Clinical Trial: An Investigation Into the Mechanism of Inhalation Cough Challenge

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: An Investigation Into the Mechanism of Inhalation Cough Challenge

Brief Summary:

Despite its commonplace use in respiratory medicine the mechanism whereby inhalation challenge with a variety of mild acid aerosols produces a dose related and predictable cough is unknown. In this proposal the investigators wish to use established cough challenge methodology to explore the mechanism of action of agents provoking cough both in health and disease.

The hypotheses to be tested include:

  • Intracellular changes in pH, rather than extracellular changes, are key in the activation of TRP receptors, the main sensor for provoking cough.
  • ATP acting through P2X channels is the mechanism of increased nerve excitability underlying cough hypersensitivity.

Detailed Summary:

The investigators have previously demonstrated that mild acids, such as citric, tartaric or phosphoric acid produce a highly reliable cough challenge and that the sensitivity of these are complex individual acids correlates within the population studied inferring a common mechanism of action.In contrast there is no correlation with the other common cough challenge methodology, capsaicin inferring that there are at least two different mechanisms for producing cough with aerosols in man.

Over the past 10 years it has been established that capsaicin works by a specific irritant receptor known as the TRPV1. A second receptor, TRPA1 has been recently discovered and we were the first group to demonstrate that inhalation of agonists of this receptor in the form of the extract of cinnamon (cinnamaldehyde) produces cough in man . TRPA1 is a very attractive candidate for the main cough receptor since it is activated by many common irritants, such as smoke, perfumes and other strong smells known to provoke coughing in patients.

The investigators have cloned the human TRP receptors and expressed them in cell lines. This in vitro work has allowed us to investigate the molecular action of the TRP receptors. Recently, the investigators and others have shown that weak acids can activate TRPA1, not as previously thought by stimulating the external surface of the cells but by altering the intracellular pH. This would explain why weak and not strong acids are better at producing cough, since weaker acids (technically those with a higher pKa) exist in solution in a form which is able to cross the cell membrane and render a change in the intracellular pH, which in turn activates TRPA1 from inside the cell.

In the first study the investigators wish to the simply alter the pH of the nebulised sol
Sponsor: Hull and East Yorkshire Hospitals NHS Trust

Current Primary Outcome: Difference in mean C5 (concentration of inhaled substance required to elicit 5 coughs) (ATP) and total cough (citric acid) between the chronic cough arm and the normal volunteer arm. [ Time Frame: Coughs will be measured in a 30 second period following the inhalation of each challenge substance. ]

Following inhalation of challenge substance, subject will be monitored for 30 seconds and number of coughs recorded. Concentration of challenge substance will increase until subject coughs at least 5 times following challenge. This will be recorded as the C5 value for each subject. The mean C5 value will be compared between the chronic cough arm and the normal volunteer arm. This will be reported as whether or not there is a statistical difference between the mean C5 for the chronic cough group and the normal volunteer group.


Original Primary Outcome: Difference in mean C5 (concentration of inhaled substance required to elicit 5 coughs) between the chronic cough arm and the normal volunteer arm. [ Time Frame: Coughs will be measured in a 30 second period following the inhalation of each challenge substance. ]

Following inhalation of challenge substance, subject will be monitored for 30 seconds and number of coughs recorded. Concentration of challenge substance will increase until subject coughs at least 5 times following challenge. This will be recorded as the C5 value for each subject. The mean C5 value will be compared between the chronic cough arm and the normal volunteer arm. This will be reported as whether or not there is a statistical difference between the mean C5 for the chronic cough group and the normal volunteer group.


Current Secondary Outcome:

Original Secondary Outcome:

Information By: Hull and East Yorkshire Hospitals NHS Trust

Dates:
Date Received: December 16, 2013
Date Started: February 2015
Date Completion:
Last Updated: August 19, 2016
Last Verified: August 2016