PET Imaging Analysis of Vitamin B1 Kinetics with [11C]Thiamine and its Derivative [11C]Thiamine Tetrahydrofurfuryl Disulfide in Rats.

PURPOSE: Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because 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 have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart. PROCEDURES: Positron emission tomography (PET) imaging with [11C]thiamine and [11C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography. RESULTS: Accumulation of [11C]TTFD was significantly higher than that of [11C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [11C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [11C]thiamine-injected group. CONCLUSIONS: PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [11C]thiamine and [11C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.

Synthesis of (11)C-Labeled Thiamine and Fursultiamine for in Vivo Molecular Imaging of Vitamin B1 and Its Prodrug Using Positron Emission Tomography.

To enable in vivo analysis of the kinetics of vitamin B1 (thiamine) and its derivatives by positron emission tomography (PET), (11)C-labeled thiamine ([(11)C]-1) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd(0)-mediated C-[(11)C]methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)pyrimidine for 7 min. The [(11)C]-1 was also converted to (11)C-labeled fursultiamine ([(11)C]-2), a prodrug of vitamin B1, by disulfide formation with S-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [(11)C]-1 and [(11)C]-2 showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [(11)C]-1 and [(11)C]-2 were shorter than 60 and 70 min, respectively. The [(11)C]CH3I-based decay-corrected radiochemical yields of [(11)C]-1 and [(11)C]-2 were 9-16% and 4-10%, respectively. The radioactivities of the final injectable solutions of [(11)C]-1 and [(11)C]-2 were 400-700 and 100-250 MBq, respectively. The radiochemical purity of both [(11)C]-1 and [(11)C]-2 was 99%, and the chemical purities of [(11)C]-1 and [(11)C]-2 were 99% and 97-99%, respectively. In vivo PET imaging of normal rats was illustrated by the distribution of [(11)C]-1 and [(11)C]-2 following intravenous injection.

Stability of cyanocobalamin in sugar-coated tablets.

The purpose of this study was to clarify the stability of cyanocobalamin (VB(12)-CN) in sugar-coated tablets containing fursultiamine hydrochloride (TTFD-HCl), riboflavin (VB(2)), and pyridoxine hydrochloride (VB(6)), and to identify the factors affecting the stability of VB(12)-CN in these sugar-coated tablets. The stability of VB(12)-CN was investigated using high-performance liquid chromatography while decomposition was evaluated kinetically. The decomposition of VB(12)-CN in sugar-coated tablets with high equilibrium relative humidity (more than 60%) under closed conditions showed complex kinetics and followed an Avrami-Erofe'ev equation, which expresses a random nucleation (two-dimensional growth of nuclei) model. We showed that equilibrium relative humidity, the incorporation of VB(2) and VB(6), and sugar coating, are the main factors influencing decomposition and that these factors cause the complex decomposition kinetics.

Fursultiamine, a vitamin B1 derivative, enhances chondroprotective effects of glucosamine hydrochloride and chondroitin sulfate in rabbit experimental osteoarthritis.

OBJECT AND DESIGN: The therapeutic effect of glucosamine hydrochloride (GH) and chondroitin sulfate (CS) in combination with fursultiamine, a vitamin B1 derivative, on the development of cartilage lesions was investigated in an animal model of osteoarthritis (OA). METHODS: The OA model was created by partial medial meniscectomy of the right knee joint (day 0). The rabbits were placed into three experimental groups: operated (OA) rabbits that received placebo treatment, OA rabbits that received GH (1000 mg/kg) + CS (800 mg/kg), and OA rabbits that received GH + CS + fursultiamine (100 mg/kg). Each treatment was initiated on day 3 and continued for 8 weeks. Macroscopic and histologic analyses were performed on the cartilage. The level of MMP-1 in OA cartilage chondrocytes was evaluated by immunohistochemistry. RESULTS: Only the group receiving combined treatment with GH + CS + fursultiamine showed a significant reduction in the severity of macroscopic and histologic lesions on tibial plateau, which is the weight bearing cartilage surface of the tibia, compared with placebo-treated OA rabbits. This treatment group also revealed a small, but significant, decrease in the body weight gain of the rabbits. In cartilage from placebo-treated OA rabbits, a significantly higher percentage of chondrocytes in superficial layer stained positive for MMP-1 compared with unoperated control. Rabbits treated with the GH + CS + fursultiamine revealed a significant reduction in the level of MMP-1. CONCLUSION: These results suggest that the chondroprotective effect of GH + CS is enhanced by the addition of fursultiamine in experimental OA. This effect was associated with a reduction in the level of MMP-1, which are known to play an important role in the pathophysiology of OA lesions.

Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent.

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.

The stability of thiamine and thiamine tetrahydrofurfuryl disulfide added to table wines.

Both thiamine hydrochloride and thiamine tetrahydrofurfuryl disulfide were added separately to table wines at concentrations equivalent to 0.3 and 1.5 microgram of free thiamine per kJ of caloric energy. The resultant mean increments in thiamine activity, measured by Lactobacillus fermenti microbiological assay after 21 months of storage, were in the range 55 to 103% of the added vitamin, indicative of high bioavailability of thiamine from this source.