Systematic review: Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders

J. Tack, Michael Camilleri, L. Chang, W. D. Chey, J. J. Galligan, B. E. Lacy, S. Müller-Lissner, E. M M Quigley, J. Schuurkes, J. H. De Maeyer, V. Stanghellini

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

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UEGW 2006-2008 and DDW 2008-2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.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.

Original languageEnglish (US)
Pages (from-to)745-767
Number of pages23
JournalAlimentary Pharmacology and Therapeutics
Volume35
Issue number7
DOIs
StatePublished - Apr 2012

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Serotonin Receptor Agonists
Safety
prucalopride
Cisapride
Serotonin Receptors
Serotonin
Potassium Channels
Pharmaceutical Preparations
Libraries
Names
Research Design
Ischemia
Pharmacokinetics
Pharmacology

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Systematic review : Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders. / Tack, J.; Camilleri, Michael; Chang, L.; Chey, W. D.; Galligan, J. J.; Lacy, B. E.; Müller-Lissner, S.; Quigley, E. M M; Schuurkes, J.; De Maeyer, J. H.; Stanghellini, V.

In: Alimentary Pharmacology and Therapeutics, Vol. 35, No. 7, 04.2012, p. 745-767.

Research output: Contribution to journalArticle

Tack, J, Camilleri, M, Chang, L, Chey, WD, Galligan, JJ, Lacy, BE, Müller-Lissner, S, Quigley, EMM, Schuurkes, J, De Maeyer, JH & Stanghellini, V 2012, 'Systematic review: Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders', Alimentary Pharmacology and Therapeutics, vol. 35, no. 7, pp. 745-767. https://doi.org/10.1111/j.1365-2036.2012.05011.x
Tack, J. ; Camilleri, Michael ; Chang, L. ; Chey, W. D. ; Galligan, J. J. ; Lacy, B. E. ; Müller-Lissner, S. ; Quigley, E. M M ; Schuurkes, J. ; De Maeyer, J. H. ; Stanghellini, V. / Systematic review : Cardiovascular safety profile of 5-HT 4 agonists developed for gastrointestinal disorders. In: Alimentary Pharmacology and Therapeutics. 2012 ; Vol. 35, No. 7. pp. 745-767.
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abstract = "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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AU - Camilleri, Michael

AU - Chang, L.

AU - Chey, W. D.

AU - Galligan, J. J.

AU - Lacy, B. E.

AU - Müller-Lissner, S.

AU - Quigley, E. M M

AU - Schuurkes, J.

AU - De Maeyer, J. H.

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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.

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