Nonsteroidal Anti-inflammatory Gastropathy Research Articles

Nonsteroidal anti-inflammatory drug gastropathy and helicobacter pylori: the search for an improbable consensus

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are known to share a number of pathogenic mechanisms, but there is no evidence to show a significant synergistic action between these two risk factors. Studies to assess possible interactions in the pathogenesis of dyspepsia and upper gastrointestinal mucosal lesions have differed in their endpoints, the definition of dyspepsia, and the regimens used for eradication of H. pylori. However, some conclusions may be drawn from the results of clinical trials. As far as dyspepsia is concerned, an association between NSAID dyspepsia and infection with H. pylori, seems likely, but it is difficult to make sense of the discrepant data that are currently available. On the contrary, neither short- nor long-term NSAID administration presents a definite major risk of gastric and duodenal injury or, above all, of ulcer-related complications (bleeding or perforation) in H. pylori–positive patients. Based on these considerations, what recommendations can be made with regard to H. pylori eradication in patients requiring treatment with NSAIDs? H. pylori and anti-inflammatory drugs are probably independent causes of gastric and duodenal damage. Patients taking NSAIDs who are found to have gastric or duodenal ulcers should, therefore, be tested for the bacterium and specifically treated, because H. pylori and NSAID-induced ulcers may be macroscopically indistinguishable. Whether asymptomatic patients taking NSAIDs should be tested and treated for H. pylori infection is still a matter of debate.

Nonsteroidal anti-inflammatory drug gastropathy at the new millennium: Mechanisms and prevention

Objectives: Nonsteroidal anti-inflammatory drug (NSAID)–induced gastrointestinal (GI) toxicity remains the most frequent adverse drug event in the United States. The objective of this review is to update clinicians in recent advances in basic and clinical investigation regarding the pathogenesis and management of NSAID gastropathy. Methods: Based upon an extensive review of the published literature and abstracts of key work within the past decade, the framework for new approaches to the prevention and treatment of NSAID-associated ulceration is summarized. Results: The pathophysiology of NSAID-induced injury to the GI tract is multifaceted and includes both prostaglandin-dependent and independent components. The pharmaceutical industry has capitalized on the identification of two different isoforms of cyclooxygenase, enabling the development of specific inhibitors of one isoform that minimizes prostaglandin-dependent mechanisms that contribute to NSAID-induced injury. Clinical trials support the efficacy and reduced toxicity of these agents. Because acid exacerbates the injury initiated by NSAIDs, potent acid suppressive therapy, typically with proton pump inhibitors, is another common approach to the treatment of NSAID-related dyspepsia as well as NSAID-induced ulcer disease. Conclusions: Recent improvements in the understanding of NSAID-induced damage and new drug development have provided the opportunity for effective anti-inflammatory therapy with reduced GI toxicity. This illustrates the importance of identifying patients at risk for potential complications and the appropriate use of strategies to prevent and treat NSAID-induced complications. Semin Arthritis Rheum 30:167-179. Copyright © 2000 by W.B. Saunders Company

Is it time to adopt proton pump inhibitors in the prevention of non-steroidal anti-inflammatory drug gastropathy?

Is it time to adopt proton pump inhibitors in the prevention of non-steroidal anti-inflammatory drug gastropathy?

Severe acute gastritis associated with Helicobacter pylori infection

We describe the case of a young female referred to our unit because of acute upper abdominal symptoms. Upper gastrointestinal endoscopy showed a gastric picture resembling lymphoma or acute non-steroidal anti-inflammatory drug gastropathy (deep, large and irregular ulcers), but the clinical history and the histological examination of gastric biopsies were consistent only with acute gastritis Helicobacter pylori-correlated. The patient was treated with omeprazole and antibiotics with complete recovery. As the patient's cat had suffered from an acute gastrointestinal distress two weeks earlier, a case of zoonosis was hypothesized and an upper gastrointestinal endoscopy was performed also on the cat. Unfortunately, we were not able to detect Helicobacter pylori in the cat gastric mucosa, but only urease-producing spiral microorganisms. Possible sources of infection and pathogenetic mechanisms of the severe gastritis are discussed.

Comparative toxicity of nonsteroidal anti-inflammatory drugs

To compare the gastrointestinal (GI) toxicities of various nonsteroidal anti-inflammatory drugs (NSAIDs), it is first necessary to dismantle the imprecise entity “NSAID gastropathy” into its component conditions, and understand their pathogenesis. In this article, toxicities are reviewed only in so far as they affect the upper GI tract, the site of approximately 80% of GI injuries caused by NSAIDs. The phenomena discussed are platelet dysfunction, causing hemorrhage from various lesions, including but not confined to ulcers; various mucosal injuries, ranging from small erosions to large ulcers; and “complications,” such as bleeding or perforations, causing admission to hospital, that may arise from ulcers but may also arise from other lesions. Ulcers, when complicated, may either be those caused by an NSAID or “peptic” ulcers that preceded NSAID therapy (having a high prevalence in the population) and gave rise to complications resulting from NSAID effects on platelets, tissues, or biologic processes, for example, healing, necrosis/apoptosis, leukocyte adherence, vasoconstriction, or generation of free radicals. NSAIDs have been compared in various ways, including fecal blood loss, endoscopic lesion development, prospective preclinical cohort studies measuring perforations, ulcers, and bleeds, post-marketing surveillance studies, and studies of the incidence of serious adverse events in populations followed in large databases linked to each individual patient record with regard to drug consumption and outcome. All methods show considerable differences between NSAIDs. Modern studies on the relative toxicities of NSAIDs are summarized and reviewed, and a number of marketed and emerging drugs that appear less toxic than classic NSAIDs are identified.

The treatment of peptic ulcer disease

The literature published in the period under review identified some areas of key clinical and scientific importance in the treatment of peptic ulcer disease. Attention was drawn to the possibility that Helicobacter pylori may be less important as an etiologic factor in ulcer disease in the United States than in the rest of the world. The usual large number of papers addressed various treatment regimens, and the issue of H. pylori resistance to antibiotics was prominent. The introduction of the cyclooxygenase enzyme 2 (COX-2)-specific inhibitors promises to significantly affect nonsteroidal anti-inflammatory drug (NSAID) gastropathy. The review period produced some excellent papers (mainly review papers) on this topic, but there is a paucity of peer-reviewed data on the clinical application of COX-2 NSAIDs. Perhaps more important is that some authors, using a variety of animal models, protested the blithe acceptance of the COX-2 concept, questioning the idea of "specificity" and identifying possible problems with respect to ulcer healing. Observations of potential clinical importance with regard to the phenomenon of acid rebound after proton-pump inhibitor therapy were presented, and the role of H. pylori in the management of nonulcer dyspepsia remains controversial, despite the publication of three of the best-designed studies to date on this important topic.

Gastropathy induced by nonsteroidal anti-inflammatory drugs: prescribing patterns among geriatric practitioners.

The objective of this study was to determine patterns among geriatric practitioners in prescribing agents that protect the gastrointestinal tract when nonsteroidal anti-inflammatory drug (NSAID) treatment is started for elderly patients. A questionnaire describing five scenarios of elderly patients requiring NSAID therapy asked respondents to choose gastrointestinal-protective agents for each scenario. Respondents were then asked to what extent four established risk factors for NSAID gastropathy (age, previous peptic ulcer, previous gastrointestinal bleeding, and heart disease) affected their choices. The choice of gastrointestinal-protective agent was compared with the training and experience of the respondents. This self-administered survey was provided to 821 randomly selected physicians from the membership of the American Geriatrics Society throughout the United States and Puerto Rico. Statistical Package for the Social Sciences (SPSS), version 6.1.4, was used to obtain frequencies. Of 821 surveys, 229 (28%) were returned. It was found that well elderly patients and nursing home residents were not treated with any gastrointestinal-protective agent by 64% (well elderly patients) and 32% (nursing home residents) of respondents. Among respondents who would prescribe, about half would choose misoprostol for a well elderly patient or a nursing home resident, whereas half or more preferred histamine H2-receptor antagonists. Twenty-three percent would not prescribe misoprostol when NSAID therapy was resumed after an active ulcer had healed, and 68% preferred H2 antagonists in that setting. The difference in response attributable to training/experience was less than 9%. Factors that did not affect prescribing patterns included the patient's age (15% to 62%) and heart disease (44% to 50%). The study concluded that age and heart disease are risk factors to which physicians give less consideration when choosing gastrointestinal-protective agents. Although misoprostol is the only agent approved by the Food and Drug Administration for prophylaxis against NSAID gastropathy, 23% of respondents chose not to prescribe misoprostol when NSAID therapy was resumed after an active ulcer had healed. Histamine H2-receptor antagonists were preferred over misoprostol for well elderly patients and nursing home residents. Training and experience were not responsible for differences among respondents' prescribing patterns.

Gastrointestinal safety of nitric oxide–derived aspirin is related to inhibition of ICE-like cysteine proteases in rats

Background & Aims: Caspases, a class of cysteine proteases, modulate apoptosis. Nitric oxide (NO)-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) are a new class of NSAID derivatives with reduced gastrointestinal toxicity. The aim of this study was to investigate whether cysteine endoproteases are involved in the pathogenesis of NSAID gastropathy and are target for NO-aspirin (NCX-4016). Methods: Rats were treated orally with aspirin or equimolar doses of NCX-4016. Caspase activities were measured by fluorometric assay. Apoptosis was quantified by an enzyme-linked immunosorbent assay for histone-associated DNA, DNA ladder on agarose gel, and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay. A primary culture of gastric chief cells was used to investigate whether NCX-4016 modulates guanosine 3',5'-cyclic monophosphate (cGMP)-dependent pathways. Results: Short- and long-term (7 days) aspirin administration resulted in a time- and dose-dependent gastric injury that was associated with apoptosis and caspase up-regulation. Z-VAD.FMK, a pancaspase inhibitor, and NO donors protected from acute damage induced by aspirin. NCX-4016 spared the gastric mucosa and caused caspase inactivation by S-nitrosylation. Inhibition of tumor necrosis factor (TNF)-α release or activity by TAPI-2 or anti–TNF-α receptor monoclonal antibodies protected against mucosal damage and caspase activation. NCX-4016 protected gastric chief cells from toxicity induced by TNF-α by activating cGMP-dependent pathways. Conclusions: Aspirin administration leads to a TNF-α–dependent activation of gastric caspases. NO-aspirin spares the gastric mucosa and inhibits caspase activity through cGMP-dependent and -independent pathways. GASTROENTEROLOGY 1999;116:1089-1106

NSAID-related gastrointestinal complications

Despite the common induction ofgastrointestinal (GI) complications by nonsteroidal anti-inflammatory drugs (NSAIDs), many aspects of pathogenesis and management remain controversial. The most important complications are bleeding and perforation arising in the esophagus, stomach, and duodenum due to NSAID effects on platelets and on a variety of mucosal lesions. Complications arise from preexisting peptic ulcer, NSAID-induced ulcers and erosions, and other lesions (not caused by NSAIDs) caused to bleed by NSAID-induced platelet dysfunction. Much confusion has arisen from the umbrella term “NSAID gastropathy” used to embrace a variety of pathogenetically distinct mucosal lesions. Failure to discriminate among the different forms of NSAID injury has hampered clinical investigation. This article offers general guidelines for prevention of NSAID complications, but there remain many unresolved issues, including the role of Helicobacter pylori infection. The best approach to management is to remove or reduce exposure to NSAIDs whenever possible. The newer NSAIDs (eg, cyclo-oxygenase (COX]-2-selective inhibitors) have a much lower risk of endoscopic ulcers and minimal platelet effects, which are likely to translate into lower risk of GI complications. However, this benefit on clinical outcome remains to be established.

The Epidemiology of NSAID Gastropathy The ARAMIS Experience

The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) is a national database for longitudinal outcome information obtained form the long-term follow-up of patients with rheumatic disease. This database has been used to investigate the parameters associated with nonsteroidal anti-inflammatory drug (NSAID) gastropathy in a population of 2747 patients with rheumatoid arthritis (RA). Theses patients were found to have a 1.3% higher risk of hospitalization each year because of a gastrointestinal (GI) adverse event than the general population. In these patients with RA, there was a five fold higher risk of hospitalization and a twofold increase in GI mortality among NSAID users compared with the general population. Age was the most significant predictor of serious GI events in our study' disability, prednisone therapy, and previous NSAID-related GI events were also identified as risk factors. An objective index of drug toxicity was developed to facilitate comparisons of the potential risks involved with specific drug regimens. consistent toxicity scores were obtained for NSAIDs, with threefold to fourfold difference between drugs having low risk versus high risk. These studies indicate a need for changes in management practices in at-risk patients and a potential role for better tolerated NSAIDs, such as the recently developed cyclooxygenase-2 selective or preferential drugs.

Recent considerations in nonsteroidal anti-inflammatory drug gastropathy

Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone. The figures for all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated. The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) Post-Marketing Surveillance Program (PMS) has prospectively followed patient status and outcomes, drug side effects, and the economic impact of illness for >11,000 arthritis patients at 8 participating institutions in the United States and Canada. Analysis of these data indicates that: (1) osteoarthritis (OA) and rheumatoid arthritis (RA) patients are 2.5–5.5 times more likely than the general population to be hospitalized for NSAID-related GI events; (2) the absolute risk for serious NSAID-related GI toxicity remains constant and the cumulative risk increases over time; (3) there are no reliable warning signals— >80% of patients with serious GI complications had no prior GI symptoms; (4) independent risk factors for serious GI events were age, prednisone use, NSAID dose, disability level, and previous NSAID-induced GI symptoms; and (5) antacids and H 2 antagonists do not prevent NSAID-induced gastric ulcers, and high-risk NSAID users who take gastro-protective drugs are more likely to have serious GI complications than patients not taking such medications. Currently, limiting NSAID use is the only way to decrease the risk of NSAID-related GI events. Ongoing ARAMIS research is aimed at developing a simple point-score system for estimating individual risks of developing serious NSAID-related GI complications.

Greater curvature antral flattening due to nonsteroidal antiinflammatory drugs.

To report on our experience concerning a recently described double-contrast finding of gastritis related to the use of non-steroidal antiinflammatory drugs (NSAIDs), namely, flattening of the greater antral curvature. The radiographic examinations of 41 subjects studied for NSAIDs gastropathy or for different reasons but with recent abuse of NSAIDs, were reviewed. The radiographs of 100 consecutive patients without history of NSAIDs use and evaluated for different questions were used as controls. Flattening of the greater curvature was present in 5 subjects (12%) with a prolonged history of NSAIDs use and in none of the controls. In three cases it was a solitary finding whereas in two it was associated with antral erosions. In our series, antral flattening was less frequent than reported in literature. Nevertheless, it may be a useful sign of NSAIDs gastropathy and may be especially relevant when representing the only evidence of gastric lesions related to NSAIDs.

The gastroenterologist's caseloadcontribution of the rheumatologist

Rheumatological conditions often give rise to gastrointestinal (GI) symptoms, and vice versa, but the greatest point of contact between rheumatologists and gastroenterologists arises through gastrointestinal toxicity resulting from the use of nonsteroidal antiinflammatory drugs (NSAIDs). Standard NSAIDs are toxic to the entire GI tract. The point prevalence of ulcers in patients on long-term NSAID treatment is about 20% and the annual incidence of complications in these patients is 1% to 4%; 1,200 patients in the United Kingdom die each year as a result. Withdrawing NSAID treatment, or reducing the dose, is not always possible, and approximately 25% of patients require continued long-term antiinflammatory treatment. Misoprostol and acid-suppressing drugs such as ranitidine and omeprazole are helpful as prophylactic treatment in high risk patients, and in healing established ulcers, especially in patients carrying Helicobacter pylori, but there is a pressing need for new, safer antiinflammatory drugs to ease the burden of NSAID gastropathy. Selective inhibition of the COX-2 isoform of cyclooxygenase has been proposed as a new and safer therapeutic option. Clinical studies with meloxicam, a selective COX-2 inhibitor, support this view. Meloxicam has been extensively studied in arthritis patients and combines antiinflammatory efficacy with a lower incidence of GI toxicity than currently available NSAIDs.

Helicobacter pylori: from bench to bedside.

With the exponential increase in research in the field of Helicobacter pylori a paradigm shift has occurred. It is now recognized that H pylori is a chronic infection of the stomach causing inflammation. Some patients remain asymptomatic, while others may develop dyspepsia, duodenal or gastric ulcer, gastric cancer or a mucosa-associated lymphoid tissue lymphoma. However, the role of H pylori in contributing to nonulcer dyspepsia or nonsteroidal anti-inflammatory drug gastropathy remains controversial. An effective vaccine against H pylori is years away. Major interest has focused on the questions "who should be investigated and therefore treated" and "what is the latest gold standard for eradication of H pylori"? In Europe, guidelines have been developed to help the practitioner answer these important questions. Canadian guidelines will soon be available. For persons with known peptic ulcer disease there should be unequivocal acceptance that the good clinical practice of eradicating H pylori will result in substantial savings in health care expenses. The original 'classical triple therapy' (bismuth, metronidazole and tetracycline [BMT]) has now been surpassed by the combination of a proton pump inhibitor (PPI) plus two antibiotics (metronidazole plus clarithromycin; amoxicillin plus clarithromycin; or amoxicillin plus metronidazole), each given twice a day for one week. In Canada, the regimen of omeprazole plus one antibiotic (amoxicillin or clarithromycin) was approved recently but gives an eradication rate that is lower than the current target of 90%. According to the European (Mäastricht) recommendations, if a single treatment attempt with PPI plus two antibiotics fails, PPI plus BMT is recommended.

NSAID Gastropathy

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is associated with substantial morbidity and mortality, which result in high costs to both the patient and society. The subset of patients who are at greatest risk for developing NSAID gastropathy continues to be better defined, but various risk factors, such as age and previous gastrointestinal tract disease, have been identified. In patients receiving older NSAIDs, the choice of NSAID should be based on differences in formulations at the lowest effective dose. Gastroprotective cotherapy should be instituted if treatment with older NSAIDs is continued in at-risk patients; misoprostol is currently the only agent approved for this indication. The impact of misoprostol on clinical gastrointestinal tract end points has recently been documented. Newer NSAIDs may have an improved safety profile over older NSAIDs; some have a clinically documented reduction in the incidence of adverse gastrointestinal tract effects. An understanding of these issues should enable the informed clinician to choose an NSAID on the basis of risk-benefit and cost-benefit considerations.

Isolated guinea pig gastric chief cells express tumour necrosis factor receptors coupled with the sphingomyelin pathway.

The tumour necrosis factor alpha (TNF), has been implicated in the pathogenesis of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy and Helicobacter pylori induced gastritis. Both conditions are characterised by high plasma pepsinogen concentrations, which are thought to reflect an increased rate of enzyme release by the pepsinogen secreting (chief) cells. The mechanisms responsible for this cell dysfunction are unknown. This study investigates whether chief cells express TNF receptors and, if so, whether their activation results in cell death. Immunohistochemical studies conducted with monoclonal antibodies (mAbs) directed against two TNF receptor associated proteins of 55 kDa (TNF-R1) and 75 kDa (TNF-R2) showed that TNF binding sites were expressed in approximately 100% gastric chief cells. Western blot analysis of whole chief cell lysates probed with the TNF-R1 and TNF-R2 mAbs gave two distinct bands of 55 and 75 kDa in the immunoprecipitate. Incubating chief cells with TNF caused concentration and time dependent cell death, which was prevented by pretreating the cells with anti-TNF receptor mAbs. Exposing the cells to TNF reduced sphingomyelin content by 25%. Sphingomyelinase (10(-6) to 10(-2) IU/ml) mimicked the effect of TNF in that it provoked a concentration and time dependent reduction in chief cell viability and increased pepsinogen release. In conclusion, gastric chief cells express two TNF receptors partially linked to the sphingomyelin pathway. TNF induced chief cell dysfunction might be responsible for the high plasma pepsinogen concentrations seen in patients with NSAID gastropathy or H pylori induced gastritis.

ピロキシカム，アンピロキシカムによる胃十二指腸粘膜障害

Nonsteroidal antiinflammatory drugs (NSAIDs) are used extensively in the treatment of rheumatic diseases. However, the inhibition of PG synthesis is major factor accounting for damage to the gastroduodenal mucosa which has given rise to the term“NSAID gastropathy”. Recently, prodrug of NSAID have been developed. Since prodrug of NSAID pass through the gastrointestinal tract in the inactive form. GI disturbance by prodrug are expected to be weak.A controlled double blind study was performed for 19 rheumatic patients in order to assess the damaging action on the gastroduodenal mucosa induced by a prodrug (inactive form) of piroxicam (ampiroxicam) in comparison with piroxicam.Subjects were recieved either of the following two drugs combinations ; (1) piroxicam and ampiroxicam placebo, (2) piroxicam placebo and ampiroxicam. Endoscopic findings were evaluated before and 2 weeks after treatment.The incidence of NSAID gastropathy was slightly lower in subjects administered ampiroxicam (50%) than in those administered piroxicam (78%) . In the ampiroxicam group with patients moderate indulgence of addictive habits, especially alcohol ingestion, were found to be significant factor promoting the development of GI damage by oral ampiroxicam. There was no correlation between the presence or absence of subjective symptomes and endoscopic findings.The results of this study indicate that ampiroxicam (prodrug of piroxicam) was slightly able to avoid GI damage. However, the incidence of ampiroxicam induced GI damage was not significantly superior to piroxicam administered group. It would therefore appear still dangerous for clinicians.

Non-steroidal Anti-inflammatory Drug Gastropathy: Causes and Treatment

Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) almost invariably cause acute gastroduodenal injury and probably account for approximately 12,000 ulcer bleeding episodes and 1200 deaths per annum in the United Kingdom. Clinically significant intestinal toxicity is also recognized but less clearly defined. The main risk factors for NSAID-related peptic ulcer complications are age, past history, use of higher risk individual NSAIDs, drug dose, concurrent use of warfarin or corticosteroids. The underlying reason for NSAID use and Helicobacter pylori status is not clearly associated with increased risk. Whether NSAIDs cause drug-induced non-ulcer dyspepsia is also controversial. Acute injury occurs more readily with aspirin than with non-aspirin NSAIDs, and the spectrum of acute injury is of little value in predicting clinically significant end points in comparison with different NSAIDs. However, acute studies of co-prescribed protective agents are highly predictive of performance in clinical practice. Gastric mucosal integrity is maintained by the interplay of three protective networks: prostaglandin synthesis, nitric oxide synthesis and the activity of the enteric nervous system. Aspirin and NSAIDs act by inhibiting prostaglandin synthesis catalysed by two cyclooxygenase enzymes. Most existing NSAIDs are unselective and inhibit the activity of the constitutive cyclooxygenase (COX) 1 enzyme in the stomach as much as the cyclooxygenase (COX) 2 enzyme which is induced at sites of inflammation such as joint disease. There are, however, prospects for selective cyclooxygenase 2 inhibitors. Some NSAIDs, particularly aspirin, have additional topical toxicity, which may in part reflect mucosal trapping. Some data favor an effect of NSAIDs in inhibiting mitochondrial oxidative phosphorylation. The principal physiological mechanisms which are compromised by NSAID use are mucosal blood flow, secretion of mucus and bicarbonate and maintenance of a hydrophobic mucosal surface. Animal data suggest that polymorphonuclear leukocytes (PMNs) are important for acute damage though the relevance to humans has yet to be established. As well as damaging the mucosa, NSAIDs impair ulcer healing and are associated with reduced epithelial proliferation and evidence of diminished angiogenesis. An interaction between prostaglandins and growth factors, as well as the synthesis of antiproliferative products of arachidonic acid metabolism may be involved. Healing of NSAID ulcers by conventional doses of H2 antagonists is slow and H2 antagonists are poor at preventing gastric ulcer development or recurrence. These problems can be overcome by the use of more potent acid suppression. Misoprostol heals NSAID-associated ulcers, though whether healing is as fast as with non-NSAID ulcers has not been formally established. Misoprostol is effective prophylactic treatment but has a significant incidence of adverse events, particularly diarrhoea. Misoprostol has been reported to prevent ulcer complications, and in endoscopic studies has been superior as prophylaxis to standard dose ranitidine. Results of its efficacy compared to proton-pump inhibitors are awaited. For many patients appropriate management is avoidance of NSAIDs or use of less potent/toxic alternatives such as ibuprofen. Reductions in prescribing arising from a prior authorization scheme show that this can be achieved. For high-risk patients requiring continuing NSAID use co-prescription of omeprazole or misoprostol should be considered.

Do non-steroidal anti-inflammatory drugs have an effect on gastric cell turnover?

To study the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on gastric cell turnover using an in vitro immunohistochemical method of bromodeoxyuridine (BrDU) uptake. Thirty patients undergoing routine upper gastrointestinal endoscopy were studied. Sixteen had taken NSAIDs daily for more than 3 months and there were 14 age-matched controls. Endoscopic gastric antral biopsies were obtained and stained immediately using the BrDU technique. Cell proliferation was expressed as a labelling index percentage (LI%) defined as the number of BrDU-labelled nuclei in 10 gastric glands, expressed as a percentage of the total cells in the gastric gland. Gastric infection with Helicobacter pylori was excluded in all patients. Of the 16 patients on NSAIDs, four had gastritis, four had erosions or ulceration and eight had a normal examination. Endoscopy was normal in all patients in the control group. The LI% (mean +/- S.E.M.) in the entire NSAID group was 4.09 +/- 0.29 and in the control group 3.57 +/- 0.29. No significant difference was observed. In the NSAID patients with gastritis and erosions or ulceration, the LI% was 4.99 +/- 0.61 and 3.07 +/- 0.32, respectively. There was no significant difference in LI% between the endoscopic subgroups of patients on NSAIDs or between patients on NSAIDs who had normal endoscopy and the control patients. These results provide evidence that refutes the hypothesis that the prevalence of NSAID gastropathy is due to an effect on gastric cell turnover.

Prevention and Treatment of Nonsteroidal Anti-inflammatory Drug-Induced Gastropathy

Numerous human studies have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with various gastroduodenal mucosal lesions, collectively referred to as NSAID gastropathy. NSAIDs should not be prescribed unless there is a clear-cut indication for them. Acetaminophen should be used initially to treat most patients with osteoarthritis. If NSAID therapy is required, the lowest possible NSAID dose should be prescribed, and the patient should be advised to reduce any modifiable risk factors. In patients who take NSAIDs occasionally and are at low risk for NSAID gastropathy, no specific prophylactic measures seem justified. In high-risk NSAID users, risk reduction and prophylaxis with misoprostol would be appropriate. If an ulcer is documented during NSAID treatment, NSAID therapy should be discontinued if possible. However, NSAID therapy need not be discontinued if it is therapeutically justifiable and if appropriate antiulcer treatment is initiated.