Multimodal mechanisms and enhanced efficiency of atrial fibrillation cardioversion by pulmonary delivery of a novel flecainide formulation
| Autor: | Giovanna C. Pedreira, Alexandre L. Bortolotto, Carlos Schuler, Luiz Belardinelli, Michael Hurrey, Sofia A. Medeiros, Bruna Araujo Silva, Fernanda Tessarolo Silva, Prashanti Madhavapeddi, Richard L. Verrier |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Time Factors medicine.medical_treatment Drug Compounding Sus scrofa Action Potentials 030204 cardiovascular system & hematology Cardioversion 03 medical and health sciences 0302 clinical medicine Bolus (medicine) Heart Conduction System Heart Rate Physiology (medical) Internal medicine Administration Inhalation Atrial Fibrillation medicine Animals Sinus rhythm 030212 general & internal medicine PR interval Flecainide Inhalation Dose-Response Relationship Drug business.industry Area under the curve Atrial fibrillation medicine.disease 2-Hydroxypropyl-beta-cyclodextrin Disease Models Animal Cardiology Cardiology and Cardiovascular Medicine business Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Journal of cardiovascular electrophysiologyREFERENCES. 31(1) |
| ISSN: | 1540-8167 |
| Popis: | Introduction Inhaled flecainide significantly alters atrial electrical properties with the potential to terminate atrial fibrillation (AF) efficiently by optimizing dose and drug formulation. Methods Seventeen Yorkshire pigs were studied. Intrapericardial acetylcholine and burst pacing were used to induce AF. Effects of a novel cyclodextrin formulation (hydroxypropyl-s-cyclodextrin [HPsCD]) of flecainide (75 mg/mL, 0.5 or 1.0 mg/kg, bolus) instilled intratracheally at 2 minutes after AF initiation were studied. Concentration time-area analyses of flecainide HPsCD were compared to the traditional acetate formulation. Results Intratracheal instillation of flecainide HPsCD accelerated the conversion of AF to sinus rhythm in a dose-proportional manner, shortening AF duration by 47% (P = .014) and 79% (P = .002) at the lower and higher doses, respectively, compared to intratracheal sterile water placebo. AF dominant frequency was reduced by 11% (P = .04) and 29% (P = .004) respective to dose. At 2 minutes after intratracheal flecainide HPsCD, atrial depolarization (Pa ) duration increased by 12% (P = .02) and 17% (P = .009) at the lower and higher doses, respectively. At this time, the PR interval was prolonged by 9% (P = .04 for the higher dose) and AV node conduction was slowed, decreasing the ventricular rate during AF by 16% (P = .002) and 28% (P = .007) for the lower and higher doses. Flecainide HPsCD achieved the more efficient conversion of AF than the acetate formulation, reflected in a markedly reduced area under the curve (P = .04). Conclusion Intratracheal instillation of the new flecainide HPsCD formulation effectively terminates AF through efficient multimodal actions including slowing of atrial conduction velocity and decreasing AF dominant frequency, allowing reduced net drug delivery and inhalation time. |
| Databáze: | OpenAIRE |
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