestinal (GI) bleeding. This prospective clinical study compared continuous infusion of esomeprazole (80 mg bolus followed by 8 mg∕h continuous infusion for 72 h) and low-dose esomeprazole (40 mg twice daily IV) treatments in GI bleeding patients with peptic ulcer presenting a high risk of re-bleeding, who were administered a successful endoscopic homeostasis. The primary end point was the occurrence of re-bleeding during hospitalization and within one month of discharge. Secondary outcomes were defined as duration of hospitalization, need of transfusion, surgical treatment, and mortality rate. After 72 h, both groups were switched to oral esomeprazole therapy for one-month. A hundred thirty-two subjects were enrolled. Re-bleeding occurred in 11 (16.7%) patients in the infusion therapy group and in 12 (18.2%) patients in the low-dose group (P=0.819) within the first 72 h. No patient experienced re-bleeding in the first month following discharge. There was no statistical significant difference between the two groups in terms of transfusion need, durations of hospitalization, need for surgery and mortality rate. PPI infusion therapy following endoscopic hemostasis treatment was not found superior to low-dose PPI therapy in the terms of re-bleeding, need of surgery and mortality. Copyright © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  20. Association of Proton Pump Inhibitors Usage with Risk of Pneumonia in Dementia Patients.

    PubMed

    Ho, Sai-Wai; Teng, Ying-Hock; Yang, Shun-Fa; Yeh, Han-Wei; Wang, Yu-Hsun; Chou, Ming-Chih; Yeh, Chao-Bin

    2017-07-01

    To determine the association between usages of proton pump inhibitors (PPIs) and subsequent risk of pneumonia in dementia patients. Retrospective cohort study. Taiwanese National Health Insurance Research Database. The study cohort consisted of 786 dementia patients with new PPI usage and 786 matched dementia patients without PPI usage. The study endpoint was defined as the occurrence of pneumonia. The Cox proportional hazard model was used to estimate the pneumonia risk. Defined daily dose methodology was applied to evaluate the cumulative and dose-response relationships of PPI. Incidence of pneumonia was higher among patients with PPI usage (adjusted hazard ratio (HR) = 1.89; 95% CI = 1.51-2.37). Cox model analysis also demonstrated that age (adjusted HR = 1.05; 95% CI = 1.03-1.06), male gender (adjusted HR = 1.57; 95% CI = 1.25-1.98), underlying cerebrovascular disease (adjusted HR = 1.30; 95% CI = 1.04-1.62), chronic pulmonary disease (adjusted HR = 1.39; 95% CI = 1.09-1.76), congestive heart failure (adjusted HR = 1.54; 95% CI = 1.11-2.13), diabetes mellitus (adjusted HR = 1.54; 95% CI = 1.22-1.95), and usage of antipsychotics (adjusted HR = 1.29; 95% CI = 1.03-1.61) were independent risk factors for pneumonia. However, usage of cholinesterase inhibitors and histamine receptor-2 antagonists were shown to decrease pneumonia risk. PPI usage in dementia patients is associated with an 89% increased risk of pneumonia. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

  1. Development and validation of a UPLC method for rapid and simultaneous analysis of proton pump inhibitors.

    PubMed

    Addo, Richard T; Davis, Kenneth; Ubale, Ruhi; Owen, Joel S; Watkins, E Blake

    2015-02-01

    Proton pump inhibitors (PPIs) are used extensively for the relief of gastroesophageal reflux, peptic ulcers, and other hypersecretory conditions. Some of the commonly used PPIs-omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole-were used in this study with the aim of developing a rapid ultra performance liquid chromatography (UPLC) method for detecting each and allowing separation and quantification of a mixture of PPIs. An analysis of samples was performed on a UPLC system equipped with a quaternary solvent delivery system, a refrigerated sample manager, a column heater, a photo diode array detector scanning from 210 to 400 nm, and a C18 analytical column (50 mm × 3.0 mm, 1.7-μm particle size). The chromatographic analysis of the PPI samples and standards was performed using gradient elution with acetonitrile and water. The calibration curve range varied for each of the PPIs ranging from a lower limit of 0.75-1.78 μg/mL to a maximum concentration of 200 μg/mL with a regression coefficient (r (2)) of ≥0.98. The accuracy and precision were calculated, and the %RSD was determined to be ≤0.21% (intraday) and ≤5% (interday). The LOD was 0.23-0.59 μg/mL and the LOQ was 0.71-1.78 μg/mL for each of the drugs analyzed. The method was capable of detecting and quantifying each drug in a mixture with good resolution and a total run time of less than 5 min. Herein, we report an efficient and rapid analytical method for the simultaneous detection of multiple PPIs in a mixture.

  2. Effect of proton pump inhibitors on the secretion of bicarbonates and pepsinogen induced by chemical stimulation of the gastric mucosa.

    PubMed

    Zolotarev, V A; Khropycheva, R P

    2013-02-01

    Proton pump inhibitors were shown to affect the sensitivity of the gastric mucosa to chemical agents. This effect is associated with inhibition of proton back-diffusion and increase in the permeability of the gastric epithelium. We studied the effect of omeprazole on gastric secretion of bicarbonates and pepsinogen induced by irritation of the gastric mucosa in narcotized rats with a hypertonic solution of high acidity (500 mM NaCl, pH 2.0). Irritation of the gastric mucosa increased the basal secretion of bicarbonates and potentiated the secretion of HCO3(-)and pepsinogen induced by electrostimulation of the vagus nerve. Omeprazole stimulated the prostaglandin-induced increase in the basal secretion of HCO3(-)and pepsinogen. By contrast, bicarbonate production in response to vagal stimulation was suppressed in the presence of omeprazole. Our results indicate that proton pump blockade has a modulatory effect on gastric secretion of bicarbonates and pepsinogen induced by chemical stimulation of the gastric mucosa.

  3. A phylogenetically distinctive and extremely heat stable light-driven proton pump from the eubacterium Rubrobacter xylanophilus DSM 9941T

    PubMed Central

    Kanehara, Kanae; Yoshizawa, Susumu; Tsukamoto, Takashi; Sudo, Yuki

    2017-01-01

    Rhodopsins are proteins that contain seven transmembrane domains with a chromophore retinal and that function as photoreceptors for light-energy conversion and light-signal transduction in a wide variety of organisms. Here we characterized a phylogenetically distinctive new rhodopsin from the thermophilic eubacterium Rubrobacter xylanophilus DSM 9941T that was isolated from thermally polluted water. Although R. xylanophilus rhodopsin (RxR) is from Actinobacteria, it is located between eukaryotic and archaeal rhodopsins in the phylogenetic tree. Escherichia coli cells expressing RxR showed a light-induced decrease in environmental pH and inhibition by a protonophore, indicating that it works as a light-driven outward proton pump. We characterized purified RxR spectroscopically, and showed that it has an absorption maximum at 541 nm and binds nearly 100% all-trans retinal. The pKa values for the protonated retinal Schiff base and its counterion were estimated to be 10.7 and 1.3, respectively. Time-resolved flash-photolysis experiments revealed the formation of a red-shifted intermediate. Of note, RxR showed an extremely high thermal stability in comparison with other proton pumping rhodopsins such as thermophilic rhodopsin TR (by 16-times) and bacteriorhodopsin from Halobacterium salinarum (HsBR, by 4-times). PMID:28290523

  4. A phylogenetically distinctive and extremely heat stable light-driven proton pump from the eubacterium Rubrobacter xylanophilus DSM 9941(T).

    PubMed

    Kanehara, Kanae; Yoshizawa, Susumu; Tsukamoto, Takashi; Sudo, Yuki

    2017-03-14

    Rhodopsins are proteins that contain seven transmembrane domains with a chromophore retinal and that function as photoreceptors for light-energy conversion and light-signal transduction in a wide variety of organisms. Here we characterized a phylogenetically distinctive new rhodopsin from the thermophilic eubacterium Rubrobacter xylanophilus DSM 9941(T) that was isolated from thermally polluted water. Although R. xylanophilus rhodopsin (RxR) is from Actinobacteria, it is located between eukaryotic and archaeal rhodopsins in the phylogenetic tree. Escherichia coli cells expressing RxR showed a light-induced decrease in environmental pH and inhibition by a protonophore, indicating that it works as a light-driven outward proton pump. We characterized purified RxR spectroscopically, and showed that it has an absorption maximum at 541 nm and binds nearly 100% all-trans retinal. The pKa values for the protonated retinal Schiff base and its counterion were estimated to be 10.7 and 1.3, respectively. Time-resolved flash-photolysis experiments revealed the formation of a red-shifted intermediate. Of note, RxR showed an extremely high thermal stability in comparison with other proton pumping rhodopsins such as thermophilic rhodopsin TR (by 16-times) and bacteriorhodopsin from Halobacterium salinarum (HsBR, by 4-times).

  5. Hydrogen-bonding interaction of the protonated schiff base with halides in a chloride-pumping bacteriorhodopsin mutant.

    PubMed

    Shibata, Mikihiro; Ihara, Kunio; Kandori, Hideki

    2006-09-05

    Bacteriorhodopsin (BR) and halorhodopsin (HR) are light-driven proton and chloride ion pumps, respectively, in Halobacterium salinarum. The amino acid identity of these proteins is about 25%, suggesting that each has been optimized for their own functions during evolution. However, it is known that the BR mutants, D85T and D85S, can pump chloride ions. This fact implies that the Schiff base region is important in determining ionic selectivity. The X-ray crystallographic structure of D85S(Br(-)) showed the presence of a bromide ion in the Schiff base region (Facciotti, M. T., Cheung, V. S., Nguyen, D., Rouhani, S., and Glaeser, R. M. (2003) Biophys. J. 85, 451-458). In this article, we report on the study of hydrogen bonds of the Schiff base and water molecules in D85S in the absence and presence of various halides, assigning their N-D and O-D stretching vibrations in D(2)O, respectively, in low-temperature Fourier-transform infrared (FTIR) spectroscopy. We found that the hydrogen bond of the Schiff base in D85S(Cl(-)) is much stronger than that in HR, being as strong as that in wild-type BR. Similar halide dependence in D85S and in solution implies that the Schiff base forms a direct hydrogen bond with a halide, consistent with the X-ray structure. Photoisomerization causes a weakened hydrogen bond of the Schiff base, and halide dependence on the stretching frequency is lost. These spectral features are similar to those in the photocycle of proton-pumping BR, though the weakened hydrogen bond is more significant for BR. However, the spectral features of water bands in D85S are closer to chloride-pumping HR because O-D stretching vibrations of water are observed only at >2500 cm(-)(1). Unlike in BR, we did not observe strongly hydrogen-bonded water molecules for halide-pumping D85S mutants. This observation agrees with our recent hypothesis that strongly hydrogen-bonded water molecules are required for the proton-pumping activity of archaeal rhodopsins. Hydrogen

  6. A plant proton-pumping inorganic pyrophosphatase functionally complements the vacuolar ATPase transport activity and confers bafilomycin resistance in yeast.

    PubMed

    Pérez-Castiñeira, José R; Hernández, Agustín; Drake, Rocío; Serrano, Aurelio

    2011-07-15

    V-ATPases (vacuolar H+-ATPases) are a specific class of multi-subunit pumps that play an essential role in the generation of proton gradients across eukaryotic endomembranes. Another simpler proton pump that co-localizes with the V-ATPase occurs in plants and many protists: the single-subunit H+-PPase [H+-translocating PPase (inorganic pyrophosphatase)]. Little is known about the relative contribution of these two proteins to the acidification of intracellular compartments. In the present study, we show that the expression of a chimaeric derivative of the Arabidopsis thaliana H+-PPase AVP1, which is preferentially targeted to internal membranes of yeast, alleviates the phenotypes associated with V-ATPase deficiency. Phenotypic complementation was achieved both with a yeast strain with its V-ATPase specifically inhibited by bafilomycin A1 and with a vma1-null mutant lacking a catalytic V-ATPase subunit. Cell staining with vital fluorescent dyes showed that AVP1 recovered vacuole acidification and normalized the endocytic pathway of the vma mutant. Biochemical and immunochemical studies further demonstrated that a significant fraction of heterologous H+-PPase is located at the vacuolar membrane. These results raise the question of the occurrence of distinct proton pumps in certain single-membrane organelles, such as plant vacuoles, by proving yeast V-ATPase activity dispensability and the capability of H+-PPase to generate, by itself, physiologically suitable internal pH gradients. Also, they suggest new ways of engineering macrolide drug tolerance and outline an experimental system for testing alternative roles for fungal and animal V-ATPases, other than the mere acidification of subcellular organelles.

  7. Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.

    PubMed

    Lam, Jameson R; Schneider, Jennifer L; Quesenberry, Charles P; Corley, Douglas A

    2017-03-01

    Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency. A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression. Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs <0.75 PPI pills/d; P value interaction = .004) and decreased after medication discontinuation (P-trend < .001). Some of the strongest associations were among persons taking >1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications. Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.

    PubMed

    Faleck, David M; Salmasian, Hojjat; Furuya, E Yoko; Larson, Elaine L; Abrams, Julian A; Freedberg, Daniel E

    2016-11-01

    Patients in the intensive care unit (ICU) frequently receive proton pump inhibitors (PPIs) and have high rates of Clostridium difficile infection (CDI). PPIs have been associated with CDI in hospitalized patients, but ICU patients differ fundamentally from non-ICU patients and few studies have focused on PPI use exclusively in the critical care setting. We performed a retrospective cohort study to determine the associations between PPIs and health-care facility-onset CDI in the ICU. We analyzed data from all adult ICU patients at three affiliated hospitals (14 ICUs) between 2010 and 2013. Patients were excluded if they had recent CDI or an ICU stay of <3 days. We parsed electronic medical records for ICU exposures, focusing on PPIs and other potentially modifiable exposures that occurred during ICU stays. Health-care facility-onset CDI in the ICU was defined as a newly positive PCR for the C. difficile toxin B gene from an unformed stool, with subsequent receipt of anti-CDI therapy. We analyzed PPIs and other exposures as time-varying covariates and used Cox proportional hazards models to adjust for demographics, comorbidities, and other clinical factors. Of 18,134 patients who met the criteria for inclusion, 271 (1.5%) developed health-care facility-onset CDI in the ICU. Receipt of antibiotics was the strongest risk factor for CDI (adjusted HR (aHR) 2.79; 95% confidence interval (CI), 1.50-5.19). There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72-3.35), and PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI, 0.48-0.83). There was also no evidence of increased risk for CDI in those who received higher doses of PPIs. Exposure to antibiotics was the most important risk factor for health-care facility-onset CDI in the ICU. PPIs did not increase risk for CDI in the ICU regardless of use of antibiotics.

  9. A therapeutic substitution policy for proton pump inhibitors: clinical and economic consequences.

    PubMed

    Schneeweiss, Sebastian; Maclure, Malcolm; Dormuth, Colin R; Glynn, Robert J; Canning, Claire; Avorn, Jerry

    2006-04-01

    With the growing need to provide prescription drug benefits to older patients and to contain costs, it will be necessary to direct that coverage so as to make expenditures as efficient as possible. We evaluated the clinical and economic consequences of coverage restriction for 3 leading proton pump inhibitors (PPIs) in a large-scale natural experiment. The study design was a time-trend analysis in the setting of a provincial drug benefits program in British Columbia, Canada. We studied all British Columbia residents aged 66 or older (N = 501,104) using linked data on all prescription drug dispensings, physician services, and hospitalizations between January 2002 and June 2004. The new policy restricted coverage to rabeprazole and required treatment failure with a histamine H2 blocker. More widely used PPIs (omeprazole, pantoprazole, and lansoprazole) had to be paid for out of pocket, unless the physician requested an exemption. The main outcome measures were utilization of PPIs, drug discontinuation rates, gastrointestinal hemorrhage rates, and drug expenditures. Utilization of the restricted PPIs declined sharply after the policy change (-14,850 daily doses per month per 10,000 residents, P < .0001), whereas use of the covered PPI increased sharply (+19,300, P < .0001), with 45% of all PPI users switching to the covered agent within 6 months. We found no increased use of H2 blockers or stopping of gastroprotective drugs. There was no increase in the monthly rate of hospitalization for gastrointestinal hemorrhage after the PPI restriction (P = .35) even though the study had the power to detect increases of 24 events per 10,000 residents with 95% confidence. There was a slight increase in physician visits 3 months after the policy change (P = .01) for a 2-month period when 9% of new rabeprazole users were switched back to a restricted PPI. In the first 6 months of the policy change, the provincial health plan saved at least 2.9 million Canadian dollars as a result

  10. Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us?

    PubMed

    Luk, Chee Phun; Parsons, Richard; Lee, Ya Ping; Hughes, Jeffery David

    2013-06-01

    Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid-related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs. To address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypo magnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database. We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. χ² analysis was conducted to investigate the association of PPI-associated hypomagnesemia with hypocalcemia and hypokalemia. Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3-5.7; p < 0.001). The risk of female subjects having hypo magnesemia (OR 0.83; 95% CI 0.71-0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI-associated hypomagnesemia (OR 1.5; 95% CI 1.2-1.7; p < 0.001). χ² analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001). All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia.

  11. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury.

    PubMed

    Xie, Yan; Bowe, Benjamin; Li, Tingting; Xian, Hong; Yan, Yan; Al-Aly, Ziyad

    2017-02-20

    Proton pump inhibitor (PPI) use is associated with an increased risk of acute kidney injury (AKI), incident chronic kidney disease (CKD), and progression to end-stage renal disease (ESRD). PPI-associated CKD is presumed to be mediated by intervening AKI. However, whether PPI use is associated with an increased risk of chronic renal outcomes in the absence of intervening AKI is unknown. To evaluate this we used the Department of Veterans Affairs national databases to build a cohort of 144,032 incident users of acid suppression therapy that included 125,596 PPI and 18,436 Histamine H2 receptor antagonist (H2 blockers) consumers. Over 5 years of follow-up in survival models, cohort participants were censored at the time of AKI occurrence. Compared with incident users of H2 blockers, incident users of PPIs had an increased risk of an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m(2) (hazard ratio 1.19; 95% confidence interval 1.15-1.24), incident CKD (1.26; 1.20-1.33), eGFR decline over 30% (1.22; 1.16-1.28), and ESRD or eGFR decline over 50% (1.30; 1.15-1.48). Results were consistent in models that excluded participants with AKI either before chronic renal outcomes, during the time in the cohort, or before cohort entry. The proportion of PPI effect mediated by AKI was 44.7%, 45.47%, 46.00%, and 46.72% for incident eGFR under 60 ml/min/1.73m(2), incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively. Thus, PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI. Hence, reliance on antecedent AKI as warning sign to guard against the risk of CKD among PPI users is not sufficient as a sole mitigation strategy.

  12. Association between baseline impedance values and response proton pump inhibitors in patients with heartburn.

    PubMed

    de Bortoli, Nicola; Martinucci, Irene; Savarino, Edoardo; Tutuian, Radu; Frazzoni, Marzio; Piaggi, Paolo; Bertani, Lorenzo; Furnari, Manuele; Franchi, Riccardo; Russo, Salvatore; Bellini, Massimo; Savarino, Vincenzo; Marchi, Santino

    2015-06-01

    Esophageal impedance measurements have been proposed to indicate the status of the esophageal mucosa, and might be used to study the roles of the impaired mucosal integrity and increased acid sensitivity in patients with heartburn. We compared baseline impedance levels among patients with heartburn who did and did not respond to proton pump inhibitor (PPI) therapy, along with the pathophysiological characteristics of functional heartburn (FH). In a case-control study, we collected data from January to December 2013 on patients with heartburn and normal findings from endoscopy who were not receiving PPI therapy and underwent impedance pH testing at hospitals in Italy. Patients with negative test results were placed on an 8-week course of PPI therapy (84 patients received esomeprazole and 36 patients received pantoprazole). Patients with more than 50% symptom improvement were classified as FH/PPI responders and patients with less than 50% symptom improvement were classified as FH/PPI nonresponders. Patients with hypersensitive esophagus and healthy volunteers served as controls. In all patients and controls, we measured acid exposure time, number of reflux events, baseline impedance, and swallow-induced peristaltic wave indices. FH/PPI responders had higher acid exposure times, numbers of reflux events, and acid refluxes compared with FH/PPI nonresponders (P < .05). Patients with hypersensitive esophagus had mean acid exposure times and numbers of reflux events similar to those of FH/PPI responders. Baseline impedance levels were lower in FH/PPI responders and patients with hypersensitive esophagus, compared with FH/PPI nonresponders and healthy volunteers (P < .001). Swallow-induced peristaltic wave indices were similar between FH/PPI responders and patients with hypersensitive esophagus. Patients with FH who respond to PPI therapy have impedance pH features similar to those of patients with hypersensitive esophagus. Baseline impedance measurements might allow for

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

    PubMed

    Richter, Joel E

    2014-09-01

    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 at

  14. 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

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

    PubMed

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

    2015-04-21

    To investigate the influence of proton pump inhibitors (PPIs) exposure on the diagnosis of Helicobacter pylori (H. pylori) gastritis and intestinal metaplasia. 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. 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 gastritis and leads to a

  16. Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis.

    PubMed

    Ghebremariam, Yohannes T; Cooke, John P; Gerhart, William; Griego, Carol; Brower, Jeremy B; Doyle-Eisele, Melanie; Moeller, Benjamin C; Zhou, Qingtao; Ho, Lawrence; de Andrade, Joao; Raghu, Ganesh; Peterson, Leif; Rivera, Andreana; Rosen, Glenn D

    2015-08-01

    The beneficial outcome associated with the use of proton pump inhibitors (PPIs) in idiopathic pulmonary fibrosis (IPF) has been reported in retrospective studies. To date, no prospective study has been conducted to confirm these outcomes. In addition, the potential mechanism by which PPIs improve measures of lung function and/or transplant-free survival in IPF has not been elucidated. Here, we used biochemical, cell biological and preclinical studies to evaluate regulation of markers associated with inflammation and fibrosis. In our in vitro studies, we exposed primary lung fibroblasts, epithelial and endothelial cells to ionizing radiation or bleomycin; stimuli typically used to induce inflammation and fibrosis. In addition, we cultured lung fibroblasts from IPF patients and studied the effect of esomeprazole on collagen release. Our preclinical study tested efficacy of esomeprazole in a rat model of bleomycin-induced lung injury. Furthermore, we performed retrospective analysis of interstitial lung disease (ILD) databases to examine the effect of PPIs on transplant-free survival. The cell culture studies revealed that esomeprazole controls inflammation by suppressing the expression of pro-inflammatory molecules including vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6). The antioxidant effect is associated with strong induction of the stress-inducible cytoprotective protein heme oxygenase-1 (HO1) and the antifibrotic effect is associated with potent inhibition of fibroblast proliferation as well as downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs). Furthermore, esomeprazole showed robust effect in mitigating the inflammatory and fibrotic responses in a murine model of acute lung injury. Finally, retrospective analysis of two ILD databases was performed to assess the effect

  17. 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

  18. Inappropriate Use of Proton Pump Inhibitors in Elderly Patients Discharged from Acute Care Hospitals.

    PubMed

    Schepisi, R; Fusco, S; Sganga, F; Falcone, B; Vetrano, D L; Abbatecola, A; Corica, F; Maggio, M; Ruggiero, C; Fabbietti, P; Corsonello, A; Onder, G; Lattanzio, F

    2016-01-01

    Proton-pump inhibitors (PPI) are extensively prescribed in older patients. However, little information is available on factors associated to PPI prescribing patterns among older patients discharged from hospital. To evaluate the appropriateness and clinical correlates of PPI prescription at discharge in a population of 1081 older patients discharged from acute care Italian hospitals. We used data from the CRiteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) study, a multicenter observational study. The appropriateness of PPI prescriptions was defined according to the Italian Medicines Agency (AIFA) rules. Correlates of overprescribing (i.e prescribing without recognized AIFA indications) and underprescribing (i.e. not prescribing despite the presence of recognized AIFA indications) were investigated by logistic regression analysis. Overprescribing was observed in 30% of patients receiving PPIs at discharge. Underprescribing was observed in 11% of patients not receiving PPIs at discharge. Overprescribing of PPIs at discharge was negatively associated with age (OR=0.88, 95%CI=0.85-0.91), depression (OR=0.58, 95%CI=0.35-0.96), use of aspirin (OR=0.03, 95%CI=0.02-0.06) and systemic corticosteroids (OR=0.02, 95%CI=0.01-0.04). The negative association with number of medications (OR=0.95, 95%CI=0.88-1.03) and overall comorbidities (OR=0.92, 95%CI=0.83-1.02) was nearly significant. Conversely, older age (OR=1.09, 95%CI=1.04-1.14), use of aspirin (OR=24.0, 95%CI=11.5-49.8) and systemic corticosteroids (OR=19.3, 95%CI=11.5-49.8) and overall comorbidities (OR=1.22, 95%CI=1.04-1.42) were independent correlates of underprescribing. Overprescribing of PPIs is more frequent in younger patients with lower burden of depression, whilst underprescribing is characterized by older age and greater burden of comorbidity and polypharmacy. Hospitalization should be considered as a clue to identify inappropriate use of PPIs and improve appropriateness of

  19. Epithelial pH and ion transport regulation by proton pumps and exchangers.

    PubMed

    Harvey, B J; Ehrenfeld, J

    1988-01-01

    This study reports on the interaction between transepithelial Na+ transport and H+ secretory and intracellular pH (pHi) regulating mechanisms in the model 'tight' epithelium of frog skin. We have used 22Na isotope fluxes and fixed end-point titration to measure undirectional Na+ fluxes, net Na absorption (J(net)Na) and proton secretion (J(net)H), and electrophysiological techniques (double-barrelled ion-sensitive microelectrodes and cell membrane current--voltage relations) to determine intracellular activities of Na+, Cl- and H+ and the conductance of apical membranes to Na+ (gNa) and of basolateral membranes to K+ (gK). In dilute mucosal solutions or in the absence of a permeant anion (Cl-) or counter-current (open-circuit conditions) to accompany Na+ uptake, the J(net)Na is electrically coupled to J(net)H via an electrogenic apical H+-ATPase (located in mitochondria-rich cells). Both fluxes proceed via mitochondria-rich cells and are inhibited by blockers of carbonic anhydrase and H+-ATPase and stimulated by aldosterone and acid load. In high NaCl-containing mucosal solutions or in short-circuit conditions, the J(net)Na becomes uncoupled from J(net)H and proceeds mainly via the principal cells in the epithelium, in which pHi is regulated by basolateral Na+/H+ and Cl-/HCO3- exchangers. Under these conditions, J(net)Na, gNa and gK vary directly and in parallel with pHi, when pHi is changed by permeable weak acids or bases. There is also co-variance between gNa and pHi accompanying spontaneous variations in J(net)Na and when Na+ transport is stimulated by aldosterone or inhibited with ouabain. We conclude that the level of intracellular H+, modulated by H+ pump and Na+/H+ and Cl-/HCO3- exchangers provides an intrinsic regulation of epithelial Na+ transport.

  20. 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

  1. Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals.

    PubMed

    Maggio, Marcello; Lauretani, Fulvio; Ceda, Gian Paolo; De Vita, Francesca; Bondi, Giuliana; Corsonello, Andrea; Cattabiani, Chiara; Lattanzio, Fabrizia; Ruggiero, Carmelinda; Nouvenne, Antonio; Meschi, Tiziana; Bandinelli, Stefania; Ferrucci, Luigi

    2013-12-01

    Proton pump inhibitors (PPIs) are highly effective in the treatment of upper gastrointestinal acid-related conditions and are fast becoming one of the most frequently prescribed treatments in adult or older persons. Recent data show that long-term use of PPIs in older subjects is associated with important undesirable effects, including a higher risk of osteoporotic fractures. The mechanisms of this association are unclear and the relationship between the use of PPIs and parameters of bone mass and geometry has never been fully explored. This study investigates the relationship between the chronic use of PPIs and the parameters of bone mass (cortical and trabecular bone mineral density - vBMDc and vBMDt) and bone geometry (cortical and trabecular cross sectional area - tCSA and cCSA) in older individuals. The study population consisted of 1038 subjects (452 men and 586 women) 65years or older, selected from the InCHIANTI study, with complete information on computerized tomography performed at tibial level (pQCT) and on medications. Participants were classified as PPI users and nonusers based on self-report of PPI use over the last 15days, with PPI users (36 subjects, 14 men and 22 women) making up 3.4% of the study population (mean age 75.7±7.4years). The relationship between use of PPIs and pQCT bone parameters was tested by multivariate linear regression analysis adjusted for age, sex and several clinical factors and/or statistically confounding variables identified by partial correlation coefficient and Spearman partial rank order correlation coefficients, as appropriate (age, sex, BMI, caloric intake, IGF-1, IL-6, calcium, estradiol, bioavailable testosterone, vitamin D, parathyroid hormone, cross-sectional muscle area, and level of physical activity). PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5±54.8 vs. 207.9±59.4, p=0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple

  2. [What is the utility of proton pump inhibitor testing in non-cardiac chest pain?].

    PubMed

    Huamán, José Wálter; Aliaga, Verónica; Domenech, Gemma; Videla, Sebastián; Saperas, Esteban

    2014-10-01

    Noncardiac chest pain (NCCP) often represents a diagnostic and therapeutic challenge. Given that gastroesophageal reflux disease (GERD) is the most common cause of NCCP, initial treatment with proton-pump inhibitors (PPI) has been proposed for all patients (PPI testing), reserving esophageal function testing solely for non-responders. The aim of the present study was to provide evidence on the clinical utility of PPI testing with high-dose pantoprazole in patients with NCCP. We carried out a study of diagnostic performance with a cohort design in patients with NCCP, who had been assessed by the Cardiology Service. All patients underwent upper endoscopy, esophageal manometry, and 24h esophageal pH monitoring before PPI testing with pantoprazole 40 mg every 12h for 1 month. Before and after treatment, we assessed the severity (intensity and frequency) of chest pain, quality of life, and anxiety and depression by means of specific questionnaires. The diagnosis of GERD was based on a pathological finding of esophageal pH monitoring. A positive response to PPI testing was defined as an improvement in chest pain >50% compared with the baseline score after 1 month of PPI therapy. We included 30 consecutive patients (17 men/13 women) with a mean age of 49 years. Of these 30 patients, 20 with NCCP had GERD (67%, 95%CI: 47%-83%). A positive response to PPI therapy was observed in 13 of the 30 (43%) patients with NCCP: 11 of the 20 (55%) patients in the GERD-positive group and 2 of the 10 (20%) in the GERD-negative group. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PPI testing was 55%, 80%, 85%, 47% and 63%, respectively. A significant reduction in chest pain after pantoprazole therapy (P=.003) and a slight non significant improvement in anxiety and depression was achieved in the GERD-positive group as compared to the GERD-negative group. In NCCP, PPI testing with pantoprazole has a low sensitivity for the diagnosis of

  3. Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all?

    PubMed

    Fohl, Alexander L; Regal, Randolph E

    2011-06-06

    Over the past two decades, proton pump inhibitors (PPIs) have emerged as highly effective and relatively safe agents for the treatment of a variety of gastrointestinal disorders. Unfortunately, this desirable pharmacological profile has also contributed to superfluous and widespread use in both the inpatient and outpatient settings. While generally well-tolerated, research published over the last decade has associated these agents with increased risks of Clostridium difficile disease, fractures likely due to calcium malabsorption and both community-acquired (CAP) and hospital-acquired pneumonias (HAP). The mechanism behind PPI-associated pneumonia may be multifactorial, but is thought to stem from compromising the stomach's "acid mantle" against gastric colonization of acid-labile pathogenic bacteria which then may be aspirated. A secondary postulate is that PPIs, through their inhibition of extra-gastric H(+)/K(+)-ATPase enzymes, may reduce the acidity of the upper aerodigestive tract, thus resulting in increased bacterial colonization of the larynx, esophagus and lungs. To date, several retrospective case control studies have been published looking at the association between PPI use and CAP. Some studies found a temporal relationship between PPI exposure and the incidence of pneumonia, but only two could define a dose-response relationship. Furthermore, other studies found an inverse correlation between duration of PPI use and risk of CAP. In terms of HAP, we reviewed two retrospective cohort studies and one prospective study. One retrospective study in a medical ICU found no increased association of HAP in PPI-exposed patients compared to no acid-lowering therapy, while the other in cardiothoracic surgery patients showed a markedly increased risk compared to those receiving H(2)RAs. The one prospective study in ICU patients showed an increased risk of HAP with PPIs, but not with H(2)RAs. In conclusion, the current literature shows a slight trend toward an

  4. 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.

  5. Glu-286 rotation and water wire reorientation are unlikely the gating elements for proton pumping in cytochrome C oxidase.

    PubMed

    Yang, Shuo; Cui, Qiang

    2011-07-06

    One of the key unresolved issues regarding proton pumping in cytochrome c oxidase (CcO) is the identity of the gating element that prevents the backflow of protons. In this study, we analyze two popular proposals for this element: isomerization of the key branching residue (Glu-286) and (re)orientation of water molecules in the hydrophobic cavity. Using a multifaceted set of computational analyses that involve CcO embedded in either an implicit or explicit treatment of lipid membrane, we show that neither Glu-286 nor active-site water likely constitutes the gating element. Detailed energetic and structural analyses of the simulation results indicate that the gating-relevant properties of these structural motifs observed in previous work are likely a result of the simplified computational models employed in those studies. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  6. Glu-286 Rotation and Water Wire Reorientation Are Unlikely the Gating Elements for Proton Pumping in Cytochrome c Oxidase

    PubMed Central

    Yang, Shuo; Cui, Qiang

    2011-01-01

    One of the key unresolved issues regarding proton pumping in cytochrome c oxidase (CcO) is the identity of the gating element that prevents the backflow of protons. In this study, we analyze two popular proposals for this element: isomerization of the key branching residue (Glu-286) and (re)orientation of water molecules in the hydrophobic cavity. Using a multifaceted set of computational analyses that involve CcO embedded in either an implicit or explicit treatment of lipid membrane, we show that neither Glu-286 nor active-site water likely constitutes the gating element. Detailed energetic and structural analyses of the simulation results indicate that the gating-relevant properties of these structural motifs observed in previous work are likely a result of the simplified computational models employed in those studies. PMID:21723815

  7. A Proton Pump Inhibitor in the Reformulation Setting: Bioequivalence and Potential Implications for Long‐Term Safety

    PubMed Central

    Beers‐Block, PM; Kim, LP; Schotland, P; Levine, JG; McCloskey, CA; Bashaw, ED

    2017-01-01

    Abstract Proton pump inhibitors (PPIs) have become known for both their therapeutic effect and good safety profile. An application was submitted to the US Food and Drug Administration for approval of a reformulated PPI product that failed bioequivalence testing, but was submitted on the basis of the long history of PPI use as a “surrogate” for equivalence. This review evaluates the safety data for PPIs, discuss variability of pharmacokinetic parameters of PPIs in the reformulation setting, and potential implications of those changes for long‐term safety. PMID:28618191

  8. Proton-pump inhibitor as palliative care for chemotherapy-induced gastroesophageal reflux disease in pancreatic cancer patients.

    PubMed

    Uwagawa, Tadashi; Misawa, Takeyuki; Iida, Tomonori; Sakamoto, Taro; Gocho, Takeshi; Wakiyama, Shigeki; Hirohara, Shoichi; Yanaga, Katsuhiko

    2010-07-01

    Relief of adverse events induced by chemotherapy is an important issue for patients, especially those with a poor prognosis, such as with pancreatic cancer. There are no reports of the relationship between gastroesophageal reflux disease (GERD) and chemotherapy, so we investigated the incidence of chemotherapy-induced GERD in patients undergoing treatment with gemcitabine or S-1 for pancreatic cancer and the effect of sodium rabeprazole (RPZ), a proton-pump inhibitor. GERD was diagnosed in 40% of the patients according to the Frequency Scale for Symptoms of GERD score, and RBZ therapy significantly improved their symptoms.

  9. 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.

  10. 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.

  11. The Ca(2+)-ATPase pump facilitates bidirectional proton transport across the sarco/endoplasmic reticulum.

    PubMed

    Espinoza-Fonseca, L Michel

    2017-03-28

    Ca(2+) transport across the sarco/endoplasmic reticulum (SR) plays an essential role in intracellular Ca(2+) homeostasis, signalling, cell differentiation and muscle contractility. During SR Ca(2+) uptake and release, proton fluxes are required to balance the charge deficit generated by the exchange of Ca(2+) and other ions across the SR. During Ca(2+) uptake by the SR Ca(2+)-ATPase (SERCA), two protons are countertransported from the SR lumen to the cytosol, thus partially compensating for the charge moved by Ca(2+) transport. Studies have shown that protons are also transported from the cytosol to the lumen during Ca(2+) release, but a transporter that facilitates proton transport into the SR lumen has not been described. In this article we propose that SERCA forms pores that facilitate bidirectional proton transport across the SR. We describe the location and structure of water-filled pores in SERCA that form cytosolic and luminal pathways for protons to cross the SR membrane. Based on this structural information, we suggest mechanistic models for proton translocation to the cytosol during active Ca(2+) transport, and into the SR lumen during SERCA inhibition by endogenous regulatory proteins. Finally, we discuss the physiological consequences of SERCA-mediated bidirectional proton transport across the SR membrane of muscle and non-muscle cells.

  12. The causes of reduced proton-pumping efficiency in type B and C respiratory heme-copper oxidases, and in some mutated variants of type A.

    PubMed

    Rauhamäki, Virve; Wikström, Mårten

    2014-07-01

    The heme-copper oxidases may be divided into three categories, A, B, and C, which include cytochrome c and quinol-oxidising enzymes. All three types are known to be proton pumps and are found in prokaryotes, whereas eukaryotes only contain A-type cytochrome c oxidase in their inner mitochondrial membrane. However, the bacterial B- and C-type enzymes have often been reported to pump protons with an H(+)/e(-) ratio of only one half of the unit stoichiometry in the A-type enzyme. We will show here that these observations are likely to be the result of difficulties with the measuring technique together with a higher sensitivity of the B- and C-type enzymes to the protonmotive force that opposes pumping. We find that under optimal conditions the H(+)/e(-) ratio is close to unity in all the three heme-copper oxidase subfamilies. A higher tendency for proton leak in the B- and C-type enzymes may result from less efficient gating of a proton pump mechanism that we suggest evolved before the so-called D-channel of proton transfer. There is also a discrepancy between results using whole bacterial cells vs. phospholipid vesicles inlaid with oxidase with respect to the observed proton pumping after modification of the D-channel residue asparagine-139 (Rhodobacter sphaeroides numbering) to aspartate in A-type cytochrome c oxidase. This discrepancy might also be explained by a higher sensitivity of proton pumping to protonmotive force in the mutated variant. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

  13. Luminal and Cytosolic pH Feedback on Proton Pump Activity and ATP Affinity of V-type ATPase from Arabidopsis*

    PubMed Central

    Rienmüller, Florian; Dreyer, Ingo; Schönknecht, Gerald; Schulz, Alexander; Schumacher, Karin; Nagy, Réka; Martinoia, Enrico; Marten, Irene; Hedrich, Rainer

    2012-01-01

    Proton pumping of the vacuolar-type H+-ATPase into the lumen of the central plant organelle generates a proton gradient of often 1–2 pH units or more. Although structural aspects of the V-type ATPase have been studied in great detail, the question of whether and how the proton pump action is controlled by the proton concentration on both sides of the membrane is not understood. Applying the patch clamp technique to isolated vacuoles from Arabidopsis mesophyll cells in the whole-vacuole mode, we studied the response of the V-ATPase to protons, voltage, and ATP. Current-voltage relationships at different luminal pH values indicated decreasing coupling ratios with acidification. A detailed study of ATP-dependent H+-pump currents at a variety of different pH conditions showed a complex regulation of V-ATPase activity by both cytosolic and vacuolar pH. At cytosolic pH 7.5, vacuolar pH changes had relative little effects. Yet, at cytosolic pH 5.5, a 100-fold increase in vacuolar proton concentration resulted in a 70-fold increase of the affinity for ATP binding on the cytosolic side. Changes in pH on either side of the membrane seem to be transferred by the V-ATPase to the other side. A mathematical model was developed that indicates a feedback of proton concentration on peak H+ current amplitude (vmax) and ATP consumption (Km) of the V-ATPase. It proposes that for efficient V-ATPase function dissociation of transported protons from the pump protein might become higher with increasing pH. This feature results in an optimization of H+ pumping by the V-ATPase according to existing H+ concentrations. PMID:22215665

  14. Nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and gastrointestinal injury: contrasting interactions in the stomach and small intestine.

    PubMed

    Marlicz, Wojciech; Loniewski, Igor; Grimes, David S; Quigley, Eamonn M

    2014-12-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) are among the most frequently prescribed groups of drugs worldwide. The use of NSAIDs is associated with a high number of significant adverse effects. Recently, the safety of PPIs has also been challenged. Capsule endoscopy studies reveal that even low-dose NSAIDs are responsible for gut mucosal injury and numerous clinical adverse effects, for example, bleeding and anemia, that might be difficult to diagnose. The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy. In this review, we discuss this important clinical problem and review relevant aspects of epidemiology, pathophysiology, and management. We also present the hypothesis that even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual. PubMed was searched using the following key words (each key word alone and in combination): gut microbiota, microbiome, non-steroidal anti inflammatory drugs, proton pump inhibitors, enteropathy, probiotic, antibiotic, mucosal injury, enteroscopy, and capsule endoscopy. Google engine search was also carried out to identify additional relevant articles. Both original and review articles published in English were reviewed. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  15. Isolation and sequence of tryptic peptides from the proton-pumping ATPase of the oat plasma membrane.

    PubMed

    Schaller, G E; Sussman, M R

    1988-02-01

    In crude extracts of plant tissue, the M(r) = 100,000 proton-pumping ATPase constitutes less than 0.01% of the total cell protein. A large-scale purification procedure is described that has been used to obtain extensive protein sequence information from this enzyme. Plasma membrane vesicles enriched in ATPase activity were obtained from extracts of oat roots by routine differential and density gradient centrifugation. Following a detergent wash, the ATPase was resolved from other integral membrane proteins by size fractionation at 4 degrees C in the presence of lithium dodecyl sulfate. After carboxymethylation of cysteine residues and removal of detergent, the ATPase was digested with trypsin and resultant peptide fragments separated by reverse phase high performance liquid chromatography. Peptides were recovered with high yield and were readily sequenced by automated Edman degradation on a gas-phase sequencer. Of the eight peptides sequenced, six showed strong homology with known amino acid sequences of the fungal proton-pumping and other cation-transporting ATPases.

  16. A rapid Fourier transform infrared spectroscopic method for analysis of certain proton pump inhibitors in binary and ternary mixtures.

    PubMed

    Khashaba, Pakinaz Y; Ali, Hassan Refat H; El-Wekil, Mohamed M

    2017-09-05

    A simple and non-destructive FTIR method was used to determine certain proton pump inhibitors (PPIs) in binary and ternary mixtures. Proton pump inhibitors (PPIs); omeprazole (OMZ), esomeprazole (EZM), lansoprazole (LAN), pantoprazole sodium (PAN sodium) and rabeprazole sodium (RAB sodium) in binary mixture with domperidone (DOM) and ternary mixture of OMZ, clarithromycin (CLM) and tinidazole (TNZ) were determined in the solid-state by FTIR spectroscopy for the first time. The method was validated according to ICH-guidelines where linearity was ranged from 20 to 850μg/g and 20-360μg/g for PPIs and DOM, respectively in binary mixtures and 10-400, 100-8000 and 150-14,000μg/g for OMZ, CLM and TNZ, respectively. Limits of detection were found to be 6-100 and 9-100μg/g for PPIs and DOM, respectively and 4, 40 and 50μg/g for OMZ, CLM and TNZ, respectively. The method was applied successfully for determination of the cited drugs in their respective pharmaceutical dosage forms. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. [Do proton pump inhibitors after endoscopic control of acute ulcer hemorrhage have an advantage over H2 receptor antagonists?].

    PubMed

    Prassler, R; Hendrich, H; Barnert, J; Richter, G; Fleischmann, R; Wienbeck, M

    1995-08-01

    During a two year period (1992-1993) we investigated whether or not, after endoscopic therapy of bleeding ulcers, the suppression of gastric acid secretion with an administration of a proton pump blocker (Omeprazol) is more effective than the administration of H2-receptor antagonist (Ranitidin) with respect to prevention of recurrent bleeding episodes, frequency of surgical intervention and mortality. 106 patients (64 men, 42 women) were treated with the proton pump blocker and 126 patients (82 men, 44 women) received the H2-receptor antagonist. Patients were treated either with an initial dose of 80 mg Omeprazol followed by 3 x 40 mg Omeprazol i.v. or with a daily dose of 3 mg/kg body weight Ranitidin i.v. No significant differences could be detected between the two treatment regimes with respect to the parameters mentioned above. Rebleeding which could be controlled by endoscopic hemostasis occurred in 19.8% vs. 17.5% (Omeprazol/Ranitidin) of patients. Surgical intervention because of rebleeding was necessary on 8.5% vs. 8.7% of the patients. Mortality due to hemorrhage was 5.7% vs. 4.0%. From these results we conclude that, following endoscopic hemostasis of bleeding ulcers, Omeprazol has no advantage over Ranitidin using our dosage regimes.

  18. 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

    2015-07-06

    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. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. [Effects of exogenous spermidine on lipid peroxidation and membrane proton pump activity of cucumber seedling leaves under high temperature stress].

    PubMed

    Tian, Jing; Guo, Shi-Rong; Sun, Jin; Wang, Li-Ping; Yang, Yan-Juan; Li, Bin

    2011-12-01

    Taking a relatively heat-resistant cucumber (Cucumis sativus) cultivar 'Jinchun No. 4' as test material, a sand culture experiment was conducted in growth chamber to investigate the effects of foliar spraying spermidine (Spd) on the lipid peroxidation, membrane proton pump activity, and corresponding gene expression of cucumber seedling leaves under high temperature stress. Compared with the control, foliar spraying Spd increased the plant height, stem diameter, dry and fresh mass, and leaf area significantly, and inhibited the increase of leaf relative conductivity, malondialdehyde (MDA) content, and lipoxygenase (LOX) activity effectively. Foliar spraying Spd also helped to the increase of leaf plasma membrane- and tonoplast H(+)-ATPase activity, but no significant difference was observed in the gene expression levels. These results suggested that exogenous Spd could significantly decrease the leaf lipid peroxidation and increase the proton pump activity, and thus, stabilize the leaf membrane structure and function, alleviate the damage induced by high temperature stress, and enhance the heat tolerance of cucumber seedlings.

  20. Air swallowing can be responsible for non-response of heartburn to high-dose proton pump inhibitor.

    PubMed

    Zentilin, P; Accornero, L; Dulbecco, P; Savarino, E; Savarino, V

    2005-06-01

    Intraluminal electrical impedance is a novel technique, which is able for the first time to provide a qualitative assessment of refluxed material moving from the stomach to the oesophagus. In other words, the presence of air can be differentiated from that of liquid, because the former is characterised by high and the latter by low impedance compared with baseline. Moreover, the combined measurement of electrical impedance and pH-metry permits to distinguish acid from non-acid liquid reflux. One of the most important clinical applications of this method is to assess the reasons for poor response of GORD patients to high-dose proton pump inhibitors. This case report describes the results of impedance in the evaluation of a young woman, who did not respond to twice-daily doses of rabeprazole. She continued to complain of heartburn as major symptom and impedance allowed us to clarify that it was not related to acid or non-acid reflux, but to air swallowing. Therefore, this technique identified aerophagia to be responsible for persistent heartburn despite high-dose proton pump inhibitor and prevented the adoption of more aggressive, but probably unuseful therapies, such as the surgical one.

  1. A pKa calculation of residues in a proton pump, bacteriorhodopsin, from structures determined by electron crystallography.

    PubMed

    Mitsuoka, Kaoru

    2014-11-01

    Bacteriorhodopsin (bR) is a light-driven proton pump, which is a membrane protein found in halophilic archeae like Halobacterium salinarum and in eubacteria [1]. When the covalently bound retinal chromophore absorbs the light energy, it changes the conformation from all-trans to 13-cis. This configuration change initiates ion translocation across the cell membrane and a proton moves from inside to outside of the cell. The bR molecules are forming two-dimensional crystals on the membranes of halophilic archeae, and therefore the atomic model of bR was first determined by electron crystallography. The determined structure can be used to determine the pKa values, through which the charge states of ionizable residues in bR determine their pH-dependent properties. The pH-dependent properties are crucial for proton translocation from ionizable residues or to ionizable residues. Detection of the intermediate states of the reaction cycle (photocycle) produced spectroscopic information, which can predict the ionization state of the ionozable residues. In the transition from the L intermediate to the M intermediate, it is known that a proton moves from the Shiff base on the retinal chromophore to Asp85, while a proton is released to the extracellar side from proton-releasing groups including Glu194 and Glu204. Experimentally the pKa value of the proton release is determined to be about 9.7, while the pKa value of Asp85 was measured to change from 2.6 to 7.5 by the proton release from the proton-releasing groups [2]. Here we used the PROPKA program [3] to calculate the pKa values of Asp85 and the proton-releasing groups from the structures at pH 5.5 and at pH 10.0 determined by electron crystallography. The calculation showed that the pKa value of Asp85 changes from 5.3 to 6.1, which qualitatively show the similar changes with the measured difference. The largest change between the structures is the shift of Arg82 by the proton release from the proton-releasing groups

  2. Concomitant Administration of a Histamine2 Receptor Antagonist and Proton Pump Inhibitor Enhances Gastric Acid Suppression.

    PubMed

    Abdul-Hussein, Mustafa; Freeman, Janice; Castell, Donald

    2015-12-01

    Because it has been hypothesized that histamine2 receptor antagonists (H2 RAs) might interfere with the action of proton pump inhibitors (PPIs) when the drugs are given concomitantly, we sought to compare the pharmacodynamic effects of simultaneous administration of a PPI and an H2 RA with the effects of each drug administered alone. Prospective, randomized, double-blind, three-way crossover study. Esophageal motility laboratory at a large teaching hospital. Twenty-one healthy volunteers. Subjects were randomized to one of three treatment arms: an H2 RA (ranitidine 300 mg) plus placebo, a PPI (omeprazole 40 mg) plus placebo, or ranitidine 300 mg plus omeprazole 40 mg, all given once/day at 8 a.m., 30 minutes before a standard breakfast, for 1 week. The subjects then received the other two treatments, with each treatment period separated by a 1-week washout period. The primary outcome was length of time that the gastric pH remained higher than 4. Secondary outcomes were median gastric pH higher than 4 and percentage of time that the gastric pH remained higher than 4. On day 7, ambulatory intragastric pH was recorded over an 8-hour period in each treatment arm. The combination of ranitidine and omeprazole resulted in a significantly longer time that the gastric pH remained higher than 4 (median 410.5 min [interquartile range (IQR) 298.5-454.25 min]) versus either omeprazole alone (median 356.7 min [IQR 254.9-419.2 min], p=0.023) or ranitidine alone (134.1 min [IQR 99.9-302.5 min], p<0.0001). Median gastric pH was also significantly higher when omeprazole and ranitidine were given in combination (pH 5.92 [IQR 4.75-6.46]) than either omeprazole alone (pH 4.88 [IQR 4.27-6.11], p=0.001) or ranitidine alone (pH 2.31 [IQR 2.04-5.27], p=0.0003). Likewise, the percentage of time that the gastric pH remained higher than 4 was significantly higher when omeprazole and ranitidine were given in combination (median 85.52%) than either omeprazole alone (74.31%, p=0.027) or

  3. Qualitative analysis of anatomopathological changes of gastric mucosa due to long term therapy with proton pump inhibitors: experimental studies x clinical studies.

    PubMed

    de Souza, Iure Kalinine Ferraz; da Silva, Alcino Lázaro; de Araújo, Alex; Santos, Fernanda Carolina Barbosa; Mendonça, Bernardo Pinto Coelho Keuffer

    2013-01-01

    For a few decades the long-term use of proton pump inhibitors has had wide application in the treatment of several gastrointestinal diseases. Since then, however, several studies have called attention to the possible development of anatomical and pathological changes of gastric mucosa, resulting from the long term use of this therapeutic modality. Recent experimental and clinical studies suggest that these changes have connection not only to the development of precancerous lesions, but also of gastric tumors. To present a qualitative analysis of anatomical and pathological changes of gastric mucosa resulting from the long-term use of proton pump inhibitors. The headings used were: proton pump inhibitors, precancerous lesions and gastric neoplasms for a non systematic review of the literature, based on Medline, Lillacs and Scielo. Twelve articles were selected from clinical (9) and experimental (3) studies, for qualitative analysis of the results. The gastric acid suppression by high doses of proton pump inhibitors induces hypergastrinemia and the consequent emergence of neuroendocrine tumors in animal models. Morphological changes most often found in these experimental studies were: enterochromaffin-like cell hyperplasia, neuroendocrine tumor, atrophy, metaplasia and adenocarcinoma. In the studies in humans, however, despite enterochromaffin-like cell hyperplasia, the other effects, neuroendocrine tumor and gastric atrophy, gastric metaplasia and or adenocarcinoma, were not identified. Although it is not possible to say that the long-term treatment with proton pump inhibitors induces the appearance or accelerates the development of gastric cancer in humans, several authors have suggested that prolonged administration of this drug could provoke the development of gastric cancer. Thus, the evidence demonstrated in the animal model as well as the large number of patients who do or will do a long-term treatment with proton pump inhibitors, justifies the maintenance of

  4. 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

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

    2008-11-12

    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 O 2 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 ba 3 from Thermus thermophilus, which is considered to be both necessary and sufficient for coupled O 2 reduction and proton pumping when appropriate gates are in place (not included in the model). Fourteen detailed structures obtained from density functional theory (DFT) geometry optimization are presented that are reasonably thought to occur during the four-electron reduction of O 2. 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 Cu B. Four types of DFT were 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 (Siegbahn, P. E. M.; Blomberg, M. A. R. Chem. Rev. 2000, 100, 421-437) and shows how the chemistry of O 2 reduction in the heme a 3 -Cu B dinuclear center can be harnessed to generate an electrochemical proton gradient across the lipid bilayer.

  5. 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

  6. The selectivity of the Na+/K+-pump is controlled by binding site protonation and self-correcting occlusion

    PubMed Central

    Rui, Huan; Artigas, Pablo; Roux, Benoît

    2016-01-01

    The Na+/K+-pump maintains the physiological K+ and Na+ electrochemical gradients across the cell membrane. It operates via an 'alternating-access' mechanism, making iterative transitions between inward-facing (E1) and outward-facing (E2) conformations. Although the general features of the transport cycle are known, the detailed physicochemical factors governing the binding site selectivity remain mysterious. Free energy molecular dynamics simulations show that the ion binding sites switch their binding specificity in E1 and E2. This is accompanied by small structural arrangements and changes in protonation states of the coordinating residues. Additional computations on structural models of the intermediate states along the conformational transition pathway reveal that the free energy barrier toward the occlusion step is considerably increased when the wrong type of ion is loaded into the binding pocket, prohibiting the pump cycle from proceeding forward. This self-correcting mechanism strengthens the overall transport selectivity and protects the stoichiometry of the pump cycle. DOI: http://dx.doi.org/10.7554/eLife.16616.001 PMID:27490484

  7. [Correlation between long-term proton pump ingibitor use, homocysteine and lipoproteins serum concentrations in patients with comorbidity of ischemic heart disease and acid peptic disease].

    PubMed

    Zharkova, A; Orlovsky, V

    2012-12-01

    Present article is devoted to the study of the correlation between vitamin B12 serum level, hyperhomocysteinaemia and dyslipidemia. During research there were discovered that the lowest vitamin B12 serum level and the highest homocysteine serum level have been registrated in associated pathology (ischemic heart disease and acid peptic disease according to long-term proton pump inhibitor use) patients. It was shown evident correlation between that changes and dyslipidemia. Тhe complex therapy that includes parenteral B12 supplementation leads to more effective correction of hyperhomocysteinaemia and dyslipidemia in patients with comorbidity of ischemic heart disease and acid peptic disease with long-term use of proton pump inhibitors.

  8. Role of protons in the pump cycle of KdpFABC investigated by time-resolved kinetic experiments.

    PubMed

    Damnjanovic, Bojana; Apell, Hans-Jürgen

    2014-05-20

    The time-resolved kinetics of the KdpFABC complex solubilized in Aminoxide WS-35 was investigated by ATP concentration jump experiments. ATP was photoreleased from its inactive precursor, caged ATP, and charge movements in the membrane domain of the KdpFABC were detected by the electrochromic dye RH421. At low ATP concentrations, the ATP binding step became rate-limiting with an apparent, pH-independent ATP binding affinity of ~70 μM. At saturating ATP concentrations, the rate-limiting step is the conformational transition (E1-P → P-E2) with a rate constant of ~1.7 s(-1) at 20 °C that was independent of K(+) concentration. This observation together with the detected fluorescence decrease indicates that K(+) (or another positive ion) is bound in the membrane domain after enzyme phosphorylation and the conformational transition to the P-E2 state. pH dependence experiments revealed different roles of H(+) in the transport mechanism. Two different functions of protons for the ion pump must be distinguished. On one hand, there are electrogenically bound "functional" protons, which are not transported but prerequisite for the performance of the ATP-driven half-cycle. On the other hand, protons bind to the transport sites, acting as weak congeners of K(+). There possibly are noncompetitively bound protons, affecting the enzyme activity and/or coupling between KdpA and KdpB subunits. Finally, the recently proposed Post-Albers model for the KdpFABC complex was supplemented with stoichiometry factors of 2 for K(+) and 3 for H(+), and additional inhibitory side reactions controlled by H(+) were introduced, which are relevant at pH <6.5 and/or in the absence of K(+).

  9. The proton pump bacteriorhodopsin is a photoreceptor for signal transduction in Halobacterium halobium.

    PubMed

    Bibikov, S I; Grishanin, R N; Marwan, W; Oesterhelt, D; Skulachev, V P

    1991-12-16

    Halobacterium halobium swims by rotating its polarly inserted flagellar bundle. The cells are attracted by green-to-orange light which they can use for photophosphorylation but flee damaging blue or ultraviolet light. It is generally believed that this kind of 'colour vision' is achieved by the combined action of two photoreceptor proteins, sensory rhodopsins-I and -II, that switch in the light the rotational sense of the bundle and in consequence the swimming direction of a cell. By expressing the bacteriorhodopsin gene in a photoreceptor-negative background we have now demonstrated the existence of a proton-motive force sensor (protometer) and the function of bacteriorhodopsin as an additional photoreceptor covering the high intensity range. When the bacteriorhodopsin-generated proton-motive force drops caused by a sudden decrease in light intensity, the cells respond by reversing their swimming direction. This response does not occur when the proton-motive force is saturated by respiration or fermentation.

  10. Hypoalbuminemia is a predictor of mortality and rebleeding in peptic ulcer bleeding under proton pump inhibitor use.

    PubMed

    Cheng, Hsiu-Chi; Yang, Er-Hsiang; Wu, Chung-Tai; Wang, Wen-Lun; Chen, Po-Jun; Lin, Meng-Ying; Sheu, Bor-Shyang

    2017-07-24

    Peptic ulcer bleeding remains a deadly disease, and a simple indicator of long-term outcomes is crucial. This study validated whether hypoalbuminemia and its related factors in patients with peptic ulcer bleeding can indicate long-term mortality and rebleeding under proton pump inhibitor use. The prospective cohort study enrolled 426 patients with peptic ulcer bleeding who had high risk stigmata at endoscopy and had received endoscopic hemostasis. They were divided into 79 patients in the hypoalbuminemia group (Hypo-AG, serum albumin <28 g/L), 135 in the marginal hypoalbuminemia group (Margin-AG, serum albumin 28-34.9 g/L), and 212 in the normal albuminemia group (Normal-AG, serum albumin ≥35 g/L). Each subject received 72-h of intravenous infusion and then the oral form of proton pump inhibitors and were monitored for 84 days to assess all-cause mortality and recurrent bleeding. The primary outcome of all-cause mortality rates were increased in a stepwise fashion in a trend from Normal-AG, Margin-AG, to Hypo-AG (0-28th day: 1.9%, 2.2%, 12.8%, p < 0.001; 29th-84th day: 2.5%, 8.0%, 10.6%, p < 0.01). The secondary outcome of recurrent bleeding rates were also increased in the same fashion (0-28th day: 6.4%, 15.4%, 24.6%, p < 0.001; 29th-84th day: 0%, 3.0%, 4.2%, p = 0.01). Abnormal albuminemia was <30 g/L related to hemoglobin levels <70 g/L, nosocomial bleeding, cirrhosis, age ≥70 years, shock, and ulcer size ≥1.0 cm independently (p < 0.05). Hypoalbuminemia in patients with peptic ulcer bleeding can be an alarm indicator of all-cause mortality and recurrent bleeding in a long-term follow-up situation under proton pump inhibitor use (NCT01591083). Copyright © 2017. Published by Elsevier B.V.

  11. Biophysical comparison of ATP-driven proton pumping mechanisms suggests a kinetic advantage for the rotary process depending on coupling ratio

    PubMed Central

    Zuckerman, Daniel M.

    2017-01-01

    ATP-driven proton pumps, which are critical to the operation of a cell, maintain cytosolic and organellar pH levels within a narrow functional range. These pumps employ two very different mechanisms: an elaborate rotary mechanism used by V-ATPase H+ pumps, and a simpler alternating access mechanism used by P-ATPase H+ pumps. Why are two different mechanisms used to perform the same function? Systematic analysis, without parameter fitting, of kinetic models of the rotary, alternating access and other possible mechanisms suggest that, when the ratio of protons transported per ATP hydrolyzed exceeds one, the one-at-a-time proton transport by the rotary mechanism is faster than other possible mechanisms across a wide range of driving conditions. When the ratio is one, there is no intrinsic difference in the free energy landscape between mechanisms, and therefore all mechanisms can exhibit the same kinetic performance. To our knowledge all known rotary pumps have an H+:ATP ratio greater than one, and all known alternating access ATP-driven proton pumps have a ratio of one. Our analysis suggests a possible explanation for this apparent relationship between coupling ratio and mechanism. When the conditions under which the pump must operate permit a coupling ratio greater than one, the rotary mechanism may have been selected for its kinetic advantage. On the other hand, when conditions require a coupling ratio of one or less, the alternating access mechanism may have been selected for other possible advantages resulting from its structural and functional simplicity. PMID:28319179

  12. Biophysical comparison of ATP-driven proton pumping mechanisms suggests a kinetic advantage for the rotary process depending on coupling ratio.

    PubMed

    Anandakrishnan, Ramu; Zuckerman, Daniel M

    2017-01-01

    ATP-driven proton pumps, which are critical to the operation of a cell, maintain cytosolic and organellar pH levels within a narrow functional range. These pumps employ two very different mechanisms: an elaborate rotary mechanism used by V-ATPase H+ pumps, and a simpler alternating access mechanism used by P-ATPase H+ pumps. Why are two different mechanisms used to perform the same function? Systematic analysis, without parameter fitting, of kinetic models of the rotary, alternating access and other possible mechanisms suggest that, when the ratio of protons transported per ATP hydrolyzed exceeds one, the one-at-a-time proton transport by the rotary mechanism is faster than other possible mechanisms across a wide range of driving conditions. When the ratio is one, there is no intrinsic difference in the free energy landscape between mechanisms, and therefore all mechanisms can exhibit the same kinetic performance. To our knowledge all known rotary pumps have an H+:ATP ratio greater than one, and all known alternating access ATP-driven proton pumps have a ratio of one. Our analysis suggests a possible explanation for this apparent relationship between coupling ratio and mechanism. When the conditions under which the pump must operate permit a coupling ratio greater than one, the rotary mechanism may have been selected for its kinetic advantage. On the other hand, when conditions require a coupling ratio of one or less, the alternating access mechanism may have been selected for other possible advantages resulting from its structural and functional simplicity.

  13. 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

  14. Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

    PubMed

    Lugini, Luana; Federici, Cristina; Borghi, Martina; Azzarito, Tommaso; Marino, Maria Lucia; Cesolini, Albino; Spugnini, Enrico Pierluigi; Fais, Stefano

    2016-08-01

    Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

  15. Proton pump inhibitor failure in gastro-oesophageal reflux disease: a perspective aided by the Gartner hype cycle.

    PubMed

    Heading, Robert C

    2017-04-01

    Some patients with gastro-oesophageal reflux disease (GORD) experience symptoms despite proton pump inhibitor (PPI) treatment. In the early years of their availability, these drugs were thought to be a highly effective treatment for GORD and realisation that symptom relief was often incomplete came as a disappointment. This review considers the evolution of thinking with the aid of the Gartner hype cycle - a graphical depiction of the process of innovation, evolution and adoption of new technologies. Acknowledging that over-simplistic concepts of GORD have been largely responsible for inflated expectations of PPI therapy is an important step forward in establishing how patients with persistent symptoms, despite PPIs, should be assessed and treated. © Royal College of Physicians 2017. All rights reserved.

  16. 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

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

    PubMed

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

    2015-01-15

    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.

  18. Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin.

    PubMed

    Han, Y-M; Park, J-M; Kangwan, N; Jeong, M; Lee, S; Cho, J Y; Ko, W J; Hahm, K B

    2015-04-01

    Gastrin is the main hormone stimulating gastric acid secretion, but it exerts proliferative and anti-apoptotic actions on various cancer cell types, in addition to its well-known trophic effect on enterochromaffin-like cells. As treatment with proton pump inhibitors (PPIs) increases the biosynthesis and secretion of gastrin, it has been postulated that treatment with PPIs could increase the risk of cancer, especially in Barrett's esophagus, gastric carcinoids, and colorectal cancer (CRC). Some tumors produce gastrin of their own, which can act in an autocrine manner to promote tumor growth. In addition, gastrin is known to foster the tumor microenvironment. However, in spite of these potentially increased cancer risks due to PPI-induced hypergastrinemia, prospective, large-scale cohort studies did not show an increase in CRC prevalence. The question as to why the long-term use of PPIs was not associated with an increased cancer risk of CRC might be answered by the fact that the PPIs antagonized the trophic effects of hypergastrinemia. Furthermore, the blockade of proton pumps or potassium channels in cancer cells could limit the abnormal glycolytic energy metabolism of cancer cells. Apart from their suppressive effect on gastric acids, PPIs exert an anti-tumor effect through the selective induction of apoptosis as well as an anti-inflammatory effect, and they protect cells from developing chemo- or radiotherapeutic resistance. Moreover, the anti-carcinogenic actions of PPIs were augmented with PPI-induced hypergastrinemia. Together with their potential targeted killing of cancer stem cells, these effects demonstrate their potential anti-cancer actions.

  19. Microbial Light-Activatable Proton Pumps as Neuronal Inhibitors to Functionally Dissect Neuronal Networks in C. elegans

    PubMed Central

    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

  20. 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.

  1. Evidence for an ATP-driven proton pump in rat thyroid phagolysosomes. Effects of protonophores and ionophores.

    PubMed

    Fouchier, F; Dang, J

    1983-11-15

    During incubations at 37 degrees C in appropriate media (buffered 0.25 M sucrose) isolated thyroid phagolysosomes degrade the thyroglobulin they contain (labelled with 131I in vivo) giving rise to trichloroacetic-acid-soluble radio-iodine. Thyroglobulin-degradation is unaffected by external pH (7 or 8) or by 20-40 mM external NaCl or KCl, while it is strongly inhibited by ionophores and protonophores. As a consequence, thyroglobulin degradation can be used as an index of the intralysosomal pH which appears to be powerfully maintained in basal conditions (no ionophore and no protonophore) by the strong impermeability of the lysosomal membranes to various compounds including ionic species MgATP which does not modify basal proteolysis prevents or minimizes the alkalinizing effects of both ionophores and protonophores. ATP can thus be concluded to promote a protonic flux inward thyroid lysosomes via the activity of a lysosomal ATP-driven proton pump regulated by the magnitude of the intralysosomal pH.

  2. 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

  3. 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

    2015-12-04

    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. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Isolation of ATPase I, the proton pump of chromaffin-granule membranes.

    PubMed Central

    Percy, J M; Pryde, J G; Apps, D K

    1985-01-01

    Chromaffin-granule membranes contain two ATPases, which can be separated by (NH4)2SO4 fractionation after solubilization with detergents, or by phase segregation in Triton X-114. ATPase I (Mr 400000) is inhibited by trialkyltin, quercetin and alkylating agents, and hydrolyses both ATP and ITP. It contains up to five types of subunit, including a low-Mr hydrophobic polypeptide that reacts with dicyclohexylcarbodi-imide; these subunits are unrelated to those of mitochondrial F1F0-ATPase, as judged by size and reaction with antibodies. ATPase II (Mr 140000) is inhibited by vanadate, and is specific for ATP; it has not been extensively purified. Proton translocation by resealed chromaffin-granule 'ghosts', measured by uptake of methylamine or by quenching of the fluorescence of 9-amino-6-chloro-2-methoxyacridine, is supported by the hydrolysis of ATP or ITP, and inhibited by quercetin or alkylating agents, but not by vanadate. ATPase I must therefore be the proton translocator involved in the uptake of catecholamines and possibly of other components of the chromaffin-granule matrix, whereas ATPase II does not translocate protons. Images Fig. 1. PMID:3000354

  5. Isolation of a new Pseudomonas halophila strain possess bacteriorhodopsin-like protein by a novel method for screening of photoactive protein producing bacteria.

    PubMed

    Fanaei, Maryam; Emtiazi, Giti

    2014-02-01

    Bacteriorhodopsin (bR) is a transmembrane protein deposited in the purple membrane of Halobacterium salinarum which absorbs energy from photons to create a photo-induced proton gradient across the membrane. A bR molecule can be considered as a natural solar device transforming light into other types of energy and therefore is of interest for a wide range of applications including two and three-dimensional memory storage, optical data processing, artificial cells, holographic media, the artificial retina and photo sensor devices. H. salinarum is a slow-growing, halophilic Archaea present in red salt waters. The present study introduces a novel bR-like pigment from a new strain of Pseudomonas halophila (with registered accession number KC959570 in the NCBI databank) which has a very significant degree of light-dependent activity. This is the first report on the presence of functional bR-like protein in the Pseudomonas family. The isolate is a fast-growing, halophilic bacterium and is comparable with other photoactive protein producer microorganisms. Also, in the present study a novel isolation method for screen light-stimulating protein producing microorganisms is introduced. For this purpose 2,3,5-triphenyltetrazolium chloride (TTC) was employed for the first time as an artificial hydrogen acceptor in the proton-transfer processes. The TTC test is an easy and susceptible method for estimating hydrogen production during the proton transport process. This is the first report of the use of TTC for photo activity measurement and selection of bacteria containing light dependent proteins.

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

    PubMed

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

    1992-05-01

    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. Linking chemical electron-proton transfer to proton pumping in cytochrome c oxidase: broken-symmetry DFT exploration of intermediates along the catalytic reaction pathway of the iron-copper dinuclear complex.

    PubMed

    Noodleman, Louis; Han Du, Wen-Ge; Fee, James A; Götz, Andreas W; Walker, Ross C

    2014-07-07

    After a summary of the problem of coupling electron and proton transfer to proton pumping in cytochrome c oxidase, we present the results of our earlier and recent density functional theory calculations for the dinuclear Fe-a3-CuB reaction center in this enzyme. A specific catalytic reaction wheel diagram is constructed from the calculations, based on the structures and relative energies of the intermediate states of the reaction cycle. A larger family of tautomers/protonation states is generated compared to our earlier work, and a new lowest-energy pathway is proposed. The entire reaction cycle is calculated for the new smaller model (about 185-190 atoms), and two selected arcs of the wheel are chosen for calculations using a larger model (about 205 atoms). We compare the structural and redox energetics and protonation calculations with available experimental data. The reaction cycle map that we have built is positioned for further improvement and testing against experiment.

  8. A new differentially pumped plunger device to measure excited-state lifetimes in proton emitting nuclei

    NASA Astrophysics Data System (ADS)

    Taylor, M. J.; Cullen, D. M.; Smith, A. J.; McFarlane, A.; Twist, V.; Alharshan, G. A.; Procter, M. G.; Braunroth, T.; Dewald, A.; Ellinger, E.; Fransen, C.; Butler, P. A.; Scheck, M.; Joss, D. T.; Saygi, B.; McPeake, C. G.; Grahn, T.; Greenlees, P. T.; Jakobsson, U.; Jones, P.; Julin, R.; Juutinen, S.; Ketelhut, S.; Leino, M.; Nieminen, P.; Pakarinen, J.; Peura, P.; Rahkila, P.; Ruotsalainen, P.; Sandzelius, M.; Sarén, J.; Scholey, C.; Sorri, J.; Stolze, S.; Uusitalo, J.

    2013-04-01

    A new plunger device has been designed and built to measure the lifetimes of unbound states in exotic nuclei beyond the proton drip-line. The device has been designed to work in both vacuum and dilute-gas environments made possible through the introduction of a low-voltage stepping motor. DPUNS will be used in conjunction with the gas-filled separator RITU and the vacuum separator MARA at the accelerator laboratory of the University of Jyväskylä, Finland, to measure the lifetimes of excited states with low population cross-sections. This is achieved by eliminating the need for a carbon foil to isolate the helium gas of RITU from the beam line thus reducing the background from beam-foil reactions. The inclusion of a high-sampling rate data acquisition card increases further the sensitivity of the device. The plunger will be used to address many key facets of nuclear structure physics with particular emphasis on the effect of deformation on proton emission rates.

  9. Structural and functional analysis of aa3-type and cbb3-type cytochrome c oxidases of Paracoccus denitrificans reveals significant differences in proton-pump design.

    PubMed

    de Gier, J W; Schepper, M; Reijnders, W N; van Dyck, S J; Slotboom, D J; Warne, A; Saraste, M; Krab, K; Finel, M; Stouthamer, A H; van Spanning, R J; van der Oost, J

    1996-06-01

    In Paracoccus denitrificans the aa3-type cytochrome c oxidase and the bb3-type quinol oxidase have previously been characterized in detail, both biochemically and genetically. Here we report on the isolation of a genomic locus that harbours the gene cluster ccoNOOP, and demonstrate that it encodes an alternative cbb3-type cytochrome c oxidase. This oxidase has previously been shown to be specifically induced at low oxygen tensions, suggesting that its expression is controlled by an oxygen-sensing mechanism. This view is corroborated by the observation that the ccoNOOP gene cluster is preceded by a gene that encodes an FNR homologue and that its promoter region contains an FNR-binding motif. Biochemical and physiological analyses of a set of oxidase mutants revealed that, at least under the conditions tested, cytochromes aa3, bb3 and cbb3 make up the complete set of terminal oxidases in P. denitrificans. Proton-translocation measurements of these oxidase mutants indicate that all three oxidase types have the capacity to pump protons. Previously, however, we have reported decreased H+/e- coupling efficiencies of the cbb3-type oxidase under certain conditions. Sequence alignment suggests that many residues that have been proposed to constitute the chemical and pumped proton channels in cytochrome aa3 (and probably also in cytochrome bb3) are not conserved in cytochrome cbb3. It is concluded that the design of the proton pump in cytochrome cbb3 differs significantly from that in the other oxidase types.

  10. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis.

    PubMed

    Alhazzani, Waleed; Alenezi, Farhan; Jaeschke, Roman Z; Moayyedi, Paul; Cook, Deborah J

    2013-03-01

    Critically ill patients may develop bleeding caused by stress ulceration. Acid suppression is commonly prescribed for patients at risk of stress ulcer bleeding. Whether proton pump inhibitors are more effective than histamine 2 receptor antagonists is unclear. To determine the efficacy and safety of proton pump inhibitors vs. histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in the ICU. We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ACPJC, CINHAL, online trials registries (clinicaltrials.gov, ISRCTN Register, WHO ICTRP), conference proceedings databases, and reference lists of relevant articles. Randomized controlled parallel group trials comparing proton pump inhibitors to histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in critically ill patients, published before March 2012. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were clinically important upper gastrointestinal bleeding and overt upper gastrointestinal bleeding; secondary outcomes were nosocomial pneumonia, ICU mortality, ICU length of stay, and Clostridium difficile infection. Trial authors were contacted for additional or clarifying information. Fourteen trials enrolling a total of 1,720 patients were included. Proton pump inhibitors were more effective than histamine 2 receptor antagonists at reducing clinically important upper gastrointestinal bleeding (relative risk 0.36; 95% confidence interval 0.19-0.68; p = 0.002; I = 0%) and overt upper gastrointestinal bleeding (relative risk 0.35; 95% confidence interval 0.21-0.59; p < 0.0001; I = 15%). There were no differences between proton pump inhibitors and histamine 2 receptor antagonists in the risk of nosocomial pneumonia (relative risk 1.06; 95% confidence interval 0.73-1.52; p = 0.76; I = 0%), ICU mortality (relative risk 1.01; 95% confidence interval 0.83-1.24; p = 0.91; I = 0

  11. Is there an overprescription of proton pump inhibitors in oncohematologic patients undergoing ambulatory oncospecific treatment?

    PubMed

    Pujal Herranz, Meritxell

    2016-09-01

    Objetivo: El objetivo de este estudio es analizar la prevalencia de inhibidores de la bomba de protones (IBP) en el paciente oncohematologico de dispensacion ambulatoria y el grado de adecuacion de su indicacion. Método: Estudio observacional descriptivo en pacientes oncohematologicos en tratamiento oncoespecifico de dispensacion ambulatoria. Se elaboro un protocolo dirigido al paciente oncohematologico a partir del protocolo de uso racional de IBP de nuestro hospital. Se cuantificaron los pacientes en tratamiento activo con IBP y se analizo la idoneidad de su indicacion. Resultados: Se incluyeron 111 pacientes (71 oncologicos, 40 hematologicos). El 56% de los pacientes oncologicos y el 63% de los hematologicos estaban en tratamiento activo con IBP. Tras revisar las indicaciones de los pacientes con IBP, el 72% de los oncologicos y el 12% de los hematologicos no presentaron una indicacion que justificara el tratamiento. Conclusiones: Es importante que el farmaceutico detecte las prescripciones inadecuadas de IBP especialmente entre la poblacion oncologica y sugiera una deprescripcion del mismo.

  12. 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

  13. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD.

    PubMed

    Baumeler, Luzia; Papakonstantinou, Eleni; Milenkovic, Branislava; Lacoma, Alicia; Louis, Renaud; Aerts, Joachim G; Welte, Tobias; Kostikas, Konstantinos; Blasi, Francesco; Boersma, Wim; Torres, Antoni; Rohde, Gernot G U; Boeck, Lucas; Rakic, Janko; Scherr, Andreas; Tamm, Michael; Stolz, Daiana

    2016-07-01

    Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD. A total of 638 patients with stable COPD for ≥6 weeks, ≥10 pack-years of smoking and Global Initiative for Chronic Obstructive Lung Disease II-IV seeking care in tertiary hospitals in eight European countries in the Predicting Outcome using Systemic Markers in Severe Exacerbations-COPD cohort was prospectively evaluated by us. Comorbidities including associated medical treatment were assessed at baseline, at exacerbation and at biannual visits. Median observation time was 24 months. The primary study outcomes were exacerbation and/or death. A total of 85 (13.3%) of COPD patients were on anti-GERD therapy. These patients had higher annual and higher severe exacerbation rates (P = 0.009 and P = 0.002), decreased quality of life (SF-36: activity score P = 0.004, St. George's Respiratory Questionnaire: physical functioning P = 0.013 and social functioning P = 0.007), higher body mass airflow obstruction, dyspnea and exercise capacity index (P = 0.033) and Modified Medical Research Council scores (P = 0.002), shorter 6-min walking distance (P = 0.0004) and a higher adjusted Charlson score (P < 0.0001). Anti-GERD therapy was associated with a shorter time to severe exacerbation (HR 2.05 95% CI 1.37-3.08). Using three multivariable Cox-regression models, this association was independent of the following: (i) adjusted Charlson score and FEV1% predicted (HR 1.91 95% CI 1.26-2.90); (ii) adjusted Charlson score, body mass, airflow obstruction, dyspnea and exercise capacity index and Modified Medical Research Council (HR 1.62 95% CI 1.04-2.54); and (iii) adjusted Charlson score, FEV1% predicted and nine classes of medication for comorbidities (HR 1.63 95% CI 1