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- Nylander, Sven, et al.
(författare)
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Synergistic action between inhibition of P2Y12/P2Y1 and P2Y12/thrombin in ADP- and thrombin-induced human platelet activation
- 2004
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 142:8, s. 1325-1331
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate if there is a synergistic effect of a combination of P2Y12 and P2Y1 inhibition and P2Y12 and thrombin inhibition, on ADP- and thrombin-induced platelet activation, respectively. The rationale being that these combinations will cause a concurrent inhibition of both Gαq and Gαi signalling.Blood from healthy volunteers was preincubated with AR-C69931MX, a reversible P2Y12 antagonist; MRS2179, a reversible P2Y1 antagonist; or melagatran, a direct reversible thrombin inhibitor; alone or in various combinations prior to activation with ADP or thrombin. Platelet function in whole blood was assessed by flow cytometry using the antibody PAC-1 to estimate the expression of active αIIbβ3 (the fibrinogen receptor GPIIb/IIIa). A synergistic effect was evaluated by comparing the concentrations in the different combinations with those of corresponding equipotent concentrations of each single inhibitor alone. The equipotent single concentrations were experimentally obtained from concentration response curves performed in parallel.A synergistic effect regarding inhibition of ADP-induced platelet activation (10 μM) was obtained with different combinations of AR-C69931MX and MRS2179.Inhibition of thrombin-induced platelet activation (2 nM) with combinations of AR-C69931MX and the thrombin inhibitor melagatran did also result in a strong synergistic effect.To our knowledge, this is the first time that data supporting a synergistic effect has been published for the inhibitor combinations described.Whether this synergistic effect in vitro also results in an improved antithrombotic effect in vivo with or without an increased risk of bleeding remains to be studied in well-conducted clinical studies.
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- Nylander, Sven, et al.
(författare)
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The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation
- 2003
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 111:1-2, s. 65-73
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to test the relative importance of the two adenosine diphosphate (ADP) receptors P2Y1 and P2Y12 in thrombin-induced platelet activation using specific receptor antagonists. Blood from healthy volunteers was incubated with MRS2179, a reversible P2Y1 antagonist, or AR-C69931, a reversible P2Y12 antagonist prior to activation with different concentrations of ADP or thrombin. Platelet function in whole blood was assayed by flow cytometry using the antibody PAC-1 to estimate the expression of conformational active αIIbβ3, the fibrinogen receptor. Complete inhibition of P2Y12 or P2Y1 abolished the ADP response, but only inhibition of P2Y12 reduced the thrombin-induced response. The relative inhibition of the thrombin response by complete inhibition of P2Y12 was most pronounced at thrombin concentrations just enough for complete PAR1 cleavage, which is sufficient to release all ADP, giving 70–86% inhibition. Above this concentration, the relative importance of P2Y12 inhibition decreased due to activation of ADP independent pathways. This study supports P2Y12 as a drug target compared with P2Y1.
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