ATP, an attractive target for the treatment of refractory chronic cough

Zhang, Mengru; Sykes, Dominic L.; Sadofsky, Laura R.; Morice, Alyn H.

doi:10.1007/s11302-022-09877-z

Cited by 12 publications

(9 citation statements)

References 105 publications

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“…The shift in perception from cough as a consequence of underlying disease to cough as a distinct clinical entity has paved the way for development of novel antitussives that act on specific cough pathways [ 24 ]. Pathophysiological underlying mechanisms such as ATP release, which may stimulate vagal C-fiber afferent sensory neurons upon binding to purinergic receptors, including the P2X3 receptor, have been identified as contributors to chronic cough [ 25 ]. This has led to the development of P2X3 receptor antagonists with potential efficacy for treating RCC and UCC and alleviating patients from the burden of excessive cough [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study

Dávila

Puente

Quirce

et al. 2023

Lung

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Purpose Chronic cough (cough that persists for ≥ 8 weeks) can cause a range of physical symptoms and psychosocial effects that significantly impair patients’ quality of life. Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are challenging to diagnose and manage, with substantial economic implications for healthcare systems. Methods This retrospective multicenter non-interventional study aimed to characterize the profile and health resource consumption of patients with RCC or UCC who attended outpatient clinics at Spanish hospitals. Data were collected from medical records of patients with RCC or UCC for up to 3 years before study inclusion. Results The patient cohort (n = 196) was representative of the chronic cough population (77.6% female, mean age 58.5 years). Two-thirds of patients (n = 126) had RCC. The most frequently visited doctors were pulmonologists (93.4% of patients) and primary care physicians (78.6%), with a mean of 5 visits per patient over three years’ observation. The most common diagnostic tests were chest x-ray (83.7%) and spirometry with bronchodilation (77.0%). The most commonly prescribed treatments were proton pump inhibitors (79.6%) and respiratory medications (87.8%). Antibiotics were prescribed empirically to 56 (28.6%) patients. Differences between RCC or UCC groups related mainly to approaches used to manage cough-associated conditions (gastroesophageal reflux disease, asthma) in patients with RCC. Conclusion RCC and UCC are responsible for high health resource utilization in Spanish hospitals. Specific treatments targeting the pathological processes driving chronic cough may provide opportunities to reduce the associated burden for patients and healthcare systems.

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Section: Discussionmentioning

confidence: 99%

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study

Dávila

Puente

Quirce

et al. 2023

Lung

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“…Gefapixant has been confirmed for its antitussive efficacy and has been approved for clinical use in some countries. 7 , 28 , 29 Hopefully, it will be the first licenced agent for CC. However, its higher selectivity for P2X2/3 heterotrimers over P2X3 homotrimers leaves taste disturbance as a common adverse effect.…”

Section: Discussionmentioning

confidence: 99%

Antitussive efficacy of the current treatment protocol for refractory chronic cough: our real-world experience in a retrospective cohort study

Zhang

Morice

et al. 2023

Ther Adv Respir Dis

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Background: The management of refractory chronic cough (RCC) is a great challenge. Neuromodulators have long been used for RCC with imperfect efficacy. Objectives: We summarized the outcomes of the current treatments used at our specialist cough clinic, which provides a guideline-led service and real-world experience for the future management of RCC. Design: This is a single-centre retrospective observational cohort study. Methods: Consecutive RCC patients (the first clinic visit between January 2016 and May 2021) were included into this observational cohort study. Medical records in the Chronic Cough Clinical Research Database were fully reviewed using uniform criteria. The included subjects were followed-up for at least 6 months after the final clinic visit via instant messages with the link to self-scaled cough-associated questionnaires. Results: Overall, 369 RCC patients were analysed with a median age of 46.6 years and a cough duration of 24.0 months. A total of 10 different treatments were offered. However, 96.2% of patients had been prescribed at least one neuromodulator. One-third of patients had alternative treatments prescribed given the poor response to the initial therapy and 71.3% favourably responded to at least one of the treatments. Gabapentin, deanxit, and baclofen had comparable therapeutic efficacy (56.0%, 56.0%, and 62.5% respectively; p = 0.88) and overall incidences of adverse effects (28.3%, 22.0%, and 32.3% respectively; p = 0.76). However, 19.1 (7.7–41.8) months after the last clinic visit, 65.0% reported improvement (24.9%) or control of their cough (40.1%); 3.8% reported a spontaneous remission and 31.2% still had a severe cough. Both HARQ ( n = 97; p < 0.001) and LCQ ( n = 58; p < 0.001) demonstrated marked improvement. Conclusion: Trying different neuromodulators is a pragmatic strategy for RCC, which helped around two-thirds of patients. Relapse is common on withdrawal or reduction of dosage. Novel medication for RCC is an urgent clinical need. Plain language summary This is the first report that fully represented a guideline-led treatment protocol for refractory chronic cough (RCC) based on a large series of patients, which evaluated the short- and long-term effects of the currently available treatments for RCC. We found that the therapeutic trial of different neuromodulators is a pragmatic strategy, which helped around two-thirds of patients. Gabapentin, deanxit (flupentixol/melitracen), and baclofen had similar therapeutic outcomes. This study may offer real-world experience for the future management of RCC.

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“…We sought to determine whether the enhancement of ATP [approximated by Eq (6)] consequent to the normal breathing of dry air might generate sufficient ATP to elicit cough by activation of P2X3 receptors in hypersensitive (asthmatic) airways (51), and, therefore, whether rehydration of the upper airways [see Eq (5)] might benefit airway function, and in the case of hypersensitive airways complement the ATP-blocking action of P2X3 antagonist drugs against chronic cough (52)(53)(54). We assumed a base case of the nasal or mouth breathing of warm air (30 0 C) in circumstances of human breathing ranging from dry (10% RH) to moist (60% RH) air.…”

Section: Condensation Layer Evolution Atp Secretion and Neural Activa...mentioning

confidence: 99%

Mouth breathing, dry air, and low water permeation promote inflammation, and activate neural pathways, by osmotic stresses acting on airway lining mucus

Edwards

Chung²

2023

QRB Discovery

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Respiratory disease and breathing abnormalities worsen with dehydration of the upper airways. We find that humidification of inhaled air occurs by evaporation of water over mucus lining the upper airways in such a way as to deliver an osmotic force on mucus, displacing it toward the epithelium. This displacement thins the periciliary layer of water beneath mucus while thickening topical water that is partially condensed from humid air on exhalation. With the rapid mouth breathing of dry air, this condensation layer, not previously reported while common to transpiring hydrogels in nature, can deliver an osmotic compressive force of up to around 100 cm H 2 O on underlying cilia, promoting ATP secretion and activating neural pathways. We derive expressions for the evolution of the thickness of the condensation layer, and its impact on cough frequency, inflammatory marker secretion, cilia beat frequency, and respiratory droplet generation. We compare our predictions with human clinical data from multiple published sources, and highlight the damaging impact of mouth breathing, dry air, and high minute volume on upper airway function. We predict the hypertonic (or hypotonic) saline mass required to reduce (or amplify) dysfunction by restoration (or deterioration) of the structure of ciliated and condensation water layers in the upper airways, and compare these predictions with published human clinical data. Preserving water balance in the upper airways appears critical in light of contemporary respiratory health challenges posed by the breathing of dirty and dry air.

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ATP, an attractive target for the treatment of refractory chronic cough

Cited by 12 publications

References 105 publications

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study

Antitussive efficacy of the current treatment protocol for refractory chronic cough: our real-world experience in a retrospective cohort study

Mouth breathing, dry air, and low water permeation promote inflammation, and activate neural pathways, by osmotic stresses acting on airway lining mucus

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