title: Pharmacodynamic interplay of the P2Y(1), P2Y(12), and TxA(2) pathways in platelets: the potential of triple antiplatelet therapy with P2Y(1) receptor antagonism.
abstract: BACKGROUND
  Previous work suggests that the extent of platelet inhibition by P2Y(1) receptor antagonism may be underappreciated, particularly in the context of dual antiplatelet therapy with aspirin and clopidogrel.
  
  
  METHODS
  Using P2Y(1), P2Y(12), and TxA(2) receptor antagonists individually and in combination, we assessed the incremental changes from baseline platelet reactivity in blood collected from healthy volunteers.
  
  
  RESULTS
  The P2Y(1) receptor antagonist further inhibited platelet activation and aggregation in several assay conditions ex vivo when combined with P2Y(12) and/or TxA(2) receptor blockers. Collagen and TRAP-induced platelet aggregation measured by light transmittance aggregometry was inhibited to a greater extent with the triple combination relative to each of the antagonists alone. The triple combination of P2Y(1), P2Y(12), and TxA(2) receptor antagonists also significantly shifted adenosine diphosphate (ADP)-stimulated platelet glycoprotein IIb/IIIa receptor and P-selectin expression compared to individual or dual antagonists.
  
  
  CONCLUSIONS
  These results substantiate that additional platelet inhibition occurs with the triple combination of P2Y(1), P2Y(12), and TxA(2) receptor antagonists and support further testing of P2Y(1) receptor antagonists as an option for alternative, synergistic, or triple antiplatelet therapy.
authors.affiliation: University of Nebraska Medical Center Department of Pharmacy Practice, Omaha, NE 68198–6045, USA. joestreich@unmc.edu
authors.forename: Julie H
authors.initials: JH
authors.lastname: Oestreich
authors.forename: Suellen P
authors.initials: SP
authors.lastname: Ferraris
authors.forename: Steven R
authors.initials: SR
authors.lastname: Steinhubl
authors.forename: Wendell S
authors.initials: WS
authors.lastname: Akers
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058472:Receptors, Purinergic P2Y1 / Q000097:blood*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000097:blood*
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D013928:Thromboxane A2; D003094:Collagen