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A nationwide program directed at stimulating the preconceptional use of folic acid (FA) for the prevention of open neural tube defects has been in effect in Puerto Rico for the last 4 years. To evaluate its effectiveness, 479 questionnaires were distributed among pregnant patients. The average age was 27 (range 14-21), and 64.9% of the pregnancies were unplanned. Preconceptional use of FA was 31.5%, despite 87.7% of patients reporting knowledge about the importance of FA use. Only 35.4% of patients who had knowledge about FA used it prior to conception. Among patients who planned their pregnancies and knew about the importance of FA, 92/168 (54.6%) used it prior to pregnancy. With these dismal results, we believe these campaigns should re-evaluate their educational strategies and consider reduction of unplanned pregnancies as part of their goals.
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Compounds that compete with folic acid (folic acid antagonists [FAAs]) become limited in their usefulness in the treatment of leukemia, malaria, and bacterial infections by the rapid development of resistance. Assays of the plasma levels of certain of these FAAs led to the observation, in about 25% of the determinations, that a higher density of growth of Streptococcus faecium var. durans (ATCC 8043) was obtained at an FAA concentration just below the completely inhibitory level than at one-half this concentration. This and other considerations suggested that FAAs may act not only as selective agents for resistant organisms but also as mutagens. Seven FAAs including amethopterin, pyrimethamine, trimethoprim, chlorguanide triazine, an experimental quinazoline, WR-158,122, and two experimental triazines, WR-99,210 and WR-38,839, were tested for mutagenicity in the Salmonella reversion assay developed by Ames et al. (1975). All were found to be negative for strains TA1535, TA1537, TA1538, TA98, and TA100, both with and without microsomal activation. These compounds were then tested as mutagens for three traits in the folic acid-requiring S. faecium. FAAs were shown to cause mutations to folic acid independence, rifampin resistance, and FAA resistance. It is postulated that the FAAs induce mutations by causing thymine deprivation in the folic acid-requiring host.
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Folate is an essential nutrient that is involved in many metabolic pathways, including amino acid interconversions and nucleotide (DNA) synthesis. In genetically susceptible individuals and populations, dysfunction of folate metabolism is associated with severe illness. Despite the importance of folate, major gaps exist in our quantitative understanding of folate metabolism in humans. The gaps exist because folate metabolism is complex, a suitable animal model that mimics human folate metabolism has not been identified, and suitable experimental protocols for in vivo studies in humans are not developed. In general, previous studies of folate metabolism have used large doses of high specific activity tritium and 14C-labeled folates in clinical patients. While stable isotopes such as deuterium and 13C-labeled folate are viewed as ethical alternatives to radiolabeled folates for studying metabolism, the lack of sensitive mass spectrometry methods to quantify them has impeded advancement of the field using this approach. In this chapter, we describe a new approach that uses a major analytical breakthrough, Accelerator Mass Spectrometry (AMS). Because AMS can detect attomole concentrations of 14C, small radioactive dosages (nCi) can be safely administered to humans and traced over long periods of time. The needed dosages are sufficiently small that the total radiation exposure is only a fraction of the natural annual background radiation of Americans, and the generated laboratory waste may legally be classified non-radioactive in many cases. The availability of AMS has permitted the longest (202 d) and most detailed study to date of folate metabolism in a healthy adult human volunteer. Here we demonstrate the feasibility of our approach and illustrate its potential by determining empirical kinetic values of folate metabolism. Our data indicate that the mean sojourn time for folate is in the range of 93 to 120 d. It took > or = 350 d for the absorbed portion of small bolus dose of 14C-folic acid to be eliminated completely from the body.
UNLABELLED: Aim of the study was to: 1) estimate plasma profile of sulphur AA in children with chronic renal failure (CRF) and in children on hemodialysis (HD), and 2) to evaluate any correlation with serum folic acid (FA) and vitamin B12. PATIENTS: 32 pts with CRF: 9 with GFR > 20 ml/min/1.73 m2 (group 1), 9 with GFR < 20 ml/min/1.73 m2 (group 2), and 14 pts on HD (group 3). METHODS: plasma homocysteine (Hcys), methionine (Met), cysteine (Cys), serine (Ser) were measured with gas chromatography. Serum FA and vit. B12 were measured using MEIA method. RESULTS: median Hcys concentrations were the lowest in group 1: 5 mumol/l vs 9 mumol/l (group 2) and 20 mumol/l (group 3) (p = 0.03). Similarly, the lowest Met levels were observed in group 1--26 mumol/l, vs 66 mumol/l (group 2) and 281 mumol/l (group 3) (p = 0.001). Median Cys level in group 1 was 98 mumol/l vs 54 mumol/l (group 2), and 122 mumol/l (group 3) (p = 0.02). No differences were found in median Ser levels: 153 mumol/l (group 1) vs 239 mumol/l (group 2) and 240 mumol/l (group 3). The median concentrations of FA were 6.3 ng/ml (group 1) vs 8 ng/ml (group 2) and 15 ng/ml (group 3) (NS). Median concentrations of vit. B12 were 256 pg/ml (group 1) vs 379 pg/ml (group 2) and 322 pg/ml (group 3) (NS). There were no correlation between sulphur AA and FA and vit. B12 levels. The only difference between pts with Hcys levels remaining in lower and upper quartile concerned Met concentration (38 vs 263 mumol/l, p < 0.02) and GFR (p < 0.01). CONCLUSIONS: Hyperhomocysteinemia develops already in moderate CRF. In pts on HD levels of Met and Cys are also raised. FA and vit. B12 concentrations are normal and do not correlate with plasma concentrations of sulphur AA.
Periconceptional use of folic acid alone or in multivitamin supplements is effective for the primary prevention of neural-tube defects. The Hungarian randomized and two-cohort controlled trials showed that periconceptional multivitamin supplementation can reduce the occurrence of some other structural birth defects, i.e. congenital abnormalities. These findings were supported by many, but not all observational studies. Recently there have been two main debated questions. The first one is whether the use of folic acid alone or folic acid-containing multivitamins is better. The second one is connected with the dilemma of whether high dose of folic acid (e.g. 5 mg) might be better than a daily multivitamin with 0.4 - 0.8 mg of folic acid. Comparison of the pooled data of two Hungarian trials using a multivitamin containing 0.8 mg folic acid and the data of the Hungarian Case-Control Surveillance of Congenital Abnormalities using high dose of folic acid seemed to be appropriate to answer these questions. Multivitamins containing 0.4 - 0.8 mg of folic acid were more effective for the reduction of neural-tube defects than high dose of folic acid. Both multivitamins and folic acid can prevent some part of congenital cardiovascular malformations. Only multivitamins were able to reduce the prevalence at birth of obstructive defects of urinary tract, limb deficiencies and congenital pyloric stenosis. However, folic acid was effective in preventing some part of rectal/anal stenosis/atresia, and high dose of folic acid had effect in preventing some orofacial clefts. The findings are consistent that periconceptional multivitamin and folic acid supplementation reduce the overall occurrence of congenital abnormalities in addition to the demonstrated effect on neural-tube defects.
BACKGROUND: Several folic acid antagonists are considered by the Food and Drug Administration (FDA) to be toxic or potentially toxic to fetuses, including some folic acid antagonists that were once considered safe, such as trimethoprim. Information on fetal exposure to folic acid antagonists is sparse. METHODS: In this study, we conducted a thorough search of English literature on human uses of various folic acid antagonists, and made an indirect estimation of potential exposure to folic acid antagonists during pregnancy by analyzing the data from the outpatient prescription drug database of the Canadian province of Saskatchewan. RESULTS: The numbers of women of reproductive age (16 to 44 years) with at least 1 prescription of dihydrofolate reductase inhibitors was 14195 in 1977, 20455 in 1991, and 16054 in 1999. Corresponding figures for other folic acid antagonists were 2136, 1954, and 2720, respectively. According to these figures, the rates of prescription given to women of reproductive age in any particular calendar year were 8.45% (95% confidence interval [CI], 8.33% - 8.57%) for dihydrofolate reductase inhibitors and 1.14% (95% CI, 0.67% - 1.61%) for other folic acid antagonists. CONCLUSIONS: Prescription of folic acid antagonists to women of reproductive age is quite frequent, and there has been no apparent decline in prescriptions in recent years. Increase in unplanned pregnancies in industrial countries, lack of adequate scientific evidence on the adverse effects of folic acid antagonists, potential ignorance in clinical practice, and conflicting needs to treat maternal diseases and to protect fetuses, can all lead to frequent prescription of potentially toxic folic acid antagonists to pregnant women, thus posing serious threat to the fetuses. In this paper, strategies that may be used to reduce the risk of fetal exposure to folic acid antagonists are proposed.
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Hierarchical chiral structures made up of dendritic oligo(L- or D-glutamic acid) moieties of folic acid derivatives induce supramolecular chirality in the self-assembled columnar structures of the folic acids. These folic acids self-assemble through the intermolecular hydrogen bonds of the pterin rings to form disklike tetramers. In the neat states, the stacked tetramers form thermotropic hexagonal columnar phases over wide temperature ranges, including room temperature. Addition of alkali metal salts induces chirality in the columnar phases. In dilute solution states in a relatively polar solvent (chloroform), the folic acid derivatives form non-chiral, self-assembled structures. In the presence of sodium triflate, the folic acid forms chiral columnar assemblies through the oligo(L-glutamic acid) moiety, similar to those formed in the liquid-crystalline (LC) states. The enantiomer of the folic acid induces columnar assemblies with reversed helicity. In the case of the diastereomer, no induced helicity is observed. Application of an apolar solvent (dodecane) drives the folic acid derivatives to form chiral assemblies in the absence of ions. In this case, lipophilic interactions promote nanophase segregation, which enhances the formation of chiral columns. Interestingly, the chiral supramolecular structure of the diastereomer induces the most intense circular dichroism. In both cases, the molecular chirality in the oligo(glutamate) moieties yields supramolecular chirality of the folic acids that self-assemble through cooperative molecular interactions.
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