Theodore J. Witek

Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease.

Background: In chronic obstructive pulmonary disease (COPD), the degree of circadian variation in forced expiratory volume in 1 second (FEV1) and the influence of anticholinergic blockade is not known. Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD. We hypothesised that tiotropium would modify the overnight change in FEV1, and this would be unaffected by the timing of drug administration. Methods: A double blind, randomised, placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning (09.00 hours), evening (21.00 hours), or an identical placebo. Patients with stable COPD (n=121, FEV1=41% predicted) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment. Results: There were no significant differences at baseline between the groups. Tiotropium improved mean (SE) FEV1 (over 24 hours) in the morning (1.11 (0.03) l) and evening (1.06 (0.03) l) groups compared with placebo (0.90 (0.03) l), and nocturnal FEV1 (mean of 03.00 and 06.00 hours) in the morning (1.03 (0.03) l) and evening (1.04 (0.03) l) groups compared with placebo (0.82 (0.03) l) at the 6 week visit (p<0.01). FEV1 before morning or evening dosing was similar, while the peak FEV1 moved later in the day with active treatment. The mean percentage change in FEV1 from 09.00 hours to 03.00 hours (the nocturnal decline in FEV1) was −2.8% in the morning group, −1.0% in the evening group, and −12.8% in the placebo group. The magnitude of the peak to trough change in FEV1 was not statistically different. Conclusions: Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre.

The MCID of the Transition Dyspnea Index is a Total Score of One Unit

The Baseline (BDI) and Transition (TDI) Dyspnea Indexes provide interview-based measurements of breathlessness related to activities of daily living. The BDI is a discriminative instrument that includes specific criteria for each of three components at a single point in time. The TDI is an evaluative instrument that includes specific criteria for each of three components to measure changes from a baseline state. Observational studies have shown that patients with COPD generally experience a gradual progression of breathing difficulty as measured by the TDI over time. Randomized controlled trials have demonstrated excellent measurement characteristics of the TDI; these include responsiveness (ability to detect change) and construct validity (a change in the TDI correlates with changes in other variables). Supporting evidence for one unit as the minimal clinically important difference (MCID) of the TDI is based on: expert preference; use of the physicians global evaluation score as an anchor; and distribution estimates (standard error of measurement and 0.5 of the standard deviation). As an alternative to the interview process, self-administered computerized (SAC) versions of the BDI/TDI have been developed to provide direct patient-reported ratings of dyspnea. To further establish the MCID of the interview-administered and/or the SAC TDI, we recommend that a patients report of global ratings of change by used as an independent standard or anchor.

Effective delivery of particles with the HandiHaler dry powder inhalation system over a range of chronic obstructive pulmonary disease severity.

The HandiHaler is a dry powder breath activated inhaler system developed for inhalation therapy for patients with airway disease. Its operation is based on the evacuation of powder from a pierced capsule. We sought to document the inspiratory flow rates attained by patients inspiring through the HandiHaler with various degrees of airflow limitation. Subjects with stable chronic obstructive pulmonary disease (COPD) were the studys population. An in vitro study of fine particle dose was conducted using an Andersen Cascade Impactor to assess medication delivery at low inspiratory flow rates. Subsequently, an in vivo study was conducted to determine inspiratory flow rates in patients with COPD as measured through a pneumotach with a custom coupler device with and without the HandiHaler. Patients were classified into three approximately equal groups of spirometric severity ranging from mild (46-65% predicted normal forced expiratory volume in 1 sec [FEV1]), to moderate (28-45%) to severe (< or = 27%). The in vitro study indicated delivery of medication at flow rates as low as 20 L/min. Twenty-six men completed the in vivo study (age 66.9 +/- 10.9 years, FEV1 = 1.02 +/- 0.45 l.). The median peak inspiratory flow rates attained in the mild (n = 8), moderate (n = 10), and severe (n = 8) categories were 45, 45.6, and 35.4 L/min respectively. The minimum peak inspiratory flow rates in the three groups were 28.2, 21.6 and 20.4 L/min. The HandiHaler device effectively delivers particles to the lung over a wide range of airflow limitation in patients with COPD.

Meaningful effect size and patterns of response of the transition dyspnea index.

Ths object of this study was to examine validity, meaningful effect sizes, and patterns of response of the Transition Dyspnea Index (TDI) in a clinical trial cohort of chronic obstructive pulmonary disease (COPD) patients. The design was a retrospective analysis of data from a randomized, double-blind placebo-controlled clinical trial. We analyzed fifty clinical investigation sites in United States. There were 921 patients with stable COPD. Tiotropium 18 microg dry powder or matching placebo was used. Patients were allowed to remain on usual care less ipratropium bromide. Construct validity was demonstrated by significant correlations (P <.05) between Baseline Dyspnea Index (BDI) and other baseline measures, as well as between TDI and changes in other measures at the end of 1 year. Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses. Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physicians global evaluation. Significantly less (P <.05) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI. Responders also had few exacerbations and better health status. The validity of the TDI is supported in a large clinical trial setting. A one-unit change in the TDI focal score represented the minimal important difference.

Airway responses to the inhalation of cotton dust and cotton bract extracts.

Background: Exposure to dust in the cotton industry is associated with respiratory dysfunction. Healthy subjects challenged with cotton bract extract (CBE) develop transient airway hyperresponsiveness. CBE, a major component of cotton dust, is potentially an important agent for studying byssinosis. Objectives: To compare airway responses to cotton dust extract (CDE) and CBE in healthy subjects. Methods: In 21 healthy, non-smoking subjects we compared the effects of CBE and CDE in a double-blind random order, following a 10-min aerosol inhalation. The response to methacholine (MCh) 2 h following CBE or CDE was measured. Lung function was recorded using maximal (MEFV) and partial expiratory flow volume (PEFV) curves, measuring MEF at 60% of baseline vital capacity below total lung capacity [MEF40%(P)] on the PEFV curve. Responders were subjects who developed a 20% or greater fall in MEF40%(P) following extract challenge. Endotoxin levels were low for CBE (5.71 EU/mg) and CDE (31.88 EU/mg). Results: There were 18 responders to CBE and 17 responders to CDE.The average maximal falls in MEF40%(P) were 70 ± 4.9 and 70 ± 4.4% of baseline (nonsignificant) following CBE and CDE, respectively. All subjects enhanced their MCh response following CBE or CDE. The MCh dose which reduced MEF40%(P) by 40% was identical for CBE and CDE (1.3 µg/ml). Conclusions: We conclude that CBE and CDE exert similar physiologic effects.

One-Year Evaluation of the Safety and Efficacy of Ipratropium Bromide HFA and CFC Inhalation Aerosols in Patients with Chronic Obstructive Pulmonary Disease

AbstractIntroduction: Ipratropium bromide (IB) is an established and effective first-line maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). A new IB metered-dose inhaler (MDI) using hydrofluoroalkane 134a propellant (IB HFA) has been developed as an alternative to the MDI containing chlorofluorocarbon (IB CFC).n Objective: To compare the long-term safety and efficacy of IB HFA and IB CFC in patients with COPD.n Study design: This was a randomised, open-label, parallel-group, 1-year, multi-centre trial. Primary endpoints included adverse events (AEs) and vital signs. Secondary endpoints included therapeutic response (>15% increase in forced expiratory volume in 1 second [FEV1] peak change from baseline), FEV1 area under the response-time curve (AUC).n Patients and interventions: Patients (n = 456) with moderate-to-severe COPD, who received either IB HFA (n = 305) or IB CFC (n = 151 ), both 42µg four times daily.n Results: There were no significant differences in the incidences of individual AEs between groups over the short and long term; respiratory disorders were the most common. The incidence of anticholinergic AEs possibly related to treatment was low (1.3% IB HFA, 0.7% IB CFC). Serious AEs occurred in 19.0% and 20.5%, and discontinuations due to AEs in 7.2% and 7.3%, of patients receiving IB HFA and IB CFC, respectively. Therapeutic bronchodilatory responses were achieved in 76–81% and 72–84% of patients, and AUC ranged from 0.117–0.148L and 0.117–0.174L, in patients receiving IB HFA and IB CFC, respectively.n Conclusions: IB HFA had similar efficacy and tolerability to IB CFC over 1 year, supporting a seamless transition from the CFC MDI to the HFA MDI in both short- and long-term treatment.

Acute pulmonary response to cotton bract extract in monkeys: Lung function and effects of mediator modifying compounds

It is well established that cotton dust inhalation can compromise lung function in textile workers. Challenges with a water-soluble extract of cotton bract (CBE) can also induce reversible airway obstruction in healthy volunteers. We have examined the effect of inhaled CBE in nonhuman primates and have attempted to inhibit the bronchoconstrictive response with mediator modifying compounds. CBE (34 mg/ml or 100 mg/ml) was administered via IPPB for 15 minutes (15 breaths/min) in 12 intubated, anesthetized, adult male monkeys (Macaca fascicularis). Breath-by-breath determinations of pulmonary resistance, dynamic compliance (Cdyn), tidal volume, and breathing frequency were calculated from the transpulmonary pressure (esophageal balloon) and airflow signals and monitored for 2 hr postchallenge. Control challenges with distilled water were also performed in 3 monkeys with the greatest response from CBE. Five animals (42%) were found to respond to CBE with peak % changes in Cdyn >45%. In 3 of these animals, we attempted to blunt the CBE response with chlorpheniramine (0.1 mg/kg i.v.) and a mast cell stabilizer lodoxamide (0.1 mg/ml aerosol). In these 3 animals the mean (±SD) peak % changes in Cdyn to CBE alone was −47.4 ± 1.8. The CBE response following chlorpheneramine was −49 ± 15.7 and following lodoxamide was −47.0 ± 5.4. These data suggest that monkeys, like humans, can develop reproducible bronchoconstriction following an aerosol challenge with CBE. Furthermore, this bronchoconstriction in the monkey is probably not explained by the action of histamine or mediator release alone and an acute inflammatory reaction may be involved.