Protonenpumpenhemmer – Nebenwirkungen und Komplikationen der langfristigen Protonenpumpenhemmereinnahme

Zusammenfassung

Protonenpumpenhemmer gehören zu den am häufigsten eingenommenen Medikamenten. Indiziert sind sie zur Behandlung von Kurzzeit- und Dauertherapie bei Sodbrennen, Refluxerkrankung, Prophylaxe und Therapie von peptischen Ulzera, in Kombination von NSAR und Steroiden sowie bei H. pylori-Eradikation. Häufig werden PPIs jedoch auch bei unspezifischen Symptomen breit eingesetzt oder dauerhaft gegeben. Dies hat sicher mit guter Verträglichkeit und bisher gering erachtetem Nebenwirkungsprofil zu tun. Nun mehren sich die Hinweise, dass die langfristige Einnahme von PPI nicht so unbedenklich sein könnte, wie angenommen. Neben Wechselwirkungen mit einigen Medikamenten, darunter die Thrombozytenaggregationshemmer, zeigten neuere Studien ein erhöhtes Risiko für Herzinfarkte, interstitielle Nephritis, chronische Nierenschädigung, Infektionen, Vitaminmangelzustände und Elektrolytverschiebungen sowie Entwicklung einer Demenz.

Abstract

Proton Pump Inhibitors are among the most common drugs taken. The indication is for treatment of heartburn, reflux disease, prophylaxis and treatment of peptic ulcers, in combination with NSAIDs and steroids as well as H. pylori-eradication. PPI’s are widely used, even with non-specific symptoms. This certainly has to do with good tolerability and a previously considered low side effect profile. At the moment, there is growing evidence that the long-term intake of PPI's may not be as safe as assumed. In addition to interactions with some drugs, including platelet aggregation inhibitors, recent studies have shown an increased risk of myocardial infarction, interstitial nephritis, chronic renal injury, infections, vitamin deficiencies and electrolyte shifts as well developing dementia.

Schlüsselwörter

gastrointestinale Blutung - pseudomembranöse Colitis - Magen - Refluxoesophagititis - Ulcus ventriculi - Darm

Key words

gastrointestinal bleeding - pseudomembranous colitis - stomach - reflux oseophagitis - ulcer ventriculi - intestine

• Literatur

• 1 Schwabe U. Arzneiverordnungs-Report 2015 Aktuelle Daten, Kosten, Trends und Kommentare; mit 233 Tabellen. Berlin, Heidelberg: Springer; 2015
• 2 Administration F-USFaD. In: http://www.fda.gov/default.htm
• 3 Richter JE. Bochenek W. Oral pantoprazole for erosive esophagitis: a placebo-controlled, randomized clinical trial. Am J Gastroenterol 2000; 95: 3071-3080
• 4 Vakil NB. Shaker R. Johnson DA. 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. Alimentary Pharmacology & Therapeutics 2001; 15: 927-935
• 5 Pilotto A. Leandro G. Franceschi M. Short- and long-term therapy for reflux oesophagitis in the elderly: a multi-centre, placebo-controlled study with pantoprazole. Alimentary Pharmacology & Therapeutics 2003; 17: 1399-1406
• 6 Robinson M. Horn J. Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003; 63: 2739-2754
• 7 Swen JJ. Nijenhuis M. de Boer A. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clinical pharmacology and therapeutics 2011; 89: 662-673
• 8 Joerger M. Huitema ADR. van den Bongard HJGD. et al. Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol 2006; 62: 71-80
• 9 Chioukh R. Noel-Hudson MS. Ribes S. et al. Proton pump inhibitors inhibit methotrexate transport by renal basolateral organic anion transporter hOAT3. Drug metabolism and disposition: the biological fate of chemicals 2014; 42: 2041-2048
• 10 Administration F-USFaD. Methotrexate sodium and Proton pump inhibitors. Drug interaction resulting in decreased elimination of methotrexate. U.S. Food and Drug Administration; 2011
• 11 Agarwala S. Pharmacokinetic effect of omeprazole on Atazanavir co-administered with ritonavir in healthy subjects [Abstract 658.] 12th Conference on Retroviruses and Opportunistic Infections. February 22–25, Boston, MA: 2005
• 12 Kämmerer W. Interaktionen: Achtung bei Tyrosinkinase-Inhibitoren. Pharmazeutische Zeitung 2009 20.
• 13 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
• 14 Focks JJ. Brouwer MA. van Oijen MG. et al. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome – a systematic review. Heart 2013; 99: 520-527
• 15 Bhatt DL. Cryer BL. Contant CF. et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. New England Journal of Medicine 2010; 363: 1909-1917
• 16 Fischbach W. Darius H. Gross M. et al. Gleichzeitige Anwendung von Thrombozytenaggregationshemmern und Protonenpumpeninhibitoren (PPIs). Der Kardiologe 2010; 4: 353-364
• 17 Miyake K. Akimoto T. Hanada Y. et al. Proton pump inhibitors are associated with lower gastrointestinal tract bleeding in low-dose aspirin users with ischaemic heart disease. Dig Liver Dis 2015; 47: 757-762
• 18 Washio E. Esaki M. Maehata Y. et al. Proton Pump Inhibitors Increase Incidence of Nonsteroidal Anti-Inflammatory Drug-Induced Small Bowel Injury: A Randomized, Placebo-Controlled Trial. Clin Gastroenterol Hepatol 2015; DOI: 10.1016/j.cgh.2015.10.022.
• 19 Wallace JL. Syer S. Denou E. et al. Proton Pump Inhibitors Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis. Gastroenterology 2011; 141: 1314-1322.e1315
• 20 Blackler RW. Gemici B. Manko A. et al. NSAID-gastroenteropathy: new aspects of pathogenesis and prevention. Current Opinion in Pharmacology 2014; 19: 11-16
• 21 Fornai M. Antonioli L. Pellegrini C. et al. Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. Pharmacological research 2016; 104: 186-196
• 22 Ciobanu L. Taulescu M. Prundus R. et al. Effects of rifaximin on indomethacin-induced intestinal damage in guinea-pigs. European review for medical and pharmacological sciences 2014; 18: 344-351
• 23 Charlot M. Ahlehoff O. Norgaard ML. et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med 2010; 153: 378-386
• 24 Shah NH. LePendu P. Bauer-Mehren A. et al. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PLoS One 2015; 10: e0124653
• 25 Chan JL. El-Serag HB. Is Proton Pump Inhibitor Use Associated With Risk of Myocardial Infarction?. Gastroenterology 2016; 150: 526-527
• 26 Shah NH. Cooke JP. Leeper NJ. Reply. Gastroenterology 2016; 150: 528
• 27 Cooke JP. Ghebremariam YT. DDAH says NO to ADMA. Arterioscler Thromb Vasc Biol 2011; 31: 1462-1464
• 28 Dayal S. Lentz SR. ADMA and hyperhomocysteinemia. Vasc Med 2005; 10 (Suppl. 01) S27-S33
• 29 van Dijk SC. Enneman AW. Swart KM. et al. Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia. Vasc Med 2016; DOI: 10.1177/1358863x15622281.
• 30 van Dijk SC. Enneman AW. Swart KMA. et al. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial. J Hypertens 2015; 33: 1897-1906 ; discussion 1906
• 31 Yepuri G. Sukhovershin R. Nazari-Shafti TZ. et al. Proton Pump Inhibitors Accelerate Endothelial Senescence. Circ Res 2016; 118: e36-e42
• 32 Sehested TS. Proton Pump Inhibitor Use Increases the Associated Risk of First-Time Ischemic Stroke. A Nationwide Cohort Study. American Heart Association Meeting Report - Presentation: 391 - Session: EP.AOS.765.
• 33 Ruffenach SJ. Siskind MS. Lien YH. Acute interstitial nephritis due to omeprazole. The American journal of medicine 1992; 93: 472-473
• 34 Myers RP. McLaughlin K. Hollomby DJ. Acute interstitial nephritis due to omeprazole. Am J Gastroenterol 2001; 96: 3428-3431
• 35 Segarra Soria MA. Teruel Lopez CJ. Calvo Gordo C. et al. Interstitial nephritis caused by omeprazole. An Med Interna 1998; 15: 618
• 36 Post AT. Voorhorst G. Zanen AL. Reversible renal failure after treatment with omeprazole. Neth J Med 2000; 57: 58-61
• 37 Torregrosa E. Rovira RE. Calvo C. et al. Acute interstitial nephritis associated with omeprazole therapy. Nefrologia: publicacion oficial de la Sociedad Espanola Nefrologia 2004; 24 (Suppl. 03) 61-63
• 38 Harmark L. van der Wiel HE. de Groot MC. et al. Proton pump inhibitor-induced acute interstitial nephritis. Br J Clin Pharmacol 2007; 64: 819-823
• 39 Simpson IJ. Marshall MR. Pilmore H. et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton) 2006; 11: 381-385
• 40 Geevasinga N. Coleman PL. Webster AC. et al. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol 2006; 4: 597-604
• 41 Antoniou T. Macdonald EM. Hollands S. et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open 2015; 3: E166-E171
• 42 Klepser DG. Collier DS. Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study. BMC Nephrol 2013; 14: 150
• 43 Leonard CE. Freeman CP. Newcomb CW. et al. Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury. Pharmacoepidemiology and Drug Safety 2012; 21: 1155-1172
• 44 Lazarus B. Chen Y. Wilson FP. et al. PRoton pump inhibitor use and the risk of chronic kidney disease. JAMA Internal Medicine 2016; 176 (02) 238-246
• 45 Termanini B. Gibril F. Sutliff VE. et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. The American journal of medicine 1998; 104: 422-430
• 46 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
• 47 Dharmarajan TS. Kanagala MR. Murakonda P. et al. Do acid-lowering agents affect vitamin B12 status in older adults?. J Am Med Dir Assoc 2008; 9: 162-167
• 48 Schenk BE. Festen HP. Kuipers EJ. et al. Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin. Aliment Pharmacol Ther 1996; 10: 541-545
• 49 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
• 50 Lam JR. Schneider JL. Zhao W. et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013; 310: 2435-2442
• 51 Zipursky J. Macdonald EM. Hollands S. et al. Proton Pump Inhibitors and Hospitalization with Hypomagnesemia: A Population-Based Case-Control Study. PLoS Med 2014; 11: e1001736
• 52 Danziger J. William JH. Scott DJ. et al. Proton-pump inhibitor use is associated with low serum magnesium concentrations. Kidney Int 2013; 83: 692-699
• 53 Schlingmann KP. Waldegger S. Konrad M. et al. TRPM6 and TRPM7 – Gatekeepers of human magnesium metabolism. Biochim Biophys Acta 2007; 1772: 813-821
• 54 Hess MW. Hoenderop JG. Bindels RJ. et al. Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther 2012; 36: 405-413
• 55 Janett S. Camozzi P. Peeters G. et al. Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors. Gastroenterology Research and Practice 2015; 2015: 7
• 56 McColl KEL. Effect of Proton Pump Inhibitors on Vitamins and Iron. Am J Gastroenterol 2009; 104: S5-S9
• 57 Hutchinson C. Geissler CA. Powell JJ. et al. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 2007; 56: 1291-1295
• 58 Wright MJ. Sullivan RR. Gaffney-Stomberg E. et al. Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res 2010; 25: 2205-2211
• 59 Hansen KE. Jones AN. Lindstrom MJ. et al. Do proton pump inhibitors decrease calcium absorption?. J Bone Miner Res 2010; 25: 2786-2795
• 60 Gray SL. LaCroix AZ. Larson J. et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Arch Intern Med 2010; 170: 765-771
• 61 Targownik LE. Lix LM. Leung S. et al. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010; 138: 896-904
• 62 Yang YX. Lewis JD. Epstein S. et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296: 2947-2953
• 63 Ngamruengphong S. Leontiadis GI. Radhi S. et al. Proton Pump Inhibitors and Risk of Fracture: A Systematic Review and Meta-Analysis of Observational Studies. Am J Gastroenterol 2011; 106: 1209-1218
• 64 Adams AL. Black MH. Zhang JL. et al. Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol 2014; 24: 286-290
• 65 Khalili H. Huang ES. Jacobson BC. et al. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 2012; 344: e372
• 66 Jefferies KC. Cipriano DJ. Forgac M. Function, structure and regulation of the vacuolar (H+)-ATPases. Arch Biochem Biophys 2008; 476: 33-42
• 67 Mizunashi K. Furukawa Y. Katano K. et al. Effect of omeprazole, an inhibitor of H+,K(+)-ATPase, on bone resorption in humans. Calcif Tissue Int 1993; 53: 21-25
• 68 Sheraly AR. Lickorish D. Sarraf F. et al. Use of gastrointestinal proton pump inhibitors to regulate osteoclast-mediated resorption of calcium phosphate cements in vivo. Current drug delivery 2009; 6: 192-198
• 69 Prause M. Seeliger C. Unger M. et al. Pantoprazole decreases cell viability and function of human osteoclasts in vitro. Mediators of inflammation 2015; 2015: 413097
• 70 Bavishi C. Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther 2011; 34: 1269-1281
• 71 Janarthanan S. Ditah I. Adler DG. et al. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol 2012; 107: 1001-1010
• 72 Pakyz AL. Jawahar R. Wang Q. et al. Medication risk factors associated with healthcare-associated Clostridium difficile infection: a multilevel model case-control study among 64 US academic medical centres. The Journal of antimicrobial chemotherapy 2014; 69: 1127-1131
• 73 Aseeri M. Schroeder T. Kramer J. et al. Gastric acid suppression by proton pump inhibitors as a risk factor for clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol 2008; 103: 2308-2313
• 74 Cunningham R. Dale B. Undy B. et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. The Journal of hospital infection 2003; 54: 243-245
• 75 Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol 2009; 104 (Suppl. 02) S10-S16
• 76 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
• 77 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
• 78 Kwok CS. Arthur AK. Anibueze CI. et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107: 1011-1019
• 79 Buendgens L. Bruensing J. Matthes M. et al. Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea. Journal of critical care 2014; 29: 696.e611-e695
• 80 Linsky A. Gupta K. Lawler EV. et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010; 170: 772-778
• 81 Leonard AD. Ho KM. Flexman J. Proton pump inhibitors and diarrhoea related to Clostridium difficile infection in hospitalised patients: a case-control study. Internal medicine journal 2012; 42: 591-594
• 82 Khanna S. Aronson SL. Kammer PP. et al. Gastric acid suppression and outcomes in Clostridium difficile infection: a population-based study. Mayo Clinic proceedings 2012; 87: 636-642
• 83 Tleyjeh IM. Bin Abdulhak AA. Riaz M. et al. Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis. PLoS One 2012; 7: e50836
• 84 Lowe DO. Mamdani MM. Kopp A. et al. Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2006; 43: 1272-1276
• 85 Faleck DM. Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit. Am J Gastroenterol 2016; 111: 1641-1648
• 86 Hagel S. Epple HJ. Feurle GE. et al. S2k-guideline gastrointestinal infectious diseases and Whipple's disease. Z Gastroenterol 2015; 53: 418-459
• 87 Cat TB. Charash W. Hebert J. et al. Potential influence of antisecretory therapy on the development of Candida-associated intraabdominal infection. The Annals of pharmacotherapy 2008; 42: 185-191
• 88 Daniell HW. Acid suppressing therapy as a risk factor for Candida esophagitis. Diseases of the esophagus: official journal of the International Society for Diseases of the Esophagus/ISDE. 2015; DOI: 10.1111/dote.12354.
• 89 Kim KY. Jang JY. Kim JW. et al. Acid suppression therapy as a risk factor for Candida esophagitis. Digestive diseases and sciences 2013; 58: 1282-1286
• 90 DuPont HL. Travellers' diarrhoea: contemporary approaches to therapy and prevention. Drugs 2006; 66: 303-314
• 91 Cobelens FG. Leentvaar-Kuijpers A. Kleijnen J. et al. Incidence and risk factors of diarrhoea in Dutch travellers: consequences for priorities in pre-travel health advice. Trop Med Int Health 1998; 3: 896-903
• 92 Jacobs C. Coss Adame E. Attaluri A. et al. Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther 2013; 37: 1103-1111
• 93 Hegar B. Hutapea EI. Advani N. et al. A double-blind placebo-controlled randomized trial on probiotics in small bowel bacterial overgrowth in children treated with omeprazole. Jornal de pediatria 2013; 89: 381-387
• 94 Compare D. Pica L. Rocco A. et al. Effects of long-term PPI treatment on producing bowel symptoms and SIBO. European journal of clinical investigation 2011; 41: 380-386
• 95 Lombardo L. Foti M. Ruggia O. et al. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010; 8: 504-508
• 96 Lo WK. Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol 2013; 11: 483-490
• 97 Fujiwara Y. Watanabe T. Muraki M. et al. Association between chronic use of proton pump inhibitors and small- intestinal bacterial overgrowth assessed using lactulose hydrogen breath tests. Hepato-gastroenterology 2015; 62: 268-272
• 98 Seto CT. Jeraldo P. Orenstein R. et al. Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility. Microbiome 2014; 2: 42
• 99 Keszthelyi D. Jansen SV. Schouten GA. et al. Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study. Aliment Pharmacol Ther 2010; 32: 1124-1128
• 100 Masclee GM. Coloma PM. Kuipers EJ. et al. Increased risk of microscopic colitis with use of proton pump inhibitors and non-steroidal anti-inflammatory drugs. Am J Gastroenterol 2015; 110: 749-759
• 101 Bonderup OK. Fenger-Gron M. Wigh T. et al. Drug exposure and risk of microscopic colitis: a nationwide Danish case-control study with 5751 cases. Inflamm Bowel Dis 2014; 20: 1702-1707
• 102 Tong J. Zheng Q. Zhang C. et al. Incidence, prevalence, and temporal trends of microscopic colitis: a systematic review and meta-analysis. Am J Gastroenterol 2015; 110: 265-276 ; quiz 277
• 103 Laheij RJ. Sturkenboom MC. Hassing RJ. et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. Jama 2004; 292: 1955-1960
• 104 Gulmez SE. Holm A. Frederiksen H. et al. 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
• 105 Hermos JA. Young MM. Fonda JR. et al. Risk of community-acquired pneumonia in veteran patients to whom proton pump inhibitors were dispensed. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2012; 54: 33-42
• 106 Johnstone J. Nerenberg K. Loeb M. Meta-analysis: proton pump inhibitor use and the risk of community-acquired pneumonia. Aliment Pharmacol Ther 2010; 31: 1165-1177
• 107 Herzig SJ. Howell MD. Ngo LH. et al. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. Jama 2009; 301: 2120-2128
• 108 Herzig SJ. Doughty C. Lahoti S. et al. Acid-suppressive medication use in acute stroke and hospital-acquired pneumonia. Annals of neurology 2014; 76: 712-718
• 109 Jena AB. Sun E. Goldman DP. Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia. Journal of general internal medicine 2013; 28: 223-230
• 110 Sarkar M. Hennessy S. Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149: 391-398
• 111 Filion KB. Chateau D. Targownik LE. et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut 2014; 63: 552-558
• 112 Bajaj JS. Zadvornova Y. Heuman DM. et al. Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol 2009; 104: 1130-1134
• 113 Campbell MS. Obstein K. Reddy KR. et al. Association between proton pump inhibitor use and spontaneous bacterial peritonitis. Digestive diseases and sciences 2008; 53: 394-398
• 114 Deshpande A. Pasupuleti V. Thota P. et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Journal of gastroenterology and hepatology 2013; 28: 235-242
• 115 Min YW. Lim KS. Min BH. et al. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Aliment Pharmacol Ther 2014; 40: 695-704
• 116 Ratelle M. Perreault S. Villeneuve JP. et al. Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Canadian journal of gastroenterology & hepatology 2014; 28: 330-334
• 117 Trikudanathan G. Israel J. Cappa J. et al. Association between proton pump inhibitors and spontaneous bacterial peritonitis in cirrhotic patients – a systematic review and meta-analysis. International journal of clinical practice 2011; 65: 674-678
• 118 O'Leary JG. Reddy KR. Wong F. et al. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol 2015; 13: 753-759.e751–752
• 119 Dultz G. Piiper A. Zeuzem S. et al. Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis. Aliment Pharmacol Ther 2015; 41: 459-466
• 120 Gupta A. Dhiman RK. Kumari S. et al. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. Journal of hepatology 2010 53. 849-855
• 121 Lo EA. Wilby KJ. Ensom MH. Use of proton pump inhibitors in the management of gastroesophageal varices: a systematic review. The Annals of pharmacotherapy 2015 49. 207-219
• 122 Huang J. Cao Y. Liao C. et al. Effect of histamine-2-receptor antagonists versus sucralfate on stress ulcer prophylaxis in mechanically ventilated patients: a meta-analysis of 10 randomized controlled trials. Crit Care 2010 14. R194
• 123 Robert-Koch-Institut. Prävention der nosokomialen beatmungsassoziierten Pneumonie. In: für K, und K, (KRINKO) I eds, Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz 2013: 1578-1590 https://www.rki.de/DE/Content/Infekt/Krankenhaushygiene/Kommission/Downloads/Pneumo_Rili.pdf?__blob=publicationFile
• 124 Juul-Hansen P. Rydning A. Clinical and pathophysiological consequences of on-demand treatment with PPI in endoscopy-negative reflux disease. Is rebound hypersecretion of acid a problem?. Scandinavian journal of gastroenterology 2011 46. 398-405
• 125 Reimer C. Sondergaard B. Hilsted L. et al. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009 137. 80-87, 87.e81
• 126 Lodrup AB. Reimer C. Bytzer P. Systematic review: symptoms of rebound acid hypersecretion following proton pump inhibitor treatment. Scandinavian journal of gastroenterology 2013 48. 515-522
• 127 Haastrup P. Paulsen MS. Begtrup LM. et al. Strategies for discontinuation of proton pump inhibitors: a systematic review. Family practice 2014 31. 625-630
• 128 Martin FC. Chenevix-Trench G. Yeomans ND. Systematic review with meta-analysis: fundic gland polyps and proton pump inhibitors. Aliment Pharmacol Ther 2016 44. 915-925
• 129 Huang CZ. Lai RX. Mai L. et al. Relative risk factors associated with the development of fundic gland polyps. European journal of gastroenterology & hepatology 2014 26. 1217-1221
• 130 Song H. Zhu J. Lu D. Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. The Cochrane database of systematic reviews 2014; 12: Cd010623
• 131 Lundell L. Vieth M. Gibson F. et al. Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharmacol Ther 2015; 42: 649-663
• 132 Gomm W. von Holt K. Thomé F. et al. Association of proton pump inhibitors with risk of dementia: A pharmacoepidemiological claims data analysis. JAMA Neurology 2016; DOI: 10.1001/jamaneurol.2015.4791.