Background: Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough.
Methods: We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730.
Findings: Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219.
Interpretation: P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives.
Funding: Afferent Pharmaceuticals.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/S0140-6736(14)61255-1 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release.
ACS Pharmacol Transl Sci
January 2025
Pharmaceutical Institute, Pharmacology and Toxicology, University of Bonn, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany.
Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors.
View Article and Find Full Text PDFExamining Cough's Role and Relief Strategies in Interstitial Lung Disease.
J Clin Med
January 2025
Corewell Health, Grand Rapids, MI 49503, USA.
Chronic cough is a distressing and prevalent symptom in interstitial lung disease (ILD), significantly impairing quality of life (QoL) and contributing to disease progression, particularly in idiopathic pulmonary fibrosis (IPF). It is associated with physical discomfort, psychological distress, and social isolation and is often refractory to conventional therapies. The pathophysiology of cough in ILD is complex and multifactorial, involving neural hypersensitivity, structural lung changes, inflammatory processes, and comorbid conditions such as gastroesophageal reflux disease (GERD).
View Article and Find Full Text PDFStructural comparisons of human and mouse fungiform taste buds.
Chem Senses
January 2025
Dept. Cell & Devel. Biology, Rocky Mountain Taste & Smell Center, Univ. Colorado School of Medicine, Aurora, CO.
Taste buds are commonly studied in rodent models, but some differences exist between mice and humans in terms of gustatory mechanisms and sensitivities. Whether these functional differences are reflected in structural differences between species is unclear. Using immunofluorescent image stacks, we compared morphological and molecular characteristics of mouse and human fungiform taste buds.
View Article and Find Full Text PDFMechanistic insights into the selective targeting of P2X3 receptor by camlipixant antagonist.
J Biol Chem
December 2024
Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA. Electronic address:
ATP-activated P2X3 receptors play a pivotal role in chronic cough, affecting more than 10% of the population. Despite the challenges posed by the highly conserved structure of P2X receptors, efforts to develop selective drugs targeting P2X3 have led to the development of camlipixant, a potent, selective P2X3 antagonist. However, the mechanisms of receptor desensitization, ion permeation, and structural basis of camlipixant binding to P2X3 remain unclear.
View Article and Find Full Text PDFAdipose stem-cell-derived microvesicles ameliorate long-term bladder ischemia-induced bladder underactivity.
J Formos Med Assoc
December 2024
Department of Life Science, College of Science, National Taiwan Normal University, 162, Section 1, Heping E. Rd., Taipei, 106, Taiwan. Electronic address:
Background/purpose: The mechanism for long-term hypoxia/ischemia induced bladder underactivity is uncertain. It requires an effectively therapeutic treatment. Therefore, we determined the pathophysiologic mechanisms of long-term bilateral partial iliac arterial occlusion (BPAO)-induced bladder underactivity and explored the therapeutic potential of adipose-derived stem cells (ADSCs) and ADSC-derived microvesicles (MVs) on BPAO-induced bladder dysfunction.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!