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Firewall62/Sandbox
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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
Routes of
administration		 Oral
Pharmacokinetic data
Biological half-life 5 hours
Excretion Renal
Identifiers
CAS Number 3286-46-2
ATC code A11DA02 (WHO)
PubChem CID 71124
Synonyms Arcalion, bisibuthiamine, enerion, youvitan
Chemical data
Formula C32H46N8O6S2
Molar mass 702.89 g/mol
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Sulbutiamine (brand name: Arcalion) is a synthetic derivative of thiamine (vitamin B1). It is a lipophilic molecule that crosses the blood-brain barrier easier than thiamine and increases the levels of thiamine and thiamine phosphate esters in the brain. Although its clinical efficacy is uncertain,[1] it is the only compound used to treat asthenia that is known to selectively target the areas that are involved in the condition.[2] In addition to its use as a treatment for chronic fatigue, sulbutiamine also appears to improve memory and erectile dysfunction. At therapeutic dosages, it has few reported adverse effects, though it may interfere with the therapeutic outcome of bipolar disorder.[3] It is available for over-the-counter sale as a nutritional supplement.

History

File:Thiamin.svg
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.[4] 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.[5] 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.[5]

The first lipophilic thiamine derivative to be discovered was allithiamine, which was isolated from garlic (Allium sativum) in 1951.[6] 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.[7] 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. It is not clear when sulbutiamine was first synthesized, but the earliest reference to it in the literature is from 1973.[9]

Therapeutic uses

Asthenia

Sulbutiamine is indicated for the treatment of asthenia, which is a condition of chronic fatigue that is cerebral rather than neuromuscular in origin. Patients with asthenia often find it difficult to carry out ordinary daily activities, but the symptoms cannot be explained by any abnormality in the neuromuscular apparatus or by hypoglycemia, hypotension, vascular disease, or cardiopulminary insufficiency.[10] Several studies have shown that sulbutiamine is effective at relieving the symptoms of asthenia. In a study of 1772 patients with an infectious disease and asthenic symptoms, sulbutiamine was administered in addition to specific anti-infective treatment for 15 days.[11] The number of patients with complete resolution of all asthenic symptoms was 916. Another study showed that sulbutiamine is effective at relieving asthenia in patients after mild craniocerebral trauma.[12] Nevertheless, the clinical efficacy of sulbutiamine is uncertain. In one study of chronic fatigue patients, sulbutiamine did not demonstrate sustained benefits over the placebo, which raises doubts about its clinical efficacy.[1] However, the authors of that study suggest that additional research is needed to evalulate the potential usefulness of sulbutiamine in the treatment of chronic fatigue.

Memory

Sulbutiamine may be beneficial for cognition. The demonstrated ability of sulbutiamine to improve memory in rats[13][14] and patients of schizophrenia[14] suggests that it enhances cognitive function. Sulbutiamine has also been shown to improve everyday activities in patients suffering from early-stage and moderate Alzheimer's disease when used in conjunction with an acetylcholinesterase inhibitor.[15]

Erectile dysfunction

According to one recent study, sulbutiamine is effective for the treatment of psychogenic erectile dysfunction.[16] Twenty patients with psychogenic erectile dysfunction received sulbutiamine for thirty days. After the treatment was over, erectile function improved in sixteen of the patients.

Availability

Sulbutiamine is available in several forms. Arcalion is supplied in 200 mg tablets, and generic sulbutiamine is supplied in tablets, capsules, and powder. The proper therapeutic dosage has been reported to be 12.5 mg/kg,[14] which corresponds to 850 mg for a 68 kg (150 lb) person. However, it should be noted that dosage recommendations vary. The manufacturer of Arcalion, for example, recommends no more than 600 mg per day.

Adverse effects

Sulbutiamine has few reported adverse effects at therapeutic dosages. According to the manufacturer of Arcalion, a mild skin allergy may occur. A mild agitation has also been observed in elderly patients. There is only one published report where the chronic overuse of sulbutiamine caused complications.[3] A patient with bipolar disorder was prescribed sulbutiamine because he was complaining of a lack of energy. He found the medication helpful and began taking 2 g per day, which was far more than he was prescribed. Subsequently, he stopped taking his other prescription medications and insisted that sulbutiamine was the only medication that helped him. The authors of the report conclude that sulbutiamine has the potential to interefere with the therapeutic outcome of bipolar disorder. The potential for chronic overuse appears to be similar to that of the B complex vitamins. For example, there is only published report where a patient suffered adverse effects from the from the chronic overuse of pyridoxine (vitamin B6), where he developed a severe sensory and a mild motor neuropathy due to the massive and prolonged ingestion of the supplement.[17]

Mechanism of action

Sulbutiamine is a lipophilic molecule that crosses the blood-brain barrier easier than thiamine. Its subsequent metabolism in the brain leads to an increase in the levels of thiamine and thiamine phosphate esters.[18][19] 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.[2] The administration of sulbutiamine potentiates cholinergic activity in the hippocampus.[13] It also 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. [20] With respect to glutamatergic activity, a change in the density of NMDA or AMPA receptors does not occur. 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.[20] The change in dopaminergic transmission in the prefrontal cortex may be a result of the modulation of glutamatergic transmission. 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 synpatosomal 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.

References

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External links

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Fat soluble
Water soluble
Combinations

M: NUT

cof, enz

drug(A8/11/12)

Psychostimulants, agents used for ADHD, and nootropics (N06B)
Centrally acting sympathomimetics
Xanthine derivatives
Glutamate receptor
CX-516 • CX-546 • CX-614 • CX-691 • CX-717 • IDRA-21 • LY-404,187 • LY-503,430 • PEPA • S-18986 • Sunifiram • Unifiram
Eugeroics / Benzhydryl compounds
Histamine H3 receptor antagonists
GABAA α5 inverse agonists
Dopamine D1 receptor agonists
α7 nicotinic agonists / PAMs
Prolyl endopeptidase inhibitors
Other psychostimulants and nootropics

M: PSO/PSI

dsrd (o, p, m, p, a, d, s), sysi/epon, spvo

proc, drug(N5A/5B/5C/6A/6B/6D)

fr:Sulbutiamine tr:Sulbutiamine
  1. ↑ 1.0 1.1 Tiev KP, Cabane J, Imbert JC (1999). "[Treatment of chronic postinfectious fatigue: randomized double-blind study of two doses of sulbutiamine (400-600 mg/day) versus placebo]". Rev Med Interne. 20 (10): 912–8. PMID 10573727. 
  2. ↑ 2.0 2.1 Van Reeth O (1999). "Pharmacologic and therapeutic features of sulbutiamine". Drugs Today (Barc). 35 (3): 187–92. PMID 12973384. 
  3. ↑ 3.0 3.1 Douzenis A, Michopoulos I, Lykouras L (2006). "Sulbutiamine, an 'innocent' over the counter drug, interferes with therapeutic outcome of bipolar disorder". World J Biol Psychiatry. 7 (3): 183–5. doi:10.1080/15622970500492616. PMID 16861144. 
  4. ↑ 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
  5. ↑ 5.0 5.1 Lonsdale D (2006). "A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives". Evid Based Complement Alternat Med. 3 (1): 49–59. doi:10.1093/ecam/nek009. PMC 1375232 Freely accessible. PMID 16550223. 
  6. ↑ Lonsdale D (2004). "Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent". Med Sci Monit. 10 (9): 199–203. PMID 15328496. 
  7. ↑ Volvert ML, Seyen S, Piette M, Evrard B, Gangolf M, Plumier JC, Bettendorff L (2008). "Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives". BMC Pharmaco. 8 (10): 10. doi:10.1186/1471-2210-8-10. PMC 2435522 Freely accessible. PMID 18549472. 
  8. ↑ Bettendorff L, Wins P. (1994). "Mechanism of thiamine transport in neuroblastoma cells. Inhibition of a high affinity carrier by sodium channel activators and dependence of thiamine uptake on membrane potential and intracellular ATP". J Biol Chem. 269 (20): 14379–85. PMID 8182042. 
  9. ↑ Fujihira E, Tarumoto Y, Ajioka M, Mori T, Nakazawa M (1973). "[Analgesic effect of o-isobutyrylthiamine disulfide on experimentally induced pain]". Yakugaku Zasshi. 93 (3): 388–91. PMID 4737603. 
  10. ↑ Layzer RB (1998). "Asthenia and the chronic fatigue syndrome". Muscle Nerve. 21 (12): 1609–11. doi:10.1002/(SICI)1097-4598(199812)21:12<1609::AID-MUS1>3.0.CO;2-K. PMID 9843061. 
  11. ↑ Shah SN; Sulbutiamine Study Group (2003). "Adjuvant role of vitamin B analogue (sulbutiamine) with anti-infective treatment in infection associated asthenia". J Assoc Physicians India. 51: 891–5. PMID 14710977. 
  12. ↑ Levin OS, Slizkova IuB (2007). "[The use of enerion in the treatment of asthenic disorders in patients after mild cranio-cerebral trauma]". Zh Nevrol Psikhiatr Im S S Korsakova. 107 (5): 44–8. PMID 18379496. 
  13. ↑ 13.0 13.1 Micheau J, Durkin TP, Destrade C, Rolland Y, Jaffard R (1985). "Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation". Pharmacol Biochem Behav. 23 (2): 195–8. doi:10.1016/0091-3057(85)90555-6. PMID 4059305. 
  14. ↑ 14.0 14.1 14.2 Bizot JC, Herpin A, Pothion S, Pirot S, Trovero F, Ollat H (2005). "Chronic treatment with sulbutiamine improves memory in an object recognition task and reduces some amnesic effects of dizocilpine in a spatial delayed-non-match-to-sample task". Prog Neuropsychopharmacol Biol Psychiatry. 29 (6): 928–35. doi:10.1016/j.pnpbp.2005.04.035. PMID 15951087. 
  15. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  16. ↑ Dmitriev DG, Gamidov SI, Permiakova OV (2005). "[Clinical efficacy of the drug enerion (sulbutiamine) in the treatment of patients with psychogenic (functional) erectile dysfunction]". Urologiia. 1 (1): 32–5. PMID 15776829. 
  17. ↑ Morra M, Philipszoon HD, D’Andrea G, Cananzi AR, L’Erario R, Milone FF (1993). "Sensory and motor neuropathy caused by excessive ingestion of vitamin B6: a case report". Funct Neurol. 8 (6): 429–32. PMID 8150322. 
  18. ↑ Bettendorff L, Weekers L, Wins P, Schoffeniels E (1990). "Injection of sulbutiamine induces an increase in thiamine triphosphate in rat tissues". Biochem Pharmacol. 40 (11): 2557–60. doi:10.1016/0006-2952(90)90099-7. PMID 2268373. 
  19. ↑ Bettendorff L (1994). "The compartmentation of phosphorylated thiamine derivatives in cultured neuroblastoma cells". Biochim Biophys Acta. 1222 (1): 7–14. doi:10.1016/0167-4889(94)90019-1. PMID 8186267. 
  20. ↑ 20.0 20.1 Trovero F, Gobbi M, Weil-Fuggaza J, Besson MJ, Brochet D, Pirot S (2000). "Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain". Neurosci Lett. 292 (1): 49–53. doi:10.1016/S0304-3940(00)01420-8. PMID 10996447. 
  21. ↑ Matsuda T, Cooper JR (1981). "Thiamine as an integral component of brain synaptosomal membranes". Proc Natl Acad Sci USA. 78 (9): 5886–9. doi:10.1073/pnas.78.9.5886. PMC 348897 Freely accessible. PMID 6272323. 
  22. ↑ Makarchikov AF, Lakaye B, Gulyai IE, Czerniecki J, Coumans B, Wins P, Grisar T, Bettendorff L (2003). "Thiamine triphosphate and thiamine triphosphatase activities: from bacteria to mammals". Cell Mol Life Sci. 60 (7): 1477–88. doi:10.1007/s00018-003-3098-4. PMID 12943234. 
  23. ↑ Bettendorff L, Hennuy B, De Clerck A, Wins P. (1994). "Chloride permeability of rat brain membrane vesicles correlates with thiamine triphosphate content". Brain Res. 652 (1): 157–60. doi:10.1016/0006-8993(94)90331-X. PMID 7953714. 
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