Nonsteroidal Anti-inflammatory Gastropathy Research Articles

From Peptic Ulcer Disease to NSAID Gastropathy

Nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is an important clinical entity, most commonly encountered in elderly female patients. The expanding use of NSAIDs in the elderly population has led to an increased incidence of NSAID-induced gastropathy. The risk of gastric bleeding in these patients is 7-fold higher than in the younger population. Long term NSAID therapy in the elderly is apparently associated with failure of normal gastric mucosal adaptation. Silent unidentified gastric lesions are likely to be common with long term NSAID therapy, as symptomatology does not parallel pathological progression. This gastropathy, in contrast to peptic ulcer disease, is responsive to prostaglandins and other cytoprotective agents. A new generation of prostaglandin-sparing NSAIDs (e.g. nabumetone), in addition to the older nonacetylated salicylates, may represent less gastrotoxic alternatives. Therefore, these agents may substantially reduce the risk of NSAID-induced gastropathy. The debate continues as to whether to use NSAIDs, and under which circumstances. More importantly, the cost-benefit implications and justification for concomitant therapy with gastroprotective agents cloud the picture. Currently, there is a definite consensus that NSAIDs should not be casually used on a chronic basis, especially in patients at risk for serious gastropathy complications. In all cases, where possible, gastric prostaglandin-sparing NSAIDs or nonacetylated salicylates should be used in lowest effective dosages. In special circumstances, gastroprotective co-therapy can be considered. NSAID therapy probably should not be used or continued in elderly patients with a history of bleeding ulcers or recent major gastric ulcer activity.

Experience with misoprostol therapy for NSAID gastropathy in children.

To determine the effect of misoprostol, a synthetic prostaglandin E1 analogue, on the gastrointestinal tract (GIT) symptoms associated with non-steroidal anti-inflammatory drug (NSAID) administration and on the haemoglobin value, in children. Retrospective chart review of children attending the paediatric rheumatology clinic at a tertiary referral hospital over a three year period, who were receiving NSAIDs and were prescribed misoprostol for treatment of GIT symptoms or anaemia. Twenty five children (mean age 12.0 (SD 2.8) (range 7-17) years were prescribed misoprostol (mean dose 308.4 (76.5) micrograms/m2/day; 9.8 (2.5) micrograms/kg/day) while NSAID therapy was continued. Of the 22 (88%) patients with GIT complaints, 18 (82%) had complete resolution of symptoms and two (9%) had some improvement. Four patients (18%) had a recurrence of symptoms after initial resolution while still receiving misoprostol. Misoprostol therapy was associated with a statistically significant increase in haemoglobin concentration (mean value before misoprostol 115 (18) g/l; after misoprostol 126 (15) g/l (p = 0.02)). The only adverse effect reported was self limited diarrhoea in one child. Misoprostol appeared to be effective in the treatment of GIT symptoms in children receiving NSAIDs and to result in significant increase in the haemoglobin concentration. Further prospective studies are needed to evaluate the role of misoprostol therapy for NSAID associated GIT complaints in the paediatric population.

Portal vein hemodynamics in cirrhotic patients with portal hypertensive gastropathy: An echo doppler study

Background & Aims: Hydrogen sulfide (H2S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine β-synthase (CBS) and cystathionine-γ-lyase (CSE). Here, we have investigated the role of H2S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy. Methods: Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H2S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium. Results: At a dose of 100 μmol/kg, NaHS attenuated by 60%–70% the gastric mucosal injury, and tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E2 (PGE2) synthesis by NSAIDs. Glibenclamide, a KATP channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a KATP opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H2S formation and CSE expression (mRNA and protein) and activity by 60%–70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation. Conclusions: These data establish a physiologic role for H2S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.

Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa.

Leukocyte adhesion to the endothelium appears to play an important role in gastric injury. This study aimed to develop immunohistochemical staining techniques to investigate the distribution and sequence of expression of both leukocyte [lymphocyte function associated antigen 1 (LFA-1)] and endothelial [intracellular adhesion molecule 1 (ICAM-1)] adhesion molecules in the mucosa after treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). In control rats there were 803 +/- 72 LFA-1-stained cells/mm2 in the deep mucosa, 134 +/- 32 cells/mm2 in the superficial mucosa, and 6.4 +/- 1.2 ICAM-1-stained blood vessels/mm2 in the total mucosa. The number of ICAM-1-stained blood vessels in the mucosa increased significantly after 30 min of treatment with intragastric aspirin (30 mM; 25.2 +/- 7.2/mm2, P < 0.01) and indomethacin (20 mg/kg; 20.7 +/- 4.4/mm2, P < 0.01) before any appreciable mucosal damage was evident. This increase was reversed by treatment with misoprostol (100 micrograms/kg) in both aspirin- (7.6 +/- 1.7/mm2, P < 0.01) and indomethacin-treated animals (10.7 +/- 2.6/mm2, P < 0.05). There was no significant increase in LFA-1-positive cells until 60 min of NSAID treatment. We conclude that the adhesion molecules LFA-1 and ICAM-1 are expressed in the normal gastric mucosa and that the number of ICAM-1-stained blood vessels increase rapidly after NSAID treatment. This increase in ICAM-1 expression may be associated with an inhibition of prostaglandin synthesis by NSAIDs. These results provide further support for the role of early vascular changes in NSAID gastropathy.

Prevalence of Helicobacter pylori infection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis.

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter (H pylori) are both associated with an increased risk of peptic ulceration and gastropathy. It is not known, however, if there is an interaction between these two agents, and thus whether or not screening for H pylori before NSAID treatment is of value. The aim of this study was to find out if H pylori potentiates the damaging effects of NSAIDs. Fifty two patients with rheumatoid arthritis requiring longterm NSAID treatment were studied. Dyspeptic symptoms were assessed according to a standardised questionnaire. Gastroscopy was performed after a one week washout period during which NSAIDs were discontinued. Gastric and duodenal mucosal damage was graded endoscopically. H pylori was identified by biopsy urease test and by histological tests. Investigations were repeated after one month's treatment with an NSAID. Patients with H pylori infection (n = 26) had a higher dyspeptic symptom score (p < 0.05). One patient with duodenal ulcer (H pylori +ve) and two with endoscopic gastritis (both H pylori +ve) were excluded from further study. Forty two subjects completed the study. After treatment there was a rise in the gastric damage score both in the H pylori +ve (p = 0.06) and the H pylori -ve (p < 0.005) groups. There was no difference in the extent of increase in grade or the final grade at the end of the treatment period between the H pylori +ve and -ve patients. It is concluded that H pylori infection is associated with increased dyspeptic symptoms in patients receiving NSAIDs but that it does not potentiate NSAID gastropathy.

Pathogenesis of nonsteroidal anti-inflammatory drug gastropathy

Gastric ulceration associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) affects approximately 15-20% of patients using these agents on a chronic basis and has a significant financial impact on health care systems. The pathogenesis of NSAID gastropathy is not fully understood, although it is generally believed that these agents produce ulcers through a combination of direct topical irritant actions and systemic inhibition of prostaglandin synthesis. A number of recent studies have focused on the early events in the pathogenesis of NSAID gastropathy, and suggest that a principal site of action of these agents is the mucosal vasculature. In this review, some of these recent advances are outlined

Gastric ulceration: critical events at the neutrophil--endothelium interface.

Neutrophil adherence to the vascular endothelium and the subsequent release of oxygen-derived free radicals and proteolytic enzymes has been implicated as a critical event in the pathogenesis of various forms of gastrointestinal ulceration. This paper reviews the evidence that events at the neutrophil-endothelium interface are important in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Endothelial injury occurs within minutes of NSAID administration and appears to be attributable to neutrophil adherence and activation. Neutrophil adherence in response to NSAIDs may occur as a consequence of inhibition of endothelial prostaglandin synthesis, but it appears to involve a lipoxygenase product, such as leukotriene B4. Prevention of neutrophil adherence to the vascular endothelium results in near-complete prevention of experimental NSAID gastropathy. Depletion of circulating neutrophils also results in reduced susceptibility to NSAID-induced mucosal injury. As prostaglandins are potent inhibitors of neutrophil adherence and activation, it is possible that the neutrophil--endothelium interface represents one of the most important targets of action of these compounds in terms of their ability to prevent or reduce the severity of NSAID-induced ulceration.

Nonsteroidal anti-inflammatory drug gastropathy--is it preventable?

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a wide spectrum of side effects, including those involving renal, hepatic and haematological function and skin rashes. It is however the gastrointestinal effects of NSAIDs which are most serious and common. It is important to try to ascertain the true relationship between NSAID use and the clinically important gastrointestinal side effects and to develop startegies which might diminish this problem. In this review, we will discuss the pathophysiology of so-called 'NSAID gastropathy', review the epidemiology of NSAID-associated gastrointestinal side effects and examine clinical trial evidence that drugs might influence the ulcer healing rate and perhaps even prevent their development.

Nonsteroidal anti-inflammatory drug gastropathy – is it preventable?

Nonsteroidal anti-inflammatory drug gastropathy – is it preventable?

Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastropathy

Interleukin 1 (IL-1) has been shown to reduce the severity of experimental gastroduodenal ulceration, but the mechanism of action is unclear. The present study examined the possibility that the mechanism underlying the protective effects of IL-1 in experimental nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is related to effects on gastric acid secretion, on prostaglandin synthesis, and/or on neutrophil function. IL-1 alpha and IL-1 beta dose-dependently (1-10 micrograms/kg) reduced the severity of gastric damage induced by indomethacin, whereas tumor necrosis factor alpha (1-10 micrograms/kg) had no effect. These effects of IL-1 were not completely attributable to a reduction in the volume or acidity of gastric secretion during the 1-hour pretreatment period. Whereas IL-1 alpha and IL-1 beta significantly inhibited pentagastrin-stimulated acid secretion, the dose-response relationship and time course of actions suggested that effects on acid secretion did not fully account for the ability of these agents to reduce indomethacin-induced gastric injury. The maximally effective dose of IL-1 beta (10 micrograms/kg) in terms of reduction of indomethacin-induced gastric injury did not significantly affect gastric prostaglandin synthesis. Neutrophil function was assessed using two in vivo assays. IL-1 beta inhibited migration of neutrophils in response to intradermal injections of N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 (LTB4) and dose-dependently (0.1-10 micrograms/kg) inhibited LTB4-induced neutropenia. These effects could be mimicked by dexamethasone (1 mg/kg SC), which inhibited the neutropenic response to LTB4 and significantly (P less than 0.001) reduced the severity of indomethacin-induced gastric damage. Both IL-1 beta and dexamethasone could significantly reduce the extent of histologically detectable leukocyte margination within the gastric mucosal microcirculation after indomethacin administration. The results of this study suggest that effects of IL-1 on gastric acid secretion or prostaglandin synthesis do not fully account for its ability to reduce the severity of experimental NSAID-induced gastropathy, whereas inhibitory effects of IL-1 on neutrophil function may contribute significantly to its protective actions. (Gastroenterology 1992 Apr;102(4 Pt 1):1176-85)

Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastropathy

Interleukin 1 (IL-1) has been shown to reduce the severity of experimental gastroduodenal ulceration, but the mechanism of action is unclear. The present study examined the possibility that the mechanism underlying the protective effects of IL-1 in experimental nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy is related to effects on gastric acid secretion, on prostaglandin synthesis, and/or on neutrophil function. IL-1α and IL-1β dose-dependently (1–10 μg/kg) reduced the severity of gastric damage induced by indomethacin, whereas tumor necrosis factor a (1–10 μg/kg) had no effect. These effects of IL-1 were not completely attributable to a reduction in the volume or acidity of gastric secretion during the 1-hour pretreatment period. Whereas IL-1α and IL-1β significantly inhibited pentagastrin-stimulated acid secretion, the dose-response relationship and time course of actions suggested that effects on acid secretion did not fully account for the ability of these agents to reduce indomethacin-induced gastric injury. The maximally effective dose of IL-1β (10 μg/ kg) in terms of reduction of indomethacin-induced gastric injury did not significantly affect gastric prostaglandin synthesis. Neutrophil function was assessed using two in vivo assays. IL-1β inhibited migration of neutrophils in response to intradermal injections of N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 (LTB4) and dose-dependently (0.1–10 ug/kg) inhibited LTB4-induced neutropenia. These effects could be mimicked by dexamethasone (1 mg/kg SC), which inhibited the neutropenic response to LTB4 and significantly (P < 0.001) reduced the severity of indomethacin-induced gastric damage. Both IL-1β and dexamethasone could significantly reduce the extent of histologically detectable leukocyte margination within the gastric mucosal microcirculation after indomethacin administration. The results of this study suggest that effects of IL-1 on gastric acid secretion or prostaglandin synthesis do not fully account for its ability to reduce the severity of experimental NSAID-induced gastropathy, whereas inhibitory effects of IL-1 on neutrophil function may contribute significantly to its protective actions.

Non-steroidal anti-inflammatory drug gastropathy and cytoprotection: pathogenesis and mechanisms re-examined.

Gastric and intestinal injury induced by non-steroidal anti-inflammatory drugs (NSAIDs) is a common and expensive adverse effect of this class of drugs. While it is likely that inhibition of prostaglandin synthesis by these agents is an important component of their ulcerogenic properties, the pathogenesis of NSAID gastropathy remains unclear. Likewise, the underlying mechanism for prostaglandin 'cytoprotection' is not fully understood, although it is clear from recent clinical trials that prostaglandin analogues are an effective treatment to prevent NSAID gastropathy. In this paper the contribution of neutrophils to the mucosal damage induced by NSAIDs is discussed, as is the possibility that prostaglandins protect the gastrointestinal mucosa from NSAID-induced ulceration at least in part through inhibitory effects on neutrophil function.

Assessing and understanding patient risk.

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is the most frequent and one of the most severe drug side effects in the United States. NSAID-associated gastropathy has been estimated to account for at least 7600 deaths and 76000 hospitalizations each year in the United States alone. Hospitalizations in rheumatoid arthritis patients occurred in 1.6% of patients; for patients with osteoarthritis the incidence appears to be substantially lower. This is based on a consecutive series of 3000 patients with rheumatoid arthritis who were followed prospectively for an average of five years by ARAMIS, the Arthritis, Rheumatism and Aging Medical Information System. Multivariate analyses assessing risk factors for serious gastrointestinal (GI) events were performed on 1694 rheumatoid arthritis patients taking NSAIDs. The most important risk factors of higher age, use of prednisone, previous NSAID GI side effects, prior GI hospitalization, functional disability (based on the American Rheumatism Association classification), and NSAID dose are variables in an algorithm which estimates the risk of a serious GI event occurring in the next 12 months. Knowledge of risk factors and their interrelationships provides a tool for identifying patients at high risk and guides therapeutic decisions.

Making sense of NSAID gastropathy and considering the therapeutic options.

There is increasing recognition that nonsteroidal anti-inflammatory drugs (NSAIDs), while quite effective in treating arthritic symptoms, are associated with gastrointestinal mucosal damage. Although therapy for patients with NSAID-induced ulcers or those at high risk of developing them is still a matter of debate, the current literature supports the use of misoprostol as the only drug effective for the prevention of both NSAID-induced gastric and duodenal ulceration. It has also been shown to treat NSAID-induced gastropathy in patients continuing their NSAID therapy. In a study of misoprostol (100 or 200 micrograms QID) plus NSAID, after three months of continuous therapy, a significantly lower frequency of gastric ulcers in the misoprostol-treated group was revealed: 100 micrograms misoprostol, 5.6%; 200 micrograms misoprostol, 1.4%; placebo, 21.7%. A recent three-month, placebo-controlled study established the efficacy of misoprostol 200 micrograms QID in the prevention of NSAID-induced duodenal ulcers in 429 patients with osteoarthritis (OA), rheumatoid arthritis (RA), or other rheumatic disease, who were receiving daily treatment with various NSAIDs. The incidence of duodenal ulcer development over three months was 1.0% in patients treated with misoprostol versus 6.3% in placebo-treated patients (P = 0.004). The same trial also evaluated the efficacy of misoprostol 200 micrograms QID versus placebo in preventing NSAID-induced gastric ulcers. The incidence of gastric ulcer over the three-month treatment period was 1.5% in patients treated with misoprostol versus 9.0% in placebo-treated patients (P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

MISOPROSTOL—A LOGICAL THERAPEUTIC APPROACH TO GASTRODUODENAL MUCOSAL INJURY INDUCED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS?

Misoprostol is a synthetic analogue of naturally occurring prostaglandin E1. The basis of the damaging actions of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract is believed to be a consequence of two events: a direct damaging action on mucosal integrity and depletion of endogenous mucosal prostaglandins (PGs). Due to the latter effect, and because current evidence indicates that PGs play an important role in maintaining the integrity of the GI tract, misoprostol has been developed as a logical therapy to prevent and heal gastric and duodenal damage caused by NSAIDs. The purpose of this review is to consider the need for such a therapy, to describe its pharmaceutical development, to review its pharmacology and to review its efficacy compared with other available agents.

Preventing Upper Gastrointestinal Bleeding in Patients Receiving Nonsteroidal Antiinflammatory Drugs

Severe upper gastrointestinal (GI) bleeding is a serious adverse effect of nonsteroidal antiinflammatory drugs (NSAIDs) and the elderly are at increased risk of developing this complication. Bleeding episodes can be prevented. Replacing NSAIDs with acetaminophen may be appropriate when a simple analgesic is needed that eliminates the risk of GI bleeding. Using the lowest effective NSAID dose may decrease the incidence and severity of NSAID gastropathy. Histamine H2-receptor antagonists, sucralfate, and misoprostol have been studied for the prevention of NSAID gastropathy, but only misoprostol prevents mucosal injury in both the stomach and duodenum. Patients who have a history of peptic ulcer disease or gastric bleeding from NSAIDs are candidates for prophylactic measures. Although other patients are at risk, no one knows who should receive prophylactic therapy for NSAID gastropathy. Future studies should attempt to define patient populations that warrant prophylactic therapy.

NSAID Gastropathy, Misoprostol, and the Standard of Care

This medicolegal presentation is designed to introduce the legal notion of the standard of care as it pertains to potential legal exposure. The medical topics of nonsteroidal antiinflammatory drug (NSAID) therapy, NSAID gastropathy, and misoprostol are discussed in relation to the standard of care. The legal theories of informed consent and informed refusal are presented as they apply to this issue. A few simple commonsense points are offered for practice integration.

Practical management of NSAID gastropathy in rheumatic patients.

Gastropathy is a relatively common complication of treatment with a non-steroidal anti-inflammatory drug (NSAID). Pre-treatment evaluation of patients is therefore of key importance. Contraindications for NSAID treatment may include a history of gastroduodenal ulcer or of NSAID gastropathy, simultaneous administration of anticoagulant therapy and the existence of risk factors for ulcer disease. After NSAID treatment has begun, clinical follow-up is highly desirable. NSAID gastropathy can be asymptomatic despite the presence of a broad spectrum of gastrointestinal mucosal changes on endoscopy, but in the majority of cases there are clinical symptoms. Management of gastropathy may involve withdrawal of NSAID treatment, replacement therapy with a different type of drug or post hoc treatment of the gastropathy with anti-ulcer compounds.

Interaction and selection of therapeutic agents in the elderly: NSAIDs and the ageing kidney.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a commonly used class of therapeutic agents in rheumatic disorders, especially in our elderly population. Although their mechanism of anti-inflammatory action may be multifarious, global prostaglandin blockade, especially in the elderly, is responsible for many of the recognized adverse effects. Complications of NSAID gastropathy represent the most serious adverse effect, its frequency becoming an alarming health problem. Various nephrotoxicity syndromes seen with NSAID use in the elderly are less prevalent and less often recognized. Commonest is reversible, hemodynamically mediated renal insufficiency due to prostaglandin blockade. Potential differences among NSAIDs are reviewed in light of the concept of compartmentalized renal prostaglandin blockade. A framework is developed for the clinical application of these potential differences, especially in the treatment of elderly patients. Along a continuum of increasing risk factors for NSAID nephrotoxicity or increasing NSAID dose, there likely exists an intermediate therapeutic window where differences among NSAIDs are most relevant.

Antiulcer Therapy in Nsaid Gastropathy: A Rheumatologist's Perspective

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy can now be recognized as an iatrogenic problem separate from classic acid peptic disease. Thus, the cost benefits of particular NSAID use is impacted by the hidden costs of common NSAID toxicity as well as gastroprotective measures necessary in those gastro-damaged by chronic NSAID use. Appropriate cytoprotective measures exist for serious gastropathy. A basis for selection of gastroprotective interventions also is available for that subset at greatest risk from continued, necessary NSAID therapy with associated potential putative consequences. Accepting this requires recognition that natural protective adaptation can fail in the face of such NSAID therapy and that the chronic gastric pathophysiology induced may be silent and ultimately catastrophic in outcome. Common symptomatic measures with H2 blockade antacid agents are contrasted with cytoprotective potential of prostaglandin analogs and sucralfate as potentially more specific responses.