TY - JOUR
T1 - Systematic review
T2 - Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders
AU - Tack, J.
AU - Camilleri, M.
AU - Chang, L.
AU - Chey, W. D.
AU - Galligan, J. J.
AU - Lacy, B. E.
AU - Müller-Lissner, S.
AU - Quigley, Eamonn Martin
AU - Schuurkes, J.
AU - De Maeyer, J. H.
AU - Stanghellini, V.
PY - 2012/4
Y1 - 2012/4
N2 - Background The nonselective 5-HT 4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim 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UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.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.
AB - Background The nonselective 5-HT 4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim 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.
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U2 - 10.1111/j.1365-2036.2012.05011.x
DO - 10.1111/j.1365-2036.2012.05011.x
M3 - Review article
C2 - 22356640
AN - SCOPUS:84858287886
VL - 35
SP - 745
EP - 767
JO - Alimentary Pharmacology and Therapeutics
JF - Alimentary Pharmacology and Therapeutics
SN - 0269-2813
IS - 7
ER -