Methylcobalamin™ Neurologic & Cognitive Methyl B12 Clinical Applications
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Methionine Synthase Supports Tumor Tetrahydrofolate Pools
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284521; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Methionine synthase supports tumor tetrahydrofolate pools Joshua Z. Wang1,2,#, Jonathan M. Ghergurovich1,3,#, Lifeng Yang1,2, and Joshua D. Rabinowitz1,2,* 1 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA 2 Department of Chemistry, Princeton University, Princeton, New Jersey, USA 3 Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA # These authors contributed equally to this work. *Corresponding author: Joshua Rabinowitz Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics, Princeton University, Washington Rd, Princeton, NJ 08544, USA Phone: (609) 258-8985; e-mail: [email protected] Conflict of Interest Disclosure: J.D.R. is a paid advisor and stockholder in Kadmon Pharmaceuticals, L.E.A.F. Pharmaceuticals, and Rafael Pharmaceuticals; a paid consultant of Pfizer; a founder, director, and stockholder of Farber Partners and Serien Therapeutics. JDR and JMG are inventors of patents in the area of folate metabolism held by Princeton University. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284521; this version posted September 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl- THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). -
The Vitamin B12 Coenzyme
THE VITAMIN B12 COENZYME D. DoLPHIN, A. W. JoHNSON, R. RoDRIGO and N. SHAW Department of Chemistry, University of Nottingham, U.K. INTRODUCTION In 19•58 Barker and his associatesl-3 recognized a new coenzyme which controlled the conversion of glutamate into ß-methylaspartate by Clostridium tetanomorpkim. The coenzyme was shown4 to be related to !f;-vitamin B12, i.e. contair ing an adenine nucleotide grouping in place of the 5,6-dimethyl benziminawle nucleotide of vitamin B12, although similar coenzymes con taining btnziminazole or 5,6-dimethylbenziminazole were produced by growing C. tetanomorphum in the presence of the a ppropriate base5. Other variations of the nucleotide base have been achieved using Propionibacterium arabinosum in the presence of other purines and benziminazoles6• The pres ence of;:he coenzymes in a wide variety of micro-organisms such as several species of Actinomycetes including Streptomyces olivaceus and S. griseus has been dem( mstrated by the glutamate isomerase assay7 or by isolation. I t appears thü Vitamin B12 and its analogues are always biosynthesized in the form of their coenzymes. Preliminary physical and chemical studies sug gested that in the 5,6-dimethylbenzirninazolyl cobamide coenzyme the cyanide gr )up of vitamin B12, cyanocobalamin, was replaced by an adenine nucleoside':, 5, 8 and the determination9 of the complete structure (I; R = 5'-de·)xyadenosyl) of the coenzyme by X-ray analysis revealed the existence c f an essentially covalent bond between the cobalt atom and the S'.. carbon üom of the additional 5'-deoxyadenosine group. The molecule Me CH 2• CO· NH2 In the vitamin 8 12 coenzyme R =5' - deoxyadenosyl = Me Me 539 D. -
Folic Acid, Pyridoxine, and Cyanocobalamin Combination
ORIGINAL INVESTIGATION Folic Acid, Pyridoxine, and Cyanocobalamin Combination Treatment and Age-Related Macular Degeneration in Women The Women’s Antioxidant and Folic Acid Cardiovascular Study William G. Christen, ScD; Robert J. Glynn, ScD; Emily Y. Chew, MD; Christine M. Albert, MD; JoAnn E. Manson, MD Background: Observational epidemiologic studies indi- and visually significant AMD, defined as confirmed in- cate a direct association between homocysteine concentra- cident AMD with visual acuity of 20/30 or worse attrib- tion in the blood and the risk of age-related macular degen- utable to this condition. eration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are Results:Afteranaverageof7.3yearsoftreatmentandfollow- lacking. Our objective was to examine the incidence of AMD up, there were 55 cases of AMD in the combination treat- in a trial of combined folic acid, pyridoxine hydrochloride ment group and 82 in the placebo group (relative risk, 0.66; (vitamin B6), and cyanocobalamin (vitamin B12) therapy. 95% confidence interval, 0.47-0.93 [P=.02]). For visually significant AMD, there were 26 cases in the combination Methods: We conducted a randomized, double-blind, treatment group and 44 in the placebo group (relative risk, placebo-controlled trial including 5442 female health care 0.59; 95% confidence interval, 0.36-0.95 [P=.03]). professionals 40 years or older with preexisting cardio- vascular disease or 3 or more cardiovascular disease risk Conclusions: These randomized trial data from a large factors. A total of 5205 of these women did not have a cohort of women at high risk of cardiovascular disease diagnosis of AMD at baseline and were included in this indicate that daily supplementation with folic acid, pyri- analysis. -
L-Carnitine, Mecobalamin and Folic Acid Tablets) TRINERVE-LC
For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only (L-Carnitine, Mecobalamin and Folic acid Tablets) TRINERVE-LC 1. Name of the medicinal product Trinerve-LC Tablets 2. Qualitative and quantitative composition Each film- coated tablets contains L-Carnitine…………………….500 mg Mecobalamin……………….1500 mcg Folic acid IP…………………..1.5mg 3. Pharmaceutical form Film- coated tablets 4. Clinical particulars 4.1 Therapeutic indications Vitamin and micronutrient supplementation in the management of chronic disease. 4.2 Posology and method of administration For oral administration only. One tablet daily or as directed by physician. 4.3 Contraindications Hypersensitivity to any constituent of the product. 4.4 Special warnings and precautions for use L-Carnitine The safety and efficacy of oral L-Carnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral L-Carnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine. Mecobalamin Should be given with caution in patients suffering from folate deficiency. The following warnings and precautions suggested with parent form – vitamin B12 The treatment of vitamin B12 deficiency can unmask the symptoms of polycythemia vera. Megaloblastic anemia is sometimes corrected by treatment with vitamin B12. But this can have very serious side effects. Don’t attempt vitamin B12 therapy without close supervision by healthcare provider. Do not take vitamin B12 if Leber’s disease, a hereditary eye disease. -
The Potential Protective Role of Vitamin K in Diabetic Neuropathy
VITAMINS The potential protective role of vitamin K in diabetic neuropathy DILIP MEHTA Viridis Biopharma 6/10 Jogani Industrial Complex ew cases of diabetes are symptomatic pain relief (3-5). V. N. Purav Marg, Chunabhatti increasing worldwide at a rapid Mumbai 400022, India The etiopathology of peripheral pace, with the total number of neuropathy is poorly understood and many [email protected] people with diabetes was projected factors, including dietary deficiencies, may www.viridisbiopharma.com Nto rise from 171 million in 2000 to 366 million contribute to the clinical manifestation of the in 2030 – an increase of nearly 200 million in condition. Deficiency of vitamin B12 (also only three decades. There are more cases of known as cobalamin), which results in a lack diabetes in women and urban populations, of a related compound, methylcobalamin, is with diabetes in developing countries projected manifested by megaloblastic anemia, and to double in the coming years (1). has been associated with significant Based on reports from the Centers for neurological pathology, especially peripheral Disease Control and Prevention, type 2 neuropathy (6-8). Vitamin B12 is also diabetes dult onset diabetes affects associated with the onset of diabetic approximately 9.3% of the general neuropathy. In patients with diabetic population in the United States in contrast to neuropathy, vitamin B12 deficiency may be 25.9% among those 65 years or older (2). aggravated by the use of antidiabetic agents Diabetes mellitus accounts for 90% of the such as metformin (9-11). Even short-term cases of diabetes patients (3,4). treatment with metformin causes a decrease The prevalence of type 2 diabetes in serum cobalamin, folic acid and an increases with age, higher then 25 body increase in homocysteine, which leads to mass index and the presence of the disease peripheral neuropathy in patients with in family history. -
Guidelines on Food Fortification with Micronutrients
GUIDELINES ON FOOD FORTIFICATION FORTIFICATION FOOD ON GUIDELINES Interest in micronutrient malnutrition has increased greatly over the last few MICRONUTRIENTS WITH years. One of the main reasons is the realization that micronutrient malnutrition contributes substantially to the global burden of disease. Furthermore, although micronutrient malnutrition is more frequent and severe in the developing world and among disadvantaged populations, it also represents a public health problem in some industrialized countries. Measures to correct micronutrient deficiencies aim at ensuring consumption of a balanced diet that is adequate in every nutrient. Unfortunately, this is far from being achieved everywhere since it requires universal access to adequate food and appropriate dietary habits. Food fortification has the dual advantage of being able to deliver nutrients to large segments of the population without requiring radical changes in food consumption patterns. Drawing on several recent high quality publications and programme experience on the subject, information on food fortification has been critically analysed and then translated into scientifically sound guidelines for application in the field. The main purpose of these guidelines is to assist countries in the design and implementation of appropriate food fortification programmes. They are intended to be a resource for governments and agencies that are currently implementing or considering food fortification, and a source of information for scientists, technologists and the food industry. The guidelines are written from a nutrition and public health perspective, to provide practical guidance on how food fortification should be implemented, monitored and evaluated. They are primarily intended for nutrition-related public health programme managers, but should also be useful to all those working to control micronutrient malnutrition, including the food industry. -
Potential Benefits of Methylcobalamin: a Review
Open Access Austin Journal of Pharmacology and Therapeutics Review Article Potential Benefits of Methylcobalamin: A Review Gupta JK* and Qureshi Shaiba Sana Department of Pharmacology, GLA University Mathura, Abstract India Methylcobalamin is an active form of vitamin B12 that helps in synthesis *Corresponding author: Jeetendra Kumar Gupta, of methionine and S-adenosylmethionine. It is required for integrity of myelin, Department of Pharmacology, Institute of Pharmaceutical neuronal function, proper red blood cell formation and DNA synthesis. The largest Research, GLA University Mathura, India group of vitamin B12 deficiency is found in typical vegetarians all over the world, which can be alleviated with its analogue Methylcobalamin. It is a beneficial Received: August 17, 2015; Accepted: September 30, drug to most of the common disorders like cardiovascular disorders, diabetes, 2015; Published: October 08, 2015 anemia, hyperhomocysteinemia and degenerative disorders. Methylcobalamin helps in the synthesis of neuronal lipids, regeneration of axonal nerves and has neuroprotective activity, which promote neurons to function in proper way and thus improves Alzheimer disease, Parkinsonism, Dementia and neuropathic syndromes. It is an approved treatment for peripheral neuropathy. Keywords: Mecobalamin; Neuropathy; Anemia; Nootropic; Dietary supplement Abbreviations essential for cell growth and replication. Sometimes the liver cannot convert cyanocobalamin into adequate amount of methylcobalamin SAMe: S-Adenosyl Methionine; ERK: Extracellular Signal- needed for proper neuronal functioning. Through enhanced Regulated Kinases; PKB: Protein Kinase B; B-globulin: Beta Globulin; methylation, it exerts its nerve cell protective effect and accelerates ENFD: Epidermal Nerve Fiber Density; DPN: Diabetic Peripheral its growth. A lot of energy is required for cyanocobalamin to remove Neuropathy; NSAIDs: Non Steroidal Anti Inflammatory Drugs; THF: its cyanide and replaces it with methyl group [3]. -
Vitamin B12 Vitamin D Iodine and Selenium
Frequently Asked Questions for VEG 1 General 1. Why has VEG 1 been developed? VEG 1 was developed to provide a convenient way of avoiding the most common weak points in a varied vegan diet: vitamin B12, iodine, vitamin D and selenium. Vitamin B12 Vitamin B12 is almost entirely absent from modern plant foods which are not contaminated by bacteria and insects. Even unwashed, organically grown plants do not contain a significant amount of B12. Vegans often have intakes of vitamin B12 well below recommended intakes. Low vitamin B12 intake by vegans routinely leads to reduced activity of some important enzymes and increased levels of homocysteine and methylmalonic acid (MMA). Even moderately elevated homocysteine is associated with increased risk of death, depression, stroke, dementia and birth defects, though it remains unclear how many of these associations reflect true cause and effect. Vegans who do not get vitamin B12 from fortified food or supplements are at increased risk of clinical deficiency symptoms such as anaemia and nervous system damage. The most common early symptoms of vitamin B12 deficiency are tiredness (from anaemia), numbness and tingling (from nervous system damage) and sore tongue. VEG 1 is designed to provide sufficient absorbed vitamin B12 to match national and international recommended intakes. It is designed to be chewed as this increases the reliability of vitamin B12 absorption by dispersing and dissolving the tablet. Vitamin D In the winter – whenever our shadows at midday are more than twice as long as we are – our skin cannot produce vitamin D effectively and even small dietary intakes may become important to avoid deficiency. -
Vitamin and Mineral Requirements in Human Nutrition
P000i-00xx 3/12/05 8:54 PM Page i Vitamin and mineral requirements in human nutrition Second edition VITPR 3/12/05 16:50 Page ii WHO Library Cataloguing-in-Publication Data Joint FAO/WHO Expert Consultation on Human Vitamin and Mineral Requirements (1998 : Bangkok, Thailand). Vitamin and mineral requirements in human nutrition : report of a joint FAO/WHO expert consultation, Bangkok, Thailand, 21–30 September 1998. 1.Vitamins — standards 2.Micronutrients — standards 3.Trace elements — standards 4.Deficiency diseases — diet therapy 5.Nutritional requirements I.Title. ISBN 92 4 154612 3 (LC/NLM Classification: QU 145) © World Health Organization and Food and Agriculture Organization of the United Nations 2004 All rights reserved. Publications of the World Health Organization can be obtained from Market- ing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 2476; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permis- sion to reproduce or translate WHO publications — whether for sale or for noncommercial distri- bution — should be addressed to Publications, at the above address (fax: +41 22 791 4806; e-mail: [email protected]), or to Chief, Publishing and Multimedia Service, Information Division, Food and Agriculture Organization of the United Nations, 00100 Rome, Italy. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization and the Food and Agriculture Organization of the United Nations concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. -
The Efficacy and Safety of Intramuscular Injections Of
Original Article Singapore Med J 2011; 52(12) : 868 The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial Chiu C K, Low T H, Tey Y S, Singh V A, Shong H K ABSTRACT both singly or in combination with other forms Introduction:Chronic, nonspecific low back of treatment. pain is a difficult ailment to treat and poses an economic burden in terms of medical Keywords: methylcobalamin, nonspecific low expenses and productivity loss. The aim of back pain, vitamin B12 this study was to determine the efficacy and Singapore Med J 2011; 52(12): 868-873 safety of intramuscular metylcobalamin in the treatment of chronic nonspecific low back INTRODUCTION pain. Low back pain (LBP) affects a substantial proportion of the population. Almost every person will encounter an Methods: This was a double-blinded, episode of back pain at some point in one’s life. Back randomised, controlled experimental study. pain does not discriminate based on gender, age, race or 60 patients were assigned to either the culture. It disables the working adult from performing his methylcobalamin group or the placebo group. duties and paralyses the society due to the cost incurred The former received intramuscular injections in terms of treatment and productivity loss. In 1988, a of 500 mcg parenteral methylcobalamin in 1 survey was conducted in a semirural area in Malaysia. Department of ml solution three times a week for two weeks, Orthopaedic A total of 2,594 individuals from a multi-racial (Malay, Surgery, and the placebo group received 1 ml normal Chinese, Indian) community were interviewed. -
Cyanocobalamin-A Case for Withdrawal
686 Journal of the Royal Society of Medicine Volume 85 November 1992 Cyanocobalamin- a case for withdrawal: discussion paper A G Freeman MD FRCP Meadow Rise, 3 Lakeside, Swindon SN3 IQE Keywords: anaemia, pernicious; optic neuropathies; chronic cyanide intoxication; hydroxocobalamin; cyanocobalamin It seems evident that controversy still surrounds the reduced ability to detoxify the cyanide in the tobacco- treatment of pernicious anaemia and other vitamin smoke to which they are exposed'0. B12 deficiency disorders. The long quest for the 'anti- Patients with tobacco amblyopia who have normal pernicious anaemia factor' in the liver seemed to serum vitamin B12 levels need not continue therapy have ended in 1948 when pure cyanocobalamin was with intramuscular hydroxocobalamin once their isolated. This was found to be very active thera- visual acuity and visual fields have returned to peutically when given by intramuscular injection and normal providing they abstain from further smoking. was non-toxic in extremely high doses'. However, those patients who have low serum vitamin Lederle, in a recent commentary2, advocates that B12 levels or evidence of -defective vitamin B12 patients with pernicious anaemia should now be absorption will need to continue-indefinitely with treated with oral cyanocobalamin. He is not without hydroxocobalamin irrespective of their smoking support in that 40% of patients with pernicious habits as will all patients with pernicious anaemia anaemia in Sweden are being similarly treated3. and other vitamin B12 deficiency disorders who are He further states that such!- treatment is cheap at risk of developing- optic neuropathy if they and effective, produces clinical and haematological are smokers. -
DRIDIETARY REFERENCE INTAKES Thiamin, Riboflavin, Niacin, Vitamin
Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline http://www.nap.edu/catalog/6015.html DIETARY REFERENCE INTAKES DRI FOR Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline A Report of the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and Subcommittee on Upper Reference Levels of Nutrients Food and Nutrition Board Institute of Medicine NATIONAL ACADEMY PRESS Washington, D.C. Copyright © National Academy of Sciences. All rights reserved. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline http://www.nap.edu/catalog/6015.html NATIONAL ACADEMY PRESS • 2101 Constitution Avenue, N.W. • Washington, DC 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was funded by the U.S. Department of Health and Human Services Office of Disease Prevention and Health Promotion, Contract No. 282-96-0033, T01; the National Institutes of Health Office of Nutrition Supplements, Contract No. N01-OD-4-2139, T024, the Centers for Disease Control and Prevention, National Center for Chronic Disease Preven- tion and Health Promotion, Division of Nutrition and Physical Activity; Health Canada; the Institute of Medicine; and the Dietary Reference Intakes Corporate Donors’ Fund.