High-dose Pyridoxine Research Articles

Safety and Efficacy of High-Dose Vitamin B6 as an Adjunctive Treatment for Antipsychotic-Induced Hyperprolactinemia in Male Patients With Treatment-Resistant Schizophrenia.

This study aimed to investigate the safety and efficacy of high-dose vitamin B6 (vB6) as an adjunct treatment for antipsychotic-induced hyperprolactinemia (AIHP) in male patients with treatment-resistant schizophrenia (TRS). In this randomized double-blinded controlled study, patients were randomized (1:1) into a control group given aripiprazole (ARI; 10 mg/day; n = 100) or an intervention group given vB6 (300 mg/12 h for 16 weeks; n = 100). Prolactin levels, psychotic symptoms [Positive and Negative Syndrome Scale (PANSS)], cognitive function [MATRICS Consensus Cognitive Battery (MCCB)], liver function, kidney function, growth hormone level, micronutrient levels, blood lipids, and adverse secondary effects (ASEs)[Treatment Emergent Symptom Scale (TESS) and Barnes-Akathisia scale] were monitored. After a 16-week treatment period, the vB6 group showed a 68.1% reduction in serum prolactin levels (from 95.52 ± 6.30 μg/L to 30.43 ± 18.65 μg/L) while the ARI group showed only a 37.4% reduction (from 89.07 ± 3.59 μg/L to 55.78 ± 7.39 μg/L). During weeks 1–4, both treatments reduced prolactin similarly. Subsequently, the ARI effect plateaued, while the vB6 effect remained robust. The vB6 group showed better alleviation of psychotic symptoms and cognitive impairment. No serious ASEs were observed; ASEs were more frequent in the ARI group. AIHP reduction efficacy of vB6 was associated with baseline prolactin and triglyceride levels, total vB6 dosage, and education level. In conclusion, compared with the ARI group, TRS patients given vB6 showed better attenuation of AIHP, lower ASE scores, and greater improvements in clinical symptoms and cognitive impairments. These results support further consideration of vB6 as a putative treatment for AIHP.Trial Registration: ChiCTR1800014755

The Screening and Treatment of Vitamin B12 Deficiency

Vitamin B12 deficiency is now more prevalent than ever. It is a common cause of megaloblastic anemia, neuropsychiatric disorders, and other clinical manifestations. Screening is required in patients with single or multiple risk factors. Measurement of serum methylmalonic acid can be used to confirm deficiency in asymptomatic high-risk patients with low-normal levels of vitamin B12. Oral administration of high-dose vitamin B12 as well as intramuscular administration are effective as corrective therapy. This review briefs about the pharmacokinetics and pharmacodynamics of Vitamin B12, risk factors associated with its deficiency, screening methods and treatment options.

Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas

Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode. We report a pilot study in 13 patients with previously untreated advanced carcinoma of the digestive tract to assess the impact of high-dose pyridoxine (PN) on the antitumor activity of regimens comprising FUra and FA. Five patients had colorectal adenocarcinoma (CRC); 5 had pancreas adenocarcinoma (PC); and 3 had squamous cell carcinoma of the esophagus (EC). Patients with CRC and with PC received oxaliplatin, irinotecan, FUra and FA, and patients with EC had paclitaxel, carboplatin, FUra and FA. PN iv from 1000 to 3000 mg/day preceded each administration of FA and FUra. Eleven patients responded. Two patients with CRC attained CRs and 3 had PRs with reduction rates ≥ 78%. Two patients with PC attained CRs, and 2 had PRs with reduction rates ≥ 79%. Responders experienced disappearance of most metastases. Of 3 patients with EC, 2 attained CRs. Median time to attain a response was 3 months. Unexpected toxicity did not occur. Results suggest that high-dose vitamin B6 enhances antitumor potency of regimens comprising FUra and FA.

Randomized trial of high-dose pyridoxine in combination with standard hormonal therapy in West syndrome

ObjectiveTo determine whether high-dose, oral pyridoxine in combination with standard adrenocorticotropic hormone (ACTH) therapy has superior effectiveness than ACTH therapy alone in increasing cessation of epileptic spasms for children with West syndrome. MethodsThis study was an open-label, randomized controlled trial with masked endpoint assessments. Eligible children with West syndrome, age ranged 3-18 months, were randomized into the intervention (n = 43) and the standard arm (n = 37) of therapy. The intervention group received oral pyridoxine at 100-300 mg/kg/day in addition to standard therapy of intramuscular ACTH at 150 IU/m2/day. Primary effectiveness outcome was a complete cessation of spasms at two weeks and sustained till six weeks. ResultsComparison of effectiveness measures between intervention and standard groups were : complete cessation of epileptic spasms (48.8% vs 58.3%; group difference -9.6%; 95% confidence interval [CI] -30% to 12.3%; p = 0.4), median EEG scores (Q1-Q3) by Jeavons Score at six weeks [3 (1-5) vs 3 (1-5); p = 0.6], median motor scores (Q1-Q3) by DASII (Development Assessment Scales for Indian Infants) at 12 weeks [35 (29-49) vs 42 (34.3-63.8), p = 0.04], and median mental scores (Q1-Q3) by DASII at 12 weeks [35 (29.5-46) vs 41.5 (31.3-60), p = 0.02]. Adverse events were comparable in both arms. ConclusionsThere was no evidence to suggest the superiority of high-dose pyridoxine in combination with ACTH versus ACTH alone for the treatment of West syndrome, considering the limitations of the study design.

ALDH7A1 Gene and Its Related Pyridoxine-Dependent Epilepsy

AbstractDespite being classically reported as caused by mutations in solute carriers genes (SLC2A1), it has been recently shown that also mutations in ALDH7A1 can cause pyridoxine-dependent epilepsy (PDE). ALDH7A1 is a gene encoding for the antiquitin, an enzyme that catalyzes the nicotinamide adenine dinucleotide-dependent dehydrogenation of L-α-aminoadipic semialdehyde/L-Δ1-piperideine 6-carboxylate. It is a highly treatable disorder, but nevertheless it is still not certain when to consider this diagnosis and how to test for it. It is possible to identify a classical form and an atypical one of PDE associated with more than 70 mutations of ALDH7A1 gene. The typical form is characterized by the onset of seizures within the first month of life and can be treated with pyridoxine in monotherapy, as they are not responsive to traditional anticonvulsant therapy. The atypical forms are equally pyridoxine-dependent, but are characterized by a later onset of seizures, sometimes up to the age of 3 years. Several brain abnormalities have been associated with ALDH7A1 mutations. Seizure control is achieved by the administration of high-dose pyridoxine, which must be started in the patient as soon as possible. However, it has been observed that pyridoxine therapy does not prevent developmental delay in most cases; in these cases, it can be recommended and useful to supplement arginine with pyridoxine therapy associated with a dietary restriction of lysine.

High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency

ObjectiveWe aimed to assess the efficacy and safety of high-dose pyridoxine treatment for seizures and its effects on development in patients with inherited glycosylphosphatidylinositol deficiencies (IGDs). MethodsIn this prospective open-label multicenter pilot study, we enrolled patients diagnosed with IGDs using flow cytometry and/or genetic tests. The patients received oral pyridoxine (20–30 mg/kg/day) for 1 year, in addition to previous treatment. ResultsAll nine enrolled patients (mean age: 66.3 ± 44.3 months) exhibited marked decreases in levels of CD16, a glycosylphosphatidylinositol-anchored protein, on blood granulocytes. The underlying genetic causes of IGDs were PIGO, PIGL, and unknown gene mutations in two, two, and five patients, respectively. Six patients experienced seizures, while all patients presented with developmental delay (mean developmental age: 11.1 ± 8.1 months). Seizure frequencies were markedly (>50%) and drastically (>90%) reduced in three and one patients who experienced seizures, respectively. None of the patients presented with seizure exacerbation. Eight of nine patients exhibited modest improvements in development (P = 0.14). No adverse events were observed except for mild transient diarrhea in one patient. ConclusionOne year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them. Moreover, such treatment was reasonably safe. These findings indicate that high-dose pyridoxine treatment may be effective against seizures in patients with IGDs, although further studies are required to confirm our findings. (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number: UMIN000024185.)

Neuropsychiatric toxicity and cycloserine concentrations during treatment for multidrug-resistant tuberculosis

BackgroundCycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited. MethodsA prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma. ResultsA total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01). ConclusionsA high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.

First person – Mugagga Kalyesubula and Ramgopal Mopuri

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Mugagga Kalyesubula and Ramgopal Mopuri are co-first authors on ‘High-dose vitamin B1 therapy prevents the development of experimental fatty liver driven by overnutrition’, published in DMM. Mugagga is a PhD student in the lab of Dr Hay Dvir at the Volcani Center – Agricultural Research Organization (ARO), Rishon LeZion, Israel and The Hebrew University of Jerusalem, Rehovot, Israel, investigating therapy development for chronic metabolic diseases such as non-alcoholic fatty liver disease. Ramgopal is a postdoctoral researcher in the lab of Dr Hay Dvir at the Volcani Center – ARO in Rishon LeZion, Israel, developing therapeutic approaches for the management of fatty liver diseases.

High-dose vitamin B1 therapy prevents the development of experimental fatty liver driven by overnutrition.

ABSTRACTFatty liver is an abnormal metabolic condition of excess intrahepatic fat. This condition, referred to as hepatic steatosis, is tightly associated with chronic liver disease and systemic metabolic morbidity. The most prevalent form in humans, i.e. non-alcoholic fatty liver, generally develops due to overnutrition and sedentary lifestyle, and has as yet no approved drug therapy. Previously, we have developed a relevant large-animal model in which overnourished sheep raised on a high-calorie carbohydrate-rich diet develop hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. Here, we tested the hypothesis that treatment with thiamine (vitamin B1) can counter the development of hepatic steatosis driven by overnutrition. Remarkably, the thiamine-treated animals presented with completely normal levels of intrahepatic fat, despite consuming the same amount of liver-fattening diet. Thiamine treatment also decreased hyperglycemia and increased the glycogen content of the liver, but it did not improve insulin sensitivity, suggesting that steatosis can be addressed independently of targeting insulin resistance. Thiamine increased the catalytic capacity for hepatic oxidation of carbohydrates and fatty acids. However, at gene-expression levels, more-pronounced effects were observed on lipid-droplet formation and lipidation of very-low-density lipoprotein, suggesting that thiamine affects lipid metabolism not only through its known classic coenzyme roles. This discovery of the potent anti-steatotic effect of thiamine may prove clinically useful in managing fatty liver-related disorders.This article has an associated First Person interview with the joint first authors of the paper.

A founder mutation in the PLPBP gene in families from Saguenay-Lac-St-Jean region affected by a pyridoxine-dependent epilepsy.

Pyridoxine‐dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in PLPBP gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay‐Lac‐St‐Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced PLPBP mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal‐5‐phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.

The effects of tryptophan and pyridoxine supplied orally to nursing piglets on weight loss and social behavior after weaning

This study evaluated the effect of oral supplementation with tryptophan (Trp) and pyridoxine (Pyr) on the growth performance and social behavior of suckling piglets before and after weaning. At day 14, six suckling piglets per sow were distributed into three treatments and allotted in a randomized block design, with eight replicates and two piglets per experimental unit. Treatments consisted of a Control - oral supplementation with L-alanine (1.70 g), D-glucose (1.74 g) and distilled water (3.44 mL); Trp - oral supplementation with Trp (3.5 g/d) and distilled water; and Trp + Pyr - oral supplementation with Trp (3.5 g/d) + Pyr (0.0095 g/d) and distilled water. Each treatment was supplied orally five times per day (2.5 mL each treatment), from 14 to 21 days old. Piglets were monitored continuously in the nursing phase for 24 h at 21, 28 and 33 days of age to assess the behavior (standing, lying, eating, socializing, sitting and drinking). Piglets receiving oral Trp + Pyr showed a decreased weight loss on the first day after weaning (P = 0.03). Performance was not affected (P > 0.05) by treatments in each studied period, such as in overall period (21 to 34 days) after weaning. Piglets receiving Trp supplementation visited the feeders more frequently from days 21 to 22 (P < 0.01) and from days 28 to 29 (P < 0.02), as well as in the overall period (P < 0.01). It is concluded that high doses of tryptophan with or without high doses of pyridoxine, supplied orally to nursing piglets, reduced the weight loss on the first day after weaning and increased the frequency of visits to the drinkers on the first day after weaning and also to the feeders, mainly from weaning until 7 days after.

Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia.

Background:It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.Objective:To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).Methods:We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200–600 pmol/L). We used multivariable Cox regression to compute 0–15-year hazard ratios for dementia.Results:For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.Conclusion:We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

Compound amino acid combined with high-dose vitamin B6 attenuate traumatic coagulopathy via inhibiting inflammation by HMGB1/TLR4/NF-\u03baB pathway

BackgroundTraumatic coagulopathy (TC) arises primarily from coagulation system failure to maintain adequate hemostasis after serious blood loss or trauma. Circulatory homeostasis restoration is the mainstay of the therapeutic approach to TC, but the effects are significantly inhibited by coagulopathy.ObjectiveTo identify the therapeutic effects and underlying mechanism of compound amino acid (CAA) combined with high-dosage of vitamin B6 (VB6) on TC.MethodsRabbit traumatic model and cellular model were used to evaluate the effect of CAA combined with high-dosage of VB6 in TC. Blood concentrations of AST and ALT were measured using the Vitros 250 device while blood APTT, PT and TT concentrations were measured using commercial diagnostics kits. Furthermore, qRT-PCR, ELISA and Western blotting were used to determine the expression of clotting factor (II, VII, IX, X and XI), inflammatory factors (TNF-α, IL-6 and IL-1β) and HMGB1/TLR4/NF-κB signaling-related proteins, respectively.ResultsIn the rabbit traumatic model, CAA combined with high-dosage of VB6 therapy inhibited the high expression of AST and ALT, but increased the expression of coagulation factors. Additionally, in both the rabbit trauma model and cellular injury model, CAA combined with high-dosage of VB6 inhibited the expression of inflammatory factors (IL-6, TNF-α and IL-1β) and proteins (HMGB1, TLR4 and p-p65) in HMGB1/TLR4/NF-κB pathway. Most importantly, over-expression of HMGB1 reversed the effect of CAA and VB6 in HUVECs and EA.hy926 cells injury model.ConclusionCAA combined with high-dosage of VB6 alleviated TC and inhibited the expression and secretion of inflammatory factors by inhibiting HMGB1-mediated TLR4/NF-κB pathway.

P1713A CASE OF DEVASTATING BARIATRIC SURGERY-RELATED ACUTE OXALATE NEPHROPATHY FIRST DIAGNOSED AFTER KIDNEY TRANSPLANTATION

Abstract Background and Aims Despite the obvious efficacy in achieving weight loss, traditional malabsorptive procedures (intestinal by-pass) used for the treatment of obesity, may be associated with enteric oxaluria. Enteric oxaluria, by causing calcium-oxalate stones and nephrocalcinosis, represents an under-recognized cause of end-stage kidney disease in patients with history of intestinal by-pass. Herein, we describe a patient with a long-standing history of intestinal by-pass who developed a devastating acute oxalate nephropathy first diagnosed after kidney transplantation. Method A white female aged 50, who started hemodialysis one year earlier because of tubule-interstitial nephritis on a kidney biopsy, and who had history of recurrent kidney stones (calcium oxalate), underwent urgent deceased-donor kidney transplantation because of exhausted vascular access for hemodialysis (tunneled CVC right giugular vein as the last resort). She had received intestinal by-pass surgery 20 yrs earlier, and had a pacemaker implantation in the left sublavian vein for AV block two years earlier. She was highly sensitized because of blood transfusions at the time of surgery. Results After transplantation, graft function had immediate recovery, serum creatinine decreasing to 2.0mg/dL (117 mmol/L) on post-operative day (POD) 3. Shortly after, serum creatinine started rising until it reached 4.0mg/dL (354mmol/L) on POD 5. Three graft biopsies (performed on POD 6, 9 and 15 post-transplant) revealed acute oxalate nephropathy ( Figure1-2 large oxalate crystals on fresh unfixed core of kidney tissue analyzed under bright field microscope using polarized light) with no sign of rejection. Serial monitoring of Luminex SAB did not reveal circulating anti-HLA donor specific antibodies. Fundus examination revealed two tiny mono-lateral retinal oxalate deposits, whereas bone biopsy did not reveal oxalate accumulation. Plasma oxalate levels were 43 mmol/L on POD 10 were urinary oxalate excretion was 29mg /day on POD 14. The patient slowly progressed to end-stage kidney disease 2-month post-transplantation despite daily high flux dialysis since POD 7, fat-free and oxalate-free diet, oral potassium and high dose pyridoxine supplements. Conclusion Patients on chronic dialysis with a previous history of bariatric surgery via intestinal by-pass may have oxalate nephropathy caused by enteric oxaluria as unknown primary renal disease. The disease may recur shortly after transplantation despite the adoption of prompt aggressive treatment for oxalate removal.

Treatment of Cisplatin Induced Neurotoxicity with High Dose Pyridoxine and Pyridostigmine (5204)

Treatment of Cisplatin Induced Neurotoxicity with High Dose Pyridoxine and Pyridostigmine (5204)

Acne related to dietary supplements

Multiple prescription medications may cause or aggravate acne. A number of dietary supplements have also been linked to acne, including those containing vitamins B6/B12, iodine, and whey, as well as "muscle building supplements" that may be contaminated with anabolic-androgenic steroids (AAS). Acne linked to dietary supplements generally resolves following supplement discontinuation. Lesions associated with high-dose vitamin B6 and B12 supplements have been described as monomorphic and although pathogenesis is unknown, a number of hypotheses have been proposed. Iodine-related acne may be related to the use of kelp supplements and has been reported as monomorphic, inflammatory pustules on the face and upper trunk. Whey protein supplements, derived from milk and used for bodybuilding, are associated with papulonodular acne involving the trunk and sometimes the face. Finally, AAS-induced acne has been described as acne fulminans, acne conglobata, and acne papulopustulosa. With studies indicating that about half of US adults report using dietary supplements, it is important that dermatologists directly ask acne patients about their supplement use and educate them on the potential risks of even seemingly innocuous dietary supplements.

Novel variants in a patient with late-onset hyperprolinemia type II: diagnostic key for status epilepticus and lactic acidosis

BackgroundHyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood.Case presentationThe 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B6 therapy no further seizures occurred.ConclusionWe describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.

Thiamine mimetics sulbutiamine and benfotiamine as a nutraceutical approach to anticancer therapy

Malignant cells frequently demonstrate an oncogenic-driven reliance on glycolytic metabolism to support their highly proliferative nature. Overexpression of pyruvate dehydrogenase kinase (PDK) may promote this unique metabolic signature of tumor cells by inhibiting mitochondrial function. PDKs function to phosphorylate and inhibit pyruvate dehydrogenase (PDH) activity. Silencing of PDK expression has previously been shown to restore mitochondrial function and reduce tumor cell proliferation. High dose Vitamin B1, or thiamine, possesses antitumor properties related to its capacity to reduce PDH phosphorylation and promote its enzymatic activity, presumably through PDK inhibition. Though a promising nutraceutical approach for cancer therapy, thiamine’s low bioavailability may limit clinical effectiveness. Here, we have demonstrated exploiting the commercially available lipophilic thiamine analogs sulbutiamine and benfotiamine increases thiamine’s anti-cancer effect in vitro. Determined by crystal violet proliferation assays, both sulbutiamine and benfotiamine reduced thiamine’s millimolar IC50 value to micromolar equivalents. HPLC analysis revealed that sulbutiamine and benfotiamine significantly increased intracellular thiamine and TPP concentrations in vitro, corresponding with reduced levels of PDH phosphorylation. Through an ex vitro kinase screen, thiamine’s activated cofactor form thiamine pyrophosphate (TPP) was found to inhibit the function of multiple PDK isoforms. Attempts to maximize intracellular TPP by exploiting thiamine homeostasis gene expression resulted in enhanced apoptosis in tumor cells. Based on our in vitro evaluations, we conclude that TPP serves as the active species mediating thiamine’s inhibitory effect on tumor cell proliferation. Pharmacologic administration of benfotiamine, but not sulbutiamine, reduced tumor growth in a subcutaneous xenograft mouse model. It remains unclear if benfotiamine’s effects in vivo are associated with PDK inhibition or through an alternative mechanism of action. Future work will aim to define the action of lipophilic thiamine mimetics in vivo in order to translate their clinical usefulness as anticancer strategies.

Assessing the genetic association between vitamin B6 metabolism and genetic generalized epilepsy

Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.

Association of High Intakes of Vitamins B6 and B12 From Food and Supplements With Risk of Hip Fracture Among Postmenopausal Women in the Nurses’ Health Study

Vitamin supplementation far exceeding recommended doses is popular in segments of the population. However, adverse effects can occur. In a previous secondary analysis of combined data from 2 double-blind randomized clinical trials (RCTs), an unexpected increased risk of hip fracture was found among those treated with high doses of vitamin B6 in combination with vitamin B12. To study if high intakes of vitamins B6 and B12 from food and supplements were associated with a risk of hip fracture in the Nurses' Health Study and to investigate whether combined high intakes of both vitamins conferred a particularly increased fracture risk. In this prospective cohort study, 75 864 postmenopausal women in the United States were followed up from June 1984 through May 2014. The dates of analysis were July 2016 to June 2018. Information on hip fracture and a wide range of potential confounders was collected at baseline and with biennial follow-up questionnaires. Extensive dietary information was collected approximately every 4 years with a semiquantitative food frequency questionnaire. Relative risks (RRs) were calculated by Cox proportional hazards regression, with cumulative average intakes of vitamins B6 and B12 as main exposures, adjusting for potential confounders. Hip fracture. During follow-up, 2304 of 75 864 women had a hip fracture. Among the women with hip fractures, the median (range) age at hip fracture was 75.8 (46.7-93.0) years and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 24.3 (4.6). Median (interquartile range) cumulative average intakes of total vitamins B6 and B12 were 3.6 (4.8) mg/d and 12.1 (11.7) μg/d, respectively. Both vitamin B6 (RR, 1.29; 95% CI, 1.04-1.59 for an intake of ≥35 vs <2 mg/d; P = .06 for linear trend) and vitamin B12 (RR, 1.25; 95% CI, 0.98-1.58 for an intake of ≥30 vs <5 μg/d; P = .02 for linear trend) were associated with increased fracture risk. Risk was highest in women with a combined high intake of both vitamins (B6 ≥35 mg/d and B12 ≥20 μg/d), exhibiting an almost 50% increased risk of hip fracture (RR, 1.47; 95% CI, 1.15-1.89) compared with women with a low intake of both vitamins (B6 <2 mg/d and B12 <10 μg/d). In this cohort study, a combined high intake of vitamins B6 and B12 was associated with an increased risk of hip fracture. The intakes were far higher than the recommended dietary allowances. These findings add to previous studies suggesting that vitamin supplements should be used cautiously because adverse effects can occur.