Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid

Walters, EH; Gibson, Peter G.; Lasserson, Toby J; Walters, Julia

doi:10.1002/14651858.cd001385.pub2

Cited by 81 publications

(56 citation statements)

References 250 publications

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“…A more recent Cochrane analysis [41] examined trials of LABAs for chronic asthma in adults and children in which the background therapy contained varied or no ICS, and excluded those in which patients were uniformly taking ICS. In this latter review of 67 trials, a median of only 62% were taking ICS.…”

Section: Discussionmentioning

confidence: 99%

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Sears

Ottosson²,

Radner³

et al. 2009

European Respiratory Journal

102

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The safety of long-acting b 2 -agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or allcause mortality and morbidity were increased with formoterol use.The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol.There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterolrandomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (.90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 mg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABAtreated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant.There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting b 2 -agonistrandomised patients. However, despite data on .68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

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Section: Discussionmentioning

confidence: 99%

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Sears

Ottosson²,

Radner³

et al. 2009

European Respiratory Journal

102

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“…Similar considerations may result in a long-acting antihistamine (Fig. 3D) (40), b2-agonist for asthma (41), and M3 antagonist for chronic obstructive pulmonary disease (COPD) (42) and hypertensive COPD (43 In Vivo Assessment of Elastase Inhibitors. In vitro testing suggested that X0 was the most effective tripeptide mimetic of the three inhibitors and that when derivatized and linked to SP-B1-25 as SP-B1-25-X2 should be more effective than SP-B1-25-X1.…”

Section: Discussionmentioning

confidence: 86%

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Guarnieri

Spencer²,

Lucey³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastaseinduced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.lung cancer | resistant infections | tuberculosis | asthma I nhalation is an important means of systemically delivering drugs that require immediate onset of action because the lungs provide a facile conduit to the bloodstream (1). Conversely, rapid lung clearance of small molecules causes a significant challenge for the development of pulmonary therapeutics. Rodent models of elastase-induced emphysema, for example, highlight the challenges for the development of effective drugs for pulmonary diseases. Potent in vitro human neutrophil elastase (HNE) inhibitors are cleared from the animals' lungs in minutes and may even exacerbate HNEinduced emphysema (2), whereas one intratracheally instilled dose of elastase causes maximum lung damage after 4 wk (3). The combination of long-term chronic pulmonary damage that characterizes the progression of emphysema with the rapid lung clearance (4) and potential nephrotoxicity (5) of small molecule drugs indicates that there is a profound need for new ways of producing pulmonary therapeutics with long lung residence time pharmacodynamics.Because emphysema is a chronic disease, any treatment will likely be administered over the course of the patient's life, and thus long-acting agents may induce an immune response that would negate the therapeutic effect. The ability of the treatment to access all regions of the vast lung surface area must also be considered. One way to slow the clearance of a small molecule inhibitor from the lung is to attach it to a larger polymer (6). For instance, the covalent linkage of a hydrophilic polymer to a peptidyl carbamate inhibitor increases the half-life by 100-fold in the lungs of hamsters and pro...

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“…The data from all of these diverse systems are in agreement and support our hypothesis that LABAs activate STAT6 to promote or exacerbate asthma. Given the inability to perform confirmatory human studies due to their inherent risk, our findings provide a potentially important molecular explanation for the epidemiologic association between use of LABAs and loss of control of asthma and excess asthmarelated mortality [11].…”

Section: Discussionmentioning

confidence: 93%

“…The structures of diverse β 2 -AR ligands are shown in S1 Fig. LABAs such as salmeterol and formoterol have become preferred inhaled asthma drugs because they improve disease control while requiring less frequent dosing relative to the older SABAs [6]. However, like first generation beta agonists, salmeterol has been linked in a small subset of patients to loss of disease control and excess asthma-related mortality [11]. The mechanism for this toxicity is unknown, but the improved specificity of LABAs for the β 2 -AR suggests that the cardiovascular toxicity seen in earlier generation agents is an unlikely cause.…”

Section: Introductionmentioning

confidence: 99%

Long-Acting Beta Agonists Enhance Allergic Airway Disease

Knight

Mak

Shaw

et al. 2015

Journal of Allergy and Clinical Immunology

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Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid

Cited by 81 publications

References 250 publications

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Long-Acting Beta Agonists Enhance Allergic Airway Disease

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