Evaluation of hepatotoxicity in rats of four synthetic valproic acid derivatives with potential anticonvulsant activity and low teratogenicity

The potential hepatotoxic effects of four synthetic valproic acid [VPA] derivatives likely to have a promising anticonvulsant activity with minimal teratogenic effects were studied in vivo and in isolated perfused livers of young rats using sodium valproate and 4-en valproic acid [4-en VPA], the main hepatotoxic metabolite of valproic acid, as positive controls. 4-en VPA [100 mg/kg] produced a significant elevation in serum transaminases [ALT and AST] and alkaline phosphatase with a decrease in total serum proteins, serum albumin and total serum bilirubin, while VPA [250 mg/kg] increased ALT and decreased total serum proteins and serum albumin when given i.p. to rats once daily for 8 days. Both compounds also produced fatty degeneration and vacuolar degeneration of the liver. When perfused in a concentration of 300 [micro]g/ml, into livers of young rats, sodium valproate and 4-en VPA produced significant elevation in ALT and AST activities in the perfusate. In both experiments, 4-en VPA was more hepatotoxic than VPA. On the other hand, three compounds namely: R-2-n-propyl-4-hexynoic acid, [ +/- ] 4-methyl-2-n-propyl-4-pentenoic acid and [ +/- ] 2-isobutylpentenoic acid did not produce any significant effect on serum levels of ALT, AST, alkaline phosphatase, albumin and bilirubin when given to rats i.p. in a dose of 100 mg/kg once daily for 8 days. The three compounds did not produce histopathological alterations in the liver and did not increase ALT and AST activities in the perfusate of isolated liver when added to the perfusion fluid in a concentration of 300[micro]g/ml. The fourth compound, [ +/- ] 2-n-propyl-4-hexynoic acid, increased total serum bilirubin and decreased albumin/globulin ratio with no effects on liver histopathology or the other biochemical measurements in vivo and in vitro. These results should encourage the continuation of research on these compounds aiming to introduce new safe antiepileptic agents

effect of caffeine and corticosterone on maternal plasma and fetal corticosterone level in pregnant mice and rats

The effect of caffeine and corticosterone administration alone and in combination on total and free maternal plasma and fetal corticosterone levels was studied in pregnant mice and rats. Animals were divided into four groups: the first was the control, the second was given caffeine 200 mg/kg [mice] or 100 mg/kg [rats] orally, the third was given cor-ticosterone 5 mg [mice] or 100 mg/kg [rats] s.c., and the fourth was given caffeine and corticosterone. Blood samples and whole litter homogenate were taken 3 h [mice] or 2 h [rats] after dosing on day 14 of gestation and were assayed for corticosterone fluorimetrically. Caffeine administration increased plasma corticosterone levels in pregnant mice and rats, but most of it was protein bound and did not pass to the fetus. Injection of exogenous corticosterone alone or in combination with caffeine raised total and free corticosterone levels in the plasma of the mother and in their fetuses. The high corticosterone fetal levels in corticosterone injected animals, compared to caffeine treated ones, may account for the high incidence of cleft palate in the former group despite of similar high plasma total corticosterone levels in both groups