Nitric oxide synthase (NOS) as therapeutic target for asthma and chronic obstructive pulmonary disease

In the respiratory tract, NO is produced by residential and inflammatory cells. NO is generated via oxidation of L-arginine that is catalysed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) are able to modulate bronchomotor tone. NO derived from the inducible isoform of NO synthase, up-regulated by different cytokines via NF-kappaB-dependent pathway, seems to be a pro-inflammatory mediator with immunomodulatory effects. The production of NO under oxidative stress conditions secondarily generates strong oxidising agents (reactive nitrogen species) that may amplify the inflammatory response in asthma and COPD. Moreover, NO can be exhaled and levels are abnormal in stable atopic asthma and during exacerbations in both asthma and COPD. Exhaled NO might therefore be a non-invasive tool to monitor the underlying inflammatory process. It is suggested that NOS regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways such as asthma and COPD.     

Interleukin-9 as a possible therapeutic target in both asthma and chronic obstructive airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are important causes of morbidity and mortality worldwide. Both asthma and COPD are characterized by airflow limitation but distinct differences occur in the pulmonary inflammatory responses in the two conditions. Treatment options for asthma and COPD are limited (especially so for COPD), and both are in need of novel therapeutic interventions. Interleukin-9 (IL-9) is a potential target for such a therapy. This Th2-type cytokine, is secreted by a number of different cell types, and has multiple effects on a wide range of cells within the lung. In this review we will summarize current knowledge about the immunobiology of IL-9 and discuss the role played by IL-9 in inflammation in both asthma and COPD, and its potential as a therapeutic target.     

Evaluating revefenacin as a therapeutic option for chronic obstructive pulmonary disease

ABSTRACT

Introduction

In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option.     

Oligonucleotides: New therapeutic approaches for asthma and chronic obstructive pulmonary disease

Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases. There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action. Oligonucleotides may be divided in two groups based on their main mechanism of action: (i) RNA-targeting; and (ii) protein-targeting. Antisense oligonucleotides and siRNAs, both of which belong to the RNA-targeting group, and the immunostimulatory sequence-based drugs, which are members of the protein-targeting group, are progressing through clinical trials. In principle, the development of these agents is facilitated by a series of significant advantages, such as those associated with delivery to the lung via inhalation, and targeting to the site of action, resulting in reduced levels of systemic exposure. Although no oligonucleotide-based drug has been approved for the treatment of asthma or COPD, this class of compounds holds significant promise in the treatment of these two diseases. Several oligonucleotide drug candidates have been evaluated in the clinic with no significant adverse safety findings, while clinical proof of concept based on short-term inhalation protocols in challenge models in humans has also been established.     

Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an increasing global health problem for which there are no effective disease-modifying therapies. COPD involves chronic inflammation of small airways and lung parenchyma, with the recruitment of inflammatory cells. This inflammatory-cell trafficking is orchestrated by multiple chemokines, so the blockade of chemokine receptors with selective antagonists might be an effective anti-inflammatory strategy in this disease. Several studies support the implication of several chemokines and their receptors in COPD, including chemokine receptors CXCR2 and CXCR3, with small-molecule receptor antagonists that are in development being potential anti-inflammatory therapies. Such a pharmacological strategy would provide a mechanism with which to inhibit leukocyte recruitment and, hence, reduce the inflammatory profile in COPD, which is currently unaffected by pharmacotherapy.     

Emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are disorders of the airways largely related to the presence of persistent inflammation. The approval of inhaled corticosteroids in the early 1970s pioneered a new age of therapy in treating chronic inflammatory airway diseases. This was the first time that an anti-inflammatory product was available to reduce the characteristic lung inflammation in airways and the associated obstruction, inflammation and hyper-responsiveness. Fast forward 40 years: corticosteroids are still an important therapeutic intervention; however, they exhibit limited use in moderate to severe asthma and COPD. Oligonucleotide therapies are an emerging class which include the antisense, the RNAi (siRNA and miRNA), the immunomodulatory, the aptamer and the decoy approaches. As these approaches are rather recent in the respiratory field, most are still early in development. Nevertheless, with limitations of current small molecule therapies and the hurdles faced with biologics, the use of oligonucleotides is relevant and the door is open to the development of this category of therapeutics. This review focuses on the major classes of oligonucleotides that are currently in late stage preclinical or clinical development for the treatment of asthma and COPD, and discusses the implications for their use as therapies for respiratory diseases.     

Modulation of nitric oxide pathways: therapeutic potential in asthma and chronic obstructive pulmonary disease

Nitric oxide (NO) is present in the exhaled breath of humans and other mammalian species. It is generated in the lower airways by enzymes of the nitric oxide synthase (NOS) family, although nonenzymatic synthesis and consumptive processes may also influence levels of NO in exhaled breath. The biological properties of NO in the airways are multiple, complex, and bidirectional. Under physiological conditions, NO appears to play a homeostatic bronchoprotective role. However, its proinflammatory properties could also potentially cause tissue injury and contribute to airway dysfunction in disease states such as asthma and chronic obstructive pulmonary disease (COPD). This article will review the physiological and pathophysiological roles of NO in the airways, discuss the rationale for the use of drugs that modulate NO pathways--nitric oxide synthase inhibitors and NO donors--to treat inflammatory airway diseases, and attempt to predict the likely therapeutic benefit of such agents.     

慢性阻塞性肺疾病治疗药物的心血管安全性

慢性阻塞性肺疾病(COPD)患者常伴发心血管疾病。吸入性长效肾上腺素β_2受体激动剂(LABA)、长效M受体阻滞剂(LAMA)是COPD稳定期管理的重要组成部分。目前普遍认为吸入性药物的安全性较高,但有研究指出COPD治疗药物可能存在潜在的罕见心血管不良风险,且部分COPD药物安全性研究试验存在缺陷,因此文章回顾了目前COPD稳定期的常用药物对心血管系统的影响,包括大环内酯类抗生素。     

从慢性阻塞性肺疾病全球倡议治疗目标谈慢性阻塞性肺疾病急性加重的抗菌治疗

慢性阻塞性肺疾病(慢阻肺)是一种可防可治的常见疾病,其特征为持续存在的呼吸道症状和气流受限,通常由有害颗粒或气体暴露引起的气道和(或)肺泡异常而导致。我国是慢阻肺高患病率、高致残率、高负担国家。慢阻肺急性加重(acute exacerbation of chronic obstructive pulmonary disease,AECOPD)是指慢阻肺自然病程中出现的急性事件,特征为呼吸困难、咳嗽和(或)咳痰加重,超越了日常状况的变化,且提示需要改变常规用药。慢阻肺急性加重是增加医疗负担和导致死亡的主要因素,慢阻肺急性加重频繁发作会对患者的生活质量、疾病进展、死亡率、医疗费用产生重大影响。感染是导致AECOPD最常见诱因,对急性加重患者选择合适的抗菌药物,对治疗效果和预后起着至关重要的作用。2019年慢性阻塞性肺疾病全球倡议(global initiative for chronic obstructive lung disease,GOLD)报告明确提出慢阻肺急性加重期的治疗目标是使本次急性加重影响最小化,并预防未来急性加重的发生。本文依据近年来循证医学证据,从GOLD治疗目标谈抗菌药物在慢阻肺急性加重治疗中的应用,以便优化临床对AECOPD的管理。     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. Beta-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. β-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease

Phosphodiesterase (PDE)4, and to a lesser extent, PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for diseases including chronic obstructive pulmonary disease. Indeed, ibudilast and theophylline are utilized clinically, and roflumilast is in late-stage clinical development. Unfortunately, however many PDE4 and dual PDE3/4 inhibitors have failed in early development due to low therapeutic ratios. The majority of these compounds are however orally administered and non-selective for either PDE3(A, B) or PDE4(A, B, C, D) subtypes. Developing an inhaled dual PDE3/4 inhibitor with subtype specificity may represent one strategy to improve the therapeutic index. Indeed combined inhibition of PDE3 and PDE4 inhibitor has additive and synergistic anti-inflammatory and bronchodilatory effects versus inhibition of either PDE3 or PDE4 alone. Given that synergy has been seen in terms of efficacy end points, an obvious concern is that synergy may also be observed in side effects. Interestingly, however, no synergy or additive effects with a combination of a PDE3 and PDE4 inhibitor in a cardiomyocyte assay were observed. This review will summarize the rationale for developing an inhaled dual PDE3/4 inhibitor, as a treatment for chronic obstructive pulmonary disease together with recent advances in trying to understand the pathogenesis of PDE inhibitor-induced mesenteric vasculitis (a key potential dose-limiting side effect of these agents), highlighting potential early and sensitive predictive biomarkers.     

治疗慢性阻塞性肺病新药阿地溴铵

阿地溴铵是一种吸入、长效、选择性毒蕈碱性胆碱能受体拮抗剂(M受体拮抗剂),用于慢性阻塞性肺病(COPD)引起的支气管痉挛的维持治疗。研究显示阿地溴铵能明显改善患者的COPD症状,且安全、耐受性好,不良反应少。现对其药效学、药动学及临床研究等做一综述。     

治疗慢性阻塞性肺疾病的新药——噻托溴胺

慢性阻塞性肺疾病(COPD)是一种由气道和肺实质的慢性炎症引起的进行性通气受限的综合征.COPD主要生理学异常是一秒钟用力呼气容积(FEV1)加速下降,下降速度由正常时的大约30 ml/年加重到60 ml/年,同时呼吸问卷调查(SGRQ)生活质量评分也降低.     

Targeting cellular senescence as a new approach to chronic obstructive pulmonary disease therapy

Increasing evidence suggests that there is acceleration of normal lung ageing in chronic obstructive pulmonary disease (COPD), with the accumulation of senescent cells in the lung, which release an array of inflammatory proteins, which drive further senescence and disease progression. This suggests that drugs that target cellular senescence (senotherapies) may treat the underlying disease process in COPD and reduce disease progression and mortality. Several existing or future drugs may inhibit the development of cellular senescence, which is driven by chronic oxidative stress (senostatics), whereas other drugs selectively remove senescent cells (senolytics). Clinical studies of senotherapies have commenced in several age-related diseases, and these approaches appear to be safe and feasible, although no clinical studies in COPD patients have yet been reported.     

ADAM8: a new therapeutic target for asthma

Background: A proteinase with a disintegrin and a metalloproteinase domain-8 (ADAM8) has been linked to asthma. Objective: To explore whether ADAM8 is a therapeutic target for asthma. Methods: We reviewed literature on ADAM8's function and expression and activities in lungs of humans and mice with allergic airway inflammation (AAI). We used these data to generate hypotheses about the contributions of ADAM8 to asthma pathogenesis. Conclusions: ADAM8 levels are increased in airway epithelium and airway inflammatory cells in mice with AAI and human asthma patients. Data from murine models of AAI indicate that ADAM8 dampens airway inflammation. It is not clear whether ADAM8 contributes directly to structural remodeling in asthmatic airways. Additional studies are required to validate ADAM8 as a therapeutic target for asthma.