title: Teratology study of derivatives of tetramethylcyclopropyl amide analogues of valproic acid in mice.
abstract: BACKGROUND
  Although valproic acid (VPA) is used extensively for treating various kinds of epilepsies, it is well known that it causes neural tube and skeletal defects in both humans and animals. The amide and urea derivatives of the tetramethylcylcopropyl VPA analogue, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (N-methoxy-TMCD) and 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMC-urea), were synthesized and shown to have a more potent anticonvulsant activity than VPA. The objective of this study was to investigate the teratogenic effects of these compounds in NMRI mice.
  
  
  METHODS
  Pregnant NMRI mice were given a single subcutaneous injection of either VPA, N-methoxy-TMCD, or TMC-urea at 1.8 and 3.6 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18. First, the live fetuses were examined to detect any external malformations, then their skeletons were double-stained for bone and cartilage and subsequently examined.
  
  
  RESULTS
  Significant increases in fetal losses and neural tube defects were observed with administration of VPA at 3.6 mmol/kg when compared to the vehicle control. In contrast, upon cesarean section, there were no significant differences between either N-methoxy-TMCD or TMC-urea and the control groups for any parameter. Skeletal examination revealed that a number of the abnormalities were induced by VPA dose-dependently at high rates of incidence. These abnormalities were mainly at the axial skeletal level. However, lower frequencies of skeletal abnormality were observed with N-methoxy-TMCD and TMC-urea than with VPA.
  
  
  CONCLUSIONS
  In addition to their more potent antiepileptic activity, these findings clearly indicate that N-methoxy-TMCD and TMC-urea are distinctly less teratogenic than VPA in NMRI mice.
authors.affiliation: Drug Safety Research Laboratories, Astellas Pharma, Inc., Osaka, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Okada
authors.forename: Yuko
authors.initials: Y
authors.lastname: Onishi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Aoki
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Eyal
authors.initials: E
authors.lastname: Sobol
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Michio
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: D000014:Abnormalities, Drug-Induced; D000577:Amides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002585:Cesarean Section; D003521:Cyclopropanes / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000002:abnormalities* / Q000187:drug effects*; D051379:Mice; D011247:Pregnancy; D012863:Skeleton; D018600:Teratology; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D014635:Valproic Acid / Q000031:analogs & derivatives*
chemical_list: C116673:2,2,3,3-tetramethylcyclopropane carboxamide; D000577:Amides; D003521:Cyclopropanes; D014635:Valproic Acid; D014508:Urea