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    Aprepitant for cough in lung cancer: a randomised placebo-controlled trial and mechanistic insights

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    Authors
    Smith, J. A.
    Harle, Amelie S
    Dockry, R.
    Holt, K.
    Russell, Philip
    Molassiotis, A.
    Yorke, Janelle
    Robinson, R.
    Birrell, M. A.
    Belvisi, M. G.
    Blackhall, Fiona H
    Show allShow less
    Affiliation
    The University of Manchester Faculty of Biology Medicine and Health, 12203, Division of Infection, Immunity and Respiratory Medicine, Manchester, United Kingdom of Great Britain and Northern Ireland.
    Issue Date
    2020
    
    Metadata
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    Abstract
    Rationale: Effective cough treatments are a significant unmet need in lung cancer patients. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of Neurokinin 1 (NK-1) receptors, a mechanism also implicated in cough. Objective: To assess aprepitant in lung cancer patients with cough and evaluate mechanisms in vagal nerve tissue. Methods: Randomised double-blind crossover trial of lung cancer patients with bothersome cough. They received three days of aprepitant or matched placebo; following a three day wash out, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease gap recording chambers, indicative of sensory nerve activation, was measured to evaluate mechanism. Measurements and main results: Twenty lung cancer patients enrolled, mean age 66years (±7.7), 60% female, 80% non-small cell cancer, 50% advanced stage and 55% WHO performance status 1. Cough frequency improved with aprepitant, reducing by 22.2%(95%CI 2.8-37.7%) over placebo whilst awake (p=0.03), 30.3%(95%CI 12.7-44.3) over 24hours (p=0.002) and 59.8%(95%CI 15.1-86.0) during sleep (p=0.081). Patient-reported outcomes all significantly improved. Substance P depolarised both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P induced depolarisation by 78% in guinea pig (p=0.0145) and 94% in human vagus (p=0.0145). Discussion: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as anti-tussive therapies. Clinical trial
    Citation
    Smith JA, Harle A, Dockry R, Holt K, Russell P, Molassiotis A, et al. Aprepitant For Cough in Lung Cancer: A Randomised Placebo-Controlled Trial and Mechanistic Insights. Am J Respir Crit Care Med. 2020.
    Journal
    American Journal of Respiratory and Critical Care Medicine
    URI
    http://hdl.handle.net/10541/623434
    DOI
    10.1164/rccm.202006-2359OC
    PubMed ID
    32966755
    Additional Links
    https://dx.doi.org/10.1164/rccm.202006-2359OC
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1164/rccm.202006-2359OC
    Scopus Count
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