|Systematic (IUPAC) name|
|Biological half-life||5 hours|
|CAS Registry Number|
|Synonyms||Arcalion, bisibuthiamine, enerion, youvitan|
|Molecular mass||702.89 g/mol|
|(what is this?)|
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. 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.
Although its clinical efficacy is uncertain, it is the only compound used to treat asthenia that is known to selectively target the areas that are involved in the condition. 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.
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. 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. 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.
The first lipophilic thiamine derivative to be discovered was allithiamine, which was isolated from garlic (Allium sativum) in 1951. 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. 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.
||The following mainly relies on primary sources.|
Sulbutiamine is indicated for the treatment of asthenia. Asthenia is a condition of chronic fatigue that is cerebral rather than neuromuscular in origin. 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. 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. Nevertheless, the clinical efficacy of sulbutiamine for the treatment of fatigue is uncertain. In a study of postinfectious chronic fatigue patients, sulbutiamine did not demonstrate sustained benefits over the placebo. 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.
Several studies have shown that sulbutiamine improves memory through the potentiation of cholinergic, dopaminergic, and glutamatergic transmission. When sulbutiamine is administered to mice, they perform better on operant conditioning tests and object recognition tests. Sulbutiamine also reduces the amnesiac effects of dizocilpine and improves memory in schizophrenics. More recently, sulbutiamine has 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. In a randomized double-blind study of Alzheimer's disease patients, the combination of sulbutiamine and donepezil improved episodic memory and daylife activities better than the combination of donepezil and a placebo.
Sulbutiamine has been shown to reduce psycho-behavioural inhibition: a pattern of fearfulness, timidity, avoidance and guardedness surrounding new stimuli, commonly found in those suffering from shyness or depression. In a study of patients suffering from major depressive disorder and accompanying psycho-behavioural inhibition, those treated with sulbutiamine for four weeks (600 mg per day) were significantly less incapacitated than the placebo group in all of the various facets (affective, cognitive, emotional, behavioural) of psycho-behavioural inhibition. Sulbutiamine was noted as having no antidepressive effect, and both treatment groups were comparable with respect to safety data (in particular, sulbutiamine had not induced any inappropriate behaviour, including suicide attempts or mania). The authors concluded that sulbutiamine hastens the resolution of psycho-behavioural inhibition occurring during major depressive disorder and can thereby "facilitate the rehabilitation of patients in their social, professional and family-life functioning".
According to one recent study, sulbutiamine is effective for the treatment of psychogenic erectile dysfunction. Group of 20 patients with psychogenic erectile dysfunction received sulbutiamine for thirty days. After the treatment was over, erectile function improved in 16 of the patients.
Sulbutiamine is available in several forms. Arcalion is supplied in 200 mg tablets, and generic sulbutiamine is supplied in tablets, capsules, and powder. The therapeutic dosage has been reported to be 12.5 mg/kg (of IM injections), 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.
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.
Mechanism of action
||The following mainly relies on primary sources.|
||Animal studies referred to are not clearly stated as such.|
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. 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. The administration of sulbutiamine potentiates cholinergic activity in the hippocampus. 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. The facilitation of central glutamatergic transmission is a likely explanation for the ability of sulbutiamine to improve memory. 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. The modulation of dopaminergic transmission may also contribute to the ability of sulbutiamine to improve memory. 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, participates in the phosphorylation of proteins, and activates chloride channels that have a large unit conductance. The activation of chloride channels by ThTP may be involved in the modulation of receptor binding.
- 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.
- 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. doi:10.1186/1471-2210-8-10. PMC 2435522. PMID 18549472.
- 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.
- Van Reeth O (1999). "Pharmacologic and therapeutic features of sulbutiamine". Drugs Today (Barc) 35 (3): 187–92. PMID 12973384.
- 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
- 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. PMID 16550223.
- Lonsdale D (2004). "Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent". Med Sci Monit 10 (9): 199–203. PMID 15328496.
- 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.
- Ammo T, Sakai T, Fujihira EL, Aizawa T (1965). "Thiamine disulfide derivatives. I. Syntheses of thiamine disulfide derivatives". Bitamin 32 (2): 260–4.; Ammo T, Sakai T, Aizawa T, Fujihira E, Naganuma A (1965). "Thiamine disulfide derivatives. II. Biological activities of thiamine disulfide derivatives". Bitamin 32 (2): 265–77.; 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Ollat, H; B Laurent; S Bakchine; BF Michel; J Touchon; B Dubois (2007). "[Effects of the association of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease". Encephale 33 (2): 211–15. PMID 17675917.
- Lôo H, Poirier MF, Ollat H, Elatki S (2000). "[Effects of sulbutiamine (Arcalion 200) on psycho-behavioral inhibition in major depressive episodes]". L'Encéphale (in French) 26 (2): 70–5. PMID 10858919.
- 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.
- "Serdia Pharmaceuticals Arcalion summary". Retrieved 1 August 2012.
- 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.
- 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.
- Parada-Turska J, Turski WA (1990). "Excitatory amino acid antagonists and memory: effect of drugs acting at N-methyl-D-aspartate receptors in learning and memory tasks". Neuropharmacology 29 (12): 1111–6. doi:10.1016/0028-3908(90)90034-O. PMID 2149871.
- Puma C, Baudoin C, Bizot JC (1998). "Effects of intraseptal infusions of N-methyl-D-aspartate receptor ligands on memory in an object recognition task in rats". Neurosci Lett 244 (2): 97–100. doi:10.1016/S0304-3940(98)00137-2. PMID 9572594.
- Pussinen R, Sirviö J (1999). "Effects of D-cycloserine, a positive modulator of N-methyl-D-aspartate receptors, and ST 587, a putative alpha-1 adrenergic agonist, individually and in combination, on the non-delayed and delayed foraging behaviour of rats assessed in the radial arm maze". J Psychopharmacol (Oxford) 13 (2): 171–9. doi:10.1177/026988119901300210. PMID 10475724.
- Staubli U, Rogers G, Lynch G (1994). "Facilitation of glutamate receptors enhances memory". Proc Natl Acad Sci USA 91 (2): 777–81. doi:10.1073/pnas.91.2.777. PMC 43032. PMID 8290599.
- Bernaerts P, Tirelli E (2003). "Facilitatory effect of the dopamine D4 receptor agonist PD168,077 on memory consolidation of an inhibitory avoidance learned response in C57BL/6J mice". Behav Brain Res 142 (1–2): 41–52. doi:10.1016/S0166-4328(02)00371-6. PMID 12798264.
- Floresco SB, Phillips AG (2001). "Delay-dependent modulation of memory retrieval by infusion of a dopamine D1 agonist into the rat medial prefrontal cortex". Behav Neurosci 115 (4): 934–9. doi:10.1037/0735-7044.115.4.934. PMID 11508732.
- Levin ED, Bettegowda C, Weaver T, Christopher NC (1998). "Nicotine-dizocilpine interactions and working and reference memory performance of rats in the radial-arm maze". Pharmacol Biochem Behav 61 (3): 335–40. doi:10.1016/S0091-3057(98)00109-9. PMID 9768569.
- 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. PMID 6272323.
- 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.
- 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.