Antiplatelet and anticoagulant effects of "HN-11 500," a selective thromboxane receptor antagonist.
The antiplatelet and anticoagulant effect of a thromboxane receptor (TX receptor) antagonist developed by Nycomed (Linz) has been studied in a placebo-controlled double-blind phase I study. Sixteen healthy male volunteers received different single oral doses of "HN-11 500" (C(14)H(15)NO(5)S(2); 1, 10, 100, 200, and 400 mg). Eight volunteers received placebo. The washout period between each dosage applied was at least 12 days. Platelet aggregation induced by the thromboxane mimetic "U 46 619" (C(21)H(34)0(4)) and platelet adhesion to siliconized glass were significantly and dose-dependently inhibited. The effect lasted between 3 and 4 h (10 mg) and 8 h (400 mg), respectively, and correlated 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 leads to >90% inhibition of platelet aggregation. The template bleeding time slightly increased but did not exceed the normal range. Furthermore, there was a wide variation of results. There were no significant changes in platelet counts, platelet-induced thrombin generation time (PITT), and blood coagulation parameters. All doses of HN-11 500 were well tolerated. HN-11 500 is a potent TX receptor antagonist (TXRA), which inhibits either platelet aggregation or platelet adhesion, which has not yet been described. In clinical routine, TXRAs have to demonstrate the effectiveness in large clinical trials for different clinical indications and to compete with single or combined administrations of cyclooxygenase (COX) inhibitors, thienovridines, thromboxane synthase inhibitors, and GIIb/IIIa inhibitors.
Schenk
J F
JF
Department of Clinical Hemostaseology and Transfusion Medicine, University of Saarland, 6641 Homburg, Germany. htjfsc@med-rz.uni-saarland.de
Radziwon
P
P
Fellier
H
H
Breddin
H K
HK
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005898:Glass; D006801:Humans; D008297:Male; D009930:Organic Chemicals; D010314:Partial Thromboplastin Time; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011517:Prothrombin Time; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012825:Silicon; D013917:Thrombin / Q000096:biosynthesis
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D009930:Organic Chemicals; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; C090807:HN 11500; D013917:Thrombin; D012825:Silicon