Metanx® is a medical food dispensed by prescription for the clinical dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Use under medical supervision. Each capsule contains:
Metanx® capsules do not contain lactose, yeast or gluten.
PHARMACOLOGY
L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active diastereoisomer of folate1 and the primary form of folate in circulation.2 It is also the form which is transported across membranes into peripheral tissues,3 particularly across the blood brain barrier.4 In the cell, 6(S)-5-MTHF is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF).1 THF is the immediate acceptor of one carbon units for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine.5 About 70% of food folate and cellular folate is comprised of 6(S)-5-MTHF. Folic acid, the synthetic form of folate, must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active.6 Genetic mutations of MTHFR result in a cell’s inability to convert folic acid to 6(S)-5-MTHF.7
Metafolin® (L-methylfolate calcium) is a substantially diastereoisomerically pure source of L-methylfolate containing not more than 1% D-methylfolate which results in not more than 0.03 milligrams of D-methylfolate in Metanx®.
D-methylfolate or 6(R)-5-methyltetrahydrofolate [6(R)-5-MTHF] is the other diastereoisomer of folate. Studies administering doses of 2.5 mg per day or higher resulted in plasma protein binding of D-methylfolate higher than L-methylfolate causing a significantly higher renal clearance of L-methylfolate when compared to D-methylfolate.8 Further, D-methylfolate is found to be stored in tissues in the body, mainly in the liver. D-methylfolate is not metabolized by the body and has been hypothesized to inhibit regulatory enzymes related to folate and homocysteine metabolism and reduces the bioavailability of L-methylfolate.9
Pyridoxal-5′-phosphate (PLP) is the active form of vitamin B6 and is used as the prosthetic group for many of the enzymes where this vitamin is involved. PLP is readily absorbed by the intestine by a process which is preceded by dephosphorylation to form pyridoxal. The phosphate group is regained during passage through the intestine. Pyridoxine, the parent compound of PLP and the most frequently used form of vitamin B6, requires reduction and phosphorylation before becoming biologically active. The PLP in Metanx® contains 25mg of pyridoxal (the active component of PLP).
Methylcobalamin (Methyl-B12) is one of the two forms of biologically active vitamin B12. Methyl-B12 is the principal form of circulating vitamin B12, hence the form which is transported into peripheral tissue. Methyl-B12 is absorbed by the intestine by a specific mechanism which uses the intrinsic factor and by a diffusion process in which approximately 1% of the ingested dose is absorbed. Cyanocobalamin and hydroxycobalamin are forms of the vitamin that require conversion to methylcobalamin.
Pharmacokinetics:8,9
Absorption and Elimination: L-methylfolate is a water soluble molecule which is primarily excreted via the kidneys.10 In a study of subjects with coronary artery disease (n=21), peak plasma levels were reached in 1-3 hours following ORAL/PARENTERAL administration.9 Peak concentrations of L-methylfolate were found to be more than seven times higher than folic acid (129 ng ml-1 vs. 14.1 ng ml-1) following ORAL/PARENTERAL administration. The mean elimination half-life is approximately 3 hours after 5mg of oral L-methylfolate, administered daily for 7 days. The mean values for Cmax, Tmax, and AUC0-12 were 129 ng ml-1, 1.3 hr., and 383 respectively.
Distribution:
Red blood cells (RBCs) appear to be the storage depot for folate, as RBC levels remain elevated for periods in excess of 40 days following discontinuation of supplementation.10 Plasma protein binding studies showed that L-methylfolate is 56% bound to plasma proteins.9
INDICATION AND USAGE
Metanx® is indicated for the distinct nutritional requirements of individuals with endothelial dysfunction2,3,4 who present with loss of protective sensation5 and neuropathic pain6,7,8 associated with diabetic peripheral neuropathy. Metanx® is indicated for the distinct nutritional requirements of patients with endothelial dysfunction and/or hyperhomocysteinemia9 who present with lower extremity ulceration(s).10,11,12
CONTRAINDICATIONS
Metanx® is contraindicated in patients with known hypersensitivity to any of the components contained in this product.
PRECAUTIONS
General:
Folic acid, when administered in daily doses above 0.1mg, may obscure the detection of B12 deficiency (specifically, the administration of folic acid may reverse the hematological manifestations of B12 deficiency, including pernicious anemia, while not addressing the neurological manifestations). L-methylfolate Calcium may be less likely than folic acid to mask vitamin B12 deficiency.13,14 Folate therapy alone is inadequate for the treatment of a B12 deficiency.
Patient Information: Metanx® is a medical food dispensed by prescription (Rx) under medical supervision and direction.
DRUG INTERACTIONS
Metanx® added to other Drugs: High dose folic acid may result in decreased serum levels for pyrimethamine and first generation anticonvulsants (carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate).25,26 This may possibly reduce first generation anticonvulsants effectiveness and/or increasing the frequency of seizures in susceptible patients.25,26 While the concurrent use of folic acid and first generation anticonvulsants or pyrimethamine may result in decreased efficacy of anticonvulsants, no such decreased effectiveness has been reported with the use of L-methylfolate. Nevertheless, caution should be used when prescribing Metanx® among patients who are receiving treatment with first generation anticonvulsants or pyrimethamine. Pyridoxal 5′-phosphate should not be given to patients receiving the drug levodopa, because the action of levodopa is antagonized by pyridoxal 5′-phosphate. However, pyridoxal 5′-phosphate may be used concurrently in patients receiving a preparation containing both carbidopa and levodopa. Capecitabine (Xeloda®) toxicity may increase with the addition of leucovorin (5-formyltetrahydrofolate) (folate).
Drugs added to Metanx®: Antibiotics may alter the intestinal microflora and may decrease the absorption of methylcobalamin. Cholestyramine, colchicines or colestipol may decrease the enterohepatic re-absorption of methylcobalamin. Metformin, para-aminosalicylic acid and potassium chloride may decrease the absorption of methylcobalamin. Nitrous oxide can produce a functional methylcobalamin deficiency. Several drugs are associated with lowering serum folate levels or reducing the amount of active folate available. First generation anticonvulsants (carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate)25,26 and lamotrigine27 (a second-generation anticonvulsant) may decrease folate plasma levels. Information on other second-generation anticonvulsants impact on folate levels is limited and cannot be ruled out. Diavalproex sodium28, topiramate29, gabapentin30, pregabalin31, levetiracetam32, tiagabine33, zonisamide34, have not reported the potential to lower folate in their respective prescribing information. Methotrexate, alcohol (in excess), sulfasalazine, cholestyramine, colchicine, colestipol, L-dopa, methylprednisone, NSAIDs (high dose), pancreatic enzymes (pancrelipase, pancratin), pentamidine, pyrimethamine, smoking, triamterene, and trimethoprim may decrease folate plasma levels. Warfarin can produce significant impairment in folate status after a 6-month therapy.
ADVERSE REACTIONS
Allergic reactions have been reported following the use of oral L-methylfolate Calcium.15 Acne, skin reactions, allergic reactions, photosensitivity, nausea, vomiting, abdominal pain, loss of appetite, increased liver function test results, paresthesia, somnolence, nausea and headaches have been reported with pyridoxal 5’-phosphate.16 Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been associated with methylcobalamin.17
DOSAGE AND ADMINISTRATION
The usual adult dose may be taken as one capsule twice daily (1 capsule B.I.D.); or two capsules once daily (2 capsules QD); or as directed under medical supervision.
HOW SUPPLIED
METANX® is a medical food dispensed by prescription (Rx) under medical supervision and direction.
Bottle of 90 0525-8049-90* Commercial Bottle Use under medical/physician supervision
Each Metanx capsule has an opaque caramel cap and opaque white body. It is imprinted with “Metanx” in red ink on the body.
*Pamlab LLC does not represent these product codes to be National Drug Codes (NDC). Product codes are formatted according to standard industry practice, to meet the formatting requirements of pharmacy and health insurance computer systems.
Storage:
Store at controlled room temperature 15oC to 30oC (59oF to 86oF) (See USP). Protect from heat, light and moisture.
PATENTS
Some or all of the following patents may apply:
U.S. Patent No. 5,997,915
U.S. Patent No. 6,011,040
U.S. Patent No. 6,254,904
U.S. Patent No. 6,441,168B1
U.S. Patent No. 6,673,381
U.S. Patent No. 7,172,778
U.S. Patent No. 7,674,490
REFERENCES
1. Donaldson, K. and K. JC., Naturally occurring forms of folic acid. II. Enzymatic conversion of methylenetetrahydrofolic acid to prefolic A-methyl-tetrahydrofolate. J Biol Chem, 1962. 237: p. 1298-304.
2. Sweeney, M.R., J. McPartlin, and J. Scott, Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health, 2007. 7: p. 41.
3. Wagner, C., Cellular folate binding proteins; function and significance. Annu Rev Nutr, 1982. 2: p. 229-48.
4. Spector, R. and A.V. Lorenzo, Folate transport in the central nervous system. Am J Physiol, 1975. 229(3): p. 777-82.
5. Selhub, J., Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging, 2002. 6(1): p. 39-42.
6. Wright, A.J., J.R. Dainty, and P.M. Finglas, Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr, 2007: p. 1-9.
7. Chen, Z., A.C. Karaplis, S.L. Ackerman, I.P. Pogribny, S. Melnyk, S. Lussier-Cacan, M.F. Chen, A. Pai, S.W. John, R.S. Smith, T. Bottiglieri, P. Bagley, J. Selhub, M.A. Rudnicki, S.J. James, and R. Rozen, Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet, 2001. 10(5): p. 433-43.
8. Stroes E, van Faasen E, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 2000; 86:1129-34.
9. Willems FF, Boers GH, Blom HJ, et al. Pharmacokinetic Study on the Utilization of 5-methyltetrahydrofolate and Folic Acid in Patients with Coronary Artery Disease. Br J Pharmacol 2004;141:825-830.
10. 5-Methyltetrahydrofolate.(Monograph), Alternative Medicine Review, 2006. 11(4):330-337
11. Verhaar Marianne C, Wever Robert MF, Kastelein John JP, van Dam Thea, Koomans Hein A, Rabelink Ton J.: 5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia. Circulation 1998; 97:237-241.
12. van Etten RW, de Koning EJP, Verhaar MC, Gaillard AJM, Rabelink TJ.: Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002; 45:1004-1010.
13. Romerio Silvana C, Linder Lilly, Nyfeler Jurg, Wenk Markus, Litynsky Piotr, Asmis Reto, Haefeli Walter E.: Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults. Atherosclerosis 2004; 176:337-344.
14. Walker MJ Jr, Morris LM. Increased cutaneous sensibility in patients with diabetic neuropathy utilizing a pharmacological approach-clinical case evidence. Clinical Case Update: Vascular Disease Management 2007;2(1):1-8.
15. Jacobs, Allen M. Abstracts of New Cardiovascular Horizons Meeting. Orally Administered L-methylfolate, Methylcobalamin, and pyridoxal 5′-phosphate Reduces the Symptoms of Diabetic Peripheral Neuropathy. Oral Presentations 2008.
16. Jacobs, Allen M. Abstracts of New Cardiovascular Horizons Meeting. L-methylfolate, methylcobalamin, and pyridoxal 5-phosphate supplementation to pregabalin partial responders for the treatment of painful diabetic neuropathy. Oral Presentations 2008.
17. Li G. Effect of Mecobalamin on Diabetic Neuropathies. Beijing Methycobal Clinical Trial Collaborative Group. Zhonghua Nei Ke Za Zhi 1999;38(1):14-17.
18. Ambrosch A. et al. Relation between homocysteinemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18:185-192.
19. Veves Aristidis, Akbari Cameron M, Primavera James, Donaghue Valerie M, Zacharoulis Dimitrios, Chrzan James S, DeGirolami Umberto, LoGerfo Frank W., Freemen Roy: Endothelial Dysfunction and the Expression of Endothelias Nitric Oxide Synthetase in Diabetic Neuropathy, Vascular Disease, and Foot Ulceration. Diabetes 1998; 47: 457-463.
20. Boykin J. V. Jr. Ischemic Vascular Disease, Nitric Oxide Deficiency, and Impaired Wound Healing. Vascular Disease Management 2006; 3(A) 2-11.
21. Boykin J. V. Jr., Baylis C. Homocysteine- A Stealth Mediator of Impaired Wound Healing: A Preliminary Study. Wounds 2006;18(4): 101-116.
22. B Akoglu, M Schrott, H Bolouri, A Jaffari, E Kutschera, WF Caspary and D Faust: The Folic Acid Metabolite L-5-Methyltetrahydrofolate Effectively Reduces Total Serum Homocysteine Level in Orthotopic Liver Transplant Recipients: A Double-Blind Placebo-Controlled Study. European Journal of Clinical Nutrition (2007), 1-6
23. Scott JM, Weir DG: The Methylfolate Trap. A Physiological Response in Man to Prevent Methyl Group Deficiency in Kwashiokor and an Explanation for Folic-Acid-Induced Exacerbation of Subacute Combined Degeneration in Pernicious Anemia. Lancet. 1981 2:337-340
24. United States Food and Drug Administration Title 21 Code of federal Regulations 101.9(j)(8).
25. PDR® For Nutritional Supplements, 2001;ISBN: 1-56363-364-7:157-167.
26. Leucovorin Calcium (folinic acid) For Injection Prescribing Information:December 2003; Mayne Pharma (USA) Inc.
Package Insert
Metanx® is a medical food dispensed by prescription for the clinical dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Use under medical supervision. Each capsule contains:
DESCRIPTION
*CAS#151533-22-1
Dietary Ingredients:
Silicified Microcrystalline Cellulose, Algae-S Powder (Schizochytrium Algal Oil [Vegetable source], Glucose Syrup Solids, Mannitol, Sodium Caseinate (milk), Soy Protein, High Oleic Sunflower Oil, 2% or less Sodium Ascorbate, Tricalcium Phosphate, Tetrasodium Diphosphate, Natural Flavors, Soy Lecithin, and Mixed Natural Tocopherols and Ascorbyl Palmitate [as antioxidants]), Hypromellose, Pyridoxal 5’ Phosphate, L-methylfolate Calcium, Methylcobalamin, Titanium Dioxide (color), Magnesium Stearate (Vegetable Source), Caramel (color), Shellac, Propylene Glycol USP, Carmine (color).
Contains Milk, Soy and Carmine.
Metanx® capsules do not contain lactose, yeast or gluten.
PHARMACOLOGY
L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active diastereoisomer of folate1 and the primary form of folate in circulation.2 It is also the form which is transported across membranes into peripheral tissues,3 particularly across the blood brain barrier.4 In the cell, 6(S)-5-MTHF is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF).1 THF is the immediate acceptor of one carbon units for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine.5 About 70% of food folate and cellular folate is comprised of 6(S)-5-MTHF. Folic acid, the synthetic form of folate, must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active.6 Genetic mutations of MTHFR result in a cell’s inability to convert folic acid to 6(S)-5-MTHF.7
Metafolin® (L-methylfolate calcium) is a substantially diastereoisomerically pure source of L-methylfolate containing not more than 1% D-methylfolate which results in not more than 0.03 milligrams of D-methylfolate in Metanx®.
D-methylfolate or 6(R)-5-methyltetrahydrofolate [6(R)-5-MTHF] is the other diastereoisomer of folate. Studies administering doses of 2.5 mg per day or higher resulted in plasma protein binding of D-methylfolate higher than L-methylfolate causing a significantly higher renal clearance of L-methylfolate when compared to D-methylfolate.8 Further, D-methylfolate is found to be stored in tissues in the body, mainly in the liver. D-methylfolate is not metabolized by the body and has been hypothesized to inhibit regulatory enzymes related to folate and homocysteine metabolism and reduces the bioavailability of L-methylfolate.9
Pyridoxal-5′-phosphate (PLP) is the active form of vitamin B6 and is used as the prosthetic group for many of the enzymes where this vitamin is involved. PLP is readily absorbed by the intestine by a process which is preceded by dephosphorylation to form pyridoxal. The phosphate group is regained during passage through the intestine. Pyridoxine, the parent compound of PLP and the most frequently used form of vitamin B6, requires reduction and phosphorylation before becoming biologically active. The PLP in Metanx® contains 25mg of pyridoxal (the active component of PLP).
Methylcobalamin (Methyl-B12) is one of the two forms of biologically active vitamin B12. Methyl-B12 is the principal form of circulating vitamin B12, hence the form which is transported into peripheral tissue. Methyl-B12 is absorbed by the intestine by a specific mechanism which uses the intrinsic factor and by a diffusion process in which approximately 1% of the ingested dose is absorbed. Cyanocobalamin and hydroxycobalamin are forms of the vitamin that require conversion to methylcobalamin.
Pharmacokinetics:8,9
Absorption and Elimination: L-methylfolate is a water soluble molecule which is primarily excreted via the kidneys.10 In a study of subjects with coronary artery disease (n=21), peak plasma levels were reached in 1-3 hours following ORAL/PARENTERAL administration.9 Peak concentrations of L-methylfolate were found to be more than seven times higher than folic acid (129 ng ml-1 vs. 14.1 ng ml-1) following ORAL/PARENTERAL administration. The mean elimination half-life is approximately 3 hours after 5mg of oral L-methylfolate, administered daily for 7 days. The mean values for Cmax, Tmax, and AUC0-12 were 129 ng ml-1, 1.3 hr., and 383 respectively.
Distribution:
Red blood cells (RBCs) appear to be the storage depot for folate, as RBC levels remain elevated for periods in excess of 40 days following discontinuation of supplementation.10 Plasma protein binding studies showed that L-methylfolate is 56% bound to plasma proteins.9
INDICATION AND USAGE
Metanx® is indicated for the distinct nutritional requirements of individuals with endothelial dysfunction2,3,4 who present with loss of protective sensation5 and neuropathic pain6,7,8 associated with diabetic peripheral neuropathy.
Metanx® is indicated for the distinct nutritional requirements of patients with endothelial dysfunction and/or hyperhomocysteinemia9 who present with lower extremity ulceration(s).10,11,12
CONTRAINDICATIONS
Metanx® is contraindicated in patients with known hypersensitivity to any of the components contained in this product.
PRECAUTIONS
General:
Folic acid, when administered in daily doses above 0.1mg, may obscure the detection of B12 deficiency (specifically, the administration of folic acid may reverse the hematological manifestations of B12 deficiency, including pernicious anemia, while not addressing the neurological manifestations). L-methylfolate Calcium may be less likely than folic acid to mask vitamin B12 deficiency.13,14 Folate therapy alone is inadequate for the treatment of a B12 deficiency.
Patient Information:
Metanx® is a medical food dispensed by prescription (Rx) under medical supervision and direction.
DRUG INTERACTIONS
Metanx® added to other Drugs: High dose folic acid may result in decreased serum levels for pyrimethamine and first generation anticonvulsants (carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate).25,26 This may possibly reduce first generation anticonvulsants effectiveness and/or increasing the frequency of seizures in susceptible patients.25,26 While the concurrent use of folic acid and first generation anticonvulsants or pyrimethamine may result in decreased efficacy of anticonvulsants, no such decreased effectiveness has been reported with the use of L-methylfolate. Nevertheless, caution should be used when prescribing Metanx® among patients who are receiving treatment with first generation anticonvulsants or pyrimethamine. Pyridoxal 5′-phosphate should not be given to patients receiving the drug levodopa, because the action of levodopa is antagonized by pyridoxal 5′-phosphate. However, pyridoxal 5′-phosphate may be used concurrently in patients receiving a preparation containing both carbidopa and levodopa. Capecitabine (Xeloda®) toxicity may increase with the addition of leucovorin (5-formyltetrahydrofolate) (folate).
Drugs added to Metanx®: Antibiotics may alter the intestinal microflora and may decrease the absorption of methylcobalamin. Cholestyramine, colchicines or colestipol may decrease the enterohepatic re-absorption of methylcobalamin. Metformin, para-aminosalicylic acid and potassium chloride may decrease the absorption of methylcobalamin. Nitrous oxide can produce a functional methylcobalamin deficiency. Several drugs are associated with lowering serum folate levels or reducing the amount of active folate available. First generation anticonvulsants (carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate)25,26 and lamotrigine27 (a second-generation anticonvulsant) may decrease folate plasma levels. Information on other second-generation anticonvulsants impact on folate levels is limited and cannot be ruled out. Diavalproex sodium28, topiramate29, gabapentin30, pregabalin31, levetiracetam32, tiagabine33, zonisamide34, have not reported the potential to lower folate in their respective prescribing information. Methotrexate, alcohol (in excess), sulfasalazine, cholestyramine, colchicine, colestipol, L-dopa, methylprednisone, NSAIDs (high dose), pancreatic enzymes (pancrelipase, pancratin), pentamidine, pyrimethamine, smoking, triamterene, and trimethoprim may decrease folate plasma levels. Warfarin can produce significant impairment in folate status after a 6-month therapy.
ADVERSE REACTIONS
Allergic reactions have been reported following the use of oral L-methylfolate Calcium.15 Acne, skin reactions, allergic reactions, photosensitivity, nausea, vomiting, abdominal pain, loss of appetite, increased liver function test results, paresthesia, somnolence, nausea and headaches have been reported with pyridoxal 5’-phosphate.16 Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been associated with methylcobalamin.17
DOSAGE AND ADMINISTRATION
The usual adult dose may be taken as one capsule twice daily (1 capsule B.I.D.); or two capsules once daily (2 capsules QD); or as directed under medical supervision.
HOW SUPPLIED
METANX® is a medical food dispensed by prescription (Rx) under medical supervision and direction.
Bottle of 90 0525-8049-90* Commercial Bottle Use under medical/physician supervision
Each Metanx capsule has an opaque caramel cap and opaque white body. It is imprinted with “Metanx” in red ink on the body.
*Pamlab LLC does not represent these product codes to be National Drug Codes (NDC). Product codes are formatted according to standard industry practice, to meet the formatting requirements of pharmacy and health insurance computer systems.
Storage:
Store at controlled room temperature 15oC to 30oC (59oF to 86oF) (See USP). Protect from heat, light and moisture.
PATENTS
Some or all of the following patents may apply:
U.S. Patent No. 5,997,915
U.S. Patent No. 6,011,040
U.S. Patent No. 6,254,904
U.S. Patent No. 6,441,168B1
U.S. Patent No. 6,673,381
U.S. Patent No. 7,172,778
U.S. Patent No. 7,674,490
REFERENCES
1. Donaldson, K. and K. JC., Naturally occurring forms of folic acid. II. Enzymatic conversion of methylenetetrahydrofolic acid to prefolic A-methyl-tetrahydrofolate. J Biol Chem, 1962. 237: p. 1298-304.
2. Sweeney, M.R., J. McPartlin, and J. Scott, Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health, 2007. 7: p. 41.
3. Wagner, C., Cellular folate binding proteins; function and significance. Annu Rev Nutr, 1982. 2: p. 229-48.
4. Spector, R. and A.V. Lorenzo, Folate transport in the central nervous system. Am J Physiol, 1975. 229(3): p. 777-82.
5. Selhub, J., Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging, 2002. 6(1): p. 39-42.
6. Wright, A.J., J.R. Dainty, and P.M. Finglas, Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr, 2007: p. 1-9.
7. Chen, Z., A.C. Karaplis, S.L. Ackerman, I.P. Pogribny, S. Melnyk, S. Lussier-Cacan, M.F. Chen, A. Pai, S.W. John, R.S. Smith, T. Bottiglieri, P. Bagley, J. Selhub, M.A. Rudnicki, S.J. James, and R. Rozen, Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet, 2001. 10(5): p. 433-43.
8. Stroes E, van Faasen E, et al. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 2000; 86:1129-34.
9. Willems FF, Boers GH, Blom HJ, et al. Pharmacokinetic Study on the Utilization of 5-methyltetrahydrofolate and Folic Acid in Patients with Coronary Artery Disease. Br J Pharmacol 2004;141:825-830.
10. 5-Methyltetrahydrofolate.(Monograph), Alternative Medicine Review, 2006. 11(4):330-337
11. Verhaar Marianne C, Wever Robert MF, Kastelein John JP, van Dam Thea, Koomans Hein A, Rabelink Ton J.: 5-Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia. Circulation 1998; 97:237-241.
12. van Etten RW, de Koning EJP, Verhaar MC, Gaillard AJM, Rabelink TJ.: Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002; 45:1004-1010.
13. Romerio Silvana C, Linder Lilly, Nyfeler Jurg, Wenk Markus, Litynsky Piotr, Asmis Reto, Haefeli Walter E.: Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults. Atherosclerosis 2004; 176:337-344.
14. Walker MJ Jr, Morris LM. Increased cutaneous sensibility in patients with diabetic neuropathy utilizing a pharmacological approach-clinical case evidence. Clinical Case Update: Vascular Disease Management 2007;2(1):1-8.
15. Jacobs, Allen M. Abstracts of New Cardiovascular Horizons Meeting. Orally Administered L-methylfolate, Methylcobalamin, and pyridoxal 5′-phosphate Reduces the Symptoms of Diabetic Peripheral Neuropathy. Oral Presentations 2008.
16. Jacobs, Allen M. Abstracts of New Cardiovascular Horizons Meeting. L-methylfolate, methylcobalamin, and pyridoxal 5-phosphate supplementation to pregabalin partial responders for the treatment of painful diabetic neuropathy. Oral Presentations 2008.
17. Li G. Effect of Mecobalamin on Diabetic Neuropathies. Beijing Methycobal Clinical Trial Collaborative Group. Zhonghua Nei Ke Za Zhi 1999;38(1):14-17.
18. Ambrosch A. et al. Relation between homocysteinemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18:185-192.
19. Veves Aristidis, Akbari Cameron M, Primavera James, Donaghue Valerie M, Zacharoulis Dimitrios, Chrzan James S, DeGirolami Umberto, LoGerfo Frank W., Freemen Roy: Endothelial Dysfunction and the Expression of Endothelias Nitric Oxide Synthetase in Diabetic Neuropathy, Vascular Disease, and Foot Ulceration. Diabetes 1998; 47: 457-463.
20. Boykin J. V. Jr. Ischemic Vascular Disease, Nitric Oxide Deficiency, and Impaired Wound Healing. Vascular Disease Management 2006; 3(A) 2-11.
21. Boykin J. V. Jr., Baylis C. Homocysteine- A Stealth Mediator of Impaired Wound Healing: A Preliminary Study. Wounds 2006;18(4): 101-116.
22. B Akoglu, M Schrott, H Bolouri, A Jaffari, E Kutschera, WF Caspary and D Faust: The Folic Acid Metabolite L-5-Methyltetrahydrofolate Effectively Reduces Total Serum Homocysteine Level in Orthotopic Liver Transplant Recipients: A Double-Blind Placebo-Controlled Study. European Journal of Clinical Nutrition (2007), 1-6
23. Scott JM, Weir DG: The Methylfolate Trap. A Physiological Response in Man to Prevent Methyl Group Deficiency in Kwashiokor and an Explanation for Folic-Acid-Induced Exacerbation of Subacute Combined Degeneration in Pernicious Anemia. Lancet. 1981 2:337-340
24. United States Food and Drug Administration Title 21 Code of federal Regulations 101.9(j)(8).
25. PDR® For Nutritional Supplements, 2001;ISBN: 1-56363-364-7:157-167.
26. Leucovorin Calcium (folinic acid) For Injection Prescribing Information:December 2003; Mayne Pharma (USA) Inc.
27. Lamictal® (lamotrigine) Prescribing Information:August 2005; GlaxoSmithKline.
28. Depakote® (divalproex sodium) Prescribing Information:January 2006; Abbott Laboratories.
29. Topamax® (topiramate) Prescribing Information:June 2005; ORTHO-McNEIL NEUROLOGICS, INC.
30. Neurontin® (gabapentin) Prescribing Information:December 2005; Parke-Davis.
31. Lyrica® (pregabalin) Prescribing Information:March 2006; Parke-Davis.
32. Keppra® (levetiracetam) Prescribing Information: March 2007; UCB, Inc.
33. Gabitril (tiagabine) Prescribing Information: March 2005: Cephalon, Inc.
34. Zonegran® (zonisamide) Prescribing Information: December 2004: Elan Pharma International Ltd.; licensed to Eisai Inc
Metafolin® is a registered trademark of Merck KGaA, Darmstadt, Germany
Xeloda® is a registered trademark of Roche Laboratories, Inc.
Distributed by:
PAMLAB, L.L.C. Covington, LA 70433
Revised 8/12