Open multicentre study of the P-2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes

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 P-2 T receptor. At 5 hospitals, 39 patients with unstable angina or non-Q wave myocardial infarction, who were receiving aspirin and heparin, were adminis tered intravenous AR-C69931MX with stepped dose increments over 3 h to a pl ateau of either 2 mug/kg/min for 21 h (Part 1; n = 12) or up to 69 h (Part 2; n = 13) or 4 mug/kg/min for up to 69 h (Part 3: n = 14). Safety paramete rs, platelet aggregation (PA) induced by ADP 3 mu mol/L (impedance aggregom etry), bleeding time (BT) and plasma concentrations of AR-C69931XX were ass essed. AR-C69931MX was well tolerated. 33 patients completed the study. The re were no deaths at 30 days and no serious adverse events attributed to AR -C69931MX. Trivial bleeding (56%) was common. Ar 24 h, mean inhibition of P A 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 an d 40.7 +/- 36.7% respectively. 90% patients had a plasma half-life for AR-C 69931XX of <9 min. In conclusion, AR-C69931MX is a potent, short-acting pla telet ADP receptor antagonist suitable for further studies as an antithromb otic agent.