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ObjectiveTo evaluate the efficacy and safety of intramuscular ultra-high-dose methylcobalamin in patients with amyotrophic lateral sclerosis (ALS).Methods373 patients with ALS (El Escorial definite or probable; laboratory-supported probable; duration ≤36 months) were randomly assigned to placebo, 25 mg or 50 mg of methylcobalamin groups. The primary endpoints were the time interval to primary events (death or full ventilation support) and changes in the Revised ALS Functional Rating Scale (ALSFRS-R) score from baseline to week 182. Efficacy was also evaluated using post-hoc analyses in patients diagnosed early (entered ≤12 months after symptom onset).ResultsNo significant differences were detected in either primary endpoint (minimal p value=0.087). However, post-hoc analyses of methylcobalamin-treated patients diagnosed and entered early (≤12 months’ duration) showed longer time intervals to the primary event (p<0.025) and less decreases in the ALSFRS-R score (p<0.025) than the placebo group. The incidence of treatment-related adverse events was similar and low in all groups.ConclusionAlthough ultra-high-dose methylcobalamin did not show significant efficacy in the whole cohort, this treatment may prolong survival and retard symptomatic progression without major side effects if started early.Trial registration number NCT00444613.

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 . . .

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 – . . .

Background Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I–II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders. Objective The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I–II cervical sprains. Methods We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0. Results A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (− 3.1 ± − 1.5 and − 2.6 ± − 1.1 cm, respectively) measured using the VAS ( p  = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p  = 0.028). A lower proportion of adverse events was reported when using the FDC. Conclusions The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I–II cervical sprains. Clinical Trials Registration NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).

A randomized placebo-controlled trial found a significant negative interaction between aspirin and B vitamins in cognitive functioning in older people with mild cognitive impairment (MCI). To validate this finding, we pooled data of this trial with that of a similar B-vitamin trial (VITACOG) to examine the effectiveness of B vitamins and their interactions with aspirin in improving global cognitive functioning and slowing brain atrophy in older people with MCI. Pooled post-hoc analyses of two randomized placebo-controlled trials. In total, 545 older people with MCI were included in the study. Placebo or B-vitamin supplements (vitamin B12, folic acid with or without vitamin B6) for 24 months. The primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). The secondary outcomes were CDR-sum of box score (CDR-SOB), memory Z-score, executive function Z-score, and whole brain atrophy rate. 71 (26.2%) and 83 (30.3%) subjects in the active and placebo group respectively were aspirin users. Overall, B vitamins reduced whole brain atrophy rate significantly (P = 0.003), but did not have significant effect on CDR-global, CDR-SOB, memory and executive function. Aspirin use had significant negative interaction effects on B vitamins in CDR-global and CDR-SOB (Beta = 0.993, P = 0.038, and Beta = 0.583, P = 0.009, respectively), but not in memory or executive function Z-scores. Among aspirin non-users, B-vitamin group subjects had more favourable changes in CDR-global and CDR-SOB (P = 0.019 and 0.057, respectively). B vitamins significantly slowed brain atrophy in aspirin non-users (P = 0.001), but not in aspirin users, though the interaction term was not significant (Beta = 0.192, P = 0.276). In older people with MCI, B vitamins had significantly favourable effects on global cognitive functioning and whole brain atrophy rate in those who were not taking aspirin, but not in aspirin users.

Objective: Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. Methods: A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 μg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. Results: A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure – the clinician rated CGI-I score – was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2–0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine (p = 0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p = 0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Conclusions: Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 (clinicaltrials.gov1).

AbstractObjectiveTo evaluate whether methylcobalamin could effectively and safely prevent hand-foot syndrome in patients with human epidermal growth factor receptor 2 (HER2) negative early breast cancer receiving adjuvant capecitabine treatment.DesignMulticentre, double blind, randomised, placebo controlled, phase 3 trial.SettingSeven hospitals in China between January 2022 and February 2024.ParticipantsWomen aged 18-75 years with pathologically confirmed HER2 negative early breast cancer who were scheduled to receive adjuvant capecitabine treatment.InterventionsEligible patients were randomly assigned in a 1:1 ratio to receive methylcobalamin at a dose of 0.5 mg orally, three times daily, or a placebo for a maximum of 24 weeks.Main outcome measuresThe primary endpoint was the incidence of grade ≥2 hand-foot syndrome occurring for the first time during capecitabine treatment in the intention-to-treat analysis.Results234 patients were randomly assigned to receive methylcobalamin (n=117) or placebo (n=117) and were included in the intention-to-treat and safety analysis. Grade ≥2 hand-foot syndrome occurred in 17 (14.5%) of 117 patients in the methylcobalamin group and 34 (29.1%) of 117 patients in the placebo group (risk difference −14.5%, 95% confidence interval −24.9% to −4.1%; one sided P value=0.003). The rate of reduction or discontinuation of capecitabine treatment because of hand-foot syndrome was 7.7% (9 of 117) in the methylcobalamin group and 13.7% (16 of 117) in the placebo group (risk difference −6.0%, 95% confidence interval −13.9% to 1.9%). The two groups showed similar incidence of any other adverse events (88 (75.2%) in the methylcobalamin group and 95 (81.2%) in the placebo group). No methylcobalamin specific adverse events were observed.ConclusionsOral methylcobalamin significantly lowered the severity of hand-foot syndrome by reducing the incidence of grade ≥2 symptoms without unexpected safety concerns in women with HER2 negative early breast cancer who were receiving adjuvant capecitabine treatment. The findings support the use of methylcobalamin to prevent capecitabine associated severe hand-foot syndrome in this patient population.Trial registrationClinicalTrials.gov NCT05165069.

Prior observational studies have found elevated homocysteine levels among patients with Alzheimer's disease and inverse associations between homocysteine levels and performance on cognitive tests among community-dwelling older adults. In this two-year randomized trial involving healthy elderly persons with elevated homocysteine levels, treatment with folate and vitamins B 12 and B 6 lowered plasma homocysteine levels but did not improve cognitive performance. In healthy elderly persons with elevated homocysteine levels, treatment with folate and vitamins B 12 and B 6 lowered plasma homocysteine levels but did not improve cognitive performance. The prevalence of cognitive impairment increases with age and represents a major public health concern in aging populations. There is evidence that circulating homocysteine concentrations may be a modifiable risk factor for cognitive decline. 1 Homocysteine concentrations have been reported to be higher in persons with suspected or confirmed Alzheimer's disease than in age-matched controls. 2 – 4 Alzheimer's disease was more likely to develop over an eight-year period in persons with plasma homocysteine concentrations above 14 μmol per liter than among those with lower concentrations. 5 Furthermore, the results of several cross-sectional and prospective studies of community-based older adults indicate that homocysteine is . . .

ObjectivesTo compare the effectiveness of oral versus intramuscular (IM) vitamin B12 (VB12) in patients aged ≥65 years with VB12 deficiency.DesignPragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain).Participants283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm.InterventionsThe IM arm received 1 mg VB12 on alternate days in weeks 1–2, 1 mg/week in weeks 3–8 and 1 mg/month in weeks 9–52. The oral arm received 1 mg/day in weeks 1–8 and 1 mg/week in weeks 9–52.Main outcomesSerum VB12 concentration normalisation (≥211 pg/mL) at 8, 26 and 52 weeks. Non-inferiority would be declared if the difference between arms is 10% or less. Secondary outcomes included symptoms, adverse events, adherence to treatment, quality of life, patient preferences and satisfaction.ResultsThe follow-up period (52 weeks) was completed by 229 patients (80.9%). At week 8, the percentage of patients in each arm who achieved normal B12 levels was well above 90%; the differences in this percentage between the oral and IM arm were −0.7% (133 out of 135 vs 129 out of 130; 95% CI: −3.2 to 1.8; p>0.999) by per-protocol (PPT) analysis and 4.8% (133 out of 140 vs 129 out of 143; 95% CI: −1.3 to 10.9; p=0.124) by intention-to-treat (ITT) analysis. At week 52, the percentage of patients who achieved normal B12 levels was 73.6% in the oral arm and 80.4% in the IM arm; these differences were −6.3% (103 out of 112 vs 115 out of 117; 95% CI: −11.9 to −0.1; p=0.025) and −6.8% (103 out of 140 vs 115 out of 143; 95% CI: −16.6 to 2.9; p=0.171), respectively. Factors affecting the success rate at week 52 were age, OR=0.95 (95% CI: 0.91 to 0.99) and having reached VB12 levels ≥281 pg/mL at week 8, OR=8.1 (95% CI: 2.4 to 27.3). Under a Bayesian framework, non-inferiority probabilities (Δ>−10%) at week 52 were 0.036 (PPT) and 0.060 (ITT). Quality of life and adverse effects were comparable across groups. 83.4% of patients preferred the oral route.ConclusionsOral administration was no less effective than IM administration at 8 weeks. Although differences were found between administration routes at week 52, the probability that the differences were below the non-inferiority threshold was very low.Trial registration numbersNCT 01476007; EUDRACT (2010-024129-20).

Deficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children. In a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention. Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 μmol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes. Our findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children. ClinicalTrials.gov NCT00717730.