Vitamin B12 Abstracts 8

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Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism.
            (Bertoglio et al., 2010) Download
OBJECTIVES:  The study objectives were to determine whether methyl B12 treatment improves behavioral measures in children with autism and whether improvement is associated with increased plasma concentrations of glutathione (GSH) and an increased redox ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), both of which have been previously identified to be low in children with autism. DESIGN:  This was a 12-week, double-blind, placebo-controlled, cross-over clinical trial of injectable methyl B12. Following this 12-week study, subjects were given the option of entering a 6-month open-label trial of methyl B12. SETTINGS/LOCATION:  All procedures took place at the UC Davis M.I.N.D. Institute. SUBJECTS:  Subjects were 3 to 8 years old with autism. INTERVENTIONS:  All subjects received 6 weeks of placebo and 6 weeks of methyl B12 at a dose of 64.5 mcg/kg every three days administered subcutaneously into the buttocks. OUTCOME MEASURES:  Blood for GSH analysis and behavioral assessments were obtained at baseline, week 6, and week 12. RESULTS:  Thirty (30) subjects completed the 12-week, double-blind study and 22 subjects completed the 6-month extension study. No statistically significant mean differences in behavior tests or in glutathione status were identified between active and placebo groups. Nine (9) subjects (30%) demonstrated clinically significant improvement on the Clinical Global Impression Scale and at least two additional behavioral measures. More notably, these responders exhibited significantly increased plasma concentrations of GSH and GSH/GSSG. CONCLUSIONS:  Comparison of the overall means between groups suggests that methyl B12 is ineffective in treating behavioral symptoms of autism. However, detailed data analysis suggests that methyl B12 may alleviate symptoms of autism in a subgroup of children, possibly by reducing oxidative stress. An increase in glutathione redox status (GSH/GSSG) may provide a biomarker for treatment response to methyl B12. Additional research is needed to delineate a subgroup of potential responders and ascertain a biomarker for response to methyl B12.


 

The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial.
            (Chiu et al., 2011) Download
INTRODUCTION:  Chronic, nonspecific low back pain is a difficult ailment to treat and poses an economic burden in terms of medical expenses and productivity loss. The aim of this study was to determine the efficacy and safety of intramuscular metylcobalamin in the treatment of chronic nonspecific low back pain. METHODS:  This was a double-blinded, randomised, controlled experimental study. 60 patients were assigned to either the methylcobalamin group or the placebo group. The former received intramuscular injections of 500 mcg parenteral methylcobalamin in 1 ml solution three times a week for two weeks, and the placebo group received 1 ml normal saline. Patients were assessed with Oswestry Disability Index questionnaire Version 2.0 and Visual Analogue Scale pain score. They were scored before commencement of the injections and at two months interval. RESULTS:  Of the 60 patients, 27 received the placebo injections and 33 were given methylcobalamin injections. A total of 58 patients were available for review at two months (placebo: n is 26; methylcobalamin: n is 32). There was a significant improvement in the Oswestry Disability Index and Visual Analogue Scale pain scores in the methylcobalamin group as compared with the placebo group (p-value less than 0.05). Only minor adverse reactions such as pain and haematoma at the injection sites were reported by some patients. CONCLUSION:  Intramuscular methylcobalamin is both an effective and safe method of treatment for patients with nonspecific low back pain, both singly or in combination with other forms of treatment.

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism.
            (Hendren et al., 2016) Download
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 ).

A vitamin B-12 supplement of 500 μg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status.
            (Hill et al., 2013) Download
Plasma vitamin B-12 is the most commonly used biomarker of vitamin B-12 status, but the predictive value for low vitamin B-12 status is poor. The urinary methylmalonic acid (uMMA) concentration has potential as a functional biomarker of vitamin B-12 status, but the response to supplemental vitamin B-12 is uncertain. A study was conducted to investigate the responsiveness of uMMA to supplemental vitamin B-12 in comparison with other biomarkers of vitamin B-12 status [plasma vitamin B-12, serum holotranscobalamin (holoTC), plasma MMA] in elderly people with moderately poor vitamin B-12 status. A double-blind, placebo-controlled, randomized 8-wk intervention study was carried out using vitamin B-12 supplements (500 μg/d, 100 μg/d, and 10 μg/d cyanocobalamin) in 100 elderly people with a combined plasma vitamin B-12 <250 pmol/L and uMMA ratio (μmol MMA/mmol creatinine) >1.5. All biomarkers had a dose response to supplemental vitamin B-12. Improvements in plasma vitamin B-12 and serum holoTC were achieved at cobalamin supplements of 10 μg/d, but even 500 μg/d for 8 wk did not normalize plasma vitamin B-12 in 8% and serum holoTC in 12% of people. The response in uMMA was comparable with plasma MMA; 15-25% of people still showed evidence of metabolic deficiency after 500 μg/d cobalamin for 8 wk. There was a differential response in urinary and plasma MMA according to smoking behavior; the response was enhanced in ex-smokers compared with never-smokers. uMMA offers an alternative marker of metabolic vitamin-B12 status, obviating the need for blood sampling.


 

Use of vitamin B12 in treatment of acute subdeltoid bursitis
(Klemes, 1953) Download
Fifty patients with acute bursitis were treated with large doses of vitamin B12 with gratifying results. 

Vitamin B12 in acute subdeltoid bursitis
            (Klemes, 1957)  Download
Several patients with acute shoulders showing calcium were given injections of 1,000 mcg of vitamin B12 with encouraging, and sometimes, dramatic results. Large doses of 1,000 mcg were given daily for a week or 10 days, and then every second day for a week or two, followed by spacing the intervals according to necessity. 

Effects of acetyl-L-carnitine and methylcobalamin for diabetic peripheral neuropathy: A multicenter, randomized, double-blind, controlled trial.
            (Li et al., 2016) Download
AIMS/INTRODUCTION:  To assess the efficacy and safety of acetyl-L-carnitine (ALC) on diabetic peripheral neuropathy compared with methylcobalamin (MC). MATERIALS AND METHODS:  This was a multicenter, randomized, parallel-group, double-blind, double-dummy, positive-controlled, non-inferior phase II clinical trial. Diabetic patients with abnormal nerve conduction test results were randomized in a 1:1 ratio to receive oral ALC 500 mg t.i.d. or MC 0.5 mg t.i.d. for 24 weeks. The neuropathy symptom score, neuropathy disability score and neurophysiological parameters were measured during follow up. RESULTS:  A total of 232 patients were randomized (ALC n = 117, MC n = 115), 88% of which completed the trial. At week 24, patients from both groups had significant reductions in both neuropathy symptom score and neuropathy disability score with no significant difference between two groups (neuropathy symptom score reduction: ALC vs MC 2.35 ± 2.23, P < 0.0001 vs 2.11 ± 2.48, P < 0.0001, intergroup P = 0.38; neuropathy disability score reduction ALC vs MC 1.66 ± 1.90, P < 0.0001 vs 1.35 ± 1.65, P < 0.0001, intergroup P = 0.23). Neurophysiological parameters were also improved in both groups. No significant difference was found between groups in the development of adverse events. CONCLUSIONS:  ALC is as effective as MC in improving clinical symptoms and neurophysiological parameters for patients with diabetic peripheral neuropathy over a 24-week period with good tolerance.


 

Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial.
            (Metaxas et al., 2017) Download
BACKGROUND:  Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12. Whenever alternative routes of administration exist, patient preferences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treatment, in a typical primary care population. METHODS:  Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly assigned to oral or IM treatment. Group O-oral was given 28 tablets of 1000 µg cyanocobalamin in a monthly punch card fitted with an electronic monitoring system. Group I-IM received four, weekly injections of 1000 µg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and analysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adher-ence and percentage of days with 2 dosing events were calcu-lated. Before and after 28 days of treatment, patients were asked to fill in a questionnaire about their preference for the therapy options and associated factors. RESULTS:  Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145-172], 49.0 pmol/l [40.4-57.5], 14.8 µmol/l [12.0-17.7] and 304 nmol/l [219-390], respective-ly, in group O-oral and 164 pmol/l [154-174], 50.1 pmol/l [38.7-61.6], 13.0 µmol/l [11.0-15.1] and 321 nmol/l [215-427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298-410] and HoloTc 156 pmol/l [116-196]; group I-IM: VB12 2796 pmol/l [1277-4314] and HoloTc 1269 pmol/l [103-2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7-16.8] and MMA 168 nmol/l [134-202]; group I-IM: Hcy 8.5 µmol/l [7.1-9.8] and MMA 156 nmol/l [121-190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninfe-rior to IM treatment was rejected. Average adherence to thera-py was 99.6 ± 1.1% and days with 2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration main-tained their preference in the case of oral treatment and changed their preference after IM treatment. CONCLUSIONS:  Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treat-ment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker re-sponse after IM treatment within a typical primary care popula-tion is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. (ClinicalTrials.gov ID NCT01832129).

Clinical Trial Assessing the Efficacy of Gabapentin Plus B Complex (B1/B12) versus Pregabalin for Treating Painful Diabetic Neuropathy.
            (Mimenza Alvarado and Aguilar Navarro, 2016)  Download
INTRODUCTION:  Painful diabetic neuropathy (PDN) is a prevalent and impairing disorder. The objective of this study was to show the efficacy and safety of gabapentin (GBP) plus complex B vitamins: thiamine (B1) and cyanocobalamine (B12) compared to pregabalin in patients with moderate to severe intensity PDN. METHOD:  Multicenter, randomized, blind study. Two hundred and seventy patients were evaluated, 147 with GBP/B1/B12 and 123 with PGB, with a 7/10 pain intensity on the Visual Analog Scale (VAS). Five visits (12 weeks) were scheduled. The GBP/B1 (100 mg)/B12 (20 mg) group started with 300 mg at visit 1 to 3600 mg at visit 5. The PGB group started with 75 mg/d at visit 1 to 600 mg/d at visit 5. Different safety and efficacy scales were applied, as well as adverse event assessment. RESULTS:  Both drugs showed reduction of pain intensity, without significant statistical difference (P = 0.900). In the GBP/B1/B12 group, an improvement of at least 30% on VAS correlated to a 900 mg/d dose, compared with PGB 300 mg/d. Likewise, occurrence of vertigo was lower in the GBP/B1-B12 group, with a significant statistical difference, P = 0.014. CONCLUSIONS:  Our study shows that GPB/B1-B12 combination is as effective as PGB. Nonetheless, pain intensity reduction is achieved with 50% of the minimum required gabapentin dose alone (800 to 1600 mg/d) in classic NDD trials. Less vertigo and dizziness occurrence was also observed in the GBP/B1/B12 group. This trial is registered with ClinicalTrials.gov NCT01364298.


 

Urinary methylmalonic acid/creatinine ratio: a gold standard test for tissue vitamin B12 deficiency.
            (Norman, 1999) Download
There is a need to evaluate vitamin B,, deficiency in the population accurately because millions of Americans apparently have tissue vitamin B,, deficiency and may respond to treatment if it is identified in time. The urinary M M N creatinine ratio test requires only a random, spot urine specimen and provides a non-invasive means to screen and accurately identify individuals who could benefit from vitamin B12 therapy.

Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial.
            (Parry-Strong et al., 2016) Download
UNLABELLED:  MAIM: To compare a single 1mg intramuscular hydroxocobalamin injection with a 3-month course of 1mg/day sublingual methylcobalamin supplements on serum vitamin B12 concentrations in participants withtype 2 diabetes treated with metformin. METHOD:  Participants on metformin treatment with vitamin B12 concentrations below 220pmol/L were recruited through hospital diabetes clinics and primary care practices. They were randomised to receive either the injection or sublingual treatment. The primary outcome was serum vitamin B12 level after 3 months adjusted for baseline assessed by analysis of covariance (ANCOVA). The trial was registered on the Australia New Zealand Clinical Trial registry (ACTRN12612001108808). RESULTS:  A total of 34 participants were randomised; 19 to the tablet, and 15 to the injection. The mean (SD) age, duration of diabetes, and duration of metformin use were, 64.2 (7.3) years, 13.7 (6.4) years, and 11.6 (5.0) years, respectively. After 3 months, the mean (SD) vitamin B12 was 372.1 (103.3) pmol/L in the tablet group (n=19) compared to 251.7 (106.8) pmol/L in the injection group (n=15), ANCOVA estimated difference -119.4 (95% CI -191.2 to -47.6), p=0.002. After 6 months, the mean (SD) serum B12 was 258.8 (58.7) pmol/L in the tablet group (n=17) and 241.9 (40.1) pmol/L in the injection group (n=15); ANCOVA estimated difference -15.2 (95% CI -50.3 to 19.8), p=0.38. Higher metformin dose was associated with lower serum B12 at 3 months, but not at baseline or 6 months. CONCLUSION:  Decreased serum vitamin B12 level in patients with type 2 diabetes who are treated with metformin can be corrected through treatment with either hydroxocobalamin injections or methylcobalamin sublingual supplements.


 

Therapeutic role of Vitamin B12 in patients of chronic tinnitus: A pilot study.
            (Singh et al., 2016) Download
True tinnitus is a phantom auditory perception arising from a source or trigger in the cochlea, brainstem, or at higher centers and has no detectable acoustic generator. The most accepted is the famous neurophysiologic model of Jastreboff, which stresses that tinnitus, is a subcortical perception and results from the processing of weak neural activity in the periphery. The aim of this study is to determine the role of Vitamin B12 in treatment of chronic tinnitus. In this randomized, double-blind pilot study, total 40 patients were enrolled, of which 20 in Group A (cases) received intramuscular therapy of 1 ml Vitamin B12 (2500 mcg) weekly for a period of 6 weeks and Group B (20) patients received placebo isotonic saline 01 ml intramuscular. The patients were subjected to Vitamin B12 assay and audiometry pre- and post-therapy. Of the total patients of tinnitus, 17 were Vitamin B12 deficient that is 42.5% showed deficiency when the normal levels were considered to be 250 pg/ml. A paired t-test showed that in Group A, patients with Vitamin B12 deficiency showed significant improvement in mean tinnitus severity index score and visual analog scale (VAS) after Vitamin B12 therapy. This pilot study highlights the significant prevalence of Vitamin B12 deficiency in North Indian population and improvement in tinnitus severity scores and VAS in cobalamin-deficient patients receiving intramuscular Vitamin B12 weekly for 6 weeks further provides a link between cobalamin deficiency and tinnitus thereby suggestive of a therapeutic role of B12 in cobalamin-deficient patients of tinnitus.

 


References

Bertoglio, K, et al. (2010), ‘Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism.’, J Altern Complement Med, 16 (5), 555-60. PubMed: 20804367
Chiu, CK, et al. (2011), ‘The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial.’, Singapore Med J, 52 (12), 868-73. PubMed: 22159928
Hendren, RL, et al. (2016), ‘Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism.’, J Child Adolesc Psychopharmacol, 26 (9), 774-83. PubMed: 26889605
Hill, MH, et al. (2013), ‘A vitamin B-12 supplement of 500 μg/d for eight weeks does not normalize urinary methylmalonic acid or other biomarkers of vitamin B-12 status in elderly people with moderately poor vitamin B-12 status.’, J Nutr, 143 (2), 142-47. PubMed: 23236022
Klemes, I. S. (1953), ‘Use of vitamin B12 in treatment of acute subdeltoid bursitis’, Ind Med Surg, 22 (8), 352-54. PubMed: 13069085
——— (1957), ‘Vitamin B12 in acute subdeltoid bursitis’, Ind Med Surg, 26 (6), 290-92. PubMed: 13428343
Li, S, et al. (2016), ‘Effects of acetyl-L-carnitine and methylcobalamin for diabetic peripheral neuropathy: A multicenter, randomized, double-blind, controlled trial.’, J Diabetes Investig, 7 (5), 777-85. PubMed: 27180954
Metaxas, C, et al. (2017), ‘Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial.’, Swiss Med Wkly, 147 w14421. PubMed: 28421567
Mimenza Alvarado, A and S Aguilar Navarro (2016), ‘Clinical Trial Assessing the Efficacy of Gabapentin Plus B Complex (B1/B12) versus Pregabalin for Treating Painful Diabetic Neuropathy.’, J Diabetes Res, 2016 4078695. PubMed: 26885528
Norman, EJ (1999), ‘Urinary methylmalonic acid/creatinine ratio: a gold standard test for tissue vitamin B12 deficiency.’, J Am Geriatr Soc, 47 (9), 1158-59. PubMed: 10484267
Parry-Strong, A, et al. (2016), ‘Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial.’, N Z Med J, 129 (1436), 67-75. PubMed: 27355231
Singh, C, et al. (2016), ‘Therapeutic role of Vitamin B12 in patients of chronic tinnitus: A pilot study.’, Noise Health, 18 (81), 93-97. PubMed: 26960786