title: Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation.
abstract: BACKGROUND
  Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC).
  
  
  OBJECTIVE
  To assess the effects of highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC.
  
  
  METHODS
  We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5-HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention-to-treat analyses, pooled using a random-effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI).
  
  
  RESULTS
  Main outcomes included stool frequency, Patient-Assessment of Constipation Quality of Life (PAC-QOL), PAC of symptoms (PAC-SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5-HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23-2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC-QOL and PAC-SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5-HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride.
  
  
  CONCLUSIONS
  Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5-HT4 agonists in the treatment of chronic constipation.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), College of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shin
authors.forename: M
authors.initials: M
authors.lastname: Camilleri
authors.forename: G
authors.initials: G
authors.lastname: Kolar
authors.forename: P
authors.initials: P
authors.lastname: Erwin
authors.forename: C P
authors.initials: CP
authors.lastname: West
authors.forename: M H
authors.initials: MH
authors.lastname: Murad
mesh_terms: D000328:Adult; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001572:Benzofurans / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D003672:Defecation / Q000187:drug effects*; D006801:Humans; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011788:Quality of Life; D011812:Quinuclidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D058828:Serotonin 5-HT4 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D053961:Azabicyclo Compounds; D001549:Benzamides; D001572:Benzofurans; D011812:Quinuclidines; D058828:Serotonin 5-HT4 Receptor Agonists; C533727:TD-5108; C517618:ATI 7505; C406662:prucalopride; D011092:Polyethylene Glycols