Effect of cyclodextrin on sensory nerve activity and the cough reflex in man: a novel anti-tussive therapy?
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
Cough is a reflex mechanism that helps clear foreign material and secretions from the airways. However, it may also be the first and most persistent symptom of many inflammatory airways diseases, including, asthma, COPD, post viral infections, pulmonary fibrosis and bronchiectasis. Chronic cough can also be present when a cause can not be identified. At present there are no effective treatments for this condition. Therefore, the identification of new drugs for the treatment of chronic cough will be of immense benefit and will greatly enhance the quality of life of many patients and sufferers. The reflex action of coughing is initiated when sensory nerves in the airway are activated. Our research looks into whether agents which prevent the sensory nerves in the airway from being activated, will also inhibit the cough reflex. This project in particular looks at cyclodextrin as a possible agent. Previous pre-clinical studies have demonstrated the inhibitory effects of cyclodextrin in preventing cough. This project seeks to take this work further and to test the inhibitory activity of cyclodextrins on the cough reflex in man.
Technical Summary
Cough is an important defense mechanism that helps clear excessive secretions and foreign material from the airways. However, it also presents as the first and most persistent symptom of many inflammatory airways diseases, including asthma, COPD, post viral infections, pulmonary fibrosis and bronchiectasis. Chronic cough can also be idiopathic in nature. To date, the only effective treatments for cough are opioids which have central and peripheral side effects. Therefore, the identification of novel therapeutic targets for the treatment of chronic cough will be of immense therapeutic benefit and will greatly enhance the quality of life of patients. The cough reflex is initiated by activation of airway sensory afferent nerves. We hypothesize that agents that inhibit sensory nerve activity will also inhibit the cough reflex. In this proposal we describe pre-clinical data demonstrating the anti-tussive activity of cyclodextrins both in vitro on sensory nerve function and in vivo in a guinea-pig cough model. The aim of this proposal is to test the anti-tussive activity of this molecule in man and to investigate the possible mechanism of action.
Organisations
- Imperial College London, United Kingdom (Lead Research Organisation)
- Guy's and St Thomas' NHS Foundation Trust, London (Collaboration)
- Laboratory of the Government Chemist (LGC) Ltd (Collaboration)
- Roquette Pharma (Collaboration)
- Thermo Fisher Scientific (Collaboration)
- King's College London, United Kingdom (Collaboration)
Publications

Belvisi MG
(2008)
Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways.
in British journal of pharmacology


Birrell MA
(2009)
TRPA1 agonists evoke coughing in guinea pig and human volunteers.
in American journal of respiratory and critical care medicine

Buckley J
(2011)
EP4 receptor as a new target for bronchodilator therapy.
in Thorax

Freund-Michel VC
(2010)
Beta(2)-agonists block tussive responses in guinea pigs via an atypical cAMP-dependent pathway.
in The European respiratory journal

Maher SA
(2009)
Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy.
in American journal of respiratory and critical care medicine

Morice AH
(2007)
ERS guidelines on the assessment of cough.
in The European respiratory journal
Guideline Title | Cough guidelines |
Description | ERS Guidelines for the assessment of cough. Eur Respir J. 2007 Jun;29(6):1256-76 |
Geographic Reach | Asia |
Policy Influence Type | Citation in clinical guidelines |
Impact | Participation in creating the above guidelines.; Influencing training of practitioners |
Description | MRC Project Grant |
Amount | £550,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2008 |
End | 09/2011 |
Title | Validation of a dosimeter used in the tussive challenge |
Description | We have characterised and validated the use of the KoKo dosimeter to assess the cough response in man. This is in keeping with published ERS guidelines. |
Type Of Material | Physiological assessment or outcome measure |
Provided To Others? | No |
Impact | Provides standardised analysis of the cough reponse between interntaional research sites. |
Description | Formulation of cyclodextrin and stability analysis for intravenous use in patients. |
Organisation | Guy's and St Thomas' NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | Laising with the company to provide data needed for use of cyclodextrin in man. |
Collaborator Contribution | Formulation of cyclodextrin and stability analysis for intravenous use in patients. |
Impact | Issues are still ongoing regarding analysis of the stability of cyclodextrin which we hope will be resolved soon so as we can progress to the clinical trial and publication of the data. |
Start Year | 2008 |
Description | HPLC analysis of cyclodextrin solution |
Organisation | Laboratory of the Government Chemist (LGC) Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Laising with the company to provide data needed for use of cyclodextrin in man. |
Collaborator Contribution | HPLC analysis of cyclodextrin solution |
Impact | Issues are still ongoing regarding analysis of the stability of cyclodextrin which we hope will be resolved soon so as we can progress to the clinical trial and publication of the data. |
Start Year | 2008 |
Description | Pharmacokinetic analysis of cyclodextrin in the blood from patients in phase 1 of the proposed clinical trial. |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Laising with the company to provide data needed for use of cyclodextrin in man. |
Collaborator Contribution | Pharmacokinetic analysis of cyclodextrin in the blood of patients from the phase 1 clinical trial. |
Impact | Issues are still ongoing regarding analysis of the stability of cyclodextrin which we hope will be resolved soon so as we can progress to the clinical trial and publication of the data. |
Start Year | 2009 |
Description | Provision of substance |
Organisation | Roquette Pharma |
Country | France |
Sector | Private |
PI Contribution | Liaising with the company to provide cyclodextrin for human use. |
Collaborator Contribution | Guided us with their technical expertise in the formulation of cyclodextrin for use in this trial. Provision of cyclodextrin and technical support in formulation of the IV solution for use in the trial. |
Impact | Issues are still ongoing regarding analysis of the stability of cyclodextrin which we hope will be resolved soon so as we can progress to the clinical trial and publication of data. |
Start Year | 2007 |
Description | Technical support for analysis of cyclodextrin |
Organisation | Thermo Fisher Scientific |
Department | Dionex |
Country | United States |
Sector | Private |
PI Contribution | Laising with the company to provide data needed for use of cyclodextrin in man. |
Collaborator Contribution | Technical support for analysis of cyclodextrin. |
Impact | Issues are still ongoing regarding analysis of the stability of cyclodextrin which we hope will be resolved soon so as we can progress to the clinical trial and publication of the data. |
Start Year | 2007 |
Description | Patient Involvement (Manchester) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Out clinical collaborators (MRC grant partners on this award) in Manchester hold an event each year to keep chronic cough patients up to date with the work they are doing in their clinic and through our research to find a cure for chronic cough. Combat my Cough is an opportunity to listen to and talk to the research team, but also for you to meet and talk to other sufferers with the condition. http://www.combatmycough.com/#!events/c1k9b |
Year(s) Of Engagement Activity | 2015,2016 |
URL | http://www.combatmycough.com/#!events/c1k9b |