Rhinitis, sinusitis, and upper airway diseasePharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point
Section snippets
Subjects
Twenty HVs, 18 patients with mild-to-moderate asthma, and 20 patients with unexplained CC of a duration of greater than 8 weeks were recruited. Asthmatic patients all had documented evidence of bronchial hyperreactivity (positive methacholine challenge result, reversibility in FEV1 >12%, or both), and those with unexplained CC had undergone full investigation and treatment trials for possible causes of cough in a specialist cough clinic (see the Methods section in this article's Online
Subjects' characteristics
Twenty HVs, 18 asthmatic patients, and 20 patients with CC completed the study, with equal numbers of male and female subjects in each group. Subjects' characteristics are summarized in Table I. There were no statistical differences in age, body mass index, lung function, anxiety, or depression scores between groups.
Model structure
The structural model was successfully implemented in NONMEM. Baseline cough frequency (E0) was fixed to zero, which is consistent with the average cough response to inhaled placebo
Discussion
To the best of our knowledge, this is the first study to apply nonlinear mixed-effects modeling to formally characterize capsaicin dose response in patients with CC, asthmatic patients, and HVs. Dose-response parameters, ED50 and Emax values, were compared by disease group and sex. In summary, although there were no statistical differences in either parameter between HVs and asthmatic patients, patients with CC had significantly higher Emax values and significantly lower ED50 values compared
References (47)
Short- and long-term reproducibility of capsaicin cough challenge testing
Pulm Pharmacol Ther
(2003)- et al.
Cough frequency, cough sensitivity and health status in patients with chronic cough
Respir Med
(2006) - et al.
Cough and glottic-stop reflex sensitivity in health and disease
Chest
(2005) - et al.
Angiotensin-converting enzyme and the cough reflex
Lancet
(1987) - et al.
A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered- dose inhalers
J Allergy Clin Immunol
(2002) - et al.
Population pharmacodynamic model of bronchodilator response to inhaled albuterol in children and adults with asthma
Chest
(2008) - et al.
Inhaled ethanol potentiates the cough response to capsaicin in patients with airway sensory hyperreactivity
Pulm Pharmacol Ther
(2008) - et al.
Antitussive effects of memantine in guinea pigs
Chest
(2012) - et al.
The effect of codeine on the urge-to-cough response to inhaled capsaicin
Pulm Pharmacol Ther
(2007) Plasticity of vagal afferent fibres mediating cough
Pulm Pharmacol Ther
(2004)
Neuroplasticity in vagal afferent neurons involved in cough
Pulm Pharmacol Ther
Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reflex in humans
Pain
Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients
Pain
ERS guidelines on the assessment of cough
Eur Respir J
Clinical cough III: measuring the cough response in the laboratory
Handb Exp Pharmacol
Chronic cough: how do cough reflex sensitivity and subjective assessments correlate with objective cough counts during ambulatory monitoring?
Thorax
Sex differences and predictors of objective cough frequency in chronic cough
Thorax
Introduction of quantitative methods in pharmacology and clinical pharmacology: a historical overview
Clin Pharmacol Ther
Magnitude of cough response to inhaled capsaicin differentiates between health and disease [abstract]
Thorax
Sex-related differences in cough reflex sensitivity in patients with chronic cough
Am J Respir Crit Care Med
Female gender as a determinant of cough threshold to inhaled capsaicin
Eur Respir J
Cough challenge in the assessment of cough reflex
Br J Clin Pharmacol
Basic concepts in population modeling, simulation, and model-based drug development—part 2: introduction to pharmacokinetic modelling methods
CPT: Pharmacometrics Syst Pharmacol
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2021, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :The power calculation was based on previous cough challenge data, where one doubling dose of the challenge agent is generally accepted to be a clinically relevant difference in cough reflex sensitivity. Thus, with 15 participants treated, this study had approximately 90% power to detect a one doubling dose change in cough reflex sensitivity of 0.3 for lesogaberan compared with placebo, assuming a standard deviation of ±0.29 [10]. Nineteen healthy volunteers were recruited, 4 of which failed screening (see consort, Fig. 2) leaving 15 completing the study.
Supported by MRC Training Fellowship and MRC Clinician Scientist Award G0701918.
Disclosure of potential conflict of interest: E. C. Y. Hilton has received research support from the Medical Research Council and is employed by Novo Nordisk UK. P. G. Baverel is employed by Pfizer. A. Woodcock has a patent from Vitalograph. P. H. Van Der Graaf is employed by and owns stock in Pfizer. J. A. Smith has received research support from the Medical Research Council, has received consultancy fees from GlaxoSmithKline and Merck, and the University Hospital South Manchester owns a patent that she has invented on describing methods for cough detection from sound recordings.