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Artemether in nanocapsules (NC\u2010ATM) is more efficient than free artemether for reducing parasitaemia and increasing survival of <jats:italic>Plasmodium berghei<\/jats:italic>\u2010infected 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mice were treated with NC\u2010ATM orally (120 mg\u00b7kg<jats:sup>\u22121<\/jats:sup> twice daily) for 4 days. Other mice received free artemether, blank NCs, and vehicle for comparison. We measured single\u2010cell contraction, intracellular Ca<jats:sup>2+<\/jats:sup> transient using fluorescent Indo\u20101AM Ca<jats:sup>2+<\/jats:sup> dye, and electrical activity using the patch\u2010clamp technique in freshly isolated left ventricular myocytes. The acute effect of free artemether was also tested on cardiomyocytes of untreated animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Artemether prolonged action potentials (AP) upon acute exposure (at 0.1, 1, and 10 \u03bcM) of cardiomyocytes from untreated mice or after in vivo treatment. This prolongation was unrelated to blockade of K<jats:sup>+<\/jats:sup> currents, increased Ca<jats:sup>2+<\/jats:sup> currents or promotion of a sustained Na<jats:sup>+<\/jats:sup> current. AP lengthening was abolished by the NCX inhibitor SEA\u20100400. Artemether promoted irregular Ca<jats:sup>2+<\/jats:sup> transients during pacing and spontaneous Ca<jats:sup>2+<\/jats:sup> events during resting periods. NC\u2010ATM prevented all effects. Blank NCs had no effects compared with vehicle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Artemether induced NCX\u2010dependent AP lengthening (explaining QTc prolongation) and disrupted Ca<jats:sup>2+<\/jats:sup> handling, both effects increasing pro\u2010arrhythmogenic risks. NCs prevented these adverse effects, providing a safe alternative to the use of artemether alone, especially to treat malaria.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15186","type":"journal-article","created":{"date-parts":[[2020,7,1]],"date-time":"2020-07-01T07:11:26Z","timestamp":1593587486000},"page":"4448-4463","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Mechanisms of artemether toxicity on single cardiomyocytes and protective effect of nanoencapsulation"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-7461","authenticated-orcid":false,"given":"Ana Carolina","family":"Moreira Souza","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Graduate Program (CiPharma), Pharmacy School Federal University of Ouro Preto  Ouro Preto Minas Gerais Brazil"},{"name":"Physiologie et M\u00e9decine Exp\u00e9rimentale du C\u0153ur et des Muscles (PhyMedExp) 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