Discovery Medicine, GSK R&D, Harlow, UK.
Br J Clin Pharmacol. 2010 Mar;69(3):252-61. doi: 10.1111/j.1365-2125.2009.03590.x.
To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect.
Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 microg kg(-1) min(-1)), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 microg kg(-1) min(-1)), and (3) a delayed administration study (15.7 microg kg(-1) min(-1)) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first.
Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml(-1)). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml(-1)) were well below pharmacologically active concentrations as determined in studies 1 and 2.
S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.
评估新型研究化合物 S-0139（一种选择性内皮素 A（ET(A)）受体拮抗剂）在人体内的药效学剂量范围，并研究其药效学效应的持续时间。
采用静脉阻塞体积描记法评估肱动脉内给予内皮素-1（ET-1）后前臂血流的变化。已有研究表明，ET(A)拮抗剂可阻断该模型中 ET-1 诱导的血管收缩。该研究分为三个部分进行：（1）探索剂量反应的初步研究（剂量范围 0.08-13.33μgkg(-1)min(-1)）；（2）确认剂量反应的随机研究（安慰剂、2.5、6.67 和 15μgkg(-1)min(-1)）；（3）探索药效学效应持续时间的延迟给药研究（15.7μgkg(-1)min(-1)）。在所有研究中，给予 S-0139 静脉输注 3 小时，在输注的最后 90 分钟内同时输注 ET-1 90 分钟。在研究（3）中，在第一次输注结束后 3 小时开始第二次 ET-1 输注。
静脉给予 S-0139 可显著抑制前臂 ET-1 诱导的血管收缩（血浆浓度 800-2000ngml(-1)）。在延迟给药研究中，当 S-0139 输注结束后 3 小时给予 ET-1 时，仍存在相同程度的抑制作用，尽管 S-0139 血浆浓度（平均值 17ngml(-1)）远低于在研究 1 和 2 中确定的药效学浓度。
S-0139 剂量依赖性地阻断前臂 ET-1 介导的血管收缩，其药效学效应持续时间超过其药代动力学特征所预期的时间。
