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Sa1100 Randomized Open Label Trial Comparing Efficacy of Oral Versus Intramuscular Vitamin B12 Supplementation for Treatment of Vitamin B12 Deficiency
... However, after the discovery of passive, transporter-independent vitamin B 12 absorption, the effectiveness of its oral applications has been increasingly re-evaluated. Thus, high vitamin B 12 doses (1000-2000 µg of CNCbl) are usually administered to ensure sufficient absorption to meet daily needs, even in the absence of transporter-mediated absorption [66][67][68][69][70][71]. The main conclusion of these studies, as well as of a Cochrane review on the efficacy of the oral versus the intramuscular route of vitamin B 12 administration for the treatment of its deficiency, is that both application routes are similarly safe and effective in normalizing vitamin B 12 serum concentrations [66][67][68][69][70][71][72]. ...
... Thus, high vitamin B 12 doses (1000-2000 µg of CNCbl) are usually administered to ensure sufficient absorption to meet daily needs, even in the absence of transporter-mediated absorption [66][67][68][69][70][71]. The main conclusion of these studies, as well as of a Cochrane review on the efficacy of the oral versus the intramuscular route of vitamin B 12 administration for the treatment of its deficiency, is that both application routes are similarly safe and effective in normalizing vitamin B 12 serum concentrations [66][67][68][69][70][71][72]. These studies also highlight the main benefits of oral over the intramuscular route of vitamin B 12 application, such as reduced patient injection-related discomfort and increased patient convenience, reduced risk of bleeding in anticoagulated patients, and reduced number of hospital visits [66][67][68][69][70][71][72]. ...
... The main conclusion of these studies, as well as of a Cochrane review on the efficacy of the oral versus the intramuscular route of vitamin B 12 administration for the treatment of its deficiency, is that both application routes are similarly safe and effective in normalizing vitamin B 12 serum concentrations [66][67][68][69][70][71][72]. These studies also highlight the main benefits of oral over the intramuscular route of vitamin B 12 application, such as reduced patient injection-related discomfort and increased patient convenience, reduced risk of bleeding in anticoagulated patients, and reduced number of hospital visits [66][67][68][69][70][71][72]. In addition to these advantages, the use of orally administered vitamin B 12 also results in a significant reduction in healthcare costs [64,65,73,74]. ...
Vitamin B12, also known as the anti-pernicious anemia factor, is an essential micronutrient totally dependent on dietary sources that is commonly integrated with food supplements. Four vitamin B12 forms—cyanocobalamin, hydroxocobalamin, 5′-deoxyadenosylcobalamin, and methylcobalamin—are currently used for supplementation and, here, we provide an overview of their biochemical role, bioavailability, and efficacy in different dosage forms. Since the effective quantity of vitamin B12 depends on the stability of the different forms, we further provide a review of their main reactivity and stability under exposure to various environmental factors (e.g., temperature, pH, light) and the presence of some typical interacting compounds (oxidants, reductants, and other water-soluble vitamins). Further, we explore how the manufacturing process and storage affect B12 stability in foods, food supplements, and medicines and provide a summary of the data published to date on the content-related quality of vitamin B12 products on the market. We also provide an overview of the approaches toward their stabilization, including minimization of the destabilizing factors, addition of proper stabilizers, or application of some (innovative) technological processes that could be implemented and contribute to the production of high-quality vitamin B12 products.
... In terms of outcomes, adverse events and cost, the overall quality of the evidence was low due to the small number of studies and limited sample sizes. [23][24][25] In their conclusions, the authors state the need for trials with improved methods for random allocation and masking, larger sample sizes and information on other relevant outcome variables that are preferably conducted in the primary care setting. ...
... As far as we know, the present trial is the largest clinical trial with the longest follow-up period, and it is the first to evaluate, in addition to VB12 levels, clinical signs and symptoms, health-related quality of life and patient preferences. The three clinical trials [23][24][25] described in the 2018 Cochrane Systematic Review 5 had a duration between 3 and 4 months and included a total of 153 patients. In the Saraswathy trial, patients in the oral route at 3 months normalised levels 20/30 (66.7%) versus 27/30 (90%) of the patients in the IM route. ...
... In the Saraswathy trial, patients in the oral route at 3 months normalised levels 20/30 (66.7%) versus 27/30 (90%) of the patients in the IM route. 25 In Kuzminski's trial, patients in the oral route at 4 months normalised levels 18/18 (100%) versus 10/14 (71.4%) of the patients in the IM route. 23 These differences were statistically nonsignificant in both studies. ...
Objectives
To compare the effectiveness of oral versus intramuscular (IM) vitamin B 12 (VB12) in patients aged ≥65 years with VB12 deficiency.
Design
Pragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain).
Participants
283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm.
Interventions
The 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 outcomes
Serum 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.
Results
The 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 B 12 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 B 12 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.
Conclusions
Oral 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 numbers
NCT 01476007; EUDRACT (2010-024129-20).
... Along with a rise in B12 levels, a hematopoietic response is important, [28,29] and we observed such a response in our study. Some other publications reported the serum B12 level, but did not follow hematopoietic responses [30,[31][32][33][34]. A strong point of this work concerns monitoring of hemoglobin and reticulocyte changes, but larger, population-based studies are needed to confirm this effect. ...
Background & Aims: Methylcobalamin nasal spray (NasoB12® ) has been developed to overcome the drawbacks of currently available therapeutic options like the poorly absorbed oral route and the painful intramuscular route. The present study was designed to evaluate the safety and efficacy of NasoB12® in patients with Vitamin B12 deficiency, with serum vitamin B12 (svB12) <200 pg/mL (148 pmol/L).
... Bolaman and colleagues treated megaloblastic anemia patients with oral and intramuscular progressively-reduced-frequency administration of cyanocobalamin (1000 µg) [52] for 90 days. In Saraswathy's research, the scientists evaluated daily oral prescription (1000 µg) vs. weekly intramuscular injection (1000 µg) [53]. Castelli's paper reports data from healthy people with low cobalamin administrated who received oral VitB12 (1000 µg/day) or intramuscular VitB12 (1000 µg every 10 days) [54]. ...
Vitamin B12 (VitB12) is a naturally occurring compound produced by microorganisms and an essential nutrient for humans. Several papers highlight the role of VitB12 deficiency in bone and heart health, depression, memory performance, fertility, embryo development, and cancer, while VitB12 treatment is crucial for survival in inborn errors of VitB12 metabolism. VitB12 is administrated through intramuscular injection, thus impacting the patients’ lifestyle, although it is known that oral administration may meet the specific requirement even in the case of malabsorption. Furthermore, the high-dose injection of VitB12 does not ensure a constant dosage, while the oral route allows only 1.2% of the vitamin to be absorbed in human beings. Nanocarriers are promising nanotechnology that can enable therapies to be improved, reducing side effects. Today, nanocarrier strategies applied at VitB12 delivery are at the initial phase and aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients’ lives. The safety of nanotechnologies is still under investigation and few treatments involving nanocarriers have been approved, so far. Here, we highlight the role of VitB12 in human metabolism and diseases, and the issues linked to its molecule properties, and discuss how nanocarriers can improve the therapy and supplementation of the vitamin and reduce possible side effects and limits.
The prevalence of vitamin В 12 deficiency is about 3—16% in the general population, while in older people, it ranges from 10 to 20%. An increase in the proportion of people on reduced-calorie diets, the widespread use of drugs that can result in vitamin В 12 deficiency, an increase in life expectancy, on the one hand, a variety of clinical manifestations and the lack of precise algorithms for laboratory diagnostics, on the other hand, suggest that the number of patients with vitamin В 12 deficiency is significantly higher. Vitamin В 12 can be absorbed by passive diffusion, regardless of intrinsic factor and other underlying causes of the deficiency. The presence of an additional route of absorption brings in new expectations for the oral administration of cyanocobalamin in therapeutic doses. Comparative clinical trials of the use of cyanocobalamin have shown that the oral route of administration is as effective as the parenteral. Considering the need for long-term, and in some cases — life-long, use of the drug, there is a need to develop dosage regimens for oral administration comparable in effectiveness to parenteral administration. The use of functional vitamin В 12 deficiency biomarkers, such as vitamin В 12 levels, cholotranscobalamin, methylmalonic acid, homocysteine, made it possible to establish that a daily dose of 1000 mkg is the most effective, which at the initial stage is as efficient as intramuscular administration. In some circumstances, maintenance therapy (intramuscularly at a dose of 1 mg/month) was more effective; thus, a differentiated approach scheme to determining the maintenance oral dose was proposed, depending on the result obtained at the initial stage of therapy. Comparative studies covering the entire spectrum from the recommended dietary allowance to the dose commonly used for cobalamin injections have shown that an oral daily dose of 1000 mcg of cyanocobalamin normalizes serum vitamin В 12 levels and causes an 80—90% decrease in plasma methylmalonic acid concentration from the assumed maximum value. The oral route of administration provides a higher patient treatment adherence.
Zelfstandige behandelcentra die zich hebben gespecialiseerd in vitamine B12-problematiek adviseren patiënten met vitamine B12-deficiëntie te behandelen met injecties. De NHG-Standaard Anemie adviseert echter tabletten. Recente wetenschappelijke publicaties laten zien dat er geen reden is om de NHG-Standaard op dit punt te herzien. Vitamine B12-deficiëntie kan in principe oraal worden behandeld.
Background:
Vitamin B12deficiency is common, and the incidence increases with age. Most people with vitamin B12deficiency are treated in primary care with intramuscular (IM) vitamin B12. Doctors may not be prescribing oral vitamin B12formulations because they may be unaware of this option or have concerns regarding its effectiveness.
Objectives:
To assess the effects of oral vitamin B12versus intramuscular vitamin B12for vitamin B12deficiency.
Search methods:
We searched CENTRAL, MEDLINE, Embase, and LILACS, as well as the WHO ICTRP and ClinicalTrials.gov. The latest search date was 17 July 2017. We applied no language restrictions. We also contacted authors of relevant trials to enquire about other published or unpublished studies and ongoing trials.
Selection criteria:
Randomised controlled trials (RCTs) comparing the effect of oral versus IM vitamin B12for vitamin B12deficiency.
Data collection and analysis:
We used standard methodological procedures expected by Cochrane. Our primary outcomes were serum vitamin B12levels, clinical signs and symptoms of vitamin B12deficiency, and adverse events. Secondary outcomes were health-related quality of life, acceptability to patients, haemoglobin and mean corpuscular volume, total homocysteine and serum methylmalonic acid levels, and socioeconomic effects. We used GRADE to assess the quality of the evidence for important outcomes. We did not perform meta-analyses due to the small number of included trials and substantial clinical heterogeneity.
Main results:
Three RCTs met our inclusion criteria. The trials randomised 153 participants (74 participants to oral vitamin B12and 79 participants to IM vitamin B12). Treatment duration and follow-up ranged between three and four months. The mean age of participants ranged from 38.6 to 72 years. The treatment frequency and daily dose of vitamin B12in the oral and IM groups varied among trials. Only one trial had low or unclear risk of bias across all domains and outcome measures. Two trials reported data for serum vitamin B12levels. The overall quality of evidence for this outcome was low due to serious imprecision (low number of trials and participants). In two trials employing 1000 μg/day oral vitamin B12, there was no clinically relevant difference in vitamin B12levels when compared with IM vitamin B12. One trial used 2000 μg/day vitamin B12and demonstrated a mean difference of 680 pg/mL (95% confidence interval 392.7 to 967.3) in favour of oral vitamin B12. Two trials reported data on adverse events (very low-quality evidence due to risk of performance bias, detection bias, and serious imprecision). One trial stated that no treatment-related adverse events were seen in both the oral and IM vitamin B12groups. One trial reported that 2 of 30 participants (6.7%) in the oral vitamin B12group left the trial early due to adverse events. Orally taken vitamin B12showed lower treatment-associated costs than IM vitamin B12in one trial (low-quality evidence due to serious imprecision). No trial reported on clinical signs and symptoms of vitamin B12deficiency, health-related quality of life, or acceptability of the treatment scheme.
Authors' conclusions:
Low quality evidence shows oral and IM vitamin B12having similar effects in terms of normalising serum vitamin B12levels, but oral treatment costs less. We found very low-quality evidence that oral vitamin B12appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12deficiency, health related-quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting.
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