Herb-CMap: a multimodal fusion framework for deciphering the mechanisms of action in traditional Chinese medicine using Suhuang antitussive capsule as a case study.

Herbal medicines, particularly traditional Chinese medicines (TCMs), are a rich source of natural products with significant therapeutic potential. However, understanding their mechanisms of action is challenging due to the complexity of their multi-ingredient compositions. We introduced Herb-CMap, a multimodal fusion framework leveraging protein-protein interactions and herb-perturbed gene expression signatures. Utilizing a network-based heat diffusion algorithm, Herb-CMap creates a connectivity map linking herb perturbations to their therapeutic targets, thereby facilitating the prioritization of active ingredients. As a case study, we applied Herb-CMap to Suhuang antitussive capsule (Suhuang), a TCM formula used for treating cough variant asthma (CVA). Using in vivo rat models, our analysis established the transcriptomic signatures of Suhuang and identified its key compounds, such as quercetin and luteolin, and their target genes, including IL17A, PIK3CB, PIK3CD, AKT1, and TNF. These drug-target interactions inhibit the IL-17 signaling pathway and deactivate PI3K, AKT, and NF-κB, effectively reducing lung inflammation and alleviating CVA. The study demonstrates the efficacy of Herb-CMap in elucidating the molecular mechanisms of herbal medicines, offering valuable insights for advancing drug discovery in TCM.

Dendrobium officinale polysaccharides-chemical properties and pharmacodynamic effects on the airways in experimental conditions.

The study aimed to analyze the effects of Dendrobium polysaccharides on the cough and airway reactivity and compare them with the effects of clinically used antitussives (codeine phosphate and butamirate citrate) and bronchodilators (salbutamol), using the guinea pig test system. Dendrobium officinale polysaccharides contained proteins (4.0 wt%) and phenolic compounds (1.7 wt%) with a molecular weight of 25,000 g/mol. The sugar analysis revealed a dominance of glucose (93.7 wt%) and a lesser amount of mannose (5.1 wt%) while other sugar quantities were negligible. Methylation analysis indicated the presence of highly branched polysaccharides. Glucose was found mainly as terminal, 1,4- and 1,6-linked. Furthermore, some 1,4- and 1,6-linked glucose units were found branched at O2, O3, and O6/O4. Mannose was terminal and 1,4-linked. NMR spectra signals indicate the presence of the (1→4)-linked α-d-glucan, (1→4)-linked ß-d-glucan branched at position O6, (1→6)-linked ß-d-glucan branched at position O3 and (1→4)-linked glucomannan. Pharmacological studies showed statistically significant antitussive activity of Dendrobium polysaccharides, exceeding the effect of clinically used antitussives, which may be partially associated with confirmed bronchodilation and the ability of polysaccharides to increase the threshold of cough receptor activation. Dendrobium polysaccharides may increase the possibility of symptomatic treatment of cough, especially in asthmatics.

Recognition of antitussive components in Farfarae Flos based on grey relational analysis and partial least squares regression. / åŸºäºŽç°è‰²å ³è”åº¦åˆ†æžå’Œåæœ€å°äºŒä¹˜å›žå½’è¾¨è¯†æ¬¾å†¬èŠ±æ­¢å’³æ´»æ€§æˆåˆ†.

OBJECTIVES: Farfarae Flos has the effect of cough suppression and phlegm elimination, with cough suppression as the main function. Studies have revealed that certain components of Farfarae Flos may be related to its cough suppressant effect, and some components have been confirmed to have cough suppressant activity. However, the antitussive material basis of Farfarae Flos has not been systematically elucidated. This study aims to elucidate the group of active ingredients in Farfarae Flos with cough suppressant activity by correlating the high performance liquid chromatography (HPLC) fingerprint of Farfarae Flos extract with its cough suppressant activity. METHODS: HPLC was used to establish the fingerprint profiles of 10 batches of Farfarae Flos extract and obtain their chemical composition data. Guinea pigs were selected as experimental animals and the citric acid-induced cough model was used to evaluate the antitussive efficacy data of 10 batches of Farfarae Flos extract. SPF-grade healthy male Hartley guinea pigs were randomly divided into the S1 to S10 groups, a positive control group, and a blank control group (12 groups in total), with 10 guinea pigs in each group. The S1 to S10 groups were respectively administered Farfarae Flos extract S1 to S10 (4 g/kg), the positive control group was administered pentoverine citrate (10 mg/kg), and the blank control group was administered purified water. Each group received continuous oral administration for 5 days. The guinea pigs were placed in 5 L closed wide-mouth bottles, and 17.5% citric acid was sprayed into the bottle with an ultrasonic atomizer at the maximum spray intensity for 0.5 minutes. The cough latency period and cough frequency in 5 minutes were recorded for each guinea pig. Grey relational analysis (GRA) and partial least squares regression (PLSR) were used to conduct spectral-effect correlation analysis of the chemical composition data of Farfarae Flos extract and the antitussive efficacy data, and predict the group of active ingredients in Farfarae Flos with antitussive activity. The bioequivalence verification was conducted to verify the predicted group of active ingredients in Farfarae Flos with antitussive activity: SPF-grade healthy male Hartley guinea pigs were randomly divided into a S9 group, an active ingredient group, a positive control group, and a blank control group (4 groups in total), with 10 guinea pigs in each group. The S9 group was administered Farfarae Flos extract S9 (4 g/kg), the active ingredient group was administered the predicted combination of antitussive active ingredients (dose equivalent to 4 g/kg of Farfarae Flos extract S9), the positive control group was administered pentoverine citrate (10 mg/kg), and the blank control group was administered purified water. Each group received continuous oral administration for 5 days, and animal modeling and observation of efficacy indicators were the same as above. RESULTS: The HPLC fingerprint of 10 batches of Farfarae Flos extract was established, and the peak area data of 14 main common peaks were obtained. The antitussive effect data of 10 batches of Farfarae Flos extract were obtained. Compared with the blank control group, the cough latence in the positive control group and S1, S2, S3, S4, S6, S7, S8, S9, S10 groups was prolonged (all P<0.01), while the cough frequency in 5 minutes in the positive control group and S1, S2, S4, S6, S8, S9, S10 groups was decreased (all P<0.05). The analysis of spectrum-effect relationship revealed that isochlorogenic acid C, isochlorogenic acid A, chlorogenic acid, isochlorogenic acid B, isoquercitrin, and rutin had high contribution to the antitussive effect of Farfarae Flos, and the 6 components were predicted to be the antitussive component group of Farfarae Flos. The verification of bioequivalence showed that there were no statistically significant differences in the antitussive effect between the S9 group and the antitussive component composition group(all P>0.05), which confirmed that isochlorogenic acid C, isochlorogenic acid A, chlorogenic acid, isochlorogenic acid B, isoquercetin, and rutin were the antitussive component group of Farfarae Flos. CONCLUSIONS: The analysis of spectrum-effect relationship combined with the verification of bioequivalence could be used to study the antitussive material basis of Farfarae Flos. The antitussive effect of Farfarae Flos is the result of the joint action of many components.

Novel α7 nicotinic acetylcholine receptor modulators as potential antitussive agents.

A novel series of α7 nicotinic acetylcholine receptor (nAChR) modulators was designed and evaluated for antitussive activity in an in vivo guinea pig model of chemically induced cough. Compound 16 at all tested doses (9.5, 3 and 1 mg/kg) significantly (p < 0.01) reduced the cumulative number of coughs and showed similar results to a positive control (codeine at 30 mg/kg). Among three different administration routes (intraperitoneal, oral and inhalation), compound 16 exerted a significant antitussive effect in guinea pigs at an inhaled dose as low as 0.4 mg/kg (p < 0.05). α7 nAChR modulators may provide a novel, non-narcotic approach to therapy in patients with acute and chronic cough.

Evidence for Alpha7 Nicotinic Receptor Activation During the Cough Suppressing Effects Induced by Nicotine and Identification of ATA-101 as a Potential Novel Therapy for the Treatment of Chronic Cough.

Studies performed in healthy smokers have documented a diminished responsiveness to tussive challenges, and several lines of experimental evidence implicate nicotine as an antitussive component in both cigarette smoke and the vapors generated by electronic cigarettes (eCigs). We set out to identify the nicotinic receptor subtype involved in the antitussive actions of nicotine and to further evaluate the potential of nicotinic receptor-selective agonists as cough-suppressing therapeutics. We confirmed an antitussive effect of nicotine in guinea pigs. We additionally observed that the alpha-4 beta-2 (α 4 ß 2)-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the α 7-selective agonist PHA 543613 dose-dependently inhibited evoked coughing. We subsequently describe the preclinical evidence in support of ATA-101, a potent and highly selective (α 7) selective nicotinic receptor agonist, as a potential candidate for antitussive therapy in humans. ATA-101, formerly known as Tc-5619, was orally bioavailable and moderately central nervous system (CNS) penetrant and dose-dependently inhibited coughing in guinea pigs evoked by citric acid and bradykinin. Comparing the effects of airway targeted administration versus systemic dosing and the effects of repeated dosing at various times prior to tussive challenge, our data suggest that the antitussive actions of ATA-101 require continued engagement of α 7 nicotinic receptors, likely in the CNS. Collectively, the data provide the preclinical rationale for α 7 nicotinic receptor engagement as a novel therapeutic strategy for cough suppression. The data also suggest that α 7 nicotinic acetylcholine receptor (nAChR) activation by nicotine may be permissive to nicotine delivery in a way that may promote addiction. SIGNIFICANCE STATEMENT: This study documents the antitussive actions of nicotine and identifies the α7 nicotinic receptor subtype as the target for nicotine during cough suppression described in humans. We additionally present evidence suggesting that ATA-101 and other α7 nicotinic receptor-selective agonists may be promising candidates for the treatment of chronic refractory cough.

Chemical Analysis by LC-MS of Cannabis sativa Root Samples from Northeast Brazil and Evaluation of Antitussive and Expectorant Activities.

Cannabis sativa is a millenary medicinal plant. However, contrary to worldwide paradigm-shifting, countries like Brazil still prohibit C. sativa cultivation and its medicinal use, even though many populations use aerial parts and roots of this plant for healthcare. As such, the objective of this work was to identify substances in the samples of the C. sativa roots, tracing a correlation with antitussive and expectorant effects. Therefore, samples of C. sativa roots were donated by the Polícia Federal Brasileira, and its aqueous extract (AECsR) was prepared with subsequent lyophilization, to maintain the material stability. After that, the material was analyzed by LC-MS to observe its chemical profile. Four samples (AECsR-A, B, C, and D) were tested in animal models of citric acid-induced cough (0.4 M) and phenol red expectoration (500 mg/kg). Using LC-MS it was possible to identify 5 molecules in C. sativa roots: p-coumaroyltyramine, tetrahydrocannabinol-C4, feruoiltyramine, anhydrocanabisativine, and cannabisativine. In experimental protocols, male mice (Mus musculus) were treated with samples of AECsR at doses of 12.5, 25, or 50 mg/kg regardless of the pharmacological test. In these tests, all samples showed the potential to treat cough and promote fluid expectoration, differing only in the dose at which these effects were observed. Therefore, the data showed that the C. sativa roots of the Brazilian Northeast showed antitussive and expectorant effects, even with intense secondary metabolites' variation, which alters its potency, but not its effect. This highlights the importance of this medicinal plant for future therapy and corroborates to traditional use.

Optimization of Naringenin Nanoparticles to Improve the Antitussive Effects on Post-Infectious Cough.

Naringenin (NRG) is a natural compound with several biological activities; however, its bioavailability is limited owing to poor aqueous solubility. In this study, NRG nanoparticles (NPs) were prepared using the wet media milling method. To obtain NRG NPs with a small particle size and high drug-loading content, the preparation conditions, including stirring time, temperature, stirring speed, and milling media amount, were optimized. The NRG (30 mg) and D-α-tocopherol polyethylene glycol succinate (10 mg) were wet-milled in deionized water (2 mL) with 10 g of zirconia beads via stirring at 50 °C for 2 h at a stirring speed of 300 rpm. As a result, the NRG NPs, with sheet-like morphology and a diameter of approximately 182.2 nm, were successfully prepared. The NRG NPs were stable in the gastrointestinal system and were released effectively after entering the blood circulation. In vivo experiments indicated that the NRG NPs have good antitussive effects. The cough inhibition rate after the administration of the NRG NPs was 66.7%, cough frequency was three times lower, and the potential period was 1.8 times longer than that in the blank model group. In addition, the enzyme biomarkers and histological analysis results revealed that the NRG NPs can effectively regulate the inflammatory and oxidative stress response. In conclusion, the NRG NPs exhibited good oral bioavailability and promoted antitussive and anti-inflammatory effects.

Preparation of Naringenin Nanosuspension and Its Antitussive and Expectorant Effects.

Naringenin (NRG) is a natural flavonoid compound abundantly present in citrus fruits and has the potential to treat respiratory disorders. However, the clinical therapeutic effect of NRG is limited by its low bioavailability due to poor solubility. To enhance the solubility, naringenin nanosuspensions (NRG-NSps) were prepared by applying tocopherol polyethylene glycol succinate (TPGS) as the nanocarrier via the media-milling method. The particle size, morphology, and drug-loading content of NRG-NSps were examined, and the stability was evaluated by detecting particle size changes in different physiological media. NRG-NSps exhibited a flaky appearance with a mean diameter of 216.9 nm, and the drug-loading content was 66.7%. NRG-NSps exhibited good storage stability and media stability. NRG-NSps presented a sustainable release profile, and the cumulative drug-release rate approached approximately 95% within 7 d. NRG-NSps improved the antitussive effect significantly compared with the original NRG, the cough frequency was decreased from 22 to 15 times, and the cough incubation period was prolonged from 85.3 to 121.6 s. Besides, NRG-NSps also enhanced expectorant effects significantly, and phenol red secretion was increased from 1.02 to 1.45 µg/mL. These results indicate that NRG-NSps could enhance the bioavailability of NRG significantly and possess a potential clinical application.

Dextromethorphan: From Cough Suppressant to Antidepressant.

Dextromethorphan (DXM) has been re-purposed several times over the past 7 decades: first as a cough suppressant, then as a compounded formulation with quinidine for treatment of pseudobulbar affect, and most recently as a compounded formulation with bupro-pion for treatment of major depressive disorder. The current article describes the history and purported mechanisms of action of DXM for each use and the uniquely rapid action and safety profile of the oral dextromethorphan- bupropion antidepressant formulation. [Journal of Psychosocial Nursing and Mental Health Services, 60(11), 9-11.].

[Optimization of extraction process of Children's Qingfei Zhisou Syrup based on pharmacodynamics].

This study determined the extraction rates of indirubin in Indigo Naturalis by ethanol reflux extraction method and water extraction method. The pharmacodynamic study against cough induced by ammonia water in the mouse model and the cough induced by citric acid in the guinea pig model were performed to optimize the extraction process of the sovereign medicinal Indigo Naturalis and the whole prescription of Children's Qingfei Zhisou Syrup. The extraction rate of indirubin by the ethanol reflux method was 51.89%, and indirubin was not detected in the product of water extraction. Two samples of Children's Qingfei Zhisou Syrup prepared with different methods can prolong the incubation period of cough and suppress the frequency of coughs in pharmacodynamic experiments. In terms of prolonging the incubation period of cough, the two samples prepared with different methods had no significant difference. In terms of reducing the frequency of coughs, the high-dose Five kinds of ethanol extracts such as indigo naturalis and three kinds of water extracts such as gypsum had better effect against the citric acid-induced cough of guinea pigs than other samples(P<0.05). The extraction rate of indirubin in Children's Qingfei Zhisou Syrup sample prepared with ethanol was higher than that with water. The two samples of Children's Qingfei Zhisou Syrup prepared with the two methods showed good antitussive effects. The sample prepared with 5 ingredients(including Indigo Naturalis) extracted with ethanol and 3 ingredients(including Gypsum Fibrosum) extracted with water had better alleviation effect on the citric acid-induced cough of guinea pig than the whole water extract sample. In conclusion, the optimum extraction scheme is ethanol extraction for 5 ingredients including Indigo Naturalis in combination with water extraction for 3 ingredients including Gypsum Fibrosum, and the Children's Qingfei Zhisou Syrup produced in this manner has better antitussive efficacy.

Anti-inflammatory, expectorant, and antitussive properties of Kyeongok-go in ICR mice.

CONTEXT: Kyeongok-go (KOG) is a traditional mixed herb preparation consisting of Panax ginseng CA Meyer (Araliaceae), Poria cocos Wolf (Polyporaceae), Rehmannia glutinosa (Gaertner) Liboschitz ex Steudel (Orobanchaceae), and honey. Various pharmacological effects of KOG are reported, but the efficacy on respiratory diseases has not been evaluated. OBJECTIVE: The anti-inflammatory, expectorant, and antitussive properties of KOG were examined using animal models of respiratory diseases. MATERIALS AND METHODS: KOG (100, 200, and 400 mg/kg) was orally administered to ICR mice (n = 8) once a day for 11 days. Anti-inflammatory effects of vehicle, xylene, KOG and DEXA (1 mg/kg) were determined by monitoring edoema and redness of treated ears, and measuring the relative and absolute weight of each ear. Expectorant properties of vehicle, KOG and AM (250 mg/kg) were evaluated by observing body surface redness, and the amount of mucous secreted by the trachea. The antitussive potential of vehicle, NH4OH, KOG and TB (50 mg/kg) was evaluated by monitoring changes in the number of coughs (for 6 min). RESULTS: KOG (400 mg/kg) treated mice showed 31.29% and 30.72% (p < 0.01) decreases in the relative and absolute weights of each ear relative to xylene control mice, 39.06% increases (p < 0.01) in TLF OD values relative to intact vehicle control mice, and 59.53% decrease (p < 0.01) in coughing compared to NH4OH control mice. Dose-dependent changes were observed in all experimental models. CONCLUSIONS: KOG may be a potential therapeutic agent for the treatment of various respiratory diseases, particularly those caused by environmental toxins.

Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects.

Dextromethorphan (DXM) is a safe and effective antitussive agent present in several over the counter cough and cold medications. At higher doses, it causes psychoactive effects, making it appealing for abuse. In this work, the pharmacokinetics and pharmacodynamics of DXM with clinical and forensic relevance were extensively reviewed. DXM and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Major metabolic pathways include sequential O-demethylation and N-demethylation of DXM, yielding dextrorphan (DXO), the major active metabolite, and 3-hydroxymorphinan, the bi-demethylated product, respectively. The demethylation order described may reverse being the resultant mid product 3-methoxymorphinan. UDP-glucuronosyltranferase produces glucuronide conjugates. Genotypic variations in enzymes and interactions with other drugs can result in large inter-individual variability in the pharmacological and toxicological effects produced. Knowing the metabolism of DXM may help to better understand the inter-individual variability in the pharmacokinetics and pharmacodynamics and to avoid adverse effects.

Noscapine protects the H9c2 cardiomyocytes of rats against oxygen-glucose deprivation/reperfusion injury.

Noscapine is an antitumor alkaloid derived from Papaver somniferum plants. Our previous study has demonstrated that exposure of noscapine on primary murine fetal cortical neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R) has neuroprotective effects. In current study, the effects of noscapine on cardiomyocytes (H9c2 cells) damage caused by 120 minutes (min) of OGD/R were evaluated and we determined whether the addition of BD1047, sigma-one receptor antagonist, prevents the protective effects of noscapine in H9c2 cells through the production of nitric oxide (NO) and apoptosis. To initiate OGD, H9c2 cells was transferred to glucose-free DMEM, and placed in a humidified incubation chamber. Cell viability was assessed with noscapine (1-5 µM) in the presence or absence of BD1047, 24 hours (h) after OGD/R. Cell viability, NO production and apoptosis ratio were evaluated by the MTT assay, the Griess method and the quantitative real-time PCR. Noscapine considerably improved the survival of H9c2 cells compared to OGD/R. Also, noscapine was extremely capable of reducing the concentrations of NO and Bax/Bcl-2 ratio expression. While the BD1047 administration alone diminished cell viability and increased the Bax/Bcl-2 ratio and NO levels. The addition of noscapine in the presence of BD1047 did not increase the cell viability relative to noscapine alone. Noscapine exerted cardioprotective effects exposed to OGD/R-induced injury in H9c2 cells, at least partly via attenuation of NO production and Bax/Bcl-2 ratio, which indicates that the sigma-one receptor activation is involved in the protection by noscapine of H9c2 cells injured by OGD/R.

What is the Role of Over 100 Excipients in Over the Counter (OTC) Cough Medicines?

Most medicines are white bitter powders that are formulated as tablets and capsules but cough medicines are an exception where the taste and appearance of the medicine are more important to the patient than the pharmacology of the active ingredient. Excipients are generally defined as any ingredient in a medicine other than the active ingredient. In most medicines excipients play a supportive role in delivering the medicine, but in the case of cough medicines, excipients have more important and complex roles and they can also be the main active ingredient of the cough medicine as menthol, glycerol, and sugars, which are declared as active ingredients. This review searched the United Kingdom electronic medicines compendium (emc) and found over 100 excipients in 60 different liquid formulations of over the counter cough medicines. The excipients were divided into functional groups: sweeteners, thickeners, flavors, colors, antimicrobials, and buffers, and the incidence and function of the different excipients is discussed. When considering the efficacy of a cough medicine, clinicians and pharmacists tend to think of the pharmacology of antitussives such as dextromethorphan or expectorants such as guaifenesin, and they rarely consider the role of excipients in the efficacy of the medicine. This review discusses the functions and importance of excipients in cough medicines and provides some new information for clinicians, pharmacists, and all interested in the treatment of cough when considering the composition and efficacy of a cough medicine.

Anticomplement and antitussive activities of major compound extracted from Chimonanthus nitens Oliv. leaf.

Chimonanthus nitens Oliv. leaf (CNOL), as a traditional Chinese medicine, has been widely used for the treatment of influenza and colds over a long history. However, the mechanism of colds related to the effects of CNOL have been little studied. In this study, the anticomplement and antitussive activities of different polarity extracts of CNOL were evaluated. Ethyl acetate extract (EAE) among different extracts not only significantly decreased cough times by 21-58% (P < 0.01), but also had anticomplement effects demonstrated by the CH50 values of 0.100 mg/ml. A total of 28 constituents (10 coumarins, 13 flavonoids and five phenolics) were identified in EAE based on the ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry technique. Eight compounds in EAE were evaluated by an ammonia-induced cough model to reveal the antitussive mechanisms and classical anticomplement pathway. The results indicated that the antitussive effects of scopoletin, kaempferol-3-O-rutinoside and kaempferol may depend on central mechanisms and that flavonoids such as compounds of kaempferol-3-O-rutinoside and kaempferol have better anticomplementary activity than coumarins like compounds of scopolin, scopoletin and isofraxidin. Taken together, kaempferol-3-O-rutinoside and kaempferol could be important chemical markers in the present study that might be used to evaluate the quality and biological activity of CNOL.

The chemical profile of active fraction of Kalimeris indica and its quantitative analysis.

Kalimeris indica (L) Sch-Bip is a medicinal plant used by the Miao ethnic group in the Guizhou province of China. It is widely used as a fresh vegetable to treat colds, diarrhea and gastric ulcers. However, few studies have been conducted on the mechanism of its effect on colds, and its quality control. The anticomplement and antitussive activities of different polar extracts of K. indica were evaluated. Fifty-nine compounds, mainly including phenols and flavonoids, were identified in K. indica extract by ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry. A method was established through ultra-high-performance liquid chromatography with a photodiode array to simultaneously determine the anticomplement and antitussive activity of five compounds in K. indica combining chemical identification with chemometrics for discrimination and quality assessment. Also, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid exhibited significantly higher anticomplementary activity than the other three compounds. The quantitative data were further analyzed by principal component analysis and orthogonal partial least-squares discriminant analysis. Heatmap visualization was conducted to clarify the distribution of the major compounds in different geographical origins. Screening pharmacological activities by a combination of chemometrics and chemical identification might be an effective method for the quality control of K. indica.

Antitussive therapy: A role for levodropropizine.

Cough is a protective reflex that serves to clear the airways of excessive secretions and foreign matter and which sometimes becomes excessive, and troublesome to patients. Cough is one of the most common reasons why individuals seek medical attention. A range of drugs have been developed in the past with antitussive activity and different mechanisms of action, but there are still very few safe and effective treatments available. The poor tolerability of most available antitussives is closely related to their action on the central nervous system (CNS). An international group of experts specialized in cough met to discuss the need to identify an effective antitussive treatment with a good tolerability profile. The aim of this expert review is to increase the knowledge about the cough mechanism and the activity of levodropropizine, a peripherally acting antitussive drug.

Quantifying test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings.

INTRODUCTION: The citric acid cough reflex test (CRT) is used to quantify cough sensitivity and evaluate the effects of cough therapies and antitussive medications. This study quantifies the test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings in healthy individuals. METHODS: Healthy adults (n = 16) inhaled increasing concentrations of citric acid (0.01-3.2 mol/L) on three alternate days (1, 3, 5) until C2 cough thresholds (i.e. two consecutive coughs within 3 s) or the highest concentrations of citric acid was reached. Participants were instructed to "cough if you need to" in the natural cough condition, and "try not to cough" in the suppressed cough condition. Following each inhalation, participants were asked to rate their urge to cough (UTC) using a modified Borg Scale. RESULTS: Natural cough thresholds (NCTs) increased across days 1-3 (0.87 doubling concentrations, 95% CI, 0.28, 1.44, p = 0.004) and 1-5 (0.87 doubling concentrations, 95% CI, 0.33, 1.41, p = 0.004). Suppressed cough thresholds (SCTs) increased across days 1-5 (0.64 doubling concentrations per day, 95% CI, 0.03, 1.22, p = 0.04). After taking the effect of day into account, NCTs and SCTs varied within-participants by 0.75 (95% CI, 0.53, 0.93) and 0.78 (95% CI, 0.55,0.98) doubling concentrations respectively. UTC ratings at NCT, or SCT did not significantly increase across days 1-3 or 1-5. Sub-threshold (0.05 mol/L) UTC ratings increased across days 1-3 (-1.43 ratings per day, 95% CI, -2.31, -0.5, p = 0.005) and 1-5 (-1.71 ratings per day, 95% CI, -2.59, -0.79, p = 0.001). UTC ratings at NCT, SCT, and sub-threshold varied within-participants after taking into account the effect of day by 1.34 (95% CI, 1.03, 1.71), 1.47 (95% CI, 1.10, 1.91) and 1.20 (95% CI, 0.91, 1.50) ratings. CONCLUSIONS: Natural and suppressed cough thresholds and UTC ratings are subject to test-retest variability. These data are important for the use of citric acid CRT as an outcome measure in longitudinal cough research, as they facilitate interpretation of whether changes in citric acid cough thresholds across days reflect true changes in cough sensitivity, rather than an artefact of repeating the test.

Interfering with airway nerves in cough associated with asthma.

Cough is a troublesome and often refractory symptom of asthma, which is associated with poor control of disease. The pathogenesis of asthmatic cough has mainly been attributed to bronchoconstriction, but recent evidence indicate that cough reflex hypersensitivity or neuronal dysfunction is a feature of asthma, even in those with mild stable disease. This is likely resistant to the mainstay treatment ICS/LABA which inhibits classic asthmatic response. Such refractory cough might manifest more predominantly in the day-time rather than night-time. Treatment options of such refractory cough or cough reflex hypersensitivity in asthma targeting the nerves (LTRAs, tiotropium, and potentially bronchial thermoplasty) are discussed.

Emerging targets for cough therapies; NK1 receptor antagonists.

Cough is mediated by vagal afferent fibres innervating the larynx and proximal airways. Pre-clinical studies suggest that vagal C fibres produce Substance P, one of the tachykinin family of neuropeptides, which has been shown to enhance cough via the neurokinin-1 (NK-1) receptor and studies in animal models have also shown that NK-1 antagonists are effective at blocking induced cough. In the past, tachykinin receptor antagonists have yielded disappointing results in treating asthma and cough, however most of the activity of the agents tested was restricted to the peripheral nervous system and also the outcomes measures evaluating cough not optimal. More recently a small proof of concept study has suggest that aprepitant, an NK-1 antagonist licensed for the prevention of chemotherapy induced nausea and vomiting, might have beneficial effects on cough frequency in patients with lung cancer. In this review we investigate the current evidence for the anti-tussive effect of these therapies and the clinical trials in progress.