Prucalopride, sold under brand namesResolor andMotegrity among others, is amedication acting as a selective, high affinity5-HT4 receptoragonist[5] which targets the impaired motility associated with chronicconstipation, thus normalizing bowel movements.[6][7][8][9][10][11] Prucalopride was approved for medical use in the European Union in 2009,[4] in Canada in 2011,[12] in Israel in 2014,[13] and in the United States in December 2018.[14]
The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.[11][15][16] Further measures are improvements in PAC-QOL[17] (a quality of life measure) and PAC-SYM[18] (a range ofstool,abdominal, andrectal symptoms associated with chronic constipation). Infrequent bowel movements,bloating, straining,abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.[19][20][21][22][23]
In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than withplacebo.[11][15][16] There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).[11][15][16] The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.[24][25]
Small clinical trials suggested that prucalopride administration results in the 5-HT4 receptor agonism-associated memory enhancing in healthy participants improving their ability to recall and increasing neural activation in the hippocampus and functionally related areas.[26][27]
Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects areheadache andgastrointestinal symptoms (abdominal pain,nausea ordiarrhea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.[2]
Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinityserotonin (5-HT4) receptor agonist with enterokinetic activities.[2]
The observed effects are exerted via highly selective action on 5-HT4 receptors:[2] prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.[5][28] Prucalopride differs from other 5-HT4 agonists such astegaserod andcisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiachuman ether-a-go-go K+ or hERG channel respectively) and this may account for the adversecardiovascular events that have resulted in the restricted availability of these drugs.[28]Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.[2]
Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed.Metabolism is not the major route of elimination.In vitro, human liver metabolism is very slow and only minor amounts ofmetabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose inurine and at least 6% infeces).Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,[29] and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.[2]
In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.[2]
In theEuropean Economic Area, prucalopride was originally authorized for thesymptomatic treatment of chronic constipation in women in whomlaxatives fail to provide adequate relief.[2] Subsequently, it has been authorized by the European Commission for use in all adults for the same indication.[30]
^abBriejer MR, Bosmans JP, Van Daele P, Jurzak M, Heylen L, Leysen JE, et al. (June 2001). "The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound".European Journal of Pharmacology.423 (1):71–83.doi:10.1016/S0014-2999(01)01087-1.PMID11438309.{{cite journal}}: CS1 maint: overridden setting (link)
^Clinical trial numberNCT00793247 for "Efficacy Study of Prucalopride to Treat Chronic Intestinal Pseudo-Obstruction (CIP)" atClinicalTrials.gov
^abcdTack J, van Outryve M, Beyens G, Kerstens R, Vandeplassche L (March 2009). "Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives".Gut.58 (3):357–65.doi:10.1136/gut.2008.162404.PMID18987031.S2CID206948212.
^abcQuigley EM, Vandeplassche L, Kerstens R, Ausma J (February 2009). "Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation--a 12-week, randomized, double-blind, placebo-controlled study".Alimentary Pharmacology & Therapeutics.29 (3):315–28.doi:10.1111/j.1365-2036.2008.03884.x.PMID19035970.S2CID40122406.
^Marquis P, De La Loge C, Dubois D, McDermott A, Chassany O (May 2005). "Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire".Scandinavian Journal of Gastroenterology.40 (5):540–51.doi:10.1080/00365520510012208.PMID16036506.S2CID34620643.
^Frank L, Kleinman L, Farup C, Taylor L, Miner P (September 1999). "Psychometric validation of a constipation symptom assessment questionnaire".Scandinavian Journal of Gastroenterology.34 (9):870–7.doi:10.1080/003655299750025327.PMID10522604.
^Koch A, Voderholzer WA, Klauser AG, Müller-Lissner S (August 1997). "Symptoms in chronic constipation".Diseases of the Colon and Rectum.40 (8):902–6.doi:10.1007/BF02051196.PMID9269805.S2CID28066729.
^McCrea GL, Miaskowski C, Stotts NA, Macera L, Paul SM, Varma MG (April 2009). "Gender differences in self-reported constipation characteristics, symptoms, and bowel and dietary habits among patients attending a specialty clinic for constipation".Gender Medicine.6 (1):259–71.doi:10.1016/j.genm.2009.04.007.PMID19467522.
^Pare P, Ferrazzi S, Thompson WG, Irvine EJ, Rance L (November 2001). "An epidemiological survey of constipation in canada: definitions, rates, demographics, and predictors of health care seeking".The American Journal of Gastroenterology.96 (11):3130–7.doi:10.1111/j.1572-0241.2001.05259.x.PMID11721760.S2CID8578282.
^Camilleri M, Beyens G, Kerstens R, Vandeplassche L (2009). "Long-term follow-up of safety and satisfaction with bowel function in response to oral prucalopride in patients with chronic constipation [Abstract]".Gastroenterology.136 (Suppl 1): 160.doi:10.1016/s0016-5085(09)60143-8.
^Van Outryve MJ, Beyens G, Kerstens R, Vandeplassche L (2008). "Long-term follow-up study of oral prucalopride (Resolor) administered to patients with chronic constipation [Abstract T1400]".Gastroenterology.134 (4 (suppl 1)): A547.doi:10.1016/s0016-5085(08)62554-8.
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