Translating Cough Mechanisms Into Better Cough Suppressants

doi:10.1016/j.chest.2017.05.016

Chest

Volume 152, Issue 4, October 2017, Pages 833-841

https://doi.org/10.1016/j.chest.2017.05.016 Get rights and content

Chronic cough is a significant problem, and in many patients cough remains refractive to both disease-specific therapies and current cough-suppressing medicines, creating a need for improved antitussive therapies. Most patients with chronic cough also display heightened sensitivity so that they experience a persistent sense of the need to cough, and often innocuous stimuli can trigger their coughing. This hypersensitivity underpins the newly described concept of cough hypersensitivity syndrome (CHS), a term that encapsulates the notion of common underlying mechanisms producing neuronal activation, sensitization and/or dysfunction, which are at the core of excessive coughing. Understanding these mechanisms has been a focus of recent research efforts in the field in the hope that new therapies can be developed to selectively target sensitized unproductive cough while maintaining the reflexive cough essential for airway protection. However, efforts to achieve this have been slower than expected, in part because of some significant challenges and limitations translating current cough models. In this review, we summarize recent advances in our understanding of the sensory circuits innervating the respiratory system that are important for cough, how cough sensory pathways become hypersensitive, and some of the recently described neural targets under development for treating chronic cough. We present the case that better use of current cough models or the development of new models, or both, is ultimately needed to advance our efforts to translate the discovery of basic cough mechanisms into effective medicines for treating patients with chronic cough.

Section snippets

Cough Neurobiology in Health and Disease

The act of coughing spans a spectrum from purely voluntary to purely reflexive (Fig 1), the former initiated by the conscious decision-making processes in the cerebral cortex and requiring no input from sensory pathways in the airways and the latter initiated by sensory pathways in the airways and not requiring central neuronal processing above the brain stem level⁹ (Fig 2). Between these extremes exists coughing that is initiated from the airways but is also under behavioral modulation by the

Novel Antitussive Therapies: Preclinical and Clinical Studies

From a clinical perspective, the treatment of cough that remains refractive to disease-specific therapy would benefit from an efficacious antitussive that blocks cough of multiple causes, which is conceivably achievable by targeting key processes in the neural pathways essential for coughing. However, given the fundamental importance of a defensive cough for maintaining airway patency and preventing pulmonary infection, the “Holy Grail” is to identify targetable mechanisms that do not simply

Conclusions: Translating Preclinical Cough Models

Curiously, compounds that have shown promise in preclinical cough models have largely been disappointing in clinical trials. This naturally brings into question whether the current preclinical animal and cellular models adequately reflect CHS in humans. Alternatively, perhaps such models are simply not being used wisely. For example, the prominent axon reflex in guinea pigs and rodents (which is not present in humans) can seriously confound preclinical antitussive studies if not adequately

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: S. B. M. is supported by a grant from the National Health and Medical Research Council of Australia No. 1078943. A. E. M. is a current NHMRC of Australia Research Fellow No. 1121376. None declared (J. A. K.).

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Influence of combined voltage-gated sodium channel Na<inf>V</inf>1.7 and Na<inf>V</inf>1.8 inhibitors on cough in a guinea pig model
2023, Respiratory Physiology and Neurobiology
Pathological excessive cough is a serious clinical problem in many patients. It is no doubt that an increased activation and sensitization of airway vagal C-fibres in disease stems from dysregulation of the neural pathways that control cough. Due to the limited efficacy and unwanted side effects of current antitussives, there is a continual demand for the development of a novel more effective antitussive. Since voltage-gated sodium channels (Na_Vs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, Na_Vs became a promising and attractive neural target. Current studies establish that Na_V1.7 and Na_V1.8 inhibitors have the potential to suppress cough. In this study, we demonstrated that inhaled aerosol of Na_V1.7 inhibitor PF-05089771 (10 μM) and Na_V1.8 inhibitor A-803467 (1 mM) mixture inhibited the capsaicin-induced cough by ≈ 60 % and citric acid-induced cough by ≈ 65 % at doses that did not modify respiratory rate. Our previous and present studies indicate that Na_V1.7 and Na_V1.8 may present promising therapeutic targets for antitussive therapy.
Chronic Refractory Cough: Long-Term Outcomes Following Cough Suppression Therapy
2023, Journal of Voice
This study aimed to determine the long-term outcomes of patients with chronic refractory cough (CRC) following treatment for cough suppression therapy (CST). Currently, there is a lack of objective data regarding the long-term outcome of behavioral treatment for CRC.
From the charts of 106 adult patients diagnosed with CRC, 24 patients were identified as having long-term data at least 3 months post-CST in the form of otolaryngologic examination, Voice Handicap Index-10 (VHI-10), and Cough Severity Index (CSI) scores. Patients underwent otolaryngologic evaluation and completed the VHI-10 and CSI assessments during pretreatment, posttreatment, and long-term follow-up visits. Patients were also divided into two groups based on their number of comorbidities.
Twenty of the 24 patients had significant reduction in cough severity after completing CST (P < 0.001). A significant difference was also found in CSI scores from pretherapy to the long-term follow-up visits (P = 0.001). No significant difference was found in CSI scores from posttherapy to long-term follow-up visits (P = 0.93). No significant difference was found in VHI-10 scores over time (P = 0.83). No correlation was found between changes in cough and voice severity and number of comorbidities at the tested level.
Findings of no significant change in CRC over the long term compared to posttherapy measures suggest that patients were able to maintain improvement in cough over the long term despite various comorbidities. The current results suggest that CST represents a satisfactory approach to treating CRC and provides patients with an ongoing tool to maintain reduced cough severity. No significant correlations between number of comorbidities and mean CSI or VHI-10 scores were found over the long term.
Pharmacological activities and pharmacokinetics of liquiritin: A review
2022, Journal of Ethnopharmacology
Citation Excerpt :
Cough is a very common condition that is usually thought to be one of the symptoms of lower airway inflammation (bronchitis), non-eosinophilic asthma, etc. (Gibson et al., 2014). Exogenous chemicals and endogenous inflammatory factors such as TNF-α and IL-6 can stimulate cough receptors and cause cough responses (Keller et al., 2017). When the concentration of liquiritin was 200 mg/kg, the cough frequency in mice with ammonia-induced cough decreased significantly, as evidenced by the reduction of the excretion of phenol red via the respiratory tract (Kuang et al., 2018).
Liquiritin is a flavonoid derived from Radix et Rhizoma Glycyrrhizae, which is a widely used traditional Chinese medicine with the effects of invigorating spleen qi, clearing heat, resolving toxins, and dispelling phlegm to stop coughs.
In this review,the pharmacokinetics and pharmacological activities of liquiritin have been summarized.
The information on liquiritin up to 2021 was collected from PubMed, Web of Science, Springer Link, and China National Knowledge Infrastructure databases. The key words were “liquiritin”, “nerve”, “tumor”, “cardiac”, etc.
The absorption mechanism of liquiritin conforms to the passive diffusion and first-order kinetics while with low bioavailability. Liquiritin can penetrate the blood-brain-barrier. Besides, liquiritin displays numerous pharmacological effects including anti-Alzheimer's disease, antidepressant, antitumor, anti-inflammatory, cardiovascular protection, antitussive, hepatoprotection, and skin protective effects. In addition, the novel preparations, new pharmacological effects,and cdusafty of liquiritin are also discussed in this review.
This review provides a comprehensive state of knowledge on the pharmacokinetics and pharmacological activities of liquiritin, and makes a forecast for its research directions and applications in clinic.
The effect of the voltage-gated sodium channel Na<inf>V</inf>1.7 blocker PF-05089771 on cough in the guinea pig
2022, Respiratory Physiology and Neurobiology
Cough in chronic respiratory diseases is a common symptom associated with significant comorbidities including visceral pain. Available antitussive therapy still has limited efficacy. Recent advances in the understanding of voltage-gated sodium channels (Na_Vs) lead to the rational hypothesis that subtype Na_V1.7 is involved in initiating cough and thus may present a promising therapeutic target for antitussive therapy. We evaluated the antitussive effect of Na_V1.7 blocker PF-05089771 administered systemically and topically in awake guinea pigs using capsaicin cough challenge. Compared to vehicle, peroral or inhaled PF-05089771 administration caused about 50–60 % inhibition of cough at the doses that did not alter respiratory rate. We conclude that the Na_V1.7 blocker PF-05089771 inhibits cough in a manner consistent with its electrophysiological effect on airway C-fibre nerve terminals.
The Multidimensional Cough Index: A Practical Scale to Measure Cough and Sputum
2021, American Journal of the Medical Sciences
There currently is a lack of easy-to-use instruments with which to assess cough. The aim of the present study was to develop a scale for measuring the characteristics of cough and sputum.
The authors developed a scale for assessing cough, including aspects such as intensity, frequency, physical impact, psychosocial impacts and sputum characteristics. The first four components were scored using a Cough Index, with a range of 0 to 20. Sputum information included volume, appearance, and hemoptysis. The scale was administered to 105 patients and re-administered to 51 about two weeks later. The patients also reported cough frequency and intensity using a 100-mm visual analogue scale (VAS) and answered the Leicester Cough Questionnaire (LCQ). Additionally, 12 patients with acute exacerbation (AE) of chronic airways disease were interviewed upon admission to and discharge from the hospital.
Analysis identified only one factor for the Cough Index, and Cronbach's alpha value was 0.819. Cough Index was significantly correlated with VAS_frequency (r = 0.651, p < 0.0001), VAS_intensity (r = 0.543, p<0.0001), and LCQ (r = -0.824, p < 0.0001). The intraclass correlation coefficient of test-retest scores was 0.779. The median Cough Index significantly decreased after AE treatment, as did the number of patients reporting increased sputum production and greenish and dark sputum. A Cough Index ≥ 4 distinguished respiratory patients from healthy subjects, with a sensitivity of 80% and a specificity of 85%.
The Multidimensional Cough Index condenses complex aspects related to cough and sputum production into a single instrument, with satisfactory validation.
Perceptions of family doctors, pulmonologists and allergists on the approach to patients with chronic cough. Results of an anonymous survey
2021, Semergen
Conocer la percepción de médicos de familia, neumólogos y alergólogos sobre el abordaje actual de la tos crónica y su impacto en la calidad de vida de los pacientes.
Encuesta transversal y anónima difundida a través de las sociedades científicas SEAIC, SEMERGEN, semFYC, SEMG y SEPAR. Los participantes fueron 620 médicos de familia, 92 neumólogos y 62 alergólogos. Se realizó un análisis descriptivo de las respuestas. Se presentaron porcentajes de respuesta, medianas e intervalos intercuartílicos. Las diferencias en los porcentajes entre especialidades se evaluaron con la χ^?.
Solo la mitad de los respondedores indicó una duración superior a 8 semanas como criterio para diagnosticar la tos crónica, y menos de la mitad consideraron la tos crónica refractaria o inexplicada una enfermedad en sí misma. El impacto de la tos crónica fue percibido como menor por los médicos de familia que por neumólogos o alergólogos. Tras un diagnóstico de tos crónica refractaria o inexplicada, las 3 especialidades consideraron como actitud más frecuente iniciar el tratamiento y asumir el seguimiento del paciente ellos mismos. La mayoría declaró no disponer de protocolos de manejo de la tos crónica y más del 90% los consideraron necesarios.
El abordaje de los pacientes con tos crónica por médicos de familia, neumólogos o alergólogos parece heterogéneo. Es necesario disponer de protocolos que unifiquen los criterios de diagnóstico, derivación y tratamiento para optimizar el abordaje y reducir el impacto de la tos crónica en los pacientes.
To understand the perception of family doctors, pulmonologists and allergists about the current approach to chronic cough and its impact on patients’ quality of life.
Cross-sectional and anonymous survey disseminated through the scientific societies SEAIC, SEMERGEN, semFYC, SEMG and SEPAR. The participants were 620 family doctors, 92 pulmonologists and 62 allergists. A descriptive analysis of the answers was conducted. Response percentages, medians and interquartile intervals were presented. The differences in the percentages between specialties were evaluated with the chi-square.
Only half of the respondents chose a duration greater than 8 weeks as a criterion for diagnosing chronic cough, and less than half considered refractory/unexplained chronic cough a disease in itself. Family doctors perceived that chronic cough had less impact on patients than did pulmonologists or allergists. After a diagnosis of refractory/unexplained chronic cough, all 3 specialties considered the most common approach to be to initiate treatment and to do the follow-up of the patient themselves. Most stated that they had no protocols for managing chronic cough, and more than 90% considered these to be necessary.
The management of patients with chronic cough by family doctors, pulmonologists or allergists seems to be heterogeneous. There is a need for protocols that standardise diagnosis, referral and treatment criteria to optimise patients’ management and reduce the impact of chronic cough.

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Chest

Translating Basic Research Into Clinical PracticeTranslating Cough Mechanisms Into Better Cough Suppressants

Section snippets

Cough Neurobiology in Health and Disease

Novel Antitussive Therapies: Preclinical and Clinical Studies

Conclusions: Translating Preclinical Cough Models

Acknowledgments

Lancet Respir Med

Pulm Pharmacol Ther

J Voice

Pulm Pharmacol Ther

Pulm Pharmacol Ther

Trends Immunol

Pulm Pharmacol Ther

Pulm Pharmacol Ther

J Allergy Clin Immunol

Auton Neurosci

Lancet

Chest

Lancet

Eur J Pharmacol

Pulm Pharmacol Ther

Pulm Pharmacol Ther

Vagal afferent innervation of the airways in health and disease

Physiol Rev

Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control

Thorax

Chronic cough hypersensitivity syndrome

Cough

Cough hypersensitivity syndrome: towards a new approach to chronic cough

Eur Respir J

Antitussive drugs—past, present, and future

Pharmacol Rev

Selective expression of a sodium pump isozyme by cough receptors and evidence for its essential role in regulating cough

J Neurosci

Sensory nerves in lung and airways

Compr Physiol

Morphologic characterization of nerves in whole-mount airway biopsies

Am J Respir Crit Care Med

Sensorimotor circuitry involved in the higher brain control of coughing

Cough

Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome

J Thorac Dis

Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways

Proc Natl Acad Sci U S A

Neurophenotypes in airway diseases. Insights from translational cough studies

Am J Respir Crit Care Med

Translating Basic Research Into Clinical Practice
Translating Cough Mechanisms Into Better Cough Suppressants