RESUMO
UNLABELLED: ESSENTIALS: It is unknown whether single rivaroxaban doses should best be administered in the morning or evening. Circadian rhythm of coagulation/fibrinolysis was measured after morning or evening intake of rivaroxaban. Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations. Evening intake of rivaroxaban better matches the morning hypofibrinolysis. BACKGROUND: A circadian variation of the endogenous coagulation system exists with hypercoagulability and hypofibrinolysis and a corresponding peak of cardiovascular thromboembolic events in the morning. So far, no information is given as to whether single daily doses of the new oral anticoagulant drug rivaroxaban should best be administered in the morning or the evening. MATERIALS AND METHODS: Sixteen healthy male or female volunteers with a mean age of 26 ± 7 years were included in this randomized, controlled, analyst-blinded cross-over clinical trial. All subjects were given three morning and three evening single doses of 10 mg rivaroxaban. Circadian rhythms of prothrombin fragment 1 + 2, plasminogen activator inhibitor, and plasmin-antiplasmin complex were measured before any medication intake, as well as after morning or evening medication intake. Rivaroxaban concentrations were determined by an anti-activated factor X assay and liquid chromatography-mass spectrometry. MAIN RESULTS: Concentrations of rivaroxaban were higher 12 h after evening intake of rivaroxaban than 12 h after morning intake (53.3 ng mL(-1) [95% confidence interval 46.0-67.8] vs. 23.3 ng mL(-1) [19.4-29.1, respectively]). Rivaroxaban intake in the evening reduced morning F1+2 concentrations better at 8:00 AM than did administration on awakening (85 ± 25 nmol L(-1) vs. 106 ± 34 nmol L(-1) , CI: 9.4-32.1). In addition, this suppression effect was longer lasting after evening intake. CONCLUSIONS: Evening intake of rivaroxaban leads to prolonged exposure to rivaroxaban concentrations and better matches the morning hypofibrinolysis. These results might help to further improve the efficacy and safety of rivaroxaban treatment.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Ritmo Circadiano , Inibidores do Fator Xa/administração & dosagem , Rivaroxabana/administração & dosagem , Adulto , Testes de Coagulação Sanguínea , Cromatografia Líquida , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Espectrometria de Massas , Valor Preditivo dos Testes , Rivaroxabana/sangue , Fatores de Tempo , Adulto JovemRESUMO
A rapid ultra-high performance liquid chromatography diode array detector (UHPLC-DAD) method was developed and validated for the simultaneous determination of all classes of non-volatile phytochemicals (iridoids, flavonoids and diterpenes) in Vitex agnus-castus (Lamiaceae) fruits, a traditional medicinal plant used against premenstrual symptoms (PMS) and other disorders. Seven marker compounds, 3,4-dihydroxybenzoic acid, p-hydroxybenzoic acid, agnuside, 5-hydroxykaempferol-3,6,7,4'-tetramethylether, 1,2-dibenzoic acid glucose, methoxy-vitexilactone, and vitetrifolin D were isolated from the methanol extract of V. agnus-castus to be used as reference substances. Chromatographic separation was performed on a Zorbax Eclipse XDB-C18 (50mm×2.1mm) UHPLC column with 1.8µm particle size, within 20min. A solvent gradient from 0.5% acetic acid to acetonitrile at a flow rate of 0.6mL/min was used as mobile phase. Analyte detection and quantification was realized at 210nm and 260nm. The UHPLC-DAD assay was validated for the quantitative analysis of agnuside, isovitexin, casticin, 5-hydroxykaempferol-3,6,7,4'-tetramethylether and vitetrifolin D. It was found to be specific, accurate, precise, and reproducible for the quantification of these compound within a concentration range of 0.7-500.0µg/mL for casticin and 5-hydroxykaempferol-3,6,7,4'-tetramethylether, 1.4-1000.0µg/mL for isovitexin and agnuside, and 12.4-1000.0µg/mL for vitetrifolin D. Intra- and inter-day variations showed relative standard deviations (RSD) of less than 3.9% and 6.4%, respectively. Tentatively assignment of 62 chromatographic features found in the UHPLC-DAD assay was carried out by coupling the UHPLC instrument to a quadrupole time-of-flight mass spectrometer via an electrospray ionization interface (ESI-QTOF-MS) operated in positive and negative ion mode. By using the established quantitative UHPLC-DAD assay to asses agnuside, isovitexin, casticin, 5-hydroxykaempferol-3,6,7,4'-tetramethylether and vitetrifolin D in V. agnus-castus derived preparations as extracts, tinctures and tablets, the applicability of the developed assay to phytopharmaceuticals was successfully proven.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Vitex/química , Benzoatos/análise , Benzoatos/química , Diterpenos/análise , Diterpenos/química , Flavonoides/análise , Flavonoides/química , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Fifteen new stilbenoids including 11 phenylbenzofurans, the stemofurans A-K (1-11), and four dihydrostilbenes, the stilbostemins A (15), C (17), E (19), and F (20), were isolated and identified from a methanolic extract of Stemona collinsae roots together with five known derivatives, the stilbenes pinosylvin (13) and 4'-methylpinosylvin (14), the dihydrostilbenes, stilbostemins B (16) and D (18), and the dihydrophenanthrene racemosol (12) as well as (+)-sesamin, coniferyl alcohol, and stigmasterol. Bioautographic tests with Cladosporium herbarum displayed antifungal activity for stilbenoids of all four structural types. Ten derivatives were tested against five microfungi using the microdilution technique linked with digital image analysis of germ tubes.
Assuntos
Antifúngicos/isolamento & purificação , Benzofuranos/isolamento & purificação , Furanos/isolamento & purificação , Plantas Medicinais/química , Estilbenos/isolamento & purificação , Alternaria/efeitos dos fármacos , Antifúngicos/química , Antifúngicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Botrytis/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Cladosporium/efeitos dos fármacos , Furanos/química , Furanos/farmacologia , Fusarium/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Raízes de Plantas/química , Estilbenos/química , Estilbenos/farmacologia , TailândiaRESUMO
The effects of an orally administered Cassia occidentalis extract were studied in chickens. A 25 mM sodium bicarbonate solution effectively extracted the toxic principle. Toxic activity was reduced, but not eliminated, when the heated extract (90 C, 40 minutes) was administered. The toxic principle was in the pellet after centrifuging the extract at 38,000 X g. Daily administration of the extract produced weight loss and muscular weakness. Microscopic examination revealed skeletal and cardiac muscle degeneration and hepatocyte vacuolation. Electron microscopic examination revealed mitochondrial disruption. Respiratory studies on liver mitochondria isolated from treated chickens demonstrated lower phosphorylation ratios, lower respiratory control ratios, and lower rates of oxygen use.
Assuntos
Cassia , Galinhas , Extratos Vegetais/intoxicação , Intoxicação por Plantas/veterinária , Plantas Medicinais , Doenças das Aves Domésticas/etiologia , Animais , Peso Corporal , Fígado/ultraestrutura , Microscopia Eletrônica , Mitocôndrias Hepáticas/metabolismo , Músculos/ultraestrutura , Intoxicação por Plantas/patologia , Doenças das Aves Domésticas/patologiaRESUMO
Aqueous and organic extractions of ground seeds of Cassia occidentalis were obtained. Chickens were dosed with extracted material to assess the toxicity of the extracts. Organic extracts with methanol, ethanol, chloroform, ethyl acetate, and benzene were ineffective in removing the toxin from the seeds. Aqueous extractions, using 25 mM sodium bicarbonate or 250 mM sodium citrate, removed the toxin from the seeds, but left the toxin bound to particulate matter in the extract. Addition of Triton X-100 to the aqueous buffers effectively solubilized the toxin from the particulate matter. Signs of intoxication in the chickens were loss of weight, weakness, diarrhea, hypothermia, occasionally ataxia, and recumbency; then death. Gross lesions included paleness of skeletal and cardiac muscles and congestion of the liver. Microscopic lesions in muscle tissue were vacuolation, proliferation of sarcolemmal nuclei, and separation of myofibrils. Electron microscopic examination revealed disruption of mitochondrial cristae and swelling and rupture of mitochondria.