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1.
J Cardiovasc Pharmacol ; 69(3): 178-182, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28045761

RESUMEN

INTRODUCTION: We examined the effects of the selective late INa inhibitor eleclazine on the 50% probability of successful defibrillation (DFT50) before and after administration of amiodarone to determine its suitability for use in patients with implantable cardioverter defibrillators (ICDs). METHODS AND RESULTS: In 20 anesthetized pigs, transvenous active-fixation cardiac defibrillation leads were fluoroscopically positioned into right ventricular apex through jugular vein. ICDs were implanted subcutaneously. Dominant frequency of ventricular fibrillation was analyzed by fast Fourier transform. The measurements were made before drug administration (control), and at 40 minutes after vehicle, eleclazine (2 mg/kg, i.v., bolus over 15 minutes), or subsequent/single amiodarone administration (10 mg/kg, i.v., bolus over 10 minutes). Eleclazine did not alter DFT50, dominant frequency, heart rate, or mean arterial pressure (MAP). Subsequent amiodarone increased DFT50 (P = 0.006), decreased dominant frequency (P = 0.022), and reduced heart rate (P = 0.031) with no change in MAP. Amiodarone alone increased DFT50 (P = 0.005; NS compared to following eleclazine) and decreased dominant frequency (P = 0.003; NS compared to following eleclazine). CONCLUSION: Selective late INa inhibition with eleclazine does not alter DFT50 or dominant frequency of ventricular fibrillation when administered alone or in combination with amiodarone. Accordingly, eleclazine would not be anticipated to affect the margin of defibrillation safety in patients with ICDs.


Asunto(s)
Amiodarona/uso terapéutico , Cardioversión Eléctrica/métodos , Oxazepinas/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Fibrilación Ventricular/tratamiento farmacológico , Fibrilación Ventricular/fisiopatología , Amiodarona/farmacología , Animales , Masculino , Oxazepinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Porcinos , Fibrilación Ventricular/terapia , Canales de Sodio Activados por Voltaje/fisiología
2.
J Cardiovasc Electrophysiol ; 26(3): 329-35, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25346368

RESUMEN

INTRODUCTION: Ventricular rate during atrial fibrillation (AF) can be reduced by slowing atrioventricular (AV) node conduction and/or by decreasing dominant frequency of AF. We investigated whether combined administration of ivabradine and ranolazine reduces ventricular rate during AF. METHODS AND RESULTS: Ivabradine (maximum clinical dose, 0.25 mg/kg, and 0.10 mg/kg, i.v.) and ranolazine (2.4 mg/kg, i.v., bolus followed by 0.135 mg/kg/min) were studied in an anesthetized pig (N = 16) model of AF. Combined administration of 0.25 mg/kg ivabradine with ranolazine reduced ventricular rate during AF by 51.9 ± 9.7 beats/min (23%, P = 0.017) and dominant frequency of AF by 2.8 ± 0.5 Hz (32%, P = 0.005). It increased PR (P = 0.0002, P = 0.0007) and A-H intervals (P = 0.047, P = 0.002) during pacing at 130 and 180 beats/min, respectively, to a greater degree than additive effects of single agents. Combined administration of 0.1 mg/kg ivabradine with ranolazine exceeded additive effects of single agents on A-H intervals and dominant frequency of AF. Moreover, ranolazine potentiated low-dose ivabradine's reduction in ventricular rate, as combined administration more than doubled effects of the higher ivabradine dose alone and was similar to the combination with the higher dose. Neither drug nor their combination affected contractility (left ventricular [LV] dP/dt), QT or His-ventricular (H-V) intervals, or mean arterial pressure during sinus rhythm or AF. CONCLUSION: Combined administration of ivabradine and ranolazine at clinically safe levels decreases ventricular rate during AF by reducing AV node conduction and AF dominant frequency without QT prolongation or depression in contractility. Targeting these actions offers intrinsic advantages over conventional nodal agents, which can reduce contractility.


Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Benzazepinas/administración & dosificación , Fármacos Cardiovasculares/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Ranolazina/administración & dosificación , Animales , Fibrilación Atrial/fisiopatología , Quimioterapia Combinada , Cobayas , Frecuencia Cardíaca/fisiología , Ivabradina , Masculino , Porcinos
3.
Heart Rhythm ; 11(12): 2288-96, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25111327

RESUMEN

BACKGROUND: If channels are functionally expressed in atrioventricular (AV) nodal tissue. OBJECTIVE: The purpose of this study was to address whether the prototypical If inhibitor, ivabradine, at clinically safe concentrations can slow AV node conduction to reduce ventricular rate (VR) during atrial fibrillation (AF). METHODS: Effects of ivabradine (0.1 mg/kg i.v. bolus) were studied in an anesthetized Yorkshire pig (N = 7) model of AF and in isolated guinea pig hearts (N = 7). RESULTS: Ivabradine reduced heart rate (P = .0001) without affecting mean arterial pressure during sinus rhythm. The agent lengthened PR intervals in a rate-dependent manner (P = .0009) by 14 ± 2.7 ms (P = .003) and 25 ± 3.0 ms (P = .0004) and increased atrial-His (A-H) intervals in a rate-dependent manner (P = .020) by 10 ± 1.7 ms and 17 ± 2.8 ms during pacing at 130 and 180 bpm, respectively (both P = .0008). Similar rate-dependent effects were observed in isolated guinea pig hearts. Ivabradine slowed VR during AF from 240 ± 21 bpm to 211 ± 25 bpm (P = .041). The ivabradine-induced increase in A-H interval was inversely correlated with VR (r = -0.85, P = .03, at 130 bpm; r = -0.95, P = .003, at 180 bpm). QT and HV intervals, AF dominant frequency (8.5 ± 0.9 to 8.7 ± 1.1 Hz, P = NS), mean arterial pressure, and left ventricular dP/dt (1672 ± 222 to 1889 ± 229 mm Hg/s, P = NS) during AF were unaffected. CONCLUSION: Ivabradine's rate-dependent increase in A-H interval is highly correlated with VR during AF. As dominant frequency was unaltered, AV node conduction slowing during high nodal activation rates appears to be the main mechanism of ivabradine's VR reduction. If inhibition in the AV node may provide a promising target to slow VR during AF without depression in contractility.


Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Nodo Atrioventricular/efectos de los fármacos , Benzazepinas/farmacología , Electrocardiografía , Función Ventricular Izquierda/efectos de los fármacos , Análisis de Varianza , Animales , Fibrilación Atrial/fisiopatología , Nodo Atrioventricular/fisiopatología , Benzazepinas/farmacocinética , Cateterismo Cardíaco , Fármacos Cardiovasculares/farmacología , Modelos Animales de Enfermedad , Fluoroscopía/métodos , Cobayas , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Ivabradina , Masculino , Quimioterapia por Pulso , Distribución Aleatoria , Valores de Referencia , Sus scrofa , Porcinos
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