PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study.

Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 µSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

The Effects of Thiamine Tetrahydrofurfuryl Disulfide on Physiological Adaption and Exercise Performance Improvement.

Thiamine, named as vitamin B1, is an important cofactor for the critical enzymes regarding to glucose metabolism, like transketolase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase. The thiamine tetrahydrofurfuryl disulfide (TTFD) is a derivative of thiamine with higher bioavailability and solubility than thiamine and has been widely applied to health maintenance and disease therapy. Higher physical activities are associated with higher thiamine supplements for efficient energy metabolism. Furthermore, the effective dose of TTFD, beneficial to exercise physiological adaption and performance, still be further validated and the safety evaluation were also an important issue to be considered for potential application. ICR (Institute of Cancer Research) strain mice were allocated as 0, 50, 100, and 500 mg/kg dose groups and administrated by oral gavage consecutively for 6 weeks. Physical activities including grip strength and aerobic endurance were measured. Various fatigue-associated biochemical variables such as lactate, glucose, blood urine nitrogen (BUN) or creatine kinase (CK), were also assessed. The levels of liver and muscle glycogen were measured as an indicator of energy storage at the end of the experiment. Toxicity assessments for long-term supplementation were also further evaluated for safety consideration. TTFD supplementation significantly increased the endurance and grip strength and demonstrated beneficial effects on lactate production and clearance rate after an acute exercise challenge. The TTFD supplementation significantly mitigated the BUN and CK indexes after extended exercise and elevated the glycogen content in the liver and muscle tissues. According to body composition, biochemical and histopathological data, daily administration of TTFD for over 6 weeks (subacute toxicity) also demonstrated reasonable safety results for long-term and adequate supplementation. The toxicity of TTFD were also considered as safety for long-term supplementation with indicated doses. Furthermore, the TTDF could be applied to not only the health promotion but also improvement of exercise physiological adaption and the TTFD could be further considered as potential ergogenic aids combined with different nutrient strategy.

Thiamine tetrahydrofurfuryl disulfide promotes voluntary activity through dopaminergic activation in the medial prefrontal cortex.

A physically active lifestyle is associated with better health in body and mind, and it is urgent that supporting agents for such lifestyles be developed. In rodents, voluntary locomotor activity as an active physical behavior may be mediated by dopaminergic neurons (DNs). Thiamine phosphate esters can stimulate DNs, and we thus hypothesized that thiamine tetrahydrofurfuryl disulfide (TTFD), a thiamine derivative, promotes locomotor activity via DNs in rats. Acute i.p. administration of TTFD enhanced rat locomotor activity in a normal cage. In vivo microdialysis revealed that TTFD-enhanced locomotor activity was synchronized with dopamine release in the medial prefrontal cortex (mPFC). Antagonism of the dopamine D1 receptor, but not D2 receptor, in the mPFC fully suppressed TTFD-enhanced locomotor activity. Finally, we found a TTFD dose-dependent increase in voluntary wheel running. Our findings demonstrate that DNs in the mPFC mediates TTFD-enhanced locomotor activity, suggesting the potential of TTFD to induce active physical behavior.

The effect of thiamin tetrahydrofurfuryl disulfide on behavior of juvenile DBA/2J mice.

Due to genetic defects or illness some individuals require higher amounts of thiamin than are typically provided by the diet. Lipid-soluble thiamin precursors can achieve high blood levels of thiamin and result in increased concentrations in the central nervous system. High intakes of thiamin have been reported as beneficial in children with autism and attention deficit/hyperactivity disorder. The current study examined the effect of thiamin tetrahydrofurfuryl disulfide (TTFD), a lipophilic precursor, on behavior in the juvenile male DBA/2J mouse. Mice given by oral gavage deionized water or deionized water providing 100 mg or 340 mg TTFD/kg body weight daily for 17 d, starting at postnatal day 18, were tested for effects on operant learning, social interaction, general activity level, and prepulse inhibition of acoustic startle, as well as effects on growth and select organ weights. Results indicate lower activity and altered social interaction at both treatment levels and decreased acoustic startle at the 100 mg/kg level. Compared to controls, percent weight gain was lower in the TTFD-treatment groups, but percent body length increase was not affected by TTFD treatment. TTFD treatment did not influence percent organ weights as percentage of body weights. TTFD treatment resulted in increased whole brain thiamin concentrations. These results support the concept that lipophilic thiamin precursors provided during early development can affect a number of behavioral parameters. In clinical trials with children with behavior disorders, attention should be given to preventing possible adverse gastrointestinal irritant effects associated with TTFD therapy.

A case of anorexia nervosa with Marchiafava-Bignami Disease that responded to high-dose intravenous corticosteroid administration.

We report the first known case of anorexia nervosa (AN) with Marchiafava-Bignami Disease (MBD) that responded to high-dose intravenous corticosteroid administration. A 16-year-old Japanese female with AN was diagnosed with MBD after rapid weight loss. During the acute stage, she suffered from a sudden onset of coma. After regaining consciousness, she presented with lack of movement, apathy, labile affect, and poverty of speech. On admission, magnetic resonance imaging showed an area of demyelination in the splenium of the corpus callosum. Positron emission tomography obtained 7 days after admission showed areas of hypoperfusion in the medial temporal lobe and in regions anterior and posterior to the central sulcus.

Human brain activation in response to olfactory stimulation by intravenous administration of odorants.

To identify the BOLD effects related to olfaction in humans, we recorded functional magnetic resonance imaging (fMRI) scans in response intravenously instilled thiamine propyl disulfide (TPD) and thiamine tetrahydrofurfuryl disulfide monohydrochloride (TTFD). TPD and TTFD evoked a strong and weak odor sensation, respectively. Since we did not spray the odor stimuli directly, this method is expected to reduce the effect caused by direct stimulation of the trigeminal nerve. For the analysis of fMRI data, statistical parametric mapping (SPM2) was employed and the areas significantly activated during olfactory processing were located. Both strong and weak odorants induced brain activities mainly in the orbitofrontal gyrus (Brodmann's area: BA 11) in the left hemisphere. TPD (a strong odorant) induced activity in the subthalamic nucleus in the left hemisphere and the precentral gyrus (BA 6) and insula in the right hemisphere. TTFD (a weak odorant) induced activity in the superior frontal gyrus (BA 11) in the right hemisphere. In both circumstances, there was an increase in blood flow at the secondary olfactory cortex (SOC) but not the primary olfactory cortex (POC), probably due to a habituation effect in the POC. From the present results, we found brain activity in not only odor-specific regions but also regions whose levels of activity were changed by an intensity difference of odor stimuli.

ST-segment elevation of electrocardiogram in a patient with Shoshin beriberi.

We report a case of a 58-year-old man with Shoshin beriberi who demonstrated ST-segment elevation and myocardial damage without coronary artery stenosis. The patient subsequently recovered with thiamine treatment. We conclude that it is important to consider Shoshin beriberi as part of the differential diagnosis in patients with shock and ST-segment elevation.

Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study.

OBJECTIVES: In a Pilot Study, the clinical and biochemical effects of thiamine tetrahydrofurfuryl disulfide (TTFD) on autistic spectrum children were investigated. SUBJECTS AND METHODS: Ten children were studied. Diagnosis was confirmed through the use of form E2, a computer assessed symptom score. For practical reasons, TTFD was administered twice daily for two months in the form of rectal suppositories, each containing 50 mg of TTFD. Symptomatic responses were determined through the use of the computer assessed Autism Treatment Evaluation Checklist (ATEC) forms. The erythrocyte transketolase (TKA) and thiamine pyrophosphate effect (TPPE), were measured at outset and on completion of the study to document intracellular thiamine deficiency. Urines from patients were examined at outset, after 30 days and after 60 days of treatment and the concentrations of SH-reactive metals, total protein, sulfate, sulfite, thiosulfate and thiocyanate were determined. The concentrations of metals in hair were also determined. RESULTS: At the beginning of the study thiamine deficiency was observed in 3 out of the 10 patients. Out of 10 patients, 6 had initial urine samples containing arsenic in greater concentration than healthy controls. Traces of mercury were seen in urines from all of these autistic children. Following administration of TTFD an increase in cadmium was seen in 2 children and in lead in one child. Nickel was increased in the urine of one patient during treatment. Sulfur metabolites in urine did not differ from those measured in healthy children. CONCLUSIONS: Thiamine tetrahydrofurfuryl disulfide appears to have a beneficial clinical effect on some autistic children, since 8 of the 10 children improved clinically. We obtained evidence of an association of this increasingly occurring disease with presence of urinary SH-reactive metals, arsenic in particular.

Pharmacokinetics of thiamin after oral administration of thiamin tetrahydrofurfuryl disulfide to humans.

We performed a pharmacokinetic analysis of the blood thiamin profile after oral administration of thiamin tetrahydrofurfuryl disulfide (TTFD) to healthy adults. To distinguish between thiamin derived from TTFD ingestion and that from previous dietary intake, the baseline thiamin level was subtracted from the apparent blood vitamin levels measured after administration. Following administration of 100 mg of TTFD, the peak blood thiamin level was almost 10 times the baseline level and the blood thiamin profile could be simulated by a two-compartment model to obtain reasonable pharmacokinetic parameters. When the blood thiamin profile for a 10-mg dose of TTFD was estimated using scaled-down pharmacokinetic parameters derived at the 100-mg dose level, a reasonable fit for the raw data obtained at 10-mg dose was obtained. Therefore, the parameters derived from the data at a dose of 100 mg appeared to be reliable. Since even 180 mg of TTFD is completely absorbed and the absorption ratio is independent of the dose, it can be concluded that gastrointestinal absorption of TTFD is good within the dose range.

[A case of beriberi heart--with special reference to the rapid effect of fursultiamine on hemodynamics].

A 33-year-old man was admitted to Kushiro City General Hospital on February 27, 1989, because of palpitation, shortness of breath and anasarca. Eight months previously he had noted the onset of pretibial edema, which had progressed to anasarca. He had had a meal only once a day for nine months. Physical examination revealed a blood pressure of 114/46 mmHg and pulse rate of 80/min. The 3rd sound was audible. No rales in the chest and no hepatosplenomegaly were noted. Ascites, pretibial edema and anasarca were present. Vibration sensation was diminished, and the deep tendon reflexes were absent in the legs. The blood thiamine level on the 4th day of hospitalization decreased to 2.9 micrograms/dl. The red cell transketolase activity and TPP effect on the 10th hospital day were 0.76 IU/gHb and 11%, respectively. A chest roentogenogram showed pulmonary congestion and cardiomegaly (CTR 61.3%). The electrocardiogram showed non-specific T wave changes. On the echocardiogram, remarkable pericardial effusion and diffuse hypertrophy of the left ventricular wall were observed. In addition, the left ventricular wall motion showed a hyperkinetic state. On the basis of these findings, the diagnosis of beriberi heart was made. The hemodynamic study performed on the 10th hospital day showed a remarkable high cardiac output (CO) of 10.7 l/min and an extremely reduced total peripheral resistance (TPR) of 352 dynes.sec.cm-5. 15 min after intravenous administration of Fursultiamine 100 mg, CO decreased to 7.24 l/min and TPR increased to 848 dynes.sec.cm-5. Following the administration of Fursultiamine 75 mg, po/day, his symptoms and abnormal findings of clinical examination data rapidly improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Thiamine tetraphydrofurfuryl disulfide in nutritional polyneuropathy.

An open trial with thiamine tetrahydrofurfuryl disulphide (TTFD) was carried out on 44 patients with nutritional polyneuropathy who were admitted to the Neurological Department, Dr. Soetomo Hospital, Surabaya, Indonesia, Thirty-four patients showed improvement of their motor functions (P less than 0.01) with slight restoration of sensory function and reflexes (P less than 0.1). Of the 18 patients who were re-examined electrophysiologically 3 months later, 6 showed remarkable improvements. No side-effects were observed during TTFD treatment. It seemed that nutritional polyneuropathy in our low socio-economic patients was mostly caused by thiamine deficiency.