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[Reducing toxicity of methotrexate with folic acid].

BACKGROUND: Methotrexate is considered to have the best ratio of efficacy to toxicity of the disease modifying antirheumatic drugs. Recently it has been shown to enhance the life expectancy of patients with rheumatoid arthritis. Some 30-60% of RA patients discontinue MTX treatment within 1 year because of side-effects. In this review, the current data about supplementation with folate or folinic acid and their effect on the toxicity and efficacy of low-dose methotrexate therapy are analysed. METHODS: A Medline search was performed using "folate", "folic acid", "folinic acid", "homocysteine", "methotrexate", "cardiovascular", "heart infarction" and "rheumatoid arthritis" as search terms. The relevant literature was reviewed and other papers referred to as references were explored. CONCLUSION: Both folate and folinic acid reduce methotrexate toxicity and the discontinuation rate, and decrease methotrexate-induced hyperhomocysteinemia. Folate is less expensive, more secure and easier to handle than folinic acid. The efficacy of methotrexate probably decreases slightly, but the benefit outweighs the risk. Folate supplementation should, therefore, be routinely prescribed to every patient taking low-dose methotrexate.

Antirheumatic Agents↗

Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools.

In a 10-wk study of folate metabolism in nonpregnant women (21-27 y, n -6 per group), subjects were fed a diet containing approximately 68 nmol/d (30 microg/d) folate from food. The remainder of the ingested folate was provided as folic acid in apple juice (as nonlabeled during wk 1-2, as [2H2]folic acid during wk 3-10) to yield a constant intake of 454, 680 or 907 nmol/d (200, 300 or 400 microg/d). Isotopic enrichment of total urinary folate and the primary catabolite para-acetamidobenzoylglutamate (ApABG) was determined. Isotopic enrichment of ApABG served as an indicator of labeling of tissue folates. A kinetic model consisting of fast- and slow-turnover nonsaturable pools and a saturable slow-turnover pool, with provisions for urinary and fecal excretion, catabolism and enterohepatic circulation, yielded a close fit to the data. Mean residence times for total body folate were 212, 169 and 124 d for folate intakes of 454, 680, and 907 nmol/d, respectively. The model predicted that variation in folate intake over this range had little effect on the mass of the large saturable folate pool; however, the fast-turnover nonsaturable pools increased in proportion to folate intake, whereas the slow nonsaturable pool also tended to increase. This model will aid in evaluation of folate turnover and in predicting kinetic consequences of physiologic conditions associated with altered folate requirements.

Adult↗

Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification.

BACKGROUND AND PURPOSE: The introduction of cereal grain folic acid fortification in 1998 has reduced homocyst(e)ine (tHcy) concentrations in the US population. We performed a case-control study to determine the risk of stroke and transient ischemic attack (TIA) associated with tHcy and low vitamin status in a postfortification US sample. METHODS: Consecutive cases with new ischemic stroke/TIA were compared with matched controls. Fasting tHcy, folate, pyridoxal 5'-phosphate (PLP), B12, and MTHFR 677C-->T genotype were measured. RESULTS: Mean PLP was significantly lower in cases than controls (39.97 versus 84.1 nmol/L, P<0.0001). After stroke risk factors were controlled for, a strong independent association was present between stroke/TIA and low PLP (adjusted odds ratio [OR], 4.6; 95% CI, 1.4 to 15.1; P<0.001) but not elevated tHcy (OR, 0.92; 95% CI, 0.4 to 2.1). CONCLUSIONS: Low B6 but not tHcy was strongly associated with cerebrovascular disease in this postfortification, folate-replete sample.

Case-Control Studies↗

Giardiasis: haematological status and the absorption of vitamin B12 and folic acid.

The haematological status, as well as the fractional absorptions of folic acid (FAFol) and vitamin B12 (FAB12) were studied in 29 children aged 0.7-13.5 years (mean 3.3 years) with chronic diarrhoea due to giardiasis. Small intestinal biopsies revealed mucosal damage in 20 children; the biopsies of the remaining nine children were normal. At the initial investigation the FAFol and FAB12 values were below normal in approximately one-sixth and one-third of patients, respectively. Bacterial overgrowth of the small intestinal tract did not seem to play a role in FAB12 malabsorption. About one-fifth of patients had mild anaemia. None of the patients showed FAB12 insufficiency and only one patient suffered from folate depletion. At follow-up, FAFol, FAB12, haemoglobin and Erc-folate concentrations increased significantly while P-B12 and P-folate remained unchanged. Iron status, as well as dietary intake of iron, appeared insufficient prior to, as well as after treatment. Serum iron, transferrin saturation and haemoglobin concentrations were lower in patients who had acquired the disease abroad or suffered from persistent diarrhoea.

Child↗

Metabolic capacity of Bacillus subtilis for the production of purine nucleosides, riboflavin, and folic acid.

We developed a stoichiometric model of Bacillus subtilis metabolism for quantitative analysis of theoretical growth and biochemicals production capacity. This work concentrated on biochemicals that are derived from the purine biosynthesis pathway; inosine, guanosine, riboflavin, and folic acid. These are examples of commercially relevant biochemicals for which Bacillus species are commonly used production hosts. Two previously unrecognized, but highly desirable properties of good producers of purine pathway-related biochemicals have been identified for optimally engineered product biosynthesis; high capacity for reoxidation of NADPH and high bioenergetic efficiency. Reoxidation of NADPH, through the transhydrogenase or otherwise, appears to be particularly important for growth on glucose, as deduced from the corresponding optimal carbon flux distribution. The importance of cellular energetics on optimal performance was quantitatively assessed by including a bioenergetic efficiency parameter as an unrestricted, ATP dissipating flux in the simulations. An estimate for the bioenergetic efficiency was generated by fitting the model to experimentally determined growth yields. The results show that the maximum theoretical yields of all products studied are limited by pathway stoichiometry at high bioenergetic efficiencies. Simulations with the estimated bioenergetic efficiency of B. subtilis, growing under glucose-limiting conditions, indicate that the yield of these biochemicals is primarily limited by energy and thus is very sensitive to the process conditions. The maximum yields that can reasonably be expected with B. subtilis on glucose were estimated to be 0.343, 0.160, and 0.161 (mol product/mol glucose) for purine nucleosides, riboflavin, and folic acid, respectively. Potential strategies for improving these maximum yields are discussed.

Bacillus↗

Targeted gene delivery to cancer cells with nanometric DNA particles enveloped with folic acid using a polymerisable anchor.

Progress in the design of gene delivery system is vital for cancer gene therapy since many physiological and intracellular barriers remain. We have developed a technology for condensing genes into nanometric delivery systems. In this paper, we present a novel strategy for decorating 30 nm DNA particles with folic acid for cancer cell recognition. Physicochemical and biological experiments show that these DNA complexes selectively bind to cells expressing the corresponding folic acid receptor.

Carrier Proteins↗

Adding zinc to supplemental iron and folic acid does not affect mortality and severe morbidity in young children.

Studies have found a substantial reduction in diarrhea and respiratory morbidity in young children receiving zinc supplementation. The impact of daily zinc supplementation administered with iron plus folic acid (IFA) in young children on all-cause hospitalizations and mortality in comparison with IFA alone was evaluated. In a double blind cluster-randomized controlled trial, 94,359 subjects aged 1-23 mo were administered a daily dose of zinc plus IFA or IFA alone for a duration of 12 mo after enrollment. The intervention group tablet contained 10 mg of elemental zinc, 12.5 mg of iron, and 50 microg of folic acid. The control group tablets were similar except that they contained a placebo for zinc. Infants aged <6 mo were administered half a tablet, and those older received 1 tablet dissolved in breast milk or water. Hospitalizations were captured by trained study physicians through the surveillance of 8 hospitals. Deaths and hospitalizations were ascertained through visits to households by study supervisors once every 2 mo. The overall death rates did not differ significantly between the 2 groups when adjusted for cluster randomization (hazard ratio = 1.02, 95% CI 0.87, 1.19). Zinc and IFA supplementation compared with IFA alone did not affect adjusted hospitalization rates (overall rate ratio = 1.08, 95% CI 0.98, 1.19; diarrhea-specific rate ratio = 1.15, 95% CI 0.99, 1.34; or pneumonia-specific rate ratio = 1.09, 95% CI 0.94, 1.25). The lack of impact of zinc on mortality and hospitalization rates in this study may have been due to the use of lower daily zinc dosing than used in some of the morbidity prevention trials or from an interaction between zinc and iron, where the addition of iron may have adversely affected potential effects of zinc on immune function and morbidity. Future research should address iron and zinc interaction effects on important functional outcomes.

Body Weight↗

[The assessment of the influence of natural coffee and its modified form on the level of homocysteine, vitamin B6 and folic acid in healthy volunteers].

UNLABELLED: The aim of our investigation was the assessment of the influence of natural coffee and that modified by water and pressure extraction (60% less of 2-methyl isoborneol) on the level of homocysteine, folic acid and vitamin B6 in healthy volunteers. MATERIAL AND METHODS: The study was conducted on 36 healthy volunteers. 20 women and 16 men; smokers constituted half of the group. The study was conducted as a double blind trial (coffee without labels) after randomization into two groups. Initially for 4 weeks, one group drank natural coffee and the other a modified one. After four weeks there was a 28-day break in drinking coffee, after which the groups swapped roles and another trial lasted for the subsequent 4 weeks. All people examined drank three servings of coffee a day brewed from 13 g of material in 180 ml of boiling water. Throughout the entire experiment the examined subjects did not change their diets and did not take any vitamin supplements. Blood for analysis was drawn four times and the following analyses were carried out. homocysteine, folic acid, vitamin B6 total, LDL and HDL-cholesterol, triglicerides, Lp(a) and fibrinogen. RESULTS: We found a significant increase level of plasma homocysteine from 9.6 to 11.4 micromol/l (p < 0.001) in persons drinking natural, unfiltered coffee. However drinking modified coffee free from irritants resulted in a tendency towards lowering the level of homocysteine (from 9.1 to 8.7 micromol/l). CONCLUSIONS: From the above study it may be concluded that lowering the content of irritants in coffee results in reducing its undesired influence on the homocysteine level. Reduction of natural coffee consumption or its change on coffee with lowering the content of irritants should be recommended to cardiovascular disease persons.

Adult↗

Postpartum folic acid supplementation of adolescents: impact on maternal folate and zinc status and milk composition.

The objectives of the present study were to assess the impact of lactation on the folate status of adolescents and determine the effect of ingestion of a low-dose postpartum (PP) folic acid supplement on maternal folate and zinc status and milk composition. Pregnant adolescents (aged 14-19 y; n = 71) were recruited; those who initiated breast-feeding on delivery were randomly assigned to a folic acid supplement lactating (SL; 300 micrograms/d, n = 14) group or to a placebo lactating (PL; n = 15) group. Subjects who initiated formula feeding were given a placebo (FF; n = 18). Dietary intakes (two 24-h recalls) were recorded and blood and milk samples were collected at 4, 8, and 12 wk PP. Of the adolescents, 71%, 48%, 67%, and 60% had folate, iron, vitamin B-12, and zinc intakes, respectively, below their predicted requirements. Despite this, most blood indexes were within normal ranges, probably reflecting the subjects' use of supplements during pregnancy. Red blood cell (r = -0.49, P < 0.05) and plasma (r = -0.42, P = 0.08) folate concentrations were negatively correlated with milk zinc concentrations. Mean red blood cell folate content declined between 4 and 12 wk PP among PL (31%) and FF (34%) subjects (P < 0.05) but not among SL subjects. Hence, 300 micrograms folic acid/d was sufficient to prevent a decline in blood folate values of these adolescents PP.

Adolescent↗