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PubMedDate not supplied

Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514.

We studied the effects of folic acid on modulating the toxicity and antitumor efficacy of LY231514. Using several human tumor cell lines adapted to growth in low folate medium, folic acid was shown to be 100- to 1000-fold less active than folinic acid at protecting cells from LY231514-induced cytotoxicity. The lethality of LY231514 was compared in mice maintained on standard diet or low folate diet. The LD50 occurred at 60- and 250-fold lower doses of LY231514 in DBA/2 and CD1 nu/nu mice, respectively, maintained on low folate diet compared to standard diet. The L5178Y/TK-/HX-murine lymphoma was much more sensitive to the antitumor action of LY231514 compared to wild type L5178Y-S tumors. For mice on low folate diet, LY231514 at 0.3 and 1 mg/kg (qd x 10, i.p.) produced 100% inhibition of L5178Y/TK-/HX-lymphoma growth, and significant lethality occurred at > or = 3 mg/kg. For mice on standard diet, LY231514 produced > 95% inhibition of tumor growth at 30 to 300 mg/kg, but all mice died at 800 mg/kg. Folic acid supplementation was demonstrated to preserve the antitumor activity of LY231514 while reducing toxicity. The combination of folic acid with LY231514 may provide a mechanism for enhanced clinical antitumor selectivity.

Animals↗
PubMed1982

Differential effects of folic acid on water content, protein and microsomal 5'-phosphodiesterase activity of the rat kidney.

The effects of folic acid administration on the weight, protein, water content and microsomal 5'-phosphodiesterase of the rat kidney were determined, to elucidate the mechanisms contributing to the renal enlargement produced by this agent. Folic acid administered ip in single doses of 100-250 mg/kg caused dose-related increases in kidney weight, water and protein content within 24 hr. Time-course studies indicated that 250 mg folic acid/kg given ip produced a progressive elevation in renal water content from 2 to 72 hr. Smaller increases in whole-kidney protein were recorded 8, 24 and 72 hr after folic acid treatment. However, a biphasic response of microsomal 5'-phosphodiesterase was produced, inhibition at 16 hr being followed by stimulation (to 140% of control) at 72 hr. In vitro studies indicated that folic acid inhibits 5'-phosphodiesterase competitively, and the early inhibition of 5'-phosphodiesterase in vivo appears to be due to a direct effect of folic acid on the enzyme.

Animals↗
PubMed2003

Model studies on the stability of folic acid and 5-methyltetrahydrofolic acid degradation during thermal treatment in combination with high hydrostatic pressure.

Stability of folic acid and 5-methyltetrahydrofolic acid in phosphate buffer (0.2 M; pH 7) toward thermal (above 65 degrees C) and combined high pressure (up to 800 MPa)/thermal (20 up to 65 degrees C) treatments was studied on a kinetic basis. Residual folate concentration after thermal and high pressure/thermal treatments was measured using reverse phase liquid chromatography. The degradation of both folates followed first-order reaction kinetics. At ambient pressure, the estimated Arrhenius activation energy (E(a)) values of folic acid and 5-methyltetrahydrofolic acid thermal degradation were 51.66 and 79.98 kJ mol(-1), respectively. It was noticed that the stability of folic acid toward thermal and combined high pressure thermal treatments was much higher than 5-methyltetrahydrofolic acid. High-pressure treatments at room temperature or higher (up to 60 degrees C) had no or little effect on folic acid. In the whole P/T area studied, the rate constant of 5-methyltetrahydrofolic acid degradation was enhanced by increasing pressure, and a remarkable synergistic effect of pressure and temperature on 5-methyltetrahydrofolic acid degradation occurred at temperatures above 40 degrees C. A model to describe the combined pressure and temperature effect on the 5-methyltetrahydrofolic acid degradation rate constant is presented.

Drug Stability↗
PubMed2005

Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage.

Key research findings relative to the question of whether maternal use of folic acid before and during pregnancy reduces the chance that offspring will be born with a congenital heart defect or an orofacial cleft are reviewed in this paper. Observational studies in general support an association between maternal use of multivitamins containing folic acid and a reduction in the occurrence of congenital heart defects and orofacial clefts. Results from one randomized controlled trial (RCT) provide the strongest evidence that multivitamins prevent congenital heart defects, but this RCT did not provide evidence that multivitamins prevent orofacial clefts. In addition, most observational and interventional studies are not designed to detect an independent effect from folic acid. Early studies suggested that periconceptional multivitamin use was associated with an increased occurrence of both miscarriages and multiple births, which has resulted in a great deal of controversy about the safety of folic acid use during pregnancy. We also review reports that were designed to answer these questions with more definitive data. When more substantial evidence about the effect of periconceptional folic acid on the occurrence of congenital heart defects and orofacial clefts is reported, we will have additional support for promoting folic acid intervention programs. All women capable of becoming pregnant should continue to consume 400 mug/d of folic acid in addition to a healthy diet as advised.

Abortion, Spontaneous↗
PubMed1997

Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid.

Elevated plasma homocysteine, an independent risk factor for cardiovascular disease (CVD) can be lowered by administration of pharmacological doses of folic acid. The effect of lower doses in apparently normal subjects is currently unknown but is highly relevant to the question of food fortification. Healthy male volunteers (n = 30) participated in a chronic intervention study (26 weeks). Folic acid supplements were administered daily at doses increasing from 100 micrograms (6 weeks), to 200 micrograms (6 weeks), to 400 micrograms (14 weeks). Fasting blood samples collected before, during and 10 weeks post intervention were analysed for plasma homocysteine, serum and red-cell folate levels. Results, expressed as tertiles of baseline plasma homocysteine concentration, showed significant (p < or = 0.001) homocysteine lowering in the top (10.90 +/- 0.83 mumol/l) and middle (9.11 +/- 0.49 mumol/l) tertiles only. In the low tertile, where the mean baseline homocysteine level was 7.07 +/- 0.84 mumol/l, no significant response was observed. Of the three folic acid doses, 200 micrograms appeared to be as effective as 400 micrograms, while 100 micrograms was clearly not optimal. There is thus a minimal level of plasma homocysteine below which folic acid has no further lowering effect, probably because an optimal folate status has been reached. A dose as low as 200 micrograms/day of folic acid is effective in lowering plasma homocysteine concentrations in apparently normal subjects. Any public health programme for lowering homocysteine levels, with the goal of diminishing CVD risk, should not be based on unnecessarily high doses of folic acid.

Adult↗
PubMed2001

Folic acid and prevention of neural tube defects in 2000 improved awareness--low peri-conceptional uptake.

Eight years have passed since recommendations were made by the Irish Department of Health on the importance of folic acid in the prevention of neural tube defects (NTD). There is currently no mandatory fortification of foodstuffs with folic acid in Ireland, with reliance placed on campaigns promoting increased dietary folate intake and supplements. We assessed knowledge and use of folic acid among 300 women attending ante-natal clinics in Dublin maternity hospitals in the year 2000 using an interviewer administered questionnaire. Qualitative information was obtained through means of a focus group. Ninety two percent of respondents had heard of folic acid and 67% knew it could prevent NTD. Thirty per cent were advised to take it peri-conceptionally but overall only 18% did so; 39% of women had planned their pregnancy. The focus group indicated that folic acid was not 'visible' enough and that fortification of food was more realistic. This study shows that improved folic acid awareness has not been accompanied by corresponding peri-conceptional uptake in 2000. Folic acid promotional campaigns should be continuous and targeted. Mandatory food fortification should be strongly considered.

Adult↗
PubMed2000

Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study.

Homocysteine is associated with atherosclerosis and enhanced cardiovascular risk. In previous studies, treatment with folic acid up to 15 mg/d failed to correct hyperhomocysteinemia in the majority of end-stage renal disease patients. A dose of 30 or 60 mg of folic acid per day was compared with 15 mg/d in an attempt to normalize hyperhomocysteinemia in 150 hemodialysis patients. In a randomized, double-blind, multicenter study, 144 patients completed the 4-wk treatment period and 121 patients completed the 6-mo follow-up. Total homocysteine plasma levels were reduced by 32.1% (15 mg/d), 29. 9% (30 mg/d), or 37.8% (60 mg/d) with no significant differences found between the three treatment groups. Baseline total homocysteine plasma concentration was an independent predictor of the response to folic acid therapy (P = 0.0001), whereas the 5, 10-methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C --> T and 1298A --> C) had no influence. Nevertheless, patients with the MTHFR 677TT genotype more frequently attained normal total homocysteine plasma levels than patients with the CC or CT genotype (P = 0.025). In response to 60 mg of folic acid per day, TT genotype patients had lower folate plasma levels compared to CC or CT genotype patients (P = 0.016). After completion of the 4-wk treatment period with 30 or 60 mg of folic acid per day, there was a marked rebound of total homocysteine plasma levels at the end of the follow-up in patients with the MTHFR 677TT genotype, which even exceeded baseline values in several patients (P = 0.0001). This study clearly demonstrates that doses of 30 or 60 mg of folic acid per day are not more effective than 15 mg/d in reducing hyperhomocysteinemia in regular hemodialysis patients. Patients with the MTHFR 677TT genotype are more likely to realize normal total homocysteine plasma levels. Folic acid at 30 or 60 mg/d but not 15 mg/d results in a rebound of total homocysteine plasma concentrations when treatment is stopped.

Analysis of Variance↗
PubMed1981

Binding of the chemoattractant folic acid by Dictyostelium discoideum cells.

The binding of the chemoattractant folic acid to intact Dictyostelium discoideum cells has been studied. A few hundred thousand ligand molecules can be bound per cell with a dissociation constant in the order of 3 X 10(-7) M. Intact cells equilibrate rapidly with extracellular folic acid, suggesting that the binding sites are located on the outer cell surface. The folic-acid-binding properties do not change during early cell development induced by starvation for nutrients. A number of putative folate-binding proteins have been identified in a detergent-solubilized plasma membrane fraction by affinity chromatography on folate-Sepharose and specific elution with free folate. One of these proteins appeared to be an integral membrane protein as was deduced from its amphiphilic behaviour. It may be that among these proteins is the chemotactic receptor for folate.

Carrier Proteins↗
PubMed2003

Weekly high-dose folic Acid supplementation is effective in lowering serum homocysteine concentrations in women.

AIMS: To compare the efficacy of a weekly high-dose (2,800 microg) folic acid supplement with a daily (400 microg) folic acid supplement in lowering homocysteine concentrations in healthy women of childbearing age. METHODS: Free-living healthy women of childbearing age (n = 138) were randomized to receive a weekly (2,800 microg), a daily (400 microg) folic acid supplement, or placebo. Blood samples were collected at baseline and at 12 weeks and analyzed for serum homocysteine and erythrocyte folate. RESULTS: At 12 weeks the mean (95% CI) serum homocysteine concentrations declined significantly (p < 0.05) in women receiving the daily [week 12 - baseline: -1.4 (-2.0, -0.70) micromol/l] and the weekly supplement [-1.3 (-2.1, -0.5) micromol/l] versus placebo [0.0 (-0.5, 0.5) micromol/l]. There was no significant difference between the two folate-treated groups (p > 0.05). At 12 weeks the mean erythrocyte folate concentration increased significantly in both supplemented groups versus placebo (p < 0.001). The increase in erythrocyte folate was significantly greater (p < 0.001) in the daily group than in the weekly group [451 (380, 521) vs. 288 (240, 335) nmol/l]. CONCLUSION: A weekly high-dose folic acid supplement was as effective as a daily supplement in lowering homocysteine concentrations in healthy women of childbearing age. Further study is needed to determine if weekly folic acid supplementation is effective in lowering homocysteine concentrations in populations with high homocysteine.

Adolescent↗
PubMed2000

Effect of riboflavin on the photolysis of folic acid in aqueous solution.

A study of the photolysis of folic acid in aqueous solution by visible radiation in the presence of riboflavin has been made. The second-order rate constants for the bimolecular interaction of folic acid and riboflavin have been determined in the pH range 4.0-9.0. The rate pH profile shows a gradual increase in the rate up to pH 6.2 (pHmax) followed by a decrease up to pH 9.0, depending upon the susceptibility of ionic species involved in the interaction. The rate of photolysis varies from 0.50 x 10(3) M(-1) min(-1) (pH 9.0) and 0.63 x 10(3) M(-1) min(-1) (pH 4.0) to 3.0 x 10(3) M(-1) min(-1) (pH 6.2) in the pH range studied. A HPLC method has been used for the assay of folic acid and its photoproducts, pterine-6-carboxylic acid and p-aminobenzoyl-L-glutamic acid in the presence of riboflavin.

Chromatography, High Pressure Liquid↗
PubMed2002

Effects of breed, parity, and folic Acid supplement on the expression of folate metabolism genes in endometrial and embryonic tissues from sows in early pregnancy.

Folic acid and glycine are factors of great importance in early gestation. In sows, folic acid supplement can increase litter size through a decrease in embryonic mortality, while glycine, the most abundant amino acid in the sow oviduct, uterine, and allantoic fluids, is reported to act as an organic osmoregulator. In this study, we report the characterization of cytoplasmic serine hydroxymethyltransferase (cSHMT), T-protein, and vT-protein (variant T-protein) mRNA expression levels in endometrial and embryonic tissues in gestating sows on Day 25 of gestation according to the breed, parity, and folic acid + glycine supplementation. Expression levels of cSHMT, T-protein, and vT-protein mRNA in endometrial and embryonic tissues were performed using semiquantitative reverse transcription-polymerase chain reaction. We also report, for the first time, an alternative splicing event in the porcine T-protein gene. Results showed that a T-protein splice variant, vT-protein, is present in all the tested sow populations. Further characterizations revealed that this T-protein splice variant contains a coding intron that can adopt a secondary structure. Results demonstrated that cSHMT mRNA expression levels were significantly higher in sows receiving the folic acid + glycine supplementation, independently of the breed or parity and in both endometrial and embryonic tissues. Upon receiving the same treatment, the vT-protein and T-protein mRNA expression levels were significantly reduced in the endometrial tissue of Yorkshire-Landrace sows only. These results indicate that modulation of specific gene expression levels in endometrial and embryonic tissues of sows in early gestation could be one of the mechanism involved with the role of folic acid on improving swine reproduction traits.

Alternative Splicing↗
PubMed2002

Long-term improvement in homocysteine levels and arterial endothelial function after 1-year folic acid supplementation.

PURPOSE: Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with endothelial dysfunction that can be improved with short-term folic acid supplementation. The current study aimed to assess whether folic acid supplementation could produce longer-term improvements in homocysteine levels and arterial endothelial function. SUBJECTS AND METHODS: Twenty-nine healthy adults with hyperhomocysteinemia were selected from 89 volunteers enrolled in a community-based atherosclerosis screening project. All subjects were given folic acid (10 mg/d) for 1 year. Fasting plasma homocysteine levels were measured by high-performance liquid chromatography. Arterial endothelial function was measured as flow-mediated dilation of the brachial artery using high-resolution B-mode ultrasound. RESULTS: Folic acid supplementation for 1 year was associated with a significant increase in mean (+/-SD) plasma folate levels (24 +/- 5 nmol/L to 40 +/- 5 nmol/L; P < 0.001) and a significant decline in homocysteine levels (9.0 +/- 1.7 micromol/L to 7.9 +/- 2.0 micromol/L; P < 0.001). Flow-mediated dilation also improved significantly, from 7.4% +/- 2.0% to 8.9% +/- 1.5% (P <0.0001), but there was no change in nitroglycerin-induced (endothelium-independent) responses. CONCLUSIONS: These results demonstrate that long-term folic acid improves arterial endothelial function and has potential implications for the prevention of atherosclerosis in adults with hyperhomocysteinemia.

Adult↗
PubMed1976

Folic acid binding protein in acute myeloid leukaemia.

Folic acid binding protein was estimated in the serum of 94 control subjects and a normal range was established. Raised levels were found in folate deficiency and chronic myeloid leukaemia. Considerably raised levels were found in untreated acute myeloid leukaemia, most often in cases with a marked monocytic element.

Blood Proteins↗
PubMed2004

Solid-phase reactor flow-injection on-line oxidizing spectrofluorimetry for determination and dissolution studies of folic acid.

A simple, sensitive and specific flow-injection spectrofluorimetric method has been developed for the determination of folic acid in pharmaceuticals. The method is based on use of a lead dioxide solid-phase reactor for on-line oxidation of folic acid into a strongly fluorescent compound with a maximum excitation wavelength of 281 nm and an emission wavelength of 450 nm. Under optimum conditions the fluorescence intensity of oxidation product is proportional to the concentration of folic acid over the range 0.008-2.5 microg mL(-1). The detection limit is 0.0001 microg mL(-1), the relative standard deviation is 0.85% for 11 replicate determinations of 0.05 microg mL(-1) folic acid, and the sample throughput is 20 h(-1). In combination with an on-line filter and dilution, an automated drug-dissolution system was established. The proposed method has been successfully applied to the determination of folic acid in pharmaceutical preparations and dissolution testing.

Flow Injection Analysis↗
PubMed2000

Folic acid antagonists during pregnancy and the risk of birth defects.

BACKGROUND: Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. METHODS: We compared data on exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs for 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects with data for 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use. RESULTS: The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs. CONCLUSIONS: Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects.

Abnormalities, Drug-Induced↗
PubMed1994

Folic acid in neurodevelopment and child psychiatry.

1. Folic acid deficiency has been associated with diverse neuropsychiatric symptoms. 2. This paper discusses the impact of folate on brain development, maturation and function and reviews the role of folate in psychiatric disorders, particularly childhood disorders. 3. A brief case report examines the use of folate in the treatment of attentional problems in a child with fragile X syndrome.

Brain↗
PubMed1977

[Folic acid substitution in advanced renal disease (author's transl)].

The plasma content of folic acid was evaluated in 27 patients with advanced renal disease. There were no significant morphologic changes within the erythrocyts of the peripheral blood and bone marrow. The hematologic response of the reticulocyts, hemoglobin and hematokrit were studied after oral treatment with folic acid. There was a significant reticulocytosis at the 5th to the 8th day after initiating the oral treatment. This reaction underlines a definite, mainly nutritional (latent) folic acid deficiency being one cause for the renal anemia in these patients. A subsequent rise of the hemoglobin or hematocrit did not occur. Further possible causes for these clinical data are being discussed.

Adult↗
PubMed2006

Periconceptional folic acid use among women giving birth at Queen Mary Maternity Hospital in Dunedin.

BACKGROUND: The New Zealand Ministry of Health advises that all women planning a pregnancy take a folic acid supplement to reduce the risk of having a neural tube defect (NTD)-affected pregnancy. There is little information available to determine if women are following this advice. OBJECTIVE: The purpose of this study was to determine periconceptional folic acid use among women in the postnatal ward of Queen Mary Maternity Hospital in Dunedin. METHODS: A questionnaire was administered to women in the postnatal ward between 14 November and 22 December 2004. RESULTS: One hundred and six women were interviewed during the study period. Forty women (39%) used folic acid supplements before conception. Sixty-seven women (64%) planned their pregnancy. The proportion of women (P<0.001) who planned their pregnancy (53%) and used folic acid before conception was higher than those who did not (11%). The proportion of women 30 years of age (55%) who took folic acid supplements before conception was higher than women aged 17 to <25 years (10%). CONCLUSION: Despite a lack of a public health campaign in New Zealand, a high proportion of participants, especially those who planned their pregnancy, took folic acid during the periconceptional period. A comprehensive public health campaign is needed to increase folic acid use. Fortification may be required to reach those women who do not plan their pregnancies.

Adolescent↗