Regional quantification of muscarinic acetylcholine receptors and β‐adrenoceptors in human airways

Ikeda, Takeshi; Anisuzzaman, Abu Syed Md; Yoshiki, Hatsumi; Sasaki, Makoto; Koshiji, Takaaki; Uwada, Junsuke; Nishimune, Atsushi; Itoh, H; Muramatsu, Ikunobu

doi:10.1111/j.1476-5381.2012.01881.x

Cited by 58 publications

(57 citation statements)

References 39 publications

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“…For this reason, it is an essential question whether Brr is a target area or not. The consideration of this part of the airways as target zone for β2 agonist bronchodilators is supported by the observation that the relative density of β-adrenergic receptors increases with the increase of airway generation number (Ikeda et al, 2012). At the same time, the amount of smooth muscle is considerably reduced in this partly alveolated region of the airways.…”

Section: Resultsmentioning

confidence: 60%

Computer Modelling as a Tool in Characterization and Optimization of Aerosol Drug Delivery

Farkas

Jókay

Füri

et al. 2015

Aerosol Air Qual. Res.

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The number of patients with obstructive airway disease has been increasing worldwide. The delivery of aerosol drugs through the respiratory system has become a central element in the management of asthma and chronic obstructive pulmonary disease (COPD). The aim of this study was to validate and apply a stochastic whole respiratory tract deposition model in order to characterize airway deposition distribution of two different marketed drugs delivered in form of dry powders (Seretide ® Diskus ® and Symbicort ® Turbuhaler, and to analyze the possibility of computerized drug delivery optimization in the future. Spirometry measurements on 17 adult volunteers have been performed. Relationships between breathing parameters measured during diagnostic spirometry and those characterising breathing during drug administration through Diskus ® and Turbuhaler ® inhalers have been derived. The doses deposited in different anatomical regions of the respiratory tract and airway generation number specific deposited doses have been computed for the participating individuals based on both mass median aerodynamic diameter (MMAD) and detailed size distribution of the two drugs. Although regional deposited doses were not very different in the two cases, airway generation number specific deposition distributions were sensitive to this input parameter, indicating the need for the whole size distribution when modelling airway deposition of aerosol drugs. Significant intersubject variability in terms of oropharyngeal, bronchial and acinar deposited doses have been found. The results highlight the necessity for and open the possibility of simulation assisted customized drug selection in the future.

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Section: Resultsmentioning

confidence: 60%

Computer Modelling as a Tool in Characterization and Optimization of Aerosol Drug Delivery

Farkas

Jókay

Füri

et al. 2015

Aerosol Air Qual. Res.

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“…The regional distribution and relative proportion of muscarinic acetylcholine receptor (mAChR) and β-adrenoceptor subtypes were evaluated in the human bronchus and lung parenchyma 7. The M 3 subtype predominantly occurred in the bronchus, but the density decreased from the segmental to subsegmental bronchus and was absent in the lung parenchyma.…”

Section: Lama/laba In the Treatment Of Copdmentioning

confidence: 99%

LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes

Hizawa¹

2015

COPD

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In the combined use of bronchodilators of different classes, ie, long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), bronchodilation is obtained both directly, through LABA-mediated stimulation of β2-adrenergic receptors, and indirectly, through LAMA-mediated inhibition of acetylcholine action at muscarinic receptors. The clinical trial data for LABAs/LAMAs in the treatment of chronic obstructive pulmonary disease (COPD) continue to be promising, and these combinations will provide the convenience of delivering the two major bronchodilator classes, recommended as first-line maintenance options in COPD treatment guidelines. COPD is a complex condition that has pulmonary and extrapulmonary manifestations. These clinical manifestations are highly variable, and several are associated with different responses to currently available therapies. The concept of a COPD phenotype is rapidly evolving from one focusing on the clinical characteristics to one linking the underlying biology to the phenotype of the disease. Identification of the peculiarities of the different COPD phenotypes will permit us to implement a more personalized treatment in which the patient’s characteristics, together with his or her genotype, will be key to choosing the best treatment option. At present in Japan, fixed combinations of inhaled corticosteroids (ICSs) and LABAs are frequently prescribed in the earlier stages of COPD. However, ICSs increase the risk of pneumonia. Notably, 10%–30% of patients with COPD with or without a history of asthma have persistent circulating and airway eosinophilia associated with an increased risk of exacerbations and sensitivity to steroids. Thus, sputum or blood eosinophil counts might identify a subpopulation in which ICSs could have potentially deleterious effects as well as a subpopulation that benefits from ICSs. In this review, I propose one plausible approach to position ICSs and LABAs/LAMAs in clinical practice, based on both the extent of airflow obstruction and the presence of an asthma component or airway eosinophilic inflammation. This approach is a tentative move toward personalized treatment for COPD patients, and with progress in knowledge and developments in physiology, lung imaging, medical biology, and genetics, identification of COPD phenotypes that provide prognostic and therapeutic information that can affect clinically meaningful outcomes is an urgent medical need.

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“…In the human lung, β-adrenergic receptors on smooth muscle, epithelial and mast cells are of the β 2 -subtype, whose density increases towards the peripheral airways. By contrast, human submucosal glands and alveolar wall cells also express β 1 -receptors [7,8]. In the healthy heart, β 1 -and β 2 -adrenergic receptors coexist in a 4:1 ratio.…”

mentioning

confidence: 97%

Beta-blockers and COPD: the show must go on

2016

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@ERSpublications Current evidence on beta-blockers efficacy and safety in COPD is encouraging but limited with future studies needed http://ow.ly/IaNL301YANIIdentification of comorbidities is now recognised as one of the pillars for a comprehensive clinical evaluation in chronic obstructive pulmonary disease (COPD) [1]. Specifically, the burden of coexisting cardiovascular disease in COPD has gained significant attention, with specific algorithms being developed for its clinical detection [2]. The relationship between the heart and COPD is of clinical relevance not only for the well-documented relationship between the two organs [3], but also for the potential mutual influence of treatments. The interactions between oral beta-blockers and inhaled β-adrenergic drugs pose significant challenges for clinicians involved in the management of patients with chronic cardiorespiratory conditions. In particular, the use of beta-blockers in COPD remains the subject of ongoing controversy [4].In this issue of the European Respiratory Journal, LIPWORTH et al.[5] provide a comprehensive summary on the use of beta-blockers in patients with COPD. In their narrative review, the authors disentangled the complex links between COPD and the heart, reviewed the available data on the use of beta-blockers for reducing exacerbations and mortality, and summarised the unmet needs in the field, with special reference to a more in-depth knowledge of how different beta-blockers can affect pulmonary function based on their pharmacology. Despite published reports of physicians being reluctant to prescribe beta-blockers in COPD patients with a history of myocardial infarction or coexisting heart failure, the authors conclude that there are compelling reasons for the use of cardioselective beta-blockers in this patient group.In order to understand the potential implications of beta-blockers on COPD a brief review of the lung innervation and anatomical distribution of receptors in the lung is required. In humans, the direct sympathetic innervation of the airway smooth muscle is very poor [6]. Somewhat counterintuitively, however, the density of β-adrenergic receptors is markedly high and their expression can be identified in different cell types. In the human lung, β-adrenergic receptors on smooth muscle, epithelial and mast cells are of the β 2 -subtype, whose density increases towards the peripheral airways. By contrast, human submucosal glands and alveolar wall cells also express β 1 -receptors [7,8]. In the healthy heart, β 1 -and β 2 -adrenergic receptors coexist in a 4:1 ratio. However, in the failing heart, β 1 -adrenergic receptor numbers decrease, paralleled by an increase in β 2 -adrenergic receptors, ultimately resulting in a 3:2 ratio [9]. In this scenario, the occurrence of interactions may not be negligible. In general, the effects of drugs that act on adrenergic receptors depend both on the intrinsic pharmacological properties of the drug (including the β 1 /β 2 ratio) and its bioavailability (intended to be high in systemic beta-b...

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Regional quantification of muscarinic acetylcholine receptors and β‐adrenoceptors in human airways

Cited by 58 publications

References 39 publications

Computer Modelling as a Tool in Characterization and Optimization of Aerosol Drug Delivery

Computer Modelling as a Tool in Characterization and Optimization of Aerosol Drug Delivery

LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes

Beta-blockers and COPD: the show must go on

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