Combining Tiotropium and Salmeterol in COPD: Effects on Airflow Obstruction and Symptoms. J.A. van Noord, J.L. Aumann, E. Janssens, J.J. Smeets, J. Zaagsma, A. Mueller, P.J. Cornelissen (Respir Med 2010 [Epub ahead of print]).
Background. Clinical information on 24-h spirometric efficacy of combining tiotropium and salmeterol compared to single-agent therapy is lacking in patients with COPD.
Methods. A randomized, double-blind, four-way crossover study of 6-week treatment periods comparing combination therapy of tiotropium 18mug plus qd or bid salmeterol 50mug versus single-agent therapy. Serial 24-h spirometry (FEV(1), FVC), effects on dyspnea (TDI focal score) and rescue salbutamol use were evaluated in 95 patients.
Results. Tiotropium plus qd salmeterol was superior to tiotropium or salmeterol alone in average FEV(1) (0–24 h) by 72 mL and 97 mL (p<0.0001), respectively. Compared to this qd regimen, combination therapy including bid salmeterol provided comparable daytime (0–12 h: 12 mL, p = 0.38) bronchodilator effects, but significantly more bronchodilation during the night-time (12–24 h: 73 mL, p<0.0001). Clinically relevant improvements in TDI focal score were achieved with bronchodilator combinations including salmeterol qd or bid (2.56 and 2.71; p<0.005 versus components). Symptom benefit of combination therapies was also reflected in less need for reliever medication. All treatments were well tolerated.
Conclusion. Compared to single-agent therapy, combination therapy of tiotropium plus salmeterol in COPD provided clinically meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication.
Comments. This is a nicely designed study that addresses a question many clinicians have about the benefit of combination long acting beta agonist(LABA) therapy with long acting anti-muscurinic (LAMA) therapy. The decision as to whether to advise patients they need to use a LABA bid may be determined by how frequent they report nocturnal symptoms or rescue inhaler use at night. It would be interesting to study the benefits of combination LABA/LAMA versus ICS/LABA and determine which patient characteristics may make one combination preferable over another.
Treatment Effects of Low-Dose Theophylline Combined with an Inhaled Corticosteroid in COPD. P.A. Ford, A.L. Durham, R.E. Russell, F. Gordon, I.M. Adcock, P.J. Barnes (Chest 2010 Mar 18. [Epub ahead of print]).
Background. Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated co-repressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low dose theophylline may be of benefit in the treatment of COPD.
Methods. To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP, 500mug b.d.) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study (NCT00241631). After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8–12.4 mg/L).
Results. In a cross-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (p<0.05). Additional cross-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum CXCL8/IL-8 (p<0.05). Furthermore, within-arm observational data also demonstrated increases in FEF(25–75) and FEV(1)% predicted (p<0.05) following combination treatment only. In an open label study, low dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes 9-fold (p<0.01) compared to FP alone from the same COPD patients.
Conclusions. Combination therapy with an inhaled corticosteroid and low dose theophylline may attenuate airway inflammation in COPD patients.
Comments, There are now several studies showing benefits of inhaled corticosteroids (ICS) in combination with long acting beta agonist medicines in reducing exacerbations and improving lung function compared to either agent alone. The potential interactions of methylxanthines and inhaled corticosteroids have been much less studied. Many patients report reductions in breathing capacity when theophylline, often in subtherapeutic levels, is discontinued without any drop in spirometry. Perhaps the interaction with steroids may be a part of the explanation for this observation in patients with COPD who are being treated with ICS. Considering that eosinophils and neutrophils are crude surrogate markers of complex inflammatory responses, assessment of changes in specific inflammatory mediators (such as CXCL8/IL-8) important in the pathophysiology of COPD will be more instructive as to the possible benefits and mechanisms of this interaction.
TNF{alpha} rs361525 Polymorphism is Associated with Increased Local Production and Downstream Inflammation in COPD; E. Sapey, A. M. Wood, A. Ahmad, R. A. Stockley (Am J Respir Crti Care Med 2010 Mar 18 [Epub ahead of print]).
Rationale. COPD has a genetic component, explaining susceptibility. TNFalpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression and bioactivity.
Objectives. To determine if a functional polymorphism was important by assessing TNFalpha expression and activity and its association with clinical severity over time.
Methods. COPD patients with rs361525 polymorphism were matched to COPD patients without. TNFalpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNFalpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured and neutrophil migration was assessed using sputum from both subject groups, in the presence and absence of TNFalpha antibody. Subjects were followed annually and compared.
Measurements and Main Results. Polymorphism patients had more chronic bronchitis, a lower BMI and a greater annual decline in FEV1 than COPD patients without. TNFalpha concentrations were 100 fold higher in airway secretions from the polymorphism patients, with no difference in TNFalpha antagonists. Their lung secretions contained more IL-8 and MPO, consistent with downstream inflammation. Sputum from polymorphism patients induced greater secretion of IL-8 from PBECs and increased neutrophil migration and these effects could be abrogated by TNFalpha antibody, demonstrating the bioactivity of TNFalpha in lung secretions from this group. CONCLUSIONS: This TNFalpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNFalpha over-expression and bio-activity with neutrophillic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.
Comments. We are just beginning to see the power of studying the genetics of COPD to gain greater insights into not only susceptibility, but also variable clinical characteristics, rate of progression, and response to medications. As we gain greater appreciation for the role of inflammation in COPD, identifying polymorphisms for various inflammatory mediators will be critical in proposing and studying novel various therapeutic targets for COPD.