长效β-肾上腺素能受体阻断药H-I 42 BS对人体β-肾上腺素能受体阻断活性及心脏选择性的评估。
The assessment in man of the beta-adrenoceptor blocking activity and cardioselectivity of H-I 42 BS, a long acting beta-adrenoceptor blocking drug.
作者信息
Pringle T H, Deering A H, Scott M G, Harron D W, Shanks R G
出版信息
Br J Clin Pharmacol. 1987 Apr;23(4):411-23. doi: 10.1111/j.1365-2125.1987.tb03070.x.
The pharmacokinetic and pharmacodynamic effects of the beta-adrenoceptor antagonist H-I 42 BS were examined in healthy subjects. In an open dose ranging study, H-I 42 BS 50, 100, 200 and 400 mg were given as single oral doses to four subjects. H-I 42 BS 400 mg caused maximum reduction in exercise heart rate (20.4 +/- 1.0%--mean +/- s.d.) at 4 h and still reduced exercise heart rate at 96 h (18.4 +/- 7.2%). Seven subjects received in double-blind, randomised order, single oral doses of H-I 42 BS 50, 100 and 200 mg, atenolol 50 and 100 mg and placebo. H-I 42 BS 400 mg was given in a single blind manner as the last dose of the study. Both H-I 42 BS and atenolol reduced supine and standing heart rate and systolic blood pressure (P less than 0.05) although atenolol had the more marked effect. The maximum percent reduction of exercise heart rate after H-I 42 BS 50 mg was 10.9 +/- 7.1%, after 100 mg was 18.7 +/- 5.8%, after 200 mg was 20.6 +/- 6.4% and after 400 mg was 21.9 +/- 8.2%. H-I 42 BS 400 mg still caused 11.0 +/- 3.5% reduction at 168 h. Atenolol 50 mg caused maximum percent reduction of exercise heart rate of 26.0 +/- 6.0% but did not reduce exercise heart rate after 24 h. The mean peak plasma concentrations for all doses of H-I 42 BS occurred at 5.1 +/- 1.5 h. The plasma elimination half-life was 47.6 +/- 8.1 h. There was a linear correlation between the dose and AUC0-infinity (r = 0.97). The cardioselectivity of H-I 42 BS and atenolol was compared. Six subjects received in double-blind random order H-I 42 BS 100 and 400 mg, atenolol 50 mg and placebo. After each dose, graded infusions of isoprenaline were given until the heart rate increased by 50 beats min-1. Dose-response curves for heart rate, diastolic blood pressure, forearm blood flow and finger tremor were constructed. There was no difference in the dose-response curves for forearm blood flow or finger tremor after H-I 42 BS 400 mg or atenolol 50 mg. Atenolol 50 mg caused more attenuation (P less than 0.01) of the diastolic blood pressure response. These results indicate that H-I 42 BS is a cardioselective beta-adrenoceptor antagonist with a long duration of action in man.
在健康受试者中研究了β-肾上腺素受体拮抗剂H-I 42 BS的药代动力学和药效学效应。在一项开放剂量范围研究中，对4名受试者单次口服给予50、100、200和400 mg的H-I 42 BS。400 mg的H-I 42 BS在4小时时使运动心率最大降低（20.4±1.0%——平均值±标准差），在96小时时仍能降低运动心率（18.4±7.2%）。7名受试者以双盲、随机顺序单次口服50、100和200 mg的H-I 42 BS、50和100 mg的阿替洛尔以及安慰剂。400 mg的H-I 42 BS作为研究的最后一剂以单盲方式给予。H-I 42 BS和阿替洛尔均降低了仰卧位和站立位心率以及收缩压（P<0.05），尽管阿替洛尔的作用更显著。50 mg的H-I 42 BS后运动心率最大降低百分比为10.9±7.1%，100 mg后为18.7±5.8%，200 mg后为20.6±6.4%，400 mg后为21.9±8.2%。400 mg的H-I 42 BS在168小时时仍导致11.0±3.5%的降低。50 mg的阿替洛尔使运动心率最大降低百分比为26.0±6.0%，但在24小时后未降低运动心率。所有剂量的H-I 42 BS的平均血浆峰浓度出现在5.1±1.5小时。血浆消除半衰期为47.6±8.1小时。剂量与AUC0-∞之间存在线性相关性（r = 0.97）。比较了H-I 42 BS和阿替洛尔的心脏选择性。6名受试者以双盲随机顺序接受100和400 mg的H-I 42 BS、50 mg的阿替洛尔和安慰剂。每次给药后，给予递增剂量的异丙肾上腺素输注，直至心率增加50次/分钟。构建了心率、舒张压、前臂血流量和手指震颤的剂量-反应曲线。400 mg的H-I 42 BS或50 mg的阿替洛尔后前臂血流量或手指震颤的剂量-反应曲线无差异。50 mg的阿替洛尔使舒张压反应的减弱更明显（P<0.01）。这些结果表明，H-I 42 BS是一种在人体中作用持续时间长的心脏选择性β-肾上腺素受体拮抗剂。
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