Final Report – 2008-09 Research & Creative Works Grants Principal Investigator: Nicholas E. Burgis, Chemistry/Biochemistry Dept. Project Title: Developing a Less Toxic Chemotherapeutic Cocktail to Treat Multiple Myeloma. This report serves to document the scholarly research activities performed by the principal investigator and collaborators during the term of the Faculty Research Grant
B12 1240tN O N - M E D I C I N A L I N G R E D I E N T S I N T E R A C T I O N S & C O N T R A D I C T I O N S P H A R M A C E U T I C A L C O M M E N T A R Y Vitamin B12
Medicinal: CyanocobalaminNon-medicinal: Cellulose, magnesium stearate vegetable grade (lubricant) Allergens
Supplemental vitamin B12 is used primarily to ensure sufficient cyanocobalamin intake. It is used in ameliorating various clinical conditions, including elevated plasma homocys-teine, AIDS, impaired mental function in the elderly, asthma and sulfite sensitivity,depression, diabetic neuropathy, low sperm count, multiple sclerosis, and tinnitus.1 Recommended Amount
Use 1 tablet 1 to 4 times per day, or as directed by a physician.
Adverse Side Effects
The body is able to achieve high blood and tissue levels of vitamin B12 without toxicity.1 Interactions
Vitamin B12, folic acid, and vitamin B6 have a recognized interactive relationship. Absorption or utilization of vitamins B12 and B6 is affected by regular alcohol intake.7 Methotrexate adversely affects the intestinal mucosa so that vitamin B12 and folic acidare not absorbed well. It may be necessary to enhance supplementation of B12 and folicacid.7 Oral contraceptives interfere with the absorption of folic acid and vitamin B6. Since thesenutrients are interactive with vitamin B12, long-term use of OC’s may impact metabolismthat is controlled by these nutrients.7 Hydralazine can deplete the body of vitamin B6.7 Triamterene interferes with folic acid absorption.7 Colchicine may interfere with theabsorption of vitamin B12.7 Corticosteroids used long-term can deplete the body of vita-mins B6, B12, and folic acid.7 Barbiturates and Phenobarbital for epilepsy can be reduced in blood levels by folic acid orvitamin B6 supplementation.7 Dilantin may deplete vitamin B6 and folic acid. However, supplementation of these nutri-ents may diminish the efficacy of Dilantin. More than 2000 micrograms of folic acid willinterfere. Vitamin B6 at 80 mg per day will reduce the efficacy of Dilantin by 50 percent.7 Estrogen replacement therapy may lower vitamin B6 and folic acid levels.7 Levodopa efficacy can be reduced by vitamin B6 supplementation.7 Tranquillizers maydeplete vitamin B12.7 Potassium supplements can interfere with vitamin B12 absorption. Because potassiumsupplementation can be required for life, B12 depletion can be a meaningful risk. Theolder age group typically associated with potassium supplements is also associated withlow plasma B12 levels.5,7 Isoniazid, a tuberculosis drug, may deplete vitamin B 6 and niacin (B3). However, supple-mentation of B6 > 50 mg per day could diminish the efficacy of this drug. Niacin is rec-ommended at 15 to 25 mg per day. Medical supervision is recommended.7 CONCERNS? COMMENTS? CALL 1. 8 0 0 . 4 3 0 . 7 8 9 8
N O N - M E D I C I N A L I N G R E D I E N T S I N T E R A C T I O N S & C O N T R A D I C T I O N S P H A R M A C E U T I C A L C O M M E N T A R Y Para-aminosalicylate may deplete both vitamin B12 and folic acid.7 Sulfasalazine interferes with folic acid absorption.7 Cimetidine, Ranitidine, omeprazole,and possibly other acid suppressing drugs can reduce absorption of vitamin B12.7 Zidovudine (Retrovir or AZT) may interfere with the absorption of vitamin B12. Metformin can interfere with the absorption of vitamin B12 and folic acid. (CPS) Precautions/Cautions
Vitamin B12 deficiency can occur over time in strict vegetarians.2 Under the right circumstances, supplementing folic acid can mask vitamin B12 depletion.
Normally folic acid is recycled as a methyl donor by being reactivated by vitamin B12, act-ing itself as a methyl donor to folic acid. When tissue folic acid levels are low, a co-existingvitamin B12 deficiency will be manifested through even greater failure of folic acid metab-olism, ultimately leading to pernicious anemia. However, persistent vitamin B12 depletionalso leads to neurological damage. The concern is that new daily supplemented folic acidcan overcome the metabolic problems that lead to pernicious anemia without avertingneurological damage. Because the neurological damage evolves slowly, supplementingfolic acid without also supplementing B12 can mask a true B12 depletion allowing neuro-logical damage to proceed unsuspected. It is always recommended that folic acid and vita-min B12 be supplemented together. Impaired neurological function in the elder population due to vitamin B12 depletion canbe an important but unsuspected factor when there is not also evidence of anemia. Manyphysicians fail to investigate vitamin B12 depletion if there is not also evidence of anemia,yet two of the most depleted nutrients in the elder population are vitamin B12 and folicacid.1 In all cases of impaired mental function or depression vitamin B12 status should bedetermined and treaded accordingly.3,4 Contraindications
Vitamin B12 is the common name of cobalamine, which is a tetrapyrrole structure that chelates an atom of cobalt inthe center of the structure. Its active forms in the body are methylcobalamin and deoxyadenosylcobalamin, both areessential cofactors for two enzymes of intracellular metabolism, with the methyl form attaching to methionine synthaseand the adenosyl form attaching to methymalonyl CoA mutase.5 Cobalamin is synthesized only by animal gut bacteria,but is distributed throughout all forms of animal tissue, with the liver being the cite of highest concentration. Thus, itis not found in plants, predisposing vegan vegetarians to potential B12 deficiency. Methymalonyl CoA mutase facilitates the conversion of propionic acid to succinic acid, which is essential to fatty acidmetabolism.5 A high level of methylmalonic acid (MMA) is associated with low levels of available cobalamin, and is usu-ally accepted as diagnostic of cobalamin deficiency.1,5 Methionine synthase mediates two crucial intracellular metabolic processes, the synthesis of nucleic acid, which con-trols growth and cellular division, and secondly, the numerous methylation reactions. Deficiency of cobalamin leads totwo well recognized clinical manifestations, pernicious anemia, also called megaloblastic anemia because the red bloodcells are larger than normal, and to cobalamin-associated neuropathy in which the spinal cord, brain, optic nerve andperipheral nerves may be affected.5,6 An important manifestation of B12 deficiency, and the failed methylation that B12 deficiency brings, is the elevation ofplasma homocysteine. Elevated plasma homocysteine is now viewed by many experts as a greater risk factor than elevat-ed cholesterol for developing coronary heart disease.9 Homocysteine must be methylated to form methionine via B12 orfolic acid, or converted to cysteine via vitamin B6. Homocysteine is a natural cellular by-product of methionine metabo-lism, intended to have a transient existence. Failure to metabolize homocysteine to methionine or cysteine leads to N O N - M E D I C I N A L I N G R E D I E N T S I N T E R A C T I O N S & C O N T R A D I C T I O N S P H A R M A C E U T I C A L C O M M E N T A R Y unresolved elevated plasma levels. Homocysteine is cytotoxic to the endothelium and is able to initiate the focal lesionsthat will become coronary atherosclerosis.9 Absorption of vitamin B12 is aided by a gastric intrinsic factor. However, even in the absence of this intrinsic factor, pas-sive absorption of an oral dose is possible, but higher than normal daily doses are required.1 The current practice is touse injectable cobalamin, and this may be the most judicious initial approach. However, early studies have demonstrat-ed that pernicious anemia, secondary to an inability to synthesize the gastric intrinsic factor, could be controlled with aB12 dosage range of 300 to 1000 mcg per day.1 One of the most impressive was a three year Swedish study with 64patients with pernicious anemia and other cobalamin-related pathologies. The patients were treated with 1000 mcg ofcobalamine orally. At the end of the study, the patients demonstrated complete normalization of blood levels and liverstorage of cobalamine, and complete clinical remission.1,10,11 Absorption may also be diminished simply as a result of growing older, even when some measure of intrinsic factor ispresent.9 This is likely to be an important reason in explaining why a significant number of the elder populationdemonstrate low plasma B12 levels. Older patients at the pharmacy should be encouraged to have their physician assesstheir B12 status.
1. Murray, Michael T., Encyclopedia of Nutritional Supplements, Prima Publishing, Rocklin, CA, 1996
2. Chanarin, Israel, Nutritional Aspects of Hematologic Disorders, in Modern Nutrition in Health and Disease, eds., Maurice E. Shils, James A.
Olson, Moshe Shike, A. Catharine Ross, ninth edition, Lippincott Williams & Wilkins, New York, 1999 3. Van Goor, et al, Review, Cobalamine deficiency and mental impairment in elderly people, Age Ageing, 24: 536-542, 19954. Shevell, M.I., and D.S. Rosenblatt, The neurology of cobalamine, Can J Neurol Sci, 19:472-486, 19925. Weir, Donald G. and John M. Scott, Vitamin B12 “Cobalamin”, in Modern Nutrition in Health and Disease, eds., Maurice E. Shils, James A. Olson, Moshe Shike, A. Catharine Ross, ninth edition, Lippincott Williams & Wilkins, New York, 1999 6. Jeffery, Douglas R., Nutrition and Diseases of the Nervous System, in Modern Nutrition in Health and Disease, eds., Maurice E. Shils, James A.
Olson, Moshe Shike, A. Catharine Ross, ninth edition, Lippincott Williams & Wilkins, New York, 1999 7. Graedon, Joe, Teresa Graedon, Deadly Drug Interactions, St Martin’s Griffin, New York, 19958. Palteil, O., et al, Clinical correlates of subnormal vitamin B12 levels in patients infected with the human immunodeficiency virus, Am J Hematol, 9. McCully, Kilmer, The Heart Revolution, HarperCollins Publishers, New York, 199910. Berlin, H., Berlin, R., Brante, G., Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor, Acta Med Scand, 11. Berlin, R., et al, Vitamin B12 body stores during oral and parenteral treatment of pernicious anemia, Acta Med Scand, 204:81-84, 1978
The Alternate-Universe Hoax: Gene Roddenberry’s Star Trek Tract #8 in the Truth For Science-Fiction Followers series Version 1d, July 19, 2006. Copyright 2006 by Roddy Kenneth Street, Jr. Copyright 2006 by Roddy Kenneth Street, Jr. All publication rights and m ass-reproduction rights are reserved to the author,but internet users are given perm ission to duplicate this digital file and dist