Chronic cough: new insights and future prospects.

Chronic cough is defined in adults as a cough that lasts for ≥8 weeks. When it proves intractable to standard-of-care treatment, it can be referred to as refractory chronic cough (RCC). Chronic cough is now understood to be a condition of neural dysregulation. Chronic cough and RCC result in a serious, often unrecognized, disease burden, which forms the focus of the current review.The estimated global prevalence of chronic cough is 2-18%. Patients with chronic cough and RCC report many physical and psychological effects, which impair their quality of life. Chronic cough also has a significant economic burden for the patient and healthcare systems. RCC diagnosis and treatment are often delayed for many years as potential treatable triggers must be excluded first and a stepwise empirical therapeutic regimen is recommended.Evidence supporting most currently recommended treatments is limited. Many treatments do not address the underlying pathology, are used off-label, have limited efficacy and produce significant side-effects. There is therefore a significant unmet need for alternative therapies for RCC that target the underlying disease mechanisms. Early clinical data suggest that antagonists of the purinergic P2X3 receptor, an important mediator of RCC, are promising, though more evidence is needed.

Objective Assessment of Cough: An Early Marker of Response to Biological Therapies in Asthma?

Cough is an important symptom of asthma. The objective assessment of chronic cough has been enhanced by the development of ambulatory cough monitoring systems. Mepolizumab has been demonstrated to reduce exacerbations in eosinophilic asthmatics long-term. We evaluate the utility of objective cough count as an outcome measure in severe eosinophilic asthma treated with mepolizumab. Consecutive, consenting patients initiated on treatment with mepolizumab had a 24-h cough count recorded at baseline; this was repeated at 1, 3 and 6 months. Asthma control questionnaire (ACQ) scores and exacerbation frequency were also recorded. The mean 24-h cough count in 11 subjects (8 females, mean age 53.6 years) was 172.4 at baseline; at 1, 3 and 6 months following initiation of treatment this decreased to 101.4, 92 and 70.8, respectively (p < 0.02). Significant improvements were also observed in mean ACQ score (3-1.6, p < 0.01) and exacerbation frequency (5.5 per year - 1.3, p < 0.01). Objective cough measurement could be used as an early, precise and clinically relevant endpoint in assessing response to asthma therapy.

Comprehensive evidence-based review on European antitussives.

Acute cough caused by viral respiratory tract infections is probably the most common illness to afflict mankind. Despite the widespread but ineffective prescribing of antibiotics, there is no specific therapy. Home remedies and over-the-counter medicines are the mainstay for treatment of this short-lived but debilitating condition where cough is a major troublesome symptom. Across Europe, there are large variations in the recommendations made by healthcare professionals for the treatment of acute cough. This has arisen through custom and practice based on the evidence of historical studies performed to standards well short of what would be considered legitimate today. Acute cough is particularly difficult to study in a controlled setting because of the high rate of spontaneous remission and a large placebo effect. Here we detail the validated modern methodology used to assess the efficacy of antitussives and review the drugs commonly used in Europe against these standards.

A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers.

AIMS: The examination of cough reflex sensitivity through inhalational challenge can be utilized to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin-induced cough in healthy volunteers. METHODS: In this randomized, placebo-controlled, six way crossover study the effect of dextromethrophan 30 mg, four doses of butamirate and placebo was evaluated on incremental capsaicin challenges performed at baseline and 2, 4, 6, 8, 12 and 24 h following dosing. The primary end point was the area under the curve (AUC(0,12h)) of log10 C5 from pre-dose to 12 h after dosing. Plasma butamirate metabolites were analyzed to evaluate pharmacokinetic and pharmacodynamic relationships. RESULTS: Thirty-four subjects (13 males, median age 25 years) completed the study. Cough sensitivity decreased from baseline in all arms of the study. Dextromethorphan was superior to placebo (P = 0.01) but butamirate failed to show significant activity with maximum attenuation at the 45 mg dose. There was no apparent relationship between pharmacokinetic and pharmacodynamic parameters for butamirate. CONCLUSIONS: We have demonstrated for the first time that dextromethorphan attenuates capsaicin challenge confirming its broad activity on the cough reflex. The lack of efficacy of butamirate could be due to formulation issues at higher doses.

Human TRPM8 and TRPA1 pain channels, including a gene variant with increased sensitivity to agonists (TRPA1 R797T), exhibit differential regulation by SRC-tyrosine kinase inhibitor.

TRPM8 (transient receptor potential M8) and TRPA1 (transient receptor potential A1) are cold-temperature-sensitive nociceptors expressed in sensory neurons but their behaviour in neuronal cells is poorly understood. Therefore DNA expression constructs containing human TRPM8 or TRPA1 cDNAs were transfected into HEK (human embryonic kidney cells)-293 or SH-SY5Y neuroblastoma cells and G418 resistant clones analysed for effects of agonists and antagonists on intracellular Ca2+ levels. Approximately 51% of HEK-293 and 12% of SH-SY5Y cell clones expressed the transfected TRP channel. TRPM8 and TRPA1 assays were inhibited by probenecid, indicating the need to avoid this agent in TRP channel studies. A double-residue mutation in ICL-1 (intracellular loop-1) of TRPM8 (SV762,763EL, mimicking serine phosphorylation) or one in the C-terminal tail region (FK1045,1046AG, a lysine knockout) retained sensitivity to agonists (WS 12, menthol) and antagonist {AMTB [N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide]}. SNP (single nucleotide polymorphism) variants in TRPA1 ICL-1 (R797T, S804N) and TRPA1 fusion protein containing C-terminal (His)10 retained sensitivity to agonists (cinnamaldehyde, allyl-isothiocyanate, carvacrol, eugenol) and antagonists (HC-030031, A967079). One SNP variant, 797T, possessed increased sensitivity to agonists. TRPA1 became repressed in SH-SY5Y clones but was rapidly rescued by Src-family inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine]. Conversely, TRPM8 in SH-SY5Y cells was inhibited by PP2. Further studies utilizing SH-SY5Y may identify structural features of TRPA1 and TRPM8 involved in conferring differential post-translational regulation.

Relationship between gastro-oesophageal reflux and airway diseases: the airway reflux paradigm.

Our understanding of the relationship between gastro-oesophageal reflux and respiratory disease has recently undergone important changes. The previous paradigm of airway reflux as synonymous with the classic gastro-oesophageal reflux disease (GORD) causing heartburn has been overturned. Numerous epidemiological studies have shown a highly significant association of the acid, liquid, and gaseous reflux of GORD with conditions such as laryngeal diseases, chronic rhinosinusitis, treatment resistant asthma, COPD and even idiopathic pulmonary fibrosis. However, it has become clear from studies on cough hypersensitivity syndrome that much reflux of importance in the airways has been missed, since it is either non- or weakly acid and gaseous in composition. The evidence for such a relationship relies on the clinical history pointing to symptom associations with known precipitants of reflux. The tools for the diagnosis of extra-oesophageal reflux, in contrast to the oesophageal reflux of GORD, lack sensitivity and reproducibility. Unfortunately, methodology for detecting such reflux is only just becoming available and much additional work is required to properly delineate its role.

La relación entre el reflujo gastroesofágico y las enfermedades de la vía aérea: el paradigma del reflujo a vía aérea / Relationship Between Gastro-Oesophageal Reflux and Airway Diseases: The Airway Reflux Paradigm

Nuestro conocimiento sobre la relación entre el reflujo gastroesofágico (RGE) y las enfermedades respiratoriasha conllevado recientemente a cambios importantes. El paradigma previo del reflujo a vía aérea(RVA) o RGE que llega hasta la vía aérea como sinónimo de la enfermedad por reflujo gastroesofágicoclásica (ERGE) con la pirosis como síntoma imprescindible ha sido definitivamente rechazado. Numerososestudios epidemiológicos han mostrado una asociación altamente significativa entre el reflujo ácido,líquido y gaseoso de la ERGE con condiciones tales como enfermedades laríngeas, rinosinusitis crónica,asma resistente al tratamiento, EPOC e inclusive fibrosis pulmonar idiopática. Hoy se sabe que graciasa estudios del síndrome de hipersensibilidad tusígena gran parte del reflujo que llega a la vía aérea noes diagnosticado debido a su escaso o nulo contenido de ácido o a su composición gaseosa. La evidenciapara esta relación se basa en la historia clínica que se˜nala una asociación sintomática con factores precipitantesconocidos del reflujo. Las exploraciones para el diagnóstico del RA no poseen la sensibilidado la reproducibilidad que han demostrado las del reflujo esofágico de la ERGE. Desafortunadamente, elacceso a la metodología para la detección de tal reflujo empezó a ser posible hace muy poco tiempo y serequiere aún muchos trabajos de investigación para perfilar correctamente su papel(AU)

Our understanding of the relationship between gastro-oesophageal reflux and respiratory disease hasrecently undergone important changes. The previous paradigm of airway reflux as synonymous withthe classic gastro-oesophageal reflux disease (GORD) causing heartburn has been overturned. Numerousepidemiological studies have shown a highly significant association of the acid, liquid, and gaseousreflux of GORD with conditions such as laryngeal diseases, chronic rhinosinusitis, treatment resistantasthma, COPD and even idiopathic pulmonary fibrosis. However, it has become clear from studies oncough hypersensitivity syndrome that much reflux of importance in the airways has been missed, sinceit is either non- or weakly acid and gaseous in composition. The evidence for such a relationship relieson the clinical history pointing to symptom associations with known precipitants of reflux. The tools forthe diagnosis of extra-oesophageal reflux, in contrast to the oesophageal reflux of GORD, lack sensitivityand reproducibility. Unfortunately, methodology for detecting such reflux is only just becoming availableand much additional work is required to properly delineate its role(AU)