Session: 301. Platelets and Megakaryocytes: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Bleeding and Clotting, Research, Drug development, Translational Research, Thromboembolism, Diseases, Thrombotic disorders, Treatment Considerations
Selectivity of the IP agonists was tested in washed human platelets and human whole blood treated with pharmacological antagonists for the prostaglandin receptors, DP1, EP2, EP4 and IP, prior to incubation with CS585, iloprost or selexipag. Selectivity was measured using aggregation and the total thrombus activation system (T-TAS). In IP-/- mice, CS585, iloprost and selexipag were administered via IV injection prior to induction of laser-induced vascular insult to the cremaster arteriole. Platelet accumulation and fibrin formation were measured at the site of injury to assess the ability of IP agonists to inhibit thrombus formation in IP-/- mice in comparison with WT mice. To determine the length of action of in vivo efficacy of CS585, iloprost and selexipag, mice were administered the IP agonists via IV injection 10 minutes, 4 hours, 18 hours and 24 hours prior to performing the laser-induced cremaster arteriole injury thrombosis model.
The inhibitory effects of all three IP agonists are completely reversed in the presence of an IP antagonist. However, antagonists for DP1, EP2, and EP4 affect the inhibitory properties of iloprost and selexipag while the effects of CS585 remain unchanged. The anti-thrombotic properties of CS585 observed in WT mice are completely reversed in mice lacking the IP receptor. WT mice administered iloprost exhibit a decrease in thrombus formation 10 minutes post-administration, but these effects are no longer observed by 4 hours post-administration. The effects of selexipag are maintained at 4 hours post-administration, but thrombus size returned to vehicle levels by 18 hours. CS585 demonstrated anti-thrombotic properties for the full 24 hours post-administration tested in this study.
Here, we show that CS585 is a highly selective IP receptor agonist that inhibits platelet activation and thrombus formation. Additionally, CS585 was shown to exhibit a sustained inhibition of thrombotic clot formation for at least 24 hours post-administration. In both in vivo and ex vivo models, we observe non-selective effects of iloprost and selexipag, in addition to confirming the limitations of length of effect in the blood previously reported in the literature. In overcoming the concerns of sustained efficacy in the blood while maintaining high selectivity for the IP receptor, CS585 represents a novel approach for the anti-platelet treatment of thrombotic diseases, with the potential to augment the therapeutic options for patients suffering from diseases like thrombosis, VTE, MI, stroke, and PAH.
Disclosures: Dahlof: Cereno Scientific: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Holinstat: Veralox Therapeutics: Consultancy, Current equity holder in private company, Patents & Royalties, Research Funding; Lexicon Pharmaceuticals: Research Funding; Cereno Scientific: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding.
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