Advertisement

Digestive Diseases and Sciences

, Volume 56, Issue 4, pp 931–950 | Cite as

Adverse Effects of Long-Term Proton Pump Inhibitor Therapy

  • Edward Sheen
  • George Triadafilopoulos
Review

Abstract

Proton pump inhibitors have an excellent safety profile and have become one of the most commonly prescribed class of drugs in primary and specialty care. Long-term, sometimes lifetime, use is becoming increasingly common, often without appropriate indications. This paper is a detailed review of the current evidence on this important topic, focusing on the potential adverse effects of long-term proton pump inhibitor use that have generated the greatest concern: B12 deficiency; iron deficiency; hypomagnesemia; increased susceptibility to pneumonia, enteric infections, and fractures; hypergastrinemia and cancer; drug interactions; and birth defects. We explain the pathophysiological mechanisms that may underlie each of these relationships, review the existing evidence, and discuss implications for clinical management. The benefits of proton pump inhibitor use outweigh its risks in most patients. Elderly, malnourished, immune-compromised, chronically ill, and osteoporotic patients theoretically could be at increased risk from long-term therapy.

Keywords

Proton pump inhibitors Safety Adverse effects Malabsorption Fractures Infections Cancer Interactions 

References

  1. 1.
    Bamberg P, Caswell CM, Frame MH, Lam SK, Wong EC. A meta-analysis comparing the efficacy of omeprazole with H2-receptor antagonists for acute treatment of duodenal ulcer in Asian patients. J Gastroenterol Hepatol. 1992;7:577–585.PubMedGoogle Scholar
  2. 2.
    Eriksson S, Langstrom G, Rikner L, Carlsson R, Naesdal J. Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis. Eur J Gastroenterol Hepatol. 1995;7:467–475.PubMedGoogle Scholar
  3. 3.
    Gisbert JP, Gonzalez L, Calvet X, Roque M, Gabriel R, Pajares JM. Proton pump inhibitors versus H2-antagonists: a meta-analysis of their efficacy in treating bleeding peptic ulcer. Aliment Pharmacol Ther. 2001;15:917–926.PubMedGoogle Scholar
  4. 4.
    Gisbert JP, Khorrami S, Calvet X, Gabriel R, Carballo F, Pajares JM. Meta-analysis: proton pump inhibitors vs. H2-receptor antagonists–their efficacy with antibiotics in Helicobacter pylori eradication. Aliment Pharmacol Ther. 2003;18:757–766.PubMedGoogle Scholar
  5. 5.
    DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100:190–200.PubMedGoogle Scholar
  6. 6.
    Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104:728–738.PubMedGoogle Scholar
  7. 7.
    Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III consensus report. Gut. 2007;56:772–781.PubMedGoogle Scholar
  8. 8.
    Ali T, Roberts DN, Tierney WM. Long-term safety concerns with proton pump inhibitors. Am J Med. 2009;122:896–903.PubMedGoogle Scholar
  9. 9.
    Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep. 2010;12:448–457.PubMedGoogle Scholar
  10. 10.
    Metz D. Proton pump inhibitor therapy: safety issues. In: Howden CW, ed. Advances in digestive disease. Bethesda, MD: AGA Institute Press; 2007:3–14.Google Scholar
  11. 11.
    Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500–1511.PubMedGoogle Scholar
  12. 12.
    Festen HP. Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol Suppl. 1991;188:1–7.PubMedGoogle Scholar
  13. 13.
    Koop H. Review article: metabolic consequences of long-term inhibition of acid secretion by omeprazole. Aliment Pharmacol Ther. 1992;6:399–406.PubMedGoogle Scholar
  14. 14.
    Schenk BE, Festen HP, Kuipers EJ, Klinkenberg-Knol EC, Meuwissen SG. Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther. 1996;10:541–545.PubMedGoogle Scholar
  15. 15.
    Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998;104:422–430.PubMedGoogle Scholar
  16. 16.
    Dharmarajan TS, Kanagala MR, Murakonda P, Lebelt AS, Norkus EP. Do acid-lowering agents affect vitamin B12 status in older adults? J Am Med Dir Assoc. 2008;9:162–167.PubMedGoogle Scholar
  17. 17.
    Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422–428.PubMedGoogle Scholar
  18. 18.
    den Elzen WP, Groeneveld Y, de Ruijter W, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008;27:491–497.Google Scholar
  19. 19.
    Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2008;27:1110–1121.PubMedGoogle Scholar
  20. 20.
    Rozgony NR, Fang C, Kuczmarski MF, Bob H. Vitamin B(12) deficiency is linked with long-term use of proton pump inhibitors in institutionalized older adults: could a cyanocobalamin nasal spray be beneficial? J Nutr Elder. 2010;29:87–99.PubMedGoogle Scholar
  21. 21.
    Bellou A, Aimone-Gastin I, De Korwin JD, et al. Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy. J Intern Med. 1996;240:161–164.PubMedGoogle Scholar
  22. 22.
    Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol. 2000;30:29–33.PubMedGoogle Scholar
  23. 23.
    Champagne ET. Low gastric hydrochloric acid secretion and mineral bioavailability. Adv Exp Med Biol. 1989;249:173–184.PubMedGoogle Scholar
  24. 24.
    Conrad ME, Schade SG. Ascorbic acid chelates in iron absorption: a role for hydrochloric acid and bile. Gastroenterology. 1968;55:35–45.PubMedGoogle Scholar
  25. 25.
    Bezwoda W, Charlton R, Bothwell T, Torrance J, Mayet F. The importance of gastric hydrochloric acid in the absorption of nonheme food iron. J Lab Clin Med. 1978;92:108–116.PubMedGoogle Scholar
  26. 26.
    Golubov J, Flanagan P, Adams P. Inhibition of iron absorption by omeprazole in rat model. Dig Dis Sci. 1991;36:405–408.PubMedGoogle Scholar
  27. 27.
    Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J. 2004;97:887–889.PubMedGoogle Scholar
  28. 28.
    Skikne BS, Lynch SR, Cook JD. Role of gastric acid in food iron absorption. Gastroenterology. 1981;81:1068–1071.PubMedGoogle Scholar
  29. 29.
    Hutchinson C, Geissler CA, Powell JJ, Bomford A. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut. 2007;56:1291–1295.PubMedGoogle Scholar
  30. 30.
    McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol. 2009;104:S5–S9.PubMedGoogle Scholar
  31. 31.
    Broeren MA, Geerdink EA, Vader HL, l Bake AW. Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med. 2009;151:755–756.PubMedGoogle Scholar
  32. 32.
    Cundy T, Dissanayake A. Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf). 2008;69:338–341.Google Scholar
  33. 33.
    Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia. Curr Opin Gastroenterol. 2011;27:180–185.PubMedGoogle Scholar
  34. 34.
    Doornebal J, Bijlsma R, Brouwer RM. An unknown but potentially serious side effect of proton pump inhibitors: hypomagnesaemia. Ned Tijdschr Geneeskd. 2009;153:A711.PubMedGoogle Scholar
  35. 35.
    Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med. 2006;355:1834–1836.PubMedGoogle Scholar
  36. 36.
    Francois M, Levy-Bohbot N, Caron J, Durlach V. Chronic use of proton-pump inhibitors associated with giardiasis: a rare cause of hypomagnesemic hypoparathyroidism? Ann Endocrinol (Paris). 2008;69:446–448.Google Scholar
  37. 37.
    Hoorn EJ, van der Hoek J, de Man RA, Kuipers EJ, Bolwerk C, Zietse R. A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis. 2010;56:112–116.PubMedGoogle Scholar
  38. 38.
    Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors–a review. Neth J Med. 2009;67:169–172.PubMedGoogle Scholar
  39. 39.
    Mackay JD, Bladon PT. Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM. 2010;103:387–395.PubMedGoogle Scholar
  40. 40.
    Metz DC, Sostek MB, Ruszniewski P, Forsmark CE, Monyak J, Pisegna JR. Effects of esomeprazole on acid output in patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion. Am J Gastroenterol. 2007;102:2648–2654.PubMedGoogle Scholar
  41. 41.
    Regolisti G, Cabassi A, Parenti E, Maggiore U, Fiaccadori E. Severe hypomagnesemia during long-term treatment with a proton pump inhibitor. Am J Kidney Dis. 2010;56:168–174.PubMedGoogle Scholar
  42. 42.
    Shabajee N, Lamb EJ, Sturgess I, Sumathipala RW. Omeprazole and refractory hypomagnesaemia. BMJ. 2008;337:a425.PubMedGoogle Scholar
  43. 43.
    Quamme GA. Recent developments in intestinal magnesium absorption. Curr Opin Gastroenterol. 2008;24:230–235.PubMedGoogle Scholar
  44. 44.
    Li M, Jiang J, Yue L. Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol. 2006;127:525–537.PubMedGoogle Scholar
  45. 45.
    Mullin JM, Valenzano MC, Whitby M, et al. Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase. Aliment Pharmacol Ther. 2008;28:1317–1325.PubMedGoogle Scholar
  46. 46.
    Evenepoel P. Alteration in digestion and absorption of nutrients during profound acid suppression. Best Pract Res Clin Gastroenterol. 2001;15:539–551.PubMedGoogle Scholar
  47. 47.
    Sheikh MS, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med. 1987;317:532–536.PubMedGoogle Scholar
  48. 48.
    Carr CJ, Shangraw RF. Nutritional and pharmaceutical aspects of calcium supplementation. Am Pharm. 1987;NS27:49–50. (54–47).PubMedGoogle Scholar
  49. 49.
    Chonan O, Takahashi R, Yasui H, Watanuki M. Effect of L-lactic acid on the absorption of calcium in gastrectomized rats. J Nutr Sci Vitaminol (Tokyo). 1998;44:869–875.Google Scholar
  50. 50.
    Chonan O, Takahashi R, Yasui H, Watanuki M. Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol (Tokyo). 1998;44:473–481.Google Scholar
  51. 51.
    Nilas L, Christiansen C, Christiansen J. Regulation of vitamin D and calcium metabolism after gastrectomy. Gut. 1985;26:252–257.PubMedGoogle Scholar
  52. 52.
    Ivanovich P, Fellows H, Rich C. The absorption of calcium carbonate. Ann Intern Med. 1967;66:917–923.PubMedGoogle Scholar
  53. 53.
    Goerss JB, Kim CH, Atkinson EJ, Eastell R, O’Fallon WM, Melton LJ 3rd. Risk of fractures in patients with pernicious anemia. J Bone Miner Res. 1992;7:573–579.PubMedGoogle Scholar
  54. 54.
    Mizunashi K, Furukawa Y, Katano K, Abe K. Effect of omeprazole, an inhibitor of H + , K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int. 1993;53:21–25.PubMedGoogle Scholar
  55. 55.
    Tuukkanen J, Vaananen HK. Omeprazole, a specific inhibitor of H + -K + -ATPase, inhibits bone resorption in vitro. Calcif Tissue Int. 1986;38:123–125.PubMedGoogle Scholar
  56. 56.
    Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology. 2010;138:896–904.PubMedGoogle Scholar
  57. 57.
    Serfaty-Lacrosniere C, Wood RJ, Voytko D, et al. Hypochlorhydria from short-term omeprazole treatment does not inhibit intestinal absorption of calcium, phosphorus, magnesium or zinc from food in humans. J Am Coll Nutr. 1995;14:364–368.PubMedGoogle Scholar
  58. 58.
    O’Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ. Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med. 2005;118:778–781.PubMedGoogle Scholar
  59. 59.
    Bo-Linn GW, Davis GR, Buddrus DJ, Morawski SG, Santa Ana C, Fordtran JS. An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium. J Clin Invest. 1984;73:640–647.PubMedGoogle Scholar
  60. 60.
    Adachi Y, Shiota E, Matsumata T, Iso Y, Yoh R, Kitano S. Bone mineral density in patients taking H2-receptor antagonist. Calcif Tissue Int. 1998;62:283–285.PubMedGoogle Scholar
  61. 61.
    Taal MW, Masud T, Green D, Cassidy MJ. Risk factors for reduced bone density in haemodialysis patients. Nephrol Dial Transplant. 1999;14:1922–1928.PubMedGoogle Scholar
  62. 62.
    Yu EW, Blackwell T, Ensrud KE, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int. 2008;83:251–259.PubMedGoogle Scholar
  63. 63.
    Merriman NA, Putt ME, Metz DC, Yang YX. Hip fracture risk in patients with a diagnosis of pernicious anemia. Gastroenterology. 2010;138:1330–1337.PubMedGoogle Scholar
  64. 64.
    Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947–2953.PubMedGoogle Scholar
  65. 65.
    Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int. 2006;79:76–83.PubMedGoogle Scholar
  66. 66.
    Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179:319–326.PubMedGoogle Scholar
  67. 67.
    Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy. 2008;28:951–959.PubMedGoogle Scholar
  68. 68.
    Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology. 2010;139:93–101.PubMedGoogle Scholar
  69. 69.
    Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955–1960.PubMedGoogle Scholar
  70. 70.
    Sanduleanu S, Jonkers D, De Bruine A, Hameeteman W, Stockbrugger RW. Non-Helicobacter pylori bacterial flora during acid-suppressive therapy: differential findings in gastric juice and gastric mucosa. Aliment Pharmacol Ther. 2001;15:379–388.PubMedGoogle Scholar
  71. 71.
    Theisen J, Nehra D, Citron D, et al. Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids. J Gastrointest Surg. 2000;4:50–54.PubMedGoogle Scholar
  72. 72.
    Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996;39:54–59.PubMedGoogle Scholar
  73. 73.
    Aybay C, Imir T, Okur H. The effect of omeprazole on human natural killer cell activity. Gen Pharmacol. 1995;26:1413–1418.PubMedGoogle Scholar
  74. 74.
    Yoshida N, Yoshikawa T, Tanaka Y, et al. A new mechanism for anti-inflammatory actions of proton pump inhibitors–inhibitory effects on neutrophil-endothelial cell interactions. Aliment Pharmacol Ther. 2000;14:74–81.PubMedGoogle Scholar
  75. 75.
    Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxbock F, Graninger W. Omeprazole treatment diminishes intra- and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit Care Med. 2002;30:1118–1122.PubMedGoogle Scholar
  76. 76.
    Estborn L, Joelson S. Occurrence of community-acquired respiratory tract infection in patients receiving esomeprazole: retrospective analysis of adverse events in 31 clinical trials. Drug Saf. 2008;31:627–636.PubMedGoogle Scholar
  77. 77.
    Laheij RJ, Van Ijzendoorn MC, Janssen MJ, Jansen JB. Gastric acid-suppressive therapy and community-acquired respiratory infections. Aliment Pharmacol Ther. 2003;18:847–851.PubMedGoogle Scholar
  78. 78.
    Gulmez SE, Holm A, Frederiksen H, Jensen TG, Pedersen C, Hallas J. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med. 2007;167:950–955.PubMedGoogle Scholar
  79. 79.
    Gau J. Does Gastric Acid-Suppressive Therapy Increase the Risk of Pneumonia in Older Adults? Presented at AGS Meeting; 2007.Google Scholar
  80. 80.
    Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149:391–398.PubMedGoogle Scholar
  81. 81.
    Hartmann M, Theiss U, Huber R, et al. Twenty-four-hour intragastric pH profiles and pharmacokinetics following single and repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole. Aliment Pharmacol Ther. 1996;10:359–366.PubMedGoogle Scholar
  82. 82.
    Dublin S, Walker RL, Jackson ML, Nelson JC, Weiss NS, Jackson LA. Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study. Pharmacoepidemiol Drug Saf. 2010;19:792–802.PubMedGoogle Scholar
  83. 83.
    Stockbruegger RW. Bacterial overgrowth as a consequence of reduced gastric acidity. Scand J Gastroenterol Suppl. 1985;111:7–16.PubMedGoogle Scholar
  84. 84.
    Ruddell WS, Axon AT, Findlay JM, Bartholomew BA, Hill MJ. Effect of cimetidine on the gastric bacterial flora. Lancet. 1980;1:672–674.PubMedGoogle Scholar
  85. 85.
    Howden CW, Hunt RH. Relationship between gastric secretion and infection. Gut. 1987;28:96–107.PubMedGoogle Scholar
  86. 86.
    Gray JD, Shiner M. Influence of gastric pH on gastric and jejunal flora. Gut. 1967;8:574–581.PubMedGoogle Scholar
  87. 87.
    Cothran DS, Borowitz SM, Sutphen JL, Dudley SM, Donowitz LG. Alteration of normal gastric flora in neonates receiving ranitidine. J Perinatol. 1997;17:383–388.PubMedGoogle Scholar
  88. 88.
    Holt TL, Coombes ID, Pillans PI, Scott IA. Neutropenia associated with omeprazole. Med J Aust. 1999;170:141–142.PubMedGoogle Scholar
  89. 89.
    Vannier E, Dinarello CA. Histamine enhances interleukin (IL)-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral blood mononuclear cells. J Biol Chem. 1994;269:9952–9956.PubMedGoogle Scholar
  90. 90.
    Sharma BK, Santana IA, Wood EC, et al. Intragastric bacterial activity and nitrosation before, during, and after treatment with omeprazole. Br Med J (Clin Res Ed). 1984;289:717–719.Google Scholar
  91. 91.
    Verdu E, Viani F, Armstrong D, et al. Effect of omeprazole on intragastric bacterial counts, nitrates, nitrites, and N-nitroso compounds. Gut. 1994;35:455–460.PubMedGoogle Scholar
  92. 92.
    Fried M, Siegrist H, Frei R, et al. Duodenal bacterial overgrowth during treatment in outpatients with omeprazole. Gut. 1994;35:23–26.PubMedGoogle Scholar
  93. 93.
    Wilton LV, Key C, Shakir SA. The pharmacovigilance of pantoprazole: the results of postmarketing surveillance on 11 541 patients in England. Drug Saf. 2003;26:121–132.PubMedGoogle Scholar
  94. 94.
    Martin RM, Dunn NR, Freemantle S, Shakir S. The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies. Br J Clin Pharmacol. 2000;50:366–372.PubMedGoogle Scholar
  95. 95.
    Leufkens H, Claessens A, Heerdink E, van Eijk J, Lamers CB. A prospective follow-up study of 5669 users of lansoprazole in daily practice. Aliment Pharmacol Ther. 1997;11:887–897.PubMedGoogle Scholar
  96. 96.
    Claessens AA, Heerdink ER, van Eijk JT, Lamers CB, Leufkens HG. Characteristics of diarrhoea in 10, 008 users of lansoprazole in daily practice: which co-factors contribute? Pharmacoepidemiol Drug Saf. 2002;11:703–708.PubMedGoogle Scholar
  97. 97.
    Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology. 1997;8:571–574.PubMedGoogle Scholar
  98. 98.
    Neal KR, Scott HM, Slack RC, Logan RF. Omeprazole as a risk factor for campylobacter gastroenteritis: case-control study. BMJ. 1996;312:414–415.PubMedGoogle Scholar
  99. 99.
    Doorduyn Y, Van Pelt W, Siezen CL, et al. Novel insight in the association between salmonellosis or campylobacteriosis and chronic illness, and the role of host genetics in susceptibility to these diseases. Epidemiol Infect. 2008;136:1225–1234.PubMedGoogle Scholar
  100. 100.
    Neal KR, Briji SO, Slack RC, Hawkey CJ, Logan RF. Recent treatment with H2 antagonists and antibiotics and gastric surgery as risk factors for Salmonella infection. BMJ. 1994;308:176.PubMedGoogle Scholar
  101. 101.
    Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid-suppressing drugs and the risk of bacterial gastroenteritis. Clin Gastroenterol Hepatol. 2007;5:1418–1423.PubMedGoogle Scholar
  102. 102.
    Doorduyn Y, Van Den Brandhof WE, Van Duynhoven YT, Wannet WJ, Van Pelt W. Risk factors for Salmonella Enteritidis and Typhimurium (DT104 and non-DT104) infections in The Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol Infect. 2006;134:617–626.PubMedGoogle Scholar
  103. 103.
    Canani RB, Cirillo P, Roggero P, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117:e817–e820.PubMedGoogle Scholar
  104. 104.
    Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047–2056. (quiz 2057).PubMedGoogle Scholar
  105. 105.
    Evans CA, Gilman RH, Rabbani GH, Salazar G, Ali A. Gastric acid secretion and enteric infection in Bangladesh. Trans R Soc Trop Med Hyg. 1997;91:681–685.PubMedGoogle Scholar
  106. 106.
    Ho JL, Shands KN, Friedland G, Eckind P, Fraser DW. An outbreak of type 4b Listeria monocytogenes infection involving patients from eight Boston hospitals. Arch Intern Med. 1986;146:520–524.PubMedGoogle Scholar
  107. 107.
    Larner AJ, Hamilton MI. Review article: infective complications of therapeutic gastric acid inhibition. Aliment Pharmacol Ther. 1994;8:579–584.PubMedGoogle Scholar
  108. 108.
    Cook GC. Infective gastroenteritis and its relationship to reduced gastric acidity. Scand J Gastroenterol Suppl. 1985;111:17–23.PubMedGoogle Scholar
  109. 109.
    Kader SA, Mansour AM, Mohran Z, el-Taoil A, Abdalla KF. A study on the relation between proton pump inhibitor and gastric giardiasis. J Egypt Soc Parasitol. 1998;28:149–157.PubMedGoogle Scholar
  110. 110.
    Reynaert H, Fernandes E, Bourgain C, Smekens L, Devis G. Proton-pump inhibition and gastric giardiasis: a causal or casual association? J Gastroenterol. 1995;30:775–778.PubMedGoogle Scholar
  111. 111.
    Cadranel JF, Eugene C. Another example of Strongyloides stercoralis infection associated with cimetidine in an immunosuppressed patient. Gut. 1986;27:1229.PubMedGoogle Scholar
  112. 112.
    Ainley CC, Clarke DG, Timothy AR, Thompson RP. Strongyloides stercoralis hyperinfection associated with cimetidine in an immunosuppressed patient: diagnosis by endoscopic biopsy. Gut. 1986;27:337–338.PubMedGoogle Scholar
  113. 113.
    Martinsen TC, Bergh K, Waldum HL. Gastric juice: a barrier against infectious diseases. Basic Clin Pharmacol Toxicol. 2005;96:94–102.PubMedGoogle Scholar
  114. 114.
    Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother. 2003;51:1339–1350.PubMedGoogle Scholar
  115. 115.
    Severe C. lostridium difficile-associated disease in populations previously at low risk—four states, 2005. MMWR Morb Mortal Wkly Rep. 2005;54:1201–1205.Google Scholar
  116. 116.
    Wilson KH, Sheagren JN, Freter R. Population dynamics of ingested Clostridium difficile in the gastrointestinal tract of the Syrian hamster. J Infect Dis. 1985;151:355–361.PubMedGoogle Scholar
  117. 117.
    Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol. 2009;104:S10–S16.PubMedGoogle Scholar
  118. 118.
    Lowe DO, Mamdani MM, Kopp A, Low DE, Juurlink DN. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis. 2006;43:1272–1276.PubMedGoogle Scholar
  119. 119.
    Wilcox MH, Mooney L, Bendall R, Settle CD, Fawley WN. A case-control study of community-associated Clostridium difficile infection. J Antimicrob Chemother. 2008;62:388–396.PubMedGoogle Scholar
  120. 120.
    Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784–790.PubMedGoogle Scholar
  121. 121.
    Pounder R, Smith J. Drug-induced changes of plasma gastrin concentration. Gastroenterol Clin North Am. 1990;19:141–153.PubMedGoogle Scholar
  122. 122.
    Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut. 2006;55:1217–1221.PubMedGoogle Scholar
  123. 123.
    Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther. 2000;14:651–668.PubMedGoogle Scholar
  124. 124.
    Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, et al. Hypergastrinaemia during long-term omeprazole therapy: influences of vagal nerve function, gastric emptying and Helicobacter pylori infection. Aliment Pharmacol Ther. 1998;12:605–612.PubMedGoogle Scholar
  125. 125.
    Gillen D, Wirz AA, Ardill JE, McColl KE. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology. 1999;116:239–247.PubMedGoogle Scholar
  126. 126.
    Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009;137:80–87. (87 e81).PubMedGoogle Scholar
  127. 127.
    Waldum HL, Qvigstad G, Fossmark R, Kleveland PM, Sandvik AK. Rebound acid hypersecretion from a physiological, pathophysiological and clinical viewpoint. Scand J Gastroenterol. 2010;45:389–394.PubMedGoogle Scholar
  128. 128.
    Abraham SC, Nobukawa B, Giardiello FM, Hamilton SR, Wu TT. Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations. Am J Pathol. 2000;157:747–754.PubMedGoogle Scholar
  129. 129.
    Kinoshita Y, Tojo M, Yano T, et al. Incidence of fundic gland polyps in patients without familial adenomatous polyposis. Gastrointest Endosc. 1993;39:161–163.PubMedGoogle Scholar
  130. 130.
    Oberhuber G, Stolte M. Gastric polyps: an update of their pathology and biological significance. Virchows Arch. 2000;437:581–590.PubMedGoogle Scholar
  131. 131.
    Stolte M, Sticht T, Eidt S, Ebert D, Finkenzeller G. Frequency, location, and age and sex distribution of various types of gastric polyp. Endoscopy. 1994;26:659–665.PubMedGoogle Scholar
  132. 132.
    el-Zimaity HM, Jackson FW, Graham DY. Fundic gland polyps developing during omeprazole therapy. Am J Gastroenterol. 1997;92:1858–1860.PubMedGoogle Scholar
  133. 133.
    Jackson FW, Gordon S. Regression of fundic gland polyps after discontinuation of omeprazole [abstract]. Am J Gastroenterol Clin Biol. 1998;9:A121.Google Scholar
  134. 134.
    Driman DK, Wright C, Tougas G, Riddell RH. Omeprazole produces parietal cell hypertrophy and hyperplasia in humans. Dig Dis Sci. 1996;41:2039–2047.PubMedGoogle Scholar
  135. 135.
    Cats A, Schenk BE, Bloemena E, et al. Parietal cell protrusions and fundic gland cysts during omeprazole maintenance treatment. Hum Pathol. 2000;31:684–690.PubMedGoogle Scholar
  136. 136.
    Sakai N, Tatsuta M, Hirasawa R, et al. Low prevalence of Helicobacter pylori infection in patients with hamartomatous fundic polyps. Dig Dis Sci. 1998;43:766–772.PubMedGoogle Scholar
  137. 137.
    Choudhry U, Boyce HW Jr, Coppola D. Proton pump inhibitor-associated gastric polyps: a retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics. Am J Clin Pathol. 1998;110:615–621.PubMedGoogle Scholar
  138. 138.
    Graham JR. Gastric polyposis: onset during long-term therapy with omeprazole. Med J Aust. 1992;157:287–288.PubMedGoogle Scholar
  139. 139.
    Jalving M, Koornstra JJ, Wesseling J, Boezen HM SDEJ, Kleibeuker JH. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther. 2006;24:1341–1348.PubMedGoogle Scholar
  140. 140.
    Kazantsev GB, Schwesinger WH, Heim-Hall J. Spontaneous resolution of multiple fundic gland polyps after cessation of treatment with lansoprazole and Nissen fundoplication: a case report. Gastrointest Endosc. 2002;55:600–602.PubMedGoogle Scholar
  141. 141.
    Naegels S, Urbain D. Omeprazole and fundic gland polyps. Am J Gastroenterol. 1998;93:855.PubMedGoogle Scholar
  142. 142.
    Stolte M, Bethke B, Seifert E, et al. Observation of gastric glandular cysts in the corpus mucosa of the stomach under omeprazole treatment. Z Gastroenterol. 1995;33:146–149.PubMedGoogle Scholar
  143. 143.
    Van Vlierberghe H, De Vos M, De Cock G, Cuvelier C, Elewaut A. Fundic gland polyps: three other case reports suggesting a possible association with acid suppressing therapy. Acta Gastroenterol Belg. 1997;60:240–242.PubMedGoogle Scholar
  144. 144.
    Collins S, Tydd T. Gastric polyps and long-term omeprazole [abstract]. J Gastroenterol Hepatology. 1998.Google Scholar
  145. 145.
    Mogadam M, Houk R. Long-term use of omeprazole is associated with development of benign epithelial gastric polyps [abstract]. Am J Gastroenterol. 1996;91:A151.Google Scholar
  146. 146.
    Reekmans A, Naegels S, Reynaert H, Urbain D. Fundic gland polyps and chronic PPI treatment: a prospective study [abstract]. Gastroenterology. 2001.Google Scholar
  147. 147.
    Vieth M, Stolte M. Fundic gland polyps are not induced by proton pump inhibitor therapy. Am J Clin Pathol. 2001;116:716–720.PubMedGoogle Scholar
  148. 148.
    Stolte M. Fundic gland polyps: a rare, innocuous, and reversible disturbance. Gastroenterology. 1993;105:1590–1591.PubMedGoogle Scholar
  149. 149.
    Abraham SC, Nobukawa B, Giardiello FM, Hamilton SR, Wu TT. Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. Am J Pathol. 2001;158:1005–1010.PubMedGoogle Scholar
  150. 150.
    Jalving M, Koornstra JJ, Boersma-van Ek W, et al. Dysplasia in fundic gland polyps is associated with nuclear beta-catenin expression and relatively high cell turnover rates. Scand J Gastroenterol. 2003;38:916–922.PubMedGoogle Scholar
  151. 151.
    Torbenson M, Lee JH, Cruz-Correa M, et al. Sporadic fundic gland polyposis: a clinical, histological, and molecular analysis. Mod Pathol. 2002;15:718–723.PubMedGoogle Scholar
  152. 152.
    Abraham SC, Park SJ, Cruz-Correa M, et al. Frequent CpG island methylation in sporadic and syndromic gastric fundic gland polyps. Am J Clin Pathol. 2004;122:740–746.PubMedGoogle Scholar
  153. 153.
    Abraham SC, Park SJ, Mugartegui L, Hamilton SR, Wu TT. Sporadic fundic gland polyps with epithelial dysplasia : evidence for preferential targeting for mutations in the adenomatous polyposis coli gene. Am J Pathol. 2002;161:1735–1742.PubMedGoogle Scholar
  154. 154.
    Wei J, Chiriboga L, Yee H, et al. Altered cellular distribution of tuberin and glucocorticoid receptor in sporadic fundic gland polyps. Mod Pathol. 2002;15:862–869.PubMedGoogle Scholar
  155. 155.
    Attard TM, Yardley JH, Cuffari C. Gastric polyps in pediatrics: an 18-year hospital-based analysis. Am J Gastroenterol. 2002;97:298–301.PubMedGoogle Scholar
  156. 156.
    Svendsen JH, Dahl C, Svendsen LB, Christiansen PM. Gastric cancer risk in achlorhydric patients. A long-term follow-up study. Scand J Gastroenterol. 1986;21:16–20.PubMedGoogle Scholar
  157. 157.
    Carter DC. Cancer after peptic ulcer surgery. Gut. 1987;28:921–923.PubMedGoogle Scholar
  158. 158.
    Caygill CP, Hill MJ, Kirkham JS, Northfield TC. Mortality from gastric cancer following gastric surgery for peptic ulcer. Lancet. 1986;1:929–931.PubMedGoogle Scholar
  159. 159.
    Freston JW. Clinical significance of hypergastrinaemia: relevance to gastrin monitoring during omeprazole therapy. Digestion. 1992;51:102–114.PubMedGoogle Scholar
  160. 160.
    Fiocca R, Villani L, Luinetti O, et al. Helicobacter colonization and histopathological profile of chronic gastritis in patients with or without dyspepsia, mucosal erosion and peptic ulcer: a morphological approach to the study of ulcerogenesis in man. Virchows Arch A Pathol Anat Histopathol. 1992;420:489–498.PubMedGoogle Scholar
  161. 161.
    Rubin CE. Are there three types of Helicobacter pylori gastritis? Gastroenterology. 1997;112:2108–2110.PubMedGoogle Scholar
  162. 162.
    Stemmermann GN. Intestinal metaplasia of the stomach. A status report. Cancer. 1994;74:556–564.PubMedGoogle Scholar
  163. 163.
    Weeks DL, Eskandari S, Scott DR, Sachs G. A H + -gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science. 2000;287:482–485.PubMedGoogle Scholar
  164. 164.
    Kuipers EJ, Uyterlinde AM, Pena AS, et al. Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety. Am J Gastroenterol. 1995;90:1401–1406.PubMedGoogle Scholar
  165. 165.
    Logan RP, Walker MM, Misiewicz JJ, Gummett PA, Karim QN, Baron JH. Changes in the intragastric distribution of Helicobacter pylori during treatment with omeprazole. Gut. 1995;36:12–16.PubMedGoogle Scholar
  166. 166.
    Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med. 1996;334:1018–1022.PubMedGoogle Scholar
  167. 167.
    Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Nordic Gerd Study Group. Gastroenterology. 1999;117:319–326.PubMedGoogle Scholar
  168. 168.
    Lundell L, Havu N, Miettinen P, et al. Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial. Aliment Pharmacol Ther. 2006;23:639–647.PubMedGoogle Scholar
  169. 169.
    Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–789.PubMedGoogle Scholar
  170. 170.
    Chey WD, Wong BC. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808–1825.PubMedGoogle Scholar
  171. 171.
    Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13, 715 carcinoid tumors. Cancer. 2003;97:934–959.PubMedGoogle Scholar
  172. 172.
    Hodgson N, Koniaris LG, Livingstone AS, Franceschi D. Gastric carcinoids: a temporal increase with proton pump introduction. Surg Endosc. 2005;19:1610–1612.PubMedGoogle Scholar
  173. 173.
    Waldum HL, Gustafsson B, Fossmark R, Qvigstad G. Antiulcer drugs and gastric cancer. Dig Dis Sci. 2005;50:S39–S44.PubMedGoogle Scholar
  174. 174.
    Robinson M. Current perspectives on hypergastrinemia and enterochromaffin-like-cell hyperplasia. Aliment Pharmacol Ther. 1999;13:5–10.PubMedGoogle Scholar
  175. 175.
    Bardram L, Thomsen P, Stadil F. Gastric endocrine cells in omeprazole-treated and untreated patients with the Zollinger-Ellison syndrome. Digestion. 1986;35:116–122.PubMedGoogle Scholar
  176. 176.
    Borch K, Renvall H, Liedberg G. Gastric endocrine cell hyperplasia and carcinoid tumors in pernicious anemia. Gastroenterology. 1985;88:638–648.PubMedGoogle Scholar
  177. 177.
    Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E. Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology. 1993;104:994–1006.PubMedGoogle Scholar
  178. 178.
    Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology. 2000;118:661–669.PubMedGoogle Scholar
  179. 179.
    Solcia E, Fiocca R, Havu N, Dalvag A, Carlsson R. Gastric endocrine cells and gastritis in patients receiving long-term omeprazole treatment. Digestion. 1992;51:82–92.PubMedGoogle Scholar
  180. 180.
    Solcia E, Rindi G, Havu N, Elm G. Qualitative studies of gastric endocrine cells in patients treated long-term with omeprazole. Scand J Gastroenterol Suppl. 1989;166:129–137 (discussion 138–129).Google Scholar
  181. 181.
    Carlsson E, Larsson H, Mattsson H, Ryberg B, Sundell G. Pharmacology and toxicology of omeprazole–with special reference to the effects on the gastric mucosa. Scand J Gastroenterol Suppl. 1986;118:31–38.PubMedGoogle Scholar
  182. 182.
    Lee H, Hakanson R, Karlsson A, Mattsson H, Sundler F. Lansoprazole and omeprazole have similar effects on plasma gastrin levels, enterochromaffin-like cells, gastrin cells and somatostatin cells in the rat stomach. Digestion. 1992;51:125–132.PubMedGoogle Scholar
  183. 183.
    Mattsson H, Havu N, Brautigam J, Carlsson K, Lundell L, Carlsson E. Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffinlike-cell carcinoids in the rat. Gastroenterology. 1991;100:311–319.PubMedGoogle Scholar
  184. 184.
    Poynter D, Pick CR, Harcourt RA, et al. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut. 1985;26:1284–1295.PubMedGoogle Scholar
  185. 185.
    Hakanson R, Larsson LI, Liedberg G, Oscarson J, Sundler F, Vang J. Effects of antrectomy or porta-caval shunting on the histamine-storing endocrine-like cells in oxyntic mucosa of rat stomach. A fluorescence histochemical, electron microscopic and chemical study. J Physiol. 1976;259:785–800.PubMedGoogle Scholar
  186. 186.
    Simonsson M, Eriksson S, Hakanson R, et al. Endocrine cells in the human oxyntic mucosa. A histochemical study. Scand J Gastroenterol. 1988;23:1089–1099.PubMedGoogle Scholar
  187. 187.
    Watson SA, Durrant LG, Crosbie JD, Morris DL. The in vitro growth response of primary human colorectal and gastric cancer cells to gastrin. Int J Cancer. 1989;43:692–696.PubMedGoogle Scholar
  188. 188.
    Renga M, Brandi G, Paganelli GM, et al. Rectal cell proliferation and colon cancer risk in patients with hypergastrinaemia. Gut. 1997;41:330–332.PubMedGoogle Scholar
  189. 189.
    Thorburn CM, Friedman GD, Dickinson CJ, Vogelman JH, Orentreich N, Parsonnet J. Gastrin and colorectal cancer: a prospective study. Gastroenterology. 1998;115:275–280.PubMedGoogle Scholar
  190. 190.
    Singh M, Dhindsa G, Friedland S, Triadafilopoulos G. Long-term use of proton pump inhibitors does not affect the frequency, growth, or histologic characteristics of colon adenomas. Aliment Pharmacol Ther. 2007;26:1051–1061.PubMedGoogle Scholar
  191. 191.
    Yang YX, Hennessy S, Propert K, Hwang WT, Sedarat A, Lewis JD. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology. 2007;133:748–754.PubMedGoogle Scholar
  192. 192.
    Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sorensen HT. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case-control study. Gastroenterology. 2007;133:755–760.PubMedGoogle Scholar
  193. 193.
    van Soest EM, van Rossum LG, Dieleman JP, et al. Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol. 2008;103:966–973.PubMedGoogle Scholar
  194. 194.
    McCarthy DM, McLaughlin T, Yazdani C, El Serag HB, Griffis DL. Effects of co-therapy with early proton pump inhibitors (PPIs) on the occurrence of side effects of other drugs with potential for interaction with PPIs: a cohort study. Gastroenterology. 2002;122(4)(Suppl. 1):A210 (abstract S1345).Google Scholar
  195. 195.
    Labenz J, Petersen KU, Rosch W, Koelz HR. A summary of Food and Drug Administration-reported adverse events and drug interactions occurring during therapy with omeprazole, lansoprazole and pantoprazole. Aliment Pharmacol Ther. 2003;17:1015–1019.PubMedGoogle Scholar
  196. 196.
    Blume H, Donath F, Warnke A, Schug BS. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf. 2006;29:769–784.PubMedGoogle Scholar
  197. 197.
    Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol. 2008;64:935–951.PubMedGoogle Scholar
  198. 198.
    Fuhr U, Jetter A. Rabeprazole: pharmacokinetics and pharmacokinetic drug interactions. Pharmazie. 2002;57:595–601.PubMedGoogle Scholar
  199. 199.
    Sachmechi I, Reich DM, Aninyei M, Wibowo F, Gupta G, Kim PJ. Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism. Endocr Pract. 2007;13:345–349.PubMedGoogle Scholar
  200. 200.
    Alkhatib AA, Elkhatib FA, Khatib OF. Gastric acid-reducing medications and clopidogrel: what are the latest FDA recommendations? Am J Gastroenterol. 2010;105:1211.PubMedGoogle Scholar
  201. 201.
    Bhatt DL, Cryer B, Contant CF, et al. COGENT. COGENT: a prospective, randomized, placebo-controlled trial of omeprazole in patients receiving aspirin and clopidogrel [abstract]. Transvascular Cardiovascular Therapeutics Annual Meeting; September 24, 2009; San Francisco, CA. http://www.slideshare.net/flaviog/bhnt.
  202. 202.
    Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301:937–944.PubMedGoogle Scholar
  203. 203.
    O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374:989–997.PubMedGoogle Scholar
  204. 204.
    Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation. 2009;120:2322–2329.PubMedGoogle Scholar
  205. 205.
    Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010;152:337–345.PubMedGoogle Scholar
  206. 206.
    Stockl KM, Le L, Zakharyan A, et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010;170:704–710.PubMedGoogle Scholar
  207. 207.
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–362.PubMedGoogle Scholar
  208. 208.
    HA StocklKM, Solow BK, Addiego JE, Ramsey S. Conflicting evidence surrounding the clopidogrel and proton pump inhibitor drug interaction—reply. Arch Intern Med. 2010;170:1508.Google Scholar
  209. 209.
    Rey E, Rodriguez-Artalejo F, Herraiz MA, et al. Gastroesophageal reflux symptoms during and after pregnancy: a longitudinal study. Am J Gastroenterol. 2007;102:2395–2400.PubMedGoogle Scholar
  210. 210.
    Diav-Citrin O, Arnon J, Shechtman S, et al. The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study. Aliment Pharmacol Ther. 2005;21:269–275.PubMedGoogle Scholar
  211. 211.
    Kallen B. Delivery outcome after the use of acid-suppressing drugs in early pregnancy with special reference to omeprazole. Br J Obstet Gynaecol. 1998;105:877–881.PubMedGoogle Scholar
  212. 212.
    Kallen BA. Use of omeprazole during pregnancy–no hazard demonstrated in 955 infants exposed during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2001;96:63–68.PubMedGoogle Scholar
  213. 213.
    Lalkin A, Loebstein R, Addis A, et al. The safety of omeprazole during pregnancy: a multicenter prospective controlled study. Am J Obstet Gynecol. 1998;179:727–730.PubMedGoogle Scholar
  214. 214.
    Nielsen GL, Sorensen HT, Thulstrup AM, Tage-Jensen U, Olesen C, Ekbom A. The safety of proton pump inhibitors in pregnancy. Aliment Pharmacol Ther. 1999;13:1085–1089.PubMedGoogle Scholar
  215. 215.
    Nikfar S, Abdollahi M, Moretti ME, Magee LA, Koren G. Use of proton pump inhibitors during pregnancy and rates of major malformations: a meta-analysis. Dig Dis Sci. 2002;47:1526–1529.PubMedGoogle Scholar
  216. 216.
    Ruigomez A, Garcia Rodriguez LA, Cattaruzzi C, et al. Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. Am J Epidemiol. 1999;150:476–481.PubMedGoogle Scholar
  217. 217.
    Gill SK, O’Brien L, Einarson TR, Koren G. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol. 2009;104:1541–1545 (quiz 1540, 1546).Google Scholar
  218. 218.
    Pasternak B, Hviid A. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects. N Engl J Med. 2010;363:2114–2123.PubMedGoogle Scholar
  219. 219.
    Mitchell AA. Studies of drug-induced birth defects, chapter 32. In: Strom BL, ed. Pharmacoepidemiology. 4th ed. New York: Wiley; 2005:501–515.Google Scholar
  220. 220.
    Dehlink E, Yen E, Leichtner AM, Hait EJ, Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study. Clin Exp Allergy. 2009;39:246–253.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Medicine and Division of Gastroenterology and HepatologyStanford University School of MedicineStanfordUSA

Personalised recommendations