levoleucovorin and Abnormalities--Drug-Induced

Topics: Abnormalities, Drug-Induced; Bone Marrow; Chemical and Drug Induced Liver Injury; Female; Hematologic Diseases; Humans; Kidney Diseases; Leucovorin; Liver; Methotrexate; Pregnancy; Psoriasis; Skin

To investigate the protective effect of folinic acid on the hatching ability and developmental defects in a retinoic acid-induced teratogenic model of chick embryo.. The experimental study was conducted at the Department of Anatomy, Regional Centre of the College of Physicians and Surgeons Pakistan, Islamabad, from February 2009 to February 2010. Chicken eggs were divided into two experimental groups and a control group. The first experimental group was injected with retinoic acid to induce a defective model, while the second experimental group was concomitantly injected folinic acid to observe its protective effects on retinoic acid-induced defects in the development and hatching process. Both groups were compared with the age-matched control group.. A total of 90 fertilised eggs were divided into three groups. The experimental groups had significantly more delayed and assisted hatchings compared to the control group (p<0.05) but the difference between the experimental groups regarding the mode and day of hatching was insignificant (p>0.05).. Irrespective of the presence of folinic acid, prenatal retinoic acid exposure significantly altered the hatchability characteristics in the experimental groups compared to the control.

Topics: Abdominal Wall; Abnormalities, Drug-Induced; Animals; Chick Embryo; Leucovorin; Limb Deformities, Congenital; Teratogenesis; Teratogens; Tretinoin; Vitamin B Complex

Jaws are formed by cephalic neural crest (CNCCs) and mesodermal cells migrating to the first pharyngeal arch (PA1). A complex signaling network involving different PA1 components then establishes the jaw morphogenetic program. To gather insight on this developmental process, in this study, we analyze the teratogenic effects of brief (1-15 min) pulses of low doses of retinoic acid (RA: 0.25-2 µM) or RA agonists administered to early Xenopus laevis (X.l.) embryos. We show that these brief pulses of RA cause permanent craniofacial defects specifically when treatments are performed during a 6-hr window (developmental stages NF15-NF23) that covers the period of CNCCs maintenance, migration, and specification. Earlier or later treatments have no effect. Similar treatments performed at slightly different developmental stages within this temporal window give rise to different spectra of malformations. The RA-dependent teratogenic effects observed in Xenopus can be partially rescued by folinic acid. We provide evidence suggesting that in Xenopus, as in the mouse, RA causes craniofacial malformations by perturbing signaling to CNCCs. Differently from the mouse, where RA affects CNCCs only at the end of their migration, in Xenopus, RA has an effect on CNCCs during all the period ranging from their exit from the neural tube until their arrival in the PA1. Our findings provide a conceptual framework to understand the origin of individual facial features and the evolution of different craniofacial morphotypes.

Topics: Abnormalities, Drug-Induced; Animals; Benzoates; Drug Antagonism; Embryo, Nonmammalian; Female; Gene Expression Regulation, Developmental; Homeodomain Proteins; In Situ Hybridization; Jaw; Jaw Abnormalities; Keratolytic Agents; Leucovorin; Morphogenesis; Neural Crest; Pulse Therapy, Drug; Retinoids; Time Factors; Transcription Factors; Tretinoin; Vitamin B Complex; Xenopus laevis; Xenopus Proteins

The objective of this study was to assess whether combined supplementation of folinic acid (FA) and Vitamin B(12) (VB(12)) could suppress ethanol-induced developmental toxicity better than FA alone in mouse embryos cultured in vitro. In this study, exposure to 4.0mg/ml ethanol for 48 h yielded growth retardation and various malformations of the embryos. FA (10(-5), 10(-4)mol/l) or VB(12) (10(-6), 10(-5)mol/l) alone supplementation improved the growth parameters moderately, however combined supplementation of the two vitamins (10(-5)mol/l FA plus 10(-6)mol/l VB(12), 10(-5)mol/l FA plus 10(-5)mol/l VB(12), 10(-4)mol/l FA plus 10(-6)mol/l VB(12) and 10(-4)mol/l FA plus 10(-5)mol/l VB(12)) showed better protective effects, including both the growth and development parameters of the embryos, than either vitamin alone at the same dosage. The present investigation indicated that combined supplementation of folic acid and VB(12) might be a better choice than folic acid alone in the prevention of ethanol-induced birth defects.

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Ethanol; Female; Leucovorin; Male; Mice; Mice, Inbred BALB C; Organ Culture Techniques; Pregnancy; Vitamin B 12

Topics: Abnormalities, Drug-Induced; Animals; Anticonvulsants; Bone and Bones; Female; Fetus; Leucovorin; Liver; Methionine; Methylation; Neural Tube Defects; Pregnancy; Rats; Rats, Wistar; S-Adenosylmethionine; Valproic Acid

Nitrous oxide (N2O)-induced teratogenicity in rats is commonly believed to be due to decreased tetrahydrofolate, which results in decreased DNA synthesis. The role of decreased methionine has been largely ignored as have the sympathomimetic effects of N2O.. A rat whole-embryo culture system was used to determine whether N2O-induced teratogenicity can be prevented with supplemental methionine or folinic acid and whether N2O-induced situs inversus is mediated by alpha 1-adrenergic stimulation. Embryos were explanted on day 9 of gestation, and those at stage 10b (late primitive streak stage) were cultured with or without N2O and the various chemicals, methionine (25 micrograms.ml-1), folinic acid (5 micrograms.ml-1), phenylephrine (range 0.5-50 microM) and prazosin (10 microM). Embryos in the N2O groups were exposed to a concentration of 75% for the first 24 h of culture. After 50 h of culture, embryos were examined for abnormalities including situs inversus.. Treatment with N2O alone resulted in increased incidences of malformations and growth retardation. Methionine, but not folinic acid or prazosin, almost completely prevented N2O-induced malformations and growth retardation. N2O itself did not cause situs inversus but increased the incidence of phenylephrine-induced situs inversus. This additive effect was blocked by prazosin.. Our results indicate that decreased methionine rather than decreased tetrahydrofolate plays the major role in N2O-induced teratogenicity in rats. They also indicate that N2O stimulates the alpha 1-adrenergic pathway in the embryo and thereby increases the incidence of phenylephrine-induced situs inversus.

Topics: Abnormalities, Drug-Induced; Animals; Culture Techniques; Embryo, Mammalian; Female; Leucovorin; Male; Methionine; Models, Biological; Nitrous Oxide; Phenylephrine; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Situs Inversus

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Drug Synergism; Embryo, Mammalian; Female; Folic Acid; Injections, Intraperitoneal; Leucovorin; Mice; Mice, Inbred ICR; Pregnancy; Pyrimethamine; Rats; Rats, Wistar; Teratogens

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

The diurnal variation of folate concentrations in mouse plasma and embryo between day 8.5 and day 9.5 of gestation (light cycle = 0900-2100) were determined by high-performance liquid chromatography. Folate concentrations in the embryo were high during the evening hours, decreased during the night, reached their lowest levels at 0500, and then increased again during the day. High levels of folates may be related to increased food intake by the pregnant mice. Small changes of the two major maternal plasma folate metabolites were observed. The relative amount of each folate metabolite in the embryo, as compared to the total folate concentration, remained in a narrow range. The main metabolites were tetrahydrofolic acid (THF) (32.4% +/- 2.1% of total folates), 5-CHO-THF (24.2% +/- 2.3%), and 10-CHO-THF (17.0% +/- 1.9%). A dramatic alteration of these ratios occurred only between 1100 and 1400. The relative content of THF increased (52.7% +/- 2.5%), whereas the relative concentration of 5-CHO-THF in the embryo decreased (6.5% +/- 1.9%). Before 1000 when the ratios of folate metabolites were stable, the rate of valproic acid-induced neural tube defects was reduced from 49% of living fetuses to 12% by coapplication of folinic acid via subcutaneously implanted minipumps. During the period in which dramatic changes in ratios between the folate metabolites in the embryo occurred, no protective effect of folinic acid on valproic acid-induced exencephaly could be observed. Our results indicate that the diurnal variation of folate metabolism in the embryo is important in regard to valproic acid teratogenesis and its protection by folate supplementation.

Topics: Abnormalities, Drug-Induced; Animals; Chromatography, High Pressure Liquid; Circadian Rhythm; Decidua; Embryo, Mammalian; Female; Fetal Resorption; Folic Acid; Leucovorin; Mice; Mice, Inbred Strains; Neural Tube Defects; Pregnancy; Valproic Acid

Methotrexate (MTX) is lethal or teratogenic to embryos of all species tested. New Zealand white rabbit embryos are relatively resistant to the embryolethal effects of MTX. However, when pregnant does were injected iv with 19.2 mg MTX/kg on gestational day 12, virtually all surviving fetuses exhibited multiple malformations of the head, limbs, and trunk. MTX is a structural analogue of folic acid that competitively inhibits dihydrofolate reductase, thereby preventing formation of folinic acid and essentially stopping one carbon metabolism. One carbon metabolism is important in the synthesis of methionine, histidine, glycine, and purine bases that are required for the de novo synthesis of DNA. Presumably these metabolic effects of MTX relate directly to its mechanism of developmental toxicity. An ameliorative treatment has been tested utilizing i.v. injection of pregnant rabbits with leucovorin (LV), a close structural analogue of folinic acid (the product of the inhibited enzyme), at various times after MTX exposure. When LV was injected at times up to 24 hours after MTX fewer malformed fetuses resulted and the incidence of specific malformations was reduced. When given at times up to 20 hours after MTX administration, LV virtually eliminated the grossly apparent effects of MTX at term. In the forelimb bud, MTX increased the extracellular space surrounding limb bud mesenchymal cells within 8-10 hours; this process continued through 16 hours and remained unabated by 24 hours. Mesenchymal cell nuclei became hyperchromatic and pyknotic during this time period. By 24 hours, a moderate amount of cellular debris was observed in the mesenchymal compartment of limb buds from approximately one-third of the embryos examined. Endothelial cell nuclei of the limb bud vasculature did not exhibit the histopathological alterations observed in the mesenchymal cells. Limb buds from embryos injected with LV at times up to 6 hours after MTX were histologically normal. When LV treatment was delayed until 16 or 20 hours after MTX, mesenchymal nuclei regained normal appearance within 2 hours of treatment; further, the abnormally large intracellular space began to decrease during the next 4 hours. Cellular debris was not a prominent feature of limb buds from LV-treated embryos examined at any time. Embryos from rabbits injected with LV at 24 hours after MTX exhibited either typical MTX-induced lesions or a sequence of reparative events similar to those described for the 16 and 20

Topics: Abnormalities, Drug-Induced; Animals; Drug Interactions; Embryonic and Fetal Development; Endothelium, Vascular; Extracellular Space; Female; Leucovorin; Limb Deformities, Congenital; Mesoderm; Methotrexate; Pregnancy; Rabbits

In vivo prevention of malformations induced by pyrimethamine was studied in the rat. The administration of calcium folinate had an almost complete antiteratogenic effect on external, visceral and skeletal malformations, provided that the vitamin was administered together with the pyrimethamine and that the treatment was continued for the following two days.

Topics: Abnormalities, Drug-Induced; Animals; Drug Combinations; Female; Leucovorin; Pyrimethamine; Rats; Rats, Inbred Strains

The teratogenic effects of nitrous oxide (N2O) administered with halothane or folinic acid (FA) were studied in two separate experiments using a total of 206 timed-pregnant Sprague-Dawley rats. In each experiment, rats were exposed to either 1) air (n = 30-40); 2) N2O (50-75% for 24 h on day 8 of pregnancy, n = 20-30); 3) test agent (i.e., 0.27% halothane for 24 h on day 8 of pregnancy; or 5 mg/kg/day of FA on day 5-13 of pregnancy, subcutaneously by osmotic pump, n = 20-30); or 4) N2O + test agent (n = 20-30). Cesarean sections were performed on day 20, and fetuses were examined for visceral and skeletal abnormalities. There were no differences in pregnancy rate, number of implantations and live fetuses per rat, and fetal weight among any of the groups. Treatment with N2O resulted in significantly higher incidences of resorptions and of major visceral and minor skeletal abnormalities. Halothane administered with N2O protected against these effects; folinic acid did not. Using an additional 65 nonpregnant rats, hepatic methionine synthase activity was measured after treatment with 50% N2O, 50% N2O plus 0.27% halothane, or 50% N2O plus 5 mg/kg/day of folinic acid. Methionine synthase activity was equally depressed in all groups. These findings do not support the commonly held theory that inactivation of methionine synthase is the sole cause of N2O teratogenicity; rather, they suggest a multifactorial etiology, which may include changes in uterine blood flow.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Abnormalities, Drug-Induced; Animals; Female; Halothane; Leucovorin; Nitrous Oxide; Pregnancy; Rats; Rats, Inbred Strains; Teratogens

The Sprague-Dawley rat was used to demonstrate the effect of nitrous oxide, with and without folinic pretreatment, on reproductive indices and fetal development. One of the objectives of the investigation was to test the hypothesis that at least some of the teratogenic effect of nitrous oxide is related to interference with folate metabolism. Groups of animals were exposed to 70-75% nitrous oxide on day 9 of pregnancy with or without folinic acid 0.1 mg i.p. 12 h before, and immediately before, exposure. Subsequent fetal development was compared with that of various control groups. There were no significant differences in fetal survival, but fetal weights were reduced in both groups exposed to nitrous oxide. Of the indices of skeletal maturity, the number of ossified sternebrae was reduced only in the nitrous oxide group not receiving folinic acid. The incidence of major skeletal abnormalities in the untreated nitrous oxide group was significantly increased to five times that of the control groups, whereas the incidence in the nitrous oxide group receiving folinic acid was not significantly different from control. It is concluded that pretreatment with folinic acid can at least partially reduce the teratogenic effects of nitrous oxide in the rat.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Embryonic and Fetal Development; Female; Fetal Organ Maturity; Leucovorin; Nitrous Oxide; Pregnancy; Rats; Rats, Inbred Strains

The reproductive performance of 36 women who had been successfully treated for gestational trophoblastic tumors with multiple courses of cytotoxic agents including methotrexate, 6-mercaptopurine, actinomycin D, and 6-azauridine, between 1962 and 1972, has been studied in comparison with 36 patients who had spontaneously aborted a hydatidiform mole but received no treatment and a control group consisting of 36 women attending an antenatal clinic. The majority of patients who wanted further pregnancies following chemotherapy had one or more successful conceptions. The incidence of abnormal pregnancies in the treated group was higher than that of the control group. Similarly, there was a higher number of abnormal pregnancies in the untreated mole patients when compared with the control group. This suggests that patients who develop trophoblastic tumors tend to have a poor obstetric history and that this is not significantly worsened by chemotherapy.

Topics: Abnormalities, Drug-Induced; Antineoplastic Agents; Azauridine; Child; Child, Preschool; Dactinomycin; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hydatidiform Mole; Infant; Infant, Newborn; Leucovorin; Male; Mercaptopurine; Methotrexate; Pregnancy; Pregnancy Complications; Trophoblastic Neoplasms; Uterine Neoplasms

Topics: Abnormalities, Drug-Induced; Animals; Cleft Palate; Female; Fetal Death; Fetus; Leucovorin; Mice; Organ Size; Phenytoin; Pregnancy; Sex Factors; Time Factors

Topics: Abnormalities, Drug-Induced; Animals; DNA; Embryo, Mammalian; Female; Fetus; Gestational Age; Leucovorin; Methotrexate; Pregnancy; Rats; Time Factors

Topics: Abnormalities, Drug-Induced; Aminopterin; Animals; Extremities; Folic Acid; Leucovorin; Regeneration; Urodela