MEETING REPORT

Int J Pharm Med 2006; 20 (4): 263-268 1364-9027/06/0004-0263/$39.95/0 © 2006 Adis Data Information BV. All rights reserved.

The 102nd Annual Conference of the American Thoracic Society 19–24 May 2006; San Diego, California, USA Anoma Ranaweera Adis International, Inc., Yardley, Pennsylvania, USA

The annual meeting of the American Thoracic Society is one of the largest gatherings of pulmonary/critical care specialists in the world. This year’s conference was attended by approximately 12 000 international delegates and featured state-of-the-art information in both basic and clinical research covering a wide range of issues (epidemiological, pathological and therapeutic) relating to the spectrum of respiratory diseases. Listed below are some of the highlights from presentations concerning asthma, chronic obstructive pulmonary disease (COPD) and pulmonary hypertension. 1. Novel Therapies for Asthma 1.1 Indacaterol

Indacaterol is a long-acting β2-adrenoceptor agonist and bronchodilator with a rapid onset of action. It is currently under joint development with Novartis and SkyePharma in clinical trials as a dry-powder inhalation therapy for asthma and COPD. Novartis has stated that once-daily administration of indacaterol is expected to offer lung function improvement lasting 24 hours and that it is being developed initially as a monotherapy for the bronchodilator market. A poster detailed the results of a phase II, randomised, placebo-controlled, crossover study that investigated the efficacy of indacaterol in patients with persistent asthma.[1] 25 patients randomly received indacaterol 400μg via a singledose dry-powder inhaler (DPI), 200μg via a multidose DPI or placebo. The adjusted mean forced expiratory volume in one second (FEV1) values were significantly higher for both indacaterol doses versus placebo at all timepoints; FEV1 was significantly higher for 400μg versus 200μg from 5 hours onwards. Once-daily indacaterol demonstrated sustained bronchodilatory efficacy throughout a 24-hour period with a rapid onset of action and a good safety profile with both inhalation devices. These study results were also supported in a separate poster

presentation detailing a double-blind, randomised, 7-day, multiple dose-ranging study of 436 patients who received once-daily indacaterol 50, 100, 200 or 400μg via multidose or single-dose DPI.[2] Results showed sustained 24-hour bronchodilation with no loss of efficacy after 7 days. Indacaterol was well tolerated at all doses. 1.2 IPL 512602

IPL 512602 is a small-molecule, orally active anti-inflammatory compound in clinical development with Inflazyme Pharmaceuticals and Sanofi-Aventis for the treatment of asthma. Phase IIa trials have been completed for the treatment of mild-to-moderate asthma. After a period of suspended development, Inflazyme has resumed investigations and begun a phase IIb trial for moderate-tosevere asthma. Results from a randomised, placebo-controlled, US-based phase IIa trial of IPL 512602 in 169 patients with mildto-moderate asthma indicated that while the compound demonstrated significant improvements in several secondary endpoints, the primary endpoint (i.e. improvement in lung function as assessed by FEV1) was not achieved.[3] However, significant improvements in secondary endpoints, including a decrease in hyper-responsiveness to methacholine, increased morning peak expiratory flow (amPEF), reductions in salbutamol (albuterol) use and improvements in Asthma Quality of Life Questionnaire (AQLQ) scores demonstrated a potential in asthma control in these patients. According to company sources, the US Food and Drug Administration has indicated that quality-of-life measures and other patientreported outcomes would be acceptable as primary endpoints for phase III trials. 1.3 Tumour Necrosis Factor-α Antagonists

An evening symposium sponsored by Genentech and Novartis entitled The Immunologic Basis of Asthma: Opportunity to Intervene and Modify Disease Progression addressed cellular

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and humoural elements of the immune system that participate in the pathophysiology and progression of asthma, and newer and investigational agents aimed at specific immunological targets that have the potential to both improve asthma control and progression of asthma. Professor Stephen Holgate from the University of Southampton, UK, noted that in patients with refractory asthma who are dependent on corticosteroids, there is evidence of the up-regulation of the tumour necrosis factor (TNF)-α axis and treatment with etanercept improves asthma control and asthma-related quality-of-life scores relative to placebo. Holgate cited a UK study where 10 patients with refractory asthma treated with etanercept 25mg twice weekly for 10 weeks showed significant increase in the concentration of methacholine required to provoke a 20% decrease in FEV1, an improvement in the asthma-related quality-of-life score and a 0.32L increase in postbronchodilator FEV1.[4]

1.4 Treatment Heterogeneity in Asthma

A scientific symposium entitled Mechanisms of Treatment Heterogeneity in Asthma looked at mechanisms driving heterogeneity of treatment response with corticosteroids, leukotriene modifiers and β2-agonists. Several factors can contribute to interpatient variability in drug efficacy and toxicity risk; these include age, sex, race, interaction with other drugs, concomitant diseases, and renal and hepatic function. In addition, an increasing number of studies have shown that genetic variability is one of the many factors that can influence response to drug therapy. Genetic polymorphism may account for interindividual differences in toxicity and efficacy of asthma medications. Numerous studies have focused on the variation of the β2adrenoceptor gene and its potential effect on drug therapy. In a presentation entitled The Functional Consequences of Beta-2 Receptor Polymorphisms, Dr Stephen Liggett from the University of Maryland School of Medicine, Baltimore, USA, cited several studies that have suggested that short-acting β-agonists such as salbutamol may produce adverse outcomes (e.g. decreased peak flow or increased risk of exacerbation). Similarly, a number of studies have also suggested an association between use of long-acting β-agonists with adverse outcomes such as asthma exacerbation and, possibly, increased risk of death.[5] These findings may be related to genetic variations of the β2-adrenoceptor gene. There are a number of single nucleotide polymorphisms in the coding region of the β2-adrenoceptor gene, two of which are common (those causing substitution of glycine for arginine at codon 16 and substitution of glutamic acid for glutamine at codon 27). Both of these polymorphisms affect β-adrenoceptor downregulation. © 2006 Adis Data Information BV. All rights reserved.

Elliot Israel from Harvard Medical School and colleagues have provided evidence to suggest that a β-adrenoceptor polymorphism at the 16 locus has clinical implications;[6] patients who were homozygous for arginine at codon 16 (B16Arg/Arg) had a reduced response to the short-acting β-agonist salbutamol compared with patients who were homozygous for glycine (B16Gly/Gy). The gly 16 polymorphism was associated with a more favourable response to regular salbutamol treatment. The study by Wechsler et al.[7] looked retrospectively at data from two studies. Salmeterol response in asthma patients homozygous for arginine at B16 (B16Arg/Arg) was compared with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, patients were randomised to regular therapy with salmeterol while simultaneously discontinuing inhaled corticosteroids therapy. In the second, patients were randomised to regular therapy with salmeterol while continuing concomitant inhaled corticosteroids. Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma showed an impaired therapeutic response to salmeterol in either the absence or presence of concurrent inhaled corticosteroid use. In the first cohort, compared with placebo, the addition of salmeterol was associated with lower amPEF in B16Arg/Arg patients as compared with B16Gly/Gly patients. In the second cohort, B16Arg/Arg patients treated with salmeterol and inhaled corticosteroids concurrently had a lower amPEF than B16Gly/Gly patients treated with the same regimen. In addition, B16Arg/Arg patients in the second cohort had lower FEV1, increased symptom scores and increased salbutamol rescue use compared with B16Gly/Gly patients. These findings suggest that B16Arg/Arg patients (around one-sixth of Whites and one-fifth of African Americans) might benefit from alternative asthma treatment strategies. Although β2-agonists have been the focus of a number of studies assessing genetic variation of β2-adrenoceptors and their potential effect on drug therapy, single nucleotide polymorphism analysis has not provided evidence for how genotypes can be used to optimise therapies for individual patients. Dr Michael Wechsler from Brigham and Women’s Hospital discussed the mechanisms determining variability of treatment response to leukotriene modifiers. Leukotriene production has been associated with the inflammatory process that may contribute to the asthma phenotype. Cysteinyl leukotrienes (LTC4, LTD4 and LTE4), products of the 5-lipoxygenase pathway of arachidonic acid metabolism, are potent proinflammatory mediators released from various cell types including eosinophils and mast cells. These pro-asthmatic mediators bind to cysteinyl leukotriene receptors found in the human airway and cause bronchoconstriction, mucus secretion, microvascular permeability and eosinophil recruitment. The goal of leukotriene receptor Int J Pharm Med 2006; 20 (4)

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antagonists is to inhibit the physiological actions of cysteinyl leukotrienes at the receptor level without any agonist activity. Results from various studies have shown that polymorphisms in the leukotriene pathway candidate genes ALOX5 and LTC4S are responsible for interpatient variability in response to leukotriene receptor antagonists.[8-10] Dr Eugene Bleecker from Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA, commented that inhaled corticosteroids are the most commonly used controller therapy for asthma. Asthma treatment with inhaled corticosteroids demonstrates significant between-person variability. Genetic variation could contribute to this variable response to inhaled glucocorticosteroids. There is evidence that multiple single nucleotide polymorphisms in the CRHR1 (corticotrophin-releasing hormone receptor 1) gene can contribute to interpatient variation in response to asthma therapy with inhaled corticosteroids.[11] It is too early to tell whether the CRHR1 polymorphisms will be useful clinical predictors of response to inhaled corticosteroids. 2. Chronic Obstructive Pulmonary Disease 2.1 Novel Therapies

Novartis presented new efficacy and safety data for two compounds in development for COPD, underscoring the strength of the company’s respiratory pipeline. Phase II data on the long-acting β2-agonist indacaterol presented in a poster session demonstrated sustained bronchodilation and fast onset of action in 635 patients with moderate-tosevere COPD. In this 7-day, randomised, double-blind, placebocontrolled, dose-ranging trial, indacaterol 50–400μg administered once daily provided sustained 24-hour bronchodilatory efficacy with an onset of action within 5 minutes and peak effect at 3 hours, and with no loss of efficacy after 7 days’ treatment. The overall safety data suggested that indacaterol 50–400μg was generally well tolerated in this patient population. In a singlearm, open-label extension in 269 COPD patients, comparison with tiotropium suggested that indacaterol was at least as effective as tiotropium. Mark Higgins, the Global Medical Brand Director for Novartis, commented that company will be investigating the efficacy of indacaterol in phase III trials in patients with obstructive airways disease.[12] NVA-237 is an inhaled antimuscarinic agent in development for COPD by Arakis and Vectura Group and is licensed to Novartis. Cholinergic airway tone is an important reversible component of airflow resistance in COPD and treatment with antimuscarinic bronchodilators is well established in the management of the condition. NVA-237 shows high affinity and slow © 2006 Adis Data Information BV. All rights reserved.

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dissociation from muscarinic receptors – an optimal profile for prolonged bronchodilation. The quaternary ammonium in the chemical structure of NVA-237 minimises oral bioavailability leading to a low incidence of systemic adverse effects. At a poster session, UK researchers presented data from a phase II study demonstrating that NVA-237 125–400μg provided early and sustained 24-hour bronchodilation in 45 patients with moderate COPD in a double-blind, randomised, crossover study.[13] Single doses of NVA-237 20–400μg provided a similar degree of bronchodilation to the short-acting β2-agonist salbutamol 180μg over the first 40 minutes postdose. Single doses of NVA-237 250 and 400μg significantly increased adjusted mean FEV1 at all timepoints over the 32 hours postdose. NVA-237 125μg increased FEV1 up to and including 28 hours postdose and at 32 hours. The lowest dose of NVA-237 (20μg) increased adjusted mean FEV1 for 14 hours postdose. The majority of adverse events were mild or moderate in severity and unrelated to dose of medication. There were no clinically significant changes in haematology, biochemistry or vital signs. The combined benefits of early bronchodilation similar to that of salbutamol, and sustained bronchodilation suggest that NVA-237 may be suitable for oncedaily administration and may offer COPD patients a convenient treatment alternative. Further data from a phase II trial on NVA-237 was presented at the conference.[14] The aim of this exploratory study was to evaluate the tolerability of 4 doses of inhaled NVA-237 administered as a dry powder and to determine the duration of action of the maximum tolerated dose in patients with obstructive airways disease. NVA-237 was well tolerated over a dose range of 60–480μg. NVA-237 480μg improved FEV1 compared to both baseline and placebo at all timepoints up to and including 32 hours postdose. Mean FEV1 was >15% above baseline with NVA-237 at the 24-hour timepoint, with mean changes from baseline of 440mL for NVA-237 and 160mL for placebo. These data suggested that single doses of NVA-237 have the potential for once-daily administration in patients with obstructive airways disease. These encouraging phase II results suggest that NVA-237 warrants further investigation as a potential treatment for patients with COPD – a disease that ranks among the world’s most common causes of death.

2.2 Combination Therapies 2.2.1 Short-Acting β-Agonist + Muscarinic Antagonists

Due to the commercial successes of combined inhaled corticosteroid/long-acting β2-agonists in asthma, it is not surprising that a significant amount of R&D investment is dedicated to exploring the efficacy of combination therapies in COPD. Of Int J Pharm Med 2006; 20 (4)

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particular interest is the concept of delivering a short-acting-βagonist (SABA) in combination with a long-acting muscarinic antagonist. Japanese researchers presented data showing that the preinhalation of procaterol (a SABA) plus tiotropium bromide produced better lung function and less dyspnoea during exercise than tiotropium alone in patients with COPD.[15] The values of FEV1 and forced vital capacity (FVC) after tiotropium inhalation with procaterol pre-inhalation were better than those recorded after tiotropium inhalation without procaterol pre-inhalation in both middle-aged and elderly patients. The dyspnoea index after tiotropium inhalation with procaterol pre-inhalation was lower than that of tiotropium inhalation without procaterol pre-inhalation. Exercise capacity (measured as oxygen uptake during exercise; VO2max) was greater with procaterol pre-inhalation. The pre-inhaled SABA has a synergistic effect on tiotropiumproduced bronchodilation in patients with COPD, resulting in better exercise performance and decreased sensation of dyspnoea during exercise. Similarly, the newly introduced transdermal β-agonist tulobuterol potentiated the clinical efficacy of tiotropium in terms of pulmonary function, dyspnoea and quality of life in patients with COPD.[16] Investigators at Tokyo University Hospital, Japan, examined the effects of tulobuterol plus tiotropium or placebo plus tiotropium on pulmonary function, exercise capacity, dyspnoea sensation and quality of life in 20 patients with COPD. The FEV1 and FVC values after tiotropium inhalation with tulobuterol were better than those after tiotropium inhalation without tulobuterol. The dyspnoea index after tiotropium inhalation with tulobuterol was lower than that of tiotropium inhalation without tulobuterol. The St George’s Respiratory Questionnaire (SGRQ) score in patients treated with both tiotropium and tulobuterol was better than that for patients treated with tiotropium alone. 2.2.2 Long-Acting β-Agonists + Corticosteroids

Budesonide/formoterol significantly improved COPD patients’ daily life. The improvements were clinically important and independent of smoking habits, according to results from a trial conducted in a real-life setting.[17] This study of physician-initiated therapy evaluated the effect of budesonide/formoterol (Symbicort® Turbuhaler®)1 on patient-reported outcomes in patients with COPD managed in a real-life setting. Eligible patients with COPD attending the physician’s office for a routine visit were invited to use budesonide/formoterol 160/4.5μg, 2 inhalations twice daily for 3 months, and were monitored using the InPractice Evaluation Programme (IPEP). The Clinical COPD Questionnaire

(CCQ) was completed by patients at baseline and on study completion. The CCQ is a validated 10-item instrument used to assess symptoms, functional state and mental state on a scale of 0 (no symptoms) to 6 (maximal symptoms); a difference in total score of ≥0.4 is clinically important. A 5-point (excellent, very good, good, acceptable, poor) global impression scale was completed by the clinician. Of 163 patients enrolled, 161 completed the study; 34% were current smokers and 57% ex-smokers. The majority added budesonide/formoterol to short-acting β2-agonists (36%), anticholinergics (36%) or theophylline (14%). At baseline, the median CCQ total score was 2.9 in current smokers and 2.2 in ex-smokers. After budesonide/formoterol, CCQ total scores improved significantly compared with baseline both for current smokers (2.1) and ex-smokers (1.5). The therapeutic association was judged by clinicians as good to excellent in 77.5% of patients. In another poster presentation by researchers from Tokyo University Hospital, the combined use of theophylline with inhaled tiotropium produced better exercise capacity than tiotropium alone in patients with stable COPD.[18] Pulmonary function testing and cycle exercise testing were performed on 16 patients with COPD (mean age 68.5 years; FEV1 43.2% predicted) before and after inhalation of tiotropium with or without the administration of theophylline (Unifil®). Theophylline 400mg or placebo was administered after dinner every night. Spirometry was repeated immediately before and 60 minutes after tiotropium or placebo inhalation. Dyspnoea was quantitatively evaluated using the slope of regression line between the Borg scale and oxygen uptake (VO2) during exercise (Borg scale slope; BSS). FEV1 and FVC after tiotropium inhalation with prior theophylline administration were better versus FEV1 and FVC after tiotropium inhalation and placebo. Similarly, the dyspnoea index (BSS) was better after tiotropium inhalation plus theophylline pre-treatment than after tiotrpium inhalation and placebo. Exercise capacity (as measured as VO2max) in patients treated with both agents was greater than in patients receiving tiotropium inhalation without theophylline.

2.3 Treating the Inflammatory Component of COPD – A Promising Future

Roflumilast is a phosphodiesterase-4 inhibitor with both anti-inflammatory and bronchodilatory properties. It is being developed by Altana Pharma (formerly Byk Gulden) as an orally administered therapy for COPD. The drug is awaiting regulatory approval for COPD in the EU and is in phase III trials for the same indication in the US. Phosphodiesterase-4 inhibition is a

1 The use of trade names is for product identification purposes only and does not imply endorsement. © 2006 Adis Data Information BV. All rights reserved.

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novel way to treat the multipathway and inflammatory process in COPD. At a mini-symposium entitled COPD: Diagnosis, Management and Outcome, researchers presented data on the effect of roflumilast on lung function in patients with severe to very severe COPD.[19] This randomised, double-blind, placebo-controlled, parallel-group study included 1513 patients (mean postbronchodilator FEV1 41% predicted). After a 4-week, single-blind, placebo run-in period, patients received roflumilast 500μg or placebo once daily for 52 weeks. Lung function was assessed by spirometry; adverse events, physical examination, ECG, vital signs and laboratory values were monitored. Roflumilast maintained FEV1 above baseline, while a decline in lung function was observed with placebo. At study endpoint, roflumilast improved pre- and postbronchodilator FEV1 by 36mL and 39mL, respectively, versus placebo. Roflumilast increased postbronchodilator forced expiratory volume in 6 seconds (FEV6; +53mL), FVC (+48mL), and forced midexpiratory flow rate (FEF25–75; +21 mL/sec) versus placebo. The majority of adverse events were mild to moderate in intensity and resolved with continuous treatment. The most frequently reported drug-related adverse events were diarrhoea (6% of patients) and nausea (3%). Roflumilast did not lead to any clinically significant changes in vital signs, ECG parameters or laboratory values. The researchers concluded that in patients with severe to very severe COPD, roflumilast 500μg improved lung function versus placebo. Lung function improvement with roflumilast was maintained for 1 year. At another COPD-focused poster discussion session these researchers discussed the effect of roflumilast on quality of life in the same group of 1513 patients with severe to very severe COPD;[20] quality of life was assessed using the SGRQ. After 52 weeks, quality of life significantly improved in both treatment arms. This improvement was reflected by a decrease in SGRQ total scores from baseline with roflumilast and placebo. In patients with very severe COPD, who are more prone to exacerbations and, thus, have greater potential for impaired quality of life, total SGRQ score increased from baseline with placebo but decreased with roflumilast. In these very severe COPD patients, SGRQ score with roflumilast treatment was 2.97 units lower than that with placebo treatment. Roflumilast was well tolerated. It was concluded that treatment with oral, once-daily roflumilast 500μg for 1 year improved quality of life in patients with very severe COPD prone to frequent exacerbations. At a third poster discussion session entitled COPD Exacerbation the researchers highlighted the effects of roflumilast on the rate of exacerbations in the same 1513 patients.[21] Exacerbations, as defined by the use of antibiotics and/or oral corticoste© 2006 Adis Data Information BV. All rights reserved.

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roids (moderate) and/or hospitalisation (severe), were assessed. The Wilcoxon-rank-sum test and subsequently a Poisson-regression model were used to estimate the treatment effect and the magnitude of the effect on exacerbation rate. The overall rate of exacerbations was low in both treatment groups (exacerbations/patient/ year: 0.86 for roflumilast versus 0.92 for placebo). In a subgroup of patients with very severe COPD and characterised by a high exacerbation rate (1.6 exacerbations/patient/year), roflumilast treatment resulted in a lower rate of exacerbations compared with placebo, with an estimated reduction of 36%. In the total population, roflumilast treatment resulted in a lower rate of moderate exacerbations requiring oral steroids as compared with placebo, with an estimated reduction of 18%. Thus, during 1 year of treatment, roflumilast 500μg once daily reduced exacerbations requiring oral corticosteroids and resulted in fewer exacerbations in COPD patients known to have a high exacerbation rate.

3. Pulmonary Arterial Hypertension Pulmonary arterial hypertension (PAH) is a highly debilitating disease characterised by severe constriction of the blood vessels in the lungs leading to very high pulmonary arterial pressures. Patients with PAH have extreme shortness of breath as the high pressures makes it difficult for the heart to pump blood through the lungs to be oxygenated – such patients ultimately die of heart failure. PAH afflicts approximately 200 000 patients worldwide. Mild to moderate PAH is currently treated with calcium channel blockers, diuretics and anticoagulants. Therapeutic options for moderate to severe PAH include intravenous prostacyclin, epoprostenol, treprostinil and an inhaled form of prostacyclin, iloprost. Elevated endothelin blood levels have been implicated in the pathogenesis of PAH. Bosentan is an oral nonselective endothelin receptor antagonist that gained US approval in December 2001. The two classes of endothein receptors, ETA and ETB, play significantly different roles in regulating blood vessel diameter. The binding of endothelin to ETB receptors located on the vascular endothelium causes vasodilation through the production of nitric oxide and prostacyclin while binding of endothelin to ETA receptors located on smooth muscle cells causes vasoconstriction. The activity of the ETB receptor is said to be counter-regulatory, protecting against excessive vasoconstriction. Selective ETA antagonists block the negative effects of endothelin by preventing vasoconstriction and cell proliferation, while preserving the beneficial effects of the ETB receptor. For this reason, selective ETA antagonists are regarded as the treatment of choice for PAH. Ambrisentan, a selective ETA receptor antagonist, is being developed by Myogen as an oral therapy for patients with PAH Int J Pharm Med 2006; 20 (4)

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and is currently in phase III clinical studies for PAH in both Europe and the US. Horst Olschewski, Professor of Medicine, Division of Pulmonology at Medical University Graz, Austria, presented phase III ambrisentan data from ARIES-2 in an oral presentation at the conference.[22] The randomised, double-blind, placebo-controlled ARIES-2 trial enrolled 192 patients with PAH, primarily from Europe. The trial met the primary efficacy endpoint of placebo-corrected mean change of 6-minute walking distance (6MWD) at week 12 compared to baseline. Ambrisentan 5mg once daily improved the placebo-corrected mean 6MWD by 59.4m and ambrisentan 2.5mg improved the placebo-corrected mean 6MWD by 32.3m. For the placebo group, the mean 6MWD at week 12 deceased from baseline by 10.1m. Significant improvements in Borg dyspnoea index and SF-36 Health Survey relative to placebo were observed for both doses of ambrisentan. Safety data showed that ambrisentan was generally well tolerated. No patients treated with ambrisentan developed serum aminotransferase concentrations >3 times the upper normal limit compared to one patient in the placebo group. References 1.

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Pearlman D, Greos L, LaForce C, et al. Indacaterol, a novel once-daily beta2agonist, provides full 24-hour bronchodilatory efficacy in patients with persistent asthma. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 79 plus poster LaForce C, Aisanov Z, Higgins M, et al. Indacaterol, a novel once-daily beta2agonist, demonstrates efficacy and safety in patients with persistent asthma: a 7-day, multiple-dose study. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 79 plus poster Langlands JM, LaForce C. The effect of IPL512,602 in patients with mildmoderate persistent asthma (NEAT Study). Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 80 plus poster Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006 Feb 16; 354 (7): 697-708 Tattersfield AE, Harrison TW. β -Adrenoceptor polymorphisms: focus moves to long-acting beta-agonists. Am J Respir Crit Care Med 2006 Mar 1; 173 (5): 473-4 Israel E, Drazen JM, Liggett SB. The effect of polymorphisms of the beta(2)adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med 2000; 162 (1): 75-80 Wechsler ME, Lehman E, Lazarus SC, et al. beta-Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173 (5): 473-4

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Asano K, Shiomi T, Hasegawa N, et al. Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics 2002; 12 (7): 565-70 Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeutic responses in asthma. Br Med Bull 2000; 56 (4): 1054-70 Lima JJ, Zhang S, Grant A. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med 2006 Feb 15; 173 (4): 379-85 Weiss ST, Lake SL, Silverman ES, et al. Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses. Proc Am Thorac Soc 2004; 1 (4): 364-7 Rennard S, Bantje T, Higgins M, et al. Indacaterol, a novel once-daily beta2agonist, provides 24-hour bronchodilator efficacy in moderate-to-severe COPD [abstract J50]. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 117 plus poster Singh D, Corris PA, Snape S. NVA237, a once-daily inhaled antimuscarinic, provides 24-hour bronchodilator efficacy with comparable bronchodilation to albuterol in patients with moderate-to-severe COPD [abstract J26]. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 113 plus poster Gunawardena KA, Wild RN, Kirkpatrick J, et al. NVA237, a once-daily antimuscarinic, demonstrates sustained bronchodilation and is well tolerated in patients with reversible obstructive airways disease [abstract J52]. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 117 plus poster Hanaoka Y, Teramoto S, Yamamoto H, et al. The preinhalation of short acting beta-adrenergic agent, procaterol hydrochloride, plus tiotropium produces better lung function and lesser dyspnea during exercise than tiotropium alone in patients with COPD. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 115 Teramoto S, Yamamoto H, Yamaguchi Y, et al. The effect of transdermal tulobuterol on the efficacy of anticholinergic inhalation of tiotropium bromide in patients with COPD. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 495 Van Den Brande P, Nihlen U, Stahl E. Budesonide/formoterol improves COPD patients’ wellbeing in daily life: results from a real-life setting. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 114 plus poster Hanaoka Y, Teramoto S, Yamamoto H, et al. Effects of sustained release of theophylline, UnifilR, and tiotropium bromide on pulmonary function and exercise performance in patients with stable chronic obstructive pulmonary disease. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 114 plus poster Calverley PM, Sanchez-Toril F, McIvor RA, et al. Effect of roflumilast on lung function: a 1-year study in patients with severe to very severe COPD. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 725 plus oral presentation McIvor RA, Calverley PM, Sanchez-Toril F, et al. Effect of roflumilast on quality of life: a 1-year study in patients with severe to very severe COPD. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 850 plus poster Fabbri LM, Sanchez-Toril F, McIvor RA, et al. Effect of roflumilast on exacerbations: a 1-year study in patients with severe to very severe COPD. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 841 plus poster Olschewski H, Galie N, Ghofrani HA, et al. Ambrisentan improves exercise capacity and time to clinical worsening in patients with pulmonary arterial hypertension: results of the ARIES-2 study. Proc Am Thoracic Soc 2006 Apr; 3 (Abstr. Suppl.): 728

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