Search

Non-steroidal anti-inflammatory drugs are among the most widely used therapeutics, primarily for the treatment for pain and inflammation. Prostaglandins mediate a number of characteristic features of the body's response to tissue injury or inflammation. These outstanding effects include their cytoprotective properties in the gastrointestinal tract and control of renal functions in the kidney. Non-steroidal anti-inflammatory drugs exert their anti-inflammatory and antipyretic effects by blocking the production of prostanoids from arachidonic acid through inhibition ofcyclooxygenase enzyme. Classic non-steroidal anti-inflammatory drugs such as meclofenamic acid and indomethacin inhibit both isoforms of cyclooxygenase non-selectively or with low selectivity, exerting their anti-inflammatory activity via inhibiting cyclooxygenase-2, and their deleterious side-effects by inhibiting cyclooxygenase-1. To provide an effective treatment for inflammatory disorders, the design of novel non-steroidal anti-inflammatory drugs is aimed at obtaining new drugs, devoid of the side-effects commonly associated with conventional non-steroidal anti-inflammatory drugs. Several approaches have been explored to counteract the gastric damaging effects of these drugs. The chemical modification of non-steroidal anti-inflammatory drugs is aimed at improving their safety profile, where several studies have described the derivatization of the carboxylate function of non-steroidal anti-inflammatory drugs with less acidic analogs, which resulted in an increased anti-inflammatory activity with reduced ulcerogenicity. The present review explores the possible ways aimed to reduce ulcerogenicity., (© 2014 John Wiley & Sons A/S.)

Background: Recent data from Western countries indicate that the aetiology of peptic ulcer disease (PUD) is changing as the prevalence of Helicobacter pylori is decreasing while the use of low-dose aspirin (LDA, ≤325 mg/day) is increasing., Aim: To investigate the changing aetiology and demographics of PUD in a well-characterised patient cohort at a large tertiary hospital in the UK between July 2005 and June 2010., Methods: Patients diagnosed with PUD following endoscopy were categorised as non-steroidal anti-inflammatory drug (NSAID)-users or non-users, and their H. pylori status determined. Comparisons between NSAID-users and non-users, and between non-aspirin NSAID-users and LDA-users were summarised using counts and corresponding percentages (for categorical variables) and means and standard deviations (for continuous variables)., Results: Overall, 386 patients were enrolled; 57% used NSAIDs (51% LDA only) and 43% were non-users. 57% of the whole cohort was H. pylori-positive (including 66% with duodenal ulcers and 47% with gastric ulcers). Compared with non-users, NSAID-users were older (mean age 68 vs. 61 years) and fewer were H. pylori-positive (52% vs. 63%). LDA-users were older (mean age 71 vs. 62 years) and more likely to be H. pylori-positive (61% vs. 41%) than those using non-aspirin NSAIDs. Twelve per cent of the patients were neither using NSAIDs nor were H. pylori-positive., Conclusions: The NSAIDs, particularly LDA, were most commonly associated with PUD in this cohort. Our findings are compatible with the decline in the prevalence of H. pylori-positive PUD and increase in non-NSAID, non-H. pylori PUD previously reported., (© 2012 Blackwell Publishing Ltd.)

Background: The use of proton pump inhibitors for prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal adverse events is well documented. However, data regarding the efficacy and safety of this approach in Japan are scarce., Aim: To evaluate the efficacy and tolerability of esomeprazole in preventing NSAID-induced peptic ulcers in Japanese at-risk patients., Methods: Male and female Japanese adult patients (aged ≥ 20 years) with endoscopically confirmed history of peptic ulcers who required long-term oral NSAID therapy for a chronic inflammatory condition were randomised to 24 weeks' treatment with esomeprazole 20 mg once daily or matching placebo. The primary end point was the Kaplan-Meier estimated proportion of ulcer-free patients., Results: Overall, 343 patients were randomised to treatment (esomeprazole, n = 175; placebo, n = 168). The Kaplan-Meier estimated ulcer-free rate over the 24-week treatment period was significantly higher (log-rank P < 0.001) in esomeprazole-treated patients (96.0%; 95% CI 92.8, 99.1) than in placebo recipients (64.4%; 95% CI 56.8, 71.9). Esomeprazole was effective at preventing peptic ulcers in both Helicobacter pylori-positive and -negative patients (96.3% vs. 95.5% of patients ulcer-free, respectively); however, in the placebo group, the proportion of ulcer-free patients at 24 weeks was markedly lower among H. pylori-positive than -negative patients (59.7% vs. 69.9%). The NSAID type did not seem to affect the estimated ulcer-free rate with esomeprazole. Treatment with esomeprazole was well tolerated., Conclusion: Esomeprazole 20 mg once daily is effective and safe in preventing ulcer recurrence in Japanese patients with a definite history of peptic ulcers who were taking an NSAID (ClinicalTrials.gov identifier: NCT00542789)., (© 2012 Blackwell Publishing Ltd.)

Background/aims: The upper gastrointestinal (GI) toxicity associated with non-steroidal anti-inflammatory drugs (NSAID) use among cirrhotic patients remains unclear. The objective of this study was to evaluate the risk of upper GI adverse events associated with celecoxib and oral and parenteral non-selective NSAIDs in cirrhotic patients., Methods: All the patients aged ≥ 20 years with a diagnosis of cirrhosis hospitalized for variceal bleeding and non-variceal upper GI adverse events (oesophageal, gastric, duodenal ulcer, bleeding; gastritis and duodenitis) in 2006 were identified using ICD-9-CM diagnosis codes from inpatient claims from the Taiwan National Health Insurance Database. In the case-crossover study design, the case period was defined as 1-30 days and the control period as 31-60 days before the date of hospitalization. The information for individual NSAID use was obtained from the outpatient pharmacy prescription database. Adjusted self-matched odds ratios (OR) and their 95% confidence intervals (CI) were estimated with a conditional logistic regression model., Results: A total of 4876 cirrhotic patients were included. The adjusted OR (95% CI) was 1.44 (0.89-2.31) for celecoxib, 1.87 (1.66-2.11) for oral non-selective NSAIDs and 1.90 (1.55-2.32) for parenteral NSAIDs overall. Risks were similar for variceal and non-variceal events. Concomitant use of proton pump inhibitors and histamine-2 receptor antagonists tended to decrease the upper GI toxicity associated with non-selective NSAIDs and celecoxib., Conclusion: The use of nsNSAIDs but not celecoxib was associated with a two-fold increased risk of variceal and non-variceal upper GI events among cirrhotic patients., (© 2012 John Wiley & Sons A/S.)

Background: Clopidogrel does not inhibit prostaglandin synthesis. As a result, clopidogrel's incidence of peptic ulcer disease (PUD) and ulcer bleeding is lower than aspirin's., Aim: To compare the healing rate in aspirin-related dyspeptic ulcer patients who were given proton pump inhibitor (PPI) plus aspirin or PPI plus clopidogrel., Methods: Patients with aspirin-related nonbleeding symptomatic ulcers were randomised to receive rabeprazole (20 mg/day) plus aspirin (100 mg/day) or rabeprazole (20 mg/day) plus clopidogrel (75 mg/day) for 12 weeks. The primary endpoint was the successful treatment of PUD as characterised by intention-to-treat at the end of therapy., Results: Two hundred and eighteen patients (109 in the aspirin group and 109 in the clopidogrel group) were enrolled. There were no statistical demographic differences between the group that received aspirin and the group that received clopidogrel. The PUD treatment success rate was also statistically equal between the clopidogrel and aspirin groups (86.2% vs. 90.0%, P = 0.531). Neither group experienced ulcer-related bleeding. Multivariate logistic regression analysis showed that large ulcer size (>10 mm) (OR: 6.29, 95% CI: 2.58-15.37) and past history of PUD (OR: 3.69, 95% CI: 1.24-10.97) were important predictors of unsuccessful therapy for aspirin-related PUD., Conclusions: Rabeprazole plus aspirin is not inferior to rabeprazole plus clopidogrel in treating aspirin-related symptomatic PUD. Large ulcer size (>10 mm) and past history of PUD are important predictors of unsuccessful therapy (NCT 01037491)., (© 2011 Blackwell Publishing Ltd.)

Background: Persons who use serotonin reuptake inhibitors (SSRIs) seem to be at increased risk of having serious upper gastrointestinal bleeding. In vitro studies have shown that SSRIs inhibit platelet aggregation. It remains unknown if SSRIs have a direct ulcerogenic effect., Aim: To investigate if there is a possible association between use of SSRIs and uncomplicated peptic ulcers., Methods: A population-based case-control study was conducted in the county of Funen, Denmark, using local prescription database and patient register. The 4862 cases all had a first diagnosis of uncomplicated peptic ulcers from 1995 to 2009. Controls (n = 19 448), matched for age and gender, were selected by risk-set sampling., Results: The adjusted odds ratios (OR) of uncomplicated peptic ulcers among current, recent and past users of SSRIs were 1.50 (95% CI 1.18-1.90), 1.56 (95% CI 0.98-2.49) and 1.32 (95% CI 1.08-1.61). There was no association with tricyclic antidepressants [OR 0.94 (95% CI 0.65-1.35)]. The adjusted OR for the SSRI-uncomplicated peptic ulcers association was 0.76 (95% CI 0.46-1.25) among users of proton pump inhibitors., Conclusions: Use of SSRI is associated with uncomplicated peptic ulcers, possibly by some effect on the healing process. We cannot exclude some effects of residual confounding or bias by frequent physician contact., (© 2010 Blackwell Publishing Ltd.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most prescribed drugs worldwide and have now probably overtaken Helicobacter pylori as the most common cause of gastrointestinal injury in Western countries. Further understanding of the pathogenesis of NSAID-induced ulcers is important to enable the development of novel and effective preventive strategies., Aims: To provide an update on recent advances in our understanding of the cellular and molecular mechanisms involved in the development of NSAID-induced ulcers., Methods: A Medline search was performed to identify relevant literature using search terms including 'nonsteroidal anti-inflammatory drugs, aspirin, gastric ulcer, duodenal ulcer, pathogenesis, pharmacogenetics'., Results: The mechanisms of NSAID-induced ulcers can be divided into topical and systemic effects and the latter may be prostaglandin-dependent (through COX inhibition) or prostaglandin-independent. Genetic factors may play an important role in determining individual predisposition., Conclusions: The pathogenesis of NSAID-induced peptic ulcers is complex and multifactorial. Recent advances in cellular and molecular biology have highlighted the importance of various prostaglandin-independent mechanisms. Pharmacogenetic studies may provide further insights into the pathogenetic mechanisms of NSAID-induced ulcers and help identify patients at increased risk.

Background: The basis for individual variation in gastroduodenal vulnerability to NSAIDs is not well understood., Aim: To assess whether a gene expression signature is associated with susceptibility to gastroduodenal ulcerations., Methods: Twenty-five Helicobacter pylori negative adults were treated for 7 days with naproxen 500 mg b.d. Subjects underwent baseline and post-treatment endoscopy, during which biopsies were taken from antrum and duodenum. RNA extraction and cDNA synthesis were performed, followed by PCR of 23 genes relevant to mucosal injury and repair. Fold changes in gene expression were compared between subjects who developed ulcers and those who did not., Results: Compared with subjects who did not develop ulcers (n = 18), subjects who developed antral ulcers (n = 7) had significantly greater mucosal up-regulation of interleukin-8 [Fold change = 33.5 (S.E.M. = 18.5) vs. -7.7 (3.2)] and of cyclo-oxygenase-2 [2.3 (1.7) vs. -10.8 (2.2)]. Conversely, non-ulcer subjects had significantly greater up-regulation of toll-like receptor-4, cyclo-oxygenase-1 and hepatocyte growth factor [14.0 (2.2) vs. -0.8 (1.0), 9.8 (2.4) vs. 0.0 (0.7) and 8.2 (2.6) vs. -2.2 (0.3) respectively]., Conclusions: NSAID-induced antral ulcers are associated with a specific pattern of gastroduodenal mucosal gene expression. These patterns may provide an insight into the molecular basis of individual susceptibility to mucosal injury.

Background: Aspirin use is with an increased risk of upper gastrointestinal complications (UGICs). Proton pump inhibitors (PPIs) decrease the risk of UGICs among aspirin users. The distribution of risk factors for UGIC and PPI utilization among aspirin users remains uncharacterized., Aim: To determine the prevalence and predictors of PPI use in high-risk aspirin users., Methods: Using questionnaires and administrative records, we collected information on aspirin and PPI utilization and risk factors for UGICs from a stratified random sample of subjects with established cardiovascular disease. We calculated the proportion of aspirin users with UGIC risk factors and determined the prevalence of PPI use among aspirin users with risk factors. Regression analysis was used to determine predictors of PPI use among aspirin users., Results: Overall response rate was 35%, of whom 86% were regular aspirin users. Seventy-one per cent of aspirin users had at least one risk factor (in addition to cardiac disease) for the development of UGICs. Although a history of UGIC was predictive of PPI use, 44% of aspirin users with a prior history of UGICs did not receive a concomitant PPI, and only 23% of subjects with additional UGIC risk factors were prescribed a PPI., Conclusion: There is a high prevalence of UGIC risk factors among aspirin users, and many are not prescribed PPIs as a gastroprotective strategy.

Background: In clinical trials of peptic ulcer prevention, the most appropriate definition of an ulcer remains challenging., Aims: To evaluate the ulcer definitions used in clinical trials of ulcer prevention among non-steroidal anti-inflammatory drug users and to determine whether any specific definition is preferred., Methods: A systematic literature search of the PubMed, Medline and EMBASE databases was conducted. Results were limited to full papers published in English from June 1987 to June 2007 that met the following criteria: randomized, controlled non-steroidal anti-inflammatory drug trials of > or =8 weeks' duration, with a primary end point of ulcer upon endoscopy., Results: Forty five publications met the inclusion criteria and were reviewed. Overall, an ulcer diameter of > or =3 mm was used in 25 publications and most included a description of ulcer depth. Of the remainder, ulcer was defined as any lesion with unequivocal/observable depth (with no lower limit for ulcer diameter; five publications) or an excavated mucosal break >3 mm (one publication), whereas nine defined a minimum ulcer size of > or =5 or >5 mm. Ulcer definition was unclear in the remaining five publications., Conclusion: In clinical trials of ulcer prevention among non-steroidal anti-inflammatory drug users, a gastric or duodenal lesion > or =3 mm in diameter with significant depth is the preferred definition.

With the aim of reducing the local gastric irritation associated with non-steroidal anti-inflammatory drugs, a series of N,N-disubstituted aminoalcohol ester derivatives of ibuprofen and ketoprofen were synthesized and evaluated. The esters were specially designed to possess the anticholinergic activity in the intact form and exhibit the anti-inflammatory action after hydrolysis to the respective parent drug. The rationale being that besides blocking the acidic carboxylic group of the parent drug, the existence of the anticholinergic effect in the intact molecule would further aid in reducing the gastrointestinal mucosal damage by decreasing the gastric secretions and motility. All the ester derivatives were found to be stable in acidic and basic buffers. The synthesized derivatives, with experimentally proven good anti-inflammatory and anticholinergic activities, showed significant reduction of ulcerogenicity in the stomach. These results are attributed to the acquired anticholinergic activity with a simultaneous reduction of acidic character compared to the parent compounds. The study offers a new strategy for design and development of compounds with safer therapeutic profile for long-term treatment of inflammation-associated disorders.

Background: Upper gastrointestinal (UGI) complications are a well-recognized risk of NSAID treatment, requiring preventive measures in high-risk patients. Adherence to gastroprotective agents (GPAs) in NSAID users has been suggested to be suboptimal., Aim: To investigate the association between adherence to GPAs (proton pump inhibitors or H(2)-receptor antagonists) and the risk of NSAID-related UGI ulcers or haemorrhage in high-risk patients., Methods: A population-based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication, identified in the Dutch IPCI database during 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate odds ratios with 95% confidence intervals (95% CI)., Results: Fifteen percent of the non-selective NSAID users received GPAs. The risk of a NSAID-related UGI complication among NSAID users increased 16% for every 10% decrease in adherence. Compared to patients with a PDC of >80%, patients with PDCs of 20-80% and <20% had a 2.5-fold (95% CI: 1.0-6.7) respectively 4.0-fold (95% CI: 1.2-13.0) increased risk., Conclusion: There is a strong inverse relationship between adherence to GPAs and the risk of UGI complications in high-risk NSAID users.

Objective: To evaluate the evidence of an interaction between selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) producing an increased risk for gastrointestinal adverse outcomes such as bleeding., Methods: We searched MEDLINE for English-language literature published between 1966 and August 2005. All studies examining gastrointestinal adverse effects from an SSRI-NSAID combination were included., Data Synthesis: Four retrospective studies examined gastrointestinal adverse outcomes from the combination of SSRIs and NSAIDs. The risk ratio for an upper gastrointestinal bleed from this drug combination (compared with not receiving either agent) ranged from 3.3-15.6, and the risk ratio for gastrointestinal adverse effects was 12.4. Two studies found that the risk for an upper gastrointestinal bleed from the drug combination exceeded the additive risk of the agents alone. The risk ratio for an upper gastrointestinal bleed from an SSRI-aspirin interaction was 1.9-7.2. In addition, the number needed to harm in terms of an upper gastrointestinal bleed from an SSRI-NSAID combination ranged from 62-75 patient-years, and the number needed to harm for gastrointestinal adverse effects was 2 patient-years., Conclusion: Concurrent use of an SSRI and NSAID increases the risk of gastrointestinal adverse outcomes such as bleeding. Clinicians must take care to avoid these negative outcomes by altering NSAID or SSRI therapy, or by providing ulcer-protective drugs.

Aim: To assess primary care physician perceptions of non-steroidal anti-inflammatory drug (NSAID) and aspirin-associated toxicity., Methods: A group of gastroenterologists and internal medicine physicians created a survey, which was administered via the Internet to a large number of primary care physicians from across the US., Results: One thousand primary care physicians participated. Almost one-third of primary care physicians recommended 325 mg rather than 81 mg of aspirin/day for cardioprotection. Fifty-nine percent thought enteric-coated or buffered aspirin reduced the risk of upper gastrointestinal (GI) bleeding. Seventy-six percent believed that Helicobacter pylori infection increased the risk of NSAID ulcers but fewer than 25% tested NSAID users for this infection. More than two-thirds were aware that aspirin co-therapy decreased the GI safety benefits of the cyclo-oxygenase 2 selective NSAIDs. However, 84% felt that aspirin with a cyclo-oxygenase 2 selective NSAID was safer than aspirin with a non-selective NSAID. When presented a patient at high risk for NSAID-related GI toxicity, almost 50% of primary care physicians recommended a proton pump inhibitor and cyclo-oxygenase 2 selective NSAID., Conclusions: This survey has identified areas of misinformation regarding the risk-benefit of NSAIDs and aspirin and the utilization of gastroprotective strategies. Further education on NSAIDs for primary care physicians is warranted.

Background: There is a lack of evidence for the efficacy of preventive medications for peptic ulcers (PUs) among long-term users of non-steroidal anti-inflammatory drugs (NSAIDs) in Japan., Aim: To estimate the preventive effect by normal dose, not high-dose histamine-H2 receptor antagonists (H2RA) for NSAID-induced ulcers., Methods: We designed two different studies to assess the efficacy of anti-ulcer agents in rheumatoid arthritis (RA) in patients treated over a long term with NSAIDs. An investigative survey divided patients into those not taking anti-ulcer agents (non-medication group); those taking mucosal protective agents (mucosal protectant group), H2RA (H2RA group), proton pump inhibitors (PPI group), or a prostaglandin E1 analog (PG) (PG group). The second study compared prospectively the preventive effects of either famotidine 20 mg bd (famotidine group) or lansoprazole 15 mg daily (lansoprazole group) in patients with PU scars., Results: The prevalence of PU in the H2RA group was significantly lower compared to the mucosal protectant group (P < 0.05), and the mucosal protectant group was not significantly different to the non-medication group. The prospective study revealed that the PU onset rate of the famotidine group was 8% (1/13), and lansoprazole group was 15% (2/13), indicating no significant differences between the two., Conclusions: In Japan, normal-dose H2RA is expected to be a new PU preventive treatment strategy in patients requiring long-term NSAID therapy.

Background: Although administration of gastroprotective drugs may reduce the risk of peptic ulcers associated with the chronic use of non-steroidal anti-inflammatory drugs or aspirin, no consensus exists as to whether this co-therapy is effective for short-term prevention, particularly in old age., Aim: To evaluate the risk of peptic ulcer associated with acute and chronic non-steroidal anti-inflammatory drugs or aspirin therapy in elderly subjects, and the influence of antisecretory treatment on this risk., Methods: The study included 676 elderly non-steroidal anti-inflammatory drugs or aspirin users and 2435 non-users who consecutively underwent upper gastrointestinal endoscopy. The use of non-steroidal anti-inflammatory drugs and/or aspirin as well as antisecretory drugs (H2-blockers and proton-pump inhibitors) was evaluated by a structured interview. Diagnosis of gastric and duodenal ulcer as well as Helicobacter pylori infection were carried out by endoscopy and histological examination of the gastric mucosa., Results: About 47.3% of patients were acute and 52.7% chronic users of non-steroidal anti-inflammatory drugs or aspirin. The risk of peptic ulcer, adjusted for age, gender, H. pylori infection and antisecretory drug use was higher in acute (gastric ulcer: odds ratio, OR = 4.47, 95% CI: 3.19-6.26 and duodenal ulcer: OR = 2.39, 95% CI: 1.73-3.31) than chronic users (gastric ulcer: OR = 2.80, 95% CI: 1.97-3.99 and duodenal ulcer: OR = 1.68, 95% CI: 1.22-2.33). Proton-pump inhibitor treatment was associated with a reduced risk of peptic ulcer in both acute (OR = 0.70, 95% CI: 0.24-2.04) and chronic (OR = 0.32, 95% CI: 0.15-0.67) non-steroidal anti-inflammatory drugs/aspirin users. Conversely, concomitant treatment with H2-blockers was associated with a significantly higher risk of peptic ulcer both in acute (OR = 10.9, 95% CI: 3.87-30.9) and chronic (OR = 6.26, 95% CI: 2.56-15.3) non-steroidal anti-inflammatory drugs/aspirin users than non-users. Proton-pump inhibitor treatment resulted in an absolute risk reduction of peptic ulcer by 36.6% in acute and 34.6% in chronic non-steroidal anti-inflammatory drugs/aspirin users; indeed, the number needed to treat to avoid one peptic ulcer in elderly non-steroidal anti-inflammatory drugs/aspirin users was three both in acute and chronic users., Conclusions: These findings suggest that proton-pump inhibitor co-treatment is advisable in symptomatic elderly patients who need to be treated with non-steroidal anti-inflammatory drugs and/or aspirin for a short period of time.

Background: Non-steroidal anti-inflammatory drugs use may protect against development of oesophageal adenocarcinoma., Aim: To define the consequences of non-steroidal anti-inflammatory drugs use in patients with Barrett's oesophagus., Methods: Records of all Barrett's oesophagus/oesophageal adenocarcinoma patients examined in Blackpool-Wyre-Fylde area were reviewed. All surviving patients completed validated questionnaires., Results: Use of non-steroidal anti-inflammatory drugs of any type and at any frequency was more prevalent in Barrett's oesophagus patients [147 (38%) Barrett's oesophagus vs. 30 (26%) oesophageal adenocarcinoma, P = 0.02]. Daily use of non-steroidal anti-inflammatory drugs was more prevalent in Barrett's oesophagus patients [88 (23%) Barrett's oesophagus vs. 14 (12%) oesophageal adenocarcinoma, P = 0.02], due to more prevalent consumption of non-aspirin non-steroidal anti-inflammatory drugs [48 (13%) Barrett's oesophagus vs. four (4%) oesophageal adenocarcinoma, P = 0.009]. There was no difference between the two groups in usage of either daily low-dose aspirin or of occasional non-steroidal anti-inflammatory drugs. In logistic regression analysis any use of non-steroidal anti-inflammatory drugs [odds ratio (OR) = 0571 (95% CI: 0.359-0.909), P = 0.018] and daily use of non-aspirin non-steroidal anti-inflammatory drugs [OR = 0.297 (95% CI: 0.097-0.911), P = 0.034] were significant protective factors. Non-steroidal anti-inflammatory drugs use did not affect the survival of oesophageal adenocarcinoma patients. Oesophageal adenocarcinoma and Barrett's oesophagus consuming non-steroidal anti-inflammatory drugs did not differ in upper gastrointestinal bleeding [26 (15%) non-steroidal anti-inflammatory drugs consumers vs. 29 (9%) non-consumers, P = 0.08], oesophageal ulcers [31 (18%) non-steroidal anti-inflammatory drug consumers vs. 49 (15%) non-consumers, P = 0.43] or stricturing [19 (11%) non-steroidal anti-inflammatory drug consumers vs. 41 (13%) non-consumers, P = 0.58]., Conclusions: (i) Daily use of non-steroidal anti-inflammatory drugs is more prevalent in Barrett's oesophagus than oesophageal adenocarcinoma patients, because of a more prevalent use of non-aspirin non-steroidal anti-inflammatory drugs. (ii) Use of non-steroidal anti-inflammatory drugs in Barrett's oesophagus patients is safe if acid suppression is adequate.

Aim: In a predefined analysis, data were pooled from eight blinded, randomized, controlled trials, and separately from three long-term, open-label trials to determine the rate of upper gastrointestinal ulcer complications with the cyclo-oxygenase-2 selective inhibitor, valdecoxib, vs. non-selective non-steroidal anti-inflammatory drugs., Methods: In randomized, controlled trials, 7434 osteoarthritis and rheumatoid arthritis patients received placebo (n = 973), valdecoxib 5-80 mg daily (n = 4362), or a non-selective non-steroidal anti-inflammatory drug (naproxen, ibuprofen or diclofenac; n = 2099) for 12-26 weeks. In long-term, open-label trials, 2871 patients received valdecoxib 10-80 mg daily for up to 1 year. All potential events were reviewed by a blinded, independent review committee based on a priori definitions of ulcer complications (perforations, obstructions, bleeds)., Results: In randomized, controlled trials, 19 of 955 potential events were adjudicated to be ulcer complications. Valdecoxib was associated with a significantly lower ulcer complication rate than non-selective non-steroidal anti-inflammatory drugs (0.68% vs. 1.96%, all patients; 0.29% vs. 2.08%, non-aspirin users; P < 0.05). In long-term, open-label trials, seven of 310 potential events were adjudicated to be ulcer complications; the annualized incidence for valdecoxib was 0.39% (seven of 1791 patient-years) for all patients and 0.2% (three of 1472 patient-years) for non-aspirin users., Conclusions: Valdecoxib, including above recommended doses, is associated with a significantly lower rate of upper gastrointestinal ulcer complications than therapeutic doses of non-selective non-steroidal anti-inflammatory drugs., (Copyright 2004 Blackwell Publishing Ltd)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the major recognized cause of iatrogenic disease, and may cause 100 000 deaths per annum through peptic ulcer complications. A number of risk factors can be identified that indicate patients at high risk. These patients can be managed by substitution of a COX-2 inhibitor or by prophylaxis with a proton pump inhibitor (PPI). Because risk factors that render patients at high risk of ulcer complications also act in the absence of NSAID use, PPI prophylaxis (or Helicobacter pylori eradication where H. pylori is the risk factor) have much to offer and controlled studies show that the incidence of recurrent peptic ulcer bleeding can be reduced substantially by PPI co-administration. Substitution of COX-2 inhibitors also has much to offer, arguably most in those without risk factors (although regulatory authorities do not accept this argument). Recent data show that PPI and COX-2 inhibitors can play complementary roles in the management of patients with moderate to severe dyspepsia and at high risk of ulcer complications.

Background: Cyclooxygenase-2 selective inhibitors were developed in order to reduce the incidence of life-threatening gastrointestinal ulcer complications compared with non-selective non-steroidal anti-inflammatory drugs. Previous outcomes studies have, variously, lacked power to investigate this endpoint, focused on broader outcomes, or been too small to quantify the influence of aspirin., Aim: To evaluate lumiracoxib, a novel cyclooxygenase-2 selective inhibitor, vs. non-selective non-steroidal anti-inflammatory drugs in an outcomes study of considerably increased size. This paper describes the study's methodology., Methods and Patients: The Therapeutic Arthritis Research and Gastrointestinal Event Trial was a randomized, double-blind, 52-week study of lumiracoxib 400 mg once daily (two to four times the recommended dose for osteoarthritis) versus naproxen 500 mg twice daily or ibuprofen 800 mg three-times daily in patients with osteoarthritis. Randomization was stratified for low-dose aspirin use and age (< or = 64, 65-74, > or= 75 years). The study was powered to investigate upper gastrointestinal ulcer complications (primary endpoint) in patients not taking aspirin and in the overall study population; other endpoints included cardiovascular, renal and hepatic measures., Conclusions: Therapeutic Arthritis Research and Gastrointestinal Event Trial was designed to provide definitive answers concerning the gastrointestinal safety of lumiracoxib, addressing the controversial issues arising from outcomes studies with other cyclooxygenase-2 selective inhibitors.

Background: Lumiracoxib (Prexige; Novartis Pharma AG, Basel, Switzerland) is a cyclooxygenase-2 selective inhibitor associated with improved gastrointestinal safety compared with nonsteroidal anti-inflammatory drugs, in patients with osteoarthritis., Aim: To compare the gastroduodenal safety of lumiracoxib with ibuprofen and celecoxib in patients with rheumatoid arthritis., Methods: A total of 893 patients with rheumatoid arthritis were randomized to lumiracoxib 400 mg once daily, lumiracoxib 800 mg once daily, ibuprofen 800 mg three times daily or celecoxib 200 mg twice daily for 13 weeks, in a double-blind randomised controlled clinical trial. The primary endpoint was the cumulative incidence of gastroduodenal ulcers over 13 weeks., Results: The incidence of gastroduodenal ulcers >/=3 mm with lumiracoxib 400 mg once daily (2.8%) or lumiracoxib 800 mg once daily (4.3%) was significantly lower than with ibuprofen (13.6%, all P < 0.01) and not different from celecoxib (1.9%). The incidence of adverse events was similar for lumiracoxib 400, 800 mg and celecoxib (78, 75 and 77%, respectively) and higher with ibuprofen (86%). Discontinuation for adverse events was highest for ibuprofen (12.5% vs. 7.9-8.8% for the other groups)., Conclusions: Lumiracoxib demonstrated gastroduodenal safety superior to ibuprofen and similar to celecoxib in patients with rheumatoid arthritis.

Background: Clopidogrel causes significantly less symptomatic peptic ulcer disease and gastrointestinal bleeding than low-dose aspirin in average-risk patients. The gastrotoxicity of clopidogrel in patients with active peptic ulcer disease is unknown., Aim: To compare the incidence of unhealed ulcers in patients receiving clopidogrel or aspirin., Methods: Patients with aspirin-induced peptic ulcer disease treated with omeprazole (20 mg/day) were randomized to receive clopidogrel (75 mg/day) or to continue with low-dose aspirin. Success was defined as ulcer/erosion healing at the eighth week., Results: One hundred and twenty-nine patients were recruited (69 received clopidogrel and 60 continued with aspirin). Thirty-one (45%) in the clopidogrel group and 25 (42%) in the aspirin group had a minor gastrointestinal bleed. No ulcer showed an adherent clot or visible vessel. The distributions of peptic ulcer disease were similar in the clopidogrel and aspirin groups (gastric ulcer: 41% vs. 40%; duodenal ulcer: 10% vs. 12%; gastric ulcer + duodenal ulcer: 6% vs. 3%; gastritis: 32% vs. 37%; duodenitis: 4% vs. 7%; gastritis + duodenitis: 0% vs. 2%). Clopidogrel and aspirin were re-started after 0.86 +/- 1.79 and 0.44 +/- 1.60 days, respectively (P = 0.170). Three (4%) patients stopped clopidogrel due to drug rash. Using per protocol analysis, the treatment success rates of clopidogrel and aspirin were 94% (62/66) and 95% (57/60), respectively., Conclusions: In patients with aspirin-associated peptic ulcer disease of low to moderate grade, both early conversion from aspirin to clopidogrel and continuation of aspirin are safe.

Aim: To study whether prophylaxis with lansoprazole could prevent relapse of ulcers after eradication of Helicobacter pylori in patients with NSAID-related peptic ulcers., Methods: Patients who presented with peptic ulcers and were found to be infected with H. pylori while receiving NSAIDs were recruited into the study. They received, twice daily, lansoprazole 30 mg, amoxicillin 1 g and clarithromycin 500 mg for 1 week, followed by lansoprazole 30 mg daily for 4 weeks. Patients with healed ulcers and H. pylori eradicated were given naproxen 750 mg daily, and randomly assigned to receive lansoprazole 30 mg daily or no treatment for 8 weeks. The primary endpoint was the cumulative recurrence of symptomatic and complicated ulcers., Results: At the end of the 8-week treatment period, significantly fewer patients (1/22, 4.5%, 95% confidence interval [CI] 0-23) in the lansoprazole group compared with the group that received H. pylori eradication alone (9/21, 42.9%, 95% CI 22-66) developed recurrence of symptomatic and complicated ulcers (log rank test P=0.0025)., Conclusions: Lansoprazole significantly reduced the cumulative relapse of symptomatic and complicated ulcers in patients requiring NSAIDs after eradication of H. pylori.

Objective: To determine the frequency of use of recommended gastroprotective strategies in a cohort of patients receiving recurrent treatment with nonsteroidal antiinflammatory drugs (NSAIDs)., Methods: A cross-sectional study was performed using administrative data from the Tennessee Medicaid (TennCare) program. The study population consisted of 76,765 recurrent recipients of NSAIDs (NSAID users), comprising 24% of the 319,402 persons ages 50 years or older enrolled in the TennCare program from January 1999 through June 2000. Frequency of use of either of 2 recommended gastroprotective strategies, involving either traditional NSAIDs combined with recommended anti-ulcer cotherapy or use of a selective cyclooxygenase 2-inhibiting drug (coxib), was measured and categorized by risk for ulcer complication., Results: Among this cohort of recurrent NSAID users, 16% received 1 of the 2 recommended gastroprotective therapies: 10% received traditional NSAIDs along with antiulcer drugs at the recommended doses and 6% received coxibs. Among those patients with > or=2 risk factors for ulcer complications (age 75 years or older, peptic ulcer or gastrointestinal bleeding in the past year, or concurrent use of oral anticoagulants or corticosteroids), 30% received such gastroprotective therapy., Conclusion: Use of recommended strategies to decrease ulcer complications in vulnerable populations is relatively uncommon.

Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are the two major causes of peptic ulcers. This article reviews the interaction of H. pylori and NSAIDs on the development of gastric mucosal histological changes, endoscopically confirmed ulcers, and ulcer complications, and assesses whether underlying H. pylori infection potentiates (or mitigates) the development of NSAID-induced ulcer disease. The weight of evidence does not suggest that H. pylori infection potentiates the risk of ulcer formation or ulcer complications in NSAID users. If such an effect occurs, it is likely to be relatively small. Some data even suggest that H. pylori may be protective against NSAID-induced gastric ulcers. Limited data raise the possibility that H. pylori infection, however, may potentiate the effect of low-dose aspirin with respect to ulcer bleeding. Both NSAIDs and H. pylori are independent risk factors for ulcer disease. Therefore, in an individual patient with an ulcer, one cannot be certain which factor is responsible for the ulcer, and both risks should be removed if possible.

Highly selective inhibitors of cyclooxygenase-2, such as rofecoxib, are hypothesized to have an improved gastrointestinal tolerability and safety profile compared with non-selective NSAIDs, which inhibit cyclooxygenase-1 and cyclooxygenase-2 non-selectively. This paper reviews data from randomized, double-blind, placebo-controlled studies which investigated the effects of rofecoxib and NSAIDs on the human gastrointestinal tract. In healthy subjects, rofecoxib 25 mg and 50 mg daily had no effect on gastric mucosal prostaglandin synthesis, whilst naproxen 1000 mg daily caused a 70% reduction. Therapeutic doses of rofecoxib 25 mg and 50 mg daily did not increase intestinal permeability or faecal blood loss in healthy subjects, whereas increases in both measures were seen with indometacin 150 mg or ibuprofen 2400 mg. A supra-therapeutic dose of rofecoxib (250 mg) given daily for 7 days did not induce an increase in gastroduodenal erosions in healthy subjects, whilst increased numbers of erosions were found in subjects given ibuprofen 2400 mg or aspirin 2600 mg. The endoscopic findings in healthy subjects were confirmed in two 6-month clinical studies involving 1516 patients with osteoarthritis; the incidences of ulcers following rofecoxib 25 mg or 50 mg daily were similar to placebo and less than ibuprofen 2400 mg. The advantage of rofecoxib over NSAIDs in these studies appears to translate into clinically relevant benefits; an analysis of 5435 patients with osteoarthritis found a significantly lower incidence of gastrointestinal perforations, ulcers and bleeds in patients taking rofecoxib compared with patients taking NSAIDs. Overall, the findings from these studies suggest that, as a result of cyclooxygenase-1 sparing, rofecoxib is significantly less gastrotoxic than non-selective NSAIDs, and may not differ from placebo.

Introduction: Although it is incontrovertible that Helicobacter pylori causes peptic ulcer disease, controversy persists regarding the impact of H. pylori infection on the incidence of NSAID-related complications and whether H. pylori eradication reduces the rate of adverse events., Methods: A symptom-driven decision analytic model was developed to compare the clinical and economic impact of H. pylori screening compared to a strategy of no H. pylori testing for individuals requiring chronic NSAID therapy. In the principal analysis, it was assumed that untreated H. pylori infection increased the ulcer risk by 50% and that successful eradication reduced the risk of adverse events to that of uninfected patients. Patients' ulcer risk and the protective effect of H. pylori eradication were evaluated using sensitivity analysis., Results: When compared to no H. pylori testing, H. pylori screening led to fewer symptomatic ulcers (no test, 5.4; H. pylori test, 4.6 per 100 patient years) and ulcer complications (no test, 2.6; H. pylori test, 2.3 per 100 patient years) and a higher cost per patient (no test, $435; H. pylori test, $556). The incremental cost attributable to the H. pylori screening strategy to prevent a symptomatic and complicated ulcer was $16,805 and $31,842, respectively. The clinical and cost-effectiveness advantage of H. pylori screening improved as patients' ulcer risk increased or the protective effect of H. pylori eradication was enhanced., Conclusions: Based upon the available evidence, H. pylori screening has the potential to reduce NSAID-related adverse events for average-risk patients at an incremental cost. Until controlled investigations definitively quantify the effect of H. pylori eradication on clinically significant NSAID-related adverse events, a compelling argument can be made for H. pylori testing for chronic NSAID users at increased risk of ulcer disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are well-recognized causes of gastroduodenal mucosal damage. This damage is mediated through the effects of both agents on acid secretion, neutrophil activity and function, and prosta- glandin metabolism. Clinical trials on the interrelation- ship between H. pylori, NSAIDs and gastroduodenal mucosal injury have yielded conflicting results. No consensus has been reached on what recommenda- tions should be implemented with regard to H. pylori eradication in patients on long-term NSAID therapy. At present, the presence of H. pylori is identified at endoscopy and eradication is carried out in symptomatic patients. Asymptomatic patients remain a dilemma that requires further investigation. Clinical practice will continue to be tailored to a patient's individual requirements. Therefore, in patients at risk of gastrointestinal haemorrhage, and on NSAID therapy, acid suppression therapy should be prescribed.

Aim: To compare the efficacy and gastrointestinal (GI) safety of nabumetone with two comparator non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac SR and piroxicam., Methods: Two randomized, double-blind, multicentre, parallel group trials were carried out in patients with moderate to severe osteoarthritis of the hip or knee. During the 6 month treatment phase, the safety and efficacy of nabumetone (1500-2000 mg/day) was compared to diclofenac SR (100 mg/day) or piroxicam (20-30 mg/day). GI safety was evaluated by reviewing all adverse events reported during the trials and presenting all cases of ulcers (complicated and uncomplicated), as well as other bleeding events that may have been associated with NSAID administration., Results: Most of the efficacy parameters showed no significant differences between the NSAIDs, although diclofenac SR was significantly better than nabumetone in one of 18 efficacy parameters. Nabumetone-treated patients experienced significantly fewer ulcer and bleeding events compared to patients treated with the comparator NSAIDs [1.1% (4/348) vs. 4.3% (15/346), P = 0.01]. Bleeding events, including outright upper or lower GI bleeding or a significant decline in haemoglobin, occurred in significantly fewer patients treated with nabumetone than with the comparator NSAIDs [1.1% (4/348) vs. 3.5% (12/346), P < 0.05]. More importantly, complications associated with either ulcers (perforation) or bleeding (leading to hospitalization or withdrawal) occurred in significantly fewer patients receiving nabumetone [0% (0/348)] than with comparator NSAIDs [1.4% (5/346), (P < 0.05)]., Conclusion: The results suggest that nabumetone was similar in efficacy by most criteria to diclofenac SR and piroxicam in relieving the symptoms of osteoarthritis; however, nabumetone's GI safety profile was generally superior to that of both comparator NSAIDs. In the pooled analysis, nabumetone was associated with a significantly lower total incidence of ulcers and bleeding events, and a significantly lower incidence of complications associated with these events.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are strongly associated with gastroduodenal ulcers, and the management of patients with NSAID-associated ulcers represents a common clinical dilemma., Aim: To assess NSAID-associated ulcer healing during treatment with either standard (20 mg) or high dosage (40 mg) omeprazole., Methods: One hundred and sixty-nine patients chronically ingesting diclofenac, ketoprofen, indomethacin or naproxen for osteoarthritis or rheumatoid arthritis, who had abdominal pain and an endoscopically proven gastroduodenal ulcer, were evaluated in a randomized, double-blind, dose regimen trial with omeprazole 20 mg o.m. (n = 81) or omeprazole 40 mg o.m. (n = 88). Ulcer healing was assessed endoscopically at 4 and 8 weeks in the case of unhealed ulcers. Patients continued their usual daily dose of anti-inflammatory medication throughout the study period., Results: One hundred and fifty-six patients completed the study (77 patients taking 20 mg omeprazole and 79 patients taking 40 mg omeprazole); 12 patients were lost during follow-up and one patient reported an adverse event. Cumulative ulcer intention-to-treat healing rates at 8 weeks were 88% (95% confidence interval (CI) = 79-95%) for the 20 mg omeprazole group and 96.2% (95% CI = 89-99%) for the 40 mg group, and 97.1% (95% CI = 90-100%) for the 20 mg omeprazole group and 98.6% (95% CI = 93-100%) for the 40 mg group by per protocol analysis. There were no statistically significant differences between the two groups. Symptom relief did not differ significantly between the two treatment groups., Conclusion: Both standard and high doses of omeprazole are equally safe and effective regimens for the treatment of NSAID-induced gastroduodenal ulcers when anti-inflammatory treatment is not discontinued.

Background: A novel class of nitric oxide-releasing nonsteroidal anti-inflammatory drug (NO-NSAID) derivatives has recently been described which exert anti-inflammatory activities but produce significantly less gastrointestinal injury than the parent NSAID from which they are derived. The present studies were performed to determine if a nitroxybutylester derivative of naproxen was less ulcerogenic to the gastrointestinal tract than its parent NSAID, and if it exerted comparable analgesic and anti-inflammatory properties to the parent NSAID., Methods: The two drugs were compared in an acute gastric injury model, an antral ulcer model and after twice-daily administration for 18 days (small intestinal damage model). Anti-inflammatory activity was examined in the carrageenan-induced paw oedema model, while analgesia was examined in the acetic acid-induced writhing model. The pharmacokinetic profiles of naproxen vs. NO-naproxen were compared by HPLC analysis., Results: NO-naproxen was found to produce significantly less gastric damage despite inducing similar increases in plasma TNF alpha to naproxen. With chronic administration, small intestinal damage was markedly less with NO-naproxen than with the parent NSAID. However, NO-naproxen exerted superior analgesic and comparable anti-inflammatory effects to naproxen. NO-naproxen was not completely converted to naproxen, but the reduced plasma levels of the latter was not the underlying reason for reduced gastrointestinal toxicity of NO-naproxen., Conclusion: NO-naproxen represents a novel, gastrointestinal-sparing NSAID derivative with superior analgesic and comparable anti-inflammatory properties to naproxen.

Aim: To determine whether misoprostol promotes the healing of non-steroidal anti-inflammatory drug-induced gastroduodenal lesions in a human experimental model., Methods: Mucosal damage and healing of mucosal biopsy sites were assessed endoscopically in 10 healthy, Helicobacter pylori-negative volunteers with a normal initial endoscopy: they were enrolled in a double-blind, double-dummy, placebo-controlled cross-over study. They received 2-week courses of misoprostol (200 micrograms b.d.) or placebo; a water-soluble non-steroidal antiinflammatory drug diclofenac 50 mg t.d.s., was given during the second week of each dosage regimen after three endoscopic biopsies had been taken from each of the duodenum, antrum and corpus., Results: The number of unhealed biopsy sites was not different after misoprostol or placebo, although the number of healed biopsy sites was greater in the corpus and duodenum than in the antrum. Misoprostol did not prevent the appearance of diclofenac-induced erosions and petechiae. Epigastric discomfort was related to the intake of diclofenac and was reduced by misoprostol. Bloating and flatulence occurred more frequently with misoprostol alone and with misoprostol plus diclofenac, than with placebo alone or placebo plus diclofenac., Conclusion: Misoprostol does not prevent new mucosal lesions induced by diclofenac in healthy volunteers and it does not accelerate the healing of the biopsy sites. Misoprostol decreases the frequency of diclofenac-induced epigastric discomfort, but it increases gas bloating and flatulence.

Background: Continuous therapy with low-dose ranitidine (150 mg b.d.) is known to be effective for the prevention of recurrent nonsteroidal anti-inflammatory drug (NSAID)-associated duodenal ulcer but not for gastric ulcer., Aim: To investigate, in a double-blind placebo-controlled study, the preventive effect of a high dose of ranitidine (300 mg b.d.) on the recurrence of both duodenal ulcers and gastric ulcers in rheumatoid arthritis patients with a continuous need for NSAIDs., Methods: Rheumatoid arthritis patients with a history of peptic ulcer disease were randomized to receive either ranitidine 300 mg b.d. or placebo for 12 months. Endoscopy was performed at study entry and after 6 and 12 months. End-point was the recurrence of gastric or duodenal ulcers., Results: The study was stopped after a blinded interim analysis; at that time 10 of the 15 included patients in each treatment group were evaluable. Recurrent duodenal ulcers had occurred in four patients treated with placebo and none of the patients treated with ranitidine (Fisher's exact one-tailed P = 0.04; 95% CI, - 0.70 to -0.10). Recurrent gastric ulcers had occurred in six patients in the placebo group and three patients in the ranitidine group (Fisher's exact one-tailed P = 0.18; 95% CI, -0.72 to 0.12). Two patients in the placebo group had developed both duodenal ulcers and gastric ulcers. No adverse events were observed., Conclusions: High dose ranitidine is effective for the prevention of recurrent duodenal ulcer but not for recurrent gastric ulcer in rheumatoid arthritis patients taking NSAIDs.

Background: The cyclo-oxygenase inhibitor indomethacin induces a pattern of gastrointestinal injury in the rat that is site-dependent. This study compared the extent of injury to different regions of the rat intestine (small intestine, caecum and colon) with the corresponding changes in arachidonic acid metabolism in these areas, following long-term, low-dose indomethachin., Methods: Rats (eight per group) received either indomethacin (3 mg.kg/day) or control diet for either 6 or 12 weeks. At termination animals were bled, examined both macroscopically and microscopically for ulcers, and assayed for blood thromboxane B2, intestinal tissue prostaglandin E2 content and production of leukotriene B4. In a further eight animals luminal indomethacin concentrations from the small intestine, caecum and colon were measured following 6 weeks of chronic drug ingestion., Results: At 6 weeks, macroscopic ulcers were observed in 2/8 (small intestine), 3/8 (caecum) and 1/8 (colon) animals. The corresponding ratios at 12 weeks were 5/8, 8/8 and 0/8. In control animals, a site-dependent gradient of the prostaglandin E2 concentration was found. In indomethacin-dosed animals the intestinal prostaglandin E2 content was reduced significantly in the caecum at 6 weeks, and in all tissues at 12 weeks. An increased leukotriene B4 production was observed in the caecum only, at 12 weeks (P < 0.01), and the blood thromboxane B2 was reduced at both time points (P < 0.05)., Conclusion: There is a site-dependent gradient of the prostaglandin E2 concentration in the rat intestine. The rat caecum is particularly sensitive to long-term low-dose indomethacin, both in terms of chronic intestinal inflammation and changes in prostanoid metabolism. This site-dependent degree of injury may be associated with a local cyclo-oxygenase inhibition.

Aims: To examine the effects of a pepsin inhibitor, pepstatin-A, a long acting H2-receptor blocker, loxtidine, exogenous pepsin and exogenous acid against indomethacin-induced antral ulceration in the rat., Results: Indomethacin (60 mg/kg s.c.) caused antral ulceration in fasted/re-fed rats over a period of 4 h. Ulceration was prevented in a dose-dependent manner by treatment with pepstatin-A (0.1-1 mg.kg hourly) or loxtidine (3 mg/kg) given orally. Acidified methylcellulose (1 mL hourly per os) enhanced damage and also prevented protection by loxtidine (3 mg/kg per os). The protection by pepstatin-A was not altered by treatment with acidified methylcellulose but was reversed by treatment with a 10-fold excess of pepsin., Conclusion: These studies suggest that mucosal degradation by pepsin, rather than direct damage by luminal acid, was the major factor in the development of indomethacin-induced antral ulceration in the rat.

The effects of oral indomethacin on intragastric pH and serum gastrin were investigated in rheumatoid arthritis patients. Nine patients (1 male, 8 female) without a history of peptic ulcer disease and 6 patients with a history of peptic ulcer disease (5 male, 1 female) were studied. To obviate Helicobacter pylori infection as a confounding factor, only patients with positive H. pylori serology were included. After a 5-day period of placebo treatment and after a 5-day period of indomethacin (50 mg t.d.s.; total dose 750 mg), 24-h intragastric pH and basal and meal-stimulated serum gastrin levels were measured in a double-blind placebo controlled cross-over study. There were no differences in the median 24-h pH values between placebo and indomethacin users irrespective of peptic ulcer disease history. Indomethacin resulted in a higher basal and stimulated gastrin response than placebo in patients with a history of peptic ulcer disease. The basal and incremental responses were lower in patients with a history of peptic ulcer disease than in patients without a history of peptic ulcer disease, both during indomethacin and placebo. The same basal and stimulated incremental serum gastrin responses were found during placebo and indomethacin treatment in patients without a history of peptic ulcer disease. No correlation was established between median 2-h post-prandial intragastric pH and post-prandial incremental serum gastrin concentration. We conclude that indomethacin does not influence the intragastric pH of rheumatoid arthritis patients irrespective of history of peptic ulcer disease.

Objective: To compare, in a Canadian health care setting, the costs and consequences of 3 strategies of misoprostol prophylaxis for osteoarthritis patients: prophylaxis for all patients taking nonsteroidal antiinflammatory drugs (NSAIDs), for no patients taking NSAIDs, and for only elderly patients (age > or = 60) taking NSAIDs., Methods: We designed a decision-analysis model which incorporated costs (estimated with ulcer patient profiles and medical records), review, and probabilities (estimated from a companion meta-analysis, selected literature review, and Ontario Ministry of Health Statistics). Effectiveness was defined as the number of episodes of gastric ulceration requiring hospitalization or outpatient management that were averted by each strategy., Results: On average, prophylaxis cost an additional $650 for every additional gastrointestinal event prevented. Prophylaxis for elderly NSAID users was cost saving if the ulcer complication rate in this group exceeds 1.2%, or if either the charges for outpatient ulcer treatment exceed $2,000, or the 3-month price of misoprostol is < or = $90., Conclusion: Our results demonstrate that, in this setting, misoprostol prophylaxis may be highly cost effective.

The proven benefit of aspirin in the secondary prevention of cardiovascular disease and its possible value in primary prevention must be weighted against its potential hazards. This paper is an overview of the gastrointestinal toxicity of aspirin, its most serious complication after intracerebral haemorrhage. Information on toxicity has been drawn only from randomised trials, thus avoiding the potential biases of observational studies. All randomised placebo controlled trials listed in the Anti-platelet Trialists Collaboration where a direct aspirin-placebo comparison was possible were included. Twenty-one trials were included, all but one of secondary prevention. There were over 75,000 person years of aspirin exposure. The pooled odds ratios for categories of gastrointestinal bleeding (e.g. haematemesis, melaena) were between 1.5-2.0; fatal bleeds were very rare. The risk of peptic ulcers was 1.3 and of upper gastrointestinal symptoms 1.7. These risks were lower than those found in observational studies. Attributable disease rates are also presented. For haematemesis for example they varied from 0.2-1.0 per 1000 person years. Toxicity was dose related. Aspirin does have significant gastrointestinal toxicity, although this is rarely fatal. More recent work has demonstrated the efficacy of low doses of aspirin (75 mg daily) but there is limited information yet available on its toxicity.

Addition of glucose and sodium citrate to azapropazone, in proportions of 1:1:1 by weight reduced gastric mucosal damage in rats and there was a trend towards reduction in radiolabelled faecal red cell loss in human volunteers compared with that with azapropazone alone. The glucose and citrate did not affect the pharmacokinetics of azapropazone, or its therapeutic efficacy. While no difference was observed in endoscopic injury and in symptomatic gastrointestinal complaints in a multicentre comparison in rheumatic patients, a striking reduction in symptoms was observed in those patients with a history of severe gastrointestinal intolerance to non-steroidal anti-inflammatory drugs.

All NSAIDs cause gastroduodenal mucosal damage. The mechanisms by which NSAIDs damage the mucosa are not fully understood. Peptic ulcers appear to be caused by an imbalance between acid output and mucosal resistance; therapeutic agents that act favourably on either variable will heal NSAID-induced ulcers, particularly if the NSAID is discontinued. Inhibition of acid secretion and/or stimulation of prostaglandin secretion are also believed to have a protective effect against NSAID-induced mucosal damage. Thus, antisecretory agents, such as the H2 blockers, and prostaglandin analogues, such as misoprostol, can provide protection against NSAID-induced gastroduodenal damage.

Non-steroidal anti-inflammatory drug (NSAID) use is associated with gastro-duodenal erosions and ulcers. Bleeding and perforation are reported complications in NSAID users. Therapeutic recommendations for NSAID-induced gastroduodenal injury are necessary because of our rapidly growing geriatric population, a steady increase in prescriptions for NSAIDs, and the widespread use of over-the-counter NSAIDs. Studies seem to indicate that there is no relationship between acute NSAID-induced mucosal injury and potential damage from chronic NSAID ingestion. Ranitidine (150 mg) b.d. effectively reduces the incidence of duodenal ulcer in NSAID users, but the same dose does not reduce the incidence of gastric ulcer. Misoprostol is effective in reducing the incidence of gastric ulcer in NSAID users, although confirmatory data on its effectiveness in preventing NSAID-induced duodenal ulcer are lacking. In addition to anti-ulcer therapy, treatment of NSAID-induced ulcers includes discontinuing the drug, reducing the dose, or switching to a less potent NSAID. Longer courses of anti-ulcer treatment may be required to achieve expected healing rates when NSAIDs are not discontinued. Results of treatment of NSAID-related ulcers with currently available anti-ulcer medications vary. Several studies have shown that 150 mg ranitidine b.d heals both gastric and duodenal NSAID-induced ulcers. Sucralfate has also been shown to heal NSAID-induced duodenal ulcers. Misoprostol treatment of NSAID-induced ulcers is not well documented, although there are placebo-controlled data that substantiate its benefit in gastric ulcer patients not taking NSAIDs.

A follow-up study of 8370 outpatients who filled over 24,000 prescriptions for tolmetin revealed no hospital admissions for acute allergic, blood, skin, or central nervous system illness within 90 days of filling a prescription or refill for the drug. There were two cases of liver disease and two cases of nephrotic syndrome in which an etiologic relationship to tolmetin seemed unlikely but could not be entirely ruled out. In addition, 11 patients were hospitalized for peptic ulcer disease and its complications. In all but two patients other risk factors were present that could readily explain the illness. The rate of hospitalization for peptic ulcer disease and its complications among tolmetin recipients appears to be of the same magnitude as that in patients who take other nonsteroidal antiinflammatory drugs in this population, and close to that of the population at large.

1 The analgesic, anti-inflammatory, antipyretic and ulcerogenic properties of the non-steroidal agents, acetylsalicylic acid, paracetamol, ibuprofen, propyphenazone and aminophenazone are compared. 2 The results show that ibuprofen has the most potent effect on all four parameters followed in descending order of potency by aminophenazone, propyphenazone, paracetamol and acetylsalicylic acid. 3 The inflamed paw technique and the adjuvant arthritis model, both in the rat and involving pathological (chronic) pain, are the most successful methods of predicting analgesic activity in man. The short-lasting oedema caused by injecting naphthoylheparamine into the rat paw is the most useful method of predicting clinical anti-inflammatory activity.

1. The mechanism of indomethacin-induced gastric ulcers was investigated by measuring tissue prostaglandins (PG) levels. 2. The effects of PGD2 and omeprazole, an H+ pump inhibitor, were also estimated. 3. Four kinds of PG--6-keto PGF1 alpha, PGF2 alpha, and PGD2--in rat gastric mucosa were measured by high performance liquid chromatography. 4. All PG levels decreased 1 h after oral administration of 2 mg/kg indomethacin, although they recovered considerably 24 h after administration. No gastric ulcers were observed throughout the experiments in rats treated with 2 mg/kg indomethacin. 5. All PG were not detected 1 h, and even 24 h after administration of 12 mg/kg indomethacin. Over 6 h after administration, gastric ulcers were observed. 6. Premedication with omeprazole prevented ulcer formation, although it did not improve gastric mucosal PG levels. Administration of PGD2 also reduced ulcer formation, and considerable amounts of PGD2 in gastric mucosa were detected. 7. It can be concluded that H+ is a determining factor in the genesis of indomethacin-induced gastric ulcers and that persistent decreases in tissue PG levels also participate in ulcer formation.

The pathogenetic role of non-steroidal anti-inflammatory drugs (NSAIDs) in peptic ulcer disease is reviewed, on the basis of available experimental and epidemiological knowledge. In addition, original clinical data are provided concerning the prophylactic and therapeutic role of the H2-receptor antagonists ranitidine and cimetidine, and colloidal bismuth subcitrate, in the treatment of NSAID-associated peptic lesions in rheumatic patients.