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Neurokinin-1 receptor antagonism for the treatment of cough in lung cancer

Amelie Harle, Fiona Blackhall, Alex Molassiotis, Kim Holt, Rachel Dockry, Philip Russell, Katy Burns, Ryan Robinson, Mark Birrell, Maria Belvisi, Jaclyn Smith
European Respiratory Journal 2016 48: PA5060; DOI: 10.1183/13993003.congress-2016.PA5060
Amelie Harle
2Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
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Fiona Blackhall
2Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
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Alex Molassiotis
4School of Nursing, Hong Kong Polytechnic University, Kowloon, Hong Kong
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Kim Holt
1Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, United Kingdom
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Rachel Dockry
1Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, United Kingdom
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Philip Russell
2Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
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Katy Burns
2Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
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Ryan Robinson
3Respiratory Pharmacology Group, Imperial College London, London, United Kingdom
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Mark Birrell
3Respiratory Pharmacology Group, Imperial College London, London, United Kingdom
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Maria Belvisi
3Respiratory Pharmacology Group, Imperial College London, London, United Kingdom
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Jaclyn Smith
1Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, United Kingdom
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Abstract

Background: Effective cough treatments are a significant unmet need. Aprepitant blocks substance P at NK-1 receptors and is licensed for chemotherapy-induced nausea and vomiting. We assessed Aprepitant in vagal tissue and a proof of concept trial in lung cancer patients with cough.

Methods: In vitro, isolated vagus nerve sections were placed in grease gap recording chambers and depolarization to test solutions measured. A randomised double-blind crossover trial enrolled lung cancer patients with cough who received aprepitant (125mg day 1, 80mg day 2&3) or matched placebo; following a 3 day wash out, patients crossed over. The primary endpoint was awake cough frequency (coughs/hr(c/h)) and patients reported cough severity and impact.

Results: Substance P depolarised guinea pig (0.083mV±0.0066, n=5) and human vagus (0.0875mV, n=2). Aprepitant (10µM) reduced substance P depolarisation by 78% in guinea pig (0.0180mV±0.0080) and 94% in human vagus (0.0050 mV). Twenty lung cancer patients enrolled: mean age 66yrs(±7.69); 60% female; 70% ex, 25% current and 5% non-smokers; performance status 0=25%, 1=55% and 2=25%. 80% had non-small cell cancer, 50% advanced stage and 20% were on cancer therapy. Awake cough frequency improved with aprepitant [baseline 15.9c/h(95%CI 10.1-28.3), aprepitant 12.8(8.7-18.8), placebo 16.2(11.3-23.0), p=0.03]. Patients reported improved cough severity [VAS baseline 57.0mm (95% CI 47.4-67.2), aprepitant 40.8(34.3-47.3), placebo 49.8(44.2-55.4), p=0.008] and impact [Manchester Cough in Lung Cancer Scale, p<0.001].

Conclusions: This is the first study to show NK-1 antagonism has anti-tussive effects in lung cancer, with only 3 days treatment. Vagal inhibition may mediate this effect.

  • Pharmacology
  • Treatments
  • Cough
  • Copyright ©the authors 2016
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Neurokinin-1 receptor antagonism for the treatment of cough in lung cancer
Amelie Harle, Fiona Blackhall, Alex Molassiotis, Kim Holt, Rachel Dockry, Philip Russell, Katy Burns, Ryan Robinson, Mark Birrell, Maria Belvisi, Jaclyn Smith
European Respiratory Journal Sep 2016, 48 (suppl 60) PA5060; DOI: 10.1183/13993003.congress-2016.PA5060

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Neurokinin-1 receptor antagonism for the treatment of cough in lung cancer
Amelie Harle, Fiona Blackhall, Alex Molassiotis, Kim Holt, Rachel Dockry, Philip Russell, Katy Burns, Ryan Robinson, Mark Birrell, Maria Belvisi, Jaclyn Smith
European Respiratory Journal Sep 2016, 48 (suppl 60) PA5060; DOI: 10.1183/13993003.congress-2016.PA5060
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