Zamifenacin (UK‐76, 654), a potent gut M₃ selective muscarinic antagonist, reduces colonic motor activity in patients with irritable bowel syndrome

Abstract

The pathophysiology of irritable bowel syndrome is poorly understood, but studies have suggested that disordered motility of both the small 1±3 and large bowel, 4±8 and abnormalities in gut visceral sensation, 9±15 may play important roles. The most consistent motor abnormality in the small bowel is a marked increase in`cluster activity' seen in the wakeful state but not during sleep, 1±3 whilst in the colon motility in many patients appears to be exaggerated, particularly after meals. 4±8 The main defect of visceral sensation appears to be hypersensitivity, and this has been demonstrated in the entire length of the gastrointestinal tract in patients with irritable bowel syndrome. 3, 9±15 Current therapy is far from satisfactory, ranging from modi®cations in diet to pharmacological intervention. SUMMARYBackground: Zamifenacin is a new potent gut M 3 selective muscarinic antagonist developed for possible use in irritable bowel syndrome. Methods: In this multicentre, double-blind, parallel group, placebo-controlled study, the effect of a single dose of zamifenacin 10 mg or 40 mg on both fasting (30 min) and fed (60 min) colonic motor activity was assessed in 36 patients with irritable bowel syndrome (aged 25±68 years; 19 male). Colonic motility was recorded using a ®ve-channel solid-state catheter introduced by colonoscopy to a depth of 35 cm in an unprepared colon. Results: Zamifenacin 40 mg profoundly reduced colonic motility, particularly after the meal (P < 0.05). This was re¯ected by a signi®cant reduction in the mean amplitude of contractions, number of contractions,

Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans

“…The darifenacin-induced delay in intestinal and colonic transit in this study is more pronounced than the effects of alosetron in patients with diarrhea-predominant IBS (31). Indeed, zamifenacin, which is also a relatively selective M 3 antagonist, reduced the postprandial colonic contractile response in IBS (19).…”

Sigmoid‐colonic motility in health and irritable bowel syndrome: a role for 5‐hydroxytryptamine

“…Sigmoid‐colonic motility was recorded using a fine (2.7 mm diameter) flexible solid‐state catheter incorporating five pressure transducers, spaced 5 cm apart (situated 0, 5, 10, 15 and 20 cm from the distal tip) and arranged radially around its circumference (Gaeltec Ltd, Isle of Skye, UK) 18,19 . The tip of catheter was attached to a colonoscope using biopsy forceps and then introduced into the unprepared bowel to a distance of 35 cm from the anus with minimal air inflation.…”

Effect of tolterodine on gastrointestinal transit and bowel habits in healthy subjects

“…constipation) were evaluated by self‐report, which is prone to recall bias and therefore not as accurate as bowel diaries for characterizing bowel habits 6 . While zamifenacin, which is also a relatively selective M3 antagonist, reduced the postprandial colonic contractile response in irritable bowel syndrome, the effects of these antimuscarinic agents on gastrointestinal transit have not been studied 7 . It is important to understand the effects of antimuscarinic agents on gastrointestinal functions because these agents are widely used to treat an overactive bladder in women who may have or be prone to develop constipation, which can impair the quality of life, particularly in the elderly.…”