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PubMed1984

Severe thrombocytopenia associated with acute folic acid deficiency and severe hemorrhage in two patients.

Severe thrombocytopenia associated with acute folic acid deficiency in two inpatients is described. Both patients had severe hemorrhagic manifestations. A similar syndrome has previously been described in patients who have undergone extensive surgery or dialysis or both. The present cases show that acute folic acid deficiency can occur in other circumstances and may go unrecognized because other signs in the peripheral blood of a megaloblastic process may be minimal. A good response was obtained with folic acid therapy.

Acute Disease↗
PubMed2006

Inhibition of folic acid uptake by catechins and tea extracts in Caco-2 cells.

In this present study it was aimed to determine whether the catechins contained in green tea and the whole extracts of Camellia sinensis (Theaceae) inhibit the uptake of folic acid by Caco-2 cell monolayers. Our results indicate that (-)-epigallocatechin 3-gallate (EGCG) and (-)-epicatechin 3-gallate (ECG) inhibit cellular folic acid uptake with IC50 values of 34.8 micromol/L and 30.8 micromol/L, respectively. Furthermore, green and black tea extracts were also found to inhibit folic acid uptake with IC50 values of approximately 7.5 and 3.6 mg/mL, respectively. According to these results, simultaneous intake of tea and folic acid may inhibit intestinal folic acid absorption. The consequences with respect to the folate status of the body will need to be examined in vivo.

Antioxidants↗
PubMed1996

[Folic acid in the prevention of neural tube defects].

Neural tube defects (spina bifida) imply a severe limitation of quality of life. 70 to 100% of these defects are preventable by additional intake of folic acid during the periconceptional period. In accordance with the recommendations of Anglo-Saxon and other authorities prevention of this grave malformation should be attempted not only after a first-affected child, but primarily in a general manner in Switzerland, too. All women of childbearing age not under contraceptives should be advised to consume a diet rich in folic acid and to take an additional daily dose of 0.4 mg folic acid as a monosubstance or with a multivitamin preparation. A supplement of folic acid to cereal grain products, mainly bread flours, is recommended. A generally elevated folic acid intake may have further beneficial effects, such as risk reduction for the occurrence of carcinoma and atherosclerosis.

Congenital Abnormalities↗
PubMed2005

Prospective evaluation of folic acid supplementation on plasma homocysteine concentrations during weight reduction: a randomized, double-blinded, placebo-controlled study in obese women.

Elevated total homocysteine concentrations and obesity are both associated with an increased risk of cardiovascular disease. However, previous studies of weight reduction on serum homocysteine concentrations have obtained inconsistent reports. We investigated the effect of folic acid supplementation on serum homocysteine concentrations via a randomized, double-blinded, placebo-controlled study. Seventy-four obese women [age (mean +/- SEM) 41 +/- 1 years; body mass index, 29.6 +/- 0.5 kgs/m2] completed a 12 weeks weight reduction program with dietary advice and light exercise. They were also randomized to take either folic acid supplementation (5 mg daily, n = 36) or placebo (n = 38) groups. This program led to a weight reduction of 7.7% and 8.9% of initial weight for folic acid supplementation and placebo groups, respectively. Serum folate concentrations increased for 3 folds (p < 0.001) in the folic acid group. In the folic acid group, there was a trend of lower fasting serum homocysteine concentrations (7.6 +/- 0.2 vs. 7.3 +/- 0.3 micromol/L), but it did not reach statistical significance (p = 0.170). However, we found that serum homocysteine concentrations decreased significantly in those with higher baseline homocysteine concentrations (8.7 +/- 1.3 vs. 7.8 +/- 1.5 micromol/L, p = 0.004), while it did not change in those with lower baseline homocysteine concentrations (6.6 +/- 0.6 vs. 6.8 +/- 1.2 micromol/L, p = 0.334). Reduction of serum homocysteine concentrations did not correlate with elevation of serum folate concentrations (p = 0.646) in obese women with higher baseline homocysteine concentrations. In conclusion, serum homocysteine concentrations can be maintained in obese women during mild to moderate weight loss. Folic acid supplementation decreased serum homocysteine concentrations in those women who had higher serum homocysteine concentrations before participating in the weight reduction program.

Adult↗
PubMed2006

Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial.

BACKGROUND: Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS: We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS: The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION: Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Anemia, Iron-Deficiency↗
PubMed2004

Chemopreventive role of folic acid in colorectal cancer.

Mortality from colorectal cancer, a leading cause of death in the U.S.A. and other western countries, has remained unchanged over the past 45 years. Therefore, the search for strategies to prevent the development and progression of colorectal cancer has markedly intensified. Chemoprevention is one such strategy. Accumulating evidence suggests that folic acid, a water soluble vitamin, could be an effective chemopreventive agent for colorectal cancer. Results from several studies have demonstrated that a diet deficient in folic acid may be associated with an increased risk of colonic neoplasia, whereas dietary supplementation of this nutrient may be chemopreventive. Although the mechanisms by which folic acid exerts its chemopreventive role in colorectal carcinogenesis remain to be fully elucidated, supplemental folic acid has been shown to arrest the loss of heterozygosity (LOH) of the tumor suppressor gene DCC (deleted in colorectal cancer) and to stabilize its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Data from in vitro studies utilizing colon cancer cell lines suggest that supplemental folic acid or its metabolite 5-methyltetrahydrofolate (5-MTF) attenuates the expression and activation of EGF-receptor (EGFR) as well as proliferation of cells. The folic acid mediated reduction of EGFR function could partly be the result of suppression of EGFR gene through increased methylation of CpG sequences within its promoter.

Animals↗
PubMed2001

[Effect of folic acid and supplemented with vitamin A and vitamin E on depressing teratogenesis induced by cyclophosphamide].

The effect of folic acid and the combined effect of folic acid(FA) + vitamin A + vitamin E on the prevention of teratogenesis induced by cyclophosphamide during pregnancy were observed. The results showed that cyclophosphamide resulted a decreased weight and length of the fetuses, an increased rate of neural tube defects and a retardation of ossification centers. The neural tube defects rates in the groups with no any supplementation, supplemented with folic acid alone and supplemented with FA + vitamin A + vitamin E were 87.27%, 42.93% and 30.08% respectively(P < 0.01). The supplementation of FA or the combined supplementation resulted also in greater fetal weight and length, increased ossification of supraoccipital bone (P < 0.01). The study suggested that the combined effect of FA, vitamin A and vitamin E was superior to FA alone.

Animals↗
PubMed2004

Folic acid food fortification in Canada.

By January 1998, most Canadian cereal grains (e.g., white flour) were being fortified with folic acid, with a large percentage being fortified by mid-1997. This was in compliance with both American and Canadian mandatory fortification deadlines of January and November 1998, respectively. It was estimated that between 0.1 to 0.2 mg of additional synthetic folic acid per day would be provided through this initiative, the goal of which was to lower the rate of neural tube defects (NTD). The current report outlines some of the changes to the health status of Canadians in relation to its folic acid food fortification initiative.

Canada↗
PubMed2001

Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro.

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme which converts 5,10-methylene tetrahydrofolate (5,10-MnTHF) to 5-methyl tetrahydrofolate. A common C to T transition (C677T) in the MTHFR gene is reported to reduce the risk for colorectal cancer and acute lymphocytic leukemia in homozygotes (TTs). It is hypothesized that because TTs have reduced MTHFR activity, more 5,10-MnTHF is available to provide methyl groups for the conversion of uracil to thymidine. Folic acid deficiency causes the intracellular accumulation of dUMP and the subsequent incorporation of uracil into DNA. The removal of uracil from DNA may result in double-stranded DNA breaks, the accumulation of which is a putative risk factor for cancer. We tested whether human lymphocytes taken from TTs (n = 10) were more able to resist uracil incorporation into DNA than controls (n = 14 CCs and 6 CTs) when cultured in medium containing 12-120 nM folic acid for 9 days. DNA uracil content of these lymphocytes was measured by CG-MS. TTs and controls showed a dose-dependent increase in DNA uracil content during folic acid deficiency (P < 0.0001, R2 = 0.23 for TTs and P < 0.0001, R2 = 0.19 for controls). DNA uracil content was not different between the two groups at any of the folic acid concentrations (two-way ANOVA: media [folic acid], P < 0.0001; genotype, P = 0.4). The results show that, in this in vitro system, the MTHFR C677T polymorphism does not affect the cell's ability to resist uracil incorporation into DNA. Chromosome breakage, as measured by micronuclei, was also shown to correlate with folic acid concentration in a preliminary experiment (P < 0.0001). Although the results appear not to support the hypothesis that a reduced risk for certain cancers in TTs is due to diversion of folic acid to thymidine synthesis, differences between the in vivo and in vitro situation make this conclusion not definitive.

DNA↗
PubMed2001

Target analogue imprinted polymers with affinity for folic acid and related compounds.

Two approaches to synthesize molecularly imprinted polymers with affinity for folic acid and other substituted pteridines have been compared. In the first approach, the folic acid analogue methotrexate was used as template and functional monomers capable of generating selective binding sites were searched in a miniaturized screening system based on binding assessment in the batch mode. Highest selectivity was seen using 2-vinylpyridine as functional monomer, which was confirmed in the chromatographic mode for a batch synthesized on a gram scale. However, the retentivity and selectivity of this phase were insufficient for anticipated applications. In a second approach, using methacrylic acid as the functional monomer, organic soluble inhibitors for the enzyme dihydrofolate reductase were used to develop sites complementary toward the pteridine substructure. This resulted in materials showing enhanced selectivity for substituted pteridines when evaluated by HPLC. Thus, methotrexate and leucovorine were selectively retained in mobile phases of either low or high aqueous content, thus showing the typical bimodal retention behavior of previously reported MIPs. In organic mobile-phase systems, the inhibitor used as template had an influence on the retentivity and selectivity of the MIP. The polymer imprinted with trimethoprim retained all folic acid analogues strongly and showed the highest selectivity among the MIPs in an organic mobile-phase system. This was supported by Scatchard analysis resulting in biphasic plots and a quantitative yield of high-energy binding sites. All templates were shown to associate strongly with MAA in CDCl(3), the strength of association correlating roughly with the template basicity and the selectivity observed in chromatography. Nonparallel complexation-induced shifts indicated formation of 1:2 template monomer complexes at concentrations corresponding to those of the prepolymerization solutions.

Folic Acid↗
PubMed2003

Periconceptional folic acid use and the prevalence of neural tube defects in The Netherlands.

OBJECTIVE: To study the effect of increased folic acid intake on the prevalence of neural tube defects (NTD) in The Netherlands. STUDY DESIGN: Using the capture-recapture method, the prevalence of NTD was estimated on the basis of five different registries on births affected by NTD. RESULTS: Total prevalence over the 1988-1998 period varied between 1.43 and 1.96 per 1000 live and still births. No decrease in total prevalence was found to have taken place during that period. Scrutiny of the last 2 years, 1997 and 1998, in which increased folic acid intake might be expected to have had an effect, did not give any indication that the prevalence of NTD was falling. CONCLUSIONS: A decrease in the Dutch prevalence of NTD during the study period could not be demonstrated due to the relatively small number of women using folic acid periconceptionally. This does not mean automatically that periconceptional folic acid use is ineffective in reducing the Dutch prevalence of NTD. Further monitoring is needed.

Dietary Supplements↗
PubMed2005

Impact of misclassification of in vitro fertilisation in studies of folic acid and twinning: modelling using population based Swedish vital records.

OBJECTIVE: To determine whether failure to adequately adjust for a reported 40% misclassification of use of in vitro fertilisation (IVF) as reported in a Swedish study could have led to a false finding that folic acid increases dizygotic twinning. DESIGN: Modelling with population based data. SETTING: Swedish vital records for 1995-9. MAIN OUTCOME MEASURES: Rates of twinning calculated according to whether women used IVF to become pregnant. Estimated unadjusted and adjusted odds ratios of the association between use of folic acid and twinning by use of IVF. RESULTS: In 1995-9, Swedish women who used IVF had an almost 20 times the chance of having twins than women who did not use IVF (rate ratio 19.7, 95% confidence interval 18.7 to 20.6). In the absence of a true effect of folic acid, the use of a 40% misclassified surrogate variable to adjust for use of IVF would have resulted in a false finding that folic acid was associated with a more than twofold increase in twinning. CONCLUSION: Use of IVF is a strong confounder because it is associated with both use of folic acid and twinning. Even when misclassification of IVF was reduced to 5%, this bias persisted in the adjusted model. Using a 40% misclassified surrogate to adjust for IVF, as reported in the Swedish study, probably led to a false finding that folic acid increased dizygotic twinning.

Data Collection↗
PubMed2001

Commercially available folic acid supplements and their compliance with the British Pharmacopoeia test for dissolution.

A recent report suggested that some folic acid preparations available in the United States failed to meet the specifications for dissolution specified by the US Pharmacopoeia (USP), of 70 per cent drug release in the first hour of testing. The Teratology Society recommends that women of childbearing age should take a daily supplement of 400 microg folic acid when they are trying to conceive, to reduce the risk of foetal neural tube defects. The consequence of this failure to meet the USP requirements may be that an inadequate dose of folate may be absorbed and thus the expected level of protection against neural tube defects not afforded. The purpose of the present study was to examine a number of brands of folic acid (400 microg), available commercially in the United Kingdom, for compliance with the British Pharmacopoeia (BP) test for dissolution. Ten tablets (or capsules) from each of 11 brands were tested using dissolution apparatus compliant with BP requirements, using 0.1 M sodium hydroxide as the dissolution medium. The results indicated that four of the brands failed to release 70 per cent of the nominal drug content in the first hour of test and thus did not comply with the test. Two of the seven brands that passed the test went on to release more than 150 per cent of the nominal 400 microg drug content. These results highlight the problems of dose uniformity and the potential health risks of slow dissolution and under-dosing in commercially available folic acid dosage forms.

Absorption↗
PubMed2003

Folic acid supplementation does not prevent ribavirin-induced anemia.

Treatment of chronic hepatitis C consists of inteferon plus ribavirin. The major adverse effect of ribavirin is hemolytic anemia, a complication that limits therapy. Folic acid supplementation is used to improve erythropoiesis in chronic hemolytic anemia. The aim of this study was to evaluate the effectiveness of folic acid supplementation in the prevention of ribavirin-induced anemia in patients being treated for hepatitis C. Twenty one patients enrolled in treatment protocols for hepatitis C received folic acid 1 mg daily and 22 did not. Groups were similar in age, gender, ribavirin dose and baseline hemoglobin. Folic acid supplementation had no effect in the decrease in hemoglobin or the measured parameters of hemolysis. No difference between males and females was noted for hemoglobin decrease or lowest hemoglobin levels. In our study, folic acid showed no beneficial effect in the prevention of ribavirin-induced anemia.

Anemia, Hemolytic↗
PubMed2000

In vitro effects of folic acid on gamma-glutamyltransferase and glutathione reductase activities in malignant lung and thymus tumors.

In vitro effects of folic acid (10(-5), 10(-4), and 10(-3)M) on activities of gamma-glutamyltransferase and glutathione reductase, the enzymes involved in glutathione metabolism, were studied in tissue samples obtained after surgical treatment of the lungs and thymus. Folic acid did not change gamma-glutamyltransferase activity in lung cancer tissue, but in thymoma tissue this substance in a concentration of 10(-3)M inhibited it by 16%. Folic acid had no effects on glutathione reductase activity in benign tumors and normal lung and thymus tissues, but increased this activity in thymoma and lung cancer tissues. Activation of glutathione reductase was probably related to binding of folic acid in the allosteric center of the enzyme, which probably induced conformational changes in the catalytic center, acceleration of electron transport from NADPH(2) to oxidized glutathione via flavin adenine nucleotide, and intense production of reduced glutathione.

Dose-Response Relationship, Drug↗
PubMed1982

Folic acid deficiency and neutrophil dysfunction.

Polymorphonuclear leukocyte functions were studied in 92 patients with protein-calorie malnutrition. Serum folic acid levels were higher than 3 ng/ml in 38 patients and 3 ng/ml or less in 54 patients. Significant differences were found between these two groups of patients with regard to phagocytosis (81.5 +/- 1.9 versus 69.2 +/- 2.0 percent, p less than 0.001) and bactericidal ability (90.6 +/- 1.1 versus 84.5 +/- 2.3 percent, p less than 0.05). Correction of folic acid deficiency in 22 patients was associated with recovery of normal phagocytosis (p less than 0.001) but not bactericidal function. Adding folic acid to the serum of eight patients also restored normal phagocytic function (p less than 0.001). A correlation was found in vivo and in vitro between changes over time in folic acid levels and in phagocytosis.

Blood Bactericidal Activity↗
PubMed2006

Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia.

The exact mechanism(s) by which hyperhomocysteinaemia promotes vascular disease remains unclear. Moreover, recent evidence suggests that the beneficial effect of folic acid on endothelial function is independent of homocysteine-lowering. In the present study the effect of a low (400 microg/70 kg/day) and high (5 mg/70 kg/day) dose folic acid supplement on endothelium-dependent relaxation in the isolated perfused mesenteric bed of heterozygous cystathionine beta-synthase deficient mice was investigated. Elevated total plasma homocysteine and impaired relaxation responses to methacholine were observed in heterozygous mice. In the presence of N(G)-nitro-L-arginine methyl ester relaxation responses in wild-type tissues were reduced, but in heterozygous tissues were abolished. Clotrimazole and 18alpha-glycyrrhetinic acid, both inhibitors of non-nitric oxide/non-prostanoid-induced endothelium-dependent relaxation, reduced responses to methacholine in wild-type but not heterozygous tissues. The combination of N(G)-nitro-L-arginine methyl ester and either clotrimazole or 18alpha-glycyrrhetinic acid completely inhibited relaxation responses in wild-type tissues. Both low and high dose folic acid increased plasma folate, reduced total plasma homocysteine and reversed endothelial dysfunction in heterozygous mice. A greater increase in plasma folate in the high dose group was accompanied by a more significant effect on endothelial function. In the presence of N(G)-nitro-L-arginine methyl ester, a significant residual relaxation response was evident in tissues from low and high dose folic acid treated heterozygous mice. These data suggest that the impaired mesenteric relaxation in heterozygous mice is largely due to loss of the non-nitric oxide/non-prostanoid component. While low dose folic acid may restore this response in a homocysteine-dependent manner, the higher dose has an additional effect on nitric oxide-mediated relaxation that would appear to be independent of homocysteine lowering.

Animals↗
PubMed2005

Awareness of the role of folic acid, dietary folate intake and plasma folate concentration in Japan.

AIM: To investigate awareness of the role of folic acid in the prevention of neural tube defects, dietary intake of folate, and plasma folate concentration. METHODS: Postal questionnaires were collected from 1190 lay female subjects in three different groups and from seven groups of 3067 health-care providers. Dietary folate was investigated by assessing food frequency charts that were kept for 3 days by 245 women, and plasma folate was assessed by analyzing the blood serum of 194 women. RESULTS: Less than 15% of citizens and mothers who had live births knew that there was a link between folic acid and neural tube defects. The exception was with myelodysplastic families, in which awareness was 92%. Awareness among health-care professionals was generally low. The highest level was found in obstetricians-gynecologists (76%) and the lowest in nurses (12%). Dietary folate intake and plasma concentration were highest in pregnant women (356 microg/day and 11.9 ng/mL) and the lowest in student nurses (217 microg/day and 6.8 ng/mL). When the recommended dietary allowance of folate in Japan is taken into consideration, 22% of the non-pregnant women and 71% of the pregnant women did not fulfill the recommended dietary allowance. CONCLUSIONS: Information on the role of periconceptional intake of folic acid is not sufficiently disseminated to young women and health-care professionals alike. Pregnant women should be repeatedly recommended to take folic acid supplements of 400 microg/day.

Adult↗