5-HT4 receptor antagonism in irritable bowel syndrome: effect of SB-207266-A on rectal sensitivity and small bowel transit.
BACKGROUND
Pre-clinical studies indicate that the 5-hydroxytryptamine (5-HT)4 receptor may be involved in the pathophysiology of irritable bowel syndrome and that antagonism of this receptor may be an effective therapeutic strategy.


OBJECTIVE
To investigate the effects of SB-207266-A, a selective 5-HT4 receptor antagonist on rectal sensitivity and small bowel transit in patients with irritable bowel syndrome.


METHODS
Eighteen patients with diarrhoea-predominant irritable bowel syndrome and a history of increased rectal sensitivity were randomized to receive either SB-207266-A (20 mg) or placebo for 10 days. Following a washout period, patients were then crossed over to receive the alternative therapy for 10 days. Rectal sensitivity and orocaecal transit time were assessed on day 10 of each treatment period. In addition, patients were asked whether they had experienced any changes in their symptoms.


RESULTS
Fifteen patients completed the study. SB-207266-A significantly increased orocaecal transit time towards normal (placebo: 5.3 h (4.0-7.2 h), mean (IQR) vs. SB-207266-A: 6.5 h (4.8-8.0 h); P=0.027) and tended to decrease rectal sensitivity (volume to discomfort 89 mL (60-150 mL), geometric mean (IQR) vs. 107 mL (75-150 mL); P=0.134). Eleven out of 15 patients reported symptomatic improvements with SB-207266-A but none with placebo. SB-207266-A was well tolerated.


CONCLUSIONS
Our results support a role for the 5-HT4 receptor in the pathophysiology of irritable bowel syndrome and suggest that the selective 5-HT4 antagonist, SB-207266-A, is worthy of further evaluation in this disorder.
Houghton
L A
LA
Department of Medicine, University Hospital of South Manchester, Manchester, UK.
Jackson
N A
NA
Whorwell
P J
PJ
Cooper
S M
SM
D000328:Adult; D000368:Aged; D002404:Catheterization; D003109:Colonic Diseases, Functional / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D003967:Diarrhea / Q000188:drug therapy / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007421:Intestine, Small / Q000187:drug effects; D008297:Male; D008365:Manometry; D008875:Middle Aged; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044422:Receptors, Serotonin, 5-HT4; D012007:Rectum / Q000503:physiopathology*; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000627:therapeutic use*
D007211:Indoles; D010880:Piperidines; D011985:Receptors, Serotonin; C096919:SB 207266; D012702:Serotonin Antagonists; D044422:Receptors, Serotonin, 5-HT4