{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:21:03Z","timestamp":1790014863568,"version":"4.0.1"},"reference-count":37,"publisher":"American Society for Clinical Investigation","issue":"1","funder":[{"name":"Center for Infectious Disease Research","award":["Internal funding"],"award-info":[{"award-number":["Internal funding"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AI103947"],"award-info":[{"award-number":["R01AI103947"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["F32-AI102567-04"],"award-info":[{"award-number":["F32-AI102567-04"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004167","name":"Medicines for Malaria Venture","doi-asserted-by":"crossref","award":["to SAC"],"award-info":[{"award-number":["to SAC"]}],"id":[{"id":"10.13039\/501100004167","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"crossref","award":["OPP1137694"],"award-info":[{"award-number":["OPP1137694"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001491","name":"Belgian American Educational Foundation","doi-asserted-by":"crossref","award":["to LF"],"award-info":[{"award-number":["to LF"]}],"id":[{"id":"10.13039\/100001491","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["SCHA 2047\/1-1"],"award-info":[{"award-number":["SCHA 2047\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,1,11]]},"abstract":"<jats:p>\n                    Malaria eradication necessitates new tools to fight the evolving and complex\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    pathogens. These tools include prophylactic drugs that eliminate\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria\u2013causing parasite\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    . Here, we use a liver-chimeric humanized mouse (FRG huHep) to demonstrate in vivo\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    liver stage development and describe the efficacy of clinically used and candidate antimalarials with prophylactic activity. We show that daily administration of atovaquone-proguanil (ATQ-PG; ATQ, 30 mg\/kg, and PG, 10 mg\/kg) protects 5 of 5 mice from liver stage infection, consistent with the use in humans as a causal prophylactic drug. Single-dose primaquine (60 mg\/kg) has similar activity to that observed in humans, demonstrating the activity of this drug (and its active metabolites) in FRG huHep mice. We also show that DSM265, a selective\n                    <jats:italic>Plasmodial<\/jats:italic>\n                    dihydroorotate dehydrogenase inhibitor with causal prophylactic activity in humans, reduces liver stage burden in FRG huHep mice. Finally, we measured liver stage\u2013to\u2013blood stage transition of the parasite, the ultimate readout of prophylactic activity and measurement of infective capacity of parasites in the liver, to show that ATQ-PG reduces blood stage patency to below the limit of quantitation by quantitative PCR (qPCR). The FRG huHep model, thus, provides a platform for preclinical evaluation of drug candidates for liver stage causal prophylactic activity, pharmacokinetic\/pharmacodynamics studies, and biological studies to investigate the mechanism of action of liver stage active antimalarials.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.92587","type":"journal-article","created":{"date-parts":[[2018,1,10]],"date-time":"2018-01-10T11:00:43Z","timestamp":1515582043000},"source":"Crossref","is-referenced-by-count":30,"title":["Assessing drug efficacy against Plasmodium falciparum liver stages in vivo"],"prefix":"10.1172","volume":"3","author":[{"given":"Erika L.","family":"Flannery","sequence":"first","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9235-0814","authenticated-orcid":true,"given":"Lander","family":"Foquet","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vorada","family":"Chuenchob","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Fishbaugher","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7738-5795","authenticated-orcid":true,"given":"Zachary","family":"Billman","sequence":"additional","affiliation":[{"name":"Departments of Laboratory Medicine and Microbiology, University of 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Camargo","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thao","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Schafer","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon K.","family":"Sack","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Yecuris Corporation, Portland, Oregon, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Saunders","sequence":"additional","affiliation":[{"name":"Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bial","sequence":"additional","affiliation":[{"name":"Yecuris Corporation, Portland, Oregon, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Campo","sequence":"additional","affiliation":[{"name":"Medicines for Malaria Venture, Geneva, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Charman","sequence":"additional","affiliation":[{"name":"Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 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