Safety of proton pump inhibitor exposure.

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.

[1]  S. Suissa,et al.  Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy , 2006, Canadian Medical Association Journal.

[2]  R. Valuck,et al.  A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. , 2004, Journal of clinical epidemiology.

[3]  K. Murray,et al.  Outcomes With Concurrent Use of Clopidogrel and Proton-Pump Inhibitors , 2010, Annals of Internal Medicine.

[4]  K. McColl,et al.  Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. , 1999, Gastroenterology.

[5]  A. C. V. van Grootheest,et al.  Proton pump inhibitor-induced acute interstitial nephritis. , 2007, British journal of clinical pharmacology.

[6]  D. Kiel,et al.  Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women. , 2008, The Journal of clinical endocrinology and metabolism.

[7]  H. Festen.  Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. , 1991, Scandinavian journal of gastroenterology. Supplement.

[8]  M. Wallander,et al.  Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. , 1999, American journal of epidemiology.

[9]  R. Heaney.  Factors influencing the measurement of bioavailability, taking calcium as a model. , 2001, The Journal of nutrition.

[10]  H. Sørensen,et al.  Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. , 2007, Gastroenterology.

[11]  D. Peura,et al.  Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience , 2009, Alimentary pharmacology & therapeutics.

[12]  J. Rossert.  Drug-induced acute interstitial nephritis. , 2001, Kidney international.

[13]  J. Hallas,et al.  Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. , 2007, Archives of internal medicine.

[14]  F. Sundler,et al.  Growth of the parathyroid glands in omeprazole-treated chickens. , 1994, Scandinavian journal of gastroenterology.

[15]  M. Wilcox,et al.  A case-control study of community-associated Clostridium difficile infection. , 2008, The Journal of antimicrobial chemotherapy.

[16]  D. Metz,et al.  On-Demand Therapy for Gastroesophageal Reflux Disease , 2007, The American Journal of Gastroenterology.

[17]  S. Cummings,et al.  Low serum vitamin B-12 levels are associated with increased hip bone loss in older women: a prospective study. , 2004, The Journal of clinical endocrinology and metabolism.

[18]  H. Larsson,et al.  Pharmacology and toxicology of omeprazole--with special reference to the effects on the gastric mucosa. , 1986, Scandinavian journal of gastroenterology. Supplement.

[19]  P. Vestergaard,et al.  Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture , 2006, Calcified Tissue International.

[20]  R. Shaker,et al.  The new proton pump inhibitor esomeprazole is effective as a maintenance therapy in GERD patients with healed erosive oesophagitis: a 6‐month, randomized, double‐blind, placebo‐controlled study of efficacy and safety , 2001, Alimentary pharmacology & therapeutics.

[21]  John K Marshall,et al.  Systematic Review of the Risk of Enteric Infection in Patients Taking Acid Suppression , 2007, The American Journal of Gastroenterology.

[22]  R. Recker.  Calcium absorption and achlorhydria. , 1985, The New England journal of medicine.

[23]  C. Scarpignato,et al.  Review article: the opportunities and benefits of extended acid suppression , 2006, Alimentary pharmacology & therapeutics.

[24]  P. Khazanie,et al.  Omeprazole Therapy Causes Malabsorption of Cyanocobalamin (Vitamin B12) , 1994, Annals of Internal Medicine.

[25]  G. Quamme.  Recent developments in intestinal magnesium absorption , 2008, Current opinion in gastroenterology.

[26]  Stewart,et al.  Iron absorption in patients with Zollinger–Ellison syndrome treated with long‐term gastric acid antisecretory therapy , 1998, Alimentary pharmacology & therapeutics.

[27]  F. Sundler,et al.  Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. , 1986, Gastroenterology.

[28]  Dominique Mottier,et al.  Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. , 2008, Journal of the American College of Cardiology.

[29]  J. Iwamoto,et al.  Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. , 2005, JAMA.

[30]  C. Ponticelli,et al.  Effect of gastric acid secretion on intestinal phosphate and calcium absorption in normal subjects. , 1995, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[31]  E. Champagne.  Low gastric hydrochloric acid secretion and mineral bioavailability. , 1989, Advances in experimental medicine and biology.

[32]  M Antonsson,et al.  Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[33]  C. Seva,et al.  Growth-promoting effects of glycine-extended progastrin. , 1994, Science.

[34]  R. Eastell,et al.  Risk of fractures in patients with pernicious anemia , 1992, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  M. Clementi,et al.  The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study , 2005, Alimentary pharmacology & therapeutics.

[36]  C. Howden,et al.  Is There a Dark Side to Long-term Proton Pump Inhibitor Therapy? , 2008, American journal of therapeutics.

[37]  J. Freston,et al.  The clinical safety of long‐term lansoprazole for the maintenance of healed erosive oesophagitis , 2009, Alimentary pharmacology & therapeutics.

[38]  E. Antman,et al.  ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use , 2008, The American Journal of Gastroenterology.

[39]  J. Wandall,et al.  Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. , 1992, Gut.

[40]  R. Bagin,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 , 2005, Critical care medicine.

[41]  L. Lix,et al.  Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. , 2010, Gastroenterology.

[42]  E. Kuipers,et al.  Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. , 1996, The New England journal of medicine.

[43]  M. Broeren,et al.  Hypomagnesemia induced by several proton-pump inhibitors. , 2009, Annals of internal medicine.

[44]  G. Sachs,et al.  Pharmacology of proton pump inhibitors , 2008, Current gastroenterology reports.

[45]  E. Aadland,et al.  The effect of omeprazole on gastric acidity and the absorption of liver cobalamins. , 1987, Scandinavian journal of gastroenterology.

[46]  D. Metz,et al.  Hip fracture risk in patients with a diagnosis of pernicious anemia. , 2010, Gastroenterology.

[47]  J. Powell,et al.  Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis , 2007, Gut.

[48]  J. Davies,et al.  Proton Pump Inhibitors Control Osteoclastic Resorption of Calcium Phosphate Implants and Stimulate Increased Local Reparative Bone Growth , 2003, The Journal of craniofacial surgery.

[49]  D. Kiel,et al.  Low Plasma Vitamin B12 Is Associated With Lower BMD: The Framingham Osteoporosis Study , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[50]  P. Manley,et al.  Proton pump inhibitors and acute interstitial nephritis: Report and analysis of 15 cases , 2006, Nephrology.

[51]  C. Donskey,et al.  Examination of Potential Mechanisms To Explain the Association between Proton Pump Inhibitors and Clostridium difficile Infection , 2009, Antimicrobial Agents and Chemotherapy.

[52]  J. Nelson,et al.  Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population‐based case‐control study , 2010, Pharmacoepidemiology and drug safety.

[53]  B. Källén.  Use of omeprazole during pregnancy--no hazard demonstrated in 955 infants exposed during pregnancy. , 2001, European journal of obstetrics, gynecology, and reproductive biology.

[54]  S. Meuwissen,et al.  Effect of short‐ and long‐term treatment with omeprazole on the absorption and serum levels of cobalamin , 1996, Alimentary pharmacology & therapeutics.

[55]  J. Ferrières,et al.  Genetic determinants of response to clopidogrel and cardiovascular events. , 2009, The New England journal of medicine.

[56]  S. Watson,et al.  Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis. , 2001, Cancer research.

[57]  J. Mackay,et al.  Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. , 2010, QJM : monthly journal of the Association of Physicians.

[58]  E. Solcia,et al.  Effects of Very Long (up to 10 Years) Proton Pump Blockade on Human Gastric Mucosa , 2009, Digestion.

[59]  C. Ponticelli,et al.  Calcium and Phosphate Plasma Levels in Dialysis Patients after Dietary Ca-P Overload , 2002, Nephron.

[60]  R. Hunt,et al.  Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904‐Z , 2008, Alimentary pharmacology & therapeutics.

[61]  E. Haddad,et al.  Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family , 2002, Nature Genetics.

[62]  C. Townsend,et al.  Roles of gastrointestinal hormones in pancreatic cancer. , 2000, Journal of hepato-biliary-pancreatic surgery.

[63]  J. Dent,et al.  Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. , 2000, Gastroenterology.

[64]  R. Russell,et al.  Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. , 1994, Journal of the American College of Nutrition.

[65]  T. Cundy,et al.  Severe hypomagnesaemia in long‐term users of proton‐pump inhibitors , 2008, Clinical endocrinology.

[66]  D. Kiel,et al.  Homocysteine as a predictive factor for hip fracture in older persons. , 2004, The New England journal of medicine.

[67]  F. Sundler,et al.  Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation , 1986 .

[68]  G. Sachs,et al.  The pharmacology of the gastric acid pump: the H+,K+ ATPase. , 1995, Annual review of pharmacology and toxicology.

[69]  G. Koren,et al.  The safety of omeprazole during pregnancy: a multicenter prospective controlled study. , 1998, American journal of obstetrics and gynecology.

[70]  M. Vela,et al.  Systematic review: proton pump inhibitor‐associated acute interstitial nephritis , 2007, Alimentary pharmacology & therapeutics.

[71]  Peter C. Austin,et al.  A population-based study of the drug interaction between proton pump inhibitors and clopidogrel , 2009, Canadian Medical Association Journal.

[72]  R. Sampliner,et al.  Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. , 2001, JAMA.

[73]  Yu-Xiao Yang,et al.  Long-term proton pump inhibitor therapy and risk of hip fracture. , 2006, JAMA.

[74]  C. O'Morain,et al.  Review article: the long‐term use of proton‐pump inhibitors , 2005, Alimentary pharmacology & therapeutics.

[75]  R. Håkanson,et al.  Chicken Parathyroid Hormone Gene Expression in Response to Gastrin, Omeprazole, Ergocalciferol, and Restricted Food Intake , 1997, Calcified Tissue International.

[76]  R. Hunt,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 , 2005, The American Journal of Gastroenterology.

[77]  S. Shi,et al.  Proton pump inhibitors: an update of their clinical use and pharmacokinetics , 2008, European Journal of Clinical Pharmacology.

[78]  A. Kang,et al.  A collagen defect in homocystinuria. , 1973, The Journal of clinical investigation.

[79]  D. Mulford,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 , 2009, Alimentary pharmacology & therapeutics.

[80]  E. Alexopoulos.  Drug-induced acute interstitial nephritis. , 1998, Renal failure.

[81]  B. Hunt,et al.  Dose–response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h , 2006, Alimentary pharmacology & therapeutics.

[82]  D. Metz,et al.  Comparison of the effects of intravenously and orally administered esomeprazole on acid output in patients with symptoms of gastro‐oesophageal reflux disease , 2005, Alimentary Pharmacology and Therapeutics.

[83]  R. Jensen,et al.  Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. , 1998, The American journal of medicine.

[84]  Y. Lien,et al.  Acute interstitial nephritis due to omeprazole. , 1992, The American journal of medicine.

[85]  S. McGrath,et al.  Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. , 2006, The New England journal of medicine.

[86]  E. Antman,et al.  Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials , 2009, The Lancet.

[87]  F. Rodríguez‐Artalejo,et al.  Gastroesophageal Reflux Symptoms During and After Pregnancy: A Longitudinal Study , 2007, The American Journal of Gastroenterology.

[88]  C. Christiansen,et al.  Regulation of vitamin D and calcium metabolism after gastrectomy. , 1985, Gut.

[89]  R. Dhonukshe-Rutten,et al.  Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. , 2003, The Journal of nutrition.

[90]  R. Dowling,et al.  Drug‐induced hypochlorhydria causes high duodenal bacterial counts in the elderly , 1998, Alimentary pharmacology & therapeutics.

[91]  R. Russell,et al.  Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. , 1991, Gastroenterology.

[92]  L. Lix,et al.  Use of proton pump inhibitors and risk of osteoporosis-related fractures , 2008, Canadian Medical Association Journal.

[93]  A. Thulstrup,et al.  The safety of proton pump inhibitors in pregnancy , 1999, Alimentary pharmacology & therapeutics.

[94]  Yusong Chen,et al.  Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study , 2003, American Journal of Gastroenterology.

[95]  F. Islami,et al.  Use of Proton Pump Inhibitors and Risk of Progression of Barrett's Esophagus to Neoplastic Lesions , 2009, The American Journal of Gastroenterology.

[96]  S. Hennessy,et al.  Proton-Pump Inhibitor Use and the Risk for Community-Acquired Pneumonia , 2008, Annals of Internal Medicine.

[97]  A Taccoen,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 , 2004, Alimentary pharmacology & therapeutics.

[98]  E. Kuipers,et al.  Systematic review: rebound acid hypersecretion after therapy with proton pump inhibitors , 2006, Alimentary pharmacology & therapeutics.

[99]  J. Tuukkanen,et al.  Omeprazole, a specific inhibitor of H+−K+-ATPase, inhibits bone resorptionin vitro , 1986, Calcified Tissue International.

[100]  K. Abe,et al.  Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans , 1993, Calcified Tissue International.

[101]  K. Lau,et al.  Cobalamin and osteoblast-specific proteins. , 1988, The New England journal of medicine.

[102]  Miyake Akira,et al.  Characterization of cloned human cholecystokinin-B receptor as a gastrin receptor , 1994 .

[103]  R. Jensen,et al.  Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. , 2006, Basic & clinical pharmacology & toxicology.

[104]  R. Fass,et al.  Systematic review: proton‐pump inhibitor failure in gastro‐oesophageal reflux disease – where next? , 2005, Alimentary pharmacology & therapeutics.

[105]  D. Johnson,et al.  Esomeprazole once daily for 6 months is effective therapy for maintaining healed erosive esophagitis and for controlling gastroesophageal reflux disease symptoms: a randomized, double-blind, placebo-controlled study of efficacy and safety , 2001, American Journal of Gastroenterology.

[106]  W. Swaim,et al.  Impaired assimilation of egg Co 57 vitamin B 12 in patients with hypochlorhydria and achlorhydria and after gastric resection. , 1973, Gastroenterology.

[107]  P. Toskes,et al.  Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12 , 1979, Digestive Diseases and Sciences.

[108]  H. Jick,et al.  Proton Pump Inhibitor Use and Risk of Hip Fractures in Patients without Major Risk Factors , 2008, Pharmacotherapy.

[109]  H. Morris,et al.  Calcium and osteoporosis. , 1997, Annales chirurgiae et gynaecologiae.

[110]  A. Murray,et al.  Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. , 2005, The American journal of medicine.

[111]  R. Wood,et al.  Hypochlorhydria from short-term omeprazole treatment does not inhibit intestinal absorption of calcium, phosphorus, magnesium or zinc from food in humans. , 1995, Journal of the American College of Nutrition.

[112]  R. Bagin,et al.  Control of 24-hour Intragastric Acidity With Morning Dosing of Immediate-release and Delayed-release Proton Pump Inhibitors in Patients With GERD , 2009, Journal of clinical gastroenterology.

[113]  Marie M. Ahlström,et al.  Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[114]  G. Sachs,et al.  Review article: the clinical pharmacology of proton pump inhibitors , 2006, Alimentary pharmacology & therapeutics.

[115]  D. Metz,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 , 2009, Alimentary pharmacology & therapeutics.

[116]  L. Grimelius,et al.  The parathyroid glands in experimentally induced hypergastrinemia in the rat. , 1977, Scandinavian journal of gastroenterology.

[117]  J. Achard,et al.  Inhibition of gastric secretion by omeprazole and efficiency of calcium carbonate on the control of hyperphosphatemia in patients on chronic hemodialysis. , 1998, Artificial organs.

[118]  G. Friedman,et al.  Gastrin and colorectal cancer: a prospective study. , 1998, Gastroenterology.

[119]  R. Bagin,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 , 2005, Alimentary pharmacology & therapeutics.

[120]  Clifford Goodman,et al.  The burden of selected digestive diseases in the United States. , 2002, Gastroenterology.

[121]  A. Hofman,et al.  Homocysteine levels and the risk of osteoporotic fracture. , 2004, The New England journal of medicine.

[122]  Miriam C J M Sturkenboom,et al.  Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. , 2004, JAMA.

[123]  R. Hunt,et al.  Review article: the unmet needs in delayed‐release proton‐pump inhibitor therapy in 2005 , 2005, Alimentary pharmacology & therapeutics.

[124]  Y. Chiu,et al.  Intravenous and oral lansoprazole are equivalent in suppressing stimulated acid output in patient volunteers with erosive oesophagitis , 2004, Alimentary pharmacology & therapeutics.

[125]  H. Blom,et al.  Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. , 1996, Biochimica et biophysica acta.

[126]  C. Reimer,et al.  Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. , 2009, Gastroenterology.

[127]  L. Schiller,et al.  Gastrointestinal absorption of calcium from milk and calcium salts. , 1987, The New England journal of medicine.

[128]  A. Barkun,et al.  Review article: acid‐related disease – what are the unmet clinical needs? , 2006, Alimentary pharmacology & therapeutics.

[129]  A. Barkun,et al.  Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. , 2005, JAMA.

[130]  A. Bhattacharyya,et al.  Medication usage and the risk of neoplasia in patients with Barrett's esophagus. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[131]  C. Howden,et al.  Review article: immediate‐release proton‐pump inhibitor therapy – potential advantages , 2005, Alimentary pharmacology & therapeutics.

[132]  G. Koren,et al.  Use of Proton Pump Inhibitors During Pregnancy and Rates of Major Malformations: A Meta-Analysis , 2002, Digestive Diseases and Sciences.

[133]  W. Bezwoda,et al.  The importance of gastric hydrochloric acid in the absorption of nonheme food iron. , 1978, The Journal of laboratory and clinical medicine.

[134]  P Michael Ho,et al.  Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. , 2009, JAMA.

[135]  J. Lewis,et al.  Chronic proton pump inhibitor therapy and the risk of colorectal cancer. , 2007, Gastroenterology.

[136]  E. Kuipers,et al.  Proton Pump Inhibitors and the Risk of Colorectal Cancer , 2008, The American Journal of Gastroenterology.

[137]  O. Chonan,et al.  Effect of L-lactic acid on calcium absorption in rats fed omeprazole. , 1998, Journal of nutritional science and vitaminology.

[138]  I. Zagon,et al.  The Functional Significance of the Cholecystokinin-C (CCK-C) Receptor in Human Pancreatic Cancer , 2004, Pancreas.

[139]  K. McColl,et al.  Helicobacter pylori eradication releases prolonged increased acid secretion following omeprazole treatment. , 2004, Gastroenterology.

[140]  C. Rich,et al.  The absorption of calcium carbonate. , 1967, Annals of internal medicine.

[141]  A. Blum,et al.  Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. , 1996, Gut.

[142]  E. Björnsson,et al.  Dyspeptic Symptom Development After Discontinuation of a Proton Pump Inhibitor: A Double-Blind Placebo-Controlled Trial , 2010, The American Journal of Gastroenterology.

[143]  Dutta Sk.  Vitamin B12 malabsorption and omeprazole therapy. , 1994 .

[144]  S. le Cessie,et al.  Long‐term use of proton pump inhibitors and vitamin B12 status in elderly individuals , 2008, Alimentary pharmacology & therapeutics.

[145]  E. Lamb,et al.  Omeprazole and refractory hypomagnesaemia , 2008, BMJ : British Medical Journal.

[146]  S. Watson,et al.  Coexpression of gastrin and gastrin receptors (CCK-B and ΔCCK-B) in gastrointestinal tumour cell lines , 1998, Gut.

[147]  C. Boland,et al.  Post-translational processing of gastrin in neoplastic human colonic tissues. , 1992, Biochemical and biophysical research communications.