NSAID-induced Gastrointestinal Injury Research Articles

Predictive value of gastrointestinal symptoms and patient risk factors for NSAID-associated gastrointestinal ulcers defined by endoscopy? Insights from a pooled analysis of two naproxen clinical trials.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat pain and rheumatic conditions. To facilitate patient management, we determined the predictive value of gastrointestinal (GI) symptoms and risk factors for the development of NSAID-associated GI injuries. Post-hoc analysis of pooled data from naproxen treatment arms of two identical, randomized, double-blind, controlled phase 3 trials in arthritis patients at risk of GI adverse events. Endoscopic incidence of GI ulcers at baseline, and 1, 3, and 6 months was employed as a surrogate parameter for GI injury. For GI symptom analysis, Severity of Dyspepsia Assessment questionnaire was used. For GI risk factor analysis, the high risk factors: previous GI injury, concomitant selective serotonin reuptake inhibitors or corticosteroids, ulcer history, concomitant low-dose aspirin, and age >65 years were employed. Data of 426 naproxen patients were analyzed. Distribution of GI symptoms between patients with and without ulcer was similar; about one third of patients developing an ulcer reported no GI pain symptoms. GI symptoms experienced under naproxen treatment were thus not indicative of GI injury. The proportion of patients developing an ulcer increased with the number of risk factors present, however, about a quarter of patients without any of the analyzed risk factors still developed an ulcer. GI symptoms and the number of risk factors are not reliable predictors of NSAID-induced GI injury to decide which patients need gastroprotection and will lead to a large group of patients with GI injuries. A preventive rather than reactive approach should be taken.

NSAID-induced gastrointestinal injury: Reduction of gastric and exacerbation of enteric lesions by omeprazole and ranitidine in rats

NSAID-induced gastrointestinal injury: Reduction of gastric and exacerbation of enteric lesions by omeprazole and ranitidine in rats

Misoprostol Inhibits Equine Neutrophil Adhesion, Migration, and Respiratory Burst in an In Vitro Model of Inflammation.

In many equine inflammatory disease states, neutrophil activities, such as adhesion, migration, and reactive oxygen species (ROS) production become dysregulated. Dysregulated neutrophil activation causes tissue damage in horses with asthma, colitis, laminitis, and gastric glandular disease. Non-steroidal anti-inflammatory drugs do not adequately inhibit neutrophil inflammatory functions and can lead to dangerous adverse effects. Therefore, novel therapies that target mechanisms of neutrophil-mediated tissue damage are needed. One potential neutrophil-targeting therapeutic is the PGE1 analog, misoprostol. Misoprostol is a gastroprotectant that induces intracellular formation of the secondary messenger molecule cyclic AMP (cAMP), which has been shown to have anti-inflammatory effects on neutrophils. Misoprostol is currently used in horses to treat NSAID-induced gastrointestinal injury; however, its effects on equine neutrophils have not been determined. We hypothesized that treatment of equine neutrophils with misoprostol would inhibit equine neutrophil adhesion, migration, and ROS production, in vitro. We tested this hypothesis using isolated equine peripheral blood neutrophils collected from 12 healthy adult teaching/research horses of mixed breed and gender. The effect of misoprostol treatment on adhesion, migration, and respiratory burst of equine neutrophils was evaluated via fluorescence-based adhesion and chemotaxis assays, and luminol-enhanced chemiluminescence, respectively. Neutrophils were pretreated with varying concentrations of misoprostol, vehicle, or appropriate functional inhibitory controls prior to stimulation with LTB4, CXCL8, PAF, lipopolysaccharide (LPS) or immune complex (IC). This study revealed that misoprostol pretreatment significantly inhibited LTB4-induced adhesion, LTB4-, CXCL8-, and PAF-induced chemotaxis, and LPS-, IC-, and PMA-induced ROS production in a concentration-dependent manner. This data indicate that misoprostol-targeting of E-prostanoid (EP) receptors potently inhibits equine neutrophil effector functions in vitro. Additional studies are indicated to further elucidate the role of EP receptors in regulating neutrophil function. Overall, our results suggest misoprostol may hold promise as a novel anti-inflammatory therapeutic in the horse.

Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications

Non-steroidal anti-inflammatory drugs (NSAIDs) are a broad class of non glucocorticoid drugs which are extensively used in anti-inflammatory, analgesic, and antipyretic therapies. However, NSAIDs may cause many side effects, most commonly in gastrointestinal(GI) tract. Cardiovascular system, kidney, liver, central nervous system and hematopoietic system are also involved. NSAID-induced GI side effects not only endanger the patients' health, increase mortality, but also greatly increase the cost of medical care. Therefore, how to reduce GI side effects is of particular concern to clinicians. The Chinese Rheumatism Data Center(CRDC) and Chinese Systemic Lupus Erythematosus Treatment and Research Group(CSTAR) compose a "Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications" , as following: (1) GI lesions are the most common side effects of NSAIDs. (2) NSAID-induced GI side effects include gastritis, esophagitis, gastric and duodenal ulcers, bleeding, perforation and obstruction. (3) With the application of capsule endoscopy and small intestinal endoscopy, growing attention is being paid to the NASID-induced small intestine mucosa damage, which is mainly erosion and ulcer. (4) Risk factors related to NSAID-induced GI ulcers include: Helicobacter pylori (Hp) infection, age> 65 years, past history of GI ulcers, high doses of NSAIDs, multiple-drug combination therapy, and comorbidities, such as cardiovascular disease and nephropathy.(5) GI and cardiovascular function should be evaluated before using NSAIDs and gastric mucosal protective agents. (6) The risk of GI ulcers and complications caused by selective cyclooxygenase-2 (COX-2) inhibitors is less than that of non-selective COX-2 inhibitors. (7)Hp eradication therapy helps to cure GI ulcers and prevent recurrence when Hp infection is positive in NSAID-induced ulcers. (8) Proton pump inhibitor (PPI) is the first choice for the prevention and treatment of NSAID-induced GI injury. Gastric mucosal protective agents also suggested.(9) H2 receptor antagonist (H2RA) can reduce the risk of NSAID-induced duodenal injury, however, the therapeutic effect of NSAID-induced gastric ulcer remains to be further confirmed. (10) Endoscopic treatment is the first recommendation for NSAID-induced peptic ulcers combined with upper GI bleeding, high-dose PPI effectively prevent rebleeding, reduce the possibility of surgery and mortality rate.

NSAID-induced Gastrointestinal Injury: A Focused Update for Clinicians.

Gastroenterologists care for users of nonsteroidal anti-inflammatory drugs (NSAIDs) when the vast population exposed to the medication class experiences a relatively uncommon serious gastrointestinal (GI) side effect. As serious adverse cardiovascular (CV) effects of these drugs have also been recognized, there remains continued confusion about the best treatment for patients who benefit from NSAID therapy and are at risk for GI and CV adverse events. Recognition of those patients at risk and strategies to reduce the adverse side effects of NSAIDs continues to provide an opportunity to improve patient outcomes. This review discusses the injury induced by these agents throughout the GI tract as well as strategies to prevent acute injury and reduce the development of serious adverse events. NSAID medication selection as well as GI cotherapy should balance individual patients' GI and CV risks.

Qing Dai attenuates nonsteroidal anti-inflammatory drug-induced mitochondrial reactive oxygen species in gastrointestinal epithelial cells.

Treatments with nonsteroidal anti-inflammatory drugs (NSAIDs) have increased the number of patients with gastrointestinal complications. Qing Dai has been traditionally used in Chinese herbal medicine for various inflammatory diseases such as ulcerative colitis. We previously reported that Qing Dai suppressed inflammations by scavenging reactive oxygen species (ROS) in ulcerative colitis patients. Thus, Qing Dai can attenuate the production of ROS, which play an important role in NSAID-induced gastrointestinal injuries. In this study, we aimed to elucidate whether Qing Dai decreased mitochondrial ROS production in NSAID-treated gastrointestinal cells by examining cellular injury, mitochondrial membrane potentials, and ROS production with specific fluorescent indicators. We also performed electron paramagnetic resonance measurement in isolated mitochondria with a spin-trapping reagent (CYPMPO or DMPO). Treatments with indomethacin and aspirin induced cellular injury and mitochondrial impairment in the gastrointestinal cells. Under these conditions, mitochondrial alterations were observed on electron microscopy. Qing Dai prevented these complications by suppressing ROS production in gastrointestinal cells. These results indicate that Qing Dai attenuated the ROS production from the NSAID-induced mitochondrial alteration in the gastrointestinal epithelial cells. Qing Dai treatment may be considered effective for the prevention NSAID-induced gastrointestinal injury.

P9 Gastrointestinal-sparing effects of a hydrogen sulfide-releasing naproxen derivative in rats with compromised mucosal defence

The gastrointestinal (GI) ulceration and bleeding caused by non-steroidal anti-inflammatory drugs (NSAIDs) is particularly prevalent in older patients with various co-morbidities. Hydrogen sulfide (H 2 S) has been shown to increase mucosal resistance to damage and accelerate ulcer healing. We evaluated the GI safety of a H 2 S-releasing naproxen derivative (ATB-346) versus naproxen in rat models of the co-morbidities in humans that increase susceptibility to GI damage and bleeding: obesity, arthritis, hypertension, elderly, and polypharmacy (concomitant use off low-dose aspirin and/or omeprazole). Co-morbid rats (Zucker obese, Freund’s adjuvant arthritis, spontaneously hypertensive or aged (19 months); n ⩾ 5 per group) and healthy controls were treated orally twice-daily for 4 days with vehicle, an anti-inflammatory dose of naproxen (10 mg/kg), equimolar (and equi-effective) dose of ATB-346 (14.5 mg/kg), or celecoxib (10 mg/kg) for 4 days. For polypharmacy, rats received the test drug plus omeprazole (10 mg/kg bid) and low-dose aspirin (10 mg/kg od). Hemorrhagic GI damage was blindly scored 3 h after the final dose of NSAID. ATB-346 suppressed gastric prostaglandin (>85%) and whole blood thromboxane (>95%) synthesis as effectively as naproxen. In healthy rats, test drugs induced very little or no GI damage at the doses tested. In arthritic rats, naproxen caused 10-times as much GI damage as in healthy controls, while ATB-346 did not elicit detectable GI damage. Obese rats given naproxen had a 9-fold increase in intestinal damage versus lean rats (47 ± 11 vs. 5 ± 2, respectively; p < 0.01), whereas ATB-346 did not elicit GI damage in either group. In aged rats, naproxen caused extensive gastric damage (score of 19 ± 4; p < 0.01), whereas those with ATB-346 (2 ± 1) were not different from vehicle-treated rats. Hypertensive rats exhibited similar susceptibility to naproxen-induced damage as healthy controls, while ATB-346 displayed no damage in normotensive or hypertensive rats. Co-administration of naproxen or celecoxib with low-dose aspirin and omeprazole resulted in extensive intestinal damage (scores of 23 ± 6 and 49 ± 6, respectively), whereas no damage was observed when ATB-346 was combined with low-dose aspirin and omeprazole. Rats with clinically relevant co-morbidities, excluding hypertension, exhibit a substantial increase in susceptibility to NSAID-induced GI injury. In contrast, the H 2 S-releasing naproxen derivative (ATB-346) spared the stomach and small intestine of damage, regardless of the model in which it was tested, and despite still inhibiting the key target enzymes for its anti-inflammatory and GI-damaging effects (COX-1 and COX-2). This novel NSAID also exhibited comparable anti-inflammatory activity to naproxen and celecoxib in arthritic rats and was significantly better tolerated when co-administered with low-dose aspirin and omeprazole. ATB-346 has superior GI safety to existing NSAIDs in models that mimic the clinical scenarios of polypharmacy and impaired GI mucosal defence. This is likely related to its ability to release the cytoprotective mediator hydrogen sulfide.

1．NSAID起因性消化管傷害の現状と対策

1．NSAID起因性消化管傷害の現状と対策

NSAID-induced gastrointestinal and cardiovascular injury

To review recent publications related to NSAID-induced adverse effects on the gastrointestinal and cardiovascular systems. This paper explores novel mechanisms of NSAID-induced gastrointestinal injury, highlights new composite endpoints evaluating adverse events of NSAIDs in the entire gastrointestinal tract, and combines published data to establish evidence-based guidance on the best use of NSAIDs to achieve optimal clinical outcomes whilst minimizing cardiovascular and gastrointestinal injuries. NSAIDs can induce peptic ulcers via epithelial cell membrane disruption and the renin angiotensin system, independent of the cyclooxygenase (COX) pathways, whereas mast cells and bile acid sensors may have a protective effect on NSAID-induced gastrointestinal damage. Patients with arthritis treated with a COX-2 inhibitor are less likely to develop upper and lower gastrointestinal complications than those who are treated with diclofenac plus a proton pump inhibitor (PPI). PPI therapy is recommended in patients receiving dual antiplatelet treatment but observational studies show that clopidogrel users taking PPIs have an increased risk of cardiovascular events. Until further reliable controlled data are available, this potential, but currently unproven, clinical interaction can be minimized by widely separating the dosing of clopidogrel and PPI. Histamine-2 antagonists may be an alternative to PPI for the prevention of peptic ulcers in patients taking low-dose aspirin.

NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes

In this review, we have discussed our current understanding of the barrier properties that are in place to protect the upper gastrointestinal mucosa from luminal acid, and the pathogenic mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce injury to the gastrointestinal tract. The changes in our view of the importance of NSAID-induced cyclo-oxygenase (COX) inhibition on the pathogenesis and prevention of NSAID-induced gastrointestinal injury is presented. The focus of this paper has been placed on the effects of NSAIDs on the mucosal surface, and specifically the effect of these powerful drugs in inducing changes in the hydrophobicity, fluidity, biomechanical and permeability properties of extracellular and membrane phospholipids. Lastly, recent evidence is presented that salicylic acid and related NSAIDs may alter the stability of membranes, inducing the formation of unstable pores that may lead to back-diffusion of luminal acid and membrane rupture. This understanding of the interaction of NSAIDs with membrane phospholipids may prove valuable in the design of novel NSAID formulations with reduced gastrointestinal side-effects.

Clinical Efficacy of Esomeprazole in the Prevention and Healing of Gastrointestinal Toxicity Associated with NSAIDs in Elderly Patients

NSAIDs are widely prescribed for the treatment of pain, inflammation and rheumatic disorders, but their use is associated with adverse gastrointestinal effects, ranging from dyspeptic symptoms and peptic ulcers to more serious complications. Elderly patients are at high risk of experiencing NSAID-induced gastrointestinal tract injury and should be considered candidates for prophylactic pharmacological therapy. In studies conducted in adult patients, proton pump inhibitors (PPIs) such as esomeprazole have been shown to prevent or reduce NSAID-induced gastrointestinal injury. The beneficial effects of esomeprazole can be ascribed largely to its ability to maintain sustained inhibition of gastric acid secretion, although there is evidence to suggest that pharmacodynamic properties unrelated to acid inhibition may also contribute to the gastroprotective effects of this agent. Although there are limited data on the use of esomeprazole specifically in elderly patient populations, studies of patients at high risk of NSAID-induced gastrointestinal toxicity because of advanced age indicate that this PPI is both effective and well tolerated when administered in conjunction with NSAIDs. Thus, esomeprazole can be regarded as a useful option for prophylactic therapy in elderly patients receiving long-term NSAID therapy.

Gastrointestinal Bleeding in Children Following Ingestion of Low‐dose Ibuprofen

Gastrointestinal Bleeding in Children Following Ingestion of Low‐dose Ibuprofen

Response to: Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage

To the Editor: Singh and Triadafilopoulos provide an informative review of the use of proton pump inhibitors (PPIs) with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) (1). We endorse the authors' call for more rigorous clinical evaluation of the overall efficacy/safety of this approach and raise a question they did not address about patients' compliance with this regimen in clinical practice. We share the authors' opinion that further study is needed in large numbers of long-term NSAID users to evaluate risk reductions for ulcer-related complications rather than surrogate endoscopic ulcers. Ideally, large trials would be conducted with PPI/NSAID cotherapy vs. other gastroprotective therapies, such as a cyclo-oxygenase-2-selective (COX-2) inhibitor or misoprostol/NSAID cotherapy. Risk reductions for ulcer-related complications have already been evaluated in large clinical trials with these latter approaches (2–4) but not with PPI/NSAID cotherapy. A pitfall of relying solely on endoscopic markers is illustrated by the authors' reference to a clinical trial that purported to demonstrate the superiority of pantoprazole over misoprostol in the prevention of endoscopically detected NSAID-induced gastrointestinal injury (5). Closer inspection of that trial reveals that the endoscopic endpoints included reflux esophagitis, which, to our knowledge, is not an NSAID-induced effect. At the best, the inclusion of irrelevant endpoints confounds interpretation of study results; at the worst, it may be misleading. The need for more thorough evaluation of PPI/NSAID cotherapy is also highlighted by the findings from several studies, which showed that PPI/NSAID cotherapy may not be as fully efficacious in protecting the upper and lower gastrointestinal system from NSAID-associated damage as these other approaches (6–10). We know of no evidence nor reason to expect that PPIs protect the small bowel from NSAID damage, whereas some supportive evidence is available for a COX-2 inhibitor and for misoprostol (6,10). Clearly, additional clinical evaluation is needed to shed much needed light on the comparative efficacy of PPI/NSAID cotherapy in the prevention of NSAID-induced gastrointestinal complications. Large trials are also needed to provide information about the long-term safety of PPI/NSAID cotherapy, which has not been evaluated as rigorously as have the safety profiles of the other gastroprotective approaches. The unanticipated cardiovascular events with rofecoxib in the VIGOR trial serve as enduring reminders of the value of evidence-based medicine. Accordingly, we urge caution before drawing conclusions about the long-term safety of PPI/NSAID cotherapy in the absence of clinical evidence. We note that an increased risk of unexpected adverse effect (community-acquired pneumonia) of acid-suppressive therapy has been reported and may be greater than is generally appreciated (11). We would also point out that mounting evidence strongly suggests that conventional NSAIDs share with the COX-2 inhibitors a potential for increased cardiovascular risks. This evidence eliminates the prior assumption that NSAIDs might be safer. The question we raise about PPI/NSAID cotherapy is this: will patients reliably comply with multiple-drug regimens or will their lack of compliance continue to expose them to unacceptable gastrointestinal risks? Compliance with multiple, separate medications is notoriously poor outside of the clinical trial setting, especially when attempting to prevent a largely asymptomatic condition, such as gastrointestinal ulceration (12,13). Single-agent therapy with a COX-2 inhibitor or the commercial combination of misoprostol/diclofenac, for example, eliminates uncertainties about compliance with both NSAID and gastroprotective therapies. For these reasons, physicians need to consider the full spectrum of therapies, including COX-2 inhibitors and misoprostol/diclofenac, when selecting therapy for their patients.

NSAID-related gastrointestinal injury

PREVIEWIn the United States, an estimated 15 million to 20 million people use nonsteroidal anti-inflammatory drugs (NSAIDs) on a long-term basis. With such statistics, it is not surprising that the most common side effect, gastrointestinal mucosal injury, remains a clinically important issue. Fortunately, this complication is largely preventable. In this review, Dr Fennerty focuses on the epidemiology, pathogenesis, risk factors, prevention, and treatment of NSAID-induced gastrointestinal injury and provides the reader with the data necessary to select care that prevents it.

Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice

Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used agents that have a high incidence of gastrointestinal side effects resulting in significant morbidity and mortality. Leukocytes have been implicated in NSAID-induced injury, but the mechanisms are unclear. We established a murine model of NSAID-induced gastrointestinal damage to assess the roles of candidate gene products in the pathogenesis of this injury. Methods: Indomethacin-induced gastrointestinal injury was assessed in wild-type and several mutant murine lines. Leukocyte involvement was assessed by neutrophil depletion, impairment of recruitment (resulting from targeted disruption of fucosyltransferase VII [FTVII]), and the absence of mature T and B cells with the use of Rag 2−/− mice. Activation and oxygen free radicals were assessed using gp91phox−/− mice that exhibit normal leukocyte recruitment but are deficient in myeloid cell activation and oxygen free radical generation. Results: Impairment of leukocyte recruitment (FTVII/−) and neutrophil depletion resulted in more than a 50% reduction in NSAID-induced injury. However, mice deficient in mature T and B cells had NSAID-induced damage comparable to control mice. Leukocyte activation was required for NSAID-induced damage because the gp91phox−/− mice were less susceptible to NSAID injury than wild-type mice. Conclusions: In this murine model system, FTVII-dependent leukocyte recruitment, leukocyte activation via gp91phox, and neutrophils are required for NSAID-induced gastrointestinal injury, whereas T and B cells are not essential.GASTROENTEROLOGY 2000;119:699-705

Nonsteroidal anti-inflammatory drug-induced gastrointestinal injury

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are the most commonly used medications worldwide. They are effective analgesic and anti-inflammatory agents. A major drawback to their use is a high frequency of adverse gastrointestinal (GI) effects that cause significant morbidity, occasional mortality, and substantial increases in cost of therapy. In this review, mechanisms of NSAID-induced GI injury are presented, and a clinical approach to diagnosis, treatment, and prevention of these adverse GI effects is provided.

INTRODUCTION TO EICOSANOIDS AND THE GASTROENTERIC TRACT

Eicosanoids are produced throughout the gastrointestinal tract and are significant mediators of physiologic and pathophysiologic processes. Understanding the precise role(s) of specific eicosanoid metabolites remains a significant challenge, but has led to the development of new pharmacologic strategies for treating NSAID-induced gastroenteropathy and IBD. Given the complex array of arachidonic acid metabolites, the development of more specific and potent inhibitors of these cyclooxygenase isoforms is important for future studies and possible therapeutic applications. Mice have been prepared that lack expression of COX-1 or COX-2. Once these animals have been carefully evaluated, understanding of the role of various pathways of eicosanoid formation in gastrointestinal function, development, and epithelial growth regulation might be improved. Considerable progress has been made in the understanding of arachidonic acid metabolism and in eicosanoid receptor biology. The identification and characterization of an inducible cyclooxygenase isoform has led to important studies evaluating the role of this enzyme in inflammation, neoplasia, and NSAID-induced gastrointestinal injury. The demonstration that COX-2 overexpression in intestinal epithelial cells leads to specific phenotypic changes, such as increased adhesion and inhibition of apoptosis, indicates that this enzyme may alter the tumorigenic potential of epithelial cells and offers hope for the future development of improved chemopreventive agents.

Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury.

The molecular basis of the injurious actions of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract is only partly understood. In this study we have obtained evidence, employing both in vitro and in vivo systems, that five NSAIDs have the ability to form a chemical association with zwitterionic phospholipids. Since this same class of phospholipids line the luminal aspects of the mucus gel layer to provide it with non-wettable properties, this intermolecular association may be the mechanism by which NSAIDs attenuate the hydrophobic barrier properties of the upper GI tract. Preassociating a number of NSAIDs with exogenous zwitterionic phospholipids prevented this increase in surface wettability of the mucus gel layer and protected rats against the injurious GI side-effects of these drugs, while enhancing their lipid permeability, antipyretic and anti-inflammatory activity.

An overview of NSAID-induced gastrointestinal injury

An overview of NSAID-induced gastrointestinal injury

Mechanisms of NSAID-induced gastrointestinal mucosal injury: a basis for preventing ulceration and symptoms from these agents.

Concepts are reviewed of the effects of anti-ulcer agents in counteracting the biochemical and cellular pathology of gastrointestinal injury by non-steroidal anti-inflammatory drugs (NSAIDs). While some measure of control of NSAID-induced mucosal damage is achieved in the upper gastrointestinal tract by the currently available anti-ulcer drugs, none can effectively counteract the major biochemical changes induced by NSAIDs. Some experimental approaches, which have been developed from recent studies in laboratory animals, are considered as a possible basis towards developing improvements in preventive procedures against NSAID-induced gastrointestinal injury in man.