1. A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation Michael Camilleri, M.D., Rene Kerstens, M.Sc., An Rykx, Ph.D., and Lieve Vandeplassche, D.V.M., Ph.D. N Engl J Med 2008;358:2344-54. R3. 조병현

2. Page  2  Constipation  15~50% of eldery(women>men)  a/w : infrequent bowel movement, hard stools, straining, bloating, feeling of incomplete evacuation after defecation  Mechanism : reduced colonic motility etc.  Prucalopride  selective, high-affinity 5-hydroxytryptamine4(5-HT4) receptor agonist  Increase colonic motility  decrease transit time  Other 5-HT4 receptor agonists  Interact in 5-HT3, 5-HT1b and hERG channel  an unfavorable cardiovascular profile and CNS symptoms Background aimed to determine the efficacy, safety, and effect on quality of life of 2-mg and 4-mg doses of oral prucalopride, given once daily for 12 weeks, in patients with severe chronic constipation

3. Page  3 Research Design and Method  Study - multicenter, randomized, double-blind, placebo-controlled, parallel-group  Patients - age : ≥18 years - chronic constipation :  two or fewer spontaneous, complete bowel movements per week for a minimum of 6 months

4. Page  4 Research Design and Method  Randomization - treatment period : 12wks - run-in phase : 2wks  two or fewer spontaneous, complete bowel movements per week - assigned consecutive numbers, starting with the lowest number - 3 groups : placebo, 2mg of prucalopride, 4mg of prucalopride - taken orally before breakfast  Disallowd medication - laxatives - except  3 or more consecutive days  15mg of bisacodyl  enema

5. Page  5 Research Design and Method  Assessments *Diaries Daily, timing, consistency, degree of straining, sensation of evacuation date & time of intake drug Primary efficacy– proportion of patients having 3 or more spontaneous, complete bowel movements per week during 12 weeks Secondary efficacy-proportion of patients with average increase of one or more spontaneous, complete bowel movements per week as compared with the baseline number *questionnaries PAC-SYM, PAC-QOL, SF-36 *Safety V/S, EKG, Lab tests, P/E,heart rate, QT interval

6. Page  6 RESULTS

7. Page  7 RESULTS

8. Page  8 RESULTS

9. Page  9 RESULTS

10. Page  10 RESULTS Serious adverse events 3 (1.4%) 7 (3.4%) 8 (3.8%) Lab abnormalities  no significant differences

11. Page  11 Conclusion  Over 12 weeks, prucalopride significantly improved bowel function and reduced the severity of symptoms in patients with severe chronic constipation.  Prucalopride given at a dose of 4 mg did not provide an incremental benefit over the 2 mg dose.  Larger and longer-term trials are required(to fully assess the risks and benefits).