Treatment Of Chronic Cough Research Articles

Impressive stability-indicating RP-HPLC method for concurrent quantification of salbutamol, guaifenesin, and sodium benzoate in cough syrup: Application of six sigma and green metrics

Abstract Analytical chemistry research has shifted towards environmentally friendly substitutes that reduce waste and avoid hazardous substances. These efforts align with broader environmental goals and inspire sustainable and responsible science. The objective of this work is to develop and validate an analytical method and verify its greenness using specific tools, including analytical GREEnness (AGREE), analytical greenness metric for sample preparation (AGREEprep), green analytical procedure index, complex green analytical procedure index, analytical Eco-Scale, analytical method volume intensity, analytical method greenness score, and HPLC-EAT (Environmental Assessment Tool). Effective treatment of chronic cough relies heavily on adequately utilizing salbutamol (SAL) and guaifenesin (GUA) in the presence of sodium benzoate (SOB) preservative. The isocratic elution mode used the Zorbax Eclipse Plus C18 column (15 cm × 4.6 mm, 3.5 µm). It could move 1.5 mL·min−1, hold 50 µL, have a column temperature of 30°C, and have an autosampler temperature of 5°C. It could detect UV light at 276 nm and had a mobile phase of 80:20 v/v buffer solution and acetonitrile. We have successfully established highly accurate calibration curves for the three components SAL, GUA, and SOB within the optimal range of 2–50 µg·mL−1. The coefficient of correlation (r) for these curves was at an impressive 0.9999 for SAL and GUA, while it was 0.9998 for SOB. The recovery values were 100.15%, 100.47%, and 100.92% for SAL, GUA, and SOB, respectively. The selectivity and sensitivity to the ingredients were confirmed according to the International Council for Harmonisation guidelines, as no interference occurred from any of the used sample components. We implemented Six Sigma, resulting in precision and productivity.

Establishment of a Mouse Model with Cough Hypersensitivity via Inhalation of Citric Acid.

Cough is one of the most common symptoms of many respiratory diseases. Chronic cough significantly impacts quality of life and imposes a considerable economic burden. Increased cough sensitivity is a pathophysiological hallmark of chronic cough. It has been observed that cough hypersensitivity is related to airway inflammation, remodeling of airway sensory nerves, and alterations in the central nervous system. However, the precise molecular mechanisms remain unclear and require further elucidation using suitable animal models. Previous studies have utilized guinea pigs as models for studying cough, but these models present several experimental limitations, including high costs, a lack of transgenic tools, and a scarcity of commercial reagents. In addition, guinea pigs typically exhibit poor environmental tolerance and high mortality when exposed to stimuli. In contrast, mice are smaller, easier to maintain, more cost-effective, and amenable to genetic manipulation, making them more suitable for mechanistic investigations. In this study, we established a mouse model with cough hypersensitivityviacontinuous inhalation of citric acid (CA). This model is straightforward to operate and yields reproducible results, making it a valuable tool for further studies on the mechanisms and potential novel treatments for chronic cough.

The Efficacy of Superior Laryngeal Nerve Block for Chronic Cough: A Scoping Review.

Chronic cough poses diagnostic and treatment challenges due to its often multifactorial nature. Chronic cough associated with laryngeal hypersensitivity is linked to sensory neuropathy of the superior laryngeal nerve and can be complex to manage. Superior laryngeal nerve (SLN) blocks are increasingly being utilized by laryngologists to treat refractory chronic cough with the intent of reducing inflammation and nerve hypersensitivity. This scoping review aims to provide an overview of the current literature examining the efficacy of SLN blocks for treatment of chronic cough, identify knowledge gaps, and guide future studies. A search strategy was developed in collaboration with a medical librarian and run in Ovid Medline, Embase (Elsevier), Web of Science Core Collection (Clarivate), CINAHL Ultimate (Ebscohost), Cochrane, and Google Scholar (via Harzing's Publish or Perish). Search scope was from the inception of each database to March 5, 2024. Inclusion criteria were broad and focused on any study that utilized SLN block(s) for the treatment of chronic cough. The searches yielded 1264 articles that were loaded into Covidence systematic review software for deduplication and screening. Title and abstract and then full-text screening were performed. Twelve studies met inclusion criteria. Study designs varied, including retrospective reviews, case series, and one placebo-controlled trial. Outcome measures included validated patient-reported cough-specific quality of life measures and/or subjective patient reports. The number of blocks primarily ranged from an average of 2-4 per patient, with follow-up durations ranging anywhere from 2 weeks to 22.5months. Adverse effects were minimal and primarily self-limiting. Other reported interventions included behavioral cough suppression therapy, used in conjunction with SLN blocks, and neuromodulators, which were often trialed prior to SLN therapy. All 12 studies reported improvement in cough, and while several studies reported significant improvements in patient-reported outcomes using Cough Severity Index and Leicester Cough Questionnaire questionnaires, only eight studies provided statistical testing with P values. The remaining studies did not perform statistical analyses or report confidence intervals, instead presenting descriptive or qualitative results. Literature on the efficacy of SLN blocks for chronic cough reveals consistent positive outcomes. There is a need for randomized controlled trials, systematic studies with larger cohorts, longitudinal follow-up, and further comparison of ipsilateral versus bilateral blocks to determine the efficacy of SLN blocks for treatment of chronic cough.

8239 Recurrent Superior Laryngeal Nerve Glucocorticoid Injections: A Likely Cause Of Secondary Adrenal Insufficiency In An Otherwise Healthy Man

Abstract Disclosure: A. Lorin: None. M.C. Pranger: None. J. Park: None. C.A. Clutter: None. Background: Secondary adrenal insufficiency is well described in the literature with various offending agents implicated. Superior laryngeal nerve (SLN) glucocorticoid injections, however, have rarely been recorded as causal agents of secondary adrenal insufficiency. We present a case of a generally healthy man with secondary adrenal insufficiency after chronic administration ofsuperior laryngeal nerve glucocorticoid injections without other identifiable etiologies. Clinical Case: A 68-year-old man with no significant medical history presented to endocrinology clinic due to persistent nausea and severe fatigue. His initial labs were notable for morning cortisol of 1.66 mcg/dL (5-25) and an undetectable ACTH (<3.2 pg/mL, 10-60) suggestive of adrenal insufficiency. FSH/LH, testosterone, FT4, and IGF-1 were otherwise normal. On initial review of his medication history, the only glucocorticoid exposure appeared to be intranasal beclomethasone, with remote courses of oral prednisone. Further history revealed that the patient was receiving superior laryngeal nerve glucocorticoid injections for chronic cough every three weeks for over a year. The injection consisted of 1:1 mixture of 1 mL of triamcinolone acetonide 200 mg/5 mL and local anesthetic, which is equivalent to triamcinolone 40 mg or hydrocortisone 200 mg. Given the volume and chronicity of the glucocorticoid injections, the patient developed secondary adrenal insufficiency as above. Since the diagnosis, the patient discontinued SLN glucocorticoid injections and was placed on physiologic hydrocortisone replacement, with gradual recovery of his HPA axis. Conclusions: Sequelae of percutaneous glucocorticoid injection into the superior laryngeal nerve for treatment of chronic cough are not well documented in terms of their effects on the HPA axis. While an effective and increasingly common treatment for chronic cough, SLN glucocorticoid injection has the potential to cause suppression of the HPA axis and cause secondary adrenal insufficiency. Excess glucocorticoid appeared to solely inhibit ACTH production, as the other anterior pituitary hormones were not affected. Understanding consequences of glucocorticoid use in any formulation is important when considering such therapies, as these may alter normal HPA function with recurrent dosing. Recovery from a disrupted HPA axis may be achieved with the use of physiologic doses of hydrocortisone replacement in the case of secondary adrenal insufficiency. Presentation: 6/3/2024

Awareness and practices of Speech Language Pathologists (SLPs) working with chronic cough in India: a call for action.

A cough persisting beyond eight weeks is referred as chronic cough (CC) and is a common symptom of many respiratory conditions and non-respiratory conditions. The role of a speech language pathologist (SLP) in CC is emerging and this study aimed to profile the awareness and practice patterns of SLPs practicing in India. Cross-sectional study. An online survey was used to profile the assessment, treatment and counselling practices in CC among SLPs working in India. It sought to identify the awareness levels among SLPs regarding their role and availability of behavioural interventions for CC. Only SLPs who dealt with CC could complete the entire survey while other SLPs, filled regarding awareness and availability of behavioural interventions. 127 eligible responses obtained from SLPs working across clinical settings in India were analysed. 75.59% (n=96) of them had not seen patients with CC in their career. 47.24% (n=60) of them were aware that behavioural interventions were available for CC. Thirty-one SLPs completed the entire survey and their practice patterns indicated that few clinicians used cough-specific protocols while largely relying on voice and swallowing related assessment and treatment for CC. This survey the lack of awareness of SLPs' role in CC and that their practices are dominated by existing procedures for voice and swallowing disorders. Increasing the awareness of SLP's role in CC may increase the caseload of patients referred and expand the SLP's scope of practice. Development of guidelines in CC practice and inclusion in coursework/curriculum are future considerations.

Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency.

Treatment of chronic cough remains a challenge. We hypothesised that inhaled alkaline hypertonic divalent salts (alkaline HDS) might provide relief for refractory chronic cough by laryngeal and tracheal hydration. We conducted an exploratory, single-blinded, nasal saline-controlled study in 12 refractory chronic cough patients to examine cough suppression efficacy of an alkaline HDS composition (SC001) at pH 8 or pH 9 administered by nasal inhalation. As control, we used nasal saline with the same hand-held pump spray aerosol device. Each subject was monitored continuously using a digital cough monitor watch for 1 week of baseline, 1 week of control treatment and 1 week of active treatment. Baseline daily cough rates ranged from 4 to 34 coughs·h-1 with mean visual analogue score 65±17 pre- and post-baseline testing. Control-adjusted efficacy of cough rate reduction ranged from 15% (p=0.015) (from Day 1) to 23% (p=0.002) (from Day 3). Control-adjusted efficacy was highest with SC001 pH 9 (n=5), ranging from 25% (p=0.03) (from Day 1) to 35% (p=0.02) (from Day 3), and lowest for SC001 pH 8 (n=7), ranging from 9% (p=0.08) (from Day 1) to 16% (p=0.02) (from Day 3). Hourly cough counts and visual analogue score correlated for baseline (r=0.254, p=0.02) and control (r=0.299, p=0.007) monitoring weeks. Treatment improved this correlation (r=0.434, p=0.00006). No adverse events were reported. Alkaline (pH 9) HDS aerosol is a promising treatment for refractory chronic cough and should be further evaluated.

A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.

Nalbuphine (NAL) is a κ-agonist/μ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed "PDE-EHR" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.

Benefit-Risk Profile of P2X3 Receptor Antagonists for Treatment of Chronic Cough: Dose-Response Model-Based Network Meta-Analysis

BackgroundRefractory or unexplained chronic cough disrupts quality of life and burdens healthcare systems around the world. The P2X3 receptor antagonist gefapixant is approved in many countries for its antitussive effects, but taste disturbances are a common adverse effect. Four newer, more selective P2X3 receptor antagonists have been developed to address this problem. Research QuestionHow does the benefit-risk profile vary across the five available P2X3 receptor antagonists? Study Design and MethodsA systematic review and network meta-analyses were conducted to evaluate the efficacy of P2X3 receptor antagonists, including gefapixant, sivopixant, eliapixant, camlipixant, and filapixant. Primary outcomes were a reduction rate in 24-hour cough frequency and incidence of taste disturbance. Dose-response curves, and median effective dose (ED50) were calculated. Effect size at ED50 was ranked according to SUCRA. The confidence was evaluated by CINeMA. ResultsSixteen randomized controlled trials involving 4,904 participants were analyzed. The gefapixant regimen demonstrated an ED50 of 90.7 mg/day for cough frequency reduction. Gefapixant showed the highest antitussive effectiveness at ED50 (reduction rate in 24-h cough frequency, median 28.1%; 95% Credible Interval 21.0 to 35.6%; ranked 1/5; moderate certainty) but the highest prevalence of taste disturbance (absolute risk difference per 100 patients, median 38; 95%CrI 27 to 51; ranked 5/5; high certainty) and the highest prevalence of discontinuation. Camlipixant had a well-balanced profile (reduction rate in 24-h cough frequency, median 14.7%; 95%CrI 5.4 to 26.0%; ranked 3/5; low certainty; and taste disturbance, absolute risk difference per 100 patients, median 2; 95%CrI 1 to 6; ranked 2/5; low certainty). Placebo had a mean of 33.1% reduction in 24-h cough frequency. InterpretationWhen used at safe doses, gefapixant had a favorable risk-benefit profile compared to the other four agents. Camlipixant showed initial promise, which may be further investigated by phase III trials currently underway. Clinical Trial RegistrationUMIN000050622

Homoeopathic treatment for chronic cough – a multicentric, prospective, exploratory trial

Context Cough is a major symptom of respiratory and some non-respiratory ailments for which patients usually seek primary medical care. Homoeopathy is frequently used for treatment of chronic cough. Objective This study aims to assess whether homoeopathy is useful for treating chronic cough resulting from Upper airway cough syndrome (UACS), Asthma and related syndromes, or Gastroesophageal reflux disease (GERD). Study Design A multi‑centre, exploratory, prospective trial. Study setting The study was conducted in the outpatient departments of 10 centres of CCRH, India from May 2018 – June 2020. Patients Patients of any gender, between 7-65 years of age, presenting with cough lasting >8 weeks, were enrolled. Main Outcome Measure(s) Cough Severity Index (CSI) and EQ-5D-5L scales were used to analyse the outcomes. Results Out of 2397 patients screened only 706 cases, with minimum four follow ups were analysed, on modified Intention to Treat (mITT) basis. CSI and EQ-5D-5L scores were used to analyse the outcomes of the study. The mean of the CSI score at baseline was 19.09 whereas it reduced to 3.89 in the eighth follow-up with p value <0.01. The mean of the EQ-5D-5L score at baseline was 50.59 which increased to 73.79 in the last follow-up, with p-value<0.05. Phosphorus, Arsenic album, Pulsatilla, Sulphur, Lycopodium and Silica were found to be the most frequently prescribed medicines.

Chronic cough in children: an evidence-based clinical practice guideline adapted for the use in Egypt using ‘Adapted ADAPTE’

BackgroundWe recently adopted a guideline for chronic cough in children in the Egyptian health system. Adapting clinical practice guidelines (CPGs) to the local healthcare setting is a valid alternative to de-novo development that can improve their uptake and implementation without demanding a substantial drain on resources. The objective of this study was to adapt evidence-based recommendations from global high-quality CPGs for children with a chronic cough to suit the Egyptian healthcare context.MethodsWe followed the Adapted ADAPTE methodological framework for guideline adaptation. This process includes three phases: set-up, adaptation, and finalization. A guideline adaptation group (GAG) and an external review group including clinical content experts and methodologists conducted the process.ResultsThe GAG adapted 10 sections of recommendations from three original CPG(s) including (i) the American College of Chest Physicians (ACCP) 2006–2020, (ii) the European Respiratory Society (ERS) 2019, (iii) the Korean Academy of Asthma, Allergy and Clinical Immunology (KAAACI) 2018. A set of CPG implementation tools was added to enhance implementability including an algorithm, a slide presentation for clinical diagnosis, investigations and treatment of chronic cough, patient education, and online resources.ConclusionThe adapted CPG provides pediatricians and related healthcare workers with applicable evidence-based recommendations for chronic cough in children in Egypt. The project also highlighted the utility of Adapted ADAPTE and the invaluable collaboration between the clinical and methodological experts for the adaptation of pediatric national guidelines.

Identifying Practice Gaps Among Otolaryngology Providers for the Treatment of Chronic Cough.

Increasing evidence over the last decade suggests that many cases of unexplained chronic cough (UCC) have a neurogenic etiology, with laryngeal hypersensitivity (LH) being identified as a key mechanism. Official guidelines since 2015 have adopted use of neuromodulators and adjuvant speech therapy as a result, but historically implementation of guidelines is slow. Our survey aimed to investigate gaps in diagnosis and management practices of otolaryngology providers in caring for patients with UCC. Cross-sectional study. Survey. 12-item survey was distributed to 110 otolaryngology practitioners experienced in diagnosis and treatment of chronic cough at a regional otolaryngology continuing education conference. Statistical analysis included Kendall's Tau Rank Correlation to measure the ordinal association between responses to questions, and Fisher's exact test to determine if there were associations between responses and years of career experience. Fortyeligible respondents underwent subsequent analysis. There was no association between frequency of identifying LH as a primary etiology and use of neuromodulators (τ = 0.23, P = .10). However, there was a significant correlation between LH and referrals to speech therapy (τ = 0.27, P = .05). Fisher's exact test did not reveal any significant differences among any responses based on practitioner experience. Our results indicate a possible disparity in treatment of UCC with neuromodulators and the utilization of speech therapy despite guideline recommendations advocating for neuromodulators with adjuvant speech therapy. Further research with larger sample sizes and more specific inquiries is necessary to elucidate this association and control for any regional differences.

The Impact of Medical Comorbidities on Cough Improvement Following Superior Laryngeal Block.

Chronic refractory cough is defined as cough lasting greater than 8 weeks and with an unclear etiology. Blockade of the internal branch superior laryngeal nerve (iSLN) has been shown to be safe and effective in the treatment of chronic cough. It remains unknown, however, if underlying comorbidities impact patient response to iSLN blockade. A total of 44 patients aged 18 years and older were seen at our institution's Laryngology clinics between 2019 and 2022 and treated with iSLN blockade. Patient demographics, comorbidities, and pre- and post-treatment cough severity index (CSI) scores were collected from electronic medical records. Two-tailed independent T tests were used to compare CSI scores between groups with and without 4 underlying comorbidities: GERD, pulmonary history, smoking history, and evidence of vocal fold paresis or asymmetry on stroboscopy. Patients with a history of GERD or smoking and those with evidence of glottic insufficiency had similar improvements in CSI compared to those who did not (22.5 ± 26.4 vs 45.0 ± 47.1, P = .36; 32.7 ± 27.8 vs 29.0 ± 38, P = .85; 41.3 ± 18.8 vs 27.2 ± 37.7, P = .195). Patients with underlying pulmonary conditions had a significantly reduced response to iSLN blockade than did patients without underlying disease (9.85 ± 15.0 vs 47.4 ± 38.1, P = .028). Underlying lung pathology may contribute to decreased iSLN blockade efficacy in the treatment of chronic refractory cough from laryngeal hypersensitivity and its treatment is likely necessary for optimal symptom reduction. Characterizing patient comorbidity profiles can help guide patient counseling on expected treatment efficacy.

Patient preferences for the treatment of chronic cough: a discrete choice experiment

BackgroundChronic cough is common, negatively affects quality of life and has limited treatment options. Inhibition of purinergic signalling is a promising therapeutic approach but is associated with taste-related adverse effects....

Efficacy, Safety and Economic Evaluation of Wolbigachul-Tang for Chronic Cough Due to Upper Airway Cough Syndrome (UACS): A Study Protocol for Randomized, Double-Blind, Active-Comparator Controlled, Parallel, Exploratory Clinical Trial.

Upper airway cough syndrome (UACS) is a common cause of chronic cough characterized by upper airway symptoms, including nasal discharge and throat discomfort. Empirical treatments for UASC-induced chronic cough, such as first-generation antihistamines, have been used; however, the long-term use of these medicines has adverse effects. Therefore, we evaluate the efficacy, safety, and economic feasibility of Wolbigachul-tang (WBGCT), an herbal medication for UASC-induced chronic cough. This is a randomized, double-blind, active-comparator-controlled, parallel, and exploratory clinical trial. Thirty patients with UASC-induced chronic cough will be recruited and randomly allocated to the WBGCT and control groups in a 1:1 allocation ratio. The investigational medicine will be administered three times per day for 2 weeks (3 g of WBGCT at a time). The primary outcome measure is the cough symptom score measured at screening, before starting the trial, and after 2 and 4 weeks. Secondary outcome measures include the cough visual analog scale, nasal discharge score, questionnaire of clinical symptoms of cough and sputum, Leicester cough questionnaire-Korean version, integrative medicine outcome scale, integrative medicine patient satisfaction scale, and 5-level EuroQol 5-dimensional questionnaire, which will be assessed before starting the trial and after 2 and 4 weeks. This study aims to investigate the efficacy, safety, and economic feasibility of WBGCT in the treatment of chronic cough. Therefore, the results of this trial provide evidence for the application of WBGCT in the treatment of UACS-induced chronic cough.

Strengthen multidisciplinary diagnosis and treatment and collaborative research on chronic cough

Chronic cough is the most common complaint in respiratory specialist clinics. The causes of chronic cough are related to respiratory system, otorhinolaryngology, gastroenterology, psychiatry and other systems. Cough hypersensitivity is the most important clinical and pathophysiological feature. Many patients with chronic cough are misdiagnosed and treated inappropriately. To improve the diagnosis and treatment of chronic cough, we should establish a multidisciplinary team and strengthen collaborative study, including cough laboratory, multidisciplinary clinic, and chronic cough ward.

Challenges with retention and recovery of impurities containing acidic moieties during analytical UHPLC method development and validation for gefapixant freebase

Gefapixant citrate is a P2X3 purinergic receptor antagonist developed for the treatment of chronic cough. Gefapixant freebase is the penultimate intermediate in the commercial manufacturing route for gefapixant citrate and contains a complex impurity profile consisting of acidic and basic analytes. A UHPLC method was developed for assay and purity determination of gefapixant freebase utilizing a Waters Acquity Charged Surface Hybrid (CSH) C18 column (2.1 mm I.D. x 10 cm length, 1.7 µm particle size) with 0.1 % phosphoric acid and acetonitrile as the mobile phases. Method optimization was performed using ACD Labs LC Simulator to achieve baseline separation of all impurities and the method was successfully validated. During routine use and method transfer for gefapixant freebase, an increase in retention time for impurities containing strongly acidic functional groups, and poor recovery of a sulfinic acid impurity were observed. Subsequent investigation determined that the CSH column aging resulting from exposure of the column packing to the acidic mobile phase was the root cause for these behaviors. The mechanism of peak-shifting was further investigated using model compounds and determined to be due to an increase in ionic interactions with the CSH stationary phase with routine column use. The increase in ionic interactions was demonstrated to correlate with the charge state of the analyte. Poor recovery for the sulfinic acid impurity was attributed to increased peak tailing for this single impurity on older columns. This knowledge was leveraged to establish additional system suitability requirements to monitor column performance for the lifecycle of the analytical procedure.

Seabuckthorn Wuwei Pulvis attenuates chronic obstructive pulmonary disease in rat through gut microbiota-short chain fatty acids axis

Ethnopharmacological relevanceSeabuckthorn Wuwei Pulvis (SWP) is a traditional Mongolian medicine used in China. It is composed of Hippophae rhamnoides (berries, 30 g), Aucklandiae costus Falc. (dry root, 25 g), Vitis vinifera F. Cordifolia (berries, 20 g), Glycyrrhiza uralensis Fisch. (dry root, 15 g), and Gardenia jasminoides J. Ellis (desiccative ripe fruit, 10 g). It is clinically applied in the treatment of chronic cough, shortness of breath and phlegm, and chest distress. Past studies demonstrated that Seabuckthorn Wuwei Pulvis improved lung inflammation and chronic bronchitis in mice. However, the effect of Seabuckthorn Wuwei Pulvis on chronic obstructive pulmonary disease (COPD) in rats and the underlying action mechanism is not fully understood. Aim of the studyTo evaluate the anti-COPD effect of Seabuckthorn Wuwei Pulvis and investigate whether its ameliorative effect is correlated with the composition of gut microbiota and its metabolites. Materials and methodsThe effects of Seabuckthorn Wuwei Pulvis on a COPD rat model were established by exposure to lipopolysaccharide (LPS) and smoking. These effects were then evaluated by monitoring the animal weight, pulmonary function, lung histological alteration, and the levels of inflammatory factors (tumor necrotic factor [TNF]-α, interleukin [IL]-8, IL-6, and IL-17). Furthermore, the serum LPS and fluorescein isothiocyanate-dextran levels were detected by using an enzyme-linked immunosorbent assay and fluorescence microplate reader, respectively. Tight junction proteins (ZO-1 and occludin-1) in the small intestine were detected by performing real-time quantitative polymerase chain reactions and Western blotting to evaluate the intestinal barrier function. The contents of short-chain fatty acids (SCFAs) in the feces of rats were determined by gas chromatography-mass spectrometry. 16S rDNA high throughput sequencing was used to investigate the effect of SWP on the gut microbiota of COPD rats. ResultsTreatment with low and median doses of SWP significantly increased the pulmonary function (forced expiratory volume [FEV] 0.3, forced vital capacity [FVC], and FEV0.3/FVC), decreased the levels of TNF-α, IL-8, IL-6, and IL-17 in the lung, and attenuated the infiltration of inflammatory cells into the lung. The low and median doses of SWP shaped the composition of gut microbiota, which increased the abundances of Ruminococcaceae, Christensenellaceae, and Aerococcaceae, increased the productions of acetic acid, propionic acid, and butyric acid, and upregulated the expression of ZO-1 and occludin-1 in the small intestine of COPD rats. ConclusionSWP improved pulmonary functions and inhibited the inflammatory response by shaping the gut microbiota, increasing SCFA production, and strengthening the intestinal barrier function in rats with COPD induced by LPS and smoking.

Emerging drugs in the treatment of chronic cough

Introduction Chronic cough is a debilitating condition that is among the most common reasons for seeking medical attention yet remains challenging to manage. Identifying an underlying respiratory, nasal or upper gastrointestinal disease triggering cough is the first step in assessment, but once this has been ruled out or adequately treated, many patients remain troubled with chronic cough. Areas covered This narrative review discusses the role of existing treatments and describes the current research landscape for the development of new therapies for chronic cough greater than 8 weeks that is refractory (RCC) or unexplained (UCC). The literature search includes published studies found on pubmed and conference abstracts until 2023. Expert opinion RCC/UCC can occur due to neuronal dysregulation of the vagus nerve or central nervous system. Hence, novel anti-tussives have targeted ion channels involved in the neuronal signaling which triggers cough. Although some therapies targeting receptors such as TRPV1 have failed to show efficacy, P2X3 antagonists have emerged as the most promising therapy for patients impacted by chronic cough. Disease specific therapies such as for idiopathic pulmonary fibrosis are in early development.

DT-0111: a novel P2X3 receptor antagonist.

Extracellular adenosine 5'-triphosphate (ATP) acts as an autocrine and paracrine agent, the actions of which on affected cells are mediated by P2 receptors (P2R), which include trans cell-membrane cationic channels (P2XRs), and G protein coupled receptors (P2YRs). The mammalian P2X receptors form homotrimeric or heterotrimeric cationic channels, each of which contains three ATP-binding sites. There are seven homotrimeric P2X receptors (P2X1-7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1/P2X5). In the lungs and airways, ATP activates P2X3 and P2X2/3 receptors (P2X3R, P2X2/3R, respectively) localized on vagal sensory nerve terminals resulting in bronchoconstriction, and cough, and probably also localized release of pro-inflammatory neuropeptides via the axon reflex. Currently, several P2X3R and P2X2/3R antagonists are being developed as drug-candidates for the treatment of chronic cough. This report presents the receptor affinity data of a novel water-soluble small molecule, DT-0111, that acts as a selective P2X3R antagonist.

Variability in P2X receptor composition in human taste nerves: implications for treatment of chronic cough.

Antagonists to the P2X purinergic receptors on airway sensory nerves relieve refractory or unexplained chronic cough (RCC/UCC) but can evoke unwanted dysgeusias because the gustatory nerves innervating taste buds express this same family of receptors. However, the subunit composition of the P2X receptors in these systems may differ, with implications for pharmacological intervention of RCC/UCC. In most species, the extrapulmonary airway nerves involved in cough predominantly express P2X3 subunits that form homotrimeric P2X3 receptors. In contrast, most sensory nerves innervating taste buds in mice express both P2X2 and P2X3 subunits, so the majority of receptors in that system are likely P2X2/P2X3 heteromers. Since neural P2X subunit composition can differ across species, we used immunohistochemistry to test whether taste nerves in humans and rhesus macaque monkeys express both P2X2 and P2X3 as in mice. In taste bud samples of fungiform papillae and larynx from humans and monkeys, all taste bud samples exhibited P2X3+ nerve fibres, but the majority lacked substantial P2X2+. Of the 35 human subjects, only four (one laryngeal and three fungiform) showed strong P2X2 immunoreactivity in taste nerves; none of the rhesus monkey samples showed immunoreactivity for P2X2. These findings suggest that for most humans, unlike mice, taste buds are innervated by nerve fibres predominantly expressing only P2X3 homomeric receptors and not P2X2/P2X3 heteromers. Thus, antagonists specific for P2X3 homomeric receptors might not be spared from affecting taste function in RCC/UCC patients.