Effect of Supplementation with Folinic Acid, Vitamin B6, and Vitamin B12 on Valproic Acid-Induced Teratogenesis in Mice

The effect of administration of folinic acid, vitamin B₆ + vitaminB₁₂, and their combination on valproic acid (VPA)-induced teratogenesiswas studied in NMRI mice. VPA (500 mg/kg, sc) was injected onDay 8 of gestation and the vitamins (two dose levels) were injectedip 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 andspina bifida occulta were also reduced (14 and 40%, respectively),but the difference was not statistically significant. On theother hand, vitamin B₆ + vitamin B₁₂ significantly reduced VPA-inducedexencephaly (23%), spina bifida occulta (80%), palate and ribmalformations, kidney abnormalities, and fetal weight retardation.A combination of the three vitamins was effective in reducingVPA-in duced exencephaly (23–30%), spina bifida occulta(60%), and palate and rib malformations. The protection againstVPA-induced malformations was not complete and was not alwaysdose related, and the reduction in exencephaly rate was onlysignificant in the absence of a reduction in resorption rate.Full-length cleft palate, sternebral malformations, and retardedsternebral and caudal ossification were, however, increasedby the high dose of combined vitamin administration. The presentstudy supports the view that VPA-induced teratogenesis may bemediated via an interaction with folate metabolism. Althoughfolinic acid and vitamin B₆ + vitamin B₁₂ can effectively reduceVPA malformations, the protection was not complete, which maysuggest the involvement of other factors. Furthermore, the doselevels should be carefully chosen since high doses of the combinedvitamins can actually increase the incidence of certain defects.     

Malignant Ventricular Arrhythmias in Chronic Chagasic Myocarditis

We studied 28 cases of chronic chagasic myocarditis (CCM) with frequent ventricular arrhythmias. Two-hundred and three conventional ECGs recorded during 3 months showed ventricular extrasystoles (VE) ranging between 0.2 and 6 per ten beats in 100%; multiform VE in 97.04%; couplets in 79.31%; ventricular tachycardia (VT) in 42.85%; and R on T in 21.67%. A 24-hour continuous recording showed that VE ranged between 3780 and 61733 (mean 16618 ± 2627); muitiform VE and couplets were present in 100% of patients, and VT was present in 78.5%. In 16 patients (group I) the frequency of VE was persistently high, without diurnal variation; 11 patients showed sustained reduction during sieeping hours and only one showed an increase during night sleep (group II). Even in group II, VE never disappeared for periods longer than 10 minutes. In five patients, four 24-hour recordings were obtained at weekly intervals, and in five other patients a second 24-hour recording was performed 10 to 24 months later. The remarkable frequency, persistence and low variability of ventricular arrhythmias in CCM suggest that such arrhythmias can be used as a most stable, reliable, but highly demanding model for testing the efficacy of antiarrhythmic drugs. (PACE, Vol. 5, March-April, 1982)     

Quantitative Plasma Disposition of Retinol and Retinyl Esters after High-Dose Oral Vitamin A Administration in the Cynomolgus Monkey

A solid-phase extraction technique followed by automated high-performanceliquid chromatography sample elution was successfully used toevaluate the effect of three pharmaceutical parameters on theplasma profile of various forms of vitamin A after an oral doseto cynomolgus monkeys. The three parameters evaluated were thechemical form of vitamin A (retinol versus retinyl acetate),the vehicle (acetone/Tween 20/water versus acetone/soybean oil),and the retinol dose (2, 10, and 50 x 10³ retinol equivalents/kg).The form of the administered compound, retinol or retinyl acetate,appeared to have no major effect on the formation of nonpolarretinoids. The ester profile in plasma differed depending onwhether the dose was administered in the water-based or theoil-based vehicle. Irrespective of the vehicle type the predominantretinoid formed was retinyl palmitate/ oleate. However, retinoldoses in the water-based vehicle formed relatively high concentrationsof retinyl laurate and retinyl my-ristate but no retinyl linolenate.The retinol dose in the oil-based vehicle formed consistent,but relatively minor, concentrations of retinyl linolenate,higher relative concentrations of retinyl linoleate, and noretinyl laurate or myristate. The dose of retinol administeredhad an impact on the diversity of the nonpolar retinoid profile.The low dose led to the presence of almost exclusively retinylpalmitate/oleate and retinyl stearate, whereas at higher dosesthe other retinyl esters became major retinol constituents.These findings are consistent with the hypothesis that, at lowdoses, the principle esterification pathway is via lecithin:retinolacyltransferase (LRAT) which produces retinyl palmitate, butat higher doses acyl-CoA:retinol acyltransferase is a prominentesterification enzyme, due to the saturation of the LRAT pathway,producing a more diverse profile of retinyl esters.     

Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague--Dawley Rats

Evaluation of Valproic Acid (VPA) Developmental Toxicity andPharmacokinetics in Sprague-Dawley Rats.BINKERD, P. E., ROWLAND,J. M., NAU, H., and HENDRICKX, A. G. (1988). Fundam Appl. Toxicol.11, 485—493. This study was undertaken to assess the pharmacokinetics and developmental toxicity of the anticonvulsant,valproic acid (VPA), a human teratogen, in Sprague-Dawley rats.Oral administration of 200-800 mg/kg VPA (5-20X human 3 therapeuticdose) from Gestational Days (GD) 8 to 17 resulted in increasingmaternal toxicity at the higher doses with 100% maternal lethalityat 800 mg/kg. Although there was an increased incidence of resorptionsat 600 mg/kg (48 ? 43%) compared to controls (18 ? 24%), itwas not statistically significant. Fetal examination on GD 20revealed dose-dependent fetal growth retardation (p 0.05) asevidenced by decreased fetal weight and length in addition tounderossi-fication of both the axial and appendicular skeleton.The incidence of skeletal defects, including abnormal vertebrae,ribs, and craniofacial dysmorphia, also increased with higherdoses of VPA. Cardiac anomalies observed in the two highesttreatment groups consisted of great vessel malformations withor without associated ventricular septal defects (VSDs). Urogenitaldefects were 3 also noted in the 600 mg/kg group. The plasmaelimination half-life on GD 8 was 1.0 ? 0.3 hr at 200 mg/kgand 2.3 ? 0.7 hr at 600 mg/kg. Maximal concentrations of totaland free drug were 341 ? 18 µg/ml and 181 ? 11 µg/ml,respectively, in the low-dose group and 911 ? 379 µg/mland 542 ? 224 µ%/ml in the high-dose group. No significantchanges in any pharmacokinetic 3 parameters (t1/2, AUC, C_max,t_max) were observed over the 10-day treatment period at eitherdose level.     

TERATOGENIC AND PHARMACOKINETIC STUDIES OF PRIMIDONE DURING PREGNANCY AND IN THE OFFSPRING OF EPILEPTIC WOMEN

ABSTRACT. Fourteen epileptic women treated with primidone, either alone or in combination with other antiepileptic drugs, were studied prospectively during their pregnancy. Plasma levels of primidone and its metabolites were monitored and correlated to findings in the offspring. Maternal serum concentrations of primidone and metabolites were generally low during pregnancy. The levels of its main metabolites–phenobarbital and PEMA–were found to drop within the first month of pregnancy in two cases. The plasma concentrations remained low until birth and rose sharply thereafter. The phenobarbital/primidone ratio (mean 0.84) and PEMA/primidone ratio (mean 0.56) in pregnant patients were found to be lower than in non-pregnant patients, except when primidone was given in combination with phenytoin in which case the expected phenobarbital/primidone (mean 2.5) and PEMA/primidone (mean 1.5) ratios were found. A ventricular septal defect was found in one of the offspring of the fourteen mothers and five children had microcephaly. There was a high incidence of poor somatic development with dystrophy ( n =3) and short stature ( n =2). Head circumferences ( n =8), lengths ( n =4) and/or weights ( n =8) were below the 10th percentile in a number of children. Four children showed marked facial dysmorphy. Our preliminary data suggest that primidone intake during pregnancy may be important in the pathogenesis of minor anomalies and in the induction of poor somatic development.     

Vaiproic Acid Teratogenicity in Mice after Various Administration and Phenobarbital-Pretreatment Regimens: The Parent Drug and Not One of the Metabolites Assayed Is Implicated as Teratogen

Vaiproic Acid Teratogenicity in Mice after Various Administrationand Phenobarbital-Pretreatment Regimens: The Parent Drug andNot One of the Metabolites Assayed Is Implicated as Teratogen.NAU, H. (1986). Fundam. Appl. Toxicol. 6,662–668. Theantiepileptic drug vaiproic acid (VPA) was administered viafour different routes in the mouse during gestational stagessensitive for interference with neural tube defect formation:a single oral intubation or injection, sc or ip, on Day 8, orinfusion via subcutaneously implanted osmotic minipumps fromDay 7 to 8 of gestation. Embryotoxicity was evaluated on Day18 (incidence of exencephaly, embryolethality and fetal weightretardation). Oral intubation of VPA resulted in significantlylower peak concentrations of VPA as well as lower embryotoxicityas compared to sc and ip administration. The metabolites ofthe ß-, - and -1 oxidation pathways were present inboth maternal serum and gestational tissues in very low concentrations(usually less than 2% of corresponding VPA levels). Infusionof VPA via osmotic minipumps (lower steady-state VPA levelsas compared to peak levels following injection of VPA) resultedin embryolethality and fetal weight retardation, but littleexencephaly. The metabolic pattern was similar in all four administrationexperiments. Phenobarbital pretreatment of the dams (previouslyshown to reduce VPA serum concentrations and induce the and-1 oxidation pathways) reduced the embryotoxicity of VPA. Theseresults suggest that VPA embryotoxicity is mediated by the parentdrug, and not one of the metabolites considered in this study.