Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Würzburg, Germany.
Eur J Pharm Biopharm. 2012 Aug;81(3):617-26. doi: 10.1016/j.ejpb.2012.04.013. Epub 2012 Apr 26.
The aim of the present investigation was to compare the onset of action and intrinsic activity of the long-acting β(2)-agonist GW597901 with the fast- and short-acting salbutamol as model compounds using an isolated human lung reperfusion model. Twelve resected human lung lobes were challenged with methacholine (MCh) and subsequently nebulised with either GW597901 or salbutamol. Prostaglandin E(2) (PGE(2)) concentrations in the perfusion fluid were compared with the dose of MCh that was required to induce a bronchoconstriction. After successful MCh provocation, nebulisation of GW597901 and salbutamol fully reversed any observed bronchoconstriction. The bronchodilating effect was more pronounced for GW597901. Salbutamol revealed an immediate onset of action while the effect of GW597901 was observed with an approximate delay of 6 min. Higher doses of MCh were required for a successful bronchial challenge in the presence of elevated PGE(2) levels (r=0.8171, p ≤ 0.05). For the first time, an isolated perfused human lung model has been established for comparing the onset of action and potency of a short- and long-acting β(2)-agonist. We therefore conclude that it is an alternative for determination of drug effect characteristics and suitable for supplementing or predicting clinical data.
本研究旨在利用离体人肺再灌注模型比较长效β(2)-激动剂 GW597901 与短效和速效沙丁胺醇的起效时间和内在活性。用 MCh 对 12 个切除的人肺叶进行挑战，随后用 GW597901 或沙丁胺醇进行雾化。与诱发支气管收缩所需的 MCh 剂量相比，比较灌流液中的前列腺素 E(2)(PGE(2))浓度。GW597901 和沙丁胺醇雾化后完全逆转了任何观察到的支气管收缩。GW597901 的支气管扩张作用更为明显。沙丁胺醇具有即刻起效的作用，而 GW597901 的作用则观察到大约 6 分钟的延迟。在 PGE(2)水平升高的情况下，需要更高剂量的 MCh 才能成功进行支气管挑战(r=0.8171，p ≤ 0.05)。首次建立了离体灌注人肺模型，用于比较短效和长效β(2)-激动剂的起效时间和效价。因此，我们得出结论，它是用于确定药物作用特征的替代方法，适用于补充或预测临床数据。
