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Related Experiment Videos

Different embryo-fetal toxicity effects for three VLA-4 antagonists.

F Crofts1, M Pino, B DeLise

  • 1Department of Drug Safety Evaluation, Aventis Inc., Bridgewater, New Jersey 08807, USA. Frances.Crofts@aventis.com

Birth Defects Research. Part B, Developmental and Reproductive Toxicology
|April 21, 2004
PubMed
Summary

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The VLA-4 antagonist IVL984 demonstrated potent teratogenicity, causing embryo lethality and cardiac malformations, including spiral septal defects, in multiple species. In contrast, IVL745 showed no teratogenic effects, and HMR1031 caused only slight embryo-fetal effects at maternally toxic doses.

Area of Science:

  • Developmental toxicology
  • Pharmacology
  • Immunology

Background:

  • Very late antigen 4 (VLA-4) is crucial for cell-cell interactions during development.
  • Genetic deficiencies in VLA-4 or its ligand VCAM-1 lead to embryonic lethality due to abnormal development.
  • Understanding VLA-4 antagonist teratogenicity is vital for drug safety.

Purpose of the Study:

  • To evaluate and compare the teratogenic potential of three VLA-4 antagonists: IVL745, HMR1031, and IVL984.
  • To identify dose-dependent effects and specific malformations induced by these compounds.
  • To assess the safety profile of VLA-4 antagonists during embryonic development.

Main Methods:

  • Standard embryo-fetal developmental toxicity studies were conducted in rats and rabbits via subcutaneous administration.

Related Experiment Videos

  • IVL984 was also tested in mice.
  • Fetuses underwent external, visceral, and skeletal examinations to identify developmental abnormalities.

    • Main Results:

    • IVL745 exhibited no significant maternal or fetal toxicity at tested doses.
    • HMR1031 caused maternal toxicity and slight fetal effects (e.g., reduced body weight, sternebral defects) at high doses.
    • IVL984 was a potent teratogen, inducing embryo lethality, cardiac malformations (including spiral septal defects), and skeletal defects at low doses, with minimal maternal toxicity except for abortions in rabbits.

    Conclusions:

    • IVL745 is not teratogenic.
    • HMR1031 demonstrates mild embryo-fetal toxicity at maternally toxic doses.
    • IVL984 is a potent teratogen, causing significant developmental abnormalities, including cardiac malformations and embryo lethality, across multiple species at non-maternally toxic doses.