Pulmonary pharmacology & therapeutics
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Pulm Pharmacol Ther · Jan 2008
ReviewThe impact of inhaled corticosteroid and long-acting beta-agonist combination therapy on outcomes in COPD.
Chronic obstructive pulmonary disease (COPD) is an under-recognized cause of morbidity and mortality worldwide that imposes an ever increasing burden on the patient and society alike. The disease encompasses multiple structural and functional components of which inflammation is at the core of the disease, affecting the lungs and other organs. Consequently, current treatment strategies are aimed at treating both the symptoms and the pulmonary inflammation underlying the complex pathophysiology of COPD. Smoking cessation is the only intervention currently shown to slow disease progression in COPD and decrease all-cause mortality, aside from lung transplant, lung-volume reduction surgery and oxygen therapy in selective patients. However, this intervention is difficult to achieve and sustain because of the addictive and chronic relapsing nature of cigarette smoking. Pharmacotherapy with bronchodilating agents, including the beta 2-agonists, anticholinergics and methylxanthines, is central to the symptomatic management of all stages of COPD. While inhaled corticosteroids (ICS) are employed to reduce inflammation in more severe patients, their role as stand alone medication in COPD is not well defined. However, increasing evidence suggests that long-acting beta 2-agonists (LABAs) and ICS have complementary and synergistic effects, when delivered as combination therapy from a single inhaler. In this respect, two preparations comprising combinations of salmeterol+fluticasone propionate (SFC) and formoterol+budesonide (FBC) are currently available and employed for treatment of more severe disease. Several large-scale studies in patients with moderate-to-severe COPD have demonstrated that treatment with SFC and FBC leads to significantly greater improvements in lung function, exacerbations, health status and breathlessness, compared with placebo or monotherapy with the component drugs. In the recently published landmark study, Towards a Revolution in COPD Health (TORCH), regular treatment with SFC narrowly missed demonstrating a statistically significant benefit on the reduction in all-cause mortality over 3 years (17.5% reduction in risk, P=0.052), further emphasizing the clinical usefulness of LABA+ICS therapy in COPD. In view of this increasing evidence for the additional effectiveness of LABA+ICS combinations compared with the individual components, and the potential benefits of LABA+ICS on lung function, disease progression and potentially on all-cause mortality, initiation of LABA+ICS combination treatment early in the COPD disease process may be warranted. ⋯ The studies discussed in this review were identified from systematic searches of Medline and the Cochrane Database, up to October 2007, for articles in English or with English abstracts describing randomized, double-blind, parallel-group/crossover trials of at least 24 weeks' duration. All searches were performed using the terms: chronic obstructive pulmonary disease, COPD, chronic obstructive airway disease, or COAD AND either salmeterol, formoterol, long-acting beta 2-adrenoceptor agonist, fluticasone propionate, budesonide, inhaled corticosteroids, or inhaled glucocorticosteroids. Additional relevant references were identified from the reference lists of selected papers. Only studies that compared a combined LABA+ICS therapy with its monotherapy components were selected for inclusion in this manuscript.
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Pulm Pharmacol Ther · Jan 2008
Randomized Controlled TrialAcute effects of sildenafil on exercise pulmonary hemodynamics and capacity in patients with COPD.
We investigated in chronic obstructive pulmonary disease (COPD) patients whether a single dose of sildenafil can attenuate the exercise-induced increase in pulmonary artery pressure, thereby allowing augmentation of stroke volume (SV), and improving maximal exercise capacity. ⋯ Regardless of mPpa at rest, sildenafil attenuates the increase in mPpa during submaximal exercise in COPD. This attenuated increase is neither accompanied by enhanced SV and CO, nor by improved maximal exercise capacity.
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Pulm Pharmacol Ther · Jan 2008
Randomized Controlled TrialEffects of airway anesthesia on dyspnea and ventilatory response to intravenous injection of adenosine in healthy human subjects.
We have recently shown that intravenous injection of adenosine causes dyspnea and hyperventilation in man, and we suggested that stimulation of vagal C-fibers in the airways and lungs is involved. To test this hypothesis further, the present study was performed in healthy subjects (n=12; age 32.4+/-10.2 yrs, 7 females) to determine if the effect of adenosine could be attenuated by blocking the airway sensory receptors by inhalation of aerosolized lidocaine, a local anesthetic. In each subject, the effects of intravenous injection of adenosine (10mg) on dyspneic sensation, minute ventilation, airway resistance and heart rate were measured after the subject inhaled lidocaine or placebo aerosol on two separate days. ⋯ The intensity of adenosine-induced dyspnea was markedly reduced after the lidocaine pretreatment compared to placebo. In a sharp contrast, the VE and heart rate responses to adenosine were not affected by lidocaine. These results lend further support to our previous studies indicating that the origin of the dyspnogenic action of intravenous adenosine is most likely vagal bronchopulmonary C-fiber sensory nerves.
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Pulm Pharmacol Ther · Jan 2008
Comparative StudyAlpha glucocorticoid receptor expression in different experimental rat models of acute lung injury.
Acute respiratory distress syndrome (ARDS) is a frequent form of hypoxiemic respiratory failure caused by the acute development of diffuse lung inflammation. Dysregulated systemic inflammation with persistent elevation of circulating inflammatory cytokines is the pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with ARDS. Glucocorticoids (GCs) have a broad range of inhibitory inflammatory effects, including inhibition of cytokines transcription, cellular activation and growth factor production. They inhibit the inflammatory pathways through two specific intracellular glucocorticoid receptors (GRs), named GR alpha and GR beta. The aim of our study was to evaluate the histologic evidence of inflammatory injury and the GR alpha uptake of resident and inflammatory cells in different experimental models of acute lung injury (ALI). ⋯ These data indicate that ALI is associated with diffuse alveolar damage, up-regulation of the inflammatory response and GR alpha overexpression. Barotrauma is the most effective mechanism inducing acute lung inflammation and GR alpha overexpression.