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PubMed2004

Folic acid does not improve endothelial function in healthy hyperhomocysteinaemic subjects.

Folic acid supplementation lowers total plasma homocysteine (tHcy) and improves endothelial function in individuals with coronary artery disease (CAD) and in those with additional CAD risk factors. In the present study, we assessed whether endothelial function is impaired in healthy subjects with hyperhomocysteinaemia but without other CAD risk factors and whether folic acid supplementation improves endothelial function in these subjects. Flow-mediated dilatation (FMD) of the brachial artery was performed on 26 healthy subjects, age 49 +/- 2 years (mean +/- S.E.M.), with high tHcy (15.6 +/- 1.5 micromol/l) and 16 healthy age-matched subjects with low tHcy (7.9 +/- 0.6 micromol/l; P < 0.001). Subjects with high tHcy were then randomized to receive 5 mg/day of folic acid or placebo for 8 weeks in a double-blind cross-over trial with a 4-week washout. FMD was not associated with tHcy and was not different between high and low tHcy groups (7.0 +/- 0.6% compared with 6.6 +/- 1.2%, P = 0.76). Treatment with folic acid decreased tHcy by 34% in hyperhomocysteinaemic subjects ( P = 0.02 compared with placebo), but had no effect on FMD (+ 0.5 +/- 0.6% compared with -0.7 +/- 0.5%; P = 0.17 compared with placebo). In healthy subjects with hyperhomocysteinaemia, but without additional cardiovascular risk, endothelial function is unimpaired and folic acid supplementation has no additional effect.

Adult↗
PubMed1959

Purification of folic acid.

Various purification procedures for folic acid were investigated. The criteria of purity were a negative Bratton-Marshall test and the absence of fluorescent spots on paper chromatograms. Since no method provided a pure product, a procedure consisting of cellulose column chromatography followed by filtration through charcoal was developed.

Folic Acid↗
PubMed2003

Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study.

BACKGROUND: Food fortification with folic acid has been introduced in several countries for the prevention of neural tube defects. Fortification has lowered total homocysteine (tHcy) concentrations in the US population, a consequence that may have health benefits. However, folic acid fortification could mask vitamin B-12 deficiency. Synthetic L-5-methyltetrahydrofolate (L-MTHF) may be more appropriate than folic acid as a fortificant because it is unlikely to mask the hematologic indicators of vitamin B-12 deficiency. OBJECTIVE: The objective of the study was to compare the effectiveness of 100 micro g folic acid/d with that of equimolar L-MTHF in lowering tHcy in healthy volunteers. DESIGN: The study was designed as a 24-wk, randomized, placebo-controlled intervention. Free-living healthy volunteers (n = 167) were randomly assigned to receive a daily supplement containing folic acid (100 microg), L-MTHF (113 microg), or placebo. Blood collected at baseline and at 8, 16, and 24 wk was analyzed for tHcy, plasma folate, and red blood cell folate (RCF) concentrations. RESULTS: At 24 wk, after adjustment for baseline values, mean (95% CI) tHcy was 14.6% (9.3, 19.5%) and 9.3% (3.7, 14.6%) lower, mean plasma folate was 34% (14, 56%) and 52% (30, 78%) higher, and mean RCF was 23% (12, 35%) and 31% (19, 44%) higher in the L-MTHF and folic acid groups, respectively, than in the placebo group. L-MTHF was more effective than was folic acid in lowering tHcy (P < 0.05). At 24 wk, the increases in plasma folate and RCF concentrations did not differ significantly between the 2 supplemented groups. CONCLUSION: Low-dose L-MTHF is at least as effective as is folic acid in reducing tHcy concentrations in healthy persons.

Adult↗
PubMed2006

Predicting bioavailable zinc from lower phytate forms, folic Acid and their interactions with zinc in vegetarian meals.

OBJECTIVE: To develop a statistical model for predicting zinc bioavailability from cereal-based vegetarian meals using relative proportion of nutrients, non-nutrients and their interactive effects. METHODS: A database on in vitro zinc dialysability (by isotopic tracer, 65Zn) of vegetarian meals (266 out of 326) from Asia, Africa, Europe /US and Latin America was used to develop a model for estimating zinc bioavailability. A multiple regression analysis adjusted for energy content was carried out for net bioavailable zinc from a meal with the predictor variables as meal contents of iron, zinc, copper, ascorbic acid, beta-carotene, riboflavin, thiamine, folic acid, tannic acid, fiber, phytate degradation products (IP6 to IP1), along with their interaction terms. Reproducibility of the model was tested with remaining 60 meals. Validation of the model was done with zinc absorption data of i) 12 young adults on 24 meals and ii) 5 adults with ileostomy on 7 meals. RESULTS: Folic acid, IP3 and IP5 were significant influencing factors for bioavailable zinc. Weighted multiple regression equation was: ln (bioavailable zinc in mg) = -1.701 + 1.285 x ln [(IP5 in mg] x (Zn in mg)] -1.222 x ln(IP5 in mg) -0.0078 x folic acid in microg -0.137 x ln [(IP3 in mg) x (Zn in mg)] with adjusted R--[2] = 0.64, p = 0.0001. The correlation between predicted and observed dialysability of meals was found to be 0.96 (p < 0.01). A significant correlation between observed and predicted amount of absorbed zinc (r = 0.85, p < 0.01) was obtained for the human data of zinc absorption in 12 healthy and 5 subjects with ileostomy. CONCLUSIONS: Bioavailable amount of zinc from vegetarian meals was influenced by IP3, IP5 and folic acid content and their interactive effect with zinc content.

Adult↗
PubMed1987

Carrier-mediated transport of folate compounds in L1210 cells. Initial rate kinetics and extent of duality of entry routes for folic acid and diastereomers of 5-methyltetrahydrohomofolate in the presence of physiological anions.

Comparison of the kinetic parameters for influx of highly purified [3H]folic acid versus [3H]methotrexate in L1210 cells under anionic buffer conditions showed a marked discordancy. In addition, the kinetics for influx of [3H]folic acid were unchanged in variant L1210 cells defective in [3H]methotrexate transport. In these variant cells, the Vmax for methotrexate was reduced 17-fold and the Km was increased 3-fold. The results show that [3H]folic acid influx is mediated by a system which has a low affinity, but a 20-fold higher capacity, for folate compounds than the classical high-affinity system mediating [3H]methotrexate influx. Since the latter system also exhibits very low affinity for [3H]folic acid, it would not be expected to contribute significantly to the total influx of [3H]folic acid. The high-capacity system for [3H]folic acid influx is different from that believed to mediate pterin influx in L1210 cells since it was not inhibited by adenine, a potent inhibitor of pterin influx. However, exposure of cells to [3H]folic acid in a nonanionic buffer resulted in marked stimulation of initial influx, and a fraction of influx under these conditions was inhibited by methotrexate. These results suggest that anions modulate the extent of multiplicity of [3H]folic acid influx by their known effects on the high-affinity, reduced folate/methotrexate system. The diastereomers, at carbon 6, of [14C]5-methyltetrahydrohomofolate shared both transport systems. The influx Km for the natural diastereomer was one-half that of the unnatural form for both transport systems. Both diastereomers showed a much greater differential in affinity between the two transport systems than did [3H]folic acid. Our results suggest that an analog which could be effectively transported by the low-affinity/high-capacity route may be useful in the treatment of tumors resistant to methotrexate due to a defective high-affinity/low capacity influx system. We also found that incubation of L1210 cells with [3H]folic acid or the natural diastereomer [14C]5-methyltetrahydrohomofolate for 10 min resulted in the formation of a nonexchangeable fraction of radioactivity amounting to 20-40% of the total accumulation. This non-exchangeable fraction may be explained by the accumulation of metabolites other than polyglutamates. Preloading of cells with methotrexate prior to incubation with [3H]folic acid prevented the accumulation of radioactivity as a nonexchangeable fraction.

Animals↗
PubMed2004

Relationship of high pretreatment folic acid level and failure of methotrexate in ectopic pregnancy: a pilot study.

OBJECTIVE: To test the hypothesis that high (> or =20.7 ng/mL) pretreatment serum folic acid level increases the failure of single-dose methotrexate for ectopic pregnancy. STUDY DESIGN: Twenty patients with ectopic pregnancy and measured pretreatment folic acid levels were divided into 2 groups based on pretreatment serum folic acid level (< or > or =20.7 ng/mL). All patients were candidates for single-dose methotrexate treatment. Variables analyzed in the 2 groups were pretreatment folic acid level, initial P-human chorionic gonadotropin (hCG) level, size of the ectopic mass, presence of fetal heart tones and clinical outcomes. RESULTS: Eleven patients had serum folic acid levels < and 9 > or =20.7 ng/mL. The mean (+/- SD) folic acid level was 13.4 ng/mL (+/- 3.2) in the group with folic acid levels <20.7 ng/mL, significantly lower than in the group with folic acid levels >20.7 ng/mL (p <0.001). The 2 groups were similar in initial hCG level, size of the ectopic mass and presence of fetal heart tones. The failure rate was significantly higher in the group with pretreatment serum folic acid levels > or = 20.7 ng/mL as compared to the group below (n = 4, 44%, vs. n = 0, 0%; p = 0.02). CONCLUSION: High pretreatment folic acid levels increase the risk of treatment failure with single-dose methotrexate.

Abortifacient Agents, Nonsteroidal↗
PubMed1998

Plasma folic acid cutoff value, derived from its relationship with homocyst(e)ine.

We established the cutoff value for plasma folic acid, using plasma homocyst(e)ine as the functional marker. To do this, we investigated the relationship of the plasma folic acid of 103 apparently healthy adults with their fasting plasma homocyst(e)ine and with their plasma homocyst(e)ine 6 h after oral methionine challenge (100 mg/kg). We also studied the relationship of their plasma folic acid with the decline of fasting plasma homocyst(e)ine after 7 days of folic acid supplementation (5 mg/day). The three approaches suggested a cutoff value of 10 nmol/L. The chances of individuals to significantly (P <0.05) lower their plasma homocyst(e)ine after folic acid supplementation proved significantly higher at plasma folic acid concentrations < or = 10 nmol/L, as compared with folic acid concentrations above this value (odds ratio, 5.02; 95% confidence interval, 1.87-13.73). We suggest adopting a 10 nmo/L plasma folic acid cutoff value on functional grounds.

Adult↗
PubMed2004

Awareness of the use of folic acid to prevent neural tube defects in a Mediterranean area.

OBJECTIVES: The risk of neural tube defects (NTDs) is decreased in women who take folic acid during the periconceptional period. The main objective of our study was to evaluate the awareness of the need for folic acid supplementation and also the actual intake during the periconceptional period to prevent neural tube defects in a Mediterranean area. STUDY DESIGN: A retrospective study was performed from 1 July to 30 November 2000. One thousand consecutive women who delivered in our hospital were interviewed during the immediate postpartum period about their knowledge of neural tube defects and folic acid intake before and during pregnancy. RESULTS: Most women (85.7%) referred not having been specifically informed about the need to take folic acid to prevent neural tube defects although approximately half of the women (50.6%) were in fact, aware of the need for folic acid intake. Eight percent (8.1%) of the women took folic acid before conception but only 6.9% did so during the effective period from 4 weeks before conception to 4 weeks after conception. Logistic regression analysis showed that awareness of the need to take folic acid together with having had preconceptional counselling and knowledge of NTDs were the strongest variables related to the fact of having taken folic acid during the correct period. CONCLUSIONS: Although the population is aware of the need to take folic acid, the real impact of the present recommendations is almost negligible. Information in primary care and preconceptional counselling to specifically inform patients about the need to take folic acid to prevent NTDs seem to be crucial to improve the final intake of folic acid during the protective period.

Adult↗
PubMed1977

Folate-responsive neurological and mental disorders: report of 16 cases. Neuropsychological correlates of computerized transaxial tomography and radionuclide cisternography in folic acid deficiencies.

Two groups of patients with folic acid responsive neurological and psychiatric disorders are reported. The first group (7 patients) had well-established acquired folate deficiency due either to defective absorption (4 cases with atrophy of jejunal mucosa) or to a deficient diet (3 cases). One patient had a subacute combined degeneration of the spinal cord while others were depressed and had weight loss, permanent muscular and intellectual fatigue, restless legs syndrome, depressed ankle jerks, diminution of the sense of vibration in the knees and a stocking-type tactile hypoesthesia. The second group (9 patients) comprised idiopathic cases of folic acid deficiency. Their main subjective complaints were chronic fatigability and familial restless legs syndrome. The neurological findings were similar to those of the patients with acquired disorders. Neuropsychological testing procedures revealed an abnormal intellectual functioning in all 16 patients. Abnormal patterns of radionuclide cisternograms and computerized transaxial tomography (CTT) were found in 11 patients. After 6-12 months of folic acid therapy a striking improvement regarding their intellectual functioning was noticed: the IQ, Kohs Block Design and Category tests were significantly improved. The correlation of neuropsychological findings with CTT and radionuclide cisternograms led to the conclusion that chronic folate deficiency could induce cerebral atrophy.

Adult↗
PubMed1999

Preventing neural tube defects. Survey of preconceptional use of folic acid.

OBJECTIVE: To determine the proportion of women who take daily folic acid supplements in the month before conception and to identify factors associated with supplement use. DESIGN: Cross-sectional survey by self-administered questionnaire. SETTING: Tertiary care teaching hospital in Hamilton, Ont. PARTICIPANTS: Four hundred eighty-four (43%) of 1132 women who delivered normal babies between November 1997 and March 1998. MAIN OUTCOME MEASURES: Reports of daily vitamin supplement use in the month before pregnancy and after pregnancy, and having heard or read about the need to take folic acid before pregnancy; sources of information about folic acid; factors associated with preconceptional vitamin use. RESULTS: Thirty-four percent of respondents reported taking vitamins before conception (use ranged from 21% for those with unplanned pregnancies to 40% for those with planned pregnancies); 80% after conception. Of all respondents, 63% were aware of the need for preconceptional folic acid. Key information sources were family doctors and the mass media: the media were more important before conception, doctors after. Being older (30 years or more), having post-secondary education, and having a planned pregnancy were associated with knowing about the benefits of folic acid; knowledge, regular exercise, perceived good health, and planned pregnancy were associated with preconceptional use of vitamins. CONCLUSIONS: Even in this sample of well educated, English-speaking women, only one third took vitamin supplements before conception, which indicates that current educational efforts do not reach most women early enough. A coordinated, multi-pronged strategy that targets and involves physicians and capitalizes on opportunities to work with schools, public health outlets, and the media is needed.

Adolescent↗
PubMed1980

Studies on the effect of folic acid supplement on folate and vitamin B12 status in children.

The effect of folic acid supplement (15 mg folic acid per day) for 5 weeks was studied on a group of 5 children aged 8-12 years who were admitted to hospital. The result was compared to a control group of 5 children who were given a placebo. After supplementation, both serum and red cell folate levels in the experimental group significantly increased, i.e., 15 fold (82.0 ng/ml) and 4 fold (880 ng/ml), respectively. Serum UFBP decreased considerably while TFBP showed no significant alteration which resulted in the elevation of the % saturation to its maximum value. These findings indicated that the supplementary folic acid not only increased both serum and red cell folate levels and saturated nearly all serum UFBP but also elevated the % saturation markedly. There were no definite changes of serum vitamin B12, UBBC, TBBC and TC levels of the experimental group from those of the control group. There were slightly but not significantly increased blood haemoglobin and haematocrit levels in both groups of children. This indicated that folic acid supplement had no definite effect on vitamin B12 and haematological findings in this study.

Carrier Proteins↗
PubMed1980

Effect of riboflavin and folic acid supplementation on some haematopoietic parameters in the rat.

The effect of riboflavin and folic acid supplementation on selected haematopoietic parameters in young rats fed diets deficient in the two vitamins was studied. Haemoglobin concentration as well as haematocrit value and red blood cell count were highest in rats which received the full dosage of both riboflavin and folic acid. Supplementation of folic acid alone gave lower values than both vitamins, however administration of only a fifth of the full dosage of riboflavin to rats receiving folic acid improved the haemoglobin values significantly. It is suggested that the observed effect my be partly due to the effect of riboflavin on folic acid metabolism.

Animals↗
PubMed2006

Folic acid and the prevention of neural tube defects: A survey of awareness among Latina women of childbearing age residing in southeast Michigan.

Periconceptional intake of folic acid is known to reduce the risk for neural tube defects (NTDs). To inform southeast Michigan Latina women of childbearing age about the benefits of food and supplemental sources of the micronutrient in the prevention of NTDs, Spanish-English bilingual health educators carried out 20 education events in supermarkets and community organizations serving Latina women. One hundred and sixty Latina women ages 19 to 50 years indicated their current folic acid awareness and stated their future intentions regarding folic acid. Of 160 women surveyed, 114 (71%) had heard of folic acid, 84 (74%) knew that folic acid prevents birth defects, 63 (55%) knew the critical time to take folic acid, and 76 (67%) identified at least one source of folic acid. After participating in the education events, 136 women (85%) reported planning to eat more folate and/or folic acid-rich foods. Although general folic acid awareness is fairly high, health promotion efforts must be coordinated at community locations serving Latina women to share folic acid's specific protective effects in the prevention of NTDs, the critical timing of intake, and its food and supplement sources.

Adult↗
PubMed2002

Incidence of open neural tube defects in Nova Scotia after folic acid fortification.

BACKGROUND: With the goal of preventing open neural tube defects (NTDs), recommendations for folic acid supplementation before conception were introduced in Canada in 1994, and by November 1998 Canadian grain products were being fortified with folic acid. We wished to determine whether the annual incidence of open NTDs in Nova Scotia, including those in stillbirths and terminated pregnancies, changed after the introduction of either folic acid supplementation or fortification. METHODS: For the 10-year period from Jan. 1, 1991, to Dec. 31, 2000, we retrospectively extracted the total number of births in Nova Scotia and the number of live births and stillbirths with open NTDs from the Nova Scotia Atlee Perinatal Database as well as the number of terminated pregnancies affected by NTDs from the Fetal Anomaly Database. We determined the total annual incidence of all open NTDs, and of the subgroups spina bifida and anencephaly, per 1000 births in the province during the periods before (1991-1994) and after (1995-1998) folic acid supplementation initiatives were begun but before folic acid fortification of grain products was implemented, and during the periods before (1991-1997) and after (1998-2000) fortification. RESULTS: In the period after supplementation initiatives were begun but before fortification was implemented, the incidence of open NTDs did not change significantly: the mean annual rate was 2.55 per 1000 births during 1991-1994 and 2.61 per 1000 births during 1995-1997 (relative risk [RR] 1.02, 95% confidence interval [CI] 0.77-1.35). After the fortification was implemented the incidence of open NTDs decreased by more than 50%: the mean annual rate was 2.58 per 1000 births during 1991-1997 and 1.17 per 1000 births during 1998-2000 (relative risk 0.46, 95% CI 0.32-0.66). INTERPRETATION: The recommendations for folic acid supplementation alone did not appear to succeed in reducing the incidence of open NTDs in Nova Scotia, whereas the fortification of grain products with folic acid did result in a significant reduction in the incidence.

Adult↗
PubMed1989

Repletion of folate-depleted rats with an amino acid-based diet supplemented with folic acid.

Folate depletion and repletion protocols are not well standardized. Weanling rats were moderately depleted of folate in 28 d with a folate-free purified diet based on 17% amino acids as the nitrogen source. They were then folate repleted for 23 d with the amino acid diet supplemented with either 125, 250, 500, 1000 or 2000 micrograms folic acid/kg. Hematology, growth and tissue folate levels were measured in subsets of the rats when they were 24 (baseline), 52 (depleted) and 75 d old (repleted). The same measurements were made in control rats that had been fed 2 mg folic acid/kg of the amino acid diet for the same period of time. Our findings show that with repletion, growth of previously depleted rats is in direct proportion with the level of supplementation up to 1000 micrograms folic acid/kg diet. Serum folate levels of repleted rats also increased in proportion to supplementation between 500 to 2000 micrograms/kg diet, and liver folate levels increased proportionally with the level of supplement within the range of 125 to 2000 micrograms/kg diet. The 2000 micrograms/kg supplement was sufficient to restore liver folate levels equivalent to that of controls, but body weight and serum folate levels failed to catch up with that of controls in the 23-d repletion period. There was a nonlinear relationship between serum and liver folate levels: serum folate remained constant at about 6 micrograms/l as liver folate increased to about 7 micrograms/g, then serum folate diverged by increasing to 120 micrograms/l with only minor increases in liver folate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1991

Synthesis and biological evaluation of a fluorescent analogue of folic acid.

A fluorescein derivative of the lysine analogue of folic acid, N alpha-pteroyl-N epilson-(4'-fluoresceinthiocarbamoyl)-L-lysine (PLF), was synthesized as a probe for dihydrofolate reductase (DHFR) and a membrane folate binding protein (m-FBP). Excitation of PLF at 282 nm and at 497 nm gave a fluorescence emission maximum at 518 nm. Binding of PLF to human DHFR or human placental m-FBP results in approximately a 20-fold enhancement in the magnitude of the fluorescence emission, suggesting that the ligand interacts with a hydrophobic region on these proteins. Additional evidence suggests that an energy transfer may occur between the pteridine and the fluorescein moieties. PLF binds to the active site of human DHFR since methotrexate (MTX) competes stoichiometrically and the denatured enzyme in the presence of PLF did not exhibit fluorescent enhancement. The dissociation constant for the fluorescein derivative with respect to human DHFR is 115 nM as compared to 111 nM for folic acid. The Ki value for the competitive inhibition of human DHFR by the fluorescent analogue of folic acid is 2.0 microM compared to 0.48 microM for folic acid. PLF was reduced to N alpha-(7,8-dihydropteroyl)-N epilson-(4'-fluoresceinthiocarbamoyl)-L-lysine (H2PLF) and assayed by the enzymatic conversion to the tetrahydro derivative. The Km value for human DHFR for the dihydrofolate analogue is 2.0 microM. The KD value for H2PLF to human DHFR is 47 nM as compared to 44 nM for dihydrofolate. The KD values for both H2PLF and PLF indicate that the fluorescein moiety does not significantly affect folate binding in enzyme binary complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1974

Formation of 10-formylfolic acid, a potent inhibitor of dihydrofolate reductase, in rat liver slices incubated with folic acid.

During investigation of folate polyglutamate biosynthesis in rat liver slices utilizing [2-(14)C]folic acid, a folate compound that behaved like a polyglutamate form in the Sephadex G-15 gel filtration system was found to accumulate. Subsequent chromatographic, spectral, chemical, and enzymic studies have indicated that the compound formed in liver slices incubated with [(14)C]folic acid with and without methotrexate was 10-formyl folate. This folate is of interest in that it is the most potent natural inhibitor of dihydrofolate reductase known and may be capable of serving a regulatory function within the cell.

Animals↗
PubMedDate not supplied

Folic acid treatment of fragile X males: a further study.

Investigations of the effect of high dose folic acid treatment of fragile X syndrome in males has produced mixed results. However, no study had examined the possible drug effects of folic acid on non-fragile X control males. Therefore, we examined the effect of folic acid on fragile X males using non-fragile X control males. Subjects were assigned randomly to an ABA or BAB design. Duration of either folic acid or placebo condition was 4 months. Folic acid or placebo was given in a double-blind fashion. At the end of each condition, the subjects' behavior was assessed. At the end of the study, parents were asked to complete a questionnaire. Using parents' responses, we examined 22 items on the Autistic Descriptors Checklist and two subscales from the Vineland Adaptive Behavior Scale which corresponded to areas of behavior parents' noted to have shown improvement. We did not find significant differences between fragile X males and control males, within subjects, nor across folic acid and placebo conditions. Thus, our follow-up study confirms and extends our original findings, as well as those of other researchers: namely, that no dramatic changes in behavior result from high dose folic acid. Moreover, subtle improvements observed in earlier investigations were not confirmed.

Adolescent↗