Vitamin B12 Abstracts 6

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Absorption of cyanocobalamin, coenzyme B 12 , methylcobalamin, and hydroxocobalamin at different dose levels.
            (Adams et al., 1971) Download
The fractional absorption of radiolabeled cyanocobalamin when given at different doses was reported to amount to 50% of a 1 μg dose, 20% of a 5 μg dose, and just over 5% of a 25-μg dose.

Bioavailability of vitamin B12. Download
            (Allen, 2010)
Vitamin B12 deficiency is common in people of all ages who consume a low intake of animal-source foods, including populations in developing countries. It is also prevalent among the elderly, even in wealthier countries, due to their malabsorption of B12 from food. Several methods have been applied to diagnose vitamin B12 malabsorption, including Schilling’s test, which is now used rarely, but these do not quantify percent bioavailability. Most of the information on B12 bioavailability from foods was collected 40 to 50 years ago, using radioactive isotopes of cobalt to label the corrinoid ring. The data are sparse, and the level of radioactivity required for in vivo labeling of animal tissues can be prohibitive. A newer method under development uses a low dose of radioactivity as (14)C-labeled B12, with measurement of the isotope excreted in urine and feces by accelerator mass spectrometry. This test has revealed that the unabsorbed vitamin is degraded in the intestine. The percent bioavailability is inversely proportional to the dose consumed due to saturation of the active absorption process, even within the range of usual intake from foods. This has important implications for the assessment and interpretation of bioavailability values, setting dietary requirements, and interpreting relationships between intake and status of the vitamin.


 

Oral versus intramuscular vitamin supplementation for hypovitaminosis in the elderly.
            (Baker et al., 1980) Download
Thiamin, folate, biotin, riboflavin, nicotinates, pantothenate, carotenes, and vitamins B6, B12, A, E and C were measured in the blood of 228 elderly ambulatory residents of a nursing home. Their mean age was 87 years (range, 60-102). None had undergone major surgical procedures; their diet was good, and each had received at least one multivitamin pill every day for 3 to 5 months before the study. A comparison group of 204 healthy volunteers, aged 20-50 was also studied. Of the 228 elderly subjects, 88 (39 percent) showed vitamin deficits despite oral vitamin supplementation. Single and multiple deficits of vitamin B6, nicotinate, vitamin B12, folate, and thiamin were found. Three months after a single intramuscular injection of multivitamins (with no other vitamin supplementation), these deficits were no longer detectable in the blood of 89-100 percent of the vitamin-deficient elderly. Intramuscular rather than oral vitamin supplementation is a more effective method for maintaining adequate blood levels of vitamins in the elderly; the intramuscualr route apparently promotes saturation of tissue stores with enough vitamins to meet the needs, and thus obviates problems of vitamin malabsorption possibly due to drug interference or small-bowel atrophy.

The disappearance of cobalamin absorption testing: a critical diagnostic loss.
            (Carmel, 2007) Download
Almost alone among B vitamins, cobalamin defi- ciency is very often linked to failures of absorption. Barely >1 µg of cobalamin is made available from most meals no matter their cobalamin content, and then only if the IF-mediated process functions properly. In 1973, Doscherholmen and Swaim (5) expanded the scope of malabsorption to include food-cobalamin malabsorption (FCM), an inability to release food-bound cobalamin and make it avail- able to gastric IF. FCM cannot be diagnosed with the Schilling test, whose radiolabeled test dose of free cobalamin bypasses the need to release food-bound cobalamin. Work from many laboratories in the 1980s and early 1990s established that FCM was associated with 30–50% of all low cobalamin levels, a frequency at least 10-fold that of the more clinically ominous malabsorption of free cobalamin that occurs when gastric IF secretion or its uptake by intestinal IF receptors fails.

Cyanocobalamin: a case for withdrawal.
            (Foulds et al., 1970) Download
SIR,-We note the growing interest in clinical and laboratory studies of cyanide and vitamin-Bl2 metabolism in certain neuro-ophthalmological conditions. The use of hydroxocobalamin in the treatment of these conditions is based on thepharmacological effect of hydroxocobalamin as a powerful cyanide antagonist, with the formation of cyanocobalamin. Recent experience confirms the therapeutic superiority of hydroxocobalamin in the treatment of tobacco amblyopia. Moreover, in the past few months one of us (J. W.) has seen four patients with early Leber’s disease who had been treated with large doses of cyanocobalamin instead of hydroxocobalamin, contrary to recommendations. All of these patients developed optic atrophy with a speed and severity which was unusual even in this condition, and this especially unfavourable outcome may have been directly due to the administration of cyanocobalamin.

The vitamin B12 absorption test, CobaSorb, identifies patients not requiring vitamin B12 injection therapy.
            (Hvas et al., 2011) Download
BACKGROUND:  Treatment with vitamin B12 has virtually no side effects; however, life-long treatment is inconvenient for the patient and constitutes a cost for society. OBJECTIVE:  To investigate whether vitamin B12 injection treatment reflects the actual need for treatment or whether some patients are treated unnecessarily with vitamin B12 injections. MATERIAL AND METHODS:  A prospective intervention study was conducted among nine general practitioners in Western Sealand County, Denmark. Forty-four patients older than 18 years who had received injection therapy with vitamin B12 for a median of eight years (range 1-26 years) were included. After discontinuation of vitamin B12 injections, blood samples were analysed monthly for hemoglobin, cobalamin, holotranscobalamin, homocysteine and methylmalonic acid. The capacity to absorb vitamin B12 was examined after a median of 13 months (range 5-32 months) by measurement of holotranscobalamin or cyanocobalamin on transcobalamin before and after 1 and 2 days intake of 3 × 9 μg of vitamin B12. Patients unable to absorb the vitamin continued treatment with vitamin B12 injection. The remaining patients participated in a follow-up study receiving 9 μg oral vitamin B12 daily or no vitamin B12 substitution. RESULTS:  Of the 44 patients studied, 35 patients were able to absorb vitamin B12. None of the patients included in the follow-up study showed biochemical signs of vitamin B12 deficiency by the end of the study. CONCLUSION:  Our results suggest that the capacity for absorbing vitamin B12 should be examined prior to the choice of treatment.

The coenzyme forms of vitamin B12: toward an understanding of their therapeutic potential
            (Kelly, 1997) Download
Although cyanocobalamin and hydroxycobalamin are the most commonly encountered supplemental forms of vitamin B12, adenosyl- and methylcobalamin are the primary forms of vitamin B12 in the human body, and are the metabolically active forms required for B12-dependent enzyme function. Evidence indicates these coenzyme forms of vitamin B12, in addition to having a theoretical advantage over other forms of B12, actually do have metabolic and therapeutic applications not shared by the other forms of vitamin B12. This article will provide an overview of the metabolism and function of adenosyl- and methylcobalamin, and will discuss the potential therapeutic relevance of the coenzyme forms of vitamin B12 in a variety of clinical conditions, including anemia, anorexia, cancer, HIV, and liver and sleep disorders.

B12 shots
            (McCurdy, 1974) Download
Subclinical nutritional deficiency is believed by many to be common and often nonspecifically symptomatic. In some cases, this may be true (eg, iron deficiency in the menstruating female). Consequently, it is not surprising that cyanocobalamin ("B12") shots are frequently administered to patients who are vaguely ill, worried but well, or merely desirous of "more pep." Cyanocobalamin is probably an innocuous placebo, but one should determine at the outset that no deficiency exists. Nevertheless, it is better to select a completely inert placebo to avoid later diagnostic and therapeutic confusion.

B12 shots". Flip side.
            (McCurdy, 1975) Download
On the flip side, let me emphasize that it is imperative to recognize the true deficiency, to treat it, and to continue treatment indefinitely. Interruption of treatment inevitably leads to a relapse after one to five years, depending on how much vitamin B12 is in storage when therapy is stopped and on the size of the inadequate trace that can be absorbed despite the block. The normal l,000ug to 1,500/ig in storage is theoretically sufficient to supply the usual 0.5ug to lug daily requirement for two to five years. This long time lag between stopping therapy and the appearance of symptoms or signs of deficiency may lull both the patient and the physician into dangerous complacency. My first article emphasized that most cyanocobalamin injections have little justification, although they may sometimes have a placebo effect. The flip side of this coin: when cyanocobalamin therapy is needed, it is really needed and needed permanently.

Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.
            (Paul and Brady, 2017) Download
CONTEXT:  Three natural forms of vitamin B12 are commercially available: methylcobalamin (MeCbl), adenosylcobalamin (AdCbl), and hydroxycobalamin (OHCbl), all of which have been shown in clinical studies to improve vitamin B12 status. They are bioidentical to the B12 forms occurring in human physiology and animal foods. In contrast, cyanocobalamin (CNCbl), a synthetic B12 compound used for food fortification and in some supplements, occurs only in trace amounts in human tissues as a result of cyanide intake from smoking or other sources. OBJECTIVE:  This study had 3 objectives: (1) To summarize and compare assimilation pathways for 4 B12 forms; (2) to determine whether supplementation with a particular B12 form (or combination of forms) presents any advantages for the general population or for individuals with single nucleotide polymorphisms (SNPs) in B12-related pathways; and (3) to address misconceptions regarding B12 forms, methylation pathways, and various SNPs reported in commercially available tests. DESIGN:  PubMed was systematically searched for articles published up to June 2016 using specific key words. Human, animal, and in vitro studies that were published in English, French, and German were included. Other studies considered were found by selecting in PubMed the suggested "related studies" and also some referenced studies. SETTING:  The study occurred in Los Angeles, CA, USA. RESULTS:  The studies reviewed provide evidence that all supplemental or food-derived B12 forms are reduced to a core cobalamin molecule, which converts to the intracellular active forms: MeCbl and AdCbl, in a ratio not influenced by the form of B12 ingested. The methyl and adenosyl components of supplemental MeCbl and AdCbl are cleaved inside cells and are not used in the synthesis of intracellular MeCbl and AdCbl, respectively. However, the overall bioavailability of each form of supplemental B12 may be influenced by many factors such as gastrointestinal pathologies, age, and genetics. Polymorphisms on B12-related pathways may affect the efficiency of absorption, blood transport, cellular uptake, and intracellular transformations. CONCLUSIONS:  Supplementing with any of the nature bioidentical forms of B12 (MeCbl, OHCbl, and/or AdCbl) is preferred instead of the use of CNCbl, owing to their superior bioavailability and safety. For the majority of the population, all B12 forms may likely have similar bioavailabilities and physiological effects; thus, it makes sense to employ the least-expensive form of B12, such as MeCbl. Individuals with particular single nucleotide polymorphisms (SNPs) affecting B12 assimilation may raise their B12 status more efficiently with 1 or more particular forms of vitamin B12. However, because those types of SNPs are not currently reported in commercial tests, individuals may require either a trial-and-error approach by supplementing with 1 particular form of B12 at a time, or they might simply use a supplement with a combination of all 3 naturally occurring forms of B12 that are commercially available for a better chance of achieving faster clinical results. That approach may or may not offset genetic polymorphisms involving B12 metabolism and related pathways.

Glutathionylcobalamin as an intermediate in the formation of cobalamin coenzymes.
            (Pezacka et al., 1990) Download
To evaluate the possible role of glutathionylcobalamin (GS-Cbl) in the intracellular metabolism of cobalamin, the following reactions were analyzed using extracts of rabbit spleen: (i) decyanation of cyanocobalamin; (ii) utilization of GS-Cbl by cobalamin reductase; (iii) participation of GS-Cbl in methionine biosynthesis; and (iv) conversion of GS-Cbl to adenosylcobalamin. Decyanation of cyanocobalamin required reduced glutathione which appeared to form a complex with the cobalamin. This complex decomposed during the extraction steps to sulfitocobalamin which was identified by high-performance liquid chromatography. Cobalamin reductase in spleen extract was more active with GS-Cbl than with aquocobalamin or cyanocobalamin as substrates (specific activities: 10.4, 2.8 and 0.93 nmol/mg/min, respectively). Methionine synthase utilized GS-Cbl as cofactor more efficiently than aquocobalamin or cyanocobalamin based on initial rates of enzyme activity. This suggests that GS-Cbl is a more direct precursor of the coenzyme required for methionine synthase. Formation of adenosylcobalaminm from GS-Cb1 was four times greater than from aquocobalamin alone. Based on these results, we propose that GS-Cbl or a closely related thiol-cobalamin adduct is a proximal precursor in cobalamin coenzyme biosynthesis.

Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II open label clinical trial.
            (Shibuya et al., 2014) Download
OBJECTIVE:  No clinically effective treatment for promoting peripheral axonal regeneration has yet been established. Several experimental studies in vitro and in vivo have shown that a high dose of methylcobalamin (MeCbl), an analogue of vitamin B12, promotes axonal growth in peripheral nerve injury. We herein assessed the safety and efficacy of an ultra-high dose MeCbl treatment for patients with peripheral neuropathy and chronic axonal degeneration. METHODS:  Fourteen patients with immune-mediated or hereditary neuropathy in the chronic progressive or stable phase were enrolled. MeCbl, 25 mg/day for 10 days followed by monthly 25 mg for 5 months, was intravenously administered. The patients were evaluated before and 1 year following treatment. The primary endpoints were safety and improvement in the Medical Research Council (MRC) sum score in at least two muscles of the 20 muscles. This trial is registered with the University Hospital Medical Information Network (UMIN) Center in Japan under the ID: UMIN000009359. RESULTS:  There were no adverse effects in twelve of the patients, whereas treatment was discontinued in two patients who had seborrheic dermatitis at 3 months and respiratory tract infection at 2 months, respectively. Therefore, twelve patients were evaluated for the primary outcomes; the MRC sum score was improved in seven of the patients and unchanged or worsened in the remaining five patients. CONCLUSION:  Intravenous ultra-high dose MeCbl treatment is a safe and potentially efficacious therapy for patients with peripheral neuropathy and chronic axonal degeneration.

 


 

References

Adams, JF, et al. (1971), ‘Absorption of cyanocobalamin, coenzyme B 12, methylcobalamin, and hydroxocobalamin at different dose levels.’, Scand J Gastroenterol, 6 (3), 249-52. PubMed: 5560708
Allen, LH (2010), ‘Bioavailability of vitamin B12.’, Int J Vitam Nutr Res, 80 (4-5), 330-35. PubMed: 21462117
Baker, H, O Frank, and SP Jaslow (1980), ‘Oral versus intramuscular vitamin supplementation for hypovitaminosis in the elderly.’, J Am Geriatr Soc, 28 (1), 42-45. PubMed: 7350214
Carmel, R (2007), ‘The disappearance of cobalamin absorption testing: a critical diagnostic loss.’, J Nutr, 137 (11), 2481-84. PubMed: 17951489
Foulds, WS, et al. (1970), ‘Cyanocobalamin: a case for withdrawal.’, Lancet, 1 (7636), 35. PubMed: 4188355
Hvas, AM, et al. (2011), ‘The vitamin B12 absorption test, CobaSorb, identifies patients not requiring vitamin B12 injection therapy.’, Scand J Clin Lab Invest, 71 (5), 432-38. PubMed: 21623649
Kelly, G (1997), ‘The coenzyme forms of vitamin B12: toward an understanding of their therapeutic potential’, Alt Med Rev, 2 (5), 459-71. PubMed:
McCurdy, PR (1974), ‘B12 shots’, JAMA, 229 (6), 703-4. PubMed: 4408023
——— (1975), ‘B12 shots”. Flip side.’, JAMA, 231 (3), 289-90. PubMed: 1172740
Paul, C and DM Brady (2017), ‘Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.’, Integr Med (Encinitas), 16 (1), 42-49. PubMed: 28223907
Pezacka, E, R Green, and DW Jacobsen (1990), ‘Glutathionylcobalamin as an intermediate in the formation of cobalamin coenzymes.’, Biochem Biophys Res Commun, 169 (2), 443-50. PubMed: 2357215
Shibuya, K, et al. (2014), ‘Safety and efficacy of intravenous ultra-high dose methylcobalamin treatment for peripheral neuropathy: a phase I/II open label clinical trial.’, Intern Med, 53 (17), 1927-31. PubMed: 25175124