CARDIAC CONTROLLED RELEASE FOR ARRHYTHMIA THERAPY - LIDOCAINE-POLYURETHANE MATRIX STUDIES

[摘要] Cardiac arrhythmias are the principal cause of sudden death due to heart disease, and current therapy is inadequate. A novel approach for formulating a lidocaine-polyurethane controlled release matrix and implanting this drug delivery system directly onto the arrhythmic epicardium is reported. Lidocaine-HCl-polyurethane matrices (28% w/w) were fabricated and studied for their in vitro drug release into physiologic buffer, and their in vivo pharmacologic effectiveness in rapidly converting ouabain-induced ventricular tachycardia in dogs to normal sinus rhythm. In vitro lidocaine release was successfully modulated as a result of variations in fabrication: compression molding, and stirring during polymer synthesis. Lidocaine release in vitro from the most rapidly releasing matrix formulation delivered more than 40% of the contained drug delivered after only 20 minutes, and the remainder slowly released over one week or more. Direct epimyocardial placement of this formulation resulted in the prompt conversion of ouabain-induced ventricular tachycardia to normal sinus rhythm in all experimental animals (n = 6) studied in 1.5 .+-. 0.77 min (mean .+-. standard error), while controls (n = 4) had persistent ventricular tachycardia for more than 60 min. Site-specific therapy was as rapid as intravenous administration, but with lower plasma lidocaine levels after comparable dosages. It is concluded that lidocaine-polyurethane controlled release matrices can be fabricated with a broad range of initial release profiles, and that these matrices can rapidly initiate the conversion of ouabain-induced ventricular tachycardia to normal sinus rhythm.

[发布日期] 1988-12-01