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1.
Heart Rhythm ; 21(7): 1134-1142, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38417598

RESUMEN

BACKGROUND: Loading of oral sotalol for atrial fibrillation requires 3 days, frequently in the hospital, to achieve steady state. The Food and Drug Administration approved loading with intravenous (IV) sotalol through model-informed development, without patient data. OBJECTIVE: We present results of the first multicenter evaluation of this recent labeling for IV sotalol. METHODS: The Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry was a multicenter observational registry of patients undergoing elective IV sotalol load for atrial arrhythmias. Outcomes, measured from hospital admission until first outpatient follow-up, included adverse arrhythmia events, efficacy, and length of stay. RESULTS: Of 167 consecutively enrolled patients, 23% were female; the median age was 68 (interquartile range, 61-74) years, and the median CHA2DS2-VASc score was 3 (interquartile range, 2-4). Overall, 99% were admitted for sotalol initiation (1% for dose escalation), with a target oral sotalol dose of either 80 mg twice daily (85 [51%]) or 120 mg twice daily (78 [47%]); 62 patients (37%) had an estimated creatinine clearance ≤90 mL/min. On presentation, 40% of patients were in sinus rhythm, whereas 26% underwent cardioversion before sotalol infusion. In 2 patients, sotalol infusion was stopped for bradycardia or hypotension. In 6 patients, sotalol was discontinued before discharge because of QTc prolongation (3), bradycardia (1), or recurrent atrial arrhythmia (2). The mean length of stay was 1.1 days, and 95% (n = 159) were discharged within 1 night. CONCLUSION: IV sotalol loading is safe and feasible for atrial arrhythmias, with low rates of adverse events, and yields shorter hospitalizations. More data are needed on the minimal duration required for monitoring in the hospital.


Asunto(s)
Antiarrítmicos , Fibrilación Atrial , Sistema de Registros , Sotalol , Humanos , Sotalol/administración & dosificación , Femenino , Masculino , Fibrilación Atrial/tratamiento farmacológico , Persona de Mediana Edad , Antiarrítmicos/administración & dosificación , Anciano , Estudios Prospectivos , Relación Dosis-Respuesta a Droga , Resultado del Tratamiento , Infusiones Intravenosas , Administración Intravenosa , Estudios de Seguimiento
2.
Behav Brain Res ; 405: 113193, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33626390

RESUMEN

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on acute pentylenetetrazole (PTZ)-induced memory impairments, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (Glu), acetylcholine esterase (AChE) activity, and c-fos protein expression in rats. E177 (5 and 10 mg/kg, i.p.) significantly prolonged step-through latency (STL) time in single-trial passive avoidance paradigm (STPAP), and shortened transfer latency time (TLT) in elevated plus maze paradigm (EPMP) (all P < 0.05). Moreover, and in the hippocampus of PTZ-treated animals, E177 mitigated abnormal levels of AChE activity, ACh and HA (all P < 0.05), but failed to modify brain levels of GABA and Glu. Furthermore, E177 alleviated hippocampal oxidative stress by significantly decreasing the elevated levels of MDA, and increasing the abnormally decreased level of GSH (all P < 0.05). Furthermore, E177 reduced elevated levels of hippocampal c-fos protein expression in hippocampal tissues of PTZ-treated animals (all P < 0.05). The observed results propose the potential of H3R antagonist E177 with an added advantage of avoiding cognitive impairment, emphasizing the H3Rs as a prospective target for future pharmacological management of epilepsy with associated memory impairments.


Asunto(s)
Conducta Animal/efectos de los fármacos , Antagonistas del GABA/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacología , Aprendizaje/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Sotalol/farmacología , Animales , Modelos Animales de Enfermedad , Antagonistas del GABA/administración & dosificación , Antagonistas de los Receptores Histamínicos H3/administración & dosificación , Masculino , Trastornos de la Memoria/inducido químicamente , Pentilenotetrazol/farmacología , Ratas , Ratas Wistar , Sotalol/administración & dosificación
3.
Sci Rep ; 11(1): 452, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33432057

RESUMEN

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.


Asunto(s)
Antagonistas Adrenérgicos beta/efectos adversos , Progresión de la Enfermedad , Ensayos Clínicos Controlados Aleatorios como Asunto , Estado Asmático/inducido químicamente , Administración Oral , Antagonistas Adrenérgicos beta/administración & dosificación , Atenolol/administración & dosificación , Atenolol/efectos adversos , Bisoprolol/administración & dosificación , Bisoprolol/efectos adversos , Enfermedades Cardiovasculares/tratamiento farmacológico , Celiprolol/administración & dosificación , Celiprolol/efectos adversos , Femenino , Humanos , Incidencia , Infusiones Intravenosas , Masculino , Practolol/administración & dosificación , Practolol/efectos adversos , Propranolol/administración & dosificación , Propranolol/efectos adversos , Riesgo , Sotalol/administración & dosificación , Sotalol/efectos adversos , Estado Asmático/epidemiología , Timolol/administración & dosificación , Timolol/efectos adversos
4.
Pharmacol Rep ; 73(2): 516-524, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33492655

RESUMEN

BACKGROUND: Due to blocking ß-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. MATERIALS AND METHODS: As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography-mass spectrometry. RESULTS: Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80-100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. CONCLUSION: Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.


Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Anticonvulsivantes/farmacología , Convulsiones/tratamiento farmacológico , Sotalol/administración & dosificación , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/farmacología , Animales , Anticonvulsivantes/farmacocinética , Reacción de Prevención/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Memoria a Largo Plazo/efectos de los fármacos , Ratones , Sotalol/farmacocinética , Sotalol/farmacología , Distribución Tisular
5.
J Cardiovasc Pharmacol Ther ; 25(5): 438-443, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32347108

RESUMEN

BACKGROUND: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies. METHODS: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation. RESULTS: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently. CONCLUSION: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.


Asunto(s)
Centros Médicos Académicos , Antiarrítmicos/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Cálculo de Dosificación de Drogas , Frecuencia Cardíaca/efectos de los fármacos , Fenetilaminas/administración & dosificación , Sotalol/administración & dosificación , Sulfonamidas/administración & dosificación , Anciano , Antiarrítmicos/efectos adversos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Boston , Monitoreo de Drogas , Femenino , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Persona de Mediana Edad , Fenetilaminas/efectos adversos , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Sotalol/efectos adversos , Sulfonamidas/efectos adversos , Torsades de Pointes/inducido químicamente , Torsades de Pointes/fisiopatología
6.
J Cardiovasc Pharmacol Ther ; 25(3): 212-218, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31707834

RESUMEN

Sotalol, a Vaughan-Williams Class III antiarrhythmic medication, is used to manage atrial arrhythmias. Due to its QT-prolonging effect and subsequent increased risk of torsade de pointes, many centers admit patients during the initial dosing period. Despite its widespread use, little information is available regarding dosing protocols during this period. In this multicenter investigation, dosing protocols in patients initiating sotalol therapy were examined to identify predictors of successful sotalol initiation. Over a 4-year period, patients admitted to 5 hospitals in the United States for inpatient telemetry monitoring during initiation for nonresearch purposes were enrolled. A 3-day course of 5 of 6 doses of sotalol was considered successful completion of the loading protocol. Of the 213 enrolled patients, over 90% were successfully discharged on sotalol. Significant bradycardia, ineffectiveness, and excessive QT prolongation were reasons for failed completion. Absence of a dose adjustment was a strong predictor of successful initiation (odds ratio: 6.6, 95% confidence interval: 1.3-32.7, P = .02). Hypertension, use of a calcium channel blocker, use of a separate ß-blocker, and presence of a pacemaker were predictors of dose adjustments. Marginal structural models (ie, inverse probability weighting based on probability of a dose adjustment) verified that these factors also predicted successful initiation via preventing any dose adjustment and suggests that considering these factors may result in a higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication. The study findings suggest that factors predicting need for dose adjustment can be used to identify patients who could undergo outpatient initiation. Prospective studies are needed to verify this approach.


Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Antiarrítmicos/administración & dosificación , Arritmias Cardíacas/tratamiento farmacológico , Frecuencia Cardíaca/efectos de los fármacos , Sotalol/administración & dosificación , Antagonistas Adrenérgicos beta/efectos adversos , Anciano , Antiarrítmicos/efectos adversos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatología , Bradicardia/inducido químicamente , Bradicardia/fisiopatología , Cálculo de Dosificación de Drogas , Monitoreo de Drogas , Femenino , Humanos , Pacientes Internos , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Medición de Riesgo , Factores de Riesgo , Sotalol/efectos adversos , Factores de Tiempo , Torsades de Pointes/inducido químicamente , Torsades de Pointes/fisiopatología , Resultado del Tratamiento , Estados Unidos
7.
Pediatr Cardiol ; 41(2): 418-422, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31664485

RESUMEN

Sotalol is a class III anti-arrhythmic agent with beta receptor blocking properties. Intravenous (IV) sotalol may be useful to treat refractory atrial and ventricular arrhythmias. A report on the efficacy and safety of IV sotalol in an infant on extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), who developed refractory ventricular arrhythmias following surgery for congenital heart disease. A 10-day old infant with severe pulmonary valve stenosis underwent surgical pulmonary valvectomy and enlargement of the main pulmonary artery. Post-operatively, the patient developed hemodynamically significant accelerated idioventricular rhythm which was not responsive to a combination of amiodarone, lidocaine, and procainamide leading to 2 cardiac arrest events and placement on ECMO. The amiodarone infusion was uptitrated to 20 mcg/kg/min, but episodes of the hemodynamically compromising arrhythmia continued. Amiodarone was discontinued and IV sotalol was initiated at 42 mg/m2/day, divided to 3 doses, and administered every 8 h, which completely suppressed the arrhythmia. The initial sotalol dose was calculated based on a daily dose of 90 mg/m2 and reduced by an age-related factor as recommended by the FDA approved prescribing information. Subsequently, acute kidney injury requiring CRRT developed. The patient remained on IV sotalol for 3 weeks and then transitioned to oral sotalol. The oral dose was increased to 44 mg/m2/day (3.5 mg every 8 h) to account for the difference in bioavailability between the IV and oral formulations. Serial sotalol levels during IV and PO therapy remained therapeutic on ECMO and CRRT. The patient maintained normal sinus rhythm on sotalol without adverse events. IV sotalol in the setting of ECMO and CRRT was safe and effective in controlling refractory hemodynamically compromising accelerated idioventricular rhythm unresponsive to amiodarone.


Asunto(s)
Antiarrítmicos/administración & dosificación , Arritmias Cardíacas/tratamiento farmacológico , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Sotalol/administración & dosificación , Administración Intravenosa , Arritmias Cardíacas/etiología , Esquema de Medicación , Oxigenación por Membrana Extracorpórea , Humanos , Recién Nacido , Masculino , Complicaciones Posoperatorias/tratamiento farmacológico , Estenosis de la Válvula Pulmonar/complicaciones , Estenosis de la Válvula Pulmonar/cirugía
8.
Clin Transl Sci ; 12(6): 648-656, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31328888

RESUMEN

Oral sotalol, used in adults for sinus rhythm control, is initiated at 80 mg b.i.d. and titrated to a maximum safe dose. The US Food and Drug Administration recommends monitoring the corrected QT interval (QTc ) for at least 3 days, until steady-state exposure of the drug is reached, before patient discharge, which can significantly impact the total cost of treatment. The objectives of this research were to design an accelerated intravenous sotalol loading and maintenance therapy that will reduce the hospital length of stay and to also evaluate the pharmacoeconomic impact in a hospital setting. Pharmacokinetic simulations of sotalol plasma concentrations vs. times profiles were performed to determine the optimal intravenous/oral transition regimen. A cost minimization analysis from the health sector perspective was conducted to assess the cost savings for these proposed accelerated regimens. For a chosen target dose of 120 mg b.i.d., two infusions of 40 mg over 1 hour and 20 mg over 0.5 hour, each followed up by an evaluation of QTc , can be administered followed immediately by the target oral maintenance dose of 120 mg at the end of the second infusion. Consequently, steady-state exposure and, therefore, steady-state QTc are obtained on the first day of therapy, facilitating an earlier hospital discharge. Two and 1-day mean total cost of -$3,123 (95% confidence interval (CI), -$3,640, -$2,607) -$4,820 (95% CI, -$5,352, -$4,288) were observed for this strategy, respectively. We are proposing an intravenous to oral transition strategy for sotalol that has the potential to significantly reduce cost and increase patient convenience.


Asunto(s)
Antiarrítmicos/administración & dosificación , Fibrilación Atrial/tratamiento farmacológico , Farmacología Clínica/métodos , Proyectos de Investigación , Sotalol/administración & dosificación , Administración Oral , Anciano , Antiarrítmicos/farmacocinética , Fibrilación Atrial/sangre , Simulación por Computador , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Monitoreo de Drogas , Electrocardiografía , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Modelos Biológicos , Estudios Retrospectivos , Sotalol/farmacocinética , Estados Unidos
10.
J Cardiovasc Pharmacol Ther ; 24(3): 288-297, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30497293

RESUMEN

INTRODUCTION: Direct comparison of the effects of antiarrhythmic agents on myocardial performance may be useful in choosing between medications in critically ill patients. Studies directly comparing multiple antiarrhythmic medications are lacking. The use of an experimental heart preparation permits examination of myocardial performance under constant loading conditions. METHODS: Hearts of Sprague Dawley rats (n = 35, 402-507 g) were explanted and cannulated in working heart model with fixed preload and afterload. Each heart was then exposed to a 3-hour infusion of procainamide (20 µg/kg/min), esmolol (100 or 200 µg/kg/min), amiodarone (10 or 20 mg/kg/d), sotalol (80 mg/m2/d), or placebo infusions (n = 5 per dose). Cardiac output, contractility (dP/dTmax), diastolic performance (dP/dTmin), and heart rate were compared between groups over time by linear mixed modeling. RESULTS: Compared with placebo, sotalol decreased contractility by an average of 24% ( P < .001) over the infusion period, as did amiodarone (low dose by 13%, P = .029; high dose by 14%, P = .013). Compared with placebo, mean cardiac output was significantly lower in animals treated with sotalol (by 22%, P = .016) and esmolol 200 µg/kg/min (by 23%, P = .012). Over time, amiodarone decreased cardiac output (20 mg/kg/d, ß = -89 [-144, -33] µL/min2 decrease, P = .002) and also worsened diastolic function, decreasing dP/dTmin by ∼18% and 22% ( P = .032 and P = .011, low and high doses, respectively). Procainamide did not have a significant effect on any measures of systolic or diastolic performance. CONCLUSIONS: In isolated hearts, amiodarone and sotalol depressed myocardial contractility, cardiac output, and diastolic function. However, procainamide did not negatively affect myocardial performance and represents a favorable agent in settings of therapeutic equivalence.


Asunto(s)
Amiodarona/administración & dosificación , Antiarrítmicos/administración & dosificación , Gasto Cardíaco/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Procainamida/administración & dosificación , Sotalol/administración & dosificación , Función Ventricular Izquierda/efectos de los fármacos , Amiodarona/toxicidad , Animales , Antiarrítmicos/toxicidad , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , Preparación de Corazón Aislado , Procainamida/toxicidad , Ratas Sprague-Dawley , Medición de Riesgo , Sotalol/toxicidad
12.
Int J Pharm Compd ; 22(6): 516-526, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30384353

RESUMEN

Compounded liquid medication is frequently required in children to allow easy dose adjustment and overcome swallowing difficulties. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients baclofen 2.0 mg/mL, carvedilol 5.0 mg/mL, hydrochlorothiazide 2.0 mg/mL, mercaptopurine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, phenobarbital 9.0 mg/mL and 15.0 mg/mL, propranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, pyrazinamide 100.0 mg/mL, spironolactone 2.0 mg/mL and 2.5 mg/mL, sotalol hydrochloride 5.0 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursodeoxycholic acid 20.0 mg/mL, and vancomycin hydrochloride 25.0 mg/mL. Suspensions were compounded with raw powders, except for mercaptopurine, pyrazinamide, and sotalol hydrochloride, which were made from commercial tablets. Stability was assessed by measuring the percentage recovery at 0 (baseline), 60 days, and 90 days after compounding for suspensions made with raw powders, which were stored at 2ÅãC to 8ÅãC. The stability of tablets, which were stored at 2ÅãC to 8ÅãC and 20ÅãC to 25ÅãC, was assessed by measuring the percentage recovery at 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by ultraviolet high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions in the conditions tested. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.


Asunto(s)
Baclofeno/química , Carvedilol/química , Hidroclorotiazida/química , Mercaptopurina/química , Metadona/química , Oseltamivir/química , Vehículos Farmacéuticos/química , Fenobarbital/química , Propranolol/química , Sotalol/química , Espironolactona/química , Almidón/química , Tacrolimus/química , Ácido Ursodesoxicólico/química , Vancomicina/química , Administración Oral , Baclofeno/administración & dosificación , Carvedilol/administración & dosificación , Composición de Medicamentos , Estabilidad de Medicamentos , Hidroclorotiazida/administración & dosificación , Concentración de Iones de Hidrógeno , Mercaptopurina/administración & dosificación , Metadona/administración & dosificación , Oseltamivir/administración & dosificación , Soluciones Farmacéuticas , Fenobarbital/administración & dosificación , Propranolol/administración & dosificación , Pirazinamida/administración & dosificación , Sotalol/administración & dosificación , Espironolactona/administración & dosificación , Suspensiones , Tacrolimus/administración & dosificación , Temperatura , Factores de Tiempo , Ácido Ursodesoxicólico/administración & dosificación , Vancomicina/administración & dosificación
13.
JAMA Cardiol ; 3(9): 877-882, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30073300

RESUMEN

Importance: Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective: To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. Design, Setting, and Participants: A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. Main Outcomes and Measures: Electrocardiographic changes 3 hours after sotalol administration. Results: A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P = .005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P = .005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n = 13 of 61 [21.0%]) than those taking levonorgestrel (n = 20 of 137 [14.6%]) or women taking no OCs (n = 24 of 207 [11.6%]; P = .01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P = .01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P < .001). Conclusions and Relevance: Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.


Asunto(s)
Antagonistas de Andrógenos/efectos adversos , Androstenos/efectos adversos , Síndrome de QT Prolongado/epidemiología , Sotalol/efectos adversos , Administración Oral , Adulto , Antagonistas de Andrógenos/administración & dosificación , Androstenos/administración & dosificación , Estudios de Cohortes , Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Femeninos/efectos adversos , Desogestrel/administración & dosificación , Desogestrel/efectos adversos , Europa (Continente) , Femenino , Humanos , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Modelos Logísticos , Síndrome de QT Prolongado/inducido químicamente , Norpregnenos/administración & dosificación , Norpregnenos/efectos adversos , Sotalol/administración & dosificación , Adulto Joven
14.
Heart Rhythm ; 15(12): 1862-1869, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30003959

RESUMEN

BACKGROUND: Arrhythmias are common in the pediatric population. In patients unable to take oral medications or in need of acute therapy, options of intravenous (IV) antiarrhythmic medications are limited. Recently IV sotalol has become readily available, but experience in children is limited. OBJECTIVE: The purpose of this study was to describe our initial experience with the use of IV sotalol in the pediatric population. METHODS: A retrospective study of all pediatric patients receiving IV sotalol was performed. Patient demographic characteristics, presence of congenital heart disease, arrhythmia type, efficacy of IV sotalol use, and adverse effects were evaluated. RESULTS: A total of 47 patients (26 (55%) male and 24 (51%) with congenital heart disease) received IV sotalol at a median age of 2.05 years (interquartile range 0.07-10.03 years) and a median weight of 12.8 kg (interquartile range 3.8-34.2 kg), and 13 (28%) received IV sotalol in the acute postoperative setting. Supraventricular arrhythmias occurred in 40 patients (85%) and ventricular tachycardia in 7 (15%). Among 24 patients receiving IV sotalol for an active arrhythmia, acute termination was achieved in 21 (88%). Twenty-three patients received IV sotalol as maintenance therapy for recurrent arrhythmias owing to inability to take oral antiarrhythmic medications; 19 (83%) were controlled with sotalol monotherapy. No patient required discontinuation of IV sotalol secondary to adverse effects, proarrhythmia, or QT prolongation. CONCLUSION: IV sotalol is an effective antiarrhythmic option for pediatric patients and may be an excellent agent for acute termination of active arrhythmias. It was well tolerated, with no patient requiring discontinuation secondary to adverse effects.


Asunto(s)
Cardiopatías Congénitas/complicaciones , Sotalol/administración & dosificación , Taquicardia Ventricular/tratamiento farmacológico , Administración Intravenosa , Adolescente , Antiarrítmicos/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Electrocardiografía Ambulatoria , Femenino , Estudios de Seguimiento , Cardiopatías Congénitas/tratamiento farmacológico , Cardiopatías Congénitas/fisiopatología , Humanos , Lactante , Masculino , Estudios Retrospectivos , Taquicardia Ventricular/complicaciones , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Resultado del Tratamiento
15.
Cardiology ; 140(3): 143-145, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30016794

RESUMEN

The pharmacologic treatment of arrhythmias has seen little advance over the past few years. Physicians treating life threatening or hemodynamically destabilizing arrhythmias depend almost entirely on intravenous (IV) amiodarone. This is regrettable due to the multiple toxicities of amiodarone and its long half-life. Once administered, it is a therapeutic commitment to long-term therapy. Given the very long terminal elimination half-life, treatment with amiodarone may interfere with baseline electrophysiologic studies and ablation procedures. Additionally, the side effect profile can be consequential, even with brief periods of treatment. Currently, sotalol, like amiodarone, is available in both IV and oral formulations, facilitating their use in emergency situations. IV sotalol has a rapid onset of action with linear pharmacokinetics. While sotalol's efficacy has mostly been evaluated in small clinical trials, 2 recent meta-analysis have been informative as to the utility of sotalol. Sotalol has similar efficacy as amiodarone, but has much more favorable adverse event profile. IV sotalol has been underutilized and could offer advantage in the treatment of AF for rate and rhythm control, as well in the pediatrics for treatment of supraventricular arrhythmias often resistant to other therapies.


Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Arritmias Cardíacas/tratamiento farmacológico , Sotalol/administración & dosificación , Administración Intravenosa , Antagonistas Adrenérgicos beta/efectos adversos , Amiodarona/administración & dosificación , Amiodarona/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Sotalol/efectos adversos
16.
Heart Lung Circ ; 27(11): 1318-1326, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29853342

RESUMEN

Sotalol is a non-selective beta-adrenergic blocking agent without intrinsic sympathomimetic activity. It has the additional unique property of producing pronounced prolongation of the cardiac action potential duration. Sotalol therapy has been indicated for the management of supraventricular arrhythmias, refractory life threatening ventricular arrhythmias and atrial fibrillation/flutter. Until recently, sotalol was only available in the oral form, however, it was approved for intravenous administration by the US Food & Drug Administration (FDA). The current recommendations are for sotalol 75-150mg to be administered intravenously over 5hours. This rate of administration does not reflect the majority of the research that has been performed with regards to intravenous sotalol. Also, the safety of intravenous bolus dosing of 100mg over 1 and 5minutes has previously been demonstrated. The antiarrhythmic action of sotalol depends on its ability to prolong refractoriness in the nodal and extra nodal tissue. Hence, by giving a lower dose over a long duration, patients may not necessarily benefit from its anti-arrhythmic potential. The purpose of this article is to review the research that has been conducted with regards to dosage and safety of intravenous sotalol, its electrophysiological effects and finally the spectrum of arrhythmias in which it has been used to date.


Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Sotalol/administración & dosificación , Antagonistas Adrenérgicos beta/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intravenosas
17.
Clin Ther ; 40(3): 450-455.e1, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29500139

RESUMEN

PURPOSE: There are few data on the risk for peripheral neuropathy associated with dronedarone, a newer antiarrhythmic medicine. The objective of this study was to assess whether dronedarone is potentially associated with an increased risk for peripheral neuropathy compared with other antiarrhythmics, including amiodarone, sotalol, flecainide, and propafenone. METHODS: The MarketScan database was used for identifying patients who were at least 18 years of age, had atrial fibrillation or flutter, and had not been diagnosed with peripheral neuropathy in the 180-day period prior to or on the date of the first prescription of an antiarrhythmic between July 20, 2009, and December 31, 2011. Peripheral neuropathy that occurred during the treatment period for a study drug was ascertained using ICD-9-CM diagnostic codes. For each antiarrhythmic, the incidence rate of peripheral neuropathy was calculated. The adjusted hazard ratio (aHR) for peripheral neuropathy for dronedarone compared with another antiarrhythmic was obtained, with control for age, sex, diabetes mellitus status, and the presence of other comorbidities. FINDINGS: The study population included 106,933 patients treated with dronedarone (n = 12,989), amiodarone (n = 45,173), sotalol (n = 22,036), flecainide (n = 14,244), or propafenone (n = 12,491). The incidence rates (per 1000 person-years) of peripheral neuropathy were 1.33 for dronedarone, 2.38 for amiodarone, 1.20 for sotalol, 1.08 for flecainide, and 1.97 for propafenone. The aHRs for peripheral neuropathy for dronedarone relative to other drugs ranged from 0.53 (95% CI, 0.21-1.34) compared with propafenone, to 0.94 (95% CI, 0.38-2.30) compared with sotalol. A new-user analysis showed similar results. IMPLICATIONS: The risks for peripheral neuropathy were not significantly different between dronedarone and other antiarrhythmics.


Asunto(s)
Antiarrítmicos/efectos adversos , Dronedarona/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Amiodarona/efectos adversos , Amiodarona/uso terapéutico , Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Estudios de Cohortes , Bases de Datos Factuales , Dronedarona/administración & dosificación , Femenino , Flecainida/administración & dosificación , Flecainida/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Propafenona/efectos adversos , Propafenona/uso terapéutico , Estudios Retrospectivos , Sotalol/administración & dosificación , Sotalol/efectos adversos
18.
Circ Arrhythm Electrophysiol ; 11(1): e005663, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29305400

RESUMEN

BACKGROUND: The VANISH trial (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease) compared the effectiveness of escalated antiarrhythmic drug therapy to catheter ablation in patients with prior myocardial infarction, an implanted defibrillator, and ventricular tachycardia (VT). The effectiveness of these interventions in patients on sotalol versus amiodarone was compared. METHODS AND RESULTS: Analysis was conducted based on whether patients had recurrent VT, despite amiodarone (amio-refractory) or nonamiodarone drugs (sotalol-refractory). Outcomes included death, VT storm, appropriate implantable cardioverter defibrillator shock, and any ventricular arrhythmia. At baseline, 169 (65.2%) were amio-refractory, and 90 (34.7%) were sotalol-refractory (1 patient on procainamide rather than sotalol). Amio-refractory patients had more renal insufficiency (23.7% versus 10%; P=0.0008), worse New York Heart Association class (82.3% II/III versus 65.5%; P=0.0003), and lower ejection fraction (29±9.7% versus 35.2±11%; P<0.0001). Within the amio-refractory group, ablation resulted in reduction of any ventricular arrhythmia compared with escalated drug therapy (hazard ratio, 0.53; 95% confidence interval, 0.31-0.9), P=0.020). Sotalol-refractory patients had trends toward higher mortality and VT storm with ablation, with no effect on implantable cardioverter defibrillator shocks. Within the escalated drug therapy arm, amio-refractory patients had a higher rate of the composite outcome (hazard ratio, 1.94; 95% confidence interval, 1.14-3.29; P=0.0144) and a trend to higher mortality (hazard ratio, 2.40; 95% confidence interval, 0.93-6.22; P=0.07), whereas mortality was not different between amio- and sotalol-refractory patients within the ablation treatment group. CONCLUSIONS: Patients with amio-refractory VT have a higher rate of ventricular arrhythmia and mortality than those with sotalol-refractory VT and derive greater benefit of catheter ablation than for patients with sotalol-refractory VT who are switched to amiodarone. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00905853.


Asunto(s)
Amiodarona/administración & dosificación , Ablación por Catéter/métodos , Sistema de Conducción Cardíaco/fisiopatología , Isquemia Miocárdica/complicaciones , Sotalol/administración & dosificación , Taquicardia Ventricular/terapia , Anciano , Antiarrítmicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Sustitución de Medicamentos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Método Simple Ciego , Taquicardia Ventricular/complicaciones , Taquicardia Ventricular/fisiopatología , Resultado del Tratamiento
19.
Equine Vet J ; 50(3): 377-383, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29023952

RESUMEN

BACKGROUND: Arrhythmias in horses may require long-term anti-arrhythmic therapy. Unfortunately, oral anti-arrhythmic drugs for use in horses are currently scarce. In human patients and small animals, sotalol, a ß-blocker with class III anti-arrhythmic properties, is often used for long-term treatment. OBJECTIVES: To determine the pharmacokinetics of sotalol at multiple oral dosages in unfasted horses, as well as the effects on electro- and echocardiographic measurements, right atrial and ventricular monophasic action potential (MAP) and effective refractory period (ERP). STUDY DESIGN: Placebo controlled, double-blinded experiment. MATERIALS AND METHODS: Six healthy, unfasted Warmblood horses were given either 0, 2, 3 or 4 mg/kg bodyweight (bwt) sotalol orally (PO) twice daily (bid) for 9 days in a randomised cross-over design. Echocardiography and surface electrocardiography were performed and plasma concentrations of sotalol and right atrial and right ventricular MAPs and ERPs were determined at steady-state conditions. Statistical analysis was performed using a repeated measures univariate analysis with post hoc Bonferroni corrections. RESULTS: Calculated mean steady-state plasma concentrations determined by nonlinear mixed-effect modelling were 287 (range 234-339), 409 (359-458) and 543 (439-646) ng/mL for 2, 3 and 4 mg/kg bwt sotalol PO bid respectively. Sotalol significantly increased the QT interval and ERPs, but, despite increasing plasma concentrations, higher dosages did not result in a progressive increase in QT interval or ERPs. Echocardiographic and other electrocardiographic measurements did not change significantly. MAP durations at 90% repolarisation were not significantly different during sotalol treatment. Besides transient local sweating, no side effects were noted. MAIN LIMITATIONS: Study size and ad libitum feeding of hay. CONCLUSIONS: Sotalol at a dose of 2, 3 and 4 mg/kg bwt PO bid increases the QT interval and ERP and might be a useful drug for long-term anti-arrhythmic therapy in horses.


Asunto(s)
Antiarrítmicos/farmacocinética , Electrocardiografía/veterinaria , Caballos , Periodo Refractario Electrofisiológico/efectos de los fármacos , Sotalol/farmacocinética , Animales , Antiarrítmicos/administración & dosificación , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Ecocardiografía/veterinaria , Femenino , Masculino , Sotalol/administración & dosificación , Sotalol/sangre
20.
Pharmacol Rep ; 69(6): 1173-1177, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29128797

RESUMEN

BACKGROUND: Sotalol as a drug blocking ß-receptors and potassium KCNH2 channels may interact with different substances that affect seizures. Herein, we present interactions between sotalol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. METHODS: Effects of sotalol and antiepileptics alone on seizures were determined in the electroconvulsive threshold test, while interactions between sotalol and antiepileptic drugs were estimated in the maximal electroshock test in mice. Motor coordination and long-term memory were evaluated, respectively, in the chimney test and passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. RESULTS: Sotalol at doses up to 100mg/kg did not affect the electroconvulsive threshold. Applied at doses 60-100mg/kg, sotalol potentiated the antielectroshock action of valproate, while at doses 80-100mg/kg that of phenytoin. Sotalol (up to 100mg/kg) did not affect the action of carbamazepine or phenobarbital in the maximal electroshock. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Finally, sotalol did not change brain concentration of valproate and phenytoin, so pharmacokinetic interactions between the drugs are not probable. CONCLUSIONS: As far as obtained data may be extrapolated into clinical conditions, sotalol may be considered as an arrhythmic drug that does not reduce the action of classical antiepileptic drugs and thereby can be used in epileptic patients with cardiac arrhythmias.


Asunto(s)
Antiarrítmicos/farmacología , Anticonvulsivantes/farmacología , Convulsiones/tratamiento farmacológico , Sotalol/farmacología , Animales , Antiarrítmicos/administración & dosificación , Anticonvulsivantes/administración & dosificación , Reacción de Prevención/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Sinergismo Farmacológico , Electrochoque , Epilepsia/tratamiento farmacológico , Femenino , Inmunoensayo de Polarización Fluorescente , Ratones , Fenitoína/administración & dosificación , Fenitoína/farmacocinética , Fenitoína/farmacología , Sotalol/administración & dosificación , Distribución Tisular , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacocinética , Ácido Valproico/farmacología
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