Epicardial controlled-release verapamil prevents ventricular tachycardia episodes induced by acute ischemia in a canine model.
Sustained-release preparations composed of verapamil-polymeric controlled-release matrices were characterized in vitro and utilized as epicardial implants in dogs with ischemic ventricular arrhythmias. Anesthetized open-chest dogs were subjected to 5 hourly, 10-min complete occlusions of the left anterior descending coronary artery followed by reperfusion. A controlled-release matrix preparation (20% verapamil, 80% polyurethane), placed on the left ventricular epicardium prior to the third occlusion, resulted in successful inhibition of ventricular tachycardia (VT) during acute ischemia in a dose-dependent manner. The largest matrix size used, 300 mg (20% verapamil), provided a net systemic dose of 0.52 +/- 0.18 mg/kg over 140 min and significantly reduced VT episodes during acute ischemia (fifth occlusion) compared to untreated controls (0.16 +/- 0.04 vs. 1.01 +/- 0.35 episodes/min, respectively; t = 2.62, p = 0.01). In controls, by the fifth occlusion ventricular fibrillation (VF) occurred after 5.41 +/- 0.78 min in 89% of animals. However, after a 300-mg verapamil matrix was placed on the left ventricular ischemic zone, VF occurred in only 45% (chi-squared = 4.1, p = 0.04, vs. controls) of the animals after 7.87 +/- 0.92 min (fifth occlusion). Systemic venous plasma verapamil levels during the 2 h following the 300-mg matrix ischemic zone implantation ranged from 8.4-22.0 ng/ml, while simultaneous regional coronary venous levels were 125.0-387.0 ng/ml. Sonomicrometry studies of left ventricular wall thickening carried out with a series of 300-mg verapamil matrix cardiac implants did not demonstrate any significant myocardial dysfunction. It is concluded that controlled-release verapamil, administered directly to the heart, was effective for preventing VT and VF associated with acute coronary ischemia, and that this route of administration was not associated with any significant deterioration of cardiac function.
Siden
R
R
University of Michigan Medical School, Ann Arbor 48109-0576.
Kadish
A
A
Flowers
W
W
Kutas
L
L
Bieneman
B K
BK
DePietro
J
J
Jenkins
J P
JP
Gallagher
K P
KP
Levy
R J
RJ
D000818:Animals; D003327:Coronary Disease / Q000150:complications*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D008297:Male; D010496:Pericardium; D011108:Polymers; D013610:Tachycardia / Q000150:complications / Q000517:prevention & control*; D014693:Ventricular Fibrillation / Q000150:complications / Q000517:prevention & control; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D003692:Delayed-Action Preparations; D004343:Drug Implants; D011108:Polymers; D014700:Verapamil