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Liposomal Amiodarone Augments Anti-arrhythmic Effects and Reduces Hemodynamic Adverse Effects in an Ischemia/Reperfusion Rat Model

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Abstract

Purpose

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.

Methods and 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.

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Acknowledgments

The authors thank Takaki Hayakawa for her technical assistance, Takeshi Aiba for his special advice about data analysis. This research was supported by Grants-in-Aid from the Ministry of Health, Labor, and Welfare of Japan; Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; grants from the Japan Heart Foundation; and grants from the Japan Cardiovascular Research Foundation.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Takashi Matsuzaki, Shoji Sanada, Hai Ying Fu, Keiji Okuda, Masaki Yamato, Yoshihiro Asano, Issei Komuro & Tetsuo Minamino

  2. Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, 565-8565, Japan

    Hiroyuki Takahama, Masanori Asakura & Masafumi Kitakaze

  3. Department of Medical Biochemistry and Global COE, University of Shizuoka Graduate School of Pharmaceutical Sciences, Shizuoka, 422-8526, Shizuoka, Japan

    Hirokazu Shigematsu, Tomohiro Asai & Naoto Oku

  4. Department of Cardiovascular Science and Technology, Kyoto Prefectural University School of Medicine, Kyoto, 602-8566, Japan

    Hiroshi Asanuma

  5. Division of Cardiovascular Disease, Mayo Clinic, Rochester, MN, 55902, USA

    Hiroyuki Takahama

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  1. Hiroyuki Takahama
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  2. Hirokazu Shigematsu
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  14. Masafumi Kitakaze
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  15. Tetsuo Minamino
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Corresponding author

Correspondence to Tetsuo Minamino.

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Takahama, H., Shigematsu, H., Asai, T. et al. Liposomal Amiodarone Augments Anti-arrhythmic Effects and Reduces Hemodynamic Adverse Effects in an Ischemia/Reperfusion Rat Model. Cardiovasc Drugs Ther 27, 125–132 (2013). https://doi.org/10.1007/s10557-012-6437-6

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  • DOI: https://doi.org/10.1007/s10557-012-6437-6

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