Targeting C-fibers for peripheral acting anti-tussive drugs

Patil, Mayur; Sun, Hui; Ren, Feng; Meeker, Sonya; Undem, Bradley J.

doi:10.1016/j.pupt.2019.03.002

Cited by 14 publications

(12 citation statements)

References 41 publications

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“…The ability of BW-031 to effectively inhibit cough, with complete suppression of cough in a majority of the animals treated with the highest dose in both models, strongly supports previous proposals that targeting peripheral nerve activity by sodium channel inhibition can be an effective strategy for inhibiting cough (Brozmanova et al, 2019;Kollarik et al, 2018;Patil et al, 2019;Sun et al, 2017;Undem and Sun, 2020). A key advantage of the strategy of using cationic sodium channel inhibitors is to limit the inhibition of nerve activity only to those neurons that express large-pore channels, like TRPV1 and TRPA1, and only under those conditions, such as inflammation or noxious irritation, where these channels are activated.…”

Section: Discussionsupporting

confidence: 83%

“…Its efficacy against cough in the ovalbumin-induced airway inflammation model suggests that the asthma-like allergic inflammation produced in this model activates large-pore ion channels (Bessac and Jordt, 2008;Choi et al, 2018;Talbot et al, 2015;Talbot et al, 2020) in a manner sufficient to allow for the effective entry of BW-031 into those sensory neurons that trigger cough in response to the citric acid. Patil et al, 2019;Ryan et al, 2018;Smith and Badri, 2019) as well as GABAB receptor agonists (Canning et al, 2012). These channels likely have different contributions to cough in different patient populations (Long et al, 2019a;Mazzone et al, 2018) but even a complete inhibition of any single receptor will not prevent activation of cough-triggering neurons by other receptors, perhaps explaining the failure of selective TRPA1 or TRPV1 antagonists to inhibit naturally-occurring cough (Belvisi et al, 2017;Birrell et al, 2009;European Medicines Agency, 2013;Khalid et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Cough etiology includes viral infections, allergens, environmental pollutants and respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, cystic fibrosis (CF), and non-CF bronchiectasis (Chung and Pavord, 2008;Gibson, 2019;Mazzone et al, 2018). Coughing is initiated when sensory neurons innervating the upper airways are stimulated by transducer ion channels, including TRPA1 and TRPV1, either by inhaled irritants or by endogenous ligands from inflamed tissue (Bonvini et al, 2015;Canning, 2006;Canning et al, 2014;Canning et al, 2004;Mazzone et al, 2018;Patil et al, 2019;Widdicombe and Fontana, 2006). Viral infection upregulates TRPV1 and TRPA1 expression (Abdullah et al, 2014;Omar et al, 2017;Zaccone et al, 2016), and increased cough reflex sensitivity can follow viral respiratory infection (Omar et al, 2017;Ryan et al, 2012;Zaccone et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

Tochitsky

Andrews

et al. 2020

Preprint

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Although multiple diseases of the respiratory system cause cough, there are few effective treatments for this common condition. We previously developed a strategy to treat pain and itch via the long-lasting inhibition of nociceptor sensory neurons with QX-314, a cationic sodium channel blocker that selectively enters only into activated nociceptors by permeating through the endogenous TRPV1 and TRPA1 large pore ion channels they express. In this study we design and characterize BW-031, a novel cationic compound with ~6-fold greater potency than QX-314 for inhibiting sodium channels when introduced inside cells and with minimal extracellular activity. We show that inhalation of aerosolized BW-031 effectively inhibits citric acid-induced cough in an allergic inflammation guinea pig cough model. These data support the use of charged sodium channel blockers for the selective inhibition of airway sensory neurons with activated large pore channels as a novel targeted therapy for treating cough.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

Tochitsky

Andrews

et al. 2020

Preprint

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“…The excitation may involve an activation of a receptor, which is capable of detecting hyperosmolarity. Among the many TRP channels, TRPV1 and TRPA1 are highly expressed by C-fibres [26].…”

Section: The Possible Mechanisms Of Hypertonic Aerosol-provoked Coughmentioning

confidence: 99%

Cough-provocation tests with hypertonic aerosols

2020

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Recent advances in cough research suggest a more widespread use of cough-provocation tests to demonstrate the hypersensitivity of the cough reflex arc. Cough-provocation tests with capsaicin or acidic aerosols have been used for decades in scientific studies. Several factors have hindered their use in everyday clinical work: i.e. lack of standardisation, the need for special equipment and the limited clinical importance of the response. Cough-provocation tests with hypertonic aerosols (CPTHAs) involve provocations with hypertonic saline, hypertonic histamine, mannitol and hyperpnoea. They probably act via different mechanisms than capsaicin and acidic aerosols. They are safe and well tolerated and the response is repeatable. CPTHAs can assess not only the sensitivity of the cough reflex arc but also the tendency of the airway smooth muscles to constrict (airway hyper-responsiveness). They can differentiate between subjects with asthma or chronic cough and healthy subjects. The responsiveness to CPTHAs correlates with the cough-related quality of life among asthmatic subjects. Furthermore, the responsiveness to them decreases during treatment of chronic cough. A severe response to CPTHAs may indicate poor long-term prognosis in chronic cough. The mannitol test has been stringently standardised, is easy to administer with simple equipment, and has regulatory approval for the assessment of airway hyper-responsiveness. Manual counting of coughs during a mannitol challenge would allow the measurement of the function of the cough reflex arc as a part of clinical routine.

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“…It appears that blocking of the NaV1.7 channels prevent action potential conduction in most jugular Cfibers but did not block the action potential initiation (Kollarik et al 2018). Inhibition of action potential activation of jugular C-fibers terminals appeared after the combination of inhaled NaV1.7 and NaV1.8 blockers (Kollarik et al 2018, Patil et al 2019. As seen, the role and function of NaVs channels at the terminals in the airways are more complex.…”

Section: Nav17 Blocker and Coughmentioning

confidence: 93%

The Prospect for Potent Sodium Voltage-Gated Channel Blockers to Relieve an Excessive Cough

Brozmanová

Pavelková²

2020

Physiol Res

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An excessive, irritable, productive or non-productive coughing associated with airway inflammation belongs to pathological cough. Increased activation of airway vagal nociceptors in pathological conditions results from dysregulation of the neural pathway that controls cough. A variety of mediators associated with airway inflammation overstimulate these vagal airway fibers including C-fibers leading to hypersensitivity and hyperreactivity. Because current antitussives have limited efficacy and unwanted side effects there is a continual demand for the development of a novel more effective antitussives for a new efficacious and safe cough treatment. Therefore, inhibiting the activity of these vagal C-fibers represents a rational approach to the development of effective antitussive drugs. This may be achieved by blocking inflammatory mediator receptors or by blocking the generator potential associated with the specific ion channels. Because voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs become a promising neural target. There is evidence that NaV1.7, 1.8 and 1.9 subtypes are predominantly expressed in airway cough-triggering nerves. The advantage of blocking these NaVs is suppressing C-fiber irrespective to stimuli, but the disadvantage is that by suppressing the nerves is may also block beneficial sensations and neuronal reflex behavior. The concept is that new antitussive drugs would have the benefit of targeting peripheral airway nociceptors without inhibiting the protective cough reflex.

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Targeting C-fibers for peripheral acting anti-tussive drugs

Cited by 14 publications

References 41 publications

Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

Cough-provocation tests with hypertonic aerosols

The Prospect for Potent Sodium Voltage-Gated Channel Blockers to Relieve an Excessive Cough

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