The use of inhaled corticosteroids has been associated with a dose-related increased risk of fracture. This may be related to systemic absorption. However, several studies have found that patients with more severe reductions in pulmonary function had reduced bone mineral density, independent of inhaled corticosteroids. The objective of this study was to evaluate the relationship between disease severity and fracture risk.A large case-control study (108,754 cases) was conducted using data from the UK General Practice Research Database. It was found that higher doses of inhaled corticosteroids were associated with greater risks of fracture. The crude odds ratio of fracture among patients exposed to .1,600 mg beclomethasone equivalents per day was 1.95 (95% confidence interval (CI) 1.68-2.27). When adjustments were made for disease severity and use of bronchodilators, the initial dose-response relationship between inhaled corticosteroids and fracture risk disappeared (adjusted odds ratio of 1.19 (95% CI 1.01-1.41)).In conclusion, patients with severe obstructive airway disease are at risk of fracture. However, adequate adjustment for disease severity is essential when the association between the use of inhaled corticosteroids and risk of osteoporotic fracture is studied in observational research.

Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.

Background -The optimal particle size of a P2 agonist or anticholinergic aerosol in patients with severe airflow obstruction is unknown. Methods -Seven stable patients with a mean forced expiratory volume in one second (FEV1) of 37.9% of the predicted value inhaled three types of monodisperse salbutamol and ipratropium bromide aerosols with particle sizes of 1.5 gm, 2.8 rtm, and 5 gm, respectively, and a placebo aerosol. The volunteers inhaled 20 ftg salbutamol and 8 ftg ipratropium bromide, after which lung function changes were determined and analysed with repeated measurements analysis of variance (ANOVA). Results -Greater improvements in FEV1, specific airway conductance (sGaw) and maximum expiratory flow at 75%150% of the forced vital capacity (MEF75/50) were induced by the 2.8 gm aerosol than by the other particle sizes. Conclusions -In patients with severe airflow obstruction the particle size of choice for a 2 agonist or anticholinergic aerosol should be approximately 3 ftm.(Thorax 1996;51:977-980) Keywords: aerosols, particle size, bronchodilators. the greatest bronchodilatation.4 To reach the smaller airways in such cases it may be necessary for the particle size of the inhaled aerosol to be decreased. In patients with severe airflow obstruction, aerosols with a smaller particle size may be more suitable. We therefore carried out experiments to determine the most suitable particle size for bronchodilator aerosols in patients with severe airflow obstruction. Methods PATIENTSEight patients (six men) started the trial but one dropped out for personal reasons. The mean (SD) age of the remaining seven was 55 (4) years, and the mean forced expiratory volume in one second (FEVI) was 37.9 (7.3)% of the predicted value. In all patients a more than 15% increase in baseline FEV1 after inhalation of 200 jg salbutamol had been measured just before the trial. None of the patients was smokers. All used inhaled corticosteroids and none used disodium cromoglycate or oral antiasthma medications. Their regular medication other than corticosteroids was discontinued 6-8 hours before the start of the trial, and long acting 12 agonists were stopped 15 hours before the trial. All patients gave their written consent before entry into the study which was approved by the hospital ethics committee.

Bronchial hyperresponsiveness is present in 40-60% of adult patients with cystic fibrosis (CF). Drugs which alter airway hyperresponsiveness have not yet been studied in CF. In this randomized placebo-controlled study, we investigated the effects of an inhaled corticosteroid, budesonide, on lung function and bronchial hyperresponsiveness in adult CF patients, with proven bronchial hyperresponsiveness to histamine. Twelve patients were treated with budesonide, 1600 micrograms day-1, and with placebo during two periods of 6 weeks in a randomized, double-blind, cross-over study. Drug effects were assessed with regard to bronchial hyperresponsiveness to histamine, spirometry and clinical symptom scores. After treatment with budesonide, no significant differences in spirometry were seen, however, bronchial hyperresponsiveness to histamine significantly improved as compared to baseline. Fifty-eight percent of the patients showed at least one doubling-dose increase in PC20 histamine. Daily symptom scores showed small, but statistically significant, improvements in dyspnoea and cough after budesonide treatment. There is increasing evidence suggesting that excessive inflammatory responses contribute to the pulmonary damage that characterizes CF. Treatment with oral corticosteroids improved the clinical course of selected CF patients, but was associated with unacceptable adverse effects. We conclude that daily inhalation of 1600 micrograms day-1 budesonide for 6 weeks induced a small, but significant, improvement in bronchial hyperresponsiveness to histamine, and symptoms of cough and dyspnoea in adult CF patients. Longer observations are needed to establish whether inhaled corticosteroids improve the long term outcome of CF.

Airway hyperresponsiveness induced by adenosine-59-monophosphate (AMP) is regarded as a reliable model for allergic asthma and for the evaluation of anti-asthmatic drugs. Single-dose inhaled corticosteroids (ICS) are known to be protective in this model, but the duration of action of these drugs in this model has never been studied.The duration of ICS protection was determined by administration of single-dose fluticasone propionate (FP; 1,000 mg) up to 26 h before AMP challenge. A randomised, double-blind, placebo-controlled, four-way crossover study was performed in 13 mild asthmatics (mean¡SD predicted forced expiratory volume in one second (FEV1) 98¡7%). Each subject received placebo and FP (at 26, 14 or 2 h prior to the AMP challenge). Furthermore, the marker exhaled nitric oxide (eNO) was studied after administration at these time points to investigate whether eNO also demonstrates the duration of action of ICS.The doubling concentrations difference (DCD) of AMP causing a 20% fall in FEV1, when FP was administered 26, 14 or 2 h prior to challenge, was significantly increased as compared with placebo: DCD (95% confidence interval) at 26 h, 0.73 (0.20-1.26), p=0.008; 14 h, 1.50 (0.99-2.01), pv0.001; and 2 h, 2.89 (2.37-3.40), pv0.001. However, eNO was not significantly affected at these time points.In conclusion, a single dose of 1,000 mg inhaled fluticasone propionate protects against adenosine-59-monophosphate airway hyperresponsiveness up to 26 h after dosing. This study suggests that adenosine-59-monophosphate challenge can be used as a sensitive marker to study the duration of action of inhaled corticosteroids.

The inhaled A(2A)-receptor agonist, GW328267X, 25 microg does not affect the allergen-induced LAR or the associated inflammatory response in asthma.

Chronic obstructive pulmonary disease (COPD) is characterised by neutrophilic inflammation in the airways and these neutrophils contribute to the production of inflammatory mediators. Dampening the production of proinflammatory mediators might be an important strategy to treat COPD and glucocorticosteroids are known to do so via inhibition of nuclear factor-kB. However, this pathway is important for the control of pro-and anti-inflammatory genes.We studied the effects of dexamethasone on production and secretion of pro-inflammatory interleukin (IL)-1b and anti-inflammatory secreted IL-1 receptor antagonist (sIL-1Ra) by human neutrophils activated with tumor necrosis factor (TNF)-a.In vitro, TNF-a-stimulated neutrophils produced significant amounts of IL-1b and sIL-1Ra; this production was inhibited by dexamethasone. However, synthesis and secretion of sIL-1Ra was inhibited at lower concentrations dexamethasone compared to IL-1b, which changed the IL-1b:sIL1Ra ratio significantly. This altered ratio resulted in a more pro-inflammatory condition, as visualised by increased intercellular adhesion molecule-1 expression on human endothelial cells. In vivo, moderate-to-severe COPD patients using inhaled glucocorticosteroids have decreased plasma sILRa levels compared with mild-to-moderate patients not on glucocorticosteroid treatment.In conclusion, dexamethasone induces a pro-inflammatory shift in the IL-1b:sIL-1Ra cytokine balance in neutrophils in vitro, which might contribute to a lack of endogenous anti-inflammatory signals to dampen inflammation in vivo.

The new inhaled corticosteroid FF, but not FP, demonstrates prolonged protection up to 26 h against AHR to AMP in asthma patients.