Benfotiamine

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Benfotiamine
Benfotiamine.svg
Benfotiamine ball-and-stick.png
Clinical data
Trade names Milgamma
Other namesS-Benzoylthiamine O-monophosphate
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
Legal status
Legal status
Identifiers
  • S-[2-{[(4-Amino-2-methylpyrimidin-5-yl)methyl] (formyl)amino}-5-(phosphonooxy)pent-2-en-3-yl] benzenecarbothioate
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.040.906 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H23N4O6PS
Molar mass 466.45 g·mol−1
3D model (JSmol)
  • O=P(O)(O)OCCC(/SC(=O)c1ccccc1)=C(/N(C=O)Cc2cnc(nc2N)C)C
  • InChI=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- Yes check.svgY
  • Key:BTNNPSLJPBRMLZ-LGMDPLHJSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic, fat-soluble, S-acyl derivative of thiamine (vitamin B1) that is approved in some countries as a medication or dietary supplement to treat diabetic sensorimotor polyneuropathy. Benfotiamine was developed in late 1950s in Japan. [1] [2]

Contents

Uses

Benfotiamine is primarily marketed as an over-the-counter drug to treat diabetic polyneuropathy. [3] A 2021 review described two clinical trials with positive results for diabetic polyneuropathy and concluded that more research is needed. [4]

As of 2017, benfotiamine was marketed as a pharmaceutical drug in many countries under the following brand names: Benalgis, Benfogamma, Benforce, Benfotiamina, Biotamin, Biotowa, Milgamma, and Vilotram. [5] 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. [5]

Adverse effects

There is little published data on adverse effects. In one study of a combination of benfotiamine, pyridoxine, and cyanocobalamin, around 8% of people taking the drug experienced nausea, dizziness, stomach ache and weight gain. [6]

Pharmacology

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 is more bioavailable than thiamine salts, [8] providing higher levels of thiamine in muscle, brain, liver, and kidney. [6]

Benfotiamine mainly acts on peripheral tissues through an increase in transketolase activity. [7] [6] [9]

Chemistry

Benfotiamine is a lipid derivative of thiamine, specifically a synthetic S-acyl Vitamin B1 analogue; its chemical name is S-benzoylthiamine O-monophosphate. [10] It has very low solubility in water or other aqueous solvents. [7]

Research

Benfotiamine has been studied in laboratory models of diabetic retinopathy, neuropathy, and nephropathy. [10] A 2021 review of its use for diabetic polyneuropathy described two clinical trials which showed improvements in neuropathic pain and neuropathic symptoms scores, the latter of which showed a dose-response effect. [4] The authors concluded that it could potentially serve as an economical supplement to enhance neuropathy treatment and that more research is needed.

Administration of benfotiamine may increase intracellular levels of thiamine diphosphate, a cofactor of transketolase. [10] Based on metabolic theories of Alzheimer's disease, since thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of Alzheimer's disease patients at autopsy, and since treatment of mouse models of Alzheimer's disease with benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits, benfotiamine administration has been proposed as a possible intervention to reverse biological and clinical processes of Alzheimer's disease. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Thiamine</span> Chemical compound

Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient for humans and animals. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thiamine are required for some metabolic reactions, including the breakdown of glucose and amino acids.

Vitamin B<sub>6</sub> Class of chemically related vitamins

Vitamin B6 is one of the B vitamins, and thus an essential nutrient. The term refers to a group of six chemically similar compounds, i.e., "vitamers", which can be interconverted in biological systems. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in more than 140 enzyme reactions in amino acid, glucose, and lipid metabolism.

<span class="mw-page-title-main">Lipoic acid</span> Chemical compound

Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA is made in animals normally, and is essential for aerobic metabolism. It is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Only the (R)-(+)-enantiomer (RLA) exists in nature and is essential for aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.

B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism and synthesis of red blood cells. They are a chemically diverse class of compounds, but are associated in diet, often occurring together in the same foods. Dietary supplements containing all eight are referred to as a vitamin B complex. Individual B vitamins are referred to by B-number or by chemical name, such as B1 for thiamine, B2 for riboflavin, and B3 for niacin, while some are more commonly recognized by name than by number, such as pantothenic acid (B5), biotin (B7), and folate (B9).

Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic changes such as urinary symptoms. These changes are thought to result from a microvascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic neuropathy include distal symmetric polyneuropathy; third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; and autonomic neuropathy.

<span class="mw-page-title-main">Peripheral neuropathy</span> Nervous system disease affecting nerves beyond the brain and spinal cord

Peripheral neuropathy, often shortened to neuropathy, is a general term describing damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerves are affected. Neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve may be affected simultaneously. Peripheral neuropathy may be acute or chronic, and may be reversible or permanent.

ATC code A11Vitamins is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products. Subgroup A11 is part of the anatomical group A Alimentary tract and metabolism.

<span class="mw-page-title-main">Thiamine pyrophosphate</span> Chemical compound

Thiamine pyrophosphate (TPP or ThPP), or thiamine diphosphate (ThDP), or cocarboxylase is a thiamine (vitamin B1) derivative which is produced by the enzyme thiamine diphosphokinase. Thiamine pyrophosphate is a cofactor that is present in all living systems, in which it catalyzes several biochemical reactions.

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.

<span class="mw-page-title-main">Alcoholic polyneuropathy</span> Medical condition

Alcoholic polyneuropathy is a neurological disorder in which peripheral nerves throughout the body malfunction simultaneously. It is defined by axonal degeneration in neurons of both the sensory and motor systems and initially occurs at the distal ends of the longest axons in the body. This nerve damage causes an individual to experience pain and motor weakness, first in the feet and hands and then progressing centrally. Alcoholic polyneuropathy is caused primarily by chronic alcoholism; however, vitamin deficiencies are also known to contribute to its development. This disease typically occurs in chronic alcoholics who have some sort of nutritional deficiency. Treatment may involve nutritional supplementation, pain management, and abstaining from alcohol.

<span class="mw-page-title-main">Fenofibrate</span> Drug of the fibrate class, mainly used to reduce cholesterol levels

Fenofibrate, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes.

<span class="mw-page-title-main">Methylcobalamin</span> Form of vitamin B12

Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin, a form of vitamin B12. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and can be obtained as bright red crystals. From the perspective of coordination chemistry, methylcobalamin is notable as a rare example of a compound that contains metal–alkyl bonds. Nickel–methyl intermediates have been proposed for the final step of methanogenesis.

<span class="mw-page-title-main">Thiamine deficiency</span> Human disease

Thiamine deficiency is a medical condition of low levels of thiamine (Vitamin B1). A severe and chronic form is known as beriberi. The two main types in adults are wet beriberi and dry beriberi. Wet beriberi affects the cardiovascular system, resulting in a fast heart rate, shortness of breath, and leg swelling. Dry beriberi affects the nervous system, resulting in numbness of the hands and feet, confusion, trouble moving the legs, and pain. A form with loss of appetite and constipation may also occur. Another type, acute beriberi, found mostly in babies, presents with loss of appetite, vomiting, lactic acidosis, changes in heart rate, and enlargement of the heart.

<span class="mw-page-title-main">Sulbutiamine</span> Chemical compound

Sulbutiamine (brand names Arcalion, Enerion) is a synthetic derivative of thiamine (vitamin B1). In France, it is used to treat symptoms of weakness or fatigue. It is also sold as a dietary supplement. Sulbutiamine was discovered in Japan as part of an effort to develop useful thiamine derivatives.

<span class="mw-page-title-main">Cyanocobalamin</span> Form of vitamin B-12

Cyanocobalamin is a form of vitamin B
12
used to treat and prevent vitamin B
12
deficiency
except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel cancer. It is used by mouth, by injection into a muscle, or as a nasal spray.

Vitamins occur in a variety of related forms known as vitamers. A vitamer of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin.

Complications of diabetes are secondary diseases that are a result of elevated blood glucose levels that occur in diabetic patients. These complications can be divided into two types: acute and chronic. Acute complications are complications that develop rapidly and can be exemplified as diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia. Chronic complications develop over time and are generally classified in two categories: microvascular and macrovascular. Microvascular complications include neuropathy, nephropathy, and retinopathy; while cardiovascular disease, stroke, and peripheral vascular disease are included in the macrovascular complications.

<span class="mw-page-title-main">Prosultiamine</span> Chemical compound

Prosultiamine (INN; also known as thiamine propyl disulfide or TPD; brand name Jubedel,) is a disulfide thiamine derivative discovered in garlic in Japan in the 1950s, and is a homolog of allithiamine. It was developed as a treatment for vitamin B1 deficiency. It has improved lipid solubility relative to thiamine and is not rate-limited by dependency on intestinal transporters for absorption, hence the reasoning for its development.

Vitamin B1 analogues are analogues of vitamin B1, thiamine. They typically have improved bioavailability relative to thiamine itself, and are used to treat conditions caused by vitamin B1 deficiency. These conditions include beriberi, Korsakoff's syndrome, Wernicke's encephalopathy and diabetic neuropathy.

<span class="mw-page-title-main">4-Amino-5-hydroxymethyl-2-methylpyrimidine</span> Chemical compound

Within the field of biochemistry, 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) also known as toxopyrimidine together with its mono phosphate (HMP-P) and pyrophosphate (HMP-PP) esters are biogenetic precursors to the important biochemical cofactor thiamine pyrophosphate (TPP), a derivative of thiamine (vitamin B1).

References

  1. Wada T, Takagi H, Minakami H, Hamanaka W, Okamoto K, Ito A, Sahashi Y (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. S2CID   10384617.
  2. Sambon M, Wins P, Bettendorff L (May 2021). "Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine". International Journal of Molecular Sciences. 22 (11): 5418. doi: 10.3390/ijms22115418 . PMC   8196556 . PMID   34063830.
  3. McCarty MF, Inoguchi T (2008). "11. Targeting Oxidant Stress as a Strategy for Preventing Vascular Complications of Diabetes and Metabolic Syndrome". In Pasupuleti VK, Anderson JW (eds.). Nutraceuticals, glycemic health and type 2 diabetes (1st ed.). Ames, Iowa: Wiley-Blackwell/IFT Press. p. 213. ISBN   9780813804286.
  4. 1 2 Zaheer A, Zaheer F, Saeed H, Tahir Z, Tahir MW (April 2021). "A Review of Alternative Treatment Options in Diabetic Polyneuropathy". Cureus. 13 (4): e14600. doi: 10.7759/cureus.14600 . PMC   8139599 . PMID   34040901.
  5. 1 2 "Benfotiamine International brands". Drugs.com. Retrieved 14 March 2017.
  6. 1 2 3 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.
  7. 1 2 3 Patel SM, Patel RP, Prajapati BG (March 2012). Patel S (ed.). "Solubility enhancement of benfotiamine, a lipid derivative of thiamine by solid dispersion technique". Journal of Pharmacy & Bioallied Sciences. J Pharm Bioallied Sci. 4 (Suppl 1): S104–S105. doi: 10.4103/0975-7406.94157 . PMC   3467834 . PMID   23066179.
  8. Bitsch R, Wolf M, Möller J, Heuzeroth L, Grüneklee D (1991). "Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamin derivative". Annals of Nutrition & Metabolism. 35 (5): 292–296. doi:10.1159/000177659. PMID   1776825.
  9. Yamazaki M (1968). "Studies on the absorption of S-benzoylthiamine O-monophosphate : (I) Metabolism in tissue homogenates". Vitamins. 38 (1): 12–20.
  10. 1 2 3 Balakumar P, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A (June 2010). "The multifaceted therapeutic potential of benfotiamine". Pharmacological Research. 61 (6): 482–488. doi:10.1016/j.phrs.2010.02.008. PMID   20188835.
  11. 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.