Prucalopride

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Prucalopride
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Systematic (IUPAC) name
4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]
Routes of
administration		 Oral
Identifiers
CAS Number 179474-81-8
ATC code A03AE04 (WHO)
PubChem CID 3052762
IUPHAR/BPS 243
Chemical data
Formula C18H26ClN3O3
Molar mass 367.870 g/mol[[Script error: No such module "String".]]
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Prucalopride (brand name Resolor, developed by Movetis) is a drug acting as a selective, high affinity 5-HT4 receptor agonist[1] which targets the impaired motility associated with chronic constipation, thus normalising bowel movements.[2][3][4][5]

Mechanism of action

Prucalopride, a first in class dihydrobenzofurancarboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities.[6] Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force to defecation.

The observed effects are exerted via highly selective action on 5-HT4 receptors[6]: prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.[1][7] Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ channel respectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs.[7] Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.[6]

Pharmacokinetics

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 of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). 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,[8] 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.[6]

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.[6]

Efficacy

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.[5][9][10] Further measures are improvements in PAC-QOL[11] (a quality of life measure) and PAC-SYM[12] (a range of stool, abdominal, and rectal 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.[13][14][15][16][17]

In three large, well designed 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 with placebo.[5][9][10] 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).[5][9][10] 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.[18][19]

Side effects

Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.[6]

Prescribing information

In the EEA, prucalopride is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. The recommended dosage in adults is 2 mg administered orally once daily; exceeding this dosage is not expected to increase efficacy. The recommended starting dose in elderly patients (>65 years) is 1 mg once daily; thereafter the dosage can be increased to 2 mg once daily, if needed.[6]

Contraindications

Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, and ulcerative colitis and toxic megacolon/megarectum.[6]

References

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External links

Drugs for
functional bowel disorders
Tertiary
amino group
Other
Belladonna and derivatives
(antimuscarinics)
tertiary amines: Atropine · Hyoscyamine
quaternary ammonium compounds: Scopolamine (Butylscopolamine, Methylscopolamine) · Methylatropine · Fentonium · Cimetropium bromide
Propulsives
  1. ↑ 1.0 1.1 Briejer, MR; Bosmans, JP; Van Daele, P; Jurzak, M; Heylen, L; Leysen, JE; Prins, NH; Schuurkes, JA (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. PMID 11438309.  edit
  2. ↑ Bouras, EP; Camilleri, M; Burton, DD; McKinzie, S (1999). "Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans". Gut. 44 (5): 682–6. doi:10.1136/gut.44.5.682. PMC 1727485 Freely accessible. PMID 10205205.  edit
  3. ↑ Bouras, EP; Camilleri, M; Burton, DD; Thomforde, G; McKinzie, S; Zinsmeister, AR (2001). "Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder". Gastroenterology. 120 (2): 354–60. doi:10.1053/gast.2001.21166. PMID 11159875.  edit
  4. ↑ Briejer, MR; Prins, NH; Schuurkes, JA (2001). "Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs". Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 13 (5): 465–72. PMID 11696108.  edit
  5. ↑ 5.0 5.1 5.2 5.3 Tack, J.; Van Outryve, M.; Beyens, G.; Kerstens, R.; Vandeplassche, L. (2008). "Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives". Gut. 58 (3): 357. doi:10.1136/gut.2008.162404. PMID 18987031.  edit
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 SmPC. Summary of product characteristics Resolor (prucalopride) October, 2009: 1-9.
  7. ↑ 7.0 7.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  8. ↑ Frampton, J. E. (2009). "Prucalopride". Drugs. 69 (17): 2463. doi:10.2165/11204000-000000000-00000. PMID 19911858.  edit
  9. ↑ 9.0 9.1 9.2 Camilleri, M.; Kerstens, R.; Rykx, A.; Vandeplassche, L. (2008). "A Placebo-Controlled Trial of Prucalopride for Severe Chronic Constipation". New England Journal of Medicine. 358 (22): 2344. doi:10.1056/NEJMoa0800670. PMID 18509121.  edit
  10. ↑ 10.0 10.1 10.2 Quigley, E. M. M.; Vandeplassche, L.; Kerstens, R.; Ausma, J. (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. doi:10.1111/j.1365-2036.2008.03884.x. PMID 19035970.  edit
  11. ↑ Marquis, P.; De La Loge, C.; Dubois, D.; McDermott, A.; Chassany, O. (2005). "Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire". Scandinavian Journal of Gastroenterology. 40 (5): 540. doi:10.1080/00365520510012208. PMID 16036506.  edit
  12. ↑ Frank, L; Kleinman, L; Farup, C; Taylor, L; Miner Jr, P (1999). "Psychometric validation of a constipation symptom assessment questionnaire". Scandinavian journal of gastroenterology. 34 (9): 870–7. doi:10.1080/003655299750025327. PMID 10522604.  edit
  13. ↑ Johanson, JF; Kralstein, J (2007). "Chronic constipation: a survey of the patient perspective". Alimentary pharmacology & therapeutics. 25 (5): 599–608. doi:10.1111/j.1365-2036.2006.03238.x. PMID 17305761. 
  14. ↑ Koch, A; Voderholzer, WA; Klauser, AG; Müller-Lissner, S (1997). "Symptoms in chronic constipation". Diseases of the colon and rectum. 40 (8): 902–6. doi:10.1007/BF02051196. PMID 9269805.  edit
  15. ↑ McCrea, G. L.; Miaskowski, C.; Stotts, N. A.; MacEra, L.; Paul, S. M.; Varma, M. G. (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. doi:10.1016/j.genm.2009.04.007. PMID 19467522.  edit
  16. ↑ Pare, P.; Ferrazzi, S.; Thompson, W. G.; Irvine, E. J.; Rance, L. (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. doi:10.1111/j.1572-0241.2001.05259.x. PMID 11721760.  edit
  17. ↑ Wald, A.; Scarpignato, C.; Kamm, M. A.; Mueller-Lissner, S.; Helfrich, I.; Schuijt, C.; Bubeck, J.; Limoni, C.; Petrini, O. (2007). "The burden of constipation on quality of life: results of a multinational survey". Alimentary Pharmacology & Therapeutics. 26 (2): 227. doi:10.1111/j.1365-2036.2007.03376.x. PMID 17593068.  edit
  18. ↑ 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. 
  19. ↑ 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. 
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