Bevital (Norway)

SummaryNicotinamide adenine dinucleotide (NAD) augmentation therapy (NAD-AT) is increasingly explored in clinical trials across multiple indications, especially neurological diseases, yet its human pharmacokinetic profile remains incompletely defined. We report findings from a phase I pharmacokinetic trial assessing systemic and cerebral responses to oral NAD precursors in healthy individuals (n = 6) and persons with Parkinson’s disease (n = 6) receiving 1,200 mg/day nicotinamide riboside or nicotinamide mononucleotide. Blood NAD increased slowly, plateauing after approximately two weeks of treatment, and declined with similarly slow kinetics following treatment discontinuation. Cerebral NAD levels increased measurably after four weeks of treatment. NAD-related metabolites showed faster increase and washout dynamics compared to NAD itself. Collectively, these data suggest that effective NAD-AT requires sustained oral administration over at least 2–4 weeks and that once-daily dosing is sufficient to maintain stable NAD levels. NAD responses exhibited considerable interindividual variability, but were not influenced by disease status or sex, indicating broad applicability.

Low concentrations of biologically active B6 vitamer, pyridoxal 5'-phosphate (PLP) are associated with an increased risk of cardiovascular disease (CVD). Vitamin A (Vit-A) promotes lipid homeostasis and the transport cholesterol. Vit-A may also stimulate the intracellular transport of PLP. This study aimed to investigate whether Vit-A is associated with variations in the relationship of systemic B6-vitamers with incident acute myocardial infarctions (AMIs). A total of 4091 patients undergoing elective coronary angiography for suspected stable angina pectoris were studied. Associations of different plasma B6 vitamers, including PLP, pyridoxal (PL), 4-pyridoxic acid (PA), and PA/PL ratio with the risk of AMI according to median concentrations of Vit-A, were explored in Cox regression models. Serum Vit-A demonstrated positive associations with PLP and PA/PL ratio at baseline (P < 0.001 for both). During a median follow-up of 7.5 y, 521 (12.7%) patients suffered an AMI. In age and sex-adjusted analyses, plasma PLP, PA, and PA/PL ratio showed an overall association with incident AMI {hazard ratio (HR) [95% confidence interval (CI)] per SD: 0.90 [0.82, 0.99; P = 0.02], 1.14 [1.05, 1.23; P < 0.001], and 1.28 [1.18, 1.39; P < 0.001], respectively}. However, low plasma PLP and high PA/PL ratio were associated with an increased risk of AMI primarily among patients with high compared with low Vit-A concentrations [HR (95% CI) per SD: 0.77 (0.68, 0.88; P < 0.001, P-interaction = 0.002) and 1.36 (1.23, 1.49; P < 0.001, P-interaction = 0.05), respectively]. The interactions persisted after multivariable adjustment (both P-interactions ≤ 0.04). The relationship between vitamin B6 indexes and AMI risk varied according to serum Vit-A concentrations. Additional research is needed to clarify the importance of Vit-A and B6 bioavailability in atherosclerotic CVD. This trial was registered at clinicaltrials.gov as NCT00354081.

Abstract Background Elevated levels of 1- and 3-methylhistidine (MH) are indicative of higher dietary meat intake, whereas 3-MH also reflects muscle catabolism. Both biomarkers have been linked to oxidative stress and cardiometabolic risk factors; however, their associations with cardiovascular outcomes and survival are unknown. Purpose To investigate prospective associations of plasma 1- and 3-MH with long-term risk of acute myocardial infarction (AMI), all-cause mortality, and cardiovascular mortality. Methods Using Cox regression analysis, risk-associations were examined among 4131 subjects undergoing coronary angiography for suspected chronic coronary syndrome. Outcome data were obtained from national health registries. Results Median levels of 1- and 3-MH were 3.9 and 2.8 µmol/L, respectively. Median follow-up was 7.4 years for AMI and 10.3 years for mortality. During follow-up, 12.9% experienced an AMI, whereas 21.9% died. After multivariable adjustments for established cardiovascular risk factors and indices of renal function, the HR (95% CI) for AMI comparing the 4th vs. 1st 1-MH quartile were 1.45 (1.10-1.91, p=0.009). Corresponding HRs for all-cause mortality and cardiovascular mortality were 1.55 (1.24-1.93, p&amp;lt;0.001) and 1.56 (1.11-2.17, p=0.009), respectively. Additional adjustments for energy-adjusted protein intake resulted in only a minor attenuation of the estimates. For 3-MH, no significant associations were observed: HRs (95% CI) comparing the 4th vs. 1st 3-MH quartile were 1.13 (0.89-1.45, p=0.31) for AMI, 0.96 (0.79-1.17, p=0.69) for all-cause mortality, and 0.95 (0.71-1.26, p=0.71) for cardiovascular mortality. Conclusion In this large cohort of patients with suspected chronic coronary syndrome, higher plasma 1-MH levels were associated with an increased risk of future AMI and 10-year all-cause and cardiovascular mortality. In contrast, 3-MH had no prognostic value.

The authors declare no conflicts of interest. The data that support the findings of this study are openly available in Immune signature and exercise at https://sportsmedicine-dortmund.shinyapps.io/beat. Further data are available at https://sportsmedicine-dortmund.shinyapps.io/beat. The raw data are available upon request from the corresponding author. Table S1: This Excel file contains two sheets. The first sheet lists all measured proteins with their abbreviations and full names. The second sheet presents the results of the linear mixed models (LMMs) for each analyte, including estimated fixed effects, standard errors, degrees of freedom (DF), t-values, raw and adjusted p-values. Significant effects (p < 0.05) are highlighted in bold. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract Exclusive breastfeeding the first six months corrected age (CA) is recommended for premature infants with very low birthweight (&lt; 1500 g) (VLBW). As an adequate micronutrient status is important for psychomotor development and growth, we have investigated whether this regime provide an adequate B vitamin status in premature infants with VLBW from term to 12 months CA.In consecutively recruited infants born premature with VLBW, levels of vitamin B12 (cobalamin), B6 (pyridoxal 5´-phosphate, PLP), B2 (riboflavin), folate, and the metabolic markers, total homocysteine (tHcy) and methylmalonic acid (MMA), were determined at term, 2, 6 and 12 months CA.One third of the infants were exclusively breastfed to 6 months CA, and these had lower cobalamin, PLP and riboflavin concentrations compared to formula fed infants, and 80% had tHcy concentrations ≥ 6.5 µmol/L indicative of cobalamin deficiency during the first 6 months of CA. Severe deficiency of one or more B vitamins was evident in 3–9% of the infants at each time point during the first 12 months of CA. Only a minority used multivitamin supplementation, and this was associated with higher PLP and riboflavin levels.Exclusive breastfeeding to 6 months CA, with inadequate multivitamin supplementation and no specific recommendation for introduction of solid food, is not providing an adequate B vitamin status in infants born premature with VLBW. Nutrition should be optimized and B vitamin status should be checked regularly during the first year of life in premature VLBW infants.

Recent studies demonstrate that Parkinson’s disease (PD) is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau, CSF soluble TREM2 (sTREM2) and severity of both motor and non-motor PD clinical symptoms. Finally, PD patient subgroups with distinct KP profiles displayed distinct PD clinical features. These data validate the KP as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

Malnutrition or risk of malnutrition is present in about one-third of patients admitted to Western hospitals and is identified by either screening for malnutrition or further nutrition assessment. To date, there are no commonly accepted biomarkers of malnutrition, which could expedite screening efforts, ease diagnosis, and hasten treatment. We aimed to investigate whether metabolomics could identify markers associated with malnutrition in hospitalized patients and performed a retrospective metabolomic cohort study in this patients' group. The study population included adult patients hospitalized in a medical unit. Malnutrition was identified by the second step of the Global Leadership Initiative on Malnutrition criteria independently of the outcome of the screening step (nutritional risk screening 2002). Amino acids were determined by targeted metabolomics using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry. Logistic regression analyses with Benjamini-Hochberg procedure to reduce false discovery rate were used to identify biomarkers associated with malnutrition. In total, 218 patients were included in the final analysis, with 62 patients having a diagnosis of malnutrition. In crude analyses, 11 metabolites were associated with malnutrition, but further adjustment attenuated the associations. After multiple adjustment, neopterin and cystatin C were positively associated with malnutrition, whereas His, Cys, and kynurenine to tryptophan ratio were negatively associated. The observed associations require confirmation in a replication cohort before they can be recommended as biomarkers of malnutrition.

It was recently reported that a higher concentration of the bacterially produced metabolite indole 3-acetate (3-IAA) in blood was linked to a better response to chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to patients diagnosed with non-metastatic PDAC. We measured circulating 3-IAA in samples from a prospective population-based cohort of 124 patients with borderline resectable or locally advanced PDAC, collected before initiating neoadjuvant chemotherapy. The majority (61%) of the patients were treated with FOLFIRINOX. We used univariable and multivariable Cox proportional hazards regression to estimate the association between pre-treatment 3-IAA and overall survival. The median serum 3-IAA concentration before chemotherapy was 290 (interquartile range 203-417) ng/mL. The unadjusted hazard ratio (HR) for pre-treatment log2(3-IAA) was 0.93, 95% confidence interval (CI) [0.74-1.16], p=0.52. When adjusting for age, ECOG, CA19-9 and tumor classification, the HR for log2(3-IAA) was 0.87, 95% CI [0.68-1.12], p=0.28. Our findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC undergoing chemotherapy may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA's predictive value in different categories of PDAC before implementation attempts in human studies are initiated.

Alterations within the tryptophan–kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan–kynurenine pathway metabolites and all‐cause mortality among CRC patients. This study utilizes data from 2102 stage I–III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3‐hydroxykynurenine (HK), xanthurenic acid (XA), 3‐hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography–tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above‐mentioned metabolites with all‐cause mortality, adjusted for potential confounders. During a median follow‐up of 3.2 years (interquartile range: 2.2–4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all‐cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine‐to‐tryptophan ratio, a marker of cell‐mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan–kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.