Olivier K N, Bennett W D, Hohneker K W, Zeman K L, Edwards L J, Boucher R C, Knowles M R
Department of Medicine, University of North Carolina, Chapel Hill 27599-7020, USA.
Am J Respir Crit Care Med. 1996 Jul;154(1):217-23. doi: 10.1164/ajrccm.154.1.8680683.
Impaired mucociliary clearance contributes to the pathophysiology of several airways diseases including cystic fibrosis, asthma, and chronic bronchitis. Extracellular triphosphate nucleotides (adenosine 5'-triphosphate [ATP], uridine 5'-triphosphate [UTP]) activate several components of the mucociliary escalator, suggesting they may have potential as therapeutic agents for airways diseases. We conducted initial (Phase I) studies of acute safety and efficacy of aerosolized UTP alone and in combination with aerosolized amiloride, the sodium channel blocker, in normal human volunteers. Safety was assessed by measurement of pulmonary function. Neither UTP alone nor in combination with amiloride caused any clinically significant adverse effects on airway mechanics, (subdivisions of) lung volumes, or gas exchange. Acute efficacy of UTP and amiloride alone and in combination, was assessed by measuring changes in the clearance of inhaled radiolabeled particles. A 2.5-fold increase in mucociliary clearance was seen in response to UTP alone and in combination with amiloride. We conclude that aerosolized UTP +/- amiloride clearly enhances mucociliary clearance without acute adverse effects in normal adults, and may have therapeutic potential to enhance airways clearance in diseases characterized by retained airways secretions.
黏液纤毛清除功能受损是包括囊性纤维化、哮喘和慢性支气管炎在内的多种气道疾病病理生理学的一个因素。细胞外三磷酸核苷酸（腺苷5'-三磷酸[ATP]、尿苷5'-三磷酸[UTP]）可激活黏液纤毛运输系统的多个组成部分，这表明它们可能具有作为气道疾病治疗药物的潜力。我们对正常人类志愿者进行了雾化UTP单独使用以及与钠通道阻滞剂雾化阿米洛利联合使用的急性安全性和有效性的初步（I期）研究。通过测量肺功能来评估安全性。单独使用UTP或与阿米洛利联合使用均未对气道力学、肺容积（细分）或气体交换产生任何具有临床意义的不良反应。通过测量吸入放射性标记颗粒清除率的变化来评估UTP和阿米洛利单独使用及联合使用的急性有效性。单独使用UTP以及与阿米洛利联合使用时，黏液纤毛清除率提高了2.5倍。我们得出结论，雾化UTP+/-阿米洛利可显著增强正常成年人的黏液纤毛清除功能且无急性不良反应，并且可能具有治疗潜力，可改善以气道分泌物潴留为特征的疾病的气道清除功能。
