{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T19:57:53Z","timestamp":1757620673700,"version":"3.44.0"},"reference-count":32,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Ambrisentan is a selective endothelin\u20101 receptor antagonist marketed for pulmonary arterial hypertension (PAH) in adults, adolescents, and children above 8\u2009years old.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>A juvenile toxicity study conducted to support clinical studies in patients under 8\u2009years old dosed rats from postnatal days 7 to 62. In subsequent investigative studies, respiratory function was assessed by ventilatory parameters and arterial blood gases, along with other endpoints.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Noisy breathing occurred, and brain weight was lower (4%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) without histologic changes at the highest dose (20\u2009mg\/kg\/day). Respiratory sounds described as clicking noises seemingly synchronous with the breathing cycle were sustained. Hypoxemia and hypercapnia associated with apneic times occurred, suggesting an intermittent physical airway blockade.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>It's postulated that the brain weight decrease was mediated by sustained hypoxemia during a period of rapid brain growth. Improper interaction of rat laryngeal tissues, in close apposition during early postnatal stages, may constitute a sensitive period. Clinical relevance is unknown; palatal\/laryngeal maturation timing in healthy children supports up to ~2\u2009years as the period for any potential risk. However, for children with PAH, chronic hypoxemia and\/or concomitant conditions associated with developmental delay could hypothetically extend the sensitive age period for potential risk through the third year of life.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2504","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T08:24:56Z","timestamp":1752308696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain Weight Effect of Ambrisentan in Juvenile Rat Toxicity Studies Associated With Breathing Sounds, Apnea, and Sustained Hypoxemia"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8439-7700","authenticated-orcid":false,"given":"Susan B.","family":"Laffan","sequence":"first","affiliation":[{"name":"GlaxoSmithKline, In\u00a0Vitro In\u00a0Vivo Translation  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohrs","family":"Loren","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, In\u00a0Vitro In\u00a0Vivo Translation  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kambara","family":"Takahito","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, In\u00a0Vitro In\u00a0Vivo Translation  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Turner","family":"Sandra","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, In\u00a0Vitro In\u00a0Vivo Translation  Collegeville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2015.06.048"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21607"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/6.5.726"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23132"},{"issue":"16","key":"e_1_2_8_6_1","first-page":"1241","article-title":"Influence of Chronic Intermittent Hypoxia on Growth Associated Protein 43 Expression in the Hippocampus of Young Rats","volume":"7","author":"Chen Y.","year":"2012","journal-title":"Neural Regeneration Research"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.5.813"},{"key":"e_1_2_8_8_1","first-page":"672","article-title":"Normal Brain Development and Aging: Quantitative Analysis In\u00a0Vivo MR Imaging in Healthy Volunteers","volume":"216","author":"Courchesne E.","year":"2000","journal-title":"Neuroradiology"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2012.05.018"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/7.7.619"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410040410"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/adc.48.10.757"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-3782(79)90022-7"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623318816295"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20729"},{"issue":"9","key":"e_1_2_8_16_1","first-page":"103","article-title":"Localization of Endothelin\u20101 mRNA Expression and Immunoreactivity in the Anterior Segment of Human Eye: Expression of ETA and ETB Receptors","volume":"9","author":"Fern\u00e1ndez\u2010Durango R.","year":"2003","journal-title":"Molecular Vision"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0822-09.2009"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19971020)387:2<167::AID-CNE1>3.0.CO;2-Z"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004290050289"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0785"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ico.0000157400.81408.2b"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.53.607"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01321770"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs234"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(98)00139-4"},{"key":"e_1_2_8_26_1","first-page":"472","volume-title":"The Developing Human: Clinically Oriented Embryology, Saunders","author":"Moore and Persaud","year":"2003"},{"key":"e_1_2_8_27_1","first-page":"1207","volume-title":"Latin Square and Related Designs. 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