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Mechanistic and Therapeutic Evaluations of Chronic Cough
[Thesis]. Manchester, UK: The University of Manchester; 2014.
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Abstract
Introduction: Patients with chronic cough suffer significantly from impaired quality of life. However, safe and well-tolerated effective treatments remain a major unmet clinical need. Afferent pathways of the cough reflex are almost entirely mediated via the vagus nerve. The vagal afferents relay information to second-order neurons in the nucleus tractus solitaries (NTS) in the brainstem. Hyper excitability of the cough reflex pathways is thought to be the main mechanism in chronic cough. Various ion channels are involved in the transduction of cough signals and generation of action potentials. The potential mechanistic and therapeutic role of neuronal ion channels warrants clinical evaluation.Methods: I recruited patients with refractory chronic cough into three separate clinical trials of ion channel antagonists (NaV, P2X3, and NMDA). The primary outcome measure was objectively recorded cough frequency using the ambulatory acoustic recording device, VitaloJAK™. In the first trial, I investigated the effect of the pan NaV blocker, lidocaine, administered via nebulization compared to placebo. To enhance blinding, I also included treatment with lidocaine throat spray. In the second trial, I enrolled patients into a randomised study of the P2X3 antagonist, oral AF-219, vs. placebo. In the third trial, I explored the feasibility of evaluating memantine (use-dependent NMDAR antagonist) in chronic cough.Results • Objective cough frequency after treatment with nebulised lidocaine was not significantly different from placebo. A small (-19%, p=0.026) difference in cough rate was seen after lidocaine throat spray compared with placebo. • The P2X3 antagonist, AF-219, compared with placebo markedly and significant improved both daytime objective cough frequency (-75%, p<0.001) and patient reported outcomes. • Memantine was associated with significant intolerable side effects and there was no meaningful reduction in either cough frequency or CQLQ scores.Conclusions: Nebulised lidocaine is not an effective anti-tussive. This could be because of the deposition site within the airways. Nebulised particles are of small sizes that allow them to be deposited primarily within the distal small airways. Stimulation of bronchial rather than pulmonary C-fibres has been shown to initiate cough. More potent and sensory neurons-selective blockers of NaV may prove to be effective and safe in improving cough. P2X3 channels appear to contribute to the hyper excitability of the afferent pathways mediating cough and their antagonists represent a promising new class of anti-tussives. NMDARs-mediated central sensitisation does not seem to play an important role in chronic cough and NMDAR antagonists are poorly tolerated.