title: Safety and tolerability of inhaled heparin in idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Justus Liebig University, Giessen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
authors.forename: Robert
authors.initials: R
authors.lastname: Nass
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.forename: Lukas
authors.initials: L
authors.lastname: Hundack
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Martina
authors.initials: M
authors.lastname: Korfei
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Boedeker
authors.forename: Gerd
authors.initials: G
authors.lastname: Staehler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kroll
authors.forename: Gerhard
authors.initials: G
authors.lastname: Scheuch
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Andreas
authors.initials: A
authors.lastname: Guenther
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D016022:Case-Control Studies; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005260:Female; D006207:Half-Life; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010865:Pilot Projects; D011788:Quality of Life; D012129:Respiratory Function Tests; D013997:Time Factors; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006493:Heparin