Alosetron, a 5HT3-receptor antagonist, is effective in the treatment of female irritable bowel syndrome patients

Northcutt, AR; Camilleri, Michael; Mayer, E.A.; Drossman, D. A.; Ge, Di; Ehsanullah, Rsb; Hamm, LR; Harding, JP; Heath, AT; Jacques, Loretta; Wolfe, Steven G.; Kong, S; McSorley, David; Mangel, AW

doi:10.1016/s0016-5085(98)83311-8

Cited by 21 publications

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“…The site(s) of action of alosetron were not established in the present study, but could be at the level of the enteric or primary sensory neurone, or via spinal or supraspinal neuronal circuits concerned with the modulation of nociceptive transmission. Based on these data, in addition to recent studies indicating that alosetron decreases symptoms of abdominal pain in patients with irritable bowel syndrome,5 7 alosetron may be of potential use in the treatment of visceral pain conditions.…”

Section: Discussionmentioning

confidence: 80%

The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

Kozlowski

2000

Gut

144

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Background-Noxious intestinal distention elicits a reflex depressor response in the sodium pentobarbitone anaesthetised rat, which can be used as an index of visceral nociception. 5-HT 3 receptor antagonists inhibit this reflex. Repeated colorectal distention (CRD) induces Fos like immunoreactivity (Fos-LI) in the rat spinal cord. Aims-To examine the eVect of the 5-HT 3 receptor antagonist alosetron on the depressor response to CRD, and on Fos expression in the lumbosacral spinal cord. Methods-Male rats were anaesthetised with sodium pentobarbitone, and mean arterial blood pressure monitored during repeated colorectal balloon inflation before and after treatment with alosetron or saline. Rats anaesthetised with urethane and treated with alosetron or saline underwent a repeated CRD paradigm, after which the lumbosacral spinal cord was removed and processed for visualisation of Fos-LI. Results-CRD elicited reproducible, volume dependent falls in arterial blood pressure, and repeated distention-eVect curves were constructed. Alosetron (1-100 µg/kg intravenously) inhibited the depressor response to CRD in a dose related manner, with an ID 50 value of 3.0 µg/kg. Following repeated CRD, numbers of Fos-LI neurones were significantly increased to 1246 (total in 12 sections at 120 µm intervals from L6 to S1) compared with 49 in sham distended animals. Pretreatment with alosetron (100 µg/kg) significantly reduced numbers of Fos-LI neurones to 479.8. Conclusion-The 5-HT 3 receptor antagonist alosetron inhibits the depressor response to CRD in a potent and dose dependent manner. It also inhibits CRD induced Fos-LI in the spinal cord. These results suggest that 5-HT 3 receptors are involved in visceral nociceptive transmission, perhaps located on primary aVerent or spinal neurones. (Gut 2000;46:474-480)

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Section: Discussionmentioning

confidence: 80%

The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

Kozlowski

2000

Gut

144

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“…For example, in a tricyclic antidepressant study, a standard measure of depression (Hamilton-D score) was used as it was anticipated that a significant proportion of enrolled patients would be depressed 30. Northcutt and colleagues60 used adequate pain relief as an outcome measure in their study of alosteron, a 5-HT 3 receptor antagonist. In a review, Talley and colleagues57 strongly proposed the need to develop sensitive symptom outcome measures as a priority among their recommendations to optimise IBS trials.…”

Section: Discussionmentioning

confidence: 99%

Treatment of irritable bowel syndrome: a review of randomised controlled trials

Akehurst

Kaltenthaler²

2001

Gut

148

100

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SummaryIrritable bowel syndrome (IBS) is a common chronic disorder that is associated with significant disability and health care costs. The purpose of this paper is to review and assess published randomised controlled trials examining the clinical eVectiveness of interventions for IBS for 1987-1998. A literature search was conducted to identify randomised controlled trials of IBS treatments: 45 studies were identified that described randomised controlled trials and of these, six fulfilled all three criteria used to assess the quality of randomised controlled trials, as described by Jadad and colleagues.

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“…In healthy volunteers, ondansetron has been shown to slow transit in the left but not the right colon 51 . Alosetron, like ondansetron, slows colonic transit, decreases stool frequency and improves consistency in IBS patients with predominant symptoms of diarrhoea 42 , 47 , 52 , 53 …”

Section: Rationale For Use Of a 5‐ht3 Receptor Antagonist In Ibsmentioning

confidence: 99%

Review article: the therapeutic potential of 5‐HT₃ receptor antagonists in the treatment of irritable bowel syndrome

Humphrey

Bountra

Clayton

et al. 1999

Aliment Pharmacol Ther

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There is evidence from studies, in both animals and humans, that 5‐HT3 receptor blockade has potential value in the treatment of irritable bowel syndrome, particularly in those patients with diarrhoea‐predominant bowel habits. New findings suggest that 5‐HT3 receptors exist on gut afferent neurones and that their activation by locally released 5‐HT leads to visceral nociceptive stimulation, in addition to increased neuronally‐mediated motor and secretory activity. If this concept is validated, it will provide a rationale for the use of 5‐HT3 receptor antagonists in patients with increased gut motility, reduced fluid absorption and low nociceptive thresholds leading to abdominal pain. Alosetron is a highly selective, potent 5‐HT3 receptor antagonist which is well absorbed with a long pharmacodynamic half‐life. Its ability to provide long‐lasting blockade of 5‐HT3 receptors throughout the body make it an ideal candidate within its class to evaluate the clinical hypothesis that sustained and ubiquitous 5‐HT3 receptor blockade is of value in the treatment of IBS.

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Alosetron, a 5HT3-receptor antagonist, is effective in the treatment of female irritable bowel syndrome patients

Cited by 21 publications

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The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

Treatment of irritable bowel syndrome: a review of randomised controlled trials

Review article: the therapeutic potential of 5‐HT₃ receptor antagonists in the treatment of irritable bowel syndrome

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Alosetron, a 5HT3-receptor antagonist, is effective in the treatment of female irritable bowel syndrome patients

Cited by 21 publications

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The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

Treatment of irritable bowel syndrome: a review of randomised controlled trials

Review article: the therapeutic potential of 5‐HT3 receptor antagonists in the treatment of irritable bowel syndrome

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Product

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Review article: the therapeutic potential of 5‐HT₃ receptor antagonists in the treatment of irritable bowel syndrome