In 2007, the results from a meta analysis of 29 clinical studies indicated that tegaserod (Zelnorm®), a 5-hydroxytryptamine4 (5-HT4) receptor agonist with gastrointestinal prokinetic activity, was associated with an increased incidence of cardiovascular ischemic events, resulting in its withdrawal from many markets around the world. Stimulation of platelet aggregation has been proposed to explain the phenomenon. However, data from recent epidemiological studies have suggested that there is no correlation between tegaserod use and the incidence of cardiovascular ischemia. In this study, the influence of tegaserod, at concentrations up to tenfold higher than the total plasma Cmax for the 6 mg clinical dose, has been investigated on platelet aggregation under standard conditions with platelet-rich plasma (PRP) obtained from healthy human subjects. Additionally, the influence of tegaserod on coronary artery tone was evaluated as an alternative pro-ischemic mechanism. The positive control, thrombopoietin, but not tegaserod, demonstrated a statistically significant increase in platelet aggregation using the same PRP samples with either adenosine diphosphate (ADP) or ADP plus 5-HT as an aggregation agonist. Tegaserod had no contractile activity in either porcine or human isolated coronary artery preparations, and only a small and variable response in canine coronary arteries at concentrations higher than those achieved clinically. Taken together, these studies do not identify a mechanism for the ischemic events that have been attributed to tegaserod in humans.
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We thank David Bourdet for providing the LC/MS/MS analytical method employed to assay tegaserod concentrations, Tamara Mihailovski and Crystal Ballard for their assistance with the platelet aggregation experiments, and Frederick Zamora and Lee Rankin for their support with the coronary artery experiments.
Conflicts of interest
Theravance, Inc. currently has two 5-HT4 receptor agonists (velusetrag and TD-8954) in clinical development. David T. Beattie, Michelle Loeb, Kathryn Kersey, Alan Hopkins and Deborah L. Higgins own stock or shares in Theravance, Inc. Mike P. Ero has no conflicts of interest to report.
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