Clinical trial: comparison of ibuprofen-phosphatidylcholine and ibuprofen on the gastrointestinal safety and analgesic efficacy in osteoarthritic patients.

BACKGROUND: Chronic use of NSAIDs is associated with gastrointestinal (GI) toxicity that increases with age. AIM: To evaluate the GI safety and therapeutic efficacy of ibuprofen chemically associated with phosphatidylcholine (PC) in osteoarthritic (OA) patients. METHODS: A randomized, double-blind trial of 125 patients was performed. A dose of 2400 mg/day of ibuprofen or an equivalent dose of ibuprofen-PC was administered for 6 weeks. GI safety was assessed by endoscopy. Efficacy was assessed by scores of analgesia and anti-inflammatory activity. Bioavailability of ibuprofen was pharmacokinetically assessed. RESULTS: Ibuprofen-PC and ibuprofen provided similar bioavailability/therapeutic efficacy. In the evaluable subjects, a trend for improved GI safety in the ibuprofen-PC group compared with ibuprofen that did not reach statistical significance was observed. However, in patients aged >55 years, a statistically significant advantage for ibuprofen-PC treatment vs. ibuprofen in the prevention of NSAID-induced gut injury was observed with increases in both mean Lanza scores and the risk of developing >2 erosions or an ulcer. Ibuprofen-PC was well tolerated with no major adverse events observed. CONCLUSION: Ibuprofen-PC is an effective osteoarthritic agent with an improved GI safety profile compared with ibuprofen in older OA patients, who are most susceptible to NSAID-induced gastroduodenal injury.

The impact of low-dose aspirin on endoscopic gastric and duodenal ulcer rates in users of a non-selective non-steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective inhibitor.

BACKGROUND: The effect of low-dose aspirin on endoscopic ulcer incidence in cyclo-oxygenase-2-selective inhibitor or non-selective non-steroidal anti-inflammatory drug users remains controversial. AIM: To compare prospectively the incidence of endoscopic ulcers in healthy subjects receiving low-dose aspirin plus celecoxib or naproxen. METHODS: In this double-blind, placebo-controlled, 1-week study, subjects (50-75 years) were randomized to receive aspirin 325 mg o.d. plus either celecoxib 200 mg o.d., naproxen 500 mg b.d., or placebo. Baseline and end of study endoscopies were performed. The primary end point was incidence of one or more gastric and duodenal ulcers. RESULTS: A lower incidence of gastric and duodenal ulcers was seen in celecoxib/aspirin-treated subjects (19%) vs. naproxen/aspirin (27%; RR: 0.63, 95% CI: 0.44-0.92). Both naproxen/aspirin and celecoxib/aspirin groups demonstrated a higher incidence of gastric and duodenal ulcers vs. placebo/aspirin (8%; RR: 3.7, 95% CI: 1.8-7.6 and RR: 2.6, 95% CI: 1.2-5.8, respectively). CONCLUSIONS: Fewer endoscopic ulcers were observed in patients treated with celecoxib/aspirin vs. naproxen/aspirin. However, celecoxib/aspirin was associated with a significantly higher incidence of gastric and duodenal ulcers than aspirin alone. Further studies are required to determine the generalizability of these findings in the aspirin users and to determine the appropriate strategy to minimize risk in susceptible patients.

Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women.

BACKGROUND: Bisphosphonates are effective treatments for osteoporosis. Since some primary amino bisphosphonates are associated with oesophageal injury, we conducted a study of the upper gastrointestinal effects of risedronate, a pyridinyl bisphosphonate. METHODS: Healthy, postmenopausal women received risedronate 5 mg (n=26), aspirin 2600 mg (n=27), or placebo (n=27) daily for 14 days and underwent endoscopy at baseline, Day 8 and Day 15. RESULTS: Oesophageal erosions were noted in one subject in the aspirin group, two in the placebo group, and none in the risedronate group, and an ulcer in one aspirin-treated subject. Gastric erosions and ulcers were observed most frequently in the aspirin group. Gastric ulcers were noted in eight subjects in the aspirin group, one in the placebo group, and none in the risedronate group (P=0.010, placebo vs. aspirin; P=0.002, risedronate vs. aspirin). Duodenal erosions and ulcers were observed in the aspirin group only. Gastroduodenal erosion scores of three or more occurred more frequently in the aspirin than in the risedronate and placebo groups (P < 0.001). CONCLUSIONS: Risedronate 5 mg was not associated with oesophageal or gastroduodenal ulcers in healthy, postmenopausal women, a population representative of patients who will receive risedronate in the clinical setting.

Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women.

BACKGROUND & AIMS: Bisphosphonates are effective treatment for osteoporosis, but upper gastrointestinal injury associated with some compounds has caused concern. This study compared the incidence of gastric ulcers after treatment with risedronate, a pyridinyl bisphosphonate, and alendronate, a primary amino bisphosphonate. Esophageal and gastroduodenal injury assessed by endoscopy scores was a secondary endpoint. METHODS: Healthy, postmenopausal women (n = 515) received 5 mg risedronate (n = 255) or 10 mg alendronate (n = 260) for 2 weeks. At baseline and on days 8 and 15, subjects underwent endoscopy and evaluator-blinded assessment of the esophageal, gastric, and duodenal mucosa. RESULTS: Gastric ulcers were observed during the treatment period in 9 of 221 (4.1%) evaluable subjects in the risedronate group compared with 30 of 227 (13.2%) in the alendronate group (P < 0.001). Mean gastric endoscopy scores for the risedronate group were lower than those for the alendronate group at days 8 and 15 (P

Prevention of NSAID-related ulcers.

The use of NSAIDs constitutes a significant risk for gastrointestinal bleeding and other ulcer complications. However, if they prove clinically effective in relieving arthritic symptoms, the new COX-2 selectively inhibiting NSAIDs may ultimately solve the problem of gastrointestinal toxicity with NSAIDs.

Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.

BACKGROUND: Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. AIM: To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. METHODS: Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. RESULTS: The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. CONCLUSIONS: In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.

Ranitidine bismuth citrate plus clarithromycin: a dual therapy regimen for patients with duodenal ulcer.

BACKGROUND: The combination of ranitidine bismuth citrate (RBC) and clarithromycin (CLR) was compared with each treatment alone for the eradication of H. pylori and healing of duodenal ulcers in patients infected with H. pylori. METHODS: This two-phase, randomized, double-blind, placebo-controlled, multicenter study evaluated 203 patients with an active duodenal ulcer treated with either (1) RBC 400 mg BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; (2) RBC 400 mg BID for 4 weeks plus placebo TID for the first 2 weeks; (3) placebo BID for 4 weeks plus CLR 500 mg TID for the first 2 weeks; or (4) placebo BID for 4 weeks plus placebo TID for the first 2 weeks. Patients with healed ulcers after treatment entered a 24-week observation phase for the assessment of H. pylori and ulcer relapse. RESULTS: Four-week ulcer healing rates were higher with RBC + CLR (71%) and RBC alone (66%) compared with placebo (15%; p < 0.05) and CLR alone (49%). H. pylori eradication rates were significantly higher with RBC + CLR (86%) compared with RBC alone (0%, p < .001) or CLR alone (24%, p < .001). Ulcer recurrence rates after 6 months were lower in patients eradicated of H. pylori infection (17%) compared with patients who remained infected (43%). All treatments were well tolerated. CONCLUSIONS: Ranitidine bismuth citrate plus clarithromycin is a simple, convenient, and well-tolerated dual therapy regimen that is effective in eradicating H. pylori and healing duodenal ulcers in patients infected with H. pylori. The eradication of H. pylori in patients with healed ulcers significantly reduces the rate of ulcer relapse.

Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects.

OBJECTIVE: To investigate the efficacy and safety of SC-58635 (celecoxib), an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 (COX-2) inhibition and is not expected to cause the typical gastrointestinal (GI), renal, and platelet-related side effects associated with inhibition of the COX-1 enzyme. METHODS: Four phase II trials were performed: a 2-week osteoarthritis efficacy trial, a 4-week rheumatoid arthritis efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 1-week study of effects on platelet function. RESULTS: The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, 19% of subjects receiving naproxen (6 of 32) developed gastric ulcers, whereas no ulcers occurred in subjects receiving SC-58635 or placebo. The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels, whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels. In all 4 trials, SC-58635 was well tolerated, with a safety profile similar to that of placebo. CONCLUSION: SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition, without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs.

An endoscopic comparison of gastroduodenal injury with over-the-counter doses of ketoprofen and acetaminophen.

OBJECTIVE: The objective of this study was to endoscopically assess in healthy subjects the gastrointestinal effects of over-the-counter (OTC) doses of ketoprofen. Ketoprofen is a potent nonsteroidal antiinflammatory agent (NSAID) recently approved for OTC use as an analgesic/antipyretic at doses of 75 mg versus the usual dose of < or = 300 mg daily. In epidemiological studies, ketoprofen at prescription doses has consistently been in the higher relative risk group of NSAIDs in the occurrence of gastrointestinal complications of therapy. The gastrointestinal effects of the OTC (US) dose of ketoprofen have not been reported. METHODS: In a randomized, double blind, three way crossover study, 24 healthy subjects received 7 days of therapy with ketoprofen 75 mg/day, acetaminophen 4000 mg/day, and placebo. Gastroduodenal endoscopy was performed before and at the end of each treatment period. The condition of the mucosa was graded compositely for the gastric antrum, fundus, body, and duodenum. RESULTS: Significantly more frequent and severe gastric mucosal injury was observed after dosing with ketoprofen compared with acetaminophen (p = 0.0001). The acetaminophen group showed no difference from placebo (p = 0.8783). Two subjects developed frank gastric ulcers with ketoprofen therapy. Marginally more frequent (p = 0.0703) and significantly more severe (p = 0.0117) duodenal mucosal injury was seen. No significant differences were observed between treatment groups with respect to subjective symptoms of gastric discomfort or adverse events. CONCLUSION: These results indicate that even at lower (OTC) doses (75 mg/day) ketoprofen is associated with significant gastrointestinal irritation.

The American College of Gastroenterology Bleeding Registry: preliminary findings.

OBJECTIVES: The American College of Gastroenterology (ACG) Institute for Clinical Research and Education conducted a survey study to assess demographics, management strategies, and outcome for patients with gastrointestinal bleeding. This pilot project was intended to determine the feasibility of surveying the ACG membership about common clinical issues. METHODS: Color-coded survey forms were sent to all ACG members and Fellows, with instructions to supply information about demographics, presenting symptoms, management, and outcome for bleeding patients and procedure-matched controls. Forms returned between June 1 and August 31, 1995, were tabulated and analyzed for differences between the bleeding group and procedure-matched controls. RESULTS: A total of 1235 forms were returned by respondents, 60% of whom were in private practice. Patient demographics indicated that bleeding patients were significantly older, more likely to be male, and more likely to use alcohol, tobacco, and prescription or over-the-counter aspirin or nonsteroidal anti-inflammatory drugs and anticoagulants than were controls. Upper GI bleeding accounted for 76% of bleeding events, with duodenal and gastric ulcers being the source in more than 50% of the upper GI bleeders. Diverticula was the most common bleeding source identified in lower GI bleeders. In the bleeding group, 78.8% were anemic, with 60.9% having hemoglobin of <10 g/dl; 31% presented with orthostatic changes in blood pressure or shock. Most bleeding subjects, regardless of source, were hospitalized, 58.2% received blood transfusions, and 45.5% received endoscopic therapy. Rebleeding (11.2%), need for surgery (7.1%), and fatalities (2.1%) were uncommon. Over-the-counter aspirin and nonsteroidal anti-inflammatory drugs were used significantly more often in the bleeding population (47.6%) than in controls (19.4%). CONCLUSIONS: The success of the GI Bleeding Registry supports the feasibility of surveying ACG members about common clinical problems. Data suggest that ACG members manage sick patients with severe gastrointestinal bleeding who require hospitalization, transfusions, and endoscopic treatment. These preliminary results will serve as an impetus to conduct further survey studies of gastrointestinal bleeding and other common digestive disease conditions.

Gastrointestinal toxicity of newer NSAIDs.

The linkage between gastroduodenal mucosal injury and nonsteroidal anti-inflammatory drugs (NSAIDs) is now well established. Fifteen percent to 20% of patients taking these agents develop gastric or duodenal ulcer, and about 3% of this group goes on to experience hemorrhage or perforation. Gastrointestinal (GI) complications occur primarily in certain high risk groups, notably elderly female patients and patients with a prior history of peptic ulcer or GI bleeding. Recently, two new NSAIDs, nabumetone and etodolac, which are reportedly safer because they selectively inhibit prostaglandin synthesis in target tissues but spare that in the stomach, have been introduced in the United States. Further, data from clinical trials of oxaprozin, an NSAID not yet available in the United States, indicate that this agent may have a better safety profile than older NSAIDs. A review of the literature concerning the mucosal toxicity of these three agents reveals that the overall ulceration and major complication rate is low. However, a direct comparison with older NSAIDS in a large group of patients in a dose with similar efficacy is lacking.

NSAID-induced gastric ulceration is dose related by weight: an endoscopic study with flurbiprofen.

Numerous studies have shown that higher doses of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased levels of mucosal injury and ulceration in both normal volunteers and patients. The present dose-ranging study was designed to determine whether escalating doses of a commonly prescribed NSAID, flurbiprofen, when expressed as mg/kg dosages, were associated with increased mucosal injury and ulceration. Subjects received either the recommended dose of 300 mg/day of flurbiprofen (N = 10), or the higher than recommended doses of 400 mg/day (N = 20) and 500 mg/day (N = 10), for a period of 7 days. Endoscopic examination was performed on day 0 and day 7, and the stomach was evaluated on day 7 for mucosal injury on a 0-4 scale, and for the presence or absence of ulcer. One gastric ulcer was seen in each of the 300- and 400-mg groups. However, in the 500 mg/day group, four gastric ulcers were seen (40%) (p = 0.04). Three of the six subjects developing gastric ulcer were of a fairly low body weight (two women, one man), and when the data were analyzed on a mg/kg basis, all six ulcers occurred in 19 of the 40 subjects receiving > 5.95 mg/kg, whereas no gastric ulcers were seen in the 21 subjects receiving dosages below that level (p < 0.01). These data suggest that, at least for this agent, a threshold level may exist above which gastric ulcers are much more likely to occur. This may in part explain why elderly debilitated, low-body-weight female patients are more prone to NSAID-related gastric ulcer.

A multicenter, double-blind, randomized, placebo-controlled comparison of nocturnal roxatidine in the treatment of active duodenal ulcer disease. Multicenter Roxatidine Cooperative Study Group.

This multicenter randomized, double-blind, 4-wk study compared the new H2-receptor antagonistic roxatidine (R) to placebo (P) for treatment of endoscopically diagnosed active duodenal ulcer disease. Subjects were evaluated after 2 and 4 wk of treatment. Those whose ulcer was unhealed at 2 wk received 2 more weeks of treatment before final evaluation. Ulcer healing (endoscopically determined) with roxatidine was more effective than placebo at both wk 0-2 (R = 33.9%, P = 21.9%, p = 0.018) and wk 2-4 (R = 68.2%, P = 29.7%, p less than 0.001), with an overall 4-wk effectiveness of 78.9% compared to 44.8% (p less than 0.001). At the end of treatment, average maximum ulcer diameter diminished 83% in R and 50% in P (p less than 0.001). Roxatidine was also more effective than placebo in decreasing abdominal pain (p less than 0.001), decreasing the number of antacid tablets taken for pain relief (p less than 0.001), improving dyspeptic symptoms (p less than 0.001), and permitting return to a normal routine for subjects with previous illness-imposed restrictions on work and/or other daily activities. The profile of laboratory values and adverse experiences demonstrated roxatidine to be safe and well-tolerated. The efficacy of roxatidine as evaluated by the healing rate of duodenal ulcer and reduction in abdominal pain emphasize its value as an addition to the family of H2-receptor antagonists.

A double-blind, placebo-controlled, 6-day evaluation of two doses of misoprostol in gastroduodenal mucosal protection against damage from aspirin and effect on bowel habits.

Ninety-one normal, healthy volunteers participated in a single-center, double-blind, placebo-controlled, randomized, parallel group study: 1) to compare the prostaglandin E1 analog, misoprostol, given at a dose of 200 micrograms bid, with the recommended dose of 200 micrograms qid in protecting the gastroduodenal mucosa against injury due to anti-inflammatory doses of aspirin (3900 mg/day); and 2) to determine whether the reduced dose was associated with a lesser incidence of gastrointestinal (GI) side effects, particularly diarrhea. All subjects received 975 mg of aspirin qid with meals and at bedtime. They were concurrently administered either misoprostol 200 micrograms qid, misoprostol 200 micrograms bid and placebo bid, or placebo qid. All subjects were endoscopically normal at the onset of the study and were re-endoscoped on the morning of the 7th day of therapy, 2 h after the morning dose of medications. Gastric and duodenal mucosa were assessed separately on a 0-7 scale which gave a greater weight to erosions than to hemorrhages. GI symptoms, especially bowel habits, were assessed by means of diary cards. Subjects in both misoprostol groups had significantly less gastric and duodenal mucosal injury than subjects who received placebo (p less than 0.007 for each pairwise comparison). There was no statistically significant difference between the two misoprostol groups (p less than 0.093). Subjects in the misoprostol 200 micrograms qid group had significantly more loose and watery bowel movements than the subjects in the misoprostol 200 micrograms bid group (p less than 0.013), whereas there were no significant differences in bowel habits between the misoprostol 200 micrograms bid and placebo groups (p less than 0.122). More subjects in the misoprostol 200 micrograms qid group reported abdominal pain, loose stools, watery stools, flatulence, dyspepsia, and nausea than in the misoprostol 200 micrograms bid and placebo groups. In conclusion, the adverse events in the misoprostol 200 micrograms bid group were not significantly different from those in the placebo group, and were significantly better than in the misoprostol 200 micrograms qid group. The lower dose retained mucosal protective activity that was statistically indistinguishable from that of misoprostol 200 micrograms qid.