Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients.

OBJECTIVES: Alosetron (Lotronex) is a new therapeutic agent for irritable bowel syndrome (IBS) in women with diarrhea-predominant IBS. This multicenter randomized, double-blind, placebo-controlled study assessed the safety and tolerability of alosetron during long-term (< or = 12 months) treatment. METHODS: A total of 859 subjects (637 female and 222 male) with IBS were enrolled from 130 sites in the United States and were randomized 3:1 to receive 1 mg alosetron or placebo b.i.d. for 48 wk; of the subjects, 649 (76%) were randomized to the alosetron group and 212 (24%) to the placebo group. Of the original group, 850 subjects received at least one dose of alosetron (n = 640) or placebo (n = 210). RESULTS: In all, 59% of the subjects completed the study. Safety data were similar in treatment groups and within age, sex, racial origin, and hormone use. Adverse events were reported by 83% (530/640) and 76% (159/210) of subjects in the alosetron and placebo groups, respectively, (p < 0.05) and were similar with the exception of constipation; 32% of subjects receiving alosetron reported constipation, compared to 5% in the placebo group (p < 0.001). Most reports (72%) of constipation were of mild or moderate severity, and 66% of subjects with constipation had single episode of 8 days median duration. Constipation occurred a median of 13 days after initiating treatment and resolved spontaneously, with laxative, or after a brief interruption of therapy. Of the subjects, 4% (11/210) in the alosetron and 5% (28/ 640) in the placebo group experienced serious adverse events. Two deaths occurred in subjects with pre-existing cardiovascular risk factors; neither death was attributed to the study drug. CONCLUSIONS: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment.

Helicobacter pylori infection rates in duodenal ulcer patients in the United States may be lower than previously estimated.

OBJECTIVE: Published studies have estimated the rate of Helicobacter pylori (H. pylori) infection in patients with duodenal ulcer disease to be as high as 95%; the majority of remaining duodenal ulcers have been attributed to the use of ulcerogenic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs). We aimed to assess the H. pylori prevalence rates of U.S. duodenal ulcer patients in large, well-controlled studies. METHODS: More than 2900 patients with endoscopically diagnosed non-NSAID duodenal ulcers were enrolled in a series of six placebo-controlled, double-blind studies conducted in the United States that assessed H. pylori using a combination of tests. Patients were considered infected with H. pylori only if culture growth was observed, or both histological and CLOtest results were positive. Patients were considered uninfected if the results of at least two tests were negative. Patients with missing test results, results of only a single test, or conflicting test results were not evaluable for H. pylori assessment. RESULTS: Of the 2394 endoscopically diagnosed evaluable duodenal ulcer patients, 73% (1737) were confirmed infected with H. pylori at study entry. CONCLUSIONS: The results of six carefully designed and controlled studies suggest that an assumed H. pylori infection rate of approximately 95% may overestimate the actual rate of H. pylori infection in duodenal ulcer patients in the United States. Although H. pylori infection is an important factor in the etiology of noniatrogenic duodenal ulcer disease, other factors may predominate in some patients and should not be overlooked in determining an appropriate course of treatment. The empiric use of antibiotic therapy for ulcer patients without confirmation of the presence of H. pylori cannot be recommended.

Twice-daily versus thrice-daily clarithromycin in combination with ranitidine bismuth citrate in the eradication of Helicobacter pylori.

BACKGROUND: Ranitidine bismuth citrate (RBC), 400 mg bid for 4 weeks, plus clarithromycin, 500 mg tid, is a regimen approved by the US Food and Drug Administration for the eradication of Helicobacter pylori in patients with duodenal ulcers. Proof that the clarithromycin portion of the regimen could be given twice daily without loss of efficacy would reduce cost and improve patient compliance. The objective of this study was to compare the H. pylori eradication rates in patients who had duodenal ulcer and were randomly assigned to 4 weeks of treatment with RBC, 400 mg bid, in conjunction with 2 weeks of therapy with either clarithromycin, 500 mg tid, or clarithromycin, 500 mg bid. PATIENTS AND METHODS: Patients who had a duodenal ulcer and were H. pylori-positive by at least two tests were randomly assigned to (1) RBC, 400 mg bid for 4 weeks, plus clarithromycin, 500 mg tid for 2 weeks, or (2) RBC, 400 mg bid for 4 weeks, plus clarithromycin, 500 mg bid for 2 weeks. H. pylori eradication was assessed 4 weeks after completion of RBC plus clarithromycin. RESULTS: Three hundred eighty-three patients from 78 centers had a duodenal ulcer and were H. pylori-positive. The modified intent-to-treat (MITT) and the per-protocol (PP) eradication rates were statistically equivalent between the twice-daily (65% MITT, 74% PP) and thrice-daily (63% MITT, 73% PP) clarithromycin treatment regimens. Incidence and types of adverse events did not differ between the two groups. CONCLUSIONS: For eradicating H. pylori in patients with duodenal ulcer, clarithromycin, 500 mg bid for 2 weeks, with RBC, 400 mg bid for 4 weeks, is equivalent to clarithromycin, 500 mg tid with RBC. The potential enhancement of patient compliance, reduced cost of clarithromycin, and equivalent efficacy would support the use of twice-daily clarithromycin in triple-therapy regimens with RBC.

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.

An alternative non-macrolide, non-imidazole treatment regimen for curing Helicobacter pylori and duodenal ulcers: ranitidine bismuth citrate plus amoxicillin. The RBC H. pylori Study Group.

BACKGROUND: Because patients who fail to be cured of H. pylori infection following macrolide or imidazole therapy are difficult to treat, there is a clear need for a reasonably effective and simple second-line treatment regimen. The purpose of these two studies was to evaluate the efficacy of ranitidine bismuth citrate (RBC) plus amoxicillin for the cure of H. pylori infection and for healing duodenal ulcers and preventing ulcer relapse. MATERIALS AND METHODS: Two identically designed randomized, double-blind, double-dummy studies were conducted in patients with an H. pylori-associated duodenal ulcer. Patients were treated with either RBC 400 mg bid for 4 weeks plus amoxicillin 500 mg qid for 2 weeks, RBC 400 mg bid for 4 weeks and placebo qid for 2 weeks, placebo bid for 4 weeks and amoxicillin 500 mg qid for 2 weeks, or placebo bid for 4 weeks and placebo qid for 2 weeks. Patients with healed ulcers after 4 weeks of treatment were eligible for entry into a 24-week observation phase for the assessment of H. pylori status (culture, histology, and CLOtest) and ulcer relapse. RESULTS: A total of 229 patients with confirmed H. pylori infection at baseline were evaluated. Of these, 132 whose ulcers had healed entered the 24-week posttreatment observation phase. The combination of RBC plus amoxicillin resulted in higher H. pylori cure rates (55%) and higher duodenal ulcer healing (74%) than did either treatment alone. All treatment were well tolerated. CONCLUSIONS: The combination of ranitidine bismuth citrate plus amoxicillin cures H. pylori infection in more than half of the patients treated. This treatment regimen shows promise as the basis for future non-macrolide, non-imidazole triple therapy regimens for curing H. pylori infection. Such regimens may be appropriate second-line treatment for patients who are resistant to or who are unable to tolerate macrolide- or imidazole-containing therapies.

Ranitidine bismuth citrate plus clarithromycin is effective for healing duodenal ulcers, eradicating H. pylori and reducing ulcer recurrence. RBC H. pylori Study Group.

AIM: To compare the efficacy of the coadministration of ranitidine bismuth citrate plus the antibiotic clarithromycin, with ranitidine bismuth citrate alone or clarithromycin alone for the healing of duodenal ulcers, eradication of H. pylori and the reduction of ulcer recurrence. METHODS: This two-phase, randomized, double-blind, placebo-controlled, multicentre study consisted of a 4-week treatment phase followed by a 24-week post-treatment observation phase. Patients with an active duodenal ulcer were treated with either ranitidine bismuth citrate 400 mg b.d. for 4 weeks plus clarithromycin 500 mg t.d.s. for the first 2 weeks; ranitidine bismuth citrate 400 mg b.d. for 4 weeks plus placebo t.d.s. for first 2 weeks; placebo b.d. for 4 weeks plus clarithromycin 500 mg t.d.s. for the first 2 weeks; or placebo b.d. for 4 weeks plus placebo t.d.s. for the first 2 weeks. RESULTS: Ulcer healing rates after 4 weeks of treatment were highest with ranitidine bismuth citrate plus clarithromycin (82%) followed by ranitidine bismuth citrate alone (74%; P = 0.373), clarithromycin alone (73%; P = 0.33) and placebo (52%; P = 0.007). Ranitidine bismuth citrate plus clarithromycin provided significantly better ulcer symptom relief compared with clarithromycin alone or placebo (P < 0.05). The coadministration of ranitidine bismuth citrate plus clarithromycin resulted in significantly higher H. pylori eradication rates 4 weeks post-treatment (82%) than did treatment with either ranitidine bismuth citrate alone (0%; P < 0.001), clarithromycin alone (36%; P = 0.008) or placebo (0%; P < 0.001). Ulcer recurrence rates 24 weeks post-treatment were lower following treatment with ranitidine bismuth citrate plus clarithromycin (21%) compared with ranitidine bismuth citrate alone (86%; P < 0.001), clarithromycin alone (40%; P = 0.062) or placebo (88%; P = 0.006). All treatments were well tolerated. CONCLUSIONS: The coadministration of ranitidine bismuth citrate plus clarithromycin is a simple, well-tolerated and effective treatment for active H. pylori-associated duodenal ulcer disease. This treatment regimen effectively heals duodenal ulcers, provides effective symptom relief, eradicates H. pylori infection and reduces the rate of ulcer recurrence. The eradication of H. pylori infection in patients with recently healed duodenal ulcers is associated with a significant reduction in the rate of ulcer recurrence.

Effects of sucralfate and ranitidine on aluminum concentrations in elderly volunteers.

Elevated aluminum concentrations have been implicated in several disease states in the elderly. We examined the effects of sucralfate, a basic aluminum salt of sucrose sulfate, and ranitidine, administered individually and in combination, on plasma and urine aluminum concentrations in the elderly in a prospective, randomized, three-arm crossover study. Subjects were 20 healthy volunteers over age 65 years, with no clinically significant comorbidities or recent use of aluminum-containing drugs or histamine (H)2-antagonists. The three regimens were ranitidine 300 mg at bedtime, sucralfate 1 g 4 times/day, and ranitidine 300 mg at bedtime plus sucralfate 1 g 4 times/day, administered for 4 weeks, with a washout period of at least 1 week between regimens. Plasma and urine aluminum concentrations were measured on days 0, 1, 7, 14, and 28 of each regimen. After 28 days, mean plasma aluminum concentrations were significantly higher in subjects receiving sucralfate alone (8.5 +/- 1.8 micrograms/L) and sucralfate plus ranitidine (5.1 +/- 1.3 micrograms/L) compared with those receiving ranitidine alone (2.4 +/- 0.7 micrograms/L). Urine aluminum concentrations were significantly higher in subjects receiving sucralfate alone (133.2 +/- 32.8 micrograms/g creatinine) and sucralfate plus ranitidine (148.1 +/- 51.9 micrograms/g creatinine) compared with those receiving ranitidine alone (11.0 +/- 3.7 micrograms/g creatinine). There was no significant difference in plasma or urine aluminum concentrations between subjects who received sucralfate alone versus those who received sucralfate plus ranitidine. Sucralfate 4 g/day in elderly subjects produces a significant increase in both plasma and urine aluminum concentrations, compared with ranitidine 300 mg/day. This increase most likely is secondary to gastrointestinal absorption of aluminum in the sucralfate formulation. The clinical relevance of this increase requires further evaluation.

Ranitidine 300 mg at bedtime is effective for gastric ulcers: a 12-wk, multicenter, randomized, double-blind, placebo-controlled comparison. The Ranitidine 300 mg HS Gastric Ulcer Study Group.

Ranitidine 150 mg twice daily is effective for the treatment of gastric ulcers. We proposed that ranitidine 300 mg once daily would also be effective. In a randomized, double-blind, placebo-controlled, multicenter, parallel-group study, adults with an endoscopically verified acute gastric ulcer > or = 5 mm were treated with either ranitidine 300 mg (n = 183) or placebo (n = 178) at bedtime for up to 12 wk. Gastric ulcer healing, determined by endoscopy, was achieved in 65% and 89% of ranitidine-treated patients by 6 and 12 wk, compared with 45% and 72% of placebo-treated patients by 6 wk and 12 wk (p < 0.001). Throughout the 12-wk study, ranitidine 300 mg was significantly more effective than placebo in relieving pain (p < 0.05), with ranitidine-treated patients also using fewer antacid tablets. Ranitidine 300 mg had a safety profile similar to that of placebo. We conclude that ranitidine 300 mg at bedtime is safe and effective for healing acute gastric ulcers.