The thesis investigates establishing a hypertussive model of cough primarily in the rabbit and with comparative experiments conducted in the guinea pig. These models were then used to investigate the effectiveness of various antitussives such as codeine and levodropropizine, as well as, putative antitussives such as anticholinergics, PDE inhibitors, bronchodilators and drugs affecting targets on sensory nerves. “Hypertussive” is a poorly recognised term and it is defined in the context of this thesis to describe an inappropriately frequent and/or loud cough response when compared to normative cough responses for the same given dose and route of a given tussive stimuli. A novel model of hypertussive cough responses was established and validated in the rabbit and guinea pig using ozone as a sensitising agent. Primary measures include cough frequency, cough magnitude, time to first cough and cough duration. In further experiments lung function parameters such as dynamic compliance and total lung resistance, and total and differential cell counts, as well as pilot experiments involving analyzing categories of cough “sounds” were measured. The thesis was also concerned with the measurement and classification of cough events and in particular the discrimination of cough events from sneeze events. Two commercially available systems and ad hoc approaches were used to evaluate how best to describe, count and classify the cough response and qualitative and quantitative judgement have been made to assess a best approach. In summary, the data in this thesis suggests that ozone is a particularly effective acutely-acting non-allergic sensitising agent capable of shifting the dose response curve of the cough response to citric acid leftward by 0.5 to 1 log units. Sensitization of the cough reflex overcame desensitization of rabbits and guinea pigs to citric acid, allowing cross-over designs to be employed. Ozone appears to act via sensitization of the peripheral airway sensory input, but I found no evidence that this was via an action on Transient Receptor Potential Ankyrin 1 (TRPA1), which has previously been suggested to be an important target for ozone. Codeine and levodropropizine were effective against hypertussive responses, but did not block the normotussive cough. Anticholinergic drugs were not effective against ozone sensitised cough nor normotussive cough responses in the rabbit, but significantly inhibited sensitised cough responses and normotussive cough responses in guinea pigs. However, salbutamol demonstrated a similar treatment profile to the anticholinergic drugs implying that bronchodilation is an important mechanism to reduce the cough response in guinea pigs. Thus, these data suggest that drug candidates that cause bronchodilation may falsely identify as antitussives in the guinea pig model. Phosphodiesterase inhibitors were effective at blocking the infiltration of leukocytes in both guinea pigs and rabbits, but did not effect the acutely sensitised cough, suggesting that in this model ozone is inducing hypertussive responses independently of leukocyte infiltration.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677167 |
| Date | January 2015 |
| Creators | Clay, Emlyn Robert |
| Contributors | Page, Clive Peter ; Spina, Domenico |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://kclpure.kcl.ac.uk/portal/en/theses/validation-and-comparison-of-ozoneinduced-hypertussive-responses-in-the-rabbit-and-guineapig(82b1fc29-9290-48b6-aeec-d34a20beafbe).html |
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