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Reverse translational analysis of clinically reported, lamotrigine-induced cardiovascular adverse events using the halothane-anesthetized dogs

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Abstract

Lamotrigine has been used for patients with epilepsy and/or bipolar disorder, overdose of which induced the hypotension, elevation of the atrial pacing threshold, cardiac conduction delay, wide complex tachycardia, cardiac arrest and Brugada-like electrocardiographic pattern. To clarify how lamotrigine induces those cardiovascular adverse events, we simultaneously assessed its cardiohemodynamic and electrophysiological effects using the halothane-anesthetized dogs (n = 4). Lamotrigine was intravenously administered in doses of 0.1, 1 and 10 mg/kg/10 min under the monitoring of cardiovascular variables, possibly providing subtherapeutic to supratherapeutic plasma concentrations. The low or middle dose of lamotrigine did not alter any of the variables. The high dose significantly delayed the intra-atrial and intra-ventricular conductions in addition to the prolongation of ventricular effective refractory period, whereas no significant change was detected in the other variables. Lamotrigine by itself has relatively wide safety margin for cardiohemodynamics, indicating that clinically reported hypotension may not be induced through its direct action on the resistance arterioles or capacitance venules. The electrophysiological effects suggested that lamotrigine can inhibit Na+ channel in the in situ hearts. This finding may partly explain the onset mechanism of lamotrigine-associated cardiac adverse events in the clinical cases. In addition, elevation of J wave was induced in half of the animals, suggesting that lamotrigine may have some potential to unmask Brugada electrocardiographic genotype in susceptible patients.

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Acknowledgements

This study was supported in part by JSPS KAKENHI (Grant Numbers 19K16505 and 20K16136). The authors thank Mrs. Yuri Ichikawa for her technical assistance.

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Authors and Affiliations

  1. Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Ai Goto, Hiroko Izumi-Nakaseko & Atsushi Sugiyama

  2. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Yoshio Nunoi, Hiroko Izumi-Nakaseko & Atsushi Sugiyama

  3. Department of Inflammation and Pain Control Research, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Shinichi Kawai & Atsushi Sugiyama

  4. Department of Translational Research and Cellular Therapeutics, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Yoshinori Takei & Atsushi Sugiyama

  5. Department of Aging Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Akio Matsumoto & Atsushi Sugiyama

Authors
  1. Ai Goto
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  2. Mihoko Hagiwara-Nagasawa
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  3. Ryuichi Kambayashi
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  4. Yoshio Nunoi
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  5. Hiroko Izumi-Nakaseko
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  6. Shinichi Kawai
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  7. Yoshinori Takei
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  8. Akio Matsumoto
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  9. Atsushi Sugiyama
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Correspondence to Atsushi Sugiyama.

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Goto, A., Hagiwara-Nagasawa, M., Kambayashi, R. et al. Reverse translational analysis of clinically reported, lamotrigine-induced cardiovascular adverse events using the halothane-anesthetized dogs. Heart Vessels 36, 424–429 (2021). https://doi.org/10.1007/s00380-020-01716-8

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  • DOI: https://doi.org/10.1007/s00380-020-01716-8

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