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Objective We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. Methods In a 32-week, open-label, two-way cross-over study, patients ( n  = 20, seven men, aged 35–70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n  = 10) or to receive the opposite sequence of treatments (arm B, n  = 10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. Results In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0–157) vs. 111 (73.7–175), P  = 0.32; week 32: 103 (55.8–173) vs. 83.6 (27.4–129), P  = 0.24]. After 16 weeks, the mean±SEM PASI decreased from 20.1 ± 2.1 to 8.8 ± 1.3 in arm A, while a greater reduction from 27.2 ± 2.1 to 5.1 ± 1.0 occurred in arm B ( P  < 0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho = 0.59, P  = 0.008) or RBC folate concentration (rho = 0.56, P  = 0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. Conclusion The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.

Oral folinic acid has shown potential to improve symptoms in children with autism spectrum disorder (ASD). However, randomized controlled trials (RCTs) are limited. This double-blind, placebo-controlled RCT aimed to compare changes in Childhood Autism Rating Scale (CARS) scores in children with ASD aged 2-10 years, among folinic acid (2 mg/kg/day, maximum of 50 mg/day) and placebo groups at 24 weeks, in comparison with baseline. Both the groups received standard care (ABA and sensory integration therapy). Secondary objectives included changes in behavioral problems measured by the Child Behavior Checklist (CBCL) and serum levels of anti-folate receptor autoantibodies and folic acid, correlated with changes in autism symptom severity. Out of the 40 participants recruited in each group, 39 and 38 participants completed the 24-week follow-up in the folinic acid and placebo groups, respectively. The change in CARS score was higher in the folinic acid group (3.6 ± 0.8) compared to the placebo group (2.4 ± 0.7, p < 0.001). Changes in CBCL total score and CBCL internalizing score were also better in the folinic acid group (19.7 ± 9.5 vs. 12.6 ± 8.4 and 15.4 ± 7.8 vs. 8.5 ± 5.7, p < 0.001 for both). High-titer anti-folate receptor autoantibodies were positive in 32/40 and 33/40 cases in the folinic acid and placebo groups, respectively (p = 0.78). In the placebo group, improvement in CARS score was comparable regardless of autoantibody status (p = 0.11), but in the folinic acid group, improvement was more pronounced in the high-titer autoantibody group (p = 0.03). No adverse reactions were reported in either group. Oral folinic acid supplementation is effective and safe in improving ASD symptoms, with more pronounced benefits in children with high titers of folate receptor autoantibodies.  CTRI/2021/07/034901, dated 15-07-2021. • Folate receptor autoantibodies are more prevalent in children with autism spectrum disorder (ASD) compared to typically developing children. • Folate receptor autoantibodies play a significant role in the neuropathogenesis of autism spectrum disorder. • Add-on oral folinic acid supplementation is safe and effective in reducing the severity of symptoms in children with ASD. • The clinical benefits are more pronounced in children with high titers of folate receptor autoantibodies.

Background/Aims. Low serum folate levels can alter inflammatory reactions. Both phenomena have been linked to Alzheimer’s disease (AD), but the effect of folic acid on AD itself is unclear. We quantified folate supplementation’s effect on inflammation and cognitive function in patients with AD over the course of 6 months. Methods. Patients newly diagnosed with AD (age > 60 years; n = 121 ; mild to severe; international criteria) and being treated with donepezil were randomly assigned into two groups with (intervention group) or without (control group) supplemental treatment with folic acid (1.25 mg/d) for 6 months. The Mini-Mental State Examination (MMSE) was administered to all patients at baseline and follow-up, and blood samples were taken before and after treatment. We quantified serum folate, amyloid beta (Aβ), interleukin-6 (IL-6), tumor necrosis factor α (TNFα), plasma homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the mRNA levels of presenilin (PS), IL-6, and TNFα in leukocytes. Data were analyzed using a repeated-measures mixed model. Results. The mean MMSE was slightly increased in the intervention group compared to that in the control group ( P < 0.05 ). Posttreatment, plasma SAM and SAM/SAH levels were significantly higher ( P < 0.05 ), while Aβ 40, PS1-mRNA, and TNFα-mRNA levels were lower in the intervention group than in the control group ( P < 0.05 ). The Aβ 42/Aβ 40 ratio was also higher in the intervention group ( P < 0.05 ). Conclusions. Folic acid is beneficial in patients with AD. Inflammation may play an important role in the interaction between folic acid and AD. This trial is registered with clinical trial registration number ChiCTR-TRC-13003246.

In epidemiologic studies, the plasma total homocysteine level has been found to be a risk factor for cardiovascular disease. In the HOPE-2 trial of high-risk patients, treatment with folic acid, vitamin B 12 , and vitamin B 6 reduced plasma total homocysteine levels. However, treatment with B vitamins was not associated with a reduction in cardiovascular risk. Treatment with folic acid, vitamin B 12 , and vitamin B 6 reduced plasma total homocysteine levels. However, treatment with B vitamins was not associated with a reduction in cardiovascular risk. Numerous studies suggest that homocysteine may be a modifiable risk factor for cardiovascular disease. In experimental studies, homocysteine causes oxidative stress, damages endothelium, and enhances thrombogenicity. 1 – 3 In general, epidemiologic studies show an independent and graded association between homocysteine levels and cardiovascular risk. 4 – 8 The observational data suggest that even mild-to-moderate elevations in homocysteine increase cardiovascular risk; this observation is important, because such increases are common and can easily be corrected with safe and inexpensive therapy. Folic acid is the most important dietary determinant of homocysteine; daily supplementation with 0.5 to 5.0 mg typically lowers plasma homocysteine levels by about . . .

Low folate and raised homocysteine concentrations in blood are associated with poor cognitive performance in the general population. As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 50–70 years with raised plasma total homocysteine and normal serum vitamin B 12 at screening, we report here the findings for the secondary endpoint: the effect of folic acid supplementation on cognitive performance. Our randomised, double blind, placebo controlled study took place between November, 1999, and December, 2004, in the Netherlands. We randomly assigned 818 participants 800 μg daily oral folic acid or placebo for 3 years. The effect on cognitive performance was measured as the difference between the two groups in the 3-year change in performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov with trial number NCT00110604. Serum folate concentrations increased by 576% (95% CI 539 to 614) and plasma total homocysteine concentrations decreased by 26% (24 to 28) in participants taking folic acid compared with those taking placebo. The 3-year change in memory (difference in Z scores 0·132, 95% CI 0·032 to 0·233), information processing speed (0·087, 0·016 to 0·158) and sensorimotor speed (0·064, −0·001 to 0·129) were significantly better in the folic acid group than in the placebo group. Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.

Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. We did a randomised, placebo-controlled trial, of children aged 1–35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12·5 mg) and folic acid (50 μg; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1–11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25 524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2–23, p=0·02) more likely to die or need treatment in hospital for an adverse event and 11% (1–23%, p=0·03) more likely to be admitted to hospital; there were also 15% (−7 to 41, p=0·19) more deaths in these groups. Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

The aim of this study was to assess the effect of nutrition education and counseling using health belief health model constructs along with iron-folic acid supplementation on hemoglobin level and adherence to IFAs during pregnancy. The study was a three-month quasi-experimental study design in Butajira town, Ethiopia. Community-based nutrition education and counseling sessions using the Health belief model, and IFAS for six weeks were given to the pregnant women. Compliance with iron-folic acid supplementation (IFAS) was assessed using pill counts based on the number of remaining pills in the retained prescribed bottles or strips. End-line data were collected from 97 interventions and 96 control groups of pregnant women after 6 weeks of nutrition education interventions. The analysis of the effect of the intervention was done using difference-in-difference and a generalized estimation equation (GEE) approach. At the end of the nutrition education intervention, there was a significant drop in the proportion of anemia in the intervention group compared to the control group. The prevalence of anemia among the intervention group declined from 27.8% at baseline to 7.2% after intervention. The change in the knowledge score regarding IFAS and maternal adherence to IFAS were significantly higher in the intervention group as compared to the control group ( p  < 0.001). In this study, the odds of adherence to IFA supplementation were 2.26 (95% CI 1.55 to 3.29) times higher among those who received nutrition education interventions as compared to the control group. Implementation of community-based nutrition education and counseling along with IFAS improved the hemoglobin level and adherence to IFAS among pregnant women. Therefore, there is need to integrate community-based nutrition education approach by using HBM constructs with antenatal IFAS distribution to improve supplementation and hemoglobin level of pregnant women.

Observational reports have found that lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Treatment with folic acid and vitamin B 12 , with or without vitamin B 6 , lowers plasma homocysteine levels. In the NORVIT trial in patients after myocardial infarction, such therapy did not decrease the rate of recurrent infarction, stroke, and sudden death. After myocardial infarction, treatment with folic acid and vitamin B 12 , with or without vitamin B 6 , did not decrease the rate of recurrent infarction, stroke, and sudden death. Case–control as well as prospective studies have demonstrated that the plasma total homocysteine level is a strong, graded, and independent risk factor for coronary heart disease (CHD) and stroke. 1 – 3 Evidence from studies involving so-called mendelian randomization, 4 demonstrating an association between CHD and the 677C→T methylenetetrahydrofolate reductase polymorphism, has provided additional support for a causal relation between homocysteine and CHD. 5 , 6 Plasma total homocysteine can be lowered with the B vitamins folic acid and vitamin B 12 , 7 and persons with high plasma levels or dietary intake of folate and vitamin B 6 have a decreased risk of CHD. 8 – . . .

Adequate micronutrient status during adolescence can break the inter-generational cycle of malnutrition. This study evaluated the effect of community-based weekly iron-folic acid supplementation (WIFAS) on serum ferritin (SF), serum folate (SFol) and hemoglobin concentration (Hb) among adolescent girls. A community-based, individually randomized-controlled trial (RCT) was conducted in four villages of Wolaita and Hadiya zones. Adolescent girls (n = 226) aged 10–19 years were recruited and randomly assigned (n = 113/group) into: (i) WIFAS and (ii) control (no intervention) groups. Anthropometry, Hb concentration, and serum ferritin (SF), SFol, and C-reactive protein (CRP) was analyzed at baseline and endline. Baseline Hb, SF, SFol and CRP concentrations were similar in both groups (P > 0.05). About 47–49% of adolescents had marginal iron store (< 50 µg/l). Hb, SF, and SFol concentrations increased in the intervention group, but not in the control group (P < 0.05). Marginal iron store decreased from 49 to 12% after 3-months of WIFAS; whereas, the proportion of adolescents with elevated SF (> 15 µg/l) was slightly higher in the WIFAS than in the control group (P = 0.06). After adjusting for confounding factors in the multiple linear regression model, a three-months WIFAS intervention was associated with an improvement of 4.10 ng/ml in serum folate, 39.1 μg/l in serum ferritin, and 1.2 g/dl in hemoglobin concentration relative to the control group (P < 0.001). WIFAS intervention for three-months was effective in reducing iron and folate deficiency in adolescent girls. Future studies should evaluate the long-term impact of intermittent WIFAS.

ObjectivesThe aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment.MethodsIn this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration–time curve from study drug infusion to infinity (AUC0-inf). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24.ResultsThe 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.ConclusionsThree-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.Trial registration numberNCT01274182; Results.