title: Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes.
abstract: Platelet aggregation is the central process in the pathophysiology of acute coronary syndromes. ADP contributes to thrombosis by activating platelets, and AR-C69931MX is a specific antagonist of this process acting at the P2T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were administered intravenous AR-C69931MX with stepped dose increments over 3 h to a plateau of either 2 microg/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 microg/kg/min for up to 69 h (Part 3: n = 14). Safety parameters, platelet aggregation (PA) induced by ADP 3 micromol/L (impedance aggregometry), bleeding time (BT) and plasma concentrations of AR-C69931XX were assessed. AR-C69931MX was well tolerated. 33 patients completed the study. There were no deaths at 30 days and no serious adverse events attributed to AR-C69931MX. Trivial bleeding (56%) was common. At 24 h, mean inhibition of PA was 96.0 +/- 8.6, 94.9 +/- 14.4 and 98.7 +/- 2.1% and BT was 9.5 +/- 8.4, 14.0 +/- 9.7 and 16.0 +/- 11.1 min for Parts 1, 2 and 3 respectively. At 1 h post-infusion, mean inhibition of PA was 36.2 +/- 39.2, 20.7 +/- 25.9 and 40.7 +/- 36.7% respectively. 90% patients had a plasma half-life for AR-C69931XX of <9 min. In conclusion, AR-C69931MX is a potent, short-acting platelet ADP receptor antagonist suitable for further studies as an antithrombotic agent.
authors: Division of Cardiovascular Medicine, University Hospital, Nottingham, UK. robertfstorey@hotmail.com
authors: R F
authors: RF
authors: Storey
authors: K G
authors: KG
authors: Oldroyd
authors: R G
authors: RG
authors: Wilcox
mesh_terms: D000208:Acute Disease; D000249:Adenosine Monophosphate / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000592:standards; D000328:Adult; D000368:Aged; D000789:Angina, Unstable / Q000150:complications / Q000188:drug therapy; D001241:Aspirin / Q000008:administration & dosage; D001780:Blood Coagulation Tests; D003257:Consumer Product Safety; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000592:standards; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12
chemical_list: D008565:Membrane Proteins; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; C117446:cangrelor; D006493:Heparin; D001241:Aspirin