Abstract 17359: Slow-release Prostacyclin Agonist using New Regional Drug Delivery System Promise Therapeutic Angiogenesis in a Porcine Chronic Myocardial Infarction
Background: Although prostacyclin is an endogenous factor for protection and regeneration of damaged tissue, the use of clinically available prostacyclin analogues for treating chronic pathological conditions, such as chronic myocardial infarction (MI) is limited owing to their short-acting nature and the associated high tolerance rate. A new reagent, ONO1301SR, which is a unique synthetic prostacyclin agonist polymerized with lactic and glycolic acid, has been demonstrated to constitutively release prostacyclin analogues to adjacent tissues suggesting its therapeutic potential via its slow-release delivery system into a specific organ such as the heart. We hypothesized that direct epicardial delivery of the ONO1301SR may have regenerating effects on the chronic MI heart.
Methods: An ameroid constrictor was placed on the left anterior descending coronary artery of Göttingen mini-pigs for 4 weeks to induce ischemic cardiomyopathy, followed by direct placement of either a 3.0- or 0.3-mg/kg ONO1301SR-immersed gelatinous sheet, or only a gelatinous sheet (control) on the anterolateral surface of the heart (n=3 in each).
Results: The plasma ONO1301SR concentration at 60 min after treatment was 7.5-fold higher in the 3.0 group than the 0.3 group, without significant difference in systemic blood pressure between the 3 groups. At 4 weeks after treatment, the ONO1301SR concentration in the heart was 100-fold higher in the 3.0 group than the 0.3 group, although the plasma concentration was under the detection limit in 0.3 group. On echocardiography, the left ventricular ejection fraction at 4 weeks after treatment was significantly greater in the 3.0 group (53 ± 2%) and 0.3 group (53 ± 1%) than the control group (36 ± 4%; P < 0.05). The expression of VEGF, bFGF, and SDF-1 in the infarct-border area was significantly greater in the 3.0 group than the control group, while capillary density were significantly higher in the 3.0 group than the control group, as evaluated by immunohistolabeling (P < 0.05).
Conclusions: The slow-release drug delivery system of ONO1301SR yielded regenerative therapeutic effects on chronic MI in porcine. Further pharmacokinetic studies in accordance with the Good Laboratory Practices standard are warranted for the clinical application.
- © 2013 by American Heart Association, Inc.