title: Investigation of the teratogenic potential of VLA-4 antagonist derivatives in rats.
abstract: Very late antigen-4 (VLA-4), which is concerned with cell-cell adhesion, plays important roles in development of the heart, and some VLA-4 antagonists cause cardiac anomalies. In this study, we evaluated the teratogenic potential of VLA-4 antagonist derivatives as screening, and investigated the conditions that induce cardiac anomalies. Seventeen compounds were orally administered to pregnant rats throughout the organogenesis period, and fetal examinations were performed. In addition, drug concentrations in the embryos were assayed. As a result, the incidence of ventricular septal defect (VSD) ranged from 0 to 100% depending on the compound. Plasma drug concentrations in the dams were related to increased incidence of VSD; however, these incidences were not increased when the concentration of the compound in the embryos at 24h after dosing was low. It is considered that continuous pharmacological activity in the embryo for more than 24h might disrupt closure of the ventricular septum.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-Ku, Tokyo 134-8630, Japan. Electronic address: sakurai.ken.t6@daiichisankyo.co.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-Ku, Tokyo 134-8630, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Matsuoka
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-Ku, Tokyo 134-8630, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Suzuki
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-Ku, Tokyo 134-8630, Japan.
authors.forename: Junzo
authors.initials: J
authors.lastname: Kinoshita
authors.affiliation: Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., 2-58, Hiromachi 1-Chome, Shinagawa-Ku, Tokyo 140-0005, Japan.
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13, Kita-Kasai 1-Chome, Edogawa-Ku, Tokyo 134-8630, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shimomura
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006345:Heart Septal Defects, Ventricular / Q000139:chemically induced*; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008297:Male; D008813:Mice, Inbred ICR; D011247:Pregnancy; D051381:Rats; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D039041:Integrin alpha4beta1; D013723:Teratogens
keywords: Developmental toxicity; Rats; VLA-4; Ventricular septal defect