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Title: An investigation into the efficacy and mechanisms of action of novel therapeutics for chronic cough
Author: Wortley, Michael
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Whilst cough is a defensive reflex, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) the cough reflex may become exaggerated and unproductive, leading to presentation of chronic cough as a troublesome symptom. Chronic cough is the most common reason that patients seek ambulatory care in the UK, and cough medications are one of the largest segments of the global over-the-counter drugs market, yet there are no cough medications (prescription or OTC) available that are both efficacious AND safe, indicating a large unmet clinical need. β-adrenergic receptor (β-AR) agonists, methylxanthines (theophylline) and fatty acid amide hydrogenase inhibitors (FAAHi) are peripherally acting drugs with a proven safety profile in humans for other uses, but are not currently recognised as anti-tussive medications. This thesis aimed to examine whether these drugs possess anti-tussive activity, and if so, the mechanisms by which they inhibit cough. These drugs were all effective at blocking the in vivo cough response to tussive stimuli in naïve guinea pigs, and in addition β-AR agonists and theophylline inhibited tussive stimulus evoked cough in guinea pigs previously exposed to cigarette-smoke, which display a clinically relevant enhanced cough phenotype. In vitro and in vivo assays of guinea pig vagus nerve/neuron activation were used to show that these compounds inhibit depolarisation of airway-innervating peripheral sensory nerves. Pharmacological and genetic tools were used to investigate the receptors and signalling pathways activated by these drugs. Whilst β-AR agonists, theophylline and FAAHi had different mechanisms of action, a common component was that all three classes of compound act on various potassium channels, thereby reducing the excitability of sensory neurons. This work suggests that drugs that inhibit peripheral sensory nerve activity have the potential to be efficacious as anti-tussives. Specifically the compounds tested have improved clinical side-effect profiles over currently used anti-tussives, and therefore have potential as therapies for chronic cough.
Supervisor: Belvisi, Maria ; Birrell, Mark Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available