Thiamine as a metabolic resuscitator after out-of-hospital cardiac arrest.

INTRODUCTION: Thiamine is a key cofactor for aerobic metabolism, previously shown to improve mortality and neurological outcomes in a mouse model of cardiac arrest. We hypothesized that thiamine would decrease lactate and improve outcomes in post-arrest patients. METHODS: Single center, randomized, blinded, placebo-controlled, Phase II trial of thiamine in adults within 4.5 hours of return of spontaneous circulation after out-of-hospital cardiac arrest (OHCA), with coma and lactate ≥ 3 mmol/L. Participants received 500 mg IV thiamine or placebo twice daily for 2 days. Randomization was stratified by lactate > 5 or ≤ 5 mmol/L. The primary outcome of lactate was checked at baseline, 6, 12, and 24 hours, and compared using a linear mixed model to account for repeated measures. Secondary outcomes included SOFA score, pyruvate dehydrogenase, renal injury, neurological outcome, and mortality. RESULTS: Of 93 randomized patients, 76 were enrolled and included in the analysis. There was no difference in lactate over 24 hours (mean difference 0.34 mmol/L (95% CI: -1.82, 2.50), p = 0.43). There was a significant interaction between randomization lactate subgroup and the effect of the intervention on mortality (p = 0.01) such that mortality was higher with thiamine in the lactate > 5 mmol/L group and lower with thiamine in the < 5 mmol/L group. This subgroup difference prompted the Data and Safety Monitoring Board to recommend the study be terminated early. PDH activity increased over 72 hours in the thiamine group. There were no differences in other secondary outcomes. CONCLUSION: In this single-center randomized trial, thiamine did not affect lactate over 24 hours after OHCA.

Thiamine as a metabolic resuscitator after in-hospital cardiac arrest.

INTRODUCTION: Elevated lactate is associated with mortality after cardiac arrest. Thiamine, a cofactor of pyruvate dehydrogenase, is necessary for aerobic metabolism. In a mouse model of cardiac arrest, thiamine improved pyruvate dehydrogenase activity, survival and neurologic outcome. AIM: To determine if thiamine would decrease lactate and increase oxygen consumption after in-hospital cardiac arrest. METHODS: Randomized, double-blind, placebo-controlled phase II trial. Adult patients with arrest within 12 hours, mechanically ventilated, with lactate ≥ 3 mmol/L were included. Randomization was stratified by lactate > 5 or ≤ 5 mmol/L. Thiamine 500 mg or placebo was administered every 12 hours for 3 days. The primary outcome of lactate was checked at baseline, 6, 12, 24, and 48 hours, and compared using a linear mixed model, accounting for repeated measures. Secondary outcomes included oxygen consumption, pyruvate dehydrogenase, and mortality. RESULTS: Enrollments stopped after 36 patients due Data Safety and Monitoring Board concern about potential harm in an unplanned subgroup analysis. There was no overall difference in lactate (mean difference at 48 hours 1.5 mmol/L [95% CI -3.1-6.1], global p = 0.88) or any secondary outcomes. In those with randomization lactate > 5 mmol/L, mortality was 92% (11/12) with thiamine and 67% (8/12) with placebo (p = 0.32). In those with randomization lactate ≤ 5 mmol/L mortality was 17% (1/6) with thiamine and 67% (4/6) with placebo (p = 0.24). There was a significant interaction between randomization lactate and the effect of thiamine on survival (p = 0.03). CONCLUSIONS: In this single center trial thiamine had no overall effect on lactate after in-hospital cardiac arrest.

A Predictive Model for Thiamine Responsive Disorders Among Infants and Young Children: Results from a Prospective Cohort Study in Lao People's Democratic Republic.

OBJECTIVE: To develop a predictive model for thiamine responsive disorders (TRDs) among infants and young children hospitalized with signs or symptoms suggestive of thiamine deficiency disorders (TDDs) based on response to therapeutic thiamine in a high-risk setting. STUDY DESIGN: Children aged 21 days to <18 months hospitalized with signs or symptoms suggestive of TDD in northern Lao People's Democratic Republic were treated with parenteral thiamine (100 mg daily) for ≥3 days in addition to routine care. Physical examinations and recovery assessments were conducted frequently for 72 hours after thiamine was initiated. Individual case reports were independently reviewed by three pediatricians who assigned a TRD status (TRD or non-TRD), which served as the dependent variable in logistic regression models to identify predictors of TRD. Model performance was quantified by empirical area under the receiver operating characteristic curve. RESULTS: A total of 449 children (median [Q1, Q3] 2.9 [1.7, 5.7] months old; 70.3% exclusively/predominantly breastfed) were enrolled; 60.8% had a TRD. Among 52 candidate variables, those most predictive of TRD were exclusive/predominant breastfeeding, hoarse voice/loss of voice, cyanosis, no eye contact, and no diarrhea in the previous 2 weeks. The area under the receiver operating characteristic curve (95% CI) was 0.82 (0.78, 0.86). CONCLUSIONS: In this study, the majority of children with signs or symptoms of TDD responded favorably to thiamine. While five specific features were predictive of TRD, the high prevalence of TRD suggests that thiamine should be administered to all infants and children presenting with any signs or symptoms consistent with TDD in similar high-risk settings. The usefulness of the predictive model in other contexts warrants further exploration and refinement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03626337.

Efficacy of thiamine supplementation in improving depressive symptoms-evidence-based review / Eficacia de la suplementación con tiamina para mejorar los síntomas depresivos-revisión basada en la evidencia

Objetivos: Revisar la evidencia existente con respecto a la efectividad de la suplementación con tiamina en pacientes consíntomas depresivos en cuanto a su mejoría, en comparación con la toma de fármacos psicotrópicos aislados o placebos. Diseño: Revisión sistemática; Emplazamiento: Atención primaria. Método: Pregunta de investigación: Población – Adultos con síntomas depresivos; Intervención – Suplementación contiamina aislada o asociada a psicofármacos; Comparación: uso de placebo o fármacos psicotrópicos; Resultado – Mejoría delos síntomas depresivos (según DSM-V). La búsqueda se realizó utilizando los términos MeSH (("Depression" OR"Depression Disorder") AND "Thiamine"”) en las fuentes seleccionadas. Se excluyeron todos los artículos de opinión,artículos de revisión clásicos y estudios ya incluidos en metanálisis o revisiones sistemáticas seleccionadas. Se utilizó laescala Strength of Recommendation Taxonomy (SORT) para asignar niveles de evidencia y fuerzas de recomendación.Resultados: La investigación resultó en 3 artículos que cumplieron con los criterios de inclusión y de los cuales se extrajeronlas conclusiones.Conclusiones: Se demostraron beneficios estadísticamente significativos de la suplementación con tiamina en algunos delos parámetros evaluados. Sin embargo, a la suplementación con tiamina se le asignó una Fuerza de Recomendación B porla Escala SORT, ya que los estudios existentes de calidad moderada son pocos, aunque orientados al paciente, y no handemostrado ser suficientes o consistentes para recomendar la generalización del uso de tiamina. Se necesitan más ensayosclínicos controlados de buena calidad científica para responder adecuadamente a esta pregunta de investigación.(AU)

Objective: to review the existing evidence regarding the effectiveness of thiamine supplementation in improving depressivesymptoms in adult patients, compared to taking psychoactive drugs alone or placebo. Design: Systematic ReviewSite: Primary Care. Methods: Research question: Population – Adults with depressive symptoms; Intervention – Thiamine supplementationalone or associated with psychotropic drugs; Comparison: use of placebo or psychotropic drugs; Outcome – Improvementof depressive symptoms (according to DSM-V). The search was performed using the MeSH terms (("Depression" OR"Depression Disorder") AND "Thiamine"") in the selected sources. All opinion articles, classic review articles, and studiesalready included in meta-analyses or previously selected reviews were excluded. The strength of recommendationtaxonomy scale (SORT) was used to assign levels of evidence and strength of recommendation.Results: The search resulted in 3 articles that met the inclusion criteria, from which conclusions were drawn. Conclusions: Statistically significant benefits of thiamine supplementation were demonstrated in some of the evaluatedparameters. However, thiamine supplementation was assigned a Strength of Recommendation B by the SORT Scale, asexisting studies of moderate quality are few, albeit patient oriented, not proving to be sufficient or consistent torecommend the generalization of the use of thiamine. More controlled clinical trials of good scientific quality are needed toadequately answer this research question.(AU)

Pharmacologic neuroprotection in ischemic brain injury after cardiac arrest.

Cardiac arrest has many implications for morbidity and mortality. Few interventions have been shown to improve return of spontaneous circulation (ROSC) and long-term outcomes after cardiac arrest. Ischemic-reperfusion injury upon achieving ROSC creates an imbalance between oxygen supply and demand. Multiple events occur in the postcardiac arrest period, including excitotoxicity, mitochondrial dysfunction, and oxidative stress and inflammation, all of which contribute to ongoing brain injury and cellular death. Given that complex pathophysiology underlies global brain hypoxic ischemia, neuroprotective strategies targeting multiple stages of the neuropathologic cascade should be considered as a means of mitigating secondary neuronal injury and improving neurologic outcomes and survival in cardiac arrest victims. In this review article, we discuss a number of different pharmacologic agents that may have a potential role in targeting these injurious pathways following cardiac arrest. Pharmacologic therapies most relevant for discussion currently include memantine, perampanel, magnesium, propofol, thiamine, methylene blue, vitamin C, vitamin E, coenzyme Q10 , minocycline, steroids, and aspirin.

Clinical diagnosis, outcomes and treatment of thiamine deficiency in a tertiary hospital.

BACKGROUND: Acute thiamine deficiency can occur in patients with or without history of alcohol abuse and can lead to life-threatening complications. Clinical diagnosis is challenging, often resulting in delayed recognition and treatment. Patients may present with heterogenous symptoms, more diverse than the historical neurological description. Cerebral MRI can contribute to the diagnosis in patients with neurological signs but it is not always feasible in emergency settings. Prompt parenteral supplementation is required to obtain the improvement of symptoms and avoid chronic complications. AIMS: To describe the clinical presentation of reported cases of thiamine deficiency, assess prescription and results of cerebral imaging, review treatments that had been prescribed in accordance or not with available guidelines, and study the short-term outcome of these patients. METHODS: This is a monocentric retrospective analysis of all reported cases of thiamine deficiency in a French tertiary hospital between January 1st 2008 and December 31st 2018. RESULTS: Fifty-six cases were identified during the study period. Forty-five (80%) patients had a history of alcohol abuse. Most patients were diagnosed based on neurological symptoms but non-specific and digestive symptoms were frequent. Thirty-four percent of patients fulfilled clinical criteria for malnutrition. A brain MRI was performed in 54% of patients and was abnormal in 63% of these cases. Eighty-five percent of patients were treated by parenteral thiamine administration and the supplementation was continued orally in 55% of them. The majority of patients initially received 1000 mg daily of IV thiamine but the dose and duration of thiamine supplementation were variable. At the time of discharge, partial or complete improvement of symptoms was noted in 59% of patients. CONCLUSION: This study highlights the clinical and radiological heterogeneity of thiamine deficiency. These observations should encourage starting thiamine supplementation early in patients with risk factors or suggestive symptoms even in non-alcoholic patients, and underline the importance of early nutritional support.

Serum Metabolomic and Lipidomic Profiling Reveals Novel Biomarkers of Efficacy for Benfotiamine in Alzheimer's Disease.

Serum metabolomics and lipidomics are powerful approaches for discovering unique biomarkers in various diseases and associated therapeutics and for revealing metabolic mechanisms of both. Treatment with Benfotiamine (BFT), a thiamine prodrug, for one year produced encouraging results for patients with mild cognitive impairment and mild Alzheimer's disease (AD). In this study, a parallel metabolomics and lipidomics approach was applied for the first exploratory investigation on the serum metabolome and lipidome of patients treated with BFT. A total of 315 unique metabolites and 417 lipids species were confidently identified and relatively quantified. Rigorous statistical analyses revealed significant differences between the placebo and BFT treatment groups in 25 metabolites, including thiamine, tyrosine, tryptophan, lysine, and 22 lipid species, mostly belonging to phosphatidylcholines. Additionally, 10 of 11 metabolites and 14 of 15 lipid species reported in previous literature to follow AD progression changed in the opposite direction to those reported to reflect AD progression. Enrichment and pathway analyses show that significantly altered metabolites by BFT are involved in glucose metabolism and biosynthesis of aromatic amino acids. Our study discovered that multiple novel biomarkers and multiple mechanisms that may underlie the benefit of BFT are potential therapeutic targets in AD and should be validated in studies with larger sample sizes.

B Vitamins Supplementation Can Improve Cognitive Functions and May Relate to the Enhancement of Transketolase Activity in A Rat Model of Cognitive Impairment Associated with High-fat Diets.

OBJECTIVE: To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity. METHODS: To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day. RESULTS: Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05). CONCLUSION: Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.

Metabolic Effects of Vitamin B1 Therapy under Overnutrition and Undernutrition Conditions in Sheep.

As a precursor for a universal metabolic coenzyme, vitamin B1, also known as thiamine, is a vital nutrient in all living organisms. We previously found that high-dose thiamine therapy prevents overnutrition-induced hepatic steatosis in sheep by enhancing oxidative catabolism. Based on this capacity, we hypothesized that thiamine might also reduce whole-body fat and weight. To test it, we investigated the effects of high-dose thiamine treatment in sheep under overnutrition and calorie-restricted undernutrition to respectively induce positive energy balance (PEB) and negative energy balance (NEB). Eighteen mature ewes were randomly assigned to three treatment groups (n = 6 each). The control group (CG) was administered daily with subcutaneous saline, whereas the T5 and T10 groups were administered daily with equivoque of saline containing 5 mg/kg and 10 mg/kg of thiamine, respectively. Bodyweight and blood biochemistry were measured twice a week for a period of 22 days under PEB and for a consecutive 30 days under NEB. Surprisingly, despite the strong effect of thiamine on liver fat, no effect on body weight or blood glucose was detectable. Thiamine did, however, increase plasma concentration of non-esterified fatty acids (NEFA) during NEB (575.5 ± 26.7, 657.6 ± 29.9 and 704.9 ± 26.1 µEqL-1 for CG, T5, and T10, respectively: p < 0.05), thereby favoring utilization of fatty acids versus carbohydrates as a source of energy. Thiamine increased serum creatinine concentrations (p < 0.05), which paralleled a trending increase in urea (p = 0.09). This may indicate an increase in muscle metabolism by thiamine. Reduction of fat content by thiamine appears more specific to the liver than to adipose tissue. Additional studies are needed to evaluate the potential implications of high-dose vitamin B1 therapy in muscle metabolism.

The pH-Dependent Controlled Release of Encapsulated Vitamin B1 from Liposomal Nanocarrier.

In this work, we firstly presented a simple encapsulation method to prepare thiamine hydrochloride (vitamin B1)-loaded asolectin-based liposomes with average hydrodynamic diameter of ca. 225 and 245 nm under physiological and acidic conditions, respectively. In addition to the optimization of the sonication and magnetic stirring times used for size regulation, the effect of the concentrations of both asolectin carrier and initial vitamin B1 on the entrapment efficiency (EE %) was also investigated. Thermoanalytical measurements clearly demonstrated that after the successful encapsulation, only weak interactions were discovered between the carriers and the drug molecules. Moreover, the dissolution profiles under physiological (pH = 7.40) and gastric conditions (pH = 1.50) were also registered and the release profiles of our liposomal B1 system were compared with the dissolution profile of the pure drug solution and a manufactured tablet containing thiamin hydrochloride as active ingredient. The release curves were evaluated by nonlinear fitting of six different kinetic models. The best goodness of fit, where the correlation coefficients in the case of all three systems were larger than 0.98, was reached by application of the well-known second-order kinetic model. Based on the evaluation, it was estimated that our liposomal nanocarrier system shows 4.5-fold and 1.5-fold larger drug retention compared to the unpackaged vitamin B1 under physiological conditions and in artificial gastric juice, respectively.

Thiamine deficiency and recovery: impact of recurrent episodes and beneficial effect of treatment with Trolox and dimethyl sulfoxide.

At present, thiamine deficiency (TD) is managed with administration of high doses of thiamine. Even so, severe and permanent neurological disorders can occur in recurrent episodes of TD. In this study, we used a murine model to assess the efficacy of TD recovery treatments using thiamine with or without additional administration of the antioxidant Trolox or the anti-inflammatory dimethyl sulfoxide (DMSO) after a single or recurrent episode of TD. TD was induced for 9 days with deficient chow and pyrithiamine, and the recovery period was 7 days with standard amounts of chow and thiamine, Trolox, and/or DMSO. After these periods, we evaluated behavior, histopathology, and ERK1/2 modulation in the brain. Deficient animals showed reductions in locomotor activity, motor coordination, and spatial memory. Morphologically, after a single episode of TD and recovery, deficient mice showed neuronal vacuolization in the dorsal thalamus and, after two episodes, a reduction in neuronal cell number. These effects were attenuated or reversed by the recovery treatments, mainly in the treatments with thiamine associated with Trolox or DMSO. Deficient animals showed a strong increase in ERK1/2 phosphorylation in the thalamus, hippocampus, and cerebral cortex after one deficiency episode and recovery. Interestingly, after recurrent TD and recovery, ERK1/2 phosphorylation remained high only in the deficient mice treated with thiamine and/or Trolox or thiamine with DMSO. Our data suggest that a protocol for TD treatment with thiamine in conjunction with Trolox or DMSO enhances the recovery of animals and possibly minimizes the late neurological sequelae.

A multicenter randomized clinical trial of pharmacological vitamin B1 administration to critically ill patients who develop hypophosphatemia during enteral nutrition (The THIAMINE 4 HYPOPHOSPHATEMIA trial).

BACKGROUND: Hypophosphatemia may be a useful biomarker to identify thiamine deficiency in critically ill enterally-fed patients. The objective was to determine whether intravenous thiamine affects blood lactate, biochemical and clinical outcomes in this group. METHOD: This randomized clinical trial was conducted across 5 Intensive Care Units. Ninety critically ill adult patients with a serum phosphate ≤0.65 mmol/L within 72 h of commencing enteral nutrition were randomized to intravenous thiamine (200 mg every 12 h for up to 14 doses) or usual care (control). The primary outcome was blood lactate over time and data are median [IQR] unless specified. RESULTS: Baseline variables were well balanced (thiamine: lactate 1.2 [1.0, 1.6] mmol/L, phosphate 0.56 [0.44, 0.64] mmol/L vs. control: lactate 1.0 [0.8, 1.3], phosphate 0.54 [0.44, 0.61]). Patients randomized to the intervention received a median of 11 [7.5, 13.5] doses for a total of 2200 [1500, 2700] mg of thiamine. Blood lactate over the entire 7 days of treatment was similar between groups (mean difference = -0.1 (95 % CI -0.2 to 0.1) mmol/L; P = 0.55). The percentage change from lactate pre-randomization to T = 24 h was not statistically different (thiamine: -32 (-39, -26) vs. control: -24 (-31, -16) percent, P = 0.09). Clinical outcomes were not statistically different (days of vasopressor administration: thiamine 2 [1, 4] vs. control 2 [0, 5.5] days; P = 0.37, and deaths 9 (21 %) vs. 5 (11 %); P = 0.25). CONCLUSIONS: In critically ill enterally-fed patients who developed hypophosphatemia, intravenous thiamine did not cause measurable differences in blood lactate or clinical outcomes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12619000121167).

The efficacy of acoustic therapy versus oral medication for chronic tinnitus: A meta-analysis.

PURPOSE: To compare the efficacy of acoustic therapy (AT) and drug therapy (DT) for chronic tinnitus. METHODS: We searched Pubmed, ScienceDirect, Chinese Journal Full-text Database (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), Embase, and Cochrane Library from the establishment of the database to December 2019. Meta-analysis was performed on the Tinnitus Handicap Inventory (THI) score and Visual Analogue Scale (VAS) with included literature using Revman 5.3 software. RESULTS: A total of 18 documents were included, including 16 Chinese documents and 2 English documents, with 1774 patients (including 962 patients treated with AT and 812 patients treated with DT). The effect of AT (by the number of cases or ears) is better than that of DT (P < 0.05). After treatment, the THI value of AT was more evident than that of DT (WMD = -4.25, (-13.24, -5.29)). And the VAS value of AT was significantly lower than that of DT (WMD = -0.73, (-1.31, -0.15)). CONCLUSION: Compared with DT, AT can significantly improve the efficacy of tinnitus and reduce the symptoms of tinnitus patients. Clinically, it can vigorously promote the application value of treating tinnitus by sound.

Association between levels of thiamine intake, diabetes, cardiovascular diseases and depression in Korea: a national cross-sectional study.

The present study aimed to determine thiamine intake levels and the association between thiamine intake, diabetes, cardiovascular diseases and mental health. Participants were interviewed to obtain data on socio-demographic characteristics, lifestyle, current medications, medical and family history. The daily intake of thiamine was assessed by a 24-h recall. The mean age of the 34 700 study subjects was 42⋅9 years (sd 22⋅8, min-max: 1-80) and 19 342 (55⋅7 %) were women. The levels of thiamine intake were 1⋅126 mg (2016), 1⋅115 mg (2017) and 1⋅087 mg (2018) for women, which were equal to or only slightly above the recommended intake of 1⋅10 mg/d for women. The levels of thiamine intake from 2014-15 and 2016-18 significantly decreased. The estimated percentage of insufficient thiamine intake was 37⋅8 % (95 % CI 37⋅3, 38⋅4). Multivariable regression analysis adjusted for potential confounders showed that thiamine intake was critically associated with lower risks of hypertension, MI or angina, type 2 diabetes, depression and dyslipidemia. The daily thiamine intake from food can reversal the risks of hypertension (OR 0⋅95; 95 % CI 0⋅90, 0⋅99), MI or angina (OR 0⋅84; 95 % CI 0⋅74, 0⋅95), type 2 diabetes (OR 0⋅86; 95 % CI 0⋅81, 0⋅93), depression (OR 0⋅90; 95 % CI 0⋅83, 0⋅97) and dyslipidemia (OR 0⋅90; 95 % CI 0⋅86, 0⋅95), respectively. Further works are needed to identify the effects of thiamine and non-communicable diseases (NCDs) and mental health. A preventive thiamine supplementation strategy should be adopted to target NCDs and mental health and risk factors associated with thiamine deficiency. The optimisation of NCD control and mental health protection is also a vital integral part of Korea's public health system.

Thiamine supplementation holds neurocognitive benefits for breastfed infants during the first year of life.

Women reliant on mostly rice-based diets can have inadequate thiamine intake, placing breastfed infants at risk of thiamine deficiency and, in turn, physical and cognitive impairments. We investigated the impact of maternal thiamine supplementation doses on infants' cognitive, motor, and language development across the first year. In this double-blind, four-parallel-arm, randomized controlled trial, healthy mothers of exclusively breastfed newborn infants were recruited in Kampong Thom, Cambodia. At 2 weeks postnatal, women (n = 335) were randomized to one of four treatment groups to consume one capsule/day with varying amounts of thiamine for 22 weeks: 0, 1.2, 2.4, and 10 mg. At 2, 12, 24, and 52 weeks of age, infants were assessed with the Mullen Scales of Early Learning (MSEL) and the Caregiver Reported Early Development Instrument (CREDI). Multiple regression and mixed effects modeling suggest that by 6 months of age, the highest maternal thiamine dose (10 mg/day) held significant benefits for infants' language development, but generally not for motor or visual reception development. Despite having achieved standardized scores on the MSEL that approximated U.S. norms by 6 months, infants showed a significant drop relative to these norms in both language domains following trial completion, indicating that nutritional interventions beyond 6 months may be necessary.

A pilot study of thiamin and folic acid in hemodialysis patients with cognitive impairment.

OBJECTIVE: This study aimed to explore the effectiveness of thiamin and folic acid supplementation on the improvement of the cognitive function in patients with maintenance hemodialysis. METHOD: In the present study, we randomly assigned patients undergoing hemodialysis who had the Montreal Cognitive Assessment (MoCA) score lower than 26 to treatment group (n = 25, thiamin 90 mg/day combined with folic acid 30 mg/day) or control group (n = 25, nonintervention). All subjects were followed up for 96 weeks. The primary outcome was the improvement of the MoCA score. The secondary outcomes included homocysteine level, survival and safety. RESULTS: Patients in treatment group had an increase of the MoCA score from 21.95 ± 3.81 at baseline to 25.68 ± 1.96 at week 96 (p < 0.001, primary outcome), as compared with the MoCA score from 20.69 ± 3.40 to 19.62 ± 3.58 in control group. Thiamin combined with folic acid treatment also resulted in lower level of serum homocysteine in treatment group compare with control group at week 96 (p < 0.05, secondary outcome). 3 patients and 9 patients died during follow-up period in treatment and control group respectively (p = 0.048). The proportion of adverse events in treatment group was significantly lower than that in control group. CONCLUSION: Hemodialysis patients with cognitive impairment treated with thiamin and folic acid had a significant improvement in MoCA score.

Case Report: Fulminant Infantile Beriberi: A Report of Six Cases.

Thiamine deficiency disorders are an under-recognized public health problem in low- and middle-income countries. Infantile beriberi, the most important symptom for children, is suspected to significantly contribute to infant mortality and lifelong neurodevelopmental morbidity. Lack of awareness, varied clinical presentation, and lack of a readily available diagnostic marker lead to frequent misdiagnoses. We report six thriving infants who presented with an acute fulminant illness with varied clinical manifestations mimicking common childhood illnesses like pneumonia and sepsis. Four of them presented with the severe cardiovascular form, called Shoshin beriberi, and severe pulmonary arterial hypertension. Empirical intravenous thiamine administered to four of the six infants resulted in dramatic recovery. Awareness of the clinical definition of infantile beriberi and treatment with empirical thiamine can be lifesaving.

Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial.

BACKGROUND: Infantile beriberi-related mortality is still common in South and Southeast Asia. Interventions to increase maternal thiamine intakes, and thus human milk thiamine, are warranted; however, the required dose remains unknown. OBJECTIVES: We sought to estimate the dose at which additional maternal intake of oral thiamine no longer meaningfully increased milk thiamine concentrations in infants at 24 wk postpartum, and to investigate the impact of 4 thiamine supplementation doses on milk and blood thiamine status biomarkers. METHODS: In this double-blind, 4-parallel arm randomized controlled dose-response trial, healthy mothers were recruited in Kampong Thom, Cambodia. At 2 wk postpartum, women were randomly assigned to consume 1 capsule, containing 0, 1.2 (estimated average requirement), 2.4, or 10 mg of thiamine daily from 2 through 24 weeks postpartum. Human milk total thiamine concentrations were measured using HPLC. An Emax curve was plotted, which was estimated using a nonlinear least squares model in an intention-to-treat analysis. Linear mixed-effects models were used to test for differences between treatment groups. Maternal and infant blood thiamine biomarkers were also assessed. RESULTS: In total, each of 335 women was randomly assigned to1 of the following thiamine-dose groups: placebo (n = 83), 1.2 mg (n = 86), 2.4 mg (n = 81), and 10 mg (n = 85). The estimated dose required to reach 90% of the maximum average total thiamine concentration in human milk (191 µg/L) is 2.35 (95% CI: 0.58, 7.01) mg/d. The mean ± SD milk thiamine concentrations were significantly higher in all intervention groups (183 ± 91, 190 ± 105, and 206 ± 89 µg/L for 1.2, 2.4, and 10 mg, respectively) compared with the placebo group (153 ± 85 µg/L; P < 0.0001) and did not significantly differ from each other. CONCLUSIONS: A supplemental thiamine dose of 2.35 mg/d was required to achieve a milk total thiamine concentration of 191 µg/L. However, 1.2 mg/d for 22 wk was sufficient to increase milk thiamine concentrations to similar levels achieved by higher supplementation doses (2.4 and 10 mg/d), and comparable to those of healthy mothers in regions without beriberi. This trial was registered at clinicaltrials.gov as NCT03616288.

Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of Benfotiamine in Healthy Subjects.

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 (Tmax) 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 (AUC0-t) or maximum observed concentration (Cmax) of TM, TMP, and TDP was less or more dose proportional over the single dose studied except Cmax of TM. Food consumption did not increase the level of TM and TDP at baseline. TM exhibited a relatively long elimination half-life (t1/2) in all doses studied, resulting in accumulation ratio (Rac) of 1.96 to 2.11 and accumulation ratio based on Cmax (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.

The role of biofactors in the prevention and treatment of age-related diseases.

The present demographic changes toward an aging society caused a rise in the number of senior citizens and the incidence and burden of age-related diseases (such as cardiovascular diseases [CVD], cancer, nonalcoholic fatty liver disease [NAFLD], diabetes mellitus, and dementia), of which nearly half is attributable to the population ≥60 years of age. Deficiencies in individual nutrients have been associated with increased risks for age-related diseases and high intakes and/or blood concentrations with risk reduction. Nutrition in general and the dietary intake of essential and nonessential biofactors is a major determinant of human health, the risk to develop age-related diseases, and ultimately of mortality in the older population. These biofactors can be a cost-effective strategy to prevent or, in some cases, even treat age-related diseases. Examples reviewed herein include omega-3 fatty acids and dietary fiber for the prevention of CVD, α-tocopherol (vitamin E) for the treatment of biopsy-proven nonalcoholic steatohepatitis, vitamin D for the prevention of neurodegenerative diseases, thiamine and α-lipoic acid for the treatment of diabetic neuropathy, and the role of folate in cancer epigenetics. This list of potentially helpful biofactors in the prevention and treatment of age-related diseases, however, is not exhaustive and many more examples exist. Furthermore, since there is currently no generally accepted definition of the term biofactors, we here propose a definition that, when adopted by scientists, will enable a harmonization and consistent use of the term in the scientific literature.