Gabapentin for refractory chronic cough

Abdulqawi, Rayid; Woodcock, Ashley; Smith, Jaclyn A.

doi:10.1016/s0140-6736(13)60337-2

Cited by 3 publications

(4 citation statements)

References 4 publications

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“…The primary efficacy end-point was the change in cough frequency per hour, assessed objectively over 24-h periods using a cough recorder (VitaloJAK; Vitalograph, Maids Moreton, UK) [ 27 , 28 ]. In each study period, cough frequency was assessed pre-dose (day 1) and at the end of each treatment week (days 7, 14 and 21).…”

Section: Methodsmentioning

confidence: 99%

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

et al. 2021

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ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A–B (n=20) or B–A (n=20). The primary efficacy endpoint was change in cough frequency assessed over 24 h (VitaloJAK). Primary safety endpoint was frequency and severity of adverse events (AEs).Thirty-seven patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg, 25%: 90% confidence interval, 11.5–36.5%; p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41–49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5–21% with eliapixant: all were mild.Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

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Section: Methodsmentioning

confidence: 99%

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

et al. 2021

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“…3b, c ), we focused on quercetin, a flavonoid found in many fruits and vegetables and sold as a dietary supplement with implications in relieving cough 17 , 21 , 53 . Since P2X3 has been clinically validated as a target for the treatment of chronic cough 22 , 23 , 54 , we characterized the effect of quercetin (Fig. 5a ) on P2X receptors to perform a more detailed examination of IP-HD allostery.…”

Section: Resultsmentioning

confidence: 99%

“…P2X3 is a target for the treatment of chronic cough 22 , 23 , 54 , and quercetin can alleviate cough symptoms 17 , 21 , 53 . However, it is unclear whether quercetin suppresses cough by targeting P2X3 on top of its anti-inflammatory properties.…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism by which quercetin alleviates cough symptoms is generally believed to result from its antioxidant and anti-inflammatory activities, but whether there are other receptor-specific mechanisms of action is unclear 18 – 21 . In addition, although gefapixant is approved for marketing in Japan in 2022, it suffers from a significant drug-related adverse effect of taste disturbance 12 , 22 – 24 . Newer small molecule drug candidates, such as BAY-1817080 (Bayer) 25 , 26 , BLU-5739 (Bellus) 27 , and S-600918 (Shionogi) 28 , which were aimed to circumvent this side effect, have slightly weaker clinical efficacy than gefapixant (Supplementary Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

Guo,

Zhang,

Zhou

et al. 2023

Nat Commun

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P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

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Cough reflex hypersensitivity: A role for neurotrophins

El-Hashim

Jaffal

2017

Experimental Lung Research

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Cough is one of the most common complaints for which sufferers seek medical assistance. However, currently available drugs are not very effective in treating cough, particularly that which follows an upper respiratory tract infection. Nonetheless, there has been a significant increase in our understanding of the mechanisms and pathways of the defensive cough as well as the hypersensitive/pathophysiological cough, both at airway and central nervous system (CNS) levels. Numerous molecules and signaling pathways have been identified as potential targets for antitussive drugs, including neurotrophins (NTs). NTs belong to a family of trophic factors and are critical for the development and maintenance of neurons in the central and peripheral nervous system including sympathetic efferents, sensory neuron afferents, and immune cells. Nerve growth factor (NGF) was the first member of the NT family to be discovered, with wide ranging actions associated with synapse formation, survival, proliferation, apoptosis, axonal and dendritic outgrowth, expression and activity of functionally important proteins such as ion channels, receptors, and neurotransmitters. In addition, NGF has been implicated in several disease states particularly neuropathic pain and most recently in the sensitization of the cough reflex. This review will briefly address the peripheral and central sensitization mechanisms of airway neurons and will then focus on NGF signaling and its role in cough hypersensitivity.

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Gabapentin for refractory chronic cough

Cited by 3 publications

References 4 publications

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance

Cough reflex hypersensitivity: A role for neurotrophins

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