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PubMed1975

Prevention of folate deficiency by food fortification. II. Absorption of folic acid from fortified staple foods.

The absorption of folic acid from maize, rice and bread fortified with pteroylglutamic acid was compared with that of an aqueous solution of pteroylglutamic acid in the same subjects. Feeding fortified maize and rice produced similar increments in folic acid concentration, which were approximately half those observed with the pteroylglutamic acid solution. Fortified bread produced a lower increment. Pteroylglutamic acid was found to resist destruction by boiling and baking at temperatures and times used for the conventional preparation of such foods. However, baking for longer periods resulted in a loss of folic acid activity. It is concluded that fortification of staple foods with folic acid may offer a practical adjunct to nutritional programs designed to improve the intake of essential nutrients.

Absorption↗
PubMed2004

Folic acid use by women receiving routine gynecologic care.

OBJECTIVE: Many health professional groups recommend folic acid supplementation for all women able to become pregnant. In this study, we document folic acid supplement use among a sample of women receiving routine gynecologic care. METHODS: A short questionnaire was administered to 322 women aged 18-45 years who were seeking routine gynecologic care at participating clinics in Little Rock, Arkansas. Questions covered knowledge and use of folic acid supplements, pregnancy intention, and demographic and socioeconomic characteristics. Primary study outcomes were self-reported folic acid awareness, daily or weekly use of folic acid supplements, and intention to begin taking folic acid. Factors affecting study outcomes were examined individually by computing crude odd ratios and adjusted for other covariates using unconditional logistic regression. RESULTS: Although 61.8% of women reported awareness of the association between folic acid and birth defects prevention, only 27.1% of these women, and 22.7% of all study participants, reported daily use of a folic acid supplement. Substantially more women (39.8%) were taking a folic acid supplement at least once per week. Age, race, educational level, folic acid awareness, marital status, pregnancy intent, and other preventive health behaviors were the most important predictors of compliance. CONCLUSION: The results indicate a need for targeted interventions directed toward minority women, young women, and those of lower socioeconomic and educational status. The routine gynecologic visit is an ideal opportunity to counsel women of reproductive age to take folic acid daily. LEVEL OF EVIDENCE: III

Adolescent↗
PubMed1997

Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements.

Periconceptual consumption of folic acid has been shown to decrease the incidence of neural tube defects. The strategy of universal fortification of staple foodstuffs with folic acid presents the possibility of life-long exposure to unmetabolized folic acid. Chief among the risks of exposure to folic acid in the circulation is that of masking the diagnosis of cobalamin deficiency in pernicious anemia and the progression of neurologic disease. Other effects are unknown. For instance, the effect of in vivo chronic exposure of adult and fetal cells to the synthetic form of the vitamin has never been investigated at the population level. This study examined the acute appearance of unmetabolized folic acid in serum in response to the consumption of some fortified foodstuffs by young and elderly volunteers. Subjects on a 5-d regimen of fortified ready-to-eat-cereal and bread in addition to their normal diet had a threshold intake of 266 micrograms folic acid per meal at which unaltered folic acid appeared in the serum. Subjects given folic acid in either isotonic saline, milk, or white bread also had a threshold > 200 micrograms. From patterns of food consumption in the United States, the implementation of flour fortification at 1.4 mg/kg is unlikely to lead to folic acid appearance in serum, assuming that consumption is spread throughout the day. Increasing this level of fortification, however, as has been advocated by some agencies, may result in the repeated appearance of folic acid in serum over many years, particularly in consumers in nontargeted populations of large amounts of fortified foods. The "safe level of intake" of 1 mg folate/d set by the US Food and Drug Administration may cause a serum folic acid effect. Furthermore, a repeated serum folic acid response is likely to be found in many women complying with the advice to take 400 micrograms folic acid/d to prevent the occurrence of neural tube defects.

Adolescent↗
PubMed1978

[Folic acid and vitamin B 12 in chronic alcoholics].

In 64 chronic alcoholics folic acid and vitamin B12 in plasma and folic acid in erythrocytes were determined. The mean values of folic acid in plasma and in erythrocytes were significantly below normal. The determination of vitamin B12 showed normal results in a group of 20 cases treated with vitamin B12 containing drugs, whereas in the group of untreated alcoholics significantly reduced values were found. Comparison of folic acid and vitamin B12 concentrations in plasma revealed a more frequent deficiency of folic acid than of vitamin B12, which was combined with anemia in half the alcoholics investigated. The need to treat chronic alcoholics with folic acid and vitamin B12 is pointed out.

Adult↗
PubMed2005

Folic acid supplementation and social deprivation.

OBJECTIVE: To assess the use of folic acid supplementation in relation to small-area measures of social deprivation. DESIGN: Cohort study. SETTING: Antenatal clinic, Women's Outpatients Services, Cumberland Infirmary, Carlisle, UK. SUBJECTS: Four hundred and fifty women attending their 18-week antenatal clinic appointment. No selection criteria were applied. Townsend scores were allocated using postcodes to provide a small-area measure (enumeration district) of social deprivation. RESULTS: Eighty-nine per cent of women took folic acid prior to their 18-week antenatal clinic appointment; 48% of women took folic acid before 4 weeks of gestation. Younger women and more socially deprived women were less likely to use folic acid supplements before 4 weeks of gestation. Women with a family history of neural tube defects were no more likely to take folic acid than were women with no family history of neural tube defects. CONCLUSION: A high proportion of women reported taking folic acid supplements during pregnancy but less than half took them at the most important time in early pregnancy. Younger women and women who were more socio-economically deprived were much less likely to take folic acid during the critical periconceptional period. Future strategies should promote prenatal folic acid supplementation in women under the age of 24 and in women of low socio-economic status. Further attention should also be given to the use of folic acid supplements in women with a family history of neural tube defects.

Adult↗
PubMed1978

Megaloblastic erythropoiesis and tissue depletion of folic acid in the cat.

Dietary requirement for folic acid was shown in the cat. Folic acid deficiency was produced by feeding young cats a deficient diet (0.125 mg of total folate/kg of dry weight by analysis) for 22 weeks. The folic acid-deficient cats grew normally, but had reduced plasma, red blood cell, and liver folate concentrations in comparison with those concentrations in cats fed a control diet (1.36 mg of total folate/kg).. Urinary excretion of formiminoglutamic acid was increased in all deficient diet cats 24 hours after L-histidine injection. Erythroblasts in bone marrow smears from folic acid-deficient cats were megaloblastic; they showed abnormal nuclear chromatin patterns and had nuclear-cytoplasmic asynchronism.

Animals↗
PubMed2005

Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies.

OBJECTIVE: To examine the effect of folic acid on the efficacy of methotrexate (MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase III randomized controlled trials (RCTs) of leflunomide in which MTX was used as a comparator. METHODS: Analyses were restricted to patients randomized to receive MTX who had rheumatoid factor data. The US study recruited 482 patients with active RA; 179 received at least 1 dose of MTX, and all were mandated to receive 1 mg of oral folic acid once or twice daily. The multinational European study recruited 999 patients with active RA; 489 received at least 1 dose of MTX, and oral folic acid was not required, although 50 received folate after developing an adverse event. Because of similar entry criteria for both studies, the data for patients with available primary outcome data at week 52 were pooled (n = 668), and the patients were grouped by folic acid use (n = 225) and nonuse (n = 443). To account for the significant between-study differences in the MTX groups, baseline covariates were adjusted using propensity scores so that folic acid users could be matched with nonusers. This allowed for a comparison of differences in American College of Rheumatology (ACR) 20% improvement criteria at week 52. RESULTS: At study entry, non-folic acid users had a significantly lower mean body weight, shorter mean RA duration, and higher mean disease activity (measured by joint counts, patient's and physician's global assessments, and acute-phase reactant levels). The mean MTX dosage at week 52 was similar in the 2 RCTs. Using propensity score matching techniques, the proportion of patients achieving an ACR 20% response at week 52 averaged 17% higher in the non-folic acid group than in the folic acid group (range 15-21%). Similarly, the proportion of patients achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%) and 12% (range 9-14%) higher, respectively, in the non-folic acid group. Adverse events were reported in 93% of US study patients and 94% of the multinational study patients. Elevated liver transaminase levels (above the upper limit of normal) were reported in 29% of the US study patients (majority receiving folic acid) and 62% of the multinational study patients (majority not receiving folic acid). CONCLUSION: After using propensity scores to adjust for differences in the baseline characteristics of folic acid users and non-folic acid users, 9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%, 50%, or 70% improvement at 52 weeks compared with those who did not receive folic acid in the 2 phase III RA clinical trials. As a post hoc analysis, the results of this data analysis should be considered "hypothesis generating" and an impetus for future studies regarding the effects of folic acid on the efficacy of MTX in RA.

Adult↗
PubMed1995

Aging. Increased responsiveness of colorectal mucosa to carcinogen stimulation and protective role of folic acid.

Recent investigations have demonstrated a protective role for folic acid in dysplasia and neoplasia, through an unknown mechanism. The current study was designed to evaluate whether the protective role of folic acid is due, in part, to its antiproliferative properties. In addition, because colorectal neoplasia is more common with increasing age, we have compared results in both old (22 months) and young (3 months) rats. Colorectal mucosal explants of rats treated with the known carcinogen methylazoxymethanol, were supplemented with folic acid. Ornithine decarboxylase was then measured as an index of cellular proliferative activity. We observed that supplemental folic acid suppressed carcinogen-induced ornithine decarboxylase activity by 64% in the old and 74% in the young rats. Furthermore, a similar phenomenon was observed for tyrosine kinase, which was measured for comparison. The suppression of hyperproliferative activity by supplemental folic acid may contribute to the protective effect of folic acid in colorectal neoplasia.

Aging↗
PubMed1979

Folic acid hypersensitivity and fever: a case report.

An apparent case of folic acid hypersensitivity and fever in a 36-year-old anephric man is reported. The patient first experienced pruritus when he received 1 mg of folic acid daily; the drug subsequently was discontinued. Three months later, after administration of 1 mg of folic acid daily, the patient became febrile and pruritic. Fever, generalized pain, chills, urticaria and pruritus persisted despite administration of acetaminophen/oxycodone tablets. Leukocytosis was not present. Challenge with a 10-mg/ml folic acid solution intradermally revealed the patient was hypersensitive to folic acid. Previous reports of folic acid-induced hypersensitivity are reviewed. Hypersensitivity to folic acid should be suspected if a patient experiences fever or rash, or both, while receiving folic acid and if neither symptom can be attributed to infection or other pathologic state.

Adult↗
PubMed2001

Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden.

Folic acid is recommended to reduce the risk of neural tube defects and other congenital malformations. Data from the Swedish Medical Birth Registry were used to study frequency of twinning in women who in early pregnancy reported the use of folic acid. Women (n = 2,569) who in early pregnancy reported the use of folic acid had an increased rate of twin deliveries after consideration of maternal age and of length of involuntary childlessness, both variables being significant confounders. The effect of folic acid was seen also in women who did not report involuntary childlessness. A similar but not statistically significant trend was seen after use of multivitamins without simultaneous use of folic acid tablets (n = 1,979). The increased risk seems to be limited to dizygotic twinning (relative risk = 2.13, 95% CI 1.64-2.74). If this association is causal, wide-spread supplementation with folic acid may represent a hazard larger than the postulated beneficial effect on neural tube defects, at least in low-risk areas.

Adult↗
PubMed2004

Oral folic acid enhances endothelial function in patients with hypercholesterolaemia receiving statins.

BACKGROUND: Folic acid therapy has been shown to improve endothelial function in patients with familial hypercholesterolaemia via a possible antioxidant mechanism. Data on the possible role of folic acid in hypercholesterolaemic patients receiving statins are lacking. In the present study we tested the hypothesis that folic acid supplementation improves endothelial function in patients with hypercholesterolaemia and treatment with statins. METHODS: Thirty-four hypercholesterolaemic patients receiving statins participated in the study; all subjects underwent measurement of endothelium-dependent, flow-mediated dilatation of the brachial artery and subsequently randomized to receive 5 mg of the folic acid (n=17) or placebo (n=17) for 4 weeks. Flow-mediated dilatation of the brachial artery was repeated at the end of the 4-week period. RESULTS: Folic acid and placebo groups were comparable regarding age, sex, smoking, hypertension, coronary artery disease, obesity, family history and blood lipids. Folic acid administration resulted in an improvement of flow-mediated dilatation (4.7+/-3.2% to 7.1+/-3.1%, P=0.02), whereas there was no improvement after placebo administration (5.7+/-3.8% to 5.6+/-2.2%, ns). No significant change in nitrate-induced, endothelium- independent dilatation was observed after folic acid or placebo (ns). CONCLUSIONS: Oral administration of folic acid (5 mg) for 4 weeks improves endothelial function in patients with hypercholesterolaemia treated with statins, with possible beneficial effects on the prognosis of these patients.

Administration, Oral↗
PubMed2006

Survival of infants with neural tube defects in the presence of folic acid fortification.

OBJECTIVE: Neural tube defects (NTDs) are preventable through preconceptional and periconceptional folic acid intake. Although decreases in the prevalence of NTDs have been reported since folic acid fortification of United States grain products began, it is not known whether folic acid plays a role in reducing the severity of occurring NTDs. Our aim was to determine whether survival among infants born with spina bifida and encephalocele has improved since folic acid fortification and to measure the effects of selected maternal, pregnancy, and birth characteristics on first-year (infant) survival rates. METHODS: A retrospective cohort study was conducted and included 2841 infants with spina bifida and 638 infants with encephalocele who were born between 1995 and 2001 and were registered in any of 16 participating birth defects monitoring programs in the United States. First-year survival rates for both spina bifida and encephalocele cohorts were measured with Kaplan-Meier estimation; factors associated with improved chances of first-year survival, including birth before or during folic acid fortification, were measured with Cox proportional-hazards regression analysis. RESULTS: Infants with spina bifida experienced a significantly improved first-year survival rate of 92.1% (adjusted hazard ratio: 0.68; 95% confidence interval: 0.50-0.91) during the period of mandatory folic acid fortification, compared with a 90.3% survival rate for those born before fortification. Infants with encephalocele had a statistically nonsignificant increase in survival rates, ie, 79.1% (adjusted hazard ratio: 0.76; 95% confidence interval: 0.51-1.13) with folic acid fortification, compared with 75.7% for earlier births. CONCLUSIONS: Folic acid may play a role in reducing the severity of NTDs in addition to preventing the occurrence of NTDs. This phenomenon contributes to our understanding of the efficacy of folic acid. Additionally, as survival of NTD-affected infants improves, health care, education, and family support must expand to meet their needs.

Dietary Supplements↗
PubMedDate not supplied

Phenytoin-folic acid interaction.

OBJECTIVE: To review information regarding the dual and interdependent drug-nutrient interaction between phenytoin and folic acid and other literature involving phenytoin and folic acid. DATA SOURCES: Information was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search terms included folic acid, phenytoin, and folic acid deficiency. Additional references were obtained from Current Contents and from the bibliographies of the retrieved references. STUDY SELECTION: All human studies examining the effects of phenytoin on serum folate concentrations and folic acid supplementation on serum phenytoin concentrations were selected. These included studies of patients with epilepsy and healthy volunteers as well as case reports. Case reports were included because of the extensive length of time needed to study this drug interaction. DATA EXTRACTION: Data extracted included gender, dosing, serum folate concentrations if available, pharmacokinetics, and adverse events. DATA SYNTHESIS: Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation. Folic acid supplementation in folate-deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough. Folate is hypothesized to be a cofactor in phenytoin metabolism and may be responsible for the "pseudo-steady-state," which is a concentration where phenytoin appears to be at steady-state, but in reality, is not. Phenytoin and folic acid therapy initiated concomitantly prevents decreased folate and phenytoin obtains steady-state concentrations sooner. CONCLUSIONS: Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.

Anticonvulsants↗
PubMed2004

Folic acid supplementation enhances repair of the adult central nervous system.

Folic acid supplementation has proved to be extremely effective in reducing the occurrence of neural tube defects (NTDs) and other congenital abnormalities in humans, suggesting that folic acid can modulate key mechanisms for growth and differentiation in the central nervous system (CNS). To prevent NTDs, however, supplemental folate must be provided early in gestation. This suggests that the ability of folic acid to activate growth and differentiation mechanisms may be confined to the early embryonic period. Here, we show that folic acid can enhance growth and repair mechanisms even in the adult CNS. Using lesion models of CNS injury, we found that intraperitoneal treatment of adult rats with folic acid significantly improves the regrowth of sensory spinal axons into a grafted segment of peripheral nerve in vivo. Regrowth of retinal ganglion cell (RGC) axons into a similar graft also was enhanced, although to a smaller extent than spinal axons. Furthermore, folic acid supplementation enhances neurological recovery from a spinal cord contusion injury, showing its potential clinical impact. The results show that the effects of folic acid supplementation on CNS growth processes are not restricted to the embryonic period, but can also be effective for enhancing growth, repair, and recovery in the injured adult CNS.

Animals↗
PubMedDate not supplied

Non-essential activation of rat liver porphobilinogen-deaminase by folic acid.

This report demonstrates the ability of folic acid to activate rat liver porphobilinogen-deaminase (PBG-D). Lineweaver-Burk analysis revealed an increase in Vmax (38%) without affecting the Km. In the concentration range assayed, secondary replots of 1/delta slope and 1/delta intersect versus 1/[folic acid] yielded straight lines, indicating the binding of a single molecule of activator to the enzyme PBG-D, with a KA = 1.66 mM. Results presented here show that folic acid acts as a non-essential activator (alpha = 1; beta = 1.6). The activating effect of folic acid has been observed employing the 35-70% ammonium sulphate precipitated fraction, desalted by dialysis or gel filtration, whereas no action was detected when other partially purified PBG-D preparations were utilized as the enzyme source, suggesting either the presence of sites saturated for the activator, or the existence of a different structural protein conformation, or both.

Animals↗
PubMed2001

Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity.

The free radical scavenging properties and possible antioxidant activity of folic acid are reported. Pulse radiolysis technique is employed to study the one-electron oxidation of folic acid in homogeneous aqueous solution. The radicals used for this study are CCl(3)O(2)(*), N(3)(*), SO(4)(*-), Br(2)(*-), *OH, and O(*-). All these radicals react with folic acid under ambient condition at an almost diffusion-controlled rate producing two types of transients. The first transient absorption maximum is around 430 nm, which decays, and a simultaneous growth at around 390 nm is observed. Considering the chemical structure of folic acid, the absorption maximum at 430 nm has been assigned to a phenoxyl radical. The latter one is proposed to be a delocalized molecular radical. A permanent product has been observed in the oxidation of folic acid with CCl(3)O(2)(*) and N(3)(*) radicals, with a broad absorption band around 370-400 nm. The bimolecular rate constants for all the radical-induced oxidation reactions of folic acid have been measured. Folic acid is seen to scavenge these radicals very efficiently. In the reaction of thiyl radicals with folic acid, it has been observed that folic acid can not only scavenge thiyl radicals but can also repair these thiols at physiological pH. While carrying out the lipid peroxidation study, in spite of the fact that folic acid is considerably soluble in water, we observed a significant inhibition property in microsomal lipid peroxidation. A suitable mechanism for oxidation of folic acid and repair of thiyl radicals by folic acid has been proposed.

Animals↗
PubMed1983

Identification of the acrasin of Dictyostelium minutum as a derivative of folic acid.

The acrasin of the slime mold Dictyostelium minutum was isolated from aggregating cells and purified. The compound was species specific and more active in the aggregative than in the vegetative stage. Three observations strongly suggest a structural relationship between the acrasin and folic acid. (1) Folic acid inhibited acrasin degradation by D. minutum. (2) Methotrexate, an antagonist of chemotaxis towards folic acid, also inhibited the response to the acrasin. (3) The chemotactic response to an excess of folic acid was delayed. The response was also delayed to simultaneously tested low amounts of a related compound, but not to unrelated compounds (Van Haastert, 1982). The response to the acrasin was observed to be delayed by excess of folic acid. The acrasinase was identified as a folic acid C9-N10 splitting enzyme. Based on chromatographic properties and biological activity of the acrasin and folate derivatives, the chemical structure of the acrasin is discussed.

Cell Aggregation↗