Brain Health // Stress Management/Emotional Health // Vitamins and Minerals By guest blogger, Dr. John Dunn I watched the unresponsive 89 year old woman in her wheel chair as her daughter gave the story. “Doctors say my mother has end stage Alzheimer's and all we can do is comfort her while she dies, but I don't believe what they tell me”. Six weeks later, eight B12 shots, some vitamins and the elderly woman was walking without assistance and cracking jokes: she was a vitamin B12 miracle. Adequate levels of B12 in the body are essential for proper function of DNA and RNA, the building blocks of every cell in our body. B12 provides energy, clarity of mind and memory, enhanced sleep, mood, immune system, physical stamina and aides in weight management. B12 supplementation is to be considered with neurologic disorders such as neuralgia, multiple sclerosis, Parkinson's disease, and in some cases can correct mania and psychosis. Studies have shown that seniors with low B12 are six times more likely to exhibit brain atrophy than those with higher levels of B12.
Deficiency of vitamin B12 can lead to irreversible brain and neurologic damage. Many people are deficient because vitamin B12 has a very unique requirement for absorption. All vitamins are either water soluble, meaning they absorb along with water when taken orally, or fat soluble meaning that they absorb along with the digestion of dietary fat. Vitamin B12 is the exception. This vitamin is unique in that it will not be absorbed unless it is bound to intrinsic factor, a molecule secreted in the stomach from the same cells that produce hydrochloric acid. Hydrochloric acid production often diminishes with age, and this decline aggravated by overconsumption of acid blockers make B12 deficiency a widespread health concern that typically goes undetected. Many think that B12 deficiency is a concern of the elderly, however the Framingham Offspring Study revealed that people over the age of 26 show just as much likelihood for B12 deficiency as those 65 and older. Vitamin B12 is the largest and most structurally complicated of all vitamins.
Humans and animals cannot make their own B12; it has to come from a carnivorous meal. There are three forms of B12: cyanocobalamin, hydroxycobalamin and methylcobalamin. Hydroxycobalamin, produced from bacteria, is what we get from our diet. Once ingested, hydroxycobalamin can be converted into the other two forms. Rich food sources of vitamin B12 include: fish, shellfish, meat (especially liver), chicken, cooked eggs, milk products and termites if you are so inclined. There is a pseudo-B12 that can be found in certain food such as algae, seaweed, Spirulina and barley but is not a form usable by the body. Gut bacteria can synthesize some B12, but it is not enough for the whole body. This is why vegans need to supplement in order to get enough B12. Standard blood tests for serum B12 are unreliable because serum B12 does not accurately reflect intracellular concentrations. Elevated serum Methyl Malonic Acid (MMA) levels are a better indicator of B12 status because this occurs only if there is a B12 deficiency.
I don't usually do this type of test because improvement of symptoms with B12 supplementation is the best test. If adequate intrinsic factor is produced, then oral and sublingual B12 supplements work well. The RDA for adults is 2.4 mcg daily; an amount I believe to be insufficient for today's stressed out population. I would suggest an adult oral dose of 50-200mcg daily for prevention of symptoms and 500 – 1,000 mcg daily for a therapeutic effect. For autistic children I prescribe a methylcobalamin nasal spray because it works more effectively than oral supplementation. B12 injections are essentially painless and provide nearly 100 percent delivery by by-passing the digestive system. If there is insufficient intrinsic factor, as with pernicious anemia, or other digestive absorption issues then injections are indicated. The frequency will depend on the individual's health history. Cyanocobalamin injections are the least expensive and cover most of the deficiency concerns I've listed.
Hydroxycobalamin provides the same benefits and will last longer. Methylcobalamin also lasts longer, and more effectively addresses neurologic concerns. I offer all three forms because some people respond better to one than another and some respond best when I add a little folic acid to the B12. When supplementing with a therapeutic dose of B12 on a regular basis it is important to also get extra folic acid or folate either in a multiple vitamin, B complex, injection or by itself. The reason is that B12 supplementation may mask a folic acid deficiency anemia on blood tests. By supplementing with folic acid this is not a concern. As folic acid is water soluble like all the other B vitamins except B12, an oral supplement works very well, from 100-1,000mcg daily. People with allergy to cobalamin should not take B12, and people with Leber's optic disease need to consult their physician before taking supplemental B12. B12 supplementation beyond what you'd get in a typical multiple vitamin formula for infants, toddlers, pregnant and lactating women should also be accompanied by a physician's guidance.
For all others, at even high doses, oral B12 has no side effects and B12 injections have minimal side effects beyond occasional bruising and or a little temporary discomfort at the injection site. In summary, B12 deficiency is a widespread health concern for most adults. Low level deficiency in healthy people can be addressed with a multiple vitamin formula (see website newsletter: Supplements – Complete Life), while people with overt symptoms will best be served by taking a B12 supplement or the occasional injection.404 Error File Not Found The page you are looking for might have been removed, had its name changed, or is temporarily unavailable.Volume 76, December 2014, Pages 21–25 BackgroundThe gold standard for cobalamin deficiency treatment is administration of cobalamin by intramuscular injection. The injection is painful and inconvenient, particularly for elderly persons. Cobalamin might also be administered intranasally. Previous studies do not provide insight into the pharmacokinetics of intranasal cobalamin administration in comparison with cobalamin injection.
AimTo quantify the pharmacokinetics of intranasally and intramuscularly administered cobalamin to determine if intranasal administration might be an alternative for intramuscular administration.MethodsTen inpatients and outpatients of a geriatrics unit were recruited and randomly assigned to receive a single dose of 1000 μg cobalamin administered either by intranasal spray or intramuscular injection (5 per group). Inclusion criteria were written informed consent, age >65 years, and a cobalamin serum concentration <200 pmol/L. Total cobalamin serum concentrations were determined 10 times within 48 hours after administration. The differences in Cmax, Tmax, and AUC0–48 h per administration route were statistically compared using ANOVA.ResultsThe average Cmax was 1 nmol/L after intranasal and 38.5 nmol/L after intramuscular administration. The average Tmax for intranasal and intramuscular administration was 42 minutes versus 342 minutes, respectively, and the AUC0–48 h was 1.3 µmol/L/min versus 45.4 µmol/L/min, respectively.
These values also differed significantly (P<0.05). The estimated bioavailability of the intranasal administration was 2%.ConclusionsThe pharmacokinetics of intranasal and intramuscular cobalamin administration in elderly, cobalamin-deficient patients differ significantly. However, the estimated 2% bioavailability of cobalamin after intranasal administration makes intranasal cobalamin administration a potentially interesting administration route for elderly patients. Netherlands Trial Registry identifier: NTR 3005.Cobalamin deficiency in human beings may take 3 to 4 years to develop due to the large cobalamin stores in the liver. Nevertheless, approximately 10% to 15% of the population aged 65 years and older has cobalamin (vitamin B12) deficiency. An even higher prevalence of 30% to 40% is reported for malnourished and sick elderly people.1 Cobalamin serves as a cofactor for methionine synthase and L-methylmalonyl-coA mutase. People with cobalamin deficiency may experience megaloblastic anemia, subacute combined degeneration of the spinal cord, peripheral polyneuropathy, cognitive impairment, and mental changes.2 Cobalamin deficiency is due to malabsorption of food-bound cobalamin and/or insufficient dietary intake.
Food-bound cobalamin is released by pepsin in the acidic environment in the stomach. Subsequently, cobalamin is bound to intrinsic factor in the duodenum. The cobalamin-intrinsic factor complex then binds to the ileal endocytic cubam receptor. The cubam receptor consists of 2 proteins: cubulin and amnionless. Together these proteins take part in the endocytosis of the intrinsic factor-cobalamin complex, which is followed by degradation of intrinsic factor in lysosomes and the release of cobalamin into plasma in complex with transcobalamin II. Cobalamin malabsorption can therefore be caused by lack of intrinsic factor, decreased pepsin or acid secretion, or other defects in the cobalamin uptake system.3 and 4Repeated administration of cobalamin by way of intramuscular injection has been the gold standard for cobalamin deficiency treatment for many years. These intramuscular injections have several disadvantages. injection-related adverse reactions (such as intramuscular hematoma) may occur, especially in elderly persons who are frequently treated with anticoagulant medication;
and health care professionals are usually needed to administer the injections. The latter increases the burden of the treatment considerably. A more convenient and safer treatment would be advantageous to both patients and the health care system in general.5Food-bound cobalamin is actively absorbed. In contrast, crystalline cyanocobalamin administered via capsules is absorbed by way of passive diffusion. Although approximately only 1% of an oral dose of crystalline cyanocobalamin is absorbed, oral administration of cyanocobalamin is effective in normalizing serum cobalamin levels.6 and 7 Oral treatment might not be an option in patients who have an absorption disorder or are unable to take oral medication.8, 9 and 10 Intranasal administration of cobalamin could be a suitable alternative to both cobalamin injections and oral administration in elderly patients.Absorption of intranasally administered cobalamin has been demonstrated in studies.11, 12, 13 and 14 However the results of those studies do not provide insight into the pharmacokinetics of intranasally administered cobalamin in elderly, cobalamin-deficient patients or in comparison with cobalamin injection.
Insight into the pharmacokinetics is necessary to determine if intranasal administration could be an alternative to intramuscular administration in elderly patients. Also, insight into the pharmacokinetics could be used to develop a dosing regimen. The objective of our pilot study was to quantify the pharmacokinetics of intranasally and intramuscularly administered cobalamin in elderly, cobalamin-deficient patients to determine if intranasal administration might be an alternative for intramuscular administration.Ours was a randomized, open, comparative pilot study conducted between September 2011 and January 2012 in Haarlem, the Netherlands. Patients were recruited from the in- and outpatient geriatrics department of the Kennemer Gasthuis, a teaching hospital with a total of 450 beds of which 15 are geriatrics beds (3250 geriatric outpatient visits a year). Cobalamin serum concentration measurements are part of standard care at this clinic. Eligible patients were aged 65 years or older who had a cobalamin serum concentration <200 pmol/L. Patients also had to be able to give written informed consent.
Patients with chronic rhinitis, a running nose, or concomitant use of intranasally administered medication were excluded from study participation to minimize possible influences on intranasal absorption. In addition, patients who were hemodynamically instable, had clinically significant infections, or were severely malnourished were excluded from participation for ethical reasons. Simplified Nutritional Appetite Questionnaire was used to determine a patient’s nutritional status.15 Patients with a score of 3 were excluded. Patients with a glomerular filtration rate ≤20 mL/min/1.73 m2 were also excluded from study participation, because cobalamin is exclusively excreted through the kidneys. The study protocol (NL33450.029.11) was approved by the Medical Ethics Committee of the Vrije Universiteit Amsterdam and the Kennemer Gasthuis Haarlem.Patients were randomly assigned to 1 of the 2 study groups, to receive a single dose of 1000 μg cobalamin administered by intranasal spray or by intramuscular injection.
A research nurse administered either 2 mL of a 500 μg/mL hydroxocobalamin solution for injection (Hydrocobamin, Nycomed BV, Hoofddorp, the Netherlands) in the muscle of the upper left or right arm, or 1 puff (0.1 mL) 500 μg cyanocobalamine (Nascobal, Par Pharmaceutical Companies Inc, Woodcliff Lake, New Jersey) in each nostril. The intranasal spray was primed before each administration. Blood samples were obtained at 0, 15, 30, 60, 120, 240, 480, 1440 (24 hours), and 2880 minutes (48 hours) following administration. These blood samples were drawn using an intravenous cannula inserted into a forearm vein. The cannula was inserted in the arm not used for injection if the patient received the cobalamin by way of intramuscular injection.Total cobalamin serum concentrations were determined using a competitive immunoassay vitamin B12 kit with a measuring range between 22 and 1476 pmol/L (Roche Diagnostics GmbH, Mannheim, Germany) on a Roche Modular Analytics E170 immunoassay analyzer (Roche Diagnostics GmbH, Mannheim, Germany).
The mean coefficient of variation in human serum of this assay is 1.9% for repeatability and 4.7% for intermediate precision. Samples were diluted with Elecsys Diluent Universal (Roche Diagnostics GmbH, Mannheim, Germany) in case the cobalamin serum concentration exceeded the upper range of the assay.A concentration-time graph was constructed for each patient using PK Solutions (version 2.0, Summit Research Services, Montrose, California). For each patient Cmax, Tmax, and AUC0–48 h were determined using PK Solutions. The average of Cmax, Tmax, and AUC0–48 h for the group receiving cobalamin intranasally and the group receiving cobalamin intramuscularly were also calculated using PK Solutions. Bioavailability of the intranasal administration was estimated by dividing the mean AUC0–48 h after intranasal administration by the mean AUC0-48 h after intramuscular administration.In our pilot study a sample size of 10 was presumed sufficient to establish if intranasal administration could be a potential alternative for intramuscular administration in elderly patients.