FitzGerald G A, Brash A R, Oates J A, Pedersen A K
J Clin Invest. 1983 Oct;72(4):1336-43. doi: 10.1172/JCI111089.
The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0 microM) in platelet-rich plasma as well as both aggregation and nucleotide release induced by collagen (95 micrograms/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1 alpha (PGI-M). PGI-M excretion was increased by dazoxiben; it rose a mean 2.4-fold from predosing control values at 0-6 h after administration of the highest dose studied (200 mg).
通过使用血栓素合酶抑制剂4-[2-(1H-咪唑-1-基)乙氧基]苯甲酸盐酸盐(达唑氧苯),研究了抑制人体中前列腺素G2向血栓素A2代谢的后果。以随机、安慰剂对照、双盲方式,每隔2周给健康志愿者单次服用25、50、100和200mg达唑氧苯。在给药前以及给药后1、4、6、8和24小时测量血清血栓素B2,并进行全血和富血小板血浆的聚集研究。血清血栓素B2和血小板对花生四烯酸(1.33mM)的聚集反应均以剂量依赖性方式被可逆性抑制。达唑氧苯未改变富血小板血浆中由1-O-烷基-2-乙酰基-sn-甘油-3-磷酸胆碱(0.4和4.0 microM)诱导的聚集,以及富血小板血浆和全血中由胶原(95微克/毫升)诱导的聚集和核苷酸释放。该化合物具有血小板抑制作用的额外证据是,在给予最高剂量(200mg)达唑氧苯后1小时,出血时间显著延长。通过测量前列环素的主要尿代谢产物2,3-二去甲-6-酮-PGF1α(PGI-M)来评估内源性前列环素的生物合成。达唑氧苯可增加PGI-M的排泄;在给予最高研究剂量(200mg)后0-6小时,其排泄量比给药前对照值平均增加2.4倍。