Antitussive Agent Research Articles

Ultra‐performance Liquid Chromatography–High‐definition Mass Spectrometry Analysis of Constituents in the Root of Radix Stemonae and those Absorbed in Blood after Oral Administration of the Extract of the Crude Drug

Radix Stemonae, first recorded in the herbal 'Additional Records of Famous Physicians' (Mingyi Bielu), has been widely used as an oral anti-tussive agent in traditional Chinese medicine (TCM) for thousands of years in China. Current analysis methods are usually time-consuming and inaccurate. The aim of this study was to develop a more rapid and sensitive method to detect the active compounds in Radix Stemonae. A rapid, sensitive and selective ultra-performance liquid chromatography-high-resolution mass spectrometric (UPLC-HDMS) method with automated data analysis software MetaboLynx(TM) was developed for analysis and identification of the bioactive components and their metabolites in rat plasma following oral administration of Radix Stemonae extract. Twenty-nine compounds in the Radix Stemonae extract and 47 compounds in the rat plasma samples were detected in the MS(E) mode in a single injection within 21 min. Among the compounds detected, 23 were identified in vitro and 42 were identified in rat plasma, either by comparing the retention time and mass spectrometry data with those of reference compounds or by mass spectrometry analysis and retrieving the reference literature. It is concluded that the screening capability of MetaboLynx(TM), together with the utilisation of MS(E) in structural elucidation, can facilitate a rapid and comprehensive detection and effective structural characterisation of Stemona alkaloids in Radix Stemonae extract, which could be applied to other Chinese medicine. The results provide helpful chemical information of Radix Stemonae extract for further pharmacology and active mechanism research.

Stereochemical Analysis of Methorphan Using (−)‐Menthyl Chloroformate

Forensic laboratories around the world have seen an increase in the number of drug seizures containing methorphan. Levomethorphan is a narcotic and a controlled substance, and its enantiomer dextromethorphan is an antitussive agent used in over-the-counter medications. For the forensic analysis of seized drugs containing methorphan, it is important to report the stereochemical composition of the drug. Ideally, a method based on common forensic laboratory instrumentation is desirable. The use of the chiral derivatizing agent (-)-menthyl chloroformate followed by routine gas chromatography-mass spectrometry analysis of the derivative was shown to successfully determine the stereochemical composition of methorphan. This approach was applied to a street seizure containing methorphan proving that it was pure dextromethorphan. The derivatives of dextro- and levomethorphan were subjected to mass spectroscopic and nuclear magnetic resonance analysis, which confirmed that the structure of the derivatives remained unchanged as a result of the derivatization process.

Antitussive Effects of Memantine in Guinea Pigs

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. 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. 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. 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.

Suppression of the cough reflex by inhibition of ERK1/2 activation in the caudal nucleus tractus solitarii of the rabbit

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.

Antitussive effects of the peripherally restricted GABAB receptor agonist lesogaberan in guinea pigs: Comparison to baclofen and other GABAB receptor-selective agonists

BackgroundGastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABAB receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABAB receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough.MethodsWe have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABAB receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid.ResultsLesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABAB receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate.ConclusionsTogether, the data suggest that lesogaberan and related GABAB receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects.

Review: Effect of drugs on human cough reflex sensitivity to inhaled capsaicin

Capsaicin, the pungent extract of red peppers, has been used in clinical research for almost three decades. Capsaicin has gained favor as the provocative agent of choice to measure cough reflex sensitivity, as it induces cough in a safe, reproducible, and dose-dependent manner. One of the major uses of capsaicin cough challenge testing has been to evaluate the effect of a pharmacological intervention on the human cough reflex. The current review summarizes the published experience with capsaicin inhalation challenge in the evaluation of drug effects on cough reflex sensitivity. A notable contrast evident between studies demonstrating a drug effect (inhibition of cough reflex sensitivity) and those that do not, is the predominance of healthy volunteers as subjects in the latter. This observation suggests that subjects with pathological cough, rather than normal volunteers, comprise the optimal group in which to evaluate the effect of potential antitussive agents on human cough reflex sensitivity.

Cough management: a practical approach

Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and pulmonologists. Cough is an important defensive reflex that enhances the clearance of secretions and particles from the airways and protects the lower airways from the aspiration of foreign materials. Therapeutic suppression of cough may be either disease-specific or symptom related. The potential benefits of an early treatment of cough could include the prevention of the vicious cycle of cough. There has been a long tradition in acute cough, which is frequently due to upper respiratory tract infections, to use symptom-related anti-tussives. Suppression of cough (during chronic cough) may be achieved by disease-specific therapies, but in many patients it is often necessary to use symptomatic anti-tussives, too. According to the current guidelines of the American College of Chest Physician on "Cough Suppressants and Pharmacologic Protussive Therapy" and additional clinical trials on the most frequent anti-tussive drugs, it should be possible to diagnose and treat cough successfully in a majority of cases. Among drugs used for the symptomatic treatment of cough, peripherally acting anti-tussives such as levodropropizine and moguisteine show the highest level of benefit and should be recommended especially in children. By improving our understanding of the specific effects of these anti-tussive agents, the therapeutic use of these drugs may be refined. The present review provides a summary of the most clinically relevant anti-tussive drugs in addition to their potential mechanism of action.

Noscapine inhibits tumor growth in TMZ-resistant gliomas

Noscapine, a common oral antitussive agent, has been shown to have potent antitumor activity in a variety of cancers. Treatment of glioblastoma multiforme (GBM) with temozolomide (TMZ), its current standard of care, is problematic because the tumor generally recurs and is then resistant to this drug. We therefore investigated the effects of noscapine on human TMZ-resistant GBM tumors. We found that noscapine significantly decreased TMZ-resistant glioma cell growth and invasion. Using the intracranial xenograft model, we showed that noscapine increased survival of animals with TMZ-resistant gliomas. Thus noscapine can provide an alternative therapeutic approach for the treatment of TMZ-resistant gliomas.

Chemical diversity investigation of Stemona species using LC-MS technologies

Stemona species (Stemonaceae) are plant resources of traditional Chinese medicine 'baibu', which had long been used as antitussive and insecticidal agents. Stemona alkaloids, featuring a pyrrolo[1,2-α]azepine or pyrido[1,2-α]azepine nucleus, are believed to be responsible for their medicinal usages 1,2. Our previous work has let to the isolation of 90-plus alkaloids from different Stemona species. In our effort to identify alkaloidal constitutents from the extract of a Vietnamese species, an LC-MS method was established for a rapid and sensitive screening of the specific compounds 3. On the basis of more than 90 alkaloids, we established a MS database of all these reference compounds by UPLC/ESI-LTQ. By picking the specific peak in the LC chromatogram, extracting its MS, MS2 and MS3 spectra, and then comparing with those of the standard samples, we can do a rapid identification of main structures in the extract. Such technology was successfully applied for the chemical diversity investigation of three Stemona species – S. sessilifolia Franch. & Sav., S. japonica Franch. & Sav., and S. tuberosa Lour. The results revealed that the alkaloids varied greatly with species and habitats, but not with collecting seasons. S. tuberosa is the commonly-used species while having the most complicated metabolites which structural types were influenced extremely by ecological environment. S. sessilifolia growing in Tsuchou, Anhui province with the highest amount of the most active stemospironine, was determined to the best species for medicinal usage. All these data, combined with the pharmaceutical experiments, supplied the scientific evidence for guiding the usage of TCM baibu.

Simultaneous Determination of Dextromethorphan and Its Metabolite Dextrorphan in Plasma Samples Using Second-order Calibration Coupled with Excitation-Emission Matrix Fluorescence

Dextromethorphan (DEX) is an antitussive agent used in many cough and cold medications, and dextrorphan (DOR) is its metabolite. Owing to their similar structures, optimization of the condition for the chromatography approach, which is in common use for determination, is both demanding and time-consuming. This paper describes a methodology that combines excitation-emission matrix fluorescence spectra with second-order calibration, and was applied to simultaneously and directly determine DEX and DOR contents in plasma samples.

Pharmacologic therapy for cough

Cough is the commonest symptom for which patients seek medical care and yet effective, well-tolerated cough medicines remain a significant unmet clinical need. The development of anti-tussive agents has probably been restricted by a number of factors; our understanding of the specific mechanisms evoking cough in different diseases and how this differs from the role of cough as a protective reflex is limited. Also well-validated tools for the assessment of cough have been lacking. These issues have not encouraged investment by the pharmaceutical industry and there have been no new licensed treatments for cough in more than 50 years. This article will use a mechanism-based approach to discuss the clinical evidence for the anti-tussive activity of currently available agents.

The diethylaminoethoxyethyl ester of diethylphenylacetic acid; a new antitussive agent.

Abstract The preparation is described of some dialkylaminoethoxyethyl esters (X) of diethylphenylacetic acid and of some corresponding esters of l-phenylcycfopentane-l-carboxylic acid and 4-phenyltetrahydropyran-4-carboxylic acid. These were required for biological study which revealed that the diethylaminoethoxyethyl ester (X; R = R' = Et) of diethylphenylacetic acid (Oxeladin) was the most potent antitussive agent of the present series.

Cough: an unmet clinical need.

Cough is among the most common complaints for which patients worldwide seek medical attention. Thus, the evaluation and treatment of cough result in tremendous financial expenditure and consumption of health care resources. Yet, despite the clinical significance of cough, research efforts aimed at improving diagnostic capabilities and developing more effective therapeutic agents have been, to date, disappointing in their limited scope and outcomes. Acute cough due to the common cold represents the most common type of cough. Currently, available medications for the symptomatic management of acute cough are inadequate due to lack of proven efficacy and/or their association with undesirable or intolerable side effects at anti-tussive doses. Subacute cough, often representing a prolonged post-viral response, is typically refractory to standard anti-tussive therapy. Few clinical trials have evaluated therapeutic options for subacute cough. Diagnostic challenges facing the clinician in the management of chronic cough include the determination of whether symptoms of upper airway cough syndrome (formerly, postnasal drip syndrome) or gastro-oesophageal reflux disease are indeed the underlying cause of cough. Chronic, refractory unexplained (formerly, idiopathic) cough must be distinguished from cough that has not been fully evaluated and treated according to current guideline recommendations. Eagerly awaited are new safe and effective anti-tussive agents for use when cough suppression is desired, regardless of underlying aetiology of cough, as well as practical, validated ambulatory cough counters to aid clinical assessment and future research in the field of cough.

Pharmacokinetics of a novel liquid controlled release codeine formulation

Codeine is an important opioid anti-tussive agent whose short half-life (2.9 ± 0.7 h) requires that it be administered at 4-h intervals when formulated as a simple aqueous solution. Liquid controlled release codeine formulations such as an older Codipertussin® formulation, which contained codeine bound to an ion exchange resin and coated with a retardant polymer, achieved an equivalent bioavailability when administered every 12 h. An accompanying paper described the development and in vitro characterization of a novel Codipertussin® formulation containing a non-coated codeine:ion exchange resin (Amberlite IR 69 F) complex. In this study, the bioavailability of codeine from this new liquid controlled release formulation was investigated in an open label, single center, randomized, steady-state, cross-over study in healthy male volunteers. Participants received either 69.7 mg codeine as the controlled release liquid form every 12 h or 23.2 mg codeine in solution every 4 h. Controlled release from the suspension of beads protracted the apparent mean half life of codeine from 3.2 h to 8.2 h, while the mean AUC0–12 h was unchanged. In vivo codeine release profiles were further derived by the numerical deconvolution method, using the data from the drug solution as weighting function for the body system. Comparison of the data obtained with the in vitro release data presented in our earlier work showed an acceptable in vitro–in vivo correlation, which was described as in vitro–in vivo relationship, indicating the power of the in vitro method to predict in vivo pharmacokinetic behavior.

Cough Recording Technology

Cough sounds are readily identifiable by the human ear and therefore have the potential to be objectively quantified for the assessment of this common symptom. In recent years several systems for objectively measuring cough in ambulatory patients have been developed. Such objective measures are already providing insights into the mechanisms underlying coughing and the efficacy of novel and established anti-tussive agents. However, further development and validation is required to achieve accurate, fully automated cough detection systems applicable to large clinical trials and clinical practice. The aim of this review is to describe current cough recording and detection technologies, how these techniques have been applied in clinical studies and potential future developments.

Akute Bronchitis

Acute bronchitis is one of the most frequent diagnoses made by family doctors and occurs in circa 5% of adults per year, cumulating during winter and autumn. Diagnosis is made purely clinically. Predominant symptoms are cough, fever, headache and pain in the limbs as well as general malaise. It can be concluded that the underlying cause is usually a viral infection. Antibiotic therapy as a routine treatment is currently not recommended as it shortens the course of the disease only marginally. Treatment is purely symptomatical, with no evidence of the usefulness of mycolytic or antitussive agents. Patients who suffer from obstruction may benefit from beta-mimetics. If symptoms last longer than three weeks, other diseases should be taken into consideration. The main differential diagnosis is pneumonia. It should be taken into account that patients show an increased prevalence for developing chronic bronchitis or bronchial asthma.

Dextromethorphan reduced fentanyl induced cough and stress hormones release. A randomized double blind controlled study

BackgroundThe previous reports demonstrated variable changes in stress hormones profile when different NMDA receptor antagonists were administered and this study traced the effect of dextromethorphan premedication as an NMDA antagonist on postoperative neuroendocrine response. As dextromethorphan is a known central antitussive agent, this study also evaluated its effect on fentanyl induced cough reflex.MethodsSixty female patients ASA class I, undergoing posterior vaginal repair surgeries under general anesthesia were studied. Patients were allocated to one of two groups: Dextromethorphan group in which the patients received oral dextromethorphan 60 mg and Placebo group in which the patients received 20 ml of water for injection orally 60 min prior to surgery. The incidence of cough was calculated following fentanyl 2 μg/kg administration and the severity was assessed by using cough assessment scale. Stress hormones were collected before surgery and again at 1 and 12 h postoperatively and compared. The appearance of adverse reactions was reported.ResultsThe incidence of reflex fentanyl cough was lower in dextromethorphan group 13% (4 patients) in comparison to placebo 36% (11 patients). Two patients developed mild and two moderate forms in the DEX group in relation to six mild, four moderate, and one severe cough form in the control group. The stress hormones were significantly higher at 1 and 12 h postoperatively in both groups in comparison to its preoperative values. However, at 1 h postoperatively, ACTH, epinephrine, and growth hormone values were significantly low in the dextromethorphan group (59.5 ± 21.7 pg/ml, 144.4 ± 11.4 pg/ml, and 3.7 ± 0.8 ng/ml, respectively) relative to the control group (72.2 ± 21.9 pg/ml, 159.6 ± 19.7 pg/ml, and 4.4 ± 1.2 ng/ml, respectively) but these changes became insignificant at 12 h.ConclusionPremedication with 60 mg dextromethorphan reduced the rise in stress hormones at 1 h postoperatively. Also, the use of dextromethorphan decreased the incidence and severity of fentanyl induced cough.

Effect of viral upper respiratory tract infection on the urge-to-cough sensation

Recently, interest has emerged in the sensation of irritation that precedes the motor act of coughing; this phenomenon has been termed the urge-to-cough (UTC). Although one previous study has demonstrated a transient enhancement of cough reflex sensitivity during acute upper respiratory tract infection (URI), the effect of URI on UTC has not previously been investigated. Employing standard cough challenge methodology, we measured cough reflex sensitivity in 24 otherwise healthy adult nonsmokers during URI and again after recovery (4-8 weeks later) by determining C(2) and C(5), the concentrations of capsaicin inducing 2 or more and 5 or more coughs, respectively. In addition, we determined the capsaicin concentration at which the UTC sensation first occurred, without an associated motor cough, and termed it C(u). Furthermore, we determined the difference between concentrations of capsaicin inducing the first motor event of cough (C(1)) and C(u), and have termed it C(Δ). During URI, cough reflex sensitivity as measured by C(1) (p = 0.033) and C(5) (p = 0.001), as well as the urge-to-cough threshold, C(u) (p = 0.046), were significantly enhanced compared to the post-recovery state. The degree of change in cough reflex sensitivity (C(5)) was significantly greater than that of the urge-to-cough threshold, C(u) (p = 0.044). Our results demonstrate that the UTC sensation is transiently enhanced during URI. We also confirm the results of the lone previous study that demonstrated transient enhancement of cough reflex sensitivity during URI. The UTC threshold may represent an additional relevant end point to measure in future studies evaluating potential antitussive agents.

Possible involvement of tetrodotoxin-resistant sodium channels in cough reflex

We examined the involvement of tetrodotoxin (TTX)-resistant sodium channels in the peripheral mechanisms of the cough reflex in mice. We also examined the possibility of using ambroxol as an effective antitussive agent, and found that it produced antitussive effects through the inhibition of TTX-resistant sodium channels. The inhalation of fenvalerate, at concentrations of 0.3, 1 and 3 μg/ml, for 5 min produced coughs in a concentration-dependent manner. Pretreatment with tetrodotoxin, at a dose of 1 μg/kg, s.c., slightly but significantly reduced the number of fenvalerate (3 μg/ml)-induced coughs. However, the number of fenvalerate-induced coughs in tetorodotoxin-treated mice was still significantly greater than those in vehicle (0.4% DMSO) alone inhaled mice. On the other hand, pretreatment with tetrodotoxin, at a dose of 1 μg/kg, s.c., almost completely reduced the number of citric acid (0.25 M)-induced coughs to the level in vehicle (saline) alone inhaled mice. Pretreatment with ambroxol, at doses of 10, 30, 100 and 300 mg/kg, p.o., dose-dependently and significantly reduced the number of fenvalerate (3 μg/ml)-induced coughs. The present findings indicate that TTX-resistant sodium channels may play an important role in the enhancement of C-fiber-mediated cough pathways. Furthermore, ambroxol may prove to be a useful cough suppressant.

Suppressive effect of pectic polysaccharides from Cucurbita pepo L. var. Styriaca on citric acid-induced cough reflex in guinea pigs

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.