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Abstract The study aims to investigate the vitamin B6 levels in Parkinson's disease (PD) patients and their association with liver enzymes and evaluate how much dysregulation is associated with levodopa dose. Furthermore, to evaluate the effect of Opicapone, a catechol‐o‐methyl‐transferase inhibitor, on vitamin B6 levels by monitoring the AST and ALT levels in patients treated with Levodopa–Carbidopa Intestinal Gel Infusion (LCIG). For these aims, serum vitamin B6 levels were measured (PD, n = 72 and controls, n = 31). The vitamin B6 level was compared with the total levodopa dose, clinical parameters, and blood homocysteine, albumin, and hemoglobin levels in PD patients. Correlations between vitamin B6 levels and AST and ALT levels, as well as the ratio ALT/AST, were analyzed. Changes in the AST and ALT levels and ALT/AST were analyzed in the patients treated with LCIG before and after the therapy (n = 24) and in the patients treated with LCIG + Opicapone before and after Opicapone treatment (n = 12). We found vitamin B6 levels were significantly lower in PD patients. Total levodopa dose and albumin levels were independently associated with vitamin B6 levels. Decreased vitamin B6 levels appeared as lower AST and ALT levels and ALT/AS. Treatment with LCIG decreased the AST and ALT levels and ALT/AST. Adjunctive therapy with Opicapone to LCIG ameliorated the decreased ALT and ALT/AST. We conclude that the ALT and ALT/AST can be useful parameters for monitoring vitamin B6 levels and Opicapone can ameliorate the dysregulated vitamin B6 in PD patients.

Abstract Vitamin B6 is an essential nutrient, which is widely used in food products, feed additives, pharmaceuticals, disease diagnosis, and other fields. Pyridoxal‐5′‐phosphate (PLP), the active form of vitamin B6, is an important coenzyme participating in a variety of enzyme reactions. At present, the oxazole method is mainly used for the production of vitamin B6, but toxic and corrosive intermediates produced in the synthesis process, which does not conform to the green manufacturing. Therefore, there is considerable interest in shifting from chemical processes to sustainable fermentation techniques and research on PLP metabolism of other valuable compounds. In this review, we will briefly describe the enzymes that PLP participated and focus on the advances in vitamin B6 biosynthesis and discuss its application to engineering bacteria that overproduce other commercially valuable substances including cadaverine, 3,4‐dihydroxyphenylacetate‐l‐alanine, γ‐aminobutyric acid, and l‐phosphinothricin. It will provide a reference for the biosynthesis of vitamin B6 or other valuable compounds in which PLP participates in the reaction, and we also look forward to the future development prospect of PLP.

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for vitamin B6. Systematic reviews of the literature were conducted by a contractor. The relationship between excess vitamin B6 intakes and the development of peripheral neuropathy is well established and is the critical effect on which the UL is based. A lowest‐observed‐effect‐level (LOAEL) could not be established based on human data. A reference point (RP) of 50 mg/day is identified by the Panel from a case–control study, supported by data from case reports and vigilance data. An uncertainty factor (UF) of 4 is applied to the RP to account for the inverse relationship between dose and time to onset of symptoms and the limited data available. The latter covers uncertainties as to the level of intake that would represent a LOAEL. This leads to a UL of 12.5 mg/day. From a subchronic study in Beagle dogs, a LOAEL of 50 mg/kg body weight (bw) per day can be identified. Using an UF of 300, and a default bw of 70 kg, a UL of 11.7 mg/day can be calculated. From the midpoint of the range of these two ULs and rounding down, a UL of 12 mg/day is established by the Panel for vitamin B6 for adults (including pregnant and lactating women). ULs for infants and children are derived from the UL for adults using allometric scaling: 2.2–2.5 mg/day (4–11 months), 3.2–4.5 mg/day (1–6 years), 6.1–10.7 mg/day (7–17 years). Based on available intake data, EU populations are unlikely to exceed ULs, except for regular users of food supplements containing high doses of vitamin B6.

Abstract Sideroblastic anemia is a heterogeneous group of disorders typified by the presence of ring sideroblasts in the bone marrow and has congenital and acquired types. Sideroblastic anemia is a rare event in pregnancy. We report a case of a 32‐year‐old female patient, gravida 4 para 3, 27th weeks pregnant, who presented to the emergency department complaining of palpitation and generalized weakness for 2 weeks. She was found to have severe normochromic normocytic anemia, with hemoglobin of 4.2 g/dl, and low reticulocytes count of 13 × 103/μl. She gave a history of recurrent anemia, which had only occurred during pregnancy. Her bone marrow aspirate showed many ring sideroblasts concluding the diagnosis of sideroblastic anemia (SA). Further investigation revealed a significantly low pyridoxine level (vitamin B6) of (8 nmol/L). The Hb level improved with vitamin B6 replacement, without any transfusion support.

Vitamin B6 is frequently utilized as a therapeutic agent for nausea and vomiting of pregnancy (NVP). Research indicates that excessive intake of vitamin B6 can have implications on neurological function, underscoring the importance of cautious consideration when administering vitamin B6 treatment during early pregnancy. This systematic review investigates the effects of high doses of vitamin B6 on pregnant women experiencing NVP. We searched the PubMed® MEDLINE® database for articles using the following terms: "pregnancy" or "nausea and vomiting during pregnancy" and "vitamin B6." Women with nausea and vomiting symptoms during pregnancy use more than the tolerable amount of vitamin B6. A total of 136 articles were identified from the PubMed® MEDLINE® database. The etiology and treatment of NVP are briefly outlined, followed by a summary and analysis of 19 relevant literature sources. Among these sources, 12 reports detailed the adverse effects of excessive vitamin B6 intake in women; 164/1226 individuals experienced neurological symptoms such as burning, tingling, paresthesia, ataxia, or perioral numbness. Additionally, out of 245 women, four experienced miscarriages and one had an intrauterine demise. The overconsumption of vitamin B6 has the potential to impact nerve function, particularly during the critical first trimester of embryonic development. It might result in adverse outcomes such as miscarriage, intrauterine fetal demise, and congenital abnormalities., (© 2024 International Federation of Gynecology and Obstetrics.)

Abstract Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the assessment of the application for renewal of authorisation of vitamin B6 (pyridoxine hydrochloride) produced by chemical synthesis as a feed additive for all animal species. The applicant has provided data demonstrating that the additive in the market complies with the conditions of the authorisation. The FEEDAP Panel confirms that the use of pyridoxine hydrochloride under the current authorised conditions of use is safe for the target species, the consumers and the environment. Pyridoxine hydrochloride is non‐irritant to skin and eyes. In the absence of data, no conclusion can be drawn on skin sensitisation potential. Pyridoxine hydrochloride may cause photosensitisation. Despite the lack of data on inhalation toxicity, the additive is not dusty and exposure through inhalation is unlikely. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

Abstract Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the assessment of the application for renewal of authorisation of pyridoxine hydrochloride (vitamin B6) produced by chemical synthesis as a feed additive for all animal species. The applicant has provided data demonstrating that the additive in the market complies with the conditions of the authorisation. The FEEDAP Panel confirms that the use of pyridoxine hydrochloride under the current authorised conditions of use is safe for the target species, the consumers and the environment. Pyridoxine hydrochloride is non‐irritant to skin and eyes and is not a skin sensitiser. It may cause photosensitisation. In the absence of inhalation toxicity studies, adverse effects in the respiratory tract cannot be fully excluded. There is no need for assessing the efficacy of the additive in the context of the renewal of the authorisation.

Classical homocystinuria is caused by pathogenic variants in the CBS gene leading to a deficiency of the vitamin B6-dependent enzyme cystathionine beta synthase. The disease is typically associated with high blood homocysteine concentrations. Clinical features include developmental delay/intellectual disability, psychiatric problems, thromboembolism, lens dislocation, and marfanoid habitus. We report on a child with classical homocystinuria presenting with acute episodes of dystonia and symmetrical basal ganglia abnormalities mimicking a mitochondrial disease. After starting treatment with vitamin B6, homocysteine levels rapidly normalized and dystonic episodes did not re-occur. Moreover, brain-imaging findings almost completely disappeared. The case illustrates that homocystinuria should be considered as a treatable differential diagnosis of dystonia., (© 2023 SSIEM.)

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na + /H + exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB 6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB 6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB 6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB 6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB 6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity., (© 2023 Wiley Periodicals LLC.)

Abstract Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derives Dietary Reference Values (DRVs) for vitamin B6. The Panel considers that plasma pyridoxal 5′‐phosphate (PLP) concentration is the biomarker of status suitable for deriving DRVs for vitamin B6. Considering that a plasma PLP concentration of 30 nmol/L, as a population mean, is indicative of an adequate vitamin B6 status, the Panel proposes to use this cut‐off value to set Average Requirements (ARs). Population Reference Intakes (PRIs) are derived for adults and children from ARs, assuming a coefficient of variation (CV) of 10%. For women, the AR and PRI are set at 1.3 and 1.6 mg/day. For men, the AR of 1.5 mg/day is derived by an allometric scaling from the AR for women, and a PRI of 1.7 mg/day is set. For all infants aged 7–11 months, an Adequate Intake of 0.3 mg/day is set, averaging the results of two extrapolation approaches based on an allometric scaling: upwards extrapolation from the estimated vitamin B6 intake of exclusively breastfed infants from birth to 6 months, and downwards extrapolation from the ARs for adults applying a growth factor. For all children, ARs are derived from adult ARs using an allometric scaling and growth factors. For children of both sexes aged 1–14 years, ARs range between 0.5 and 1.2 mg/day. For children aged 15–17 years, the Panel derives the same ARs as for adults. PRIs for children aged 1–17 years range between 0.6 and 1.7 mg/day. Extrapolation of ARs by an allometric scaling considered differences in reference body weight. For pregnant and lactating women, additional requirements are considered, based on the uptake of vitamin B6 by the fetal and maternal tissues and the losses through breast milk, and PRIs of 1.8 and 1.7 mg/day, respectively, are derived.

Abstract Pyridoxine hydrochloride is a form of vitamin B6, an essential micronutrient. Oral administration routes of pyridoxine hydrochloride via feed or water are considered as bioequivalent. Pyridoxine hydrochloride is considered to be safe for all animal species at the commercial use levels. The FEEDAP Panel concludes that the use of pyridoxine hydrochloride as a nutritional additive does not give rise to concern for consumers. Pyridoxine hydrochloride is not an irritant to skin and eyes; it is not a skin sensitizer. The Panel notes that pyridoxine hydrochloride may cause photosensitisation. The pyridoxine hydrochloride considered in this opinion has a high dusting potential. A calculation of exposure by inhalation for persons handling the substance in a premixture factory resulted in an intake of 3.1 mg/person/day. Together with exposure by food sources, total exposure would not exceed 60 % of the UL. In the absence of inhalation toxicity studies, adverse effects in the respiratory tract cannot be fully excluded. Pyridoxine occurs widely in nature (in most plant feed materials). Its use in animal nutrition is not expected to substantially increase the concentration in the environment. Therefore, a risk for the environment resulting from the use of pyridoxine in animal nutrition is not foreseen. Due to the long history of use and its established nutritional role in domestic animals, pyridoxine hydrochloride is regarded as an effective source of vitamin B6.

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP). We included 261 patients enrolled in the Peripheral Neuropathy Research Registry who had a complete dataset including a plasma vitamin B6 value. Patients with vitamin B6 deficiency (0-4.9 μg/L) were excluded. We performed a chi-square test for independence and analyzed the logistic relation of elevated plasma B6 level to nerve conduction studies (NCS), neurological examination findings, and patient-reported symptoms controlling for age and time elapsed since neuropathy symptom onset. Plasma B6 level was not related to neuropathy severity. There was no logistic relation of elevated plasma B6 level to NCS results, examination features including toe strength, vibration sense, and deep tendon reflexes, or patient-reported numbness or pain intensity. This study suggests that moderately elevated plasma B6 levels, even in the 100 to 200 μg/L range, are not associated with significantly worse neuropathy signs or symptoms. Although standard supplementation of B6 does not appear to have a major negative affect on CIAP, this study does not directly answer whether stopping supplementation will have a beneficial effect. Very few patients in the study had vitamin B6 levels >300 μg/L, suggesting that screening for vitamin B6 toxicity may be left to the discretion of the physician., (© 2021 Peripheral Nerve Society.)

Valproic acid (VPA) is an efficient antiepileptic drug widely used for the treatment of epilepsy and other seizures in both children and adults. It is also reported to have side and toxic effects on many organs and tissues. Vitamin B 6 (Vit B 6 ) is a well-described water-soluble vitamin, which has an antioxidant effect. In this study, we aimed to investigate the protective effect of Vit B 6 on VPA-induced brain injury. Male Sprague-Dawley rats were divided into four groups. Group I, control animals; Group II, Vit B 6 (50 mg/kg/day) given rats; Group III, VPA (500 mg/kg/day) given rats; Group IV, VPA and Vit B 6 given rats at same dose and time. VPA and Vit B 6 were administered intraperitoneally and orally, respectively, for 7 days. At the end of the experiments, the rats were sacrificed and brain tissues were taken. Protein carbonyl and sialic acid levels, xanthine oxidase, adenosine deaminase, acetylcholine esterase, lactate dehydrogenase, myeloperoxidase activities, total oxidant status, and reactive oxygen species levels were found to be increased, while glutathione and total antioxidant capacity levels, catalase, superoxide dismutase, glutathione-S-transferase, paraoxonase, and glutathione reductase activities were found to be decreased in the VPA group. Administration of Vit B 6 reversed these defects in the VPA group. These findings indicate that Vit B 6 has a protective effect on VPA-induced brain damage., (© 2021 Wiley Periodicals LLC.)

Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10-129 vs median tHcy: 14.5 μmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 μmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-β-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria., (© 2021 SSIEM.)

Background: Peripheral neuropathy (PN) is common in patients with diseases that are in turn associated with deficiency of the B-vitamins, and vitamin treatment has shown mixed results., Methods: This systematic review and meta-analysis studied the association between PN/pain and B-vitamin biomarkers and investigated whether vitamin treatment can ameliorate the symptoms. PubMed and Web of Science were searched according to the study protocol., Results: A total of 46 observational and seven interventional studies were identified and included in the data synthesis. The presence of PN was associated with lowered B12 levels (pooled estimate [95% CIs] = 1.51 [1.23-1.84], n = 34, Cochran Q Test I 2  = 43.3%, p = 0.003) and elevated methylmalonic acid (2.53 [1.39-4.60], n = 9, I 2  = 63.8%, p = 0.005) and homocysteine (3.48 [2.01-6.04], n = 15, I 2  = 70.6%, p < 0.001). B12 treatment (vs. the comparators) showed a non-significant association with symptom improvement (1.36 (0.66-2.79), n = 4, I 2  = 28.9%). Treatment with B1 was associated with a significant improvement in symptoms (5.34 [1.87-15.19], n = 3, I 2  = 64.6%, p = 0.059). Analysis of seven trials combined showed a non-significant higher odds ratio for improvement under treatment with the B-vitamins (2.58 [0.98-6.79], I 2  = 80.0%, p < 0.001)., Conclusions: PN is associated with lowered plasma vitamin B12 and elevated methylmalonic acid and homocysteine. Overall, interventional studies have suggested that B-vitamins could improve symptoms of PN. Available trials have limitations and generally did not investigate vitamin status prior to treatment. Well-designed studies, especially in non-diabetes PN, are needed. This meta-analysis is registered at PROSPERO (ID: CRD42020144917)., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation., (© 2020 SSIEM.)