Multimodal mechanisms and enhanced efficiency of atrial fibrillation cardioversion by pulmonary delivery of a novel flecainide formulation.

Autor: Tessarolo Silva F; Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.; Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil., Pedreira GC; Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.; Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil., Medeiros SA; Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.; Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil., Bortolotto AL; Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.; Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil., Araujo Silva B; Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.; Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil., Hurrey M; InCarda Therapeutics, Newark, California., Madhavapeddi P; InCarda Therapeutics, Newark, California., Schuler C; InCarda Therapeutics, Newark, California., Belardinelli L; InCarda Therapeutics, Newark, California., Verrier RL; Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Jazyk: angličtina
Zdroj: Journal of cardiovascular electrophysiology [J Cardiovasc Electrophysiol] 2020 Jan; Vol. 31 (1), pp. 205-213. Date of Electronic Publication: 2019 Dec 03.
DOI: 10.1111/jce.14289
Abstrakt: 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-ß-cyclodextrin [HPßCD]) 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 HPßCD were compared to the traditional acetate formulation.
Results: Intratracheal instillation of flecainide HPßCD 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 HPßCD, atrial depolarization (P a ) 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 HPßCD 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 HPßCD 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.
(© 2019 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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