Sulbutiamine

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Sulbutiamine
Skeletal formula of sulbutiamine
Space-filling model of the sulbutiamine molecule
Systematic (IUPAC) name
[4-[(4-amino-2-methyl-pyrimidin-5-yl)methyl-formyl-amino]-3-[2-[(4-amino-2-methyl-pyrimidin-5-yl)methyl-formyl-amino]-5-(2-methylpropanoyloxy)pent-2-en-3-yl]disulfanyl-pent-3-enyl] 2-methylpropanoate
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral
Pharmacokinetic data
Biological half-life 5 hours
Excretion Renal
Identifiers
CAS Number 3286-46-2 N
ATC code A11DA02 (WHO)
PubChem CID: 71124
ChemSpider 16736830 YesY
UNII 42NCM1BW43 YesY
KEGG D01319 YesY
Synonyms Arcalion, bisibuthiamine, enerion, youvitan
Chemical data
Formula C32H46N8O6S2
Molecular mass 702.89 g/mol
  • Nc2nc(C)ncc2CN(C=O)C(/C)=C(/CCOC(=O)C(C)C)SSC(/CCOC(=O)C(C)C)=C(/C)N(C=O)Cc1cnc(C)nc1N
  • InChI=1S/C32H46N8O6S2/c1-19(2)31(43)45-11-9-27(21(5)39(17-41)15-25-13-35-23(7)37-29(25)33)47-48-28(10-12-46-32(44)20(3)4)22(6)40(18-42)16-26-14-36-24(8)38-30(26)34/h13-14,17-20H,9-12,15-16H2,1-8H3,(H2,33,35,37)(H2,34,36,38)/b27-21-,28-22- YesY
  • Key:CKHJPWQVLKHBIH-ZDSKVHJSSA-N YesY
 NYesY (what is this?)  (verify)

Sulbutiamine (brand name: Arcalion) is a synthetic derivative of thiamine (vitamin B1). As a dimer of two modified thiamine molecules, it is a lipophilic compound that crosses the blood–brain barrier more readily than thiamine and increases the levels of thiamine and thiamine phosphate esters in the brain.[1] Sulbutiamine was discovered in Japan in an effort to develop more useful thiamine derivatives since it was hoped that increasing the lipophilicity of thiamine would result in better pharmacokinetic properties.[2]

Although its clinical efficacy is uncertain,[3] it is the only compound used to treat asthenia that is known to selectively target the areas that are involved in the condition.[4] In addition to its use as a treatment for chronic fatigue, sulbutiamine may improve memory, reduce psycho-behavioural inhibition, and improve erectile dysfunction. At therapeutic dosages, it has few reported adverse effects. It is available for over-the-counter sale as a nutritional supplement.

History

Thiamine

The history of sulbutiamine is closely tied to the study of thiamine in Japan. A deficiency of thiamine causes a nervous system disorder called beriberi.[5] Until the twentieth century, beriberi was prevalent in Japan and other Asian countries due to the widespread dependence on white rice as a staple food. The relationship between beriberi and diet was first noted by a navy surgeon named Takaki Kanehiro.[6] Additional work resulted in the discovery of thiamine, which was isolated in 1926 and synthesized in 1936. The establishment of a Vitamin B Research Committee in Japan led to additional scientific investigation into the properties of thiamine and its derivatives.[6]

The first lipophilic thiamine derivative to be discovered was allithiamine, which was isolated from garlic (Allium sativum) in 1951.[7] Allithiamine is an allyl disulfide derivative. After the discovery of allithiamine, several additional derivatives were synthesized with the hope that they would have better pharmacokinetic properties than thiamine. Thiamine is unable to diffuse across plasma membranes because it has a positively charged thiazole moiety. Instead, it must be transported across plasma membranes by high affinity carriers, and the rate of transport is low.[8] Sulbutiamine overcomes the poor oral bioavailability of thiamine because it is highly lipophilic. The synthesis of sulbutiamine was reported by Taisho Pharmaceutical Co. in 1965.[9]

Therapeutic uses

Sulbutiamine is indicated for the treatment of asthenia. Asthenia is a condition of chronic fatigue that is cerebral rather than neuromuscular in origin.[10][needs update]

Availability

Sulbutiamine is available in several forms. Arcalion is supplied in 200 mg tablets,[11] and generic sulbutiamine is supplied in tablets, capsules, and powder. The manufacturer of Arcalion recommends no more than 600 mg per day.[11]

Adverse effects

Sulbutiamine has few reported adverse effects at therapeutic dosages. According to the manufacturer of Arcalion, a mild skin allergy may occur, and mild agitation has also been observed in elderly patients.[11]

Mechanism of action

Thiamine triphosphate

Lua error in package.lua at line 80: module 'strict' not found. Lua error in package.lua at line 80: module 'strict' not found. Sulbutiamine is a lipophilic molecule that crosses the blood–brain barrier more easily than thiamine. Its metabolism in the brain leads to an increase in the levels of thiamine and thiamine phosphate esters.[1][12] While the exact mechanism of action of sulbutiamine is unknown, it is thought to occur through the upregulation of the reticular activating system, which is the center of arousal and motivation in the brain.[4] The administration of sulbutiamine potentiates glutamatergic activity in the prefrontal cortex through a reduction in the density of kainate glutamate receptors, which may occur in response to a modulation of intrasynaptic glutamate.[13] The facilitation of central glutamatergic transmission is a likely explanation for the ability of sulbutiamine to improve memory.[14][15][16][17] In addition to its action on cholinergic and glutamatergic transmission, the administration of sulbutiamine reduces the release of dopamine in the prefrontal cortex, which increases the density of D1 dopamine receptors through a compensatory mechanism.[13] The modulation of dopaminergic transmission may also contribute to the ability of sulbutiamine to improve memory.[18][19][20] A possible explanation for the pharmacodynamics of sulbutiamine is the increased availability of thiamine triphosphate (ThTP). Although the full physiological role of ThTP is unknown, it is an integral component of synaptosomal membranes,[21] participates in the phosphorylation of proteins,[22] and activates chloride channels that have a large unit conductance.[23] The activation of chloride channels by ThTP may be involved in the modulation of receptor binding.

See also

References

  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Inouye K, Katsura E. "Etiology and pathology of beriberi." In: Shimazono N, Katsura E, editors. Beriberi and Thiamine Igaku Shoin Ltd (1965) p. 1–28
  6. ↑ 6.0 6.1 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.; Lua error in package.lua at line 80: module 'strict' not found.; DE granted 1620538, Ammo T, Sakai T, Fujihira E, Aizawa T, "Vitamin-B1-Derivat, Verfahren zu dessen Herstellung und dessen Verwendung [Vitamin B1 derivative, process for its preparation and its use]", published 1969-10-16, issued 1977-12-31, assigned to Taisho Pharma Co Ltd . DE1620538 in turn claims a priority date of 1965-03-18 from the Japanese patent application JP19650015344.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 11.0 11.1 11.2 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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