Tegaserod for female patients suffering from IBS with mixed bowel habits or constipation: a randomized controlled trial

OBJECTIVES: Though the greatest proportion of irritable bowel syndrome (IBS) patients report a mixed bowel pattern (IBS-Mixed), no available therapies have been rigorously evaluated in this subgroup. This study aimed to evaluate the efficacy and safety of the 5-HT₄ agonist tegaserod in women with IBS-Mixed and IBS with constipation (IBS-C).
METHODS: This prospective, double-blind, randomized, placebo-controlled, multicenter study was conducted in 100 centers in North America, South America, and Europe. Women with IBS-Mixed or IBS-C received tegaserod 6 mg or placebo twice daily. The primary efficacy variable was the patient's assessment of satisfactory relief over the 4-wk treatment period. The proportion of patients reporting satisfactory relief for ≥3 of 4 treatment weeks (75% rule) and individual IBS symptoms were assessed.
RESULTS: In total, 661 women were randomized (IBS-Mixed 324, IBS-C 337). Baseline symptom assessments identified clear differences between the two cohorts. Tegaserod provided significant improvement in satisfactory relief of IBS symptoms over 4 wk (OR 1.75, 95% CI 1.35–2.25, P < 0.001) in both IBS-Mixed and IBS-C patients. Using the 75% rule, 52.3% of tegaserod-receiving IBS-M patients and 43.3% of IBS-C patients were responders ( vs 36.3, OR 1.88, 95% CI 1.16–3.04, P < 0.010; and 28.9, OR 1.90, 95% CI 1.19–3.05, P < 0.008 for placebo, respectively). The most frequent adverse events leading to study discontinuation in tegaserod-treated patients were diarrhea (1.5%) and abdominal pain (0.9%). Overall 7% of IBS-C patients reported diarrhea compared to 12% of IBS-Mixed (placebo 2.4%, 1.8%, respectively).
CONCLUSIONS: Tegaserod is effective in treating overall IBS symptoms in patients with IBS-Mixed and IBS-C.     

Effect of cisplatin on myoelectric activity of the stomach and small intestine in dogs

The effect of cisplatin on interdigestive myoelectric activity (IDMA) of the gastric antrum, duodenum and jejunum, plasma concentration of motilin, and animal behavior was studied in seven conscious dogs with gastric cannulas and platinum electrodes implanted on the serosal surface of antrum and upper small intestine. Cisplatin given intravenously in a dose of 2 mg/kg resulted in complete interruption of IDMA and produced predominantly phase II-like activity, lasting as long as 24 hr. Six of the seven dogs exhibited retropropagation of spike bursts from the jejunum to the antrum which was accompanied by emesis. Retropropagation of spike bursts did not occur in one dog who did not exhibit emesis. In addition, abnormal spike bursts occurred frequently, including simultaneously occurring spike bursts in both duodenum and jejunum and nonpropagating short spike bursts in isolated segments of the upper small intestine. As phase III of IDMA disappeared, plasma motilin concentrations remained comparable to those in phase II of normal IDMA but without the cyclic increases. These studies indicate that cisplatin interrupts the regular cycle of IDMA as well as the plasma motilin cycle and produces retropropagation of spike bursts and abnormal spike bursts. These changes in both motility and plasma motilin levels may play a part in the mechanism of emesis induced by cisplatin in dogs.This work was supported in part by The Genesee Hospital Gastrointestinal Research Fund and by U.S. Public Health Service Research Grants CA11198 and CA11083.     

Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial.

BACKGROUND AND AIMS: Chronic constipation is a common gastrointestinal disorder. The aim of this study was to evaluate the efficacy, safety, and tolerability of tegaserod, a serotonin subtype 4 receptor partial agonist in patients with chronic constipation. METHODS: This was a randomized, double-blind, placebo-controlled study. After a 2-week baseline, patients received tegaserod 2 mg twice daily (n = 450), tegaserod 6 mg twice daily (n = 451), or placebo (n = 447) for 12 weeks, followed by a 4-week withdrawal period. Responders were those patients having been treated for at least 7 days with an increase of > or =1 complete spontaneous bowel movement/week vs. baseline during weeks 1-4 (primary variable) and weeks 1-12 (secondary variable). Other secondary variables included patient assessment of constipation symptoms (number of bowel movements, stool form, abdominal bloating/distention, straining, and abdominal pain/discomfort), and global assessment of constipation and bowel habits. RESULTS: Responder rates for complete spontaneous bowel movement during weeks 1-4 were significantly greater ( P < 0.0001) in the tegaserod 2 mg twice daily (41.4%) and 6 mg twice daily groups (43.2%) vs. placebo (25.1%). This effect was maintained over 12 weeks. Statistically significant improvements over placebo were observed across the majority of secondary variables for both tegaserod doses. No rebound effect was observed after treatment withdrawal. Tegaserod was well tolerated; headache and nasopharyngitis, the most frequent adverse events, were more common in the placebo group than in either tegaserod group. CONCLUSIONS: Over 12 weeks, tegaserod treatment produced significant improvements in chronic constipation symptoms and was also safe and well tolerated.     

Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis

BACKGROUND & AIMS: An attenuated form of familial adenomatous polyposis has been described, but the phenotype remains poorly understood. METHODS: We performed genetic testing on 810 individuals from 2 attenuated familial adenomatous polyposis kindreds harboring an identical germline adenomatous polyposis coli gene mutation. Colonoscopy was performed on mutation-positive persons. RESULTS: The disease-causing mutation was present in 184 individuals. Adenomatous polyps were present in 111 of 120 gene carriers who had colonoscopy at an average age of 41 years. The median number of adenomas was 25 (range, 0-470), with striking variability of polyp numbers and a proximal colonic predominance of polyps. Colorectal cancer occurred in 27 mutation carriers (average age, 58 years; range, 29-81 years), with 75% in the proximal colon. The cumulative risk of colorectal cancer by age 80 was estimated to be 69%. An average of 3.4 recurrent polyps (range, 0-29) were found in the postcolectomy rectal remnant over a mean of 7.8 years (range, 1-34 years), with 1 rectal cancer. CONCLUSIONS: This investigation shows that attenuated familial adenomatous polyposis in the kindreds examined shows a much smaller median number of polyps than typical familial adenomatous polyposis, a wide variability in polyp number even at older ages, and a more proximal colonic location of polyps and cancer, yet it is associated with an extremely high risk of colon cancer. The phenotype of attenuated familial adenomatous polyposis mimics typical familial adenomatous polyposis in some cases but in others is difficult to distinguish from sporadic adenomas and colorectal cancer, thus making genetic testing particularly important.     

Utility of the Rome I and Rome II criteria for irritable bowel syndrome in U.S. women

OBJECTIVES: Using interview data from a large, community-based sample of American women, we assessed the lifetime prevalence of irritable bowel syndrome (IBS) using questions consistent with the Rome II criteria, determined the sensitivity of Rome I and II in women diagnosed with IBS by their community physician, and identified whether there are differences in the patients identified by Rome I versus II. METHODS: A geographically diverse national probability sample of women diagnosed with IBS was identified and interviewed by telephone screening of a national, random digit dialing sample of households. A parallel national survey of adult females was conducted to determine the lifetime prevalence of IBS in U.S. women. Screening and interviews were conducted by experienced, female interviewers. IBS was defined by variations on the Rome I/II criteria. RESULTS: In the national community sample, lifetime IBS prevalence was 5.4% using Rome II. Full interviews were completed in 1,014 IBS patients. In the IBS sample, Rome I was significantly more sensitive than Rome II (84% vs 49%, p < 0.001). There was 47% agreement between Rome I and II. Of patients with IBS by Rome I, 58% met Rome II. Only 17.7% did not meet either Rome I or II. CONCLUSIONS: Rome I was more sensitive than Rome II in this community sample of female IBS patients. Rome I/II do not necessarily identify the same IBS patients. These findings have important implications for clinical research in IBS patients and raise questions about whether the Rome II criteria are sensitive enough to be useful in clinical practice.     

Bethanechol or cimetidine in the treatment of symptomatic reflux esophagitis: a double-blind control study

We conducted a double-blind study to compare the effectiveness of oral bethanechol chloride or cimetidine in treating reflux esophagitis to evaluate the drugs' effects on the symptoms of esophagitis and its verification by endoscopy. Forty-three patients were treated with either 300 mg of cimetidine or 25 mg of bethanechol chloride, each administered four times a day for six weeks. In addition to this drug treatment, the patients all received conventional medical therapy. Patients who were treated with either of the two drugs experienced a decrease in symptoms and less severe endoscopic lesions. While cimetidine treatment resulted in complete endoscopic healing in 15 of 22 patients, bethanechol treatment resulted in the same healing in 11 of 21 patients. During therapy, neither endoscopic lesions or symptoms worsened. Our study indicated that either cimetidine or bethanechol is an effective drug in treating reflux esophagitis. The effects of the two drugs can be favorably compared.     

Watery diarrhea associated with pancreatic islet cell carcinoma.

A patient with severe watery diarrhea and a non-beta islet cell carcinoma of the pancreas producing five hormones (secretin, serotonin, enteroglucagon, vasoactive intestinal polypeptide, and pancreatic glucagon) is described. We have demonstrated massive pancreatic hypersecretion to be a major factor in this patient's diarrhea. Possible inter-relationships of the actions of five hormones present in excess in the patient are discussed.