China
Africa
Explore chapters and articles related to this topic
Nonclassical Ion Channels in Depression
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
In contrast with the profound involvement of P2X7Rs in a wide variety of depression-associated behaviors, P2X2R and P2X3R knockout mice displayed no deficits in normal motor function, learning and memory behaviors, exploratory behavior, anxiety-like behaviors, and passive coping response to behavioral trials65. However, P2X2Rs were found to contribute fundamental roles in functions of the peripheral sensory system, such as pain66. Moreover, a reversible and selective P2X3R and P2X2/3R antagonist (MK-7264, gefapixant) is highly effective against hyperalgesia67. Despite the significant advances in understanding the role of the P2X7R subtype in depression, there is still a lack of compelling evidence for contributions by other subtypes, although future studies are likely to resolve clear functions for other subtypes in neurological and psychological functions and disorders.
Pulmonary – Treatable traits
Published in Vibeke Backer, Peter G. Gibson, Ian D. Pavord, The Asthmas, 2023
Vibeke Backer, Peter G. Gibson, Ian D. Pavord
Purinergic signalling, a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP, plays a role in cough reflex hypersensitivity. Purinergic P2X receptors are a family of ligand-gated, non-selective cation channels that open in response to extracellular ATP and comprises seven members termed P2X1–P2X7. P2X3 receptors are now recognised as major players in mediating primary sensory effects of ATP and are found in airway nociceptive fibres. A novel P2X3 receptor antagonist (Gefapixant) has shown promising results in significantly reducing cough frequency in patients with unexplained chronic cough (UCC), suggesting that this might be an important treatable trait in patients with airway disease. In addition, treatments that modify the influence of higher centre control on the cough reflex, such as gabapentin, can also be useful. A systematic review of non-pharmacological interventions for patients with refractory chronic cough (RCC) also suggests benefit of the use of two to four sessions of a combination of education, cough suppression techniques, breathing exercises and counselling to achieve improvements in cough reflex sensitivity and cough-related quality of life for these individuals although further research is needed to more comprehensively establish effective components, treatment duration and frequency of this package. A smaller group of patients suffers of UCC, where no other disease exists than cough. Altered cough reflex sensitivity could also manifest as a reduced sensitivity or effectiveness of the cough reflex such as in relation to an underlying neuromuscular disease or medication. Such patients would then benefit from cough augmentation techniques.
Pharmacotherapeutic Options for Chronic Refractory Cough
Published in Expert Opinion on Pharmacotherapy, 2020
Two subsequent dose-ranging studies found that gefapixant at a lower dosage (30 mg or 50 mg b.i.d.) effectively decreased objective cough frequency and improved PROs while reducing the taste side-effects [56]. Both the antitussive and taste effects were generally dose-dependent, but gefapixant doses less than 30 mg were not significantly effective in reducing 24-hour cough frequency compared with the placebo, and the dose higher than 30 mg did not provide any additional benefit in reducing objective cough frequency. The incidence of dysgeusia was approximately 50% in patients receiving 30 mg or 50 mg of gefapixant, but it increased to 70.4% at 100 mg [56]. In a recent 12-week, phase 2b study of 253 patients with refractory or unexplained chronic cough, gefapixant at a dose of 50 mg b.i.d. significantly reduced cough frequency and improved PROs compared to the placebo [57]. Effect size relative to placebo in objective cough frequency was −37.0% (95% CI −53.3 to −14.9; p = 0.0027) with the treatment (Table 2). Dysgeusia occurred in 48% of patients given 50 mg gefapixant. In this trial, objective cough frequency was measured 2 weeks after the end of treatment; interestingly, the improvement in cough frequency appeared to be sustained at week 14, although statistical testing was not done [57]. Currently, large-scale phase 3 trials investigating the use of gefapixant (15 mg or 45 mg b.i.d.) in more than 2000 patients with CRC are undergoing [55].
Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: A randomized, double-blind, controlled, parallel-group, Phase 2b trial: Discussions from a Twitter journal club @respandsleepjc (#rsjc)
Published in Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, 2021
Christopher Kawala, Anju Anand, Matthew Stanbrook
Chronic cough (lasting >8 weeks) is common, affecting 4-16% of adults.1–3 Patients who have chronic cough despite treatment of their asthma, nonasthmatic eosinophilic bronchitis, gastroesophageal reflux disease (GERD), and/or upper airway cough syndrome are classified as having refractory chronic cough. Conversely, patients with chronic cough with no underlying cause identified are considered to have unexplained chronic cough. Cough hypersensitivity syndrome is a diagnosis that can be applied to either of these groups of patients and is hypothetically due to disordered sensory neural function.4 Previous studies have demonstrated that patients with refractory chronic cough respond to therapies that modulate neuronal function (e.g., morphine,5 gabapentin,6 amitriptyline7). The purinergic receptor P2X3 is an ion channel found on peripheral sensory nerves and is expressed on fibers innervating the airways.8 Gefapixant is a P2X3 receptor antagonist and has been shown to reduce objective cough frequency by 75%.9 However, in this small, 2-week proof-of-concept study, patients received a high dose (600 mg by mouth [PO], twice per day [BID]), which led to a universal complaint of taste disturbance, with 25% of patients dropping out of the study. Ensuing studies have determined that the drug efficacy is retained at a lower dose of 50 mg PO BID.10 More recently, a Phase 2 b, randomized, double-blind, placebo controlled, parallel group study was published, and this article was reviewed at our Twitter journal club.11 The critical appraisal is found in Table 1.
Emerging drugs in the treatment of chronic cough
Published in Expert Opinion on Emerging Drugs, 2023
Danica Brister, Mustafaa Wahab, Moaaz Rashad, Nermin Diab, Martin Kolb, Imran Satia
Treatment with gefapixant can result in reduction in cough frequency as high as 65% within an individual. This may reduce cough frequencies from a median baseline of approximately 20 coughs/h down to 7–8 coughs/h. However, this is still not considered a normal cough rate because healthy controls cough<0.5 coughs/h. Higher doses may result in greater reductions in cough frequency but is challenging because this results in a higher proportion of taste disturbances. The results of the phase 3 studies of the more selective camlipixant are eagerly anticipated because of the potential for greater improvements in cough frequency but not being limited by taste disturbances.