| [Objective]To study the embryonic developmental toxicity of topiramate(TPM) in rats in low dosage or high dosage or in combination with valproate acid( VPA).[Methods]Gravid female SD rats were divided randomly into five groups. The rats in the experimental groups(group A, B and C) were administered with TPM 40 mg/kg, TPM 80 mg/kg and TPM 40 mg/kg + VPA 300 mg/kg respectively by gavage on day 6 through 15 of gestation. The rats in the negative control group (group D) were administered with distilled water in the same way as in the experimental groups. And the rats in the positive control group (group E) were treated with cyclophosphamide(CP) at a dose of 10 mg/kg on day 11 of gestation by ip. Mother's weight was weighed on day 0, 6, 9, 12, 15, 18 and 20 respectively. Litters were delivered by cesarean section on day 20 of pregnancy. The rate of living, dead and absorbed fetus was calculated, the parameters of embryonic and fetal development were analyzed, and external abnormality was examined. After double stained with alizarin red S and alcian blue, half of the fetus skeleton was examined.[Results]1. Effects on maternal ratsTPM had influence on maternal food intake at this experimental condition. Maternal body weight gain was decelerated in experimental rats (89.6±16.5 g, 74.8 g±10.7, 91.5±20.3 g for group A, B, C respectively,verse group D 109.5±14.2 g) ,( t value was 2.9, 6.4, 2.3 respectively,and P value was 0.01,< 0.001 and 0.03 respectively).2. Embryonic toxicity The rate of living fetus decreased(96.15 %, 87.61 %, 85.71 % vs 97.34 %), and the comprising rate of the living fetus with dead fetus + absorbed fetus in planting had significant difference in group B and group C compared those in group D(χ2 value was 7.7, 9.95 and P value was 0.0055, 0.0016 respectively),and there's no significant difference in group A (χ2 value was 0.25, P value was 0.6198).3. Developing parameters of the fetus Compared with group D,fetus body weight decreased(3.25±0.27 g, 2.72±0.31 g, 3.16±0.29 g vs 3.56±0.28 g),body length decreased(3.24±0.20 cm,3.04±0.22 cm, 3.21±0.21 cm vs 3.59±0.17 cm),and tail length decreased(1.26±0.05 cm,1.17±0.08 cm,1.26±0.15 cm vs 1.36±0.11 cm)in group A, B, C. And all have significant difference(P value all < 0.01). 4. Fetus external appearance No apparent external malformation was observed, but the rate of the external variation as umbilical hernia and short tail increased in treated groups as compared with those in group D ( 5 %, 7.84 %, 9.9 % vs 0.89 %. P value > 0.05, < 0.05, < 0.05 respectively).5. Effects on fetus skeletal development TPM effected fetus skeletal development both in low and high dosage. No apparent bone malformation was observed, but the rate of bone variation was higher in treated groups compared with those in the negative control group. The vaviations were mainly about bipartite ossification and abnormal shape of the sternebrae and vertebra, and not ossified sternebrae.5.1 Reduced cranium ossificationThe complete ossified supraoccipital rate in group A, B, C was 82 %, 70 %, 76 % respectively,while in group D was 89.5 %.Compared with group D , it showed no significant difference for group A ,while for group B and C, the difference is significant (P value was 0.269, 0.012, 0.028 respectively).5.2 The skeletal vaviations such as bipartite ossification, reduced ossification and abnormal shape of the sternebrae and vertebra, and not ossified sternebrae were increased in TPM treated groups. There's no significant difference in group A and D ( P > 0.05) ,while in group B, C with group D, the difference is significant...
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