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@article{Armstrong:2020:10.1111/jth.14826,
author = {Armstrong, PC and Ferreira, PM and Chan, MV and Lundberg, Slingsby MH and Crescente, M and Shih, C-C and Kirkby, NS and Hobbs, AJ and Warner, TD},
doi = {10.1111/jth.14826},
journal = {Journal of Thrombosis and Haemostasis},
pages = {1705--1713},
title = {Combination of cyclic nucleotide modulators with P2Y(12) receptor antagonists as anti-platelet therapy},
url = {http://dx.doi.org/10.1111/jth.14826},
volume = {18},
year = {2020}
}

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TY  - JOUR
AB  - BackgroundEndotheliumderived prostacyclin and nitric oxide elevate platelet cyclic nucleotide levels and maintain quiescence. We previously demonstrated that a synergistic relationship exists between cyclic nucleotides and P2Y12 receptor inhibition. A number of clinically approved drug classes can modulate cyclic nucleotide tone in platelets including activators of NOsensitive guanylyl cyclase (GC) and phosphodiesterase (PDE) inhibitors. However, the doses required to inhibit platelets produce numerous side effects including headache.ObjectiveWe investigated using GCactivators in combination with P2Y12 receptor antagonists as a way to selectively amplify the antithrombotic effect of both drugs.MethodsIn vitro light transmission aggregation and platelet adhesion under flow were performed on washed platelets and platelet rich plasma. Aggregation in whole blood and a ferric chlorideinduced arterial thrombosis model were also performed.ResultsThe GCactivator BAY70 potentiated the action of the P2Y12 receptor inhibitor prasugrel active metabolite in aggregation and adhesion studies and was associated with raised intraplatelet cyclic nucleotide levels. Furthermore, mice administered submaximal doses of the GC activator cinaciguat together with the PDE inhibitor dipyridamole and prasugrel, showed significant inhibition of ex vivo platelet aggregation and significantly reduced in vivo arterial thrombosis in response to injury without alteration in basal carotid artery blood flow.ConclusionsUsing in vitro, ex vivo, and in vivo functional studies, we show that low dose GC activators synergize with P2Y12 inhibition to produce powerful antiplatelet effects without altering blood flow. Therefore, modulation of intraplatelet cyclic nucleotide levels alongside P2Y12 inhibition can provide a strong, focused antithrombotic regimen while minimizing vasodilator side effects.
AU  - Armstrong,PC
AU  - Ferreira,PM
AU  - Chan,MV
AU  - Lundberg,Slingsby MH
AU  - Crescente,M
AU  - Shih,C-C
AU  - Kirkby,NS
AU  - Hobbs,AJ
AU  - Warner,TD
DO  - 10.1111/jth.14826
EP  - 1713
PY  - 2020///
SN  - 1538-7836
SP  - 1705
TI  - Combination of cyclic nucleotide modulators with P2Y(12) receptor antagonists as anti-platelet therapy
T2  - Journal of Thrombosis and Haemostasis
UR  - http://dx.doi.org/10.1111/jth.14826
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000530429800001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://onlinelibrary.wiley.com/doi/full/10.1111/jth.14826
UR  - http://hdl.handle.net/10044/1/79100
VL  - 18
ER  -

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