Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine (vitamin B1) that is marketed as a pharmaceutical drug in most countries, including European Medicines Agency's member countries, Ukraine, Russia, India, Korea and Japan, and as a thiamine derivative supplement for treating diabetic neuropathy. It is marketed as a dietary supplement in some countries such as the United States and China. Combination drugs with pyridoxine or cyanocobalamin are also marketed in a few countries. Benfotiamine was developed and invented in Japan then reported internationally by Wada, Takagi, Minakami et al. in 1961.[1] 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] In countries where Benfotiamine is not regulated as a pharmaceutical product, Benfotiamine is marketed as an antioxidant dietary supplement. Pharmacopoeia describing benfotiamine include the Japanese Pharmaceutical Codex and the Korean Pharmaceutical Codex, instead of the Japanese Pharmacopoeia and the Korean Pharmacopoeia. Benfotiamine is neither described in the European Pharmacopoeia nor the United States Pharmacopoeia nor the Pharmacopoeia of the People's Republic of China. 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] 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] Benfotiamine is a synthetic S-acyl Vitamin B1 analogue; its chemical name is S-benzoylthiamine O-monophoshate.[9] Benfotiamin is a lipid derivative of thiamine vitamin. It has very low solubility in water or other aqueous solvents.[7] 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] Benfotiamine has been studied in laboratory models of diabetic retinopathy, neuropathy, and nephropathy.[11] An 8-week clinical trial study with 84 patients suggested that benfotiamine led to significant improvement of alcoholic polyneuropathy.[12] There are several clinical trial studies suggesting effectiveness of benfotiamine in managing diabetic neuropathies.[13][14][15][16][17][18] As of 2015 there had been one clinical study of benfotiamine in diabetic nephropathy,[19] and one clinical trial on benfotiamine reducing genomic damage in hemodialysis patients.[20] 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.[21]