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.

Publications

10 25 50
 
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 Academic/University
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