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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.

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.

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.

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.

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.

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.

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.

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.

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.

In many species including humans, antagonists of NMDA-type glutamate receptors such as dextromethorphan, when used at sufficient doses, have been found to be relatively safe and effective antitussives. Similarly, now in five different species (guinea pigs, rabbits, cats, dogs and pigs), neurokinin receptor antagonists have also proven to be safe and effective antitussive agents. Both of these classes of drugs act centrally to prevent cough. A brief review of what is known about the central encoding of cough is presented, as are the advantages of centrally acting antitussives. Also discussed are new insights into cough and NMDA receptor signaling that may lead to the development of more effective antitussive agents with limited side effects and broad application in treating cough associated with a variety of aetiologies.

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine, which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule - instead of a double bond between carbons 7 and 8 DHC possesses a single bond. DHC is used as an analgesic and antitussive agent and for the management of dyspnea and opioid addiction. Limited data is available on the potency of DHC to other opioids. The analgesic effect of DHC is similar to codeine and approximately twice as potent as tramadol for an oral route. In contrast to codeine and tramadol, DHC analgesia seem to be irrespective of CYP2D6 activity due to parent compound analgesic effects, multiple metabolic pathways and limited role of dihydromorphine in DHC analgesia. As the drug is commonly available appropriate titration and dosing and knowledge of its metabolism and possible adverse effects are important for safe prescription of DHC.

Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current efforts in clinical validation of TRPV1 antagonists revolve around various pain indications; therefore, clinical evaluation of TRPV1 antagonists as antitussive agents will have to await those outcomes.

Cough is the one of the most common respiratory symptoms for which medical attention is required and may have a great impact on quality of adults9 life, thus often requiring an empiric treatment with antitussive agents .There are evidence that NSAIDs are also used to improve cough concerning common cold. We have performed a prospective study evaluating 149 patients affected by URTI treated with some combination of NSAIDs and antitussives. Cough was measured by means of a verbal category descriptive (VCD) score. We have considered two periods, 7 and 10 days respectively, from the start of the treatment. On VCD score was conducted an analysis of persistence of cough (Kaplan Meier) taking into account absence of coughing (score=0) or its presence (score>0). The drugs more frequently used was levodropropizine and ketoprofen lysine salt. There was a statistically significant difference in time resolution of cough between the group receiving ketoprofen lysine salt and levodropropizine (a peripheral antitussive) and the group treated with ketoprofen lysine salt and central acting antitussives, in favor of the first combination. In patients treated with ketoprofen lysine salt and a central acting antitussives the median persistence of cough was 11 days, while in the group treated with ketoprofen lysine salt and levodropropizine the median was of 7 days. The present study suggests that the association of antitussives with NSAIDs, such as levodropropizine with NSAIDs, is efficacious in the reduction of coughing days and that the combination levodropropizine and ketoprofen lysine salt shows better result compared with levodropropizine and central antitussive.

Background. The effectiveness of a homeopathic syrup on cough has been demonstrated in an adult population in a previous double-blind randomized study. The present prospective observational study investigated children affected by wet acute cough caused by non-complicated URTIs, comparing those who received the homeopathic syrup versus those treated with the homeopathic syrup plus antibiotic. Objectives. The aims were: 1) to assess whether the addition of antibiotics to a symptomatic treatment had a role in reducing the severity and duration of acute cough in a pediatric population, as well as in improving cough resolution; 2) to verify the safety of the two treatments. Methods. Eighty-five children were enrolled in an open study: 46 children received homeopathic syrup alone for 10 days and 39 children received homeopathic syrup for 10 days plus oral antibiotic treatment (amoxicillin/clavulanate, clarithromycin, and erythromycin) for 7 days. To assess cough severity we used a subjective verbal category-descriptive (VCD) scale. Results. Cough VCD score was significantly (P

PURPOSE This study aims to investigate the additive effect of the Hedera helix (HH) and Rhizoma coptidis (RC) extracts mixture on antitussive and expectorant activities in animals. MATERIALS AND METHODS The expectorant assay was performed with phenol red secretion in mice trachea. Mice or guinea pigs were randomly divided into groups of 8 each, including negative and positive control groups. After gastric administration of the test extracts in mice, 2.5% phenol red solution (0.2 mL) was intraperitoneally injected. Trachea was dissected and optical density of tracheal secretion was measured. After gastric administration of the test extracts in guinea pigs, the antitussive activities were assessed using a citric acid-induced cough measurement. RESULTS The extracts of HH and RC significantly increased tracheal secretion and inhibited cough. The mixture of HH and RC extracts in a 1:1 concentration at a dose of 200 mg/kg showed a more potent effect on phenol red secretion (25.25±3.14) and cough inhibition (61.25±5.36) than the individual use of each extracts [phenol red secretion; HH 13.39±4.22 (p=0.000), RC 20.78±2.50 (p=0.010), cough inhibition; HH 9.89±4.14 (p=0.010), RC 30.25±7.69 (p=0.000)]. A 3:1 ratio mixture of HH to RC demonstrated an optimal expectorant effect (p

The purpose of this review is to highlight some important issues regarding current centrally acting antitussive drugs as well as discuss the implications of these matters on the development of future cough suppressants. Drugs that act in the central nervous system to inhibit cough are termed centrally acting and this designation is based exclusively on evidence obtained from animal models. This classification can include drugs that act both at peripheral and central sites following systemic administration. These drugs are intended to reduce the frequency and/or intensity of coughing resulting from disorders of any etiology. There are a number of central cough suppressants identified by their efficacy in animal models and the most prominent of these are codeine and dextromethorphan. Although the exact neural elements on which these drugs act are currently unknown, they are thought to inhibit a functionally identified component of the central system for cough known as the gating mechanism. The efficacy of codeine and dextromethorphan in humans has recently been questioned. These drugs are less effective on cough induced by upper airway disorders than in pathological conditions involving the lower airways in humans. The reasons for this difference in antitussive sensitivity are not clear. We propose that sensory afferents from different regions of the airways actuate coughing in humans by antitussive sensitive and insensitive control elements in the central nervous system. This hypothesis is consistent with results from an animal model in which laryngeal and tracheobronchial cough had different sensitivities to codeine. Other factors that may be very important in the action of central antitussive drugs in humans include the role of sensations produced by a tussigenic stimulus as well as plasticity of central pathways in response to airway inflammation. Resolution of these issues in the human will be a challenging process, but one which will lay the foundation for the development of more effective cough suppressants.

Background: Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis. Methods: Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms "cough," "double-blind placebo-controlled," "antitussive," "mucolytic," "cough clearance," "common cold," "protussive," "guaifenesin," "glycerol," and "zinc." Results: Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further. Conclusions: These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants.

Background: Iodo-resiniferatoxin (I-RTX) has recently been described as an ultra potent antagonist of the transient receptor potential vanilloid-1 (TRPV1). Methods: The ability of I-RTX to inhibit cough induced by inhalation of two putative TRPV1 stimulants (capsaicin and citric acid) was tested in non-anaesthetised guinea pigs. Results: Pretreatment with I-RTX either intraperitoneally (0.03–0.3 µmol/kg) or by aerosol (0.1–3 µM) reduced the number of coughs produced by inhalation of citric acid (0.25 M) and capsaicin (30 µM) in a dose dependent manner. Capsazepine (CPZ) also reduced citric acid and capsaicin induced cough, but the activity of I-RTX was 10–100 times more potent than CPZ in all the experimental conditions tested. Conclusions: I-RTX is a novel and potent antitussive drug which inhibits cough mediated by agents possibly acting via TRPV1 activation.

Cough is frequently associated with a wide array of respiratory infections, ailments and disorders. Consequently, cough is the number one symptomatic reason why people visit medical healthcare providers. Nonetheless, when cough-suppressant therapy is required by patients, many physicians are limited primarily to a single pharmacological class of antitussive agent, namely, opioids. Opioids, such as codeine, dominate the antitussive prescription market. These drugs act centrally within the CNS to attenuate cough due to a variety of causes. However, opioids often elicit significant receptor-related μopioid (MOP) untoward side effects such as constipation, respiratory depression, sedation, tolerance and addiction. The development of novel drugs that maintain or improve upon the antitussive efficacy of the opioids and do not possess MOP liabilities would represent a substantial improvement over currently available cough treatments. New antitussive pharmacological targets include non-MOP opioids, specifically, ...

Bakumondo-to (Maimendong tang) is a traditional oriental herbal medicine that has been used as an antitussive agent. We previously demonstrated that Bakumondo-to attenuates airway hyperresponsiveness induced by ozone. However, the mechanism(s) responsible for this effect remains unclear. In the present study, we examined the mechanism whereby Bakumondo-to inhibits ozone-induced airway hyperresponsiveness. First, we examined the effect of Bakumondo-to on prostanoids production, which are key mediators to airway hyperresponsiveness after ozone exposure. Second, we studied its effects on the vagal neuroeffector transmission, because vagal nerve is likely to play an important role in airway hyperresponsiveness after ozone.We measured the effects of Bakumondo-to on the concentrations of prostanoids in bronchoalveolar lavage fluid before and after ozone. We evaluated the effects of Bakumondo-to on the contraction of guinea pig tracheal smooth muscle evoked by electrical field stimulation (EFS) or the exogenous application of acetylcholine (ACh). Isometric tension of tracheal strips was measured in the presence of indomethacin (10(-6) M) and of guanethidine (10(-6) M).Ozone caused significant increase in prostaglandin E2 (PGE2) and thromboxane B2 (TXB2); however, Bakumondo-to did not affect the increase in these prostanoids. Bakumondo-to (0.01 mg/mL-1 mg/mL) significantly suppressed the contraction evoked by EFS, but did not affect the ACh-evoked contraction, indicating that Bakumondo-to suppressed tracheal smooth muscle contraction pre-junctionally.These results suggest that the mechanism by which Bakumondo-to inhibits airway hyperresponsiveness depends on inhibiting the release of acetylcholine from vagal nerve terminals.

The antitussive activity of Emblica officinalis Gaertn. (E. officinalis, Fam. Euphorbiaceae) was tested in conscious cats by mechanical stimulation of the laryngopharyngeal and tracheobronchial mucous areas of airways. The results showed that at a dose of 50 mg/kg body wt. perorally, the cough suppressive effect of E. officinalis is not unambiguous. A higher dose (200 mg/kg body wt.) of this substance perorally was more effective, especially in decreasing the number of cough efforts (NE), frequency of cough (NE/min(-1)) and the intensity of cough attacks in inspirium (IA+) and expirium (IA-) was more pronounced. These results showed that the cough suppressive activity of E. officinalis is dose-dependent. We could also demonstrate that the antitussive activity of E. officinalis is less effective than shown by the classical narcotic antitussive drug codeine, but more effective than the non-narcotic antitussive agent dropropizine. It is supposed that the antitussive activity of the dry extract of Emblica officinalis is due not only to antiphlogistic, antispasmolytic and antioxidant efficacy effects, but also to its effect on mucus secretion in the airways.

Cough is an important defensive pulmonary reflex that removes irritants, fluids or foreign materials from the airways. However, often cough is non-productive and requires suppression. Opioid mu receptor agonists, such as codeine are commonly used as antitussive agents and are among the most widely administered drugs in the world. Codeine suppresses the responsiveness of one or more components of the central reflex pathway for cough and is an efficacious antitussive drug for cough due to diverse aetiologies. However, opioids produce side effects that include sedation, addiction potential and constipation. Therefore, novel cough suppressant therapies should maintain or improve upon the antitussive efficacy profile of opioids. Moreover, these novel therapies should have a safety profile significantly better than current antitussive therapies. Presently, we discuss preclinical findings showing that activation of the 'opioid-like' receptor (NOP(1)) inhibits cough in the guinea pig and cat.

Placebo treatment has been reported to improve subjective and objective measures of disease in up to 30–40% of patients with a wide range of clinical conditions. A review of 8 clinical trials on the effects of antitussive medicines on cough associated with acute upper respiratory tract infection shows that 85% of the reduction in cough is related to treatment with placebo, and only 15% attributable to the active ingredient Treatment with a cough medicine can be viewed as consisting of three components: pharmacological, physiological (demulcent) and placebo. The placebo effect is related to belief in the effectiveness of the treatment and this idea must in some way influence the central control of cough. Studies on the placebo effect of analgesics indicate that the placebo effect may be mediated by endogenous opioid neurotransmitters and this may explain the analgesic potency of opioid medicines such as morphine. In the present paper a model is proposed to explain the antitussive effects of placebo treatment on the basis of endogenous opioid neurotransmitters. With active pharmacological ingredients contributing only 15% to the effects of cough treatment it seems reasonable to conduct more research on the other components of treatment such as placebo.