Original Contribution
The American Journal of Gastroenterology (2005) 100, 652–663; doi:10.1111/j.1572-0241.2005.41081.x
Effect of CCK-1 Antagonist, Dexloxiglumide, in Female Patients with Irritable Bowel Syndrome: A Pharmacodynamic and Pharmacogenomic Study
Filippo Cremonini MD1, Michael Camilleri MD1, Sanna McKinzie MS1, Paula Carlson BS1, Christopher E Camilleri1, Duane Burton1, George Thomforde BS1, Raul Urrutia MD1 and Alan R Zinsmeister PhD1
1Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit; and Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota
Correspondence: Michael Camilleri, MD, Mayo Clinic – Charlton 8-110, 200 First Street S.W., Rochester, MN 55905
Received 1 July 2004; Revised 0000; Accepted 20 September 2004.
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 t1/2 (p= 0.004), and slower ascending colon emptying t1/2 (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.
