tegaserod and Colonic-Diseases--Functional

The 5-HT(4) partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5-HT(4) receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5-HT(4) receptors enhances the release of acetylcholine and calcitonin gene related peptide from stimulated nerve terminals. This action strengthens neurotransmission in prokinetic pathways, enhancing gastrointestinal motility. The knockout of 5-HT(4) receptors in mice not only slows gastrointestinal activity but also, after 1 month of age, increases the age-related loss of enteric neurons and decreases the size of neurons that survive. 5-HT(4) receptor agonists, tegaserod and RS67506, increase numbers of enteric neurons developing from precursor cells and/or surviving in culture; they also increase neurite outgrowth and decrease apoptosis. The 5-HT(4) receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5-HT(4)-mediated. 5-HT(4) receptor agonists, therefore, are neuroprotective and neurotrophic for enteric neurons. Because the age-related decline in numbers of enteric neurons may contribute to the dysmotilities of the elderly, the possibility that the neuroprotective actions of 5-HT agonists can be utilized to prevent the occurrence or worsening of these conditions should be investigated.

Topics: Animals; Colonic Diseases, Functional; Constipation; Enteric Nervous System; Gastrointestinal Agents; Humans; Indoles; Neurons; Neuroprotective Agents; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Receptor Agonists; Synapses

In the USA, tegaserod is contraindicated in patients with a history of bowel obstruction, abdominal adhesions or symptomatic gall-bladder disease due to a non-significant difference in abdominal surgery between tegaserod-using and placebo-using patients in Phase III trials.. To calculate the incidence of abdominal and pelvic surgery in tegaserod-using and placebo-using patients in randomized controlled trials and to assess the possible association between medication and surgery, using pre-specified criteria in a blind adjudication procedure.. Primary study selection criteria included: (i) randomized controlled trial; (ii) comparison of tegaserod vs. placebo; and (iii) results reporting the incidence of abdominal and pelvic surgery. A panel of experts in epidemiology and functional bowel disorders reviewed the history of each patient who underwent surgery. Experts were blind with regard to whether patients used tegaserod or placebo. Using pre-specified criteria, experts rated the likelihood of an association between medication use and surgery.. Thirteen randomized controlled trials (n =9857 patients) met the primary study selection criteria. No significant difference in the incidence of abdominal/pelvic surgery was identified between tegaserod-using and placebo-using patients: pelvic surgery, 0.16% vs. 0.19% (P = 0.80); abdominal surgery (non-cholecystectomy), 0.15% vs. 0.19% (P = 0.61); cholecystectomy, 0.13% vs. 0.03% (P = 0.17); total abdominal/pelvic surgery, 0.44% vs. 0.41% (P = 1.00). Post-adjudication, there was no significant difference in the incidence of abdominal/pelvic surgery between tegaserod-using and placebo-using patients.. Data from randomized controlled trials demonstrate a similar incidence of abdominal/pelvic surgery in tegaserod-using and placebo-using patients.

Topics: Abdomen; Adolescent; Clinical Trials, Phase III as Topic; Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Pelvis; Randomized Controlled Trials as Topic

The treatment of irritable bowel syndrome with constipation (IBS-C) has historically been based on the severity of symptoms, with education, reassurance, dietary advice, bulking agents and laxative therapy offered as appropriate. Tegaserod (Zelnorm, Zelmac) is the first selective serotonin 5-HT(4) receptor partial agonist to be approved for the treatment of this syndrome. Tegaserod is active against multiple irritable bowel syndrome (IBS) symptoms; it stimulates gut motility and reduces visceral sensitivity and pain. The drug does not cure IBS and was not designed to treat the diarrhoea-predominant version. Its efficacy in men has not been established. Three large well designed clinical trials of tegaserod 6 mg twice daily for 12 weeks in patients (mainly women) with IBS-C have demonstrated superiority versus placebo in global relief from symptoms. Global relief response rates were 38.4-46.8% with tegaserod 6 mg twice daily and 28.3-38.8% with placebo (p < 0.05-0.0001 vs placebo). The relative increases in response rates with tegaserod 6 mg twice daily over the already high responses in the placebo groups ranged from 12-65% after 4-12 weeks of treatment. A response was seen within the first week. The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels during this time. Diarrhoea has been associated with tegaserod in clinical trials (an incidence of about 10% versus 5% with placebo, usually occurring in the first week of treatment), but the drug is otherwise well tolerated. There were no apparent changes in the tolerability profile with extended tegaserod treatment (

Topics: Biological Availability; Colonic Diseases, Functional; Constipation; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestinal Absorption; MEDLINE; Randomized Controlled Trials as Topic; Treatment Outcome

Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.

Topics: Carbolines; Colonic Diseases, Functional; Humans; Indoles; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Antidepressive Agents; Benzofurans; Carbazoles; Carbolines; Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Physical Examination; Pyridines

Topics: Colonic Diseases, Functional; Constipation; Female; Humans; Indoles; Placebos; Randomized Controlled Trials as Topic; Safety; Serotonin Receptor Agonists; Treatment Outcome

Tegaserod is a selective partial agonist acting on serotonergic type 4 receptors (5-HT(4)). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT(4) agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.

Topics: Animals; Biological Availability; Clinical Trials as Topic; Colonic Diseases, Functional; Drug Interactions; Half-Life; Humans; Indoles; Intestinal Absorption; Serotonin Receptor Agonists; Tissue Distribution

Irritable bowel syndrome (IBS) is a common disorder with major health status and economic effects. Symptom criteria are of paramount importance in diagnosis, but differences among the Manning, Rome I, and Rome II criteria may lead to variable identification of people with the disorder. Practice guidelines are based on evidence and, to a greater degree, on consensus; therefore, experts vary on the specifics of ordering particular diagnostic tests. There is an overlap of IBS symptoms with those of celiac sprue, and selected patients should be tested for the latter disease. Symptom confusion with biliary pain and overlap with chronic pelvic pain could contribute to the predisposition of IBS patients to undergo cholecystectomy and hysterectomy. Development and documentation of effective therapy has been difficult, but depending on the selection of subgroups, there is evidence for usefulness of smooth muscle relaxants, loperamide, and antidepressants. Various forms of psychological therapy and new serotonin-modulating agents seem especially promising. The placebo effect of the physician-patient relationship has important therapeutic benefit.

Topics: Anti-Bacterial Agents; Carbolines; Celiac Disease; Clinical Trials as Topic; Colonic Diseases, Functional; Diagnosis, Differential; Female; Forecasting; Gastrointestinal Agents; Humans; Indoles; Male; Prognosis; Risk Assessment; Severity of Illness Index

To assess the clinical effectiveness of tegaserod for the treatment of irritable bowel syndrome (IBS).. Systematic review.. Six placebo-controlled, randomized controlled trials (RCTs) retrieved from electronic searches (Medline, Embase, FDA website) and hand-searching.. Any outcome was accepted.. In a small pharmacodynamic study, tegaserod 4 mg/day accelerated orocecal transit compared with placebo, but did not affect gastric emptying rate and colonic transit. Five placebo-controlled studies evaluated Subject's Global Assessment of gastrointestinal (GI) symptoms in predominantly female patients who fulfilled Rome criteria for constipation-predominant IBS. Responder rates were higher with tegaserod 1-24 mg/day than with placebo, although it was not possible in this review to evaluate the consistency of this effect, to fully quantify the effect size, or identify patients who may gain most benefit from this treatment.. Currently published data on tegaserod for IBS are limited (two of six RCTs published in full, four as abstracts). Tegaserod may be an appropriate treatment for occasional use for relief of GI symptoms associated with constipation-predominant IBS. Further research, comparing tegaserod with alternative treatments for GI symptoms of IBS, should help define the place of this drug in therapy.

Topics: Adolescent; Adult; Child; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Humans; Indoles

Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT(4) receptor partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who identify abdominal pain or discomfort and constipation as their predominant symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS. Tegaserod is rapidly absorbed following oral administration; peak plasma concentrations (C(max)) are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the C(max) by 20 to 40%. Systemic exposure to tegaserod is not significantly altered at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is approximately 98% bound to plasma proteins, primarily to alpha(1)-acid glycoprotein, and has a volume of distribution at steady-state of 368 +/- 223L. Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT(4) receptors and is devoid of promotile activity. The second is direct glucuronidation which leads to generation of three isomeric N-glucuronides. The plasma clearance of tegaserod is 77 +/- 15 L/h, with an estimated terminal half-life of 11 +/- 5 hours following intravenous administration. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine, primarily as M 29.0. The pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg given twice daily for 5 days, with no relevant accumulation. The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild to moderate hepatic or renal impairment. Tegaserod should not be used in patients with severe hepatic or renal impairment. No clinically relevant drug-drug interactions with tegaserod have been identified. In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP) 1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate), digoxin, warfa

Topics: Animals; Clinical Trials as Topic; Colonic Diseases, Functional; Dose-Response Relationship, Drug; Drug Interactions; Female; Gastrointestinal Agents; Humans; Indoles; Kidney Diseases; Lactation; Liver Diseases; Pregnancy; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists

Topics: Antidepressive Agents, Tricyclic; Antidiarrheals; Behavior Therapy; Carbolines; Cathartics; Colonic Diseases, Functional; Diagnosis, Differential; Humans; Indoles; Loperamide; North America; Parasympatholytics; Randomized Controlled Trials as Topic; Research Design; Serotonin Antagonists; Serotonin Receptor Agonists; Severity of Illness Index; Treatment Outcome

Tegaserod is a medication that has been shown to be of benefit in women with irritable bowel syndrome (IBS) associated with abdominal pain, bloating, and constipation. Tegaserod is a selective serotonin receptor subtype 4 partial agonist designed to interact with the network of cells and nerves throughout the gastrointestinal tract that use serotonin. Tegaserod has been shown to modulate both gastrointestinal motility and visceral sensitivity. Specifically, it increases the peristaltic reflex and decreases visceral sensitivity. Clinical studies have shown that tegaserod improves symptoms of abdominal pain, bloating, and constipation in women with IBS. This article discusses the role of serotonin in gastrointestinal tract physiology, the structure and pharmacokinetic profile of tegaserod, and clinical applications of this new drug.

Topics: Abdominal Pain; Animals; Colonic Diseases, Functional; Constipation; Female; Gastrointestinal Motility; Humans; Indoles; Serotonin; Serotonin Receptor Agonists

Tegaserod, a potent, partial serotonin 4 receptor (5-HT4) agonist, is an effective agent for the treatment of females with constipation-predominant irritable bowel syndrome. Tegaserod enhances gastric motility, stimulates peristaltic reflux and intestinal secretion, inhibits visceral sensitivity, and/or shortens colonic transit time. This agent may help women who have failed to respond to diet and exercise, laxatives, and other forms of therapy. The optimal dose of tegaserod is 6 mg twice daily and results in decreased number of days per month with pain, bloating, and days without bowel movements. Tegaserod is less effective in males than females in the treatment of constipation-predominant irritable bowel syndrome. Tegaserod is well tolerated. Diarrhea is the most frequent adverse effect. The diarrhea tends to occur most frequently during the first few months of therapy and decreases with continued administration.

Topics: Clinical Trials, Phase III as Topic; Colonic Diseases, Functional; Constipation; Diarrhea; Female; Humans; Indoles; Male; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; United States

Tegaserod (Zelmac), an aminoguanidine indole derivative of serotonin, is a selective partial agonist highly selective for 5-HT(4) receptor with an affinity constant in the nanomolar range. Tegaserod does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and distributes widely into tissues. Pharmacokinetics of oral tegaserod are linear in the 2--12 mg dose range. After oral administration tegaserod is metabolized mainly pre-systemically; when absorbed, intact tegaserod is excreted as N-glucuronides mainly via the bile. No clinically relevant drug--drug interactions were identified. Tegaserod has proven safe in toxicity studies. In pharmacodynamic studies, tegaserod stimulated the peristaltic reflex in vitro, increased canine intestinal and colonic motility and transit, reduced visceral afferent firing or sensation in response to distension in animals, and accelerated gastric, small bowel and colonic transit in healthy patients, and small bowel transit in patients with constipation-predominant irritable bowel syndrome. Three large phase III randomized, double-blinded, and placebo-controlled trials were performed predominantly in females (approximately 85%) with constipation-predominant irritable bowel syndrome. Overall, phase III results support efficacy as assessed by the subject's global assessment of relief with significant improvement in secondary endpoints such as abdominal pain, bowel frequency and consistency. Tegaserod was well-tolerated; the most frequent adverse event was transient diarrhoea.

Topics: Abdominal Pain; Absorption; Administration, Oral; Animals; Colonic Diseases, Functional; Diarrhea; Dogs; Female; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Indoles; Male; Patient Satisfaction; Randomized Controlled Trials as Topic; Treatment Outcome

The most important component of the treatment of irritable bowel syndrome (IBS) is to establish a therapeutic physician-patient relationship, coupled with patient education. We describe a stepwise approach to management, including judicious use of invasive tests, and setting realistic treatment goals that address the dominant symptoms, their severity, and psychosocial factors.

Topics: Abdominal Pain; Antidepressive Agents; Antidiarrheals; Carbolines; Cholinergic Antagonists; Colonic Diseases, Functional; Constipation; Diagnosis, Differential; Diarrhea; Diet; Follow-Up Studies; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Middle Aged; Parasympatholytics; Patient Education as Topic; Physician-Patient Relations; Psychotherapy; Randomized Controlled Trials as Topic; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Topics: Abdominal Pain; Animals; Carbolines; Colonic Diseases, Functional; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Male; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors

Topics: Adult; Carbolines; Clinical Trials as Topic; Colonic Diseases, Functional; Diagnosis, Differential; Diet; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestines; Male; Psychotherapy; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

Existing pharmacotherapeutic options for the treatment of patients with irritable bowel syndrome (IBS) are limited in treating the multiple symptoms associated with the disorder. There is much interest in the use of serotonin agents as new therapeutics. Acting primarily through 5-HT3 and 5-HT4 receptors, serotonin elicits changes in motor function and possibly visceral sensation. Two serotonin agents were developed specifically for IBS: tegaserod, a 5-HT4 receptor partial agonist, and alosetron, a 5-HT3 receptor antagonist (which is no longer available). Phase III clinical trial data show that during a 12-week treatment period with tegaserod, IBS patients with abdominal pain and discomfort, bloating, and constipation experienced significant global relief (i.e., improvement in overall well-being, abdominal pain, and bowel habit) compared with placebo. Improvement in bowel movement frequency and consistency was achieved and pain was relieved by 1 week. During 12 weeks of treatment, alosetron was shown to elicit significant relief of abdominal pain and discomfort compared with placebo or mebeverine in female IBS patients with diarrhea. Alosetron slowed colonic transit and treatment efficacy was apparent after a week of treatment. Another 5-HT4 receptor agonist, prucalopride, which is being developed for chronic constipation, accelerates colonic transit and increases stool frequency. Therefore, this agent may be of benefit in IBS patients with constipation.

Topics: Abdominal Pain; Benzofurans; Clinical Trials as Topic; Colonic Diseases, Functional; Constipation; Gastrointestinal Motility; Humans; Indoles; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; United States

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.

Topics: Benzofurans; Carbolines; Clinical Trials as Topic; Colonic Diseases, Functional; Female; Humans; Indoles; Male; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Abdominal Pain; Animals; Benzyl Compounds; Carbolines; Central Nervous System; Colitis, Ulcerative; Colon; Colonic Diseases, Functional; Colonoscopy; Controlled Clinical Trials as Topic; Diarrhea; Digestion; Electromyography; Female; Follow-Up Studies; Gastric Emptying; Gastroenteritis; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Intestines; Male; Myenteric Plexus; Neurons; Neurotransmitter Agents; Placebos; Pressure; Propylamines; Receptors, Opioid, kappa; Rectum; Risk Factors; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Time Factors

Tegaserod is a serotonin (5-hydroxytryptamine; 5-HT) receptor partial agonist which has been investigated for the treatment of irritable bowel syndrome (IBS). Specifically, it binds with high affinity to human 5-HT4 receptors, thereby stimulating the release of neurotransmitters and the peristaltic reflex in vitro. Small bowel transit (increased colonic filling over 6 hours) was accelerated in patients with constipation-predominant irritable bowel syndrome (IBS) receiving oral tegaserod 2mg twice daily for 1 week compared with those receiving placebo. In addition, there was a mean 20% increase of proximal colonic emptying in these patients. Oral tegaserod 2 (p < 0.05) or 6mg twice daily improved symptoms of abdominal discomfort, bloating and constipation (assessed using a Subjects' Global Assessment Scale) compared with placebo in patients with constipation-predominant IBS in a double-blind, dose-ranging study. The most frequent adverse events in patients with constipation-predominant IBS receiving oral tegaserod were transient diarrhoea and flatulence. No clinically relevant changes in blood pressure, pulse rate, QRS or QTc interval were reported with tegaserod doses of 25 to 100mg.

Topics: Clinical Trials as Topic; Colonic Diseases, Functional; Electroencephalography; Humans; In Vitro Techniques; Indoles; Placebos; Serotonin Receptor Agonists

Tegaserod has been shown to be an effective therapy for the multiple symptoms of irritable bowel syndrome (IBS) in Western populations. However, little information is available regarding the use of tegaserod in the Asia-Pacific population.. To evaluate the efficacy, safety, and tolerability of tegaserod versus placebo in patients with IBS from the Asia-Pacific region.. A total of 520 patients from the Asia-Pacific region with IBS, excluding those with diarrhoea predominant IBS.. Patients were randomised to receive either tegaserod 6 mg twice daily (n=259) or placebo (n=261) for a 12 week treatment period. The primary efficacy variable (over weeks 1-4) was the response to the question: "Over the past week do you consider that you have had satisfactory relief from your IBS symptoms?" Secondary efficacy variables assessed overall satisfactory relief over 12 weeks and individual symptoms of IBS.. The mean proportion of patients with overall satisfactory relief was greater in the tegaserod group than in the placebo group over weeks 1-4 (56% v 35%, respectively; p<0.0001) and weeks 1-12 (62% v 44%, respectively; p<0.0001). A clinically relevant effect was observed as early as week 1 and was maintained throughout the treatment period. Reductions in the number of days with at least moderate abdominal pain/discomfort, bloating, no bowel movements, and hard/lumpy stools were greater in the tegaserod group compared with the placebo group. Headache was the most commonly reported adverse event (12.0% tegaserod v 11.1% placebo). Diarrhoea led to discontinuation in 2.3% of tegaserod patients. Serious adverse events were infrequent (1.5% tegaserod v 3.4% placebo).. Tegaserod 6 mg twice daily is an effective, safe, and well tolerated treatment for patients in the Asia-Pacific region suffering from IBS and whose main bowel symptom is not diarrhoea.

Topics: Adult; Colonic Diseases, Functional; Diarrhea; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Indoles; Male; Middle Aged; Treatment Outcome

Tegaserod is a 5-hydroxytryptamine-4 receptor partial agonist. Oral administration causes gastrointestinal effects resulting in increased gastrointestinal motility and attenuation of visceral sensation.. : To determine the long-term safety and tolerability of tegaserod in patients suffering from irritable bowel syndrome with constipation as the predominant symptom of altered bowel habits.. A multicentre, open-label study with flexible dose titration of tegaserod in out-patients suffering from constipation-predominant irritable bowel syndrome.. A total of 579 patients with constipation-predominant irritable bowel syndrome were treated with tegaserod. Of these, 304 (53%) completed the trial. The most common adverse events, classified as related to tegaserod for any dose, were mild and transient diarrhoea (10.1%), headache (8.3%), abdominal pain (7.4%) and flatulence (5.5%). Forty serious adverse events were reported in 25 patients (4.4% of patients) leading to discontinuation in six patients. There was one serious adverse event, acute abdominal pain, classified as possibly related to tegaserod. There were no consistent differences in adverse events between patients previously exposed to tegaserod and those treated de novo. No pattern-forming tegaserod-related abnormalities in haematological and biochemical laboratory tests, urinalysis, blood pressure, pulse rate or electrocardiograms were found.. Tegaserod appears to be well tolerated in the treatment of patients with constipation-predominant irritable bowel syndrome. The adverse event profile, clinical laboratory evaluations, vital signs and electrocardiogram recordings revealed no evidence of any unexpected adverse events, and suggest that treatment is safe over a 12-month period.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Colonic Diseases, Functional; Constipation; Diarrhea; Female; Follow-Up Studies; Gastrointestinal Agents; Humans; Indoles; Male; Middle Aged; Patient Dropouts; Serotonin Receptor Agonists

Certain GI prokinetic agents have been shown to affect cardiac repolarization, which may be associated with life-threatening arrhythmias. The selective 5-hydroxytryptamine type 4 receptor partial agonist tegaserod is a novel promotile agent developed for the treatment of functional motility disorders such as irritable bowel syndrome (IBS). The aim of the study was to investigate the cardiac safety profile of tegaserod through analysis of electrocardiographic data from clinical studies conducted in patients with IBS and a study conducted in healthy male subjects.. In three randomized, double blind, placebo-controlled, parallel group clinical studies, 2516 IBS patients with symptoms of abdominal pain and constipation received tegaserod 2 or 6 mg b.i.d. (n = 1679) or placebo (n = 837) for 12 wk. In an additional study, 36 healthy male subjects received iv. single doses of tegaserod (0.8 mg to 20 mg) or placebo. Standard 12-lead electrocardiograms were recorded at baseline and during treatment. Baseline values were compared with data collected during the treatment period.. The proportion of patients with prolongation of the QTc interval was the same for placebo and tegaserod, as was the frequency of overall electrocardiographic abnormalities. No ventricular or supraventricular tachycardia was observed. Comparable electrocardiographic results were obtained during placebo and tegaserod treatment. In healthy volunteers, tegaserod at i.v. doses resulting in plasma concentrations up to 100 times those measured after therapeutic doses (6 mg b.i.d.) did not influence electrocardiographic parameters.. Tegaserod is devoid of electrocardiographic effects and is not expected to adversely influence cardiac function. These data confirm preclinical findings.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Colonic Diseases, Functional; Double-Blind Method; Electrocardiography; Female; Gastrointestinal Agents; Humans; Indoles; Male; Middle Aged

Irritable bowel syndrome is a common functional gastrointestinal disorder which affects up to 20% of the population, with a predominance in females.. To evaluate the efficacy and safety of tegaserod in female patients with irritable bowel syndrome characterized by symptoms of abdominal pain/discomfort and constipation.. In a randomized, double-blind, multicentre study, 1519 women received either tegaserod, 6 mg b.d. (n = 767), or placebo (n = 752) for 12 weeks, preceded by a 4-week baseline period without treatment and followed by a 4-week open withdrawal period. The primary efficacy evaluation was the patient's symptomatic response as measured by the Subject's Global Assessment of Relief. Other efficacy variables included abdominal pain/discomfort, bowel habits and bloating.. Tegaserod produced significant (P < 0.05) improvements in the Subject's Global Assessment of Relief and other efficacy variables. These improvements were seen within the first week, and were maintained throughout the treatment period. After withdrawal of treatment, the symptoms rapidly returned. Overall, tegaserod was well tolerated. Diarrhoea was the most frequent adverse event; however, this led to discontinuation in only 1.6% of tegaserod-treated patients.. Tegaserod, 6 mg b.d., produced rapid and sustained improvement of symptoms in female irritable bowel syndrome patients and was well tolerated.

Topics: Adult; Colonic Diseases, Functional; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Indoles; Middle Aged; Patient Satisfaction; Prospective Studies; Serotonin Receptor Agonists; Treatment Outcome

Tegaserod is a selective serotonin (5-HT4) receptor partial agonist effective in providing relief from abdominal pain, bloating, and constipation in patients with irritable bowel syndrome. Tegaserod therapy may be associated with early transient diarrhea, which is related to its mechanism of action. This study was performed in patients with irritable bowel syndrome and symptoms of diarrhea to further assess the safety of tegaserod.. After a 2-wk baseline, patients were randomized (2:2:1) in a double-blind manner to receive 4 mg of tegaserod a day (n = 35), 12 mg of tegaserod a day (n = 34), or placebos (n = 17) for 8 wk. Patients had to fulfill > or =2 Rome diarrhea criteria > or =25% of the time. Adverse events were recorded.. Diarrhea, abdominal pain, headache, flatulence, and fatigue were the most frequently reported adverse events. The frequency rates of diarrhea were 49%, 18%, and 35% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; when the tegaserod data were pooled, the frequency of diarrhea was similar to that of the placebo group (33% and 35%, respectively). No complications of diarrhea (e.g., dehydration and electrolyte abnormalities) were reported. Five patients (6%), all from the tegaserod groups, discontinued study participation because of diarrhea and/or abdominal pain. No serious adverse events were reported.. In this study, tegaserod at doses of 4 and 12 mg/day was safe and not associated with complications of diarrhea or serious adverse events.

Topics: Adult; Aged; Colonic Diseases, Functional; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Indoles; Intestines; Male; Middle Aged; Safety

To investigate the efficacy and safety of tegaserod, a novel 5-HT(4) receptor partial agonist, in a randomized, double-blind, placebo-controlled, 12-week treatment, multicentre study.. Eight hundred and eighty-one patients with irritable bowel syndrome, characterized by abdominal pain, bloating and constipation, received tegaserod, 2 mg b.d. or 6 mg b.d., or placebo for 12 weeks.. Tegaserod, 2 mg b.d. and 6 mg b.d., showed a statistically significant relief of overall irritable bowel syndrome symptoms, measured by a weekly, self-administered questionnaire. At end-point, treatment differences from placebo were 12.7% and 11.8% for 2 mg b.d. and 6 mg b.d., respectively. The effect of tegaserod was noted as early as week 1, and was sustained over the 12-week treatment period. Individual irritable bowel syndrome symptoms assessed daily also showed a statistically significant improvement of abdominal discomfort/pain, number of bowel movements and stool consistency, and a favourable trend for reducing days with significant bloating. Adverse events were similar in all groups, with transient diarrhoea being the only adverse event seen more frequently with tegaserod than placebo.. Based upon the results of this study, tegaserod offers rapid and sustained relief of the abdominal pain and constipation associated with irritable bowel syndrome. Tegaserod is also well tolerated.

Topics: Abdominal Pain; Adult; Colonic Diseases, Functional; Constipation; Dose-Response Relationship, Drug; Female; Humans; Indoles; Male; Middle Aged; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists; Surveys and Questionnaires; Treatment Outcome

This study evaluated the effects of a partial 5-hydroxytryptamine (5-HT)(4) agonist, tegaserod, on gastric small bowel and colonic transit in constipation-predominant irritable bowel syndrome (IBS).. After a 1 week run-in period, 24 patients with constipation-predominant IBS were randomized to 1 week of tegaserod, 2 mg twice daily, or placebo treatment. Scintigraphic gastric emptying, small bowel transit, and colonic transit were determined before administration of study drug and after 1 week on the medication. Colonic transit was also measured using radiopaque markers and a single radiograph on day 5.. Gastric emptying was unaltered by tegaserod. Proximal colonic filling at 6 hours, a measure of orocecal transit, was accelerated by tegaserod (70.4% +/- 1.3% [mean +/- SEM] vs. placebo, 46.4 +/- 1.9; P = 0.015). Proximal colonic emptying half-time and geometric center at 48 hours were also accelerated by tegaserod compared with baseline, but not compared with placebo. Mean colonic transit time was similar in both groups at baseline and after drug administration (tegaserod, 59.5 +/- 2.1 hours; placebo, 62.1 +/- 2.1 hours).. Tegaserod accelerates orocecal transit, tends to accelerate colonic transit, and deserves further study in patients with constipation-predominant IBS.

Topics: Adult; Aged; Colon; Colonic Diseases, Functional; Constipation; Double-Blind Method; Gastrointestinal Transit; Guanidines; Humans; Indoles; Intestine, Small; Middle Aged; Radionuclide Imaging; Serotonin Receptor Agonists; Stomach; Time Factors

Topics: Cathartics; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Humans; Indoles; Male; Physician-Patient Relations; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Clinical Trials as Topic; Colonic Diseases, Functional; Diarrhea; Female; Gastrointestinal Agents; Humans; Indoles

The lack of validated outcome measures is a key limitation for the evaluation of drug efficacy in the treatment of irritable bowel syndrome (IBS). In clinical trials with tegaserod, the Subject's Global Assessment (SGA) of Relief (a global measure that includes overall wellbeing, abdominal pain/discomfort, and bowel function) was used to identify responders. A total of 1680 patients with IBS with constipation were included in two clinical studies comparing tegaserod with placebo. The SGA of Relief was obtained weekly by a single, self-administered question with five possible answers. Responders for the SGA of Relief reported statistically significant (P<.001) and clinically relevant improvements in multiple IBS-related symptoms compared with nonresponders. Response was also associated with a significant improvement in quality of life. The SGA of Relief is reliable as a new outcome measure for assessing response to therapy in IBS patients and has demonstrated responsiveness and reproducibility.

Topics: Adolescent; Adult; Aged; Child; Clinical Trials, Phase III as Topic; Colonic Diseases, Functional; Double-Blind Method; Female; Gastrointestinal Agents; Health Status Indicators; Humans; Indoles; Male; Middle Aged; Multicenter Studies as Topic; Patient Satisfaction; Quality of Life; Randomized Controlled Trials as Topic; Reproducibility of Results; Treatment Outcome

Topics: Colonic Diseases, Functional; Gastrointestinal Agents; Humans; Indoles; Serotonin Antagonists

Topics: Colonic Diseases, Functional; Constipation; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Indoles; Ovarian Cysts; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists

Topics: Colonic Diseases, Functional; Drug Approval; Female; Gastrointestinal Agents; Humans; Indoles

Topics: Carbolines; Colonic Diseases, Functional; Diagnosis, Differential; Drug Approval; Female; Gastrointestinal Agents; Humans; Indoles; Male; United States; United States Food and Drug Administration

Topics: Antidepressive Agents, Tricyclic; Antidiarrheals; Behavior Therapy; Carbolines; Cathartics; Colonic Diseases, Functional; Diagnosis, Differential; Evidence-Based Medicine; Humans; Indoles; Loperamide; North America; Parasympatholytics; Randomized Controlled Trials as Topic; Serotonin Antagonists; Serotonin Receptor Agonists; Severity of Illness Index

Topics: Colonic Diseases, Functional; Contraindications; Gastrointestinal Agents; Humans; Indoles; Serotonin Receptor Agonists

Topics: Clinical Trials as Topic; Colonic Diseases, Functional; Food Hypersensitivity; Gastrointestinal Agents; Humans; Indoles; Lactose Intolerance; Quality of Life; Serotonin Receptor Agonists

Topics: Benzofurans; Carbolines; Colonic Diseases, Functional; Female; Gastrointestinal Agents; Guanidines; Humans; Indoles; Male; Serotonin Antagonists