title: Effect of CCK-1 antagonist, dexloxiglumide, in female patients with irritable bowel syndrome: a pharmacodynamic and pharmacogenomic study.
abstract: BACKGROUND
  Cholecystokinin (CCK) is involved in gastrointestinal motor response to meals. The potential role of CCK receptor antagonists in functional gastrointestinal disorders is unclear.
  
  
  OBJECTIVE
  To evaluate the effects of dexloxiglumide, a CCK-1 receptor antagonist, on gastrointestinal transit (GIT) and symptoms in patients with constipation-predominant IBS (C-IBS); and to explore the influence of CCK-1 receptor polymorphisms on gut transit and the pharmacodynamic response to therapy.
  
  
  METHODS
  A total of 36 patients with C-IBS and normal to slow baseline colonic transit (CT) were randomized (double-blind, parallel design) to 7 days of dexloxiglumide 200 mg or placebo t.i.d. Daily bowel habits diaries and weekly relief of IBS symptoms were recorded. At the end of treatment, GIT and CT were measured. Peripheral blood DNA was examined for polymorphisms in genes controlling CCK: four related to CCK-1, one to the CCK gene promoter, and one related to CCK-2. The distributions of allelic variants and association with gastric emptying in response to dexloxiglumide and placebo were assessed.
  
  
  RESULTS
  Dexloxiglumide was associated with accelerated gastric emptying t(1/2) (p= 0.004), and slower ascending colon emptying t(1/2) (p < 0.01), with no significant effect on overall CT or satisfactory relief of IBS. There was an association between CCK 779T > C polymorphism and slower rate of gastric emptying (p= 0.04).
  
  
  CONCLUSIONS
  Dexloxiglumide accelerates gastric emptying and delays proximal but not overall CT in patients with C-IBS. Dexloxiglumide does not accelerate transit in C-IBS. The role of CCK-1 gene polymorphisms in delaying gastric emptying and in determining response to therapy deserves further study.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Filippo
authors.initials: F
authors.lastname: Cremonini
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Sanna
authors.initials: S
authors.lastname: McKinzie
authors.forename: Paula
authors.initials: P
authors.lastname: Carlson
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Camilleri
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.forename: George
authors.initials: G
authors.lastname: Thomforde
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000328:Adult; D003248:Constipation / Q000188:drug therapy; D004311:Double-Blind Method; D005260:Female; D005746:Gastric Emptying; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D010349:Patient Compliance; D010421:Pentanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; C103490:dexloxiglumide