title: Effect of MKC-733, a 5-HT receptor partial agonist, on bowel motility and symptoms in subjects with constipation: an exploratory study.
abstract: BACKGROUND
  MKC-733, a 5-HT(3) receptor partial agonist, is a novel enteroprokinetic compound.
  
  
  OBJECTIVE
  The aim of this study was to explore the effects of MKC-733 on bowel motility and symptoms in a small group of subjects with constipation. Tolerability was also examined.
  
  
  METHODS
  The study was conducted in a single-blind and dose-escalation manner on 14 male and female subjects with constipation aged 22-67 years. After a 1 week run-in period, subjects were treated with placebo (b.i.d.) for 1 week, and 0.2 and 0.5 mg of MKC-733 (b.i.d.) for 2 weeks sequentially. Geometric mean and per cent elimination of surrogate markers of bowel motility were measured by a radio-opaque marker technique at the end of each treatment period. They were analysed on the whole group and subgroups with low (n = 6) and high (n = 8) bowel motility based upon the geometric mean value after placebo treatment. Subjects kept diaries of their bowel habits and gastrointestinal symptoms.
  
  
  RESULTS
  Percent elimination increased after treatment with 0.5 mg MKC-733 compared with placebo treatment in the whole group (70.4 +/- 33.5% vs. 47.1 +/- 36.6%, mean +/- SD, P < 0.05). In the low bowel motility group, both geometric mean and percent elimination increased after treatment with 0.5 mg MKC-733 compared with placebo (7.1 +/- 0.9 vs. 5.9 +/- 0.5, P < 0.05; 60.0 +/- 35.8% vs. 13.3 +/- 19.4%, P < 0.05). Stool frequency increased after the first-week treatment with MKC-733 compared with placebo (P < 0.05). Numbers of sensation of incomplete evacuation and gastrointestinal symptoms decreased to half and less after the treatment with MKC-733. No serious adverse effect was noted.
  
  
  CONCLUSIONS
  Multiple doses of 0.5 mg MKC-733 improve bowel motility, which was clearly demonstrated in the subjects with decreased bowel motility. MKC-733 at the doses studied might be effective in increasing stool frequency and reduce gastrointestinal symptoms related to constipation. MKC-733 was well tolerated. Further studies will be needed to clarify efficacy and safety of MKC-733 on a larger population.
authors.affiliation: Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan. tomoe@kitasato-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: S
authors.initials: S
authors.lastname: Yokota
authors.forename: M
authors.initials: M
authors.lastname: Sawada
authors.forename: M
authors.initials: M
authors.lastname: Majima
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtani
authors.forename: Y
authors.initials: Y
authors.lastname: Kumagai
mesh_terms: D000328:Adult; D000368:Aged; D003248:Constipation / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D005243:Feces; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011812:Quinuclidines / Q000009:adverse effects / Q000627:therapeutic use*; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D011725:Pyridines; D011812:Quinuclidines; D017366:Serotonin Receptor Agonists; C482040:Pumosetrag