{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:25:45Z","timestamp":1764174345954,"version":"3.41.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,12,29]],"date-time":"2016-12-29T00:00:00Z","timestamp":1482969600000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:p>The combination of artemether plus lumefantrine is a type of artemisinin\u2010based combination therapy (ACT) recommended by the World Health Organization for uncomplicated falciparum malaria except in the first trimester of pregnancy. The first trimester restriction was based on the marked embryotoxicity in animals (including embryo death and cardiac and skeletal malformations) of artemisinins such as artesunate, dihydroartemisinin, and artemether. Before recommending ACTs for use in the first trimester, the World Health Organization has requested that all information relevant to the assessment of risk of ACTs to the embryo be made available to the public. This report describes the results of embryo\u2010fetal development studies of artemether alone, lumefantrine alone, and the combination in rats and rabbits as well as toxicokinetic studies of lumefantrine in pregnant rabbits. The developmental no\u2010effect levels for lumefantrine were 300 mg\/kg\/day in rats (based on a 25% decrease in litter size at 1000 mg\/kg\/day) and 1000 mg\/kg\/day in rabbits. The calculated safety margins based on human equivalent dose and plasma<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>and AUC values were in the range of 2.5\u2010 to 17\u2010fold. The developmental no\u2010effect levels for artemether were 3 mg\/kg\/day in rats and 25 mg\/kg\/day in rabbits. Lumefantrine caused no teratogenicity and was not a potent embryotoxin in rats and rabbits. Expected artemisinin\u2010like findings were seen with artemether alone and with artemether\/lumefantrine combined except that no malformations were observed. There were no findings in pregnant rats and rabbits that would cause increased concern for the use of artemether\u2013lumefantrine in the first trimester compared to other ACTs.<\/jats:p>","DOI":"10.1002\/bdrb.21189","type":"journal-article","created":{"date-parts":[[2016,12,29]],"date-time":"2016-12-29T08:55:15Z","timestamp":1483001715000},"page":"243-257","source":"Crossref","is-referenced-by-count":9,"title":["Developmental toxicity studies of lumefantrine and artemether in rats and rabbits"],"prefix":"10.1002","volume":"107","author":[{"given":"Robert L.","family":"Clark","sequence":"first","affiliation":[{"name":"Artemis Pharmaceutical Research Jacksonville FL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen","family":"Youreneff","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony M.","family":"DeLise","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation East Hanover NJ USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,12,29]]},"reference":[{"volume-title":"Statistical inference under order restrictions","year":"1972","author":"Barlow R. 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