This article reviews findings from recently published randomized controlled clinical trials to address the question whether a long-acting inhaled bronchodilator should be the initial choice for maintenance therapy in patients with stable, symptomatic chronic obstructive pulmonary disease (COPD).
Results of recent clinical trials suggest that a long-acting inhaled bronchodilator, either once-daily tiotropium or twice-daily salmeterol or formoterol, has advantages over a regularly-scheduled short-acting anticholinergic inhaled bronchodilator (ipratropium) as initial maintenance therapy in patients with at least moderate, stable, symptomatic COPD (forced expired volume in 1 second </= 60-70% predicted; mean, approximately 37-45% predicted). For tiotropium, these advantages encompass several important outcomes, including lung function, rescue inhaler use, dyspnea, frequency of exacerbations, and hospitalization for COPD, in addition to greater convenience and therefore potentially better adherence to prescribed therapy, whereas side effects are similar except for a greater incidence of dry mouth.
Current evidence supports the recommendation of the Global Initiative for Chronic Obstructive Lung Disease guidelines of at least one of the two classes of long-acting inhaled bronchodilators as initial maintenance therapy for symptomatic COPD. In patients who do not respond satisfactorily to tiotropium or a long-acting inhaled beta-agonist as the initially prescribed single maintenance agent, the Global Initiative for Chronic Obstructive Lung Disease guidelines recommend the addition of the alternate class of long-acting inhaled bronchodilator as the next step. Further clinical trials are required to investigate whether this recommendation is preferable to that of adding an inhaled corticosteroid, which has been shown to have additive benefits to those of a long-acting beta-agonist with respect to bronchodilation and, variably, dyspnea, rescue bronchodilator use, and quality of life. The choice of agents will depend ultimately on how well the patient responds to a trial of the drug in terms of both efficacy and side effects, and patient preference and cost.
"The mechanism behind its long duration of action relates to the slow rate of dissociation from its target, the human M 3 muscarinic receptor (Disse et al., 1999). Long duration of action (preferably 24 h) is an important feature of drugs intended to treat chronic diseases, enabling both prolonged efficacy (Tashkin, 2005) and a simple, once-daily dosage regime that improves patient compliance (Tamura and Ohta, 2007). Other drugs are currently being evaluated in clinical trials for their ability to function as LAMAs with a potential for once-daily administration, i.e., aclidinium [also known as LAS34273 from Almirall Prodesfarma (Barcelona, Spain), currently in phase IIb trials] and glycopyrrolate [NVA-237, from Novartis (Basel, Switzerland), in phase III trials]. "
[Show abstract][Hide abstract] ABSTRACT: The preclinical pharmacological profile of 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one monohydrochloride (olodaterol, previously known as BI 1744 CL), a novel, enantiomeric pure, inhaled human beta(2)-adrenoceptor (hbeta(2)-AR) agonist, was compared with marketed drugs, such as salmeterol and formoterol. In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (219- and 1622-fold against the hbeta(1)- and hbeta(3)-ARs, respectively). Likewise, olodaterol was able to potently reverse contraction induced by different stimuli in isolated human bronchi. In vivo, antagonistic effects of single doses of olodaterol and formoterol were measured against acetylcholine challenges in anesthetized guinea pigs and dogs for up to 24 h by using the Respimat Soft Mist inhaler. Heart rate and metabolic parameters (serum potassium, lactate, and glucose) were monitored to evaluate systemic pharmacodynamic effects in the dog model. In both models, olodaterol provided bronchoprotection over 24 h. Formoterol applied at an equally effective dose did not retain efficacy over 24 h. In both models olodaterol showed a rapid onset of action comparable with formoterol. Taken together, the preclinical behavior of olodaterol suggests that this novel beta(2)-AR agonist has the profile for once-daily dosing in humans concomitant with a fast onset of action and a favorable systemic pharmacodynamic profile.
Journal of Pharmacology and Experimental Therapeutics 04/2010; 334(1):53-62. DOI:10.1124/jpet.110.167007 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper analyses three patents, published in 2005 by Sofotec GmbH & Co. KG, for the treatment of respiratory diseases that include asthma and chronic obstructive pulmonary disease (COPD). The patent applications claim the combination of anticholinergics and different bronchodilators or anti-inflamatories as β-mimetics, PDE4 inhibitors and glucocorticoids.
[Show abstract][Hide abstract] ABSTRACT: Long-acting beta-agonists may increase the risk for fatal and nonfatal asthma exacerbations.
To assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with long-acting beta-agonists.
English- and non-English-language searches of MEDLINE, EMBASE, and Cochrane databases; the U.S. Food and Drug Administration Web site; and references of selected reviews through December 2005.
Randomized, placebo-controlled trials that lasted at least 3 months and evaluated long-acting beta-agonist use in patients with asthma. All trials allowed the use of as-needed short-acting beta-agonists.
Outcomes measured were Peto odds ratio (OR) and risk difference of severe exacerbations requiring hospitalization, life-threatening exacerbations requiring intubation and ventilation, and asthma-related deaths. The OR for asthma-related deaths was obtained from the Salmeterol Multi-center Asthma Research Trial (SMART).
Pooled results from 19 trials with 33 826 participants found that long-acting beta-agonists increased exacerbations requiring hospitalization (OR, 2.6 [95% CI, 1.6 to 4.3]) and life-threatening exacerbations (OR, 1.8 [CI, 1.1 to 2.9]) compared with placebo. Hospitalizations were statistically significantly increased with salmeterol (OR, 1.7 [CI, 1.1 to 2.7]) and formoterol (OR, 3.2 [CI, 1.7 to 6.0]) and in children (OR, 3.9 [CI, 1.7 to 8.8]) and adults (OR, 2.0 [CI, 1.1 to 3.9]). The absolute increase in hospitalization was 0.7% (CI, 0.1% to 1.3%) over 6 months. The risk for asthma-related deaths was increased (OR, 3.5 [CI, 1.3 to 9.3]), with a pooled risk difference of 0.07% (CI, 0.01% to 0.1%).
The small number of deaths limited the reliability in assessing this risk, and 28 studies did not report information on the outcomes of interest.
Long-acting beta-agonists have been shown to increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.
Annals of internal medicine 07/2006; 144(12):904-12. DOI:10.7326/0003-4819-144-12-200606200-00126 · 17.81 Impact Factor
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