Department of Internal Medicine, Faculty of Medicine, Justus Liebig University, Giessen, Germany.
J Aerosol Med Pulm Drug Deliv. 2010 Jun;23(3):161-72. doi: 10.1089/jamp.2009.0780.
Abnormalities in alveolar coagulation occur in idiopathic pulmonary fibrosis (IPF). Anticoagulants attenuate bleomycin-induced lung fibrosis in animals. In this study, we first examined the pharmacokinetics of inhaled heparin in healthy subjects. Second, we investigated the safety and tolerability of heparin inhalation in IPF patients.
Coagulation assays were performed in blood and bronchoalveolar lavage fluid samples from 19 healthy volunteers after inhalation of increasing amounts of unfractionated heparin. The acute effects of heparin inhalation on lung function and exercise capacity and the safety and tolerability of chronic heparin inhalation for 28 days were assessed in 20 IPF patients in an open-label exploratory pilot study.
In healthy subjects, inhalation of 150,000 IU heparin ("filled dose") significantly increased the partial thromboplastin time and anti-factor Xa activity in blood samples indicating the threshold dose. The local alveolar anticoagulant effect was detectable up to 72 h, and the alveolar half-life was estimated at 28 h. In IPF-patients, no acute deleterious effects on pulmonary function, gas exchange, or exercise capacity were noted after inhalation of the threshold dose. During chronic treatment, where one-fourth of the threshold dose was inhaled every 12 h for 28 days to obtain a steady-state anticoagulant activity in the alveolar space approximating the anticoagulant activity observed after threshold dose inhalation, no heparin-related side effects, such as hemoptysis or heparin-induced antibodies and thrombocytopenia, were detected in any patient, and median lung function values, exercise capacity, and quality of life scores appeared largely unaltered. Three adverse and one serious adverse events were noted; however, the relation of these events to the heparin inhalation was assessed as "unlikely" or "no relation" in each case.
Inhaled heparin appears to be safe and well tolerated in IPF patients. Future clinical trials are required to demonstrate the long-term safety and efficacy of inhaled heparin in IPF.
特发性肺纤维化 (IPF) 存在肺泡内凝血异常。抗凝剂可减轻动物的博来霉素诱导的肺纤维化。在这项研究中，我们首先检查了健康受试者吸入肝素的药代动力学。其次，我们研究了 IPF 患者吸入肝素的安全性和耐受性。
19 名健康志愿者吸入递增剂量的未分级肝素后，检测血液和支气管肺泡灌洗液样本中的凝血试验。在一项开放性探索性试点研究中，20 例 IPF 患者接受 28 天的肝素吸入治疗，评估肝素吸入对肺功能和运动能力的急性影响以及长期肝素吸入的安全性和耐受性。
在健康受试者中，吸入 150,000IU 肝素（“充满剂量”）可显著增加血液样本中的部分凝血活酶时间和抗因子 Xa 活性，表明达到了阈值剂量。局部肺泡抗凝作用可检测到 72 小时，肺泡半衰期估计为 28 小时。在 IPF 患者中，吸入阈值剂量后，未观察到对肺功能、气体交换或运动能力的急性有害影响。在慢性治疗中，每 12 小时吸入四分之一的阈值剂量，以获得肺泡空间内近似于阈值剂量吸入后观察到的抗凝活性的稳定态抗凝活性，在任何患者中均未检测到肝素相关的副作用，如咯血或肝素诱导的抗体和血小板减少症，并且中位数肺功能值、运动能力和生活质量评分似乎基本不变。有 3 例不良事件和 1 例严重不良事件，但在每种情况下，这些事件与肝素吸入的关系均被评估为“不太可能”或“无关系”。
吸入肝素在 IPF 患者中似乎是安全且耐受良好的。需要进一步的临床试验来证明 IPF 患者吸入肝素的长期安全性和疗效。
