Hamood Al Kindi1, Arghya Paul2, Zhipeng You3, Oleg Nepotchatykh4, Adel Schwertani3, Satya Prakash5, Dominique Shum-Tim6. 1. Division of Cardiothoracic Surgery and Surgical Research, Royal Victoria Hospital, McGill University Health Center, Montreal, Quebec, Canada. 2. Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kan. 3. Division of Cardiology, Montreal General Hospital, Montreal, Quebec, Canada. 4. Department of Chemistry, McGill University, Montreal, Quebec, Canada. 5. Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. 6. Division of Cardiothoracic Surgery and Surgical Research, Royal Victoria Hospital, McGill University Health Center, Montreal, Quebec, Canada. Electronic address: dshumtim@yahoo.ca.
Abstract
OBJECTIVE: The aim of the present study was to construct a new drug delivery system for milrinone using microparticles. This novel technology enhances drug bioavailability and decreases toxicity, with future implications for the treatment of end-stage heart failure. METHODS: Polylactic-co-glycolic acid microparticles (PLGA-MPs) loaded with milrinone were prepared using a double emulsion-solvent evaporation technique. In vitro release kinetics was evaluated at physiologic conditions. A total of 24 female Lewis rats underwent left coronary artery ligation. One week after ligation, all rats were randomized to 1 of 3 groups (n=8 per group). Group I received an intravenous injection of PLGA-MPs alone; group II, a bolus intravenous injection of milrinone; and group III an intravenous injection of milrinone-PLGA-MPs. All injections were administrated slowly by way of the tail vein over 10 minutes. Transthoracic echocardiography, noninvasive heart rate monitoring, and blood pressure measurements were performed at different predetermined intervals before and for 24 hours after the injection. All rats survived for 24 hours and were then killed by euthanasia. Serum plasma was taken for cytokine assays and determination of milrinone levels using high-performance liquid chromatography. RESULTS: Group III had a significantly greater left ventricular ejection fraction at 90 minutes and 3, 6, and 12 hours after treatment compared with the other groups. The milrinone plasma level was significantly greater in group III than in the other groups (group I, 0 ng/mL; group II, 1.7±2.4 ng/mL; group III, 9.1±2.2 ng/mL; P<.05). The intercellular adhesion molecule and cytokine-induced neutrophil chemoattractant-1 levels were significantly lower in group III than in the other 2 groups (P<.05). CONCLUSIONS: Drug encapsulation using microparticles can prolong the effects of milrinone. We propose a new strategy for future drug delivery in patients with end-stage heart failure.
OBJECTIVE: The aim of the present study was to construct a new drug delivery system for milrinone using microparticles. This novel technology enhances drug bioavailability and decreases toxicity, with future implications for the treatment of end-stage heart failure. METHODS:Polylactic-co-glycolic acid microparticles (PLGA-MPs) loaded with milrinone were prepared using a double emulsion-solvent evaporation technique. In vitro release kinetics was evaluated at physiologic conditions. A total of 24 female Lewis rats underwent left coronary artery ligation. One week after ligation, all rats were randomized to 1 of 3 groups (n=8 per group). Group I received an intravenous injection of PLGA-MPs alone; group II, a bolus intravenous injection of milrinone; and group III an intravenous injection of milrinone-PLGA-MPs. All injections were administrated slowly by way of the tail vein over 10 minutes. Transthoracic echocardiography, noninvasive heart rate monitoring, and blood pressure measurements were performed at different predetermined intervals before and for 24 hours after the injection. All rats survived for 24 hours and were then killed by euthanasia. Serum plasma was taken for cytokine assays and determination of milrinone levels using high-performance liquid chromatography. RESULTS: Group III had a significantly greater left ventricular ejection fraction at 90 minutes and 3, 6, and 12 hours after treatment compared with the other groups. The milrinone plasma level was significantly greater in group III than in the other groups (group I, 0 ng/mL; group II, 1.7±2.4 ng/mL; group III, 9.1±2.2 ng/mL; P<.05). The intercellular adhesion molecule and cytokine-induced neutrophil chemoattractant-1 levels were significantly lower in group III than in the other 2 groups (P<.05). CONCLUSIONS: Drug encapsulation using microparticles can prolong the effects of milrinone. We propose a new strategy for future drug delivery in patients with end-stage heart failure.