吸入硫喷妥对哮喘患者变应原诱导的气道反应的影响。

The effect of inhaled thiorphan on allergen-induced airway responses in asthmatic subjects.

作者信息

Diamant Z, Van der Veen H, Kuijpers E A, Bakker P F, Sterk P J

机构信息

Department of Pulmonology, Leiden University Hospital, The Netherlands.

出版信息

Clin Exp Allergy. 1996 May;26(5):525-32.

PMID:8735864

Abstract

BACKGROUND

Neuropeptides are likely to be implicated in the pathophysiology of allergen-induced airway responses. However, upon release in the airways, neuropeptides are potentially inactivated by neutral endopeptidase (NEP).

OBJECTIVE

We hypothesized that NEP-inhibition by inhaled thiorphan (TH) would increase allergen-induced early (EAR) and late (LAR) asthmatic responses, and allergen-induced airway hyperresponsiveness to histamine in asthmatic subjects in vivo. The dose and dosing intervals of TH were derived from previous pharmacokinetic and dose-finding studies.

METHODS

Nine non-smoking, atopic, asthmatic men with dual asthmatic responses to inhaled house-dust mite extract participated in a double-blind, placebo-controlled, cross-over study. During each study period PC20 histamine was measured 24 h before, and 3 and 24 h post-allergen. TH (1.25 mg/mL, 0.5 mL) or placebo (P) were aerosolized pre-allergen, and three times at 2 h intervals post-allergen (total dose of TH: 2.5 mg). Forced expiratory volume in one second (FEV1) was recorded and expressed as percentage fall from baseline. The EAR (0-3 h) and the LAR (3-8 h) were defined as maximum percentage fall from the pre-allergen baseline and as corresponding areas under the time-response curves (AUC).

RESULTS

As compared with P, TH failed to induce an acute effect on FEV1 at any of the timepoints (P > 0.08). There was no significant difference between P and TH in the EAR and the LAR: neither in terms of maximum percentage fall from baseline (mean +/- SEM: EAR: 22.3 +/- 4.7% (P) and 20.4 +/- 4.1% (TH), P = 0.75; LAR: 25.2 +/- 4.7% (P) and 26.4 +/- 5.8% (TH), P = 0.77) nor in terms of AUC (P = 0.76). Correspondingly, the changes in PC20 histamine were not different between the two treatments (P > 0.40).

CONCLUSION

We conclude that four adequate doses of the inhaled NEP-inhibitor, thiorphan, failed to potentiate allergen-induced airway responses in asthma. These results suggest that either neuropeptides do not play a predominant role in allergen-induced airway responses, or that allergen challenge induces NEP-dysfunction in humans in vivo.

摘要

背景

神经肽可能参与变应原诱导的气道反应的病理生理学过程。然而，在气道中释放后，神经肽可能会被中性内肽酶（NEP）灭活。

目的

我们假设吸入噻吗洛尔（TH）抑制NEP会增强变应原诱导的哮喘患者体内的早期（EAR）和晚期（LAR）哮喘反应，以及变应原诱导的气道对组胺的高反应性。TH的剂量和给药间隔来自先前的药代动力学和剂量探索研究。

方法

9名对吸入屋尘螨提取物有双重哮喘反应的非吸烟特应性哮喘男性参与了一项双盲、安慰剂对照、交叉研究。在每个研究期间，在变应原前24小时、变应原后3小时和24小时测量组胺PC20。变应原前雾化TH（1.25mg/mL，0.5mL）或安慰剂（P），变应原后每隔2小时雾化3次（TH总剂量：2.5mg）。记录一秒用力呼气量（FEV1），并表示为相对于基线的下降百分比。EAR（0 - 3小时）和LAR（3 - 8小时）定义为相对于变应原前基线的最大下降百分比以及时间 - 反应曲线下的相应面积（AUC）。

结果

与P相比，TH在任何时间点均未对FEV1产生急性影响（P>0.08）。P和TH在EAR和LAR方面无显著差异：无论是相对于基线的最大下降百分比（平均值±SEM：EAR：22.3±4.7%（P）和20.4±4.1%（TH），P = 0.75；LAR：25.2±4.七%（P）和26.4±5.8%（TH），P = 0.77），还是在AUC方面（P = 0.76）。相应地，两种治疗之间组胺PC20的变化无差异（P>0.40）。