Cardiovascular Toxicology

, Volume 13, Issue 3, pp 234–243

Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro

  • Ken Kitahara
  • Yuji Nakamura
  • Yayoi Tsuneoka
  • Satomi Adachi-Akahane
  • Hikaru Tanaka
  • Hiroshi Yamazaki
  • Akira Takahara
  • Junichi Yamazaki
  • Takanori Ikeda
  • Atsushi Sugiyama
Article

Abstract

Electropharmacological effects of oseltamivir were studied in comparison with pilsicainide using halothane-anesthetized dogs (n = 4) and isolated left atrium of guinea pigs (n = 5). Oseltamivir (0.3, 3 and 30 mg/kg, i.v.) or pilsicainide (1 and 3 mg/kg, i.v.) was additionally administered to the dogs. The low dose of oseltamivir provided clinically relevant plasma concentrations with Cmax of 4 μM. The low and middle doses of oseltamivir increased cardiac output, whereas the middle dose increased blood pressure and delayed intra-atrial conduction and ventricular repolarization. The high dose of oseltamivir exerted negative chronotropic, inotropic and hypotensive effects, while it delayed intra-atrial, atrioventricular nodal and intra-ventricular conduction and ventricular repolarization. Use-dependent delay of ventricular repolarization was observed after oseltamivir, whereas reverse use-dependent prolongation was induced by pilsicainide. Moreover, oseltamivir more selectively suppressed intra-atrial conduction than intra-ventricular conduction, which was less selective for pilsicainide. Action potential assay using isolated atrium indicated that oseltamivir (10 μM) decreased Vmax more than pilsicainide (10 μM) and that oseltamivir (10–100 μM) prolonged action potential duration, which was not induced by pilsicainide (1–10 μM). Thus, oseltamivir in clinically relevant to its 10 times higher doses is relatively safe, whereas 10–100 times higher doses possess unique electrophysiological profile.

Keywords

Oseltamivir Pilsicainide QT Torsades de pointes Cardiac death 

References

  1. 1.
    Tullu, M. S. (2009). Oseltamivir. Journal of Postgraduate Medicine, 55, 225–230.PubMedCrossRefGoogle Scholar
  2. 2.
    Dutkowski, R., Thakrar, B., Froehlich, E., Suter, P., Oo, C., & Ward, P. (2003). Safety and pharmacology of oseltamivir in clinical use. Drug Safety, 26, 787–801.PubMedCrossRefGoogle Scholar
  3. 3.
    Wells, Q., Hardin, B., Raj, S. R., & Darbar, D. (2010). Sotalol-induced torsades de pointes precipitated during treatment with oseltamivir for H1N1 influenza. Heart Rhythm, 10, 1454–1457.CrossRefGoogle Scholar
  4. 4.
    Hama, R. (2008). Fatal neuropsychiatric adverse reactions to oseltamivir: Case series and overview of causal relationships. The International Journal of Risk and Safety in Medicine, 20, 5–36.Google Scholar
  5. 5.
    Kimura, S., Niwa, Y., Iwajima, Y., Nagano, Y., Yamamoto, S., Ohi, Y., et al. (2012). High doses of oseltamivir phosphate induce acute respiratory arrest in anaesthetized rats. Basic & Clinical Pharmacology & Toxicology, 111, 232–239.Google Scholar
  6. 6.
    Casscells, S. W., Granger, E., Kress, A. M., Linton, A., Madjid, M., & Cottrell, L. (2009). Use of oseltamivir after influenza infection is associated with reduced incidence of recurrent adverse cardiovascular outcomes among military health system beneficiaries with prior cardiovascular diseases. Circulation Cardiovascular Quality and Outcomes, 2, 108–115.PubMedCrossRefGoogle Scholar
  7. 7.
    Sugiyama, A. (2008). Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. British Journal of Pharmacology, 154, 1528–1537.PubMedCrossRefGoogle Scholar
  8. 8.
    Ishizaka, T., Takahara, A., Iwasaki, H., Mitsumori, Y., Kise, H., Nakamura, Y., et al. (2008). Comparison of electropharmacological effects of bepridil and sotalol in halothane-anesthetized dogs. Circulation Journal, 72, 1003–1011.PubMedCrossRefGoogle Scholar
  9. 9.
    Yoshida, H., Sugiyama, A., Satoh, Y., Ishida, Y., Kugiyama, K., & Hashimoto, K. (2002). Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model. Circulation Journal, 66, 857–862.PubMedCrossRefGoogle Scholar
  10. 10.
    Wu, L. M., Orikabe, M., Hirano, Y., Kawano, S., & Hiraoka, M. (2003). Effects of Na+ channel blocker, pilsicainide, on HERG current expressed in HEK-293 cells. Journal of Cardiovascular Pharmacology, 42, 410–418.PubMedCrossRefGoogle Scholar
  11. 11.
    Iwasaki, H., Takahara, A., Nakamura, Y., Satoh, Y., Nagai, T., Shinkai, N., et al. (2009). Simultaneous assessment of pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects on atria of chronic atrioventricular block dogs. Journal of Pharmacological Sciences, 110, 410–414.PubMedCrossRefGoogle Scholar
  12. 12.
    Van de Water, A., Verheyen, J., Xhonneux, R., & Reneman, R. S. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods, 22, 207–217.PubMedCrossRefGoogle Scholar
  13. 13.
    Sugiyama, A., & Hashimoto, K. (2002). Effects of a typical IKr channel blocker sematilide on the relationship between ventricular repolarization, refractoriness and onset of torsades de pointes. Japanese Journal of Pharmacology, 88, 414–421.PubMedCrossRefGoogle Scholar
  14. 14.
    Hashimoto, K., Haruno, A., Matsuzaki, T., Sugiyama, A., & Akiyama, K. (1991). Effects of antiarrhythmic drugs on canine ventricular arrhythmia models: Which electrophysiological characteristics of drugs are related to their effectiveness? Cardiovascular Drugs and Therapy, 5(suppl. 4), 805–818.PubMedCrossRefGoogle Scholar
  15. 15.
    Ino, T., Atarashi, H., Kuruma, A., Onodera, T., Saitoh, H., & Hayakawa, H. (1998). Electrophysiologic and hemodynamic effects of a single oral dose of pilsicainide hydrochloride, a new class 1c antiarrhythmic agent. Journal of Cardiovascular Pharmacology, 31, 157–164.PubMedCrossRefGoogle Scholar
  16. 16.
    Nouchi, H., Takahara, A., Nakamura, H., Namekata, I., Sugimoto, T., Tsuneoka, Y., et al. (2008). Chronic left atrial volume overload abbreviates the action potential duration of the canine pulmonary vein myocardium via activation of IK channel. European Journal of Pharmacology, 597, 81–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Sakanashi, M., Noguchi, K., Matsuzaki, T., Ojiri, Y., Nakasone, J., Itomine, T., et al. (1993). Effects of pilsicainide on systemic hemodynamics and cardiac function of anesthetized dogs. Cardioscience, 4, 241–250.PubMedGoogle Scholar
  18. 18.
    Hume, J. R., & Grant, A. O. (2004). Agents used in cardiac arrhythmias. In B. G. Katzung (Ed.), Basic and clinical pharmacology (9th ed., pp. 216–240). New York: McGraw-Hill.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ken Kitahara
    • 1
    • 2
  • Yuji Nakamura
    • 1
  • Yayoi Tsuneoka
    • 3
  • Satomi Adachi-Akahane
    • 1
  • Hikaru Tanaka
    • 3
  • Hiroshi Yamazaki
    • 4
  • Akira Takahara
    • 3
    • 5
  • Junichi Yamazaki
    • 2
  • Takanori Ikeda
    • 2
  • Atsushi Sugiyama
    • 1
  1. 1.Department of Pharmacology, Faculty of MedicineToho UniversityOta-kuJapan
  2. 2.Division of Cardiovascular Medicine, Department of Internal Medicine, Faculty of MedicineToho UniversityOta-kuJapan
  3. 3.Department of Pharmacology, Faculty of Pharmaceutical SciencesToho UniversityFunabashiJapan
  4. 4.Laboratory of Drug Metabolism and PharmacokineticsShowa Pharmaceutical UniversityMachidaJapan
  5. 5.Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical SciencesToho UniversityFunabashiJapan

Personalised recommendations