SYNERGISTIC EMBRYOTOXICITY OF COMBINATION PYRIMETHAMINE AND FOLIC-ACID IN RATS

The increased embryotoxicity of pyrimethamine (PYM) with concomitant o ral dosing of folic acid (FA) was examined in rats. The preventive eff ects of folinic acid (FNA) on PYM embryotoxicity were also examined. S ix groups were constructed: PYM I (PYM 1.2 mg/kg/day), FA (FA 50 mg/kg /day), PYM I + FA (1.2 and 50 mg/kg/day, respectively), PYM II (2.7 mg /kg/day), PYM II + FNA (2.7 and 12 mg/kg/day, respectively), and a veh icle control group. The agents were administered for 11 days from day 7 throughout 17 of gestation. PYM and FA were administered by gavage a nd FNA was administered intraperitoneally. Visceral and skeletal malfo rmations were observed in the fetuses of both PYM I + FA and PYM II gr oups; these included dilatation of the lateral ventricle and fused rib s. No malformed fetuses were observed in the fetuses of the other four groups. External malformations were observed only in the fetuses of P VM II groups; these included cleft palate, cleft lips, and brachygnath ia, among others. These results show that the concomitant gavage dosin g of FA augments PYM embryotoxicity. The preventive effects of FNA wer e also confirmed.