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• W2079447102 abstract "Proton pump (H+/K+–adenosine triphosphatase) inhibitors (PPIs) are widely used to treat patients with acid-related disorders because they are generally perceived to be safe and effective. However, as with any pharmacologic agent, they have the potential for side effects. Many studies have examined the side effects of long-term or short-term PPI exposure. We review the mechanism of action of PPIs, focusing on recently released products that might have greater risks of adverse effects than older products because of increased potency and/or duration of action. We summarize the data available on the putative adverse effects of PPI therapy and propose guidelines for clinicians who prescribe these agents to limit the potential for adverse outcomes in users of these effective therapeutic agents. Proton pump (H+/K+–adenosine triphosphatase) inhibitors (PPIs) are widely used to treat patients with acid-related disorders because they are generally perceived to be safe and effective. However, as with any pharmacologic agent, they have the potential for side effects. Many studies have examined the side effects of long-term or short-term PPI exposure. We review the mechanism of action of PPIs, focusing on recently released products that might have greater risks of adverse effects than older products because of increased potency and/or duration of action. We summarize the data available on the putative adverse effects of PPI therapy and propose guidelines for clinicians who prescribe these agents to limit the potential for adverse outcomes in users of these effective therapeutic agents. Podcast interview: www.gastro.org/gastropodcast. Podcast interview: www.gastro.org/gastropodcast. Proton pump (H+/K+–adenosine triphosphatase [ATPase]) inhibitors (PPIs) have been available in the United States as acid-suppressing agents since the mid-1980s.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar They are widely used (sales of PPIs are in excess of $10 billion per year1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 3Sandler R.S. Everhart J.E. Donowitz M. et al.The burden of selected digestive diseases in the United States.Gastroenterology. 2002; 122: 1500-1511Abstract Full Text Full Text PDF PubMed Google Scholar) because they are generally safe and effective; they have essentially replaced histamine H2-receptor antagonists (H2RAs) for most chronic indications because of these perceived advantages.2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 4Metz D.C. Inadomi J.M. Howden C.W. et al.On-demand therapy for gastroesophageal reflux disease.Am J Gastroenterol. 2007; 102: 642-653Crossref PubMed Scopus (69) Google Scholar However, as for other pharmacologic agents, they have the potential for side effects.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 5Nealis T.B. Howden C.W. Is there a dark side to long-term proton pump inhibitor therapy?.Am J Ther. 2008; 15: 536-542Crossref PubMed Scopus (0) Google Scholar, 6Raghunath A.S. O'Morain C. McLoughlin R.C. Review article: the long-term use of proton-pump inhibitors.Aliment Pharmacol Ther. 2005; 22: 55-63Crossref PubMed Google Scholar In general, when selecting any therapeutic strategy, physicians need to determine if the risks outweigh the gain.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 4Metz D.C. Inadomi J.M. Howden C.W. et al.On-demand therapy for gastroesophageal reflux disease.Am J Gastroenterol. 2007; 102: 642-653Crossref PubMed Scopus (69) Google Scholar, 5Nealis T.B. Howden C.W. Is there a dark side to long-term proton pump inhibitor therapy?.Am J Ther. 2008; 15: 536-542Crossref PubMed Scopus (0) Google Scholar Much research has evaluated the potential side effects of PPIs (Figure 1). Most of these putative effects are a direct consequence of inhibition of acid production by parietal cells (hypochlorhydria or reflex hypergastrinemia), but idiosyncratic effects, metabolic issues from interactions with hepatic cytochrome P450, immunosuppression, and other effects have been proposed.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 4Metz D.C. Inadomi J.M. Howden C.W. et al.On-demand therapy for gastroesophageal reflux disease.Am J Gastroenterol. 2007; 102: 642-653Crossref PubMed Scopus (69) Google Scholar, 7Jensen R.T. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas.Basic Clin Pharmacol Toxicol. 2006; 98: 4-19Crossref PubMed Scopus (120) Google Scholar The potential for side effects from use of PPIs is an important issue not only because these drugs are used so frequently but also because newer agents, with longer serum half-lives and potentially greater inhibition of acid output, are now available.8Galmiche J.P. Bruley Des Varannes S. Ducrotte P. et al.Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers.Aliment Pharmacol Ther. 2004; 19: 655-662Crossref PubMed Scopus (0) Google Scholar, 9Hunt R.H. Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in 2005.Aliment Pharmacol Ther. 2005; 22: 10-19Crossref PubMed Google Scholar, 10Hunt R.H. Armstrong D. James C. et al.Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers.Am J Gastroenterol. 2005; 100: 1949-1956Crossref PubMed Scopus (76) Google Scholar, 11Hunt R.H. Armstrong D. Yaghoobi M. et al.Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z.Aliment Pharmacol Ther. 2008; 28: 187-199Crossref PubMed Scopus (47) Google Scholar, 12Katz P.O. Scheiman J.M. Barkun A.N. Review article: acid-related disease—what are the unmet clinical needs?.Aliment Pharmacol Ther. 2006; 23: 9-22Crossref PubMed Scopus (57) Google Scholar, 13Metz D.C. Vakily M. Dixit T. et al.Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.Aliment Pharmacol Ther. 2009; 29: 928-937Crossref PubMed Scopus (96) Google Scholar, 14Peura D.A. Metz D.C. Dabholkar A.H. et al.Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience.Aliment Pharmacol Ther. 2009; 30: 1010-1021Crossref PubMed Scopus (26) Google Scholar, 15Scarpignato C. Pelosini I. Review article: the opportunities and benefits of extended acid suppression.Aliment Pharmacol Ther. 2006; 23: 23-34Crossref PubMed Scopus (0) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar We review the mechanism of action of PPIs, with specific attention to potential differences in recently released products (stereotypic isomers and drugs with longer serum half-lives) and recent data on side effects. We also summarize a risk-benefit approach that can be used to determine which patients should receive PPIs; we recommend ways to minimize the potential for adverse effects among users of these effective therapeutic agents. PPIs are prodrugs; they require activation by parietal cells in the presence of gastric acid, which leads to formation of an active sulfenamide moiety. This moiety binds irreversibly to the hydrogen potassium ATPase on the secretory canaliculus of actively secreting parietal cells, which inhibits the ability of cells to produce hydrochloric acid.2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 4Metz D.C. Inadomi J.M. Howden C.W. et al.On-demand therapy for gastroesophageal reflux disease.Am J Gastroenterol. 2007; 102: 642-653Crossref PubMed Scopus (69) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar, 18Sachs G. Shin J.M. Howden C.W. Review article: the clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther. 2006; 23: 2-8Crossref PubMed Scopus (275) Google Scholar The prodrug is systemically absorbed or delivered directly into the bloodstream, resulting in a relatively short half-life in serum; during this time, it is distributed to the stomach and other organs.19Howden C.W. Metz D.C. Hunt B. et al.Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h.Aliment Pharmacol Ther. 2006; 23: 975-984Crossref PubMed Scopus (0) Google Scholar, 20Kovacs T.O.G. Lee C.Q. Chiu Y.L. et al.Intravenous and oral lansoprazole are equivalent in suppressing stimulated acid output in patient volunteers with erosive oesophagitis.Aliment Pharmacol Ther. 2004; 20: 883-889Crossref PubMed Scopus (0) Google Scholar, 21Lee R.D. Vakily M. Mulford D. et al.Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor—evidence for dosing flexibility.Aliment Pharmacol Ther. 2009; 29: 824-833Crossref PubMed Scopus (0) Google Scholar, 22Metz D.C. Devlin J.W. Vakily M. et al.Greater immediate gastric acid suppression with lansoprazole 30 mg administered as a 2-minute intravenous bolus injection versus a 30-minute infusion.Pharmacotherapy. 2008; 28: 301-307Crossref PubMed Scopus (0) Google Scholar, 23Metz D.C. Miner P.B. Heuman D.M. et al.Comparison of the effects of intravenously and orally administered esomeprazole on acid output in patients with symptoms of gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2005; 22: 813-821Crossref PubMed Scopus (0) Google Scholar In the stomach, the prodrug is activated by a 2-step process; it is first converted to its sulfenamide derivative and then protonated to form a benzimidazole, which binds irreversibly with the canalicular H+/K+-ATPase. Binding blocks the exchange of hydrogen (out) for potassium (in), which prevents the cell from producing acid.2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar Because all PPIs are weak bases with first-step dissociation constants that are within the acidic range (pKa1s range from 3.8 to 4.9, with rabeprazole having the highest pKa1), they concentrate in the parietal cell secretory canaliculus, where the pH is approximately 1.0.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar, 18Sachs G. Shin J.M. Howden C.W. Review article: the clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther. 2006; 23: 2-8Crossref PubMed Scopus (275) Google Scholar The second step in activation has a low pKa2 for all PPIs (approximately 1.0), which permits the formation of the benzimidazole moiety that binds to all available actively secreting pumps and inactivates them.2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar, 18Sachs G. Shin J.M. Howden C.W. Review article: the clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther. 2006; 23: 2-8Crossref PubMed Scopus (275) Google Scholar Other low pH spaces, such as the renal medulla or the resorptive surfaces of bone (with high densities of osteoclasts), do not seem to have a low enough pH to permit the second step of PPI activation.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 24Rzeszutek K. Sarraf F. Davies J.E. Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth.J Craniofac Surg. 2003; 14: 301-307Crossref PubMed Google Scholar, 25Tuukkanen J. Vaananen H.K. Omeprazole, a specific inhibitor of H+-K+-ATPase, inhibits bone resorption in vitro.Calcif Tissue Int. 1986; 38: 123-125Crossref PubMed Scopus (0) Google Scholar Elsewhere in the body PPIs follow first-order kinetics; blood levels of PPIs decrease as the drugs are metabolized in the liver (primarily by cytochrome P450 enzymes) and then excreted in the urine (primarily) or stool.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 4Metz D.C. Inadomi J.M. Howden C.W. et al.On-demand therapy for gastroesophageal reflux disease.Am J Gastroenterol. 2007; 102: 642-653Crossref PubMed Scopus (69) Google Scholar The proton pump consists of 2 transmembrane subunits: an α subunit with 10 transmembrane domains and a β subunit with a single transmembrane domain.4Metz D.C. Inadomi J.M. Howden C.W. et al.On-demand therapy for gastroesophageal reflux disease.Am J Gastroenterol. 2007; 102: 642-653Crossref PubMed Scopus (69) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar, 18Sachs G. Shin J.M. Howden C.W. Review article: the clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther. 2006; 23: 2-8Crossref PubMed Scopus (275) Google Scholar All PPIs bind to a cysteine located in transmembrane region 6 (cysteine [C] 813) of the α subunit, forming a covalent disulfide bond that keeps the pump in an open position, prevents the reuptake of potassium, and blocks the exchange of hydrogen for potassium.17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar, 18Sachs G. Shin J.M. Howden C.W. Review article: the clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther. 2006; 23: 2-8Crossref PubMed Scopus (275) Google Scholar PPIs also bind to other cysteines (eg, dexlansoprazole/lansoprazole and rabeprazole to C321, pantoprazole to C822, and esomeprazole/omeprazole, dexlansoprazole/lansoprazole, and rabeprazole to C892), but these interactions do not appear to provide any additional inhibition beyond the activity at C813 alone.16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar Even high, once-daily doses of PPIs are believed to only inhibit about 75% of the proton pumps of each parietal cell, because even a maximally stimulated secretory canalicular surface cannot expand sufficiently to accommodate and activate all intracellular pumps.16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 17Sachs G. Shin J.M. Briving C. et al.The pharmacology of the gastric acid pump: the H+,K+ ATPase.Annu Rev Pharmacol Toxicol. 1995; 35: 277-305Crossref PubMed Google Scholar, 18Sachs G. Shin J.M. Howden C.W. Review article: the clinical pharmacology of proton pump inhibitors.Aliment Pharmacol Ther. 2006; 23: 2-8Crossref PubMed Scopus (275) Google Scholar Therefore, once blood levels have decreased below the threshold required to permit delivery of additional prodrug to the secretory canalicular space, activation of residual intracellular pumps by subsequent meals could restore acid secretion.13Metz D.C. Vakily M. Dixit T. et al.Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.Aliment Pharmacol Ther. 2009; 29: 928-937Crossref PubMed Scopus (96) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar Pharmacodynamic crossover studies have shown that acid inhibition (after appropriate administration in fasting patients 30–60 minutes before breakfast) ranges from 10.1 hours for pantoprazole 40 mg to 14.1 hours for esomeprazole 40 mg (the durations of action of lansoprazole 30 mg, rabeprazole 20 mg, and omeprazole 20 mg are within this range).16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar, 26Miner Jr, P. Katz P.O. Chen Y. et al.Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study.Am J Gastroenterol. 2003; 98: 2616-2620Crossref PubMed Scopus (393) Google Scholar Equivalent dose ranges of esomeprazole and omeprazole were not compared in these studies, although other studies indicated that the purified enantiomer esomeprazole has a slightly longer serum half-life than an equivalent dose of its racemic cousin omeprazole.2Shi S. Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics.Eur J Clin Pharmacol. 2008; 64: 935-951Crossref PubMed Scopus (276) Google Scholar, 16Shin J.M. Sachs G. Pharmacology of proton pump inhibitors.Curr Gastroenterol Rep. 2008; 10: 528-534Crossref PubMed Scopus (297) Google Scholar As a consequence of reduced acid output from long-term PPI therapy, the increased basal gastric pH inhibits somatostatin release from D cells in the gastric antrum, leading to unimpeded gastrin release from G cells and increased serum levels of gastrin at rest.1Metz D. Proton pump inhibitor therapy: safety issues.in: Howden C.W. Advances in digestive disease. AGA Institute Press, Bethesda, MD2007: 3-14Google Scholar, 13Metz D.C. Vakily M. Dixit T. et al.Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.Aliment Pharmacol Ther. 2009; 29: 928-937Crossref PubMed Scopus (96) Google Scholar Studies with all the marketed PPIs revealed increased serum levels of gastrin with therapy, although they might not reach the abnormal range in all individuals (patients with Helicobacter pylori–associated gastritis tend to have greater gastrin responses following therapy with PPIs than uninfected individuals).5Nealis T.B. Howden C.W. Is there a dark side to long-term proton pump inhibitor therapy?.Am J Ther. 2008; 15: 536-542Crossref PubMed Scopus (0) Google Scholar, 6Raghunath A.S. O'Morain C. McLoughlin R.C. Review article: the long-term use of proton-pump inhibitors.Aliment Pharmacol Ther. 2005; 22: 55-63Crossref PubMed Google Scholar, 8Galmiche J.P. Bruley Des Varannes S. Ducrotte P. et al.Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers.Aliment Pharmacol Ther. 2004; 19: 655-662Crossref PubMed Scopus (0) Google Scholar, 10Hunt R.H. Armstrong D. James C. et al.Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers.Am J Gastroenterol. 2005; 100: 1949-1956Crossref PubMed Scopus (76) Google Scholar, 11Hunt R.H. Armstrong D. Yaghoobi M. et al.Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904-Z.Aliment Pharmacol Ther. 2008; 28: 187-199Crossref PubMed Scopus (47) Google Scholar, 14Peura D.A. Metz D.C. Dabholkar A.H. et al.Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience.Aliment Pharmacol Ther. 2009; 30: 1010-1021Crossref PubMed Scopus (26) Google Scholar, 27Hunfeld N.G.M. Geus W.P. Kuipers E.J. Systematic review: rebound acid hypersecretion after therapy with proton pump inhibitors.Aliment Pharmacol Ther. 2007; 25: 39-46Crossref PubMed Scopus (58) Google Scholar, 28Kuipers E.J. Lundell L. Klinkenberg-Knol E.C. et al.Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication.N Engl J Med. 1996; 334: 1018-1022Crossref PubMed Scopus (752) Google Scholar, 29Freston J.W. Hisada M. Peura D.A. et al.The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis.Aliment Pharmacol Ther. 2009; 29: 1249-1260Crossref PubMed Scopus (0) Google Scholar, 30Lamberts R. Brunner G. Solcia E. Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa.Digestion. 2001; 64: 205-213Crossref PubMed Scopus (84) Google Scholar As many as 30% of patients who take PPIs find their symptoms are inadequately controlled at certain times of the 24-hour cycle (primarily at night).31Fass R. Shapiro M. Dekel R. et al.Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease—where next?.Aliment Pharmacol Ther. 2005; 22: 79-94Crossref PubMed Scopus (350) Google Scholar This might result, in part, from poor timing of therapy in relation to meals, but other possibilities are that the patients do not really have acid-peptic disease or they metabolize a once-daily standard dose of PPI therapy too rapidly, which permits recovery of acid secretion.9Hunt R.H. Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in 2005.Aliment Pharmacol Ther. 2005; 22: 10-19Crossref PubMed Google Scholar, 12Katz P.O. Scheiman J.M. Barkun A.N. Review article: acid-related disease—what are the unmet clinical needs?.Aliment Pharmacol Ther. 2006; 23: 9-22Crossref PubMed Scopus (57) Google Scholar, 15Scarpignato C. Pelosini I. Review article: the opportunities and benefits of extended acid suppression.Aliment Pharmacol Ther. 2006; 23: 23-34Crossref PubMed Scopus (0) Google Scholar A number of approaches have been proposed to improve intragastric pH control with PPIs for patients who rapidly metabolize the drug: (1) increasing the once-daily dose, (2) increasing the dose frequency, (3) administering the PPI with ligands, such as gastrin derivatives that directly activate proton pumps and allow for better acid secretory inhibition, or (4) administering the drug with alkaline products to indirectly activate existing proton pumps (by stimulating the feedback inhibition arc).9Hunt R.H. Review article: the unmet needs in delayed-release proton-pump inhibitor therapy in 2005.Aliment Pharmacol Ther. 2005; 22: 10-19Crossref PubMed Google Scholar, 12Katz P.O. Scheiman J.M. Barkun A.N. Review article: acid-related disease—what are the unmet clinical needs?.Aliment Pharmacol Ther. 2006; 23: 9-22Crossref PubMed Scopus (57) Google Scholar, 13Metz D.C. Vakily M. Dixit T. et al.Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.Aliment Pharmacol Ther. 2009; 29: 928-937Crossref PubMed Scopus (96) Google Scholar, 15Scarpignato C. Pelosini I. Review article: the opportunities and benefits of extended acid suppression.Aliment Pharmacol Ther. 2006; 23: 23-34Crossref PubMed Scopus (0) Google Scholar The first 2 approaches have not been shown to be effective and the third approach has not made it beyond preclinical trials, but the fourth approach has resulted in an product that was approved by the US Food and Drug Administration (FDA): immediate-release omeprazole.32Conrad S.A. Gabrielli A. Margolis B. et al.Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients.Crit Care Med. 2005; 33: 760-765Crossref PubMed Scopus (132) Google Scholar Immediate-release omeprazole is believed to inhibit gastric acid production to a greater extent than standard omeprazole because it raises the gastric pH, which activates the pumps without the need for a meal to be administered after dosing.33Castell D. Bagin R. Goldlust B. et al.Comparison of the effects of immediate-release omeprazole powder for oral suspension and pantoprazole delayed-release tablets on nocturnal acid breakthrough in patients with symptomatic gastro-oesophageal reflux disease.Aliment Pharmacol Ther. 2005; 21: 1467-1474Crossref PubMed Scopus (0) Google Scholar, 34Howden C.W. Ballard E.D. Koch F.K. et al.Control of 24-hour intragastric acidity with morning dosing of immediate-release and delayed-release proton pump inhibitors in patients with GERD.J Clin Gastroenterol. 2009; 43: 323-326Crossref PubMed Scopus (0) Google Scholar Critics of this approach have suggested that any symptomatic benefit encountered with this agent arises because the drug is coadministered with an antacid that allows for initial control of symptoms before the drug is absorbed.35Howden C.W. Review article: immediate-release proton-pump inhibitor therapy—potential advantages.Aliment Pharmacol Ther. 2005; 22: 25-30Crossref PubMed Google Scholar No studies have determined whether immediate-release omeprazole actually stimulates gastrin release, which would support its dual activities as a proton pump activator and an inhibitor. Other approaches have recently been used to improve the pharmacodynamic profile of PPIs. The development of purified enantiomers of PPIs that potentially increase the area under the serum concentration curve allows prolonged delivery to the parietal cell and a better pharmacodynamic response (the first of these was esomeprazole, but dexlansoprazole is also available).10Hunt R.H. Armstrong D. James C. et al.Effect on intragastric pH of a PPI with a prolonged plasma half-life: comparison between tenatoprazole and esomeprazole on the duration of acid suppression in healthy male volunteers.Am J Gastroenterol. 2005; 100: 1949-1956Crossref PubMed Scopus (76) Google Scholar, 13Metz D.C. Vakily M. Dixit T. et al.Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy.Aliment Pharmacol Ther. 2009; 29: 928-937Crossref PubMed Scopus (96) Google Scholar, 14Peura D.A. Metz D.C. Dabholkar A.H. et al.Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience.Aliment Pharmacol Ther. 2009; 30: 1010-1021Crossref PubMed Scopus (26) Google Scholar, 21Lee R.D. Vakily M. Mulford D. et al.Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor—evidence for dosing flexibility.Aliment Pharmacol Ther. 2009; 29: 824-833Crossref PubMed Scopus (0) Google Scholar, 26Miner Jr, P. Katz P.O. Chen Y. et al.Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study.Am J Gastroenterol. 2003; 98: 2616-2620Crossref PubMed Scopus (393) Google Scholar, 36Jo" @default.
• W2079447102 created "2016-06-24" @default.
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• W2079447102 date "2010-10-01" @default.
• W2079447102 modified "2023-10-18" @default.
• W2079447102 title "Safety of Proton Pump Inhibitor Exposure" @default.
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