Sulbutiamine
Encyclopedia
Sulbutiamine 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 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
. 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. It is not clear when sulbutiamine was first synthesized, but the earliest reference to it in the literature is from 1973.
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 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 receptor
s, 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 receptor
s 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 synpatosomal 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.
Thiamine
Thiamine or thiamin or vitamin B1 , named as the "thio-vitamine" is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate derivatives are...
(vitamin B1). As a dimer of two modified thiamine molecules, it is a lipophilic compound that crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
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
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
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 also appears to improve memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
and erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
. At therapeutic dosages, it has few reported adverse effects, though it may interfere with the therapeutic outcome of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. It is available for over-the-counter sale
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
as a nutritional supplement.
History
Beriberi
Beriberi is a nervous system ailment caused by a thiamine deficiency in the diet. Thiamine is involved in the breakdown of energy molecules such as glucose and is also found on the membranes of neurons...
. 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
Allithiamine
Allithiamine , or thiamine allyl disulfide , is a lipid-soluble form of vitamin B1 which occurs naturally in garlic. It is more bioavailable than the water-soluble form of vitamin B1, thiamine, and is the preferred form to be taken in case of a vitamin deficiency....
, which was isolated from garlic
Garlic
Allium sativum, commonly known as garlic, is a species in the onion genus, Allium. Its close relatives include the onion, shallot, leek, chive, and rakkyo. Dating back over 6,000 years, garlic is native to central Asia, and has long been a staple in the Mediterranean region, as well as a frequent...
(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
Thiazole
Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen; the term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular formula C3H3NS...
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
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
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.
Asthenia
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 is uncertain. In a study of postinfectious chronic fatigue patients, sulbutiamine did not demonstrate sustained benefits over the placebo, which raises doubts about its clinical efficacy. 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
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 dizocilpineDizocilpine
Dizocilpine , also known as MK-801, is a non-competitive antagonist of the N-methyl-d-aspartate receptor, a glutamate receptor. Glutamate is the brain's primary excitatory neurotransmitter...
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
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
when used in conjunction with an acetylcholinesterase inhibitor
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...
. In a randomized double-blind study of Alzheimer's disease patients, the combination of sulbutiamine and donepezil
Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...
improved episodic memory and daylife activities better than the combination of donepezil and a placebo.
Erectile dysfunction
According to one recent study, sulbutiamine is effective for the treatment of psychogenic erectile dysfunction. 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, 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, and mild agitation has also been observed in elderly patients. There is only one published report where the chronic overuse of sulbutiamine caused complications. A 2006 report of a patient with bipolar disorder taking 2 g a day (far above a therapeutic dosage) concluded that such high doses of sulbutiamine may interfere with bipolar treatment. A patient with bipolar disorder was prescribed sulbutiamine because he was complaining of a lack of energy. The patient found the medication helpful, and began taking 2 g per day, far more than prescribed. Subsequently he stopped taking the 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 interfere with the therapeutic outcome of bipolar disorder, although this was an indirect effect since the patient's suspension of his other medications ultimately caused the issue with his treatment.Mechanism of action
Reticular activating system
The reticular activating system is an area of the brain responsible for regulating arousal and sleep-wake transitions.- History and Etymology :...
, which is the center of arousal and motivation in the brain. The administration of sulbutiamine potentiates cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
activity in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
. It also potentiates glutamatergic activity in the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
through a reduction in the density of kainate glutamate receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
s, 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
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the prefrontal cortex, which increases the density of D1 dopamine receptor
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
s 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
Thiamine triphosphate
Thiamine triphosphate is found in most organisms, bacteria, fungi, plants and animals.-Function:It has been proposed that ThTP has a specific role in nerve excitability but this has never been confirmed and recent results suggest that ThTP probably plays a role in cell energy metabolism...
(ThTP). Although the full physiological role of ThTP is unknown, it is an integral component of synpatosomal 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.