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1.
Artigo em Inglês | MEDLINE | ID: mdl-30995590

RESUMO

Vitamin K1 (phylloquinone) is one of the vitamin Ks. Several studies have previously investigated the role of vitamin K1 status in respect to disease, but without consistent results. Since vitamin K deficiency has been associated with different disease states it is important to develop a biochemical analysis with sufficient sensitivity and a low limit of quantitation (LOQ). The vitamin Ks are very fat-soluble. This non-polar nature has given rise to several challenges during the method development, because vitamin K1 sticks to materials used during the process and is lost during evaporation. We found that reducing the sample preparation as much as possible offline, instead using online SPE-LC-MS/MS improves recovery and gives satisfactory chromatograms. An Protein BEH C4 column, 300 Š(50 × 2.1 mm, 1.7 µm particle size) was used as trap column and a Phenyl-Hexyl-LC-column, 100 Š(100 × 2.1 mm, 2.6 µm particle size) was used as analytical column. The mobile phases consisted of 30 µmol/L NH4F in water and 30 µmol/L NH4F in MeOH. A triple quadrupole tandem mass spectrometer with atmospheric pressure chemical ionization (APCI) ion source, positive ion mode, was used to perform the mass spectrometric measurements. The method is simple, highly sensitive and fast. The method was validated for vitamin K1 with good analytical performance. With a LOQ of 0.05 nmol/L it is to our knowledge the vitamin K1 method with lowest LOQ reported to date in the literature. It can easily be automated and applied in a routine diagnostic laboratory. Blood collection tubes with different additives were tested and showed no difference. Stability of vitamin K1 in serum was tested at different temperatures (-20 °C, 4 °C and in light and dark at 20 °C over a period of 30 days) and showed that vitamin K1 is light sensitive in serum even after only one day.


Assuntos
Cromatografia Líquida/métodos , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Vitamina K 1/sangue , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
2.
J Nutr ; 149(1): 18-25, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590596

RESUMO

Background: Phylloquinone is the primary form of vitamin K in the diet and circulation. Large intra- and interindividual variances in circulating phylloquinone have been partially attributed to age. However, little is known about the nondietary factors that influence phylloquinone absorption and metabolism. Similarly, it is not known if phylloquinone absorption is altered by the individual's existing vitamin K status. Objective: The purpose of this secondary substudy was to compare plasma response with deuterium-labeled phylloquinone intake in older and younger adults after dietary phylloquinone depletion and repletion. Methods: Forty-two older [mean ± SD age: 67.2 ± 8.0 y; body mass index (BMI; in kg/m2): 25.4 ± 4.6; n = 12 men, 9 women] and younger (mean ± SEM age: 31.8 ± 6.6 y; BMI: 25.5 ± 3.3; n = 9 men, 12 women) adults were maintained on sequential 28-d phylloquinone depletion (∼10 µg phylloquinone/d) and 28-d phylloquinone repletion (∼500 µg phylloquinone/d) diets. On the 23rd d of each diet phase, participants consumed deuterated phylloquinone-rich collard greens (2H-phylloquinone). Plasma and urinary outcome measures over 72 h were compared by age group, sex, and dietary phase via 2-factor repeated-measures ANOVA. Results: The plasma 2H-phylloquinone area under the curve (AUC) did not differ in response to phylloquinone depletion or repletion, but was 34% higher in older than in younger adults (P = 0.02). However, plasma 2H-phylloquinone AUC was highly correlated with the serum triglyceride (TG) AUC (r2 = 0.45). After adjustment for serum TG response, the age effect on the plasma 2H-phylloquinone AUC was no longer significant. Conclusions: Plasma 2H-phylloquinone response did not differ between phylloquinone depletion and repletion in older and younger adults. The age effect observed was explained by the serum TG response and was completely attenuated after adjustment. Plasma response to phylloquinone intake, therefore, seems to be a predominantly lipid-driven effect and not dependent on existing vitamin K status. More research is required to differentiate the effect of endogenous compared with exogenous lipids on phylloquinone absorption. This trial was registered at clinicaltrials.gov as NCT00336232.


Assuntos
Triglicerídeos/sangue , Vitamina K 1/sangue , Vitamina K 1/química , Adolescente , Adulto , Idoso , Envelhecimento , Área Sob a Curva , Transporte Biológico , Deutério , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina K 1/administração & dosagem , Vitamina K 1/farmacocinética , Vitamina K 3/metabolismo , Vitamina K 3/urina , Adulto Jovem
3.
J Pharm Biomed Anal ; 159: 82-91, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-29980023

RESUMO

Warfarin exerts its anticoagulation activity by blocking the vitamin K-epoxide cycle. A quantitative understanding of how warfarin and related genes interact with the vitamin K-epoxide cycle and the associated change of coagulation activity in the human body may help study the pharmacodynamics of warfarin. The plasma concentration of vitamin K1 (VK1) and vitamin K1 2,3-epoxide (VK1O) could reflect the status of vitamin K-epoxide cycle. However, their determination is a challenging task due to their extremely low concentrations in human plasma and the severe interferences caused by co-extracted lipids. In this study, we developed an LC-APCI-MS/MS method for the simultaneous determination of VK1 and VK1O in human plasma using stable deuterium-labeled vitamin K1 (vitamin K1-d7) as the internal standard (IS). Plasma samples were prepared through protein denaturation followed by one-step liquid extraction with cyclohexane. Chromatographic separation of analytes from isobaric interferences and endogenous ion suppressor was performed on a Synergi Hydro-RP column (150 mm × 4.6 mm, 4 µm) under the reversed-phase condition with isocratic elution. The selective reaction monitoring (SRM) transitions were chosen as m/z = 451.5→187.3 for VK1, m/z = 467.5→161.2 for VK1O, and m/z = 458.6→194.3 for IS in APCI positive mode. The assay was linear in the range of 100-10,000 pg/mL for the two analytes and achieved considerable extraction recoveries (87.8-93.3%, 91.0-96.9%, and 92.0% for VK1, VK1O, and IS, respectively), negligible matrix effects (93.6-96.0%, 96.3-100.1%, and 95.5%), and high selectivity with a small sample volume requirement (0.2 mL) and short run time (15 min). The validated method was successfully applied in a clinical pharmacodynamic study of warfarin, and the clotting activity was found to be negatively correlated with the plasma concentration ratio of VK1O to VK1.


Assuntos
Anticoagulantes/farmacocinética , Ensaios de Triagem em Larga Escala/métodos , Espectrometria de Massas em Tandem/métodos , Vitamina K 1/análogos & derivados , Vitamina K 1/sangue , Varfarina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Cromatografia Líquida/métodos , Cromatografia Líquida/normas , Ensaios de Triagem em Larga Escala/normas , Humanos , Espectrometria de Massas em Tandem/normas
4.
Nutrients ; 10(6)2018 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891757

RESUMO

Vitamin K was originally discovered as a cofactor required to activate clotting factors and has recently been shown to play a key role in the regulation of soft tissue calcification. This property of vitamin K has led to an increased interest in novel methods for accurate vitamin K detection. Molecularly Imprinted Polymers (MIPs) could offer a solution, as they have been used as synthetic receptors in a large variety of biomimetic sensors for the detection of similar molecules over the past few decades, because of their robust nature and remarkable selectivity. In this article, the authors introduce a novel imprinting approach to create a MIP that is able to selectively rebind vitamin K1. As the native structure of the vitamin does not allow for imprinting, an alternative imprinting strategy was developed, using the synthetic compound menadione (vitamin K3) as a template. Target rebinding was analyzed by means of UV-visible (UV-VIS) spectroscopy and two custom-made thermal readout techniques. This analysis reveals that the MIP-based sensor reacts to an increasing concentration of both menadione and vitamin K1. The Limit of Detection (LoD) for both compounds was established at 700 nM for the Heat Transfer Method (HTM), while the optimized readout approach, Thermal Wave Transport Analysis (TWTA), displayed an increased sensitivity with a LoD of 200 nM. The sensor seems to react to a lesser extent to Vitamin E, the analogue under study. To further demonstrate its potential application in biochemical research, the sensor was used to measure the absorption of vitamin K in blood serum after taking vitamin K supplements. By employing a gradual enrichment strategy, the sensor was able to detect the difference between baseline and peak absorption samples and was able to quantify the vitamin K concentration in good agreement with a validation experiment using High-Performance Liquid Chromatography (HPLC). In this way, the authors provide a first proof of principle for a low-cost, straightforward, and label-free vitamin K sensor.


Assuntos
Materiais Biomiméticos , Técnicas Biossensoriais , Impressão Molecular/métodos , Polímeros/síntese química , Vitamina K 1/metabolismo , Sítios de Ligação , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Teste de Materiais , Estudo de Prova de Conceito , Ligação Proteica , Conformação Proteica , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade , Vitamina K 1/sangue , Vitamina K 1/química , Vitamina K 3/metabolismo
5.
Cochrane Database Syst Rev ; 2: CD008342, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29401369

RESUMO

BACKGROUND: Vitamin K is necessary for the synthesis of coagulation factors. Term infants, especially those who are exclusively breast fed, are deficient in vitamin K and consequently may have vitamin K deficiency bleeding (VKDB). Preterm infants are potentially at greater risk for VKDB because of delayed feeding and subsequent delay in the colonization of their gastrointestinal system with vitamin K producing microflora, as well as immature hepatic and hemostatic function.  OBJECTIVES: To determine the effect of vitamin K prophylaxis in the prevention of vitamin K deficiency bleeding (VKDB) in preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 11), MEDLINE via PubMed (1966 to 5 December 2016), Embase (1980 to 5 December 2016), and CINAHL (1982 to 5 December 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs of any preparation of vitamin K given to preterm infants. DATA COLLECTION AND ANALYSIS: We evaluated potential studies and extracted data in accordance with the recommendations of Cochrane Neonatal. MAIN RESULTS: We did not identify any eligible studies that compared vitamin K to no treatment.One study compared intravenous (IV) to intramuscular (IM) administration of vitamin K and compared various dosages of vitamin K. Three different prophylactic regimes of vitamin K (0.5 mg IM, 0.2 mg vitamin K1, or 0.2 mg IV) were given to infants less than 32 weeks' gestation. Given that only one small study met the inclusion criteria, we assessed the quality of the evidence for the outcomes evaluated as low.Intramuscular versus intravenousThere was no statistically significant difference in vitamin K levels in the 0.2 mg IV group when compared to the infants that received either 0.2 or 0.5 mg vitamin K IM (control) on day 5. By day 25, vitamin K1 levels had declined in all of the groups, but infants who received 0.5 mg vitamin K IM had higher levels of vitamin K1 than either the 0.2 mg IV group or the 0.2 mg IM group.Vitamin K1 2,3-epoxide (vitamin K1O) levels in the infants that received 0.2 mg IV were not statistically different from those in the control group on day 5 or 25 of the study. All of the infants had normal or supraphysiologic levels of vitamin K1 concentrations and either no detectable or insignificant amounts of prothrombin induced by vitamin K absence-II (PIVKA II).Dosage comparisonsDay 5 vitamin K1 levels and vitamin K1O levels were significantly lower in the 0.2 mg IM group when compared to the 0.5 mg IM group. On day 25, vitamin K1O levels and vitamin K1 levels in the 0.2 mg IM group and the 0.5 mg IM group were not significantly different. Presence of PIVKA II proteins in the 0.2 mg IM group versus the 0.5 mg IM group was not significantly different at day 5 or 25 of the study. AUTHORS' CONCLUSIONS: Preterm infants have low levels of vitamin K and develop detectable PIVKA proteins during the first week of life. Despite being at risk for VKDB, there are no studies comparing vitamin K versus non-treatment and few studies that address potential dosing strategies for effective treatment. Dosage studies suggest that we are currently giving doses of vitamin K to preterm infants that lead to supraphysiologic levels. Because of current uncertainty, clinicians will have to extrapolate data from term infants to preterm infants. Since there is no available evidence that vitamin K is harmful or ineffective and since vitamin K is an inexpensive drug, it seems prudent to follow the recommendations of expert bodies and give vitamin K to preterm infants. However, further research on appropriate dose and route of administration is warranted.


Assuntos
Sangramento por Deficiência de Vitamina K/prevenção & controle , Vitamina K/administração & dosagem , Vitaminas/administração & dosagem , Biomarcadores/metabolismo , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Recém-Nascido Prematuro , Injeções Intramusculares , Injeções Intravenosas , Fígado/metabolismo , Precursores de Proteínas/metabolismo , Protrombina/análise , Protrombina/metabolismo , Vitamina K/sangue , Vitamina K 1/análogos & derivados , Vitamina K 1/sangue
6.
J Clin Lab Anal ; 32(5): e22381, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29333616

RESUMO

BACKGROUND: New high-performance liquid chromatography (HPLC) method was developed for the determination of vitamin K1 and two forms of vitamin K2 (MK-4 and MK-7) in human serum, and the levels of vitamin K were determined in 350 samples of postmenopausal women. METHODS: Vitamin K was determined by HPLC with fluorescence detection after postcolumn zinc reduction. The detection was performed at 246 nm (excitation) and 430 nm (emission). The internal standard and 2 mL of ethanol were added to 500 µL of serum. The mixture was extracted with 4 mL of hexane, and solid phase extraction was then used. RESULTS: The HLPC method was fully validated. The intra- and interday accuracy and precision were evaluated on two QC samples by multiple analysis, and CV were less than 10%. The limit of quantification for MK-4 was found at 0.04 ng/mL, for K1 0.03 ng/mL, and for MK-7 0.03 ng/mL. The mean recoveries of the corresponding compounds were 98%-110%. Serum levels of MK-4, K1 , and MK-7 in postmenopausal women with osteoporosis were 0.890 ± 0.291 ng/mL, 0.433 ± 0.394 ng/mL, and 1.002 ± 1.020 ng/mL, respectively (mean ± SD). Serum levels of MK-4, K1 , and MK-7 in postmenopausal women without osteoporosis were 0.825 ± 0.266 ng/mL, 0.493 ± 0.399 ng/mL, and 1.186 ± 1.076 ng/mL, respectively (mean ± SD). CONCLUSION: New HPLC method for the determination of vitamins K1 , MK-4, and MK-7 in serum was evaluated and validated. This method is highly specific and sensitive with the low limit of quantification.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluorescência , Pós-Menopausa/sangue , Vitamina K 1/sangue , Vitamina K 2/sangue , Feminino , Humanos , Fatores de Tempo , Vitamina K 2/classificação
7.
Am J Clin Nutr ; 106(4): 1041-1051, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28814399

RESUMO

Background: Previously, we showed that vegetable oil is necessary for carotenoid absorption from salad vegetables. Research is needed to better define the dose effect and its interindividual variation for carotenoids and fat-soluble vitamins.Objective: The objective was to model the dose-response relation between the amount of soybean oil in salad dressing and the absorption of 1) carotenoids, phylloquinone, and tocopherols in salad vegetables and 2) retinyl palmitate formed from the provitamin A carotenoids.Design: Women (n = 12) each consumed 5 vegetable salads with salad dressings containing 0, 2, 4, 8, or 32 g soybean oil. Blood was collected at selected time points. The outcome variables were the chylomicron carotenoid and fat-soluble vitamin area under the curve (AUC) and maximum content in the plasma chylomicron fraction (Cmax). The individual-specific and group-average dose-response relations were investigated by fitting linear mixed-effects random coefficient models.Results: Across the entire 0-32-g range, soybean oil was linearly related to the chylomicron AUC and Cmax values for α-carotene, lycopene, phylloquinone, and retinyl palmitate. Across 0-8 g of soybean oil, there was a linear increase in the chylomicron AUC and Cmax values for ß-carotene. Across a more limited 0-4-g range of soybean oil, there were minor linear increases in the chylomicron AUC for lutein and α- and total tocopherol. Absorption of all carotenoids and fat-soluble vitamins was highest with 32 g oil (P < 0.002). For 32 g oil, the interindividual rank order of the chylomicron AUCs was consistent across the carotenoids and fat-soluble vitamins (P < 0.0001).Conclusions: Within the linear range, the average absorption of carotenoids and fat-soluble vitamins could be largely predicted by the soybean oil effect. However, the effect varied widely, and some individuals showed a negligible response. There was a global soybean oil effect such that those who absorbed more of one carotenoid and fat-soluble vitamin also tended to absorb more of the others. This trial was registered at clinicaltrials.gov as NCT02867488.


Assuntos
Carotenoides/farmacocinética , Dieta , Absorção Intestinal/efeitos dos fármacos , Óleo de Soja/administração & dosagem , Verduras/química , Vitamina A/análogos & derivados , Vitaminas/farmacocinética , Adulto , Área Sob a Curva , Disponibilidade Biológica , Carotenoides/sangue , Quilomícrons , Relação Dose-Resposta a Droga , Feminino , Humanos , Luteína/sangue , Luteína/farmacocinética , Licopeno , Modelos Biológicos , Solubilidade , Óleo de Soja/farmacologia , Tocoferóis/sangue , Tocoferóis/farmacocinética , Vitamina A/sangue , Vitamina K 1/sangue , Vitamina K 1/farmacocinética , Vitaminas/sangue , Adulto Jovem
8.
Eur J Clin Nutr ; 71(12): 1423-1428, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28812579

RESUMO

BACKGROUND/OBJECTIVES: This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status. SUBJECTS/METHODS: In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross-sectionally among 507 postmenopausal women. RESULTS: Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (rs=0.28) than men (rs=0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long-chain menaquinones showed good relative validity (rs=0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (rs=0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (rs=-0.09 (-0.18; -0.01)) and long-chain menaquinones (rs=-0.13 (-0.21; -0.04)), but not with short-chain menaquinones (rs=-0.04 (-0.13; 0.05)). CONCLUSIONS: The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake.


Assuntos
Dieta , Inquéritos e Questionários , Vitamina K 1/administração & dosagem , Vitamina K 2/administração & dosagem , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Rememoração Mental , Países Baixos , Avaliação Nutricional , Estado Nutricional , Reprodutibilidade dos Testes , Vitamina K 1/sangue , Vitamina K 2/sangue , Adulto Jovem
9.
J Nutr ; 147(5): 888-895, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28356433

RESUMO

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.


Assuntos
Deficiência de Vitaminas/complicações , Doenças Cardiovasculares/etiologia , Hipertensão/complicações , Vitamina K 1/sangue , Idoso , Envelhecimento , Anti-Hipertensivos/uso terapêutico , Deficiência de Vitaminas/sangue , Composição Corporal , Calcinose/etiologia , Proteínas de Ligação ao Cálcio/sangue , Doenças Cardiovasculares/sangue , Proteínas da Matriz Extracelular/sangue , Feminino , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Masculino , Infarto do Miocárdio/etiologia , Isquemia Miocárdica/etiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/etiologia
10.
Talanta ; 164: 233-243, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28107923

RESUMO

Due to lack of suitable bioanalytical methods in previous literature, for simultaneous estimation of Vitamin K1 isomers, in compliance with the current regulatory expectation, we aimed to develop a sensitive and rapid method with UFLC-APCI-MS/MS (ultrafast liquid chromatography - tandem mass spectrometry) using human plasma. A simple and cost effective procedure was implemented with the combination of protein precipitation and liquid extraction, to isolate the targets from plasma sample, while achieving an insignificant matrix effects and high recovery (≥88.2%). A short 9.0min run time per sample was accomplished by using water in methanol (1.0% v/v) and acetonitrile, which pumped at 0.8mL/min, on to the COSMOSIL® packed column, for separating the trans and cis isomers of Vitamin K1 along with the corresponding stable labeled D7 internal standards (ISs). The analytes and ISs were quantified, at their parent to product ion mass transitions of 451.3 →187.1m/z and 458.1→194.3m/z respectively, using an APCI (atmospheric pressure chemical ionization) source of the tandem mass, in MRM (multiple reaction monitoring) mode. Performance of the method over the calibration range: 0.1-150.0ng/mL, while using a low sample volume (0.3mL), was successfully evaluated through full method validation in compliance with the latest regulations. Fully validated method with significant results was applied to human pharmacokinetic study, and had a potential to further advance the clinical research programs and generic drug development of Vitamin K1, intended for the regulatory submission.


Assuntos
Pressão Atmosférica , Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Espectrometria de Massas em Tandem/métodos , Vitamina K 1/sangue , Vitamina K 1/farmacocinética , Adulto , Humanos , Isomerismo , Modelos Lineares , Masculino , Fatores de Tempo , Vitamina K 1/química , Vitamina K 1/isolamento & purificação
11.
Clin Nutr ; 36(2): 438-443, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-26795217

RESUMO

BACKGROUND: Vitamin D, and possibly vitamin K, has an established association to fracture risk. Other vitamins are, however, less studied. AIM: To determine whether specific micronutrients other than 25(OH)D and vitamin K play a role in risk of hip fracture and bone turnover. METHODS: In this case-control study, blood was drawn for measurements of vitamins A, B6, B12, C, E, and folic acid as well as the bone turnover markers osteocalcin and bone-specific alkaline phosphatase upon admission for hip fracture in 116 patients and in 73 home-dwelling non fractured controls. Results for vitamin K1 and 25(OH)D from the same populations have been reported previously. RESULTS: Low vitamin A, C, and E concentrations were independently associated with a risk of hip fracture. The adjusted odds ratio (95% confidence interval) per 10 µmol/L increase in vitamin A concentration was 0.74 (0.65-0.84); for 1 µmol/L vitamin C and E: 0.94 (0.92-0.97) and 0.81 (0.74-0.89) respectively. The results were principally unchanged when 25(OH)D, vitamin K1, Body Mass Index, and other potential confounders were adjusted for. All vitamins except B12 and folic acid correlated positively with total osteocalcin and negatively with bone-specific alkaline phosphatase. CONCLUSIONS: Low vitamin A, C, and E concentrations are associated with an increased risk of hip fracture, possibly mediated through bone turnover mechanisms. This case-control study is registered at: ClinicalTrials.gov. NCT01738776. The patient related outcome is also registered at: ClinicalTrials.gov. NCT01009268.


Assuntos
Fraturas do Quadril/sangue , Fraturas do Quadril/epidemiologia , Micronutrientes/sangue , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/sangue , Ácido Ascórbico/sangue , Índice de Massa Corporal , Remodelação Óssea/efeitos dos fármacos , Estudos de Casos e Controles , Feminino , Ácido Fólico/sangue , Humanos , Masculino , Osteocalcina/sangue , Fatores de Risco , Vitamina A/sangue , Vitamina B 12/sangue , Vitamina D/sangue , Vitamina E/sangue , Vitamina K 1/sangue
12.
Clin Nutr ; 36(2): 601-607, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27234935

RESUMO

BACKGROUND & AIMS: Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis. METHODS: In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins). RESULTS: Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency. CONCLUSIONS: Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated.


Assuntos
Dieta , Diálise Renal , Insuficiência Renal Crônica/sangue , Vitamina K 1/administração & dosagem , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas na Dieta/administração & dosagem , Feminino , Humanos , Masculino , Micronutrientes/administração & dosagem , Pessoa de Meia-Idade , Avaliação Nutricional , Estado Nutricional , Prevalência , Recomendações Nutricionais , Insuficiência Renal Crônica/tratamento farmacológico , Estudos Retrospectivos , Vitamina K 1/sangue , Deficiência de Vitamina K/sangue , Deficiência de Vitamina K/diagnóstico , Deficiência de Vitamina K/tratamento farmacológico , Circunferência da Cintura
13.
Can J Diet Pract Res ; 78(1): 11-19, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27779902

RESUMO

PURPOSE: Patients with diabetes (DM) and chronic kidney disease (CKD) are at increased risk for suboptimal bone health. The study objective was to investigate the relationships between vitamin D (vitD), vitamin K1 (vitK1), and calcium intake with bone mineral density (BMD) and vitamin D status in an ambulatory population with DM and CKD. METHODS: Adults (age 18-80 years; n = 62) with DM and CKD (stages 1-4) were recruited from the Northern Alberta Renal Program. Primary outcome variables included vitD, vitK1, and calcium intake; serum 25(OH)D, 1,25(OH)2D; and BMD as measured by dual X-ray absorptiometry. Statistical significance was determined at P < 0.05. RESULTS: Participants met the estimated average requirement or adequate intake for vitD, vitK1, and calcium intake in 73% (n = 45), 66% (n = 39), and 52% (n = 31), respectively, with a combined intake of micronutrient supplementation and diet. Participants had serum 25(OH)D concentrations ≥75 nmol/L (n = 41), normal BMDs (n = 48), and 66% (n = 41/62) were taking vitD supplements (>1000 IU/D). BMD was positively influenced by serum 25(OH)D. However, serum 25(OH) ≥100 nmol/L was associated with lower BMD (absolute and T-scores) for whole-body and spine (P ≤ 0.05). VitK1 intake (≥200 µg/day) was associated with higher whole-body and femoral-neck BMDs (absoluteand T-scores; P ≤ 0.05). CONCLUSION: VitD status and BMD in adults with DM and CKD was influenced by vitD supplementation and vitK1 intake.


Assuntos
Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Vitamina D/administração & dosagem , Vitamina D/sangue , Vitamina K 1/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alberta , Glicemia/metabolismo , Cálcio na Dieta/administração & dosagem , Cálcio na Dieta/sangue , Diabetes Mellitus/sangue , Dieta , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas na Dieta/administração & dosagem , Suplementos Nutricionais , Feminino , Humanos , Masculino , Micronutrientes/administração & dosagem , Micronutrientes/sangue , Pessoa de Meia-Idade , Avaliação Nutricional , Estado Nutricional , Insuficiência Renal Crônica/sangue , Vitamina K 1/sangue , Adulto Jovem
14.
J Nutr ; 146(11): 2274-2280, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27733530

RESUMO

BACKGROUND: Data from a nationally representative sample of 18- to 64-y-old Irish adults conducted in 1999 highlighted low phylloquinone intakes. That survey, however, did not include older adults (aged ≥65 y), a subgroup that is potentially at higher risk of low phylloquinone intakes, or a biomarker of vitamin K status. OBJECTIVES: The objectives of this work were to measure the phylloquinone intake and its adequacy and the serum percentage of undercarboxylated osteocalcin (%ucOC), a vitamin K status biomarker, in a nationally representative sample of Irish adults aged 18-90 y, and to compare these newer data on dietary phylloquinone in adults aged 18-64 y with those from the previous survey. METHODS: Data and biobanked serum samples from the National Adult Nutrition Survey, a randomly selected sample of Irish adults aged 18-90 y (N = 1500), were accessed. Phylloquinone intakes were estimated from 4-d food diary data and were compared across age groups (18-35, 36-50, 51-64, and ≥65 y). Serum %ucOC was assessed by immunoassay (n = 692). RESULTS: The mean ± SD intake of phylloquinone from all sources was 85.2 ± 59.1 µg/d, 99% of which was derived from food. Phylloquinone intakes and serum %ucOC were significantly (P < 0.05) lower (14-25%) and higher (27-39%), respectively, in the 18- to 35-y age group than in the 36- to 50-y, 51- to 64-y, and ≥65-y age groups (no differences between these 3 groups; P > 0.2 in all cases). Mean phylloquinone intakes had increased (P < 0.01) modestly (6 µg/d) in 18-64-y-olds across a decade. Of the total study population, 55% had phylloquinone intakes below the United Kingdom recommended intake of 1 µg ⋅ kg body weight-1 ⋅ d-1 CONCLUSION: Our study shows that younger adults (aged 18-35 y) appear to be at higher risk of inadequate vitamin K intake and lower vitamin K status, the health implications of which are unclear and warrant further investigation.


Assuntos
Análise de Alimentos , Vitamina K 1/administração & dosagem , Vitamina K 1/sangue , Adolescente , Adulto , Biomarcadores , Registros de Dieta , Inquéritos sobre Dietas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necessidades Nutricionais , Adulto Jovem
15.
Biosens Bioelectron ; 86: 48-55, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27318569

RESUMO

We report an approach for the simultaneous estimation of vitamin K1 (VK1) and heparin via cascaded channel multianalyte sensing probe employing fiber optic surface plasmon resonance technique. Cladding from two well separated portions of the fiber is removed and are respectively coated with thin films of silver (channel-1) and copper (channel-2). The nanohybrid of multiwalled carbon nanotube in chitosan is fabricated over silver layer for the sensing of VK1 whereas core shell nanostructure of polybrene@ZnO is coated over copper layer for the sensing of heparin. Spectral interrogation method is used for the characterization of the sensor. Analyte selectivity of both the channels is performed by carrying out experiments using independent solutions of VK1 and heparin. Experiments performed on the solution of the mixture of VK1 and heparin show red shifts in both the channels on changing the concentration of both the analytes in the mixture. The operating range of both VK1 and heparin is from 0 to 10(-3)g/l. The limit of detection of the sensor is 2.66×10(-4)µg/l and 2.88×10(-4)µg/l for VK1 and heparin respectively which are lower than the reported ones. The additional advantages of the present sensor are low cost, possibility of online monitoring and remote sensing.


Assuntos
Testes de Coagulação Sanguínea/instrumentação , Tecnologia de Fibra Óptica/instrumentação , Heparina/sangue , Ressonância de Plasmônio de Superfície/instrumentação , Vitamina K 1/sangue , Análise Química do Sangue/instrumentação , Misturas Complexas/sangue , Desenho de Equipamento , Análise de Falha de Equipamento , Análise de Injeção de Fluxo/instrumentação , Humanos , Microquímica/instrumentação , Nanotubos de Carbono/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Óxido de Zinco/química
16.
Nutr J ; 15(1): 53, 2016 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-27175730

RESUMO

BACKGROUND: Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect of MK-4 supplementation on CAC and brachial ankle pulse wave velocity (baPWV). METHODS: This study is a single arm design to take 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. RESULTS: A total of 26 patients were enrolled. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (-0.7 %), respectively. In patients with high PIVKA-2, -18 % annual reduction of baPWV was observed. CONCLUSION: Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (-0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. TRIAL REGISTRATION: This study was registered as UMIN 000002760.


Assuntos
Cardiomiopatias/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Suplementos Nutricionais , Hemostáticos/administração & dosagem , Rigidez Vascular/efeitos dos fármacos , Vitamina K 2/análogos & derivados , Idoso , Índice Tornozelo-Braço , Índice de Massa Corporal , Vasos Coronários/metabolismo , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Análise de Onda de Pulso , Fatores de Risco , Vitamina K 1/administração & dosagem , Vitamina K 1/sangue , Vitamina K 2/administração & dosagem , Vitamina K 2/sangue
17.
Am J Cardiovasc Drugs ; 16(4): 267-74, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27084708

RESUMO

BACKGROUND: Oral anticoagulant therapy (OAT) with a vitamin K antagonist (VKA) is the choice of treatment for preventing thromboembolism in patients with mechanical heart valve prosthesis (MHP). The percentage of time in the therapeutic range (TTR%) expresses the OAT quality. We planned a case-control study in order to determine vitamin K1 plasmatic concentrations in MHP patients and to correlate these with TTR%. MATERIALS AND METHODS: Of 756 MHP patients receiving OAT, 125 patients (61 younger than 65 years, and 64 older than 65 years) and 120 healthy blood donors, matched for sex and age, were enrolled in the study. All subjects completed a living questionnaire regarding diet, and underwent blood collection. Vegetable and fruit intake was categorized as optimal or suboptimal, and the high-performance liquid chromatography method was used to determine vitamin K1 levels. RESULTS: Neither the patients nor controls had been taking vitamin supplements prior to the start of the study. The median vitamin K1 level was 290 pg/L in 72 controls with optimal intake, and 274 pg/L in 48 controls with suboptimal intake, while the median vitamin K1 level in MHP patients with optimal intake was 409 pg/L, significantly higher (p < 0.001) than the 133.5 pg/L in patients with suboptimal intake. Vitamin K1 concentration in MHP patients appears to be linked to an age-related threshold: in patients younger than 65 years of age, the median vitamin K1 level was 431 pg/L, significantly higher (p < 0.05) than the 290 pg/L in patients older than 65 years of age. No clear relation was found between vitamin K1 levels and TTR% (Pearson = 0.14). However, patients with vitamin K1 >160 pg/L showed a TTR% >60 %. Among patients younger than 65 years, subjects with vitamin K1 >160 pg/L showed a median TTR of 66 %, this being significantly higher (p < 0.001) than the 46 % level shown by patients with vitamin K1 <160 pg/L. CONCLUSIONS: Vitamin K1 concentrations in MHP patients seem to be related to both diet and age.


Assuntos
Anticoagulantes/uso terapêutico , Vitamina K 1/sangue , Administração Oral , Adulto , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão/métodos , Dieta/métodos , Feminino , Frutas , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Próteses e Implantes , Verduras
18.
Clin Chem Lab Med ; 54(7): 1201-10, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26630696

RESUMO

BACKGROUND: Given the growing interest in the health benefits of vitamin K, there is great need for development of new high-throughput methods for quantitative determination of vitamin K in plasma. We describe a simple and rapid method for measurement of plasma vitamin K1 (phylloquinone [PK]) and K2 (menaquinones [MK]-4 and -7). Furthermore, we investigated the association of fasting plasma vitamin K with functional vitamin K insufficiency in renal transplant recipients (RTR). METHODS: We used HPLC-tandem mass spectrometry with atmospheric pressure chemical ionization for measurement of plasma PK, MK-4, and MK-7. Solid-phase extraction was used for sample clean-up. Mass spectrometric detection was performed in multiple reaction monitoring mode. Functional vitamin K insufficiency was defined as plasma desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) >500 pmol/L. RESULTS: Lower limits of quantitation were 0.14 nmol/L for PK and MK-4 and 4.40 nmol/L for MK-7. Linearity up to 15 nmol/L was excellent. Mean recoveries were >92%. Fasting plasma PK concentration was associated with recent PK intake (ρ=0.41, p=0.002) and with plasma MK-4 (ρ=0.49, p<0.001). Plasma PK (ρ=0.38, p=0.003) and MK-4 (ρ=0.46, p<0.001) were strongly correlated with plasma triglyceride concentrations. Furthermore, we found that MK-4-triglyceride ratio, but not PK-triglyceride ratio, was significantly associated with functional vitamin K insufficiency (OR 0.22 [0.07-0.70], p=0.01) in RTR. CONCLUSIONS: The developed rapid and easy-to-use LC-MS/MS method for quantitative determination of PK, MK-4, and MK-7 in human plasma may be a good alternative for the labor-intensive and time-consuming LC-MS/MS methods and enables a higher sample throughput.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Vitamina K 1/sangue , Vitamina K 2/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Osteoporos Int ; 27(4): 1645-1652, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26630974

RESUMO

UNLABELLED: The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures. INTRODUCTION: This case-cohort study aims to investigate the associations between serum vitamin K1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association. METHODS: The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994-2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases (n = 1090) and in a randomly selected subcohort (n = 1318). Cox proportional hazards regression with quartiles of serum vitamin K1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K1 ≥ 0.76 and 25(OH)D ≥ 50 nmol/l, II: vitamin K1 ≥ 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K1 < 0.76 and 25(OH)D ≥ 50 nmol/l, and IV: vitamin K1 < 0.76 and 25(OH)D < 50 nmol/l. RESULTS: Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18-1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum α-tocopherol. No increased risk was observed in the groups low in one vitamin only. CONCLUSION: Combination of low concentrations of vitamin K1 and 25(OH)D is associated with increased risk of hip fractures.


Assuntos
Fraturas do Quadril/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Vitamina K 1/sangue , Deficiência de Vitamina K/complicações , Idoso , Estudos de Coortes , Feminino , Seguimentos , Fraturas do Quadril/sangue , Fraturas do Quadril/epidemiologia , Humanos , Masculino , Noruega/epidemiologia , Fatores de Risco , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina K/sangue , Deficiência de Vitamina K/epidemiologia
20.
Clin Biochem ; 48(18): 1246-51, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26282719

RESUMO

OBJECTIVES: Decreased concentration of menaquinone-4 (MK-4) seems to be an important risk factor of vascular calcification in haemodialysis (HD) patients. Optimal dietary intake, as well as serum MK-4 reference range, in HD has not been determined, yet. The aim of the present study was to assess daily vitamin K1 and MK-4 intakes and their relation to serum MK-4 concentration in HD patients. DESIGN AND METHODS: Daily vitamin K1 and MK-4, micro- and macronutrients and energy intakes were assessed using 3-day food diary completed by patients and serum MK-4 concentration was measured by HPLC [limit of quantification (LOQ): 0.055 ng/mL] in 85 HD patients (51 males) and 22 apparently healthy subjects. RESULTS: Daily MK-4 intake was significantly lower (by 29%) among HD, while K1 consumption was similar in both groups. Daily MK-4 intake was associated with fat and protein consumption in HD (r=0.43, p<0.001 and r=0.33, p=0.004, respectively). In HD serum MK-4 concentration was more frequently below LOQ (in 41% HD and 5% controls, p<0.001) and in those HD with quantifiable values was lower than in the controls (by 42%). The correlations between MK-4 concentrations and both MK-4 and K1 daily intakes were weaker in HD (r=0.38 and r=0.30 respectively) than in the control group (r=0.47 and r=0.45, respectively). In multiple regression analysis the variability of serum MK-4 concentrations in HD patients was explained by its daily intake. CONCLUSIONS: Decreased serum MK-4 concentration in HD patients is caused by lower dietary MK-4 intake, mainly due to diminished meat consumption, and in addition, probably reduced K1 conversion.


Assuntos
Hemostáticos/administração & dosagem , Diálise Renal , Insuficiência Renal Crônica/sangue , Vitamina K 1/administração & dosagem , Vitamina K 2/análogos & derivados , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Registros de Dieta , Gorduras na Dieta/administração & dosagem , Proteínas na Dieta/administração & dosagem , Ingestão de Energia , Feminino , Hemostáticos/sangue , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Recomendações Nutricionais , Valores de Referência , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Calcificação Vascular , Vitamina K 1/sangue , Vitamina K 2/administração & dosagem , Vitamina K 2/sangue
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