RESUMEN
Amiodarone and mexiletine are used for ventricular arrhythmias, for which a combination therapy of both anti-arrhythmic drugs (AADs) is not uncommon. Therapeutic drug monitoring (TDM) can be beneficial for clinical guidance of therapy, especially to correctly identify adverse events. Desethylamiodarone, the active metabolite of amiodarone, accumulates over time and is associated with serious adverse events. Therefore, simultaneous TDM for amiodarone, desethylamiodarone and mexiletine is advantageous in clinical practice. The presented LC-MS/MS method was validated for selectivity, matrix effect, linearity, accuracy, precision, carry-over and stability. The method was continuously evaluated during eight months of clinical use. The method was shown to be linear within the measured range of 0.1 to 10 mg/L for each component. The matrix effect was considered negligible. No interfering responses were found for amiodarone, desethylamiodarone and the isotopic-labeled internal standards. A constant and reproducible within-run contribution of 45.3 %, originating from the system, was identified for mexiletine. The systemic contribution to the peak area of the lowest quantifiable concentration of mexiletine affected the selectivity and carry-over effect measurements. Multiple measurements showed that regression adjusted concentrations were accurate and reproducible, indicating calibration correction was applicable. Sample stability was found to be within limits for all storage conditions and freeze-thaw cycles. Furthermore, long-term method evaluation with external controls resulted in stable measurements with a percentage coefficient of variance between 1.3 % and 6.3 %. The presented practical and reliable method is applicable for clinical TDM and will allow clinical practitioners to guide drug therapy of amiodarone and mexiletine.
Asunto(s)
Amiodarona , Mexiletine , Espectrometría de Masas en Tándem , Amiodarona/sangre , Amiodarona/análogos & derivados , Humanos , Espectrometría de Masas en Tándem/métodos , Mexiletine/sangre , Mexiletine/análogos & derivados , Mexiletine/química , Reproducibilidad de los Resultados , Cromatografía Liquida/métodos , Modelos Lineales , Monitoreo de Drogas/métodos , Antiarrítmicos/sangre , Antiarrítmicos/farmacocinética , Límite de Detección , Estabilidad de Medicamentos , Sensibilidad y EspecificidadRESUMEN
Late sodium current (INa) inhibitors are a new subclass of antiarrhythmic agents. To overcome the drawbacks, e.g., low efficacy and inhibition effect on K+ current, of the FDA-approved late INa inhibitor ranolazine, chain amide 6a-6q, 1,4-disubstituted piperazin-2-ones 7a-7s, and their derivatives 8a-8n were successively designed, synthesized, and evaluated in vitro on the NaV1.5-transfected HEK293T cells by the whole-cell patch clamp recording assay at the concentration of 40 µM. Among the new skeleton compounds, 7d showed the highest efficacy (IC50 = 2.7 µM) and good selectivity (peak/late ratio >30 folds), as well as excellent pharmacokinetics properties in mice (T1/2 of 3.5 h, F = 90%, 3 mg/kg, po). It exhibited low hERG inhibition and was able to reverse the ATX-II-induced augmentation of late INa phenotype of LQT3 model in isolated rabbit hearts. These results suggest the application potentials of 7d in the treatments of arrhythmias related to the enhancement of late INa.
Asunto(s)
Piperazinas , Animales , Conejos , Células HEK293 , Humanos , Piperazinas/farmacología , Piperazinas/química , Piperazinas/síntesis química , Piperazinas/farmacocinética , Antiarrítmicos/farmacología , Antiarrítmicos/química , Antiarrítmicos/farmacocinética , Antiarrítmicos/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacocinética , Ratones , Síndrome de QT Prolongado/inducido químicamente , Relación Estructura-Actividad , Masculino , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Corazón/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Canal de Potasio ERG1/antagonistas & inhibidores , Canal de Potasio ERG1/metabolismo , Trastorno del Sistema de Conducción CardíacoRESUMEN
OBJECTIVE: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. METHODS: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. RESULTS: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. CONCLUSION: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.
Asunto(s)
Amiodarona , Enfermedad Hepática Inducida por Sustancias y Drogas , Humanos , Dronedarona , Amiodarona/efectos adversos , Amiodarona/farmacocinética , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , DifilinaRESUMEN
PURPOSE: Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. METHODS: This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. RESULTS: The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. CONCLUSIONS: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.
Asunto(s)
Antiarrítmicos/farmacocinética , Modelos Biológicos , Ésteres del Ácido Sulfúrico/farmacocinética , Animales , Antiarrítmicos/administración & dosificación , Perros , Evaluación Preclínica de Medicamentos , Femenino , Eliminación Hepatobiliar , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Eliminación Intestinal , Masculino , Microsomas Hepáticos , Ratas , Eliminación Renal , Ésteres del Ácido Sulfúrico/administración & dosificación , Distribución TisularRESUMEN
State-dependent sodium channel blockers are often prescribed to treat cardiac arrhythmias, but many sodium channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a sodium channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the sodium channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-sodium channel interaction by Moreno et al. Specifically, we find that (1) the vast majority of lidocaine bound to sodium channels is in the neutral form, i.e., the binding of charged lidocaine to sodium channels is negligible, and (2) neutral lidocaine binds almost exclusively to inactivated channels and, upon binding, immobilizes channels in the inactivated state. We then develop a novel 3-variable lidocaine-sodium channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates an extensive amount of the voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.
Asunto(s)
Corazón/efectos de los fármacos , Lidocaína/farmacología , Lidocaína/farmacocinética , Modelos Cardiovasculares , Miocardio/metabolismo , Canales de Sodio Activados por Voltaje/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Arritmias Cardíacas/metabolismo , Biología Computacional , Simulación por Computador , Frecuencia Cardíaca/fisiología , Humanos , Cinética , Cadenas de Markov , Técnicas de Placa-Clamp , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinética , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro-in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration-effect relationship into in vivo effective human doses, using the calculated in vitro area under the curve (AUC) of amiodarone as the pharmacokinetic metric. The upper benchmark dose (BMDU) was calculated and compared with clinical doses eliciting neurological adverse effects in patients. The AUCs in the in vitro brain cell culture after 14-day repeated dosing of nominal concentration equal to 1.25 and 2.5 µM amiodarone were 1.00 and 1.99 µg*h/mL, respectively. The BMDU was 385.4 mg for intravenous converted to 593 mg for oral application using the bioavailability factor of 0.65 as reported in the literature. The predicted dose compares well with neurotoxic doses in patients supporting the hypothesis that impaired ChAT activity may be related to the molecular/cellular mechanisms of amiodarone neurotoxicity. Our study shows that predicting effects from in vitro data together with IVIVE can be used at the initial stage for the evaluation of potential adverse drug reactions and safety assessment in humans.
Asunto(s)
Amiodarona/toxicidad , Antiarrítmicos/toxicidad , Modelos Biológicos , Síndromes de Neurotoxicidad/etiología , Amiodarona/administración & dosificación , Amiodarona/farmacocinética , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Síndromes de Neurotoxicidad/fisiopatología , Ratas , Distribución Tisular , Pruebas de ToxicidadRESUMEN
Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Perros/genética , Genotipo , Orosomucoide/metabolismo , Polimorfismo Genético , Amitriptilina/farmacocinética , Anestésicos Locales/farmacocinética , Animales , Antiarrítmicos/farmacocinética , Antidepresivos Tricíclicos/farmacocinética , Perros/sangre , Perros/metabolismo , Regulación de la Expresión Génica/fisiología , Inhibidores de la Proteasa del VIH/farmacocinética , Indinavir/farmacocinética , Lidocaína/farmacocinética , Orosomucoide/genética , Unión Proteica , Verapamilo/farmacocinéticaRESUMEN
Dronedarone and ticagrelor have high co-administration potential in patients with both acute coronary syndrome and atrial fibrillation. The objective of the present in vivo study was to investigate the potential interaction between dronedarone (5 and 10 mg/kg) and ticagrelor (5 and 10 mg/kg) when administered orally to rats. Forty Sprague-Dawley rats were randomly distributed into eight groups; consisting of a dronedarone only group, a ticagrelor only group, a dronedarone with ticagrelor-pretreatment group, and a ticagrelor with dronedarone-pretreatment group. Pharmacokinetic exposure (AUCinf = 1472 ng·h/mL) associated with administration of 10 mg/kg of dronedarone increased significantly, with delayed T max in the group that received ticagrelor-pretreatment when compared to the dronedarone only group (AUCinf = 723 ng·h/mL). In addition, pharmacokinetic exposure (AUCinf = 2391 ng·h/mL) associated with administration of 10 mg/kg of ticagrelor increased significantly, with increased K el (0.31 h-1) and decreased V z/F (14.6 L/kg) in the dronedarone-pretreatment group when compared to the ticagrelor only group (AUCinf = 1616 ng·h/mL; K el = 0.21 h-1; V z/F = 31.3 L/kg). Results of our study suggest that further investigation of a potential interaction between dronedarone and ticagrelor in humans is justified and that caution may need to be exercised when dronedarone and ticagrelor pharmacotherapies concomitantly.
Asunto(s)
Dronedarona/farmacocinética , Ticagrelor/farmacología , Administración Oral , Animales , Antiarrítmicos/farmacocinética , Humanos , Masculino , Inhibidores de Agregación Plaquetaria/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Aim: The study aims to investigate the clinical implication of nonfunctional poor metabolizer (PM) alleles and intermediate metabolizer (IM) alleles of CYP2D6, including the CYP2D6*10 allele which shows substrate-dependent decrease in enzymatic activity, in antiarrhythmic therapy using propafenone. Materials & methods: We examined serum propafenone concentrations and metabolic ratio, which was expressed as serum concentrations of propafenone to 5-hydroxypropafenone, in 66 Japanese patients with tachyarrhythmias. Results: The peak propafenone concentration and metabolic ratio in CYP2D6 PM allele carriers were higher than those in extensive metabolizer (EM)/EM, EM/IM and IM/IM genotype groups. Conclusion: Results suggest that CYP2D6 PM alleles affect peak propafenone concentration, but the CYP2D6 IM allele CYP2D6*10 has no clinical implication in propafenone dosing.
Asunto(s)
Antiarrítmicos/farmacocinética , Citocromo P-450 CYP2D6/genética , Propafenona/farmacocinética , Anciano , Alelos , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Biotransformación , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Polimorfismo Genético , Propafenona/análogos & derivados , Propafenona/sangre , Propafenona/uso terapéuticoRESUMEN
Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
Asunto(s)
Antiarrítmicos/efectos adversos , Electrocardiografía/efectos de los fármacos , Reacción en el Punto de Inyección/diagnóstico , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , Adolescente , Adulto , Antiarrítmicos/administración & dosificación , Antiarrítmicos/farmacocinética , Fibrilación Atrial/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Reacción en el Punto de Inyección/etiología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Atrial fibrillation is a common clinical manifestation in hospitalized patients with coronavirus disease 2019 (COVID-19). Medications used to treat atrial fibrillation, such as antiarrhythmic drugs and anticoagulants, may have significant drug interactions with emerging COVID-19 treatments. Common unintended nontherapeutic target effects of COVID-19 treatment include potassium channel blockade, cytochrome P 450 isoenzyme inhibition or activation, and P-glycoprotein inhibition. Drug-drug interactions with antiarrhythmic drugs and anticoagulants in these patients may lead to significant bradycardia, ventricular arrhythmias, or severe bleeding. It is important for clinicians to be aware of these interactions, drug metabolism changes, and clinical consequences when choosing antiarrhythmic drugs and anticoagulants for COVID-19 patients with atrial fibrillation. The objective of this review is to provide a practical guide for clinicians who are managing COVID-19 patients with concomitant atrial fibrillation.
Asunto(s)
Antiarrítmicos/uso terapéutico , Anticoagulantes/uso terapéutico , Antivirales/uso terapéutico , Fibrilación Atrial/terapia , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Antivirales/efectos adversos , Antivirales/farmacocinética , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Interacciones Farmacológicas , Interacciones Microbiota-Huesped , Humanos , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Neumonía Viral/virología , Medición de Riesgo , Factores de Riesgo , SARS-CoV-2 , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Switching between antiarrhythmic drugs is timed to minimize arrhythmia recurrence and adverse reactions. Dronedarone and amiodarone have similar electrophysiological profiles; however, little is known about the optimal timing of switching, given the long half-life of amiodarone. METHODS: The ARTEMIS atrial fibrillation (AF) Loading and Long-term studies evaluated switching patients with paroxysmal/persistent AF from amiodarone to dronedarone. Patients were randomized based on the timing of the switch: immediate, after a 2-week, or after a 4-week washout of amiodarone. Patients who did not convert to sinus rhythm after amiodarone loading underwent electrical cardioversion. The primary objectives were, for the Loading study, to evaluate recurrence of AF ≤60 days; and for the Long-term study, to profile the pharmacokinetics of dronedarone and its metabolite according to different timings of dronedarone initiation. RESULTS: In ARTEMIS AF Loading, 176 were randomized (planned 768) after a 28 ± 2 days load of oral amiodarone. Atrial fibrillation recurrence trended less in the immediate switch versus 4-week washout group (hazard ratio [HR] = 0.65 [97.5% CI: 0.34-1.23]; P = .14) and in the 2-week washout versus the 4-week washout group (HR = 0.75 [97.5% CI: 0.41-1.37]; P = .32). In ARTEMIS AF Long-term, 108 patients were randomized (planned 105). Pharmacokinetic analyses (n = 97) showed no significant differences for dronedarone/SR35021 exposures in the 3 groups. CONCLUSION: The trial was terminated early due to poor recruitment and so our findings are limited by low numbers. However, immediate switching from amiodarone to dronedarone appeared to be well tolerated and safe.
Asunto(s)
Amiodarona/administración & dosificación , Antiarrítmicos/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Dronedarona/administración & dosificación , Sustitución de Medicamentos , Anciano , Amiodarona/efectos adversos , Amiodarona/farmacocinética , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Fibrilación Atrial/diagnóstico , Dronedarona/efectos adversos , Dronedarona/farmacocinética , Sustitución de Medicamentos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Resultado del TratamientoRESUMEN
Coronavirus disease 2019 (COVID-19) outbreak is a public health emergency of international concerns because of a highly pathogenic human coronavirus (HCoV), actually named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite much emerging data about the epidemiological association between cardiovascular diseases and COVID-19, little is still known about atrial fibrillation and its optimal management in this clinical contest. The aim of our review is to describe the pharmacological interactions between cardiovascular drugs more commonly used in atrial fibrillation management and experimental COVID-19 therapies, based on EU and US summaries of product characteristics.
Asunto(s)
Antiarrítmicos/uso terapéutico , Anticoagulantes/uso terapéutico , Antivirales/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Anticoagulantes/efectos adversos , Anticoagulantes/farmacocinética , Antivirales/efectos adversos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Interacciones Farmacológicas , Interacciones Huésped-Patógeno , Humanos , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Neumonía Viral/virología , Factores de Riesgo , SARS-CoV-2 , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Landiolol hydrochloride, a highly cardio-selective beta-1 blocker with an ultra-short-acting half-life of 4 minutes, was originally approved by Japan for treatment of intraoperative tachyarrhythmias. This review aims to provide an integrated overview of the current state of knowledge of landiolol hydrochloride in the management of arrhythmia in critical settings. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library to retrieve relevant articles with a total of 65 records identified. RESULTS: The high ß1 selectivity (ß1/ß2 ratio of 255:1) of landiolol causes a more rapid heart rate (HR) decrease compared to esmolol while avoiding decreases in mean arterial blood pressure. Recently, it has been found useful in left ventricular dysfunction patients and fatal arrhythmia requiring emergency treatment. Recent random clinical trials (RCT) have revealed therapeutic and prophylactic effects on arrhythmia, and very low-dose landiolol might be effective for preventing postoperative atrial fibrillation (POAF) and sinus tachycardia. Likewise, landiolol is an optimal choice for perioperative tachycardia treatment during cardiac surgery. The high ß1 selectivity of landiolol is useful in heart failure patients as a first-line therapy for tachycardia and arrhythmia as it avoids the typical depression of cardiac function seen in other ß-blockers. Application in cardiac injury after percutaneous coronary intervention (PCI), protection for vital organs (lung, kidney, etc.) during sepsis, and stabilizing hemodynamics in pediatric patients are becoming the new frontier of landiolol use. CONCLUSION: Landiolol is useful as a first-line therapy for the prevention of POAF after cardiac/non-cardiac surgery, fatal arrhythmias in heart failure patients and during PCI. Moreover, the potential therapeutic effect of landiolol for sepsis in pediatric patients is currently being explored. As positive RCT results continue to be published, new clinical uses and further clinical studies in various settings by cardiologists, intensivists and pediatric cardiologists are being conducted.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/prevención & control , Frecuencia Cardíaca/efectos de los fármacos , Morfolinas/uso terapéutico , Urea/análogos & derivados , Antagonistas de Receptores Adrenérgicos beta 1/efectos adversos , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Adulto , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Cuidados Críticos , Femenino , Humanos , Masculino , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Factores de Riesgo , Resultado del Tratamiento , Urea/efectos adversos , Urea/farmacocinética , Urea/uso terapéutico , Adulto JovenRESUMEN
Pharmacologic management of atrial fibrillation (AF) is a pressing problem. This arrhythmia afflicts >5 million individuals in the United States and prevalence is estimated to rise to 12 million by 2050. Although the pill-in-the-pocket regimen for self-administered AF cardioversion introduced over a decade ago has proven useful, significant drawbacks exist. Among these are the relatively long latency of effects in the range of hours along with potential for hypotension and other adverse effects. This experience prompted development of a new strategy for increasing plasma concentrations of antiarrhythmic drugs rapidly and for a limited time, namely, pulmonary delivery. In preclinical studies in Yorkshire pigs, intratracheal administration of flecainide was shown to cause a rapid, reproducible increase in plasma drug levels. Moreover, pulmonary delivery of flecainide converted AF to normal sinus rhythm by prolonging atrial depolarization, which slows intra-atrial conduction and seems to be directly correlated with efficacy in converting AF. The rapid rise in plasma flecainide levels optimizes its anti-AF effects while minimizing adverse influences on ventricular depolarization and contractility. A more concentrated and soluble formulation of flecainide using a novel cyclodextrin complex excipient reduced net drug delivery for AF conversion when compared to the acetate formulation. Inhalation of the beta-adrenergic blocking agent metoprolol slows ventricular rate and can also terminate AF. In human subjects, oral inhalation of flecainide acetate with a hand-held, breath-actuated nebulizer results in signature prolongation of the QRS complex without serious adverse events. Thus, pulmonary delivery is a promising advance in pharmacologic approach to management of AF.
Asunto(s)
Antiarrítmicos/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Flecainida/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Metoprolol/administración & dosificación , Administración por Inhalación , Animales , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Modelos Animales de Enfermedad , Composición de Medicamentos , Flecainida/efectos adversos , Flecainida/farmacocinética , Humanos , Metoprolol/efectos adversos , Metoprolol/farmacocinética , Nebulizadores y Vaporizadores , Resultado del TratamientoRESUMEN
Vanillin is a popular flavoring agent in the food, tobacco, and perfume industries. In this paper, we investigated the effect of vanillin on the transport rates of drugs with different levels of permeability (acyclovir, hydrochlorothiazide, propranolol and carbamazepine) through a Caco-2 cell bidirectional transport experiment. We also explored the underlying mechanism using an in silico technique and fluorescence anisotropy measurements. The influence of vanillin on the pharmacokinetics of drugs whose transport rates were affected by vanillin in vitro was then studied in vivo. Results showed that vanillin (100 µM) increased the cumulative amount of passively transported drugs (2.1-fold of hydrochlorothiazide, 1.49-fold of propranolol, 1.35-fold of acyclovir, and 1.34-fold of carbamazepine) in vitro. Molecular dynamics simulations revealed that vanillin disordered the structure of the lipid bilayer and reduced the energy barrier of drugs across the center of the membrane. The anisotropy of TMA-DPH also decreased in Caco-2 cells after treatment with vanillin (25 and 100 µM) and indicated an increase in membrane fluidity, which was dose-dependent. An oral bioavailability study indicated that vanillin (100 mg kg-1) significantly enhanced the Cmax and AUC0-6 of hydrochlorothiazide by 1.42-fold and 1.28-fold, respectively, and slightly elevated the Cmax of propranolol. In conclusion, vanillin can significantly increase the absorption of drugs with moderate oral bioavailability in vitro and in vivo by loosening the membrane. Thus, the concurrent consumption of drugs with food containing vanillin may result in increased drug plasma concentration and pose potential health risks.
Asunto(s)
Benzaldehídos/farmacología , Absorción Intestinal/efectos de los fármacos , Extractos Vegetales/farmacología , Aciclovir/farmacocinética , Administración Oral , Animales , Antiarrítmicos/farmacocinética , Anticonvulsivantes/farmacocinética , Antivirales/farmacocinética , Área Bajo la Curva , Benzaldehídos/administración & dosificación , Disponibilidad Biológica , Transporte Biológico , Células CACO-2/metabolismo , Carbamazepina/farmacocinética , Diuréticos/farmacocinética , Humanos , Hidroclorotiazida/farmacocinética , Técnicas In Vitro , Masculino , Extractos Vegetales/administración & dosificación , Propranolol/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Since deuterium replacement has a potential to modulate pharmacodynamics, pharmacokinetics and toxicity, we developed deuterated dronedarone; poyendarone, and assessed its cardiovascular effects. Poyendarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s was intravenously administered to the halothane-anesthetized dogs (n = 4), which provided peak plasma concentrations of 108 ± 10 and 1120 ± 285 ng/mL, respectively. The 0.3 mg/kg shortened the ventricular repolarization period. The 3 mg/kg transiently increased the heart rate at 5 min but decreased at 45 min, and elevated the total peripheral vascular resistance and left ventricular preload, whereas it reduced the mean blood pressure at 5 min, left ventricular contractility and cardiac output. The transient tachycardic action is considered to be induced by the hypotension-induced, reflex-mediated increase of sympathetic tone. The 3 mg/kg delayed both intra-atrial and intra-ventricular conductions, indicating Na+ channel inhibitory action. Moreover, the 3 mg/kg transiently shortened the ventricular repolarization period at 5 min. No significant change was detected in the late repolarization by poyendarone, indicating it might not hardly significantly alter rapidly activating delayed-rectifier K+ current (IKr). Poyendarone prolonged the atrial effective refractory period greater than the ventricular parameter. When compared with dronedarone, poyendarone showed similar pharmacokinetics of dronedarone, but reduced ß-adrenoceptor blocking activity as well as the cardio-suppressive effect. Poyendarone failed to inhibit IKr and showed higher atrial selectivity in prolonging the effective refractory period of atrium versus ventricle. Thus, the deuteration may be an effective way to improve the cardiovascular profile of dronedarone. Poyendarone is a promising anti-atrial fibrillatory drug candidate.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antiarrítmicos/administración & dosificación , Deuterio , Dronedarona/administración & dosificación , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Administración Intravenosa , Animales , Antiarrítmicos/farmacocinética , Canales de Potasio de Tipo Rectificador Tardío/efectos de los fármacos , Canales de Potasio de Tipo Rectificador Tardío/metabolismo , Perros , Dronedarona/análogos & derivados , Dronedarona/farmacocinética , Femenino , Sistema de Conducción Cardíaco/metabolismo , Periodo Refractario Electrofisiológico/efectos de los fármacosRESUMEN
Amiodarone is an iodinated benzofuran derivative, a highly lipophilic drug with unpredictable pharmacokinetics. Although originally classified as a class III agent due to its ability to prolong refractoriness in cardiac regions and prevent/terminate re-entry, amiodarone shows antiarrhythmic properties of all four antiarrhythmic drug classes. Amiodarone is a potent coronary and peripheral vasodilator and can be safely used in patients with left ventricular dysfunction after myocardial infarction or those with congestive heart failure or hypertrophic cardiomyopathy. Its use is regularly accompanied with QT and QTc-interval prolongation but rarely with ventricular proarrhythmia. It is the most powerful pharmacological agent for long-term sinus rhythm maintenance in patients with atrial fibrillation. Amiodarone, particularly if co-administered with beta-blockers, reduces the rate of arrhythmic death due to ventricular tachyarrhythmias in patients with heart failure, but its benefit on cardiovascular and overall survival in these patients is uncertain. In addition, amiodarone is an important adjuvant drug for the reduction of shocks in patients with an implantable cardioverter-defibrillator. Over the past 40 years, amiodarone became the most prescribed antiarrhythmic. Nevertheless, the slow onset of its antiarrhythmic action requires a loading dose while the high risk of non-cardiac toxicity and common drug-drug interactions limit its long-term use. Furthermore patients treated with amiodarone require a close supervision by the treating physician. Therefore amiodarone is generally considered a secondary therapeutic option. Long-term treatment with amiodarone should be based on the use of minimal doses for satisfactory arrhythmia outcome and serial screening for thyroid, liver and pulmonary toxicity.
Asunto(s)
Amiodarona/uso terapéutico , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Amiodarona/efectos adversos , Amiodarona/farmacocinética , Amiodarona/farmacología , Animales , Antiarrítmicos/efectos adversos , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacología , Arritmias Cardíacas/fisiopatología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , HumanosRESUMEN
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 MolecularRESUMEN
BACKGROUND: Many patients receiving dabigatran treatment might also require bisoprolol therapy. However, there is a possibility that bisoprolol as significant P-glycoprotein inhibitor might interact with dabigatran. STUDY QUESTION: To investigate the impact of concomitant bisoprolol therapy on dabigatran plasma level in patients with nonvalvular atrial fibrillation. STUDY DESIGN: A pilot drug interaction study in 29 patients with nonvalvular atrial fibrillation on dabigatran therapy. Bisoprolol was administrated in 18 patients. Blood samples were collected at baseline (in the morning, before any medication was administered) and at hour 2 (2 hours after administration of dabigatran and bisoprolol). RESULTS: The dabigatran plasma level was significantly higher at baseline and at hour 2 in patients treated with bisoprolol compared with patients without bisoprolol therapy. In addition, we have shown that this increase is affected by dabigatran dosage and concomitant treatment with proton-pump inhibitor and digoxin. The impact of bisoprolol on dabigatran concentration was still significant despite these confounders. CONCLUSIONS: This study demonstrated the interaction between dabigatran and bisoprolol, which is modulated with dabigatran dosage and concomitant treatment with proton-pump inhibitor and digoxin.