A slow-releasing form of prostacyclin agonist (ONO1301SR) enhances endogenous secretion of multiple cardiotherapeutic cytokines and improves cardiac function in a rapid-pacing–induced model of canine heart failure

Abstract

Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM.

A sustained-release drug-delivery system of synthetic prostacyclin agonist, ONO-1301SR: a new reagent to enhance cardiac tissue salvage and/or regeneration in the damaged heart

“…In contrast, our group used the rapid-pacing-induced canine model [23] and the delta-sarcoglycan-deficient hamster model [21] that was a different model from that of Hirata’s group. Our group directly delivered into the heart in order to maximise the therapeutic effects of this reagent and minimise systemic complications.…”

“…Our group directly delivered into the heart in order to maximise the therapeutic effects of this reagent and minimise systemic complications. Firstly, ONO-1301SR was intramyocardially injected in rapid LV-paced canines with their LV ejection fraction being <40 % [23]. As a result, global and regional LV functions were recovered in 4 weeks after the treatment, in association with increased microvessel number, decreased myocyte diameter and decreased fibrous component in the LV myocardium [23].…”

“…Firstly, ONO-1301SR was intramyocardially injected in rapid LV-paced canines with their LV ejection fraction being <40 % [23]. As a result, global and regional LV functions were recovered in 4 weeks after the treatment, in association with increased microvessel number, decreased myocyte diameter and decreased fibrous component in the LV myocardium [23]. However, the direct intramyocardial injection of ONO-1301SR used in this report was concerned by inconsistent delivery of the reagent and injection-related myocardial injury.…”

“…However, it may be theorised that enhanced effects will be achieved by the local placement which maximise ONO-1301 delivery into the targeted area with minimal systemic effects, since paracrinal actions of the effector cells are augmented in positive relation to the magnitude of the ONO-1301 stimuli [20, 21, 23]. …”

“…1) [16–19]. ONO-1301 was initially developed as an anti-platelet drug; however, a number of the basic studies including those from our laboratory documented that a very small dose of ONO-1301 activates endothelial cells, vascular smooth muscle cells and fibroblasts to release multiple pro-angiogenic/anti-inflammatory factors from their cytoplasm [16, 20–23]. In addition, ONO-1301 has several theoretical advantages as a drug over other synthetic prostaglandin agonists, such as beraprost, epoprostenol, iloprost or treprostinil, since ONO-1301 has been shown to exert long-lasting prostacyclin activities [16, 24, 25].…”