Abstract 13191: Short (2 hour) Intravenous Infusion of Purified Poloxamer-188 (MST-188) Elicits Prolonged (1-2 weeks) Improvement in Biomarkers in Dogs with Advanced Heart Failure
Background: MST-188 (purified poloxamer 188) is a rheologic and membrane stabilizing agent shown to improve LV function in animals with experimental myocardial infarction or with dystrophin deficiency. Its activity likely results from improved microvascular blood flow and/or repair of damaged cell membranes. The latter can limit unregulated calcium entry into the cell and, therefore, calcium overload. We recently showed that 2 hour infusion of MST-188 also improves LV function in dogs with advanced HF with improvements lasting up to weeks post drug administration.
Hypothesis: We tested the hypothesis that 2-hour infusion of MST-188 normalizes plasma biomarkers in dogs with HF (LV ejection fraction, EF ~30%) that include n-terminal pro-brain natriuretic peptide (nt-pro BNP), troponin-I (TnI), tumor necrosis factor-α (TNFα), interlukin-6 (IL-6), C-reactive protein (CRP), matrix metalloproteinase-2 (MMP-2) and pro-collagen 1 n-terminal peptide (PINP).
Methods: 21 HF dogs were randomized to 2 hours infusion of MST-188 (450 mg/kg, n=7 or 225 mg/kg, n=7)) or v/v normal saline (control, n=7). Plasma levels of biomarkers were measured using commercially available ELISA assays at baseline, at end of 2 hour infusion, and at 1 week and 2 weeks post-infusion.
Results: Saline infusion in control dogs had no effect on any of the biomarkers. Treatment with both doses of MST-188 increased EF and reduced plasma levels of TnI, nt-Pro BNP, TNFα, IL-6, CRP and MMP-2 at 1 week and 2 weeks post-treatment in a dose-dependent manner but had no effect on PINP. Data (high dose MST-188 and saline control) are shown in the table.
Conclusions: A 2 hour infusion of MST-188 in dogs with HF elicits improvements in key biomarkers of LV remodeling, cell death, inflammation and to a lesser extent collagen deposition that persisted for at least 2 weeks post-treatment. The findings support continued development of MST-188 for treatment of HF.
Author Disclosures: H.N. Sabbah: Research Grant; Significant; Mast Therapeutics, Inc.. Consultant/Advisory Board; Modest; Mast Therapeutics, Inc.. R. Gupta: None. M. Emanuele: Employment; Significant; Mast Therapeutics, Inc..
- © 2014 by American Heart Association, Inc.