The pharmacological properties of the novel selective 5‐HT<sub>3</sub> receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat

Clayton, Nick M.; Sargent, R; Butler, A.; Gale, Jeremy D.; Maxwell, Miles; Hunt, A. A. E.; Barrett, Vikki; Cambridge, D.; Bountra, C; Humphrey, P. P. A.

doi:10.1046/j.1365-2982.1999.00148.x

Cited by 39 publications

(17 citation statements)

References 31 publications

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“…Unfortunately ischaemic colitis remains a concern even at 0.5mg daily despite careful monitoring, with an incidence of 2 per 1000 with alosetron33 and it seems unlikely that alosetron will ever be marketed worldwide. Ondansetron's potency in blocking the 5-HT3 receptor is 3–10 times lower than alosetron,34 which may explain the low incidence of side effects in our study. Ramosetron is another 5-HT3RA, proven effective in IBS-D,35 but unfortunately only marketed in Japan.…”

Section: Discussionmentioning

confidence: 59%

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Garsed

Chernova

Hastings

et al. 2013

Gut

192

158

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BackgroundIrritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D.Methods120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment.ResultsOndansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo −0.9, 95% CI −1.1 to −0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001.ConclusionsOndansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.

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Section: Discussionmentioning

confidence: 59%

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Garsed

Chernova

Hastings

et al. 2013

Gut

192

158

View full text Add to dashboard Cite

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“…32 It potently inhibited the depressor response to CRD, with an ID 50 of 3 μg/kg. The 1.5 ml distention volume at which the ID 50 is calculated was chosen as it produces a submaximal vasomotor response, of a similar magnitude to that evoked by 60– 80 mm Hg barostat inflation (unpublished observations), and thus is well above the nociceptive threshold of approximately 30 mm Hg.…”

Section: Discussionmentioning

confidence: 96%

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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“…In addition, ondansetron has been reported to slow transit in the fasting state in mice (45,46) and rats (12).…”

Section: Discussionmentioning

confidence: 99%

Slowing intestinal transit by PYY depends on serotonergic and opioid pathways

Lin

Neevel

Chen

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Slowing intestinal transit by PYY depends on serotonergic and opioid pathways. Am J Physiol Gastrointest Liver Physiol 286: G558-G563, 2004; 10.1152/ ajpgi.00278.2003.-Slowing of intestinal transit by fat is abolished by immunoneutralization of peptide YY (PYY), demonstrating a key role for this gut peptide. How PYY slows intestinal transit is not known. We tested the hypothesis that the slowing of intestinal transit by PYY may depend on an ondansetron-sensitive serotonergic pathway and a naloxone-sensitive opioid pathway. In a fistulated dog model, occluding Foley catheters were used to compartmentalize the small intestine into proximal (between fistulas) and distal (beyond midgut fistula) half of gut. Buffer (pH 7.0) was perfused into both proximal and distal gut, and PYY was delivered intravenously. Ondansetron or naloxone was mixed with buffer and delivered into either the proximal or distal half of gut. Intestinal transit was measured across the proximal half of the gut. The slowing of intestinal transit by PYY was abolished when either ondansetron or naloxone was delivered into the proximal, but not the distal gut, to localize the two pathways to the efferent limb of the slowing response. In addition, 5-HT slows intestinal transit with marker recovery decreased from 76.2 Ϯ 3.6% (control) to 33.5 Ϯ 2.4% (5-HT) (P Ͻ 0.0001) but was reversed by naloxone delivered into the proximal gut with marker recovery increased to 79.9 Ϯ 7.2% (P Ͻ 0.0005). We conclude that the slowing of intestinal transit by PYY depends on serotonergic neurotransmission via an opioid pathway. ileal brake; intestinal motility; 5-HT; enteric nervous system PEPTIDE YY (PYY), a distal gut peptide released in response to a fatty meal, slows intestinal transit when administered intravenously (47). In addition to this slowing effect on intestinal transit, PYY is considered an inhibitory peptide, because it suppresses gastrin-stimulated acid secretion (1, 42), pancreatic exocrine secretion (1, 40), CCK release (41), and gastric emptying (47). These inhibitory effects of exogenous PYY suggest that it may be responsible for the ileal brake (49), a response that suppresses the digestive activities of the upper gastrointestinal tract when nutrients such as fat reach the distal gut. Immunoneutralization studies (38) confirmed that PYY is a key mediator of the slowing of intestinal transit by the fat-induced ileal brake. It is not known, however, how PYY slows intestinal transit.Previously, we created a fistulated dog model that divided the small intestine into proximal and distal segments. We used it to show that placing fat in the distal half of small intestine slowed transit in the proximal half of small intestine. Because the luminal content of the proximal and distal intestinal segments were not in continuity, this observation indicated that the fat-induced ileal brake occurred via a reflex, whereby the distal segment exposed to fat served as the afferent limb of the reflex and the proximal segment in which intestinal transit was measured serv...

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The pharmacological properties of the novel selective 5‐HT₃ receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat

Cited by 39 publications

References 31 publications

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

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

Slowing intestinal transit by PYY depends on serotonergic and opioid pathways

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The pharmacological properties of the novel selective 5‐HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat

Cited by 39 publications

References 31 publications

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

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

Slowing intestinal transit by PYY depends on serotonergic and opioid pathways

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The pharmacological properties of the novel selective 5‐HT₃ receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat