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Drug therapies for reducing gastric acidity in people with cystic fibrosis.
Ng, SM, Moore, HS
The Cochrane database of systematic reviews. 2021;(4):CD003424
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Abstract
BACKGROUND Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review. OBJECTIVES To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic and non-electronic database searches, handsearches of relevant journals, abstract books and conference proceedings. Both authors double checked the reference lists of the searches Most recent search of the Group's Trials Register: 26 April 2021. On the 26 April 2021 further searches were conducted on the clinicaltrials.gov register to identify any ongoing trials that may be of relevance. The WHO ICTRP database was last searched in 2020 and is not currently available for searching due to the Covid-19 pandemic. SELECTION CRITERIA All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS The searches identified 40 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The included trials were generally not reported adequately enough to allow judgements on risk of bias. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.
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[Different Membrane Environments Generate Multiple Functions of P-type Ion Pumps].
Fujii, T
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2021;(11):1217-1222
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P-type ion pumps (P-type ATPases) are involved in various fundamental biological processes. For example, the gastric proton pump (H+,K+-ATPase) and sodium pump (Na+,K+-ATPase) are responsible for secretion of gastric acid and maintenance of cell membrane potential, respectively. In this review, we summarize three topics of our studies. The first topic is gastric H+,K+-ATPase associated with Cl--transporting proteins (Cl-/H+ exchanger ClC-5 and K+-Cl- cotransporter KCC4). In gastric parietal cells, we found that ClC-5 is predominantly expressed in intracellular tubulovesicles and that KCC4 is predominantly expressed in the apical membrane. Gastric acid (HCl) secretion may be accomplished by the two different complexes of H+,K+-ATPase and Cl--transporting protein. The second topic focuses on the Na+,K+-ATPase α1-isoform (α1NaK) associated with the volume-regulated anion channel (VRAC). In the cholesterol-enriched membrane microdomains of human cancer cells, we found that α1NaK has a receptor-like (non-pumping) function and that binding of low concentrations (nM level) of cardiac glycosides to α1NaK activates VRAC and exerts anti-cancer effects without affecting the pumping function of α1NaK. The third topic is the Na+,K+-ATPase α3-isoform (α3NaK) in human cancer cells. We found that α3NaK is abnormally expressed in the intracellular vesicles of attached cancer cells and that the plasma membrane translocation of α3NaK upon cell detachment contributes to the survival of metastatic cancer cells. Our results indicate that multiple functions of P-type ion pumps are generated by different membrane environments and their associated proteins.
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Pharmacological Approach to Gastric Acid Suppression: Past, Present, and Future.
Herszényi, L, Bakucz, T, Barabás, L, Tulassay, Z
Digestive diseases (Basel, Switzerland). 2020;(2):104-111
Abstract
Less than 2 centuries have elapsed since the identification of hydrochloric acid in the stomach. The clarification of the molecular mechanisms allowed the effective therapeutic suppression of gastric acid secretion. The spectacular advances in the treatment of acid-related disorders represent a synthesis of the contributions of several brilliant pharmacologists, basic scientists, and clinical physicians. Effective gastric acid suppressive therapy has dramatically improved the therapy and outcome of acid-related disorders. The introduction of proton pump inhibitors (PPIs) in clinical practice has significantly changed the medical management of upper gastrointestinal disorders. PPIs represent the "gold-standard" therapy in acid-related disorders. However, some challenges persist in the therapy of acid related diseases, including management of patients who respond inadequately to PPI therapy, more effective gastroprotection, or more powerful antisecretory treatment for the eradication of Helicobacter pylori infection. New antisecretory drugs are currently being developed and investigated to further provide a more effective and profound gastric acid secretion inhibition. The major advance has been the development of acid pump -antagonists, the potassium channel acid blocking drugs (-P-CABs). Long-term studies comparing P-CABs with PPIs will help to define the exact place and safety profile of this class of drug in the management of acid-related disorders.
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Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.
Surofchy, DD, Frassetto, LA, Benet, LZ
Pharmaceutical research. 2019;(11):155
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PURPOSE The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION https://clinicaltrials.gov/ct2/show/NCT02758015.
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The Gastric and Intestinal Microbiome: Role of Proton Pump Inhibitors.
Minalyan, A, Gabrielyan, L, Scott, D, Jacobs, J, Pisegna, JR
Current gastroenterology reports. 2017;(8):42
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PURPOSE OF REVIEW The discovery of Helicobacter pylori and other organisms colonizing the stomach and the intestines has shed some light on the importance of microbiome in maintaining overall health and developing pathological conditions when alterations in biodiversity are present. The gastric acidity plays a crucial role in filtering out bacteria and preventing development of enteric infections. In this article, we discuss the physiology of gastric acid secretion and bacterial contribution to the composition of gastric and intestinal barriers and review the current literature on the role of proton pump inhibitors (PPIs) in the microbial biodiversity of the gastrointestinal tract. RECENT FINDINGS Culture-independent techniques, such as 16S rRNA sequencing, have revolutionized our understanding of the microbial biodiversity in the gastrointestinal tract. Luminal and mucosa-associated microbial populations are not identical. Streptococcus is overrepresented in the biopsies of patients with antral gastritis and may also be responsible for the development of peptic ulcer disease. The use of PPIs favors relative streptococcal abundance irrespective of H. pylori status and may explain the persistence of dyspeptic symptoms in patients on PPI therapy. Increased risk of enteric infections has also been seen in patients taking PPIs. The overuse of PPIs leads to significant shift of the gastrointestinal microbiome towards a less healthy state. With the advent of PPIs, many studies have demonstrated the significant changes in the microbial composition of both gastric and intestinal microbiota. Although they are considered relatively safe over-the-counter medications, PPIs in many cases are over- and even inappropriately used. Future studies assessing the safety of PPIs and their role in the development of microbiome changes should be encouraged.
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Drug therapies for reducing gastric acidity in people with cystic fibrosis.
Ng, SM, Moore, HS
The Cochrane database of systematic reviews. 2016;(8):CD003424
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Free full text
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Abstract
BACKGROUND Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review. OBJECTIVES To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 12 May 2016. SELECTION CRITERIA All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS The searches identified 39 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The included trials were generally not reported adequately enough to allow judgements on risk of bias.However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.
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Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects.
Kraft, WK, Chang, PS, van Iersel, ML, Waskin, H, Krishna, G, Kersemaekers, WM
Antimicrobial agents and chemotherapy. 2014;(7):4020-5
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Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a ≥ 10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87-1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility.
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Prostaglandin pathways in duodenal chemosensing.
Akiba, Y, Kaunitz, JD
Journal of gastroenterology and hepatology. 2014;(0 4):93-8
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Acid-sensing pathways, which trigger mucosal defense mechanisms in response to luminal acid, involve the rapid afferent-mediated "capsaicin pathway" and the sustained "prostaglandin (PG) pathway." Luminal acid quickly increases protective PG synthesis and release from epithelia, although the mechanism by which luminal acid induces PG synthesis is still mostly unknown. Acid exposure augments purinergic ATP-P2Y signaling by inhibition of intestinal alkaline phosphatase activity. Since P2Y activation increases intracellular Ca2+, we further hypothesized that ATP-P2Y signals increase the generation of H2O2 derived from dual oxidase, a member of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family activated by Ca2+. Our recent studies suggest that acid exposure increases H2O2 output, followed by phospholipase A2 and cyclooxygenase activation, increasing PG synthesis. Released prostaglandin E2 augments protective HCO3- and mucus secretion via EP4 receptor activation. Thus, the PG pathway as a component of duodenal acid sensing consists of acid-related intestinal alkaline phosphatase inhibition, ATP-P2Y signals, dual oxidase 2-derived H2O2 production, phospholipase A2 activation, prostaglandin E2 synthesis, and EP4 receptor activation. The PG pathway is also involved in luminal bacterial sensing in the duodenum via activation of pattern recognition receptors, including Toll-like receptors and nucleotide-binding oligomerization domain 2. The presence of acute mucosal responses to luminal bacteria suggests that the duodenum is important for host defenses and may reduce bacterial loading to the hindgut using H2O2, complementing gastric acidity and anti-bacterial bile acids.
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Review article: methods of measuring gastric acid secretion.
Ghosh, T, Lewis, DI, Axon, AT, Everett, SM
Alimentary pharmacology & therapeutics. 2011;(7):768-81
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BACKGROUND Gastric acid has an important pathophysiological role in human beings. Numerous methods have been evaluated over the years in an attempt to measure gastric acid and stomach acidity, to study the role of gastric acid in gastrointestinal diseases in humans and to evaluate the effects of acid suppressing drugs. AIM: To review methods that have been used to measure gastric acid and gastric acidity. METHODS Searches of the electronic databases PUBMED, MEDLINE and EMBASE, were performed with articles restricted to English language and human subjects. References were also identified from the bibliographies of selected articles. RESULTS Methods for measuring gastric acid include both invasive and non-invasive techniques. Invasive tests include the conventional gastric acid aspiration tests, gastric pH measurement techniques and endoscopic methods. Non-invasive methods use urinary analysis, breath analysis, serum pepsinogens assay, scintigraphic techniques, impedence tomography and alkaline tide for measurement of gastric acid. CONCLUSIONS Several methods of measuring gastric acid exist. Invasive tube tests are uncomfortable and time consuming, whereas most of the non-invasive methods are at best semiquantitative and useful in detecting low or absent acid secretion. Further attempts to explore new methods for measuring gastric acid are therefore warranted.
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Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial.
Wright, MJ, Sullivan, RR, Gaffney-Stomberg, E, Caseria, DM, O'Brien, KO, Proctor, DD, Simpson, CA, Kerstetter, JE, Insogna, KL
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;(10):2205-11
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Proton pump inhibitors (PPIs) are the most potent gastric acid suppressing drugs available, and their use is widespread. An emerging concern about chronic PPI therapy is whether these drugs impair intestinal calcium absorption, resulting in a negative calcium balance and thereby potentially causing bone loss. The objective of this study was to evaluate the acute effect of the PPI esomeprazole or placebo on intestinal calcium absorption in healthy adults. Twelve young adults participated in a placebo-controlled, double-blind, crossover study. There were two 3-week interventions that included a 14-day adjustment period (designed to stabilize calcium homeostasis) followed by 6 days of a diet containing 800 mg of calcium and 2.1 g/kg of protein (intervention). During the last 3 days of the adjustment period and throughout the intervention period, subjects consumed esomeprazole or placebo. Half the subjects underwent 24-hour continuous gastric acid pH monitoring. Intestinal calcium absorption was measured using dual-stable calcium isotopes at the end of each intervention. Treatment with esomprazole significantly increased gastric pH (mean pH on PPI 5.38 +/- 0.13, mean pH on placebo 2.70 +/- 0.44, p = .005). Neither calcium absorption (PPI 34.2% +/- 2.4%, placebo 31.5% +/- 2.1%, p = .24) nor urinary calcium (PPI 321 +/- 38 mg/34 hours, placebo 355 +/- 37 mg/34 hours, p = .07) differed between the PPI and placebo groups. It is concluded that short-term gastric acid suppression by PPIs does not attenuate intestinal calcium absorption in healthy young adults.