{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T20:13:09Z","timestamp":1770840789061,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2012,8,13]],"date-time":"2012-08-13T00:00:00Z","timestamp":1344816000000},"content-version":"vor","delay-in-days":0,"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":[[2012,10]]},"abstract":"<jats:p>Sitaxentan sodium (<jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>helin) is a once daily, orally bioavailable, highly selective endothelin A receptor antagonist. Initially approved for the treatment of pulmonary arterial hypertension, sitaxentan was withdrawn in 2010 following the recognition of a pattern of idiosyncratic liver injury. During development of this drug, a series of nonclinical studies investigated the effects of orally administered sitaxentan on fertility, embryofetal development, and pre\u2010 and postnatal development in the rat; results of these studies are reported here. In the fertility study, sitaxentan did not affect mating behavior, fertility, sperm morphology, or estrous cycle. Sitaxentan was teratogenic in the embyrofetal development study, which was expected based on its pharmacologic mechanism of action. Teratogenic effects included malformations of the head, mouth, face, and large blood vessels. In the pre\u2010 and postnatal study, sitaxentan administration was associated with reduced pup survival, large or abnormally shaped livers, and delays in markers of auditory and sexual development. Sitaxentan was detected in plasma of suckling pups receiving milk from females dosed with sitaxentan. These nonclinical study findings were reflected in the sitaxentan product label warnings. Birth Defects Res (Part B) 00:1\u201010, 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/bdrb.21021","type":"journal-article","created":{"date-parts":[[2012,8,13]],"date-time":"2012-08-13T12:41:16Z","timestamp":1344861676000},"page":"327-336","source":"Crossref","is-referenced-by-count":12,"title":["An Evaluation of Reproductive and Developmental Toxicity of Sitaxentan (<scp>T<\/scp>helin) in Rats"],"prefix":"10.1002","volume":"95","author":[{"given":"David M.","family":"Cross","sequence":"first","affiliation":[{"name":"Pfizer Ltd. Sandwich Kent UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Horsley","sequence":"additional","affiliation":[{"name":"Pfizer Ltd. Sandwich Kent UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mazin","family":"Derzi","sequence":"additional","affiliation":[{"name":"Pfizer Ltd. Cambridge MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith","family":"Owen","sequence":"additional","affiliation":[{"name":"Pfizer Ltd. Sandwich Kent UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona L.","family":"Stavros","sequence":"additional","affiliation":[{"name":"Jackrabbit Consulting LLC San Diego CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,8,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.04.017"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.74.1.223"},{"issue":"5","key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1242\/dev.125.5.813","article-title":"Cranial and cardiac neural crest defects in endothelin\u2010A receptor\u2010deficient mice","volume":"125","author":"Clouthier DE","year":"1998","journal-title":"Development"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.136R001"},{"key":"e_1_2_6_6_1","doi-asserted-by":"crossref","unstructured":"CrossD DerziM HorsleyE OwenK StavrosF.2012.Evaluation of sitaxentan (Thelin\u00ae) toxicity in juvenile rats and regulatory interactions during the development of aEuropean Medicines Agency Paediatric Investigation Plan. 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