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Vitamins are essential components of enzyme systems involved in normal growth and function. The quantitative estimation of the proportion of dietary vitamins, that is in a form available for utilization by the human body, is limited and fragmentary. This review provides the current state of knowledge on the bioavailability of thirteen vitamins and choline, to evaluate whether there are differences in vitamin bioavailability when human foods are sourced from animals or plants. The bioavailability of naturally occurring choline, vitamin D, vitamin E, and vitamin K in food awaits further studies. Animal-sourced foods are the almost exclusive natural sources of dietary vitamin B-12 (65% bioavailable) and preformed vitamin A retinol (74% bioavailable), and contain highly bioavailable biotin (89%), folate (67%), niacin (67%), pantothenic acid (80%), riboflavin (61%), thiamin (82%), and vitamin B-6 (83%). Plant-based foods are the main natural sources of vitamin C (76% bioavailable), provitamin A carotenoid β-carotene (15.6% bioavailable), riboflavin (65% bioavailable), thiamin (81% bioavailable), and vitamin K (16.5% bioavailable). The overview of studies showed that in general, vitamins in foods originating from animals are more bioavailable than vitamins in foods sourced from plants.

Purpose: Safety, tolerability and pharmacokinetics of single and multiple ascending doses (SADs/MADs) of benfotiamine were assessed after oral administration in two randomized, double-blind, placebo-controlled, phase I trials., Methods: Healthy subjects were sequentially enrolled into one of five SAD (150-1200 mg) or three MAD (150, 300 or 600 mg) cohorts. In SAD study, each cohort of 12 subjects (n = 10, active; n = 2, placebo) were administrated once-daily doses. In MAD study, each cohort of 16 subjects (n = 12, active; n = 4, placebo) were administrated once-daily on day 1 and twice-daily on day 4-9, followed by a single morning dose on day 10., Results: In the SAD study, the median time to reach maximum concentration (T max ) arrived 1.0 to 2.0 h for thiamine (TM), 3.5 to 8.0 h for thiamine monophosphate (TMP), and 8.0 to 24.0 h for thiamine diphosphate (TDP) after administration of benfotiamine. The area under concentration-time curve from 0 to last measurable concentration (AUC 0-t ) or maximum observed concentration (C max ) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except C max of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t 1/2 ) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on C max (Rac, Cmax ) of 1.60 to 1.88 following 7 days of multiple dosing. Comparable accumulation results were also obtained for TDP after multiple dosing. The incidence and severity of adverse events (AEs) were similar between benfotiamine and placebo. The commonly reported drug-related AEs were increased ALT and urinary WBC., Conclusion: Both SAD and MAD studies of benfotiamine in healthy subjects were safe and well tolerated. TM and TDP exhibited moderate accumulation on repeated administration of benfotiamine., Competing Interests: Wei Cao reports grants from National Major Scientific and Technological Special Project, during the conduct of the study. Wei Cao and Chunjiu Zhong holds shares of Shanghai Rixin Biotech Ltd Company that dedicates to develop new drugs against Alzheimer’s disease. The other authors have declared that they have no conflicts of interest regarding the context of this article., (© 2021 Sheng et al.)

The most commonly used oral antidiabetic drug, metformin, is a substrate of the hepatic uptake transporter OCT1 (gene name SLC22A1 ). However, OCT1 deficiency leads to more pronounced reductions of metformin concentrations in mouse than in human liver. Similarly, the effects of OCT1 deficiency on the pharmacokinetics of thiamine were reported to differ between human and mouse. Here, we compared the uptake characteristics of metformin and thiamine between human and mouse OCT1 using stably transfected human embryonic kidney 293 cells. The affinity for metformin was 4.9-fold lower in human than in mouse OCT1, resulting in a 6.5-fold lower intrinsic clearance. Therefore, the estimated liver-to-blood partition coefficient is only 3.34 in human compared with 14.4 in mouse and may contribute to higher intrahepatic concentrations in mice. Similarly, the affinity for thiamine was 9.5-fold lower in human than in mouse OCT1. Using human-mouse chimeric OCT1, we showed that simultaneous substitution of transmembrane helices TMH2 and TMH3 resulted in the reversal of affinity for metformin. Using homology modeling, we suggest several explanations, of which a different interaction of Leu155 (human TMH2) compared with Val156 (mouse TMH2) with residues in TMH3 had the strongest experimental support. In conclusion, the contribution of human OCT1 to the cellular uptake of thiamine and especially of metformin may be much lower than that of mouse OCT1. This may lead to an overestimation of the effects of OCT1 on hepatic concentrations in humans when using mouse as a model. In addition, comparative analyses of human and mouse orthologs may help reveal mechanisms of OCT1 transport. SIGNIFICANCE STATEMENT: OCT1 is a major hepatic uptake transporter of metformin and thiamine, but this study reports strong differences in the affinity for both compounds between human and mouse OCT1. Consequently, intrahepatic metformin concentrations could be much higher in mice than in humans, impacting metformin actions and representing a strong limitation of using rodent animal models for predictions of OCT1-related pharmacokinetics and efficacy in humans. Furthermore, OCT1 transmembrane helices TMH2 and TMH3 were identified to confer the observed species-specific differences in metformin affinity., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Maternal supplementation during lactation could increase milk B-vitamin concentrations, but little is known about the kinetics of milk vitamin responses., Objectives: We compared acute effects of maternal lipid-based nutrient supplement (LNS) consumption (n = 22 nutrients, 175%-212% of the RDA intake for the nutrients examined), as a single dose or at spaced intervals during 8 h, on milk concentrations and infant intake from milk of B-vitamins., Methods: This randomized crossover trial in Quetzaltenango, Guatemala included 26 mother-infant dyads 4-6 mo postpartum who were randomly assigned to receive 3 treatments in a random order: bolus 30-g dose of LNS (Bolus); 3 × 10-g doses of LNS (Divided); and no LNS (Control), with control meals. Mothers attended three 8-h visits during which infant milk consumption was measured and milk samples were collected at every feed. Infant intake was assessed as $\mathop \sum \nolimits&#95;{i\ = \ 1}^n ( {{\rm{milk\ volum}}{{\rm{e}}&#95;{{\rm{feed\ }}n}} \times \ {\rm{nutrient\ concentratio}}{{\rm{n}}&#95;{{\rm{feed}}\ n}}} )$ over 8 h., Results: Maternal supplementation with the Bolus or Divided dose increased least-squares mean (95% CI) milk and infant intakes of riboflavin [milk: Bolus: 154.4 (138.2, 172.5) μg · min-1 · mL-1; Control: 84.5 (75.8, 94.3) μg · min-1 · mL-1; infant: Bolus: 64.5 (56.1, 74.3) μg; Control: 34.5 (30.0, 39.6) μg], thiamin [milk: Bolus: 10.9 (10.1, 11.7) μg · min-1 · mL-1; Control: 7.7 (7.2, 8.3) μg · min-1 · mL-1; infant: Bolus: 5.1 (4.4, 6.0) μg; Control: 3.4 (2.9, 4.0) μg], and pyridoxal [milk: Bolus: 90.5 (82.8, 98.9) μg · min-1 · mL-1; Control: 60.8 (55.8, 66.3) μg · min-1 · mL-1; infant: Bolus: 39.4 (33.5, 46.4) μg; Control: 25.0 (21.4, 29.2) μg] (all P < 0.001). Only the Bolus dose increased cobalamin in milk [Bolus: 0.054 (0.047, 0.061) μg · min-1 · mL-1; Control: 0.041 (0.035, 0.048) μg · min-1 · mL-1, P = 0.039] and infant cobalamin intake [Bolus: 0.023 (0.020, 0.027) μg; Control: 0.015 (0.013, 0.018) μg, P = 0.001] compared with Control. Niacin was unaffected., Conclusions: Maternal supplementation with LNS as a Bolus or Divided dose was similarly effective at increasing milk riboflavin, thiamin, and pyridoxal and infant intakes, whereas only the Bolus dose increased cobalamin. Niacin was unaffected in 8 h. This trial was registered at clinicaltrials.gov as NCT02464111., (Published by Oxford University Press on behalf of the American Society for Nutrition 2020.)

Thiamine is substrate of the hepatic uptake transporter organic cation transporter 1 (OCT1), and pathological lipid metabolism was associated with OCT1-dependent thiamine transport. However, it is unknown whether clinical pharmacokinetics of thiamine is modulated by OCT1 genotype. We analyzed thiamine transport in vitro, thiamine blood concentrations after high-dose and low-dose (nutritional) intake, and heritability of thiamine and thiamine-phosphate blood concentrations. The variant OCT1*2 had reduced and OCT1*3 to OCT1*6 had deficient thiamine uptake activity. However, pharmacokinetics of thiamine did not differ depending on OCT1 genotype. Further studies in primary human hepatocytes indicated that several cation transporters, including OCT1, OCT3, and THTR-2, contribute to hepatic uptake of thiamine. As much as 54% of the variation in thiamine and 75% in variation of thiamine monophosphate plasma concentrations was determined by heritable factors. Apparently, thiamine is not useful as a probe drug for OCT1 activity, but the high heritability, particularly of thiamine monophosphate, may stimulate further genomic research., (© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Thiamine-coated nanoparticles were prepared by two different preparative methods and evaluated to compare their mucus-penetrating properties and fate in vivo. The first method of preparation consisted of surface modification of freshly poly(anhydride) nanoparticles (NP) by simple incubation with thiamine (T-NPA). The second procedure focused on the preparation and characterization of a new polymeric conjugate between the poly(anhydride) backbone and thiamine prior the nanoparticle formation (T-NPB). The resulting nanoparticles displayed comparable sizes (about 200 nm) and slightly negative surface charges. For T-NPA, the amount of thiamine associated to the surface of the nanoparticles was 15 μg/mg. For in vivo studies, nanoparticles were labelled with either 99m Tc or Lumogen® Red. T-NPA and T-NPB moved faster from the stomach to the small intestine than naked nanoparticles. Two hours post-administration, for T-NPA and T-NPB, >30% of the given dose was found in close contact with the intestinal mucosa, compared with a 13.5% for NP. Interestingly, both types of thiamine-coated nanoparticles showed a greater ability to cross the mucus layer and interact with the surface of the intestinal epithelium than NP, which remained adhered in the mucus layer. Four hours post-administration, around 35% of T-NPA and T-NPB were localized in the ileum of animals. Overall, both preparative processes yielded thiamine decorated carriers with similar physico-chemical and biodistribution properties, increasing the versatility of these nanocarriers as oral delivery systems for a number of biologically active compounds., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 [ 11 C]thiamine and [ 11 C]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 [ 11 C]TTFD was significantly higher than that of [ 11 C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [ 11 C]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 [ 11 C]thiamine-injected group., Conclusions: PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [ 11 C]thiamine and [ 11 C]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.

Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT 1 ) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT 1 , "lock-in" thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain., (© 2017 John Wiley & Sons A/S.)

Aim: In the last years with the increase of bariatric surgery, first of all as a result of new indications, a rise in the incidence of nutrient-related complications has been observed. Currently little is known about the impact of post-bariatric malnutrition and neurological complications. Wernicke's encephalopathy is a severe neurological syndrome which occurs as a result of thiamine deficiency. Wernicke-Korsakoff syndrome must be considered a serious neurological complication of bariatric surgery with significant morbidity and mortality, with rapidly progressing neurological symptoms, and must be treated immediately., Case Report: We report the case of a 35 years-old male patient, affected by morbid obesity, anxious-depressive syndrome and alcohol use disorder, who after adjustable gastric banding implanted in another hospital developed a severe malnutrition and neurological syndrome. The patient showed poor adherence to the follow-up and to the dietary indications and after all, we needed to place a PEG for enteral nutrition in order to resolve the malnutrition condition and the neurological syndrome. Our experience emphasizes that preoperative selection and assessment of a patient's nutritional status according to guidelines, is required to identify potential problems, and that bariatric surgeons or physicians caring for patient who have undergone bariatric surgery should be familiar with the constellation of nutritional and neurological disorder that may occur after surgery., Conclusion: We want to remark the importance of preoperative selection of the patients, the follow-up and the cooperation between patient and physician in order to obtain the best result and avoid severe complications.

Background: Vitamins are chemical compounds whose derivatives are involved in vital metabolic pathways of all living organisms. The complete endogenous biosynthesis of vitamins can be performed by many bacteria, yeast and plants, but humans need to acquire most of these essential nutrients with food. In recent years, new types of action of the well-recognized vitamins or their more sophisticated relationships have been reported., Conclusion: In this review we present the current knowledge of factors that can influence the yield and regulation of vitamin B1, B2, B3 and B9 biosynthesis in plants which can be important for human nutrition. A summary of modern methods applied for vitamin analysis in biological materials is also provided. Contributions of selected vitamins to the homeostasis of the human organism, as well as their relations to the progress or prevention of some important diseases such as cancer, cardiovascular diseases, diabetes and Alzheimer's disease are discussed in the light of recent investigations. Better understanding of the mechanisms of vitamin uptake by human tissues and possible metabolic or genetic backgrounds of vitamin deficiencies can open new perspectives on the medical strategies and biotechnological processes of food fortification., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: Fursultiamine and benfotiamine are lipophilic thiamine derivatives used as oral sources of thiamine. Although there are many publications on the pharmacokinetic (PK) properties of thiamine-containing products, no direct comparisons between these agents . We aimed to compare the PK profiles of these lipophilic thiamine derivatives and to compare the extent of the increase in bioavailability to that of naïve thiamine., Methods: Two randomized, single-dose, 2-way crossover, full PK studies were conducted in healthy Korean male subjects (n = 24 per group). Among the test compounds, fursultiamine was compared with benfotiamine (reference A in study A) and thiamine nitrate (reference B in study B). All formulations were multivitamin preparations containing the test or reference formulation as the major thiamine source. In study A, the plasma and hemolysate concentrations of thiamine and its metabolites were measured, while only the plasma thiamine concentration was assayed in study B., Findings: The systemic thiamine exposure of the test compound was slightly greater than that of reference A, based on the geometric mean ratio (%) of the AUC last value for plasma (116.6%) and hemolysate (137.5%). The thiamine diphosphate (TDP) distribution between plasma and hemolysate showed clear differences according to the formulations, in that more TDP was present in the hemolysate when thiamine was given as the test formulation. The AUC last value of plasma thiamine showed a >300% increase when thiamine was given as the test formulation in study B. The summed total exposure to thiamine (thiamine + TDP in both plasma and hemolysate) observed as a point estimate after the administration of fursultiamine was slightly greater than that with benfotiamine; however, the 90% CI was within the conventional bioequivalence range., Implications: These findings support clear benefits of lipophilic thiamine derivatives in the absorption of thiamine in healthy volunteers. Clinical Research Information Service identifiers: KCT0001419 (study A), KCT0001628 (study B)., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Aims: Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy., Methods: A single application of 10 mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24 h., Results: At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals., Conclusions: This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.

Amorphous silica (SiO2) in the form of nanoparticles (NPs) is widely used as a food additive E551 in many enriched foods and food supplements. The aim of this study was to evaluate the effect of oral administration of SiO2 NPs on assimilation and metabolism of vitamins B1, B2 and B6 in laboratory rats. Amorphous SiO2 «Orisil-300 ®» was used with the size of the primary NPs 20-60 nm according to the electronic, atomic force microscopy and dynamic light scattering. The experiment was conducted on 8 groups of growing male Wistar rats (with initial body weight 70-80g) number, respectively, 7, 7, 10, 10, 12, 12, 14 and 16 animals. Animals of the 1st, 3rd, 4th and 5th groups received through­out the experiment balanced semi-synthetic diet. Animals of the 2nd group received a diet depleted of vitamins B1, B2 and B6 until day 21; animals of the 6th, 7th and 8th groups -the same diet from the 1st to the 21th day, and then, before the closure of the experiment, the diet provided with the indicated B vitamins at 100% of normal level. From day 22 of experiment and until the end at day 29 the animals of the 3rd and 6th groups received deionized water (placebo) through intragastric gavage; rat of the 4th and 7th groups -aqueous suspension of SiO2 dose of 1 mg/kg body weight /day, and the 5th and 8th group -100 mg/kg/day. Urinary excretion of thiamine, riboflavin, 4-pyridoxilic acid and liver and brain content of vitamins B1 and B2 (after acid and enzyme hydrolysis) were deter­mined by fluorimetric methods. It was found that rats in group 2 lagged in weight gain at day 21 significantly compared to group 1, and developed a marked deficiency of vitamins B1, B2 and B6 according to studied safety parameters. In groups from 6 to 8 at day 29 par­tial recovery was achieved in vitamin status. Administration of SiO2 to animal of groups 4 and 5, with normal consumption of B vitamins, had no significant effect on any param­eters of vitamin status in comparison to group 3. However, intragastric administration of SiO2 led in animals of groups 7 and 8 to an increase in the urinary excretion of vitamins B1 and B2 and lowering of their content in liver as compared to group 6. Administration of SiO2 had no effect on indices of vitamin B6 sufficiency. Possible reasons are discussed for the adverse lowering impact of SiO2 NPs on the availability of vitamins B1 and B2 and their increased clearance from the body.

Purpose: To investigate the role of organic cation transporters (Octs) and multidrug and toxin extrusion protein 1 (Mate1) in the disposition of thiamine., Methods: The uptake of [(3)H]thiamine was determined in Oct1-, Oct2-, and Oct3-expressing HEK293 cells and freshly isolated hepatocytes. A pharmacokinetic study of thiamine-d3 following intravenous infusion (1 and 100 nmol/min/kg) was conducted in male Oct1/2(+/+) and Oct1/2(-/-) mice. A MATE inhibitor, pyrimethamine, (5 mg/kg) was administered intravenously. The plasma and breast milk concentrations of thiamine were determined in female mice., Results: Thiamine is a substrate of Oct1 and Oct2, but not Oct3. Oct1/2 defect caused a significant reduction in the uptake of [(3)H]thiamine by hepatocytes in vitro, and elevated the plasma thiamine concentration by 5.8-fold in vivo. The plasma clearance of thiamine-d3 was significantly decreased in Oct1/2(-/-) mice. At the higher infusion rate of 100 nmol/min/kg thiamine-d3, Oct1/2 defect or pyrimethamine-treatment caused a significant reduction in the renal clearance of thiamine-d3. The total thiamine and thiamine-d3 concentrations were moderately reduced in the intestine of Oct1/2(-/-) mice but were unchanged in the kidney, liver, or brain. The milk-to-plasma concentration ratio of thiamine was decreased by 28-fold in the Oct1/2(-/-) mice., Conclusions: Oct1 is possibly responsible for the plasma clearance of thiamine via tissue uptake and for milk secretion. Oct1/2 and Mate1 are involved in the renal tubular secretion of thiamine.

Intramuscular injections of the vitamin complex containing: thiamine chloride (B1), riboflavin (B2), lipoic acid (N), calcium pantothenate (B5), pyridoxine hydrochloride (B6), folic acid (B9), ascorbic acid (C) can reduce the blood glucose level in serum of rats with alloxan diabetes, stabilize activity of some enzymes of energy metabolism, lactate dehydrogenase and pyruvate dehydrogenase complex.

Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride., (© 2014, The American College of Clinical Pharmacology.)

Background: Thiamine deficiency is common in parts of Asia and causes beriberi. Pharmacokinetics of thiamine in deficient populations are unknown., Objective: We characterized thiamine pharmacokinetics in Cambodian mothers and their breastfed infants., Design: Total plasma thiamine, whole-blood thiamine diphosphate (TDP), and breast milk total thiamine were measured in 16 healthy Cambodian mothers and their infants before and after mothers received oral thiamine hydrochloride (100 mg for 5 d). Assays were also performed in 16 healthy American mothers., Results: On day 1, Cambodian mothers were thiamine deficient, with median (range) total plasma thiamine and TDP concentrations of 2.4 nmol/L (0-4.4 nmol/L) and 58.0 nmol/L (27-98 nmol/L), respectively. After a single oral dose, the mean ± SD maximal concentration of thiamine and net area under the thiamine concentration-time curve were 73.4 ± 45.6 nmol/L and 465 ± 241 h · nmol ∙ L⁻¹. Day 6 median maternal total plasma thiamine and TDP concentrations were normal [18.6 nmol/L (13.4-25.3 nmol/L) and 76.5 nmol/L (48-107 nmol/L), respectively; P ≤ 0.001 compared with day 1]. Median Cambodian total breast milk thiamine concentration increased from 180 nmol/L (85-359 nmol/L) on day 1 to 403 nmol/L (314-415 nmol/L) on day 2 and 503 nmol/L (360-808 nmol/L) on day 6; the corresponding American breast milk value was 500 nmol/L (114-622 nmol/L). Median Cambodian infant total plasma thiamine and TDP concentrations increased from 3.0 nmol/L (0-7.3 nmol/L) and 38.5 nmol/L (23-57 nmol/L), respectively, on day 1 to 5.6 nmol/L (0-9.7 nmol/L) and 45.5 nmol/L (32-70 nmol/L), respectively, on day 6., Conclusions: Thiamine-deficient Cambodian mothers effectively absorb oral thiamine, with sharp increases in breast milk thiamine concentrations, but their breastfed infants remain thiamine deficient after 5 d of maternal supplementation. Longer-term maternal supplementation may be necessary to correct thiamine deficiency in breastfed infants. This trial was registered at clinicaltrials.gov as NCT01864057.

The relationship between supplemental vitamins and various types of cancer has been the focus of recent investigation, and supplemental vitamins have been reported to modulate cancer rates. A significant association has been demonstrated between cancer and low levels of thiamine in the serum. Genetic studies have helped identify a number of factors that link thiamine to cancer, including the solute carrier transporter (SLC19) gene, transketolase, transcription factor p53, poly(ADP-ribose) polymerase-1 gene, and the reduced form of nicotinamide adenine dinucleotide phosphate. Thiamine supplementation may contribute to a high rate of tumor cell survival, proliferation and chemotherapy resistance. Thiamine has also been implicated in cancer through its effects on matrix metalloproteinases, prostaglandins, cyclooxygenase-2, reactive oxygen species, and nitric oxide synthase. However, some studies have suggested that thiamine may exhibit some antitumor effects. The role of thiamine in cancer is controversial. However, thiamine deficiency may occur in patients with cancer and cause serious disorders, including Wernicke's encephalopathy, that require parenteral thiamine supplementation. A very high dose of thiamine produces a growth-inhibitory effect in cancer. Therefore, further investigations of thiamine in cancer are needed to clarify this relationship.

Thiamine and benfotiamine are vitamin B1 and pro-vitamin B1 substances, respectively. Vitamin B1 plays an essential role in energy metabolism, and its deficiency leads to neurologic and cardiovascular pathologies, as seen in alcoholics. This study presents new data about the effects of thiamine hydrochloride or benfotiamine treatment given to rats with acute alcohol intoxication, on the distribution of thiamine and its phosphate esters in liver, plasma and erythrocytes. The treatments were effective in increasing thiamine levels in plasma, erythrocytes and liver cells. The benfotiamine-treated group had its total plasma thiamine increased by 100%. In erythrocytes, thiamine levels were 4- and 25-fold higher in the groups treated with thiamine and benfotiamine, respectively, compared with the untreated groups. Liver thiamine was increased by 60% in the treated groups compared with the untreated groups. Thus, we verified the high bioavailability especially of benfotiamine within 6h of ethanol administration., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects., Methods: This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated., Results: The AUC₀₋₁₀ hr and C(max) values increased nonlinearly between 100 mg and 1500 mg. The slope of the AUC₀₋₁₀ hr vs dose, as well as the C(max) vs dose, plots are steepest at the lowest thiamine doses., Conclusion: Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process., Trial Registration: ClinicalTrials.gov: NCT00981877.

Thiamine (Vitamin B1) is an essential vitamin that must be obtained from the diet for proper neurological function. At higher doses, thiamine and benfotiamine (S-benzoylthiamine O-monophosphate, BT)-a phosphorylated derivative of thiamine-have antinociceptive effects in animals and humans, although how these compounds inhibit pain is unknown. Here, we found that Prostatic acid phosphatase (PAP, ACPP) can dephosphorylate BT in vitro, in dorsal root ganglia (DRG) neurons and in primary-afferent axon terminals in the dorsal spinal cord. The dephosphorylated product S-benzoylthiamine (S-BT) then decomposes to O-benzoylthiamine (O-BT) and to thiamine in a pH-dependent manner, independent of additional enzymes. This unique reaction mechanism reveals that BT only requires a phosphatase for conversion to thiamine. However, we found that the antinociceptive effects of BT, thiamine monophosphate (TMP) and thiamine-a compound that is not phosphorylated-were entirely dependent on PAP at the spinal level. Moreover, pharmacokinetic studies with wild-type and Pap(-/-) mice revealed that PAP is not required for the conversion of BT to thiamine in vivo. Taken together, our study highlights an obligatory role for PAP in the antinociceptive effects of thiamine and phosphorylated thiamine analogs, and suggests a novel phosphatase-independent function for PAP.

Combined vitamin preparations containing thiamine (vitamin B1), pyridoxine (vitamin B6), and cyanocobalamin (vitamin B12) are widely used in medical practice. The results of investigations have confirmed that it is expedient to potentiate an analgesic effect due to the concurrent use of vitamin B group and nonsteroidal anti-inflammatory drugs given to relieve significant neuropathic pain. Milgamma compositum (Wörwag Pharma, Germany) is one of the most studied drugs on the Russian market, which contains a combination of vitamin B group (including benfotiamin).

Wernicke syndrome is a rare neurological pathology due to a deficit in vitamin B1. The syndrome is common among alcohol abusers, patients with malignant tumor or gastrointestinal diseases, those who undergo hemodialysis or long-term peritoneal dialysis, pregnant women with hyperemesis, women who breast-feed, patients with hyperthyroidism or anorexia nervosa or gastric or jejunal-ileal bypass surgery for obesity, patients submitted to gastric surgery or prolonged total parenteral nutrition or prolonged intravenous therapy. We report a case of Wernicke syndrome due to afferent loop syndrome characterized by incoercible vomiting.

Thiamine supplementation may prevent and reverse early-stage diabetic nephropathy. This probably occurs by correcting diabetes-linked increased clearance of thiamine, maintaining activity and expression of thiamine pyrophosphate-dependent enzymes that help counter the adverse effects of high glucose concentrations-particularly transketolase. Evidence from experimental and clinical studies suggests that metabolism and clearance of thiamine is disturbed in diabetes leading to tissue-specific thiamine deficiency in the kidney and other sites of development of vascular complications. Thiamine supplementation prevented the development of early-stage nephropathy in diabetic rats and reversed increased urinary albumin excretion in patients with type 2 diabetes and microalbuminuria in two recent clinical trials. The thiamine monophosphate prodrug, Benfotiamine, whilst preventing early-stage development of diabetic nephropathy experimentally, has failed to produce similar clinical effect. The probable explanations for this are discussed. Further definitive trials for prevention of progression of early-stage diabetic nephropathy by thiamine are now required., (© 2011 Blackwell Publishing Ltd.)

Background/aim: Zeolites are the hydratised alumosilicates of alcali and earthalcali cations, which have a long three-dimensional crystal structure. Preparations on the basis of zeolites are used for adsorption of organic and nonorganic toxic substances and they, also, find more and more use in veterinary and human medicine and pharmacy. The aim of this study was to evaluate the possibilities of zeolite to adsorb vitamins B1, B2 and B6 in acid and neutral solutions, as well as the characteristics of the process (saturability, reversibility and competitiveness)., Methods: The specific and sensitive HPLC method with fluorescent detector was used for determination of vitamins B1, B2 and B6. Analyte separation and detection were carried out by applying the reverse-phase method on column C18. An in vitro experiment was done by testing the influence of pH value (2 and 7), concentration of vitamin solution (1, 2 and 5 mg/L), the length of contact with zeolite (10-180 min) and cation competitiveness on the exchange capacity, which is achieved by media and zeolite contact, as well as a possible vitamins desorption through changing pH value of the solution at 37 degrees C. Jon competitiveness was examined by adding commercial feed mixture (grower) with a defined content of the examined vitamins in zeolite solutions the pH = 2 and pH = 7., Results: Vitamins B1, B2 and B6 were stable in both pH=2 and pH = 7 solutions at 37 degrees C, in the defined time intervals. In acid solution concentrations of vitamins significantly declined in the first 10 min, with no significant decline in further 30 min for all the three concentrations tests. In neutral solution, after the addition of 1% zeolite, decrease in vitamins concentrations was slightly lower than in acid solution, but also significant in the first 10 min of the contact with zeolite. It was found that zeolite, which adsorbed vitamins in acid solution, transferred in the neutral one released a significant quantity of adsorbed vitamins after 30 min of extraction on 37 degrees C. Vitamins B1, B2 and B6, from a commercial feed mixture in pH = 2 solution, at 37 degrees C, were significantly adsorbed on zeolite after 30 min of the contact (21.87%, 20.15% and 4.53%, respectively), while in neutral solution there was no statistically significant adsorption. Conclusion. Zeolite significantly adsorbs vitamins B1, B2 and B6 in acid and neutral solutions at 37 degrees C, already in the first 10 min of the contact. Adsorption was irreversible, but partly reversible after changing pH from acid to neutral. This is a significant ions competition for adsorption on zeolite in neutral solution, so no statistically significant vitamins B1, B2 and B6 adsorption occurs, while in acid solution competition is less, thus zeolite significantly adsorbs these vitamins, although in less degree than in conditions with no concurrent ions.

The anti-fatigue effect of dicethiamine hydrochloride (DCET) was assessed and compared to that of thiamine hydrochloride (VB(1)HCl) in rats. The absorbability and tissue distribution of thiamine after oral administration of DCET and VB(1)HCl were also examined. To create fatigued animals, male SD rats were placed in plastic cages containing 1.5cm of water for 5 consecutive days. The extent of fatigue was evaluated by a weight-loaded forced swimming test. After oral administration of DCET or VB(1)HCl to non-fatigued rats, blood and tissues were serially collected to determine the concentrations of thiamine and its phosphate esters. Pharmacokinetic analysis was performed to examine the thiamine profile in the body after administration of DCET or VB(1)HCl. Swimming time was significantly shorter for the fatigued vehicle group than the non-fatigued group. DCET (30 and 100mg/kg) significantly prolonged the swimming time compared to the fatigued vehicle group. The anti-fatigue effect of VB(1)HCl (70.1mg/kg) was not significant in our set of results. Both DCET and VB(1)HCl were rapidly absorbed into the circulating blood as thiamine and eventually became localized in the organs. Thiamine was distributed at higher concentrations to the blood, heart, thigh muscles, cerebellum, hippocampus, and thalamus after administration of DCET compared to VB(1)HCl. These results indicate that DCET is a vitamin B(1) derivative that has excellent absorbability and transformability in tissues and suggest that DCET as an oral therapy may be useful against combined mental and physical fatigue, such as that often encountered in contemporary society.

In this study, we examined the intestinal uptake of thiamin (vitamin B(1)), riboflavin (vitamin B(2)) and pyridoxine (vitamin B(6)) administered at high concentration using intestinal epithelial Caco-2 cells as an in vitro model of drugs and food absorption. The effect of vitamin concentration, culture age, transport direction and incubation temperature on vitamin transport was determined. The vitamin transport was expressed as an apparent permeability coefficient and changes in cumulative fraction transported across epithelial membrane in time. It was found that transepithelial transport of these vitamins is dependent on the experimental factors. At low concentrations an active transport mechanism was observed, whereas at high vitamin concentration a passive transport dominated. At high vitamin concentration the transepithelial flux of vitamins in both directions was similar, which proves the mechanism of passive transport.

We investigated the feasibility of enhancing the reproduction of steelhead Oncorhynchus mykiss and landlocked Atlantic salmon Salmo salar in lakes where the consumption of alewives Alosa pseudoharengus and other forage fishes containing thiaminase can cause them to become thiamine deficient and thereby reduce the survival of their fry. We evaluated feeding fingerling steelhead excess thiamine hydrochloride (THC1) for 1 or 2 weeks or equimolar amounts of thiamine mononitrate, thiamine-tetrahydrofurfuryl-disulfide, benfotiamine, or dibenzoyl thiamine (DBT). We found minimal internal reserves of thiamine after 6 months. We also compared the ability of injections of thiamine and its analogs to prevent mortality in thiamine-deficient steelhead and Atlantic salmon sac fry and found all forms to be effective, although benfotiamine was the least effective on an equimolar basis. Further, we injected yearling steelhead and found that DBT was tolerated at approximately 11,200 nmol/g of body weight, about 10 times more than thiamine in any other form. When yearling steelhead were injected with near-maximal doses of thiamine hydrochloride and several analogs and then fed a thiamine-deficient diet, DBT was retained for approximately 2 years--in contrast to other forms, which were retained for less than about 6 months. Therefore, these results suggest that neither feeding nor injecting young hatchery salmonids with DBT is likely to enhance their reproduction for more than 2 years after stocking. However, injecting DBT in nearly mature fish (either cultured fish from hatcheries or wild fish captured in lakes) may provide them with enough thiamine to successfully spawn within 2 years even though they consume mainly thiaminase-containing forage fishes.

Transketolase, a key enzyme in the pentose phosphate pathway, has been suggested as a target for inhibition in the treatment of cancer. Compound 5a ('N3'-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of the transketolase cofactor thiamine, is a potent transketolase inhibitor but suffers from poor pharmacokinetics due to high clearance and C(max) linked toxicity. An efficient way of improving the pharmacokinetic profile of 5a is to prepare oxidized prodrugs which are slowly reduced in vivo yielding longer, sustained blood levels of the drug. The synthesis of such prodrugs and their evaluation in rodent models is reported.

The controlled release of vitamin B1 (VB1, thiamine hydrochloride) from mesoporous silica tablets coated with a series of sol-gel coatings was investigated. Tetraethoxysilane (TEOS), n-propyltriethoxysilane (PTES), n-octyltriethoxysilane (OTES), bis(trimethoxysilyl)hexane (TSH), bis(triethoxysilyl)octane (TSO), bis (trimethoxysilylpropyl)amine (TSPA), and bis[(3-trimethoxysilyl)propyl]ethylenediamine (TSPED) were used as precursors for the coatings. The effects of organosilane type and concentration, the number of coatings, drying temperature, and release media on VB1 release from the coated mesoporous silica tablets were comprehensively examined. The TSH, TSO, TSPA, and TSPED coatings were found to be more effective in suppression of release than the other coatings. VB1 release decreases with the increase in the number of coatings and drying temperature. It was found that there is an optimal coating solution concentration for the controlled release. In general, more VB1 is released in 0.01 M HCl solution than in 0.05 M phosphate buffer solution at pH 7.4 because of the electrostatic repulsions between the protonated VB1 cations and the positively charged mesoporous silica carrier/coatings. The experimental results show that drug release can be easily controlled by changing the organosilane type and the number of coating. The method used in this study is an effective and flexible way for controlled release due to the high drug loading and the easy control of release rate.

Melarsoprol is the main drug used for the treatment of late-stage sleeping sickness, although it causes severe side-effects such as encephalopathy and polyneuropathy leading to death in some patients. Recent data suggest that melarsoprol and its active metabolite melarsenoxide interfere with thiamin transport and metabolism in E. coli and yeast, but there are no data concerning their possible effects on thiamin metabolism in mammalian cells. We tested both drugs on thiamin transport in cultured mouse neuroblastoma cells using (14)C-labeled thiamin. Melarsoprol, competitively inhibits high-affinity thiamin transport in mouse neuroblastoma cells with a K(i) of 44 micromol/L. However, the active compound melarsenoxide has no inhibitory effect. This suggests that the side effects of melarsoprol treatment are unlikely to be due to inhibition of thiamin transport by melarsenoxide, its main metabolite in the brain.

Thiamin (B1) is an essential micronutrient for normal growth and development. Mammals obtain thiamin through intestinal absorption, while in the kidney thiamin is reabsorbed to prevent its loss in the urine, both processes are specialized, carrier-mediated and involve thiamin transporters-1 and 2 (THTR-1 and THTR-2, respectively; products of the SLC19A2 and SLC19A3 genes). Although thiamin appears to play an important role in neonatal growth, little is currently known about the possible regulation of intestinal and renal thiamin uptake during developmental maturation. We addressed these issues by examining intestinal and renal thiamin uptake and expression of THTR-1 and THTR-2 during early stages of life. We utilized wild-type mice (mice express orthologues of both thiamin transporters) and transgenic mice expressing human SLC19A2 or SLC19A3 promoter-reporter transgenes as a model system and examined carrier-mediated thiamin uptake, mTHTR-1 and 2 protein and mRNA levels and luciferase activity in suckling (13 days), weanling (25-27 days), and adult (60-65 days) mice. Carrier-mediated thiamin uptake by jejunal and renal brush border membrane vesicles (BBMV) both decreased with maturation (suckling>weanling>adult) and were associated with a reduction in mTHTR-1 and mTHTR-2 protein, mRNA levels, and the activity of human SLC19A2 and SLC19A3 promoter-reporter constructs in the intestines and kidneys of transgenic mice. These results are the first to demonstrate that intestinal and renal thiamin uptake are developmentally regulated during early stages of life, mediated through mTHTR-1 and mTHTR-2, and suggest the possible involvement of transcriptional regulatory mechanism(s) in this regulation., (Copyright (c) 2005 Wiley-Liss, Inc.)

Presently is no consensus of opinion of the size of human optimal daily allowance as for thiamine and riboflavin, so for magnesium, what their content in polyvitamin and mineral preparations testify to. The study was conducted in 60 volunteers, who once took oral dosing of magnesium -bearing preparation "Magnerot" (500 mg of magnesium orotat converting to Mg2+ 32,8 Mg) and "Centrum" (100 mg of magnesium oxide converting to Mg2+ - 60,3 Vg) or vitamins B1 and B2 in 10, 20 and 30 mg doses. The received data testify that during the application of both of these preparations, equal concentration of this element takes place, though in case of magnesium oxide it happens later. As for the used vitamin B1 and B2 doses, it is determined that 10 mg is the optimal dose for treating their hypoavitaminosis.

Background: Commercially produced dried broken rice is widely used to prepare complementary foods for Thai infants, and it is both convenient and acceptable to persons from all socioeconomic classes. However, inadequate levels of calcium, iron, thiamine, and folate are common in complementary foods for breastfed infants., Objective: We developed dried broken rice fortified with these nutrients at levels recommended by the 2001 guidelines of the World Health Organization., Methods: The fortification process involved predrying broken rice at 90 degrees C for 1 hour, soaking in a nutrient solution (2:1 ratio of rice to solution), and drying at 70 degrees C for 1 hour and 50 minutes. Calcium lactate or calcium lactate gluconate was the calcium source, and ferrous sulfate, ferrous lactate, or ferric sodium ethylenediaminetetraacetic acid (NaFeEDTA) was the iron source. The vitamin sources were thiamine hydrochloride and folic acid. The product contained 40 mg of calcium, 5.3 mg of iron, 0.08 mg of thiamine, and 11 microg of folate per 20-g serving., Results: Approximately 5% and 10% of calcium and iron, respectively, were lost during processing, with a thiamine loss of approximately 13%, and a folate loss ranging from 17% to 23%. The thiamine loss during accelerated storage (42 degrees C for three months) was not significant (p > .05)., Conclusions: NaFeEDTA was the most appropriate iron fortificant because it provided prolonged product stability and high in vitro dialyzability.

Differentiation of intestinal epithelial cells is associated with up-and-down regulation of expression of a variety of genes including those involved in nutrient uptake. Nothing is known about possible differentiation-dependent regulation of the intestinal thiamin uptake process and the cellular and molecular mechanisms involved in such regulation. Using as models human-derived intestinal epithelial Caco-2 cells and crypt/villus epithelial cells isolated from wild-type and transgenic mice carrying promoters for human thiamin transporter-1 and -2 (hTHTR-1 and hTHTR-2), we addressed this issue. Our results showed that differentiation of Caco-2 cells is associated with a significant up-regulation in carrier-mediated thiamin uptake. Up-regulation was associated with a significant increase in the level of expression of hTHTR-1 and hTHTR-2 protein and mRNA as well as in activity of the corresponding transfected human thiamin transporter-1 (SLC19A2) and -2 (SLC19A3) promoters. Deletion analysis identified the differentiation-responsive region to be at position -356 to -275 bp for the SLC19A2 promoter and at position -77 to -13 bp for the SLC19A3 promoter. In addition, a critical and specific role in the differentiation-mediated effects for an NF1 binding site (-348 to -345 bp) in the SLC19A2 promoter and a SP1/GC-box binding site (-48 to -45 bp) in the SLC19A3 promoter were established using mutational analysis. The physiological relevance of in vitro findings with Caco-2 cells was confirmed in wild-type and transgenic mice by demonstrating that thiamin uptake and mRNA levels of the mouse THTR-1 and THTR-2, as well as activity of human SLC19A2 and SLC19A3 promoters expressed in transgenic mice, were all significantly higher in intestinal villus compared with crypt epithelial cells. These studies demonstrate for the first time that differentiation of intestinal epithelial cells is associated with an up-regulation in thiamin uptake process and that this up-regulation appears to be mediated via transcriptional regulatory mechanisms that involve the SLC19A2 and SLC19A3 genes.

We studied six infants with thiamine-responsive congenital lactic acidosis and normal pyruvate dehydrogenase complex activity in vitro, through clinical and biochemical analysis. In addition to elevated lactate and pyruvate levels, the data revealed increased urinary excretion of alpha-ketoglutarate, alpha-ketoadipate, and branched chain ketoacids, indicating functional impairment of thiamine-requiring enzymes, such as pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, alpha-ketoadipate dehydrogenase, and branched chain amino acid dehydrogenase. The metabolism of thiamine has not been investigated in patients with thiamine-responsive congenital lactic acidosis. We evaluated two specific transport systems, THTR-1 (SLC19A2) and THTR-2 (SLC19A3), and a pyrophosphorylating enzyme of thiamine, thiamine pyrophosphokinase (hTPK 1), in addition to pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex activity; no abnormality was found. Although the clinical features of thiamine-responsive congenital lactic acidosis are heterogeneous and clinical responses to thiamine administration vary, we emphasize the importance of early diagnosis and initiation of thiamine therapy before the occurrence of permanent brain damage. Careful monitoring of lactate and pyruvate would be useful in determining thiamine dosage.

Thiamin participates in metabolic pathways contributing to normal cellular functions, growth, and development. The molecular mechanism of the human intestinal thiamin absorption process involves the thiamin transporters-1 (hTHTR-1) and -2 (hTHTR-2), products of the SLC19A2 and SLC19A3 genes. Little is known about adaptive regulation of the intestinal thiamin uptake process or the molecular mechanism(s) involved during thiamin deficiency. In these studies, we addressed these issues using wild-type mice and transgenic animals carrying the promoters of the hTHTR-1 and -2. We show that, in thiamin deficiency, a significant and specific upregulation in intestinal carrier-mediated thiamin uptake occurs and that this increase is associated with an induction in protein and mRNA levels of mTHTR-2 but not mTHTR-1; in addition, an increase in the activity of the SLC19A3, but not the SLC19A2, promoter was observed in the intestine of transgenic mice. Similar findings were detected in the kidney; however, expression of both thiamin transporters and activity of both human promoters were upregulated in this organ in thiamin deficiency. We also examined the effect of thiamin deficiency on the level of expression of mTHTR-1 and mTHTR-2 messages and activity of the human promoters in the heart and brain of transgenic mice and found an increase in mTHTR-1 mRNA and a rise in activity of the SLC19A2 promoter in thiamin-deficient mice. These results show that the intestinal and renal thiamin uptake processes are adaptively upregulated during dietary thiamin deficiency, that expression of mTHTR-1 and mTHTR-2 is regulated in a tissue-specific manner, and that this upregulation is mediated via transcriptional regulatory mechanism(s).

Background: This work aimed to investigate, in the rat, the acute in vitro effect of red wine and the effect of chronic red wine ingestion on the intestinal absorption of thiamine and folate and to compare them with the effects of ethanol alone., Methods: The effects of red wine and of an ethanol solution (same ethanol concentration as that in the red wine, i.e., 12% [v/v]) on rat jejunal apparent permeability (Papp) to H-thiamine and H-folate in the mucosal-to-serosal direction were investigated. Red wine and ethanol were tested both chronically (21-day consumption) and acutely in vitro., Results: Acutely, both red wine and ethanol 12% (v/v) (both diluted 1:5) reduced (to 65 and 60% of control, respectively) the mucosal-to-serosal Papp to H-thiamine across rat jejunum. Chronic (21-day) ethanol (12% [v/v]) consumption also decreased the Papp to H-thiamine (to 33% of control), but red wine consumption for the same period did not change it. Mucosal-to-serosal Papp to H-folate across rat jejunum was not changed by chronic ingestion of red wine or ethanol. Similarly, it was not affected by acute exposition of the tissue to red wine or ethanol. Acute ethanol (0.05% [v/v]) did not affect the Papp to H-thiamine or H-folate in jejunal tissues obtained from control and red wine-treated rats, but it significantly increased the Papp to both H-thiamine and H-folate (to 183 and 197% of control, respectively) in tissues from chronically ethanol-treated rats., Conclusions: Acute and chronic red wine or ethanol had no effect on the intestinal absorption of folate. However, ethanol, both acutely and chronically, decreased the jejunal absorption of thiamine, and red wine reduced the jejunal absorption of thiamine, but only when tested acutely. These findings show that it is not correct to extrapolate from results obtained with ethanol alone on intestinal permeability to the effect of alcoholic beverage consumption.

Thiamine (T) analogues pyrithiamine, oxythiamine or amprolium in amounts 10-1000 times higher than labelled T, were i.p. injected into rats together with 14C-T (30 microg; 46.25 KBq). The radioactivity associated with T and its phosphoesters in the plasma and cerebral cortex, brainstem, cerebellum, and sciatic nerve were determined at time intervals from 0.25 to 240 h from injection. The experimental data obtained were processed with a mathematical compartmental model that calculated the fractional rate constants. These are the amount of content in a given compartment that is replaced in 1 h and expressed in per hour. The results showed that all three analogues inhibited thiamine entry from plasma. Instead, oxythiamine enhanced T phosphorylation to T pyrophosphate (TPP); amprolium and oxythiamine enhanced TPP dephosphorylation to monophosphate (TMP); pyrithiamine reduced TPP dephosphorylation and TMP formation, while none of the analogues modified TMP dephosphorylation to T. In conclusion, in living rats, the action of T analogues was much more complex than could be expected from their structure and action in vitro.

Mucoadhesive microspheres made of oppositely charged dextran derivatives and cellulose acetate butyrate (Ad-MS) were evaluated for their ability to improve the bioavailability of theophylline (TH) and thiamine disulfide (TDS). A drug suspension (or solution) and non-adhesive microspheres (MS) were used as references. In vitro drug release profiles from MS and Ad-MS were similar for each drug, whereas their gastrointestinal transits differed. The plasma concentration after oral administration of drug suspension (or solution), MS and Ad-MS was investigated in rats. In the case of TH, sustained plasma level profiles were observed after MS or Ad-MS administration, with similar C(max), T(max) and MRT( infinity ) values. AUC( infinity ) values of the suspension, MS and Ad-MS were statistically equivalence. These indicated that Ad-MS achieved a sustained plasma level profile without a decrease of AUC. In the case of TDS, MRT( infinity ) and AUC( infinity ) of Ad-MS were significantly larger than those of the solution and MS, indicating that the plasma level was sustained and the extent of bioavailability was increased. These results suggested that Ad-MS is a promising device for improvement of bioavailability of drugs those absorption windows are limited to upper part of the gastrointestinal tract.

We assessed the effects of intake of thiamin, arginine, caffeine, and citric acid (TACC) on lipid metabolism in healthy subjects. Thirty-one subjects with high percent body fat (> or = 25.0%) were randomly assigned to a 12-wk intervention with daily intake of TACC-supplemented tea (1.1, 1240, 52, and 540 mg, respectively; n=16) or control tea (n=15). The percent body fat decreased significantly during the intervention in both groups, especially in the TACC group. A percentage decrease in triceps skinfold was significantly greater in the TACC group than in the control group. The decrease in abdominal visceral fat in obese subjects was significantly greater in the TACC group than in the control group. Serum triglyceride was significantly lower during intervention than that during the non-intervention period in the TACC group. These results suggest that TACC may be effective in reducing body fat in obese subjects.

Thiamine is an essential, positively charged (under physiologic conditions), water-soluble vitamin requiring transport into brain. Brain thiamine deficiency has been linked to neurodegenerative disease by subsequent impairment of thiamine-dependent enzymes used in brain glucose/energy metabolism. In this report, we evaluate brain uptake and efflux of [3H]thiamine using the in situ rat brain perfusion technique. To confirm brain distribution was not related to blood-brain barrier endothelial cell uptake, we compared parenchymal and cell distribution of [3H]thiamine using capillary depletion. Our work supports previous literature findings suggesting blood-brain barrier thiamine uptake is via a carrier-mediated transport mechanism, yet extends the literature by redefining the kinetics with more sensitive methodology. Significantly, [3H]thiamine brain accumulation was influenced by a considerable efflux rate. Evaluation of the efflux mechanism demonstrated increased stimulation by the presence of increased vascular thiamine. The influx transport mechanism and efflux rate were each comparable throughout brain regions despite documented differences in glucose and thiamine metabolism. The observation that [3H]thiamine blood-brain barrier influx and efflux is regionally homogenous may have significant relevance to neurodegenerative disease linked to thiamine deficiency.

Thiamine (vitamin B(1)) was investigated as a tumor-specific ligand for gadolinium nanoparticles. Solid nanoparticles containing gadolinium hexanedione (1.5 mg/mL) were engineered from oil-in-water microemulsion templates and coated with thiamine ligands. Thiamine ligands were synthesized by conjugating thiamine to either distearoylphosphatidylethanolamine (DSPE) or fluorescein via a poly(ethylene glycol) (PEG) spacer (Mw 3350). The efficiency of thiamine ligand attachment to nanoparticles was evaluated using gel permeation chromatography (GPC). Cell association studies were carried using a methotrexate-resistant breast cancer cell line, MTX(R)ZR75, transfected with thiamine transporter genes (THTR1 and THTR2). Thiamine-coated nanoparticle association with THTR1 and THTR2 cells was significantly greater than that with control breast cancer cells (MTX(R)ZR75 transfected with the empty expression vector pREP4) (p < 0.01; t-test). The nanoparticle cell association was significantly dependent on the extent of thiamine ligand coating on nanoparticles, expression of thiamine transporters in cells, temperature of incubation, and the concentration of competitive inhibitor (free thiamine). Further studies are warranted to assess the potential of the engineered thiamine-coated gadolinium (Gd) nanoparticles in neutron capture therapy of tumors.

Background: Thiamine supplementation is necessary in patients with thiamine deficiency syndromes. Experimental evidence suggests that tissue uptake and the elimination of thiamine are dose-dependent., Aim: The aim of the present study was to investigate the effect of different i.v. infusion rates of thiamine on blood concentrations of thiamine and its active metabolite thiamine pyrophosphate (TPP) and on renal excretion of thiamine., Methods: Twelve healthy subjects received in a two-period block randomized study 150 mg thiamine intravenously over either 1 or 24 h., Results: The maximum blood concentrations (Cmax) of thiamine were significantly higher after the more rapid infusion (RI; 2300 ng/mL) than after the slower infusion (SI; 177 ng/mL). The AUC of thiamine was identical after both infusion protocols. There was a slightly (10%) increased AUC of TPP (P < 0.08) after SI, whereas C(max) values were comparable. Urinary excretion of thiamine was significantly decreased from 83.6% of the applied dose after RI to 57.6% after the SI., Conclusions: Our data suggest an increased tissue uptake of thiamine when it is given as an SI compared with a RI of the same dose. It is concluded, therefore, that an SI of thiamine may be superior to RI or bolus injections to treat severe deficiency syndromes.

Thiamine (vitamin B(1)) is essential for normal cellular functions and growth. Mammals cannot synthesize thiamine and thus must obtain the vitamin via intestinal absorption. The intestine is exposed to a dietary thiamine source and a bacterial source in which the vitamin is synthesized by the normal microflora of the large intestine. Very little is known about thiamine uptake in the large intestine. The aim of this study was, therefore, to address this issue. Our results with human-derived colonic epithelial NCM460 cells as a model system showed thiamine uptake to be 1) temperature- and energy dependent, 2) Na(+) independent, 3) increased with increasing buffer pH from 5 to 8 and after cell acidification but inhibited by amiloride, 4) saturable as a function of concentration, 5) inhibited by thiamine structural analogs but not by unrelated organic cations, and 6) inhibited by modulators of a Ca(2+)/calmodulin-mediated pathway. NCM460 cells and native human colonic mucosa expressed the recently cloned human thiamine transporter THTR-1 (product of the SLC19A2 gene) at both mRNA and protein levels. These results demonstrate for the first time that human NCM460 colonocytes possess a specific carrier-mediated system for thiamine uptake that appears to be under the regulation of an intracellular Ca(2+)/calmodulin-mediated pathway. It is suggested that bacterially synthesized thiamine in the large intestine may contribute to thiamine nutrition of the host, especially toward cellular nutrition of the local colonocytes.

Our work deals with a method for the identification of the dynamics of nonlinear (patho-)physiological systems by learning from data. The key idea which underlies our approach consists in the integration of qualitative modeling methods with fuzzy logic systems. The major advantage which derives from such an integrated framework lies in its capability both to represent the structural knowledge of the system at study and to determine, by exploiting the available experimental data, a functional approximation of the system dynamics that can be used as a reasonable predictor of the patient's future state. We have successfully applied our method in the identification of the intracellular kinetics of thiamine from data collected in the intestine cells.