The rationale, efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome

Abstract

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.

Guidelines on the irritable bowel syndrome: mechanisms and practical management

“…Furthermore, recent observations that plasma 5-HT concentrations are reduced in IBS patients with constipation,169 240 but raised in those with diarrhoea,169 394 especially those showing postprandial symptoms,394 provide further support for its involvement in the motor and sensory dysfunction associated with this condition. Thus there has been considerable interest in these receptors as possible therapeutic targets for IBS, with agonists at the 5-HT 4 receptor predicted to enhance gastrointestinal propulsion (that is, to be prokinetics)379 395 396 and antagonists at the 5-HT 3 receptor to slow gastrointestinal transit and reduce visceral sensation 379 397 – 399…”

“…Tegaserod has been assessed in multiple, large, and well designed clinical trials379 395 400 401 and has also been shown to have promotility effects in both the small and the large bowel 396. A Cochrane review identified seven high quality placebo controlled trials of tegaserod in IBS-C, which included 4040 patients treated for up to a maximum of 20 weeks, and a small study in IBS-D 401.…”

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

“…5 The G-protein coupled 5-HT 4 receptor (5-HT 4 R) is widely studied, primarily because agonists at these receptors have prokinetic effects on intestinal motility. In the human colon, 5-HT 4 Rs are a therapeutic target for treatment of functional bowel disorders including chronic constipation (CC) and constipation predominant irritable bowel syndrome (IBS-C) [23][24][25][26][27][28] while in the upper gut 5-HT 4 R agonists promote gastric emptying 29,30 and have been used clinically to treat gastroparesis. 31 Despite the clinical success of 5-HT 4 Additional complexity derives from differential 5-HT 4 R expression between anatomical regions and between different species.…”

Tegaserod for Constipation‐Predominant Irritable Bowel Syndrome

“…27 In addition, durations of therapy were not the same. Another concern was a large placebo response rate of 30% or more, 35 and dosages used in the studies varied. According to a Cochrane database review, tegaserod 4 and 12 mg/day significantly improved patients' global assessments of symptoms compared with placebo.…”