tegaserod and Flatulence

The post-withdrawal characteristics of tegaserod treatment in patients with irritable bowel syndrome with constipation remain undefined.. To evaluate the effects of continuous tegaserod treatment, versus intermittent or withdrawal of treatment in patients with irritable bowel syndrome with constipation.. In a randomized, open-label trial, all patients initially received tegaserod 6 mg b.d. Responders were randomized to continue or withdraw from treatment for 8 weeks and symptom recurrence was assessed. Tegaserod was re-introduced in withdrawal patients who experienced symptom recurrence, allowing an assessment of intermittent treatment. Two separate analyses assessed the effects of intermittent and withdrawal of treatment on symptom recurrence.. Five hundred irritable bowel syndrome with constipation patients initially received tegaserod; 410 completed treatment. Time to symptom recurrence was shorter in withdrawal patients than those maintained on tegaserod. Significantly more patients maintained on tegaserod had not experienced symptom recurrence by week 8, compared with intermittent (86.5% vs. 58.1%, respectively) or withdrawal of treatment (69.2% vs. 11.3%, respectively) (P < 0.0001 for both). Significant treatment effects were observed for bloating (P < 0.01) and abdominal pain/discomfort (P < 0.02). Most adverse events were mild to moderate.. Irritable bowel syndrome with constipation patients who receive continuous or intermittent tegaserod are less likely to experience symptom recurrence than patients withdrawn from treatment.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Constipation; Female; Flatulence; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Recurrence; Treatment Outcome; Withholding Treatment

The purpose of the present study was to assess the pharmacokinetics of the novel selective 5-HT4 receptor agonist SDZ HTF 919 (HTF) including food effect, absolute bioavailability, interoccasion and intersubject variabilities.. In the randomized, open-label, three treatment, four period crossover study, HTF was administered to 12 young healthy male subjects as a 12 mg tablet (twice under fasted and once under fed conditions) and a 3 mg intravenous (i.v.) infusion over 40 min (fasted). Pharmacokinetic parameters were obtained by noncompartmental methods. A more comprehensive pharmacokinetic characterization was achieved by integrated modelling of oral (p.o.) and i.v. data. To describe the absorption phase a Weibull function and a classical first order input function were compared.. Noncompartmental pharmacokinetic analysis revealed a rapid absorption (tmax 1.3 h, fasted), an absolute bioavailability of 11+/-3%, a biphasic disposition phase with a terminal half-life of 11+/-5 h, a clearance of 77+/-15 l h-1, and a volume of distribution at steady state of 368+/-223 l. The coefficients of interoccasion and interindividual variability in Cmax and AUC ranged between 17 and 28%. Food intake caused a delay (tmax 2.0 h) and decrease in absorption with consequently lower systemic exposure ( approximately 5% absolute bioavailability). Integrated p.o./i.v. pharmacokinetic modelling with a Weibull input function allowed accurate description of individual profiles. Modelling of the data from the p.o. dosing improved the description of the terminal phase by inclusion of the i. v. data and additionally provided quantitative characterization of the absorption phase.. The pharmacokinetics of HTF could be well described by an integrated modelling approach for both p.o. and i.v. data. The derived model will provide guidance in the design of future studies.

Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Eating; Electrocardiography; Fasting; Flatulence; Headache; Humans; Indoles; Infusions, Intravenous; Male; Metabolic Clearance Rate; Serotonin Receptor Agonists; Treatment Outcome

Topics: Abdominal Pain; Constipation; Diarrhea; Female; Flatulence; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Probiotics

Bloating in irritable bowel syndrome (IBS) may result from impaired intestinal gas transit and is reduced by the 5-HT4 agonist tegaserod. Abnormal serotonergic function underlies many IBS symptoms, but the role of 5-HT4 pathways in regulating gas dynamics under healthy conditions is unexplored. We hypothesized that 5-HT4 activation by tegaserod stimulates gas transit in healthy individuals.. Sixteen normal volunteers underwent jejunal perfusion of gas mixtures (88% N2, 5.5% O2, 6.5% CO2) at 11.2 mL/min x 3 h under control conditions and 3 h after oral tegaserod 6 mg on separate days. Gas collected from an intrarectal catheter was quantified using a barostat.. Under control conditions, gas evacuation after a lag period (1,959 +/- 428 s) was predominantly pulsatile with expulsion of 1,984 +/- 90 mL. A mean of 29 +/- 2 boluses with volumes of 72 +/- 5 mL were expelled. In 10 subjects with physiologic degrees of gas retention in control studies (248 +/- 73 mL), tegaserod increased expulsion from 1,768 +/- 73 to 1,973 +/- 37 mL and decreased retention to 43 +/- 37 mL (p < 0.05). Total volumes expelled as boluses were greater after tegaserod (1,708 +/- 73 vs 1,846 +/- 59 mL, p < 0.05) from increased bolus numbers in four subjects and increased bolus volumes in seven. Nonpulsatile continuous flow tended to increase with tegaserod (43 +/- 7 vs 126 +/- 43 mL, p= 0.10). Tegaserod did not increase evacuation in individuals without physiologic gas retention.. The 5-HT4 agonist tegaserod promotes evacuation of jejunally perfused gas mixtures in healthy humans. These findings provide the foundation for future investigations into use of 5-HT4 agonists in conditions of pathologic gas retention.

Topics: Administration, Oral; Adult; Female; Flatulence; Gases; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Indoles; Male; Middle Aged