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PubMed2006

A comparative study of intragastric acidity during post-breakfast and pre-dinner administration of low-dose proton pump inhibitors: a randomized three-way crossover study.

BACKGROUND: The absorption and bioavailability of proton pump inhibitors is influenced by food intake. Proton pump inhibitors bind to the parietal cell active proton pump, which is maximally stimulated after dinner: usually the largest meal of the day. However, it has not been fully clarified whether the efficacy of proton pump inhibitors differs between post-breakfast and pre-dinner dosing. AIM: To perform a pH-monitoring study to clarify this issue for two low-dose proton pump inhibitors. SUBJECTS AND METHODS: The subjects were 20 healthy male volunteers (seven Helicobacter pylori-positive and 13 H. pylori-negative), who were divided into two groups of 10 and administered 15 mg lansoprazole or 10 mg rabeprazole, respectively. All subjects underwent ambulatory intragastric 24-h pH- monitoring under three conditions allocated randomly: (i) without medication, (ii) seventh day of post-breakfast administration and (iii) eighth day of pre-dinner administration of each drug. RESULTS: There was no significant difference in the percentage time during which pH > or =4.0 in the 24-h period between post-breakfast and pre-dinner administration of both drugs (56.6% vs. 55.8%; P = 0.557), although intragastric acidity during administration of both drugs was significantly lower than that without medication. CONCLUSIONS: The timing of drug administration does not significantly influence the efficacy of low-dose proton pump inhibitors.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Simultaneous monitoring of intracellular pH and proton excretion during glycolysis by Streptococcus mutans and Streptococcus sanguis: effect of low pH and fluoride.

A system was developed by which 2',7'-bis(carboxyethyl)-4 or 5-carboxyfluorescein could be used to monitor intracellular pH at the same time that proton excretion was being measured. Streptococcal cells were loaded with the dye, and after the addition of glucose protons were excreted and the intracellular pH increased quickly and remained higher than the extracellular pH of 7.0. The excretion of protons stopped and the intracellular pH returned to the original level when glucose was depleted. The intracellular level of ATP remained high during glucose metabolism and decreased with the depletion of glucose. At extracellular pH of 5.5, and 5.0, the intracellular pH of fasting cells was higher than the extracellular pH value. After addition of glucose there were initial lags of proton excretion and of increases in intracellular pH at the acidic extracellular pH values. In the presence of fluoride, a lag in proton excretion and a simultaneous decrease in intracellular pH were observed, indicating a partial and transient inhibition of proton-ATPase activity.

Adenosine Triphosphate↗
PubMed1997

Effect of sodium and potassium ions on intracellular pH and proton excretion in glycolyzing cells of Streptococcus mutans NCTC 10449 under strictly anaerobic conditions.

The effect of sodium and potassium ions on intracellular acid production and acid excretion by glycolyzing cells of Streptococcus mutans was examined. S. mutans NCTC 10449 grown under glucose-limited and strictly anaerobic conditions in a continuous culture system was loaded with bis(carboxyethyl)-carboxyfluorescein, a pH-sensitive fluorescent dye, washed and suspended in 0.00-0.30 M NaCl/KCl solution. The dye allowed for the continuous monitoring of intracellular pH while proton excretion was measured simultaneously with a pH-stat. Sodium ions inhibited and potassium ions, at low pH, accelerated the amount of measurable acid excreted extracellularly. In the presence of both NaCl and KCl, proton excretion following the addition of glucose was slightly higher or similar to that observed in the presence of 0.15 M KCl alone. Sodium and potassium ions did not affect the proton-ATPase enzyme or the intracellular level of ATP, suggesting that these ions did not directly effect proton pumping activity itself. The inhibition of proton excretion by sodium ions was considered to have probably occurred as a result of an indirect inhibition of proton-ATPase activity by the low intracellular pH induced by sodium ions.

Adenosine Triphosphate↗
PubMed1983

The stoichiometry of proton translocation through H+-ATPase of rat-liver mitochondria.

The ratio of the number of protons transported directly by H+-ATPase of intact mitochondria and that of the hydrolyzed ATP (the proton translocation quotient) is determined. A special kinetic method which makes possible determination of ATPase and H+-translocase activities in the same experiment has been used to estimate the proton translocation quotient for mitochondrial H+-ATPase. The quotient is found to be, on average, equal to 3.31 mol/mol. It is shown that the protonophore 3,5-di-tert-butyl-4-hydroxybenzylidenemalononitrile can greatly decrease the proton translocation quotient. This supports our assumption concerning a labile coupling between H+-translocase and ATPase in mitochondria [I. A. Gorskaya, K. F. Sholtz, S. A. Moreva, A. V. Kotelnikova (1979) Biochemistry (Engl. Transl. Biokhimiya) 44, 765-770]. A decrease in the translocation quotient in the presence of the protonophore is likely to be due to the ability of this uncoupler to take back the translocated protons into the mitochondrial matrix before their release into the medium. An electrostatic model of the molecular mechanism of H+-translocase and ATPase coupling in the H+-ATPase complex is discussed. The model is in agreement with the results obtained: transport of more than two protons per each hydrolyzed ATP molecule, and variable efficiency of the process.

Adenosine Triphosphatases↗
PubMed1985

Current-voltage relationships for proton flow through the F0 sector of the ATP-synthase, carbonylcyanide-p-trifluoromethoxyphenylhydrazone or leak pathways in submitochondrial particles.

Respiring submitochondrial particles from which the F1 sector of ATP-synthase was displaced generated a membrane potential in the range of 115-140 mV. Addition of oligomycin raised the membrane potential by approximately 40 mV. The lower membrane potential in particles with F1 displaced is attributed to partial dissipation of the proton electrochemical gradient as a consequence of proton flow through the open proton channels provided by the F0 sectors of the ATP-synthase. The characteristics of proton flow through the open F0 channels were studied by varying the rate of electron transport-driven proton translocation which permitted the establishment of a range of steady-state membrane potentials. Open F0 channels appeared to have a gated response to the membrane potential such that they were inoperative when the potential fell below approximately 110 mV. The membrane potential was measured as a function of respiratory rate in intact Mg-ATP submitochondrial particles that had been treated with low concentrations of the protonophore carbonylcyanide-p-trifluoromethoxyphenylhydrazone. In general a linear dependence of membrane potential upon respiratory rate was observed except at the lowest concentrations of protonophore and highest respiratory rates, presumably because the effect of the protonophore was then offset by an increased rate of proton translocation driven by the respiratory chain. The effect of increasing concentrations of carbonylcyanide-p-trifluoromethoxyphenylhydrazone on the membrane potential of respiring submitochondrial particles was studied. It was found that equal amounts of the protonophore lowered the membrane potential to a lesser extent at lower values of the membrane potential. Treatment of Mg-ATP submitochondrial particles with oligomycin slightly increased (by approximately 10 mV) the size of the respiration-dependent membrane potential, but did not alter the profile of membrane potential as a function of succinate oxidation rate. The latter was controlled by titration with malonate. This result indicates that the F0 sector of the ATP-synthase does not significantly contribute to leak pathways in intact submitochondrial particles.

Adenosine Triphosphate↗
PubMed1994

An investigation on the role of vacuolar-type proton pumps and luminal acidity in calcium sequestration by nonmitochondrial and inositol-1,4,5-trisphosphate-sensitive intracellular calcium stores in clonal insulin-secreting cells.

To test whether in RINm5F rat insulinoma cells luminal acidity and the activity of a vacuolar-type proton pump are involved in calcium sequestration by intracellular calcium stores sensitive to inositol 1,4,5-trisphosphate (InsP3) we examined the effects of various proton-conducting ionophores and ammonium chloride, and of bafilomycin, a specific inhibitor of vacuolar proton pumps, on this parameter. Bafilomycin in concentrations up to 1 microM did not affect calcium sequestration by nonmitochondrial, InsP3-sensitive stores at all; 50 microM carbonylcyanide m-chlorophenylhydrazone, 50 microM monensin and 30 mM NH4Cl, which are diverse ways to dissipate transmembrane pH gradients, did not inhibit calcium sequestration. This argues against signficant involvement of internal acidity and vacuolar proton pumps in calcium sequestration by InsP3-sensitive stores in RINm5F cells. The proton-potassium-exchanging ionophore nigericin (20-100 microM), however, inhibited calcium sequestration by nonmitochondrial and InsP3-sensitive stores. This effect was dependent on the presence of potassium and could be reversed by inclusion of carbonylcyanide m-chlorophenylhydrazone or acetate in the incubation medium. Thus, the inhibitory effect of nigericin appears to be based on proton extrusion coupled to potassium influx across the membrane of calcium stores in RINm5F cells, creating an internal alkalinization of these stores. The effect of nigericin implies the continuous maintenance of an outside-to-inside potassium concentration gradient by nonmitochondrial calcium stores in RINm5F cells. This feature will be of potential interest in the identification of InsP3-sensitive calcium-storing organelles.

Ammonium Chloride↗
PubMed1998

Monte Carlo method to study the proton fluence for treatment planning.

The proton beam at the Hahn Meitner Institute (HMI) in Berlin will be used for proton therapy of eye melanoma in the near future. As part of the pre-therapeutic studies, Monte Carlo calculations have been performed to investigate the primary fluence distribution of the proton beam including the influence of scattering foils, range shifters, modulator wheels, and collimators. Any material in the beam path will modify the therapeutic beam because of energy loss, multiple scattering, range straggling, and nuclear reactions. The primary fluence information is a pre-requisite for most pencil-beam treatment planning algorithms. The measured beam penumbra has been used as one of the parameters to characterize a proton beam for further calculations in a treatment planning algorithm. However, this phenomenological quantity represents only indirect information about the properties of the proton beam. In this work, an alternative parameterization of the beam exiting the vacuum window of the accelerator, as well as the beam right in front of the patient collimator, is introduced. A beam is fully characterized if one knows (for instance from Monte Carlo simulations) the particle distribution in energy, position, and angle, i.e., the phase space distribution. Therefore, parameters derived from this distribution can provide an alternative input in treatment planning algorithms. In addition, the method of calculation is introduced as a tool to investigate the influence of modifications in the beam delivery system on the behavior of the therapeutic proton beam.

Algorithms↗
PubMed1979

Components and mechanism of action of ATP-driven proton pumps.

We have studied the composition of ATP-driven proton pumps from bovine heart mitochondria and have reconstituted the oligomycin-sensitive ATPase complex from its individual components. The complex contains 9 to 10 subunits of which 5 are assembled in the soluble F1 protein, 2 are required for the attachment of F1 to the membrane and 2 form the proton channel within the membrane. With the help of information obtained from studies of the chloroplast and the bacterial proton pumps, we can tentatively assign a function to each of the subunits of the pump. The position of F1 outside of the membrane seen in electron micrographs of negatively stained preparations, does not appear to be an artifact. Evidence from immunological studies, chemical derivatizations as well as further electron microscopy (positive staining and freeze-etching), support this statement. We describe in this paper a 28 000-dalton polypeptide which has been isolated from the mitochondria membrane and is required for the reconstitution of oligomycin-sensitive ATPase and 32Pi-ATP exchange activity. We propose a mechanism of action of the proton pump in which the key energy-yielding reaction is the binding of Mg2+ to the protein. The function of the proton gradient is to displace Mg2+ from this site to permit cyclic repetition of the binding process. Essential for this scheme is the cyclic opening and closing of the proton channel. We have outlined our present approaches to test this hypothesis.

Adenosine Triphosphatases↗
PubMed2001

Structures and proton-pumping strategies of mitochondrial respiratory enzymes.

Enzymes of the mitochondrial respiratory chain serve as proton pumps, using the energy made available from electron transfer reactions to transport protons across the inner mitochondrial membrane and create an electrochemical gradient used for the production of ATP. The ATP synthase enzyme is reversible and can also serve as a proton pump by coupling ATP hydrolysis to proton translocation. Each of the respiratory enzymes uses a different strategy for performing proton pumping. In this work, the strategies are described and the structural bases for the action of these proteins are discussed in light of recent crystal structures of several respiratory enzymes. The mechanisms and efficiency of proton translocation are also analyzed in terms of the thermodynamics of the substrate transformations catalyzed by these enzymes.

Animals↗
PubMed2003

Optimization of beam parameters and treatment planning for intensity modulated proton therapy.

One of the objectives of the ongoing research and development work at the Northeast Proton Therapy Center (NPTC) in Boston is to perform optimized intensity modulated proton therapy (IMPT) treatments. Such treatments may be delivered by magnetically scanning a narrow proton pencil beam across the target volume, while both the scanning speed and the intensity of the beam are modulated. Localization of the proton dose in space allows one to yield dose distributions that are highly conformal to the target volume, thus minimizing the dose delivered to the surrounding healthy tissue. The aim of the current research is to determine technically optimal and clinically relevant specifications for the scanned beam delivery system, which is being developed in collaboration with Ion Beam Applications (IBA); and to create a link between the treatment planning and the beam delivery. IMPT treatment planning is performed for patient cases treated at the NPTC, with KonRad Pro software developed at the German Cancer Research Center (DKFZ). For the IMPT delivery, the proton intensity maps, optimized for discrete pencil beam spots, need to be translated into continuous scanning patterns. At the same time it is necessary to minimize the discrepancy between the planned and delivered doses which may result from such conversion, as well as from the technical limitations of the delivery system. Possibilities have been investigated for improving the proton dose conformity by optimizing the beam and scanning nozzle parameters, and by taking the specifics and limitations of the system into account in the treatment planning stage.

Chordoma↗
PubMed2005

V-ATPase inhibition prevents recovery from anoxia in Artemia franciscana embryos: quiescence signaling through dissipation of proton gradients.

The metabolic downregulation critical for long-term survival of Artemia franciscana embryos under anoxia is mediated, in part, by a progressive intracellular acidification. However, very little is known about the mechanisms responsible for the pH transitions associated with exposure to, and recovery from, oxygen deprivation. In the present study, we demonstrate with 31P-NMR that incubation of intact embryos with the V-ATPase inhibitor bafilomycin A1 severely limits intracellular alkalinization during recovery from anoxia without affecting the restoration of cellular nucleotide triphosphate levels. Based on these data, it appears that oxidative phosphorylation and ATP resynthesis can only account for the first 0.3 pH unit alkalinization observed during aerobic recovery from the 1 pH unit acidification produced during 1 h of anoxia. The additional 0.7 pH unit increase requires proton pumping by the V-ATPase. Aerobic incubation with bafilomycin also suggests that V-ATPase inhibition alone is not enough to induce an acute dissipation of proton gradients under anoxia. In intact embryos, the dissipation of proton gradients and uncoupling of oxidative phosphorylation with carbonyl cyanide 3-chlorophenylhydrazone (CCCP) leads to an intracellular acidification similar to that seen after 1 h of anoxia. Subsequent exposure to anoxia, in the continued presence of CCCP, yields little additional acidification, suggesting that proton gradients are normally dissipated under anoxia. When combined with protons generated from net ATP hydrolysis, these data show that the dissipation of proton chemical gradients is sufficient to account for the reversible acidification associated with quiescence in these embryos.

Acid-Base Equilibrium↗
PubMed2004

Theoretical identification of proton channels in the quinol oxidase aa3 from Acidianus ambivalens.

Heme-copper oxidases are membrane proteins found in the respiratory chain of aerobic organisms. They are the terminal electron acceptors coupling the translocation of protons across the membrane with the reduction of oxygen to water. Because the catalytic process occurs in the heme cofactors positioned well inside the protein matrix, proton channels must exist. However, due to the high structural divergence among this kind of proteins, the proton channels previously described are not necessarily conserved. In this work we modeled the structure of the quinol oxidase from Acidianus ambivalens using comparative modeling techniques for identifying proton channels. Additionally, given the high importance that water molecules may have in this process, we have developed a methodology, within the context of comparative modeling, to identify high water probability zones and to deconvolute them into chains of ordered water molecules. From our results, and from the existent information from other proteins from the same superfamily, we were able to suggest three possible proton channels: one K-, one D-, and one Q-spatial homologous proton channels. This methodology can be applied to other systems where water molecules are important for their biological function.

Acidianus↗
PubMed2005

Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication.

Proton pump inhibitors have become one of the cornerstones in the treatment of Helicobacter pylori infection. Rabeprazole (Pariet) is a substituted benzimidazole proton pump inhibitor with potent gastric acid suppression properties. Its high acid-base dissociation constant allows activation over a broader pH range, resulting in quick, irreversible binding to the H+/K+-ATPase pump, and a more rapid onset of action compared with omeprazole, lansoprazole and pantoprazole. Unlike other proton pump inhibitors, the metabolism of rabeprazole is primarily via a nonenzymatic reduction to the thioether derivative, and the cytochrome P450 isoenzyme 2C19 is only partly involved in its metabolism. The effect of genetic polymorphism in cytochrome P450 isoenzyme 2C19 on the pharmacokinetics and pharmacodynamics of rabeprazole is therefore limited. In humans, once-daily dosing of 5-40 mg of rabeprazole inhibits gastric acid secretion in a dose-dependent manner. In vitro studies have shown that rabeprazole possesses more potent antibacterial properties against the growth of H. pylori than other proton pump inhibitors. Furthermore, its thioether derivative has more potent inhibitory in vitro activity against the growth and motility of clarithromycin-resistant H. pylori than other proton pump inhibitors or commonly used antimicrobials. Despite these inherent favorable characteristics of rabeprazole, randomized controlled trials have largely shown equivalence amongst proton pump inhibitors when used with two antibiotics in the eradication of H. pylori, with cure rates of 75-89% on an intent-to-treat basis. However, rabeprazole appears to consistently achieve such comparable eradication rates even when used at reduced doses (10 mg twice daily) as part of clarithromycin-based triple therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Comparative risk assessment of secondary cancer incidence after treatment of Hodgkin's disease with photon and proton radiation.

Probabilities for secondary cancer incidence have been estimated for a patient with Hodgkin's disease for whom treatment has been planned with different radiation modalities using photons and protons. The ICRP calculation scheme has been used to calculate cancer incidence from dose distributions. For this purpose, target volumes as well as critical structures have been outlined in the CT set of a patient with Hodgkin's disease. Dose distributions have been calculated using conventional as well as intensity-modulated treatment techniques using photon and proton radiation. The cancer incidence has been derived from the mean doses for each organ. The results of this work are: (a) Intensity-modulated treatment of Hodgkin's disease using nine photon fields (15 MV) results in nearly the same cancer incidence as treating with two opposed photon fields (6 MV). (b) Intensity-modulated treatment using nine proton fields (maximum energy 177.25 MeV) results in nearly the same cancer incidence as treating with one proton field (160 MeV). (c) Irradiation with protons using the spot scanning technique decreases the avoidable cancer incidence compared to photon treatment by a factor of about two. This result is independent of the number of beams used. Our work suggests that there are radiotherapy indications in which intensity-modulated treatments will result in little or no reduction of cancer incidence compared to conventional treatments. However, proton treatment can result in a lower cancer incidence than photon treatment.

Adult↗
PubMed2001

Clinical efficacy of proton pump inhibitor therapy in neurologically impaired children with gastroesophageal reflux: prospective study.

OBJECTIVE: To study the effects of proton pump inhibitors in reducing vomiting, gastrointestinal bleeding, and chest infections in institutionalised neurologically impaired children with gastroesophageal reflux. DESIGN: Prospective study. SETTING: A regional hospital, Hong Kong. PATIENTS: Neurologically impaired children with refractory gastroesophageal reflux. MAIN OUTCOME MEASURES: Episodes of vomiting, gastrointestinal bleeding, and pneumonia in the baseline and proton pump inhibitor treatment periods. RESULTS: Nine children received proton pump inhibitor therapy for a median duration of 81 days. Mean reflux index was 9.3% (standard deviation, 5%). Dosage of omeprazole used was 1.0-2.3 mg/kg/d. Vomiting was reduced significantly with proton pump inhibitor treatment (median vomiting index [baseline]=0.4, median vomiting index [proton pump inhibitors]=0.2; P<0.05). No significant decrease in gastrointestinal bleeding or chest infection was observed. CONCLUSION: Proton pump inhibitors significantly reduced vomiting episodes in neurologically impaired children with gastroesophageal reflux.

Child↗
PubMed2003

Laser and proton radiation to reduce uveal melanoma-associated exudative retinal detachments.

PURPOSE: To assess whether laser-induced hyperthermia in conjunction with proton irradiation of choroidal melanoma may more rapidly decrease exudative retinal detachments. DESIGN: Case-control study. METHODS: This was a single-center prospective phase 1 study of choroidal melanoma patients with exudative retinal detachments. These tumors did not overhang the optic disc, involve the fovea, or have greater than 40% involvement of the ciliary body. Patients were treated with laser-induced hyperthermia and proton radiation; results were compared with those of similar patients treated at the same institution with only proton radiation. Patients were followed up in an identical manner for loss of subretinal fluid, visual acuity change, and visual field alterations. RESULTS: All 11 patients treated with combined laser and proton therapy had resorption of subretinal fluid with a mean duration of retinal detachment of 193 days, compared with 263 days in the group treated with only proton therapy (P<.04). At 1 year, visual acuity was similar in both groups. CONCLUSIONS: Combined laser-induced hyperthermia and proton radiation may dissipate exudative detachments more rapidly than radiation alone.

Case-Control Studies↗
PubMed1989

Proton translocation by the F1F0ATPase of Escherichia coli. Mutagenic analysis of the a subunit.

Cassette site-directed mutagenesis was employed to generate mutations in the a subunit (uncB (a) gene) of F1F0ATP synthase. Using sequence homology with similar subunits of other F1F0ATP synthases as a guide, 20 mutations were targeted to a region of the a subunit thought to constitute part of the proton translocation mechanism. ATP-driven proton pumping activity is lost with the substitution of lys, ile, val, or glu for arginine 210. Substitution of val, leu, gln, or glu for asparagine 214 does not completely block proton conduction, however, replacement of asparagine 214 with histidine does reduce enzyme activity below that necessary for significant function. Two or three mutations were constructed in each of four nonpolar amino acids, leucine 207, leucine 211, alanine 217, and glycine 218. Certain specific mutations in these positions result in partial loss of F1F0ATP synthase activity, but only the substitution of arginine for alanine 217 reduces ATP-driven proton pumping activity to undetectable levels. It is concluded that of the six amino acids studied, only arginine 210 is an essential component of the proton translocation mechanism. Fractionation of cell-free extracts of a subunit mutation strains generally reveals normal amounts of F1 specifically bound to the particulate fraction. One possible exception is the arginine 210 to isoleucine mutation which results in somewhat elevated levels of free F1 detectable in the soluble fraction. For nearly all a subunit mutations, F1F0-mediated ATP hydrolysis activity remains sensitive to inhibition by dicyclohexylcarbodiimide in spite of the fact that the mutations block proton translocation.

Adenosine Triphosphate↗
PubMed1993

Isolation of a protein activator of the clathrin-coated vesicle proton pump.

An activator of the clathrin-coated vesicle proton translocating ATPase has been purified 1600-fold from bovine brain. The activator, which requires detergent (polyoxyethylene 9-lauryl ether) for release from clathrin-coated vesicles, is heat-stable, trypsin-sensitive, and has an apparent molecular mass of about 6 kDa as determined by high performance liquid chromatography. The activator stimulates the purified H(+)-ATPase of coated vesicles over 50-fold under acidic conditions. Similarly, the activator stimulates proton pumping catalyzed by the reconstituted proton pump. Importantly, this stimulation of proton pumping is observed only when the activator is reconstituted into the interior of the proteoliposomes. Moreover, the activator protein is demonstrated to protect, and co-sediment with, purified proton pump during glycerol gradient centrifugation performed in the presence of ATP. These observations support the notion that this activator serves to determine the pH set point of acidic endomembranes through interactions with the transmembranous sectors of the proton pump.

Animals↗