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Introduction: Chronic cough has increasingly been recognized as a distinct clinical entity that affects a significant portion of the global population. Despite advancements in understanding its pathophysiology, treatment options remain limited. Opioid analgesics have long been used for cough, and some have proven clear antitussive potential. However, these have yet to be approved by regulatory authorities for the treatment of chronic cough. Several novel synthetic opioid modulators that demonstrated antitussive effects in early-stage studies also failed to translate into clinical practice., Areas Covered: This mini review aims to summarize the implications of opioid receptors in the development of cough medicines and highlight recent advances in opioid analgesics in cough trials. PUB MED/CINAHL/Web of Science/Scopus was searched (September 2024)., Expert Opinion: Our understanding of the precise sites of action and the involvement of peripheral opioid receptors in cough remains limited. Despite these gaps in knowledge, opioids remain a viable option for some patients until more novel effective treatments are available. Due to the frequent opioid side effects, new opioid derivatives with improved properties are needed. The development of tailored or biased delta-opioid receptor ligands and mixed agonists of opioid receptor-like 1/mu receptors may offer hope for new opioid-based drug discovery for chronic cough.

Background: Cough is a common clinical complaint in small animal practice with limited treatment options for chronic underlying conditions., Objectives: The present study aimed to evaluate the efficacy of three antitussive drugs in a novel, minimally invasive canine acute cough model., Methods: Five clinically healthy Beagles were used to create an acute cough model by administering sterile saline via a transtracheally placed central venous catheter. Single-dose antitussive effects of butorphanol, maropitant and Danpron were assessed. Cough frequency was measured before and at hourly intervals up to 3 h post-administration of each drug, with a linear mixed model used for statistical analysis., Results: Butorphanol (0.3 m/kg, IM) significantly reduced cough frequency at 1 and 3 h post-administration. Danpron (0.1 mL/kg, IM) also significantly reduced cough frequency 1 h post-administration; however, this effect was not sustained at 3 h. Maropitant (1 mg/kg, IM) did not significantly reduce cough frequency. The cough induction method was effective and minimally invasive, with no adverse effects., Conclusion: The present study demonstrated that butorphanol has a potent and prolonged antitussive effect in an acute canine cough model, whereas Danpron shows a transient effect. These findings provide valuable insights into the comparative efficacy of commonly used antitussive drugs in dogs., (© 2024 The Author(s). Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

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., (© The Author(s) 2024. Published by Oxford University Press.)

Refractory chronic cough is a disabling disease with very limited therapeutic options. A better understanding of cough pathophysiology has led to the development of emerging drugs targeting cough receptors. Recent strides have illuminated novel therapeutic avenues, notably centred on modulating transient receptor potential (TRP) channels, purinergic receptors, and neurokinin receptors. By modulating these receptors, the goal is to intervene in the sensory pathways that trigger cough reflexes, thereby providing relief without compromising vital protective mechanisms. These innovative pharmacotherapies hold promise for improvement of refractory chronic cough by offering improved efficacy and potentially mitigating adverse effects associated with current recommended treatments. A deeper comprehension of their precise mechanisms of action and clinical viability is imperative for optimising therapeutic interventions and elevating patient care standards in respiratory health. This review delineates the evolving landscape of drug development in this domain, emphasising the significance of these advancements in reshaping the paradigm of cough management., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Ethnopharmacological Relevance: "Snow-white waterlily" (Nymphaea candida) dried flower possesses various efficacy in Uighur medicine such as reducing fever and nourishing the liver, anti-inflammatory and cough relieving, moistening the throat and quenching thirst., Aim of the Study: Polyphenols are characteristic component of N. candida as well as its quality markers, and the purpose of this study was to conduct investigations into anti-inflammatory, antitussive, antipyretic, and analgesic activities of the polyphenol-enriched fraction from N. candida (NCTP) in order to validate the traditional efficacy of this plant., Materials and Methods: The polyphenols in NCTP were analyzed by HPLC, and an acute oral toxicity study was conducted for NCTP. The anti-inflammatory activities of NCTP were evaluated using xylene induced ear edema, capillary permeability, cotton pellet granuloma, and carrageenan-induced rat paw edema, of which multiple biochemical indices were measured in carrageenan-induced rat paw edema such as prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2),5-lipoxygenase (5-LOX), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) activities; the analgesic activities were investigated using acetic acid writhing, hot plate test, and formalin test; the anti-tussive and antipyretic effects were tested by ammonia induced cough in mice and yeast-induced fever respectively., Results: NCTP with LD50 of 5222 mg/kg was low toxicity and safety. NCTP (200 mg/kg) could significantly reduce ear swelling and capillary permeability by 30.63% and 31.37%, respectively. NCTP revealed 15.76% inhibiting activities in cotton pellet granuloma in mice at a dosage of 200 mg/kg. Furthermore, NCTP (50, 100, and 200 mg/kg) substantially decreased carrageenin-induced paw edema in rats between 1 and 5 h, and NCTP could decrease PGE2, 5-LOX, COX-2 levels as well as IL-6, IL-1β, TNF-α activities compared with the control group; NCTP could decrease MDA contents in carrageenin-induced rise, and increase SOD and GSH activities. Furthermore, the dose-dependent inhibition effect of NCTP on pain was revealed in the hot plate experiment. In addition to reducing the amount of writhes brought on by acetic acid, NCTP (50, 100, and 200 mg/kg) significantly inhibited pain latency against both stages of the formalin test. Moreover, NCTP (50, 100, 200 mg/kg) showed the better antitussive activities in mice in a dose-dependent manner. In the yeast-induced pyrexia test, dosages of 50, 100, and 200 mg/kg resulted in a statistically significant drop in rectal temperature., Conclusion: The experimental results proved the analgesic, anti-inflammatory, anti-tussive and antipyretic activities of the polyphenol-enriched fraction from N. candida, and supported the traditional use of this plant as well., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships, and confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice., Methods: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment., Results: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn., Conclusions: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe. This review describes current unlicenced treatments for chronic cough and details treatments currently in development for refractory chronic cough and cough in idiopathic pulmonary fibrosis, as well as compounds previously explored., (© 2023. The Author(s).)

Ethnopharmacological Relevance: Xingbei antitussive granules (XB) is a classic Chinese Medicine prescription for treating post-infectious cough(PIC), based on the Sanao Decoction from Formularies of the Bureau of People's Welfare Pharmacies in the Song Dynasty and Jiegeng decoction from Essentials of the Golden Chamber in the Han Dynasty. However, the therapeutic effects and pharmacological mechanisms are still ambiguous. In the present study, we endeavored to elucidate these underlying mechanisms., Aims of the Study: This study aimed to explore the potential impact and mechanism of XB on PIC, and provide a scientific basis for its clinical application., Materials and Methods: Cigarette smoking (CS) combined with lipopolysaccharide (LPS) nasal drops were administered to induce the PIC guinea pig with cough hypersensitivity status. Subsequently, the model guinea pigs were treated with XB and the cough frequency was observed by the capsaicin cough provocation test. The pathological changes of lung tissue were assessed by HE staining, and the levels of inflammatory mediators, mast cell degranulating substances, and neuropeptides were detected. The protein and mRNA expression of transient receptor potential vanilloid type 1(TRPV1), proteinase-activated receptor2(PAR2), and protein kinase C (PKC) were measured by Immunohistochemical staining, Western blot, and RT-qPCR. Changes in the abundance and composition of respiratory bacterial microbiota were determined by 16S rRNA sequencing., Results: After XB treatment, the model guinea pigs showed a dose-dependent decrease in cough frequency, along with a significant alleviation in inflammatory infiltration of lung tissue and a reduction in inflammatory mediators. In addition, XB high-dose treatment significantly decreased the levels of mast cell Tryptase as well as β-hexosaminidase (β-Hex) and downregulated the expression of TRPV1, PAR2, and p-PKC. Simultaneously, levels of neuropeptides like substance P (SP), calcitonin gene-related peptide (CGRP), neurokinin A (NKA), and nerve growth factor (NGF) were improved. Besides, XB also can modulate the structure of respiratory bacterial microbiota and restore homeostasis., Conclusion: XB treatment alleviates cough hypersensitivity and inflammatory responses, inhibits the degranulation of mast cells, and ameliorates neurogenic inflammation in PIC guinea pigs whose mechanism may be associated with the inhibition of Tryptase/PAR2/PKC/TRPV1 and the recovery of respiratory bacterial microbiota., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cough medicines have been in use for over a century to treat the common and troublesome, but often helpful, symptoms of cough in children. They contain various combinations of "anti-tussive" drugs including opioids, antihistamines, herbal preparations, mucolytics, decongestants and expectorants. Whilst theoretically attractive for symptom relief when children are suffering, as time has passed these popular over the counter medicines have been shown to lack efficacy, delay more serious underlying diagnoses, and can cause complications and sometimes death. This has resulted in clinician concerns, a citizen petition to the American Food and Drug Association in 2007, some self-regulation from manufacturers and escalating restrictions on their use from regulatory agencies across the world over the last twenty years. This article will review the protective role of cough, juxtapose the conflicting treatment goals of suppressing a dry cough and promoting expectoration for a wet cough, consider the evidence basis for prescribing cough medicines in comparison to other more specific treatments such as for asthma [beta agonists] or infection [antibiotics], regulatory interventions, and conclude with the view that over counter cough medicines should not be used in children, especially young children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease with an unknown cause. It is characterized by symptoms such as cough and breathlessness, which significantly impact patients' quality of life. Cough, in particular, has emerged as a burdensome symptom for individuals with IPF. The etiology of cough in IPF patients is believed to be complex, involving factors related to the disease itself, such as increased sensitivity of cough nerves, lung structural changes, inflammation, and genetic factors, as well as comorbidities and medication effects. Unfortunately, effective treatment options for cough in IPF remain limited, often relying on empirical approaches based on studies involving chronic cough patients in general and the personal experience of physicians. Medications such as opioids and neuromodulators are commonly prescribed but have shown suboptimal efficacy, imposing significant physical, psychological, and economic burdens on patients. However, there is hope on the horizon, as specific purinergic P2 receptor ligand-gated ion channel (P2X3) inhibitors have demonstrated promising antitussive effects in ongoing clinical trials. This review aims to provide a comprehensive overview of the evaluation and management of cough in IPF patients, as well as highlight emerging pharmacological and non-pharmacological approaches that target the cough reflex and are currently being investigated in clinical settings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cough is a frequent symptom accompanied by lung cancer. More potent antitussive treatment for this complex and distressing symptom is required, but anti-cancer chemotherapy cannot fully manage the cough. Inhibition of vagal nerves might control coughing in patients with troublesome lung cancer-related cough and P2X 3 inhibitory therapy may be useful for targeting neuronal function. We report the case of a woman in her late 70s who never smoked and had advanced lung cancer. She visited our hospital complaining of serious deterioration of a non-productive cough. She was diagnosed with relapse of lung cancer, but she requested 2-week anti-tussive therapy before second-line chemotherapy. Gefapixant (P2X 3 antagonist) add-on at a dose of 90 mg/day (45 mg twice daily as the usual dosage in Japan) improved her cough as indicated by an improvement in the visual analog scale for cough from 70 to 20 mm and in the Japanese version of the Leicester Cough Questionnaire from 8.2 to 16.3, despite a deterioration in lung cancer after 2 weeks. There are no current guidelines for cough accompanied by lung cancer; however, our findings suggest that P2X 3 inhibition is a potent therapeutic option for lung cancer-related cough.

Objective: To determine objective and subjective endpoints most suitable for evaluating antitussive efficacy of dextromethorphan hydrobromide (DXM) in children. Spontaneous resolution of acute cough and large placebo effects are impediments to evaluating antitussive efficacy. Another impediment is paucity of age-appropriate, validated cough assessment tools., Methods: This was a multiple-dose, double-blind, placebo-controlled, randomized, pilot clinical study in children, aged 6-11 years, with cough due to the common cold. Eligible subjects met entry criteria and qualified by completing a run-in period where coughs were recorded with a cough monitor after they were dosed with sweet syrup. They were subsequently randomized to receive DXM or placebo over 4 days. Coughs were recorded during the initial 24 h; subjective assessments of cough severity and frequency were self-reported daily during treatment., Results: Data from 128 evaluable subjects (67 DXM; 61 placebo) were analyzed. Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. Also, greater reductions in cough severity and frequency were self-reported with DXM. These findings were statistically significant and medically relevant. No effects were detected between treatments for nighttime cough rates or impact of cough on sleep. Multiple doses of DXM and placebo were generally well-tolerated., Conclusion: Evidence of DXM antitussive efficacy was shown in children using objective and subjective assessment tools validated in pediatric populations. Diurnal variation of cough frequency over 24 h reduced the assay sensitivity needed to detect treatment differences at nighttime, as coughs/hour decreased during sleep for both groups., (© 2023 Consumer Healthcare Products Association. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Cough is the body's reflex when the throat or airway is irritated by a foreign body, such as irritants, microbes, and fluids. Cough caused due to a disorder or infection can last for a few days to a couple of weeks and is usually self-limiting and self-resolving. However, in certain cases, cough can persist for months, disrupting everyday activities, affecting the patient's mental health, and causing pain and fatigue. There are a number of different therapeutic strategies to manage acute and chronic cough, depending on the cause. Dry cough can be treated using opioids, nonopioids, antitussives, and antihistamines. Expectorants and mucolytics are widely used in the management of productive cough. The underlying cause of cough should be appropriately managed with specific therapy. The choice of treatment regimen is dependent on the patient's medical history, symptoms, and preexisting conditions. Based on the literature review and clinical practice, a comprehensive approach to the management of cough as a symptom has been proposed., (© Journal of the Association of Physicians of India 2011.)

Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at N -methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.

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 V s) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, Na V s became a promising and attractive neural target. Current studies establish that Na V 1.7 and Na V 1.8 inhibitors have the potential to suppress cough. In this study, we demonstrated that inhaled aerosol of Na V 1.7 inhibitor PF-05089771 (10 μM) and Na V 1.8 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 V 1.7 and Na V 1.8 may present promising therapeutic targets for antitussive therapy., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Cough variant asthma (CVA) is a chronic inflammatory disease characterized by cough as the main symptom. Suhuang antitussive capsule (Suhuang), one of traditional Chinese patent medicines, mainly treats CVA clinically. Previous studies have shown that Suhuang significantly improved CVA, post-infectious cough (PIC), sputum obstruction and airway remodeling. However, the effect of Suhuang on ovalbumin-induced (OVA-induced) metabolic abnormalities in CVA is unknown., Aim of the Study: This study aimed to identify potential metabolites associated with efficacy of Suhuang in the treatment of CVA, and determined how Suhuang regulates metabolites, and differential metabolites reduce inflammation and oxidative stress., Materials and Methods: Rats were given 1 mg OVA/100 mg aluminum hydroxide in the 1st and 7th days by intraperitoneal injection and challenged by atomizing inhalation of 1% OVA saline solution after two weeks to establish the CVA model. Rats were intragastrically (i.g.) administrated with Suhuang at 1.4 g/kg and β-hydroxybutyric acid (β-HB) were given with different concentrations (87.5 and 175 mg/kg/day) by intraperitoneal injection for 2 weeks. After 26 days, GC-MS-based metabolomic approach was applied to observe metabolic changes and search differential metabolites. The number of coughs, coughs latencies, enzyme-linked immunosorbent assay (ELISA), histological analysis and quantitative-polymerase chain reaction (Q-PCR) were used to investigate the effects of Suhuang. Then β-HB on CVA rats, NLRP3 inflammasome and GSK3β/AMPK/Nrf2 signalling pathway were detected by western blotting., Results: The results showed that Suhuang treatment significantly enhanced the serum level of β-HB. Interestingly, exposure to exogenous β-HB was also protective against OVA-induced CVA. β-HB significantly reduced the number of coughs and lengthened coughs latencies, improved lung injury, reduced the secretion of various cytokines, and directly inhibited the NLRP3 inflammasome. In addition, β-HB increased the nuclear accumulation of Nrf2 by activating the GSK3β/AMPK signaling axis, and then inactivating the NF-κB signaling pathway, effectively protecting OVA-induced CVA from oxidative stress and inflammation., Conclusions: The results of this study shows that β-HB can reduce inflammation and oxidative stress, the increased production of β-HB in serum might be the crucial factor for Suhuang to exert its effect in the treatment of CVA., Competing Interests: Declaration of competing interest The authors declare no conflict of interest related to this paper., (Copyright © 2022. Published by Elsevier B.V.)

Objective: To assess the clinical efficacy of compound pholcodine syrup and compound codeine phosphate oral solution on lung cancer-related cough. Methods: A total of 60 patients diagnosed with middle-advanced stage lung cancer and had lung cancer-related cough in the Department of Geriatric Oncology of Chongqing University Cancer Hospital from January to May 2022 were prospectively enrolled. According to the random number table method, the patients were divided into two groups: observation group and control group. The observation group [ n =30, with 21 males and 9 females, and aged (62.3±10.4) years] received compound pholcodine syrup treatment, while the control group [ n =30, with 21 males and 9 females, and aged (62.0±8.1) years] received compound codeine phosphate oral solution treatment. The dosage of the two drugs was 15 ml each time, 3 times a day, and the treatment course was 5 days. The antitussive effectiveness, cough severity and quality of life (Leicester Cough Questionnaire in Mandarin-Chinese scale) were observed and compared between the two groups 3 days and 5 days after the treatment. Results: All 60 patients completed the study. Both regimens were effective in controlling lung cancer-related cough. After 3 days treatment, the antitussive effective rate of the observation group and the control group was 83.3% (25/30) and 73.3% (22/30), respectively, with no statistically significant difference ( P =0.347). Likewise, after 5 days treatment, the antitussive effective rate of observation group and control group was 90.0% (27/30) and 86.6% (26/30), respectively, with no statistically significant difference ( P =0.687). There was no statistically significant difference in the cough severity between observation group [moderate and severe cough: 56.7% (17/30)] and control group [moderate and severe cough: 67.7% (20/30)] ( P =0.414). After 3 days treatment, cough symptoms were relieved in both groups. Patients with mild cough accounted for 73.3% (22/30) in the observation group and 56.7% (17/30) in the control group, and the difference was not statistically significant ( P =0.331). Moreover, after 5 days treatment, there was also no significant difference in mild cough between observation group [86.7% (26/30)] and control group [66.7% (20/30)] ( P =0.067). Meanwhile, there were no significant differences in the physiological score, psychological score, social score and total score of the Leicester Cough Questionnaire in Mandarin-Chinese scale before the treatment, after 3 days and 5 days treatment between the two groups (all P >0.05). The incidence of both xerostomia and constipation in the observation group was 0, which was lower than those of the control group [20.0% (6/30) and 20.0% (6/30)] (both P <0.05). Conclusions: Both compound pholcodine syrup and compound codeine phosphate oral solution are effective in treating lung cancer-related cough with similar antitussive effectiveness. Compound pholcodine syrup has a lower incidence of xerostomia and constipation than control group, with a better safety profile.

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors except J.H. are employees of Philip Morris International. J.H. was an employee of Philip Morris International at the time the experiments were performed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Zukamu granules (ZKMG), as the preferred drug for the treatment of colds in Uygur medical theory, has been used for 1500 years. It is also widely used in China and included in the National Essential Drugs List (2018 edition). It has unique anti-inflammatory, antitussive and analgesic effects., Aim of the Study: Aiming at the research of traditional Chinese medicine (TCM) with the characteristics of overall regulation of body diseases and the immune regulation mechanism with the concept of integrity, this paper put forward the integrated application of network composite module analysis and animal experiment verification to study the immune regulation mechanism of TCM., Materials and Methods: The active components and targets of ZKMG were predicted, and network module analysis was performed to explore their potential immunomodulatory mechanisms. Then acute lung injury (ALI) mice and idiopathic pulmonary fibrosis (IPF) rats were used as pathological models to observe the effects of ZKMG on the pathological conditions of infected ALI and IPF rats, determine the contents of Th1, Th2 characteristic cytokines and immunoglobulins, and study the intervention of GATA3/STAT6 signal pathway., Results: The results of network composite module analysis showed that ZKMG contained 173 pharmacodynamic components and 249 potential targets, and four key modules were obtained. The immunomodulatory effects of ZKMG were related to T cell receptor signaling pathway. The validation results of bioeffects that ZKMG could carry out bidirectional immune regulation on Th1/Th2 cytokines in the stage of ALI and IPF, so as to play the role of regulating immune homeostasis and organ protection., Conclusions: The network composite module analysis and verification method is an exploration to study the immune regulation mechanism of TCM by combining the network module prediction analysis with animal experiments, which provides a reference for subsequent research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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.].

Background: Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting β2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA., Methods: Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 μg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis., Results: The median cough VAS score (median from 6.0 to 2.0 in the M group, 5.0 to 1.0 in the BF group and 6.0 to 1.0 in the MBF group, all p < 0.001), daytime CSS (all p < 0.01) and night-time CSS (all p < 0.001) decreased significantly in all three groups after treatment for 8 weeks. Meanwhile, the LogC5 and sputum Eos% improved significantly in all three groups after 8 weeks treatment (all p < 0.05). No significant differences were found in the changes of the VAS score, daytime and night-time CSSs, LogC5 and sputum Eos% among the three groups from baseline to week 8 (all p > 0.05). The BF and MBF groups also showed significant decreases in FeNO after 8 weeks treatment (p = 0.001 and p = 0.008, respectively), while no significant change was found in the M group (p = 0.457). Treatment with MBF for 8 weeks significantly improved the FEV 1 /FVC as well as the MMEF% pred and decreased the blood Eos% (all p < 0.05)., Conclusions: Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013., (© 2022. The Author(s).)

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., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Concerns over serious respiratory depression in children led to two European Union (EU) referral procedures (in 2013 and 2015) to review the benefit-risk balance of codeine in this population when used for pain relief, cough or cold. Consequently, codeine should no longer be used in children aged < 12 years and restrictions were introduced for treatment in children ≥ 12 years., Objective: This multinational collaborative study aimed to assess the effectiveness of these risk minimisation measures by evaluating changes in prescribing of codeine and alternative treatments., Method: Children under 12 and 12-18 years old were followed between 2010 and 2017 to analyse quarterly trends in prescribing of codeine and alternative treatments in electronic health records from France, Germany, Norway, Spain and the United Kingdom using interrupted time series analysis., Results: Overall prescribing of codeine in children decreased in all five countries, reaching near zero prevalence in children under 12 years of age. This was accompanied by an increase in use of other opioid analgesics in France (from 0.15 to 0.56 prevalence per 100 person-years immediately after the first referral), Norway (from 0.0006 to 0.0013 at the end of the study), the United Kingdom (from 0.018 to 0.05 at the end of the study), and an increase in non-opioid analgesics in Norway (from 0.045 to 0.075 at the end of the study) after the referral on pain relief indication. The referral on cough/cold indication led to a decrease in use of opioid and non-opioid antitussives in children aged < 12 years in France (from 10 to 7 and 20 to 16, respectively) and had no impact in other countries. Overall prescribing trends for codeine and alternatives were similar across both age groups within each country., Conclusion: The decrease in use of codeine shows that healthcare professionals followed the adopted measures and switched prescribing practices for pain management in children aged < 18 years towards opioid or non-opioid analgesics depending on national clinical and reimbursement settings. Whist the magnitude of the first referral on pain differed between countries, the second referral on cough/cold had only a minimal impact on the use of codeine and antitussives., (© 2022. The Author(s).)

Background and Objective: Cough from URTI is common, leads to discomfort, sleep loss and stress in caregivers, leading to use of ineffective and potentially harmful over-the-counter medications. Honey is cost-effective and safe for children above one year of age. It is readily available and is a potentially valuable demulcent for treatment of childhood cough. The study aimed to determine the effect of honey on cough frequency and severity among children with URTI in outpatient setting., Methods: A single-blind randomised control trial involving children presenting with cough from URTI attending the GOPC of FMC Keffi. Eighty-four children presenting with cough from URTI were recruited, randomised into two groups of 42 and administered Honey (intervention) and Diphenhydramine (control) in three consecutive bedtime doses. Socio-demographic and clinical data including cough frequency, severity and impact on children and caregivers was collected using Paediatric Cough Questionnaire and Kingston Caregiver Stress Scale tool. Data was analysed using SPSS version 25. A p<0.05 was considered statistically significant., Results: Majority (56.0%) of the participants were males, with a mean age +SD of 4±1.47 years. Median cough frequency score for intervention and control groups pre and post intervention decreased (5.00 and 0.00 vs 5.00 and 3.00, p<0.001). Median cough severity score decreased (4.00 and 0.00 vs 4.00 and 3.00, p<0.001), Post intervention pooled caregivers' burden significantly reduced, (5.00 and 11.00 for intervention and control respectively) and sleep pattern improved among children and caregivers (0.00, 2.00 p<0.001; and 0.00, 2.00 p<0.001, for children and caregivers respectively., Conclusion: Night-time honey doses given to children with cough from URTI significantly reduces symptoms and improves children and caregivers sleep compared to Diphenhydramine DPH., Competing Interests: The Authors declare that no competing interest exists., (Copyright © 2022 by West African Journal of Medicine.)

Cough serves a protective physiologic function as a vital defensive reflex preventing aspiration. However, exposure to viral infections or other triggers induces, in some individuals, a chronic cough (CC) that causes a significant symptomatic burden. Most cases of CC are due to conditions that respond to appropriate therapeutic trials (upper airway cough syndrome; asthma; reflux). Unfortunately, a significant subgroup of patients will have refractory CC, which does not respond to treatment of known underlying causes of CC. Currently, available therapeutic options for refractory CC are inadequate due to limited efficacy and frequently intolerable adverse effects. Current professional society guideline recommendations are discussed, and a promising pipeline of antitussive drugs in development is introduced, including purinergic 2X3 receptor antagonists, neurokinin-1 receptor antagonists, oral mixed ĸ-opioid receptor agonists/µ-opioid receptor antagonists, and voltage-gated sodium channel blockers.

In this study, the inter-individual variability of antitussive effect of Farfarae Flos was observed, and then the Farfarae Flos treated mice were divided into the mice with good or poor antitussive effect. Then a UHPLC-Q TOF-MS method was developed and validated to quantify 13 fecal metabolites of Farfarae Flos, and the results showed concentrated differences between the two subgroups. The results of 16 S rRNA gene sequencing analysis showed that mice with good or poor antitussive effects were also different at the structure of gut microbiota in phylum and genus, as well as the related 6 pathways. In addition, the differential fecal metabolites of Farfarae Flos between the two subgroups were probably related with 5 bacterial that participating in the CQAs and flavonoids metabolism. This study explained the inter-individual variability of the antitussive effect of Farfarae Flos from the perspective of gut microbiota. However, the specific bacterial that participate in the metabolism of Farfarae Flos as well as the antitussive effects of Farfarae Flos need to be further validated., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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.

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 V s) lead to the rational hypothesis that subtype Na V 1.7 is involved in initiating cough and thus may present a promising therapeutic target for antitussive therapy. We evaluated the antitussive effect of Na V 1.7 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 V 1.7 blocker PF-05089771 inhibits cough in a manner consistent with its electrophysiological effect on airway C-fibre nerve terminals., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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 β 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 α 7 nicotinic receptor subtype as the target for nicotine during cough suppression described in humans. We additionally present evidence suggesting that ATA-101 and other α 7 nicotinic receptor-selective agonists may be promising candidates for the treatment of chronic refractory cough., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Ethnopharmacological Relevance: Fritillariae thunbergii Miq (FTM)exhibit versatile biological activities including the significant antitussive and expectorant activities. As a herbal medicine, the therapeutic effects of FTM may be expressed by multi-components which have complicated integration effects on multi-targets. With the time going, the different processing methods of FTM has been changed a lot. Thus，the study described the effect of processing methods to FTM and its quality., Material and Method: Studies were undertaken by using UHPLC-LTQ Orbitrap MS and pharmacodynamic models. All reagents were involved of analytical grade. While a HPLC-ELSD's method has been developed and validated, a certified Quality System is conformed to ICH requirements. The experimental animals followed the animal welfare guidelines., Aim of the Study: We aimed to found the differences after the different processing methods of FTM, and to demonstrate the changes could be selected as quality control indicators, and established a method for simultaneous determination of these for quality control., Results: we have previously found two new steroidal alkaloids: zhebeininoside and imperialine-3-β-D-glucoside from the different processing methods of FTM, which is the difference between the different processing methods of FTM, mainly on the steroidal alkaloids. The activity analysis of zhebeininoside, imperialine-3-β-D-glucoside, verticine and verticinone showed that the mouse model of cough expectorant has antitussive effect. The positive drug selected was dextromethorphan syrup. The positive group showed biological activity, but the blank group showed nothing. The model group showed illness which means that the model was effective. There are two ways of the mechanism of action of the expectorant action which can make sputum thin, reduce its viscosity, and be easy to cough up, or can accelerate the movement of mucous cilia in the respiratory tract and promote the discharge of sputum. In our study, the content of phenol red was significantly reduced in the administration group., Conclusions: To sum up, our results suggest that zhebeininoside and other three components cloud be selected as quality control indicators, and a method for simultaneous determination of zhebeininoside and other three components was established for quality control., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

Background: Remifentanil reduces cough during extubation. Ramosetron, a 5-HT 3 receptor antagonist, is a potent antiemetic. Regarding the antitussive property of 5-HT receptor agonists, ramosetron can mediate the cough reflex by increasing the remifentanil requirement. This study evaluated the effect of ramosetron on the optimal effect-site concentration (Ce) of remifentanil for preventing emergence cough from sevoflurane anesthesia in female patients., Methods: Forty-seven randomly selected female patients undergoing laparoscopic cholecystectomy received either ramosetron 0.3 mg (n = 23) or the same volume of normal saline (n = 24) intravenously at the end of surgery. The remifentanil Ce using target-controlled infusion in 50% of patients (EC 50 ) and 95% of patients (EC 95 ) were assessed using Dixon's up-and-down or isotonic regression method with a bootstrapping approach., Results: Using Dixon's up-and-down method, the EC 50 of remifentanil in the control group (1.33 ± 0.38 ng/mL) was comparable to that of ramosetron group (1.50 ± 0.69 ng/mL) (P = 0.615). Using isotonic regression analysis, the EC 50 (83% confidence interval) did not differ between the two groups (1.17 [0.86-1.43] ng/mL and 1.13 [0.68-1.56] ng/mL in control and ramosetron groups). However, the EC 95 (95% confidence interval) was significantly lower in the control group than in the ramosetron group (1.90 [1.45-1.96] ng/mL and 2.92 [2.35-2.97] ng/mL)., Conclusion: Remifentanil Ce for preventing emergence cough was higher in the ramosetron group than in the control group. It may indicate the lowering effect of ramosetron on the antitussive activity of remifentanil., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Government opioid policies-such as the North Carolina Strengthen Opioid Misuse Prevention (STOP) Act-have aided in lowering the days' supply of opioid prescriptions. However, what effect do these laws have on codeine-containing antitussive syrup? We aimed to assess the effect of the North Carolina STOP Act on ED opioid prescriptions written for >5 days for acute pain/non-pain diagnoses and whether it had an effect on the prescribing of codeine-containing antitussive syrup., Methods: A retrospective study of two emergency departments, with an average annual census of 70 000 and 22 000 patients, from January to August of 2017 and 2018. We applied logistic regression techniques to calculate the odds of an opioid prescription for >5 days. Opioid medication categories were formed to determine relational proportions. Two-tailed z-tests were used to test the difference in proportions., Results: Our study included 5366 verifiable opioid prescriptions. The percentage of an opioid prescription for >5 days decreased by 3.3% (95% CI -1.8% to -4.7%, p<0.05) after the North Carolina STOP Act (9.8% to 6.5%; 95% CI 5.5% to 7.5%, p<0.05). There was no statistically significant change in the prescribing of codeine syrup for >5 days pre-STOP and post- STOP Act, respectively (91.5% and 90.4%; difference=-1.1%, p=0.83)., Conclusion: The North Carolina STOP Act was associated with a reduction in the overall percentage of opioid prescriptions for >5 days for acute pain/non-pain diagnoses. However, there was no statistically significant effect on the prescribing of codeine-containing antitussive syrup., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to investigate the anti-inflammatory, antitussive, expectorant, and anti-asthmatic effects of Qinbaohong Oral Liquid in mouse experiments and explore its action mechanism based on network pharmacology. The mouse auricle swelling was induced by xylene for detecting the anti-inflammatory effect of Qinbaohong Oral Liquid, whose antitussive effect was then examined in mice with cough after exposure to ammonium hydroxide. The expectorant effect was determined based on the excretion of phenol red into the mouse trachea. The mouse model of asthma induced by histamine phosphate and acetylcholine chloride was used to observe the anti-asthmatic effect. The chemical components of Qinbaohong Oral Liquid were retrieved from TCMSP and literature, followed by target prediction based on BATMAN-TCM. The targets of inflammation, cough, expectoration, and asthma collected from GeneCards were intersected with drug targets for GO and KEGG enrichment analysis using Metascape. The results were imported into STRING for exploring protein-protein interactions and screening the key targets. As demonstrated by our findings, Qinbaohong Oral Liquid at 4.5 and 9.0 mL·kg~(-1) obviously decreased the weight(P&lt;0.05) and thickness(P&lt;0.01) of the right swelling ear and also the weight diffe-rence(swelling degree) between the two ears(P&lt;0.05), prolonged the incubation period of cough(P&lt;0.05), reduced the frequency of cough within 3 min(P&lt;0.05), and increased the excretion of phenol red into the mouse trachea(P&lt;0.01). Qinbaohong Oral Li-quid at 2.3, 4.5, and 9.0 mL·kg~(-1) dramatically prolonged the incubation period of asthma(P&lt;0.05). A total of 324 chemical components and 1 245 targets were harvested for the Qinbaohong Oral Liquid, together with 10 272 inflammation targets, 4 400 cough targets, 192 expectoration targets, and 7 533 asthma targets. Their intersection revealed that the anti-inflammatory, antitussive, expectorant and anti-asthmatic effects of Qinbaohong Oral Liquid were correlated with such GO biological processes as the regulation of ion transport and blood circulation and such KEGG pathways as cancer-related signaling pathways and neuroactive ligand-receptor interaction. Qinbaohong Oral Liquid has been confirmed by both experiments and network pharmacology analysis to be efficient in anti-inflammation, stopping cough, eliminating phlegm, and relieving asthma.

Our previous studies implicated the voltage-gated sodium channel subtype Na V 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of Na V 1.7 conductance can achieve therapeutic benefit in the absence of side effects on cardiovascular function, gastrointestinal motility or respiration. To this end, we have evaluated the antitussive effects of the Na V 1.7 selective blocker Compound 801 administered systemically in awake guinea pigs or administered topically in anesthetized guinea pigs. We also evaluated the antitussive effects of ambroxol, a low affinity Na V blocker modestly selective for tetrodotoxin resistant Na V subtypes. Both Compound 801 and ambroxol dose-dependently inhibited action potential conduction in guinea pig vagus nerves (assessed by compound potential), with ambroxol nearly 100-fold less potent than the Na V 1.7 selective Compound 801 in this and other Na V 1.7-dependent guinea pig and human tissue-based assays. Both drugs also inhibited citric acid evoked coughing in awake or anesthetized guinea pigs, with potencies supportive of an Na V 1.7-dependent mechanism. Notably, however, the antitussive effects of systemically administered Compound 801 were accompanied by hypotension and respiratory depression. Given the antitussive effects of topically administered Compound 801, we speculate that the likely insurmountable side effects on blood pressure and respiratory drive associated with systemic dosing make topical formulations a viable and perhaps unavoidable therapeutic strategy for targeting Na V 1.7 in cough., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Investigate the current situation of lung cancer cough diagnosis and treatment and the awareness of related issues among Chinese medical providers. Methods: Doctors, nurses, pharmacists from the oncology department, respiratory department, or general department were investigated using an electronic questionnaire from January 29 to March 29, 2021. There were 25 questions about lung cancer in the questionnaire. The questionnaire was including the most common accompanying symptoms in patients with lung cancer, the incidence of lung cancer-related cough, the assessment of the proportion of central antitussive drugs, and the commonly used central antitussives. Results: Questionnaires from 2 424 medical providers were collected from 402 hospitals in 21 provincial administrative units. Cough was the most common symptom in lung cancer. Most physicians believed that the incidence of lung cancer-related cough was 51%~75%, while the proportion of patients satisfied with the treatment was only 11%~20%. The evaluation of lung cancer-related cough was seriously insufficient. The leading cause of lung cancer-related cough was tumors. And the main problem was the inadequate antitussive effect of drugs in lung cancer-related cough management. The proportion of central antitussive medication usage in the secondary and tertiary hospitals was 93.9% and 92.0%, significantly higher than 75.0% in Primary hospitals (χ²=8.390, P =0.015). The proportion of the physicians who underhanded that codeine is at risk of addiction was 76.6% and 72.0% in the secondary and tertiary hospitals, which were significantly higher than 53.9% in Primary hospitals (χ²=9.240, P =0.010). In different occupations, the proportions of doctors and pharmacists who knew the risk of addicting to codeine were 73.0% and 82.6%, which were significantly higher than the 66.4% of nurses (χ²=21.200, P< 0.001). The Chinese medical providers were lack of training about the basic knowledge of using central antitussive medication. Conclusions: The proportion of patients who were satisfied with the effect of cough treatment is low. The medical staff did not have enough awareness of this. There was an urgent need to develop a consensus and standardize lung cancer cough diagnosis and treatment in China.

Recently, efficient extraction of natural products from traditional Chinese medicines (TCMs) by green solvents is deemed an essential area of green technology and attracts extensive attentions. In this work, a green protocol for simultaneous ultrasonic-extraction of the native compounds with different polarities of TCMs by using a hybrid ionic liquids (HILs)-water system was reported for the first time. As a case study, three superior ILs (1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4]), 1-ethyl-3-methylimidazolium acetate ([EMIM][OAc]), and 1-allyl-3-methylimidazolium chloride ([AMIM]Cl)) were chosen as the compositions of the HILs system, and the TCMs Suhuang antitussive capsule (SH) containing different-polarity lignans was selected. Primarily, an ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method in the multiple reaction monitoring (MRM) mode was established for qualitative and quantitative analysis of 18 lignans. After majorization by uniform design experiment, the HILs prepared with [AMIM]Cl, [EMIM][BF4], and [EMIM][OAc] at a volume ratio of 1:5:5 could simultaneously extract multi-polarity lignans compared to single IL. Subsequently, the conditions of ultrasonic extraction employing with HILs and traditional organic solvent were optimized by the response surface methodology, respectively. The results indicated that the extract efficiency of the HILs system for target compounds was significantly improved compared with the traditional organic solvent-extraction, i.e. the content of total lignans in ethanol system was up to 47 mg/g, while that in the HILs system was up to 69 mg/g, with an increasing of 47%. Additionally, 1 H-NMR and 13 C-NMR spectra were used to characterize the hydrogen-bond interactions in the HILs-lignan mixtures. Extraction with the HILs in TCMs is a new application schema of ILs, which not only avoids the use of volatile toxic organic solvents, but also shows the potential to be comprehensively applied for the extraction of bioactive compounds from TCMs., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The post-viral acute cough is the most common symptom in childhood. Consequently, the use of cough relievers is frequent. Many products for treating cough contain natural components. An ancient tradition has always established herbal medicine and honey as effective and safe means to relieve cough. Nevertheless, very few studies adequately investigated the real effectiveness and safety of natural products in treating acute cough. There is some evidence, provided by pediatric randomized controlled trials, about honey, one multicomponent product (containing Plantagolanceolata, Grindelia robusta, Helichrysum italicum , and honey), and Pelargonium sidoides . Other group of substances, including glycerol and isolated natural compounds, can help manage cough but robust evidence still lacks in children. There is an urgent need to perform rigorous studies that confirm the natural products' efficacy and safety for relieving post-viral acute cough. Key points : Acute post-viral cough is prevalent in childhood and adolescence. There is a growing interest concerning the use of natural remedies for post-viral cough. Many herbal medicines could be used satisfactorily for this issue., Competing Interests: The authors declare that they have no competing interests.

Ethnopharmacological Relevance: Hanchuan Zupa Granule (HCZP), a traditional Chinese ethnodrug, has the functions of supressing a cough, resolving phlegm, warming the lungs, and relieving asthma. In clinical practice employing traditional Chinese medicine (TCM), HCZP is commonly used to treat acute colds, cough and abnormal mucous asthma caused by a cold, or "Nai-Zi-Lai" in the Uygur language. Studies have confirmed the use of HCZP to treat cough variant asthma (CVA) and other respiratory diseases. However, the pharmacological mechanisms of HCZP remain unrevealed., Aim of the Study: To investigate the anti-tussive and anti-asthmatic effects and the possible pharmacological mechanisms of HCZP in the treatment of CVA., Materials and Methods: A guinea pig CVA animal model was established by intraperitoneal injection of ovalbumin (OVA) combined with intraperitoneal injection of aluminium hydroxide adjuvant and atomized OVA. Meanwhile, guinea pigs with CVA received oral HCZP (at dosages of 0.571, 0.285 and 0.143 g/kg bodyweight). The number of coughs induced by aerosol capsaicin was recorded, and the airway hyperresponsiveness (AHR) of CVA guinea pigs was detected with the FinePointe series RC system. H&E staining of lung tissues was performed to observe pathological changes. ELISA was used to detect inflammatory cytokines. qRT-PCR and western blotting analyses were used to detect the expression of Th1-specific transcription factor (T-bet), Th2-specific transcription factor (GATA3), and Toll-like receptor 4 (TLR4) signal transduction elements. These methods were performed to assess the protective effects and the potential mechanisms of HCZP on CVA., Results: Great changes were found in the CVA guinea pig model after HCZP treatment. The number of coughs induced by capsaicin in guinea pigs decreased, the body weights of guinea pigs increased, and inflammation of the eosinophilic airway and AHR were reduced simultaneously. These results indicate that HCZP has a significant protective effect on CVA. A pharmacological study of HCZP showed that the levels of interleukin-4 (IL-4) and IL-5 and tumour necrosis factor-α (TNF-α) in serum decreased. The amount of interferon-γ (IFN-γ) increased, mRNA and protein expression of TLR4 and GATA3 weakened, and mRNA and protein expression of T-bet increased., Conclusions: HCZP ameliorated the symptoms of guinea pigs with CVA induced by OVA by regulating the Th1/Th2 imbalance and TLR4 receptors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough. Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue. Methods : Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro , the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism. Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (±7.7); 60% were female and 80% had non-small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8-37.7%) over placebo while awake ( P  = 0.03), 30.3% (95% CI, 12.7-44.3) over 24 hours ( P  = 0.002), and 59.8% (95% CI, 15.1-86.0) during sleep ( P  = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P-induced depolarization by 78% in guinea pig ( P  = 0.0145) and 94% in human vagus ( P  = 0.0145). Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.