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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.

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.

Systemic ischemic-reperfusion injury following cardiac arrest results in multisystem organ failure, brain injury and death. The aim of this trial is to investigate whether the combined use of cortisol, ascorbic acid (vitamin C), and thiamine during the early post-resuscitation period reduces the neurologic injury among out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM). This is a single-blind, multi-center, randomized, placebo-controlled trial to be conducted in nine tertiary university-affiliated hospitals in South Korea. A total of 160 OHCA survivors treated with TTM will be randomly assigned to the treatment or control groups (1:1 ratio). For the treatment group, patients will intravenously receive a combination dose of ascorbic acid (50 mg/kg, maximum single dose 3 g), thiamine (200 mg), and cortisol (100 mg) that will be mixed in three separate 50mL bags of 0.9% saline, respectively, every 12 hours for 3 days. For the placebo group, patients will receive three separate 50mL bags of 0.9% saline intravenously in the same manner. The primary outcome is the peak neuron-specific enolase level at 48-72 hours after the return of spontaneous circulation. The potential benefits of ascorbic acid, thiamine, and cortisol as neuroprotective agents have been reported in previous preclinical trials. This trial is the first clinical trial to assess the neuroprotective effectiveness of a combination of ascorbic acid, thiamine, and cortisol for OHCA survivors. ClinicalTrials.gov NCT04921189.

Background Musculoskeletal disorders are an important cause of work absence. Clinical practice guidelines recommend nonsteroidal anti-inflammatory drugs (NSAIDs) for grade I–II cervical sprains. The combination of thiamine + pyridoxine + cyanocobalamin vitamins has been used, alone and in combination with NSAIDs, for pain and inflammation in musculoskeletal disorders. Objective The objective of this study was to demonstrate the analgesic synergy of dexketoprofen, and the combination of vitamins thiamine + pyridoxine + cyanocobalamin in a fixed-dose combination (FDC) for the treatment of acute pain caused by grade I–II cervical sprains. Methods We conducted a multicentre, prospective, randomized, double-blind, phase IIIb clinical study comparing two treatment groups: (1) dexketoprofen 25 mg/vitamin B (thiamine 100 mg, pyridoxine 50 mg and cyanocobalamin 0.50 mg) in an FDC (two or more active ingredients combined in a single dosage form) versus (2) dexketoprofen 25 mg monotherapy (single drug to treat a particular disease), one capsule or tablet orally, every 8 h for 7 days. Final mean, average change, and percentage change in pain perception (measured using a visual analogue scale [VAS]) were compared with baseline between groups. A p value < 0.05 was considered statistically significant. Analyses were conducted using SPSS software, v.29.0. Results A statistically significant reduction in pain intensity was observed from the third day of treatment with the FDC compared with monotherapy (− 3.1 ± − 1.5 and − 2.6 ± − 1.1 cm, respectively) measured using the VAS ( p  = 0.011). Regarding the degree of disability, using the Northwick Park Neck Pain Questionnaire (NPQ), statistical difference was observed for the final measurement (7.5%, interquartile range [IQR] 2.5, 10.5; vs. 7.9%, IQR 5.0, 13.8; p  = 0.028). A lower proportion of adverse events was reported when using the FDC. Conclusions The FDC of dexketoprofen/thiamine + pyridoxine + cyanocobalamin vitamins demonstrated superior efficacy and a better safety profile compared with dexketoprofen monotherapy for pain treatment in patients with grade I–II cervical sprains. Clinical Trials Registration NCT05001555, registered 29 July 2021 ( https://clinicaltrials.gov/study/NCT05001555 ).

Background Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed. Methods The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed. Discussion VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide. Trial registration ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019

Background: Oxidative stress and systemic inflammation during cardiac surgery can lead to postoperative complications. Although vitamin C and thiamine (vitamin B1) have individually demonstrated protective effects, their combined effects remain underexplored. This study aimed to evaluate the efficacy of combined vitamin C and B1 therapy versus that of vitamin C alone in reducing inflammatory and cardiac biomarkers and improving postoperative outcomes in patients undergoing cardiac surgery. Methods: In this prospective, double-blind, randomized controlled trial, 64 patients scheduled for elective cardiac surgery at a tertiary care center were randomized to receive either 1000 mg vitamin C or a combination of 1000 mg vitamin C and 100 mg vitamin B1 at four perioperative time points. Primary outcomes included changes in inflammatory biomarkers [C-reactive protein, interleukin-6 (IL-6), and white blood cells], and cardiac biomarkers [creatine kinase-MB, Troponin-I, and lactate dehydrogenase]. Secondary outcomes included hemodynamic parameters and left ventricular function. Results: Compared with vitamin C alone, combined vitamin B1 and vitamin C significantly reduced postoperative cardiac biomarker levels. IL-6 levels were significantly lower immediately in the combined group; however, this effect was not sustained at 24 h post-surgery. Up to 24 h after surgery, no significant differences in hemodynamic stability or left ventricular ejection were observed between the groups. Notably, the combined therapy group demonstrated a lower incidence of postoperative arrhythmias and shorter dobutamine duration within 24 postoperatively. Conclusions: Combined vitamin C and B1 therapy significantly reduced markers of myocardial injury and early inflammatory responses (IL-6) in patients undergoing cardiac surgery, suggesting its potential as a protective agent.

Background: Anxiety, stress, and sleep disturbances significantly affect overall health. Research suggests that vitamins B1 and B2 may play a role in mood regulation and neuroprotection. This study aimed to investigate the effects of vitamin B1 and B2 supplementation in alleviating anxiety and stress and improving sleep quality. Methods: This study was a parallel randomized, double-blind, placebo-controlled clinical trial. Participants (n = 43) were randomized to receive one of the following two interventions: 100 mg of vitamin B1 and 100 mg of vitamin B2 or placebo. Intervention outcomes were assessed at baseline and week four, including SAS (Self-Rating Anxiety Scale), PSS (Perceived Stress Scale), PSQI (Sleep Quality Index), ESS (Sleepiness Scale), and measurement of urinary vitamin B1 and B2 levels. Results: After four weeks, urinary vitamin B1 levels increased from 158 ± 108.9 ng to 1333.1 ± 1204.5 ng (p < 0.01), and urinary vitamin B2 levels increased from 308.0 ± 198.3 ng to 6123.2 ± 4847.2 ng in the supplement group (p < 0.01). The PSS scores decreased significantly in the supplement group from 21.5 ± 4.1 to 15.5 ± 4.5 (p < 0.05), while the placebo group showed a change from 20.3 ± 4.3 to 19.8 ± 5.5. Vitamins B1 and B2 did not have a significant effect on anxiety improvement (p > 0.05). The PSQI scores decreased in the supplement group from 8.0 ± 3.12 to 6.3 ± 2.0 (p < 0.05), while the placebo group worsened from 5.7 ± 2.7 to 7.4 ± 2.9. Meanwhile, the ESS scores in the supplement group decreased from 13.0 ± 3.4 to 9.1 ± 3.9 (p < 0.05), demonstrating a significant improvement compared to the placebo group. Conclusions: The clinical trial findings demonstrated that while vitamin B1 and B2 supplements helped reduce stress, enhance sleep, and reduce sleepiness, they had no discernible impact on reducing anxiety. Future studies should focus on the long-term effects of vitamin B1 and B2 supplements, exploring the combined effects of combined vitamin B1 and B2 medications for the treatment of stress and sleep disorders.

Aim: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). Patients–methods: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. Results: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. Conclusions: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.

Background Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism. Methods We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (200 mg) or placebo both immediately before and again after the surgery. Our primary endpoint was post-operative lactate levels. Additional endpoints included pyruvate dehydrogenase activity, global and cellular oxygen consumption, post-operative complications, and hospital and intensive care unit length of stay. Results Sixty-four patients were included. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 [683, 1200] nmol/L vs. 9 [8, 13] nmol/L, p  < 0.001). There was no difference between the groups in the primary endpoint of lactate levels immediately after the surgery (2.0 [1.5, 2.6] mmol/L vs. 2.0 [1.7, 2.4], p  = 0.75). Relative pyruvate dehydrogenase activity was lower immediately after the surgery in the thiamine group as compared to the placebo group (15 % [11, 37] vs. 28 % [15, 84], p  = 0.02). Patients receiving thiamine had higher post-operative global oxygen consumption 1 hour after the surgery (difference: 0.37 mL/min/kg [95 % CI: 0.03, 0.71], p  = 0.03) as well as cellular oxygen consumption. We found no differences in clinical outcomes. Conclusions There were no differences in post-operative lactate levels or clinical outcomes between patients receiving thiamine or placebo. Post-operative oxygen consumption was significantly increased among patients receiving thiamine. Trial registration clinicaltrials.gov NCT02322892 , December 14, 2014

Abstract Rationale Acute kidney injury (AKI) is common in patients with sepsis and has been associated with high mortality rates. The provision of thiamine to patients with sepsis may reduce the incidence and severity of sepsis-related AKI and thereby prevent renal failure requiring renal replacement therapy (RRT). Objectives To test the hypothesis that thiamine supplementation mitigates kidney injury in septic shock. Methods This was a secondary analysis of a single-center, randomized, double-blind trial comparing thiamine to placebo in patients with septic shock. Renal function, need for RRT, timing of hemodialysis catheter placement, and timing of RRT initiation were abstracted. The baseline creatinine and worst creatinine values between 3 and 24 hours, 24 and 48 hours, and 48 and 72 hours were likewise abstracted. Results There were 70 patients eligible for analysis after excluding 10 patients in whom hemodialysis was initiated before study drug administration. Baseline serum creatinine in the thiamine group was 1.2 mg/dl (interquartile range, 0.8–2.5) as compared with 1.8 mg/dl (interquartile range, 1.3–2.7) in the placebo group (P = 0.3). After initiation of the study drug, more patients in the placebo group than in the thiamine group were started on RRT (eight [21%] vs. one [3%]; P = 0.04). In the repeated measures analysis adjusting for the baseline creatinine level, the worst creatinine levels were higher in the placebo group than in the thiamine group (P = 0.05). Conclusions In this post hoc analysis of a randomized controlled trial, patients with septic shock randomized to receive thiamine had lower serum creatinine levels and a lower rate of progression to RRT than patients randomized to placebo. These findings should be considered hypothesis generating and can be used as a foundation for further, prospective investigation in this area.