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The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile. In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon. Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as "maintenance plus reliever therapy" (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles. We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as "anti-inflammatory reliever"., Competing Interests: Declaration of competing interest RB and OS are former employees of Astra and/or AstraZeneca, Sweden, but retired many years ago. We have initiated and written this article independent of AstraZeneca. AstraZeneca was given the opportunity to review the final draft. The authors retained full editorial control. RB holds stocks with AstraZeneca., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting β 2 -agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide's physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting β 2 -agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD.

Background: Steroid-resistant asthma develops after adenoviral bronchiolitis., Objective: We sought to determine the effect of steroids on allergic lung inflammation in the presence of latent adenoviral infection., Methods: Guinea pigs with latent adenoviral (n = 12) or sham (n = 12) infections were sensitized and challenged with ovalbumin (OA) or sham sensitized and challenged with saline solution. The effect of steroids (20 mg/kg administered intraperitoneally) on OA-induced lung inflammation was examined by using quantitative histology as the outcome measure., Results: Latent adenoviral infection increased CD8(+) cells in the airway wall and CD8(+) cells, macrophages, B cells, and CD4(+) cells in the lung parenchyma. Ovalbumin challenge, on the other hand, increased eosinophils, macrophages, B cells, and CD4(+) cells in both the airway wall and lung parenchyma independent of the effect of latent adenoviral infection. In the sham-infected groups steroid treatment caused the expected reduction in the eosinophilic infiltrate induced by OA challenge in the airways without affecting the other cells. In the presence of both latent adenoviral infection and OA challenge, steroid treatment had no effect on allergen-induced eosinophilia but reduced CD8(+) cells in the airways and CD8(+) cells, CD4(+) cells, and B cells in the parenchyma., Conclusion: Latent adenoviral infection and OA challenge result in different types of lung inflammation, and the presence of latent adenoviral infection causes OA-induced eosinophilic airway inflammation to become steroid resistant.

An animal model is described for testing the effects of anti-asthma drugs on mediator-induced airway inflammation. An in situ segment of trachea is slowly perfused with normal saline in spontaneously breathing, anaesthetised rats. Both the anti-asthma drug and the inflammatory mediator can be applied directly to the airway mucosal surface at the same and/or different times. The amount of plasma in samples of perfusate is monitored. Application of a mediator, such as bradykinin, results in an increase in the amount of plasma in the tracheal lumen (and hence in the perfusate). Plasma in the perfusate can be estimated without injecting a labelled tracer for plasma exudation by using a protein native fluorescence (PNF) method as described by Miller-Larsson & Brattsand (3).

There has been a lack of small animal models for the secondary allergic response (SAR) seen after bronchial challenge in many asthmatic patients. We have found that challenge with particulate instead of soluble antigen will provoke an SAR-like bronchial obstruction in the guinea-pig. The particulate form was obtained by coupling the antigen covalently to Sepharose beads (approximately 100 microns). Different experiments suggest that SAR is obtained only when the challenge is induced via IgE-mediated mechanisms and when the antigen is sufficiently large to provoke frustrated phagocytosis by the invading inflammatory cells. As judged in lungs sections SAR was related to bronchiolitis.