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Background: Traditionally, vitamin B1 status is assessed by a functional test measuring erythrocyte transketolase (ETK) activity or direct measurement of erythrocyte thiamine diphosphate (eThDP) concentration. However, such analyses are logistically challenging, and do not allow assessment of vitamin B1 status in plasma/serum samples stored in biobanks. Using a multiplex assay, we evaluated plasma concentrations of thiamine and thiamine monophosphate (TMP), as alternative, convenient measures of vitamin B1 status. Methods: We investigated the relationships between the established biomarker eThDP and plasma concentrations of thiamine and TMP, and compared the response of these thiamine forms to thiamine fortification using samples from 196 healthy Cambodian women (aged 18–45 years.). eThDP was measured by high performance liquid chromatography with fluorescence detection (HPLC-FLD) and plasma thiamine and TMP by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Plasma thiamine and TMP correlated significantly with eThDP at baseline and study-end (p < 0.05). Among the fortification groups, the strongest response was observed for plasma thiamine (increased by 266%), while increases in plasma TMP (60%) and eThDP (53%) were comparable. Conclusions: Plasma thiamine and TMP correlated positively with eThDP, and all thiamine forms responded significantly to thiamine intervention. Measuring plasma concentrations of thiamine forms is advantageous due to convenient sample handling and capacity to develop low volume, high-throughput, multiplex assays.

Thiamine (vitamin B1) is a precursor of the well-known coenzyme of central metabolic pathways thiamine diphosphate (ThDP). Highly intense glucose oxidation in the brain requires ThDP-dependent enzymes, which determines the critical significance of thiamine for neuronal functions. However, thiamine can also act through the non-coenzyme mechanisms. The well-known facilitation of acetylcholinergic neurotransmission upon the thiamine and acetylcholine co-release into the synaptic cleft has been supported by the discovery of thiamine triphosphate (ThTP)-dependent phosphorylation of the acetylcholine receptor-associated protein rapsyn, and thiamine interaction with the TAS2R1 receptor, resulting in the activation of synaptic ion currents. The non-coenzyme regulatory binding of thiamine compounds has been demonstrated for the transcriptional regulator p53, poly(ADP-ribose) polymerase, prion protein PRNP, and a number of key metabolic enzymes that do not use ThDP as a coenzyme. The accumulated data indicate that the molecular mechanisms of the neurotropic action of thiamine are far broader than it has been originally believed, and closely linked to the metabolism of thiamine and its derivatives in animals. The significance of this topic has been illustrated by the recently established competition between thiamine and the antidiabetic drug metformin for common transporters, which can be the reason for the thiamine deficiency underlying metformin side effects. Here, we also discuss the medical implications of the research on thiamine, including the role of thiaminases in thiamine reutilization and biosynthesis of thiamine antagonists; molecular mechanisms of action of natural and synthetic thiamine antagonists, and biotransformation of pharmacological forms of thiamine. Given the wide medical application of thiamine and its synthetic forms, these aspects are of high importance for medicine and pharmacology, including the therapy of neurodegenerative diseases.

Background This is a post hoc analysis of combined cohorts from two previous Phase II clinical trials to assess the effect of thiamine administration on kidney protection and mortality in patients with septic shock. Methods Patient-level data from the Thiamine in Septic Shock Trial (NCT01070810) and the Thiamine for Renal Protection in Septic Shock Trial (NCT03550794) were combined in this analysis. The primary outcome for the current study was survival without the receipt of renal replacement therapy (RRT). Analyses were performed on the overall cohort and the thiamine-deficient cohort (thiamine < 8 nmol/L). Results Totally, 158 patients were included. Overall, thiamine administration was associated with higher odds of being alive and RRT-free (adjusted odds ratio [aOR]: 2.05 [95% confidence interval (CI) 1.08–3.90]) and not needing RRT (aOR: 2.59 [95% CI 1.01–6.62]). In the thiamine-deficient group, thiamine administration was associated with higher odds of being alive and RRT-free (aOR: 8.17 [95% CI 1.79–37.22]) and surviving to hospital discharge (aOR: 6.84 [95% CI 1.54–30.36]). There was a significant effect modification by baseline thiamine deficiency for alive and RRT-free (interaction, p  = 0.016) and surviving to hospital discharge ( p  = 0.019). Conclusion In the combined analysis of two previous randomized trials, thiamine administration was associated with higher odds of being alive and RRT-free at hospital discharge in patients with septic shock. This signal was stronger in patients with thiamine deficiency.

Thiamine (vitamin B1) and its phosphates are essential for almost all organisms. Thiamine diphosphate (ThDP) is the major intracellular derivative which is considered the only form functioning as a coenzyme. Thiamine triphosphate (ThTP), another ubiquitous derivative, lacks a clear physiological function and is usually kept at low levels. However, it can accumulate up to 87% of total thiamine in animal tissues lacking cytosolic thiamine triphosphatase (THTPA) activity. Studies of ThTP coenzyme function have always faced the problem of ThTP hydrolysis to ThDP. To avoid such interference a synthetic stable ThTP analog, bismethylene ThTP (bmThTP), has been synthesized. Given that ThTP accumulation is caused by cytosolic THTPA suppression, cytosolic ThDP-dependent transketolase (TKT) is the primary target for probing (bm)ThTP’s coenzyme function. Indeed, bmThTP acts as a TKT coenzyme, with the apparent Km(bmThTP) of 16.3 µM. However, bmThTP binding slightly differs from that of ThTP. Molecular docking was used to estimate affinities of ThDP, ThTP and bmThTP, also allowing us to avoid ThTP hydrolysis. Despite almost identical localization within the active site, bmThTP could not bind as well as ThTP, resulting in a 2.36 kcal/mol difference in estimated ΔG. Based on our data, calculated Km(ThTP) for TKT is about 0.07–0.08 µM, only 1.6–2 times that of Km(ThDP). Such a small difference implies that ThTP could physiologically act as the main TKT coenzyme form upon its accumulation in muscles, at least in a few known animal species.

Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Charcot–Marie–Tooth (CMT) neuropathy is a polygenic disorder of peripheral nerves with no effective cure. Thiamine (vitamin B1) is a neurotropic compound that improves neuropathies. Our pilot study characterizes therapeutic potential of daily oral administration of thiamine (100 mg) in CMT neuropathy and its molecular mechanisms. The patient hand grip strength was determined before and after thiamine administration along with the blood levels of the thiamine coenzyme form (thiamine diphosphate, ThDP), activities of endogenous holo-transketolase (without ThDP in the assay medium) and total transketolase (with ThDP in the assay medium), and transketolase activation by ThDP [1 – (holo-transketolase/total transketolase),%], corresponding to the fraction of ThDP-free apo-transketolase. Single cases of administration of sulbutiamine (200 mg) or benfotiamine (150 mg) reveal their effects on the assayed parameters within those of thiamine. Administration of thiamine or its pharmacological forms increased the hand grip strength in the CMT patients. Comparison of the thiamin status in patients with different forms of CMT disease to that of control subjects without diagnosed pathologies revealed no significant differences in the average levels of ThDP, holo-transketolase, or relative content of holo and apo forms of transketolase. However, the regulation of transketolase by thiamine/ThDP differed in the control and CMT groups: in the assay, ThDP activated transketolase from the control individuals, but not from CMT patients. Thiamine administration paradoxically decreased endogenous holo-transketolase in CMT patients; this effect was not observed in the control group. Correlation analysis revealed sex-specific differences in the relationship between the parameters of thiamine status in both the control subjects and patients with the CMT disease. Thus, our findings link physiological benefits of thiamine administration in CMT patients to changes in their thiamine status, in particular, the blood levels of ThDP and transketolase regulation.

Background Low-carbohydrate diets (LCD) are popular for weight loss but lack evidence about micronutrient sufficiency in real-life use. This study assessed the intake and biochemical status of selected micronutrients in people voluntarily following LCDs. Methods A cross-sectional study was conducted (2018-20) among 98 adults recruited as self-reporting either LCD ( n  = 49) or diets not restricting carbohydrates (controls; n  = 49). Diets were assessed using the 130-item EPIC-Norfolk food-frequency questionnaire. Red-blood-cell thiamine diphosphate (TDP) was measured for thiamine status using HPLC. Plasma magnesium, zinc, copper, and selenium were measured using inductively coupled plasma mass spectrometry. Between-group biomarker comparisons were conducted using ANCOVA and adjusted for age, sex, body mass index (BMI), and diabetes status. Results LCD-followers (26% male, median age 36 years, median BMI 24.2 kg/m 2 ) reported adhering to LCDs for a median duration of 9 months (IQR 4–36). The most followed LCD type was ‘their own variations of LCD’ (30%), followed by ketogenic (23%), ‘palaeolithic’ (15%), and Atkins diets (8%). Among controls, 41% were male (median age 27 years, median BMI 23 kg/m 2 ). Median macronutrient intakes for LCD vs control groups were carbohydrate 16%Energy (E) vs. 50%E; protein 25%E vs. 19%E; and fat 55%E vs 34%E (saturated fat 18%E vs. 11%E). Two-thirds of LCD followers (32/49) and half of the controls (24/49) reported some use of dietary supplements ( p  = 0.19). Among LCD-followers, assessing from food data only, 21 (43%) failed to meet the reference nutrient intake (RNI) for thiamine (vs.14% controls, p  = 0.002). When thiamine from supplementation (single- or multivitamin) was included, there appeared to be no difference in thiamine intake between groups. Still, red-blood-cell TDP was lower in LCD-followers than controls (407 ± 91 vs. 633 ± 234 ng/gHb, p  < 0.001). Three LCD-followers were thiamine-deficient (RBC thiamine < 275 ng/gHb) vs. one control. There were no significant differences in dietary intakes or plasma concentrations of magnesium, zinc, copper, and selenium between groups. Conclusions Following LCDs is associated with lower thiamine intake and TDP status than diets without carbohydrate restriction, incompletely corrected by supplement use. These data, coupled with a lack of RCT evidence on body weight control, do not support recommending LCDs for weight management without appropriate guidance and diet supplementation.

IntroductionThiamine (vitamin B1) deficiency remains a concern in Cambodia where women with low thiamine intake produce thiamine-poor milk, putting their breastfed infants at risk of impaired cognitive development and potentially fatal infantile beriberi. Thiamine fortification of salt is a potentially low-cost, passive means of combating thiamine deficiency; however, both the dose of thiamine required to optimise milk thiamine concentrations as well as usual salt intake of lactating women are unknown.Methods and analysisIn this community-based randomised controlled trial, 320 lactating women from Kampong Thom, Cambodia will be randomised to one of four groups to consume one capsule daily containing 0, 1.2, 2.4 or 10 mg thiamine as thiamine hydrochloride, between 2 and 24 weeks postnatal. The primary objective is to estimate the dose where additional maternal intake of thiamine no longer meaningfully increases infant thiamine diphosphate concentrations 24 weeks postnatally. At 2, 12 and 24 weeks, we will collect sociodemographic, nutrition and health information, a battery of cognitive assessments, maternal (2 and 24 weeks) and infant (24 weeks only) venous blood samples (biomarkers: ThDP and transketolase activity) and human milk samples (also at 4 weeks; biomarker: milk thiamine concentrations). All participants and their families will consume study-provided salt ad libitum throughout the trial, and we will measure salt disappearance each fortnight. Repeat weighed salt intakes and urinary sodium concentrations will be measured among a subset of 100 participants. Parameters of Emax dose–response curves will be estimated using non-linear least squares models with both ‘intention to treat’ and a secondary ‘per-protocol’ (capsule compliance ≥80%) analyses.Ethics and disseminationEthical approval was obtained in Cambodia (National Ethics Committee for Health Research 112/250NECHR), Canada (Mount Saint Vincent University Research Ethics Board 2017–141) and the USA (University of Oregon Institutional Review Board 07052018.008). Results will be shared with participants’ communities, as well as relevant government and scientific stakeholders via presentations, academic manuscripts and consultations.Trial registration numberNCT03616288.

The isolation, structural elucidation, and synthesis of pure thiamin were achieved in 1936, marking a milestone in vitamin research. As an organic compound soluble in water, thiamin is essential for carbohydrate metabolism in plants and animals, and in its active form—as part of the thiamin pyrophosphate coenzyme—performs these functions. Thereby, thiamin represents an essential vitamin to human health and is involved in several pathways that regulate several pathophysiological mechanisms. Cardiovascular disease is significantly impacted by thiamine imbalance and its supplementation offers substantial improvements to the associated conditions. In this comprehensive review, we aimed to examine the dual role of thiamine deficiency and accumulation, focusing on an analysis of the causes of thiamine deficiency. We detailed the effects of thiamine deficiency on metabolism and on cardiovascular risk and heart failure, explaining the molecular mechanisms involved in metabolic dysfunction, and highlighting the role of B1 vitamin supplementation in diabetes mellitus management and atherosclerosis development and progression. Indeed, B1 supplementation counteracts oxidative stress and inflammation, significantly ameliorating glycemic and lipemic profiles. Additionally, we reported the beneficial effects of thiamine in counteracting cardiotoxicity induced by cancer therapy. Although preclinical data strongly support the benefits of thiamine, clinical trial findings are in contrast and contradictory, hampered by limitations such as small sample sizes and inadequate follow-up. Further research is needed to investigate thiamine’s potential benefits, overcoming current study limitations and evaluating its use as a supplemental therapy alongside standard treatments in different high-cardiovascular-risk conditions.

Background Diuretic treatment for heart failure may lead to an increased urinary thiamine excretion and in long-term thiamine deficiency, which may further compromise cardiac function. This study evaluated the effect of high dose thiamine supplementation in heart failure patients. Methods Nine patients with diuretic treatment for symptomatic chronic heart failure and a left ventricular ejection fraction (LVEF) <40% were randomly assigned to receive thiamine (300 mg/day) or placebo for 28 days. After a wash-out of 6 weeks, the patients crossed-over to a second treatment period. The primary outcome was a change in LVEF. Results Mean age was 56.7 ± 9.2 years (range 44.9–75.4 years). Baseline LVEF was similar for both treatment groups (29.5% in the thiamine group and 29.5% in the placebo group, P  = 0.911). After 28 days of thiamine treatment, the LVEF increased to 32.8% which was significantly ( P  = 0.024) different from the LVEF in the placebo group (28.8%). This corresponds to a treatment effect for LVEF of 3.9% in absolute terms. Conclusions This study suggests that thiamine supplementation has beneficial effects on cardiac function in patients with diuretic drugs for symptomatic chronic heart failure. Subclinical thiamine deficiency is probably an underestimated issue in these outpatients.