title: Sustained release of milrinone delivered via microparticles in a rodent model of myocardial infarction.
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.
authors.affiliation: Division of Cardiothoracic Surgery and Surgical Research, Royal Victoria Hospital, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Hamood
authors.initials: H
authors.lastname: Al Kindi
authors.affiliation: Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kan.
authors.forename: Arghya
authors.initials: A
authors.lastname: Paul
authors.affiliation: Division of Cardiology, Montreal General Hospital, Montreal, Quebec, Canada.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: You
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Oleg
authors.initials: O
authors.lastname: Nepotchatykh
authors.affiliation: Division of Cardiology, Montreal General Hospital, Montreal, Quebec, Canada.
authors.forename: Adel
authors.initials: A
authors.lastname: Schwertani
authors.affiliation: Biomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Satya
authors.initials: S
authors.lastname: Prakash
authors.affiliation: Division of Cardiothoracic Surgery and Surgical Research, Royal Victoria Hospital, McGill University Health Center, Montreal, Quebec, Canada. Electronic address: dshumtim@yahoo.ca.
authors.forename: Dominique
authors.initials: D
authors.lastname: Shum-Tim
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D015815:Cell Adhesion Molecules / Q000097:blood; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000097:blood; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004337:Drug Carriers; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000737:chemistry; D008863:Microspheres; D020105:Milrinone / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011917:Rats, Inbred Lew; D012995:Solubility; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D015815:Cell Adhesion Molecules; D016207:Cytokines; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D018836:Inflammation Mediators; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D020105:Milrinone