An open-label study of the tolerability and potential efficacy of memantine for treating refractory chronic cough

Blocking NMDA receptors with memantine in refractory chronic cough patients is poorly tolerated and demonstrates no improvement in cough https://bit.ly/3kgx2g

Chronic Cough is associated with increased reporting of Autonomic Symptoms

Background Patients with some neuronal hypersensitivity syndromes experience increased autonomic symptoms. Chronic cough is thought to be a neuronal hypersensitivity disorder and, therefore, may be associated with increased autonomic symptoms. Methods 96 chronic cough subjects were recruited from the tertiary cough clinic based at Wythenshawe Hospital, Manchester, UK; 76 healthy controls were also recruited. Subjects were aged >18 years. Those with significant respiratory disease, significant smoking history or taking medication known to affect cough or autonomic function were excluded. Subjects completed the Composite Autonomic Symptom Score (COMPASS) 31 autonomic symptom questionnaire, the Cough Quality of Life Questionnaire (CQLQ) and a cough severity visual analogue scale (VAS). Results 96 chronic cough subjects and 76 healthy volunteers were included in the final analysis. Mann–Whitney U-tests comparing COMPASS 31 scores in both groups showed that the total COMPASS 31 score was significantly higher in the patient group (median 18.4, interquartile range (IQR) 7.5–32.0) than the control group (median 3.6, IQR 1.1–9.5; p<0.001). The chronic cough subjects had significantly higher symptom scores than the healthy volunteer groups in all domains (p≤0.001) except vasomotor symptoms (p=0.770). There was a positive association between COMPASS 31 and CQLQ in the patient group (p<0.001, r=0.432) but not COMPASS 31 and VAS (p=0.227). Interpretation Chronic cough patients do indeed report more frequent and severe autonomic symptoms than healthy volunteers, indicating that this population may suffer from dysautonomia. At present, it remains unclear whether this occurs as a result of the cough or whether both the cough and dysfunction are part of some wider vagal pathology

Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Non-invasive phenotyping of chronic respiratory diseases would be highly beneficial in the personalised medicine of the future. Volatile organic compounds can be measured in the exhaled breath and may be produced or altered by disease processes. We investigated whether distinct patterns of these compounds were present in chronic obstructive pulmonary disease (COPD) and clinically relevant disease phenotypes.</p> <p>Methods</p> <p>Breath samples from 39 COPD subjects and 32 healthy controls were collected and analysed using gas chromatography time-of-flight mass spectrometry. Subjects with COPD also underwent sputum induction. Discriminatory compounds were identified by univariate logistic regression followed by multivariate analysis: 1. principal component analysis; 2. multivariate logistic regression; 3. receiver operating characteristic (ROC) analysis.</p> <p>Results</p> <p>Comparing COPD <it>versus</it> healthy controls, principal component analysis clustered the 20 best-discriminating compounds into four components explaining 71% of the variance. Multivariate logistic regression constructed an optimised model using two components with an accuracy of 69%. The model had 85% sensitivity, 50% specificity and ROC area under the curve of 0.74. Analysis of COPD subgroups showed the method could classify COPD subjects with far greater accuracy. Models were constructed which classified subjects with ≥2% sputum eosinophilia with ROC area under the curve of 0.94 and those having frequent exacerbations 0.95. Potential biomarkers correlated to clinical variables were identified in each subgroup.</p> <p>Conclusion</p> <p>The exhaled breath volatile organic compound profile discriminated between COPD and healthy controls and identified clinically relevant COPD subgroups. If these findings are validated in prospective cohorts, they may have diagnostic and management value in this disease.</p

Effect of centrally and peripherally acting GABA

From PubMed via Jisc Publications RouterHistory: received 2021-06-18, revised 2021-09-07, accepted 2021-09-22Publication status: aheadofprintCurrently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABA receptors in both the peripheral and central nervous systems inhibit cough. To compare the effect of central and peripherally acting GABA agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120mg MR), with baclofen (40mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p=0.04], but had no effect on ED50 [geometric mean 47.4μM (95%CI 24.4-91.7) vs 37.6 μM (95%CI 19.2-73.5), p=0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p=0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2μM (95%CI 37.2-151.8), p=0.002). This data suggests the anti-tussive actions of GABA agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system. [Abstract copyright: Copyright © 2021. Published by Elsevier Ltd.

A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin evoked coughs in patients with refractory chronic cough

OBJECTIVE: Baclofen is a centrally acting γ-aminobutyric acid type B (GABA(B)) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABA(B) agonist, but its effects on refractory chronic cough are unknown. DESIGN: We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening. RESULTS: 22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sd age 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8–17.0) years; mean (95% CI) 45 (29–67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study. CONCLUSIONS: Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABA(B) receptors in refractory chronic cough