Introdução: Especula-se que exista uma possível relação entre a ingestão de vitamina K e a diminuição da gordura corporal. Além disso, embora os resultados permaneçam controversos, há um número crescente de estudos que apoiam um papel chave dessa vitamina na melhora do perfil lipídico, da sensibilidade à insulina e na redução do risco de diabetes mellitus tipo 2, contudo pouco se sabe sobre quais mecanismos estariam envolvidos. Objetivo: Investigar as relações entre a ingestão de vitamina K (na forma de filoquinona - PK), gordura corporal, perfil lipídico e marcadores da homeostase da glicose em adultos e idosos. Métodos: Estudo transversal com 298 indivíduos de ambos os sexos, participantes do inquérito ISA - Capital 2015. Amostras de sangue foram coletadas para determinação do perfil lipídico, glicemia de jejum e concentrações de insulina; e índice de estimativa de resistência à insulina (HOMAIR), índice de estimativa da função de células β-pancreáticas (HOMA-β) e índice de estimativa da sensibilidade à insulina (QUICKI) foram calculados. A ingestão de vitamina K foi avaliada por meio de um recordatório alimentar de 24hrs (repetido em 75% da amostra), e a investigação quantitativa da massa gorda foi conduzida por meio da absorciometria de feixe duplo (DXA). Indivíduos com ingestão de vitamina K inferior aos valores de AI foram divididos em subgrupos de acordo com o estado nutricional e faixa etária. Foi realizada a Correlação de Spearman em grupos estratificados de acordo com o Índice de Massa Corporal (IMC) e com o Índice de Gordura Corporal (IGC). Para avaliar as associações entre a ingestão de vitamina K e cada uma das medidas bioquímicas e de adiposidade, foi realizada a regressão linear múltipla. Resultados: Dentre os avaliados, 46% eram do sexo masculino (n=136), com idade mediana de 61 anos (20 - 94 anos), e 56,4% apresentavam sobrepeso ou obesidade (n=168). A mediana de ingestão de vitamina K foi de 102,7 μg, ou 59,9 μg,/1000 kcal, sem diferença de acordo com sexo ou idade. A ingestão de vitamina K apresentou correlação negativa com o HOMA-IR (r = -0,603; p = 0,0134) e correlação positiva com QUICKI (r = 0,603; p = 0,0134) entre os adultos eutróficos do sexo masculino (n = 16). Em idosas com baixo peso (n = 12), a ingestão de vitamina K foi negativamente correlacionada com o Colesterol Total (CT) (r = -0,644; p = 0,0443). Entre as mulheres com elevado IGC e ingestão de vitamina K inferior aos valores de AI (n = 117), foram observadas correlações negativas entre a ingestão de vitamina K e HOMA-IR (r = -0,187; p = 0,0451) e correlações positivas com QUICKI (r = 0,187; p = 0,0451). Conclusões: Os resultados encontrados sugerem uma possível relação entre a ingestão dietética de filoquinona, gordura corporal, perfil lipídico e marcadores da homeostase da glicose, em amostra de adultos e idosos. / Introduction: Recent research have investigated a possible inverse relationship between vitamin K intake and body fat. In addition, although the results remain controversial, there is an increasing number of studies supporting a key role of this vitamin in improving lipid profile, insulin sensitivity and reducing the risk of type 2 diabetes mellitus, but little is known about what mechanisms would be involved. Objective: To investigate the relationship between vitamin K intake (in the form of phylloquinone - PK), body fat, lipid profile and markers of glucose homeostasis in adults and elderly. Methods: Cross-sectional study with 298 individuals of both sexes, participants in the ISA - Capital 2015 survey. Blood samples were collected for determination of lipid profile, fasting glycemia and insulin concentrations, and homeostasis model assesment estimate for insulin resistance (HOMA-IR), homeostasis model assessment estimate for β-cell function (HOMA-β) and the quantitative insulin sensitivity check index (QUICKI) were calculate accordingly. Vitamin K intake was assessed by a 24-hour dietary recall (repeated in 75% of the sample) and quantitative investigation of fat mass was conducted using dual-energy x-ray absorptiometry (DXA). Subjects with vitamin K intake lower than AI values were divided into subgroups according to nutritional status and age group. Spearman correlation was performed in stratified groups according to Body Mass Index (BMI) and Fat Mass Index (FMI). To evaluate the associations between vitamin K intake and each of the biochemical and adiposity measures, multiple linear regression were performed. Results: Among the sample, 46% were male (n = 136), with a median age of 61 years (20 - 94 years), and 56.4% were overweight or obese (n= 168). The median vitamin K intake was 102.7 μg, or 59.9 μg, / 1000 kcal, with no difference according to sex or age. Vitamin K intake presented negative correlation with HOMA-IR (r = -0.603; p = 0.0134) and positive correlation with QUICKI (r = 0.603; p=0.0134) among normal weight male adults (n=16). In underweight elderly women (n=12), vitamin K intake was negatively correlated with total cholesterol (TC) (r = -0.644, p = 0.0443). Among females with high FMI and vitamin K intake lower than AI values (n=117), vitamin K intake was negatively correlated with HOMA-IR (r = -0.187; p = 0.0451) and positively correlated with QUICKI (r 12 = 0.187; p = 0.0451). Conclusions: Results suggest a possible relationship between dietary intake of phylloquinone, body fat, lipid profile and glucose homeostasis, among a sample of adults and elderly.

Introdução. A varfarina tem sido considerada a principal terapêutica anticoagulante oral há aproximadamente 50 anos, estando entre os dez medicamentos mais envolvidos com reações adversas a medicamentos (RAM), apresenta estreita janela terapêutica e complexo regime posológico, exibe enorme variabilidade doseresposta e elevado risco de interações medicamentosas (IM). Objetivo. Identificar e avaliar as IM e RAM relacionadas com a administração da varfarina. Casuística e Métodos. Trata-se de um estudo transversal. Os dados foram coletados retrospectivamente através do banco de dados informatizado do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo pertencente ao Sistema Único de Saúde. As prescrições de janeiro/2004 a dezembro/2010 dos pacientes que utilizaram varfarina foram analisadas, sendo os pacientes divididos em dois grupos: estudo (uso de vitamina K até 168 horas após prescrição de varfarina) e controle. Posteriormente, as prescrições medicamentosas que não continham varfarina foram excluídas da análise. As informações coletadas incluíram idade, gênero, raça, unidade de atendimento, diagnóstico clínico, doses e medicamentos, e exames laboratoriais. As IM com varfarina foram classificadas em risco A, B, C, D e X de acordo a base de dados da Lexi-Interact(TM) Online. Foi realizada análise descritiva e analítica (p<0,05). Resultados e Discussão. Foram identificados 3048 pacientes, os quais receberam 154161 prescrições medicamentosas (42120 continham varfarina). A idade média foi de 55,8 (±19,3) anos, 53,2% do gênero feminino, prevalência de idosos (48,1%) e do diagnóstico outras doenças cerebrovasculares específicas (4,3%). Os valores médios da international normalized ratio (INR) (2,4±1,7) e dose de varfarina (5,1±1,8mg) encontraram-se dentro dos preconizados pelos protocolos terapêuticos. Foi observado que 66,4% dos pacientes realizaram uso de polifarmácia, o que pode elevar o risco de IM. Além disso, 63,2% dos pacientes apresentaram prescrição(ões) de medicamentos classificados como risco D e/ou X, com média de 1,4 (±0,4) medicamento/prescrição, destacando-se o ácido acetilsalicílico e amiodarona. Quando comparado grupo de estudo (n=429) versus controle (n=2619), houve diferença estatisticamente significativa na idade média (anos) (59,0±18,8 vs. 55,5±19,3; p<0,000), número médio de medicamentos/prescrição (7,1±2,8 vs. 6,2±2,8; p<0,000), número médio de medicamentos de Risco D e X de IM por prescrição (1,4±1,3 vs. 1,0±1,0; p<0,000), albumina sérica (g/dL) (3,4±0,6 vs. 3,7±0,6; p<0,000), aspartato aminotransferase (U/L) (60,7± 200,6 vs. 41,5±84,5; p<0,005) e INR (4,9±3,4 vs. 2,1±0,7; p<0,000), fatores estes que podem ter contribuído para ocorrência de RAM no grupo de estudo. Conclusão. Observou-se elevada ocorrência de possíveis IM e RAM nos usuários de varfarina, as quais podem comprometer a efetividade e segurança do tratamento farmacológico. Como possíveis fatores de risco para ocorrência de RAM, destacam-se elevados valores de idade, número de medicamentos/prescrição, prescrição de medicamentos classificados como risco D e/ou X, de INR e de aspartato aminotransferase, e valores diminuídos de albumina sérica. / Introduction. Warfarin has been considered the main oral anticoagulant therapy about 50 years ago and is among the ten drugs most commonly involved in adverse drug reactions (ADR), has a narrow therapeutic index and complex dosage regimen, exhibits enormous variability dose-response and high risk drug-drug interactions (DDI). Objective. To Identify and evaluate DDI and ADR related to the administration of warfarin. Casuistry and Methods. This was a cross sectional study. Data were collected retrospectively through the computerized database of the Faculty of Medicine of Ribeirao Preto Hospital, University of Sao Paulo linked to the Unified Health System. The prescriptions of the January/2004 to December/2010 of patients using warfarin were analyzed, and the patients were divided into two groups: study (utilization of vitamin K until 168 hours after prescribing warfarin) and control. Thereafter, the drug prescriptions that did not contain warfarin were excluded from analysis. Information collected included age, gender, race, patient service center, clinical diagnosis, dosages and drugs, and laboratory exams. The warfarin DDI were classified at risk A, B, C, D and X according to the database Lexi-Interact (TM) Online. Descriptive and analytical analysis were performed (p<0.05). Results and Discussion. We identified 3048 patients who received 154,161 drug prescriptions (42,120 contained warfarin). The mean age was 55.8 (±19.3) years, 53.2% female, prevalence of elderly (48.1%) and other cerebrovascular diseases specific diagnosis (4.3%). The average values of international normalized ratio (INR) (2.4±1.7) and warfarin dose (5.1±1.8mg) were within those recommended by therapeutic protocols. It was observed that 66.4% of patients received polypharmacy, which can raise the risk of DDI. In addition, 63.2% of patients had prescription(s) of drugs classified as D or X risk, with an average of 1.4 (±0.4) drugs per prescription, especially aspirin and amiodarone. Compared study group (n=429) versus control (n =2619), there was a statistically significant difference in mean age (years) (59.0±18.8 vs. 55.5±19.3; p<0.000), average number of medications/prescriptions (7.1±2.8 vs. 6.2±2.8; p<0.000), mean number of drugs with risk D and X DDI/prescription (1.4±1.3 vs. 1.0±1.0, p<0.000), serum albumin (g/dL) (3.4±0.6 vs. 3.7±0.6; p<0.000), aspartate aminotransferases (U/L) (60.7±200.6 vs. 41.5±84.5; p<0.005) and INR (4.9±3.4 vs. 2.1±0.7; p<0.000), factors that may have contributed to the occurrence of ADR in the study group. Conclusion. There was a high occurrence of possible DDI and ADR in patients treated with warfarin, which may compromise the effectiveness and safety of pharmacological treatment. Noteworthy is the high values of age, number of medications/prescriptions, prescription drugs classified as risk D or X, INR and aspartate aminotransferases, and lower values of serum albumin as potential risk factors for the occurrence of ADR.

Introdução. A varfarina tem sido considerada a principal terapêutica anticoagulante oral há aproximadamente 50 anos, estando entre os dez medicamentos mais envolvidos com reações adversas a medicamentos (RAM), apresenta estreita janela terapêutica e complexo regime posológico, exibe enorme variabilidade doseresposta e elevado risco de interações medicamentosas (IM). Objetivo. Identificar e avaliar as IM e RAM relacionadas com a administração da varfarina. Casuística e Métodos. Trata-se de um estudo transversal. Os dados foram coletados retrospectivamente através do banco de dados informatizado do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo pertencente ao Sistema Único de Saúde. As prescrições de janeiro/2004 a dezembro/2010 dos pacientes que utilizaram varfarina foram analisadas, sendo os pacientes divididos em dois grupos: estudo (uso de vitamina K até 168 horas após prescrição de varfarina) e controle. Posteriormente, as prescrições medicamentosas que não continham varfarina foram excluídas da análise. As informações coletadas incluíram idade, gênero, raça, unidade de atendimento, diagnóstico clínico, doses e medicamentos, e exames laboratoriais. As IM com varfarina foram classificadas em risco A, B, C, D e X de acordo a base de dados da Lexi-Interact(TM) Online. Foi realizada análise descritiva e analítica (p<0,05). Resultados e Discussão. Foram identificados 3048 pacientes, os quais receberam 154161 prescrições medicamentosas (42120 continham varfarina). A idade média foi de 55,8 (±19,3) anos, 53,2% do gênero feminino, prevalência de idosos (48,1%) e do diagnóstico outras doenças cerebrovasculares específicas (4,3%). Os valores médios da international normalized ratio (INR) (2,4±1,7) e dose de varfarina (5,1±1,8mg) encontraram-se dentro dos preconizados pelos protocolos terapêuticos. Foi observado que 66,4% dos pacientes realizaram uso de polifarmácia, o que pode elevar o risco de IM. Além disso, 63,2% dos pacientes apresentaram prescrição(ões) de medicamentos classificados como risco D e/ou X, com média de 1,4 (±0,4) medicamento/prescrição, destacando-se o ácido acetilsalicílico e amiodarona. Quando comparado grupo de estudo (n=429) versus controle (n=2619), houve diferença estatisticamente significativa na idade média (anos) (59,0±18,8 vs. 55,5±19,3; p<0,000), número médio de medicamentos/prescrição (7,1±2,8 vs. 6,2±2,8; p<0,000), número médio de medicamentos de Risco D e X de IM por prescrição (1,4±1,3 vs. 1,0±1,0; p<0,000), albumina sérica (g/dL) (3,4±0,6 vs. 3,7±0,6; p<0,000), aspartato aminotransferase (U/L) (60,7± 200,6 vs. 41,5±84,5; p<0,005) e INR (4,9±3,4 vs. 2,1±0,7; p<0,000), fatores estes que podem ter contribuído para ocorrência de RAM no grupo de estudo. Conclusão. Observou-se elevada ocorrência de possíveis IM e RAM nos usuários de varfarina, as quais podem comprometer a efetividade e segurança do tratamento farmacológico. Como possíveis fatores de risco para ocorrência de RAM, destacam-se elevados valores de idade, número de medicamentos/prescrição, prescrição de medicamentos classificados como risco D e/ou X, de INR e de aspartato aminotransferase, e valores diminuídos de albumina sérica. / Introduction. Warfarin has been considered the main oral anticoagulant therapy about 50 years ago and is among the ten drugs most commonly involved in adverse drug reactions (ADR), has a narrow therapeutic index and complex dosage regimen, exhibits enormous variability dose-response and high risk drug-drug interactions (DDI). Objective. To Identify and evaluate DDI and ADR related to the administration of warfarin. Casuistry and Methods. This was a cross sectional study. Data were collected retrospectively through the computerized database of the Faculty of Medicine of Ribeirao Preto Hospital, University of Sao Paulo linked to the Unified Health System. The prescriptions of the January/2004 to December/2010 of patients using warfarin were analyzed, and the patients were divided into two groups: study (utilization of vitamin K until 168 hours after prescribing warfarin) and control. Thereafter, the drug prescriptions that did not contain warfarin were excluded from analysis. Information collected included age, gender, race, patient service center, clinical diagnosis, dosages and drugs, and laboratory exams. The warfarin DDI were classified at risk A, B, C, D and X according to the database Lexi-Interact (TM) Online. Descriptive and analytical analysis were performed (p<0.05). Results and Discussion. We identified 3048 patients who received 154,161 drug prescriptions (42,120 contained warfarin). The mean age was 55.8 (±19.3) years, 53.2% female, prevalence of elderly (48.1%) and other cerebrovascular diseases specific diagnosis (4.3%). The average values of international normalized ratio (INR) (2.4±1.7) and warfarin dose (5.1±1.8mg) were within those recommended by therapeutic protocols. It was observed that 66.4% of patients received polypharmacy, which can raise the risk of DDI. In addition, 63.2% of patients had prescription(s) of drugs classified as D or X risk, with an average of 1.4 (±0.4) drugs per prescription, especially aspirin and amiodarone. Compared study group (n=429) versus control (n =2619), there was a statistically significant difference in mean age (years) (59.0±18.8 vs. 55.5±19.3; p<0.000), average number of medications/prescriptions (7.1±2.8 vs. 6.2±2.8; p<0.000), mean number of drugs with risk D and X DDI/prescription (1.4±1.3 vs. 1.0±1.0, p<0.000), serum albumin (g/dL) (3.4±0.6 vs. 3.7±0.6; p<0.000), aspartate aminotransferases (U/L) (60.7±200.6 vs. 41.5±84.5; p<0.005) and INR (4.9±3.4 vs. 2.1±0.7; p<0.000), factors that may have contributed to the occurrence of ADR in the study group. Conclusion. There was a high occurrence of possible DDI and ADR in patients treated with warfarin, which may compromise the effectiveness and safety of pharmacological treatment. Noteworthy is the high values of age, number of medications/prescriptions, prescription drugs classified as risk D or X, INR and aspartate aminotransferases, and lower values of serum albumin as potential risk factors for the occurrence of ADR.

Introdução: Especula-se que exista uma possível relação entre a ingestão de vitamina K e a diminuição da gordura corporal. Além disso, embora os resultados permaneçam controversos, há um número crescente de estudos que apoiam um papel chave dessa vitamina na melhora do perfil lipídico, da sensibilidade à insulina e na redução do risco de diabetes mellitus tipo 2, contudo pouco se sabe sobre quais mecanismos estariam envolvidos. Objetivo: Investigar as relações entre a ingestão de vitamina K (na forma de filoquinona - PK), gordura corporal, perfil lipídico e marcadores da homeostase da glicose em adultos e idosos. Métodos: Estudo transversal com 298 indivíduos de ambos os sexos, participantes do inquérito ISA - Capital 2015. Amostras de sangue foram coletadas para determinação do perfil lipídico, glicemia de jejum e concentrações de insulina; e índice de estimativa de resistência à insulina (HOMAIR), índice de estimativa da função de células &#946;-pancreáticas (HOMA-&#946;) e índice de estimativa da sensibilidade à insulina (QUICKI) foram calculados. A ingestão de vitamina K foi avaliada por meio de um recordatório alimentar de 24hrs (repetido em 75% da amostra), e a investigação quantitativa da massa gorda foi conduzida por meio da absorciometria de feixe duplo (DXA). Indivíduos com ingestão de vitamina K inferior aos valores de AI foram divididos em subgrupos de acordo com o estado nutricional e faixa etária. Foi realizada a Correlação de Spearman em grupos estratificados de acordo com o Índice de Massa Corporal (IMC) e com o Índice de Gordura Corporal (IGC). Para avaliar as associações entre a ingestão de vitamina K e cada uma das medidas bioquímicas e de adiposidade, foi realizada a regressão linear múltipla. Resultados: Dentre os avaliados, 46% eram do sexo masculino (n=136), com idade mediana de 61 anos (20 - 94 anos), e 56,4% apresentavam sobrepeso ou obesidade (n=168). A mediana de ingestão de vitamina K foi de 102,7 &#956;g, ou 59,9 &#956;g,/1000 kcal, sem diferença de acordo com sexo ou idade. A ingestão de vitamina K apresentou correlação negativa com o HOMA-IR (r = -0,603; p = 0,0134) e correlação positiva com QUICKI (r = 0,603; p = 0,0134) entre os adultos eutróficos do sexo masculino (n = 16). Em idosas com baixo peso (n = 12), a ingestão de vitamina K foi negativamente correlacionada com o Colesterol Total (CT) (r = -0,644; p = 0,0443). Entre as mulheres com elevado IGC e ingestão de vitamina K inferior aos valores de AI (n = 117), foram observadas correlações negativas entre a ingestão de vitamina K e HOMA-IR (r = -0,187; p = 0,0451) e correlações positivas com QUICKI (r = 0,187; p = 0,0451). Conclusões: Os resultados encontrados sugerem uma possível relação entre a ingestão dietética de filoquinona, gordura corporal, perfil lipídico e marcadores da homeostase da glicose, em amostra de adultos e idosos. / Introduction: Recent research have investigated a possible inverse relationship between vitamin K intake and body fat. In addition, although the results remain controversial, there is an increasing number of studies supporting a key role of this vitamin in improving lipid profile, insulin sensitivity and reducing the risk of type 2 diabetes mellitus, but little is known about what mechanisms would be involved. Objective: To investigate the relationship between vitamin K intake (in the form of phylloquinone - PK), body fat, lipid profile and markers of glucose homeostasis in adults and elderly. Methods: Cross-sectional study with 298 individuals of both sexes, participants in the ISA - Capital 2015 survey. Blood samples were collected for determination of lipid profile, fasting glycemia and insulin concentrations, and homeostasis model assesment estimate for insulin resistance (HOMA-IR), homeostasis model assessment estimate for &#946;-cell function (HOMA-&#946;) and the quantitative insulin sensitivity check index (QUICKI) were calculate accordingly. Vitamin K intake was assessed by a 24-hour dietary recall (repeated in 75% of the sample) and quantitative investigation of fat mass was conducted using dual-energy x-ray absorptiometry (DXA). Subjects with vitamin K intake lower than AI values were divided into subgroups according to nutritional status and age group. Spearman correlation was performed in stratified groups according to Body Mass Index (BMI) and Fat Mass Index (FMI). To evaluate the associations between vitamin K intake and each of the biochemical and adiposity measures, multiple linear regression were performed. Results: Among the sample, 46% were male (n = 136), with a median age of 61 years (20 - 94 years), and 56.4% were overweight or obese (n= 168). The median vitamin K intake was 102.7 &#956;g, or 59.9 &#956;g, / 1000 kcal, with no difference according to sex or age. Vitamin K intake presented negative correlation with HOMA-IR (r = -0.603; p = 0.0134) and positive correlation with QUICKI (r = 0.603; p=0.0134) among normal weight male adults (n=16). In underweight elderly women (n=12), vitamin K intake was negatively correlated with total cholesterol (TC) (r = -0.644, p = 0.0443). Among females with high FMI and vitamin K intake lower than AI values (n=117), vitamin K intake was negatively correlated with HOMA-IR (r = -0.187; p = 0.0451) and positively correlated with QUICKI (r 12 = 0.187; p = 0.0451). Conclusions: Results suggest a possible relationship between dietary intake of phylloquinone, body fat, lipid profile and glucose homeostasis, among a sample of adults and elderly.

VKORC1 est une enzyme membranaire du réticulum endoplasmique, responsable de la réduction de la vitamine K époxyde en vitamine K quinone, activant la synthèse des facteurs de coagulation. VKORC1 constitue ainsi une cible thérapeutique privilégiée des anticoagulants de type anti-vitamine K (AVKs). Cependant, certaines mutations de VKORC1 induisent une dérégulation physiologique et/ou une résistance aux AVKs. En l’absence de données structurales, plusieurs modèles topologiques de VKORC1 ont été proposés à partir des données biochimiques et biophysiques, fréquemment contradictoires. La topologie de VKORC1 ainsi que l'implication des résidus de cystéine (strictement conservés chez toutes les VKORs) dans le mécanisme enzymatique de la protéine restent incertaines. Nous avons construit, par des méthodes in silico, un modèle 3D de la VKORC1 humaine sauvage (hVKORC1WT) à l'échelle atomique. Des simulations de dynamique moléculaire de la protéine, en considérant tous les résidus de cystéine sous leur forme oxydée (SH), nous ont permis d'identifier les résidus de cystéine les plus susceptibles de former des ponts disulfures. Nous avons par conséquent décrit les conformations métastables de hVKORC1WT mimant les états fonctionnels de la protéine. L’étude de la reconnaissance des formes époxyde et réduites de la vitamine K par les conformations prédites de hVKORC1WT a mis en évidence leur sélectivité réciproque. Les conformations de hVKORC1WT ciblées par chaque forme de la vitamine K et leur rôle dans le mécanisme de réduction de la molécule ont ainsi été caractérisés. Nous avons postulé à partir de ces résultats le mécanisme enzymatique détaillé de hVKORC1WT et proposé la structure-cible des AVKs. Les interactions entre la cible prédite - hVKORC1WT à l'état actif - et trois AVKs différents ont été décrites en termes d’énergie libre de liaison. Ces résultats ont été corrélés avec les constantes d'inhibition mesurées in vivo, validant nos prédictions théoriques. Notre protocole, développé pour hVKORC1WT, est applicable aux formes mutées de l’enzyme. Il permettra la description des mécanismes modifiant l'activité réductase de hVKORC1 et/ou provoquant une résistance aux AVKs. Cette description ouvre la voie à la conception d'une nouvelle génération d'inhibiteurs surmontant les résistances aux AVKs. Notre concept et le protocole établi pour l’étude de hVKORC1 peuvent être étendus à l'analyse des VKORs mammaliennes et aux autres enzymes de la famille des oxydoréductases. / VKORC1 is an endoplasmic reticulum membrane-resident enzyme, responsible for vitamin K epoxide reduction to vitamin K quinone that activates coagulation factors synthesis. VKORC1 is thus a prominent target of vitamin K agonists (VKAs) in anticoagulant therapies. However, some VKORC1 mutations lead to physiological dysregulation and/or VKAs resistance. No VKORC1 structural data is available, and postulated topological models are based on biochemical and biophysical experimental observations frequently contradicting. Topology of VKORC1 and involvement of cysteines residues (highly conserved in VKORs) in the protein enzymatic mechanism remain unclear. We built an in silico 3D model of the wild-type human VKORC1 (hVKORC1WT) at the atomistic scale. Molecular dynamics simulations of the protein model, carrying all the cysteines residues in their oxidized form (SH), were used for identification of cysteines residues which may plausibly form disulfide bridges. We thus described hVKORC1WT metastable conformations depicting the functionally relevant states of protein. Study of the vitamin K (in epoxide and in reduced forms) recognition by the predicted conformations of hVKORC1WT revealed their reciprocal selectivity. The hVKORC1WT conformations targeted by each vitamin K form were established and their role in the reduction mechanism of this molecule was explained. Using our results, we postulated the comprehensive enzymatic mechanism of hVKORC1WT and we proposed the 3D structure as the VKAs target. Interactions between the predicted target - hVKORC1WT active state - and three different VKAs were characterized. The obtained affinities (free binding energy) were in good correlation with in vivo measured inhibition constants (Ki), thus validating our theoretical predictions. Our protocol developed for hVKORC1WT is suitable for a study of its mutants. Description of the enzymatic mechanisms of mutated hVKORC1 will lead to understanding of the modified reductase activity or/and to explaining of its resistance to VKAs. Such data are crucial for the development of novel strategies in the design of a new generation of inhibitors overcoming VKAs resistance. Our concept and the established in silico protocol can be extended to analysis of mammalian VKORs and other oxidoreductases family proteins.

Anticoagulants, also known as antithrombotics, are among the most commonly prescribed medications in the United States. Understanding how these medications work, the propensity for interactions with other drugs, dietary factors, and disease states is important for clinicians assessing and providing care to patients in all environments. In this review, we seek to provide essential information for the home health care provider for evaluating patients receiving anticoagulants commonly prescribed in the home health care setting. The low-molecular-weight heparins and vitamin K antagonists are the most commonly used agents for outpatient anticoagulation. New agents, such as the direct factor Xa inhibitors and direct thrombin inhibitors have recently been approved with additional new agents in the approval process and development pipeline. We seek to review the most pertinent information for each of these classes of medications providing information on pharmacology, interactions with other drugs, diet, and diseases and important clinical information.

Purpose. The use of antiplatelet agents in patients hospitalized with ischemic stroke was studied. Methods. Patients with a primary or secondary diagnosis of noncardiogenic, thrombotic ischemic stroke from January 2002 through December 2004 were included in the analysis. Patients were then subdivided into four treatment groups and one no-treatment group based on whether they were charged for any of four antiplatelet regimens (low-dose aspirin [≤325 mg daily], extended-release dipyridamole 200 mg with aspirin 25 mg, clopidogrel 75 mg, and clopidogrel 75 mg [as the bisulfate] plus low-dose aspirin) at any time during hospitalization. Patients who did not receive any of these medications during hospitalization were defined as the no-treatment group. A patient's illness severity was measured and compared with other patients in the data set. Results. A total of 44,108 patients were assigned to the treatment group, and 14,255 patients were assigned to the no-treatment group. In general, longer lengths of stay and higher institutional costs were associated with the no-treatment group. Patients in the no-treatment group consistently displayed more comorbid conditions than did patients in the treatment group. The no-treatment group exhibited higher usage rates of both fibrinolytic agents and vitamin K. More patients in the treatment group were discharged to home or rehabilitation, while more patients in the no-treatment group were either discharged to another nursing facility or died before discharge. Conclusion. A retrospective analysis of a large national hospital database revealed that one quarter of patients who suffered an acute stroke did not receive antiplatelet drugs during their patient stay. Outcomes for such patients were poorer than for patients who had received antiplatelet therapy.

BACKGROUND:Anticoagulation with vitamin K antagonists such as warfarin has historically been used for the long term management of patients with thromboembolic disease. However, these agents have a slow onset of action which requires bridging therapy with heparin and its analogues, which are available only in parenteral route. To overcome these limitations, new oral anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors have been developed. The aim of this article is to systematically review the phase 3 clinical trials of new oral anticoagulants in common medical conditions.METHODS:We searched PubMed (Medline) from January 2007 to February 2013 using "Oral anticoagulants", "New oral anticoagulants", "Randomized controlled trial", "Novel anticoagulants", "Apixaban", "Rivaroxaban", "Edoxaban", "Dabigatran etexilate", "Dabigatran" and a combination of the above terms. The available evidence from the phase 3 RCTs was summarized on the basis of individual drug and the medical conditions categorized into "atrial fibrillation", "acute coronary syndrome", "orthopedic surgery", "venous thromboembolism" and "medically ill patients".RESULTS:Apixaban, rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk, superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding, non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed. Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism. However, compared to enoxaparin, apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients. Additional studies evaluating the specific reversal agents of these new drugs for the management of life-threatening bleeding or other adverse effects are necessary.CONCLUSION:Considering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.

La Vitamine K (VK) est largement reconnue pour son rôle dans la coagulation sanguine toutefois, de plus en plus de travaux indiquent son implication dans la fonction cérébrale. La VK est requise pour l'activation de différentes protéines, par exemple la protéine Gas6, et la ménaquinone-4 (MK-4), le principal vitamère K dans le cerveau, est impliquée dans le métabolisme des sphingolipides. Dans un rapport précédent, nous avons montré qu'un régime alimentaire faible en VK tout au long de la vie était associé à des déficits cognitifs chez des rats âgés. La warfarine sodique est un puissant antagoniste de la VK qui agit en bloquant le cycle de la VK, provoquant un «déficit relatif de VK » au niveau cellulaire. À la lumière du rôle émergent de la VK dans le cerveau, la warfarine pourrait représenter un facteur de risque pour la fonction cérébrale. Ce travail est donc pertinente en raison de la forte proportion d'adultes traîtés à la warfarine sodique. Dans la présente étude, 14 rats mâles Wistar ont été traités avec 14 mg de warfarine/kg /jour (dans l'eau potable) et des injections sous-cutanées de VK (85 mg/kg), 3x/sem, pendant 10 semaines. Quatorze rats témoins ont été traités avec de l'eau normale et injectés avec une solution saline. Les rats ont été soumis à différents tests comportementaux après quoi les niveaux de phylloquinone, MK-4, sphingolipides (cérébroside, sulfatide, sphingomyéline, céramide et gangliosides), et les sous-types de gangliosides (GT1b, GD1a, GM1, GD1b), ont été évalués dans différentes régions du cerveau. Comparativement aux rats du groupe contrôle, les rats traités à la warfarine présentaient des latences plus longues au test de la piscine de Morris (p <0,05) ainsi qu'une hypoactivité et un comportement exploratoire plus faible au test de « l’open field » (p <0,05). Le traitement par warfarine a également entraîné une diminution spectaculaire du niveau de MK-4 dans toutes les régions du cerveau (p <0,001), une altération des concentrations de sphingolipidiques, en particulier dans le cortex frontal et le mésencéphale (p <0,05), et une perte de différences régionales sphingolipidiques, notamment pour les gangliosides. Le traitement par warfarine a été associé à un niveau inférieur de GD1a dans l'hippocampe et un niveau supérieur de GT1b dans le cortex préfrontal et le striatum. En conclusion, la déficience en VK induite par warfarine altère les niveaux de VK et sphingolipides dans le cerveau, avec de potentiels effets néfastes sur les fonctions cérébrales. / Vitamin K (VK) is widely known for its role in blood coagulation, however many studies suggest its involvement in brain function. VK is required for the activation of various cerebral proteins (e.g., Gas6) and menaquinone-4 (MK-4), the main K vitamer in brain, is involved in sphingolipid metabolism. Furthermore, life-long intake of a low VK diet has been associated with cognitive deficits in old rats. Warfarin (W) is a potent VK antagonist that acts by blocking the VK cycle causing a “relative VK deficiency” at the cellular level. In light of this and the emerging role of VK in brain, W could represent a risk factor for cerebral function. The finding of this study is important according to the large proportion of adults with thromboembolic diseases being treated with warfarin drugs. This study was conducted in a rat model where the impact of W was investigated with respect to cognition, behavior, and brain menaquinone-4 (MK-4) and sphingolipid status. Fourteen Wistar male rats were treated with 15 mg W/kg/d (in drinking water) and subcutaneous VK (85 mg/kg), 3X/wk, for 10 wks; 14 control rats were treated with normal water and injected with saline. At the end of the treatment period, rats were subjected to different behavioral tests, afterwhich their brains assessed for VK (phylloquinone and MK-4) and sphingolipids (gangliosides, ceramides, cerebrosides, sphingomyelin and sulfatides) and gangliosides subtypes (GT1b, GD1a, GM1, GD1b). Mean latencies to find the hidden platform were higher in the W compared to the control group (p<0.05) suggesting cognitive deficits as well as hypoactivity and lower exploratory behaviour in the open field test (p<0.05). Warfarin treatment also resulted in a dramatic decrease in MK-4 concentration in all brain regions (p<0.001), altered sphingolipid level, especially in frontal cortex and midbrain (p<0.05), and in a loss of sphingolipid regional differences, notably for gangliosides. W treatment was associated with lower GD1a in the hippocampus and higher GT1b in the striatum and prefrontal cortex. In conclusion, warfarin-induced VK deficiency alters VK and sphingolipid status in brain with potential detrimental effects on brain functions.

La Vitamine K (VK) est largement reconnue pour son rôle dans la coagulation sanguine toutefois, de plus en plus de travaux indiquent son implication dans la fonction cérébrale. La VK est requise pour l'activation de différentes protéines, par exemple la protéine Gas6, et la ménaquinone-4 (MK-4), le principal vitamère K dans le cerveau, est impliquée dans le métabolisme des sphingolipides. Dans un rapport précédent, nous avons montré qu'un régime alimentaire faible en VK tout au long de la vie était associé à des déficits cognitifs chez des rats âgés. La warfarine sodique est un puissant antagoniste de la VK qui agit en bloquant le cycle de la VK, provoquant un «déficit relatif de VK » au niveau cellulaire. À la lumière du rôle émergent de la VK dans le cerveau, la warfarine pourrait représenter un facteur de risque pour la fonction cérébrale. Ce travail est donc pertinente en raison de la forte proportion d'adultes traîtés à la warfarine sodique. Dans la présente étude, 14 rats mâles Wistar ont été traités avec 14 mg de warfarine/kg /jour (dans l'eau potable) et des injections sous-cutanées de VK (85 mg/kg), 3x/sem, pendant 10 semaines. Quatorze rats témoins ont été traités avec de l'eau normale et injectés avec une solution saline. Les rats ont été soumis à différents tests comportementaux après quoi les niveaux de phylloquinone, MK-4, sphingolipides (cérébroside, sulfatide, sphingomyéline, céramide et gangliosides), et les sous-types de gangliosides (GT1b, GD1a, GM1, GD1b), ont été évalués dans différentes régions du cerveau. Comparativement aux rats du groupe contrôle, les rats traités à la warfarine présentaient des latences plus longues au test de la piscine de Morris (p <0,05) ainsi qu'une hypoactivité et un comportement exploratoire plus faible au test de « l’open field » (p <0,05). Le traitement par warfarine a également entraîné une diminution spectaculaire du niveau de MK-4 dans toutes les régions du cerveau (p <0,001), une altération des concentrations de sphingolipidiques, en particulier dans le cortex frontal et le mésencéphale (p <0,05), et une perte de différences régionales sphingolipidiques, notamment pour les gangliosides. Le traitement par warfarine a été associé à un niveau inférieur de GD1a dans l'hippocampe et un niveau supérieur de GT1b dans le cortex préfrontal et le striatum. En conclusion, la déficience en VK induite par warfarine altère les niveaux de VK et sphingolipides dans le cerveau, avec de potentiels effets néfastes sur les fonctions cérébrales. / Vitamin K (VK) is widely known for its role in blood coagulation, however many studies suggest its involvement in brain function. VK is required for the activation of various cerebral proteins (e.g., Gas6) and menaquinone-4 (MK-4), the main K vitamer in brain, is involved in sphingolipid metabolism. Furthermore, life-long intake of a low VK diet has been associated with cognitive deficits in old rats. Warfarin (W) is a potent VK antagonist that acts by blocking the VK cycle causing a “relative VK deficiency” at the cellular level. In light of this and the emerging role of VK in brain, W could represent a risk factor for cerebral function. The finding of this study is important according to the large proportion of adults with thromboembolic diseases being treated with warfarin drugs. This study was conducted in a rat model where the impact of W was investigated with respect to cognition, behavior, and brain menaquinone-4 (MK-4) and sphingolipid status. Fourteen Wistar male rats were treated with 15 mg W/kg/d (in drinking water) and subcutaneous VK (85 mg/kg), 3X/wk, for 10 wks; 14 control rats were treated with normal water and injected with saline. At the end of the treatment period, rats were subjected to different behavioral tests, afterwhich their brains assessed for VK (phylloquinone and MK-4) and sphingolipids (gangliosides, ceramides, cerebrosides, sphingomyelin and sulfatides) and gangliosides subtypes (GT1b, GD1a, GM1, GD1b). Mean latencies to find the hidden platform were higher in the W compared to the control group (p<0.05) suggesting cognitive deficits as well as hypoactivity and lower exploratory behaviour in the open field test (p<0.05). Warfarin treatment also resulted in a dramatic decrease in MK-4 concentration in all brain regions (p<0.001), altered sphingolipid level, especially in frontal cortex and midbrain (p<0.05), and in a loss of sphingolipid regional differences, notably for gangliosides. W treatment was associated with lower GD1a in the hippocampus and higher GT1b in the striatum and prefrontal cortex. In conclusion, warfarin-induced VK deficiency alters VK and sphingolipid status in brain with potential detrimental effects on brain functions.