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Glucocorticoids (corticosteroids; steroids) are among the world's most widely prescribed drugs. They are effective in many inflammatory and immune diseases, but they also fail in some seemingly similar diseases. This article discusses new approaches to deal with steroid resistance.

No abstract is provided for this article.

Cytokines play a critical role in orchestrating and perpetuating inflammation in asthma and chronic obstructive pulmonary disease (COPD), and several specific cytokine and chemokine inhibitors are now in development for the future therapy of these diseases. Anti-interleukin (IL)‐5 is very effective at reducing peripheral blood and airway eosinophil numbers, but does not appear to be effective against symptomatic asthma. Inhibition of IL‐4 with soluble IL‐4 receptors has shown promising early results in asthma. Inhibitory cytokines, such as IL-10, interferons and IL-12 are less promising, as systemic delivery causes side-effects. Inhibition of tumour necrosis factor‐α may be useful in severe asthma and for treating severe COPD with systemic features. Many chemokines are involved in the inflammatory response of asthma and COPD and several low-molecular-weight inhibitors of chemokine receptors are in development. CCR3 antagonists (which block eosinophil chemotaxis) and CXCR2 antagonists (which block neutrophil and monocyte chemotaxis) are in clinical development for the treatment of asthma and COPD respectively. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful; several such classes of drug are now in clinical development and any risk of side-effects with these nonspecific inhibitors may be reduced by the use of inhalational route of delivery.

Purpose To describe the updated coronary computed tomographic angiography (CCTA)-based coronary artery bypass graft (CABG) anatomic SYNTAX Score (aSS) and assess its utility and reproducibility for assessing the completeness of revascularization after CABG. Methods The CCTA-CABG aSS is a visual assessment using CCTA post-CABG which quantifies the failure in effectively grafting stenotic coronary segments, and therefore assesses the completeness of surgical revascularization. It is calculated by subtracting the aSS of successfully anastomosed coronary segments from the aSS of the native coronary tree. The inter-observer reproducibility of the CCTA-CABG aSS was evaluated in 45 consecutive patients with three-vessel disease with or without left main disease who underwent a CCTA 30 days (±7 days) after CABG. Results The CCTA-CABG aSSwas evaluated in 45 consecutive patients with 117 bypass grafts and 152 anastomoses. The median native coronary aSS was 35.0 (interquartile range [IQR]: 27.0-41.0), whilst the median CCTA-CABG aSS was 13.0 (IQR: 9.0-20.5). The inter-observer level of agreement for the native coronary aSS and the CCTA-CABG aSSwere both substantial with respective Kappas of 0.67 and 0.61. Conclusions The CCTA-CABG aSS was feasible in all patients who underwent CABG for complex coronary artery disease with substantial inter-observer reproducibility, and therefore can be used to quantify the completeness of revascularization after CABG.

Inhaled corticosteroids (ICS) are now very widely used in high doses in the management of COPD patients. In sharp contrast to the situation in asthma, ICS provide little or no benefit in COPD patients and may have long-term detrimental effects. High doses of ICS fail to reduce disease progression or mortality, even when combined with a long-acting β<sub>2</sub>-agonist (LABA). Several trials have demonstrated that ICS reduce exacerbations by 20–25%, particularly in patients with more severe disease, but these studies are confounded by poor trial design and more appropriate analysis shows no benefit. Indeed, the benefit of combination inhalers seems to be largely due to the effect of the LABA, and long-acting bronchodilators – including tiotropium – provide similar benefits in reducing exacerbations. However, there may be some COPD patients, for example those with concomitant asthma, who benefit from ICS. Yet it has not been possible to identify any clinical factors that predict corticosteroid responsiveness in COPD patients in the large clinical trials. There is increasing evidence that high doses of ICS may have detrimental effects on bones and may increase the risk of pneumonia. ICS fail to suppress inflammation in COPD patients because there is a marked reduction in histone deacetylase-2, the nuclear enzyme that corticosteroids require to switch off activated inflammatory genes. In the future, alternative anti-inflammatory treatments will be needed for COPD or therapeutic strategies which reverse the molecular pathways that causes corticosteroid resistance.

Rationale: SH2-containing inositol phosphatase-1 (SHIP1) is an endogenous inhibitor of the phosphoinositide-3-kinase pathway that is involved in the activation of inflammatory cells. AQX-1125 is a first in class oral SHIP1 activator with a novel anti-inflammatory mode of action and safety profile in pre-clinical studies. Objectives: To determine the effect of once daily AQX-1125 on lung function, airway responsivness to methacholine, sputum eosinophils and fractional exhaled nitric oxide (FeNO) in asthmatic patients after IAC. Methods: A randomized, double-blind, placebo-controlled, 2-way cross-over study was performed in 22 steroid-naive patients with mild asthma. AQX-1125 or placebo were administered orally for 7 days. IAC was performed on day 6 (2 h post-dose), followed by methacholine challenge (day 7) and induced sputum collection. Results: AQX-1125 significantly abrogated the late phase response compared with placebo (FEV1 4-10h: mean difference 150ml; p>0.027); and increased minimum FEV1 during LAR (mean difference 180ml; p=0.014); increased FEV1 0-10h (mean difference 97.5ml; p>0.05) but had no effect on the early phase response. AQX-1125 showed a trend in reduction of sputum eosinophils & macrophages & also reduced methacholine responsiveness but these did not achieve significance. There was no effect on FeNO. AQX-1125 was well tolerated with mild self limited GI side effects described in 5/22 subjects on active treatment. Conclusion: AQX-1125, a novel oral SHIP1 activator, significantly reduces the late phase response to IAC, with trends to reduce airway inflammation and hyperresponsiveness.

Fully biodegradable stents may avoid the potential long-term complications of metallic drug-eluting stents such as late and very late stent thrombosis. We sought to evaluate the structural changes in a bioabsorbable DES and its interaction with the coronary vessel wall over time using optical coherence tomography (OCT). We investigated 14 consecutive patients undergoing implantation of a bioabsorbable everolimus-eluting coronary stent (BVS: Abbott Laboratories, IL, USA), composed of a poly-L-lactic acid backbone, coated with a degradable polymer/everolimus matrix. OCT (LightLab Imaging, Inc., Westford, MA) was performed immediately after stent implantation, at 6 months and at 24 months follow-up. All patients tolerated OCT imaging without complications. At baseline, OCT could detect the interface between the BVS stent and other tissues or fluid, but the inside of the strut appeared black, giving a unique box appearance. After 6 months, the struts were still clearly visible; however, their optical properties had changed considerably. In patients undergoing two years follow up (n=5, full dataset will be available at time of presentation) the majority of struts was not visible anymore and all visible struts were embedded into the vessel wall with complete tissue coverage. In contrast to 6months follow-up, at 2 years no intraluminal thrombi or dissections were visible. At 2 years follow-up the majority of stent struts were not visible by OCT. All the visible struts were covered and apposed. The lumen surface was smooth without intraluminal thrombi or dissections.

We studied the effects of dexamethasone and cyclosporin A on the airway hyperresponsiveness (AHR) and the influx of inflammatory cells into the bronchoalveolar lavage (BAL) fluid seen 18 to 24 hr after exposure to aerosolized ovalbumin in actively ovalbumin-sensitized Brown-Norway rats. Allergen exposure resulted in an approximately sevenfold increase in bronchial responsiveness to inhaled acetylcholine associated with a significant increase in eosinophils and lymphocytes in BAL fluid. Dexamethasone (0.5 mg/kg administered Intraperitoneally for 3 days) abolished the AHR and the increase in eosinophil and lymphocyte counts. However, cyclosporin A at two doses (5 and 50 mg given orally for 5 days) did not significantly prevent the induction of AHR while producing a significant inhibition of the eosinophil and lymphocyte influx. Dexamethasone (0.5 mg/kg for 3 days) or cyclosporin A (5 mg/kg for 5 days) on their own had no effect on airway responsiveness. We conclude that specific Inhibition of T-lymphocyte activation in this Brown-Norway rat model is not sufficient to inhibit the induction of AHR despite suppressing allergen-induced eosinophilia in BAL fluid. However, corticosteroids, which have inhibitory effects on a wider range of inflammatory cells, are more effective. Our observations are in line with the potent effect of corticosteroids in airway inflammatory conditions such as asthma.

Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo.