Liposomal amiodarone augments anti-arrhythmic effects and reduces hemodynamic adverse effects in an ischemia/reperfusion rat model.
OBJECTIVE
Although amiodarone is recognized as the most effective anti-arrhythmic drug available, it has negative hemodynamic effects. Nano-sized liposomes can accumulate in and selectively deliver drugs to ischemic/reperfused (I/R) myocardium, which may augment drug effects and reduce side effects. We investigated the effects of liposomal amiodarone on lethal arrhythmias and hemodynamic parameters in an ischemia/reperfusion rat model.


RESULTS
We prepared liposomal amiodarone (mean diameter: 113 ± 8 nm) by a thin-film method. The left coronary artery of experimental rats was occluded for 5 min followed by reperfusion. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads accumulated in the I/R myocardium. Amiodarone was measurable in samples from the I/R myocardium when liposomal amiodarone, but not amiodarone, was administered. Although the intravenous administration of amiodarone (3 mg/kg) or liposomal amiodarone (3 mg/kg) reduced heart rate and systolic blood pressure compared with saline, the decrease in heart rate or systolic blood pressure caused by liposomal amiodarone was smaller compared with a corresponding dose of free amiodarone. The intravenous administration of liposomal amiodarone (3 mg/kg), but not free amiodarone (3 mg/kg), 5 min before ischemia showed a significantly reduced duration of lethal arrhythmias (18 ± 9 s) and mortality (0 %) during the reperfusion period compared with saline (195 ± 42 s, 71 %, respectively).


CONCLUSIONS
Targeting the delivery of liposomal amiodarone to ischemic/reperfused myocardium reduces the mortality due to lethal arrhythmia and the negative hemodynamic changes caused by amiodarone. Nano-size liposomes may be a promising drug delivery system for targeting I/R myocardium with cardioprotective agents.
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, 565-8565, Japan.
Hiroyuki
H
Takahama
Hirokazu
H
Shigematsu
Tomohiro
T
Asai
Takashi
T
Matsuzaki
Shoji
S
Sanada
Hai Ying
HY
Fu
Keiji
K
Okuda
Masaki
M
Yamato
Hiroshi
H
Asanuma
Yoshihiro
Y
Asano
Masanori
M
Asakura
Naoto
N
Oku
Issei
I
Komuro
Masafumi
M
Kitakaze
Tetsuo
T
Minamino
D000638:Amiodarone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D008081:Liposomes; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D053758:Nanoparticles / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D008081:Liposomes; D000638:Amiodarone