title: Systematic review: cardiovascular safety profile of 5-HT(4)  agonists developed for gastrointestinal disorders.
abstract: BACKGROUND
  The nonselective 5-HT(4) receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs).
  
  
  OBJECTIVE
  To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT(4) agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy.
  
  
  METHODS
  Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.
  
  
  RESULTS
  Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT(4) agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT(4) agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT(1) receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT(4) agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT(4) agonists with no hERG or 5-HT(1) affinity (renzapride, clebopride, mosapride).
  
  
  CONCLUSIONS
  5-HT(4) agonists for GI disorders differ in chemical structure and selectivity for 5-HT(4) receptors. Selectivity for 5-HT(4) over non-5-HT(4) receptors may influence the agent's safety and overall risk-benefit profile. Based on available evidence, highly selective 5-HT(4) agonists may offer improved safety to treat patients with impaired GI motility.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Leuven, Belgium. jan.tack@med.kuleuven.be
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.forename: M
authors.initials: M
authors.lastname: Camilleri
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.forename: W D
authors.initials: WD
authors.lastname: Chey
authors.forename: J J
authors.initials: JJ
authors.lastname: Galligan
authors.forename: B E
authors.initials: BE
authors.lastname: Lacy
authors.forename: S
authors.initials: S
authors.lastname: Müller-Lissner
authors.forename: E M M
authors.initials: EM
authors.lastname: Quigley
authors.forename: J
authors.initials: J
authors.lastname: Schuurkes
authors.forename: J H
authors.initials: JH
authors.lastname: De Maeyer
authors.forename: V
authors.initials: V
authors.lastname: Stanghellini
mesh_terms: D002318:Cardiovascular Diseases / Q000139:chemically induced*; D020117:Cisapride / Q000009:adverse effects / Q000494:pharmacology; D005765:Gastrointestinal Agents / Q000009:adverse effects* / Q000494:pharmacology; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D058828:Serotonin 5-HT4 Receptor Agonists / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D005765:Gastrointestinal Agents; D007211:Indoles; D058828:Serotonin 5-HT4 Receptor Agonists; C105050:tegaserod; D020117:Cisapride