tegaserod and Irritable-Bowel-Syndrome

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common gastrointestinal disorders imposing considerable impact on the quality of life and well-being of affected individuals. A paucity of evidence-based treatment options exist for CIC and IBS-C sufferers. Tegaserod, a 5-HT

Topics: Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Quality of Life; Serotonin; Serotonin Receptor Agonists

Tegaserod is a 5-HT. An independent committee conducted an external adjudication to evaluate 24 possible cardiovascular ischemic events (tegaserod: n = 20; placebo: n = 4) identified internally. A second independent external adjudication further evaluated these events.. A total of 18,645 patients were included (tegaserod: n = 11,614; placebo: n = 7031). The first adjudication identified 14 (0.075%) events (tegaserod: n = 13 [0.11%]; placebo: n = 1 [0.014%]). All patients had ≥1 cardiovascular risk factor, and 11 had ≥2. The second adjudication identified 390 events, 24 (0.13%) were classified as probable new or worsening events (tegaserod: 18 [0.16%]; placebo: 6 [0.09%]). For tegaserod, 7 (0.06%) were coronary or cerebrovascular ischemic events compared with 1 (0.01%) for placebo (odds ratio, 4.24; 95% confidence interval, 0.52-34.74; P = .273). All tegaserod patients reporting cardiovascular events had ≥1 risk, including cardiovascular disease, hyperlipidemia, ≥55 years of age, hypertension, diabetes, obesity, and smoking. Women <65 years of age without a history of cardiovascular ischemic events and ≤1 cardiovascular risk factor receiving tegaserod experienced no major adverse cardiovascular event(s).. Two independent, external adjudications suggest that tegaserod is safe for women <65 years of age with irritable bowel syndrome with constipation, no history of cardiovascular ischemic events, and ≤1 cardiovascular risk factor.

Topics: Adult; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome

Tegaserod was the first US Food and Drug Administration-approved drug for irritable bowel syndrome with constipation (IBS-C) in women and was recently reapproved for use. Recognizing that clinical trials were performed almost 20 years ago, we performed an integrated analysis on patient-reported outcomes relevant to current practice including previously unpublished data.. Data from 4 12-week, randomized, placebo-controlled trials evaluating tegaserod 6 mg b.i.d. in patients with IBS-C were pooled. We analyzed 2 groups: all women (overall population) and women younger than 65 years without a history of cardiovascular ischemic events (indicated population). The primary end point was subjective global assessment of IBS-C symptom relief. Responders rated themselves as "considerably" or "completely" relieved ≥50% of the time or at least "somewhat relieved" 100% of the time over the last 4 weeks.. The overall and indicated populations included 2,939 (tegaserod [n = 1,478]; placebo [n = 1,461]) and 2,752 (tegaserod [n = 1,386]; placebo [n = 1,366]) participants, respectively. The pooled odds ratios (95% confidence interval) for clinical response during the last 4 weeks in the overall and indicated populations with tegaserod were 1.37 (1.18, 1.59; P < 0.001) and 1.38 (1.18, 1.61; P < 0.001). In the overall and indicated populations, clinical response rates for tegaserod during the last 4 weeks were 43.3% and 44.1% versus 35.9% and 36.5% with placebo (P < 0.001). Adverse events were similar between groups. No significant cardiovascular events related to tegaserod were observed in patients with ≤1 cardiac risk factor.. Tegaserod 6 mg b.i.d. reduced IBS-C symptoms in overall and US Food and Drug Administration-indicated populations (women aged <65 years with no history of cardiovascular ischemic events).

Topics: Adult; Constipation; Female; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists

Tegaserod (Zelnorm®) is a 5-hydroxytryptamine (serotonin) type 4 receptor agonist for the treatment of hypomotility disorders of the lower gastrointestinal tract associated with the irritable bowel syndrome with constipation (IBS-C).. The authors provide the reader with a better understanding on tegaserod mechanism of action, on its pharmacodynamics and pharmacokinetic properties, on safety and tolerability, with a summary of the key published clinical trials conducted in patients with irritable bowel syndrome (IBS). Its effects on colon inflammation have also been described.. Tegaserod was withdrawn in 2007 due to increased risks of cardiovascular adverse effects. The manufacturer denied this, because pre-existing cardiovascular disease or risk factors were attributed to all affected patients. Thus, no causal relationship between tegaserod use and cardiovascular events was clearly shown. A matched case-control study of tegaserod-treated with untreated patients found no association between tegaserod and adverse cardiovascular outcomes. Despite its adverse effects, tegaserod resulted to be effective in treating chronic constipation in adult women aged < 65 years with IBS-C, while the safety and effectiveness of tegaserod in men with IBS-C have not been established. Tegaserod was resubmitted to the Food and Drug Administration in 2018 for use in a low-risk population. Moreover, tegaserod has also been shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients. Treatment with tegaserod seems also to exert a protective effect in inflamed colons, reducing the severity of colitis in animal models.

Topics: Animals; Humans; Indoles; Irritable Bowel Syndrome; Serotonin; Serotonin Receptor Agonists

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder affecting 1 in 10 people and associated with poor psychological health, reduced quality of life, and increased health care expenditure.

Topics: Constipation; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Network Meta-Analysis; Treatment Outcome

Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished.. This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients.. We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

Topics: Clinical Trials as Topic; Humans; Indoles; Irritable Bowel Syndrome; Lactones; Ligands; Quality of Life; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Sesquiterpenes

The diagnosis of irritable bowel syndrome (IBS) should be considered when patients have had abdominal pain/discomfort, bloating, and change in bowel habits for 6 months. Patients may experience variation between periods of constipation and diarrhea. When evaluating patients with IBS, physicians should be alert for red flag symptoms, such as rectal bleeding, anemia, nighttime pain, and weight loss. Physicians also should consider other medical conditions that manifest similarly to IBS. Clinicians who are confident in diagnosing IBS based on symptoms typically do not obtain many tests unless the patient has red flag symptoms. Various etiologic mechanisms have been proposed for IBS, including abnormal bowel motility, inflammation, altered mucosal permeability, genetic predisposition, and visceral hypersensitivity. Lack of certainty about the etiology makes it difficult to develop effective management approaches; thus, management is directed toward symptom relief. Dietary changes, such as avoiding fermentable carbohydrates, may benefit some patients, especially those with bloating. Constipation-dominant IBS can be managed with antispasmodics, lubiprostone, or linaclotide, whereas diarrhea-dominant IBS can be managed with loperamide or alosetron, though the latter drug can cause ischemic colitis. For long-term therapy, tricyclic antidepressants or selective serotonin reuptake inhibitors have good efficacy. Peppermint oil and probiotics also may provide benefit.

Topics: Antidepressive Agents; Cognitive Behavioral Therapy; Diagnosis, Differential; Diet; Exercise Therapy; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Loperamide

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and it is characterized by episodes of abdominal pain and altered bowel functions. The specific bowel disturbances of diarrhea, constipation or an alternation between the two defines the IBS subtypes of diarrhea-predominant, constipation-predominant, and mixed or alternating IBS. Because of the abnormalities in bowel states associated with each IBS subtype, it is not likely that one agent would successfully treat all three subtypes. As a result, clinical trials have focused, for the most part, on one IBS subtype. Over the past 2 decades very few agents have achieved regulatory approval for the treatment of IBS. In the present article we review publications reporting on phase 2 and phase 3 studies evaluating agents to potentially be used in the treatment of patients with IBS.

Topics: Alprostadil; Benzamides; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbolines; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Lubiprostone; Peptides; Phenylalanine; Phloroglucinol; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin

Gut-acting therapies are common therapies for irritable bowel syndrome (IBS). Most of these peripheral acting agents are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in treating symptoms of IBS. The clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 antagonist alosetron in the treatment of women with severe IBS with diarrhea refractory to traditional therapy.

Topics: Alprostadil; Antidiarrheals; Carbolines; Dietary Fiber; Dietary Supplements; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Laxatives; Lubiprostone; Parasympatholytics; Serotonin Antagonists; Serotonin Receptor Agonists

Ischaemic colitis (IC) is the most common form of ischaemic injury to the gastrointestinal (GI) tract. IC typically presents with the sudden onset of lower abdominal pain, cramping and rectal bleeding, and is usually self-limited with low morbidity, although it may cause gangrenous or fulminant colitis, especially when the right colon is involved. Multiple medical conditions, as well as several pharmacological agents, are associated with IC, including irritable bowel syndrome (IBS) and drugs used for its treatment that act on gut serotonin 5-HT receptors. These include the selective 5-HT(3) receptor antagonist alosetron, currently approved for the treatment of severe diarrhoea-predominant IBS in women who fail to respond to conventional treatment, and cilansetron, another 5-HT(3) receptor antagonist that is no longer in clinical development. In addition, the 5-HT(4) receptor partial agonist tegaserod, which was approved for the treatment of constipation-predominant IBS in women, was associated with IC in the postmarketing setting, as was renzapride, a 5-HT(4) agonist/5-HT(3) antagonist. Although several hypotheses have been proposed, the pathophysiological basis for development of IC with 5-HT(3) receptor antagonists or 5-HT(4) receptor agonists remains unknown. Of interest, several population-based studies demonstrated that a diagnosis of IBS (independent of serotonergic therapies) increases the risk of developing IC 2- to 4-fold. As a result, IBS patients with the acute onset of abdominal pain, tenderness, diarrhoea or lower intestinal bleeding, especially those with predisposing conditions or medications, should be evaluated promptly for IC. The management of IC remains supportive; most cases of non-gangrenous IC, as seen in the alosetron and tegaserod databases, have been transient and have resolved spontaneously without complications or death. Despite the small number of deaths associated with alosetron in patients with complications of constipation and because of the ongoing requirement to prescribe alosetron under a risk management plan, misconceptions persist regarding the definition, incidence, severity and outcome of IC in clinical trials and the postmarketing setting. In this article, the frequency and clinical characteristics of IC associated with the use of alosetron and other serotonergic agents are examined, evidence of an association between IC and IBS is reviewed, and a scoring system to aid in the diagnosis of IC in any clinical situatio

Topics: Animals; Carbolines; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists

A multimodal approach is state-of-the art for effective treatment of functional gastrointestinal disorders (FGD) like irritable bowel syndrome and functional dyspepsia. Based on the now established view that the pathogenesis of FGD is multicausal, evidence-based therapeutic options comprise education about the nature of the disorder, dietary modifications, relaxation techniques, behavioral changes, and pharmacological treatments. These therapies are variously combined depending on the severity of the FGD and the individual needs of the patient. Our overview portrays the options for the therapy of FGD and proposes that these are best provided by an interdisciplinary team of primary care physicians, gastroenterologists, and psychosomatic medicine specialists.

Topics: Abdominal Pain; Antidepressive Agents; Biofeedback, Psychology; Clinical Trials as Topic; Combined Modality Therapy; Dyspepsia; Feeding Behavior; Forecasting; Humans; Indoles; Irritable Bowel Syndrome; Meta-Analysis as Topic; Patient Compliance; Probiotics; Psychotherapy; Quality of Life; Relaxation Therapy; Serotonin Receptor Agonists; Stress, Psychological; Surveys and Questionnaires

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (C-IBS) are commonly reported gastrointestinal (GI) disorders that have a major impact on health and quality of life. Patients experience a range of symptoms of which infrequency of bowel movement is but one and report that straining, the production of hard stools, and unproductive urges are more bothersome than stool infrequency. Additionally, in C-IBS, patients report abdominal pain and bloating as particularly troubling. Traditional treatments, such as laxatives, are often ineffective, especially in more severe constipation over the long term. In a population-based survey of constipation sufferers, half were not satisfied with their current treatment, due predominantly to poor efficacy. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists stimulate GI motility and intestinal secretion, and tegaserod has demonstrated efficacy in improving bowel habit. Tegaserod also improves constipation-associated symptoms including bloating, abdominal discomfort, stool consistency, and straining in patients with both CIC and C-IBS. However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects. Further 5-HT(4) receptor agonists, including prucalopride and TD-5108 are in development and show exciting results in clinical studies in CIC patients, suggesting further product approvals are likely. Headache and diarrhea are the most commonly reported adverse event with this class of agent. Recently a novel prosecretory agent has been approved for the treatment of both CIC and C-IBS. Lubiprostone stimulates chloride secretion through activation of type-2 chloride channels, increasing intestinal secretion and transit, and its use has been associated with improvements in bowel habit and symptoms of constipation. Nausea, diarrhea, and headache are the most commonly reported adverse events. Linaclotide also stimulates intestinal chloride secretion, but this molecule achieves this indirectly, through the activation of guanylate cyclase C. Data are emerging, but the efficacy and safety profile of this agent in the treatment of CIC and C-IBS appears encouraging.

Topics: Alprostadil; Azabicyclo Compounds; Benzofurans; Chloride Channels; Chronic Disease; Constipation; Gastrointestinal Agents; Gastrointestinal Motility; Guanylate Cyclase; Humans; Indoles; Irritable Bowel Syndrome; Laxatives; Lubiprostone; Peptides; Safety; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome

Irritable bowel syndrome (IBS) is a chronic functional disorder. 5-Hydroxytryptamine (5-HT) is a key modulator of gastrointestinal sensorimotor function. Many patients have IBS that can be difficult to treat, which has led to the development of newer agents, such as 5-HT(3) antagonists and 5-HT(4) agonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the efficacy of all available 5-HT agents in IBS.. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to June 2008). Trials recruiting adults with IBS in primary, secondary, or tertiary care comparing 5-HT(3) antagonists or 5-HT(4) agonists with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.. The strategic search identified 1,593 citations. A total of 29 RCTs were eligible for inclusion; placebo was compared with 5-HT(3) antagonists in 11 RCTs, with tegaserod in 11, and with mixed 5-HT(3) antagonists/5-HT(4) agonists in 7. The study quality was generally high. The RR of IBS symptoms persisting with 5-HT(3) antagonists vs. placebo was 0.78 (95% CI: 0.71-0.86), with a similar benefit for both alosetron and cilansetron. Tegaserod was also superior to placebo (RR=0.85; 95% CI: 0.80-0.90). Renzapride and cisapride had no benefit in IBS.. Alosetron, cilansetron, and tegaserod are all effective in the treatment of IBS. Serious adverse events were rare in the eligible RCTs included in this systematic review.

Topics: Adult; Age Factors; Aged; Carbazoles; Carbolines; Dose-Response Relationship, Drug; Drug Administration Schedule; Education, Medical, Continuing; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists; Severity of Illness Index; Sex Factors; Treatment Outcome

Topics: Adult; Antidepressive Agents, Tricyclic; Carbolines; Cognitive Behavioral Therapy; Desipramine; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Parasympatholytics; Practice Guidelines as Topic

Tegaserod, a selective and partial agonist at the 5-hydroxytryptamine (5-HT [serotonin]) receptor subtype 4 (5-HT4), is the only United States Food and Drug Administration-approved drug for the treatment of constipation-predominant irritable bowel syndrome (IBS) in women. The drug's stimulation of 5-HT4 receptors on intestinal enterocytes increases peristaltic activity and fluid secretion into the gut lumen, facilitating stool passage. In addition, affinity of tegaserod for 5-HT4 receptors modulates visceral sensitivity, which helps alleviate abdominal pain associated with constipation-predominant IBS. The drug's pharmacokinetic and pharmacodynamic parameters do not differ significantly with age or sex. Tegaserod safely and effectively relieves overall gastrointestinal symptoms and abdominal discomfort and normalizes bowel habits in patients with constipation-predominant IBS. It is associated with few drug interactions. In clinical studies, tegaserod was well tolerated, and its adverse-effect profile was similar to that of placebo. Severe diarrhea, as well as abdominal pain, flatulence, headache, and nausea, were the most commonly reported events. Patients who experience severe diarrhea should discontinue the drug. With the data available, tegaserod remains an option for patients with constipation-predominant IBS.

Topics: Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome

The treatment of irritable bowel syndrome due to the heterogeneous clinical symptoms and coexisting psychiatric disorders is still controversial. Although several agents with different mechanisms of action are widely used in clinical practice, there are only few drugs available with strong evidence of their efficacy, safety and tolerability at present. The etiology of irritable bowel syndrome is considered to be multifactorial: experimental and clinical research on visceral hypersensitivity, motility and brain-gut axis involving its neurotransmitters and receptors created the foundation of novel therapeutic approaches. Albeit nowadays several drugs (alosetron, tegaserod) have been registered in a few countries for the treatment of irritable bowel syndrome, further large clinical trials are required related to the new chemical entities.

Topics: Adrenergic alpha-Agonists; Analgesics, Opioid; Anti-Bacterial Agents; Antidepressive Agents; Carbolines; Chloride Channel Agonists; Cholecystokinin; Corticotropin-Releasing Hormone; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Muscarinic Antagonists; Neurokinin-1 Receptor Antagonists; Neurotrophin 3; Parasympatholytics; Probiotics; Receptors, Neurokinin-2; Serotonin Agents; Somatostatin

IBS is a complex disorder that encompasses a wide profile of symptoms. The symptoms of chronic constipation frequently resemble those of constipation-predominant IBS. Current drug treatments for irritable bowel syndrome (IBS) are of limited value. Many target specific symptoms only. Tegaserod, a 5HT(4) partial agonist, represents a novel mechanism of action in the treatment of IBS and chronic constipation.. The objective of this review was to evaluate the efficacy and tolerability of tegaserod for the treatment of IBS and chronic constipation in adults and adolescents aged 12 years and above.. MEDLINE 1966-December 2006 and EMBASE 1980 to December 2006 were searched. The text and key words used included "tegaserod", "HTF 919", "irritable bowel", "constipation" and "colonic diseases, functional". The Cochrane Central Register of Controlled Trials, and the Inflammatory Bowel Disease Review Group Specialized Trials Register were also searched. Searches stopped on 15th December 2006. Relevant articles were retrieved, and their reference lists were also reviewed.. Randomised or quasi-randomised controlled trials comparing tegaserod with placebo, no treatment or any other intervention (pharmacological or non-pharmacological) in subjects aged 12 years and above with a diagnosis of IBS or chronic constipation, focusing on clinical endpoints were considered for review.. Study inclusion and exclusion, data extraction and quality assessment was undertaken by two authors independently. Meta-analysis was performed where study populations, designs, outcomes, and statistical reporting allowed combination of data in a valid way, using the summary statistics relative risk for dichotomous data and weighted mean difference for continuous data, both with 95% CI. Thirteen short-term placebo-controlled studies fulfilled the inclusion criteria. These were predominantly conducted in women. Ten studies evaluated the efficacy of tegaserod on global gastrointestinal (GI) symptoms in patients with constipation-predominant IBS (C-IBS). One small study evaluated safety in patients with diarrhoea-predominant IBS. Two studies evaluated the effectiveness of tegaserod for the treatment of chronic constipation.. In patients with C-IBS, the relative risk (RR) of being a responder in terms of global relief of GI symptoms during the last 4 weeks of treatment was significantly higher with both tegaserod 12 mg and 4 mg doses compared with placebo. Although the pooled results indicate statistically significant benefit with tegaserod, the a priori minimal clinically important differences set in two of three studies were not reached. The responder rate for this endpoint was also higher when considered for the first 4 weeks of treatment (tegaserod 12 mg only). Tegaserod did not significantly improve the patients' individual symptoms of abdominal pain and discomfort although bowel habit showed a statistically significant improvement with tegaserod 4 mg and there was a non-significant trend in this outcome in favour of tegaserod 12 mg. In patients with chronic constipation, the RR of being a responder in terms of complete spontaneous bowel movements per week with tegaserod 12 mg was 1.54 (95% CI 1.35 to 1.75), WMD for this endpoint compared with placebo 0.6 (95% CI 0.42 to 0.78). Differences between tegaserod and placebo in increases in frequency of bowel movements were small (less than one per week). The proportion of patients with either diagnosis who experienced diarrhea was significantly higher in the tegaserod 12 mg group compared with placebo (RR 2.80, 95% CI 2.13 to 3.68), with a number needed to harm (NNH) of 20. Effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies.. Tegaserod appears to improve the overall symptomatology of IBS, and the frequency of bowel movements in those with chronic constipation. The clinical importance of these modest improvements is not clear. There are currently few data on its effect on quality of life. In addition, more information is needed about its efficacy in men. It would also be of interest to know whether treatment with tegaserod leads either directly, or indirectly, to changes in visceral sensitivity or psychopathology, which are also considered important in the pathophysiology of these conditions.

Topics: Adolescent; Adult; Chronic Disease; Constipation; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic

A growing body of evidence implicates abnormal serotonergic regulation of gastrointestinal function in the pathogenesis of the irritable bowel syndrome (IBS). Drugs targeting this system are therefore attractive concepts. The partial 5-HT4 receptor agonist tegaserod might be predicted to have positive therapeutic effects on a constipated and uncomfortable gut. However, IBS runs a chronic, benign course and carries no associated mortality, so it is imperative that the safety profile of new pharmacological agents made available to physicians is exemplary. The authors review the evidence for 5-HT in the aetiology of IBS and its symptoms, and the data available concerning the partial 5-HT4 receptor agonist tegaserod, in terms of rationale, efficacy and safety.

Topics: Biological Availability; Constipation; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Receptors, Serotonin, 5-HT4; Serotonin; Signal Transduction

The epidemiology and current understanding of the pathophysiology of irritable bowel syndrome is reviewed, beginning with a historical perspective. The roles of genetics, environment, allergy, infection and inflammation, bacterial overgrowth, hormones and motility abnormalities are discussed. Using the current evidence-based literature, the practical approach of diagnosis and treatment is outlined, including traditional modalities and newer therapeutic agents such as serotonin modulators.

Topics: Antidepressive Agents; Carbolines; Dietary Fiber; Food Hypersensitivity; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Indoles; Irritable Bowel Syndrome; Parasympatholytics; Prevalence; Retrospective Studies; Serotonin Antagonists; United States

Although irritable bowel syndrome (IBS) is a common disorder, IBS is traditionally considered to be a condition that primarily affects young and middle-aged adults. However, increasing evidence suggests that prevalence of IBS in older adults may be similar to that in younger adults; therefore, the diagnosis should be considered when a geriatric patient presents with unexplained abdominal symptoms. Because incidences of other conditions with similar symptoms are higher in the geriatric population, use of certain diagnostic tests (eg, colonoscopy) is warranted in this patient population. In addition, because older adults are more likely than younger adults to suffer from comorbid conditions, polypharmacy is common in this patient population, and this should be considered when diagnosing and treating these patients.

Topics: Aged; Carbolines; Diagnosis, Differential; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Risk Factors

Symptoms of constipation are commonly seen in medical practice. Once other medical causes have been excluded, distinguishing patients who have constipation-predominant irritable bowel syndrome (IBS) from those with functional constipation has been considered useful in terms of planning management. However, the criteria used to distinguish IBS from functional constipation are arguably arbitrary, and the availability of new therapeutic approaches may render such distinctions of little practical relevance. In this article, the author presents a review of the management implications of differentiating constipation-predominant IBS from functional constipation.

Topics: Biofeedback, Psychology; Cathartics; Constipation; Gastrointestinal Transit; Humans; Indoles; Irritable Bowel Syndrome; Manometry; Pelvic Floor

Topics: Antidepressive Agents; Dietary Fiber; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Parasympatholytics; Serotonin Receptor Agonists

Topics: Female; Humans; Indoles; Irritable Bowel Syndrome; Serotonin Receptor Agonists

IBS is a complex disorder that encompasses a wide profile of symptoms. Current drug treatments for irritable bowel syndrome (IBS) are of limited value. Many target specific symptoms only. Tegaserod, a 5HT(4) partial agonist, represents a novel mechanism of action in the treatment of IBS.. The objective of this review was to evaluate the efficacy and tolerability of tegaserod for the treatment of IBS in adults and adolescents aged 12 years and above.. MEDLINE 1966-November 2002 and EMBASE 1980-November 2002 were searched. The text and key words used included "tegaserod", "HTF 919", "irritable bowel", and "colonic diseases, functional". The Cochrane Central Register of Controlled Trials, the Inflammatory Bowel Disease Review Group Specialized Trials Register, and Science Citation Index were also searched. Proceedings from the British Society of Gastroenterology Annual Meeting, and Digestive Disease Week (1998-2002) were hand searched. The manufacturer of tegaserod was contacted. Relevant articles were retrieved, and their reference lists were also reviewed.. Randomised or quasi-randomised controlled trials comparing tegaserod with placebo, no treatment or any other intervention (pharmacological or non-pharmacological) in subjects aged 12 years and above with a diagnosis of IBS, focusing on clinical endpoints were considered for review.. Study inclusion and exclusion, data extraction and quality assessment was undertaken by two reviewers independently. Meta-analysis was performed where study populations, designs, outcomes, and statistical reporting allowed combination of data in a valid way, using the summary statistic relative risk with 95% CI. Eight short-term placebo-controlled studies fulfilled our inclusion criteria. These were predominantly conducted in women. Seven studies evaluated the efficacy of tegaserod on global gastrointestinal (GI) symptoms in patients with constipation-predominant IBS (C-IBS). One small study evaluated safety in patients with diarrhoea-predominant IBS.. The relative risk (RR) of being a responder in terms of global relief of GI symptoms was significantly higher with tegaserod 12 mg (RR 1.19, 95% CI 1.09, 1.29) and tegaserod 4 mg (RR 1.15, 95% CI 1.02, 1.31) compared with placebo, with a number needed to treat (NNT) of 14 and 20 respectively. When all tegaserod doses were combined and compared with placebo (n=4040), the RR of being a responder was 1.17 (95% CI 1.08, 1.27), with a NNT of 17. Although the pooled results indicate statistically significant benefit with tegaserod, the a priori minimal clinically important differences set in two of the four pooled studies were not reached. Tegaserod did not significantly improve the patients' individual symptoms of abdominal pain and discomfort although bowel habit showed a statistically significant improvement with tegaserod 4 mg and there was a non-significant trend in favour of tegaserod 12 mg. When GI symptoms were assessed separately, those indicative of GI motility such as number of bowel movements and days without bowel movements were generally improved with tegaserod although the proportion of patients experiencing diarrhoea was significantly higher in the tegaserod 12 mg group compared with placebo (RR 2.75, 95% CI 1.90, 3.97), with a number needed to harm (NNH) of 20. Effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies.. Tegaserod appears to improve the overall symptomatology of IBS but there are currently few data on its effect on quality of life. In addition, more information is needed about its efficacy in men. It would also be of interest to know whether treatment with tegaserod leads either directly, or indirectly, to changes in visceral sensitivity or psychopathology, which are also considered important in the pathophysiology of this condition.

Topics: Adolescent; Adult; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic

Tegaserod is a new partial agonist of serotonin 5-HT4 receptors specifically developed for the treatment of nondiarrhoeal forms of irritable bowel syndrome (IBS). Among its various effects is the stimulation of the peristaltic reflex with its promotility action appearing to affect the whole length of the gastrointestinal tract. Tegaserod has been assessed in a number of international multicentre trials and its use leads to an improvement in abdominal pain and bowel dysfunction as well as global well-being, at the expense of remarkably few adverse effects. It is noteworthy that it also appears to improve bloating, a benefit that has not been previously reported for a medication used in IBS. The optimal dose is 6 mg twice daily and the advantage of tegaserod over placebo in different trials varies from 5-20% with the number needed to treat ranging from 5-15 depending on the time at which this effect is calculated during the course of a trial. Recent experience with other drugs acting on 5-HT receptors has focused attention on possible safety issues such as prolongation of the QTc interval on the electrocardiogram and ischaemic colitis. However, data from efficacy trials and studies specifically designed to address the safety of tegaserod have not revealed any evidence of cardiotoxicity or the potential for causing ischaemic colitis. Furthermore, investigation of possible interactions with other drugs such as warfarin or the oral contraceptive have not resulted in any prescribing restrictions. Inappropriate prescription of tegaserod to a subgroup of IBS patients for which the drug was not designed, does not appear to have any serious consequences. Most of the efficacy data on tegaserod has been accumulated in females, simply as a result of the failure to recruit adequate numbers of males or restriction of trials to females. There is therefore insufficient information to assess whether there might be any potential gender differences in responsiveness. For this reason, the drug is currently only licensed for use in females.

Topics: Animals; Clinical Trials as Topic; Drug Interactions; Humans; Indoles; Irritable Bowel Syndrome; Risk Assessment; Serotonin Receptor Agonists

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation. Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems. Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy. Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not eff

Topics: Drug Interactions; Humans; Indoles; Irritable Bowel Syndrome; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists

Tegaserod is a drug in a new class of compounds called aminoguanidine indoles and is structurally similar to serotonin (5-HT) with modifications that make the drug selective for the 5-HT(4) receptor. Tegaserod has a stimulatory effect on gastrointestinal (GI) motility that has been demonstrated in animal studies and in healthy adults. Tegaserod also increases GI secretion and reduces rectal sensitivity. Tegaserod is currently approved by the FDA for the treatment of women with constipation-predominant irritable bowel syndrome (C-IBS). Eight large Phase III clinical trials involving > 5000 IBS patients support the clinical efficacy of tegaserod in this group of patients. Patients who were treated with tegaserod had an overall improvement in IBS symptoms (Subject's Assessment of Global Relief) as well as in secondary end points, such as abdominal pain and discomfort, stool consistency, change in bowel movements and relief of bloating. Tegaserod was well-tolerated. The most common adverse reaction in clinical trials was diarrhoea, which was usually temporary and mild, although severe diarrhoea requiring hospitalisation has been rarely (< 1%) reported.

Topics: Animals; Clinical Trials, Phase III as Topic; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin Receptor Agonists

Studies from the Western hemisphere have established the efficacy and safety of tegaserod in women with irritable bowel syndrome and constipation. This review summarizes the results of recent studies from around the world that confirm the efficacy and safety of tegaserod, and expand our understanding of the role of this drug in the treatment of patients with irritable bowel syndrome.

Topics: Adult; Constipation; Female; Gastrointestinal Agents; Global Health; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists

Gastrointestinal symptoms are the most common side-effects of tegaserod therapy. In data pooled from Phase III randomized controlled trials in patients with irritable bowel syndrome with constipation, diarrhoea was reported by 8.8% of patients treated with tegaserod 6 mg b.d. vs. 3.8% of patients treated with placebo. Similar rates were observed in international post-US marketing randomized controlled trials. In most patients, tegaserod-induced diarrhoea was mild and transient. In randomized controlled trials, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of irritable bowel syndrome patients discontinued tegaserod due to diarrhoea. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea and flatulence) was similar in tegaserod-treated and placebo-treated patients. Pooled analysis of Phase III and post-US marketing randomized controlled trials did not demonstrate significant differences between tegaserod-treated and placebo-treated patients in the incidence of abdominal/pelvic surgery. No episodes of ischaemic colitis were reported in tegaserod-using patients in any Phase III or post-marketing randomized controlled trials, and post-marketing surveillance indicated that the rate of ischaemic colitis in tegaserod-using patients was lower than that in non-tegaserod-using patients. Pooled analysis of Phase III randomized controlled trials demonstrated an increase in the incidence of headaches in tegaserod-treated (6 mg b.d.) vs. placebo-treated patients (15% vs. 12.3%, respectively; P < 0.05), although post-US marketing randomized controlled trials did not demonstrate this increase. Other extra-gastrointestinal adverse events occurred with similar frequency in tegaserod-treated and placebo-treated patients. Tegaserod-treated patients in randomized controlled trials did not demonstrate significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. In summary, tegaserod exhibits a favourable safety and tolerability profile in irritable bowel syndrome patients based on data from clinical trials.

Topics: Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Constipation; Gastrointestinal Agents; Gastrointestinal Diseases; Headache; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists

This article reviews the efficacy and tolerability of traditional therapies for irritable bowel syndrome (IBS) and concludes that they are limited by both poor efficacy and adverse effects. Serotonin, a neurotransmitter found mainly in the gut, appears to represent a link in IBS pathophysiological processes -- altered gut motility, abnormal intestinal secretion and visceral hypersensitivity. Recently, available treatments for IBS have targeted serotonin receptors that are involved in motor, sensory and secretory functions of the gut. Serotonergic agents, such as alosetron (a 5-HT3 receptor antagonist) and tegaserod (a selective 5-HT4 receptor partial agonist), provide global relief of the multiple symptoms of IBS with diarrhoea and IBS with constipation, respectively, and represent important additions to the IBS treatment armamentarium.

Topics: Animals; Antidepressive Agents; Antidiarrheals; Carbolines; Cathartics; Humans; Indoles; Intestines; Irritable Bowel Syndrome; Parasympatholytics; Serotonin; Serotonin Agents

Topics: Adult; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.

Topics: Constipation; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Topics: Adult; Aged; Antidepressive Agents; Carbolines; Dietary Fiber; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Serotonin Antagonists; Serotonin Receptor Agonists

Approved in July 2002, tegaserod maleate is a partial 5-hydroxytryptamine 4-receptor agonist used to improve symptoms of constipation-predominant irritable bowel syndrome (IBS). The physiologic actions of tegaserod relate to its ability to stimulate gastric and intestinal motility.. This article reviews available data on the pharmacokinetic and pharmacodynamic properties and clinical efficacy of tegaserod.. Searches of MEDLINE and PubMed from 1966 to the present were conducted using the search terms tegaserod, tegaserod maleate, irritable bowel syndrome, and Rome criteria. Abstracts presented at national meetings between 1997 and 2002 were reviewed and included if perceived to be reliable and relevant.. In clinical trials, tegaserod was associated with significantly better scores on the subject's global assessment of relief compared with placebo (P < 0.05). The absolute efficacy of tegaserod compared with placebo varied between trials and averaged 10% to 12%. Tegaserod had a good safety profile; diarrhea was the only adverse effect that occurred more often in tegaserod recipients than in placebo recipients. No electrocardiographic changes were observed at therapeutic concentrations of tegaserod. Long-term (1-year) treatment with tegaserod appeared to be well tolerated. The recommended dosage for patients aged >18 years with constipation-predominant IBS is 6 mg PO BID before meals for 4 to 6 weeks, with an additional 4 to 6 weeks of treatment if initial therapy is partially effective.. The addition of tegaserod to the arsenal of moderately effective medication currently used in the treatment of IBS may be helpful in patients with constipation-predominant IBS. Continuous postmarketing surveillance and reporting of adverse reactions are essential to further characterize the safety profile of this new agent.

Topics: Clinical Trials as Topic; Drug Interactions; Humans; Indoles; Irritable Bowel Syndrome; Practice Guidelines as Topic; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin Receptor Agonists

Irritable bowel syndrome (IBS) is a commonly encountered condition seen in multiple medical specialties. Recent research has brought dramatic advances in our understanding of the epidemiology, burden of illness, diagnosis, and management of IBS. It is now widely accepted that the prevalence of IBS is between 10% and 20% of the US population and that the direct and indirect costs associated with IBS are significant. The processes required for diagnosis of IBS remain controversial. Scant evidence exists to support exhaustive diagnostic evaluations, and IBS is no longer considered a diagnosis of exclusion. The use of standardized symptom-based criteria remains to be perfected, and the diagnosis is often arrived at only after multiple laboratory, endoscopic, and radiologic examinations. The effects of treatment for IBS mirror the heterogeneous nature of the condition. No single medication has proven to be universally effective, and multiple therapeutic approaches exist. Greater understanding of gastrointestinal neurophysiology has led to promising advances in medical and nonmedical approaches to IBS.

Topics: Antidepressive Agents, Tricyclic; Carbolines; Cost of Illness; Desipramine; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Psychotherapy; Serotonin Antagonists; United States

Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.

Topics: Antidepressive Agents; Benzofurans; Carbolines; Cisapride; Constipation; Drug Industry; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Arrhythmias, Cardiac; Asian People; Benzamides; Case-Control Studies; Cisapride; Cross-Over Studies; Double-Blind Method; Electrocardiography; Female; Humans; Indoles; Irritable Bowel Syndrome; Long QT Syndrome; Male; Morpholines; Moxifloxacin; Piperidines; Placebos; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

The symptoms of irritable bowel syndrome (IBS) are commonly seen in fibromyalgia (FM) patients. This study aimed to evaluate the effect of 5-hydroxytryptamin-4 receptor partial agonist (tegaserod) on the symptoms of FM among the patients who receive the medicine because of IBS. Forty-one female patients with IBS and constipation, which were subjects to tegaserod treatment, were examined by rheumatologist and 14 were found to suffer from FM. The fibromyalgia impact questionnaire (FIQ) and clinical examination were done before tegaserod treatment and 1 month after. The IBS status, the total FIQ score, the number of tender points and pain in tender points were lowered significantly after the treatment (p < 0.001 for all variables). The results of this pilot study provide the preliminary evidence that FM patients can benefit from treatment by 5-hydroxytryptamin-4 receptor partial agonist. Additional studies are needed to support this conclusion.

Topics: Adult; Aged; Comorbidity; Constipation; Female; Fibromyalgia; Follow-Up Studies; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Pilot Projects; Serotonin Receptor Agonists; Surveys and Questionnaires; Treatment Outcome

Tegaserod relieves overall and multiple individual constipation-predominant irritable bowel syndrome (IBS-C) symptoms. However, mechanisms for the relief of abdominal pain/discomfort are not well understood. The effects of tegaserod on rectal sensitivity to distension were measured by the nociceptive flexion RIII reflex, as evidenced by spinal hyperexcitability (i.e. increase or facilitation of the RIII reflex), in IBS-C patients. A randomized, double-blind, placebo-controlled, parallel study was performed in 30 women with IBS-C. The effects of slow ramp rectal distension on the RIII reflex, recorded from the lower limb, were measured before [first experimental day (D1)] and after 7 days [day 8 (D8)] of placebo (n=15) or 6 mg tegaserod bid (n=15). Pressure-volume and sensation-volume relationships were measured during distension, and patients reported their IBS symptoms daily. On D1, rectal distension facilitated the RIII reflex in both treatment groups. On D8 vs D1 these facilitatory effects were significantly lower (P<0.001, analysis of variance) after tegaserod (mean reduction: -30.3+/-11.9%) than placebo (mean reduction: -10.1+/-12.9%). No significant changes in the volume-sensation relationship or differences in compliance were observed with tegaserod or placebo. In conclusion, tegaserod reduces the facilitatory effects of rectal distension on the RIII reflex in women with IBS-C.

Topics: Adult; Compliance; Constipation; Double-Blind Method; Female; Humans; Indoles; Irritable Bowel Syndrome; Manometry; Middle Aged; Placebos; Rectum; Reflex; Serotonin Receptor Agonists

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).. 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.. 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).. Tegaserod is effective in treating overall IBS symptoms in patients with IBS-Mixed and IBS-C.

Topics: Adult; Constipation; Double-Blind Method; Female; Follow-Up Studies; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Patient Satisfaction; Prospective Studies; Treatment Outcome

The aims of this study were to investigate the relationship of genetic polymorphisms of the serotonin reuptake transporter and the clinical subtypes of irritable bowel syndrome and its influence on the efficacy of tegaserod in Chinese irritable bowel syndrome patients with constipation. Genetic polymorphisms were analyzed in 87 patients and 96 controls, then 41 irritable bowel syndrome patients with constipation received tegaserod for 4 weeks. The primary efficacy variable was the responder rate measured by Subject's Global Assessment of Relief. Secondary efficacy assessed the changes of individual symptoms weekly. There was no significant difference in genotype frequencies between the patients as a whole and the control group. The frequency of the L/L genotype in the serotonin transporter gene-linked polymorphic region was significantly higher in patients with constipation than in controls (25.0% vs. 7.3%). Responder rates to tegaserod were significantly higher in the S/S (85.0%) and L/S (70.0%) than in the L/L genotype (36.4%). All secondary variables also significantly improved in the S/S and L/S groups compared to the L/L group. This study suggests the hypothesis that individuals with the L/L genotype are vulnerable to development of irritable bowel syndrome with constipation, and patients with the L/L genotype respond poorly to treatment with a routine dose of tegaserod.

Topics: Adult; Alleles; China; DNA; Female; Gastrointestinal Agents; Gene Frequency; Genetic Predisposition to Disease; Humans; Indoles; Irritable Bowel Syndrome; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Prevalence; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Treatment Outcome

In irritable bowel syndrome (IBS), the modulation of neural pathways may be altered and we have recently shown that postprandial recto-sigmoid tone modification is impaired. On pathophysiological grounds, we do not know whether this alteration may have a role in symptom onset and, in particular, whether an effective drug, such as tegaserod, can improve this response together with symptom severity.. Twenty-two female patients with constipation-predominant IBS (IBS-C), diagnosed according to Rome II criteria, were studied. All subjects underwent an evaluation of the presence and severity of IBS symptoms and the recto-sigmoid barostat test to measure fasting and postprandial recto-sigmoid tone and phasic contractility. They were then randomly assigned to receive either tegaserod 6 mg b.i.d (12 patients) or placebo tablets (10 patients) for 4 wk, according to a double-blind protocol. Symptom assessment and recto-sigmoid tone and contractility were re-evaluated at the end of the treatment.. Both symptom severity and postprandial modification of recto-sigmoid tone improved only in the tegaserod group and a significant correlation was evident between the improvement of bloating and the improvement of postprandial recto-sigmoid tone modification. No effect of tegaserod on recto-sigmoid motility index or correlation between motility index and symptom improvement was evident.. In IBS-C female patients, the administration of tegaserod improves symptom severity and is accompanied by an improvement of recto-sigmoid tone response to a meal.

Topics: Adult; Colon, Sigmoid; Constipation; Female; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Muscle Tonus; Rectum; Serotonin Receptor Agonists

The 5-HT(4) receptor agonist tegaserod (6 mg b.i.d.) provides significantly better overall multiple symptom relief compared with placebo in patients with irritable bowel syndrome with constipation (IBS-C). The clinical benefit and safety of tegaserod in IBS-C patients has been demonstrated worldwide in several studies. The aim of this study was to obtain further safety and tolerability data in patients with IBS in the Asia-Pacific region, and to assess patients' satisfaction and compliance with treatment and willingness to re-use tegaserod in a post-marketing setting.. A multicenter, single-arm, open-label trial was conducted at 869 outpatient centers in 10 countries. Men and women with IBS, whose predominant bowel symptom was not diarrhea (non-D-IBS), received tegaserod for 4-12 weeks. Safety and tolerability were assessed by recording adverse events (AE). Patients were questioned about compliance, satisfaction with treatment and willingness to use tegaserod in future.. Data were available from 14 537 patients (18% men, 82% women). Four percent of patients reported at least one AE. The most common AE were diarrhea (2%) and abdominal pain (1%), and most treatment-related AE occurred in the first week of treatment. Serious AE (SAE) were observed in eight patients, and no deaths were reported. Most patients (79%) reported to be satisfied or very satisfied with treatment, and 76% stated they would use tegaserod in the future. Compliance was 97%.. Tegaserod has a favorable safety and tolerability profile for treating non-D-IBS and IBS-C in men and women in the Asia-Pacific region. Satisfaction with tegaserod treatment can be expected in the majority of patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asia, Eastern; Child; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Serotonin Receptor Agonists

Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.

Topics: Adult; Constipation; Double-Blind Method; Drug Therapy, Combination; Female; Gastrointestinal Motility; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Radionuclide Imaging; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Tegaserod is approved for the treatment of constipation-predominant irritable bowel syndrome (C-IBS) in females. The aim of this study was to evaluate the effect of tegaserod on colonic transit time (CTT) and symptoms in male patients with C-IBS.. Forty-four males with C-IBS (Rome II) were enrolled. After a baseline washout period of 2 weeks, 40 patients were randomized to 6 mg twice daily of tegaserod or placebo for 12 weeks. Daily bowel habits and weekly satisfactory relief of symptoms were recorded. Total and segmental CTT were measured using radiopaque markers at baseline and after treatment.. The mean +/- SD for the total colonic, right colonic, left colonic and rectosigmoid transit time (in hours) were 18.96 +/- 3.92, 7.74 +/- 1.55, 5.64 +/- 1.51 and 5.58 +/- 2.2 in the tegaserod group compared to 22.47 +/- 3.73, 9.69 +/- 2.33, 6.6 +/- 1.32 and 6.18 +/- 2.22 in the placebo group at the end of 12 weeks. There was a statistically significant difference in the total, right and left CTT in the tegaserod group (P < 0.05) at the end of treatment. Global satisfactory relief at the end of 12 weeks was 75% in the tegaserod group and 50% in the placebo group (P > 0.05). Greater stool frequency occurred in the tegaserod group (P > 0.05). There was a significant decrease in the stool consistency at the end of 12 weeks in patients treated with tegaserod (P < 0.05).. Tegaserod causes significant acceleration of CTT in male patients with C-IBS. Although there was a trend towards improvement in bowel symptoms in the treated group, this effect was not statistically significant.

Topics: Adult; Constipation; Double-Blind Method; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin Receptor Agonists

To determine the effect of a laxative alone and in combination with tegaserod in alleviating pain and improving stool frequency in adolescents with constipation predominant irritable bowel syndrome.. Forty-eight postpubertal adolescents of both sexes with constipation predominant irritable bowel syndrome, as defined by Rome II criteria, were randomly allocated to Group A (n = 27) for treatment with a laxative (polyethylene glycol 3350 oral solution) only or Group B (n = 21) for combination therapy with the laxative and tegaserod. Symptoms of abdominal pain (scale 0-10) and frequency of bowel movements were recorded daily in the pre-treatment phase and the post-treatment phase after a 7-day 'washout' period. Patients served as their own controls.. Treatment with the laxative alone (Group A) resulted in significant increase in frequency of bowel movements (P < 0.05), but not significant improvement in pain (P > 0.05). Treatment with the combination of the laxative and tegaserod (Group B) led to significant increase in the frequency of bowel movements and also significant reduction in pain (P < 0.05).. The laxative alone improved stooling but not pain in adolescents with constipation predominant irritable bowel syndrome. Addition of tegaserod resulted in alleviation of pain as well.

Topics: Abdominal Pain; Adolescent; Cathartics; Constipation; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Pain Measurement; Patient Satisfaction; Prospective Studies

To investigate the serotonin reuptake transporter (SERT) genetic polymorphisms in the 5-hydroxytryptamine (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) and the variable number tandem repeats (VNTRs) in intron 2 among Chinese people, and their relationship to the pathogenesis of irritable bowel syndrome (IBS); and to investigate the impact of SERT genotypes on the efficacy of 5-HT(4) receptor agonist tegaserod in constipation predominant type (C-IBS) patients.. PCR was used to detect the genetic polymorphisms in 87 patients with IBS confirmed with Rome II criteria and 96 healthy subjects, then 41 C-IBS patients received tegaserod 6 mg twice daily for 4 weeks. Each patient recorded his or her symptoms in a diary. Efficacy was assessed by patient's experience of overall symptoms and severity of constipation before and after the treatment.. The 5-HTTLPR genotypes frequencies were: S/S 52.9%, S/L 31.0%, L/L 16.1% in IBS patients; and S/S 57.3%, S/L 35.4%, L/L 7.3% in control. VNTRs genotypes were STin2.10/10: 2.3%, STin2.12/10: 17.2%, STin2.12/12: 80.5% in IBS patients; and STin2.10/10: 2.1%, STin2.12/10: 11.4%, STin2.12/12: 86.5% in control. There was no significant difference in the two genotypes frequencies between IBS and control groups (P > 0.05). However, the allele frequency of the L/L genotype was significantly higher in the C-IBS group than in control (25.0% vs 7.3%, P < 0.05). The clinical responder rates of tegaserod in S/S (85.0%) and S/L (70.0%) genotypes differed significantly from that (36.4%) in L/L genotype (P < 0.05). The scores of Subject's Global Assessment of relief after treatment were: S/S 1.35 +/- 0.81, S/L 1.70 +/- 0.95 vs L/L 2.27 +/- 0.45 (P < 0.05). All other variables for assessment of efficacy including stool frequency, stool consistency and sensation of bowel complete evacuation in L/L genotype were also significantly poorer than those in S/S and S/L (P < 0.05).. 5-HTTLPR and VNTRs genetic polymorphisms existed in Chinese people. In general, the genotypes were not involved in the pathogenesis of IBS. However people with L/L genotype were vulnerable for development of C-IBS. The 5-HTTLPR genetic polymorphisms influenced the efficacy of tegaserod treatment in C-IBS patients with L/L being poorer than S/S and S/L genotypes.

Topics: Adult; Female; Gastrointestinal Agents; Gene Frequency; Genotype; Humans; Indoles; Introns; Irritable Bowel Syndrome; Male; Middle Aged; Minisatellite Repeats; Polymerase Chain Reaction; Polymorphism, Genetic; Serotonin Plasma Membrane Transport Proteins

Symptoms of irritable bowel syndrome are often cyclical and thus may require repeated rather than continuous therapy. Tegaserod is effective and well-tolerated for irritable bowel syndrome with constipation but data on retreatment are lacking.. To assess whether tegaserod retreatment is as efficacious and well-tolerated as initial treatment in a primary care setting.. This open-label trial was designed to evaluate the effectiveness of tegaserod under real-life conditions. Irritable bowel syndrome with constipation patients received tegaserod 6 mg b.d. for 12 weeks; response was assessed at weeks 4 and 12. Responders (those achieving satisfactory relief for at least 2 of the previous 4 weeks) at weeks 4 and/or 12 entered an 8-week withdrawal period where symptom recurrence was assessed. Patients experiencing recurrence could receive tegaserod 6 mg b.d. for another 4 weeks (retreatment phase) and on completion, could choose to continue tegaserod in a 6-month extension study.. A total of 513 patients received initial treatment with tegaserod; 85.0% (436 of 513) responded. 403 responders entered the withdrawal period; symptoms recurred in 83.9% (338 of 403) after a mean of 38 days. Of the 307 patients who subsequently entered retreatment 89.3% (274 of 307) responded. Among patients entering the retreatment period, 269 (87.6%) had responded within the first 4 weeks of initial treatment. Of these, 243 (90.3%) responded to tegaserod retreatment. Adverse events were infrequent and similar during 4 weeks of the initial treatment period (11.1%) and on retreatment (10.4%). The extension study, completed by 188 of 232 (81.0%) patients, demonstrated good long-term tolerability of tegaserod.. Irritable bowel syndrome with constipation patients can be successfully treated, and retreated, with tegaserod 6 mg b.d. Tegaserod was well-tolerated during initial and retreatment periods.

Topics: Adolescent; Adult; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Recurrence; Retreatment; Retrospective Studies; Treatment Outcome

To evaluate the safety/tolerability and efficacy of tegaserod, a 5-HT4 receptor partial agonist, in the treatment of patients with non-diarrhoea irritable bowel syndrome (non-D-IBS) in Switzerland.. This was an 8-week, open-label, prospective, multicentre study. Patients (> or =18 years old) met the Rome II diagnostic criteria for IBS, excluding those with diarrhoea for > or =14 days in the previous 3 months. Details of IBS symptoms experienced in the preceding week were recorded at visit 1 (day 1). Eligible patients received 6 mg tegaserod twice daily for 8 weeks. Adverse events (AEs) and serious AEs were recorded, along with detailed assessment of diarrhoeal episodes. Efficacy assessments included the overall number and percentage of responders after 8 weeks' treatment.. A total of 850 patients (72% women; mean age, 51.4 years) were enrolled, and 843 received at least one dose of tegaserod. AEs were reported in 38% of patients, of which 13% were drug-related. Diarrhoea occurred early during treatment (13% in the first week, 7% thereafter), was mild to moderate in severity, was transient and was resolved with continued treatment. In total, 208 patients left the study early, primarily due to AEs. Diarrhoea accounted for 68 of these discontinuations. Nine serious AEs were reported but these were not related to tegaserod treatment. Sixty-six percent of patients responded to tegaserod on the Subject's Global Assessment of relief after 8 weeks. Benefits were also seen across individual IBS symptoms.. Tegaserod (6 mg twice daily) appears to be safe, well-tolerated and effective in the treatment of non-D-IBS over 8 weeks.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diarrhea; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Sample Size; Serotonin Receptor Agonists

It has been proposed that treatments for irritable bowel syndrome with constipation (IBS-C) should provide rapid symptomatic relief, be intermittent, and effective upon repeated use.. To evaluate the efficacy and safety of tegaserod on IBS symptoms, and its impact on quality of life and health economic measures.. Women (> or = 18 years of age) with IBS-C according to the Rome II criteria.. Prospective, double blind, placebo controlled, randomised trial. Women with IBS-C either received tegaserod 6 mg twice daily or placebo for one month. Patients with at least a partial response entered a treatment free interval. Upon symptom recurrence, tegaserod treated patients were re-randomised to tegaserod or placebo for an additional month. Primary efficacy variables were response (overall IBS symptoms and abdominal discomfort/pain) to first and repeated treatment. Analysis was by intention to treat.. 2660 patients and 1191 patients were randomised for first and repeated treatment respectively. Tegaserod was superior to placebo for each primary efficacy variable (first treatment: 33.7% v 24.2% responders respectively for relief of IBS symptoms and 31.3% v 22.1% for relief of abdominal discomfort/pain; repeated treatment: 44.9% v 28.7%, and 42.4% v 27.1%, all p < 0.0001). Tegaserod was superior to placebo for every secondary efficacy variable (relief of abdominal discomfort/pain, bloating and constipation; stool frequency and consistency). A response to tegaserod was observed within the first treatment week. Tegaserod produced greater satisfaction, work productivity, and improved quality of life than placebo (p < 0.05).. Tegaserod provides rapid and sustained relief of IBS-C symptoms both during first and repeated treatment.

Topics: Adolescent; Adult; Aged; Constipation; Double-Blind Method; Drug Administration Schedule; Efficiency; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Patient Satisfaction; Prospective Studies; Quality of Life; Serotonin Receptor Agonists; Treatment Outcome

Tegaserod is a promotility agent with proven efficacy and safety in patients with irritable bowel syndrome with constipation.. To assess tegaserod's effect on work productivity and daily activity.. Women, 18-65 years old and meeting Rome II criteria for irritable bowel syndrome with constipation, were randomized to a double-blind, placebo-controlled, multicentre study of tegaserod 6 mg b.d. or placebo. Productivity loss and daily activity impairment because of irritable bowel syndrome were measured with the Work Productivity and Activity Impairment questionnaire for irritable bowel syndrome, modified to exclude diarrhoea as a symptom. Assessments were made at baseline, weeks 2 and 4.. A total of 2660 women were randomized and, of these, 1675 [tegaserod (n = 1363), placebo (n = 312)] were employed and completed Work Productivity and Activity Impairment for irritable bowel syndrome questionnaires. Compared with placebo, tegaserod significantly reduced work and daily activity impairment at weeks 2 and 4. Tegaserod reduced absenteeism by 2.6% (P = 0.004), presenteeism by 5.4% (P < 0.0001), overall work productivity loss by 6.3% (P < 0.0001), and activity impairment by 5.8% (P < 0.0001) at week 4 (vs. baseline). Assuming a 40-h workweek, tegaserod reduced work productivity loss by 2.5 h/week.. Tegaserod significantly reduced work productivity loss and daily activity impairment at 2 weeks, and this benefit was maintained at 4 weeks.

Topics: Absenteeism; Adolescent; Adult; Aged; Constipation; Double-Blind Method; Employment; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Prospective Studies; Serotonin Receptor Agonists; Surveys and Questionnaires; Treatment Outcome; Work

To determine the efficacy and tolerability of tegaserod in the treatment of symptoms of irritable bowel syndrome (IBS) IBS-C patients.. An open label (quasi interventional) study.. Patients were enrolled between October 2000 and August 2001 at 4 centres (AKUH, Karachi; Mayo Hospital, Lahore; PIMS, Islamabad; Hayatabad Teaching Complex, Peshawar).. Tegaserod was administered in a dose of 6 mg (twice-a-day) orally for a period of 6 weeks. Symptoms were assessed before and during treatment using a questionnaire.. The mean age of patients was 37.5 years and 81(69.2%) were males. The study enrolled 117 patients and 101 patients completed the study. Number of bowel movements, symptoms of straining at defecation, stool consistency, bloating, urgency and abdominal pain improved significantly following treatment (p<0.05). Analysis of data in both genders separately showed statistically significant improvement in symptoms of urgency, straining at defecation, abdominal pain and number of bowel movements following treatment. Side effects of diarrhoea and vertigo (6 and 1 patients respectively) necessitating discontinuation of treatment were infrequent.. Tegaserod given in a dose of 6 mg b.d. is effective and well tolerated in IBS-C patients. It is equally effective in males and females in relieving the symptoms of abdominal pain, bloating, straining at defecation as well as increased in the mean number of bowel movements per week.

Topics: Adult; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Treatment Outcome

Tegaserod has been shown to be an effective therapy for the multiple symptoms of irritable bowel syndrome (IBS) in Western and Asia-Pacific populations. This study evaluated the efficacy, safety and tolerability of tegaserod versus placebo in patients with IBS.. Patients with IBS (excluding those whose primary bowel symptom was diarrhoea) were randomized to receive either tegaserod 6 mg b.i.d. (n = 327) or placebo (n = 320) for a 12-week double-blind treatment period. The primary efficacy variable (over weeks 1 to 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 the individual IBS symptoms.. Overall satisfactory relief was greater in the tegaserod group than in the placebo group. Over weeks I to 4, the odds ratio was 1.54, that is, the odds of satisfactory relief were 54% higher in the tegaserod group than in the placebo group (95% confidence interval for odds ratio (CI) (1.14, 2.08), P = 0.0049). Over weeks 1 to 12, the odds ratio was 1.78, that is, the odds of satisfactory relief were 78% higher in the tegaserod group than in the placebo group (95% CI (1.35, 2.34), P < 0.0001). A statistically significant therapeutic gain over placebo was observed for the majority of weeks from week 1 to week 12 (except weeks I and 4), with a mean therapeutic gain of 7.3 and 10.6 percentage points over weeks 1-4 and weeks 1-12, respectively. Headache was the most commonly reported adverse event (8.0% tegaserod versus 4.7% placebo). Diarrhoea was reported by 9.2% of patients on tegaserod (1.3% on placebo) and led to discontinuation in 2.8% of tegaserod patients.. Tegaserod 6 mg b.i.d. is an effective, safe and well-tolerated treatment in patients suffering from IBS without diarrhoea as primary bowel symptom.

Topics: Adolescent; Adult; Aged; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Treatment Outcome

Tegaserod is a 5-HT(4) receptor partial agonist that increases peristaltic activity of the intestinal tract. It is approved for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). IBS is a chronic gastrointestinal disorder of function that is reported to be associated with an increased incidence of abdominal surgery including cholecystectomy. The effect of tegaserod on nongut digestive organs, such as the gallbladder and biliary tract, has not been previously investigated. Therefore, this study aimed to evaluate the effects of tegaserod on gallbladder contractility and on functional status of the sphincter of Oddi during both the interdigestive and the digestive periods in healthy female subjects and in female patients with IBS-C.. During a 6-wk, double-blind, placebo-controlled crossover study, gallbladder contractility and concomitant change in luminal diameter of the common hepatic duct (CHD) and the common bile duct (CBD, both proximal and distal) in response to a standard liquid meal were quantified using real-time ultrasonography. Changes in luminal diameter of the CHD and the CBD were used as a surrogate marker for sphincter of Oddi function. Ultrasound measurements were conducted every 15 min from 45 min before, to 60 min after the test meal to observe the impact of tegaserod on gallbladder volume and any concomitant change in the diameters of the CHD and the CBD that developed in response to gallbladder contraction. The ultrasound measurements of gallbladder contractility, along with the CHD and the CBD diameters, were repeated after each of the two 2-wk periods of treatment with tegaserod or placebo. The recommended dose of tegaserod (6 mg b.i.d.) for IBS-C patients was used in healthy female subjects (n = 13) and female patients with IBS-C (n = 20). Twice this dose (12 mg b.i.d.) was also evaluated in an additional 20 female patients with IBS-C. Statistical evaluations were conducted using a two-sided analysis of variance (ANOVA).. Gallbladder contractility variables including ejection fraction, ejection rate and ejection period, fasting and residual volume, and maximal emptying, were similar after 2 wk of treatment with tegaserod 6 mg b.i.d. and placebo in healthy female subjects and female patients with IBS-C. There were no significant changes in the luminal diameters of the CHD or the CBD after tegaserod compared to placebo in any cohort. Additionally, no significant dilation (> or =7 mm in diameter) of the CHD or CBD was observed during maximal gallbladder emptying. Similar results were also observed when tegaserod was given at 12 mg b.i.d. in patients with IBS-C. Tegaserod treatment had no significant effect on plasma CCK concentration in response to the test meal. No significant abdominal pain or unexpected adverse events were reported during the study.. This study showed no significant pharmacodynamic effect of tegaserod on gallbladder contractility or on CBD and CHD diameters as a surrogate marker of sphincter of Oddi function during both the interdigestive (fasting) and the digestive (postprandial) periods in healthy female subjects and female patients with IBS-C.

Topics: Biliary Tract; Common Bile Duct; Cross-Over Studies; Double-Blind Method; Eating; Female; Gallbladder; Hepatic Duct, Common; Humans; Indoles; Irritable Bowel Syndrome; Muscle Contraction; Serotonin Receptor Agonists; Ultrasonography

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

To determine the efficacy and safety of tegaserod 6 mg b.i.d. in the treatment of constipation-predominant irritable bowel syndrome (C-IBS).. An 8-week, double-blind, randomized, parallel group, placebo-controlled, multicenter study in 510 Chinese patients who met the Rome II criteria for C-IBS. The study consisted of a 2-week baseline period, a 4-week randomized, double-blind treatment period with either tegaserod 6 mg b.i.d. or placebo (tegaserod:placebo = 1:1), followed by a 2-week withdraw period. Efficacy was assessed by patient's perception of overall symptoms of IBS during the previous week and severity of the patient's constipation during the last week and patient's assessment of their individual IBS symptoms. Safety was assessed by adverse events, laboratory evaluations, blood pressure and heart rates, Physical examination and ECG evaluations.. The weekly severity of patients' perception of overall IBS symptoms was significantly lower in the tegaserod group from week 1 onwards and throughout the treatment period. The effects of tegaserod on secondary IBS efficacy parameters were consistently better in the tegaserod group starting in week 1 and lasting throughout the treatment period and withdraw period. Regarding adverse events during the treatment period, about 10% of the patients in the tegaserod group experienced an adverse event compared to 6% in the placebo group. Diarrhea, abdominal pain and dizziness were more frequent in the tegaserod group but had a low frequency. No serious adverse was observed due to tegaserod.. Tegaserod 6 mg b.i.d. was effective in relieving overall IBS symptoms, constipation, abdominal discomfort and pain, bloating, etc with significant effects starting in week 1 and continuing throughout the treatment period. Tegaserod was generally well-tolerated and has no clinically relevant safety findings.

Topics: Adolescent; Adult; Aged; Constipation; Double-Blind Method; Female; Follow-Up Studies; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Treatment Outcome

Topics: Abdominal Pain; Constipation; Humans; Indoles; Irritable Bowel Syndrome; Serotonin

Topics: Chronic Disease; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Serotonin Receptor Agonists

More than one decade ago, rising cases of ischemic colitis (IC) prompted the Federal Drug Administration to revoke alosetron's approval as treatment of irritable bowel syndrome (IBS). The aim of this study was to identify medical therapies associated with development of IC.. The Federal Adverse Event Reporting System was queried for the time between January 2004 and September 2015. We identified reports listing IC as treatment complication and extracted suspected causative and concomitantly administered drugs, indications for their use and outcomes.. After eliminating duplicates, we found 2811 cases of IC (68.4 % women; 59.4 ± 0.4 years). Patients with IBS accounted for 3.9 % of the cases, mostly attributed to tegaserod or alosetron. Chemotherapeutic and immunosuppressive drugs, sex hormones, and anticoagulants were the most commonly suspected causes. Bisphosphonates, nonsteroidal anti-inflammatory drugs, antipsychotics, triptans, interferon therapy, and laxative use prior to colonoscopy were among the more commonly listed treatments. In 8 %, the adverse event contributed to the patient's death with male sex and older age predicting fatal outcomes.. Beyond confirming known risks of IC, the results identified several potential culprits of ischemic colitis. This information may not only explain the development of this serious adverse event, but could also guide treatment decisions, cautioning healthcare providers when considering these agents in persons with known risk factors or other drugs that may increase their risk of IC.

Topics: Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antineoplastic Agents; Antipsychotic Agents; Autoimmune Diseases; Bone Density Conservation Agents; Carbolines; Colitis, Ischemic; Colonoscopy; Databases, Factual; Diphosphonates; Estrogens; Female; Gonadal Steroid Hormones; Humans; Immunosuppressive Agents; Indoles; Interferons; Irritable Bowel Syndrome; Laxatives; Male; Mental Disorders; Middle Aged; Neoplasms; Osteoporosis; Preoperative Care; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Sex Factors; Tryptamines; United States

Topics: Anti-Bacterial Agents; Biofeedback, Psychology; Carbolines; Colitis; Diet; Dysentery; Dyspepsia; Egypt; Female; Firmicutes; Greece; Helicobacter pylori; History, 17th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; Humans; Indoles; Intestines; Irritable Bowel Syndrome; Marketing; NAV1.5 Voltage-Gated Sodium Channel; Penicillins; Phenethylamines; Practice Guidelines as Topic; Rifamycins; Rifaximin; Serotonin; Social Support; Spirit Possession

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain

Topics: Cardiovascular Diseases; Constipation; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Platelet Aggregation; Risk Assessment; Serotonin Receptor Agonists

Tegaserod, a 5-HT4 agonist, is effective for treating irritable bowel syndrome and chronic constipation. However, sales of this drug were recently suspended due to concerns about a higher rate of cardiovascular events in patients receiving tegaserod over placebo in clinical trials. Our aim was to review patients in our practice prescribed tegaserod to determine if any of them had suffered a cardiovascular event or other significant adverse effects while on this therapy. Additionally, we attempted to determine the efficacy of tegaserod in clinical practice.. Patients with irritable bowel syndrome or chronic constipation in our practice prescribed tegaserod were identified through a search of billing codes and charts reviews. These patients were contacted and questioned about symptoms of cardiovascular events or other adverse events while on tegaserod. The efficacy of this drug was determined by a symptom scale during and after stopping tegaserod.. Sufficient data for analysis was retrieved for 51 of 67 patients prescribed tegaserod. Of these, 37 patients (72.5%) experience no adverse events and 14 patients (27.4%) experienced at least one adverse event, including 6 patients (11.8%) with major adverse events (2 patients (3.9%) with atypical chest pain; 4 patients (7.8%) with syncope; and 2 patients (3.9%) who died. One patient died from advanced pancreatic cancer. The other, who had multiple cardiovascular risk factors as well as a previous myocardial infarction, suffered a cardiac arrest 2 days postoperatively following a below knee amputation, and had actually been off tegaserod for 7 days after hospital admission. Patients graded the severity of both abdominal pain and constipation as worse after stopping therapy compared to during therapy (p<0.0002 and p<0.0001, respectively).. The risk of cardiovascular events during tegaserod therapy may be increased in patients with other risk factors. However, this drug is effective for treating irritable bowel syndrome and chronic constipation, and might be used in a select patient population with severe symptoms but without other risk factors for cardiovascular events.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Chronic Disease; Constipation; Diarrhea; Female; Follow-Up Studies; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Receptors, Serotonin, 5-HT4; Risk Factors; Safety; Treatment Outcome; Young Adult

The overall objective of this study was to develop a pH-dependent sustained release tablet formulation of a model drug, tegaserod maleate (TM), which is a poorly water soluble and acid labile drug in gastric milieu. The formulation's goal was to allow the dosage form to pass through the stomach intact, start disintegrating in the upper small intestine and slowly release the active in a controlled manner. Partition coefficient, contact angle and drug-excipient compatibility were investigated as part of the preformulation studies. A pH-dependent sustained release tablet was prepared using a combination of Eudragit L100 and Eudragit S100. The effects of solubilizer, disintegrant, binder, coating polymer concentration, pore former, and plasticizer on the drug release rate were determined. The results demonstrated that approximately 90% of the drug was released in a sustained release manner in the pH 6.8 phosphate buffer within 12 h while no drug was detected when subjected to drug release studies in 0.1 mol/L hydrochloric acid for 2 h. The drug release mechanism involved stress points and/or pore formation in the coated film. The coated tablets were stable at 40 degrees C/75% RH for 3 months. These results highlighted the feasibility of this coated tablet system containing TM, which may contribute to the successful treatment of irritable bowel syndrome.

Topics: Delayed-Action Preparations; Drug Incompatibility; Drug Stability; Drug Storage; Excipients; Humans; Hydrogen-Ion Concentration; Indoles; Intestine, Small; Irritable Bowel Syndrome; Polymethacrylic Acids; Serotonin Receptor Agonists; Solubility; Tablets

Direct-to-consumer advertisement (DTCA) and physician promotion of drugs can influence patient and physician behaviors. We sought to determine the relationship between promotion of tegaserod and the number of office visits for abdominal pain, constipation, and bloating; diagnoses of irritable bowel syndrome (IBS); and tegaserod prescriptions.. We used an Integrated Promotional Services database to estimate tegaserod DTCA and promotion expenditures; the National Ambulatory/Hospital Medical Care Surveys (1997-2005) to estimate the number of ambulatory care visits for abdominal pain, constipation, and bloating and diagnoses of IBS; and IMS Health's National Prescription Audit Plus (Fairfield, CT) to estimate the number of prescriptions. We constructed segmented and multivariate regression models to analyze the data.. In the 3 months immediately following the start of tegaserod DTCA, there was a significant increase in physician visits (by 1 million; 95% confidence interval [CI], 0.5-1.6 million) and IBS diagnoses (by 397,025; 95% CI, 3909-790,141). Subsequently, the trend of visits and IBS diagnoses was reduced. In multivariate analyses that examined the overall relationship of promotion with visits, diagnoses, and prescriptions, only the relationship between physician promotion and tegaserod prescribing was significant; every $1 million spent on physician promotion resulted in an additional 4108 prescriptions (95% CI, 2526-5691).. The initial DTCA of tegaserod was associated with a significant, immediate increase in physician visits and IBS diagnoses. This trend reversed and, in multivariate models, neither DTCA nor physician promotion correlated with visits or diagnoses. Physician promotion (although not DTCA) correlated with tegaserod prescription volume.

Topics: Advertising; Databases, Factual; Drug Costs; Drug Industry; Drug Utilization; Female; Gastrointestinal Agents; Health Care Costs; Health Promotion; Humans; Indoles; Irritable Bowel Syndrome; Male; Multivariate Analysis; Patient Participation; Physician-Patient Relations; Practice Patterns, Physicians'; Prescriptions; Probability

Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 +/- 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.

Topics: Adult; Cardiovascular Diseases; Case-Control Studies; Databases as Topic; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Logistic Models; Male; Middle Aged; Odds Ratio; Prospective Studies; Risk Assessment; Risk Factors; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Time Factors

Topics: Alprostadil; Chronic Disease; Drug and Narcotic Control; Drug Approval; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Lubiprostone; United States; United States Food and Drug Administration

Interstitial cystitis (IC) often coexists with irritable bowel syndrome (IBS). IBS may be explained by small-intestinal bacterial overgrowth (SIBO), which increases immune activation and visceral hypersensitivity. This prospective pilot study tested hypotheses that IC patients with gastrointestinal (GI) symptoms have SIBO, that nonabsorbable antibiotic use improves symptoms, and that improvement is sustained by prokinetic therapy.. Consecutive IC patients with GI symptoms had lactulose breath testing (LBT). Those with abnormal results received rifaximin 1,200-1,800 mg/day for 10 days then tegaserod 3 mg/nightly. Questionnaires addressed IC and GI global improvement.. Of 21 patients, 17 (81%) had abnormal LBTs. Of 15 patients treated, GI global improvement was moderate to great in 11 (73%) and sustained in ten (67%). IC global improvement was moderate to great in six (40%) and sustained in seven (47%).. A majority of IC patients and GI symptoms had an abnormal LBT suggesting SIBO. Rifaximin improved symptoms, which was sustained by tegaserod.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Breath Tests; Cystitis, Interstitial; Female; Gastrointestinal Agents; Humans; Indoles; Intestine, Small; Irritable Bowel Syndrome; Middle Aged; Pilot Projects; Prospective Studies; Rifamycins; Rifaximin; Serotonin Receptor Agonists; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome

Small intestinal bacterial overgrowth (SIBO) occurs in irritable bowel syndrome (IBS) and fibromyalgia. Since restless legs syndrome (RLS) occurs with fibromyalgia, a link between IBS, SIBO, and RLS was studied.. BS patients with abnormal lactulose breath tests received rifaximin 1,200 mg day(-1) for 10 days, followed by tegaserod 3 mg, long-term, and 1 month of zinc 220 mg day(-1) and once-daily probiotic (N = 11) or rifaximin monotherapy (N = 2). IBS symptom improvement was assessed after rifaximin. RLS symptoms, IBS symptoms, and overall IBS global improvement were assessed at last posttreatment visit: 8/10 patients were followed long-term (mean, 139 days; range, 54-450 days).. Ten of 13 patients exhibited > or =80% improvement from baseline in RLS symptoms. Five maintained complete resolution of RLS symptoms. Global gastrointestinal symptom improvement was great (n = 6), moderate (n = 5), or mild (n = 2).. This study suggests that SIBO associated with IBS may be a factor in some RLS patients and SIBO therapy provides long-term RLS improvement.

Topics: Adult; Breath Tests; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Indoles; Intestine, Small; Irritable Bowel Syndrome; Male; Middle Aged; Pilot Projects; Restless Legs Syndrome; Rifamycins; Rifaximin; Serotonin Receptor Agonists; Surveys and Questionnaires; Treatment Outcome

The efficacy of electroacupuncture (EA) for treating patients with diarrhea-predominant IBS has been confirmed in the authors' former research, but the regulatory mechanism of EA in IBS is still unknown. The aim of this study was to explore the relationship between the effect of EA on treating IBS rats and the activation and proliferation of mast cell (MC), the secretion of substance P(SP), and vasoactive intestinal polypeptide (VIP). The IBS rat model was set up with stress of binding limbs and colorectal distention. All rats were randomly assigned to four groups (Normal, Model, Tegaserod and EA). Hematoxylin and eosin staining has been used to observe the pathological change in the rats' colonic mucosa and an AWR scoring system has been applied to evaluate improvement of visceral hypersensitivity in various methods of the different groups. Toluidine blue improved method (TBI) and immunohistochemistry have also been involved in observations of mucous mast cells in the colon, change of c-fos positive cells, and secretion of SP, SPR, VIP, VIPR in the local colon. Firstly, the threshold of visceral sensitivity in the rats model with IBS was remarkably reduced (P < 0.01). The MC count in colonic mucosa and c-fos positive cells count increased significantly (P < 0.01) with positive correlation within each. Secondly, EA on ST-25 and Tegaserod pouring into the stomach can inhibit the proliferation and activation of MC in the colon and regulate secretion of SP, SPR, VIP, VIPR (P < 0.01, P < 0.05), while the effect of EA is obviously superior to Tegaserod. We concluded, firstly, that the abnormal proliferation and activation of mucous mast cells in the colon, and oversecretion of neuropeptides such as SP, VIP and their receptors could be one of key mechanisms of etiology of IBS. Secondly, the inhibition of activation and proliferation and the secretion of SP, VIP could be major effects of EA when treating rats with IBS.

Topics: Animals; Electroacupuncture; Immunohistochemistry; Indoles; Irritable Bowel Syndrome; Male; Mast Cells; Rats; Rats, Sprague-Dawley; Substance P; Vasoactive Intestinal Peptide

Topics: Behavior Therapy; Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Serotonin Receptor Agonists; Stress, Psychological

Several high-profile drug withdrawals for safety issues have brought into focus the FDA's process for approving drugs and monitoring adverse experiences with those agents after marketing has begun. Gastroenterologists and their patients have been affected adversely by removal from the marketplace of two licensed agents for irritable bowel syndrome (IBS): alosetron and tegaserod. The criteria used by the FDA for assessment of the risks and benefits of drugs used for functional bowel problems seem to be different than those used for the treatment of other conditions and have resulted in drastic limitation of access to these drugs rather than just warnings about risks as they are discovered. Decisions that affect the availability of drugs for patients with functional bowel disease should be discussed with clinicians who take care of those patients before going into effect. The absence of this sort of consultation leaves physicians with serious limitations on their abilities to take care of patients.

Topics: Adverse Drug Reaction Reporting Systems; Carbolines; Clinical Trials as Topic; Drug Approval; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Product Surveillance, Postmarketing; Risk; Serotonin Receptor Agonists; United States; United States Food and Drug Administration

The authors conducted a well-designed, multinational, large study of women younger than 65 yr of age with irritable bowel syndrome (IBS) with a mixed pattern of diarrhea and constipation (IBS-M) or constipation (IBS-C) and showed that a statistically greater percentage of patients in each group responded to tegaserod compared with patients treated with placebo. Practicality looms large, however, in that the Food and Drug Administration (FDA) disallowed the continued marketing of tegaserod because of cardiovascular safety concerns, and it now is only available under a restricted access program. The wisdom of this decision aside, it is disturbing that the FDA revealed a zero-tolerance for any significant risk of disease when a drug (e.g., tegaserod) was used for a nonlife-threatening condition; the FDA chose to neglect any potential benefit of significant improvement in quality of life, while at the same time allowing the continued availability of sildenifil for erectile dysfunction and other medications (e.g., rosiglitazone and nonsteroidal anti-inflammatory drugs [NSAIDs]), each with a far greater risk of cardiovascular complications. Whether tegaserod will be re-released and, if so, under what conditions, is yet to be determined, as is the question of whether the FDA will decide to allow a more transparent decision-making process with input from all interested parties affected by their decision.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Constipation; Drug and Narcotic Control; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Paternalism; United States; United States Food and Drug Administration

Topics: Drug Approval; Drug Industry; Humans; Indoles; Irritable Bowel Syndrome; Risk Assessment; Serotonin 5-HT4 Receptor Agonists; United States; United States Food and Drug Administration

To formally document the effectiveness of tegaserod as a prokinetic agent in intensive care patients.. The audit was designed in consultation with the Northern Territory Drug and Therapeutics Committee. Tegaserod was added to the feeding protocol and prokinetic algorithm in the ICU, and a prospective audit was performed of patients receiving the medication between May and September 2006.. Over the 5-month period, 40 patients received tegaserod after failing to respond to two doses of metoclopramide. Median daily volume of gastric aspirate was reduced from 1220mL in the 24 hours before tegaserod to 887.5mL in the first 24 hours after its introduction, and to 280mL in the second 24 hours (P=0.01 and P<0.001, respectively). Tegaserod was an effective prokinetic agent in 85% (34) patients. Attributable diarrhoea occurred in 13% (5) patients, but did not require intervention.. Tegaserod is an effective alternative prokinetic agent for ICU patients with a safer side-effect profile. We believe it warrants further investigation.

Topics: Enteral Nutrition; Female; Gastric Emptying; Gastrointestinal Contents; Humans; Indoles; Intensive Care Units; Irritable Bowel Syndrome; Male; Medical Audit; Medical Records; Middle Aged; Serotonin Receptor Agonists

Topics: Drug Approval; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Indoles; Irritable Bowel Syndrome; Ischemia; Marketing of Health Services; Serotonin Receptor Agonists; Technology, Pharmaceutical; United States

Irritable bowel syndrome (IBS) is a chronic, relapsing disease characterised by abdominal pain and altered bowel movements. This review assesses the clinical trials of the partial serotonin receptor agonist tegaserod in women with constipation type IBS. Significantly more women treated with tegaserod obtained sufficient relief from symptoms during at least 2 out of 4 weeks, but the absolute therapeutic gain of approximately 10 percent was not deemed clinically relevant. Two marketing authorisation applications in the European Union have been rejected due to the minor therapeutic gain. Tegaserod was removed from the market in the USA in March 2007 due to an increased risk of severe cardiovascular adverse events.

Topics: Constipation; Evidence-Based Medicine; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Registrational studies of patients treated with tegaserod for irritable bowel syndrome (IBS) suggest an increased risk for cholecystectomy versus treatment with placebo.. To study cholecystectomy rates in association with tegaserod within a large administrative medical claims database.. Patients were drawn from a large population within the US with commercial medical insurance. The primary analysis consisted of a comparison of the observed incidence rate for cholecystectomy claims among a large cohort of new-to-therapy tegaserod users with an incidence rate published for tegaserod-naive patients classified with IBS within the same insured population.. An inception cohort of 7475 individuals with up to 103 weeks of claims history following initiation of therapy with tegaserod was identified. After a follow-up of 3 months (and thus similar to the longest registrational trials), the observed cholecystectomy incidence rate was 340 per 10,000 person-years (95% CI 258, 442). The rate of cholecystectomy was highest in the earliest months of observation following initiation of tegaserod. The observed cholecystecomy incidence rate is 2.9 times higher than an IBS-specific rate of 119 per 10,000 person-years as published for patients so classified within the same insured population.. Based on a large, inception cohort, we report a strong temporal association between the initiation of tegaserod therapy and an increased rate for cholecystectomy. The effect size at 3 months was similar to the relative risk for cholecystectomy reported in registrational studies comparing tegaserod with placebo. As misclassification of initial diagnosis for patients presenting with biliary colic-like symptoms may occur, precise measurements of tegaserod-related relative risk for cholecystectomy from observational studies are problematic and will require prospective studies.

Topics: Adolescent; Adult; Child; Child, Preschool; Cholecystectomy; Female; Gastrointestinal Agents; Humans; Incidence; Indoles; Infant; Insurance Claim Review; Irritable Bowel Syndrome; Male; Middle Aged; Serotonin Receptor Agonists; Time Factors; United States

Topics: Asia; Constipation; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin Receptor Agonists

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

This study was designed to assess the diagnostic and symptom profile of patients receiving tegaserod in routine clinical practice, and to identify their demographic characteristics, as well as the association between these characteristics and diagnosis.. This prospective, observational study collected data from physicians on the symptoms and/or diagnosis, age range and gender for patients to whom they prescribed tegaserod. Details of the physician characteristics included whether they were a family physician or a specialist, and the region of Canada in which their practice was located.. A total of 500 patients were enrolled at 85 sites in Canada. The majority (85%) of the patients were enrolled by family physicians, and the remainder by community-based specialists. The patients were predominantly female (87%) and the highest percentages were in the 35-44 (23%) and 45-54 (25%) age groups. Nearly all patients (96%) were prescribed tegaserod on the basis of both symptoms and diagnosis. The most frequently reported symptoms were abdominal pain and/or discomfort (87%), bloating (80%) and constipation (75%). Most patients (57%) presented with all three of these symptoms. Constipation-predominant Irritable Bowel Syndrome (IBS-C) was the most common diagnosis (55%), followed by IBS alternating between constipation and diarrhea (IBS-A) (23%). Based on this, 67% of patients were given tegaserod strictly according to the label, although it was appropriately prescribed to 87%.. In Canada, tegaserod is prescribed to patients with symptoms of abdominal pain and/or discomfort, bloating and constipation. Most of them will also have a diagnosis of either IBS-C or IBS. It is generally being prescribed appropriately.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Ambulatory Care; Canada; Cohort Studies; Community Health Services; Constipation; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Care; Prospective Studies

Topics: Advertising; Antidepressive Agents; Behavior Therapy; Cathartics; Complementary Therapies; Constipation; Dietary Fiber; Drug Industry; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Serotonin Receptor Agonists

To establish a model of chronic visceral hypersensitivity in rats and to investigate the effect of tegaserod, a partial 5-hydroxytryptamine-4 receptor agonist, on visceral hypersensitivity.. Neonate Sprague-Dawley rats at 8-21 days after birth underwent colorectal distension once daily. Adult rats aged 8-10 postnatal weeks underwent colorectal distension and the abdominal withdrawal reflex (AWR) during the distension was determined. The AWR score was recorded before and after intraperitoneal administration of either tegaserod (treatment group: 0.3 mg/kg) or vehicle (control group).. Changes in the AWR score were dependent on the pressure intensity of the colorectal distension (P < 0.01). At pressures of 40, 60 and 80 mmHg, the AWR scores in the model rats with visceral hypersensitivity were significantly higher than those recorded in the control group (1.95 +/- 0.16 vs 1.35 +/- 0.15, 2.82 +/- 0.12 vs 2.17 +/- 0.13, 3.20 +/- 0.14 vs 2.59 +/- 0.14, P < 0.01). Compared with the controls, tegaserod significantly decreased the AWR scores at the distension pressures of 40, 60 and 80 mmHg (1.95 +/- 0.50 vs 1.32 +/- 0.55, 3.05 +/- 0.48 vs 2.32 +/- 0.54, 3.25 +/- 0.63 vs 2.77 +/- 0.51, P < 0.05).. Adult rats can develop chronic visceral hypersensitivity after transient colorectal mechanical irritation during their postnatal period. Tegaserod increases the pain threshold to noxious stimuli, suggesting an antinociceptive property in its effect on visceral hypersensitivity.

Topics: Animals; Animals, Newborn; Colonic Diseases; Disease Models, Animal; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Pain; Rats; Rats, Sprague-Dawley; Rectal Diseases; Serotonin Receptor Agonists

Topics: Humans; Indoles; Irritable Bowel Syndrome; Serotonin Receptor Agonists

We sought to develop a budget impact model that assesses the economic effect of adding tegaserod for the management of irritable bowel syndrome (IBS) with constipation to the formulary of a managed care organization (MCO). The model estimates the per patient economic impact and the per member, per month (PMPM) economic impact of patients 6 months before and 6 months after the initiation of tegaserod. Resource utilization data, taken from medical and pharmacy administrative claims data, were based on a retrospective, longitudinal study of 3365 patients administered tegaserod through a large, geographically diverse MCO. Costs were estimated for 2 patient subgroups, women with IBS and other gastrointestinal (GI) diagnoses. Sensitivity analyses were performed by varying several model input parameters. The base-case model resulted in an incremental PMPM budget impact associated with the use of tegaserod of 0.01 dollars. Total per patient budget impact (for all resources, including tegaserod) for a 6-month period was 274.34 dollars for women with IBS and 301.84 dollars for women with other GI diagnoses. Overall, 25.9% (29.0% for women with IBS group and 21.9% for women with other GI diagnoses group) of the cost of tegaserod was offset by decreases in resource utilization. Key drivers of post-tegaserod reductions in resource costs were hospital stays, outpatient office visits, emergency department visits, endoscopic procedures, and nonendoscopic procedures. Tegaserod therapy can decrease GI-related resource utilization, resulting in a significant cost-offset percentage. When the associated budget impact of adding tegaserod to its formulary is absorbed across an entire MCO population, the PMPM impact of tegaserod is small.

Topics: Adult; Budgets; Constipation; Cost of Illness; Drug Costs; Drug Prescriptions; Female; Formularies as Topic; Gastrointestinal Agents; Health Care Costs; Humans; Indoles; Irritable Bowel Syndrome; Longitudinal Studies; Managed Care Programs; Middle Aged; Models, Statistical; Retrospective Studies; Serotonin Receptor Agonists; United States; Utilization Review

This study sought to determine the real-world effectiveness of tegaserod therapy on gastrointestinal (GI)-related resource utilization in a managed care population with a retrospective, longitudinal pre-/post-parallel cohort study of tegaserod users and a matched reference cohort of tegaserod nonusers through medical and pharmacy claims data from a large, geographically diverse, managed care organization. Continuously enrolled benefit-eligible patients newly initiated on tegaserod therapy (index prescription) were identified between August 1, 2002, and June 30, 2003, and were categorized (using International Statistical Classification of Diseases, 9th Revision, Clinical Modification codes) as having irritable bowel syndrome (IBS) or another GI-related disorder (e.g., gastroesophageal reflux disease). GI-related resource utilization (office visits, hospitalizations, emergency department visits, endoscopic and nonendoscopic procedures, and GI drug prescriptions) was determined for the 6-month period before and after the index prescription date for tegaserod users and nonusers. The study population consisted of 3365 tegaserod users and 3364 matched nonusers. Within-cohort differences before and after therapy were tested using the Wilcoxon signed rank test. The mean age of 3365 tegaserod users and 3364 matched nonusers was 47 years (+/-15 years); 92% were women, 47% had an index diagnosis of IBS, and 53% had an index diagnosis of another GI-related disorder. Within-cohort GI resource utilization comparisons before and after therapy initiation showed significant decreases (P < .01) in all utilization categories, except GI drug prescriptions, for tegaserod users; these decreases were not consistently observed for matched nonusers. Tegaserod use appeared to be associated with consistent decreases in GI-related resource utilization after 6 months of therapy; similarly consistent reductions were not observed in tegaserod nonusers. These early findings suggest that tegaserod may provide important clinical and economic benefits.

Topics: Adult; Drug Prescriptions; Emergency Service, Hospital; Female; Gastrointestinal Agents; Hospitalization; Humans; Indoles; Insurance Claim Review; Irritable Bowel Syndrome; Longitudinal Studies; Managed Care Programs; Middle Aged; Office Visits; Outcome Assessment, Health Care; Retrospective Studies; Serotonin Receptor Agonists; United States; Utilization Review

Irritable bowel syndrome (IBS) has been associated with substantial time lost from work (absenteeism) and reduced productivity at work (presenteeism), which are the indirect costs of illness. This article presents a productivity model demonstrating the indirect costs associated with IBS and the reduction in those costs for a cohort of female employees hypothetically treated with tegaserod, a new selective serotonin (5-hydroxytryptamine [5-HT]) type 4 (5-HT4) receptor agonist, which is approved by the US Food and Drug Administration for treating women with IBS-C. The model is based on economic and epidemiologic published literature and clinical trial results. In this model, tegaserod treatment resulted in 1882 dollars in avoided lost productivity per treated female employee. Considering only the benefits of decreased work loss and the costs of medical therapy, the model predicts a benefit/cost ratio of 3.75 in the base case. From an employer's perspective, medical therapy for IBS with tegaserod is cost-effective under a series of assumptions for the treatment of women with IBS with constipation.

Topics: Absenteeism; Adult; Constipation; Cost of Illness; Cost-Benefit Analysis; Efficiency; Employer Health Costs; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Middle Aged; Models, Econometric; Models, Statistical; Occupational Health; Retrospective Studies; Serotonin Receptor Agonists; United States

Tegaserod, a potent partial agonist of the serotonin 5-HT4 receptor, is used to treat women with constipation-predominant irritable bowel syndrome. Since the drug's approval, the manufacturer has received infrequent although serious reports of diarrhea and ischemic colitis in patients taking the drug. These instances have led to a recent warning letter to physicians and a change in the prescription labeling of tegaserod. We describe the development of ischemic colitis in a woman who was treated with tegaserod and review the relationship among ischemic colitis, tegaserod use, and irritable bowel syndrome. Potential mechanisms involved in the occurrence of ischemic colitis in patients receiving tegaserod are also discussed.

Topics: Adult; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Tegaserod, a prokinetic 5-HT4 receptor agonist, has demonstrated efficacy and tolerability in irritable bowel syndrome (IBS) patients with constipation (IBS-C) in controlled clinical trials. Its use in primary care has not been investigated.. To determine whether tegaserod is effective and well tolerated by primary care IBS-C patients.. Patients received tegaserod 6 mg b.i.d. for 12 weeks and were assessed for response, abdominal pain/discomfort, bloating, stool consistency/frequency and straining at weeks 4 and 12. Previous successful treatment with the withdrawn drug, cisapride, was noted. A 9-month study extension was offered to patients completing 12 weeks of tegaserod treatment.. 212 patients entered the 12-week treatment period; 166 completed as planned. Response rates were 64.2% at week 4 and 70.3% at week 12. After 12 weeks, abdominal pain/discomfort and bloating were reduced from baseline (p < 0.0001; mean change -1.02 and -0.91 points, respectively), stool frequency increased (0.78-0.97 stools/day) and stool consistency improved (2.45-3.42; lumpy stools became softer). Tegaserod was well tolerated; the most common adverse events were headache (13.2%) and diarrhea (9.4%). One hundred and twenty patients entered the 9-month extension study, 85 completed and tegaserod continued to be well tolerated.. In ambulatory primary care IBS-C patients, tegaserod is an effective and well-tolerated long-term treatment.

Topics: Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Primary Health Care; Treatment Outcome

Topics: Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome

Topics: Colitis, Ischemic; Constipation; Humans; Indoles; Irritable Bowel Syndrome

Topics: Carbolines; Double-Blind Method; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Diarrhea; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome

Topics: Antidepressive Agents; Cisapride; Female; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Carbolines; Diet; Dietary Fiber; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Probiotics; Psychotherapy; Serotonin Receptor Agonists

Topics: Carbolines; Humans; Indoles; Irritable Bowel Syndrome; Polypharmacy; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Dyspepsia; Gastroesophageal Reflux; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Indoles; Irritable Bowel Syndrome

Topics: Abdominal Pain; Cathartics; Constipation; Humans; Indoles; Irritable Bowel Syndrome; Patient Satisfaction

Topics: Colitis, Ischemic; Diarrhea; Humans; Indoles; Irritable Bowel Syndrome; Serotonin Receptor Agonists

To examine the effects of 5-HT4 receptor partial agonist tegaserod on response to rectal distention (RD) and on nNOS expression in spinal cord, and to investigate the mechanism of tegaserod influencing visceral sensation.. Neonatal SD rats randomLy received colonic irritation by acetic acid from postnatal day 8 to day 21 as visceral hypersensitive model (Group H); or by saline intrarectally as control group (Group C). Five subgroups of Group H were i.p. injected randomLy with saline, vehicle (1-methyl-2-thpyrrolidone) or tegaserod at doses of 0.1, 0.3 and 1.0 mg/kg, respectively. Two subgroups of Group C were i.p. injected with saline or tegaserod at dose of 1.0 mg/kg. Ten minutes after injection rectal distention was performed, AWR was recorded and nNOS expression in spinal cord (L6-S1) was analyzed quantitatively by NADPH-diaphorase histochemistry.. Tegaserod significantly inhibited AWR in Group H, but had no effect in Group C. Tegaserod (1.0 mg/kg) inhibited AWR more significantly in Group H than in Group C at the largest volume of distention (1.2 mL). In Group H, tegaserod (1.0 mg/kg) significantly decreased overall nNOS positive cells in spinal cord to 40% of saline. The greatest attenuation was in dorsal horn (31% of H-saline). Tegaserod (0.1 mg/kg) did not affect the overall nNOS(P>0.20), but decreased the number of nNOS positive cells in central canal (79% of H-saline P<0.01).. Tegaserod inhibits response to rectal distention in rats with visceral hypersensitivity and dose dependently attenuates spinal nNOS expression, especially in dorsal horn and central canal. nNOS may be involved in the modulation of visceral sensitivity by tegaserod.

Topics: Animals; Animals, Newborn; Dilatation, Pathologic; Dose-Response Relationship, Drug; Female; Indoles; Irritable Bowel Syndrome; Male; Nitric Oxide Synthase Type I; Random Allocation; Rats; Rats, Sprague-Dawley; Rectum; Serotonin Receptor Agonists; Spinal Cord

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Colitis, Ischemic; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Serotonin Receptor Agonists

Topics: Abdominal Pain; Animals; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin Receptor Agonists

Topics: Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome