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Study Objective: To compare the efficacy and safety of ipratropium bromide reformulated with the chlorofluorocarbon (CFC)-free propellant hydrofluoroalkane (HFA)-134a (ipratropium bromide HFA) to that of the marketed ipratropium bromide inhalation aerosol (containing CFC) in patients with COPD., Design: This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial. The primary efficacy parameter was acute bronchodilator response. The primary end points were peak change in FEV(1) from baseline and area under the response-time curve., Setting: Thirty-one clinical centers in the United States participated in this project., Patients: A total of 507 patients with moderate-to-severe COPD were randomized, and 444 patients completed the trial., Interventions: Twelve weeks of treatment four times daily with one of the following: ipratropium bromide HFA, 42 microg; ipratropium bromide HFA, 84 microg; HFA placebo; ipratropium bromide inhalation aerosol, 42 microg; or CFC placebo., Measurements and Results: Patients in all active treatment groups had significant bronchodilator responses as shown by increases in mean FEV(1) from baseline of at least 15%. Bronchodilator response in all active treatment groups was also significantly more than their respective placebo treatments based on FEV(1), area under the time-response curve from 0 to 6 h, and peak response. FVC results were similar to those seen with FEV(1). There were no significant differences in adverse events, laboratory findings, or ECG findings among the treatment groups., Conclusions: Ipratropium bromide HFA, 42 and mgr;g, provided bronchodilation comparable to the marketed ipratropium bromide CFC, 42 and mgr;g, over 12 weeks of regular use.

Study Objective: To compare the bronchodilator efficacy and safety of tiotropium and placebo., Design: A 3-month, randomized, double-blind, placebo-controlled, multicenter trial., Setting: Outpatient., Patients: Four hundred seventy patients with stable COPD (mean FEV(1) = 38.6% predicted)., Interventions: Tiotropium 18 microg (N = 279) or placebo (N = 191) given once daily via a lactose-based dry-powder inhaler device., Measurements and Results: Spirometry was evaluated on days 1, 8, 50, and 92. Data were expressed as the mean trough (ie, before morning dose; 23 to 24 h after previous dose) and average response observed in the 3 h after the dose was received. Tiotropium produced significant improvement in trough FEV(1) and FVC, averaging 12% greater than baseline on day 8; these improvements were maintained on days 50 and 92. The average postdose FEV(1) was 16% greater than baseline on day 1 and 20% greater than baseline on day 92; FVC was 17% greater than baseline on day 1 and 19% greater than baseline on day 92. Tiotropium was significantly more effective than placebo in both trough and average FEV(1) and FVC response (p < 0.001). These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate, as well as a reduction in "as-needed" albuterol use. Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium, and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo. The most common reported adverse event after tiotropium was dry mouth (9.3% vs 1.6% relative to placebo; p < 0.05)., Conclusions: These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD.

Study Objectives: To determine whether the combination of ipratropium bromide and albuterol results in greater and more consistent pulmonary function test (PFT) response rates than ipratropium bromide or albuterol alone in patients with COPD., Design: Retrospective review of two recently completed 3-month, randomized, double-blind, parallel, multicenter, phase III trials., Setting: Outpatient., Patients: A total of 1,067 stable patients with COPD., Interventions: Ipratropium bromide (36 microg qid), albuterol base (180 microg qid), or an equivalent combination of ipratropium bromide and albuterol sulfate (42 microg and 240 microg qid, respectively)., Measurements and Results: PFT response rates were analyzed using 12% and 15% increases in FEV1 compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEV1 was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p < 0.05; all comparisons within 30 min). In addition, a 15% or more increase in FEV1 was seen in > 80% of patients who received the combination of ipratropium and albuterol sulfate during the initial PFT and continued to be observed 3 months after initial testing., Conclusions: Use of a combination of ipratropium bromide and albuterol sulfate is superior to the individual agents in identifying PFT reversibility in patients with COPD.

Study Objective: To document temporal usage trends for commonly used respiratory medications in patients with COPD., Design: We retrospectively evaluated baseline concomitant medications of 3,720 patients with COPD enrolled in 10 bronchodilator clinical trials from 1987 to 1995. The proportion of patients in each trial using inhaled corticosteroids, inhaled beta-adrenergics, inhaled anticholinergics, oral theophylline, and oral corticosteroids was analyzed using the Cochran-Armitage trend test., Patients: All patients had stable, moderate-to-severe COPD without evidence of asthma or atopy. Reversibility to beta3-agonists was not a requirement., Results: The percentage of patients using inhaled corticosteroids increased significantly over time (p < 0.001) from 13.2% in 1987 to 41.4% in 1995. The percentage of patients receiving oral theophylline decreased significantly (p < 0.001) over this same time interval (63.4 to 29.0%). In addition, the percentage of patients using oral corticosteroids and the percentage using oral beta-adrenergics decreased moderately (p < 0.05) (30.1 to 16.4% and 11.7 to 4.5%, respectively); the percentage of patients using inhaled anticholinergics increased slowly (p < 0.05) (48.2 to 53.8%). The percentage of patients receiving inhaled beta-adrenergics did not significantly (p > 0.05) change., Conclusions: The observed changes in use of inhaled corticosteroids and theophylline were not likely related to differences in disease severity or other patient characteristics in the evaluated trials, but related to changing prescribing and COPD management practices.

Study Objective: To conduct a post hoc pharmacoeconomic evaluation of two double-blind, randomized, prospective, parallel group studies comparing the long-term efficacy and safety of ipratropium combined with albuterol in a single inhalational canister against either bronchodilator agent alone in patients with COPD., Patients: One thousand sixty-seven patients with COPD., Methods: The dose of each bronchodilator was two puffs four times a day (42 microg of ipratropium bromide, 240 microg of albuterol sulfate). Pulmonary function testing was performed on days 1, 29, 57, and 85 of treatment. Outcomes, health-care resource consumption, and costs were compared for the three treatment groups over the 85-day study period. A total of 1,067 patients were randomized in the two studies (albuterol alone, n = 347; ipratropium alone, n = 362; albuterol plus ipratropium, n = 358)., Results: Improvement in FEV1 and area under the FEV1 response-time curve from time 0 to 4 h (FEV1AUC0-4) was significantly greater for the combination of albuterol plus ipratropium than either agent alone on all test days. Compared with albuterol, patients receiving ipratropium and ipratropium plus albuterol experienced significantly fewer COPD exacerbations and patient-days of exacerbation. In addition, the increased frequency of exacerbations observed in the albuterol group was associated with a significant increase in the number of patient hospital days and antibiotic and corticosteroid use. As a result, the total cost of treatment over the study period was significantly less for ipratropium ($156 per patient) and ipratropium plus albuterol ($197 per patient) than for albuterol ($269 per patient). Increased cost-effectiveness, defined as total estimated treatment cost per mean change in FEV1AUC0-4, was observed in both treatment arms containing ipratropium., Conclusions: The inclusion of ipratropium in a pharmacologic treatment regimen is associated with a lower rate of exacerbations in COPD. The result is lower total treatment costs and improved cost-effectiveness.

Inhaled antimuscarinics, often called anticholinergics in clinical medicine, are established as first line bronchodilators in COPD. Tiotropium has been developed as a new generation antimuscarinic following ipratropium. Tiotropium is a specific, highly potent antimuscarinic, demonstrating very slow dissociation from muscarinic receptors. Dissociation from M2-receptors is faster than from M3 or M1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of M3 and M1 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long lasting bronchodilatation and bronchoprotection in patients with COPD and asthma. In asthma, protection against methacholine challenge exceeded the study period of 48 hours. In COPD, bronchodilatation of about 80% of the plateau was demonstrated after the first dose. Following chronic once daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more importantly a rising baseline, achieving steady state within 2 weeks. Tiotropium achieves very stable long lasting effects with comparatively low variation of bronchodilatation between peak and trough (the level before the next administration). Stable 24 hour effectiveness profiles the compound as the first once daily bronchodilator. Clinical correlates of kinetic receptor subtype selective blockade remain to be shown. Plasma levels of tiotropium at trough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors is likely to be responsible for the long duration of action.

To evaluate the role of inhaled ipratropium bromide in acute asthma, a double-blind study of 384 emergency department patients compared the effect of the combination of ipratropium and albuterol with that of albuterol alone. Patients were randomized to receive nebulizer treatments with either 2.5 mg of albuterol or 2.5 mg of albuterol mixed with 0.5 mg of ipratropium bromide at entry and at 45 min. Spirometry, vital signs, and oxygen saturation were measured before and at 45 and 90 min following the nebulizer treatments. Serum potassium levels were obtained at entry and 90 min. The two groups did not differ significantly in age (mean +/- SD = 33.4 +/- 9.3 and 32.5 +/- 9.7 years for the albuterol and ipratropium group and the albuterol group, respectively), baseline FEV1 (mean +/- SD = 1.22 +/- 0.42 and 1.25 +/- 0.44 L respectively), or prior use of asthma medications. At 45 min, there were significantly more responders (15% increase in FEV1 over baseline) in the group receiving albuterol and ipratropium compared with albuterol and saline solution (85% and 78%, respectively; p = 0.045), but the median change in FEV1 from baseline did not differ (0.530 L for the albuterol and ipratropium group and 0.420 L for the albuterol and saline solution group; p = 0.347). By 90 min, the percentage of responders did not differ (88% and 89%, respectively), and the median change in FEV1 was 0.680 L for the group receiving albuterol and ipratropium and 0.650 L for the group receiving albuterol and saline solution (p = 0.693). There were no significant adverse events experienced by patients in either group. Furthermore, there were no significant differences in the number of patients requiring additional therapy in the emergency department or hospitalization. We conclude that in this population of inner city asthmatics, we were unable to demonstrate significant additive benefit of nebulized ipratropium bromide to nebulized albuterol.

Partial expiratory flow-volume (PEFV) curves are a useful tool in airway challenge studies, but unlike the maximal expiratory flow-volume (MEFV) curve, lung function parameters require manual calculation from the flow-volume tracing. We describe an algorithm written in QuickBASIC that analyzes a PEFV curve superimposed on a MEFV curve by (1) identifying the PEFV curve, (2) locating the maximal expiratory flow at the point on the PEFV curve that corresponds to 60% of the baseline forced vital capacity (FVC) below total lung capacity (TLC), termed MEF40%(P), and (3) identifying the size of the PEFV curve along the TLC axis. A report of these parameters is also provided. This algorithm was validated using flow-volume curves from a clinical study in which eight subjects performed two sets of MEFV and PEFV curves separated by approximately 1 hr. Paired comparison of MEF40%(P) determined by the algorithm and two independent manual calculations correlated strongly and yielded no statistically significant differences between the two methods. We conclude that this algorithm provides rapid and accurate determinations of PEFV parameters.

Immunological status and its relation to respiratory findings were studied in 42 female textile workers occupationally exposed to hemp dust and in 49 female control workers. Skin prick tests with hemp or flax dust extracts from different parts of the mill in hemp workers demonstrated the following frequencies of positive tests to antigens: a mixture of hemp and flax extracts (64%), followed by flax extracts (48%), hemp from combing machines (41%), hemp from carding machines (38%), hemp from spinning and weaving machines (33%), and hemp from softening machines (20%). The prevalence of positive skin tests to hemp or flax allergens in control workers was consistently lower, ranging from 21 to 5%. Increased total serum IgE was recorded in 35.7% of hemp workers compared to only 5.0% of control workers (P < 0.05). Hemp workers with positive skin tests had significantly higher prevalences of chronic respiratory symptoms than those with negative skin tests. There were, however, no differences for acute symptoms between workers with positive and negative skin tests. Across-shift changes and baseline lung function were not different when compared by immunologic status. We showed additionally that a water-soluble extract of hemp dust causes a dose-related contraction of nonsensitized guinea pig tracheal smooth muscle when studied in vitro. Our results suggest that frequent immunologic abnormalities can be documented in hemp workers but, with the exception of chronic respiratory symptoms, in general, these do not correlate with respiratory findings.

Several bronchodilator drugs commonly used in respiratory therapy contain sodium metabisulfite as an antioxidant preservative. When aerosolized, these agents may release the irritant gas SO2 as a result of bisulfite decomposition. We found that agents that contain bisulfites generated SO2 concentrations of 2.0 ppm and greater, while bronchodilator solutions without bisulfite did not. Such levels are known to induce or to exacerbate asthmatic symptoms. Levels of SO2 were higher when solutions were nebulized with compressed air from a tank or electric compressor than when they were nebulized from a hand-bulb nebulizer. No significant lot-to-lot variations were found in the solutions tested.

It has been suggested that exposure to formaldehyde (FA) induces asthmatic symptomatology. We have previously studied healthy and asthmatic individuals and found that lung function was unaltered by controlled exposures to 2.0 ppm FA with and without mild exercise. Our present study extends these observations to a group of hospital laboratory workers routinely exposed to FA. Fifteen laboratory workers were exposed in double-blind, random sequence to 0 and 2 ppm FA for 40 min in an environmental chamber with temperature and relative humidity held constant at 23 degrees C and 50%, respectively. These exposures were repeated on two more occasions with a 10-min exercise regimen (450 kpm/min) after being in the chamber 5 min. In addition, a symptom diary and measurements of peak expiratory flow rate (PEFR) were recorded for 24 hr after exposure. Lung function remained unaltered for all 4 exposure days; e.g., mean FEV1.0 for the group did not change by more than 3% at any testing time on any exposure day. Also, there were no delayed obstructive changes as measured by PEFR recordings. Symptoms were mild and transient with unusual odor and eye irritation the most frequent complaint. No lower airway symptoms were reported. We conclude that this group of healthy laboratory workers did not experience any acute or delayed lung function changes from exposure to 2.0 ppm FA at rest and with exercise and that irritative symptoms were few.

Differences in the shape of the maximum expiratory flow volume (MEFV) curve have been associated with pathologic states and physiologic differences between normal individuals. We describe variations in a new parameter, angle beta, which characterizes the general configuration of the MEFV curve among healthy subjects and subjects with disease in 5,140 white individuals. Women had consistently larger beta angles than men. There was a progressive decline in beta with advancing age. Cigarette smokers had lower beta angles than did lifetime never-smokers. Subjects with abnormal lung function patterns had lower beta angles than individuals with a normal pattern. Finally, individuals with asthma, chronic bronchitis, dyspnea and wheezing had significantly lower beta angles than healthy individuals. Further clinical and epidemiologic studies are needed to evaluate this measurement's possible value in pulmonary function evaluation.

Immunological and respiratory findings were studied in a group of 45 female spice-factory workers (mean age: 39 years; mean exposure: 17 years). In addition a group of 45 female control workers matched by sex, age, and smoking habit were also studied. Intradermal skin testing with mixed spice dust allergen demonstrated positive skin reactions in 73.3% of exposed and in 33.3% of control workers (P less than 0.001). Increased IgE serum levels were found in 36.8% of exposed and in 9.7% of the control workers (P less than 0.01). The prevalence of chronic respiratory symptoms was significantly higher in the exposed workers than in the control workers (P less than 0.01). There was, however, no consistent correlation between skin reactivity and chronic respiratory symptoms. There was a high prevalence of acute symptoms during the work shift. These complaints were more frequent in workers with positive skin tests for the symptoms of cough, chest tightness, and irritated and dry throat. Ventilatory capacity was measured by recording maximum expiratory flow-volume (MEFV) curves. There were statistically significant mean reductions during the work shift for all measured lung function parameters in workers with positive skin reactions. In those workers with negative skin reactions only FEF50 and FEF25 reached statistical significance. Aqueous extracts of different spices (chilli pepper, paprika, caraway, coriander leaves, coriander seeds, cinnamon, ginger, onion, curry, and parsley) caused a dose-related contractile response of isolated guinea pig tracheal smooth muscle. These data suggest that immunologic reactions to spices are frequent in spice workers and may be related to acute symptoms and lung function changes, but not to chronic changes. The data further suggest that, in addition to any immunologic response these spices may produce in vivo, they probably also provoke direct irritant reactions in the airways as suggested by in vitro data.

The acute effect of herbal tea dust extracts on lung function was studied in 15 of 25 healthy subjects responding to the inhalation of these extracts. Bronchial inhalation challenge was performed with tea extracts (sage, dog rose and gruzyan) and with normal saline solution as a control substance to assess their baseline airway reactivity to an isotonic aerosol. Lung function testing was performed before exposure and at 0, 15, 30, and 60 minutes after the cessation of exposure. The same subjects were also tested by challenge with methacholine. Lung function was measured by recording FVC, FEV1, FEF50, FEF25, SGaw, and Raw. Subjects were skin tested by the skin prick method and serum IgE levels were determined. The findings suggested that neither baseline nonspecific airway reactivity nor specific markers of immediate sensitivity to tea predict airway responses to tea extracts. Further evaluation of immunologic markers may help to explain the onset and progression of airway disease in workers.

Most seemingly healthy persons challenged with an aerosol of cotton bract extract develop some degree of bronchospasm. The role of nonspecific reactivity of the airways in this reaction to cotton bract extract is undefined. We examined the relationship between airway responses to cotton bract extract and to methacholine, as well as between airway responses to cotton bract extract and to a bronchodilator. Twenty-two healthy subjects were screened for sensitivity to inhaled cotton bract extract. Pulmonary function was measured using partial expiratory flow-volume curves on which flow at 60 percent of the control vital capacity below total lung capacity was measured (MEF40%[P]) following ten minutes of inhalation of cotton bract extract. In the group screened, 12 were found to be responders to the extract, with drops in MEF40%(P) of 20 percent or more, and ten were found to be nonresponders. On separate days, we measured the responses of our subjects' airways to inhaled metaproterenol and methacholine. The mean threshold dose for methacholine in the responding group was 26.8 mg/ml, as compared to 55.6 mg/ml for the nonresponders (t = 2.52; p less than 0.05). Furthermore, the mean percent increase in MEF40%(P) following inhalation of metaproterenol was 41 percent in responders and 24 percent in nonresponders (t = 2.19; p less than 0.05). We conclude that some responders to cotton bract extract exhibit greater reactivity of the airways than nonresponders.

Cotton textile workers have an increased prevalence of both obstructive and restrictive lung function patterns compared with control subjects. Similar abnormal patterns may occur with respiratory diseases of other etiologies, notably those associated with cigarette smoking. The shape of the maximum expiratory flow volume (MEFV) curve has been used to characterize patterns of lung function abnormality. To better evaluate the respiratory effects of cotton dust exposure and to contrast them with those of cigarette smoking, we defined a new functional parameter (angle beta) related to the shape of the MEFV curve. We compared 477 cotton textile workers, both current smokers and never smokers, 45 years and older, with 932 similarly aged control subjects from three communities. Smokers, regardless of their occupational exposure or sex, have smaller beta values than nonsmokers. Cotton textile workers, despite a greater prevalence of abnormal lung function, have beta values that do not differ from those of persons without occupational exposure to cotton dust. We suggest that morphologic patterns of flow volume curves reflect separate effects of cotton dust exposure and smoking and may be related to different sites of airway injury.