RESUMEN
BACKGROUND: A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5-fluorouracil (5-FU). Capecitabine and its metabolites are highly water-soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patients with a low SMM could be changed, for example, by reaching higher maximum plasma concentrations. In this study, we aimed to examine whether the association between a low SMM and increased toxicity and shorter survival could be explained by altered PK of capecitabine and its metabolites. METHODS: Previously, a population PK model of capecitabine and metabolites in patients with solid tumors was developed. In our analysis, we included patients from this previous analysis for which evaluable abdominal computed tomography (CT)-scans were available. SMM was measured on CT-scans, by single slice evaluation at the third lumbar vertebra, using the Slice-o-Matic software. The previously developed population PK model was extended with SMM as a covariate, to assess the association between SMM and capecitabine and metabolite PK. RESULTS: PK and SMM data were available from 151 cancer patients with solid tumors. From the included patients, 55% had a low SMM. No relevant relationships were found between SMM and the PK parameters of capecitabine and, the active and toxic metabolite, 5-FU. SMM only correlated with the PK of the, most hydrophilic, but inactive and non-toxic, metabolite α-fluoro-ß-alanine (FBAL). Patients with a low SMM had a smaller apparent volume of distribution and lower apparent clearance of FBAL. CONCLUSIONS: No alterations in PK of capecitabine and the active and toxic metabolite 5-FU were observed in patients with a low SMM. Therefore, the previously identified increased toxicity and shorter survival in patients with a low SMM, could not be explained by changes in pharmacokinetic characteristics of capecitabine and metabolites.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Femenino , Fluorouracilo/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/farmacocinética , Factores Sexuales , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinéticaRESUMEN
Genomic imprinting, an epigenetic phenomenon that causes the expression of a small set of genes in a parent-of-origin-specific manner, is thought to have co-evolved with placentation. Many imprinted genes are expressed in the placenta, where they play diverse roles related to development and nutrient supply function. However, only a small number of imprinted genes have been functionally tested for a role in nutrient transfer capacity in relation to the structural characteristics of the exchange labyrinthine zone. Here, we examine the transfer capacity in a mouse model deficient for the maternally expressed Phlda2 gene, which results in placental overgrowth and a transient reduction in fetal growth. Using stereology, we show that the morphology of the labyrinthine zone in Phlda2-/+ mutants is normal at E16 and E19. In vivo placental transfer of radiolabeled solutes 14C-methyl-D-glucose and 14C-MeAIB remains unaffected at both gestational time points. However, placental passive permeability, as measured using two inert hydrophilic solutes (14C-mannitol; 14C-inulin), is significantly higher in mutants. Importantly, this increase in passive permeability is associated with fetal catch-up growth. Our findings uncover a key role played by the imprinted Phlda2 gene in modifying placental passive permeability that may be important for determining fetal growth.
Asunto(s)
Intercambio Materno-Fetal , Proteínas Nucleares/genética , Placenta/metabolismo , 3-O-Metilglucosa/farmacocinética , Animales , Femenino , Eliminación de Gen , Impresión Genómica , Inulina/farmacocinética , Manitol/farmacocinética , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismo , Embarazo , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinéticaRESUMEN
PURPOSE: To investigate corneal clearance time using a topical rho-kinase inhibitor, netarsudil, after descemetorhexis without endothelial keratoplasty (DWEK). METHODS: Twenty eyes from 10 patients with Fuchs endothelial corneal dystrophy had DWEK with cataract surgery. For the first eye of each participant, netarsudil was administered immediately after surgery until corneal clearance. For the second eye, netarsudil was withheld 2 weeks beyond the time for corneal clearance of the first eye and then administered only if corneal edema was still present. Interpatient and intrapatient comparisons were made for pachymetry, endothelial cell count, intraocular pressure, and time to corneal clearance. RESULTS: Intrapatient comparison demonstrated no significant difference in preoperative pachymetry (P value 0.58), endothelial cell counts (P value 0.97), and intraocular pressure (P value 0.46) between eyes treated with netarsudil immediately after DWEK and those with delayed netarsudil use. Average time for corneal clearance in eyes treated with netarsudil immediately after surgery was 4.6 ± 1.7 weeks, which was significantly shorter than eyes not treated with netarsudil immediately at 8 ± 1.9 weeks (P < 0.01). Corneal clearance occurred in eyes between 1 and 2 weeks after addition of netarsudil as a "rescue" drop. Interpatient comparison demonstrated significantly greater endothelial cell counts in eyes treated with netarsudil immediately compared with eyes with a delay in netarsudil use (P = 0.05). CONCLUSIONS: Netarsudil significantly reduces the time to corneal clearance after DWEK. Furthermore, increased endothelial cell counts in eyes with immediate netarsudil use versus delayed netarsudil use suggests that the immediate perioperative period is crucial in cell regeneration and migration.
Asunto(s)
Benzoatos/farmacocinética , Córnea/metabolismo , Lámina Limitante Posterior/cirugía , Queratoplastia Endotelial de la Lámina Limitante Posterior , Distrofia Endotelial de Fuchs/cirugía , Inhibidores de Proteínas Quinasas/farmacocinética , beta-Alanina/análogos & derivados , Administración Oftálmica , Anciano , Anciano de 80 o más Años , Paquimetría Corneal , Lámina Limitante Posterior/metabolismo , Femenino , Distrofia Endotelial de Fuchs/metabolismo , Humanos , Presión Intraocular , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas , Proyectos Piloto , Tonometría Ocular , Agudeza Visual , beta-Alanina/farmacocinética , Quinasas Asociadas a rho/antagonistas & inhibidoresRESUMEN
Personalised dosing of performance-enhancing food supplements is a hot topic. ß-alanine is currently dosed using a fixed dose; however, evidence suggests that this might favour light compared to heavy subjects. A weight-relative dose seems to reverse this problem. In the present study, a novel dosing strategy was tested. A fragmented dose, composed of a fixed fragment of 800 mg and a weight-relative fragment of 10 mg/kg body weight, was compared to a fixed dose of 1600 mg and a weight-relative dose of 20 mg/kg body weight in a cohort of 20 subjects with a body weight ranging 48-139 kg (79.9 ± 24.4 kg). The results show that, following a fragmented dose, the influence of body weight on the pharmacokinetic response (iAUC) over a 210 min period was absent (r = -0.168; p = 0.478), in contrast to the fixed or weight-relative dose. The pharmacokinetic response also seemed more homogenous (CV% = 26%) following a fragmented dose compared to the fixed (33%) and the weight-relative dose (31%). The primary advantage of the easy-to-calculate fragmented dosing strategy is that it does not systematically favour or impair a certain weight group. Thorough dosage studies are lacking in the current field of sports and food supplements, therefore similar considerations can be made towards other (ergogenic) food supplements.
Asunto(s)
Peso Corporal , Sustancias para Mejorar el Rendimiento/farmacocinética , beta-Alanina/administración & dosificación , beta-Alanina/farmacocinética , Adulto , Carnosina/análisis , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based ß-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10â¯mg/kg.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Indazoles/química , Receptores de Glucagón/antagonistas & inhibidores , beta-Alanina/síntesis química , Secuencia de Aminoácidos , Animales , Glucemia/efectos de los fármacos , Metabolismo de los Hidratos de Carbono , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Hipoglucemiantes/farmacocinética , Hígado/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Unión Proteica , Ratas , Relación Estructura-Actividad , beta-Alanina/farmacocinéticaRESUMEN
Drawing on previously published data, a mathematical model is proposed to describe the synthesis of carnosine in muscle using a slow release ß-alanine supplement (SR-CarnoSyn®). The model pre-supposes that the rate of synthesis for any given dose of ß-alanine (within the range 1.6-6.4 g day-1) is constant with time, but is first order with respect to daily ß-alanine dose. Simultaneously with synthesis, decay in carnosine is also assumed to be occurring, the rate in this case being a function of the concentration of carnosine. Decay in carnosine appears describable by first-order kinetics. By integration of the two rate reactions, a single mathematical equation was derived to describe the synthesis of carnosine and which closely fitted the experimental data over 56 days. The model, if validated by additional studies, could be used to compliment empirical observations of the changes in carnosine in muscle with supplementation, and allow objective examination of a number of possible influences affecting the rate constants of synthesis and decay.
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Carnosina/biosíntesis , Preparaciones de Acción Retardada/farmacocinética , Suplementos Dietéticos , Modelos Estadísticos , Músculo Esquelético/efectos de los fármacos , beta-Alanina/farmacocinética , Carnosina/agonistas , Esquema de Medicación , Cálculo de Dosificación de Drogas , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Factores de TiempoRESUMEN
Once-daily (p.m.) netarsudil ophthalmic solution 0.02% (Rhopressa) is approved in the United States for lowering elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Netarsudil, a Rho kinase (ROCK) inhibitor that lowers IOP primarily by increasing trabecular outflow, produces statistically and clinically significant reductions in mean IOP from baseline, with comparable effects on nocturnal and diurnal IOP. In three phase III trials of patients with elevated IOP, the ocular hypotensive efficacy of once-daily netarsudil 0.02% met the criteria for noninferiority to twice-daily timolol 0.5% at all time points over 3 months in patients with baseline IOP less than 25 mmHg. The most frequent adverse event (AE) was generally mild conjunctival hyperemia, the severity of which did not increase with continued dosing. Netarsudil was associated with minimal treatment-related serious or systemic AEs, likely due to the lack of systemic exposure. This report summarizes the available preclinical and clinical data on netarsudil.
Asunto(s)
Benzoatos/administración & dosificación , Ojo/efectos de los fármacos , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Presión Intraocular/efectos de los fármacos , Hipertensión Ocular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , beta-Alanina/análogos & derivados , Administración Oftálmica , Animales , Benzoatos/efectos adversos , Benzoatos/farmacocinética , Interacciones Farmacológicas , Ojo/enzimología , Ojo/fisiopatología , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/enzimología , Glaucoma de Ángulo Abierto/fisiopatología , Humanos , Hipertensión Ocular/diagnóstico , Hipertensión Ocular/enzimología , Hipertensión Ocular/fisiopatología , Soluciones Oftálmicas , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Resultado del Tratamiento , beta-Alanina/administración & dosificación , beta-Alanina/efectos adversos , beta-Alanina/farmacocinética , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismoRESUMEN
Introductions: [N-methyl-C-11]α-Methylaminoisobutyric acid (MeAIB) is an artificial amino acid radiotracer used for PET study, which is metabolically stable in vivo. In addition, MeAIB is transported by system A neutral amino acid transport, which is observed ubiquitously in all types of mammalian cells. It has already been shown that MeAIB-PET is useful for malignant lymphoma, head and neck cancers, and lung tumors. However, there have been no reports evaluating the usefulness of MeAIB-PET in the diagnosis of brain tumors. The purpose of this study is to investigate the efficacy of system A amino acid transport PET imaging, MeAIB-PET, in clinical brain tumor diagnosis compared to [S-methyl-C-11]-L-methionine (MET)-PET. Methods: Thirty-one consecutive patients (male: 16, female: 15), who were suspected of having brain tumors, received both MeAIB-PET and MET-PET within a 2-week interval. All patients were classified into two groups: Group A as a benign group, which included patients who were diagnosed as low-grade astrocytoma, grade II or less, or other low-grade astrocytoma (n=12) and Group B as a malignant group, which included patients who were diagnosed as anaplastic astrocytoma, glioblastoma multiforme (GBM), or recurrent GBM despite prior surgery or chemoradiotherapy (n=19). PET imaging was performed 20 min after the IV injection of MeAIB and MET, respectively. Semiquantitative analyses of MeAIB and MET uptake using SUVmax and tumor-to-contralateral normal brain tissue (T/N) ratio were evaluated to compare these PET images. ROC analyses for the diagnostic accuracy of MeAIB-PET and MET-PET were also calculated. Results: In MeAIB-PET imaging, the SUVmax was 1.20 ± 1.29 for the benign group and 2.94 ± 1.22 for the malignant group (p < 0.005), and the T/N ratio was 3.77 ± 2.39 for the benign group and 16.83 ± 2.39 for the malignant group (p < 0.001). In MET-PET, the SUVmax was 3.01 ± 0.94 for the benign group and 4.72 ± 1.61 for the malignant group (p < 0.005), and the T/N ratio was 2.64 ± 1.40 for the benign group and 3.21 ± 1.14 for the malignant group (n.s.). For the analysis using the T/N ratio, there was a significant difference between the benign and malignant groups with MeAIB-PET with p < 0.001. The result of ROC analysis using the T/N ratio indicated a better diagnosis accuracy for MeAIB-PET for brain tumors than MET-PET (p < 0.01). Conclusions: MeAIB, a system A amino acid transport-specific radiolabeled agents, could provide better assessments for detecting malignant type brain tumors. In a differential diagnosis between low-grade and high-grade astrocytoma, MeAIB-PET is a useful diagnostic imaging tool, especially in evaluations using the T/N ratio. Clinical trial registration: This trial was registered with UMIN000032498.
Asunto(s)
Astrocitoma/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico , Tomografía de Emisión de Positrones/métodos , Radiofármacos/normas , Adolescente , Adulto , Anciano , Sistema de Transporte de Aminoácidos A , Neoplasias Encefálicas/diagnóstico por imagen , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Metionina/farmacocinética , Metionina/normas , Persona de Mediana Edad , Curva ROC , Radiofármacos/farmacocinética , Adulto Joven , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinética , beta-Alanina/normasRESUMEN
ß-Alanine is one of the more popular sport supplements used by strength/power athletes today. The popularity of ß-alanine stems from its ability to enhance intracellular muscle-buffering capacity thereby delaying fatigue during high-intensity exercise by increasing muscle carnosine content. Recent evidence also suggests that elevated carnosine levels may enhance cognitive performance and increase resiliency to stress. These benefits are thought to result from carnosine's potential role as an antioxidant. This review will discuss these new findings including recent investigations examining ß-alanine supplementation and increased resiliency to posttraumatic stress and mild traumatic brain injury. This review will focus on the physiology of carnosine, the effect of ß-alanine ingestion on carnosine elevations, and the potential ergogenic benefits it has for competitive and tactical athletes.
Asunto(s)
Carnosina/metabolismo , Suplementos Dietéticos , beta-Alanina/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Interacciones Farmacológicas , Ejercicio Físico/fisiología , Humanos , beta-Alanina/administración & dosificación , beta-Alanina/farmacocinéticaRESUMEN
Introducción: muy pocos suplementos nutricionales han demostrado científicamente su eficacia como ayuda ergogénica. Esta revisión analizará el monohidrato de creatina (MC), el β-hidroxi-β-metilbutirato (HMB), el bicarbonato sódico (BS), la β-alanina y la cafeína. Objetivos: analizar la eficacia, mecanismos de acción, dosis, efectos adversos y algunos deportes que se pueden beneficiar de su consumo. Métodos: búsqueda en la base de datos PubMed de revisiones bibliográficas de los últimos 15 años y artículos originales de los últimos 5 años de las sustancias estudiadas. Resultados: dosis de MC de 20 g/día durante 4-7 días son eficaces para mejorar la fuerza y la potencia muscular y el rendimiento en sprints cortos y repetidos. El HMB en dosis de 3 g/día durante un mínimo de 2 semanas contribuye al aumento de la masa magra y de la masa libre de grasa. La ingesta de 0,3 g/kg de BS mejora el rendimiento en pruebas de 400-1.500 m de atletismo y en sprints intermitentes. Por su parte, dosis de 80 mg/kg/día de β-alanina durante 4-10 semanas pueden mejorar el rendimiento en ejercicios intermitentes de alta intensidad. Finalmente, la cafeína en dosis de 2 mg/kg mejora la capacidad de reacción y en dosis de 3-6 mg/kg mejora el rendimiento en pruebas de resistencia aeróbica. Conclusiones: los suplementos revisados presentan una demostrada eficacia en el rendimiento físico, pero hay que tener en cuenta que la mayoría de los estudios se han realizado con deportistas de nivel recreativo. Generalmente, la mejora del rendimiento físico con estos suplementos es menor cuanto mejor es el nivel deportivo del individuo; sin embargo, un incremento de apenas un 1% permite a veces avanzar varios puestos en una final. Finalmente, se debe llamar la atención sobre la importancia de optimizar la alimentación antes de plantearse la introducción de suplementos deportivos, especialmente en niños y jóvenes. Las sustancias que hemos analizado poseen una base científica que respalda su efecto ergogénico. Todas ellas se pueden encontrar en el mercado con Certificado de Calidad y Pureza (AU)
Introduction: Very few nutritional supplements have scientifically demonstrated their effectiveness as an ergogenic aid. This review will examine creatine monohydrate (MC), the β-hydroxy-β-methylbutyrate (HMB), sodium bicarbonate (BS), the β-alanine and caffeine. Objectives: To analyze the efficacy, mechanisms of action, dose, side effects and some sports that can benefit from their consumption. Methods: Searching in PubMed bibliographic database reviews from the last 15 years and original articles from the last 5 years of the studied substances. Results: Doses of 20 mg/day for 4-7 days are effective in improving strength and muscular power and performance in short and repeated sprints. HMB at doses of 3 g/day for at least 2 weeks contributes to increased lean mass and fat-free mass. The intake of 0.3 g/kg of BS improves performance on tests of 400-1,500 meters in athletics and intermittent sprints. Meanwhile, doses of 80 mg/kg/day of β-alanine for 4-10 weeks may improve performance in high-intensity intermittent exercise. Finally, caffeine at doses of 2 mg/kg improves responsiveness and 3-6 mg/kg improves performance in endurance tests. Conclusions: The revised supplements have shown their efficacy in physical performance, but it is needed to keep in mind that most studies have been conducted with recreational-level athletes. Generally, the better the individual´s fitness level is the less improvement in physical performance the supplement shows. However, an increase of only 1% may sometimes allow the athlete to advance several positions in a final. Finally, we should draw attention to the importance of optimizing nutrition before considering the introduction of sports supplements, especially in children and youth. All analyzed substances have scientific basis supporting its ergogenic effect. All of them can be found in the market with Certificate of Quality and Purity (AU)
Asunto(s)
Humanos , Rendimiento Atlético/fisiología , Sustancias para Mejorar el Rendimiento/análisis , Fenómenos Fisiológicos en la Nutrición Deportiva/fisiología , Creatina/farmacocinética , Cafeína/farmacocinética , Bicarbonato de Sodio/farmacocinética , beta-Alanina/farmacocinética , Leucina/farmacocinéticaRESUMEN
Dabigatran is a direct thrombin inhibitor that has been approved for preventing stroke in patients with atrial fibrillation. In this study, we aimed to assess the associations between the dabigatran concentration (calculated through plasma-diluted thrombin time, as assessed using the Hemoclot assay) and the activated partial thromboplastin time (aPTT) and activated clotting time (ACT). We recruited 137 patients with atrial fibrillation who were receiving a normal dose of dabigatran (300 mg/d) or a reduced dose of dabigatran (220 mg/d, usually administered to patients who were elderly, had moderate renal dysfunction, or who were also receiving verapamil). We then assessed the aPTT, ACT, and Hemoclot results of the patients and calculated the plasma dabigatran concentration. The mean plasma concentration of dabigatran was 127 ± 88 ng/ml, although no significant differences in dabigatran concentration, ACT, or aPTT were observed when we compared the 2 doses of dabigatran (300 or 220 mg/d). The dabigatran concentration was within the therapeutic levels in most patients, although a high value (>300 ng/ml) was observed in several patients, which indicated a high risk of bleeding. The dabigatran concentration was strongly and positively correlated with ACT and aPTT (r = 0.87, p <0.001; and r = 0.76, p <0.001; respectively). Multivariate analysis revealed that verapamil use was independently associated with elevated dabigatran concentrations (p <0.001). Therefore, ACT and aPTT may be useful for bedside assessment of the anticoagulant activity of dabigatran, and verapamil use may be a risk factor for elevated dabigatran concentrations.
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Antitrombinas/administración & dosificación , Antitrombinas/farmacocinética , Fibrilación Atrial/tratamiento farmacológico , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Monitoreo de Drogas/métodos , beta-Alanina/análogos & derivados , Anciano , Coagulación Sanguínea , Dabigatrán , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Factores de Riesgo , Tiempo de Trombina , beta-Alanina/administración & dosificación , beta-Alanina/farmacocinéticaAsunto(s)
Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Monitoreo de Drogas , Sustitución de Medicamentos , Hemorragia/inducido químicamente , Tromboembolia/prevención & control , Anticoagulantes/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Dabigatrán , Semivida , Hemorragia/sangre , Humanos , Pruebas de Función Renal , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Morfolinas/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Piridinas/efectos adversos , Piridinas/sangre , Piridinas/uso terapéutico , Piridonas/efectos adversos , Piridonas/farmacocinética , Piridonas/uso terapéutico , Rivaroxabán , Tiazoles/efectos adversos , Tiazoles/sangre , Tiazoles/uso terapéutico , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Tiofenos/uso terapéutico , Tromboembolia/sangre , Warfarina/efectos adversos , Warfarina/farmacocinética , Warfarina/uso terapéutico , beta-Alanina/efectos adversos , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinética , beta-Alanina/uso terapéuticoRESUMEN
CONTEXT: Severe bleeding associated with dabigatran frequently requires intensive care management. An antidote is currently unavailable and data reporting the effect of dialysis on elimination of dabigatran are encouraging, but limited. Objective. To report the effect of intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) at enhancing elimination of dabigatran. MATERIALS AND METHODS: Patients were identified by existing collaborative networks. Pre-filter dabigatran plasma concentrations were measured in all patients, and in dialysate of three patients. RESULTS: Seven patients received dialysis, five with active bleeding and two requiring emergent surgery. Five received IHD and two received CRRT. The plasma elimination half-life of dabigatran was 1.5-4.9 h during IHD, and 14.0-27.5 h during CRRT. Mean dabigatran plasma clearance during IHD was 85-169 mL/min in three patients. Time to obtain a subtherapeutic dabigatran concentration depended on the initial concentration, being 8-18 h for IHD in three patients while 4 h was insufficient in a supratherapeutic case. A 38% rebound in dabigatran levels occurred after one case during IHD, and thrombin time increased after IHD in another, but not after 144 h CRRT or 17 h IHD in two others; data were incomplete in three cases. The amount removed during IHD was proportional to the pre-IHD concentration and clearance, but was consistently low at 3.3-17.4 mg in three patients where this was determined. Moderate bleeding occurred while obtaining vascular access in one patient. Two patients died from intracerebral bleeding, and the influence of treatments could not be determined in these cases. DISCUSSION AND CONCLUSIONS: IHD enhanced elimination of dabigatran more efficiently than CRRT, but their net effect remains poorly defined. Dialysis decisions, including modality and duration, must be individualized based on a risk-benefit assessment.
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Antitrombinas/efectos adversos , Bencimidazoles/efectos adversos , Coagulación Sanguínea/efectos de los fármacos , Hemorragia/terapia , Diálisis Renal/métodos , Terapia de Reemplazo Renal/métodos , beta-Alanina/análogos & derivados , Anciano , Anciano de 80 o más Años , Antitrombinas/sangre , Antitrombinas/farmacocinética , Bencimidazoles/sangre , Bencimidazoles/farmacocinética , Pruebas de Coagulación Sanguínea , Hemorragia Cerebral/sangre , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/terapia , Dabigatrán , Monitoreo de Drogas , Resultado Fatal , Femenino , Semivida , Hemorragia/sangre , Hemorragia/inducido químicamente , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , beta-Alanina/efectos adversos , beta-Alanina/sangre , beta-Alanina/farmacocinéticaRESUMEN
BACKGROUND: Dabigatran and rivaroxaban are new oral anticoagulants that are eliminated through the kidneys. Their use in dialysis patients is discouraged because these drugs can bioaccumulate to precipitate inadvertent bleeding. We wanted to determine whether prescription of dabigatran or rivaroxaban was occurring in the dialysis population and whether these practices were safe. METHODS AND RESULTS: Prevalence plots were used to describe the point prevalence (monthly) of dabigatran and rivaroxaban use among 29977 hemodialysis patients with atrial fibrillation. Poisson regression compared the rate of bleeding, stroke, and arterial embolism in patients who started dabigatran, rivaroxaban, or warfarin. The first record of dabigatran prescription among hemodialysis patients occurred 45 days after the drug became available in the United States. Since then, dabigatran and rivaroxaban use in the atrial fibrillation-end-stage renal disease population has steadily risen where 5.9% of anticoagulated dialysis patients are started on dabigatrian or rivaroxaban. In covariate adjusted Poisson regression, dabigatran (rate ratio, 1.48; 95% confidence interval, 1.21-1.81; P=0.0001) and rivaroxaban (rate ratio, 1.38; 95% confidence interval, 1.03-1.83; P=0.04) associated with a higher risk of hospitalization or death from bleeding when compared with warfarin. The risk of hemorrhagic death was even larger with dabigatran (rate ratio, 1.78; 95% confidence interval, 1.18-2.68; P=0.006) and rivaroxaban (rate ratio, 1.71; 95% confidence interval, 0.94-3.12; P=0.07) relative to warfarin. There were too few events in the study to detect meaningful differences in stroke and arterial embolism between the drug groups. CONCLUSIONS: More dialysis patients are being started on dabigatran and rivaroxaban, even when their use is contraindicated and there are no studies to support that the benefits outweigh the risks of these drugs in end-stage renal disease.
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Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Bencimidazoles/uso terapéutico , Fallo Renal Crónico/complicaciones , Morfolinas/uso terapéutico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Diálisis Renal , Tiofenos/uso terapéutico , beta-Alanina/análogos & derivados , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Fibrilación Atrial/complicaciones , Fibrilación Atrial/metabolismo , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Dabigatrán , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Utilización de Medicamentos , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Fallo Renal Crónico/metabolismo , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Distribución de Poisson , Pautas de la Práctica en Medicina/tendencias , Estudios Retrospectivos , Riesgo , Rivaroxabán , Accidente Cerebrovascular/etiología , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Warfarina/efectos adversos , Warfarina/farmacocinética , Warfarina/uso terapéutico , beta-Alanina/efectos adversos , beta-Alanina/farmacocinética , beta-Alanina/uso terapéuticoRESUMEN
Dabigatran, a new direct thrombin inhibitor, achieves strong anticoagulation that is more predictable than warfarin. Nevertheless, a patient on dabigatran therapy (DT) may suffer from thrombotic or bleeding events. The routine monitoring of DT is not recommended, and standard coagulation tests are not sensitive enough for the assessment of DT activity. The aim of this study was to examine the clinical usefulness of the Hemoclot(®) Thrombin Inhibitor (HTI) assay in the assessment of dabigatran plasma levels in patients with non-valvular AF. Nineteen patients (12 men, 7 women) on DT were included in this preliminary prospective observational study. Dabigatran was administrated twice daily in a two dose regimens: 150 mg (5 patients) and 110 mg (14 patients). Blood samples were taken for the assessment of trough and peak levels of dabigatran. Dabigatran concentrations were measured with the HTI assay. The average dabigatran trough level was 69.3 ± 55.5 ng/ml and the average dabigatran peak level was 112.7 ± 66.6 ng/ml. The dabigatran trough plasma concentration was in the established reference range in 15 patients and the dabigatran peak plasma concentration was in the established reference range in 9 patients, respectively. Despite the fact that the activated partial thromboplastin and thrombin times were generally changed (prolonged), these tests failed to identify the patients with too low or too high dabigatran concentrations. The study confirmed the high sensitivity of the HTI assay for the assessment of dabigatran plasma levels. When compared to standard coagulation tests, the HTI is a more suitable assay for the monitoring of patients treated with dabigatran. Monitoring of DT may be beneficial in selected patients; however, further studies will be needed for the final clarification of this issue.
Asunto(s)
Antitrombinas , Fibrilación Atrial , Bencimidazoles , Monitoreo de Drogas , beta-Alanina/análogos & derivados , Anciano , Anciano de 80 o más Años , Antitrombinas/administración & dosificación , Antitrombinas/farmacocinética , Fibrilación Atrial/sangre , Fibrilación Atrial/tratamiento farmacológico , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Dabigatrán , Monitoreo de Drogas/instrumentación , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , beta-Alanina/administración & dosificación , beta-Alanina/farmacocinéticaRESUMEN
Compared to Vitamin K antagonists (VKA), novel oral anticoagulants (NOACs) appear to be safer in terms of major bleeding risks with added advantage of having fixed dosing schedules when used in patients with non-valvular atrial fibrillation (AF). We sought to study the differences as sources and severity of anticoagulant-associated haemorrhage in patients with AF in the year preceding introduction of NOACs (first cohort) as compared to post approval of the NOACs (second cohort) by retrospectively reviewing the hospital admissions, as well as the pharmacodynamic and pharmacokinetic interactions between time periods. There were 359 patients for the first cohort and 405 patients for the second cohort, including 57 patients prescribed NOACs. There was no significant difference in age, deaths, source of bleeding, or rate of pharmacokinetic or pharmacodynamic interaction between the two time periods. Comparing all VKA patients to patients prescribed NOAC's, there were non-significant but higher rates of intracerebral bleed, significantly higher rates of pharmacokinetic (194 (25.4%) versus 0 (0%), p<.001) and similar rates of pharmacodynamic interactions (505 (66.1%) versus 39 (68.4%), p=.70). Drug-renal interactions were seen in 7 of the 57 (12.3%) NOAC-treated patients, in which all seven had acute renal failure that may have prolonged the effects of the anticoagulants. NOACs hold promise in that drug interactions are far less common than those seen in VKAs, and intracerebral bleeds appear to be less common in randomised trials as well as our review. For patients on dabigatran or rivaroxaban, consideration should be given to serial monitoring of renal function.
Asunto(s)
Anticoagulantes , Fibrilación Atrial , Bencimidazoles , Hemorragia , Hospitalización , Morfolinas , Tiofenos , Vitamina K/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Factores de Edad , Anciano , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/mortalidad , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Estudios de Cohortes , Dabigatrán , Femenino , Hemorragia/inducido químicamente , Hemorragia/mortalidad , Hemorragia/terapia , Humanos , Masculino , Morfolinas/administración & dosificación , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Rivaroxabán , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Tiofenos/farmacocinética , beta-Alanina/administración & dosificación , beta-Alanina/efectos adversos , beta-Alanina/farmacocinéticaRESUMEN
BACKGROUND: Patients with acute coronary syndrome and concomitant atrial fibrillation may require antithrombotic triple therapy but clinical evidence of safety and efficacy is poor. We have therefore studied the combination of different antithrombotic medicines for coagulation activation in an in vivo model in the skin microvasculature. METHODS AND RESULTS: Platelet activation (ß-thromboglobulin [ß-TG]) and thrombin generation (prothrombin fragment 1 + 2 [F1+2 ], thrombin-antithrombin complex [TAT]) were studied in an open-label, randomized, parallel group trial in 60 healthy male subjects (n = 20 per group) who received ticagrelor and acetylsalicylic acid (ASA) in combination with dabigatran (150 mg bid), rivaroxaban (20 mg od) or phenprocoumon (INR 2.0-3.0). Coagulation biomarkers in shed blood were assessed at 3 h after monotherapy with the medicines under study, at 3 h after triple therapy dosing and at steady state trough conditions. Single doses of ticagrelor, dabigatran or rivaroxaban caused comparable decreases in shed blood ß-TG and were more pronounced than phenprocoumon at an INR of 2.0-3.0. In contrast, thrombin generation was more affected by rivaroxaban and phenprocoumon than by dabigatran. During triple therapy a similarly sustained inhibition of platelet activation and thrombin generation with a maximum decrease of ß-TG, F1+2 and TAT at 3 h post-dosing was noted, which remained below pre-dose levels at trough steady state. CONCLUSION: A triple therapy at steady state with ticagrelor plus ASA in combination with dabigatran or rivaroxaban is as effective as a combination with phenprocoumon for platelet activation and thrombin generation in vivo.
Asunto(s)
Adenosina/análogos & derivados , Anticoagulantes/administración & dosificación , Aspirina/administración & dosificación , Bencimidazoles/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Fibrinolíticos/administración & dosificación , Morfolinas/administración & dosificación , Fenprocumón/administración & dosificación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Tiofenos/administración & dosificación , Trombosis/tratamiento farmacológico , beta-Alanina/análogos & derivados , Adenosina/administración & dosificación , Adenosina/efectos adversos , Adenosina/farmacocinética , Administración Oral , Adulto , Anticoagulantes/efectos adversos , Antitrombina III , Aspirina/efectos adversos , Austria , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Biomarcadores/sangre , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Dabigatrán , Quimioterapia Combinada , Fibrinolíticos/efectos adversos , Voluntarios Sanos , Humanos , Relación Normalizada Internacional , Masculino , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Fragmentos de Péptidos/sangre , Péptido Hidrolasas/sangre , Fenprocumón/efectos adversos , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Prospectivos , Protrombina , Rivaroxabán , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Trombina/metabolismo , Trombosis/sangre , Trombosis/diagnóstico , Ticagrelor , Adulto Joven , beta-Alanina/administración & dosificación , beta-Alanina/efectos adversos , beta-Alanina/farmacocinética , beta-Tromboglobulina/metabolismoAsunto(s)
Antitrombinas/farmacocinética , Bencimidazoles/farmacocinética , Morfolinas/farmacocinética , Accidente Cerebrovascular/prevención & control , Tiofenos/farmacocinética , beta-Alanina/análogos & derivados , Anciano , Antitrombinas/uso terapéutico , Bencimidazoles/uso terapéutico , Dabigatrán , Humanos , Masculino , Morfolinas/uso terapéutico , Rivaroxabán , Tiofenos/uso terapéutico , beta-Alanina/farmacocinética , beta-Alanina/uso terapéuticoRESUMEN
The target-specific oral anticoagulants have recently been introduced as alternatives to warfarin for both prophylactic and therapeutic indications. Although their efficacy and side-effect profiles have been favorable, there is significant concern about management of hemorrhage with these agents as there is no direct reversal agent available. It is important for clinicians to be aware of these agents and the issues that surround them. Most of the management of hemorrhage is based on expert opinion and case reviews. Given the potentially catastrophic consequences of acute hemorrhage while patients are on anticoagulation, specific treatments are needed. Some methods that have been described include activated charcoal, hemodialysis, prohemostatic agents, and transfusions. Target-specific therapies have been shown to be effective in early studies in animal models; however, the effects in humans are still under investigation. More investigation is needed on the management of bleeding complications from target-specific oral anticoagulants.
Asunto(s)
Anticoagulantes/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/terapia , Administración Oral , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Transfusión Sanguínea/métodos , Carbón Orgánico/uso terapéutico , Dabigatrán , Monitoreo de Drogas , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/farmacocinética , Humanos , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Piridonas/efectos adversos , Piridonas/farmacocinética , Diálisis Renal/métodos , Rivaroxabán , Tiofenos/efectos adversos , Tiofenos/farmacocinética , beta-Alanina/efectos adversos , beta-Alanina/análogos & derivados , beta-Alanina/farmacocinéticaRESUMEN
Dabigatran, a direct thrombin inhibitor, is increasingly used clinically as one of the new oral anticoagulants. This review summarizes the assays available to measure its activity and includes the relative sensitivity of the different assays for this agent. In addition to plasma-based clotting tests, assays commonly used in surgical/emergency settings, such as activated clotting time and thromboelastometry/thromboelastography, are reviewed. In addition, the thrombin generation assay is discussed as an important method to determine the potential risk of thrombosis or bleeding and its relevance to the measurement of direct thrombin inhibitors.