Reverse translational analysis of clinically reported, lamotrigine-induced cardiovascular adverse events using the halot
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ORIGINAL ARTICLE
Reverse translational analysis of clinically reported, lamotrigine‑induced cardiovascular adverse events using the halothane‑anesthetized dogs Ai Goto1 · Mihoko Hagiwara‑Nagasawa2 · Ryuichi Kambayashi2 · Yoshio Nunoi2 · Hiroko Izumi‑Nakaseko1,2 · Shinichi Kawai3 · Yoshinori Takei4 · Akio Matsumoto5 · Atsushi Sugiyama1,2,3,4,5 Received: 26 May 2020 / Accepted: 16 October 2020 © Springer Japan KK, part of Springer Nature 2020
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 N a+ 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. Keywords Lamotrigine · Adverse events · Na+ channel · Brugada syndrome
Introduction * Atsushi Sugiyama [email protected]‑u.ac.jp 1
Department of Pharmacology, Toho University Graduate School of Medicine, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
2
Department of Pharmacology, Faculty of Medicine, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
3
Department of Inflammation and Pain Control Research, Faculty of Medicine, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
4
Department of Translational Research and Cellular Therapeutics, Faculty of Medicine, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
5
Department of Aging Pharmacology, Faculty of Medicine, Toho University, 5‑21‑16 Omori‑nishi, Ota‑ku, Tokyo 143‑8540, Japan
Lamotrigine has been used for patients with epilepsy and/ or bipolar disorder, overdose of which caused hypotension, cardiac conduction
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