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An increasing number of patients complain to medical institutions about a cough that persists for more than 8 weeks, namely chronic cough. The cough observed in patients with chronic cough is not responsive to conventional antitussive agents such as dihydrocodeine and dextromethorphan, and this is a major clinical problem. The most common pathology of chronic cough in Japan is dry cough. Two causes of dry cough are increased sensitivity of cough receptors (cough hypersensitivity) and increased contraction of bronchial smooth muscle. Among these, the mechanisms of cough hypersensitivity are diverse, and understanding these mechanisms is important for the diagnosis and treatment of chronic cough. In this paper I will review the regulatory mechanisms of cough hypersensitivity, especially the regulation of Aδ fiber excitability by C fibers. Furthermore, the central mechanisms involved cough reflex are discussed in relation to central acting antitussives.

Objective This study aimed to elucidate the effects of early macrolide administration on genetically confirmed pertussis-induced cough in adolescents and adults. Methods This single-center, retrospective cohort study examined the effects of the early administration of macrolides and antitussive agents on cough secondary to pertussis. We divided the patients into two groups based on the median duration from the beginning of the cough to the initiation of macrolide administration: early macrolide administration group (EMAG) and non-early macrolide administration group (NEMAG). The clinical improvement of cough was defined as maintaining a cough awareness score of ≤3 points for 3 consecutive days. Patients The medical records of 40 patients diagnosed with pertussis (≥12 years old) who were able to maintain a cough diary and received no other antibiotics aside from macrolides were included in the study. A diagnosis of pertussis was made using the loop-mediated isothermal amplification (LAMP) test. Results The EMAG (24 patients) showed a significantly shorter total cough period than the NEMAG [16 patients; 20.0 (95% confidence interval (CI), 16-28) vs. 30.5 (95% CI, 27-40) days; log-rank test, p=0.002]. There was no significant difference in the post-administration cough periods between the EMAG and NEMAG [11.0 (95% CI, 7-19) vs. 13.0 (95% CI, 5-23) days; log-rank test, p=0.232]. Antitussive agents did not affect the cough. Conclusion The early administration of macrolides, but not antitussive agents, is effective for treating pertussis. Therefore, macrolides should be administered as soon as possible for this disease.

Background: Cough is one of the most common medical symptoms for which medical advice is sought. Although cough is a protective reflex responsible for clearing the airways from secretions and foreign bodies, it can be a troublesome symptom that causes discomfort to patients. Due to the increasing interest in herbal remedies in both developed and developing countries, in the current study, we aimed to overview medicinal herbs containing essential oils used as antitussive agents according to Traditional Persian Medicine (TPM) textbooks. We summarized the relevant scientific evidence on their possible pharmacological effects. Methods: To collect the evidence for the treatment of cough or “seaal” (cough in ancient books) from TPM sources, five main medicinal Persian manuscripts were studied. The antitussive herbs were listed and their scientific names were identified and authenticated following botanical reference books. ScienceDirect and PubMed online databases were searched for related mechanisms of action of the reported medicinal plants. Results: Forty-nine herbs containing essential oils have been recommended in TPM for the treatment of cough; 21 of them had at least one known mechanism of action for cough suppression in the scientific literature. According to this review, most of the cited medicinal plants were assessed for either nitric oxide inhibitory or antitussive/expectorant activities. Conclusion: In addition to advantageous effects of antitussive herbs recommended by TPM, the present review highlighted some recent evidence-based data on these promising herbs that could be used as an outline for future research on their medicinal use.

The study of acute and chronic toxicity of the homeopathic preparation syrup Stodal, produced by the Laboratory of Boiron, France, widely used in medical practice as an effective antitussive agent. Stodal with a single intragastric administration to outbred mice and rats at doses of 5, 10, 15, 20 and 25 ml / kg and intraperitoneal administration to rats at doses of 2.5; 5; 7.5; 10 and 12.5 ml / kg did not cause death of animals. In experiments on mice in females with intraperitoneal administration of homeopathic syrup Stodal LD 50 was 17.2 (13.1 - 22.6) ml/kg and in males LD 50 was 19.6 (16.1 - 24.0) ml/kg. Homeopathic syrup Stodal with daily oral administration to rats and rabbits in doses of 1 ml / kg and 10 ml/kg for one month did not cause changes in the General condition, behavior, appearance and pronounced changes in body weight of animals. Toxic effects of stodal syrup were not observed in clinical and laboratory, pathomorphological and histological studies performed in the conventional volume.

Codeine continues to be widely used as an analgesic, antidiarrhoeal and antitussive agent. Its analgesic effect depends on its biotransformation to morphine, a strong opioid. The highly variable biotransformation of codeine to morphine, catalysed by CYP2D6, underlies the pronounced interindividual variability of its analgesic response. Randomized controlled trials have demonstrated that codeine administered alone has the poorest analgesic effect among all commonly used analgesics in acute postoperative pain. Moreover, it is highly unlikely that the low dose of codeine contributes to the pain-relieving effect of the non-opioid component in combination analgesic products. In addition, there is a lack of reliable clinical evidence to support the use of codeine as an antitussive in acute or chronic cough. Codeine use, through its active metabolite morphine, has the potential to lead to abuse and dependence. The World Health Organization (WHO) removed codeine from the essential medicines list for children in 2011. Based on the available information in the scientific literature on the efficacy and safety of codeine, the WHO should seriously consider removing it also from the list of essential medicines for adults, which would be a strong signal for all health professionals to prescribe and dispense codeine with the utmost caution.

Cough, as we are well aware, is one of the commonest defensive mechanisms that humans exhibit to keep the major and minor airways clear of foreign bodies and contaminants. While not every cough has to be suppressed pharmacologically, there are conditions where such suppression serves useful. While suppression of cough is one aspect of management of cough-related disorders, drugs that help in producing or increasing the amount of sputum (or expectoration), drugs that break down the sputum, drugs that provide symptomatic relief by soothing the pharyngeal mucosa are part of therapy. In addition, antibiotics and other adjuvants are also used in therapy. Details of these agents that are commonly used in the management of cough and cough-related disorders are elucidated in this chapter.

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.

Farfarae Flos (FF) is widely used for the treatment of cough, bronchitis, and asthmatic disorders in the Traditional Chinese Medicine (TCM). According to the experience of TCM, only the flower bud can be used as herbal drug, and its medicinal quality becomes lower after blooming. However, the underlying scientific basis for this phenomenon is not fully understood. In this study, the chemical components and the bioactivities of the FF collected at three different development stages were compared systematically. NMR based fingerprint coupled with multivariate analysis showed that the flower buds differed greatly from the fully opened flower both on the secondary and primary metabolites, and the animal experiments showed that the fully opened flower exhibited no antitussive or expectorant effect. In addition, the endogenous metabolites correlated with the antitussive and expectorant effect of FF were also identified. These findings are useful for understanding the rationality of the traditional use of FF, and also suggested the components responsible for the antitussive and expectorant effect of FF.

There seem to be several pitfalls in an anatomic, diagnostic protocol for the evaluation of chronic cough. Instead, it is reasonable to propose that non-asthmatic chronic cough depends on the combined effects of an underlying, abnormally enhanced cough reflex and aggravating factors. Unexplained chronic cough is distressingly common despite a systematic diagnostic approach. It is often related to bronchial hypersensitivity and nonspecific bronchial inflammation. Inhaled corticosteroid (ICS) is effective for asthmatic cough. ICS is less effective in non-asthmatic cough than in asthma but not ineffective. It can be modestly effective in a significant portion of patients with non-asthmatic cough. Cough itself can induce upper airway mucosal inflammation, which could enhance the cough reflex and viciously aggravate cough. Therefore, an antitussive agent is not a just symptom controller but can play a major role in successful cough control. Cough can be more effectively controlled by behavioral interventions, with psychological counseling in addition to a pharmacological approach. ICS and antihistamines can reduce cough regardless of its cause, so therapeutic diagnosis is a misconception in the diagnosis of cough. (Korean J Med 2017;92:506-513)

A wide range of disease processes may present with cough and definitive treatment depends on identifying the cause. Specific treatment of the cause should control the cough, but this may not occur in all cases, and in a sizeable proportion of patients, no associated cause can be found. In the settings of acute cough, symptomatic treatment is often the first line of therapy. Symptomatic treatment must be also considered when the cough interferes with the patient’s daily activities; however most of antitussive preparations have not been shown to be more effective than placebo in adequately performed clinical trials. In this chapter the main antitussive drugs are examined, but for the sake of completeness, it is also discussed some other drugs often used to treat cough, though some of them are not commonly classified as antitussive agents. Finally, it is reported recent therapeutic approach to refractory cough represented by the combination of behavioural therapy and the neuromodulator drugs.

A wide range of disease processes may present with cough, and definitive treatment depends on identifying the cause. Specific treatment of the cause should control the cough, but this may not occur in all cases, and in a sizeable proportion of patients, no associated cause can be found. In the settings of acute cough, symptomatic treatment is often the first line of therapy. Symptomatic treatment must be also considered when the cough interferes with the patient’s daily activities; however most of antitussive preparations have not been shown to be more effective than placebo in adequately performed clinical trials. In this chapter the main antitussive drugs are examined, but for the sake of completeness, it is also discussed some other drugs often used to treat cough, though some of them are not commonly classified as antitussive agents. Finally, it is reported a recent therapeutic approach to refractory cough, represented by the combination of behavioural therapy and the neuromodulator drugs.

Cough is one of the most common complaints in human medicine. In veterinary medicine cough is equally frequent and plays a significant role in an owner's perception of their pet's quality of life. In human and veterinary medicine, therapy for chronic cough is often ineffective. The complexity of the cough pathway and species differences have made it difficult to develop an effective antitussive agent for veterinary patients. The few effective antitussive agents currently available are associated with significant adverse effects. Fortunately, several promising drugs currently being studied in human clinical trials may offer options for use of novel antitussive therapies in small animal patients. This article reviews current understanding about cough pathophysiology, diagnostic strategies used to uncover underlying etiology of cough, and examines available options for controlling cough, including novel antitussive therapies used in human medicine.

Particulate matter (PM) is a type of air pollutant that poses a risk to human health. In the ocular system, PM causes or aggravates dry eye syndrome (DES) by damaging the corneal and conjunctival epithelia. Liriope platyphylla has been used traditionally as an expectorant, antitussive agent, and tonic in Korea. However, the effects of Liriope platyphylla extract (LPE) on PM-induced ocular damage have not been elucidated. In this study, we evaluated the in vivo protective effect of LPE against PM-induced DES in rats. Topical administration of LPE attenuated the PM-induced decrease in tear volume and reduced corneal epithelial irregularity and damage. LPE also protected against PM-induced disruption of the corneal mucin-4 layer and reduction in the conjunctival goblet cell density. These findings suggest that LPE has protective effects against PM-induced DES.

Chronic cough is a common and troublesome clinical problem and currently there are no effective treatments [1]. While individual specialist cough clinics have been set up in some European countries, there is no formal mechanism to develop common management approaches. Furthermore, the vast majority of clinical trials of novel anti-tussive treatment have been conducted in a limited number of sites in the UK and USA, with little in the way of cough clinical trial infrastructure across Europe [2–7]. The NEw Understanding in the tReatment Of COUGH (NEUROCOUGH) Clinical Research Collaboration (CRC) seeks to address this through creating a platform allowing clinicians, together with researchers in academia and industrial partners across Europe and beyond, to exchange ideas and facilitate collaborations geared towards improved care and treatment for patients with cough. The core aims of NEUROCOUGH are to: 1) create a registry of Europe-wide specialist cough clinics operating according to agreed and standardised protocols; 2) establish a Europe-wide registry of “clinical trial ready” chronic cough patients suitable for multicentre experimental medicine studies and later phase precision medicine clinical trials; 3) seek public engagement to provide input into NEUROCOUGH based on the priorities and unmet needs of patients; and 4) encourage early career researchers and clinicians into the field of cough. In time, we envisage that NEUROCOUGH will bring clinicians, scientists, patients and industry together for larger-scale cough projects in a way that to date has not been possible. NEUROCOUGH will place Europe at the forefront of clinical improvements in chronic cough and provide a strong platform for attracting major clinical trials of anti-tussives, thus speeding up drug discovery with the ultimate aim of providing better treatments for patients with chronic cough.

In this study, a simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed for the simultaneous determination of 18 compounds, namely, morphine, codeine, tuberostemonine, thebaine, papaverine, scopoletin, liquiritin, narcotine, gynaroside, hyperoside, hesperidin, isoliquiritin, liquiritigenin, luteolin, isoliquiritigenin, apigenin, formononetin and glycyrrhizic acid in traditional Chinese medicine of antitussive. Analytes were chromatographically separated on a Waters C18 column under gradient elution with a mobile phase of water containing 0.1‰ HOAc (A) and methanol (MeOH) containing 0.1‰ HOAc (B). Detection was accomplished by multiple-reaction-monitoring scanning with an electrospray ionization source under positive and negative ion switching modes. Samples were prepared with dilution and ultrasonic extraction. All components were detected within the linear regime (r2 ≥ 0.9924) at the concentration ranges tested. The precision ranged from 1.3 to 4.6%, the accuracy was between 85.6 and 116.7% and the results of method validation tests were all within the required limits. The validated quantification method was successfully applied to analyze 40 batches of commercial traditional Chinese medicine of antitussive. These results will provide a basis for quality control of production process and the further pharmacokinetic study of traditional Chinese medicine of antitussive in vivo.

OBJECTIVES: Smoking has been associated with several respiratory problems including cough, phlegm production, dry throat, itchy throat, and hoarse voice. The objective of this study was to evaluate the effect of a botanical extract-based blend, Fresh Clear (FC), on the respiratory system of a smoking population. FC consists of 3 of botanical extracts: broccoli seed (Brasssica oleracea), Luo Han Guo (Siraitia grovenorii), and Honeysuckle Flower Bud (Lonicera japonica). Broccoli seed is rich in Sulforaphane, which was reported to promote healthy inflammatory balance, as well as to positively impact oxidative stress and DNA-damaging substances. Both Luo-han-guo and Honeysuckle Flower Bud have been used as traditional Chinese medicines for the treatment of pharyngitis, pharyngeal pain, as well as an antitussive remedy and anti-inflammatory and anti-oxidative agent in China and East Asia. METHODS: This is an open-label, self-controlled study. Eighty smoking volunteers who had mild or moderate throat discomfort without respiratory diseases and other severe diseases were recruited. Volunteers were asked to consume FC at a dose of 1.45 g, 2 times/day for 8 weeks. Their symptoms of cough, phlegm production, dry throat, itchy throat, and hoarse voice were evaluated at week 0 (Baseline), week 4, and week 8 by questionnaire. Ultimately, 75 volunteers completed the study, 44 males and 31 females. Average age was 47.0 ± 10.6 years. All volunteers had smoked for over 3 years. RESULTS: We found significant amelioration of the listed throat symptoms as compared to baseline after 4- and 8- weeks FC consumption. Effective ratios at week 4 and week 8 respectively were 88% and 94% in cough, 91% and 95% in phlegm production, 90% and 90% in dry throat, 92% and 95% in itchy throat, and 94% and 89% in hoarse voice. CONCLUSIONS: 8 weeks consumption of FC was shown to ameliorate smoking-induced throat symptoms in a smoking population with a smoking history of over 3 years. FUNDING SOURCES: Nu Skin Enterprises.

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Eur Respir J. 46 (2015) PA3852, http://dx.doi.org/10.1183/13993003.congress-2015.PA3852. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Zingiber officinale is used for the management of fever, bronchial asthma and cough for thousands of years. While the link to a particular indication has been established in human, the active principle of the formulation remains unknown. Herein, we have investigated a water extracted polysaccharides (WEP) containing fraction from its rhizome. Utilizing a traditional aqueous extraction protocol and using chemical, chromatographic and spectroscopic methods a fraction containing a branched glucan and polygalaturonan in a ratio of 59:1 was characterized. This glucan, which has a molecular mass of 36 kDa, is made up of terminal-, (1,4)- and (1,4,6)-linked α-Glcp residues. Oral administration of WEP in doses of 25 and 50 mg/kg body weight significantly inhibited the number of citric acid-induced cough efforts in guinea pigs. It does not alter the specific airway smooth muscle reactivity significantly. Thus, traditional aqueous extraction method provides molecular entities, which induces antitussive activity without addiction.

Cough and the accompanying sensation known as the urge-to-cough are complex neurobiological phenomena dependent on sensory and motor neural processing at many levels of the neuraxis. In addition to the excitatory neural circuits that provide the positive drive for inducing cough and the urge-to-cough, recent studies have highlighted the existence of likely inhibitory central neural processes that can be engaged to suppress cough sensorimotor processing. In many respects, the balance between excitatory and inhibitory central cough control may be a critical determinant of cough in health and disease which argues for the importance of understanding the biology of these putative central inhibitory processes. This brief review summarises the current knowledge of the central circuits that govern voluntary and involuntary cough suppression and posits the notion of targeting central suppressive mechanisms as a treatment for disordered cough in disease.

Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity via elevation of endocannabinoids. Primary vagal ganglia neurons, tissue bioassay, in vivo electrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents. FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides N-arachidonoylethanolamide (anandamide), palmitoylethanolamide, N-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated via a cannabinoid CB2/Gi/o-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels. These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.

Cough is the most common complaint for which outpatients in the United States seek medical attention, and yet available therapeutic options for cough lack proven efficacy and are further limited by safety and abuse liabilities. Thus, safe and effective cough suppressants are needed. Recent preclinical studies described the antitussive effects of memantine, an N-methyl-d-aspartate receptor channel blocker used in the treatment of Alzheimer's disease. The goals of the present study were to compare the antitussive effects of memantine, dextromethorphan, and codeine in guinea pigs; to relate the dose-dependent actions of memantine in these studies to peak plasma concentrations achieved following oral administration; and to provide the first ever evaluation of the antitussive effect of memantine in humans. In guinea pigs, memantine and codeine were comparable in efficacy and potency but both were superior to dextromethorphan in the citric acid cough challenge model. The pharmacokinetic analyses suggest that memantine was active in guinea pigs at micromolar plasma concentrations. Subsequently, 14 healthy volunteers as well as 14 otherwise healthy adults with acute viral upper respiratory tract infection (URI) underwent capsaicin cough challenges 6 hours after ingestion of 20 mg memantine and matched placebo in a randomized, double-blind, crossover fashion. In healthy volunteers, memantine significantly inhibited cough reflex sensitivity (P = 0.034). In subjects with URI, responsiveness to capsaicin was markedly increased, and in these patients, the inhibition of cough reflex sensitivity by memantine relative to placebo did not reach statistical significance (P = 0.088). These data support further research to investigate the potential of memantine as a clinically useful antitussive.

A dark brown polymeric complex was isolated from flowering parts of medicinal plant Arnica montana L. by hot alkaline extraction followed by neutralization and multi-step extractions with organic solvents. It was recovered in 5.7% yield, on GPC showed two peaks of molecular mass of 9 and 3.5kDa. The compositional analyses of Arnica complex revealed the presence of carbohydrates (26%), uronic acids (12%), phenolics (1.25mM or 213mg of GAE/1g), and low protein content (∼1%). The carbohydrate moiety was rich mainly in rhamnogalacturonan and arabinogalactan. The antitussive tests showed the reduction of the cough efforts by Arnica complex, however, its total antitussive effect was lower compared with that of codeine, the strongest antitussive agent. The bronchodilatory activity of Arnica complex was similar to salbutamol, a classic antiasthmatic drug, and was confirmed by significantly decreased values of specific airways resistance in vivo and by considerably attenuated the amplitude of acetylcholine and histamine-induced contractions in vitro. Arnica complex did not show any cytotoxic effect on mouse fibroblast cultures and human lung cells, up to the dose of 500μg/mL.

Background Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO2 rebreathing test in patients with chronic cough of any origin. Methods Twenty-four outpatients (aged 39-70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg levodropropizine, 15 mg dihydrocodeine, or a matching placebo. Subsequently, patients breathed a mixture of 93% oxygen and 7% CO2 for 5 min. Fractional end-tidal CO2 (Fetco2) and inspiratory minute ventilation ( V ˙ i) were continuously monitored. Changes in breathing pattern variables were also assessed. Results At variance with dihydrocodeine, levodropropizine and placebo did not affect respiratory responses to hypercapnia (P Conclusions The results are consistent with a peripheral action by levodropropizine; the assessment of ventilatory responses to CO2 may represent a useful tool to investigate the central respiratory effects of antitussive agents. Trial Registry European Union Clinical Trials Register (EudraCT No.: 2013-004735-68); URL: https://www.clinicaltrialsregister.eu/

Codeine has been prescribed to pediatric patients for many decades as both an analgesic and an antitussive agent. Codeine is a prodrug with little inherent pharmacologic activity and must be metabolized in the liver into morphine, which is responsible for codeine’s analgesic effects. However, there is substantial genetic variability in the activity of the responsible hepatic enzyme, CYP2D6, and, as a consequence, individual patient response to codeine varies from no effect to high sensitivity. Drug surveillance has documented the occurrence of unanticipated respiratory depression and death after receiving codeine in children, many of whom have been shown to be ultrarapid metabolizers. Patients with documented or suspected obstructive sleep apnea appear to be at particular risk because of opioid sensitivity, compounding the danger among rapid metabolizers in this group. Recently, various organizations and regulatory bodies, including the World Health Organization, the US Food and Drug Administration, and the European Medicines Agency, have promulgated stern warnings regarding the occurrence of adverse effects of codeine in children. These and other groups have or are considering a declaration of a contraindication for the use of codeine for children as either an analgesic or an antitussive. Additional clinical research must extend the understanding of the risks and benefits of both opioid and nonopioid alternatives for orally administered, effective agents for acute and chronic pain.

A high molecular mass polysaccharide-polyphenolic conjugate has been isolated from flowering parts of Lythrum salicaria by hot alkaline extraction. Its chemical analysis revealed 74% of carbohydrates and 17% of phenolics. Compositional analysis of carbohydrate part showed a high GalA content (49%), Rha (25%), Gal (13%) and Ara (9%) residues, and indicated thus rhamnogalacturonan associated with arabinogalactan in Lythrum conjugate. Antitussive activity tests, performed in three doses of Lythrum conjugate - 25, 50 and 75 mg/kg of animal body weight, showed the reduction of the number of cough efforts even 5h after administration. However, their antitussive effects were lower in comparison with that of codeine, the strongest narcotic antitussive agent. The tests evaluating the influence of different doses on airways smooth muscle reactivity revealed more significant effect of Lythrum conjugate in comparison with that of salbutamol, a commercial bronchodilator used in a clinical practice. Measurements of specific airway resistance pointed at both, the dose-dependent bronchodilatory activity and possible participation of bronchodilation on antitussive effect of Lythrum conjugate. This study represents the first sight into pharmacodynamic properties of Lythrum polysaccharide-polyphenolic glycoconjugate.

Codonopsis lanceolata belongs to the Campanulaceae family, which is a perennial herb. It is widely used as an antitussive agent and an expectorant in oriental medicine. Codonopsis lanceolata contains large amounts of polysaccharide and phenolic compounds and is known to have anti-oxidative effect and improve immunity. We evaluated the efficacy and the skin safety and stability of cosmetic that is applied Codonopsis lanceolata extract fermented by lactic acid bacteria. As result, formulation of Codonopsis lanceolata extract improved the human skin moisturizing effect, increased TEWL 196%, skin hydration 15%, and the sebum rate 131%.

OBJECTIVE: A common side-effect of angiotensin-converting enzyme inhibitors (ACEi) is a persistent dry cough. Physicians and pharmacists who fail to recognise a dry cough to be ACEi-related may attempt to treat it with antitussives, instead of recommended ACEi substitution. The aim of this study was to quantify such prescription behaviour, as well as its influence on therapy compliance. DESIGN AND METHODS: Drug dispensing data were retrieved from the IADB.nl database in The Netherlands. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEi initiation than the other way around. Therapy compliance in both groups was assessed using the proportion of days covered (PDC) method; patients with a PDC ≥ 80% were considered compliant. RESULTS: 1601 patients were incident users of both ACEi and antitussives within a half-year time span. There was a significant excess of patients prescribed antitussive agents after ACEi initiation (1075 versus 526), yielding a sequence ratio of 2.0 (95% confidence interval 1.8-2.3). Therapy compliance in patients receiving antitussives after ACEi initiation was 58%, significantly lower than therapy compliance in control patients, which was 77% (P

Acute bronchitis is a disease characterized by inflammation of the large airways within the lung accompanied by a cough lasting from 1 to 3 weeks. The inflammation occurs as a result of an airway infection or environmental trigger, with viral infections accounting for an estimated 89% to 95% of cases. Symptomatic treatment of cough is primarily required for patients, though in most cases the condition is self-limiting. Therapy consists of both nonpharmacological and pharmacological options to include antibiotics and antivirals, antitussive agents, protussive agents, and beta-2-agonists. This article reviews the treatment options for acute bronchitis and recommends criteria for use.

The caudal nucleus tractus solitarii (cNTS), the predominant site of termination of cough-related afferents, has been shown to be a site of action of some centrally acting antitussive agents. A role of ERK1/2 has been suggested in acute central processing of nociceptive inputs. Because pain and cough share similar features, we investigated whether ERK1/2 activation could also be involved in the central transduction of tussive inputs. For this purpose, we undertook the present research on pentobarbital sodium-anesthetized, spontaneously breathing rabbits by using microinjections (30–50 nl) of an inhibitor of ERK1/2 activation (U0126) into the cNTS. Bilateral microinjections of 25 mM U0126 caused rapid and reversible reductions in the cough responses induced by both mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. In particular, the cough number and peak abdominal activity decreased. Bilateral microinjections of 50 mM U0126 completely suppressed the cough reflex without affecting the Breuer-Hering inflation reflex, the pulmonary chemoreflex, and the sneeze reflex. These U0126-induced effects were, to a large extent, reversible. Bilateral microinjections of 50 mM U0124, the inactive analog of U0126, at the same cNTS sites had no effect. This is the first study that provides evidence that ERK1/2 activation within the cNTS is required for the mediation of cough reflex responses in the anesthetized rabbit. These results suggest a role for ERK1/2 in the observed effects via nontranscriptional mechanisms, given the short time involved. They also may provide hints for the development of novel antitussive strategies.

Background The treatment of cough is a significant clinical unmet need because there is little evidence that current therapies are effective. Based on evidence supporting a role for N-methyl d -aspartate receptors (NMDARs) in cough, we hypothesized that memantine, a low-affinity, uncompetitive NMDAR channel blocker in routine use for the treatment of Alzheimer disease, could be an effective, well-tolerated, antitussive therapy. The aim of this study was to establish preclinical evidence that memantine has antitussive effects. Methods We studied the influence of memantine on experimentally induced coughing in response to citric acid and bradykinin inhalation in guinea pigs. We also compared the potency and efficacy of memantine as an antitussive to other NMDAR antagonists, dextromethorphan and ketamine, and to the γ-aminobutyric acid class B receptor agonist baclofen. Results Compared with control subjects, 10 mg/kg memantine significantly reduced the cumulative number of coughs evoked by both citric acid (median, 24.0 [interquartile range (IQR), 13.0-25.5] vs 1.5 [IQR, 0.3-10.3] coughs; P = .012) and bradykinin aerosols (median, 16.0 [IQR, 9.5-18.5] vs 0.0 [IQR, 0-0.75] coughs; P = .002). Memantine 10 mg/kg produced a similar reduction in the cumulative number of coughs to baclofen 3 mg/kg and demonstrated comparatively greater cough suppression than 30 mg/kg dextromethorphan or 30 mg/kg ketamine. This dose of memantine produced no sedative or respiratory depressive effects. Conclusions This study illustrates that memantine has marked antitussive effects in guinea pigs, most likely mediated through NMDAR channel blockade. Memantine, therefore, has the potential to be a safe, effective, and well-tolerated antitussive agent.

Vitex negundo Linn. (Verbenaceae) is used in traditional medical system for respiratory disorders. This study was carried out to investigate its cough-relieving potential. The antitussive effect of the butanolic extract of V. negundo (Vn) on sulphur dioxide (SO(2))-induced cough was examined in mice. Safety profile of Vn was carried out by observing acute neurotoxicity, median lethal dose (LD(50)) and behavioural signs. Vn dose-dependently (250-1000 mg kg(-1)) inhibited the cough provoked by SO(2) gas in mice and exhibited maximum protection after 60 min of administration. At 1000 mg kg(-1), Vn caused maximum cough-suppressive effects i.e. cough inhibition at 60 min was 67.4%, as compared to codeine (10 mg kg(-1)), dextromethorphan (10 mg kg(-1)) and saline having cough-inhibitory potential 75.7%, 74.7% and 0%, respectively. LD(50) value of V. negundo was found to be greater than 5000 mg kg(-1). In toxicity tests, no signs of neural impairment and acute behavioural toxicity were observed at antitussive doses and extract has been well tolerated at higher doses. These results indicate that V. negundo exhibits antitussive effect and it was found devoid of toxicity.

Several water-soluble pectic polysaccharides were isolated from the pumpkin fruit biomass and characterized by composition, structural features and molecular properties. The pectic polysaccharides were tested for antitussive activity by studying the effects of citric acid-induced cough reflex in guinea pigs and reactivity of the airway smooth muscle in vivo conditions in comparison to the narcotic drug codeine. Oral administration of all pectic polysaccharides from pumpkin inhibited the number of coughs induced by citric acid in guinea pigs, but to various extents. The results indicated that the antitussive activity of the pectic polysaccharides is affected by their molecular and structural properties, whereby a synergistic action between the polysaccharide and non-carbohydrate components on the biological response has been suggested as well. The cough depressive efficacy of most of the tested polysaccharides was comparable and even higher than that of codeine. Moreover, the application of these polysaccharides provoked any side effects what is their advantage towards the conventional opioid-derived antitussive agents.

Antitussive drugs are amongst the most widely used medications worldwide; however no new class of drugs has been introduced into the market for many years. Natural compounds offer interesting pharmacological perspectives for antitussive drug development. In this study, we have analyzed a pectic arabinogalactan isolated from Adhatoda vasica by aqueous extraction and precipitation with ethanol. This polysaccharide is branched and consisted mainly of 1,3-/1,3,6-linked galactopyranosyl and 1,5-/1,3,5-linked arabinofuranosyl residues. Peroral administration of this arabinogalactan (50 mg kg −1 body weight) inhibited the number of coughs induced by citric acid in guinea pigs and slightly decreased the values of specific airway resistance.

Aromatic vapors of monoterpenoids such as menthol and camphor are known to possess antitussive effects for the symptomatic relief of upper respiratory tract. The lactams 10 and 11 of menthol and camphor, respectively, have been synthesised and evaluated first time for their antitussive activity in citric acid-induced cough in guinea pig model. The effect of nitrogen insertion in the chemical architecture of menthol and camphor on the antitussive activity was reflected by the significant decrease of the cough frequency and increase in the cough latency exhibited by aerosolized 10 and 11. Prior exposure of aerolsolised 10 for 5 min at different concentrations (15, 30, and 60 μg/l) significantly reduced cough response induced by citric acid and also increased latency to initial cough response. Similarly 11 has showed greater inhibitory cough response in comparison to camphor at concentrations such as 125, 250, and 500 μg/l. However, latency to initial cough response was only increased at the concentrations of 250 and 500 μg/l.

Three new indole alkaloids, named kopsihainins A-C (1-3), and two known compounds, kopsinine (4) and methyl demethoxycarbonylchanofruticosinate (5), were isolated from the stems of Kopsia hainanensis. Their structures were determined using extensive spectroscopic methods. The two main constituents 4 and 5 exhibited significant antitussive activity in a citric acid induced guinea pig cough model. The antitussive effect of 4 was demonstrated to interact with the δ-opioid receptor. This is the first report of antitussive effects of aspidofractinine type and chanofruticosinate type alkaloids.

To evaluate the potential expectorant and antitussive activity of a traditional Chinese medicine.The water extract and four fractions of the aerial part of Reineckia carnea were orally administrated to coughing mice induced by ammonium hydroxide and mice injected with phenol red, respectively, to investigate their medification effect on coughing and mucus secretion.90% Ethanol fraction significantly lengthened the latent period of cough and decreased cough frequency caused by ammonium hydroxide at the dose of 0.372 g/kg (p0.05). Sixty percent ethanol fraction reduced the cough frequency as well as the mucus secretion from mouse tracheas obviously at the dose of 0.570 g/kg (p0.05) by measuring the tracheal output of phenol red in mice. The medication effects in multiple doses of the active fractions were then performed and it has been proved that the 60% ethanol and 90% ethanol fraction were curatively effective on expectoration and coughing, respectively both at the high and middle dose, which supplied proofs for the further research on chemical constituents in both of two effective fractions.

The mechanism of action of naringin has been investigated in different models of experimentally induced cough in guinea pigs. In contrast to codeine phosphate (6 mg/kg, intravenous administration [i. v.]), naringin (15, 30, and 60 mg/kg, i. v.) had no central antitussive effect on cough elicited by electrical stimulation of the superior laryngeal nerve. Naringin (0.5, 1.0, and 2.0 µmol) could not prevent the cough reflex induced by stimulation of the trachea after intracerebroventricular injection (i. c. v.), while codeine phosphate (0.5 µmol) was highly effective. Further characterizing the peripheral mechanism of naringin, we found that its effect (50 mg/kg, i. v.) was not affected by the depletion of sensory neuropeptides, whereas levodropropizine (10 mg/kg, i. v.) lost its capacity to prevent cough in the capsaicin-desensitized guinea pig. Furthermore, pretreatment with glibenclamide (10 mg/kg, intraperitoneal [i. p.]) significantly reduced the antitussive effect of pinacidil (5 mg/kg, subcutaneous [s. c.]), but could not antagonize the antitussive effect of naringin (30 mg/kg, s. c.). Our present results suggest that naringin is not a central antitussive drug. And naringin does not exert its peripheral antitussive effect through either the sensory neuropeptides system or the modulation of ATP-sensitive K (+) channels.

Aims of the study Stemona alkaloids with distinctly different chemical skeletons are recently reported as the active components in the antitussive herb Baibu derived from the root-tubers of Stemona tuberosa . This study aims to determine if alkaloids of this herb contribute equally to the antitussive functions, act on the same sites of cough reflex, and play any role in inducing central respiratory depressant effects. Materials and methods Antitussive potency of four major alkaloids was evaluated on guinea pigs with citric acid aerosol to induce cough. The action sites of the alkaloids on cough reflex pathway were tested with electrical stimulation of the superior laryngeal nerve in guinea pigs. The central respiratory effects of croomine were also tested on guinea pigs. Results Croomine, neotuberostemonine and stemoninine showed similar antitussive potency, while tuberostemonine showed much weaker antitussive potency. Neotuberostemonine, tuberostemonine and stemoninine acted on the peripheral cough reflex pathway, while croomine acted on the central part. Croomine also showed obvious central respiratory depressant effects. Conclusions The four major Stemona alkaloids in Stemona tuberosa do not contribute equally to antitussive potency in guinea pigs. Neotuberostemonine, tuberostemonine and stemoninine target on peripheral cough reflex pathway. Croomine acts on central sites in the cough reflex pathway and demonstrates central respiratory depressant effects, which can partly account for the adverse reactions reported for the herb.

AIMSAngiotensin-converting enzyme inhibitors (ACEi) are frequently prescribed for various cardiovascular and renal diseases. A common side-effect of these drugs is a persistent dry cough. Physicians who fail to recognize a dry cough to be ACEi-related may attempt to treat it with antitussive agents instead of recommended ACEi substitution. Prescription behaviour in the general population considering treatment of the side-effect with antitussive agents has not been studied before.METHODSDrug dispensing data between 2000 and 2007 were retrieved from the IADB.nl database. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEi initiation than the other way around. A logistic regression model was fitted to determine predictors.RESULTSWe identified 27 446 incident users of ACEi therapy. One thousand and fifty-four patients were incident users of both ACEi and antitussives within a half-year time span. There was an excess of patients being prescribed antitussive agents after ACEi initiation (703 vs. 351), adjusted sequence ratio 2.2 [confidence interval (CI) 1.9, 2.4]. Female patients were more likely to be prescribed antitussive agents following ACEi therapy initiation, odds ratio 1.4 (CI 1.1, 1.9), age and co-medications were not significant predictors.CONCLUSIONSThere was a significant and clinically relevant excess of patients receiving antitussives after ACEi initiation. The results suggest that cough as a side-effect of ACEi is not recognized as being ACEi-related or is symptomatically treated with antitussive agents instead of ACEi substitution. The estimated frequency of antitussive treatment of ACEi-induced dry cough is 15%.

An antitussive agent should reduce the amount of coughing experienced by the patient sufficiently for the patient to appreciate an improvement in cough severity and regard the improvement as sufficient to outweigh any adverse effects or risks associated with the treatment. In recent years the development of objective cough counting devices and cough-specific quality of life tools have vastly improved our ability to appropriately assess the effectiveness of anti-tussive agents and hopefully will lead to the development of safe and effective treatments in the future. This article summarizes current knowledge of methodologies available for assessing cough therapies, the patient groups to study, and the design of clinical trials.

A series of 3-pyridinyl-tropane analogues based on previously reported compound 1 have been synthesized and shown to bind to the nociceptin receptor with high affinity. From the SAR study and our lead optimization efforts, compound 10 was found to possess potent oral antitussive activity in the capsaicin-induced guinea pig model. The rationale for compound selection and the biological profile of the optimized lead (10) are disclosed.