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Thiamine tetrahydrofurfuryl disulfide: A little known therapeutic agent

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Thiamine tetrahydrofurfuryl disulfide: A little known therapeutic agent

Abstract

Thiamine tetrahydrofurfuryl disulfide (TTFD) is the synthetic counterpart of allithiamine, occurring naturally in garlic. Allithiamine was discovered in Japan in 1951. Its extensive research was reported by a group known as the Vitamin B Research Committee of Japan, and given this name because of its existence in the bulbs of many of the allium species of plants. It was found to be a disulfide derivative of thiamine, produced as a result of enzymatic action on the thiamine molecule in garlic bulbs when the bulb is cut or crushed. Subsequent experimental work in both animals and human subjects revealed that its metabolic effect was much more powerful than the thiamine from which it was derived. Japanese investigators created a number of synthetic forms and investigated their use in a number of human disease conditions. Although some derivatives have been synthesized without a disulfide bond in the molecule, these investigators emphasized that the disulfide was an extremely important part of its biologic action and TTFD is the most modern of the disulfide derivatives. Because at least part of its beneficial effects are the same as water soluble thiamine salts, this review deals first with the clinical uses of thiamine (vitamin B1) in medicine.
Thiamine tetrahydrofurfuryl disulfi de: a little known
therapeutic agent
Derrick Lonsdale
Preventive Medicine Group, Westlake, Ohio,U.S.A.
Source of support: Self fi nancing.
Summary
Thiamine tetrahydrofurfuryl disulfi de (TTFD) is the synthetic counterpart of allithiamine, occur-
ring naturally in garlic. Allithiamine was discovered in Japan in 1951. Its extensive research was
reported by a group known as the Vitamin B Research Committee of Japan, and given this name
because of its existence in the bulbs of many of the allium species of plants. It was found to be a di-
sulfi de derivative of thiamine, produced as a result of enzymatic action on the thiamine molecule
in garlic bulbs when the bulb is cut or crushed. Subsequent experimental work in both animals
and human subjects revealed that its metabolic effect was much more powerful than the thiamine
from which it was derived. Japanese investigators created a number of synthetic forms and inves-
tigated their use in a number of human disease conditions. Although some derivatives have been
synthesized without a disulfi de bond in the molecule, these investigators emphasized that the di-
sulfi de was an extremely important part of its biologic action and TTFD is the most modern of the
disulfi de derivatives. Because at least part of its benefi cial effects are the same as water soluble thi-
amine salts, this review deals fi rst with the clinical uses of thiamine (vitamin B1) in medicine.
key words: thiamine disulfi de • neurological disease
Full-text PDF: http://www.MedSciMonit.com/pub/vol_10/no_9/4785.pdf
Word count: 2404
Tables:
Figures:
References: 65
Author’s address: Derrick Lonsdale M.D, 24700 Center Ridge Road, Westlake, Ohio 44145, U.S.A, e-mail: dlonsdale@pol.net
Received: 2004.01.14
Accepted: 2004.04.07
Published: 2004.09.01
RA199
Review Ar ticle
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© Med Sci Monit, 2004; 10(9): RA199-203
PMID: 15328496
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Search Strategy and Exclusion Criteria
Some important references were obtained from a book
written by the Vitamin B research Committee of Japan, a
group of university based scientists convened to study the
widespread occurrence of Beriberi in Japan. It was trans-
lated into English and published by a Japanese publishing
rm in Tokyo in 1965. The remainder of the references are
from both indexed and non-indexed medical journals. The
criteria for their selection are based on their relative rarity
in dealing with the largely ignored use of thiamine and its
derivatives in therapy.
BACKGROUND
A number of reviews on the therapeutic bene ts of thia-
mine and its disul de derivatives have been published [15].
Much of the research performed in Japan was published in
1965 in an English translation written by members of a sci-
enti c group known as the Vitamin B Research Committee
[6]. This book provides a comprehensive historical review
of Beriberi, its now well-known association with thiamine
metabolism, and a thorough account of the research details
of the disul de derivatives of thiamine. Thiamine de cien-
cy gives rise to symptoms in man that are different from the
classical presentation of beriberi, the disease that is com-
monly associated with this de ciency [7].
BIOCHEMISTRY OF THIAMINE AND ITS DISULFIDE DERIVATIVE
TTFD
Thiamine consists of a pyridinium ring joined to a thiazo-
lium ring by a methylene bridge. Disul de derivatives are
synthesized by attaching a prosthetic mercaptan to the sulfur
atom of the thiazolium ring. When this molecule comes into
contact with cell membranes, the disul de is fractured and
the prosthetic group remains outside the cell. The remain-
der of the molecule passes through the cell membrane, the
thiazolium ring closes and the cell now has an intact mol-
ecule of free thiamine in the cytosol. This transit through
cell membranes provides a high concentration of the vita-
min in the cell and the reaction does not require the trans-
port system needed for intracellular absorption of thiamine
[6] This advantage has been shown to give a high concen-
tration of thiamine in the blood. An administered dose of
TTFD given to human subjects shows much higher concen-
trations of thiamine than a comparable dose of a water-sol-
uble thiamine salt [3]. It is this ability to pass through the
lipid barrier of cell membranes that has given rise to its be-
ing sometimes referred to as fat-soluble. For clinical admin-
istration it is readily soluble in aqueous solution and can be
given intravenously.
Thiamine, entering the cell, must be phosphorylated to form
thiamine pyrophosphate (TPP), the cofactor to a number
of enzymes, including pyruvate dehydrogenase, branched
chain amino acid dehydrogenase and transketolase (TKA).
Of laboratory use in depicting intracellular thiamine de -
ciency, TKA occurs twice in the hexosemonophosphate shunt
and occurs in erythrocytes. Not so well known for its impor-
tance, TPP must then be phosphorylated again to form thi-
amine triphosphate (TTP), a vital component in the CNS
and in cell membrane physiology in general. In the brain,
TTP donates a phosphate to adenosine to form adenosine
triphosphate (ATP). Thus it is vitally important in ener-
gy balance in that tissue [8]. Because of its ready access to
cells, it has been shown that TTFD increases the concen-
tration of TTP in heart muscle, providing a strong negative
chronotropic and positive inotropic effect in heart muscle
[9] that was not affected by either atropine or propranolol
[10]. More recent studies have strongly supported its poten-
tial therapeutic use [11,12]. It has been demonstrated that
the metabolic fate of the prosthetic group, after fracture of
the disul de bond, results in a number of sulfur containing
compounds [13]. The therapeutic activity of the separated
prosthetic group, if any, has not been studied.
CLINICAL USE OF WATER-SOLUBLE THIAMINE SALTS
The pathology associated with Beriberi, in which thiamine
de ciency is closely associated, was shown to have a profound
effect on functions of the autonomic nervous system [6].
It has long been known that a high intake of glucose auto-
matically stresses the mechanism involved in entry of pyru-
vate into the citric acid cycle and the high intake of sugar in
the U.S. appears to be an explanation of calorie/thiamine
imbalance that constitutes relative thiamine de ciency, in
spite of food supplementation. Functional dysautonomia,
a term applied to a common constellation of symptoms,
has been associated with evidence of thiamine de ciency
in two publications [1415]. A patient has been described
with asymmetry in autonomic control whose pulse pressures
were widely different in the two arms [16].
One of the earliest experiments performed in human sub-
jects showed that classical symptoms usually ascribed to psy-
chosomatic disease were generated by mild to moderate
de ciency of thiamine [17]. Since TPP is the cofactor for
the enzyme transketolase it readily explains the nding of
an abnormal erythrocyte transketolase in many patients to-
day whose neurological and psychiatric symptoms are re-
lieved with large doses of thiamine associated with appro-
priate diet [1821].
Thiamine was synthesized for the rst time in 1936 [22] and
when Peters [23] discovered the action of thiamine pyro-
phosphate it produced a surge of basic science and clinical
research activity that was brought together in a publication
that celebrated the synthesis of this vitamin. This recorded
696 previously published reports of successful vitamin B1
therapy in more than 230 different diseases and syndromes
[24]. In the present medical model a cure for each dis-
ease entity is the focus of modern pharmaceutical research.
Another model can at least be suggested that seeks to sup-
port the patients self-healing [25,26].
It has been shown that administration of thiamine in large
doses has a central cholinergic effect. Thiamine was used to
treat a small group of patients with Alzheimer Disease [27].
Eleven patients had higher Mini-Mental State Examination
(MMSE) scores while they were receiving thiamine and the
difference as compared with control patients was highly sig-
ni cant statistically. Meador and associates also found some
improvement in the Alzheimer Disease Assessment Scale
(ADAS) in Alzheimer Disease [28]. Gibson and Zhang [29]
have noted that thiamine-dependent processes are dimin-
ished in brains of patients with several neurodegenerative
diseases and the decline in thiamine-dependent enzymes can
Review Article Med Sci Monit, 2004; 10(9): RA199-203
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be readily linked to the symptoms and pathology of these
disorders. They noted that the reason for these changes is
an important experimental and clinical question. The inter-
actions of thiamine with oxidative processes may be part of
a spiral of events that lead to neurodegeneration. Thiamine
dependency caused intermittent episodes of cerebellar atax-
ia in a 6-year old child [30,31]. His episodes of ataxia were
precipitated each time by infection, inoculation or a mild
head injury, factors that appeared to be stresses or triggers
to which he would probably not have succumbed without
the underlying metabolic defect in energy metabolism. He
required 300 mgs of thiamine a day for basic prevention
and up to 600 mgs with advent of any infection.
BASIC SCIENCE STUDIES OF TTFD
The disul de makes TTFD more powerful in its actions com-
pared with the readily available water-soluble thiamine salts,
since it does not require the rate limiting transport system
required for thiamine. Because of this there is a rapid build-
up of intracellular thiamine to be phosphorylated [8]. It is
suggested that TTFD would be a better choice than water-
soluble thiamine salts in the treatment of neurodegenera-
tive diseases [29].
Thiamine propyl disul de (TPD) produced an intense gar-
lic odor from the patient [6]. Attempts to remove this odor
resulted in many experimental molecules, of which TTFD
is the best and most modern. Although other lipophilic
derivatives of thiamine have been studied [32], it is the di-
sul des that have received the most attention since the dis-
covery of allithiamine in garlic [33]. Aside from the bioa-
vailability of thiamine that results from its administration
to animals and humans, the metabolism of the prosthetic
group has been well studied [3437], though the pharma-
ceutical action, if any, of this fragment has not been exam-
ined clinically to our knowledge. After oral administration
of TTFD to human subjects, urinary recovery of the 35S-la-
bel on the prosthetic group was 90% and 80% after intra-
venous injection. The average urinary excretion of the thi-
amine moiety was 30% [38]. This suggests that about 50%
of the administered TTFD given by oral ingestion is hydro-
lyzed in the gastrointestinal tract, and the route of admin-
istration may be extremely important in the process of get-
ting the intact disul de TTFD molecule into body tissues,
thus affecting its form of administration for clinical use. It
was shown that thiamine derivatives were acceptor substrates
to thioltansferase activity [39].
Like the studies that showed the cholinergic effect of water-
soluble thiamine [27], experimental data with TTFD sup-
ported this effect [40]. Weanling DBA/J2 mice experience
audiogenically-stimulated seizures between 19 and 24 days
after birth. These seizures are known to be cholinergic in
origin and the reason for their appearance and spontaneous
disappearance in this strain is unknown. Pretreatment with
TTFD, administered by intraperitoneal injection, increased
their seizure response to audiogenic stimulus. The result-
ing seizures were more severe and prolonged the time until
spontaneous disappearance occurred, strongly suggesting
that it enhanced the cholinergic mechanism involved.
Other basic science experiments have shown evidence of the
cholinergic effect of TTFD. It was found that injecting it into
a closed loop of denervated dog jejunum caused peristalsis
[41]. A number of studies were reported by the Vitamin B
Research Committee of Japan [6]. When rodents were giv-
en foods supplemented by thiamine propyl disul de (TPD)
the body weight increased at a faster rate than in those re-
ceiving water soluble thiamine salts or no thiamine supple-
ment. Administration of TPD, that has the same biologic ef-
fects as TTFD, was effective in prevention of both lead and
trichlorethylene intoxication produced experimentally in
animal studies. Mice, when pretreated with 1 mg of TPD
given intravenously, were partially protected from a dose of
150 µg/10g body weight of potassium cyanide. The death
rate in controls was 70.6% and only 11.7% in the pretreat-
ed animals. The investigators went on to show that this was
because TPD stimulated the activity of the enzyme rhoda-
nese that occurs in liver and converts toxic cyanide ions to
non-toxic thiocyanate, an important part of the transsulfu-
ration pathway. These investigators also noted that S-acyl
derivatives of thiamine are devoid of the preventive effect
against intoxication of this nature that characterize the di-
sul de derivatives. They ascribed this difference to absence
of the S-S bond. Although the disul de derivatives are eas-
ily reduced to thiamine in the presence of cystine or glu-
tathione, the S-acyl-thiamine molecules resist this simple
reduction, being reduced to thiamine only after enzymatic
action in liver or kidney.
Ultracytochemical studies in animals revealed that thiamine
and TTFD increased the presence of acetylcholinesterase
[42], and daily administration of TTFD to pregnant CF-1
mice and SD rats at a dose as high as 300 mg/Kg (equiva-
lent to 50100 times the usual human therapeutic dosage)
during the critical stages of organ differentiation failed to
produce any signi cant developmental abnormality [43].
Intraperitoneally administered TTFD and TPD showed a
strong inhibitory effect on carrageenin induced rat paw ede-
ma that was not observed when administered orally. This
anti-in ammatory effect was not seen with non-disul de de-
rivatives or with water-soluble thiamine [44]. This supports
the data that show the method of administration and the
choice of thiamine derivative make a possible difference to
the therapeutic outcome.
CLINICAL USES OF TTFD
Clinical use of TTFD in Japan is well established. It has been
used in the treatment of diabetic neuropathy [45], in post-
operative paralytic ileus [46] and its effect was tested on
muscle strength in athletes [47].
In a 12-week open trial, TTFD produced some bene ts in
Alzheimers Disease [48]. Four infants with repeated apnea
who had abnormal Brainstem Auditory Evoked Potentials
(BAEP) responded to therapeutic doses of TTFD and their
BAEP tracings improved [49]. Defective thiamine homeos-
tasis has been reported to be important in Sudden Infant
Death Syndrome (SIDS) [50,51]. Davis and associates [52]
found high blood levels of thiamine in SIDS victims, sug-
gesting that thiamine might be present in its free, unphos-
phorylated form. This study strongly suggests that thiamine
homeostasis is a factor in the etiology of SIDS [53].
A partial response was observed in Leighs Disease (Subacute
Necrotizing Encephalomyelopathy) by using TPD [54] and
Med Sci Monit, 2004; 10(9): RA199-203 Lonsdale D Thiamine tetrahydrofurfuryl disul de: a little known therapeutic agent
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TTFD [55], and it was found in a clinical trial that TTFD
provided some bene t in advanced mental deterioration of
Downs Syndrome children [56].
Lonsdale et al. [57] reported a pilot study, using TTFD in
the form of rectal suppositories, to treat 10 children with
autistic spectrum disease (ASD). This was followed by an in-
crease in urinary heavy metals. Abnormal erythrocyte tran-
sketolase tests indicated thiamine de ciency in 3 of the 8
children before treatment and in one individual at the ter-
mination of the study, in spite of the fact that thiamine was
being given in therapeutic doses. This suggests that thia-
mine de ciency may be related, at least in some cases, to
oxidative stress in this condition [29]. Although it is clear
that a larger study is needed, TTFD shows promise as a ther-
apeutic tool in the poorly understood biochemistry in ASD
children. This disease is emerging in epidemic form [58].
A clear-cut diagnostic marker is yet to be found for the bio-
chemical changes that are reported and the treatment ap-
plied [5961]. The role of vaccines and the effect of metal-
containing preservatives have been reviewed [62].
Thiamine has been shown to remove lead from the tissues
in experimentally induced toxicity in animals [6365]. As
one of the transitional metals, all of which depend on their
SH reactivity for their toxicity, the action by thiamine should
be the same for all. The prosthetic mercaptan from TTFD
may have an important clinical effect irrespective of the thi-
amine molecule introduced to the cell. Although not stud-
ied, it is possible that it is this part of the TTFD molecule
that removes SH-reactive metals from tissues, allowing their
excretion in urine.
CONCLUSIONS
Thiamine tetrahydrofurfuryl disul de is a valuable thera-
peutic tool and it should be better known. It appears to be
bene cial in many conditions. Thus, we have to conclude
that multiple pathophysiological situations are at least part-
ly associated with defective energy metabolism, particular-
ly in the central nervous system. The work of Gibson and
Zhang [29] support the potential importance of therapeu-
tic thiamine.
The clinical use of TTFD has been used by the author under
Independent Investigator Licence 11019 from the Federal
Drug Administration, issued in 1973.
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... For example, this moiety is found in N-formylloline, an alkaloid produced by grass [2], and acts as an intermediate in biochemical processes, such as methanogenesis [3]. Some examples of formamide-containing drugs are benfotiamine (diabetic neuropathy) [4], leucovorin (toxic effects of methotrexate and pyrimethamine) [5], vincristine (anticancer) [6], and fursultiamine (thiamine deficiency) [7]. Considering the prevalence and importance of the formamide functionality, many researchers have developed efficient methods for attaching a formyl group to an amine [8][9][10]. ...
... 6 Au-Fe3O4 (2.8 mol%) was used as a catalyst. 7 An air balloon was used instead of O2. 8 An average value of three runs (91%, 90%, and 88%). 9 Result with 1a (0.50 mmol) in MeOH (2.0 mL). 10 Yield of isolated product. ...
Article
Full-text available
Bimetallic catalysts are gaining attention due to their characteristics of promoting reactivity and selectivity in catalyzed reactions. Herein, a new catalytic N-formylation of secondary amines using AuPd–Fe3O4 at room temperature is reported. Methanol was utilized as the formyl source and 1.0 atm of O2 gas served as an external oxidant. The bimetallic catalyst, consisting of Au and Pd, makes the reaction more efficient than that using each metal separately. In addition, the catalyst can be effectively recycled owing to the Fe3O4 support.
... For example, this moiety is found in N-formylloline, an alkaloid produced by grass [2], and acts as an intermediate in biochemical processes, such as methanogenesis [3]. Some examples of formamide-containing drugs are benfotiamine (diabetic neuropathy) [4], leucovorin (toxic effects of methotrexate and pyrimethamine) [5], vincristine (anticancer) [6], and fursultiamine (thiamine deficiency) [7]. Considering the prevalence and importance of the formamide functionality, many researchers have developed efficient methods for attaching a formyl group to an amine [8][9][10]. ...
... 6 Au-Fe3O4 (2.8 mol%) was used as a catalyst. 7 An air balloon was used instead of O2. 8 An average value of three runs (91%, 90%, and 88%). 9 Result with 1a (0.50 mmol) in MeOH (2.0 mL). 10 Yield of isolated product. ...
Article
Full-text available
Bimetallic catalysts are gaining attention due to their characteristics of promoting reactivity and selectivity in catalyzed reactions. Herein, a new catalytic N-formylation of secondary amines using AuPd–Fe3O4 at room temperature is reported. Methanol was utilized as the formyl source and 1.0 atm of O2 gas served as an external oxidant. The bimetallic catalyst, consisting of Au and Pd, makes the reaction more efficient than that using each metal separately. In addition, the catalyst can be effectively recycled owing to the Fe3O4 support.
... It was an allyl disulfide derivate known as allithiamine. It is more readily absorbed in the intestine, more stable than thiamine, and is not decomposed by thiaminase [22,[134][135][136][137]. Then, based upon the molecular structure of allithiamine, a class of synthetic derivatives have been synthesized, such as sulbutiamine (O-isobutyryl thiamine disulfide), fursultiamine (thiamine tetrahydrofurfuryl disulfide), benfotiamine (S-benzoylthiamine O-monophosphate; see Figure 5), etc. ...
Article
Full-text available
This review summarizes the current knowledge on essential vitamins B1, B2, B3, and B5. These B-complex vitamins must be taken from diet, with the exception of vitamin B3, that can also be synthetized from amino acid tryptophan. All of these vitamins are water soluble, which determines their main properties, namely: they are partly lost when food is washed or boiled since they migrate to the water; the requirement of membrane transporters for their permeation into the cells; and their safety since any excess is rapidly eliminated via the kidney. The therapeutic use of B-complex vitamins is mostly limited to hypovitaminoses or similar conditions, but, as they are generally very safe, they have also been examined in other pathological conditions. Nicotinic acid, a form of vitamin B3, is the only exception because it is a known hypolipidemic agent in gram doses. The article also sums up: (i) the current methods for detection of the vitamins of the B-complex in biological fluids; (ii) the food and other sources of these vitamins including the effect of common processing and storage methods on their content; and (iii) their physiological function.
... In contrast, when FT contacts the cell membrane, the disulfide is destroyed, the rest of the molecule penetrates the membrane, and the thiazolium ring is closed by a reduction reaction. This non-carriermediated transit through cell membranes leads to an accumulation of thiamine in cells [51]. This reaction has the advantage that does not demand the transport system required for intracellular absorption of thiamine [52]. ...
Article
Full-text available
Drug-induced hearing loss is a major type of acquired sensorineural hearing loss. Cisplatin and aminoglycoside antibiotics have been known to cause ototoxicity, and excessive accumulation of intracellular reactive oxygen species (ROS) are suggested as the common major pathology of cisplatin- and aminoglycoside antibiotics-induced ototoxicity. Fursultiamine, also called thiamine tetrahydrofurfuryl disulfide, is a thiamine disulfide derivative that may have antioxidant effects. To evaluate whether fursultiamine can prevent cisplatin- and kanamycin-induced ototoxicity, we investigated their preventive potential using mouse cochlear explant culture system. Immunofluorescence staining of mouse cochlear hair cells showed that fursultiamine pretreatment reduced cisplatin- and kanamycin-induced damage to both inner and outer hair cells. Fursultiamine attenuated mitochondrial ROS accumulation as evidenced by MitoSOX Red staining and restored mitochondrial membrane potential in a JC-1 assay. In addition, fursultiamine pretreatment reduced active caspase-3 and TUNEL signals after cisplatin or kanamycin treatment, indicating that fursultiamine decreased apoptotic hair cell death. This study is the first to show a protective effect of fursultiamine against cisplatin- and aminoglycoside antibiotics-induced ototoxicity. Our results suggest that fursultiamine could act as an antioxidant and anti-apoptotic agent against mitochondrial oxidative stress.in cochlear hair cells
... 18 For the peer review companion paper, see Luo et al. 19 In the meantime, others have confirmed that gemfibrozil not only reduces amyloid pathology in a mouse model of Alzheimer's disease but also improves memory 20 Age-related macular degeneration continues to be the leading cause of legal blindness in industrialized nations, although VEGF inhibitor antibodies and binding proteins have made the exudative form of choroidal neovascularization treatable. The present inventors have demonstrated that fursultiamine (thiamine tetrahydrofurfuryl disulfide, TTFD), which is used in the treatment of thiamine deficiency, 21 reduces the increased expression of the angiogenesis promoter HIF-1a in the ARPE-19 retinal pigment epithelial cell line under hypoxic conditions, and it inhibits choroidal vascular endothelial cell growth in the ex vivo mouse choroid sprouting assay. In both models, the effect of fursultiamine became apparent at 20 mM, and it was complete at 100 mM. ...
... TTFD is the synthetic equivalent of allithiamine, a naturally occurring disulfide derivative of thiamine [9]. Well studied by Japanese researchers, it partially protected TTFD pre-treated mice from cyanide poisoning [10]. ...
... The use of TTFD as a therapeutic agent is hardly known in the West [47]. Thiamine deficiency from dietary abuse, together with genetic mutations that appear to be relatively common, are producing widespread polysymptomatic disease, often misdiagnosed as psychological [48]. ...
Article
The resurgence of interest in cancer metabolism has linked alterations in the regulation and exploitation of metabolic pathways with an anabolic phenotype that increases biomass production for the replication of new daughter cells. To support the increase in the metabolic rate of cancer cells, a coordinated increase in the supply of nutrients, such as glucose, as well as micronutrients functioning as enzyme cofactors is required. The majority of co-enzymes are derivatives of water-soluble vitamins such as niacin, folate, pantothenic acid, pyridoxine, biotin, riboflavin and thiamine (Vitamin B1). Continuous dietary intake of these micronutrients is essential for maintaining normal health. How cancer cells adaptively regulate cellular homeostasis of cofactors and how they can regulate expression and function of metabolic enzymes in cancer is under-appreciated. Exploitation of cofactor-dependent metabolic pathways with the advent of anti-folates highlights the potential vulnerabilities and importance of vitamins in cancer biology. Vitamin supplementation products are easily accessible and patients often perceive them as safe and beneficial without full knowledge of their effects. Thus, understanding the significance of enzyme cofactors in cancer cell metabolism will provide for important dietary strategies and new molecular targets to reduce disease progression. Recent studies have demonstrated the significance of thiamine-dependent enzymes in cancer cell metabolism. Therefore, this hypothesis discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells.
... High doses of the membrane-permeable pharmacological form of thiamine, thiamine tetrahydrofurfuryl disulfide (fursultiamine), which is a synthetic analog of the naturally occurring allithiamine, have been successfully used in humans (Lonsdale, 2004). A recent toxicology study according to OECD Guideline 407, performed in mice, has shown that thiamine tetrahydrofurfuryl disulfide has no adverse effects of a long-term supplementation with up to 500 mg per kg (equivalent to 40 mg per kg in humans), improving glucose metabolism and endurance (Huang et al., 2018). ...
Article
Glutamate dehydrogenase (GDH) is essential for the brain function and highly regulated, according to its role in metabolism of the major excitatory neurotransmitter glutamate. Here we show a diurnal pattern of the GDH acetylation in rat brain, associated with specific regulation of GDH function. Mornings the acetylation levels of K84 (near the ADP site), K187 (near the active site) and K503 (GTP‐binding) are highly correlated. Evenings the acetylation levels of K187 and K503 decrease, and the correlations disappear. These daily variations in the acetylation adjust the GDH responses to the enzyme regulators. The adjustment is changed when the acetylation of K187 and K503 shows no diurnal variations, as in the rats after a high dose of thiamine. The regulation of GDH function by acetylation is confirmed in a model system, where incubation of the rat brain GDH with acetyl‐CoA changes the enzyme responses to GTP and ADP, decreasing the activity at sub‐saturating concentrations of substrates. Thus, the GDH acetylation may support cerebral homeostasis, stabilizing the enzyme function during diurnal oscillations of the brain metabolome. Daytime and thiamine interact upon the (de)acetylation of GDH in vitro. Evenings the acetylation of GDH from control animals increases both IC50GTP and EC50ADP. Mornings the acetylation of GDH from thiamine‐treated animals increases the enzyme IC50GTP. Molecular mechanisms of the GDH regulation by acetylation of specific residues are proposed. For the first time, diurnal and thiamine‐dependent changes of the allosteric regulation of the brain GDH due to the enzyme acetylation are shown.
Article
Iron is an essential element for the mammalian body however, its homeostasis must be regulated accurately for appropriate physiological functioning. Alterations in physiological iron levels can lead to moderate to severe iron disorders like chronic and acute iron deficiency (anemia) or iron overload. Hepcidin plays an important role in regulating homeostasis between circulating iron and stored iron in the cells as well as the absorption of dietary iron in the intestine. Inflammatory disorders restrict iron absorption from food due to increased circulating levels of hepcidin. Increased production of hepcidin causes ubiquitination of ferroportin (FPN) leading to its degradation, thereby retaining iron in the spleen, duodenal enterocytes, macrophages, and hepatocytes. Hepcidin inhibitors and antagonists play a consequential role to ameliorate inflammation-associated anemia. Many natural and synthesized compounds, able to reduce hepcidin expression during inflammation have been identified in recent years. Few of which are currently at various phases of clinical trial. This article comprises a comprehensive review of therapeutic approaches for the efficient treatment of anemia associated with inflammation. Many strategies have been developed targeting the hepcidin-FPN axis to rectify iron disorders. Hepcidin modulation with siRNAs, antibodies, chemical compounds, and plant extracts provides new insights for developing advanced therapeutics for iron-related disorders. Hepcidin antagonist's treatment has a high potential to improve iron status in patients with iron disorders, but their clinical success needs further recognition along with the identification and application of new therapeutic approaches.
Article
Full-text available
Цель исследования: Представить читателю данные о фармакологической активности сульбутиамина (одного из липофильных производных тиамина), о механизмах его терапевтического эффекта, о его показаниях к применению и о доказательной базе для его применения в психиатрии, наркологии и неврологии, а также при некоторых общесоматических патологиях. Методология проведения работы: Мы провели поиск и изучение литературных данных о тиамине и сульбутиамине в поисковых системах и базах данных PubMed, Google Scholar, Science Direct, с использованием соответствующих ключевых слов. Результаты: Найденные нами в ходе составления настоящего обзора литературные данные свидетельствуют о том, что сульбутиамин может обладать рядом ценных для клинической практики свойств, в частности, антиоксидантным, нейропротективным, ноотропным, психостимулирующим, энергизирующим и антиастеническим действием и, возможно, также умеренными антидепрессивными, анксиолитическими и анальгетическими свойствами. Он может быть эффективным в составе комплексной терапии деменции Альцгеймера, депрессивных и тревожных расстройств, расстройств аутистического спектра, синдрома дефицита внимания и гиперактивности, астенических состояний разного генеза и др. Область применения результатов: Результаты этого обзора заслуживают самого широкого применения в психиатрии, наркологии и неврологии. Ключевые слова: сульбутиамин, тиамин, липофильные аналоги тиамина, астения, депрессивные расстройства, расстройства аутистического спектра, синдром дефицита внимания и гиперактивности Purpose: To provide the reader the comprehensive scientific data regarding the pharmacological activity of sulbuthiamine (one of the lipophilic derivatives of thiamine), the putative mechanisms of its therapeutic effect, indications for its use in medicine, and, finally, the existing evidence base for its use in psychiatry, addiction medicine and neurology, as well as in some somatic pathologies. Methodology: To this goal, we have searched and studied the available scientific data on thiamine and sulbutiamine using search engines and databases PubMed, Google Scholar, Science Direct, with the use of corresponding keywords. Results: The data we have obtained in the process of compiling this review indicate that sulbuthiamine can have several properties which are valuable for clinical practice. It can have antioxidant, neuroprotective, nootropic, psychostimulant, energizing and antiasthenic effects and, possibly, also moderate antidepressant, anxiolytic and analgesic properties. It might be effective as a part of combination therapy in Alzheimer dementia, major depression, anxiety disorders, autistic spectrum disorders, attention deficit hyperactivity disorder, asthenia of different origin, and so on. Practical implications: The results we have presented in this review deserve the widest application in psychiatry, addiction medicine and neurology. Keywords: sulbuthiamine, thiamine, lipophilic thiamine analogues, asthenia, depressive disorders, autism spectrum disorders, attention deficit hyperactivity syndrome
Article
The effect of TTFD chiefly on muscle strength in athletes, mainly track and field, in training camp was examined. The double-blind method was used. The test group (T-group) was given 150mg/day of TTFD while the control group (P-group) was given 3mg/day of TTFD. The duration of administration was two weeks. The following results were obtained.1) In the following test items, T-group (150mg/day) showed higher values than P-group (3mg/day) in a significant difference:sargent test (morning) at 5% levelsargent test (evening) at 2.5% levelleft grip strength (evening) at 5% levelright grip strength (morning) at 10% levelNo significant differences were found in other test items.2) In the P-group, difference between 2 week stage (non-treated period) and 4 week stage (treated period) was observed to have a trend for decline in the various test items. On the contrary, in the T-group, no decline was observed and a trend for a rise was found in all test items.3) No adverse effects attributable to TTFD were noted with administration of 3mg/ day nor 150mg/day for 2 weeks.4) The influence of administration of TTFD 150mg/day was discussed on effectiveness of training as shown by the increase of motor ability.
Article
In the first study of isolated thiamine deficiency, which Smith and two of us (R. D. W. and H. L. M.1) made in 1939, 4 young women were maintained on a basal diet which provided 0.15 mg. of thiamine per day (0.075 mg. per thousand calories of the diet) for 147 days. Vitamin A, vitamin D, ascorbic acid (vitamin C), niacin (nicotinic acid), riboflavin, iron and calcium were provided as supplements to this diet. The study of severe restriction of thiamine was repeated in 1940 with 4 young women who were maintained on the same basal diet for 88 days.2 In the later study vitamins of the B complex, other than thiamine, were provided by administration of 20 Gm. of autoclaved brewers' yeast per day. This yeast after autoclaving did not contain any thiamine. Its content of the other factors of the vitamin B complex was less severely
Article
The functioning of the brain is affected by the molecular concentrations of many substances that are normally present in the brain. The optimum concentrations of these substances for a person may differ greatly from the concentrations provided by his normal diet and genetic machinery. Biochemical and genetic arguments support the idea that orthomolecular therapy, the provision for the individual person of the optimum concentrations of important normal constituents of the brain, may be the preferred treatment for many mentally ill patients. Mental symptoms of avitaminosis sometimes are observed long before any physical symptoms appear. It is likely that the brain is more sensitive to changes in concentration of vital substances than are other organs and tissues. Moreover, there is the possibility that for some persons the cerebrospinal concentration of a vital substance may be grossly low at the same time that the concentration in the blood and lymph is essentially normal. A physiological abnormality such as decreased permeability of the blood-brain barrier for the vital substance or increased rate of metabolism of the substance in the brain may lead to a cerebral deficiency and to a mental disease. Diseases of this sort may be called localized cerebral deficiency diseases. It is suggested that the genes responsible for abnormalities (deficiencies) in the concentration of vital substances in the brain may be responsible for increased penetrance of the postulated gene for schizophrenia, and that the so-called gene for schizophrenia may itself be a gene that leads to a localized cerebral deficiency in one or more vital substances.
Article
Steinschneider presented good evidence that infants who died suddenly and unexpectedly frequently have premonitory symptoms which enable the alert physician to recognize the danger (Pediat 50:646, 1972). Fehily (Br. Med. J. 2:590, 1944) described a syndrome of sudden death in Chinese infants in Hong Kong called “breast milk toxicity syndrome”. It commonly occurred in infants who were breast fed by their B1 avitaminotic mothers and was related to caloric intake. When maternal calorie intake was forcibly reduced by Japanese invaders, the syndrome disappeared. It reappeared when rationing of rice was discontinued. Rarity of the syndrome under the age of 1 month and over 5 months, a peak incidence at 3-4 months, predilection for “well nourished” males, higher incidence in early spring, death during sleep and lack of autopsy histopathology, were identical to the epidemiology of modern S.I.D.S. with the exception of breast Vs bottle feeding. Japanese investigators showed that thiamine deficiency produced autonomic dysfunction and detected histopathology within the central and peripheral components of the system. In 9 infants within this age group, symptoms of autonomic dysfunction suggested candidacy for S.I.D.S. and included life threatening apnea in all. Monitoring in hospital confirmed the symptoms. All of the infants were treated with thiamine hydrochloride, varying from 30 to 300 mg/day. No damaging side effects were seen and symptoms disappeared rapidly in all. All are well in follow up and only 2 have remained extensively dependent upon thiamine.
Article
Functional dysautonomia has been reported in relation to a large number of human disorders [1,2]. Conventionally, it is usually regarded as a complication of a given disease, as for example, in diabetes [3], although it has been observed as a condition in its own right [4–8]. The case of a patient with an array of symptoms, many of them clearly dysautonomic, is reported here. An unusual feature was the finding of asymmetric blood pressures in the two arms. In particular, there was a marked difference in pulse pressures which decreased by 50% after nutritional therapy.
Article
The study of vitamin biochemistry is still in a relatively early stage of development. The discovery of allithiamine in Japan gave a strong impetus to the study of thiamine as a potential therapeutic agent rather than a simple vitamin replacement. When it was discovered that allithiamine was a naturally occurring substance that is formed when thiamine combines with a principle in garlic bulbs, a massive research effort was mounted by Japanese investigators. This resulted in a range of synthetic derivatives which were demonstrated to have some remarkable properties. It is surprising that more use has not been made of this information. Little is known in the West about these compounds and this is the purpose of this review.