Effective Antitussives Research Articles

Preliminary investigation of the aqueous leaf extract of Chrysophyllum albidum George Don (Sapotaceae) in laboratory-induced cough

Cough is the most common symptom of respiratory diseases, however, in distressing and severe cases, opioids are effective, but their use has been challenged by side effects such as sedation, constipation; also, by some addictive liability, as well as the compromise of respiratory function. Therefore, there is a dire need for effective antitussives that will override the limitations of the opioids. Chrysophyllum albidum (Linn), family Sapotaceae, and also known as African star apple is primarily a forest tree species with its natural occurrences in diverse ecozones in Uganda, Nigeria and Niger Republic. Across Nigeria, it is known by several local names, for example, as ‘Agbalumo’ in Yoruba, and is generally regarded as a plant with diverse ethno-medicinal uses, including the treatment of cough and asthma. The present study was designed to evaluate possible antitussive activity of Chrysophyllum albidum. Cough was induced in the animals using 25 % ammonium hydroxide- and acetic acid (concentrated), after which the mice were randomized into treatment groups as follows: (Group 1, normal control), 10 mg/kg dextromethorphan (Group 2), 5.7 mg/kg codeine (Group 3), 100, 200 and 400 mg/kg, Chrysophyllum albidum (groups 4, 5 and 6). Cough induction was carried out in an enclosed dessicator for one minute and the number of coughs was, counted and recorded for five minutes. The animals were further exposed at 30, 60, 90 and 120 minutes. The same procedure was repeated for acetic acid-induced cough. Chrysophyllum albidum showed significant antitussive activity (p<0.001) in both ammonium hydroxide and acetic acid-induced cough model. The findings in this study validates the folkloric use of Chrysophyllum albidum in alleviating cough.

The Prospect for Potent Sodium Voltage-Gated Channel Blockers to Relieve an Excessive Cough.

An excessive, irritable, productive or non-productive coughing associated with airway inflammation belongs to pathological cough. Increased activation of airway vagal nociceptors in pathological conditions results from dysregulation of the neural pathway that controls cough. A variety of mediators associated with airway inflammation overstimulate these vagal airway fibers including C-fibers leading to hypersensitivity and hyperreactivity. Because current antitussives have limited efficacy and unwanted side effects there is a continual demand for the development of a novel more effective antitussives for a new efficacious and safe cough treatment. Therefore, inhibiting the activity of these vagal C-fibers represents a rational approach to the development of effective antitussive drugs. This may be achieved by blocking inflammatory mediator receptors or by blocking the generator potential associated with the specific ion channels. Because voltage-gated sodium channels (NaVs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, NaVs become a promising neural target. There is evidence that NaV1.7, 1.8 and 1.9 subtypes are predominantly expressed in airway cough-triggering nerves. The advantage of blocking these NaVs is suppressing C-fiber irrespective to stimuli, but the disadvantage is that by suppressing the nerves is may also block beneficial sensations and neuronal reflex behavior. The concept is that new antitussive drugs would have the benefit of targeting peripheral airway nociceptors without inhibiting the protective cough reflex.

Evidence for neuropathic processes in chronic cough

Chronic cough is a very common symptom for which patients seek medical attention but can often be difficult to manage, because associated causes may remain elusive and treatment of any associated causes does not always provide adequate relief. Current antitussives have limited efficacy and undesirable side-effects. Patients with chronic cough typically describe sensory symptoms suggestive of upper airway and laryngeal neural dysfunction. They often report cough triggered by low-level physical and chemical stimuli supporting the recently emerging concept of ‘cough hypersensitivity syndrome’. Chronic cough is a neuropathic condition that could be secondary to sensory nerve damage caused by inflammatory, infective and allergic factors. Mechanisms underlying peripheral and central augmentation of the afferent cough pathways have been identified. Successful treatment of chronic cough with agents used for treating neuropathic pain, such as gabapentin and amitriptyline, would also support this concept. Further research of neuropathic cough may lead to the discovery of more effective antitussives in the future.

Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome.

Chronic cough is a common symptom that can be difficult to manage because associated causes may remain elusive and treatment of any associated cause may not provide relief. Current antitussives have limited efficacy and undesirable side-effects. Patients with chronic cough describe sensory symptoms suggestive of upper airway and laryngeal neural dysfunction, and report cough triggered by low-level physical and chemical stimuli supporting the concept of cough reflex hypersensitivity. Mechanisms underlying peripheral and central augmentation of the afferent cough pathways have been identified. Chronic cough is a neuropathic condition that could be secondary to sensory nerve damage caused by inflammatory, infective and allergic factors. Recent success in the treatment of chronic cough with agents used for treating neuropathic pain such as gabapentin and amitryptiline would also support this concept. Research into neuropathic cough may lead to the discovery of more effective antitussives.

Recent additions in the treatment of cough.

Worldwide, cough is regarded as a challenging clinical problem due to its frequency and often limited therapeutic options. Chronic cough that remains refractory to usual medical treatment causes significant quality of life impairment in people with this problem. We have examined current evidence on recent additions in the treatment of cough, specifically treatment of refractory chronic cough with speech pathology and gabapentin. Relevant randomised control trials, reviews and case reports were identified through a PubMed and SCOPUS search of English-language literature referring to these concepts over the last eight years. Of the one hundred and two articles comprising this review the majority investigated the role of the transient receptor potential (TRP) receptors TRP Vanilloid 1 (TRPV1) and TRPA1 in cough and the potential of TRP antagonists as effective anti-tussives. However, these have only been tested in the laboratory and therefore their clinical effectiveness is unknown. Behavioural treatments such as speech pathology have gained momentum and this was evident in the increasing number of articles investigating its positive effect on cough. Investigation on the effectiveness of neuromodulating medications in the treatment of cough have been supported primarily through case series reports and prospective reviews however; their use (particularly gabapentin) has been significantly advanced through recently conducted randomised controlled trials. Recent additions in the treatment of chronic cough have been significant as they consider cough to have a unifying diagnosis of cough hypersensitivity with or without the presence of a neuropathic basis. Primarily, effective treatments for chronic cough target these areas and include behavioural treatment such as speech pathology and pharmaceutical treatment with neuromodulating medications such as gabapentin.

Chronic cough as a neuropathic disorder

Chronic cough is a common symptom that can be a daunting challenge for clinicians since treatment of the underlying cause does not always provide adequate relief, an obvious cause can remain elusive, and current antitussives have fairly poor efficacy and undesirable side-effects. Patients with chronic cough typically describe a range of sensory symptoms suggestive of upper-airway and laryngeal neural dysfunction. Additionally, patients often report cough triggered by low-level physical and chemical stimuli, which is suggestive of cough-reflex hyperresponsiveness. Pathophysiological mechanisms underlying peripheral and central augmentation of the afferent cough pathways have been identified, and compelling evidence exists for a neuropathy of vagal sensory nerves after upper-respiratory viral infections or exposure to allergic and non-allergic irritants. In this Personal View, we argue that chronic cough is a neuropathic disorder that arises from neural damage caused by a range of inflammatory, infective, and allergic factors. In support of this idea, we discuss evidence of successful treatment of chronic cough with agents used for treatment of neuropathic pain, such as gabapentin and amitriptyline. Regarding cough as a neuropathic disorder could lead to new, more effective antitussives.

Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels

Cough is a protective reflex and defence mechanism in healthy individuals, which helps clear excessive secretions and foreign material from the lungs. Cough often presents as the first and most persistent symptom of many respiratory diseases and some non-respiratory disorders, but can also be idiopathic, and is a common respiratory complaint for which medical attention is sought. Chronic cough of various aetiologies is a regular presentation to specialist respiratory clinics, and is reported as a troublesome symptom by a significant proportion of the population. Despite this, the treatment options for cough are limited. The lack of effective anti-tussives likely stems from our incomplete understanding of how the tussive reflex is mediated. However, research over the last decade has begun to shed some light on the mechanisms which provoke cough, and may ultimately provide us with better anti-tussive therapies. This review will focus on the in vitro and in vivo models that are currently used to further our understanding of the sensory innervation of the respiratory tract, and how these nerves are involved in controlling the cough response. Central to this are the Transient Receptor Potential (TRP) ion channels, a family of polymodal receptors that can be activated by such diverse stimuli as chemicals, temperature, osmotic stress, and mechanical perturbation. These ion channels are thought to be molecular pain integrators and targets for novel analgesic agents for the treatment of various pain disorders but some are also being developed as anti-tussives.

Understanding cough and its management in lung cancer

This article summarizes the current understanding of cough in lung cancer, strategies for its management and highlights areas where further research is warranted.Cough is common, severe and distressing for many lung cancer patients. Currently few effective cough interventions exist for lung cancer patients. This review proposes some of the mechanisms that may underlie cough in lung cancer and presents the existing data on antitussive therapy in cancer patients. A greater focus on the cough mechanisms may enable effective antitussives to be developed in the future for lung cancer patients. A brief overview of the validated cough assessment tools is provided. The use of such tools will enable robust clinical endpoints to be determined for future cough intervention studies. A 'cough treatment pyramid' is presented to provide a pragmatic approach to the management of cough in lung cancer patients. Despite the small number of publications on cough in lung cancer, some recent research has characterized cough for the first time in lung cancer patients. Its impact on quality of life domains such as psychological, social and physical is significant. The lung cancer symptom cluster of cough, breathlessness and fatigue has also been described. A recently developed cough severity assessment tool has provided researchers with a short well validated seven-item questionnaire to determine this important cough characteristic. In addition, a Cochrane Database Systematic Review on Interventions for Cough in Cancer has also been published. These studies are all described in the present review. Understanding the impact of a symptom such as cough, the assessment of cough and its potential underlying mechanisms is crucial if we are to manage this symptom effectively. Current cough management in lung cancer patients is lagging behind the management of other cancer symptoms. There is now an increasing need to diagnose and treat cough more effectively, as lung cancer patients are living longer with chronic symptoms such as cough.

Therapeutic Options for Acute Cough Due to Upper Respiratory Infections in Children

Cough due to upper respiratory tract infections (URIs) is one of the most frequent complaints encountered by pediatric health-care providers, and one of the most disruptive symptoms for children and families. Despite the frequency of URIs, there is limited evidence to support the few therapeutic agents currently available in the United States (US) to treat acute cough due to URI. Published, well-designed, contemporary research supporting the efficacy of narcotics (codeine, hydrocodone) and US Food and Drug Administration (FDA)-approved over-the-counter (OTC) oral antitussives and expectorants (dextromethorphan, diphenhydramine, chlophedianol, and guaifenesin) is absent for URI-associated pediatric cough. Alternatively, honey and topically applied vapor rubs may be effective antitussives.

Chronic ‘cough hypersensitivity syndrome’: A more precise label for chronic cough

Chronic cough remains a challenge to many clinicians because there is often no diagnostic link to causation, and because indirect antitussives are largely ineffective. Chronic cough can also be a predominant symptom associated with many chronic respiratory diseases such as COPD, asthma and pulmonary fibrosis. Chronic cough itself does impair the quality of life and is associated with psychological impairment. The symptoms associated with chronic cough include persistent tickling or irritating sensation in the chest or throat, hoarse voice, dysphonia or vocal cord dysfunction. Currently, the clinical diagnosis of cough is associated with chronic cough caused by airway eosinophilic conditions such as asthma, gastrooesophageal reflux disease or post-nasal drip (or upper airway syndrome), which implies cause and effect, or with chronic cough associated with other diseases such as COPD, cancer or heart failure, that does not necessarily imply cause and effect. A recently-recognised category is idiopathic cough, with no associated or causative diagnosis. We suggest that there is a better label needed for chronic cough, that includes the common association with a hypersensitive cough response to tussive stimuli such as capsaicin or citric acid. This would invoke a hypersensitive syndrome, and there are good reasons to use a new label that would encompass the problem of chronic cough: the chronic ‘cough hypersensitivity syndrome’. This would focus the problem on the cough symptomatology and lead to greater focus on understanding the mechanisms of cough sensitisation, with the ultimate aim of obtaining more effective antitussives.

A streetcar named urge-to-cough

in the Tennessee Williams play A Streetcar Named Desire , we learn that Blanche DuBois is considerably more complex than meets the eye. So too is a recently identified sensation associated with the production of cough, known as the “urge-to-cough” ([3][1], [4][2]). In this issue of the Journal

The Efficacy of a NOP1 Agonist (SCH486757) in Subacute Cough

Currently, opiates are widely used as antitussives but have substantial side effects. Recently, it has been proposed that NOP1 receptor agonists may be useful as a novel approach to cough suppression. Therefore, we compared the effect of NOP1 receptor agonist SCH486757 with matched placebo and codeine in a multicentre, double-blind, parallel-group study in patients with subacute cough. The primary outcome was change in cough severity scores, with the key secondary outcome change in objective daytime cough counts. We studied 91 subjects with subacute cough [59 (65%) female, median age = 41(range = 18-64) years, and median cough duration = 33 (range = 16-99) days]. Subjects were randomised to receive either SCH486757 100 mg, codeine 30 mg, or matched placebo twice daily for 5 days. Cough severity was scored throughout using a diary card and objective cough frequency recorded for 8 h at baseline and on the first and last treatment days. There were no significant differences in changes in average cough severity scores from baseline to treatment between SCH486757 and placebo [mean change = -0.57 (-30.1%) vs. mean change = -0.49 (-19.7%); P = 0.56] or between codeine and placebo [mean change = -0.72 (-33.2%); P = 0.07 compared to placebo). Changes in objective cough counts also showed no differences between the three treatment groups. There were some hints of possible limited antitussive efficacy with SCH486757. Unfortunately, the maximum clinical dose is limited by its tendency to produce somnolence. If the therapeutic ratio of NOP1 agonists could be improved, these drugs may still prove to contain effective antitussives.

Central regulation of the cough reflex: Therapeutic implications

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.

Currently Available Cough Suppressants for Chronic Cough

Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.

Review Series: Chronic cough: Future directions in chronic cough: mechanisms and antitussives

Cough is an important defensive reflex of the respiratory tract needed to clear and protect the upper airways; however, it may become exaggerated and interfere with quality of life. Although chronic cough may be successfully treated when associated with the common causes such as asthma and eosinophilic bronchitis, gastrooesophageal reflux disease and post-nasal drip syndrome or rhinosinusitis, increasingly, idiopathic cough or cough with no associated cause is recognised. Chronic cough is often associated with an increased response to tussive agents such as capsaicin, used as an index of the cough reflex. Some airway receptors mediate or influence cough through activation of vagal afferent pathways which converge on brain stem respiratory networks and of supramedullary centres. Plastic changes in intrinsic and synaptic excitability at the brain stem, spinal or ganglionic level may be the mechanism by which the cough reflex is enhanced in chronic cough. Subjective and objective measurements of cough in the clinic are now available but a major unmet need in chronic cough is the availability of effective antitussives. Future directions in chronic cough include the pathophysiological mechanisms of the enhanced cough reflex, and the discovery of effective antitussives that can successfully alleviate chronic cough.

Effective antitussives for the cough patient: An unmet need

Chronic cough is a prevalent symptom in the community but it is likely that only a small fraction of chronic coughers seek medical attention. Chronic cough can be controlled by addressing the ‘cause’ of the cough, but not all cough is controlled using this approach; an ‘idiopathic’ cough or cough of unknown aetiology is becoming more well-recognized. In these patients and in those whose cough has not responded to treatment of the cause(s), there is a lack of efficacious antitussive therapies (‘non-specific’ antitussives). Even in those whose cough is controlled by treatment of the cause, an efficacious antitussive for symptomatic relief would be useful for breakthrough symptoms. It is necessary to address the mechanisms underlying chronic cough, particularly the process of sensitization, both peripherally and centrally, that is the basis of chronic cough; such a process may persist even in the absence of the initiating event that first induced the cough. Currently-available antitussives in both acute and chronic cough are not very effective. Novel targets that may result in effective antitussives have been identified and with the development of clinical tools to measure cough accurately and reliably (e.g. cough counts and cough-specific quality-of-life questionnaires) and the evoked cough response (e.g. citric acid or capsaicin challenges), clinical trials should be performed. The chronic cough population is clinically heterogeneous but is characterized by an enhanced cough reflex; this should be the target population for study. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.

Reflexogenic prolongation of respiratory pauses: A potential mode of action of antitussives

Four clinically effective antitussives and 37059 (1-Ethylaminoethyl-5-methoxy-benzocyclobutene), a substance with singular pharmacodynamic potencies on expiratory activity, are tested with a specified procedure for their potentialities to prolong the reflexogenic retardation of respiration induced in pigeons by a laryngeal stimulus.

Pharmacological Aspects of Drug Dependence

Publisher Summary Drug dependence in man does not develop to many of the classes of drugs that induce tolerance, and tolerance does not develop to some of the drugs to which man may become dependent. Both tolerance and dependence develop to two major classes of central nervous system depressants, narcotic analgesics and the sedative hypnotics. The clinical techniques for evaluating a drug's capacity to induce physical dependence have been discussed in this chapter. The factors that influence the development of physical dependence and the postulates concerning the mechanism underlying its development have also been reviewed. The factors that favor the optimal development of physical dependence to the narcotic analgesics are related to the nature of the particular drug, to the manner of its administration, and to the species. Although, the clinical literature dealing with psychogenic or psychic dependence is enormous, only recent laboratory studies have initiated to determine whether this phenomenon could be demonstrated in animals. The search for an analgesic drug devoid of morphine's undesirable properties continues unabated. A morphine derivative has been found in which the analgesic property has been dissociated from the most undesirable property of all-that of producing physical dependence. A variety of other drugs have been produced that resemble morphine, or more frequently codeine, in their over-all spectra of pharmacological actions. A variety of antagonists have been developed in the morphinan and benzomorphan series. Many of these have been assayed as analgesics in man. It is recently found that some of the narcotic analgesics produce analgesia but do not produce physical dependence. Moreover substances that are effective antitussives and that completely lack the capacity to induce physical dependence have also been discovered in recent years.

鎮咳薬の化学的薬理学的研究 (第2報)

It has been found that 1-(3′, 4′-dihydroxyphenazyl)-4-(2-hydroxypropyl) piperazine dihydrochloride (TN-1261) is an effective antitussives of having 12% (with dogs) and 10% (with cats) of codein action. The action towards centripetal path (the action for stretch receptor impulse), the comparison of medication dosage in the different administration process, the influence of decerebration by midcollicular transaction, the action towards medullary cough center and the action towards centrifugal path of respiration have determined that the action site was central nervous, being different from the narcotic antitussive effect of morphine group.