[Aminopterin in the treatment of malignant leukemia and its antidote--folic acid].
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Aminopterin↗
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Results for “FOLIC ACID”
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[Electronic structure of elements traced in the study of the antitumoral activity of folic acid antimetabolites].
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Antimetabolites↗
Optic neuropathy from folic acid deficiency without alcohol abuse.
A 47-year-old woman with a 2-month history of bilateral progressive visual loss was found to have a bilateral retrobulbar optic neuropathy. Her serum vitamin B(12) concentration and hemoglobin level were normal, but her serum folic acid concentration was decreased. The patient had a minimal alcohol intake and moderate tobacco use that had been unchanged for over 20 years; however, she had markedly altered her diet 4 years earlier in the setting of clinical depression. After treatment with oral folic acid and diet modification without change in her tobacco or alcohol use, the patient's visual function returned to normal. This case supports the role of folic acid deficiency as an important cause of some cases of nutritional optic neuropathy.
Diet Therapy↗
Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study.
OBJECTIVE: Elevated levels of plasma total homocysteine (tHcy) are identified as independent risk factors for coronary heart disease and for fetal neural tube defects. tHcy levels are negatively associated with folic acid, pyridoxine and cobalamine, and positively associated with coffee consumption and smoking. A total of 600 ml of filtered coffee results in a tHcy increase that 200 mug of folic acid or 40 mg of pyridoxine supplementation might eliminate. DESIGN: Randomised, blinded study with two consecutive trial periods. SETTING: Free living population. Volunteers. SUBJECTS: A total of 121 healthy, nonsmoking men and women (78%) aged 29-65 y. INTERVENTIONS: (1) A coffee-free period of 3 weeks, (2) 600 ml coffee/day and a supplement of 200 mug folic acid/day or placebo for 4 weeks, (3) 3-week coffee-free period, (4) 600 ml coffee/day and 40 mg pyridoxine/day or placebo for 4 weeks. MAIN OUTCOME MEASURES: The difference between the change in tHcy in the supplement group and the change in tHcy in the placebo group during the 4-week trial period. RESULTS: Coffee abstention resulted in a tHcy decrease of 1.04 mumol/l for the whole group. In the subsequent coffee period, a further decrease of 0.17 mumol/l was observed in the folic acid group whereas an increase of 1.26 mumol/l was observed in the placebo group, the difference was 1.43 mumol/l (95% CI: 0.80, 2.07). Pyridoxine supplement had no impact on tHcy levels. CONCLUSIONS: Supplementation of 200 mug folic acid/day eliminates the tHcy increasing effect of 600 ml filtered coffee in subjects not already on folic acid supplements. A supplement of 40 mg pyridoxine/day does not have the same effect.
Adult↗
Determination of dissociation constants of folic acid, methotrexate, and other photolabile pteridines by pressure-assisted capillary electrophoresis.
Pressure-assisted CE (PACE) was applied to determine the previously inaccessible complete set of pK values for folic acid and eight related multiprotic compounds. PACE allowed the determination of all acidity macroconstants at low (<or=0.1 mM) concentration without interferences of selfassociation or photodegradation throughout the pH range. The accuracy of the constants was verified by NMR-pH, UV-pH, and potentiometric titrations and the data could be converted into physiological ionic strength. It was shown that even three overlapping pK values can be determined by CE with good precision (<0.06) and accuracy if an appropriately low sample throughput is used. Experimental aspects of PACE for the quantitation of acid-base properties are analyzed. The site-specific basicity data obtained for folic acid and methotrexate (MTX) reveal that apparently slight constitutional differences between folic acid and MTX carry highly different proton-binding propensities at analogous moieties, especially at the pteridine N(1) locus, providing straightforward explanation for the distinctive binding to dihydrofolate reductase at the molecular level.
Electrophoresis, Capillary↗
The effect of folic acid on gingival health.
On days 0 and 30 of a double blind study, two groups of 15 subjects each were evaluated using a plaque index, a gingival index, a gingival exudate flow and fasting plasma folic acid levels. Group I received 2 mg of folic acid twice daily for 30 days while Group II received a placebo. Results of the study seem to indicate that folic acid supplemented to the diet may increase the resistance of the gingiva to local irritants and thus lead to a reduction in inflammation.
Adult↗
[Significance of the folic acid].
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Folic Acid↗
Folic acid and vitamin B12 are more effective than vitamin B6 in lowering fasting plasma homocysteine concentration in patients with coronary artery disease.
OBJECTIVE: To investigate whether vitamin B(6) supplementation had a beneficial effect on lowering fasting plasma homocysteine concentrations in coronary artery disease (CAD) patients. DESIGN: A single-blind intervention study. SETTING: The study was performed at the Taichung Veterans General Hospital, the central part of Taiwan. SUBJECTS: A total of 50 subjects were identified by cardiac catheterization to have at least 70% stenosis of one major coronary artery. In all, 42 patients successfully completed this study. INTERVENTIONS: Patients were randomly assigned to one of five groups and treated with a daily dose of placebo (n=8), 5 mg vitamin B(6) (n=8), 10 mg vitamin B(6) (n=8), 50 mg vitamin B(6) (n=9), or 5 mg folic acid combined with 0.25 mg vitamin B(12) (n=9) for 12 weeks. MAIN OUTCOME MEASURES: Nutrient intakes were recorded by using 24-h diet recalls when patients returned to the cardiology clinic before the intervention (week 0) and at week 12. Vitamin B(6) status was assessed by direct measures (plasma pyridoxal 5'-phosphate) and indirect measures (erythrocyte alanine and aspartate aminotransaminase activity coefficient). Fasting plasma homocysteine, serum folic acid, and vitamin B(12) were measured. RESULTS: Fasting plasma homocysteine concentration did not respond to high or low doses of vitamin B(6) when compared with a placebo treatment after 12 weeks of supplementation. The mean fasting plasma homocysteine concentration, however, decreased significantly after 12 weeks of folic acid combined with vitamin B(12) supplementation (P=0.047). Further, within group, mean fasting plasma homocysteine concentration was nonsignificantly increased by 25.5, 16.2, and 18.3% in placebo, 10 mg/day and 50 mg/day vitamin B(6) supplemented groups, respectively; whereas folic acid combined with vitamin B(12) supplementation significantly reduced fasting plasma homocysteine concentration by 32% (P<0.001). CONCLUSIONS: Our results indicate that vitamin B(6) supplementation alone is less effective than folic acid combined with vitamin B(12) in lowering plasma homocysteine concentrations in CAD patients. SPONSORSHIP: This study was supported by the National Science Council, Taiwan, Republic of China (NSC-91-2320-B-040-023).
Adult↗
Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia.
To investigate effects of supplementation of folic acid on the expression of adhesion molecules VCAM-1 in the aortas of rats with hyperhomocysteinemia. Thirty male SD rats (200 +/- 20 g) were invided into 3 groups (n = 10 for each group): control group(Control), high Met group(Met) and Met plus Folate group(Met + Folate), fed. for 45 days. Plasma Hcy levels were higher with the high-methionine diet (140.68 +/- 36.87 micromol/L vs 6.47 +/- 1.10 micromol/L in control rats) an effect which was reduced by folate. Respectively, the aortic expression of adhesion molecules VCAM-1 at protein and mRNA levels were higher in the Met groups than those in the control groups or the Met + Folate groups. A high methionine diet for 45 days was sufficient to induce hyperhomocysteinemia. Folate supplementation prevented elevation of Hcy levels in the blood, and reduced expression of the adhesion molecule VCAM-1. Hyperhomocysteinemia is now regarded as one of the important risk factors for cardiovascular and cerebralvascular disorders.[Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 38(15):1042-50.] Several plausible mechanisms for Hcy-induecd atherosclerosis have been proposed. These include endothelial dysfunction, enhancement of oxidative stress, reduction in NO bioavailability, and augmentation of thrombus formation.[Holven KB, Holm T, Aukrust P, et al. Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects . Am J Med 2001;110(7):536-42; Guba SC, Fonseca V, Fink LM. Hyperhomocysteinemia and thrombosis. Semin Thromb Hemost 1999;25(3):291-309.] However, the precise molecular mechanism is still unclear. Recent reports have suggested a role for inflammatory processes in the pathogenesis of atherosclerosis.[Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2(2):108-15.] Dysfunction of endothelial cells is the key process promoting inflammatory reactions. On injury, endothlial cells are capable of producing various cytokines that participate in inflammatory reactions in the arterial wall. Although results from in vitro studies suggest that Hcy, at pathophysiological concentrations, stimulates chemokine expression in vascular cells, it is unknown whether hyperhomocysteinemia can initiate similar changes, leading to enhanced momocyte adhesion/binding to the vascular endothelium in vivo.[Zeng X, Dai J, Remick DG, Wang X. Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes. Circ Res 2003;93(4):311-20.] On the basis of the potential pathogenic role of chemokines in atherogenesis, the objective of the present study was to investigate that homocsteine may exert its effect in part though adhesion molecules VCAM-1 and that folic acid supplementation may downregulate these inflammatory responses. Male Sprague-Dawley rats (bred from animal centers of Tongji Medical College, Huazhong Science and Technology University) aged 8 weeks were divided into 3 groups(n=10 for each group) and maintained for 45 days on the following diets before the experiments: (1) regular diet; (2) high-metheionine diet, consisting of regular diet plus 1.7% methionine; and (3) high-methionine plus folate -rich diet, consisting of regular diet plus 1.7% methionine and 0.006% folate.[Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res 2000;21(2-3):129-d37.] Plasma and serum samples wee colleced and stored at -80 degrees C after 45 days until analysis. The plasma homocysteine concentration of rats in three groups were determined by high-pressue liquid chromatography. To detect the endothelial expression of adhesion molecules VCAM-1, the thoracic aorta was isolated and dived into segments. These segments were immersion-fixed in 10% neutral-buffered formalin overlight and then embedded in paraffin. Sequential 5 mum paraffin-embedded cross sections were prepared. Immunohistochemical analyisis was performed to detect vascular cell adhesion molecule(VCAM)-1, The fixed cryosections were immediately blcked in 10% horse serum and phosphate baffered saline(PBS) at room temperature for 30 min. Goat polyclonal andibodies against rat VCAM-1(Santa Cruz Biotechnology) were diluted 1:100 in PBS and incubated with the cryosections for 1 h of room temperature. After three washes, the sections were incubated with biotin-conjugated rabbit anti-goat immunoglobulins(Dako) at 1:250 dilution in PBS. After three washes, the samples were mounted in 90% glycerol-PBS. Photographs were taken by use of a light microscope at a mignification of x200.
Animals↗
The effect of inhibitors of folic acid absorption on the transfer rate constants in the rat everted proximal jejunum: a method for their evaluation from a three-compartment model.
When solute transfer through the intestinal in vitro everted sac preparation is described by a three-compartment system, solute transfer rate constants can be derived for the mucosal and serosal permeability barriers. A catenary variant has been presented as well as a mammillary one where paracellular movement of solute is additionally allowed for. The first order differential rate equations governing the change in solute concentration in all three compartments with respect to time have been solved and the explicit analytical solutions provided. Since these solutions are cumbersome to use in the estimation of the required rate constants, a least squares procedure has been applied directly to the differential form of the rate equations in order to derive the rate constants without recourse to the analytical solutions. Verification of the solutions and of the estimated rate constants was by substitution of the latter into the former to test the goodness of fit for folic acid absorption data. Both variants take into account the simultaneous fluid movement which occurs during absorption experiments and which complicates the interpretation of absorption data. The mammillary model showed that only 10% of folic acid movement could pass directly through the paracellular pathways and that the bulk of folate movement is probably through the epithelial cells. However the catenary model without paracellular movement gave just as good fit to the data and was used subsequently. Experiments investigating the effect of substances implicated in folate malabsorption were analyzed in terms of the catenary model for folic acid absorption, in order to investigate their effects on the transfer rate constants free from the complicating effects on fluid movement. When pronounced inhibition took place, as with methotrexate, the mucosal rate constants were reduced, whereas the serosal rate constants were elevated. Also, the forward (k12) mucosal rate constant correlated significantly with the overall folate transfer in contrast to the other rate constants. These observations are consonant with the concept of a mucosally sited entry step exerting a controlling influence over the transfer rate of folic acid rather than a serosally sited exit process and with the conclusion that this may be the site of action of substances causing folate malabsorption.
Animals↗
Effect of diet and folic acid addition on digestibility and ruminal fermentation in growing steers.
Eight ruminally fistulated steers (352 +/- 27 kg BW) were used in a replicated 4 x 4 Latin square design. Treatments were 1) 70% rolled barley +30% timothy hay (HC), 2) HC+folic acid (2 mg/kg BW; HC+F), 3) 30% rolled barley + 70% timothy hay (HF), and 4) HF+F. Total tract apparent digestibility of DM and CP were greater (P < or = .05) in steers fed the HC diet, whereas that of ADF and NDF was greater (P < .001) in steers fed the HF diet. Supplemental dietary folic acid had no effect on either of the forementioned variables, regardless of whether the animal received the HC or the HF diet. To compare ruminal DM disappearance, nylon bags containing either hay or barley were incubated in the rumen of each steer for 4, 8, 12, 24, and 48 h. Ruminal DM disappearance of hay and barley was affected (P < .05) by the type of diet fed but not by the addition of folic acid to either diet. Ruminal fluid was sampled on three consecutive days, at the following postprandial hours: 1, 2, 4, 8, 12, and 23. Differences in ruminal pH and individual VFA among treatments were attributable to the type of diet fed. Changes in ruminal VFA concentrations at various times after feeding were altered with folic acid addition; however, these modifications were not sufficient to affect in a significant way either ruminal or total tract digestibility.
Animal Feed↗
FUdR induction of the X chromosome fragile site: evidence for the mechanism of folic acid and thymidine inhibition.
Experiments designed to illuminate the mechanism by which folic acid and thymidine inhibit expression of the Xq28 fragile site in human lymphocytes are described. The fragile site is induced by 5-fluorodeoxyuridine (FUdR), a potent inhibitor of thymidylate synthetase, in the presence of otherwise inhibiting concentrations of folic acid but not in the presence of thymidine. These results indicate that the fragile site is expressed because of depletion of deoxythymidine monophosphate (dTMP) available for DNA synthesis.
Cells, Cultured↗
Inhibition of the growth of an ame-thopterin-refractory tumor by dietary restriction of folic acid.
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Carcinosarcoma↗
[Effect of exogenic folic acid on the yield and amino acid composition of the seeds of Pisum sativum L. and Hordeum vulgare L].
Effects of exogenous folic acid (FA) on the productivity of Pisum sativum L. and Hordeum vulgare L. have been studied. After flowering, the plants were treated with optimum concentration of FA (25 mg per 1 water). This treatment increased the weight of the seeds by 17-19% (samplings of 1000 pcs were compared), whereas the yield became 26-29% higher. Amino acid analysis revealed a notable increase in the content of folate-dependent amino acids (e.g., glutamate, glycin, and methionine). Analysis of total folate content demonstrated that tetrahydrofolic coenzymes were significantly increased in experimental seeds. Treatment of the plants with exogenous FA increased both the content of chlorophyll in the leaves and their continuance of function. The results obtained led to the conclusion that FA treatment increases the productivity of pea and barley, by affecting the yield, weight, and quality of the seed.
Amino Acids↗
Separation of folic acid reductase from Streptococcus faecium (ATCC 8043).
A strain of Streptococcus faecium (ATCC 8043) which is highly resistant to the antifolic acid compound, amethopterin, was gently ruptured by exposing protoplasts of the organism to a hypotonic solution. The crude lysate resulting there-from was treated by various chemical and physical techniques designed to separate folic acid reductase from dihydrofolic acid reductase. In the process, the enzyme was purified approximately 160-fold; however, throughout the process, the enzyme preparation maintained the ability to reduce folic acid to tetrahydrofolic acid. Attempts to isolate mutants showing a deficiency in either folic acid reductase or dihydrofolic acid reductase were unsuccessful. Based on these results, it is concluded that folic acid is reduced to tetrahydrofolic acid by one enzyme in S. faecium (ATCC 8043). The crude lysate was also subjected to ultracentrifugation. An analysis of the supernatant fluid and the sediment indicated that the reductive activity is located in the soluble fraction of the cell.
Bacterial Proteins↗
Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile.
To verify whether the decreasing neural tube defects birth prevalence rates in Chile are due to folic acid fortification or to pre-existing decreasing trends, we performed a population survey using a network of Estudio Colaborativo Latino Americano de Malformaciones Congenitas (ECLAMC, Latin American Collaborative Study of Congenital Malformations) maternity hospitals in Chile, between the years 1982 and 2002. Within each maternity hospital, birth prevalence rates of spina bifida and anencephaly were calculated from two pre-fortification periods (1982-1989 and 1990-2000), and from one fortified period (2001-2002). There was no historical trend for spina bifida birth prevalence rates before folic acid fortification, and there was a 51% (minimum 27%, maximum 66%) decrease in the birth prevalence rates of this anomaly in the fortified period. The relative risks of spina bifida were homogeneous among hospitals in the two period comparisons. There was no historical trend for the birth prevalence of anencephaly comparing the two pre-fortified periods, but the relative risks were heterogeneous among hospitals in this comparison. There was a 42% (minimum 10%, maximum 63%) decrease in the birth prevalence rate of anencephaly in the fortified period as compared with the immediately pre-fortified period, with homogeneous relative risks among hospitals. Within the methodological constraints of this study we conclude that the birth prevalence rates for both spina bifida and anencephaly decreased as a result of folic acid fortification, without interference of decreasing secular trends.
Anencephaly↗