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Métodos Terapéuticos y Terapias MTCI
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1.
AAPS PharmSciTech ; 23(6): 182, 2022 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-35773361

RESUMEN

The goal of this study was to develop a bilosomal gel formulation to enhance transdermal permeability of dronedarone hyrdrochloride (DRN) which suffers from poor oral absorption and limited bioavailability. To overcome this obstacle, bilosomes were successfully prepared using 23 full-factorial design. Span®40, cholesterol, sodium deoxycholate (bile salt), clove oil (permeability enhancer), and either Tween® 60 or Tween® 80 (edge activator) were used in bilosome preparation by ethanol injection method. In this design, independent variables were X1, edge activator type; X2, edge activator amount (mg); and X3, permeability enhancer concentration (% w/v). Optimal formula (B2) of the highest desirability of (0.776) demonstrated minimum vesicle size (VS) of 312.4 ± 24.42 nm, maximum absolute value of zeta potential (ZP) - 36.17 ± 2.57 mV, maximum entrapment efficiency (EE %) of 80.95 ± 3.01%, maximum deformability Index (DI) of 8.24 ± 1.26 g and maximum drug flux after 12 h (J12) of 21.23 ± 1.54 µg/cm2 h upon ex vivo permeation study. After 12 h, 70.29 ± 6.46% of DRN was released from B2. TEM identification of B2 showed spherical shaped nanosized vesicles which were physically stable for 3 months at different temperatures. B2 was incorporated into carboxymethylcellulose gel base for easiness of dermal application. B2 gel demonstrated good physical properties, non-Newtonian psuedoplastic flow, and enhanced release (57.0 ± 8.68% of DRN compared to only 13.3 ± 1.2% released from drug suspension after 12 h) and enhanced skin permeation.


Asunto(s)
Aceite de Clavo , Absorción Cutánea , Administración Cutánea , Aceite de Clavo/metabolismo , Dronedarona , Sistemas de Liberación de Medicamentos/métodos , Nanogeles , Tamaño de la Partícula , Polisorbatos/metabolismo , Piel/metabolismo
2.
Clin Appl Thromb Hemost ; 27: 10760296211052968, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34894780

RESUMEN

The emerging data supports rhythm control to prevent major adverse cardiac events (MACE) in high-risk patients with atrial fibrillation (AF). Limited data demonstrated rivaroxaban 10 mg combining dronedarone seemed feasible. This study aimed at investigating clinical events in a dronedarone-treated cohort. This exploratory, retrospective chart review was conducted in nonpermanent AF patients receiving dronedarone for ≥ 3 months between 2009/1 and 2016/2. In Taiwan, dronedarone's labeled indication was strict to age ≥ 70 or 65 to 70 years with either hypertension, diabetes, prior stroke, or left atrium >50 mm. We divided all into 4 groups using antithrombotic strategies to evaluate the safety, effectiveness, and MACE endpoints. A total of 689 patients (mean CHA2DS2-VASc score 3.8 ± 1.4) were analyzed: rivaroxaban 10 mg (n = 93, 13.5%), warfarin (n = 89, 12.9%), antiplatelet (n = 331, 48.0%), and none (n = 176, 25.5%). During the follow-up period (mean 946 ± 493.8 days), the rivaroxaban group did not report any stroke or thromboembolism (ishcmeic stroke rate: antiplatelet [0.6%], none [1.1%]; hemorrahgic stroke rate: warfarin [2.2%]; thromboembolism rate: warfarin [2.2%]). There was no significant difference in safety, effectiveness, and MACE endpoints between groups. Also, >104 weeks of dronedarone use was the independent predictor for MACE after adjusting the strategy and other covariates (hazard ratio 0.14 [95% confidence interval 0.04-0.44], P = .001). Our findings warrant concomitant rivaroxaban 10 mg and dronedarone for further investigation. Regardless of antithrombotic strategies, a more extended persistence of dronedarone was associated with fewer MACE.


Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Dronedarona/administración & dosificación , Frecuencia Cardíaca/fisiología , Rivaroxabán/administración & dosificación , Tromboembolia/prevención & control , Warfarina/administración & dosificación , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Fibrinolíticos , Estudios de Seguimiento , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Estudios Retrospectivos , Tromboembolia/etiología , Resultado del Tratamiento
3.
Toxicol Lett ; 319: 187-196, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31756459

RESUMEN

The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450) kinetics, especially CYP3A4, have received wide concern in recent years. Flavonoids, a group of important natural substances with various pharmacological activities, distribute widely among vegetables, fruits and herbs. The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions. However, little is known about activation effects of flavonoids on CYP3A4. The aim of this study was to investigate activation of CYP3A4 by flavonoids, explore the molecular mechanism, and assess the biological effects on dronedarone (DND) induced toxicity. The results showed that flavone, tangeretin, sinensetin and 6-hydroxyflavone increased the cell viability by decreasing DND-induced cytotoxicity. These four flavonoids could activate the metabolism of DND in hamster pharmacokinetics study. Furthermore, both molecular docking and circular dichroism analysis partially illustrated the molecular mechanism of heterotropic activation. Finally, the pharmacophore model suggested B aromatic ring, hydrophobic groups at 7-position and hydrogen bond acceptors at 4-position may play a vital role in activation of flavonoids on CYP3A4. Taken together, our findings would provide useful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.


Asunto(s)
Antiarrítmicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Dronedarona/toxicidad , Activadores de Enzimas/farmacología , Flavonoides/farmacología , Animales , Antiarrítmicos/farmacocinética , Dicroismo Circular , Cricetinae , Dronedarona/farmacocinética , Activación Enzimática , Interacciones de Hierba-Droga , Enlace de Hidrógeno , Masculino , Mesocricetus , Modelos Moleculares , Simulación del Acoplamiento Molecular
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