##article.abstract##
Background: Artemisinin-based combination therapies (ACTs) have become first line antimalarial drugs globally and are available over-the-counter (OTC). This allows for unsupervised malaria treatment with ACTs. Some antimalarial drugs have been associated with cardiotoxicity. There is thus a need to evaluate the cardiac safety of artemetherlumefantrine (AL) and artesunate amodiaquine (ASAQ), the ACTs of choice for the treatment of malaria in Nigeria.
Method: As part of a larger study that evaluated the comparative safety and efficacy of AL and ASAQ, a of 32 participants were enrolled into an electrocardiographic (ECG) study. Participants were randomly allocated to receive either AL or ASAQ under supervision at standard dosage for three days. A standard 12-lead ECG was done to compare baseline (day 0) ECG readings with post treatment values daily on days 1 - 3 and then on days 7, 14, 21 and 28.
Results: Sinus tachycardia was the commonest ECG changed at enrollment. A remarkable reduction of sinus tachycardia was observed after fever resolution (p = 0.008) for AL and (p = 0.001) for ASAQ respectively. Changes in ECG intervals were not significantly different during the follow up period following AL or ASAQ treatment (p > 0.05). There was no record of cardiac arrhythmia on ECG and no clinical evidence of cardiac disturbance throughout the study.
Conclusion: AL and ASAQ have no clinically significant prolongation of cardiac parameters or rhythm disturbance at the therapeutic doses used during the study.
Keywords: Electrocardiogram, cardiotoxicity, sinus-tachycardia, malaria, ACTs, Nigeria
Résumé
Contexte : Les thérapies combinées à base d’artémisinine (ACT) sont devenues des médicaments antipaludiques de première ligne dans le monde et sont disponibles en vente libre (OTC). Cela permet un traitement non supervisé du paludisme avec ACT. Certains médicaments antipaludiques ont été associés à une cardiotoxicité. Il y a donc un besoin d’évaluer la sécurité cardiaque d’artéméther-luméfantrine (AL) et d’artésunate-amodiaquine (ASAQ), les ACT de choix pour le traitement du paludisme au Nigéria.
Méthode : Dans le cadre d’une étude plus vaste qui a évalué l’innocuité et l’efficacité comparatives d’AL et d’ASAQ, un sous-segment de 32 participants a été inscrit à une étude électrocardiographique (ECG). Les participants ont été répartis au hasard pour recevoir soit AL ou ASAQ sous surveillance à la dose standard pendant trois jours. Un ECG standard à 12-indices a été effectué pour comparer les lectures ECG de référence (jour 0) avec les valeurs posttraitement quotidiennement les jours 1 à 3, puis les jours 7, 14, 21 et 28.
Résultats : La tachycardie sinusale était la modification ECG la plus courante à l’inscription. Une réduction remarquable de la tachycardie sinusale a été observée après la résolution de la fièvre (p = 0,008) pour AL et (p = 0,001) pour ASAQ respectivement. Les changements dans les intervalles ECG n’étaient pas significativement différents au cours de la période de suivi suivant un traitement AL ou ASAQ (p> 0,05). Il n’y avait aucun enregistrement d’arythmie cardiaque à l’ECG et aucune preuve clinique de troubles cardiaques tout au long de l’étude.
Conclusion : AL et ASAQ n’ont pas d’allongement cliniquement significatif des paramètres cardiaques ou de perturbation du rythme aux doses thérapeutiques utilisées pendant l’étude.
Mots - clés : électrocardiogramme, cardiotoxicité, tachycardie sinusale, paludisme, ACT, Nigeria
Correspondence: Prof. Catherine O Falade, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria, Email: lillyfunke@yahoo.com
##submission.citations##
World Health Organization. World Malaria Report. World Health Organization. 2016.
World Health Organization. Monitoring Antimalarial Drug Resistance, World Health Organization. Geneva, Switzerland; 2002.
Fenando SD, Gunawardena DM, Bandara MRSS, et al. The impact of repeated malaria attacks on the school performance of children. Am J Trop Med Hyg. 2003; 69(6): 582-588
Bouchaud O, Imbert P, Touze JE, et al. Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base. Malar J. 2009 ;8:289.
Ogunkunle OO, Fehintola FA, Ogungbamigbe T and Falade CO. Comparative Cardiac Effects of Chlorproguanil/Dapsone and Chloroquine during Treatment of Acute Uncomplicated Falciparum Malaria Infection in Nigerian Children. Afr J Biomed Res. 2011; 14(3):161–167.
Sowunmi A, Falade CO, Oduola AM, et al. Cardiac effects of halofantrine in children suffering from acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg. 1998; 92(4):446–448.
Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet Lond Engl. 1993 ;341(8852):1054–1056.
Supanaranond W, Davis TM, Pukrittayakamee S, et al. Disposition of oral quinine in acute falciparum malaria. Eur J Clin Pharmacol. 1991;40(1):49–52.
Federal Ministry of Health (FMoH). Federal Republic OF Nigeria National Antimalaria Treatment Policy. 2005.
Ajayi IO, Browne EN, Garshong B, et al. Feasibility and acceptability of artemisinin-based combination therapy for the home management of malaria in four African sites. Malar J. 2008;7:6.
van Vugt M, Ezzet F, Nosten F, et al. No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine. Am J Trop Med Hyg. 1999 Dec;61(6):964–967.
Falade CO, Ogundele AO, Yusuf BO, Ademowo OG and Ladipo SM. High efficacy of two artemisinin-based combinations (artemether-lumefantrine and artesunate plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria. Trop Med Int Health TM IH. 2008 May;13(5):635–643.
Traebert M, Dumotier B, Meister L, et al. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004 Jan;484(1):41–48.
White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis. 2007 Aug;7(8):549–558.
Maude RJ, Plewes K, Faiz MA, et al. Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria? Am J Trop Med Hyg. 2009 Jan;80(1):126–132.
Falade CO, Ogunkunle OO, Dada-Adegbola HO, et al. Evaluation of the efficacy and safety of artemether-lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria in Nigerian infants and children. Malar J. 2008 Nov;7:246.
Trape, J.F. 1985. Rapid evaluation of malaria parasite density and standardization of thick smear examination for epidemiological investigations. Trans. R. Soc. Trop. Med. Hyg. 1985 79: 181–184.
WHO. Guidelines for the treatment of malaria: Second edition: Geneva, World Health Organization 2010. 19. Bazzet H 1920. An analysis of time relation of electrocardiograms. Heart. 7:353–370.
Assi S-B, Aba YT, Yavo JC, et al. Safety of a fixed-dose combination of artesunate and amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in real-life conditions of use in Côte d’Ivoire. Malar J. 2017 Jan;16.
Davies P and Maconochie I. The relationship between body temperature, heart rate and respiratory rate in children. Emerg Med J EMJ. 2009 Sep;26(9):641–643.
Karjalainen J and Viitasalo M. Fever and cardiac rhythm. Arch Intern Med. 1986 Jun;146(6):1169–1171.
Adjei GO, Oduro-Boatey C, Rodrigues OP, et al. Electrocardiographic study in Ghanaian children with uncomplicated malaria, treated with artesunate-amodiaquine or artemether-lumefantrine. Malar J. 2012 Dec;11:420.
Touze JE, Heno P, Fourcade L, Deharo JC, Thomas G, Bohan S, et al. The effects of antimalarial drugs on ventricular repolarization. Am J Trop Med Hyg. 2002 Jul; 67 (1):54–60.