levoleucovorin and Abnormalities--Multiple

Data from our previous work indicate that Lamotrigine (LTG) is teratogenic in the mouse. In the present study, we attempted to determine the possible protective effects of exogenous folate on LTG-induced fetal anomalies in TO mouse. Experiment I entailed administering 4 mg/kg of folinic acid (FA) and (25 mg/kg) of LTG intraperitoneally three times on gestation day (GD) 8 to a group of mice; other groups were a group that received similar volumes of saline, a group that received LTG and Saline, a group that received FA and saline. Experiment 2 involved administering groups of mice with daily 3 doses FA (or proportionate volume of saline) on GD 5 through 10 and either 3 doses of saline on GD8, or 3 doses of LTG on GD8. Maternal plasma concentrations of FA, vitamin B12 and homocysteine were determined an hour after the last injection from one-half of all animals. The other half were allowed to go to term (GD18) when they were euthanized and their fetuses were examined for visceral and skeletal malformations. A high incidence of resorption, abortion, embryolethality, congenital malformations, and intrauterine growth restriction (IUGR), was observed in the LTG-treated group. Folic acid and B12 levels were decreased and homocysteine concentration increased significantly in LTG groups. Mice receiving LTG with FA had normal levels of folate, Vitamin B12 and homocysteine levels, and the fetuses had fewer birth defects similar to the controls which were given saline only. Supplemental FA ameliorated to a great extent the LTG-induced embryonic resorption and malformations and restored the FA status.

Topics: Abnormalities, Multiple; Animals; Fetus; Lamotrigine; Leucovorin; Mice; Triazines

The effect of administration of folinic acid, vitamin B6 + vitamin B12, and their combination on valproic acid (VPA)-induced teratogenesis was studied in NMRI mice. VPA (500 mg/kg, sc) was injected on Day 8 of gestation and the vitamins (two dose levels) were injected ip 1 hr before, immediately before, and 1 hr after VPA administration. Folinic acid significantly reduced VPA-induced resorptions (21-24%), and palate, rib, and sternebral malformations. Exencephaly and spina bifida occulta were also reduced (14 and 40%, respectively), but the difference was not statistically significant. On the other hand, vitamin B6 + vitamin B12 significantly reduced VPA-induced exencephaly (23%), spina bifida occulta (80%), palate and rib malformations, kidney abnormalities, and fetal weight retardation. A combination of the three vitamins was effective in reducing VPA-induced exencephaly (23-30%), spina bifida occulta (60%), and palate and rib malformations. The protection against VPA-induced malformations was not complete and was not always dose related, and the reduction in exencephaly rate was only significant in the absence of a reduction in resorption rate. Full-length cleft palate, sternebral malformations, and retarded sternebral and caudal ossification were, however, increased by the high dose of combined vitamin administration. The present study supports the view that VPA-induced teratogenesis may be mediated via an interaction with folate metabolism. Although folinic acid and vitamin B6 + vitamin B12 can effectively reduce VPA malformations, the protection was not complete, which may suggest the involvement of other factors. Furthermore, the dose levels should be carefully chosen since high doses of the combined vitamins can actually increase the incidence of certain defects.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Animals; Drug Interactions; Embryo, Mammalian; Female; Leucovorin; Mice; Mice, Inbred Strains; Pregnancy; Pyridoxine; Teratogens; Valproic Acid; Vitamin B 12

Hematological and histological studies of the rabbit brachydactyly mutant were made to clarify the question of the blood abnormality that had previously been implicated in the teratogenic process leading to congenital amputation. The hemoglobin of fetal and adult br/br rabbits, studied by electrophoresis and cyanmethemoglobin assay, exhibited no differences from that of controls. The br/br fetuses were polycythemic and severely macrocytic. Fetal limb vessels showed thrombosis leading to hemorrhages in the extremities. The hepatic tissue was abnormal, being particularly poor in hematopoietic cells; blood cell macrocytosis was attributed to impaired erthropoiesis. Treatment of pregnant rabbits with folic acid plus vitamin B12 or with folinic acid was able simultaneously to prevent the fetal blood cell macrocytosis and the congenital abnormalities.

Topics: Abnormalities, Multiple; Animals; Blood Cell Count; Drug Therapy, Combination; Electrophoresis, Cellulose Acetate; Erythrocytes, Abnormal; Erythropoiesis; Extremities; Female; Folic Acid; Hematologic Diseases; Hemoglobinometry; Homozygote; Inbreeding; Leucovorin; Limb Deformities, Congenital; Liver; Maternal-Fetal Exchange; Pregnancy; Rabbits; Vitamin B 12