title: The inability of tegaserod to affect platelet aggregation and coronary artery tone at supratherapeutic concentrations.
abstract: In 2007, the results from a meta analysis of 29 clinical studies indicated that tegaserod (Zelnorm®), a 5-hydroxytryptamine(4) (5-HT(4)) 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 C                         (max) 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.
authors: D.L. Higgins Consulting, 115 Crestview Court, San Carlos, CA 94070, USA.
authors: Deborah L
authors: DL
authors: Higgins
authors: Mike P
authors: MP
authors: Ero
authors: Michelle
authors: M
authors: Loeb
authors: Kathryn
authors: K
authors: Kersey
authors: Alan
authors: A
authors: Hopkins
authors: David T
authors: DT
authors: Beattie
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013552:Swine; D055815:Young Adult
chemical_list: D007211:Indoles; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C105050:tegaserod; D000244:Adenosine Diphosphate