Effect of a novel 5-HT3 receptor agonist MKC-733 on upper gastrointestinal motility in humans


Professor R. C. Spiller, Division of Gastroenterology, University Hospital, Nottingham, NG7 2UH, UK.
E-mail: robin.spiller@nottingham.ac.uk


Background : Although 5-HT3 antagonists have been used to treat chemotherapy-induced emesis and diarrhoea-predominant irritable bowel syndrome, the effects of 5-HT3 agonists in humans are unknown.

Aim : To determine the effect of MKC-733, a selective 5-HT3 receptor agonist, on upper gastrointestinal motility.

Methods : Oral MKC-733 (0.2, 1 and 4 mg) was compared with placebo in three randomized, double-blind, cross-over studies in healthy males. Antroduodenal manometry was recorded for 8 h during fasting and 3 h post-prandially (n = 12). Gastric emptying and small intestinal transit were determined by gamma-scintigraphy (n = 16). Gastric emptying, accommodation and antral motility were determined by echoplanar magnetic resonance imaging (n = 12).

Results : MKC-733 (4 mg) increased the number of migrating motor complexes recorded in the antrum and duodenum (P < 0.001), but had no effect on post-prandial motility. MKC-733 delayed scintigraphically assessed liquid gastric emptying (P = 0.005) and accelerated small intestinal transit (P = 0.038). Echoplanar magnetic resonance imaging confirmed the delayed gastric emptying (P < 0.001) and demonstrated a significant increase in cross-sectional area of the proximal stomach (P < 0.01).

Conclusions : MKC-733 delays liquid gastric emptying in association with relaxation of the proximal stomach, stimulates fasting antroduodenal migrating motor complex activity and accelerates small intestinal transit.