PMID- 28986203 OWN - NLM STAT- MEDLINE DCOM- 20190114 LR - 20220129 IS - 1522-9629 (Electronic) IS - 1094-5539 (Linking) VI - 48 DP - 2018 Feb TI - Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study. PG - 88-96 LID - S1094-5539(17)30192-X [pii] LID - 10.1016/j.pupt.2017.10.001 [doi] AB - BACKGROUND: COPD is an inflammatory airway disease characterised by progressive airflow limitation and air trapping, leading to lung hyperinflation and exercise limitation. Acute worsening of symptoms, including dyspnea, cough and sputum production, occurs during exacerbations which are associated with significantly reduced health related quality of life, and increased morbidity and mortality. Chronic bronchial mucus production and productive cough are risk factors for exacerbations. Medicines targeting bronchoconstriction and airway inflammation are the current mainstays of COPD therapy. However, there is growing concern with an increased risk of pneumonia in patients with COPD receiving regular inhaled corticosteroids and there is therefore a need to find safer alternative treatments. Previous studies have indicated that inhalation of unfractionated heparin (UFH) treats local inflammation, mucus hypersecretion and lung injury, without systemic anticoagulation, and is safe. Therefore, our primary objective was to demonstrate that inhaled UFH significantly improves lung function (FEV(1)) over 21 days of treatment in patients with COPD receiving pulmonary rehabilitation and that UFH provides a novel, safe and effective way of treating this complex disease. METHODS: Forty patients with moderate to very severe COPD admitted to the IRCCS San Raffaele Pisana Hospital for 21 days pulmonary rehabilitation were randomised to receive nebulised inhaled UFH (75,000 or 150,000 IU BID) or placebo for 21 days. All patients also received nebulised salbutamol (1 mg) and beclomethasone dipropionate (400 mug) BID over the same period. Lung function was measured at day 0, 7, 14 and 21 of treatment and at a follow-up visit 7 days post-treatment. Exercise capacity (6MWT) and dyspnoea (Borg score) were measured before and after treatment. In pre-clinical studies, the ability of basic proteins found in COPD sputum to neutralise the anticoagulant activity of heparin was determined using the AMAX heparin assay kit. MAIN RESULTS: At both doses, UFH significantly increased FVC following 7 days of treatment and 150,000 IU BID significantly increased FEV1 (+249 +/- 69 ml compared with placebo) at this time, an effect maintained to the 28 day follow-up. Clinically significant improvement in exercise capacity and dyspnoea were seen after 21 days of treatment with both doses of UFH. There were no serious adverse events or effects on systemic coagulation. Pre-clinical studies demonstrated that the basic proteins lactoferrin, platelet factor-4 (PF-4), IL-8 and polyarginine, as a model of the eosinophil cationic protein (ECP), found in COPD sputum neutralise the anticoagulant activity of heparin. CONCLUSION: Inhaled nebulised UFH is safe and provides additional clinical benefit for patients with moderate to very severe COPD through effects that are independent of its anticoagulant activity. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Shute, Janis K AU - Shute JK AD - Institute of Biological and Biomedical Sciences, University of Portsmouth, UK. Electronic address: jan.shute@port.ac.uk. FAU - Calzetta, Luigino AU - Calzetta L AD - Department of Systems Medicine, University of Rome Tor Vergata, Italy. Electronic address: luigino.calzetta@uniroma2.it. FAU - Cardaci, Vittorio AU - Cardaci V AD - IRCCS San Raffaele Pisana, Rome, Italy. Electronic address: vittorio.cardaci@sanraffaele.it. FAU - di Toro, Stefania AU - di Toro S AD - IRCCS San Raffaele Pisana, Rome, Italy. Electronic address: stefyditoro@hotmail.it. FAU - Page, Clive P AU - Page CP AD - Sackler Institute of Pulmonary Pharmacology, King's College, London, UK. Electronic address: clive.page@kcl.ac.uk. FAU - Cazzola, Mario AU - Cazzola M AD - Department of Systems Medicine, University of Rome Tor Vergata, Italy. Electronic address: mario.cazzola@uniroma2.it. LA - eng GR - G1000758/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20171003 PL - England TA - Pulm Pharmacol Ther JT - Pulmonary pharmacology & therapeutics JID - 9715279 RN - 0 (Bronchodilator Agents) RN - 0 (Glucocorticoids) RN - 9005-49-6 (Heparin) RN - KGZ1SLC28Z (Beclomethasone) RN - QF8SVZ843E (Albuterol) SB - IM MH - Administration, Inhalation MH - Aged MH - Aged, 80 and over MH - Albuterol/*administration & dosage MH - Animals MH - Beclomethasone/*administration & dosage MH - Bronchodilator Agents/administration & dosage MH - Double-Blind Method MH - Drug Therapy, Combination MH - Female MH - Follow-Up Studies MH - Forced Expiratory Volume MH - Glucocorticoids/administration & dosage MH - Heparin/*administration & dosage/adverse effects MH - Humans MH - Male MH - Middle Aged MH - Nebulizers and Vaporizers MH - Pilot Projects MH - Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology MH - Quality of Life MH - Respiratory Function Tests MH - Severity of Illness Index MH - Swine MH - Time Factors OTO - NOTNLM OT - Anticoagulant activity OT - COPD OT - Clinical trial OT - Inhaled OT - Lung function OT - Unfractionated heparin EDAT- 2017/10/08 06:00 MHDA- 2019/01/15 06:00 CRDT- 2017/10/08 06:00 PHST- 2017/08/07 00:00 [received] PHST- 2017/09/28 00:00 [revised] PHST- 2017/10/01 00:00 [accepted] PHST- 2017/10/08 06:00 [pubmed] PHST- 2019/01/15 06:00 [medline] PHST- 2017/10/08 06:00 [entrez] AID - S1094-5539(17)30192-X [pii] AID - 10.1016/j.pupt.2017.10.001 [doi] PST - ppublish SO - Pulm Pharmacol Ther. 2018 Feb;48:88-96. doi: 10.1016/j.pupt.2017.10.001. Epub 2017 Oct 3.