{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T01:30:13Z","timestamp":1769304613270,"version":"3.49.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T00:00:00Z","timestamp":1620432000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T00:00:00Z","timestamp":1620432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Sigma-tau Industrie Farmaceutiche Riunite S.p.A., Italy, currently Alfasigma S.p.A, Bologna. Italy"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Malar J"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)\u2013piperaquine (APQ) Eurartesim<jats:sup>\u00ae<\/jats:sup> during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Participants were recruited through Health Care Provider\u2019s safety registry in 15 centres across 6 European countries in the period 2013\u20132016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett\u2019s (QTcB) or Fridericia\u2019s (QTcF) methods, at baseline and after treatment. QTcB and\/or QTcF prolongation were defined by a value &gt;\u2009450\u00a0ms for males and children and &gt;\u2009470\u00a0ms for females.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8\u00a0years old (13.2) and 25.9\u00a0kg\/m<jats:sup>2<\/jats:sup> (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p\u2009&lt;\u20090.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17\/143 participants (11.9%), only 2 of them reporting QTcF\u2009&gt;\u2009500\u00a0ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of &gt;\u200960\u00a0ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65\u00a0years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255\/257 (99.2%).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries.<\/jats:p>\n                <jats:p><jats:italic>Trial registration<\/jats:italic> This study has been registered in EU Post-Authorization Studies Register as EUPAS6942<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12936-021-03750-x","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T09:03:07Z","timestamp":1620464587000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Longitudinal study based on a safety registry for malaria patients treated with artenimol\u2013piperaquine in six European countries"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9410-9327","authenticated-orcid":false,"given":"Nicolas","family":"Vignier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Bouchaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Angheben","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Bottieau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Calleri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Salas-Coronas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Martin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Manuel","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthieu","family":"Mechain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christophe","family":"Rapp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Dieter","family":"Nothdurft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Velasco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Azucena","family":"Bardaj\u00ed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerardo","family":"Rojo-Marcos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leo G.","family":"Visser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Hatz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeno","family":"Bisoffi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Jelinek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Duparc","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yann","family":"Bourhis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silva","family":"Tommasini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Iannucelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Bacchieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovan Giuseppe","family":"Mattera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilio","family":"Merlo Pich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald H.","family":"Behrens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,5,8]]},"reference":[{"key":"3750_CR1","unstructured":"ECDC. Malaria\u2014annual epidemiological report for 2018. ECDC. 2020. https:\/\/www.ecdc.europa.eu\/en\/publications-data\/malaria-annual-epidemiological-report-2018."},{"key":"3750_CR2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1093\/trstmh\/trs019","volume":"107","author":"C Naing","year":"2013","unstructured":"Naing C, Mak JW, Aung K, Wong JYR. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in endemic countries: meta-analysis of randomised controlled studies. Trans R Soc Trop Med Hyg. 2013;107:65\u201373.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"3750_CR3","unstructured":"WHO. Guidelines for the treatment of malaria. 3rd edn. Geneva: World Health Organization; 2015. 316 p. https:\/\/www.who.int\/publications\/i\/item\/9789241549127. Accessed 11 Nov 2020."},{"key":"3750_CR4","unstructured":"Eurartesim. Summary of product characteristics. European Medicines Agency. 2011. https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/eurartesim-epar-product-information_en.pdf. Accessed 24 Nov 2020."},{"key":"3750_CR5","doi-asserted-by":"publisher","first-page":"251","DOI":"10.4269\/ajtmh.1994.51.251","volume":"51","author":"TG Brewer","year":"1994","unstructured":"Brewer TG, Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg. 1994;51:251\u20139.","journal-title":"Am J Trop Med Hyg"},{"issue":"Suppl 1","key":"3750_CR6","doi-asserted-by":"publisher","first-page":"S33","DOI":"10.1016\/0035-9203(94)90469-3","volume":"88","author":"TG Brewer","year":"1994","unstructured":"Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg. 1994;88(Suppl 1):S33-36.","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"3750_CR7","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/S0940-2993(99)80128-6","volume":"51","author":"W Classen","year":"1999","unstructured":"Classen W, Altmann B, Gretener P, Souppart C, Skelton-Stroud P, Krinke G. Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs. Exp Toxicol Pathol. 1999;51:507\u201316.","journal-title":"Exp Toxicol Pathol"},{"key":"3750_CR8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.2165\/00003495-200565010-00004","volume":"65","author":"TME Davis","year":"2005","unstructured":"Davis TME, Hung T-Y, Sim I-K, Karunajeewa HA, Ilett KF. Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65:75\u201387.","journal-title":"Drugs"},{"key":"3750_CR9","doi-asserted-by":"publisher","first-page":"126","DOI":"10.4269\/ajtmh.2009.80.126","volume":"80","author":"RJ Maude","year":"2009","unstructured":"Maude RJ, Plewes K, Faiz MA, Hanson J, Charunwatthana P, Lee SJ, et al. Does artesunate prolong the electrocardiograph QT interval in patients with severe malaria? Am J Trop Med Hyg. 2009;80:126\u201332.","journal-title":"Am J Trop Med Hyg"},{"key":"3750_CR10","doi-asserted-by":"publisher","first-page":"e1003040","DOI":"10.1371\/journal.pmed.1003040","volume":"17","author":"XHS Chan","year":"2020","unstructured":"Chan XHS, Win YN, Haeusler IL, Tan JY, Loganathan S, Saralamba S, et al. Factors affecting the electrocardiographic QT interval in malaria: a systematic review and meta-analysis of individual patient data. PLoS Med. 2020;17:e1003040.","journal-title":"PLoS Med"},{"key":"3750_CR11","doi-asserted-by":"publisher","first-page":"3261","DOI":"10.1128\/AAC.05688-11","volume":"56","author":"F Borsini","year":"2012","unstructured":"Borsini F, Crumb W, Pace S, Ubben D, Wible B, Yan G-X, et al. In vitro cardiovascular effects of dihydroartemisin-piperaquine combination compared with other antimalarials. Antimicrob Agents Chemother. 2012;56:3261\u201370.","journal-title":"Antimicrob Agents Chemother"},{"key":"3750_CR12","doi-asserted-by":"publisher","first-page":"2752","DOI":"10.1111\/bcp.13372","volume":"83","author":"P Chotsiri","year":"2017","unstructured":"Chotsiri P, Wattanakul T, Hoglund RM, Hanboonkunupakarn B, Pukrittayakamee S, Blessborn D, et al. Population pharmacokinetics and electrocardiographic effects of dihydroartemisinin-piperaquine in healthy volunteers. Br J Clin Pharmacol. 2017;83:2752\u201366.","journal-title":"Br J Clin Pharmacol"},{"key":"3750_CR13","doi-asserted-by":"publisher","first-page":"e7871","DOI":"10.1371\/journal.pone.0007871","volume":"4","author":"Q Bassat","year":"2009","unstructured":"Bassat Q, Mulenga M, Tinto H, Piola P, Borrmann S, Men\u00e9ndez C, et al. Dihydroartemisinin\u2013piperaquine and artemether\u2013lumefantrine for treating uncomplicated malaria in African children: a randomised, non-inferiority trial. PLoS ONE. 2009;4:e7871.","journal-title":"PLoS ONE"},{"key":"3750_CR14","doi-asserted-by":"publisher","first-page":"e11880","DOI":"10.1371\/journal.pone.0011880","volume":"5","author":"N Valecha","year":"2010","unstructured":"Valecha N, Phyo AP, Mayxay M, Newton PN, Krudsood S, Keomany S, et al. An open-label, randomised study of dihydroartemisinin\u2013piperaquine versus artesunate\u2013mefloquine for falciparum malaria in Asia. PLoS ONE. 2010;5:e11880.","journal-title":"PLoS ONE"},{"key":"3750_CR15","unstructured":"The Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: ICH. https:\/\/www.ich.org\/products\/guidelines\/efficacy\/efficacy-single\/article\/questions-answers-the-clinical-evaluation-of-qtqtc-interval-prolongation-and-proarrhythmic-poten.html. Accessed 26 Aug 2019."},{"issue":"9","key":"3750_CR16","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1038\/s41598-018-37112-6","volume":"28","author":"C Funck-Brentano","year":"2019","unstructured":"Funck-Brentano C, Bacchieri A, Valentini G, Pace S, Tommasini S, Voiriot P, et al. Effects of dihydroartemisinin-piperaquine phosphate and artemether\u2013lumefantrine on QTc interval prolongation. Sci Rep. 2019;28(9):777.","journal-title":"Sci Rep"},{"key":"3750_CR17","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/S1473-3099(18)30297-4","volume":"18","author":"XHS Chan","year":"2018","unstructured":"Chan XHS, Win YN, Mawer LJ, Tan JY, Brugada J, White NJ. Risk of sudden unexplained death after use of dihydroartemisinin\u2013piperaquine for malaria: a systematic review and Bayesian meta-analysis. Lancet Infect Dis. 2018;18:913\u201323.","journal-title":"Lancet Infect Dis"},{"key":"3750_CR18","doi-asserted-by":"publisher","first-page":"2291","DOI":"10.1016\/j.jacc.2008.02.068","volume":"51","author":"I Goldenberg","year":"2008","unstructured":"Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008;51:2291\u2013300.","journal-title":"J Am Coll Cardiol"},{"key":"3750_CR19","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/s12936-015-0664-9","volume":"14","author":"R Baiden","year":"2015","unstructured":"Baiden R, Oduro A, Halidou T, Gyapong M, Sie A, Macete E, et al. Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-based combination Eurartesim\u00ae (dihydroartemisinin\/piperaquine), in public health facilities in Burkina Faso, Mozambique, Ghana, and Tanzania. Malar J. 2015;14:160.","journal-title":"Malar J"},{"key":"3750_CR20","doi-asserted-by":"publisher","first-page":"e0174503","DOI":"10.1371\/journal.pone.0174503","volume":"12","author":"AR Oduro","year":"2017","unstructured":"Oduro AR, Owusu-Agyei S, Gyapong M, Osei I, Adjei A, Yawson A, et al. Post-licensure safety evaluation of dihydroartemisinin piperaquine in the three major ecological zones across Ghana. PLoS ONE. 2017;12:e0174503.","journal-title":"PLoS ONE"},{"key":"3750_CR21","doi-asserted-by":"publisher","first-page":"e0164851","DOI":"10.1371\/journal.pone.0164851","volume":"11","author":"AM Kabanywanyi","year":"2016","unstructured":"Kabanywanyi AM, Baiden R, Ali AM, Mahende MK, Ogutu BR, Oduro A, et al. Multi-country evaluation of safety of dihydroartemisinin\/piperaquine post-licensure in African Public hospitals with electrocardiograms. PLoS ONE. 2016;11:e0164851.","journal-title":"PLoS ONE"},{"key":"3750_CR22","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1186\/s12936-019-2909-5","volume":"18","author":"E Sevene","year":"2019","unstructured":"Sevene E, Banda CG, Mukaka M, Maculuve S, Macuacua S, Vala A, et al. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: an open label non-randomized interventional trial. Malar J. 2019;18:277.","journal-title":"Malar J"},{"key":"3750_CR23","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1016\/S0140-6736(18)30291-5","volume":"391","author":"West African Network for Clinical Trials of Antimalarial Drugs (WANECAM)","year":"2018","unstructured":"West African Network for Clinical Trials of Antimalarial Drugs (WANECAM). Pyronaridine-artesunate or dihydroartemisinin\u2013piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b\/4 trial. Lancet. 2018;391:1378\u201390.","journal-title":"Lancet"},{"issue":"9","key":"3750_CR24","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/s41598-018-37113-5","volume":"29","author":"C Funck-Brentano","year":"2019","unstructured":"Funck-Brentano C, Ouologuem N, Duparc S, Felices M, Sirima SB, Sagara I, et al. Evaluation of the effects on the QT-interval of 4 artemisinin-based combination therapies with a correction-free and heart rate-free method. Sci Rep. 2019;29(9):883.","journal-title":"Sci Rep"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-021-03750-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12936-021-03750-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-021-03750-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T16:29:24Z","timestamp":1628612964000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/s12936-021-03750-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,8]]},"references-count":24,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["3750"],"URL":"https:\/\/doi.org\/10.1186\/s12936-021-03750-x","relation":{},"ISSN":["1475-2875"],"issn-type":[{"value":"1475-2875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,8]]},"assertion":[{"value":"29 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study followed a centralized regulatory submission at the European Medicines Agency (Approval 2013, prot. n\u00b0 3381). Ethical approval was received also by Hospital Ethics Committee in all the Countries participating in the study. Patients were enrolled after Informed consent signature.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors contributed, have reread and consented to the publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"GGM and EMP are full-time employee of Alfasigma S.p.A.. ST, MI, AB, were full employee for Alfasigma S.p.A at the time of the design, implementation and data analysis. OB, TJ, AB, ZB, EB, LV, CH, SD and RHB were on Euratesim<sup>\u00ae<\/sup> advisory board of Alfasigma and the legacy company Sigma-tau Industrie Farmaceutiche Riunite and received financial support for the study. NV declared that he has no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"214"}}