{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:33:01Z","timestamp":1753882381931,"version":"3.41.2"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T00:00:00Z","timestamp":1722988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T00:00:00Z","timestamp":1722988800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases","award":["R21AI149730"],"award-info":[{"award-number":["R21AI149730"]}]},{"name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases","award":["R01AI117017"],"award-info":[{"award-number":["R01AI117017"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,8,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Ivermectin, a broad-spectrum anti-parasitic drug, has been proposed as a novel vector control tool to reduce malaria transmission by mass drug administration. Ivermectin and some metabolites have mosquito-lethal effect, reducing\n              <jats:italic>Anopheles<\/jats:italic>\n              mosquito survival. Ivermectin inhibits liver stage development in a rodent malaria model, but no inhibition was observed in a primate malaria model or in a human malaria challenge trial. In the liver, cytochrome P450 3A4 and 3A5 enzymes metabolize ivermectin, which may impact drug efficacy. Thus, understanding ivermectin metabolism and assessing this impact on\n              <jats:italic>Plasmodium<\/jats:italic>\n              liver stage development is critical. Using primary human hepatocytes (PHHs), we characterized ivermectin metabolism and evaluated the efficacy of ivermectin and its primary metabolites M1 (3\u2033-\n              <jats:italic>O<\/jats:italic>\n              -demethyl ivermectin) and M3 (4-hydroxymethyl ivermectin) against\n              <jats:italic>Plasmodium falciparum<\/jats:italic>\n              liver stages. Two different modes of ivermectin exposure were evaluated: prophylactic mode (days 0\u20133 post-infection) and curative mode (days 3\u20135 post-infection). We used two different PHH donors and modes to determine the inhibitory concentration (IC\n              <jats:sub>50<\/jats:sub>\n              ) of ivermectin, M1, M3, and the known anti-malarial drug pyrimethamine, with IC\n              <jats:sub>50<\/jats:sub>\n              values ranging from 1.391 to 14.44, 9.95\u201323.71, 4.767\u20138.384, and 0.9073\u20135.416 \u00b5M, respectively. In our PHH model, ivermectin and metabolites M1 and M3 demonstrated inhibitory activity against\n              <jats:italic>P. falciparum<\/jats:italic>\n              liver stages in curative treatment mode (days 3\u20135) and marginal activity in prophylactic treatment mode (days 0\u20133). Ivermectin had improved efficacy when co-administered with ketoconazole, a specific inhibitor of cytochrome P450 3A4 enzyme. Further studies should be performed to examine ivermectin liver stage efficacy when co-administered with CYP3A4 inhibitors and anti-malarial drugs to understand the pharmacokinetic and pharmacodynamic drug-drug interactions that enhance efficacy against human malaria parasites\n              <jats:italic>in vitro<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01272-23","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T13:00:30Z","timestamp":1718974830000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy of ivermectin and its metabolites against\n            <i>Plasmodium falciparum<\/i>\n            liver stages in primary human hepatocytes"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-0900","authenticated-orcid":false,"given":"Pradeep","family":"Annamalai Subramani","sequence":"first","affiliation":[{"name":"Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phornpimon","family":"Tipthara","sequence":"additional","affiliation":[{"name":"Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6125-0036","authenticated-orcid":true,"given":"Surendra Kumar","family":"Kolli","sequence":"additional","affiliation":[{"name":"Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Nicholas","sequence":"additional","affiliation":[{"name":"Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA"},{"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha J.","family":"Barnes","sequence":"additional","affiliation":[{"name":"Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison M.","family":"Ogbondah","sequence":"additional","affiliation":[{"name":"Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4807-9681","authenticated-orcid":true,"given":"Kevin C.","family":"Kobylinski","sequence":"additional","affiliation":[{"name":"Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand"},{"name":"Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Tarning","sequence":"additional","affiliation":[{"name":"Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand"},{"name":"Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3707-7979","authenticated-orcid":true,"given":"John H.","family":"Adams","sequence":"additional","affiliation":[{"name":"Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","volume-title":"World malaria report 2023","author":"WHO","year":"2023","unstructured":"WHO. 2023. World malaria report 2023. WHO, Geneva, Switzerland."},{"key":"e_1_3_4_3_2","volume-title":"Entectocide and ectocide products for malaria transmission control","author":"WHO","year":"2022","unstructured":"WHO. 2022. Entectocide and ectocide products for malaria transmission control. 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