Biollaz J, Stahl E, Hsieh J Y, Distlerath L, Jaeger A, Leuenberger P, Schelling J L
Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Eur J Clin Pharmacol. 1988;33(6):603-7. doi: 10.1007/BF00542495.
Two formulations of L-648,051 (L) were studied [intravenous (i.v.) and aerosol (A)] in two separate trials. Study I (i.v.) involved 4 normal male subjects in a single blind dose ranging study where good systemic tolerability and safety was shown. However, dose dependent local irritation at the injection site was observed at all dose levels (35, 52.5 and 70 mg/5 min infusion). L has a high systemic clearance rate (1.2 1/min), a small volume of distribution (4.41) and a short plasma half-life (2.4 min). Study II (A) involved 16 normal male volunteers who received incremental aerosolized doses of L from 0.1 to 1.6 mg in a double-blind, placebo controlled, dose ranging study. Complaints of mild local irritation or discomfort in the upper respiratory tract were the only significant findings. No dose relationship of these complaints could be shown. In conclusion, L is a safe and well tolerated drug when administered by aerosol. It causes dose related local, but not systemic, adverse experiences when administered i.v. In view of this tolerability and of its demonstrated activity against LTD4-challenge in animals, clinical efficacy studies with the aerosol formulation are warranted.
在两项独立试验中研究了L-648,051（L）的两种剂型[静脉注射（i.v.）和气雾剂（A）]。研究I（静脉注射）在一项单盲剂量范围研究中纳入了4名正常男性受试者，结果显示出良好的全身耐受性和安全性。然而，在所有剂量水平（35、52.5和70mg/5分钟输注）均观察到注射部位有剂量依赖性局部刺激。L具有高全身清除率（1.2升/分钟）、小分布容积（4.4升）和短血浆半衰期（2.4分钟）。研究II（气雾剂）纳入了16名正常男性志愿者，他们在一项双盲、安慰剂对照、剂量范围研究中接受了递增剂量的雾化L，剂量从0.1至1.6mg。唯一的显著发现是上呼吸道有轻度局部刺激或不适的主诉。这些主诉与剂量无关。总之，L通过气雾剂给药时是一种安全且耐受性良好的药物。静脉注射给药时会引起剂量相关的局部而非全身不良反应。鉴于这种耐受性及其在动物中对LTD4激发试验所显示的活性，有必要对气雾剂剂型进行临床疗效研究。
