Peer reviewer: Frank I Tovey, OBE, ChM, FRCS, Honorary Research Felllow, Department of Surgery, University College London, London, United Kingdom
S- Editor Tian L L- Editor O'Neill M E- Editor Lin YP
The proton pump inhibitors (PPIs) as a class are remarkably safe and effective for persons with peptic ulcer disorders. Serious adverse events are extremely rare for PPIs, with case reports of interstitial nephritis with omeprazole, hepatitis with omeprazole and lansoprazole, and disputed visual disturbances with pantoprazole and omeprazole. PPI use is associated with the development of fundic gland polyps (FGP); stopping PPIs is associated with regression of FGP. In the absence of Helicobacter pylori infection, the long-term use of PPIs has not been convincingly proven to cause or be associated with the progression of pre-existing chronic gastritis or gastric atrophy or intestinal metaplasia. Mild/modest hypergastrinemia is a physiological response to the reduction in gastric acid secretion due to any cause. The long-term use of PPIs has not been convincingly proven to cause enterochromaffin-like cell hyperplasia or carcinoid tumors. PPIs increase the risk of community acquired pneumonia, but not of hospital acquired (nosocomial) pneumonia. There is no data to support particular care in prescribing PPI therapy due to concerns about risk of hip fracture with the long-term use of PPIs. Long-term use of PPIs does not lead to vitamin B12 deficiencies, except possibly in the elderly, or in persons with Zollinger-Ellison Syndrome who are on high doses of PPI for prolonged periods of time. There is no convincingly proven data that PPIs increase the risk of Clostridium difficile-associated diarrhea in persons in the community. The discontinuation of PPIs may result in rebound symptoms requiring further and even continuous PPI use for suppression of symptoms. As with all medications, the key is to use PPIs only when clearly indicated, and to reassess continued use so that long-term therapy is used judiciously. Thus, in summary, the PPIs are a safe class of medications to use long-term in persons in whom there is a clear need for the maintenance of extensive acid inhibition.
The risk of minor adverse effects from proton pump inhibitors (PPIs) is low, approximately 1%-3%, with rates of withdrawal from clinical research studies being 1%-2%, with no significant differences noted between the PPIs[1-6]. The risk of symptomatic adverse effects with the PPIs is low as well. In pooled data from published trials involving 2812 patients, omeprazole was reported as causing headache (2.4%), diarrhea (1.9%), nausea (0.9%), and rash (1.1%), a profile similar to that of cimetidine and ranitidine. In a prospective follow-up study of 5669 patients on lansoprazole, the most common reported adverse effects were diarrhea (4.1%), headache (2.9%), and nausea (2.6%). A similar profile has been reported for pantoprazole: diarrhea, 1.5%; headache, 1.3%; dizziness, 0.7%; pruritus, 0.5%; rash, 0.4%; and nausea, 0.015%. Compiled data from 3556 patients taking rabeprazole for up to one year demonstrated that the most common adverse effect was headache with an incidence (2.4%) similar to placebo (3.1%).
Serious adverse events are rare, with case reports of interstitial nephritis with omeprazole, hepatitis with omeprazole and lansoprazole[10-12], and disputed visual disturbances with pantoprazole and omeprazole[13,14]. An anticipated physiological effect of acid suppression with PPIs is an elevated serum gastrin concentration, which occurs with all PPIs. Gastrin elevation may be higher with omeprazole than with pantoprazole, and higher with lansoprazole than with omeprazole[15-17], and higher with rabeprazole than with omeprazole. This variation in PPI-associated elevation of gastrin concentration is not clinically relevant.
Some persons with dyspeptic conditions such as gastroesophageal reflux disease (GERD) may need to be maintained long-term on PPIs. For this reason, we have reviewed the literature on possible long-term adverse effects of PPIs. Narrative or qualitative reviews, when compared to their systematic review cousins, trade off depth in favor of breadth. After all, reviews can be comprehensive and primary, or narrow in scope and heavily guarded against various biases. Narrative reviews remain, despite a heavy battering by hordes of high quality randomized controlled trials and mathematically endowed structured reviews, on their pedestal as a premier venue for medical educators and historians. This review fits in that important tradition, and purports to fill a need for a comprehensive review on the safety of long-term use PPIs. Mulrow published criteria for minimizing bias in narrative reviews. Deeks summed up these as being rigorous, informative, comprehensive, and explicit. Collins and Fauser, in their editorial, enforced the view of the importance of “balancing the strengths of systemic and narrative reviews”. To achieve this balance and complement a primarily journalistic approach, a search of PubMed, Google Scholar and UpToDate for articles published since 1999 on the topic of “PPI” and “safety” (and related MESH terms) was conducted to identify English language meta-analysis, publications in one of the top biomedical journals in this field (NEJM, Annals, Lancet, JAMA, American Journal of Gastroenterology, Gastroenterology, American Journal of Gastroenterology, Alimentary Pharmacology and therapeutics, Drugs, BMJ) as well as major North American and European guidelines. Checklists have been proposed for systematic and qualitative research[22,23], aiding in the review. We present this information on the long-term safety of PPIs with a series of questions, a summary of the literature, and our proposed answer.
In contrast, in H. pylori positive persons, H. pylori is associated with antral or body acute or chronic gastritis, atrophy and metaplasia. H. pylori-associated chronic gastritis may progress to gastric atrophy, intestinal metaplasia, and gastric cancer[25,27,30,31], or may not. H. pylori and PPIs may cause progression or acceleration from gastric antrum-predominant chronic gastritis to body-predominant chronic gastritis, and it is controversial whether gastric body-predominant atrophic gastritis (gastric atrophy) is a risk factor for gastric cancer. H. pylori eradication may cause regression of gastric atrophy or intestinal metaplasia[26,27,29,34-37] or may not[33,38-44].
Thus, the long-term use of PPIs has not been convincingly proven to cause or accelerate the progression of pre-existing chronic gastritis, corpus gastric atrophy or intestinal metaplasia.
PPIs modestly increase serum gastrin concentration in persons who are H. pylori-negative or positive[46,47]. While PPI’s may increase apoptosis, PPIs do not increase risk of gastric or esophageal cancer[49-51].
It is controversial whether the hypergastrinemia associated with the use of PPIs increase enterochromaffin-like (ECL) cell numbers, as well as linear or micronodular hyperplasia - Yes[52-54] in H. pylori positive persons, and No[43,56,57]. Hypergastrinemia associated with Zollinger-Ellison Syndrome (ZES), rarely is associated with an increase in ECL cell growth or ECL carcinoid. Furthermore, there is only one published report in world literature of a ZES patient treated with PPIs for associated gastric hypersecretion, who developed gastric cancer. This is probably a chance association.
Thus, mild/modest hypergastrinemia is a physiological response to a reduction in acid secretion due to any cause. The long-term use of PPIs has not been convincingly proven to cause ECL cell hyperplasia or carcinoid tumors. Even when hypergastrinemia is marked and prolonged (such as with ZES or MEN-1), gastric carcinoids are rare.
PPI use is associated with parietal cell hyperplasia, and an up to fourfold increased incidence of fundic gland polyps (FGP)[60-62]. FGP also occur in the presence of H. pylori infection, likely incidentally[63,64]. Eradication of H. pylori or stopping long-term use of PPIs is associated with regression of FGP[62,65,66]. FGP in sporadic cases is rarely associated with dysplasia, but never gastric adenocarcinoma. Dysplasia may occur in 25%-44% of gastric polyps in persons with familial adenomatous polyposis[63,68].
In summary, PPI use is associated with the development of FGP. FGP occur in the presence or absence of H. pylori infection. The eradication of H. pylori or stopping PPI is associated with regression of FGP. FGP may rarely become dysplastic, but almost exclusively this rare event is seen in persons with familial adenomatous polyposis.
PPIs may mask the symptoms of gastric cancer (GC), heal malignant gastric ulcers, or shorten survival in the patient with GC.
PPIs reduce gastric acid, and thereby reduce the bioavailability of drugs requiring intragastric acidity to maximize their absorption and bioavailability. Examples of such drugs would include ketoconazole, itraconazole and indinipur, and may reduce the effects of locally acting drugs such as sucralfate.
PPIs may alter the intestinal first pass metabolism or the hepatic clearance of some drugs, and thereby modify their pharmacodynamics. They have no effect on n-acetyl-transfer or xanthine oxidase activities, and may show a rare class action effect on vitamin K antagonists. PPIs have a low drug interaction through phase I/II effects[5,75], and may differ in their possibility of causing drug interactions. Omeprazole and lansoprazole have a high affinity for CYP2C19 and CYP3A4 but these cytochromes contribute little to rabeprazole metabolism. Pantoprazole is completely metabolized by these cytochrome enzymes, but it uniquely has no drug interactions with a wide range of drugs[72,76-78].
PPIs, with the exception of pantoprazole, have been associated with reduced effectiveness of clopidogrel and a resulting 40% increased risk of coronary stent occlusions. There is no consensus yet on how to manage this.
Thus, PPIs have an effect in common with all acid lowering therapy to reduce the absorption of acid-dependent medications. The metabolism of PPIs by hepatic cytochrome enzymes varies significantly between drugs.
PPIs reduce gastric acidity, and in patients treated long-term with high dose PPIs duodenal absorption of organic and non-organic iron may be reduced. This effect however is small, and PPIs are not associated with an increased risk of latent iron deficiency or iron deficiency.
PPIs reduce gastric acidity, which is necessary to activate pepsinogen to pepsin to release vitamin B12 from B12-containing foods. PPIs used short-term may minimally reduce the absorption of protein-bound B12 in food[83-85]. In elderly patients who may already have gastric atrophy (possibly from H. pylori infection), PPIs used long-term may reduce serum vitamin B12 concentrations[85-87]. Five out of six studies have shown that PPIs used long-term in non-elderly patients do not reduce serum vitamin B12 concentrations, and therefore body B12 stores[81,88-93].
In ZES patients treated long-term with high dose PPIs, the serum concentration of vitamin B12 may be reduced. And yet, in cystic fibrosis (CF) children with reduced secretion of pancreatic bicarbonate and increased duodenal acidity, there is no reduction in the intestinal absorption of B12.
PPIs alter osteoclastic vacuolar mechanisms which may reduce bone absorption, and thereby actually reduce the risk of OP. PPIs have no known adverse effect on vitamin D absorption or metabolism.
What is the link between PPI use and metabolic bone disease? There is a highly variable effect of acid suppression on calcium absorption[98,99]. In persons with achlorhydria due to pernicious anemia, Ca2+ absorption is normal or reduced[100,101].
The real question is whether PPI use is associated with an increased risk of osteoporosis/osteopenia, and more importantly with bone fractures. In case controlled studies, PPI use long-term is associated with an increased risk of bone fractures, and this increased risk depends on the duration and dose of chronic use of the PPI (e.g. Manitoba Population Health Research Data Repository). Use of PPI ≥ 5 years can increase the risk of osteoporotic fractures by 1.62-fold (95% CI: 1.02-2.58). Other studies confirm that use of PPI ≥ 7 years increases the risk of osteoporotic hip fractures by 4.55-fold (95% CI: 1.68-12.29) and PPI use for 6-12 mo has been reported to be associated with an increased risk of osteoporotic hip and spine fractures[103-105]. Osteoporotic fractures of the hip and spine may be associated with many factors, which must be carefully taken into account in any case-controlled study which suggests a new association, such as the use of PPIs. However, case control studies on the risk of OP may be criticized on a methodological basis, such as the lack of appropriate stratification of the risk of other factors known to be associated with an increased risk of OP. The Canadian Association of Gastroenterology (CAG) position paper suggests that “current data would not support particular care in prescribing PPI therapy due to concern about risk of hip fracture”.
What is the physiological background to speculating that PPIs might result in pulmonary complications? PPI use is associated with increased intragastric aerobic bacteria, and with the production of acetaldehyde from alcohol. The increased bacterial colonization of the stomach observed with PPI users may be associated with pulmonary micro-aspiration and lung colonization[109,110]. In addition, it is postulated that secretions from the oropharynx may pass by micro-aspiration into the lower lung airways. Furthermore, lung colonization may occur as a result of mechanisms other than micro-aspiration of gastric contents, because different organisms may grow from cultures of gastric juice and from bronchoalveolar lavage.
From the clinical perspective, the risk of community acquired pneumonia (CAP) is 0.6 per 100 person years. In persons on PPIs, the odds ratio (OR) is 1.89 (95% CI: 1.36-2.62) for current PPI use and 1.5 (95% CI: 1.3-1.7) for past PPI use (95% CI: 0.9-1.6, and 0.8-1.3, respectively).
In the short-term, PPI use increases the risk of CAP: use of PPI for 2 d, OR = 6.53 (95% CI: 3.95-10.80); for 7 d, OR = 3.79 (95% CI: 2.65-5.42); for 14 d, OR = 3.21 (95% CI: 2.46-4.18); but long-term use of PPIs does not increase the risk of CAP, and furthermore meta-analyses have shown that there is no significant association between PPIs and CAP.
In contrast, PPIs do not increase the risk of hospital acquired (nosocomial) pneumonia (NP). In fact, there is a reduced risk of NP in patients with nasogastric tubes on a PPI. For ventilated pediatric patients in ICU, there is no increased risk of NP[117-119].
Thus, short-term PPI use increases the risk of CAP, but PPI use does not increase the risk of hospital acquired pneumonia.
There are numerous risk factors for CDAD (use of antibiotics, age, contact with an infected patient or healthcare worker, crowding, lack of cleanliness, post-pyloric tube feeding, patient immunosuppression). These factors must be taken into account for the attribution of risk, e.g. before assigning a possible role to a new factor, such as PPIs. Some observational studies show an association between PPI use and risk of CDAD[121-132]. For example, for PPI use and CDAD in chronic renal failure patients, the AOR is 5.7 (95% CI: 1.3-39.1) (P = 0.02). In meta-analyses of studies of CDAD and PPIs, the AOR is 1.96 (95% CI: 1.28-3.00). Some of these reports involve a hypervirulent strain of C. difficile, and after correcting for other factors such as antibiotic use, there is no association with PPIs. The bottom line is that there is no convincingly proven data that PPIs increase the risk of CDAD[134,135].
It is thought that PPIs have a minor effect on altering the intestinal bacterial microbiota. Observational studies have suggested that PPIs may or may not increase risk of enteric infections.
The use and subsequent withdrawal of PPIs may be associated with an exaggeration of, or new onset of, acid-related symptoms. PPIs are a medication that is generously prescribed for a variety of symptoms that are thought, and not necessarily confirmed, to be acid-induced. One reason for this is the relatively low number of adverse effects that have been shown in the short- or long-term. One study suggests that symptoms that commence following the discontinuation of PPIs due to rebound acid hypersecretion may be as troublesome as the symptoms that the PPIs were being used to treat in the first place. Because of these rebound symptoms, there may be a need for further and continuous PPI use. As with all medications, the key is to use PPIs only when clearly indicated, and to reassess continued use so that long-term therapy is used judiciously.
The risk of false-negative urea breath tests (UBT) for the diagnosis of an H. pylori infection is lower for pantoprazole[142,143]. While it is recommended that acid suppression therapy should be discontinued prior to a UBT, the false-negative effect is lower for pantoprazole.
The biological plausibility is poor for the possibility that PPI use is associated with an increased risk of colorectal cancer or adenomatous polyps, and there is no clinical data to suggest this possibility.
Peer reviewer: Frank I Tovey, OBE, ChM, FRCS, Honorary Research Felllow, Department of Surgery, University College London, London, United Kingdom
S- Editor Tian L L- Editor O'Neill M E- Editor Lin YP
|1.||Spencer CM, Faulds D. Lansoprazole. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy in acid-related disorders. Drugs. 1994;48:404-430.|
|2.||Besancon M, Simon A, Sachs G, Shin JM. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem. 1997;272:22438-22446.|
|3.||Langtry HD, Wilde MI. Lansoprazole. An update of its pharmacological properties and clinical efficacy in the management of acid-related disorders. Drugs. 1997;54:473-500.|
|4.||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.|
|5.||Fitton A, Wiseman L. Pantoprazole. A review of its pharmacological properties and therapeutic use in acid-related disorders. Drugs. 1996;51:460-482.|
|6.||Wilde MI, McTavish D. Omeprazole. An update of its pharmacology and therapeutic use in acid-related disorders. Drugs. 1994;48:91-132.|
|7.||Benet LZ, Zech K. Pharmacokinetics--a relevant factor for the choice of a drug? Aliment Pharmacol Ther. 1994;8 Suppl 1:25-32.|
|8.||Tucker GT. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther. 1994;8 Suppl 1:33-38.|
|9.||Unge P, Andersson T. Drug interactions with proton pump inhibitors. Drug Saf. 1997;16:171-179.|
|10.||Koury SI, Stone CK, La Charité DD. Omeprazole and the development of acute hepatitis. Eur J Emerg Med. 1998;5:467-469.|
|11.||Viana de Miguel C, Alvarez García M, Sánchez Sánchez A, Carvajal García-Pando A. [Lansoprazole-induced hepatitis]. Med Clin (Barc). 1997;108:599.|
|12.||Yip D, Kovac S, Jardine M, Horvath J, Findlay M. Omeprazole-induced interstitial nephritis. J Clin Gastroenterol. 1997;25:450-452.|
|13.||Schönhöfer PS, Werner B, Tröger U. Ocular damage associated with proton pump inhibitors. BMJ. 1997;314:1805.|
|14.||García Rodríguez LA, Mannino S, Wallander MA, Lindblom B. A cohort study of the ocular safety of anti-ulcer drugs. Br J Clin Pharmacol. 1996;42:213-216.|
|15.||Bruley des Varannes S, Levy P, Lartigue S, Dellatolas F, Lemaire M, Galmiche JP. Comparison of lansoprazole with omeprazole on 24-hour intragastric pH, acid secretion and serum gastrin in healthy volunteers. Aliment Pharmacol Ther. 1994;8:309-314.|
|16.||Koop H, Kuly S, Flug M, Schneider A, Rose K. Comparison of 24-h intragstric pH and 24-h gastrin profiles during therapy with the proton pump inhibitors pantoprazole and omeprazole (abstract). Gut. 1994;35:A79.|
|17.||Londong W. Effect of pantoprazole on 24-h intragastric pH and serum gastrin in humans. Aliment Pharmacol Ther. 1994;8 Suppl 1:39-46.|
|18.||Williams MP, Sercombe J, Hamilton MI, Pounder RE. A placebo-controlled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy male subjects. Aliment Pharmacol Ther. 1998;12:1079-1089.|
|19.||Mulrow CD. The medical review article: state of the science. Ann Intern Med. 1987;106:485-488.|
|20.||Deeks J. Do antibiotics help children with acute otitis media? How to use an overview. Evidence-based general practice. 2nd Edition. Edinburgh: Churchill-Livingstone 1998; .|
|21.||Collins JA, Fauser BC. Balancing the strengths of systematic and narrative reviews. Hum Reprod Update. 2005;11:103-104.|
|22.||Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151:W65-W94.|
|23.||Clark JP. How to peer review a qualitative manuscript. Peer review in health sciences. 2nd ed. London: BMJ Books 2003; 219-235.|
|24.||Diebold MD, Richardson S, Duchateau A, Bigard MA, Colin R, Cortot A, Fauchère JL, Zeitoun P. Factors influencing corpus argyrophil cell density and hyperplasia in reflux esophagitis patients treated with antisecretory drugs and controls. Dig Dis Sci. 1998;43:1629-1635.|
|25.||Lundell L, Havu N, Miettinen P, Myrvold HE, Wallin L, Julkunen R, Levander K, Hatlebakk JG, Liedman B, Lamm M. Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial. Aliment Pharmacol Ther. 2006;23:639-647.|
|26.||Lamberts R, Brunner G, Solcia E. Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa. Digestion. 2001;64:205-213.|
|27.||Kuipers EJ, Lundell L, Klinkenberg-Knol EC, Havu N, Festen HP, Liedman B, Lamers CB, Jansen JB, Dalenback J, Snel P. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med. 1996;334:1018-1022.|
|28.||Lundell L, Miettinen P, Myrvold HE, Pedersen SA, Thor K, Andersson A, Hattlebakk J, Havu N, Janatuinen E, Levander K. Lack of effect of acid suppression therapy on gastric atrophy. Nordic Gerd Study Group. Gastroenterology. 1999;117:319-326.|
|29.||Kuipers EJ, Uyterlinde AM, Peña AS, Roosendaal R, Pals G, Nelis GF, Festen HP, Meuwissen SG. Long-term sequelae of Helicobacter pylori gastritis. Lancet. 1995;345:1525-1528.|
|30.||Klinkenberg-Knol EC, Nelis F, Dent J, Snel P, Mitchell B, Prichard P, Lloyd D, Havu N, Frame MH, Romàn J. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology. 2000;118:661-669.|
|31.||Moayyedi P, Wason C, Peacock R, Walan A, Bardhan K, Axon AT, Dixon MF. Changing patterns of Helicobacter pylori gastritis in long-standing acid suppression. Helicobacter. 2000;5:206-214.|
|32.||Hirschowitz BI. Pernicious anemia and stomach cancer. Scand J Gastroenterol. 2001;36:896.|
|33.||Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Mashiba H, Sasaki N, Taniyama K. Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during long-term acid-suppressive treatment in Japan. Aliment Pharmacol Ther. 2000;14:1345-1352.|
|34.||Ohkusa T, Fujiki K, Takashimizu I, Kumagai J, Tanizawa T, Eishi Y, Yokoyama T, Watanabe M. Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Ann Intern Med. 2001;134:380-386.|
|35.||Kuipers EJ, Nelis GF, Klinkenberg-Knol EC, Snel P, Goldfain D, Kolkman JJ, Festen HP, Dent J, Zeitoun P, Havu N. Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial. Gut. 2004;53:12-20.|
|36.||Kuipers EJ. Proton pump inhibitors and Helicobacter pylori gastritis: friends or foes? Basic Clin Pharmacol Toxicol. 2006;99:187-194.|
|37.||Malfertheiner P, Megraud F, O'Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56:772-781.|
|38.||Robinson M. Drugs, bugs, and esophageal pH profiles. Yale J Biol Med. 1999;72:169-172.|
|39.||Stolte M, Meining A, Schmitz JM, Alexandridis T, Seifert E. Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during 12 months of treatment with omeprazole and lansoprazole in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 1998;12:247-253.|
|40.||McColl KE, Murray LS, Gillen D. Omeprazole and accelerated onset of atrophic gastritis. Gastroenterology. 2000;118:239.|
|41.||McColl KE. Helicobacter pylori infection and long term proton pump inhibitor therapy. Gut. 2004;53:5-7.|
|42.||Gillen D, McColl KE. Problems associated with the clinical use of proton pump inhibitors. Pharmacol Toxicol. 2001;89:281-286.|
|43.||Singh P, Indaram A, Greenberg R, Visvalingam V, Bank S. Long term omeprazole therapy for reflux esophagitis:follow-up in serum gastrin levels,EC cell hyperplasia and neoplasia. World J Gastroenterol. 2000;6:789-792.|
|44.||Geboes K, Dekker W, Mulder CJ, Nusteling K. Long-term lansoprazole treatment for gastro-oesophageal reflux disease: clinical efficacy and influence on gastric mucosa. Aliment Pharmacol Ther. 2001;15:1819-1826.|
|45.||Dockray GJ. Clinical endocrinology and metabolism. Gastrin. Best Pract Res Clin Endocrinol Metab. 2004;18:555-568.|
|46.||Arroyo Villarino MT, Lanas Arbeloa A, Esteva Díaz F, Ortego Fernández de Retana J, Sainz Samitier R. Effects of long-term treatment with lansoprazole and omeprazole on serum gastrin and the fundic mucosa. Rev Esp Enferm Dig. 1997;89:347-356.|
|47.||Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, Bloemena E, Nelis GF, Festen HP, Jansen EH, Biemond I, Lamers CB, Meuwissen SG. Hypergastrinaemia during long-term omeprazole therapy: influences of vagal nerve function, gastric emptying and Helicobacter pylori infection. Aliment Pharmacol Ther. 1998;12:605-612.|
|48.||Przemeck SM, Varro A, Berry D, Steele I, Wang TC, Dockray GJ, Pritchard DM. Hypergastrinemia increases gastric epithelial susceptibility to apoptosis. Regul Pept. 2008;146:147-156.|
|49.||Bateman DN, Colin-Jones D, Hartz S, Langman M, Logan RF, Mant J, Murphy M, Paterson KR, Rowsell R, Thomas S. Mortality study of 18 000 patients treated with omeprazole. Gut. 2003;52:942-946.|
|50.||Crane SJ, Locke GR 3rd, Harmsen WS, Diehl NN, Zinsmeister AR, Melton LJ 3rd, Romero Y, Talley NJ. Subsite-specific risk factors for esophageal and gastric adenocarcinoma. Am J Gastroenterol. 2007;102:1596-1602.|
|51.||La Vecchia C, Tavani A. A review of epidemiological studies on cancer in relation to the use of anti-ulcer drugs. Eur J Cancer Prev. 2002;11:117-123.|
|52.||Solcia E, Fiocca R, Havu N, Dalväg A, Carlsson R. Gastric endocrine cells and gastritis in patients receiving long-term omeprazole treatment. Digestion. 1992;51 Suppl 1:82-92.|
|53.||Lamberts R, Creutzfeldt W, Strüber HG, Brunner G, Solcia E. Long-term omeprazole therapy in peptic ulcer disease: gastrin, endocrine cell growth, and gastritis. Gastroenterology. 1993;104:1356-1370.|
|54.||Klinkenberg-Knol EC, Festen HP, Meuwissen SG. Pharmacological management of gastro-oesophageal reflux disease. Drugs. 1995;49:695-710.|
|55.||Merchant SH, VanderJagt T, Lathrop S, Amin MB. Sporadic duodenal bulb gastrin-cell tumors: association with Helicobacter pylori gastritis and long-term use of proton pump inhibitors. Am J Surg Pathol. 2006;30:1581-1587.|
|56.||Creutzfeldt W, Lamberts R, Stöckmann F, Brunner G. Quantitative studies of gastric endocrine cells in patients receiving long-term treatment with omeprazole. Scand J Gastroenterol Suppl. 1989;166:122-128; discussion 138-139.|
|57.||Pashankar DS, Israel DM, Jevon GP, Buchan AM. Effect of long-term omeprazole treatment on antral G and D cells in children. J Pediatr Gastroenterol Nutr. 2001;33:537-542.|
|58.||Genta RM, Rindi G, Fiocca R, Magner DJ, D'Amico D, Levine DS. Effects of 6-12 months of esomeprazole treatment on the gastric mucosa. Am J Gastroenterol. 2003;98:1257-1265.|
|59.||Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006;98:4-19.|
|60.||el-Zimaity HM, Jackson FW, Graham DY. Fundic gland polyps developing during omeprazole therapy. Am J Gastroenterol. 1997;92:1858-1860.|
|61.||Raghunath AS, O'Morain C, McLoughlin RC. Review article: the long-term use of proton-pump inhibitors. Aliment Pharmacol Ther. 2005;22 Suppl 1:55-63.|
|62.||Jalving M, Koornstra JJ, Wesseling J, Boezen HM, DE Jong S, Kleibeuker JH. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther. 2006;24:1341-1348.|
|63.||Wu TT, Kornacki S, Rashid A, Yardley JH, Hamilton SR. Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis. Am J Surg Pathol. 1998;22:293-298.|
|64.||Sakai N, Tatsuta M, Hirasawa R, Iishi H, Baba M, Yokota Y, Ikeda F. Low prevalence of Helicobacter pylori infection in patients with hamartomatous fundic polyps. Dig Dis Sci. 1998;43:766-772.|
|65.||Watanabe N, Seno H, Nakajima T, Yazumi S, Miyamoto S, Matsumoto S, Itoh T, Kawanami C, Okazaki K, Chiba T. Regression of fundic gland polyps following acquisition of Helicobacter pylori. Gut. 2002;51:742-745.|
|66.||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.|
|67.||Jalving M, Koornstra JJ, Götz JM, van der Waaij LA, de Jong S, Zwart N, Karrenbeld A, Kleibeuker JH. High-grade dysplasia in sporadic fundic gland polyps: a case report and review of the literature. Eur J Gastroenterol Hepatol. 2003;15:1229-1233.|
|68.||Bertoni G, Sassatelli R, Nigrisoli E, Pennazio M, Tansini P, Arrigoni A, Rossini FP, Ponz de Leon M, Bedogni G. Dysplastic changes in gastric fundic gland polyps of patients with familial adenomatous polyposis. Ital J Gastroenterol Hepatol. 1999;31:192-197.|
|69.||Taylor TV, Boom SJ, Blower AL, McMahon RF, Lawler W. Healing of a malignant gastric ulcer with cimetidine. J R Coll Surg Edinb. 1988;33:339-340.|
|70.||Tønnesen H, Knigge U, Bülow S, Damm P, Fischerman K, Hesselfeldt P, Hjortrup A, Pedersen IK, Pedersen VM, Siemssen OJ. Effect of cimetidine on survival after gastric cancer. Lancet. 1988;2:990-992.|
|71.||Langman MJ, Dunn JA, Whiting JL, Burton A, Hallissey MT, Fielding JW, Kerr DJ. Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer. British Stomach Cancer Group. Br J Cancer. 1999;81:1356-1362.|
|72.||Blume H, Donath F, Warnke A, Schug BS. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf. 2006;29:769-784.|
|73.||Hartmann M, Zech K, Bliesath H, Steinijans VW, Koch H, Wurst W, Mascher H. Pantoprazole lacks induction of CYP1A2 activity in man. Int J Clin Pharmacol Ther. 1999;37:159-164.|
|74.||Labenz J, Petersen KU, Rösch 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.|
|75.||Huber R, Kohl B, Sachs G, Senn-Bilfinger J, Simon WA, Sturm E. Review article: the continuing development of proton pump inhibitors with particular reference to pantoprazole. Aliment Pharmacol Ther. 1995;9:363-378.|
|76.||Masubuchi N, Li AP, Okazaki O. An evaluation of the cytochrome P450 induction potential of pantoprazole in primary human hepatocytes. Chem Biol Interact. 1998;114:1-13.|
|77.||Portolés A, Calvo A, Terleira A, Laredo L, Resplandy G, Gorostiaga C, Moreno A. Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial. J Clin Pharmacol. 2006;46:1195-1203.|
|78.||Vakily M, Amer F, Kukulka MJ, Andhivarothai N. Coadministration of lansoprazole and naproxen does not affect the pharmacokinetic profile of methotrexate in adult patients with rheumatoid arthritis. J Clin Pharmacol. 2005;45:1179-1186.|
|79.||Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180:713-718.|
|80.||PPI interactions with clopidogrel revisited. Med Lett Drugs Ther. 2009;51:13-14.|
|81.||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.|
|82.||Koop H, Bachem MG. Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy. J Clin Gastroenterol. 1992;14:288-292.|
|83.||Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994;120:211-215.|
|84.||Saltzman JR, Kemp JA, Golner BB, Pedrosa MC, Dallal GE, Russell RM. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr. 1994;13:584-591.|
|85.||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.|
|86.||Kapadia C. Cobalamin (Vitamin B12) deficiency: is it a problem for our aging population and is the problem compounded by drugs that inhibit gastric acid secretion? J Clin Gastroenterol. 2000;30:4-6.|
|87.||Wolters M, Ströhle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med. 2004;39:1256-1266.|
|88.||den Elzen WP, Groeneveld Y, de Ruijter W, Souverijn JH, le Cessie S, Assendelft WJ, Gussekloo J. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008;27:491-497.|
|89.||Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol. 2000;30:29-33.|
|90.||Maton PN, Vinayek R, Frucht H, McArthur KA, Miller LS, Saeed ZA, Gardner JD, Jensen RT. Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology. 1989;97:827-836.|
|91.||Mitchell SL, Rockwood K. The association between antiulcer medication and initiation of cobalamin replacement in older persons. J Clin Epidemiol. 2001;54:531-534.|
|92.||Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother. 2002;36:812-816.|
|93.||Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, Bloemena EC, Sandell M, Nelis GF, Snel P, Festen HP, Meuwissen SG. Atrophic gastritis during long-term omeprazole therapy affects serum vitamin B12 levels. Aliment Pharmacol Ther. 1999;13:1343-1346.|
|94.||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.|
|95.||Insogna KL. The effect of proton pump-inhibiting drugs on mineral metabolism. Am J Gastroenterol. 2009;104 Suppl 2:S2-S4.|
|96.||McColl KE. Effect of proton pump inhibitors on vitamins and iron. Am J Gastroenterol. 2009;104 Suppl 2:S5-S9.|
|97.||Sarges R, Gallagher A, Chambers TJ, Yeh LA. Inhibition of bone resorption by H+/K(+)-ATPase inhibitors. J Med Chem. 1993;36:2828-2830.|
|98.||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.|
|99.||Serfaty-Lacrosniere C, Wood RJ, Voytko D, Saltzman JR, Pedrosa M, Sepe TE, Russell RR. 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.|
|100.||Eastell R, Vieira NE, Yergey AL, Wahner HW, Silverstein MN, Kumar R, Riggs BL. Pernicious anaemia as a risk factor for osteoporosis. Clin Sci (Lond). 1992;82:681-685.|
|101.||Recker RR. Calcium absorption and achlorhydria. N Engl J Med. 1985;313:70-73.|
|102.||Richards JB, Goltzman D. Proton pump inhibitors: balancing the benefits and potential fracture risks. CMAJ. 2008;179:306-307.|
|103.||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.|
|104.||Geller JL, Adams JS. Proton pump inhibitor therapy and hip fracture risk. JAMA. 2007;297:1429; author reply 1429-1430.|
|105.||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.|
|106.||Laine L. Proton pump inhibitors and bone fractures? Am J Gastroenterol. 2009;104 Suppl 2:S21-S26.|
|107.||Moayyedi P, Cranney A. Hip fracture and proton pump inhibitor therapy: balancing the evidence for benefit and harm. Am J Gastroenterol. 2008;103:2428-2431.|
|108.||Väkeväinen S, Tillonen J, Salaspuro M, Jousimies-Somer H, Nuutinen H, Färkkilä M. Hypochlorhydria induced by a proton pump inhibitor leads to intragastric microbial production of acetaldehyde from ethanol. Aliment Pharmacol Ther. 2000;14:1511-1518.|
|109.||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.|
|110.||Theisen J, Nehra D, Citron D, Johansson J, Hagen JA, Crookes PF, DeMeester SR, Bremner CG, DeMeester TR, Peters JH. 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.|
|111.||Simms HH, DeMaria E, McDonald L, Peterson D, Robinson A, Burchard KW. Role of gastric colonization in the development of pneumonia in critically ill trauma patients: results of a prospective randomized trial. J Trauma. 1991;31:531-536; discussion 536-537.|
|112.||Martinez-Pellús AE, Merino P, Bru M, Conejero R, Seller G, Muñoz C, Fuentes T, Gonzalez G, Alvarez B. Can selective digestive decontamination avoid the endotoxemia and cytokine activation promoted by cardiopulmonary bypass? Crit Care Med. 1993;21:1684-1691.|
|113.||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.|
|114.||Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149:391-398.|
|115.||Sultan N, Nazareno J, Gregor J. Association between proton pump inhibitors and respiratory infections: a systematic review and meta-analysis of clinical trials. Can J Gastroenterol. 2008;22:761-766.|
|116.||Yamanaka Y, Mammoto T, Kita T, Kishi Y. A study of 13 patients with gastric tube in place after esophageal resection: use of omeprazole to decrease gastric acidity and volume. J Clin Anesth. 2001;13:370-373.|
|117.||Yildizdas D, Yapicioglu H, Yilmaz HL. Occurrence of ventilator-associated pneumonia in mechanically ventilated pediatric intensive care patients during stress ulcer prophylaxis with sucralfate, ranitidine, and omeprazole. J Crit Care. 2002;17:240-245.|
|118.||Levy MJ, Seelig CB, Robinson NJ, Ranney JE. Comparison of omeprazole and ranitidine for stress ulcer prophylaxis. Dig Dis Sci. 1997;42:1255-1259.|
|119.||Kantorova I, Svoboda P, Scheer P, Doubek J, Rehorkova D, Bosakova H, Ochmann J. Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial. Hepatogastroenterology. 2004;51:757-761.|
|120.||Fordtran JS. Colitis due to Clostridium difficile toxins: underdiagnosed, highly virulent, and nosocomial. Proc (Bayl Univ Med Cent). 2006;19:3-12.|
|121.||Hauben M, Horn S, Reich L, Younus M. Association between gastric acid suppressants and Clostridium difficile colitis and community-acquired pneumonia: analysis using pharmacovigilance tools. Int J Infect Dis. 2007;11:417-422.|
|122.||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.|
|123.||Dubberke ER, Reske KA, Yan Y, Olsen MA, McDonald LC, Fraser VJ. Clostridium difficile--associated disease in a setting of endemicity: identification of novel risk factors. Clin Infect Dis. 2007;45:1543-1549.|
|124.||Kazakova SV, Ware K, Baughman B, Bilukha O, Paradis A, Sears S, Thompson A, Jensen B, Wiggs L, Bessette J. A hospital outbreak of diarrhea due to an emerging epidemic strain of Clostridium difficile. Arch Intern Med. 2006;166:2518-2524.|
|125.||Cunningham R, Dale B, Undy B, Gaunt N. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243-245.|
|126.||Yearsley KA, Gilby LJ, Ramadas AV, Kubiak EM, Fone DL, Allison MC. Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther. 2006;24:613-619.|
|127.||Peled N, Pitlik S, Samra Z, Kazakov A, Bloch Y, Bishara J. Predicting Clostridium difficile toxin in hospitalized patients with antibiotic-associated diarrhea. Infect Control Hosp Epidemiol. 2007;28:377-381.|
|128.||Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.|
|129.||Al-Tureihi FI, Hassoun A, Wolf-Klein G, Isenberg H. Albumin, length of stay, and proton pump inhibitors: key factors in Clostridium difficile-associated disease in nursing home patients. J Am Med Dir Assoc. 2005;6:105-108.|
|130.||Beaulieu M, Williamson D, Pichette G, Lachaine J. Risk of Clostridium diffi1ile-associated disease among patients receiving proton-pump inhibitors in a Quebec medical intensive care unit. Infect Control Hosp Epidemiol. 2007;28:1305-1307.|
|131.||Jayatilaka S, Shakov R, Eddi R, Bakaj G, Baddoura WJ, DeBari VA. Clostridium difficile infection in an urban medical center: five-year analysis of infection rates among adult admissions and association with the use of proton pump inhibitors. Ann Clin Lab Sci. 2007;37:241-247.|
|132.||Akhtar AJ, Shaheen M. Increasing incidence of clostridium difficile-associated diarrhea in African-American and Hispanic patients: association with the use of proton pump inhibitor therapy. J Natl Med Assoc. 2007;99:500-504.|
|133.||Aseeri M, Schroeder T, Kramer J, Zackula R. 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.|
|134.||Pépin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, Leblanc M, Rivard G, Bettez M, Primeau V. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41:1254-1260.|
|135.||Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294:2989-2995.|
|136.||Williams C, McColl KE. Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther. 2006;23:3-10.|
|137.||Elphick DA, Chew TS, Higham SE, Bird N, Ahmad A, Sanders DS. Small bowel bacterial overgrowth in symptomatic older people: can it be diagnosed earlier? Gerontology. 2005;51:396-401.|
|138.||Garcia Rodríguez LA, Ruigómez A. Gastric acid, acid-suppressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology. 1997;8:571-574.|
|139.||Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol. 2009;104 Suppl 2:S10-S16.|
|140.||Vakil N. Acid inhibition and infections outside the gastrointestinal tract. Am J Gastroenterol. 2009;104 Suppl 2:S17-S20.|
|141.||Reimer C, Søndergaard 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.e1.|
|142.||Levine A, Shevah O, Shabat-Sehayek V, Aeed H, Boaz M, Moss SF, Niv Y, Avni Y, Shirin H. Masking of 13C urea breath test by proton pump inhibitors is dependent on type of medication: comparison between omeprazole, pantoprazole, lansoprazole and esomeprazole. Aliment Pharmacol Ther. 2004;20:117-122.|
|143.||Parente F, Sainaghi M, Sangaletti O, Imbesi V, Maconi G, Anderloni A, Bianchi Porro G. Different effects of short-term omeprazole, lansoprazole or pantoprazole on the accuracy of the (13)C-urea breath test. Aliment Pharmacol Ther. 2002;16:553-557.|