Activity of aclidinium bromide, a new long-acting muscarinic antagonist: a phase I study.

AIM: Aclidinium bromide is a muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This phase I trial in healthy subjects investigated the bronchodilator activity of aclidinium and its ability to reduce methacholine-induced bronchoconstriction. METHODS: This double-blind, partial-crossover study randomized 12 subjects to treatment with single doses of aclidinium (50, 300 or 600 microg) or placebo. Drug activity was assessed for 24 h after administration by specific airway conductance (sGaw), airways resistance (Raw) and bronchial responsiveness (PC35 sGaw methacholine). RESULTS: Aclidinium significantly increased sGaw compared with placebo at all assessments and doses (sGaw mean +/- SD AUC (l kPa(-1) h) for placebo 24.4 +/- 4.37, for 50 microg 29.0 +/- 7.08, for 300 microg 31.2 +/- 6.68 and for 600 microg 32.7 +/- 7.95) (P < 0.009), except 50 microg at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 microg compared with placebo at all assessments (Raw mean +/- SD AUC (kPa s(-1) l(-1) h) for placebo 7.7 +/- 3.46, for 300 microg 5.8 +/- 2.33, for 600 microg 6.3 +/- 3.11) (P < 0.04) except 600 microg at 24 h. Differences between aclidinium 300 and 600 microg vs. placebo in PC35 doubling concentration were significant at all assessments (mean +/- SD AUC (mg ml(-1) h) for placebo 100.0 +/- 30.27, for 50 microg 117.2 +/- 33.33, for 300 microg 168.9 +/- 28.66 and for 600 microg 179.1 +/- 15.73 (P < 0.0001). For all endpoints, there was a significant difference between aclidinium 50 microg and the higher doses (P < 0.0001). Aclidinium was not detected in plasma and was well tolerated. CONCLUSION: Aclidinium produced statistically significant and sustained bronchodilation over 24 h, suggesting long-acting efficacy and providing a rationale for future studies in patients with COPD.

The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma.

BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study enrolled 7241 patients aged 5 to 66 years with recent-onset, mild persistent asthma to assess early intervention with the inhaled corticosteroid budesonide on long-term asthma control. OBJECTIVE: The open-label phase of the START study was included to determine the effect on lung function and asthma control of adding budesonide to the reference group patients who had not initially received inhaled corticosteroids. METHODS: Patients were randomized to double-blind treatment with budesonide, 200 mug (those aged < 11 years) or 400 mug once daily, or placebo plus the usual asthma therapy for 3 years, after which all patients received 2 years of open-label treatment with budesonide once daily. RESULTS: During the full 5-year study period, postbronchodilator FEV(1) percent predicted decreased, irrespective of randomized treatment during the double-blind phase, by an average of 2.22% (SE, 0.15%). However, patients with inhaled budesonide in the double-blind phase had a significantly lower risk (odds ratio, 0.61; P < .001) of a severe asthma-related event during the full 5-year study period than those in the reference group. Moreover, patients in the reference group used more additional asthma medications during both the open-label and double-blind phases. CONCLUSIONS: In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use.

Role of the tachykinin NK(1) receptor in mediating contraction to 5-hydroxytryptamine and antigen in the mouse trachea.

Neuroimmune interactions are important in airway diseases such as asthma. We evaluated the role of the tachykinin NK(1) receptor in the contractile response of isolated trachea from tachykinin NK(1) receptor wild type (WT) and knockout (KO) mice, to the antigen ovalbumin and the contractile agonist serotonin (5-hydroxytryptamine). One percent ovalbumin induced contractions of tracheas obtained from ovalbumin-immunized and exposed mice. The tracheas from WT animals showed larger contractions compared to the KO mice. Tracheas from sensitized and ovalbumin-exposed animals released 5-hydroxytyptamine upon addition of ovalbumin. No higher levels of 5-hydroxytryptamine were released from tracheas of WT animals. Tracheas of non-sensitized animals did not release 5-hydroxytryptamine upon ovalbumin challenge. Responses to ovalbumin were abrogated by methysergide, a broad 5-hydroxytryptamine receptor antagonist. Exogenous 5-hydroxytryptamine contracted tracheas but WT tracheas responded significantly more. Atropine and tetrodotoxin (TTX) reduced 5-hydroxytryptamine-induced contractions of the WT tracheas, while they did not affect 5-hydroxytryptamine-induced contractions of KO tracheas. 5-Hydroxytryptamine-induced contractions from atropine- or TTX-treated WT tracheas did not differ significantly from the contractions of the KO tracheas. Single tachykinin NK(1) receptor antagonists SR140,333 and RP67,580 had no effect on 5-hydroxytryptamine-induced contractions. In conclusion, the 5-hydroxytryptamine-induced tracheal contraction includes a cholinergic mechanism that requires the presence of the tachykinin NK(1) receptor.

Effectiveness of early budesonide intervention in Caucasian versus Asian patients with asthma: 3-year results of the START study.

OBJECTIVE AND BACKGROUND: Few studies have assessed the effectiveness of inhaled corticosteroid therapy exclusively in Asian patients with asthma. The present analysis compared the efficacy of early intervention with inhaled budesonide in Caucasian and Asian patients over the first 3 years of the inhaled Steroid Treatment As Regular Therapy in early asthma study. METHODS: Patients aged 5-66 years with mild persistent asthma of

Murine TLR4 is implicated in cigarette smoke-induced pulmonary inflammation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. We investigated whether Toll-like receptor 4 (TLR4) is implicated in cigarette smoke (CS)-induced pulmonary inflammation in a murine model of COPD. METHODS: C3H/HeOuJ (Tlr4(WT)) and C3H/HeJ (Tlr4(defective)) mice were exposed to air or CS for 5 weeks (subacute) and 26 weeks (chronic), and pulmonary inflammation was evaluated. RESULTS: In Tlr4(WT) mice, subacute and chronic CS exposure induced a substantial pulmonary infiltration of macrophages, neutrophils, lymphocytes and dendritic cells (DCs), that was absent in air-exposed mice. CS exposure increased the costimulatory marker expression on DCs, the levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in bronchoalveolar lavage (BAL) fluid and induced the pulmonary expression of matrix metalloproteinase-12 (MMP-12), TLR4 and TLR2. In contrast, after subacute CS exposure, Tlr4(defective) mice showed a limited (5-fold lower) increase of DCs and lymphocytes in BAL fluid, lower costimulatory marker expression on DCs and lower MCP-1 and TNF-alpha levels in BAL fluid compared to Tlr4(WT) animals. After chronic CS exposure, however, the difference in pulmonary inflammation between Tlr4(WT) and Tlr4(defective) mice was less pronounced and both strains showed similar MCP-1 and TNF-alpha levels in BAL and similar pulmonary MMP-12, TLR4 and TLR2 expression. CONCLUSIONS: We demonstrated that the TLR4 mutation in C3H/HeJ mice is protective against CS-induced pulmonary influx of neutrophils, DCs and lymphocytes upon subacute CS exposure. However, TLR4 is only of minor importance in chronic CS-induced inflammation in mice.

Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma.

STUDY OBJECTIVES: Asthmatic patients lose lung function faster than normal subjects. The effectiveness of early intervention with inhaled corticosteroids on this decline in lung function is not established in recent-onset disease. DESIGN: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma study was a randomized, double-blind study in 7,165 patients (5 to 66 years old), with persistent asthma for < 2 years to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events and the decline in lung function. Patients received budesonide (200 mug qd for children < 11 years old and 400 mug qd for others) or placebo for 3 years in addition to usual asthma medications. RESULTS: Treatment with budesonide significantly improved prebronchodilator and postbronchodilator FEV(1) percentage of predicted and reduced the mean declines from baseline for postbronchodilator FEV(1) at 1 year and 3 years: - 0.62% and - 1.79% for budesonide and - 2.11% and - 2.68% for placebo, respectively (p < 0.001). The decline was more marked for male patients, active smokers, and patients > 18 years old, and the smallest treatment effects were in adolescents. CONCLUSIONS: Long-term, once-daily treatment with low-dose budesonide improved both prebronchodilator and postbronchodilator FEV(1) in patients with recent-onset, persistent asthma, and reduced the loss of lung function over time.

The severity of airways obstruction as a determinant of treatment response in COPD.

Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV1) to decide when to initiate combination treatment with a long-acting beta2-agonist and an inhaled corticosteroid. Assessment of baseline FEV1 as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 microg salmeterol (Sal), 500 microg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV1 < 50% and FEV1 > or = 50% predicted subgroups (n = 949/513 respectively). Treatment effects on clinical outcomes-- lung function, exacerbations, health status, diary card symptoms, and adverse events--were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV1; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV1 < 50% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV1; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV1, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.

Matrix metalloproteinase-12 and cathepsin D expression in pulmonary macrophages and dendritic cells of cigarette smoke-exposed mice.

An imbalance between proteinases and their inhibitors is believed to play an essential role in the development of chronic obstructive pulmonary disease (COPD) and pulmonary emphysema. COPD is mainly caused by cigarette smoking, and is characterized by an increase in inflammatory cells in small airways and lung parenchyma. We examined the mRNA expression of several proteinases in lungs of mice exposed to cigarette smoke or control air. After 1, 3 and 6 months' smoke exposure there was a significant increase of matrix metalloproteinase (MMP)-12 and Cathepsin D mRNA, compared to air-exposed mice. To determine the cellular origin of MMP-12 and Cathepsin D, we isolated dendritic cells (DCs) and macrophages from the lungs of mice. There was an increase in MMP-12 mRNA after smoke exposure in both macrophage and DC populations, whereas Cathepsin D was predominantly expressed in macrophages. Immunohistochemistry clearly revealed the expression of Cathepsin D protein in alveolar macrophages of cigarette smoke-exposed mice, in contrast to air-exposed littermates. Western blots on lung tissue demonstrated an increase of MMP-12 protein in cigarette smoke-exposed animals. These results indicate that cigarette smoke increases the expression of MMP-12 and Cathepsin D in the lungs of mice, and that not only macrophages but also DCs produce MMP-12.

Positioning of glucocorticosteroids in asthma and allergic rhinitis guidelines (versus other therapies).

Asthma and allergic rhinitis are both characterized by airway inflammation, and glucocorticosteroids form the cornerstone of their pharmacologic treatment. All patients with asthma should be prescribed rapid-acting inhaled beta2-agonists as needed to use as rescue therapy in case of symptoms. As soon as patients experience symptoms at least once a week, controller medications should be started on a daily basis to achieve and maintain control of their asthma. Intranasal corticosteroids are given as first-line therapy for moderate to severe persistent rhinitis. Depending on the dominant symptom, H1-antihistamines, decongestants, or ipratropium can be added after re-evaluation.

Pharmacokinetic and pharmacodynamic properties of inhaled beclometasone dipropionate delivered via hydrofluoroalkane-containing devices.

Inhaled corticosteroids have a key role in the treatment of asthma and chronic obstructive pulmonary disease. In recent times, beclometasone dipropionate has been reformulated in pressurised metered dose inhalers (pMDIs), using hydrofluoroalkanes (HFAs) as a propellant. Extensive toxicological testing has shown that HFA-propellants are well tolerated. Among the reformulated beclometasone dipropionate-containing pMDIs, only the characteristics of the two Qvar formulations have been thoroughly explored. Compared to the reference beclometasone dipropionate formulation, the mass median aerodynamic diameter of the Qvar formulations are substantially smaller (1.1 vs 4.0 microm), whereas that of Modulite averages 2.6 microm. Scintigraphic and pharmacokinetic studies indicate a higher lung deposition for both the Qvar and the Beclazone formulations, compared with reference beclometasone dipropionate formulation. Since the 2- to 3-fold increase in pulmonary deposition results in a 2.6- to 3-fold difference in relative efficacy for Qvar, half the dose of the reference beclometasone dipropionate formulation has been currently recommended in adult patients with asthma, a recommendation that is supported by a large number of clinical trials. Conversely, the design of the studies conducted to compare the efficacy of Qvar with fluticasone propionate and budesonide does not allow establishing their equivalence on a milligram per milligram basis. Good studies on the bioequivalence between the reference beclometasone dipropionate formulation and the Modulite or Beclazone formulations are not available.

Matrix metalloproteinases in asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are both highly prevalent, chronic inflammatory lung diseases that lead to significant morbidity and mortality. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes that play a critical role in normal development and physiological tissue remodeling and repair. In addition, they play an important role in the regulation of the kinetics and function of inflammatory cells. There is increasing evidence that MMPs are involved in the pathogenesis of both asthma and COPD, and several MMPs are possible therapeutic targets in these common chronic airway diseases.

Short-term cigarette smoke exposure enhances allergic airway inflammation in mice.

RATIONALE: Epidemiologic studies suggest that tobacco smoke contributes to the prevalence and occurrence of exacerbations in asthma. The effect of active smoking in adolescents with atopy is poorly understood. OBJECTIVES: We developed an experimental model to investigate the influence of smoking on antigen-induced airway inflammation and airway responsiveness in mice that were previously sensitized. METHODS: Ovalbumin (OVA)-sensitized BALB/c mice were exposed to air or mainstream smoke (5 days/week) and to phosphate-buffered saline (PBS) or OVA aerosol (3 times/week) for 2 weeks (n = 8 for each group). RESULTS: Airway responsiveness to intravenously injected carbachol was increased (p < 0.05) in smoke- and OVA-exposed mice compared with all other groups. There was an additive effect of smoke and OVA exposure on total cell numbers, macrophages, and dendritic cells in bronchoalveolar lavage fluid and on CD4+ and CD8+ T lymphocytes and dendritic cells in lung tissue (p < 0.05 compared with mice exposed to smoke and PBS and to mice exposed to air and OVA). Concurrent smoke and OVA exposure augmented OVA-specific IgE in serum compared with air and OVA exposure. In lavage fluid supernatant, eotaxin was increased in air- and OVA-exposed mice. The further increase observed in the group exposed to both OVA and cigarette smoke came close to formal significance (p = 0.06). Thymus- and activation-regulated chemokine was augmented in mice exposed to either smoke or OVA, without additional effect. CONCLUSIONS: Our data indicate that acute concurrent exposure to allergen and mainstream cigarette smoke enhances airway inflammation and airway responsiveness in previously sensitized mice.

Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide.

BACKGROUND: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. OBJECTIVE: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. METHODS: In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). RESULTS: Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. CONCLUSIONS: Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.

Identification and characterization of human pulmonary dendritic cells.

Dendritic cells (DC) are specialized antigen-presenting cells, linking innate and adaptive immune responses, and thus play an important role in immunologically mediated diseases, including pulmonary diseases such as asthma and respiratory viral infections. Although much is known about the characteristics of lung DC in animal models, very few data concerning human lung DC are available. The goal of our study was to identify and characterize dendritic cells in human lung by preparing single-cell suspensions from surgical resection specimens and subsequent labeling with the recently developed blood dendritic cell antigen (BDCA) markers. A straightforward isolation procedure was developed to avoid phenotypical and functional changes induced by extensive purification methods. In this way, human lung DC were directly identified without the need for an additional adherence step for further purification. For the first time, we demonstrate the presence of three previously unidentified DC subsets in human lung digests: myeloid DC type 1 (BDCA1+/HLA-DR+), myeloid DC type 2 (BDCA3+/HLA-DR+), and plasmacytoid DC (BDCA2+/CD123+). The presence of CD1a+ DC in the human lung was confirmed. The identification and characterization of different human pulmonary DC subtypes is of great importance for the future development of DC-based immunotherapies.

Burden and clinical features of chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality and represents a substantial economic and social burden throughout the world. It is the fifth leading cause of death worldwide and further increases in its prevalence and mortality are expected in the coming decades. The substantial morbidity associated with COPD is often underestimated by health-care providers and patients; likewise, COPD is frequently underdiagnosed and undertreated. COPD develops earlier in life than is usually believed. Tobacco smoking is by far the major risk for COPD and the prevalence of the disease in different countries is related to rates of smoking and time of introduction of cigarette smoking. Contribution of occupational risk factors is quite small, but may vary depending on a country's level of economic development. Severe deficiency for alpha-1-antitrypsin is rare and the impact of other genetic factors on the prevalence of COPD has not been established. COPD should be considered in any patient presenting with cough, sputum production, or dyspnoea, especially if an exposure to risk factors for the disease has been present. Clinical diagnosis needs to be confirmed by standardised spirometric tests in the presence of not-fully-reversible airflow limitation. COPD is generally a progressive disease. Continued exposure to noxious agents promotes a more rapid decline in lung function and increases the risk for repeated exacerbations. Smoking cessation is the only intervention shown to slow the decline. If exposure is stopped, the disease may still progress due to the decline in lung function that normally occurs with aging, and some persistence of the inflammatory response.

Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study.

For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous, composite, guideline-based measures of control: totally and well-controlled asthma. Treatment was stepped-up until total control was achieved (or maximum 500 microg corticosteroid twice a day). Significantly more patients in each stratum (previously corticosteroid-free, low- and moderate-dose corticosteroid users) achieved control with salmeterol/fluticasone than fluticasone. Total control was achieved across all strata: 520 (31%) versus 326 (19%) patients after dose escalation (p < 0.001) and 690 (41%) versus 468 (28%) at 1 year for salmeterol/fluticasone and fluticasone, respectively. Asthma became well controlled in 1,071 (63%) versus 846 (50%) after dose escalation (p < 0.001) and 1,204 (71%) versus 988 (59%) at 1 year. Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone. Across all strata, 68% and 76% of the patients receiving salmeterol/fluticasone and fluticasone, respectively, were on the highest dose at the end of treatment. Exacerbation rates (0.07-0.27 per patient per year) and improvement in health status were significantly better with salmeterol/fluticasone. This study confirms that the goal of guideline-derived asthma control was achieved in a majority of the patients.

Efficacy of flow- vs impedance-guided autoadjustable continuous positive airway pressure: a randomized cross-over trial.

STUDY OBJECTIVES: Autoadjustable continuous positive airway pressure (CPAP) devices are increasingly used in the treatment of obstructive sleep apnea (OSA). Since different measurements of upper airway obstruction are applied, it is uncertain whether these devices are equally effective in controlling sleep-disordered breathing. Hypothesizing that differences in therapeutic efficacy were to come out, we compared the performance of the AutoSet device (ResMed; Sydney, Australia), which features autoadjustable positive airway pressure (APAP) guided by detection of flow limitation (APAPfl), with the SOMNOsmart device (Weinmann; Hamburg, Germany), which features APAP guided by the forced oscillation technique (APAPfot). DESIGN: A double-blind, randomized, cross-over trial. SETTING: The sleep disorders center and sleep laboratory of a university hospital. PATIENTS AND INTERVENTIONS: An overnight CPAP autotitration procedure was performed in 30 patients with OSA. A split-night protocol allowed that each patient used both devices. MEASUREMENTS AND RESULTS: Using polysomnography, sleep, indexes of sleep-disordered breathing, snoring, and CPAP levels were recorded. No significant differences were found in conventional sleep variables. While the apnea-hypopnea index (AHI) was lower with APAPfl (3.5 +/- 5.6/h) as compared to APAPfot (9.9 +/- 31.0/h), the difference was not statistically significant (mean +/- SD). The snoring index, however, was significantly lower with APAPfl (35.3 +/- 53.7/h vs 111.6 +/- 175.4/h, respectively; p = 0.01). The median and 95th percentile pressure levels rose from wakefulness to sleep in APAPfl, but decreased in APAPfot. Higher pressure variability was present in the latter method. CONCLUSIONS: These findings suggest that the APAPfl is superior to APAPfot in the control of snoring. While a lower AHI was achieved with APAPfl, at the expense of a higher median pressure but less pressure variability, the difference with APAPfot was not statistically significant.

The role of the tachykinin NK1 receptor in airway changes in a mouse model of allergic asthma.

BACKGROUND: Tachykinins are present in sensory nerves and in nonneuronal cells like macrophages. Human data suggest a role for these peptides in asthma, but the exact role of tachykinins and their receptors in allergic airway inflammation is still a matter of debate. OBJECTIVE: The aim of this study was to determine the role of the tachykinin NK1 receptor in allergic airway responses in a mouse model. METHODS: Tachykinin NK1 receptor wild-type and knockout animals were sensitized intraperitoneally to ovalbumin and subsequently exposed from days 14 to 21 to aerosolized ovalbumin (1% ). On day 22, the immunologic and histologic changes were evaluated, and lung function measurements were performed. RESULTS: Mice lacking the tachykinin NK1 receptor and their wild-type litter mates developed inflammatory cell infiltrates in the airways and ovalbumin-specific IgE on sensitization and exposure to ovalbumin compared with saline-exposed controls. No differences were detected between wild-type and knockout mice. The substance P content of alveolar macrophages was not influenced by ovalbumin or by the lack of the NK1 receptor. Ovalbumin-induced hyperresponsiveness was not observed, but at baseline, the knockout mice were more reactive despite similar morphology. Ovalbumin induced more goblet cell hyperplasia in wild-type animals compared with knockout animals. No differences in airway wall thickness were observed. CONCLUSION: These data suggest that tachykinin NK1 receptors do not affect allergic airway inflammation or endogenous substance P content of alveolar macrophages but influence baseline responsiveness and promote features of remodeling such as goblet cell hyperplasia.

Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial.

An accelerated loss of lung function is one of the defining characteristics of chronic obstructive pulmonary disease (COPD). To date, the only successful intervention shown to conclusively attenuate the loss of lung function over time is smoking cessation. Pharmacological interventions including inhaled corticosteroids and ipratropium bromide have not altered the rate of decline of lung function. Tiotropium is an inhaled anticholinergic that provides 24-hour bronchodilation with once-daily dosing due to prolonged muscarinic M3 receptor blockade. Controlled clinical trials have suggested sustained efficacy for periods of up to one year. We therefore initiated a four-year, controlled clinical trial (UPLIFT, Understanding the Potential Long-Term Impacts on Function with Tiotropium) in patients with COPD to evaluate the long-term effects of tiotropium on the rate of decline in lung function and health status as well as the frequency of exacerbations. The design of such large, long-term clinical trials presents unique methodological challenges including the definition of endpoints, the quality and variability of spirometric measurements and premature patient discontinuations from the trial. The present manuscript outlines the rationale for the UPLIFT study, and reviews the study design and the steps taken to address methodological challenges experienced in other long term studies. Careful design and implementation of the UPLIFT trial is anticipated to yield high quality results that will help in increasing our understanding of the long term natural history of COPD in a global population as well as to elucidate the role that tiotropium can play in affecting the course of this debilitating disease.