Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?

Maxton, D. G.; Morris, Julie; Whorwell, Peter J.

doi:10.1046/j.1365-2036.1996.30172000.x

Cited by 94 publications

(73 citation statements)

References 12 publications

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“…However, neither trimebutine maleate, ondansetron, nor atropine sulfate attenuated abdominal contractions in this study, indicating that peripheral opiate, 5-hydroxytryptamine 3 , and muscarinic receptors do not participate in the viscerosensory response. These findings are in agreement with those of previous studies (Poynard et al, 1994;Maxton et al, 1996). Other candidate receptors known to be associated with visceral pain are tachykinin NK 2 , calcitonin gene-related peptide, and N-methyl-D-aspartate receptors (McLean et al, 1997;Plourde et al, 1997;Olivar and Laird, 1999); however, further studies will be required to clarify the involvement of these receptors in the viscerosensory responses caused by colorectal distention in rabbits.…”

supporting

confidence: 82%

Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

Okano

Ikeura²,

Inatomi³

2002

J Pharmacol Exp Ther

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Irritable bowel syndrome (IBS) is a common disorder mainly characterized by altered bowel habits and visceral pain. In this study, we investigated the role of tachykinin NK 1 receptors in the visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective tachykinin NK 1 receptor antagonists TAK-637 [(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-Intracolorectal administration of 0.8% acetic acid solution enhanced the nociceptive response to colorectal distention, producing a significant increase in the number of abdominal muscle contractions. Under these conditions, intraduodenal TAK-637 (0.1-3 mg/kg) dose dependently decreased the number of distention-induced abdominal contractions, and a significant inhibitory effect was observed with doses of 0.3 to 3 mg/kg. Another tachykinin NK 1 antagonist, (Ϯ)-CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of TAK-637 (which has very weak tachykinin NK 1 receptor antagonistic activity), trimebutine maleate, ondansetron, and atropine sulfate did not inhibit the abdominal response. The main metabolite of TAK-637, which has more potent tachykinin NK 1 receptor antagonistic activity but permeates the central nervous system less well than TAK-637, produced less inhibition of the viscerosensory response. When given intrathecally, TAK-637 and (Ϯ)-CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that tachykinin NK 1 receptors play an important role in mediating visceral pain and that TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing tachykinin NK 1 receptors, mainly in the spinal cord. They also suggest that TAK-637 may be useful in treating functional bowel disorders such as IBS.

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confidence: 82%

Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

Okano

Ikeura²,

Inatomi³

2002

J Pharmacol Exp Ther

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“…43,44 Furthermore, clinical trials of ondansetron on diarrhoea-predominant irritable bowel syndrome have been rather disappointing. 40,41 Thus, there is currently a strong need for more effective forms of therapy for irritable bowel syndrome particularly as it represents such a large work load for gastroenterologists as well as primary care physicians. 45±47 The results of this study show that a selective M 3 receptor antagonist can signi®cantly inhibit food-stimulated distal colonic motility with relatively minor anticholinergic side-effects.…”

Section: Discussionmentioning

confidence: 99%

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

Houghton¹,

Rogers

Whorwell³

et al. 1997

Aliment Pharmacol Ther

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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,

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“…The increased fasting small bowel water did not appear to be associated with symptoms like bloating in our volunteers and in one clinical trial, ondansetron did not worsen bloating. 37 Our technique only measures volume, although if combined with orocaecal transit time, a flow index can be calculated as we did in a previous study, 13 but this measurement was not made in the current study.…”

Section: Discussionmentioning

confidence: 99%

Effects of a 5‐HT₃ antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging

Marciani

Wright

Foley

et al. 2010

Aliment Pharmacol Ther

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SUMMARYBackground 5-HT 3 antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility.

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Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?

Abstract: The results of this study justify evaluation of the therapeutic potential of selective 5-HT antagonists in both functional dyspepsia and irritable bowel syndrome.

Cited by 94 publications

References 12 publications

Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

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

Effects of a 5‐HT₃ antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging

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Selective 5‐hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?

Abstract: The results of this study justify evaluation of the therapeutic potential of selective 5-HT antagonists in both functional dyspepsia and irritable bowel syndrome.

Cited by 94 publications

References 12 publications

Effects of Tachykinin NK1 Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

Effects of Tachykinin NK1 Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

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

Effects of a 5‐HT3 antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging

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Product

Resources

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Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

Effects of Tachykinin NK₁ Receptor Antagonists on the Viscerosensory Response Caused by Colorectal Distention in Rabbits

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

Effects of a 5‐HT₃ antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging