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    Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation.
    (2020) Souza, Ana Carolina Moreira; Guimarães, Andrea Grabe; Cruz, Jader dos Santos; Miranda, Artur Santos; Farah, Charlotte; Oliveira, Liliam Teixeira; Lucas, Alexandre; Aimond, Franck; Sicard, Pierre; Mosqueira, Vanessa Carla Furtado; Richard, Sylvain
    Background and Purpose: The artemisinin derivative, artemether, has antimalarial activity with potential neurotoxic and cardiotoxic effects. Artemether in nanocapsules (NC-ATM) is more efficient than free artemether for reducing parasitaemia and increasing survival of Plasmodium berghei-infected mice. NCs also prevent prolongation of the QT interval of the ECG. Here, we assessed cellular cardiotoxicity of artemether and how this toxicity was prevented by nanoencapsulation. Experimental Approach: Mice were treated with NC-ATM orally (120 mg kg−1 twice daily) for 4 days. Other mice received free artemether, blank NCs, and vehicle for comparison. We measured single-cell contraction, intracellular Ca2+ transient using fluorescent Indo-1AM Ca2+ dye, and electrical activity using the patch-clamp tech nique in freshly isolated left ventricular myocytes. The acute effect of free artemether was also tested on cardiomyocytes of untreated animals. Key Results: Artemether prolonged action potentials (AP) upon acute exposure (at 0.1, 1, and 10 μM) of cardiomyocytes from untreated mice or after in vivo treatment. This prolongation was unrelated to blockade of K+ currents, increased Ca2 + currents or promotion of a sustained Na+ current. AP lengthening was abolished by the NCX inhibitor SEA-0400. Artemether promoted irregular Ca2+ transients during pacing and spontaneous Ca2+ events during resting periods. NC-ATM prevented all effects. Blank NCs had no effects compared with vehicle. Conclusion and Implications: Artemether induced NCX-dependent AP lengthening (explaining QTc prolongation) and disrupted Ca2+ handling, both effects increasing pro-arrhythmogenic risks. NCs prevented these adverse effects, providing a safe alternative to the use of artemether alone, especially to treat malaria.