Antiplatelet and anticoagulant effects of "HN-11 500," a selective thromboxane receptor antagonist

The antiplatelet and anticoagulant effect of a thromboxane receptor (TX rec eptor) antagonist developed by Nycomed (Linz) has been studied in a placebo -controlled double-blind phase I study. Sixteen healthy male volunteers rec eived different single oral doses of "HN-11 500" (C14H15NO5S2; 1, 10, 100, 200, and 400 mg). Eight volunteers received placebo. The washout period bet ween each dosage applied was at least 12 days. Platelet aggregation induced by the thromboxane mimetic "U 46 619" (C21H34O4) and platelet adhesion to siliconized glass were significantly and dose-dependently inhibited. The ef fect lasted between 3 and 4 h (10 mg) and 8 h (400 mg), respectively, and c orrelated well with the pharmacokinetic data. Platelet aggregation seems to be more sensitive to monitor the effects of HN-11 500 on platelet function than platelet adhesion. Plasma levels of 300 ng/ml HN-11 500 probably lead s to > 90% inhibition of platelet aggregation. The template bleeding time s lightly increased but did not exceed the normal range. Furthermore, there w as a wide variation of results. There were no significant changes in platel et counts, platelet-induced thrombin generation time (PITT), and blood coag ulation parameters. All doses of HN-11 500 were well tolerated. HN-11 500 i s a potent TX receptor antagonist (TXRA), which inhibits either platelet ag gregation or platelet adhesion, which has not yet been described. In clinic al routine, TXRAs have to demonstrate the effectiveness in large clinical t rials for different clinical indications and to compete with single or comb ined administrations of cyclooxygenase (COX) inhibitors, thienovridines, th romboxane synthase inhibitors, and GIIb/IIIa inhibitors. (C) 2001 Elsevier Science Ltd. All rights reserved.