Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 385, Issue 1, pp 103–109 | Cite as

The inability of tegaserod to affect platelet aggregation and coronary artery tone at supratherapeutic concentrations

  • Deborah L. Higgins
  • Mike P. Ero
  • Michelle Loeb
  • Kathryn Kersey
  • Alan Hopkins
  • David T. BeattieEmail author


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 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.


Tegaserod Platelet aggregation Coronary artery Cardiovascular ischemia 



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.


  1. Anderson JL, May HT, Bair TI et al (2009) Lack of association of tegaserod with adverse cardiovascular outcomes in a matched case-control study. J Cardiovasc Pharmacol Theraput 14:170–175CrossRefGoogle Scholar
  2. Beattie DT, Smith JA, Marquess D et al (2004) The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol 143:549–560PubMedCrossRefGoogle Scholar
  3. Beattie DT, Armstrong SR, Shaw JP et al (2008) The in vivo gastrointestinal activity of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity. Naunyn Schmiedeberg’s Arch Pharmacol 378:139–147CrossRefGoogle Scholar
  4. Briejer MR, Akkermans LMA, Schuurkes JAJ (1995) Gastrointestinal prokinetic benzamides: the pharmacology underlying stimulation of motility. Pharmacol Rev 47:631–651PubMedGoogle Scholar
  5. Buchheit KH, Gamse R, Giger R et al (1995) The serotonin 5-HT4 receptor. 2. Structure–activity studies of the indole carbazimidamide class of agonists. J Med Chem 38:2331–2338PubMedCrossRefGoogle Scholar
  6. Camilleri M (2001) Review article: tegaserod. Aliment Pharmacol Theraput 15:277–289CrossRefGoogle Scholar
  7. Carel I, Ghaleh B, Edouard A et al (2001) Comparative effects of frovatriptan and sumatriptan on coronary and internal carotid vascular haemodynamics in conscious dogs. Br J Pharmacol 132:1071–1083PubMedCrossRefGoogle Scholar
  8. Chan KY, de Vries R, Leijten FPJ et al (2009) Functional characterization of contractions to tegaserod in human isolated proximal and distal coronary arteries. Eur J Pharmacol 619:61–67PubMedCrossRefGoogle Scholar
  9. Clinical and Laboratory Standards Institute (2008) Platelet function testing by aggregometry; approved guideline. Document H58-A, WayneGoogle Scholar
  10. De Maeyer JH, Lefebvre RA, Schuurkes JA (2008) 5-HT(4) receptor agonists: similar but not the same. Neurogastroenterol Motil 20:99–112PubMedCrossRefGoogle Scholar
  11. Gerson L (2007) Comment. Gastroenterol 133:721–722Google Scholar
  12. Gong H, Nakamura T, Hattori K et al (2000) A novel 5-HT(2) antagonist, sarpogrelate hydrochloride, shows inhibitory effects on both contraction and relaxation mediated by 5-HT receptor subtypes in porcine coronary arteries. Pharmacol 61:263–268CrossRefGoogle Scholar
  13. Jennings LK, White MM (2007) Platelet aggregation. In: Michelson AD (ed) Platelets, 2nd edn. Elsevier, Amsterdam, pp 495–518CrossRefGoogle Scholar
  14. Johanson JF (2004) Review article: tegaserod for chronic constipation. Aliment Pharmacol Theraput 20(suppl 7):20–24CrossRefGoogle Scholar
  15. Louglin J, Quinn S, Rivero E et al (2010) Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study. J Cardiovasc Pharmacol Theraput 15:151–157CrossRefGoogle Scholar
  16. Muller-Lissner SA, Fumagalli I, Bardhan KD et al (2001) Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Theraput 15:1655–1666CrossRefGoogle Scholar
  17. Nilsson T, Longmore J, Shaw D et al (1999) Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol 372:49–56PubMedCrossRefGoogle Scholar
  18. Oda A, Miyakawa Y, Druker BJ et al (1996) Thrombopoietin primes human platelet aggregation induced by shear stress and by multiple agonists. Blood 87:4664–4670PubMedGoogle Scholar
  19. Podczasy JJ, Lee J, Vucenik I (1997) Evaluation of whole-blood lumiaggregation. Clin Appl Thromb Hemost 3:190–195CrossRefGoogle Scholar
  20. Riess H, Braun G, Hiller E (1986) Critical evaluation of platelet aggregation in whole human blood. Am J Clin Pathol 85:50–56PubMedGoogle Scholar
  21. Serebruany VL, El Mouelhi M, Pfannkuche H-J, Rose K, Marro M, Angiolillo DJ (2010) Investigations on 5-HT4 receptor expression and effects of tegaserod on human platelet aggregation in vitro. Am J Therap 17:543–552CrossRefGoogle Scholar
  22. Sgard F, Faure C, Graham D (1996) Evidence for 5-HT1D beta but not 5-HT1D alpha receptor subtype expression in canine large coronary arteries and saphenous vein. Cardiovasc Res 31:793–799PubMedGoogle Scholar
  23. Smith JAM, Beattie DT, Cuthbert AW et al (2008) The in vitro pharmacological profile of TD-5108, a selective 5-HT4 receptor agonist with high intrinsic activity. Naunyn Schmiedeberg’s Arch Pharmacol 378:125–137CrossRefGoogle Scholar
  24. Zhou L, Schmaier AH (2005) Platelet aggregation testing in platelet-rich plasma: description of procedures with the aim to develop standards in the field. Am J Clin Pathol 123:172–183PubMedCrossRefGoogle Scholar
  25. Zucker MB (1989) Platelet aggregation measured by the photometric method. Meth Enzymol 169:117–133PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Deborah L. Higgins
    • 1
  • Mike P. Ero
    • 2
  • Michelle Loeb
    • 3
  • Kathryn Kersey
    • 3
  • Alan Hopkins
    • 3
  • David T. Beattie
    • 3
    Email author
  1. 1.D.L. Higgins ConsultingSan CarlosUSA
  2. 2.Machaon Diagnostics, Inc., Specialized Coagulation LaboratoryOaklandUSA
  3. 3.Theravance, Inc.South San FranciscoUSA

Personalised recommendations