Treatment Of Obstructive Airway Disease Research Articles

Inhaled RNA Therapeutics for Obstructive Airway Diseases: Recent Advances and Future Prospects.

Obstructive airway diseases, e.g., chronic obstructive pulmonary disease (COPD) and asthma, represent leading causes of morbidity and mortality worldwide. However, the efficacy of currently available inhaled therapeutics is not sufficient for arresting disease progression and decreasing mortality, hence providing an urgent need for development of novel therapeutics. Local delivery to the airways via inhalation is promising for novel drugs, because it allows for delivery directly to the target site of action and minimizes systemic drug exposure. In addition, novel drug modalities like RNA therapeutics provide entirely new opportunities for highly specific treatment of airway diseases. Here, we review state of the art of conventional inhaled drugs used for the treatment of COPD and asthma with focus on quality attributes of inhaled medicines, and we outline the therapeutic potential and safety of novel drugs. Subsequently, we present recent advances in manufacturing of thermostable solid dosage forms for pulmonary administration, important quality attributes of inhalable dry powder formulations, and obstacles for the translation of inhalable solid dosage forms to the clinic. Delivery challenges for inhaled RNA therapeutics and delivery technologies used to overcome them are also discussed. Finally, we present future prospects of novel inhaled RNA-based therapeutics for treatment of obstructive airways diseases, and highlight major knowledge gaps, which require further investigation to advance RNA-based medicine towards the bedside.

Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator

BackgroundNavafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β2-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma.MethodsThis was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50–2100 μg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1 s (FEV1) for each treatment period.ResultsSixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache (n = 10, 62.5%) and nasopharyngitis (n = 7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5 min post-dose). Doses ≥200 μg resulted in improvements in trough FEV1 (mean change from baseline range 0.186–0.463 L) with sustained bronchodilation for 24–36 h. Plasma concentrations increased in a dose-proportional manner, peaking ~ 1 h post-dose, with a derived terminal elimination half-life of 15.96–23.10 h.ConclusionsIn this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36 h.Trial registrationClinicalTrials.gov; No.: NCT02573155

Tiotropium in asthma: From bench to bedside.

Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended as add-on treatment for uncontrolled asthma despite treatment with inhaled corticosteroids and/or long-acting beta-2 agonists. This review traces the journey of tiotropium from its historical origins through early preclinical testing to human clinical trials and real-life studies. A search was performed in PubMed using search terms 'tiotropium' and 'asthma.' Relevant references cited in those articles were reviewed. English language articles published from December 2008-December 2018 were screened. Articles evaluating the efficacy, cost-effectiveness, real-life evidence, and steroid-sparing effect of tiotropium with inadequately controlled asthma were included. Anticholinergics have a long history of use in the treatment of obstructive airway diseases. Evidence indicates that tiotropium's mechanism of action consists of bronchodilation and diminished mucus secretion, with preclinical evidence suggesting an anti-inflammatory effect as well. Phase 2 and 3 clinical trials have demonstrated that tiotropium is efficacious and safe, resulting in significant improvements in lung function in adults, adolescents, and children across asthma severities. Emerging evidence suggests that add-on tiotropium might potentially enable reductions in inhaled corticosteroid dose in patients with uncontrolled asthma. Further, tiotropium is a cost-effective treatment option that is also effective in the clinical practice setting. An increasing body of evidence indicates that tiotropium can play a significant role in the treatment of patients with uncontrolled asthma.

Soft TCPTP Agonism-Novel Target to Rescue Airway Epithelial Integrity by Exogenous Spermidine.

A reparative approach of disrupted epithelium in obstructive airway diseases, namely asthma and chronic obstructive pulmonary disease (COPD), may afford protection and long-lasting results compared to conventional therapies, e.g., corticosteroids or immunosuppressant drugs. Here, we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. It may include and surpass single-inhibitors of stress and secondary growth factor pathway signaling, i.e., the new medicinal chemistry in lung diseases. Enhanced polyamine biosynthesis has been charged with aggravating prognosis by competing for L-arginine at detriment of nitric oxide (NO) synthesis with bronchoconstrictive effects. Although excess spermine, a higher polyamine, is harmful to airways physiology, spermidine can pivot the cell homeostasis during stress conditions by the activation of TCPTP. In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. Moreover, a further beneficial effect of spermidine may derive from its ability to promote autophagy, possibly in a TCPTP-dependent way. Since doses of spermidine in the micromolar range are sufficient to activate TCPTP, low amounts of spermidine administered in sustained release modality may provide an optimal pharmacologic profile for the treatment of obstructive airway diseases.

The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease

Muscarinic receptor antagonists and β-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and β-adrenoceptors are physiological antagonists for smooth muscle tone in airways and bladder. Muscarinic agonism may attenuate β-adrenoceptor-mediated relaxation more than other contractile stimuli. Chronic treatment with one drug class may regulate expression of the target receptor but also that of the opposing receptor. Prejunctional β2-adrenoceptors can enhance neuronal acetylcholine release. Moreover, at least in the airways, muscarinic receptors and β-adrenoceptors are expressed in different locations, indicating that only a combined modulation of both systems may cause dilatation along the entire bronchial tree. While all of these factors contribute to a rationale for a combination of muscarinic receptor antagonists and β-adrenoceptor agonists, the full value of such combination as compared to monotherapy can only be determined in clinical studies.

Computed Tomography-Guided Tissue Engineering of Upper Airway Cartilage

Normal laryngeal function has a large impact on quality of life, and dysfunction can be life threatening. In general, airway obstructions arise from a reduction in neuromuscular function or a decrease in mechanical stiffness of the structures of the upper airway. These reductions decrease the ability of the airway to resist inspiratory or expiratory pressures, causing laryngeal collapse. We propose to restore airway patency through methods that replace damaged tissue and improve the stiffness of airway structures. A number of recent studies have utilized image-guided approaches to create cell-seeded constructs that reproduce the shape and size of the tissue of interest with high geometric fidelity. The objective of the present study was to establish a tissue engineering approach to the creation of viable constructs that approximate the shape and size of equine airway structures, in particular the epiglottis. Computed tomography images were used to create three-dimensional computer models of the cartilaginous structures of the larynx. Anatomically shaped injection molds were created from the three-dimensional models and were seeded with bovine auricular chondrocytes that were suspended within alginate before static culture. Constructs were then cultured for approximately 4 weeks post-seeding and evaluated for biochemical content, biomechanical properties, and histologic architecture. Results showed that the three-dimensional molded constructs had the approximate size and shape of the equine epiglottis and that it is possible to seed such constructs while maintaining 75%+ cell viability. Extracellular matrix content was observed to increase with time in culture and was accompanied by an increase in the mechanical stiffness of the construct. If successful, such an approach may represent a significant improvement on the currently available treatments for damaged airway cartilage and may provide clinical options for replacement of damaged tissue during treatment of obstructive airway disease.

The Influences of Low BMI On the Treatment of Fixed Airway Obstruction

T U E S D A Y 733 The Influences of Low BMI On the Treatment of Fixed Airway Obstruction June-Hyuk Lee, Sung-Woo Park, MD, Dojin Kim, Ansoo Jang, MD; Soonchunhyang univ bucheon hospital, Soonchunhyang Univ. Hospital, Bucheon, Soon Chum Hyang University Hospital, Bucheon. RATIONALE: Body mass index(BMI) has been thought to be associated with development or treatment of obstructive airway disease. HighBMI, so called obesity, was associated with the severity of asthma or extent of emphysematous change. But, it has not been known the effect of low BMI on obstructive lung disease. We tried to evaluate the influence of low BMI on fixed airway obstruction. METHODS: 245 patients with fixed airway obstruction were enrolled. The levels of BMI of all subjects were less than 18. Subjects were classified into grade according to FEV1. RESULTS: Absolute values of BMI were significantly associated with the degree of airway obstruction and also significantly associated with lung function. The subjects who have high grade of fixed airway obstruction showed significantly more frequent(P 5 0.02) and longer duration of hospitalizaion(P5 0.007). CONCLUSIONS: Low BMI has an influence on hospitalization for the patient with fixed airway obstruction.

Safety and Tolerability of Fel d 1-Derived Peptide Antigen Desensitization in Subjects with Controlled Asthma

T U E S D A Y 733 The Influences of Low BMI On the Treatment of Fixed Airway Obstruction June-Hyuk Lee, Sung-Woo Park, MD, Dojin Kim, Ansoo Jang, MD; Soonchunhyang univ bucheon hospital, Soonchunhyang Univ. Hospital, Bucheon, Soon Chum Hyang University Hospital, Bucheon. RATIONALE: Body mass index(BMI) has been thought to be associated with development or treatment of obstructive airway disease. HighBMI, so called obesity, was associated with the severity of asthma or extent of emphysematous change. But, it has not been known the effect of low BMI on obstructive lung disease. We tried to evaluate the influence of low BMI on fixed airway obstruction. METHODS: 245 patients with fixed airway obstruction were enrolled. The levels of BMI of all subjects were less than 18. Subjects were classified into grade according to FEV1. RESULTS: Absolute values of BMI were significantly associated with the degree of airway obstruction and also significantly associated with lung function. The subjects who have high grade of fixed airway obstruction showed significantly more frequent(P 5 0.02) and longer duration of hospitalizaion(P5 0.007). CONCLUSIONS: Low BMI has an influence on hospitalization for the patient with fixed airway obstruction.

Penehyclidine hydrochloride: a potential drug for treating COPD by attenuating Toll-like receptors

BackgroundThe aim of this review was to evaluate and summarize the available scientific information on penehyclidine hydrochloride (PHC) for the treatment of chronic obstructive pulmonary disease (COPD) as a result of its ability to attenuate Toll-like receptors. Penehyclidine hydrochloride is an anticholinergic drug manufactured in China, with both antimuscarinic and antinicotinic activity. PHC is used widely in the clinic as a reversal agent in cases of organic phosphorus poisoning and soman poisoning, but also may also have an important role as a bronchodilator in the treatment of obstructive airway disease, including asthma and, in particular, COPD.MethodsOur bibliographic sources included the CAPLUS, MEDLINE, REGISTRY, CASREACT, CHEMLIST, CHEMCATS, and CNKI databases, updated to September 2012. In order to assess the data in detail, we used the search terms “penehyclidine hydrochloride,” “COPD,” “muscarinic receptor,” and “toll-like receptors.” Papers were restricted to those published in the English and Chinese languages, and to “paper” and “review” as the document type. Patents were also reviewed.ResultsOur survey mainly yielded the results of research on PHC and the mechanisms of COPD. COPD is a preventable and treatable disease with some significant extrapulmonary manifestations that may contribute to its severity in some patients. Recently, it has been shown that muscarinic receptors may interact with Toll-like receptors. Basic and clinical studies of the relationship between the mechanism of action and the effects of PHC in the respiratory tract have been studied by a number of laboratories and institutions. The main advantages of PHC are that it has few M2 receptor-associated cardiovascular side effects and attenuates Toll-like receptors.ConclusionPHC may be a promising candidate agent in the treatment of COPD in the future because of its ability to attenuate Toll-like receptors. This review should be of help to those intending to research this topic further.

Pharmaceutical aerosols for the treatment and prevention of Tuberculosis

Historically, pharmaceutical aerosols have been employed for the treatment of obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease, but in the past decades their use has been expanded to treat lung infections associated with cystic fibrosis and other respiratory diseases. Tuberculosis (TB) is acquired after inhalation of aerosol droplets containing the bacilli from the cough of infected individuals. Even though TB affects other organs, the lungs are the primary site of infection, which makes the pulmonary route an ideal alternative route to administer vaccines or drug treatments. Optimization of formulations and delivery systems for anti-TB vaccines and drugs, as well as the proper selection of the animal model to evaluate those is of paramount importance if novel vaccines or drug treatments are to be successful. Pharmaceutical aerosols for patient use are generated from metered dose inhalers, nebulizers, and dry powder inhalers (DPIs). In addition to the advantages of providing more efficient delivery of the drug, low cost, and portability, pharmaceutical dry powder aerosols are more stable than inhalable liquid dosage forms and do not require refrigeration. Methods to manufacture dry powders in respirable sizes include micronization, spray drying, and other proprietary technologies. Inhalable dry powders are characterized in terms of their drug content, particle size, and dispersibility to ensure deposition in the appropriate lung region and effective aerosolization from the device. These methods will be illustrated as they were applied for the manufacture and characterization of powders containing anti-tubercular agents and vaccines for pulmonary administration. The influence of formulation, selection of animal model, method of aerosol generation, and administration on the efficacy demonstrated in a given study will be illustrated by the evaluation of pharmaceutical aerosols of anti-TB drugs and vaccines in guinea pigs by our group.

How Can 1 + 1 = 3? β2-Adrenergic and Glucocorticoid Receptor Agonist Synergism in Obstructive Airway Diseases: Fig. 1.

For a long time it was believed that β(2)-adrenergic receptor agonists used in the treatment of obstructive airway diseases worked primarily on airway smooth muscle cells, causing relaxation, whereas glucocorticoids primarily improved airway function via their anti-inflammatory action, indicating that their clinical synergism occurred at the organism rather than the cellular level. However, it is now becoming clear that both drug classes can affect airway function at multiple levels, including an integrated effect on several cell types. This article summarizes data on the molecular interaction between the two receptor systems, particularly with relevance to phenomena of β(2)-adrenergic receptor desensitization and glucocorticoid insensitivity in the airways. These molecular interactions may contribute to the observed clinical synergism between both drug classes in the treatment of obstructive airway diseases.

Bronchodilator activity of bitter tastants in human tissue

Bronchodilator activity of bitter tastants in human tissue

Epac as a novel effector of airway smooth muscle relaxation

Dysfunctional regulation of airway smooth muscle tone is a feature of obstructive airway diseases such as asthma and chronic obstructive pulmonary disease. Airway smooth muscle contraction is directly associated with changes in the phosphorylation of myosin light chain (MLC), which is increased by Rho and decreased by Rac. Although cyclic adenosine monophosphate (cAMP)-elevating agents are believed to relieve bronchoconstriction mainly via activation of protein kinase A (PKA), here we addressed the role of the novel cAMP-mediated exchange protein Epac in the regulation of airway smooth muscle tone. Isometric tension measurements showed that specific activation of Epac led to relaxation of guinea pig tracheal preparations pre-contracted with methacholine, independently of PKA. In airway smooth muscle cells, Epac activation reduced methacholine-induced MLC phosphorylation. Moreover, when Epac was stimulated, we observed a decreased methacholine-induced RhoA activation, measured by both stress fibre formation and pull-down assay whereas the same Epac activation prevented methacholine-induced Rac1 inhibition measured by pull-down assay. Epac-driven inhibition of both methacholine-induced muscle contraction by Toxin B-1470, and MLC phosphorylation by the Rac1-inhibitor NSC23766, were significantly attenuated, confirming the importance of Rac1 in Epac-mediated relaxation. Importantly, human airway smooth muscle tissue also expresses Epac, and Epac activation both relaxed pre-contracted human tracheal preparations and decreased MLC phosphorylation. Collectively, we show that activation of Epac relaxes airway smooth muscle by decreasing MLC phosphorylation by skewing the balance of RhoA/Rac1 activation towards Rac1. Therefore, activation of Epac may have therapeutical potential in the treatment of obstructive airway diseases.

Diode Laser in the Endoscopic Treatment of Obstructive Airway Disease: Two Years Experience in Istanbul

Laser therapy is a well-known technique which has been safely used for almost thirty years to treat endobronchial obstruction. Nd : YAG and Nd : YAP lasers are commonly used lasers, whose safety and efficacy have been investigated in several large series. Diode laser is a new laser system which has been mainly used in urology, endovascular surgery, ENT, and dermatology. In recent years it has been effectively used in endobronchial treatments. In this study, 61 patients who underwent endobronchial treatment with a diode laser in the Interventional Pneumology Unit of our hospital were retrospectively evaluated. Fifty-one patients were male. Mean age was 54.72 ± 13.81 years, and a total of 90 laser applications were given. In 39 cases, palliation of a malign obstruction was achieved while cure was achieved in 19 cases with benign obstruction. No major complication other than minor hemorrhage in 4 cases and temporary hypoxia in 2 cases was observed. Diode laser can be used as an effective and safe modality for endobronchial treatment.

Retail sales of inhalation devices in European countries: So much for a global policy

To evaluate the retail sales of pressurised metered-dose inhalers (pMDIs), dry-powder inhalers (DPIs) and liquids for nebulisation in 16 European countries. Retail sales data relating to pMDIs, DPIs and liquids for nebulisation delivering short- and long-acting bronchodilators, corticosteroids and combinations between 2002 and 2008 were obtained from the IMS sales database. The IMS database ensured that wholesalers' stock sales accurately matched that of retail pharmacies and included purchases by panel pharmacies directly from pharmaceutical manufacturers, specialist wholesalers and distribution cooperatives. Mean inhaler retail sales (expressed as percentages of total sales) were 47.5% for pMDIs, 39.5% for DPIs and 13% for nebulisers. The distribution of inhaler sales differed significantly between the countries with pMDI sales greatest in the United Kingdom and Hungary compared to other countries, where DPI sales prevailed. Sales of nebulisation liquids were high in Italy. The pMDI was the most frequently prescribed inhaler for bronchodilators. In contrast, retail sales of DPIs were similar to those of pMDIs for inhaled corticosteroids, and higher in the case of inhalers with combined long-acting β(2)-agonist and corticosteroid. We found a high degree of variability in inhaler prescription between European countries. Differing health policies, costs, health insurance issues, pharmaceutical/commercial aspects and prescribers' and patients' preferences may explain this variation. We suggest a need for more uniform, outcome-led inhaler prescribing practice across Europe to improve the efficacy and cost effectiveness of the treatment of obstructive airways diseases.

Epac as a novel relaxant factor in airway smooth muscle

Obstructive airway diseases are characterized by airway narrowing and progressive lung function decline. Elevations of cAMP by β2‐adrenoceptors reverse airway smooth muscle contraction, a process classically assigned to protein kinase A (PKA). Here we report on a novel cAMP mechanism which regulates airway smooth muscle relaxation. Specific activation of Epac (exchange protein directly activated by cAMP) relaxes pre‐contracted guinea pig tracheal open‐rings independent of PKA. Importantly, human airway smooth muscle also expresses Epac and activated Epac relaxes pre‐contracted human airway smooth muscle. Contraction of smooth muscle cells is believed to depend on Rho/Rac balancing. Regulation of cytoskeleton dynamics by Rho increases myosin light chain (MLC) phosphorylation and stress fiber formation, whereas activation of Rac has the opposite effect. Toxin B‐1470‐inhibited Rac1 attenuated in guinea pig tracheal rings Epac‐mediated airway smooth muscle relaxation, suggesting a key role for Rac1 in the relaxing properties of Epac. Indeed, activation of Epac induced GTP‐loading Rac1 and minimized metacholine‐induced stress fiber formation and MCL phosphorylation in airway smooth muscle. We identify Epac as a novel relaxing factor in airway smooth muscle, most likely by shifting the Rho/Rac balance towards Rac1. Therefore, activation of Epac may have therapeutical potential in the treatment of obstructive airway diseases.

Influence of the saponins from Hedera helix on the β2-adrenergic responsiveness of living cells investigated by β2-adrenergic receptor internalization studies and determination of intracellular cAMP levels

α-Hederin, hederacoside C and hederagenin are saponins of dry extracts obtained from ivy leaves (Hedera helix L.). These extracts are used in the treatment of obstructive airway diseases characterized by hypersecretion of viscous mucus and coughing. Based on spirometric and plethysmographic measurements, clinical relevant improvements in lung function have been observed, and statistically significant efficacy of a dried ivy leaf extract (5–7,5 : 1) has been shown [1]. Moreover, ivy leaf extracts show spasmolytic activity, reducing smooth muscle spasm in vitro [2], as well as bronchodilatory effects shown in a study with asthmatic patients [1], which, as we know today, is mainly due to their triterpene saponin content.

Erratum to: Indacaterol, a novel inhaled, once-daily, long-acting beta2-agonist for the treatment of obstructive airways diseases

Erratum to: Indacaterol, a novel inhaled, once-daily, long-acting beta2-agonist for the treatment of obstructive airways diseases

The overlap syndrome of asthma and COPD: what are its features and how important is it?

There is a need to re-evaluate the concept of asthma and chronic obstructive pulmonary disease (COPD) as separate conditions, and to consider situations when they may coexist, or when one...

Indacaterol, a novel inhaled, once-daily, long-acting beta2-agonist for the treatment of obstructive airways diseases

Indacaterol is a novel once-daily, long-acting beta(2)-agonist developed for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. The present review summarizes the preclinical and clinical data of indacaterol, including recent data from phase II and III trials. These clinical studies suggest that indacaterol produces rapid and sustained bronchodilation in patients with COPD, and asthma of different severities. Until now, clinical studies of up to 1-year's duration have been at least partially published, which have confirmed the suitability of indacaterol for once-daily dosing, along with a favorable overall safety and tolerability profile in the long-term treatment of COPD. Data on relevant outcomes in asthma are more limited, especially with regard to chronic treatment. Therefore, it appears that indacaterol monotherapy will have its therapeutic potential primarily in COPD, where anti-inflammatory treatment is not fully established and issues about a potential risk of long-acting beta(2)-agonist use causing increased mortality have not been raised. As data from more advanced clinical trials have been published, a more complete picture of the full therapeutic potential of indacaterol in COPD has emerged, including patient-reported outcomes (eg, symptoms and quality of life) or additional pivotal outcomes (eg, exacerbation rates, disease progression, exercise capacity, and the development of hyperinflation). Finally, the pharmacological profile of indacaterol makes it an attractive partnering agent for future fixedcombination therapies in both asthma and COPD, eg, with once-daily inhaled corticosteroids or long-acting antimuscarinergic bronchodilators. The outlook and potential of indacaterol are further discussed.