Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (

Selective COX-2 inhibitors and gastrointestinal mucosal injury: pharmacological and therapeutic considerations.

It is well recognized that nonsteroidal antiinflammatory drugs (NSAIDs) induce gastrointestinal (GI) ulcerations, perforation and bleeding, which clearly limit their therapeutic value. The recent introduction of NSAIDs with selective cyclooxygenase-2 (COX-2) inhibitory effect is a major pharmacologic milestone in therapeutics. Selective COX-2 inhibitors exhibit considerable dissociation between their antiinflammatory/analgesic action and their GI toxicity. However, from a therapeutic consideration, there are still several unresolved and confusing issues with these drugs such as: the pharmacologic classification of the COX-2 selectivity; therapeutic value as antirheumatic/analgesic drugs; potential toxicity in patients at risk for the development of ulcer-related complications or patients with inflammatory bowel disease and potential renal toxicity. Although existing clinical efficacy studies with celecoxib and rofecoxib, two selective COX-2 inhibitors, were associated with considerably lower ulcerogenic rates when compared with nonselective NSAIDs, there are no long term outcome studies with these drugs similar to the MUCOSA trial performed with misoprostol. Furthermore, the selectivity of COX-2 inhibitors appears to be specific to the stomach and duodenum but not the kidney. While awaiting additional long term studies with selective COX-2 inhibitors, we recommend instituting prophylactic therapy with misoprostol in patients at risk for the development of ulcer related complications. In conclusion, we believe that the introduction of selective COX-2 inhibitors will revolutionize the treatment of pain and inflammation. However, additional basic and clinical studies are required to address the pharmacologic and therapeutic uncertainties for this class of drugs.

Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo.

OBJECTIVE: To determine the upper gastrointestinal (GI) tolerability of celecoxib, naproxen, and placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: An analysis of 5, 12-week, randomized, double blind, parallel group, placebo controlled clinical trials was conducted. In these trials, patients were randomized to: naproxen 500 mg bid (n = 1,099), placebo (n = 1,136), celecoxib 50 mg bid (n = 690) (subtherapeutic dose), celecoxib 100 mg (n = 1,131) or 200 mg bid (n = 1,125) (therapeutic dose), or celecoxib 400 mg bid (n = 434) (supratherapeutic dosage). The incidence and time until moderate to severe abdominal pain, dyspepsia, nausea, and any of the aforementioned 3 upper GI symptoms (composite endpoint) were determined using time-to-event analysis. RESULTS: The cumulative incidences of moderate to severe abdominal pain, dyspepsia, or nausea (composite endpoint) were: naproxen 500 mg (12.0%; 95% CI 9.9%-14.0%), celecoxib 50 mg bid (7.1%; 95% CI 5.0%-9.2%), celecoxib 100 mg bid (7.8%; 95% CI 6.0%-9.5%), celecoxib 200 mg bid (8.1%; 95% CI 6.4%-9.9%), celecoxib 400 mg bid (6.0%; 95% CI 3.6%-8.4%), and placebo (8.5%; 95% CI 6.5%-10.8%). After controlling for independent predictors of the composite endpoint, relative risks (RR) for the various treatments relative to naproxen 500 mg bid were: celecoxib 50 mg (RR 0.54; 95% CI 0.37-0.77; p < 0.001), celecoxib 100 mg (RR 0.60; 95% CI 0.45-0.80; p < 0.001), celecoxib 200 mg bid (RR 0.63; 95% CI 0.47-0.83; p = 0.001), celecoxib 400 mg bid (RR 0.56; 95% CI 0.35-0.89; p = 0.015), and placebo (RR 0.63; 95% CI 0.47-0.85; p = 0.002). After controlling for independent predictors of the composite endpoint, celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint, with p values ranging from 0.40 to 0.96. CONCLUSION: The upper GI tolerability of celecoxib is superior to naproxen. A dose-response relationship between celecoxib and upper GI symptoms was not apparent.

Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.

OBJECTIVE: The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2-24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25-400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100-400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patient's treatment assignment or the study in which the patient participated. RESULTS: In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05 vs placebo) and 1.68% for NSAIDs (p = 0.002 vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%. CONCLUSIONS: The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.

Superiority of lansoprazole vs ranitidine in healing nonsteroidal anti-inflammatory drug-associated gastric ulcers: results of a double-blind, randomized, multicenter study. NSAID-Associated Gastric Ulcer Study Group.

BACKGROUND: The usefulness of nonsteroidal anti-inflammatory drugs (NSAIDs) is limited by adverse gastrointestinal tract events. OBJECTIVE: To identify the optimal antisecretory therapy for healing of gastric ulcer in patients using NSAIDs and the impact of concurrent Helicobacter pylori infection on ulcer healing. DESIGN: Prospective, double-blind, multicenter, parallel-group study. SETTING: Gastroenterology practices in ambulatory and referral center settings. PATIENTS: Three hundred fifty-three patients with an active, nonmalignant gastric ulcer at least 5 mm in diameter confirmed by endoscopy and biopsy and who continued to receive stable doses of NSAIDs. INTERVENTION: Patients were randomized to receive ranitidine hydrochloride, 150 mg twice daily, or lansoprazole, 15 mg or 30 mg once daily, for 8 weeks. MEASUREMENTS: Healing was assessed by endoscopy at 4 and 8 weeks in an intent-to-treat population. Helicobacter pylori status was assessed by histological examination. RESULTS: After 8 weeks of treatment, healing was observed in 61 (53%) of 115, 81 (69%) of 118, and 85 (73%) of 117 patients receiving ranitidine lansoprazole, 15 mg, and lansoprazole, 30 mg, respectively (P<.05 for ranitidine vs both lansoprazole doses; 95% confidence interval, 3.2-28.0 for ranitidine vs lansoprazole, 15 mg, and 7.4-31.8 for ranitidine vs lansoprazole, 30 mg). The gastric ulcer healing rates were similar between H pylori-infected and -noninfected patients, with a statistically significant increase with the use of lansoprazole vs ranitidine. CONCLUSIONS: In patients who require continuous treatment with NSAIDs, lansoprazole is superior to ranitidine for healing of NSAID-associated gastric ulcers. Healing is not delayed by the presence of H pylori infection.

Comparison of the upper gastrointestinal safety of Arthrotec 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers.

A 6-week, multicenter, double-masked, placebo-controlled, parallel-group study compared the upper gastrointestinal (UGI) safety of Arthrotec 75 (diclofenac sodium 75 mg-misoprostol 200 microg; G.D. Searle & Co., Skokie, Illinois) administered twice daily with that of nabumetone 1500 mg administered once daily in 1203 patients with symptomatic osteoarthritis (OA) of the hip or knee. All patients had a documented clinical history of endoscopically confirmed gastric, pyloric-channel, or duodenal ulcer or > or = 10 erosions in the stomach or duodenum. UGI endoscopy was performed at baseline and again at week 6 or early withdrawal. Treatment with Arthrotec 75 resulted in a significantly lower combined incidence of endoscopically confirmed gastric and duodenal ulcers compared with nabumetone (4% vs 11%), and its rate of endoscopically confirmed ulceration was equivalent to that of placebo. The incidence of gastric ulcers alone was also significantly lower with Arthrotec 75 than with nabumetone (1% vs 9%). The incidence of duodenal ulcer with Arthrotec 75 was not significantly different from that with nabumetone (4% vs 3%). Types of adverse events were similar for all treatment groups, with GI adverse events predominating. Arthrotec 75 was well tolerated by the majority of patients. The results of this study demonstrate that Arthrotec 75 has a superior UGI safety profile, causing significantly fewer UGI ulcers, in comparison with nabumetone in patients with symptomatic OA and a documented history of ulcers or > or = 10 erosions.

Prevention of gastrointestinal complications associated with nonsteroidal antiinflammatory drugs.

Nonsteroidal antiinflammatory drugs (NSAID), although used frequently for the treatment of arthritis and musculoskeletal disorders, may produce deleterious effects related to the gastrointestinal (GI) tract, including dyspeptic symptoms, erosions, ulcers, and serious GI complications (i.e., bleeding, perforation, and gastric outlet obstruction). Endoscopic studies with the synthetic prostaglandin E1 analog misoprostol, various acid-reducing agents (e.g., H2 receptor antagonists and proton pump inhibitors), and surface-active drugs such as sucralfate, have been shown to prevent NSAID induced gastric and/or duodenal ulcers. The Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA) trial was a 6 month, randomized, double blind, placebo controlled study to investigate whether concurrent administration of misoprostol would significantly reduce the occurrence of serious upper GI complications in patients with rheumatoid arthritis (RA) who were receiving NSAID. Results showed that overall complications were reduced by 40% (p = 0.049) among patients receiving misoprostol (25 patients with definite serious GI events among 4404 patients treated) compared with those receiving placebo (42 out of 4439 patients). Thus, cotherapy with misoprostol resulted in a statistically significant reduction in the incidence of serious NSAID induced upper GI complications compared with placebo in patients with RA.

Prevalence and cost of hospitalization for gastrointestinal complications related to peptic ulcers with bleeding or perforation: comparison of two national databases.

The purpose of this study was to determine the prevalence and cost of hospitalization for upper gastrointestinal complications, including peptic ulcers with hemorrhage or perforation. Upper gastrointestinal complications and corresponding economic data were obtained from two sources. The first was a 20% sample of all community hospital discharges (about 6 million per year) from 11 states for 1991 and 1992 Hospital Cost Utilization Project; HCUP-3). The second source of data was a claims database for employees of large US corporations and their dependents for 1992, 1993, and 1994 (about 3.5 million covered lives per year; MarketScan). A group of ICD-9 codes for the diagnosis of peptic and gastroduodenal ulcers with bleeding or perforation were used to identify hospital admissions because of upper gastrointestinal complications. Similar patterns were observed across the MarketScan and HCUP-3 databases regarding hospitalization with diagnoses related to gastrointestinal complications identified according to the ICD-9 codes. The average age of patients with upper gastrointestinal complications was 66 years in the HCUP-3 database and 52 years in the MarketScan database. The average annual rates of upper gastrointestinal complications as a primary or secondary diagnosis were 6.4 and 6.7 per 1000 discharges for 1991 and 1992, respectively (HCUP-3), and 4.3, 4.2, and 4.9 per 1000 admissions for 1992, 1993, and 1994, respectively (MarketScan). The average length of stay for upper gastrointestinal complications as a primary diagnosis was 7.8 days in 1991 and 7.5 days in 1992 (HCUP-3) and 6.1, 5.1, and 5.1 days in 1992, 1993, and 1994, respectively (MarketScan). The national average total charge for hospitalization for gastrointestinal problems as a primary diagnosis was $12,970 in 1991 and $14,294 in 1992 (HCUP-3). The average total reimbursement for hospitalizations related to upper gastrointestinal problems was $15,309 in 1992, $12,987 in 1993, and $13,150 in 1994 (MarketScan). Hospital admissions for upper gastrointestinal complications are expensive. The rate and cost per admission are higher for the older population. The results on the elements covered by both databases are consistent. Therefore the databases complement each other on the type of information abstracted.

Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers. A one-year study.

The objective of this study was to determine the long-term efficacy of misoprostol in preventing diclofenac-induced gastroduodenal ulcers in rheumatoid arthritis and osteoarthritis patients. Three hundred eighty-four patients who had an endoscopically confirmed gastric or duodenal lesion that had healed with misoprostol therapy were randomized to receive misoprostol or placebo coadministered with diclofenac for up to 52 weeks. Endoscopic examinations were repeated at weeks 12, 24, and 52. The development of a gastric and/or duodenal ulcer was considered a prophylaxis failure. Results in the evaluable cohort of patients demonstrated that gastroduodenal ulcer incidences were lower with misoprostol than placebo for all study periods (0-12 weeks, 7% vs 23%; 0-24 weeks, 11% vs 26%; and 0-52 weeks, 15% vs 31%). Misoprostol did not interfere with the antiarthritic effects of diclofenac. In conclusion, misoprostol coadministered with diclofenac for 12 months to patients with rheumatoid arthritis or osteoarthritis significantly reduced the incidence of diclofenac-induced gastroduodenal ulcers (P < or = 0.018).

Epidemiology and prevention of non-steroidal anti-inflammatory drug effects in the gastrointestinal tract.

Lesions of the gastric, duodenal and intestinal mucosae are found in large numbers of patients using non-steroidal anti-inflammatory drugs (NSAIDs); however, no markers have yet been isolated to identify patients at risk for developing gastrointestinal problems or to predict which patients with lesions are at risk for developing catastrophic complications. There appears to be a poor correlation between the presence of ulcer disease and the appearance of symptoms while patients are using NSAIDs. The ideal treatment--namely, withdrawal from NSAIDs--may not always be practicable in patients who require the analgesic benefit of these otherwise generally innocuous agents. It is incumbent on the clinician to identify the agent most appropriate for the needs of the individual, and to supplement NSAID therapy, where appropriate, with a means of preventing or minimizing adverse effects. Four classes of drugs are used to prevent NSAID-related gastric mucosal damage: histamine (H2)-receptor antagonists (ranitidine, cimetidine, nizatidine, famotidine); gastric acid-pump inhibitor (omeprazole); barrier agent (sucralfate); and prostaglandin analogue (misoprostol). The current therapies (H2 antagonists and barriers) have not lived up to their promise for preventing gastroduodenal erosion. Moreover, such protection as they provide is limited to the duodenal mucosa; they afford no protection to the gastric mucosa. Preliminary data indicate that an acid pump inhibitor may be useful, but large-scale studies have yet to be reported. Acute and long-term studies of the prostaglandin analogue misoprostol have shown that this agent has an important role as an adjunctive therapy to prevent both gastric and duodenal ulceration due to NSAIDs.

Prevention and treatment of ulcers induced by nonsteroidal anti-inflammatory drugs: an update.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most frequently used for the treatment of rheumatic disease due to their anti-inflammatory and analgesic properties. All NSAIDs have the potential to cause damage to the gastrointestinal (GI) tract and have been associated with the induction of peptic ulcers and massive life-threatening bleeding. The therapeutic approaches for the treatment and prevention of NSAID-induced ulcers is critically reviewed using data derived from carefully controlled, world-wide clinical studies with anti-ulcer drugs. Histamine (H2) antagonists, omeprazole, sucralfate and E-prostaglandin (PGE) analogs are effective for the treatment of NSAID-induced gastric and duodenal ulcers, if NSAIDs are discontinued. However, if NSAIDs are continued while GI damage is present, the PGE analogs misoprostol, arbaprostil and enprostil have shown efficacy in healing NSAID-induced ulcers. Furthermore, one limited clinical study demonstrated that omeprazole has efficacy in healing NSAID-associated ulcers. Neither H2 antagonists, sucralfate and sulglycotide (a cytoprotective drug) have shown efficacy in preventing NSAID-induced gastric ulcers. However H2 antagonists have shown efficacy in preventing NSAID-induced duodenal ulcers. In contrast, only misoprostol prevents the development of NSAID-induced gastric and duodenal ulcers. Such pharmacological observations suggest that the pathophysiologic mechanisms for the induction of NSAID-induced gastric ulcer are distinctly different from those of NSAID-induced duodenal ulcers. Mild diarrhea and GI intolerance were the predominant adverse reactions experienced by patients receiving synthetic PGEs, particularly enprostil and arbaprostil. From the published data, we conclude that misoprostol is the only anti-ulcer drug proven to be well tolerated and effective for the treatment and prevention of NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAIDs therapy.

Gastric erosions induced by nonsteroidal anti-inflammatory drugs: clinical significance, pathogenesis, and therapeutic perspectives.

The development of ulceration and ulcer complications by nonsteroidal anti-inflammatory drugs (NSAIDs) is now well established. Gastric erosions occur in about 60% of patients receiving long-term NSAID therapy. Many clinicians consider such erosions benign in nature and not requiring therapeutic intervention. Recent evidence, however, indicates that gastric erosions predispose rheumatic patients to frank ulcerations and ulcer complications. This brief overview summarizes the clinical dilemma in the diagnosis and treatment of NSAID-induced gastric erosions. Current data suggest that misoprostol has important therapeutic benefits for the treatment and prevention of gastric erosions in patients receiving long-term NSAID therapy.

Prevention of nonsteroidal anti-inflammatory drug-induced gastroduodenal ulcers: role of mucosal protective and gastric antisecretory drugs.

One of the most serious side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is upper gastrointestinal mucosal damage that may result in erosions, ulcerations and other serious complications. NSAIDs reduce endogenous prostaglandins, and this reduction is relevant to their pharmacology and toxicity. The stomach and to some extent the duodenum are the major organs involved in the mucosal toxicity of NSAIDs. With the availability of the synthetic prostaglandin misoprostol, it has become possible to prevent NSAID-induced gastroduodenal ulcers without compromising the beneficial antirheumatic and analgesic effects of NSAID therapy. In fact, misoprostol is the only drug with established long-term efficacy in preventing NSAID-induced gastroduodenal ulcers in rheumatic patients. The purpose of this communication is to critically review the efficacy of gastric antisecretory drugs, mucosal protective drugs and misoprostol when used for the prevention of NSAID-induced ulcers, considering only data from well-controlled, randomized, double-blind clinical studies. The histamine H2-receptor antagonist ranitidine has been shown to be effective in preventing NSAID-induced duodenal ulcers, but has no efficacy in preventing NSAID-induced gastric ulcers. In a direct comparative trial with ranitidine, misoprostol (200 micrograms qid) was significantly more effective than ranitidine (150 mg bid) in preventing gastric ulcers in chronic NSAID users. The inactivity of ranitidine in preventing gastric ulcers indicates that the pathogenesis of NSAID-induced gastric ulcers is not related to gastric acid. Limited but conflicting data exist with omeprazole. The mucosal-coating drug sucralfate has not been found effective in preventing NSAID ulcers. In fact, in a direct comparative trial, misoprostol (200 micrograms qid) was significantly more effective than sucralfate (1 g qid) in preventing gastric ulcers in patients receiving chronic NSAID therapy. No meaningful data exist with organic bismuth salts, a group of drugs which has mucosal coating and protective properties. From this brief overview, we conclude: (1) mucosal-coating compounds have no therapeutic role in preventing NSAID-induced ulceration; (2) gastric antisecretory drugs are not effective in preventing NSAID-induced gastric ulcers, and (3) misoprostol is the only antiulcer drug proven to be effective for preventing NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAID. Misoprostol represents a major therapeutic advance for the management of NSAID-induced mucosal injury.

Anti-inflammatories and gastroduodenal damage: therapeutic options.

The association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the development of upper gastrointestinal (GI) damage is well established. Studies have indicated that 12-30% of NSAID users will develop gastric ulcers and that 2-19% will develop duodenal ulcers. Furthermore, many NSAID-induced ulcers are "silent" and are only discovered when complications occur. When possible, the most effective method of preventing NSAID-induced gastropathy is discontinuation of NSAIDs or a reduction in the NSAID dosage. For patients who require continued NSAID therapy, four classes of drugs have been evaluated for their potential protective effects against NSAID-induced gastroduodenal damage:H2-receptor antagonists (eg, ranitidine), proton pump inhibitors (eg, omeprazole), acid-barrier compounds (eg, sucralfate), and prostaglandin E1 analogues (eg, misoprostol). H2-receptor antagonists have not been shown to be effective in preventing NSAID-induced gastric ulcers, and sucralfate has not been shown to be effective in preventing NSAID-induced gastric or duodenal ulcers. Similarly, newer proton pump inhibitors, such as omeprazole, do not appear to protect the stomach against NSAID-induced damage. In contrast, misoprostol has proven its efficacy in preventing both gastric and duodenal ulcers in arthritis patients taking NSAID therapy.

Prevention and treatment of ulcers induced by nonsteroidal anti-inflammatory drugs.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can cause varying degrees of gastroduodenal mucosal damage. These agents are most frequently used for the treatment of rheumatic diseases because they are highly effective in reducing joint pain and swelling. Histamine H2-receptor antagonists, omeprazole, sucralfate, and misoprostol are drugs available for the treatment of gastric mucosal damage caused by NSAIDs. In controlled clinical studies, all these drugs effectively heal gastric and duodenal injury if NSAIDs are discontinued. However, current data suggest that if NSAIDs are continued while gastrointestinal damage is present, only misoprostol and omeprazole have demonstrated efficacy in healing gastric mucosal injury. Misoprostol also effectively heals NSAID-induced duodenal injury. At this time, no data exist on the efficacy of other antiulcer drugs in healing duodenal erosions or ulceration if NSAID administration is continued. Regarding prevention of NSAID-induced gastric ulcer, controlled clinical studies with H2 antagonists and sucralfate have failed to show any therapeutic benefit. Ranitidine, however, has shown efficacy in preventing NSAID-induced duodenal ulcers. The coadministration of misoprostol with NSAIDs to patients who have either osteoarthritis or rheumatoid arthritis prevents the development of gastric and duodenal ulcers. Based on current published information, this property distinguishes misoprostol from other antiulcer drugs.

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)

HIV-1 gp41 antigen demonstration in esophageal ulcers with acquired immunodeficiency syndrome.

Esophageal ulcers associated with acquired immunodeficiency syndrome (AIDS) may be chronic, debilitating, and resistant to antifungal or antiviral therapy. The therapeutic management of these lesions remains controversial due to the difficulty in identifying pathogenic agent(s). We review previously published cases and describe three AIDS patients with esophageal ulcers that stained by immunoperoxidase techniques for human immunodeficiency virus (HIV)-1 surface glyloprotein (gp41). All three showed symptomatic resolution and healing of their ulcers with corticosteroid therapy. We believe this documentation of HIV-1 gp41 antigen within mononuclear cells of esophageal ulcers in AIDS supports a role of the HIV-1 virus in the pathophysiology of idiopathic esophageal ulcers in patients with AIDS. These cases further support a role for corticosteroid therapy in the treatment of esophageal ulcers resistant to antifungal and antiviral therapy in patients with AIDS.

Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer. A randomized, controlled trial.

OBJECTIVES: To compare the efficacy and frequency of adverse experiences of misoprostol and sucralfate in the prevention of gastric ulcers in patients receiving nonsteroidal anti-inflammatory drug (NSAID) therapy. DESIGN: A prospective, randomized, single-blind, multicenter trial. PATIENTS: Patients with osteoarthritis receiving treatment with ibuprofen, piroxicam, or naproxen and experiencing abdominal pain were eligible. INTERVENTIONS: Patients who were expected to receive at least 3 months of NSAID therapy and who did not have a gastric ulcer at the time of the initial screening endoscopy were randomized to receive misoprostol, 200 micrograms four times a day, or sucralfate, 1 g four times a day. A gastric ulcer was defined as a lesion of the gastric mucosa 0.3 cm or greater in diameter. Patients were followed clinically, and repeat endoscopies were performed after 4, 8, and 12 weeks. MAIN MEASUREMENT: The development of a gastric ulcer, which was regarded as a prophylaxis failure. RESULTS: Two hundred fifty-three patients were evaluable for efficacy analysis. A gastric ulcer developed in 2 of the 122 (1.6%, 95% CI, 0.3% to 6.4%) patients on misoprostol, compared with 21 of 131 patients on sucralfate (16%, CI, 10.4% to 23.7%). The difference in ulcer rates was 14.4% (CI, 10.4% to 19.5%; P less than 0.001). CONCLUSION: In patients receiving chronic NSAID therapy for osteoarthritis, treatment with misoprostol for 3 months was associated with a significantly lower frequency of gastric ulcer formation, compared with treatment with sucralfate (P less than 0.001).

Treatment and prevention of NSAID induced gastroduodenal mucosal damage.

The use of aspirin and other nonsteroidal antiinflammatory drugs (NSAID) is associated with various degrees of gastroduodenal damage. The agents currently available for the treatment of NSAID induced gastric mucosal damage are histamine2-receptor antagonists, antacids, sucralfate and prostaglandin (PG) analogs. Although all of these agents are effective in healing gastric and duodenal injury if NSAID therapy is discontinued, currently available data suggest that there may be significant differences among these drugs in healing or preventing mucosal injury when NSAID therapy is continued. In particular, the synthetic PG misoprostol appears to be therapeutically superior to agents in the other drug classes in these settings.

Nonsteroidal anti-inflammatory drugs and acute upper gastrointestinal bleeding: a prospective study.

One of the most serious side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is upper gastrointestinal mucosal damage that may result in hemorrhage, perforation, or even death. To determine the association between NSAID ingestion and acute upper gastrointestinal bleeding, we prospectively evaluated all hospitalized patients who underwent upper endoscopy for hematemesis and/or melena over a 12-month period at the Veterans Administration Medical Center of New Orleans and Tulane Medical Center. Forty of the 139 patients (29%) at the Veterans Administration Medical Center and 21 of the 90 patients (23%) at Tulane Medical Center were using NSAIDs at the time of referral for endoscopy. Erosive gastritis was the most common cause of bleeding attributed to NSAIDs (P less than .005). Seventy percent of the patients with acute upper gastrointestinal bleeding who used NSAIDs were over age 55, compared with 55% of patients not using NSAIDs (P less than .05). This study indicates that NSAID use is found in 27% of hospitalized patients presenting with acute upper gastrointestinal bleeding. Future prospective studies are needed to establish whether prophylactic therapy with synthetic prostaglandins may affect the prevalence of upper gastrointestinal bleeding in patients using NSAIDs.