Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

The smoking cessation efficacy of varying doses of nicotine patch delivery systems 4 to 5 years post-quit day.

BACKGROUND: This study was undertaken to evaluate the long-term smoking cessation efficacy of varying doses of transdermal nicotine delivery systems 4 to 5 years post-quit day. METHODS: A follow-up study was conducted 48 to 62 months after quit day among patients who were enrolled in the Transdermal Nicotine Study Group investigation. The latter study included group smoking cessation counseling and randomized assignment to 21, 14, or 7 mg nicotine patches or placebo patches. Seven of nine smoking cessation research centers participated in the long term follow-up investigation. RESULTS: The self-reported continuous quit rate among patients originally assigned 21 mg (20.2%) was significantly higher than rates for patients assigned 14 mg (10.4%), 7 mg (11.8%), or placebo patches (7.4%). Log rank survival analysis found no difference in relapse rates after 1 year postcessation. Smokers under age 30 years were significantly less likely to be abstinent at long term follow-up compared to smokers > or = 30 years of age (3 vs 13%, respectively). Mean weight gain in confirmed continuous quitters was 10.1 kg in men and 8.0 kg in women. Of the 63 continuous abstainers surveyed, 30 respondents (48%) reported that they no longer craved cigarettes, and no individual reported daily craving for cigarettes. CONCLUSIONS: Nicotine patch therapy with 21 mg/day patches resulted in a significantly higher long-term continuous abstinence rate compared to lower dose patches and placebo. Relapse rates among the various treatment conditions were similar after 1 year postcessation.

A comparative study of the clinical efficacy of nedocromil sodium and placebo. How does cromolyn sodium compare as an active control treatment?

Nedocromil sodium and cromolyn sodium are the only two currently available nonsteroid anti-inflammatory agents for treatment of asthma. Clinical differences between the two agents remain under continuous investigation with reports differentiating the two on the basis of atopy of the patient and reversibility of bronchoconstriction. This study investigated the efficacy of nedocromil sodium (4 mg, qid) for treatment of mild-to-moderate asthma in comparison to placebo using cromolyn sodium (2 mg, qid) as an active control treatment. Patients were primarily allergic asthmatics (with at least 15% reversibility) previously maintained on a regimen of regular bronchodilator therapy. During a 2-week run-in period, the patient's slow-release theophylline therapy was removed, and the patients were randomized to treatment after deterioration of asthma control (asthma symptom summary score of 3 for 7 of the 14 days). After 8 weeks of treatment, patients were returned to as occasion requires bronchodilator therapy, as per the 2-week baseline period. The results demonstrate that patients treated with nedocromil sodium showed statistically significant improvements during the primary time period (mean weeks 3 through 8) over placebo-treated patients as evidenced by all indexes of asthma symptoms, pulmonary function measures, and decreased bronchodilator reliance (p<0.05). Patients treated with cromolyn sodium demonstrated similar improvements over placebo-treated patients. Comparisons between nedocromil sodium and cromolyn sodium showed the two agents to be comparable in this group of primarily allergic patients with reversible disease. Between-group differences were noted for 3 of the 13 variables (nighttime asthma, FEV1, and forced expiratory flow rate between 25 % and 75% of the FVC) in favor of cromolyn sodium when the data were pooled during the primary time period. The number of patients missing 1 or more days from work/school/regular activity due to asthma was significantly fewer compared with placebo, and favoring nedocromil sodium over cromolyn sodium. No differences were observed among the three treatments for adverse events. This study demonstrated that in primarily allergic patients with reversible airways disease, nedocromil sodium and cromolyn sodium are both significantly more effective than placebo for treatment of mild-to-moderate asthma.

Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease.

A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital capacity (FVC) and 25-75% forced expiratory flow (FEF25-75%). On test day 1 the peak increase in FEV1 for the ipratropium bromide + albuterol subjects was 26% greater than those on placebo + albuterol (p < 0.003). The area under the 8-hour FEV1 curve was 64% greater in those given ipratropium bromide on test day 1 (p < 0.0002). Similar increases were seen in FVC and FEF25-75%. The peak improvements in FEV1 and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.

Fluticasone propionate reduces oral prednisone use while it improves asthma control and quality of life.

This study examined the ability of fluticasone propionate aerosol to reduce oral prednisone requirements in patients with severe asthma. Ninety-six patients dependent on oral prednisone were treated for 16 wk with placebo or fluticasone propionate aerosol (750 or 1,000 micrograms twice daily). Their dosage of oral prednisone was adjusted weekly according to predetermined criteria. A total of 69% and 88% of patients treated with fluticasone propionate 750 and 1,000 micrograms twice daily, respectively, compared with 3% of placebo-treated patients used no prednisone by the end of the study. In the fluticasone propionate groups, FEV1 and peak expiratory flow rates at the last evaluable visit/date improved and the number of night awakenings and symptomatic albuterol use declined relative to placebo values (p < 0.05). Patient-rated asthma symptoms improved in the groups receiving fluticasone propionate but not in the placebo group (p < 0.005). Fluticasone propionate aerosol was well-tolerated, and it improved some dimensions of health-related quality of life measured using a standard patient survey. Fluticasone propionate aerosol (750 or 1,000 micrograms twice daily) effectively and safely allowed most asthmatics dependent on oral corticosteroids to reduce or eliminate oral prednisone use while improving pulmonary function and quality of life.

Treatment of stable chronic bronchitis with iodinated glycerol: a double-blind, placebo-controlled trial.

In a double-blind trial, 29 patients were treated for stable, chronic bronchitis with iodinated glycerol (Organidin, 60 mg four times daily; n = 16) or placebo (n = 13). The study consisted of a 2-week single-blind lead-in period, followed by a 6-week double-blind treatment period, and assessed a total of 50 response variables. In this set of patients, treatment with iodinated glycerol was associated with statistically significant (P < 0.05) and/or positive trend (P < 0.1) toward improvement in cough frequency, cough severity, difficulty in raising sputum, sputum thickness, sputum stickiness, forced expiratory flow at FVC25%-75%, cell concentration in sputum, and several measures of physician assessment of patient condition. Iodinated glycerol was well tolerated during the 6-week treatment period; no adverse effects were reported and no patient receiving iodinated glycerol withdrew from the study prematurely. In conclusion, this study demonstrates that iodinated glycerol, 60-mg tablets given in a total daily dose of 240 mg, is safe and effective therapy for reducing symptoms in patients with stable, chronic bronchitis.

Evaluation of the safety and efficacy of multiple doses of azelastine to adult patients with bronchial asthma over time.

Azelastine is a new oral antiasthma agent with bronchodilating and antiallergic properties. This 12-wk study compared azelastine (2, 4, 6, and 8 mg) and placebo given twice a day in asthmatics 12 to 60 yr of age requiring daily bronchodilator therapy. Patients were allowed albuterol aerosol, short-acting theophylline, and pseudoephedrine only as needed. The study was completed by 221 asthmatic subjects. No significant differences in symptoms, medication, or pulmonary function existed between groups at baseline. Analysis of the zero hour FEV1 before azelastine administration on eight occasions during the 12 wk of therapy indicated an increasing slope for azelastine 6 mg that was statistically different from that of placebo; similarly, the slope for azelastine 4 mg showed the same trend, but it did not reach statistical significance. All azelastine groups had significant reductions of as-needed medication after 1 wk; only in the 4-mg and 6-mg groups was this reduction sustained for 12 wk. Asthma symptom scores and peak expiratory flow measurements remained stable in the azelastine groups despite significant reductions in concomitant medication administration. Side effects were minor and included: altered taste (30.1 to 51.9%), drowsiness (6.0 to 16.9%), and dry mouth (3.8 to 6.1%). The occurrence of these adverse events decreased with time throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Procaterol metered-dose inhaler: a multiclinic study evaluating the efficacy and safety in patients with asthma.

Procaterol hydrochloride aerosol, a potent beta 2-adrenergic bronchodilator, was evaluated in a double-blind, placebo-controlled study for efficacy and safety in 210 patients with documented mild to moderate reversible airway obstruction. Patients were randomized to receive procaterol in two inhalations (high dose) or one inhalation (low dose), 0.01 mg/inhalation, three times daily, or placebo. Pulmonary function tests were recorded at five and 30 minutes and hourly for eight hours after the first dose and following 1 and 2 weeks of treatment. Both doses of procaterol produced significantly greater improvement in PFTs at one hour and for up to seven hours after dosing compared with placebo (p less than 0.05). Mean percent increases in FEV1 were 35% in the high-dose group and 29% in the low-dose group at week 2. The high-dose group showed no loss of duration of bronchodilation with continued dosing. Improvement in PFTs and peak flow rates was significantly greater in the high-dose than in the low-dose group (p less than 0.05). Tremor was the most frequent side effect. Procaterol had no effect on electrocardiograms, heart rate, blood pressure, or clinical laboratory tests. The high dose of procaterol aerosol was shown to be an effective and well-tolerated bronchodilator with a rapid onset and long duration of action.

Multicenter study of bitolterol and isoproterenol nebulizer solutions in nonsteroid-using patients.

Bitolterol mesylate, 1.0 mg, or isoproterenol hydrochloride, 1.5 mg, was administered three times daily for 3 months in a double-blind, multicenter study via closed-port, intermittent-flow, compressor-driven nebulizer system (CPIF) to 182 nonsteroid-using patients with asthma. Mean baseline FEV1 was approximately 60% of predicted normal for both groups. Pulmonary function tests and vital signs were measured before and for up to 8 hours after treatments on test days 1, 30, 60, and 90. Mean maximum increases in FEV1 were 51%, 54%, 52%, and 55% for bitolterol versus 48%, 46%, 50%, and 43% for isoproterenol on these monthly test days. The mean FEV1 response remained greater than 15% over zero time (baseline) for greater than or equal to 8 hours after medication with bitolterol on each of four monthly pulmonary function test days and 2 1/2 to 5 hours for isoproterenol. Median durations of bronchodilator activity for bitolterol were 7.3, 6.5, 6.5, and 6.0 hours versus 4.0, 1.7, 3.7, and 1.9 hours for isoproterenol on the monthly test days. On these test days, 37% to 49% of the patients treated with bitolterol had a duration of action of at least 8 hours compared with 16% to 29% after isoproterenol treatment. The onset of activity was within 5 minutes for both drugs. Bitolterol provided superior bronchodilator activity with fewer adverse effects compared with isoproterenol, and there was no evidence for drug tolerance during this 3-month study.

Comparison of the bronchodilator effects of nebulized bitolterol mesylate and isoproterenol hydrochloride in steroid-dependent asthma.

This study of 183 ambulatory patients with steroid-dependent asthma was conducted to evaluate the efficacy and safety of nebulized bitolterol mesylate solution (0.2%) compared to isoproterenol hydrochloride solution (0.3%). A double-blind, randomized, parallel-group, repetitive-dose design was followed at nine centers for 3 months. Patients received either 1.0 mg of bitolterol or 1.5 mg of isoproterenol three times a day with a closed, intermittent-flow nebulization system. Pulmonary function was evaluated on four 8-hour office visits at approximately 30-day intervals. Efficacy was based on a 15% increase in FEV1 over baseline. Both medications resulted in bronchodilatation within 5 minutes, whereas nebulized bitolterol was statistically superior (p less than 0.05) to nebulized isoproterenol in terms of duration of action and area under the curve. The mean FEV1 response to bitolterol therapy remained greater than 15% over baseline for 5 to 8 hours on the four test days compared to 2 to 4.75 hours for isoproterenol therapy. Both medications were well tolerated. Adverse reactions were transient, and most were mild to moderate. Tremor was the most frequent side effect occurring in approximately 30% of the patients in both groups. There were no clinically significant laboratory changes or electrocardiographic findings. Nebulized bitolterol mesylate was found to be a safe and effective bronchodilator in steroid-dependent patients with asthma.

Bitolterol compared to isoproterenol in advanced chronic obstructive pulmonary disease.

Twenty-eight patients with advanced emphysema and/or chronic bronchitis and severe airflow obstruction were randomly assigned to receive either bitolterol or isoproterenol aerosol delivered by a metered dose device which was administered three times daily. Randomization resulted in similar patients with like degrees of airflow obstruction and responsiveness to a test dose of inhaled bronchodilator. Significantly greater improvement in airflow was achieved by administration of bitolterol compared to isoproterenol. Pharmacologic responses continued after 90 days of daily dosing. Both drugs were well tolerated and side effects included mild degrees of tachycardia for both drugs. Two patients assigned to isoproterenol stopped therapy during the study due to side effects. This study indicates that bitolterol is more effective than isoproterenol in degree and duration of bronchodilatation in patients with advanced chronic obstructive pulmonary disease.

Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol.

Controversy exists concerning possible tachyphylaxis of the acute bronchodilating effect of albuterol, especially with regard to the duration of its acute bronchodilating action. We evaluated 140 patients with bronchial asthma in a prospective double-blind controlled study of possible tachyphylaxis to albuterol aerosol as compared to isoproterenol aerosol. We demonstrated statistically significant tachyphylaxis with regard to duration of acute bronchodilating effect. We believe that this tachyphylaxis is not clinically significant because there was no tachyphylaxis with regard to peak bronchodilating effect and because the duration of bronchodilating effect remains significantly greater, both quantitatively and statistically, when compared to isoproterenol aerosol. Moreover, it appeared that most of the tachyphylaxis was present at four weeks of therapy. There was a small increment of tachyphylaxis after eight weeks of therapy, but no further increase in tachyphylaxis was demonstrated after 13 weeks of inhaled albuterol therapy. We therefore feel that clinically significant tachyphylaxis to inhaled albuterol aerosol must be quite unusual and that chronic therapy with inhaled albuterol aerosol is probably both safe and efficacious for bronchospastic disorders.

Respiratory care protocol: an approach to in-hospital respiratory therapy.

The difficulty of delivering respiratory therapy according to currently accepted standards is an important problem in many hospitals. As a result of this problem in our hospital, we developed a new therapy delivery system--the Respiratory Care Protocol. In response to an order for Respiratory Care Protocol from an attending physician, a senior respiratory therapist evaluates the patient, prescribes specific respiratory therapy according to a protocol, and then daily re-evaluates the patient and makes appropriate therapeutic changes, including discontinuing respiratory therapy when appropriate. The Respiratory Care Protocol has been well-accepted by patients, physicians, and respiratory therapists, and by Joint Commission on Accreditation of Hospitals evaluation teams. We believe that our use of the Respiratory Care Protocol has led to improved quality and to the reduced cost of our in-hospital respiratory care.

Transbronchial lung biopsy via the fiberoptic bronchoscope in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host.

The differential diagnosis of diffuse pulmonary infiltrates in the immunosuppressed patient is broad. Many of the etiologies are amenable to specific therapy. Although endobronchial brush biopsy has been used to identify many infections, including Pneumocystis carinii, it was less effective in the diagnosis of noinfectious infiltrates. Transbronchial lung biopsy via the fiberoptic bronchoscope provided lung tissue that could be studied histologically, which increased the diagnostic yield without the morbidity and mortality of open or percutaneous lung biopsies.-