Amidic modification of valproic acid reduces skeletal teratogenicity in mice.
BACKGROUND
The antiepileptic drug valproic acid (VPA) is well known to cause neural tube and skeletal defects in both humans and animals. The amidic VPA analogues valpromide (VPD) and valnoctamide (VCD) have much lower teratogenicity than VPA inducing exencephaly in mice. The objective of this study was to investigate the teratogenic effects of VPA, VPD, and VCD on the skeleton of NMRI mice.


METHODS
Pregnant NMRI mice were given a single subcutaneous injection of VPA (400 and 800 mg/kg), VPD (800 mg/kg), or VCD (800 mg/kg) on the morning of gestation day (GD) 8. Cesarean section was carried out on GD 18. Live fetuses were double-stained for bone and cartilage and their skeletons were examined.


RESULTS
Significant increases in fetal loss and exencephaly rate were observed with VPA at 800 mg/kg compared to the vehicle control. There were no significant differences between either VPD or VCD and the control groups for any parameter at cesarean section. A number of abnormalities were dose-dependently induced at high incidences by VPA in both the cartilage and bone of vertebrae, ribs and sternum. In contrast, lower frequencies of abnormality were exhibited with VPD and VCD than VPA in all skeletons affected by VPA.


CONCLUSIONS
These findings clearly indicate that VPD and VCD are distinctly less teratogenic than VPA in the induction of not only neural tube defects, but also skeletal abnormalities. A structure-teratogenicity relationship of VPA on the skeleton is suspected.
Okada
Akinobu
A
Safety Research Laboratories, Drug Development Division, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan.
Kurihara
Hiroshi
H
Aoki
Yoshinobu
Y
Bialer
Meir
M
Fujiwara
Michio
M
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000577:Amides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities*; D002356:Cartilage / Q000002:abnormalities*; D002585:Cesarean Section; D005260:Female; D005333:Fetus / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009436:Neural Tube Defects / Q000139:chemically induced; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*
D000577:Amides; D000927:Anticonvulsants; C045179:valnoctamide; D014635:Valproic Acid; C004651:dipropylacetamide