Scuri M, Allegra L, Abraham W M
Division of Pulmonary and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.
Pulm Pharmacol Ther. 1998;11(4):277-80. doi: 10.1006/pupt.1998.0149.
In a previous study, a single dose of zileuton (10 mg/kg, po) given 2 h before antigen challenge, had a minimal effect on the antigen-induced early airway response (EAR), although it was effective in blocking the late airway response (LAR). Because our previous data indicated that 5-lipoxygenase (5-LO) products contribute to the severity of the antigen-induced EAR in these animals, we hypothesized that the lack of effect of zileuton on the EAR may have had to do with inadequate tissue levels. Therefore, in this study, we determined if multiple dosing with zileuton, which theoretically could improve tissue levels, would provide protection against the antigen-induced EAR as well as the LAR. Each sheep was used in each of the three trials (> or = 15 days apart), the order of which was randomized. For trial 1, the sheep were treated with zileuton (10 mg/kg in 0.1% methylcellulose, p.o.) once a day for 4 days; for trials 2, the sheep were treated with zileuton (10 mg/kg, p.o.) for 2 days; and, for trial 3, the animals were treated with vehicle (0.1% methylcellulose) for 4 days as in trial 1. In all trials, antigen challenge followed 1 h after the last treatment. In the placebo trial, antigen challenge resulted in characteristic EAR (407 +/- 102%, increase over baseline) and LAR (335 +/- 75%, increase over baseline). The antigen-induced effects were completely blocked by the 4-day treatment (EAR = 24 +/- 3%; LAR = 17 +/- 3%, P < 0.05 vs. placebo). In the 2-day trial, the immediate increase in R1, after antigen challenge was only partially blocked (EAR = 163 +/- 16%, P < 0.10 vs. placebo and P < 0.05 vs. 4-day trial), but the late response was completely blocked (24 +/- 3%). The protection against the EAR obtained with the 4-day treatment was significantly better (P < 0.05) than that obtained with the 2-day treatment. The results of this study show that multiple dosing with the 5-LO inhibitor, zileuton, provides protection against the antigen-induced EAR as well as LAR. The effect on the EAR is dependent on the treatment time, with dosing 4 days before antigen challenge providing a more significant effect than either dosing 2 days before challenge (this study) or on the same day as antigen challenge as was seen by us previously. This effect may be related to increased tissue levels of the drug.
在先前的一项研究中，在抗原激发前2小时给予一剂齐留通（10毫克/千克，口服），对抗原诱导的早期气道反应（EAR）影响极小，尽管它能有效阻断晚期气道反应（LAR）。因为我们先前的数据表明，5-脂氧合酶（5-LO）产物会加重这些动物抗原诱导的EAR的严重程度，所以我们推测齐留通对EAR缺乏作用可能与组织药物水平不足有关。因此，在本研究中，我们确定理论上可提高组织药物水平的齐留通多次给药是否能预防抗原诱导的EAR以及LAR。每只绵羊在三项试验（间隔≥15天）中均被使用，试验顺序随机。试验1中，绵羊每天口服齐留通（10毫克/千克，溶于0.1%甲基纤维素），共4天；试验2中，绵羊口服齐留通（10毫克/千克），共2天；试验3中，动物如试验1一样接受载体（0.1%甲基纤维素）处理4天。在所有试验中，最后一次处理后1小时进行抗原激发。在安慰剂试验中，抗原激发导致典型的EAR（较基线增加407±102%）和LAR（较基线增加335±75%）。4天的处理完全阻断了抗原诱导的效应（EAR = 24±3%；LAR = 17±3%，与安慰剂相比P<0.05）。在2天的试验中，抗原激发后R1的即刻增加仅被部分阻断（EAR = 163±16%，与安慰剂相比P<0.10，与4天试验相比P<0.05），但晚期反应被完全阻断（24±3%）。4天处理获得的对EAR的保护明显优于2天处理（P<0.05）。本研究结果表明，5-LO抑制剂齐留通多次给药可预防抗原诱导的EAR以及LAR。对EAR的作用取决于处理时间，在抗原激发前4天给药比在激发前2天给药（本研究）或如我们之前所见在抗原激发当天给药产生的效果更显著。这种效应可能与药物组织水平升高有关。
