AEROVENT

ESTUDIOS CLÍNICOS

The non-genomic mechanisms by which glucocorticoids modulate β2 agonist-induced bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX) or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in he presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist68 induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation, and that potentially mediated the rapid effects of steroids on β2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol78 induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and β2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease.

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The potential benefits of inhaled corticosteroids for the treatment of acute asthma exacerbations include direct delivery to the airways and reduced systemic exposure. However, their effect in young children is still controversial. Several studies failed to note any positive effects of inhaled corticosteroids in the acute setting. The two studies of Schuh et al. (1, 4) included only children who presented to the emergency department with very severe asthma and forced expiratory volume in one second (FEV1) less than 60% (1) or 50– 79% of predicted. The other studies claimed that the acute use of inhaled corticosteroids provides only modest benefit in the control of asthma attack in children and that a combination of inhaled beta2-agonist and corticosteroids yields better results than inhaled corticosteroids alone. Two recent evidence-based reviews reported good results for repeated high doses given in the initial phase of the exacerbation.
It is apparently the high dose that is the key factor for clinical success, reaching up to 5 times the recommended amount.
For the last 25 years, inhaled budesonide has been the only drug used in our pediatric asthma clinic for maintenance therapy as well as for treatment of episodic asthma exacerbations, however, budesonide became unavailable nationwide over a 3-month period, from December 2004 to March 2005, during which children in our clinic, including newly diagnosed ones, were treated with fluticasone. The aim of the present study was to compare the clinical efficacy of inhaled budesonide 200 mcg and inhaled fluticasone 125 mcg in controlling asthma exacerbations in young children at home.

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Glucocorticoid (GC) anti-inflammatory effects generally require a prolonged onset of action and involve genomic processes. Because of the rapidity of some of the GC effects, however, the concept that non-genomic actions may contribute to GC mechanisms of action has arisen. While the mechanisms have not been completely elucidated, the non-genomic effects may play a role in the management of inflammatory diseases. For instance, we recently reported that GCs ‘rapidly’ enhanced the effects of bronchodilators, agents used in the treatment of allergic asthma. In this review article, we discuss the nongenomic effects of GCs on pathways relevant to the pathogenesis of inflammatory diseases and the putative role of the membrane GC receptor. Since GC side effects are often considered to be generated through its genomic actions, understanding GC non-genomic effects will help design GCs with a better therapeutic index.

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Asthma is a common chronic disease in children, ranked among the top 10 conditions worldwide in terms of disability-adjusted life years for children aged 5–14 years. During 2001–2013, its prevalence in children aged <17 years in the US was 8.91%. Although its global mortality rate is low (0.7/100 000), acute asthma attacks and uncontrolled asthma can cause disability, affecting both the patients and their parents or caregivers. A US study found that school-aged children with asthma missed 1.54 times more school days than those without asthma, with their caregivers missing 1.16 times more working days than those of children without asthma.
Children with asthma often experience an exacerbation of the condition, with a US survey reporting that 52% of patients experienced at least one exacerbation requiring an emergency department visit. A study reported that the quality of life score of children with asthma decreased from 6.2 to 4.2 during hospitalizations. Systemic corticosteroids (SC) are effective in the treatment of acute asthma exacerbation. A review concluded that treatment with SC within 1 h of exacerbation significantly reduced admission rates by 60% (95% confidence interval [CI]: 0.21–0.78) compared with that without corticosteroid treatment. The first‑line therapy for chronic asthma is inhaled corticosteroids (ICS); however, their effect on asthma exacerbation remains under debate.