Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tegaserod is a serotonin (5-hydroxytryptamine; 5-HT) receptor partial agonist which has been investigated for the treatment of irritable bowel syndrome (IBS). Specifically, it binds with high affinity to human 5-HT4 receptors, thereby stimulating the release of neurotransmitters and the peristaltic reflex in vitro. Small bowel transit (increased colonic filling over 6 hours) was accelerated in patients with constipation-predominant irritable bowel syndrome (IBS) receiving oral tegaserod 2mg twice daily for 1 week compared with those receiving placebo. In addition, there was a mean 20% increase of proximal colonic emptying in these patients. Oral tegaserod 2 (p < 0.05) or 6mg twice daily improved symptoms of abdominal discomfort, bloating and constipation (assessed using a Subjects' Global Assessment Scale) compared with placebo in patients with constipation-predominant IBS in a double-blind, dose-ranging study. The most frequent adverse events in patients with constipation-predominant IBS receiving oral tegaserod were transient diarrhoea and flatulence. No clinically relevant changes in blood pressure, pulse rate, QRS or QTc interval were reported with tegaserod doses of 25 to 100mg.
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PMID:Tegaserod. 1049 76

Tegaserod (Zelmac), an aminoguanidine indole derivative of serotonin, is a selective partial agonist highly selective for 5-HT(4) receptor with an affinity constant in the nanomolar range. Tegaserod does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and distributes widely into tissues. Pharmacokinetics of oral tegaserod are linear in the 2--12 mg dose range. After oral administration tegaserod is metabolized mainly pre-systemically; when absorbed, intact tegaserod is excreted as N-glucuronides mainly via the bile. No clinically relevant drug--drug interactions were identified. Tegaserod has proven safe in toxicity studies. In pharmacodynamic studies, tegaserod stimulated the peristaltic reflex in vitro, increased canine intestinal and colonic motility and transit, reduced visceral afferent firing or sensation in response to distension in animals, and accelerated gastric, small bowel and colonic transit in healthy patients, and small bowel transit in patients with constipation-predominant irritable bowel syndrome. Three large phase III randomized, double-blinded, and placebo-controlled trials were performed predominantly in females (approximately 85%) with constipation-predominant irritable bowel syndrome. Overall, phase III results support efficacy as assessed by the subject's global assessment of relief with significant improvement in secondary endpoints such as abdominal pain, bowel frequency and consistency. Tegaserod was well-tolerated; the most frequent adverse event was transient diarrhoea.
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PMID:Review article: tegaserod. 1120 4

Tegaserod is a medication that has been shown to be of benefit in women with irritable bowel syndrome (IBS) associated with abdominal pain, bloating, and constipation. Tegaserod is a selective serotonin receptor subtype 4 partial agonist designed to interact with the network of cells and nerves throughout the gastrointestinal tract that use serotonin. Tegaserod has been shown to modulate both gastrointestinal motility and visceral sensitivity. Specifically, it increases the peristaltic reflex and decreases visceral sensitivity. Clinical studies have shown that tegaserod improves symptoms of abdominal pain, bloating, and constipation in women with IBS. This article discusses the role of serotonin in gastrointestinal tract physiology, the structure and pharmacokinetic profile of tegaserod, and clinical applications of this new drug.
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PMID:Tegaserod: a new 5-HT4 agonist. 1174 42

Irritable bowel syndrome (IBS) is a common functional bowel disorder of unknown aetiology. It is defined by the presence of gastrointestinal (GI) symptoms including abdominal pain/discomfort, bloating and bowel motor dysfunction. No available therapy is yet effective against all the symptoms of the disorder. Current treatments therefore target individual symptoms but may be accompanied by unpleasant side-effects. Tegaserod is a novel selective serotonin receptor type-4 (5-HT4) partial agonist with structural similarity to 5-HT Tegaserod stimulates small bowel and colonic motility and helps to normalise GI function. Clinical trials using a patient's assessment of efficacy demonstrate that tegaserod significantly improves key symptoms of IBS: abdominal pain/discomfort, bloating and constipation. Tegaserod is well tolerated with an excellent safety profile and represents a significant treatment advance in this difficult-to-treat disorder.
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PMID:Tegaserod: a novel, selective 5-HT4 receptor partial agonist for irritable bowel syndrome. 1183 35

It has been suggested that serotonin (5-hydroxytryptamine) type-4 (5-HT4) receptors modulate the sensitivity of intrinsic afferents of the intestinal mucosa. We studied the involvement of 5-HT4receptors in the modulation of extrinsic afferent sensitivity of the intestinal wall. During distension ramps, mechanoreceptive rectal afferents in sacral dorsal roots were examined in decerebrate anaesthesia-free cats using the selective 5-HT4receptor partial agonist, tegaserod (HTF 919), and the 5-HT4receptor antagonist, SB 203186. The static discharge rate of the afferents evoked by rectal distension decreased after intravenous (i.v.) administration of tegaserod at intraluminal pressures above 30 mmHg, with the most effective reduction occurring at 50 mmHg. The effect was dose-dependent, with maximal reduction occurring at 1.2 mg kg-1 bodyweight, and could be partly reversed by i.v. administration of SB 203186. Tegaserod did not alter the pressure-volume relationship (compliance) of the rectum. It is tentatively concluded that 5-HT4receptor activation has an inhibitory effect on intramural mechanoreceptors in the cat's rectum. Our results are in line with the observation that tegaserod relieves the sensory symptoms of patients suffering from irritable bowel syndrome.
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PMID:Serotonin type-4 receptors modulate the sensitivity of intramural mechanoreceptive afferents of the cat rectum. 1206 5

Tegaserod, a potent, partial serotonin 4 receptor (5-HT4) agonist, is an effective agent for the treatment of females with constipation-predominant irritable bowel syndrome. Tegaserod enhances gastric motility, stimulates peristaltic reflux and intestinal secretion, inhibits visceral sensitivity, and/or shortens colonic transit time. This agent may help women who have failed to respond to diet and exercise, laxatives, and other forms of therapy. The optimal dose of tegaserod is 6 mg twice daily and results in decreased number of days per month with pain, bloating, and days without bowel movements. Tegaserod is less effective in males than females in the treatment of constipation-predominant irritable bowel syndrome. Tegaserod is well tolerated. Diarrhea is the most frequent adverse effect. The diarrhea tends to occur most frequently during the first few months of therapy and decreases with continued administration.
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PMID:Tegaserod for the treatment of constipation-predominant irritable bowel syndrome. 1212 Jan 85

Tegaserod is a selective partial agonist acting on serotonergic type 4 receptors (5-HT(4)). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT(4) agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.
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PMID:Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome. 1215 Jun 98

The efforts of clinical researchers, lay organizations and pharmaceutical companies have increased the public profile of irritable bowel syndrome and made it a respectable diagnosis. Diagnostic symptom criteria encourage a firm clinical diagnosis, which is the foundation of a logical management strategy. This begins with education. Reassurance that no structural disease threatens should be tempered with the reality that symptoms are likely to recur over many years. Patients expect diet and lifestyle advice, even if this is not specific to irritable bowel syndrome. Only a few of those with irritable bowel syndrome see doctors, and even fewer see specialists. Therefore, the treating physician should ascertain the reason for the visit, the patient's fears and the presence of any comorbid illness, such as depression, that might require treatment in its own right. No drug treatment is useful for all of the symptoms of irritable bowel syndrome, and many patients require no drug at all. If used, drugs should target the predominant symptom. Alosetron, a 5-HT3 antagonist, is effective in treating women with irritable bowel syndrome who also have diarrhoea. Tegaserod, a 5-HT4 agonist, is useful for women with irritable bowel syndrome who are constipated. Most patients with irritable bowel syndrome need psychological support. Reassurance, discussion and relaxation techniques can be provided by the family doctor. Difficult psychopathology may require referral to a mental health professional, and the gastroenterologist can settle diagnostic uncertainties. In all cases, successful treatment depends on a confident diagnosis and the strength of the doctor-patient relationship.
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PMID:The treatment of irritable bowel syndrome. 1218 40

Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.
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PMID:Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds. 1218 41

Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT(4) receptor partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who identify abdominal pain or discomfort and constipation as their predominant symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS. Tegaserod is rapidly absorbed following oral administration; peak plasma concentrations (C(max)) are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the C(max) by 20 to 40%. Systemic exposure to tegaserod is not significantly altered at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is approximately 98% bound to plasma proteins, primarily to alpha(1)-acid glycoprotein, and has a volume of distribution at steady-state of 368 +/- 223L. Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT(4) receptors and is devoid of promotile activity. The second is direct glucuronidation which leads to generation of three isomeric N-glucuronides. The plasma clearance of tegaserod is 77 +/- 15 L/h, with an estimated terminal half-life of 11 +/- 5 hours following intravenous administration. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine, primarily as M 29.0. The pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg given twice daily for 5 days, with no relevant accumulation. The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild to moderate hepatic or renal impairment. Tegaserod should not be used in patients with severe hepatic or renal impairment. No clinically relevant drug-drug interactions with tegaserod have been identified. In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP) 1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate), digoxin, warfarin and oral contraceptives have indicated no clinically relevant interactions and no requirement for dosage adjustment.
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PMID:Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with promotile activity. 1240 41


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