Revista de Ciencias J. D. Yakobi-Hancock, L. A. Ladino and J. P. D. Abbatt  Weingartner, E., Burtscher, H. and Baltensperger, U. (1997). Hygroscopic properites of carbon and diesel soot particles, Atmospheric Environment Atmospheric Environment, 31(15), 2311–2327. Facultad de Ciencias Naturales y Exactas Universidad del Valle  Yakobi-Hancock, J. D., L. Ladino, and J. Abbatt (2013). Feldspar minerals as
Helicobacter pylori infection and the use of nsaids
Best Practice & Research Clinical Gastroenterology Vol. 15, No. 5, pp. 775±785, 2001 doi:10.1053/bega.2001.0234, available online at http://www.idealibrary.com on6 Helicobacter pylori infection and the use of Franco Bazzoli MDLuca De Luca MD Department of Internal Medicine and Gastroenterology, University of Bologna, Policlinico S. Orsola, Italy David Y. Graham* MDDepartment of Medicine, Veterans' Aairs Medical Center and Baylor Col ege of Medicine, Houston, Texas, Helicobacter pylori infection and the use of non-steroidal anti-in¯ammatory drugs (NSAIDs) can each result in gastroduodenal ulcers and ulcer complications. Recent studies have suggested that there is an interaction between the two causes such that elimination of H. pylori before NSAID treatment decreases the occurrence of ulcers. This led to the conclusion of the Maastricht 2000 meeting that H. pylori eradication should be considered before embarking on long-term NSAID therapy. One of the main sources of confusion is related to the fact that prospective endoscopic studies testing various drugs for prevention of NSAID ulcers among chronic NSAID users are probably not directly applicable to problems of clinical ulcers and of ulcer complications. It has become clear that, to be interpretable clinically, such studies must provide separate analyses based on H. pylori status, history of ulcer, or an ulcer complication.
Overall, the data strongly support the notion that eradication therapy is bene®cial for primary prophylaxis. In contrast, one would expect little bene®t when NSAIDs caused the clinical ulcer (secondary prevention) and, at best, H. pylori eradication has a modest eect on the prevention of recurrent ulcer bleeding in NSAID users who have suered ulcer complications.
The data support the notion that H. pylori eradication therapy should be given to al H. pylori- infected patients with peptic ulcers irrespective of whether or not they have used NSAIDs.
Proton pump inhibitors are superior to placebo for the prevention of ulcer recurrence but are inferior to ful -dose misoprostol for the prevention of ulcers among those with NSAID ulcers and no H. pylori infection. Selective COX-2 inhibitors appear to reduce markedly, but not eliminate, ulcer complications among chronic NSAID users.
Key words: Helicobacter pylori; NSAIDs; peptic ulcer; gastric ulcer; duodenal ulcer; anti- secretory therapy.
Helicobacter pylori infection and non-steroidal anti-in¯ammatory drugs (NSAIDs) are the main aetiological risk factors for the majority of gastroduodenal ulcers and their *Address correspondence to: Veterans' Aairs Medical Center (111D), 2002 Holcombe Blvd., Houston, c 2001 Harcourt Publishers Ltd.
776 F. Bazzoli, L. De Luca and D. Y. Graham complications.There are con¯icting results regarding the role that H. pylori plays in the pathogenesis of ulcers induced by NSAIDs. The interaction between NSAIDs and H. pylori is not one of simple addition or multiplication, and the discrepant ®ndings reported re¯ect complex interaction between H. pylori and N Over 30 million individuals in the world habitually use NSAIDs; half of the users are over 60 years of age. The fact that the prevalence of H. pylori infection in this age group is high (e.g. 80%)suggests that many, if not most NSAID users with ulcers or ulcer complications will also have an H. pylori infection. Knowledge regarding the inter- relationships between H. pylori and NSAID-associated gastroduodenal lesions is important for both treatment and prevention of ulcers and ulcer complications.
Both H. pylori and NSAIDs are pathogenic factors which exert damaging eects on the mucosa and, in individual cases, could be independent, additive, synergistic, or even antagonistic.Most of the studies that have been reported have not examined the clinical situation as it occurs in practice. The tendency has been to study the eect of various interventions on endoscopic ulcers' which are often asymptomatic lesions found in studies where endoscopy is done as part of a clinical study in chronic NSAID users and which probably dier greatly from those ulcers that cause complications.
Many endoscopic ulcers would actually not qualify as ulcers' and are typically de®ned as mucosal breaks 3 mm or greater with apparent depth. We call many of these ulcers for study purposes only'. There are far fewer studies where patients presenting with a symptomatic ulcer or with an ulcer complication are followed with or without an intervention. It is likely that studies of the primary prophylaxis of ulcers and ulcer complications or the secondary prophylaxis of endoscopic and clinical ulcers would produce dierent conclusions. For example, cross-sectional studies of chronic NSAID users from the general population of rheumatology patients have not shown a dierence in prevalence of ulcers among those with or without H. pylori infection.
Similar results have been reported in a follow-up endoscopic ulcer study of what were relatively highly selected chronic NSAID users.
FINDING AN ULCER IN CHRONIC NSAID USERS: EFFECT OF H. PYLORI INFECTION The risk of developing a new ulcer in an H. pylori-infected individual is in the range of 0.5 to 1% per year. This contrasts markedly to patients with H. pylori ulcer disease where the risk of developing a recurrence over a 1-year period is in the range of 50 to 80%. The risk of a patient with an H. pylori ulcer developing an ulcer complication is also in the range of 1 to 2% per year. Again, the likelihood of a recurrent ulcer complication among patients who had previously experienced an ulcer complication is much higher: at least 12% per year. Thus if a clinical study enrolled 500 chronic NSAID users, and followed them for 1 year, the outcome of the trial would be markedly in¯uenced by the proportion of patients from each dierent risk group entered in the trial. We would expect that approximately 0.5 to 1% of those with H. pylori infection would develop new H. pylori ulcers irrespective of whether they entered the trial or not. Even if all 500 patients had active H. pylori infections, at most ®ve would develop ulcers not directly attributable to the NSAIDs. In contrast, any enrolled patient who had a prior H. pylori ulcer would have a high likelihood of an H. pylori recurrence (at least 50%) during the study and could have a major in¯uence on the outcome that would be wholly independent of the use of NSAIDs. An example would be a study comparing an H2-receptor antagonist, which is already known to reduce the rate of Helicobacter pylori infection and NSAIDs 777 recurrence of H. pylori ulcers, and a placebo. Such a study would have a bias against the placebo arm. For example, let us assume that 10% of the 500 patients had prior H. pylori ulcers and (luckily) they were randomly distributed between groups (i.e. 25 per group). The proportion of H. pylori ulcers in the H2-receptor antagonist arm would thus be proportional to the eectiveness of the therapy in preventing the recurrence of H. pylori ulcers. If the H2-receptor antagonists were completely eective (0 recurrences) and the recurrence rate of H. pylori ulcers in the placebo group was 50%, there would be 12 H. pylori ulcers among those receiving placebo. These would be added to the endoscopic ulcers occurring in each group, making the outcome dependent on both the eectiveness of the active therapy in preventing H. pylori ulcers and its eectiveness in preventing endoscopic NSAID ulcers. For example, if, as in many trials, the 1-year prevalence of endoscopic NSAID ulcers was 15%, both groups could have 38 NSAID ulcers. If the H2-receptor antagonist were completely eective in preventing H. pylori ulcer recurrences and there was a modest reduction in NSAID ulcers (e.g. 30% reduction in the number of ulcers) the total number of ulcers in the H2-receptor antagonist group would be 60% of 38, or 27 compared to 50 (38 NSAID plus 12 H. pylori ulcer recurrences). The authors would falsely conclude that the H2- receptor antagonists were highly protective (P 0.006) against NSAID ulcers. In reality, the comparison should have been 27 ulcers in the H2-receptor antagonist group (10.8%) versus 38 (15.2%) in the placebo group (P 1.0). Overall, one can conclude that if there is no interaction between H. pylori and NSAIDs, and the comparison drug has anti-ulcer eects, it is essential to exclude all those with a history of H. pylori ulcers or with ulcer complication. Otherwise one runs the risk of a major bias in favour of the drug with anti-ulcer properties. Alternatively, one must keep track of them and be prepared to analyse them separately. Because, as noted below, H. pylori and NSAIDs are likely to have an interaction, it is essential to do separate analyses based on H. pylori status, history of ulcer, or an ulcer complication.
IDENTIFICATION OF CHRONIC NSAID USERS AT RISK FOR DEVELOPMENT OF AN ULCER OR ULCER COMPLICATION Dyspeptic symptoms have not proven to be a reliable warning sign for increased risk for either an NSAID ulcer or development of a serious gastrointestinal complication of NSAID use. Uncontroversial factors that are associated with risk include advanced age, past history of an ulcer or ulcer complication (see above), high NSAID dose, the NSAID used, concomitant use of anticoagulants, serious systemic disorders, and (almost certainly) use of corticosteroids at a dose 410 mg of prednisolone daily. All of these magnify the risk of bleeding peptic ulcers in patients taking NSAIDs. Indications where there is controversy include the indication for the NSAID, sex of the patient, smoking or alcohol history, and H. pylori status.
EPIDEMIOLOGY OF NSAID-ASSOCIATED GASTROINTESTINAL Numerous studies have shown that the use of NSAIDs is associated with an approximately fourfold enhancement of the risk of gastrointestinal complications and death in elderly patients taking non-aspirin NPopulation-based studies and an endoscopy-based prospective sreport discordant results regarding risks 778 F. Bazzoli, L. De Luca and D. Y. Graham among NSAID users in relation to H. pylori infection. The problem is further com- plicated by the entry criteria in studies, the types of NSAID ulcer, and the dierent predominant type of H. pylori gastric damage (i.e. atrophic pangastritis with reduced acid secretion versus super®cial gastritis with normal acid secretion) in dierent countries. Moreover, many studies suer from methodological biases, including the use of two or more NSAIDs, lack of knowledge of the type of NSAID, dosage and duration of treatment with NSAIDs. Many studies used univariate analysis, which does allow one to consider possible interactions between multiple factors and coexisting conditions.However, studies of patients with established ulcers who take NSAIDs show a net bene®t from H. pylori eradication therapy H. pylori infection causes gastric mucosal in¯ammation. The critical factors are unknown and could include enzymes such as urease, proteolytic enzymes, antioxidant and metabolic enzymes, lipase and phospholipase AEpithelium damage is due to direct as well as toxin-mediated and indirect, immunomediated mechanisms. Increased mucosal interleukin-8 promotes neutrophil chemotaxis, followed by macrophage and lymphocyte migration into the gastric mucosa. These defence mechanisms against H. pylori infection lead to the release of lysosomal enzymes, platelet-activating factor, oxygen free radicals, chemotactic leukotrienes and an increased synthesis of prostaglandins PGE2 and PGI2. H. pylori infection is also associated with an increase in the rate of TNFa- and Fas/FasL-mediated apo The pathogenesis of NSAID-associated gastropathy is only partially known, but it is well accepted that these drugs can lead to ulcerative lesions through direct epithelial damage with various forms and degrees of desquamaand, most prominently, through systemic inhibition of cyclo-oxygenase (COX-1 and COX-2) aecting the cyto- protective role of prostaglandin synthesis. The consequence of prostaglandin inhibition result in a reduced synthesis of mucus and bicarbonate, and alterations in vascular permeability, and in change in the small vessels promoting stasis and ischaemia.
It has been suggested that H. pylori infection may play a protective role in NSAID users by limiting the decrease in local tissue prostaglandin induced by NSAIDs.
Immunohistochemical studies have shown increased expression of COX-2 in the gastric mucosa of infected patients consistent with the presence of acute in¯ammation with no change in the expression of the protective' CIn general, H. pylori increases mucosal prostaglandins and NSAIDs inhibit them. One would expect that NSAIDs would eliminate or reduce any bene®cial anti-NSAID activity related to H. pylori-stimulated prostaglandin injury. In fact, Laine et alshowed a decrease in prostaglandin synthesis in both H. pylori-positive and H. pylori-negative subjects who were chronically given naproxen. The hypotheses related to a bene®cial eect of H. pylori related to prostaglandin synthesis are reminiscent of the proposals that mild damaging agents such as antacids or sucralfate might protect by prostaglandin- mediated cytoprotection. It was subsequently recognized that pre-treatment with NSAIDs eliminated any bene®cial eect by inhibiting the expected prostaglandin synthesis. For example, sucralfate failed in clinical trials to show any protective eect despite the fact that it was shown to be a mild irritant and to produce adaptive cytoprotectionThere are few data to support a bene®cial eect of an H. pylori infection. For example, Lanza et studied the eects of H. pylori infection on the severity of acute gastric mucosa damage induced by administration of naproxen and Helicobacter pylori infection and NSAIDs 779 aspirin in 61 volunteers. They found no relationship between the infection and the severity of the endoscopic lesions. In addition, the percentage of acute endoscopic gastric ulcers was the same in H. pylori-positive subjects (16.5%) and H. pylori-negative subjects (17.5%). On the other hand, in a recent placebo-controlled, double-blind, randomized trial available only in abstract form, Cryer et alprospectively assessed the eect of H. pylori on gastric mucosal injury in subjects exposed to low-dose aspirin (ASA). The authors claim that H.pylori gastritis signi®cantly worsens gastric mucosal injury in patients chronically taking low-dose ASA and the bacteria appear to be a risk factor for low-dose ASA-induced gastric ulcers. Moreover, two other studies also available only as abstracsuggest that H. pylori infection may increase the risk on clinical gastrointestinal events. Lanas and suggest that H. pylori is a risk factor associated with peptic ulcer bleeding in low-dose aspirin users, and this risk was associated with duodenal ulcer bleeding but was not in¯uenced by infection with CagA-positive H. pylori strains. However, overall, the data are consistent with the notion that H. pylori status does not aect the severity of gastric mucosal damage following acute exposure to NFinally, in a prospective study in volunteers receiving naproxen, Shiotani et alevaluated whether mucosal damage or protection could be related to levels of mucosal nitric oxide or interleukin-8, histological parameters including the density of H. pylori, polymorphonuclear cells or luminal pH. The authors demonstrated that only subjects with high intraluminal pH and severe corpus gastritis were protected. In this instance, H. pylori acted as a biological antisecretory aas is consistent with the fact that antisecretory therapy can reduce the severity of acute NSAID gastroduodenal injury. The protective eect of severe gastritis was suggested long ago in studies of NSAID-induced gastric micro- In summary, there are no creditable data for a protective eect of an H. pylori infection for the prevention of NSAID-induced gastric mucosal damage short of H. pylori-induced severe gastritis with marked reduction in acid production.
THERAPEUTIC ASPECTS The role of H. pylori infection in patients with NSAID-associated peptic ulcers has been recently addressed in large, randomized, multicenter The OMNIUM s compared omeprazole (20 mg given once a day) and misoprostol (200 mg given twice a day) for the prevention of recurrent ulcers in patients with arthritis who were receiving NSAID therapy. After 6 months, 12% of the patients receiving placebo and 10% of those receiving misoprostol, but only 3% of those receiving omeprazole, had duodenal ulcers. Gastric ulcers recurred in 32% of the patients receiving placebo, in 10% of those receiving misoprostol, and in 13% of those receiving omepr Omeprazole was superior to placebo for the prevention of ulcer recurrence in chronic NSAID users. However, omeprazole was not signi®cantly better than a non-acid inhibiting dose (400 mg/day) of misoprostol (14.5 versus 19.6%, respectively; P 0.93) and 400 mg of misoprostol was actually superior to omeprazole for the prevention of gastric ulcers among chronic NSAID users without H. pylori infection (8.2 versus 16.6% for misoprostol and omeprazole, respectively; P 5 0.05). Omeprazole was also not statistically dierent from misoprostol for the prevention of gastric ulcers among chronic NSAID users with H. pylori infection. Omeprazole was also not signi®cantly dierent than 300 mg of ranitidine for the prevention of gastric ulcers in chronic NSAID users without an H. pylori infection (14.6 versus 116%, respectively; P Overall, duodenal ulcers were over-represented among H. pylori-infected NSAID 780 F. Bazzoli, L. De Luca and D. Y. Graham users. Over-representation of duodenal ulcer among H. pylori-infected chronic NSAID users has now been recognized as a general phenomenon.
EFFECT OF H. PYLORI INFECTION ON ULCER HEALING The HELP NSAIDs senrolled patients with current or previous endoscopically documented NSAID-associated gastric or duodenal ulceration and/or moderate± severe dyspepsia. Both clinical conditions were studied because the authors felt that H. pylori eradication might have a dierent eect on each end-point. A total of 285 patients were randomized to receive eradication therapy (omeprazole plus two antibiotics) or omeprazole plus placebo (control group) for 1 week. An unexpected ®nding was a low eradication rate in patients receiving anti-H. pylori therapy and a relatively high apparent eradication rate in the control group (respectively 66 versus 14%). Patients who had received eradication therapy had a slight delay in gastric ulcer healing (50 versus 88% at 4 weeks; 72 versus 100% at 8 weeks) consistent with the known reduction in ecacy of proton pump inhibitors associated with eradication of H. pylori. Other studies have also shown a slight but generally not signi®cant reduction in gastroduodenal ulcer healing associated with H. pylori eradication.While some have suggested that a slight delay in ulcer healing might cause one to reconsider H. pylori eradication, few would take that argument seriously. As expected, eradication of H. pylori infection did not prevent ulcer recurrence in chronic NSAID users. H. pylori eradication would only be expected to prevent recurrence of H. pylori ulcers and it was previously shown that ulcer recurrence after H. pylori eradication was typically associated with the use of The fact that one can never be con®dent of the actual aetiology of an individual ulcer has complicated the interpretation of clinical studies. For example, some studies have shown a major bene®t of H. pylori eradication therapy compared to antisecretory drugs for the prevention of bleeding relapse in H. pylori-positive patients with NSAID- associated peptic ulcers. In two dierent studies, Labenz and and Jaspersen et reported that, 12 to 24 months from ulcer healing, bleeding relapse was documented in 27 to 33% of patients treated with proton pump inhibitors and in no patient treated with eradication therapy for H. pylori. Again, one would not expect eradication of H. pylori to have a secondary preventive eect against true or unequivocal NSAID ulcers, or their complications.
H. pylori eradication appears to have a primary preventive eect. For example, Chan et studied patients who were ulcer-free at an initial endoscopy, who were not taking NSAIDs at the time of study entry and who had no past history suggesting peptic ulcer disease. These patients were randomized to receive eradication therapy or control treatment for 2 weeks, while starting 2-month course of naproxen (250 mg three times daily). At 8 weeks there was a marked reduction in the incidence of gastric ulcers in the eradication treatment group (from 26 to 7%). This observation has DEVELOPMENT OF SAFER NSAIDS: COX-2 INHIBITORS Several modi®cations in the formulation of NSAIDs have been introduced in recent years to reduce their toxicity. COX-2 inhibitors (coxibs) have been recently developed and seem to have markedly reduced the capacity of NSAIDs to cause injury to the Helicobacter pylori infection and NSAIDs 781 gastrointestinal mucosaLiterature concerning the eects of COX-2 inhibitors on prevention of ulcer complications is only beginning to become available.
Two coxibs that have selectivity for COX-2 at doses substantially higher than those required to aect in¯ammation are currently available and have been studied exten- sively: celecoxib and rofecoxib. Coxibs do not cause more mucosal injury than placebo when used in treating osGoldstein et ahave presented results of a meta-analysis on 14 randomized, controlled trials of 11 008 patients with rheumatoid arthritis and osteoarthritis, treated with placebo (n 1864) or celecoxib (n 6376 ) or NSAIDs (n 2768) for 2±24weeks. NSAIDs have been associated with a higher risk of gastrointestinal adverse events clinically signi®cant of 1.48% (95% CI: 0.35±2.62%) than celecoxib, and there has not been shown a higher risk with celecoxib versus placebo (95% CI 0.08 to 0.47%). Bombardier and randomized 8076 patients with rheumatoid arthritis to receive either rofecoxib 50 mg daily or naproxen 500 mg twice daily, their primary target being to evaluate clinical upper gastrointestinal events (ulcers, perforations, bleeding). Although the two drugs had similar ecacy against rheumatoid arthritis, the rate of development of gastrointestinal events per year was 2.1% with rofecoxib versus 4.5% with naproxen (relative risk 0.5; P 5 0.001) and the respective rates of con®rmed complications were 0.6 and 1.4% (relative risk 0.4; P 0.005). Another randomized studydemonstrated that all dierent dosages of celecoxib (100 mg or 200 mg or 400 mg twice per day) were ecacious in the treat- ment of rheumatoid arthritis and did not aect COX-1 activity in the gastrointestinal Data for pooled analysis, obtained from four independent double-blind 12-week endoscopic trials in osteo-rheumatoid arthritis, were collected in a sto evaluate the eect of H. pylori infection on the incidence of gastroduodenal ulcers in patients receiving placebo, celecoxib or NSAIDs. The percentage of ulcers in the celecoxib group was 8% in H. pylori-positive patients and 5.1% in those without infection, OR 1.6 (95% CI: 0.90 to 2.84); in the placebo group it was 7.1% in H. pylori-positive subjects and 2.2% in those H. pylori-negative, OR 3.5 (95% CI: 0.62 to 19.5). In the traditional NSAID group ulcers were seen in 28.4% with H. pylori infection versus 20% among the H. pylori-negative patients. These results suggest an H. pylori±NSAID interaction. The large double-blind comparisons of selective COX-2 inhibitors and NSAIDs for the prevention of ulcer complications are not yet published in full. Preliminary data show that the proportion with ulcer complications was markedly less with the selective COX-2 inhibitors compared to traditional NSAIDs but that the risk was not zero among COX-2 users. It is clear that these studies will require careful reading to understand how much risk remains and how much is attributable to H. pylori infection.
Despite the enthusiasm for these promising new NSAIDs, some questions remain regarding COX-2 inhibitors. In fact, COX-2 might generate endogenous prostanoids that are biologically important. Mizuno et alhave suggested that an increases in mucosal COX-2 expression may be necessary for the normal healing of gastroduodenal ulcers. Nonetheless, there has been no evidence for abnormal wound healing seen with the COX-2 inhibitors. McAdam and co-workerhave recently reported that long- term therapy with celecoxib might increase the rate of thrombotic events in patients who were at increased risk for cardiovascular disease. Because the COX-2 inhibitors do not aect platelet function, they cannot substitute for aspirin. An increase in cardiovascular events was not seen in the large studies where low-dose aspirin was COX-2 inhibitors inhibit over-expression of the COX-2 gene early in carcino- genesis, and thereby inhibit the proliferation and adhesion of tumour cells, induce 782 F. Bazzoli, L. De Luca and D. Y. Graham apoptosis and inhibit the formation of aberrant In rat models these drugs have been shown to inhibit signi®cantly both the early and the late stages of chemically-induced colonic neoHowever, so far human data are not available and the results of ongoing trials are eagerly awIn an Irish sit was shown, in 76 patients with colorectal cancer, that this neoplasia may be related to survival and that COX-2 may play a role in tumorigenesis. Recently, Steinbach et published the results of a study where, in patients with FAP, the higher dosage of celecoxib (100 mg or 400 mg twice daily) reduced the number of colonic polyps by 28% (P 0.003), and led to a 30.7% reduction in the polyp burden (the sum of poly diameters) (P 0.001) compared with placebo. The results of these studies suggest that although the highly selective COX-2 inhibitors oer considerable promise in the treatment of in¯ammatory arthritis, careful surveillance will be important to determine whether elimination of H. pylori and use of selective COX-2 inhibitors will essentially eliminate ulcer disease.
Data have accumulated showing an interaction between H. pylori and NSAIDs. Overall, the risks of a serious complication appear increased among H. pylori infected NSAID users and it is now recommended that H. pylori eradication be considered prior to embarking on long term NSAID therapy (The Maastricht Consensus Report 2±2000.
Malfertheiner et al. In preparation). The data support the notion that H. pylori . H. pylori infection increases the risk of complications among NSAID users, and thus consideration should be given to its eradication whenever long-term NSAID therapy is considered . all patients taking NSAIDs who have ulcer disease should be tested for H. pylori and, if present, the infection should be eradicated . all studies of the eect of NSAIDs on the gastroduodenal mucosa must provide separate analyses based on H. pylori status, history of ulcer, or ulcer complications . endpoints unrelated to the outcome but likely to be favourably in¯uenced by the active therapy, such as heartburn, should not be included as an important outcome measure in endoscopic studies as they provide misleading suggestions regarding the bene®ts likely to be seen clinically . studies should focus on primary and secondary prevention of clinically important outcomes, such as clinical ulcers or ulcer complications, and not on endoscopic ulcers which relate poorly to the clinical situitation . the actual risk of selective COX-2 inhibitors in causing life-threatening complications among patients with and without H. pylori infection should be determined ± as well as identifying the risk factors that predict an untoward Helicobacter pylori infection and NSAIDs 783 infection increases the risk of duodenal ulcers but may not increase the risk of gastric ulcers in NSAID users. From a clinical point of view, it is impossible to distinguish between H. pylori and NSAID-associated peptic ulcers and we believe it is prudent in ulcer patients with both to eradicate H. pylori and stop the NSAID. If an NSAID must be restarted, one should consider cotherapy with a prostaglandin, a proton pump inhibitor, or both, or use of a speci®c COX-2 inhibitor.
1. Hawkey CJ. Non steroidal anti-in¯ammatory drugs and peptic ulcers. Bristish Medical Journal 1990; 300: * 2. Langman MJS, Weil J, Wainwright P et al. Risks of bleeding peptic ulcer associated with individual non- steroidal anti-in¯ammatory drugs. Lancet 1994; 343: 1075±1082.
3. Hawkey CJ. What consideration should be given to Helicobacter pylori in treating nonsteroidal anti- in¯ammatory drug ulcers? European Journal of Gastroenterology and Hepatology 1999; 12 (supplement 1): 4. Taylor DN & Blaser MJ. The epidemiology of Helicobacter pylori infection. Epidemiology Review 1991; 13: 5. Malfertheiner P & Labenz J. Does Helicobacter pylori status aect nonsteroidal anti-in¯ammatory drug- associated gastroduodenal pathology? American Journal of Medicine 1998; 104: 35S±40S.
6. Kim JG & Graham DY. The Misoprostol Study Group. Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy. American Journal of Gastroenterology 1994; 89: 203±207.
7. Voutilainen M, Sokka T, Juhola M et al. Nonsteroidal anti-in¯ammatory drug-associated upper gastrointestinal lesions in rheumatoid arthritis patients. Scandinavian Journal of Gastroenterology 1998; 33: * 8. Henriksson AE, Edman AC, Nilsson I et al. Helicobacter pylori and the relation to other risk factors in patients with acute bleeding peptic ulcer. Scandinavian Journal of Gastroenterology 1998; 33: 1030±1033.
9. Goldstein JL, Agrawal NM, Silverstein F et al. In¯uence of H. pylori infection and/or low dose aspirin on gastroduodenal ulceration in patients treated with placebo, celecoxib or NSAIDS. Gastroenterology 1999; 10. Loeb DS, Talley NJ, Ahlquist DA et al. Long-term nonsteroidal anti-in¯ammatory drug use and gastroduodenal injury: the role of Helicobacter pylori. Gastroenterology 1992; 102: 1899±1905.
11. Hawkey CJ. Nonsteroidal anti-in¯ammatory drug gastropathy. Gastroenterology 2000; 119: 521±535.
12. Stack WA, Hawkey GM, Atherton JC et al. Interactions of risk factors for peptic ulcer bleeding.
Gastroenterology 1999; 116: A97.
*13. Weil J, Langman MJS, Wainwright P et al. Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-in¯ammatory drugs. Gut 2000; 46: 27±31.
14. Aalykke C, Lauritsen JM, Hallas J et al. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-in¯ammatory drugs: a case-control study. Gastroenterology 1999; 116: 1305±1309.
*15. Wu CY, Poon SK, Chen GH et al. Interaction between Helicobacter pylori and non-steroidal anti- in¯ammatory drugs in peptic ulcer bleeding. Scandinavian Journal of Gastroenterology 1999; 34: 234±237.
16. Labenz J, Peitz U, Kohl H et al. Helicobacter pylori increases the risk of peptic ulcer bleeding: a case- control study. Italian Journal of Gastroenterology and Hepatology 1999; 31: 110±114.
17. Huang JQ, Lad RJ, Sridhar S et al. H. pylori infection increases the risk of nonsteroidal anti-in¯ammatory drugs-induced gastroduodenal ulceration. Gastroenterology 1999; 116: A192.
*18. Wolfe MM, Lichtenstein DR & Singh G. Gastrointestinal toxicity of nonsteroidal antiin¯ammatory drugs.
New England Journal of Medicine 1999; 340: 1888±1899.
19. Hawkey CJ. Letter to editor Reply-on dissonances. Helicobacter pylori and NSAIDs. Alimentary Pharmacology and Therapy 2000; 14: 499±500.
20. Nilius M & Malferthainer P. Helicobacter pylori enzymes. Alimentary Pharmacology and Therapy 1996; 10 (supplement 1): 65±71.
21. Fiorucci S, Antonelli E, Santucci L et al. Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats. Gastroenterology 1999; 116: 1089±1106.
22. Caselli M, LaCorte R, DeCarlo L et al. Histological ®ndings in gastric mucosa in patients treated with non-steroidal anti-in¯ammatory drugs. Journal of Clinical Pathology 1995; 48: 553±555.
784 F. Bazzoli, L. De Luca and D. Y. Graham 23. Rainsford KD. Mechanism of gastrointestinal toxicity of non-steroidal anti-in¯ammatory drugs.
Scandinavian Journal of Gastroenterology 1989; 24 (supplement 163): 9±16.
24. Kakiuchi Y, Kawano S, Tsuji S et al. Helicobacter pylori up-regulates type 2 cyclooxygenase in gastric epithelial cells. Gastroenterology 1999; 116: A431.
25. Laine L, Cominelli F, Sloane R et al. Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production: a controlled double-blind trial. Alimentary Pharmacology and Therapy 1995; 9: 127±135.
26. Agrawal NM, Roth S, Graham DY et al. Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-in¯ammatory drug-induced gastric ulcer. A randomized, controlled trial. Annals of Internal Medicine 1991; 115: 195±200.
27. Lanza FL, Evans DG & Graham DY. Eect of Helicobacter pylori infection on the severity of gastroduodenal mucosal injury after the acute administration of naproxen or aspirin to normal volunteers. American Journal of Gastroenterology 1991; 86: 735±737.
28. Cryer B, Mallat D & Feldman M. In¯uence of Helicobacter pylori on low dose aspirin (ASA)±induced gastric mucosal injury. A placebo-controlled, double-blind, randomized trial. Gastroenterology 2000; 118: 29. Lanas A, Fuentes J, Benito R et al. Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Gastroenterology 2000; 118: A1461.
30. Laine L, Bombardier C, Hawkey C et al. In¯uence of H. pylori and other potential risk factors on clinical gastrointestinal events in a double-blind outcome study of rofecoxib vs. naproxen. Gastroenterology 2000; 31. Santucci L, Fiorucci S & Patoia L. Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens. Digestive Diseases and Sciences 1995; 40: 2074±2080.
32. Thillainayagam AV, Tabaqchali S, Warrington SJ et al. Interrelationships between Helicobacter pylori infection, nonsteroidal anti-in¯ammatory drugs and gastroduodenal disease: a prospective study in healthy volunteers. Digestive Diseases and Sciences 1994; 39: 1085±1089.
33. Shiotani A, Yamoaka Y, El-Zimaity II et al. Interaction between H. pylori and NSAIDs: predictive value of density of PMNs, mucosal IL-8 or mucosal and gastric juice nitrite levels on NSAID-induced gastric mucosal injury and ulcer formation. Gastroenterology 2000; 118: A4800.
34. Graham DY & Yamoaka Y. H. pylori and cag A: relationships with gastric cancer, duodenal ulcer, and re¯ux esophagitis and its complications. Helicobacter 1998; 3: 145±151.
35. Graham DY & Smith JL. Aspirin and the stomach. Annals of Internal Medicine 1986; 104: 390±398.
36. Croft DN & Wood PH. Gastric mucosa and susceptibility to occult gastrointestinal bleeding caused by aspirin. British Medical Journal 1967; 1: 137±141.
37. Hawkey CJ, Karrasch JA, Szczepanski L et al. Omeprazole compared with misoprostol for ulcer associated with non steroidal anti-in¯ammatory drugs. Omeprazole versus Misoprostol for NSAIDs- induced Ulcer Management (OMNIUM) Study Group. New England Journal of Medicine 1998; 338: 38. Yeomans ND, Tulassay Z, Juhasz L et al. A comparison of omeprazole with ranitidine for ulcers associated with non steroidal anti-in¯ammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. New England Journal of Medicine 1998; 338: 719±726.
39. Cullen D, Bardhan KD, Eisner M et al Primary gastroduodenal prophylaxis with omeprazole for non- steroidal anti-in¯ammatory drugs users. Alimentary Pharmacology and Therapy 1998; 12: 135±140.
*40. Graham DY. NSAID ulcers: prevalence and prevention. Modern Rheumatology 2000; 10: 2±7.
41. Huang J-QLR & Hunt RH. Role of Helicobacter pylori infection in NSAID-associated gastropathy. In Hunt RH & Tytgat CN (eds). Helicobacter pylori: Basic Mechanisms to Clinical Cure 2000, pp 443±452.
Dordrecht: Kluwer Academic, 2000.
42. Hawkey CJ, TulassayZ, Szczepanski L et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-in¯ammatory drugs: HELP-NSAIDs study. Lancet 1998; 352: 1016±1021.
*43. Chan FK, Sung JJ, Suen R et al. Does eradication of Helicobacter pylori impair healing of nonsteroidal anti- in¯ammatory drugs associated bleeding peptic ulcers? A prospective randomized study. Alimentary Pharmacology and Therapy 1998; 12: 1201±1205.
44. KC Lai, SK Lam, WM Hui et al. Eradication of Helicobacter pylori could not prevent development of gastrointestinal complications in patients requiring long-term low-dose aspirin. Gastroenterology 2000; 45. Bianchi Porro GB & Parente F. Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in long-term NSAID users. Response to omeprazole dual therapy. Gut 1996; 39: 22±26.
Helicobacter pylori infection and NSAIDs 785 46. Graham DY, Lew GM, Klein PD et al. Eect of treatment of Helicobacter pylori infection on the long- term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Annals of Internal Medicine 1992; 116: 705±708.
47. Labenz J & Borsch G. Role of Helicobacter pylori eradication in the prevention of peptic ulcer bleeding relapse. Digestion 1994; 55: 19±23.
48. Jaspersen D, Scho TK, Brennenstuhl M et al. Helicobacter pylori eradication reduces the rate of rebleeding in ulcer hemorrhage. Gastrointestinal Endoscopy 1995; 41: 5±7.
*49. Chan FKL, Sung JJY & Chung SCS et al. Randomised trial of eradication of H. pylori before non-steroidal anti-in¯ammatory drug therapy to prevent peptic ulcers. Lancet 1997; 350: 975±979.
50. Koelz HR, Bolten W, Dragosics B et al. Primary prophylaxis of NSAID-induced gastroduodenal ulcers and dyspepsia in H. pylori (HP)-positive patients: randomized, double-blind, placebo-controlled treatment of HP infection vs. omeprazole. Gastroenterology 2000; 118: A250.
51. Smecuol EG, Sugai E, Vazquez H et al. Acute dose of celecoxib, a new speci®c cycloxigenase-2 (COX-2) inhibitor, do not aect the overall gut permeability. Gastroenterology 2000; 118: A1449.
52. Hawkey CJ, Laine L, Simon T et al. Comparison of the eect of rofecoxib (a ciclooxygenase 2 inhibitor), ibuprofen and placebo on the gastroduodenal mucosa of patients with osteoarthritis. Arthritis and Rheumatology 2000; 43: 370±377.
*53. Laine L, Harper S, Simon T et al. A randomized trial comparing the eect of rofecoxib, a ciclooxygenase 2 inhibitor, with that or ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.
Gastroenterology 1999; 117: 776±783.
54. Goldstein JL, Agrawal NM, Silverstein F et al. Celecoxib is associated with a signi®cantly lower incidence of clinically signi®cant upper gastrointestinal (UGI) events in osteoarthritis (OA) and rheumatoid arthritis (RA) patients as compared to NSAIDs. Gastroenterology 2000; 118: A174.
*55. Bombardier C, Laine L, Reicin A et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. New England Journal of Medicine 2000; 343: 1520±1528.
56. Simon LS, Weaver AL, Graham DY et al. Anti-in¯ammatory and upper gastrointestinal eects of celecoxib in rheumatoid arthritis: a randomized control ed trial. Journal of the American Medical Association 1999; 282: 1921±1928.
57. Mizuno H, Sakamoto C, Matsuda K et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the speci®c antagonist delays healing in mice. Gastroenterology 1997; 112: 387±497.
58. McAdam BF, Catella-Lawson F, Mardini IA et al. Systemic biosynthesis of prostacyclin by ciclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proceedings of the National Academy of Sciences of the USA 1999; 96: 272±277.
59. Janne PA & Mayer RJ. Chemoprevention of colorectal cancer. New England Journal of Medicine 2000; 342: 60. Kawamori T, Rao CV, Seibert K et al. Chemopreventive activity of celecoxib, a speci®c cyclooxygenase-2 inhibitor against colon carcinogenesis. Cancer Research 1998; 58: 409±412.
61. Kune GA. Colorectal cancer chemoprevention: aspirin, other NSAID and COX-2 inhibitors. Australian and New Zealand Journal of Surgery 2000; 70: 452±455.
62. Sheehan KM, Sheehan K, O'Donoghue DP et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. Journal of the American Medical Association 1999; 282: 1254±1257.
63. Steinbach G, Lynch PM, Philips RKS et al. The eect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. New England Journal of Medicine 2000; 342: 1946±1952.
Jaargang 16 ö nummer 3 ö september 2013 Kwartaaluitgave van de Nederlandse Vereniging voor Fysiotherapie binnen de Lymfologie Oedeemfysiotherapie ö OncologiefysiotherapieBachelor ö Master THE COMPRESSION COMPANY Van de redactie Oedeminus is een kwartaaluitgave van de NVFL, Van de voorzitter