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.

Minimal important difference of the transition dyspnoea index in a multinational clinical trial.

Dyspnoea is a primary symptom of chronic obstructive pulmonary disease (COPD). The baseline (BDI) and transition (TDI) dyspnoea indices are commonly used instruments to assess breathlessness and the impact of intervention. Its validity and pattern of response in multinational clinical trials has not been established. In a retrospective analysis of a cohort of 997 COPD patients who received tiotropium, salmeterol or placebo, in addition to usual care, the validity and pattern of response of the BDI and TDI were examined. The BDI was significantly correlated with the dyspnoea diary (DD) score and the symptom and activity components of the St. George's respiratory questionnaire (SGRQ), establishing concurrent validity. Furthermore, the TDI was also correlated with the changes in DD, SGRQ symptom and activity scores. Construct validity was established by the association between baseline forced expiratory volume in one second (FEV1) and BDI and AFEVI with TDI. Physician's global evaluation (PGE) was significantly associated with BDI as well as APGE with TDI. Significant correlations have also been observed when the cohorts were classified according to native English and native non-English speaking countries. A change in PGE of 1 category (i.e. 2 units on an 8-point scale) was associated with a mean TDI of approximately 1 unit (0.9-1.3 mean focal score), lending further support to the clinical significance of this change inherent in the instrument's descriptors. TDI responders (i.e. focal score < or = 1 unit) used less supplemental salbutamol, had fewer exacerbations and had significantly improved health status as measured by impacts and total SGRQ scores compared with nonresponders. In conclusion, the transition dyspnoea index is a valid instrument when used in a multinational clinical trial and the patterns of response confirm a 1-unit change in the transition dyspnoea index focal score as being clinically important.

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 study's 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.

Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD.

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.

The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group.

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.

The fate of inhaled drugs: the pharmacokinetics and pharmacodynamics of drugs administered by aerosol.

Prior to a drug achieving its effects (ie, pharmacodynamics), there are numerous events within the body that determine its ultimate fate. The effects of the "body on the drug" has been referred to as pharmacokinetics-how the favorable lung-to-systemic effects predicted from this exercise translate into practice. Inhaled drugs have enjoyed the major feature of having "local" effects on the target organ of the lung. Broadly, lower doses can be used and adverse effects are often less than with oral or parenteral administration. Nevertheless, key features of respiratory drugs and their administration can impact their fate and ultimate utility. This review has provided some relevant examples of basic pharmacokinetics principles as related to inhaled products, with emphasis on those factors that help to partition lung-to-systemic effects.

Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease.

Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.

Anticholinergic bronchodilators.

Antimuscarinic treatment of airway disease has a long and colorful history leading to its present day use as an effective bronchodilator in chronic obstructed pulmonary disease (COPD) as well as an antisecretory drug for watery rhinorrhea. Present formulations are limited to ipratropium bromide, a safe and effective respiratory therapeutic. The bronchodilation from ipratropium, as documented by spirometry, has been well established both alone and in combination with albuterol. Evidence suggests that anticholinergics can affect other important aspects of COPD, such as dynamic hyperinflation, and further studies are warranted to confirm long-term physiologic effects and associated health outcomes. Finally, current development of the long-acting compound tiotropium has provided hope for the next generation of antimuscarinic agents represented by once-daily therapy.

Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection: a randomized clinical trial.

CONTEXT: Attachment of most rhinovirus subtypes to cells depends on a cellular receptor, the intercellular adhesion molecule 1 (ICAM-1). A recombinant soluble ICAM-1 (tremacamra, formerly BIRR 4) has shown possible efficacy in early studies. OBJECTIVE: To determine the efficacy and safety of intranasal administration of tremacamra in experimental rhinovirus colds in humans. DESIGN: Four randomized, double-blind, placebo-controlled trials conducted in January to March 1996. SETTING AND SUBJECTS: Volunteers between the ages of 18 and 60 years who had an antibody titer of 1:4 or less to the challenge virus. Subjects were isolated in a hotel room during study days 0 to 8; symptoms were recorded through day 14. A total of 198 subjects were randomized, of whom 196 received drug or placebo and were included in the safety analysis. A total of 177 subjects were included in the efficacy analysis. INTERVENTIONS: Tremacamra or placebo was given beginning 7 hours before inoculation with rhinovirus type 39 (preinoculation studies) or 12 hours after (postinoculation studies). Tremacamra as an inhaled solution or as a powder (each given preinoculation and postinoculation for a total of 4 studies) and placebo were given in 6 doses at 3-hour intervals daily during days 1 through 7. Recipients of active treatment received 367 microg of tremacamra per nostril per dose for a total of 4.4 mg/d. MAIN OUTCOME MEASURES: Effect of tremacamra on infection, as determined by virus isolation and seroconversion, and on illness, as determined by symptom scores, clinical colds, and nasal mucus weights. Treatment-by-study interaction was not significant, so results were pooled for the main analysis. RESULTS: A total of 88 (92%) of the 96 subjects in the placebo groups and 69 (85%) of the 81 subjects in the active treatment groups were infected (P=.19). For placebo vs tremacamra, respectively, the total symptom score (+/- 95% confidence interval [CI]) was 17.6 (+/- 2.7) vs 9.6 (+/- 2.9), the proportion of clinical colds was 64/96 (67% +/- 9%) vs 36/81 (44% +/- 11%), and the nasal mucus weight was 32.9 (+/- 8.8) g vs 14.5 (+/- 9.4) g (P<.001 for all comparisons). Tremacamra was not associated with adverse effects or evidence of absorption through the nasal mucosa and did not interfere with development of neutralizing antibody. CONCLUSION: Tremacamra reduced the severity of experimental rhinovirus colds. Whether tremacamra will be useful clinically will require further study.

The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with 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.

Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease.

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.

Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD.

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.

Analysis of inhaled corticosteroid and oral theophylline use among patients with stable COPD from 1987 to 1995.

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.

Frequency and natural history of rhinovirus infections in adults during autumn.

Human rhinovirus (HRV) accounts for a significant portion of common-cold illness, with the peak incidence being in the early fall. Three hundred forty-six adults who had self-diagnosed colds of 48 h or less were enrolled in a study during September and October 1994 to determine the frequency and clinical course of HRV infections. Nasal wash specimens for viral culture and reverse transcription-PCR (RT-PCR) for HRV RNA and human coronavirus OC43 and 229E RNA detection were collected on enrollment, and participants recorded their symptoms twice daily for 14 days. Middle ear pressure (MEP) was measured with a digital tympanometer on days 1 and 7. Picornaviruses (224 HRV and 7 enterovirus isolates) were detected by culture in 67% (231 of 346) of the subjects. Among 114 samples negative by culture, HRV was detected by RT-PCR in 52 (46%) for an overall picornavirus infection rate of 82% (283 of 346 subjects). Among the remaining 62 negative samples, human coronavirus RNA was detected by RT-PCR in 5 patients, so that 288 (83%) of patients had documented viral infection. The first symptom noticed most often was sore throat (40%) in HRV culture- or PCR-positive patients and stuffy nose in HRV-negative patients (27%). No differences in symptom scores over time or in the presence of individual symptoms were noted between groups. The median duration of the cold episodes was 11 days in HRV culture-positive patients, 9.5 days in HRV RT-PCR-positive patients, and 11.5 days in HRV-negative patients. On enrollment, abnormal MEPs (< or = -100 or > or = +100 mm of H2O) were found for 21% of HRV culture-positive patients, 14% of HRV RT-PCR-positive patients, and 10% of HRV-negative patients. No important differences in the clinical course of HRV culture-positive, HRV culture-negative and RT-PCR-positive, or HRV-negative colds were found. These results represent the highest frequency of virologically confirmed natural colds to date and document the importance of rhinoviruses as the cause of colds during fall months.

An evaluation of nasal response following different treatment regimes of oxymetazoline with reference to rebound congestion.

This was a randomized, double-blind vehicle controlled study aimed at investigating the effects on nasal function of 7 days treatment with the topical decongestant oxymetazoline (0.05% w/v). Fifty healthy volunteers took part in the study and these were randomly allocated to three treatment groups (i) daily oxymetazoline (b.i.d. 150 microliters per nostril) (ii) intermittent oxymetazoline, with oxymetazoline being substituted for vehicle at the morning doses on days 1, 3, and 7; and (iii) daily vehicle (b.i.d. 150 microliters per nostril). The nasal airway was assessed by measurement of nasal airway resistance (NAR) using posterior rhinomanometry, subjective scaling of nasal patency by means of a visual analogue scale (VAS), and clinical visual examination. On days 1, 2, 3, and 7, NAR and VAS measurements were obtained before the morning dose and up to 6 hours after dosing; clinical visual examinations were also performed before dosing on these days. NAR and VAS measurements were also made following withdrawal of treatment on Days 8 and 9. Nonparametric analysis of the results showed that therapeutic tolerance to oxymetazoline did not develop over the 7-day treatment period, and visual examination of the nasal mucosa failed to find significant evidence of rhinitis. Evidence of rebound nasal congestion was found following 3 days of oxymetazoline treatment, with baseline NAR within the daily and intermittent oxymetazoline groups being significantly greater on Day 3 compared to Day 1 (p < 0.05). However, there was a trend toward increasing baseline NAR in the vehicle group over the course of the study, suggesting that the vehicle may have contributed to the rebound congestion. Following the withdrawal of treatments, only the intermittent oxymetazoline group had significantly higher NAR on Days 8 and 9 compared to Day 1 (p < 0.05). Subjective VAS measurements generally followed trends in NAR.

A comparison of ipratropium and albuterol vs albuterol alone for the treatment of acute asthma.

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.

Characterization of daytime sleepiness and psychomotor performance following H1 receptor antagonists.

BACKGROUND: While first generation H1-receptor antagonists are widely used, there are relatively few data describing their comparative effects on subjective daytime sleepiness and psychomotor performance. OBJECTIVE: To compare the effects of first generation H1 receptor antagonists on subjective daytime sleepiness and psychomotor performance. METHODS: We conducted two single-dose, cross-over studies. In the first, we validated our methodology in 18 healthy subjects by examining the response to diphenhydramine (50 mg), terfenadine (60 mg), and placebo. In the second trial, we evaluated the relative effects following diphenhydramine (50 mg), diphenhydramine (25 mg), chlorpheniramine (4 mg), and placebo. Psychomotor tests included choice reaction time, hand steadiness, and a test that divided attention between tracking and reaction time. Introspective drowsiness was measured using a visual analog scale and the Stanford Sleepiness Scale. Assessments were made prior to dosing and at one, three, and five hours after dosing; a 7-hour post-drug assessment was included in the second trial. RESULTS: In the first trial, 50 mg diphenhydramine produced significant impairment relative to placebo in both subjective and objective assessments (P < .05). Responses following terfenadine did not differ from placebo. In the second study, all three regimens produced subjective and objective soporific effects to a significantly greater degree than placebo. For example, significant introspective sleepiness was noted three hours following all three regimens (P < .05) and slower choice reaction times were noted one and three hours after dosing (P < .05). The general rank order of effects was diphenhydramine (50 mg), followed by diphenhydramine (25 mg), followed by chlorpheniramine (4 mg). Significant differences among the three regimens were, for the most part, confined to greater soporific effects from diphenhydramine relative to chlorpheniramine (P < .05). CONCLUSIONS: Taken together, our observations confirm that subjective and objective measures of sleepiness and psychomotor performance occur following single doses of diphenhydramine and chlorpheniramine, but not terfenadine. Differences in soporific effects do exist among regimens of first-generation compounds.

Immunological and respiratory reactions in workers exposed to organic dusts.

The relationship of skin reactivity and serum immunoglobulin E (IgE) levels to the prevalence of chronic respiratory symptoms and to ventilatory capacity is examined in workers exposed to different organic aerosols. The results from group of control workers similarly tested are also presented. Workers exposed to occupational allergens had positive skin tests more frequently than did controls, except for soy bean workers. Workers with positive skin tests to occupational allergens had a higher prevalence of almost all symptoms than those with negative skin tests although the differences did not always reach statistical significance. Workers with positive skin reactions in general had significantly higher serum IgE levels than did workers with negative skin reactions. There were across-shift reductions of ventilatory capacity in all groups of exposed workers, varying for forced vital capacity from 1.7% to 13.3%, for forced expiratory volume from 0.4%-21.9%, for maximum flow rates at 50% from 1.5% to 16.1% and for maximum flow rates at the last 25% of control vital capacity from 0% to 24.9%. There was, however, no correlation between acute and chronic lung function changes and skin reactivity or IgE values. Our data suggest that although exposure to organic aerosols may be associated with frequent immunologic reactions, these findings do not predict objective respiratory impairment.