Folio Acid Research Articles

Folic acid-preventable spina bifida and anencephaly

1. Brief description of the condition/disease Spina bifida and anencephaly are among the most common and severe birth defects. Almost all affected persons with spina bifida have lower-body paralysis and significant physical disability. In many countries, spina bifida is the most common cause of infantile paralysis. Anencephaly is a common birth defect that contributes to fetal and infant mortality. An estimated 50-75% of these birth defects can be prevented by providing adequate intakes of synthetic folic acid (pteroylmonoglutamic acid) before and during the first trimester of pregnancy. Preventing folic-acid-preventable spina bifida and anencephaly presents all outstanding opportunity to improve the health of children throughout the world. Moreover, substantial evidence suggests that, in adults, suboptimal intake of folic acid is a major factor for increasing the risk of cardiovascular disease. 2. Current burden and rating within the overall burden of disease Each year, 300 000 to 400 000 infants worldwide are born with spina bifida and anencephaly. In China, 100 000 infants are born annually with these two birth defects, which are the leading cause of infant mortality. The rates are also high in Mexico and Central America. Together these conditions contribute significantly to infant morbidity and mortality. 3. Feasibility (biological) of elimination/eradication Approximately 75% of spina bifida and anencephaly are folic-acid-preventable, and it is biologically possible to prevent all folic-acid-preventable spina bifida and anencephaly. The prevention impact would be approximately equal to the prevention derived from poliomyelitis vaccines. The biological feasibility of preventing spina bifida and anencephaly using folic acid-containing vitamin supplements has been demonstrated in randomized controlled trials and other studies. Data from these studies indicate a 50-100% reduction in risk for women taking the supplement before conception and during the first trimester of pregnancy. No randomized controlled studies indicate that dietary changes alone will prevent these birth defects. The U.S. Public Health Service recommends that all women who could become pregnant should consume 400 [micro]g of folio acid daily to prevent these birth defects. Many other countries have policy statements seeking to increase consumption. The United States Institute of Medicine recommended in April 1998 that all women who could become pregnant should consume 400 [micro]g daily of synthetic folic acid to prevent birth defects. 4. Estimated costs and benefits of elimination/eradication Folic acid fortification of flour is feasible and inexpensive. In the USA, formal analysis of costs and benefits of fortification of wheat flour and other grains indicate that a fortification strategy would be highly cost-beneficial. Because costs associated with the purchase and distribution of folic-acid-containing supplements would be higher, programmes depending on pill consumption would break even. …

Effects of dietary folate deficiency on fatty acid composition of myelin cerebroside in growth rats.

Effects of dietary folate deficiency on the fatty acid composition of myelin cerebroside in growing rats were studied. In non-hydroxy fatty acids, an average ratio of 24:1/24:0 was 1.27 in control rats and 0.87 in folate deficient rats, respectively. In hydroxy-fatty acids, a significant decrease in both Ch24:0 and Ch24:1 was observed in folate deficient rats. These results indicate that folio acid may play a certain role in desaturation and/or hydroxylation of long chain fatty acids in the brain of growing rats.

SYSTEMIC CONRTICOSTEROIDS AND FOLIC ACID ANATONISTS IN THE TREATMENT OF GENRALIZED PUSTULAR PSOBLASIS EVALUATION AND PROGNOSIS BASED ON THE STUDY OF 104 CASES

SUMMARY.— Treatment with systemically administered corticosteroids and folio acid antagonists was evaluated in 104 patients with generalized pustular psoriasis. Seventy-three were given steroids; the remainder were not. Seventeen patients died. There were more deaths and fewer lasting remissions in the steroid-treated group. Although steroids can control the pustular phase, the incidence and severity ot side effects seriously reduced their long-term value. Steroid treated patients tended to suffer increasingly severe generalized pustular relapses often precipitated by attempted withdrawal of the steroid. Satisfactory control with minimal or no side effects was achieved in only 12 out of 73 patients. Forty-seven patients received folic acid antagonists, predominantly methotrexate. In 37 the pustules were cleared by the drug at some stage. Response to methotrexate was less satisfactory in patients previously treated with steroids, but it was of particular value in covering steroid withdrawal in patients whose disease had become refractory to the latter or in whom serious steroid side effects had developed. There were 8 deaths among the methotrexate treated patients, 3 of which were directly attributable to the drug. In 16 other patients treatment had to be discontinued because of side effects. Methotrexate w as responsible mainly for the minor short-term complications and steroids for the more serious long-term ones. The outlook for spontaneous and long-lasting remission was much greater in younger patients and in those with a previous history of long-standing ordinary psoriasis.

Inhibition by pyrimidine analogues of the synthesis of folic acid by trachoma agents

SUMMARYTrimethoprim, a 2,4-diaminopyrimidine derivative which inhibits the growth of some bacteria by interfering with folic acid synthesis, inhibited the growth of several strains of the trachoma agent. Inhibition was most clearly demonstrated by measuring prolongation of mean death time of groups of chick embryos inoculated with a single lethal dose of agent. Over a certain range, prolongation was proportional to the logarithm of concentration of inhibitor; higher concentrations were toxic for the embryo. On a weight basis, trimethoprim was not as active as sulphafurazole. Inoculation in conjunction with sulphafurazole resulted in slight potentiation of activity. A related pyrimidine derivative, the antimalarial drug pyrimethamine, also significantly inhibited the growth of one strain of trachoma.In cell culture, trimethoprim decreased the number of inclusions formed by a suspension of the trachoma agent and induced morphological changes in the inclusions similar to those caused by sulphafurazole.Inhibition of the growth of the trachoma agent in the chick embryo was reversed by leucovorin calcium. It is concluded that, as with bacteria, the drug acts by blocking the folio acid cycle and that the trachoma agent most probably contains a dihydrofolate reductase.

Isolation of a new naturally occurring pteridine from bacteria, and its relation to folic acid biosynthesis

A new naturally occurring pteridine has been isolated from two different micro-organisms. It has been shown to be identical with synthetic xanthopterin sulfate and is presumed to arise as a biproduct of excess pteridine ring production (for folio acid synthesis) in these organisms.

Possible role of an enterohepatic shunt as a determinant of serum bilirubin concentrations in normal human newborns

deficiency to develop when the patient began to improve from the aplastic crisis since this is the time of marked erythroid hyperplasia. Serial studies would make it possible to determine whether evidence of folio acid deficiency is more definite at one stage of the crisis than at another. DR. SHOJANIA. I should like to emphasize that folic acid deficiency is almost certainly not the cause of most aplastic crises. However, mild deficiency of folic acid is quite common and may be a contributing factor at least in some instances.

The Urinary Excretion of Orally Administered Tritium-labeled Folic Acid as a Test of Folic Acid Absorption

AbstractThe urinary excretion of radioactivity following an oral test dose of tritium-labeled folio acid was determined in a group of 40 subjects which included controls and patients with a variety of malabsorptive disorders. The results were compared with the occurrence of folic acid deficiency, as detected by subnormal serum L. casei folate levels, and with a variety of other tests available for the evaluation of intestinal absorption, including the determination of folio acid absorption based on the microbiological assay of peak serum Str. faecalis folate concentrations following the oral test dose.The urinary excretion of H3FA in 15 subjects with normal intestinal absorption ranged from 26.0 to 57.8 per cent of the oral test dose, with a mean of 40.7 per cent. The H3FA excretion in 25 patients with intestinal malabsorption ranged from 1.9 to 38.7 per cent, with a mean of 15.3 per cent. Twenty patients in this group excreted less than 26 per cent. Those five patients who excreted greater than 26 per cent were considered to have normal absorption of folic acid since absorption studies of peak serum Str. faecalis folate levels were within the normal range.The results of the H3FA urinary excretion test correlated well with other parameters of intestinal absorption, particularly in the instances of severe malabsorption, although three cases with malabsorption were observed in which H3FA excretion was subnormal and peak serum Str. faecalis folate concentrations were normal. Folic acid deficiency was observed in 12 patients and its incidence appeared to be related to the severity of impairment of folic acid absorption in the majority of cases.It is concluded that the H3FA urinary excretion test is a simple, rapid and reliable index of folic acid absorption.

Differentiation between Vitamin B12—deficient and Folic Acid—deficient Megaloblastic Anemias with C14—Histidine

Abstract Intermediary metabolism of the monocarbon pool and histidine in normal subjects and patients with megaloblastic anemia was studied by continuous measurement of pulmonary excretion of C14O2 and urinary excretion of C14 after injection of L-histidine-2(ring)-C14. Cumulative pulmonary and renal excretion of C14 for 1 month by two normal subjects approximates 45 per cent of the amount injected. Within 4 months after injection of the dose used in this study, the resultant average tissue radiation decreases below the average natural terrestrial and cosmic radiation level. Simultaneous determination of two parameters, (1) cumulative 1-hour pulmonary C14 excretion and (2) the time of occurrence of maximum C14O2specific activity (Tmax), may permit rapid and unequivocal differentiation between folic acid deficiency and vitamin B12 deficiency in the pathogenesis of megaloblastic anemia. Folio acid deficiency results in marked diminution of pulmonary C14 excretion (approximately 0.1 per cent of injection C14 in 1 hour) and marked prolongation of C14O2-specific activity Tmax (approximately 3 hours), while both parameters are normal (approximately 1 per cent and less than 1 hour, respectively) in patients with vitamin B12 deficiency and megaloblastic anemia. Measurement during periods of reticulocyte response to either folio acid or vitamin B12 demonstrate normal C14O2-specific activity Tmax but decreased pulmonary C14 excretion. These observations suggest that prolongation of C14O2-specific activity Tmax is a sensitive index of folic acid deficiency or block and that if Tmax is normal, pulmonary C14 excretion is a sensitive index of the relative partition of the active monocarbon pool between pathways for oxidation and pathways for nucleic acid synthesis. This type of breath analysis seems to provide a quantitative dynamic representation of metabolic function which may be particularly useful in differentiating between the alterations of intermediary metabolism that occur in patients with folic acid-deficient megaloblastic anemia and in patients with vitamin B12-deficient megaloblastic anemia.

N-(5-Arylazo-4-Pyrimidyl)-Amino-Acids as Growth Inhibitors of Streptococcus faecalis

IT was shown by Tanaka et al.1,2 that 5-arylazo pyrimidines having different groups (for example, hydroxyl, methyl or amino) at the 2, 4 and 6 positions are strong folio acid antagonists and that some of these possess marked anti-neoplastic properties. They also found that the nature of substituents in the benzene ring of the phenylazo radical was the determining factor for this activity.

A correlation between nuclear diameters of oral epithelial squamous cells and blood vitamin B12 levels of children with nutritional dystrophy. Studies on nutrition of children at Hirosaki area (83rd report).

It was reported recently that diameters of oral squamous epithelial cells were influenced by deficiency of vitamin B12 or of folic acid. The existence of deficiency in vitamin B12 or/and folio acid was highly probable among the children with nutritional dystrophy in. Hirosaki area. In 36 cases with nutritional dystrophy, the nuclear diameters of squamous epithelial cells were measured microscopically by using mouth washings, and their correlation to blood vitamin B12 levels, estimated nlicrohiologically, was examined. At the same time superposition of folic acid deficiency was checked by testing formiminoglutamic acid in urine. The correlation coefficients between blood vitamin B12 and the nuclear diameter of squamous epithelial cells were -0.72 in the cases without folio acid deficiency and -0.42 in those with it. Even though these two figures showed a not very significant difference, it may be said that the nuclear diameter of oral epithelial cells from nutritional dystrophy more closely correlated to blood vitamin B12 levels in the cases without folio acid deficiency than in those with it. In other words, folic acid deficiency, as was reported, also gave an influence on the nuclear diameter of epithelial cells, so a superposition of folio acid deficiency lessened the correlation coefficient between blood vitamin B12 levels and the nuclear diameters in our results.

Para-amino-benzoic acid and sulphanilamide in the nutrition of Neurospora crassa.

THE action of sulphanilamide, an antivitamin of p-amino-benzoic acid, has been traced to an impairment of the synthesis of methionine and adenine, besides some other compounds1. In some cases p-amino-benzoic acid could reverse the inhibitory effects of sulphanilamide, whereas folio acid could not2. In our present work, we studied the reversal of the toxicity of sulphanilamide in Neurospora crassa 8a (wild) and the substitution of p-amino-benzoie acid in a strain without the acid (No. 1633) of the same mould.

Enzymic cleavage of folic acid by extracts from human blood cells: I. Preparation and co-factor requirements of the enzyme system

1. 1. Preparation is described of an enzyme system from human blood which can degrade folic acid to yield p-aminobenzoylglutamic acid and 2-amino-4-hydroxy-6-formyl-pteridine. 2. 2. The enzyme system requires ATP, Mn ++ and glutathione as cofactors and shows optimum activity at pH 5. 3. 3. The enzyme is apparently present in blood in an inactive state. Activity is liberated on treatment with hydrochloric acid. 4. 4. Evidence is given for the presence of heat-labile inhibitors which may be separated from the active fraction by (NH 4) 2SO 4 fractionation. These inhibitors depress the cleavage of folic acid when the cofactors requirements are supplied by extracts prepared from blood but not when ATP, Mn ++ and glutathione are present. 5. 5. Thiol compounds like cystein or thioglycollic acid cannot replace glutathione as a cofactor for the enzyme. Coenzyme A can partially serve this purpose. 6. 6. The suggestion is made that these active mechanisms for cleavage of folio acid in animal tissues may be important for the metabolic disposal of folic acid, as also for the biosynthesis of biologically important unconjugated pteridines like 2-amino-4-hydroxy-6-formyl-pteridine which is a very potent inhibitor of xanthine oxidase.

Inhibiting action of some analogues of folic acid on the growth of plant tumours.

ANALOGUES of folio acid have been found capable of inhibiting the growth of the Rous sarcoma in chickens1 and sarcoma 180 in mice2, of causing a remission in leukaemic children3 and of prolonging the survival of leukaemic mice4. The effect of twelve of these analogues (all samples of folic acid and its analogues were kindly supplied by Lederle Laboratories, Pearl River, New York) on the growth of tumours induced by the crown gall bacterium on carrot tissue has been tested. Cylinders of tissue 10 mm. diameter × 6 mm. high were removed as described in a previous communication5, and inoculated with virulent crown gall bacteria. Four days later, when the first signs of tumour formation became visible along the line of the cambium, 0.05 ml. of a 1/1,000 solution of the folic acid analogue to be tested was dropped on to, and spread over, the surface of the tissue. The amount of substance applied was 0.05 mgm. per fragment. Sterile distilled water was applied to the control group. Twenty carrot fragments were used in each test. The accompanying table shows the percentage of fragments which had developed macroscopically visible tumours four weeks after treatment had been applied.

A New Synthesis of Pteridines

THERE is a growing biological interest in derivatives of pteridine (I: R1, R2, R3, R4 = H) as a source of antagonists for folic acid (I: R1 = OH; R2 = NH2 ; R4 = H; R3 = CH2.NH.C6H4.CO.NHCH(COOH): CH2CH2COOH-p), since this vitamin plays an important part in the growth of certain bacteria and normal and malignant tissue. Thus, Hertz1 has reported that abnormal growth in the chick genital tract evoked by stilbA"strol was inhibited by methyl folio acid (I: R1 = OH; R2 = NH2; R4 = CH3; R3 = CH2.NH.C6H4.CO.NHCH(COOH).CH2CH2-COOH-p), which is a powerful antagonist (Martin et al.2), an effect which was reversed by giving folic acid. Little et al.3 and Woll4 have reported inhibition of growth of the Rous chicken sarcoma by means of antagonists, and Bass and Freeman5 found that the inhibition of a lymphoma (lymphoma 6C3HED) in the mouse by mustard gas was to some extent prevented by giving folic acid. Meyer6 claims a favourable clinical effect in acute leukaemia with methylpteroic acid (I: R1 = OH; R2 = NH2; R4 = H; R3 = CH2.N(CH3)C6H4COOH-p). Other antagonists of simple structure are reported by Daniel et al.7.