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1.
Sci Rep ; 8(1): 10469, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992990

RESUMO

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.


Assuntos
Dopamina/metabolismo , Fursultiamina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Fursultiamina/administração & dosagem , Fursultiamina/uso terapêutico , Locomoção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos
2.
Mol Imaging Biol ; 20(6): 1001-1007, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29560588

RESUMO

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.


Assuntos
Radioisótopos de Carbono/química , Fursultiamina/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Tiamina/farmacocinética , Animais , Fursultiamina/química , Cinética , Masculino , Miocárdio/metabolismo , Ratos Sprague-Dawley , Tiamina/química , Fatores de Tempo
3.
J Org Chem ; 80(12): 6250-8, 2015 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-25984933

RESUMO

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.


Assuntos
Radioisótopos de Carbono/química , Fursultiamina/síntese química , Pró-Fármacos/síntese química , Tiamina/síntese química , Animais , Fursultiamina/química , Injeções Intravenosas/métodos , Imagem Molecular , Tomografia por Emissão de Pósitrons , Pró-Fármacos/química , Pirimidinas/química , Ratos , Compostos de Sulfidrila/química , Tiamina/química
4.
Nutr Res ; 29(12): 867-72, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19963160

RESUMO

Impaired energy metabolism is considered a possible cause of fatigue. The thiamine derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is prescribed and is also an over-the-counter drug for the attenuation of fatigue. It is readily absorbed from the intestinal tract and converted into thiamine pyrophosphate (TPP), which plays an important role as a cofactor for enzymes of metabolic pathways involved in the production of adenosine triphosphate (ATP). We postulated that TTFD has an anti-fatigue effect by improving energy metabolism during physical-fatigue loading. Here, we initially used the forced swimming test to determine whether daily TTFD or thiamine for 5 days has anti-fatigue effects on weight-loaded rats. The swimming duration of TTFD-, but not of thiamine-treated rats, was significantly longer than that of control rats (P < .05). Based on these findings, we examined changes in the levels of thiamine and its phosphate esters in various organs and the effect of TTFD on ATP levels in skeletal muscle after forced swimming, to determine the cellular mechanisms of the anti-fatigue effect of TTFD. Daily TTFD resulted in a characteristic distribution of thiamine and its phosphate esters in rat skeletal muscle, liver, kidney, heart, brain, and plasma. Furthermore, daily TTFD attenuated the decrease in ATP content in the skeletal muscle caused by forced swimming with a weight load for a defined period (150 s). These results indicate that TTFD exerts anti-fatigue effects by improving energy metabolism during physical fatigue.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Fadiga/fisiopatologia , Fursultiamina/farmacologia , Resistência Física/efeitos dos fármacos , Esforço Físico/fisiologia , Complexo Vitamínico B/farmacologia , Trifosfato de Adenosina/análise , Animais , Fadiga/prevenção & controle , Fursultiamina/metabolismo , Masculino , Músculo Esquelético/química , Especificidade de Órgãos , Fosforilação , Ratos , Ratos Sprague-Dawley , Natação , Tiamina/análogos & derivados , Tiamina/análise , Tiamina/sangue , Complexo Vitamínico B/metabolismo
5.
J Pharmacol Sci ; 92(4): 387-99, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12939524

RESUMO

trans-1,2-Cyclohexanediol, the major metabolite of the cilexetil moiety of candesartan cilexetil (CC), has been reported to have potent pro-arrhythmic effects in dogs with congestive heart failure (CHF), especially when co-administered with digoxin. To verify this and to clarify the clinical relevance and the underlying mechanisms, a series of in vivo and in vitro experiments was conducted. When CC up to 300 mg/kg was administered orally to intact dogs, no changes in the electrocardiograms (ECG) or the required cumulative doses of ouabain to induce ventricular arrhythmias were observed. In dogs with CHF, intravenous bolus administration of trans-1,2-cyclohexanediol at 4 mg/kg followed by continuous infusion at 0.1 mg x kg(-)(1) x min(-)(1) had no effects on the ECG parameters, the type, incidence, and onset time of digoxin-induced arrhythmias or the metabolism of digoxin. In an in vitro experiment using isolated guinea pig papillary muscle, trans-1,2-cyclohexanediol (1 - 100 micromol/L) showed no effects on any parameter of the action potentials. Because no effects were observed in these experiments where the exposure levels of trans-1,2-cyclohexanediol were extremely high compared to those in humans given the maximum therapeutic dose of CC, it is unlikely that CC would induce arrhythmias in clinical use even in patients treated with cardiac glycosides.


Assuntos
Arritmias Cardíacas/sangue , Benzimidazóis/metabolismo , Compostos de Bifenilo/metabolismo , Cicloexanóis/sangue , Cicloexanóis/farmacologia , Digoxina/sangue , Tetrazóis , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Arritmias Cardíacas/induzido quimicamente , Digoxina/toxicidade , Cães , Interações Medicamentosas/fisiologia , Cobaias , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/induzido quimicamente , Técnicas In Vitro , Masculino , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia
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