title: A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel a randomised phase I study.
abstract: DZ-697b is a new orally active antiplatelet agent that inhibits collagen and ristocetin-mediated platelet activation. It does not require metabolisation to generate its active compound and has a safer profile than clopidogrel in pre-clinical studies. We compared the antithrombotic effects and bleeding time prolongations of three DZ-697b doses with clopidogrel 300 mg. In a four-treatment, three-period, crossover-design, 20 healthy subjects (31 + or - 7 years, 85% males) were randomised to single oral doses of DZ-697b (60, 120 and 360 mg), and clopidogrel (300 mg) (n=15 in each treatment with crossing-over). Antithrombotic effects were assessed by measuring six-hour post-dose changes from baseline in thrombus size in the Badimon chamber and platelet adhesion using Diamed Impact-R platelet function assay. Bleeding times were also measured pre-dose and at six hours post-dose. DZ-697b caused dose-dependent reductions in thrombus size at both high- and low-shear rates (mean reductions at 60, 120 and 360 mg doses of: 13.0%, 18.7%, 26.4% and 11.4%, 12.7%, 22.1% respectively, p<0.05 for all). Effect of clopidogrel (reductions of 18.7% and 11.0% respectively, p<0.05 for both) was closest to DZ-697b 120 mg. Reductions in platelet adhesion were also dose-dependent. Bleeding time ratio from baseline were shorter with DZ-697b versus clopidogrel (1.3, 1.4 and 1.5 versus 1.9, p<0.05 for all). The oral agent DZ-697b shows potent, dose-dependent, antithrombotic effects that are comparable to 300 mg clopidogrel at the 120 mg dose. Despite having equal or greater antiplatelet potency than 300 mg clopidogrel, bleeding time prolongations are significantly shorter with DZ-697b.
authors.affiliation: Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: M Urooj
authors.initials: MU
authors.lastname: Zafar
authors.forename: Borja
authors.initials: B
authors.lastname: Ibáñez
authors.forename: Brian G
authors.initials: BG
authors.lastname: Choi
authors.forename: David A
authors.initials: DA
authors.lastname: Vorchheimer
authors.forename: Antonio
authors.initials: A
authors.lastname: Piñero
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Jin
authors.forename: Raman K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Badimon
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001760:Bleeding Time; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine