{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T19:59:43Z","timestamp":1760644783048},"reference-count":21,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2004,4,13]],"date-time":"2004-04-13T00:00:00Z","timestamp":1081814400000},"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":[[2004,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND:<\/jats:bold> Integrins such as VLA\u20104 (Very late antigen 4, integrin \u03b1<jats:sub>4<\/jats:sub>\u03b2<jats:sub>1<\/jats:sub>) play key roles in cell\u2013cell interactions that are critical for development. Homozygous null knockouts of the VLA\u20104 \u03b1<jats:sub>4<\/jats:sub>\u2010subunit or VCAM\u20101 (VLA\u20104 cell surface ligand) in mice result in failure of the allantois and chorion to fuse leading to interrupted placentation and cardiac development and embryo lethality. Embryo\u2010fetal studies of three VLA\u20104 antagonists, IVL745, IVL984, and HMR1031 [Crofts et al., Birth Defects Res B 71:55\u201368 (this issue), 2004] with exposure on gestation days (GD) 6\u201317 (rat), 6\u201318 (rabbit) or 6\u201315 (mouse) showed that only IVL984 treatment resulted in embryo lethality and cardiac defects. Objectives of the current study were to determine the critical period for inducing IVL984\u2010related embryo\u2010fetal effects, and to test the hypothesis that these effects were due to higher embryo drug concentrations. <jats:bold>METHODS:<\/jats:bold> IVL984 was administered at 40\u2009mg\/kg\/day to pregnant rats on GD 4 and 5, GD 6 and 7, GD 8 and 9, GD 10 and 11, or GD 12 and 13. Animals were euthanized on GD 21 and uteri and fetuses were examined. A treatment period of GD 10\u201312 was selected for subsequent toxicokinetic (TK) studies in which IVL984, HMR1031, or IVL745 was administered to pregnant rats and rabbits. On GD 12, maternal plasma, extra\u2010embryonic tissue (placenta and amniotic fluid), and embryonic tissue were collected and analyzed for drug concentrations. <jats:bold>RESULTS:<\/jats:bold> In the IVL984 critical period study in pregnant rats, treatment on GD 10 and 11 resulted in increased post\u2010implantation loss, skeletal variations, and spiral septal defects similar to those observed in standard embryo\u2010fetal development studies with treatment throughout organogenesis. There were no embryo\u2010fetal effects after treatment on GD 4 and 5, GD 6 and 7, or GD 8 and 9. There was a single aorta malformation after treatment on GD 12 and 13. In the TK studies, IVL745, HMR1031, and IVL984 were all detectable in embryonic tissue and there was no evidence for accumulation. Rat and rabbit embryo exposures (AUC or dose\u2010adjusted AUC) on GD 12 could not explain the observed teratology (IVL984&lt;HMR1031&lt;IVL745). Further analyses incorporating pharmacological activity, clearance, and protein binding data provided a positive correlation between embryonic exposure and teratogenic potency. <jats:bold>CONCLUSIONS:<\/jats:bold> The critical period for IVL984 in the rat, GD 10 to 11, corresponds to the expression of \u03b1\u20104 integrin on the chorion and VCAM\u20101 on the allantois and myocardium as well as chorioallantoic fusion and formation of the spiral septum. Embryo drug levels adjusted for pharmacological activity, clearance, and protein binding provide a possible explanation for the differing teratogenic potency of IVL984, HMR1031, and IVL745. <jats:italic>Birth Defects Res B<\/jats:italic> 71:69\u201379, 2004. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdrb.20000","type":"journal-article","created":{"date-parts":[[2004,4,13]],"date-time":"2004-04-13T22:00:45Z","timestamp":1081893645000},"page":"69-79","source":"Crossref","is-referenced-by-count":13,"title":["Critical period for a teratogenic VLA\u20104 antagonist: Developmental effects and comparison of embryo drug concentrations of teratogenic and non\u2010teratogenic VLA\u20104 antagonists"],"prefix":"10.1002","volume":"71","author":[{"given":"F.","family":"Crofts","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Rohatagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Pino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B.","family":"DeLise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Guittin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Barbellion","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Brunel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P.","family":"Lockey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Lerman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,4,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002040050007"},{"key":"e_1_2_7_3_1","first-page":"35","volume-title":"Developmental 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