{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:56:10Z","timestamp":1791118570636,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2008,8,13]],"date-time":"2008-08-13T00:00:00Z","timestamp":1218585600000},"content-version":"vor","delay-in-days":12,"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":[[2008,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND:<\/jats:bold> The antimalarial, artesunate, is teratogenic and embryolethal in rats, with peak sensitivity on Days 10 and 11 postcoitum (pc). <jats:bold>METHODS:<\/jats:bold> We compared the developmental toxicity of structurally related artemisinins, dihdyroartemisinin (DHA), artemether (ARTM), and arteether (ARTE) to that of artesunate after oral administration to rats on Day 10 pc. In separate studies, embryolethality was characterized after single intravenous (IV) administration of artesunate on Day 11 pc, and toxicokinetic parameters following oral and IV administration were compared. Lastly, to determine whether maternal hematologic effects occurred at doses that affect embryonic erythroblasts, artesunate was orally administered on Day 11 pc at a dose that caused 100% embryolethality. <jats:bold>RESULTS:<\/jats:bold> All artemisinins caused the same pattern of embryolethality and fetal cardiovascular and skeletal abnormalities as previously shown for artesunate. In the IV study, marked postimplantation loss occurred at 1.5 and 3\u2009mg\/kg artesunate, but not at 0.75\u2009mg\/kg. Among the toxicokinetic parameters evaluated, only the DHA AUC<jats:sub>0\u2010t<\/jats:sub> was similar at embryolethal oral and IV doses of artesunate. An embryolethal dose of artesunate caused a 15% decrease in maternal reticulocyte counts and no other hematologic effects. <jats:bold>CONCLUSIONS:<\/jats:bold> Several structurally related artemisinins cause similar developmental toxicity, suggesting an artemisinin class effect. Equally embryotoxic oral and IV treatments of one artemisinin compound (artesunate) produced similar systemic exposure to the artesunate metabolite, DHA, suggesting that DHA may be the proximate developmental toxicant. Embryolethal doses of artesunate only caused minor changes in maternal reticulocyte counts indicating that adult hematology parameters are not as sensitive as embryonic erythroblasts. <jats:italic>Birth Defects Res (Part B)<\/jats:italic> 83:397\u2013406, 2008. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdrb.20165","type":"journal-article","created":{"date-parts":[[2008,8,15]],"date-time":"2008-08-15T05:45:42Z","timestamp":1218779142000},"page":"397-406","source":"Crossref","is-referenced-by-count":51,"title":["Developmental toxicity of artesunate in the rat: comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count"],"prefix":"10.1002","volume":"83","author":[{"given":"Robert L.","family":"Clark","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Lerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estella M.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Gristwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tacey E.K.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,8,13]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"118","article-title":"Embryotoxicity and teratogenicity studies on artemether in mice, rats and rabbits","volume":"5","author":"Chen LJ","year":"1984","journal-title":"Acta Pharmacol Sin"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20027"},{"key":"e_1_2_6_4_1","first-page":"230","volume-title":"Practical nonparametric statistics","author":"Conover SJ","year":"1980"},{"key":"e_1_2_6_5_1","first-page":"1096","article-title":"A multiple comparisons procedure comparing several treatments with a control","volume":"55","author":"Dunnett CW","year":"1965","journal-title":"J Am Stat Soc"},{"key":"e_1_2_6_6_1","unstructured":"GuoX\u2010B FuL\u2010C YuC\u2010G JianH\u2010X LiG\u2010Q.1990.A study on tolerance and toxic side\u2010effects of artesunate intravenous injection on healthy volunteers\/Clinical trials Phase I. In: Li G\u2010Q Guo XB Fu Y editors. Clinical trials on qinghaosu and its derivatives. pp39\u201343."},{"key":"e_1_2_6_7_1","volume-title":"Nonparametric statistical methods","author":"Hollander M","year":"1999"},{"key":"e_1_2_6_8_1","first-page":"157","volume-title":"Medical embryology, cardiovascular system","author":"Langman J","year":"1982"},{"key":"e_1_2_6_9_1","first-page":"42","article-title":"Teratogenicity of sodium artesunate","volume":"13","author":"Li ZL","year":"1988","journal-title":"Zhong Yao Tong Bao"},{"key":"e_1_2_6_10_1","unstructured":"LittellRC MillikenGA StroupWW WolfingerRD.1996. SAS system for MIXED models. 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Assessment of the safety of artemisinin compounds in pregnancy: report of two informal consultations convened by WHO in 2002.http:\/\/www.who.int\/tdr\/publications\/publications\/artemisinin\u2013pregn.htm."},{"key":"e_1_2_6_25_1","first-page":"657","article-title":"Contragestational effects of dihydroartemisinin and artesunate (in Chinese)","volume":"31","author":"Xu JH","year":"1996","journal-title":"Yao Hsueh Hsueh Pao\u2013Acta Pharmaceut Sin"}],"container-title":["Birth Defects Research Part B: Developmental and Reproductive Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdrb.20165","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdrb.20165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T18:58:16Z","timestamp":1699988296000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdrb.20165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8]]},"references-count":24,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2008,8]]}},"alternative-id":["10.1002\/bdrb.20165"],"URL":"https:\/\/doi.org\/10.1002\/bdrb.20165","archive":["Portico"],"relation":{},"ISSN":["1542-9733","1542-9741"],"issn-type":[{"value":"1542-9733","type":"print"},{"value":"1542-9741","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,8]]}}}