Warfarin drug interaction with vitamin K and other foodstuffs / Interacción de la droga warfarina con la vitamina K y otros productos alimenticios

Vitamin K is found in higher concentrations in dark green plant and in vegetable oils. The adequate intake of vitamin K is 90 and 120ug/day for adult elderly men and women, respectively. The main function of vitamin K is to act as an enzymatic cofactor for hepatic prothrombin synthesis, blood coagulation factors, and anticoagulant proteins. Prominent among the many available anticoagulants is warfarin, an antagonist of vitamin K, which exerts its anticoagulant effects by inhibiting the synthesis of vitamin K1 and vitamin KH2. From the beginning of the therapy it is necessary that the patients carry out the monitoring through the prothrombin time and the international normalized ratio. However, it is known that very low intake and/or fluctuations in vitamin K intake are as harmful as high consumption. In addition, other foods can interact with warfarin, despite their content of vitamin K. The aim of this study was to gather information on the drug interaction of warfarin with vitamin K and with dietary supplements and other foods.

La vitamina K se encuentra en concentraciones más altas en plantas de color verde oscuro y en aceites vegetales. La ingesta adecuada de vitamina K es de 90 y 120 ug/día para hombres y mujeres adultos mayores, respectivamente. La función principal de la vitamina K es actuar como un cofactor enzimático para la síntesis de protrombina hepática, factores de coagulación de la sangre y proteínas anticoagulantes. Entre los muchos anticoagulantes disponibles destaca la warfarina, un antagonista de la vitamina K, que ejerce sus efectos anticoagulantes al inhibir la síntesis de la vitamina K1 y la vitamina KH2. Desde el inicio de la terapia, es necesario que los pacientes realicen el monitoreo a través del tiempo de protrombina y la proporción normalizada internacional. Sin embargo, se sabe que una ingesta muy baja y/o fluctuaciones en la ingesta de vitamina K son tan dañinas como un consumo alto. Además, otros alimentos pueden interactuar con la warfarina, a pesar de su contenido de vitamina K. El objetivo de este estudio fue recopilar información sobre la interacción de los medicamentos de la warfarina con la vitamina K y con los suplementos dietéticos y otros alimentos.

Warfarin Safety: A Cross-Sectional Study of the Factors Associated with the Consumption of Medicinal Plants in a Brazilian Anticoagulation Clinic.

OBJECTIVE: The aim of this study was to analyze factors associated with the consumption of medicinal plants by patients being treated with warfarin in a Brazilian anticoagulation clinic and to study the safety of medicinal plant use in patients on warfarin therapy. METHODS: The study was performed as an observational cross-sectional analysis. Study participants were outpatients on long-term warfarin therapy for at least 2 months for atrial fibrillation or prosthetic cardiac valves. Interviews were carried out concerning information about the habits of medicinal herb consumption, and logistic regression analysis was performed to identify factors associated with the consumption of herbs. The scientific names of the medicinal plants were identified to search for information on the effects on the hemostasis of the interactions between the medicinal herbs reported and warfarin. RESULTS: The mean age of the 273 patients included was 60.8 years; 58.7% were women. Medicinal plants were used by 67% of the participants. No association between demographic and clinical data and the use of medicinal plants was identified. Patients reported a total of 64 different plants, primarily consumed in the form of tea. The plants were mainly used to treat respiratory tract and central nervous system disorders. About 40% of the plants cited have been reported to potentially interfere with the anticoagulation therapy, principally by potentiating the effects of warfarin, which could, increase the risk of bleeding. CONCLUSION: The use of medicinal plants was highly common and widespread in patients receiving warfarin as an anticoagulation therapy. Univariate analysis of variables associated with the consumption of herbs showed no statistically significant difference in the consumption of medicinal plants for any of the sociodemographic and clinical data. The medicinal plants that were reportedly consumed by the patients could affect hemostasis. This study reinforces the need for further studies evaluating the habits of patients consuming medicinal plants and their clinical implications, and will help to design strategies to manage the risks associated with warfarin-herbal interactions.

Study of warfarin utilization in hospitalized patients: analysis of possible drug interactions.

Background Drug-drug interactions in patients taking warfarin may contribute to a higher risk of adverse events. Objective To identify and evaluate the prevalence and characteristics of potential DDIs with warfarin. Methods A cross-sectional study was performed in a Brazilian tertiary hospital. The electronic prescriptions of the patients receiving warfarin between January 2004 and December 2010 were analyzed. Socio-demographic, clinical, and therapeutic variables were collected. Warfarin drug-drug interactions were classified as either risk A, B, C, D, or X according to the Lexi-Interact™ Online database. Results A total of 3048 patients were identified who were prescribed warfarin. Of the 154,161 total drug prescriptions issued, 42,120 (27.3 %) were for warfarin. Evaluation of the prescriptions showed that 63.1 and 0.1 % of patients received concomitant drugs classified as having class D or X risk. It was found that 20,539 (48.7 %) prescriptions had at least one drug with a D or X risk. Patients were prescribed an average of 1.4 (±0.4) concomitant medications with a class D or X warfarin-DDI risk, the most frequent being acetylsalicylic acid and amiodarone. Conclusion The results demonstrate a high prevalence of concomitant drug prescriptions with the potential for clinically relevant DDIs with warfarin, the most frequent being acetylsalicylic acid and amiodarone.

Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics.

Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. We determined the frequencies of alleles, single carriers, and double carriers of single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes in a Puerto Rican cohort and gauged the impact of these polymorphisms on warfarin dosage using a published algorithm. A total of 92 DNA samples were genotyped using Luminex x-MAP technology. The polymorphism frequencies were 6.52%, 5.43% and 28.8% for CYP2C9 *2, *3 and VKORC1-1639 C>A polymorphisms, respectively. The prevalence of combinatorial genotypes was 16% for carriers of both the CYP2C9 and VKORC1 polymorphisms, 9% for carriers of CYP2C9 polymorphisms, 35% for carriers of the VKORC1 polymorphism, and the remaining 40% were non-carriers for either gene. Based on a published warfarin dosing algorithm, single, double and triple carriers of functionally deficient polymorphisms predict reductions of 1.0-1.6, 2.0-2.9, and 2.9-3.7 mg/day, respectively, in warfarin dose. Overall, 60% of the population carried at least a single polymorphism predicting deficient warfarin metabolism or responsiveness and 13% were double carriers with polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin among patients with gene polymorphisms, potentially reducing the risk of stroke or bleeding.

Respuesta terapéutica inadecuada a la warfarina en un paciente genéticamente susceptible / Inadequate therapeutic response to warfarin in a patient genetically warfarin-sensitive

La warfarina es uno de los anticoagulantes orales más usados en la terapéutica médica, cuya dosificación requiere un monitoreo serológico (INR: International Normalized Ratio) debido a su rango terapéutico estrecho y la potencial gravedad de sus efectos adversos. La enzima codificada por el gene CYP2C9 es el principal metabolizador de la warfarina. Se ha determinado la existencia de dos variantes de este gene, relativamente frecuentes en la población, que determinan un fenotipo metabolizador lento. Los portadores de estos alelos variantes requieren dosis menores de warfarina para lograr la anticoagulación y están expuestos a mayor riesgo de sangrado durante la anticoagulación oral con este fármaco. Se describe el caso clínico de un paciente que estando bajo tratamiento profiláctico con warfarina sufre un aumento disparado del INR y un episodio de hematuria. Se analizó el genotipo del paciente demostrándose que era homocigoto para uno de estos alelos variantes (genotipo: CYP2C9 *3/*3). Se discuten las aplicaciones de la farmacogenética en el manejo clínico de estos pacientes y la prevención de los efectos adversos de un fármaco con un rango terapéutico estrecho. (AU)

Use of retinoic acid as a fluorescent probe to study conformational change of the albumin molecule.

The binding of retinoic acid to serum albumin induces quenching of the protein fluorescence when it is excited at 280 nm, on the other hand the bound ligand acquires intrinsic fluorescence. Albumin has two kinds of binding sites for retinoic acid with an affinity constant of 10(5) M-1 and 10(4) M-1 respectively. The binding is entropically driven and produces a conformational change at the environment of the albumin tryptophan residues. This change was described by an equilibrium constant assuming two conformational states of the albumin tryptophan residues. Retinoic acid binds to the albumin fatty acid binding sites, producing a perturbation in the warfarin and benzodiazepine binding sites of this protein.