Schenk J F, Radziwon P, Fellier H, Breddin H K
Department of Clinical Hemostaseology and Transfusion Medicine, University of Saarland, 6641 Homburg, Germany.
Thromb Res. 2001 Jul 15;103(2):79-91. doi: 10.1016/s0049-3848(01)00276-6.
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.
在一项安慰剂对照的双盲I期研究中，对Nycomed（林茨）研发的血栓素受体（TX受体）拮抗剂的抗血小板和抗凝作用进行了研究。16名健康男性志愿者接受了不同单次口服剂量的“HN-11 500”（C₁₄H₁₅NO₅S₂；1、10、100、200和400毫克）。8名志愿者接受安慰剂。每次给药之间的洗脱期至少为12天。血栓素模拟物“U 46 619”（C₂₁H₃₄O₄）诱导的血小板聚集以及血小板与硅化玻璃的黏附均受到显著且剂量依赖性的抑制。该作用分别持续3至4小时（10毫克剂量）和8小时（400毫克剂量），且与药代动力学数据相关性良好。血小板聚集似乎比血小板黏附更能敏感地监测HN-11 500对血小板功能的影响。血浆中300纳克/毫升的HN-11 500水平可能导致血小板聚集抑制率>90%。模板出血时间略有增加，但未超出正常范围。此外，结果存在较大差异。血小板计数、血小板诱导的凝血酶生成时间（PITT）和凝血参数均无显著变化。所有剂量的HN-11 500耐受性良好。HN-11 500是一种有效的TX受体拮抗剂（TXRA），它能抑制血小板聚集或血小板黏附，这一点尚未见报道。在临床常规中，TXRA必须在针对不同临床适应症的大型临床试验中证明其有效性，并与环氧化酶（COX）抑制剂、噻吩吡啶类、血栓素合酶抑制剂以及GIIb/IIIa抑制剂的单一或联合给药相竞争。
