Benfotiamine

{{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 449055379 | IUPAC_name = S-[2-{[(4-Amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate | image = Benfotiamine.svg | image2 = Benfotiamine ball-and-stick.png | tradename = Milgamma | Drugs.com = International Drug Names | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = OTC | routes_of_administration = Oral | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref =  Y | CAS_number = 22457-89-2 | ATC_prefix = A11 | ATC_suffix = DA03 | PubChem = 3032771 | ChEMBL_Ref =  N | ChEMBL = 1491875 | ChEBI_Ref =  N | ChEBI = 41039 | ChemSpiderID_Ref =  Y | ChemSpiderID = 2297665 | UNII_Ref =  Y | UNII = Y92OUS2H9B | synonyms = S-Benzoylthiamine O-monophosphate | C=19 | H=23 | N=4 | O=6 | P=1 | S=1 | molecular_weight = 466.448 g/mol | smiles = O=P(O)(O)OCCC(/SC(=O)c1ccccc1)=C(/N(C=O)Cc2cnc(nc2N)C)C | StdInChI_Ref =  Y | StdInChI = 1S/C19H23N4O6PS/c1-13(23(12-24)11-16-10-21-14(2)22-18(16)20)17(8-9-29-30(26,27)28)31-19(25)15-6-4-3-5-7-15/h3-7,10,12H,8-9,11H2,1-2H3,(H2,20,21,22)(H2,26,27,28)/b17-13- | StdInChIKey_Ref =  Y | StdInChIKey = BTNNPSLJPBRMLZ-LGMDPLHJSA-N }}

Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine (vitamin B1) that sold as a medication or dietary supplement to treat diabetic neuropathy. Combination drugs with pyridoxine or cyanocobalamin are also marketed.

Benfotiamine was developed and invented in Japan then reported internationally by Wada, Takagi, Minakami et al. in 1961.[1]

Uses

Benfotiamine is primarily marketed as an over-the-counter drug to treat diabetic neuropathy;[2] clinical trials results are mixed, finding it mildly useful or no different from placebo.[3][4]

Adverse effects

There is little published data on adverse effects; in one study of a combination drug of benfotiamine, pyridoxine, and cyanocobalamin, around 8% of people taking the drug experienced nausea, dizziness, stomach ache and weight gain.[5]

Pharmacology

Benfotiamine is more bioavailable than thiamine salts,[6] providing higher levels of thiamine in muscle, brain, liver, and kidney.[5]

Benfotiamine is dephosphorylated to S-benzoylthiamine by ecto-alkaline phosphatases present in the intestinal mucosa, and is then hydrolyzed to thiamine by thioesterases in the liver.[7]

Benfotiamine mainly acts on peripheral tissues through an increase in transketolase activity.[7][5][8]

Chemistry

Benfotiamine is a synthetic S-acyl Vitamin B1 analogue; its chemical name is S-benzoylthiamine O-monophosphate.[9] Benfotiamin is a lipid derivative of thiamine vitamin. It has very low solubility in water or other aqueous solvents.[7]

Society and culture

As of 2017, benfotiamine was marketed as a pharmaceutical drug in Argentina, Bosnia & Herzegowina, Bulgaria, Colombia, Czech Republic, Estonia, Georgia, Germany, Hong Kong, Hungary, India, Indonesia, Japan, Latvia, Lithuania, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Russian Federation, Taiwan, and Vietnam under the following brand names: Benalgis, Benfogamma, Benforce, Benfotiamina, Biotamin, Biotowa, Milgamma, and Vilotram.[10]

It was also marketed in some jurisdictions as a combination drug with cyanocobalamin as Milgamma, in combination with pyridoxine as Milgamma, in combination with metformin as Benforce-M, and with thiamine as Vitafos.[10]

Research

Benfotiamine has been studied in laboratory models of diabetic retinopathy, neuropathy, and nephropathy.[11] As of 2015 there had been one clinical study of benfotiamine in diabetic nephropathy.[12]

Administration of benfotiamine may increase intracellular levels of thiamine diphosphate, a cofactor of transketolase,[11] and based on metabolic theories of Alzheimer's disease, it has been studied in preclinical models of Alzheimer's disease.[13]

References
  1. Wada, T.; Takagi, H.; Minakami, H.; Hamanaka, W.; Okamoto, K.; Ito, A.; Sahashi, Y. (21 July 1961). "A New Thiamine Derivative, S-Benzoylthiamine O-Monophosphate". Science. 134 (3473): 195–196. Bibcode:1961Sci...134..195W. doi:10.1126/science.134.3473.195. PMID 13782394.
  2. McCarty, Mark F.; Inoguchi, Toyoshi (2008). "11. Targeting Oxidant Stress as a Strategy for Preventing Vascular Complications of Diabetes and Metabolic Syndrome". In Pasupuleti, Vijai K.; Anderson, James W. (eds.). Nutraceuticals, glycemic health and type 2 diabetes (1st ed.). Ames, Iowa: Wiley-Blackwell/IFT Press. p. 213. ISBN 9780813804286.
  3. Javed, S; Alam, U; Malik, RA (December 2015). "Burning through the pain: treatments for diabetic neuropathy". Diabetes, Obesity & Metabolism. 17 (12): 1115–25. doi:10.1111/dom.12535. PMID 26179288.
  4. Javed, S; Petropoulos, IN; Alam, U; Malik, RA (January 2015). "Treatment of painful diabetic neuropathy". Therapeutic Advances in Chronic Disease. 6 (1): 15–28. doi:10.1177/2040622314552071. PMC 4269610. PMID 25553239.
  5. Panel on Food Additives and Nutrient Sources added to Food (2008). "Scientific Opinion: Benfotiamine, thiamine monophosphate chloride and thiamine pyrophosphate chloride, as sources of vitamin B1 added for nutritional purposes to food supplements" (PDF). The EFSA Journal. 864: 1–31.
  6. Bitsch, Roland; Wolf, Martin; Moeller, Joerg; Heuzeroth, Lothar; Grueneklee, Dieter (1991). "Bioavailability Assessment of the Lipophilic Benfotiamine as Compared to a Water-Soluble Thiamin Derivative". Ann Nutr Metab. 35 (5): 292–296. doi:10.1159/000177659. PMID 1776825.
  7. Patel, S. M.; Patel, R. P.; Prajapati, B. G. (2012). Patel, S (ed.). "Solubility enhancement of benfotiamine, a lipid derivative of thiamine by solid dispersion technique". Journal of Pharmacy & Bioallied Sciences. US National Library of Medicine and National Institutes of Health: J Pharm Bioallied Sci. 4 (Suppl 1): S104–S105. doi:10.4103/0975-7406.94157. PMC 3467834. PMID 23066179.
  8. Yamazaki, M (1968). "Studies on the absorption of S-benzoylthiamine O-monophosphate : (I) Metabolism in tissue homogenates". Vitamins. 38 (1): 12–20.
  9. Balakumar, P; Rohilla, A; Krishan, P; Solairaj, P; Thangathirupathi, A (June 2010). "The multifaceted therapeutic potential of benfotiamine". Pharmacological Research. 61 (6): 482–8. doi:10.1016/j.phrs.2010.02.008. PMID 20188835.
  10. "Benfotiamine International brands". Drugs.com. Retrieved 14 March 2017.
  11. Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A (2010). "The multifaceted therapeutic potential of benfotiamine". Pharmacol Res. 61 (6): 482–8. doi:10.1016/j.phrs.2010.02.008. PMID 20188835.
  12. Raval, AD; Thakker, D; Rangoonwala, AN; Gor, D; Walia, R (12 January 2015). "Vitamin B and its derivatives for diabetic kidney disease". The Cochrane Database of Systematic Reviews. 1: CD009403. doi:10.1002/14651858.CD009403.pub2. PMID 25579852.
  13. Gibson, GE; Hirsch, JA; Cirio, RT; Jordan, BD; Fonzetti, P; Elder, J (July 2013). "Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes". Molecular and Cellular Neurosciences. 55: 17–25. doi:10.1016/j.mcn.2012.09.001. PMC 3609887. PMID 22982063.
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