부산대학교 도서관

Introduction: Despite reperfusion in patients with ST-elevation myocardial infarction and acute ischemic stroke; reperfusion injury, microvascular dysfunction, thrombosis, and obstruction remain important causes of persistent ischemia and infarct expansion leading to poor clinical outcome. AZD3366, a recombinant human apyrase engineered to enhance hydrolysis of extracellular adenosine tri-/diphosphate (ATP/ADP) to adenosine monophosphate and subsequently adenosine, has exhibited anti-thrombotic, anti-inflammatory, and tissue protective properties in preclinical studies.Methods: In this phase 1 randomized single-blind placebo-controlled study in healthy subjects (NCT04588727), 7 cohorts of 8 subjects received a single short IV infusion of AZD3366 (2-640 mg [n=6]) or placebo (n=2). A further 3 cohorts of 5 healthy Japanese/1 cohort of 8 healthy Chinese subjects were included within this dose range. A separate group of 24 subjects received 160 mg of AZD3366 in combination with aspirin and ticagrelor (n=12) or aspirin and ticagrelor alone (n=12). The primary objective was to assess safety and tolerability; secondary objectives included assessment of pharmacokinetics (PK) and pharmacodynamics of AZD3366.Results: Overall, 103 subjects were randomized; mean age 37.2 (± 9) years, 100 were male. AZD3366 treatment alone or in combination with ticagrelor and aspirin did not result in any clinically relevant safety or tolerability findings. Peak AZD3366 plasma concentrations were reached within 0.5 h post-dosing, followed by monophasic or biphasic decline with a terminal PK half-life of approximately 140 h. Complete ADP-stimulated platelet aggregation inhibition was reached within 10 mins post-dosing; duration ranged from 4 h at 2 mg to ~35 days at 640 mg (Figure).Conclusions: AZD3366 alone or in combination with aspirin and ticagrelor was generally safe, well tolerated, and achieved complete platelet inhibition with a dose-dependent duration.