{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T02:16:33Z","timestamp":1775614593183,"version":"3.50.1"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T00:00:00Z","timestamp":1576627200000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Malar J"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Drug efficacy against <jats:italic>kelch 13<\/jats:italic> mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration\u2013time profile of these ozonides in humans and a novel, semi-automated readout was introduced.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the <jats:italic>Plasmodium falciparum<\/jats:italic> clinical isolate Cam3.I<jats:sup>R539T<\/jats:sup>.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48\u00a0h, OZ439 and OZ609 will be highly potent against <jats:italic>kelch 13<\/jats:italic> mutant isolates, such as <jats:italic>P. falciparum<\/jats:italic> Cam3.I<jats:sup>R539T<\/jats:sup>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12936-019-3056-8","type":"journal-article","created":{"date-parts":[[2019,12,18]],"date-time":"2019-12-18T12:02:58Z","timestamp":1576670578000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay"],"prefix":"10.1186","volume":"18","author":[{"given":"Annabelle","family":"Walz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Didier","family":"Leroy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Andenmatten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"M\u00e4ser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-0912","authenticated-orcid":false,"given":"Sergio","family":"Wittlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,12,18]]},"reference":[{"key":"3056_CR1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","volume":"361","author":"AM Dondorp","year":"2009","unstructured":"Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455\u201367.","journal-title":"N Engl J Med"},{"key":"3056_CR2","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1056\/NEJMc0805011","volume":"359","author":"H Noedl","year":"2008","unstructured":"Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359:2619\u201320.","journal-title":"N Engl J Med"},{"key":"3056_CR3","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1038\/nm.4381","volume":"23","author":"B Blasco","year":"2017","unstructured":"Blasco B, Leroy D, Fidock DA. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat Med. 2017;23:917\u201328.","journal-title":"Nat Med"},{"key":"3056_CR4","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature12876","volume":"505","author":"F Ariey","year":"2014","unstructured":"Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50\u20135.","journal-title":"Nature"},{"key":"3056_CR5","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1126\/science.1260867","volume":"347","author":"J Straimer","year":"2015","unstructured":"Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347:428\u201331.","journal-title":"Science."},{"key":"3056_CR6","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1128\/AAC.01636-09","volume":"54","author":"B Witkowski","year":"2010","unstructured":"Witkowski B, Lelievre J, Barragan MJ, Laurent V, Su XZ, Berry A, et al. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother. 2010;54:1872\u20137.","journal-title":"Antimicrob Agents Chemother"},{"key":"3056_CR7","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/S1473-3099(13)70252-4","volume":"13","author":"B Witkowski","year":"2013","unstructured":"Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S, et al. Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in vitro and ex vivo drug-response studies. Lancet Infect Dis. 2013;13:1043\u20139.","journal-title":"Lancet Infect Dis."},{"key":"3056_CR8","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/nrd4573","volume":"14","author":"TN Wells","year":"2015","unstructured":"Wells TN, Hooft van Huijsduijnen R, Van Voorhis WC. Malaria medicines: a glass half full? Nat Rev Drug Discov. 2015;14:424\u201342.","journal-title":"Nat Rev Drug Discov."},{"key":"3056_CR9","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.exppara.2006.09.016","volume":"115","author":"C Snyder","year":"2007","unstructured":"Snyder C, Chollet J, Santo-Tomas J, Scheurer C, Wittlin S. In vitro and in vivo interaction of synthetic peroxide RBx11160 (OZ277) with piperaquine in Plasmodium models. Exp Parasitol. 2007;115:296\u2013300.","journal-title":"Exp Parasitol"},{"key":"3056_CR10","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/0001-706X(93)90083-N","volume":"55","author":"W Huber","year":"1993","unstructured":"Huber W, Koella JC. A comparison of three methods of estimating EC50 in studies of drug resistance of malaria parasites. Acta Trop. 1993;55:257\u201361.","journal-title":"Acta Trop"},{"key":"3056_CR11","doi-asserted-by":"publisher","first-page":"5792","DOI":"10.1128\/AAC.00287-13","volume":"57","author":"NJ White","year":"2013","unstructured":"White NJ. Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization. Antimicrob Agents Chemother. 2013;57:5792\u2013807.","journal-title":"Antimicrob Agents Chemother"},{"key":"3056_CR12","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12936-017-1696-0","volume":"16","author":"F Baumgartner","year":"2017","unstructured":"Baumgartner F, Jourdan J, Scheurer C, Blasco B, Campo B, Maser P, et al. In vitro activity of anti-malarial ozonides against an artemisinin-resistant isolate. Malar J. 2017;16:45.","journal-title":"Malar J."},{"key":"3056_CR13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1111\/j.1365-2125.2011.04103.x","volume":"73","author":"R McGready","year":"2012","unstructured":"McGready R, Phyo AP, Rijken MJ, Tarning J, Lindegardh N, Hanpithakpon W, et al. Artesunate\/dihydroartemisinin pharmacokinetics in acute falciparum malaria in pregnancy: absorption, bioavailability, disposition and disease effects. Br J Clin Pharmacol. 2012;73:467\u201377.","journal-title":"Br J Clin Pharmacol"},{"key":"3056_CR14","doi-asserted-by":"publisher","first-page":"5484","DOI":"10.1128\/AAC.00044-12","volume":"56","author":"D Saunders","year":"2012","unstructured":"Saunders D, Khemawoot P, Vanachayangkul P, Siripokasupkul R, Bethell D, Tyner S, et al. Pharmacokinetics and pharmacodynamics of oral artesunate monotherapy in patients with uncomplicated Plasmodium falciparum malaria in western Cambodia. Antimicrob Agents Chemother. 2012;56:5484\u201393.","journal-title":"Antimicrob Agents Chemother"},{"key":"3056_CR15","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1128\/AAC.01868-12","volume":"57","author":"B Witkowski","year":"2013","unstructured":"Witkowski B, Khim N, Chim P, Kim S, Ke S, Kloeung N, et al. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia. Antimicrob Agents Chemother. 2013;57:914\u201323.","journal-title":"Antimicrob Agents Chemother"},{"key":"3056_CR16","doi-asserted-by":"publisher","first-page":"e30949","DOI":"10.1371\/journal.pone.0030949","volume":"7","author":"LM Sanz","year":"2012","unstructured":"Sanz LM, Crespo B, De-Cozar C, Ding XC, Llergo JL, Burrows JN, et al. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS ONE. 2012;7:e30949.","journal-title":"PLoS ONE"},{"key":"3056_CR17","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1093\/jac\/dkw174","volume":"71","author":"JS McCarthy","year":"2016","unstructured":"McCarthy JS, Baker M, O\u2019Rourke P, Marquart L, Griffin P, Hooft van Huijsduijnen R, et al. Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers. J Antimicrob Chemother. 2016;71:2620\u20137.","journal-title":"J Antimicrob Chemother."},{"key":"3056_CR18","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1177\/0091270010385578","volume":"51","author":"A Gautam","year":"2011","unstructured":"Gautam A, Ahmed T, Sharma P, Varshney B, Kothari M, Saha N, et al. Pharmacokinetics and pharmacodynamics of arterolane maleate following multiple oral doses in adult patients with P. falciparum malaria. J Clin Pharmacol. 2011;51:1519\u201328.","journal-title":"J Clin Pharmacol."},{"key":"3056_CR19","doi-asserted-by":"publisher","first-page":"4501","DOI":"10.1128\/AAC.00574-16","volume":"60","author":"T Yang","year":"2016","unstructured":"Yang T, Xie SC, Cao P, Giannangelo C, McCaw J, Creek DJ, et al. Comparison of the exposure time dependence of the activities of synthetic ozonide antimalarials and dihydroartemisinin against K13 wild-type and mutant Plasmodium falciparum strains. Antimicrob Agents Chemother. 2016;60:4501\u201310.","journal-title":"Antimicrob Agents Chemother"},{"key":"3056_CR20","doi-asserted-by":"publisher","first-page":"e00172-17","DOI":"10.1128\/mBio.00172-17","volume":"8","author":"J Straimer","year":"2017","unstructured":"Straimer J, Gnadig NF, Stokes BH, Ehrenberger M, Crane AA, Fidock DA. Plasmodium falciparum K13 Mutations differentially impact ozonide susceptibility and parasite fitness in vitro. MBio. 2017;8:e00172-17.","journal-title":"MBio."},{"key":"3056_CR21","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S1473-3099(15)00320-5","volume":"16","author":"AP Phyo","year":"2016","unstructured":"Phyo AP, Jittamala P, Nosten FH, Pukrittayakamee S, Imwong M, White NJ, et al. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2016;16:61\u20139.","journal-title":"Lancet Infect Dis."},{"key":"3056_CR22","doi-asserted-by":"publisher","first-page":"e1002132","DOI":"10.1371\/journal.pbio.1002132","volume":"13","author":"C Dogovski","year":"2015","unstructured":"Dogovski C, Xie SC, Burgio G, Bridgford J, Mok S, McCaw JM, et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol. 2015;13:e1002132.","journal-title":"PLoS Biol"},{"key":"3056_CR23","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1314981","volume":"371","author":"EA Ashley","year":"2014","unstructured":"Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411\u201323.","journal-title":"N Engl J Med"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-019-3056-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12936-019-3056-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-019-3056-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:42:03Z","timestamp":1608165723000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/s12936-019-3056-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":23,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["3056"],"URL":"https:\/\/doi.org\/10.1186\/s12936-019-3056-8","relation":{},"ISSN":["1475-2875"],"issn-type":[{"value":"1475-2875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"17 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"427"}}