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-HT(4) 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.

Factors motivating dyspepsia patients to enter clinical research.

One of the most influential factors in science and medicine has been the development of placebo-controlled clinical trials. However, recruitment of patients for clinical trials is sometimes a major problem in clinical research. Successful patient recruitment may be enhanced with a clear understanding of the motivating factors that determine a patient's decision to enter a study. We have developed the Patients' Expectations, Attitudes and Knowledge (PEAK) Program consisting of questionnaires designed to study the factors motivating patients to enter a clinical trial, as well as capturing the experiences of research participants. A total of 247 female patients with dyspepsia (mean age: 43.9; range: 18.0-78.0 years) who entered either of two prospective double-blind, randomized, placebo-controlled multicenter trials in the USA completed PEAK Entry questionnaires during the first study visit. Based on their responses, the top three factors motivating patients to join the clinical trial were: interest in receiving investigational treatment with average score (AS) of 4.33 +/- 0.08 (M +/- SEM) on a 5-point scale, possibility of getting skilled professional care (AS = 4.07 +/- 0.09), and altruism expressed as an intention to help develop a new drug for the sake of other people (AS = 3.89 +/- 0.09). Age, ethnicity, and educational status significantly affected motivational factors of patients. These results indicate that recruitment can be enhanced by targeting these motivations in physician/patient communications, informed consent process and advertising for study participants.

Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function.

Disorders of gastrointestinal function are common and significantly reduce quality-of-life, as well as negatively impacting healthcare costs. Consequently, there is much interest in understanding the pathogenesis of these disorders. Increasing, albeit as yet limited, evidence has implicated alterations in 5-hydroxytryptamine (5-HT) release, and the subsequent interaction of 5-HT with specific 5-HT receptor subtypes, in the altered gut function of patients with irritable bowel syndrome (IBS) and other functional bowel diseases. Alterations to enterochromaffin cells and/or 5-HT signaling can result in gastrointestinal dysmotility, visceral hypersensitivity and secretomotor abnormalities in the gut. Evidence is beginning to link disturbed 5-HT physiology with the pathophysiology of diarrhea and constipation in IBS, and with slow-transit constipation. This review discusses the current evidence on the pathobiology of these systems.

G protein-coupled receptor desensitization as a measure of signaling: modeling of arrestin recruitment to activated CCK-B receptors.

Gastrin is one of the principle hormonal mediators of gastric acid secretion, and its cognate receptor (CCK-B) is a member of the superfamily of GPCRs. Patients with hypergastrinemia may present with a variety of symptoms, including gastric ulcers or malignant tumors. Thus, the molecular mechanisms that terminate CCK-B receptor signaling, as well as an ability to measure gastrin bioactivity in a timely manner, have important clinical implications. In order to assess CCK-B receptor regulation, we have constructed a single cell biosensor containing the CCK-B receptor and an arrestin/GFP chimera. The gastrin biosensor responded to both immunologically detectable gastrin-17 and undetectable pentagastrin, and was able to determine the gastrin bioactivity of serum from a patient with clinical hypergastrinemia. We determined that the CCK-B receptor binds arrestin with a pharmacology mirroring CCK-B receptor signaling through inositol phosphate, and that the rate of arrestin dissociation from internalized receptor mirrors receptor recycling to the plasma membrane. Moreover, the CCK-B recycling rate is intermediate between that of Class A GPCRs such as the beta2-adrenergic receptor and Class B GPCRs such as the vasopressin type 2 receptor. Mathematical modeling of these results indicates that a common receptor conformation may underlie both CCK-B signaling and desensitization. In addition to its use in drug screening, this methodology should generalize to other receptors for use in diagnosis and monitoring of bioactive ligands involved in GPCR-based disease.

Effect of tegaserod on esophageal pain threshold, regurgitation, and symptom relief in patients with functional heartburn and mechanical sensitivity.

BACKGROUND & AIMS: Tegaserod, a 5-HT4-receptor partial agonist, effectively treats irritable bowel syndrome with constipation. The role of tegaserod in functional disorders of the upper gastrointestinal (GI) tract is unclear. The aims of this study were to determine if tegaserod improves esophageal pain with mechanical and chemical stimuli, GI symptom profile, and global preference in patients with functional heartburn. METHODS: Patients with functional heartburn, as defined by Rome II criteria, underwent esophageal barostat and acid-infusion sensory tests. Mechanical hypersensitivity was required for entry. The baseline GI symptom profile was rated before treatment. Patients were blinded to treatment and randomly assigned to tegaserod 6 mg twice daily or placebo for 14 days, and crossed-over to the alternate treatment after 7 to 10 days of washout. Patients underwent sensory tests and rated GI symptoms after each treatment. Global treatment preference was completed at the end of the study. RESULTS: Forty-two patients (15 men, 27 women; age, 20-68 y) completed the study. The predominant baseline symptoms in addition to heartburn included upper-abdominal pain, upper-abdominal discomfort, regurgitation, chest pain, early satiety, and postmeal bloating. Tegaserod significantly increased balloon pressure to pain (P = .04) and the mean (P = .002) and maximum wall tension at pain (P = .0004). Tegaserod did not alter pain with acid infusion. Tegaserod significantly decreased the frequency of occurrence of heartburn/acid reflux (P = .004), regurgitation (P = .048), and distress from regurgitation (P = .039). The global preference for tegaserod was 63.4% vs 12.2% for placebo. CONCLUSIONS: Tegaserod improved the esophageal pain threshold to mechanical distention, and distressing upper-GI symptoms in patients with functional heartburn.

Safety, tolerability, and efficacy of tegaserod over 13 months in patients with chronic constipation.

OBJECTIVE: To assess the long-term safety and tolerability of tegaserod in patients with chronic constipation (CC). METHODS: This 13-month, uncontrolled extension study enrolled CC patients who completed a 12-wk randomized, double-blind, placebo-controlled core study. Patients receiving tegaserod 6 or 2 mg b.i.d. during the core study continued on the same dose; those receiving placebo were switched to tegaserod 6 mg b.i.d (placebo-to-tegaserod). Safety and tolerability were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs, and electrocardiograms. Symptom evaluations included patient satisfaction with bowel habit and bothersomeness of constipation, abdominal distension/bloating, and abdominal discomfort/pain. RESULTS: A total of 842 patients entered the extension study; 451 (54%) completed. AEs typically occurred within the first month of tegaserod treatment. Long-term treatment neither increased AE incidence nor revealed new safety risks. Headache (11.3%, 14.5%, and 16.1% in the tegaserod 6 mg b.i.d., 2 mg b.i.d., and placebo-to-tegaserod groups, respectively) and abdominal pain (8.8%, 8.8%, 10.9%) were the most common AEs. Diarrhea, the most common drug-related AE (4.9%, 2.5%, 8.0%), rarely led to discontinuation (0.7%, 0.0%, 2.2%). Diarrhea was transient, resolved without treatment interruption or rescue medication, and had no clinically significant consequences. Of 27 serious AEs, none were considered treatment related. No deaths or reports of ischemic colitis occurred in tegaserod-treated patients. No clinically relevant changes occurred in other safety parameters. Safety findings were similar in patients switched from placebo to tegaserod and those maintained on tegaserod. CONCLUSIONS: Tegaserod has a favorable safety profile and is well tolerated during continuous long-term treatment in patients with CC.

Gastrointestinal bleeding in adult patients with Meckel's diverticulum: the role of technetium 99m pertechnetate scan.

Obscure gastrointestinal (GI) bleeding is often challenging for the primary care physician, but with improved diagnostic testing the cause of this blood loss is determined in most patients. However, approximately 5% of the time no underlying cause is found. One common etiology in patients younger than 40 years of age is a Meckel's diverticulum. The technetium 99m pertechnetate scan is the standard test for making this diagnosis. However, the sensitivity of the scan is only 62% in the adult population. In this case report, a patient with profound, hemodynamically significant GI blood loss had multiple negative studies. Subsequently, an abnormal vascular lesion was detected and during exploratory laparotomy, a Meckel's diverticulum was found and removed. Although the technetium pertechnetate scan is falsely negative in a number of cases, there are ways to increase its sensitivity and possibly avoid repeated testing.

Vasoactive intestinal polypeptide type-1 receptor regulation. Desensitization, phosphorylation, and sequestration.

The vasoactive intestinal polypeptide type-1 (VPAC(1)) receptor is a class II G protein-coupled receptor, distinct from the adrenergic receptor superfamily. The mechanisms involved in the regulation of the VPAC(1) receptor are largely unknown. We examined agonist-dependent VPAC(1) receptor signaling, phosphorylation, desensitization, and sequestration in human embryonic kidney 293 cells. Agonist stimulation of cells overexpressing this receptor led to a dose-dependent increase in cAMP that peaked within 5-10 min and was completely desensitized after 20 min. Cells cotransfected with the VPAC(1) receptor (VPAC(1)R) and G protein-coupled receptor kinases (GRKs) 2, 3, 5, and 6 exhibited enhanced desensitization that was not evident with GRK 4. Immunoprecipitation of the epitope-tagged VPAC(1) receptor revealed dose-dependent phosphorylation that was increased with cotransfection of any GRK. Agonist-stimulated internalization of the VPAC(1)R peaked in 10 min, and neither overexpressed beta-arrestin nor its dominant-negative mutant altered internalization. However, a dynamin-dominant negative mutant did inhibit VPAC(1) receptor internalization. Interestingly, VPAC(1)R specificity in desensitization was not evident by study of the overexpressed receptor; however, we determined that human embryonic kidney 293 cells express an endogenous VPAC(1)R that did demonstrate dose-dependent GRK specificity. Therefore, VPAC(1) receptor regulation involves agonist-stimulated, GRK-mediated phosphorylation, beta-arrestin translocation, and dynamin-dependent receptor internalization. Moreover, study of endogenously expressed receptors may provide information not evident in overexpressed systems.