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PubMed1986

Syntheses and antifolate activity of 5-methyl-5-deaza analogues of aminopterin, methotrexate, folic acid, and N10-methylfolic acid.

Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepared by hydrogenolysis of its known 6-chloro precursor, was treated with guanidine to give 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile which was converted via the corresponding aldehyde and hydroxymethyl compound to 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine. Reductive condensation of the nitrile 8 with diethyl N-(4-amino-benzoyl)-L-glutamate followed by ester hydrolysis gave 5-methyl-5-deazaaminopterin. Treatment of 12 with formaldehyde and Na(CN)BH3 afforded 5-methyl-5-deazamethotrexate, which was also prepared from 15 and dimethyl N-[(4-methylamino)benzoyl]-L-glutamate followed by ester hydrolysis. 5-Methyl-10-ethyl-5-deazaaminopterin was similarly prepared from 15. Biological evaluation of the 5-methyl-5-deaza analogues together with previously reported 5-deazaaminopterin and 5-deazamethotrexate for inhibition of dihydrofolate reductase (DHFR) isolated from L1210 cells and for their effect on cell growth inhibition, transport characteristics, and net accumulation of polyglutamate forms in L1210 cells revealed the analogues to have essentially the same properties as the appropriate parent compound, aminopterin or methotrexate (MTX), except that 20 and 21 were approximately 10 times more growth inhibitory than MTX. In in vivo tests against P388/0 and P388/MTX leukemia in mice, the analogues showed activity comparable to that of MTX, with the more potent 20 producing the same response in the P388/0 test as MTX but at one-fourth the dose; none showed activity against P388/MTX. Hydrolytic deamination of 12 and 20 produced 5-methyl-5-deazafolic acid and 5,10-dimethyl-5-deazafolic acid, respectively. In bacterial studies on the 2-amino-4-oxo analogues, 5-deazafolic acid proved to be a potent inhibitor of Lactobacillus casei DHFR and also the growth of both L. casei ATCC 7469 and Streptococcus faecium ATCC 8043. Its 5-methyl congener 22 is also inhibitory toward L. casei, but its IC50 for growth inhibition is much lower than its IC50 values for inhibition of DHFR or thymidylate synthase from L. casei, suggesting an alternate site of action.

Aminopterin↗
PubMed2002

Folic acid treatment reduces chemokine release from peripheral blood mononuclear cells in hyperhomocysteinemic subjects.

Elevated plasma homocysteine concentration is an independent risk factor for cardiovascular disease. However, the mechanisms by which hyperhomocysteinemia induces vascular disease are uncertain. An early step in atherogenesis involves leukocyte migration into the arterial wall, a process regulated in part by chemokines. We hypothesized that homocysteine may exert its atherogenic effect in part through chemokine-mediated mechanisms, and in the present study, we examined the effects of folic acid supplementation for 6 weeks on chemokine levels in hyperhomocysteinemic individuals. Data showed the following: (1) Compared with control subjects, hyperhomocysteinemic subjects had elevated plasma levels of the CXC chemokines, epithelial neutrophil-activating peptide (ENA)-78 (P<0.05), and growth-regulated oncogene (GRO)alpha (P=0.088), and homocysteine was significantly correlated with ENA-78 and GROalpha. (2) During folic acid treatment, normalization of homocysteine levels was accompanied by a marked reduction in oxidized low density lipoprotein-stimulated release of CXC chemokines (ie, GROalpha, ENA-78, and interleukin-8) and CC chemokines (ie, monocyte chemoattractant peptide-1 and RANTES) in peripheral blood mononuclear cells from these individuals. (3) The oxidized low density lipoprotein-induced release of ENA-78 from peripheral blood mononuclear cells from control subjects was significantly reduced when cells were incubated in the presence of folic acid. These data may suggest that homocysteine exerts atherogenic effects in part by enhancing chemokine responses in cells involved in atherogenesis and that folic acid supplementation may downregulate these inflammatory responses.

Adult↗
PubMed2005

Community mobilization and social marketing to promote weekly iron-folic acid supplementation: a new approach toward controlling anemia among women of reproductive age in Vietnam.

Community-based social marketing and mobilization increased knowledge and participation in preventive weekly iron-folic acid supplementation among women of reproductive age in Vietnam. Rates of buying and taking the weekly supplement containing 60 mg elemental iron and 3.5 mg folic acid among non-pregnant women of reproductive age was between 55% and 92%. Free distribution to pregnant women of the weekly supplement containing 120 mg iron and 3.5 mg folic acid covered almost all pregnant women during the project. In developing countries where community women's groups and health networks are strong, preventive supplementation can be successfully promoted to encourage active participation in the prevention and control of iron-deficiency anemia.

Adult↗
PubMed2000

Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin B12 (cobalamin) in pregnancy and gynecology.

Classically, deficiency of folic acid (folate) or vitamin B12 (cobalamin) was recognized by the presence of a macrocytic anemia resulting from megaloblastic changes in the bone marrow. A markedly changing paradigm has identified both new mechanisms for altered folate and cobalamin status and new sequelae and clinical interrelationships that include altered mechanisms of absorption, a changing pattern of neurologic deficits, an increased risk of vascular occlusive lesions, and an important relationship with the mechanisms of neoplastic transformation. Several of these newer characterizations relate to issues of neoplasia in the nonpregnant woman and to issues in pregnancy, such as the potential for developmental abnormalities of the fetal nervous system.

Anemia, Megaloblastic↗
PubMed2004

Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy.

Intravital two-photon microscopy was used to follow the uptake and trafficking of fluorescent conjugates of folic acid in the rat kidney. Intravenously administered folate-linked dye molecules quickly filled the plasma volume but not cellular components of the blood. Glomerular filtration occurred immediately and binding to proximal tubule cells was seen within seconds. Fluorescence from a pH-insensitive conjugate of folic acid, folate Texas red (FTR), was readily observed on the apical surface of the proximal tubules and in multiple cellular compartments, but little binding or uptake could be detected in any other kidney cells. Fluorescence from a pH-sensitive conjugate of folic acid, folate fluorescein, was seen only on the apical surface of proximal tubule cells, suggesting that internalized folate conjugates are localized to acidic compartments. The majority of the FTR conjugate internalized by proximal tubules accumulated within a lysosomal pool, as determined by colocalization studies. However, portions of FTR were also shown by electron microscopy to undergo transcytosis from apical to basal domains. Additional studies with colchicine, which is known to depolymerize microtubules and interrupt transcytosis, produced a marked reduction in endocytosis of FTR, with accumulation limited to the subapical region of the cell. No evidence of cytosolic release of either folate conjugate was observed, which may represent a key difference from the cytosolic deposition seen in neoplastic cells. Together, these data support the argument that folate conjugates (and, by extrapolation, physiological folate) bind to the apical surface of proximal tubule cells and are transported into and across the cells in endocytic compartments.

Animals↗
PubMed2004

Comparative analysis of serum homocysteine, folic acid and Vitamin B12 levels in patients with noise-induced hearing loss.

OBJECTIVE: The aim of the present study was to determine the levels of homocysteine, folic acid, and Vitamin B12 in subjects with noise-induced hearing loss. Furthermore, possible links between these parameters and noise-induced hearing loss were aimed to be evaluated. METHODS: In the present study, blood samples were obtained from all subjects after overnight fasting for biochemical analysis. We examined the levels of homocysteine, Vitamin B12 and folic acid levels in subjects with noise-induced hearing loss. Twenty-eight male patients with noise-induced hearing loss (mean age 37 +/- 5 year) were included in the study group whereas the control group was composed of 32 healthy male volunteers (mean age 36 +/- 4 year). RESULTS: It was found that homocysteine levels of subjects with noise-induced hearing loss as significantly high compared to healthy controls (P < 0.05). On the other hand, Vitamin B12 and folic acid levels of patients with noise-induced hearing loss were determined to be significantly low compared to the controls (P < 0.05 and < 0.01, respectively). CONCLUSION: Our findings indicate that there might be a link between increased homocysteine levels and noise-induced hearing loss. Since increased homocysteine levels cause elevated levels of free radicals in addition to its atherogenic and thrombogenic effects. Further experimental studies are needed to decipher how this relationship is linked.

Adult↗
PubMedDate not supplied

[Role of folic-acid deficiency in deficiency diseases of the nervous system. Apropos of 12 cases including an anatomo-clinical case].

The authors report 12 cases of neurological syndromes due to folic acid deficiency, due in 8 cases to chronic alcoholism. In 5 cases there was polyneuritis, 3 cases had cerebellar atrophy, whilst 4 patients had subacute combined degeneration of the cord. Folic acid deficiency occurred alone in five cases out of twelve, as in 3 cases vitamin B1 deficiency was associated, and in four cases there was malabsorption of vitamin B12. A neuropathological study of these cases showed: 1) moderate involvement of the mamillary tubercles as observed in deficiency encephalopathies. 2) severe peripheral nerve involvement especially of axonal type. 3) involvement of the anterior horns of the spinal cord with appearances of central chromatolysis and a few atrophic neurones.

Adult↗
PubMed2003

Prevalence of trisomy 21 following folic acid food fortification.

Polymorphisms of maternal genes responsible for normal folate metabolism may be associated with an increased risk of fetal trisomy 21. By January 1998, most of Canada's flour was being fortified with folic acid. We investigated whether the prevalence of antenatally and postnatally detected trisomy 21 changed before and after folic acid food fortification. A total of 218,977 women underwent second trimester maternal serum screening for trisomy 21 in the 48 months before fortification and 117,986 women were screened in the 29 months after fortification. There were 375 identified cases of trisomy 21 before fortification (1.71 per 1,000), compared to 201 cases thereafter (1.70 per 1,000) for a crude prevalence ratio (PR) of 0.99 (95% confidence interval [CI] 0.84-1.18). The associated risk of trisomy 21 did not change after adjustment for mean maternal age (adjusted PR 0.99 [95% CI 0.82-1.19]). Similarly, no significant decline in the monthly prevalence of trisomy 21 was observed using autoregressive integrated moving average time series analysis (P = 0.24). In conclusion, we failed to observe a decline in the occurrence of trisomy 21 following folic acid food fortification.

Adult↗
PubMed2002

The Chilean flour folic acid fortification program reduces serum homocysteine levels and masks vitamin B-12 deficiency in elderly people.

Hyperhomocysteinemia is considered a risk factor for cardiovascular disease and is prevalent in the elderly. Supplementation with folic acid, vitamin B-6 and B-12 lowers homocysteine levels. In January 2000, the Chilean government initiated a flour folic acid fortification program to decrease the occurrence of neural tube defects. The aim of this study was to evaluate the effect of this program on serum homocysteine and folate levels in elderly subjects after 6 mo. A total of 108 elderly people were studied. We measured serum folate, homocysteine and vitamin B-12 levels before the fortification started and 6 mo later. At baseline, folate deficiency (<6.8 nmol/L) was present in 1.8%, vitamin B-12 deficiency (<165 pmol/L) in 27.6% and hyperhomocysteinemia (>14 micromol/L) in 31% of the sample. Six months later, serum folate levels increased from 16.2 +/- 6.2 to 32.7 +/- 7.1 nmol/L (P < 0.001), homocysteine levels decreased from 12.95 +/- 3.7 to 11.43 +/- 3.6 micromol/L (P < 0.001) and vitamin B-12 levels were unchanged. Flour fortification with folic acid had a moderate lowering effect on homocysteine levels. Given that vitamin B-12 deficiency was more common than folate deficiency, it may be more appropriate to add vitamin B-12 to food, at least in foods for this age group.

Aged↗
PubMed1983

[Vitamin B12 as a regulator and methotrexate as an antagonist of folic acid metabolism. Pathophysiologic and clinical aspects].

Biochemical investigations show a decreased bioavailability of 5-methyl-tetrahydrofolic acid in vitamin B12 deficient human cell cultures and bone marrow cells. Tetrahydrofolic acid cannot be liberated from its storage form. This so-called methyl-folate-trap results in a functional folic acid deficiency which is the pathogenetic principle of the defect in the cell proliferation in patients with vitamin B12 deficiency. This knowledge of biochemical mechanisms leads to the identification of rare disorders in the metabolism of vitamin B12 and folic acid. After methotrexate treatment a rescue effect with its antidote Leucovorin can only be achieved, if the ratio antidote: methotrexate is at least 10:1. This ratio is important in cell cultures as well as in bone marrow cells in vivo. The results lead to a formula for the calculation of the optimal dosis to reach a secure rescue for individual patients after high-dose methotrexate treatment. This makes the high-dose methotrexate regimen a treatment modality for malignant tumors without any side effects.

DNA↗
PubMed1992

Disturbed reproductive performance in extreme folic acid deficient golden hamsters.

We studied the effects of folic acid-deficient diets on maternal red blood cell folate level and reproductive performance in golden hamsters (Mesocricetus auratus, Waterhouse). Animals on the same day of oestrous cycle were put together and finally divided into three groups. Each group comprised at least 12 mature female hamsters. The animals were given three different diets, which were commenced before mating. The feeding regimens comprised a standard diet (group 1), or a folic acid-deficient diet which started either 2 weeks (group 2) or 16 weeks (group 3) prior to mating. The regimens were continued until sacrifice of the animals on day 9 of pregnancy. Pregnancy was realized by caging a male with a selected female during the night of ovulation. Just prior to sacrifice, blood samples were drawn to measure maternal folic acid levels in red blood cells. The pregnant uteri were removed and the embryonic sacs were carefully dissected away from the uterus. The number of sacs per pregnant animal was noted. Extreme folic acid deficiencies were confirmed in the pregnant golden hamsters on a folic acid-deficient diet which started 16 weeks prior to mating as compared to those on a standard diet and on a folic acid-deficient diet which started 2 weeks prior to mating. This deficiency appears to interfere with normal reproductive performance. It caused early embryonic loss several days after mating and resulted, finally, in restoration of the oestrous cycle.

Animals↗
PubMed2006

One-third of pregnant and lactating women may not be meeting their folate requirements from diet alone based on mandated levels of folic acid fortification.

Many women are advised to consume a folic acid-containing prenatal supplement for the duration of pregnancy and lactation. Whether this remains necessary after folic acid fortification of the food supply in North America has yet to be determined. Our objective was to assess the dietary folate intake of a sample of pregnant and lactating women at mandated and predicted folic acid-fortification levels and determine the prevalence of inadequate and excessive intakes. Weighed food records (for 3 d) were collected from predominantly university-educated women (32 +/- 4 y of age) at 36 wk of pregnancy (n = 61) and at 4 and 16 wk of lactation (n = 60). Dietary folate intakes during pregnancy and lactation, assuming fortification at mandated levels (140-150 micro g/100 g), were 562 +/- 106 and 498 +/- 99 micro g/d dietary folate equivalents (DFE), respectively. The prevalence of inadequacy for folate, or the proportion of individuals with usual folate intakes less than their nutrient requirement, was 36% for women during pregnancy (estimated average requirement of 520 micro g/d DFE), and 32% during lactation (estimated average requirement of 450 micro g/d DFE). Assuming fortification at twice the mandated level, mean dietary intakes during pregnancy and lactation were 786 +/- 132 and 716 +/- 150 micro g/d DFE, respectively, producing only a 3% prevalence of folate inadequacy. Grains contributed approximately 41% of total folate intake followed by fruits and vegetables (approximately 21%). To conclude, at mandated levels of fortification many pregnant and lactating women are unlikely to meet their folate requirements from dietary sources alone; however, the actual level of inadequacy cannot be determined until the level of folic acid in the food supply is known with greater precision.

Adult↗
PubMed2004

[Liberation of folic acids from composite chitosan films].

Thin films were prepared by the method of evaporation of aqueous solutions of chitosan or its mixtures with poloxamer 407, gelatin, or polyvinyl alcohol. Films of varying thickness were cross-linked with phosphate ions. They contained micronized folic acid in a concentration of 9.1% or 3.2%. Prolonged several hours' liberation of folic acid into isotonic phosphate buffer at pH 5.5, 6.0, and 6.5 was examined. In the initial stage, the mechanism of liberation was governed by diffusion of the dissolved fraction, at higher pH values a higher rate of dissolution of the substance played its role. In some composites, sorption of folic acid to chitosan in an extent dependent on the composition of composites and current acidity of the medium was demonstrated.

Biocompatible Materials↗
PubMed1985

Fetal hydantoin syndrome: inhibition of placental folic acid transport as a potential mechanism for fetal growth retardation in the rat.

Maternal hydantoin ingestion during pregnancy results in a well defined clinical entity termed "fetal hydantoin syndrome". The clinical characteristics of this syndrome includes growth retardation, and congenital anomalies. Because folic acid is essential for protein synthesis and growth, and since hydantoin interferes with intestinal transport of folic acid, we postulated that part of the fetal hydantoin syndrome may be due to inhibition of placental folic acid by maternal hydantoin. Therefore, we studied in vivo placental folate transport in a well-established model for fetal hydantoin syndrome in the rat. Our results indicate that maternal hydantoin ingestion, significantly decreased fetal weight and placental and fetal uptake of folate compared to controls. To determine whether maternal hydantoin ingestion has a generalized or specific effect on placental function, we examined placental and fetal zinc transport in the same model. Our results indicate that zinc transport is not altered by hydantoin ingestion. We conclude that maternal hydantoin ingestion results in fetal growth retardation which may be due in part to inhibition of placental folate transport.

Animals↗
PubMed1976

Effects of kidney extract on the folic acid induced proliferation of the rat kidney.

Single injection of a high dose of folic acid causes a proliferation of the kidney with an increase of the 3H-thymidine incorporation into the DNA of kidney cortex slices in rats. An aqueous extract from rat kidneys inhibits the increase of 3H-thymidine incorporation. The inhibition begins after 4 hours. The maximum effect is observed between 11 and 17 hours after injection of the kidney extract. The kidney extract also inhibits the increase of the DNA content per kidney after folic acid injection. Heart, lung, spleen and liver extracts and bovine serum albumin do not lead to inhibition of the 3H-thymidine incorporation into the DNA of kidney cortex sclices.

Animals↗