Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction

Satia, Imran; Tsamandouras, Nikolaos; Holt, Kimberley; Badri, Huda; Woodhead, Mark; Ogungbenro, Kayode; Felton, Timothy; O'Byrne, Paul M.; Fowler, Stephen J.; Smith, Jaclyn A.

doi:10.1016/j.jaci.2016.04.045

Cited by 84 publications

(95 citation statements)

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“…The number of coughs in the 15 seconds following each inhalation was counted The challenge continued until the maximum tolerated dose or the final concentration was inhaled (6,22). The maximum number of coughs evoked at any concentration (E max ) was the main endpoint, but the concentration evoking 50% of the maximal response (ED 50 ) was also reported.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the threshold for provoking cough by capsaicin (C2 or the C5 concentration of capsaicin required to elicit at least 2 or 5 coughs, respectively) has been found to be lowered in various populations of patients with Chronic Obstructive Pulmonary(4,26), asthma (22,26), Idiopathic Pulmonary Fibrosis (27) and also refractory chronic cough patients(4,5,28) compared to healthy controls. These data imply that TRPV1 function is frequently increased in a disease setting.…”

Section: Discussionmentioning

confidence: 99%

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XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough

Belvisi

Birrell

Wortley

et al. 2017

Am J Respir Crit Care Med

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130

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What is the current scientific knowledge on this subject? Conclusive data regarding the importance of TRPV1 as a treatment target in chronic cough has been lacking due the absence of a safe, potent and efficacious tool compound for use in clinical studies. In a previous study, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in treatment resistant chronic cough patients but the reduction in capsaicin-evoked cough was only small. What does this study add to the field?This study rules out TRPV1 as an effective therapeutic target in refractory chronic cough patients. It also highlights the importance of pharmacodynamic pre-clinical and clinical models in the interpretation of negative clinical trial data, but questions the use of cough challenge models in target identification. Word Count 3917 words METHODS:XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig.Twenty patients with refractory chronic cough participated in a double-blind, randomised, placebocontrolled, crossover study evaluating the effect of 14 days XEN-D0501 (oral, 4mg bd) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough and patient reported outcomes. MEASUREMENTS AND MAIN RESULTS:XEN-D0501 was more efficacious and 1000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus. In vivo, XEN-D0501 completely inhibited capsaicin-induced cough whereas 100-times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline XEN-D0501 -19.3(±16.4) coughs vs. placebo -1.8(±5.8), p<0.0001), but not spontaneous awake cough frequency (mean change from baseline XEN-D0501 6.7c/h(±16.9) vs. placebo 0.4c/h(±13.7), p =0.41).CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough

Belvisi

Birrell

Wortley

et al. 2017

Am J Respir Crit Care Med

Self Cite

130

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“…However, the divergent profile of tussive responses described in clinical challenge studies among patients with different chronic lung diseases and even in patients within one disease group (e.g. asthma) supports the hypothesis of disease-specific neurophenotypes [35,38]. As such it will become necessary to identify which patient subgroups may be more susceptible to therapeutics targeting neuronal hyperresponsiveness.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the threshold for provoking cough by capsaicin (often referred to as the C2 or the C5: concentration of capsaicin required to elicit two or five coughs, respectively) has been found to be lowered in various populations of COPD [33][34][35], asthmatic [33, [35][36][37][38][39], IPF [40] and chronic idiopathic cough [35,41] patients who have chronic cough compared to healthy controls. These data imply that TRPV1 function is increased in a disease setting.…”

Section: Trpv1mentioning

confidence: 99%

The emerging role of transient receptor potential channels in chronic lung disease

Belvisi

Birrell

2017

Eur Respir J

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Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis are a major and increasing global health burden with a high unmet need. Drug discovery efforts in this area have been largely disappointing and so new therapeutic targets are needed. Transient receptor potential ion channels are emerging as possible therapeutic targets, given their widespread expression in the lung, their role in the modulation of inflammatory and structural changes and in the production of respiratory symptoms, such as bronchospasm and cough, seen in chronic lung disease.

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“…For example, the interactions between bronchospasm and cough are poorly understood. Our previous work in stable asthma has demonstrated that cough responses to citric acid and capsaicin are not correlated with methacholine BHR or FEV 1 1 2. The effects of acute bronchoconstriction on cough responses evoked by capsaicin inhalation have only been studied in healthy volunteers where minimal bronchoconstriction (mean FEV 1 fall 8.8%) had no effect on the capsaicin concentration provoking two coughs (C2) 3.…”

Section: Introductionmentioning

confidence: 99%

The interaction between bronchoconstriction and cough in asthma

Satia

Badri

Woodhead

et al. 2017

Thorax

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Variable airflow obstruction is a pathophysiological hallmark of asthma; however, the interactions between acute bronchoconstriction and the cough reflex are poorly understood. We performed a randomised, single-blind, placebo-controlled, crossover study to investigate the interaction between bronchoconstriction and cough in asthma. Capsaicin was administered to evoke coughs and methacholine to induce bronchoconstriction. We demonstrated that acute bronchoconstriction increased capsaicin-evoked coughs, which improved as airway calibre spontaneously resolved. However, capsaicin-evoked coughing had no impact on methacholine-induced bronchoconstriction. This study provides evidence that bronchoconstriction increases the activation of capsaicin-responsive airway nerves, but the precise mechanisms and mediators involved require further evaluation.Trial registration numberISRCTN14900082.

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Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction

Abstract: Patients with stable asthma exhibited exaggerated capsaicin-evoked cough responses consistent with neuronal dysfunction. Nonatopic asthmatic patients had the highest cough responses, suggesting this mechanism might be most important in type 2-low asthma phenotypes.

Cited by 84 publications

References 30 publications

XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough

XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough

The emerging role of transient receptor potential channels in chronic lung disease

The interaction between bronchoconstriction and cough in asthma

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