Thomas J. Simon

A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2–specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis

BACKGROUND & AIMSnProstaglandin production in the normal gastrointestinal tract, believed to be critical for mucosal integrity, is mediated by cyclooxygenase (COX)-1, whereas prostaglandin production at inflammatory sites seems to occur via induction of COX-2. We hypothesized that COX-2-specific inhibition with rofecoxib (25 mg once daily) in the treatment of patients with osteoarthritis would cause fewer gastroduodenal ulcers than an equally effective dose of ibuprofen (800 mg 3 times a day), a nonspecific COX inhibitor.nnnMETHODSnA total of 742 osteoarthritis patients without ulcers on baseline endoscopy were randomly assigned to receive rofecoxib (25 or 50 mg once daily), ibuprofen (800 mg 3 times daily), or placebo. Endoscopy was repeated at 6, 12, and 24 weeks. At 16 weeks, by study design, 95% of the placebo group and 5% of the other groups were discontinued.nnnRESULTSnThe cumulative incidence of gastroduodenal ulcers >/=3 mm with rofecoxib (25 or 50 mg once daily) was significantly (P < 0.001) lower than with ibuprofen and was statistically equivalent to placebo at week 12 (placebo, 9.9%; 25 mg rofecoxib, 4.1%; 50 mg rofecoxib, 7.3%; and ibuprofen, 27.7%). At 24 weeks, ulcer rates were 25 mg rofecoxib, 9. 6%; 50 mg rofecoxib, 14.7%; and ibuprofen, 45.8% (P < 0.001, ibuprofen vs. 25 and 50 mg rofecoxib).nnnCONCLUSIONSnRofecoxib, at doses 2-4 times the dose demonstrated to relieve symptoms of osteoarthritis, caused significantly less gastroduodenal ulceration than ibuprofen, with ulcer rates comparable to placebo.

Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs

BACKGROUNDnAcid suppression with famotidine, a histamine H2-receptor antagonist, provides protection against gastric injury in normal subjects receiving short courses of aspirin or naproxen. The efficacy of famotidine in preventing peptic ulcers in patients receiving long-term therapy with nonsteroidal antiinflammatory drugs (NSAIDs) is not known.nnnMETHODSnWe studied the efficacy of two doses of famotidine (20 mg and 40 mg, each given orally twice daily), as compared with placebo, in preventing peptic ulcers in 285 patients without peptic ulcers who were receiving long-term NSAID therapy for rheumatoid arthritis (82 percent) or osteoarthritis (18 percent). The patients were evaluated clinically and by endoscopy at base line and after 4, 12, and 24 weeks of treatment. The evaluators were unaware of the treatment assignment. The primary end point was the cumulative incidence of gastric or duodenal ulceration at 24 weeks.nnnRESULTSnThe cumulative incidence of gastric ulcers was 20 percent in the placebo group, 13 percent in the group of patients receiving 20 mg of famotidine twice daily (P = 0.24 for the comparison with placebo), and 8 percent in the group receiving 40 mg of famotidine twice daily (P = 0.03 for the comparison with placebo). The proportion of patients in whom duodenal ulcers developed was significantly lower with both doses of famotidine than with placebo (13 percent in the placebo group, 4 percent in the low-dose famotidine group [P = 0.04], and 2 percent in the high-dose famotidine group [P = 0.01]). Both doses of famotidine were well tolerated.nnnCONCLUSIONSnTreatment with high-dose famotidine significantly reduces the cumulative incidence of both gastric and duodenal ulcers in patients with arthritis receiving long-term NSAID therapy.

Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: A randomized, double‐blind, placebo‐controlled trial

OBJECTIVEnThis randomized, double-blind study tested the hypothesis that rofecoxib, a drug that specifically inhibits cyclooxygenase 2, would cause fewer gastroduodenal ulcers than ibuprofen (in a multicenter trial), and its side effects would be equivalent to those of placebo (in a prespecified analysis combining the results with another trial of identical design).nnnMETHODSnSeven hundred seventy-five patients with osteoarthritis were randomized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily, ibuprofen 800 mg 3 times daily, or placebo. Gastroduodenal ulceration was assessed by endoscopy at 6, 12, and (for active treatment) 24 weeks. The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks, respectively.nnnRESULTSnUlcers were significantly less common (P < 0.001) following treatment with rofecoxib (25 mg or 50 mg) than with ibuprofen after 12 weeks (5.3% and 8.8% versus 29.2%, respectively) or 24 weeks (9.9% and 12.4% versus 46.8%, respectively). In the combined analysis, the 12-week ulcer incidence with 25 mg rofecoxib (4.7%) and with placebo (7.3%) satisfied prespecified criteria for equivalence.nnnCONCLUSIONnAt 2-4 times the therapeutically effective dose, rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen. Rofecoxib at a dose of 25 mg (the highest dose recommended for osteoarthritis) satisfied prespecified criteria for equivalence to placebo.

Effects of alendronate on gastric and duodenal mucosa.

Objectives:This single-center, double-blind, randomized study assessed the effect of alendronate 5 and 10 mg on the gastroduodenal mucosa.Methods:Overall, 95 postmenopausal women without a recent history of major upper gastrointestinal (GI) disease and not taking gastric-irritant drugs, were screened with an upper GI endoscopy. Fourteen women (15% of the total) were found to have baseline endoscopic gastric and/or duodenal abnormalities, including mucosal hemorrhages (n = 4), erosions (n = 11), and ulcers (n = 3). Two additional women had baseline esophageal abnormalities. Thus, 79 postmenopausal women (mean age 51 yr, range 41–64 yr), free of esophageal, gastric and/or duodenal erosions or ulcer, were enrolled. Subjects received placebo, alendronate 5 mg/day or 10 mg/day, or aspirin 650 mg q.i.d. for 14 days. Endoscopy was repeated on Day 8 and on Day 15. Gastric and duodenal mucosae were graded separately using a 5-point scale for erosive mucosal injury.Results:The proportions of subjects with a gastric or duodenal erosion score ≥ 2 (presence of at least one mucosal erosion) on either Day 8 or 15 were four of 22 (18.2%) in the placebo group; four of 22 (18.2%) in the alendronate 5 mg group; five of 21 (23.8%) in the alendronate 10 mg group; and 14 of 14 (100.0%) in the aspirin group. Thirty-five of 76 (46%) subjects were H. pylori-positive (Pyloritek test), and were equally distributed across treatment groups.Conclusions:Alendronate 5 and 10 mg/day for 2 wk was associated with a lower incidence of gastric erosions than aspirin. The incidence of gastric erosions in the alendronate groups did not differ significantly from the placebo group. In this study, unlike aspirin, alendronate did not induce gastric erosions.

Comparative tolerability profile of omeprazole in clinical trials.

The tolerability of omeprazole was compared to control agents in 68 clinical studies that enrolled a total of 4846 patients, of whom 3096 received omeprazole. The incidence of adverse experiences was independent of omeprazole dose administered, the age of the patients, and the disease treated (duodenal ulcer or endoscopically verified gastroesophageal reflux disease). The most common clinical adverse experiences were headache, diarrhea, abdominal pain, and nausea. The most common laboratory adverse experiences were elevated aspartate aminotransferase and elevated alanine aminotransferase. Omeprazole was well tolerated, and the incidence of clinical and laboratory adverse experiences was similar in patients receiving omeprazole, placebo, cimetidine, or ranitidine.

The Oral NK1 Antagonist Aprepitant for Prevention of Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy

This paper reviews the clinical profile of the neurokinin-1 (NK1) receptor antagonist aprepitant, the first approved antiemetic in its class, developed for use in the prevention of chemotherapy-induced nausea and vomiting (CINV). CINV, which ranges from mild nausea to protracted vomiting with dehydration, can significantly affect the wellbeing and quality of life of patients with cancer. CINV remains a problem despite recent advances in preventive measures, notably the introduction of the serotonin 5-HT3 receptor antagonists. With standard dual therapy (a 5-HT3 antagonist plus a corticosteroid) emesis still occurs in up to 50% of patients in the acute phase (0–24 hours following emetogenic chemotherapy), especially during multiple cycles of chemotherapy as the initial effectiveness of dual therapy is not sustained. For the same reasons, emesis still occurs in up to 80% of patients in the delayed phase (2–5 days following chemotherapy). Furthermore, the likelihood of CINV is increased among patients receiving multiple cycles of chemotherapy.Aprepitant has been evaluated clinically as a single agent and in combination with other antiemetic agents. The addition of a 3-day regimen of aprepitant to a 5-HT3 receptor antagonist and a corticosteroid was found to enhance antiemetic protection significantly in patients receiving highly emetogenic, cisplatin-based chemotherapy. This improvement was particularly robust in the delayed phase of CINV and was also well maintained over multiple cycles — two situations in which a need for better antiemetic prophylaxis had been especially conspicuous. Although care must be taken to use aprepitant according to the labeling guidelines to minimize the potential for drug interactions, aprepitant was generally well tolerated among the >3000 patients or participants exposed to it. Aprepitant has therefore emerged as an important clinical advance in the supportive care of patients with cancer.

Original ContributionsEffects of alendronate on gastric and duodenal mucosa

Abstract Objectives: This single-center, double-blind, randomized study assessed the effect of alendronate 5 and 10 mg on the gastroduodenal mucosa. Methods: Overall, 95 postmenopausal women without a recent history of major upper gastrointestinal (GI) disease and not taking gastric-irritant drugs, were screened with an upper GI endoscopy. Fourteen women (15% of the total) were found to have baseline endoscopic gastric and/or duodenal abnormalities, including mucosal hemorrhages (n = 4), erosions (n = 11), and ulcers (n = 3). Two additional women had baseline esophageal abnormalities. Thus, 79 postmenopausal women (mean age 51 yr, range 41–64 yr), free of esophageal, gastric and/or duodenal erosions or ulcer, were enrolled. Subjects received placebo, alendronate 5 mg/day or 10 mg/day, or aspirin 650 mg q.i.d. for 14 days. Endoscopy was repeated on Day 8 and on Day 15. Gastric and duodenal mucosae were graded separately using a 5-point scale for erosive mucosal injury. Results: The proportions of subjects with a gastric or duodenal erosion score ≥ 2 (presence of at least one mucosal erosion) on either Day 8 or 15 were four of 22 (18.2%) in the placebo group; four of 22 (18.2%) in the alendronate 5 mg group; five of 21 (23.8%) in the alendronate 10 mg group; and 14 of 14 (100.0%) in the aspirin group. Thirty-five of 76 (46%) subjects were H. pylori -positive (Pyloritek test), and were equally distributed across treatment groups. Conclusions: Alendronate 5 and 10 mg/day for 2 wk was associated with a lower incidence of gastric erosions than aspirin. The incidence of gastric erosions in the alendronate groups did not differ significantly from the placebo group. In this study, unlike aspirin, alendronate did not induce gastric erosions.