Systematic review: cardiovascular safety profile of 5‐HT₄ agonists developed for gastrointestinal disorders

Abstract

SummaryBackgroundThe nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs).AimTo perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy.MethodsArticles 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UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data.ResultsRetrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised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-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride).Conclusions5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility.

Use of Prucalopride for Chronic Constipation: A Systematic Review and Meta-analysis of Published Randomized, Controlled Trials

“…However, there are several systematic reviews and meta-analyses evaluating the role of prucalopride [59][60][61][62][63][64][65][66][67][68] in the management of chronic constipation and their findings are consistent with the findings of the current study. Although the scope of the current article is the evaluation of clinical effectiveness and adverse events related to prucalopride only, previously reported systematic reviews [59][60][61][62][63][64][65][66][67][68] have reported its safety, efficacy, pharmacokinetics, and tolerability providing supporting evidence to our conclusions. As reported by Tack et al 69 "Prucalopride is an important addition to the therapeutic abilities for treating chronic constipation, especially in females poorly responding to laxatives.…”

Increased expression of tight junction protein�occludin is associated with the protective effect of mosapride against aspirin‑induced gastric injury

“…In this study, gastric ulceration was significantly relieved and the hexosamine content of gastric mucus was significantly increased, as were the gastric mucosal levels of PGE2 (12,17). However, cisapride is associated with adverse cardiovascular events and has therefore been replaced by mosapride, a novel selective 5-HT4 receptor agonist with safer profiles (18,19). A study by Fujisawa et al (11) found that treatment with a low dose of mosapride inhibited gastric mucosa injury induced by indomethacin, and their results showed that 0.5 mg/kg mosapride was the optimal dose.…”

Emerging Pharmacologic Therapies for Constipation-predominant Irritable Bowel Syndrome and Chronic Constipation

“…The serious cardiac adverse events (palpitations, myocardial infarction, ventricular fibrillation, torsades de pointes and sudden death) and medication interactions that led to the withdrawal of the less selective serotonergic agonists cisapride and tegaserod have not been observed with prucalopride. 71 The comparative effectiveness of prucalopride versus the more commonly recommended osmotic agent PEG was recently evaluated in a single center RCT from Romania. 72 Two hundred and forty CIC patients received either PEG 3350 and electrolytes (26 g) or prucalopride (1-2 mg) for 28 days.…”