Institute of Pharmaceutical Science, King's College London, London, SE1 9NH, UK.
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, SE1 9NH, UK.
Drug Deliv Transl Res. 2018 Jun;8(3):760-769. doi: 10.1007/s13346-018-0490-z.
Inhaled adenosine receptor agonists induce bronchoconstriction and inflammation in asthma and are used as bronchial challenge agents for the diagnosis of asthma and in respiratory drug development. Recently developed dry powder aerosols of adenosine have several advantages over nebulised adenosine 5'-monophosphate (AMP) as bronchial challenge agents. However, reverse translation of this bronchial challenge technique to pre-clinical drug development is limited by the difficulty of administering powder aerosols to animals. The aim of the current study was to develop methods for delivering powder aerosols of adenosine receptor agonists to sensitised guinea pigs (as a model of allergic asthma) and evaluate their effect as challenge agents for the measurement of airway responsiveness. The PreciseInhale system delivered micronised AMP and adenosine powders, with mass median aerodynamic diameters of 1.81 and 3.21 μm and deposition fractions of 31 and 48% in the lungs, respectively. Bronchoconstrictor responses in passively sensitised, anaesthetised, spontaneously breathing guinea pigs were compared to responses to nebulised and intravenously administered AMP and adenosine. AMP- and adenosine-induced bronchoconstriction following all routes of administration with the magnitude of response ranking intravenous > dry powder > nebulisation, probably reflecting differences in exposure to the adenosine agonists delivered by the different routes. In conclusion, the PreciseInhale system delivered AMP and adenosine dry powder aerosols accurately into the lungs, suggesting this method can be used to investigate drug effects on airway responsiveness.
吸入性腺苷受体激动剂可诱发哮喘患者的支气管收缩和炎症，被用作哮喘诊断的支气管激发剂，并用于呼吸药物研发。与雾化的腺苷 5′-单磷酸（AMP）相比，最近开发的腺苷干粉气雾剂作为支气管激发剂具有多项优势。然而，这种支气管激发技术在临床前药物开发中的逆向转化受到将粉末气雾剂施用于动物的困难的限制。本研究旨在开发将腺苷受体激动剂干粉气雾剂输送至致敏豚鼠（作为变应性哮喘模型）的方法，并评估其作为气道反应性测量的挑战剂的效果。PreciseInhale 系统输送了雾化的 AMP 和腺苷粉末，其质量中值空气动力学直径分别为 1.81μm 和 3.21μm，肺部沉积分数分别为 31%和 48%。比较了被动致敏、麻醉、自主呼吸的豚鼠对雾化和静脉给予 AMP 和腺苷的支气管收缩反应。所有给药途径的 AMP 和腺苷诱导的支气管收缩反应，其反应强度的排序为静脉内给药>干粉给药>雾化给药，这可能反映了不同给药途径所给予的腺苷激动剂暴露程度的差异。总之，PreciseInhale 系统可准确地将 AMP 和腺苷干粉气雾剂输送至肺部，提示该方法可用于研究药物对气道反应性的影响。
