Commentary: towards a cardiac safe prokinetic

Abstract

Professor Tack and his colleagues should be commended for having provided the scientific community with a comprehensive review on cardiovascular (CV) safety of 5-HT4-agonists.1 Functional gastrointestinal disorders (FGIDs) are common conditions in primary care and specialty practices, but many affected patients report a lack of satisfaction with available treatments. Despite the unmet need for more effective pharmacotherapy, drug development has been challenging.2 The challenges include the lack of perception that FGIDs are legitimate diseases; the multidimensional and complex pathophysiology underlying these conditions; the lack of biological markers for diagnosis and treatment response; the heterogeneity of the affected patient population; the lack of consensus regarding best outcome measures for clinical trials; and, last but not least, the perception of an increased risk–benefit ratio associated with drug treatments for FGIDs.3 Many patients report more than one disorder, concomitantly. The disorders, although often intermittent, are costly for the society and persistent for many of the sufferers.4 The presence of extra-digestive co-morbidities and associated co-therapies further increase the costs and reduce treatment-related safety by way of an increased risk of drug-to-drug interactions. As serotonin (5-hydroxytryptamine, 5-HT) exerts pleiotropic activities in the gut, including control of GI motility, secretion and sensation, drugs acting on 5-HT receptors have been developed as potential therapeutic agents for FGIDs.5 However, some agents have been withdrawn or restricted, based on postmarketing assessments and perceptions of unfavourable risk/benefit profiles. In a life-threatening situation, even a considerable level of risk can be accepted, provided that the benefits are consistent. However, in benign, functional disorders an unequivocal benefit, with little or no risk, is sought. With the exception of domperidone, all effective prokinetics are endowed with a partial or full agonism towards 5-HT4-receptors.5 While the activity of metoclopramide and domperidone was confined to the upper GI tract, that of cisapride and tegaserod extended to the lower GI tract,6 with prucalopride behaving as a predominantly enterokinetic compound (Table 1).5 Despite very active research, withdrawal from the market of both cisapride7 and tegaserod8 slowed the development of new compounds, whose CV safety had to be thoroughly investigated.9 Meanwhile, comparative pharmacological studies have revealed that not all 5-HT4-agonists are the same. Indeed, their affinity for other 5-HT receptors, as for cisapride (5-HT3-antagonist) and tegaserod (5-HT2B-antagonist), hampers their prokinetic efficacy, and their affinity for other non 5-HT-receptors (like, for instance, D2-receptors) or channels (e.g. hERG) explains their adverse effects.10 The comprehensive analysis by Tack et al.1 will represent a reference point for both scientists and clinicians, who can find precise information on the CV safety profile of a given drug. By pointing out that cardiac adverse effects of GI prokinetics are related to interaction with molecular targets different from 5-HT4-receptors, the authors have provided the long-awaited reassurance about the CV safety of new potent and highly selective 5-HT4-agonists, such as the recently approved prucalopride, and the new investigational drugs, velusetrag and naronapride. Declaration of personal interests: Carmelo Scarpignato has served as a speaker, consultant and/or advisory board member for Alfa Wassermann, AstraZeneca, Boeheringer-Ingelheim, Giuliani Pharmaceuticals, Pfizer, Recordati, Sigma-Tau, Shire and Warner-Chilcott, and has in the past received funding from Giuliani Pharmaceuticals and Pfizer. Declaration of funding interests: None.