Faculty Collaboration Database

Effect of CCK-1 antagonist, dexloxiglumide, in female patients with irritable bowel syndrome: a pharmacodynamic and pharmacogenomic study. Am J Gastroenterol 2005 Mar;100(3):652-63

Date

03/04/2005

Pubmed ID

15743365

DOI

10.1111/j.1572-0241.2005.41081.x

Scopus ID

2-s2.0-16844364043 (requires institutional sign-in at Scopus site)   91 Citations

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.

AIMS: 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.

Author List

Cremonini F, Camilleri M, McKinzie S, Carlson P, Camilleri CE, Burton D, Thomforde G, Urrutia R, Zinsmeister AR

Author

Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Constipation
Double-Blind Method
Female
Gastric Emptying
Gastrointestinal Transit
Humans
Irritable Bowel Syndrome
Patient Compliance
Pentanoic Acids
Polymorphism, Genetic
Receptors, Cholecystokinin